# US 8,785,460 B2 · Tricyclic compounds and use thereof

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- Number: US 8,785,460 B2
- Document ID: US8785460B2
- Status: Granted
- Kind: B2
- Application number: 12/357,158
- Filed: 2009-01-21
- Published: 2009-07-23
- Granted: 2014-07-22
- Earliest claimed: 2008-01-22
- Assignees: Takeda Pharmaceutical Company Limited
- Applicants: Kazuyoshi Aso; Katsumi Kobayashi; Takafumi Takai; Takuto Kojima; Kazuyuki Tokumaru; Michiyo Mochizuki; Yasutaka Hoashi
- Inventors: Kazuyoshi Aso; Katsumi Kobayashi; Takafumi Takai; Takuto Kojima; Kazuyuki Tokumaru; Michiyo Mochizuki; Yasutaka Hoashi
- Web page: https://patentgrep.com/patent/US8785460B2

## CPC

- C07D 487/04: Ortho-condensed systems
- A61P 25/00: Drugs for disorders of the nervous system
- 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 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 239/70: condensed with carbocyclic rings or ring systems
- C07D 498/04: Ortho-condensed systems
- A61K 31/4188: condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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

There is provided a compound of the formula (I′): wherein x is a nitrogen or CRx, Rx is a hydrogen, etc., R1 is an optionally substituted hydrocarbon group, etc., R2 is an optionally substituted hydrocarbon group, etc., ring A is 5- to 8-membered heterocyclic ring, etc., and each of Y1, Y2 and Y3 is an optionally substituted carbon or a nitrogen, etc.; or a salt thereof or a prodrug thereof, which have CRF receptor antagonistic activity and use thereof.

## Claims

### Claim 1

9-Chloro-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1-(2-methoxy-4,6-dimethylpyrimidin-5-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole or a salt thereof.

### Claim 2 (depends on 1)

The compound according to claim 1 wherein 9-chloro-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1-(2-methoxy-4,6-dimethylpyrimidin-5-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole is (+)-9-chloro-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1-(2-methoxy-4,6-dimethylpyrimidin-5-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole.

### Claim 3 (depends on 1)

The compound according to claim 1 wherein 9-chloro-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1-(2-methoxy-4,6-dimethylpyrimidin-5-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole is (+9-chloro-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1-(2-methoxy-4,6-dimethylpyrimidin-5-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole.

### Claim 4

9-Chloro-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1-(6-methoxy-2-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole or a salt thereof.

### Claim 5 (depends on 4)

The compound according to claim 4 wherein 9-chloro-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1-(6-methoxy-2-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole is (+)-9-chloro-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1-(6-methoxy-2-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole.

### Claim 6 (depends on 4)

The compound according to claim 4 wherein 9-chloro-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1-(6-methoxy-2-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole is (+9-chloro-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1-(6-methoxy-2-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole.

### Claim 7

9-Chloro-1-(2,4-dichlorophenyl)-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole or a salt thereof.

### Claim 8 (depends on 7)

The compound according to claim 7 wherein 9-chloro-1-(2,4-dichlorophenyl)-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole is (+)-9-chloro-1-(2,4-dichlorophenyl)-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole.

### Claim 9 (depends on 7)

The compound according to claim 7 wherein 9-chloro-1-(2,4-dichlorophenyl)-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole is (−)-9-chloro-1-(2,4-dichlorophenyl)-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole.

### Claim 10

1-(2,4-Dichlorophenyl)-N,N-diethyl-9-fluoro-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-amine or a salt thereof.

### Claim 11

9-Chloro-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1-(2-methoxy-4,6-dimethylpyrimidin-5-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole;
9-Chloro-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1-(6-methoxy-2-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole;
9-Chloro-1-(2,4-dichlorophenyl)-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole; or
1-(2,4-Dichlorophenyl)-N,N-diethyl-9-fluoro-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-amine,
or a salt thereof.

### Claim 12

9-Chloro-1-[2-(difluoromethoxy)-4,6-dimethylpyrimidin-5-yl]-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole or a salt thereof.

### Claim 13

A pharmaceutical composition comprising a compound selected from the group consisting of:
9-Chloro-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1-(2-methoxy-4,6-dimethylpyrimidin-5-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole;
(+)-9-chloro-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1-(2-methoxy-4,6-dimethylpyrimidin-5-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole;
(+9-chloro-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1-(2-methoxy-4,6-dimethylpyrimidin-5-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole;
9-Chloro-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1-(6-methoxy-2-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole;
(+)-9-chloro-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1-(6-methoxy-2-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole;
(−)-9-chloro-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1-(6-methoxy-2-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole;
9-Chloro-1-(2,4-dichlorophenyl)-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole;
(+)-9-chloro-1-(2,4-dichlorophenyl)-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole;
(−)-9-chloro-1-(2,4-dichlorophenyl)-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole;
1-(2,4-Dichlorophenyl)-N,N-diethyl-9-fluoro-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-amine; and
9-Chloro-1-[2-(difluoromethoxy)-4,6-dimethylpyrimidin-5-yl]-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole;
or a salt thereof,
and a pharmaceutically acceptable carrier.