# US 7,407,977 B2 · Substituted N-acyl-2-aminothiazoles

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- Number: US 7,407,977 B2
- Document ID: US7407977B2
- Status: Granted
- Kind: B2
- Application number: 11/193,766
- Filed: 2005-07-29
- Published: 2006-02-09
- Granted: 2008-08-05
- Earliest claimed: 2004-08-05
- Assignees: Hoffman-La Roche Inc.
- Inventors: Jianping Cai; Adrian Wai-Hing; Fariborz Firooznia; Kevin Richard Guertin; Lida Qi
- Web page: https://patentgrep.com/patent/US7407977B2

## CPC

- C07D 277/60: condensed with carbocyclic rings or ring systems
- A61P 1/12: Antidiarrhoeals
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- 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 11/06: Antiasthmatics
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 277/84: Naphthothiazoles
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D 513/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

There are presented compounds of the formula or a pharmaceutically acceptable salt thereof, which are useful in the treatment of diabetes, diabetic retinopathy, asthma and diarrhea.

## Claims

### Claim 1

A compound of the formula
or a pharmaceutically acceptable salt thereof, wherein
X is —CH2—, —CH2CH2—, —(CH2)3— and O(CH2)—;
R is a 5- or 6- membered saturated or unsaturated carbocyclic or heterocyclic ring which optionally may contain one or more hetero atoms and said rings being optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, acetamidomethyl, alkoxycarbonyl amidomethyl, a nitrile group, a sulfonamido group, alkylsulfonyl, alkoxy, benzyl, benzoyl, arylsulfonyl and acyl which benzyl, benzoyl or arylsulfonyl is optionally substituted by halogen, trihalo lower alkyl, lower alkyl, alkoxy, alkylsulfonyl or cyano; and
R1 is selected from the group consisting of hydrogen, halogen, lower alkyl, alkoxy or a nitrile group.

### Claim 2 (depends on 1)

The compound of claim 1 having the formula (IA)
or a pharmaceutically acceptable salt thereof, wherein
X is —CH2—, —CH2CH2—, —(CH2)3— and O(CH2)—;
R is a 5- or 6- membered saturated or unsaturated carbocyclic or heterocyclic ring which optionally may contain one or more hetero atoms and said rings being optionally substituted with one or more substituents selected from the group consisting of halogen, lower-alkyl, a nitrile group, alkylsulfonyl, alkoxy and acyl.

### Claim 3 (depends on 2)

The compound of claim 2 wherein X is —CH2—.

### Claim 4 (depends on 3)

The compound of claim 3 wherein R1 is hydrogen, halogen or lower-alkoxy.

### Claim 5

A compound of the formula
or the pharmaceutically acceptable salts thereof
wherein R is phenyl or a heterocyclic ring selected from the group consisting of thienyl, pyridinyl, pyrazolyl, imidazolyl, furyl or piperidinyl, which phenyl or heterocyclic ring is optionally substituted with 1 to 3 substituents selected from the group consisting of halogen, hydroxy, nitrile, lower-alkyl, sulfonamido, lower-alkyl-sulfonyl, lower-alkoxy-carbonyl, lower-alkoxy-C(O)—NH—CH2—, benzyl which is optionally substituted with CF3, benzoyl which is optionally substituted with CF3, or phenylsulfonyl
which is optionally substituted with CF3
X is —CH2—, —CH2CH2CH2—, —(CH2)3— and O(CH2)—; and
R1 is selected from the group consisting of hydrogen, halogen, lower alkyl, alkoxy or a nitrile group.

### Claim 6 (depends on 1)

A compound of claim 1 selected from the group consisting of
N-(8H-Indeno[1,2-d]thiazol-2-yl)-benzamide;
4-Fluoro-N-(8H-indeno[1,2-d]thiazol-2-yl)-benzamide;
4-Cyano-N-(8H-indeno[1,2-d]thiazol-2-yl)-benzamide;
N-(8H-indeno[1,2-d]thiazol-2-yl)-4-methyl-benzamide;
Thiophene-2-carboxylic acid (8H-indeno[1,2-d]thiazol-2-yl)-amide;
N-(8H-indeno[1,2-d]thiazol-2-yl)nicotinamide;
N-(8H-indeno[1,2-d]thiazol-2-yl)isonicotinamide;
2-Methyl-2H-pyrazole-3-carboxylic acid (8H-indeno[1,2-d]thiazol-2-yl)-amide;
N-(6-chloro-8H-indeno[1,2-d]thiazol-2-yl)-isonicotinamide;
1H-Pyrazole-4-carboxylic acid (8H-indeno[1,2-d]thiazol-2-yl)-amide;
N-(4,5-Dihydro-naphtho[1,2-d]thiazol-2-yl)-isonicotinamide;
N-(5,6-Dihydro-4H-3-thia-1-aza-benzo[e]azulen-2-yl)-isonicotinamide;
N-(4H-Chromeno[4,3-d]thiazol-2-yl)-isonicotinamide;
N-Naphtho[1,2-d]thiazol-2-yl-isonicotinamide and
3-Methyl-3H-imidazole-4-carboxylic acid (8H-indeno[1,2-d]thiazol-2-yl)-amide trifluoroacetate.

### Claim 7 (depends on 1)

A compound of claim 1 selected from the group consisting of
4-(8H-Indenol[1,2-d]thiazol-2-ylcarbamoyl)-piperidine-1-carboxylic acid tert-butyl ester;
3-(trifluoromethyl-benzoyl)-piperidine-4-carboxylic acid (8H-indeno[1,2-d]thiazol-2-yl)-amide;
1-(3-trifluoromethyl-benzyl)-piperidine-4-carboxylic acid (9H-indeno[1,2-d]thiazol-2-yl)-amide;
1-(3-Trifluoromethyl-benzenesulfonyl)-piperidine-4-carboxylic acid (8H-indeno[1,2-d]thiazol-2-yl-amide;
N-(8H-Indeno[1,2-d]thiazol-2-yl) 3-fluorobenzamide;
N-(8H-Indeno[1,2-d]thiazol-2-yl) 3-hydroxybenzamide;
N-(8H-Indeno[1,2-d]thiazol-2-yl) 2-methylpent-5-enoylamide;
N-(8H-Indeno[1,2-d]thiazol-2-yl) 2-methylbutanoylamide;
N-(8H-Indeno[1,2-d]thiazol-2-yl) 5-methylsulfonylthiophene-2-carboxyamide;
N-(8H-Indeno[1,2-d]thiazol-2-yl) 2-furoylamide and
N-(6-Fluoro-8H-Indeno[1,2-d]thiazol-2-yl) 4-hydroxynicotinamide.

### Claim 8 (depends on 1)

A compound of claim 1 selected from the group consisting of
N-(6-Fluoro-8H-Indeno[1,2-d]thiazol-2-yl) (4-aminosulfonyl)benzamide;
N-(6-Fluoro-8H-Indeno[1,2-d]thiazol-2-yl) (4-t-butoxycarbonylmethyl)benzamide;
N-(6-Fluoro-8H-Indeno[1,2-d]thiazol-2-yl) thiophene-3-carboxyamide;
N-(4,5-Dihydro-naphtho[1,2-d]thiazol-2-yl) 4-hydroxynicotinamide;
N-(4,5-Dihydro-naphtho[1,2-d]thiazol-2-yl) thiophene-3-carboxyamide;
N-(4,5-Dihydro-7-methoxynaphtho[1,2-d]thiazol-2-yl) 4-hydroxynicotinamide;
N-(4,5-Dihydro-7-methoxynaphtho[1,2-d]thiazol-2-yl) 5-methylsulfonylthiophene-2-carboxyamide;
N-(5,6-Dihydro-4H-3-thia-1-aza-benzo[e]azulen-2-yl) 4-hydroxynicotinamide;
N-(5,6-Dihydro-4H-3-thia-1-aza-benzo[e]azulen-2-yl) thiophene-3-carboxyamide;
N-(8H-Indeno[1,2-d]thiazol-2-yl) 3-chloro-4-hydroxybenzamide and
N-(8H-Indeno[1,2-d]thiazol-2-yl) (4-aminosulfonyl)benzamide.

### Claim 9

A pharmaceutical composition comprising a compound of the formula
or a pharmaceutically acceptable salt thereof, wherein
X is —CH2—, —CH2CH2—, —(CH2)3— and O(CH2)—
R is a 5- or 6-membered saturated or unsaturated carbocyclic or heterocyclic ring which optionally may contain one or more hetero atoms and said rings being optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, lower alkyl, acetamidomethyl, alkoxycarbonyl amidomethyl, a nitrile group, a sulfonamido group, alkylsulfonyl, alkoxy, benzyl, benzoyl, arylsulfonyl and acyl which benzyl, benzoyl, or arylsulfonyl is optionally substituted by halogen, trihalo lower alkyl, lower alkyl, alkoxy, alkylsulfonyl or cyano; and
R1 is selected from the group consisting of hydrogen, halogen, lower alkyl, alkoxy or a nitrile group
together with a pharmaceutically acceptable excipient.