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US 2011/0034440 A1Published application
Homocysteine synthase inhibitor
AssigneeMitsubishi Tanabe Pharma Corporation
InventorsAkira Nakao, Hiroko Suzuki, Ryo Tatsumi, Maki Seki, Minoru Tanaka, Tomofumi Setsuta, Hiroshi Iwasaki
Life of this patent
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Abstract
The invention provides a homocysteine synthase inhibitor useful for the prophylaxis or treatment of diseases involving homocysteine synthase. The homocysteine synthase inhibitor is a compound of the formula (I) wherein each symbol is as defined herein, or a pharmacologically acceptable salt thereof, or a solvate thereof.
Claims15
An amide derivative represented by the following formula (I)
- wherein
- R1 is a hydrogen atom or a C1-C3 alkyl group,
- R2 is an optionally substituted heterocyclic group (said heterocyclic group contains at least one nitrogen atom in the ring), or —N(R2a)(R2b),
- R2a and R2b are independently selected and each is a hydrogen atom, a C1-C6 alkyl group, a haloalkyl group or an optionally substituted aryl group,
- R3 is a hydrogen atom,
- R4, R5, R6, R7 are independently selected and each is a hydrogen atom or a C1-C4 alkyl group,
- L is a linker represented by the following formula
- wherein s is an integer of 0-2,
- t is an integer of 0-2,
- R8a, R8b, R8c and R8d are independently selected and each is a hydrogen atom or a C1-C3 alkyl group,
- Ar is a substituent represented by any of the following formulas (II)-(IV),
- wherein
- l is an integer of 0-4,
- k is an integer of 0-4,
- Cy1 and Cy2 are independently selected and each is a carbocyclic group, a heterocyclic group or a heteroaryl group,
- X is a bond, an oxygen atom or a sulfur atom,
- R9 is a halogen atom or R12,
- wherein
- R12 is
- a hydrogen atom,
- an optionally substituted C1-C6 alkyl group,
- an optionally substituted C2-C6 alkenyl group,
- an optionally substituted C2-C6 alkynyl group,
- an optionally substituted C3-C8 cycloalkyl group,
- an optionally substituted heterocyclic group,
- an optionally substituted aryl group,
- an optionally substituted heteroaryl group, or
- an optionally substituted arylalkyl group,
- R10 is
- a halogen atom,
- a cyano group,
- an optionally substituted C1-C6 alkyl group,
- —CF3,
- —O—R13
- —CO—R14,
- an optionally substituted amino group,
- an optionally substituted aryl group,
- an optionally substituted heteroaryl group,
- an optionally substituted heterocyclic group, or
- an —S(O)m—C1-C6 alkyl group wherein m is an integer of 0-2,
- R11 is a halogen atom, an optionally substituted C1-C4 alkyl group or CF3,
- R13 is a hydrogen atom, a C1-C4 alkyl group, or —CF3,
- R14 is a hydroxy group, a C1-C6 alkyl group, a C1-C6 alkoxy group, or an optionally substituted amino group,
- A is
- an optionally substituted aryl group,
- an optionally substituted aryl-C1-C4 alkyl group,
- an optionally substituted heteroaryl-C1-C4 alkyl group,
- a C3-C6 alkynyl group,
- an optionally substituted C3-C8 cycloalkyl group, or
- a group represented by any of the following formulas (V)-(VIII)
- wherein
- -----
- is a single bond or a double bond,
- n is an integer of 0-2,
- g is an integer of 0-2,
- h is an integer of 0-1,
- i is an integer of 1-2,
- R15 is a C1-C4 alkyl group, a C1-C4 alkoxy group, a cyano group or a halogen atom,
- R16 is a C1-C4 alkyl group,
- W is ═CH— or ═N—, and
- D is an oxygen atom, a sulfur atom, ═N-(E)u-R17 or ═CH—R17, u is an integer of 0-1, E is —SO2— or —CO—, R17 is a hydrogen atom, a C1-C4 alkyl group, an aryl group, a C1-C4 alkylamino group, a C1-C6 alkoxy group, an arylamino group or an aryloxy group, or a pharmacologically acceptable salt thereof, or a solvate thereof.
58 more elements
An amide derivative selected from the following compounds, or a pharmacologically acceptable salt thereof, or a solvate thereof:
- N2-(5-acetyl-2-methylphenyl)-N2-{2-[1,3-dihydro-2H-isoindol-2-yl(methyl)amino]-2-oxoethyl}-N1-[2-(isopropylamino)ethyl]glycinamide,
- N2-(5-acetyl-2-methylphenyl)-N2-{2-[1,3-dihydro-2H-isoindol-2-yl(methyl)amino]-2-oxoethyl}-N1-[2-(ethylamino)ethyl]glycinamide,
- N2-{2-[1,3-dihydro-2H-isoindol-2-yl(methyl)amino]-2-oxoethyl}-N2-[2-methyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-N1-[2-(isopropylamino)ethyl]glycinamide,
- N2-{2-[1,3-dihydro-2H-isoindol-2-yl(methyl)amino]-2-oxoethyl}-N1-[2-methyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-N1-[2-(ethylamino)ethyl]glycinamide,
- N2-{2-[(5-fluoro-1,3-dihydro-2H-isoindol-2-yl)(methyl)amino]-2-oxoethyl}-N2-[2-methyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-N1-[2-(ethylamino)ethyl]glycinamide,
- N2-(5-cyano-2-methylphenyl)-N2-{2-[1,3-dihydro-2H-isoindol-2-yl(methyl)amino]-2-oxoethyl}-N1-[2-(isopropylamino)ethyl]glycinamide,
- N2-(5-cyano-2-methylphenyl)-N2-{2-[1,3-dihydro-2H-isoindol-2-yl(methyl)amino]-2-oxoethyl}-N1-[2-(ethylamino)ethyl]glycinamide,
- N2-{2-[1,3-dihydro-2H-isoindol-2-yl(methyl)amino]-2-oxoethyl}-N2-[2-methyl-5-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-N1-[2-(isopropylamino)ethyl]glycinamide,
- N2-{2-[1,3-dihydro-2H-isoindol-2-yl(methyl)amino]-2-oxoethyl}-N2-[2-methyl-5-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-N1-[2-(ethylamino)ethyl]glycinamide,
- N2-{2-[(4-fluoro-1,3-dihydro-2H-isoindol-2-yl)(methyl)amino]-2-oxoethyl}-N2-[2-methyl-5 (5-methyl-1,2,4-oxadiazol-yl)phenyl]-N1-[2-(ethylamino)ethyl]glycinamide,
- N2-{2-[(5-fluoro-1,3-dihydro-2H-isoindol-2-yl)(methyl)amino]-2-oxoethyl}-N2-[2-methyl-5 (5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-N1-[2-(ethylamino)ethyl]glycinamide,
- N2-{2-[(5-fluoro-1,3-dihydro-2H-isoindol-2-yl)(methyl)amino]-2-oxoethyl}-N2-[2-methyl-5-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-N1-[2-(isopropylamino)ethyl]glycinamide,
- N2-{2-[(5-methoxy-1,3-dihydro-2H-isoindol-2-yl)(methyl)amino]-2-oxoethyl}-N2-[2-methyl-5-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-N1-[2-(ethylamino)ethyl]glycinamide,
- N2-{2-[2,3-dihydro-1H-inden-2-yl(methyl)amino]-2-oxoethyl}-N2-[2-methyl-5-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-N1-[2-(ethylamino)ethyl]glycinamide,
- N2-{2-[1,3-dihydro-2H-isoindol-2-yl(methyl)amino]-2-oxoethyl}-N2-[2-methyl-5-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]-N1-[2-(isopropylamino)ethyl]glycinamide,
- N2-{2-[1,3-dihydro-2H-isoindol-2-yl(methyl)amino]-2-oxoethyl}-N2-[2-methyl-5-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]-N1-[2-(ethylamino)ethyl]glycinamide,
- N2-{2-[(5-fluoro-1,3-dihydro-2H-isoindol-2-yl)(methyl)amino]-2-oxoethyl}-N2-[2-methyl-5-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]-N1-[2-(ethylamino)ethyl]glycinamide,
- N2-{2-[1,3-dihydro-2H-isoindol-2-yl(methyl)amino]-2-oxoethyl}-N2-[2-methyl-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl]-N1-[2-(isopropylamino)ethyl]glycinamide,
- N2-{2-[1,3-dihydro-2H-isoindol-2-yl(methyl)amino]-2-oxoethyl}-N1-[2-methyl-5-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl]-N1-[2-(ethylamino)ethyl]glycinamide,
- N2-{2-[1,3-dihydro-2H-isoindol-2-yl(methyl)amino]-2-oxoethyl}-N2-[5-(4-ethyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-2-methylphenyl]-N1-[2-(ethylamino)ethyl]glycinamide,
- N2-{2-[1,3-dihydro-2H-isoindol-2-yl(methyl)amino]-2-oxoethyl}-N2-(2-methyl-5-pyrimidin-2-ylphenyl)-N1-[2-(ethylamino)ethyl]glycinamide,
- N2-{2-[1,3-dihydro-2H-isoindol-2-yl(methyl)amino]-2-oxoethyl}-N2-(1-ethyl-7-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-N1-[2-(isopropylamino)ethyl]glycinamide,
- N2-{2-[1,3-dihydro-2H-isoindol-2-yl(methyl)amino]-2-oxoethyl}-N2-(1-ethyl-7-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-yl)-N1-[2-(ethylamino)ethyl]glycinamide,
- N2-{2-[1,3-dihydro-2H-isoindol-2-yl(methyl)amino]-2-oxoethyl}-N2-(3,6-dimethyl-1,2-benzisoxazol-5-yl)-N1-[2-(isopropylamino)ethyl]glycinamide,
- N2-{2-[1,3-dihydro-2H-isoindol-2-yl(methyl)amino]-2-oxoethyl}-N2-(3,6-dimethyl-1,2-benzisoxazol-5-yl)-N1-[2-(ethylamino)ethyl]glycinamide,
- N2-{2-[1,3-dihydro-2H-isoindol-2-yl(methyl)amino]-2-oxoethyl}-N2-(3,5-dimethyl-1,2-benzisoxazol-6-yl)-N1-[2-(isopropylamino)ethyl]glycinamide,
- N2-{2-[1,3-dihydro-2H-isoindol-2-yl(methyl)amino]-2-oxoethyl}-N2-(3,5-dimethyl-1,2-benzisoxazol-6-yl)-N1-[2-(ethylamino)ethyl]glycinamide,
- N2-{2-[1,3-dihydro-2H-isoindol-2-yl(methyl)amino]-2-oxoethyl}-N2-(3,6-dimethyl-1,3-benzoxazol-2 (3H)-on-5-yl)-N1-[2-(isopropylamino)ethyl]glycinamide,
- N2-{2-[1,3-dihydro-2H-isoindol-2-yl(methyl)amino]-2-oxoethyl}-N2-(3,6-dimethyl-1,3-benzoxazol-2 (3H)-on-5-yl)-N1-[2-(ethylamino)ethyl]glycinamide,
- N2-{2-[1,3-dihydro-2H-isoindol-2-yl(methyl)amino]-2-oxoethyl}-N2-(3,5-dimethyl-1,3-benzoxazol-2 (3H)-on-6-yl)-N1-[2-(isopropylamino)ethyl]glycinamide,
- N2-{2-[1,3-dihydro-2H-isoindol-2-yl(methyl)amino]-2-oxoethyl}-N2-(3,5-dimethyl-1,3-benzoxazol-2 (3H)-on-6-yl)-N1-[2-(ethylamino)ethyl]glycinamide,
- N2-{2-[(4-fluoro-1,3-dihydro-2H-isoindol-2-yl)(methyl)amino]-2-oxoethyl}-N2-[2-methyl-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl]-N1-[2-(ethylamino)ethyl]glycinamide,
- N2-(4-acetyl-2-methylphenyl)-N2-{2-[1,3-dihydro-2H-isoindol-2-yl(methyl)amino]-2-oxoethyl}-N1-[2-(ethylamino)ethyl]glycinamide,
- N2-(4-acetyl-2-methylphenyl)-N2-{2-[(5-fluoro-1,3-dihydro-2H-isoindol-2-yl)(methyl)amino]-2-oxoethyl}-N1-[2-(ethylamino)ethyl]glycinamide,
- N2-{2-[1,3-dihydro-2H-isoindol-2-yl(methyl)amino]-2-oxoethyl}-N2-(6-methyl-3-oxo-2,3-dihydro-1H-inden-5-yl)-N1-[2-(ethylamino)ethyl]glycinamide,
- N2-{2-[(5-fluoro-1,3-dihydro-2H-isoindol-2-yl)(methyl)amino]-2-oxoethyl}-N2-(6-methyl-3-oxo-2,3-dihydro-1H-inden-5-yl)-N1-[2-(ethylamino)ethyl]glycinamide,
- N2-{2-[(4-fluoro-1,3-dihydro-2H-isoindol-2-yl)(methyl)amino]-2-oxoethyl}-N2-(6-methyl-3-oxo-2,3-dihydro-1H-inden-5-yl)-N1-[2-(ethylamino)ethyl]glycinamide,
- N2-{2-[1,3-dihydro-2H-isoindol-2-yl(methyl)amino]-2-oxoethyl}-N2-[2-methyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]-N1-[2-(ethylamino)ethyl]glycinamide, and
- N2-{2-[(5-fluoro-1,3-dihydro-2H-isoindol-2-yl)(methyl)amino]-2-oxoethyl}-N2-[2-methyl-4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]-N1-[2-(ethylamino)ethyl]glycinamide.
36 more elements
-15. (canceled)
Dependencies are inferred from the claim text.