US 2004/0106622 A1 · Aryl-substituted alicylic compound and medical composition comprising the same

Abstract

An aryl-substituted alicyclic compound of the formula (I): 1 wherein U is 1,4,5,6-tetrahydropyrimidin-2-yl, etc., A is phenylene, etc., B is piperidine-1,4-diyl, etc., Z is —CONH—, etc., R3 is hydrogen, etc., R5 is hydrogen, aryl, etc., R6 is a mono-substituted amino (e,g., benzyloxycarbonylamino), R7 is hydrogen, etc., and a process for preparation thereof, and a pharmaceutical composition containing the same. The compound of the present invention has a high selectivity for αvβ3 integrin, and exhibits a potent inhibitory activity thereto, and hence, it is useful as a preventive or/and a therapeutic agent for a disease in which αvβ3 integrin is involved.

An aryl-substituted alicyclic compound of the following formula (I), a prodrug thereof, a pharmaceutically acceptable salt thereof or an N-oxide derivative thereof, or a hydrate or solvate thereof.

104
wherein u is a group of the following formula:
105
A is a group of the following formula:
106
B is a group of the following formula:
107
Z is —CONR4(CH2)q—, —NR4CO(CH2)q— or —COCH2(CH2)q—,
T is —CH2—, an oxygen atom, a sulfur atom or —NRd—,
X is an oxygen atom or a sulfur atom,
W1, W2, W3 and W4 are the same or different, and each is —CH— or a nitrogen atom,
D and E are the same or different, and each is —CH— or a nitrogen atom,
Ra is the same or different, and each is a hydrogen atom, a halogen atom, a hydroxy group, a C1-6 alkyl group, a C3-7 cycloalkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, an aryl group, an aralkyl group, a C1-6 alkyloxy group, a C1-6 alkyloxycarbonyl group, a formyl group, a C1-6 alkylcarbonyl group, a carboxyl group, a C1-6 alkylcarbonyloxy group, an amino group, a C1-3 alkylamino group, a di(C1-3 alkyl)amino group, a formylamino group, a C1-3 alkylcarbonylamino group, an arylcarbonylamino group, a nitro group, a cyano group, a trifluoromethyl group, a trifluoromethoxy group or a trifluoroethoxy group, or
when two Ra groups attach to the same carbon atom, then they combine to form an oxo group or a thioxo group, or together with said carbon atom to form a spiro ring,
Rb is the same or different, and each is a hydrogen atom, a halogen atom, a hydroxy group, a C1-6 alkyl group, a C3-7 cycloalkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, an aryl group, an aralkyl group, a C1-6 alkyloxy group, a C1-6 alkyloxycarbonyl group, a formyl group, a C1-6 alkylcarbonyl group, a carboxyl group, a C1-6 alkylcarbonyloxy group, an amino group, a C1-3 alkylamino group, a di(C1-3 alkyl)amino group, a formylamino group, a C1-3 alkylcarbonylamino group, an arylcarbonylamino group, a nitro group, a cyano group, a trifluoromethyl group, a trifluoromethoxy group or a trifluoroethoxy group,
Rc is the same or different, and each is a hydrogen atom, a halogen atom, a hydroxy group, a C1-6 alkyl group, a C3-7 cycloalkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, an aryl group, an aralkyl group, a C1-6 alkyloxy group, a C1-6 alkyloxycarbonyl group, a formyl group, a C1-6 alkylcarbonyl group, a carboxyl group, a C1-6 alkylcarbonyloxy group, an amino group, a C1-3 alkylamino group, a di(C1-3 alkyl)amino group, a formylamino group, a C1-3 alkylcarbonylamino group, an arylcarbonylamino group, a nitro group, a cyano group, a trifluoromethyl group, a trifluoromethoxy group or a trifluoroethoxy group,
or two Rc groups may combine to form —(CR8R9)t—,
Rd is a hydrogen atom, a C1-6 alkyl group, a C3-7 cycloalkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, an aryl group, an aralkyl group, a formyl group, a C1-6 alkylcarbonyl group or a C1-6 alkyloxycarbonyl group,
R1 and R2 are the same or different, and each is a hydrogen atom, a C1-10 alkyl group, a C3-7 cycloalkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, an aryl group, an aralkyl group, a C1-6 alkylcarbonyl group, a C1-6 alkyloxycarbonyl group, a C1-6 alkylsulfonyl group or an arylsulfonyl group,
or R1 and R2 may combine to form —(CR1OR11)u— or —(CH2)vY(CH2)w—,
R3 and R4 are the same or different, and each is a hydrogen atom, a C1-6 alkyl group, a C3-7 cycloalkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, an aryl group or an aralkyl group,
R5 is a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C3-7 cycloalkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, an aryl group or an aralkyl group,
R6 is a hydrogen atom, a halogen atom, a hydroxy group, a C1-6 alkyl group, a C3-7 cycloalkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, an aryl group, an aralkyl group, a C1-6 alkyloxy group, a C3-7 cycloalkyloxy group, a C2-6 alkenyloxy group, a C2-6 alkynyloxy group, an aryloxy group, an aralkyloxy group, a C1-6 alkylcarbonyloxy group, a C3-7 cycloalkylcarbonyloxy group, a C2-6 alkenylcarbonyloxy group, a C2-6 alkynylcarbonyloxy group, an arylcarbonyloxy group, an aralkylcarbonyloxy group, an amino group or a mono-substituted amino group (in which the substituent thereof is a formyl, a C1-10 alkylcarbonyl, a C3-7 cycloalkylcarbonyl, a C2-10 alkenylcarbonyl, a C2-10 alkynylcarbonyl, an arylcarbonyl, an aralkylcarbonyl, a C7-15 polycyclo-C-3 alkylcarbonyl, a C1-16 alkyloxycarbonyl, a polyfluoro-C1-16 alkyloxycarbonyl, a C3-7 cycloalkyloxycarbonyl, a C2-16 alkenyloxycarbonyl, a C2-16 alkynyloxycarbonyl, an aryloxycarbonyl, a C3-7 cycloalkyl-C1-6 alkyloxycarbonyl, an aralkyloxycarbonyl, a Cl1-10 alkylaminocarbonyl, a C3-7 cycloalkylaminocarbonyl, a C2-10 alkenylaminocarbonyl, a C2-10 alkynylaminocarbonyl, an arylaminocarbonyl, an aralkylaminocarbonyl, a C1-10 alkylsulfonyl, a C3-7 cycloalkylsulfonyl, a C2-10 alkenylsulfonyl, a C2-10 alkynylsulfonyl, an arylsulfonyl, an aralkylsulfonyl, a C7-15 polycyclo-C0-3 alkylsulfonyl, a C1-10 alkylaminosulfonyl, a C3-7 cycloalkylaminosulfonyl, a C2-10 alkenylaminosulfonyl, a C2-10 alkynylaminosulfonyl, an arylaminosulfonyl or an aralkylaminosulfonyl),
R7 is a hydrogen atom, a C1-6 alkyl group, a C3-7 cycloalkyl group, an aryl group or an aralkyl group,
R8, R9, R10 and R11 are the same or different, and each is a hydrogen atom, a C1-3 alkyl group or an aryl group,
Y is an oxygen atom, a sulfur atom or —NR12—,
R12 is a hydrogen atom, a C1-6 alkyl group, a C3-7 cycloalkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, an aryl group, an aralkyl group, a C1-6 alkylcarbonyl group or a C1-6 alkyloxycarbonyl group,
g is an integer of 1 to 4,
h is an integer of 0 to 3,
k is an integer of 1 to 3,
m and n are the same or different, and each is an integer of 0 to 3, but the sum of m and n should be an integer of 1 to 3,
p is an integer of 1 to 4,
q is 0 or 1,
t is an integer of 1 to 3,
u is an integer of 3 to 7,
v and w are the same or different, and each is an integer of 1 to 4, but the sum of v and w should be an integer of 2 to 6,
provided that (i) when E is a nitrogen atom, then Z is —CONR4(CH2)q or COCH2(CH2)q—, (ii) in the above definition, the alkyl group, the cycloalkyl group, the alkenyl group, the alkynyl group, and the alkyl moiety of the aralkyl group may optionally be substituted by 1 to 3 atoms or groups selected from a halogen, a C1-6 alkyloxy, an amino and a hydroxy, and the aryl group and the aryl moiety may optionally be substituted by 1 to 5 atoms or groups selected from a halogen, a C1-6 alkyl, a C3-7 cycloalkyl, an aryl, an aralkyl, an amino, an amino-C1-6 alkyl, a formylamino, a C1-3 alkylcarbonylamino, a C1-6 alkylamino, a C1-6 alkylamino-C1-6 alkyl, a di(C1-6 alkyl)amino, a di(C1-6 alkyl)amino-C1-6 alkyl, an arylcarbonylamino, a C1-6 alkylaminocarbonylamino, an arylaminocarbonylamino, a C1-4 alkyloxy, a C1-4 alkylthio, a C1-4 alkylsulfonyl, a C1-4 alkyloxy-C1-6 alkyl, a carboxyl, a carboxyl-C1-6 alkyl, a C1-4 alkyloxycarbonyl, a hydroxy, a hydroxy-C1-6 alkyl, a cyano, a trifluoromethyl, a trifluoromethoxy, a C1-4 alkylcarbonyloxy and a nitro.

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Aryl-substituted alicylic compound and medical composition comprising the same

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Aryl-substituted alicylic compound and medical composition comprising the same

Life of this patent

Abstract

Claims10