2-Aryl Imidazo[1,2-a]Pyridine-3-Acetamide Derivatives, Preparation Methods and Uses Thereof

• US 20130203754A1
• Filed: 06/09/2011
• Published: 08/08/2013
• Est. Priority Date: 06/25/2010
• Status: Active Grant

• Current Assignee: Institute of Pharmacology and Toxicology Academy of Military Medical Sciences PLA China
• Original Assignee: Institute of Pharmacology and Toxicology Academy of Military Medical Sciences PLA China
• Inventors: Yang, Rifang, Zhao, Nan, Yun, Liuhong, Zhang, Youzhi, Li, Yunfeng, Li, Yongzhen, Qin, Juanjuan, Feng, Zhongyao
• Granted Patent: US 8,980,887 B2
• Time in Patent Office: Days
• US Class Current: 514/233.2
• 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 25/08 Antiepileptics; Anticonvulsants
• 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 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

Disclosed are 2-arylimidazo[1,2-a]pyridine-3-acetamide derivatives represented by formula I, their tautomer, racemate or optical isomer, their pharmaceutically acceptable salt, or their solvates, wherein R¹, R², R³ and R⁴ are defined as in the specification. Preparation methods of said compounds and use of said compounds in treating and/or preventing central nervous system disease associated with TSPO functional disorder

Claims

1. A compound of Formula I, its tautomer, its racemic or optical isomer, its pharmaceutically acceptable salt (which is water soluble), or its solvate,

2. The compound of Formula I, its tautomer, its racemic or optical isomer, its pharmaceutically acceptable salt, or its solvate, according to claim 1, wherein, R³ has 1-2 substituents, and R³ is at 4-, 5-, 6-, or 7-position of imidazo[1,2-a]pyridine ring;

R⁴ has 1-3 substituents, and R⁴ is at o-, m- or p-position of benzene ring.

3. The compound of Formula I, its tautomer, its racemic or optical isomer, its pharmaceutically acceptable salt, or its solvate, according to claim 1, wherein R³ and R⁴ are independently selected from F, Cl, Br, I, C₁-C₆ alkyl, C₁-C₃ alkoxylethyl, and C₁-C₆ alkoxyl.

4. The compound of Formula I according to claim 1, its tautomer, its racemic or optical isomer, its pharmaceutically acceptable salt, or its solvate,

wherein R¹ is ethyl or methoxyethyl.

5. The compound of Formula I, its tautomer, its racemic or optical isomer, its pharmaceutically acceptable salt, or its solvate, according to claim 1, which is selected from the following compounds:

N-benzyl-N-ethyl-2-(4-chlorophenyl)-7-methylimidazo[1,2-a]pyridine-3-acetamide;

N-ethyl-N-(2-pyridinylmethyl)-2-(4-chlorophenyl)-7-methylimidazo[1,2-a]pyridine-3-acetamide.hydrochloride;

N-(2-methoxyethyl)-N-(2-pyridinylmethyl)-2-(4-methylphenyl)-7-methylimidazo[1,2-a]pyridine-3-acetamide.hydrochloride;

N-(2-methoxyethyl)-N-(3-pyridinylmethyl)-2-(4-methylphenyl)-7-methylimidazo[1,2-a]pyridine-3-acetamide.hydrochloride;

N-benzyl-N-ethyl-2-(4-methoxyphenyl)-7-methylimidazo[1,2-a]pyridine-3-acetamide;

N-ethyl-N-(2-pyridinylmethyl)-2-(4-methoxyphenyl)-7-methylimidazo[1,2-a]pyridine-3-acetamide.hydrochloride;

N-ethyl-N-(3-pyridinylmethyl)-2-(4-methoxyphenyl)-7-methylimidazo[1,2-a]pyridine-3-acetamide.hydrochloride;

N-ethyl-N-(4-pyridinylmethyl)-2-(4-methoxyphenyl)-7-methylimidazo[1,2-a]pyridine-3-acetamide.hydrochloride;

N-(2-methoxyethyl)-N-(2-pyridinylmethyl)-2-(4-methoxyphenyl)-7-methylimidazo[1,2-a]pyridine-3-acetamide.hydrochloride;

N-(2-methoxyethyl)-N-(3-pyridinylmethyl)-2-(4-methoxyphenyl)-7-methylimidazo[1,2-a]pyridine-3-acetamide.hydrochloride;

N-(2-methoxyethyl)-N-(2-morpholinylethyl)-2-(4-methylphenyl)-7-methylimidazo[1,2-a]pyridine-3-acetamide.hydrochloride;

N-(2-methoxyethyl)-N-(2-morpholinylethyl)-2-(4-methylphenyl)-6-methylimidazo[1,2-a]pyridine-3-acetamide.hydrochloride;

N-ethyl-N-(4-pyridinylmethyl)-2-(4-methylphenyl)-6-methylimidazo[1,2-a]pyridine-3-acetamide.hydrochloride; and

N-ethyl-N-(4-pyridinylmethyl)-2-(4-chlorophenyl)-6-methylimidazo[1,2-a]pyridine-3-acetamide.hydrochloride.

6. A method for preparing the compound of Formula I, its tautomer, its racemic or optical isomer, its pharmaceutically acceptable salt, or its solvate according to claim 1, comprising the following steps:

a) converting an aromatic hydrocarbon compound of Formula VIII;

7. A method for preparing the compound of Formula I, its tautomer, its racemic or optical isomer, its pharmaceutically acceptable salt, or its solvate according to claim 1, comprising the following steps:

a) converting an aromatic hydrocarbon compound of Formula VIII;

8. A pharmaceutical composition, comprising at least one the compound of Formula I, its tautomer, its racemic or optical isomer, its pharmaceutically acceptable salt, or its solvate, according to claim 1, and optionally a pharmaceutically acceptable carrier or adjuvant.

13. The compound of Formula I, its tautomer, its racemic or optical isomer, its pharmaceutically acceptable salt, or its solvate, according to claim 3, wherein R³ and R⁴ are independently selected from F, Cl, methyl, ethyl, methoxyethyl, methoxy, and ethoxy.

14. The compound of Formula I according to claim 1, its tautomer, its racemic or optical isomer, its pharmaceutically acceptable salt, or its solvate, wherein R² is benzyl, 2-pyridinylmethyl, 3-pyridinylmethyl, 4-pyridinylmethyl, or 2-morpholinylethyl.

15. The compound of Formula I according to claim 1, its tautomer, its racemic or optical isomer, its pharmaceutically acceptable salt, or its solvate, wherein R³ is 6-methyl or 7-methyl.

16. The compound of Formula I according to claim 1, its tautomer, its racemic or optical isomer, its pharmaceutically acceptable salt, or its solvate, wherein R⁴ is 4-chloro, 3,4-dichloro, 4-methyl, or 4-methoxy.

9. A method of treating, preventing, or controlling a translocator protein (TSPO)-associated condition comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of Formula I:

10. The method according to claim 9 wherein the TSPO-associated condition is a central nervous system disease.

11. The method according to claim 10 wherein central nervous system disease associated with TSPO dysfunction to be treated, prevented, or controlled is depression, anxiety, mania, cognitive defect, schizophrenia, pains, convulsion, drug dependence, sleep disorders, ingestion disorders, nerve injury, or stress disorders.

17. The method according to claim 9 wherein the compound regulates TSPO activity.

18. The method according to claim 9 wherein the compound comprises a TSPO ligand.

12. A method for combating cell apoptosis in vivo or in vitro, combating a tumor, inflammatory immunoregulation, neuroprotection, or regulating TSPO activity, comprising a step of administering an effective amount of the compound of Formula I: