IP Library Granted Patent US 7,169,772
Granted Patent B2
US 7,169,772 · App. 10/495,494 · Granted Jan 30, 2007

4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine derivatives or salts thereof

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Quick Facts
Patent No.
US 7,169,772
App. No.
10/495,494
Granted
Jan 30, 2007
Kind
B2
Abstract

4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine derivatives, which have excellent arginine vasopressin V 2 activity and are useful for a drug for the treatment of central diabetes insipidus and/or nocturia.

Claims (38)

1. A 4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine compound represented by Formula (I) or a pharmaceutically acceptable salt thereof:

wherein the symbols have the following meanings:

R 1 : —OH, —O-lower alkyl, or an optionally substituted amino;

R 2 : lower alkyl which may be substituted with one or more halogen, or halogen;

R 3 and R 4 : one is —H, lower alkyl, or halogen, and the other is an optionally substituted nonaromatic cyclic amino or an optionally substituted aromatic cyclic amino; and

R 5 : —H, lower alkyl, or halogen.

2. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein R 1 is —OH, —O-lower alkyl, a group represented by the following Formula (II), or a group represented by the following Formula (III):

wherein the symbols have the following meanings:

A: a single bond, lower alkylene, or -lower alkylene-C(═O)—;

R 11 : lower alkyl which may be substituted with a group selected from the group consisting of —OH, —O-lower alkyl, —CO 2 H, —CO 2 -lower alkyl, and carbamoyl which may be substituted with one or two lower alkyl, or —H;

R 12 : (1) when A is a single bond or lower alkylene, R 12 is aryl, cycloalkyl, aromatic heterocycle, or nonaromatic heterocycle, each of which may be substituted, or —H, —OH, —O-lower alkyl, —CO 2 H, —CO 2 -lower alkyl, or carbamoyl which may be substituted with one or two lower alkyls; and

 (2) when A is -lower alkylene-C(═O)—, R 12 is a group represented by the above Formula (III), or a group represented by the following Formula (IV),

B: a single bond, or lower alkylene;

R 12A : aryl, cycloalkyl, aromatic heterocycle, or nonaromatic heterocycle, each of which may be substituted, or —H, —OH, —O-lower alkyl, —CO 2 H, —CO 2 -lower alkyl, or carbamoyl which may be substituted with one or two lower alkyls; and

R 13 and R 14 : optionally substituted nonaromatic cyclic amino, bonded together with an adjacent nitrogen atom.

3. The compound or pharmaceutically acceptable salt thereof according to claim 2 , wherein R 1 is a group represented by Formula (II), or a group represented by Formula (III).

4. The compound or pharmaceutically acceptable salt thereof according to claim 3 , wherein R 3 is an optionally substituted nonaromatic cyclic amino, or an optionally substituted aromatic cyclic amino; R 4 is —H, lower alkyl, or halogen; and R 5 is —H.

5. The compound or pharmaceutically acceptable salt thereof according to claim 4 , wherein R 4 is —H.

6. The compound according to any one of claim 1 to claim 5 , wherein the compound is selected from the group consisting of.

(2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene}-N-(pyridin-2-ylmethyl)acetamide;

(2Z)-N-(2-amino-2-oxoethyl)-2-[1(2-chloro-4-pyrrolidin-1-ylbenzoyl)-4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene]acetamide;

(2Z)-2-{4,4-difluoro-1-[4-(3-methyl-1H-pyrazol-1-yl)-2-(trifluoromethyl)benzoyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene}acetamide;

(2Z)-N-(2-amino-2-oxoethyl)-2-{4,4-difluoro-1-[4-[(3R)-3-methylpyrrolidin-1-yl]-2-(trifluoromethyl)benzoyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene}acetamide;

(2Z)-2-{4,4-difluoro-1-[4-[(3R)-3-methylpyrrolidin-1-yl]-2-(trifluoromethyl)benzoyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene}-N-(2-hydroxyethyl)acetamide;

(2Z)-N-(2-amino-2-oxoethyl)-2-{4,4-difluoro-1-[4-(3S)-3-methylpyrrolidin-1-yl]-2-(trifluoromethyl)benzoyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene}acetamide;

(2Z)-2-{4,4-difluoro-1-[4[(3-methyl-1H-pyrazol-1-yl)-2-(trifluoromethyl)benzoyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene]-N-(2-hydroxyethyl)acetamide;

(2Z)-N-(2-amino-2-oxoethyl)-2-(1{2-chloro-4-[(3R)-3-methylpyrrolidin-1-yl]benzoyl}-4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene)acetamide;

(2Z)-N-(2-amino-2-oxoethyl)-2-(1-{2-chloro-4-[(3S)-3-methylpyrrolidin-1-yl]benzoyl}-4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene)acetamide;

(2Z)-2-{4,4-difluoro-1-[4-(4-methyl-1H-pyrazol-1-yl)-2-(trifluoromethyl)benzoyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene}acetamide;

(2Z)-N-(2-amino-2-oxoethyl)-2-{1-[4-(3,4-dimethylpyrrolidin-1yl)-2-(trifluoromethyl)benzoyl]-4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene}acetamide;

(2Z)-2-{4,4-difluoro-1-[2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene}acetamide; and

a pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof of claim 1 as an active ingredient.

8. A 4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine compound represented by Formula (V) or a pharmaceutically acceptable salt thereof

wherein the symbols have the following meanings:

R 21 : lower alkyl;

R 22 : chloro or trifluoromethyl; and

R 23 and R 24 : one is —H, and the other is an optionally protected hydrazino group.

Assignments (1)
CHANGE OF NAME Recorded Nov 16, 2005
From: YAMANOUCHI PHARMACEUTICAL CO., LTD.
To: ASTELLAS PHARMA INC.
Reel/Frame 016784/0361 →