IP Library › Granted Patent US 8,202,858

Granted Patent B2

US 8,202,858 · App. 11/659,798 · Granted Jun 19, 2012

Vasopressin V

Assignee: Vantia Limited

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Quick Facts

Patent No.: US 8,202,858
App. No.: 11/659,798
Granted: Jun 19, 2012
Kind: B2

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Abstract

The present invention concerns compounds inter alia according to general formula 1 a . Compounds according to the invention are vasopressin V 1a receptor antagonists. Pharmaceutical compositions of the compounds are useful as treatment of dysmenorrhoea.

Claims (146)

1. A compound according to general formula 1a, or a compound which is a tautomer or a pharmaceutically acceptable salt thereof,

wherein G is a group of formula 4a or 5a,

wherein:

A 3 and A 12 are independently —C(R 8 )═CH—;

A 4 and A 13 are independently C(R 9 );

A 5 and A 14 are independently C(R 10 );

A 6 is NH or N-alkyl;

A 7 and A 11 are C;

A 8 is NH or N(CH 2 ) b R 11 ;

A 9 is N;

A 10 is CH;

wherein the ring constituted by A 7 , A 8 , A 9 , A 10 and A 11 is aromatic;

R 1 , R 2 and R 3 are independently selected among H, alkyl, O-alkyl, NO 2 , F, Cl and Br;

R 4 is selected among H, alkyl, aryl, heteroaryl, —(CH 2 ) c —R 12 and

R 7 is selected among H, alkyl, aryl, heteroaryl and —(CH 2 ) g —R 14 ;

R 8 is selected among alkoxy, F, Cl, Br, CN, NH 2 , NO 2 , NH(alkyl), and N(alkyl) 2 ;

R 9 and R 10 are independently H, alkyl, alkoxy, F, Cl, Br, CN, NH 2 , NO 2 , NH(alkyl), or N(alkyl) 2 ;

R 11 is independently selected among H, alkyl, aryl, heteroaryl, F, OH, O-alkyl, S-alkyl, O-acyl, NH 2 , NH-alkyl, N(alkyl) 2 , NH-acyl, N(alkyl)-acyl, CO 2 H, CO 2 -alkyl, CONH 2 , CONH-alkyl, CON(alkyl) 2 , CN and CF 3 ;

R 12 is selected among aryl, heteroaryl, F, OH, O-alkyl, S-alkyl, O-acyl, NH 2 , NH-alkyl, N(alkyl) 2 , NH-acyl, N(alkyl)-acyl, CO 2 H, CO 2 -alkyl, CONH 2 , CONH-alkyl, CON(alkyl) 2 , CN and CF 3 ;

R 13 is selected among H, alkyl, aryl, heteroaryl, (CH 2 ) h —R 15 and Z—R 16 ;

R 14 and R 15 are independently selected among H, alkyl, alkenyl, aryl, heteroaryl, F, OH, O-alkyl, S-alkyl, O-acyl, NH 2 , NH-alkyl, N(alkyl) 2 , NH-acyl, N(alkyl)-acyl, CO 2 H, CO 2 -alkyl, CO-alkyl, CO-aryl, CONH 2 , CONH-alkyl, CON(alkyl) 2 , alkenyl-CO 2 -alkyl, alkenyl-aryl, CN and CF 3 ;

R 16 is selected among H, alkyl, alkenyl, aryl, heteroaryl, O-aryl, —(CH 2 ), R 17 , cyclopropyl-aryl and O—(CH 2 ) i —R 17 ;

R 17 is selected among H, alkyl, aryl, heteroaryl, F, OH, O-alkyl, S-alkyl, O-acyl, NH 2 , NH-alkyl, N(alkyl) 2 , NH-acyl, N(alkyl)-acyl, CO 2 H, CO 2 -alkyl, CONH 2 , CONH-alkyl, CON(alkyl) 2 , CN and CF 3 ;

W is selected among O and NH;

X is selected among (CH 2 ) m , C(═O) and S(═O) j ;

Y is selected among O, S, NH and N-alkyl;

Z is selected among —C(═O), —C(═O)—O and —S(═O) k ;

b and c are independently selected among 0, 1, 2 and 3;

d and e are independently selected among 1 and 2;

g, h and i are independently selected among 1, 2 and 3;

j and k are independently selected among 1 and 2; and

m and n are independently selected among 0, 1 and 2;

wherein heteroaryl is pyridyl, 2-chloropyridyl, 4-methylpyridyl, thienyl, 3-chlorothienyl, 2,3-dimethylthiophenyl, furyl, 2-methylfuryl, pyrrole, N-methylpyrrole, oxazole, imidazole, pyrazole, or triazole; and

wherein at least one of R 1 , R 2 , or R 3 is other than hydrogen.

2. The compound according to claim 1 , wherein G is selected among:

3. The compound according to claim 1 , wherein G is:

4. The compound according to claim 1 , wherein W is NH.

5. The compound according to claim 1 , wherein R 4 is alkyl.

6. The compound according to claim 1 , wherein d is 2 and e is 2.

7. The compound according to claim 1 , wherein R 13 is alkyl.

8. The compound according to claim 1 , wherein n is 0.

9. The compound according to claim 1 , wherein R 2 is H, R 4 is a piperidine where d is 2 and e is 2, W is NH, X is C(═O) and n is 0, as shown in formula 18a:

wherein R 1 is selected among methyl, chlorine and fluorine, and R 3 is H; or R 1 is H, and R 3 is selected among methyl, chlorine and fluorine, and R 13 is alkyl.

10. The compound according to claim 1 , wherein X is C(═O), n is 0 and R 4 is a piperidine where d is 2 and e is 2, as shown in formula 19a:

wherein G is selected among general formulae 10a, 13a, 16a, and 17a, and R 13 is alkyl

11. The compound according to claim 1 , wherein R 2 is H and W is NH as shown in formula 20a:

wherein either R 1 is selected among methyl, chlorine and fluorine, and R 3 is H; or R 1 is H, and R 3 is selected among methyl, chlorine and fluorine; and G is selected from general formulae 10a, 13a, 16a, and 17a:

12. The compound according to claim 1 , wherein R 2 is H, W is NH and X is C(═O) as shown in formula 21a:

wherein R 1 is selected among methyl, chlorine and fluorine, and R 3 is H; or R 1 is H, and R 3 is selected among methyl, chlorine and fluorine; and R 4 is alkyl.

13. The compound according to claim 1 , wherein X is C(═O) as shown in formula 22a:

wherein G is selected among general formulae 10a, 13a, 16a, and 17a, and R 4 is alkyl:

14. The compound according to claim 1 , wherein R 2 and R 3 are both H, W is NH and X is C(═O) as shown in formula 23a:

wherein G is selected among general formulae 10a, 16a and 17a, R 1 is selected among methyl, chlorine and fluorine, and R 4 is alkyl

15. The compound according to claim 1 , wherein R 2 and R 3 are both H, R 4 is a piperidine where d is 2 and e is 2, W is NH, X is C(═O) and n is 0 as shown in formula 24a:

wherein G is selected among general formulae 10a, 16a and 17a, R 1 is selected among methyl, chlorine and fluorine, and R 13 is alkyl

16. The compound according to claim 1 , selected among the group consisting of:

1-(3,3-Dimethyl-butyl)-piperidine-4-carboxylic acid 2-chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo-[f]azulene-9-carbonyl)-benzylamide;

1-(3,3-Dimethyl-butyl)-piperidine-4-carboxylic acid 3-chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo-[f]azulene-9-carbonyl)-benzylamide;

1-(3,3-Dimethyl-butyl)-piperidine-4-carboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-methyl-benzylamide;

1-(3,3-Dimethyl-butyl)-piperidine-4-carboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide;

1-(3,3-Dimethyl-butyl)-piperidine-4-carboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-3-methyl-benzylamide;

1-(3,3-Dimethyl-butyl)-piperidine-4-carboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-3-fluoro-benzylamide;

1-Cyclopropylmethyl-piperidine-4-carboxylic acid 2-chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide;

1-Cyclopropylmethyl-piperidine-4-carboxylic acid 3-chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide;

1-Cyclopropylmethyl-piperidine-4-carboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide;

1-Cyclopropylmethyl-piperidine-4-carboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-methyl-benzylamide;

1-Cyclopropylmethyl-piperidine-4-carboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-3-methyl-benzylamide;

1-Cyclopropylmethyl-piperidine-4-carboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-3-fluoro-benzylamide;

Cyclobutanecarboxylic acid 2-chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide;

Cyclobutanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide;

Cyclopentanecarboxylic acid 2-chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide;

Cyclopentanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide;

Cyclopropanecarboxylic acid 2-chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide;

Cyclopropanecarboxylic acid 3-chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide;

Cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-methyl-benzylamide;

Cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-3-fluoro-benzylamide;

Cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide;

Cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-3-methyl-benzylamide;

N-[2-Chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzyl]-propionamide;

N-[2-Chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzyl]-2,2-dimethyl-propionamide;

N-[2-Chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzyl]-isobutyramide;

N-[2-Chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzyl]-butyramide;

N-[4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzyl]-propionamide;

N-[4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzyl]-2,2-dimethyl-propionamide;

N-[4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzyl]-isobutyramide;

N-[4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzyl]-acetamide;

N-[4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzyl]-butyramide;

N-[4-(6-Chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzyl]-formamide;

N-[4-(6-Chloro-3-ethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzyl]-propionamide;

Cyclopropanecarboxylic acid 4-(6-chloro-3-ethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide;

N-[2-Fluoro-4-(6-fluoro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzyl]-propionamide;

N-[2-Fluoro-4-(6-fluoro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzyl]-isobutyramide;

Cyclopropanecarboxylic acid 2-fluoro-4-(6-fluoro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; and

N-[4-(9-Chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulene-6-carbonyl)-2-methyl-benzyl]-isobutyramide.

17. The compound according to claim 1 wherein one of R 1 , R 2 and R 3 is selected among methyl, chlorine and fluorine, and the others are hydrogen.

18. The compound according to claim 2 , wherein R 1 , R 2 , and R 3 are each independently selected among H, alkyl, F, Cl, and Br; R 8 is selected among F, Cl, and Br; R 4 is alkyl; —W— is —NH—; and X— is —C(O)—.

19. The compound according to claim 13 , wherein R 4 is branched alkyl or cycloalkyl.

20. The compound according to claim 1 , wherein said compound is:

1-(3,3-Dimethyl-butyl)-piperidine-4-carboxylic acid 2-chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo-[f]azulene-9-carbonyl)-benzylamide;

1-(3,3-Dimethyl-butyl)-piperidine-4-carboxylic acid 3-chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo-[f]azulene-9-carbonyl)-benzylamide;

1-(3,3-Dimethyl-butyl)-piperidine-4-carboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-methyl-benzylamide;

1-(3,3-Dimethyl-butyl)-piperidine-4-carboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide;

1-(3,3-Dimethyl-butyl)-piperidine-4-carboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-3-methyl-benzylamide; or

1-(3,3-Dimethyl-butyl)-piperidine-4-carboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-3-fluoro-benzylamide.

21. The compound according to claim 1 , wherein said compound is:

1-Cyclopropylmethyl-piperidine-4-carboxylic acid 2-chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide;

1-Cyclopropylmethyl-piperidine-4-carboxylic acid 3-chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide;

1-Cyclopropylmethyl-piperidine-4-carboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide;

1-Cyclopropylmethyl-piperidine-4-carboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-methyl-benzylamide;

1-Cyclopropylmethyl-piperidine-4-carboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-3-methyl-benzylamide; or

1-Cyclopropylmethyl-piperidine-4-carboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-3-fluoro-benzylamide.

22. The compound according to claim 1 , wherein said compound is:

Cyclobutanecarboxylic acid 2-chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide;

Cyclobutanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide;

Cyclopentanecarboxylic acid 2-chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide; or

Cyclopentanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide.

23. The compound according to claim 1 , wherein said compound is:

Cyclopropanecarboxylic acid 2-chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide;

Cyclopropanecarboxylic acid 3-chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide;

Cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-methyl-benzylamide;

Cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-3-fluoro-benzylamide;

Cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraazabenzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide;

Cyclopropanecarboxylic acid 4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-3-methyl-benzylamide;

Cyclopropanecarboxylic acid 4-(6-chloro-3-ethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-fluoro-benzylamide; or

Cyclopropanecarboxylic acid 2-fluoro-4-(6-fluoro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzylamide.

24. The compound according to claim 1 , wherein said compound is:

N-[2-Chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzyl]-propionamide;

N-[-2-Chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzyl]-2,2-dimethyl-propionamide;

N-[2-Chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-benzyl]-isobutyramide;

N-[2-Chloro-4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,-9-tetraaza-benzo[f]azulene-9-carbonyl)-benzyl]-butyramide;