4-(AMINOMETHYL)CYCLOHEXANAMINE DERIVATIVES AS CALCIUM CHANNEL BLOCKERS
Methods and compounds effective in ameliorating conditions characterized by unwanted calcium channel activity, particularly unwanted T-type calcium channel activity are disclosed. Specifically, a series of compounds containing 4-(aminomethyl)cyclohexanamine derivatives as shown in formula (1).
1 . A method to treat a condition modulated by calcium ion channel activity, which method comprises administering to a subject in need of such treatment an amount of the compound of formula (1) effective to ameliorate said condition, wherein said compound is of the formula:
or a pharmaceutically acceptable salt or conjugate thereof, wherein
A is C(O)NH or NHC(O);
X is an optionally substituted alkylene (1-4C), heteroalkylene (2-4C), alkenylene (2-4C), or heteroakenylene (2-4C);
m, n and p are independently 0 or 1;
Ar is an optionally substituted aryl (6-10C) or heteroaryl (5-12 ring members);
each Y is independently H, SR′, SOR′, SO 2 R′, wherein each R′ is independently H or an optionally substituted group selected from alkyl (1-6C), alkenyl (2-6C), alkynyl (2-6C), heteroalkyl (2-6C), heteroalkenyl (2-6), heteroalkynyl (2-6C); or each Y is an optionally substituted group selected from alkyl (1-10C), alkenyl (2-10C), alkynyl (2-10C), heteroalkyl (2-10C), heteroalkenyl (2-10C), heteroalkynyl (2-10C), aryl (6-12C)-alkyl (1-6C) or heteroaryl (5-12 ring members)-alkyl (1-6C); or two Y may together form an optionally substituted heterocyclic ring (4-6 ring members);
wherein the optional substituents on X, Y and Ar may be one or more halo, CN, NO 2 , CF 3 , OCF 3 , COOR′, CONR′ 2 , OR′, SR′, SOR′, SO 2 R′, NR′ 2 , NR′(CO)R′, NR′C(O)OR′, NR′C(O)NR′ 2 , NR′SO 2 NR′ 2 , NR′SO 2 R′, wherein each R′ is independently H or an optionally substituted group selected from alkyl (1-6C), alkenyl (2-6C), alkynyl (2-6C), heteroalkyl (2-6C) heteroalkenyl (2-6), heteroalkynyl (2-6C); or each substituent is alkyl (1-6C), alkenyl (2-6C), alkynyl (2-6C), heteroalkyl (2-6C), heteroalkenyl (2-6C), heteroalkynyl (2-6C); aryl (6-10C), heteroaryl (5-12 ring members), O-aryl (6-10C), O-heteroaryl (5-12 ring members), aryl (6-12C)-alkyl (1-6C) or heteroaryl (5-12 ring members)-alkyl (1-6C); and wherein optional substituents on X and Y may be additionally selected from ═O, ═NOR′.
2 . The method of claim 1 wherein said condition is modulated by T-type calcium channel activity.
3 . The method of claim 1 wherein said condition is cardiovascular disease, epilepsy, diabetes, cancer, chronic or acute pain, sleep disorders, Parkinson's disease, psychosis, overactive bladder, renal disease, addiction, neuroprotection or male birth control.
4 . The method of claim 1 wherein said condition is cardiovascular disease, epilepsy, cancer, or chronic or acute pain.
5 . The method of claim 1 wherein Ar is an optionally substituted phenyl, oxadiazolyl, thiazolyl, pyridinyl, or isoxazolyl.
6 . The method of claim 1 wherein Ar is an optionally substituted phenyl.
7 . The method of claim 1 wherein at least one of m and n is 1.
8 . The method of claim 1 wherein A is NHC(O) if n is 0.
9 . The method of claim 1 wherein p is 0.
10 . The method of claim 1 wherein p is 1.
11 . The method of claim 10 wherein X is an optionally substituted alkylene (1-2C) or an optionally substituted alkenylene (2C).
12 . The method of claim 10 wherein X is methylene.
13 . The method of claim 1 wherein the optional substituents on Ar are independently selected from fluoro, chloro, trifluoromethyl, methyl, ethyl, trifluoromethoxy, t-butyl, t-butyloxy, methoxy, phenyl, or tolyl.
14 . The method of claim 1 wherein at least one Y is H.
15 . The method of claim 1 wherein one Y is an optionally substituted alkyl (1-10C), heteroalkyl (2-10C), aryl(6-10C)alkyl(1-6C), heteroaryl (5-12 ring members)-alkyl (1-6C).
16 . The method of claim 1 wherein Y is an optionally substituted alkyl (1-10C), or heteroalkyl (2-10C).
17 . The method of claim 1 wherein Y is an optionally substituted aryl(6-10C)alkyl(1-3C) or heteroaryl(5-12 ring members)-alkyl (1-3C).
18 . The method of claim 1 wherein two Y together form an optionally substituted heterocyclic ring (4-6 ring members).
19 . The method of claim 1 wherein the compound is of formula 2:
or a pharmaceutically acceptable salt or conjugate thereof, wherein Y is as defined in claim 1 and each R is independently H, fluoro, chloro, trifluoromethyl, methyl, ethyl, trifluoromethoxy, t-butyl, t-butyloxy or methoxy.
20 . The method of claim 1 wherein the compound is:
or a pharmaceutically acceptable salt of one of these.
21 . A pharmaceutical composition comprising a compound of formula (1):
or a pharmaceutically acceptable salt or conjugate thereof, wherein
A is C(O)NH or NHC(O);
X is an optionally substituted alkylene (1-4C), heteroalkylene (2-4C), alkenylene (2-4C), or heteroakenylene (2-4C);
m, n and p are independently 0 or 1;
Ar is an optionally substituted aryl (6-10C) or heteroaryl (5-12 ring members);
each Y is independently H, SR′, SOR′, SO 2 R′, wherein each R′ is independently H or an optionally substituted group selected from alkyl (1-6C), alkenyl (2-6C), alkynyl (2-6C), heteroalkyl (2-6C), heteroalkenyl (2-6), heteroalkynyl (2-6C); or each Y is an optionally substituted group selected from alkyl (1-10C), alkenyl (2-10C), alkynyl (2-10C), heteroalkyl (2-10C), heteroalkenyl (2-10C), heteroalkynyl (2-10C), aryl (6-12C)-alkyl (1-6C) or heteroaryl (5-12 ring members)-alkyl (1-6C); or two Y may together form an optionally substituted heterocyclic ring (4-6 ring members);
wherein the optional substituents on X, Y and Ar may be one or more halo, CN, NO 2 , CF 3 , OCF 3 , COOR′, CONR′ 2 , OR′, SR′, SOR′, SO 2 R′, NR′ 2 , NR′(CO)R′, NR′C(O)OR′, NR′C(O)NR′ 2 , NR′SO 2 NR′ 2 , NR′SO 2 R′, wherein each R′ is independently H or an optionally substituted group selected from alkyl (1-6C), alkenyl (2-6C), alkynyl (2-6C), heteroalkyl (2-6C) heteroalkenyl (2-6), heteroalkynyl (2-6C); or each substituent is alkyl (1-6C), alkenyl (2-6C), alkynyl (2-6C), heteroalkyl (2-6C), heteroalkenyl (2-6C), heteroalkynyl (2-6C); aryl (6-10C), heteroaryl (5-12 ring members), O-aryl (6-10C), O-heteroaryl (5-12 ring members), aryl (6-12C)-alkyl (1-6C) or heteroaryl (5-12 ring members)-alkyl (1-6C); and wherein optional substituents on X and Y may be additionally selected from ═O, ═NOR′;
with the provisos that Ar is not naphthyl and the two Y groups do not together form a pyrrolidin-2-onyl ring.
22 . The pharmaceutical composition of claim 21 wherein Ar is an optionally substituted phenyl, oxadiazolyl, thiazolyl, pyridinyl, or isoxazolyl.
23 . The pharmaceutical composition of claim 21 wherein Ar is an optionally substituted phenyl.
24 . The pharmaceutical composition of claim 21 wherein at least one of m and n is 1.
25 . The pharmaceutical composition of claim 21 wherein A is NHC(O) if n is 0.
26 . The pharmaceutical composition of claim 21 wherein p is 0.
27 . The pharmaceutical composition of claim 21 wherein p is 1.
28 . The pharmaceutical composition of claim 27 wherein X is an optionally substituted alkylene (1-2C) or an optionally substituted alkenylene (2C).
29 . The pharmaceutical composition of claim 27 wherein X is methylene.
30 . The pharmaceutical composition of claim 27 wherein the optional substituents on Ar are independently selected from fluoro, chloro, trifluoromethyl, methyl, ethyl, trifluoromethoxy, t-butyl, t-butyloxy, methoxy, phenyl, or tolyl.
31 . The pharmaceutical composition of claim 21 wherein at least one Y is H.
32 . The pharmaceutical composition of claim 21 wherein one Y is an optionally substituted alkyl (1-10C), heteroalkyl (2-10C), aryl(6-10C)alkyl(1-6C), or heteroaryl (5-12 ring members)-alkyl (1-6C).
33 . The pharmaceutical composition of claim 21 wherein Y is an optionally substituted alkyl (1-10C), or heteroalkyl (2-10C).
34 . The pharmaceutical composition of claim 21 wherein Y is an optionally substituted aryl(6-10C)alkyl(1-3C) or heteroaryl(5-12 ring members)-alkyl (1-3C).
35 . The pharmaceutical composition of claim 21 wherein two Y together form an optionally substituted heterocyclic ring (4-6 ring members).
36 . The pharmaceutical composition of claim 21 wherein the compound is of formula 2:
or a pharmaceutically acceptable salt or conjugate thereof, wherein Y is as defined in claim 21 and each R is independently H, fluoro, chloro, trifluoromethyl, methyl, ethyl, trifluoromethoxy, t-butyl, t-butyloxy or methoxy.
37 . The pharmaceutical composition of claim 21 wherein the compound is:
or a pharmaceutically acceptable salt of one of these.