DI-T-BUTYLPHENYL PIPERAZINES AS CALCIUM CHANNEL BLOCKERS
Methods and compounds effective in ameliorating conditions characterized by unwanted calcium channel activity, particularly unwanted N-type and/or T-type calcium channel activity are disclosed. Specifically, a series of compounds containing di-t-butyl phenyl piperazine derivatives of the general 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
R 1 are independently C(CH 3 ) 3 or C(CF 3 ) 3 ;
each R 2 is independently selected from halo, CN, NO 2 , CF 3 , OCF 3 , COOR′, CONR′ 2 , OR′, SR′, SOR′, SO 2 R′, NR′ 2 , NR′(CO)R′, NR′SO 2 R′, —Si(CH 3 ) 3 , —CH 2 CN, —C(CH 3 ) 2 CN, —C(CH 3 ) 2 CH 2 OR′, —C(CH 3 ) 2 CO 2 R′, —C(CH 3 ) 2 CONHR′, —C(CH 3 ) 2 CONR′ 2 , ═O, and ═NOR′, 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 (2-6C), heteroalkynyl (2-6C); or R 2 may be one or more optionally substituted groups selected from alkyl (1-6C), alkenyl (2-6C), alkynyl (2-6C), heteroalkyl (2-6C), heteroalkenyl (2-6C), heteroalkynyl (2-6C);
m is 0-4 and n is 0-1;
X is alkylenyl (1-3C) or heteroalkylenyl (1-3C);
Ar is an optionally substituted aryl (6-10C) or heteroaryl (5-12 ring members);
wherein the optional substituents on Ar are independently selected from halo, CN, NO 2 , CF 3 , OCF 3 , COOR′, CONR′ 2 , OR′, SR′, SOR′, SO 2 R′, NR′ 2 , NR′(CO)R′, NR′SO 2 R′, —Si(CH 3 ) 3 , —CH 2 CN, —C(CH 3 ) 2 CN, —C(CH 3 ) 2 CH 2 OR′, —C(CH 3 ) 2 CO 2 R′, —C(CH 3 ) 2 CONHR′ and —C(CH 3 ) 2 CONR′ 2 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 (2-6C), heteroalkynyl (2-6C); or the optional substituents may be one or more optionally substituted groups selected from 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).
2 . The method of claim 1 wherein said condition is chronic or acute pain, a mood disorder, a neurodegenerative disorder, a hearing disorder, a gastrointestinal disorder, a genitorurinary disorder, neuroprotection, a metabolic disorder, cardiovascular disease, epilepsy, diabetes, cancer, a sleep disorder, Parkinson's disease, schizophrenia or male birth control.
3 . The method of claim 1 wherein said condition is chronic or acute pain.
4 . The method of claim 1 wherein R 1 is C(CH 3 ) 3 .
5 . The method of claim 1 wherein m is 0-2.
6 . The method of claim 1 wherein m is 0.
7 . The method of claim 1 wherein n is 0.
8 . The method of claim 1 wherein Ar is an optionally substituted furanyl, pyridinyl, thiadizolyl, phenyl, thiophenyl, pyrazolyl, thiazolyl, napthyl, naphthyridinyl, imidazolyl, isoxazolyl, pyrazolopyridinyl, oxazolyl, benzothiophenyl, quinolinyl or isothiazolyl.
9 . A pharmaceutical composition comprising a compound of the formula:
or a pharmaceutically acceptable salt or conjugate thereof, in admixture with a pharmaceutically acceptable excipient, wherein
R 1 are independently C(CH 3 ) 3 or C(CF 3 ) 3 ;
each R 2 is independently selected from halo, CN, NO 2 , CF 3 , OCF 3 , COOR′, CONR′ 2 , OR′, SR′, SOR′, SO 2 R′, NR′ 2 , NR′(CO)R′, NR′SO 2 R′, —Si(CH 3 ) 3 , —CH 2 CN, —C(CH 3 ) 2 CN, —C(CH 3 ) 2 CH 2 OR′, —C(CH 3 ) 2 CO 2 R′, —C(CH 3 ) 2 CONHR′, —C(CH 3 ) 2 CONR′ 2 , ═O, and ═NOR′, 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 (2-6C), heteroalkynyl (2-6C); or R 2 may be one or more optionally substituted groups selected from alkyl (1-6C), alkenyl (2-6C), alkynyl (2-6C), heteroalkyl (2-6C), heteroalkenyl (2-6C), heteroalkynyl (2-6C);
m is 0-4 and n is 0-1;
X is alkylenyl (1-3C) or heteroalkylenyl (1-3C);
Ar is an optionally substituted aryl (6-10C) or heteroaryl (5-12 ring members);
wherein the optional substituents on Ar are independently selected from halo, CN, NO 2 , CF 3 , OCF 3 , COOR′, CONR′ 2 , OR′, SR′, SOR′, SO 2 R′, NR′ 2 , NR′(CO)R′, NR′SO 2 R′, —Si(CH 3 ) 3 , —CH 2 CN, —C(CH 3 ) 2 CN, —C(CH 3 ) 2 CH 2 OR′, —C(CH 3 ) 2 CO 2 R′, —C(CH 3 ) 2 CONHR′ and —C(CH 3 ) 2 CONR′ 2 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 (2-6C), heteroalkynyl (2-6C); or the optional substituents may be one or more optionally substituted groups selected from 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).
10 . The pharmaceutical composition of claim 9 wherein R 1 is C(CH 3 ) 3 .
11 . The pharmaceutical composition of claim 9 wherein m is 0-2.
12 . The pharmaceutical composition of claim 9 wherein m is 0.
13 . The pharmaceutical composition of claim 9 wherein n is 0.
14 . The pharmaceutical composition of claim 9 wherein Ar is an optionally substituted furanyl, pyridinyl, thiadizolyl, phenyl, thiophenyl, pyrazolyl, thiazolyl, napthyl, naphthyridinyl, imidazolyl, isoxazolyl, pyrazolopyridinyl, oxazolyl, benzothiophenyl, quinolinyl or isothiazolyl.