Methods using proton pump inhibitors and nitric oxide donors

6,852,739

09/512829

February 25, 2000

The present invention describes novel nitrosated and/or nitrosylated proton pump inhibitor compounds, and novel compositions comprising at least one proton pump inhibitor compound that is optionally substituted with at least one NO and/or N02 group, and, optionally, at least one compound that donates, transfers or releases nitric oxide, stimulates endogenous synthesis of nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor or is a substrate for nitric oxide synthase, and/or at least one nonsteroidal antiinflammatory drug, selective COX-2 inhibitor, antacid, bismuth-containing reagent, acid-degradable antibacterial compound, and mixtures thereof. The present invention also provides methods for treating and/or preventing gastrointestinal disorders; facilitating ulcer healing; decreasing the recurrence of ulcers; improving gastroprotective properties, anti-Helicobacter pylori properties or antacid properties of proton pump-inhibitors; decreasing or reducing the gastrointestinal toxicity associated with the use of nonsteroidal antiinflammatory compounds; treating Helicobacter pylori and viral infections. The compounds and/or compositions of the present invention can also be provided in the form of a pharmaceutical kit.

Garvey, David S. (Dover, MA, US); Letts, L. Gordon (Dover, MA, US); Tam, Sang William (Dover, MA, US)

Nitromed Inc. (Lexington, MA, US)

1. A method for treating Crohn's disease, ulcerative colitis, a peptic ulcer, a stress ulcer, a bleeding peptic ulcer, a duodenal ulcer, infectious enteritis, colitis, diverticulitis, gastric hyperacidity, dyspepsia, gastroparesis, Zollinger-Ellison syndrome, gastroesophageal reflux disease, a Helicobacter Pylori associated disease, short-bowel syndrome, or a hypersecretory state associated with systemic mastocytosis or basophilic leukemia and hyperhistaminemia; for facilitating ulcer healing, or for decreasing the recurrence of an ulcer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of at least one proton pump inhibitor 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.

2. 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 proton pump inhibitor compound, 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, wherein 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 and the at least one nonsteroidal antiinflammatory drug and/or selective COX-2 inhibitor are at least two different compounds.

3. A method for treating an infection caused by 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 proton pump inhibitor compound 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.

4. A method for treating Crohn's disease, ulcerative colitis, a stress ulcer, infectious enteritis, colitis, diverticulitis, gastric hyperacidity, gastroparesis, Zollinger-Ellison syndrome, gastroesophageal reflux disease, a Helicobacter Pylori associated disease, short-bowel syndrome, or a hypersecretory state associated with systemic mastocytosis or basophilic leukemia and hyperhistaminemia in a patient in need thereof comprising administering to the patient a therapeutically effective amount of at least one proton pump inhibitor 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.

5. The method of claim 1 , further comprising administering at least one antacid.

6. The method of claim 1 , 2 , 3 , or 4 , wherein the at least one proton pump inhibitor compound is a substituted benzimidazole, a substituted quinoline, a substituted pyrimidine, a substituted thiadiazole, a substituted sulfinylnicotinamide, a substituted thienoimidazole, or a substituted imidazopyridine.

7. The method of claim 6 , wherein the substituted 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)pyridine, RO 18-5362 or IY 81149; wherein the substituted 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 substituted pyrimidine is a substituted quinazoline, a tetrahydroisoquinolin-2-yl pyrimidine or YH 1885; wherein the substituted thiadiazole is 3-substituted 1,2,4-thiadiazolo(4,5-a) benzimidazole or a 3-substituted imidazo(1,2-d)-thiadiazole; wherein the substituted sulfinylnicotinamide is a 2-sulfinylnicotinamide; wherein the substituted thienoimidazole is a pyridylsulfinylbenzimidazole, a pyridylsulfinyl thieno imidazole, a theinoimidazole-toluidine, a 4,5-dihydrooxazole, a thienoimidazole-toluidine or Hoe-731; wherein the substituted imidazopyridine is a imidazo(1,2-a)pyridine, a pyrrolo(2,3-b)pyridine or a pharmaceutically acceptable salt thereof.

8. The method of claim 7 , further comprising administering a pharmaceutically acceptable carrier.

9. The method of claim 1 , 2 , 3 , or 4 , 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.

10. The method of claim 9 , wherein the S-nitrosothiol is S-nitroso-N-acetylcysteine, S-nitroso-captopril, S-nitroso-N-acetylpenicillanine, S-nitroso-homocysteine, S-nitroso-cysteine or S-nitroso-glutathione.

11. The method of claim 9 , wherein the S-nitrosothiol is: (i) HS(C(R e)(R f)) m SNO; (ii) ONS(C(R e)(R f)) m R e ; or (iii) H 2 N—CH(CO 2 H)—(CH 2) m —C(O)NH—CH(CH 2 SNO)—C(O)NH—CH 2 —CO 2 H; wherein m is an integer from 2 to 20; R e and R f 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(R e)(R f)) k —T—Q, or R e and R f taken together with the carbons 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 —NO 2 ; and T is independently a covalent bond, a carbonyl, an oxygen, —S(O) o — or —N(R a)R i —, wherein o is an integer from 0 to 2, R a is a lone pair of electrons, a hydrogen or an alkyl group; R i 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, —CH 2 C(T—Q)(R e)(R f), or —(N 2 O 2 —) − .M + , wherein M + is an organic or inorganic cation; with the proviso that when R i is —CH 2 —C(T—Q)(R e)(R f) or —(N 2 O 2 —).M + ; then “—T—Q” can be a hydrogen, an alkyl group, an alkoxyalkyl group, an aminoalkyl group, a hydroxy group or an aryl group.

12. The method of claim 1 , 2 , 3 or 4 , wherein the at least one proton pump inhibitor compound or the 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 administered separately.

13. The method of claim 1 , 2 , 3 or 4 , wherein the at least one proton pump inhibitor compound or the 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 administered together in the form of a composition.

14. The method of claim 1 , 2 , 3 or 4 , wherein the at least one proton pump inhibitor compound 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 administered orally, bucally topically, by injection, by inhalation, or by transdermal application.

15. The method of claim 14 , wherein the at least one proton pump inhibitor compound 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 administered orally in a solid dosage form or a liquid dosage form.

16. The method of claim 15 , 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.

17. The method of claim 15 , wherein the liquid dosage form is an emulsion, a solution, a suspension, a syrup, or an elixir.

18. 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 in a patient in need thereof comprising administering a therapeutically effective amount of at least one proton pump inhibitor compound and at least one S-nitrosothiol.

19. The method of claim 18 , further comprising administering a therapeutically effective amount of at least one nonsteroidal antiinflammatory drug and/or selective COX-2 inhibitor.

20. A method for treating an ulcer in a patient in need thereof comprising administering a therapeutically effective amount of at least one proton pump inhibitor and at least one S-nitrosothiol.

21. The method of claim 20 , wherein the ulcer is a peptic ulcer, a stress ulcer, a bleeding peptic ulcer, a duodenal ulcer, or gastritis.

22. A method for treating Crohn's disease, ulcerative colitis, a peptic ulcer, a stress ulcer, a bleeding peptic ulcer, a duodenal ulcer, infectious enteritis, colitis, diverticulitis, gastric hyperacidity, dyspepsia, gastroparesis, Zollinger-Ellison syndrome, gastroesophageal reflux disease, a Helicobacter Pylori associated disease, short-bowel syndrome, or a hypersecretory state associated with systemic mastocytosis or basophilic leukemia and hyperhistaminemia; for facilitating ulcer healing, or for decreasing the recurrence of an ulcer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of at least one proton pump inhibitor or a pharmaceutically acceptable salt thereof, and at least one S-nitrosothiol.

23. The method of claim 18 , 20 or 22 , 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.

24. The method of claim 18 , 20 or 22 , wherein the S-nitrosothiol is: (i) HS(C(R e)(R f)) m SNO; (ii) ONS(C(R e)(R f)) m R e ; or (iii) H 2 N—CH(CO 2 H)—(CH 2) m —C(O)NH—CH(CH 2 SNO)—C(O)NH—CH 2 —CO 2 H; wherein m is an integer from 2 to 20; R e and R r 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(R e)(R f)) k —T—Q, or R e and R f taken together with the carbons 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 —NO 2 ; and T is independently a covalent bond, a carbonyl, an oxygen, —S(O) o — or —N(R o)R i —, wherein o is an integer from 0 to 2, R a is a lone pair of electrons, a hydrogen or an alkyl group; R i 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, —CH 2 —C(T—Q)(R e)(R f), or —(N 2 O 2 —) − .M + , wherein M + is an organic or inorganic cation; with the proviso that when R i is —CH 2 —C(T—Q)(R e)(R f) or —(N 2 O 2 —) − .M + ; then “—T—Q” can be a hydrogen, an alkyl group, an alkoxyalkyl group, an aminoalkyl group, a hydroxy group or an aryl group.

25. The method of claim 18 , 20 or 22 , wherein the at least one proton pump inhibitor compound is a substituted benzimidazole, a substituted quinoline, a substituted pyrimidine, a substituted thiadiazole, a substituted sulfinylnicotinamide, a substituted thienoimidazole, or a substituted imidazopyridine.

26. The method of claim 25 , wherein the substituted benzimidazole is omeprazole, lansoprazole, pantoprazole, rabeprazole, leminoprazole, timoprazole, tenatoprazole, disulprazole, esomeprazole, 2-(2-benzimidazolylipyridine, 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 substituted 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 substituted pyrimidine is a substituted quinazoline, a tetrahydroisoquinolin-2-yl pyrimidine or YH 1885; wherein the substituted thiadiazole is 3-substituted 1,2,4-thiadiazolo(4,5-a) benzimidazole or a 3-substituted imidazo(1,2-d)thiadiazole; wherein the substituted sulfinylnicotinamide is a 2-sulfinylnicotinamide; wherein the substituted thienoimidazole is a pyridylsulfinylbenz imidazole, a pyridylsulfinyl thieno imidazole, a theinoimidazole-toluidine, a 4,5-dihydrooxazole, a thienoimidazole-toluidine or Hoe-731; wherein the substituted imidazopyridine is a imidazo(1,2-a)pyridine, a pyrrolo(2,3-b)pyridine or a pharmaceutically acceptable salt thereof.

27. The method of claim 18 , 20 or 22 , wherein the at least one proton pump inhibitor compound or the pharmaceutically acceptable salt thereof, and the at least one S-nitrosothiol are administered separately.

28. The method of claim 18 , 20 or 22 , wherein the at least one proton pump inhibitor compound or the pharmaceutically acceptable salt thereof, and the at least one S-nitrosothiol are administered together in the form of a composition.

29. The method of claim 18 , 20 or 22 , wherein the at least one proton pump inhibitor compound or a pharmaceutically acceptable salt thereof, and the at least one S-nitrosothiol are administered orally, bucally, topically, by injection, by inhalation, or by transdermal application.

30. The method of claim 18 , 20 or 22 , wherein the at least one proton pump inhibitor compound or a pharmaceutically acceptable salt thereof, and the at least S-nitrosothiol are administered orally in a solid dosage form or a liquid dosage form.

31. The method of claim 30 , 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.

32. The method of claim 30 , wherein the liquid dosage form is an emulsion, a solution, a suspension, a syrup, or an elixir.

514/338

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