Compounds and methods to treat cardiac failure and other disorders

• US 6,448,257 B1
• Filed: 03/24/2000
• Issued: 09/10/2002
• Est. Priority Date: 05/22/1998
• Status: Expired due to Term

• Current Assignee: Scios, Inc. (Johnson & Johnson)
• Original Assignee: Scios, Inc. (Johnson & Johnson)
• Inventors: Liu, David Y., Lewicki, John A., Schreiner, George F., Mavunkel, Babu J.
• Primary Examiner(s): CHANG, CELIA C
• Application Number:
  US09/535,316
• Time in Patent Office: 900 Days
• Field of Search: 514/292, 546/84
• US Class Current: 514/292
• CPC Class Codes: C07D 209/08 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 209/24 with an alkyl or cycloalkyl radical attached to the ring nitrogen atom
• CPC Class Codes: C07D 235/06 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• 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 471/04 Ortho-condensed systems

Abstract

Compounds of the formula:

wherein the dotted line represents an optional bond;

and the pharmaceutically acceptable salts thereof,

wherein X¹ is an alkyl bridge optionally containing an O, S, or N heteroatom that forms an aliphatic 5-7 membered ring and is optionally substituted by one or more of halo, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR, or NROCR where R is H or alkyl (1-6C), or by one or more CN or═O, or by one or more aliphatic or aromatic 5- or 6-membered rings optionally containing 1-2 heteroatoms;

R¹ is

 wherein

X² is CO or an isostere thereof;

m is 0 or 1;

Y is optionally substituted alkyl, optionally substituted aryl, or optionally substituted arylalkyl or two Y taken together may form an alkylene (2-3C) bridge;

n is 0-4;

Z¹ is CH or N;

X³ is CH or CHR where R is H or alkyl (1-6C), or an isostere thereof; and

Ar, R² and R³ are as defined in the specification. These compounds are selective inhibitors of p38α kinase.

Claims

1. The compound of the formula:

or having the structure of formula (A) or (B) wherein the positions on the benzo moiety of the tricyclic nucleus occupied by R³ and the substituent

are reversed,

wherein R² is H, or is alkyl (1-6C) or aryl, each of said alkyl or aryl optionally including one heteroatom which is O, S or N, and optionally substituted by one or more substituents selected from the group consisting of halo, CN,═

O, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR, and NROCR where R is H or alkyl (1-6C), and wherein when R² is alkyl said alkyl may be substituted by one or more substituents selected from the group consisting of piperazinyl, pyridinyl, piperidinyl and phenyl or wherein R² is —

(CO) O NR₂ wherein n is an integer of 0-6 and R is H or alkyl (1-6C);

R³ is H, halo, NO₂, alkyl (1-6C), alkenyl (1-6C), alkynyl (1-6C), CN, OR, SR, NR₂, RCO, COOR, CONR₂, OOCR, or NROCR where R is H alkyl (1-6C); and

each X⁴ is independently halo, alkyl (1-6C), OR, or NR₂, wherein R is H or alkyl (1-6C) and p is 0, 1, 2 or 3.

2. The compound of claim 1 wherein p is 0 or p is 1 or 2 and each X⁴ is halo or OR where R is alkyl (1-3C).

3. The compound of claim 1 wherein R² is H.

4. The compound of claim 1 wherein R³ is H, halo, or OR, wherein R is alkyl (1-6C).

5. The compound of claim 4 wherein R³ is methoxy.

6. The compound of claim 3 where R³ is H.

7. The compound of claim 1 wherein the position of the substituent

and the substituent illustrated as R³ are reversed.

8. The compound of claim 1 wherein the substituents R³ and

in formulas (A) and (B) are in the positions as shown.

9. The compound of claim 1 wherein R² is a polar group.

10. The compound of claim 1 wherein R² is —

(CO) O—

(CH₂)_n NR₂ wherein in is 0-6 and R is H or alkyl (1-6C).

11. The compound of claim 1 which is

12. A pharmaceutical composition which comprises an effective amount of the compound of claim 1 along with at least one pharmaceutically acceptable excipient.

13. A method to treat a condition characterized by a proinflammation response which method comprises administering to a subject in need of such treatment an effective amount of the compound of claim 1 or a pharmaceutical composition thereof.

14. The method of claim 13 wherein said condition characterized by inflammation is acute respiratory distress syndrome, asthma, chronic obstructive pulmonary disease, uveitis, IBD, acute renal failure, head trauma, ischemic/reperfusion injury, osteoarthritis, rheumatoid arthritis or psoriasis.

15. A method to treat a heart condition associated with cardiac failure which method comprises administering to a subject in need of such treatment an effective amount of the compound of claim 1 or a pharmaceutical composition thereof.

16. The method of claim 15 wherein said heart condition is congestive heart failure, cardiomyopathy, restenosis, or myocarditis.

17. The method of claim 13 wherein said condition characterized by inflammation is vasculitis, atherosclerosis, rheumatoid spondylitis, gouty arthritis, multiple sclerosis, silicosis, pulmonary sarcosis, sepsis, septic shock, endotoxic shock, toxic shock syndrome, brain failure characterized by ischemia and reperfusion injury, CNS injuries, inflammatory eye conditions, glomerulonephritis, inflammatory bowel diseases, graft vs. host disease, bone resorption diseases, type II diabetes, pyresis, cachexia, viral diseases, cerebral malaria, tumor metastases, and acute pain or is caused from surgical procedures.