Claims
- 1. A compound of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (IX), formula (X), formula (XI), formula (XII), formula (XEi), formula (XIV), formula (XV) or formula (XVI), or a pharmaceutically acceptable salt thereof:
wherein the compound of formula (I) is: 25wherein: when side b is a double bond, and sides a and c are single bonds, —X′—Y′—Z′— is:
(a)—CR4(R5)—CR5(R5′—CR4(R5)—; (b) -c(O)—CR4(RI—CR5(Rl)—; (c) —CRW(RW—CR5(R5Wl—C(o)—; (d) —(CR5(R5′))k—O(O)—(e) —C(O)—O—(CR5(R5′))k—; (f) - CR4(R41)—NR3cR5(R5′); (g) &R5(R51)—NR3(O)—(h) —CR4═CR4—S—. (i) —S—CR═CRW′—; (j) —SN═CRl—; (k) —CR4═N—S—. (l) —N═CR4—O—; (m) —O—CR4═N—; (n) —NR3—CR4═N—; (o) —N═CR4—S—(p) —S—CR═N—; (q) —C(O)—NR3—CR5′(R5l—; (r) —R3N—CR5═C R′—; (s) —CR═CR—NR3—; (t) —O—N═CR4—; (u) —CR═N—O—, (v) —N═N—S—; (w) —S—N═N—; (x) —R3N—CR4═N—; (y) —N═CR4—NR3—; (z) —R3N—N═N—; (aa) —N═N—NR3—; (bb) —CR4(R4)—O—CR5(R5′)—; (cc) —CR4(R4)—CR5(R5′—; (dd) —CR4(R4)- C(O)&R5(R5′)—; (ee) —CR4(R)—CR5(R5′)—C(S)—; (ff) —(CR5(R51))k—O—C(S)—; (gg) —C(S)—O—(CR5(R7′))k—; (hh) —(CR5(R5′))k—NR3—C(S)—; (ii) —C(S)—NR3—(CR5(R5′))k—; (jj) —(CR5(R5′))k—S—C(O)—; (kk) —C(O)—S—(CRW(R ))k—; (ll) —O—CR═CR—; (mm) —CR═CR5—O—; (nn) —C(O)- NR3—S—; (oo) —S—NR3—C(O)—; (pp) —C(O)—NRW—O—; (qq) —O—NR3—C(O)—; (rr) —NR3—CR4═CR═—; (ss) —CR4═N—NR3—; (tt) —NR3—N═CR4; (uu) —C(O)—NR3—NR3—; (vv) —NR3—NR3—C(O)—; (ww) —C(O)—O—NR3—; (xx) —NR3—O—C(O)—; (yy) —CR4R4′—CR5R5′; (zz) —C(O)—CR4R4′—(aaa) —CR4R4 —C(O)—; (bbb) —C(S)—CR4R4; (ccc) —CR4R4′(S)—; (ddd) —C(═NR3)—CeR4R4—; or (eee) —CR4R4—C(═NR3)—; when sides a and c are double bonds and side b is a single bond, —X′—Y′—Z′— is:
(a) ═CRW—O—CR═; (b) ═CR4—NR3—CR5═; (c) ═N—SRC═; (d) ═CR—S—N═; (e) ═N4—CR═; (f) ═CR4-—N═; (g) ═N—SN═; (h) ═N—O—N═; (i) ═N—NR3—CR4═; (j) ═CR4—NR3—N═; (k) ═N—NR3—N═; (l) ═CCR4-SCR5═; or (m) CR4—CR4(R4′)—CR5═; R1 is:
(a) —S(O)2—CH3; (b) —S(O)2—NR8(D1); (c) —S(0)2—N(D1)—C(O)—CF3 (d) —S(O)—(NH)—NH(D1); (e) —S(O)—(NH)—N(D1)—C(O)—CF3 (f) —P(O)(CIH3)NH(D1); (g) —P(O)(CH3)2; (h) —C(S)—NH(D1); (i) —S(O)(NH)CH3; (j) —P(O)(CF4)OD1; or (k) —P(O)(CH3)NH(D1); R1′is:
(a) hydrogen; (b) halogen; (c) methyl; or (d) CHOH; 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; (7) lower alkyl; (8) N3; (9) —CO2D1; (10) —CO27lower alkyl; (11) —(C(R5)(R6))z—OD1; (12) —(C(R5)(R6))Z—O—ower 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)-Olower alkyl; or (11) alkylsulfinyl; (e) benzoheteroaryl which includes the benzo fused analogs of (d); (f) —NR′l RW′; (g) —SRW′; (h) —RO1; (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)ODI; (11) —C(R12)(R13)—O—lower alkyl; (12) lower alkyl—CO2—RW2; (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 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; (7) N3; (8) —C(RW2)(R13)—OD1; (9) C(Rl2)(RW3)—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(Rl2)(RI3)-0D1; (11) —C(R O2)(R3)—O—lower alkyl; (12) lower alkyl—CO,—R2; (13) benzyloxy; (14) —O—(lower alkyl)—C02R12; or (15) —O—(lower alkyl)—NRl2Re3; (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(RW2)(RW3)—OD1; (11) —C(Rl)(RW3)—O—lower alkyl; (12) lower alkyl—CO2—R12; (13) benzyloxy; (14) —O—(lower alkyl)—CO2RW2, or (15) —O—(lower alkyl)—NR12Rl3; (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 0, 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) N; (9) —C(R5)(R6)—OD1; or (10) —C(R5)(R6)—O—lower alkyl; (r) K; (s) aryl; (t) arylalkyl; (u) cycloalkylalkyl; (v) —C(O)Rll; (u) hydrogen; (v) arylalkenyl; (w) arylalkoxy; (x) alkoxy; (y) aryloxy; (z) cycloalkoxy; (aa) arylthio; (bb) alkylthio; (cc) arylalkylthio; or (dd) cycloalkylthio; R3is:
(a) hydrogen; (b) haloalkyl; (c) CN; (d) lower alkyl; (e) —(C(Re)(Rf)),—U—V; (f) K; (g) unsubstituted or substituted:
(1) lower alkyl—Q; (2) lower alkyl-- lower alkyl—Q; (3) lower alkyl—O—lower alkyl—Q; (4) lower alkyl—O—Ql (5) lower alkyl-SQ; (6) lower alkyl—O—Q; (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; (7) lower alkyl; (8) N3; (9) —CO2D1; (10) —CO2—lower alkyl; (11) —(C(R5)(R6))OD1; (12) —(C(R5)(R)).—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-Co2Re0; (x) lower alkyl—C(O)NRW′(R°); (y) heterocyclicalkyl; or (z) heterocyclic ring—C(O)—; R4, R4′, R5and 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) alkyltmio; (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; said 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-.ower alkyl—Q, (5) lower alkyl—O—lower alkyl—Q; (6) lower alkyl—O—Q; (7) lower alkyl—S—Ql (8) lower alkyl—O—K; (9) lower alkyl—S—K; (10) lower alkyl-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) arylalkyltio; (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 RW 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, R4and R5, R4 and R5, R4and R5, or R4 and RW 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)(RI5)—OD1; or (9) —C(Re4)(Rl5)—O—lower alkyl; (c) lower alkyl; (d) -CIJOR8; (e) CN; (f) -CL2CN; (g) haloalkyl; (h) —CON(RW)(RW); (i) halo; or (j) —OR8; R8 is:
(a) hydrogen; (b) K; or (c) R9; alternatively, R7 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—CO D1; (6) lower alkyl—NHD1; (7) CN; (8) CO2D1; or (9) haloalkyl; (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—CO2Dl; (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; R+ and R30′ 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; (6) lower alkyl; (7) N3; (8) —CO2D1; (9) —CO2—lower alkyl; (10) C(RW2)(R 13)—OD1; (11) —C(R12)(Re3)—O—lower alkyl; (12) lower alkyl—CO2Dl; (13) lower alkyl—CO2R12(14) benzyloxy; (15) —O—(lower alkyl)—CO2Dl; (16) —O—(lower alkyl)—CO2R2; or (17) —O—(lower alkyl)—NR12Rl3; (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; (7) N3; (8) —C(R 2)(R13)—OD1; or (9) C(RW2)(RW3)-Oower alky; (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; (7) N3; (8) —C(RW2)(Rl3)—OD1; or (9) —C(RW2)(RW3)—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; (7) N3; (8) —C(R12)(RW3)—OD1; or (9) —C(R12)(Rl3)—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; 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 -W-Eb—(C(R,)(Rf)),-EC(C(R,)(Rf)).7Wd(C(R.)(Rf))y-K-Ej-Wg—(C(R.)(R,)).7U-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) —(CH2CH,O)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)0—; or (e) —N(Ra)Ri—; o is an integer from 0 to 2; Q is:
(a) —C(O)—U—Dl; (b) —CO2lower alkyl; (c) tetrazolyl-5-yl; (d) —C(R)(R8)(S—D1); (e) —C(R7)(R8)(O—D1); or (f) —C(R7)(R8)(0—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 I must contain at least one nitrite, nitrate, thionitrite or thionitrate group; wherein the compound of formula (II) is: 26wherein: 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) ═CRW—CRl′═CR—; (b) ═N—CRW═CRle; (c) ═N—CR═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—; R2and R2e taken together are: 27or 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) —CRW═N—CRW′═; (d) —N═CR4—N═; (e) —CR═CR4′—N═; (f) —N═CRl—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—CRW═; (b) —C(O)—NR3—CR4═; (c) —C(O)-SCRW═; 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) ═CRW—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, R1′R2, R3, R4, R411 R5 and R5′are as defined herein; with the proviso that the compounds of formula II must contain at least one nitrite, nitrate, thionitrite or thionitrate group; wherein the compound of formula (IE) is: 28wherein: X3is:
(a) —C(O)—U—D1; (b) —CH2—U—D1; (c) —CH—C(O)—CL3 (d) CH—CHl—C(O)—U—D1; (e) &IH—O—D1; or (f) —C(O)H Y3 is:
(a) (CR5(R5′)) UD1; (b) —CH 3; (c) —CHIOC(O)Re;or (d) —C(O)H; alternatively, X3 and Y3 taken together are —CR82(R83)—CR82′(R83)—; 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)R; or (i) —OC(O)R; 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)Rl; (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) ═CRR87; or (d) ═NRl; 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)R8 (6) lower alkyl; (7) —S(O)O—lower alkyl; or (8) —OD1; R1, R2, R51 R5′, R6,U, D1, o and k are as defined herein; with the proviso that the compounds of formula Im must contain at least one nitrite, nitrate, thionitrite or thionitrate group.; wherein the compound of formula (IV) is: 29wherein: X4 and Z4 are each independently:
(a) N; or (b) CR21; R20 is:
(a) —S(0)2—CH3; (b) —S(O)2—NR8(D1); or (c) —S(O)2—N(D1)—C(O)—CF, R21 and R21 are each independently:
(a) hydrogen; (b) lower alkyl; (c) alkoxy; (d) alkylthio; (e) haloalkyl; (f) haloalkoxy; (g) CN; (h) —CO2D1; (i) —CO2R14; (j) lower alkyl—O—Dl; (k) lower alkyl—CO2Dl; (l) lower alkyl—COWR4 (m) halo; (n) —O—D1; (o) —N3; (p) —NO2; (q) —NR14D1; (r) —N(D)C(O)R4; (s) —NHK; (t) aryl; (u) arylalkylthio; (v) arylalkoxy; (w) alkylamino; (x) aryloxy; (y) alkylarylalkylamino; (z) cycloalkylalkylamino; or (aa) cycloalkylalkoxy; R7 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; (8) N, (9) —CO2D1; (10) —CO2—lower alkyl; (11) —C(R14)(R15)—OD1; (12) —OD1; (13) lower alkylCO,—R74; or (14) lower alkyl—CO,-D1; (b) -T—C(R7)(R24)—(C(R7)(R26))0—C(R27)(Re)—U—Dl; 30(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 R7 and Rl are joined to form a covalent bond; Y, is:
(a) CR7R; (b) oxygen; or (c) sulfur; R29 and R7 are each independently:
(a) hydrogen; (b) lower alkyl; (c) (CIi,).—OD1; (d) halo; or R29 and R30 taken together are an oxo group; s is an integer from 2 to 4; R8, D1, T, U, K and o are as defined herein; with the proviso that the compounds of formula IV must contain at least one nitrite, nitrate, thionitrite or thionitrate group. wherein the compound of formula (V) is: 31wherein: X5 is:
(a) oxygen; or (b) sulfur; R31 is:
(a) alkoxy; (b) haloalkoxy; (c) alkylthio; (d) haloalkyl; (e) halo; or (f) lower alkyl; R32, R33, R34, R35, R36 and R37 are each independently:
(a) hydrogen; (b) halo; (c) lower alkyl; (d) cydoalkyl; (e) haloalkyl; (f) —OD1; (g) —OR43; (h) —SD1; (j) —S(O)R4; (k) —S(O)2R43; (l) unsubstituted, mono- or di-substituted benzyl, wherein the substituents are each independently:
(1) haloalkyl; (2) CN; (3) halo; (4) lower alkyl; (5)—OR43; (6) —SR43; (7) —S(O)R43; or (8) —S(O)2R41; (m) phenyl or mono- or di-substituted phenyl, wherein the substituents are each independently:
(1) haloalkyl; (2) CN; (3) halo; (4) lower alkyl; (5) —OR43; (6) —SR43 (7) —S(O)Rl; or (8) —S(O)2R41, or R32 together with R7 form an oxo group; or R34 together with R7 form an oxo group; or R36 together with R37 form an oxo group; or R32 and R33 are joined so that, together with the carbon atom to which they are attached, they form a saturated monocyclic ring of 3, 4, 5, 6 or 7 members, and, optionally, contain one heteroatom; or R33 and R34 are joined so that, together with the carbon atoms to which they are attached, they form a saturated or aromatic monocyclic ring of 3, 4, 5, 6 or 7 members; or R33 and R36 are joined so that, together with the carbon atoms to which they are attached, they form a saturated or aromatic monocyclic ring of 3, 4, 5, 6 or 7 members; or R34 and R35 are joined so that, together with the carbon atom to which they are attached, they form a saturated monocyclic ring of 3, 4, 5, 6 or 7 members, and optionally, contain one heteroatom; or R34 and R36 are joined so that, together with the carbon atoms to which they are attached, they form a saturated or aromatic monocyclic ring of 3, 4, 5, 6 or 7 members; or R36 and R37 are joined so that, together with the carbon atom to which they are attached, they form a saturated monocyclic ring of 3, 4, 5, 6 or 7 members, and, optionally, contain one heteroatom; R38 and R39 are hydrogen or R38 and R39 when taken together are oxo; R40, R41 and R42 are each independently:
(c) hydrogen; (d) halo; (c) lower alkyl; (d) alkoxy; (e) alkylthio; (f) —S(O)—lower alkyl; (g) haloalkyl; (h) CN; (i) —N, (j) —NO2; (k) -SCF,; or (l) -OCF,; R43 is:
(a) lower alkyl; or (b) benzyl, optionally mono- or di-substituted, wherein the substituents are each independently:
(1) haloalkyl; (2) CN; (3) halo; or (4) lower alkyl; alternatively, X5 and U taken together with the carbon atom to which they are attached form a 5-, 6-, or 7-membered heterocyclic ring; n at each occurrence is an integer from 0 to 1; and D1, U and K are as defined herein; with the proviso that the compounds of formula V must contain at least one nitrite, nitrate, thionitrite or thionitrate group; wherein the compound of formula (VI) is: 32wherein: X6 is:
(a) oxygen; (b) sulfur; (c) CH,; (d) —S(O).; (e) —NH; or (f) —C(O); Z6 is:
(a) K; (b) —C(O)CH,; or (c) hydrogen; R45 is:
(a) lower alkyl; or (b) mono-, di-, tri-, tetra- or per-substituted lower alkyl, wherein the substituent is halo; R46 is:
(a) mono or disubstituted aromatic ring of 5 atoms containing one 0, S or N atom, and, optionally, 1, 2 or 3 additional N atoms, wherein the substituents are each independently:
(1) hydrogen; (2) lower alkyl; (3) halo; (4) -0—lower alkyl; (5) —S—lower alkyl; (6) haloalkyl; (7) —COCH, or (8) —S(0)2—lower alkyl; (b) mono or disubstituted aromatic ring of 6 atoms containing 0, 1, 2, 3 or 4 nitrogen atoms, wherein the substituents are each independently:
(1) hydrogen; (2) lower alkyl; (3) halo; (4) -0—lower alkyl; (5) —S—lower alkyl; (4) -0-haloalkyl; (5) —S—haloalkyl; (6) haloalkyl; (7) CN; (8) —N3; (9) —COCH3 (10) —S(0)27lower alkyl; (11) alkenyl; or (12) alkynyl; (c) cycloalkylalkyl; (d) unsubstituted, mono-, di-, tri-, or tetra substituted phenyl or naphthyl, wherein the substituents are each independently:
(1) halo; (2) CN; (3) haloalkyl; (4) —N3; (5) vinyl; (6) acetylenyl; (7) lower alkyl; (8) alkoxy; (9) haloalkoxy; (10) alkylthio;or (11) haloalkylthio; (e) unsubstituted, mono-, di-, tri-, or tetra substituted benzoheteroaryl, wherein the substituents are each independently:
(1) halo; (2) CN; or (3) haloalkyl; (f) substituted lower alkyl; (g) substituted alkenyl; (h) cycloalkyl; or (i) lower alkyl-0—lower alkyl; R47 is:
(a) —C(O)—lower alkyl; (b) -CN; (c) —CO2D1; (d) —CO2A7ower alkyl ester; (e) —C(O)—NHD1; (f) —S(O)—lower alkyl; (g) —S(O)2—lower alkyl; (h) —NO2; (i) haloalkyl; (j) halo; (k) K; (l) —S(O).NRWR; or (m) —S(O).NR2R13; R48 is:
(a) hydrogen; or (b) lower alkyl; or R47 and R48 taken together with the atoms to which they are attached form a 5, 6, or 7-membered unsubstituted, mono-, di-, or trisubstituted saturated or unsaturated cyclic ring optionally containing a —S(O),-group, wherein the substituents are each independently:
(a) oxo; (b)lower alkyl; (c) OD1; or (d) ═N-0D1; R10, R11, R12, R13, K, D1and o are as defined herein; with the proviso that the compounds of formula VI must contain at least one nitrite, nitrate, thionitrite or thionitrate group; wherein the compound of formula (VIII) is: 33wherein: X7 is:
(a) oxygen; (b) sulfur; (c) —NRl1; (d) —N—O—R52; or (e) —N—NR52R53; Y7 is:
(a) hydrogen; (b) halo; (c) lower alkyl; (d) alkenyl; or (e) alkynyl; Z7 is:
(a) —C(O)—; (b) oxygen; (c) —S(O)0—; (d) —NR93-, or (e) covalent bond; 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; (e heterocyclic ring; or (g) heterocyclicalkyl; R93 is:
(a) hydrogen; or (b) lower alkyl; R1 R3, R4, K, D1 and o are as defined herein; with the proviso that the compounds of formula VII must contain at least one nitrite, nitrate, thionitrite or thionitrate group. wherein the compound of formula (VHI) is: 34wherein: X8 is:
(a) oxygen; (b) sulfur; (c) NR,; or (d) —CRlR59; A1, A2, A3, and A4 are each independently carbon or nitrogen, with the proviso that at least two of A1, A2, A3, and A4are carbon atoms; R54 is:
(a) haloalkylalkyl; (b) halo; (c) alkylthio; (d) alkoxy; (e) —NO2; (f) CN; (g) lower alkyl-CN; (h) heterocyclic ring; (i) lower alkyl; (j) arylalkyl; (k) cycloalkyl; or (l) phenyl or mono- or di-substituted phenyl, wherein the substituents are each independently:
(1) alkylthio; (2) nitro; or (3) alkylsulfonyl; R55 is:
(a) —COD1; (b) —C(O)—N(RW)(R8); (c) —CO27ower alkyl; (d) —C(O)—N(D1)—S(O)2—(C(Re)(Rf)),—U—V; or (e) —CO27ower alkyl—U—V; R56 is:
(a) hydrogen; (b) phenyl; (c) thienyl; (d) alkynyl; (e) alkenyl; or (f) alkyl; Rg is:
(a) hydrogen; (b) lower alkyl; (c) arylalkyl; (d) alkoxy; (e) aryloxy; (f) arylalkoxy; (g) haloalkyl; (h) haloalkoxy; (i) alkylamino; (j) arylamino; (k) arylalkylamino; (l) nitro; (m) sulfonamido; (n) carboxamido; (o) aryl; (p) —C(O)—aryl; or (q) —C(O)—alkyl; alternatively, Rg and the monocyclic ring radical of which A1, A2 A3, and A4 comprise four of the six atoms are:
(a) naphthyl; (b) quinolyl; (c) isoquinolyl; (d) quinolizinyl; (e) quinoxalinyl; or (f) dibenzofuryl; R58 and R59 are each independently:
(a) hydrogen; (b) lower alkyl; (c) lower alkyl-phenyl; (d) haloalkyl; (e) halo; (f) —NO2; (g) CN; (h) lower alkyl-CN; (i) alkoxy; (j) alkylthio; or (k) alkenyl; alternatively, Rl and R59 taken together along with the atoms to which they are attached are cycloalkyl; R8, Ri, Re, Rf, D1, U, V, a and p are as defined herein; with the proviso that the compounds of formula VIm must contain at least one nitrite, nitrate, thionitrite or thionitrate group; wherein the compound of formula (IX) is: 35wherein: X9 is —C(O)—U—D1and Y is —CH27CRe(W5)—U—D1;; or X9 is —CHXIR5(W5)—U—D1and Y9 is C(O)—U—Dl; or X9 and Y9 taken together are:
(a) —C(O)—O—CRl(R4 )—CWR(R)—; (b) —(CRW(RW))k-CI(Rs )—CR5(Rl)—; (c) —C(O)—(CR4(R4))k—CR5()—; (d) —(CR4(R4′))k—CR5(R5′)—C(O)- or (e) —C(O)—CR4(R4) —CR5(R7)—; wherein X9 is the first carbon atom of a, b, c, d and e; R1, R2, R41 R4′R, R5′, U, D1and k are as defined herein; with the proviso that the compounds of formula IX contain at least one nitrite, nitrate, thionitrite or thionitrate group; wherein the compound of formula (X) is: 36wherein: when side h, k, and j are single bonds, and side i and l are a double bond, —X10—Yhu 10—Z10— is: 37when sides i, k and l are single bonds, and sides h and j are double bonds, —X10— —Y10—Z10— is: 38when side h and j are single bonds, and side k and i is a single or a double bond, —X10—T10—Z10— is: 39P10 is:
(a) —N═; (b) —NR3—; (c) —O—; or (d) —S—; Q10 and Q10 are each independently:
(a) CRl; or (b) nitrogen; A10B10—C10D10— is:
(a) —CR4═CR4′—CR5═CR5′—; (b) —CR4(R4)—CR5(R)—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)—(g) —CR4(R4)—C(0)—CR5(R)—; (h) —C(O)—CRe(R4)—CRW(RW) —; (i) —CR4(R4′) CR5(R5′—O—C(0)—; (j) —CR4(R4)—O—C(0)CR5(R5′) ; (k) —C(O)—CR4(R4′)—CR5(R5W)—; (l) —CR4(R4′)—CR5(R)—C(O)—O—; (m) —CR4(R4′)—C(O)—CR5(R5′)—; (n) —C(O)—O—CR4(R4)—CR5(R5)—; (o) —R12(R3&(0)—; (p) —C(O)—O—CR12(k3)—; (q) —O—C(0)—CR12(R13)—; (r) —CR12(R13)C(O) O; (s) —N═CR4—CR4′═CR5—; (t) —CR═N—CR4′═CR5—; (u) —CR4═CR4′—N═CR5—; (v) —CR4═CR5-cR5═N—; (w) —N═CR4—CR4′═N—; (x) —N═CR—N═CR′—; (y) —CR4═N—CR4′═N—; (z) —S—CR═N—(aa) —S—N═CR4—; (bb) —N═N—NR3—(cc) —CR4═N—S—; (dd) —N═CR4—S—, (ee) —O—CR4═N—; (ff) -C—N═CR—; or (gg) —N═CR4-o—; —A10′B10′D10′is:
(a) —CR4═CR5-ClR5—(b) —CR(R4′)—CR5(R)—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) —CR═N—NR3—; (m) —CR4═N—N═; (n) —CR4═N—CRs═; (o) —CR═CR5—NR3—; (p) —CR═CR5—N═; (q) —S—CR4═CR5—; (r) —CR═CR5; (s) —CR═CR—O—; (t) —CR4═CR5—S—; (u) —CR═N—S—; (v) —CR4═N—O—; (w) —N═CR-S; (x) —N═CR4—O—; (y) —S—CR4═N—; (z) —O—CR4═N—; (aa) —N═N—S—, (b) —N═N—O—, (cc) —SN═N—; (dd) —O—N═N—; (ee) —R4═CR5-S; (ff) —CR4(R4)—CR5(R5′)—S—; (gg) —CR4(R4)—CR7(RW)—O—; (hh) —S—CR(R4)—CR5(R5)- or (ii) —O—CR4(R4′)—CR5(R5)—; R60 and R61 are each independently:
(a) lower alkyl; (b) haloalkyl; (c) alkoxy; (d) alkylthio; (e) lower alkyl—OD1; (f) —C(O)H; (h) —(CI,2)q—CO2—lower alkyl; (i) —(CH2)q—CO2D1; (j) —O—(CH,)q—S—lower alkyl; (k) —(CF2)q—S—lower alkyl; (l) —S(O)2,-ower alkyl; (m) —(CH,)q—NR12RW3; or (n) —C(O)N(RW)(R8); R1, R2 R3 R4, R4′, R, R8 R12 R13, T, D1 and q are as defined herein;
with the proviso that the compounds of formula X must contain at least one nitrite, nitrate, thionitrite or thionitrate group; wherein the compound of formula (XI) is: 40wherein: X11 is:
(a) oxygen; or (b) CH2; Y11 is:
(a) oxygen; (c) —N-O]D; (d) —Nlower alkyl; (e) —N-0-aryl; (f) —N—C(O)—O—lower alkyl; (g) —N—N(R8)(R8); or (h) —N—N(R8)—S(O)27lower alkyl; R62, R63, R64 and R65 are each independently:
(a) hydrogen; (b) lower alkyl; (c) alkoxy; (d) halo; (e) CN; (f) OD1; (g) aryloxy; (h) NR12R13 (i) —CF; (j) —NO2; (k) alkylthio; (l) —S(O)0—lower alkyl; (m) —C(O)N(R8)(RW); (n) —CO2D1 (o) —CO2—lower alkyl; or (p) —NRl—C(O)—lower alkyl; R66 is:
(a) hydrogen; (b) lower alkyl; (c) alkenyl; (d) alkoxyalkyl; or (e) cycloalkylalkyl; R8, R12, R131 o, K and D1 are as defined herein; with the proviso that the compounds of formula XI must contain at least one nitrite, nitrate, thionitrite or thionitrate group; wherein the compound of the formula (XI) is: 41wherein: X12 is: 42(e) —NR73(R74); (f) hydrogen; or (g) K; Z12 is: 43R67 is:
(a) hydrogen; (b) lower alkyl; (c) lower alkyl—OD1; (d) —OD1; (e) haloalkyl; or 44R68 is:
(a) lower alkyl; (b) halo; (c) alkoxy (d) haloalkyl; (e) alkylthio; (f) haloalkylthio; (g) —OCH2—(h) unsubstituted, mono-, or di-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; or (2) lower alkyl (i) —S(O) O-ower alkyl; (j) —S(O) —lower haloalkyl; (k) amino; (l) alkylamino; (m) dialkylamino; (n) —N(H)SO2,-ower alkyl; (o) N(H)SO2—lower haloalkyl; (p) nitro; (q) cyano; (r) —CO2D1; (s) carboxylic ester; (t) lower alkyl—OD1; (q) carboxamide; or (r) —C(O)N(RW2)D1; R69 is:
(a) lower alkyl; (b) hydrogen; (c) alkoxy (d) mono-, di-, tri, tetra- or penta-substituted phenyl, wherein the substituent are each independently:
(1) hydrogen; (2) halo; (3) alkoxy; (4) alkylthio; (5) —S(O)04ower alkyl; (6) lower alkyl; (7) haloalkyl; (8) —CO2D1; (9) —lower alkyl—CO2D1; (10) —OD1; (11) —lower alkyl—OD1; or (12) haloalkoxy; (e) 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) aryloxy; (7) arylthio; (8) —CO2D1; (9) —C(O)NH(D1) (10) haloalkyl; or (11) —OD1; R70 is:
(a) lower alkyl; (b) hydrogen; or (c) mono- or di-substituted phenyl, wherein the substituent are each independently:
(1) hydrogen; (2) halo; (3) alkoxy; (4) haloalkyl; or (5) lower alkyl; R71 is:
(a) benzoyl, or mono-, or disubstituted benzoyl, wherein the substituents are each independently:
(1) halo; (2) lower alkyl; or (3) alkoxy; (b) benzyl, mono- or disubstituted benzyl, wherein the substituents are each independently:
(1) halo; (2) lower alkyl; or (3) alkoxy; (c) lower alkyl-pyridinyl, or unsubstituted, mono-, or disubstituted pyridinyl, wherein the substituents are each independently:
(1) halo; (2) lower alkyl; or (3) alkoxy; (d) —C(O)-pyridinyl, or mono-, or disubstituted (O)-pyridinyl wherein the substituents are each independently:
(3) halo; (4) lower alkyl; or (3) alkoxy; (e) hydrogen; (f) aryl; (g) cycloalkyl; (h) cycloalkylalkyl; R72 is:
(a) lower alkenyl—CO2D1; or (c) K; R73 is unsubstituted or mono substituted lower alkyl, wherein the substituents are each independently:
(a) hydroxy; (b) alkoxy; (c) nitro; (c) —NLt; (d) alkylamino; (e) dialkylamino; (f) carboxyl; (g) carboxylic ester; or (h) carboxamide; R74 is:
(a) hydrogen; (b) lower alkyl; or (c) —C(O)R7; R75 is:
(a) lower alkyl; (b) haloalkyl (c) substituted lower alkyl; (d) cycloalkyl; (e) unsubstituted, mono-, di- or tri-substituted phenyl or naphthyl, wherein the substituents are each independently:
(1) halo; (2) alkoxy; (3) —S(O)0—lower alkyl; (4) hydroxy; (5) —S(O)0-haloalkyl; (6) lower alkyl; (7) haloalkyl; (8) —CO2D1; (9) —CO2—lower alkyl; (10) —S(O)2NR8(D1); (11) —lower alkyl-0—lower alkyl; (12) -CN; (13) lower alkyl—OD1; (14) arylalkoxy; (15) —C(O)NR8(D1); or (16) aryl; (f) mono-, di- or tri-substituted heteroaryl, wherein the heteroaryl is a monocyclic aromatic ring of 5 atoms, said ring having one heteroatom which is selected from 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) halo; (2) alkoxy; (3) —S(O),71ower alkyl; (4) hydroxy; (5) —S(O),-haloalkyl; (6) lower alkyl; (7) haloalkyl; (8) —CO2D1; (9) —CO2—lower alkyl; (10) —S(0)2NR8(D1); (11) —lower alkyl—O—lower alkyl; (12) —N(D1)S(O)2—lower alkyl; (13) lower alkyl—OD1; (14) —N(D1)S(O)2-haloalkyl; (15) —C(O)NR8(D1); or (16) aryl; R76 is:
(a) alkyl; (b) substituted alkyl; (c) alkyl—N(D1)S(O)2-aryl; (d) substituted alkyl-cycloalkyl; (e) substituted alkyl-heterocyclic ring; or (f) arylalkoxy; R77 is:
(a) —OD1; (b) alkoxy; or (c) —NR78R79; R78 and R79 are each independently:
(a) hydrogen; (b) hydroxy; (c) alkoxy; (d) lower alkyl; or (e) substituted lower alkyl; or R78 and R79 taken together with the nitrogen to which they are attached form a heterocyclic ring; R80 and R81 are each independently:
(a) hydrogen; (b) lower alkyl; or (c) halo; R89 and R89′ are each independently:
(a) hydrogen; or (b) lower alkyl; or R89 and R89′ taken together with the carbon to which they are attached form a cycloalkyl ring; m is an integer from 0 to 6; D1, R1, R!1 R12, K, X5, a, p and o are as defined herein; and with the proviso that the compounds of formula XII must contain at least one nitrite, nitrate, thionitrite or thionitrate group; wherein the compound of formula (XII) is: 45wherein: X13 and y13 are each independently:
(a) ═C(H)—; or (b) ═N—; R90 is:
(a) lower alkyl; (b) lower alkyenD:; (c) alkenyl; (d) lower alkyl-CN; (e) lower alkyl—CO2Dl; (f) aryl; (g) heterocyclic ring; or (i) heterocyclicalkyl; R91 is:
(a) mono di- o r tri-substituted phenyl, wherein the subsfituents are each independently:
(1) hydrogen; (2) halo; (3) alkoxy; (4) alkylthio; (5) CN; (6) haloalkyl; (7) lower alkyl; (8) —CO2D; (9) —CO2lower alkyl; (10) lower alkyl-0D1; (11) lower alkyl—NRIRl3; (12) lower alkyl—CO2D1; or (13) —OD1; (b)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) alkoxy; (4) alkylthio; (5) CN; (6) haloalkyl; (7) lower alkyl; (8) —CO2D1; (9) —CO2—lower alkyl; (10) lower alkyl—OD1; (11) lower alkyl—NR12R13W (12) lower alkyl—CO2D1; or (13) —OD1; D1, R1, R12, and R13, are as defined herein; and with the proviso that the compounds of formula XIII must contain at least one nitrite, nitrate, thionitrite or thionitrate group; wherein the compound of formula (XIV) is: 46wherein: X14 is:
(a) —C(O)—; or (b) —C(S)—; Y14 is:
(a) —O—; or (b) —S—; A14.-.B14-D14 is:
(a) —CR4═CR4′—CR5═CR5′—; (b) —CR4(R4 )—CR5(R )—C(O)—; (c) —CR4(R4)—C(O)—CR5(R7′)—; (d) —C(O)—CR4(R4e)—CR(R) (e) —CR4(R5)—O—C(O)—; (f) —C(O)—O—CR4(R5) (g) —O—C(O)—CRW(R5)—; (h) —S—N═CR4—; (i) —O—N═CR4—; (j) —CR4(R5)—NR3—C(O)—; (k) —C(O)—NR3—CR(R5)—; (l) —NR3—C(O)—CR4(R5)—; (m) —CR4(R5)—S—C(O)—; (n) —C(o)—S—cR(Re)-—; (o) —S—C(O)—CR4(R5)—; (p) —CR4═CR4W—C(O)—; (q) —C(O)- CR4═CR4′; (r) —O—CR4═CR4′—; (s) —S—CR═CR4—; (t) —NR3—CR═CRW—; (u) —S—NR3—C(O)—; (v) —O—NR3—C(O)—; or (w) —NR3—N═CR4—;, R1, R2, R3, R4, R4, R5 and R5′ are as defined herein; and with the proviso that the compounds of formula XIV must contain at least one nitrite, nitrate, thionitrite or thionitrate group; wherein the compound of formula (XV) is: 47wherein: X15 is:
(a) —C(O)—; (b) —CF4—; (c) —CH(OD1)—; (d) -C═N—O—lower alkyl—; (e) —O—; (f) —S(O)O—; (g) —NR92; or (g) covalent bond; Y15 is:
(a) aryl; or (b) cycloalkyl; Z15 is:
(a) hydrogen; (b) alkyl; (c) haloalkyl; (d) cycloalkyl; (e) alkoxy; (f) alkylthio; (g) cycloalkylalkylthio; (h) cycloalkylalkoxy; (i) —OD1; (j) halo; (k) cyano; (l) —C(O)OD; (m) —C(O)—lower alkyl; R92 is:
(a) hydrogen; (b) lower alkyl; (c) —C(O)—lower alkyl; or (d) K; R1, D1, K and o are as defined herein; and with the proviso that the compounds of formula XV contain at least one nitrite, nitrate, thionitrite or thionitrate group; wherein the compound of formula (XVI) is: 48X16 is:
(a) hydrogen; (b) halogen; (c) methyl; or (d) ethyl; Z16 is:
(a) hydrogen; or (b) methyl; R93 is:
(a) chloro; or (b) fluoro; R94 and R94′ are each independently:
(a) hydrogen; or (b) fluoro; R95 is:
(a) chloro; (b) fluoro; (c) hydrogen; (d) methyl; (e) ethyl; (f) methoxy; (g) ethoxy; or (i) hydroxy; R96 is:
(a) chloro; (b) fluoro; (c) trifluoromethyl; or (d) methyl; R98 is:
(a) lower alkyl; (b) lower alkenyl; (c) alkoxy; or (d) alkylthio; K and X13 are as defined herein; and with the proviso that the compounds of formula XVI must contain at least one nitrite, nitrate, thionitrite or thionitrate group.
- 2. A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
- 3. A method for treating, preventing or reducing inflammation, pain or fever in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 2.
- 4. A method for treating or preventing a gastrointestinal disorder, or improving the gastrointestinal properties of a COX-2 inhibitor in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 2.
- 5. The method of claim 4, wherein the gastrointestinal disorder is an inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, a peptic ulcer, a stress ulcer, a bleeding ulcer, gastric hyperacidity, dyspepsia, gastroparesis, Zollinger-Ellison syndrome, gastroesophageal reflux disease, a bacterial infection, short-bowel (anastomosis) syndrome, or a hypersecretory state associated with systemic mastocytosis or basophilic leukemia and hyperhistaminemia.
- 6. A method for facilitating wound healing in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 2.
- 7. The method of claim 6, wherein the wound is an ulcer.
- 8. A method for treating or reversing renal or other toxicities in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 2.
- 9. A method for treating or preventing a disorder resulting from elevated levels of COX-2 in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 2.
- 10. The method of claim 9, wherein the disorder resulting from elevated levels of COX-2 is angiogenesis, arthritis, asthma, bronchitis, menstrual cramps, premature labor, tendinitis, bursitis, skin-related condition, neoplasia, inflammation in disease, ophthalmic disorder, pulmonary inflammation, central nervous system disorder, allergic rhinitis, respiratory distress syndrome, endotoxin shock syndrome, atherosclerosis, inflammation and/or microbial infection, cardiovascular disorder, urinary and/or urological disorder, endothelial dysfunction, preservation of organs and tissues, inhibition and/or prevention of activation, adhesion and infiltration of neutrophils at the site of inflammation, or inhibition and/or prevention of platelet aggregation.
- 11. The composition of claim 2, further comprising at least one therapeutic agent.
- 12. The composition of claim 11, wherein the therapeutic agent is a steroid, a nonsteroidal antiinflammatory compound, a 5-lipoxygenase inhibitor, a leukotriene B4 receptor antagonist, a leukotriene A4 hydrolase inhibitor, a 5-HT agonist, a 3-hydroxy-3-methylglutaryl coenzyme A inhibitor, a H receptor antagonist, an antineoplastic agent, an antiplatelet agent, a decongestant, a diuretic, a sedating or non-sedating anti-histamine, an inducible nitric oxide synthase inhibitor, an opioid, an analgesic, a Helicobacter pylori inhibitor, a proton pump inhibitor, an isoprostane inhibitor, or a mixture thereof.
- 13. A method for treating, preventing or reducing inflammation, pain or fever in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 11.
- 14. A method for treating or preventing a gastrointestinal disorder, or improving the gastrointestinal properties of a COX-2 inhibitor in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 11.
- 15. The method of claim 14, wherein the gastrointestinal disorder is an inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, a peptic ulcer, a stress ulcer, a bleeding ulcer, gastric hyperacidity, dyspepsia, gastroparesis, Zollinger-Ellison syndrome, gastroesophageal reflux disease, a bacterial infection, short-bowel (anastomosis) syndrome, or a hypersecretory state associated with systemic mastocytosis or basophilic leukemia and hyperhistaminemia.
- 16. A method for facilitating wound healing in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 11.
- 17. The method of claim 16, wherein the wound is an ulcer.
- 18. A method for treating or reversing renal or other toxicities in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 11.
- 19. A method for treating or preventing a disorder resulting from elevated levels of COX-2 in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 11.
- 20. The method of claim 19, wherein the disorder resulting from elevated levels of COX-2 is angiogenesis, arthritis, asthma, bronchitis, menstrual cramps, premature labor, tendinitis, bursitis, skin-related condition, neoplasia, inflammation in disease, ophthalmic disorder, pulmonary inflammation, central nervous system disorder, allergic rhinitis, respiratory distress syndrome, endotoxin shock syndrome, atherosclerosis, inflammation and/or microbial infection, cardiovascular disorder, urmary and/or urological disorder, endothelial dysfunction, preservation of organs and tissues, inhibition and/or prevention of activation, adhesion and infiltration of neutrophils at the site of inflammation, or inhibition and/or prevention of platelet aggregation.
- 21. A composition comprising at least one compound of claim 1 or a pharmaceutically acceptable salt thereof, and at least one compound that donates, transfers or releases nitric oxide, or induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase.
- 22. The composition of claim 21 further comprising a pharmaceutically acceptable carrier.
- 23. The composition of claim 21, wherein the compound that donates, transfers, or releases nitric oxide, or induces the production of endogenous nitric oxide or endothelium-derived relaxing factor or is a substrate for nitric oxide synthase is an S-nitrosothiol.
- 24. The composition of claim 23, wherein the S-nitrosothiol is S-nitroso—N-acetylcysteine, S-nitroso-captopril, S-nitroso—N-acetylpenicillamine, S-nitroso-homocysteine, initroso-cysteine, S-nitroso-glutathione, or S-nitroso-cysteinyl-glycine.
- 25. The composition of claim 23, wherein the S-nitrosothiol is:
(i) HS(C(Re)(Rf))mmSNO; (ii) ONS(C(Re)(Rf))mmRe; or (iii) H2N—CH(CO2H)—(CH2)mm—C(O)NH—CH(CH2SNO)—C(O)NH—CH2—CO2H; wherein mm is an integer from 2 to 20; 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 alkoxy, 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 carbamoyl, a urea, a nitro, -T-Q-, or (C(Re)(Rf))k-T-Q, or Re and Rf taken together are an oxo, a methanthial, a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group; Q is —NO or —NO2; and T is independently a covalent bond, a carbonyl, an oxygen, —S(O)0— or —N(Ra)Ri—, wherein o is an integer from 0 to 2, Ra is a lone pair of electrons, a hydrogen or an alkyl group; R, 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, —CH2-C(T-Q)(Re)(Rf), C(T-Q)(Re)(Rf), or —(N2O2—)−.M+, wherein M+ is an organic or inorganic cation; with the proviso that when R1 is —CH2—C(T-Q)(Re)(Rf) 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.
- 26. The composition of claim 21, wherein the compound that donates, transfers, or releases nitric oxide, or induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase is L-arginine, L-homoarginine, N-hydroxy-L-arginine, nitrosated L-arginine, nitrosylated L-arginine, nitrosated N-hydroxy-L-arginine, nitrosylated N-hydroxy-L-arginine, citrulline, ornithine, glutamine, or an arginase inhibitor.
- 27. The composition of claim 21, wherein the compound that donates, transfers, or releases nitric oxide, or induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase is:
(i) a compound that comprises at least one ON—O—, ON—N— or ON-C— group; (ii) a compound that comprises at least one 02N—O—, 02N—N—, 02N—S—or —O2N-C— group; (iii) a N-oxo—N-nitrosoamine having the formula: RlR2—N(O-M+)—NO, wherein R1 and R2 are each independently a polypeptide, an amino acid, a sugar, an oligonucleotide, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted hydrocarbon, or a heterocyclic group, and M+is an organic or inorganic cation.
- 28. The composition of claim 27, wherein the compound comprising at least one ON—O—, ON—N— or ON-C— group is an ON—O—polypeptide, an ON—N-polypepetide, an ON—C—polypeptide, an ON—O—amino acid, an ON—N-amino acid, an ON—C—amino acid, an ON—O—sugar, an ON—N-sugar, an ON—C—sugar, an ON—O—oligonucleotide, an ON—N—oligonucleotide, an ON—C—oligonucleotide, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic ON—O—hydrocarbon, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic ON—N-hydrocarbon, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic ON—C—hydrocarbon, an ON—O—heterocyclic compound, an ON—N-heterocyclic compound or a ON—C—heterocyclic compound.
- 29. The composition of claim 27, wherein compound comprising at least one 02N—O—, 02N—N—, 02N—S—or O2N-C— group is an O2N—O—polypeptide, an O2N—N—polypeptide, an 02N—S—polypeptide, an 02N—C—polypeptide, an O2N-0-amino acid, O2N—N-amino acid, 02N—S—amino acid, an ON—C—amino acid, an 02N—O—sugar, an 02N—N-sugar, 02N—S—sugar, an 02N—C—sugar, an 02N—O—oligonucleotide, an 02N—N-oligonucleotide, an 02N—S—oligonucleotide, an 02N—C—oligonucleotide, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted 02N—O—hydrocarbon, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted 02N—N-hydrocarbon, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted 02N—S—hydrocarbon, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted 02N—C—hydrocarbon, an 02N—O—heterocyclic compound, an 02N—N-heterocyclic compound, an O2N-Sheterocyclic compound or an 02N—C—heterocyclic compound.
- 30. The composition of claim 21, further comprising at least one therapeutic agent.
- 31. The composition of claim 30, wherein the therapeutic agent is a steroid, a nonsteroidal antiinflammatory compound, a 5-lipoxygenase inhibitor, a leukotriene B4 receptor antagonist, a leukotriene A4 hydrolase inhibitor, a 5-HT agonist, a 3-hydroxy-3-methylglutaryl coenzyme A inhibitor, a H receptor antagonist, an antineoplastic agent, an antiplatelet agent, a decongestant, a diuretic, a sedating or non-sedating anti-histamine, an inducible nitric oxide synthase inhibitor, an opioid, an analgesic, a Helicobacter pylori inhibitor, a proton pump inhibitor, an isoprostane inhibitor, or a mixture thereof.
- 32. A method for treating, preventing or reducing inflammation, pain or fever in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 21 or 30.
- 33. A method for treating or preventing a gastrointestinal disorder, or improving the gastrointestinal properties of a COX-2 inhibitor in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 21 or 30.
- 34. The method of claim 33, wherein the gastrointestinal disorder is an inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, a peptic ulcer, a stress ulcer, a bleeding ulcer, gastric hyperacidity, dyspepsia, gastroparesis, Zollinger-Ellison syndrome, gastroesophageal reflux disease, a bacterial infection, short-bowel (anastomosis) syndrome, or a hypersecretory state associated with systemic mastocytosis or basophilic leukemia and hyperhistamlnemia.
- 35. A method for facilitating wound healing in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 21 or 30.
- 36. The method of claim 35, wherein the wound is an ulcer.
- 37. A method for treating or reversing renal or other toxicities in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 21 or 30.
- 38. A method for treating or preventing a disorder resulting from elevated levels of COX-2 in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 21 or 30.
- 39. The method of claim 38, wherein the disorder resulting from elevated levels of COX-2 is angiogenesis, arthritis, asthma, bronchitis, menstrual cramps, premature labor, tendinitis, bursitis, skin-related condition, neoplasia, inflammation in disease, ophthalmic disorder, pulmonary inflammation, central nervous system disorder, allergic rhinitis, respiratory distress syndrome, endotoxin shock syndrome, atherosclerosis, inflammation and/or microbial infection, cardiovascular disorder, urinary and/or urological disorder, endothelial dysfunction, preservation of organs and tissues, inhibition and/or prevention of activation, adhesion and infiltration of neutrophils at the site of inflammation, or inhibition and/or prevention of platelet aggregation.
- 40. A kit comprising at least one compound of claim 1 or a pharmaceutically acceptable salt thereof.
- 41. A kit comprising at least one compound of claim 1 or a pharmaceutically acceptable salt thereof, and at least one compound that donates, transfers or releases nitric oxide, or induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase.
- 42. The kit of claim 41, wherein the compound of claim 1 or a pharmaceutically acceptable salt thereof, and the at least one compound that donates, transfers or releases nitric oxide, induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase are separate components in the kit or are in the form of a composition in the kit.
- 43. A kit comprising at least one compound of claim 1 or a pharmaceutically acceptable salt thereof, and at least one therapeutic agent.
- 44. The kit of claim 43, wherein the compound of claim 1 or a pharmaceutically acceptable salt thereof, and the at least one therapeutic agent are separate components in the kit or are in the form of a composition in the kit.
- 45. A compound selected from the group consisting of 4-{5-(4-chlorophenyl)-3-((nitrooxy)methyl)-3-hydropyrazolyl) benzenesulfonamide, 4-{5((nitrooxy)methyl)-3-phenylisoxazol-4-yl}benzenesulfonamide, 2-(1-methyl-4-(nitrosothio)-4-piperidyl) ethyl 3-(N-((4-(5-methyl-3-phenylisoxazol-4-yl)phenyl)sulfonylicarbamoyl)propanoate, (2-{1-((4-chlorophenyl)methyl)-5-methoxy-2-methylindol-3-yl}ethyl)nitrooxy, 1-(3-(4-fluorophenyl)-7-(nitrooxymethyl)(3a-hydroimidazolo(1,2-a)pyridin-2-yl))-4-(methylsulfonyl)benzene, ethyl 6chloro-8-((nitrooxy)methyl)-2-(trifluoromethyl)-2H-chromene-3 carboxylate, 2-{1-((4-chlorophenyl)carbonyl)-5-methoxy-2-methylindol-3-yl}—N-(2-methyl-2-(nitrosothio)propyl)acetamide, ethyl (2Z)-3-(4-chlorophenyl)-3-(4-(methylsulfonyl)phenyl)-2-(2-(nitrooxy)ethyl)prop-2-enoate, (2Z)-3-(4chlorophenyl)-3-(4-(methylsulfonyl)phenyl)-2-(2-(nitrooxy)ethyl)prop-2-enoic acid, (2—Z)-3-(4-chlorophenyl)-2-(2-hydroxyethyl)—N-(2-methyl-2-(nitrosothio)propyl)-3-(4-(methylsulfonyl)phenyl)prop-2-enamide, 1-(5-methyl-1-(2-methyl-2-(nitrosothio) propyl)pyrrol-2-yl)-4-(methylsulfonyl) benzene, 3{4-(1-methyl-1-(nitrosothio)ethyl)-2-oxo-1,3-oxazolidin-3-yl}propyl (2Z)-4-acetyloxy-2-(4-flurophenyl)-3-(4-(methylsulfonyl) phenyl)but-2-enoate, (2Z)-3-(4-fluorophenyl)-3-{N-methyl—N-(2-methyl-2-(nitrosothio) propyl)carbamoyl}-2-(4-(methylsulfonyl)phenyl)prop-2-enyl acetate, 2-(1-methyl (nitrosothio)piperidyl)ethyl (2Z)-3-(4-acetyloxy-2-(4-fluorophenyl)-3-(4-(methylsulfonyl)phenyl)but-2-enoate, (3Z)-4-(4-chlorophenyl)-3-(ethoxycarbonyl)-4-(4-(methylsulfonyl)phenyl)but-3-enoic acid, 3-methyl—N-{(4-(5-methyl-3-phenylisoxazol-4-yl)phenyl)sulfonyl}-3-(nitrosothio)butanamide, 2-methyl-2-(nitrosothio)propyl-5-(4-chlorophenyl)-1-(4-sulfamoylphenyl) pyrazole-3-carboxylate, 4-(4-fluorophenyl)-5-(4-(methylsulfonyl)phenyl)-2-({4-((nitroxy)-methyl)phenyllmethyl)-2-hydroxypyridazin-3-one, 1-(1-(2-hydroxyethyl)-4-benzylpyrazol-3-yl)-4-(methylsulfonyl)benzene, 4-(methylsulfonyl)-1-{1-(2-(nitrooxy)ethyl)-4-benzylpyrazol-5-yl}benzene, 4-(1-cyclohexyl-. 3-(hydroxymethyl)pyrazol-5-yl)-1-(methylsulfonyl)benzene and 4-{1-cyclohexyl-3-(nitrooxy)methyl)pyrazol-5-yl}-1-(methylsulfonyl)benzene.
- 46. A composition comprising at least one compound of claim 45 and a pharmaceutically acceptable carrier.
- 47. A kit comprising at least one compound of claim 45.
- 48. A composition comprising at least one parent COX-2 inhibitor of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (IX), formula (X), formula (XI), formula (XII), ), formula (XIII), formula (XIV), formula (XV) or formula (XVI), or a pharmaceutically acceptable salt thereof, and at least one compound that donates, transfers or releases nitric oxide, or induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase.
- 49. The composition of claim 48 further comprising a pharmaceutically acceptable carrier.
- 50. The composition of claim 48, wherein the compound that donates, transfers, or releases nitric oxide, or induces the production of endogenous nitric oxide or endothelium-derived relaxing factor or is a substrate for nitric oxide synthase is an S-nitrosothiol.
- 51. The composition of claim 50, wherein the S-nitrosothiol is S-nitroso—N-acetylcysteine, S-nitroso-captopril, S-nitroso—N-acetylpenicillamine, S-nitroso-homocysteine, S-nitroso-cysteine, S-nitroso-glutathione, or S-nitroso-cysteinyl-glycine.
- 52. The composition of claim 50, wherein the S-nitrosothiol is:
(i) HS(C(Re)(Rf))m.SNO; (ii) ONS(C(Re)(Rf))mmRe; or (iii) HN—CH(CO2H)—(Clt).—C(O)NH—CH(CH2SNO)—C(O)NH—CH2—CO2H; wherein mm is an integer from 2 to 20; 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 alkoxy, 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 carbamoyl, a urea, a nitro, -T-Q-, or (C(Re)(Rf))kCT—Q, or Re and Rf taken together are an oxo, a methanthial, a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group; Q is —NO or —NO2; and T is independently a covalent bond, a carbonyl, an oxygen, —S(O)o— or N(Ra)Ri—, wherein o is an integer from 0 to 2, Ra is a lone pair of electrons, a hydrogen or an alkyl group; R1 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, —CH2—C(T-Q)(Re)(Rf), or —(N2O2—)−.M+, wherein M+ is an organic or inorganic cation; with the proviso that when Ri is —CH2—C(T-Q)(Re)(Rf) 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.
- 53. The composition of claim 48, wherein the compound that donates, transfers, or releases nitric oxide, or induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase is L-arginine, L-homoarginine, N-hydroxy-L-arginine, nitrosated L-arginine, nitrosylated L-arginine, nitrosated N-hydroxy-L-arginine, nitrosylated N-hydroxy-L-arginine, citrulline, ornithine, glutamine, or an arginase inhibitor.
- 54. The composition of claim 48, wherein the compound that donates, transfers, or releases nitric oxide, or induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase is:
(i) a compound that comprises at least one ON—O—, ON—N— or ON-C— group; (ii) a compound that comprises at least one 02N—O—, 02N—N—, O2N—S—or -02N-C— group; (iii) a N-oxo—N-nitrosoamine having the formula: R1R2—N(O-M+)—NO, wherein R1 and R2 are each independently a polypeptide, an amino acid, a sugar, an oligonucleotide, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted hydrocarbon, or a heterocyclic group, and M+is an organic or inorganic cation.
- 55. The composition of claim 54, wherein the compound comprising at least one ON—O—, ON—N— or ON-C— group is an ON—O—polypeptide, an ON—N-polypepetide, an ON—C—polypeptide, an ON—O—amino acid, an ON—N-amino acid, an ON—C—amino acid, an ON—O—sugar, an ON—N-sugar, an ON—C—sugar, an ON—O—oligonucleotide, an ON—N-oligonucleotide, an ON—C—oligonucleotide, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic ON—O—hydrocarbon, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic ON—N-hydrocarbon, a straight or branched, saturated or unsaturated, substituted or unsubstituted, aliphatic or aromatic ON—C—hydrocarbon, an ON—O—heterocyclic compound, an ON—N-heterocyclic compound or a ON—C—heterocyclic compound.
- 56. The composition of claim 54, wherein compound comprising at least one 02N—O—, ON—N—, O2N—S—or 02N-C— group is an 02N—O—polypeptide, an 02N—N-polypeptide, an 02N—S—polypeptide, an 02N—C—polypeptide, an 02N—O—amino acid, 02N-N-amino acid, 02N—S—amino acid, an 02N—C—amino acid, an 02N&sugar, an 02N—N-sugar, 02N—S—sugar, an 02N—C—sugar, an 02N-Ooligonucleotide, an 02N—N-oligonucleotide, an 02N—S—oligonucleotide, an 02N—C—oligonucleotide, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted ; O2Nhydrocarbon, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted 02N—N-hydrocarbon, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted 02N—S—hydrocarbon, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted 02N—C—hydrocarbon, an O2N-0-heterocyclic compound, an 02N—N-heterocyclic compound, an 02N—S—heterocyclic compound or an ON—C—heterocyclic compound.
- 57. The composition of claim 48, further comprising at least one therapeutic agent.
- 58. The composition of claim 57, wherein the therapeutic agent is a steroid, a nonsteroidal antiinflammatory compound, a 5-lipoxygenase inhibitor, a leukotriene B4 receptor antagonist, a leukotriene A4 hydrolase inhibitor, a 5-HT agonist, a 3-hydroxy-3-methylglutaryl coenzyme A inhibitor, a 14 receptor antagonist, an antineoplastic agent, an antiplatelet agent, a decongestant, a diuretic, a sedating or non-sedating anti-histamine, an inducible nitric oxide synthase inhibitor, an opioid, an analgesic, a Helicobacter pylori inhibitor, a proton pump inhibitor, an isoprostane inhibitor, or a mixture thereof.
- 59. A method for treating, preventing or reducing inflammation, pain or fever in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 48 or 57.
- 60. A method for treating or preventing a gastrointestinal disorder, or improving the gastrointestinal properties of a COX-2 inhibitor in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 48 or 57.
- 61. The method of claim 60, wherein the gastrointestinal disorder is an inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, a peptic ulcer, a stress ulcer, a bleeding ulcer, gastric hyperacidity, dyspepsia, gastroparesis, Zollinger-Ellison syndrome, gastroesophageal reflux disease, a bacterial infection, short-bowel (anastomosis) syndrome, or a hypersecretory state associated with systemic mastocytosis or basophilic leukemia and hyperhistaminemia.
- 62. A method for facilitating wound healing in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 48 or 57.
- 63. The method of claim 62, wherein the wound is an ulcer.
- 64. A method for treating or reversing renal or other toxicities in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 48 or 57.
- 65. A method for treating or preventing a disorder resulting from elevated levels of COX-2 in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 48 or 57.
- 66. The method of claim 65, wherein the disorder resulting from elevated levels of COX-2 is angiogenesis, arthritis, asthma, bronchitis, menstrual cramps, premature labor, tendinitis, bursitis, skin-related condition, neoplasia, inflammation in disease, ophthalmic disorder, pulmonary inflammation, central nervous system disorder, allergic rhinitis, respiratory distress syndrome, endotoxin shock syndrome, atherosclerosis, inflammation and/or microbial infection, cardiovascular disorder, urinary and/or urological disorder, endothelial dysfunction, preservation of organs and tissues, inhibition and/or prevention of activation, adhesion and infiltration of neutrophils at the site of inflammation, or inhibition and/or prevention of platelet aggregation.
- 67. A kit comprising at least one parent COX-2 inhibitor and at least one compound that donates, transfers, or releases nitric oxide, or induces the production of endogenous nitric oxide or endothelium-derived relaxing factor or is a substrate for nitric oxide synthase, or a pharmaceutically acceptable salt thereof.
- 68. The kit of claim 67, further comprising at least one therapeutic agent.
- 69. The kit of claim 67, wherein the parent COX-2 inhibitor and the compound that donates, transfers, or releases nitric oxide, or induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, or is a substrate for m nitric oxide synthase are separate components in the kit.
- 70. The kit of claim 67, wherein the parent COX-2 inhibitor and the compound that donates, transfers, or releases nitric oxide, or induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase are in the form of a composition in the kit.
RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Application No. 60/171,623 filed Dec. 23, 1999 and U.S. Provisional Application No. 60/226,085 filed Aug. 18, 2000.
Provisional Applications (2)
|
Number |
Date |
Country |
|
60226085 |
Aug 2000 |
US |
|
60171623 |
Dec 1999 |
US |
Patent Application
20010041726
