US 2002/0058657 A1Published application

2-[1H]-quinolone and 2-[1H]-quinoxalone inhibitors of factor Xa

AssigneeMillennium Pharmaceuticals, Inc.

InventorsBing-Yan Zhu, Robert M. Scarborough

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Abstract

Novel compounds of general formula I: 1 including their pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivative having activity against mammalian factor Xa is described. Compositions containing such compounds are also described. The compounds and compositions are useful in vitro or in vivo for preventing or treating conditions in mammals characterized by undesired thrombosis.

Claims16

Dependent claims

A compound of having the following formula:

110
wherein:
A is a member selected from the group consisting of R2, —NR3R4, —C(═O)NR3R4,
111
where R2, R3, R4, R5, R6, R7, R8, and R9 are independently selected from the group consisting of H, OH, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, C6-12carbocyclic aryl, a five to ten membered heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S;
and C1-6alkylheterocyclic ring system having in the ring system 5 to 10 atoms with 1 to 4 of such atoms being selected from the group consisting of N, O and S;
where R6 taken with either of R7 and R8, and/or R7 taken with R8, can each form a 5 to 6 membered heterocyclic ring containing from 1 to 4 atoms selected from the group consisting of N, O and S;
m is an integer from 0-3;
Z is a member selected from the group consisting of a direct link, C1-8alkyl, C3-8cycloalkyl, C2-8alkenyl, C2-8alkynyl, C1-8carbocyclic aryl, or a five to ten membered heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S;
n is an integer from 0-3;
D is a member selected from the group consisting of a direct link, —CH2—, —O—, —N(R2), —C(═O)—, —S—, —SO2—, —SO2—N(R2)—, —N(R2)—SO2—, —OC(═O)—, —C(═O)O—, —C(═O)—N(2)— and —N(R2)—C(═O)—, where R2 is as described above;
R1 is a member selected from the group consisting of H, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, halogen, polyhaloalkyl, C0-8alkyl—C(═O)OH, C0-8alkyl—C(═O)O—C1-8alkyl, —CN, —NO2, C0-8alkyl—OH, C0-8alkyl—SH, —C(═O)—NR2R3, —O—R2 and —O—C(═O)R2, an unsubstituted amino group, a mono or disubstituted amino group, wherein the substituted amino groups are independently substituted by at least one member selected from the group consisting of H, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, polyhaloalkyl, —SO2R2, C0-8alkyl—C(═O)OH and C0-8alkyl—C(═O)O—C1-8alkyl, where R2 and R3 is as described above;
q is an integer from 0-3;
X is N or —CR12;
R11 and R12 are independently a member selected from the group consisting of H, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, C6-12carbocyclic aryl, C1-6alkylaryl, C1-6alkyl—C3-8cycloalkyl, —O—R2, —O—C(═O)R2, —C1-8alkyl—O—R10, —C1-8alkyl—O—C(═O)R10, —C1-8alkyl—C(═O)OR10, C1-8alkyl—O—C(═O)OR10, —C1-8alkyl—C(═O)—NR10R10, C1-8alkyl—NR10R10, —C1-8alkyl—NR10C(═O)R10, —SR10, where R2 is as described above and R10 is a member selected from the group consisting of H, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, and wherein when two R10 groups are present they may be taken together to form a saturated or unsaturated ring with the atom to which they are both attached, preferably a partially or fully saturated ring;
p is an integer from 0-3;
E is a member selected from the group consisting of a direct link, —O—, —N(R11), where R11 is as set forth above, phenylene, a bivalent 5 to 12 member heteroaryl group containing 1 to 4 heteroatoms selected from the group consisting of N, O and S, and a five to ten membered nonaromatic bivalent heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S, wherein said heteroaryl and said nonaromatic heterocyclic ring structure may be independently substituted by from 0 to 5 R14 groups;
J is a member selected from the group consisting of a direct link, a bivalent C3-8cycloalkyl group, phenylene, a 5 to 12 member bivalent heteroaryl group containing 1 to 4 heteroatoms selected from the group consisting of N, O and S, and a five to ten membered nonaromatic bivalent heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S wherein said heteroaryl and said nonaromatic heterocyclic ring structure may be independently substituted by from 0 to 5 R14 groups;
each R14 group is a member selected from the group consisting of H, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, halogen, polyhaloalkyl, C0-8alkyl-C(═O)OH, C0-8alkyl-C(═O)O—C1-8alkyl, —CN, —NO2, C0-8alkyl-OH, C0-8alkyl-SH, —O—R2 and —O—C(═O)R2, an unsubstituted amino group, a mono or disubstituted amino group, wherein the substituted amino groups are independently substituted by at least one member selected from the group consisting of H, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, polyhaloalkyl, C0-8alkyl-C(═O)OH and C0-8alkyl-C(═O)O—C1-8alkyl;
G is a member selected from the group consisting of:
H;
—CN;
—OR1717;
112
wherein
t is an integer from 0 to 6,
u is the integer 0 or 1, and R17, R18, R19, R20, R21, R22, R23, R24, R25 and R26 are independently selected from the group consisting of H, —OH, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, C6-12carbocyclic aryl, a five to ten membered heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S;
and C1-6alkylheterocyclic ring system having in the ring system 5 to 10 atoms with 1 to 4 of such atoms being selected from the group consisting of N, O and S;
where r18 taken with R19, R22 taken with either of R24 and R25, and R24 taken with R25, can each independently form a 5 to 6 membered heterocyclic ring containing from 1 to 4 atoms selected from the group consisting of N, O and S;
with the proviso that when G is H, —CN, —OR17, either E or J must contain at least one N atom;
and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives thereof.

28 more elements

A compound of formula II:

113
A is a member selected from the group consisting of:
R2, —NR3R4, —C(═O) NR3R4,
114
where R2, R3, R4, R5, R6, R7, R8, and R9 are independently selected from the group consisting of H, —OH, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, C6-12carbocyclic aryl, a five to ten membered heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S;
and C1-6alkylheterocyclic ring system having in the ring system 5 to 10 atoms with 1 to 4 of such atoms being selected from the group consisting of N, O and S;
where R6 taken with either of R7 and R8, and/or R7 taken with R8, can each form a 5 to 6 membered heterocyclic ring containing from 1 to 4 atoms selected from the group consisting of N, O and S;
Z is a member selected from the group consisting of a direct link, C1-8alkyl, C3 cycloalkyl, C2 alkenyl, C2-8alkynyl, C1-8carbocyclic aryl, or a five to ten membered heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S;
D is a member selected from the group consisting of a direct link, —CH2—, —O—, —N(R2), —C(═O)—, —S—, —SO2—, —SO2—N(R2)—, —N(R2)—SO2—, —OC(═O)—, —C(═O)O—, —C(═O)—N(2)— and —N(R2)—C(═O)—, where R2 is as described above;
R1 is a member selected from the group consisting of H, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, halogen, polyhaloalkyl, C0-8alkyl—C(═O)OH, C0-8alkyl—C(═O)O—C1-8alkyl, —CN, —NO2, C0-8alkyl—OH, C0-8alkyl—SH, —C(═O)—NR2R3, —O—R2 and —O—C(═O)R2, an unsubstituted amino group, a mono or disubstituted amino group, wherein the substituted amino groups are independently substituted by at least one member selected from the group consisting of H, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, polyhaloalkyl, —SO2R2, C0-8alkyl—C(═O)OH and C0-8alkyl—C(═O)O—C1-8alkyl, where R2 and R3 is as described above;
q is an integer from 0-3;
R11 is independently a member selected from the group consisting of H C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, C6-12carbocyclic aryl, C1-6alkylaryl, C1-6alkyl—C3-8cycloalkyl, —O—R2, —O—C(═O)R2, —C1-8alkyl—O—R10, —C1-8alkyl—O—C(═O)R10, —C1-8alkyl—C(═O)OR10, C1-8alkyl—O—C(═O)OR10, —C1-8alkyl—C(═O)—NR10R10, C1-8alkyl—NR10R10, —C1-8alkyl—NR10C(═O)R10, —SR10, where R2 is as described above and R10 is a member selected from the group consisting of H, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, and wherein when two R10 groups are present they may be taken together to form a saturated or unsaturated ring with the atom to which they are both attached, preferably a partially or fully saturated ring;
p is an integer from 0-2;
E is a member selected from the group consisting of a direct link, —O—, —N(R11), where R11 is as set forth above, phenylene, a bivalent 5 to 12 member heteroaryl group containing 1 to 4 heteroatoms selected from the group consisting of N, O and S, and a five to ten membered nonaromatic bivalent heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S, wherein said heteroaryl and said nonaromatic heterocyclic ring structure may be independently substituted by from 0 to 5 R14 groups;
J is a member selected from the group consisting of a direct link, a bivalent C3-8cycloalkyl group, phenylene, a 5 to 12 member bivalent heteroaryl group containing 1 to 4 heteroatoms selected from the group consisting of N, O and S, and a five to ten membered nonaromatic bivalent heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S wherein said heteroaryl and said nonaromatic heterocyclic ring structure may be independently substituted by from 0 to 5 R14 groups;
each R14 group is a member selected from the group consisting of H, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, halogen, polyhaloalkyl, C0-8alkyl-C(═O)OH, C0-8alkyl-C(═O)O—C1-8alkyl, —CN, —NO2, C0-8alkyl-OH, C0-8alkyl-SH, —O—R2 and —O—C(═O)R2, an unsubstituted amino group, a mono or disubstituted amino group, wherein the substituted amino groups are independently substituted by at least one member selected from the group consisting of H, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, polyhaloalkyl, C0-8alkyl-C(═O)OH and C0-8alkyl-C(═O)O—C1-8alkyl;
G is a member selected from the group consisting of:
H;
—CN;
—OR1717;
115
wherein
t is an integer from 0 to 6,
u is the integer 0 or 1, and R17, R18, R19, R20, R21, R22, R23, R24, R25 and R26 are independently selected from the group consisting of H, —OH, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, C6-12carbocyclic aryl, a five to ten membered heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S;
and C1-6alkylheterocyclic ring system having in the ring system 5 to 10 atoms with 1 to 4 of such atoms being selected from the group consisting of N, O and S;
where r18 taken with R19, R22 taken with either of R24 and R25, and R24 taken with R25, can each independently form a 5 to 6 membered heterocyclic ring containing from 1 to 4 atoms selected from the group consisting of N, O and S;
with the proviso that when G is H, —CN, —OR17, either E or J must contain at least one N atom;
and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives thereof.

25 more elements

A compound of formula III:

116
wherein:
R8 is selected from the group consisting of H, —OH, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, C6-12carbocyclic aryl, a five to ten membered heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S;
and C1-6alkylheterocyclic ring system having in the ring system 5 to 10 atoms with 1 to 4 of such atoms being selected from the group consisting of N, O and S;
R1 is a member selected from the group consisting of H, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, halogen, polyhaloalkyl, C0-8alkyl-C(═O)OH, C0-8alkyl-C(═O)O—C1-8alkyl, —CN, —NO2, C0-8alkyl-OH, C0-8alkyl-SH, —C(═O) NR2R3, —O—R2 and O—C(═O)R2, an unsubstituted amino group, a mono or disubstituted amino group, wherein the substituted amino groups are independently substituted by at least one member selected from the group consisting of H, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, polyhaloalkyl, —SO2R2, C0-8alkyl-C(═O)OH and C0-8alkyl-C(═O)O—C1-8alkyl, where R2 and R3 is as described above;
R2 is selected from the group consisting of H, —OH, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, C6-12carbocyclic aryl, a five to ten membered heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S;
and C1-6alkylheterocyclic ring system having in the ring system 5 to 10 atoms with 1 to 4 of such atoms being selected from the group consisting of N, O and S;
q is 0-3;
R11 is a member selected from the group consisting of H, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, C6-12carbocyclic aryl, C1-6alkylaryl, C1-6alkyl-C3-8cycloalkyl, —O—R2, —O—C(═O)R2, C1-8alkyl-OR10, C1-8alkyl-O—C(═O)R10, —C1-8alkyl-C(═O)OR10, C1-8alkyl-O—C(═O)OR1 O, C1-8alkyl-C(═O) NR1 —OR10, —C1-8alkyl-NR10R10, —C1-8alkyl-NR10C(═)10, —SR10, where R2 is as described above and R10 is a member selected from the group consisting of H, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, and wherein when two R10 groups are present they may be taken together to form a saturated or unsaturated ring with the atom to which they are both attached;
p is an integer from 0-2;
E is a member selected from the group consisting of a direct link, —O—, —N(R11), where R11 is as set forth above, phenylene, a bivalent 5 to 12 member heteroaryl group containing 1 to 4 heteroatoms selected from the group consisting of N, O and S, and a five to ten membered nonaromatic bivalent heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S, wherein said heteroaryl and said nonaromatic heterocyclic ring structure may be independently substituted by from 0 to 5 R14 groups;
J is a member selected from the group consisting of a direct link, a bivalent C3-8cycloalkyl group, phenylene, a 5 to 12 member bivalent heteroaryl group containing 1 to 4 heteroatoms selected from the group consisting of N, O and S, and a five to ten membered nonaromatic bivalent heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S wherein said heteroaryl and said nonaromatic heterocyclic ring structure may be independently substituted by from 0 to 5 R14 groups;
each R14 group is a member selected from the group consisting of H, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, halogen, polyhaloalkyl, C0-8alkyl-C(═O)OH, C0-8alkyl-C(═O)O—C1-8alkyl, —CN, —NO2, C0-8alkyl-OH, C0-8alkyl-SH, —O—R2 and —O—C(═O)R2, an unsubstituted amino group, a mono or disubstituted amino group, wherein the substituted amino groups are independently substituted by at least one member selected from the group consisting of H, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, polyhaloalkyl, C0-8alkyl-C(═O)OH and C0-8alkyl-C(═O)O—C1-8alkyl;
G is a member selected from the group consisting of:
H;
—CN;
—OR17;
117
wherein
t is an integer from 0 to 6,
u is the integer 0 or 1, and R17, R18, R19, R20, R21, R22, R23, R24, R25 and R26 are independently selected from the group consisting of H, —OH, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, C6-12carbocyclic aryl, a five to ten membered heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S;
and C1-6alkylheterocyclic ring system having in the ring system 5 to 10 atoms with 1 to 4 of such atoms being selected from the group consisting of N, O and S;
where r18 taken with R19, R22 taken with either of R24 and R25, and R24 taken with R25, can each independently form a 5 to 6 membered heterocyclic ring containing from 1 to 4 atoms selected from the group consisting of N, O and S;
with the proviso that when G is H, —CN, —OR17, either E or J must contain at least one N atom;
and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives thereof.

22 more elements

A compound of formula IV:

121
wherein:
A is a member selected from the group consisting of:
R2, —NR3R4, —C(═O) NR3R4,
122
where R2, R3, R4, R1, R6, R7, R8, and R9 are independently selected from the group consisting of H, —OH, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl,
C6-12carbocyclic aryl, a five to ten membered heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S;
and C1-6alkylheterocyclic ring system having in the ring system 5 to 10 atoms with 1 to 4 of such atoms being selected from the group consisting of N, O and S;
where r6 taken with either of R7 and R8, and/or R7 taken with R8, can each form a 5 to 6 membered heterocyclic ring containing from 1 to 4 atoms selected from the group consisting of N, O and S;
Z is a member selected from the group consisting of a direct link, C1-8alkyl, C3-8cycloalkyl, C2-8alkenyl, C2-8alkynyl, C1-8carbocyclic aryl, or a five to ten membered heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S;
n is 0-3;
D is a member selected from the group consisting of:
—CH2—, —O—, N R2, C(═O)—, —S—, —SO2—, —SO2—NR2, —NR2—SO2, —OC(═O)—, —C(═O) NR2, and —NR2—C(═O);
R1 and R14 are independently a member selected from the group consisting of H, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, halogen, polyhaloalkyl, C0-8alkyl-C(═O)OH, C0-8alkyl-C(═O)O—C1-8alkyl, —CN, —NO2, C0-8alkyl-OH, C0-8alkyl-SH, —O—R2 and —O—C(═O)R2, an unsubstituted amino group, a mono or disubstituted amino group, wherein the substituted amino groups are independently substituted by at least one member selected from the group consisting of H, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, polyhaloalkyl, C0-8alkyl-C(═O)OH and C0-8alkyl-C(═O)O—C1-8alkyl;
q is 0-3;
R11 is a member selected from the group consisting of H, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, C6-12carbocyclic aryl, C1-6alkylaryl, C1-6alkyl-C3-8cycloalkyl, —O—R2, —O—C(═O)R2, C1-8alkyl—O—R10, C1-8alkyl—O—C(═O)R10, —C1-8alkyl-C(═O)OR10, —C1-8alkyl—O—C(═O)OR10, C1-8alkyl-C(═O)NR10R10, —C1-8alkyl-NR10R10, —C1-8alkyl-NR10C(═O)R10, —SR10, where R2 is as described above and R10 is a member selected from the group consisting of H, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, and wherein when two R10 groups are present they may be taken together to form a saturated or unsaturated ring with the atom to which they are both attached;
G is a member selected from the group consisting of:
H;
—CN;
—OR17;
123
wherein
t is an integer from 0 to 6,
u is the integer 0 or 1, and R17, R18, R19, R20, R21, R22, R23, R24, R25 and R26 are independently selected from the group consisting of H, —OH, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, C6-12carbocyclic aryl, a five to ten membered heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S;
and C1-6alkylheterocyclic ring system having in the ring system 5 to 10 atoms with 1 to 4 of such atoms being selected from the group consisting of N, O and S;
where r18 taken with R19, R22 taken with either of R24 and R25, and R24 taken with R25, can each independently form a 5 to 6 membered heterocyclic ring containing from 1 to 4 atoms selected from the group consisting of N, O and S;
with the proviso that when G is H, —CN, —OR17, either E or J must contain at least one N atom;
and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives thereof.

25 more elements

A compound of formula V:

126
wherein:
R2, R6, and R9 are independently selected from the group consisting of H, —OH, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, C6-12carbocyclic aryl, a five to ten membered heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S;
and C1-6alkylheterocyclic ring system having in the ring system 5 to 10 atoms with 1 to 4 of such atoms being selected from the group consisting of N, O and S;
R11 is independently a member selected from the group consisting of H C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, C6-12carbocyclic aryl, C1-6alkylaryl, C1-6alkyl—C3-8cycloalkyl, —O—R2, —O—C(═O)R2, —C1-8alkyl—O—R10, —C1-8alkyl—O—C(═O)R10, —C1-8alkyl—C(═O)OR10, C1-8alkyl—O—C(═O)OR10, —C1-8alkyl—C(═O)—NR10R10, C1-8alkyl—NR10R10, —C1-8alkyl—NR10C(═O)R10, —SR10, where R2 is as described above and R10 is a member selected from the group consisting of H, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, and wherein when two R10 groups are present they may be taken together to form a saturated or unsaturated ring with the atom to which they are both attached, preferably a partially or fully saturated ring;
each R14 group is a member selected from the group consisting of H, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, halogen, polyhaloalkyl, C0-8alkyl-C(═O)OH, C0-8alkyl-C(═O)O—C1-8alkyl, —CN, —NO2, C0-8alkyl-OH, C0-8alkyl-SH, —O—R2 and —O—C(═O)R2, an unsubstituted amino group, a mono or disubstituted amino group, wherein the substituted amino groups are independently substituted by at least one member selected from the group consisting of H, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, polyhaloalkyl, C0-8alkyl-C(═O)OH and C0-8alkyl-C(═O)O—C1-8alkyl;
and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives thereof.

4 more elements

Dependencies are inferred from the claim text.

Facts

Application: 09/773,374Filed 1 Feb 2001
Priority: 1 Feb 2000
Published: 16 May 2002
Term ends: Not estimatedThe source records don’t support an estimate.

Classification7 codes

C07D 401/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
A61P 7/02
Drugs for disorders of the blood or the extracellular fluid: antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
A61P 9/02
Drugs for disorders of the cardiovascular system: non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
C07D 241/44
Benzopyrazines: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or…

Family

Application60/179,389Us provisional application · filed 1 Feb 2000
Application60/191,722Us provisional application · filed 24 Mar 2000
US 6,777,413 B2Related patent
US 2002/0058657 A1This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound of having the following formula:

110
wherein:
A is a member selected from the group consisting of R2, —NR3R4, —C(═O)NR3R4,
111
where R2, R3, R4, R5, R6, R7, R8, and R9 are independently selected from the group consisting of H, OH, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, C6-12carbocyclic aryl, a five to ten membered heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S;
and C1-6alkylheterocyclic ring system having in the ring system 5 to 10 atoms with 1 to 4 of such atoms being selected from the group consisting of N, O and S;
where R6 taken with either of R7 and R8, and/or R7 taken with R8, can each form a 5 to 6 membered heterocyclic ring containing from 1 to 4 atoms selected from the group consisting of N, O and S;
m is an integer from 0-3;
Z is a member selected from the group consisting of a direct link, C1-8alkyl, C3-8cycloalkyl, C2-8alkenyl, C2-8alkynyl, C1-8carbocyclic aryl, or a five to ten membered heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S;
n is an integer from 0-3;
D is a member selected from the group consisting of a direct link, —CH2—, —O—, —N(R2), —C(═O)—, —S—, —SO2—, —SO2—N(R2)—, —N(R2)—SO2—, —OC(═O)—, —C(═O)O—, —C(═O)—N(2)— and —N(R2)—C(═O)—, where R2 is as described above;
R1 is a member selected from the group consisting of H, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, halogen, polyhaloalkyl, C0-8alkyl—C(═O)OH, C0-8alkyl—C(═O)O—C1-8alkyl, —CN, —NO2, C0-8alkyl—OH, C0-8alkyl—SH, —C(═O)—NR2R3, —O—R2 and —O—C(═O)R2, an unsubstituted amino group, a mono or disubstituted amino group, wherein the substituted amino groups are independently substituted by at least one member selected from the group consisting of H, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, polyhaloalkyl, —SO2R2, C0-8alkyl—C(═O)OH and C0-8alkyl—C(═O)O—C1-8alkyl, where R2 and R3 is as described above;
q is an integer from 0-3;
X is N or —CR12;
R11 and R12 are independently a member selected from the group consisting of H, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, C6-12carbocyclic aryl, C1-6alkylaryl, C1-6alkyl—C3-8cycloalkyl, —O—R2, —O—C(═O)R2, —C1-8alkyl—O—R10, —C1-8alkyl—O—C(═O)R10, —C1-8alkyl—C(═O)OR10, C1-8alkyl—O—C(═O)OR10, —C1-8alkyl—C(═O)—NR10R10, C1-8alkyl—NR10R10, —C1-8alkyl—NR10C(═O)R10, —SR10, where R2 is as described above and R10 is a member selected from the group consisting of H, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, and wherein when two R10 groups are present they may be taken together to form a saturated or unsaturated ring with the atom to which they are both attached, preferably a partially or fully saturated ring;
p is an integer from 0-3;
E is a member selected from the group consisting of a direct link, —O—, —N(R11), where R11 is as set forth above, phenylene, a bivalent 5 to 12 member heteroaryl group containing 1 to 4 heteroatoms selected from the group consisting of N, O and S, and a five to ten membered nonaromatic bivalent heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S, wherein said heteroaryl and said nonaromatic heterocyclic ring structure may be independently substituted by from 0 to 5 R14 groups;
J is a member selected from the group consisting of a direct link, a bivalent C3-8cycloalkyl group, phenylene, a 5 to 12 member bivalent heteroaryl group containing 1 to 4 heteroatoms selected from the group consisting of N, O and S, and a five to ten membered nonaromatic bivalent heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S wherein said heteroaryl and said nonaromatic heterocyclic ring structure may be independently substituted by from 0 to 5 R14 groups;
each R14 group is a member selected from the group consisting of H, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, halogen, polyhaloalkyl, C0-8alkyl-C(═O)OH, C0-8alkyl-C(═O)O—C1-8alkyl, —CN, —NO2, C0-8alkyl-OH, C0-8alkyl-SH, —O—R2 and —O—C(═O)R2, an unsubstituted amino group, a mono or disubstituted amino group, wherein the substituted amino groups are independently substituted by at least one member selected from the group consisting of H, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, polyhaloalkyl, C0-8alkyl-C(═O)OH and C0-8alkyl-C(═O)O—C1-8alkyl;
G is a member selected from the group consisting of:
H;
—CN;
—OR1717;
112
wherein
t is an integer from 0 to 6,
u is the integer 0 or 1, and R17, R18, R19, R20, R21, R22, R23, R24, R25 and R26 are independently selected from the group consisting of H, —OH, C1-8alkyl, C2-8alkenyl, C2-8alkynyl, C3-8cycloalkyl, C6-12carbocyclic aryl, a five to ten membered heterocyclic ring system containing 1-4 heteroatoms selected from the group consisting of N, O and S;
and C1-6alkylheterocyclic ring system having in the ring system 5 to 10 atoms with 1 to 4 of such atoms being selected from the group consisting of N, O and S;
where r18 taken with R19, R22 taken with either of R24 and R25, and R24 taken with R25, can each independently form a 5 to 6 membered heterocyclic ring containing from 1 to 4 atoms selected from the group consisting of N, O and S;
with the proviso that when G is H, —CN, —OR17, either E or J must contain at least one N atom;
and all pharmaceutically acceptable isomers, salts, hydrates, solvates and prodrug derivatives thereof.

28 more elements

Facts

Application

09/773,374Filed 1 Feb 2001

Priority

1 Feb 2000

Published

16 May 2002

Term ends

Not estimatedThe source records don’t support an estimate.

Classification7 codes

C07D 401/12
Containing two hetero rings: linked by a chain containing hetero atoms as chain links
A61P 7/02
Drugs for disorders of the blood or the extracellular fluid: antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
A61P 9/02
Drugs for disorders of the cardiovascular system: non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
C07D 241/44
Benzopyrazines: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or…