Benzocycloalkylenylamine derivatives as muscarinic receptor antagonists

• US 20020004494A1
• Filed: 05/22/2001
• Published: 01/10/2002
• Est. Priority Date: 05/25/2000
• Status: Active Grant

• Current Assignee: Syntec Incorporated (Atos SE)
• Original Assignee: Syntec Incorporated (Atos SE)
• Inventors: Weikert, Robert James, Stabler, Russell Stephen, Madera, Ann Marie
• Granted Patent: US 6,500,822 B2
• Time in Patent Office: Days
• US Class Current: 514/79
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/06 Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 13/06 Anti-spasmodics
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 207/27 with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
• CPC Class Codes: C07D 211/76 attached in position 2 or 6
• CPC Class Codes: C07D 223/10 attached in position 2
• CPC Class Codes: C07D 225/02 not condensed with other rings
• CPC Class Codes: C07D 239/10 Oxygen or sulfur atoms
• CPC Class Codes: C07D 241/08 with oxygen atoms directly attached to ring carbon atoms
• CPC Class Codes: C07D 243/04 having the nitrogen atoms in positions 1 and 3
• CPC Class Codes: C07D 243/08 not condensed with other rings
• CPC Class Codes: C07D 265/10 with oxygen atoms directly attached to ring carbon atoms
• CPC Class Codes: C07D 267/06 having the hetero atoms in positions 1 and 3
• CPC Class Codes: C07D 267/10 : not condensed with other rings
• CPC Class Codes: C07D 267/22 : Eight-membered rings
• CPC Class Codes: C07D 279/06 : not condensed with other rings
• CPC Class Codes: C07D 401/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings
• CPC Class Codes: C07D 409/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/14 : containing three or more hetero rings
• CPC Class Codes: C07D 411/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings

Abstract

This invention relates to compounds which are generally muscarinic M2/M3 receptor antagonists and which are represented by Formula I:

wherein X, Y, and Z are O, S, or NR⁴, and the other substituents are as defined in the specification; and prodrugs, individual isomers, racemic or non-racemic mixtures of isomers, and pharmaceutically acceptable salts or solvates thereof. The invention further relates to pharmaceutical compositions containing such compounds and methods for their use as therapeutic agents.

Claims

1. A compound comprising Formula I

2. The compound of claim 1, wherein p is 2.

3. The compound of claim 1, wherein n is 3.

4. The compound of claim 2, wherein n is 3.

5. The compound of claim 2, wherein one of X, Y or Z is NR⁴, and the others are CH₂.

6. The compound of claim 5, wherein R⁴ is hydrogen.

7. The compound of claim 2, wherein m is 1.

8. The compound of claim 2, wherein m is 2.

9. The compound of claim 7, wherein Y is NR⁴, and X and Z are CH₂.

10. The compound of claim 9, wherein Y is NH, and X and Z are CH₂.

11. The compound of claim 8, wherein one of X, Y or Z is NR⁴ and the others are CH₂.

12. The compound of claim 11, wherein R⁴ is H.

13. The compound of claim 3, wherein one of X, Y or Z is NR⁴ and the others are CH₂.

14. The compound of claim 13, wherein p is 2.

15. The compound of claim 14, wherein one of X, Y or Z is NH and the others are CH₂.

16. The compound of claim 14, wherein m is 2.

17. The compound of claim 16, wherein X is NH, and Y and Z are CH₂.

18. The compound of claim 16, wherein Y is NH, and X and Z are CH₂.

19. The compound of claim 16, wherein Z is NH, and X and Y are CH₂.

20. The compound of claim 2, wherein m is 2, n is 3, and one of X, Y or Z is 0 and the others are CH₂.

21. The compound of claim 1 comprising 3,5-dimethyl-isoxazole-4-sulfonic acid 7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-amino}-5,6,7,8-tetrahydro-naphthalen-2-yl ester;

4-(2-dimethylamino-ethanesulfonyl)-1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-2-one;

4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-5-one;

4-{5-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-pentyl}-[1,4]diazepan-5-one;

1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-2-one;

1-{4-[(7-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,4]diazepan-2-one;

or 3-{4-[(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-[1,3]oxazepan-2-one,

or a prodrug, an individual isomer, a racemic or non-racemic mixture of isomers, or pharmaceutically acceptable salt or solvate thereof.

22. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 in admixture with a pharmaceutically acceptable carrier.

23. The pharmaceutical composition of claim 22, wherein the compound is suitable for administration to a subject having a disease state which is alleviated by treatment with a M2/M3 muscarinic receptor antagonist.

24. A method of treatment comprising administering to a subject in need of such treatment, a therapeutically effective amount of at least one compound of claim 1.

25. A method of treatment comprising administering to a subject in need of such treatment, a therapeutically effective amount of the composition of claim 20.

26. The method of treatment of claim 24, wherein the disease state is alleviated with a M2/M3 muscarinic antagonist.

27. The method of treatment of claim 26, wherein the disease state is associated with smooth muscle disorders comprising diseases of the genitourinary or gastrointestinal tract, or of respiratory states.

28. The method of treatment of claim 27, wherein the disease state is associated with the genitourinary tract.

29. The method of treatment of claim 28, wherein the disease state comprises overactive bladder, detrusor hyperactivity, urgency, frequency, reduced bladder capacity, incontinence episodes, changes in bladder capacity, micturition threshold, unstable bladder contractions, sphincteric spasticity, outlet obstruction, outlet insufficiency, pelvic hypersensitivity, idiopathic conditions or detrusor instability.

30. The method of treatment of claim 27, wherein the disease state comprises respiratory states from allergies or asthma.

31. The method of treatment of claim 27, wherein the disease state comprises gastrointestinal tract disorders.

32. A process for preparing a compound as claimed in claim 1 which process comprises reacting a compound having a general formula