Urea derivatives as calcium channel blockers
View Patent ↗Urea derivatives which comprise piperidine or piperazine rings and further substitution are effective in ameliorating conditions characterized by unwanted calcium ion channel activity.
1. A compound of the formula:
and salts thereof,
wherein A is benzene;
B is piperidine;
R 1 is H or alkyl (1-8C), alkenyl (2-8C) or alkynyl (2-8C);
Z is N;
each R 3 is independently a substituent selected from the group consisting of ═O, alkyl (1-8C), alkenyl (2-8C), alkynyl (2-8C), acyl, aryl, alkylaryl, halo, CHF 2 , CF 3 , OCF 3 , OCHF 2 , OCOR, CN, NO 2 , NR 2 , OR, SR, COR, COOR, CONR 2 , SOR, SO 2 R, SO 3 R, NRCOR, NRCOOR, OCONR 2 , SONR, SO 2 NR, OOCR, NRSOR and NRSO 2 R, wherein R is H or alkyl (1-8C), alkenyl (2-8C), alkynyl (2-8C), aryl, or alkylaryl, wherein two R on the same nitrogen may form a 5-7 membered ring, and wherein two substituents on adjacent carbons may form a 5-7 membered ring;
wherein each R 4 is independently H or alkyl (1-4C);
m is 0-3;
n is 0-2;
each Ar is phenyl; and
wherein each A or B and each Ar moiety in formula (1) may be substituted by one or more substituents selected from the group consisting of ═O (in nonaromatic cyclic moieties), alkyl (1-8C), alkenyl (2-8C), alkynyl (2-8C), acyl, aryl, alkylaryl, halo, CHF 2 , CF 3 , OCF 3 , OCHF 2 , OCOR, CN, NO 2 , NR 2 , OR, SR, COR, COOR, CONR 2 , SOR, SO 2 R, SO 3 R, NRCOR, NRCOOR, OCONR 2 , SONR, SO 2 NR, OOCR, NRSOR and NRSO 2 R, wherein R is H or alkyl (1-8C), alkenyl (2-8C), alkynyl (2-8C), aryl, or alkylaryl, wherein two R on the same nitrogen may form a 5-7 membered ring, and wherein two substituents on adjacent carbons may form a 5-7 membered ring, and
wherein any alkyl, alkenyl, alkynyl or aryl set forth above may further be substituted by ═O, alkyl (1-8C), alkenyl (2-8C), alkynyl (2-8C), acyl, aryl, alkylaryl, halo, CHF 2 , CF 3 , OCF 3 , OCHF 2 , OCOR, CN, NO 2 , NR 2 , OR, SR, COR, COOR, CONR 2 , SOR, SO 2 R, SO 3 R, NRCOR, NROR, NRCOOR, OCONR 2 , SONR, SO 2 NR, OOCR, NRSOR and NRSO 2 R, wherein R is H or alkyl (1-8C), alkenyl (2-8C), alkynyl (2-8C), aryl, or alkylaryl, wherein two R on the same nitrogen may form a 5-7 membered ring, and wherein two substituents on adjacent carbons may form a 5-7 membered.
2. The compound of claim 1 , wherein R 1 is H.
3. The compound of claim 1 , wherein n is 0.
4. The compound of claim 1 , wherein m is 0.
5. The compound of claim 1 , wherein n is 2 and R 3 is ═O or COOH.
6. The compound of claim 1 , wherein each R 4 is H.
7. The compound of claim 1 , which is
4-[(1-methyl-piperidin-4-yl)-phenyl-methyl]-piperazine-1-carboxylic acid benzhydryl-amide;
4-[(1-methyl-piperidin-3-yl)-phenyl-methyl]-piperazine-1-carboxylic acid benzhydryl-amide;
4-[(1-methyl-piperidin-4-yl)-(4-fluoro-phenyl)-methyl]-piperazine-1-carboxylic acid benzhydryl-amide;
4-[(1-methyl-piperidin-4-yl)-(4-chloro-phenyl)-methyl]- piperazine-1-carboxylic acid benzhydryl-amide;
4-[(1-benzyl-piperidin-4-yl)-phenyl-methyl]-piperazine-1-carboxylic acid benzhydryl-amide;
4-[piperidin-4-yl-phenyl-methyl]-piperazine-1-carboxylic acid benzhydryl-amide;
4-[(1-methyl-piperidin-4-yl)-(2,4-dimethyl-phenyl)-methyl]-piperazine-1-carboxylic acid benzhydryl-amide;
4-[(1-methyl-piperidin-4-yl)-(2-chloro-phenyl)-methyl]-piperazine-1-carboxylic acid benzhydryl-amide;
4-[(1-methyl-piperidin-4-yl)-(3-chloro-phenyl)-methyl]-piperazine-1-carboxylic acid benzhydryl-amide;
4-(diphenyl-methyl)-piperazine-1-carboxylic acid benzhydryl-methyl-amide; or
4-[methyl-(1-methyl-piperidin-4-yl)- phenyl-methyl]-piperazine-1-carboxylic acid benzhydryl-amide, or
a salt thereof.
8. The compound of claim 1 which is coupled to polyethylene glycol.