Tetrahydrocarbazol derivatives as ligands for G-protein-coupled receptors (GPCR) | Patent Number 07122570

This invention provides new tetrahydrocarbazole derivatives that act as ligands for G-protein-coupled receptors (GPCR), especially as antagonists of the gonadotropin-releasing hormone (GnRH). A pharmaceutical composition that contains these new tetrahydrocarbazole derivatives as well as a process for the production of the new tetrahydrocarbazole derivatives are also provided. Moreover, this invention relates to the administration of tetrahydrocarbazole derivatives for treating pathologic conditions that are mediated by GPCR, especially for inhibiting GnRH, in mammals, especially humans, who require such an administration, as well as the use of tetrahydrocarbazole derivatives for the production of a pharmaceutical agent for treating GPCR-mediated pathologic conditions, especially for inhibiting GnRH.

This application claims the benefit of the filing date of U.S. Provisional Application Ser. No. 60/341,878 filed Dec. 21, 2001.

This invention relates to new tetrahydrocarbazole derivatives, the ligands of G-protein-coupled receptors, and especially antagonists of the gonadotropin-releasing hormone, their production, their use as well as pharmaceutical compositions that comprise these tetrahydrocarbazole derivatives. This invention also relates to a process for treating pathologic conditions that are mediated by G-protein-coupled receptors in a mammal, especially a human.

TECHNICAL BACKGROUND

The structural element that is common to all members of the family of the G-protein-coupled receptors (GPCR) is the presence of seven transmembrane-alpha-helical segments that are connected to one another by alternating intracellular and extracellular loops, whereby the amino-terminus is found on the extracellular side, and the carboxy-terminus is found on the intracellular side. The family of GPCRs can be divided into several subfamilies (essentially families A, B and C) with additional sequence homologies within these subfamilies. Since GPCRs are involved primarily in signal reception and transmission, a number of physiological functions are influenced by them. GPCR ligands are therefore potentially suitable as medications for therapy and prevention of a large number of pathologic conditions. A small overview on diseases that can be treated with GPCR ligands is provided in Table I in S. Wilson et al., Pharmaceutical News 2000, 7(3).

The majority of known GPCR ligands are of peptidic structure. Peptidic receptor ligands, however, often have some significant drawbacks, such as, for example, low bioavailability and metabolic instability. Therefore, in recent years, an intensified search has been run for ligands in the form of small, non-peptidic molecules. So-called “privileged structures†play a special role in the search for new, non-peptidic receptor ligands. These “privileged structures†are those basic molecular structures that prepare ligands for a number of different receptors. The term “privileged structures†was used for the first time by Evans et al. in connection with the benzodiazepine-based CCK (cholecystokinin)-A antagonists from the natural substance Asperlicin (B. E. Evans et al., J. Med. Chem. 1988, 31, 2235). For proteases, it has already been known for a long time, for example, that certain structure classes can be used as inhibitors for various enzymes. While in the past primarily mechanism-based inhibitors were described for various proteases, more recently, however, and more and more often, examples of compounds that readily fit into the active binding regions of various enzymes because of their three-dimensional structure have been found (cf. M. Whittaker, Cur. Opin. Chem. Biol. 1998, 2, 386; A. S. Ripka et al., ibid., 441). Such “privileged structures†were also already described for GPCRs. Examples to this end, in addition to the above-mentioned benzodiazepines, are also peptoids, 4-substituted 4-arylpiperidines, but also special β-Turn mimetic agents that are made rigid (B. A. Bunin et al., Ann. Rep. Med. Chem. 1999, 34, 267; R. N. Zuckermann et al., J. Med. Chem. 1994, 37, 2678; G. C B. Harriman, Tetrahedron Lett. 2000, 41, 8853). A survey to this end is found in A. A. Patchett et al., Ann. Rep. Med. Chem. 1999, 35, 289. With the tetrahydrocarbazole derivatives according to this invention, another class of “privileged structures†is made available for GPCRs.

Although this invention generally prepares ligands for GPCRs, the compounds that are prepared by this invention are especially suitable as ligands for a certain representative of the class of GPCRs, namely the gonadotropin-releasing hormone receptor (GnRH receptor). The GnRH receptor can be classified in subfamily A of the GPCRs (cf. U. Gether et al., Endocrine Reviews 2000, 21(1), 90).

GnRH is a hormone that mainly, but not exclusively, is synthesized in mammals by the nerve cells of the hypothalamus, is transported via the portal veins into the pituitary gland and is released in a regulated manner to the gonadotropic cells. By interaction with its receptor that has seven transmembrane domains, GnRH stimulates the production and the release of gonadotropic hormones by means of the second messenger inositol-1,4,5-triphosphate and Ca²⁺ ions. The gonadotropin-luteinizing hormone (LH) that is released by GnRH and the follicle-stimulating hormone (FSH) stimulate the production of sex steroids and the gamete maturation in both sexes. In addition to GnRH (also referred to as GnRH1), there are two other forms of GnRH, namely GnRH2 and 3.

The GnRH receptor is used as a pharmacological target in a number of diseases, which are dependent on a functioning sex hormone production, for example prostate cancer, premenopausal breast cancer, endometriosis and uterine fibroids. In the case of these diseases, GnRH superagonists or GnRH antagonists can be used successfully. In particular, the male birth control in combination with a substitution dose of androgens forms a possible further indication.

An advantage of GnRH antagonists in comparison to GnRH superagonists is their immediate effectiveness in the blocking of the gonadotropin secretion. Superagonists initially produce an overstimulation of the hypophysis, which results in increased gonadotropin and sex steroid releases. This hormonal reaction is only completed after a certain delay based on the desensitization and downward-adjustment of the GnRH receptor concentrations. Therefore, GnRH superagonists, both alone and in combination with testosterone, may not be able to suppress sperm production in males effectively and thus are not suitable for male birth control. In contrast to this, peptidic GnRH antagonists, especially in combination with a substitution dose of androgen, are able to bring about a significant oligozoospermia in humans.

Peptidic GnRH antagonists, however, have a number of drawbacks. They have a considerably lower effectiveness as superagonists and consequently have to be administered at considerably higher dosages. Their oral bio-availability is also low, so that they have to be administered by injection. Repeated injections lead in turn to a reduction in compliance. Moreover, the synthesis of peptidic GnRH antagonists in comparison to non-peptidic compounds is costly and labor-intensive.

Quinoline derivatives as non-peptidic GnRH antagonists are disclosed in, for example, WO 97/14682. To date, however, it was not possible to market any non-peptidic GnRH antagonists.

TECHNICAL OBJECT

The object on which this invention is based consists in providing new compounds that are suitable for treatment of pathologic conditions that are mediated by GPCR and that have in particular a GnRH-inhibiting (GnRH-antagonistic) action. The new GPCR ligands, preferably GnRH antagonists, should as much as possible be superior to the known peptide compounds and represent an effective alternative or improvement relative to known non-peptidic compounds. The new GPCR ligands, especially GnRH antagonists, are to have primarily high effectiveness and as high an oral bio-availability as possible. In addition, they should be able to be synthesized simply and with as low costs as possible. Pharmaceutical compositions that contain the new non-peptidic GPCR compounds, especially GnRH antagonists, are also provided by this invention.

Another object on which this invention is based is the provision of new GPCR ligands, preferably GnRH antagonists, for use as pharmaceutical agents or for use for the production of pharmaceutical agents that comprise the GPCR ligands, preferably GnRH antagonists.

Moreover, an object of this invention is to provide a process for treating pathologic conditions that are mediated by GPCR, especially for inhibiting GnRH, in a mammal, especially a human.

All of these objects are achieved in a surprising way by the provision of new tetrahydrocarbazole derivatives, the pharmaceutical compositions that contain these tetrahydrocarbazole derivatives, the process for the production of these tetrahydrocarbazole derivatives as well as the process for treating pathologic conditions that are mediated by GPCR, preferably for inhibiting GnRH, in a mammal, especially a human, by administering the tetrahydrocarbazole derivatives or the use of the tetrahydrocarbazole derivatives for the production of pharmaceutical agents for treating pathologic conditions that are mediated by GPCR, especially for GnRH inhibition.

SUMMARY OF THE INVENTION

In a first aspect, this invention provides new tetrahydrocarbazole derivatives of general formula (I).

In a second aspect, pharmaceutical compositions are provided that comprise at least one of the new tetrahydrocarbazole derivatives of general formula (I).

In a third aspect, this invention provides tetrahydrocarbazole derivatives of general formula (I) for use as pharmaceutical agents.

In another aspect, this invention relates to the use of a tetrahydrocarbazole derivative of general formula (I) for the production of a pharmaceutical agent for treating pathologic conditions that are mediated by GPCR, especially for inhibiting the GnRH. This invention also relates to a process for treating pathologic conditions that are mediated by GPCR, especially for inhibiting GnRH in a mammal, preferably a human, whereby an effective amount of a compound of general formula (I) according to the invention is administered to a mammal, preferably a human, who requires such a treatment.

In addition, this invention provides a process for the production of tetrahydrocarbazole derivatives of general formula (I). This process comprises, for example, the steps of condensation of a cyclohexanone derivative that is anchored to a solid phase and suitably substituted with a suitably substituted phenylhydrazine derivative, a subsequent derivatization depending on the desired structure of the final compound and finally cleavage from the solid phase and isolation of the product.

DETAILED DESCRIPTION OF THE INVENTION

In a first aspect of this invention, new tetrahydrocarbazole compounds of general formula (I)

are provided, in which

radical R¹ is a hydrogen atom, a C₂–C₆ alkenyl radical or a C₁–C₆ alkyl radical, and can optionally be substituted with an aryl radical, hetaryl radical or the group —COOR¹¹, whereby the aryl or hetaryl radical can be substituted with up to three substituents, which are selected independently of one another from the group that consists of —NO₂, —CH₃, —CF₃, —OCH₃, —OCF₃ and halogen atoms, and

radical R¹¹ is a hydrogen atom, a C₁–C₁₂ alkyl radical, a C₁–C₁₂ aralkyl radical, an aryl radical, a hetaryl radical or the group —COCH₃, and optionally can be substituted with a substituent that is selected from the group that consists of —CONH₂, —COCH₃, —COOCH₃, —SO₂CH₃ and aryl radicals;

radicals R², R³, R⁴ and R⁵, independently of one another, in each case are a hydrogen atom, a halogen atom, the group —COOH, —CONH₂, —CF₃, —OCF₃, —NO₂, —CN, a C₁–C₆ alkyl radical, a C₁–C₆ alkenyl radical, a C₁–C₆ alkoxy radical, a C₁–C₁₂ aralkyl radical, an aryl or hetaryl radical;

radical R⁶ is the group —CONR⁸R⁹, —COOR⁸, —CH₂₁NR⁸R⁹, —CH₂R⁸, —CH₂OR⁸ or a C₁–C₁₂ alkenyl radical, which optionally is substituted with radicals R⁸ and R⁹,

whereby radicals R⁸ and R⁹, independently of one another, in each case are a hydrogen atom, a C₁–C₁₂ alkyl radical, a C₁–C₁₂ aralkyl radical, a C₁–C₁₂ hetaralkyl radical, an aryl radical or hetaryl radical, which can be substituted with one or more substituents, which are selected from the group that consists of —OH, —NH₂, —CONHR¹⁰, —COOR¹⁰, —NH—C(â• NH)—NH₂ and halogen atoms,

whereby radical R¹⁰ is a hydrogen atom, a C₁–C₁₂ alkyl radical, a C₁–C₁₂ aralkyl radical, an aryl radical or hetaryl radical, and optionally is substituted with the group —CON(R¹¹)₂,

or whereby radicals R⁸ and R⁹ together can form a ring structure that either consists exclusively of carbon atoms or, in mixed form, consists of carbon atoms and heteroatoms;

radical R⁷ is a hydrogen atom, a C₁–C₁₂ alkyl radical, a C₁–C₁₂ alkenyl radical, a C₁–C₁₂ aralkyl radical, an aryl radical or a hetaryl radical, the group —NR¹² R¹³, —NHCOR¹⁴, —NHCONHR¹⁴, —NHCOOR⁴ or —NHSO₂R¹⁴, and optionally can be substituted with one or more substituents, which are selected from the group that consists of —OH, —NH₂, —CONH₂, —COOH and halogen atoms,

radicals R¹² and R¹³, independently of one another, in each case are a hydrogen atom, a C₂–C₆ alkenyl radical or a C₁–C₁₂ alkyl radical and optionally can be substituted with one or more aryl or hetaryl radicals, which in turn can be substituted with up to three substituents, which independently of one another are selected from the group that consists of —NO₂, —CH₃, —CF₃, —OCH₃, —OCF₃ and halogen atoms,

and radical R⁴ is a hydrogen atom, a C₁–C₁₂ alkyl radical, a C₁–C₁₂ alkenyl radical, a C₁–C₁₂ aralkyl radical, an aryl radical or a hetaryl radical, which optionally can be substituted with one or more substituents, which are selected from the group that consists of —NO₂, —CH₃, —OR¹¹, —CF₃, —OCF₃, —OH, —N(R¹¹)₂, —OCOR¹¹, —COOH, —CONH₂, —NHCONHR¹¹, —NHCOOR¹¹ and halogen atoms;

and radicals R^a, R^b, R^c, R^d, R^e and R^f, independently of one another, in each case are a hydrogen atom, a halogen atom, the group —COOH, —CONH₂, —CF₃, —OCF₃, —NO₂, —CN, a C₁–C₆ alkyl radical, C₁–C₆ alkoxy radical, an aryl radical or a hetaryl radical;

provided that the compound of general formula (I) is not selected from the group that consists of 3-amino-1,2,3,4-tetrahydrocarbazole-3-carboxylic acid, 3-amino-6-methoxy-1,2,3,4-tetrahydrocarbazole-3-carboxylic acid, 3-amino-6-benzyloxy-1,2,3,4-tetrahydrocarbazole-3-carboxylic acid, 3-acetamido-1,2,3,4-tetrahydrocarbazole-3-carboxylic acid, methyl-3-acetamido-1,2,3,4-tetrahydrocarbazole-3-carboxylate, -(−)-menthyl-3-acetamido-1,2,3,4-tetrahydrocarbazole-3-carboxylate or 3-tert-butoxycarbonyl-amino-1,2,3,4-tetrahydrocarbazole-3-carboxylic acid.

Compounds of general formula (I) as indicated above with all meanings for the radicals that are contained in (I) that are indicated above are an embodiment of the invention, whereby radical R¹¹ is a heteroalkyl radical or a hetaryalkyl radical.

The basic tetrahydrocarbazole structures of the compounds that are excluded by name above from the compounds that fall under the definition of general formula (I) were presented by Y. Maki et al. in Chem. Pharm. Bull. 1973, 21 (11), 2460–2465 as well as by R. Millet et al. in Letters in Peptide Science 1999, 6, 221–233.

The terms that are indicated to explain the compounds of general formula (I) have in particular the following meaning:

C₁–C₆ or C₁–C₁₂ “alkyl radical†is defined as a branched or unbranched, cyclic or noncyclic, optionally substituted alkyl group with 1 to 6 or 1 to 12 carbon atoms. Representative examples of such alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, 2,2-dimethylpropyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl and n-dodecyl groups as well as cyclic groups, especially cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl groups, 1-cyclopropyl, 1-cyclobutyl, 1-cyclopentyl, 1-cyclohexyl, 1-cycloheptylethyl, 2-cyclopropyl, 2-cyclobutyl, 2-cyclopentyl, 2-cyclohexyl, 2-cycloheptylethyl groups and the like, but they are not limited to the latter.

C₂–C₆ “Alkenyl radical†is defined as a branched or unbranched, cyclic or non-cyclic, unsaturated alkenyl group, optionally substituted in one or more places, with 2 to 6 carbon atoms. Representative examples of such alkenyl groups include vinyl, allyl, prop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, pent-1-enyl, pent-2-enyl, pent-3-enyl, pent-4-enyt, penta-1,3-dienyl, penta-1,4-dienyl, penta-2,3-dienyl, isoprenyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, hex-5-enyl, hexa-1,3-dienyl, hexa-1,4-dienyl, hexa-1,5-dienyl, hexa-2,4-dienyl, hexa-2,5-dienyl, hexa-1,4-dienyl, hexa-1,3,5-trienyl groups and the like, but they are not limited to the latter.

C₂–C₆ “Alkoxy radical†is defined as a branched or unbranched, cyclic or non-cyclic, optionally substituted alkoxy group with 2 to 6 carbon atoms. Representative examples of such alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclohexyloxy groups and the like, but they are not limited to the latter.

C₁–C₁₂ “Aralkyl radical†is defined as an alkyl radical with 1 to 12 carbon atoms that is substituted by one or more aryl radicals. Representative examples of such aralkyl groups for the purposes of this invention include benzyl, 1-phenylethyl, 1-phenylpropyl, 1-phenylbutyl, 1-phenylhexyl, 1-phenyl-2-methylethyl, 1-phenyl-2-ethylethyl, 1-phenyl-2,2-dimethylethyl, benzhydryl, triphenylmethyl, 2- or 3-naphthylmethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl groups and the like, but they are not limited to the latter. Accordingly, a “hetaralkyl radical†is an alkyl radical that is substituted by a heteroaryl radical.

“Aryl radical†is defined as an optionally substituted monocyclic or polycyclic aromatic group. Representative examples of such aryl groups include phenyl groups, naphthyl groups, and the like, but they are not limited to the latter.

The designation “hetaryl radical†is identical to the designation “heteroaryl radical†and stands for an aryl group, as defined above, that in the structure thereof comprises one or more heteroatoms, in particular nitrogen, phosphorus, oxygen, sulfur and arsenic atoms. Representative examples of such hetaryl or heteroaryl groups include unsubstituted hetaryl radicals as well as substituted hetaryl radicals, in particular imidazolyl, pyridyl, quinolinyl groups and the like, but they are not limited to the latter.

The designation “ring structure†comprises optionally substituted monocyclic or polycyclic ring structures with a different number of ring members, but in particular five-, six- and seven-membered ring structures. In these ring structures, in addition to carbon atoms, one or more heteroatoms, such as in particular nitrogen, phosphorus, oxygen, sulfur and arsenic atoms, can also be included. The ring structures can comprise saturated, but also partially or completely unsaturated, structural elements. Representative examples of such ring structures include aza, oxa, thia, phosphacyclopentane, phosphacyclohexane, phosphacycloheptane, diaza, dioxa, dithia, diphosphacyclopentane, diphosphacyclohexane, and diphosphacycloheptane basic ring structures and the like, as well as basic ring structures with mixed heteroatom exchange, but they are not limited to the latter.

“Halogen atoms†comprise in particular fluorine, chlorine, bromine and iodine atoms, especially preferably chlorine atoms.

At this point, it can also be pointed out that in addition to the compounds of general formula (I) that are mentioned in the art, as defined above, physiologically compatible derivatives or analogs, in particular also salts of these compounds are also included by this invention.

In addition, it can be noted at this point that the designation “receptor ligand†or “ligand†for the purposes of this invention is to designate any compound that binds in any way to a receptor (in this invention, the receptor is a GPCR receptor, preferably a GnRH receptor) and triggers either an activation, an inhibition or other conceivable action in the case of this receptor. The term “ligand†thus comprises agonists, antagonists, partial agonists/antagonists and other ligands that cause an action in the reactor that is similar to the action of agonists, antagonists or partial agonists/antagonists. The compounds of general formula (I) according to the invention are preferably antagonists of the GnRH.

New tetrahydrocarbazole derivatives of general formula (I) according to the invention, in which radical R⁷ is not a hydrogen atom, if radical R⁶ is simultaneously an alkyl radical, are an embodiment of this invention.

Compounds of general formula (I) in which radical R⁷ is not a hydrogen atom in any case are another embodiment of this invention.

Preferred new tetrahydrocarbazole derivatives of general formula (I) according to the invention are any compounds in which the radicals R^a, R^b, R^c, R^d, R^e and R^f are hydrogen atoms.

Also preferred new tetrahydrocarbazole derivatives of general formula (I) according to the invention are any compounds in which radical R¹ is a hydrogen atom.

Preferred new tetrahydrocarbazole derivatives of general formula (I) according to the invention are in addition any compounds in which radicals R², R³, R⁴ and/or R⁵ are not hydrogen atoms. Especially preferred in this case are any compounds of general formula (I) in which radicals R², R³, R⁴ and R⁵, independently of one another, are methyl, chloro or methoxy radicals. Quite especially preferred in this case are any compounds of general formula (I) in which at least radical R² is not a hydrogen atom, especially the compounds

Phenylmethyl-[(1S,2S)-1-[[[(3R)-3-[[[(1S)-1-(aminocarbonyl)-2-methylpropyl]amino]-carbonyl]-2,3,4,9-tetrahydro-8-methyl-1H-carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate (compound No. 150a in the examples),

Phenylmethyl-[(1S,2S)-1-[[[(3R)-3-[[[(1S)-1-(aminocarbonyl)-2-methylpropyl]amino]-carbonyl]-6-chloro-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]-carbonyl]-2-methylbutyl]carbamate (148a),

Phenylmethyl-[(1S,2S)-1-[[[(3R)-3-[[[(1S)-1-(aminocarbonyl)-2-methylpropyl]amino]-carbonyl]-2,3,4,9-tetrahydro-8-methoxy-1H-carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate (147a).

Preferred new tetrahydrocarbazole derivatives of general formula (I) according to the invention are also any compounds in which R⁶ is a hydrophobic radical that comprises alkyl, aryl and/or hetaryl structures and that carries a hydrogen bridge-donor-acceptor system at a distance of two to four single bonds, counting from the carbon atoms that are substituted by radicals R⁶ and R⁷. Especially preferred are compounds of general formula (I), whereby radical R⁶ is:

• • a carbonyl phenylalanylamide radical, in particular the compound phenylmethyl-[(1S,2S)-1-[[[(3R)-3-[[[(1S)-2-amino-2-oxo-1-(phenylmethyl)ethyl]amino]carbony]-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate (66),
  • a carbonyl isoleucylamide radical, in particular the compound phenylmethyl [(1S,2S)-1-[[[(3R)-3-[[[(1S,2S)-1-(aminocarbonyl)-2-methylbutyl]amino]carbonyl]-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate (64),
  • a carbonyl valyl-4-aminobenzoic acid amide radical, in particular the compound phenylmethyl [(1S,2S)-1-[[[(3R)-3-[[[(1S)-1-[[[4-(aminocarbonyl)phenyl]amino]-carbonyl]-2-methylpropyl]amino]carbonyl]-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate (45),
  • a carbonyl valyl-N-methylamide radical, in particular the compound phenylmethyl [(1S,2S)-2-methyl-1-[[[(3R)-2,3,4,9-tetrahydro-3-[[[(1S)-2-methyl-1-[(methylamino)carbonyl]-propyl]amino]carbonyl]-1H-carbazol-3-yl]amino]carbonyl]butyl]carbamate (222a),
  • a methyloxymethyl-4-pyridyl radical, in particular the compound 2,3,4,9-tetrahydro-3-(3-phenylpropyl)-O-(4-pyridinylmethyl)-1H-carbazole-3-methanol (287),
  • a carboxyl radical, in particular the compound 2,3,4,9-tetrahydro-3-(3-phenylpropyl)-1H-carbazole-3-carboxylic acid (273),
  • or a propenoic acid ethyl ester radical, in particular the compound ethyl 3-[2,3,4,9-tetrahydro-3-(3-phenylpropyl)-1H-carbazol-3-yl]-2-propenoate (289).

Also especially preferred are compounds of general formula (I), in which radical R⁶ is:

• • a carbonylvalylamide radical, in particular the compound phenylmethyl [(1S,2S)-1-[[[(3R)-3-[[[(1S)-1-(aminocarbonyl)-2-methylpropyl]amino]carbonyl]-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate (58),
  • a carbonylthreonylamide radical, in particular the compound phenylmethyl [(1S,2S)-1-[[[(3R)-3-[[[(1S,2R)-1-(aminocarbonyl)-2-hydroxypropyl]amino]-carbonyl]-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate,
  • a cyclic carboxamide radical (such as, for example, a carbonylpropylamide radical, in particular the compound phenylmethyl [(1S,2S)-1-[[[(3R)-3-[[(2S)-2-(aminocarbonyl)-1-pyrrolidinyl]carbonyl]-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]-carbonyl]-2-methylbutyl]carbamate (181a)
  • or a carbonyloctahydroindolyl-2-carboxamide radical, in particular the compound phenylmethyl [(1S,2S)-1-[[[(3R)-3-[[(2S)-2-(aminocarbonyl)octahydro-1H-indol-1-yl]carbonyl]-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]carbonyl]-2-methylbutyl]-carbamate (190a)),
  • a 4-carboxamidophenylcarboxamide radical, in particular the compound phenylmethyl [(1S,2S)1-[[[(3R)-3-[[[4-(aminocarbonyl)phenyl]amino]carbonyl]-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate (62),
  • a methylaminomethyl-2-pyridyl radical, in particular the compound 2,3,4,9-tetrahydro-3-(3-phenylpropyl)-N-(2-pyridinylmethyl)-1H-carbazole-3-methanamine (279),
  • a carbonylvalinol radical, in particular the compounds phenylmethyl [(1S,2S)-1-[[[(3S)-3-[[[(1S)-1-(hydroxymethyl)-2-methylpropyl]amino]carbonyl]-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate (267b)
  • and 2,3,4,9-tetrahydro-N-[(1S)-1-(hydroxymethyl)-2-methylpropyl]-3-(3-phenylpropyl)-1H-carbazole-3-carboxamide (276)
  • or a methylvalinol radical, in particular the compound (2S)-3-methyl-2-[[[2,3,4,9-tetrahydro-3-(3-phenylpropyl)-1H-carbazol-3-yl]methyl]amino]-1-butanol (284).

Preferred, new tetrahydrocarbazole derivatives of general formula (I) according to the invention are also any compounds in which R⁷ is a hydrophobic radical that comprises alkyl, aryl and/or hetaryl structures. Especially preferred in this case are compounds of general formula (I), in which radical R⁷ is:

• • a 2,3-biphenylpropionylamino radical, in particular the compound N-[[(3R)-2,3,4,9-tetrahydro-3-[(1-oxo-2,3-diphenylpropyl)amino]-1H-carbazol-3-yl]carbonyl]-L-valyl-L-aspartamide (18),
  • an indanoylamino radical, in particular the compound (3R)-N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-3-[[(2,3-dihydro-1H-inden-1-yl)carbonyl]amino]-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide (162a),
  • an indolylacetylamino radical, in particular the compound (3S)-N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro-3-[(1H)-indol-3-ylacetyl)amino]-1H-carbazole-3-carboxamide (164b),
  • a 2-naphthylacetylamino radical, in particular the compound (3S)-N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro-3-[(2-naphthalenylacetyl)amino]-1H-carbazole-3-carboxamide (161b),
  • or a 3-propionylamino radical. A further preferred compound is N-[[(3R)-2,3,4,9-N-[[(3R)-2,3,4,9-tetrahydro-3-[[(2S,3S)-3-methyl-1-oxo-2-[(1-oxo-3-phenylpropyl)amino]pentyl]-amino]-1H-carbazol-3-yl]carbonyl]-L-valyl-L-aspartamide (22).

Also especially preferred are compounds of general formula (I) in which R⁷ is:

• • a phenylmethylcarboxamide radical that is substituted in the aromatic system, in particular the compounds (3R)-N-[(1S)-1 -(aminocarbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro-3-[[(4-methylphenyl)acetyl]amino]-1H-carbazole-3-carboxamide (165a),
  • N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]2,3,4,9-tetrahydro-3-[[(4-methoxyphenyl)-acetyl]amino]-1H-carbazole-3-carboxamide (175),
  • (3R)-N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-3-[[(3-bromophenyl)acetyl]amino]-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide (96),
  • (3R)-N-[(1S)-1-aminocarbonyl)-2-methylpropyl]-3-[[(4-fluorophenyl)acetyl]amino]-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide (91),
  • (3R)-N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-3-[[(4-chlorophenyl)acetyl]amino]-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide (167a);
  • a phenylhexylamine radical, in particular the compound (3R)-N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro-3-[(6-phenylhexyl)amino]-1H-carbazole-3-carboxamide (234a);
  • or a phenylpropyl radical, in particular the compounds 6,8-dichloro-2,3,4,9-tetrahydro-3-(3-phenylpropyl)-1H-carbazole-3-carboxylic acid (275) and
  • ethyl-6,8-dichloro-2,3,4,9-tetrahydro-3-(3-phenylpropyl)-1H-carbazole-3-carboxylate (272).

Preferred are also any new compounds of general formula (I) according to the invention that are present in R-configuration in the carbon atom that is substituted by radicals R⁶ and R⁷, if radicals R⁶ and R⁷ together form an alpha-aminocarboxylic acid structural element.

Most preferred for the purposes of this invention are the compounds phenylmethyl [(1S,2S)-1-[[[(3R)-3-[[[(1S)-1-(aminocarbonyl)-2-methylpropyl]amino]carbonyl]-6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate (184a), phenylmethyl [(1S,2S)-1-[[[(3R)-3-[[[(1S)-1-(hydroxymethyl)-2-methylpropyl]amino]carbonyl]-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate (267a), (2S)-1-[[(3R)-3-[[(4-chlorophenyl)acetyl]amino]-2,3,4,9-tetrahydro-8-methoxy-1H-carbazol-3′-yl]carbonyl]-2-pyrrolidine carboxamide (189a) and 6,8-dichloro-2,3,4,9-tetrahydro-3-(3-phenylpropyl)-N-(2-pyridinylmethyl)-1H-carbazole-3-methanamine (283).

Other representatives of new compounds of general formula (I) according to the invention including their production are indicated in the examples.

The new tetrahydrocarbazole derivatives (I) according to the invention, as defined above, are ligands of GPCR and can be used in particular for inhibition, i.e., as antagonists of the gonadotropin-releasing hormone, for example for male birth control, for hormone therapy, for treatment of female subfertility or infertility, for female contraception and to combat tumors.

In male birth control, the compounds according to the invention bring about a reduction in spermatogenesis. A combined administration with androgens, e.g., testosterone or testosterone derivatives, such as, for example, testosterone esters, preferably takes place. In this case, the administration of testosterone derivatives can be carried out by, for example, injection, e.g., by intramuscular depot injection.

Compounds (1) according to the invention, optionally in combination with other hormones, e.g., estrogens and/or progestins, can also be used in hormone therapy, for example for treating endometriosis, uterus leiomyomas and uterine fibroids. Especially preferred are combinations of the GnRH antagonists according to the invention and tissue-selective partial estrogen agonists such as Raloxifene®. In addition, the compounds according to the invention can be used in hormone replacement therapy. Moreover, compounds (1) according to the invention can be used for increasing female fertility, for example by inducing ovulation, and treating sterility.

In contrast, new compounds (1) according to the invention are also suitable for contraception in females. Thus, the GnRH antagonist according to the invention can be administered on days 1 to 15 of the cycle together with estrogen, preferably with very low estrogen dosages. On days 16 to 21 of the intake cycle, progestagen is added to the estrogen-GnRH-antagonist combination. The GnRH antagonist according to the invention can be administered continuously over the entire cycle time. In this way, a reduction in the hormone dosages and thus a reduction in the side effects of unphysiological hormone levels can be achieved. In addition, advantageous effects in women who suffer from polycystic ovarian syndrome and androgen-dependent diseases, such as acne, seborrhea and hirsutism, can be achieved. An improved cycle monitoring relative to previous administration methods can also be expected. Further indications are benign prostate hyperplasia, gonad protection in chemotherapy, controlled ovarian stimulation/artificial reproduction techniques, infantile development disorders, e.g., Pubertas praecox and polycystic ovaries.

Finally, compounds (I) according to the invention, as defined above, can also be used for the treatment of hormone-dependent tumor diseases, such as premenopausal breast cancer, prostate cancer, ovarian cancer and endometrial cancer, by the endogenous sex steroid hormones being suppressed.

New compounds (1) according to the invention, as defined above, are suitable as GPCR ligands, in particular GnRH antagonists for treating the above-indicated pathologic conditions for administration to mammals, in particular to humans, but also for the purposes of veterinary medicine, e.g., in the case of domestic and working animals but also in the case of wild animals.

The administration can be carried out in the known way, for example, orally or non-orally, in particular topically, rectally, intravaginally, nasally or by injections or implantation. Oral administration is preferred. New compounds (I) according to the invention are brought into a form that can be administered and are optionally mixed with pharmaceutically compatible vehicles or diluents. Suitable adjuvants and vehicles are described in, for example, Ullmann's Encyclopedia of Technical Chemistry, Vol. 4, (1953), 1–39; Journal of Pharmaceutical Sciences, Vol. 52 (1963), 918 ff; issued by Czetsch-Lindenwald, “Hilfsstoffe für Pharmazie und angrenzende Gebiete [Adjuvants for Pharmaceutics and Related Fields]†; Pharm. Ind. 2, 1961, 72 ff; Dr. H. P. Fiedler, “Lexikon der Hilfsstoffe für Pharmazie, Kosmetik und angrenzende Gebiete [Dictionary of Adjuvants for Pharmaceutics, Cosmetics and Related Fields],†Cantor, K. G., Aulendorf in Württemberg, 1971.

Oral administration can be carried out, for example, in solid form as tablets, capsules, gel capsules, coated tablets, granulates or powders, but also in the form of a drinkable solution. For oral administration, the new compounds of general formula (I) according to the invention, as defined above, can be combined with known and commonly used physiologically compatible adjuvants and vehicles, such as, e.g., gum arabic, talc, starch, sugar, such as, e.g., mannitol, methyl cellulose, lactose, gelatin, surfactants, magnesium stearate, cyclodextrins, aqueous or non-aqueous vehicles, diluents, dispersing agents, emulsifiers, lubricants, preservatives and flavoring substances (e.g., ethereal oils). The compounds according to the invention can also be dispersed in a microparticulate, e.g., nanoparticulate composition.

The non-oral administration can be carried out by, for example, intravenous, subcutaneous or intramuscular injection of sterile aqueous or oily solutions, suspensions or emulsions, by implants or by ointments, creams or suppositories. An administration as a timed-release form can optionally also be carried out. Implants can contain inert materials, e.g., biodegradable polymers or synthetic silicones, such as, e.g., silicone rubber. Intravaginal administration can be carried out by, e.g., vaginal rings. Intrauterine administration can be carried out by, e.g., diaphragms, etc. Moreover, a transdermal administration, in particular by a formulation suitable in this respect and/or suitable means such as, e.g., a patch, is also provided.

As already mentioned above, new compounds (I) according to the invention can also be combined with other pharmaceutical active ingredients. Within the scope of a combination therapy, the individual active components can be administered simultaneously or separately, specifically either on the same path (e.g., orally) or on separate paths (e.g., orally and as an injection). They can be present or administered in a unit dose in the same or different amounts. A specific dosage regimen can also be used if this seems suitable. In this way, several of the new compounds (I) according to the invention can also be combined with one another.

The dosage can vary within a wide range depending on the type of indication, the severity of the disease, the type of administration, the age, sex, body weight and sensitivity of the subject that is to be treated. This corresponds to the abilities of one skilled in the art to determine a “pharmacologically effective amount†of the combined pharmaceutical composition. Unit dosages of 1 μg to 100 mg, especially preferably 1 μg to 10 mg, and most preferably 1 μg to 1 mg per kg of body weight of the subject that is to be treated are preferred. The administration can be carried out in an individual dose or several separate dosages.

Accordingly, in another aspect of this invention, pharmaceutical compositions, as described above, that comprise at least one of new compounds (I) according to the invention, as defined above, as well as optionally pharmaceutically compatible vehicles and/or adjuvants, are also included by this invention. Preferred and especially preferred pharmaceutical compositions are any that comprise at least one of the above-mentioned preferred or especially preferred new compounds (I) according to the invention, in particular the above compounds that are mentioned by name. In pharmaceutical compositions according to this invention, in addition to at least one compound of general formula (I), as defined above, still other pharmaceutical active ingredients can also be present, as already presented above in more detail.

In the pharmaceutical compositions according to the invention, at least one of new compounds (I) according to the invention, as defined above, is present in one of the above-mentioned preferred, especially preferred or most preferred unit doses, specifically preferably in a form of administration that makes oral administration possible.

Moreover, in another aspect, this invention provides compounds of general formula (I), as defined above, for use as pharmaceutical agents.

Tetrahydrocarbazole compounds of general formula (I) that are preferred according to the invention, as defined above, for use as pharmaceutical agents are in turn any compounds that were mentioned above as preferred and especially preferred compounds, in particular the preferred compounds according to the invention that are mentioned by name as well as the compounds that are mentioned in the examples.

Relative to compounds (I) according to the invention that comprise pharmaceutical compositions as well as relative to compounds (I) according to the invention for use as pharmaceutical agents, reference is made to the remarks regarding the new compounds (I) according to the invention, as defined above, regarding possible uses and means of administration.

In another aspect, this invention also provides the use of at least one tetrahydrocarbazole derivative of general formula (I) according to the invention, as defined above, whereby—as initially defined—the tetrahydrocarbazoles that are disclosed in the publications by Millet et al. and Maki et al. are excluded from the meaning of general formula (I), for the production of a pharmaceutical agent for treating GPCR-mediated diseases, especially for inhibiting the gonadotropin-releasing hormone (GnRH).

Moreover, in another aspect, this invention provides the use of at least one compound of general formula (I) according to the invention, as defined above, but including the compounds excluded by name above, from the publications by Millet et al. and Maki et al., namely 3-amino-1,2,3,4-tetrahydrocarbazole-3-carboxylic acid, 3-amino-6-methoxy-1,2,3,4-tetrahydrocarbazole-3-carboxylic acid, 3-amino-6-benzyloxy-1,2,3,4-tetrahydro-carbazole-3-carboxylic acid, 3-acetamido-1,2,3,4-tetrahydrocarbazole-3-carboxylic acid, methyl-3-acetamido-1,2,3,4-tetrahydrocarbazole-3-carboxylate, (−)-menthyl-3-acetamido-1,2,3,4-tetrahydrocarbazole-3-carboxylate and 3-tert-butoxycarbonyl-amino-1,2,3,4-tetrahydrocabazole-3-carboxylic acid, for the production of a pharmaceutical agent for inhibiting the GnRH, preferably for male birth control, for hormone therapy, for treating female subfertility and infertility, for female contraception and to combat tumors. Stated more clearly, the designation “a compound of general formula (I) as defined above, but including the compounds excluded by name above†means a compound of general formula (I)

in which:

radical R¹ is a hydrogen atom, a C₂–C₆ alkenyl radical or a C₁–C₆ alkyl radical and optionally can be substituted with an aryl radical, a hetaryl radical or the group —COOR¹¹, whereby the aryl radical or hetaryl radical can be substituted with up to three substituents, which are selected, independently of one another, from the group that consists of —NO₂, —CH₃, —CF₃, —OCH₃, —OCF₃ and halogen atoms, and

radical R¹¹ is a hydrogen atom, a C₁–C₁₂ alkyl radical, a C₁–C₁₂ aralkyl radical, an aryl radical, a hetaryl radical or the group —COCH₃, and optionally can be substituted with a substituent that is selected from the group that consists of —CONH₂, —COCH₃, —COOCH₃, —SO₂CH₃ and aryl radicals;

radicals R², R³, R⁴ and R⁵, independently of one another, in each case are a hydrogen atom, a halogen atom, the group —COOH, —CONH₂, —CF₃, —OCF₃, —NO₂, —CN, a C₁–C₆ alkyl radical, a C₁–C₆ alkenyl radical, a C₁–C₆ alkoxy radical, a C₁–C₁₂ aralkyl radical, an aryl radical or a hetaryl radical;

radical R⁶ is the group —CONR⁸R⁹, —COOR⁸, —CH₂NR⁸R⁹, —CH₂R⁸, —CH₂OR⁸ or a C₁–C₁₂ alkenyl radical, which optionally is substituted with radicals R⁸ and R⁹,

whereby radicals R⁸ and R⁹, independently of one another, in each case are a hydrogen atom, a C₁–C₁₂ alkyl radical, a C₁–C₁₂ aralkyl radical, a C₁–C₁₂ hetaralkyl radical, an aryl radical or hetaryl radical, which can be substituted with one or more substituents, which are selected from the group that consists of —OH, —NH₂, —CONHR¹⁰, —COOR¹⁰, —NH—C(—NH)—NH₂ and halogen atoms,

whereby radical R¹⁰ is a hydrogen atom, a C₁–C₁₂ alkyl radical, a C₁–C₁₂ aralkyl radical, an aryl or hetaryl radical and optionally is substituted with the group —CON(R¹¹)₂,

or whereby radicals R⁸ and R⁹ together can form a ring structure that either exclusively consists of carbon atoms or, mixed, consists of carbon and heteroatoms;

radical R⁷ is a hydrogen atom, a C₁–C₁₂ alkyl radical, a C₁–C₁₂ alkenyl radical, a C₁–C₁₂ aralkyl radical, an aryl radical or hetaryl radical, the group —NR²R¹³, —NHCOR¹⁴, —NHCONHR⁴, —NHCOOR⁴ or —NHSO₂R⁴, and optionally can be substituted with one or more substituents that are selected from the group that consists of —OH, —NH₂, —CONH₂, —COOH and halogen atoms,

radicals R¹² and R¹³, independently of one another, in each case are a hydrogen atom, a C₂–C₆ alkenyl radical or a C₁–C₁₂ alkyl radical, and optionally can be substituted with one or more aryl radicals or hetaryl radicals, which can be substituted in turn with up to three substituents, which are selected, independently of one another, from the group that consists of —NO₂, —CH₃, —CF₃, —OCH₃, —OCF₃ and halogen atoms,

and radical R¹⁴ is a hydrogen atom, a C₁–C₁₂ alkyl radical, a C₁–C₁₂ alkenyl radical, a C₁–C₁₂ aralkyl radical, an aryl radical or a hetaryl radical, which optionally can be substituted with one or more substituents, which are selected from the group that consists of —NO₂, —CH₃, —OR¹¹, —CF₃, —OCF₃, —OH, —N(R¹¹)₂, —OCOR¹¹, —COOH, —CONH₂, —NHCONHR¹¹, —NHCOOR¹¹, and halogen atoms;

and radicals R^a, R^b, R^c, R^d, R^e and R^f, independently of one another, in each case are a hydrogen atom, a halogen atom, the group —COOH, —CONH₂, —CF₃, —OCF₃, —NO₂, —CN, a C₁–C₆ alkyl radical, C₁–C₆ alkoxy radical, an aryl radical or a hetaryl radical.

The indications already mentioned in connection with the new compounds of general formula (I) according to the invention, as defined above (i.e., excluding the compounds mentioned by name above and disclosed in the publications by Maki et al. and Millet et al.) were already provided above in reference to the new compounds (I) according to the invention. The preferred and especially preferred compounds in the use of the above-defined compounds for the production of a pharmaceutical agent for inhibiting the GnRH are identical to the preferred and especially preferred compounds already mentioned above in connection with the new compounds of general formula (I) according to the invention, as defined above.

In another aspect, this invention provides the use of a compound (I) according to the invention as defined above, but also including compounds initially excluded by name for male birth control or for female contraception. Preferred and especially preferred compounds according to the invention for this use are any compounds that were already initially mentioned as preferred or especially preferred compounds of general formula (I) according to the invention, as defined above.

Moreover, this invention provides a process for male birth control or for female contraception that comprises the administration of an amount of a compound according to the invention that is effective for male birth control or for female contraception as defined in the paragraph directly above, to a subject, preferably a mammal, especially preferably a human.

In another aspect, this invention relates to a process for treating GPCR-mediated pathologic conditions. The process comprises the administration of at least one compound (I) according to the invention, as defined above, to a mammal, especially a human, in whom such a treatment is necessary. The administration is usually carried out in a pharmaceutically effective amount. As already explained above in reference to the new compounds (I) according to the invention as well as the pharmaceutical compositions according to the invention, one skilled in the art must rely on his technical knowledge to determine a pharmaceutically effective amount based on the special requirements of the individual case. Compounds (I) according to the invention, however, are preferably administered in a unit dose of 1 μg to 100 mg, especially preferably 1 μg to 10 mg and most preferably 1 μg to 1 mg per body weight to the subject under treatment. The preferred form of administration is oral administration. It is also provided to administer one or more of compounds (I) according to the invention in combination with at least one other active ingredient, as already explained above.

Moreover, this invention also relates to a process for inhibiting GnRH in a patient, comprising the administration of a pharmaceutically effective amount of a compound of general formula (I), as defined above, but including the compounds excluded by name above to a patient who requires such a treatment. The process is preferably used in male birth control, hormone therapy, female contraception, treatment of female subfertility or infertility and to combat tumors.

Finally, in a last aspect, this invention also provides a process for the production of new tetrahydrocarbazole derivatives of general formula (I) according to the invention. The process for the production of the compounds of general formula (I) according to the invention can be performed in a different way, thus, e.g., in liquid phase or as partial or complete solid-phase synthesis. The selection of suitable synthesis conditions for the production of individual representatives of the compounds of general formula (I) can be made by one skilled in the art based on his general technical knowledge. Below, a process for the production of compounds of general formula (I) according to the invention is first described in general terms. Then, a specific variant of the process, namely a solid-phase process, is described. For further illustration of this invention, numerous representatives of the compounds of general formula (I) are found in the listed examples.

A process for the production of the compounds of general formula (I) according to the invention is preferably performed as follows:

The central tetrahydrocarbazole skeleton is accessible by a Fischer-indole synthesis that is known in the art. To this end, a suitably substituted cyclohexanone derivative that is optionally provided with protective groups is condensed with the phenylhydrazine derivative that is desired in each case, also suitably substituted and optionally provided with protective groups (e.g., according to Britten & Lockwood, J. C. S. Perkin I 1974, 1824 or according to Maki et al., Chem. Pharm. Bull. 1973, 21, 240). In particular, the cyclohexanone skeleton is substituted in positions 3,3′, 5,5′ and 6,6′ by radicals R^a to R^f as well as in positions 4,4′ by the radicals or optionally by precursors of radicals R⁶ and R⁷. The phenylhydrazine skeleton is optionally substituted by radicals R² to R⁵. Phenylhydrazine derivatives that are not commercially available can be produced by the process that is known to one skilled in the art. Position isomers that are optionally produced upon the condensation of the cyclohexanone derivative and the phenylhydrazine derivative can be separated by chromatographic methods, such as, e.g., HPLC.

After the synthesis of the central tetrahydrocarbazole skeleton, radical R¹ can be introduced by N-alkylation of the nitrogen atom in 9-position with corresponding R¹-halides with use of a base (e.g., according to Pecca & Albonico, J. Med. Chem. 1977, 20, 487 or also according to Mooradian et al., J. Med. Chem. 1970, 13, 327).

Radicals R⁶ and R⁷, as was already indicated above, are introduced in a different way depending on their type, which is explained in more detail below.

In these radicals, α-aminocarboxylic acid structures are accessible by treatment of ketones with NH₄(CO)₃ and KCN under Schotten-Baumann conditions that are known in the art and subsequent alkaline hydrolysis of the formed hydantoin (Britten & Lockwood, J. C. S. Perkin I 1974, 1824).

Amide radicals are preferably produced with the process from peptide chemistry that is known in the art. To this end, the acid component is activated with an activating reagent such as DCC or else HATU (Tetrahedron Lett. 1994, 35, 2279) and is condensed in the presence of a base such as DIPEA and/or DMAP with the amino component.

Ester radicals can be obtained according to analogous conditions with use of the desired alcohols. The solvent that is used in this case is preferably anhydrous.

Secondary or tertiary amine radicals are obtained from primary amines either by nucleophilic substitution of alkyl halides or by reductive amination of aldehydes/ketones (e.g., J. Org. Chem. 1996, 61, 3849 or Synth. Comm. 1994, 609).

Sulfonamide radicals are obtained from the corresponding amines by reaction with sulfonic acid chlorides.

Urea radicals are obtained if the amines are reacted with corresponding isocyanates.

Urethane radicals can be produced by corresponding alcohols being preactivated with carbonyldihydroxy benzotriazole ((HOBt)₂CO) and then reacted with amines (Warass et al., LIPS 1998, 5, 125).

Alcohols are accessible from carboxylic acid esters by reduction with LiAlH₄.

Aldehyde radicals are obtained from alcohol precursors by being oxidized with DMSO/oxalyl chloride, for example, under Swem conditions that are known in the art (Pansavath et al., Synthesis 1998, 436).

Substituted amine radicals are obtained by reductive amination of amines with aldehydes (J. Org. Chem. 1996, 61, 3849).

Ether radicals can be obtained by the alcohol precursors with a base such as NaH being deprotonated under Williams conditions that are known in the art and then reacted with an alkyl halide.

Double bonds in the radicals can be introduced by an aldehyde or ketone precursor being reacted according to Wittig conditions that are known in the art with corresponding phosphonylides.

A solid-phase process for the production of the compounds of formula (I) according to the invention preferably comprises steps (a) to (d) that are explained in more detail below:

Step (a) essentially proceeds analogously to a Fischer-indole synthesis, e.g., according to Britten & Lockwood, J. C. S. Perkin I 1974, 1824; Maki et al., Chem. Pharm. Bull. 1973, 21, 240 or Hutchins & Chapman, Tetrahedron Lett. 1996, 37, 4869 and comprises the condensation of a cyclohexanone derivative (II) that contains group G and that is anchored to a solid phase SP via a linker L that is suitable for forming radical R⁶

whereby in the event that radical R⁷ is a hydrogen atom, a C₁–C₁₂ alkyl radical, a C₁–C₁₂ aralkyl radical or a hetaryl radical, group G is equal to radical R⁷, and in the event that radical R⁷ has a different meaning than is indicated in formula (I) for R⁷, group G is equal to a group —NH-Pg, whereby Pg stands for a protective group with a phenylhydrazine derivative (III) that is substituted by R² to R⁵

in the presence of an acid, preferably acetic acid, and a metal salt; preferably ZnCl₂. As a solvent, DMF is preferred. Radicals R^a to R^f are defined as indicated above in formula (I). Certain substituents or groups can optionally also be present in protected form, whereby the protective groups are removed at a suitable time in the course of the process again according to a process that is known in the art.

For the purpose of this invention, especially Rink amide resins (Rink, Tetrahedron Lett. 1989, 28, 3787), HMB resins (Sheppard et al., Int. J. Peptide Protein Res. 1982, 20, 451), Wang resins (Lu et al., J. Org. Chem. 1981, 46, 3433) or chlorotrityl resins (Barlos et al., Int. J. Peptide Protein Res. 1991, 38, 562) are suitable as solid phase SP, if the cyclohexanone derivative (II) is to be anchored by means of an (amino-)carboxylic acid to solid phase SP. To anchor the alcohol precursors of the cyclohexanone derivative (II), the DHP linker (Liu & Elman, J. Org. Chem. 1995, 60, 7712) can be used. Aromatic compound precursors of the cyclohexanone derivative (II) can be anchored in a “traceless†manner to triazine resins (Bräse et al., Angew. Chem. Int. Ed. 1998, 37, 3413).

Protective group Pg that is optionally included in group G and that protects an α-amino group —NH₂ is preferably an “Fmoc†(9-fluorenylmethoxycarbonyl) protective group, but can also be another commonly used amino protective group, e.g., from the series of alkoxycarbonyl protective groups (such as, e.g., the “Z†(benzyloxycarbonyl) group or the “Boc†(tert-butoxycarbonyl) group) or another suitable protective group, e.g., a “trityl†(triphenylmethyl) protective group.