# US 8,541,462 B2 · Tetrahydrocarbazole derivatives as ligands of G-protein coupled receptors

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- Number: US 8,541,462 B2
- Document ID: US8541462B2
- Status: Granted
- Kind: B2
- Application number: 13/358,055
- Filed: 2012-01-25
- Published: 2012-05-17
- Granted: 2013-09-24
- Earliest claimed: 2007-04-27
- Assignees: AEterna Zentaris GmbH
- Applicants: Tilmann Schuster; Klaus Paulini; Peter Schmidt; Silke Baasner; Emmanuel Polymeropoulos; Eckhard Guenther; Michael Teifel
- Inventors: Tilmann Schuster; Klaus Paulini; Peter Schmidt; Silke Baasner; Emmanuel Polymeropoulos; Eckhard Guenther; Michael Teifel
- Web page: https://patentgrep.com/patent/US8541462B2

## CPC

- C07K 5/06191: {containing heteroatoms different from O, S, or N}
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/02: Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/08: for nausea, cinetosis or vertigo; Antiemetics
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 5/00: Drugs for disorders of the endocrine system
- A61P 5/04: for decreasing, blocking or antagonising the activity of the hypothalamic hormones
- A61P 5/08: for decreasing, blocking or antagonising the activity of the anterior pituitary hormones
- A61P 5/24: of the sex hormones
- A61P 5/36: Antigestagens
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/12: Antihypertensives
- A61P 11/02: Nasal agents, e.g. decongestants
- A61P 11/06: Antiasthmatics
- A61P 11/14: Antitussive agents
- A61P 13/08: of the prostate
- A61P 13/10: of the bladder
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 15/08: for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
- A61P 15/10: for impotence
- A61P 15/18: Feminine contraceptives
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/04: for non-specific disorders of the connective tissue
- A61P 19/06: Antigout agents, e.g. antihyperuricemic or uricosuric agents
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/02: for peripheral neuropathies
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 25/06: Antimigraine agents
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- A61P 25/22: Anxiolytics
- A61P 25/24: Antidepressants
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/18: for HIV
- A61P 35/00: Antineoplastic agents
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 5/0827: {containing heteroatoms different from O, S, or N}
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

The present invention provides novel tetrahydrocarbazole compounds according to formula (I) as ligands of G-protein coupled receptors (GPCR) which are useful in the treatment and/or prophylaxis of physiological and/or pathological conditions in mammals mediated by GPCR or of physiological and/or pathological conditions which can be treated by modulation of these receptors.

## Claims

### Claim 1

A method of treating a condition in a subject in need of such treatment, the method comprising administering a therapeutically effective amount of at least one tetrahydrocarbazole to the subject to treat the condition,
wherein the condition is a benign tumor disease, a malignant tumor disease, male fertility control, controlled ovarian stimulation in in vitro fertilization (COS/ART), prostate cancer, breast cancer, endometrial cancer, ovarian cancer, benign prostate hyperplasia (BPH), endometriosis, uterine fibroids, uterine myomas, endometrium hyperplasia, pubertas praecox, polycystic ovary syndrome, or a hormone-dependent tumor disease,
wherein the at least one tetrahydrocarbozole is selected from the group consisting of:
Compound 31 (S)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid {(S)-1-[5-(3-ethyl-ureido)-[1,3,4]oxadiazol-2-yl]-2-methyl-butyl}-amide;
Compound 36 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid {(S)-2-methyl-1-[(morpholin-4-ylmethyl)-carbamoyl]-butyl}amide
Compound 51 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid [(S)-1-(2-diethylamino-ethylcarbamoyl)-2-methyl-butyl]-amide;
Compound 52 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid {(S)-2-methyl-1-[(tetrahydro-pyran-4-ylmethyl)-thiocarbamoyl]-butyl}-amide;
Compound 54 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid [(S)-2-methyl-1-(2-morpholin-4-yl-ethylthiocarbamoyl)-butyl]-amide;
Compound 60 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid {(S)-2-methyl-1-[(pyridin-4-ylmethyl)-thiocarbamoyl]-butyl}-amide;
Compound 69 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid [(S)-1-(3-hydroxy-4-methoxy-phenylcarbamoyl)-2-methyl-butyl]-amide;
Compound 71 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid [(S)-1-(2-hydroxy-4-methoxy-phenylcarbamoyl)-2-methyl-butyl]-amide;
Compound 73 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid [(S)-1-(4-hydroxy-cyclohexylcarbamoyl)-2-methyl-butyl]-amide;
Compound 74 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid [(S)-1-(3-imidazol-1-yl-propylthiocarbamoyl)-2-methyl-butyl]-amide;
Compound 114 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid [(S)-2-methyl-1-(4-[1,2,4]triazol-1-yl-butylthiocarbamoyl)-butyl]-amide;
Compound 118 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid {(S)-2-methyl-1-[(5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-thiocarbamoyl]-butyl}-amide;
Compound 137 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid [(S)-2-methyl-1-(quinolin-6-ylcarbamoyl)-butyl]-amide;
Compound 144 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid [(S)-2-methyl-1-(N′-phenyl-hydrazinocarbonyl)-butyl]-amide;
Compound 164
Compound 167
(R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-
methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-
tetrahydro-1H-carbazole-3-carboxylic acid {(S)-1-[(3-
ethyl-ureido)-methyl]-2-methyl-butyl}-amide;
Compound 173
(R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-
methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-
tetrahydro-1H-carbazole-3-carboxylic acid {(S)-1-[(3-
ethyl-thioureido)-methyl]-2-methyl-butyl}-amide;
Compound 178
(R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-
methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-
tetrahydro-1H-carbazole-3-carboxylic acid [(S)-1-(2-tert-
butyl-2H-tetrazol-5-ylcarbamoyl)-2-methyl-butyl]-amide;
Compound 183
(R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-
methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-
tetrahydro-1H-carbazole-3-carboxylic acid (S)-2-methyl-
1-[(pyrimidin-5-ylmethyl)-carbamoyl]-butyl}-amide;
Compound 188
1-tert-butyl-4-(3-{(S)-2-[((R)-3-{(S)-2-[2-(2-fluoro-
phenyl)-acetylamino]-3-methyl-pentanoylamino}-8-
trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole-3-
carbonyl)-amino]-3-methyl-pentanoylamino}-propyl)-4H-
tetrazol-1-ium; Trifluoro-acetate;
Compound 190
(R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-
methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-
tetrahydro-1H-carbazole-3-carboxylic acid [(S)-2-
methyl-1-(3-pyridin-4-ylmethyl-ureidomethyl)-butyl]-amide;
Compound 205
(R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-
methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-
tetrahydro-1H-carbazole-3-carboxylic acid [(S)-2-
methyl-1-(3-pyridin-4-ylmethyl-thioureidomethyl)-butyl]-amide;
Compound 219
(R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-
methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-
tetrahydro-1H-carbazole-3-carboxylic acid [(S)-2-
methyl-1-(morpholin-4-ylcarbamoyl)-butyl]-amide;
Compound 230
(R)-3-[(S)-3-Methyl-2-(2-pyridin-3-yl-acetylamino)-
pentanoylamino]-8-trifluoromethyl-2,3,4,9-
tetrahydro-1H-carbazole-3-carboxylic acid ((S)-2-
methyl-1-thiocarbamoyl-butyl)-amide;
Compound 236
(R)-3-[(S)-3-Methyl-2-(2-pyridin-4-yl-acetylamino)-
pentanoylamino]-8-trifluoromethyl-2,3,4,9-
tetrahydro-1H-carbazole-3-carboxylic acid ((S)-2-
methyl-1-thiocarbamoyl-butyl)-amide;
Compound 239
(R)-3-{(S)-2-[3-(4-Methoxy-benzyl)-ureido]-3-methyl-
pentanoylamino}-8-trifluoromethyl-2,3,4,9-
tetrahydro-1H-carbazole-3-carboxylic acid ((S)-2-
methyl-1-thiocarbamoyl-butyl)-amide;
Compound 242
(R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-
methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-
tetrahydro-1H-carbazole-3-carboxylic acid [(S)-1-(N′-
benzoyl-hydrazinocarbonyl)-2-methyl-butyl]-amide;
Compound 244
(R)-3-{(S)-2-[3-(2-Fluoro-benzyl)-ureido]-3-methyl-
pentanoylamino}-8-trifluoromethyl-2,3,4,9-
tetrahydro-1H-carbazole-3-carboxylic acid [(S)-2-
methyl-1-(N′-phenyl-hydrazinocarbonyl)-butyl]-amide;
Compound 249
(R)-3-{(2S,3S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-
3-methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-
tetrahydro-1H-carbazole-3-carboxylic acid [(1S,2S)-
2-methyl-1-(4-phenyl-thiazol-2-yl)-butyl]-amide;
Compound 250
(R)-3-{(2S, 3S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl-
pentanoylamino}-8-trifluoromethyl-2,3,4,9-
tetrahydro-1H-carbazole-3-carboxylic acid {(1S,2S)-1-
[4-(4-methoxy-phenyl)-thiazol-2-yl]-2-methyl-butyl}-amide;
Compound 251
2-{(1R,2S)-1-[((R)-3-{(2S,3S)-2-[2-(2-Fluoro-
phenyl)-acetylamino]-3-methyl-pentanoylamino}-8-
trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole-3-
carbonyl)-amino]-2-methyl-butyl}-thiazole-4-carboxylic acid ethyl ester;
Compound 256
2-{(1S,2S)-1-[((R)-3-{(2S,3S)-2-[2-(2-Fluoro-
phenyl)-acetylamino]-3-methyl-pentanoylamino}-8-
trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole-3-
carbonyl)-amino]-2-methyl-butyl}-thiazole-4-carboxylic acid; and
Compound 258
2-{(1S,2S)-1-[((R)-3-{(2S,3S)-2-[3-(2-Fluoro-
benzyl)-ureido]-3-methyl-pentanoylamino}-8-
trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole-3-
carbonyl)-amino]-2-methyl-butyl}-thiazole-4-carboxylic acid ethyl ester.

### Claim 2 (depends on 1)

The method of claim 1, wherein the at least one compound is
Compound 52 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid {(S)-2-methyl-1-[(tetrahydro-pyran-4-ylmethyl)-thiocarbamoyl]-butyl)-amide.

### Claim 3 (depends on 1)

The method of claim 1, where the at least one compound is administered in a unit dose of from 0.001 mg to 100 mg per kg of body weight of the subject.

### Claim 4 (depends on 1)

The method of claim 1, where the at least one compound is administered in a unit dose of from 0.001 mg to 100 mg per kg of body weight of the subject.

### Claim 5 (depends on 2)

The method of claim 2, wherein the condition is a benign tumor disease.

### Claim 6 (depends on 2)

The method of claim 2, wherein the condition is a malignant tumor disease.

### Claim 7 (depends on 2)

The method of claim 2, wherein the condition is male fertility control.

### Claim 8 (depends on 2)

The method of claim 2, wherein the condition is controlled ovarian stimulation in in vitro fertilization (COS/ART).

### Claim 9 (depends on 2)

The method of claim 2, wherein the condition is prostate cancer.

### Claim 10 (depends on 2)

The method of claim 2, wherein the condition is breast cancer.

### Claim 11 (depends on 2)

The method of claim 2, wherein the condition is endometrial cancer.

### Claim 12 (depends on 2)

The method of claim 2, wherein the condition is ovarian cancer.

### Claim 13 (depends on 2)

The method of claim 2, wherein the condition is benign prostate hyperplasia (BPH).

### Claim 14 (depends on 2)

The method of claim 2, wherein the condition is endometriosis.

### Claim 15 (depends on 2)

The method of claim 2, wherein the condition is uterine fibroids.

### Claim 16 (depends on 2)

The method of claim 2, wherein the condition is uterine myomas.

### Claim 17 (depends on 2)

The method of claim 2, wherein the condition is endometrium hyperplasia.

### Claim 18 (depends on 2)

The method of claim 2, wherein the condition is pubertas praecox.

### Claim 19 (depends on 2)

The method of claim 2, wherein the condition is polycystic ovary syndrome.

### Claim 20 (depends on 2)

The method of claim 2, wherein the condition is a hormone-dependent tumor disease.