# US 6,281,237 B1 · N-phenyl benzimidazolecarboxamide and N-phenyl indolecarboxamide derivatives

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 6,281,237 B1
- Document ID: US6281237B1
- Status: Granted
- Kind: B1
- Application number: 09/540,478
- Filed: 2000-03-31
- Granted: 2001-08-28
- Earliest claimed: 1999-04-01
- Assignees: Neurogen Corporation
- Inventors: Raymond F. Horvath; Ping Ge; Taeyoung Yoon; Alan Hutchison
- Web page: https://patentgrep.com/patent/US6281237B1

## CPC

- C07D 235/14: Radicals substituted by nitrogen atoms (by nitro radicals C07D235/10)
- C07D 209/14: Radicals substituted by nitrogen atoms, not forming part of a nitro radical
- G01N 2333/726: G protein coupled receptor, e.g. TSHR-thyrotropin-receptor, LH/hCG receptor, FSH
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

Disclosed are compounds of the forumla: or the pharmaceutically acceptable non-toxic salts thereof wherein; A is N or CH; R1 and R2 represents hydrogen or lower alkyl; G, R3, R4, R5, R6, R7 and R8 are variables defined herein. These compounds are modulators of CRF receptors and are therefore useful for treating affective disorders, anxiety, depression, eating disorders, and stress disorders in humans and other animals. Methods of treatment of such disorders and well as packaged pharmaceutical compositions are also provided. Compounds of the invention are also useful as probes for the localization of CRF receptors and as standards in assays for CRF receptor binding. Methods of using the compounds in receptor localization studies are given.

## Claims

### Claim 1

A compound of the formula:
or a pharmaceutically acceptable non-toxic salt thereof wherein:
A represents N;
G represents halogen, trifluoromethyl, trifluoromethoxy, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy, hydroxy(C1-C6) alkyl, (C1-C6)alkoxy(C1-C6)alkyl, —SH, (C1-C6)alkylthio-, thio (C1-C6)alkyl or (C1-C6)alkyl thio(C1-C6)alkyl;
R1 represents hydrogen, (C1-C6)alkyl, or hydroxy(C1-C6)alkyl;
R2 represents hydrogen or (C1-C6)alkyl; and
R3, and R4 are the same or different and represent hydrogen, halogen, trifluoromethyl, trifluoromethoxy, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, —SH, (C1-C6)alkylthio, thio(C1-C6) alkyl or (C1-C6)alkyl thio(C1-C6)alkyl;
R5, R6, R7 and R8 are the same or different and represent hydrogen, halogen, trifluoromethyl, trifluoromethoxy, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkoxy, hydroxy(C1-C6)alkoxy, hydroxy, hydroxy(C1-C6)alkyl, (C1-C6) alkoxy(C1-C6)alkyl, —SH, (C1-C6)alkylthio, thio(C1-C6)alkyl or (C1-C6)alkyl thio(C1-C6)alkyl.

### Claim 2

A compound of the formula:
or a pharmaceutically acceptable non-toxic salt thereof wherein:
A represents N;
G represents halogen, trifluoromethyl, trifluoromethoxy, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy, hydroxy(C1-C6) alkyl, (C1-C6)alkoxy(C1-C6)alkyl, —SH, (C1-C6)alkylthio-, thio(C1-C6)alkyl or (C1-C6)alkyl thio(C1-C6)alkyl;
R1 represents hydrogen, (C1-C6)alkyl or hydroxy(C1-C6)alkyl;
R2 represents hydrogen or (C1-C6)alkyl;
R3 and R4 are the same or different and represent hydrogen, halogen, trifluoromethyl, trifluoromethoxy, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkoxy, hydroxy(C1-C6)alkoxy, hydroxy, hydroxy(C1-C6)alkyl, (C1-C6) alkoxy(C1-C6)alkyl, —SH, (C1-C6)alkylthio, thio(C1-C6)alkyl or (C1-C6)alkyl thio(C1-C6)alkyl, with the proviso that R3 and R4 cannot both be hydrogen simultaneously; and
R5, R6, R7 and R8 are the same or different and represent hydrogen, halogen, trifluoromethyl, trifluoromethoxy, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkoxy, hydroxy(C1-C6)alkoxy, hydroxy, hydroxy(C1-C6)alkyl, (C1-C6) alkoxy(C1-C6)alkyl, —SH, (C1-C6)alkylthio, thio(C1-C6)alkyl or (C1-C6)alkyl thio(C1-C6)alkyl.

### Claim 3

A compound of the formula:
or a pharmaceutically acceptable non-toxic salt thereof wherein:
Q represents
G represents halogen, trifluoromethyl, trifluoromethoxy, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy, hydroxy(C1-C6) alkyl, (C1-C6)alkoxy(C1-C6)alkyl, —SH, (C1-C6)alkylthio, thio(C1-C6)alkyl or (C1-C6)alkyl thio(C1-C6)alkyl;
R1 represents hydrogen or (C1-C6)alkyl;
R2 represents hydrogen or (C1-C6)alkyl;
R3 and R4 are the same or different and represent hydrogen, halogen, trifluoromethyl, trifluoromethoxy, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, thiol, (C1-C6)alkylthiol, thio(C1-C6) alkyl or (C1-C6)alkyl thio(C1-C6)alkyl, with the proviso that R3 and R4 cannot both be hydrogen; and
R5, R6, R7 and R8 are the same or different and represent hydrogen, halogen, trifluoromethyl, trifluoromethoxy, nitrile, (C1-C6) alkyl, (C1-C6)alkoxy, hydroxy, hydroxy(C1-C6)alkyl, (C1-C6) alkoxy(C1-C6)alkyl, thiol, (C1-C6)alkylthiol, thio(C1-C6) alkyl or (C1-C6)alkyl thio(C1-C6)alkyl.

### Claim 4 (depends on 2)

A compound according to claim 2, wherein R5 and R6 independently represent hydrogen, halogen, hydroxy, trifluoromethyl, cyano, C1-C3 alkyl, or C1-C3 alkoxy.

### Claim 5 (depends on 3)

A compound according to claim 3, wherein R5 and R6 independently represent hydrogen, fluoro, chloro, hydroxy, trifluoromethyl, or methyl.

### Claim 6 (depends on 4)

A compound according to claim 4, wherein G is C1-C3 alkyl, C1-C3 alkoxy, or halogen.

### Claim 7 (depends on 4)

A compound according to claim 4, wherein R5 and R6 are in the 5-and 6-position respectively and independently represent hydrogen, fluoro, chloro, methyl, ethyl, ethoxy or methoxy, and G is methyl, methoxy, or chloro.

### Claim 8 (depends on 5)

A compound according to claim 5, wherein R7 and R8 are independently hydrogen, C1-C6 alkoxy, C1-C6 alkyl, halogen, or trifluoromethyl.

### Claim 9 (depends on 4)

A compound according to claim 4 where Q is
where G is C1-C2 alkyl and R7 and R8 are independently hydrogen, C1-C2 alkoxy, C1-C2 alkyl, halogen, or trifluoromethyl.

### Claim 10 (depends on 2)

A compound according to claim 2, wherein Q is trimethylphenyl.

### Claim 11 (depends on 6)

A compound according to claim 6, wherein Q is trimethylphenyl.

### Claim 12 (depends on 4)

A compound according to claim 4, wherein R1 is C2-C4 alkyl.

### Claim 13 (depends on 6)

A compound according to claim 6, wherein R1 is C2-C3 alkyl.

### Claim 14 (depends on 2)

A compound according to claim 2, where R1 is isopropyl.

### Claim 15 (depends on 8)

A compound according to claim 8, wherein R1 is isopropyl.

### Claim 16 (depends on 12)

A compound according to claim 12, wherein R2 is hydrogen.

### Claim 17 (depends on 13)

A compound according to claim 13, wherein R2 is hydrogen.

### Claim 18 (depends on 1)

A compound according to claim 1, which is N-{[1-(4-methoxy-2-methylphenyl) benzimidazol-2-yl]methyl}-N-(methylethyl) (2,4,6-trimethylphenyl)carboxamide.

### Claim 19 (depends on 1)

A compound according to claim 1, which is N-{[1-(4-methoxyphenyl) benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trichlorophenyl)carboxamide.

### Claim 20 (depends on 1)

A compound according to claim 1, which is N-{[1-(4-methoxyphenyl) benzimidazol-2-yl]methyl}-N-(methylethyl)(2-methylphenyl)carboxamide.

### Claim 21 (depends on 1)

A compound according to claim 1, which is N-{[1-(4-methylphenyl) benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4-dimethylphenyl)carboxamide.

### Claim 22 (depends on 1)

A compound according to claim 1, which is N-{[1-(4-methylphenyl) benzimidazol-2-yl]methyl}-N-(methylethyl)(2-methoxyphenyl)carboxamide.

### Claim 23 (depends on 1)

A compound according to claim 1, which is N-{[1-(4-methoxyphenyl) benzimidazol-2-yl]methyl}-N-(methylethyl)(3-fluoro-2-methylphenyl)carboxamide.

### Claim 24 (depends on 1)

A compound according to claim 1, which is N-{[1-(4-methoxyphenyl) benzimidazol-2-yl]methyl}-N-(methylethyl)(4-chloro-2-methoxyphenyl)carboxamide.

### Claim 25 (depends on 1)

A compound according to claim 1, which is N-{[1-(4-methoxyphenyl) benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4-dichlorophenyl)carboxamide.

### Claim 26 (depends on 1)

A compound according to claim 1, which is N-{[1-(4-methoxyphenyl) benzimidazol-2-yl]methyl}-N-(methylethyl)(2,6-dimethylphenyl)carboxamide.

### Claim 27 (depends on 1)

A compound according to claim 1, which is N-{[1-(3-methoxyphenyl) benzimidazol-2-yl]methyl}-N-(methylethyl) (2,4,6-trimethylphenyl)carboxamide.

### Claim 28 (depends on 1)

A compound according to claim 1, which is N-{[1-(3-methoxyphenyl) benzimidazol-2-yl]methyl}-N-(methylethyl) (2,4,6-trimethylphenyl)carboxamide.

### Claim 29 (depends on 1)

A compound according to claim 1, which is N-{([1-(2-methoxyphenyl) benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide.

### Claim 30 (depends on 1)

A compound according to claim 1, which is N-{[1-(2-methylphenyl) benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide.

### Claim 31 (depends on 1)

A compound according to claim 1, which is N-{[1-(4-chloro-2-methylphenyl) benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide.

### Claim 32 (depends on 1)

A compound according to claim 1, which is N-{[1-(4-methylphenyl) benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide.

### Claim 33 (depends on 1)

A compound according to claim 1, which is N-{[1-(4-methoxyphenyl) benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide.

### Claim 34 (depends on 1)

A compound according to claim 1, which is N-{[1-(2-chlorophenyl) benzimidazol-2-yl]methyl}-N-(methylethyl) (2,4,6-trimethylphenyl)carboxamide.

### Claim 35 (depends on 1)

A compound according to claim 1, which is N-{[1-(4-fluorophenyl) benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide.

### Claim 36 (depends on 1)

A compound according to claim 1, which is N-{[1-(4-chlorophenyl) benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide.

### Claim 37 (depends on 1)

A compound according to claim 1, which is N-{[1-(4-methoxyphenyl) benzimidazol-2-yl]methyl}-N-(methylethyl)(2-fluoro-4-trifluoromethylphenyl)carboxamide.

### Claim 38 (depends on 1)

A compound according to claim 1, which is N-{([l-(4-hydroxyphenyl) benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide.

### Claim 39 (depends on 1)

A compound according to claim 1, which is N-{[5-fluoro-1-(4-methoxyphenyl) benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide.

### Claim 40 (depends on 1)

A compound according to claim 1, which is N-{[6-methoxy-1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl) (2,4,6-trimethylphenyl)carboxamide.

### Claim 41 (depends on 1)

A compound according to claim 1, which is N-{[6-ethoxy-1-(4-methoxyphenyl) benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide.

### Claim 42 (depends on 1)

A compound according to claim 1, which is N-{[6-chloro-1-(4-methoxyphenyl) benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide.

### Claim 43 (depends on 1)

A compound according to claim 1, which is N-{[1-(4-methoxyphenyl)-5 -methylbenzimidazol-2-yl]methyl}-N-(methylethyl) (2,4,6-trimethylphenyl)carboxamide.

### Claim 44 (depends on 1)

A compound according to claim 1, which is N-{[1-(2,4-dimethylphenyl) benzimidazol-2-yl]methyl)}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide.

### Claim 45 (depends on 1)

A compound according to claim 1, which is N-{[1-(4-ethoxyphenyl) benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide.

### Claim 46 (depends on 1)

A compound according to claim 1, which is N-{[1-(4-hydroxy-2-methylphenyl) benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide.

### Claim 47 (depends on 1)

A compound according to claim 1, which is N-{[1-(3-hydroxy-4-methoxyphenyl) benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide.

### Claim 48 (depends on 1)

A compound according to claim 1, which is N-{[1-(4-methoxyphenyl) benzimidazol-2-yl]methyl}-N-(methylethyl)(2,6-dimethyl-4-methoxyphenyl)carboxamide.

### Claim 49 (depends on 1)

A compound according to claim 1, which is N-{[5-fluoro-1-(4-methoxyphenyl) benzimidazol-2-yl]methyl}-N-(methylethyl)(2,6-dimethyl-4-methoxyphenyl)carboxamide.

### Claim 50 (depends on 1)

A compound according to claim 1, which is N-{[1-(4-methoxyphenyl)-5 -methylbenzimidazol-2-yl]methyl)-N-(methylethyl)(2,6-dimethyl-4-methoxyphenyl)carboxamide.

### Claim 51 (depends on 1)

A compound according to claim 1, which is selected from:
N-[(1-phenylbenzimidazol-2-yl)methyl]-N-(methylethyl) (2,4,6-trimethylphenyl) carboxamide;
N-[(1-phenylbenzimidazol-2-yl)methyl]-N-(methylethyl) (2,4,6-trimethylphenyl) carboxamide;
N-[(1-phenylbenzimidazol-2-yl)methyl]-N-(methylethyl) (2,4,6-trimethylphenyl) carboxamide;
N-{[1-(2,4,6-trimethylphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl) (2,4,6-trimethylphenyl) carboxamide;
N-{[1-(2,4,6-trimethylphenyl)benzimidazol-2-yl]methyl}-N-(cyclopropyl) (2,4,6-trimethylphenyl)carboxamide;
N-[(i-phenylbenzimidazol-2-yl)methyl]-N-(cyclopropyl)(2,4-dimethylphenyl)carboxamide;
N-{[1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl) (4-trifluoromethylphenyl)carboxamide;
N-{[1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(dimethylethyl) (2,4,6-trimethylphenyl)carboxamide;
N-{[1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}(2,4,6-trimethylphenyl)carboxamide;
N-{[1-(4-(2-hydroxyethoxy)phenyl)benzimidazol-2-yl]methyl}-N-(methylethyl) (2,4,6-trimethylphenyl)carboxamide;
N-{[6-hydroxy-1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl) (2,4,6-trimethylphenyl)carboxamide;
N-{[6-chloro-1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl) (2,6-dimethyl-4-methoxyphenyl)carboxamide;
N-{[5-methyl-1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl) (4-methoxy-2-methylphenyl)carboxamide;
N-([5-amino-1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl) (2,4,6-trimethylphenyl)carboxamide;
N-{[5-methyl-1-(4-trifluoromethylphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl) (2,4,6-trimethylphenyl)carboxamide;
N-{[5-methyl-1-(4-trifluoromethylphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl) (4-chloro-2,6-dimethylphenyl)carboxamide;
N-{[1-(4-moxyphenyl)-5-trifluoromethylbenzimidazol-2-yl]methyl}-N-(methylethyl) (4-hydroxy-2,6-dimethylphenyl)carboxamide;
N-{[1-(4-(2-hydroxyethoxy)-2-methylphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl) (2,4,6-trimethylphenyl)carboxamide; and
N-{[1-(4-methoxyphenyl)-5-trifluoromethyl benzimidazol-2-yl]methyl}-N-(3-hydroxypropyl) (2,4,6-trimethylphenyl)carboxamide.

### Claim 52 (depends on 1)

A compound according to claim 1, which is:
N-{[1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl) (4-chloro-2,6-dimethylphenyl)carboxamide.

### Claim 53 (depends on 1)

A compound according to claim 1, which is:
N-{[5-methyl-1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl) (4-chloro-2,6-dimethylphenyl)carboxamide.

### Claim 54 (depends on 1)

A compound according to claim 1, which is:
N-{[5-bromo-1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl) (2,4,6-trimethylphenyl)carboxamide.

### Claim 55 (depends on 1)

A compound according to claim 1, which is:
N-{[1-(4-fluoro-2-methylphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl) (2,4,6-trimethylphenyl)carboxamide.

### Claim 56 (depends on 1)

A compound according to claim 1, which is:
N-{[1-(4-methoxy-2-methylphenyl)-5-trifluoromethylbenzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide.

### Claim 57 (depends on 1)

A compound according to claim 1, which is:
N-{[5-tert-butoxycarbamyl-1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide.

### Claim 58 (depends on 1)

A compound according to claim 1, which is:
N-{[5-dimethylamino-1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide.

### Claim 59 (depends on 1)

A compound according to claim 1, which is:
N-{[1-(4-hydroxy-2-methylphenyl)-5-trifluoromethyl benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide.

### Claim 60 (depends on 1)

A compound according to claim 1, which is:
N-{[1-(4-(2-hydroxyethoxy)-2-methylphenyl)-5-trifluoromethylbenzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide.

### Claim 61 (depends on 1)

A compound according to claim 1, which is:
N-{[1-(4-methoxyphenyl)-5-trifluoromethylbenzimidazol-2-yl]methyl}-N-(methylethyl) (4-dimethylamino-2,6-dimethylphenyl)carboxamide.

### Claim 62 (depends on 1)

A compound according to claim 1, which is:
N-{[5-diethylamino-1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide.

### Claim 63 (depends on 1)

A compound according to claim 1, which is:
N-{ [1-(4-methoxyphenyl)-5-trifluoromethylbenzimidazol-2-yl]methyl}-N-[1-(hydroxymethyl)ethyl](2,4,6-trimethylphenyl)carboxamide.

### Claim 64 (depends on 1)

A compound according to claim 1, which is:
N-{[1-(4-methoxyphenyl)-5-trifluoromethyl benzimidazol-2-yl]methyl}-N-[2-hydroxy-1-(hydroxymethyl)ethyl](2,4,6-trimethylphenyl)carboxamide.

### Claim 65 (depends on 1)

A compound according to claim 1, which is:
N-{[5-iodo-1-(4-methoxyphenyl)benzimidazol-2-yl]methyl}-N-(methylethyl) (2,4,6-trimethylphenyl)carboxamide.

### Claim 66 (depends on 1)

A compound according to claim 1, which is:
N-{[1-(4-hydroxyphenyl)-5-trifluoromethyl benzimidazol-2-yl]methyl}-N-(methylethyl)(2,4,6-trimethylphenyl)carboxamide.

### Claim 67 (depends on 1)

A pharmaceutical composition comprising a compound according to claim 1 and at least one pharmaceutically acceptable carrier or excipient.