Ethers, secondary amines and derivatives thereof as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto

• US 10,450,276 B2
• Filed: 08/22/2016
• Issued: 10/22/2019
• Est. Priority Date: 05/18/2006
• Status: Active Grant

• Current Assignee: Arena Pharmaceuticals Incorporated
• Original Assignee: Arena Pharmaceuticals Incorporated
• Inventors: Teegarden, Bradley, Chapman, Dennis, Decaire, Marc, Dosa, Peter I., Feichtinger, Konrad, Jayakumar, Honnappa, Tran, Thuy-Anh, Strah-Pleynet, Sonja, Xu, Jay
• Primary Examiner(s): Saeed, Kamal A
• Application Number:
  US15/242,911
• Publication Number:
  US 20170166533A1
• Time in Patent Office: 1,156 Days
• Field of Search: None
• CPC Class Codes: A61K 31/415 1,2-Diazoles
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/24 Antidepressants
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07D 207/335 Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 207/34 with hetero atoms or 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 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• 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
• 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 present invention pertains to certain compounds of Formula (Ia) and pharmaceutical compositions thereof that modulate the activity of the 5-HT_2A serotonin receptor.

Compounds and pharmaceutical compositions thereof are directed to methods useful in the treatment of platelet aggreagation, coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, atrial fibrillation, blood clot formation, asthma or symptoms thereof, agitation or a symptom thereof, behavioral disorders, drug induced psychosis, excitative psychosis, Gilles de la Tourette'"'"'s syndrome, manic disorder, organic or NOS psychosis, psychotic disorder, psychosis, acute schizophrenia, chronic schizophrenia, NOS schizophrenia and related disorders, and sleep disorders, sleep disorders, diabetic-related disorders, progressive multifocal leukoencephalopathy and the like.

The present invention also relates to the methods for the treatment of 5-HT_2A serotonin receptor associated disorders in combination with other pharmaceutical agents administered separately or together.

Claims

1. A method for treating a 5-HT_2A associated disorder in an individual comprising administering to the individual in need thereof a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (Ia);

2. The method according to claim 1, wherein the compound has Formula (Ic):

3. The method according to claim 2, wherein Q is —

NR^4aR^4b.

4. The method according to claim 3, wherein

R^4a is H;

and

R^4b is C_1-6 alkyl, C_3-7 cycloalkyl, C_1-6 haloalkyl, heterocyclyl, or heteroaryl, wherein each is optionally substituted with 1, 2, 3, 4, or 5 substituents selected independently from the group consisting of C_1-4 alkoxy, C_1-5 alkyl, C_1-4 alkylsulfonyl, amino, carbo-C_1-6-alkoxy, carboxamide, cyano, hydroxyl, imino, and phenyl.

5. The method according to claim 4, wherein R¹ is C_1-6 alkyl, R² is H, and R³ is H, Cl, or Br.

6. The method according to claim 5, wherein Z is absent and R⁸ is aryl, C_3-10 cycloalkyl, or heteroaryl each optionally substituted with substituents selected independently from the group consisting of C_1-6 alkoxy, C_1-6 alkyl, cyano, halogen, C_1-6 haloalkoxy, and C_1-6 haloalkyl.

7. The method according to claim 1, wherein the 5-HT2A associated disorder is a sleep disorder.

8. The method according to claim 1, wherein the 5-HT2A associated disorder is progressive multifocal leukoencephalopathy.

9. The method according to claim 1, wherein the 5-HT2A associated disorder is hypertension.

10. The method according to claim 1, wherein the 5-HT2A associated disorder is pain.

11. The method according to claim 1, wherein the 5-HT2A associated disorder is claudication.

12. The method according to claim 1, wherein the 5-HT2A associated disorder is peripheral artery disease.

13. The method according to claim 1, wherein the 5-HT2A associated disorder is vasoconstriction.

14. The method according to claim 1, wherein the 5-HT2A associated disorder is vasospasm.

15. The method according to claim 1, wherein the 5-HT2A associated disorder is thrombosis.

16. The method according to claim 1, wherein the 5-HT2A associated disorder is stroke.