US2011281836A1PendingUtilityA1
Silent desensitizers of neuronal NACHR and methods of use thereof
Individually held — no corporate assignee on recordPriority: May 23, 2008Filed: Nov 19, 2010Published: Nov 17, 2011
Est. expiryMay 23, 2028(~1.8 yrs left)· nominal 20-yr term from priority
A61P 43/00A61P 5/00A61P 5/14A61P 9/12A61P 25/18A61P 25/00A61P 25/34A61P 25/30A61P 25/14A61P 25/04A61P 25/08A61P 25/16A61P 3/04A61P 25/28A61P 29/00A61P 25/22A61P 25/36A61P 3/00A61P 25/32C07D 401/14A61P 1/12C07D 409/14A61P 1/00C07D 401/12A61P 1/04A61P 21/00C07D 405/14A61P 17/00A61P 11/14
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Claims
Abstract
One aspect of the present invention relates to heterocyclic compounds that are ligands for nicotinic acetylcholine receptors. A second aspect of the invention relates to the use of a compound of the invention for modulation of a mammalian nicotinic acetylcholine receptor.
Claims
exact text as granted — not AI-modified1 . A compound of formula I:
or a pharmaceutically-acceptable tautomer, salt, solvate and/or ester thereof,
wherein
Y is O, S or N(R C );
R C is hydrogen, alkyl or aralkyloxycarbonyl;
Het is optionally-substituted heterocyclyl;
Z is optionally-substituted arylene or optionally-substituted heteroarylene;
R 1 , R 3 and R 4 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halo, hydroxy, alkoxy, amino, alkylamino, dialkylamino, cyano, nitro, formyl, carboxy, alkyloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, haloalkyl, haloalkoxy, haloalkylamino, di(haloalkyl)amino, silyl and silyloxy, wherein said alkyl, alkenyl and alkynyl may be substituted with one, two, three or four substituents selected from the group consisting of hydroxy, alkoxy, amino, alkylamino, dialkylamino, cyano, nitro, formyl, carboxy, alkyloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, haloalkyl, haloalkoxy, haloalkylamino, di(haloalkyl)amino, silyl and silyloxy;
R 2 is
R A is hydrogen or alkyl;
R B is hydrogen or alkyl;
n is 0, 1, 2, 3 or 4; and
X is hydrogen, halo, hydroxyl, alkyloxy, trifluoromethyl or alkyl.
2 . The compound of claim 1 , wherein Y is O.
3 . The compound of claim 1 , wherein Y is S:
4 . The compound of claim 1 , wherein Y is N(R C ).
5 . The compound of claim 1 , wherein Y is N(R C ); and R C is hydrogen.
6 . The compound of claim 1 , wherein Y is N(R C ); and R C is alkyl.
7 . The compound of claim 1 , wherein Y is N(R C ); and R C is —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH 2 CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —CH(CH 3 )CH 2 CH 3 or —CH(CH 2 CH 3 ) 2 .
8 . The compound of any one of claims 1 - 7 , wherein Het is an optionally-substituted azetidenyl or an optionally-substituted pyrrolidinyl.
9 . The compound of any one of claims 1 - 7 , wherein Het is
10 . The compound of any one of claims 1 - 7 , wherein Het is
11 . The compound of claim 9 or 10 , wherein R is hydrogen.
12 . The compound of claim 9 or 10 , wherein R is alkyl.
13 . The compound of claim 9 or 10 , wherein R is —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH 2 CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —CH(CH 3 )CH 2 CH 3 or —CH(CH 2 CH 3 ) 2 .
14 . The compound of claim 9 or 10 , wherein R is aralkyloxycarbonyl.
15 . The compound of claim 9 or 10 , wherein R is benzyloxycarbonyl (Boc).
16 . The compound of any one of claims 1 - 15 , wherein Z is
A is a bond to R 2 ; W is O, S or N(R D ); and
R D is hydrogen, alkyl or aralkyloxycarbonyl.
17 . The compound of any one of claims 1 - 15 , wherein Z is
and A is a bond to R 2 .
18 . The compound of any one of claims 1 - 15 , wherein Z is
A is a bond to R 2 ; W is O, S or N(R D ); and R D is hydrogen, alkyl or aralkyloxycarbonyl.
19 . The compound of claim 18 , wherein W is O.
20 . The compound of claim 18 , wherein W is S.
21 . The compound of claim 18 , wherein W is N(R D ).
22 . The compound of claim 21 , wherein R D is hydrogen.
23 . The compound of claim 21 , wherein R D is alkyl.
24 . The compound of claim 21 , wherein R D is —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH 2 CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —CH(CH 3 )CH 2 CH 3 or —CH(CH 2 CH 3 ) 2 .
25 . The compound of any one of claims 1 - 15 , wherein Z is
and A is a bond to R 2 .
26 . The compound of any one of claims 1 - 15 , wherein Z is
and A is a bond to R 2 .
27 . The compound of any one of claims 1 - 26 , wherein R 1 is hydrogen, halo or alkyl.
28 . The compound of any one of claims 1 - 26 , wherein R 1 is hydrogen.
29 . The compound of any one of claims 1 - 26 , wherein R 1 is chloro.
30 . The compound of any one of claims 1 - 26 , wherein R 1 is —CH 3 .
31 . The compound of any one of claims 1 - 30 , wherein R 3 is hydrogen, halo or alkyl.
32 . The compound of any one of claims 1 - 30 , wherein R 3 is hydrogen.
33 . The compound of any one of claims 1 - 30 , wherein R 3 is chloro.
34 . The compound of any one of claims 1 - 30 , wherein R 3 is —CH 3 .
35 . The compound of any one of claims 1 - 34 , wherein R 4 is hydrogen, halo or alkyl.
36 . The compound of any one of claims 1 - 34 , wherein R 4 is hydrogen.
37 . The compound of any one of claims 1 - 34 , wherein R 4 is chloro.
38 . The compound of any one of claims 1 - 34 , wherein R 4 is —CH 3 .
39 . The compound of any one of claims 1 - 38 , wherein R 2 is
40 . The compound of any one of claims 1 - 38 , wherein R 2 is
41 . The compound of any one of claims 1 - 38 , wherein R 2 is
42 . The compound of any one of claims 1 - 38 , wherein R 2 is
43 . The compound of any one of claims 1 - 38 , wherein R 2 is
44 . The compound of any one of claims 39 - 43 , wherein n is 0.
45 . The compound of any one of claims 39 - 43 , wherein n is 1.
46 . The compound of any one of claims 39 - 43 , wherein n is 2.
47 . The compound of any one of claims 39 - 43 , wherein n is 3.
48 . The compound of any one of claims 39 - 43 , wherein n is 4.
49 . The compound of any one of claims 39 - 48 , wherein X is hydrogen.
50 . The compound of any one of claims 39 - 48 , wherein X is halo.
51 . The compound of any one of claims 39 - 48 , wherein X is fluoro.
52 . The compound of any one of claims 39 - 48 , wherein X is hydroxy.
53 . The compound of any one of claims 39 - 48 , wherein X is trifluoromethyl.
54 . The compound of any one of claims 39 - 48 , wherein X is alkyl.
55 . The compound of any one of claims 39 - 48 , wherein X is —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH 2 CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —CH(CH 3 )CH 2 CH 3 or —CH(CH 2 CH 3 ) 2 .
56 . The compound of any one of claims 39 - 55 , wherein R A is hydrogen.
57 . The compound of any one of claims 39 - 55 , wherein R A is alkyl.
58 . The compound of any one of claims 39 - 55 , wherein R A is —CH 2 or —CH 2 CH 3 .
59 . The compound of any one of claims 39 - 58 , wherein R B is hydrogen.
60 . The compound of any one of claims 39 - 55 , wherein R B is alkyl.
61 . The compound of any one of claims 39 - 55 , wherein R B is —CH 2 or —CH 2 CH 3 .
62 . A compound selected from the group consisting of:
63 . A pharmaceutical composition comprising a compound of any one of claims 1 - 62 , or a pharmaceutically-acceptable tautomer, salt, solvate and/or ester thereof, and a pharmaceutically acceptable excipient.
64 . A method of modulating a nicotine receptor in a subject comprising administering to the subject an effective amount of a compound of any one of claims 1 - 62 , or a pharmaceutically-acceptable tautomer, salt, solvate and/or ester thereof.
65 . A method of treating of one or more conditions or diseases associated aging, addiction, pain, obesity, schizophrenia, epilepsy, mania and manic depression, anxiety, Alzheimer's disease, learning deficit, cognition deficit, attention deficit, memory loss, Lewy Body Dementia, Attention Deficit Hyperactivity Disorder, Parkinson's disease, Huntington's disease, Tourette's syndrome, amyotrophic lateral sclerosis, inflammation, stoke and spinal-cord injury; inflammation, inflammatory skin conditions, Chron's disease, inflammatory bowel disease, ulcerative colitis, diarrhea, endocrine disorders, thyrotoxicosis, pheochromocytoma, hypertension, and cough, comprising administering a therapeutically effective amount of a nicotinic desensitizer of a compound of any one of claims 1 - 62 , or a pharmaceutically-acceptable tautomer, salt, solvate and/or ester thereof, to a subject in need thereof.
66 . A method of weight control, comprising administering a therapeutically effective amount of a compound of any one of claims 1 - 62 , or a pharmaceutically-acceptable tautomer, salt, solvate and/or ester thereof, to a subject in need thereof, thereby resulting in weight control of said subject.
67 . A method for treating addiction in a subject, comprising administering a therapeutically effective amount of a compound of any one of claims 1 - 62 , or a pharmaceutically-acceptable tautomer, salt, solvate and/or ester thereof, to a subject in need thereof, thereby treating a combination addiction.
68 . The method of claim 67 , wherein said addiction is a nicotine addiction, an alcohol addiction or a cocaine addiction.
69 . A method for treating combination addiction in a subject, comprising administering a therapeutically effective amount of a compound of any one of claims 1 - 62 , or a pharmaceutically-acceptable tautomer, salt, solvate and/or ester thereof, to a subject in need thereof, thereby treating a combination addiction.
70 . The method of claim 69 , wherein the combination addiction is an addiction to nicotine and alcohol, or an addiction to nicotine and cocaine.Join the waitlist — get patent alerts
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