Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof

• US 9,034,899 B2
• Filed: 05/11/2010
• Issued: 05/19/2015
• Est. Priority Date: 05/12/2009
• Status: Active Grant

• Current Assignee: Consynance Therapeutics Incorporated
• Original Assignee: Albany Molecular Research Incorporated
• Inventors: Liu, Shuang, Molino, Bruce F., Nacro, Kassoum
• Primary Examiner(s): Ward, Paul V.
• Application Number:
  US12/777,728
• Publication Number:
  US 20100292242A1
• Time in Patent Office: 1,834 Days
• Field of Search: 546/139, 514/307
• US Class Current: 514/307
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• 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 25/06 Antimigraine agents
• 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 3/02 Nutrients, e.g. vitamins, minerals
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• 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 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 217/02 : with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
• CPC Class Codes: C07D 217/12 : with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
• CPC Class Codes: C07D 217/14 : other than aralkyl radicals
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems

Abstract

Novel aryl, heteroaryl, and non-aromatic heterocyle substituted tetrahydroisoquinolines are described in the present invention. These compounds are used in the treatment of various neurological and physiological disorders. Methods of making these compounds are also described in the present invention.

Claims

1. A compound of formula (I):

2. The compound of claim 1, wherein R¹ is H, C₁-C₆ alkyl, or gem-dialkyl of which each alkyl is C₁-C₄.

3. The compound of claim 1, wherein R² is H, halogen, —

OR¹¹, —

S(O)_nR¹², —

CN, —

C(O)R¹², —

C(O)NR¹¹R¹², C₁-C₆ alkyl, or substituted C₁-C₆ alkyl.

4. The compound of claim 1, wherein R³ is a heteroaryl selected from the group consisting of pyridyl, 2-oxo-pyridin-1-yl, quinolinyl, isoquinolinyl, quinolizinyl, 1H-pyrrolo[2,3-b]pyridinyl, imidazo[1,2-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl, thieno[2,3-b]pyridinyl, thieno[3,2-b]pyridinyl, furo[2,3-b]pyridinyl, furo[3,2-b]pyridinyl, 2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, and 3-oxo-[1,2,4]triazolo[4,3-a]pyridinyl, each of which is optionally and independently substituted from 1 to 4 times with substituents as defined in R¹⁴.

5. The compound of claim 1, wherein R³ is a non-aromatic heterocycle selected from the group consisting of piperidinyl and 2-oxopiperidinyl, each of which is optionally and independently substituted from 1 to 4 times with substituents as defined in R¹⁴.

6. The compound of claim 1, wherein R⁴ is H, Cl, F, CH₃, OH, or OCH₃.

7. The compound of claim 1, wherein R⁵, R⁶, and R⁷ are each independently selected from the group consisting of H, halogen, —

OR¹¹, —

NR¹¹R¹², —

NR¹¹C(O)R¹², S(O)_nR¹², —

CN, —

C(O)R¹², —

C(O)NR¹¹R¹², C₁-C₆ alkyl, and substituted C₁-C₆ alkyl.

8. The compound of claim 7, wherein R⁷ is H.

9. The compound of claim 8, wherein R⁵ and R⁶ are each H, F, Cl, OH, OCH₃, or CH₃.

10. The compound of claim 1, wherein R⁸ is H, OH, CH₃, or F.

11. The compound of claim 1, wherein:

R¹ is H, C₁-C₆ alkyl, or gem-dialkyl of which each alkyl is C₁-C₄;

R² is H, halogen, —

OR¹¹, —

S(O)₂R¹², C₁-C₆ alkyl, or substituted C₁-C₆ alkyl;

R³ is heteroaryl or non-aromatic heterocycle;

R⁴ is H, F, or Cl; and

R⁵, R⁶, and R⁷ are each independently H, halogen, —

OR¹¹, —

NR¹¹R¹², —

S(O)₂R¹², —

C(O)R¹², C₁-C₆ alkyl, or substituted C₁-C₆ alkyl.

12. A compound according to claim 1, selected from the group consisting of:

1-(4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)pyridin-2(1H)-one;

4-(3,4-dichlorophenyl)-6-fluoro-7-(pyridin-2-yl)-1,2,3,4-tetrahydroisoquinoline;

7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline;

7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline;

7-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline;

and an oxide thereof, or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound according to claim 1.

13. A compound of formula (I):

14. A compound of formula (I):

15. The compound according to claim 14, selected from the group consisting of:

7-([1,2,4] triazolo [1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-6-fluoro-1,2,3,4-tetrahydroisoquinoline;

7-([1,2,4] triazolo [1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-6-fluoro-1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline;

7-([1,2,4] triazolo [1,5-a]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,1-dimethyl-1,2,3,4-tetrahydroisoquinoline;

4-(3,4-dichlorophenyl)-7-(5-methyl-[1,2,4] triazolo [1,5-a]pyridin-6-yl)-1,2,3,4-tetrahydroisoquinoline;

4-(3,4-dichlorophenyl)-7-(7-methyl-[1,2,4] triazolo [1,5-a]pyridin-6-yl)-1,2,3,4-tetrahydroisoquinoline;

4-(3,4-dichlorophenyl)-7-(8-methyl-[1,2,4] triazolo [1,5-a]pyridin-6-yl)-1,2,3,4-tetrahydroisoquinoline;

4-(3,4-dichlorophenyl)-7-(2-methyl-[1,2,4] triazolo [1,5-a]pyridin-6-yl)-1,2,3,4-tetrahydroisoquinoline;

6-(4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-[1,2,4]triazolo [1,5-a]pyridin-2(3H)-one;

and an oxide thereof, or a pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the compound according to claim 14.