7-([1,2,4]TRIAZOLO[1,5-a]PYRIDIN-6-YL)-4-(3,4-DICHLOROPHENYL)-1,2,3,4-TETRAHYDROISOQUINOLINE AND USE THEREOF

• US 20100292243A1
• Filed: 05/11/2010
• Published: 11/18/2010
• Est. Priority Date: 05/12/2009
• Status: Active Grant

• Current Assignee: Consynance Therapeutics Incorporated
• Original Assignee: Albany Molecular Research Incorporated
• Inventors: Molino, Bruce F., Liu, Shuang, Nacro, Kassoum
• Granted Patent: US 8,802,696 B2
• Time in Patent Office: Days
• US Class Current: 514/252.12
• 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 13/10 of the bladder
• 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 25/02 for peripheral neuropathies
• 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 25/22 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 3/02 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 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

Novel [1,2,4]triazolo[1,5-a]pyridinyl-6-yl-substituted tetrahydroisoquinolines are described in the present invention. These compounds and crystalline forms SA1 and N-2 are used in the treatment of various neurological and physiological disorders. Methods of making these compounds and crystalline forms SA-1 and N-2 are also described in the present invention.

Claims

1. A compound of formula (I):

2. The compound according to claim 1, wherein the compound is a (+)-stereoisomer.

3. The compound according to claim 1, wherein the compound is a (−

)-stereoisomer.

4. The compound according to claim 1, wherein the compound is in the S configuration.

5. The compound according to claim 1, wherein the compound is in the R configuration.

6. The compound according to claim 1, wherein the compound is a (S)(+)-stereoisomer.

7. The compound according to claim 1, wherein the compound is a (R)(−

)-stereoisomer.

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

9. A method of treating a disorder which is created by or is dependent upon decreased availability of norepinephrine, dopamine, or serotonin, said method comprising:

administering to a patient in need of such treatment a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

10. The method according to claim 9, wherein the disorder is selected from the group consisting of attention deficit hyperactivity disorder (ADHD), cognition impairment, anxiety disorders, generalized anxiety disorder (GAD), panic disorder, bipolar disorder or manic depression or manic-depressive disorder, obsessive compulsive disorder (OCD), posttraumatic stress disorder (PTSD), acute stress disorder, social phobia, simple phobias, pre-menstrual dysphoric disorder (PMDD), social anxiety disorder (SAD), major depressive disorder (MDD), postnatal depression, dysthymia, depression associated with Alzheimer'"'"'s disease, Parkinson'"'"'s disease, or psychosis, supranuclear palsy, eating disorders, obesity, anorexia nervosa, bulimia nervosa, binge eating disorder, diabetes, ischemic diseases, pain, substance abuse disorders, chemical dependencies, nicotine addiction, cocaine addiction, amphetamine addiction, alcohol addiction, Lesch-Nyhan syndrome, neurodegenerative diseases, Parkinson'"'"'s disease, late luteal phase syndrome or narcolepsy, psychiatric symptoms, anger, rejection sensitivity, movement disorders, extrapyramidal syndrome, Tic disorders, restless leg syndrome (RLS), tardive dyskinesia, supranuclear palsy, sleep related eating disorder (SRED), night eating syndrome (NES), stress urinary incontinence (SUI), migraine, neuropathic pain, diabetic neuropathy, lower back pain, fibromyalgia syndrome (FS), osteoarthritis pain, arthritis pain, chronic fatigue syndrome (CFS), sexual dysfunction, premature ejaculation, male impotence, thermoregulatory disorders (e.g., hot flashes associated with menopause), and irritable bowel syndrome (IBS).

11. The method according to claim 9 further comprising:

administering a therapeutically effective amount of a serotonin 1A receptor antagonist or a pharmaceutically acceptable salt thereof.

12. The method according to claim 11, wherein the serotonin 1A receptor antagonist is selected from the group consisting of WAY 100135 and spiperone.

13. The method according to claim 9 further comprising:

administering a therapeutically effective amount of a selective neurokinin-1 receptor antagonist or a pharmaceutically acceptable salt thereof.

14. The method according to claim 9 further comprising:

administering a therapeutically effective amount of a norepinephrine precursor or a pharmaceutically acceptable salt thereof.

15. The method according to claim 14, wherein the norepinephrine precursor is selected from the group consisting of L-tyrosine and L-phenylalanine.

16. The method according to claim 9, wherein the compound is a (+)-stereoisomer.

17. The method according to claim 9, wherein the compound is a (−

)-stereoisomer.

18. The method according to claim 9, wherein the compound is in the S configuration.

19. The method according to claim 9, wherein the compound is in the R configuration.

20. The method according to claim 9, wherein the compound is a (S)(+)-stereoisomer.

21. The compound according to claim 9, wherein the compound is a (R)(−

)-stereoisomer.

22. A method of inhibiting synaptic norepinephrine uptake in a patient comprising:

administering to the patient a therapeutically effective inhibitory amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

23. The method according to claim 22, wherein the compound is a (+)-stereoisomer.

24. The method according to claim 22, wherein the compound is a (−

)-stereoisomer.

25. The method according to claim 22, wherein the compound is a (S)(+)-stereoisomer.

26. The compound according to claim 22, wherein the compound is a (R)(−

)-stereoisomer.

27. A method of inhibiting synaptic serotonin uptake in a patient comprising:

administering to the patient a therapeutically effective inhibitory amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

28. The method according to claim 27, wherein the compound is a (+)-stereoisomer.

29. The method according to claim 27, wherein the compound is a (−

)-stereoisomer.

30. The method according to claim 27, wherein the compound is a (S)(+)-stereoisomer.

31. The compound according to claim 27, wherein the compound is a (R)(−

)-stereoisomer.

32. A method of inhibiting synaptic dopamine uptake in a patient comprising:

administering to the patient a therapeutically effective inhibitory amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

33. The method according to claim 32, wherein the compound is a (+)-stereoisomer.

34. The method according to claim 32, wherein the compound is a (−

)-stereoisomer.

35. The method according to claim 32, wherein the compound is a (S)(+)-stereoisomer.

36. The compound according to claim 32, wherein the compound is a (R)(−

)-stereoisomer.

37. A method of suppressing the desire of humans to smoke comprising:

administering to a human in need of such suppression an effective amount, to relieve the desire to smoke, of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

38. The method according to claim 37, wherein the compound is a (+)-stereoisomer.

39. The method according to claim 37, wherein the compound is a (−

)-stereoisomer.

40. The method according to claim 37, wherein the compound is a (S)(+)-stereoisomer.

41. The compound according to claim 37, wherein the compound is a (R)(−

)-stereoisomer.

42. A method of suppressing the desire of humans to consume alcohol comprising:

administering to a human in need of such suppression an effective amount, to relieve the desire to consume alcohol, of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

43. The method according to claim 42, wherein the compound is a (+)-stereoisomer.

44. The method according to claim 42, wherein the compound is a (−

)-stereoisomer.

45. The method according to claim 42, wherein the compound is a (S)(+)-stereoisomer.

46. The compound according to claim 42, wherein the compound is a (R)(−

)-stereoisomer.