Substituted 2,3,4,5-Tetrahyrdo-1H-Pyrido[4,3-B]Indoles, Methods for the Production and Use Thereof

• US 20100120792A1
• Filed: 04/01/2008
• Published: 05/13/2010
• Est. Priority Date: 04/05/2007
• Status: Active Grant

• Current Assignee: Alla Chem LLC
• Original Assignee: Alla Chem LLC
• Inventors: Mitkin, Oleg Dmitrievich, Ivachtchenko, Alexandre Vasilievich, Okun, llya Matusovich, Frolov, Evgueni Borisovich, Savchuk, Nikolay Filippovich, Ivashchenko, Andrey Alexandrovich, Tkachenko, Sergey Yevgenievich, Lavrovsky, Yan
• Granted Patent: US 8,541,437 B2
• Time in Patent Office: Days
• US Class Current: 514/255.50
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• CPC Class Codes: A61K 31/444 containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• 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 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• 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 471/04 Ortho-condensed systems

Abstract

The invention relates to antagonists of serotonin 5-HT₆ receptors simultaneously regulating homeostasis of Ca⁺² ions in cells, representing substituted 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles of the general formula 1, pharmaceutically acceptable salts and/or hydrate thereof. In the general formula 1:

R¹ represents amino group substituent selected from optionally substituted C₁-C₅ alkyl; R², is one or more substituents selected from hydrogen, halogen, C₁-C₃ alkyl, CF₃, OCF₃; Ar is phenyl optionally substituted with halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, substituted amino group, or CF₃; or optionally substituted aromatic 6-membered heterocycle comprising 1-2 nitrogen atoms in the cycle; W represents ethylene group —CH₂—CH₂—, ethenyl group —CH═CH—, or ethynyl group —C≡C—. The invention also relates to the novel compounds selected from the compounds of the general formula 1, methods for their preparation, pharmaceutical compositions and methods of their use.

Claims

1-40. -40. (canceled)

41. A compound of the formula 1;

or a pharmaceutically acceptable salt, or hydrate thereof;

wherein R¹ is C₁-C₅ alkyl;

R²_i is independently hydrogen, halogen, C₁-C₃ alkyl, CF₃, OCF₃ or OCH₃;

i is 1, 2, 3, or 4;

Ar is unsubstituted phenyl or substituted phenyl substituted with halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, a substituted amino group or trifluoromethyl;

or Ar is a substituted or unsubstituted 6-membered aromatic heterocycle, with one to two nitrogen atoms in the heterocycle; and

W is an ethylene group, ethenyl group or ethynyl group;

with the exception of;

2-methyl-5-phenethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 2-methyl-5-[2-(pyridin-2-yl)ethyl)]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 2-methyl-5-[2-(pyridin-4-yl)ethyl)]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 2,8-dimethyl-5-[2-(pyridin-4-yl)ethyl)]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 2-methyl-8-trifluoromethyl-5-[2-(pyridin-4-yl)ethyl)]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 2-methyl-8-carboxy-5-[2-(pyridin-4-yl)ethyl)]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 2-methyl-8-ethyloxycarbonyl-5-[2-(pyridin-4-yl)ethyl)]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 2-C₁-C₅ alkyl-5-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles, 2-C₁-C₅ alkyl-8-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles, 2-benzyl-5-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 2-benzyl-8-chloro-5-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,5-tetrahydro-1,4-pyrido[4,3-b]indole, 2-benzyl-8-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 2,7-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 7-chloro-2-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 7-trifluoromethyl-2-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 2,8-dimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 8-bromo-2-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 8-chloro-2-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 8-trifluoromethyl-2-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 2,6-dimethyl-8-chloro-5-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 2,7,8-trimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 7,8-dichloro-2-methyl-5-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 2,8-dimethyl-7-chloro-5-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 2,7-dimethyl-8-chloro-5-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 2,8,9-trimethyl-5-[2-(6-methylpyridin-3-yl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole, 2-methyl-8-chloro-5-[2-(pyridin-3-yl)ethyl]2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole and 2-methyl-5-[2-(2-methylpyridin-3-yl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole or a pharmaceutically acceptable salt thereof.

42. The compound according to claim 41, wherein W is an ethenyl group.

43. The compound according to claim 42, wherein the compound is:

wherein R² is hydrogen, F, CH₃, CF₃, OCF₃ or OCH₃; and

Ar is substituted phenyl or substituted pyridyl.

44. The compound according to claim 42, wherein the compound is:

or a pharmaceutically acceptable salt or hydrate thereof.

45. The compound according to claim 41, of the formula 1.2, or a pharmaceutically acceptable salt or hydrate thereof:

46. The compound according to claim 45, wherein the compound is:

wherein R² is hydrogen, F, CH₃, CF₃, OCF₃ or OCH₃.

47. The compound according to claim 45, wherein the compound is:

or a pharmaceutically acceptable salt or hydrate thereof.

48. The compound according to claim 41, of the formula 1.3, or a pharmaceutically acceptable salt or hydrate thereof:

49. The compound according to claim 48, wherein the compound is:

wherein R² is hydrogen, F, CH₃, CF₃, OCF₃ or OCH₃.

50. The compound according to claim 49, wherein the compound is:

or a pharmaceutically acceptable salt or hydrate thereof.

51. A formulation comprising a compound or a pharmaceutically acceptable salt or hydrate thereof, of claim 41 and a pharmaceutically acceptable carrier with the exception of a formulation including a compound of the general formula A:

wherein R¹ is CH₃, C₂H₅, or PhCH₂;

R² is 6-CH₃-3-Py-(CH₂)₂—

; and

R³ is hydrogen, CH₃, or Br.

52. The formulation according to claim 51, which is in the form of a tablet, capsule or an injectable liquid.

59. A therapeutic cocktail for treatment of cognitive disorders and neurodegenerative diseases in an animal or human comprising a neuroprotective medicament of a compound of claim 41, or a pharmaceutically acceptable salt or hydrate thereof, in the form of a tablet, capsule or injection placed in a pharmaceutically acceptable packing.

60. A method of treating a cognitive disorder or neurodegenerative disease in a subject in need thereof comprising administering to the subject an effective dose of the therapeutic cocktail of claim 59.

53. A method of antagonizing a 5-HT₆ serotonin receptor and simultaneously regulating Ca⁺² ion homeostasis in a cell, comprising administering to the cell a compound of formula 1;

or a pharmaceutically acceptable salt or hydrate thereof;

wherein R¹ is C₁-C₅ alkyl;

R² is independently hydrogen, halogen, C₁-C₃ alkyl, CF₃, OCF₃ or OCH₃;

i is 1, 2, 3 or 4;

Ar is unsubstituted phenyl or substituted phenyl substituted with halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, a substituted amino group or trifluoromethyl;

or Ar is a substituted or unsubstituted 6-membered aromatic heterocycle with one to two nitrogen atoms in the heterocycle; and

W is an ethylene group, ethenyl group or ethynyl group.

54. A method of treating a cognitive disorder or neurodegenerative disease in a subject in need thereof comprising administering an effective dose to the subject of a compound of formula 1;

or a pharmaceutically acceptable salt or hydrate thereof;

wherein R¹ is C₁-C₅ alkyl;

R² is independently hydrogen, halogen, C₁-C₃ alkyl, CF₃, OCF₃ or OCH₃;

i is 1, 2, 3 or 4;

Ar is unsubstituted phenyl or substituted phenyl substituted with halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, a substituted amino group or trifluoromethyl;

or Ar is a substituted or unsubstituted 6-membered aromatic heterocycle with one to two nitrogen atoms in the heterocycle; and

W is an ethylene group, ethenyl group or ethynyl group.

55. The method according to claim 54, wherein the disorder or disease is Alzheimer'"'"'s, Huntington'"'"'s, a psychotic disorder, schizophrenia, depression, an anxiety disorder, hypoxia-ischemia, a convulsive state, cerebral damage, lathyrism, amyotrophic lateral sclerosis, or premature senility.

56. The method according to claim 55, wherein the compound is:

or a pharmaceutically acceptable salt or hydrate thereof.

57. A method of treating obesity in a subject in need thereof comprising administering an effective dose to the subject of a compound of formula 1;

or a pharmaceutically acceptable salt or hydrate thereof;

wherein R^I is C₁-C₅ alkyl;

R² is independently hydrogen, halogen, C₁-C₃ alkyl, CF₃, OCF₃ or OCH₃;

i is 1, 2, 3 or 4;

Ar is unsubstituted phenyl or substituted phenyl substituted with halogen, C₁-C₆ alkyl, C₁-C₆ alkoxy, a substituted amino group or trifluoromethyl;

or Ar is a substituted or unsubstituted 6-membered aromatic heterocycle with one to two nitrogen atoms in the heterocycle; and

W is an ethylene group, ethenyl group or ethynyl group.

58. The method of claim 57, wherein the compound is:

or a pharmaceutically acceptable salt or hydrate thereof.