p38 MAP kinase inhibitors

• US 6,479,507 B2
• Filed: 04/19/2001
• Issued: 11/12/2002
• Est. Priority Date: 10/20/1997
• Status: Expired due to Fees

• Current Assignee: Syntec Incorporated (Atos SE)
• Original Assignee: Syntec Incorporated (Atos SE)
• Inventors: Sjogren, Eric Brian, Cheng, Soan, Goldstein, David Michael, Martin, Teresa Alejandra Trejo
• Primary Examiner(s): Gerstl, Robert
• Application Number:
  US09/839,712
• Publication Number:
  US 20010044538A1
• Time in Patent Office: 572 Days
• Field of Search: 546/112, 546/113, 546/114, 546/115, 514/301, 514/302
• US Class Current: 514/301
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• 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 11/00 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 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• 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 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 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/06 for tuberculosis
• CPC Class Codes: A61P 37/04 Immunostimulants
• 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 9/02 Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
• 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: C07D 213/26 Radicals substituted by halogen atoms or nitro radicals
• CPC Class Codes: C07D 213/70 Sulfur atoms
• CPC Class Codes: C07D 213/74 Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 213/75 Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 237/20 : Nitrogen atoms nitro radicals C07D237/12
• CPC Class Codes: C07D 241/18 : Oxygen or sulfur atoms
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: C07D 491/04 : Ortho-condensed systems

Abstract

The present invention relates to compounds of Formula (I)

that are p-38 MAP kinase inhibitors, pharmaceutical compositions containing them, methods for their use, and methods for preparing these compounds.

Claims

1. A compound selected from the group of compounds represented by Formula (I):

wherein;

R¹ is heteroaryl;

------ represents a bond between B and CR¹;

B is carbon;

R² is aryl or heteroaryl; and

Q is —

O—

, or —

S—

wherein;

R⁴ is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, acyl, aralkyl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, —

OR⁵ (where R⁵ is hydrogen, alkyl, heteroalkyl or heterocyclylalkyl), —

SO₂R″

(where R″

is alkyl, amino, monosubstituted amino or disubstituted amino), —

CONR′

R″

(where R′ and

R″

independently represent hydrogen, alkyl or heteroalkyl), -(alkylene)-Z or -(alkylene)-CO-(alkylene)-Z wherein;

Z is cyano;

—

COOR⁷ where R⁷ is hydrogen or alkyl;

—

CONR⁸R⁹ where R⁸ is hydrogen or alkyl, R⁹ is alkoxy or -(alkylene)-COOR⁷, or R⁸ and R⁹ together with the nitrogen atom to which they are attached form a heterocycle;

—

C(═

NR¹⁰)(NR¹¹R¹²) where R¹⁰, R¹¹ and R¹² independently represent hydrogen or alkyl, or R¹⁰ and R¹¹ together are —

(CH₂)_n—

where n is 2 or 3 and R¹² is hydrogen or alkyl;

or

—

COR¹³ where R13 is alkyl, heteroalkyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; and

 

is a group represented by formula (S);

 

where;

R⁶ is hydrogen, alkyl, heteroalkyl, heterocyclylalkyl, halo, cyano, nitro, amino, monosubstituted amino, disubstituted amino, —

COOR¹⁴, -(alkylene)-COOR¹⁴ (where R¹⁴ is hydrogen or alkyl), —

CONR¹⁵R¹⁶ (where R¹⁵ and R¹⁶ independently represent hydrogen or alkyl, or R¹⁵ and R¹⁶ together with the nitrogen atom to which they are attached form a heterocycle), —

S(O)_nR¹⁷ (where n is an integer from 0 to 2 and R¹⁷ is alkyl, amino, monosubstituted amino or disubstituted amino), —

OR¹⁸ (where R¹⁸ is hydrogen, alkyl, heteroalkyl or heterocyclylalkyl), —

NRC(O)R″

[where R is hydrogen, alkyl or hydroxyalkyl and R″

is hydrogen, alkyl, cycloalkyl or -(alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino, heterocyclyl or —

S(O)_nR′

(where n is 0 to 2 and R′

is alkyl)], —

NRSO₂R″

[where R is hydrogen or alkyl and R″

is alkyl or -(alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino or —

S(O)_nR′

(where n is 0 to 2 and R′

is alkyl)]; and

R³ is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylthio, aralkyl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, halo, cyano, nitro, amino, monosubstituted amino, disubstituted amino, acylamino, sulfonylamino, —

OR¹⁹ (where R¹⁹ is hydrogen, alkyl, heteroalkyl;

or heterocyclylalkyl), —

COOR²⁰ (where R²⁰ is hydrogen or alkyl), —

CONR²¹R²² (where R²¹ and R²² independently represent hydrogen, alkyl or heteroalkyl, or R²¹ and R²² together with the nitrogen atom to which they are attached form a heterocycle), —

S(O)_nR²³ (where n is an integer from 0 to 2 and R²³ is alkyl, heteroalkyl, amino, monosubstituted amino or disubstituted amino), -(alkylene)-Z″

or -(alkylene)-CO(alkylene)-Z″

wherein;

Z″

is

cyano;

—

COOR²⁴ where R²⁴ is hydrogen or alkyl;

—

CONR²⁵R²⁶ where R²⁵ and R²⁶ independently represent hydrogen or alkyl, or R²⁵ and R²⁶ together with the nitrogen atom to which they are attached form a heterocycle;

—

C(═

NR²⁷)(NR²⁸R²⁹) where R²⁷, R²⁸ and R²⁹ independently represent hydrogen or alkyl, or R²⁷ and R²⁸ together are —

(CH₂)_n—

where n is 2 or 3 and R²⁹ is hydrogen or alkyl;

or

—

COR³⁰ where R³⁰ is alkyl, heteroalkyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; and

their pharmaceutically acceptable salts, prodrugs, individual isomers, and mixtures of isomers, provided that both R³ and R⁶ are not either amino, monosubstituted amino or disubstituted amino.

2. The compound of claim 1 wherein

is a group represented by formula (S).

3. The compound of claim 2 wherein, R² is an aryl ring.

4. The compound of claim 3 wherein:

 

is a group represented by formula (S);

Q is —

O—

; and

R⁶ is hydrogen, alkyl, alkoxy or halo.

5. The compound of claim 4 wherein, R³ is at the 7-position and is hydrogen, alkyl, cycloalkyl, heteroalkyl, heterocyclylalkyl, halo, —

OR¹⁹ (where R¹⁹ is hydrogen, alkyl, heteroalkyl or heterocyclylalkyl), -(alkylene)-Z″

or -(alkylene)-CO-(alkylene)-Z″

wherein;

Z″

is

—

COOR²⁴ where R²⁴ is alkyl;

—

CONR²⁵R²⁶ where R²⁵ and R²⁶ independently represent hydrogen or alkyl or R²⁵ and R²⁶ together with the nitrogen atom to which they are attached form a heterocycle;

or

—

C(═

NR²⁷)(NR²⁸R²⁹) where R²⁷, R²⁸ and R²⁹ independently represent hydrogen or alkyl, or R²⁷ and R²⁸ together are —

(CH₂)_n—

where n is 2 or 3 and R²⁹ is hydrogen or alkyl.

10. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable excipient.

11. A method of treatment of a disease in a mammal treatable by administration of a p38 MAP kinase inhibitor, comprising administration to the mammal a therapeutically effective amount of a compound of claim 1.

12. The method of claim 11, wherein the disease is an inflammatory disease.

6. The compound of claim 15 wherein, R¹ is a 4-pyridyl or 4-pyrimidinyl ring optionally substituted with a substituent selected from heteroalkyl, —

NRR′

(where R and R′

are, independently of each other, hydrogen, alkyl, heterocyclylalkyl or heteroalkyl), —

NR^aC(O) R^{b [where Ra} is hydrogen or alkyl and R^b is hydrogen;

alkyl or -(alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino, cycloalkyl, heterocyclyl, optionally substituted phenyl, imidazole or —

S(O)_nR′

(where n is 0 to 2 and R′

is alkyl)], —

NRSO₂R″

[where R is hydrogen or alkyl and R″

is alkyl or -(alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino or —

S(O)_nR′

(where n is 0 to 2 and R′

is alkyl)] or —

OR (where R is alkyl or heteroalkyl).

7. The compound of claim 6 wherein:

R² is a phenyl ring optionally substituted with one or two substituents selected from alkyl, halo or —

OR where R is alkyl;

R³ is hydrogen, methyl, ethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl, 3-methylamino-propyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 2-(morpholin-4-yl)ethyl, 3-(morpholin-4-yl)propyl, 2-(piperidin-1-yl)ethyl, 3-(piperidin-1-yl)propyl, 2-(piperazin-1-yl)ethyl, 3-(piperazin-1-yl)propyl, hydroxy, methoxy, 2-hydroxyethoxy, 3-hydroxy-propoxy, 2-methylaminoethoxy, 3-methylaminopropoxy, 2-dimethylaminoethoxy, 3-dimethylaminopropoxy, 2-(morpholin-4-yl)ethoxy, 3-(morpholin-4-yl)propoxy, 2-(piperidin-1-yl)ethoxy, 3-(piperidin-1-yl)propoxy, 2-(piperazin-1-yl)ethoxy or 3-(piperazin-1-yl)propoxy; and

R⁶ is hydrogen, methyl, methoxy, fluoro or chloro.

8. The compound of claim 7 wherein:

R¹ is a 4-pyridyl ring optionally substituted with a substituent selected from amino, methylamino, dimethylamino, acetylamino, methylsulfonylamino, 2-hydroxyethyl, 2-hydroxyethylamino, 3-hydroxypropylamino, 2-aminoethylamino, 2-aminoethyl, 3-aminopropyl, 2-dimethylaminoethyl, methoxy, 2-hydroxyethoxy or 2-dimethylaminoethoxy; and

R³ and R⁶ are hydrogen.

9. The compound of claim 8 wherein R² is a phenyl ring substituted with one or two substituents selected from methyl, fluoro, chloro or methoxy.