Nitrosated proton pump inhibitors, compositions and methods of use

Abstract

The invention describes novel nitrosated proton pump inhibitor compounds and pharmaceutically acceptable salts thereof, and novel compositions comprising at least one nitrosated proton pump inhibitor compound, 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 therapeutic agent. The invention also provides novel compositions comprising at least one nitrosated proton pump inhibitor compound, and at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase and/or at least one therapeutic agent. The invention also provides novel kits comprising at least one nitrosated proton pump inhibitor compound, and, optionally, at least one nitric oxide donor and/or at least one therapeutic agent. The invention also provides methods for treating 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 bacterial infections and/or viral infections.

1 - 53 . (canceled)  
     
     
         54 . A compound of Formula (II) or a pharmaceutically acceptable salt thereof, 
 wherein the compound of Formula (II) is:                          wherein    R x  is hydrogen or                          R y  is hydrogen or                          R 8  is a lower alkyl group, an alkoxyalkyl group, an alkylaryl group, a cycloalkyl group, a cycloalkylalkyl group, an aryl group, an alkylaryl group, or X;    R 9  at each occurrence is independently a hydrogen, a lower alkyl group, an alkylthio group, a halogen, a cyano group an alkanoyl group, a haloalkyl group, a carbamoyl group, —NR 87 X, —OX, or —CO 2 R 12 ;    R 71  is a hydrogen, a lower alkyl group, an alkoxy group, or —OX;    d is an integer from 1 to 5;    J is CH or nitrogen;    o is an integer from 0 to 2;    R 87  and R 87 ′ are each independently hydrogen, a lower alkyl group, D 1  or X; or R 87  and R 87 ′ taken together with the nitrogen to which they are attached form a heterocyclic ring;    R 12  is a lower alkyl group or X, with the proviso that Y in the definition of X must be oxygen or sulfur (—S—);    D 1  is: 
 (i)—C(R 6 R 6 ′)—T—C(O)—X;  
 (ii)—C(O)—X;  
 (iii)—S(O) 2 —X;  
 (iv)—C(R 6 R 6 ′)—T—S(O) 2 —X;  
 (v)—C(R 6 R 6 ′)—X; or  
 (vi) an inorganic cation;  
   R 6  and R 6 ′ are each independently a hydrogen, a lower alkyl group, an aryl group;    X is:    (1)—Y—(CR 4 R 4 ′) p —T—(CR 4 R 4 ′) p —ONO 2 ;    (2)—Y—(CR 4 R 4 ′) p —ONO 2 ;    (3)                          wherein T is ortho, meta or para;    (4)                          (5)—Y—(CR 4 R 4 ′) p —V—B—T—(CR 4 R 4 ′) p —ONO 2 ;    (6)—Y—(CR 4 R 4 ′) p —T—C(O)—(CR4R 4 ′) 0 —(CH 2 )—ONO—;    (7)—Y—(CR 4 R 4 ′) p —C(Z)—(CH 2 ) q —T—(CR 4 R 4 ′) q —(CH 2 )—ONO 2 ;    (8)—Y—(CR 4 R 4 ′) p —T—(CH 2 ) q —V—(CR 4 R 4 ′) q —(CH 2 )—ONO 2 ;    (9)—Y—(CR 4 R 4 ′) p —V—(CH 2 ) q —V—(CR 4 R 4 ′) q —(CH 2 )—ONO 2 ;    (10)—Y—(CR 4 R 4 ′) o —(W) q —(CR 4 R 4 ′) o —(CH 2 )—ONO 2 ;    (11)—NR j —O—(CH 2 ) o —V—(CR 4 R 4 ′) q —(CH 2 )—ONO 2 ;    (12)—NR j —O—(CH 2 ) o —(W) q —(CR 4 R 4 ′) q —(CH 2 )—ONO 2 ;    (13)—O—NR j —(CH 2 ) o —(W) q —(CR 4 R 4 ′) q —(CH 2 )—ONO 2 ;    (14)—Y—(CH 2 ) o —(W) q —(CH 2 ) o —V—(CR 4 R 4 ′) o Q′—(CR 4 R 4 ′) o —(CH 2 )—ONO 2 ;    (15)—Y—(CR 4 R 4 ′) p —V—(CH 2 ) o —(W) q —(CR 4 R 4 ′) q —(CH 2 )—ONO 2 ;    (16)—O—NR j —(CH 2 ) o —V—(CR 4 R 4 ′) q —(CH 2 )—ONO 2 ;    (17)—Y—(CR 4 R 4 ′) o —Q′—(CR 4 R 4 ′) o —V—(CR 4 R 4 ′) o —(CH 2 )—ONO 2 ;    (18)—Y—(CR 4 R 4 ′) o —Q′—(CR 4 R 4 ′) o —(W) q —(CR 4 R 4 ′) o —(CH 2 )—ONO 2 ;    (19)—Y—(CR 4 R 4 ′) p —T—(CR 4 R 4 ′) p —Q′—(CR 4 R 4 ′) o —(CH 2 )—ONO  2 ;    (20)—Y—(CR 4 R 4 ′) q —C(Z)—(CR 4 R 4 ′) o —(CH 2 )—ONO 2 ;    (21)—Y—(CR 4 R 4 ′) p —Q′—(CR 4 R 4 ′) o —(CH 2 )—ONO 2 ;    (22)—Y—(CR 4 R 4 ′) q —P(O)MM′;    (23)—Y—(CR 4 R 4 ′) o —Q′—(CR 4 R 4 ′) o —(CH 2 )—ONO 2 ;    (24)—Y—(CR 4 R 4 ′) o —Q′—(CR 4 R 4 ′) o —T—(CR 4 R 4 ′) o —(CH 2 )—ONO 2 ;    (25)—Y—(CR 4 R 4 ′) q —(W) q (CR 4 R 4 ′) o —Q′—(CR 4 R 4 ′) o —(CH 2 )—ONO 2 ;    (26)—Y—(CR 4 R 4 ′) q —V—(CR 4 R 4 ′) o —Q′—(CR 4 R 4 ′) o —(CH 2 )—ONO 2 ;    (27)—Y—(CR 4 R 4 ′) p —(T) o —(W) q —(CR 4 R 4 ′) o —(CH 2 )—ONO 2 ;    (28)—Y—(CR 4 R 4 ′) p —(W) q —(T) o —(CR 4 R 4 ′) o —(CH 2 )—ONO 2 ;    (29)—Y—(CR 4 R 4 ′) q —C(Z)—V—(CR 4 R 4 ′) q —(CH 2 )—ONO 2 ;    (30)—Y—(CR 4 R 4 ′) o —C(R 4 )(ONO 2 )—(CR 4 R 4 ′) q —(T) o —(W) q —(T) o —(CR 4 R 4 ′) o —R 5 ;    (31)—Y—(CR 4 R 4 ′) o —V—(CR 4 R 4 ′) o —Q′—(CR 4 R 4 ′) o —(CH 2 )—ON 0   2 ;    (32)—Y—(CR 4 R 4 ′) q —C(Z)—Q′—(CR 4 R 4 ′) o —(CH 2 )—ONO 2 ;    (33)—Y—(CR 4 R 4 ′) p —V—(CR 4 R 4 ′) p —(CH 2 )—ONO 2 ;    (34)—Y—(CR 4 R 4 ′) p —V—(CH 2 ) q —(T) o —(CR 4 R 4 ′) q —(CH 2 )—ONO 2 ;    (35)—Y—(CR 4 R 4 ) p —(T) o —Q′—(T) o —(CR 4 R 4 ′) q —(CH 2 )—ONO,;    (36)—Y—(CR 4 R 4 ′) q —C(Z)—(CR 4 R 4 ′) q —V—(CR 4 ′) o —Q′—(CR 4 R 4 ′) o —(CH 2 )—ONO 2 ;    (37)—Y—(CR 4 R 4 ′) q —C(Z)—(CR 4 R 4 ′) q —(W) q —(CR 4 R 4 ′) o —Q′—(CR 4 R 4 ′) o —(CH 2 )—ONO 2 ;    (38)—NR j —O—(CH 2 ) o —V—(CR 4 R 4 ′) o —Q′—(CH 2 )—ONO 2 ;    (39)—NR j —O—(CH 2 ) o —(W) q —(CR 4 R 4 ′) o —Q′(CH 2 ) —ONO 2 ;    (40)—O—NR j —(CH 2 ) o —(W) q —(CR 4 R 4 ′) o Q′—(CH 2 )—ONO 2 ;    (41)—O—NR j —(CH 2 ) o —V—(CR 4 R 4 ′) o —Q′—(CH 2 )—ONO 2 ;    (42)—NR j —NR j —(CR 4 R 4 ′) p —(W) q —(T) o —(CR 4 R 4 ′) o —(CH 2 )—ONO 2 ; or    (43)—Y—(CR 4 R 4 ′) o Q′—(CR 4 R 4 ′) o —ONO 2 ; or    (44)—Y—(CR 4 R 4 ′)—V—(CR 4 R 4 ′) o —Q—(CR 4 R 4 ′) o —ONO 2 ;    R 4  and R 4 ′at each occurrence are independently a hydrogen, lower alkyl group, —OH, —CH 2 OH, —ONO 2 , —NO 2  or —CH 2 ONO 2 ; or R 4  and R 4 ∝taken together with the carbon atom to which they are attached are a cycloalkyl group or a heterocyclic ring;    V is—C(O)—T—, —T—C(O)—, —T—C(O)—T or T—C(O)—C(O)—T;    W is a covalent bond or a carbonyl group;    T at each occurrence is independently an oxygen, (S(O) o ) o  or NR j ;    R j  is a hydrogen, an alkyl group, an aryl group, a heterocyclic ring, an alkylcarbonyl group, an alkylaryl group, an alkylsulfinyl group, an alkylsulfonyl group, an arylsulfinyl group, an arylsulfonyl group, a sulfonamido group, a N-alkylsulfonamido group, a N,N -diarylsulfonamido group, a N-arylsulfonamido group, a N-alkyl-N-arylsulfonamido group, a carboxamido group or a hydroxyl group;    p at each occurrence is independently an integer from 1 to 6;    q at each occurrence is independently an integer from 1 to 3;    Y is oxygen, sulfur (—S—), NR j  or a covalent bond;    B is either phenyl or (CH 2 ) O ;    Q′ is a cycloalkyl group, a heterocyclic ring or an aryl group;    Z is (═O), (═N—OR 5 ), (═N—NR 5 R′ 5 ) or (═CR 5 R′ 5 );    M and M′ are each independently —O 31  H 3 N + —(CR 4 R′ 4 ) q —CH 2 ONO 2  or —T—(CR 4 R′ 4 ) O —CH 2 ONO 2 ;    R 5  and R 5 ′at each occurrence are independently a hydrogen, a hydroxyl group, an alkyl group, an aryl group, an alkylsulfonyl group, an arylsulfonyl group, a carboxylic ester, an alkylcarbonyl group, an arylcarbonyl group, a carboxamido group, an alkoxyalkyl group, an alkoxyaryl group, a cycloalkyl group or a heterocyclic ring;    o is as defined herein; and    with the proviso that the compounds of Formula (II) must contain at least one nitrate group.    
     
     
         55 . The compound of  claim 54 , wherein X is:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein T′ may be ortho, meta or para  
         
           
             
             
                 
                 
             
           
           
             
             
                 
                 
             
           
           
             
             
                 
                 
             
           
           
             
             
                 
                 
             
           
           
             
             
                 
                 
             
           
         
         wherein:  
         Y′ is oxygen or sulfur;  
         T′ is oxygen, sulfur or NR 6 ;  
         X 5  is oxygen, (S(O) o ) o  or NR 6 ;  
         R 7  is a lower alkyl group or an aryl group;  
         R 8  at each occurrence is independently is a hydrogen, a hydroxyl group, a lower alkyl group, an aryl group, —NO 2 , —CH 2 , —ONO 2  or —CH 2 —OH;  
         n′ and m′ are each independently an integer from 0 to 10;  
         R 6  and o are as defined herein; and with the proviso for Formula 8 for X, Y′ and X 5  cannot be oxygen.  
       
     
     
         56 . The compound of  claim 54 , wherein the compound of Formula (II) is a nitrosated pyridino[2,3-c]pyridine.  
     
     
         57 . The compound of  claim 56 , wherein the nitrosated pyridino[2,3-c]pyridine is a nitrosated 4-amino-3-carbonyl quinoline, a nitrosated 4-amino-3-acylnaphthyride, a nitrosated 4-aminoquinoline, a nitrosated 4-amino-3-acylquinoline, a nitrosated 1-[8-ethoxy-4-[(1-phenylethyl)amino]-1,7-naphthyridin-3-yl]-1-butano nitrosated 1-[4-[(2-aminophenyl)thio]-8-methoxy-3-quinolinyl]-1-butanone or a nitrosated 3-butyryl-4-(2-methylphenylamino)-8-(2-hydroxyethoxy)quinoline or a pharmaceutically acceptable salt thereof.  
     
     
         58 . A composition comprising the compound of  claim 54  and a pharmaceutically acceptable carrier.  
     
     
         59 . 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 58 .  
     
     
         60 . The method of  claim 59 , wherein the gastrointestinal disorder is an inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, constipation, 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.  
     
     
         61 . A method for improving gastroprotective properties, the anti- Helicobacter pylori  properties or antacid properties of a proton pump inhibitor comprising administering to a patient in need thereof a therapeutically effective amount of the composition of  claim 58 .  
     
     
         62 . A method for decreasing 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 the composition of  claim 58 .  
     
     
         63 . A method for treating a bacterial infection in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of  claim 58 .  
     
     
         64 . The method of  claim 63 , wherein the bacterial infection is a  Helicobacter pylori  associated disease.  
     
     
         65 . The method of  claim 63 , further comprising administering to a patient a therapeutically effective amount of at least one antibacterial compound.  
     
     
         66 . A method for treating a viral infection in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of  claim 58 .  
     
     
         67 . The method of  claim 66 , 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.  
     
     
         68 . The composition of  claim 58 , further comprising at least one therapeutic agent.  
     
     
         69 . The composition of  claim 68 , wherein the therapeutic agent is a nonsteroidal antiinflammatory compound, a selective cyclooxygenase-2 (COX-2) inhibitor, an antacid, a bismuth-containing reagent, an antibacterial compound, a H 2  antagonists, a  Helicobacter pylori  inhibitor, a gastroprokinetic compound, or a mixture of two or more thereof.  
     
     
         70 . The composition of  claim 69 , wherein the nonsteroidal antiinflammatory compound is acetaminophen, aspirin, diclofenac, ibuprofen, ketoprofen, indomethacin or naproxen.  
     
     
         71 . 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 68 .  
     
     
         72 . The method of  claim 71 , wherein the gastrointestinal disorder is an inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, constipation, 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.  
     
     
         73 . A method for improving gastroprotective properties, anti- Helicobacter pylori  properties or antacid properties of a proton pump inhibitor comprising administering to a patient in need thereof a therapeutically effective amount of the composition of  claim 68 .  
     
     
         74 . A method for decreasing 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 the composition of  claim 68 .  
     
     
         75 . A method for treating a bacterial infection in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of  claim 68 .  
     
     
         76 . The method of  claim 75 , wherein the bacterial infection is a  Helicobacter pylori  associated disease.  
     
     
         77 . A method for treating a viral infection in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of  claim 68 .  
     
     
         78 . The method of  claim 77 , 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.  
     
     
         79 . A composition comprising at least one compound of  claim 54  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.  
     
     
         80 . The composition of  claim 79 , further comprising a pharmaceutically acceptable carrier.  
     
     
         81 . The composition of  claim 79 , 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.  
     
     
         82 . The composition of  claim 81 , 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.  
     
     
         83 . The composition of  claim 81 , wherein the S-nitrosothiol is: 
 (i) HS(C(R c )(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. 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 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 urea, a nitro, —T—Q′—, or —(C(R g )(R h )) k —T—Q′or R e  and R f  taken together are an oxo, a methanthial, a heterocyclic ring, a cycloalkyl group, an oxime, a hydrazone 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 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, —CH 2 —C(T—Q′)(R g )(R h ), 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 g )(R h ) 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; and R g  and R h  at each occurrence are independently R e .    
     
     
         84 . The composition of  claim 79 , 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, nitrosated L-homoarginine, nitrosylated L-homoarginine), citrulline, ornithine, glutamine, lysine, an arginase inhibitor or a nitric oxide mediator.  
     
     
         85 . The composition of  claim 79 , 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—or ON—N— group;    (ii) a compound that comprises at least one O 2 N—O—, O 2 N—N— or O 2 N—S— or group;    (iii) a N-oxo-N-nitrosoamine having the formula: R 1″ R 2″ N—N(O—M + )—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.    
     
     
         86 . The composition of  claim 85 , wherein the compound comprising at least one ON—O— or ON—N— group is an O—N-polypeptide, an ON—N-polypeptide, an ON—O-amino acid, an ON—N-amino acid, an ON—O-sugar, an ON—N-sugar, an ON—O-oligonucleotide, an ON—N-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, an ON—O-heterocyclic compound or an ON—N-heterocyclic compound.  
     
     
         87 . The composition of  claim 85 , wherein compound comprising at least one O 2 N—O—, O 2 N—N— or O 2 N—S— group is an O 2 N—O-polypeptide, an O 2 N—N-polypeptide, an O 2 N—S -polypeptide, an O 2 N—O-amino acid, O 2 N—N-amino acid, O 2 N—S-amino acid, an O 2 N—O-sugar, an O 2 N—N-sugar, O 2 N—S-sugar, an O 2 N—O-oligonucleotide, an O 2 N—-N-oligonucleotide, an O 2 N—S-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, an O 2 N—O -heterocyclic compound, an O 2 N—N-heterocyclic compound or an O 2 N—S-heterocyclic compound.  
     
     
         88 . The composition of  claim 79 , further comprising at least one therapeutic agent.  
     
     
         89 . The composition of  claim 88 , wherein the therapeutic agent is a nonsteroidal antiinflammatory compound, a selective cyclooxygenase-2 (COX-2) inhibitor, an antacid, a bismuth-containing reagent, an antibacterial compound, a H 2  antagonists, a  Helicobacter pylori  inhibitor, a gastroprokinetic compound, or a mixture of two or more thereof.  
     
     
         90 . The composition of  claim 89 , wherein the nonsteroidal antiinflammatory compound is acetaminophen, aspirin, diclofenac, ibuprofen, ketoprofen, indomethacin or naproxen.  
     
     
         91 . 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 79  or  88 .  
     
     
         92 . The method of  claim 91 , wherein the gastrointestinal disorder is an inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome, constipation, 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.  
     
     
         93 . A method for improving gastroprotective properties, anti- Helicobacter pylori  properties or antacid properties of a proton pump inhibitor comprising administering to a patient in need thereof a therapeutically effective amount of the composition of  claim 79  or  88 .  
     
     
         94 . A method for decreasing 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 the composition of  claim 79  or  88 .  
     
     
         95 . A method for treating a bacterial infection in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of  claim 79  or  88 .  
     
     
         96 . The method of  claim 95 , wherein the bacterial infection is a  Helicobacter pylori  associated disease.  
     
     
         97 . A method for treating a viral infection in a patient in need thereof comprising administering to the patient a therapeutically effective amount of the composition of  claim 79  or  88 .  
     
     
         98 . The method of  claim 97 , 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.  
     
     
         99 . A kit comprising at least one compound of  claim 54 .  
     
     
         100 . The kit of  claim 99 , further comprising (i) 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; (ii) at least one therapeutic agent; or (iii) 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 and at least one therapeutic agent.  
     
     
         101 . The kit of  claim 100 , 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, or is a substrate for nitric oxide synthase; the at least one therapeutic agent; or 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 and at least one therapeutic agent; are in the form of separate components in the kit.  
     
     
         102 . A kit comprising the composition of  claim 68 ,  79  or  88 .