CGRP receptor antagonists

• US 7,842,686 B2
• Filed: 01/21/2009
• Issued: 11/30/2010
• Est. Priority Date: 07/21/2006
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Termin, Andreas P., Yoo, Sanghee, Joshi, Pramod, Hadida Ruah, Sara S., Cao, Jingrong, Anderson, Corey Don, Bergeron, Daniele
• Primary Examiner(s): Kifle; Bruck
• Application Number:
  US12/356,745
• Publication Number:
  US 20090186882A1
• Time in Patent Office: 678 Days
• Field of Search: 514/211.04, 514/211.06, 514/211.07, 514/221, 514/224.5, 514/230.5, 514/249, 540/491, 540/517, 544/52, 544/70, 544/105, 544/353
• US Class Current: 514/211.04
• 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 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/36 Opioid-abuse
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• 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 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 413/12 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 present invention relates to CGRP receptor antagonists, pharmaceutical compositions thereof, and methods therewith for treating CGRP receptor-mediated diseases and conditions.

Claims

1. A compound of formula I:

2. The compound according to claim 1, wherein m is 1 and p is 1.

3. The compound according to claim 1, wherein X is O, NR^A, S, SO, or SO₂ and Y is a bond, C(R^X)₂, or —

C(R^X)₂—

C(R^X)₂—

.

4. The compound according to claim 1, wherein X is O or S.

5. The compound according to claim 1, wherein Y is a bond.

6. The compound according to claim 1, wherein Y is C(R^X)₂.

7. The compound according to claim 1, wherein one R^X is C1-C6 aliphatic optionally substituted with one or more halo, OH, C1-C4 alkoxy, C1-C4 alkoxy carbonyl, or di-(C1-C4 alkyl) amino.

8. The compound according to claim 1, wherein one R^X is phenyl or heteroaryl optionally substituted with one or more substituents independently selected from C1-C6 aliphatic, cyano, halo, halo-C1-C6 aliphatic, aryl-C1-C6 aliphatic, heteroaryl-C1-C6 aliphatic, aralkyloxy, di(C1-C6 aliphatic)amino, O—

C1-C6 aliphatic, S(O)—

C1-C6 aliphatic, or S(O)₂—

C1-C6 aliphatic.

9. The compound according to claim 1, wherein two R^X, taken together with the carbon atom that they are attached to, form an optionally substituted 3-9 membered cycloaliphatic or heterocyclic, monocyclic, bicyclic, or tricyclic ring.

10. The compound according to claim 1, wherein one R^X is —

C(O)NH—

R^M, —

NHC(O)—

R^M, —

NHC(O)O—

R^M, wherein R^M is an optionally substituted phenyl, heteroaryl or heterocyclic group.

11. The compound according to claim 1, wherein both R^W are hydrogen.

12. The compound according to claim 1, wherein one R^W is hydrogen and the other R^W is C1-C6 aliphatic optionally substituted with one or more halo, OH, C1-C4 alkoxy, C1-C4 alkoxy carbonyl, or di-(C1-C4 alkyl) amino.

13. The compound according to claim 1, wherein R^A is hydrogen.

14. The compound according to claim 1, wherein each Q is independently a bond or a C1-C6 aliphatic chain wherein up to two non-adjacent methylene units of Q are optionally replaced by CO, CO₂, CONR, OCONR, NRCO, NRCO₂, NRCONR, SO, SO₂, NRSO₂, SO₂NR, NRSO₂NR, O, S, or NR, wherein R is hydrogen or C1-C6 alkyl.

15. The compound according to claim 14, wherein each R^M is independently R′

.

16. The compound according to claim 1, wherein ring A is:

17. The compound according to claim 1, wherein said compound is of formulae I-A or I-B:

20. A pharmaceutical composition comprising a compound according to claim 1 or claim 19, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

21. A method for the treatment of a disease or disorder in a patient, wherein said disease or disorder is selected from headache or pain comprising administering to the patient a therapeutically effective amount of a composition according to claim 20.

22. The method according to claim 21, wherein said disease or disorder is selected from pain and said method is useful for the treatment of chronic pain;

neurogenic inflammatory pain;

neuropathic pain;

eye pain and tooth pain.

23. The method according to claim 21, wherein said disease or disorder is selected from headache and said method is useful for the treatment of migraine;

cluster headache and chronic tension type headache.

18. A compound of formula I′

;

19. A compound selected from: