0001 This invention relates to a method of preventing or treating cartilage damage by administering a gamma-aminobutyric acid (GABA) analog.

BACKGROUND OF THE INVENTION 0002 Cartilage damage is a major problem that afflicts many people worldwide. Many people engaged in athletic activities suffer from sprains and torn cartilage resulting from the physical activity. Cartilage damage is particularly prevalent within the aging population, as it generally is associated with degenerative diseases such as osteoarthritis. 0003 Osteoarthritis (OA) is primarily a disorder of cartilage and subchondral bone, although other tissues in and around affected joints are involved. OA is a result of a complex system of interrelated mechanical, biochemical, and molecular mechanisms. OA is itself noninflammatory, although the cartilage damage that accompanies OA can initiate an inflammatory process secondary to OA. Many mechanisms can initiate the cellular and tissue events that constitute a final common pathway for osteoarthritis, including: congenital joint abnormalities; genetic defects (primary generalized OA); infectious, metabolic, endocrine, and neuropathic diseases; virtually any disease process that alters the normal structure and function of hyaline cartilage (e.g., RA, gout, chondrocalcinosis); and acute or chronic trauma (including fracture) to the hyaline cartilage or tissue surrounding it (e.g., prolonged overuse of a joint or group of joints, as in certain occupationsfoundry work, coal mining, and bus driving). 0004 Treatment includes rehabilitation, patient education, drug therapy, and surgery when all conservative treatment has failed. Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) are the primary agents used to treat OA-related pain. These agents inhibit prostaglandin release by blocking cyclooxygenase-mediated conversion of cell membrane lipids from arachidonic acid. Muscle relaxants used to treat OA include diazepam, cyclobenzaprine, carisoprodol, and methocarbamol (usually in low doses). Analgesic drugs occasionally may be useful. Tricyclic antidepressants may be helpful for depressed patients. Each of these drugs only treat secondary conditions associated with cartilage damage such as inflammation, muscle tension, pain, or depression, but do not prevent or treat the primary condition, which is damage to the cartilage. 0005 PCT International Application Publication No. WO 98/58641 describes a method of preventing and treating inflammatory diseases comprising administering to a subject suffering from such disease or suspected of developing such disease and in need of treatment an effective amount of a GABA analog. A preferred embodiment utilizes a cyclic amino acid compound of Formula I 2

0006 wherein R1 is hydrogen or lower alkyl and n is an integer of from 4 to 6, and the pharmaceutically acceptable salts thereof. Another preferred embodiment utilizes a GABA analog of Formula II 3

0007 or a pharmaceutically acceptable salt thereof, wherein: 0008 R1 is straight or branched alkyl of from 1 to 6 carbon atoms, phenyl, or cycloalkyl of from 3 to 6 carbon atoms; 0009 R2 is hydrogen or methyl; and 0010 R3 is hydrogen, methyl, or carboxyl. 0011 U.S. Pat. No. 6,001,876 describes a method of treating pain, especially for treatment of chronic pain disorders, using a compound of Formula II above. 0012 PCT International Application Publication No. WO 99/37296 describes a method of treating muscular and skeletal pain comprising administering to a subject suffering from such pain an effective amount of a GABA analog, especially a compound of Formula I or II above. 0013 However, applicant's remarkable discoverydisclosed in the instant applicationthat GABA analogs having the characteristic of being inhibitors of cartilage damage, or a pharmaceutically acceptable salt thereof, are useful for preventing or treating cartilage damage is not found or suggested in WO 98/58641, U.S. Pat. No. 6,001,876, or WO 99/37296. 0014 Because many agents used to prevent or treat diseases with a component of cartilage damage actually treat secondary aspects such as inflammation or pain, but do not prevent or treat the damage to cartilage that underlies the diseases, the need for new therapies continues. We have now discovered the surprising result that a GABA analog having the characteristic of being an inhibitor of cartilage damage, or a pharmaceutically acceptable salt thereof, are useful to prevent or treat cartilage damage. All that is required to prevent and/or treat the cartilage damage according to the invention is to administer to a subject in need of treatment a cartilage damage preventing and/or treating amount of a GABA analog having the characteristic of being an inhibitor of cartilage damage, or a pharmaceutically acceptable salt thereof. None of the above references teach the instant method of preventing and/or treating cartilage damage. 0015 Several GABA analogs are known. Gabapentin, a cyclic GABA analog, is now commercially available (Neurontin, Warner-Lambert Company) and extensively used clinically for treatment of epilepsy and neuropathic pain. Such cyclic GABA analogs are described in U.S. Pat. No. 4,024,175 and its divisional U.S. Pat. No. 4,087,544. Another series of GABA analogs is described in U.S. Pat. No. 5,563,175.

SUMMARY OF THE INVENTION 0016 This invention provides a method of preventing or treating cartilage damage in a mammal suffering therefrom, comprising administering a therapeutically effective amount of a GABA analog having the characteristic of being an inhibitor of cartilage damage, or a pharmaceutically acceptable salt thereof. 0017 A preferred embodiment of the invention method utilizes a GABA analog that is a cyclic amino acid compound of Formula I 4

0018 wherein R1 is hydrogen or lower alkyl and n is an integer of from 4 to 6, and the pharmaceutically acceptable salts thereof. An especially preferred embodiment utilizes a compound of Formula I where R1 is hydrogen and n is 5, which compound is 1-(aminomethyl)-cyclohexane acetic acid, known generically as gabapentin. Other preferred GABA analogs, or a pharmaceutically acceptable salt thereof, are compounds of Formula I wherein the cyclic ring is substituted, for example with alkyl such as methyl or ethyl. Typical of such compounds include (1-aminomethyl-3-methylcyclohexyl) acetic acid, (1-aminomethyl-3-methylcyclopentyl) acetic acid, and (1-aminomethyl-3,4-dimethylcyclopentyl) acetic acid. 0019 In another preferred embodiment, the invention method utilizes a GABA analog of Formula II 5

0020 or a pharmaceutically acceptable salt thereof, wherein: 0021 R1 is a straight or branched unsubstituted alkyl of from 1 to 6 carbon atoms, unsubstituted phenyl, or unsubstituted cycloalkyl of from 3 to 6 carbon atoms; 0022 R2 is hydrogen or methyl; and 0023 R3 is hydrogen, methyl, or carboxyl. 0024 Diastereomers and enantiomers of compounds of Formula II can be utilized in the invention method. 0025 An especially preferred embodiment of the invention method employs a compound of Formula II where R2 and R3 are both hydrogen, and R1 is (CH2)0-2-iC4H9 as an (R), (S), or (R,S) isomer. 0026 A more preferred embodiment of the invention method utilizes a compound of Formula II named 3-aminomethyl-5-methyl-hexanoic acid, or especially (S)-3-(aminomethyl)-5-methylhexanoic acid, now known generically as pregabalin. Pregabalin is also known as CI-1008 and S-()-3-IBG.0027 Another preferred embodiment of the invention method utilizes a compound of Formula II named 3-(1-aminoethyl)-5-methylheptanoic acid or 3-(1-aminoethyl)-5-methylhexanoic acid. 0028 Another preferred embodiment of the invention method utilizes a GABA analog that is a compound of Formulas III, IIIC, IIIF, IIIG, or IIIH 6

0029 or a pharmaceutically acceptable salt thereof wherein: 0030 n is an integer of from 0 to 2; 0031 m is an integer of from 0 to 3; 0032 R is sulfonamide, 0033 amide, 0034 phosphonic acid, 0035 heterocycle, 0036 sulfonic acid, or 0037 hydroxamic acid; 0038 A is a bridged ring selected from 7

0039 wherein 0040

is the point of attachment;

0041 Z1 to Z4 are each independently selected from hydrogen and methyl; 0042 o is an integer of from 1 to 4; and 0043 p is an integer of from 0 to 2. 0044 In Formula 1 above R cannot be sulfonic acid when m is 2 and n is 1. (Suman-Chaulan N., et al., European Journal of Pharmacology, 1993;244:293-301.) 0045 Another preferred embodiment of the invention method utilizes a compound of Formulas III, IIIC, IIIF, IIIG, or IIIH selected from: 0046 (1-Aminomethyl-cyclohexylmethyl)-phosphonic acid; 0047 (1R-trans)(1-Aminomethyl-3-methyl-cyclohexylmethyl)-phosphonic acid; 0048 (trans)(1-Aminomethyl-3,4-dimethyl-cyclopentylmethyl)-phosphonic acid; 0049 (1R-trans)(1-Aminomethyl-3-methyl-cyclopentylmethyl)-phosphonic acid; 0050 (1S-cis)(1-Aminomethyl-3-methyl-cyclopentylmethyl)-phosphonic acid; 0051 (1S-trans)(1-Aminomethyl-3-methyl-cyclopentylmethyl)-phosphonic acid; 0052 (1R-cis)(1-Aminomethyl-3-methyl-cyclopentylmethyl)-phosphonic acid; 0053 (1,3,4)(1-Aminomethyl-3,4-dimethyl-cyclopentylmethyl)-phosphonic acid; 0054 (1,3,4)(1-Aminomethyl-3,4-dimethyl-cyclopentylmethyl)-phosphonic acid; 0055 (R)(1-Aminomethyl-3,3-dimethyl-cyclopentylmethyl)-phosphonic acid; 0056 (S)(1-Aminomethyl-3,3-dimethyl-cyclopentylmethyl)-phosphonic acid; 0057 (1-Aminomethyl-3,3-dimethyl-cyclobutylmethyl)-phosphonic acid; 0058 2-(1-Aminomethyl-cyclohexyl)-N-hydroxy-acetamide; 0059 (1S-trans)2-(1-Aminomethyl-3-methyl-cyclohexyl)-N-hydroxy-acetamide; 0060 (trans)2-(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-N-hydroxy-acetamide; 0061 (1S-cis)2-(1-Aminomethyl-3-methyl-cyclopentyl)-N-hydroxy-acetamide; 0062 (1R-trans)2-(1-Aminomethyl-3-methyl-cyclopentyl)-N-hydroxy-acetamide; 0063 (1R-cis)2-(1-Aminomethyl-3-methyl-cyclopentyl)-N-hydroxy-acetamide; 0064 (1S-trans)2-(1-Aminomethyl-3-methyl-cyclopentyl)-N-hydroxy-acetamide; 0065 (1,3,4)2-(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-N-hydroxy-acetamide; 0066 (1,3,4)2-(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-N-hydroxy-acetamide; 0067 (S)2-(1-Aminomethyl-3,3-dimethyl-cyclopentyl)-N-hydroxy-acetamide; 0068 (R)2-(1-Aminomethyl-3,3-dimethyl-cyclopentyl)-N-hydroxy-acetamide; 0069 2-(1-Aminomethyl-3,3-dimethyl-cyclobutyl)-N-hydroxy-acetamide; 0070 N-2-(1-Aminomethyl-cyclohexyl)-ethyl-methanesulfonamide; 0071 (1S-cis)N-2-(1-Aminomethyl-3-methyl-cyclohexyl)-ethyl-methanesulfonamide; 0072 (trans)N-2-(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-ethyl-methanesulfonamide; 0073 (1S-cis)N-2-(1-Aminomethyl-3-methyl-cyclopentyl)-ethyl-methanesulfonamide; 0074 (1R-trans)N-2-(1-Aminomethyl-3-methyl-cyclopentyl)-ethyl-methanesulfonamide; 0075 (1R-cis)N-2-(1-Aminomethyl-3-methyl-cyclopentyl)-ethyl-methanesulfonamide; 0076 (1S-cis)N-2-(1-Aminomethyl-3-methyl-cyclopentyl)-ethyl-methanesulfonamide; 0077 (1,3,4)N-2-(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-ethyl-methanesulfonamide; 0078 (1,3,4)N-2-(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-ethyl-methanesulfonamide; 0079 (S)N-2-(1-Aminomethyl-3,3-dimethyl-cyclopentyl)-ethyl-methanesulfonamide; 0080 (R)N-2-(1-Aminomethyl-3,3-dimethyl-cyclopentyl)-ethyl-methanesulfonamide; 0081 N-2-(1-Aminomethyl-3,3-dimethyl-cyclobutyl)-ethyl-methanesulfonamide; 0082 (1S-cis)3-(1-Aminomethyl-3-methyl-cyclohexylmethyl)-4H-1,2,4oxadiazol-5-one; 0083 (trans)3-(1-Aminomethyl-3,4-dimethyl-cyclopentylmethyl)-4H-1,2,4oxadiazol-5-one; 0084 (1S-cis)3-(1-Aminomethyl-3-methyl-cyclopentylmethyl)-4H-1,2,4oxadiazol-5-one; 0085 (1R-trans)3-(1-Aminomethyl-3-methyl-cyclopentylmethyl)-4H-1,2,4oxadiazol-5-one; 0086 (1R-cis)3-(1-Aminomethyl-3-methyl-cyclopentylmethyl)-4H-1,2,4oxadiazol-5-one; 0087 (1S-trans)3-(1-Aminomethyl-3-methyl-cyclopentylmethyl)-4H-1,2,4oxadiazol-5-one; 0088 (1,3,4)3-(1-Aminomethyl-3,4-dimethyl-cyclopentylmethyl)-4H-1,2,4oxadiazol-5-one; 0089 (1,3,4)3-(1-Aminomethyl-3,4-dimethyl-cyclopentylmethyl)-4H-1,2,4oxadiazol-5-one; 0090 (S)3-(1-Aminomethyl-3,3-dimethyl-cyclopentylmethyl)-4H-1,2,4oxadiazol-5-one; 0091 (R)3-(1-Aminomethyl-3,3-dimethyl-cyclopentylmethyl)-4H-1,2,4oxadiazol-5-one; 0092 3-(1-Aminomethyl-3,3-dimethyl-cyclobutylmethyl)-4H-1,2,4oxadiazol-5-one; 0093 3-(1-Aminomethyl-cyclohexylmethyl)-4H-1,2,4oxadiazole-5-thione; 0094 (1S-cis)3-(1-Aminomethyl-3-methyl-cyclohexylmethyl)-4H-1,2,4oxadiazole-5-thione; 0095 (trans)3-(1-Aminomethyl-3,4-dimethyl-cyclopentylmethyl)-4H-1,2,4oxadiazole-5-thione; 0096 (1S-cis)3-(1-Aminomethyl-3-methyl-cyclopentylmethyl)-4H-1,2,4oxadiazole-5-thione; 0097 (1R-trans)3-(1-Aminomethyl-3-methyl-cyclopentylmethyl)-4H-1,2,4oxadiazole-5-thione; 0098 (1R-cis)3-(1-Aminomethyl-3-methyl-cyclopentylmethyl)-4H-1,2,4oxadiazole-5-thione; 0099 (1S-trans)3-(1-Aminomethyl-3-methyl-cyclopentylmethyl)-4H-1,2,4oxadiazole-5-thione; 0100 (1,3,4)3-(1-Aminomethyl-3,4-dimethyl-cyclopentylmethyl)-4H-1,2,4oxadiazole-5-thione; 0101 (1,3,4)3-(1-Aminomethyl-3,4-dimethyl-cyclopentylmethyl)-4H-1,2,4oxadiazole-5-thione; 0102 (S)3-(1-Aminomethyl-3,3-dimethyl-cyclopentylmethyl)-4H-1,2,4oxadiazole-5-thione; 0103 (R)3-(1-Aminomethyl-3,3-dimethyl-cyclopentylmethyl)-4H-1,2,4oxadiazole-5-thione; 0104 3-(1-Aminomethyl-3,3-dimethyl-cyclobutylmethyl)-4H-1,2,4oxadiazole-5-thione; 0105 C-1-(1H-Tetrazol-5-ylmethyl)-cyclohexyl-methylamine; 0106 (1S-cis)C-3-Methyl-1-(1H-tetrazol-5-ylmethyl)-cyclohexyl-methylamine; 0107 (trans)C-3,4-Dimethyl-1-(1H-tetrazol-5-ylmethyl)-cyclopentyl-methylamine; 0108 (1S-cis)C-3-Methyl-1-(1H-tetrazol-5-ylmethyl)-cyclopentyl-methylamine; 0109 (1R-trans)C-3-Methyl-1-(1H-tetrazol-5-ylmethyl)-cyclopentyl-methylamine; 0110 (1R-cis)C-3-Methyl-1-(1H-tetrazol-5-ylmethyl)-cyclopentyl-methylamine; 0111 (1S-trans)C-3-Methyl-1-(1H-tetrazol-5-ylmethyl)-cyclopentyl-methylamine; 0112 (1,3,4)C-3,4-Dimethyl-1-(1H-tetrazol-5-ylmethyl)-cyclopentyl-methylamine; 0113 (1,3,4)C-3,4-Dimethyl-1-(1H-tetrazol-5-ylmethyl)-cyclopentyl-methylamine; 0114 (S)C-3,3-Dimethyl-1-(1H-tetrazol-5-ylmethyl)-cyclopentyl-methylamine; 0115 (R)C-3,3-Dimethyl-1-(1H-tetrazol-5-ylmethyl)-cyclopentyl-methylamine; 0116 C-3,3-Dimethyl-1-(1H-tetrazol-5-ylmethyl)-cyclobutyl-methylamine; 0117 N-2-(1-Aminomethyl-cyclohexyl)-ethyl-C,C,C-trifluoro-methanesulfonamide; 0118 (1S-cis)N-2-(1-Aminomethyl-3-methyl-cyclohexyl)-ethyl-C,C,C-trifluoro-methanesulfonamide; 0119 (trans)N-2-(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-ethyl-C,C,C-trifluoro-methanesulfonamide; 0120 (1R-cis)N-2-(1-Aminomethyl-3-methyl-cyclopentyl)-ethyl-C,C,C-trifluoro-methanesulfonamide; 0121 (1S-trans)N-2-(1-Aminomethyl-3-methyl-cyclopentyl)-ethyl-C,C,C-trifluoro-methanesulfonamide; 0122 (1S-cis)N-2-(1-Aminomethyl-3-methyl-cyclopentyl)-ethyl-C,C,C-trifluoro-methanesulfonamide; 0123 (1R-trans)N-2-(1-Aminomethyl-3-methyl-cyclopentyl)-ethyl-C,C,C-trifluoro-methanesulfonamide; 0124 (1,3,4)N-2-(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-ethyl-C,C,C-trifluoro-methanesulfonamide; 0125 (1,3,4)N-2-(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-ethyl-C,C,C-trifluoro-methanesulfonamide; 0126 (S)N-2-(1-Aminomethyl-3,3-dimethyl-cyclopentyl)-ethyl-C,C,C-trifluoro-methanesulfonamide; 0127 (R)N-2-(1-Aminomethyl-3,3-dimethyl-cyclopentyl)-ethyl-C,C,C-trifluoro-methanesulfonamide; 0128 N-2-(1-Aminomethyl-3,3-dimethyl-cyclobutyl)-ethyl-C,C,C-trifluoro-methanesulfonamide; 0129 3-(1-Aminomethyl-cyclohexylmethyl)-4H-1,2,4thiadiazol-5-one; 0130 (1S-cis)3-(1-Aminomethyl-3-methyl-cyclohexyhnethyl)-4H-1,2,4thiadiazol-5-one; 0131 (trans)3-(1-Aminomethyl-3,4-dimethyl-cyclopentylmethyl)-4H-1,2,4thiadiazol-5-one; 0132 (1R-cis)3-(1-Aminomethyl-3-methyl-cyclopentylmethyl)-4H-1,2,4thiadiazol-5-one; 0133 (1S-trans)3-(1-Aminomethyl-3-methyl-cyclopentylmethyl)-4H-1,2,4thiadiazol-5-one; 0134 (1S-cis)3-(1-Aminomethyl-3-methyl-cyclopentymethyl)-4H-1,2,4thiadiazol-5-one; 0135 (1R-trans)3-(1-Aminomethyl-3-methyl-cyclopentylmethyl)-4H-1,2,4thiadiazol-5-one; 0136 (1,3,4)3-(1-Aminomethyl-3,4-dimethyl-cyclopentylmethyl)-4H-1,2,4thiadiazol-5-one; 0137 (1,3,4)3-(1-Aminomethyl-3,4-dimethyl-cyclopentylmethyl)-4H-1,2,4thiadiazol-5-one; 0138 (S)3-(1-Aminomethyl-3,3-dimethyl-cyclopentylmethyl)-4H-1,2,4thiadiazol-5-one; 0139 (R)3-(1-Aminomethyl-3,3-dimethyl-cyclopentylmethyl)-4H-1,2,4thiadiazol-5-one; 0140 3-(1-Aminomethyl-3,3-dimethyl-cyclobutylmethyl)-4H-1,2,4thiadiazol5-one; 0141 C-1-(2-Oxo-2,3-dihydro-24-1,2,3,5oxathiadiazol-4-ylmethyl)-cyclohexyl-methylamine; 0142 (1S-cis)C-3-Methyl-1-(2-oxo-2,3-dihydro-24-1,2,3,5oxathiadiazol-4-ylmethyl)-cyclohexyl-methylamine; 0143 (trans)C-3,4-Dimethyl-1-(2-oxo-2,3-dihydro-24-1,2,3,5oxathiadiazol-4-ylmethyl)-cyclopentyl-methylamine; 0144 (1S-cis)C-3-Methyl-1-(2-oxo-2,3-dihydro-24-1,2,3,5oxathiadiazol-4-ylmethyl)-cyclopentyl-methylamine; 0145 (1R-trans)C-3-Methyl-1-(2-oxo-2,3-dihydro-24-1,2,3,5oxathiadiazol-4-ylmethyl)-cyclopentyl-methylamine; 0146 (1R-cis)C-3-Methyl-1-(2-oxo-2,3-dihydro-24-1,2,3,5oxathiadiazol-4-ylmethyl)-cyclopentyl-methylamine; 0147 (1S-trans)C-3-Methyl-1-(2-oxo-2,3-dihydro-24-1,2,3,5oxathiadiazol-4-ylmethyl)-cyclopentyl-methylamine; 0148 (1,3,4)C-3,4-Dimethyl-1-(2-oxo-2,3-dihydro-24-1,2,3,5oxathiadiazol-4-ylmethyl)-cyclopentyl-methylamine; 0149 (1,3,4)C-3,4-Dimethyl-1-(2-oxo-2,3-dihydro-24-1,2,3,5oxathiadiazol-4-ylmethyl)-cyclopentyl-methylamine; 0150 (S)C-3,3-Dimethyl-1-(2-oxo-2,3-dihydro-24-1,2,3,5oxathiadiazol-4-ylmethyl)-cyclopentyl)-methylamine; 0151 (R)C-3,3-Dimethyl-1-(2-oxo-2,3-dihydro-24-1,2,3,5oxathiadiazol-4-ylmethyl)-cyclopentyl-methylamine; 0152 C-3,3-Dimethyl-1-(2-oxo-2,3-dihydro-24-1,2,3,5oxathiadiazol-4-ylmethyl)-cyclobutyl-methylamine; 0153 (1-Aminomethyl-cyclohexyl)-methanesulfonamide; 0154 (1R-trans)(1-Aminomethyl-3-methyl-cyclohexyl)-methanesulfonamide; 0155 (trans)(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-methanesulfonamide; 0156 (1S-trans)(1-Aminomethyl-3-methyl-cyclopentyl)-methanesulfonamide; 0157 (1R-cis)(1-Aminomethyl-3-methyl-cyclopentyl)-methanesulfonamide; 0158 (1R-trans)(1-Aminomethyl-3-methyl-cyclopentyl)-methanesulfonamide; 0159 (1S-cis)(1-Aminomethyl-3-methyl-cyclopentyl)-methanesulfonamide; 0160 (1,3,4)(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-methanesulfonamide; 0161 (1,3,4)(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-methanesulfonamide; 0162 (R)(1-Aminomethyl-3,3-dimethyl-cyclopentyl)-methanesulfonamide; 0163 (S)(1-Aminomethyl-3,3-dimethyl-cyclopentyl)-methanesulfonamide; 0164 (1-Aminomethyl-3,3-dimethyl-cyclobutyl)-methanesulfonamide; 0165 (1-Aminomethyl-cyclohexyl)-methanesulfonic acid; 0166 (1R-trans)(1-Aminomethyl-3-methyl-cyclohexyl)-methanesulfonic acid; 0167 (trans)(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-methanesulfonic acid; 0168 (1S-trans)(1-Aminomethyl-3-methyl-cyclopentyl)-methanesulfonic acid; 0169 (1S-cis)(1-Aminomethyl-3-methyl-cyclopentyl)-methanesulfonic acid; 0170 (1R-trans)(1-Aminomethyl-3-methyl-cyclopentyl)-methanesulfonic acid; 0171 (1R-cis)(1-Aminomethyl-3-methyl-cyclopentyl)-methanesulfonic acid; 0172 (1,3,4)(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-methanesulfonic acid; 0173 (1,3,4)(1-Aminomethyl-3,4-dimethyl-cyclopentyl)-methanesulfonic acid; 0174 (R)(1-Aminomethyl-3,3-dimethyl-cyclopentyl)-methanesulfonic acid; 0175 (S)(1-Aminomethyl-3,3-dimethyl-cyclopentyl)-methanesulfonic acid; 0176 (1-Aminomethyl-3,3-dimethyl-cyclobutyl)-methanesulfonic acid; 0177 (1-Aminomethyl-cyclopentylmethyl)-phosphonic acid; 0178 2-(1-Aminomethyl-cyclopentyl)-N-hydroxy-acetamide; 0179 N-2-(1-Aminomethyl-cyclopentyl)-ethyl-methanesulfonamide; 0180 3-(1-Aminomethyl-cyclopentylmethyl)-4H-1,2,4oxadiazol-5-one; 0181 3-(1-Aminomethyl-cyclopentylmethyl)-4H-1,2,4oxadiazole-5-thione; 0182 C-1-(1H-Tetrazol-5-ylmethyl)-cyclopentyl-methylamine; 0183 N-2-(1-Aminomethyl-cyclopentyl)-ethyl-C,C,C-trifluoro-methanesulfonamide; 0184 3-(1-Aminomethyl-cyclopentylmethyl)-4H-1,2,4thiadiazol-5-one; 0185 C-1-(2-Oxo-2,3-dihydro-24-1,2,3,5oxathiadiazol-4-ylmethyl)-cyclopentyl-methylamine; 0186 (1-Aminomethyl-cyclopentyl)-methanesulfonamide; 0187 (1-Aminomethyl-cyclopentyl)-methanesulfonic acid; 0188 (9-Aminomethyl-bicyclo3.3.1non-9-ylmethyl)-phosphonic acid; 0189 2-(9-Aminomethyl-bicyclo3.3.1non-9-yl)-N-hydroxy-acetamide; 0190 N-2-(9-Aminomethyl-bicyclo3.3.1non-9-yl)-ethyl-methanesulfonamide; 0191 3-(9-Aminomethyl-bicyclo3.3.1non-9-ylmethyl)-4H-1,2,4oxadiazol-5-one; 0192 3-(9-Aminomethyl-bicyclo3.3.1non-9-ylmethyl)-4H-1,2,4oxadiazole-5-thione; 0193 C-9-(1H-Tetrazol-5-ylmethyl)-bicyclo3.3.1non-9-yl-methylamine; 0194 N-2-(9-Aminomethyl-bicyclo3.3.1non-9-yl)-ethyl-C,C,C-trifluoro-methanesulfonamide; 0195 3-(9-Aminomethyl-bicyclo3.3.1non-9-ylmethyl)-4H-1,2,4thiadiazol-5-one; 0196 C-9-(2-Oxo-2,3-dihydro-24-1,2,3,5oxathiadiazol-4-ylmethyl)-bicyclo3,3,1 non-9-yl-methylamine; 0197 (9-Aminomethyl-bicyclo3.3.1non-9-yl)-methanesulfonamide; 0198 (9-Aminomethyl-bicyclo3.3.1non-9-yl)-methanesulfonic acid; 0199 (2-Aminomethyl-adamantan-2-ylmethyl)-phosphonic acid; 0200 2-(2-Aminomethyl-adamantan-2-yl)-N-hydroxy-acetamide; 0201 N-2-(2-Aminomethyl-adamantan-2-yl)-ethyl-methanesulfonamide; 0202 3-(2-Aminomethyl-adamantan-2-ylmethyl)-4H-1,2,4oxadiazol-5-one; 0203 3-(2-Aminomethyl-adamantan-2-ylmethyl)-4H-1,2,4oxadiazole-5-thione; 0204 C-2-(1H-Tetrazol-5-ylmethyl)-adamantan-2-yl-methylamine; 0205 N-2-(2-Aminomethyl-adamantan-2-yl)-ethyl-C,C,C-trifluoro-methanesulfonamide; 0206 3-(2-Aminomethyl-adamantan-2-ylmethyl)-4H-1,2,4thiadiazol-5-one; 0207 C-2-(2-Oxo-2,3-dihydro-24-1,2,3,5oxathiadiazol-4-ylmethyl)-adamantan-2-yl-methylamine; 0208 (2-Aminomethyl-adamantan-2-yl)-methanesulfonamide; 0209 (2-Aminomethyl-adamantan-2-yl)-methanesulfonic acid; 0210 (1-Aminomethyl-cycloheptylmethyl)-phosphonic acid; 0211 2-(1-Aminomethyl-cycloheptyl)-N-hydroxy-acetamide; 0212 N-2-(1-Aminomethyl-cycloheptyl)-ethyl-methanesulfonamide; 0213 3-(1-Aminomethyl-cycloheptylmethyl)-4H-1,2,4oxadiazole-5-thione; 0214 N-2-(1-Aminomethyl-cycloheptyl)-ethyl-C,C,C-trifluoro-methanesulfonamide; 0215 C-1-(2-Oxo-2,3-dihydro-2 14-1,2,3,5oxathiadiazol-4-ylmethyl)-cycloheptyl-methylamine; 0216 (1-Aminomethyl-cycloheptyl)-methanesulfonamide; and 0217 (1-Aminomethyl-cycloheptyl)-methanesulfonic acid. 0218 Another preferred embodiment of the invention method utilizes a compound of Formulas III, IIIC, IIIF, IIIG, or IIIH, wherein preferred compounds are those wherein R is a sulfonamide selected from NHSO2R15 or SO2NHR15 wherein R15 is straight or branched alkyl or trifluoro-methyl. 0219 Another preferred embodiment of the invention method utilizes a compound of Formulas III, IIIC, IIIF, IIIG, or IIIH, wherein especially preferred is N-2-(1-aminomethyl-cyclohexyl)-ethyl-methanesulfonamide. 0220 Another preferred embodiment of the invention method utilizes a compound of Formulas III, IIIC, IIIF, IIIG, or IIIH, wherein other preferred compounds are those wherein R is a phosphonic acid, PO3H2. 0221 Another preferred embodiment of the invention method utilizes a compound of Formulas III, IIIC, IIIF, IIIG, or IIIH, wherein especially preferred are (1-aminomethyl-cyclohexylmethyl)-phosphonic acid and (2-aminomethyl-4-methyl-pentyl)-phosphonic acid. 0222 Another preferred embodiment of the invention method utilizes a compound of Formulas III, IIIC, IIIF, IIIG, or IIIH, wherein other preferred compounds are those wherein R is a heterocycle selected from: 8

0223 Another preferred embodiment of the invention method utilizes a compound of Formulas III, IIIC, IIIF, IIIG, or IIIH, wherein especially preferred are C-1-(1H-tetrazol-5-ylmethyl)cyclohexyl-methylamine and 4-methyl-2-(1H-tetrazol-5-ylmethyl)-pentylamine. 0224 An especially preferred embodiment of the invention method utilizes a compound of Formula III wherein: 0225 m is an integer of from 0 to 2; 0226 p is an integer of 2; and 9

0227 Still more preferred is an embodiment of the invention method which utilizes a compound of Formulas III, IIIC, IIIF, IIIG, or IIIH named 3-(1-aminomethyl-cyclohexylmethyl)-4H-1,2,4oxadiazol-5-one, or a pharmaceutically acceptable salt thereof. 0228 Still more preferred is an embodiment of the invention method which utilizes a compound of Formulas III, IIIC, IIIF, IIIG, or IIIH named 3-(1-aminomethyl-cyclohexylmethyl)-4H-1,2,4oxadiazol-5-one hydrochloride. 0229 Also preferred is an embodiment of the invention method which utilizes a compound of Formulas III, IIIC, IIIF, IIIG, or IIIH named 3-(1-aminomethyl-cycloheptylmethyl)-4H-1,2,4oxadiazol-5-one, or a pharmaceutically acceptable salt thereof. 0230 Also more preferred is an embodiment of the invention method which utilizes a compound of Formulas III, IIIC, IIIF, IIIG, or IIIH named 3-(1-aminomethyl-cycloheptylmethyl)-4H-1,2,4oxadiazol-5-one hydrochloride. 0231 Also preferred is an embodiment of the invention method which utilizes a compound of Formulas III, IIIC, IIIF, IIIG, or IIIH named C-1-(1H-tetrazol-5-ylmethyl)-cycloheptyl-methylamine, or a pharmaceutically acceptable salt thereof. 0232 Also more preferred is an embodiment which utilizes a compound of Formulas III, IIIC, IIIF, IIIG, or IIIH named C-1-(1H-tetrazol-5-ylmethyl)-cycloheptyl-methylamine. 0233 Another preferred embodiment of the invention method utilizes a GABA analog that is a compound of Formula IV 10

0234 or a pharmaceutically acceptable salt thereof wherein: 0235 R1 is hydrogen, straight or branched alkyl of from 1 to 6 carbon atoms or phenyl; 0236 R2 is straight or branched alkyl of from 1 to 8 carbon atoms, 0237 straight or branched alkenyl of from 2 to 8 carbon atoms, 0238 cycloalkyl of from 3 to 7 carbon atoms, 0239 alkoxy of from 1 to 6 carbon atoms, 0240 -alkylcycloalkyl, 0241 -alkylalkoxy, 0242 -alkyl OH 0243 -alkylphenyl, 0244 -alkylphenoxy, 0245 -phenyl or substituted phenyl; and 0246 R1 is straight or branched alkyl of from 1 to 6 carbon atoms or phenyl when R2 is methyl. 0247 Preferred is an embodiment of the invention method employing a compound of Formula IV wherein R1 is hydrogen, and R2 is alkyl. 0248 Another preferred embodiment of the invention method employing a compound of Formula IV wherein R1 is methyl, and R2 is alkyl. 0249 Still another preferred embodiment of the invention method utilizes a compound of Formula IV wherein R1 is methyl, and R2 is methyl or ethyl. 0250 Especially preferred is an embodiment of the invention method utilizing a compound of Formula IV selected from: 0251 3-Aminomethyl-5-methylheptanoic acid; 0252 3-Aminomethyl-5-methyl-octanoic acid; 0253 3-Aminomethyl-5-methyl-nonanoic acid; 0254 3-Aminomethyl-5-methyl-decanoic acid; 0255 3-Aminomethyl-5-methyl-undecanoic acid; 0256 3-Aminomethyl-5-methyl-dodecanoic acid; 0257 3-Aminomethyl-5-methyl-tridecanoic acid; 0258 3-Aminomethyl-5-cyclopropyl-hexanoic acid; 0259 3-Aminomethyl-5-cyclobutyl-hexanoic acid; 0260 3-Aminomethyl-5-cyclopentyl-hexanoic acid; 0261 3-Aminomethyl-5-cyclohexyl-hexanoic acid; 0262 3-Aminomethyl-5-trifluoromethyl-hexanoic acid; 0263 3-Aminomethyl-5-phenyl-hexanoic acid; 0264 3-Aminomethyl-5-(2-chlorophenyl)-hexanoic acid; 0265 3-Aminomethyl-5-(3-chlorophenyl)-hexanoic acid; 0266 3-Aminomethyl-5-(4-chlorophenyl)-hexanoic acid; 0267 3-Aminomethyl-5-(2-methoxyphenyl)-hexanoic acid; 0268 3-Aminomethyl-5-(3-methoxyphenyl)-hexanoic acid; 0269 3-Aminomethyl-5-(4-methoxyphenyl)-hexanoic acid; and 0270 3-Aminomethyl-5-(phenylmethyl)-hexanoic acid. 0271 Another especially preferred embodiment of the invention method uses a compound of Formula IV selected from: 0272 (3R,4S)-3-Aminomethyl-4,5-dimethyl-hexanoic acid; 0273 3-Aminomethyl-4,5-dimethyl-hexanoic acid; 0274 (3R,4S)-3-Aminomethyl-4,5-dimethyl-hexanoic acid MP; 0275 (3S,4S)-3-Aminomethyl-4,5-dimethyl-hexanoic acid; 0276 (3R,4R)-3-Aminomethyl-4,5-dimethyl-hexanoic acid MP; 0277 3-Aminomethyl-4-isopropyl-hexanoic acid; 0278 3-Aminomethyl-4-isopropyl-heptanoic acid; 0279 3-Aminomethyl-4-isopropyl-octanoic acid; 0280 3-Aminomethyl-4-isopropyl-nonanoic acid; 0281 3-Aminomethyl-4-isopropyl-decanoic acid; and 0282 3-Aminomethyl-4-phenyl-5-methyl-hexanoic acid. 0283 Another preferred embodiment of the invention method uses a compound of Formula IV selected from: 0284 (3S,5S)-3-Aminomethyl-5-methoxy-hexanoic acid; 0285 (3S,5S)-3-Aminomethyl-5-ethoxy-hexanoic acid; 0286 (3S,5S)-3-Aminomethyl-5-propoxy-hexanoic acid; 0287 (3S,5S)-3-Aminomethyl-5-isopropoxy-hexanoic acid; 0288 (3S,5S)-3-Aminomethyl-5-tert-butoxy-hexanoic acid; 0289 (3S,5S)-3-Aminomethyl-5-fluoromethoxy-hexanoic acid; 0290 (3S,5S)-3-Aminomethyl-5-(2-fluoro-ethoxy)-hexanoic acid; 0291 (3S,5S)-3-Aminomethyl-5-(3,3,3-trifluoro-propoxy)-hexanoic acid; 0292 (3S,5S)-3-Aminomethyl-5-phenoxy-hexanoic acid; 0293 (3S,5S)-3-Aminomethyl-5-(4-chloro-phenoxy)-hexanoic acid; 0294 (3S,5S)-3-Aminomethyl-5-(3-chloro-phenoxy)-hexanoic acid; 0295 (3S,5S)-3-Aminomethyl-5-(2-chloro-phenoxy)-hexanoic acid; 0296 (3S,5S)-3-Aminomethyl-5-(4-fluoro-phenoxy)-hexanoic acid; 0297 (3S,5S)-3-Aminomethyl-5-(3-fluoro-phenoxy)-hexanoic acid; 0298 (3S,5S)-3-Aminomethyl-5-(2-fluoro-phenoxy)-hexanoic acid; 0299 (3S,5S)-3-Aminomethyl-5-(4-methoxy-phenoxy)-hexanoic acid; 0300 (3S,5S)-3-Aminomethyl-5-(3-methoxy-phenoxy)-hexanoic acid; 0301 (3S,5S)-3-Aminomethyl-5-(2-methoxy-phenoxy)-hexanoic acid; 0302 (3S,5S)-3-Aminomethyl-5-(4-nitro-phenoxy)-hexanoic acid; 0303 (3S,5S)-3-Aminomethyl-5-(3-nitro-phenoxy)-hexanoic acid; 0304 (3S,5S)-3-Aminomethyl-5-(2-nitro-phenoxy)-hexanoic acid; 0305 (3S,5S)-3-Aminomethyl-6-hydroxy-5-methyl-hexanoic acid; 0306 (3S,5S)-3-Aminomethyl-6-methoxy-5-methyl-hexanoic acid; 0307 (3S,5S)-3-Aminomethyl-6-ethoxy-5-methyl-hexanoic acid; 0308 (3S,5S)-3-Aminomethyl-5-methyl-6-propoxy-hexanoic acid; 0309 (3S,5S)-3-Aminomethyl-6-isopropoxy-5-methyl-hexanoic acid; 0310 (3S,5S)-3-Aminomethyl-6-tert-butoxy-5-methyl-hexanoic acid; 0311 (3S,5S)-3-Aminomethyl-6-fluoromethoxy-5-methyl-hexanoic acid; 0312 (3S,5S)-3-Aminomethyl-6-(2-fluoro-ethoxy)-5-methyl-hexanoic acid; 0313 (3S,5S)-3-Aminomethyl-5-methyl-6-(3,3,3-trifluoro-propoxy)-hexanoic acid; 0314 (3S,5S)-3-Aminomethyl-5-methyl-6-phenoxy-hexanoic acid; 0315 (3S,5S)-3-Aminomethyl-6-(4-chloro-phenoxy)-5-methyl-hexanoic acid; 0316 (3S,5S)-3-Aminomethyl-6-(3-chloro-phenoxy)-5-methyl-hexanoic acid; 0317 (3S,5S)-3-Aminomethyl-6-(2-chloro-phenoxy)-5-methyl-hexanoic acid; 0318 (3S,5S)-3-Aminomethyl-6-(4-fluoro-phenoxy)-5-methyl-hexanoic acid; 0319 (3S,5S)-3-Aminomethyl-6-(3-fluoro-phenoxy)-5-methyl-hexanoic acid; 0320 (3S,5S)-3-Aminomethyl-6-(2-fluoro-phenoxy)-5-methyl-hexanoic acid; 0321 (3S,5S)-3-Aminomethyl-6-(4-methoxy-phenoxy)-5-methyl-hexanoic acid; 0322 (3S,5S)-3-Aminomethyl-6-(3-methoxy-phenoxy)-5-methyl-hexanoic acid; 0323 (3S,5S)-3-Aminomethyl-6-(2-methoxy-phenoxy)-5-methyl-hexanoic acid; 0324 (3S,5S)-3-Aminomethyl-5-methyl 6-(4-trifluoromethyl-phenoxy)-hexanoic acid; 0325 (3S,5S)-3-Aminomethyl-5-methyl 6-(3-trifluoromethyl-phenoxy)-hexanoic acid; 0326 (3S,5S)-3-Aminomethyl-5-methyl 6-(2-trifluoromethyl-phenoxy)-hexanoic acid; 0327 (3S,5S)-3-Aminomethyl-5-methyl 6-(4-nitro-phenoxy)-hexanoic acid; 0328 (3S,5S)-3-Aminomethyl-5-methyl 6-(3-nitro-phenoxy)-hexanoic acid; 0329 (3S,5S)-3-Aminomethyl-5-methyl 6-(2-nitro-phenoxy)-hexanoic acid; 0330 (3S,5S)-3-Aminomethyl-6-benzyloxy-5-methyl-hexanoic acid; 0331 (3S,5S)-3-Aminomethyl-7-hydroxy-5-methyl-heptanoic acid; 0332 (3S,5S)-3-Aminomethyl-7-methoxy-5-methyl-heptanoic acid; 0333 (3S,5S)-3-Aminomethyl-7-ethoxy-5-methyl-heptanoic acid; 0334 (3S,5S)-3-Aminomethyl-5-methyl-7-propoxy-heptanoic acid; 0335 (3S,5S)-3-Aminomethyl-7-isopropoxy-5-methyl-heptanoic acid; 0336 (3S,5S)-3-Aminomethyl-7-tert-butoxy-5-methyl-heptanoic acid; 0337 (3S,5S)-3-Aminomethyl-7-fluoromethoxy-5-methyl-heptanoic acid; 0338 (3S,5S)-3-Aminomethyl-7-(2-fluoro-ethoxy)-5-methyl-heptanoic acid; 0339 (3S,5S)-3-Aminomethyl-5-methyl-7-(3,3,3-trifluoro-propoxy)-heptanoic acid; 0340 (3S,5S)-3-Aminomethyl-7-benzyloxy-5-methyl-heptanoic acid; 0341 (3S,5S)-3-Aminomethyl-5-methyl-7-phenoxy-heptanoic acid; 0342 (3S,5S)-3-Aminomethyl-7-(4-chloro-phenoxy)-5-methyl-heptanoic acid; 0343 (3S,5S)-3-Aminomethyl-7-(3-chloro-phenoxy)-5-methyl-heptanoic acid; 0344 (3S,5S)-3-Aminomethyl-7-(2-chloro-phenoxy)-5-methyl-heptanoic acid; 0345 (3S,5S)-3-Aminomethyl-7-(4-fluoro-phenoxy)-5-methyl-heptanoic acid; 0346 (3S,5S)-3-Aminomethyl-7-(3-fluoro-phenoxy)-5-methyl-heptanoic acid; 0347 (3S,5S)-3-Aminomethyl-7-(2-fluoro-phenoxy)-5-methyl-heptanoic acid; 0348 (3S,5S)-3-Aminomethyl-7-(4-methoxy-phenoxy)-5-methyl-heptanoic acid; 0349 (3S,5S)-3-Aminomethyl-7-(3-methoxy -phenoxy)-5-methyl-heptanoic acid; 0350 (3S,5S)-3-Aminomethyl-7-(2-methoxy -phenoxy)-5-methyl-heptanoic acid; 0351 (3S,5S)-3-Aminomethyl-5-methyl-7-(4-trifluoromethyl-phenoxy)heptanoic acid; 0352 (3S,5S)-3-Aminomethyl-5-methyl-7-(3-trifluoromethyl-phenoxy)heptanoic acid; 0353 (3S,5S)-3-Aminomethyl-5-methyl-7-(2-trifluoromethyl-phenoxy)heptanoic acid; 0354 (3S,5S)-3-Aminomethyl-5-methyl-7-(4-nitro-phenoxy)-heptanoic acid; 0355 (3S,5S)-3-Aminomethyl-5-methyl-7-(3-nitro-phenoxy)-heptanoic acid; 0356 (3S,5S)-3-Aminomethyl-5-methyl-7-(2-nitro-phenoxy)-heptanoic acid; 0357 (3S,5S)-3-Aminomethyl-5-methyl-6-phenyl-hexanoic acid; 0358 (3S,5S)-3-Aminomethyl-6-(4-chloro-phenyl)-5-methyl-hexanoic acid; 0359 (3S,5S)-3-Aminomethyl-6-(3-chloro-phenyl)-5-methyl-hexanoic acid; 0360 (3S,5S)-3-Aminomethyl-6-(2-chloro-phenyl)-5-methyl-hexanoic acid; 0361 (3S,5S)-3-Aminomethyl-6-(4-methoxy-phenyl)-5-methyl-hexanoic acid; 0362 (3S,5S)-3-Aminomethyl-6-(3-methoxy-phenyl)-5-methyl-hexanoic acid; 0363 (3S,5S)-3-Aminomethyl-6-(2-methoxy-phenyl)-5-methyl-hexanoic acid; 0364 (3S,5S)-3-Aminomethyl-6-(4-fluoro-phenyl)-5-methyl-hexanoic acid; 0365 (3S,5S)-3-Aminomethyl-6-(3-fluoro-phenyl)-5-methyl-hexanoic acid; 0366 (3S,5S)-3-Aminomethyl-6-(2-fluoro-phenyl)-5-methyl-hexanoic acid; 0367 (3S,5R)-3-Aminomethyl-5-methyl-7-phenyl-heptanoic acid; 0368 (3S,5R)-3-Aminomethyl-7-(4-chloro-phenyl)-5-methyl-heptanoic acid; 0369 (3S,5R)-3-Aminomethyl-7-(3-chloro-phenyl)-5-methyl-heptanoic acid; 0370 (3S,5R)-3-Aminomethyl-7-(2-chloro-phenyl)-5-methyl-heptanoic acid; 0371 (3S,5R)-3-Aminomethyl-7-(4-methoxy-phenyl)-5-methyl-heptanoic acid; 0372 (3S,5R)-3-Aminomethyl-7-(3-methoxy-phenyl)-5-methyl-heptanoic acid; 0373 (3S,5R)-3-Aminomethyl-7-(2-methoxy-phenyl)-5-methyl-heptanoic acid; 0374 (3S,5R)-3-Aminomethyl-7-(4-fluoro-phenyl)-5-methyl-heptanoic acid; 0375 (3S,5R)-3-Aminomethyl-7-(3-fluoro-phenyl)-5-methyl-heptanoic acid; 0376 (3S,5R)-3-Aminomethyl-7-(2-fluoro-phenyl)-5-methyl-heptanoic acid; 0377 (3S,5R)-3-Aminomethyl-5-methyl-oct-7-enoic acid; 0378 (3S,5R)-3-Aminomethyl-5-methyl-non-8-enoic acid; 0379 (E)-(3S,5S)-3-Aminomethyl-5-methyl-oct-6-enoic acid; 0380 (Z)-(3S,5S)-3-Aminomethyl-5-methyl-oct-6-enoic acid; 0381 (Z)-(3S,5S)-3-Aminomethyl-5-methyl-non-6-enoic acid; 0382 (E)-(3S,5S)-3-Aminomethyl-5-methyl-non-6-enoic acid; 0383 (E)-(3S,5R)-3-Aminomethyl-5-methyl-non-7-enoic acid; 0384 (Z)-(3S,5R)-3-Aminomethyl-5-methyl-non-7-enoic acid; 0385 (Z)-(3S,5R)-3-Aminomethyl-5-methyl-dec-7-enoic acid; 0386 (E)-(3S,5R)-3-Aminomethyl-5-methyl-undec-7-enoic acid; 0387 (3S,5S)-3-Aminomethyl-5,6,6-trimethyl-heptanoic acid; 0388 (3S,5S)-3-Aminomethyl-5,6-dimethyl-heptanoic acid; 0389 (3S,5S)-3-Aminomethyl-5-cyclopropyl-hexanoic acid; 0390 (3S,5S)-3-Aminomethyl-5-cyclobutyl-hexanoic acid; 0391 (3S,5S)-3-Aminomethyl-5-cyclopentyl-hexanoic acid; and 0392 (3S,5S)-3-Aminomethyl-5-cyclohexyl-hexanoic acid. 0393 Still another more preferred embodiment of the invention method utilizes a compound of Formula IV selected from: 0394 (3S,5R)-3-Aminomethyl-5-methyl-heptanoic acid; 0395 (3S,5R)-3-Aminomethyl-5-methyl-octanoic acid; 0396 (3S,5R)-3-Aminomethyl-5-methyl-nonanoic acid; 0397 (3S,5R)-3-Aminomethyl-5-methyl-decanoic acid; 0398 (3S,5R)-3-Aminomethyl-5-methyl-undecanoic acid; 0399 (3S,5R)-3-Aminomethyl-5-methyl-dodecanoic acid; 0400 (3S,5R)-3-Aminomethyl-5,9-dimethyl-decanoic acid; 0401 (3S,5R)-3-Aminomethyl-5,7-dimethyl-octanoic acid; 0402 (3S,5R)-3-Aminomethyl-5,8-dimethyl-nonanoic acid; 0403 (3S,5R)-3-Aminomethyl-6-cyclopropyl-5-methyl-hexanoic acid; 0404 (3S,5R)-3-Aminomethyl-6-cyclobutyl-5-methyl-hexanoic acid; 0405 (3S,5R)-3-Aminomethyl-6-cyclopentyl-5-methyl-hexanoic acid; 0406 (3S,5R)-3-Aminomethyl-6-cyclohexyl-5-methyl-hexanoic acid; 0407 (3S,5R)-3-Aminomethyl-7-cyclopropyl-5-methyl-heptanoic acid; 0408 (3S,5R)-3-Aminomethyl-7-cyclobutyl-5-methyl-heptanoic acid; 0409 (3S,5R)-3-Aminomethyl-7-cyclopentyl-5-methyl-heptanoic acid; 0410 (3S,5R)-3-Aminomethyl-7-cyclohexyl-5-methyl-heptanoic acid; 0411 (3S,5R)-3-Aminomethyl-8-cyclopropyl-5-methyl-octanoic acid; 0412 (3S,5R)-3-Aminomethyl-8-cyclobutyl-5-methyl-octanoic acid; 0413 (3S,5R)-3-Aminomethyl-8-cyclopentyl-5-methyl-octanoic acid; 0414 (3S,5R)-3-Aminomethyl-8-cyclohexyl-5-methyl-octanoic acid; 0415 (3S,5S)-3-Aminomethyl-6-fluoro-5-methyl-hexanoic acid; 0416 (3S,5S)-3-Aminomethyl-7-fluoro-5-methyl-heptanoic acid; 0417 (3S,5R)-3-Aminomethyl-8-fluoro-5-methyl-octanoic acid; 0418 (3S,5R)-3-Aminomethyl-9-fluoro-5-methyl-nonanoic acid; 0419 (3S,5S)-3-Aminomethyl-7,7,7-trifluoro-5-methyl-heptanoic acid; 0420 (3S,5R)-3-Aminomethyl-8,8,8-trifluoro-5-methyl-octanoic acid; 0421 (3S,5R)-3-Aminomethyl-5-methyl-8-phenyl-octanoic acid; 0422 (3S,5S)-3-Aminomethyl-5-methyl-6-phenyl-hexanoic acid; and 0423 (3S,5R)-3-Aminomethyl-5-methyl-7-phenyl-heptanoic acid. 0424 Another preferred embodiment of the invention method utilizes a GABA analog which is a compound of Formulas (1A) or (1B) 11

0425 or a pharmaceutically acceptable salt thereof wherein: 0426 n is an integer of from 0 to 2; 0427 R is sulfonamide, 0428 amide, 0429 phosphonic acid, 0430 heterocycle, 0431 sulfonic acid, or 0432 hydroxamic acid; 0433 A is hydrogen or methyl; and 12

0434 straight or branched alkyl of from 1 to 11 carbons, or 0435 (CH2)1-4-Y(CH2)0-4-phenyl wherein Y is O, S, NR3 wherein: 0436 R3 is alkyl of from 1 to 6 carbons, cycloalkyl of from 3 to 8 carbons, benzyl or phenyl wherein benzyl or phenyl can be unsubstituted or substituted with from 1 to 3 substituents each independently selected from alkyl, alkoxy, halogen, hydroxy, carboxy, carboalkoxy, trifluoromethyl, and nitro. 0437 A preferred embodiment utilizes a GABA analog which is a compound of Formulas (1A) or (1B), wherein R is a sulfonamide selected from NHSO2R15 and SO2NHR15, wherein R15 is straight or branched alkyl or trifluoromethyl. 0438 An especially preferred embodiment utilizes a compound of Formulas (1A) or (1B) selected from: 0439 4-Methyl-2-(1H-tetrazol-5-ylmethyl)-pentylamine; 0440 3-(2-Aminomethyl-4-methyl-pentyl)-4H-1,2,4oxadiazole-5-thione, HCl; 0441 (2-Aminomethyl-4-methyl-pentyl)-phosphonic acid; 0442 3-(3-Amino-2-cyclopentyl-propyl)-4H-1,2,4oxadiazol-5-one; 0443 3-(3-Amino-2-cyclopentyl-propyl)-4H-1,2,4thiadiazol-5-one; 0444 2-Cyclopentyl-3-(2-oxo-2,3-dihydro-24-1,2,3,5oxathiadiazol-4-yl)-propylamine; 0445 3-(3-Amino-2-cyclobutyl-propyl)-4H-1,2,4oxadiazol-5-one; 0446 3-(3-Amino-2-cyclobutyl-propyl)-4H-1,2,4thiadiazol-5-one; and 0447 2-Cyclobutyl-3-(2-oxo-2,3-dihydro-24-1,2,3,5oxathiadiazol-4-yl)-propylamine. 0448 Another preferred embodiment utilizes a compound of Formulas (1A) or (1B), wherein R is a phosphonic acid, PO3H2. 0449 Another preferred embodiment utilizes a compound of Formulas (1A) or (1B), wherein R is 13

0450 More preferred is an embodiment that utilizes a compound of Formulas (1A) or (1B), wherein R is 14

0451 Still more preferred is an embodiment that utilizes a compound of Formulas (1A) or (1B) named 3-(2-aminomethyl-4-methyl-pentyl)-4H-1,3,4oxadiazol-5-one, or a pharmaceutically acceptable salt thereof. 0452 Still more preferred is an embodiment that utilizes a compound of Formulas (1A) or (1B) named 3-(2-aminomethyl-4-methyl-pentyl)-4H-1,2,4oxadiazol-5-one hydrochloride. 0453 Another embodiment of the present invention utilizes a GABA analog that is a compound of Formulas V, VI, VII, or VIII 15

0454 or a pharmaceutically acceptable salt thereof, wherein n is integer of from 1 to 4, where there are stereocenters, each center may be independently R or S. 0455 A preferred embodiment utilizes a compound of Formulas V, VI, VII, or VIII, wherein n is an integer of from 2 to 4. 0456 Another preferred embodiment utilizes a compound of Formula V. 0457 A still more preferred embodiment utilizes a compound of Formulas V, VI, VII, or VIII selected from: 0458 (1,6,8)(2-Aminomethyl-octahydro-inden-2-yl)-acetic acid; 0459 (2-Aminomethyl-octahydro-inden-2-yl)-acetic acid; 0460 (2-Aminomethyl-octahydro-pentalen-2-yl)-acetic acid; 0461 (2-Aminomethyl-octahydro-pentalen-2-yl)-acetic acid; 0462 (3-Aminomethyl-bicyclo3.2.0hept-3-yl)-acetic acid; and; 0463 (3-Aminomethyl-bicyclo3.2.0hept-3-yl)-acetic acid. 0464 (2-Aminomethyl-octahydro-inden-2-yl)-acetic acid; 0465 Another still more preferred embodiment utilizes a compound of Formulas V, VI, VII, or VIII selected from: 0466 (1,5)(3-Aminomethyl-bicyclo3.1.0hex-3-yl)-acetic acid, 0467 (1,5)(3-Aminomethyl-bicyclo3.2.0hept-3-yl)-acetic acid, 0468 (1,5)(2-Aminomethyl-octahydro-pentalen-2-yl)-acetic acid, 0469 (1,6)(2-Aminomethyl-octahydro-inden-2-yl)-acetic acid, 0470 (1,7)(2-Aminomethyl-decahydro-azulen-2-yl)-acetic acid, 0471 (1,5)(3-Aminomethyl-bicyclo3.1.0hex-3-yl)-acetic acid, 0472 (1,5)(3-Aminomethyl-bicyclo3.2.0hept-3-yl)-acetic acid, 0473 (1,5)(2-Aminomethyl-octahydro-pentalen-2-yl)-acetic acid, 0474 (1,6)(2-Aminomethyl-octahydro-inden-2-yl)-acetic acid, 0475 (1,7)(2-Aminomethyl-decahydro-azulen-2-yl)-acetic acid, 0476 (1,3,5)(3-Aminomethyl-bicyclo3.1.0hex-3-yl)-acetic acid, 0477 (1,3,5)(2-Aminomethyl-octahydro-pentalen-2-yl)-acetic acid, 0478 (1,6,8)(2-Aminomethyl-octahydro-inden-2-yl)-acetic acid, 0479 (1,7,9)(2-Aminomethyl-decahydro-azulen-2-yl)-acetic acid, 0480 (1,3,5)(3-Aminomethyl-bicyclo3.1.0hex-3-yl)-acetic acid, 0481 (1,3,5)(3-Aminomethyl-bicyclo3.2.0hept-3-yl)-acetic acid, 0482 (1,3,5)(2-Aminomethyl-octahydro-pentalen-2-yl)-acetic acid, 0483 (1,6,8)(2-Aminomethyl-octahydro-inden-2-yl)-acetic acid, 0484 (1,7,9)(2-Aminomethyl-decahydro-azulen-2-yl)-acetic acid, 0485 ((1R,3R,6R)-3-Aminomethyl-bicyclo4.1.0hept-3-yl)-acetic acid, 0486 ((1R,3S,6R)-3-Aminomethyl-bicyclo 4.1.0hept-3-yl)-acetic acid, 0487 ((1S,3S,6S)-3-Aminomethyl-bicyclo4.1.0hept-3-yl)-acetic acid, 0488 ((1S,3R,6S)-3-Aminomethyl-bicyclo4.1.0hept-3-yl)-acetic acid, 0489 ((1R,3R,6S)-3-Aminomethyl-bicyclo4.2.0oct-3-yl)-acetic acid, 0490 ((1R,3S,6S)-3-Aminomethyl-bicyclo4.2.0oct-3-yl)-acetic acid, 0491 ((1S,3S,6R)-3-Aminomethyl-bicyclo4.2.0oct-3-yl)-acetic acid, 0492 ((1S,3R,6R)-3-Aminomethyl-bicyclo4.2.0oct-3-yl)-acetic acid, 0493 ((3R,5R,7S)-5-Aminomethyl-octahydro-inden-5-yl)-acetic acid, 0494 ((3R,5S,7S)-5-Aminomethyl-octahydro-inden-5-yl)-acetic acid, 0495 ((3S,5S,7R)-5-Aminomethyl-octahydro-inden-5-yl)-acetic acid, 0496 ((3S,5R,7R)-5-Aminomethyl-octahydro-inden-5-yl)-acetic acid, 0497 ((2R,4S,8R)-2-Aminomethyl-decahydro-naphthalen-2-yl)-acetic acid, 0498 ((2S,4S,8R)-2-Aminomethyl-decahydro-naphthalen-2-yl)-acetic acid, 0499 ((2S,4R,8S)-2-Aminomethyl-decahydro-naphthalen-2-yl)-acetic acid, 0500 ((2R,4R,8S)-2-Aminomethyl-decahydro-naphthalen-2-yl)-acetic acid, 0501 ((2R,4S,9R)-2-Aminomethyl-decahydro-benzocyclophepten-2-yl)-acetic acid, 0502 ((2S,4S,9R)-2-Aminomethyl-decahydro-benzocyclophepten-2-yl)-acetic acid, 0503 ((2S,4R,9S)-2-Aminomethyl-decahydro-benzocyclophepten-2-yl)-acetic acid, 0504 ((2R,4R,9S)-2-Aminomethyl-decahydro-benzocyclophepten-2-yl)-acetic acid, 0505 ((1R,3R,6S)-3-Aminomethyl-bicyclo4.1.0hept-3-yl)-acetic acid, 0506 ((1R,3S,6S)-3-Aminomethyl-bicyclo4.1.0hept-3-yl)-acetic acid, 0507 ((1S,3S,6R)-3-Aminomethyl-bicyclo4.1.0hept-3-yl)-acetic acid, 0508 ((1S,3R,6R)-3-Aminomethyl-bicyclo4.1.0hept-3-yl)-acetic acid, 0509 ((1R,3R,6R)-3-Aminomethyl-bicyclo4.2.0oct-3-yl)-acetic acid, 0510 ((1R,3S,6R)-3-Aminomethyl-bicyclo4.2.0oct-3-yl)-acetic acid, 0511 ((1S,3S,6S)-3-Aminomethyl-bicyclo4.2.0oct-3-yl)-acetic acid, 0512 ((1S,3R,6S)-3-Aminomethyl-bicyclo4.2.0oct-3-yl)-acetic acid, 0513 ((3R,5R,7R)-5-Aminomethyl-octahydro-inden-5-yl)-acetic acid, 0514 ((3R,5S,7R)-5-Aminomethyl-octahydro-inden-5-yl)-acetic acid, 0515 ((3S,5S,7S)-5-Aminomethyl-octahydro-inden-5-yl)-acetic acid, 0516 ((3S,5R,7S)-5-Aminomethyl-octahydro-inden-5-yl)-acetic acid, 0517 ((2R,4R,8R)-2-Aminomethyl-decahydro-naphthalen-2-yl)-acetic acid, 0518 ((2S,4S,8R)-2-Aminomethyl-decahydro-naphthalen-2-yl)-acetic acid, 0519 ((2S,4R,8S)-2-Aminomethyl-decahydro-naphthalen-2-yl)-acetic acid, 0520 ((2R,4S,8S)-2-Aminomethyl-decahydro-naphthalen-2-yl)-acetic acid, 0521 ((2R,4R,9R)-2-Aminomethyl-decahydro-benzocyclophepten-2-yl)-acetic acid, 0522 ((2S,4R,9R)-2-Aminomethyl-decahydro-benzocyclophepten-2-yl)-acetic acid, 0523 ((2S,4S,9S)-2-Aminomethyl-decahydro-benzocyclophepten-2-yl)-acetic acid, and 0524 ((2R,4S,9S)-2-Aminomethyl-decahydro-benzocyclophepten-2-yl)-acetic acid. 0525 A more preferred embodiment utilizes a compound of Formulas V, VI, VII, or VIII named (1,3,5)(3-aminomethyl-bicyclo3.2.0hept-3-yl)-acetic acid, or a pharmaceutically acceptable salt thereof. 0526 A still more preferred embodiment utilizes a compound of Formulas V, VI, VII, or VIII named (1,3,5)(3-aminomethyl-bicyclo3.2.0hept-3-yl)-acetic acid hydrochloride.

DETAILED DESCRIPTION OF THE INVENTION 0527 As noted above, the method of this invention utilizes any GABA analog having the characteristic of being an inhibitor of cartilage damage, or a pharmaceutically acceptable salt thereof. For the purposes of the instant invention, a GABA analog having the characteristic of being an inhibitor of cartilage damage is any compound derived from or based upon gamma-aminobutyric acid that provides a cartilage damage inhibiting effect in accordance with this invention. 0528 A compound that is a GABA analog having the characteristic of being an inhibitor of cartilage damage may be readily identified by one of ordinary skill in the pharmaceutical or medical arts by assaying a GABA analog in any number of well known assays for measuring cartilage effects of a compound, and determining the GABA analog's effects on cartilage damage. These assays include in vitro assays that utilize cartilage samples or in vivo assays in whole animals. In in vitro assays, an amount of a GABA analog or control vehicle may be administered with a cartilage damaging agent to cartilage, and the cartilage damage inhibiting effects in both tests studied by gross examination or histopathologic examination of the cartilage, or by measurement of biological markers of cartilage damage such as, for example, proteoglycan content or hydroxyproline content. In in vivo assays, an amount of a GABA analog or control vehicle may be administered with a cartilage damaging agent to an animal, and the effects of the GABA analog being assayed on cartilage in the animal may be evaluated by gross examination or histopathologic examination of the cartilage, by observation of the effects in an acute model on functional limitations of the affected joint that result from cartilage damage, or by measurement of biological markers of cartilage damage such as, for example, proteoglycan content or hydroxyproline content. Several methods of identifying a GABA analog having the characteristic of being an inhibitor of cartilage damage are described below. The amount to be administered in an assay to identify a GABA analog having the characteristic of being an inhibitor of cartilage damage is dependent upon the particular assay employed, but in any event is not higher than the well known maximum amount of a compound that the particular assay can effectively accommodate. 0529 Any GABA analog having the characteristic of being an inhibitor of cartilage damage is readily available, either commercially, or by synthetic methodology, well-known to those skilled in the art of organic chemistry. A preferred GABA analog to be utilized in the method of this invention is selected from the cyclic amino acids of Formula I. These are described in U.S. Pat. No. 4,024,175 and its divisional U.S. Pat. No. 4,087,544, which are both incorporated herein by reference. 0530 Another preferred method utilizes a GABA analog of Formula II, and these compounds are described in U.S. Pat. No. 5,563,175, which is incorporated herein by reference. 0531 Another preferred method utilizes a GABA analog of Formula III, IIIC, IIIF, IIIG, or IIIH, and these compounds are described in PCT International Application Publication No. WO 99/31075, which is herein incorporated by reference. 0532 Another preferred method utilizes a GABA analog of Formula IV, which are described in PCT International Application Publication No. WO 00/76958, which is herein incorporated by reference. 0533 Other preferred GABA analogs to be utilized in the method of the present invention are compounds of Formulas (1A) and (1B), which are described in PCT International Application Publication No. WO 99/31074, which is herein incorporated by reference. 0534 PCT International Application Publication No. WO 01/28978, which is herein incorporated by reference, describes other preferred GABA analogs to be utilized in the method of the present invention, which are compounds of Formulas V, VI, VII, and VIII. 0535 Other preferred GABA analogs for use in the present invention method are described in PCT International Application No. WO 99/31057, which is herein incorporated by reference. Such GABA analogs are compounds of Formula (1D) and (1E) 16

0536 or a pharmaceutically acceptable salt thereof wherein: 0537 n is an integer of from 0 to 2; 0538 R is sulfonamide, 0539 amide, 0540 phosphonic acid, 0541 heterocycle, 0542 sulfonic acid, or 0543 hydroxamic acid; and 0544 X is O, S, S(O), S(O)2, or NR1 wherein R1 is hydrogen, straight or branched alkyl of from 1 to 6 carbons, benzyl, C(O)R2 wherein R2 is straight or branched alkyl of 1 to 6 carbons, benzyl or phenyl or CO2R3 wherein R3 is straight or branched alkyl of from 1 to 6 carbons, or benzyl wherein the benzyl or phenyl groups can be unsubstituted or substituted by from 1 to 3 substituents selected from halogen, trifluoromethyl, and nitro. 0545 Other preferred GABA analogs that may be utilized in the method of the present invention are described in PCT International Application No. WO 98/17627, which is herein incorporated by reference. This embodiment uses a GABA analog that is a compound of formula 17

0546 or a pharmaceutically acceptable salt thereof wherein: 0547 R is hydrogen or lower alkyl; 0548 R1 is hydrogen or lower alkyl; 18

0549 straight or branched alkyl of from 7 to 11 carbon atoms, or 0550 (CH2)(1-4)X(CH2)(0-4)-phenyl wherein 0551 X is O, S, NR3- wherein 0552 R3 is alkyl of from 1 to 6 carbons, cycloalkyl of from 3 to 8 carbons, benzyl or phenyl; 0553 wherein phenyl and benzyl can be unsubstituted or substituted with from 1 to 3 substituents each independently selected from alkyl, alkoxy, halogen, hydroxy, carboxy, carboalkoxy, trifluoromethyl, amino, and nitro. 0554 Other preferred GABA analogs that may be utilized in the method of the present invention are described in PCT International Application No. WO 99/61424, which is herein incorporated by reference. This embodiment of the invention method uses a GABA analog that is a compound of formulas (1), (2), (3), (4), (5), (6), (7), or (8) 19

0555 or a pharmaceutically acceptable salt thereof or a prodrug thereof wherein: 0556 R1 to R10 are each independently selected from hydrogen or a straight or branched alkyl of from 1 to 6 carbons, benzyl, or phenyl; 0557 m is an integer of from 0 to 3; 0558 n is an integer of from 1 to 2; 0559 o is an integer of from 0 to 3; 0560 p is an integer of from 1 to 2; 0561 q is an integer of from 0 to 2; 0562 r is an integer of from 1 to 2; 0563 s is an integer of from 1 to 3; 0564 t is an integer of from 0 to 2; and 0565 u is an integer of from 0 to 1. 0566 All U.S. patents and WO publications referenced above are hereby incorporated by reference. 0567 The terms are as defined below or as they otherwise occur in the specification. 0568 As used herein, the phrase cartilage damage means a disorder of hyaline cartilage and subchondral bone characterized by hypertrophy of tissues in and around the involved joints, which may or may not be accompanied by deterioration of hyaline cartilage surface. 0569 The phrase having the characteristic of being an inhibitor of cartilage damage means having the ability to prevent, block, or inhibit damage to cartilage. 0570 It should be appreciated that the terms uses, utilizes, and employs, and their derivatives thereof, are used interchangeably when describing an embodiment of the present invention. 0571 The phrase lower alkyl means a straight or branched alkyl group or radical having from 1 to 6 carbon atoms, and includes methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, and the like. 0572 The term alkyl is a straight or branched group of from 1 to 8 carbon atoms, unless stated otherwise, including but not limited to methyl, ethyl, propyl, n-propyl, isopropyl, butyl, 2-butyl, tert-butyl, and octyl. Alkyl can be unsubstituted or substituted by hydroxy or from 1 to 3 fluorine atoms. Preferred groups are methyl and ethyl. 0573 The term alkenyl is a straight or branched group of from 2 to 8 carbon atoms containing 1 or 2 or 3 double bonds including but not limited to ethenyl, propen-1-yl, propen-2-yl, propen-3-yl, 1-hexen-3-yl, and hept-1,3-dien-7-yl. Alkenyl can be unsubstituted or substituted by from 1 to 3 fluorine atoms. 0574 The term cycloalkyl means a cyclic group of from 3 to 7 carbon atoms including but not limited to cyclopropyl, cyclobutyl, and cycloheptyl. 0575 The benzyl and phenyl groups may be unsubstituted or substituted with from 1 to 3 groups each independently selected from halogen, especially fluoro, alkoxy, alkyl, and NH2. 0576 Halogen includes fluorine, chlorine, bromine, and iodine. 0577 The term alkoxy means the group O-alkyl wherein alkyl is as defined above. 0578 The terms used to define the invention of compounds of Formulas (1A), (1B), III, IIIC, IIIF, IIIG, and IIIH are as described below. 0579 Sulfonamides are those of formula NHSO2R15 or SO2NHR15 wherein R15 is a straight or branched alkyl group of from 1 to 6 carbons or a trifluoromethyl. 0580 Amides are compounds of formula NHCOR12 wherein R12 is straight or branched alkyl of from 1 to 6 carbons, benzyl, and phenyl. 0581 Phosphonic acids are PO3H2. 0582 Sulfonic acids are SO3H. 0583 Hydroxamic acid is 21

0584 Heterocycles are groups of from 1 to 2 rings, with from 1 to 6 heteroatoms selected from oxygen, nitrogen, and sulfur. 0585 Preferred heterocycles are 22

0586 The term alkyl is a straight or branched group of from 1 to 11 carbon atoms including but not limited to methyl, ethyl, propyl, n-propyl, isopropyl, butyl, 2-butyl, tert-butyl, pentyl, hexyl, and n-hexyl, heptyl, octyl, nonyl, decyl, and undecyl except as where otherwise stated. 0587 The cycloalkyl groups are from 3 to 8 carbons and are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl unless otherwise stated. 0588 The benzyl and phenyl groups may be unsubstituted or substituted by from 1 to 3 substituents selected from hydroxy, carboxy, carboalkoxy, halogen, CF3, nitro, alkyl, and alkoxy. Preferred are halogens. 0589 Alkoxy is as defined above for alkyl. 0590 Halogen is fluorine, chlorine, and bromine and preferred are fluorine and chlorine. 0591 Carboalkoxy is COOalkyl wherein alkyl is as described above. Preferred are carbomethoxy and carboethoxy. 0592 All that is required to practice the method of this invention is to administer a GABA analog having the characteristic of being an inhibitor of cartilage damage, or a pharmaceutically acceptable salt thereof, in an amount that is therapeutically effective to prevent or treat the cartilage damaging condition. Such cartilage damage-inhibiting amount will generally be from about 1 to about 300 mg/kg of subject body weight. Typical doses will be from about 10 to about 5000 mg/day for an adult subject of normal weight. In a clinical setting, regulatory agencies such as, for example, the Food and Drug Administration (FDA) in the U.S. may require a particular therapeutically effective amount. 0593 In determining what constitutes an effective amount or a therapeutically effective amount of a GABA analog having the characteristic of being an inhibitor of cartilage damage, or a pharmaceutically acceptable salt thereof, for treating or preventing cartilage damage according to the invention method, a number of factors will generally be considered by the medical practitioner or veterinarian in view of the experience of the medical practitioner or veterinarian, published clinical studies, the subject's (ie, mammal's) age, sex, weight and general condition, as well as the type and extent of the disease, disorder or condition being treated, and the use of other medications, if any, by the subject. As such, the administered dose may fall within the ranges or concentrations recited above, or may vary outside, ie, either below or above, those ranges depending upon the requirements of the individual subject, the severity of the condition being treated, and the particular therapeutic formulation being employed. Determination of a proper dose for a particular situation is within the skill of the medical or veterinary arts. Generally, treatment may be initiated using smaller dosages of the GABA analog that are less than optimum for a particular subject. Thereafter, the dosage can be increased by small increments until the optimum effect under the circumstance is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired. 0594 Pharmaceutical compositions of a GABA analog having the characteristic of being an inhibitor of cartilage damage, or a pharmaceutically acceptable salt thereof, are produced by formulating the active compound in dosage unit form with a pharmaceutical carrier. Some examples of dosage unit forms are tablets, capsules, pills, powders, aqueous and nonaqueous oral solutions and suspensions, and parenteral solutions packaged in containers containing either one or some larger number of dosage units and capable of being subdivided into individual doses. 0595 Some examples of suitable pharmaceutical carriers, including pharmaceutical diluents, are gelatin capsules; sugars such as lactose and sucrose; starches such as corn starch and potato starch; cellulose derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, methyl cellulose, and cellulose acetate phthalate; gelatin; talc; stearic acid; magnesium stearate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and oil of theobroma; propylene glycol, glycerin; sorbitol; polyethylene glycol; water; agar; alginic acid; isotonic saline, and phosphate buffer solutions; as well as other compatible substances normally used in pharmaceutical formulations. 0596 The compositions to be employed in the invention can also contain other components such as coloring agents, flavoring agents, and/or preservatives. These materials, if present, are usually used in relatively small amounts. The compositions can, if desired, also contain other therapeutic agents commonly employed to treat cartilage damage. Further, the compositions can, if desired, also contain other therapeutic agents commonly employed to treat secondary symptoms such as, for example, inflammation or pain that may or may not accompany cartilage damage. For example, the compositions may contain aspirin, naprosyn, or similar anti-inflammatory analgesic agents. 0597 The percentage of the active ingredients in the foregoing compositions can be varied within wide limits, but for practical purposes it is preferably present in a concentration of at least 10% in a solid composition and at least 2% in a primary liquid composition. The most satisfactory compositions are those in which a much higher proportion of the active ingredient is present, for example, up to about 95%. 0598 Preferred routes of administration of a GABA analog having the characteristic of being an inhibitor of cartilage damage, or a pharmaceutically acceptable salt thereof, are oral or parenteral. For example, a useful intravenous dose is between 5 and 50 mg, and a useful oral dosage is between 20 and 800 mg. The dosage is within the dosing range used in treatment of diseases resulting in cartilage damage such as osteoarthritis, or as would be determined by the needs of the patient as described by the physician. 0599 The GABA analog having the characteristic of being an inhibitor of cartilage damage, or a pharmaceutically acceptable salt thereof, may be administered in any form. Preferably, administration is in unit dosage form. A unit dosage form of the GABA analog, or a pharmaceutically acceptable salt thereof, to be used in this invention may also comprise other compounds useful in the therapy of diseases resulting in cartilage damage. 0600 The advantages of using a compound of Formulas I, II, III, IIIC, IIIF, IIIG, IIIH, IV, (1A), (1B), V, VI, VII, or VIII, or a pharmaceutically acceptable salt thereof, including gabapentin, pregabalin, 3-(1-aminomethyl-cyclohexylmethyl)-4H-1,2,4oxadiazol-5-one hydrochloride, 3-(1-aminomethyl-cycloheptylmethyl)-4H-1,2,4oxadiazol-5-one hydrochloride, C-1-(1H-tetrazol-5-ylmethyl)-cycloheptyl-methylamine, 3-(2-aminomethyl-4-methyl-pentyl)-4H-1,2,4oxadiazol-5-one hydrochloride, (1,3,5)(3-aminomethyl-bicyclo3,2,0hept-3-yl)-acetic acid hydrochloride, or (3S,5R)-3-aminomethyl-5-methyl-octanoic acid, in the instant invention include the relatively nontoxic nature of the compounds, the ease of preparation, the fact that the compounds are well-tolerated, and the ease of IV and oral administration of the drugs. Further, typically the drugs are not metabolized in the body. 0601 Another important advantage is that the independent anti-inflammatory and pain reducing properties described above for GABA analogs, in combination with the new and unexpected cartilage damage-inhibiting effect of the instant invention, are surprisingly found in one relatively nontoxic agent. The instant invention may, if desired, allow the amount of an anti-inflammatory agent and/or pain relieving agent used in the treatment of patients suffering from cartilage damage and inflammation and/or pain to be reduced or even eliminated. It is known that anti-inflammatory and analgesic agents may produce undesirable side effects such as gastro-intestinal bleeding and ulceration. These side effects may be reduced or eliminated by using the instant invention to supplement or substitute treatments using anti-inflammatory and/or analgesic agents. 0602 The invention method is useful in human and veterinary medicines for treating or preventing cartilage damage in a mammal. A mammal includes humans, cats, dogs, horses, cows, pigs, and sheep. 0603 Some of the compounds utilized in a method of the present invention are capable of further forming pharmaceutically acceptable salts, including, but not limited to, acid addition and/or base salts. The acid addition salts are formed from basic compounds, whereas the base addition salts are formed from acidic compounds. All of these forms are within the scope of the compounds useful in the method of the present invention. 0604 Pharmaceutically acceptable acid addition salts of the basic compounds useful in the method of the present invention include nontoxic salts derived from inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, hydrofluoric, phosphorous, and the like, as well nontoxic salts derived from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, malate, tartrate, methanesulfonate, and the like. Also contemplated are salts of amino acids such as arginate and the like and gluconate, galacturonate (see, for example, Berge S. M. et al., Pharmaceutical Salts, J. of pharma. Sci., 1977;66:1). 0605 An acid addition salt of a basic compound useful in the method of the present invention is prepared by contacting the free base form of the compound with a sufficient amount of a desired acid to produce a nontoxic salt in the conventional manner. The free base form of the compound may be regenerated by contacting the acid addition salt so formed with a base, and isolating the free base form of the compound in the conventional manner. The free base forms of compounds prepared according to a process of the present invention differ from their respective acid addition salt forms somewhat in certain physical properties such as solubility, crystal structure, hygroscopicity, and the like, but otherwise free base forms of the compounds and their respective acid addition salt forms are equivalent for purposes of the present invention. 0606 A pharmaceutically acceptable base addition salt of an acidic compound useful in the method of the present invention may be prepared by contacting the free acid form of the compound with a nontoxic metal cation such as an alkali or alkaline earth metal cation, or an amine, especially an organic amine. Examples of suitable metal cations include sodium cation (Na), potassium cation (K), magnesium cation (Mg2), calcium cation (Ca2), and the like. Examples of suitable amines are N,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine (see, for example, Berge, supra., 1977). 0607 A base addition salt of an acidic compound useful in the method of the present invention may be prepared by contacting the free acid form of the compound with a sufficient amount of a desired base to produce the salt in the conventional manner. The free acid form of the compound may be regenerated by contacting the salt form so formed with an acid, and isolating the free acid of the compound in the conventional manner. The free acid forms of the compounds useful in the method of the present invention differ from their respective salt forms somewhat in certain physical properties such as solubility, crystal structure, hygroscopicity, and the like, but otherwise the salts are equivalent to their respective free acid for purposes of the present invention. 0608 Certain of the compounds useful in the method of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. 0609 Certain of the compounds useful in the method of the present invention possess one or more chiral centers, and each center may exist in the R or S configuration. A method of the present invention may utilize any diastereomeric, enantiomeric, or epimeric form of a GABA analog, or a pharmaceutically acceptable salt thereof, as well as mixtures thereof. 0610 Additionally, certain compounds useful in the method of the present invention may exist as geometric isomers such as the entgegen (E) and zusammen (Z) isomers of alkenyl groups. A method of the present invention may utilize any cis, trans, syn, anti, entgegen (E), or zusammen (Z) isomer of a GABA analog, or a pharmaceutically acceptable salt thereof, as well as mixtures thereof. 0611 Certain compounds useful in the method of the present invention can exist as two or more tautomeric forms. Tautomeric forms of the compounds may interchange, for example, via enolization/de-enolization and the like. A method of the present invention may utilize any tautomeric form of a GABA analog, or a pharmaceutically acceptable salt thereof, as well as mixtures thereof 0612 Intermediates for the synthesis of a GABA analog, or a pharmaceutically acceptable salt thereof, useful in the invention method, and pharmaceutically acceptable salts thereof, may be prepared by one of ordinary skill in the art of organic chemistry by adapting various synthetic procedures that are well-known in the art of organic chemistry. These synthetic procedures may be found in the literature in, for example, Reagents for Organic Synthesis, by Fieser and Fieser, John Wiley & Sons, Inc, New York, 2000; Comprehensive Organic Transformations, by Richard C. Larock, VCH Publishers, Inc, New York, 1989; the series Compendium of Organic Synthetic Methods, 1989, by Wiley-Interscience; the text Advanced Organic Chemistry, 4th edition, by Jerry March, Wiley-Interscience, New York, 1992; or the Handbook of Heterocyclic Chemistry by Alan R. Katritzky, Pergamon Press Ltd, London, 1985, to name a few. Alternatively, a skilled artisan may find methods useful for preparing the intermediates in the chemical literature by searching widely available databases such as, for example, those available from the Chemical Abstracts Service, Columbus, Ohio, or MDL Information Systems GmbH (formerly Beilstein Information Systems GmbH), Frankfurt, Germany. 0613 Preparations of the compounds useful in a method of the present invention may use starting materials, reagents, solvents, and catalysts that may be purchased from commercial sources or they may be readily prepared by adapting procedures in the references or resources cited above. Commercial sources of starting materials, reagents, solvents, and catalysts useful in preparing invention compounds include, for example, The Aldrich Chemical Company, and other subsidiaries of Sigma-Aldrich Corporation, St. Louis, Mo., BACHEM, BACHEM A.G., Switzerland, or Lancaster Synthesis Ltd, United Kingdom. 0614 Syntheses of some compounds useful in the method of the present invention may utilize starting materials, intermediates, or reaction products that contain a reactive functional group. During chemical reactions, a reactive functional group may be protected using protecting groups that render the reactive group substantially inert to the reaction conditions employed. A protecting group is introduced onto a starting material prior to carrying out the reaction step for which a protecting group is needed. Once the protecting group is no longer needed, the protecting group can be removed. It is well within the ordinary skill in the art to introduce protecting groups during a synthesis of a GABA analog, or a pharmaceutically acceptable salt thereof, and then later remove them. Procedures for introducing and removing protecting groups are known and referenced such as, for example, in Protective Groups in Organic Synthesis, 2nd ed., Greene T. W. and Wuts P. G., John Wiley & Sons, New York: N.Y., 1991, which is hereby incorporated by reference. Thus, for example, protecting groups such as the following may be utilized to protect amino, hydroxyl, and other groups: carboxylic acyl groups such as, for example, formyl, acetyl, and trifluoroacetyl; alkoxycarbonyl groups such as, for example, ethoxycarbonyl, tert-butoxycarbonyl (BOC), ,,-trichloroethoxycarbonyl (TCEC), and -iodoethoxycarbonyl; aralkyloxycarbonyl groups such as, for example, benzyloxycarbonyl (CBZ), para-methoxybenzyloxycarbonyl, and 9-fluorenylmethyloxycarbonyl (FMOC); trialkylsilyl groups such as, for example, trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBDMS); and other groups such as, for example, triphenylmethyl (trityl), tetrahydropyranyl, vinyloxycarbonyl, ortho-nitrophenylsulfenyl, diphenylphosphinyl, para-toluenesulfonyl (Ts), mesyl, trifluoromethanesulfonyl, and benzyl. Examples of procedures for removal of protecting groups include hydrogenolysis of CBZ groups using, for example, hydrogen gas at 50 psi in the presence of a hydrogenation catalyst such as 10% palladium on carbon, acidolysis of BOC groups using, for example, hydrogen chloride in dichloromethane, trifluoroacetic acid (TFA) in dichloromethane, and the like, reaction of silyl groups with fluoride ions, and reductive cleavage of TCEC groups with zinc metal. 0615 Preparations of a GABA analog, or a pharmaceutically acceptable salt thereof, useful in the method of the present invention are incorporated by reference to the patents or patent application publications described above, or are illustrated in the Schemes below. 0616 Compounds of Formulas III, IIIC, IIIF, IIIG, and IIIH may be prepared according to the following methods. Sulfonamides can be synthesized by the general route outlined in Scheme 1. 23

0617 Reagents: 0618 (i) Diethylcyanomethyl phosphonate, NaH, tetrahydrofuran; 0619 (ii) Nitromethane, tetrabutylammonium fluoride, tetrahydrofuran; 0620 (iii) Borane methyl sulphide, toluene; 0621 (iv) Triethylamine, R15SO2Cl, tetrahydrofuran; 0622 (v) 10% PdC, hydrogen gas, methanol. 0623 Tetrazoles can be synthesized by the general route outlined in Scheme 2. 24

0624 Reagents: 0625 (i) Trimethylsilylazide, Trimethylaluminium (2M in hexanes), toluene; 0626 (ii) Raney Nickel, Methanol. 0627 Amides can be synthesized by the general route outlined in Scheme 3. 25

0628 Reagents: 0629 (i) Diethylcyanomethyl phosphonate, NaH, tetrahydrofuran; 0630 (ii) Nitromethane, tetrabutylammonium fluoride, tetrahydrofuran; 0631 (iii) Borane methyl sulphide, toluene; 0632 (iv) Triethylamine, R15COCl, tetrahydrofuran; 0633 (v) 10% PdC, hydrogen gas, methanol. 0634 Heterocycles such as 26

0635 can be synthesized by the general route outlined in Scheme 4. 27

0636 (i) NH2OH.HCl, Et3N; 0637 (ii) iBuOCOCl, pyridine followed by reflux in xylene; 0638 (iii) Fe/HCl. 0639 Compound 1 (1-nitromethyl-cyclohexyl)-acetonitrile can be treated with hydroxylamine hydrochloride in the presence of a base such as triethylamine to give compound 2. 0640 The heterocyclic compound 3 can be prepared from compound 2 by treatment with iso-butyl chloroformate in the presence of a base such as pyridine followed by reflux in a solvent such as xylene. The nitro compound (compound 3) can be converted to the required amine by reduction, for example, with iron and hydrochloric acid. 0641 Heterocycles such as 28

0642 can be synthesized by the general route outlined in Scheme 5a. 29

0643 Heterocycles such as 31

0644 can be synthesized by the general route outlined in Scheme 5b. 32

0645 Heterocycles such as 33

0646 can be synthesized by the general route shown in Scheme 6 below: 34

0647 (i) NH2OH.HCl, Et3N; 0648 (ii) 1,1-thiocarbonyldiimidazole followed by DBU or DBN; 0649 (iii) Fe/HCl. 0650 Compound 1(nitromethyl-cyclohexyl)acetonitrile can be treated with hydroxylamine hydrochloride in the presence of a base such as triethylamine to give compound 2. 0651 The heterocyclic compound 3 can be prepared from compound 2 by treatment with 1,1-thiocarbonyldiimidazole followed by a base such as 1,8-diazabicyclo-4,5,0-undec-7-ene (DBU) or 1,5-diazabicyclo2.2.2octane (DBN). 0652 The nitro compound (compound 3) can be converted to the required amine by reduction, for example, with iron and hydrochloric acid. Heterocycles such as 35

0653 can be synthesized following the general route as shown in Scheme 7. 36

0654 (i) NH2OH.HCl, Et3N; 0655 (ii) 1,1-thiocarbonyldiimidazole followed by silica gel or BF3. OEt2; 0656 (iii) Fe/HCl. 0657 Compound 1 (nitromethyl-cyclohexyl)acetonitrile can be treated with hydroxylamine hydrochloride in the presence of a base such as triethylamine to give compound 2. 0658 The heterocyclic compound 3 can be prepared from compound 2 by treatment with 1,1-thiocarbonyldiimidazole followed by treatment with silica gel or boron trifluoride etherate. 0659 The nitro compound (compound 3) can be converted to the required amine by reduction, for example, with iron and hydrochloric acid. 0660 Heterocycles such as 37

0661 can be synthesized following the general route outlined in Scheme 8: 38

0662 (i) NH2OH.HCl, Et3N; 0663 (ii) Pyridine, SOCl2; 0664 (iii) Fe/HCl. 0665 Compound 1 (nitromethyl-cyclohexyl)acetonitrile can be treated with hydroxylamine hydrochloride in the presence of a base such as triethylamine to give compound 2. 0666 The heterocyclic compound 3 can be prepared from compound 2 by treatment with thionyl chloride in the presence of a base such as pyridine. 0667 The nitro compound (compound 3) can be converted to the required amine by reduction, for example, with iron and hydrochloric acid. 0668 The following examples are illustrative of the preparation of compounds of Formulas III, IIIC, IIIF, IIIG, or IIIH; they are not intended to limit the scope.

EXAMPLE 1 0669

0670 Reagents: 0671 (i) Diethylcyanomethyl phosphonate, NaH, tetrahydrofuran; 0672 (ii) Nitromethane, tetrabutylammonium fluoride, tetrahydrofuran; 0673 (iii) Borane methyl sulphide, toluene; 0674 (iv) Triethylamine, methanesulphonyl chloride, tetrahydrofuran; 0675 (v) 10% PdC, hydrogen gas, methanol then HCl. 0676 Cyclohexylidene-Acetonitrile (2) 0677 Sodium hydride (60% in oil, 0.80 g, 20 mmol) was suspended in 50 mL tetrahydrofuran and chilled in ice under nitrogen. Diethylcyanomethyl phosphonate (3.85 g, 22 mmol) was added dropwise in 10 mL tetrahydrofuran and stirring continued for 15 minutes to give a clear solution. Cyclohexanone (1.90 g, 19 mol) was added in 5 mL tetrahydrofuran and the reaction mixture allowed to warm up to room temperature. The liquor was decanted and the residue washed three times with ether. The liquor and washings were combined, washed with dilute hydrochloric acid and water, dried over magnesium sulphate, filtered, and evaporated to dryness. The residue was purified by chromatography on silica eluting with heptane/ethyl acetate 4:1 to give the required product as a colorless oil (1.5 g, 67%). 0678 1H NMR 400 MHz (CDCl3): 1.50 (m, 6H), 2.25 (t, J5.6 Hz, 2H), 2.49 (t, J6.8 Hz, 2H), 5.04 (s, 1H). IR max 2933, 2859, 2217, 1633, 1449 0679 (1-Nitromethyl-cyclohexyl)-acetonitrile (3) 0680 The nitrile (compound 2, 0.78 g, 6.44 mmol), nitromethane (0.80 g, 13.11 mmol) and tetrabutyl ammonium fluoride (1.0 M in tetrahydrofuran, 10 mL, 10 mmol) were heated in 20 mL tetrahydrofuran to 70 C. overnight. The reaction mixture was diluted with ethyl acetate and washed with dilute hydrochloric acid and water, dried over magnesium sulphate, filtered, and evaporated to dryness. The residue was purified by chromatography on silica eluting with heptane/ethyl acetate 3:1 to give the required product as a yellow oil (0.83 g, 71%). 0681 1H NMR 400 MHz (CDCl3): 1.57 (s, 10H), 2.63 (s, 2H), 4.52 (s, 2H). Analysis calculated for C9H13N2O2: C, 59.32; H, 7.74; N, 15.37. Found: C, 59.40; H, 7.65; N, 15.18. 0682 2-(1-Nitromethyl-cyclohexyl)-ethylamine (4) 0683 Borane methyl sulphide (2.0 M in toluene, 1.3 mL, 2.6 mmol) was added to compound 3 (0.4 g, 2.2 mmol) in toluene (10 mL) under nitrogen. After heating to 60 C. for 3 hours, the mixture was allowed to cool, and 15 mL methanol was added followed by 15 mL 4 M HCl in dioxane. After reflux for 1 hour, the mixture was evaporated to dryness. Crystallization from ethyl acetate gave the required product as colorless crystals (0.23 g, 47%); mp 170-173 C. 0684 1H NMR 400 MHz (d6-DMSO): 1.30-1.50 (m, 10H), 1.64-1.69 (m, 2H), 2.82-2.86 (m, 2H), 4.57 (s, 2H), 7.89 (s, 3H). Analysis calculated for C9H18N2O2.HCl.0.2H2O: C, 47.77; H, 8.64: N, 12.38. Found: C, 47.80; H, 8.66; N, 12.64. 0685 N-2-(1-Nitromethyl-cyclohexyl)-ethyl-methanesulfonamide (5) 0686 Triethylamine (0.64 g, 6.3 mmol) was added dropwise to a mixture of the amine hydrochloride salt (compound 4, 0.70 g, 3.1 mmol) and methane sulfonyl chloride (0.36 g, 6.3 mmol) in tetrahydrofuran (35 mL). After stirring at room temperature for 2 hours, the mixture was filtered, diluted with ethyl acetate, and washed with dilute hydrochloric acid, saturated sodium bicarbonate solution, and water, dried over magnesium sulphate, filtered, and evaporated to dryness. The residue was crystallized from ethyl acetate/heptane to give colorless crystals (0.39 g, 47%); mp 86-88 C. 0687 1H NMR 400 MHz (d6-DMSO): 1.35-1.50 (m, 10H), 1.55-1.60 (m, 2H), 2.89 (s, 3H), 2.99-3.06 (m, 2H), 4.55 (s, 2H), 6.93 (t, J6 Hz, 1H). Analysis calculated for C10H20N2O4S: C, 45.44; H, 7.63; N, 10.60; S, 12.13. Found: C, 45.77; H, 7.64; N, 10.58; S, 12.17. 0688 N-2-(1-Aminomethyl-cyclohexyl)-ethyl-methanesulfonamide hydrochloride (6) 0689 Ten percent Palladium on carbon was added under nitrogen to a solution of compound 5 (0.35 g, 1.3 mmol) in methanol (50 mL). The mixture was shaken under 40 psi hydrogen for 6 hours and then filtered through keiselguhr. The filtrate was evaporated to dryness. 4N HCl in dioxane was added followed by ether to give the product as a colorless crystalline solid (0.33 g, 92%); mp 196-199 C. 0690 1H NMR 400 MHz (d6-DMSO): 1.25-1.45 (m, 10H), 1.55-1.60 (m, 5H), 2.70-2.75 (m, 2H), 2.90-2.95 (m, 5H), 6.86 (t, J6.0 Hz, 1H), 7.86 (bs, 3H). Analysis calculated for C10H22N2O2S.HCl.0.25H2O: C, 43.63; H, 8.60; N, 10.17. Found: C, 43.43; H, 8.64; N, 9.95.

EXAMPLE 2 0691

0692 Reagents: 0693 (i) Trimethylsilylazide, trimethylaluminium (2 M in hexanes), toluene; 0694 (ii) Raney Nickel, hydrogen gas, methanol then HCl. 0695 1-(1H-Tetrazol-5-ylmethyl)-cyclohexanecarbonitrile (2) 0696 To a solution of the bis nitrile (Griffiths G., Mettler H., Mills L. S., and Previdoli F., Helv. Chim. Acta, 74:309 (1991)) (1.48 g, 10 mmol) in toluene (20 mL) under nitrogen was added trirnethylsilylazide (1.15 g, 10 mmol) followed by trimethylaluminium (5 mL, 2.0 M in hexanes, 10 mmol). After heating to 90 C. overnight, the mixture was allowed to cool and added carefully to ethyl acetate, ice and 6N hydrochloric acid. The aqueous phase was extracted with ethyl acetate, and the extracts washed with water, dried over magnesium sulphate, and evaporated to dryness. Crystallization gave the required compound (158 mg, 8%). 0697 C-1-(1H-Tetrazol-5-ylmethyl)-cyclohexyl-methylamine hydrochloride (3) 0698 The tetrazole (compound 8, 158 mg, 0.83 mmol) in methanol was added to a washed suspension of Raney nickel in methanol. The mixture was shaken under 40 psi hydrogen for 3.5 hours and then filtered to remove the catalyst and evaporated to dryness. The residue was partitioned between ethyl acetate and dilute hydrochloric acid. The aqueous phase was separated and evaporated to dryness. Recrystallization from methanol/ether gave the required product (44 mg, 23%); mp 176-179 C. 0699 1H NMR 400 MHz (d6-DMSO): 1.20-1.60 (m, 10H), 2.84 (s, 2H), 3.07 (s, 2H), 8.06 (bs, 3H).

EXAMPLE 3 0700

0701 Reagents: 0702 (i) Diethylcyanomethyl phosphonate, NaH, tetrahydrofuran; 0703 (ii) Nitromethane, tetrabutylammonium fluoride, tetrahydrofuran; 0704 (iii) Borane methyl sulphide, toluene; 0705 (iv) Triethylamine, acetyl chloride, tetrahydrofuran; 0706 (v) 10% PdC, hydrogen gas, methanol then HCl 0707 Cyclohexylidene-Acetonitrile (2) 0708 Sodium hydride (60% in oil, 0.80 g, 20 mmol) was suspended in 50 mL tetrahydrofuran and chilled in ice under nitrogen. Diethylcyanomethyl phosphonate (3.85 g, 22 mmol) was added dropwise in 10 mL tetrahydrofuran and stirring continued for 15 minutes to give a clear solution. Cyclohexanone (1.90 g, 19 mmol) was added in 5 mL tetrahydrofuran and the reaction mixture allowed to warm up to room temperature. The liquor was decanted and the residue washed three times with ether. The liquor and washings were combined, washed with dilute hydrochloric acid and water, dried over magnesium sulphate, filtered, and evaporated to dryness. The residue was purified by chromatography on silica eluting with heptane/ethyl acetate 4:1 to give the required product as a colorless oil (1.5 g, 67%). 0709 1H NMR 400 MHz (CDCl3): 1.50 (m, 6H), 2.25 (t, J5.6 Hz, 2H), 2.49 (t, J6.8 Hz, 2H), 5.04 (s, 1H). IR max 2933, 2859, 2217, 1633, 1449. 0710 (1-Nitromethyl-cyclohexyl)-acetonitrile (3) 0711 The nitrile (compound 2, 0.78 g, 6.44 mmol), nitromethane (0.80 g, 13.11 mmol) and tetrabutyl ammonium fluoride (1.0 M in tetrahydrofuran, 10 mL, 10 mmol) were heated in 20 mL tetrahydrofuran to 70 C. overnight. The reaction mixture was diluted with ethyl acetate and washed with dilute hydrochloric acid and water, dried over magnesium sulphate, filtered, and evaporated to dryness. The residue was purified by chromatography on silica eluting with heptane/ethyl acetate 3:1 to give the required product as a yellow oil (0.83 g, 71%). 0712 1H NMR 400 MHz (CDCl3): 1.57 (s, 10H), 2.63 (s, 2H), 4.52 (s, 2H). Analysis calculated for C9H13N2O2: C, 59.32; H, 7.74; N, 15.37. Found: C, 59.40; H, 7.65; N, 15.18. 0713 2-(1-Nitromethyl-cyclohexyl)-ethylamine (4) 0714 Borane methyl sulphide (2.0 M in toluene, 1.3 mL, 2.6 mmol) was added to compound 3 (0.4 g, 2.2 mmol) in toluene (10 mL) under nitrogen. After heating to 60 C. for 3 hours, the mixture was allowed to cool, and 15 mL methanol was added followed by 15 mL 4 M HCl in dioxane. After reflux for 1 hour, the mixture was evaporated to dryness. Crystallization from ethyl acetate gave the required product as colorless crystals (0.23 g, 47%); mp 170-173 C. 0715 1H NMR 400 MHz (d6-DMSO): 1.30-1.50 (m, 10H), 1.64-1.69 (m, 2H), 2.82-2.86 (m, 2H), 4.57 (s, 2H), 7.89 (s, 3H). Analysis calculated for C9H18N2O2.HCl.0.2H2O: C, 47.77; H, 8.64; N, 12.38. Found: C, 47.80; H, 8.66; N, 12.64. 0716 N-2-(1-Nitromethyl-cyclohexyl)-ethyl-acetamide (5) 0717 The amine hydrochloride salt (compound 4, 0.50 g, 2.25 mmol) was reacted with acetyl chloride (0.20 g, 2.55 mmol) and triethylamine (0.45 g, 4.45 mmol) in tetrahydrofuran following the procedure described in Example 1, Step 4. Purification by chromatography on silica eluting with ethyl acetate gave the required product as a crystalline solid (0.35 g, 69%); mp 68-70 C. 0718 1H NMR 400 MHz (CDCl3): 1.40-1.60 (m, 10H), 1.60-1.65 (m, 2H), 1.98 (s, 3H), 3.30-3.40 (m, 2H), 4.40 (s, 2H), 5.59 (bs, 1H). 0719 N-2-(1-Aminomethyl-cyclohexyl)-ethyl-acetamide hydrochloride (6) 0720 Compound 5 (0.30 g, 1.3 mmol) was hydrogenated in the presence of 10% palladium on carbon following the procedure described in Example 1, Step 5 to give the product as the hydrochloride salt (0.35 g, 100%). 0721 1H NMR 400 MHz (d6-DMSO): 1.20-1.40 (m, 10H), 1.40-1.50 (m, 2H), 1.81 (s, 3H), 2.75 (q, J6.0 Hz, 2H), 2.95-3.05 (m, 2H), 7.99 (bs, 3H), 8.06 (t, J4.8 Hz, 1H). IR max 3265, 2929, 1628, 1553, 1446, 1373, 1298.

EXAMPLE 4 0722 3-(1-Aminomethyl-cyclohexylmethyl)-4H-1,2,4oxadiazol-5-one; hydrochloride 1-(tert-Butoxycarbonylamino-methyl)-cyclohexyl-acetic acid (2) 0723 A solution of Gabapentin (1) (9.37 g, 0.0547 mol) in 125 mL 1N NaOH and 50 mL THF was cooled to 0 C. and a solution of di-tert-butyl dicarbonate (13.1 g, 0.06 mol) in 200 mL THF was slowly added. The reaction mixture was stirred at room temperature 2 hours and concentrated on a rotary evaporator to remove THF. The concentrate was saturated with KH2PO4 and extracted 3EtOAc. The EtOAc extracts were washed 2 brine and dried over MgSO4. Evaporation yielded 14.8 g (100%) white solid, mp 109-111 C. 0724 1HNMR (CDCl3) 1.2-1.4 (m, 19H), 2.27 (s, 2H), 3.11 (d, 2H, J6.84 Hz), 4.95 (broad, 1H). MS (APCI) m/z 272 (M1). Analysis calculated for C14H25NO4: C, 61.97; H, 9.29; N, 5.16. Found: C, 62.36; H, 9.27; N, 5.19. 0725 (1-Carbamoylmethyl-cyclohexylmethyl)-carbamic acid tert-butyl ester (3) 0726 1-(tert-Butoxycarbonylamino-methyl)-cyclohexyl-acetic acid (2) (152 g, 0.56 mol) was taken up in 1 L THF and triethylamine (66.2 g, 0.65 mol) and cooled to 10 C. Over a 1-hour period, isobutyraldehyde was added (84.7 g, 0.62 mol), and the heterogeneous mixture was stirred at 0 C. for 15 minutes. Ammonia gas was bubbled into the cold reaction mixture for 30 minutes, and the mixture was allowed to warm to room temperature. After 16 hours stirring, the reaction mixture was evaporated to dryness on a rotary evaporator, and the residue was taken up in water, extracted 3 EtOAc, washed 2 brine and dried over MgSO4. Evaporation yielded an oil which was crystallized from pentane to yield 116.5 g (77%) white crystals; mp 123-125 C. 0727 1HNMR (CDCl3) 1.2-1.6 (m, 19H), 2.12 (s, 2H), 3.13 (d, 2H, J7.08 Hz), 4.97 (s, 1H), 5.43 (s, 1H), 7.34 (s, 1H). MS (APCI) 271 m/z. (M1). Analysis calculated for C14H26N2O3: C, 62.19; H, 9.69; N, 10.36. Found: C, 62.00; H, 9.72; N, 9.96. 0728 (1-Cyanomethyl-cyclohexylmethyl)-carbamic acid tert-butyl ester (4) 0729 Cyanuric chloride (39.5 g, 0.214 mol) was added to (1-carbamoylmethyl-cyclohexylmethyl)-carbamic acid tert-butyl ester (3) (116 g, 0.429 mol) in 400 mL DMF. An ice-water bath was used to moderate the exotherm, and the reaction mixture was stirred at room temperature for 1.5 hours. The mixture was poured into ice-water containing 120 g (1.43 mol) NaHCO3 and was extracted 4EtOAc. The extracts were washed 1 water, 2 brine and dried over Na2SO4. Evaporation yielded an oil which was taken up in 3:1 hexane/EtOAc and filtered through silica gel. Evaporation yielded white crystals (86.5 g, 80%); mp 54-58 C. 0730 1HNMR (CDCl3) 1.3-1.5 (m, 19H), 2.30 (s, 2H), 3.15 (d, 2h, J7.00 Hz), 4.60 (broad, 1H). MS (APCI) m/z 253 (M1). Analysis calculated for C14H24N2O2: C, 66.63; H, 9.59; N, 11.10. Found: C, 66.64; H, 9.52; N, 10.80. 0731 1-(N-Hydroxycarbamimidoylmethyl)-cyclohexylmethyl-carbamic acid tert-butyl ester (5) 0732 A suspension of hydroxylamine hydrochloride (69.5 g, 1.00 mol) in DMSO (300 mL) was cooled in ice-water, and triethylamine (106.7 g, 1.05 mol) was added. The resulting exotherm brought the temperature to 20 C. The mixture was stirred at this temperature 15 minutes, and triethylamine hydrochloride was filtered off and washed with THF. The filtrate was concentrated to remove THF, and (1-cyanomethyl-cyclohexylmethyl)-carbamic acid tert-butyl ester (4) (50.4 g, 0.2 mol) was added, and the mixture was heated at 75 C. for 15 hours. After cooling, the reaction mixture was diluted with water (1 L) and extracted 3EtOAc. The EtOAc extracts were washed 1 saturated KH2PO4, 1 saturated NaHCO3, 2 brine and dried over Na2SO4. Evaporation yielded a gummy solid which was triturated in Et2O to give white crystals, 25.2 g (44%); mp 125-127 C. 0733 1HNMR (CDCl3) 1.3-1.5 (m 19H), 1.99 (s, 2H), 3.12 (d, 2H J6.84 Hz), 4.93 (t, 1H, J6.84 Hz), 5.40 (s, 1H). MS (APCI) m/z 286 (M1). Analysis calculated for C14H27N3O3: C, 58.92; H, 9.54; N, 14.72. Found: C, 58.96; H, 9.80; N, 14.65. 0734 BOC-Gabapentin Amidoxime Carbamate (6) 0735 A solution of 1-(N-Hydroxycarbamimidoylmethyl)-cyclohexylmethyl-carbamic acid tert-butyl ester (5) (25.1 g, 0.088 mol) and pyridine (7.82 g, 0.099 mol) in DMF (200 mL) was cooled in ice-water as isobutyraldehyde (12.32 g, 0.09 mol) was added dropwise. After 15 minutes, the bath was removed and the mixture was stirred at room temperature 2 hours, diluted with water, and extracted 3EtOAc. The extracts were washed 1 water, 2 brine and dried over Na2SO4. Evaporation yielded an oil, 34 g (100%) which was used without further purification. MS (APCI) m/z 386 (M1). 0736 1-(5-Oxo-4,5-dihydro-1,2,4oxadiazol-3-ylmethyl)-cyclohexylmethyl-carbamic acid tert-butyl (7) 0737 BOC-Gabapentin amidoxime carbamate (33.88 g, 0.088 mol) was taken up in xylene (250 mL) and heated under reflux 2.5 hours. The xylene was evaporated off and the residue taken up in Et2O and extracted 375 mL 1N NaOH. The alkaline extracts were acidified with saturated KH2PO4 and extracted 3 Et2O. The Et2O extracts were washed 1 saturated KH2PO4, 2 brine and dried over Na2SO4. Evaporation yielded 17.9 g (65%) of a cream-colored solid, mp 140-143 C. 0738 1HNMR (CDCl3) 1.0-1.6 (m, 19H), 2.42 (s, 2H), 3.00 (d, 2H, J7.32 Hz), 4.86 (t, 1H, J7.08 Hz), 11.30 (s, 1H). MS (APCI) m/z 312 (M1). Analysis calculated for C15H25N3O4: C, 57.86; H, 8.09; N, 13.49. Found: C, 58.21; H, 8.31; N, 13.30. 0739 3-(1-Aminomethyl-cyclohexylmethyl)-4H-1,2,4oxadiazol-5-one; hydrochloride (8) 0740 A solution of BOC-Gabapentin oxadiazolone (17.7 g, 0.0568 mol) in 4 M HCl in dioxane (200 mL) was allowed to stand 1.5 hours. Concentration to half volume followed by addition of Et2O gave a precipitate which was filtered off and recrystallized from MeOH to give white crystals (12.98 g, 92.7%), mp 209-212 C. 0741 1HNMR (DMSO-d6) 1.2-1.5 (m, 10H), 2.64 (s, 4H), 2.79 (s, 2H), 7.98 (s, 3H), 12.35 (s, 1H). MS (APCI) m/z 212 (M1). Analysis calculated for C10H17N3O2.HCl: C, 48.49; H, 7.32; N, 16.96; Cl, 14.31. Found: C, 48.71; H, 7.18; N, 17.03; Cl, 14.32.

EXAMPLE 5 0742 1-(5-Thioxo-4,5-dihydro-1,2,4oxadiazol-3-ylmethyl)-cyclohexylmethyl-carbamic acid tert-butyl ester (9) 0743 A mixture of 1-(N-Hydroxycarbamimidoylmethyl)-cyclohexylmethyl-carbamic acid tert-butyl ester (4.85 g, 0.017 mol), 90% 1,1-thiocarbonyldiimidazole (3.96 g, 0.02 mol) and DBU (10.39 g, 0.068 mol) in MeCN (150 mL) was stirred at room temperature 19 hours. The reaction mixture was evaporated to dryness, suspended in saturated KH2PO4 and extracted 3EtOAc. The EtOAc extracts were washed 2 saturated KH2PO4, 2 brine and dried over Na2SO4. Evaporation followed by filtration through silica gel, eluting with 3:1 EtOAc/hexane yielded, upon evaporation, a solid which was recrystallized from Et2O/hexane to give a pale pink solid, 2.6 g (47%), mp 160-161 C. 0744 1HNMR (CDCl3) 1.1-1.6 (m, 19H), 2.53 (s, 2H), 3.00 (d, 2H, J7.33 Hz), 4.90 (t, 1H, J7.08 Hz), 12.88 (s, 1H). MS (APCI) m/z 328 (M1). Analysis calculated for C15H25N3O3S: C, 55.02; H, 7.70; N, 12.83; S, 9.79. Found: C, 55.34; H, 7.80; N, 12.72; S, 9.43. 0745 3-(1-Aminomethyl-cyclohexylmethyl)-4H-1,2,4oxadiazole-5-thione; hydrochloride (10) 0746 1-(5-Thioxo-4,5-dihydro-1,2,4oxadiazol-3-ylmethyl)-cyclohexylmethyl-carbamic acid tert-butyl ester (9) 0747 (2.5 g, 0.0076 mol) was taken up in 4 M HCl in 1,4-dioxane (75 mL) and stirred at room temperature. The precipitate which formed was filtered off and recrystallized from MeOHEt2O to yield 1.31 g (66%) white solid, mp 210-212 C. 0748 1HNMR (DMSO-d6) 1.2-1.5 (m, 10H), 2.79-2.85 (m, 4H), 7.99 (s, 3H). MS (APCI) m/z 228 (M1). Analysis calculated for C 10H17N3OS.HCl: C, 45.53; H, 6.88; N, 15.93; S, 12.16; Cl, 13.44. Found: C, 45.92; H, 6.71; N, 15.83; S, 11.81; Cl, 13.48.

EXAMPLE 6 0749

0750 Reagents: 0751 (i) Trimethylsilylazide, dibutyl tin oxide, toluene 0752 (ii) Nickel catalyst, Methanol 0753 Synthesis of 9-(1H-Tetrazol-5-ylmethyl)-bicyclo3.3.1nonane-9-carbonitrile (2) 0754 To a solution of the bis nitrile (ref WO 9733859) (1.2 g, 6.38 mmol) in toluene (10 mL) was added trimethylsilylazide (1.48 g, 12.87 mmol) followed by dibutyl tin oxide (0.16 g, 0.64 mmol). After heating to 95 for 3 days the mixture was diluted with ethyl acetate, washed with 1N HCl and water, dried over magnesium sulphate, and evaporated to dryness. Crystallization gave the required compound (0.3 g, 20%); mp 189-191 C. 0755 400 MHz NMR (d6-DMSO) 1.50-1.70 (m, 4H), 1.75-2.10 (m, 10H), 3.48 (s, 2H). 0756 Synthesis of C-9-(1H-Tetrazol-5-ylmethyl)-bicyclo3.3.1non-9-yl--methylamine hydrochloride (3) 0757 The tetrazole obtained in Step 1 (0.60 g, 2.59 mmol) in methanol (100 mL) was added to a washed suspension of nickel catalyst in methanol. The mixture was shaken under 40 psi hydrogen overnight and then filtered to remove the catalyst and evaporated to dryness. The residue was dissolved in methanol and ethereal hydrogen chloride added. Addition of ether and filtration gave the required product (0.19 g, 22%). mp 232-236 C. 0758 400 MHz NMR (d6-DMSO) 1.40-1.70 (m, 8H), 1.75-1.95 (m, 4H), 2.05-2.15 (m, 2H), 3.13 (s, 2H), 3.29 (s, 2H), 8.0 (bs, 3H).

EXAMPLE 7 0759

0760 Reagents: 0761 (i) Ethylcyanoacetate, NaH, THF; 0762 (ii) KCN, EtOH, water, reflux; 0763 (iii) Trimethylsilylazide, dibutyltin oxide, toluene; 0764 (iv) Nickel catalyst, Methanol 0765 Synthesis of 2-(1H-Tetrazol-5-ylmethyl)-adamantane-2-carbonitrile (4) 0766 Prepared in the same manner as 9-(1H-Tetrazol-5-ylmethyl)-bicyclo3.3.1nonane-9-carbonitrile in Example 4. 0767 Synthesis of C-2-(1H-Tetrazol-5-ylmethyl)-adamantan-2-yl-methylamine hydrochloride (5) 0768 The nitrile obtained in Step 3 was prepared in an analogous manner to (0.47 g, 1.9 mmol) was shaken with nickel catalyst (one spatula full, washed) under 50 psi hydrogen overnight. Filtration through kieselguhr and evaporation followed by treatment with methanol and ethereal hydrogen chloride gave the required product which was crystallized from methanol and acetonitrile (25 mg, 5%); mp 250-252 C. 0769 400 MHz NMR 1.49 (s, 2H), 1.54 (d, J13.7 Hz, 2H), 1.59 (d, J13.7 Hz), 1.67 (s, 2H), 1.83 (s, 1H), 1.90 (s, 1H), 1.97 (d, J12.9 Hz, 2H), 2.19 (d, J12.7 Hz, 2H), 3.15 (s, 2H), 3.34 (s, obscured by water), 7.99 (bs, 3H). Mass Spec ES 248 (100%, (MH)).

EXAMPLE 8 0770

0771 Reagents: 0772 (i) Ethyl cyanoacetate, ammonium acetate, acetic acid, toluene 0773 (ii) Potassium cyanide, aqueous ethanol 0774 (iii) Trimethylsilylazide, dibutyltin oxide, toluene 0775 (iv) nickel catalyst, methanol s Synthesis of (trans)Cyan-(3,4-dimethyl-cyclopentylidene)-acetic acid ethyl ester (2) 0776 Trans-3,4-dimethyl cyclopentanone (2.91 g, 25.94 mmol), ethyl cyanoacetate (2.93 g, 25.93 mmol), ammonium acetate (0.20 g, 2.60 mmol), and acetic acid (0.31 g, 5.17 mmol) were heated together in refluxing toluene under a Dean-Stark trap for 24 hours. After cooling and filtration through kieselguhr, evaporation gave the required product as an off-white solid (5.0 g, 93%). 0777 400 MHz NMR 0 1.08 (d, J6.0 Hz, 3H), 1.09 (d, J6.4 Hz, 3H), 1.34 (t, J7.2 Hz, 3H), 1.55-1.70 (m, 2H), 2.30-2.45 (m, 2H), 3.08 (dd, J20.0 Hz, 8.0 Hz, 1H), 3.43 (dd, J20.0 Hz, 7.0 Hz, 1H), 4.26 (q, J7.1 Hz, 2H). Mass Spec ES208.19 (MH), 225.19, 230.16 (100%, (MNa)). 0778 Synthesis of (trans)1-Cyanomethyl-3,4-dimethyl-cyclopentanecarbonitrile (3) 0779 The product from Step 1 (5.0 g, 24,1 mmol) was refluxed with potassium cyanide (1.57 g, 24.2 mmol) in ethanol/10% water (50 mL) overnight. Evaporation to dryness and purification by chromatography eluting with ethyl acetate/heptane 1:1 gave the required product as a yellow oil 2.9 g (74%). tlc rf 0.45 ethyl acetate/heptane 1:1. 0780 400 MHz NMR 1.05 (d, J8.4 Hz, 3H), 1.07 (d, J8.8 Hz, 3H), 1.49 (dd, J13.2, 11.6 Hz, 1H), 1.60-1.70(m, 1H), 1.75-1.90(m, 1H), 1.96(dd, J13.6, 14.8 Hz, 1H), 2.19 (dd, J14.0, 8.4 Hz, 1H), 2.48 (dd, J13.2, 6.4 Hz, 1H), 2.73 (s, 2H). 0781 Synthesis of (trans)3,4-Dimethyl-1-(1H-tetrazol-5-ylmethyl)-cyclopentanecarbonitrile (4) 0782 The bis-nitrile from Step 2 (1.62 g, 10 mmol) was heated with trimethylsilyl azide (2.84 g, 24.7 mmol) and di-butyl tin oxide (0.24 g, 0.96 mmol) in toluene (50 mL) to 100 C. overnight. The reaction mixture was diluted with ethyl acetate and washed with dilute hydrochloric acid and water. The solution was dried over magnesium sulphate and evaporated to dryness. Purification by chromatography eluting with ethyl acetate gave the required product as a colorless oil 0.94 g, (46%). Mass Spec ES206.23 (MH), 228.26 (MNa). 0783 400 MHz NMR CDCl3 1.04 (d, J7.2 Hz, 3H), 1.05 (d, J6.4 Hz), 1.56 (dd, J11.6, 11.6 Hz, 1H), 1.55-1.65 (m, 1H), 1.65-1.75 (m, 1H), 1.83 (dd, J13.6, 9.2 Hz, 1H), 2.27 (dd, J14.0, 8.0 Hz), 2.35 (dd, J13.0, 6.8 Hz, 1H), 3.36 (s, 2H). 0784 Synthesis of (trans)C-3,4-Dimethyl-1-(1H-tetrazol-5-ylmethyl)-cyclopentyl-methylamine hydrochloride (5) 0785 The tetrazole obtained in Step 3 (0.90 g, 0.44 mmol) and nickel catalyst (one spatula full, washed) were shaken together in methanol (200 mL) overnight. The mixture was filtered through kieselguhr and evaporated to dryness. The residue was treated with methanol and ethereal hydrogen chloride and then stirred with di-tertiarybutyl dicarbonate (0.80 g, 3.67 mmol) and sodium bicarbonate (0.80 g, 9.52 mmol) in aqueous dioxane (1:1, 20 mL) overnight. The mixture was diluted with ethyl acetate and the aqueous phase separated, acidified, and extracted 3 with ethyl acetate. The extracts were dried over magnesium sulphate, filtered and evaporated to give a colorless oil. This oil was stirred with 4 M hydrogen chloride in dioxane (5 mL) overnight and then evaporated to dryness to give the required product 0.24 g (76%). 0786 400 MHz d6-DMSO 0.88 (d, J6.4 Hz, 3H), 0.89 (d, J5.6 Hz, 3H), 1.15-1.25 (m, 3H), 1.35-1.45 (m, 1H), 1.70-1.80 (m, 2H), 2.82 (d, J13.2 Hz, 1H), 2.89 (d, J13.2 Hz, 1H), 3.04 (d, J15.2 Hz, 1H), 3.05 (d, J15.2 Hz, 1H). Mass Spec ES210 100%, (MH). Elemental analysis calculated for C10H19N5HCl.0.5H2O: C, 47.14; H, 8.31; N, 27.49. Found: C, 47.23; H, 7.97; N, 27.16. 0787 Compounds of Formula IV wherein R1 and R2 are as defined above may be prepared according to the following methods. 0788 General Synthetic Schemes 45

0789 a) LiAlH4; 0790 b) pyridinium dichromate; 0791 c) triethylphosphonoacetate, NaH; 0792 d) Nitromethane DBU; 0793 e) i. H2 Pd/C; ii. HCl; iii ion exchange chromatography. 46

0794 XOEt or chiral oxazolidine auxiliary. 0795 a) Triethylphosphonoacetate, NaH; 0796 b) i. NaOH, ii. Pivaloyl chloride, Et3N, XH; 0797 c) R1MgBr, CuBr2 DMS; 0798 d) NaHMDS, BrCH2CO2tBu; 0799 e) RtBu i. LiOH, H2O2; ii. BH3, iii. TsCl, ET3N, iv. NaN3, DMSO; 0800 f) REt i. LiOH, H2O2; ii. BH3, iii. PTSA, THF; iv HBr EtOH, v. NaN3 DMSO; 0801 g) i. H2 Pd/C; ii. HCl, iii. Ion exchange chromatography.

Specific Examples

Synthesis of Example 9 0802 3-Aminomethyl-5-methylheptanoic acid 47

0803 a) PDC, CH2Cl2; 0804 b) NaH, triethylphosphonoacetate; 0805 c) DBU, CH3NO2; 0806 d) H2, 10% Pd/C; 0807 e) 6N HCl, reflux, ion exchange resin (Dowex 50WX8, strongly acidic). 0808 3-Methyl-1-pentanal 11 0809 To a stirred suspension of pyridinum dichromate (112.17 g, 298.1 mmol) in dichloromethane 500 mL was added 3-methyl-1-pentanol 10 (15 g, 146.79 mmol). After stirring for 2.5 hours, ether 400 mL was added, and stirring was continued for another 5 minutes. The filtrate from the mixture was concentrated to a small volume and applied to a column of Florisil. The compound was eluted with petroleum ether, and further chromatographed on silica gel column using 10% ether in petroleum ether as eluent gave 11 (6.5 g, 44%). 0810 1H-NMR (CDCl3) 9.72, (d, CHO), 2.38 (dd, 1H, CH2CHO), 2.19 (dd, 1H, CH2CHO), 1.95 (m, 1H, C2H5(CH3)CHCH2), 1.4-1.0 (m), 0.9-0.8 (m). 0811 Ethyl 5-methyl-2-heptenoate 12 0812 Sodium hydride (60% dispersion, 2.4 g, 65 mmol) was washed with hexane and suspended in dimethoxyethane 60 mL. While cooling in ice water bath triethyl phosphonoacetate was slowly added, calcd. 5 minutes. The reaction was stirred for 15 minutes at 0 C. and a solution of 3-methyl-1-pentanal 11 (6.5 g, 65 mmol) in methoxyethane 20 mL was added. After refluxing overnight, it was concentrated, water and hexane were added, the organic phase was separated, and the aqueous portion discarded. The solution was washed twice with brine and dried on magnesium sulfate. The solvent was evaporated to give 12 (6.75 g, 61%). 0813 1H-NMR (CDCl3) 6.89 (m, 1H, CH2CH:CHCOOEt), 5.77 (d, 1H, CH2CH:CHCOOEt), 4,16 (q, 2H, COOCH2CH3), 2.15 and 1.98 (1H each and a multiplet, CH2CH:CHCOOEt), 1.48 (m, 1H, C2H5(CH3)CHCH2), 1.30-1.10 (m), and 0.83. 0814 Ethyl 5-methyl-3-nitromethylheptanoate 13 0815 Ethyl 5-methyl-2-heptanoate 12 (6.75 g, 39.70 mmol), DBU (6.0 g, 39.7 mmol), nitromethane (21.97 g, 359.9 mmol) in acetonitrile 80 mL was stirred at room temperature under nitrogen atmosphere overnight. The mixture was concentrated to an oil. A solution of the oil in ether was washed with 1N HCl, brine and dried. It was evaporated to give a light oil which was chromatographed on silica gel, eluting with 5% to 10% ether in Pet. ether to give 13 (3.6 g, 42%). 0816 1H-NMR (CDCl3) 4.49-4.39 (m), 4,12-4.07 (m), 3.61 (m), 2.36 (m), 1.36-1.18 (m), 0.86-0.79. 0817 3-Aminomethyl-5-methylbeptanoic acid (Example 9) 0818 Ethyl 5-methyl-3-nitromethylheptanoate 13 (3.6 g) was hydrogenated in ethanol in the presence of 20% Pd/C and evaporated to give 14. Six normal hydrochloric acid 30 mL was added and refluxed overnight. The solvent was evaporated at reduced pressure, and the residue was azeotroped with toluene. Aqueous solution of the residue was applied to Dowex 50WX 8-100 ion exchange resin that had been washed to neutral pH with HPLC grade water. The column was eluted with water until eluent was neutral pH, and then with 0.5N. NH4OH solution to give factions containing 3-aminomethyl-5-methylheptanoic acid. The fractions were combined and further chromatographed on a C18 column. The compound was eluted with 40% water in methanol and crystallized from methanol-ether to give Example 9 630 mg. 1H-NMR (CD3OD) 2.83 (m, 1H), 2.75 (m, 1H), 2.35 (m, 1H), 2.15 (m, 1H), 1.95 (1H, bs), 1.38 (1H, m), 1.3-1.15 (m, 2H), 1.14-0.95 (m, 2H). 0.80 (m, 2CH3). MS found molecular ion at (M1) 174 and other ions at 156, 139, and 102. Anal. Calcd. for C9H19NO2: C, 62.39; H 11.05; N 8.08. Found C, 62.00; H, 10.83; N, 7.98. 0819 In a similar way the following examples can be prepared. 0820 3-Aminomethyl-5-methyl-heptanoic acid; 0821 3-Aminomethyl-5-methyl-octanoic acid; 0822 3-Aminomethyl-5-methyl-nonanoic acid; 0823 3-Aminomethyl-5-methyl-decanoic acid; 0824 3-Aminomethyl-5-methyl-undecanoic acid; 0825 3-Aminomethyl-5-methyl-dodecanoic acid; 0826 3-Aminomethyl-5-methyl-tridecanoic acid; 0827 3-Aminomethyl-5-cyclopropyl-hexanoic acid; 0828 3-Aminomethyl-5-cyclobutyl-hexanoic acid; 0829 3-Aminomethyl-5-cyclopentyl-hexanoic acid; 0830 3-Aminomethyl-5-cyclohexyl-hexanoic acid; 0831 3-Aminomethyl-5-trifluoromethyl-hexanoic acid; 0832 3-Aminomethyl-5-phenyl-hexanoic acid; 0833 3-Aminomethyl-5-(2-chlorophenyl)-hexanoic acid; 0834 3-Aminomethyl-5-(3-chlorophenyl)-hexanoic acid; 0835 3-Aminomethyl-5-(4-chlorophenyl)-hexanoic acid; 0836 3-Aminomethyl-5-(2-methoxyphenyl)-hexanoic acid; 0837 3-Aminomethyl-5-(3-methoxyphenyl)-hexanoic acid; 0838 3-Aminomethyl-5-(4-methoxyphenyl)-hexanoic acid; and 0839 3-Aminomethyl-5-(phenylmethyl)-hexanoic acid. 0840 Synthesis of Example 10: (3R,4S)3-Aminomethyl-4,5-dimethyl-hexanoic acid 48

0841 Reagents and Conditions: 0842 a) (R)-()-4-phenyl-2-oxazolidinone, (CH3)3CCOCl, Et3N, LiCl, THF, 20 to 23 C.; 0843 b) MeMgCl, CuBrSMe2, THF, 35 C.; 0844 c) NaHMDS, BrCH2CO2tBu, THF, 78 C. to 40 C.; 0845 d) LiOH, H2O2, THF, H2O, 25 C.; 0846 e) BH3SMe2, THF, 0 to 25 C.; 0847 f) pTsCl, pyridine, 25 C.; 0848 g) NaN3, DMSO, 60 C.; 0849 h) Raney nickel, MeOH, H2; i) 3M HCl, reflux, ion exchange resin (Dowex 50WX8, strongly acidic). 0850 R-(E)3-(4-Methyl-pent-2-enoyl)-4-phenyl-oxazolidin-2-one 16 0851 Trimethylacetyl chloride (7.8 g, 0.065 mol) was added to acid 14 (6.9 g, 0.06 mol) and triethylamine (18 g, 0.187 mol) in THF (200 mL) at 20 C. After 1 hour, lithium chloride (2.35 g, 0.55 mol) and (R)-()-4-phenyl-2-oxazolidinone (8.15 g, 0.05 mol) were added and the thick suspension warmed to room temperature. After 20 hours, the suspension was filtered and the filtrate concentrated. The resultant solid was recrystallized from hexane/ethyl acetate (5:1) to give the oxazolidinone 16 as a white solid (8.83 g, 68%). 1H NMR (CDCl3) 7.35 (m, 5H), 7.18 (dd, 1H, J15.4 and 1.2 Hz), 7.02 (dd, 1H, J15.4 and 6.8 Hz), 5.45 (dd, 1H, J8.8 and 3.9 Hz), 4.68 (t, 1H, J8.8 Hz), 4.22 (dd, 1H, J8.8 and 3.9 Hz), 2.50 (m, 1H), 1.04 (d, 1H, J1.4 Hz), 1.02 (d, 1H, J1.4 Hz). MS, m/z (relative intensity): 260 MH, 100%. 0852 (3R,3R*)3-(3,4-Dimethyl-pentanoyl)-4-phenyl-oxazolidin-2-one 17 0853 To copper(I) bromide-dimethyl sulphide complex in THF (45 mL) at 20 C. was added methylmagnesium chloride (as a 3 M solution in THF). After 20 minutes, the oxazolidinone 16 (3.69 g, 0.014 mol) in THF (20 mL) was added dropwise over 10 minutes. After 2.5 hours, the reaction was quenched through the addition of a saturated aqueous solution of ammonium chloride. The resultant two layers were separated and the aqueous phase extracted with ether. The combined organic phases were washed with 1 M hydrochloric acid, then with 5% aqueous ammonium hydroxide. The organic phases were dried (MgSO4) and concentrated to give the oxazolidinone 17 as a white solid (3.39 g, 88%). 1H NMR (CDCl3) 7.30 (m, 1H), 5.40 (dd, 1H, J8.8 and 3.7 Hz), 4.63 (t, 1H, J8.8 Hz), 4.21 (dd, 1H, J8.8 and 3.7 Hz), 2.85 (dd, 1H, J16.1 and 5.6 Hz), 2.8 (dd, 1H, J16.1 and 8.5 Hz), 1.90 (m, 1H), 1.56 (m, 2H), 0.83 (d, 3H, J6.8 Hz), 0.78 (d, 3H, J6.8 Hz), 0.75 (d, 3H, J6.8 Hz). MS, m/z (relative intensity): 276 MH, 100%. 0854 3R-(3R*(R*),4S*)-4,5-Dimethyl-3-(2-oxo-4-phenyl-oxazolidine-3-carbonyl)-hexanoic acid tert-butyl ester 18 0855 Sodium bis(trimethylsilyl)amide (14.4 mL, 0.014 mol of a 1 M solution in THF) was added to a solution of the oxazolidinone 17 (3.37 g, 0.012 mol) in THF (35 mL) at 78 C. After35 minutes, tert-butyl bromoacetate (3.5 g, 0.018 mol) was added and the solution immediately warmed to 40 C. After 3 hours, the reaction was quenched through the addition of a saturated aqueous solution of ammonium chloride. The resultant two layers were separated and the aqueous phase extracted with ether. The combined organic phases were dried (MgSO4) and concentrated. Flash chromatography (9:1 to 5:1 hexane/ethyl acetate gradient) gave the ester 18 (3.81 g, 82%) as a white solid. 1H NMR (CDCl3) 7.35 (m, 5H), 5.37 (dd, 1H, J8.4 and 3.1 Hz), 4.67 (t, 1H, J8.7 Hz), 4.41 (dt, 1H, J12.0 and 3.5 Hz), 4.25 (dd, 1H, J8.68 and 3.1 Hz), 2.65 (dd, 1H, J16.9 and 12.0 Hz), 2.25 (dd, 1H, J16.9 and 3.5 Hz), 1.6 (m, 1H), 1.45 (m, 1H), 1.23 (s, 9H), 1.02 (d, 1H, J6.5 Hz), 0.93 (d, 1H, J6.7 Hz), 0.80 (d, 1H, J7.0 Hz). MS, m/z (relative intensity): 429 MHCH3CN, 100%, 388 MH, 20%. 0856 (3R,4S)-2-(1,2-Dimethyl-propyl)-succinic acid 4-tert-butyl ester 19 0857 To the oxazolidinone 18 (3.62 g, 9.3 mmol) in THF (54 mL)/water (15 mL) was added a premixed solution of lithium hydroxide (20 mL of a 0.8 M aqueous solution, 0.016 mol)/H2O2 (5.76 mL of a 30% aqueous solution). After 7 hours, the solution was diluted with water and sodium bisulfite added (10 g). After stirring for a further 0.5 hours, the two layers were separated and the aqueous phase extracted with ether. The aqueous phase was then rendered acidic (pH 2) with 1 M hydrochloric acid and extracted with ether. The combined organic phases were dried (MgSO4) and concentrated. Flash chromatography (5:1 hexane/ethyl acetate) gave the acid 19 (2.1 g, 95%) as a colorless oil. 0858 1H NMR (CDCl3) 3.0 (m, 1H), 2.55 (dd, 1H, J16.6 and 11.2 Hz), 2.27 (dd, 1H, J16.6 and 3.4 Hz), 1.70 (m, 1H), 1.53 (m, 1H), 1.45 (m, 1H), 1.43 (s, 9H), 0.95 (d, 1H, J6.8 Hz), 0.90 (d, 1H, J6.6 Hz), 0.83 (d, 1H, J6.8 Hz). MS, m/z (relative intensity): 243 MH, 100%. 0859 (3R,4S)-3-Hydroxymethyl-4,5-dimethyl-hexanoic acid tert-butyl ester 20 0860 Borane-methyl sulfide complex (16 mL, 0.032 mol of a 2 M solution in THF) was added to a stirred solution of the acid 19 (1.96 g, 8 mmol) in THF (20 mL) at 0 C. After 20 hours, methanol was added until effervescence ceased and the solution concentrated. Flash chromatography (5:1 hexane/ethyl acetate gradient) gave the alcohol 20 (1.29 g, 70%) as a colorless oil. 1H NMR (CDCl3) 3.62 (m, 1H), 2.32 (m, 1H), 2.14 (m, 1H), 1.6 (m, 1H), 1.45 (s, 9H), 1.35 (m, 1H), 0.93 (d, 1H, J6.8 Hz), 0.86 (d, 1H, J6.8 Hz), 0.77 (d, 1H, J6.9 Hz). MS, m/z (relative intensity): 175 MtBu, 100%. 0861 (3R,4S)-4,5-Dimethyl-3-(toluene-4-sulfonyloxymethyl)-hexanoic acid tert-butyl ester 21 0862 p-Toluenesulfonyl chloride (847 mg, 4.4 mmol) was added to a stirred solution of the alcohol 6 (850 mg, 3.7 mmol), DMAP (10 mg, 0.08 mmol) and triethylamine (1.23 mL, 8.88 mmol) in CH2Cl2 (20 mL) at 0 C. and the solution warmed to room temperature. After 15 hours, the solution was washed with 1N hydrochloric acid then with brine. The combined organic phases were dried (MgSO4) and concentrated. Flash chromatography (100 to 92% hexane/ethyl acetate gradient) gave the tosylate 7 (1.22 g, 86%) as a thick gum. 1H NMR (CDCl3) 7.80 (d, 2H, J8.2 Hz), 7.25 (d, 2H, J8.2 Hz), 3.92 (m, 1H), 2.38 (s, 3H), 2.20 (m, 2H), 1.95 (m, 1H), 1.40 (m, 1H), 1.32 (s, 9H), 1.27 (m, 1H), 0.78 (d, 1H, J6.6 Hz), 0.73 (d, 1H, J6.6 Hz), 0.63 (d, 1H, J7.1 Hz). MS, m/z (relative intensity): 311 85%, 198 100%, 157 95%. 0863 (3R,4S)-3-Azidomethyl-4,5-dimethyl-hexanoic acid tert-butyl ester 22 0864 A solution of the tosylate 21 (1.19 g, 3.1 mmol) and sodium azide (402 mg, 6.2 mmol) in DMSO (15 mL) was warmed to 60 C. for 2.5 hours. Water (100 mL) was added and the solution extracted with ether. The combined organic phases were dried (MgSO4) and concentrated. Flash chromatography (9:1 hexane/ethyl acetate) gave the azide 22 (628 mg, 80%) as a colorless oil. 1H NMR (CDCl3) 3.4 (dd, 1H, J12.21 and 6.11 Hz), 3.3 (dd, 1H, J21.11 and 6.59 Hz), 2.30 (dd, 1H, J15.14 and 3.66 Hz), 2.25 (m, 1H), 2.05 (dd, 1H, J15.14 and 9.04 Hz), 1.55 (m, 1H), 1.45 (s, 9H), 1.35 (m, 1H), 0.95 (d, 1H, J6.59 Hz), 0.90 (d, 1H, J6.83 Hz), 0.80 (d, 1H, J7.08 Hz). MS (m/z): (relative intensity): 228 MN2, 35%, 172 MN2-tBu, 100%. 0865 (3R,4S)-3-Aminomethyl-4,5-dimethyl-hexanoic acid tert-butyl ester 23 and 4R-4R*(S*)4-(1,2-Dimethyl-propyl)-pyrrolidin-2-one 24 0866 The azide 8 (640 mg, 2.5 mmol) and Raney nickel (1 g) in methanol (50 mL) were shaken under an atmosphere of hydrogen for 4 hours. The solution was filtered and the filtrate concentrated to give a mixture of the amine 23 and lactam 24 which was used without further purification in the next step. 0867 (3R,4S)-3-Aminomethyl-4,5-dimethyl-hexanoic acid (Example 10) 0868 A solution of the amine 23 and lactam 24 (500 mg) in 3 M hydrochloric acid were heated to reflux for 9 hours, then stirred at room temperature for 15 hours. The solution was concentrated and the resultant solid subjected to a sequential purification which involved ion exchange chromatography (Dowex 50WX8, strongly acidic), oxalate salt formation then further purification by ion exchange chromatography (Dowex 50WX8, strongly acidic) to give the Example 10 (343 mg) as a white solid. 1H NMR (D2O) 2.87 (m, 2H), 2.22 (dd, 1H, J15.4 and 3.4 Hz), 2.12 (m, 1H), 1.93 (dd, 1H, J15.4 and 9.5 Hz), 1.38 (m, 1H), 1.12 (m, 1H), 0.77 (d, 1H, J6.6 Hz), 0.74 (d, 1H, J6.6 Hz), 0.70 (d, 1H, J6.8 Hz). MS, m/z (relative intensity): 174 MH, 100%. 0869 In a similar way, the following examples can be prepared: 0870 3-Aminomethyl-4,5-dimethyl-hexanoic acid; 0871 (3R,4S)-3-Aminomethyl-4,5-dimethyl-hexanoic acid MP; 0872 (3S,4S)-3-Aminomethyl-4,5-dimethyl-hexanoic acid; 0873 (3R,4R)-3-Aminomethyl-4,5-dimethyl-hexanoic acid MP; 0874 3-Aminomethyl-4-isopropyl-hexanoic acid; 0875 3-Aminomethyl-4-isopropyl-heptanoic acid; 0876 3-Aminomethyl-4-isopropyl-octanoic acid; 0877 3-Aminomethyl-4-isopropyl-nonanoic acid; 0878 3-Aminomethyl-4-isopropyl-decanoic acid; and 0879 3-Aminomethyl-4-phenyl-5-methyl-hexanoic acid. 50

0880 A compound of structure 30 could be prepared from a compound of structure 29 by treatment with an aqueous acid such as hydrochloric acid and alike at a temperature between room temperature and reflux. As an alternative, a compound of structure 30 can be prepared from a compound of structure 32 by treatment with trifluoroacetic acid in a solvent such as CH2Cl2 or EtOAc and alike. C0mpound 32 could be prepared by base mediate hydrolysis of a Boc protected lactam such as compound 31 which itself could be prepared from a compound of structure 29 by treatment with di-tert-butyl dicarbonate in a solvent such as THF and alike. The treatment of the Boc-lactam 31 with aqueous sodium hydroxide for example would give rise to the acid 32. 0881 A compound of structure 29 could be prepared from compound of structure 28 (n0) by treatment with sodium or lithium metal in ammonia. Preferably, the reaction is carried out with sodium metal in ammonia. Alternatively, a compound of structure 29 could be prepared from compound of structure 28 (n1 or 2) by treatment with ceric ammonium nitrate in a mixture of acetonitrile and water. Other methods known in the literature for the removal of substituted alkoxy benzyl groups from nitrogen are described in Green, Protective Groups in Organic Synthesis, Wiley, 2 ed, 1991 and could be utilized. 0882 A compound of structure 28 could be prepared from a compound of structure 27 (where LG is a suitable leaving group such as a halide or an alkyl sulphonate, preferably an iodide would be used) by carbon-carbon bond forming reactions known in the art. Several methods exist in the literature for the coupling of organohalides or organoalkyl sulphonates with organometallic reagents in the presence of various metal salts as summarized in Comprehensive Organic Synthesis, volume 3:413 which could be utilized. For example, a compound of structure 28 could be prepared from a compound of structure 27 (where LG is iodide) by treatment with a suitable secondary halide (chloride or iodide) in the presence of magnesium metal, iodine and copper bromide dimethylsulphide in a solvent such as tetrahydrofuran and alike. Alternatively the method according to El Marini, Synthesis, 1992:1104 could be used. Hence, a compound of structure 28 could be prepared from a compound of structure 27 (where LG is iodide) by treatment with suitable methyl-substituted secondary halide such as an iodide in the presence of magnesium, iodine and lithium tetrachlorocuprate in a solvent such as tetrahydrofuran and alike. 0883 A compound of structure 27 incorporates a suitable leaving group, which would undergo nucleophilic substitution with suitable nucleophile. Examples of such leaving groups include halides such as chloride, bromide, or iodide, and sulphonic esters such as mesylate, tosylate, triflate, nosylate, and alike. A compound of structure 27 (where LGiodide) could be prepared from a compound of structure 26 through treatment with iodine, triphenylphosphine, and imidazole in a solvent such as toluene and alike. 0884 A compound of structure 26 could be prepared from compound of structure 25 by treatment with a metal borohydride, such as sodium borohydride in a solvent such as tetrahydrofuran or DME and alike. 0885 Compound 25 could be prepared in a similar fashion to the procedures of Zoretic et al, J. Org. Chem., 1980;45:810-814 or Nielsen et al J. Med. Chem., 1990;33:71-77 using an appropriate benzylamine, such as but not limited to benzylamine, 4-methoxybenzylamine or 2,4-dimethoxybenzylamine. 0886 As an alternative approach, a compound of structure 26 could be treated with sodium metal and ammonia to give 4-hydroxymethyl-pyrrolidinone which could be iodinated affording 4-iodomethyl-pyrrolidinone. 4-iodomethyl-pyrrolidinone could then be coupled with organometallic reagents according to the above procedures avoiding protection of the lactam nitrogen as below. 51

0887 Analogous to the above methods a lactam of structure 33 (see Nielsen et. al., J. Med. Chem., 1990;33:71-77 for general method of preparation) could be employed thus establishing fixed stereochemistry at C3 of the fmal amino acids. 52

0888 Compounds which could be prepared in this manner include: 0889 3-Aminomethyl-5-methyl-6-phenyl-hexanoic acid; 0890 3-Aminomethyl-6-(4-chloro-phenyl)-5-methyl-hexanoic acid; 0891 3-Aminomethyl-6-(3-chloro-phenyl)-5-methyl-hexanoic acid; 0892 3-Aminomethyl-6-(2-chloro-phenyl)-5-methyl-hexanoic acid; 0893 3-Aminomethyl-6-(4-fluoro-phenyl)-5-methyl-hexanoic acid; 0894 3-Aminomethyl-6-(3-fluoro-phenyl)-5-methyl-hexanoic acid; 0895 3-Aminomethyl-6-(2-fluoro-phenyl)-5-methyl-hexanoic acid; 0896 3-Aminomethyl-5-methyl-7-phenyl-heptanoic acid; 0897 3-Aminomethyl-7-(4-chloro-phenyl)-5-methyl-heptanoic acid; 0898 3-Aminomethyl-7-(3-chloro-phenyl)-5-methyl-heptanoic acid; 0899 3-Aminomethyl-7-(2-chloro-phenyl)-5-methyl-heptanoic acid; 0900 3-Aminomethyl-7-(4-fluoro-phenyl)-5-methyl-heptanoic acid; 0901 3-Aminomethyl-7-(3-fluoro-phenyl)-5-methyl-heptanoic acid; 0902 3-Aminomethyl-7-(2-fluoro-phenyl)-5-methyl-heptanoic acid; 0903 (3S)-3-Aminomethyl-6-cyclopropyl-5-methyl-hexanoic acid; 0904 (3S)-3-Aminomethyl-6-cyclobutyl-5-methyl-hexanoic acid; 0905 (3S)-3-Aminomethyl-6-cyclopentyl-5-methyl-hexanoic acid; 0906 (3S)-3-Aminomethyl-6-cyclohexyl-5-methyl-hexanoic acid; 0907 (3S)-3-Aminomethyl-7-cyclopropyl-5-methyl-heptanoic acid; 0908 (3S)-3-Aminomethyl-7-cyclobutyl-5-methyl-heptanoic acid; 0909 (3S)-3-Aminomethyl-7-cyclopentyl-5-methyl-heptanoic acid; 0910 (3S)-3-Aminomethyl-7-cyclohexyl-5-methyl-heptanoic acid; 0911 (3S)-3-Aminomethyl-8-cyclopropyl-5-methyl-octanoic acid; 0912 (3S)-3-Aminomethyl-8-cyclobutyl-5-methyl-octanoic acid; 0913 (3S)-3-Aminomethyl-8-cyclopentyl-5-methyl-octanoic acid; 0914 (3S)-3-Aminomethyl-8-cyclohexyl-5-methyl-octanoic acid; 0915 (3S)-3-Aminomethyl-5-methyl-heptanoic acid; 0916 (3S)-3-Aminomethyl-5-methyl-octanoic acid; 0917 (3S)-3-Aminomethyl-5-methyl-nonanoic acid; 0918 (3S)-3-Aminomethyl-5-methyl-decanoic acid; 0919 (3S)-3-Aminomethyl-5-methyl-undecanoic acid; 0920 (3S)-3-Aminomethyl-5,7-dimethyl-octanoic acid; 0921 (3S)-3-Aminomethyl-5,8-dimethyl-nonanoic acid; 0922 (3S)-3-Aminomethyl-5,9-dimethyl-decanoic acid; 0923 (3S)-3-Aminomethyl-5,6-dimethyl-heptanoic acid; 0924 (3S)-3-Aminomethyl-5,6, 6-trimethyl-heptanoic acid; 0925 (3S)-3-Aminomethyl-5-cyclopropyl-hexanoic acid; 0926 (3S)-3-Aminomethyl-6-fluoro-5-methyl-hexanoic acid; 0927 (3S)-3-Aminomethyl-7-fluoro-5-methyl-heptanoic acid; 0928 (3S)-3-Aminomethyl-8-fluoro-5-methyl-octanoic acid; 0929 (3S)-3-Aminomethyl-7,7,7-trifluoro-5-methyl-heptanoic acid; 0930 (3S)-3-Aminomethyl-8,8,8-trifluoro-5-methyl-octanoic acid; 0931 (3S)-3-Aminomethyl-5-methyl-hept-6-enoic acid; 0932 (3S)-3-Aminomethyl-5-methyl-oct-7-enoic acid; 0933 (3S)-3-Aminomethyl-5-methyl-non-8-enoic acid; 0934 (E)-(3S)-3-Aminomethyl-5-methyl-oct-6-enoic acid; 0935 (Z)-(3S)-3-Aminomethyl-5-methyl-oct-6-enoic acid; 0936 (E)-(3S)-3-Aminomethyl-5-methyl-non-6-enoic acid; 0937 (Z)-(3S)-3-Aminomethyl-5-methyl-non-6-enoic acid; 0938 (E)-(3S)-3-Aminomethyl-5-methyl-non-7-enoic acid; 0939 (Z)-(3S)-3-Aminomethyl-5-methyl-non-7-enoic acid; 0940 (E)-(3S)-3-Aminomethyl-5-methyl-dec-7-enoic acid; 0941 (Z)-(3S)-3-Aminomethyl-5-methyl-dec-7-enoic acid; 0942 3-Aminomethyl-6-cyclopropyl-5-methyl-hexanoic acid; 0943 3-Aminomethyl-6-cyclobutyl-5-methyl-hexanoic acid; 0944 3-Aminomethyl-6-cyclopentyl-5-methyl-hexanoic acid; 0945 3-Aminomethyl-6-cyclohexyl-5-methyl-hexanoic acid; 0946 3-Aminomethyl-7-cyclopropyl-5-methyl-heptanoic acid; 0947 3-Aminomethyl-7-cyclobutyl-5-methyl-heptanoic acid; 0948 3-Aminomethyl-7-cyclopentyl-5-methyl-heptanoic acid; 0949 3-Aminomethyl-7-cyclohexyl-5-methyl-heptanoic acid; 0950 3-Aminomethyl-8-cyclopropyl-5-methyl-octanoic acid; 0951 3-Aminomethyl-8-cyclobutyl-5-methyl-octanoic acid; 0952 3-Aminomethyl-8-cyclopentyl-5-methyl-octanoic acid; 0953 3-Aminomethyl-8-cyclohexyl-5-methyl-octanoic acid; 0954 3-Aminomethyl-5-methyl-heptanoic acid; 0955 3-Aminomethyl-5-methyl-octanoic acid; 0956 3-Aminomethyl-5-methyl-nonanoic acid; 0957 3-Aminomethyl-5-methyl-decanoic acid; 0958 3-Aminomethyl-5-methyl-undecanoic acid; 0959 3-Aminomethyl-5,7-dimethyl-octanoic acid; 0960 3-Aminomethyl-5,8-dimethyl-nonanoic acid; 0961 3-Aminomethyl-5,9-dimethyl-decanoic acid; 0962 3-Aminomethyl-5,6-dimethyl-heptanoic acid; 0963 3-Aminomethyl-5,6, 6-trimethyl-heptanoic acid; 0964 3-Aminomethyl-5-cyclopropyl-hexanoic acid; 0965 3-Aminomethyl-6-fluoro-5-methyl-hexanoic acid; 0966 3-Aminomethyl-7-fluoro-5-methyl-heptanoic acid; 0967 3-Aminomethyl-8-fluoro-5-methyl-octanoic acid; 0968 3-Aminomethyl-7,7,7-trifluoro-5-methyl-heptanoic acid; 0969 3-Aminomethyl-8,8,8-trifluoro-5-methyl-octanoic acid; 0970 3-Aminomethyl-5-methyl-hept-6-enoic acid; 0971 3-Aminomethyl-5-methyl-oct-7-enoic acid; 0972 3-Aminomethyl-5-methyl-non-8-enoic acid; 0973 (E)-3-Aminomethyl-5-methyl-oct-6-enoic acid; 0974 (Z)-3-Aminomethyl-5-methyl-oct-6-enoic acid; 0975 (E)-3-Aminomethyl-5-methyl-non-6-enoic acid; 0976 (Z)-3-Aminomethyl-5-methyl-non-6-enoic acid; 0977 (E)-3-Aminomethyl-5-methyl-non-7-enoic acid; 0978 (Z)-3-Aminomethyl-5-methyl-non-7-enoic acid; 0979 (E)-3-Aminomethyl-5-methyl-dec-7-enoic acid; and 0980 (Z)-3-Aminomethyl-5-methyl-dec-7-enoic acid. 53

0981 A compound of structure 40 could be prepared from compound of structure 39 through treatment with diethylaminosulphur trifluoride in a solvent such as methylene chloride at a temperature between 78 C. and room temperature. Other methods for the fluorination of alcohols are known and could be utilized as exemplified in Wilkinson, Chem. Rev. 1992;92:505-519. Compounds of structure 40 can be converted to the requisite y-amino acid as described in method 3 above. 0982 A compound of structure 39 could be prepared from compound of structure 38 through treatment with osmium tetroxide and sodium periodate in a solvent such as THF and water and reduction of the resultant intermediate with sodium borohydride in a solvent such as ethanol. 0983 Compounds of structures 38 and 34 could be prepared from compound of structure 33 according to the principles described in method 3. 0984 An alternative procedure for the synthesis of alcohol 39 (n0) involves the treatment of a compound of structure 36 with a metal borohydride, such as sodium borohydride in a solvent such as tetrahydrofuran or DME and alike to give a compound of structure 37, the fluorination of which could be achieved in a similar manner to the preparation of a compound of structure 40. A compound of structure 36 could be prepared from compound of structure 35 through treatment with sodium or lithium chloride in aqueous DMSO at a temperature between room temperature and reflux. Preferably the reaction is carried out using sodium chloride in aqueous DMSO at reflux. A compound of structure 35 could be prepared from compound of structure 34 through treatment with a suitable methyl malonic acid diester, such as dimethyl methylmalonate and alike with sodium hydride in a solvent such as DMSO or THF and alike. Preferably the reaction is carried out by adding NaH to a solution of dimethyl methylmalonate in DMSO followed by the addition of the lactam 34 (where LG is preferably iodide or as defined in method 3) pre-dissolved in DMSO. 0985 Compounds 39 and 37 can be converted to the free amino acids bearing a hydroxyl group by the methods described above. 0986 The following compounds could be prepared in this manner: 0987 (3S)-3-Aminomethyl-6-fluoro-5-methyl-hexanoic acid; 0988 (3S)-3-Aminomethyl-6-fluoro-5-methyl-hexanoic acid; 0989 (3S)-3-Aminomethyl-7-fluoro-5-methyl-heptanoic acid; 0990 (3S)-3-Aminomethyl-8-fluoro-5-methyl-octanoic acid; 0991 (3S)-3-Aminomethyl-9-fluoro-5-methyl-nonanoic acid; 0992 (3S)-3-Aminomethyl-7-hydroxy-5-methyl-heptanoic acid; and 0993 (3S)-3-Aminomethyl-6-hydroxy-5-methyl-hexanoic acid. 54

0994 A compound of structure 41 could be prepared from compound of structure 39 through treatment with a suitable alkyl iodide (or alkyl sulphonate), such as methyl iodide and alike, and a base such as n-butyl lithium or sodium hydride and alike, in a solvent such as DMSO or THF and alike. Preferably the reaction is carried out by adding NaH to a solution of the alcohol in DMSO followed by the addition of the alkyl iodide and heating of the reaction mixture at a temperature between room temperature and reflux. The conversion of compounds of structure 41 to they-amino acids has been described above. 0995 Alternatively, compounds of structure 41 could be derived from compounds of structure 42 (where LGiodide, bromide or an sulphonic acid ester, as exampled in method 3) by treatment of an appropriate alkoxy anion in a solvent such as DMSO or THF and alike. A compound of structure 42 would also serve as a substrate for carbon-carbon bond forming procedures as outlined in method 3. 0996 Compounds which could be prepared in this manner include: 0997 (3S)-3-Aminomethyl-7-hydroxy-5-methyl-heptanoic acid; 0998 (3S)-3-Aminomethyl-7-methoxy-5-methyl-heptanoic acid; 0999 (3S)-3-Aminomethyl-7-ethoxy-5-methyl-heptanoic acid; 1000 (3S)-3-Aminomethyl-5-methyl-7-propoxy-heptanoic acid; 1001 (3S)-3-Aminomethyl-7-fluoromethoxy-5-methyl-heptanoic acid; 1002 (3S)-3-Aminomethyl-7-(2-fluoro-ethoxy)-5-methyl-heptanoic acid; 1003 (3S)-3-Aminomethyl-5-methyl-7-(3,3,3-trifluoro-propoxy)-heptanoic acid; 1004 (3S)-3-Aminomethyl-6-hydroxy-5-methyl-hexanoic acid; 1005 (3S)-3-Aminomethyl-6-methoxy-5-methyl-hexanoic acid; 1006 (3S)-3-Aminomethyl-6-ethoxy-5-methyl-hexanoic acid; 1007 (3S)-3-Aminomethyl-5-methyl-6-propoxy-hexanoic acid; 1008 (3S)-3-Aminomethyl-6-fluoromethoxy-5-methyl-hexanoic acid; 1009 (3S)-3-Aminomethyl-6-(2-fluoro-ethoxy)-5-methyl-hexanoic acid; and 1010 (3S)-3-Aminomethyl-5-methyl-6-(3,3,3-trifluoro-propoxy)-hexanoic acid. 55

1011 Compounds of structure 53 could be prepared from a compound of structure 45 as shown above and by the general procedures described in Hoekstra et. al., Organic Process Research and Development, 1997;1:26-38. 1012 Compounds of structure 45 can be prepared from compounds of structure 44 by treatment with a solution of chromium trioxide in water/sulfuric acid. Alternative methods of cleaving the olefin in 44 could be utilized as detailed in Hudlicky, Oxidations in Organic Chemistry, ACS Monograph 186, ACS 1990:77. 1013 Compounds of structure 44 (where R2alkyl, branched alkyl, cycloalkyl, alkyl-cycloalkyl) could be prepared from (S)-citronellyl bromide by carbon-carbon bond forming reactions known in the art and as described in method 3. The substitution of the halide in (S)-citronellyl bromide with alkoxy anions could also be used to provide compounds of structure 44 where Ralkoxy or phenoxy ethers (and appropriate substitutions thereof as according to Formula 1). Alternatively (S)-citronellol could be utilized to afford compounds of structure 44 by treatment of (S)-citronellol with a base such as sodium hydride, and treatment of the resultant alkoxide with an appropriate alkyl halide to afford ethers. In another method (S)-citronellyl bromide (or an appropriate sulphonic ester such as, but not limited to, methanesulfonic acid (S)-3,7-dimethyl-oct-6-enyl ester) could be reduced with an appropriate metal borohydride or with an aluminum hydride species, such as LAH, to provide (R)-2,6-dimethyl-oct-2-ene. 1014 To one skilled in the art it will be appreciated that rational choice of either R- or S-citronellol or R- or S-citronellyl bromide would give rise to the requisite isomer at C5 of the fmal amino acid. 1015 Compounds which could be prepared in this manner include: 1016 (3S,5S)-3-Aminomethyl-7-methoxy-5-methyl-heptanoic acid; 1017 (3S,5S)-3-Aminomethyl-7-ethoxy-5-methyl-heptanoic acid; 1018 (3S,5S)-3-Aminomethyl-5-methyl-7-propoxy-heptanoic acid; 1019 (3S,5S)-3-Aminomethyl-7-isopropoxy-5-methyl-heptanoic acid; 1020 (3S,5S)-3-Aminomethyl-7-tert-butoxy-5-methyl-heptanoic acid; 1021 (3S,5S)-3-Aminomethyl-7-fluoromethoxy-5-methyl-heptanoic acid; 1022 (3S,5S)-3-Aminomethyl-7-(2-fluoro-ethoxy)-5-methyl-heptanoic acid; 1023 (3S,5S)-3-Aminomethyl-5-methyl-7-(3,3,3-trifluoro-propoxy)-heptanoic acid; 1024 (3S,5S)-3-Aminomethyl-7-benzyloxy-5-methyl-heptanoic acid; 1025 (3S,5S)-3-Aminomethyl-5-methyl-7-phenoxy-heptanoic acid; 1026 (3S,5S)-3-Aminomethyl-7-(4-chloro-phenoxy)-5-methyl-heptanoic acid; 1027 (3S,5S)-3-Aminomethyl-7-(3-chloro-phenoxy)-5-methyl-heptanoic acid; 1028 (3S,5S)-3-Aminomethyl-7-(2-chloro-phenoxy)-5-methyl-heptanoic acid; 1029 (3S,5S)-3-Aminomethyl-7-(4-fluoro-phenoxy)-5-methyl-heptanoic acid; 1030 (3S,5S)-3-Aminomethyl-7-(3-fluoro-phenoxy)-5-methyl-heptanoic acid; 1031 (3S,5S)-3-Aminomethyl-7-(2-fluoro-phenoxy)-5-methyl-heptanoic acid; 1032 (3S,5S)-3-Aminomethyl-7-(4-methoxy-phenoxy)-5-methyl-heptanoic acid; 1033 (3S,5S)-3-Aminomethyl-7-(3-methoxy -phenoxy)-5-methyl-heptanoic acid; 1034 (3S,5S)-3-Aminomethyl-7-(2-methoxy -phenoxy)-5-methyl-heptanoic acid; 1035 (3S,5S)-3-Aminomethyl-5-methyl-7-(4-trifluoromethyl-phenoxy)heptanoic acid; 1036 (3S,5S)-3-Aminomethyl-5-methyl-7-(3-trifluoromethyl-phenoxy)heptanoic acid; 1037 (3S,5S)-3-Aminomethyl-5-methyl-7-(2-trifluoromethyl-phenoxy)heptanoic acid; 1038 (3S,5S)-3-Aminomethyl-5-methyl-7-(4-nitro-phenoxy)-heptanoic acid; 1039 (3S,5S)-3-Aminomethyl-5-methyl-7-(3-nitro-phenoxy)-heptanoic acid; 1040 (3S,5S)-3-Aminomethyl-5-methyl-7-(2-nitro-phenoxy)-heptanoic acid; 1041 (3S,5R)-3-Aminomethyl-7-cyclopropyl-5-methyl-heptanoic acid; 1042 (3S,5R)-3-Aminomethyl-7-cyclobutyl-5-methyl-heptanoic acid; 1043 (3S,5R)-3-Aminomethyl-7-cyclopentyl-5-methyl-heptanoic acid; 1044 (3S,5R)-3-Aminomethyl-7-cyclohexyl-5-methyl-heptanoic acid; 1045 (3S,5R)-3-Aminomethyl-8-cyclopropyl-5-methyl-octanoic acid; 1046 (3S,5R)-3-Aminomethyl-8-cyclobutyl-5-methyl-octanoic acid; 1047 (3S,5R)-3-Aminomethyl-8-cyclopentyl-5-methyl-octanoic acid; 1048 (3S,5R)-3-Aminomethyl-8-cyclohexyl-5-methyl-octanoic acid; 1049 (3S,5R)-3-Aminomethyl-5-methyl-heptanoic acid; 1050 (3S,5R)-3-Aminomethyl-5-methyl-octanoic acid; 1051 (3S,5R)-3-Aminomethyl-5-methyl-nonanoic acid; 1052 (3S,5R)-3-Aminomethyl-5-methyl-decanoic acid; 1053 (3S,5R)-3-Aminomethyl-5-methyl-undecanoic acid; 1054 (3S,5R)-3-Aminomethyl-5,9-dimethyl-decanoic acid; 1055 (3S,5R)-3-Aminomethyl-5,8-dimethyl-nonanoic acid; 1056 (3S,5S)-3-Aminomethyl-7-fluoro-5-methyl-heptanoic acid; 1057 (3S,5R)-3-Aminomethyl-8-fluoro-5-methyl-octanoic acid; 1058 (3S,5R)-3-Aminomethyl-8,8,8-trifluoro-5-methyl-octanoic acid; 1059 (3S,5R)-3-Aminomethyl-5-methyl-7-phenyl-heptanoic acid; 1060 (3S,5R)-3-Aminomethyl-7-(4-chloro-phenyl)-5-methyl-heptanoic acid; 1061 (3S,5R)-3-Aminomethyl-7-(3-chloro-phenyl)-5-methyl-heptanoic acid; 1062 (3S,5R)-3-Aminomethyl-7-(2-chloro-phenyl)-5-methyl-heptanoic acid; 1063 (3S,5R)-3-Aminomethyl-7-(4-methoxy-phenyl)-5-methyl-heptanoic acid; 1064 (3S,5R)-3-Aminomethyl-7-(3-methoxy-phenyl)-5-methyl-heptanoic acid; 1065 (3S,5R)-3-Aminomethyl-7-(2-methoxy-phenyl)-5-methyl-heptanoic acid; 1066 (3S,5R)-3-Aminomethyl-7-(4-fluoro-phenyl)-5-methyl-heptanoic acid; 1067 (3S,5R)-3-Aminomethyl-7-(3-fluoro-phenyl)-5-methyl-heptanoic acid; 1068 (3S,5R)-3-Aminomethyl-7-(2-fluoro-phenyl)-5-methyl-heptanoic acid; and 1069 (3S,5R)-3-Aminomethyl-5, 1 0-dimethyl-undecanoic acid. 56

1070 A compound of structure 58 can be prepared from a compound of structure 57 by treatment with borontrifluoride diethyletherate and triethylsilane in a solvent such as CH2Cl2. Alternatively the method described in Meyers, J. Org. Chem., 1993;58:36-42, could be utilized thus treating a compound of structure 57 with sodium cyanoborohydride in a solvent such as THF/methanol with 3% HCl in methanol. 1071 A compound of structure 57 can be prepared from a compound of structure 56 by treatment with dimethylamine in a solvent such as DMF and alike according to the procedure of Koot, Tetrahedron Lett., 1992;33:7969-7972. 1072 A compound of structure 56 can be prepared from a compound of structure 54 by treatment of a suitable primary halide 55 (iodide, bromide, or chloride) under standard transmetallation conditions with tBuLi and treatment of the resultant organometallic reagent with suitable copper salt, such as but not limited to, copper bromide or copper iodide. The resultant organo-cuprate is added to lactam (see Koot et al, J. Org. Chem., 1992;57:1059-1061 for the preparation of the chiral lactam 54) in a solvent such as THF and alike. The procedure of Koot, Tetrahedron Lett., 1992;33:7969-7972 exemplifies this method. 1073 To one skilled in the art it will be appreciated that rational choice of either R- or S-primary halides 55 would give rise to the requisite isomer at C5 of the final amino acid. 1074 Compounds which could be prepared in this manner include: 1075 (3S,5S)-3-Aminomethyl-5-methoxy-hexanoic acid; 1076 (3S,5S)-3-Aminomethyl-5-ethoxy-hexanoic acid; 1077 (3S,5S)-3-Aminomethyl-5-propoxy-hexanoic acid; 1078 (3S,5S)-3-Aminomethyl-5-isopropoxy-hexanoic acid; 1079 (3S,5S)-3-Aminomethyl-5-tert-butoxy-hexanoic acid; 1080 (3S,5S)-3-Aminomethyl-5-fluoromethoxy-hexanoic acid; 1081 (3S,5S)-3-Aminomethyl-5-(2-fluoro-ethoxy)-hexanoic acid; 1082 (3S,5S)-3-Aminomethyl-5-(3,3,3-trifluoro-propoxy)-hexanoic acid; 1083 (3S,5S)-3-Aminomethyl-5-phenoxy-hexanoic acid; 1084 (3S,5S)-3-Aminomethyl-5-(4-chloro-phenoxy)-hexanoic acid; 1085 (3S,5S)-3-Aminomethyl-5-(3-chloro-phenoxy)-hexanoic acid; 1086 (3S,5S)-3-Aminomethyl-5-(2-chloro-phenoxy)-hexanoic acid; 1087 (3S,5S)-3-Aminomethyl-5-(4-fluoro-phenoxy)-hexanoic acid; 1088 (3S,5S)-3-Aminomethyl-5-(3-fluoro-phenoxy)-hexanoic acid; 1089 (3S,5S)-3-Aminomethyl-5-(2-fluoro-phenoxy)-hexanoic acid; 1090 (3S,5S)-3-Aminomethyl-5-(4-methoxy-phenoxy)-hexanoic acid; 1091 (3S,5S)-3-Aminomethyl-5-(3-methoxy-phenoxy)-hexanoic acid; 1092 (3S,5S)-3-Aminomethyl-5-(2-methoxy-phenoxy)-hexanoic acid; 1093 (3S,5S)-3-Aminomethyl-5-(4-nitro-phenoxy)-hexanoic acid; 1094 (3S,5S)-3-Aminomethyl-5-(3-nitro-phenoxy)-hexanoic acid; 1095 (3S,5S)-3-Aminomethyl-5-(2-nitro-phenoxy)-hexanoic acid; 1096 (3S,5S)-3-Aminomethyl-6-methoxy-5-methyl-hexanoic acid; 1097 (3S,5S)-3-Aminomethyl-6-ethoxy-5-methyl-hexanoic acid; 1098 (3S,5S)-3-Aminomethyl-5-methyl-6-propoxy-hexanoic acid; 1099 (3S,5S)-3-Aminomethyl-6-isopropoxy-5-methyl-hexanoic acid; 1100 (3S,5S)-3-Aminomethyl-6-tert-butoxy-5-methyl-hexanoic acid; 1101 (3S,5S)-3-Aminomethyl-6-fluoromethoxy-5-methyl-hexanoic acid; 1102 (3S,5S)-3-Aminomethyl-6-(2-fluoro-ethoxy)-5-methyl-hexanoic acid; 1103 (3S,5S)-3-Aminomethyl-5-methyl-6-(3,3,3-trifluoro-propoxy)-hexanoic acid; 1104 (3S,5S)-3-Aminomethyl-5-methyl-6-phenoxy-hexanoic acid; 1105 (3S,5S)-3-Aminomethyl-6-(4-chloro-phenoxy)-5-methyl-hexanoic acid; 1106 (3S,5S)-3-Aminomethyl-6-(3-chloro-phenoxy)-5-methyl-hexanoic acid; 1107 (3S,5S)-3-Aminomethyl-6-(2-chloro-phenoxy)-5-methyl-hexanoic acid; 1108 (3S,5S)-3-Aminomethyl-6-(4-fluoro-phenoxy)-5-methyl-hexanoic acid; 1109 (3S,5S)-3-Aminomethyl-6-(3-fluoro-phenoxy)-5-methyl-hexanoic acid; 1110 (3S,5S)-3-Aminomethyl-6-(2-fluoro-phenoxy)-5-methyl-hexanoic acid; 1111 (3S,5S)-3-Aminomethyl-6-(4-methoxy-phenoxy)-5-methyl-hexanoic acid; 1112 (3S,5S)-3-Aminomethyl-6-(3-methoxy-phenoxy)-5-methyl-hexanoic acid; 1113 (3S,5S)-3-Aminomethyl-6-(2-methoxy-phenoxy)-5-methyl-hexanoic acid; 1114 (3S,5S)-3-Aminomethyl-5-methyl 6-(4-trifluoromethyl-phenoxy)-hexanoic acid; 1115 (3S,5S)-3-Aminomethyl-5-methyl 6-(3-trifluoromethyl-phenoxy)-hexanoic acid; 1116 (3S,5S)-3-Aminomethyl-5-methyl 6-(2-trifluoromethyl-phenoxy)-hexanoic acid; 1117 (3S,5S)-3-Aminomethyl-5-methyl 6-(4-nitro-phenoxy)-hexanoic acid; 1118 (3S,5S)-3-Aminomethyl-5-methyl 6-(3-nitro-phenoxy)-hexanoic acid; 1119 (3S,5S)-3-Aminomethyl-5-methyl 6-(2-nitro-phenoxy)-hexanoic acid; 1120 (3S,5S)-3-Aminomethyl-6-benzyloxy-5-methyl-hexanoic acid; 1121 (3S,5R)-3-Aminomethyl-6-cyclopropyl-5-methyl-hexanoic acid; 1122 (3S,5R)-3-Aminomethyl-6-cyclobutyl-5-methyl-hexanoic acid; 1123 (3S,5R)-3-Aminomethyl-6-cyclopentyl-5-methyl-hexanoic acid; 1124 (3S,5R)-3-Aminomethyl-6-cyclohexyl-5-methyl-hexanoic acid; 1125 (3S,5R)-3-Aminomethyl-5-methyl-heptanoic acid; 1126 (3S,5R)-3-Aminomethyl-5-methyl-octanoic acid; 1127 (3S,5R)-3-Aminomethyl-5-methyl-nonanoic acid; 1128 (3S,5R)-3-Aminomethyl-5-methyl-decanoic acid; 1129 (3S,5R)-3-Aminomethyl-5-methyl-undecanoic acid; 1130 (3S,5R)-3-Aminomethyl-5-methyl-dodecanoic acid; 1131 (3S,5R)-3-Aminomethyl-5,7-dimethyl-octanoic acid; 1132 (3S,5R)-3-Aminomethyl-5,8-dimethyl-nonanoic acid; 1133 (3S,5R)-3-Aminomethyl-5,9-dimethyl-decanoic acid; 1134 (3S,5R)-3-Aminomethyl-5,10-dimethyl-undecanoic acid; 1135 (3S,5S)-3-Aminomethyl-5,6-dimethyl-heptanoic acid; 1136 (3S,5S)-3-Aminomethyl-5,6, 6-trimethyl-heptanoic acid; 1137 (3S,5S)-3-Aminomethyl-5-cyclopropyl-hexanoic acid; 1138 (3S,5S)-3-Aminomethyl-6-fluoro-5-methyl-hexanoic acid; 1139 (3S,5S)-3-Aminomethyl-7-fluoro-5-methyl-heptanoic acid; 1140 (3S,5R)-3-Aminomethyl-8-fluoro-5-methyl-octanoic acid; 1141 (3S,5S)-3-Aminomethyl-7,7,7-trifluoro-5-methyl-heptanoic acid; 1142 (3S,5R)-3-Aminomethyl-8,8,8-trifluoro-5-methyl-octanoic acid; 1143 (3S,5S)-3-Aminomethyl-5-methyl-6-phenyl-hexanoic acid; 1144 (3S,5S)-3-Aminomethyl-6-(4-chloro-phenyl)-5-methyl-hexanoic acid; 1145 (3S,5S)-3-Aminomethyl-6-(3-chloro-phenyl)-5-methyl-hexanoic acid; 1146 (3S,5S)-3-Aminomethyl-6-(2-chloro-phenyl)-5-methyl-hexanoic acid; 1147 (3S,5S)-3-Aminomethyl-6-(4-methoxy-phenyl)-5-methyl-hexanoic acid; 1148 (3S,5S)-3-Aminomethyl-6-(3-methoxy-phenyl)-5-methyl-hexanoic acid; 1149 (3S,5S)-3-Aminomethyl-6-(2-methoxy-phenyl)-5-methyl-hexanoic acid; 1150 (3S,5S)-3-Aminomethyl-6-(4-fluoro-phenyl)-5-methyl-hexanoic acid; 1151 (3S,5S)-3-Aminomethyl-6-(3-fluoro-phenyl)-5-methyl-hexanoic acid; 1152 (3S,5S)-3-Aminomethyl-6-(2-fluoro-phenyl)-5-methyl-hexanoic acid; 1153 (3S,5R)-3-Aminomethyl-5-methyl-7-phenyl-heptanoic acid; 1154 (3S,5R)-3-Aminomethyl-7-(4-chloro-phenyl)-5-methyl-heptanoic acid; 1155 (3S,5R)-3-Aminomethyl-7-(3-chloro-phenyl)-5-methyl-heptanoic acid; 1156 (3S,5R)-3-Aminomethyl-7-(2-chloro-phenyl)-5-methyl-heptanoic acid; 1157 (3S,5R)-3-Aminomethyl-7-(4-methoxy-phenyl)-5-methyl-heptanoic acid; 1158 (3S,5R)-3-Aminomethyl-7-(3-methoxy-phenyl)-5-methyl-heptanoic acid; 1159 (3S,5R)-3-Aminomethyl-7-(2-methoxy-phenyl)-5-methyl-heptanoic acid; 1160 (3S,5R)-3-Aminomethyl-7-(4-fluoro-phenyl)-5-methyl-heptanoic acid; 1161 (3S,5R)-3-Aminomethyl-7-(3-fluoro-phenyl)-5-methyl-heptanoic acid; 1162 (3S,5R)-3-Aminomethyl-7-(2-fluoro-phenyl)-5-methyl-heptanoic acid; 1163 (3S,5S)-3-Aminomethyl-5-methyl-hept-6-enoic acid; 1164 (3S,5R)-3-Aminomethyl-5-methyl-oct-7-enoic acid; 1165 (3S,5R)-3-Aminomethyl-5-methyl-non-8-enoic acid; 1166 (E)-(3S,5S)-3-Aminomethyl-5-methyl-oct-6-enoic acid; 1167 (Z)-(3S,5S)-3-Aminomethyl-5-methyl-oct-6-enoic acid; 1168 (Z)-(3S,5S)-3-Aminomethyl-5-methyl-non-6-enoic acid; 1169 (E)-(3S,5S)-3-Aminomethyl-5-methyl-non-6-enoic acid; 1170 (E)-(3S,5R)-3-Aminomethyl-5-methyl-non-7-enoic acid; 1171 (Z)-(3S,5R)-3-Aminomethyl-5-methyl-non-7-enoic acid; 1172 (Z)-(3S,5R)-3-Aminomethyl-5-methyl-dec-7-enoic acid; and 1173 (E)-(3S,5R)-3-Aminomethyl-5-methyl-undec-7-enoic acid. 57

1174 A compound of structure 60 can be prepared from a compound of structure 59 through treatment with an appropriately substituted phenol (including phenol itself) under conditions described by Mitsunobu, Synthesis, 1981:1. 1175 A compound of structure 59 could be prepared from compound of structure 39 by treatment with sodium or lithium metal and alike in ammonia. Preferably, the reaction is carried out with sodium metal in ammonia. 1176 The direct hydrolysis of compound 60 would give rise to the desired amino acid or the approach via hydrolysis of the Boc protected lactam could be utilized. 1177 Compounds which could be prepared in this manner include: 1178 (3S)-3-Aminomethyl-5-methyl-7-phenoxy-heptanoic acid; 1179 (3S)-3-Aminomethyl-7-(4-chloro-phenoxy)-5-methyl-heptanoic acid; 1180 (3S)-3-Aminomethyl-7-(3-chloro-phenoxy)-5-methyl-heptanoic acid; 1181 (3S)-3-Aminomethyl-7-(2-chloro-phenoxy)-5-methyl-heptanoic acid; 1182 (3S)-3-Aminomethyl-7-(4-fluoro-phenoxy)-5-methyl-heptanoic acid; 1183 (3S)-3-Aminomethyl-7-(3-fluoro-phenoxy)-5-methyl-heptanoic acid; 1184 (3S)-3-Aminomethyl-7-(2-fluoro-phenoxy)-5-methyl-heptanoic acid; 1185 (3S)-3-Aminomethyl-7-(4-methoxy-phenoxy)-5-methyl-heptanoic acid; 1186 (3S)-3-Aminomethyl-7-(3-methoxy -phenoxy)-5-methyl-heptanoic acid; 1187 (3S,)-3-Aminomethyl-7-(2-methoxy -phenoxy)-5-methyl-heptanoic acid; 1188 (3S)-3-Aminomethyl-5-methyl-7-(4-trifluoromethyl-phenoxy)-heptanoic acid; 1189 (3S)-3-Aminomethyl-5-methyl-7-(3-trifluoromethyl-phenoxy)-heptanoic acid; 1190 (3S)-3-Aminomethyl-5-methyl-7-(2-trifluoromethyl-phenoxy)-heptanoic acid; 1191 (3S)-3-Aminomethyl-5-methyl-7-(4-nitro-phenoxy)-heptanoic acid; 1192 (3S)-3-Aminomethyl-5-methyl-7-(3-nitro-phenoxy)-heptanoic acid; 1193 (3S)-3-Aminomethyl-5-methyl-7-(2-nitro-phenoxy)-heptanoic acid; 1194 (3S)-3-Aminomethyl-6-(3-chloro-phenoxy)-5-methyl-hexanoic acid; 1195 (3S)-3-Aminomethyl-6-(2-chloro-phenoxy)-5-methyl-hexanoic acid; 1196 (3S)-3-Aminomethyl-6-(4-fluoro-phenoxy)-5-methyl-hexanoic acid; 1197 (3S)-3-Aminomethyl-6-(3-fluoro-phenoxy)-5-methyl-hexanoic acid; 1198 (3S)-3-Aminomethyl-6-(2-fluoro-phenoxy)-5-methyl-hexanoic acid; 1199 (3S)-3-Aminomethyl-6-(4-methoxy-phenoxy)-5-methyl-hexanoic acid; 1200 (3S)-3-Aminomethyl-6-(3-methoxy-phenoxy)-5-methyl-hexanoic acid; 1201 (3S)-3-Aminomethyl-6-(2-methoxy-phenoxy)-5-methyl-hexanoic acid; 1202 (3S)-3-Aminomethyl-5-methyl 6-(4-trifluoromethyl-phenoxy)-hexanoic acid; 1203 (3S)-3-Aminomethyl-5-methyl 6-(3-trifluoromethyl-phenoxy)-hexanoic acid; 1204 (3S)-3-Aminomethyl-5-methyl 6-(2-trifluoromethyl-phenoxy)-hexanoic acid; 1205 (3S)-3-Aminomethyl-5-methyl 6-(4-nitro-phenoxy)-hexanoic acid; 1206 (3S)-3-Aminomethyl-5-methyl 6-(3-nitro-phenoxy)-hexanoic acid; 1207 (3S)-3-Aminomethyl-5-methyl 6-(2-nitro-phenoxy)-hexanoic acid; 1208 (3S)-3-Aminomethyl-5-methyl-6-phenoxy-hexanoic acid; and 1209 (3S)-3-Aminomethyl-6-(4-chloro-phenoxy)-5-methyl-hexanoic acid. 58

1210 A compound of structure 64 could be prepared from compound of structure 63 by treatment of 63 with hydrogen at 50 psi in the presence of a catalyst such as such as Raney nickel in the presence of a base such as triethyl amine in an organic solvent for example methanol. The resulting product is then treated with an aqueous acid such as 6N HCl at a temperature between room temperature and reflux. The resulting mixture could be subjected to ion exchange chromatography to isolate the product 64. 1211 A compound of structure 63 can be prepared from a compound of structure 62B by treatment with an appropriate base, such as but not limited too sodium hydride, n-butyl lithium and alike, and an alkylating reagent such as t-butylbromoacetate or benzylbromoacetate in a solvent such as DMSO or THF an alike. Preferably, the reaction is carried out by treating a solution of a compound of structure 62B in THF with sodium hydride and alkylation of the resultant anion with t-butylbromoacetate. 1212 A compound of structure 62B can be prepared from a compound of structure 62A by treatment with sodium chloride in a solvent such as aqueous DMSO at a temperature between 50 C. and reflux. 1213 A compound of structure 62A can be prepared from a compound of structure 61 by treatment with an appropriate alkylmetalhalide such as an alkyl lithium reagent or an organomagnesium halide in a solvent such as THF or ether in the presence of a copper salt, such as but not limited to copper iodide, copper bromide dimethylsulphide. Alternatively, the reaction may be carried out by the treatment of the nitrile in a solvent such as ether at, or below, room temperature with an alkylmagnesium chloride. 1214 A compound such as 61 can be prepared according to known literature procedures between the condensation of isobutylaldheyde and methylcyanoacetate. 59

1215 Doubly branched 3-substituted GABA analogs 72 can be prepared in two steps from the azide 71 through hydrogenation of the azide 71 in the presence of a noble metal catalyst such as 5% palladium on carbon and hydrolysis of the resulting lactam with a strong acid such as 6 N HCl at reflux. The final product 72 can then be isolated using ion exchange chromatography. 1216 Compound 71 can be prepared in two steps by treatment of a lactone such as 70 with HBr in a solvent such as ethanol at a temperature such as 0 C. and reacting the resulting bromide with sodium azide in a solvent such as dimethyl sulfoxide at a temperature between 10 C. and 80 C. 1217 Lactone 70 can be prepared in two steps by oxidation of a compound such as 69 with an oxidant such as sodium periodate in the presence of a catalytic amount of ruthenium trichloride in a solvent such as acetonitrile at a temperature between 0 C. and 100 C. and treatment of the resulting compound with potassium carbonate in methanol followed at a temperature between 25 C. and 70 C. and then treatment with an acid such as p-toluene sulfonic acid in a solvent such as THF at reflux or an aqueous acid such as HCl in water at ambient temperature. 1218 A compound such as 69 can be prepared by a by reduction of a compound such as 68 with a hydride reducing agent such as lithium aluminum hydride in a solvent such as ether or THF and reaction of the resulting alcohol with an acylating agent such as acetic anhydride in the presence of a base such as triethyl amine or pyridine or the like. 1219 Compounds of structure 68 can be prepared by reaction of a compound such as 67 with hydrogen at approximately 50 psi in the presence of a noble metal catalyst such as 5% palladium on carbon in a solvent such as ethanol. A compound of the formula 67 can be prepared by reaction of a compound of structure 66 with a solution of ethanol saturated with hydrogen bromide gas. A compound such as 66 can be prepared from a compound such as 65 by treatment of a compound such as one with a strong base such as lithium diisopropyl amine in a solvent such as THF at a temperature such as 78 C. and reaction of the resulting anion with a compound such as benzyl bromide or benzyl iodide. Compounds of the structure 66 (RH or lower alkyl) can be prepared in optical form from methods known in the literature (Davies, J. Org. Chem., 1999;64(23):8501-8508; Koch J. Org. Chem., 1993;58(10):2725-37; Afonso, Tetrahedron, 1993;49(20):4283-92; Bertus, Tetrahedron, Asymmetry 1999;10(7):1369-1380; Yamamoto, J. Am. Chem. Soc., 1992; 114(20):7652-60).

Specific Examples

EXAMPLE 11 1220 Synthesis of 3-Aminomethyl-5-methyl-octanoic acid 60

1221 1-Benzyl-4-hydroxymethyl-pyrrolidine-2-one 74 1222 Sodium borohydride (8.0 g, 0.211 mol) was added to a solution of methyl-1-benzyl-5-oxo-3-pyrrolidnecarboxylate 73 (See Zoretic et al J. Org. Chem., 1980;45:810-814 for general method of synthesis) (32.0 g, 0.137 mol) in 1,2-dimethoxyethane (600 mL) and refluxed for 19 hours. The reaction was cooled to room temperature and 200 mL of water was added. The reaction was quenched with 1 M citric acid and concentrated under reduced pressure. The residue was extracted with dichloromethane, dried over magnesium sulfate, and evaporated to dryness to give 17.47 g, 62% of the alcohol 74 as clear oil. 1223 1H NMR (CDCl3) 7.30 (m, 5H), 4.38 (d, 1H, J14.7), 4.46 (d, 1H, J14.7), 3.56 (m, 2H), 3.36 (m, 1H), 3.10 (m, 1H), 2.52 (m, 2H), 2.26 (m, 1H). MS, m/z (relative intensity): 207 M2H, 66%. IR (KBr) 3345, 2946, 2866, 1651, 1445, 1025, 737, and 698 cm1. 1224 1-Benzyl-4-iodomethyl-pyrrolidin-2-one 75 1225 To alcohol lactam 74 (11.18 g, 0.056 mol) in 210 mL toluene was added in turn, triphenylphosphine (20.0 g, 0.076 mol), imidazole (10.8 g, 0.159 mol), and iodine (19.0 g, 0.075 mol). After stirring the suspension for 1.5 hours, the supernatant was poured into another flask. The sticky yellow residue was washed twice with ether and the solutions were combined. The solvent was evaporated and the residue was chromatographed on silica, eluting with 1:1 acetone/hexane to give 7.92 g, 46% of the iodolactam 75 as yellow oil. 1H NMR (CDCl3) 7.25 (m, 5H), 4.38 (d, 1H, J14.6), 4.46 (d, 1H, J14.6), 3.38 (dd, 1H, J7.8 and 2.2), 3.20 (dd, 1H, J5.6 and 4.4), 3.12 (dd, 1H, J7.3 and 2.4), 2.96 (dd, 1H, J5.8 and 4.4), 2.60 (m, 2H), 2.22 (dd, 1H, J10.5 and 9.7). MS, m/z (relative intensity): 224 MHBn, 94%, 317 M2H, 64%. IR 3027, 2917, 1688, 1438, 1267, and 701 cm1. 1226 1-Benzyl-4-(2-methyl-pentyl)-pyrrolidin-2-one 76 1227 To a suspension of magnesium turnings (0.50 g, 0.021 mol) in 15 mL of dry THF under nitrogen, was added an iodine crystal and 2-bromopentane (2.88 g, 0.019 mol). After an exothermic reaction which was periodically cooled in an ice bath, the reaction was stirred at room temperature for 2 hours. Eight milliliters of Li2CuCl4 (made from 84 mg LiCl and 134 mg CuCl2 in 10 mL of dry THF) was added at 0 C. followed by dropwise addition of 1-Benzyl-4-iodomethyl-pyrolidine-2-one 75 in 15 mL dry THF, and the resulting suspension was let stir at 0 C. for 3 hours. Stirring was continued at room temperature for 1 hour before quenching with a saturated solution of ammonium chloride. Water was added to dissolve the precipitate formed, and the solution was then extracted with ether and dried over magnesium sulfate. The solvent was evaporated under vacuum and the residue chromatographed on silica eluting with 1:1 acetone/hexane to give 1.13 g, 69% of the 1-benzyl-4-(2-methyl-pentyl)-pyrrolidin-2-one 76. 1H NMR (CDCl3) 7.30 (m, 5H), 4.44 (m, 2H), 3.32 (m, 1H), 2.86 (m, 1H), 2.56 (m, 1H), 2.40 (m, 1H), 2.10 (m, 1H), 1.30 (m, 6H), 1.10 (m, 1H), 0.90 (m, 6H). MS, m/z (relative intensity): 261 M2H, 100%, 301 MHCH3CN, 82%, 260 MH, 72%. 1228 4-(2-Methyl-pentyl)-pyrrolidin-2-one 77 1229 A 250 mL 3-neck flask equipped with a dry ice condenser was chilled to 78 C. Ammonia (80 mL) was condensed into the flask and 1-benzyl-4-(2-methyl-pentyl)-pyrrolidin-2-one 76 (1.67 g, 0.006 mol) in 15 mL THF was added. Freshly cut sodium beads were added until a deep blue color persisted. The cooling bath was removed and the reaction stirred at reflux (33 C.) for 1 hour. The reaction was quenched with ammonium chloride and the excess ammonia was allowed to evaporate. The resulting residue was diluted with water, extracted with dichloromethane, and dried over magnesium sulfate. Evaporation of the solvent followed by chromatography on silica eluting with 1:1 acetone/hexane gave 0.94 g, 86% of the 4-(2-Methyl-pentyl)-pyrrolidin-2-one 77. 1H NMR (CDCl3) 6.25 (br, 1H), 3.44 (m, 1H), 2.95 (m, 1H), 2.54 (m, 1H), 2.40 (m, 1H), 1.98 (m, 1H), 1.30 (m, 6H), 0.80 (m, 6H). MS, m/z (relative intensity): 212 M2HCH3CN, 100%, 171 M2H, 72%, 170 M1H, 65%. 1230 3-Aminomethyl-5-methyl-octanoic acid (Example 11) 1231 The 4-(2-methyl-pentyl)-pyrrolidin-2-one 77 (0.94 g, 0.007 mol) was dissolved in 70 mL of 6N HCl and refluxed for 20 hours. The solution was evaporated under vacuum and an aqueous solution of the residue was applied to Dowex 50WX 8-100 (strongly acidic) ion exchange resin that had been washed with HPLC grade water. The column was eluted, first with water until the eluent was at constant pH, and then with 5% ammonium hydroxide solution. The ammonium hydroxide fractions were evaporated and azeotroped with toluene. The white solid was washed with acetone filtered and dried in a vacuum oven for 24 hours to give the amino acid 0.61 g, 59%. 1H NMR (CD3OD) 3.00 (m, 1H), 2.85 (m, 1H), 2.48 (m, 1H), 2.30 (m, 1H), 2.14 (brm, 1H), 1.60 (brm, 1H), 1.38 (m, 4H), 1.18 (m, 2H), 0.60 (m, 6H). MS, m/z (relative intensity): 188 MH, 100%.

EXAMPLE 12 1232 Synthesis f3-Aminomethyl-5,7-dimethyl-octanoic acid 61

1233 1-(4-Methoxy-benzyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester 79 1234 To 4-metoxybenzylamine (42 g, 0.306 mol) in methanol (40 mL) at 0 C. was added the dimethyl itaconate (48 g, 0.306 mol) in methanol (13 mL). The solution was stirred at room temperature for 4 days. 1N HCl was added to the solution followed by ether. The two layers were separated and the aqueous phase extracted with ether. The combined organic phases were dried (MgSO4). Upon filtration of the drying agent the desired material 79 precipitated from solution that was collected and dried under vacuum. 23.26 g, 29%. MS, m/z (relative intensity): 264 MH, 100%. Anal. Calcd for C14H17N1O4: C, 63.87; H, 6.51; N, 5.32. Found: C, 63.96; H, 6.55; N, 5.29. 1235 4-Hydroxymethyl-1-(4-methoxy-benzyl)-pyrrolidine-2-one 80 1236 NaBH4 (15 g, 0.081 mol) was added in portions to ester 79 in ethanol (600 mL) at room temperature. After 4.5 hours water (200 mL) was carefully added to the reaction and the solution stirred at room temperature overnight. The resultant solid was removed by filtration and the filtrate concentrated to give alcohol 80 as an oil. 15.33 g, 81%. MS, m/z (relative intensity): 235 MH, 100%. 1237 4-Iodomethyl-1-(4-methoxy-benzyl)-pyrrolidin-2-one 81 1238 To alcohol 80 (12.9 g, 0.055 mol) in PhMe was added triphenylphosphine (20 g, 0.077 mol), imidazole (10.8 g, 0.16 mol), and iodine (19 g, 0.075 mol). The suspension was stirred at room temperature 5 hours. A saturated aqueous solution of sodium thiosulphate was added and the two layers separated. The aqueous phase was extracted with ether and the combined organic phases washed with brine, dried (MgSO4) and concentrated. Flash chromatography (6:1 to 4:1 toluene/acetone) of the residue gave iodide 81 as an oil. 11.9 g, 63%. MS, m/z (relative intensity): 346 MH, 100%. 1239 4-(2,4-Dimethyl-pentyl)-1-(4-methoxy-benzyl)-pyrrolidin-2-one 82 1240 A procedure similar to the preparation of 1-benzyl-4-(2-methyl-pentyl)-pyrrolidin-2-one 76 was utilized to give 4-(2,4-dimethyl-pentyl)-1-(4-methoxy-benzyl)-pyrrolidin-2-one as an oil. 1.22 g, 29%. MS, m/z (relative intensity): 304 MH, 100%. 1241 4-(2,4-Dimethyl-pentyl)-pyrrolidin-2-one 83 1242 To the lactam (1.17 g, 3.86 mmol) in MeCN (20 mL) at 0 C. was added ceric ammonium nitrate (4.2 g, 7.7 mmol) in H2O (10 mL). After 50 minutes a further portion of ceric ammonium nitrate (2.1 g, 3.86 mmol) was added, and after 1 hour the mixture was absorbed onto silica and flash chromatographed to give an oil. MS, m/z (relative intensity): 183 MH, 100%. 1243 3-Aminomethyl-5,7-dimethyl-octanoic acid (Example 12) 1244 A procedure similar to the preparation of 3-aminomethyl-5-methyl-octanoic acid (Example 3) was utilized to give the amino acid as a solid. MS, m/z (relative intensity): 202 MH, 100%.

EXAMPLE 13 1245 Synthesis of (S)-3-Aminomethyl-5-methyl-octanoic acid 62

1246 (S)-4-Hydroxymethyl-1-((S)-1-phenyl-ethyl)-pyrrolidin-2-one 84 1247 To the ester 33 (49 g, 0.198 mol) in EtOH (600 mL) was added sodium borohydride (22 g, 0.595 mol). After 7 hours, 1 M citric acid was carefully added and, after effervescence had ceased, water was added to fully quench the reaction. The ethanol was removed under reduced pressure and ethyl acetate added. The resultant two layers were separated, the aqueous phase was extracted with EtOAc, and the combined organic phases dried (MgSO4) and concentrated to give a heavy oil. MS, m/z (relative intensity): MH, 100%. 1248 (S)-4-Iodomethyl-1-((S)-1-phenyl-ethyl)-pyrrolidin-2-one 85 1249 A procedure similar to the iodination of compound 80 was utilized giving iodide 85 as an oil. 35.2 g, 56%. Anal. Calcd for C13H16I1N1O1: C, 47.43; H, 4.90; N, 4.25. Found: C, 47.41; H, 4.83; N, 4.17. 1250 4-(2-Methyl-pentyl)-1-((S)-1-phenyl-ethyl)-pyrrolidin-2-one 86 1251 A procedure similar to the preparation of 1-benzyl-4-(2-methyl-pentyl)-pyrrolidin-2-one 76 was utilized to give 2.71 g, 81.0% of 86 as an oil. MS, m/z (relative intensity): 274 M1H, 100%, 315 MHCH3CN, 65%. 1252 (S)-4-(2-Methyl-pentyl)-pyrrolidin-2-one 87 1253 A procedure similar to the preparation of 4-(2-methyl-pentyl)-pyrrolidin-2-one 77 was used to give 1.14 g, 72.8% of 87 as an oil. MS, m/z (relative intensity): 170 M1H, 10%, 211 M1HCH3CN, 90%.

EXAMPLE 13 1254 (S)-3-Aminomethyl-5-methyl-octanoic acid 1255 A procedure similar to the preparation of 3-aminomethyl-5-methyl-octanoic acid (Example I1) was used to give the amino acid (example 5) 0.88 g, 74.3%. 1H NMR (CD3OD) 2.95 (m, 1H), 2.80 (m, 1H), 2.40 (m, 1H), 2.25 (m, 1H), 2.05 (brm, 1H), 1.50 (brm, 1H), 1.30 (m, 4H), 1.10 (m, 2H), 0.90 (m, 6H). MS, m/z (relative intensity): 188 M1H, 100%, 186 M1H, 100%, 229 M1HCH3CN, 30%.

EXAMPLE 14 1256 Synthesis of (S)-3-Aminomethyl-7-methoxy-5-methyl-heptanoic acid 63

1257 (S)-4-(2-Methyl-pent-4-enyl)-1-((S)-1-phenyl-ethyl)-pyrrolidin-2-one 88 1258 A procedure similar to the preparation of 1-benzyl-4-(2-methyl-pentyl)-pyrrolidin-2-one 76 was followed giving the adduct 88 as an oil. 6 g, 74%. MS, m/z (relative intensity): 272 MH, 100%. 1259 (S)-4-(4-Hydroxy-2-methyl-butyl)-1-((S)-1-phenyl-ethyl)-pyrrolidin-2-one 89 1260 OsO4 (2 mL of a 4% wt solution in t-BuOH) was added to the alkene 88 (5.8 g, 0.021 mol) in THF/H2O (3:1, 100 mL). After 1 hour, sodium periodate (11.4 g, 0.053 mol) was added. After 2 hours, the suspension was filtered and the solids washed with dichloromethane. The filtrate was concentrated and the residue azeotroped with toluene. The residue was dissolved in ethanol and sodium borohydride (2.5 g) added. The suspension was stirred at room temperature overnight. 1N citric acid was added and the mixture diluted with ether. The resultant two layers were separated and the aqueous phase was extracted with ether and the combined organic dried (MgSO4) and concentrated. Flash chromatography (1:1 hexane/EtOAc) of the residue gave an oil. 4.2 g, 73%. MS, m/z (relative intensity): 276 MH, 100%. 1261 (S)-4-(4-Methoxy-2-methyl-butyl)-1-((S)-1-phenyl-ethyl)-pyrrolidin-2-one 90 1262 To alcohol 89 (2 g, 7.66 mmol) in DMSO (60 mL) at room temperature was added NaH (368 mg, 60% in oil). After 30 minutes the methyl iodide (1.08 g, 7.66 mmol) was added and the solution stirred at room temperature overnight, upon which the reaction was diluted with water (500 mL). The solution was extracted with ether, and the combined organic extracts were dried (MgSO4) and concentrated. Flash chromatography (90% to 50% hexane/acetone) of the residue gave the product 90 as an oil (1.1 g, 52%). MS m/z 290 (MH, 100%). 1263 (S)-4-(4-Methoxy-2-methyl-butyl)-pyrrolidin-2-one 91 1264 A procedure similar to the synthesis of 4-(2-methyl-pentyl)-pyrrolidin-2-one 77 was utilized giving lactam 91 as an oil. MS m/z 186 (MH, 100%).

EXAMPLE 14 1265 (S)-3-Aminomethyl-7-methoxy-5-methyl-heptanoic acid 1266 A procedure similar to the synthesis of example 3 was followed. The resultant amino acid isolated from ion-exchange chromatography was recrystallized from methanol/ethyl acetate to give the example 6 as a white solid. MS m/z 204 (MH, 100%). Anal. Calcd for C10H21N1O3: C, 59.09; H, 10.41; N, 6.89. Found: C, 58.71; H, 10.21; N, 6.67.

EXAMPLE 15 1267 Synthesis of (S)-3-Aminomethyl-6-fluoro-5-methyl-hexanoic acid 64

1268 2-Methyl-2-(S)-5-oxo-1-((S)-1-phenyl-ethyl)-pyrrolidin-3-ylmethyl-malonic acid dimethyl ester 92 1269 To dimethyl methylmalonate (1.06 g, 7.29 mmol) in DMSO (7 mL) at room temperature was added NaH (291 mg of a 60% dispersion in oil). After the effervescence had ceased the lactam 85 (2 g, 7.29 mol) in DMSO (5 mL) was added. After 1 hour water was added and the aqueous solution extracted with ether. The combined organic extracts were dried (MgSO4) and concentrated. Flash chromatography (1:1 hexane/acetone) of the residue gave the product as an oil (1.7 g, 81%). MS m/z 348 (MH, 100%). 1270 2-Methyl-3-(S)-5-oxo-1-((S)-1-phenyl-ethyl)-pyrrolidin-3-yl-propionic acid methyl ester 93 1271 The ester 92 (483 mg, 1.4 mmol), NaCl (104 mg, 1.8 mmol), water (105 L) and DMSO (5 mL) were heated to reflux for 2 hours. The solution was cooled to room temperature water was added and the aqueous solution extracted with ether. The combined organic extracts were dried (MgSO4) and concentrated. Flash chromatography (80% to 66% hexane/acetone) of the residue gave the product as an oil (160 mg, 40%). MS m/z 290 (MH, 100%). 1272 (S)-4-(3-Hydroxy-2-methyl-propyl)-1-((S)-1-phenyl-ethyl)-pyrrolidin-2-one 37 1273 To the ester 93 (4.82 g, 0.017 mol) in EtOH (100 mL) was added NaBH4 (3.7 g, 0.10 mol) and the mixture heated to reflux for 2.5 hours. The solution was cooled to 0 C. and 1 M citric acid carefully added followed by water. The solution was concentrated to half volume added and extracted with ether. The combined organic extracts were dried (MgSO4) and concentrated. Flash chromatography (1:1 hexane/acetone) of the residue gave the product as an oil (2.6 g, 59%). MS m/z 262 (MH, 100%). 1274 (S)-4-(3-Fluoro-2-methyl-propyl)-1-((S)-1-phenyl-ethyl)-pyrrolidin-2-one 94 1275 To DAST (1 g, 6.2 mmol) in CH2Cl2 (20 mL) at 78 C. was added the alcohol 37 in CH2Cl2 (10 mL). After 1 hour at 78 C. the solution was warmed to room temperature. After 7 hours the solution was carefully quenched with a saturated aqueous solution of sodium bicarbonate and the two layers separated. The organic phase was dried (MgSO4) and concentrated. Flash chromatography (90% to 66% hexane/acetone) of the residue gave the product as an oil (600 mg, 37%). MS m/z 264 (MH, 100%). 1276 (S)-4-(3-Fluoro-2-methyl-propyl)-pyrrolidin-2-one 95 1277 A procedure similar to the preparation of 4-(2-methyl-pentyl)-pyrrolidin-2-one 77 was utilized affording the lactam as an oil (242 mg, 68%). MS m/z 159 (M, 100%).

EXAMPLE 15 1278 (S)-3-Aminomethyl-6-fluoro-5-methyl-hexanoic acid 1279 A procedure similar to the synthesis of example 11 was followed. The resultant amino acid isolated from ion-exchange chromatography was recrystallized from methanol/ethyl acetate to give example 15 as a white solid. MS m/z 177 (M, 100%). Anal. Calcd for C8H16F1N1O2:0.02 H2O: C, 54.11; H, 9.10; N, 7.89. Found: C, 53.75; H, 9.24; N, 7.72.

EXAMPLE 16 1280 Synthesis of (S)-3-Aminomethyl-6-methoxy-5-methyl-hexanoic acid 65

1281 (S)-4-(3-Methoxy-2-methyl-propyl)-1-((S)-1-phenyl-ethyl)-pyrrolidin-2-one 96 1282 A procedure similar to the synthesis of (S)-4-(4-methoxy-2-methyl-butyl)-1-((S)-1-phenyl-ethyl)-pyrrolidin-2-one 90 was utilized giving ether 96 as an oil (90 mg, 37%). MS m/z 276 (MH, 100%). 1283 (S)-4-(3-Methoxy-2-methyl-propyl)-pyrrolidin-2-one 97 1284 A procedure similar to the synthesis of 4-(2-methyl-pentyl)-pyrrolidin-2-one 77 was utilized giving 97 as an oil (760 mg, 93%). MS m/z 171 (MH, 100%).

EXAMPLE 16 1285 (S)-3-Aminomethyl-6-methoxy-5-methyl-hexanoic acid 1286 A procedure similar to the synthesis of example 11 was followed. The resultant amino acid isolated from ion-exchange chromatography was recrystallized from methanol/ethyl acetate to give Example 16 as a white solid. MS m/z 190 (MH, 100%). Anal. Calcd for C9H19N1O3: C, 57.12; H, 10.12; N, 7.40. Found: C, 57.04; H, 10.37; N, 7.30. A second batch precipitated from the mother liquors (1:5 ratio of C5 isomers by 1H NMR). MS m/z 190 (MH, 100%).

EXAMPLE 17 1287 Synthesis of (3S,5R)-3-Aminomethyl-5-methyl-octanoic acid hydrochloride 66

1288 (R)-2,6-Dimethyl-non-2-ene 98 1289 To (S)-citronellyl bromide (50 g, 0.228 mol) in THF (800 mL) at 0 C. was added LiCl (4.3 g) followed by CuCl2 (6.8 g). After 30 minutes methylmagnesium chloride (152 mL of a 3 M solution in THF, Aldrich) was added and the solution warmed to room temperature. After 10 hours the solution was cooled to 0 C. and a saturated aqueous solution of ammonium chloride carefully added. The resultant two layers were separated and the aqueous phase extracted with ether. The combined organic phases were dried (MgSO4) and concentrated to give an oil. 32.6 g; 93%. Used without further purification. 13C. NMR (100 MHz; CDCl3) 131.13, 125.28, 39.50, 37.35, 32.35, 25.92, 25.77, 20.31, 19.74, 17.81, 14.60. 1290 (R)-4-Methyl-heptanoic acid 99 1291 To alkene 98 (20 g, 0.13 mol) in acetone (433 mL) was added a solution of CrO3 (39 g, 0.39 mol) in H2SO4 (33 mL)/H2O (146 mL) over 50 minutes. After 6 hours a further amount of CrO3 (26 g, 0.26 mol) in H2SO4 (22 mL)/H2O (100 mL) was added. After 12 hours the solution was diluted with brine and the solution extracted with ether. The combined organic phases were dried (MgSO4) and concentrated. Flash chromatography (gradient of 6:1 to 2:1 hexane/EtOAc) gave the product 99 as an oil. 12.1 g; 65%. MS, m/z (relative intensity): 143 MH, 100%. 1292 (4R,5S)-4-Methyl-3-((R)-4-methyl-heptanoyl)-5-phenyl-oxazolidin-2-one 100 1293 To the acid 99 (19 g, 0.132 mol) and triethylamine (49.9 g, 0.494 mol) in THF (500 mL) at 0 C. was added trimethylacetylchloride (20 g, 0.17 mol). After 1 hour LiCl (7.1 g, 0.17 mol) was added followed by the oxazolidinone (30 g, 0.17 mol). The mixture was warmed to room temperature and after 16 hours the filtrate was removed by filtration and the solution concentrated under reduced pressure. Flash chromatography (7:1 hexane/EtOAc) gave the product 100 as an oil. 31.5 g; 79%. D5.5 (c 1 in CHCl3). MS, m/z (relative intensity): 304 MH, 100%. 1294 (3S,5R)-5-Methyl-3-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl)-octanoic acid tert-butyl ester 101 1295 To oxazolidinone 100 (12.1 g, 0.04 mol) in THF (200 mL) at 50 C. was added NaHMDS (48 mL of a 1 M solution in THF). After 30 t-butylbromoacetate (15.6 g, 0.08 mol) was added. The solution was stirred for 4 hours at 50 C. and then warmed to room temperature. After 16 hours a saturated aqueous solution of ammonium chloride was added and the two layers separated. The aqueous phase was extracted with ether and the combined organic phases dried (MgSO4) and concentrated. Flash chromatography (9:1 hexane/EtOAc) gave the product 101 as a white solid 12 g; 72%. D30.2 (c 1 in CHCl3). 13C NMR (100 MHz; CDCl3) 176.47, 171.24, 152.72, 133.63, 128.87, 125.86, 80.85, 78.88, 55.34, 39.98, 38.77, 38.15, 37.58, 30.60, 28.23, 20.38, 20.13, 14.50, 14.28. 1296 (S)-2-((R)-2-Methyl-pentyl)-succinic acid 4-tert-butyl ester 102 1297 To ester 101 (10.8 g, 0.025 mol) in H2O (73 mL) and THF (244 mL) at 0 C. was added a premixed solution of LiOH (51.2 mL of a 0.8 M solution) and H2O2 (14.6 mL of a 30% solution). After 4 hours a further 12.8 mL LiOH (0.8 M solution) and 3.65 mL of H2O2 (30% solution) was added. After 30 minutes sodium bisulfite (7 g), sodium sulfite (13 g), and water (60 mL) was added followed by hexane (100 mL) and ether (100 mL). The two layers were separated and the aqueous layer extracted with ether. The combined organic phases were concentrated to an oil that was dissolved in heptane (300 mL). The resultant solid was filtered off and the filtrate dried (MgSO4) and concentrated to afford an oil (6 g, 93%) which was used without further purification. MS, m/z (relative intensity): 257 MH, 100%. 1298 (3S,5R)-3-Hydroxymethyl-5-methyl-octanoic acid tert-butyl ester 103 1299 To acid 102 (3.68 g, 0.014 mol) in THF (100 mL) at 0 C. was added BH3.Me2 (36 mL of a 2 M solution in THF, Aldrich) upon which the solution was warmed to room temperature. After 15 hours ice was carefully added (in order to control the effervescence) to the solution followed by brine. The solution was extracted with ether and the combined organic phases dried (MgSO4) and concentrated under reduced pressure. Flash chromatography (4:1 hexane/EtOAc) gave alcohol 103 as an oil (2.0 g, 59%). 13C NMR (100 MHz; CDCl3) 173.56, 80.85, 65.91, 39.74, 39.20, 38.90, 35.65, 29.99, 28.31, 20.18, 19.99, 14.56. 1300 (3S,5R)-5-Methyl-3-(t luene-4-sulfonyloxymethyl)-octanoic acid tert-butyl ester 104 1301 To alcohol 103 (1.98 g, 8.1 mmol) in CH2Cl2 (40 mL) at room temperature was added triethylamine (2.4 g, 0.024 mol), DMAP (20 mg) and tosyl chloride (2.3 g, 0.012 mol). After 14 hours 1N HCl was added and the two layers separated. The aqueous phase was extracted with ether and the combined organic phases dried (MgSO4) and concentrated. Flash chromatography (95% hexane/EtOAc) gave tosylate 104 as an oil (2.94 g, 91%). 13C NMR (100 MHz; CDCl3) 171.60, 144.92, 133.07, 130.02, 128.12, 80.80, 72.15, 39.73, 38.09, 37.89, 32.67, 29.71, 28.22, 21.83, 20.10, 19.54, 14.49. 1302 (3S,5R)-3-Azidomethyl-5-methyl-octanoic acid tert-butyl ester 105 1303 Tosylate 104 (2.92 g, 7.3 mmol) and sodium azide (1.43 g, 0.02 mol) were warmed to 50 C. in DMSO (30 mL). After 2 hours the solution was cooled to room temperature and diluted with water. The solution was extracted with ether and the combined organic phases dried (MgSO4) and concentrated to give an oil 1.54 g, 79%. Further purification by flash chromatography (95% hexane/EtOAc) gave an oil. D8.3 (c 1 in CHCl3). 13C NMR (100 MHz; CDCl3) 172.01, 80.73, 54.89, 39.73, 39.46, 39.00, 33.40, 29.85, 28.30, 20.15, 19.82, 14.52. 1304 (S)-4-((R)-2-Methyl-pentyl)-pyrrolidin-2-one 107 and (3S,5R)-3-aminomethyl-5-methyl-octanoic acid tert-butyl ester 106 1305 Azide 105 was treated with 5% Pd/C and shaken under an atmosphere of hydrogen for 20 hours where upon a further 200 mg of 5% Pd/C added. After 6 hours the filtrate was concentrated to afford an oil which by 1H NMR was found to be a mixture of primary amine 106 and lactam 107 (1.75 g) which was used without further purification.

EXAMPLE 17 1306 (3S,5R)-3-Aminomethyl-5-methyl-octanoic acid hydrochloride 1307 The mixture of the amine 106 and the lactam 107 (1.74 g) was treated with 3N HCl (40 mL) and the solution warmed to 50 C. for 4 hours then cooled to room temperature. After 12 hours the solution was concentrated and the residue recrystallized from ethyl acetate to give the amino acid as a white solid 605 mg. MS, m/z (relative intensity): 188 MH, 100%. Anal. Calcd for C10H21N1O2:H1Cl1 C, 53.68; H, 9.91; N, 6.26. Found: C, 53.83; H, 10.12; N, 6.07.

EXAMPLE 18 1308 Synthesis of (3S,5R)-3-Aminomethyl-5-methyl-heptanoic acid 67

1309 Methanesulfonic acid (S)-3,7-dimethyl-oct-6-enyl ester 108 1310 To S-()-citronellol (42.8 g, 0.274 mol) and triethylamine (91 mL, 0.657 mol) in CH2Cl2 (800 mL) at 0 C. was added methanesulphonyl chloride (26 mL, 0.329 mol) in CH2Cl2 (200 mL). After 2 hours at 0 C. the solution was washed with 1N HCl then brine. The organic phase was dried (MgSO4) and concentrated to afford an oil (60.5 g, 94%) which was used without further purification. 1H NMR (400 MHz; CDCl3) 5.05 (1H, m), 4.2 (2H, m), 2.95 (3H, s), 1.98 (2H, m), 1.75 (1H, m), 1.6 (3H,s), 1.5 (4H, m), 1.35 (2H, m), 1.2 (1H, m), 0.91 (3H, d, J6.5 Hz). 1311 (R)-2,6-Dimethyl-oct-2-ene 109 1312 To alkene 108 (60 g, 0.256 mol) in THF (1 L) at 0 C. was added lithium aluminum hydride (3.8 g, 0.128 mol). After 7 hours, a further 3.8 g of lithium aluminum hydride was added and the solution warmed to room temperature. After 18 hours, a further 3.8 g of lithium aluminum hydride was added. After a further 21 hours, the reaction was carefully quenched with 1N citric acid and the solution diluted further with brine. The resultant two phases were separated and the organic phase was dried (MgSO4) and concentrated to afford an oil which was used without further purification. MS, m/z (relative intensity): 139 MH, 100%. 1313 (R)-4-Methyl-hexanoic acid 110 1314 A procedure similar to the synthesis of (R)-4-methyl-heptanoic acid 99 was utilized giving the acid as an oil (9.3 g, 56%). MS, m/z (relative intensity): 129 MH, 100%. 1315 (4R,5S)-4-Methyl-3-((R)-4-methyl-hexanoyl)-5-phenyl-oxazolidin-2-one 111 1316 A procedure similar to the synthesis of (4R,5S)-4-methyl-3-((R)-4-methylheptanoyl)-5-phenyl-oxazolidin-2-one 100 was utilized giving oxazolidinone 111 as an oil (35.7 g, 95%). MS, m/z (relative intensity): 290 MH, 100%. 1317 (3S,5R)-5-Methyl-3-1-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-yl)-methanoyl-heptanoic acid tert-butyl ester 112 1318 A procedure similar to the preparation of (3S,5R)-5-methyl-3-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl)-octanoic acid tert-butyl ester 101 was followed giving 112 as an oil (7.48 g; 31%). 1319 (S)-2-((R)-2-Methyl-butyl)-succinic acid 4-tert-butyl ester 113 1320 To ester 112 (7.26 g, 0.018 mol) in H2O (53 mL) and THF (176 mL) at 0 C. was added a premixed solution of LiOH (37 mL of a 0.8 M solution) and H2O2 (10.57 mL of a 30% solution) and the solution warmed to room temperature. After 2 hours sodium bisulfite (7 g), sodium sulfite (13 g), and water (60 mL) was added and the two layers were separated and the aqueous layer extracted with ether. The combined organic phases were concentrated to an oil that was dissolved in heptane (200 mL). The resultant solid was filtered off and the filtrate dried (MgSO4) and concentrated to afford an oil (4.4 g) that was used without further purification. 1321 (3S,5R)-3-Hydroxymethyl-5-methyl-heptanoic acid tert-butyl ester 114 1322 A procedure similar to the preparation of (3S,5R)-3-hydroxymethyl-5-methyl-octanoic acid tert-butyl ester 103 was utilized giving alcohol 114 as an oil (2.68 g, 69%). MS, m/z (relative intensity): 216 89%, 174 M(CH3)3C, 100%. 1323 (3S,5R)-5-Methyl-3-(toluene-4-sulfonyloxymethyl)-heptanoic acid tert-butyl ester 115 1324 To 114 alcohol (2.53 g, 0.011 mmol) in CH2Cl2 (140 mL) at 0 C. was added pyridine (2.6 g, 0.033 mol), DMAP (100 mg), and tosyl chloride (3.15 g, 0.016 mol) and the solution warmed to room temperature for 3.5 hours whereupon more DMAP and TsCl (3.15 g) were added. After 14 hours 1N HCl was added and the two layers separated. The organic phase was washed with brine then or dried (MgSO4) and concentrated. Flash chromatography (95% to 86%hexane/EtOAc) gave tosylate 115 as an oil (1.53 g, 36%). 13C NMR (100 MHz; CDCl3) 130.03, 128.12, 72.18, 37.89, 37.71, 32.67, 31.49, 29.88, 28.22, 21.83, 19.07, 11.37. 1325 (3S,5R)-3-Azidomethyl-5-methyl-heptanoic acid tert-butyl ester 116 1326 A procedure similar to the preparation of (3S,5R)-3-azidomethyl-5-methyl-octanoic acid tert-butyl ester 105 was utilized giving an oil 0.956 g, 97%. MS, ml/z (relative intensity): 228 MN2, 80%. 1327 (S)-4-((R)-2-Methyl-butyl)-pyrrolidin-2-one 118 and (3S,5R)-3-Aminomethyl-5-methyl-heptanoic acid tert-butyl ester 117 1328 Azide 116 (689 mg) was treated with 20% Pd/C (90 mg) in THF (20 mL) and shaken under an atmosphere of hydrogen for 36 hours. The catalyst was removed by filtration and the resultant oil used without further purification.

EXAMPLE 18 1329 (3S,5R)-3-Aminomethyl-5-methyl-heptanoic acid 1330 The mixture of amine 117 and lactam 118 was treated with 6N HCl and the solution warmed to 50 C. for 17 hours then cooled to room temperature and concentrated. The resultant oil was subjected to ion-exchange chromatography (Dowex, strongly acidic resin) using 5% ammonium hydroxide to give a cream solid which was recrystallized from methanol/ethyl acetate to give (3S, SR)-3-aminomethyl-5-methyl-heptanoic acid, example 10. MS, m/z (relative intensity): 174 MH, 100%. Anal. Calcd for C19H19N1O2. C, 62.39; H, 11.05; N, 8.08. Found: C, 62.23; H, 11.33; N, 7.89.

EXAMPLE 19 1331 Synthesis of (3S,5S)-3-Aminomethyl-5-methyl-octanoic acid 68

1332 (S)-2,6-Dimethyl-non-2-ene 119 1333 CuCl2 (5.36 g, 39.7 mmol) and LiCl (3.36, 80.0 mmol) were stirred together in dry THF (40 mL) for 15 minutes. The resulting solution was added to methylmagnesium chloride, 3.0 M in THF (168 mL) at 0 C. under nitrogen atmosphere and stirred at that temperature for 15 minutes. To the reaction suspension was added slowly (R)-()-Citronellyl bromide (55.16 g, 251.8 mmol) in THF (100 mL), and stirred at 0 C. for 2.5 hours. It was warmed to room temperature and stirring was continued for an additional 1 hour. The mixture was cooled to 0 C. and quenched with saturated ammonium chloride solution. The suspension was then extracted into ether, washed with water, and dried over MgSO4 The solution was concentrated under reduced pressure to afford 36.3 g; 94% of (S)-2,6-Dimethyl-non-2-ene as an oil. MS, m/z (relative intensity): 153 M1H, 100%, 194 M1HCH3CN, 45%. 1334 (S)-4-Methyl-heptanoic acid 120 1335 To the (S)-2,6-Dimethyl-non-2-ene 119 (39.0 g, 253.2 mmol) in acetone (1L) at 0 C. was added Jones reagent (2.7 M, 600 mL) dropwise over 1.5 hours and let stir at room temperature for 18 hours. The reaction mixture was poured into a saturated solution of Na2SO4 and extracted into ether. It was washed with brine and concentrated in vacuo. The oily residue was dissolved in methanol (70 mL) and 1 M NaOH (700 mL) and then stirred for 30 minutes. The aqueous solution was washed with CH2Cl2, acidified with 10% HCl and extracted into CH2Cl2. The solution was dried over MgSO4 and concentrated to dryness to give 24.22 g; 66% of (S)-4-Methyl-heptanoic acid as an oil. MS, m/z (relative intensity): 143 M1H, 100%. 1336 (4R,5S)-4-Methyl-3-((S)-4-methyl-heptanoyl)-5-phenyl-oxazolidin-2-one 121 1337 A procedure similar to the preparation of (4R,5S)-4-methyl-3-((R)-4-methyl-heptanoyl)-5-phenyl-oxazolidin-2-one 100 was utilized giving (4R,5S)-4-methyl-3-((S)-4-methyl-heptanoyl)-5-phenyl-oxazolidin-2-one 121 6.2 g; 80.0%, as an oil. MS, m/z (relative intensity): 304 M1H, 90%, 355 M1HCH3CN, 60%. 1338 (3S,5S)-5-Methyl-3-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl)-octanoic acid tert-butyl ester 122 1339 n-BuLi, 1.6 M in Hexane (18.0 mL, 30.1 mmol) was added dropwise to a solution of diisopropylamine (4.6 mL, 32.6 mmol) in dry THF (50 mL) under nitrogen at 5 C. keeping the temperature below 0 C. during addition. The mixture was let stir at 5 C. for 20 minutes and then cooled to 78 C. 121 (7.6 g, 25.1 mmol) in dry THF (12 mL) was added to the LDA solution and stirred at 78 C. for 30 minutes. t-Butylbromo acetate (4.8 mL, 32.6 mmol) as added to the reaction and stirring at 78 C. was continued for 2 hours. It was let warm to room temperature before stirring for an additional 18 hours. The reaction was quenched with a saturated solution NaH2PO4, extracted into ethyl acetate, and dried over MgSO4. The solution was concentrated to give a solid residue which was dissolved in hot hexane. The hexane solution was allowed to cool to room temperature before cooling further in an ice bath. The resulting precipitate was collected and allowed to air dry to give 122 as a fluffy white solid. 4.3 g; 41%. MS, m/z (relative intensity): 362 MC(CH3)31H, 100%, 418 M1H, 20%. 1340 (S)-2-((S)-2-Methyl-pentyl)-succinic acid 4-tert-butyl ester and (3S,5S)-3-Hydroxymethyl-5-methyl-octanoic acid tert-butyl ester 123 1341 To the ester 122 in a mixture of THF (203.0 mL) and water (61.0 mL) at 0 C. was added a premixed solution of 30% H2O2 (12.2 mL) and LiOH (0.8 M, 42.7 mL). The resulting solution was stirred at 0 C. for 4 hours. To the reaction was added sodium bisulfite (7 g), sodium sulfite (13 g), and water (60 mL). A 1:1 mixture of ether/hexane (200 mL) was then added and the organic phase was separated. The aqueous phase was extracted with ether and the combined organic extract was dried over MgSO4 and concentrated in vacuo. The residue was dissolved in heptane and let stir for 5 minutes. The resulting precipitate was filtered and the filtrate was concentrated to dryness to give as an oil. 1342 (3S,5S)-3-Hydroxymethyl-5-methyl-octanoic acid tert-butyl ester 123 1343 A procedure similar to the preparation of (3S,5R)-3-hydroxymethyl-5-methyl-octanoic acid tert-butyl ester 103 was followed giving 123 as an oil. 4.0 g; 76.0%. MS, m/z (relative intensity): 230 MC(CH3)31HCH3CN, 100%, 189 MC(CH3)31H, 70%. 1344 (3S,5S)-5-Methyl-3-(toluene-4-sulfonyloxymethyl)-octanoic acid tert-butyl ester 124 1345 A procedure similar to the preparation of (3S,5R)-5-methyl-3-(toluene-4-sulfonyloxymethyl)-octanoic acid tert-butyl ester 104 was followed giving 6.9 g of 124. MS, m/z (relative intensity): 343 MC(CH3)31H, 70%, 384 MC(CH3)31HCH3CN, 100%. 1346 (3S,5S)-3-Azidomethyl-5-methyl-heptanoic acid tert-butyl ester 125 1347 A procedure similar to the preparation of (3S,5R)-3-azidomethyl-5-methyl-octanoic acid tert-butyl ester 105 was followed giving 2.9 g; 66% of 125 as an oil. MS, m/z (relative intensity): 212 MC(CH3)31H, 45%. 1348 (3S,5S)-3-Aminomethyl-5-methyl-octanoic acid tert-butyl ester 126 1349 A mixture of 125 (2.8 g, 10.4 mmol) and 10% Pd/C (1.0 g) in methanol (50.0 mL) was hydrogenated at 41 PSI for 96 hours. The solution was filtered to give 1.7 g of crude 126 which was used in the next step without further purification. MS, m/z (relative intensity): 244 M1H, 100%, 285 M1HCH3CN, 25%.

EXAMPLE 19 1350 (3S,5S)-3-Aminomethyl-5-methyl-octanoic acid 1351 A procedure similar to the preparation of example 18 (3S,5R)-3-aminomethyl-5-methyl-heptanoic acid was followed giving example 19. 380 mg; 29.0%. 1H NMR (CD3OD) 2.90 (dd, J3.9, 8.8 Hz, 1H), 2.80 (dd, J7.6, 5.1 Hz, 1H), 2.40 (dd, J3.2, 12.51 Hz, 1H), 2.20 (dd, J8.8, 6.8 Hz, 1H), 2.05 (m, 1H), 1.55 (m, 1H), 1.30 (m, 3H), 1.10 (m, 2H), 0.85 (m, 6H); MS, m/z (relative intensity): 187 M1H, 100%, 211 M1HCH3CN, 30%.

EXAMPLE 20 1352 Synthesis of (3S,5S)-3-Aminomethyl-5-methyl-heptanoic acid 69

1353 (S)-2,6-Dimethyl-oct-2-ene 127 1354 (R)-()-Citronellyl bromide (49.1 g, 224.2 mmol) was dropwise added to a solution of LAH 1.0 M in THF (336 mL, 336 mmol) at 0 C. over a 45-minute period. Stirring was continued for an additional 4 hours at 0 C. The reaction was slowly quenched with a saturated solution of ammonium chloride followed by the addition of ether (100 mL). The resulting white slurry was filtered and the filtrate was dried over MgSO4 The solution was concentrated under reduced pressure to 10 afford 26.2 g; 83% of 127 as an oil. MS, m/z (relative intensity): 180 M1HCH3CN, 100%, 139 M1H, 90%. 1355 (S)-4-Methyl-hexanoic acid 128 1356 A procedure similar to that used to prepare compound 120 was used giving 15.9 g of 128 as an oil. MS, m/z (relative intensity): 129 M1H, 100%, 170 M1HCH3CN, 70%. 1357 (4R,5S)-4-Methyl-3-((S)-4-methyl-hexanoyl)-5-phenyl-oxazolidin-2-one 129 1358 A procedure similar to that used to prepare (4R,5S)-4-Methyl-3-((S)-4-methyl-heptanoyl)-5-phenyl-oxazolidin-2-one 121 was used giving 35.0 g of crude (4R,5S)-4-methyl-3-((S)-4-methyl-hexanoyl)-5-phenyl-oxazolidin-2-one 129 as an oil. It was used in the next step without further purification. MS, m/z (relative intensity): 290 M1H, 100%, 331 M1HCH3CN, 20%. 1359 (3S,5S)-5-Methyl-3-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl)-heptanoic acid tert-butyl ester 130 1360 A procedure similar to that used to prepare (3S,5S)-5-methyl-3-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl)-octanoic acid tert-butyl ester 122 was used to give 4.6.0 g, 25.4% of 130 as a white solid. MS, m/z (relative intensity): 348 MC(CH3)31H, 100%, 443 M1HCH3CN, 100%, 402 M1H, 55%, 404 M1H, 45%. 1361 (3S,5S)-3-Hydroxymethyl-5-methyl-heptanoic acid tert-butyl ester 131 1362 A procedure similar to that used to prepare (3S,5S)-3-Hydroxymethyl-5-methyl-octanoic acid tert-butyl ester 123 was giving 1.2 g, 52.1% of 131 as an oil. MS, m/z (relative intensity): 175 MC(CH3)31H, 100%, 173 MC(CH3)31H, 100%, 216 MC(CH3)31HCH3CN, 95%. 1363 (3S,5S)-5-Methyl-3-(toluene-4-sulfonyloxymethyl)-heptanoic acid tert-butyl ester 132 1364 A procedure similar to the preparation of (3S,5R)-5-methyl-3-(toluene-4-sulfonyloxymethyl)-octanoic acid tert-butyl ester 104 was followed giving 2.1 g of 132 as an oil. The product was used in the next step without further purification. MS, m/z (relative intensity): 329 MC(CH3)31H, 85%, 370 MC(CH3)31HCH3CN, 65%. 1365 (3S,5S)-3-Azidomethyl-5-methyl-heptanoic acid tert-butyl ester 133 1366 A procedure similar to the preparation of (3S,5R)-3-azidomethyl-5-methyl-octanoic acid tert-butyl ester 105 was followed giving 0.76 g, 54.0% of 133 as an oil. MS, m/z (relative intensity): 198 MC(CH3)3-1H, 100%1367 (3S,5S)-3-Aminomethyl-5-methyl-heptanoic acid tert-butyl ester 134 1368 A procedure similar to that used for (3S,5S)-3-aminomethyl-5-methyl-octanoic acid tert-butyl ester 126 was used giving 0.62 g of 134 as an oil. The product was used in the next step without further purification. MS, m/z (relative intensity): 230 M1H, 100%, 271 M1HCH3CN, 45%.

EXAMPLE 20 1369 (3S,5S)-3-Aminomethyl-5-methyl-heptanoic acid 1370 A procedure similar to that used for Example 19 was used giving (3S,5S)-3-aminomethyl-5-methyl-heptanoic acid (0.3 g, 65.1%) as a white solid. 1H NMR (CD3OD) 2.80-3.00 (m, 2H), 2.40 (m, 1H), 2.20 (dd, J8.2, 7.1 Hz, 1H), 2.05 (m, 1H), 1.30-1.50 (m, 3H), 1.00-1.20 (m, 2H), 0.9 (m, 6H); MS, m/z (relative intensity): 187 M1H, 100%, 211 M1HCH3CN, 30%. MS, m/z (relative intensity): 174 M1H, 100%, 172 M1H, 100%, 215 M1HCH3CN, 20%.

EXAMPLE 21 1371 Synthesis of (3S,5R)-3-Aminomethyl-5-methyl-nonanoic acid hydrochloride 70

1372 (R)-4-Methyl-octanoic acid 136 1373 Lithium chloride (0.39 g, 9.12 mmol) and copper (I) chloride (0.61 g, 4.56 mmol) were combined in 45 mL THF at ambient temperature and stirred 15 minutes, then cooled to 0 C. at which time ethyl magnesium bromide (1 M solution in THF, 45 mL, 45 mmol) was added. (S)-citronellyl bromide (5.0 g, 22.8 mmol) was added dropwise and the solution was allowed to warm slowly to ambient temperature with stirring overnight. The reaction was quenched by cautious addition of sat. NH4Cl (aq), and stirred with Et2O and sat. NH4Cl (aq) for 30 minutes. The phases were separated and the organic phase dried (MgSO4) and concentrated. The crude product was used without purification. 1374 To a solution of alkene 135 (3.8 g, 22.8 mmol) in 50 mL acetone at 0 C. was added Jones' reagent (2.7 M in H2SO4 (aq), 40 mL, 108 mmol) and the solution was allowed to warm slowly to ambient temperature with stirring overnight. The mixture was partitioned between Et2O and H2O, the phases were separated, and the organic phase washed with brine, dried (MgSO4), and concentrated. The residue was purified by flash chromatography (8:1 hexanes:EtOAc) to afford 2.14 g (59%) of acid 136 as a colorless oil: LRMS: m/z 156.9 (M); 1H NMR (CDCl3): 2.33 (m, 2H), 1.66 (m, 1H), 1.43 (m, 2H), 1.23 (m, 5H), 1.10 (m, 1H), 0.86 (m, 6H). Jones' reagent was prepared as a 2.7M solution by combining 26.7 g CrO3, 23 mL H2SO4, and diluting to 100 mL with H2O. 1375 (4R,5S)-4-Methyl-3-((R)-4-methyl-octanoyl)-5-phenyl-oxazolidin-2-one 137 1376 To acid 136 (2.14 g, 13.5 mmol) in 25 mL CH2Cl2 at 0 C. was added 3 drops DMF, followed by oxalyl chloride (1.42 mL, 16.2 mmol) resulting in vigorous gas evolution. The solution was warmed directly to ambient temperature, stirred 30 minutes, and concentrated. Meanwhile, to a solution of the oxazolidinone (2.64 g, 14.9 mmol) in 40 mL THF at 78 C. was added n-butyl lithium (1.6 M solution in hexanes, 9.3 mL, 14.9 mmol) dropwise. The mixture was stirred for 10 minutes at which time the acid chloride in 10 mL THF was added dropwise. The reaction was stirred 30 minutes at 78 C., then warmed directly to ambient temperature and quenched with sat. NH4Cl. The mixture was partitioned between Et2O and sat. NH4Cl (aq), the phases were separated, and the organic phase dried (MgSO4), and concentrated to furnish 3.2 g of oxazolidinone 137 as a colorless oil. LRMS: m/z 318.2 (M); 1H NMR (CDCl3): 7.34 (m, 5H), 5.64 (d, J7.3 Hz, 1H), 4.73 (quint, J6.8 Hz, 1H), 2.96 (m, 1H), 2.86 (m, 1H), 1.66 (m, 1H), 1.47 (m, 2H), 1.26 (m, 5H), 1.13 (m, 1H), 0.88 (m, 9H). The crude product was used without purification. 1377 (3S,5R)-5-Methyl-3-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl)-nonanoic acid tert-butyl ester 138 1378 To a solution of diisopropylamine (1.8 mL, 12.6 mmol) in 30 mL THF at 78 C. was added n-butyl lithium (1.6 M solution in hexanes, 7.6 mL, 12.1 mmol), and the mixture stirred 10 minutes at which time oxazolidinone 137 (3.2 g, 10.1 mmol) in 10 mL THF was added dropwise. The solution was stirred for 30 minutes, t-butyl bromoacetate (1.8 mL, 12.1 mmol) was added quickly dropwise at 50 C., and the mixture was allowed to warm slowly to 10 C. over 3 hours. The mixture was partitioned between Et2O and sat. NH4Cl (aq), the phases were separated, and the organic phase dried (MgSO4), and concentrated. The residue was purified by flash chromatography (16:1 to 8:1 hexanes:EtOAc) to provide 2.65 g (61%) of ester 138 as a colorless crystalline solid, mp84-86 C. D2317.1 (c1.00, CHCl3); 1H NMR (CDCl3): 7.34 (m, SH), 5.62 (d, J7.3 Hz, 1H), 4.73 (quint, J6.8 Hz, 1H), 4.29 (m, 1H), 2.67 (dd, J9.8, 16.4 Hz, 1H), 2.40 (dd,J5.1, 16.4 Hz, 1H), 1.69 (m, 1H), 1.38 (s, 9H), 1.28 (m, 7H), 1.08 (m, 1H), 0.88 (m, 9H); 13C NMR (CDCl3) 176.45, 171.22, 152.71, 133.64, 128.86, 125.86, 80.83, 78.87, 55.33, 40.02, 38.21, 37.59, 36.31, 30.86, 29.29, 28.22, 23.14, 20.41, 14.36, 14.26. Anal. Calcd for C25H37NO5: C, 69.58; H, 8.64; N, 3.25. Found: C, 69.37; H, 8.68; N, 3.05. 1379 (S)-2-((R)-2-Methyl-hexyl)-succinic acid 4-tert-butyl ester 139 1380 To a solution of ester 138 (2.65 g, 6.14 mmol) in 20 mL THF at 0 C. was added a precooled (0 C.) solution of LiOH monohydrate (1.0 g, 23.8 mmol) and hydrogen peroxide (30 wt % aqueous solution, 5.0 mL) in 10 mL H2O. The mixture was stirred vigorously for 90 minutes, then warmed to ambient temperature and stirred 90 minutes. The reaction was quenched at 0 C. by addition of 100 mL 10% NaHSO3 (aq), then extracted with Et2O. The phases were separated, and the organic phase washed with brine, dried (MgSO4), and concentrated. The crude acid 139 was used without purification. 1381 (3S,5R)-3-Hydroxymethyl-5-methyl-nonanoic acid tert-butyl ester 140 1382 To a solution of the crude acid 139 (6.14 mmol) in 30 mL THF at 0 C. was added borane-dimethyl sulfide complex (2.0 M solution in THF, 4.6 mL, 9.2 mmol), and the mixture was allowed to warm slowly to ambient temperature overnight. Additional BH3-DMS was added until the acid was completely consumed (ca. 5 mL). The reaction was quenched by addition of MeOH, then partitioned between Et2O and sat. NaHCO3 (aq). The phases were separated, and the organic phase washed with brine, dried (MgSO4), and concentrated to provide alcohol 140. LRMS: m/z 226.1; 1H NMR (CDCl3): 3.63 (dd, J11.0, 4.2 Hz, 1H), 3.42 (dd, J11.0, 6.8 Hz, 1H), 2.30 (dd, J14.9, 7.6 Hz, 1H), 2.20 (dd, J14.9, 5.6 Hz, 1H), 2.03 (m, 2H), 1.42 (s, 9H), 1.24 (m, 6H), 1.02 (m, 2H), 0.85 (m, 6H). The crude product was used without purification. 1383 (3S,5R)-5-Methyl-3-(toluene-4-sulfonyloxymethyl)-nonanoic acid tert-butyl ester 141 1384 To alcohol 140 (6.14 mmol) in 30 mL CH2Cl2 at 0 C. was added DMAP (0.1 g),p-toluenesulfonyl chloride (1.37 g, 7.2 mmol), and then triethylamine (1.8 mL, 13 mmol) was added quickly dropwise. The mixture was warmed immediately to ambient temperature following addition and stirred overnight, and did not proceed to completion. The mixture was partitioned between Et2O and 1N HCl (aq), the phases were separated, and the organic phase washed with sat. NaHCO3 (aq), dried (MgSO4), and concentrated to provide tosylate 141. The product was used without further purification. 1385 (3S,5R)-3-Azidomethyl-5-methyl-nonanoic acid tert-butyl ester 142 1386 A procedure similar to the preparation of (3S,5R)-3-azidomethyl-5-methyl-octanoic acid tert-butyl ester 105 was followed giving azide 142 as a colorless oil. LRMS: m/z 200.1; 1H NMR (CDCl3): 3.31 (dd, J12.2, 4.2 Hz, 1H), 3.19 (dd, J12.2, 5.9 Hz, 1H), 2.22 (m, 1H), 2.10 (m, 1H), 1.39 (s, 9H), 1.21 (m, 8H), 1.00 (m, 2H), 0.81 (m, 6H).

EXAMPLE 21 1387 (3S,5R)-3-Aminomethyl-5-methyl-nonanoic acid hydrochloride 1388 The azide 142 (1.0 g) was hydrogenated in the presence of 20% Pd/C, EtOH, at 45 psi of H2 for 15 hours to provide the crude amino ester 143 which was concentrated and used without purification. To the amino ester 143 was added 6 mL 6N HCl (aq) and the mixture was heated to reflux 90 minutes, cooled, and concentrated. Recrystallization from EtOAc:hexanes provided 0.38 g (45% from azide) of (3S,5R)-3-aminomethyl-5-methyl-nonanoic acid hydrochloride as a colorless crystalline solid (HCl salt), and a second crop of 82 mg (10% from azide) was also obtained. mp146-156 C. LRMS: m/z 200.1 (M); 1H NMR (CDCl3): 2.87 (dd, J13.2, 5.4 Hz, 1H), 2.79 (dd, J13.2, 7.3 Hz, 1H), 2.29 (d, J6.8 Hz, 2H), 2.08 (m, 1H), 1.31 (m, 1H), 1.09 (m, 7H0, 0.92 (m, 1H), 0.68 (m, 6H). Anal. Calcd for C11H24NO2Cl: C, 55.57; H, 10.17; N, 5.89. Found: C, 55.69; H, 10.10; N, 5.86.

EXAMPLE 22 1389 Synthesis of (3S,5S)-3-Aminomethyl-5-methyl-nonanoic acid 71

1390 The (S)-acid 145 was prepared from (R)-citronellyl bromide according to the procedure outlined above for (R)-4-methyl-octanoic acid 136. The yield was comparable and the 1H NMR spectrum was identical to that of the (R)-acid enantiomer. LRMS: m/z 158.9 (M1). 1391 Oxazolidinone 146 was prepared from acid 145 as described above for (4R,5S)-4-methyl-3-((R)-4-methyl-octanoyl)-5-phenyl-oxazolidin-2-one 137. LRMS: m/z 290.1 (M27); 1H NMR (CDCl3): 7.38 (m, 3H), 7.28 (m, 2H), 5.64 (d, J7.1 Hz, 1H), 4.74 (quint, J6.8 Hz, 1H), 2.92 (m, 2H), 1.71 (m, 1H), 1.42 (m, 7H), 1.18 (m, 1H), 0.88 (m, 9H). 1392 t-Butyl ester 147 was prepared from oxazolidinone 146 as described above for compound 138. LRMS: m/z 348.1 (M83). 1393 Alcohol 149 was prepared from the t-butyl ester 147 as described above for (3S,5R)-3-hydroxymethyl-5-methyl-nonanoic acid tert-butyl ester 140. LRMS: m/z 156.9 (M100); 1H NMR (CDCl3): 3.60 (dd, J11.0, 4.6 Hz, 1H), 3.45 (dd, J11.0, 6.8 Hz, 1H), 2.24 (m, 2H), 2.04 (m, 2H), 1.42 (s, 9H), 1.17-1.38 (m, 7H), 1.11 (m, 1H), 0.84 (m, 6H).

EXAMPLE 22 1394 (3S,5S)-3-Aminomethyl-5-methyl-nonanoic acid 1395 (3S,5S)-3-Aminomethyl-5-methyl-nonanoic acid was obtained from 149 as described above for (3S,5R)-3-aminomethyl-5-methyl-nonanoic acid hydrochloride. The crude HCl salt thus obtained was purified by ion exchange chromatography on Dowex 50WX8 50-100 mesh, H-Form resin, using 10% NH4OH as eluent to provide the free base. The waxy solid was washed twice with Et2O and dried to furnish an amorphous white solid, mp 144-146 C. LRMS: m/z 172.0 (M28); 1H NMR (CDCl3): 2.76 (d, J5.9 Hz, 2H), 2.14 (m, 1H), 1.96 (m, 2H), 1.25 (m, 1H), 1.12 (m, 6H), 0.96 (m, 2H), 0.66 (m, 6H).

EXAMPLE 23 1396 Synthesis of (3S,5R)-3-Aminomethyl-5-methyl-decanoic acid 72

1397 (R)-2,6-Dimethylundec-2-ene 153 1398 A procedure similar to the preparation of (S)-2,6-dimethyl-non-2-ene 119 was used giving 153 as a colorless oil (20.16 g, 98%). 1H NMR (400 MHz, CDCl3) 5.10-5.06 (m, 1H), 2.10-1.89 (m, 2H), 1.66 (s, 3H), 1.58 (s, 3H), 1.34-1.23 (m, 4H), 1.15-1.06 (m, 2H), 0.88-0.81 (m, 11H). 1399 (R)-4-methylnonanoic acid 154 1400 (R)-2,6-Dimethylundec-2-ene 153 (10.03 g, 55.03 mmol) was dissolved in acetone (270 mL) and cooled to 0 C. Jones reagent (CrO3/H2SO4) (2.7 M, 120 mL) was added dropwise, and the reaction allowed to warm to room temperature over 18 hours. The reaction was poured on to water/Na2SO4 (200 mL), and the aqueous layer extracted with ethyl acetate (4100 mL). The combined organics were dried over MgSO4, filtered, and rotovapped to give an oil. The crude oil was dissolved in CH2Cl2 (400 mL) and cooled to 78 C. Ozone was bubbled into reaction until blue to remove traces of the impurity (6E)(3S)-3,7-dimethylocta-1,6-diene. Dimethylsulfide (5 mL) was added, and the reaction stirred at room temperature for 2 hours. The solvent was removed, and the crude material chromatographed on silica eluting with 20% EtOAc/hex to give oil. The oil was dissolved in ether (100 mL) and extracted with 10% NaOH (225 mL). The aqueous layers were combined and extracted with ether (50 mL). The aqueous layer was cooled to 0 C. and acidified with HCl. The acidic layer was extracted with EtOAc (3100 mL), and the combined extracts dried over MgSO4, filtered and rotovapped to give 154 as an oil (6.86 g, 54%). 1H NMR (400 MHz, CDCl3) 2.40-2.25 (m, 4H), 1.70-1.62 (m, 2H), 1.47-1.11 (m, 8H), 0.87-0.84 (m, 6H); D11.4 (c1 in CHCl3). 1401 (4R,5S)-4-Methyl-3-((R)-4-methyl-nonanoyl)-5-phenyl-oxazolidin-2-one 155 1402 Compound 154 (6.504 g, 37.76 mmol) was dissolved in THF (95 mL) and cooled to 0 C. Triethylamine (19.74 mL, 141.6 mmol) was added dropwise, followed by dropwise addition of trimethylacetyl chloride (6.98 mL, 56.64 mmol). The thick white suspension was stirred at 0 C. for 90 minutes. LiCl (1.86 g, 41.54 mmol), (4R)-4-methyl-5-phenyl-1,3-oxazolidin-2-one (6.824 g, 38.51 mmol), and THF (70 mL) were added, and the reaction warmed to room temperature overnight. The solvent was evaporated. The solids were taken up in EtOAc, filtered off, and washed generously with EtOAc. The filtrate was washed with water (250 mL), and brine. The organics were dried over MgSO4, filtered, and rotovapped. The crude material was chromatographed on silica eluting with 10% EtOAc/hexanes to give 155 as an oil (10.974 g, 88%). 1H NMR (400 MHz, CDCl3) 7.44-7.35 (m, 3H), 7.31-7.26 (m, 2H), 5.66 (d, J7.33 Hz, 1H), 4.76 (quint, J7.03 Hz, 1H), 3.04-2.96 (m, 1H), 2.93-2.86 (m, 1H), 1.74-1.66 (m, 1H), 1.52-1.47 (m, 1H), 1.46-1.36 (m, 2H), 1.27-1.16 (m, 2H), 0.92-0.87 (m, 8H); D34.1 (c1 in CHCl3). 1403 (3S,5R)-5-Methyl-3-((4R,5S)4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl)-decanoic acid tert-butyl ester 156 1404 A procedure similar to the preparation of (3S,5S)-5-methyl-3-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl)-octanoic acid tert-butyl ester 122 was followed giving (3S,5R)-5-methyl-3-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl)-decanoic acid tert-butyl ester 156 as an oil (0.668 g, 90%). 1H NMR (400 MHz, CDCl3) 7.41-7.28 (m, 5H), 5.63 (d, J7.33 Hz, 1H), 4.74 (quint, J6.84 Hz, 1H), 4.33-4.26 (m, 1H), 2.68 (dd, J16.4, 9.77 Hz, 1H), 2.41 (dd, J16.6, 4.88 Hz, 1H), 1.68 (quint, J6.6 Hz, 1H), 1.50-1.32 (m, 10H), 1.28-1.21 (m, 1H), 1.15-1.08 (m, 1H), 0.90-0.86 (m, 9H); MS (APCI) m/z 348 (M-97, 100%); D18.8 (c1 in CHCl3). 1405 (S)-2-((R)-2-Methyl-heptyl)-succinic acid 4-tert-butyl ester 157 1406 Compound 156 (5.608 b, 12.59 mmol) was dissolved in THF/H2O (60 mL/14 mL) and cooled to 0 C. LiOH (1N, 18.89 mL) and H2O2 (35%, 4.45 mL, 50.4 mmol) were combined, and then added to the reaction dropwise keeping T<5 C. the reaction was stirred at 0 C. for 4 hours, and quenched with Na2SO3 (6.3 g) and NaHSO3 (3.4 g) in 50 mL H2O added dropwise. The reaction was stirred for 15 minutes, and the layers separated. The aqueous layer was extracted with EtOAc (3100 mL), and the combined extracts dried over MgSO4, filtered, and rotovapped to give an oil. The crude material was dissolved in EtOAc (10 mL) and added dropwise to heptane (250 mL). The suspension was stirred for 20 minutes, and the solids filtered and washed with heptane. The filtrate was washed with 60 C. H2O (100 mL), dried over MgSO4, filtered, and rotovapped to give 157 as an oil (3.52 g). the material was used directly in the next step. 1407 (3S,5R)-3-Hydroxymethyl-5-methyl-decanoic acid tert-butyl ester 158 1408 Compound 157 (3.52 g, 12.3 mmol) was dissolved in anhydrous THF (123 mL) and cooled to 0 C. Borane dimethylsulfide complex (10 M, 3.69 mL) was added dropwise, and the reaction then warmed to room temperature and stirred for 1 hour. The reaction was cooled to 0 C., and quenched with MeOH (20 mL) added dropwise. The reaction was stirred for 18 hours, and the solvent rotovapped off. The crude material was chromatographed on silica eluting with 20% EtOAc/hexanes to give 158 (2.28 g, 68%) as an oil. 1H NMR (400 MHz, CDCl3) 3.65-3.59 (m, 1H), 3.43 (dd, J11.1, 6.96 Hz, 1H), 2.31 (dd, J14.9, 7.57 Hz, 1H), 2.21 (dd, J15.1, 5.62 Hz, 1H), 2.06-2.02 (m, 1H), 1.43 (s, 9H), 1.40-1.25 (m, 4H), 1.07-1.13 (m, 1H), 1.03-0.96 (m, 1H), 0.86-0.84 (m, 6H); MS (APCI) m/z 216 (M56, 100%). 1409 (3S,5R)-5-Methyl-3-(toluene-4-sulfonyloxymethyl)-decanoic acid tert-butyl ester 159 1410 Compound 158 (2.27 g, 8.33 mmol) was dissolved in CH2Cl2 (30 mL) and cooled to 0 C. Tosyl chloride (1.91 g, 10.0 mmol) and catalytic DMAP were added, followed by dropwise addition of triethylamine (2.55 mL, 18.33 mmol). The reaction was then stirred at 0 C. for 18 hours. The solvent was rotovapped off (removed under reduced pressure), and the crude material washed with EtOAc and filtered. The solids were washed with EtOAc, and the filtrate washed with 0.5N HCl (20 mL), brine (30 mL), dried over MgSO4, filtered, and rotovapped. The oil was chromatographed on silica eluting with a 5% EtOAc/hexanes gradient to 10% EtOAc/hexanes to give 159 (3.399 g, 96%) as an oil. 1H NMR (400 MHz, CDCl3) 7.75 (d, J8.30 Hz, 2H), 7.31 (d, J8.30 Hz, 2H), 3.99 (dd, J9.65, 3.54 Hz, 1H), 3.89 (dd, J9.52, 5.37 Hz, 1H), 2.42 (s, 3H), 2.28 (dd, J14.7, 6.23 Hz, 1H), 2.19-2.14 (m, 1H), 2.10 (dd, J14.9, 6.35 Hz, 1H), 1.38 (s, 9H), 1.31-1.17 (m, 3H), 1.08-0.81 (m, 2H), 0.79-0.76 (m, 6H); D10.1 (c1 in CHCl3). 1411 (3S,5R)-3-Azidomethyl-5-methyl-decanoic acid tert-butyl ester 160 1412 Compound 159 (3.01 g, 7.05 mmol), sodium azide (1.26 g, 19.40 mmol) and DMSO (12 mL) were combined and heated to 60 C. for 3 hours. EtOAc (100 mL) was added to the reaction and filtered. The solids were washed with EtOAc (20 mL), and the filtrated evaporated. The crude material was chromatographed on silica eluting with 5% EtOAc/hexanes to give 160 as an oil (1.86 g, 89%). 1413 (3S,5R)-3-Aminomethyl-5-methyl-decanoic acid tert-butyl ester 161 1414 A solution of compound 160 (1.86 g, 6.25 mmol) in THF (50 mL) was shaken over 5% Pd/C under hydrogen and pressure for 8 hours with three purges of hydrogen. The catalyst was filtered off and the filtrate evaporated. The crude material was chromatographed on silica eluting with methanol to give 161 as an oil (1.21 g, 71%). 1H NMR (400 MHz, CDCl3) 2.70 (dd, J12.9, 4.40 Hz, 1H), 2.54 (dd, J12.7, 6.59 Hz, 1H), 2.26 (dd, J14.5, 6.96, 1H), 2.12 (dd, J14.5, 6.47 Hz, 1H), 1.91 (m, 1H), 1.91 (m, 1H), 1.43 (s, 12H), 1.39-1.25 (m, 4H), 1.14-1.07 (m, 1H), 1.03-0.97 (m, 1H), 0.86-0.82 (m, 6H).

EXAMPLE 23 1415 (3S,5R)-3-Aminomethyl-5-methyl-decanoic acid 1416 Compound 161 (1.20 g, 4.44 mmol) was heated to 50 C. in 3N HCl (30 mL) for 4 hours. The solvent was evaporated, and the oil washed with toluene, and evaporated. The crude material was passed through an ion exchange column (Dowex 50WX8-100, strongly acidic) eluting with water, then 0.5N NH4OH. Isolate (3S,5R)-3-aminomethyl-5-methyl-decanoic acid as a white solid (0.725 g, 75%): mp174-175 C.; 1H NMR (400 MHz, CDCl3) 2.83 (dd, J12.69, 4.88 Hz, 1H), 2.70 (dd, J13.1, 7.45 Hz, 1H), 2.08 (d, J6.59 Hz, 2H), 1.98 (m, 1H), 1.28-1.20 (m, 1H), 1.19-1.09 (m, 2H), 0.99-0.91 (m, 2H), 0.66 (m, 6H); MS (APCI) m/z 215 (M, 10%), 174 (M41, 100%); D5.7 (c1.025 in H2O).

EXAMPLE 24 1417 Synthesis of (3S,5S)-3-Aminomethyl-5-methyl-decanoic acid 73

1418 (S)-2,6-Dimethyl-undec-2-ene 162 1419 nPropylmagnesium chloride/ether solution (2.0 M, 228 mL) was cooled to 20 C. under a N2 atmosphere. LiCl (3.87 g, 91.25 mmol), CuCl2 (6.13 g, 45.63 mmol), and distilled THF (456 mL) were combined and stirred for 30 minutes. The Li2CuCl4 solution was added via cannula to the Grignard reagent, and the resulting solution stirred for 30 minutes at 20 C. R-()-Citronellyl bromide (50 g, 228.1 mmol) was dissolved in THF (60 mL) and added dropwise to the Grignard solution. The reaction was stirred at 0 C. for 1 hour. The reaction was cooled to 40 C. and quenched with NH4Cl (saturated, 200 mL) added dropwise. The layers were separated and the aqueous layer extracted with ether (3100 mL). The combined organics were dried over MgSO4, filtered, and rotovapped to give an oil. The crude material was chromatographed on silica eluting with hexanes to give 162 as a colorless oil (9.15 g, 22%). 1H NMR (400 MHz, CDCl3) 5.10-5.06 (m, 1H), 2.10-1.89 (m, 2H), 1.66 (s, 3H), 1.58 (s, 3H), 1.34-1.23 (m, 4H), 1.15-1.06 (m, 2H), 0.88-0.81 (m, 11H). 1420 (S)-4-Methylnonanoic acid 163 1421 Compound 162 (7.97 g, 43.7 mmol) was dissolved in acetone (214 mL) and cooled to 0 C. Jones reagent (CrO3/H2SO4) (2.7 M, 95 mL) was added dropwise, and the reaction allowed to warm to room temperature over 18 hours. The reaction was poured on to water/Na2SO4 (200 mL), and the aqueous layer extracted with ethyl acetate (4100 mL). The combined organics were dried over MgSO4, filtered, and rotovapped to give an oil. The crude oil was chromatographed on silica eluting with hexanes to give 163 as an oil (5.56 g, 74%). 1H NMR (400 MHz, CDCl3) 2.40-2.25 (m, 4H), 1.70-1.62 (m, 2H), 1.47-1.11 (m, 8H), 0.87-0.84 (m, 6H); MS APCI m/z 170.9 (M1, 100%). 1422 (4R,5S)-4-Methyl-3-((S)-4-methyl-nonanoyl)-5-phenyl-oxazolidin-2-one 164 1423 A procedure similar to that used to prepare compound 155 was used except that (S)-4-methylnonanoic acid 163 (5.56 g, 32.27 mmol) was used as a reactant to give 164 as an oil (10.70 g 100%). 1H NMR (400 MHz, CDCl3) 7.42-7.34 (m, 3H), 7.28 (d, J6.59 Hz, 2H), 5.64 (d, J7.33 Hz, 1H), 4.74 (quint, J6.78 Hz, 1H), 2.94-2.85 (m, 2H), 1.73-1.67 (m, 1H), 1.47-1.43 (m, 1H), 1.39-1.22 (m, 7H), 0.90-0.84 (m, 8H). 1424 (3S,5S)-5-Methyl-3-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidine-3-carbonyl)-decanoic acid tert-butyl ester 165 1425 A procedure similar to that used to prepare compound 156 was used to give 165 as a solid (4.25 g, 61%). MS (APCI) m/z 446 (M1, 10%), 390 (M55, 100%, tBu). 1426 (S)-2-((S)-2-Methyl-heptyl)-succinic acid 4-tert-butyl ester 166 1427 A procedure similar to that used for compound 157 was used except that ester 165 (8.42 g, 18.89 mmol) was used as a reactant to give 166 as an oil (5.81 g). The material was used directly in the next step. MS (APCI) m/z 285 (M1, 100%). 1428 (3S,5S)-3-Hydroxymethyl-5-methyl-decanoic acid tert-butyl ester 167 1429 A procedure similar to that used to prepare compound 158 was used except that (S)-2-((S)-2-methyl-heptyl)-succinic acid 4-tert-butyl ester 166 (5.78 g, 20.18 mmol) was used as a reactant to give 167 as an oil (4.18 g, 76%). 1H NMR (400 MHz, CDCl3) 3.64-3.58 (m, 1H), 3.84-3.42 (m, 1H), 2.28-2.20 (m, 1H), 2.09-2.02 (m, 1H), 1.43 (s, 9H), 1.26-1.18 (m, 8H), 1.11-1.04 (m, 2H), 0.87-0.83 (m, 6H); MS (APCI) m/z 217 (M55, 50%, tBu). 1430 (3S,5S)-5-Methyl-3-(toluene-4-sulfonyloxymethyl)-decanoic acid tert-butyl ester 168 1431 A procedure similar to that used to prepare compound 159 was used except that (3S,5S)-3-Hydroxymethyl-5-methyl-decanoic acid tert-butyl ester 167 (4.164 g, 15.29 mmol) was used as a reactant to give 168 as an oil (4.17 g, 64%). 1H NMR (400 MHz, CDCl3) 7.75 (d, J8.30 Hz, 2H), 7.31 (d, J8.30 Hz, 2H), 3.97 (dd, J9.52, 4.15 Hz, 1H), 3.90 (dd, J9.52, 5.13 Hz, 1H), 2.42 (s, 3H), 2.28, 2.19-2.13 (m, 2H), 1.37 (s, 9H), 1.27-1.01 (m, 11H), 0.85 (t, J7.08 Hz, 3H), 0.76 (d, J6.35 Hz, 3H). 1432 (3S,5S)-3-Azidomethyl-5-methyl-decanoic acid tert-butyl ester 169 1433 A procedure similar to that used to prepare compound 160 was used except (3S,5S)-5-methyl-3-(toluene-4-sulfonyloxymethyl)-decanoic acid tert-butyl ester 168 (4.155 g, 9.74 mmol) was used as a reactant to give 169 as an oil (2.77 g, 96%). MS (APCI) m/z 270 (M27, 30%, N2), 214 (M87, 100%, tBu, N2). 1434 (3S,5S)-3-Aminomethyl-5-methyl-decanoic acid tert-butyl ester 170 1435 A procedure similar to that used to prepare compound 161 was used except that (3S,5S)-3-Azidomethyl-5-methyl-decanoic acid tert-butyl ester 169 (2.50 g, 8.405 mmol) was used as a reactant to give 170 as an oil (1.648 g, 72%). MS (APCI) m/z 272 (M1, 100%).

EXAMPLE 24 1436 (3S,5S)-3-Aminomethyl-5-methyl-decanoic acid 1437 A procedure similar to that used for Example 15 was used except tert-butyl (3S,5S)-3-(aminomethyl)-5-methyldecanoate 170 (1.6 g, 6.00 mmol) was used as a reactant to give Example 16 as a white solid (72%). MS (APCI) m/z 272 (M1, 100%). mp174-175 C.; 1H NMR (400 MHz, CD3OD) 2.91 (dd, J12.9, 3.91 Hz, 1H), 2.83 (dd, J12.7, 7.57 Hz, 1H), 2.43 (dd, J15.6, 3.17 Hz, 1H), 2.19 (dd, J15.6, 8.80 Hz, 1H), 2.08-2.04 (m, 1H), 1.53 (m, 1H), 1.38-1.27 (m, 7H), 1.78-1.03 (m, 2H), 0.90-0.86 (m, 6H), 0.66 (m, 6H); MS (APCI) m/z 216 (M1, 100%), 214 (M1, 100%); D21.4 (c1 in MeOH).

EXAMPLE 25 1438 Synthesis of (3R,4R)-3-Aminomethyl-4,5-dimethyl-hexanoic acid 74

1439 (S)-2-Benzyl-3-methyl-butan-1-ol 172 1440 Ref. JACS 1997; 119:6510. Amide 171. 1441 Large Scale Procedure for the Synthesis of Acetic Acid (S)-2-benzyl-3-methyl-butyl ester 173 from 171 1442 A of n-butyl lithium (10 M in hexane, 100 mL, 1000 mmol, 3.9 equiv.) was added to a solution of diisopropylamine (108.9 g, 150.9 mL, 1.076 mol, 4.20 equiv.) in THF (600 mL), at 78 C. The resulting solution was stirred for 10 minutes and warmed to 0 C., and held at the temperature for 10 minutes. Borane-ammonia complex (31.65 g, 1.025 mmol, and 4.0 equiv) was added in one portion, and the suspension was stirred at 0 C. for 15 minutes, and at 23 C. for 15 minutes, and then cooled to 0 C. A solution of amide 171 (86 g, 256.41 mmol, 1 equiv.) in THF was added to the cold hydride via a cannula over 3 minutes. The reaction was stirred at 23 C. for overnight, then cooled to 0 C. Excess hydride was quenched by the slow addition of 3N HCl (700 mL). The reaction mixture was diluted with more aqueous HCl (3N, 200 mL), and brine and then extracted with ether (415 mL). The ether solution was concentrated to a small volume, and 200 mL 2N NaOH was added, and stirred at 23 C. for 2.5 hours. More ether was added and the layers were separated. The aqueous layer was saturated with salt and extracted with ether (3200 mL). The combined organic was washed with brine and dried on sodium sulfate. The residue was flash chromatographed (Pet. ether-25% ether-TEA ) to give alcohol 172, 50 g. NMR (CDCl3) 7.35-7.16 (m, 5H, C6H5), 3.55 (app. t, 2H, CH2OH), 2.71 (dd, 1H, ArCH2CH), 2.52 (dd, 1H, ArCH2CH), 1.87 (m, 1H, CHCH(Me), 1.67 (m, 1H, CH(Me)2), 0.98 (d, 3H, CH3) and 0.96 (d, 3H, CH3). 1443 A sample 3.3 g was saved for characterization and the rest was immediately acetylated (triethylamine 50 mL, DMAP 4.6 g, acetic acid anhydride 32 mL) overnight at room temperature. Work up followed by chromatography on silica gel eluted with pet ether and then 10% ether in pet ether gave 62 g of 173. NMR (CDCl3) 7.30-7.14 (m, 5H, C6H5), 3.98 (m, 2H, CH2OAc), 2.71 (dd, 1H, ArCH2CH), 2.51 (dd, 1H, ArCH2CH), 1.99 (s, 3H, CH3CO), 1.82 (m, 1H, CHCH(Me) and CH(Me)2), 0.97 (d, 3H, CH3) and 0.95 (d, 3H, CH3). 1444 (S)-Acetoxymethyl-4-methyl-pentanoic acid 174 and (S)-4-Isopropyl-dihydro-furan-2-one 175 1445 Acetate 173 (15 g, 68.18 mmol) was dissolved in CH3CN (150 mL), carbon tetrachloride (150 mL) and HPLC grade water (300 mL) and stirred. Sodium periodate (262.50 g, 1220 mmol) was added followed by ruthenium chloride (650 mg, 3.136 mmol). After overnight stirring it was diluted with ether and water, and filtered through a pad of Celite. The organic portion was separated and the aqueous phase was further extracted with ether. After drying on magnesium sulfate the solvent was evaporated. Potassium carbonate (42 g) was added to the residue and refluxed overnight in methanol (250 mL) and cooled to room temperature. After evaporation, water was added to dissolve the solid, and conc. HCl was added to bring the pH to 2. Chloroform was added and extracted overnight. The organic phase was separated, and aqueous was further extracted with chloroform. The combined organic extracts were dried, evaporated, and the product was purified on a silica gel column and the compound was eluted with 20% ether in methylene chloride. Fractions were monitored by tic, and spots were detected with I2/KI solution. Fractions were combined to give 4.6 g of lactone 175. NMR (CDCl3) 4.38 (dd, 1H, CHaHbO), 3.93 (app. t, 1H, CHaHbO), 2.54 (dd, 1H, CHcHd CO), 2.23 (m, 2H, CHCH(Me) and CHcHd CO), 1.60 (m, 1H, CH(Me)2), 0.92 (d, 3H, CH3) and 0.85 (d, 3H, CH3). 1446 (3R,4R)-3-Benzyl-4-isopropyl-dihydro-furan-2-one 176 1447 Lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 92 mL, 92 mmol) was added in 3 to 5 minutes to a solution of (S)--(2-propyl)--butyrolactone 175 (11.68 g, 91.25 mmol) in dry THF 100 ML at 78 C. under argon atmosphere. It was stirred for 1 hour and a solution of benzyl iodide (21.87 g, 100.37 mmol) in dry THF was added rapidly. Stirring was continued for 1.5 hours and quenched at 78 C. by the addition of a solution of brine followed by ethyl acetate. The organic phase was separated and the aqueous was further extracted with ether. Chromatography on silica gel first eluted with 5% methylene chloride in pet ether, and fmally with 10% ether in pet ether gave desired compound 11.6 g, 58%. NMR (CDCl3) 7.19 (m, 5H, C6H5), 4.02 (app. t, 1H, CHaHbO), 3.87 (dd, 1H, CHaHbO), 2.98 (d, 2H, ArCH2), 2.57 (q, 1H, BnCHCO), 2.05 (m, 1H, CHCH(Me)2, 1.55 (m, 1H, CH(Me)2), 0.81 (d, 3H, CH3) and 0.72 (d, 3H, CH3). 1448 (2R,3R)-2-Benzyl-3-bromomethyl-4-methyl-pentanoic acid ethyl ester 177 1449 Lactone 176 (6.5 g, 29.8 mmol) was dissolved in absolute ethanol (80 mL) and cooled in ice bath. Anhydrous HBr was bubbled through the solution for 1 hour and stirred at room temperature overnight while maintaining reaction under dry atmosphere. It was poured onto ice cooled mixture of pet ether and brine. The organic phase was separated, and the aqueous was further extracted with pet ether. The combined organic solution was washed repeatedly with cold water and dried. Solvent was removed in vacuo to give crude compound 7.0 g. NMR (CDCl3) 7.27 (m, 5H, C6H5), 4.02 (m, 2H, CH3CH2O), 3.70 (dd, 1H, CHaHbBr), 3.55 (dd, 1H, CHaHbBr), 2.97 (m, 2H, ArCH2), 2.83 (q, 1H, BnCHCO), 2.11 (m, 1H, CHCH(Me)2, 1.97 (m, 1H, CH(Me)2), 1.10 (t, 3H, CH3CH2O), 0.96 (d, 3H, CH3) and 0.93 (d, 3H, CH3). 1450 (2R,3R)-2-Benzyl-3,4-dimethyl-pentanoic acid ethyl ester 178 1451 Bromoester 177 (7.25 g, about 80% pure), in ethanol (100 mL) containing triethylamine (3.2 mL) was hydrogenated overnight in the presence of 20% Pd/C (1.0 g). It was filtered through a pad of Celite, and the cake was washed with ethanol. Solvent was evaporated, and the residue was taken up in ether, whereupon solid (Et3N.HCl) separated. The solid was removed by filtration. The filtrate was concentrated, and the procedure was repeated to eliminate all hydrochloride salt. Product was chromatographed on a silica gel column which was eluted with pet ether to give the desired debrominated compound 3.35 g. NMR (CDCl3) 7.21 (m, 5H, C6H5), 3.95 (m, 2H, CH3CH2O), 2.85 (m, 2H, ArCH2), 2.64 (q, 1H, BnCHCO), 1.85 (m, 1H, CHCH(Me)2, 1.62 (m, 1H, CH(Me)2), 1.05 (t, 3H, CH3CH2O), 0.95 (d, 3H, CH3) 0.84 (d, 3H, CH3) and 0.82 (d, 3H, CH3). MS gave 290 (MCH3CN), 249 (M1), and others at 203. Further elution with ether gave lactone (2.25 g) that was carried over from previous step. 1452 Acetic acid (2R,3R)-2-benzyl-3,4-dimethyl-pentyl-ester 179 1453 Ethyl ester 178 (3.20 g, 12.85 mmol) was dissolved in anhydrous ether and cooled in ice bath under inert atmosphere. Lithium aluminum hydride (500 mg, 13.15 mmol) was added, and the suspension was stirred at room temperature overnight. Excess LAH was destroyed by careful addition of ethyl acetate while the reaction was stirred in ice bath. Saturated sodium sulfate was added cautiously to coagulate the alumina that separated at room temperature as white precipitate. The reaction mixture was diluted with methylene chloride, and anhydrous sodium sulfate was added to dry the mixture. After filtration the solution was concentrated to give an oil 3.0 g. 1454 The material (3.0 g) was dissolved in dichloromethane (30 mL) and triethylamine (2.5 mL), DMAP (200 mg), and acetic anhydride (1.5 mL) were added. It was stirred at room temperature for 3 hours, and diluted with ether. The ether solution was washed with waster, 1N HCl, saturated sodium bicarbonate, brine and dried. The solution was concentrated in vacuo to give the acetoxy compound 179 3.16 g. NMR (CDCl3) 7.19 (m, 5H, C6H5), 4.03 (m, 2H, CH3CH2O), 2.69 (m, 2H, ArCH2), 2.09 (m, 1H, BnCHCH2O), 2.02 (s, 3H, CH3CO), 1.68 (m, 1H, CH3CHCH(Me)2, 1.23 (m, 1H, CH(Me)2), 0.87 (d, 3H, CH3), 0.84 (d, 3H, CH3) and 0.81 (d, 3H, CH3). 1455 (R)-4-((R)-1,2-Dimethyl-propyl)-dihydro-furan-2-one 180 1456 To a solution of aromatic compound 179 (5.0 g, 20.16 mmol) in HPLC grade acetonitrile (60 mL), carbon tetrachloride (60 mL), and water (120 mL) was added sodium periodate (86.24 g, 403.32 mmol, 20 equiv.), followed by RuCl3 (414 mg, 10 mol%). The mixture was stirred vigorously overnight at room temperature, and diluted with methylene chloride (400 mL). The mixture was filtered through a pad of Celite to remove the solid precipitate. The organic portion was separated, and the aqueous was further extracted with methylene chloride. After the combined organic portions concentrated, the residue was dissolved in ether and applied to a column of Florisil. The compound was eluted with 3% methanol in ether, evaporated to a paste that was dissolved in methanol (100 mL). Potassium carbonate (8.0 g) was added, and the mixture was refluxed for 6 hours. The solvent was evaporated, and the solid residue was dissolved in water. The pH was adjusted to 2 by the careful addition of concentrated HCl while being cooled in ice water bath and stirred. Chloroform (200 mL) was added to the solution and stirred as such overnight at room temperature. The organic phase was separated, and the aqueous portion was further extracted with chloroform. After drying, the solvent was evaporated to give the lactone 180 5.0 g. NMR (CDCl3) 4.36 (app. t, 1H, CHaHbO), 3.85 (app. t, 1H, CHaHbO), 2.46 (m, 2H, CHcHd CO), 2.13 (m, 2H, CHCH2CO), 1.60 (m, 1H, CH(Me)2), 1.35 (m, 1H, CH3CHCH(Me)2), 0.86 (d, 3H, CH3) and 0.72 (t, 3H, CH3). 1457 (3R,4R)-3-Bromomethyl-4,5-dimethyl-hexanoic acid ethyl ester 181 1458 Lactone 180 (5.0 g) was dissolved in absolute ethanol (25 mL) and flushed with argon. While being cooled in ice water bath, anhydrous HBr gas was bubbled through the mixture for 45 minutes and allowed to stand at room temperature overnight. The mixture was poured into ice-salt water and hexane. The organic phase was separated, and the aqueous was further extracted with hexane. The combined organic extract was dried and evaporated. Flash chromatography with 10% ether in pet ether on a silica gel column gave the bromoester 181 3.54 g. NMR (CDCl3) 64.14 (q, 2H, CH3H2O), 3.60 (dd, 1H, CHaHbBr), 3.41 (dd, 1H, CHcHb Br), 2.54 (dd, 1H, ChaHbCO), 2.44 (dd, 1H, ChaHbCO), 2.22 (m, 1H, OCCH2CHCH2Br), 1.67 (m, 1H, CHCH3CH(Me)2, 1.37 (m, 1H, CH(Me)2), 1.26 (t, 3H, CH3CH2O), 0.94 (d, 3H, CHCH3CH(Me)2, 0.81 (d, 3H, ((CH3)2)CHCH3CH) and 0.79 (d, 3H, ((CH3)2)CHCH3CH). 1459 (3R,4R)-3-Azidomethyl-4,5-dimethyl-hexanoic acid ethyl ester 182 and Example 25 (3R,4R)-3-Aminomethyl-4,5-dimethyl-hexanoic acid 1460 Bromoester 181 (3.54 g, 13.34 mmol), sodium azide (1.04 g, 16.13 mmol) in anhydrous DMF (8.0 mL) was stirred at room temperature overnight. Water (16 mL) and hexane were added, the organic portion was separated, and the aqueous portion was further extracted with hexane. It was dried and evaporated to give azido ester 3.0 g. NMR (CDCl3) 4.14 (q, 2H, CH3H2O), 3.48 (dd, 1H, CHaHbN3), 3.21 (dd, 1H, CHcHb N3), 2.34 (m 2H, ChaHbCO), 2.20 (m, 1H, OCCH2CHCH2 N3), 1.60 (m, 1H, CHCH3CH(Me)2. Compound was submitted for hydrogenation (HPL, 66480100). The hydrogenated crude was dissolved in 6N HCl and refluxed overnight. The solvent was evaporated in vacuo the residue was azeotroped with toluene. The crude was further purified by loading onto an ion exchange column chromatography (Dowex 50 Wb8-100), washed to neutral eluent with HPLC grade water followed by elution of compound with 0.5N NH4OH solution. Crystallization of product from methanol gave 720 mg. NMR (CD3OD) 3.04 (dd, 1H, CHaHbNH2), 2.82 (dd, 1H, CHcHb NH2),2.52 (dd, 1H, ChaHbCO), 2.40 (dd, 1H, ChaHbCO), 2.07 (m, 1H, OCCH2CHCH2NH2), 1.67 (m, 1H, CHCH3CH(Me)2, 1.35 (m, 1H, CH(Me)2), 0.97 (d, 3H, CHCH3CH(Me)2, 0.88 (d, 3H, ((CH3)2)CHCH3CH) and 0.83 (d, 3H, ((CH3)2)CHCH3CH). D5.3 (c, MeOH, 1.9 mg/mL). Anal. Calcd for C9H19NO2: C, 62.39; H, 11.05; N, 8.08. Found C, 62.01; H, 11.35; N, 7.88. MS showed ions at 215 (MCH3CN), 197 (MNa), 174 (MH). Analysis of derivative by reverse phase HPLC, Hypersil BDS C18 5 micron and mobile phase 50/50 CH3CN-water containing 0.1% TFA gave 99.93% purity at retention time of 8.21 minutes.

EXAMPLES 26-28 1461 Synthesis of 3-Aminomethyl-4-isopropyl-heptanoic acid 76

1462 2-Cyano-4-methyl-2-pentenoic acid methyl ester 61 1463 A solution of isobutyraldehyde (30.0 g, 416 mmol), methyl-cyano-acetate (20.6 g, 208 mmol), ammonium hydroxide (3.2 g, 41.6 mmol) and acetic acid (5.0 g, 83.2 mmol) in 500 mL of toluene is warmed to reflux under a Dean-Stark trap for 12 hours. The mixture is cooled to room temperature and extracted with saturated NaHSO3 (3100 mL), saturated NaHCO3 (3100 mL), and 100 mL of brine. The organic layer is dried over Na2SO4, and the solvent is evaporated. The remaining oil is distilled under high vacuum (0.5 mm Hg, B.P.11 5-120 C.) to give 28.8 g of 2-cyano-4-methyl-2-pentenoic acid methyl ester 61 as an oil (90% yield). 1464 2-Cyano-3-isopropyl-hexanoic acid methyl ester 183 1465 A 2.0 M solution of propyl magnesium chloride in Et2O (9.8 mL, 19.6 mmol) is added to a solution of 2-cyano-4-methyl-2-pentenoic acid (3.0 g, 19.6 mmol) in 50 mL of THF which is cooled in an IPA/dry ice bath to 40 C. under argon. The solution is stirred for 4 hours, and the reaction is quenched by addition of 50 mL of saturated KH2PO4. The THF is evaporated, and the remaining oil is chromatographed under medium pressure over silica gel with 50% CH2Cl2/hexane. Yield1.9 g (50%) of 2-cyano-3-isopropyl-hexanoic acid methyl ester as an oil. 1466 2-Cyano-2-(1-isopropyl-butyl)-succinic acid 4-tert-butyl ester 1-methyl ester 184 1467 A solution of 2-cyano-3-isopropyl-hexanoic acid methyl ester (1.9 g, 9.6 mmol) in 10 mL of THF is added to a slurry of NaH (washed with hexane, 0.23 g, 9.6 mmol) in 20 mL of THF which is cooled in an ice water bath under argon. The solution is stirred for 10 minutes, and t-butyl bromoacetate (2.1 g, 10.6 mmol) is added. The solution is warmed to room temperature. After 12 hours, the reaction is quenched by addition of 50 mL of saturated KH2PO4 and the THF is evaporated. The organic products are extracted into Et2O (350 mL), and the combined organic layers are dried over MgSO4. The solvent is evaporated, and the remaining oil is chromatographed under medium pressure over silica gel in 25% hexane/CH2Cl2. Yield of 2-cyano-2-(1-isopropyl-butyl)succinic acid 4-tert-butyl ester 1-methyl ester1.3 g (42%) as an oil. 1468 3-Cyano-4-isopropyl-heptanoic acid t-butyl ester 185 1469 A mixture of 2-cyano-2-(1-isopropyl-butyl)-succinic acid 4-tert-butyl ester 1-methyl ester (1.3 g, 4.2 mmol), NaCl (0.25 g, 4.2 mmol), and H2O (0.15 g, 8.3 mmol) in 25 mL of DMSO is warmed to 130 C. for 12 hours. The mixture is cooled to room temperature and diluted with 100 mL of brine. The organic products are extracted into Et2O (350 mL). The organic layers are combined and washed with 50 mL of H2O and 50 mL of brine. Drying over Na2SO4 and evaporation of the solvent gives 0.8 g (75% yield) of 3-cyano-4-isopropyl-heptanoic acid t-butyl ester as an oil. 1470 4-(1-Isopropyl-butyl)-2-pyrrolidone 186 1471 3-Cyano-4-isopropyl-heptanoic acid t-butyl ester (0.8 g, 3.2 mmol) is reduced under 50 psi of H2 in MeOH containing TEA and Ra Ni. When the theoretical amount of H2 is taken up, the catalyst is removed by filtration, and the solvent is evaporated to give 0.6 g (100% yield) of 4-(1-isopropyl-butyl)-2-pyrrolidone as an oil.

EXAMPLE 26 1472 3-Aminomethyl-4-isopropyl-heptanoic acid 1473 4-(1-Isopropyl-butyl)-2-pyrrolidone (0.6 g, 2.3 mmol) is warmed to reflux in 50 mL of 6.0 M HCl for 12 hours. The solution is cooled to room temperature and filtered through Celite. The filtrate is evaporated, and the solid remaining is recrystallized from MeOH/EtOAc. Yield 0.035 g (6% yield) of 3-aminomethyl-4-isopropyl-heptanoic acid as an HCl salt, mp 160-170 C. 1H NMR (CD3OD) 0.9 (m, 9H), 1.30 (m, 5H), 1.78 (m, 1H), 2.30 (m, 2H), 2.45 (m, 1H), 2.95 (m, 2H). MS (APCI, CH3CN, H2O) 201 (M, 100%).

EXAMPLE 27 1474 3-Aminomethyl-4-isopropyl-octanoic acid 1475 Prepared according to the procedure of Example 26. Yield0.13 g (15%) of 3-aminomethyl-4-isopropyl-octanoic acid. mp160-170 C. 1H NMR (CD3OD) 0.9 (m, 9H), 1.30 (m, 7H), 1.78 (m, 1H), 2.30 (m, 1H), 2.45 (m, 2H), 2.95 (m, 2H). MS (APCI, CH3CN, H2O) 198 (M17, 100%), 216 (M, 50%).

EXAMPLE 28 1476 3-Aminomethyl-4-isopropyl-hexanoic acid 1477 Prepared according to the procedure of Example 26. Yield0.11 g (42%) of 3-aminomethyl-4-isopropyl-hexanoic acid. mp170-180 C. 1H NMR (CD3OD) 0.9 (m, 9H), 1.18 (m, 1H), 1.39 (m, 3H), 1.78 (m, 1H), 2.30 (m, 1H), 2.45 (m, 1H), 2.95 (m, 2H). MS (APCI, CH3CN, H2O) 188 (M, 100%).

EXAMPLE 29 1478

1479 (i) MeO2CCHPPh3, THF, 40 C.; (ii) MeNO2, DBU; (iii) Raney Nickel, H2, MeOH; (iv) PdC, MeOH, H2; (v) 6N HCl 1480 Synthesis of the Unsaturated Ester 188 1481 (S)-()-citronellal 187 (2.0 mL, 11.03 mmol) was stirred at 40 C. in dry tetrahydrofuran (30 mL) with methyl triphenylphosphoranylidene acetate (3.69 g, 11.03 mmol). After 8 hours the mixture was cooled to room temperature and stirred overnight. The solvent was removed in vacuo and the residue stirred with n-pentane (50 mL). After 1 hour the solid was removed by filtration and the solvent removed in vacuo to give an oil which was purified by flash chromatography (silica, ethyl acetate:heptane 1:9) to give 2.05 g (88%) of 188 as a clear oil. 1H NMR (400 MHz) (CDCl3) 0.90 (3H, d, J6 Hz); 1.12-1.40 (2H, m); 1.60 (3H, s); 1.62 (1H, m); 1.68 (3H, s); 2.01 (3H, m); 2.21 (1H, m); 3.73 (3H, s); 5.08 (1H, m); 5.82 (1H, d, J16 Hz); 6.94 (1H, m). 1482 MS (CI) (m/z): 211 (MH, 75%), 179 (78%), 151 (100%). 1483 IR (thin film) (cm1) : 1271, 1436, 1728, 2917. 1484 Synthesis of the Nitroester 189 1485 The ester 188 (2.02 g, 9.6 mmol) was dissolved in nitromethane (25 mL) with 1,8-diazabicyclo5,4,0undec-7-ene (1.44 mL, 9.6 mmol) and stirred at room temperature. After 23 hours the mixture was diluted with diethyl ether (150 mL) and washed with water (50 mL) and then 2N HCl (50 mL). The organic phase was collected, dried (MgSO4), and the solvent removed in vacuo. The residue was purified by flash chromatography (silica, ethyl acetate:heptane 3:7) to give 2.26 g (87%) of 189 as a clear oil. Note that this and all subsequent compounds are equimolar mixtures of 2 diastereoisomers. 1H NMR (400 MHz) (CDCl3) 0.90 (23H, each d, J6 Hz); 1.09-1.58 (10H, m); 1.602 (6H, s); 1.685 (6H, s); 1.94 (4H, m); 2.42 (4H, m); 2.66 (2H, m); 3.70 (6H, s); 4.42 (4H, m); 5.07 (2H, m). 1486 MS (CI) (m/z): 272 (MH, 90%), 240 (100%), 151 (100%). 1487 IR (thin film) (cm1) : 1554, 1739, 2918. 1488 Synthesis of the Lactam 191 1489 The nitro ester 189 (2.09 g, 7.7 mmol) was dissolved in methanol (75 mL) and shaken over Raney Nickel (catalytic, prewashed with water and then methanol) under an atmosphere of hydrogen gas (39 psi) at 35 C. After 17 hours the mixture was filtered through Celite. The solvent was removed in vacuo to give an oil. 1H NMR showed there had been partial reduction of the double bond so this was carried on without further purification. A sample of this partial reduced product (440 mg, 2.1 mmol) was dissolved in methanol (40 mL) and shaken over 5% PdC under an atmosphere of hydrogen gas. After 18 hours the catalyst was removed by filtration through Celite to obtain 442 mg (99% from partial reduced material) as a clear oil which did not need purification. Note that this and all subsequent compounds are equimolar mixtures of 2 diastereoisomers. 1H NMR (400 MHz) (CDCl3) : 0.88 (18H, m); 1.04-1.58 (20H, m); 1.96 (2H, m); 2.40 (2H, m); 2.58 (2H, m); 2.98 (2H, m); (3.45 (2H, m), 5.82 (2H, br s). MS (CI) (m/z): 212 (MH, 100%). 1490 Synthesis of Example 29 1491 The lactam 191 (428 mg, 2.0 mmol) was heated to reflux in 6N HCl (20 mL). After 5 hours the mixture was cooled to room temperature and washed with dichloromethane (210 mL). The aqueous phase was collected and the solvent removed in vacuo. The residue was dissolved in water (10 mL) and freeze-dried to give 382 mg (71%) of Example 29 as a white solid. Note that this compound is an equimolar mixture of 2 diastereoisomers. 1H NMR (400 MHz) (d6-DMSO) 0.82 (18H, m); 0.95-1.55 (20H, m); 2.05-2.45 (6H, m); 2.75 (4H, m); 7.98 (6H, br s). 1492 MS (CI) (m/z): 230 (MHHCl, 90%), 212 (100%). Microanalysis: Calculated for C13H28NO2Cl: C, 58.74; H, 10.62; N, 5.27. Found: C 58.46; H 10.50; N 5.33. 1493 To one skilled in the art, the use of (R)-()-citronellal would afford compounds of opposite C5-stereochemistry to Example 29. 1494 Syntheses of compounds of Formulas (1A) or (1B) are described below in Scheme 19 and Examples 30-33. 1495 Tetrazoles of Formula (1A) can be synthesized by the route outlined in Scheme 19. 78

1496 The following examples are illustrative of the instant invention, they are not intended to limit the scope.

EXAMPLE 30 1497 4-Methyl-2-(1H-tetrazol-5-ylmethyl)-pentylamine 1498 Compound 3 in Scheme 19 2-(2-Cyano-ethylcarbamoyl)-methyl-4-methyl-pentyl-carbamic acid tert-butyl ester. 1499 A solution of compound 2 (8.0 g, 0.03 mol) (prepared in the usual manner from (BOC)2 and pregabalin) was taken up in 250 mL dry THF and cooled in an ice water bath. Triethyl amine (4.62 mL, 0.033 mol) was added followed by the addition of isobutyl chloroformate (4 mL, 0.031 mol). The reaction was stirred a 0 C. for about 15 minutes during which time a precipitate formed. In a separate flask was placed 3-aminoproprionitrile fumarate (3.95 g, 0.03 mol) in 35 mL of 1 M NaOH and 300 mL of THF. This mixture was cooled to 0 C. and treated with the mixed anhydride formed above in four portions. Before each portion was added, 35 mL of 1 M NaOH was added to the mixture. The reaction was stirred for 24 hours and was then concentrated to remove THF. The resulting aqueous was extracted with three times ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulfate. The solvents were removed under pressure to give 6.6 g green oil. MS(APCI) m/z 312 (M1). 1500 Compound 4 in Scheme 19 4-Methyl-2-(1-(2-cyano-ethyl)-tetrazol-5-ylmethyl)-pentyl-carbamic acid tert-butyl ester and compound 5 4-Methyl-2-(1H-tetrazol-5-ylmethyl)-pentyl-carbamic acid tert-butyl ester. 1501 The cyanoamide (6.5 g, 0.0209 mol) and triphenylphosphine (11.06 g, 0.042 mol) were dissolved in 300 mL of dry THF. The solution was treated with DEAD (6.7 mL, 0.0425 mol) and TMSN3 (5.75 mL, 0.043 mol). The reaction was stirred for 24 hours, and the reaction mixture was cooled to 0 C. and treated with 900 mL of an aqueous solution containing 46.9 g of (NH4)2Ce(IV)NO3. The reaction mixture was concentrated to remove THF and extracted with three portions of CH2Cl2. The combined organic layers were dried with brine and Na2SO4, and the solvents were removed under reduced pressure to give a clear oil which was passed through a plug of silica gel to give the product admixed with triphenylphosphine oxide. This crude mixture was dissolved in 200 mL THF and 50 mL of 2N NaOH. The mixture was heated to reflux for 2 hours then stirred at room temperature overnight. The THF was removed under reduced pressure and the resulting residue diluted with water. After extraction with ether, the aqueous phase was acidified to pH 7 and extracted with 21 mL of 4N HCl. The aqueous phase was then saturated with solid KH2PO4. The aqueous mixture was extracted with CH2Cl2. The organic extracts were washed with brine and dried over Na2SO4. Evaporation if the organic solvents under reduced pressure resulted in isolation of 3.4 g of an amber oil. 1502 4-Methyl-2-(1H-tetrazol-5-ylmethyl)-pentylamine 1503 The material from the previous step (0.9 g, 3.18 mmol) was taken up in 20 mL of 4 M HCl in dioxane. The reaction was allowed to stand for 1 hour. A solid formed, 10 mL of ether was added, and the reaction was filtered to give Example 30 as 780 mg of a white solid; MS(APCI) m/z 184 (M1).

EXAMPLE 31 1504 IsobutylGABA Oxadiazolonethione (G) is Also Named 3-(2-Aminomethyl-4-methyl-pentyl)-4H-1,2,4oxadiazole-5-thione; HCl 79

1505 BOC-IsobutylGABA (B) 1506 A solution of di-tert-butyl dicarbonate (13.1 g, 0.06 mol) in THF (200 mL) was added, over a 10-minute period, to a solution of isobutylGABA (9.95 g, 0.056 mol) in 1N NaOH (125 mL) and THF (50 mL) cooled in an ice-water bath. The reaction mixture was stirred at room temperature 3 hours, concentrated to remove THF, saturated with saturated KH2PO4 and extracted 3EtOAc. The extracts were washed 2brine, dried over MgSO4, and evaporated to yield 13.8 g (95%) of a white solid, mp 84-88 C. MS (APCI) m/z 260 (M1). 1507 BOC-IsobutylGABA Amide (C) 1508 A solution of BOC-IsobutylGABA (6.78 g, 0.026 mol) and triethylamine (3.0 g, 0.030 mol) was cooled to 0 C. and isobutyl chloroformate (3.9 g, 0.029 mol) was slowly added. After stirring 20 minutes at 0 C., ammonia gas was bubbled into the reaction mixture for 30 minutes, and then the mixture was stirred at room temperature 18 hours. The mixture was concentrated to remove THF, suspended in water, and extracted 3EtOAc. The extracts were washed 110% Na2CO3, 2brine, and dried over Na2SO4. Evaporation yielded 4.9 g (73%) of an oil which was used without further purification. MS (APCI) m/z 259 (M1). 1509 BOC-IsobutylGABA Nitrile (D) 1510 A solution of BOC-IsobutylGABA amide (4.6 g, 0.0178 mol) in DMF (15 mL) was added, all at once, to cyanuric chloride (1.66 g, 0.009 mol) and stirred 30 minutes at room temperature. The reaction mixture was poured into a cold solution of NaHCO3 (4.2 g, 0.05 mol) in water (150 mL). Solid K2CO3 was added to bring the pH to 9 and the mixture was extracted 2CH2C12, washed 1brine, and dried over Na2SO4. Evaporation yielded an oil, which was filtered through silica gel, eluting with CH2Cl2-EtOAc which yielded 3.8 g oil (89%), which was used without further purification. MS (APCI) m/z 240 (M), 239 (M1); IR (Filn) 2215 cm1. 1511 BOC-IsobutylGABA Amidoxime (E) 1512 A solution of hydroxylamine was prepared by adding triethylamine (7.62 g, 0.075 mol) to a suspension of hydroxylamine hydrochloride (5.21 g, 0.075 mol) in DMSO (25 mL). After 15 minutes, the triethylamine hydrochloride was filtered off, and BOC-IsobutylGABA nitrile (3.61 g, 0.015 mol) was added to the filtrate. The mixture was heated at 75 C. for 17 hours. The mixture was diluted with water and extracted 3EtOAc. The extracts were washed 2brine, dried over Na2SO4, and evaporated to give an oil which was filtered through a short silica gel column, eluting with CH2Cl2-EtOAc to give 3.2 g (78%) oil. 1H NMR (CDCl3) 0.84 (d, 6H, J6.35 Hz), 1.11 (m, 2H), 1.40 (s, 9H), 1.63 (m, 1H), 3.05 (m, 1H), 3.15 (m, 1H), 4.85 (m, 1H), 5.43 (m 1H); MS (APCI) 274 (M1). 1513 BOC-IsobutylGABA Oxadiazolonethione (F) 1514 A solution containing BOC-IsobutylGABA amidoxime (0.5 g, 0.00183 mol), DBU (1.12 g, 0.00736 mol) and 90% 1,1-thiocarbonyldiimidazole (0.398 g, 0.002 mol) in MeCN (12 mL) was stirred at room temperature 16 hours. The reaction mixture was evaporated to dryness, taken up in EtOAc, and washed with KHSO4 solution. The EtOAc layer was extracted with 1N NaOH (100 mL). The alkaline extract was washed with Et2O and acidified with saturated KH2PO4 and extracted 3EtOAc. The extracts were washed 1water, 1brine and dried over MgSO4. Evaporation yielded an oil, 0.25 g (43%). 1H NMR (CDCl3) 0.84 (d, 6H, J6.59 Hz), 1.1 (m, 2H), 1.41 (s, 9H), 1.65 (m, 1H), 1.85 (m, 1H), 2.60 (m, 2H), 3.1 (m, 2H), 4.94 (m, 1H), 12.8 (s, 1H). MS (APCI) 316 (M1). 1515 IsobutylGABA Oxadiazolonethione (G) is Also Named 3-(2-Aminomethyl-4-methyl-pentyl)-4H-1,2,4oxadiazole-5-thione; HCl 1516 BOC-IsobutylGABA oxadiazolonethione (0.25 g, 0.79 mmol) was taken up in 4 M HCl in dioxane (10 mL) at room temperature for 1 hour. Evaporation followed by recrystallization of the residue from MeCN yielded Example 31 as cream-colored crystals, 0.108 g, mp 183-185 C. 1H NMR (DMSO-d6) 0.84 (d, 6H, J6.59 Hz), 1.1 (m, 2H), 1.41 (s, 9H), 1.65 (m, 1H), 0.80 (d, 6H, J6.59 Hz), 1.06 (m, 1H), 1.25 (m, 1H), 1.55 (m, 1H), 2.1 (m, 1H), 2.7 (m, 4H), 7.95 (s, 3H); MS (APCI) 216 (M1). Anal. Calcd for C9H17N3OSHCl: C, 42.93; H, 7.21; N, 16.69; Cl, 14.08. Found: C, 43.38; H, 7.24; N, 16.29; Cl, 14.17.

EXAMPLE 32 1517 IsobutylGABA Oxadiazolone (J) is Also Named 3-(2-Aminomethyl-4-methylpentyl)-4H-1,2,4oxadiazole-5-one HCl 80

1518 BOC-IsobutylGABA Amidoxime Carbamate (H) 1519 Isobutyl chloroformate (0.253 g, 0.00185 mol) was added dropwise to a solution of BOC-IsobutylGABA amidoxime (0.5 g, 0.00183 mol) and pyridine (0.158 g, 0.002 mol) in DMF (10 mL) at 0 C. After 30 minutes at that temperature, the reaction mixture was diluted with water and extracted 3EtOAc. The extracts were washed 1water, 1brine and dried over MgSO4 Evaporation yielded an oil, 0.7 g (100%) which was used without further purification. MS (APCI) m/z 374 (M1). 1520 BOC-IsobutylGABA Oxadiazolone (I) 1521 BOC-IsobutylGABA amidoxime carbamate (0.7 g, 0.00183 mol) was taken up in xylene (20 mL) and heated under reflux 2 hours. Evaporation yielded a dark glassy oil which was taken up in Et2O and extracted with 1N NaOH. The alkaline phase was acidified with saturated KH2PO4 and extracted 3EtOAc. The extracts were washed with brine, dried over MgSO4 and evaporated to yield a brown oil, 0.25 g (46%), which was used without further purification. MS (APCI) m/z 300 (M1). 1522 IsobutylGABA Oxadiazolone (J) is Also Named 3-(2-Aminomethyl-4-methyl-pentyl)-4H-1,2,4oxadiazole-5-one; HCl 1523 BOC-IsobutylGABA oxadiazolone (0.25 g, 0.835 mmol) was taken up in 4 M HCl in dioxane and allowed to stand 2.5 hours. Evaporation followed by recrystallization of the residue from MeCN-Et2O yielded Example 32 as a tan solid, 53 mg (27%), mp 181-184 C. 1H NMR (DMSO-d6) 0.80 (d, 6H, J6.35 Hz), 1.1 (m, 2H), 1.25 (s, 9H), 1.60 (m, 1H), 2.10 (m, 1H), 2.5-2.8 (m, 4H), 7.95 (s, 3H), 12.39 (s, 1H). MS (APCI) 216 (M1). Anal. Calcd for C9H17N3O2.HCl: C, 45.86; H, 7.70; N, 17.83; Cl, 15.04. Found: C, 45.40; H, 7.55; N, 16.79; Cl, 15.81.

EXAMPLE 33 1524 Aminomethyl-4-methyl-pentyl)-phosphonic acid (9) 81

1525 Preparation of 2-Isobutyl-succinic acid-4-t-butyl ester-1-methyl ester (2): 1526 4-Methylpentanoic acid methyl ester (10.0 g, 76.8 mmol) is added to a solution of LDA in 150 mL of THF at 78 C. under Ar. After 15 minutes, the anion solution is added by cannula to a solution of t-butyl bromoacetate (22.5 g, 115.2 mmol) in 50 mL of THF at 78 C., and the solution is stirred for 45 minutes. The reaction mixture is then warmed to room temperature, and treated with 100 mL of saturated KH2PO4. The THF is evaporated, and the organics are extracted into Et2O (350 mL). The Et2O is washed with 10% Na2S2O3 and dried with MgSO4. The solvent is evaporated, and the remaining oil is distilled under vacuum (0.1 mm Hg) to give 11.1 g (59% yield) of 2-isobutyl-succinic acid-4-t butyl ester-1-methyl ester boiling at 65 C. to 72 C. NMR (H1, 400 MHz, CDCl3) 0.9 (6H, m); 1.2 (1H, m); 1.4 (9H, s); 1.5 (2H, m); 2.3 (1H, dd); 2.5 (1H, dd); 2.8 (1H, m); 3.6 (3H, s). 1527 Preparation of 2-isobutyl-succinic acid-4-t-butyl ester (3): 1528 2-Isobutylsuccinic acid-4-t-butyl ester-1-methyl ester (11.1 g, 45.4 mmol) and LiOH.H2O (2.0 g, 47.7 mmol) are stirred in 180 mL of 3:1 IPA/H2O at room temperature overnight. The reaction mixture is extracted with Et2O (325 mL). The aqueous phase is acidified to pH4, with saturated KH2PO4 and extracted with Et2O (350 mL). The Et2O is dried over MgSO4, and evaporated to give 8.0 g (77% yield) of 2-isobutyl-succinic acid-4-t-butyl ester as an oil. NMR (H1, 400 MHz, CDCl3) 0.9 (6H, m); 1.3 (1H, m); 1.4 (9H, s); 1.6 (2H, m); 2.3 (1H, dd); 2.6 (1H, dd); 2.8 (1H, m). 1529 Preparation of 4-Isobutyl-dihydro-furan-2-one (4): 1530 A solution of 2-isobutyl-succinic acid-4-t-butyl ester (8.0 g, 34.7 mmol) in 100 mL of THF is cooled to 0 C. under Ar and borane dimethyl sulphide complex (2.6 g, 34.7 mmol) is added. The reaction mixture is stirred at 0 C. for 10 minutes, and at room temperature overnight. The solution is cooled to 0 C. and 100 mL of MeOH is added. The solvents are evaporated, and the remaining oil is dried under hi-vacuum for 2 hours. The oil remaining is taken up in 100 mL of THF, and a catalytic amount of p-toluene sulfonic acid is added. The solution is warmed to reflux overnight. After being cooled to room temperature, the solvent is evaporated, and the oil is taken up in Et2O (100 mL). The Et2O solution is extracted with 2.0N Na2CO3 (250 mL) followed by 100 mL of brine and dried over MgSO4. Evaporation of Et2O followed by medium pressure chromatography (MPLC) of the remaining oil in 20% EtOAc/Hexanes gives 4.4 g (89% yield) of 4-isopropyldihydro-furan-2-one as an oil. NMR (H1, 400 MHz, CDCl3) 0.9 (6H, m); 1.3 (2H, dd); 1.5 (1H, m); 2.1 (1H, m); 2.6 (2H, m); 3.6 (1H, m); 4.4(1 H, m). 1531 Preparation of 3-Bromomethyl-3-isobutyl-propionic acid ethyl ester (5): 1532 A solution of 4-isopropyl-dihydro-furan-2-one (4.4 g, 30.9 mmol) in absolute EtOH (50 mL) is cooled to 0 C. and saturated with HBr by passing HBr gas through it for 10 minutes. The solution is warmed to room temperature and stirred for 2.5 hours. It is diluted with 150 mL of brine and extracted with Et2O (3100 mL). Drying over MgSO4 followed by evaporation of the solvent gives 4.9 g (63% yield) of 3-bromomethyl-3-isobutyl-propionic acid ethyl ester as an oil. NMR (H1, 300 MHz, CDCl3) 0.9 (6H, d); 8 1.3 (5H, m); 1.6 (1H, m); 2.3 (1 H, m); 8 2.5 (1H, dd); 3.2 (1H, dd); 3.6 (1H, dd); 4.1 (2H, q). 1533 Preparation of 3-(Diethoxy-phosphorylmethyl)-5-methyl-hexanoic acid ethyl ester (6): 1534 3-Bromomethyl-3-isobutyl-propionic acid ethyl ester (4.6 g, 18.3 mmol) is warmed in a 170 C. oil bath under Ar. Triethyl phosphite (3.6 g, 22 mmol) is added dropwise over 2 hours. When addition is complete, the oil bath temperature is raised to 190 C. for 4 hours. The reaction mixture is cooled to room temperature, and the product is purified by MPLC in EtOAc to give 2.7 g (48% yield) of 3-(diethoxy-phosphorylmethyl)-5-methyl-hexanoic acid ethyl ester. NMR (H1, 400 MHz, CDCl3) 0.8 (6H, d); 1.2 (5H, m); 1.3 (6H, m); 1.6 (1H, m); 1.7 (1H, d); 1.8 (1H, d); 2.3 (2H, m); 2.5 (1H, dd); 4.1 (6H, m). 1535 Preparation of 3-(Diethoxy-phosphorylmethyl)-5-methyl-hexanoic acid (7): 1536 3-(Diethoxy-phosphorylmethyl)-5-methyl-hexanoic acid ethyl ester (1.0 g, 3.2 mmol) and NaOH (1.8 mL, 2.0 M) are combined in 10 mL of EtOH at 0 C. After 15 minutes, the reaction mixture is warmed to room temperature and stirred overnight. The EtOH is evaporated, and 50 mL of 2.0 M NaOH is added. The solution is extracted with Et2O (250 mL), and then acidified to pH1 with concentrated HCl. The acidic solution is extracted with EtOAc (350 mL), and the combined extracts are dried over MgSO4 and evaporated to give 0.65 g (72% yield) of 3-(diethoxy-phosphorylmethyl)-5-methyl-hexanoic acid as an oil. NMR (H1, 400 MHz, CDCl3) 0.9 (6H, d); 1.3 (8H, m); 1.6 (1H, m); 1.8 (2H, m); 2.3 (1 H, m); 2.5 (2H, m); 4.1 (4H, m). 1537 Preparation of 2-(Benzyloxycarbonylamino-methyl)-4-methyl-pentyl)phosphonic acid diethyl ester (8): 1538 A solution 3-(Diethoxy-phosphorylmethyl)5-methyl-hexanoic acid (0.65 g, 2.3 mmol), diphenyl-di-phosphoryl-azide (0.76 g, 2.8 mmol), triethyl amine (0.47 g, 4.6 mmol), and benzyl alcohol (0.5 g, 4.6 mmol) in 100 mL of toluene is warmed to reflux overnight. The toluene is evaporated, and the remaining oil is taken up in 50 mL of EtOAc. The EtOAc solution is washed with 1.0N HCl (250 mL), saturated NaHCO3 (250 mL), and 50 mL of brine. Drying over Na2SO4 followed by evaporation of the solvent gives an oil which is purified by MPLC in EtOAc. Yield of 2-(benzyloxycarbonylamino-methyl)-4-methyl-pentyl-phosphonic acid diethyl ester0.46 g (52%). NMR (H1, 400 MHz, CDCl3) 0.9 (6H, m); 1.1-1.4 (9H, m); 1.7 (2H, m); 2.0 (1H, m); 3.1 (1H, m); 3.3 (1H, m); 4.1 (4H, q); 5.0 (2H, s); 5.7 (1H, bs); 7.3 (5H, m). 1539 Preparation of (2-Aminomethyl-4-methyl-pentyl)-phosphonic acid (9): 1540 A solution of 2-(benzyloxycarbonylamino-methyl)-4-methyl-pentyl-phosphonic acid diethyl ester (0.46 g, 1.2 mmol) in 20 mL of 47% aqueous HBr is warmed at reflux overnight. The solution is cooled to room temperature, and the H2O is evaporated. The remaining solid is taken up in 10 mL of H2O, filtered through Celite 545, and passed through a Dowex 50 ion exchange column (Bed Volume30 mL). The column is eluted with 200 mL of H2O, 150 mL of 3% NH4OH, and 150 mL of 10% NH4OH. The basic eluates are combined and evaporated to give 0.14 g of a white solid. After drying under vacuum at 60 C. with P2O2, the yield of 0.11 g (47%) of Example 33, (2-Aminomethyl-4-methyl-pentyl)-phosphonic acid, was obtained. NMR (H1, 400 MHz, CD3OD) 0.9 (6H, m); 1.2 (2H, t); 1.4 (1H, m); 1.7(2H, m); 2.1 (1H, m); 2.7 (1H, dd); 3.0 (1H, dd). MS (m/e) 196 (M1, 100%. Analysis for C7H18NO3P: Calculated: C, 43.07; H, 9.29; N, 7.18. Found: C, 43.08; H, 8.62; N, 6.89. 1541 The following examples are illustrative of the preparation of compounds of Formulas V-VIII.

EXAMPLE 34 1542 ()-(1,6)(2-Aminomethyl-octahydro-inden-2-yl)-acetic acid hydrochloride 82

1543 Step (i) 1544 Sodium hydride (0.11 mg, 2.7 mmol) was stirred with THF (5 mL) at 0 C. under argon. Triethylphosphonoacetate (0.5 mL) was added dropwise and the solution stirred for 10 minutes. The ketone (0.37 g, 7.7 mmol) in THF (5 mL) was added dropwise with stirring and left to warm to room temperature. After 18 hours, the reaction mixture was separated between water (80 mL) and diethyl ether (320 mL). Solvent was removed in vacuo to give a yellow oil, which was purified via flash chromatography (silica, heptane/EtOAc 19:1). To give 0.34 g (62%) of the ester as a colorless oil: 1545 1H NMR (CDCl3) (400 MHz): 1.05-1.29 (9H, m, ring protonsCH3), 1.76-1.78 (2H, m, ring protons), 1.87-1.97 (2H, m, ring protons), 2.0-2.16 (2H, m, ring protons), 2.51-2.56 (1H, dd, J5.7, 27.5 Hz, ring protons), 3.12-3.18 (1 H, dd, J5.4, 18.8 Hz, ring protons), 4.12-4.20 (2H, m, CH2), 5.77 (1H, s, CH). MS (ES) m/e 209 MH) 100%. 1546 Step (ii) 1547 Ester (0.34 g, 1.63 mmol) was dissolved in THF (5 mL), with stirring under argon. Nitromethane (0.25 mL) was added and the reaction mixture heated to 60 C. TBAF (2.3 mL) was added dropwise to the hot solution over 1 hour and stirred for 4 hours. The reaction mixture was partitioned between 2N HCl and diethyl ether, and the diethyl ether layer was washed with brine. Solvent was removed in vacuo to give a yellow oil, which was purified via flash chromatography (silica, heptane/EtOAc, 19:1), to give 0.264 g (60%) of the product as a colorless oil. 1548 1H NMR (CDCl3) (400 MHz): 0.97-1.30 (11H, m, ring protonsCH3), 1.73-1.95 (6H, m, 2CH4 ring protons), 2.5 (1H, d, J16.6 Hz, CH2CO2Et), 2.7 (1H, d, J16.6 Hz, CH2CO2Et, 4.12-4.18 (2H, m, CH2), 4.49-4.51 (1H, d, J11.5 Hz, CH2NO2), 4.73-4.75 (1H, d, J11.5 Hz, CH2NO2). 1549 Step (iii) 1550 Nitroester (0.24 g, 0.9 mmol) was dissolved in methanol with Nickel sponge. Reaction was hydrogenated at 50 psi, 30 C. for 15 hours. The reaction mixture was filtered through celite, and the solvent removed in vacuo to give the product 0.18 g (85%) as a yellow solid. This product was a mixture of lactam and amino ester. 1551 Step (iv) 1552 Amino ester was taken up in 6N HCl (5 mL) and dioxane (2.5 mL), and heated to reflux for 4 hours. The solution was washed with dichloromethane (35 mL), and the aqueous fraction was evaporated in vacuo to give 0.196 g (99%) of Example 34 as a colorless solid. 1553 1H NMR (DMSO) (400 MHz): 0.86-1.04 (2H, m), 1.08-1.17 (6H, m), 1.60-1.78 (6H, m), 2.35-2.39 (1H, d, J16 Hz, CH2CO2H), 2.46 (1H, m, CH2CO2H), 2.83-2.87 (1H, d, J13 Hz, CH2NH2), 2.97-3.00 (1H, d, J13 Hz, CH2NH2), 7.91 (2H, bs, NH2). 1554 MS (ES) m/e 212 MH 100%. 1555 HPLC, Prodigy C18 column, 5% methanol/acetonitrile. Retention time3.00 minutes, and a purity of 99%.

EXAMPLE 35 1556 ()-(1,5)(2-Aminomethyl-octahydro-pentalen-2-yl)-acetic acid hydrochloride 83

1557 Step (i) 1558 Sodium hydride (0.6 g, 14.5 mmol) was stirred with THF (50 mL) at 0 C. under argon. Triethylphosphonoacetate (2.9 mL) was added dropwise and the solution stirred for 10 minutes. The ketone (1.8 g, 14.5 mmol) in THF (10 mL) was added dropwise with stirring and left to warm to room temperature. After 18 hours, the reaction mixture was separated between water (250 mL) and diethyl ether (350 mL). Solvent was removed in vacuo to give a yellow oil, which was purified via flash chromatography (silica, heptane/EtOAc 19:1). To give 1.95 g (69%) of the ester was a colorless oil. 1H NMR (CDCl3) (400 MHz): 1.14-1.19 (2H, m, CH2), 1.25-1.29 (3H, m, CH3), 1.55-1.79 (4H, m, 2CH2), 2.03-2.10 (4H, m, 2CH2), 2.45-2.55 (1H, dd, CH), 3.05-3.15 (1H, dd, CH), 4.12-4.17 (2H, q, J7.3, 14.4 Hz, COCH2, 5.76 (1H, m, CH). 1559 Step (ii) 1560 Ester (1.9 g, 10 nunol) was dissolved in THF (15 mL), with stirring under argon. Nitromethane (1.4 mL) was added, and the reaction mixture heated to 60 C. TBAF (14 mL) was added dropwise to the hot solution over 1 hour, and stirred for 5 hours. The reaction mixture was separated between 2N HCl and diethyl ether, and then the ether layer was washed with brine. Diethyl ether was removed in vacuo to give an orange oil, which was purified via flash chromatography (silica, heptane/EtOAc, 19:1), to give 1.59 g (64%) of the product as a colorless oil. 1H NMR (CDCl3) (400 MHz): 1.14-1.31 (7H, m, CH3ring protons), 1.64-1.72 (5H, m, ring protons), 1.03-1.09 (1H, m, ring protons), 2.00-2.05 (2H, m, ring protons), 2.57-2.61 (1H, d, J16.4 Hz, CH2CO2Et), 2.71-2.75 (1H, d, J16.4 Hz, CH2CO2Et), 4.12-4.18 (2H, q, J7.1, 14.2 Hz, OCH2CH3), 4.56-4.59 (1H, d, J11.5 Hz, CH2NO2), 4.77-4.80 (1H, d, J11.5 Hz, CH2NO2). IR (neat) 2957, 2870, 1731, 1547, 1374, 1182, 1030 cm1. 1561 Step (iii) 1562 Nitroester (1.59 g, 5.9 mmol) was dissolved in methanol (40 mL) with Nickel sponge. Reaction was hydrogenated at 50 psi, 30 C. for 5 hours. The reaction mixture was filtered through celite, and the solvent removed in vacuo to give the lactam 1.08 g (97%) as an off-white solid. 1H NMR (CDCl3) (400 MHz): 1.08-1.11 (2H, m, ring protons), 1.23-1.28 (2H, m, ring protons), 1.62-1.68 (4H, m), 1.82-1.89 (2H, m), 2.00-2.06 (2H, m), 2.30-2.40 (2H, m, CH2CO), 3.29-3.30 (2H, M, CH2NH), 5.45 (1H, bs, NH). MS (ES) m/e 180 MH 3%, 359 2MH 21%, 381 2MNa 100%. 1563 Step (iv) 1564 Lactam was taken up in 6N HC 1 (20 mL) and dioxane (8 mL), and heated to reflux for 4 hours. The solution was washed with dichloromethane (310 mL), and the aqueous fraction was evaporated in vacuo to give 0.65 g (84%) of Example 35 as a colorless solid. 1H NMR (DMSO) (400 MHz): 1.0-1.18 (4H, m, ring protons), 1.52-1.72 (6H, m, ring protons), 1.95-2.02 (2H, m, ring protons), 2.33-2.67 (2H, m, CH2CO2H), 2.90-2.94 (1H, d, J12.9 Hz, CH2NH2), 3.00-3.03 (1H, d, J12.7 Hz, CH2NH2), 7.94 (2H, bs, NH2). MS (ES) m/e 198 MH 100%. LCMS (ELSD) Prodigy ODS3 50 mm2 mm column, 5%-50% MeCN/H2O. Retention time2.30 minutes, mass found198. 100% purity.

EXAMPLE 36 1565 (1,3,5)(2-Aminomethyl-octahydro-pentalen-2-yl)-acetic acid hydrochloride 84

1566 Step (i) 1567 To a suspension of NaH (0.45 g, 11.3 mmol) in THF (25 mL), at 0 C. under argon, was slowly added (over 10 minutes) triethylphosphonoacetate (2.3 mL, 11.6 mmol), followed by 5 (1.29 g, 10.4 mmol in 23 mL THF). The reaction was allowed to warm to room temperature and left to stir for 4 hours, after which it was diluted with water (100 mL), extracted with ether (2200 mL), washed with saturated brine (50 mL), and dried (MgSO4). Column chromatography (9:1 heptane/ethyl acetate) gave the product as a colorless oil, 1.75 g, 86%. IR (thin film) (cm1) 2964, 1713, 1655, 1371, 1208, 1125, 1040. 1H NMR (CDCl3): 5.72 (1H, m), 4.14 (2H, q, J7.2), 3.02-2.92 (1H, m), 2.72-2.54 (3H, m), 2.52-2.42 (1H, m), 2.28-2.20 (1H, m), 1.85-1.31 (6H, m), 1.27 (3H, t, J7.2). (m/z AP195 (MI1) at 100%. 1568 Step (ii) 1569 To a solution of 6 (2.75 g, 22.2 mmol) in THF (22 mL) was added TBAF (24 mL, 24.0 mmol) followed by nitromethane (4.4 mL, 8.14 mmol). The reaction was heated (oil bath at 60 C.) for 4.75 hours, after which it was diluted with ethyl acetate (100 mL) and washed with 2 M HCl (30 mL), followed by saturated brine (40 mL), dried (MgSO4), and concentrated under reduced pressure. Column chromatography (9:1 heptane/ethyl acetate) gave the product as a colorless oil, 0.73 g, 20%. The product was found by 1H NMR to be a 9:1 mixture of diastereoisomers. 1H NMR (CDCl3): 4.67 (1H, s), 4.60 (1H, s), 4.15 (2H, q, J7.2), 4.14 (2H, q, 7.2), 2.58 (2H, s), 2.49 (2H, s), 2.12-2.0 (2H2H, m), 1.63-1.49 (4H4H, m), 1.44-1.36 (2H2H, m), 1.28 (3H, t, J7.2), 1.27 (3H, t, J7), 1.16-1.04 (2H2H, m). 1570 Step (iii) 1571 Compound 7 (0.88 g, 3.45 mmol) in methanol (100 mL) with nickel sponge catalyst underwent hydrogenation at 30 C. and a pressure of 56 psi; this was left for 5 hours. Before use, the nickel sponge catalyst was washed several times, first with water and then methanol. After hydrogenation was complete, the reaction mixture was filtered through celite and the resulting solution concentrated in vacuo to give a yellow solid, 0.62 g, 80%. 1H NMR (CDCl3): 5.43 (1H, br s), 3.15 (2H, s), 2.56-2.44 (3H, m), 1.99 (2H, dd, J12.6, 8.2), 1.64-1.50 (2H, m), 1.44-1.34 (3H, m), 1.22-1.14 (2H, m). m/z ES 226 (MI1) at 100%. 1572 Step (iv) 1573 Compound 8 (0.61 g, 2.7 mmol) in dioxane (10 mL) and 6 M HCl (30 mL) was heated to reflux (oil bath at 100 C.) for 4 hours. After cooling, the reaction was diluted with water (40 mL) and the reaction mixture washed with dichloromethane (340 mL) and concentrated in vacuo to yield Example 36 as a white crystalline product as a 6:1 ratio of diastereoisomers. The product was recrystallized twice from ethyl acetate/methanol to give a 10:1 mixture of diastereoisomers. m/z ES 198 (MI1) at 100%. 1574 1H NMR (D2O): 3.03 (2H, s), 2.50-2.36 (4H, m), 1.84 (2H, dd, J12, 8), 1.41 (4H, s), 1.02 (2H, m). HPLC columnProdigy ODS 3, room temperature0.87, Purity100%.

EXAMPLE 37 1575 (1,6,8)(2-octahydro-inden-2-yl)-acetic acid hydrochloride 85

1576 Synthesis of Compound 1 1577 Indian-2-one (1.0 g, 7.7 mmol), ethylene glycol (0.43 mL, 7.6 mmol), and para-toluene sulphonic acid were refluxed in benzene (40 mL) using a Dean-Stark trap for 6 hours. The mixture was allowed to cool and was then diluted with ethyl acetate (100 mL) and washed with saturated sodium hydrogen carbonate solution (60 mL). The organic layer was separated off, and the aqueous layer was extracted further with ethyl acetate (250 mL). The combined organic fractions were washed with brine, dried (MgSO4), and the solvent was evaporated under reduced pressure. The residue was chromatographed (SiO2, heptane/ethyl acetate, 97:3) to give the acetal 1 (1.14 g, 85%) as a colorless oil; Rf(heptane/ethyl acetate, 8:2) 0.36; vmax(film)/cm1 1483, 1331, 1291, 1105; H (400 MHz; CDCl3): 7.19-7.14 (4H, m, Ph), 4.02 (4H, s, 2CH2CO2, 3.18 (4H, s, 2CH2O). 1578 Synthesis of Compound 2 1579 Acetal 1 (0.5 g, 2.84 mmol) in ethanol (50 mL) was shaken over a catalytic amount of 5% rhodium on alumina under a hydrogen atmosphere (70 Psi, 50 C.) for 16 hours. The catalyst was filtered off, and the solvent was evaporated under reduced pressure to give the acetal 2 (0.51 g, 99%) as a colorless oil; max,.(film)/cm1 2923, 1449, 1337, 1192, 1115, 1089; H (400 MHz; CDCl3): 3.89-3.86 (4H, m, 2CH2O), 2.10-2.00 (2H, m), 1.88 (2H, dd, J13.9, 7.6), 1.81 (2H, dd, J13.7, 7.0), 1.56-1.26 (6H, m). 1580 Synthesis of Compound 3 1581 Acetal 2 (1.01 g, 5.54 mmol) was stirred in a mixture of 2N hydrochloric acid (10 mL) and acetone (10 mL) for 24 hours. After this time, tlc showed complete consumption of the starting acetal. Saturated sodium carbonate solution (20 mL) was added, and the mixture was extracted with ether (325 mL). The combined ether fractions were washed with brine, dried (MgSO4), and the solvent was evaporated under reduced pressure. The residue was chromatographed (SiO2, pentane/ether, 95:5) to give the ketone 3 (0.75 g, 97%) as a colorless oil; Rf (heptane/ethyl acetate, 8:2) 0.42; max(film)/cm1 1743 (CO); H (400 MHz; CDCl3): 2.37-2.28 (2H, m), 2.20 (2H, dd, J18.5, 7.5), 2.12 (2H, dd, J18.7, 6.3), 1.65-1.24 (10H, m). 1582 Synthesis of Compound 4 1583 Triethyl phosphonoacetate (1.13 mL, 5.70 mmol) was added dropwise to a stirring suspension of sodium hydride (0.22 g of a 60% dispersion in oil, 5.43 mmol) in THF (15 mL) at 0 C. under argon. After 20 minutes, ketone 3 (0.75 g, 5.43 mmol) in THF (6 mL) was added dropwise. The mixture was allowed to warm to room temperature and stirred for 16 hours. Water (5 mL) was added, and the mixture was extracted with ether (15 mL3). The combined organic fractions were washed with brine and dried (MgSO4). The solvent was evaporated under reduced pressure. The residue was chromatographed (SiO2, heptane/ethyl acetate, 95:5) to give the ester 4 (0.81 g, 72%) as a colorless oil; Rf(heptane/ethyl acetate, 8:2) 0.66; max(film)/cm1 1715 (CO), 1652 (CC); H (400 MHz; CDCl3): 5.80 (1H, quint, J2.2, CHCO2Et), 4.15 (2H, q, J7.1, CO2CH2Me), 2.79 (1H, dd, J19.5, 8.1), 2.69 (1H, ddt, J19.8, 7.3, 2.3), 2.47 (1H, dd, J17.3, 7.2), 2.34 (1H, ddt, J17.3, 5.6, 1.8), 2.14 (1H, m), 2.02 (1H, m), 1.60-1.22 (8H, m); m/z (ES) 209 (MH, 57%), 455 (2MK, 67). 1584 Synthesis of Compounds 5 and 6 1585 Ester 4 (0.45 g, 2.16 mmol), nitromethane (0.24 mL, 4.31 mmol), and tetra-butylammonium fluoride (3.10 mmol of a 1 M solution in THF, 3.10 mmol) were heated to 65 C. in THF for 4 hours. The mixture was allowed to cool, diluted with ethyl acetate (20 mL), and acidified with dilute hydrochloric acid (15 mL). The organic layer was separated off, and the aqueous layer was further extracted with ethyl acetate (215 mL). The combined organic fractions were washed with brine, dried (MgSO4), and the solvent was evaporated under reduced pressure. The residue was chromatographed (SiO2, heptane/ethyl acetate, 98:2) to give a 9:1 ratio of nitro-esters 5 and 6 (0.35 g, 60%) as a yellow oil; Rf(heptane/ethyl acetate, 9:1) 0.28; max(film)/cm1 1732 (CO), 1547 (NO2), 1375 (NO2); major isomer 5: H (400 MHz; CDCl3): 4.61 (2H, s, CH2NO2), 4.15 (2H, q, J7.2, OCH2Me), 2.70 (2H, s, CH2CO2Et), 2.06 (2H, m), 1.81 (2H, dd, J13.9, 7.1), 1.56 (2H, dd, J13.1, 6.8), 1.51-1.22 (8H, m)1.28 (3H, t, J7.2). 1586 Synthesis of Compounds 7 and 8 1587 The mixture of 5 and 6 (0.81 g, 3.01 mmol) in methanol (30 mL) was shaken over a catalytic amount of nickel sponge catalyst under a hydrogen atmosphere (50 Psi, 30 C.) for 12 hours. The mixture was filtered, and the solvent was evaporated under reduced pressure to give a 9:1 mixture of amino-esters 7 and 8 (0.42 g, 72%) as a white solid; max(film)/cm1 3214 (NH), 1706 (CO); major isomer 7: H (400 MHz; CDCl3): 5.57 (1H, br s, NH), 3.20 (2H, s, CH2NH), 2.36 (2H, s, CH2CO), 2.04-1.94 (2H, m), 1.77 (2H, dd, J13.2, 7.0), 1.62 (2H, dd, J13.4, 6.7), 1.60-1.20 (8H, m); m/z (ES) 387 (2MH, 97%). 1588 Synthesis of Example 37 1589 (1,6,8)(2-Aminomethyl-octahydro-inden-2-yl)-acetic acid hydrochloride. The mixture of 7 and 8 (0.42 g, 2.17 mmol) was dissolved in 1,4-dioxane (8 mL) and hydrochloric acid (20 mL of a 6N solution), and the mixture was refluxed for 6 hours. After cooling, the mixture was diluted with water (20 mL) and washed with dichloromethane (215 mL). The aqueous layer was evaporated under reduced pressure to give a 9:1 mixture of acids 9 and 10 (0.43 g, 79%) as a white solid. Recrystallization using ethyl acetate/methanol gave acid Example 37 exclusively (0.27 g); H (400 MHz; d6-DMSO): 12.3 (1H, br s, CO2H), 7.94 (2H, br s, NH2), 2.90 (2H, s, CH2NH2), 2.52 (2H, s, CH2CO2H), 1.97 (2H, br s), 1.65 (2H, dd, J13.5, 6.7), 1.54-1.20 (10H, m); m/z (ES) 212 (MH, 100%); (Found: C, 56.4; H, 8.74; N, 5.43 C12H21NO2.1HCl.0.5H2O requires C, 56.1; H, 9.03; N, 5.45%); LCMS (Prodigy C18 50 mm4.6 mmid column, 5%-50% Acetonitrile/water); Retention Time1.53 minutes, 98% purity.

EXAMPLE 38 1590 ((1,6,8)(2-Aminomethyl-octahydro-inden-2-yl)-acetic acid hydrochloride 86

1591 Synthesis of Compound 1 1592 n-Butyllithium (5.1 mL of a 2.5 M solution in hexanes, 12.75 mmol) was added dropwise to a stirring mixture of nitromethane (0.34 mL, 6.3 mmol) in THF (20 mL) and HMPA (2 mL) at 78 C. under argon. The mixture was allowed to warm to 60 C. and stirred for 1 hour. The mixture was cooled to 78 C. and 3 (0.79 g, 5.73 mmol) was added. The mixture was allowed to warm to 60 C. and stirred for a further 2 hours. The mixture was quenched by addition of saturated ammonium chloride solution (5 mL). After warming to room temperature, dilute hydrochloric acid (10 mL) and ether (30 mL) were added. The organic layer was separated, and the aqueous layer was further extracted with ether (225 mL). The combined organic fractions were washed with brine, dried (MgSO4), and the solvent was evaporated under reduced pressure. The residue was chromatographed (SiO2, heptane/ethyl acetate, 95:5) to give the nitro-alcohol 1 (0.50 g, 43%) as a white solid; Rf(heptane/ethyl acetate, 9:1) 0.14; max(CH2Cl2)/cm1 3424 (OH), 1548 (NO2), 1379 (NO2); H (400 MHz; CDCl3): 4.45 (2H, s, CH2NO2), 3.26 (1H, s, OH), 2.04-1.95 (2H, m), 1.85-1.80 (4H, m), 1.64-1.24 (8H, m). 1593 Synthesis of Compound 2 1594 A mixture of 1 (0.50 g, 2.49 mmol) and concentrated sulphuric acid (1 drop) was heated to 50 C. in acetic anhydride (1 mL) for 5 minutes. The mixture was allowed to cool and then partitioned between ether (100 mL) and water (50 mL). The ether layer was washed with brine, dried (MgSO4), and the solvent was evaporated under reduced pressure to give the nitro-acetate 2 (0.49 g, 82%) as a colorless oil; Rf(heptane/ethyl acetate, 9:1) 0.44; max(film)/cm1 1739 (CO), 1551 (NO2), 1375 (NO2); H (400 MHz; CDCl3): 4.88 (2H, s, CH2NO2), 2.38-2.00 (8H, m), 2.07 (3H, s, MeCO), 1.62-1.32 (6H, m). 1595 Synthesis of Compound 3 1596 Potassium methoxide (0.15 g, 2.04 mmol) in methanol (3 mL) was added dropwise to a stirring solution of 2 (0.49 g, 2.04 mmol) in methanol (5 mL) at 0 C. After 10 minutes, the mixture was partitioned between ether (100 mL) and water (50 mL). The ether layer was washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was chromatographed (SiO2, pentane/ether, 98:2) to give the nitro-alkene 3 (0.21 g, 57%) as a pale yellow oil; Rf(heptane/ethyl acetate, 8:2) 0.54; max(film)/cm1 1643 (CC), 1509 (NO2), 1342 (NO2); H (400 MHz; CDCl3): 7.12 (1H, quint,J2.0, CHNO2), 3.01 (1H, ddt, J20.5, 8.0, 2.1), 2.90 (1H, ddt, J20.5, 7.3, 2.1), 2.54 (1H, ddt, J17.8, 7.1, 2.0), 2.43 (1H, ddt, J17.7, 5.6, 1.9), 2.21 (1H, m), 2.12 (1H, m), 1.60-1:24 (8H, m). 1597 Synthesis of Compound 4 1598 Ethyl acetate (0.12 mL, 1.22 mmol) in THF (2 mL) was added dropwise to a stirring solution of lithium bis(trimethylsilyl)amide (1.22 mL of a 1 M solution in THF, 1.22 mmol) at 78 C. under argon. After 20 minutes, 3 (0.21 g, 1.16 mmol) in THF (1 mL) was added, and the mixture was stirred for 2 hours. The mixture was quenched by addition of saturated ammonium chloride solution (3 mL) and allowed to warm to room temperature. The mixture was diluted with ether (20 mL) and dilute hydrochloric acid (15 mL) was added. The organic layer was separated, and the aqueous layer was further extracted with ether (210 mL). The combined organic fractions were washed with brine, dried (MgSO4), and the solvent was evaporated under reduced pressure. The residue was chromatographed (SiO2, heptane/ethyl acetate, 99:1) to give the nitro-ester 4 (0.13 g, 41%) as a colorless liquid; Rf(heptane/ethyl acetate, 9:1) 0.32; max(film)/cm1 1731 (CO), 1547 (NO2), 1375 (NO2); H (400 MHz; CDCl3): 4.73 (2H, s, CH2NO2), 4.14 (2H, q, J7.1, CO2CH2Me), 2.58 (2H, s, CH2CO2Et), 2.07 (2H, m), 1.71-1.66 (4H, m), 1.60-1.24 (8H, m), 1.26 (3H, t, J7.2, CO2CH2Me); m/z (ES) 270 (MH, 100%). 1599 Synthesis of Compound 5 1600 4 (0.122 g, 0.45 mmol) in methanol (40 mL) was shaken over a catalytic amount of nickel sponge catalyst under a hydrogen atmosphere (60 Psi, 30 C.) for 6 hours. The mixture was filtered and the solvent was evaporated under reduced pressure to give amino-ester 5 (0.084 g, 96%) as a white solid; max(film)/cm1 3228 (NH), 1665 (CO); H (400 MHz; CDCl3): 5.49 (1H, br s, NH), 3.34 (2H, s, CH2NH), 2.25 (2H, s, CH2CO), 2.10-1.98 (2H, m),1.77 (2H, dd, J13.2, 7.1), 1.65 (2H, dd, J13.2, 6.8), 1.62-1.20 (8H, m). 1601 Synthesis of Example 38 1602 (2-Aminomethyl-octahydro-inden-2-yl)-acetic acid 5 (0.083 g, 0.43 mmol) was dissolved in 1,4-dioxane (2 mL) and hydrochloric acid (8 mL of a 6N solution), and the mixture was refluxed for 5 hours. After cooling, the mixture was diluted with water (20 mL) and washed with dichloromethane (215 mL). The aqueous layer was evaporated under reduced pressure to give the acid 6 (0.097 g, 91%) as a white solid. This was recrystallized using ethyl acetate/methanol to give pure Example 38 (0.057 g); H (400 MHz; d6-DMSO): 7.90 (2H, br s, NH2), 3.02 (2H, s, CH2NH2), 2.43 (2H, s, CH2CO2H), 2.00 (2H, br s), 1.53-1.24 (12H, m); m/z (ES) 212 (MH, 100%); LCMS (Prodigy C18 50 mm4.6 mmid column, 5%-50% Acetonitrile/water) Retention Time1.12 minutes, 100% purity.

EXAMPLE 39 1603 (1,3,5)(3-Aminomethyl-bicyclo3.2.0hept-3-yl)-acetic acid hydrochloride 87

1604 Synthesis of Compound 1 1605 Lithium aluminum hydride (69.4 mL of a 1 M solution in ether, 69.4 mmol) was added dropwise to a stirring solution of cis-cyclobutane-1,2-dicarboxylic acid (5 g, 34.7 mmol) in THF (60 mL) at 0 C. under argon. The mixture was allowed to warm to room temperature and stirred for 16 hours. The mixture was cooled to 0 C. and quenched by careful addition of water (2.7 mL), sodium hydroxide solution (2.7 mL of a 15% w/v solution), and water (8.1 mL). The mixture was stirred for 15 minutes, and the precipitate was removed by filtration. The solvent was evaporated under reduced pressure to give the alcohol 1 as a colorless oil (4.0 g, 98%); H (400 MHz; CDCl3): 3.85 (2H, m), 3.6 (2H, m), 3.2 (2H, s), 2.7 (2H, m), 2 (2H, m); 1.55 (2H, m); C (400 MHz; CDCl3): 63.15, 37.83, 20.40. 1606 Synthesis of Compound 2 1607 Mesyl chloride (6.2 mL, 79.1 mmol) was added dropwise to a stirring solution of 1 (4.0 g, 34.4 mmol) in dichloromethane (150 mL) at 40 C. under argon. Triethylamine (12.0 mL, 86.0 mmol) was then added dropwise, and the mixture was allowed to warm slowly to room temperature. After stirring for 16 hours, the mixture was quenched by addition of dilute hydrochloric acid (50 mL). The organic layer was separated, and the aqueous layer was further extracted with dichloromethane (250 mL). The combined organic fractions were washed with brine, dried (MgSO4), and the solvent was evaporated under reduced pressure. The residue was chromatographed (SiO2, heptane/ethyl acetate, 6:4) to give the mesylate 2 (6.1 g, 73%) as a white solid; Rf(heptane/ethyl acetate, 1:1) 0.18. H (400 MHz; CDCl3): 4.3 (4H, m), 3.05 (6H, s), 2.9 (2H, m), 2.2 (2H, m), 1.8 (2H, m); c(400 MHz; CDCl3): 69.51, 37.45, 35.28, 21.09. 1608 Synthesis of Compound 3 1609 Anhydrous lithium bromide (10.6 g, 121.8 mmol) was added to a stirring mixture of 2 (5.95 g, 24.4 mmol) in acetone (50 mL) under argon, and the mixture was refluxed for 2 hours. After cooling, the acetone was evaporated under reduced pressure, and the residue was taken up in ether (50 mL), washed with water (50 mL), brine, dried (MgSO4), and the solvent was evaporated under reduced pressure. The residue was chromatographed (SiO2, heptane/ethyl acetate, 95:5) to give the dibromide 3 (5.36 g, 86%) as an orange liquid; Rf(heptane-ethyl acetate, 8:2), 0.82. H (400 MHz; CDCl3): 3.6 (2H, m), 3.45 (2H, m), 2.85 (2H, m), 2.1 (2H, m), 1.7 (2H, m; c(400 MHz; CDCl3): 39.70, 33.79, 23.95. 1610 Synthesis of Compound 4 1611 To a cooled (0 C.) suspension of potassium hydride (1.58 g, 39.5 mmol) (previously washed 3 times with pentane) in tetrahydrofuran (22 mL) was added, under an argon atmosphere, a solution of methyl methylthiomethyl sulfoxide (1.36 mL, 13.04 mmol, previously dried over molecular sieves for 3 hours) in tetrahydrofuran (3 mL) over 1 hour. After stirring for a further 30 minutes, a solution of 3 (3.17 g, 13.1 mmol) in THF (2 mL) was added, at 0 C., over 1 hour. The reaction mixture was then allowed to warm up to room temperature and was stirred overnight. The mixture was quenched by addition of aqueous ammonium chloride (6 mL, 25%). After 10 minutes, the solid was filtered off and the filtrate concentrated. The residue was taken up in ether (20 mL) and 9N sulfuric acid (0.05 mL) was added. After stirring for 30 hours, saturated sodium hydrogen carbonate was added. The ether phase was separated and concentrated to 5 mL. Saturated sodium hydrogen sulphite (1.5 g) solution was added and the mixture stirred for 30 minutes. The phases were separated. The ethereal phase was stirred for further 30 minutes with a saturated sodium hydrogen sulphite (0.5 g) solution. The phases were separated, and the collected aqueous phases were treated with aqueous sodium hydroxide (5 mL, 20%) and extracted with ether. The ether phase was dried (MgSO4) and evaporated under reduced pressure to give 4 as a yellow liquid (0.16 g, 11%). H (400 MHz; CDCl3): 3.0 (2H, m), 2.15-2.45 (6H, m), 1.65 (2H, m). 1612 Synthesis of Compound 5 1613 Triethyl phosphonoacetate (0.32 mL, 1.61 mmol) was added dropwise to a stirring suspension of sodium hydride (0.059 g of a 60% dispersion in oil, 1.47 mmol) in THF (2 mL) at 0 C. under argon. After 20 minutes, ketone 4 (0.16 g, 1.45 mmol) in THF (1 mL) was added dropwise. The mixture was allowed to warm to room temperature and stirred for 16 hours. Water (5 mL) was added, and the mixture was extracted with ethyl acetate. The combined organic fractions were washed with brine and dried (MgSO4). The solvent was evaporated under reduced pressure. The residue was chromatographed (SiO2, heptane-ethyl acetate, 95:5) to give the ester 5 (0.166 g, 0.92 mmol, 64%) as a colorless oil; H (400 MHz; CDCl3): 5.9 (1H, s), 4.2 (2H, q), 3.15 (1H, d), 2.9 (1H, m), 2.8 (1H, m); 2.65 (2H, m), 2.3 (1H, d), 2.15 (2H, m), 1.5 (2H, m), 1.3 (3H, t); C (400 MHz; CDCl3): 169.51, 166.98, 113.37, 59.62, 43.23, 38.79, 38.45, 36.20, 25.62, 24.95, 14.44. 1614 Synthesis of Compound 6 1615 Ester 5 (0.152 g, 0.84 mmol), nitromethane (0.092 mL, 1.7 mmol), and tetra-butylammonium fluoride (1.03 mL of a 1 M solution in THF, 1.03 mmol) were heated to 65 C. in THF (1 mL) for 4 hours. The mixture was allowed to cool, diluted with ether (30 mL), and acidified with 2N hydrochloric acid (5 mL). The organic layer was washed with brine, dried (MgSO4), and the solvent was evaporated under reduced pressure. The residue was chromatographed (SiO2, heptane/ether, 95:5) to give nitro-ester 6 (0.085 g, 0.35 mmol, 41%) as a colorless liquid; H (400 MHz; CDCl3): 4.4 (2H, s), 4.15 (2H, q), 2.75 (2H, bs), 2.7 (2H, s), 2.3 (2H, m); 2.1 (2H, m), 1.65 (4H, m), 1.15 (3H, t); C (400 MHz; CDCl3): 171.48, 79.68, 60.52, 50.10, 44.15, 41.06, 37.36, 25.76, 14.28. 1616 Synthesis of Compounds 7A and 7B 1617 Nitro-ester 6 (0.076 g, 0.31 mmol) in methanol (10 mL) was shaken over a catalytic amount of nickel sponge catalyst under a hydrogen atmosphere (50 Psi, 30 C.) for 12 hours. The mixture was filtered, and the solvent was evaporated under reduced pressure to give a mixture of lactam 7A and amino-ester 7B (0.05 g) as a white solid. This was used without further purification and characterization. 1618 Synthesis of Example 39 1619 7A and 7B (0.05 g) were dissolved in hydrochloric acid (2 mL of a 6N solution), and the mixture was refluxed for 4 hours. After cooling, solvent was evaporated under reduced pressure to give the acid as a white solid. This was recrystallized using ethyl acetate/methanol to give pure Example 39 (0.045 g, 0.2 mmol, 64%); H (400 MHz; D2O): 3 (2H, s), 2.85 (4H, ms), 2.35 (2H, m), 2.1 (2H, m), 1.75 (4H, m). C (400 MHz; D2O): 167.5, 46.64, 43.89, 42.03, 40.89, 36.08, 23.91. m/z (ES) 184 (MH, 100%).

EXAMPLE 40 1620 ()-(1,5)(3-aminomethyl-bicyclo3.2.0hepty-3-yl)-ascetic acid hydrochloride 88

1621 Synthesis of Compound 1 1622 Lithium aluminum hydride (134.8 mL of a 1 M solution in ether, 134.8 mmol) was added dropwise to a stirring solution of cis-cyclobutane-1,2-dicarboxylic acid (9.71 g, 67.39 mmol) in THF (120 mL) at 0 C. under argon. The mixture was allowed to warm to room temperature and stirred for 16 hours. The mixture was cooled to 0 C. and quenched by careful addition of water (5.2 mL), sodium hydroxide solution (5.2 mL of a 15% w/v solution), and water (15.7 mL). The mixture was stirred for 15 minutes, and the precipitate was removed by filtration. The solvent was evaporated under reduced pressure to give the alcohol 1 as a pale yellow oil (6.73 g, 57.64 mmol, 85%); H (400 MHz; CDCl3): 3.85 (2H, m), 3.6 (2H, m), 2.9 (2H, s), 2.7 (2H, m), 2 (2H, m); 1.55 (2H, m). 1623 Synthesis of Compound 2 1624 Mesyl chloride (29.3 mL, 373.8 mmol) was added dropwise to a stirring solution of 1 (8.85 g, 75.8 mmol) in dichloromethane (500 mL) at 40 C. under argon. Triethylamine (63.4 mL, 454.4 mmol) was then added dropwise, and the mixture was allowed to warm slowly to room temperature. After stirring for 16 hours, the mixture was quenched by addition of dilute hydrochloric acid (100 mL). The organic layer was separated, and the aqueous layer was further extracted with dichloromethane (2100 mL). The combined organic fractions were washed with brine, dried (MgSO4), and the solvent was evaporated under reduced pressure. The residue was chromatographed (SiO2, heptane-ethyl acetate, 6:4) to give the mesylate 2 (15.89 g, 58.3 mmol, 77%) as a white solid; H (400 MHz; CDCl3): 3.0 (6H, m), 2.6 (2H, m), 2.05 (2H, m), 1.8 (2H, m). 1625 Synthesis of Compound 3 1626 Anhydrous lithium bromide (25 g, 287.3 mmol) was added to a stirring mixture of 2 (15.84 g, 57.4 mmol) in acetone (150 mL) under argon, and the mixture was refluxed for 2 hours. After cooling, the acetone was evaporated under reduced pressure, and the residue was taken up in ether (100 mL), washed with water (100 mL), brine, dried (MgSO4), and the solvent was evaporated under reduced pressure to give the dibromide 3 (13.5 g, 55.8 mmol, 97%) as an orange liquid; H (400 MHz; CDCl3): 3.5 (4H, m), 2.45 (2H, m), 2.05 (2H, m), 1.6 (2H, m). 1627 Synthesis of Compound 4 1628 To a cooled (0 C.) suspension of potassium hydride (1.08 g, 27 mmol) (previously washed 3 times with pentane) in THF (15 mL) was added, under an argon atmosphere, a solution of methyl methylthiomethyl sulfoxide (0.93 mL, 8.92 mmol, previously dried over molecular sieves for 3 hours) in THF (2 nL) over a period of 1 hour. After stirring for a further 30 minutes, a solution of 3 (2.16 g, 8.93 mmol) in THF (1 mL) was added, at 0 C., over a period of 1 hour. The reaction mixture was then allowed to warm up to room temperature and was stirred overnight. The mixture was quenched by addition of aqueous ammonium chloride (6 mL, 25%). After 10 minutes, the solid was filtered off and the filtrate concentrated. The residue was taken up in ether (20 mL), and 9N sulfuric acid (0.03 mL) was added. After stirring for 30 hours, saturated sodium hydrogen carbonate was added. The ether phase was separated and concentrated to 5 mL. Saturated sodium hydrogen sulphite (1.5 g) solution was added and the mixture stirred for 30 minutes. The phases were separated. The ethereal phase was stirred for further 30 minutes with a saturated sodium hydrogen sulphite (0.5 g) solution. The phases were separated, and the collected aqueous phases were treated with aqueous sodium hydroxide (5 mL, 20%) and extracted with ether. The ether phase was dried (MgSO4), and the solvent was evaporated under reduced pressure to give 4 as a yellow liquid (0.141 H, 15%); SH (400 MHz; CDCl3): 2.25 (4H, m), 2.0 (4H, m), 1.7 (2H, m). 1629 Synthesis of Compound 5 1630 Triethyl phosphonoacetate (0.28 mL, 1.41 mmol) was added dropwise to a stirring suspension of sodium hydride (0.052 g of a 60% dispersion in oil, 1.29 mmol) in THF (2 mL) at 0 C. under argon. After 20 minutes, ketone 4 (0.141 g, 1.28 mmol) in THF (1 mL) was added dropwise. The mixture was allowed to warm to room temperature and stirred for 16 hours. Water (5 mL) was added, and the mixture was extracted. The combined organic fractions were washed with brine and dried (MgSO4). The solvent was evaporated under reduced pressure. The residue was chromatographed (SiO2, heptane/ethyl acetate, 95:5) to give the ester 5 (0.092 g, 0.51 mmol, 40%) as a colorless oil; H (400 MHz; CDCl3): 5.85 (1H, s), 4.1 (2H, q), 3.1 (1H, d.d), 2.45 (1H, d.d), 2.2 (2H, m), 1.75 (2H, m), 1.4 (2H, m), 1.25 (3H, t); C (400 MHz; CDCl3): 170.53, 166.57, 115.13, 59.62, 47.06, 45.69, 39.89, 37.24, 28.52, 28.17, 14.44. 1631 Synthesis of Compound 6 1632 Ester 5 (0.09 g, 0.5 mmol), nitromethane (0.055 mL, 1.02 mmol), and tetra-butylammonium fluoride (0.61 mL of a 1 M solution in THF, 0.61 mmol) were heated to 65 C. in THF (1 mL) for 4 hours. The mixture was allowed to cool, diluted with ether (30 mL), and acidified with 2N hydrochloric acid (5 mL). The organic layer was washed with brine, dried (MgSO4), and the solvent was evaporated under reduced pressure. The residue was chromatographed (SiO2, heptane/ether, 95:5) to give nitro-ester 6 (0.063 g, 0.26 mmol, 52%) as a colorless liquid. H (400 MHz; CDCl3): 4.65 (2H, ABq), 4.15 (2H, q), 2.65 (2H, ABq), 1.2-1.95 (3H, t and m, 13H); C (400 MHz; CDC13): 171.28, 82.42, 60.56, 49.97, 45.80, 45.32, 42.88, 40.19, 40.09, 27.64, 14.26. 1633 Synthesis of Compounds 7A and 7B 1634 Nitro-ester 6 (0.063 g, 0.26 mmol) in methanol (10 mL) was shaken over a catalytic amount of nickel sponge catalyst under a hydrogen atmosphere (50 Psi, 30 C.) for 12 hours. The mixture was filtered, and the solvent was evaporated under reduced pressure to give a mixture of lactam 7A and amino-ester 7B (0.051 g) as a white solid. This was used without further purification and characterization. 1635 Synthesis of Example 40 1636 7A and 7B (0.051 g) were dissolved in hydrochloric acid (2 mL of a 6N solution), and the mixture was refluxed for 4 hours. After cooling, solvent was evaporated under reduced pressure to give the acid as a white sold. This was recrystallized using ethyl acetate/methanol to give pure Example 40 (0.046 g, 0.21 mmol, 81%); H (400 MHz; D2O): 3.3 (2H, ABq), 2.7 (2H, ABq), 2 (2H, m), 1.35-1.85 (8H, m); C (400 MHz; D2O): 174.8, 47.50, 46.59, 44.28, 43.61, 41.64, 38.37, 38.09, 25.88. m/z (ES) 184 (MH, 100%).

EXAMPLE 41 1637 (1,3,5)(3-Aminomethyl-bicyclo3.2.0hept-3-yl)-acetic acid hydrochloride 89

1638 Synthesis of Compound (2) 1639 Dibromide 1 (5.7 g, 22.3 mmol), ethyl cyanoacetate (4.8 mL, 44.5 mmol) and potassium carbonate (6.15 g, 44.5 mmol) were stirred together in DMF (100 mL) for 48 hours. Dilute hydrochloric acid (100 mL) was added, and the mixture was extracted with ether (3100 mL). The combined organic fractions were washed with brine, dried (MgSO4), and the solvent was evaporated under reduced pressure. The residue was chromatographed (SiO2, heptane-ethyl acetate, 98:2) to give the cyanoester 2 (4.3 g, 100%) as a 68:32 mixture of diastereoisomers: Rf(heptane-ethyl acetate, 9:1) 0.28; max(film)/cm1 2241 (CN), 1741 (CO); Major diastereoisomer: H(400 MHz; CDCl3) 4.30 (2H, q, J7.1, CO2CH2Me), 2.98 (2H, m), 2.56-2.22 (6H, m), 1.70 (2H, m), 1.35 (3H, t, J7.1, Me); Minor diastereoisomer: H (400 MHz; CDCl3) 4.26 (2H, q, J 7.1, CO2CH2Me), 3.05 (2H, m), 2.56-2.22 (6H, m), 1.99 (2H, m), 1.33 (3H, t, J 7.1, Me). 1640 Synthesis of Compound (3) 1641 Cyanoester 2 (0.76 g, 3.91 mmol), water (0.14 mL, 7.82 mmol) and lithium chloride (0.66 g, 15.6 mmol) were heated to 150 C. in DMSO (40 mmL) for 22 hours. The mixture was allowed to cool, diluted with water (150 mL), and extracted with ether (350 mL). The combined ether fractions were washed with brine, dried (MgSO4), and the solvent was evaporated under reduced pressure. The residue was chromatographed (SiO2, heptane-ethyl acetate, 95:5) to give the cyanide 3 (0.21 g, 44%) as a 60:40 mixture of diastereoisomers; Rf(heptane-ethyl acetate, 9:1) 0.44; max(film)/cm1 2238 (CN); Major diastereoisomer: H (400 MHz; CDCl3) 2.97 (1H, m), 2.87 (2H, m), 2.32-2.18 (2H, m), 2.10-1.96 (3H, m), 1.92-1.78 (2H, m), 1.48-1.38 (1H, m); Minor diastereoisomer: H (400 MHz; CDCl3) 3.13 (1H, m), 2.87 (2H, m), 2.32-2.18 (2H, m), 2.10-1.96 (3H, m), 1.92-1.78 (2H, m), 1.48-1.38 (1H, m). 1642 Synthesis of Compound (4) 1643 Cyanide 3 (0.86 g, 7.1 mmol) in THF (30 mL) was added dropwise over 1 hour to a stirring mixture of lithium hexamethyldisilazide (7.8 mL of a 1 M solution in THF, 7.8 mmol) in THF (40 mL) at 78 C. under argon. The mixture was allowed to warm to 40 C. and stirred for 2 hours. The mixture was cooled to 78 C. and dimethylallyl bromide (1.3 mL, 10.6 mmol) was added. The mixture was stirred for a further 2 hours at 78 C. and then allowed to warm to room temperature overnight. Saturated ammonium chloride solution (20 mL) was added, and the mixture was diluted with ether (50 mL) and dilute hydrochloric acid (30 mL). The aqueous layer was further extracted with ether (250 mL), and the combined 15 organic fractions were washed with brine, dried (MgSO4), and the solvent was evaporated under reduced pressure. The residue was chromatographed (SiO2, heptane-ethyl acetate, 98:2) to give the cyanoalkene 4 (0.96 g, 72%) as a colorless oil; Rf(heptane-ethyl acetate, 95:5) 0.38; max(film)/cm1 2230 (CN),1673 (CC); H (400 MHz; CDCl3) 5.27 (1H, tt, J 7.6, 1.3, CHCMe2), 2.89 (2H, m), 2.30-2.22 (4H, m), 2.10 (2H, d, J 14.2), 1.94 (2H, m), 1.84-1.62 (2H, m), 1.65 (3 H, s, Me), 1.55 (3H, s, Me); m/z (AP) 190 (MH, 100%). 1644 Synthesis of Compound (5) 1645 Cyanoalkene 4 (0.96 g, 5.1 mmol) and sodium hydroxide (10.2 mL of a 2.5 M solution in methanol, 25.5 mmol) were stirred together in dichloromethane (80 mL) at 78 C. Ozone was passed through the mixture which immediately went orange. After 2 hours, the mixture turned to a green color, and the solution was purged with oxygen for 5 minutes and then with nitrogen. The stirring mixture was diluted with ether (100 mL) and water (100 mL) and allowed to warm to room temperature overnight. The aqueous layer was further extracted with ether (250 mL), and the combined organic fractions were washed with brine, dried (MgSO4), and the solvent was evaporated under reduced pressure. The residue was chromatographed (SiO2, heptane-ethyl acetate, 95:5) to give the cyanoester 5 (0.70 g, 71%) as a yellow oil; Rf(heptane-ethyl acetate, 8:2) 0.36; max(film)/cm1 2233 (CN), 1740 (CO); H (400 MHz; CDCl3) 3.75 (3H, s, OMe), 2.94 (2H, m), 2.63 (2H, s, CH2CO2Me), 2.35-2.21 (4H, m), 2.00 (2H, m), 1.86 (2H, m); m/z (AP) 194 (MH, 95%). 1646 Synthesis of Compound (6) 1647 Cyanoester 5 (0.81 g, 4.2 mmol) in methanol (100 mL) was shaken over a catalytic amount of nickel sponge catalyst under a hydrogen atmosphere (60 Psi, 30 C.) for 6 hours. The mixture was filtered, and the solvent was evaporated under reduced pressure to give lactam 6 (0.64 g, 92%) as a white solid; max(film)/cm1 1692 (CO); H (400 MHz; CDCl3 5.52 (1H, br s, NH), 3.54 (2H, s, CH2NH), 2.80 (2H, m), 2.26 (2H, m), 2.16 (2H, s, CH2CO), 1.93 (2H, ddd, J 13.4, 8.1, 2.4), 1.74 (2H, dd, J 13.0, 3.2), 1.64 (2H, m). 1648 Synthesis of (1,3,5)(3-Aminomethyl-bicyclo3.2.0hept 3-yl)-acetic acid hydrochloride (Example 41) 1649 Lactam 6 (0.64 g, 3.87 mmol) was dissolved in 1,4-dioxane (4 mL) and hydrochloric acid (16 mL of a 6N solution), and the mixture was refluxed for 6 hours. After cooling, the mixture was diluted with water (20 mL) and washed with dichloromethane (215 mL). The aqueous layer was evaporated under reduced pressure to give acid 7 (0.67 g, 79%) as a white solid. Recrystallization using ethyl acetate/methanol gave Example 41 exclusively (0.26 g);H (400 MHz; d6-DMSO) 7.98 (2H, br s, NH2), 3.13 (2H, s, CH2NH2), 2.70 (2H, s), 2.17-2.14 (4H, m), 1.85 (2H, dd, J 13.3, 8.0), 1.63 (2H, m), 1.55 (2H, dd, J 12.9, 5.1); m/z (ES) 184 (MH, 100%); LCMS (Prodigy C18, 50 mm4.6 mmid column, 5-50% Acetonitrile/water) Retention Time2.40 minutes, 98% purity. 1650 The following compounds are made by one of the methods of Examples 34 to 41. 1651 (1,5)(3-Aminomethyl-bicyclo3.1.0hex-3-yl)-acetic acid, 1652 (1,5)(3-Aminomethyl-bicyclo3.2.0hept-3-yl)-acetic acid, 1653 (1,5)(2-Aminomethyl-octahydro-pentalen-2-yl)-acetic acid, 1654 (1,6)(2-Aminomethyl-octahydro-inden-2-yl)-acetic acid, 1655 (1,7)(2-Aminomethyl-decahydro-azulen-2-yl)-acetic acid, 1656 (1,5)(3-Aminomethyl-bicyclo3.1.0hex-3-yl)-acetic acid, 1657 (1,5)(3-Aminomethyl-bicyclo3.2.0hept-3-yl)-acetic acid, 1658 (1,5)(2-Aminomethyl-octahydro-pentalen-2-yl)-acetic acid, 1659 (1,6)(2-Aminomethyl-octahydro-inden-2-yl)-acetic acid, 1660 (1,7)(2-Aminomethyl-decahydro-azulen-2-yl)-acetic acid, 1661 (1,3,5)(3-Aminomethyl-bicyclo3.1.0hex-3-yl)-acetic acid, 1662 (1,3,5)(3-Aminomethyl-bicyclo3.2.0hept-3-yl)-acetic acid, 1663 (1,3,5)(2-Aminomethyl-octahydro-pentalen-2-yl)-acetic acid, 1664 (1,6,8)(2-Aminomethyl-octahydro-inden-2 yl)-acetic acid, 1665 (1,7,9)(2-Aminomethyl-decahydro-azulen-2-yl)-acetic acid, 1666 (1,3,5)(3-Aminomethyl-bicyclo3.1.0hex-3-yl)-acetic acid, 1667 (1,3,5)(3-Aminomethyl-bicyclo3.2.0hept-3-yl)-acetic acid, 1668 (1,3,5)(2-Aminomethyl-octahydro-pentalen-2-yl)-acetic acid, 1669 (1,6,8)(2-Aminomethyl-octahydro-inden-2-yl)-acetic acid, 1670 (1,7,9)(2-Aminomethyl-decahydro-azulen-2-yl)-acetic acid, 1671 ((1R,3R,6R)-3-Aminomethyl-bicyclo4.1.0hept-3-yl)-acetic acid, 1672 ((1R,3S,6R)-3-Aminomethyl-bicyclo4.1.0hept-3-yl)-acetic acid, 1673 ((1S,3S,6S)-3-Aminomethyl-bicyclo4.1.0hept-3-yl)-acetic acid, 1674 ((1S,3R,6S)-3-Aminomethyl-bicyclo4.1.0hept-3-yl)-acetic acid, 1675 ((1R,3R,6S)-3-Aminomethyl-bicyclo4.2.0oct-3-yl)-acetic acid, 1676 ((1R,3S,6S)-3-Aminomethyl-bicyclo4.2.0oct-3-yl)-acetic acid, 1677 ((1S,3S,6R)-3-Aminomethyl-bicyclo4.2.0oct-3-yl)-acetic acid, 1678 ((1S,3R,6R)-3-Aminomethyl-bicyclo4.2.0oct-3-yl)-acetic acid, 1679 ((3R,5R,7S)-5-Aminomethyl-octahydro-inden-5-yl)-acetic acid, 1680 ((3R,5S,7S)-5-Aminomethyl-octahydro-inden-5-yl)-acetic acid, 1681 ((3R,5S,7R)-5-Aminomethyl-octahydro-inden-5-yl)-acetic acid, 1682 ((3R,5R,7R)-5-Aminomethyl-octahydro-inden-5-yl)-acetic acid, 1683 ((2R,4S,8R)-2-Aminomethyl-decahydro-naphthalen-2-yl)-acetic acid, 1684 ((2S,4S,8R)-2-Aminomethyl-decahydro-naphthalen-2-yl)-acetic acid, 1685 ((2S,4R,8S)-2-Aminomethyl-decahydro-naphthalen-2-yl)-acetic acid, 1686 ((2R,4R,8S)-2-Aminomethyl-decahydro-naphthalen-2-yl)-acetic acid, 1687 ((2R,4S,9R)-2-Aminomethyl-decahydro-benzocyclophepten-2-yl-acetic acid, 1688 ((2S,4S,9R)-2-Aminomethyl-decahydro-benzocyclophepten-2-yl-acetic acid, 1689 ((2R,4R,9S)-2-Aminomethyl-decahydro-benzocyclophepten-2-yl)-acetic acid, 1690 ((2R,4R,9S)-2-Aminomethyl-decahydro-benzocyclophepten-2-yl)-acetic acid, 1691 ((1R,3R,6S)-3-Aminomethyl-bicyclo4.1.0hept-3-yl)-acetic acid, 1692 ((1R,3S,6S)-3-Aminomethyl-bicyclo4.1.0hept-3-yl)-acetic acid, 1693 ((1S,3S,6R)-3-Aminomethyl-bicyclo4.1.0hept-3-yl)-acetic acid, 1694 ((1S,3R,6R)-3-Aminomethyl-bicyclo4.1.0hept-3-yl)-acetic acid 1695 ((1R,3R,6R)-3-Aminomethyl-bicyclo4.2.0oct-3-yl)-acetic acid, 1696 ((1R,3S,6R)-3-Aminomethyl-bicyclo4.2.0oct-3-yl)-acetic acid, 1697 ((1S,3S,6S)-3-Aminomethyl-bicyclo4.2.0oct-3-yl)-acetic acid, 1698 ((1S,3R,6S)-3-Aminomethyl-bicyclo4.2.0oct-3-yl)-acetic acid, 1699 ((3R,5R,7R)-5-Aminomethyl-octahydro-inden-5-yl)-acetic acid, 1700 ((3R,5S,7R)-5-Aminomethyl-octahydro-inden-5-yl)-acetic acid, 1701 ((3S,5S,7S)-5-Aminomethyl-octahydro-inden-5-yl)-acetic acid, 1702 ((3S,5R,7S)-5-Aminomethyl-octahydro-inden-5-yl)-acetic acid, 1703 ((2R,4R,8R)-2-Aminomethyl-decahydro-naphthalen-2-yl)-acetic acid, 1704 ((2S,4S,8R)-2-Aminomethyl-decahydro-naphthalen-2-yl)-acetic acid, 1705 ((2S,4R,8S)-2-Aminomethyl-decahydro-naphthalen-2-yl)-acetic acid, 1706 ((2R,4S,8S)-2-Aminomethyl-decahydro-naphthalen-2-yl)-acetic acid, 1707 ((2R,4R,9R)-2-Aminomethyl-decahydro-benzocyclophepten-2-yl)-acetic acid, 1708 ((2S,4R,9R)-2-Aminomethyl-decahydro-benzocyclophepten-2-yl)-acetic acid, 1709 ((2R,4S,9S)-2-Aminomethyl-decahydro-benzocyclophepten-2-yl)-acetic acid, and 1710 ((2R,4S,9R)-2-Aminomethyl-decahydro-benzocyclophepten-2-yl)-acetic acid. 1711 The following methods relate specifically to the preparation of Example 42, (1,3,5)(3-Aminomethyl-bicyclo3.2.0hept-3-yl)-acetic acid. 90

1712 Nitromethane is added to the unsaturated ester in a solvent such as dimethylsulphoxide or N,N-dimethylformamide with a base such as potassium carbonate, sodium carbonate or cesium carbonate, at a temperature of from 0 C. to 120 C. This process achieves higher yields of the nitro ester and reduces the yield of deconjugated ester compared to previous routes. 91

1713 a) An alkyl cyanoacetate, for example ethyl cyanoacetate, is added to a mixture of cyclopentanone of formula (1) in a solvent selected from toluene, benzene, xylenes, or n-heptane to which acetic acid and -alanine or ammonium acetate, or piperidine are added. The mixture is stirred at a temperature from 0 C. to 150 C. with removal of water by, for example, use of a Dean-Stark trap or activated molecular sieves, to produce the alkene of formula (2); 1714 b) Adding the product of step a) above to a mixture of benzylmagnesium chloride or benzylmagnesium bromide or benzylmagnesium iodide, in a dry solvent selected from tetrahydrofuran, 1,4-dioxane, n-heptane, toluene, diethyl ether, or tert-butyl methyl ether at a temperature from 100 C. to 110 C. to produce the addition product of formula (3); 1715 c) Adding the product of step b) above to a mixture of a base selected from potassium hydroxide, sodium hydroxide, lithium hydroxide, or cesium hydroxide in a solvent selected from ethylene glycol, 2-methoxyethyl ether, 1,4-dioxane, or diethylene glycol and stirring the mixture at a temperature from 25 C. to 250 C. to produce the carboxylic acid of formula (4); 1716 d) Adding the product of step c) above to a mixture of iodomethane in a solvent selected from dichloromethane, chloroform, tetrahydrofuran, toluene, or 1,4-dioxane to which a base such as 1,8-diazabicyclo5.4.0undec-7-ene (DBU), triethylamine, or 1,5-diazabicyclo4.3.0non-5-ene (DBN) is added and stirred at a temperature from 40 C. to 110 C. to produce the ester of formula (5); or adding the product of step c) above to a mixture of methanol and a concentrated acid such as sulphuric acid or hydrochloric acid at a temperature ranging from 0 C. to 100 C.; or adding the product of step c) above to trimethylsilyldiazomethane and methanol in benzene or toluene at a temperature from 40 C. to 100 C.; or adding the product of step c) above to diazomethane in a solvent such as benzene, toluene, dichloromethane, or diethyl ether at a temperature from 40 C. to 40 C.; 1717 e) Adding the product of step d) above to a mixture of carbon tetrachloride or ethyl acetate and acetonitrile to which water, sodium periodate, and ruthenium (III) chloride are added, and stirred at a temperature from 40 C. to 80 C. to produce carboxylic acid of formula (6); 1718 f) Adding the product of step e) above to a mixture of a base selected from triethylamine or diisopropylethylamine and a solvent selected from toluene, benzene, xylenes, tetrahydrofuran, diethyl ether, or n-heptane to which diphenylphosphoryl azide (DPPA) is added and stirring at a temperature from 0 C. to 150 C. to produce the isocyanate of formula (7); or adding the product of step e) above to ethyl chloroformate or isobutyl chloroformate and a base such as triethylamine or diisopropylethylamine in tetrahydrofuran or acetone or diethyl ether at a temperature of 40 C. to 78 C. followed by addition of sodium azide in water and tetrahydrofuran or acetone followed by addition of toluene or benzene and refluxing; and 1719 g) Adding the product of step f) above to a solvent selected from toluene, benzene, xylenes, or n-heptane to which methanol or tert-butanol was added to give (8) and then adding (8) to aqueous hydrochloric acid at a concentration of from 0.01 M to 12 M in the presence or absence of a solvent such as 1,4-dioxane, acetic acid or water to produce the amino acid (9); or adding the product of step f) above to a solvent selected from toluene, benzene, xylenes, or n-heptane to which benzyl alcohol was added to give (8) and then hydrogenating (8) over nickel or palladium or platinum to give lactam which was then hydrolyzed using aqueous hydrochloric acid at a concentration of from 0.01 M to 12 M in the presence or absence of a solvent such as 1,4-dioxane, acetic acid, or water to produce Example 42. 92

1720 a) Cyanoester (2) is added to allylmagnesium chloride or bromide or 2-butenylmagnesium chloride in a dry solvent selected from tetrahydrofuran, 1,4-dioxane, n-heptane, toluene, diethyl ether, or tert-butyl methyl ether at a temperature from 100 C. to 110 C. to produce the addition product of formula (10); 1721 b) Adding the product of step a) above to a mixture of a base selected from potassium hydroxide, sodium hydroxide, lithium hydroxide, or cesium hydroxide in a solvent selected from ethylene glycol, 2-methoxyethyl ether, 1,4-dioxane, or diethylene glycol and stirring the mixture at a temperature from 25 C. to 250 C. to produce the carboxylic acid of formula (11); 1722 c) Adding the product of step b) above to a mixture of iodomethane in a solvent selected from dichloromethane, chloroform, tetrahydrofuran, toluene, or 1,4 dioxane to which a base such as 1,8-diazabicyclo5.4.0undec-7-ene (DBU), triethylamine, or 1,5-diazabicyclo4.3.0non-5-ene (DBN) was added and stirred at a temperature from 40 C. to 110 C. to produce the ester of formula (11); or adding the product of step b) above to a mixture of methanol and a concentrated acid such as sulphuric acid or hydrochloric acid at a temperature ranging from 0 C. to 100 C.; or adding the product of step b) above to trimethylsilyldiazomethane and methanol in benzene or toluene at a temperature from 40 C. to 100 C.; or adding the product of step b) above to diazomethane in a solvent such as benzene, toluene, dichloromethane, or diethyl ether at a temperature from 40 C. to 40 C.; and 1723 d) Adding the product of step c) above to a mixture of carbon tetrachloride or ethyl acetate and acetonitrile to which water, sodium periodate, and ruthenium (III) chloride were added, and stirred at a temperature from 40 C. to 80 C. to produce Example 42. 93

1724 a) An organometallic reagent such as vinyl lithium or vinyl magnesium chloride or bromide in a solvent such as tetrahydrofuran or diethyl ether at a temperature from 100 C. to 0 C. is added to the cyanoester (2) to give (13); 1725 b) Adding the product of step a) above to a mixture of a base selected from potassium hydroxide, sodium hydroxide, lithium hydroxide, or cesium hydroxide in a solvent selected from ethylene glycol, 2-methoxyethyl ether, 1,4-dioxane, or diethylene glycol and stirring the mixture at a temperature from 25 C. to 250 C. to produce the carboxylic acid of formula (14); 1726 c) Adding the product of step b) above to a mixture of iodomethane in a solvent selected from dichloromethane, chloroform, tetrahydrofuran, toluene, or 1,4-dioxane to which a base such as 1,8-diazabicyclo5.4.0undec-7-ene (DBU), triethylamine, or 1,5-diazabicyclo4.3.0non-5-ene (DBN) is added and stirred at a temperature from 40 C. to 110 C. to produce the ester of formula (15); or adding the product of step b) above to a mixture of methanol and a concentrated acid such as sulphuric acid or hydrochloric acid at a temperature ranging from 0 C. to 100 C.; or adding the product of step b) above to trimethylsilyldiazomethane and methanol in benzene or toluene at a temperature from 40 C. to 100 C.; or adding the product of step b) above to diazomethane in a solvent such as benzene, toluene, dichloromethane, or diethyl ether at a temperature from 40 C. to 40 C.; 1727 d) The product of step c) above is ozonolyzed in a solvent such as chloroform or dichloromethane or methanol followed by addition of a quench such as triphenylphosphine or dimethylsulphide at a temperature from 100 C. to 0 C. to give (16); 1728 e) The product of step d) above in a solvent such as methanol or ethanol was reacted with ammonia solution or ammonia gas followed by reduction using sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride, or by reduction by hydrogenation in the presence of a catalyst such as nickel, palladium, or platinum to give (17); and 1729 f) The product of step e) above is hydrolyzed using aqueous hydrochloric acid at a concentration of from 0.01 M to 12 M in the presence or absence of a solvent such as 1,4-dioxane, acetic acid, or water to produce Example 42. 94

1730 The unsaturated ester and benzyl thioisocyanate is stirred in a solvent mixture made up of tetrahydrofuran, diethyl ether, or 1,4-dioxane, a coordinating solvent such as HMPA or DMPU and an alcohol such as tert-butanol with samarium diiodide at a temperature of 100 C. to 0 C.; the resulting ester is hydrogenated in a solvent such as methanol, ethanol, ethyl acetate using a catalyst such as nickel, palladium, platinum, or rhodium at a temperature from 20 C. to 100 C. to give the amino ester. 95

1731 a) An organometallic reagent such as vinyl lithium or vinyl magnesium chloride or bromide is mixed with dimethylzinc, zinc chloride, copper (I) iodide, copper (I) bromide dimethyl sulphide complex, or copper (I) cyanide in the presence of a Lewis acid such as boron trifluoride etherate or aluminum chloride in a solvent such as tetrahydrofuran or diethyl ether at a temperature from 100 C. to 0 C., and the unsaturated ester (1) is added to give addition product (2); 1732 b) The product of step a) above is ozonolyzed in a solvent such as chloroform or dichloromethane or methanol followed by addition of a quench such as triphenylphosphine or dimethylsulphide at a temperature from 100 C. to 0 C. to give (3); 1733 c) The product of step b) above in a solvent such as methanol or ethanol was reacted with ammonia solution or ammonia gas followed by reduction using sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride, or by reduction by hydrogenation in the presence of a catalyst such as nickel, palladium, or platinum to give (4); and 1734 d) The product of step c) above is hydrolyzed using aqueous hydrochloric acid at a concentration of from 0.01 M to 12 M in the presence or absence of a solvent such as 1,4-dioxane, acetic acid, or water to produce Example 42. 1735 Method 4B 96

1736 a) An organometallic reagent such as allylmagnesium chloride or bromide is mixed with dimethylzinc, zinc chloride, copper (I) iodide, copper (I) bromide dimethyl sulphide complex, or copper (I) cyanide in the presence of a Lewis acid such as boron trifluoride etherate or aluminum chloride in a solvent such as tetrahydrofuran or diethyl ether at a temperature from 100 C. to 0 C. and the unsaturated ester (1) is added to give addition product (6); or an organometallic reagent such as benzylmagnesium chloride or bromide is mixed with dimethylzinc, zinc chloride, copper (I) iodide, copper (I) bromide dimethyl sulphide complex, or copper (I) cyanide in the presence of a Lewis acid such as boron trifluoride etherate or aluminum chloride in a solvent such as tetrahydrofuran or diethyl ether at a temperature from 100 C. to 0 C., and the unsaturated ester (1) is added to give addition product (7); 1737 b) Adding the product of step a) above to a mixture of carbon tetrachloride or ethyl acetate and acetonitrile to which water, sodium periodate, and ruthenium (III) chloride are added, and stirred at a temperature from 40 C. to 80 C. to produce carboxylic acid of formula (8); 1738 c) Adding the product of step b) above to a mixture of a base selected from triethylamine or diisopropylethylamine and a solvent selected from toluene, benzene, xylenes, tetrahydrofuran, diethyl ether, or n-heptane to which diphenylphosphoryl azide (DPPA) is added and stirring at a temperature from 0 C. to 150 C. to produce the isocyanate of formula (9); or adding the product of step b) above to ethyl chloroformate or isobutyl chloroformate and a base such as triethylamine or diisopropylethylamine in tetrahydrofuran or acetone or diethyl ether at a temperature of 40 C. to 78 C. followed by addition of sodium azide in water and tetrahydrofuran or acetone followed by addition of toluene or benzene and refluxing; 1739 d) Adding the product of step c) above to a solvent selected from toluene, benzene, xylenes, or n-heptane to which methanol or tert-butanol was added to give (10) and then adding (10) to aqueous hydrochloric acid at a concentration of from 0.01 M to 12 M in the presence or absence of a solvent such as 1,4-dioxane, acetic acid, or water to produce the amino acid (5); or adding the product of step 1740 c) above to a solvent selected from toluene, benzene, xylenes, or n-heptane to which benzyl alcohol was added to give (10) and then hydrogenating (10) over nickel or palladium or platinum to give lactam which was then hydrolyzed using aqueous hydrochloric acid at a concentration of from 0.01 M to 12 M in the presence or absence of a solvent such as 1,4-dioxane, acetic acid, or water to produce Example 42. 1741 Method 5 97

1742 a) Compound (1) and potassium cyanide or sodium cyanide and water and ethanol or methanol are refluxed together with removal of water by, for example, use of a Dean-Stark trap to give (2); 1743 b) The product of step a) is stirred with ethanol or toluene or benzene, and the solution is saturated with gaseous hydrochloric acid at a temperature from 30 C. to 40 C. to give (3); 1744 c) The product of step b) above is hydrogenated in methanol, ethanol, or ethyl acetate using a catalyst such as nickel, palladium, platinum, or rhodium at a temperature from 15 C. to 60 C. to give (4); and 1745 d) The product of step c) above is hydrolyzed using aqueous hydrochloric acid at a concentration of from 0.01 M to 12 M in the presence or absence of a solvent such as 1,4-dioxane, acetic acid, or water to produce Example 42. 1746 The newly discovered ability of a GABA analog having the characteristic of being an inhibitor of cartilage damage, or a pharmaceutically acceptable salt thereof, to treat or prevent cartilage damage has been established in animal models as described below.

Biological Method 1 1747 Induction of Experimental Osteoarthritis in Rabbit (EOA in Rabbit) 1748 Normal rabbits were anaesthetized and anteromedial incisions of the right knees performed. The anterior cruciate ligaments were visualized and sectioned. The wounds were closed and the animals were housed in individual cages, exercised, and fed ad libitum. Rabbits were given either vehicle (water), gabapentin, or 3-(1-aminomethyl-cyclohexylmethyl)-4h-1,2,4oxadiazol-5-one hydrochloride (10 rabbits per group). Each group was dosed three times per day with the gabapentin group receiving 100-mg/kg/dose and the 3-(1-aminomethyl-cyclohexylmethyl)-4h-1,2,4oxadiazol-5-one hydrochloride group receiving 50-mg/kg/dose. The rabbits were euthanized 8 weeks after surgery and the proximal end of the tibia and the distal end of the femur were removed from each animal. 1749 Macroscopic Grading 1750 The cartilage changes on the femoral condyles and tibial plateaus were graded separately under a dissecting microscope (Stereozoom, Bausch & Lomb, Rochester, N.Y.). The depth of erosion was graded on a scale of 0 to 4 as follows: grade 0normal surface; Grade 1minimal fibrillation or a slight yellowish discoloration of the surface; Grade 2erosion extending into superficial or middle layers only; Grade 3erosion extending into deep layers; Grade 4erosion extending to subchondral bone. The surface area changes was measured and expressed in mm2. Representative specimens will also be used for histologic grading (see below). 1751 Histologic Grading 1752 Histologic evaluation was performed on sagittal sections of cartilage from the lesional areas of the femoral condyle and tibial plateau. Serial sections (5 um) were prepared and stained with safranin-O. The severity of OA lesions was graded on a scale of 0-14 by two independent observers using the histologic-histochemical scale of Mankin et al. This scale evaluates the severity of OA lesions based on the loss of safranin-O staining (scale 0-4), cellular changes (scale 0-3), invasion of tidemark by blood vessels (scale 0-1) and structural changes (scale 0-6). On this latter scale, 0 indicates normal cartilage structure and 6 indicates erosion of the cartilage down to the subchondral bone. The scoring system was based on the most severe histologic changes in the multiple sections. 1753 Representative specimens of synovial membrane from the medial and lateral knee compartments were dissected from underlying tissues. The specimens were fixed, embedded, and sectioned (5 um) as above, and stained with hematoxylin-eosin. For each compartment, two synovial membrane specimens were examined for scoring purposes and the highest score from each compartment was retained. The average was calculated and considered as a unit for the whole knee. The severity of synovitis was graded on a scale of 0 to 10 by two independent observers, adding the scores of 3 histologic criteria: synovial lining cell hyperplasia (scale 0-2); villous hyperplasia (scale 0-3); and degree of cellular infiltration by mononuclear and polymorphonuclear cells (scale 0-5): 0 indicates normal structure. 1754 Statistical Analysis 1755 Mean values and SEM was calculated and statistical analysis was done using the Mann-Whitney U-test. 1756 The results of these studies are presented below in Tables 1-4. In Table 1, the results indicate that gabapentin reduced cartilage damage. Gabapentin reduced the size of the lesion on the tibial plateaus but had no significant effects on grade of damage in the tibia or on the femoral condyles. The compound named 3-(1-aminomethyl-cyclohexylmethyl-4H-1,2,4oxadiazol-5-one hydrochloride reduced the damage score for both the femoral condyles and the tibial plateaus. This test compound also reduced the lesion size on the plateaus. In support of these observations, the latter compound also reduced histologic damage as shown in Table 2 and 3. Moreover, both compounds reduced evidence of synovial changes as shown in Table 4. In conclusion, these results show that gabapentin, and especially the test compound, have significant effects on the damage to cartilage and other tissues that occur in this model of cartilage damage. 1TABLE 1Cartilage Macroscopic Lesions on Femoral Condyles and Tibial PlateausFemoral CondylesTibial PlateausNo. ofSizeGradeSizeGradeGroupAnimals(mm2)(0-4)(mm2)(0-4)OA (water)108.55 1.61.95 0.37.80 1.41.50 0.3Gabapentin105.43 1.01.25 0.23.35 1.00.75 0.2(300 mg/kg/po/day)(p < 0.03)3-(1-Aminomethyl-106.93 3.10.67 0.21.95 0.80.55 0.2cyclohexylmethyl)-(p < 0.04)(p < 0.002)(p < 0.02)4H-1,2,4oxadiazol-5-one hydrochloride-(150 mg/kg/po/day)

1757

2TABLE 2Histological-Histochemical Grading of Cartilage Lesions onFemoral CondylesSafranin-ONo. ofStructureCellsStainingTotalGroupAnimals(0-6)(0-3)(0-4)(0-13)OA (water)102.71 0.41.97 0.12.03 0.46.71 0.8Gabapentin101.92 0.31.71 0.21.08 0.34.71 0.6(300 mg/kg/day)3-(1-Aminomethyl-101.35 0.31.60 0.21.25 0.34.20 0.6cyclohexylmethyl)-(p < 0.01)(p < 0.04)4H-1,2,4oxadiazol-5-one hydrochloride(150 mg/kg/po/day)

1758

3TABLE 3Histological-Histochemical Grading of Cartilage Lesions on Tibial PlateausTotalNo. ofStructureCellsSafranin-O(0-13)GroupAnimals(0-6)(0-3)Staining (0-4)(p)OA (water)101.87 0.41.33 0.20.80 0.33.93 0.8Gabapentin101.08 0.31.08 0.20.55 0.32.72 0.7(300 mg/kg/day)3-(1-Aminomethyl-100.90 0.20.60 0.20.18 0.11.77 0.4cyclohexylmethyl)-(p > 0.02)4H-1,2,4oxadiazol-5-onehydrochloride(150 mg/kg/po/day)

1759

4TABLE 4Histological Grading of Synovial MembraneSynovialVillousCellularNo. ofLiningHyperplasiaInfiltrationTotalGroupAnimals(0-2 Scale)(0-3 Scale)(0-5 Scale)(0-10)OA100.95 0.12.20 0.10.80 0.23.95 0.3Gabapentin101.05 0.21.35 0.20.50 0.22.90 0.4(300 mg/kg/day)(p < 0.003)(p < 0.04)3-(1-Aminomethyl-100.85 0.11.15 0.10.35 0.22.35 0.3cyclohexylmethyl)-(p < 0.001)(p < 0.002)4H-1,2,4oxadiazol-5-onehydrochloride(150 mg/kg/po/day)

1760 The foregoing study establishes that GABA analogs such as a compound named 3-(1-aminomethyl-cyclohexylmethyl)-4H-1,2,4oxadiazol-5-one hydrochloride and gabapentin are effective for the treatment of cartilage damage in human and other mammalian disorders. Such a treatment offers a distinct advantage over existing treatments that only modify pain and other secondary symptoms. The effectiveness of 3-(1-aminomethyl-cyclohexylmethyl)-4H-1,2,4oxadiazol-5-one hydrochloride and gabapentin in this model indicates that 3-(1-aminomethyl-cyclohexylmethyl)-4H-1,2,4oxadiazol-5-one hydrochloride, gabapentin, and other GABA analogs will have clinically useful effects in preventing and/or treating cartilage damage.

Biological Method 2 1761 Monosodium Iodoacetate-Induced Osteoarthritis in Rat Model of Cartilage Damage (MIA Rat) 1762 One end result of the induction of osteoarthritis in this model, as determined by histologic analysis, is the development of an osteoarthritic condition within the affected joint, as characterized by the loss of Toluidine blue staining and formation of osteophytes. Associated with the histologic changes is a concentration-dependent degradation of joint cartilage, as evidenced by affects on hind-paw weight distribution of the limb containing the affected joint, the presence of increased amounts of proteoglycan or hydroxyproline in the joint upon biochemical analysis, or histopathological analysis of the osteoarthritic lesions. As it is well known that GABA analogs are not effective for relieving pain when administered in an acute model, such as the instant MIA Rat model, which has a duration of just 14 days, the hind-paw weight distribution effects observed below for the GABA analogs result from the GABA analogs ability to directly inhibit damage to cartilage. 1763 In the MIA Rat model on Day 0, the hind-paw weight differential between the right arthritic joint and the left healthy joint of male Wistar rats (150 g) were determined with an incapacitance tester, model 2KG (Linton Instrumentation, Norfolk, United Kingdom). The incapacitance tester has a chamber on top with an outwardly sloping front wall that supports a rat's front limbs, and two weight sensing pads, one for each hind paw, that facilitates this determination. Then the rats were anesthetized with isofluorine, and the right, hind leg knee joint was injected with 1.0 mg of mono-iodoacetate (MIA) through the infrapatellar ligament. Injection of MIA into the joint resulted in the inhibition of glycolysis and eventual death of surrounding chondrocytes. The rats were further administered either a GABA analog or vehicle (in the instant case, water) daily for 14 days. The GABA analog was typically administered at a dose of 30 mg of GABA analog per kilogram of rat per day (30 mg/kg/day), but may be administered at other doses such as, for example, 10 mg/kg/day, 60 mg/kg/day, or 100 mg/kg/day according to the requirements of the compound being studied. It is well within the level of ordinary skill in the pharmaceutical arts to determine a proper dosage of a GABA analog in this model. In the instant experiment, administration of the GABA analog was optionally by oral administration or intravenous administration via an osmotic pump. After 7 and 14 days, the hind-paw weight distribution was again determined. Typically, the animals administered vehicle alone placed greater weight on their unaffected left hind paw than on their right hind paw, while animals administered a GABA analog having the characteristic of being an inhibitor of cartilage damage, or a pharmaceutically acceptable salt thereof, showed a more normal (i.e., more like a healthy animal) weight distribution between their hind paws. Percent inhibition of cartilage damage was calculated as the percent change in hind-paw weight distribution for treated animals versus control animals: 1

Percent inhibition of cartilage damage = \frac{(W_{G}) 100}{(W_{C})}

1764 wherein: 1765 WC is the hind-paw weight differential between the healthy left limb and the arthritic limb of the control animal administered vehicle alone, as measured on Day 14; and 1766 WG is the hind-paw weight differential between the healthy left limb and the arthritic limb of the animal administered a GABA analog, as measured on Day 14. 1767 The results of the hind-paw weight distribution data are shown below in Table 5 in the column labelled % Inhibition. 5TABLE 5DailyAdmin-Doseistration%GABA Analog(mg/kg)RouteInhibition3-(1-aminomethyl-30aoral47 20cyclohexylmethyl)-4H-1,2,4oxadiazol-5-onehydrochlorideGabapentin100aOral17 11Pregabalin30aOral3 123-(1-aminomethyl-30Osmotic pump46 10cyclohexylmethyl)-4H-1,2,4oxadiazol-5-onehydrochloride3-(2-aminomethyl-4-methyl-30Osmotic pump35 8pentyl)-4H-1,2,4-oxadiazol-5-onehydrochloride3-(1-aminomethyl-30Osmotic pump62 8cycloheptylmethyl)-4H-1,2,4oxadiazol-5-onehydrochlorideC-1-(1H-tetrazol-5-ylmethyl)-30Osmotic pump33 17cycloheptyl-methylamineGabapentin60Osmotic pump33 133-(2-amino-1-cyclopentyl-ethyl)-30Osmotic pump1044H-1,2,4oxadiazol-5-onehydrochloride(1, 3, 5) (3-aminomethyl-30Osmotic pump3 34bicyclo3.2.0.hept-3-yl)-aceticacid hydrochlorideaTwice daily dosing of the indicated dose

1768 The MIA Rat data reported above in Table 5 establish that GABA analogs, including gabapentin, 3-(1-aminomethyl-cyclohexylmethyl)-4H-1,2,4oxadiazol-5-one hydrochloride, 3-(2-aminomethyl-4-methyl-pentyl)-4H-1,2,4-oxadiazol-5-one hydrochloride, 3-(2-amino-1-cyclopentyl-ethyl)-4H-1,2,4-oxadiazol-5-one hydrochloride, and 3-(1-aminomethyl-cycloheptylmethyl)-4H-1,2,4oxadiazol-5-one hydrochloride, are effective at preventing or treating cartilage damage. 1769 In order to measure biochemical or histopathological end points in the MIA Rat model, some of the animals in the above study were then sacrificed, and the amounts of free proteoglycan in both the osteoarthritic right knee joint and the contralateral left knee joint were determined by biochemical analysis. The amount of free proteoglycan in the contralateral left knee joint provides a baseline value for the amount of free proteoglycan in a healthy joint. The amount of proteoglycan in the osteoarthritic right knee joint in animals further administered a GABA analog, and the amount of proteoglycan in the osteoarthritic right knee joint in animals further administered vehicle alone, were independently compared to the amount of proteoglycan in the contralateral left knee joint. The amounts of proteoglycan lost in the osteoarthritic right knee joints were expressed as percent loss of proteoglycan compared to the contralateral left knee joint control. 1770 The results are shown below in Table 6 in the column labelled, Proteoglycan loss (%). Also shown in Table 6, in the column labelled Inhibition of Proteoglycan loss (%), is the percent inhibition of proteoglycan loss, which was calculated as (proteoglycan loss from joint (%) with vehicle)(proteoglycan loss from joint with GABA analog)(proteoglycan loss from joint (%) with vehicle)100. 6TABLE 6Inhibition ofExampleCompoundProteoglycanProteoglycanNo.Administeredaloss (%)loss (%)1a3-(1-aminomethyl-6.7063cyclohexylmethyl)-4H-1,2,4oxadiazol-5-onehydrochloride1bVehicle (water)18.10N/Ab2a(1, 3, 5)(3-aminomethyl-16.6048bicyclo3.2.0hept-3-yl)-acetic acid hydrochloride2bVehicle (water)31.90N/AaCompound was administered intravenously by osmotic pump at a dose of 30 mg/kg/day unless otherwise indicated; bN/A means not applicable.

1771 The MIA Rat data reported above in Table 6 establish that 3-(1-aminomethyl-cyclohexylmethyl)-4H-1,2,4oxadiazol-5-one hydrochloride and (1,3,5)(3-aminomethyl-bicyclo3.2.0hept-3-yl)-acetic acid hydrochloride are each independently effective for the treatment of cartilage damage in mammalian patients, including human. 1772 The following examples illustrate the invention pharmaceutical compositions containing a cartilage damage treating effective amount of a GABA analog, and a pharmaceutically acceptable carrier, diluent, or excipient. The examples are representative only, and are not to be construed as limiting the invention in any respect.

Formulation Example 1 1773 Tablet Formulation: 7IngredientAmount (mg)3-(1-aminomethyl-cyclohexylmethyl)-4H-251,2,4oxadiazol-5-one hydrochlorideLactose50Cornstarch (for mix)10Cornstarch (paste)10Magnesium stearate (1%)5Total100

1774 3-(1-Aminomethyl-cyclohexylmethyl)-4H-1,2,4oxadiazol-5-one hydrochloride, lactose, and cornstarch (for mix) are blended to uniformity. The cornstarch (for paste) is suspended in 200 mL of water and heated with stirring to form a paste. The paste is used to granulate the mixed powders. The wet granules are passed through a No. 8 hand screen and dried at 80 C. The dry granules are lubricated with the 1% magnesium stearate and pressed into a tablet. Such tablets can be administered to a human from one to four times a day for treatment of cartilage damage.

Formulation Example 2 1775 Coated Tablets: 1776 The tablets of Formulation Example 1 are coated in a customary manner with a coating of sucrose, potato starch, talc, tragacanth, and colorant.

Formulation Example 3 1777 Injection Vials: 1778 The pH of a solution of 500 g of gabapentin and 5 g of disodium hydrogen phosphate is adjusted to pH 6.5 in 3 L of double-distilled water using 2 M hydrochloric acid. The solution is sterile filtered, and the filtrate is filled into injection vials, lyophilized under sterile conditions, and aseptically sealed. Each injection vial contains 25 mg of gabapentin.

Formulation Example 4 1779 Suppositories: 1780 A mixture of 25 g of (1,3,5)(3-aminomethyl-bicyclo3.2.0hept-3-yl)-acetic acid hydrochloride, 100 g of soya lecithin, and 1400 g of cocoa butter is fused, poured into molds, and allowed to cool. Each suppository contains 25 mg of (1,3,5)(3-aminomethyl-bicyclo3.2.0hept-3-yl)-acetic acid hydrochloride.

Formulation Example 5 1781 Solution: 1782 A solution is prepared from 1 g of 3-(2-aminomethyl-4-methyl-pentyl)-4H-1,2,4-oxadiazol-5-one hydrochloride, 9.38 g of NaH2PO4.12H2O, 28.48 g of Na2HPO4.12H2O, and 0.1 g benzalkonium chloride in 940 mL of double-distilled water. The pH of the solution is adjusted to pH 6.8 using 2 M hydrochloric acid. The solution is diluted to 1.0 L with double-distilled water, and sterilized by irradiation. A 25 mL volume of the solution contains 25 mg of 3-(2-aminomethyl-4-methyl-pentyl)-4H-1,2,4-oxadiazol-5-one hydrochloride.

Formulation Example 6 1783 Ointment: 1784 500 mg of 3-(1-aminomethyl-cycloheptylmethyl)-4H-1,2,4oxadiazol-5-one hydrochloride is mixed with 99.5 g of petroleum jelly under aseptic conditions. A 5 g portion of the ointment contains 25 mg of 3-(1-aminomethyl-cycloheptylmethyl)-4H-1,2,4oxadiazol-5-one hydrochloride.

Formulation Example 7 1785 Capsules: 1786 2 kg of 3-(1-aminomethyl-cyclohexylmethyl)-4H-1,2,4oxadiazol-5-one hydrochloride are filled into hard gelatin capsules in a customary manner such that each capsule contains 25 mg of 3-(1-aminomethyl-cyclohexylmethyl)-4-H-1,2,4oxadiazol-5-one hydrochloride.

Formulation Example 8 1787 Ampoules: 1788 A solution of 2.5 kg of gabapentin is dissolved in 60 L of double-distilled water. The solution is sterile filtered, and the filtrate is filled into ampoules. The ampoules are lyophilized under sterile conditions and aseptically sealed. Each ampoule contains 25 mg of gabapentin. 1789 As shown above, the invention method offers a distinct advantage over existing treatments for diseases that comprise cartilage damage, wherein the existing treatments modify pain or secondary symptoms, but do not show a disease modifying effect. The effectiveness of gabapentin, 3-(1-aminomethyl-cyclohexylmethyl)-4H-1,2,4oxadiazol-5-one hydrochloride, 3-(2-aminomethyl-4-methyl-pentyl)-4H-1,2,4-oxadiazol-5-one hydrochloride, 3-(1-aminomethyl-cycloheptylmethyl)-4H-1,2,4oxadiazol-5-one hydrochloride, 3-(2-amino-1-cyclopentyl-ethyl)-4H-1,2,4oxadiazol-5-one hydrochloride, or (1,3,5)(3-aminomethyl-bicyclo3.2.0hept-3-yl)-acetic acid hydrochloride in MIA Rat indicate that GABA analogs are useful for preventing or treating cartilage damage. 1790 Having described the invention method, various embodiments of the invention are hereupon claimed.