US 6,649,629 B2 · Nitrosated and nitrosylated cyclooxygenase-2 inhibitors, compositions and methods of use

Abstract

The present invention describes novel nitrosated and/or nitrosylated cyclooxygenase 2 (COX-2) inhibitors and novel compositions comprising at least one nitrosated and/or nitrosylated cyclooxygenase 2 (COX-2) 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 optionally, at least one therapeutic agent, such as, steroids, nonsteroidal antiinflammatory compounds (NSAID), 5-lipoxygenase (5-LO) inhibitors, leukotriene B4 (LTB4) receptor antagonists, leukotriene A4 (LTA4) hydrolase inhibitors, 5-HT agonists, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitors, H2 antagonists, antineoplastic agents, antiplatelet agents, decongestants, diuretics, sedating or non-sedating anti-histamines, inducible nitric oxide synthase inhibitors, opioids, analgesics, Helicobacter pylori inhibitors, proton pump inhibitors, isoprostane inhibitors, and mixtures thereof. The present invention also provides novel compositions comprising at least one parent COX-2 inhibitor and at least one nitric oxide donor, and, optionally, at least one therapeutic agent. The present invention also provides kits and methods for treating inflammation, pain and fever; for treating and/or improving the gastrointestinal properties of COX-2 inhibitors; for facilitating wound healing; for treating and/or preventing renal toxicity; and for treating and/or preventing other disorders resulting from elevated levels of cyclooxygenase-2.

A compound of Formula (II) or a pharmaceutically acceptable salt thereof:

wherein:
A—B is:
(a) N—C;
(b) C—N;
or
(c) N—N;
when 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—;
(h) ═CR4—CR5═N—;
or
(i) ═CR2′—CR5═N—;
R2 and R2′ taken together are:
or R2′ and R5 taken together with the carbon atoms to which they are attached are:
(a) cycloalkyl;
or
(b) heterocyclic ring;
R97 is:
(a) hydrogen;
(b) alkylthio;
(c) alkylsulfinyl;
(d) alkylsulfonyl;
(e) cyano;
(f) carboxyl;
(g) amino;
(h) lower alkyl;
(i) haloalkyl;
(j) hydroxy;
(k) alkoxy;
(l) haloalkoxy;
(m) alkylarylalkylamino;
(n) aminoalkyl;
(o) aminoaryl;
(p) sulfonamido;
(q) alkylsulfonamido;
(r) arylsulfonamido;
(s) heterocyclic ring;
(t) hydroxyalkyl;
or
(u) nitro;
a is an integer from 1 to 3;
when 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 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 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)—;
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′ is:
(a) hydrogen;
(b) halogen;
(c) methyl;
or
(d) CH2OH;
R2 is:
(a) lower alkyl;
(b) cycloalkyl;
(c) mono-, di- or tn-substituted phenyl or naphthyl, wherein the substituents are each independently:
(1) hydrogen;
(2) halo;
(3) alkoxy;
(4) alkylthio;
(5) CN;
(6) haloalkyl;
(7) lower alkyl;
(8) N3;
(9) —CO2D1;
(10) —CO2-lower alkyl;
(11) —(C(R5)(R6))z—OD1;
(12) —(C(R5)(R6))z—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;
(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;
(6) lower alkyl;
(7) N3;
(8) —CO2D1;
(9) —CO2-lower alkyl;
(10) —C(R12)(R13)—OD1;
(11) —C(R12)(R13)—O-lower alkyl;
(12) lower alkyl-CO2—R12;
(13) benzyloxy;
(14) —O-(lower alkyl)-CO2R12;
(15) —O-(lower alkyl)-NR12R13;
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 has 1 or 2 heteroatoms selected from O, S, or N and, optionally, 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;
(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;
(6) lower alkyl;
(7) N3;
(8) —CO2D1;
(9) —CO2-lower alkyl;
(10) —C(R12)(R13)—ODu;
(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;
(o) phenylacetylene, mono- or di-substituted phenylacetylene, wherein the substituents are each independently:
(1) halo;
(2) alkoxy;
(3) alkylthio;
(4) CN;
(5) haloalkyl;
(6) lower alkyl;
(7) N3;
(8) —CO2D1;
(9) —CO2-lower alkyl;
(10) —C(R12)(R13)—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, consisting of 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;
(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)R11;
(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;
(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 tn-substituted phenyl or naphthyl, wherein the substituents are each independently:
(1) hydrogen;
(2) halo;
(3) alkoxy;
(4) alkylthio;
(5) CN;
(6) haloalkyl;
(7) lower alkyl;
(8) N3;
(9) —CO2D1;
(10) —CO2-lower alkyl;
(11) —(C(R5)(R6))z—OD1;
(12) —(C(R5)(R6))z—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 di- substituted benzyl, wherein the substituents are each independently:
(1) halo;
(2) lower alkyl;
(3) alkoxy;
(4) alkylthio;
(5) CN;
(6) haloalkyl;
(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;
tsaid substituents are each independently:
(1) halo;
(2) lower alkyl;
(3) alkoxy;
(4) alkylthio;
(5) CN;
(6) haloalkyl;
(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 di-substituted 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;
(7) N3;
(8) —C(R14)(R15)—OD1;
or
(9) —C(R14)(R15)—O-lower alkyl;
(c) lower alkyl;
(d) —CH2OR8;
(e) CN;
(f) —CH2CN;
(g) haloalkyl;
(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;
and
optionally 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 tn-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;
(e) benzyl, mono-, di- or tn-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;
(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;
R10 and R10′ are each independently:
(a) hydrogen;
or
(b) R11;
R11 is:
(a) lower alkyl;
(b) cycloalkyl;
(c) unsubstituted, mono-, di- or tn-substituted phenyl or naphthyl, wherein the substituents are each independently:
(1) halo;
(2) alkoxy;
(3) alkylthio;
(4) CN;
(5) haloalkyl;
(6) lower alkyl;
(7) N3;
(8) —CO2D1;
(9) —CO2-lower alkyl;
(10) —C(R12)(R13)—OD1;
(11) —C(R12)(R13)—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 tn-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;
(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 with 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;
(7) N3;
(8) —C(R12)(R13)—OD1;
or
(9) —C(R12)(R13)—O-lower alkyl;
(f) unsubstituted, mono- or di-substituted benzocarbocycle, wherein the carbocycle is a 5, 6, or 7-membered ring has optionally a carbonyl group, wherein said substituents are each independently:
(1) halo;
(2) lower alkyl;
(3) alkoxy;
(4) alkylthio;
(5) CN;
(6) haloalkyl;
(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 R15 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;
D1is:
(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))x—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—;
(b) alkyl;
(c) aryl;
(d) —(C(Re)(Rf))h—;
(e) heterocyclic ring;
(f) arylheterocyclic ring;
or
(g) —(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;
(b) alkyl;
(c) cycloalkoxy;
(d) halogen;
(e) hydroxy;
(f) hydroxyalkyl;
(g) alkoxyalkyl;
(h) arylheterocyclic ring;
(i) cycloalkylalkyl;
(j) heterocyclicalkyl;
(k) alkoxy;
(l) haloalkoxy;
(m) amino;
(n) alkylamino;
(o) dialkylamino;
(p) arylamino;
(q) diarylamino;
(r) alkylarylamino;
(s) alkoxyhaloalkyl;
(t) haloalkoxy;
(u) sulfonic acid;
(v) alkylsulfonic acid;
(w) arylsulfonic acid;
(x) arylalkoxy;
(y) alkylthio;
(z) arylthio;
(aa) cyano;
(bb) aminoalkyl;
(cc) aminoaryl;
(dd) alkoxy;
(ee) aryl;
(ff) arylalkyl;
(gg) carboxamido;
(hh) alkylcarboxamido;
(ii) arylcarboxamido;
(jj) amidyl;
(kk) carboxyl;
(ll) carbamoyl;
(mm) alkylcarboxylic acid;
(nn) arylcarboxylic acid;
(oo) alkylcarbonyl;
(pp) arylcarbonyl;
(qq) ester;
(rr) carboxylic ester;
(ss) alkylcarboxylic ester;
(tt) arylcarboxylic ester;
(uu) haloalkoxy;
(vv) sulfonamido;
(ww) alkylsulfonamido;
(xx) arylsulfonamido;
(yy) alkylsulfonyl,
(zz) alkylsulfonyloxy,
(aaa) arylsulfonyl,
(bbb) arylsulphonyloxy
(ccc) sulfonic ester;
(ddd) carbamoyl;
(eee) urea;
(fff) nitro;
or
(ggg) —U—V;
or
Re and Rf taken together are:
(a) oxo;
(b) thial;
or
Re and Rf taken together with the carbon to which they are attached are:
(a) heterocyclic ring;
(b) cycloalkyl group;
or
(c) bridged cycloalkyl group;
k is an integer from 1 to 2;
T at each occurrence is independently:
(a) a covalent bond,
(b) carbonyl,
(c) an oxygen,
(d) —S(O)o—;
or
(e) —N(Ra)Ri—;
o is an integer from 0 to 2;
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);
Ra is:
(a) a lone pair of electron;
(b) hydrogen;
or
(c) lower alkyl;
Ri is:
(a) hydrogen;
(b) alkyl;
(c) aryl;
(d) alkylcarboxylic acid;
(e) arylcarboxylic acid;
(f) alkylcarboxylic ester;
(g) arylcarboxylic ester;
(h) alkylcarboxamido;
(i) arylcarboxamido;
(j) alkylsulfinyl;
(k) alkylsulfonyl;
(l) alkylsulfonyloxy,
(m) arylsulfinyl;
(n) arylsulfonyl;
(o) arylsulphonyloxy;
(p) sulfonamido;
(q) carboxamido;
(r) carboxylic ester;
(s) aminoalkyl;
(t) aminoaryl;
(u) —CH2—C(U—V)(Re)(Rf);
(v) a bond to an adjacent atom creating a double bond to that atom;
or
(w) —(N2O2—)−.M+, wherein M+ is an organic or inorganic cation;
with the proviso that the compounds of Formula II must contain at least one nitrite, nitrate, thionitrite or thionitrate group.

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Nitrosated and nitrosylated cyclooxygenase-2 inhibitors, compositions and methods of use

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Nitrosated and nitrosylated cyclooxygenase-2 inhibitors, compositions and methods of use

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Abstract

Claims55