Inhibitors of p38-αkinase

• US 6,410,540 B1
• Filed: 08/27/1999
• Issued: 06/25/2002
• Est. Priority Date: 08/28/1998
• Status: Expired due to Term

• Current Assignee: Scios, Inc. (Johnson & Johnson)
• Original Assignee: Scios, Inc. (Johnson & Johnson)
• Inventors: Chakravarty, Sarvajit, Dugar, Sundeep, Luedtke, Gregory R., Liu, David Y., Goehring, R. Richard, Lewicki, John A., Schreiner, George F., Mavunkel, Babu J.
• Primary Examiner(s): Jarvis, William R. A.
• Application Number:
  US09/385,494
• Time in Patent Office: 1,033 Days
• Field of Search: 514/330, 514/252.13, 514/254.09
• US Class Current: 514/252.13
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/426 1,3-Thiazoles
• CPC Class Codes: A61K 31/4365 the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/4535 containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/4545 containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• CPC Class Codes: A61K 31/4709 Non-condensed quinolines and containing further heterocyclic rings
• CPC Class Codes: A61K 31/4725 containing further heterocyclic rings
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/4965 Non-condensed pyrazines
• CPC Class Codes: A61K 31/497 containing further heterocyclic rings
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/522 having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• 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 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 17/06 : Antipsoriatics
• CPC Class Codes: A61P 19/02 : for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 27/00 : Drugs for disorders of the senses
• 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 3/12 : for electrolyte homeostasis
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• 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: 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

The invention is directed to methods to treat conditions mediated by p38-αkinase using compounds of the formula

and the pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof,

wherein

Z is N or CR¹, R¹ is a noninterfering substituent,

each of X¹ and X² is a linker,

Ar¹ and Ar² are identical or different, and represent optionally substituted C1-C20 hydrocarbyl residues wherein at least one of Ar¹ and Ar² is an optionally substituted aryl group, with the proviso that when X² is CH₂ or an isostere thereof, X¹ is CO or an isostere thereof, and Ar² is optionally substituted phenyl, Ar¹ is other than an optionally substituted indolyl, benzimidazolyl or benzotriazolyl substituent, and wherein said optionally substituted phenyl is not an optionally substituted indolyl, benzimidazolyl, or benzotriazolyl,

Y is a noninterfering substituent, wherein n is an integer from 0-4, and

wherein m is an integer from 0-4 and 1 is an integer from 0-3.

Claims

1. A method to treat a condition mediated by p38α

kinase which method comprises administering to a subject in need of such treatment a compound of the formula;

and the pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof,

wherein

Z is N or CR¹,

wherein R¹ is selected from the group consisting of optionally substituted alkyl, alkoxy, aryl, arylalkyl, aryloxy, heteroaryl, amino, ureayl, carbamate, polyhaloalkoxy, halogen, acyl, carboxy, and hydroxy,

each of X¹ and X² is a linker,

wherein each said linker is independently saturated or unsaturated alkylene optionally containing 1-4 carbonyl, 1-4 SO₂, and/or 1-3 heteroatoms, including a linker which is itself CO, SO₂, SO or is itself a heteroatom, and said alkylene or suitable heteroatom optionally substituted with a substituent selected from the group consisting of halo, alkyl, alkoxy, cycloalkyl, aryl, aryloxy, arylalkyl, haloalkyl, polyhaloalkyl, haloalkoxy, polyhaloalkoxy, cycloheteroalkyl, cycloheteroalkylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, arylthio, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, acyl, aminocarbonyl, arylcarbonyl, heteroarylcarbonyl, cyano, carboxy, hydroxy, tetrazolyl, imidazole, oxazole, triazole, and —

SOR wherein R is hydroxy, alkyl, aryl, alkoxy, aryloxy, cycloalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkoxy and cycloheteroalkylalkoxy,

Ar¹ and Ar² are identical or different, and represent optionally substituted aryl groups containing one or more rings optionally including one or more heteroatoms, selected from the group of O, N and S;

wherein Ar¹ and Ar² do not comprise an optionally substituted indolyl substituent; and

with the proviso that when X² is CH₂ or an isostere thereof, X¹ is CO or an isostere thereof, and Ar² is optionally substituted phenyl, Ar¹ is other than benzimidazolyl or benzotriazolyl;

wherein Y is selected from the group consisting of optionally substituted alkyl, alkoxy, cycloalkyl, cycloheteroalkyl , aryl, cycloheteroalkyl, heteroaryl, halogen, alkylaminocarbonyl, arlyaminocarbonyl, heteroarylaminocarbonyl, acyl, carboxy, hydroxy, aminocarbonyl, arylcarbonyl, heteroarylcarbonyl, cyano, amino, and alkylamino,

wherein n is an integer from 0-4, and

wherein m is an integer from 0-4 and 1 is an integer from 0-3.

2. The method defined in claim 1, wherein

when Z is N, X² is the same as X¹, or X² is — O—

, —

O[C(Rx)₂]_r—

wherein Rx is optionally substituted alkyl, alkenyl or alkynyl and r is an integer from 1 to 4, —

NR²CO—

, —

SO₂NR₂—

, —

NR²—

, —

S—

, —

SO—

, SO₂, wherein R² is H, optionally substituted alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, carboxy, or acyl;

or

wherein when Z is CR¹, X² is X¹ or is —

O[C(Rx)₂]_r wherein Rx is —

SO₂—

.

3. The method defined in claim 1 wherein said alkylene group is C1-C4.

4. The method defined in claim 1,

wherein said haloalkyl or polyhaloalkyl group as a substituent on said linker is CF₃ or CF₃CH₂;

and

wherein said haloalkoxy or polyhaloalkoxy group as a substituent on said linker is CF₃O or CF₃CH₂O.

5. The method defined in claim 1, wherein at least one said aryl group has 6 to 12 carbon atoms and 0 to 3 heteroatoms.

6. The method defined in claim 5, wherein at least one said aryl group has 6 to 8 carbon atoms and 1 or 2 heteroatoms.

7. The method defined in claim 1, wherein at least one said aryl group is phenyl or residues of optionally benzo-fused heterocycles containing up to 3 heteroatoms selected from the group consisting of S, N and O.

8. The method defined in claim 1, wherein at least one said aryl group is a saturated or unsaturated 5- to 7-membered heterocycle.

9. The method defined in claim 8 wherein at least one said aryl group is a saturated or unsaturated 5- to 6-membered heterocycle.

10. The method defined in claim 1, wherein at least one said aryl group is selected from the group consisting of isoquinolyl, quinolyl, benzimidazolyl, benzotriazolyl, benzothiazolyl, benzofuranyl, pyridyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, morpholinyl and piperidyl.

21. The method defined in claim 1 further comprising administering said compound and an additional therapeutic agent.

22. The method defined in claim 1 wherein the compound is at least one compound selected from the group consisting of:

11. A method to treat a condition mediated by p38α

kinase which method comprises administering to a subject in need of such treatment a compound of the formula;

and the pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof,

wherein Ar¹ is optionally substituted furanyl, thiophenyl, phenyl system containing 0, 1 or 2 N as heterocyclic atoms, or naphthyl system containing 0, 1, 2 or 3 N as heterocyclic atoms,

X¹ is CO or an isostere thereof;

Y is optionally substituted alkyl (1-6C), optionally substituted aryl (6-10C), or optionally substituted arylalkyl (7-11C);

n is 0-1;

Z is N or CH;

X² is CH₂ or an isostere thereof; and

Ph is optionally substituted phenyl.

12. The method of claim 11 wherein Ph is unsubstituted, or

wherein n is 0, or

wherein Z is CH.

13. The method of claim 12 wherein n is 0 and Z is CH.

14. The method of claim 11 wherein Ar¹ is optionally substituted phenyl.

15. The method of claim 11 wherein Ar¹X¹ is benzoyl, 4-methoxybenzoyl, 4-cyanobenzoyl, 4-phenylbenzoyl, 3-methoxybenzoyl, 3,5-dimethoxybenzoyl, 2-chlorobenzoyl, 2-bromobenzoyl, 2-iodobenzoyl, 2-methoxybenzoyl, 2-methylbenzoyl, 2-(2-carbomethoxy ethen-1-yl) benzoyl, 2-naphthoyl, 1-naphthoyl, 2-furanoyl, 2-thiophenoyl, 2-dimethylaminobenzoyl, 3-dimethylaminobenzoyl, 4-dimethylaminobenzoyl, 2-pyridoyl, 3-pyridoyl, 4-pyridoyl, 3,4,5-trimethoxybenzoyl, 2-acetamidobenzoyl, 3-acetamidobenzoyl, 4-acetamidobenzoyl, 4-formamidobenzoyl, 2-aminobenzoyl, 3-aminobenzoyl, 4-aminobenzoyl, 4,5-dimethoxybenzoyl, 2,4-dimethoxybenzoyl, 2-hydroxybenzoyl, 2-benzoxybenzoyl, 3,5-bis-trifluoromethylbenzoyl, 2,6-dimethoxybenzoyl, 2-methylaminobenzoyl, 3-methylaminobenzoyl, 4-methylaminobenzoyl, 2-hydroxy-4-aminobenzoyl, 2-chloro-4-aminobenzoyl, 2-chloro-4-methylaminobenzoyl, 2-chloro-4-dimethylaminobenzoyl, 2-methoxy-4-nitrobenzoyl, 2-methoxy-4-aminobenzoyl, 4-guanidinobenzoyl, phenylsulfonyl, 4-amino-3-pyridoyl, 2-aminobenzoyl, 2-methoxy-4-hydroxybenzoyl, 2-methoxy-4-benzyloxybenzoyl, or 2-methoxy-4-methoxybenzoyl.

16. The method of claim 11 wherein formula (1) is 1-benzoyl-4-benzyl piperidine, 1-(3-methoxybenzoyl)-4-benzyl piperidine, 1-(4-phenylbenzoyl)-4-benzyl piperidine, 1-(2-chlorobenzoyl-4-benzyl piperidine, 1-(2-bromobenzoyl)-4-benzyl piperidine, 1-(2-iodobenzoyl)-4-benzyl piperidine, 1-(2-methoxybenzoyl)-4-benzyl piperidine, 1-(2-methylbenzoyl)-4-benzyl piperidine, 1-(2-naphthoyl)-4-benzyl piperidine, 1-(4-dimethylaminobenzoyl)-4-benzyl piperidine, 1-(4-acetamidobenzoyl)-4-benzyl piperidine, 1-(4-formamidobenzoyl)-4-benzyl piperidine, 1-(4-aminobenzoyl)-4-benzyl piperidine, 1-(2,4-dimethoxybenzoyl)-4-benzyl piperidine, 1-(2,6-dimethoxybenzoyl)-4-benzyl piperidine, 1-(2-chloro-4-aminobenzoyl)-4-benzyl piperidine, 1-(2-chloro-4-methylaminobenzoyl)-4-benzyl piperidine, 1-(2-chloro-4-dimethylaminobenzoyl)-4-benzyl piperidine, cis-1-(2-bromobenzoyl)-3-methyl-4-benzyl piperidine, 1-(2-methoxy-4-hydroxybenzoyl)-4-benzylpiperidine, 1-(2-methoxy-4-methoxybenzoyl)-4-benzylpiperidine, 1-(2-methoxy-4-benzyloxybenzoyl)-4-benzylpiperidine, or 1-(2-methoxy-4-methoxybenzoyl)-4-(4-fluorobenzyl)piperidine.

17. The method of claim 11 wherein said condition is characterized by a proinflammation response.

18. The method of claim 17 wherein said condition characterized by inflammation is acute respiratory distress syndrome, asthma, chronic obstructive pulmonary disease, uveitis, acute renal failure, head trauma, ischemic/reperfusion injury, multiple sclerosis, IBD, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, other arthritic conditions, sepsis, septic shock, endotoxic shock, Gram-negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, stroke, reperfusion injury, CNS injury, psoriasis, restenosis, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcosis, a bone resorption disease, graft-versus-host reaction, Crohn'"'"'s Disease, ulcerative colitis, or pyresis.

19. The method of claim 11 wherein said condition is a heart condition associated with cardiac failure.

20. The method of claim 19 wherein said chronic heart condition is congestive heart failure, cardiomyopathy or myocarditis.

23. A pharmaceutical composition for treating conditions characterized by enhanced p38-α

activity which composition comprises

a therapeutically effective amount of a compound of the formula

 

and the pharmaceutically acceptable salts thereof, or a pharmaceutical composition thereof,

wherein

Z is N or CR¹,

wherein R¹ is selected from the group consisting of optionally substituted alkyl, alkoxy, aryl, arylalkyl, aryloxy, heteroaryl, amino, ureayl, carbamate, polyhaloalkoxy, halogen, acyl, carboxy, and hydroxy,

each of X¹ and X² is a linker,

wherein each said linker is independently saturated or unsaturated alkylene optionally containing 1-4 carbonyl, 1-4 SO₂, and/or 1-3 heteroatoms, including a linker which is itself CO, SO₂, SO or is itself a heteroatom, and said alkylene or suitable heteroatom optionally substituted with a substituent selected from the group consisting of halo, alkyl, alkoxy, cycloalkyl, aryl, aryloxy, arylalkyl, haloalkyl, polyhaloalkyl, haloalkoxy, polyhaloalkoxy, cycloheteroalkyl, cycloheteroalkylalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, arylthio, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, acyl, aminocarbonyl, arylcarbonyl, heteroarylcarbonyl, cyano, carboxy, hydroxy, tetrazolyl, imidazole, oxazole, triazole, and —

SOR wherein R is hydroxy, alkyl, aryl, alkoxy, aryloxy, cycloalkyl, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylalkoxy or cycloheteroalkylalkoxy,

Ar¹ and Ar² are identical or different, and represent optionally substituted aryl groups containing one or more rings optionally including one or more heteroatoms, selected from the group of O, N and S;

wherein Ar¹ and Ar² do not comprise an optionally substituted indolyl substituent, and

with the proviso that when X² is CH₂ or an isostere thereof, X¹ is CO or an isostere thereof, and Ar² is optionally substituted phenyl, Ar¹ is other than benzimidazolyl or benzotriazolyl;

wherein Y is selected from the group consisting of optionally substituted alkyl, alkoxy, cycloalkyl, cycloheteroalkyl , aryl, cycloheteroalkyl, heteroaryl, halogen, alkylaminocarbonyl, arlyaminocarbonyl, heteroarylaminocarbonyl, acyl, carboxy, hydroxy, aminocarbonyl, arylcarbonyl, heteroarylcarbonyl, cyano, amino, and alkylamino,

wherein n is an integer from 0-4, and

wherein m is an integer from 0-4 and 1 is an integer from 0-3.

24. The composition of claim 23 which further contains an additional therapeutic agent.

25. The composition of claim 24 wherein said additional therapeutic agent is a corticosteroid, a monoclonal antibody, or an inhibitor of cell division.