# US 6,723,721 B2 · CRF receptor antagonists and methods relating thereto

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- Number: US 6,723,721 B2
- Document ID: US6723721B2
- Status: Granted
- Kind: B2
- Application number: 10/027,789
- Filed: 2001-12-20
- Published: 2002-10-03
- Granted: 2004-04-20
- Earliest claimed: 1998-11-12
- Assignees: Neurocrine Biosciences, Inc.
- Inventors: Mustapha Haddach; Zhiqiang Guo; James R. McCarthy
- Web page: https://patentgrep.com/patent/US6723721B2

## CPC

- C07D 471/16: Peri-condensed systems
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/14: Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 9/12: Antihypertensives
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/08: Antiepileptics; Anticonvulsants
- A61P 25/22: Anxiolytics
- A61P 25/24: Antidepressants
- A61P 25/30: for treating abuse or dependence
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 37/02: Immunomodulators
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 487/16: Peri-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Compounds are disclosed which have utility in the treatment of a variety of disorders, including the treatment of disorders manifesting hypersecretion of CRF in a warm-blooded animals, including stroke. The compounds of this invention have the following structures: wherein n, m, R, R1, R2, X and Ar are as defined herein, including stereoisomes and pharmaceutically acceptable salts thereof.

## Claims

### Claim 1

A method for treating stroke in a warm-blooded animal in need thereof, comprising administering to the animal an effective amount of a compound having the following structure:
or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein:
n is 1
m is 0, 1, 2 or 3;
X is N or CR′;
R′ is hydrogen, halogen or C1-6 alkyl;
R is an optional substituent which, at each occurrence, is independently C1-6alkyl, C3-6alkenyl, C1-6alkylidenyl or C1-6alkylAr;
R1 is —C(H)0,1(R3)(R4);
R2 is hydrogen or C1-6alkyl;
R3 is hydrogen, keto, C1-6alkyl, mono- or di(C3-6cycloalkyl)methyl, C1-6cycloalkyl, C3-6alkenyl, hydroxyC1-6alkyl, C1-6alkylcarbonyloxyC1-6alkyl, or C1-6alkyloxyC1-6alkyl, and
R4 is hydrogen, Ar1, Ar1C1-6alkyl, OAr1, C1-8alkyl, C1-6alkyloxy, C3-6cycloalkyl, mono- or di(C3-6cycloalkyl)methyl, C3-6alkenyl, C3-6alkynyl, C1-6alkyloxyC1-6alkyl, C1-6alkoxyAr1, hydroxyC1-6alkyl, thienylC1-6alkyl, furanylC1-6alkyl, C1-6alkylthioC1-6alkyl, morpholinyl, mono- or di(C1-6alkyl)aminoC1-6alkyl, amino, (C1-6alkyl)amino, di(C1-6alkyl)amino, (C1-6alkylAr1)amino, (C1-6alkyl)(Ar1)amino, C1-9alkylcarbonylC1-6alkyl, C1-6alkylcarbonyloxyC1-6alkyl, sulfonyl(C1-8alkyl), C(═O)C1-6alkyl, C1-8alkyl substituted with phthalimide, Ar1, OAr1, NHAr1, C(═O)Ar1, C(═O)NHAr1 or —C(═O)NH2 or a radical of the formula —(C1-6alkanediyl)-Y—(CO)0,1—Ar1 where Y is O, NH or a direct bond, or
R3 and R4 taken together with the carbon atom to which they are attached form a C3-8cycloalkyl, a C5-8cycloalkenyl, a C3-12heterocycle, phenyl, naphthyl, or a C5-8cycloalkyl fused to Ar1, each of which being optionally substituted with one or more substituents independently selected from C1-6alkyl;
Ar is phenyl, naphthyl or an aromatic C3-12heterocycle, each being optionally substituted with 1, 2 or 3 substituents independently selected from halo, C1-6alkyl, trifluoromethyl, O(trifluoromethyl), hydroxy, cyano, C1-6alkyloxy, phenyoxy, benzoxy, C1-6alkylthio, nitro, amino, mono- or di(C1-6alkyl)amino, (C1-6alkyl)(C1-6alkanoyl)amino, or piperidinyl, or wherein two substituents taken together are a C1-6alkylidinyl or a C1-6alkylidenyl having one, two or three carbon atoms replaced with a heteroatom individually selected from oxygen, nitrogen or sulfur; and
Ar1 is phenyl, naphthyl or an aromatic C3-12heterocycle, each of which being optionally substituted with 1, 2 or 3 substituents independently selected from halo, C1-6alkyl, C1-6alkyloxy, di(C1-6alkyl)amino, di(C1-6alkyl)aminoC1-6alkyl, trifluoromethyl, sulfonyl(C1-6alkyl), and C1-6alkyl substituted with morpholinyl.

### Claim 2

A method for treating depression, anxiety disorder, panic disorder, obsessive-compulsive disorder, abnormal aggression, unstable angina, reactive hypertension, anorexia nervosa, bulimia, irritable bowel syndrome, stress-induced immune suppression, inflammation, Cushing's disease, substance abuse or withdrawal, infantile spasms, or epilepsy in a warm-blooded animal in need thereof, comprising administering to the animal an effective amount of a compound having the following structure:
or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein:
n is 1;
m is 0, 1, 2 or 3;
X is N or CR′;
R′ is hydrogen, halogen or C1-6 alkyl;
R is an optional substituent which, at each occurrence, is independently C1-6alkyl, C3-6alkenyl, C1-6alkylidenyl or C1-6alkylAr;
R1 is —C(H)0,1(R3)(R4);
R2 is hydrogen or C1-6alkyl;
R3 is hydrogen, keto, C1-6alkyl, mono- or di(C3-6cycloalkyl)methyl, C3-6cycloalkyl, C3-6alkenyl, hydroxyC1-6alkyl, C1-6alkylcarbonyloxyC1-6alkyl, or C1-6alkyloxyC1-6alkyl, and
R4 is hydrogen, Ar1, Ar1C1-6alkyl, OAr1C1-8alkyl, C1-6alkyloxy, C3-6cycloalkyl, mono- or di(C3-6cycloalkyl)methyl, C3-6alkenyl, C1-6alkynyl, C1-6alkyloxyC1-6alkyl, C1-6alkoxyAr1, hydroxyC1-6alkyl, thienylC1-6alkyl, furanylC1-6alkyl, C1-6alkylthioC1-6alkyl, morpholinyl, mono- or di(C1-6alkyl)aminoC1-6alkyl, amino, (C1-6alkyl)amino, di(C1-6alkyl)amino, (C1-6alkylAr1)amino, (C1-6alkyl)(Ar1)amino, C1-6alkylcarbonylC1-6alkyl, C1-6alkylcarbonyloxyC1-6alkyl, sulfonyl(C1-8alkyl), C(═O)C1-6alkyl, C1-8alkyl substituted with phthalimide, Ar1, OAr1, NHAr1, C(═O)Ar1, C(═O)NHAr1 or —C(═O)NH2, or a radical of the formula —(C1-6alkanediyl)-Y—(CO)0,1—Ar1 where Y is O, NH or a direct bond, or
R3 and R4 taken together with the carbon atom to which they are attached form a C3-8cycloalkyl, a C5-8cycloalkenyl, a C3-12heterocycle, phenyl, naphthyl, or a C5-8cycloalkyl fused to Ar1, each of which being optionally substituted with one or more substituents independently selected from C1-6alkyl;
Ar is phenyl, naphthyl or an aromatic C3-12heterocycle, each being optionally substituted with 1, 2 or 3 substituents independently selected from halo, C1-6alkyl, trifluoromethyl, O(trifluoromethyl), hydroxy, cyano, C1-6alkyloxy, phenyoxy, benzoxy, C1-6alkylthio, nitro, amino, mono- or di(C1-6alkyl)amino, (C1-6alkyl)(C1-6alkanoyl)amino, or piperidinyl, or wherein two substituents taken together are a C1-6alkylidinyl or a C1-6alkylidenyl having one, two or three carbon atoms replaced with a heteroatom individually selected from oxygen, nitrogen or sulfur; and
Ar1 is phenyl, naphthyl or an aromatic C3-12heterocycle, each of which being optionally substituted with 1, 2 or 3 substituents independently selected from halo, C1-6alkyl, C1-6alkyloxy, di(C1-6alkyl)amino, di(C1-6alkyl)aminoC1-6alkyl, trifluoromethyl, sulfonyl(C1-6alkyl), and C1-6alkyl substituted with morpholinyl.

### Claim 3 (depends on 1, 2)

The method of any of claims 1 or 2 wherein the compound has the structure

### Claim 4 (depends on 1, 2)

The method of any of claims 1 or 2 wherein the compound has the structure

### Claim 5 (depends on 1, 2)

The method of any of claims 1 or 2 wherein m is 0.

### Claim 6 (depends on 5)

The method of claim 5 wherein the compound has the structure:

### Claim 7 (depends on 5)

The method of claim 5 wherein the compound has the structure:

### Claim 8 (depends on 1, 2)

The method of any of claims 1 or 2 wherein m is 1.

### Claim 9 (depends on 8)

The method of claim 8 wherein the compound has the structure:

### Claim 10 (depends on 8)

The method of claim 8 wherein the compound has the structure:

### Claim 11 (depends on 1, 2)

The method of any of claims 1 or 2 wherein X is CR′ and R′ is hydrogen.

### Claim 12 (depends on 1, 2)

The method of any of claims 1 or 2 wherein X is N.

### Claim 13 (depends on 1, 2)

The method of any of claims 1 or 2 wherein R is C1-6alkyl.

### Claim 14 (depends on 1, 2)

The method of any of claims 1 or 2 wherein R is methyl or ethyl.

### Claim 15 (depends on 1, 2)

The method of any of claims 1 or 2 wherein R is ethyl.

### Claim 16 (depends on 1, 2)

The method of any of claims 1 or 2 wherein Ar is 2,4,6-trimethylphenyl, 2-chloro-4-methylphenyl, 2-chloro-4-methoxyphenyl, 2-bromo-4-methylphenyl, 2-methyl-4-chlorophenyl, 2-methyl-4-bromophenyl, 2-bromo-4-isopropylphenyl, 2,4-dichlorophenyl, 2,6-dimethyl-4-bromophenyl, 4-chlorophenyl, 2,4-dimethoxyphenyl, 2,4-dimethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-methyl-4-methoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 4-trifluoromethylphenyl, 2,4,6-trifluorophenyl, 2-methyl-4-N(ethyl)2phenyl, 2-bromo-4-(OCF3)phenyl, 4-dimethylamino-2-methylpyridin-3-yl, 4-dimethylamino-6-methylpyridin-3-yl, 4-dimethylamino-pyridin-3-yl, 4-N(CH3)(Ac)phenyl, 5-methylisoxazol-3-yl, 3,4-methylenedioxyphenyl, or 3,4-ethylenedioxyphenyl.

### Claim 17 (depends on 1, 2)

The method of any of claims 1 or 2 wherein Ar is 2,4,6-trimethylphenyl, 2-methyl-4-chlorophenyl, 2-chloro-4-methylphenyl, 2,4-dichlorophenyl, 2,6-dimethyl-4-bromophenyl, 2-bromo-4-methylphenyl, 4-methoxyphenyl, or 4-chlorophenyl.

### Claim 18 (depends on 1, 2)

The method of any of claims 1 or 2 wherein R1 is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, n-pentyl, iso-pentyl, neo-pentyl, —CH(ethyl)2, —CH(n-propyl)2, —CH(n-butyl)2, —CH2CH2OCH3, —CH(methyl)(CH2OCH3), —CH(ethyl)(CH2OCH3), —CH(n-propyl)(CH2OCH3), —CH(n-butyl)(CH2OCH3), —CH(tert-butyl)(CH2OCH3), —CH(CH2OCH3)2, —CH(benzyl)(CH2OCH3), —CH(4-chlorobenzyl)(CH2OCH3), —CH(CH2OCH3)(CH2CH2SCH3), —CH(ethyl)(CH2Obenzyl), —CH(methyl)(ethyl), —CH(methyl)(n-propyl), —CH(methyl)(n-butyl), —CH(methyl)(n-pentyl), —CH(methyl)(CH2CH2CH2CH(CH3)2), —CH(ethyl)(n-propyl), —CH(ethyl)(n-butyl), —CH(ethyl)(n-pentyl), —CH(n-propyl)(n-butyl), —CH(n-propyl)(n-pentyl), cyclopropyl, cyclobutyl, cyclohexyl, 2-methylcyclohexyl, 3-methylcyclohexyl, 1,2,3,4-tetrahydronaphthyl (1 and 2), benzyl, 2-chlorobenzyl, —CH(methyl)(benzyl), —CH(ethyl)(benzyl), —CH(n-propyl)(benzyl), —CH(n-butyl)(benzyl), —CH2(cyclopropyl), —CH2(cyclobutyl), —CH2CH(methyl)CH2CH3, —CH2CH(ethyl)CH2CH3, —CH2C(methyl)3, —CH2C≡CH, —CH2C(═O)ethyl, —C(═O)cyclopropyl, —C(═O)NHbenzyl, —C(═O)methyl, —C(═O)benzyl, —C(═O)phenyl, —C(═O)ethyl, —C(═O)CH2C(═O)Oethyl, —C(═O)CH(phenyl)ethyl, C(═O)pyridyl, —C(═O)(4-N,N-dimethylamino)phenyl, —C(═O)CH2Omethyl, —C(═O)CH(ethyl)2, —C(═O)n-butyl, —C(═O)CH2CH2(methyl)2, —C(═O)n-propyl, —C(═O)CH2CH2phenyl, —CH2pyridyl, —CH2CH2NHphenyl, —CH2CH2C(═O)Oethyl, —CH2CH2CH2phenyl, —CH2CH2—N-phthalimide, —CH2CH2CH2C(═O)Oethyl, —CH2CH2Oethyl, —CH2CH(methyl)2, —CH2C(═O)pyrrolidinophenyl, —CH2CH2Ophenyl, —CH2CH2CH2CH2—N-phthalimide, —CH2CH2CH2CH(methyl)2, —CH2C(═O)NH2, —CH2-4-(SO2CH3)phenyl, or —CH2CH2pyrrolyl.

### Claim 19 (depends on 1, 2)

The method of any of claims 1 or 2 wherein R1 is —CH(ethyl)2, —CH(n-propyl)2, —CH(ethyl)(n-butyl), or —CH(ethyl)(n-pentyl).

### Claim 20 (depends on 2)

The method of claim 2 for treating depression.

### Claim 21 (depends on 2)

The method of claim 2 for treating anxiety disorder.

### Claim 22 (depends on 2)

The method of claim 2 for treating panic disorder.

### Claim 23 (depends on 2)

The method of claim 2 for treating obsessive-compulsive disorder.

### Claim 24 (depends on 2)

The method of claim 2 for treating abnormal aggression.

### Claim 25 (depends on 2)

The method of claim 2 for treating unstable angina.

### Claim 26 (depends on 2)

The method of claim 2 for treating reactive hypertension.

### Claim 27 (depends on 2)

The method of claim 2 for treating anorexia nervosa.

### Claim 28 (depends on 2)

The method of claim 2 for treating bulimia.

### Claim 29 (depends on 2)

The method of claim 2 for treating irritable bowel syndrome.

### Claim 30 (depends on 2)

The method of claim 2 for treating stress-induced immune suppression.

### Claim 31 (depends on 2)

The method of claim 2 for treating inflammation.

### Claim 32 (depends on 2)

The method of claim 2 for treating Cushing's disease.

### Claim 33 (depends on 2)

The method of claim 2 for treating substance abuse or withdrawal.

### Claim 34 (depends on 2)

The method of claim 2 for treating infantile spasms.

### Claim 35 (depends on 2)

The method of claim 2 for treating epilepsy.