Heteroaryl derivatives as alpha7 nAChR modulators

Patent metadata

Field	Value
Publication number	US-9393247-B2
Application number	US-201514705144-A
Country	US
Kind code	B2
Filing date	May 6, 2015
Priority date	Feb 23, 2011
Publication date	Jul 19, 2016
Grant date	Jul 19, 2016

Abstract

Disclosed is a compound of formula I:

wherein Z, m and R 1 -R 6 are as described herein, as a modulator of nicotinic acetylcholine receptors particularly the α7 subtype, in a subject in need thereof, as well as analogues, prodrugs, isotopically substituted analogs, metabolites, pharmaceutically acceptable salts, polymorphs, solvates, isomers, clathrates, and co-crystal thereof, for use either alone or in combinations with suitable other medicaments, and pharmaceutical compositions containing such compounds and analogues. Also disclosed are a process of preparation of the compounds and the intended uses thereof in therapy, particularly in the prophylaxis and therapy of disorders such as Alzheimer's disease, mild cognitive impairment, senile dementia, and the like.

First claim

The invention claimed is:

1. A method of preventing or treating a disease or its symptoms or a disorder mediated partially or completely by nicotinic acetylcholine receptors, said method comprising administering to a subject having or susceptible to said disease or its symptoms or disorder with a therapeutically effective amount of a compound of formula I, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof,

wherein:
Z is S, O, or NR a , wherein R a is hydrogen, optionally substituted alkyl, or cycloalkyl;
R 1 is selected from the group consisting of optionally substituted aryl, cycloalkyl, optionally substituted heteroaryl, and optionally substituted heterocyclyl;
R 2 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, perhaloalkyl, cycloalkyl, and (R 7 )(R 8 )N—;
R 3 is selected from the group consisting of optionally substituted alkyl, cycloalkyl, heterocyclyl, (R 7 )(R 8 )N—, (R 7 )N(OR 8 )—, and R 7 A 1 -;
[R 4 ] m is ‘m’ times repetition of ‘R 4 ’ groups, each R 4 is independently selected from the group consisting of halogen, R 7 A 1 -, and alkyl, wherein m=0, 1 or 2; or two R 4 groups and the carbon atoms to which they are attached together form an optionally substituted 5- to 6-membered cyclic system;
R 5 and R 6 are independently hydrogen or alkyl; or R 5 and R 6 together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclic ring system containing a nitrogen atom;
wherein R 7 and R 8 are independently selected from the group consisting of hydrogen and optionally substituted alkyl; and
A 1 is selected from the group consisting of 0 and S;
wherein,
the term “optionally substituted alkyl” means an alkyl group unsubstituted or substituted with 1 to 6 substituents selected independently from the group consisting of oxo, halogen, nitro, cyano, aryl, heteroaryl, cycloalkyl, R 10a SO 2 —, R 10 A 1 -, R 10a OC(═O)—, R 10a C(═O)O—, (R 10 )(H)NC(═O)—, (R 10 )(alkyl)NC(═O)—, R 10a C(═O)N(H)—, (R 10 )(H)N—, (R 10 )(alkyl)N—, (R 10 )(H)NC(=A 1 )N(H)—, and (R 10 )(alkyl)NC(=A 1 )N(H)—;
the term “optionally substituted aryl” means (i) an aryl group unsubstituted or substituted with 1 to 3 substituents selected independently from the group consisting of halogen, nitro, cyano, hydroxy, C 1 to C 6 alkyl, C 3 to C 6 cycloalkyl, C 1 to C 6 perhaloalkyl, alkyl-O—, perhaloalkyl-O—, alkyl-N(alkyl)-, alkyl-N(H)—, H 2 N—, alkyl-SO 2 —, perhaloalkyl-SO 2 —, alkyl-C(═O)N(alkyl)-, alkyl-C(═O)N(H)—, alkyl-N(alkyl)C(═O)—, alkyl-N(H)C(═O)—, H 2 NC(═O)—, alkyl-N(alkyl)SO 2 —, alkyl-N(H)SO 2 —, H 2 NSO 2 —, 3- to 6-membered heterocycle containing 1 to 2 heteroatoms selected from the group consisting of N, O and S, wherein said 3- to 6-membered heterocycle is optionally substituted with alkyl, or alkyl-C(═O)— or (ii) said substituted or unsubstituted aryl ring optionally fused with cycloalkane ring or heterocycle ring containing 1 to 3 heteroatoms selected from S, O, and N across a bond, wherein the said cycloalkane ring or heterocycle ring is optionally substituted with oxo, alkyl, or alkyl-C(═O)—;
the term “optionally substituted heterocyclyl” means a (i) heterocyclyl group unsubstituted or substituted on ring carbons with 1 to 6 substituents selected independently from the group consisting of oxo, halogen, nitro, cyano, aryl, heteroaryl, alkyl, R 10 A 1 -, R 10a OC(═O)—, R 10a C(═O)O—, (R 10 )(H)NC(═O)—, (R 10 )(alkyl)NC(O)—, R 10a C(═O)N(H)—, (R 10 )(H)N—, (R 10 )(alkyl)N—, (R 10 )(H)NC(=A 1 )N(H)—, and (R 10 )(alkyl)NC(=A 1 )N(H)—; (ii) heterocyclyl group optionally substituted on ring nitrogen(s) with one or more substituents selected from the group consisting of heteroaryl, alkyl, R 10a C(═O)—, R 10a SO 2 —, R 10a OC(═O)—, (R 10 )(H)NC(═O)—, (R 10 )(alkyl)NC(═O)—, and aryl unsubstituted or substituted with 1 to 3 substituents selected independently from halogen, alkyl, cyano, and nitro;
the term “optionally substituted heteroaryl” means a heteroaryl group unsubstituted or substituted with 1 to 3 substituents selected independently from the group consisting of halogen, nitro, cyano, hydroxy, C 1 to C 6 alkyl, C 3 to C 6 cycloalkyl, C 1 to C 6 perhaloalkyl, alkyl-O—, perhaloalkyl-O—, alkyl-N(alkyl)-, alkyl-N(H)—, H 2 N—, alkyl-SO 2 , perhaloalkyl-SO 2 —, alkyl-C(═O)N(alkyl)-, alkyl-C(═O)N(H)—, alkyl-N(alkyl)-C(═O)—, alkyl-N(H)C(═O)—, H 2 NC(═O), alkyl-N(alkyl)SO 2 —, alkyl-N(H)SO 2 —, H 2 NSO 2 —, and 3- to 6-membered heterocycle containing 1 to 2 heteroatoms selected from the group consisting of N, O, and S, wherein the heterocycle is optionally substituted with one to four substituents selected from the group consisting of alkyl and alkyl-C(═O)—;
the term “optionally substituted 5- to 6-membered cyclic system” means the 5- to 6-membered cyclic system unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of oxo, halogen, nitro, cyano, aryl, heteroaryl, alkyl, R 10a C(═O)—, R 10a SO 2 —, R 10 A 1 , R 10a OC(═O)—, R 10a C(═O)O—, (R 10 )(H)NC(═O)—, (R 10 )(alkyl)NC(═O)—, R 10a C(═C)N(H)—, (R 10 )(H)N—, (R 10 )(alkyl)N—, (R 10 )(H)NC(=A 1 )N(H)—, and (R 10 )(alkyl)NC(=A 1 )N(H)—;
the term “3- to 10-membered optionally substituted heterocyclic ring system” means a 3- to 10-membered heterocyclic ring system unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of oxo, halogen, nitro, cyano, aryl, heteroaryl, alkyl, alkenyl, alkynyl, R 10a C(═O)—, R 10a SO 2 —, R 10 A 1 -, R 10a OC(═O)—, R 10a C(═O)O—, (R 10 )(H)NC(═O)—, (R 10 )(alkyl)NC(═O)—, R 10a C(═O)N(H)—, (R 10 )(H)N—, (R 10 )(alkyl)N—, (R 10 )(H)NC(=A 1 )N(H)—, and (R 10 )(alkyl)NC(=A 1 )N(H)—; wherein R 10 is selected from hydrogen, alkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl;
and R 10a is selected from the group consisting of alkyl, perhaloalkyl, aryl, heteroaryl, cycloalkyl, and heterocyclyl;
wherein the disease or its symptom, or the disorder, is selected from the group consisting of Alzheimer's disease, mild cognitive impairment, senile dementia, vascular dementia, dementia of Parkinson's disease, attention deficit disorder, attention deficit hyperactivity disorder, dementia associated with Lewy bodies, AIDS dementia complex, Pick's disease, dementia associated with Down's syndrome, Huntington's disease, cognitive deficits associated with traumatic brain injury, cognitive decline associated with stroke, poststroke neuroprotection, cognitive and sensorimotor gating deficits associated with schizophrenia, cognitive deficits associated with bipolar disorder, cognitive impairments associated with depression, acute pain, post-surgical or post-operative pain, chronic pain, inflammation, inflammatory pain, neuropathic pain, smoking cessation, need for new blood vessel growth associated with wound healing, need for new blood vessel growth associated with vascularization of skin grafts, lack of circulation, arthritis, rheumatoid arthritis, psoriasis, Crohn's disease, ulcerative colitis, pouchitis, inflammatory bowel disease, celiac disease, periodontitis, sarcoidosis, pancreatitis, organ transplant rejection, acute immune disease associated with organ transplantation, chronic immune disease associated with organ transplantation, septic shock, toxic shock syndrome, sepsis syndrome, depression, and rheumatoid spondylitis.

2. The method of claim 1 , wherein R 2 is selected from the group consisting of hydrogen, optionally substituted alkyl, and (R 7 )(R 8 )N—.

3. The method of claim 2 , wherein R 2 is selected from the group consisting of hydrogen, methyl, dimethylamino, and dimethylaminome

Assignees

• Lupin Ltd

Inventors

• Sinha Neelima
• Jana Gourhari
• Sachchidanand Sachchidanand
• Kurhade Sanjay Pralhad
• Karche Navnath Popat
• Hajare Anil Kashiram
• Tilekar Ajay Ramchandra
• Palle Venkata P
• Kamboj Rajender Kumar

Classifications

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P25/34

  Tobacco-abuse · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title