US2017224687A1PendingUtilityA1
Compounds for modulating trpv3 function
Est. expiryMay 10, 2027(~0.8 yrs left)· nominal 20-yr term from priority
Inventors:Jayhong A. ChongChristopher FangerGlenn R. LarsenMagdalene M. MoranHoward P. NgAmy RipkaDennis John UnderwoodManfred WeigeleXiaoguang Zhen
A61P 25/00A61P 29/00A61K 31/517A61K 31/519A61P 19/02A61P 17/00
51
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Claims
Abstract
The present application relates to compounds and methods for treating pain and other conditions related to TRPV 3 .
Claims
exact text as granted — not AI-modifiedWe claim:
1 . A method for inhibiting a TRPV3 mediated current, comprising contacting a cell with an effective amount of a compound of Formula (I) or a salt thereof:
wherein
said compound inhibits a TRPV3 mediated current with an IC 50 of 10 micromolar or less;
Q is a 6-membered heteroaryl;
A is aryl optionally substituted by 1-5 instances of R 3 ;
L is (CH 2 ) m CH═CH(CH 2 ) n or (CH) m cyclopropyl(CH) n , wherein the cyclopropyl is optionally substituted with 1-3 instances of R 3 ;
Ar′ is heteroaryl optionally substituted by 1-5 instances of R 4 ;
each R 1 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 4 alkyl, C 1 -C 6 haloalkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, earboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, —NHSO 2 NH 2 , or —OCH 2 CH 2 N(R 7 ) 2 , or two adjacent R 1 groups are C 1 -C 4 alkylenedioxy;
each R 3 and R 4 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 4 alkyl, C 1 -C 6 haloalkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl; C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, alkoxyaminocarbonyl, —NHSO 2 NH 2 , —OCH 2 CH 2 NR 7 , or azido, or two adjacent substituents together represent C 1 -C 4 alkylenedioxy, —NHSO 2 NH—, or —NHC(O)NH— forming a heterocycle with the carbons to which they are attached, wherein each R 3 and R 4 is optionally substituted with 1-5 instances of R 6 ;
each R 5 is independently halo, hydroxy, hydroxyalkyl, hydroxyalkoxy, C 1 -C 10 alkyl, C 1 -C 4 alkyl, C 1 -C 6 haloalkyl, C 1 -C 10 alkoxy, alkoxyalkyl, alkoxyalkoxy, C 1 -C 6 haloalkoxy, C 6 -C 10 aryl, C 4 -C 10 heteroaryl, C 7 -C 12 aralkyl, C 5 -C 12 heteroaralkyl, C 2 -C 8 heterocyclyl, C 2 -C 12 alkenyl, C 2 -C 12 alkynyl, C 5 -C 10 cycloalkenyl, C 4 -C 10 heterocycloalkenyl, carboxy, carboxylate, cyano, nitro, amino, aminoalkyl, C 1 -C 6 alkylamino, C 1 -C 6 alkylaminoalkyl, C 1 -C 6 dialkylamino, C 1 -C 6 dialkylaminoalkyl, mercapto, SO 3 H, —S-alkyl, —S(O)alkyl, S(O) 2 alkyl, sulfate, S(O)NH 2 , S(O) 2 NH 2 , phosphonyl, oxo, acyl, aminocarbonyl, C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 dialkylaminocarbonyl, C 1 -C 10 alkoxycarbonyl, C 1 -C 10 thioalkoxycarbonyl, hydrazinocarbonyl, C 1 -C 6 alkyl hydrazinocarbonyl, C 1 -C 6 dialkyl hydrazinocarbonyl, hydroxyaminocarbonyl, or alkoxyaminocarbonyl, or two adjacent R 5 groups are C 1 -C 4 alkylenedioxy;
each R 6 is independently halo, alkyl, amino, hydroxy, alkoxy, or cyano;
R 7 is H or C 1 -C 6 alkyl;
each m and n is independently 0, 1, 2, or 3;
p is 0, 1, or 2; and
q is 0, 1, 2, 3, or 4.
2 . The method of claim 1 , wherein said compound inhibits a TRPV3 mediated current with an IC 50 of 1 micromolar or less.
3 . The method of claim 1 , wherein said compound inhibits a TRPV3 mediated current with an IC 50 of 100 nanomolar or less.
4 . The method of claim 1 , wherein Q is a nitrogen-containing heteroaryl.
5 . The method of claim 1 , wherein the compound of Formula (I) is represented by Formula (Ia) or (Ib):
wherein q is 0, 1, 2, or 3.
6 . The method of claim 5 , wherein A is phenyl substituted by 1-3 instances of R 3 ; or A is
7 . The method of claim 6 , wherein at least one instance of R 3 is C 1 -C 4 alkyl.
8 . The method of claim 6 , wherein each R 3 is independently alkyl.
9 . The method of claim 6 , wherein A is
and R 3 is methyl.
10 . The method of claim 5 , wherein L is (CH 2 ) m CH═CH(CH 2 ) n .
11 . The method of claim 10 , wherein L is trans ethenyl.
12 . The method of claim 5 , wherein Ar′ is a 6-membcrcd nitrogen-containing heteroaryl comprising 1 or 2 nitrogens.
13 . The method of claim 12 , wherein Ar′ is substituted with 1-3 instances of R 4 , and each R 4 is independently halo, hydroxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, or amino.
14 . The method of claim 13 , wherein at least one R 4 is hydroxy.
15 . The method of claim 12 , wherein Ar′ is
optionally substituted with one or more R 4 .
16 . The method of claim 1 , wherein said compound is selected from the group consisting of:
17 . The method of claim 1 , wherein the compound of Formula (I) is represented by Formula (Ic):
wherein q is 0, 1, or 2.
18 . The method of claim 17 , wherein A is phenyl substituted by 1-3 instances of R 3 ; or A is
19 . The method of claim 18 , wherein at least one instance of R 3 is C 1 -C 4 alkyl.
20 . The method of claim 18 , wherein each R 3 is independently alkyl.
21 . The method of claim 18 , wherein A is
and R 3 is methyl.
22 . The method of claim 17 , wherein L is (CH 2 ) m CH═CH(CH 2 ) n .
23 . The method of claim 22 , wherein L is trans ethenyl.
24 . The method of claim 17 , wherein Ar′ is a 6-membered nitrogen-containing heteroaryl comprising 1 or 2 nitrogens.
25 . The method of claim 24 , wherein Ar′ is substituted with 1-3 instances of R 4 , and each R 4 is independently halo, hydroxy, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, or amino.
26 . The method of claim 25 , wherein at least one R 4 is hydroxy.
27 . The method of claim 24 , wherein Ar′ is
optionally substituted with one or more R 4 .Join the waitlist — get patent alerts
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