CROSS REFERENCE 0001 This application claims priority under Title 35, United States Code 119(e) from Provisional Application Ser. No. 60/179,506, filed Feb. 1, 2000.

TECHNICAL FIELD 0002 The present invention relates to a novel process for making geminal bisphosphonates. The process provides for bisphosphorylation using phosphorus trihalide, molten phosphorous acid as a reactant/solvent, and a base as an acid acceptor/solvent.

BACKGROUND OF THE INVENTION 0003 Polyphosphonic acids and their pharmaceutically-acceptable salts have been proposed for use in the treatment of diseases of bone and calcium metabolism. Such diseases include osteoporosis, hyperparathyroidism, hypercalcemia of malignancy, ostolytic bone metastases, myosistis ossifcans progressiva, calcinoisis universalis, arthritis, neuritis, bursitis, tendonitis and other inflammatory conditions. In particular bisphosphonates, like ethane-1-hydroxy-1,1-diphosphonic acid (EHDP), propane-3-amimo-1-hydroxy-1,1-diphosphonic acid (APD), dichloromethane diphosphonic acid (C12MDP), 3-amino-1-hydroxy-propylidene-diphosphonic acid. (PAMIDRONATE), 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid (ALENDRONATE) and 1-hydroxy-2-(3-pyridinyl)ethylidene-1,1-bisphosphonic acid (RISEDRONATE) have been the subject of considerable research efforts in this area. Paget's disease and heterotropic ossification are currently successfully treated with EHDP. The diphosphonates tend to inhibit the resorption of bone tissue, which is beneficial to patients suffering from excessive bone loss. However, in spite of certain analogies in activity, bisphosphonates do not exhibit the same degree of activity and some have serious drawbacks with respect to the degree of toxicity in animals and the tolerability or the negative side effects in humans. 0004 Several methods for making bisphosphonates have been disclosed. For example, European Patent Application 0 494 644, Instituto Gentili and PCT application WO 96/33199 disclose methods for making amino-bisphosphonates. However, just as there are differences in the activities of the different bisphosphonates, so too are there differences in the method of making these compounds. Depending on the reaction conditions, the viscosity of the reaction mixture and/or the formation of large amounts of elemental phosphorus by-products limit the scale on which the bisphosphorylation reaction can be readily carried out. 0005 It is therefore desirable to use a scaleable process to produce geminal bisphosphonates that achieves high yields with little residual elemental phosphorous by-products and that can be safely practiced on the commercial scale.

SUMMARY OF THE INVENTION 0006 The present invention is directed to a process for making geminal bisphosphonates of the general formula: 2

0007 wherein Q is oxygen, NR4, sulfur, selenium, or a single bond; mn is an integer from 0 to about 5, Z is a ring selected from the group consisting of pyridine, pyridazine, pyrimidine, and pyrazine; R1 is independently hydrogen, substituted or unsubstituted amino, amido, hydroxy, alkoxy, halogen, carboxylate, substituted or unsubstituted alkyl (saturated or unsaturated) having from 1 to about 6 carbon atoms, substituted or unsubstituted aryl, or substituted or unsubstituted benzyl; each R2 is independently, hydrogen, or substituted or unsubstituted alkyl (saturated or unsaturated) having from 1 to about 4 carbon atoms; R3 is one or more substituents selected from the group consisting of hydrogen, substituted or unsubstituted alkyl (saturated or unsaturated) having from 1 to about 6 carbon atoms, substituted and unsubstituted aryl, substituted and unsubstituted benzyl, hydroxy, halogen, carbonyl, alkoxy, nitro, amido, amino, substituted amino, carboxylate, and combinations thereof; R4 is hydrogen, substituted alkyl (saturated or unsaturated) having from 1 to about 4 carbon atoms, or acyl; resulting from bisphosphorylation of an aminocarboxylic acid in the presence of phosphorus trihalide, molten phosphorous acid and base such as morpholine to form a geminal bisphosphonate.

DETAILED DESCRIPTION OF THE PRESENT INVENTION 0008 The present invention is directed to a novel process for making geminal bisphosphonates. Said process involves the use of molten phosphorous acid, an amino carboxylic acid, phosphorous trihalide, and base in the bisphosphorylation step. The reaction is carried out at a temperature of from about 45 C. to about 90 C., preferably from about 55 C. to about 85 C., more preferably from about 60 C. to about 75 C. The presence of an additional solvent is optional. Particularly preferred geminal bisphosphonates made by this process are 1-hydroxy-2-(3-pyridinyl)ethylidine bisphosphonic acid, 4-amino-1-hydroxybutylidene-1,1-bisphonic acid, and 3-amino-1-hydroxypropylidene-diphosphonic acid. Most preferred is risedronate, 1-hydroxy-2-(3-pyridinyl)ethylidene-1,1-bisphosphonicacid.

Definitions and Usage of Terms 0009 The following is a list of definitions for terms used herein: 0010 As used herein, alendronate denotes 4-amino-1-hydroxybutylidene-1,1-bisphonic acid. 0011 As used herein, alkenyl means a hydrocarbon substituent with one or more double bonds, straight or branched chain, unsubstituted or substituted. 0012 As used herein, alkoxy means a substituent having the structure Q-O-, where Q is alkyl or alkenyl. 0013 As used herein, alkyl means a saturated hydrocarbon substituent, straight or branched chain, unsubstituted or substituted. 0014 As used herein, alkylthio means a substituent having the structure Q-S-, where Q is alkyl or alkenyl. 0015 As used herein, aminocarboxylic acid is a saturated or unsaturated substituted or unsubstituted alkyl with a carboxylic acid group attached to one end and an amine group either attached to one of the carbons of the alkyl chain or as a heteroatom in a saturated or unsaturated substituted or unsubstituted heterocyclic ring. 0016 As used herein, base means a basic reagent which is added to a reaction mixture to facilitate bisphosphorylation. Bases include organic and inorganic bases. Preferred bases include those which have easily filterable or otherwise removable salts. Specifically, preferred bases include N,N-diisopropylethylamine, triethylamine, trimethylamine, 4-dimethylaminopyridine, pyridine, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate and morpholine. The more preferred bases are triethylamine, trimethylamine, potassium carbonate, pyridine and morpholine. The most preferred base is morpholine. The base may be added as the free base or in its salt form. 0017 As used herein, biohydrolyzable ester is an ester moiety that does not interfere with the therapeutic activity of the compound, or that is readily metabolized by a human or other mammal. 0018 As used herein, bisphosphorylation is the chemical reaction resulting in the production of a product containing two phosphoryl groups on the same carbon. 0019 As used herein, carbocyclic ring is a saturated, unsaturated, or aromatic, hydrocarbon ring radical. Carbocyclic rings are monocyclic or are fused, bridged, or spiro polycyclic ring systems. Monocyclic rings contain from 3 to 9 atoms, preferably 4 to 7 atoms, and most preferably 5 or 6 atoms. Polycyclic rings contain from 7 to 17 atoms, preferably from 7 to 14 atoms, and most preferably 9 or 10 atoms. 0020 As used herein, halogen is a chloro, bromo, fluoro, or iodo atom radical. Bromo and chloro are the most preferred halogens. 0021 As used herein, heterocyclic ring is a saturated, unsaturated, or aromatic, ring radical comprised of carbon atoms and one or more heteroatoms in the ring. Heterocyclic rings are monocyclic or are fused, bridged, or spiro polycyclic ring systems. Monocyclic rings contain from 3 to 9 atoms, preferably 4 to 7 atoms, and most preferably 5 or 6 atoms. Polycyclic rings contain from 7 to 17 atoms, preferably from 7 to 14 atoms, and most preferably 9 or 10 atoms. 0022 As used herein, inorganic acid is a mineral acid such as sulfuric, nitric, hydrochloric, phosphoric, and phosphorous. 0023 As used herein, methylene is a CH2 radical. 0024 As used herein, molten phosphorous acid means phosphorous acid heated to from about 45 C. to 95 C., preferably from about 55 C. to about 85 C., more preferably from about 60 C. to about 75 C. 0025 As used herein, organic acid is an organic carboxylic acid, such as formic acid, acetic acid, chloroacetic acid, dichloroacetic acid, propionic acid, benzoic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, and methane sulfonic acid. 0026 As used herein, phosphorus trihalide is a tri-halogen substituted phosphorus. The more preferred phosphorus trihalide is phosphorus oxychloride, phosphorus oxybromide, phosphorus tribromide or phosphorus trichloride. Most preferred is phosphorus trichloride. 0027 As used herein, Pamidronate denotes 3-amino-1-hydroxypropylidene-diphosphonic acid. 0028 The term risedronate, as used herein, denotes and 1-hydroxy-2-(3-pyridinyl)ethylidene-1,1-bisphosphonicacid and has the following structure: 3

0029 The compound risedronate is further described in U.S. Pat. No. 5,583,122, Benedict et al., assigned to the Procter & Gamble Co., issued Dec. 10, 1996, and An American Conference, Bisphosphonates: Current Status and future Prospects, The Royal College of Physicians, London, England, May 21-22, 1990, organized by IBC Technical Services, both references hereby are incorporated by reference. 0030 The term bisphosphonate active ingredient includes the bisphosphonate free acid, bisphosphonate salts, and bisphosphonate esters, or any mixture thereof. Any pharmaceutically-acceptable, non-toxic salt or ester of bisphosphonate may be used as the risedronate active ingredient in the novel oral dosage forms of the present invention. The salts of bisphosphonate may be acid addition salts, in particular the hydrochloride, but any pharmaceutically-acceptable, non-toxic organic or inorganic acid salt may be used. In addition, salts formed with the phosphonic acid group may be used, including, but not limited to alkali metal salts (K, Na) and alkaline earth metal salts (Ca, Mg) the Ca and Na salts being preferred. 0031 Particularly, other esters of bisphosphonate which are suitable for use as the active ingredient herein are straight chain or branched chain C1-C18 alkyl esters, including, but not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, amyl, hexyl, heptyl, octyl, nonyl, decyl, lauryl, myristyl, cetyl, and stearyl; straight chain or branched C2-C18 alkenyl, esters, including but not limited to vinyl, alkyl, undecenyl, and linolenyl; C3-C8 cycloalkyl esters, including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl; aryl ester, including, but not limited to phenyl, toluyl, xylyl, and naphthyl; alicyclic esters, including, but not limited to, menthyl; and arylalkyl esters, including, but not limited to benzyl, and phenethyl. 0032 As defined above and as used herein, substituent groups may themselves be substituted. Such substitution may be with one or more substituents. Such substituents include those listed in C. Hansch and A. Leo, Substituent Constants for Correlation Analysis in Chemistry and Biology (1979), incorporated by reference herein. Preferred substituents include (for example) alkyl, alkenyl, alkoxy, hydroxy, oxo, amino, aminoalkyl (e.g. aminomethyl, etc.), cyano, halogen, alkoxy, alkoxyacyl (e.g., carboethoxy, etc.), thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl (e.g., piperidinyl, morpholinyl, pyrrolidinyl, etc.), imino, thioxo, hydroxyalkyl, aryloxy, arylalkyl, and combinations thereof. 0033 As used herein, solvent, is a substance capable of dissolving another substance to form a uniform solution. The solvent may either be polar or non-polar. Solvents for the bisphosphorylation reaction include but are not limited to inorganic acids, organic acids, and organic bases.

The Process 0034 The bisphosphorylation step of the present process invention is conducted such that the corresponding aminocarboxylic acid is dissolved in molten phosphorous acid and reacted with phosphorus trihalide in the presence of a base, where the base is preferably morpholine or pyridine. The reaction is carried out in the temperature range between about 45 C. to about 90 C., preferably between about 55 C. to about 90 C., more preferably between about 55 C. to about 85 C., and most preferably between about 60 C. to about 75 C. The process described herein is readily adapted to industrial production. 0035 Without a solvent, such as excess phosphorous acid, and a base the reaction mixture would be very viscous. The phosphorous acid and bases added in the process act as a solvent to give a uniform reaction mixture or solution. The amount of phosphorus trihalide added in relation to the aminocarboxylic acid is from about 1.7 equivalent to about 2.5 equivalents, preferably about 2 equivalents. The amount of phosphorous acid and phosphorus trihalide should be controlled to avoid the formation of pyrophoric elemental phosphorus. Phosphorus trichloride reacts with phosphorous acid under the reaction conditions consuming some of the phosphorus trichloride and liberating hydrochloric acid gas. Generally, the amount of phosphorous acid added in relation to the amiocarboxylic acid is from about 1.5 to about 6 equivalents, preferably from about 2 to about 6 equivalents, more preferably from about 2 to about 5.5 equivalents, most preferably 5 equivalents. The base is added in an amount appropriate to achieve the desired viscosity. The amount of base added in relation to the phosphorous acid is from about 0.2 to 0.8 equivalents, more preferably from about 0.4 to about 0.6 equivalents. The process described herein is readily adapted to industrial production. 0036 This process is illustrated by the following general scheme: 4

0037 wherein Q is oxygen, NR4, sulfur, selenium, or a single bond; mn is an integer from 0 to about 5, Z is a ring selected from the group consisting of pyridine, pyridazine, pyrimidine, and pyrazine; R1 is independently hydrogen, substituted or unsubstituted amino, amido, hydroxy, alkoxy, halogen, carboxylate, substituted or unsubstituted alkyl (saturated or unsaturated) having from 1 to about 6 carbon atoms, substituted or unsubstituted aryl, or substituted or unsubstituted benzyl,; each R2 is independently, hydrogen, or substituted or unsubstituted alkyl (saturated or unsaturated) having from 1 to about 4 carbon atoms; R3 is one or more substituents selected from the group consisting of hydrogen, substituted or unsubstituted alkyl (saturated or unsaturated) having from 1 to about 6 carbon atoms, substituted and unsubstituted arly, substituted and unsubstituted benzyl, hydroxy, halogen, carbonyl, alkoxy, nitro, amido, amino, substituted amino, carboxylate, and combinations thereof; R4 is hydrogen, substituted alkyl (saturated or unsaturated) having from 1 to about 4 carbon atoms, or acyl; resulting from bisphosphorylation of an aminocarboxylic acid in the presence of phosphorus trihalide, molten phosphorous acid and base such as morpholine to form a geminal bisphosphonate. 0038 The following non-limiting examples illustrate the processes of the present invention.

EXAMPLE 1

Bisphosphorylation of 3-PAA HCl to give 1-Hydroxy-2-(3-pyridinyl)ethylidene-1,1-bisphosphonic acid 0039

0040 1-Hydroxy-2-(3-pyridinyl)ethylidene-1,1-bisphosphonic acid 0041 The reaction is run on the 65 mol scale in a 30 gal reactor. The mixture of 5 eq phosphorous acid and 3-PAA.HCl, with morpholine.HCl, is melted together until complete solution is obtained at about 70-75 C. The reaction mixture is cooled to 68 C. and 2 eq of PCl3 is metered in over 2.5-4 hours while maintaining the temperature at 68 C. The reaction is allowed to continue 15-30 min. after the addition is complete. Then the reaction mixture is hydrolyzed in aqueous hydrochloric acid at 80 C. for 0.5 hr to yield, after crystallization from aqueous acid/IPA, 14.2 Kg of NE-58019 in a 77.6% isolated yield.

EXAMPLE 2

Bisphosphorylation of 3-PAA HCl to give 1-Hydroxy-2-(3-pyridinyl)ethylidene-1,1-bisphosphonic acid 0042

0043 The mixture of 5 eq. phosphorous acid, 1.5 eq. pyridine.HCl and 3-PAA is melted together until a uniform melt is formed (80-90 C.). Then 2.1 eq. of pyridine are added. The reaction is cooled to about 70 C. and 2 eq. of PCl3 are slowly added. The mixture is heated at about 70 C. for 3.5 hours. Water and HCl are added, the reaction hydrolyzed for about 30 to about 45 minutes at 75 C. to yield risedronate after crystallization from aqueous acid/IPA.

EXAMPLE 3

Bisphosphorylation of B-alanine to give pamidronate 0044

0045 The mixture of 5 eq. phosphorous acid and -alanine is heated to form a melt. Morpholine (1 eq.) is slowly added. The reaction is cooled to about 70 C. and 2 eq. of PCl3 are added. The mixture is heated for about 3.5 hours. Then the reaction is hydrolyzed in aqueous acid at about 75 C. for about 0.5 hours. Crystallization from aqueous acid/IPA, affords pamidronate.

EXAMPLE 4

Bisphosphorylation of 4-amino butyric acid to form 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid 0046

0047 The mixture of 5 eq. phosphorous acid, 4-aminobutyric acid and morpholine HCl is melted together until uniform solution is formed. The reaction mixture is cooled to about 70 C. and 2 eq. of PCl3 are carefully added. The mixture is heated for about 5.5 hours before the reaction mixture is hydrolyzed in aqueous acid at about 80 C. and alendronate is isolated from an ethanolic solution.

Compositions 0048 The compounds made herein may be used in pharmaceutical compositions. The term pharmaceutical composition means a dosage form comprised of a safe and effective amount of an active ingredient and pharmaceutically-acceptable excipients. The pharmaceutical compositions described herein are comprised of from about, 0.1% to about 99%, preferably from about 0.5% to about 95% of an active ingredient, and from about 1% to about 99.9%, preferably from 5.00% to about 99.90% of pharmaceutically-acceptable excipients. For risedronate the composition comprises, preferably 0.25% to 40%, preferably from about 0.5% to about 30% of a risedronate active ingredient and from about 60% to about 97%, preferably from about 70% to about 99.5% of pharmaceutically-acceptable excipients. 0049 The phrase safe and effective amount, as used herein means an amount of a compound or composition high enough to significantly positively modify the symptoms and/or condition to be treated, but low enough to avoid serious side effects (at a reasonable benefit/risk ratio), within the scope of sound medical judgment. The safe and effective amount of active ingredient for use in the method of the invention herein will vary with the particular condition being treated, the age and physical condition of the patient being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular active ingredient being employed, the particular pharmaceutically-acceptable excipients utilized, and like factors within the knowledge and expertise of the attending physician. 0050 The term pharmaceutically-acceptable excipients as used herein includes any physiologically inert, pharmacologically inactive material known to one skilled in the art, which is compatible with the physical and chemical characteristics of the particular active ingredient selected for use. Pharmaceutically-acceptable excipients include, but are not limited to, polymers, resins, plasticizers, fillers, lubricants, binders, disintegrants, solvents, co-solvents, buffer systems, surfactants, preservatives, sweetening agents, flavoring agents, pharmaceutical grade dyes and pigments. All or part of the pharmaceutically-acceptable excipients contained in the pharmaceutical compositions described herein is used to make the film coating which is to be utilized in the novel oral dosage forms described herein. 0051 The term oral dosage form as used herein means any pharmaceutical composition intended to be administered to the stomach of an individual via the mouth of said individual, and for purposes of the present invention, the preferred delivery form is in the form of a modified oval tablet (preferably film coated) containing granules or particles of active ingredient. 0052 As stated hereinabove, pharmaceutically-acceptable excipients include, but are not limited to polymers, resins, plasticizers, fillers, lubricants, binders, disintegrants, solvents, co-solvents, surfactants, preservatives, sweetener agents, flavoring agents, buffer systems, pharmaceutical-grade dyes and pigments. 0053 The preferred solvent for the pharmaceutical composition is water. 0054 Flavoring agents among those useful herein include those described in Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Company, 1990, pp. 1288-1300, incorporated by reference herein. Dyes, or pigments among those useful herein include those described in Handbook of Pharmaceutical Excipients, Second Edition pp. 126-134, 1994 by the American Pharmaceutical Association & the Pharmaceutical Press, incorporated by reference herein. 0055 Preferred co-solvents include, but are not limited to, ethanol, glycerin, propylene glycol, polyethylene glycol. 0056 Preferred buffer systems include, but are not limited to potassium acetate, boric carbonic, phosphoric, succinic, malic, tartaric, citric, acetic, benzoic, lactic, glyceric, gluconic, glutaric and glutamic. Particularly preferred are phosphoric, tartaric, citric, and potassium acetate. 0057 Preferred surfactants include, but are not limited to, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene monoalkyl ethers, sucrose monoesters and lanolin esters and ethers. 0058 Preferred preservatives include, but are not limited to, phenol, alkyl esters of parahydroxybenzoic acid, benzoic acid and the salts thereof, boric acid and the thereof, sorbic acid and the salts thereof, chorbutanol, benzyl alcohol, thimerosal, phenylmercuric acetate and nitrate, nitromersol, benzalkonium chloride, cetylpyridinium chloride, methyl paraben, and propyl paraben. Particularly preferred are the salts of benzoic acid, cetylpyridinium chloride, methyl paraben and propyl paraben. 0059 Preferred sweeteners include, but are not limited to, sucrose, glucose, saccharin, and aspartame. Particularly preferred are sucrose and saccharin. 0060 Preferred binders include, but are not limited to methycellulose, sodium carboxymethycellulose, hydroxypropylmethylcellulose, carbomer, povidone, acacia, guar gum, xanthan gum and tragacanth. Particularly preferred are methycellulose, carbomer, xanthan gum, guar gum, povidone and sodium carboxymethycellulose. 0061 Preferred fillers include, but are not limited to lactose, sucrose, maltodextrin, mannitol, starch, and microcrystalline cellulose. 0062 Preferred plasticizers include, but are not limited to polyethylene glycol, propylene glycol, dibutyl phthalate, and castor oil, acetylated monoglycerides, and triacetin. 0063 Preferred lubricants include, but are not limited to, magnesium stearate, stearic acid, and talc. 0064 Preferred disintegrants include, but are not limited to, crospovidone, sodium carboxymethyl starch, sodium starch glycolate, sodium carboxymethyl cellulose, alginic acid, clays, and ion exchange resins. 0065 Preferred polymers, include but are not limited to hydroxypropylmethylcellulose (HPMC) alone and/or in combination with hydroxypropylcellulose (HPC), carboxymethylcellulose, acrylic resins such as Eudragit RL30D, manufactured by Rohm Pharma GmbH Weiderstadt, West Germany, methylcellulose, ethylcellulose, and polyvinylpyrrolidone or other commercially available film-coating preparations such as Dri-Klear, manufactured by Crompton & Knowles Corp., Mahwah, N.J. or Opadry manufactured by Colorcon, West Point, Pa. 0066 The bisphosphonates of the present invention are generally more biologically potent in inhibiting bone resorption. Thus, the compositions of the present invention allow for greater flexibility in dosage administration and dosing intervals. For example, the compositions of the present invention, including oral compositions, may be dosed, daily, weekly, biweekly or monthly.