New Compounds

• US 20090149460A1
• Filed: 06/17/2008
• Published: 06/11/2009
• Est. Priority Date: 03/28/2002
• Status: Abandoned Application

• Current Assignee: Martin Nylof, Stefan Berg, Sven Hellberg, Yafeng Xue
• Original Assignee: Martin Nylof, Stefan Berg, Sven Hellberg, Yafeng Xue
• Inventors: Xue, Yafeng, Berg, Stefan, Hellberg, Sven, Nylof, Martin
• Application Number:
  US12/140,510
• Publication Number:
  US 20090149460A1
• Time in Patent Office: Days
• US Class Current: 514/235.200
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/16 Masculine contraceptives
• CPC Class Codes: A61P 15/18 Feminine contraceptives
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 25/24 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 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• 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 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 403/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings

Abstract

The present invention provides new compounds of formula Ia and Ib:

as well as a process for their preparation and new intermediates used therein, pharmaceutical formulations containing said therapeutically active compounds and to the use of said active compounds in therapy.

Claims

1-41. -41. (canceled)

42. A method of prevention and/or treatment of conditions associated with glycogen synthase kinase-3, comprising administering to a mammal, including man in need of such prevention and/or treatment, a therapeutically effective amount of a compound of formula Ia

wherein the compound is in the form of a base or a pharmaceutically acceptable salt thereof, and wherein:

P is a 6-membered ring containing one nitrogen;

R¹ is hydrogen;

R² is C_0-6alkylcyano;

R³ is C_0-6alkylNR⁴R⁵;

m is 1;

n is 1;

R⁴ is selected from the group consisting of hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_0-6alkylC_3-6cycloalkyl, C_0-6alkylaryl, C_0-6alkylheteroaryl, C_1-6alkylNR¹⁴R¹⁵, and a 5- or 6-membered heterocyclic group containing one or two heteroatoms independently selected from N, O, and S, wherein the heterocyclic group is optionally substituted by a group Y;

R⁵ is selected from the group consisting of hydrogen, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_0-6alkylC_3-6cycloalkyl, C_0-6alkylaryl, C_0-6alkylheteroaryl, and C_1-6alkylNR¹⁴R¹⁵;

or R⁴ and R⁵ together with the N to which they are attached may form a 6-membered heterocyclic group containing one nitrogen and one oxygen; and

wherein any C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_0-6alkylC_3-6cycloalkyl, C_0-6alkylaryl, and C_0-6alkylheteroaryl group defined under R² to R⁵ is optionally substituted by one or more groups Z;

R¹⁴ and R¹⁵ are independently selected from hydrogen, C_1-6alkyl, and C_0-6alkylC_3-6cycloalkyl, wherein R¹⁴ and R¹⁵ optionally together form a 5- or 6-membered heterocyclic group containing one or more heteroatoms independently selected from N, O, and S, wherein the heterocyclic group is optionally substituted by a group Y;

Z is independently selected from the group consisting of oxo, halogen, nitro, CN, OR¹⁶, C_1-6alkyl, C_0-6alkylaryl, C_0-6alkylC_3-6cycloalkyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, OC_1-6alkylNR¹⁶R¹⁷, NR¹⁶R¹⁷, CONR¹⁶R¹⁷NR¹⁶(CO)R¹⁷, O(CO)C_1-6alkyl, (CO)OC_1-6alkyl, COR¹⁶, (SO₂)NR¹⁶R¹⁷, SO₂R¹⁶, SOR¹⁶, (CO)C_1-6alkylNR¹⁶R¹⁷, (SO₂)C_1-6alkylNR¹⁶R¹⁷, phenyl, heteroaryl, and a 5- or 6-membered heterocyclic group containing one or two heteroatoms independently selected from N, O, and S, wherein the phenyl, heteroaryl, and heterocyclic groups are optionally substituted by a group Y;

Y is selected from the group consisting of oxo, halogen, nitro, CN, OR¹⁶, C_1-6alkyl, C_0-6alkylaryl, C_0-6alkylC_3-6cycloalkyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, OC_1-6alkylNR¹⁶R¹⁷, NR¹⁶R¹⁷, CONR¹⁶R¹⁷, NR¹⁶(CO)R¹⁷, O(CO)C_1-6alkyl, (CO)OC_1-6alkyl, COR¹⁶, (SO₂)NR¹⁶R¹⁷, SO₂R¹⁶, SOR¹⁶, (CO)C_1-6alkylNR¹⁶R¹⁷ (SO₂)C_1-6alkylNR¹⁶R¹⁷, phenyl, C_0-6alkylaryl, and heteroaryl, wherein the phenyl, C_0-6alkylaryl, and heteroaryl groups are optionally substituted with one or more substituents selected from the group consisting of halogen, nitro, CN, OR¹⁶, C_1-6alkyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoromethoxy, difluoromethoxy, and trifluoromethoxy;

R¹⁶ and R¹⁷ are independently selected from hydrogen and C_1-6alkyl, and wherein R¹⁶ and R¹⁷ optionally together form a 5- or 6-membered heterocyclic group containing one or more heteroatoms independently selected from N, O, and S.

43. A method according to claim 42 wherein in said compound of formula Ia,

R⁵ is C_1-6ylNR¹⁴R¹⁵, and

R⁴ is selected from hydrogen, C_1-6alkyl;

or

R⁴ and R⁵ together with the N to which they are attached form a 6-membered heterocyclic group containing one or more heteroatoms selected independently from N and O, wherein said heterocyclic group may optionally be substituted by a group Y;

and wherein R¹⁴ and R¹⁵ may together form a 5-membered heterocyclic group containing one or more heteroatoms, selected independently from N, and O

Y is selected from C_1-6alkyl, C_0-6alkylaryl, NR¹⁶R¹⁷, phenyl, wherein the phenyl may be optionally substituted with nitro and trifluoromethyl;

wherein R¹⁶ and R¹⁷ may together form a 5-membered heterocyclic group containing one N heteroatom,

in the form of a base or a pharmaceutically acceptable salt thereof.

44. A method according to claim 42 wherein in said compound of formula Ia,

P is pyridyl;

R² is CN;

R³ is C_0-6alkylNR⁴R⁵;

wherein R⁴ and R⁵ may together form a 5- or 6-membered heterocyclic group containing one or more heteroatoms selected independently from N and O,

in the form of a base or a pharmaceutically acceptable salt thereof.

45. A method according to claim 42 wherein in said compound of formula Ia, R⁴ and R⁵ together form a 6-membered heterocyclic group containing one or more heteroatoms selected independently from N and O,

in the form of a base or a pharmaceutically acceptable salt thereof.

46. A method according to claim 42 wherein in said compound of formula Ia is a compound selected from:

2-Hydroxy-3-{5-[(4-methylpiperazin-1-yl)carbonyl]pyridin-2-yl}-1H-indole-5-carbonitrile;

2-Hydroxy-3-[6-(2-morpholin-4-ylethoxy)pyrimidin-4-yl]-1H-indole-5-carbonitrile;

3-(5-{[3-(Dimethylamino)pyrrolidin-1-yl]methyl}pyridin-2-yl)-2-hydroxy-1H-indole-5-carbonitrile;

2-Hydroxy-3-{5-[(4-methylpiperidin-1-yl)methyl]pyridin-2-yl}-1H-indole-5-carbonitrile;

3-[5-(Azetidin-1-ylmethyl)pyridin-2-yl]-2-hydroxy-1H-indole-5-carbonitrile;

2-Hydroxy-3-[5-(piperidin-1-ylmethyl)pyridin-2-yl]-1H-indole-5-carbonitrile;

3-[5-(Morpholin-4-ylcarbonyl)pyridin-2-yl]-5-nitro-1H-indol-2-ol, or

2-Hydroxy-3-[5-(morpholin-4-ylsulfonyl)pyridin-2-yl]-1H-indole-5-carbonitrile;

or a pharmaceutically acceptable salt thereof.

47. A method according to claim 42 wherein in said compound of formula Ia is a compound selected from:

2-Hydroxy-3-{4-[(4-methylpiperazin-1-yl)carbonyl]pyridin-2-yl}-1H-indole-5-carbonitrile;

2-Hydroxy-3-{5-[(4-methylpiperazin-1-yl)methyl]pyridin-2-yl}-1H-indole-5-carbonitrile;

2-Hydroxy-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indole-5-carbonitrile;

2-Hydroxy-3-{5-(pyrrolidin-1-ylmethyl)pyridin-2-yl}-1H-indole-5-carbonitrile;

2-Hydroxy-3-{5-[(4-methyl-1,4-diazepan-1-yl)methyl]pyridin-2-yl}-1H-indole-5-carbonitrile;

2-Hydroxy-3-{5-[(4-pyrrolidin-1-ylpiperidin-1-yl)methyl]pyridin-2-yl}-1H-indole-5-carbonitrile;

3-{5-[(4-Methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indol-2-ol;

6-Chloro-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indol-2-ol;

6-Bromo-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indol-2-ol;

5-Bromo-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indol-2-ol;

3-Fluoro-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-2-oxoindoline-6-carbonitrile;

3-{5-[(4-Benzylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-2-hydroxy-1H-indole-5-carbonitrile;

2-Hydroxy-3-{5-[(4-isopropylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indole-5-carbonitrile;

3-{5-[(4-Ethylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-2-hydroxy-1H-indole-5-carbonitrile;

3-[5-(Morpholin-4-ylmethyl)pyridin-2-yl]-5-thien-2-yl-1H-indol-2-ol;

5-(2-Furyl)-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indol-2-ol;

3-{3-Bromo-5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-5-nitro-1H-indol-2-ol;

3-[5-(Morpholin-4-ylmethyl)pyridin-2-yl]-5-(trifluoromethyl)-1H-indol-2-ol;

6-(2-Hydroxy-5-nitro-1H-indol-3-yl)-N-(2-morpholin-4-ylethyl)nicotinamide;

6-(2-Hydroxy-5-nitro-1H-indol-3-yl)-N-methyl-N-(1-methylpiperidin-4-yl)nicotinamide;

5-Nitro-3-{5-[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]pyridin-2-yl}-1H-indol-2-ol;

3-(5-{[3-(Dimethylamino)pyrrolidin-1-yl]carbonyl}pyridin-2-yl)-5-nitro-1H-indol-2-ol;

6-(5-Cyano-2-hydroxy-1H-indol-3-yl)-N-methyl-N-(2-pyrrolidin-1-ylethyl)pyridine-3-sulfonamide;

3-{5-[(4-Methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-5-(2-methyl-1,3-thiazol-4-yl)-1H-indol-2-ol;

3-[5-(Morpholin-4-ylmethyl)pyridin-2-yl]-5-nitro-1H-indol-2-ol;

6-(5-Cyano-2-hydroxy-1H-indol-3-yl)-N-(2-pyrrolidin-1-ylethyl)pyridine-3-sulfonamide;

2-Hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indole-5-carbonitrile;

2-Hydroxy-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indole-6-carbonitrile;

5,6-Dibromo-3-[5-(morpholin-4-ylmethyl)pyridin-2-yl]-1H-indol-2-ol, or

2-Hydroxy-3-{5-[(4-methylpiperazin-1-yl)sulfonyl]pyridin-2-yl}-1H-indole-6-carbonitrile;

or a pharmaceutically acceptable salt thereof.

48. A method of prevention and/or treatment according to claims 42 wherein said condition associated with glycogen synthase kinase-3 is selected from:

dementia, Alzheimer'"'"'s Disease, Parkinson'"'"'s Disease, Frontotemporal dementia Parkinson'"'"'s Type, Parkinson dementia complex of Guam, HIV dementia, diseases with associated neurofibrillar tangle pathologies and dementia pugilistica.

49. A method according to claim 48, wherein the condition is Alzheimer'"'"'s Disease.

50. A method of prevention and/or treatment according to claim 42 wherein said condition is selected from:

amyotrophic lateral sclerosis, corticobasal degeneration, Down syndrome, Huntington'"'"'s Disease, postencephalitic parkinsonism, progressive supranuclear palsy, Pick'"'"'s Disease, Niemann-Pick'"'"'s Disease, stroke, head trauma and other chronic neurodegenerative diseases, Bipolar Disease, affective disorders, depression, schizophrenia or cognitive disorders.

51. A method of prevention and/or treatment according to claim 42 wherein said condition is selected from:

predemented states, Mild Cognitive Impairment, Age-Associated Memory Impairment, Age-Related Cognitive Decline, Cognitive Impairment No Dementia, mild cognitive decline, mild neurocognitive decline, Late-Life Forgetfulness, memory impairment and cognitive impairment, vascular dementia, dementia with Lewy bodies or Frontotemporal dementia.

52. A method according to claim 50 wherein the condition is Bipolar Disease.