US 6,686,353 B1 · Diarylalkyl cyclic diamine derivatives as chemokine receptor antagonists

Abstract

Cyclic diamines of formula (I) or their pharmacologically acceptable acid addition salts, and their medical applications are described. These compounds inhibit the action of chemokines such as MIP-1a and/or MCP-1 on target cells, and are useful as a therapeutic drug and/or preventative drug in diseases, such as atherosclerosis, rheumatoid arthritis, and the like where blood monocytes and lymphocytes infiltrate into tissue.

A cyclic diamine selected from the group consisting of a compound of the formula (I) below:

and a pharmaceutically acceptable acid addition salt thereof
wherein R1 and R2 are the same or different from each other and are phenyl group or aromatic heterocyclic group having 1-3 heteratoms, selected from oxygen atoms, sulfur atoms, nitrogen atoms or combinations thereof, in which the phenyl or aromatic heterocyclic group is optionally substituted by one or more halogen atoms, hydroxy groups, C1-C8 lower alkyl groups, C1-C6 lower alkoxy groups, phenyl groups, benzyl groups, phenoxy groups, methylenedioxy groups, C1-C6 hydroxyalkyl groups, carboxy groups, C2-C7 alkoxycarbonyl groups, C2-C7 alkanoyl amino groups, dioxolanyl groups, or by group represented by the formula:
—NR5R6, or is condensed with a benzene ring to form a condensed ring, wherein the substituents for the phenyl or aromatic heterocyclic group and the condensed ring condensed with a benzene ring are optionally substituted by any substituents independently selected from halogen atoms, hydroxy groups, or C1-C6 lower alkoxy groups, and R5 and R6 are the same or different from each other and are hydrogen atoms, C1-C6 lower alkyl groups, or C2-C6 lower alkenyl groups;
R3 represents a hydrogen atom, hydroxy group, cyano group, C1-C6 lower alkoxy group or C2-C7 lower alkanoyloxy group,
j represents an integer of 0-3;
k is 3;
R4 is a group represented by:
—A1—R7 1)
wherein R7 is a phenyl group which is optionally substituted with one or more groups which are the same or different and are halogen atoms, hydroxy groups, amino groups, C1-C6 lower alkyl groups, C1-C6 lower alkoxy groups, cyano groups, nitro groups, trifluoromethyl groups, C2-C7 alkoxycarbonyl groups, C2-C7 alkanoyl groups, C1-C6 alkylsulfonyl groups, trifluoromethylsulfonyl groups, (unsubstituted) phenylsulfonyl groups optionally substituted with a hydroxy group, 1-pyrrolylsulfonyl groups, C1-C6 hydroxyalkylsulfonyl groups, C1-C6 alkanoylamino groups, or a group represented by formula:
—CONR8R9 in which R8 and R9, are the same or different from each other, and are hydrogen atoms or C1-C6 lower alkyl groups;
A1 is a group represented by the formula:
—(CH2)m— or a group represented by formula:
—(CH2)p—G—(CH2)q— in which G represents G1 or G2 wherein G1 represents —O—, —CO—, —SO2—, —CO—O—, —CONH—, —NHCO—, —NHCONH—, or —NH-SO2—, and G2 is —(C═NH)NH—SO2—, —CO—NH—NH—CO—, —CO—NH—NH—CO—NR10—, —CO—NH—CH2—CO—, —CO—NH—NH—SO2—, or —CO—N(CH2—CO—OCH3)—NH—CO—, R10 is a hydrogen atom or a phenyl group;
m is an integer of 0-3;
p is an integer of 1-3;
and q represents 0 or 1;
—A2—R11 2)
wherein A2 is —CO— or —SO2—;
R11 is:
a) a phenyl group optionally substituted with one or more groups which are the same or different and are halogen atoms, C1-C6 lower alkyl groups, C1-C6 lower alkoxy groups, groups represented by formula —CH2—NR12R13 or groups represented by the formula:
b) an aromatic monocyclic heterocyclic group having 1-3 heteroatoms, selected from oxygen atoms, sulfur atoms, nitrogen atoms or combinations thereof, optionally substituted with one or more groups which are the same or different and are halogen atoms, C1-C6 lower alkyl groups, or C1-C6 lower alkoxy groups, or
c) a group of the formula:
—CH2—NR15R16
where R12, R13, R14 and R15 are the same or different groups, and are hydrogen atoms, or C1-C6 lower alkyl groups and R16 is a phenyl group or a phenylalkyl group optionally substituted with one or more of the same or different groups and are halogen atoms, C1-C6 lower alkyl group, or C1-C6 lower alkoxy group;
—(CH2)n—R17 3)
wherein n is an integer of 1-4;
and R17 represents a hydrogen atom, cyano group, C2-C7 alkoxycarbonyl group, C1-C6 hydroxyalkyl group, C2-C6 lower alkynyl group, C3-C6 cycloalkyl group, C3-C7 alkenoyl group, a group represented by the formula:
—(CHOH)CH2OR18, a group represented by the formula:
—CO—NH—NH—CO—OR19, a group represented by the formula:
a group represented by the formula:
a group represented by the formula:
a group represented by the formula:
a group represented by the formula:
a group represented by the formula:
a group represented by the formula:
a group represented by the formula:
a group represented by the formula:
a group represented by the formula:
a group represented by the formula:
in which n is an integer of 1-4;
R18 is a C1-C6 lower alkyl group, C2-C6 lower alkenyl group, or C2-C6 lower alkynyl group and R19 is a C1-C6 lower alkyl group;
wherein R17 is a group which, where applicable, is optionally substituted at any possible sites by one or more of the same or different groups, said substituents selected from halogen atoms, hydroxy groups, C1-C6 lower alkoxy groups, or C1C6 lower alkoxy groups,
—(CH2)r—A3—R20 4)
wherein r represents an integer of 0-3;
A3 represents a single bond, —CO—,
—CO—NH—NH—CO—, —CO—NH—NH—CO—NH—, —CO—NH—CH2—CO—, —CO—NH—NH-SO2—, —(CHOH)—CH2—, or —(CHOH)—CH2OCH2—;
R20 represents an aromatic heterocyclic group containing 1-3 heteroatoms, selected from oxygen atoms, sulfur atoms, nitrogen atoms or combinations thereof in which the aromatic heterocyclic group is optionally substituted with one or more groups which are the same or different and are halogen atoms, C1-C6 lower alkyl groups, C1-C6 lower alkoxy groups, or pyrrolyl groups or is condensed with a benzene ring to form a condensed ring;
or
—CH2—CO—NR21R22 5)
wherein R21 is a hydrogen atom or a C1-C6 lower alkyl group;
R22 represents a hydrogen atom, C1-C6 lower alkyl group, or a group represented by the formula:
a group represented by the formula:
or R21 and R22 taken together with the nitrogen to which they are attached form a 4 to 7-membered saturated heterocycle, which may contain an oxygen atom, sulfur atom, or another nitrogen atom;
where s represents 0 or 1;
t represents an integer of 0-2;
R23 represents a hydrogen atom, hydroxy group, phenyl group, C1-C6 lower alkyl group, or C1-C6 lower alkoxy group;
R24 represents a hydrogen atom or phenyl group which is optionally substituted with a hydroxy group;
R25 represents a hydrogen atom, phenyl group which may be substituted by a hydroxy group, C2-C7 alkoxycarbonyl group, C1-C6 lower alkyl group, C1-C6 alkylthio group, or 3-indolyl group;
and R26 represents a hydroxy group, amino group, C1-C6 lower alkoxy group, or phenylalkyloxy group;
with the proviso that when R3 is a hydrogen atom, then j is not 0;
that when R3 is a hydrogen atom, a substituent for R7 is not a hydroxy, C1-C6 lower alkyl, nor C1-C6 lower alkoxy group;
that when R3 is a hydrogen atom, G1 is not —O— nor —CO—;
that when R3 is a hydrogen atom and R11 is a phenyl group, the substituent for R11 is not a C1-C6 lower alkyl group;
that when R3 is a hydrogen atom, R17 is not a hydrogen atom, C2-C7 alkoxycarbonyl group, nor C1-C6 hydroxyalkyl group;
that when R3 is a hydrogen atom, r is not 0;
that when R3 is a hydrogen atom, A3is not a single bond or —CO—;
that when R3 is a cyano group, then R7 is not unsubstituted;
that when R3 is a cyano group, a substituent for R7 is not a halogen atom, C1-C6 lower alkyl group, nor C1-C6 lower alkoxy group;
that when R3 is a hydrogen atom and j is not 0, then R7 is not a 2-methoxyphenyl group and R4 is not a —CH2—CONH—R7 nor (CH2)—CO—R20;
and
that when R3 is a cyano group or hydroxy group, then R20 is not a pyridyl group.

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Diarylalkyl cyclic diamine derivatives as chemokine receptor antagonists

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Diarylalkyl cyclic diamine derivatives as chemokine receptor antagonists

Life of this patent

Abstract

Claims18