Patent
VLA-4 antagonists
| العنوان: | VLA-4 antagonists |
|---|---|
| Patent Number: | 7,514,409 |
| تاريخ النشر: | April 07, 2009 |
| Appl. No: | 10/591820 |
| Application Filed: | March 07, 2005 |
| مستخلص: | Compounds of Formula I are antagonists of VLA-4, and as such are useful in the inhibition or prevention of cell adhesion and cell-adhesion mediated pathologies. These compounds may be formulated into pharmaceutical compositions and are suitable for use in the treatment of inflammatory bowel disease including ulcerative colitis and Crohn's disease, multiple sclerosis, asthma, and rheumatoid arthritis. |
| Inventors: | Hagmann, William K. (Westfield, NJ, US); Lin, Linus S. (Westfield, NJ, US); Liu, Ping (Westfield, NJ, US); Mumford, Richard A. (Red Bank, NJ, US); Reger, Thomas S. (San Diego, CA, US); Smith, Nicholas D. (San Diego, CA, US); Stock, Nicholas S. (San Diego, CA, US); Zunic, Jasmine (San Diego, CA, US) |
| Assignees: | Merck & Co., Inc. (Rahway, NJ, US) |
| Claim: | 1. A compound of formula I: [chemical expression included] or a pharmaceutically acceptable salt thereof, wherein: A is N or N + —O − ; X and Y are independently selected from halogen, C 1-3 alkyl, and C 1-3 alkoxy; R 1 is selected from (1) hydrogen, (2) C 1-10 alkyl, (3) —(C 1-10 alkyl)-aryl, (4) —(C 1-10 alkyl)-O—C 1-10 alkyl, (5) —(C 1-10 alkyl)-OC(O)—C 1-10 alkyl, (6) —(C 1-10 alkyl)-OC(O)-aryl, (7) —(C 1-10 alkyl)-OC(O)O—C 1-10 alkyl and (8) —(C 1-10 alkyl)N + (C 1-3 alkyl) 3 ; wherein alkyl is optionally substituted with one to three substituents independently selected from R a , and aryl is optionally substituted with one to three substituents independently selected from R b ; R 2 is hydrogen or methyl; R 3 and R 4 are independently selected from (1) hydrogen, (2) —NR d R e , (3) —NR d S(O) m R e , (4) —NR d C(O)R e , (5) —NR d C(O)OR e , and (6) —NR d C(O)NR d R e , with the proviso that R 3 and R 4 are not both hydrogen; R a is selected from (1) —OR d , (2) —NR d S(O) m R e , (3) —NO 2 , (4) halogen, (5) —S(O) m R d , (6) —SR d , (7) —S(O) 2 OR d , (8) —S(O) m NR d R e , (9) —NR d R e , (10) —O(CR f R g) n NR d R e , (11) —C(O)R d , (12) —CO 2 R d , (13) —CO 2 (CR f R g) n CONR d R e , (14) —OC(O)R d , (15) —CN, (16) —C(O)NR d R e , (17) —NR d C(O)R e , (18) —OC(O)NR d R e , (19) —NR d C(O)OR e , (20) —NR d C(O)NR d R e , (21) —CR d (N—OR e), (22) CF 3 , (23) —OCF 3 , (24) C 3-8 cycloalkyl, and (25) heterocyclyl; wherein cycloalkyl and heterocyclyl are optionally substituted with one to three groups independently selected from R c ; R b is selected from (1) a group selected from R a , (2) C 1-10 alkyl, (3) C 2-10 alkenyl (4) C 2-10 alkynyl, (5) aryl, and (6) —(C 1-10 alkyl)-aryl, wherein alkyl, alkenyl, alkynyl, and aryl are optionally substituted with one to three substituents selected from a group independently selected from R c ; R c is (1) halogen, (2) amino, (3) carboxy, (4) C 1-4 alkyl, (5) C 1-4 alkoxy, (6) aryl, (7) —(C 1-4 alkyl)-aryl, (8) hydroxy, (9) CF 3 , (10) OC(O)C 1-4 alkyl, (11) OC(O)NR f R g , or (12) aryloxy; R d and R e are independently selected from hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, Cy and —(C 1-10 alkyl)-Cy, wherein alkyl, alkenyl, alkynyl and Cy are optionally substituted with one to four substituents independently selected from R c ; or R d and R e together with the atom(s) to which they are attached form a heterocyclic ring of 4 to 7 members containing 0-2 additional heteroatoms independently selected from O, S and N—R h , and wherein said heterocyclic ring is optionally fused with a C 3-8 carbocyclic ring or is optional substituted with 1 to 4 groups independently selected from C 1-10 alkyl; R f and R g are independently selected from hydrogen, C 1-10 alkyl, Cy and —(C 1-10 alkyl)-Cy; or R f and R g together with the carbon to which they are attached form a ring of 5 to 7 members containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen; R h is selected from R f and —C(O)R f ; Cy is selected from cycloalkyl, heterocyclyl, aryl, and heteroaryl; and m is 1 or 2. |
| Claim: | 2. A compound of claim 1 wherein one of X and Y is halogen and the other is selected from halogen, C 1-3 alkyl and C 1-3 alkoxy. |
| Claim: | 3. A compound of claim 1 wherein R 1 is hydrogen, C 1-4 alkyl, —(C 1-4 alkyl)OC(O)—C 1-4 alkyl, or —(C 1-4 alkyl)OC(O)—C 1-4 alkyl. |
| Claim: | 4. A compound of claim 1 wherein R 3 is hydrogen, and R 4 is NR d R e . |
| Claim: | 5. A compound of claim 1 wherein R 3 is NR d R e and R 4 is hydrogen. |
| Claim: | 6. A compound of claim 1 having the formula Ia: [chemical expression included] or a pharmaceutically acceptable salt thereof, wherein A is N or N + O − ; R 1 is selected from hydrogen, C 1-10 alkyl, —(C 1-4 alkyl)-aryl, —(C 1-4 alkyl)-O—C 1-4 alkyl, and —(C 1-4 alkyl)-OC(O)—C 1-4 alkyl; one of R 3 and R 4 is NR d R e and the other is hydrogen. |
| Claim: | 7. A compound of claim 6 wherein R d is hydrogen and R e is t-butyl or cyclobutyl. |
| Claim: | 8. A compound of claim 6 wherein R 3 is hydrogen, and R d and R e together with the nitrogen atom to which they are attached form a heterocyclic ring of 4 to 7 members containing no additional heteroatom and optionally substituted with 1 or 2 groups independently selected from C 1-4 alkyl. |
| Claim: | 9. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. |
| Current U.S. Class: | 514/19 |
| Patent References Cited: | 6229011 May 2001 Chen et al. 6288267 September 2001 Hull et al. 6291511 September 2001 Durette et al. 6388084 May 2002 Kaplan et al. 6559174 May 2003 Lin et al. 6583139 June 2003 Thorsett et al. 6806365 October 2004 Chen et al. 6855706 February 2005 Tanaka et al. 6855708 February 2005 Lin et al. 6903075 June 2005 Durette et al. 6943180 September 2005 Doherty et al. 7008949 March 2006 Konradi et al. WO 02/074761 September 2002 |
| Other References: | Lin et al., “Very late antigen 4 (VLA4) antagonists as anti-inflammatory agents,” Curr. Op. Chem. Biol., 1998, 2, 453-7. cited by examiner Yang et al., “VLA-4 Antagonists: Potent Inhibitors of Lymphocyte Migration,” Med. Res. Rev., 2003, 23, 369-392. cited by examiner Lobb et al., “Small molecule antagonists of alpha4 integrins: novel drugs for asthma,” Exp. Op. Investigational Drugs, 1999, 8, 935-45. cited by examiner Tilley, “VLA-4 antagonists,” Exp. Op. Ther. Patents, 2002, 12, 991-1008. cited by examiner George A. Doherty, et al., Bioorganic & Medicinal Chemistry Letters, vol. 13 (17), pp. 2937-2938 (2003). cited by other |
| Assistant Examiner: | Bradley, Christina Marchetti |
| Primary Examiner: | Tsang, Cecilia |
| Attorney, Agent or Firm: | Yang, Mollie M. Camara, Valerie J. |
| رقم الانضمام: | edspgr.07514409 |
| قاعدة البيانات: | USPTO Patent Grants |
| الوصف غير متاح. |