US 2004/0072883 A1 · Cyclooxygenase-2 selective inhibitors, compositions and methods of use

Abstract

The invention describes novel cyclooxygenase 2 (COX-2) selective inhibitors and novel compositions comprising at least one cyclooxygenase 2 (COX-2) selective inhibitor, and, optionally, at least one compound that donates, transfers or releases nitric oxide, stimulates endogenous synthesis of nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor or is a substrate for nitric oxide synthase, and/or at least one therapeutic agent. The invention also provides novel kits comprising at least one COX-2 selective inhibitor, optionally nitrosated and/or nitrosylated, and, optionally, at least one nitric oxide donor, and/or, optionally, at least one therapeutic agent. The novel cyclooxygenase 2 selective inhibitors of the invention can be optionally nitrosated and/or nitrosylated. The invention also provides methods for treating inflammation, pain and fever; for treating and/or improving the gastrointestinal properties of COX-2 selective inhibitors; for facilitating wound healing; for treating and/or preventing renal and/or respiratory toxicity; for treating and/or preventing other disorders resulting from elevated levels of cyclooxygenase-2; and for improving the cardiovascular profile of COX-2 selective inhibitors.

A compound of Formula (I), (II), (III), (IV), (V), (VI), (VII) or (VIII), or a pharmaceutically acceptable salt thereof;

wherein the compound of Formula (I) is:
13
wherein:
when side b is a double bond, and sides a and c are single bonds, —X1-Y1-Z1- is:
(a) —CR4(R5)—CR5(R5′)—CR4(R5)—;
(b) —C(O)—CR4(R4′)—CR5(R5′)—;
(c) —CR4(R4′)—CR5(R5′)—C(O)—;
(d) —(CR5(R5′))k—O—C(O)—;
(e) —C(O)—O—(CR5(R5′))k—;
(f) —CR4(R4′)—NR3—CR5(R5′)—;
(g) —CR5(R5′)—NR3—C(O)—;
(h) —CR4═CR4′—S—;
(i) —s—CR4═CR4′—;
(j) —S—N═CR4—;
(k) —CR4═N—S—;
(l) —N═CR4—O—;
(m) —O—CR4═N—;
(n) —NR3—CR4═N—;
(o) —N═CR4—S—;
(p) —S—CR4═N—;
(q) —C(O)—NR3—CR5′(R5′)—;
(r) —R3N—CR5═CR5′—;
(s) —CR4═CR5—NR3—;
(t) —O—N═CR4—;
(u) —CR4═N—O—;
(v) —N═N—S—;
(w) —S—N═N—;
(x) —N═CR4—NR3—;
(y) —R3N—N═N—;
(z) —N═N—NR3—;
(aa) —CR4(R4′)—O—CR5(R5′)—;
(bb) —CR4(R4′)—S—CR5(R5′)—;
(cc) —CR4(R4′)—C(O)—CR5(R5′)—;
(dd) —CR4(R4′)—CR5(R5′)—C(S)—;
(ee) —(CR5(R5′))k—O—C(S)—;
(ff) —C(S)—O—(CR5(R5′))k—;
(gg) —(CR5(R5′))k—NR3—C(S)—;
(hh) —C(S)—NR3—(CR5(R5′))k—;
(ii) —(CR5(R5′))k—S—C(O)—;
(jj) —C(O)—S—(CR5(R5′))k—;
(kk) —O—CR4═CR5;
(ll) —CR4═CR5—O—;
(mm) —C(O)—NR3—S—;
(nn) —S—NR3OC(O)—;
(oo) —C(O)—NR3—O—;
(pp) —O—NR3—C(O)—;
(qq) —NR3—CR4═CR5—;
(rr) —CR4═N—NR3—;
(ss) —NR3—N═CR4—;
(tt) —C(O)—NR3—NR3—;
(uu) —NR3—NR3—C(O)—;
(vv) —C(O)—O—NR3—;
(ww) —NR3—C(O)—;
(xx) —O—CR4R4′—C(S)—;
(zz) —O—CR4R4′—C(O)—;
(aaa) —C(S)—CR4R4′—O—;
or
(yy) —C(O)—CR4R4′—O—;
when sides a and c are double bonds and side b is a single bond, —X1-Y1-Z1- is:
(a) ═CR4—O—CR5═;
(b) ═CR4—NR3—CR5═;
(c) ═N—S—CR4═;
(d) ═CR4—S—N═;
(e) ═N—O—CR4═;
(f) ═CR4—O—N═;
(g) ═N—S—N═;
(h) ═N—O—N═;
(i) ═N—NR3—CR4═;
(j) ═CR4—NR3—N═;
(k) ═N—NR3—N═;
(l) ═CR4—S—CR5═;
or
(m) ═CR4—CR4(R4′)—CR5═;
R1 is:
(a) —S(O)2—CH3;
(b) —S(O)2—NR8(D1);
(c) —S(O)2—N(D1)—C(O)—CF3;
(d) —S(O)—(NH)—NH(D1);
(e) —S(O)—(NH)—N(D1)-C(O)—CF3;
(f) —P(O)(CH3)NH(D1);
(g) —P(O)(CH3)2;
(h) —C(S)—NH(D1);
(i) —S(O)(NH)CH3;
(j) —P(O)(CH3)OD1;
or
(k) —P(O)(CH3)NH(D1);
R1′ at each occurrence is independently:
(a) hydrogen;
(b) halogen;
(c) methyl;
or
(d) CH2OH;
R2 is:
(a) lower alkyl;
(b) cycloalkyl;
(c) mono-, di- or tri-substituted phenyl or naphthyl, wherein the substituents are each independently:
(1) hydrogen;
(2) halo;
(3) alkoxy;
(4) alkylthio;
(5) CN;
(6) haloalkyl, preferably CF3;
(7) lower alkyl;
(8) N3;
(9) —CO2D1;
(10) —CO2-lower alkyl;
(11)—(C(R5)(R6))n—OD1;
(12) —(C(R5)(R6))n—O-lower alkyl;
(13) lower alkyl-CO2—R5;
(14) —OD1;
(15) haloalkoxy;
(16) amino;
(17) nitro;
(18) alkylsulfinyl;
or
(19) heteroaryl;
(d) mono-, di- or tri-substituted heteroaryl, wherein the heteroaryl is a monocyclic aromatic ring of 5 atoms, said ring having one heteroatom which is S, O, or N, and, optionally, 1, 2, or 3 additional N atoms;
or the heteroaryl is a monocyclic ring of 6 atoms, said ring having one heteroatom which is N, and, optionally, 1, 2, 3, or 4 additional N atoms;
wherein the substituents are each independently:
(1) hydrogen;
(2) halo;
(3) lower alkyl;
(4) alkoxy;
(5) alkylthio;
(6) CN;
(7) haloalkyl, preferably CF3;
(8) N3;
(9) —C(R5)(R6)—OD1;
(10) —C(R5)(R6)—O-lower alkyl;
or
(11) alkylsulfinyl;
(e) benzoheteroaryl which includes the benzo fused analogs of (d);
(f) —NR10R11;
(g) —SR11;
(h) —OR11;
(i) —R11;
(j) alkenyl;
(k) alkynyl;
(l) unsubstituted, mono-, di-, tri- or tetra-substituted cycloalkenyl, wherein the substituents are each independently:
(1) halo;
(2) alkoxy;
(3) alkylthio;
(4) CN;
(5) haloalkyl, preferably CF3;
(6) lower alkyl;
(7) N3;
(8) —CO2D1;
(9) —CO2-lower alkyl;
(10) —C(R12)(R13)—OD;
(11) —C(R12)(R13)—O-lower alkyl;
(12) lower alkyl-CO2—R12;
(13) benzyloxy;
(14) —O-(lower alkyl)-CO2R12;
(15) —O-(lower alkyl)-NR12 R3;
or
(16) alkylsulfinyl;
(m) mono-, di-, tri- or tetra-substituted heterocycloalkyl group of 5, 6 or 7 members, or a benzoheterocycle, wherein said heterocycloalkyl or benzoheterocycle contains 1 or 2 heteroatoms selected from O, S, or N and, optionally, contains a carbonyl group or a sulfonyl group, and wherein said substituents are each independently:
(1) halo;
(2) lower alkyl;
(3) alkoxy;
(4) alkylthio;
(5) CN;
(6) haloalkyl, preferably CF3;
(7) N3;
(8) —C(R12)(R13)—OD1;
(9) —C(R12)(R13)—O-lower alkyl;
or
(10) alkylsulfinyl;
(n) styryl, mono or di-substituted styryl, wherein the substituent are each independently:
(1) halo;
(2) alkoxy;
(3) alkylthio;
(4) CN;
(5) haloalkyl, preferably CF3;
(6) lower alkyl;
(7) N3;
(8) —CO2D1;
(9) —CO2-lower alkyl;
(10) —C(R12)(R3)—OD1;
(11) —C(R 2)(R13)—O-lower alkyl;
(12) lower alkyl-CO2—R12;
(13) benzyloxy;
(14) —O-(lower alkyl)-CO2R12;
or
(15) —O-(lower alkyl)-NR2R13;
(o) phenylacetylene, mono- or di-substituted phenylacetylene, wherein the substituents are each independently:
(1) halo;
(2) alkoxy;
(3) alkylthio;
(4) CN;
(5) haloalkyl, preferably CF3;
(6) lower alkyl;
(7) N3;
(8) —CO2D1;
(9) —CO2-lower alkyl;
(10) —C(R12)(R3)—OD1;
(11) —C(R12)(R13)—O-lower alkyl;
(12) lower alkyl-CO2—R12;
(13) benzyloxy;
(14) —O-(lower alkyl)-CO2R12;
or
(15) —O-(lower alkyl)-NR12R13;
(p) fluoroalkenyl;
(q) mono- or di-substituted bicyclic heteroaryl of 8, 9 or 10 members, containing 2, 3, 4 or 5 heteroatoms, wherein at least one heteroatom resides on each ring of said bicyclic heteroaryl, said heteroatoms are each independently O, S and N and said substituents are each independently:
(1) hydrogen;
(2) halo;
(3) lower alkyl;
(4) alkoxy;
(5) alkylthio;
(6) CN;
(7) haloalkyl, preferably CF3;
(8) N3;
(9) —C(R5)(R6)—OD1;
or
(10) —C(R5)(R6)—O-lower alkyl;
(r) K;
(s) aryl;
(t) arylalkyl;
(u) cycloalkylalkyl;
(v) —C(O)R1;
(u) hydrogen;
(v) arylalkenyl;
(w) arylalkoxy;
(x) alkoxy;
(y) aryloxy;
(z) cycloalkoxy;
(aa) arylthio;
(bb) alkylthio;
(cc) arylalkylthio;
or
(dd) cycloalkylthio;
R3 is:
(a) hydrogen;
(b) haloalkyl, preferably CF3;
(c) CN;
(d) lower alkyl;
(e) —(C(Re)(Rf))p—U-V;
(f) K;
(g) unsubstituted or substituted:
(1) lower alkyl-Q;
(2) lower alkyl-O-lower alkyl-Q;
(3) lower alkyl-S-lower alkyl-Q;
(4) lower alkyl-O-Q;
(5) lower alkyl-S-Q;
(6) lower alkyl-O-V;
(7) lower alkyl-S-V;
(8) lower alkyl-O-K;
or
(9) lower alkyl-S-K;
wherein the substituent(s) reside on the lower alkyl group;
(h) Q;
(i) alkylcarbonyl;
(j) arylcarbonyl;
(k) alkylarylcarbonyl;
(l) arylalkylcarbonyl;
(m) carboxylic ester;
(n) carboxamido;
(o) cycloalkyl;
(p) mono-, di- or tri-substituted phenyl or naphthyl, wherein the substituents are each independently:
(1) hydrogen;
(2) halo;
(3) alkoxy;
(4) alkylthio;
(5) CN;
(6) haloalkyl, preferably CF3;
(7) lower alkyl;
(8) N3;
(9) —CO2D1;
(10) —CO2-lower alkyl;
(11) —(C(R5)(R6))z—OD1;
(12) —(C(R5)(R6))n—O-lower alkyl;
(13) lower alkyl-CO2—R5;
(14) —OD1;
(15) haloalkoxy;
(16) amino;
(17) nitro;
or
(18) alkylsulfinyl;
(q) alkenyl;
(r) alkynyl;
(s) arylalkyl;
(t) lower alkyl-OD1;
(u) alkoxyalkyl;
(v) aminoalkyl;
(w) lower alkyl-CO2R10;
(x) lower alkyl-C(O)NR10(R10);
(y) heterocyclicalkyl;
or
(z) heterocyclic ring-C(O)—;
R4, R4′, R5 and R5′ are each independently:
(a) hydrogen;
(b) amino;
(c) CN;
(d) lower alkyl;
(e) haloalkyl;
(f) alkoxy;
(g) alkylthio;
(h) Q;
(i) —O-Q;
(j) —S-Q;
(k) K;
(l) cycloalkoxy;
(m) cycloalkylthio;
(n) unsubstituted, mono-, or di-substituted phenyl or unsubstituted, mono-, or disubstituted benzyl, wherein the substituents are each independently:
(1) halo;
(2) lower alkyl;
(3) alkoxy;
(4) alkylthio;
(5) CN;
(6) haloalkyl, preferably CF3;
(7) N3;
(8) Q;
(9) nitro;
or
(10) amino;
(o) unsubstituted, mono-, or di-substituted heteroaryl or unsubstituted, mono-, or di-substituted heteroarylmethyl, wherein the heteroaryl is a monocyclic aromatic ring of 5 atoms, said ring having one heteroatom which is S, O, or N, and, optionally, 1, 2, or 3 additional N atoms;
or the heteroaryl is a monocyclic ring of 6 atoms, said ring having one heteroatom which is N, and, optionally, 1, 2, 3, or 4 additional N atoms;
said substituents are each independently:
(1) halo;
(2) lower alkyl;
(3) alkoxy;
(4) alkylthio;
(5) CN;
(6) haloalkyl, preferably CF3;
(7) N3;
(8) —C(R6)(R7)—OD1;
(9) —C(R6)(R7)—O-lower alkyl;
or
(10) alkylsulfinyl
(p) —CON(R8)(R8);
(q) —CH2OR8;
(r) —CH2OCN;
(s) unsubstituted or substituted:
(1) lower alkyl-Q;
(2) —O-lower alkyl-Q;
(3) —S-lower alkyl-Q;
(4) lower alkyl-O-lower alkyl-Q;
(5) lower alkyl-S-lower alkyl-Q;
(6) lower alkyl-O-Q;
(7) lower alkyl-S-Q;
(8) lower alkyl-O-K;
(9) lower alkyl-S-K;
(10) lower alkyl-O-V;
or
(11) lower alkyl-S-V;
wherein the substituent(s) resides on the lower alkyl;
(t) cycloalkyl;
(u) aryl;
(v) arylalkyl;
(w) cycloalkylalkyl;
(x) aryloxy;
(y) arylalkoxy;
(z) arylalkylthio;
(aa) cycloalkylalkoxy;
(bb) heterocycloalkyl;
(cc) alkylsulfonyloxy;
(dd) alkylsulfonyl;
(ee) arylsulfonyl;
(ff) arylsulfonyloxy;
(gg) —C(O)R10;
(hh) nitro;
(ii) amino;
(jj) aminoalkyl;
(kk) —C(O)-alkyl-heterocyclic ring;
(ll) halo;
(mm) heterocyclic ring;
(nn)-CO2D1;
(oo) carboxyl;
(pp) amidyl;
or
(qq) alkoxyalkyl;
alternatively, R4 and R5 together with the carbons to which they are attached are:
(a) cycloalkyl;
(b) aryl;
or
(c) heterocyclic ring;
alternatively, R4 and R4′ or R5 and R5′ taken together with the carbon to which they are attached are:
(a) cycloalkyl;
or
(b) heterocyclic ring;
alternatively, R4 and R5, R4′ and R5′, R4 and R5′, or R4′ and R5 when substituents on adjacent carbon atoms taken together with the carbons to which they are attached are:
(a) cycloalkyl;
(b) heterocyclic ring;
or
(c) aryl;
R6 and R7 are each independently:
(a) hydrogen;
(b) unsubstituted, mono- or di-substituted phenyl;
unsubstituted, mono- or disubstituted benzyl;
unsubstituted, mono- or di-substituted heteroaryl;
mono- or di-substituted heteroarylmethyl, wherein said substituents are each independently:
(1) halo;
(2) lower alkyl;
(3) alkoxy;
(4) alkylthio;
(5) CN;
(6) haloalkyl, preferably CF3;
(7) N3;
(8) —C(R4)(R15)—OD1;
or
(9) —C(R14)(R15)—O-lower alkyl;
(c) lower alkyl;
(d) —CH2OR8;
(e) CN;
(f) —CH2CN;
(g) haloalkyl, preferably fluoroalkyl;
(h) —CON(R8)(R8);
(i) halo;
or
(j) —OR8;
R8 is:
(a) hydrogen;
(b) K;
or
(c) R9;
alternatively, R5 and R5′, R6 and R7 or R7 and R8 together with the carbon to which they are attached form a saturated monocyclic ring of 3, 4, 5, 6 or 7 atoms;
optionally containing up to two heteroatoms selected from oxygen, S(O)o or NRi;
R9 is:
(a) lower alkyl;
(b) lower alkyl-CO2D1;
(c) lower alkyl-NHD1;
(d) phenyl or mono-, di- or tri-substituted phenyl, wherein the substituents are each independently:
(1) halo;
(2) lower alkyl;
(3) alkoxy;
(4) alkylthio;
(5) lower alkyl-CO2D1;
(6) lower alkyl-NHD1;
(7) CN;
(8) CO2D1;
or
(9) haloalkyl, preferably fluoroalkyl;
(e) benzyl, mono-, di- or tri-substituted benzyl, wherein the substituents are each independently:
(1) halo;
(2) lower alkyl;
(3) alkoxy;
(4) alkylthio;
(5) lower alkyl-CO2D1;
(6) lower alkyl-NHD1;
(7) CN;
(8) —CO2D1;
or
(9) haloalkyl, preferably CF3;
(f) cycloalkyl;
(g) K;
or
(h) benzoyl, mono-, di-, or trisubstituted benzoyl, wherein the substituents are each independently:
(1) halo;
(2) lower alkyl;
(3) alkoxy;
(4) alkylthio;
(5) lower alkyl-CO2D1;
(6) lower alkyl-NHD1;
(7) CN;
(8) —CO2D1;
or
(9) haloalkyl, preferably CF3;
R10 and R10′ are each independently:
(a) hydrogen;
or
(b) R11;
R11 is:
(a) lower alkyl;
(b) cycloalkyl;
(c) unsubstituted, mono-, di- or tri-substituted phenyl or naphthyl, wherein the substituents are each independently:
(1) halo;
(2) alkoxy;
(3) alkylthio;
(4) CN;
(5) haloalkyl, preferably CF3;
(6) lower alkyl;
(7) N3;
(8) —CO2D1;
(9) —CO2-lower alkyl;
(10) —C(R 2)(R13)—OD1;
(11) —C(R 2)(R 3)—O-lower alkyl;
(12) lower alkyl-CO2D1;
(13) lower alkyl-CO2R12;
(14) benzyloxy;
(15) —O-(lower alkyl)-CO2D1;
(16) —O-(lower alkyl)-CO2R12;
or
(17) —O-(lower alkyl)-NR12R13;
(d) unsubstituted, mono-, di- or tri-substituted heteroaryl, wherein the heteroaryl is a monocyclic aromatic ring of 5 atoms, said ring having one heteroatom which is S, O, or N, and, optionally, 1, 2, or 3 additional N atoms;
or said heteroaryl is a monocyclic ring of 6 atoms, said ring having one heteroatom which is N, and, optionally 1, 2, or 3 additional N atoms, and wherein said substituents are each independently:
(1) halo;
(2) lower alkyl;
(3) alkoxy;
(4) alkylthio;
(5) CN;
(6) haloalkyl, preferably CF3;
(7) N3;
(8) —C(R12)(R13)—OD1;
or
(9) —C(R12)(R13)—O-lower alkyl;
(e) unsubstituted, mono- or di-substituted benzoheterocycle, wherein the benzoheterocycle is a 5, 6, or 7-membered ring which contains 1 or 2 heteroatoms independently selected from O, S, or N, and, optionally, a carbonyl group or a sulfonyl group, wherein said substituents are each independently:
(1) halo;
(2) lower alkyl;
(3) alkoxy;
(4) alkylthio;
(5) CN;
(6) haloalkyl, preferably CF3;
(7) N3;
(8) —C(R12)(R13)—OD1;
or
(9) —C(R2)(R3)—O-lower alkyl;
(f) unsubstituted, mono- or di-substituted benzocarbocycle, wherein the carbocycle is a 5, 6, or 7-membered ring which optionally contains a carbonyl group, wherein said substituents are each independently:
(1) halo;
(2) lower alkyl;
(3) alkoxy;
(4) alkylthio;
(5) CN;
(6) haloalkyl, preferably CF3;
(7) N3;
(8) —C(R12)(R13)—OD1;
or
(9) —C(R12)(R13)—O-lower alkyl;
(g) hydrogen;
or
(h) K
R12 and R13 are each independently:
(a) hydrogen;
(b) lower alkyl;
or
(c) aryl;
or
R12 and R13 together with the atom to which they are attached form a saturated monocyclic ring of 3, 4, 5, 6 or 7 atoms;
R14 and R are each independently:
(a) hydrogen;
or
(b) lower alkyl;
or
R14 and R15 together with the atom to which they are attached form a carbonyl, a thial, or a saturated monocyclic ring of 3, 4, 5, 6 or 7 atoms;
Q is:
(a) —C(O)—U-D1;
(b) —CO2-lower alkyl;
(c) tetrazolyl-5-yl;
(d) —C(R7)(R8)(S-D1);
(e) —C(R7)(R8)(O-D1);
or
(f) —C(R7)(R8)(O-lower alkyl);
X5 is:
(a) —(CR31R32)a—;
(b) —(CR31R32)bb-A1-;
(c) -A —(CR31R32)bb—;
(d) —CR31R32-A1-CR31R32;
(e) —CR31═;
or
(f) -A1;
A1 is:
(a) oxygen;
(b) thio;
(c) sulfinyl;
(d) sulfonyl;
or
(c) —N(R33)—;
R31 and R32 are each independently:
(a) hydrogen;
(b) lower alkyl;
(c) substituted lower alkyl;
(d) lower alkoxy;
(e) lower haloalkyl;
or
(f) halo;
or
R31 and R32 taken together are;
(a) oxo;
(b) thial;
(c) oxime;
or
(d) hydrazone;
R33 is:
(a) lower alkyl;
(b) hydrogen;
or
(c) —C(O)H;
a is an integer equal to 1 or 3;
bb is an integer equal to 2 or 3;
D1 is:
(a) hydrogen or
(b) D;
D is:
(a) V;
or
(b) K;
U is:
(a) oxygen;
(b) sulfur;
or
(c) —N(Ra)(Ri)—;
V is:
(a) —NO;
(b) —NO2;
or
(c) hydrogen
K is —Waa-Eb-(C(Re)(Rf))p-Ec—(C(Re)(Rf))n-Wd-(C(Re)(Rf))y-Wi-Ej-Wg-(C(Re)(Rf))z—U—V;
wherein aa, b, c, d, g, i and j are each independently an integer from 0 to 3;
p, x, y and z are each independently an integer from 0 to 10;
W at each occurrence is independently:
(a) —C(O)—;
(b) —C(S)—;
(c) -T-;
(d) —(C(Re)(Rf))h—;
(e) alkyl;
(f) aryl;
(g) heterocyclic ring;
(h) arylheterocyclic ring, or
(i) —(CH2CH2O)q—;
E at each occurrence is independently a -T- group, an alkyl group, an aryl group, a heterocyclic ring, —(C(Re)(Rf))h—, an arylheterocyclic ring or —(CH2CH2O)q—;
h is an integer form 1 to 10;
q is an integer from 1 to 5;
Re and Rf are each independently a hydrogen, an alkyl, a cycloalkoxy, a halogen, a hydroxy, an hydroxyalkyl, an alkoxyalkyl, an arylheterocyclic ring. a cycloalkylalkyl, a heterocyclicalkyl, an alkoxy, a haloalkoxy, an amino, an alkylamino, a dialkylamino, an arylamino, a diarylamino, an alkylarylamino, an alkoxyhaloalkyl, a haloalkoxy, a sulfonic acid, a sulfonic ester, an alkylsulfonic acid, an arylsulfonic acid, an arylalkoxy, an alkylthio, an arylthio, a cyano, an aminoalkyl, an aminoaryl, an aryl, an arylalkyl, a carboxamido, a alkylcarboxamido, an arylcarboxamido, an amidyl, a carboxyl, a carbamoyl, an alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarbonyl, an arylcarbonyl, an ester, a carboxylic ester, an alkylcarboxylic ester, an arylcarboxylic ester, a haloalkoxy, a sulfonamido, an alkylsulfonamido, an arylsulfonamido, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfonyl, an arylsulfonyloxy, a urea, a nitro, -T-Q′-, or —(C(Rg)(Rh))k-T-Q′ or Re and Rf taken together are an oxo, a thial, a heterocyclic ring, a cycloalkyl group, an oxime, a hydrazone or a bridged cycloalkyl group;
Q′ is —NO or —NO2;
k is an integer from 1 to 3;
T is independently a covalent bond, a carbonyl, an oxygen, —S(O)O— or —N(Ra)Ri—,
o is an integer from 0 to 2,
Ra is a lone pair of electrons, a hydrogen or an alkyl group;
Ri is a hydrogen, an alkyl, an aryl, an alkylcarboxylic acid, an arylcarboxylic acid, an alkylcarboxylic ester, an arylcarboxylic ester, an alkylcarboxamido, an arylcarboxamido, an alkylsulfinyl, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfinyl, an arylsulfonyloxy, an arylsulfonyl, a sulfonamido, a carboxamido, a carboxylic ester, an aminoalkyl, an aminoaryl, —OR′i, —CH2—C(T-Q′)(Rg)(Rh), a bond to an adjacent atom creating a double bond to that atom or —(N2O2—)−.M+, wherein M+is an organic or inorganic cation;
with the proviso that when Ri is —CH2—C(T-Q′)(Rg)(Rh) or —(N2O2—).M+;
then “-T-Q′” can be a hydrogen, an alkyl group, an alkoxyalkyl group, an aminoalkyl group, a hydroxy group or an aryl group;
Rg and Rh at each occurrence are independently Re;
R′i is independently selected from Ri;
wherein the compound of Formula (II) is:
14
wherein:
A-B is:
(a) N—C;
(b) C—N;
or
(c) N—N;
when A-B is N—C, sides d and f are double bonds, and sides e and g are single bonds, —X2-Y2-Z2- is:
(a) ═CR4—CR4′═CR5—;
(b) ═N—CR4═CR4—;
(c) ═N—CR4═N—;
(d) ═CR4—N═CR4′;
(e) ═CR4—N═N—;
(f) ═N—N═CR4—;
(g) ═N—N═N—;
or
(h) ═CR4—CR5═N—;
when A-B is C—N, sides e and g are double bonds, and sides d and f are single bonds, —X2-Y2-Z2- is:
(a) —CR4═N—N═;
(b) —N═N—CR4═;
(c) —CR4═N—CR4′═;
(d) —N═CR4—N═;
(e) —CR4═CR4′-N═;
(f) —N═CR4—CR5═;
(g) —CR4═CR5—CR5′═;
or
(h) —N═N—N═;
when A-B is C—N, side g is a double bond, and sides d, e and f are single bonds, —X2—Y2-Z2- is:
(a) —C(O)—O—CR4═;
(b) —C(O)—NR3—CR4═;
(c) —C(O)—S—CR4═;
or
(d) —C(H)R4—C(OH)R5—N═;
when A-B is N—C, sides d is a double bond, and sides e, f and g are single bonds, —X2—Y2-Z2- is:
(a) ═CR4—O—C(O)—;
(b) ═CR4—NR3—C(O)—;
(c) ═CR4—S—C(O)—;
or
(d) ═N—C(OH)R4—C(H)R5—;
when sides f is a double bond, and sides d, e and g are single bonds, —X2—Y2-Z2- is:
(a) —CH(R4)—CR5═N—;
or
(b) —C(O)—CR4═CR5—;
when sides e is a double bond, and sides d, f and g are single bonds, —X2—Y2-Z2- is:
(a) —N═CR4—CH(R5)—;
or
(b) —CR4═CR5—C(O)—;
when sides d, e, f and g are single bonds, —X2—Y2-Z2- is:
(a) —C(O)—CR4(R4′)—C(O)—;
and
with the proviso that when A-B is C—N, then X5 must be —(CR31R32)a or —(CR31R32)bb-A1;
and
wherein R1, R1′, R2, R3, R4, R4′, R5, R5′, X5 A1, R31, R32, a and bb are as defined herein;
wherein the compound of Formula (III) is:
15
wherein:
X3 is:
(a) —C(O)—U-D1;
(b) —CH2—U-D1;
(c) —CH2—C(O)—CH3;
(d) —CH2—CH2—C(O)—U-D1;
(e) —CH2—O-D1;
(f) —C(O)H or
(g) —C(O)-U-R12;
Y3 is:
(a) —(CR5(R5′))k—U-D1;
(b) —CH3;
(c) —CH2OC(O)R6;
or
(d) —C(O)H;
R82, R82′, R83 and R83′ are each independently:
(a) hydrogen;
(b) hydroxy;
(c) alkyl;
(d) alkoxy;
(e) lower alkyl-OD1;
(f) alkylthio;
(g) CN;
(h) —C(O)R84;
or
(i) —OC(O)R85;
R84 is:
(a) hydrogen;
(b) lower alkyl;
or
(c) alkoxy;
R85 is:
(a) lower alkyl;
(b) alkoxy
(c) unsubstituted, mono-, di- or tri-substituted phenyl or pyridyl, wherein the substituents are each independently:
(1) halo;
(2) alkoxy;
(3) haloalkyl;
(4) CN;
(5) —C(O)R84;
(6) lower alkyl;
(7) —S(O)0-lower alkyl;
or
(8) —OD1;
alternatively, R82 and R83 or R82′ and R83′ taken together are:
(a) oxo;
(b) thial;
(c) ═CR86R87;
or
(d) ═NR88;
R86 and R87 are each independently:
(a) hydrogen;
(b) lower alkyl;
(c) lower alkyl-OD1;
(d) CN;
or
(e) —C(O)R84;
R88 is:
(a) OD1;
(b) alkoxy;
(c) lower alkyl;
or
(d) unsubstituted, mono-, di- or tri-substituted phenyl or pyridyl, wherein the substituents are each independently:
(1) halo;
(2) alkoxy;
(3) haloalkyl;
(4) CN;
(5) —C(O)R84;
(6) lower alkyl;
(7) —S(O)0-lower alkyl;
or
(8) —OD1;
X6 is:
(a) —(CR31R32)a—;
(b) —(CR31R32)bb-A1-;
or
(e) —CR31═;
and
wherein R1, R1′, R2, R5, R5′, R6, R12, R31, R32, A1, U, D1, a, bb, o and k are as defined herein;
wherein the compound of Formula (IV) is:
16
wherein:
X4 and Z4 are each independently:
(a) N;
or
(b) CR21;
R20 is:
(a) —S(O)2—CH3;
(b) —S(O)2—NR8(D1);
or
(c) —S(O)2—N(D1)-C(O)—CF3;
R21 and R21′ are each independently:
(a) hydrogen;
(b) lower alkyl;
(c) alkoxy;
(d) alkylthio;
(e) haloalkyl, preferably fluoroalkyl;
(f) haloalkoxy, preferably fluoroalkoxy;
(g) CN;
(h) —CO2D1;
(i) —CO2R14;
(j) lower alkyl-O-D1;
(k) lower alkyl-CO2D1;
(l) lower alkyl-CO2R14;
(m) halo;
(n) —O-D1;
(o) —N3;
(p) —NO2;
(q) —NR14D1;
(r) —N(D1)C(O)R14;
(s) —NHK;
(t) aryl;
(u) arylalkylthio;
(v) arylalkoxy;
(w) alkylamino;
(x) aryloxy;
(y) alkylarylalkylamino;
(z) cycloalkylalkylamino;
or
(aa) cycloalkylalkoxy;
R22 is:
(a) mono-, di- or tri-substituted phenyl or pyridinyl (or the N-oxide thereof), wherein the substituent are each independently:
(1) hydrogen;
(2) halo;
(3) alkoxy;
(4) alkylthio;
(5) CN;
(6) lower alkyl;
(7) haloalkyl, preferably fluoroalkyl;
(8) N3;
(9) —CO2D1;
(10) —CO2-lower alkyl;
(11) —C(R14)(R15)—OD1;
(12) —OD1;
(13) lower alkyl-CO2—R14;
or
(14) lower alkyl-CO2-D1;
(b) -T-C(R23)(R24)(C(R25)(R26))o—C(R27)(R28)—U-D1;
17
(d) arylalkyl;
or
(e) cycloalkylalkyl;
wherein:
R14 and R15 are each independently:
(a) hydrogen;
or
(b) lower alkyl;
R23, R24, R25, R26, R27, R28 are each independently:
(a) hydrogen;
or
(b) lower alkyl;
or
R23 and R27, or R27 and R28 together with the atoms to which they are attached form a carbocyclic ring of 3, 4, 5, 6 or 7 atoms, or R23 and R25 are joined to form a covalent bond;
Y5 is:
(a) CR29R30;
(b) oxygen;
or
(c) sulfur;
R29 and R30 are each independently:
(a) hydrogen;
(b) lower alkyl;
(c) (CH2)o—OD1;
(d) halo;
or
R29 and R30 taken together are an oxo group;
s is an integer from 2 to 4;
and
wherein R1′, R8, X5, D1, T, U, K and o are as defined herein;
wherein the compound of Formula (V) is:
18
wherein:
X7 is:
(a) oxygen;
(b) sulfur;
(c) —NR51;
(d) —N—O—R52;
or
(e) —N—NR52R53;
Y7 at each occurrence is independently:
(a) hydrogen;
(b) halo;
(c) lower alkyl;
(d) alkenyl;
or
(e) alkynyl;
Z7 is:
(a) —(CR31R32)a—;
R49 is:
(a) R3;
or
(b) R4;
R50 and R50′ are each independently:
(a) hydrogen;
(b) halo;
(c) lower alkyl;
(d) aryl;
(e) arylalkyl;
(f) cycloalkyl;
(g) cycloalkylalkyl;
(h) —OD1;
(i) lower alkyl-OD1;
(j) carboxamido;
(k) amidyl;
or
(l) K;
R51 is:
(a) lower alkyl;
(b) alkenyl;
(c) cycloalkyl;
(d) cycloalkylalkyl;
(e) aryl;
(f) arylalkyl;
(g) heterocyclic ring;
or
(h) lower alkyl-heterocyclic ring;
R52 and R53 are each independently:
(a) lower alkyl;
(b) cycloalkyl;
(c) cycloalkylalkyl;
(d) aryl;
(e) arylalkyl;
(f) heterocyclic ring;
or
(g) heterocyclicalkyl;
and
wherein R1, R3, R4, R31, R32, K, D1 and a are as defined herein;
wherein the compound of Formula (VI) is:
19
wherein:
X9 is —C(O)-U-D1 and Y9 is —CH2—CR5(R5′)—U-D1;
or
X9 is —CH2—CR5(R5′)—U-D1 and Y9 is —C(O)-U-D1;
or
X9 and Y9 taken together are:
(a) —C(O)—O—CR4(R4′)—CR5(R5′)—;
(b) —(CR4(R4′))k—CR5(R5′)—CR5(R5′)—;
(c) —C(O)—(CR4(R4′))k—CR5(R5′)—;
(d) —(CR4(R4′))k—CR5(R5′)—C(O)—;
or
(e) —C(O)—CR4(R4′)—CR5(R5′)—;
wherein X9 is the first carbon atom of a, b, c, d and e;
and
wherein R1, R1′, R2, R4, R4′, R5, R5′, X6, U, D1 and k are as defined herein;
wherein the compound of Formula (VII) is:
20
wherein:
when side h, k, and j are single bonds, and side i and l are a double bond, —X10—Y10-Z10- is:
21
when sides i, k and l are single bonds, and sides h and j are double bonds, —X10—Y10-Z10- is:
22
when side h and j are single bonds, l is a double bond, and side k and i is a single or a double bond, —X10—Y10-Z10- is:
23
P10 is:
(a) —N═;
(b) —NR3—;
(c) —O—;
or
(d) —S—;
Q10 and Q10′ are each independently:
(a) CR60;
or
(b) nitrogen;
A10-B10-C10-D10- is:
(a) —CR4═CR4′—CR5═CR5′—;
(b) —CR4(R4′)—CR5(R5′)—CR4(R4′)—C(O)—;
(c) —CR4(R4′)—CR5(R5′)—C(O)—CR4(R4′)—;
(d) —CR4(R4′)—C(O)—CR4(R4′)—CR5(R5′)—;
(e) —C(O)—CR4(R4′)—CR5(R5′)—CR4(R4′)—;
(f) —CR4(R4)—CR5(R5′)—C(O)—;
(g) —CR4(R4′)—C(O)—CR5(R5′)—;
(h) —C(O)—CR4(R4′)—CR5(R5′)—;
(i) —CR4(R4′)—CR5(R5′)—O—C(O)—;
(j)-CR4(R4′)—O—C(O)—CR5(R5′)—;
(k) —O—C(O)—CR4(R4′)—CR5(R5′)—;
(l) —CR4(R4′)—CR5(R5′)—C(O)—O—;
(m) —CR4(R4′)—C(O)—O—CR5(R5′)—;
(n) —C(O)—O—CR4(R4′)—CR5(R5′)—;
(o) —CR12(R13)—O—C(O)—;
(p) —C(O)—O—CR12(R13)—;
(q) —O—C(O)—CR12(R13)—;
(r) —CR12(R13)—C(O)—O—;
(s) —N═CR4—CR4′═CR5—;
(t) —CR4═N—CR4′═CR5—;
(u) —CR4═CR4′—N═CR5;
(v) —CR4═CR5—CR5′═N—;
(w) —N═CR4—CR4′═N—;
(x) —N═CR4—N═CR4′—;
(y) —CR4═N—CR4′═N—;
(z) —S—CR4═N—;
(aa) —S—N═CR4—;
(bb) —N═N—NR3—
(cc) —CR4═N—S—;
(dd) —N═CR4—S—;
(ee) —O—CR4═N—;
(ff) —O—N═CR4—;
or
(gg) —N═CR4—O—;
A10′-B10′-D10′ is:
(a) —CR4═CR5—CR5′═
(b) —CR4(R4′)—CR5(R5′)—CR4(R4′)—;
(c) —C(O)—CR4(R4′)—CR5(R5′)—;
(d) —CR4(R4′)—CR5(R5′)—C(O)—;
(e) —N═CR4—CR5═;
(g) —N═N—CR4═;
(h) —N═N—NR3—;
(i) —N═N—N═;
(j) —N═CR4—NR3—;
(k) —N═CR4—N═;
(l) —CR4═N—NR3—;
(m) —CR4═N—N═;
(n) —CR4═N—CR5═;
(o) —CR4═CR5—NR3—;
(p) —CR4═CR5—N═;
(q) —S—CR4═CR5—;
(r) —O—CR4═CR5;
(s) —CR4═CR5—O—;
(t) —CR4═CR5—S—;
(u) —CR4═N—S—;
(v) —CR4═N—O—;
(w) —N═CR4—S—;
(x) —N═CR4—O—;
(y) —S—CR4═N—;
(z) —O—CR4═N—;
(aa) —N═N—S—;
(bb) —N═N—O—;
(cc) —S—N═N—;
(dd) —O—N═N—;
(ee) —CR4═CR5—S;
(ff) —CR4(R4′)—CR5(R5′)—S—;
(gg) —CR4(R4′)—CR5(R5′)—O—;
(hh) —S—CR4(R4′)—CR5(R5′)—;
or
(ii) —O—CR4(R4′)—CR5(R5′)—;
R60 and R61 are each independently:
(a) lower alkyl;
(b) haloalkyl, preferably fluoroalkyl;
(c) alkoxy;
(d) alkylthio;
(e) lower alkyl-OD1;
(f) —C(O)H;
(h) —(CH2)q—CO2-lower alkyl;
(i) —(CH2)q—CO2D1;
(j) —O—(CH2)q—S-lower alkyl;
(k) —(CH2)q—S-lower alkyl;
(l) —S(O)2-lower alkyl;
(m) —(CH2)q—NR12R13;
or
(n) —C(O)N(R8)(R8);
and
wherein R1, R1′, R2, R3, R4, R4′, R5, R5′, R8, R12, R13, X5, T, D1 and q are as defined herein;
wherein the compound of Formula (VIII) is:
24
wherein:
X14 is:
(a) —C(O)—;
or
(b) —C(S)—;
Y14 is:
(a) —O—;
or
(b) —S—;
A14-B14-D14- is:
(a) —CR4═CR4′—CR═CR5″—;
(b) —CR4(R4′)—CR5(R5′)—C(O)—;
(c) —CR4(R4′)—C(O)—CR5(R5′)—;
(d) —C(O)—CR4(R4′)—CR5(R5′)—;
(e) —CR4(R5)—O—C(O)—;
(f) —C(O)—O—CR4(R5)—;
(g) —O—C(O)—CR4(R5)—;
(h) —S—N═CR4—;
(i) —O—N═CR4—;
(j) —CR4(R5)—NR3—C(O)—;
(k) —C(O)—NR3—CR4(R)—;
(l) —NR3—C(O)—CR4(R5)—;
(m) —CR4(R5)—S—C(O)—;
(n) —C(O)—S—CR4(R5)—;
(o) —S—C(O)—CR4(R5)—;
(p) —CR4═CR4′—C(O)—;
(q) —C(O)—CR4═CR4′—;
(r) —O—CR4═CR4′—;
(s) —S—CR4═CR4′—;
(t) —NR3—CR4═CR5—;
(u) —S—NR3—C(O)—;
(v) —O—NR3—C(O)—;
or
(w) —NR3—N═CR4—;
and
wherein R1, R1′, R2, R3, R4, R4′, R5, R5′ and X5 are as defined herein.

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Cyclooxygenase-2 selective inhibitors, compositions and methods of use

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Cyclooxygenase-2 selective inhibitors, compositions and methods of use

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Abstract

Claims58