Claims
- 1. A proton pump inhibitor compound comprising at least one NO group, at least one NO2 group, or at least one NO and NO2 group, or a pharmaceutically acceptable salt thereof, wherein the at least one NO group, the at least one NO2 group, or the at least one NO and NO2 group is linked to the proton pump inhibitor compound through an oxygen atom, a nitrogen atom or a sulfur atom.
- 2. The proton pump inhibitor compound of claim 1, wherein the compound comprising at least one NO group, at least one NO2 group, or at least one NO and NO2 group is a compound of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI) or formula (VII), or a pharmaceutically acceptable salt thereof:
wherein the compound of formula (I) is: 21wherein A is S, S(O), or S(O)2; B is —CNR7R7′ or nitrogen; J is CH or nitrogen; R1 is a hydrogen, an alkoxy group, a lower alkyl group, or an alkylthio group; R2 is a hydrogen, an alkoxy group, a lower alkyl group, an alkylthio group, a haloalkoxy group, an alkoxyalkyl group, —NR7R7′, —OD1, or —SD1; or R2 and R1 taken together with the carbon chain to which they are attached form a cycloalkyl ring or a heterocyclic ring; or R2 and R3 taken together with the carbon chain to which they are attached form a cycloalkyl ring or a heterocyclic ring; R3 and R11 are each independently a hydrogen, an alkoxy group, a lower alkyl group, or an alkylthio group; or R3 and R11 taken together with the carbon chain to which they are attached form a cycloalkyl ring or a heterocyclic ring; R4 and R5 are each independently a hydrogen, an alkyl group, a halo group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cyano group, an aryl group, a heterocyclic ring, —NR7R7′, —OD1, or —CO2R12; or R4 and R5 taken together are: 22wherein R6 is oxygen or N═O—R7; R7 and R7′ are each independently hydrogen, a lower alkyl group or D; or R7 and R7′ taken together with the nitrogen to which they are attached form a heterocyclic ring; R10 is a hydrogen; or R10 and R1 taken together with the carbon chain to which they are attached form a cycloalkyl ring; R12 is a lower alkyl group or D; D1 is a hydrogen or D; D is Q or K; Q is —NO or —NO2; K is —Wa-Eb-(C(Re)(Rf))p-Ec-(C(Re)(Rf))y—Wd—(C(Re)(Rf))y—Wi-Ej-Wg—(C(Re)(Rf))z-T-Q; a, 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 —C(O)—, —C(S)—, -T-, —(C(Re)(Rf))h—, an alkyl group, an aryl group, a heterocyclic ring, an arylheterocyclic ring, or —(CH2CH2O)q—; E at each occurrence is independently -T-, an alkyl group, an aryl group, —(C(Re)(Rf))h—, a heterocyclic ring, 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, an alkylaryl, 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 cycloalkylthio, a cycloalkenyl, a cyano, an aminoalkyl, an aminoaryl, an aryl, an arylalkyl, an alkylaryl, a carboxamido, a alkylcarboxamido, an arylcarboxarnido, 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, a sulfonic ester, a urea, a phosphoryl, a nitro, -T-Q , or (C(Re)(Rf))k-T-Q, or Re and Rf taken together with the carbon atoms to which they are attached form a carbonyl, a methanthial, a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group; k is an integer from 1 to 3; T at each occurrence 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 alkylaryl, an alkylsulfinyl, an alkylsulfonyl, an arylsulfinyl, an arylsulfonyl, a sulfonamido, a carboxamido, a carboxylic ester, an amino alkyl, an amino aryl, —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+, or Re or Rf are T-Q or (C(Re)(Rf))k-T-Q, then the “-T-Q” subgroup can be a hydrogen, an alkyl, an alkoxy, an alkoxyalkyl, an aminoalkyl, a hydroxy, a heterocyclic ring or an aryl group; and with the proviso that the compound of formula (I) must contain at least one nitrite, nitrate, thionitrite or thionitrate group; wherein the compound of formula (II) is: 23wherein R8 is a lower alkyl group, an alkoxyalkyl group, an alkylaryl group, a cycloalkyl group, a cycloalkylalkyl group, an aryl group, an alkylaryl group, or K; R9 at each occurrence is independently a hydrogen, a lower alkyl group, an akylthio group, a halogen, a cyano group an alkanoyl group, a haloalkyl group, a carbamoyl group, —NR7D1, —OD1, or —CO2R12; R71 is a hydrogen, a lower alkyl group, an alkoxy group, or —OD1; J, K, D1, R7, R12, q and o are as defined herein; and with the proviso that the compound of formula (II) must contain at least one nitrite, nitrate, thionitrite or thionitrate group; wherein the compound of formula (III) is: wherein 24R13 and R14 are each independently a hydrogen a lower alkyl group, an alkoxyalkyl, or a lower alkyl-OD1; or R13 and R14 taken together along with the carbon atoms to which they are attached form a cycloalkyl group or an aryl group; R17 is a hydrogen or a lower alkyl group; Y3 is: 25wherein R15 is a hydrogen or a lower alkyl group; R16 is a hydrogen, a halogen, or a lower alkyl group; R63 is a lower alkyl group or a phenyl group; A1, A2 and A3 comprise the other subunits of a 5- or 6-membered monocyclic aromatic ring and A1, A2 and A3 are each independently:
(i) CRo, wherein Ro at each occurrence is hydrogen or —OD1; (ii) N—Rp, wherein Rp at each occurrence is independently a covalent bond to an adjacent ring atom in order to render the ring aromatic, a hydrogen, or K; (iii) a sulfur atom; (iv) an oxygen atom; or (v) Ba=Bb, wherein Ba and Bb are each independently a nitrogen atom or CRo;
wherein Ro at each occurrence is hydrogen or —OD1; D1 and K are as defined herein; and with the proviso that the compound of formula (III) must contain at least one nitrite, nitrate, thionitrite or thionitrate group; wherein the compound of formula (IV) is: 26wherein R18 and R19 at each occurrence are each independently a hydrogen, a lower alkyl group, a halogen, a nitro group, an alkoxy group, —OD1, —NR20R21, —O(O)CR20, —O(O)COR20, —O(O)CNR20R21, —N(R20)C(O)R21, —N(R20)C(O)NR20R21, or —N(R20)C(O)OR21; or R18 and R19 when taken together along with the carbon atoms to which they are attached form a heterocyclic ring or a phenyl ring optionally substituted with up to four substituents selected from a hydrogen, a lower alkyl group, a halogen, a nitro group, an alkoxy group, —OD1, —NR20R21, —O(O)CR20, —O(O)COR20, —O(O)CNR20R21, —N(R20)C(O)R21, —N(R20)C(O)NR20R21, or —N(R20)C(O)OR21; R20 and R21 at each occurrence are each independently a hydrogen, a lower alkyl group, an aryl group, a lower alkylaryl group, or K; X4 is —C(═R)R22, a heterocyclic ring, —NR20R21, a halogen, an alkoxy group, an arylalkoxy group, a cycloalkoxy group, a heterocyclicalkoxy group, an alkylsulfonyl group, an alkylsulfinyl group, an arylsulfonyl group, an arylsulfinyl group an arylalkylsulfonyl group, an arylalkylsulfinyl group, a heterocyclicsulfonyl group, or a heterocyclicsulfinyl group; R22 is a hydrogen, an alkyl group, an alkoxy group, an aryl group, an alkylaryl group, a heterocyclic ring, an —O-heterocyclic ring, or an alkylheterocyclic ring; D1, R6, and K are defined as herein; and with the proviso that the compound of formula (IV must contain at least one nitrite, nitrate, thionitrite or thionitrate group; wherein the compound of formula (V) is: 27wherein X5 is: 28R23 is a hydrogen, a dialkylamino group, —NR7R7′, or a heterocyclic ring; R24 is a hydrogen or halogen; R25 is a hydrogen, —OD1, or lower alkyl-OD1; R27 at each occurrence is independently a hydrogen or an alkoxy group; R28, R29, and R30 are each independently a hydrogen, a lower alkyl group, a dialkylamino group, a heterocyclic ring, or a lower alkyl-OD1; R31 is a hydrogen, a dialkylamino group, or an alkoxy group; R33 is a hydrogen or a lower alkyl group; n is an integer from 0 to 1; R7, R7′, D1 and q are as defined herein; and with the proviso that the compound of formula (V) must contain at least one nitrite, nitrate, thionitrite or thionitrate group; wherein the compound of formula (VI) is: 29wherein A4, A5, and A6 are each independently a sulfur or CR34 with the proviso that one of A4, A5, or A6 is a sulfur and the other two are CR34; R34 at each occurrence is independently a hydrogen, a halogen, a cyano, a nitro, a trifluoromethyl, a lower alkyl group, a heterocyclic ring, a lower alkyl-OD1, an alkoxy, a haloalkoxy, an alkylthio, an alkylsulfinyl, an alkylsulfonyl, an alkylcarbonyl, an alkoxycarbonyl, a carbamoyl, a N-alkylcarbamoyl, a N,N-di-alkylcarbamoyl, an ester, a cycloalkyl, an aryl, an alkylaryl, an aryloxy, an arylalkoxyoxy, an arylamino, a alkylarylamino, an arylthio, an arylsulfonyl, an arylsulfinyl, or a sulfonamido; R35 and R36 are each independently a hydrogen or a lower alkyl group; or R35 and R41 taken together with the carbon chain to which they are attached form a cycloalkyl ring; R26 is: 30wherein X6 is nitrogen, and Y6 is CR37; or X6 is CR37, and Y6 is nitrogen; R37 is a hydrogen, a halogen, a lower alkyl group, a trifluoromethyl, an alkoxy group, a haloalkoxy group, an aryl group, an arylalkoxy group, a heterocyclic ring, or an aryloxy; Z6 is —NR38R39, SR40, or an arylalkoxy group; R38 and R39 are each independently a hydrogen, a lower alkyl group, an aryl group, an alkylaryl group, or a cycloalkyl group; or R38 and R39 taken together with the nitrogen to which they are attached form a heterocyclic ring; R40 is a hydrogen, a halogen, a lower alkyl group, an alkylaryl group, an alkenyl group, or a haloalkyl group; R41, R42, R43, and R44 are each independently a hydrogen, a halogen, a lower alkyl group, an alkoxy group, a haloalkoxy group, an alkoxyaryl group, an alkylthio group, an alkysulfinyl group, an alkylsulfonyl group, a cyano group, —Y—OD1, —Y—SD1, —Y—NR20R21, —Y—O(O)CR20, —Y—O(O)CNR20R21, —Y—N(R20)C(O)R21, or —Y—N(R20)S(O)2R21; Y is —(CH2)a— or a phenyl group; R45 and R46 are each independently a hydrogen, a lower alkyl group, a cycloalkyl group, an alkenyl group, or an alkynyl group; D1, R20, R21, and a are as defined herein; and with the proviso that the compound of formula (VI) must contain at least one nitrite, nitrate, thionitrite or thionitrate group; wherein the compound of formula (VII) is: 31wherein R60 is a lower alkyl group, an aryl group, a haloalkyl group, a lower alkyl-OD1, or heterocyclic ring; A7 is oxygen or —ND1; X7 is a hydrogen or a halogen; Y7 is: 32or X7, A7, and Y7 taken together along with the carbon atoms to which they are attached is: 33wherein R61 is a hydrogen, a halogen, a lower alkyl group, —OD1, or —NHC(O)O-lower alkyl; R62 is a hydrogen, a halogen, or a lower alkyl group; D1 is as defined herein; and with the proviso that the compound of formula (VII) must contain at least one nitrite, nitrate, thionitrite or thionitrate group.
- 3. The compound of claim 2, wherein the compound of Formula (I) is a nitrosated benzimidazole, a nitrosylated benzimidazole, a nitrosated and nitrosylated benzimidazole, the compound of Formula (II) is a nitrosated quinoline, a nitrosylated quinoline, a nitrosated and nitrosylated quinoline, the compound of Formula (III) is a nitrosated pyrimidine, a nitrosylated pyrimidine, a nitrosated and nitrosylated pyrimidine, the compound of Formula (IV) is a nitrosated thiadiazole, a nitrosylated thiadiazole, a nitrosated and nitrosylated thiadiazole, the compound of Formula (V) is a nitrosated sulfinylnicotinamide, a nitrosylated sulfinylnicotinamide, a nitrosated and nitrosylated sulfinylnicotinamide, the compound of Formula (VI) is a nitrosated thienoimidazole, a nitrosylated thienoimidazole, a nitrosated and nitrosylated thienoimidazole, the compound of Formula (VII) is a nitrosated imidazopyridine, a nitrosylated imidazopyridine, or a nitrosated and nitrosylated imidazopyridine.
- 4. The compound of claim 3, wherein the benzimidazole is omeprazole, lansoprazole, pantoprazole, rabeprazole, leminoprazole, timoprazole, tenatoprazole, disulprazole, esomeprazole, 2-(2-benzimidazolyl)-pyridine, a tricyclic imidazole, a thienopydidine benzimidazole, a fluoroalkoxy substituted benzimidazole, a dialkoxy benzimidazole, a N-substituted 2-(pyridylalkenesulfinyl) benzimidazole, a cycloheptenepyridine, a 5-pyrrolyl-2-pyridylmethylsulfinyl benzimidazole, a alkylsulfinyl benzimidazole, a fluoro-pyridylmethylsulfinyl benzimidazole, an imidazo[4,5-b]pydridine, RO 18-5362 or IY 81149; wherein the quinoline is a 4-amino-3—carbonyl quinoline, a 4-amino-3-acylnaphthyride, a 4-aminoquinoline, a 4-amino-3-acylquinoline or a 3-butyryl-4-(2-methylphenylamino)-8-(2-hydroxyethoxy)quinoline; wherein the pyrimidine is a quinazoline, a tetrahydroisoquinolin-2-yl pyrimidine or YH 1885; wherein the thiadiazole is 3-substituted 1,2,4-thiadiazolo[4,5-a]benzimidazole or a 3-substituted imidazo[1,2-d]-thiadiazole; wherein the sulfinylnicotinamide is a 2-sulfinylnicotinamide; wherein the thienoimidazole is a pyridylsulfinylbenz imidazole, a pyridylsulfinyl thieno imidazole, a theinoimidazole-toluidine, a 4,5-dihydrooxazole, a thienoimidazole-toluidine or Hoe-73 1; wherein the imidazopyridine is a imidazo[1,2-a]pyridine, a pyrrolo[2,3-b]pyridine or a pharmaceutically acceptable salt thereof.
- 5. A composition comprising the compound of claim 2 and a pharmaceutically acceptable carrier.
- 6. The composition of claim 5, further comprising at least one of a nonsteroidal antiinflammatory drug, a selective COX-2 inhibitor, an antacid, a bismuth-containing reagent, and an acid-degradable antibacterial compound.
- 7. A method for treating a gastrointestinal disorder, facilitating ulcer healing, or decreasing the recurrence of an ulcer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 5.
- 8. The method of claim 7, further comprising administering to the patient a therapeutically effective amount of an antacid.
- 9. The method of claim 7, wherein the gastrointestinal disorder is an inflammatory bowel disease, Crohn's disease, irritable bowel syndrome, ulcerative colitis, a peptic ulcer, a stress ulcers, a bleeding peptic ulcer, a duodenal ulcer, infectious enteritis, colitis, diverticulitis, gastric hyperacidity, dyspepsia, gastroparesis, Zollinger-Ellison syndrome, gastroesophageal reflux disease, Helicobacter Pylori associated disease, short-bowel syndrome, or a hypersecretory state associated with systemic mastocytosis or basophilic leukemia and hyperhistaminemia.
- 10. A method for improving the gastroprotective properties, the anti-Helicobacter pylori properties, or the antacid properties of a proton pump inhibitor comprising administering to a patient in need thereof a therapeutically effective amount of the composition of claim 5.
- 11. The method of claim 10, further comprising administering to the patient a therapeutically effective amount of a bismuth-containing reagent.
- 12. A method for decreasing or reversing gastrointestinal toxicity or facilitating ulcer healing resulting from administration of a nonsteroidal antiinflammatory drug and/or a selective COX-2 inhibitor to a patient comprising administering to a patient in need thereof a therapeutically effective amount of at least one composition of claim 5, and, optionally, at least one nonsteroidal antiinflammatory drug and/or selective COX-2 inhibitor.
- 13. The method of claim 12, wherein the least one composition and the at least one nonsteroidal antiinflammatory drug and/or selective COX-2 inhibitor are administered together in the form of a composition
- 14. The method of claim 12, wherein the least one composition and the at least one nonsteroidal antiinflammatory drug and/or selective COX-2 inhibitor are administered separately.
- 15. A method for treating Helicobacter pylori comprising administering to a patient in need thereof a therapeutically effective amount of at least one acid degradable antibacterial compound and at least one composition of claim 5.
- 16. A method for treating a viral infection comprising administering to a patient in need thereof a therapeutically effective amount of the composition of claim 5.
- 17. The method of claim 16, wherein the viral infection is orthomyxoviridae, paramyxoviridae, picornaviridae, rhabdoviridae, coronavaridae, togaviridae, bunyaviridae, arenaviridae, reteroviridae, adenoviridae, proxviridae, papovaviridae, herpetoviridae, herpesviridae, herpes simplex viruses, cytomegalovirus, herpes varicella-zoster, Epstein-Barr, HHV6, HHV7, pseudorabies or rhinotracheitis.
- 18. The method of claim 7, 10, 12, 15 or 16, wherein the composition is administered orally, bucally, topically, by injection, by inhalation, or by transdermal application.
- 19. The method of claim 18, wherein the composition is administered orally in a solid dosage form or a liquid dosage form.
- 20. The method of claim 19, wherein the solid dosage form is a capsule, a tablet, an effervescent tablet, a chewable tablet, a pill, a powder, a sachet, a granule or a gel.
- 21. The method of claim 19, wherein the liquid dosage form is an emulsion, a solution, a suspension, a syrup, or an elixir.
- 22. A composition comprising at least one compound of claim 2 or a pharmaceutically acceptable salt thereof, and at least one compound that donates, transfers, or releases nitric oxide, induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase.
- 23. The composition of claim 22, further comprising a pharmaceutically acceptable carrier.
- 24. The composition of claim 22, wherein the compound that donates, transfers, or releases nitric oxide, induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase is an S-nitrosothiol.
- 25. The composition of claim 24, wherein the S-nitrosothiol is S-nitroso-N-acetylcysteine, S-nitroso-captopril, S-nitroso-N-acetylpenicillamine, S-nitroso-homocysteine, S-nitroso-cysteine or S-nitroso-glutathione.
- 26. The composition of claim 22, wherein the S-nitrosothiol is:
(i) HS(C(Re)(Rf))mSNO; (ii) ONS(C(Re)(Rf))mRe; and (iii) H2N—CH(CO2H)—(CH2)m—C(O)NH—CH(CH2SNO)—C(O)NH—CH2—CO2H; wherein m 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, an alkylaryl, 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 cycloalkylthio, a cycloalkenyl, a cyano, an aminoalkyl, an aminoaryl, an aryl, an arylalkyl, an alkylaryl, 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, a sulfonic ester, a urea, a phosphoryl, a nitro, -T-Q, or (C(Re)(Rf))k-T-Q, or Re and Rf taken together with the carbon atoms to which they are attached form a carbonyl, 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; Ri is a hydrogen, an alkyl, an aryl, an alkylcarboxylic acid, an aryl carboxylic acid, an alkylcarboxylic ester, an arylcarboxylic ester, an alkylcarboxamido, an arylcarboxamido, an alkylaryl, an alkylsulfinyl, an alkylsulfonyl, an arylsulfinyl, an arylsulfonyl, a sulfonamido, a carboxamido, a carboxylic ester, an amino alkyl, an amino aryl, —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.
- 27. The composition of claim 22, wherein the compound that donates, transfers, or releases nitric oxide, induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide 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, omithine, glutamine, lysine, polypeptides comprising at least one of these amino acids or an inhibitor of the enzyme arginase.
- 28. The composition of claim 22, wherein the compound that donates, transfers, or releases nitric oxide, induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide 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 O2N—O—, O2N—N—, O2N—S— or —O2N—C— group; (iii) a N-oxo-N-nitrosoamine having the formula: R1R2N—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.
- 29. The composition of claim 28, 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.
- 30. The composition of claim 28, wherein compound comprising at least one O2N—O—, O2N—N—, O2N—S— or O2N—C— group is an O2N—O-polypeptide, an O2N—N-polypeptide, an O2N—S-polypeptide, an O2N—C-polypeptide, an O2N—O-amino acid, O2N—N-amino acid, O2N—S-amino acid, an O2N—C-amino acid, an O2N—O-sugar, an O2N—N-sugar, O2N—S-sugar, an O2N—C-sugar, an O2N—O-oligonucleotide, an O2N—N-oligonucleotide, an O2N—S-oligonucleotide, an O2N—C-oligonucleotide, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O2N—O-hydrocarbon, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O2N—N-hydrocarbon, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O2N—S-hydrocarbon, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O2N—C-hydrocarbon, an O2N—O-heterocyclic compound, an O2N—N-heterocyclic compound, an O2N—S-heterocyclic compound or an O2N—C-heterocyclic compound.
- 31. The composition of claim 30, wherein the compound comprising at least one O2N—O—, O2N—N—, O2N—S— or O2N—C— group is isosorbide dinitrate, isosorbide mononitrate, clonitrate, erythrityltetranitrate, mannitol hexanitrate, nitroglycerin, pentaerythritoltetranitrate, pentrinitrol and propatylnitrate.
- 32. The composition of claim 22, further comprising at least one of a nonsteroidal antiinflammatory drug, a selective COX-2 inhibitor, an antacid, a bismuth-containing reagent, and an acid-degradable antibacterial compound.
- 33. A method for treating or preventing a gastrointestinal disorder, facilitating ulcer healing, or decreasing the recurrence of an ulcer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 22.
- 34. The method of claim 33, further comprising administering to the patient a therapeutically effective amount of an antacid.
- 35. The method of claim 33, wherein the gastrointestinal disorder is an inflammatory bowel disease, Crohn's disease, irritable bowel syndrome, ulcerative colitis, a peptic ulcer, a stress ulcers, a bleeding peptic ulcer, a duodenal ulcer, infectious enteritis, colitis, diverticulitis, gastric hyperacidity, dyspepsia, gastroparesis, Zollinger-Ellison syndrome, gastroesophageal reflux disease, Helicobacter Pylori associated disease, short-bowel syndrome, or a hypersecretory state associated with systemic mastocytosis or basophilic leukemia and hyperhistaminermia.
- 36. A method for improving the gastroprotective properties, the anti-Helicobacter pylori properties, or the antacid properties of a proton pump inhibitor comprising administering to a patient in need thereof a therapeutically effective amount of the composition of claim 22.
- 37. The method of claim 36, further comprising administering to the patient a therapeutically effective amount of a bismuth-containing reagent.
- 38. A method for decreasing or reversing gastrointestinal toxicity or facilitating ulcer healing resulting from administration of a nonsteroidal antiinflammatory drug and/or a selective COX-2 inhibitor to a patient comprising administering to a patient in need thereof a therapeutically effective amount of at least one composition of claim 22, and, optionally, at least one nonsteroidal antiinflammatory drug and/or selective COX-2 inhibitor.
- 39. The method of claim 38, wherein the at least one composition and the at least one nonsteroidal antiinflammatory drug and/or selective COX-2 inhibitor are administered together in the form of a composition.
- 40. The method of claim 38, wherein the at least one composition and the at least one nonsteroidal antiinflammatory drug and/or selective COX-2 inhibitor are administered separately.
- 41. A method for treating Helicobacter pylori comprising administering to a patient in need thereof a therapeutically effective amount of at least one acid degradable antibacterial compound and at least one composition of claim 22.
- 42. A method for treating a viral infection comprising administering to a patient in need thereof a therapeutically effective amount of the composition of claim 22.
- 43. The method of claim 42, wherein the viral infection is orthomyxoviridae, paramyxoviridae, picornaviridae, rhabdoviridae, coronavaridae, togaviridae, bunyaviridae, arenaviridae, reteroviridae, adenoviridae, proxviridae, papovaviridae, herpetoviridae, herpesviridae, herpes simplex viruses, cytomegalovirus, herpes varicella-zoster, Epstein-Barr, HHV6, HHV7, pseudorabies or rhinotracheitis.
- 44. The method of claim 33, 36, 38, 41 or 42, wherein the composition is administered orally, bucally, topically, by injection, by inhalation, or by transdermal application.
- 45. The method of claim 44, wherein the composition is administered orally in a solid dosage form or a liquid dosage form.
- 46. The method of claim 45, wherein the solid dosage form is a capsule, a tablet, an effervescent tablet, a chewable tablet, a pill, a powder, a sachet, a granule or a gel.
- 47. The method of claim 45, wherein the liquid dosage form is an emulsion, a solution, a suspension, a syrup, or an elixir.
- 48. A method for treating a gastrointestinal disorder, facilitating ulcer healing, or decreasing the recurrence of an ulcer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 5 or a pharmaceutically acceptable salt thereof, and at least one compound that donates, transfers, or releases nitric oxide, induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase.
- 49. The method of claim 48, further comprising administering at least one antacid.
- 50. The method of claim 48, wherein the gastrointestinal disorder is an inflammatory bowel disease, Crohn's disease, irritable bowel syndrome, ulcerative colitis, a peptic ulcer, a stress ulcers, a bleeding peptic ulcer, a duodenal ulcer, infectious enteritis, colitis, diverticulitis, gastric hyperacidity, dyspepsia, gastroparesis, Zollinger-Ellison syndrome, gastroesophageal reflux disease, Helicobacter Pylori associated disease, short-bowel syndrome, or a hypersecretory state associated with systemic mastocytosis or basophilic leukemia and hyperhistaminemia.
- 51. A method for improving the gastroprotective properties, the anti-Helicobacter properties or the antacid properties of a proton pump inhibitor compound comprising administering to a patient in need thereof a therapeutically effective amount of a bismuth complex comprising at least one composition of claim 22.
- 52. A method for decreasing or reversing gastrointestinal toxicity or facilitating ulcer healing resulting from administration of a nonsteroidal antiinflammatory drug and/or a selective COX-2 inhibitor to a patient comprising administering to a patient in need thereof a therapeutically effective amount of at least one composition of claim 5, and at least one compound that donates, transfers, or releases nitric oxide, induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase, and, optionally, at least one nonsteroidal antiinflammatory drug and/or selective COX-2 inhibitor.
- 53. A method for treating Helicobacter pylori comprising administering to a patient in need thereof a therapeutically effective amount of at least one acid degradable antibacterial compound, at least one composition of claim 5 or a pharmaceutically acceptable salt thereof, and at least one compound that donates, transfers, or releases nitric oxide, induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase.
- 54. A method for treating a viral infection comprising administering to a patient in need thereof a therapeutically effective amount of at least one composition of claim 5 and at least one compound that donates, transfers, or releases nitric oxide, induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase.
- 55. The method of claim 54, wherein the viral infection is orthomyxoviridae, paramyxoviridae, picomaviridae, rhabdoviridae, coronavaridae, togaviridae, bunyaviridae, arenaviridae, reteroviridae, adenoviridae, proxviridae, papovaviridae, herpetoviridae, herpesviridae, herpes simplex viruses, cytomegalovirus, herpes varicella-zoster, Epstein-Barr, HHV6, HHV7, pseudorabies or rhinotracheitis.
- 56. A kit comprising at least one compound of claim 2 or a pharmaceutically acceptable salt thereof, and at least one compound that donates, transfers, or releases nitric oxide, induces the production of endogenous nitric oxide or endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase.
- 57. The kit of claim 56, wherein the compound of claim 2 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, stimulates endogenous synthesis of nitric oxide 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.
- 58. The kit of claim 56, further comprising at least one of a nonsteroidal antiinflammatory drug, a selective COX-2 inhibitor, an antacid, a bismuth-containing reagent and an acid-degradable antibacterial compound.
- 59. A compound selected from the group consisting of {2-[(2-pyridylmethyl)sulfinyl]benzimidazolyl}methyl-3-{N-[2-methyl-2-(nitrosothio)-propyl]-N-benzylcarbamoyl}propanoate, {2-({[3-methyl-4-(2,2,2-trifluoroethyl)-2-pyridyl]methyl}sulfinyl)benzimidazolyl]-methyl-3-{N-[2-methyl-2-(nitrosothio)-propyl]-N-benzylcarbamoyl}propanoate, or 2-[2-(nitrosothio)adamantan-2-yl]ethyl 2-({[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl]methyl}sulfinyl)benzimidazolecarboxylate
RELATED APPLICATIONS
[0001] This application is a divisional under 35 USC § 121 of U.S. application Ser. No. 09/512,829, filed Feb. 25, 2000, pending, that claims priority under 35 USC § 119 to U.S. Provisional Application No. 60/122,111 filed Feb. 26, 1999.
Provisional Applications (1)
|
Number |
Date |
Country |
|
60122111 |
Feb 1999 |
US |
Divisions (1)
|
Number |
Date |
Country |
| Parent |
09512829 |
Feb 2000 |
US |
| Child |
10866303 |
Jun 2004 |
US |
Patent Application
20040266828
