FLUORO-CONTAINING DERIVATIVES OF HYDROGENATED PYRIDO[4,3-B]INDOLES WITH NEUROPROTECTIVE AND COGNITION ENHANCING PROPERTIES, PROCESS FOR PREPARING, AND USE

• US 20100056790A1
• Filed: 11/18/2009
• Published: 03/04/2010
• Est. Priority Date: 09/20/2007
• Status: Active Grant

• Current Assignee: Elena Sablin
• Original Assignee: D2E, LLC
• Inventors: Beznosko, Nadezhda, Bachurin, Sergey, Aksinenko, Alexey, Sablin, Sergey, Beznosko, Bogdan, Sokolov, Vladimir
• Granted Patent: US 7,935,823 B2
• Time in Patent Office: Days
• US Class Current: 546/87
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• 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 25/14 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 25/22 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 25/32 Alcohol-abuse
• CPC Class Codes: A61P 25/34 Tobacco-abuse
• CPC Class Codes: A61P 25/36 Opioid-abuse
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 31/18 for HIV
• 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: 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

Some exemplary embodiments comprise fluoro-containing derivatives of pyrido[4,3-b]indoles (and exemplary methods of making the same) that may be administered to a mammal (including a human) in an effective amount for potential use in the treatment or prophylaxis of neurological disorders including AD, mild cognitive impairment, senile and vascular dementia, HD, ALS, Parkinson'"'"'s disease, AIDS-related dementia, ischaemic cerebral pathologies, neuropathic pain, ADHD (attention deficit disorder/hyperactivity syndrome), eating disorders such as anorexia and bulimia, panic attacks, withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia (in particular the cognitive deficit of schizophrenia), stroke and also disorders associated with spinal trauma and/or head injury. These derivatives may also be useful for the treatment of borderline personality disorder, obesity, and for use as geroprotectors. The compounds may also be used as “pharmacological tools” for an investigation of the mechanism of protection against neurodegeneration disorders in vivo or in vitro.

Claims

1. A compound having a general formula:

wherein

the solid line accompanied by the dotted line () represents a single or double bond;

R^f is selected from a fluorine atom, two fluorine atoms, or a trifluoromethyl group;

R¹ is selected from a H, (C₁-C₆) alkyl;

hydroxyl (C₂-C₆) alkyl;

(hetero) aryl (C₂-C₆) alkyl;

(C₃-C₇) cycloalkyl;

(C₂-C₆) alkenyl;

(C₁-C₆) alkylsulfonyl;

(hetero) arylsulfonyl;

(C₁-C₆) alkanoyl;

(hetero)) aroyl, (C₁-C₆) alkoxycarbonyl;

(C₁-C₆) alkoxy (C₁-C₆) alkyl;

(hetero) aryloxy (C₁-C₆) alkyl;

amino (C₁-C₆) alkyl, wherein the amino group may be optionally substituted by alkyl, (hetero) aryl, alkenyl, alkanoyl, (hetero) aroyl and other;

or a group CONR⁸R⁹ or SO₂NR⁸N⁹, wherein R⁸ and R⁹ independently represent hydrogen or (C₁-C₆) alkyl, or R⁸ and R⁹ together with the nitrogen atom to which they are attached may form a nitrogen-containing heterocyclic or nitrogen-containing heteroaryl group;

R² and R³ are chosen independently from a hydrogen and a methyl group; and

R⁴, R⁵, R⁶ and R⁷ each represent, independently of each other, a hydrogen or halogen atom or a trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, (C₁-C6) alkyl, (C₁-C₆) alkoxy, phenoxy, phenyl or pyridyl group optionally substituted with a halogen atom or a methyl, methoxy, cyano, trifluoromethyl, or hydroxyl group.

2. A compound according to claim 1, in which R¹ is methyl, R⁵ is methyl, and R^f is fluorine.

3. A compound according to claim 1, in which R¹ is methyl, R⁵ is chlorine, and R^f is fluorine.

4. A compound according to claim 1, in which R¹ is methyl, R⁵ is methyl, and R^f is trifluoromethyl.

5. A compound according to claim 1, in which R¹ is methyl, R⁵ is chlorine, and R^f is trifluoromethyl.

6. A compound according to claim 1, in which R¹ is methyl, R⁵ is fluorine, and R^f is fluorine.

7. A compound according to claim 1, in which R¹ is methyl, R⁵ is bromine, and R^f is fluorine.

8. A compound according to claim 1, in which R¹ is methyl, R⁵ is hydrogen, and R^f is fluorine.

9. A compound according to claim 1, in which R¹ is methyl, R⁵ is trifluoromethyl, and R^f is fluorine.

10. A compound according to claim 1, in which R¹ is methyl, R⁵ is methoxy, and R^f is fluorine.

11. A compound according to claim 1, in which R¹ is methyl, R⁵ is trifluoromethoxy, and R^f is fluorine.

12. A compound according to claim 1, in which R¹ is ethyl, R⁵ is hydrogen, and R^f is fluorine.

13. A compound according to claim 1, in which R¹ is ethyl, R⁵ is methyl, and R^f is fluorine.

14. A compound according to claim 1, in which R¹ is ethyl, R⁵ is fluorine, and R^f is fluorine.

15. A compound according to claim 1, in which R¹ is ethyl, R⁵ is chlorine, and R^f is fluorine.

16. A compound according to claim 1, in which R¹ is ethyl, R⁵ is methoxy, and R^f is fluorine.

17. A compound according to claim 1, in which R¹ is ethyl, R⁵ is trifluoromethoxy, and R^f is fluorine.

18. A compound according to claim 1, in which R¹ is methyl, R⁵ is methyl, R^f is fluorine and R⁷ is methyl.

19. A compound or a pharmacologically acceptable salt thereof, which is selected from a group consisting of:

5-[2-(5-fluoropyridin-3-yl)ethyl]-2-i-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

5-[2-(5-fluoropyridin-3-yl)ethyl]-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

8-fluoro-5-[2-(5-fluoropyridin-3-yl)ethyl]-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

8-chloro-5-[2-(5-fluoropyridin-3-yl)ethyl]-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

8-bromo-5-[2-(5-fluoropyridin-3-yl)ethyl]-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

5-[2-(5-fluoropyridin-3-yl)ethyl]-8-methoxy-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

5-[2-(5-fluoropyridin-3-yl)ethyl]-2,6,8-trimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

6,8-difluoro-5-[2-(5-fluoropyridin-3-yl)ethyl]-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

5-[2-(5-fluoropyridin-3-yl)ethyl]-2-methyl-8-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

5-[2-(5-fluoropyridin-3-yl)ethyl]-2-methyl-8-(trifluoromethoxy)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

2-ethyl-5-[2-(5-fluoropyridin-3-yl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

2-ethyl-5-[2-(5-fluoropyridin-3-yl)ethyl]-8-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

2-benzyl-5-[2-(5-fluoropyridin-3-yl)ethyl]-8-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

2-ethyl-8-fluoro-5-[2-(5-fluoropyridin-3-yl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole; and

8-chloro-2-ethyl-5-[2-(5-fluoropyridin-3-yl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole.

20. A compound or a pharmacologically acceptable salt thereof, which is selected from a group consisting of:

5-[2-(5-fluoropyridin-3-yl)ethyl]-2-iso-propyl-2,3,4,5-tetrahydro-1H pyrido[4,3-b]indole;

5-[2-(5-fluoropyridin-3-yl)ethyl]-2,8-diethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

8-fluoro-5-[2-(5-fluoropyridin-3-yl)ethyl]-2-iso-propyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

8-chloro-5-[2-(5-fluoropyridin-3-yl)ethyl]-2-iso-propyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

8-bromo-5-[2-(5-fluoropyridin-3-yl)ethyl]-2-ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

5-[2-(5-fluoropyridin-3-yl)ethyl]-8-methoxy-2-ethyl-2,3,4,5-tetrahydro-4H-pyrido[4,3-b]indole;

5-[2-(5-fluoropyridin-3-yl)ethyl]-2-ethyl-6,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

6,8-difluoro-5-[2-(5-fluoropyridin-3-yl)ethyl]-2-ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

5-[2-(5-fluoropyridin-3-yl)ethyl]-2-ethyl-8-(trifluoromethyl)-2,3,4,5-tetrahydro-4H-pyrido[4,3-b]indole;

5-[2-(5-fluoropyridin-3-yl)ethyl]-2-ethyl-8-(trifluoromethoxy)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

2-tret-butyl-5-[2-(5-fluoropyridin-3-yl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

2-iso-propyl-5-[2-(5-fluoropyridin-3-yl)ethyl]-8-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

2-tret-butyl-5-[2-(5-fluoropyridin-3-yl)ethyl]-8-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

2-tret-butyl-8-fluoro-5-[2-(5-fluoropyridin-3-yl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

8-chloro-2-tret-butyl-5-[2-(5-fluoropyridin-3-yl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

5-[2-(5-fluoropyridin-3-yl)ethyl]-2,8-diethyl-6-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

8-ethyl-5-[2-(5-fluoropyridin-3-yl)ethyl]-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

8-ethyl-5-[2-(5-fluoropyridin-3-yl)ethyl]-2,6-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

8-ethyl-5-[2-(5-fluoropyridin-3-yl)ethyl]-2-iso-propyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

8-ethyl-5-[2-(5-fluoropyridin-3-yl)ethyl]-2-iso-propyl-6-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

8-ethyl-5-[2-(5-fluoropyridin-3-yl)ethyl]-2-tret-butyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

8-ethyl-5-[2-(5-fluoropyridin-3-yl)ethyl]-2-tret-butyl-6-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

2-methyl-5-{2-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

2,8-dimethyl-5-{2-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

8-fluoro-2-methyl-5-{2-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

8-chloro-2-methyl-5-{2-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

2-methyl-8-(trifluoromethyl)-5-{2-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

5-[2-(6-fluoropyridin-3-yl)ethyl]-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

5-[2-(6-fluoropyridin-3-yl)ethyl]-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

8-fluoro-5-[2-(6-fluoropyridin-3-yl)ethyl]-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

5-[2-(2-fluoropyridin-4-yl)ethyl]-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

5-[2-(2-fluoropyridin-4-yl)ethyl]-2,8-dimethyl-2,3,4,5-tetrahydro-4H-pyrido[4,3-b]indole;

8-fluoro-5-[2-(2-fluoropyridin-4-yl)ethyl]-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

5-[2-(3-fluoropyridin-4-yl)ethyl]-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

5-[2-(3-fluoropyridin-4-yl)ethyl]-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

8-fluoro-5-[2-(3-fluoropyridin-4-yl)ethyl]-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

2-methyl-5-{2-[2-(trifluoromethyl)pyridin-4-yl]ethyl}-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

2,8-dimethyl-5-{2-[2-(trifluoromethyl)pyridin-4-yl]ethyl}-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

8-fluoro-2-methyl-5-{2-[2-(trifluoromethyl)pyridin-4-yl]ethyl}-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole;

2-{5-[2-(5-fluoropyridin-3-yl)ethyl]-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl}ethanol;

2-{5-[2-(5-fluoropyridin-3-yl)ethyl]-8-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl}ethanol; and

2-{8-fluoro-5-[2-(5-fluoropyridin-3-yl)ethyl]-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl}ethanol.