Nitrosated and nitrosylated proton pump inhibitors, compositions and methods of use

1. A proton pump inhibitor compound of formula (I), or a pharmaceutically acceptable salt thereof, having at least one NO group, at least one NO 2 group, or at least one NO and NO 2 group; wherein the at least one NO group, the at least one NO 2 group, or the at least one NO and NO 2 group is linked to the proton pump inhibitor compound through an oxygen atom, a nitrogen atom or a sulfur atom:

wherein the compound of formula (I) is:

wherein

A is S, S(O), or S(O) 2 ;

B is —CNR 7 R 7 ′ or nitrogen;

J is CH or nitrogen;

R 1 is a hydrogen, an alkoxy group, a lower alkyl group, or an alkylthio group;

R 2 is a hydrogen, an alkoxy group, a lower alkyl group, an alkylthio group, a haloalkoxy group, an alkoxyalkyl group, —NR 7 R 7 ′, —OD 1 , or SD 1 ; or R 2 and R 1 taken together with the carbon chain to which they are attached form a cycloalkyl ring or a heterocyclic ring; or R 2 and R 3 taken together with the carbon chain to which they are attached form a cycloalkyl ring or a heterocyclic ring;

R 3 and R 11 are each independently a hydrogen, an alkoxy group, a lower alkyl group, or an alkylthio group; or R 3 and R 11 taken together with the carbon chain to which they are attached form a cycloalkyl ring or a heterocyclic ring;

R 4 and R 5 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, —NR 7 R 7 ′, —OD 1 , or —CO 2 R 12 ; or R 4 and R 5 taken together are:

wherein

R 6 is oxygen or N═O—R 7 ;

R 7 and R 7 ′ are each independently hydrogen, a lower alkyl group or D; or R 7 and R 7 ′ taken together with the nitrogen to which they are attached form a heterocyclic ring;

R 10 is a hydrogen; or R 10 and R 1 taken together with the carbon chain to which they are attached form a cycloalkyl ring;

R 12 is a lower alkyl group or D;

D 1 is a hydrogen or D;

D is Q or K;

Q is —NO or —NO 2 ;

K is —W a -E b —(C(R e )(R f )) p -E c —(C(R e )(R f )) x —W d —(C(R e )(R f )) y —W i -E j —W g —(C(R e )(R f )) 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(R e )(R f )) h , an alkyl group, an aryl group, a heterocyclic ring, an arylheterocyclic ring, or —(CH 2 CH 2 O) q —;

E at each occurrence is independently -T-, an alkyl group, an aryl group, —(C(R e )(R f )) h , a heterocyclic ring, an arylheterocyclic ring, or —(CH 2 CH 2 O) q —;

h is an integer form 1 to 10;

q is an integer from 1 to 5;

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 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(R a )R i ;

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 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, —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 + , or R e or R f are T-Q or (C(R e )(R f )) 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.

2. The compound of claim 1 , wherein the compound of Formula (I) is a substituted benzimidazole or a pharmaceutically acceptable salt thereof; having at least one NO group, at least one NO 2 group, or at least one NO and NO 2 group, wherein the at least one NO group, the at least one NO 2 group, or the at least one NO and NO 2 group is linked to the proton pump inhibitor compound through an oxygen atom, a nitrogen atom or a sulfur atom.

3. The compound of claim 2 , wherein the compound of Formula (I) is omeprazole, lansoprazole, pantoprazole, rabeprazole, leminoprazole, timoprazole, tenatoprazole, disuprazole, esomeprazole, RO 18-5362, or IY 81149; or a pharmaceutically acceptable salt thereof having at least one NO group, at least one NO 2 group, or at least one NO and NO 2 group, wherein the at least one NO group, the at least one NO 2 group, or the at least one NO and NO 2 group is linked to the proton pump inhibitor compound through an oxygen atom, a nitrogen atom or a sulfur atom.

4. 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.

5. A proton pump inhibitor compound selected from the group consisting of omeprazole, lansoprazole, pantoprazole, rabeprazole, leminoprazole, timoprazole, tenatoprazole, disuprazole and esomeprazole, having at least one NO group, at least one NO 2 group, or at least one NO and NO 2 group, or a pharmaceutically acceptable salt thereof, wherein the at least one NO group, the at least one NO 2 group, or the at least one NO and NO 2 group is linked to the proton pump inhibitor compound through an oxygen atom, a nitrogen atom or a sulfur atom.

6. A composition comprising the compound of claim 5 or 1 and a pharmaceutically acceptable carrier.

7. The composition of claim 6 , 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.

8. A composition comprising at least one compound of claim 5 or 1 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.

9. The composition of claim 8 , further comprising a pharmaceutically acceptable carrier.

10. The composition of claim 8 , 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.

11. The composition of claim 10 , 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.

12. The composition of claim 8 , wherein the S-nitrosothiol is:

(i) HS(C(R e )R f ) m SNO;

(ii) ONS(C(R e )(R f )) m R e ; and

(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 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 —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 30 ; then “-T-Q” can be a hydrogen, an alkyl group, an alkoxyalkyl group, an aminoalkyl group, a hydroxy group or an aryl group.

13. The composition of claim 8 , 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.

14. The composition of claim 8 , 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 O 2 N—O—, O 2 N—N—, O 2 N—S— or —O 2 N—C— group;

(iii) a N-oxo-N-nitrosoamine having the formula: R 1 R 2 N—N(O-M 30 )—NO, wherein R 1 and R 2 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.

15. The composition of claim 14 , 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.

16. The composition of claim 14 , wherein compound comprising at least one O 2 N—O—, O 2 N—, O 2 N—S— or O 2 N—C- group is an O 2 N—O-polypeptide, an O 2 N—N-polypeptide, an O 2 N—S-polypeptide, an O 2 N—C-polypeptide, an O 2 N—O-amino acid, O 2 N—N-amino acid, O 2 N—S-amino acid, an O 2 N—C-amino acid, an O 2 N—O-sugar, an O 2 N—N-sugar, O 2 N—S-sugar, an O 2 N—C-sugar, an O 2 N—O-oligonucleotide, an O 2 N—N-oligonucleotide, an O 2 N—S-oligonucleotide, an O 2 N—C-oligonucleotide, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O 2 N—O-hydrocarbon, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O 2 N—N-hydrocarbon, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O 2 N—S-hydrocarbon, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O 2 N—C-hydrocarbon, an O 2 N—O-heterocyclic compound, an O 2 N—N-heterocyclic compound, an O 2 N—S-heterocyclic compound or an O 2 N—C-heterocyclic compound.

17. The composition of claim 16 , wherein the compound comprising at least one O 2 N—O—, O 2 N—N—, O 2 N—S— or O 2 N—C— group is isosorbide dinitrate, isosorbide mononitrate, clonitrate, erythrityltetranitrate, mannitol hexanitrate, nitroglycerin, pentaerythritoltetranitrate, pentrinitrol and propatylnitrate.

18. The composition of claim 8 , 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.

19. A method for treating an ulcer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 6 .

20. The method of claim 19 , further comprising administering to the patient a therapeutically effective amount of an antacid.

21. The method of claim 19 , wherein the ulcer is a peptic ulcer, a stress ulcers, a bleeding peptic ulcer or a duodenal ulcer.

22. The method of claim 19 , wherein the composition is administered orally, bucally, topically, by injection, by inhalation, or by transdermal application.

23. The method of claim 22 , wherein the composition is administered orally in a solid dosage form or a liquid dosage form.

24. The method of claim 23 , 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.

25. The method of claim 23 , wherein the liquid dosage form is an emulsion, a solution, a suspension, a syrup, or an elixir.

26. A method for treating an ulcer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 8 .

27. The method of claim 26 , further comprising administering to the patient a therapeutically effective amount of an antacid.

28. The method of claim 26 , wherein the ulcer is a peptic ulcer, a stress ulcers, a bleeding peptic ulcer or a duodenal ulcer.

29. The method of claim 26 , wherein the composition is administered orally, bucally, topically, by injection, by inhalation, or by transdermal application.

30. The method of claim 29 , wherein the composition is 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.

33. A method for treating an ulcer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of claim 6 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.

34. The method of claim 33 , further comprising administering at least one antacid.

35. The method of claim 33 , wherein the ulcer is a peptic ulcer, a stress ulcers, a bleeding peptic ulcer or a duodenal ulcer.

36. A kit comprising at least one compound 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.

37. The kit of claim 36 , wherein the at least one compound or a pharmaceutically acceptable salt thereot 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.

38. The kit of claim 36 , 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.

39. 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, 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.

40. The kit of claim 39 , wherein the at least one 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 separate components in the kit or are in the form of a composition in the kit.