5-Sulfonyl-1-Piperidinyl Substituted Indole Derivatives as 5-Ht6 Receptor Antagonists for the Treatment of Cns Disorders

• US 20080318933A1
• Filed: 10/05/2005
• Published: 12/25/2008
• Est. Priority Date: 10/07/2004
• Status: Abandoned Application

• Current Assignee: Glaxo Group Limited (Glaxosmithkline Holdings Ltd.)
• Original Assignee: Glaxo Group Limited (Glaxosmithkline Holdings Ltd.)
• Inventors: Johnson, Christopher Norbert, Ahmed, Mahmood, Miller, Neil Derek, Witty, David R, Rivers, Dean Andrew, Milner, Peter Henry
• Application Number:
  US11/576,070
• Publication Number:
  US 20080318933A1
• Time in Patent Office: Days
• US Class Current: 514/217.08
• 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 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• 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 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 25/32 Alcohol-abuse
• CPC Class Codes: A61P 25/34 Tobacco-abuse
• CPC Class Codes: A61P 25/36 Opioid-abuse
• 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 3/04 Anorexiants; Antiobesity 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: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings

Abstract

The present invention relates to novel indole derivatives such as compounds of the formula (I):

which possess antagonist potency at the 5-HT₆ receptor and the use of such compounds or pharmaceutically acceptable salts or solvates thereof in the treatment of Alzheimer'"'"'s disease and other CNS disorders.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof:

wherein;

R¹ represents hydrogen or C_1-6 alkyl optionally substituted by one or more halogen or cyano groups;

R² represents C_1-6 alkyl or R² may be linked to R¹ to form a (CH₂)₂, (CH₂)₃ or (CH₂)₄ group;

m represents an integer from zero to 4, such that when m is greater than 1, two R² groups may be linked to form a CH₂, (CH₂)₂, CH₂OCH₂ or (CH₂)₃ group;

p represents an integer from zero to 2;

represents a single or a double bond;

R³ represents C_1-6 alkyl or ═

O;

n represents an integer from zero to 2;

R⁴ represents halogen, cyano, haloC_1-6 alkyl, haloC_1-6 alkoxy, C_1-6 alkyl, C_1-6 alkoxy, C_1-6 alkanoyl or a group —

CONR⁵R⁶;

q represents an integer from zero to 3;

R⁵ and R⁶ independently represent hydrogen or C_1-6 alkyl or together with the nitrogen atom to which they are attached form a nitrogen containing heterocyclyl or nitrogen containing heteroaryl group;

A represents an -aryl, -heteroaryl, -aryl-aryl, -aryl-heteroaryl, -heteroaryl-aryl or -heteroaryl-heteroaryl group;

wherein said aryl and heteroaryl groups of A may be optionally substituted by one or more substituents which may be the same or different, and which are selected from the group consisting of halogen, hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, C_1-6 alkyl, trifluoromethanesulfonyloxy, pentafluoroethyl, C_1-6 alkoxy, arylC_1-6 alkoxy, C_1-6 alkylthio, C_1-6 alkoxyC_1-6 alkyl, C_3-7 cycloalkylC_1-6 alkoxy, C_1-6 alkanoyl, C_1-6 alkoxycarbonyl, C_1-6 alkylsulfonyl, C_1-6 alkylsulfinyl, C_1-6 alkylsulfonyloxy, C_1-6 alkylsulfonylC_1-6 alkyl, arylsulfonyl, arylsulfonyloxy, arylsulfonylC_1-6 alkyl, C_1-6 alkylsulfonamido, C_1-6 alkylamido, C_1-6 alkylsulfonamidoC_1-6 alkyl, C_1-6 alkylamidoC_1-6 alkyl, arylsulfonamido, arylcarboxamido, arylsulfonamidoC_1-6 alkyl, arylcarboxamidoC_1-6 alkyl, aroyl, aroylC_1-6 alkyl, arylC_1-6 alkanoyl, CONR⁹R¹⁰ and SO₂NR⁹R¹⁰, wherein R⁹ and R¹⁰ independently represent hydrogen or C_1-6 alkyl or R⁹ and R¹⁰ together with the nitrogen atom to which they are attached may form a nitrogen containing heterocyclyl or nitrogen containing heteroaryl group.

2. A compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein R¹ represents hydrogen or C_1-6 alkyl.

3. A compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt or solvate thereof, wherein A represents an optionally substituted phenyl, thiazolyl or pyrazolyl, wherein the optional substituents are selected from the group consisting of halogen, CN, C_1-3 alkyl and C_1-3 alkoxy.

4. A compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt or solvate thereof, which is a compound of E1-E65.

5. A pharmaceutical composition which comprises a compound as defined in claim 1, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or excipient.

10. A method of treating depression, anxiety, Alzheimer'"'"'s disease, age related cognitive decline, ADHD, obesity, mild cognitive impairment, schizophrenia, cognitive deficits in schizophrenia and stroke which comprises administering a safe and therapeutically effective amount to a patient in need thereof of a compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt or solvate thereof.

6-9. -9. (canceled)