Novel diazepan derivatives

• US 20070249589A1
• Filed: 04/19/2007
• Published: 10/25/2007
• Est. Priority Date: 04/20/2006
• Status: Active Grant

• Current Assignee: F Hoffmann-La Roche AG (Roche Holding AG)
• Original Assignee: Hoffmann-La Roche Incorporated (Roche Holding AG)
• Inventors: Mattei, Patrizio, Roche, Olivier, Green, Luke, Ricklin, Fabienne, Aebi, Johannes, Zahm, Peter
• Granted Patent: US 7,632,829 B2
• Time in Patent Office: Days
• US Class Current: 514/218
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/14 Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07D 243/14 1,4-Benzodiazepines; Hydrogenated 1,4-benzodiazepines
• 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 401/14 : containing three or more hetero rings
• 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 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/10 : Spiro-condensed systems

Abstract

The invention is concerned with novel diazepan derivatives of formula (I)

wherein A, X, R³, R⁴, R⁵, R⁶, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, m and n are as defined in the description and in the claims, as well as physiologically acceptable salts thereof. These compounds are antagonists of CCR-2 receptor, CCR-5 receptor and/or CCR-3 receptor and can be used as medicaments.

Claims

1. Compounds of formula (I)

2. The compounds of claim 1 wherein A is aryl, said aryl being optionally substituted by one to three substituents independently selected from the group consisting of halogen, benzyloxy, heteroaryl-C_1-6 alkoxy, C_1-6 alkyl, C_1-6 alkoxy and halo C_1-6 alkoxy, or said aryl being optionally substituted by C_1-6 alkylenedioxy.

3. The compounds of claim 2 wherein R¹ and R² are, independently to each other, hydrogen, C_1-6 alkyl, C_3-6 alkenyl, C_3-6 alkynyl, hydroxy C_2-6 alkyl, C_1-6 alkoxy C_2-6 alkyl, C_3-7 cycloalkyl, C_3-7 cycloalkyl C_1-6 alkyl, C_7-10 bicycloalkyl, phenyl C_1-3 alkyl, heteroaryl C_1-3 alkyl, heterocyclyl or heterocyclyl C_1-6 alkyl;

and R³ and R⁴ are, independently to each other, hydrogen, hydroxy, C_1-6 alkyl, C_1-6 alkoxy, C_3-7 cycloalkyl, C_3-7 cycloalkyl C_1-6 alkyl, C_1-6 alkoxycarbonyl, carboxyl, hydroxy-C_1-6 alkyl, C_1-6 alkoxy-C_1-6 alkyl, halogen or halo C_1-6 alkyl;

or

R³ and R⁴, together with the carbon atom to which they are attached, form C_3-7 cycloalkyl or heterocyclyl optionally substituted by one to three substituents independently selected from the group consisting of C1-₄ alkyl, halo C_1-4 alkyl and halogen.

4. The compounds of claim 3 wherein the cycloalkyl of said C_3-7 cycloalkyl and said C_3-7 cycloalkyl C_1-6 alkyl, the phenyl of said phenyl C_1-3 alkyl, the heteroaryl of said heteroaryl C_1-3 alkyl and the heterocyclyl of said heterocyclyl and said heterocyclyl C_1-6 alkyl are substituted by one to three substituents independently selected from the group consisting of R^d.

5. The compounds of claim 2 wherein R¹ and R², together with the nitrogen atom to which they are attached, form heterocyclyl optionally substituted by one to three substituents independently selected from the group consisting of R^d, and one of the ring carbon atoms of said heterocyclyl formed by R¹ and R² being optionally replaced with a carbonyl group;

and R³ and R⁴ are, independently to each other, hydrogen, hydroxy, C_1-6 alkyl, C_1-6 alkoxy, C_3-7 cycloalkyl, C_3-7 cycloalkyl C_1-6 alkyl, C_1-6 alkoxycarbonyl, carboxyl, hydroxy-C_1-6 alkyl, C_1-6 alkoxy-C_1-6 alkyl, halogen or halo C_1-6 alkyl;

or

R³ and R⁴, together with the carbon atom to which they are attached, form C_3-7 cycloalkyl or heterocyclyl optionally substituted by one to three substituents independently selected from the group consisting of C_1-4 alkyl, halo C_1-4 alkyl and halogen.

6. The compounds of claim 5 wherein one of the ring carbon atoms of the heterocyclyl formed by R¹ and R² may be a ring carbon atom of another ring which is C_3-7 cycloalkyl or heterocyclyl, one or two ring carbon atoms of said another ring being optionally replaced by a carbonyl group, and said another ring being optionally substituted by C_1-6 alkyl.

7. The compounds of claim 2 wherein R¹ is hydrogen, C_1-6 alkyl, C_3-6 alkenyl, C_3-6 alkinyl, hydroxy C_1-6 alkyl, C_1-6 alkoxy C_1-6 alkyl, C_3-7 cycloalkyl, C_3-7 cycloalkyl C_1-6 alkyl, C_7-10 bicycloalkyl, phenyl C_1-3 alkyl, heteroaryl C_1-3 alkyl, heterocyclyl or heterocyclyl C_1-6 alkyl.

8. The compounds of claim 7 wherein the cycloalkyl of said C_3-7 cycloalkyl and said C_3-7 cycloalkyl C_1-6 alkyl, the phenyl of said phenyl C_1-3 alkyl, the heteroaryl of said heteroaryl C_1-3 alkyl and the heterocyclyl of said heterocyclyl and said heterocyclyl C_1-6 alkyl are optionally substituted by one to three substituents independently selected from the group consisting of R^d.

9. The compounds of claim 1 wherein A is heteroaryl, said heteroaryl being optionally substituted by one to three substituents independently selected from the group consisting of halogen, benzyloxy, heteroaryl-C_1-6 alkoxy, C_1-6 alkyl, C_1-6 alkoxy and halo C_1-6 alkoxy, or said heteroaryl being optionally substituted by C_1-6 alkylenedioxy.

10. The compounds of claim 9 wherein R¹ and R² are, independently to each other, hydrogen, C_1-6 alkyl, C_3-6 alkenyl, C_3-6 alkynyl, hydroxy C_2-6 alkyl, C_1-6 alkoxy C_2-6 alkyl, C_3-7 cycloalkyl, C_3-7 cycloalkyl C_1-6 alkyl, C_7-10 bicycloalkyl, phenyl C_1-3 alkyl, heteroaryl C_1-3 alkyl, heterocyclyl or heterocyclyl C_1-6 alkyl;

and wherein R³ and R⁴ are, independently to each other, hydrogen, hydroxy, C_1-6 alkyl, C_1-6 alkoxy, C_3-7 cycloalkyl, C_3-7 cycloalkyl C_1-6 alkyl, C_1-6 alkoxycarbonyl, carboxyl, hydroxy-C_1-6 alkyl, C_1-6 alkoxy-C_1-6 alkyl, halogen or halo C_1-6 alkyl;

or

R³ and R⁴, together with the carbon atom to which they are attached, form C_3-7 cycloalkyl or heterocyclyl optionally substituted by one to three substituents independently selected from the group consisting of C_1-4 alkyl, halo C_1-4 alkyl and halogen.

11. The compounds of claim 10 wherein the cycloalkyl of said C_3-7 cycloalkyl and said C_3-7 cycloalkyl C_1-6 alkyl, the phenyl of said phenyl C_1-3 alkyl, the heteroaryl of said heteroaryl C_1-3 alkyl and the heterocyclyl of said heterocyclyl and said heterocyclyl C_1-6 alkyl are substituted by one to three substituents independently selected from the group consisting of R^d.

12. The compounds of claim 9 wherein R¹ and R², together with the nitrogen atom to which they are attached, form heterocyclyl optionally substituted by one to three substituents independently selected from the group consisting of R^d, and one of the ring carbon atoms of said heterocyclyl formed by R¹ and R² being optionally replaced with a carbonyl group;

and R³ and R⁴ are, independently to each other, hydrogen, hydroxy, C_1-6 alkyl, C_1-6 alkoxy, C_3-7 cycloalkyl, C_3-7 cycloalkyl C_1-6 alkyl, C_1-6 alkoxycarbonyl, carboxyl, hydroxy-C_1-6 alkyl, C_1-6 alkoxy-C_1-6 alkyl, halogen or halo C_1-6 alkyl;

or

R³ and R⁴, together with the carbon atom to which they are attached, form C_3-7 cycloalkyl or heterocyclyl optionally substituted by one to three substituents independently selected from the group consisting of C_1-4 alkyl, halo C_1-4 alkyl and halogen.

13. The compounds of claim 12 wherein one of the ring carbon atoms of the heterocyclyl formed by R¹ and R² may be a ring carbon atom of another ring which is C_3-7 cycloalkyl or heterocyclyl, one or two ring carbon atoms of said another ring being optionally replaced by a carbonyl group, and said another ring being optionally substituted by C_1-6 alkyl.

14. The compounds of claim 9 wherein R¹ is hydrogen, C_1-6 alkyl, C_3-6 alkenyl, C_3-6 alkinyl, hydroxy C_1-6 alkyl, C_1-6 alkoxy C_1-6 alkyl, C_3-7 cycloalkyl, C_3-7 cycloalkyl C_1-6 alkyl, C_7-10 bicycloalkyl, phenyl C_1-3 alkyl, heteroaryl C_1-3 alkyl, heterocyclyl or heterocyclyl C_1-6 alkyl.

15. The compounds of claim 14 wherein the cycloalkyl of said C_3-7 cycloalkyl and said C_3-7 cycloalkyl C_1-6 alkyl, the phenyl of said phenyl C_1-3 alkyl, the heteroaryl of said heteroaryl C_1-3 alkyl and the heterocyclyl of said heterocyclyl and said heterocyclyl C_1-6 alkyl are optionally substituted by one to three substituents independently selected from the group consisting of R^d.

16. The compounds of claim 1, wherein

R³ and R⁴ are, independently to each other, hydrogen, C_1-6 alkyl, C_3-7 cycloalkyl, C_3-7 cycloalkyl C_1-6 alkyl, halogen or halo C_1-6 alkyl;

R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³ are hydrogen;

R^d is hydroxy, cyano, NR^aR^b, halogen, C_1-6 alkyl, halo C_1-6 alkyl, hydroxy C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkoxy C_1-6 alkyl, C_1-6 alkoxycarbonyl, acyl, —

C(O)NR^aR^b, —

NR^a—

C(O)—

R^b, —

NR^a—

C(O)—

OR^b, —

NR^a—

C(O)—

NR^b, —

NR^a—

SO₂—

R^b, —

NR^aSO₂—

NR^bR^c, —

OC(O)NR^aR^b, —

OC(O)OR^a, C_1-6 alkylsulfonyl, C_1-6 alkylsulfinyl, C_1-6 alkylthio, phenyl, phenyl C_1-3 alkyl, heteroaryl, heteroaryl C_1-3 alkyl and heterocyclyl, and the phenyl of said phenyl and said phenyl C_1-3 alkyl, the heteroaryl of said heteroaryl and said heteroaryl C_1-3 alkyl, and the heterocyclyl being optionally substituted by one to three substituents independently selected from the group consisting of hydroxy, cyano, NR^aR^b, halogen, C_1-6 alkyl, halo C_1-6 alkyl, hydroxy C_1-6 alkyl, C_1-6 alkoxycarbonyl, acyl, —

C(O)NR^aR^b, —

NR^a—

C(O)—

R^b, —

NR^a—

C(O)—

OR^b, —

NR^a—

C(O)—

NR^b, —

NR^a—

SO₂—

R^b, —

NR^a—

SO₂—

N^bR^c, —

OC(O)NR^aR^b, —

OC(O)OR^a, C_1-6 alkylsulfonyl, C_1-6 alkylsulfinyl and C_1-6 alkylthio, and one or two ring carbon atoms of the heterocyclyl being optionally replaced with a carbonyl group.

17. The compounds of claim 1, wherein A is phenyl optionally substituted by one to three substituents independently selected from the group consisting of halogen, benzyloxy, heteroaryl-C_1-6 alkoxy, C_1-6 alkyl, C_1-6 alkoxy and halo C_1-6 alkoxy, or A is phenyl optionally substituted by C_1-6 alkylenedioxy.

18. The compounds of claim 1, wherein A is phenyl substituted by one or two halogen atoms independently selected from the group consisting of chlorine and fluorine.

19. The compounds of claim 1, wherein A is phenyl substituted by two halogen atoms independently selected from the group consisting of chlorine and fluorine at its 3,4 or 3,5 position.

20. The compounds of claim 1, wherein X is —

N(R¹)(R²).

21. The compounds of claim 20, wherein at least one of R¹ and R² is other than hydrogen.

22. The compounds of claim 20, wherein R¹ is hydrogen, C_1-6 alkyl, or hydroxy C_2-6 alkyl and R² is C_3-7 cycloalkyl, heterocyclyl, heterocyclyl C_1-6 alkyl, C_7-10 bicycloalkyl, hydroxy C_2-6 alkyl or C_1-6 alkoxy C_2-6 alkyl, in which the cycloalkyl and the heterocyclyl of said heterocyclyl and said heterocyclyl C_1-6 alkyl are optionally substituted by one or two substituents independently selected from the group consisting of C_1-6 alkyl, hydroxy, heteroaryl and C_1-6 alkoxy.

23. The compounds of claim 20, wherein R¹ is hydrogen and R² is heterocyclyl.

24. The compounds of claim 20, wherein m+n is an integer of 1 or 2.

25. The compounds of claim 20, wherein R³, R⁴, R⁵ and R⁶ are hydrogen.

26. The compounds of claim 20, wherein R¹ and R², together with the nitrogen atom to which they are attached, form heterocyclyl optionally substituted by one to three substituents independently selected from the group consisting of R^d, and one of the ring carbon atoms of said heterocyclyl formed by R¹ and R² being optionally replaced with a carbonyl group;

and/or one of the ring carbon atoms of the heterocyclyl formed by R¹ and R² may be a ring carbon atom of another ring which is C_3-7 cycloalkyl or heterocyclyl, one or two ring carbon atoms of said another ring being optionally replaced by a carbonyl group, and said another ring being optionally substituted by C_1-6 alkyl.

27. The compounds of claim 26, wherein the heterocyclyl formed by R¹ and R², together with the nitrogen atom to which they are attached, is a mono-cyclic radical of five or six ring atoms in which one more ring atom, in addition to the nitrogen atom, may be a heteroatom independently selected from N, O and S(O)_n (where n is an integer from 0 to 2).

28. The compounds of claim 26, wherein the heterocyclyl formed by R¹ and R², together with the nitrogen atom to which they are attached, is piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl or 1,1-dioxo-thiomorphlinyl.

29. The compounds of claim 26, wherein the heterocyclyl formed by R¹ and R², together with the nitrogen atom to which they are attached, is piperidyl or pyrrolidinyl.

30. The compounds of claim 26, wherein the heterocyclyl formed by R¹ and R², together with the nitrogen atom to which they are attached, is optionally substituted by one or two substituents independently selected from the group consisting of hydroxy, phenyl and hydroxy C_1-6 alkyl, and/or

one of the ring carbon atoms of the heterocyclyl formed by R¹ and R² may be shared by another ring which is five or six membered mono-cyclic heterocyclyl, one or two ring carbon atoms of said another ring being optionally replaced by a carbonyl group.

31. The compounds of claim 26, wherein m+n is an integer of 1 to 3.

32. The compounds of claim 26, wherein R³, R⁴, R⁵ and R⁶ are hydrogen.

33. The compounds of claim 1, which is

1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-(4-piperidin-1-yl-butyl)-[1,4]diazepan-5-one,

1-[(E)-3-(3-Chloro-4-fluoro-phenyl)-acryloyl]-4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one,

1-[(E)-3-(4-Chloro-3-fluoro-phenyl)-acryloyl]-4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one,

8-(3-{4-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-propyl)-1,3,8-triaza-spiro[4.5]decane-2,4-dione,

1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-[3-(4-hydroxy-4-phenyl-piperidin-1yl)-propyl]-[1,4]diazepan-5-one,

(±

)-1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-[3-(3-hydroxy-piperidin-1-yl)-propyl]-[1,4]diazepan-5-one,

8-(3-{4-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-propyl)-1-oxa-3,8-diaza-spiro[4.5]decan-2-one,

1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-[3-(tetrahydro-pyran-4-ylamino)-ethyl]-[1,4]diazepan-5-one,

(S)-1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-[3-(2-hydroxymethyl-pyrrolidin-1-yl)-ethyl]-[1,4]diazepan-5-one, or

1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-(2-pyrrolidin-1-yl-ethyl)-[1,4]diazepan-5-one.

34. The compounds of claim 1, which is

1-[(E)-3-(3-Chloro-4-fluoro-phenyl)-acryloyl]-4-[3-((−

, cis)-3-hydroxy-4-methyl-piperidin-1-yl)-propyl]-[1,4]diazepan-5-one,

1-[(E)-3-(3-Chloro-4-fluoro-phenyl)-acryloyl]-4-[3-(3-hydroxy-4,4-dimethyl-piperidin-1-yl)-propyl]-[1,4]diazepan-5-one,

(cis)-1-[(E)-3-(3-Chloro-4-fluoro-phenyl)-acryloyl]-4-[3-(3-hydroxy-5-methyl-piperidin-1-yl)-propyl]-[1,4]diazepan-5-one,

1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-[2-hydroxy-3-(3-hydroxy-4-methyl-piperidin-1-yl)-propyl]-[1,4]diazepan-5-one,

1-[(E)-3-(3,4-Dichloro-phenyl)-acryloyl]-4-[(S)-2-hydroxy-3-((−

)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-[1,4]diazepan-5-one,

1-[(E)-3-(3-Chloro-4-fluoro-phenyl)-acryloyl]-4-[(S)-2-hydroxy-3-(3-hydroxy-4,4-dimethyl-piperidin-1-yl)-propyl]-[1,4]diazepan-5-one,

1-[(E)-3-(3-Chloro-4-fluoro-phenyl)-acryloyl]-4-[(S)-2-hydroxy-3-(cis-3-hydroxy-5-methyl-piperidin-1-yl)-propyl]-[1,4]diazepan-5-one,

1-[(E)-3-(4-Chloro-3-fluoro-phenyl)-acryloyl]-4-[4-((−

)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-butyl]-[1,4]diazepan-5-one,

(cis)-1-[(E)-3-(3-Chloro-4-fluoro-phenyl)-acryloyl]-4-[4-(3-hydroxy-5-methyl-piperidin-1-yl)-butyl]-[1,4]diazepan-5-one,

1-[(E)-3-(3-Chloro-phenyl)-acryloyl]-4-[3-((−

)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-[1,4]diazepan-5-one, or

1-[(E)-3-(5,6-Dichloro-pyridin-3-yl)-acryloyl]-4-[3-((−

)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-[1,4]diazepan-5-one.

35. A process for manufacturing compounds of formula (I)

36. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

37. A method for the treatment of diseases treatable by a CCR-2 receptor antgonist comprising a therapeutically effective amount of the compound of claim 1.