INHIBITION OF P38 KINASE USING SYMMETRICAL AND UNSYMMETRICAL DIPHENYL UREAS

• US 20090093526A1
• Filed: 10/31/2007
• Published: 04/09/2009
• Est. Priority Date: 12/22/1997
• Status: Abandoned Application

• Current Assignee: Bayer Healthcare LLC (Bayer AG)
• Original Assignee: Bayer Healthcare LLC (Bayer AG)
• Inventors: Lowinger, Timothy B., Wang, Ming, Dumas, Jacques, Scott, William J., Smith, Roger A., Wood, Jill E., Khire, Uday, Miller, Scott, Turner, Tiffany, Gunn, David E., Sibley, Robert, Hatoum-Mokdad, Holia, Brennan, Catherine, Rodriguez, Marell, Osterhout, Martin
• Application Number:
  US11/932,397
• Publication Number:
  US 20090093526A1
• Time in Patent Office: Days
• US Class Current: 514/357
• CPC Class Codes: A61K 31/17 having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine isoureas, isothioureas A61K31/155; sulfonylureas A61K31/64
• CPC Class Codes: A61K 31/341 not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
• CPC Class Codes: A61K 31/381 having five-membered rings
• CPC Class Codes: A61K 31/4035 Isoindoles, e.g. phthalimide
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/5375 1,4-Oxazines, e.g. morpholine
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/10 for osteoporosis
• 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 41/00 Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

This invention relates to the use of a group of aryl ureas in treating cytokine mediated diseases and proteolytic enzyme mediated diseases, and pharmaceutical compositions for use in such therapy.

Claims

1. A method of treating a disease, other than cancer, mediated by p-38, comprising administering a compound of formula I

2. A method according to claim 1, comprising administering a compound of formula Ia

3. A method according to claim 2, wherein

R³ is H;

halogen;

C_1-10-alkyl optionally substituted by halogen, up to perhalo, NO₂, —

SO₂F or —

SO₂CF₃;

R⁴ is H, C_1-10-alkyl, C_1-10-alkoxy, halogen or NO₂;

R⁵ is H, C_1-100-alkyl optionally substituted by halogen, up to perhalo;

R⁶ is H, hydroxy, C_1-10-alkoxy optionally substituted by at least one hydroxy group;

—

COOR¹;

—

OR¹CONHR¹;

—

NHCOR¹;

—

SR¹;

phenyl optionally substituted by halo

or C_1-10-alkoxy;

NH₂;

—

N(SO₂R¹)₂, furyloxy, thiophene, pyrole or methyl substituted pyrole,

4. A method according to claim 2, wherein R³ is Cl, F, C_4-5-branched alkyl, —

SO₂F or —

SO₂CF₃; and

R⁶ is hydroxy;

C_1-10-alkoxy optionally substituted by at least one hydroxy group;

—

COOR¹;

—

OR¹CONHR¹;

—

NHCOR¹;

—

SR¹;

phenyl optionally substituted by halo or C_1-10-alkoxy;

NH₂;

—

N(SO₂R¹)₂, furyloxy,

5. A compound according to claim 2, wherein R^4′

is C_1-10-alkyl or halogen;

R^5′

is H, C_1-10-alkyl, halogen, CF₃, halogen, NO₂ or NH₂; and

R^6′

is H, C_1-10-alkyl, halogen, —

NHCOCH₃, —

N(CH₃)COCH₃, NO₂,

6. A method according to claim 2, wherein R^5′

is C_1-10-alkyl, halogen, CF₃, halogen, NO₂ or NH₂.

7. A method according to claim 2, wherein R^6′

is C_1-10-alkyl, halogen, —

NHCOCH₃, —

N(CH₃)COCH₃, NO₂,

8. A method according to claim 4, wherein R³ is t-butyl or CF₃ and R⁶ is —

OCH₃.

9. A method according to claim 2, wherein the disease is mediated by a cytokine or protease regulated by p38.

10. A method according to claim 2, wherein the disease is mediated by TNFα

, MMP-1, MMP-3, IL-1, IL-6 or IL-8.

11. A method according to claim 2, wherein the disease is an inflammatory or immunomodulatory disease.

12. A method according to claim 2, wherein the disease is osteoarthritis, rheumatoid arthritis, osteoporosis, asthma, septic shock, inflammatory bowel disease, or the result of host-versus-graft reactions.

13. A method according to claim 1, wherein the compound of formula I is

N-(5-tert-Butyl-2-methoxyphenyl)-N′

-(4-phenyloxphenyl)urea;

N-(5-tert-Butyl-2-methoxyphenyl)-N′

-(4-(4-pyridinyloxy)phenyl)urea;

N-(5-Tert-Butyl-2-methoxyphenyl)-N′

-(4-(4-pyridinylmethyl)phenyl)urea;

N-(5-tert-Butyl-2-methoxyphenyl)-N′

-(4-(4-(4,7-methano-1H-isoindole-1,3(2H)-dionyl)methyl)phenyl)urea;

N-(5-tert-Butyl-2-phenylphenyl)-N′

-(2,3-dichlorophenyl)urea;

N-(5-tert-Butyl-2-(3-thienyl)phenyl)-N′

-(2,3-dichlorophenyl)urea;

N-(5-tert-Butyl-2-(N-methylaminocarbonyl)methoxyphenyl)-N′

-(2,3-dichlorophenyl)urea;

N-(5-tert-Butyl-2-(N-methylaminocarbonyl)methoxyphenyl)-N′

-(1-naphthyl)urea;

N-(5-tert-Butyl-2-(N-morpholinocarbonyl)methoxyphenyl)-N′

-(2,3-dichlorophenyl)urea;

N-(5-tert-Butyl-2-(N-morpholinocarbonyl)methoxyphenyl)-N′

-(1-naphthyl)urea;

N-(5-tert-Butyl-2-methoxyphenyl)-N′

-(4-(3-pyridinyl)methylphenyl)urea;

N-(5-tert-Butyl-2-(3-tetrahydrofuranyloxy)phenyl)-N′

-(2,3-dichlorophenyl)urea;

N-(5-Trifluoromethyl-2-methoxyphenyl)-N′

-(4-methylphenyl)urea;

N-(5-Trifluoromethyl-2-methoxyphenyl)-N′

-(4-methyl-2-fluorophenyl)urea;

N-(5-Trifluoromethyl-2-methoxyphenyl)-N′

-(4-fluoro-3-chlorophenyl)urea;

N-(5-Trifluoromethyl-2-methoxyphenyl)-N′

-(4-methyl-3-chlorophenyl)urea;

N-(5-Trifluoromethyl-2-methoxyphenyl)-N′

-(4-methyl-3-fluorophenyl)urea;

N-(5-Trifluoromethyl-2-methoxyphenyl)-N′

-(2,4-difluorophenyl)urea;

N-(5-Trifluoromethyl-2-methoxyphenyl)-N′

-(4-phenyloxy-3,5-dichlorophenyl)urea;

N-(5-Trifluoromethyl-2-methoxyphenyl)-N′

-(4-(4-pyridinylthio)phenyl)urea;

N-(5-Trifluoromethyl-2-methoxyphenyl)-N′

-(4-(4-pyridinyloxy)phenyl)urea;

N-(5-Trifluoromethyl-2-methoxyphenyl)-N′

-(3-(4-pyridinylthio)phenyl)urea;

N-(5-Trifluoromethyl-2-methoxyphenyl)-N′

-(4-(3-(N-methylaminocarbonyl)-phenyloxy)phenyl)-urea;

N-(5-Fluorosulfonyl)-2-methoxyphenyl)-N′

-(4-methylphenyl)urea;

N-(5-(Difluoromethanesulfonyl)-2-methoxyphenyl)-N′

-(4-methylphenyl)urea;

N-(5-(Difluoromethanesulfonyl)-2-methoxyphenyl)-N′

-(4-fluorophenyl)urea;

N-(5-(Difluoromethanesulfonyl)-2-methoxyphenyl)-N′

-(4-methyl-2-fluorophenyl)urea;

N-(5-(Difluoromethanesulfonyl)-2-methoxyphenyl)-N′

-(4-methyl-3-fluorophenyl)urea;

N-(5-(Difluoromethanesulfonyl)-2-methoxyphenyl)-N′

-(4-methyl-3-chlorophenyl)urea;

N-(5-(Difluoromethanesulfonyl)-2-methoxyphenyl)-N′

-(4-fluoro-3-chlorophenyl)urea;

N-(5-(Difluoromethanesulfonyl)-2-methoxyphenyl)-N′

-(4-fluoro-3-methylphenyl)urea;

N-(5-(Difluoromethanesulfonyl)-2-methoxyphenyl)-N′

-(2,3-dimethylphenyl)urea;

N-(5-(Trifluoromethanesulfonyl)-2-methoxphenyl)-N′

-(4-methylphenyl)urea;

N-(3-methoxy-2-naphthyl)-N′

-(2-fluorophenyl)urea);

N-(3-Methoxy-2-naphthyl)-N′

-(4-methylphenyl)urea;

N-(3-Methoxy-2-naphthyl)-N′

-(3-fluorophenyl)urea;

N-(3-Methoxy-2-naphthyl)-N′

-(4-methyl-3-fluorophenyl)urea;

N-(3-Methoxy-2-naphthyl)-N′

-(2,3-dimethylphenyl)urea;

N-(3-Methoxy-2-naphthyl)-N′

-(1-naphthyl)urea;

N-(3-Methoxy-2-naphthyl)-N′

-(4-(4-pyridinylmethyl)phenyl)urea;

N-(3-Methoxy-2-naphthyl)-N′

-(4-(4-pyridinylthio)phenyl)urea;

N-(3-Methoxy-2-naphthyl)-N′

-(4-(4-methoxyphenyloxy)phenyl)urea; and

N-(3-Methoxy-2-naphthyl)-N′

-(4-(4-(4,7-methano-1H-isoindole-1,3(2H)-dionyl)methyl)phenyl)urea.

N-(2-Hydroxy-4-nitro-5-chlorophenyl)-N′

-(phenyl)urea;

or

N-(2-Hydroxy-4-nitro-5-chlorophenyl)-N′

-(4-(4-pyridinylmethly)phenyl)urea.

14. A compound of formula I

15. A compound according to claim 14, wherein

R³ is H, halogen or C_1-10-alkyl optionally substituted by halogen, up to perhalo, NO₂, —

SO₂F or —

SO₂CF₃;

R⁴ is H, C_1-10-alkyl, C_1-10-alkoxy, halogen or NO₂;

R⁵ is H, C_1-10-alkyl optionally substituted by halogen, up to perhalo;

R⁶ is H, hydroxy, C_1-10-alkoxy optionally substituted by at least one hydroxy group;

—

COOR¹;

—

OR¹CONHR¹;

—

NHCOR¹;

—

SR¹;

phenyl optionally substituted by halo

or C_1-10-alkoxy;

NH₂;

—

N(SO₂R¹)₂, furyloxy,

16. A compound according to claim 14, wherein R³ is Cl, F, C_4-5-branched alkyl, —

SO₂F or —

SO₂CF₃; and

R⁶ is hydroxy;

C_1-10-alkoxy optionally substituted by at least one hydroxy group;

—

COOR¹;

—

OR¹CONHR¹;

—

NHCOR¹;

—

SR¹;

phenyl optionally substituted by halo or C_1-10-alkoxy;

NH₂;

—

N(SO₂R¹)₂, furyloxy,

17. A compound according to claim 14, wherein R^4′

is C_1-10-alkyl or halogen;

R^5′

is H, C_1-10-alkyl, halogen, CF₃, halogen, NO₂ or NH₂; and

R^6′

is H, C_1-10-alkyl, halogen, —

NHCOCH₃, —

N(CH₃)COCH₃, NO₂,

18. A compound according to claim 14, wherein R³ is t-butyl or CF₃ and R⁶ is —

OCH₃.

19. A compound according to claim 14, which is

N-(5-tert-Butyl-2-(N-methylaminocarbonyl)methoxyphenyl)-N′

-(2,3-dichlorophenyl)urea;

N-(5-tert-Butyl-2-(N-methylaminocarbonyl)methoxyphenyl)-N′

-(1-naphthyl)urea;

N-(5-tert-Butyl-2-(N-morpholinocarbonyl)methoxyphenyl)-N′

-(2,3-dichlorophenyl)urea;

N-(5-tert-Butyl-2-(N-morpholinocarbonyl)methoxyphenyl)-N′

-(1-naphthyl)urea;

N-(5-tert-Butyl-2-(3-tetrahydrofuranyloxy)phenyl)-N′

-(2,3-dichlorophenyl)urea;

N-(5-Difluoromethanesulfonyl)-2-methoxyphenyl)-N′

-(4-methylphenyl)urea;

N-(5-(Difluoromethanesulfonyl)-2-methoxyphenyl)-N′

-(4-fluorophenyl)urea;

N-(5-(Difluoromethanesulfonyl)-2-methoxyphenyl)-N′

-(4-methyl-2-fluorophenyl)urea;

N-(5-(Difluoromethanesulfonyl)-2-methoxyphenyl)-N′

-(4-methyl-3-fluorophenyl)urea;

N-(5-(Difluoromethanesulfonyl)-2-methoxyphenyl)-N′

-(4-methyl-3-chlorophenyl)urea;

N-(5-(Difluoromethanesulfonyl)-2-methoxyphenyl)-N′

-4-fluoro-3-chlorophenyl)urea;

N-(5-(Difluoromethanesulfonyl)-2-methoxyphenyl)-N′

-(4-fluoro-3-methylphenyl)urea;

N-(5-(Difluoromethanesulfonyl)-2-methoxyphenyl)-N′

-(2,3-dimethylphenyl)urea;

or

N-(5-(Trifluoromethanesulfonyl)-2-methoxphenyl)-N′

-(4-methylphenyl)urea.

21. A pharmaceutical composition comprising a compound of claim 14, and a physiologically acceptable carrier.

20. A compound of formula II

22. A pharmaceutical composition comprising a compound of claim 20, and a physiologically acceptable carrier.