US 2010/0249176 A1Published application

Heterocycle amide t-type calcium channel antagonists

OwnerJames C. Barrow, Thomas S. Reger +2inventors

InventorsJames C. Barrow, Thomas S. Reger, Youheng Shu, Zhi-Qiang Yang

Life of this patent

Estimating the term…

Abstract

The present invention is directed to heterocycle amide compounds which are antagonists of T-type calcium channels, and which are useful in the treatment or prevention of disorders and diseases in which T-type calcium channels are involved. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which T-type calcium channels are involved.

Claims18

Dependent claims

A compound of the formula I:

wherein:
A is heteroaryl;
R1a, R1b and R1c may be absent if the valency of A does not permit such substitution and are independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) hydroxyl,
(4) —On-phenyl or —On-napthyl, where n is 0 or 1 (wherein if n is 0, a bond is present) and where the phenyl or napthyl is unsubstituted or substituted with one or more substituents selected from R13,
(5) —On-heterocycle, where n is 0 or 1 (wherein if n is 0, a bond is present) and where the heterocycle is unsubstituted or substituted with one or more substituents selected from R13,
(6) —On—C1-6alkyl, where n is 0 or 1 (wherein if n is 0, a bond is present) and where the alkyl is unsubstituted or substituted with one or more substituents selected from R13,
(7) —On—C3-6cycloalkyl, where n is 0 or 1 (wherein if n is 0, a bond is present) and where the cycloalkyl is unsubstituted or substituted with one or more substituents selected from R13,
(8) —C2-4alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents selected from R13,
(9) —NR10R11, wherein R10 and R11 are independently selected from the group consisting of:
(a) hydrogen,
(b) C1-6alkyl, which is unsubstituted or substituted with R13,
(c) C3-6alkenyl, which is unsubstituted or substituted with R13,
(d) cycloalkyl which is unsubstituted or substituted with R13,
(e) phenyl, which is unsubstituted or substituted with R13, and
(f) heterocycle, which is unsubstituted or substituted with R13,
or R10 and R11 taken together with the nitrogen atom to which they are attached form a pyrrolidine, piperidine, azetidine or morpholine ring, which is unsubstituted or substituted with R13,
(10) —S(O)2—NR10R11,
(11) —S(O)q—R12, where q is 0, 1 or 2 and where R12 is selected from the definitions of R10 and R11,
(12) —CO2H,
(13) —CO2—R12,
(14) —CN, and
(15) —NO2;
or R1a and R1b taken together form a cyclopentyl, cyclohexyl, dihydrofuranyl or dihydropyranyl ring, which is unsubstituted or substituted with one or more substituents selected from —CH3, (═CH2), keto, and hydroxyl;
R2 and R3 are independently selected from the group consisting of:
(1) hydrogen,
(2) hydroxyl,
(3) halogen
(4) C1-6alkyl, which is unsubstituted or substituted with one or more substituents selected from R13,
(5) C3-6cycloalkyl, which is unsubstituted or substituted with one or more substituents selected from R13,
(6) —O—C1-6alkyl, which is unsubstituted or substituted with one or more substituents selected from R13,
(7) —O—C3-6cycloalkyl, which is unsubstituted or substituted with one or more substituents selected from R13,
or R2 and R3 and the carbon atom to which they are attached form a keto group,
or R2 and R3 and the carbon atom to which they are attached form a C3-6cycloalkyl ring, which is unsubstituted or substituted with R13;
R4 is selected from the group consisting of:
(1) hydrogen,
(2) C1-6alkyl, which is unsubstituted or substituted with one or more substituents selected from R13,
(3) —C3-6cycloalkyl, which is unsubstituted or substituted with one or more substituents selected from R13,
(4) C2-6alkenyl, which is unsubstituted or substituted with one or more substituents selected from R13,
(5) C2-6alkynyl, which is unsubstituted or substituted with one or more substituents selected from R13,
(6) phenyl, which is unsubstituted or substituted with one or more substituents selected from R13,
(7) —(C═O)—NR10R11, and
(8) —(C═O)—O—C1-6alkyl, which is unsubstituted or substituted with one or more substituents selected from R13,
R5a, R5b and R5c are independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) hydroxyl,
(4) —On—C1-6alkyl, where n is 0 or 1 (wherein if n is 0, a bond is present) and where the alkyl is unsubstituted or substituted with one or more substituents selected from R13,
(5) —On—C3-6cycloalkyl, where n is 0 or 1 (wherein if n is 0, a bond is present) and where the cycloalkyl is unsubstituted or substituted with one or more substituents selected from R13,
(6) —C2-4alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents selected from R13,
(7) —On-phenyl or —On-napthyl, where n is 0 or 1 (wherein if n is 0, a bond is present) and where the phenyl or napthyl is unsubstituted or substituted with one or more substituents selected from R13,
(8) —On-heterocycle, where n is 0 or 1 (wherein if n is 0, a bond is present) and where the heterocycle is unsubstituted or substituted with one or more substituents selected from R13,
(9) —(C═O)—NR10R11,
(10) —NR10R11,
(11) —S(O)2—NR10R11,
(12) —NR10—S(O)2R11,
(13) —S(O)q—R12, where q is 0, 1 or 2 and where R12 is selected from the definitions of R10 and R11,
(14) —CO2H,
(15) —CN,
(16) —NO2;
(17) or R5a and R5b taken together form a pyrrolyl or imidazolyl ring, which is unsubstituted or substituted with —CH3, (═CH2), keto, or hydroxyl;
R13 is selected from the group consisting of:
(1) halogen,
(2) hydroxyl,
(3) —(C═O)m—On—C1-6alkyl, where m is 0 or 1 and n is 0 or 1 (wherein if m is 0 or n is 0, a bond is present, and wherein if m is 0 and n is 0, a single bond is present) where the alkyl is unsubstituted or substituted with one or more substituents selected from R14,
(4) —On—(C1-3)perfluoroalkyl,
(5) —(C═O)m—On—C3-6cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents selected from R14,
(6) —(C═O)m—C2-4alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents selected from R14,
(7) —(C═O)m—On-phenyl or —(C═O)m—On-napthyl, where the phenyl or napthyl is unsubstituted or substituted with one or more substituents selected from R14,
(8) —(C═O)m—On-heterocycle, where the heterocycle is unsubstituted or substituted with one or more substituents selected from R14,
(9) —(C═O)—NR10R11,
(10) —NR10R11,
(11) —S(O)2—NR10R11,
(12) —S(O)q—R12,
(13) —CO2H,
(14) —CN, and
(15) —NO2;
R14 is selected from the group consisting of:
(1) hydroxyl,
(2) halogen,
(3) C1-6alkyl,
(4) —C3-6cycloalkyl,
(5) —O—C1-6alkyl,
(6) —O(C═O)—C1-6alkyl,
(7) —NH—C1-6alkyl,
(8) phenyl,
(9) heterocycle,
(10) —CO2H, and
(11) —CN;
or a pharmaceutically acceptable salt thereof.

89 more elements

A compound which is selected from the group consisting of:

2-(1-benzofuran-5-yl)-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide;
2-(2-ethyl-1,3-benzoxazol-5-yl)-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide;
2-quinolin-3-yl-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide;
2-(1H-indol-6-yl)-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide;
2-(3-chloro-1H-indol-6-yl)-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide;
2-(3-methyl-1H-indol-6-yl)-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide;
2-(1H-pyrrolo[2,3-b]pyridine-3-yl)-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide;
2-(1H-indazole-6-yl)-N-((1R)-1-{5-[(2,2,2-trifluoroethyl)oxo]pyridin-2-yl}ethyl)acetamide;
2-(5-chloro-1H-benzimidazol-2-yl)-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide;
2-(1H-pyrrolo[2,3-b]pyridin-3-yl)-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide;
2-(1H-pyrrolo[3,2-b]pyridin-3-yl)-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide;
2-(1H-pyrrolo[2,3-c]pyridin-3-yl)-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide;
2-(1H-indol-6-yl)-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide;
2-(5-chloro-1H-benzimidazol-2-yl)-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide;
2-(1-benzofuran-5-yl)-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide;
2-(2-methyl-1,3-benzoxazol-5-yl)-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide;
2-(2-ethyl-1,3-benzoxazol-5-yl)-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide;
N-{(1R)-1-[5-(benzyloxy)pyridin-2-yl]ethyl}-2-(1H-indol-6-yl)acetamide;
2-(1H-indol-6-yl)-N-[(1R)-1-(5-{[(1S)-1-methylpropyl]oxy}pyridin-2-yl)ethyl]acetamide;
N-[(1R)-1-(5-ethoxypyridin-2-yl)ethyl]-2-(1H-indol-6-yl)acetamide;
2-(3-methyl-1H-indol-6-yl)-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide;
2-(1-methyl-1H-indol-6-yl)-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide;
2-(3-cyclohex-1-en-1-yl-1H-indol-6-yl)-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide;
2-(3-cyclohexyl-1H-indol-6-yl)-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide;
2-(3-iodo-1H-indol-6-yl)-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide;
2-(3-ethyl-1H-indol-6-yl)-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide;
2-(3-chloro-1H-indol-6-yl)-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide;
2-(3-bromo-1H-indol-6-yl)-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide;
2-(3-cyano-1H-indol-6-yl)-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide;
2-{3-iodo-1-[(4-methylphenyl)sulfonyl]-1H-indol-6-yl}-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)-pyridin-2-yl]ethyl}acetamide;
2-{1-[(4-methylphenyl)sulfonyl]-1H-indol-6-yl}-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide;
2-(3-cyclopropyl-1H-indol-6-yl)-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}-acetamide;
2-(3-phenyl-1H-indol-6-yl)-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide;
2-[3-bromo-1-(2,2,2-trifluoroethyl)-1H-indol-6-yl]-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide;
2-(1H-indazol-6-yl)-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide;
2-imidazo[1,2-a]pyridin-7-yl-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide;
2-quinolin-3-yl-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide;
2-(1H-pyrrolo[2,3-b]pyridin-3-yl)-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide;
2-(1H-pyrrolo[3,2-b]pyridin-3-yl)-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide;
or a pharmaceutically acceptable salt thereof.

37 more elements

Dependencies are inferred from the claim text.

Facts

Application: 12/739,203Filed 23 Oct 2008
Published: 30 Sep 2010
Term ends: Not estimatedThe source records don’t support an estimate.

Classification38 codes

C07D 405/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
A61P 1/02
Drugs for disorders of the alimentary tract or the digestive system: stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
A61P 1/14
Drugs for disorders of the alimentary tract or the digestive system: prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics,…
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics

Family

No related US applications are recorded in the indexed filing history.

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Abstract

A compound of the formula I:

wherein:
A is heteroaryl;
R1a, R1b and R1c may be absent if the valency of A does not permit such substitution and are independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) hydroxyl,
(4) —On-phenyl or —On-napthyl, where n is 0 or 1 (wherein if n is 0, a bond is present) and where the phenyl or napthyl is unsubstituted or substituted with one or more substituents selected from R13,
(5) —On-heterocycle, where n is 0 or 1 (wherein if n is 0, a bond is present) and where the heterocycle is unsubstituted or substituted with one or more substituents selected from R13,
(6) —On—C1-6alkyl, where n is 0 or 1 (wherein if n is 0, a bond is present) and where the alkyl is unsubstituted or substituted with one or more substituents selected from R13,
(7) —On—C3-6cycloalkyl, where n is 0 or 1 (wherein if n is 0, a bond is present) and where the cycloalkyl is unsubstituted or substituted with one or more substituents selected from R13,
(8) —C2-4alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents selected from R13,
(9) —NR10R11, wherein R10 and R11 are independently selected from the group consisting of:
(a) hydrogen,
(b) C1-6alkyl, which is unsubstituted or substituted with R13,
(c) C3-6alkenyl, which is unsubstituted or substituted with R13,
(d) cycloalkyl which is unsubstituted or substituted with R13,
(e) phenyl, which is unsubstituted or substituted with R13, and
(f) heterocycle, which is unsubstituted or substituted with R13,
or R10 and R11 taken together with the nitrogen atom to which they are attached form a pyrrolidine, piperidine, azetidine or morpholine ring, which is unsubstituted or substituted with R13,
(10) —S(O)2—NR10R11,
(11) —S(O)q—R12, where q is 0, 1 or 2 and where R12 is selected from the definitions of R10 and R11,
(12) —CO2H,
(13) —CO2—R12,
(14) —CN, and
(15) —NO2;
or R1a and R1b taken together form a cyclopentyl, cyclohexyl, dihydrofuranyl or dihydropyranyl ring, which is unsubstituted or substituted with one or more substituents selected from —CH3, (═CH2), keto, and hydroxyl;
R2 and R3 are independently selected from the group consisting of:
(1) hydrogen,
(2) hydroxyl,
(3) halogen
(4) C1-6alkyl, which is unsubstituted or substituted with one or more substituents selected from R13,
(5) C3-6cycloalkyl, which is unsubstituted or substituted with one or more substituents selected from R13,
(6) —O—C1-6alkyl, which is unsubstituted or substituted with one or more substituents selected from R13,
(7) —O—C3-6cycloalkyl, which is unsubstituted or substituted with one or more substituents selected from R13,
or R2 and R3 and the carbon atom to which they are attached form a keto group,
or R2 and R3 and the carbon atom to which they are attached form a C3-6cycloalkyl ring, which is unsubstituted or substituted with R13;
R4 is selected from the group consisting of:
(1) hydrogen,
(2) C1-6alkyl, which is unsubstituted or substituted with one or more substituents selected from R13,
(3) —C3-6cycloalkyl, which is unsubstituted or substituted with one or more substituents selected from R13,
(4) C2-6alkenyl, which is unsubstituted or substituted with one or more substituents selected from R13,
(5) C2-6alkynyl, which is unsubstituted or substituted with one or more substituents selected from R13,
(6) phenyl, which is unsubstituted or substituted with one or more substituents selected from R13,
(7) —(C═O)—NR10R11, and
(8) —(C═O)—O—C1-6alkyl, which is unsubstituted or substituted with one or more substituents selected from R13,
R5a, R5b and R5c are independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) hydroxyl,
(4) —On—C1-6alkyl, where n is 0 or 1 (wherein if n is 0, a bond is present) and where the alkyl is unsubstituted or substituted with one or more substituents selected from R13,
(5) —On—C3-6cycloalkyl, where n is 0 or 1 (wherein if n is 0, a bond is present) and where the cycloalkyl is unsubstituted or substituted with one or more substituents selected from R13,
(6) —C2-4alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents selected from R13,
(7) —On-phenyl or —On-napthyl, where n is 0 or 1 (wherein if n is 0, a bond is present) and where the phenyl or napthyl is unsubstituted or substituted with one or more substituents selected from R13,
(8) —On-heterocycle, where n is 0 or 1 (wherein if n is 0, a bond is present) and where the heterocycle is unsubstituted or substituted with one or more substituents selected from R13,
(9) —(C═O)—NR10R11,
(10) —NR10R11,
(11) —S(O)2—NR10R11,
(12) —NR10—S(O)2R11,
(13) —S(O)q—R12, where q is 0, 1 or 2 and where R12 is selected from the definitions of R10 and R11,
(14) —CO2H,
(15) —CN,
(16) —NO2;
(17) or R5a and R5b taken together form a pyrrolyl or imidazolyl ring, which is unsubstituted or substituted with —CH3, (═CH2), keto, or hydroxyl;
R13 is selected from the group consisting of:
(1) halogen,
(2) hydroxyl,
(3) —(C═O)m—On—C1-6alkyl, where m is 0 or 1 and n is 0 or 1 (wherein if m is 0 or n is 0, a bond is present, and wherein if m is 0 and n is 0, a single bond is present) where the alkyl is unsubstituted or substituted with one or more substituents selected from R14,
(4) —On—(C1-3)perfluoroalkyl,
(5) —(C═O)m—On—C3-6cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents selected from R14,
(6) —(C═O)m—C2-4alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents selected from R14,
(7) —(C═O)m—On-phenyl or —(C═O)m—On-napthyl, where the phenyl or napthyl is unsubstituted or substituted with one or more substituents selected from R14,
(8) —(C═O)m—On-heterocycle, where the heterocycle is unsubstituted or substituted with one or more substituents selected from R14,
(9) —(C═O)—NR10R11,
(10) —NR10R11,
(11) —S(O)2—NR10R11,
(12) —S(O)q—R12,
(13) —CO2H,
(14) —CN, and
(15) —NO2;
R14 is selected from the group consisting of:
(1) hydroxyl,
(2) halogen,
(3) C1-6alkyl,
(4) —C3-6cycloalkyl,
(5) —O—C1-6alkyl,
(6) —O(C═O)—C1-6alkyl,
(7) —NH—C1-6alkyl,
(8) phenyl,
(9) heterocycle,
(10) —CO2H, and
(11) —CN;
or a pharmaceutically acceptable salt thereof.

89 more elements

Facts

Application

12/739,203Filed 23 Oct 2008

Published

30 Sep 2010

Term ends

Not estimatedThe source records don’t support an estimate.

Classification38 codes

C07D 405/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
A61P 1/02
Drugs for disorders of the alimentary tract or the digestive system: stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
A61P 1/14
Drugs for disorders of the alimentary tract or the digestive system: prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics,…
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics