LFA-1 antagonist compounds

• US 6,667,318 B2
• Filed: 11/26/2001
• Issued: 12/23/2003
• Est. Priority Date: 11/28/2000
• Status: Expired due to Fees

• Current Assignee: Genentech, Inc. (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: Burdick, Daniel J., Marsters, James C., Reynolds, Mark E., Stanley, Mark S., Oare, David, Gadek, Thomas R.
• Primary Examiner(s): AULAKH, CHARANJIT
• Application Number:
  US09/994,546
• Publication Number:
  US 20020119994A1
• Time in Patent Office: 757 Days
• Field of Search: 514/326, 514/365, 514/369, 514/422, 546/214, 548/182, 548/200, 548/517, 549/473
• US Class Current: 514/326
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• 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 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• 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 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: C07D 207/16 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 277/06 with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 307/54 Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links

Abstract

The invention relates to novel compounds having formula (I)

wherein Cy, X, Y, L and R_1-6 are as defined herein. The compounds bind CD11/CD18 adhesion receptors such as Lymphocyte Function-associated Antigen-1 (LFA-1) and are therefore useful for treating disorders mediated by LFA-1 such as inflammation and autoimmune diseases.

Claims

1. A compound of formula (I)

wherein

Cy is a non-aromatic heterocycle optionally substituted with hydroxyl, mercapto, thioalkyl, halogen, oxo, thio, amino, aminoalkyl, amidine, guanidine, nitro, alkyl, alkoxy or acyl;

X is —

CH₂—

NR₆—

[divalent hydrocarbon chain]—

wherein said divalent hydrocarbon chain is optionally substituted with hydroxyl, mercapto, halogen, amino, aminoalkyl, nitro, oxo or thio;

Y is a heterocycle optionally substituted with hydroxyl, mercapto, halogen, oxo, thio, thioalkyl, amino, aminoalkyl, carbocycle or heterocycle ring, hydrocarbon, a halo-substituted hydrocarbon, amino, amidine, guanidine, cyano, nitro, alkoxy or acyl;

L is —

[divalent hydrocarbon chain]—

NR₆—

CH₂—

wherein said divalent hydrocarbon chain is optionally substituted with hydroxyl, halogen, oxo or thio and R₆ is H or alkyl;

R₁ is H, OH, amino, O-carbocycle or alkoxy optionally substituted with amino, a carbocycle or heterocycle;

R_2-5 are independently H, hydroxyl, mercapto, halogen, cyano, amino, amidine, guanidine, nitro or alkoxy;

R₆ is H or a hydrocarbon chain optionally substituted with a carbocycle or a heterocycle; and

salts, solvates and hydrates thereof.

2. A compound according to claim 1, wherein Cy is a 5- or 6-member non-aromatic heterocycle optionally substituted with hydroxyl, mercapto, thioalkyl halogen, oxo, thio, amino, aminoalkyl, amidine, guanidine, nitro, alkyl, alkoxy or acyl.

3. A compound according to claim 2, wherein said heterocycle comprises one or two heteroatoms and is optionally substituted with hydroxyl, oxo, mercapto, thio, alkyl or alkanoyl.

4. A compound according to claim 3, wherein said heterocycle is selected from the group consisting of piperidine, piperazine, morpholine, tetrahydrofuran, tetrahydrothiophene, oxazolidine, cyclopropa-pyrrolidine and thiazolidine optionally substituted with hydroxy, oxo, mercapto, thio, alkyl or alkanoyl.

5. A compound according to claim 4, wherein said heterocycle is selected from the group consisting of piperidine, piperazine, morpholine, tetrahydrofuran, tetrahydrothiophene, oxazolidine, thiazolidine optionally substituted with hydroxy, oxo, mercapto, thio, alkyl or alkanoyl.

6. A compound according to claim 1, wherein X is —

CH₂—

NR₆—

C(O)—

wherein the carbonyl —

C(O)—

portion thereof is covalently bound to Cy and R₆ is H or alkyl.

7. A compound according to claim 1, wherein Y is a heterocycle optionally substituted with hydroxyl or halogen.

8. A compound according to claim 7, wherein Y is furan-2-yl or thiophene-2-yl.

9. A compound according to claim 1, wherein L is —

CH═

CH—

C(O)—

NR₆—

CH₂—

, or —

C(O)—

NR₆—

CH₂—

;

wherein each R₆ is independently H or alkyl.

10. A compound according to claim 9, wherein R₁ is H, OH, amino, O-carbocycle or alkoxy optionally substituted with a carbocycle.

11. A compound according to claim 10, wherein R₁ is H or C_1-4 alkyloxy.

12. A compound according to claim 1, wherein at least one of R₂ and R₃ is halogen and the other is H or halogen.

13. A compound according to claim 12, wherein R₂ and R₃ are both Cl.

14. A compound according to claim 13, wherein R₄ and R₅ are both H.

15. A pharmaceutical composition comprising a compound according to claim 1 with a pharmaceutically acceptable adjuvant, diluent or carrier.

16. A method of inhibiting binding of a LFA-1 to a protein ligand comprising contacting LFA-1 with a compound of claim 1.

17. A method of treating a disease or condition mediated by LFA-1 in a mammal comprising administering to said mammal an effective amount of a compound according to claim 1.

18. A method according to claim 17, wherein said disease or condition is arthritis, psoriasis, organ transplant rejection, asthma, and inflammatory bowel disease.

19. A method according to claim 17, wherein said disease or condition is an inflammatory disease or condition.

20. A compound of formula (Ib)

wherein

Cy is a non-aromatic heterocycle optionally substituted with hydroxyl, mercapto, thioalkyl, halogen, oxo, thio, amino, aminoalkyl, amidine, guanidine, nitro, alkyl, alkoxy or acyl;

Y is a heterocycle optionally substituted with hydroxyl, mercapto, halogen, oxo, thio, thioalkyl, amino, aminoalkyl, carbocycle or heterocycle ring, hydrocarbon, a halo-substituted hydrocarbon, amino, amidine, guanidine, cyano, nitro, alkoxy or acyl;

L is a divalent hydrocarbon chain optionally substituted with hydroxyl, halogen, oxo or thio;

R₁ is H, OH, amino, O-carbocycle or alkoxy optionally substituted with amino, a carbocycle or heterocycle;

R₂ and R₃ are independently H, hydroxyl, mercapto, halogen, cyano, amino, amidine, guanidine, nitro or alkoxy;

R₆ is H or a hydrocarbon chain optionally substituted with a carbocycle or a heterocycle; and

salts, solvates and hydrates thereof.

21. A compound of formula (If)

wherein

Cy is a non-aromatic heterocycle optionally substituted with hydroxyl, mercapto, thioalkyl, halogen, oxo, thio, amino, aminoalkyl, amidine, guanidine, nitro, alkyl, alkoxy or acyl;

Y is a heterocycle optionally substituted with hydroxyl, mercapto, halogen, oxo, thio, thioalkyl, amino, aminoalkyl, carbocycle or heterocycle ring, hydrocarbon, a halo-substituted hydrocarbon, amino, amidine, guanidine, cyano, nitro, alkoxy or acyl;

R₁ is H, OH, amino, O-carbocycle or alkoxy optionally substituted with amino, a carbocycle or heterocycle;

R₂ and R₃ are independently H, hydroxyl, mercapto, halogen, cyano, amino, amidine, guanidine, nitro or alkoxy;

R₆ is H or a hydrocarbon chain optionally substituted with a carbocycle or a heterocycle; and

salts, solvates and hydrates thereof.