Claims
- 1. A compound of Formula (I), (II), (III), (IV), (V), (VI) (VII), (VIII), (IX), (X), (XI), (XII) or (XIII), or a pharmaceutically acceptable salt thereof;
wherein the compound of Formula (I) is: 44wherein A is S(O)o; W1 is —C—NR87R87′, —CH or nitrogen; W2 is: 45J is CH or nitrogen; o is an integer from 0 to 2; R1 is a hydrogen, an alkoxy group, a lower alkyl group, or an alkylthio group; R2 is a hydrogen, a halogen, an alkoxy group, a lower alkyl group, an alkylthio group, a haloalkoxy group, an alkoxyalkyl group, —NR87R87′, —OX, or —SX; or R2 and R3 taken together with the carbon atoms to which they are attached form a cycloalkyl ring, an aryl group or a heterocyclic ring, and with the proviso that R2 must be OX, or —SX in W2; 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, an aryl group or a heterocyclic ring; R32 and R47 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, —NR87R87′, —OX, or —CO2R12; or R32 and R47 taken together are: 46wherein R86 is oxygen or N═O—R87; R87 and R87′ are each independently hydrogen, a lower alkyl group, D1 or X; or R87 and R87′ 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 X, with the proviso that Y in the definition of X must be oxygen or sulfur (—S—); D1 is:
(i) —C(R6R6′)—T—C(O)—X; (ii) —C(O)—X; (iii) —S(O)2—X; (iv) —C(R6R6′)—T—S(O)2—X; (v) —C(R6R6′)—X; or (vi) an inorganic cation; R6 and R6′ are each independently a hydrogen, a lower alkyl group, an aryl group; X is:
(1) —Y—(CR4R4′)p—T—(CR4R4′)p—ONO2; (2) —Y—(CR4R4′)p—ONO2; 47wherein T is ortho, meta or para; 48(5) —Y—(CR4R4′)p—V—B—T—(CR4R4′)p—ONO2; (6) —Y—(CR4R4′)p—T—C(O)—(CR4R4′)o—(CH2)—ONO2; (7) —Y—(CR4R4′)p—C(Z)—(CH2)q—T—(CR4R4′)q—(CH2)—ONO2; (8) —Y—(CR4R4′)p—T—(CH2)q—V—(CR4R4′)q—(CH2)—ONO2; (9) —Y—(CR4R4′)p—V—(CH2)q—V—(CR4R4′)q—(CH2)—ONO2; (10) —Y—(CR4R4′)o—(W)q—(CR4R4′)o—(CH2)—ONO2; (11) —NRj—O—(CH2)o—V—(CR4R4′)q—(CH2)—ONO2; (12) —NRj—O—(CH2)o—(W)q—CR4R4′)q—(CH2)—ONO2; (13) —O—NRj—(CH2)o—(W)q—CR4R4′)q—(CH2)—ONO2; (14) —Y—(CH2)o—(W)q—(CH2)o—V—(CR4R4′)o—Q′—(CR4R4′)o—(CH2)—ONO2; (15) —Y—(CR4R4′)p—V—(CH2)o—(W)q—CR4R4′)q—(CH2)—ONO2; (16) —O—NRj—(CH2)o—V—(CR4R4′)q—CH2)—ONO2; (17) —Y—(CR4R4′)o—Q′—(CR4R4′)o—V—(CR4R4′)o—(CH2)—ONO2; (18) —Y—(CR4R4′)o—Q′—(CR4R4′)o—(W)q—(CR4R4′)o—(CH2)—ONO2; (19) —Y—(CR4R4′)p—T—(CR4R4′)p—Q′—(CR4R4′)o—(CH2)—ONO2; (20) —Y—(CR4R4′)q—C(Z)—(CR4R4′)o—(CH2)—ONO2; (21) —Y—(CR4R4′)p—Q′—(CR4R4′)o—(CH2)—ONO2; (22) —Y—(CR4R4′)q—P(O)MM′; (23) —Y—(CR4R4′)o—Q′—(CR4R4′)o—(CH2)—ONO2; (24) —Y—(CR4R4′)o—Q′—(CR4R4′)o—T—(CR4R4′)o—(CH2)—ONO2; (25) —Y—(CR4R4′)q—(W)q—(CR4R4′)o—Q′—(CR4R4′)o—(CH2)—ONO2; (26) —Y—(CR4R4′)q—V—(CR4R4′)o—Q′—(CR4R4′)o—(CH2)—ONO2; (27) —Y—(CR4R4′)p—(T)o—(W)q—(CR4R4′)o—(CH2)—ONO2; (28) —Y—(CR4R4′)p—(W)q—(T)o—(CR4R4′)o—(CH2)—ONO2; (29) —Y—(CR4R4′)q—C(Z)—V—(CR4R4′)q—CH2)—ONO2; (30) —Y—(CR4R4′)o—C(R4)(ONO2)—(CR4R4′)q—(T)o—(W)q—(T)o—(CR4R4′)o—R5; (31) —Y—(CR4R4′)o—V—(CR4R4′)o—Q′—(CR4R4′)o—(CH2)—ONO2; (32) —Y—(CR4R4′)q—C(Z)—Q′—(CR4R4′)o—(CH2)—ONO2; (33) —Y—(CR4R4′)p—V—(CR4R4′)p—(CH2)—ONO2; (34) —Y—(CR4R4′)p—V—(CH2)q—(T)o—(CR4R4′)q—(CH2)—ONO2; (35) —Y—(CR4R4′)p—(T)o—Q′—(T)o—(CR4R4′)q—CH2)—ONO2; (36) —Y—(CR4R4′)q—C(Z)—(CR4R4′)q—V—(CR4R4′)o—Q′—(CR4R4′)o—(CH2)—ONO2; (37) —Y—(CR4R4′)q—C(Z)—(CR4R4′)q—(W)q—(CR4R4′)o—Q′—(CR4R4′)o—(CH2)—ONO2; (38) —NRj—O—(CH2)o—V—(CR4R4′)o—Q′—(CH2)—ONO2; (39) —NRj—O—(CH2)o—(W)q—(CR4R4′)o—Q′—(CH2)—ONO2; (40) —O—NRj—(CH2)o—(W)q—(CR4R4′)o—Q′—(CH2)—ONO2; (41) —O—NRj—(CH2)o—V—(CR4R4′)o—Q′—(CH2)—ONO2; (42) —NRj—NRj—(CR4R4′)p—(W)q—(T)o—(CR4R4′)o—(CH2)—ONO2; or (43) —Y—(CR4R4′)o—Q′—(CR4R4′)o—ONO2; or (44) —Y—(CR4R4′)o—V—(CR4R4′)o—Q—(CR4R4′)o—ONO2; R4 and R4′ at each occurrence are independently a hydrogen, lower alkyl group, —OH, —CH2OH, —ONO2, —NO2 or —CH2ONO2; or R4 and R4′ 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)—CO)—T; W is a covalent bond or a carbonyl group; T at each occurrence is independently an oxygen, (S(O)o)o or NRj; Rj 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—), NRj or a covalent bond; B is either phenyl or (CH2)o; Q′ is a cycloalkyl group, a heterocyclic ring or an aryl group; Z is (═O), (═N—OR5), (═N—NR5R′5) or (═CR5R′5); M and M′ are each independently —O− H3N+—(CR4R′4)q—CH2ONO2 or —T—(CR4R′4)o—CH2ONO2; R5 and R5′ 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 (I) must contain at least one nitrate group, and with the further proviso for compounds of Formula (I):
when D1 is —C(R6R6′)—T—C(O)—X, T is oxygen, R6 and R6′ are each independently a hydrogen or a lower alkyl group, X is Formula 1, R4 and R4′ are both hydrogen, Y cannot be oxygen, NRj or a covalent bond when T is oxygen; when D1 is —C(R6R6′)—X, R6 and R6′ are each independently a hydrogen or a lower alkyl group, X is Formula 2, R4 and R4′ are both hydrogen, Y cannot be a covalent bond or oxygen; and with the proviso that the compounds of Formula (I) are not ACS registry numbers 384339-54-2, 384339-53-1, 326850-42-4, 302543-91-5 or 301669-76-1; wherein the compound of Formula (II) is: 49wherein Rx is hydrogen or 50Ry is hydrogen or 51R8 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; 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, —NR87X, —OX, or —CO2R12; R71 is a hydrogen, a lower alkyl group, an alkoxy group, or —OX; d is an integer from 1 to 5; and wherein o, X, D1, R12, R87, R87′ and o are as defined herein; and with the proviso that the compounds of Formula (II) must contain at least one nitrate group; wherein the compound of Formula (III) is: 52wherein R13 and R14 are each independently a hydrogen a lower alkyl group, an alkoxyalkyl, or a lower alkyl-OX; 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: 53wherein 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 —OX; (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 X; (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 —OX; D1 and X are as defined herein, and with the proviso that the compound of Formula (III) must contain at least one nitrate group; wherein the compound of Formula (IV) is: 54wherein R18 and R19 at each occurrence are each independently a hydrogen, a lower alkyl group, a halogen, a nitro group, an alkoxy group, —OX, —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 carbons 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 X; X4 is —C(═R86)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, R86, and X are defined as herein, and with the proviso that the compound of Formula (IV) must contain at least one nitrate group; wherein the compound of Formula (V) is: 55wherein X15 is: 56wherein R23 is a hydrogen, a dialkylamino group, —NR87R87′, or a heterocyclic ring; R24 is a hydrogen or halogen; R25 is a hydrogen, —OX, or lower alkyl-OX; 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-OX; R31 is a hydrogen, a dialkylamino group, or an alkoxy group; R33 is a hydrogen or a lower alkyl group; g is an integer from 0 to 1; R87, R87′, X and d are as defined herein, and with the proviso that the compound of Formula (V) must contain at least one nitrate group; wherein the compound of Formula (VI) is: 57wherein A4, A5, and A6 are each independently a sulfur or CR34 with the proviso that at least one of A4, A5, or A6 is a sulfur atom 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-OX, 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 R36 taken together with the carbon chain to which they are attached form a cycloalkyl ring; R26 is: 58wherein 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, B1—OX, B1—SX, —B1—NR20R21, —B1—O(O)CR20, —B1—O(O)CNR20R21, —B1—N(R20)C(O)R21, or —B1—N(R20)S(O)2R21; R45 and R46 are each independently a hydrogen, a lower alkyl group, a cycloalkyl group, an alkenyl group, or an alkynyl group; B1 is —C—NR87R87′ or nitrogen; D1, A, X, R20, R21, R87 and R87′ are as defined herein, and with the proviso that the compound of Formula (VI) must contain at least one nitrate group; wherein the compound of Formula (VII) is: 59wherein R60 is a lower alkyl group, an aryl group, a haloalkyl group, a lower alkyl-OX, or heterocyclic ring; A7 is oxygen, —CH═CH— or —ND1; X7 is a hydrogen or a halogen; Z7 is —CH2OD or —NDD1; D is hydrogen, —NO2 or D1; Y7 is: 60or X7, A7, and Y7 taken together along with the carbon atoms to which they are attached is: 61wherein R61 is a hydrogen, a halogen, a lower alkyl group, —OX, or —NHC(O)O-lower alkyl; R62 is a hydrogen, a halogen, or a lower alkyl group; and wherein D1 and X are as defined herein, and with the proviso that the compound of Formula (VII) must contain at least one nitrate group; wherein the compound of Formula (VIII) is: 62wherein D1 and D are as defined herein, and with the proviso that the compound of Formula (VIII) must contain at least one nitrate group; wherein the compound of Formula (IX) is: 63wherein R98 and R99 taken together are: 64wherein D1 and R87 are as defined herein; and with the proviso that the compound of Formula (IX) must contain at least one nitrate group; wherein the compound of Formula (X) is: 65wherein R100 at each occurrence is independently a hydrogen, a halogen, an alkoxy group or a haloalkoxy group; wherein D1 is as defined herein; and with the proviso that the compound of Formula (X) must contain at least one nitrate group; wherein the compound of Formula (XI) is: 66wherein R100, D and D1 are as defined herein; and with the proviso that the compound of Formula (XI) must contain at least one nitrate group; wherein the compound of Formula (XII) is: 67wherein R100, J and D1 are as defined herein; and with the proviso that the compound of Formula (XII) must contain at least one nitrate group; wherein the compound of Formula (XIII) is: 68wherein R1, R2, A and D1 are as defined herein; and with the proviso that the compound of Formula (XIII) must contain at least one nitrate group.
- 2. The compound of claim 1, wherein X is:
- 3. The compound of claim 1, wherein the compound of Formula (I) is a nitrosated imidazolo[5,4,-b]pyridine, the compound of Formula (II) is a nitrosated pyridino[2,3-c]pyridine, the compound of Formula (III) is a nitrosated pyrimidine, the compound of Formula (IV) is a nitrosated thiadiazole, the compound of Formula (IV) is a nitrosated sulfinylnicotinamide, the compound of Formula (VI) is a nitrosated thienoimidazole, the compound of Formula (VII) is a nitrosated imidazopyridine, the compound of Formula (VIII) is a nitrosated BE-18591, the compound of Formula (IX) is a nitrosated YJA-20379-5 or a nitrosated YJA-20379-2, the compound of Formula (X) is a nitrosated pyrazole compound, the compound of Formula (XI) is a nitrosated KR 60436 or a nitrosated DBM 819, the compound of Formula (XII) is a nitrosated thiazolyl-guanidine compound.
- 4. The compound of claim 3, wherein the nitrosated imidazolo[5,4,-b]pyridine is a nitrosated omeprazole, a nitrosated lansoprazole, a nitrosated pantoprazole, a nitrosated rabeprazole, a nitrosated leminoprazole, a nitrosated timoprazole, a nitrosated tenatoprazole, a nitrosated disulprazole, a nitrosated esomeprazole, a nitrosated 2-(2-benzimidazolyl)-pyridine, a nitrosated tricyclic imidazole, a nitrosated thienopydidine benzimidazole, a nitrosated fluoroalkoxy substituted benzimidazole, a nitrosated dialkoxy benzimidazole, a nitrosated N-substituted 2-(pyridylalkenesulfinyl) benzimidazole, a nitrosated cycloheptenepyridine, a nitrosated 5-pyrrolyl-2-pyridylmethylsulfinyl benzimidazole, a nitrosated alkylsulfinyl benzimidazole, a nitrosated fluoro-pyridylmethylsulfinyl benzimidazole, a nitrosated imidazo(4,5-b)pydridine, a nitrosated RO 18-5362, a nitrosated Hoe-731, a nitrosated TY 11345, a nitrosated IY 81149 or a nitrosated NC-1300; 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 YJA-20379-8, a nitrosated YJA-20379-6 or a nitrosated 3-butyryl-4-(2-methylphenylamino)-8-(2-hydroxyethoxy)quinoline; wherein the nitrosated pyrimidine is a nitrosated quinazoline, a nitrosated tetrahydroisoquinolin-2-yl pyrimidine or a nitrosated YH 1885; wherein the nitrosated thiadiazole is a nitrosated 3-substituted 1,2,4-thiadiazolo(4,5-a) benzimidazole or a nitrosated 3-substituted imidazo(1,2-d)-thiadiazole; wherein the nitrosated sulfinylnicotinamide is a nitrosated 2-sulfinylnicotinamide; wherein the nitrosated thienoimidazole is a nitrosated pyridylsulfinylbenzimidazole, a nitrosated pyridylsulfinyl, a nitrosated thieno, a nitrosated imidazole, a nitrosated theinoimidazole-toluidine, a nitrosated 4,5-dihydrooxazole or a nitrosated thienoimidazole-toluidine; wherein the nitrosated imidazopyridine is a nitrosated Sch 28080, a nitrosated imidazo(1,2-a)pyridine or a nitrosated pyrrolo(2,3-b)pyridine; wherein the nitrosated pyrazole compound is a nitrosated 1-((2-chlorophenyl)methyl)-1H-pyrazole-3-methanol; wherein the nitrosated thiazolyl-guanidine compound is a nitrosated (4-(1H-indol-3-yl)-5-methyl-2-thiazolyl-guanidine or a nitrosated (4-(5-(phenylmethoxy)-1H-indol-3-yl)-2-thiazolyl-guanidine or a pharmaceutically acceptable salt thereof.
- 5. A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
- 6. 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.
- 7. The method of claim 6, 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.
- 8. 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 5.
- 9. 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 5.
- 10. 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 5.
- 11. The method of claim 10, wherein the bacterial infection is a Helicobacter pylori associated disease.
- 12. The method of claim 10, further comprising administering to a patient a therapeutically effective amount of at least one antibacterial compound
- 13. 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 5.
- 14. The method of claim 13, 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.
- 15. The composition of claim 5, further comprising at least one therapeutic agent.
- 16. The composition of claim 15, 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 H2 antagonists, a Helicobacter pylori inhibitor, a gastroprokinetic compound, or a mixture of two or more thereof.
- 17. The composition of claim 16, wherein the nonsteroidal antiinflammatory compound is acetaminophen, aspirin, diclofenac, ibuprofen, ketoprofen, indomethacin or naproxen.
- 18. 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 15.
- 19. The method of claim 18, 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.
- 20. 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 15.
- 21. 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 15.
- 22. 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 15.
- 23. The method of claim 22, wherein the bacterial infection is a Helicobacter pylori associated disease.
- 24. 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 15.
- 25. The method of claim 24, 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.
- 26. A composition comprising at least one compound of claim 1 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.
- 27. The composition of claim 26, further comprising a pharmaceutically acceptable carrier.
- 28. The composition of claim 26, 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.
- 29. The composition of claim 28, 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.
- 30. The composition of claim 28, wherein the S-nitrosothiol is:
(i) HS(C(Re)(Rf))mSNO; (ii) ONS(C(Re)(Rf))mRe; or (iii) H2N—CH(CO2H)—(CH2)m—C(O)NH—CH(CH2SNO)—ClO)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. 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(Rg)(Rh))k—T—Q′ or Re and Rf taken together are anoxo, a methanthial, a heterocyclic ring, a cycloalkyl group, an oxime, a hydrazone 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 arylcarboxylic acid, an alkylcarboxylic ester, an arylcarboxylic ester, an alkylcarboxamido, an arylcarboxamido, an alkylsulfinyl, an alkylsulfonyl, an alkylsulfonyloxy, an arylsulfinyl, an arylsulfonyloxy, an arylsulfonyl, a sulfonamido, a carboxamido, a carboxylic ester, an aminoalkyl, an aminoaryl, —CH2—C(T—Q′)(Rg)(Rh), or —(N2O2—)−.M+, wherein M+ is an organic or inorganic cation; with the proviso that when Ri is —CH2—C(T—Q′)(Rg)(Rh) 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; and Rg and Rh at each occurrence are independently Re.
- 31. The composition of claim 26, 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.
- 32. The composition of claim 26, 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—N— or ON—N— group; (ii) a compound that comprises at least one O2N—O—, O2N—N— or O2N—S— or group; (iii) a N-oxo-N-nitrosoamine having the formula: R1″R2″N—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.
- 33. The composition of claim 32, wherein the compound comprising at least one ON—N— or ON—N— group is an ON—O-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.
- 34. The composition of claim 32, wherein compound comprising at least one O2N—O—, O2N—N— or O2N—S— group is an O2N—O-polypeptide, an O2N—N-polypeptide, an O2N—S-polypeptide, an O2N—O-amino acid, O2N—N-amino acid, O2N—S-amino acid, an O2N—O-sugar, an O2N—N-sugar, O2N—S-sugar, an O2N—O-oligonucleotide, an O2N—N-oligonucleotide, an O2N—S-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, an O2N—O-heterocyclic compound, an O2N—N-heterocyclic compound or an O2N—S-heterocyclic compound.
- 35. The composition of claim 26, further comprising at least one therapeutic agent.
- 36. The composition of claim 35, 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 H2 antagonists, a Helicobacter pylori inhibitor, a gastroprokinetic compound, or a mixture of two or more thereof.
- 37. The composition of claim 36, wherein the nonsteroidal antiinflammatory compound is acetaminophen, aspirin, diclofenac, ibuprofen, ketoprofen, indomethacin or naproxen.
- 38. 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 26 or 35.
- 39. The method of claim 38, 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.
- 40. 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 26 or 35.
- 41. 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 26 or 35.
- 42. 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 26 or 35.
- 43. The method of claim 42, wherein the bacterial infection is a Helicobacter pylori associated disease.
- 44. 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 26 or 35.
- 45. The method of claim 44, 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.
- 46. A kit comprising at least one compound of claim 1.
- 47. The kit of claim 46, 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.
- 48. The kit of claim 47, 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
- 49. A kit comprising the composition of claim 15, 26 or 35.
- 50. A compound selected from the group consisting of:
2-(nitrooxy)ethyl 2-(((3-methyl-4-(2,2,2-trifluoroethoxy)-2 pyridyl)methyl)sulfinyl)benzimidazolecarboxylate; 3-(nitrooxy)propyl 2-(((3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl)methyl)sulfinyl)benzimidazolecarboxylate; 5-(nitrooxy)pentyl 2-(((3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl)methyl)sulfinyl)benzimidazolecarboxylate; 3-(nitrooxy)-2-((nitrooxy)methyl)propyl 2-(((3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl)methyl)sulfinyl)benzimidazolecarboxylate; 6-(nitrooxy)hexyl 2-(((3-methyl-4-(2,2,2-trifluoroethoxy)-2 pyridyl)methyl)sulfinyl)benzimidazolecarboxylate; or a pharmaceutically acceptable salt thereof.
- 51. A composition comprising at least one compound of claim 50 and a pharmaceutically acceptable carrier.
- 52. The composition of claim 51, 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.
- 53. A kit comprising at least one compound of claim 50.
RELATED APPLICATIONS
[0001] This application claims priority to U.S. application Ser. No. 60/399,715 filed Aug. 1, 2002.
Provisional Applications (1)
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Number |
Date |
Country |
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60399715 |
Aug 2002 |
US |
Patent Application
20040024014
