US 8,299,072 B2Granted

Pyrazolylmethylamine compounds as calcium channel modulators and preparation method thereof

AssigneeKorea Institute of Science and Technology

InventorsGhilsoo Nam, Kyung Il Choi, Hye Ran Kim, Seon Hee Seo, Yoon Jee Kim, Hee Sup Shin, Dong Jin Kim, Ae Nim Pae, Hye Jin Chung, Hyunah Choo, Hyewhon Rhim, Yong Seo Cho, Eun Joo Roh, Gyo Chang Keum, Kee Hyun Choi, Kye Jung Shin, Hoh Gyu Hahn, Chan Seong Cheong, Jae Kyun Lee, Kee Dal Nam, Yong Koo Kang, Youngsoo Kim, Woong Seo Park, Eunice Eun-Kyeong Kim, Key-Sun Kim, Hesson Chung, Dong Yun Shin, Chi man Song

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Abstract

The present invention relates to pyrazolylmethylamine-piperazine derivatives and their pharmaceutically acceptable salts effective as calcium channel modulators and a method of manufacturing the same. The present invention also relates to the medicinal use of the above compounds as therapeutic treatment of diseases due to their effect as calcium channel modulators.

Claims10

Dependent claims

A compound selected from the group consisting of pyrazolylmethylamine-piperazine derivatives represented by the following formula 1 and their pharmaceutically acceptable salts thereof,

wherein
Y represents —(CH2)n—C(O)—;
or —C(O)—(CH2)n—, wherein n is an integer of 1-4;
R1 and R2, which may be same or different, respectively represent a hydrogen atom;
C1-C8 alkyl group;
phenyl group;
phenyl group substituted with at least one substituent selected from the group consisting of halo, hydroxy, carboxy, carboalkoxy, nitro, cyano, amino, mercapto, thioalkyl, C1-C8 alkyl, C1-C8 cycloalkyl, C1-C8 haloalkyl, C1-C8 alkoxy groups, and C3-C8 heterocycloalkyl group comprising at least one heteroatom selected from O, S, and N;
benzyl group;
benzyl group substituted with at least one substituent selected from the group consisting of halo, hydroxy, carboxyl, carboalkoxy, nitro, cyano, amino, mercapto, thioalkyl, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 alkoxy groups, and 5-7 membered heterocycloalkyl groups comprising at least one heteroatom selected from O, S and N;
phenethyl group;
or heteroaryl group comprising at least one heteroatom selected from O, S and N, wherein the heteroaryl group is selected from furyl, pyridyl, pyrimidyl, and piperonyl groups;
and
R3 represents a hydrogen atom;
C1-C8 alkyl group;
heteroaryl group comprising at least one heteroatom selected from O, S and N, wherein the heteroaryl group is selected from furyl, pyridyl, pyrimidyl, and piperonyl groups;
phenyl group;
phenyl group substituted with at least one substituent selected from the group consisting of halo, hydroxy, carboxy, carboalkoxy, nitro, cyano, amino, mercapto, thioalkyl, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 cycloalkyl, C1-C8 alkoxy groups, and C3-C8 heterocycloalkyl group comprising at least one heteroatom selected from O, S, and N;
benzyl group;
benzyl group substituted with at least one substituent selected from the group consisting of halo, hydroxy, carboxy, carboalkoxy, nitro, cyano, amino, mercapto, aryl, haloaryl, thioalkyl, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, arylcarbonyl, phenyl, and benzyl groups, and 5-7 membered heterocycloalkyl groups comprising at least one heteroatom selected from O, S and N, wherein the aryl can be substituted with at least one substituent selected from the group consisting of halo, alkyl, alkoxy, and phenoxy groups;
or R3 represents a benzoyl group;
or furanoyl group.

18 more elements

A compound selected from the group consisting of pyrazolylmethylamine-piperazine derivatives represented by the following formula 1 and their pharmaceutically acceptable salts thereof,

wherein said compound includes:
3-{[4-(2,3-dimethyl)phenylpiperazin-1-yl]methylcarboxamido}methyl-5-methyl-1-phenyl-1H-pyrazole (Compound No. 1);
3-[(4-phenylpiperazin-1-yl)methylcarboxamido]methyl-5-methyl-1-phenyl-1H-pyrazole (Compound No. 2);
3-[(4-benzhydrylpiperazin-1-yl)methylcarboxamido]methyl-5-methyl-1-phenyl-1H-pyrazole (Compound No. 3);
3-{[4-(2,4-dimethylphenyl)piperazin-1-yl]methylcarboxamido}methyl-5-methyl-1-phenyl-1H-pyrazole (Compound No. 4);
3-{[4-(3-trifluoromethyl)benzylpiperazin-1-yl]methylcarboxamido}methyl-5-methyl-1-phenyl-1H-pyrazole (Compound No. 5);
3-{[4-(3,4-dichlorobenzyl)piperazin-1-yl]methylcarboxamido}methyl-5-methyl-1-phenyl-1H-pyrazole (Compound No. 6);
3-{[4-(4-trifluoromethyl)benzylpiperazin-1-yl]methylcarboxamido}methyl-5-methyl-1-phenyl-1H-pyrazole (Compound No. 7);
3-{[4-(2,3,4-trimethoxy)benzylpiperazin-1-yl]methylcarboxamido}methyl-5-methyl-1-phenyl-1H-pyrazole (Compound No. 8);
3-[(4-phenylpiperazin-1-yl)methylcarboxamido]methyl-5-isobutyl-1-phenyl-1H-pyrazole (Compound No. 9);
3-{[4-(2,3-dimethylphenyl)piperazin-1-yl]methylcarboxamido}methyl-5-isobutyl-1-phenyl-1H-pyrazole (Compound No. 10);
3-[(4-phenylpiperazin-1-yl)methylcarboxamido]methyl-5-furyl-1-phenyl-1H-pyrazole (Compound No. 11);
3-{[4-(2,3-dimethylphenyl)piperazin-1-yl]methylcarboxamido}methyl-5-furyl-1-phenyl-1H-pyrazole (Compound No. 12);
3-{[4-(3-trifluoromethylbenzyl)piperazin-1-yl]methylcarboxamido}methyl-5-furyl-1-phenyl-1H-pyrazole (Compound No. 13);
3-{[4-(4-trifluoromethylbenzyl)piperazin-1-yl]methylcarboxamido}methyl-5-furyl-1-phenyl-1H-pyrazole (Compound No. 14);
3-{[4-(3-trifluoromethylbenzyl)piperazin-1-yl]methylcarboxamido}methyl-5-isobutyl-1-phenyl-1H-pyrazole (Compound No. 15);
3-{[4-(4-trifluoromethylbenzyl)piperazin-1-yl]methylcarboxamido}methyl-5-isobutyl-1-phenyl-1H-pyrazole (Compound No. 16);
3-{[4-(2,3,4-trimethoxy)benzylpiperazin-1-yl]methylcarboxamido}methyl-5-isobutyl-1-phenyl-1H-pyrazole (Compound No. 17);
3-{[4-(2,3,4-trimethoxy)benzylpiperazin-1-yl]methylcarboxamido}methyl-5-furyl-1-phenyl-1H-pyrazole (Compound No. 18);
3-[(4-benzhydrylpiperazin-1-yl)methylcarboxamido]methyl-5-isobutyl-1-phenyl-1H-pyrazole (Compound No. 19);
3-[(4-benzhydrylpiperazin-1-yl)methylcarboxamido]methyl-5-furyl-1-phenyl-1H-pyrazole (Compound No. 20);
3-[(4-piperonylpiperazin-1-yl)methylcarboxamido]methyl-5-isobutyl-1-phenyl-1H-pyrazole (Compound No. 21);
3-[(4-piperonylpiperazin-1-yl)methylcarboxamido]methyl-5-furyl-1-phenyl-1H-pyrazole (Compound No. 22);
3-{[4-(3,4-dichloro)benzylpiperazin-1-yl]methylcarboxamido}methyl-5-furyl-1-phenyl-1H-pyrazole (Compound No. 23);
3-{[4-(3,4-dichloro)benzylpiperazin-1-yl]methylcarboxamido}methyl-5-isobutyl-1-phenyl-1H-pyrazole (Compound No. 24);
3-{[4-(4-chlorophenyl)(phenyl)methylpiperazin-1-yl]methylcarboxamido}methyl-5-methyl-1-phenyl-1H-pyrazole (Compound No. 25);
3-{[4-(4-chlorophenyl)(phenyl)methylpiperazin-1-yl]methylcarboxamido}methyl-5-furyl-1-phenyl-1H-pyrazole (Compound No. 26);
3-[(4-phenylpiperazin-1-yl)methylcarboxamido]methyl-5-propyl-1-phenyl-1H-pyrazole (Compound No. 27);
3-{[4-(2,3-dimethyl)phenylpiperazin-1-yl]methylcarboxamido}methyl-5-propyl-1-phenyl-1H-pyrazole (Compound No. 28);
3-{[4-(2,4-dimethyl)phenylpiperazin-1-yl]methylcarboxamido}methyl-5-propyl-1-phenyl-1H-pyrazole (Compound No. 29);
3-[(4-benzhydrylpiperazin-1-yl)methylcarboxamido]methyl-5-propyl-1-phenyl-1H-pyrazole (Compound No. 30);
3-{[4-(3-trifluoromethyl)benzylpiperazin-1-yl]methylcarboxamido}methyl-5-propyl-1-phenyl-1H-pyrazole (Compound No. 31);
3-{[4-(4-trifluoromethyl)benzylpiperazin-1-yl]methylcarboxamido}methyl-5-propyl-1-phenyl-1H-pyrazole (Compound No. 32);
3-[(4-piperonylpiperazin-1-yl)methylcarboxamido]methyl-5-propyl-1-phenyl-1H-pyrazole (Compound No. 33);
3-{[4-(2-pyridyl)piperazin-1-yl]methylcarboxamido}methyl-5-methyl-1-phenyl-1H-pyrazole (Compound No. 34);
3-{[4-(2-pyrimidyl)piperazin-1-yl]methylcarboxamido}methyl-5-methyl-1-phenyl-1H-pyrazole (Compound No. 35);
3-{[4-(2-pyridyl)piperazin-1-yl]methylcarboxamido}methyl-5-isobutyl-1-phenyl-1H-pyrazole (Compound No. 36);
3-{[4-(2-pyrimidyl)piperazin-1-yl]methylcarboxamido}methyl-5-isobutyl-1-phenyl-1H-pyrazole (Compound No. 37);
3-{[4-(2-(pyridyl)piperazin-1-yl]methylcarboxamido}methyl-5-furyl-1-phenyl-1H-pyrazole (Compound No. 38);
3-{[4-(2-pyrimidyl)piperazin-1-yl]methylcarboxamido}methyl-5-furyl-1-phenyl-1H-pyrazole (Compound No. 39);
3-{[4-(4-t-butyl)benzylpiperazin-1-yl]methylcarboxamido}methyl-5-methyl-1-phenyl-1H-pyrazole (Compound No. 40);
3-{[4-(2,4,6-trimethyl)benzylpiperazin-1-yl]methylcarboxamido}methyl-5-methyl-1-phenyl-1H-pyrazole (Compound No. 41);
3-{[4-(4-t-butyl)benzylpiperazin-1-yl]methylcarboxamido}methyl-5-isobutyl-1-phenyl-1H-pyrazole (Compound No. 42);
3-{[4-(2,4,6-trimethyl)benzylpiperazin-1-yl]methylcarboxamido}methyl-5-isobutyl-1-phenyl-1H-pyrazole (Compound No. 43);
3-{[4-(2,3-dimethylphenyl)piperazin-1-yl]methylcarboxamido}methyl-5-(4-methoxy)phenyl-1-phenyl-1H-pyrazole (Compound No. 44);
3-{[4-(2,4-dimethylphenyl)piperazin-1-yl]methylcarboxamido}methyl-5-(4-methoxy)phenyl-1-phenyl-1H-pyrazole (Compound No. 45);
3-[4-furoylpiperazin-1-yl)methylcarboxamido]methyl-5-methyl-1-phenyl-1H-pyrazole (Compound No. 46);
3-[(4-furoylpiperazin-1-yl)methylcarboxamido]methyl-5-isobutyl-1-phenyl-1H-pyrazole (Compound No. 47);
3-{[4-(2-cyanophenyl)piperazin-1-yl]methylcarboxamido}methyl-5-methyl-1-phenyl-1H-pyrazole (Compound No. 48);
3-{[4-(2-cyanophenyl)piperazin-1-yl]methylcarboxamido}methyl-5-propyl-1-phenyl-1H-pyrazole (Compound No. 49);
3-{[4-(2,3-dimethylphenyl)piperazin-1-yl]methylcarboxamido}methyl-5-(4-thiomethyl)phenyl-1-phenyl-1H-pyrazole (Compound No. 50);
3-{[4-(2,4-dimethylphenyl)piperazin-1-yl]methylcarboxamido}methyl-5-(4-thiomethyl)phenyl-1-phenyl-1H-pyrazole (Compound No. 51);
3-{[4-(3-hydroxyphenyl)piperazin-1-yl]methylcarboxamido}methyl-5-methyl-1-phenyl-1H-pyrazole (Compound No. 52);
3-{[4-(3-hydroxyphenyl)piperazin-1-yl]methylcarboxamido}methyl-5-isobutyl-1-phenyl-1H-pyrazole (Compound No. 53);
3-[(4-phenylpiperazin-1-yl)methylcarboxamido]methyl-5-(4-thiomethyl)phenyl-1-phenyl-1H-pyrazole (Compound No. 54);
3-{[4-(3-hydroxyphenyl)piperazin-1-yl]methylcarboxamido}methyl-5-(4-thiomethyl)phenyl-1-phenyl-1H-pyrazole (Compound No. 55);
3-{[4-(2,3-dimethylphenyl)piperazin-1-yl]methylcarboxamido}methyl-5-propyl-1-(4-carboxyl)phenyl-1H-pyrazole (Compound No. 56);
3-{[4-(2,3-dimethylphenyl)piperazin-1-yl]methylcarboxamido}methyl-5-isobutyl-1-(4-carboxyl)phenyl-1H-pyrazole (Compound No. 57);
3-{[4-(2,3-dimethylphenyl)piperazin-1-yl]methylcarboxamido}methyl-5-methyl-1-(4-carboxyl)phenyl-1H-pyrazole (Compound No. 58);
3-{[4-(2,3-dimethylphenyl)piperazin-1-yl]methylcarboxamido}methyl-5-(4-morpholino)phenyl-1-phenyl-1H-pyrazole (Compound No. 59);
3-[(4-phenylpiperazin-1-yl)methylcarboxamido]methyl-5-(4-morpholino)phenyl-1-phenyl-1H-pyrazole (Compound No. 60);
3-{[4-(2,4-dimethylphenyl)piperazin-1-yl]methylcarboxamido}methyl-5-(4-morpholino)phenyl-1-phenyl-1H-pyrazole (Compound No. 61);
3-{[4-(3-trifluorobenzyl)piperazin-1-yl]methylcarboxamido}methyl-5-(4-morpholino)phenyl-1-phenyl-1H-pyrazole (Compound No. 62);
3-{[4-(4-trifluorobenzyl)piperazin-1-yl]methylcarboxamido}methyl-5-(4-morpholino)phenyl-1-phenyl-1H-pyrazole (Compound No. 63);
3-{[4-(2,3-dimethylphenyl)piperazin-1-yl]carbonylmethylamino}methyl-5-methyl-1-phenyl-1H-pyrazole (Compound No. 64);
3-[(4-benzhydrylpiperazin-1-yl)carbonylmethylamino]methyl-5-methyl-1-phenyl-1H-pyrazole (Compound No. 65);
3-[(4-phenylpiperazin-1-yl)carbonylmethylamino]methyl-5-methyl-1-phenyl-1H-pyrazole (Compound No. 66);
3-[(4-phenylpiperazin-1-yl)carbonylmethylamino]methyl-5-isobutyl-1-phenyl-1H-pyrazole (Compound No. 67);
3-[(4-benzhydrylpiperazin-1-yl)carbonylmethylamino]methyl-5-isobutyl-1-phenyl-1H-pyrazole (Compound No. 68);
3-{[4-(2,4-dimethylphenyl)piperazin-1-yl]carbonylmethylamino}methyl-5-isobutyl-1-phenyl-1H-pyrazole (Compound No. 69);
3-[(4-phenylpiperazin-1-yl)carbonylmethylamino]methyl-5-furyl-1-phenyl-1H-pyrazole (Compound No. 70);
3-[(4-benzhydrylpiperazin-1-yl)carbonylmethylamino]methyl-5-furyl-1-phenyl-1H-pyrazole (Compound No. 71);
3-{[4-(2,4-dimethyl)phenylpiperazin-1-yl]carbonylmethylamino}methyl-5-furyl-1-phenyl-1H-pyrazole (Compound No. 72);
3-{[4-(2,4-dimethyl)phenylpiperazin-1-yl]carbonylmethylamino}methyl-5-methyl-1-phenyl-1H-pyrazole (Compound No. 73);
3-{[4-(3,4-dichloro)benzylpiperazin-1-yl]carbonylmethylamino}methyl-5-methyl-1-phenyl-1H-pyrazole (Compound No. 74);
3-{[4-(3,4-dichlorobenzyl)piperazin-1-yl]carbonylmethylamino}methyl-5-isobutyl-1-phenyl-1H-pyrazole (Compound No. 75);
3-{[4-(2,3-dimethylphenyl)piperazin-1-yl]carbonylmethylamino}methyl-5-isobutyl-1-phenyl-1H-pyrazole (Compound No. 76);
3-{[4-(2,3-dimethylphenyl)piperazin-1-yl]carbonylmethylamino}methyl-5-furyl-1-phenyl-1H-pyrazole (Compound No. 77);
3-{[4-(3,4-dichlorobenzyl)piperazin-1-yl]carbonylmethylamino}methyl-5-furyl-1-phenyl-1H-pyrazole (Compound No. 78);
3-[(4-piperonylpiperazin-1-yl)carbonylmethylamino]methyl-5-isobutyl-1-phenyl-1H-pyrazole (Compound No. 79);
3-[(4-piperonylpiperazin-1-yl)carbonylmethylamino]methyl-5-furyl-1-phenyl-1H-pyrazole (Compound No. 80);
3-{[4-(2,3,4-trimethoxybenzyl)piperazin-1-yl]carbonylmethylamino}methyl-5-isobutyl-1-phenyl-1H-pyrazole (Compound No. 81);
3-{[4-(2,3-dimethylphenyl)piperazin-1-yl]carbonylmethylamino}methyl-5-propyl-1-phenyl-1H-pyrazole (Compound No. 82);
3-{[4-(2,4-dimethylphenyl)piperazin-1-yl]carbonylmethylamino}methyl-5-propyl-1-phenyl-1H-pyrazole (Compound No. 83);
3-[(4-phenylpiperazin-1-yl)carbonylmethylamino]methyl-5-propyl-1-phenyl-1H-pyrazole (Compound No. 84);
3-[(4-phenylpiperazin-1-yl)methylcarboxamido]methyl-5-methyl-1-[(4-methoxy)phenyl]-1H-pyrazole (Compound No. 85);
3-[(4-phenylpiperazin-1-yl)methylcarboxamido]methyl-5-[(4-piperidino)phenyl]-1-phenyl-1H-pyrazole (Compound No. 86);
3-[(4-phenylpiperazin-1-yl)methylcarboxamido]methyl-5-isobutyl-1-[(4-methoxy)phenyl]-1H-pyrazole (Compound No. 87);
3-{(4-(2,3-dimethylphenyl)piperazin-1-yl]methylcarboxamido}methyl-5-isobutyl-1-[(4-methoxy)phenyl]-1H-pyrazole (Compound No. 88);
3-[(4-phenylpiperazin-1-yl)methylcarboxamido]methyl-5-(2-pyridyl)-1-phenyl-1H-pyrazole (Compound No. 89);
3-{(4-(2,3-dimethylphenyl)piperazin-1-yl]methylcarboxamido}methyl-5-(2-pyridyl)-1-phenyl-1H-pyrazole (Compound No. 90);
3-[(4-phenylpiperazin-1-yl)methylcarboxamido]methyl-5-[(4-methyl)phenyl]-1-phenyl-1H-pyrazole (Compound No. 91);
3-{(4-(2,3-dimethylphenyl)piperazin-1-yl]methylcarboxamido}methyl-5-[(4-methyl)phenyl]-1-phenyl-1H-pyrazole (Compound No. 92);
3-[(4-phenylpiperazin-1-yl)methylcarboxamido]methyl-5-methyl-1-benzyl-1H-pyrazole (Compound No. 93);
3-{(4-(2,3-dimethylphenyl)piperazin-1-yl]methylcarboxamido}methyl-5-methyl-1-benzyl-1H-pyrazole (Compound No. 94);
3-{[4-(2,3-dimethylphenyl)piperazin-1-yl]carbonylmethylamino}methyl-5-methyl-1H-pyrazole (Compound No. 95);
and their pharmaceutically acceptable salts thereof.

94 more elements

Dependencies are inferred from the claim text.

Facts

Application: 12/568,243Filed 28 Sep 2009
Priority: KR 10-2008-010124915 Oct 2008
Published: US 2010/0094006 A115 Apr 2010
Granted: 30 Oct 2012
Term ends: Not estimatedThe source records don’t support an estimate.

Classification6 codes

C07D 231/12
Having two or three double bonds between ring members or between ring members and non-ring members: with only hydrogen atoms, hydrocarbon or…
C07D 401/04
Containing two hetero rings: directly linked by a ring-member-to-ring-member bond
C07D 405/04
Containing two hetero rings: directly linked by a ring-member-to-ring-member bond
C07D 405/10
Containing two hetero rings: linked by a carbon chain containing aromatic rings