Rho-kinase inhibitors

• US 20050192304A1
• Filed: 04/18/2005
• Published: 09/01/2005
• Est. Priority Date: 01/23/2002
• Status: Abandoned Application

• Current Assignee: Bayer Healthcare LLC (Bayer AG)
• Original Assignee: Bayer Healthcare LLC (Bayer AG)
• Inventors: Dumas, Jacques, Nagarathnam, Dhanapalan, Feurer, Achim, Boyer, Stephen, Bennabi, Samir, Wang, Chunguang, Hatoum-Mokdad, Holia, Pluempe, Hans
• Application Number:
  US11/107,793
• Publication Number:
  US 20050192304A1
• Time in Patent Office: Days
• US Class Current: 514/275
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• 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 9/10 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 9/12 Antihypertensives
• CPC Class Codes: A61P 9/14 Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07D 239/48 Two nitrogen atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/12 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 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 471/04 : Ortho-condensed systems

Abstract

Disclosed are compounds and derivatives thereof, their synthesis, and their use as Rho-kinase inhibitors. These compounds are useful for inhibiting tumor growth, treating erectile dysfunction, and treating other indications mediated by Rho-kinase, e.g., coronary heart disease.

Claims

1. A compound of formula I

2. A compound of formula I according to claim 1, wherein

R₁ and R₂ are each independently H, halo, C_1-12 alkyl optionally substituted by halo up to perhalo, C_2-12, alkenyl, C_2-12-alkynyl, NO₂, NH₂, NR₆R₇, alkyl, furyl, thienyl, pyridyl, phenyl optionally substituted with NO₂, trifluoromethyl or NR₆R₇;

or

R₁ and R₂ together form a ring of from 5 to 7 members optionally interrupted by N and optionally substituted on N by benzyl;

R₃ is NH₂ or —

NH—

phenyl optionally substituted with halo, C₁-C₄ alkyl, trifluoromethyl, nitro or amino;

R₄ is

or indol-5-yl (optionally) substituted on the N with pyridyl;

X is a linker substituted at the 3 or 4 position of the ring and is selected from O, S, —

S—

CH₂—

, —

CH₂—

S—

, —

(CH₂)_m—

, or —

C═

O)—

;

A is phenyl optionally substituted by C_1-4 alkylthio or OH,

pyridyl,

quinolyl or

isoquinolyl;

each R₅ independently is halo, C₁-C₁₂ alkyl, optionally substituted by halo, up to the perhalo level, C_2-12-alkenyl, C_2-12-alkynyl, NO₂, NH₂ or trifluoromethyl;

n is 0, 1, 2, 3 or 4;

m is 1 or 2; and

R₆ and R₇ are each independently H, C₁-C₆ alkyl, or phenyl optionally substituted with halo, CF₃, Cl —

C₄ alkyl, nitro or amino.

3. A compound according to claim 1, wherein X is not S or A is not pyridyl.

4. A compound according to claim 1, wherein X is not S or —

S—

CH₂.

5. A compound according to claim 1, wherein n is 1-4.

6. A compound according to claim 1, wherein n is 1-4 and each R₅ is independently is halo, C₃-C₁₂ alkyl optionally substituted by halo up to the perhalo level, C_2-12-alkenyl, C_2-12-alkynyl, NO₂, NH₂ or trifluoromethyl.

7. A compound according to claim 1, which is 4-({4-[(2-amino-6-ethyl-4-pyrimidinyl)amino]phenyl}sulfanyl)phenol, N-(2-amino-6-methyl-4-pyrimidinyl)-N-[4-(3-pyridinylsulfanyl)phenyl]amine, N-(2-amino-6-methyl-4-pyrimidinyl)-N-[3-(4-pyridinylsulfanyl)phenyl]amine, N-(2-anilino-6-methyl-4-pyrimidinyl)-N-[4-(4-pyridinylsulfanyl)phenyl]amine, N, (2-amino-6-methyl-4-pyrimidinyl)-N-[4-(5-quinolinyloxy)phenyl]amine, N-(2-amino-6-phenyl-4-pyrimidinyl)-N-[3,5-dichloro-4-(4-pyridinylsulfanyl)phenyl]amine, N-[2-amino-6-(3-nitrophenyl)-4-pyrimidinyl]-N-[3-fluoro-4-(4-pyridinylsulfanyl)phenyl]amine, N-[2-amino-6-(2-furyl)-4-pyrimidinyl]-N-[3-fluoro-4-(4-pyridinylsulfanyl)phenyl]amine, N-[2-amino-6-(2-thienyl)-4-pyrimidinyl]-N-[3-fluoro-4-(4-pyridinylsulfanyl)phenyl]amine, N-[2-amino-6-ethoxyphenyl)-4-pyrimidinyl]-N-[3-fluoro-4(4-pyridinylsulfanyl)phenyl]amine.

8. A compound according to claim 1, of the formula

9. A compound according to claim 1, of the formula

10. A compound according to claim 1, of the formula

11. A method of treating an indication mediated by Rho-kinase, comprising administering a compound of claim 1.

12. A method of treating hypertension, atherosclerosis, restenosis, cerebral ischemia, cerebral vasospasm, neuronal degeneration, spinal cord injury, cancer of the breast, colon, prostate, ovaries, brain or lung, thrombotic disorders, asthma, glaucoma, osteoporosis or erectile dysfunction, comprising administering to host in need thereof a compound according to claim 1.

13. A process according to claim 11, wherein the host is a human.

14. A process according to claim 12, wherein the host is a human.

15. A process for the preparation of a compound of claim 1, comprising reacting

16. A method of treating atherosclerosis, comprising administering a compound of claim 1.

17. A method of treating hypertension, comprising administering a compound of claim 1.