IP Library › Granted Patent US 7,132,436

Granted Patent B2

US 7,132,436 · App. 10/296,552 · Granted Nov 7, 2006

Inhibitors of 11-β-hydroxy steroid dehydrogenase type 1

Assignee: Biovitrum AB

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Quick Facts

Patent No.: US 7,132,436
App. No.: 10/296,552
Granted: Nov 7, 2006
Kind: B2

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Abstract

The present invention relates to compounds with the formula (I) and also to pharmaceutical compositions comprising the compounds, to processes for their preparation, as well as to the use of the compounds in medicine and for the preparation of a medicament which acts on the human 11-β-hydroxysteroid dehydrogenase type 1 enzyme.

Claims (213)

1. A compound of the formula (I):

wherein

T is selected from thienyl substituted with one or more of bromo, chloro; phenyl substituted as follows:

a) either T is phenyl, wherein the phenyl is substituted with one or more phenyl;

b) T is phenyl substituted with chloro in position 3 and methyl in position 2;

c) T is phenyl substituted with chloro in position 2 and 4, and methyl in position 6;

d) T is phenyl substituted with bromo in position 4 and fluoro in position 2 and 5;

e) T is phenyl substituted with chloro in position 2, 3, and 4;

f) T is phenyl substituted with chloro in position 2, 4, and 5;

g) T is phenyl substituted with bromo in position 4 and methyl in position 2;

h) T is phenyl substituted with chloro in position 2 and 6;

i) T is phenyl substituted with chloro in position 2, 4, and 6; or

j) T is phenyl substituted with bromo in position 4 and chloro in position 5;

A is selected from an aryl ring or heteroaryl ring, which can further be optionally substituted in one or more positions independently of each other by hydrogen, C 1-6 -alkyl, halogenated C 1-6 -alkyl, halogen, C 1-6 -alkoxy, nitro, C 1-6 -alkoxycarbonyl, C 1-6 -alkylsulfonyl, acetylamino or aryloxy, wherein the aryloxy can further be optionally substituted in one or more positions independently of each other by hydrogen and halogen;

B is selected from hydrogen and C 1-6 -alkoxycarbonyl or is linked to A to give a cyclic structure selected from the group consisting of:

as well as pharmaceutically acceptable salts, hydrates and solvates thereof.

2. A compound according to claim 1 , wherein

A is selected from 1-benzothien-3-yl, 3-(2,5-dimethylfuryl), pyridinyl; thienyl optionally substituted with one or more of chloro, methylsulfonyl; phenyl optionally substituted with one or more of ethoxycarbonyl, nitro, fluoro, methyl, methoxy, acetylamino, chloro, 4-chlorophenoxy, trifluoromethyl;

B is selected from hydrogen, carbethoxy or is linked to A to give a cyclic structure selected from the croup consisting of:

3. A compound selected from the group consisting of:

Ethyl 2-{[(3-chloro-2-methylphenyl)sulfonyl]amino)}-4-phenyl-1,3-thiazole-5-carboxylate,

3-Chloro-2-methyl-N-[4-(3-nitrophenyl)-1,3-thiazol-2-yl]benzenesulfonamide,

3-Chloro-2-methyl-N-[4-phenyl)-1,3-thiazol-2-yl]benzenesulfonamide,

3-Chloro-N-[4-(4-fluoro-3-methylphenyl)-1,3-thiazol-2-yl]-2-methylbenzenesulfonamide,

2,4,6-Trichloro-N-[4-(3-nitrophenyl)-1,3-thiazol-2-yl]benzenesulfonamide,

2,4,6-Trichloro-N-(4-phenyl-1,3-thiazol-2-yl)benzenesulfonamide,

2,4,6-Trichloro-N-[4-(4-fluoro-3-methylphenyl)-1,3-thiazol-2-yl]benzenesulfonamide,

2,4,6-Trichloro-N-[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]benzenesulfonamide,

N-[4-(3-nitrophenyl)-1,3-thiazol-2-yl][1,1′-biphenyl]-4-sulfonamide,

N-(4-phenyl-1,3-thiazol-2-yl)[1,1′-biphenyl]-4-sulfonamide,

N-[4-(4-Fluoro-3-methylphenyl)-1,3-thiazol-2-yl][1,1′-biphenyl]-4-sulfonamide,

N-[4-(4-Methoxyphenyl)-1,3-thiazol-2-yl][1,1′-biphenyl]-4-sulfonamide,

2,4-Dichloro-6-methyl-N-[4-(3-nitrophenyl)-1,3-thiazol-2-yl]benzenesulfonamide,

2,4-Dichloro-6-methyl-N-(4-phenyl)-1,3-thiazol-2-yl]benzenesulfonamide,

2,4-Dichloro-N-[4-(4-fluoro-3-methylphenyl)-1,3-thiazol-2-yl]-6-methylbenzenesulfonamide,

2,4-Dichloro-N-[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]-6-methylbenzenesulfonamide,

N-[4-(2-{[(3-chloro-2-methylphenyl)sulfonyl]amino}-1,3-thiazol-4-yl)phenyl]acetamide,

3-Chloro-2-methyl-N-[4-(3-pyridinyl)-1,3-thiazol-2-yl]benzenesulfonamide,

3-Chloro-N-[4-(2-chloro-5-nitrophenyl)-1,3-thiazol-2-yl]-2-methylbenzenesulfonamide,

3-Chloro-N-(7-methoxy-4,5-dihydronaphtho[1,2-d][1,3]thiazol-2-yl]-2-methylbenzenesulfonamide,

3-Chloro-N-(4-(5-chloro-2-thienyl)1-3-thiazol-2-yl]-2-methylbenzenesulfonamide,

3-Chloro-N-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-2-methylbenzenesulfonamide,

N-[4-(2-{[(2,4,6-trichlorophenyl)sulfonyl]amino}-1,3-thiazol-4-yl)phenyl]acetamide,

2,4,6-Trichloro-N-[4-(3-pyridinyl)-1,3-thiazol-2-yl]benzenesulfonamide,

2,4,6-Trichloro-N-[4-(2-chloro-5-nitrophenyl)-1,3-thiazol-2-yl]benzenesulfonamide,

2,4,6-Trichloro-N-[7-methoxy-4,5-dihydronaphtho[1,2-d][1,3]thiazol-2-yl]benzenesulfonamide,

2,4,6-Trichloro-N-[4-(5-chloro-2-thienyl)-1,3-thiazol-2-yl]benzenesulfonamide,

2,4,6-Trichloro-N-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]benzenesulfonamide,

N-[4-{2[([1,1′-biphenyl]-4-ylsulfonyl]amino]-1,3-thiazol-4-yl)phenyl)acetamide,

N-[4-(3-pyridinyl)-1,3-thiazol-2-yl][1,1′-biphenyl]-4-sulfonamide,

N-[4-(2-chloro-5-nitrophenyl)-1,3-thiazol-2-yl][1,1′-biphenyl]-4-sulfonamide,

N-(7-methoxy-4,5-dihydronaphtho[1,2-d][1,3-thiazol-2-yl][1,1′-biphenyl]-4-sulfonamide,

N-[4-(5-chloro-2-thienyl)-1,3-thiazol-2-yl][1,1′-biphenyl]-4-sulfonamide,

N-[4-(2-chlorophenyl)-1,3-thiazol-2-yl][1,1′-biphenyl]-4-sulfonamide,

N-[4-(2-{[(2,4-dichloro-6-methylphenyl)sulfonyl]amino)-1,3-thiazol-4-yl) phenyl]acetamide,

2,4-Dichloro-6-methyl-N-[4-(3-pyridinyl)1,3-thiazol-2-yl]benzenesulfonamide,

2,4-Dichloro-N-[4-(2-chloro-5-nitrophenyl)-1,3-thiazol-2-yl]-6-methylbenzenesulfonamide,

2,4-Dichloro-N-(7-methoxy-4,5-dihydronaphtho[1,2-d][1,3]thiazol-2-yl)-6-methylbenzenesulfonamide,

2,4-Dichloro-N-[4-(5-chloro-2-thienyl)-1,3-thiazol-2-yl]-6-methylbenzenesulfonamide,

2,4-Dichloro-N-[4-(2,5-dimethyl-3-furyl)-1,3-thiazol-2-yl]-6-methylbenzenesulfonamide,

N-[4-(1-benzothien-3-yl)-1,3-thiazol-2-yl]-2,4-dichloro-6-methylbenzenesulfonamide,

3-Chloro-N-[4-(3-chloro-2-thienyl)-1,3-thiazol-2-yl]-2-methylbenzenesulfonamide,

2,4,6-Trichloro-N-[4-(3-chloro-2-thienyl)-1,3-thiazol-2-yl]benzenesulfonamide,

2,4-Dichloro-N-[4-(3-chloro-2-thienyl)-1,3-thiazol-2-yl]-6-methylbenzenesulfonamide,

2,4-Dichloro-N-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-6-methylbenzenesulfonamide,

Ethyl 2-[{[1,1′-biphenyl]-4-ylsulfonyl)amino]-4-phenyl-1,3-thiazole-5-carboxylate,

3-Chloro-N-[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]-2-methylbenzenesulfonamide,

N-[4-(2-{[(4-Bromo-2,5-difluorophenyl)sulfonyl]amino}-1,3-thiazol-4-yl) phenyl]acetainide,

2,3,4-Trichloro-N-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]benzenesulfonamide,

2,4,5-Trichloro-N-[4-(3-chloro-2-thienyl)-1,3-thiazol-2-yl]benzenesulfonamide,

2,3,4-Trichloro-N-[4-(3-chloro-2-thienyl]-1,3-thiazol-2-yl]benzenesulfonamide,

4-Bromo-N-[4-(3-chloro-2-thienyl)-1,3-thiazol-2-yl]-2,5-difluorobenzenesulfonamide,

4,5-Dichloro-N-(7-methoxy-4,5-dihydronaphtho[1,2-d][1,3]thiazol-2-yl)-2-thiophenesulfonamide,

4,5-Dichloro-N-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-2-thiophenesulfonamide,

N-[4-(2-{[2,4,5-Trichlorophenyl]sulfonyl}amino)-1,3-thiazol-4-yl]phenyl]acetamide,

2,3,4-Trichloro-N-(7-methoxy-4,5-dihydronaphtho[1,2-d][1,3]thiazol-2-yl) benzenesulfonamide,

4-Bromo-5-chloro-N-[4-(3-chloro-2-thienyl)-1,3-thiazol-2-yl]-2-thiophenesulfonamide,

3-Bromo-5-chloro-N-(7-methoxy-4,5-dihydronaphtho[1,2-d][1,3]thiazol-2-yl)-2-thiophenesulfonamide,

3-Bromo-5-chloro-N-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-2-thiophenesulfonamide,

N-[4-(2-{[2,6-Dichlorophenyl]sulfonyl}amino)-1,3-thiazol-4-yl]phenyl]acetamide,

2,6-Dichloro-N-[4-(3-chloro-2-thienyl)-1,3-thiazol-2-yl]benzenesulfonamide,

2,4,6-Trichloro-N-(7,8-dimethoxy-4,5-dihydronaphtho[1,2-d][1,3]thiazol-2-yl)benzenesulfonamide,

2,3,4-Trichloro-N-{4-[2-chloro-4 -(4-chlorophenoxy)phenyl]-1,3-thiazol-2-yl}benzenesulfonamide,

2,3,4-Trichloro-N-{4-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}benzenesulfonamide,

4-Bromo-N-{4-[2-chloro-4-(4-chlorophenoxy)phenyl]-1,3-thiazol-2-yl}-2,5-difluorobenzenesulfonamide,

4-Bromo-N-{4-[2,6-dichloro-4-trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2,5-difluorobenzenesulfonamide,

4,5-Dichloro-N-[2-chloro-6-fluorophenyl]-1,3-thiazol-2-yl]-2-thiophenesulfonamide,

4-Bromo-5-chloro-N-{4-[2-chloro-4-(4-chlorophenoxy)phenyl]-1,3-thiazol-2-yl}-2-thiophenesulfonamide,

4-Bromo-5-chloro-N-{4-[2,6-dichloro-4-trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-2-thiophenesulfonamide,

2,4-Dichloro-N-[4-(2-chloro-6-fluoropheny)-1,3-thiazol-2-yl]-6-methylbenzenesulfonamide,

2,4,6-Trichloro-N-{4-[2,6-dichloro-4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}benzenesulfonamide,

4-Bromo-N-[4-(2-chloro-6-fluorophenyl)-1,3-thiazol-2-yI]-2-methylbenzenesulfonamide,

2,4,6-Trichloro-N-{4-[2-chloro-4-chlorophenoxy]phenyl}-1,3-thiazol-2-yl}benzenesulfonamide,

N-[4-2- {[(4-Bromo-5-chloro-2-thienyl)sulfonyl]amino}-1,3-thiazol-4-yl)phenyl]acetamide,

3-Chloro-N-(4,5-dihydrothieno[3,2-e][1,3]benzothiazol-2-yl)-2-methylbenzenesulfonamide,

2,4,6-Trichloro-N-(4,5-dihydrothieno[3,2-e][1,3]benzothiazol-2-yl)benzenesulfonamide,

N-(4,5-Dihydrothieno[3,2-e][1,3]benzothiazol-2-yl)[1,1′-biphenyl]-4-sulfonamide,

2,4-Dichloro-N-(4,5-dihydrothieno[3,2-e][1,3]benzothiazol-2-yl)-6-methylbenzenesulfonamide,

3-Chloro-N-[6-chloro-8-methylsulfonyl)-4,5-dihydrothieno[3,4-e][1,3]benzothiazol-2-yl]-2-methylbenzensulfonamide,

2,4-Dichloro-N-[6-chloro-8-(methylsulfonyl)-4,5-dihydrothieno[3,4-e][1,3]benzothiazol-2-yl]-6-methylbenzenesulfonamide,

N-[6-Chloro-8-(methylsulfonyl)-4,5-dihydrothieno[3,4-e][1,3]benzothiazol-2-yl][1,1′-biphenyl]-4-sulfonamide,

N-(2-{[(3-Chloro-2-methylphenyl)sulfonyl]amino}naphtho[1,2-d][1,3]thiazol-6-yl)acetamide and

N-(8-Nitro-4,5-dihydronaphtho[1,2-d][1,3]thiazol-2-yl)(1,1′-biphenyl]-4-sulfonamide, or pharmaceutically acceptable salts thereof.

4. A process for the preparation of a compound according to claim 1 comprising at least one of the following steps:

a) sulfonamide coupling by reacting a 2-aminothiazole with a sulfonylchloride in the presence of a base,

b) sulfonamide coupling by reacting a 2-aminothiazole derivative with a sulfonylchloride in the presence of a base,

c) formation of a thiazole ring by reacting an optionally substituted thiourea with an α-haloketone,

d) formation of a thiazole ring by reacting a thiourea with a ketone.

5. A method for the treatment of diabetes, syndrome X, obesity, glaucoma, hyperlipidemia, hyperglycemia or hyperinsulinemia, said method comprising administering to a mammal in need of such treatment an effective amount of a compound of the formula (I) according to claim 1 as well as pharmaceutically acceptable salts, hydrates and solvates thereof.

6. A pharmaceutical composition comprising at least one compound of the formula (I) as defined in claim 1 , and a pharmaceutically acceptable carrier.

7 .A compound selected from the group consisting of:

N-(4-phenyl-1,3-thiazol-2-yl)-4-propylbenzenesulfonamide,

N-[4-(4-fluoro-3-methylphenyl)-1,3-thiazol-2-yl]-4-propylbenzenesulfonamide,

N-[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]-4-propylbenzenesulfonamide,

N-[4-(2-{[(4-propylphenyl)sulfonyl]amino)-1,3-thiazol-4-yl)phenyl]acetamide,

N-[4(2-chloro-5-nitrophenyl)-1,3-thiazol-2-yl]-4-propylbenzenesulfonamide,

4-Propyl-N-[4-(3-pyridinyl)-1,3-thiazol-2-yl]benzenesulfonamide,

N-(7-methoxy-4,5-dihydronaphtho[1,2-d][1,3]thiazol-2-yl]-4-propylbenzenesulfonamide,

N-[4-(5-chloro-2-thienyl)-1,3-thiazol-2-yl]-4-propylbenzenesulfonamide,

N-[4-(3-chloro-2-thienyl)-1,3-thiazol-2-yl]-4-propylbenzenesulfonamide,

N-(4,5-Dihydrothieno[3,2-e][1,3]benzothiazol-2-yl)-4-propylbenzenesulfonamide,

N-[6-Chloro-8-(methylsulfonyl)-4,5-dihydrothieno[3,4-e][3,4-e][1,3]benzothiazol-2-yl]-4-propylbenzenesulfonamide,

N-(2-{[(4-Propylphenyl)sulfonyl]amino}-4,5-dihydronaphtho[1 ,2-d][1,3]thiazol-6-yl)acetamide,

N-(8-Nitro-4,5-dihydronaphtho[1,2-d][1,3]thiazol-2-yl)-4-propylbenzenesulfonamide,

N-[4-(2-chlorophenyl)-1,3-thiazol-2-yl]-4-propylbenzenesulfonamide and

N-[4-(2-Chloro-6-fluorophenyl)-1,3-thiazol-2-yl]-4-propylbenzenesulfonamide, or pharmaceutically acceptable salts thereof.

8. A compound according to claim 1 , wherein B is linked to A to give a cyclic structure selected from the group consisting of:

9. The method according to claim 5 , wherein

B is selected from hydrogen, carbethoxy or is linked to A to give a 6-membered aryl or a cyclic structure selected from the group consisting of:

10. The method according to claim 5 , wherein the compound is selected from: