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

Patent metadata

Field	Value
Publication number	US-10450276-B2
Application number	US-201615242911-A
Country	US
Kind code	B2
Filing date	Aug 22, 2016
Priority date	May 18, 2006
Publication date	Oct 22, 2019
Grant date	Oct 22, 2019

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.

First claim

What is claimed is:

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);

or a pharmaceutically acceptable salt, hydrate or solvate thereof, and a pharmaceutically acceptable carrier,
wherein:
V is O or NH;
W is C 1-4 alkylene optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 substituents selected independently from the group consisting of C 1-3 alkyl, C 1-4 alkoxy, carboxy, cyano, C 3-7 cycloalkyl, C 1-3 haloalkyl, halogen, and oxo;
Q is —NR 4a R 4b or —OR 4c , wherein:
R 4a is H, C 1-12 acyl, carbo-C 1-12 -alkoxy, or C(═O)O-aryl, wherein said C 1-12 acyl, carbo-C 1-12 -alkoxy, and —C(═O)O-aryl is optionally substituted with 1, 2, 3, 4, or 5 substituents selected independently from the group consisting of C 1-5 acyloxy, C 1-6 alkylcarboxamide, amino, C 1-6 alkylamino, C 2-5 dialkylamino, C 1-6 alkylimino, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, halogen, nitro, and phenyl;
R 4b is C 1-6 alkyl, aryl, 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 1-5 acyl, C 1-5 acyloxy, C 2-6 alkenyl, C 1-4 alkoxy, C 1-5 alkyl, C 1-6 alkylamino, C 2-5 dialkylamino, C 1-4 alkylcarboxamide, C 2-6 alkynyl, C 1-4 alkylsulfonamide, C 1-4 alkylsulfinyl, C 1-4 alkylsulfonyl, C 1-4 alkylthio, C 1-4 alkylureyl, amino, carbo-C 1-6 -alkoxy, carboxamide, carboxy, cyano, C 3-6 cycloalkyl, C 2-6 dialkylcarboxamide, halogen, C 1-4 haloalkoxy, C 1-4 haloalkyl, C 1-4 haloalkylsulfinyl, C 1-4 haloalkylsulfonyl, C 1-4 haloalkylthio, hydroxyl, imino, nitro, sulfonamide and phenyl; and
R 4c is H, or R 4c is C 1-6 alkyl, C 1-12 acyl, aryl, 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 1-5 acyl, C 1-5 acyloxy, C 2-6 alkenyl, C 1-4 alkoxy, C 1-5 alkyl, C 1-6 alkylamino, C 2-5 dialkylamino, C 1-4 alkylcarboxamide, C 2-6 alkynyl, C 1-4 alkylsulfonamide, C 1-4 alkylsulfinyl, C 1-4 alkylsulfonyl, C 1-4 alkylthio, C 1-4 alkylureyl, amino, C 1-6 alkylamino, C 2-5 dialkylamino, carbo-C 1-6 -alkoxy, carboxamide, carboxy, cyano, C 3-6 cycloalkyl, C 2-6 dialkylcarboxamide, halogen, C 1-4 haloalkoxy, C 1-4 haloalkyl, C 1-4 haloalkylsulfinyl, C 1-4 haloalkylsulfonyl, C 1-4 haloalkylthio, heterocyclyl, hydroxyl, imino, nitro, sulfonamide and phenyl;

Z is C 1-4 alkylene optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 substituents selected independently from the group consisting of C 1-3 alkyl, C 1-4 alkoxy, carboxy, cyano, C 1-3 haloalkyl, halogen and oxo; or Z is absent;
R 1 is selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 3-7 cycloalkyl;
R 2 is selected from the group consisting of H, C 1-6 acyl, C 1-6 acyloxy, C 2-6 alkenyl, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 alkylcarboxamide, C 2-6 alkynyl, C 1-6 alkylsulfonamide, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 1-6 alkylureyl, amino, C 1-6 alkylamino, C 2-8 dialkylamino, carbo-C 1-6 -alkoxy, carboxamide, carboxy, cyano, C 3-7 cycloalkyl, C 2-8 dialkylcarboxamide, C 2-8 dialkylsulfonamide, halogen, C 1-6 haloalkoxy, C 1-6 haloalkyl, C 1-6 haloalkylsulfinyl, C 1-6 haloalkylsulfonyl, C 1-6 haloalkylthio, hydroxyl, thiol, nitro and sulfonamide;
R 3 is selected from the group consisting of H, C 2-6 alkenyl, C 1-6 alkyl, C 1-6 alkylcarboxamide, C 2-6 alkynyl, C 1-6 alkylsulfonamide, carbo-C 1-6 -alkoxy, carboxamide, carboxy, cyano, C 3-7 cycloalkyl, C 2-8 dialkylcarboxamide, halogen, heteroaryl and phenyl; and wherein each of said C 2-6 alkenyl, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkylsulfonamide, C 3-7 cycloalkyl, heteroaryl and phenyl groups are optionally substituted with 1, 2, 3, 4, or 5 substituents selected independently from the group consisting of C 1-5 acyl, C 1-5 acyloxy, C 2-6 alkenyl, C 1-4 alkoxy, C 1-5 alkyl, C 1-6 alkylamino, C 2-8 dialkylamino, C 1-4 alkylcarboxamide, C 2-6 alkynyl, C 1-4 alkylsulfonamide, C 1-4 alkylsulfinyl, C 1-4 alkylsulfonyl, C 1-4 alkylthio, C 1-4 alkylureyl, amino, carbo-C 1-6 -alkoxy, carboxamide, carboxy, cyano, C 3-6 cycloalkyl, C 2-6 dialkylcarboxamide, halogen, C 1-4 haloalkoxy, C 1-4 haloalkyl, C 1-4 haloalkylsulfinyl, C 1-4 haloalkylsulfonyl, C 1-4 haloalkylthio, hydroxyl, nitro and sulfonamide;
R 5 , R 6 and R 7 are each selected independently from the group consisting of H, C 1-6 acyl, C 1-6 acyloxy, C 2-6 alkenyl, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 alkylcarboxamide, C 2-6 alkynyl, C 1-6 alkylsulfonamide, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 1-6 alkylureyl, amino, C 1-6 alkylamino, C 2-5 dialkylamino, C 1-6 alkylimino, carbo-C 1-6 -alkoxy, carboxamide, carboxy, cyano, C 3-7 cycloalkyl, C 2-8 dialkylcarboxamide, C 2-5 dialkylsulfonamide, halogen, C 1-6 haloalkoxy, C 1-6 haloalkyl, C 1-6 haloalkylsulfinyl, C 1-6 haloalkylsulfonyl, C 1-6 haloalkylthio, heterocyclyl, hydroxyl, thiol, and nitro; and
R 8 is C 1-8 -alkyl, aryl, C 3-10 cycloalkyl, heteroaryl, or heterocyclyl each optionally substituted with substituents selected independently from the group consisting of C 1-6 acyl, C 1-6 acyloxy, C 2-6 alkenyl, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 alkylcarboxamide, C 2-6 alkynyl, C 1-6 alkylsulfonamide, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 1-6 alkylureyl, amino, C 1-6 alkylamino, C 2-8 dialkylamino, C 1-6 alkylimino, carbo-C 1-6 -alkoxy, carboxamide, carboxy, cyano, C 3-7 cycloalkyl, C 3-7 cycloalkyloxy, C 2-8 dialkylcarboxamide, C 2-8 dialkylsulfonamide, halogen, C 1-6 haloalkoxy, C 1-6 haloalkyl, C 1-6 haloalkylsulfinyl, C 1-6 haloalkylsulfonyl, C 1-6 haloalkylthio, heteroaryl, heterocyclyl, hydroxyl, thiol, nitro, phenoxy and phenyl, wherein said C 2-6 alkenyl, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkylamino, C 1-6 alkylimino, C 2-8 dialkylamino, heteroaryl, heterocyclyl, phenyl, and phenoxy, and each said substituent is optionally substituted with 1, 2, 3, 4, or 5 substituents selected independently from the group consisting of C 1-6 acyl, C 1-6 acyloxy, C 2-6 alkenyl, C 1-6 alkoxy, C 1-6 alkyl, C 1-6 alkylcarboxamide, C 2-6 alkynyl, C 1-6 alkylsulfonamide, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, C 1-6 alkylthio, C 1-6 alkylureyl, amino, C 1-6 alkylamino, C 2-5 dialkylamino, carbo-C 1-6 -alkoxy, carboxamide, carboxy, cyano, C 3-7 cycloalkyl, C 2-8 dialkylcarboxamide, halogen, C 1-6 haloalkoxy, C 1-6 haloalkyl, C 1-6 haloalkylsulfinyl, C 1-6 haloalkylsulfonyl, C 1-6 haloalkylthio, heterocyclyl, hydroxyl, thiol and nitro; and
wherein the 5-HT 2A associated disorder is selected from the group consisting of: a sleep disorder, progressive multifocal leukoencephalopathy, hypertension, pain, claudication, peripheral artery disease, vasoconstriction, vasospasm, thrombosis, and stroke.

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

wherein:
R 5 , R 6 , and R 7 are each H;
V is O; and
W is —CH 2 CH 2 — optionally substituted with 1 to 2 substituents selected independently from the group consisting of C 1-3 alkyl and oxo.

3. The method according to claim 2 , wherein Q

Assignees

• Arena Pharm Inc

Inventors

• Teegarden Bradley
• Chapman Dennis
• Decaire Marc
• Dosa Peter I
• Feichtinger Konrad
• Jayakumar Honnappa
• Tran Thuy-Anh
• Strah-Pleynet Sonja
• Xu Jay

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title