Imidazo[1,2-α]pyridine derivatives as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto

• US 10,058,549 B2
• Filed: 01/06/2017
• Issued: 08/28/2018
• Est. Priority Date: 08/15/2007
• Status: Active Grant

• Current Assignee: Arena Pharmaceuticals Incorporated
• Original Assignee: Arena Pharmaceuticals Incorporated
• Inventors: Xiong, Yifeng, Feichtinger, Konrad, Ren, Albert S., Ullman, Brett
• Primary Examiner(s): Anderson, James D.
• Application Number:
  US15/400,670
• Publication Number:
  US 20170151236A1
• Time in Patent Office: 599 Days
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61P 11/06 Antiasthmatics
• 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 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 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

rmidazo[1,2-α]pyridine derivatives 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 insomnia, dyssomnia, parasomnia and related sleep disorders, platelet aggregation, coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, atrial fibrillation, thrombosis, asthma or symptoms thereof, agitation or symptoms thereof, behavioral disorders, drug induced psychosis, excitative psychosis, Gilles de Ia Tourette'"'"'s syndrome, manic disorder, organic or NOS psychosis, psychotic disorders, psychosis, acute schizophrenia, chronic schizophrenia, NOS schizophrenia and related disorders, diabetic- related disorders, progressive multifocal leukoencephalopathy and the like. The present invention also relates to methods for the treatment of 5-HT_2A serotonin receptor mediated disorders in combination with other pharmaceutical agents administered separately or together.

Claims

1. A method of treating agitation in a subject in need thereof, comprising administering an effective amount of a compound of Formula (Ia) to the subject:

2. The method of claim 1, wherein R¹ and R² are each independently selected from the group consisting of H, C₁-C₆ acyloxy, C₁-C₆ alkoxy, C₁-C₆ alkyl, C₁-C₆ alkylsulfonyl, aryl, aryl-C₁-C₄-alkylenyl, carbo-C₁-C₆ alkoxy, carboxy, cyano, C₃-C₇ cycloalkyl, C₁-C₆ haloalkoxy, C₁-C₆ haloalkyl, halogen, heteroaryl, heterocyclyl, and hydroxyl.

3. The method of claim 1, wherein:

R⁸ and R⁹ are each independently selected from the group consisting of H, C₁-C₃ alkyl, aryl, C₁-C₃ alkoxy, C₃-C₇ cycloalkyl, C₁-C₃ haloalkyl, halogen and hydroxyl;

or R⁸ and R⁹ taken together form oxo;

or

R⁸ and R⁹ together with the atom to which they are both bonded form a C₃-C₇ cycloalkyl ring.

4. The method of claim 1, wherein the compound is Formula (Ic):

5. The method of claim 4, wherein:

R¹ is selected from the group consisting of H, methyl, t-butyl, phenyl and trifluoromethyl;

R² is selected from the group consisting of H, cyano, chloro and bromo;

R⁸ and R⁹ are each independently selected from the group consisting of H and F;

or

R⁸ and R⁹ together form oxo; and

R¹² and R¹⁴ are each independently selected from the group consisting of H, fluoro and chloro.

6. The method of claim 1, wherein the compound is Formula (Ie):

7. The method of claim 6, wherein:

R⁶ and R⁷ are both H;

R⁸ and R⁹ are each independently selected from the group consisting of H and F;

or

R⁸ and R⁹ together form oxo; and

R¹⁰, R¹¹, R¹², R¹³ and R¹⁴ are each independently selected from the group consisting of H, methyl, methoxy, dimethylamino, —

NHSO₂CH₃, methylsulfonyl, carboxamide, carboxy, cyano, cyclohexyl, fluoro, chloro, trifluoromethoxy, difluoromethoxy, trifluoromethyl, morpholin-4-yl, pyrrolidin-1-yl, thien-2-yl, hydroxyl, nitro, phenyl and sulfonic acid.

8. The method of claim 1, wherein the compound is selected from the group consisting of:

(3-bromoimidazo[1,2-a]pyridin-8-yl)(4-(2,4-difluorophenethyl)piperazin-1-yl)methanone;

8-(4-(2,4-difluorophenethyl)piperazine-1-carbonyl)imidazo[1,2-a]pyridine-3-carbonitrile;

(4-(2,4-difluorophenethyl)piperazin-1-yl)(imidazo[1,2-a]pyridin-8-yl)methanone;

1-(4-fluorophenyl)-2-(4-(imidazo[1,2-a]pyridine-8-carbonyl)piperazin-1-yl)ethanone;

(4-(4-fluorophenethyl)piperazin-1-yl)(imidazo[1,2-a]pyridin-8-yl)methanone;

(4-(4-fluorophenethyl)piperazin-1-yl)(2-(trifluoromethyl)imidazo[1,2-a]pyridin-8-yl)methanone;

(2-tert-butylimidazo[1,2-a]pyridin-8-yl)(4-(4-fluorophenethyl)piperazin-1-yl)methanone;

(4-(4-fluorophenethyl)piperazin-1-yl)(2-methylimidazo[1,2-a]pyridin-8-yl)methanone;

(4-(4-fluorophenethyl)piperazin-1-yl)(2-phenylimidazo[1,2-a]pyridin-8-yl)methanone;

(4-(2-fluoro-2-(4-fluorophenyl)ethyl)piperazin-1-yl)(imidazo[1,2-a]pyridin-8-yl)methanone;

(3-chloroimidazo[1,2-a]pyridin-8-yl)(4-(2,4-difluorophenethyl)piperazin-1-yl)methanone;

imidazo[1,2-a]pyridin-8-yl(4-(4-methoxyphenethyl)piperazin-1-yl)methanone;

(4-(3,4-dimethoxyphenethyl)piperazin-1-yl)(imidazo[1,2-a]pyridin-8-yl)methanone;

(4-(3-fluorophenethyl)piperazin-1-yl)(imidazo[1,2-a]pyridin-8-yl)methanone;

(4-(4-chlorophenethyl)piperazin-1-yl)(imidazo[1,2-a]pyridin-8-yl)methanone;

(4-(3-chlorophenethyl)piperazin-1-yl)(imidazo[1,2-a]pyridin-8-yl)methanone;

(4-(2-chlorophenethyl)piperazin-1-yl)(imidazo[1,2-a]pyridin-8-yl)methanone;

(4-(2-fluorophenethyl)piperazin-1-yl)(imidazo[1,2-a]pyridin-8-yl)methanone;

(4-(2,4-dichlorophenethyl)piperazin-1-yl)(imidazo[1,2-a]pyridin-8-yl)methanone;

1-(2,4-difluorophenyl)-2-(4-(imidazo[1,2-a]pyridine-8-carbonyl)piperazin-1-yl)ethanone;

2-(4-(imidazo[1,2-a]pyridine-8-carbonyl)piperazin-1-yl)-1-(4-(pyrrolidm-1-yl)phenyl)ethanone;

2-(4-(imidazo[1,2-a]pyridine-8-carbonyl)piperazin-1-yl)-1-(4-(trifluoromethoxy)phenyl)ethanone;

N-(2-hydroxy-5-(2-(4-(imidazo[1,2-a]pyridine-8-carbonyl)piperazin-1-yl)acetyl)phenyl)methanesulfonamide;

1-(2-chloro-5-(trifluoromethyl)phenyl)-2-(4-(imidazo[1,2-a]pyridine-8-carbonyl)piperazin-1-yl)ethanone;

1-(biphenyl-4-yl)-2-(4-(imidazo[1,2-a]pyridine-8-carbonyl)piperazin-1-yl)ethanone;

2-(4-(imidazo[1,2-a]pyridine-8-carbonyl)piperazin-1-yl)-1-(4-(methylsulfonyl)phenyl)ethanone;

(4-(2,4-difluorophenethyl)piperazin-1-yl)(5,7-dimethylimidazo[1,2-a]pyridin-8-yl)methanone;

1-(4-cyclohexylphenyl)-2-(4-(imidazo[1,2-a]pyridine-8-carbonyl)piperazin-1-yl)ethanone;

1-(4-(difluoromethoxy)phenyl)-2-(4-(imidazo[1,2-a]pyridine-8-carbonyl)piperazin-1-yl)ethanone;

2-(4-(imidazo[1,2-a]pyridine-8-carbonyl)piperazin-1-yl)-1-phenylpropan-1-one;

1-(4-chloro-2-fluoro-5-methylphenyl)-2-(4-(imidazo[1,2-a]pyridine-8-carbonyl)piperazin-1-yl)ethanone;

1-(5-chloro-2-methoxy-4-methylphenyl)-2-(4-(imidazo[1,2-a]pyridine-8-carbonyl)piperazin-1-yl)ethanone;

1-(3,5-bis(trifluoromethyl)phenyl)-2-(4-(imidazo[1,2-a]pyridine-8-carbonyl)piperazin-1-yl)ethanone;

2-(4-(imidazo[1,2-a]pyridine-8-carbonyl)piperazin-1-yl)-1-(4-(trifluoromethyl)phenyl)ethanone;

2-(4-(imidazo[1,2-a]pyridine-8-carbonyl)piperazin-1-yl)-1-(4-(thiophen-2-yl)phenyl)ethanone;

(4-(2,4-difluorophenethyl)piperazin-1-yl)(7-methoxyimidazo[1,2-a]pyridin-8-yl)methanone;

2-hydroxy-5-(2-(4-(imidazo[1,2-a]pyridine-8-carbonyl)piperazin-1-yl)acetyl)benzamide;

2-(4-(imidazo[1,2-a]pyridine-8-carbonyl)piperazin-1-yl)-1-(2-(trifluoromethyl)phenyl)ethanone;

4-(2-(4-(imidazo[1,2-a]pyridine-8-carbonyl)piperazin-1-yl)acetyl)benzonitrile;

1-(4-hydroxyphenyl)-2-(4-(imidazo[1,2-a]pyridine-8-carbonyl)piperazin-1-yl)ethanone;

1-(4-(dimethylamino)phenyl)-2-(4-(imidazo[1,2-a]pyridine-8-carbonyl)piperazin-1-yl)ethanone;

1-(5-chloro-2-methoxy-4-methyl-3-nitrophenyl)-2-(4-(imidazo[1,2-a]pyridine-8-carbonyl)piperazin-1-yl)ethanone;

2-(4-(imidazo[1,2-a]pyridine-8-carbonyl)piperazin-1-yl)-1-(4-morpholinophenyl)ethanone; and

(6-bromoimidazo[1,2-a]pyridin-8-yl)(4-(2,4-difluorophenethyl)piperazin-1-yl)methanone.

9. The method of claim 1, wherein the agitation is associated with a disorder selected from the group consisting of dementia, Alzheimer'"'"'s disease, Lewy Body, Parkinson'"'"'s disease, Huntington'"'"'s disease, dementia due to brain stroke, a psychiatric disorder, and a combination thereof.

10. The method of claim 1, wherein the subject is a cognitively intact elderly subject.

11. The method of claim 1, wherein the administration is by oral, rectal, nasal, topical, buccal, sub-lingual, vaginal, parenteral, intramuscular, sub-cutaneous, intravenous, and combinations thereof.

12. The method of claim 1, wherein the compound is administered at a dose of about 0.001 milligram to about 500 milligrams per day.