US 2004/0023969 A1 · Combination of an allosteric alkyne inhibitor of matrix metalloproteinase-13 with celecoxib or valdecoxib

Abstract

The invention provides a combination, comprising an allosteric alkyne inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, with celecoxib, or a pharmaceutically acceptable salt thereof, or valdecoxib, or a pharmaceutically acceptable salt thereof. This invention also provides a method of treating a disease that is responsive to inhibition of MMP-13 and cyclooxygenase-2, comprising administering to a patient suffering from such a disease the invention combination comprising an allosteric alkyne inhibitor of MMN-13, or a pharmaceutically acceptable salt thereof, with celecoxib, or a pharmaceutically acceptable salt thereof, or valdecoxib, or a pharmaceutically acceptable salt thereof. This invention also provides a pharmaceutical composition, comprising the invention combination comprising an allosteric alkyne inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, with celecoxib, or a pharmaceutically acceptable salt thereof, or valdecoxib, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. The invention combinations may also be further combined with other pharmaceutical agents depending on the disease being treated.

A combination, comprising valdecoxib, or a pharmaceutically acceptable salt thereof, and an allosteric alkyne inhibitor of MMP-13 of Formula (A)

47
or a pharmaceutically acceptable salt thereof, or an N-oxide thereof,
wherein:
W1 is O, S, or NR3, wherein R3 is hydrogen, (C1-C6)alkyl, hydroxyl or cyano;
W2 is selected from:
hydrogen;
trifluoromethyl;
NH2;
(C1-C10)alkylN(H);
[(C1-C10)alkyl]2N, wherein each (C1-C10)alkyl moiety is the same or different;
(C1-C6)alkyl;
(C3-C6)alkenyl;
(C3-C6)alkynyl;
phenyl;
naphthyl;
phenyl-(C1-C10)alkyl;
naphthyl-(C1-C10)alkyl;
(C3-C10)cycloalkyl-(C1-C10)alkyl;
an aromatic 5-membered or 6-membered monocyclic heterocycle comprising carbon atoms and from 1 to 4 heteroatoms selected from O, S, N(H), and N—(C1-C10)alkyl;
a nonaromatic 5-membered or 6-membered monocyclic heterocycle comprising carbon atoms and from 1 to 3 heteroatoms selected from O, S, N(H), and N—(C1-C10)alkyl;
wherein in W2 each (C1-C10)alkyl, (C1-C6)alkyl, (C3-C6)alkenyl, (C3-C6)alkynyl, phenyl, naphthyl, phenyl-(C1-C10)alkyl, naphthyl-(C1-C10)alkyl, (C3-C10)cycloalkyl-(C1-C10)alkyl, aromatic heterocycle, and nonaromatic heterocycle group is independently unsubstituted or substituted by from 1 to 3 groups, which may be identical or different, selected from halo, NH2, (C1-C10)alkylN(H), [(C1-C10)alkyl]2N, wherein each (C1-C10)alkyl moiety is the same or different, cyano, trihalo(C1-C6)alkyl, (C1-C6)acyl, C(═O)OR4, —OR4, and SR4;
R4 is hydrogen or (C1-C6)alkyl;
or
W2 and W1 may be taken together to form a diradical group W2-W1 of formula
W3═X4—N;
W3 is N or CR5 wherein R5 is selected from:
hydrogen;
OR6;
R6;
(C1-C6)alkyl;
(C3-C8)cycloalkyl;
a saturated heterocycle comprising from 3 to 8 ring members which are carbon atoms and one heteroatom selected from O, S, N(H), and N—(C1-C10)alkyl;
phenyl;
naphthyl;
(C5-C10)heteroaryl comprising carbon atoms and from 1 to 4 heteroatoms selected from O, S, N(H), and N—(C1-C10)alkyl;
phenyl-(C1-C10)alkyl;
and
naphthyl-(C1-C10)alkyl;
R6 is selected from hydrogen, (C1-C6)alkyl, phenyl-(C1-C10)alkyl, and naphthyl-(C1-C10)alkyl;
wherein in W3 each (C1-C6)alkyl, (C3-C8)cycloalkyl, saturated heterocycle, phenyl, naphthyl, (C5-C10)heteroaryl, phenyl-(C1-C10)alkyl, and naphthyl-(C1-C10)alkyl group is independently unsubstituted or substituted by (CH2)p—OH or (CH2)p—NH2;
p is an integer of from 0 to 4 inclusive;
X4 is N or CR7, wherein R7 is selected from:
hydrogen;
NR8R9;
OR8;
SR8;
(C1-C6)alkyl;
(C3-C8)cycloalkyl;
a saturated heterocycle comprising from 3 to 8 ring members which are carbon atoms and one heteroatom selected from O, S, N(H), and N—(C1-C10)alkyl;
phenyl;
naphthyl;
(C5-C10)heteroaryl comprising carbon atoms and from 1 to 4 heteroatoms selected from O, S, N(H), and N—(C1-C10)alkyl;
phenyl-(C1-C10)alkyl;
and
naphthyl-(C1-C10)alkyl;
R8 and R9 are the same or different, and are selected from hydrogen;
(C1-C6)alkyl;
phenyl-(C1-C10)alkyl;
and naphthyl-(C1-C10)alkyl;
wherein in X4 each (C1-C6)alkyl, (C3-C8)cycloalkyl, saturated heterocycle, phenyl, naphthyl, (C5-C10)heteroaryl, phenyl-(C1-C10)alkyl, and naphthyl-(C1-C10)alkyl group is independently unsubstituted or substituted by (CH2)p—OH or (CH2)p—NH2, wherein p is an integer from 0 to 4 inclusive;
X1, X2 and X3 independently of each other are N or C—R, wherein R is selected from:
hydrogen;
(C1-C6)alkyl;
hydroxyl;
(C1-C6)alkoxy;
halo;
trifluoromethyl;
cyano;
nitro;
S(O)n1R4, wherein R4 is as defined above;
NR10R11;
n1 is an integer of from 0 to 2 inclusive;
R10 and R11 are the same or different, and are independently selected from hydrogen;
(C1-C6)alkyl;
phenyl-(C1-C10)alkyl;
and
naphthyl-(C1-C10)alkyl;
or
R10 and R11 may be taken together with the nitrogen atom to which they are bonded to form a 5-membered or 6-membered ring containing carbon atoms, the nitrogen atom to which R10 and R11 are attached, and optionally a second heteroatom selected from O, S, N(H), and N(C1-C10)alkyl,
wherein not more than two of the groups X1, X2, and X3 simultaneously are a nitrogen atom;
n is an integer of from 0 to 8 inclusive;
Z is C(R12)(R13);
Each R12 and R13 independently of each other are selected from:
hydrogen;
(C1-C6)alkyl;
trihalo(C1-C6)alkyl;
halo;
NH2;
(C1-C6)alkylN(H);
[(C1-C6)alkyl]2N, wherein each (C1-C6)alkyl moiety is the same or different;
OR4;
SR4;
and
C(═O)OR4, wherein R4 is as defined above;
or
R12 and R13 on the same carbon atom may be taken together with the carbon atom to which they are attached to form a carbonyl group;
and
Z can contain 1 carbon-carbon double bond when two R12 groups are absent and n is an integer of from 2 to 8;
and
Z can contain 2 carbon-carbon double bonds when four R12 groups are absent or three R12 and one R13 groups are absent and n is an integer of from 3 to 8;
and
Z can contain 1 carbon-carbon triple bond when two each of R12 and R13 are absent and n is an integer of from 2 to 8;
and
Z can contain 2 carbon-carbon triple bonds when four each of R12 and R13 are absent and n is an integer of from 4 to 8;
and
One C(R12)(R13) group in Z can be replaced with O, N(H), N(C1-C6)alkyl, S, S(O), or S(O)2;
A is selected from:
phenyl;
an aromatic 5-membered or 6-membered monocyclic heterocycle comprising carbon atoms and from 1 to 4 heteroatoms selected from O, S, N(H), and N—(C1-C10)alkyl;
a nonaromatic 5-membered or 6-membered monocycle comprising carbon atoms and from 0 to 4 heteroatoms selected from O, S, N(H), and N—(C1-C10)alkyl;
naphthyl;
an aromatic 8-membered to 12-membered bicycle comprising two aromatic rings independently selected from 5-membered or 6-membered rings, wherein the rings may be the same or different and bonded or fused to each other, and wherein the bicycle comprises carbon atoms and from 1 to 6 hetero atoms selected from O, S, N(H), and N—(C1-C10)alkyl;
an aromatic 8-membered to 12-membered bicycle comprising one aromatic 5-membered or 6-membered ring and one non-aromatic 5-membered or 6-membered ring, wherein the rings may be bonded or fused to each other, and wherein the bicycle comprises carbon atoms and from 0 to 6 hetero atoms selected from O, S, N(H), and N—(C1-C10)alkyl;
and
a non-aromatic 8-membered to 12-membered bicycle comprising two non-aromatic rings independently selected from 5-membered or 6-membered rings, wherein the rings may be the same or different and bonded or fused to each other, and wherein the bicycle comprises carbon atoms and from 0 to 4 hetero atoms selected from O, S, N(H), and N—(C1-C10)alkyl;
Each R2 may be the same or different, and is independently selected from:
hydrogen;
(C1-C6)alkyl;
halo;
cyano;
nitro;
trihalo(C1-C6)alkyl;
NR10R11;
OR14;
SR14;
S(O)R14;
S(O)2R14;
(C1-C6)acyl;
(CH2)kNR10R11;
X5(CH2)kNR10R11;
(CH2)kSO2NR14R15;
X5(CH2)kC(═O)OR14;
(CH2)kC(═O)OR14;
X5(CH2)kC(═O)NR14R15;
(CH2)kC(═O)NR14R15;
and
X6-R16;
X5 is O, S, N(H), or N(C1-C6)alkyl;
k is an integer of from 0 and 3 inclusive;
R10 and R11 are as defined above;
R14 and R15 may be the same or different, and independently are hydrogen or (C1-C6)alkyl;
X6 is a single bond, —CH2—, O, or S, S(O), or S(O)2;
R16 is selected from:
phenyl;
an aromatic 5-membered or 6-membered monocyclic heterocycle comprising carbon atoms and from 1 to 4 heteroatoms selected from O, S, N(H), and N—(C1-C10)alkyl;
cyclopentyl;
cyclohexyl;
and
a nonaromatic 5-membered or 6-membered monocyclic heterocycle comprising carbon atoms and from 1 to 3 heteroatoms selected from O, S, N(H), and N—(C1-C10)alkyl;
wherein in R16 each phenyl, aromatic 5-membered or 6-membered, heterocyclic ring, cyclopentyl, cyclohexyl, and non-aromatic 5-membered or 6-membered heterocyclic ring group independently is unsubstituted or substituted with from 1 to 3 groups independently selected from (C1-C6)alkyl, halo, trihalo(C1-C6)alkyl, hydroxyl, (C1-C6)alkoxy, SH, (C1-C6)alkylthio, NH2, (C1-C6)alkylN(H), [(C1-C6)alkyl]2N, wherein each (C1-C6)alkyl moiety may be the same or different;
q is an integer of from 0 to 7 inclusive;
R1 is a group selected from:
hydrogen;
(C1-C6)alkyl;
(C3-C6)alkenyl;
and
(C3-C6)alkynyl,
wherein in R1 each (C1-C6)alkyl, (C3-C6)alkenyl, and
(C3-C6)alkynyl group is independently unsubstituted or substituted with from 1 to 3 groups independently selected from NH2, (C1-C6)alkylN(H), [(C1-C6)alkyl]2N, wherein each (C1-C6)alkyl moiety may be the same or different, (C1-C6)alkyl, cyano, trihalo(C1-C6)alkyl, C(═O)OR4, OR4, SR4, wherein R4 is as defined above, and a group of formula (1)
48
m is an integer of from 0 to 8 inclusive,
Y is CR18R19;
Each R18 and R19 independently of each other, is selected from:
hydrogen;
(C1-C6)alkyl;
phenyl;
trihalo(C1-C6)alkyl;
halo;
NH2;
(C1-C6)alkylN(H);
[(C1-C6)alkyl]2N, wherein each (C1-C6)alkyl moiety may be the same or different;
OR4;
SR4;
and
C(═O)OR4;
R4 is as defined above;
Y can contain 1 carbon-carbon double bond when two R18 groups are absent and m is an integer of from 2 to 8;
and
Y can contain 2 carbon-carbon double bonds when four R18 groups are absent or three R18 and one R19 groups are absent and m is an integer of from 3 to 8;
and.
Y can contain 1 carbon-carbon triple bond when two each of R18 and R19 are absent and m is an integer of from 2 to 8;
and
Y can contain 2 carbon-carbon triple bonds when four each of R18 and R19 are absent and m is an integer of from 4 to 8;
and
One C(R18)(R19) group in Y can be replaced with O, N(H), N(C1-C6)alkyl, S, S(O), or S(O)2;
B is a group selected from:
phenyl;
an aromatic 5-membered or 6-membered monocyclic heterocycle comprising carbon atoms and from 1 to 4 heteroatoms selected from O, S, N(H), and N—(C1-C10)alkyl;
a nonaromatic 5-membered or 6-membered monocycle comprising carbon atoms and from 0 to 4 heteroatoms selected from O, S, N(H), and N—(C1-C10)alkyl;
naphthyl;
an aromatic 8-membered to 12-membered bicycle comprising two aromatic rings independently selected from 5-membered or 6-membered rings, wherein the rings may be the same or different and bonded or fused to each other, and wherein the bicycle comprises carbon atoms and from 1 to 6 hetero atoms selected from O, S, N(H), and N—(C1-C10)alkyl;
an aromatic 8-membered to 12-membered bicycle comprising one aromatic 5-membered or 6-membered ring and one non-aromatic 5-membered or 6-membered ring, wherein the rings may be bonded or fused to each other, and wherein the bicycle comprises carbon atoms and from 0 to 6 hetero atoms selected from O, S, N(H), and N—(C1-C10)alkyl;
and
a non-aromatic 8-membered to 12-membered bicycle comprising two non-aromatic rings independently selected from 5-membered or 6-membered rings, wherein the rings may be the same or different and bonded or fused to each other, and wherein the bicycle comprises carbon atoms and from 0 to 4 hetero atoms selected from O, S, N(H), and N—(C1-C10)alkyl;
r is an integer of from 0 to 7 inclusive,
Each R17 may be the same or different and independently is selected from:
hydrogen;
(C1-C6)alkyl;
halo;
cyano;
nitro;
trihalo(C1-C6)alkyl;
NR10R11;
OR14;
SR14;
S(O)R14;
S(O)2R14;
(C1-C6)acyl;
(CH2)kNR10R11;
X5(CH2)kNR10R11;
(CH2)kSO2NR14R15;
X5(CH2)kC(═O)OR14;
(CH2)kC(═O)OR14;
X5(CH2)kC(═O)NR14R15;
(CH2)kC(═O)NR14R15;
and
X6-R16, wherein X5, k, R10, R11, R14, R15, X6, and R16 are as defined above.

214 more elements

Combination of an allosteric alkyne inhibitor of matrix metalloproteinase-13 with celecoxib or valdecoxib

Life of this patent

Combination of an allosteric alkyne inhibitor of matrix metalloproteinase-13 with celecoxib or valdecoxib

Life of this patent

Abstract

Claims10