WO2000050037A1 - Inhibiteurs de la pompe a proton nitroses et nitrosyles, compositions et procedes d'utilisation - Google Patents

Inhibiteurs de la pompe a proton nitroses et nitrosyles, compositions et procedes d'utilisation Download PDF

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Publication number
WO2000050037A1
WO2000050037A1 PCT/US2000/002524 US0002524W WO0050037A1 WO 2000050037 A1 WO2000050037 A1 WO 2000050037A1 US 0002524 W US0002524 W US 0002524W WO 0050037 A1 WO0050037 A1 WO 0050037A1
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group
compound
nitric oxide
hydrogen
patient
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PCT/US2000/002524
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English (en)
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David S. Garvey
L. Gordon Letts
Sang William Tam
Tiansheng Wang
Stewart K. Richardson
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Nitromed, Inc.
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Priority to JP2000600648A priority Critical patent/JP2002537336A/ja
Priority to AU32196/00A priority patent/AU781133B2/en
Priority to CA2362930A priority patent/CA2362930C/fr
Priority to EP00910039A priority patent/EP1154771A4/fr
Publication of WO2000050037A1 publication Critical patent/WO2000050037A1/fr
Priority to AU2005202553A priority patent/AU2005202553A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/433—Thidiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • 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 N0 2 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.
  • the proton pump located in the apical membrane of the parietal cell, is responsible for the secretion of acid in the stomach when it is stimulated by the enzyme adenosine triphosphate (H + , K + )-ATPase.
  • Proton pump inhibitors are a class of anti-secretory compounds used in the management of gastrointestinal disorders. They suppress gastric acid secretion by the specific inhibition of the (H * , K ⁇ )-ATPase enzyme system at the secretory surface of the gastric parietal cell.
  • omeprazole and lansoprazole are used clinically in the United States. Structurally they contain a sulfinyl group bridging between substituted benzimidazole and pyridine rings. At a neutral pH, omeprazole and lansoprazole are chemically stable, are weak bases, are lipid-soluble, and do not show any inhibitory activity. Once these compounds reach the parietal cells and diffuse into the secretory canaliculi, they become protonated. The protonated compounds rearrange to form sulfenic acid and then a sulfenamide.
  • the latter interacts covalently with sulfhydryl groups at critical sites in the extracellular (luminal) domain of the membrane spanning (H + , K + )-ATPase. Inhibition occurs when two molecules of the inhibitor are bound per molecule of the enzyme.
  • the specificity of these proton pump inhibitors arises from the selective distribution of the (H + , K + )-ATPase, the acid- catalyzed rearrangement of the compounds to generate the active inhibitor, and the trapping of the protonated compound and the cationic sulfenamide within the acidic canaliculi and adjacent to the target enzyme.
  • Omeprazole and lansoprazole are typically administered orally as delay- release capsules.
  • the compounds are stable at a neutral pH, but are destroyed by gastric acid. Therefore, if the integrity of the gelatin-coated capsule is destroyed in any way and the patient swallows the enteric-coated grains, the neutral pH in the mouth and the esophagus will break down the microencapsulation, and the compounds will be degraded by the gastric acid in the stomach.
  • the delay release capsules when appropriately taken, release the omeprazole and lansoprazole after the granules leave the stomach.
  • proton pump inhibitors are not unanimously recognized as gastroprotective agents.
  • Campylobacter pylori the bacteria responsible for peptic ulcer disease, gastric lymphoma and adenocarcinoma.
  • U.S. Patent Nos. 5,599,794 and 5,629,305 describe the administration of proton pump inhibitors in combination with acid-degradable antibacterial compounds for the treatment of infections caused by Helicobacter pylori.
  • omeprazole and lansoprazole The most common side effects of proton pump inhibitors, such as omeprazole and lansoprazole, are nausea, diarrhea, abdominal colic, and central nervous system effects such as headaches and dizziness. Occasionally skin rashes and transient elevations of plasma activities of hepatic aminotransferase have been reported. The drugs can also result in bacterial overgrowth in the gastrointestinal tract and the development of nosocomial pneumonia.
  • the present invention provides proton pump inhibitors to which is linked at least one NO and/or N0 2 group (i.e., nitrosylated and/or nitrosated).
  • the proton pump inhibitors can be, for example, substituted benzimidazoles and substituted azabenzimidazoles, including, for example, omeprazole, pantoprazole, rabeprazole, leminoprazole, lansoprazole, timoprazole, tenatoprazole, disulprazole, esomeprazole, RO 18-5362 and IY 81149.
  • the present invention also provides compositions comprising such compounds in a pharmaceutically acceptable carrier.
  • compositions comprising at least one proton pump inhibitor, that is optionally substituted with at least one NO and /or N0 2 group (i.e., nitrosylated and /or nitrosated), and at least one compound that donates, transfers or releases nitric oxide and/or stimulates endogenous production of nitric oxide (NO) or endothelium-derived relaxing factor (EDRF) in vivo and/or is a substrate for nitric oxide synthase.
  • NO nitric oxide
  • EDRF endothelium-derived relaxing factor
  • Yet another aspect of the present invention provides methods for treating gastrointestinal disorders, methods for improving the gastroprotective properties, anti-Helicobacter properties and antacid properties of proton pump inhibitors, methods for facilitating ulcer healing and methods for decreasing the rate of recurrence of ulcers in a patient in need thereof comprising administering to the patient at least one proton pump inhibitor that is substituted with at least one NO and /or N0 2 group, or by administering to the patient at least one proton pump inhibitor, that is optionally substituted with at least one NO and /or N0 2 group, and at least one compound that donates, transfers or releases nitric oxide and/or stimulates endogenous production of nitric oxide or EDRF in vivo.
  • the proton pump inhibitor that is optionally substituted with at least one NO and /or
  • N0 2 group, and nitric oxide donor can be administered separately or as components of the same composition in one or more pharmaceutically acceptable carriers.
  • the present invention also provides methods to decrease or reverse gastrointestinal toxicity resulting from the administration of nonsteroidal antiinflammatory drugs (NSAIDs) and /or selective COX-2 inhibitors, and methods to facilitate ulcer healing resulting from the administration of NSAIDs and /or selective COX-2 inhibitors, in a patient in need thereof by administering the compounds and /or compositions of the present invention.
  • NSAIDs nonsteroidal antiinflammatory drugs
  • the present invention also provides methods to treat infections caused by Helicobacter pylori and /or viruses in patients in need thereof by administering the compounds and /or compositions of the present invention.
  • Lanzoprazole at 200 ⁇ mol/kg did not significantly inhibit the formation of gastric lesions relative to vehicle alone.
  • Example 2 (nitrosylated lanzoprazole) at 200 ⁇ mol/kg inhibited the formation of gastric lesions relative to vehicle alone (p ⁇ 0.05) and lanzoprazole (p ⁇ 0.05).
  • DETAILED DESCRIPTION OF THE INVENTION As used throughout the disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings.
  • Gastrointestinal disorder refers to any disease or disorder of the upper and lower gastrointestinal tract of a patient including, for example, inflammatory bowel disease, Crohn's disease, irritable bowel syndrome, ulcerative colitis, peptic ulcers, stress ulcers, bleeding peptic ulcers, duodenal ulcers, infectious enteritis, colitis, diverticulitis, gastric hyperacidity, dyspepsia, gastroparesis, Zollinger- Ellison syndrome, gastroesophageal reflux disease, Helicobacter Pylori associated disease, short-bowel (anastomosis) syndrome, hypersecretory states associated with systemic mastocytosis or basophilic leukemia and hyperhistaminemia that result, for example, from neurosurgery, head injury, severe body trauma or burns.
  • Ultra gastrointestinal tract refers to the esophagus, the stomach, the duodenum and the jejunum.
  • “Lower gastrointestinal tract” refers to the ileum, the colon, the cecum and the rectum.
  • ulcers refers to lesions of the upper gastrointestinal tract lining that are characterized by loss of tissue. Such ulcers include gastric ulcers, duodenal ulcers and gastritis.
  • RNA viral infections include, but are not limited to, orthomyxoviridae, paramyxoviridae, picornaviridae, rhabdoviridae, coronavaridae, togaviridae, bunyaviridae, arenaviridae and reteroviridae.
  • the DNA viral infections include, but are not limited to, adenoviridae, proxviridae, papovaviridae, herpetoviridae and herpesviridae.
  • the most preferable viral infections are those of the herpetoviridae family, such as, for example, herpes simplex viruses HSV-1 and HSV-2, cytomegalovirus (CMV), herpes varicella-zoster (VZV), Epstein-Barr (EBV), HHV6, HHV7, pseudorabies and rhinotracheitis, and the like.
  • CMV cytomegalovirus
  • VZV herpes varicella-zoster
  • EBV Epstein-Barr
  • HHV6, HHV7 pseudorabies and rhinotracheitis
  • Proton pump inhibitor refers to any compound that reversibly or irreversibly blocks gastric acid secretion by inhibiting the H + /K + -ATP ase er-zyme system at the secretory surface of the gastric parietal cell.
  • NSAID refers to a nonsteroidal anti-inflammatory compound or a nonsteroidal anti-inflammatory drug. NSAIDs inhibit cyclooxygenase, the enzyme responsible for the biosyntheses of the prostaglandins and certain autocoid inhibitors, including inhibitors of the various isozymes of cyclooxygenase (including but not limited to cyclooxygenase-1 and -2), and as inhibitors of both cyclooxygenase and lipoxygenase.
  • Cyclooxygenase-2 (COX-2) inhibitor refers to a compound that selectively inhibits the cyclooxygenase-2 enzyme over the cyclooxygenase-1 enzyme.
  • the compound has a cyclooxygenase-2 IC 50 of less than about 0.5 ⁇ M, and also has a selectivity ratio of cyclooxygenase-2 inhibition over cyclooxygenase-1 inhibition of at least 50, and more preferably of at least 100. Even more preferably, the compound has a cyclooxygenase-1 IC 50 of greater than about 1 ⁇ M, and more preferably of greater than 20 ⁇ M.
  • the compound can also inhibit the enzyme, lipoxygenase.
  • Patient refers to animals, preferably mammals, more preferably humans.
  • Transdermal refers to the delivery of a compound by passage through the skin and into the blood stream.
  • Transmucosal refers to delivery of a compound by passage of the compound through the mucosal tissue and into the blood stream.
  • Poration enhancement refers to an increase in the permeability of the skin or mucosal tissue to a selected pharmacologically active compound such that the rate at which the compound permeates through the skin or mucosal tissue is increased.
  • Carriers or “vehicles” refers to carrier materials suitable for compound administration and include any such material known in the art such as, for example, any liquid, gel, solvent, liquid diluent, solubilizer, or the like, which is non-toxic and which does not interact with any components of the composition in a deleterious manner.
  • Nitric oxide adduct or “NO adduct” refers to compounds and functional groups which, under physiological conditions, can donate, release and /or directly or indirectly transfer any of the three redox forms of nitrogen monoxide (NO + , NO " , NO»), such that the biological activity of the nitrogen monoxide species is expressed at the intended site of action.
  • Nitric oxide releasing or “nitric oxide donating” refers to methods of donating, releasing and /or directly or indirectly transferring any of the three redox forms of nitrogen monoxide (NO + , NO-, NO«), such that the biological activity of the nitrogen monoxide species is expressed at the intended site of action.
  • Nitric oxide donor or “NO donor” refers to compounds that donate, release and /or directly or indirectly transfer a nitrogen monoxide species, and /or stimulate the endogenous production of nitric oxide or endothelium-derived relaxing factor (EDRF) in vivo and /or elevate endogenous levels of nitric oxide or EDRF in vivo.
  • NO donor also includes compounds that are substrates for nitric oxide synthase.
  • Alkyl refers to a lower alkyl group, a haloalkyl group, an alkenyl group, an alkynyl group, a bridged cycloalkyl group, a cycloalkyl group or a heterocyclic ring, as defined herein.
  • Lower alkyl refers to branched or straight chain acyclic alkyl group comprising one to about ten carbon atoms (preferably one to about eight carbon atoms, more preferably one to about six carbon atoms).
  • Exemplary lower alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, neopentyl, iso-amyl, hexyl, octyl, and the like.
  • Haloalkyl refers to a lower alkyl group, an alkenyl group, an alkynyl group, a bridged cycloalkyl group, a cycloalkyl group or a heterocyclic ring, as defined herein, to which is appended one or more halogens, as defined herein.
  • exemplary haloalkyl groups include trifluoromethyl, chloromethyl, 2- bromobutyl, l-bromo-2-chloro-pentyl, and the like.
  • alkenyl refers to a branched or straight chain C 2 -C 10 hydrocarbon (preferably a C 2 -C 8 hydrocarbon, more preferably a C 2 -C 6 hydrocarbon) which can comprise one or more carbon-carbon double bonds.
  • alkenyl groups include propylenyl, buten-1-yl, isobutenyl, penten-1-yl, 2,2-methylbuten-l-yl, 3- methylbuten-1-yl, hexan-1-yl, hepten-1-yl, octen-1-yl, and the like.
  • Alkynyl refers to an unsaturated acyclic C 2 -C 10 hydrocarbon (preferably a C 2 -C 8 hydrocarbon, more preferably a C 2 -C 6 hydrocarbon) which can comprise one or more carbon-carbon triple bonds.
  • exemplary alkynyl groups include ethynyl, propynyl, butyn-1-yl, butyn-2-yl, pentyl-1-yl, pentyl-2-yl, 3-methylbutyn-l-yl, hexyl- 1-yl, hexyl-2-yl, hexyl-3-yl, 3,3-dimethyl-butyn-l-yl, and the like.
  • Bridged cycloalkyl refers to two or more cycloalkyl groups, heterocyclic groups, or a combination thereof fused via adjacent or non-adjacent atoms. Bridged cycloalkyl groups can be unsubstituted or substituted with one, two or three substituents independently selected from alkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, carboxyl, alkylcarboxylic acid, aryl, amidyl, ester, alkylcarboxylic ester, carboxamido, alkylcarboxamido, oxo and nitro.
  • Exemplary bridged cycloalkyl groups include adamantyl, decahydronapthyl, quinuclidyl, 2,6- dioxabicyclo[3.3.0]octane, 7-oxabycyclo[2.2.1]heptyl, 8-azabicyclo[3,2,l]oct-2-enyl and the like.
  • Cycloalkyl refers to a saturated or unsaturated cyclic hydrocarbon comprising from about 3 to about 8 carbon atoms. Cycloalkyl groups can be unsubstituted or substituted with one, two or three substituents independently selected from alkyl, alkoxy, amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, aryl, amidyl, ester, hydroxy, halo, carboxyl, alkylcarboxylic acid, alkylcarboxylic ester, carboxamido, alkylcarboxamido, oxo and nitro.
  • Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cyclohepta,l,3-dienyl, and the like.
  • Heterocyclic ring or group refers to a saturated, unsaturated cyclic or polycyclic hydrocarbon group having about 3 to about 12 carbon atoms (preferably about 4 to about 6 carbon atoms) where 1 to about 4 carbon atoms are replaced by one or more nitrogen, oxygen and /or sulfur atoms. Sulfur maybe in the thio, sulfinyl or sulfonyl oxidation state.
  • the heterocyclic ring or group can be fused to an aromatic hydrocarbon group.
  • Heterocyclic groups can be unsubstituted or substituted with one, two or three substituents independently selected from alkyl, alkoxy, amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, hydroxy, oxo, thial, halo, carboxyl, carboxylic ester, alkylcarboxylic acid, alkylcarboxylic ester, aryl, arylcarboxylic acid, arylcarboxylic ester, amidyl, ester, carboxamido, alkylcarboxamido, arylcarboxamido, sulfonic acid, sulfonic ester, sulfonamido and nitro.
  • heterocyclic groups include pyrrolyl, 3-pyrrolinyl,4,5,6-trihydro-2H-pyranyl, pyridinyl, 1,4- dihydropyridinyl, pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, imidazolyl, indolyl, thiophenyl, furanyl, tetrhydrofuranyl, tetrazolyl, 2- pyrrolinyl, 3-pyrrolinyl, pyrrolindinyl, oxazolindinyl 1,3-dioxolanyl, 2,6- dioxabicyclo[3,3,0]octanyl, 2-imidazonlinyl, imidazolindinyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl
  • Heterocyclic compounds refer to mono- and polycyclic compounds comprising at least one aryl or heterocyclic ring.
  • Aryl refers to a monocyclic, bicyclic, carbocyclic or heterocyclic ring system comprising one or two aromatic rings.
  • exemplary aryl groups include phenyl, pyridyl, napthyl, quinoyl, tetrahydronaphthyl, furanyl, indanyl, indenyl, indoyl, and the like.
  • Aryl groups can be unsubstituted or substituted with one, two or three substituents independently selected from alkyl, alkoxy, amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, hydroxy, carboxyl, carboxylic ester, alkylcarboxylic acid, alkylcarboxylic ester, aryl, arylcarboxylic acid, arylcarboxylic ester, alkylcarbonyl, arylcarbonyl, amidyl, ester, carboxamido, alkylcarboxamido, carbomyl, sulfonic acid, sulfonic ester, sulfonamido and nitro.
  • Exemplary substituted aryl groups include tetrafluorophenyl, pentafluorophenyl, sulfonamide, alkylsulfonyl, arylsulfon
  • Alkylaryl refers to an alkyl group, as defined herein, to which is appended an aryl group, as defined herein.
  • exemplary alkylaryl groups include benzyl, phenylethyl, hydroxybenzyl, fluorobenzyl, fluorophenylethyl, and the like.
  • Arylalkyl refers to an aryl radical, as defined herein, attached to an alkyl radical, as defined herein.
  • Cycloalkylalkyl refers to a cycloalkyl radical, as defined herein, attached to an alkyl radical, as defined herein.
  • Heterocyclicalkyl refers to a heterocyclic ring radical, as defined herein, attached to an alkyl radical, as defined herein.
  • Cycloalkenyl refers to an unsaturated cyclic hydrocarbon having about 3 to about 10 carbon atoms (preferably about 3 to about 8 carbon atoms, more preferably about 3 to about 6 carbon atoms) comprising one or more carbon- carbon double bonds.
  • Arylheterocyclic ring refers to a bi- or tricyclic ring comprised of an aryl ring, as defined herein, appended via two adjacent carbon atoms of the aryl ring to a heterocyclic ring, as defined herein.
  • exemplary arylheterocyclic rings include dihydroindole, 1,2,3,4-tetra-hydroquinoline, and the like.
  • Alkoxy refers to R 50 O-, wherein R 50 is an alkyl group, as defined herein.
  • exemplary alkoxy groups include methoxy, ethoxy, t-butoxy, cyclopentyloxy, and the like.
  • Arylalkoxy or alkoxyaryl refers to an alkoxy group, as defined herein, to which is appended an aryl group, as defined herein.
  • exemplary arylalkoxy groups include benzyloxy, phenylethoxy, chlorophenylethoxy, and the like.
  • Alkoxyalkyl refers to an alkoxy group, as defined herein, appended to an alkyl group, as defined herein.
  • exemplary alkoxyalkyl groups include methoxymethyl, methoxyethyl, isopropoxymethyl, and the like.
  • Alkoxyhaloalkyl refers to an alkoxy group, as defined herein, appended to a haloalkyl group, as defined herein.
  • exemplary alkoxyhaloalkyl groups include 4- methoxy-2-chlorobutyl and the like.
  • Cycloalkoxy refers to R 54 0-, wherein R 54 is a cycloalkyl group or a bridged cycloalkyl group, as defined herein.
  • Exemplary cycloalkoxy groups include cyclopropyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • Haloalkoxy refers to a haloalkyl group, as defined herein, to which is appended an alkoxy group, as defined herein.
  • exemplary haloalkyl groups include 1,1,1-trichloroethoxy, 2-bromobutoxy, and the like.
  • Organic cation refers to a positively charged organic ion.
  • exemplary organic cations include alkyl substituted ammonium cations, and the like.
  • Inorganic cation refers to a positively charged metal ion.
  • Exemplary inorganic cations include Group I metal cations such as for example, sodium, potassium, and the like.
  • Hydroalkyl refers to a hydroxy group, as defined herein, appended to an alkyl group, as defined herein.
  • Amino refers to -NH 2 .
  • Nirate refers to -0-N0 2 .
  • Nirite refers to -O-NO.
  • Thionitrate refers to -S-N0 2 .
  • Niro refers to the group -N0 2 and “nitrosated” refers to compounds that have been substituted therewith.
  • Niroso refers to the group -NO and “nitrosylated” refers to compounds that have been substituted therewith.
  • Halogen or “halo” refers to iodine (I), bromine (Br), chlorine (Cl), and/or fluorine (F).
  • Alkylamino refers to R 50 NH-, wherein R 50 is an alkyl group, as defined herein. Exemplary alkylamino groups include methylamino, ethylamino, butylamino, cyclohexylamino, and the like.
  • Arylamino refers to R 55 NH-, wherein R 55 is an aryl group, as defined herein.
  • Dialkylamino refers to R 50 R 52 N-, wherein R 50 and R 52 are each independently an alkyl group, as defined herein. Exemplary dialkylamino groups include dimethylamino, diethylamino, methyl propargylamino, and the like.
  • Diarylamino refers to R 55 R 60 N-, wherein R 55 and R 60 are each independently an aryl group, as defined herein.
  • Alkylarylamino refers to R 50 R 55 N-, wherein R 50 is an alkyl group, as defined herein, and R 55 is an aryl group, as defined herein.
  • Aminoalkyl refers to an amino group, an alkylamino group, a dialkylamino group, an arylamino group, a diarylamino group, an alkylarylamino group or a heterocyclic ring, as defined herein, to which is appended an alkyl group, as defined herein.
  • Aminoaryl refers to an amino group, an alkylamino group, a dialkylamino group, an arylamino group, a diarylamino group, an alkylarylamino group or a heterocyclic ring, as defined herein, to which is appended an aryl group, as defined herein.
  • Method refers to -C(S)-.
  • Sulfonic acid refers to -S(0) 2 OR 76 , wherein R 76 is a hydrogen, an organic cation or an inorganic cation.
  • Alkylsulfonic acid refers to a sulfonic acid group, as defined herein, appended to an alkyl group, as defined herein.
  • Arylsulfonic acid refers to an sulfonic acid group, as defined herein, appended to an aryl group, as defined herein
  • Sulfonic ester refers to -S(0) 2 OR 58 , wherein R 58 is an alkyl group, an aryl group, an alkylaryl group or an aryl heterocyclic ring, as defined herein.
  • “Sulfonamido” refers to -S(0) 2 -N(R 51 )(R 57 ), wherein R 51 and R 57 are each independently a hydrogen atom, an alkyl group, an aryl group, an alkylaryl group, or an arylheterocyclic ring, as defined herein, and R 51 and R 57 when taken together are a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group, as defined herein.
  • Alkylsulfonamido refers to a sulfonamido group, as defined herein, appended to an alkyl group, as defined herein.
  • Arylsulfonamido refers to a sulfonamido group, as defined herein, appended to an aryl group, as defined herein.
  • Sulfamoyl refers to R 51 S(0) 2 -N(R 57 )-, wherein R 51 and R 57 are each independently a hydrogen atom, an alkyl group, an aryl group, an alkylaryl group, or an arylheterocyclic ring, as defined herein, and R 51 and R 57 when taken together are a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group, as defined herein.
  • Alkylthio refers to R 50 S-, wherein R 50 is an alkyl group, as defined herein.
  • Arylthio refers to R 55 S-, wherein R 55 is an aryl group, as defined herein.
  • Cycloalkylthio refers to R 54 S-, wherein R 54 is a cycloalkyl group or a bridged cycloalkyl group, as defined herein.
  • exemplary cycloalkylthio groups include cyclopropylthio, cyclopentylthio, cyclohexylthio, and the like.
  • Alkylsulfinyl refers to R 50 -S(O)-, wherein R 50 is an alkyl group, as defined herein.
  • Alkylsulfonyl refers to R 50 -S(O) 2 -, wherein R 50 is an alkyl group, as defined herein.
  • Arylsulfinyl refers to R 55 -S(0)-, wherein R 55 is an aryl group, as defined herein.
  • Arylsulfonyl refers to R 55 -S(0) 2 -, wherein R 55 is an aryl group, as defined herein.
  • “Amidyl” refers to R 51 C(0)N(R 57 )- wherein R 51 and R 57 are each independently a hydrogen atom, an alkyl group, an aryl group, an alkylaryl group, or an arylheterocyclic ring, as defined herein.
  • Ester refers to R 51 C(0)0- wherein R 51 is a hydrogen atom, an alkyl group, an aryl group, an alkylaryl group, or an arylheterocyclic ring, as defined herein.
  • Carbamoyl refers to -0-C(0)N(R 51 )(R 57 ), wherein R 51 and R 57 are each independently a hydrogen atom, an alkyl group, an aryl group, an alkylaryl group or an arylheterocyclic ring, as defined herein, or R 51 and R 57 taken together are a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group, as defined herein.
  • Carboxyl refers to -C(0)OR 76 , wherein R 76 is a hydrogen, an organic cation or an inorganic cation, as defined herein.
  • Carbonyl refers to -C(0)-.
  • Alkylcarbonyl or “alkanoyl” refers to R 50 -C(O)-, wherein R 50 is an alkyl group, as defined herein.
  • Arylcarbonyl or “aroyl” refers to R 55 -C(0)-, wherein R 55 is an aryl group, as defined herein.
  • Carboxylic ester refers to -C(0)OR 58 , wherein R 58 is an alkyl group, an aryl group, an alkylaryl group or an aryl heterocyclic ring, as defined herein.
  • R 58 is an alkyl group, an aryl group, an alkylaryl group or an aryl heterocyclic ring, as defined herein.
  • Alkylcarboxylic acid and “alkylcarboxyl” refer to an alkyl group, as defined herein, appended to a carboxyl group, as defined herein.
  • Alkylcarboxylic ester refers to an alkyl group, as defined herein, appended to a carboxylic ester group, as defined herein.
  • Arylcarboxylic acid refers to an aryl group, as defined herein, appended to a carboxyl group, as defined herein.
  • Arylcarboxylic ester and “arylcarboxyl” refer to an aryl group, as defined herein, appended to a carboxylic ester group, as defined herein.
  • Carboxamido refers to -C(0)N(R 51 )(R 57 ), wherein R 51 and R 57 are each independently a hydrogen atom, an alkyl group, an aryl group, an alkylaryl group or an arylheterocyclic ring, as defined herein, and R ⁇ and R j7 when taken together are a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group, as defined herein.
  • Alkylcarboxamido refers to an alkyl group, as defined herein, appended to a carboxamido group, as defined herein.
  • Arylcarboxamido refers to an aryl group, as defined herein, appended to a carboxamido group, as defined herein.
  • Rea refers to -N(R 59 )-C(0)N(R 51 )(R 57 ) wherein R 51 , R 57 , and R 59 are each independently a hydrogen atom, an alkyl group, an aryl group, an alkylaryl group, or an arylheterocyclic ring, as defined herein, or R 51 and R 57 taken together are a heterocyclic ring, a cycloalkyl group or a bridged cycloalkyl group, as defined herein.
  • Phosphoryl refers to -P(R 70 )(R 71 )(R 72 ), wherein R 70 is a lone pair of electrons, sulfur or oxygen, and R 71 and R 72 are each independently a covalent bond, a hydrogen, a lower alkyl, an alkoxy, an alkylamino, a hydroxy or an aryl, as defined herein.
  • nitric oxide species in vivo have a wide spectrum of advantages and applications.
  • the present invention is based on the discovery of the effects of such compounds together with one or more proton pump inhibitors and /or one or more proton pump inhibitors directly or indirectly linked with one or more nitric oxide moieties.
  • Treatment or prevention of gastrointestinal disorders, improved gastroprotective properties, decreased rate of recurrence of peptic ulcers and faster ulcer healing can be obtained by the use of the nitrosated and/or nitrosylated proton pump inhibitors of the present invention.
  • Treatment or prevention of gastrointestinal disorders, improved gastroprotective properties, decreased rate of recurrence of peptic ulcers and faster ulcer healing can also be obtained by the use of one or more proton pump inhibitors, that are optionally directly or indirectly linked with one or more nitric oxide moieties, in conjunction with one or more compounds that donate, release or transfer nitric oxide or stimulate endogenous production of nitric oxide or EDRF in vivo or are substrates for nitric oxide synthase.
  • Proton pump inhibitors are compounds that selectively inhibit gastric acid secretion by the specific inhibition of the (H + , K + )-ATPase enzyme system at the secretory surface of the gastric parietal cell.
  • a nitric oxide donor is a compound that contains at least one nitric oxide adduct and releases or chemically transfers a biologically active nitrogen monoxide species.
  • the compounds and compositions of the present invention are novel and can be used to treat numerous gastrointestinal diseases and disorders.
  • Such gastrointestinal disorders include, for example, inflammatory bowel disease, Crohn's disease, irritable bowel syndrome, ulcerative colitis, peptic ulcers, stress ulcers, bleeding peptic ulcers, duodenal ulcers, infectious enteritis, colitis, diverticulitis, gastric hyperacidity, gastric hyperacidity, dyspepsia, gastroparesis,
  • the compounds and compositions of the present invention can also be used as a pre-anesthetic medication in emergency operations to reduce the danger of aspiration of acidic gastric contents
  • the proton pump inhibitors used in the compounds and compositions of the present invention can be any of those known in the art, such as those exemplified herein.
  • Omeprazole i.e., 5-methoxy-2((4-methoxy-3,5-dimethyl-2- pyridinyl)methyl)-sulfinyl)-lH-benzimidazole, (marketed under the trade name PRILOSEC ® by Astra Merck, Wayne, PA) and lansoprazole, i.e., 2-(((3-methyl-4- (2,2,2-trifluoro-ethoxy)-2-pyridinyl)methyl)sulfinyl)-lH-benzimidazole (marketed under the trade name PREVACID ® by TAP Pharmaceutical Inc., Deerfield, IL) are two of the most widely used compounds that inhibit gastric acid secretion.
  • rabeprazole i.e., 2-(((4-(3-methoxypropoxy)-3-methyl- 2-pyridinyl)methyl)sulfinyl)-lH-benzimidazole (marketed under the trade name ACIPHEX ® by Eisai, Inc.), pantoprazole, i.e., 5-(difluoromethoxy)-2-(((3,4- dimethoxy-2-pyridinyl)methyl)sulfinyl)-lH-benzimidazole, leminoprazole, timoprazole, tenatoprazole, disulprazole, esomeprazole, RO 18-5362, IY 81149.
  • Another group of proton pump inhibitors are substituted quinolines, which include, for example, 3-butyl-4-(2-methylphenylamino)-8-(2- hydroxyethoxy)-quinoline.
  • the proton pump inhibitors of the present invention can be nitrosated and /or nitrosylated through one or more sites such as oxygen (hydroxyl condensation), sulfur (sulfhydryl condensation), carbon and nitrogen.
  • the proton pump inhibitor compounds that are nitrosated and/or nitrosylated in accordance with the invention and/or are included in the compositions of the invention can be any of those known in the art, including those exemplified below.
  • the present invention describes nitrosated and /or nitrosylated proton pump inhibitors of Formula (I) or a pharmaceutically acceptable salt thereof:
  • A is S, S(O), or S(0) 2 ;
  • B is -CNR 7 R 7 ' or nitrogen;
  • J is CH or nitrogen;
  • R j 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., or -SD ⁇ or R 2 and R j 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 n are each independently a hydrogen, an alkoxy group, a lower alkyl group, or an alkylthio group; or R 3 and R ⁇ 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 j , or -C0 2 R 12 ; or R 4 and R 5 taken together are:
  • 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 j 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 j is a hydrogen or D
  • D is Q or K
  • Q is -NO or -N0 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 r E r 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 0) 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 0) 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
  • T at each occurrence is independently a covalent bond, a carbonyl, an oxygen,
  • o is an integer from 0 to 2;
  • R a is a lone pair of electrons, a hydrogen or an alkyl group;
  • R 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 0 2 -) " «M + , wherein M + is an organic or inorganic cation; with the provis
  • R can be a substituent on any disubstituted nitrogen contained within the radical where R, is as defined herein.
  • 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 K;
  • R 9 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, -NR 7 D j , -OD lr or -C0 2 R 12 ;
  • R 71 is a hydrogen, a lower alkyl group, an alkoxy group, or -OD j ,- J, K, D j , R 7 , R 12 , q and o are as defined herein; and with the proviso that the compounds of Formula (II) must contain at least one nitrite, nitrate, thionitrite or thionitrate group.
  • Another embodiment of the present invention describes compounds of Formula (III) or pharmaceutically acceptable salts thereof:
  • R 13 and R 14 are each independently a hydrogen a lower alkyl group, an alkoxyalkyl, or a lower alkyl-OD ⁇ or R 13 and R 14 taken together along with the carbons to which they are attached form a cycloalkyl group or an aryl group;
  • R 17 is a hydrogen or a lower alkyl group;
  • Y 3 is:
  • R 15 is a hydrogen or a lower alkyl group
  • R 16 is a hydrogen, a halogen, or a lower alkyl group
  • R 63 is a lower alkyl group or a phenyl group
  • a u A 2 and A 3 comprise the other subunits of a 5- or 6-membered monocyclic aromatic ring and A u A 2 and A 3 are each independently:
  • B a B b , wherein B a and B b are each independently a nitrogen atom or CR 0 ; wherein R 0 at each occurrence is hydrogen or -OD.; D j and K are as defined herein; and with the proviso that the compounds of Formula (III) must contain at least one nitrite, nitrate, thionitrite or thionitrate group.
  • R lg and R 19 at each occurrence are each independently a hydrogen, a lower alkyl group, a halogen, a nitro group, an alkoxy group, -OD j , -NR 20 R 21 , -O(O)CR 20 , -O(O)COR 20 , -O(O)CNR 20 R 21 , -N(R 20 )C(O)R 21 , -N(R 20 )C(O)NR 20 R 21 , or
  • R 20 and R 21 at each occurrence are each independently a hydrogen, a lower alkyl group, an aryl group, a lower alkylaryl group, or K;
  • R 22 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;
  • D j , R 6 , and K are defined as herein; and with the proviso that the compounds of Formula (IV) must contain at least one nitrite, nitrate, thionitrite or thionitrate group.
  • Another embodiment of the present invention describes compounds of Formula (N) or pharmaceutically acceptable salt thereof:
  • R 23 is a hydrogen, a dialkylamino group, -NR 7 R 7 ', or a heterocyclic ring;
  • R 24 is a hydrogen or halogen
  • R 25 is a hydrogen, -OD lr or lower alkyl-OD j ;
  • R 27 at each occurrence is independently a hydrogen or an alkoxy group
  • R 28 , R 29 , and R 30 are each independently a hydrogen, a lower alkyl group, a dialkylamino group, a heterocyclic ring, or a lower alkyl-OD ⁇
  • R 31 is a hydrogen, a dialkylamino group, or an alkoxy group
  • R 33 is a hydrogen or a lower alkyl group; n is an integer from 0 to 1; R 7 , R 7 ', D j and q are as defined herein; and with the proviso that the compounds of Formula (V) must contain at least one nitrite, nitrate, thioni trite or thionitrate group.
  • Another embodiment of the present invention describes compounds of Formula (VI) or pharmaceutically acceptable salts thereof:
  • a 4 , A 5 , and A 6 are each independently a sulfur or CR 34 with the proviso that one of A 4 , A 5 , or A 6 is a sulfur and the other two are CR 34 ;
  • R 34 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- OD,, 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 s
  • R 35 and R 36 are each independently a hydrogen or a lower alkyl group; or R 35 and R 4I taken together with the carbon chain to which they are attached form a cycloalkyl ring;
  • R 26 is:
  • X 6 is nitrogen, and Y 6 is CR 37 ; or X 6 is CR 37 , and Y 6 is nitrogen;
  • R 37 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;
  • Z 6 is -NR 38 R 39 , SR 40 , or an arylalkoxy group
  • R 38 and R 39 are each independently a hydrogen, a lower alkyl group, an aryl group, an alkylaryl group, or a cycloalkyl group; or R 38 and R 39 taken together with the nitrogen to which they are attached form a heterocyclic ring;
  • R 40 is a hydrogen, a halogen, a lower alkyl group, an alkylaryl group, an alkenyl group, or a haloalkyl group;
  • R 41 , R 42 , R 43 , and R 44 are each independently a hydrogen, a halogen, a lower alkyl group, an alkoxy group, a haloalkoxy group, an alkoxyaryl group, an alkylthio group, an alkysulfinyl group, an alkylsulfonyl group, a cyano group, -Y-OD,, Y-SD-, -Y-NR 20 R 21 , -Y-O(O)CR 20 , -Y-O(O)CNR 20 R 21 , -Y-N(R 20 )C(O)R 21 , or -Y-N(R 20 )S(O) 2 R 21 ;
  • Y is -(CH 2 ) a - or a
  • R 45 and R 46 are each independently a hydrogen, a lower alkyl group, a cycloalkyl group, an alkenyl group, or an alkynyl group; D j , R 20 , R 21 , and a are as defined herein; and with the proviso that the compounds of Formula (VI) must contain at least one nitrite, nitrate, thionitrite or thionitrate group.
  • R 60 is a lower alkyl group, an aryl group, a haloalkyl group, a lower alkyl- OD j , or heterocyclic ring;
  • a 7 is oxygen or -ND,
  • X 7 is a hydrogen or a halogen
  • Y 7 is:
  • R 61 is a hydrogen, a halogen, a lower alkyl group, -OD lr or -NHC(0)0-lower alkyl;
  • R 62 is a hydrogen, a halogen, or a lower alkyl group; and D j is as defined herein.
  • Compounds of the present invention that have one or more asymmetric carbon atoms may exist as the optically pure enantiomers, pure diastereomers, mixtures of enantiomers, mixtures of diastereomers, racemic mixtures of enantiomers, diastereomeric racemates or mixtures of diastereomeric racemates. It is to be understood that the present invention anticipates and includes within its scope all such isomers and mixtures thereof.
  • the present invention is intended to include within its scope compounds which may exist in more than one resonance form and the effects that the resonance form may have on the positions at D j substituents designated in the structures described herein.
  • Another embodiment of the present invention provides processes for making the novel compounds of the present invention and to the intermediates useful in such processes. The reactions are performed in solvents appropriate to the reagents and materials used are suitable for the transformations being effected. It is understood by one skilled in the art of organic synthesis that the functionality present in the molecule must be consistent with the chemical transformation proposed. This will, on occasion, necessitate judgment by the routineer as to the order of synthetic steps, protecting groups required, and deprotection conditions.
  • the nitrosated and nitrosylated proton pump inhibitors of the present invention can be synthesized as shown in reaction Schemes 1 through 7 presented herein.
  • the parent proton pump inhibitor compounds can be nitrosated and /or nitrosylated through one or more sites such as oxygen, sulfur, carbon and /or nitrogen using the methods described in the examples herein and using conventional methods known to one skilled in the art.
  • known methods for nitrosating and nitrosylating compounds are described in U.S. Patent Nos. 5,380,758 and 5,703,073; WO 97/27749; WO 98/19672; and Oae et al, Org. Prep. Proc.
  • the substituted imidazole nitrogen group of formula 1 is converted to the anion by treatment with one equivalent of a strong non-nucleophilic base, such as sodium hydride or potasium hydride, in an aprotic solvent, such as tetrahydrofuran (THF) or dimethylformamide (DMF).
  • a strong non-nucleophilic base such as sodium hydride or potasium hydride
  • an aprotic solvent such as tetrahydrofuran (THF) or dimethylformamide (DMF).
  • THF tetrahydrofuran
  • DMF dimethylformamide
  • the carbamate of formula I A, IB, or IC where p, X, R e and R f are as defined herein, is prepared by reacting the imidazole anion with a suitably functionalized chloroformate in an inert solvent, such as THF or DMF. Typically the coupling reaction is performed at a temperature ranging from -78
  • Preferred methods for the formation of chloroformates are reacting one equivalent of a X functionalized alcohol with one equivalent of phosgene at a temperature ranging from -78 °C to 0 °C in an inert solvent, such as ether or THF and in the presence of an amine base, such as pyridine or triethylamine. Removal of the amine hydrochloride by filtration affords a solution of the desired chloroformate which may be used directl or concentrated and redissolved in the anhydrous solution of choice prior to the coupling reaction with the imidazole anion to afford the carbamate of formula IA, IB, or IC.
  • an inert solvent such as ether or THF
  • an amine base such as pyridine or triethylamine
  • the chloroformate would be prepared by reacting phosgene with an alcohol containing a protected alcohol or thiol moiety.
  • Preferred protecting groups for an alcohol moiety are silyl ethers, such as a trimethylsilyl ether, a tert-butyldimethylsilyl ether, or a tert- butyldiphenylsilyl ether.
  • deprotection of the hydroxyl moiety is the preferred method for removing silyl ether protecting groups
  • a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, or nitrosonium tetrafluoroborate
  • a suitable anhydrous solvent such as dichloromethane, THF, DMF, or acetonitrile
  • an amine base such as pyridine or triethylamine
  • Preferred protecting groups for the thiol moiety are as a thioester, such as a thioacetate or a thiobenzoate or as a disulfide.
  • a thioester such as a thioacetate or a thiobenzoate or as a disulfide.
  • Deprotection of the thiol moiety (zinc in dilute aqueous acid, triphenylphosphine in water and sodium borohydride are preferred methods for reducing disulfide groups while aqueous base or sodium methoxide in methanol is typically used to hydrolyze thioesters) followed by reaction with a suitable nitrosylating agent such, as thionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite, such as tert-butyl nitrite, or nitrosonium tetrafluoroborate, in a suitable anhydrous solvent, such
  • Nitrosation of the carbamate product may be accomplished by first converting the deprotected alcohol to a leaving group such as a mesylate or a tosylate. This reaction is typically performed at a temperature of 0 °C to room temperature in an inert solvent, such as ether, THF, or dichloromethane with the alcohol, methansulfonyl chloride or para- toluensulfonyl chloride, and an amine base, such as triethylamine or pyridine, as the reactants. The corresponding iodide is then prepared by reacting the mesylate or tosylate with sodium iodide in acetone.
  • an inert solvent such as ether, THF, or dichloromethane
  • an amine base such as triethylamine or pyridine
  • the halide may also be formed from the alcohol by treatment of the hydroxyl moiety with a phosphorus reagent, such as triphenylphosphine, in the presence of a halide source, such as carbon tetrabromide or N-iodosuccimide, in an inert solvent, such as THF. Treatment of the bromide or iodide with silver nitrate in an inert solvent, such as acetonitrile, affords the compound of formula IC.
  • the halide containing carbamate may be formed directly by preparing a halide containing chloroformate from a halide containing alcohol. Preferred halides are bromide and iodide.
  • IA X ONO
  • nitrite, nitrate, or thionitrite containing alkoxyethyl ester is representative of the K group, as defined herein, may be prepared as shown in Scheme 2.
  • the hydroxyl group of formula 2 is converted to the ester of formula HA, HB, or IIC, where p, R e , Rf and X are as defined herein, by reaction with an appropriate nitrite, thionitrite, or nitrate containing activated acylating agent.
  • Preferred methods for the formation of esters are reacting the alcohol with the preformed acid chloride or anhydride of the nitrite, thionitrite, or nitrate containing acid.
  • Preferred methods for preparing acid chlorides are treating the carboxylic acid with oxalyl chloride and a catalytic amount of DMF in an inert solvent, such as ether, THF, dichloromethane, or toluene.
  • Preferred methods for preparing mixed anhydride are reacting the carboxylic acid with a chloroformate such as isobutylchloroformate in the presence of an amine base, such as triethylamine in an inert solvent, such as ether, THF, dichloromethane, or toluene.
  • the alcohol and nitrite, thionitrite, or nitrate containing acid may be condensed in the presence of a dehydrating agent, such as dicyclohexylcarbodiimide (DCC) or l-ethyl-3 (3-dimethylaminopropyl) carbodiimide hydrochloride (EDAC-HC1) with or without a catalyst, such as 4- dimethylaminopyridine (DMAP) or 1-hydroxybenzotriazole (HOBt).
  • DCC dicyclohexylcarbodiimide
  • EDAC-HC1 l-ethyl-3 (3-dimethylaminopropyl) carbodiimide hydrochloride
  • DMAP 4- dimethylaminopyridine
  • HOBt 1-hydroxybenzotriazole
  • the activated acylating agent would be prepared from an acid containing a protected alcohol or thiol moiety.
  • Preferred protecting groups for an alcohol moiety are silyl ethers, such as a trimethylsilyl ether, a tert-butyldimethylsilyl ether, or a tert-butyldiphenylsilyl ether.
  • deprotection of the hydroxyl moiety is the preferred method for removing silyl ether protecting groups
  • a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, or nitrosonium tetrafluoroborate
  • a suitable anhydrous solvent such as dichloromethane, THF, DMF, or acetonitrile
  • an amine base such as pyridine or triethylamine
  • Preferred protecting groups for the thiol moiety are as a thioester, such as a thioacetate or a thiobenzoate, or as a disulfide.
  • a thioester such as a thioacetate or a thiobenzoate
  • disulfide a disulfide.
  • Deprotection of the thiol moiety (zinc in dilute aqueous acid, triphenylphosphine in water and sodium borohydride are preferred methods for reducing disulfide groups while aqueous base or sodium methoxide in methanol is typically used to hydrolyze thioesters) followed by reaction with a suitable nitrosylating agent such, as thionyl chloride nitrite or thionyl dinitrite, a lower alkyl nitrite, such as tert-butyl nitrite, or nitrosonium tetrafluoroborate, in a suitable an
  • Nitrosation of the ester product may be accomplished by first converting the deprotected alcohol to a leaving group, such as a mesylate or a tosylate. This reaction is typically performed at a temperature of 0 °C to room temperature in an inert solvent, such as ether, THF, or dichloromethane with the alcohol, methansulfonyl chloride or para-toluensulfonyl chloride, and an amine base, such as triethylamine or pyridine, as the reactants. The corresponding iodide is then prepared by reacting the mesylate or tosylate with sodium iodide in acetone.
  • a leaving group such as a mesylate or a tosylate.
  • the halide may also be formed from the alcohol by treatment of the hydroxyl moiety with a phosphorus reagent, such as triphenylphosphine, in the presence of a halide source, such as carbon tetrabromide or N-iodosuccimide, in an inert solvent, such as THF. Treatment of the bromide or iodide with silver nitrate in an inert solvent, such as acetonitrile affords the compound of formula IIC.
  • the halide containing ester may be formed directly by preparing a halide containing active acylating agent from a halide containing acid. Preferred halides are bromide and iodide.
  • Coupling of the alcohol with the halide containing active acylating agent followed by reaction of the ester product with silver nitrate in an inert solvent, such as acetonitrile affords the compound of formula IIC.
  • Preferred coupling methods for the formation of esters from alcohols are those methods described herein (e.g. with the preformed acid chloride or anhydride or with the carboxylic acid and a dehydration agent, such as DCC or EDAC-HC1).
  • R 14 , R 17 , A,, A 2 , A 3 , R e , R f , Y 3 , and p are as defined herein, and a nitrite, nitrate, or thionitrite containing acyloxymethyl ester is representative of the R 13 group may be prepared as shown in Scheme 3.
  • the hydroxyl group of formula 3 is converted to the ester of formula IIIA, IIIB, or IIIC, where p, R e , Rf and X are as defined herein, by reaction with an appropriate nitrite, thionitrite, or nitrate containing activated acylating agent.
  • esters are reacting the alcohol with the preformed acid chloride or symmetrical anhydride of the nitrite, thionitrite, or nitrate containing acid.
  • Preferred methods for preparing acid chlorides are treating the carboxylic acid with oxalyl chloride and a catalytic amount of DMF in an inert solvent, such as ether, THF, dichloromethane, or toluene.
  • Preferred methods for preparing mixed anhydride are reacting the carboxylic acid with a chloroformate, such as isubutylchloroformate, in the presence of an amine base, such as triethylamine in an inert solvent solvent, such as ether, THF, dichloromethane, or toluene.
  • a chloroformate such as isubutylchloroformate
  • an amine base such as triethylamine
  • an inert solvent solvent such as ether, THF, dichloromethane, or toluene.
  • the alcohol and nitrite, thionitrite, or nitrate containing acid may be condensed in the presence of a dehydrating agent, such as DCC or EDAC-HC1 with or without a catalyst, such as DMAP or HOBt.
  • the activated acylating agent would be prepared from an acid containing a protected alcohol or thiol moiety.
  • Preferred protecting groups for an alcohol moiety are silyl ethers, such as a trimethylsilyl ether, a tert-butyldimethylsilyl ether, or a tert-butyldiphenylsilyl ether.
  • deprotection of the hydroxyl moiety is the preferred method for removing silyl ether protecting groups
  • a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, or nitrosonium tetrafluoroborate
  • a suitable anhydrous solvent such as dichloromethane, THF, DMF, or acetonitrile
  • an amine base such as pyridine or triethylamine affords the compound of formula IIIA.
  • Preferred protecting groups for the thiol moiety are as a thioester, such as a thioacetate or a thiobenzoate or as a disulfide. Deprotection of the thiol moiety
  • aqueous base or sodium methoxide in methanol is typically used to hydrolyze thioesters
  • a suitable nitrosylating agent such as thionyl chloride nitrite or thionyl dinitrite, a lower alkyl nitrite, such as tert-butyl nitrite, or nitrosonium tetrafluoroborate
  • a suitable anhydrous solvent such as methylene chloride, THF, DMF, or acetonitrile
  • an amine base such as pyridine or triethylamine
  • Nitrosation of the ester product may be accomplished by first converting the deprotected alcohol to a leaving group, such as a mesylate or a tosylate. This reaction is typically performed at a temperature of 0 °C to room temperature in an inert solvent, such as ether, THF, or dichloromethane with the alcohol, methansulfonyl chloride or para-toluensulfonyl chloride, and an amine base, such as triethylamine or pyridine as the reactants. The corresponding iodide is then prepared by reacting the mesylate or tosylate with sodium iodide in acetone.
  • a leaving group such as a mesylate or a tosylate.
  • the halide may also be formed from the alcohol by treatment of the hydroxyl moiety with a phosphorus reagent, such as triphenylphosphine, in the presence of a halide source, such as carbon tetrabromide or N-iodosuccimide, in an inert solvent, such as THF. Treatment of the bromide or iodide with silver nitrate in an inert solvent, such as acetonitrile, affords the compound of formula IIIC.
  • the halide containing ester may be formed directly by preparing a halide containing active acylating agent from a halide containing acid. Preferred halides are bromide and iodide.
  • Preferred coupling methods for the formation of esters from alcohols are those methods described herein (e.g. with the preformed acid chloride or anhydride or with the carboxylic acid and a dehydration agent, such as DCC or EDAC-HC1).
  • the acid of the formula 4 is converted to the ester of formula IV A, IVB, or IVC, where p, Rg, Rf and X are as defined herein, by reaction with an appropriate nitrite, thionitrite, or nitrate containing alcohol.
  • Preferred methods for the preparation of esters are initially forming the mixed anhydride via reaction of 4 with a chloroformate, such as isobutylchloroformate, in the presence of a non nucleophilic base, such as triethylamine, in an anhydrous inert solvent, such as dichloromethane, diethylether or THF.
  • a chloroformate such as isobutylchloroformate
  • a non nucleophilic base such as triethylamine
  • an anhydrous inert solvent such as dichloromethane, diethylether or THF.
  • the mixed anhydride is then reacted with the nitrite, thionitrite, or nitrate containing alcohol preferably in the presence of a condensation catalyst, such as DMAP.
  • the acid 4 may be first converted to the acid chloride by treatment with oxalyl chloride in the presence of a catalytic amount of DMF.
  • the acid chloride is then reacted with the nitrite, thionitrite, or nitrate containing alcohol preferably in the presence of a condensation catalyst, such as DMAP, and a tertiary amine base, such as triethylamine, to afford the ester of formula IV A, IVB, or IVC.
  • a condensation catalyst such as DMAP
  • a tertiary amine base such as triethylamine
  • the acid 4 and nitrite, thionitrite, or nitrate containing alcohol may be coupled to afford the ester of formula IV A, IVB, or IVC by treatment with a dehydration agent, such as DCC or EDAC-HC1, with or without a catalyst, such as DMAP or
  • the ester would be prepared by reacting the carboxylic acid with an alcohol containing a protected alcohol or thiol moiety.
  • Preferred protecting groups for an alcohol moiety are silyl ethers, such as a trimethylsilyl ether, a tert-butyldimethylsilyl ether, or a tert-butyldiphenylsilyl ether.
  • deprotection of the hydroxyl moiety is the preferred method for removing silyl ether protecting groups
  • a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, or nitrosonium tetrafluoroborate
  • a suitable anhydrous solvent such as dichloromethane, THF, DMF, or acetonitrile
  • an amine base such as pyridine or triethylamine
  • Preferred protecting groups for the thiol moiety are as a thioester, such as a thioacetate or a thiobenzoate or as a disulfide.
  • a thioester such as a thioacetate or a thiobenzoate or as a disulfide.
  • Deprotection of the thiol moiety (zinc in dilute aqueous acid, triphenylphosphine in water and sodium borohydride are preferred methods for reducing disulfide groups while aqueous base or sodium methoxide in methanol is typically used to hydrolyze thioesters) followed by reaction with a suitable nitrosylating agent such, as thionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite, such as tert-butyl nitrite, or nitrosonium tetrafluoroborate, in a suitable anhydrous solvent, such
  • Nitrosation of the ester product containing a deprotected alcohol moiety may be accomplished by first converting the alcohol to a leaving group, such as a mesylate or a tosylate. This reaction is typically performed at a temperature of 0 °C to room temperature in an inert solvent, such as ether, THF, or dichloromethane with the alcohol, methansulfonyl chloride or para- toluensulfonyl chloride, and an amine base, such as triethylamine or pyridine, as the reactants. The corresponding iodide is then prepared by reacting the mesylate or tosylate with sodium iodide in acetone.
  • a leaving group such as a mesylate or a tosylate.
  • the halide may also be formed from the alcohol by treatment of the hydroxyl moiety with a phosphorus reagent , such as triphenylphosphine, in the presence of a halide source, such as carbon tetrabromide or N-iodosuccimide, in an inert solvent, such as THF. Treatment of the bromide or iodide with silver nitrate in an inert solvent, such as acetonitrile, affords the compound of formula IVC.
  • the halide containing ester may be formed directly by preparing a halide containing active acylating agent from a halide containing acid. Preferred halides are bromide and iodide.
  • the hydroxyl group of formula 5 is converted to the ester of formula VA, VB, or VC, where p, R e , Rf and X are as defined herein, by reaction with an appropriate nitrite, thionitrite, or nitrate containing activated acylating agent.
  • Preferred methods for the formation of esters are reacting the alcohol with the preformed acid chloride or symmetrical anhydride of the nitrite, thionitrite, or nitrate containing acid.
  • Preferred methods for preparing acid chlorides are treating the carboxylic acid with oxalyl chloride and a catalytic amount of DMF in an inert solvent, such as ether, THF, dichloromethane, or toluene.
  • Preferred methods for preparing mixed anhydride are reacting the carboxylic acid with a chloroformate, such as isubutylchloroformate, in the presence of an amine base, such as triethylamine, in an inert solvent solvent, such as ether, THF, dichloromethane, or toluene.
  • a chloroformate such as isubutylchloroformate
  • an amine base such as triethylamine
  • an inert solvent solvent such as ether, THF, dichloromethane, or toluene.
  • the alcohol and nitrite, thionitrite, or nitrate containing acid may be condensed in the presence of a dehydrating agent, such as
  • DCC or EDAC-HC1 with or without a catalyst, such as DMAP or HOBt.
  • the activated acylating agent would be prepared from an acid containing a protected alcohol or thiol moiety.
  • Preferred protecting groups for an alcohol moiety are silyl ethers, such as a trimethylsilyl ether, a tert-butyldimethylsilyl ether, or a tert-butyldiphenylsilyl ether.
  • deprotection of the hydroxyl moiety is the preferred method for removing silyl ether protecting groups
  • a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, or nitrosonium tetrafluoroborate
  • a suitable anhydrous solvent such as dichloromethane, THF, DMF, or acetonitrile
  • an amine base such as pyridine or triethylamine affords the compound of formula VA.
  • Preferred protecting groups for the thiol moiety are as a thioester, such as a thioacetate or a thiobenzoate or as a disulfide. Deprotection of the thiol moiety
  • aqueous base or sodium methoxide in methanol is typically used to hydrolyze thioesters
  • a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite, such as tert-butyl nitrite, or nitrosonium tetrafluoroborate
  • a suitable anhydrous solvent such as methylene chloride, THF, DMF, or acetonitrile
  • an amine base such as pyridine or triethylamine
  • Nitrosation of the ester product may be accomplished by first converting the deprotected alcohol to a leaving group, such as a mesylate or a tosylate. This reaction is typically performed at a temperature of 0 °C to room temperature in an inert solvent, such as ether, THF, or dichloromethane with the alcohol, methansulfonyl chloride or para-toluensulfonyl chloride, and an amine base, such as triethylamine or pyridine as the reactants. The corresponding iodide is then prepared by reacting the mesylate or tosylate with sodium iodide in acetone.
  • a leaving group such as a mesylate or a tosylate.
  • the halide may also be formed from the alcohol by treatment of the hydroxyl moiety with a phosphorus reagent, such as triphenylphosphine in the presence of a halide source, such as carbon tetrabromide or N-iodosuccimide in an inert solvent, such as THF. Treatment of the bromide or iodide with silver nitrate in an inert solvent, such as acetonitrile, affords the compound of formula VC.
  • a phosphorus reagent such as triphenylphosphine
  • a halide source such as carbon tetrabromide or N-iodosuccimide
  • an inert solvent such as THF
  • the halide containing ester may be formed directly by preparing a halide containing active acylating agent from a halide containing acid.
  • Preferred halides are bromide and iodide. Coupling of the alcohol with the halide containing active acylating agent followed by reaction of the ester product with silver nitrate in an inert solvent, such as acetonitrile, affords the compound of formula VC.
  • Preferred coupling methods for the formation of esters from alcohols are those methods described herein (e.g. with the preformed acid chloride or anhydride or with the carboxylic acid and a dehydration agent, such as DCC or EDAC-HC1).
  • VA X ONO
  • VB X SNO
  • R 26 , R 35 , R 36 , A, A 4 , A 5 , A 6 , R e , R f , and p are as defined herein, and a nitrite, nitrate, or thionitrite containing carbamate is representative of the
  • D, group, as defined herein may be prepared as shown in Scheme 6.
  • the substituted imidazole nitrogen group of formula 6 is converted to the anion by treatment with one equivalent of a strong non-nucleophilic base, such as sodium hydride or potasium hydride in an aprotic solvent, such as THF or DMF.
  • a strong non-nucleophilic base such as sodium hydride or potasium hydride in an aprotic solvent, such as THF or DMF.
  • the carbamate of formula VIA, VIB, or VIC where p, X, R e and Rf are as defined herein, is prepared by reacting the imidazole anion with a suitably functionalized chloroformate in an inert solvent, such as THF or DMF.
  • the coupling reaction is performed at a temperature ranging between -78 °C and room temperature.
  • Preferred methods for the formation of cloroformates are reacting one equivalent of X functionalized alcohol with one equivalent of phosgene at a tempeature ranging from -78 °C to 0 °C in an inert solvent, such as ether or THF, and in the presence of an amine base, such as pyridine or triethylamine. Removal of the amine hydrochloride by filtration affords a solution of the desired chloroformate which may be used directly or concentrated and redissolved in the anhydrous solution of choice prior to the coupling reaction with the imidazole anion to afford the carbamate of the formula VIA, VIB, or
  • the chloroformate would be prepared by reacting phosgene with an alcohol containing a protected alcohol or thiol moiety.
  • Preferred protecting groups for an alcohol moiety are silyl ethers, such as a trimethylsilyl ether, a tert-butyldimethylsilyl ether, or a tert- butyldiphenylsilyl ether.
  • deprotection of the hydroxyl moiety is the preferred method for removing silyl ether protecting groups
  • a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, or nitrosonium tetrafluoroborate
  • a suitable anhydrous solvent such as dichloromethane, THF, DMF, or acetonitrile
  • an amine base such as pyridine or triethylamine
  • Preferred protecting groups for the thiol moiety are as a thioester, such as a thioacetate or a thiobenzoate or as a disulfide.
  • a thioester such as a thioacetate or a thiobenzoate or as a disulfide.
  • Deprotection of the thiol moiety (zinc in dilute aqueous acid, triphenylphosphine in water and sodium borohydride are preferred methods for reducing disulfide groups while aqueous base or sodium methoxide in methanol is typically used to hydrolyze thioesters) followed by reaction with a suitable nitrosylating agent, such as thionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite, such as tert-butyl nitrite, or nitrosonium tetrafluoroborate, in a suitable anhydrous solvent, such
  • Nitrosation of the carbamate product may be accomplished by first converting the deprotected alcohol to a leaving group, such as a mesylate or a tosylate.
  • This reaction is typically performed at a temperature of 0 °C to room temperature in an inert solvent, such as ether, THF, or dichloromethane, with the alcohol, methansulfonyl chloride or para- toluensulfonyl chloride, and an amine base, such as triethylamine or pyridine, as the reactants.
  • the corresponding iodide is then prepared by reacting the mesylate or tosylate with sodium iodide in acetone.
  • the halide may also be formed from the alcohol by treatment of the hydroxyl moiety with a phosphorus reagent, such as triphenylphosphine, in the presence of a halide source, such as carbon tetrabromide or N-iodosuccimide, in an inert solvent, such as THF. Treatment of the bromide or iodide with silver nitrate in an inert solvent such as acetonitrile affords the compound of formula VIC.
  • the halide containing carbamate may be formed directly by preparing a halide containing chloroformate from a halide containing alcohol. Preferred halides are bromide and iodide. Coupling of the imidazole anion with the halide containing chloroformate followed by reaction of the carbamate product with silver nitrate in an inert solvent such as acetonitrile affords the compound of formula VIC.
  • the hydroxyl group of formula 7 is converted to the ester of formula VIIA, VIIB, or VIIC, where p, R e Rf and X are as defined herein, by reaction with an appropriate nitrite, thionitrite, or nitrate containing activated acylating agent.
  • esters are reacting the alcohol with the preformed acid chloride or symmetrical anhydride of the nitrite, thionitrite, or nitrate containing acid.
  • Preferred methods for preparing acid chlorides are treating the carboxylic acid with oxalyl chloride and a catalytic amount of DMF in an inert solvent, such as ether, THF, dichloromethane, or toluene.
  • Preferred methods for preparing mixed anhydride are reacting the carboxylic acid with a chloroformate, such as isubutylchloroformate, in the presence of an amine base, such as triethylamine, in an inert solvent solvent, such as ether, THF, dichloromethane, or toluene.
  • a chloroformate such as isubutylchloroformate
  • an amine base such as triethylamine
  • an inert solvent solvent such as ether, THF, dichloromethane, or toluene.
  • the alcohol and nitrite, thionitrite, or nitrate containing acid may be condensed in the presence of a dehydrating agent, such as DCC or EDAC ⁇ C1 with or without a catalyst, such as DMAP or HOBt.
  • the activated acylating agent would be prepared from an acid containing a protected alcohol or thiol moiety.
  • Preferred protecting groups for an alcohol moiety are silyl ethers, such as a trimethylsilyl ether, a tert-butyldimethylsilyl ether, or a tert-butyldiphenylsilyl ether.
  • deprotection of the hydroxyl moiety is the preferred method for removing silyl ether protecting groups
  • a suitable nitrosylating agent such as thionyl chloride nitrite, thionyl dinitrite, or nitrosonium tetrafluoroborate
  • a suitable anhydrous solvent such as dichloromethane, THF, DMF, or acetonitrile
  • an amine base such as pyridine or triethylamine
  • Preferred protecting groups for the thiol moiety are as a thioester, such as a thioacetate or a thiobenzoate or as a disulfide.
  • a thioester such as a thioacetate or a thiobenzoate or as a disulfide.
  • Deprotection of the thiol moiety (zinc in dilute aqueous acid, triphenylphosphine in water and sodium borohydride are preferred methods for reducing disulfide groups while aqueous base or sodium methoxide in methanol is typically used to hydrolyze thioesters) followed by reaction with a suitable nitrosylating agent, such as thionyl chloride nitrite, thionyl dinitrite, a lower alkyl nitrite, such as tert-butyl nitrite, or nitrosonium tetrafluoroborate, in a suitable anhydrous solvent, such
  • Nitrosation of the ester product may be accomplished by first converting the deprotected alcohol to a leaving group, such as a mesylate or a tosylate. This reaction is typically performed at a temperature of 0 °C to room temperature in an inert solvent, such as ether, THF, or dichloromethane with the alcohol, methansulfonyl chloride or para-toluensulfonyl chloride, and an amine base, such as triethylamine or pyridine as the reactants. The corresponding iodide is then prepared by reacting the mesylate or tosylate with sodium iodide in acetone.
  • a leaving group such as a mesylate or a tosylate.
  • the halide may also be formed from the alcohol by treatment of the hydroxyl moiety with a phosphorus reagent, such as triphenylphosphine in the presence of a halide source, such as carbon tetrabromide or N-iodosuccimide in an inert solvent, such as THF. Treatment of the bromide or iodide with silver nitrate in an inert solvent, such as acetonitrile, affords the compound of formula VIIC.
  • a phosphorus reagent such as triphenylphosphine
  • a halide source such as carbon tetrabromide or N-iodosuccimide
  • an inert solvent such as THF
  • the halide containing ester may be formed directly by preparing a halide containing active acylating agent from a halide containing acid.
  • Preferred halides are bromide and iodide.
  • Preferred coupling methods for the formation of esters from alcohols are those methods described herein (e.g. with the preformed acid chloride or anhydride or with the carboxylic acid and a dehydration agent, such as DCC or EDAC-HC1).
  • the compounds of the present invention include proton pump inhibitors, such as those described herein, which have been nitrosated and /or nitrosylated through one or more sites such as oxygen (hydroxyl condensation), sulfur (sulfhydryl condensation), carbon and/or nitrogen.
  • the nitrosated and/or nitrosylated proton pump inhibitors of the present invention are capable of donating, transfering and /or releasing a biologically active form of nitrogen monoxide (i.e., nitric oxide).
  • Nitrogen monoxide can exist in three forms: NO- (nitroxyl), NO # (uncharged nitric oxide) and NO + (nitrosonium).
  • NO* is a highly reactive shortlived species that is potentially toxic to cells. This is critical because the pharmacological efficacy of NO depends upon the form in which it is delivered.
  • NO # nitric oxide radical
  • NO + nitrosonium
  • functionalities capable of transferring and /or releasing NO + and NO- are also resistant to decomposition in the presence of many redox metals. Consequently, administration of charged NO equivalents (positive and /or negative) is a more effective means of delivering a biologically active NO to the desired site of action.
  • nitric oxide and compounds that release nitric oxide i.e., compounds that release nitric oxide or otherwise directly or indirectly deliver or transfer nitric oxide to a site of its activity, such as on a cell membrane, in vivo, and /or elevate or stimulate production of endogenous nitric oxide or EDRF in vivo and /or is a substrate for nitric oxide synthase).
  • “In combination,” as used herein can mean that (i) the proton pump inhibitor, optionally substituted with at least one NO and/or N0 2 group, and nitric oxide donor can be present together in the same composition; (ii) the proton pump inhibitor, optionally substituted with at least one NO and /or N0 2 group, and nitric oxide donor can be administered separately; and/or (iii) the proton pump inhibitor, optionally substituted with at least one NO and/or N0 2 group, and nitric oxide donor can be together in the form of a kit.
  • nitric oxide encompasses uncharged nitric oxide (NO») and charged nitrogen monoxide species, preferably charged nitrogen monoxide species, such as nitrosonium ion (NO + ) and nitroxyl ion (NO-).
  • the reactive form of nitric oxide can be provided by gaseous nitric oxide.
  • the nitrogen monoxide releasing, delivering or transferring compounds have the structure F- NO, wherein F is a nitrogen monoxide releasing, delivering or transferring moiety, and include any and all such compounds which provide nitrogen monoxide to its intended site of action in a form active for its intended purpose.
  • NO adducts encompasses any nitrogen monoxide releasing, delivering or transferring compounds, including, for example, S-nitrosothiols, nitrites, nitrates, S-nitrothiols, sydnonimines, 2-hydroxy-2-nitrosohydrazines (NONOates), (E)-alkyl-2-[(E)-hydroxyimino]-5-nitro-3-hexene amines or amides, nitrosoamines, furoxans as well as substrates for the endogenous enzymes which synthesize nitric oxide.
  • the "NO adducts" can be mono-nitrosylated, poly- nitrosylated, mono-nitrosated and/or poly-nitrosated or a combination thereof at a variety of naturally susceptible or artificially provided binding sites for biologically active forms of nitrogen monoxide.
  • S-nitrosothiols are compounds that include at least one -S-NO group.
  • S-nitroso- polypeptides the term “polypeptide” includes proteins and polyamino acids that do not possess an ascertained biological function, and derivatives thereof); S- nitrosylated amino acids (including natural and synthetic amino acids and their stereoisomers and racemic mixtures and derivatives thereof); S-nitrosylated sugars; S-nitrosylated, modified and unmodified, oligonucleotides (preferably of at least 5, and more preferably 5-200 nucleotides); straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted S-nitrosylated hydrocarbons; and S-nitroso heterocyclic compounds.
  • S-nitroso amino acids where the nitroso group is linked to a sulfur group of a sulfur-containing amino acid or derivative thereof.
  • Such compounds include, for example, S-nitroso-N- acetylcysteine, S-nitroso-captopril, S-nitroso-N-acetylpenicillamine, S-nitroso- homocysteine, S-nitroso-cysteine and S-nitroso-glutathione.
  • Suitable S-nitrosylated proteins include thiol-containing proteins (where the NO group is attached to one or more sulfur groups on an amino acid or amino acid derivative thereof) from various functional classes including enzymes, such as tissue-type plasminogen activator (TPA) and cathepsin B; transport proteins, such as lipoprotems; heme proteins, such as hemoglobin and serum albumin; and biologically protective proteins, such as lmmunoglobulms, antibodies and cytokines.
  • TPA tissue-type plasminogen activator
  • cathepsin B transport proteins, such as lipoprotems
  • heme proteins such as hemoglobin and serum albumin
  • biologically protective proteins such as lmmunoglobulms, antibodies and cytokines.
  • nitrosylated proteins are described in WO 93/09806, the disclosure of which is incorporated by reference herein in its entirety. Examples include polynitrosylated albumin where one or more thiol or other nucleophilic centers
  • S-nitrosothiols include: ( ) HS(C(R e )(R f )) m SNO; (n) ONS(C(R e )(R f )) m R e ; and
  • 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 ammo, an alkylamino, a dialkylamino, an arylamino, a diarylamino, an alkylarylamino, an alkoxyhaloalkyl, a haloalkoxy, a sulfonic acid, a sulfonic ester, an alkylsulf
  • 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 -N0 2 ;
  • T is independently a covalent bond, a carbonyl, an oxygen, -S(0) 0 - or -N(R a )R.-, wherein o is an integer from 0 to 2, R a is a lone pair of electrons, a hydrogen or an alkyl group; R.
  • R j can be a substituent on any disubstituted nitrogen contained within the radical wherein R, is as defined herein.
  • Nitrosothiols can be prepared by various methods of synthesis. In general, the thiol precursor is prepared first, then converted to the S-nitrosothiol derivative by nitrosation of the thiol group with NaN0 2 under acidic conditions
  • Acids which can be used for this purpose include aqueous sulfuric, acetic and hydrochloric acids.
  • the thiol precursor can also be nitrosylated by reaction with an organic nitrite such as tert-butyl nitrite, or a nitrosonium salt such as nitrosonium tetraflurorborate in an inert solvent.
  • NO adducts for use in the present invention, where the NO adduct is a compound that donates, transfers or releases nitric oxide, include compounds comprising at least one ON-O-, ON-N- or ON-C- group.
  • the compounds that include at least one ON-O-, ON-N- or ON-C- group are preferably ON-O-, ON-N- or ON-C-polypeptides (the term "polypeptide" includes proteins and polyamino acids that do not possess an ascertained biological function, and derivatives thereof); ON-O, ON-N- or ON-C-amino acids (including natural and synthetic amino acids and their stereoisomers and racemic mixtures); ON-O-, ON-N- or ON-C-sugars; ON-O-, ON-N- or ON-C- modified or unmodified oligonucleotides (comprising at least 5 nucleotides, preferably 5-200 nucleotides); ON-O-, ON-N-
  • NO adducts for use in the present invention include nitrates that donate, transfer or release nitric oxide, such as compounds comprising at least one 0 2 N-0-, 0 2 N-N-, 0 2 N-S- or 0 2 N-C- group.
  • Preferred among these compounds are 0 2 N-0-, O-N-N-, 0 2 N-S- or 0 2 N-C- polypeptides (the term "polypeptide” includes proteins and also polyamino acids that do not possess an ascertained biological function, and derivatives thereof); 0 2 N-0-, 0 2 N-N-, 0 2 N-S- or 0 2 N-C- amino acids (including natural and synthetic amino acids and their stereoisomers and racemic mixtures); 0 2 N-0-, 0 2 N-N-, 0 2 N-S- or 0 2 N-C-sugars; 0 2 N-0-, 0 2 N-N-, 0 2 N-S- or 0 2 N-C- modified and unmodified oligonucleotides (comprising at least 5 nucleotides, preferably 5-200 nucleotides);
  • Preferred examples of compounds comprising at least one 0 2 N-0-, 0 2 N-N-, 0 2 N-S- or 0 2 N-C- group include isosorbide dinitrate, isosorbide mononitrate, clonitrate, erythrityltetranitrate, mannitol hexanitrate, nitroglycerin, pentaerythritoltetranitrate, pentrinitrol and propatylnitrate.
  • R 1 R 2 -N(0-M + )-NO N-oxo-N-nitrosoamines that donate, transfer or release nitric oxide and are represented by the formula: R 1 R 2 -N(0-M + )-NO, where R 1 and R 2 are each independently a polypeptide, an amino acid, a sugar, a modified or unmodified oligonucleotide, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted hydrocarbon, or a heterocyclic group, and where M + is an organic or inorganic cation, such as, for example, an alkyl substituted ammonium cation or a Group I metal cation.
  • R 1 -(S)-N0 2 Another group of NO adducts are thionitrates that donate, transfer or release nitric oxide and are represented by the formula: R 1 -(S)-N0 2 , where R 1 is a polypeptide, an amino acid, a sugar, a modified or unmodified oligonucleotide, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted hydrocarbon, or a heterocyclic group.
  • R 1 is a polypeptide or hydrocarbon with a pair or pairs of thiols that are sufficiently structurally proximate, i.e., vicinal, that the pair of thiols will be reduced to a disulfide.
  • Compounds which form disulfide species release nitroxyl ion (NO-) and uncharged nitric oxide (NO*).
  • Compounds where the thiol groups are not sufficiently close to form disulfide bridges generally provide nitric oxide as the NO- form and not as the uncharged NO* form.
  • the present invention is also directed to compounds that stimulate endogenous NO or elevate levels of endogenous endothelium-derived relaxing factor (EDRF) in vivo or are substrates for the enzyme, nitric oxide synthase.
  • EDRF endothelium-derived relaxing factor
  • Such compounds include, for example, L-arginine, L-homoarginine, and N- hydroxy-L-arginine, including their nitrosated and nitrosylated analogs (e.g., nitrosated L-arginine, nitrosylated L-arginine, nitrosated N-hydroxy-L-arginine, nitrosylated N-hydroxy-L-arginine, nitrosated L-homoarginine and nitrosylated L-homoarginine), precursors of L-arginine and/or physiologically acceptable salts thereof, including, for example, citrulline, ornithine, glutamine, lysine, polypeptides comprising at least one of these amino acids, inhibitors of the enzyme arginase (e.g., N-hydroxy-L-arginine and 2(S)-amino-6-boronohexanoic acid) and the substrates for nitric oxide synthase, cytokines, a
  • EDRF is a vascular relaxing factor secreted by the endothelium, and has been identified as nitric oxide (NO) or a closely related derivative thereof (Palmer et al, Nature, 327:524-526 (1987); Ignarro et al, Proc. Natl. Acad. Sci. USA, 84:9265-9269 (1987)).
  • NO nitric oxide
  • Another aspect of the invention provides methods for preventing and /or treating gastrointestinal disorders by administering to the patient in need thereof a therapeutically effective amount of the compounds and /or compositions described herein.
  • Such gastrointestinal disorders include, for example, inflammatory bowel disease, Crohn's disease, irritable bowel syndrome, ulcerative colitis, peptic ulcers, stress ulcers, bleeding peptic ulcers, duodenal ulcers, infectious enteritis, colitis, diverticulitis, gastric hyperacidity, dyspepsia, gastroparesis, Zollinger-Ellison syndrome, gastroesophageal reflux disease, Helicobacter Pylori associated disease, short-bowel (anastomosis) syndrome, hypersecretory states associated with systemic mastocytosis or basophilic leukemia and hyperhistaminemia that result, for example, from neurosurgery, head injury, severe body trauma or burns.
  • the patient can be administered at least one nitrosated and/or nitrosylated proton pump inhibitor of the invention to prevent and/or treat the gastrointestinal disorder.
  • the patient can be administered at least one antacid and at least one nitrosated and /or nitrosylated proton pump inhibitor of the invention to prevent or treat the gastrointestinal disorder.
  • the patient can be administered at least one nitrosated and /or nitrosylated proton pump inhibitor of the invention and at least one compound that donates, transfers or releases nitric oxide, or elevates endogenous levels of nitric oxide or EDRF, or is a substrate for nitric oxide synthase, to prevent and /or treat the gastrointestinal disorder.
  • the patient can be administered at least one antacid, at least one nitrosated and /or nitrosylated proton pump inhibitor of the invention, and at least one compound that donates, transfers or releases nitric oxide, or elevates endogenous levels of nitric oxide or EDRF, or is a substrate for nitric oxide synthase, to prevent and /or treat the gastrointestinal disorder.
  • the patient can be administered at least one proton pump inhibitor and at least one compound that donates, transfers or releases nitric oxide, or elevates endogenous levels of nitric oxide or EDRF, or is a substrate for nitric oxide synthase, to prevent and/or treat the gastrointestinal disorder.
  • the patient can be administered at least one antacid, at least one proton pump inhibitor, and at least one compound that donates, transfers or releases nitric oxide, or elevates endogenous levels of nitric oxide or EDRF, or is a substrate for nitric oxide synthase, to prevent and /or treat the gastrointestinal disorder.
  • the antacid, proton pump inhibitor that is optionally substituted with at least one NO and /or N0 2 group, and /or the nitric oxide donor can be administered separately or as components of the same composition. These compounds and /or compositions can also be provided in the form of a pharmaceutical kit.
  • the proton pump inhibitors substituted with at least one NO and /or N0 2 group and preferred nitric oxide donors are described in detail herein.
  • Appropriate antacids for use in this aspect of the invention include any antacid known in the art, including, for example, aluminum hydroxide, magnesium hydroxide, magnesium carbonate, calcium carbonate and co-dried gels, such as, for example, aluminum hydroxide-magnesium carbonate co-dried gel.
  • Another aspect of the present invention provides methods to improve the gastroprotective properties, anti-Helicobacter properties and antacid properties of proton pump inhibitors by administering to a patient in need thereof a therapeutically effective amount of the compounds and /or compositions described herein.
  • the patient can be administered at least one nitrosated and /or nitrosylated proton pump inhibitor of the invention to improve the gastroprotective properties, anti-Helicobacter properties and antacid properties of the proton pump inhibitor.
  • the patient can be administered a bismuth-complex comprising at least one nitrosated and /or nitrosylated proton pump inhibitor of the invention to improve the gastroprotective properties, anti-Helicobacter properties and antacid properties of the proton pump inhibitor.
  • the patient can be administered at least one nitrosated and /or nitrosylated proton pump inhibitor of the invention and at least one compound that donates, transfers or releases nitric oxide, or elevates endogenous levels of nitric oxide or EDRF, or is a substrate for nitric oxide synthase, to improve the gastroprotective properties, anti-Helicobacter properties and antacid properties of the proton pump inhibitor.
  • the patient can be administered a bismuth complex comprising at least one nitrosated and /or nitrosylated proton pump inhibitor of the invention and at least one compound that donates, transfers or releases nitric oxide, or elevates endogenous levels of nitric oxide or EDRF, or is a substrate for nitric oxide synthase, to improve the gastroprotective properties, anti-Helicobacter properties and antacid properties of the proton pump inhibitor.
  • a bismuth complex comprising at least one nitrosated and /or nitrosylated proton pump inhibitor of the invention and at least one compound that donates, transfers or releases nitric oxide, or elevates endogenous levels of nitric oxide or EDRF, or is a substrate for nitric oxide synthase, to improve the gastroprotective properties, anti-Helicobacter properties and antacid properties of the proton pump inhibitor.
  • the patient can be administered at least one proton pump inhibitor and at least one compound that donates, transfers or releases nitric oxide, or elevates endogenous levels of nitric oxide or EDRF, or is a substrate for nitric oxide synthase, to improve the gastroprotective properties, anti-Helicobacter properties and antacid properties of the proton pump inhibitor.
  • the patient can be administered a bismuth- complex comprising at least one proton pump inhibitor and at least one compound that donates, transfers or releases nitric oxide, or elevates endogenous levels of nitric oxide or EDRF, or is a substrate for nitric oxide synthase, to improve the gastroprotective properties, anti-Helicobacter properties and antacid properties of the proton pump inhibitor.
  • the bismuth-containing reagent, proton pump inhibitor, that is optionally, substituted with at least one NO and/or N0 2 group, and/or nitric oxide donor can be administered separately or as components of the same composition.
  • the proton pump inhibitors, optionally substituted with at least one NO and /or N0 2 group, and nitric oxide donors are described in detail herein.
  • Bismuth complexes are prepared by boiling the aqueous solution of the free base of the proton pump inhibitor with at least one bismuth-containing reagent, including, for example, bismuth citrate, bismuth salicylate, bismuth tartaric acid or mixtures thereof as described in U. S. Patent No. 5,403,830 and in Ivanov et al, /. Pharm. Pharmacol, 48:297-301 (1996), the disclosures of which are incorporated by reference herein in their entirety.
  • Another aspect of the present invention provides methods to facilitate ulcer healing and decrease the recurrence of ulcers by administering to a patient in need thereof a therapeutically effective amount of the compounds and/or compositions described herein.
  • the patient can be administered at least one nitrosated and /or nitrosylated proton pump inhibitor of the invention to facilitate ulcer healing and decrease the recurrence of ulcers.
  • the patient can be administered at least one nitrosated and/or nitrosylated proton pump inhibitor of the invention and at least one compound that donates, transfers or releases nitric oxide, or elevates endogenous levels of nitric oxide or EDRF, or is a substrate for nitric oxide synthase to facilitate ulcer healing and decrease the recurrence of ulcers.
  • the patient can be administered at least one proton pump inhibitor and at least one compound that donates, transfers or releases nitric oxide, or elevates endogenous levels of nitric oxide or EDRF, or is a substrate for nitric oxide synthase, to facilitate ulcer healing and decrease the recurrence of ulcers.
  • the proton pump inhibitor that is optionally, substituted with at least one NO and/or N0 2 group, and/or nitric oxide donor can be administered separately or as components of the same composition.
  • the proton pump inhibitor, optionally substituted with at least one NO and /or N0 2 group, and nitric oxide donors are described in detail herein.
  • Another aspect of the present invention provides methods to decrease or reverse gastrointestinal toxicity and facilitate ulcer healing resulting from, for example, the administration of nonsteroidal antiinflammatory drugs (NSAIDs), selective COX-2 inhibitors, and the like.
  • NSAIDs nonsteroidal antiinflammatory drugs
  • the present invention provides methods of administering a therapeutically effective amount of the compounds and /or compositions described herein, and, optionally, administering a therapeutically effective amount of at least one NSAID or selective COX-2 inhibitor.
  • the patient can be administered at least one nitrosated and /or nitrosylated proton pump inhibitor of the invention, and, optionally, at least one NSAID and /or selective COX-2 inhibitor, to decrease or reverse gastrointestinal toxicity and /or to facilitate ulcer healing resulting from the NSAID and/or selective COX-2 inhibitor treatment.
  • the patient can be administered at least one NSAID and /or selective COX-2 inhibitor with a therapeutically effective amount of at least one nitrosated and /or nitrosylated proton pump inhibitor of the invention and at least one compound that donates, transfers or releases nitric oxide, or elevates endogenous levels of nitric oxide or EDRF, or is a substrate for nitric oxide synthase, to decrease or reverse gastrointestinal toxicity and/or to facilitate ulcer healing resulting from the NSAID and /or selective COX-2 inhibitor treatment.
  • the patient can be administered at least one NSAID and /or selective COX-2 inhibitor with a therapeutically effective amount of at least one proton pump inhibitor and at least one compound that donates, transfers or releases nitric oxide, or elevates endogenous levels of nitric oxide or EDRF, or is a substrate for nitric oxide synthase, to decrease or reverse gastrointestinal toxicity and /or to facilitate ulcer healing resulting from the NSAID and /or selective COX-2 inhibitor treatment.
  • the NSAID and /or selective COX-2 inhibitor, nitrosated and /or nitrosylated proton pump inhibitor, proton pump inhibitor, and/or nitric oxide donor can be administered separately or as components of the same composition.
  • These compounds and/or compositions can also be provided in the form of a pharmaceutical kit.
  • NSAIDs include, for example, aspirin (e.g., acetylsalicylic acid), salicylate esters and salts, acetate esters of salicylic acid, diflurophenyl derivatives (e.g., diflunisal), salicylsalicylic acids (e.g., salsalate), salts of salicylic acids (e.g., sodium salicylate), salicylamide, sodium thiosalicylate, choline salicylate, magnesium salicylate, combinations of choline and magnesium salicylates, 5-aminosalicylic acid (e.g., mesalamine), salicylazosulfapyridine (e.g., sulfasalazine), methylsalicylate, and the like.
  • aspirin e.g., acetylsalicylic acid
  • salicylate esters and salts e.g., acetate esters of salicylic acid
  • NSAIDs are the pyrazolon derivatives, which include, for example, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine, dipyrone and apazone (azapropazone).
  • NSAIDs are the para- aminophenol derivatives, which are the so-called "coal tar” analgesics, including, for example, phenacetin and its active metabolite acetaminophen.
  • Another group of compounds include indomethacin, a methylated indole derivative, and the structurally related compound sulindac.
  • Yet another group of compounds is the fenamates which are derivatives of N-phenylanthranilic acid (e.g., mefenamic, meclofenamic, flufenamic, tolfenamic and etofenamic acids).
  • Another contemplated NSAID is tolmetin.
  • NSAIDs are the propionic acid derivatives. Principal members of this group are, for example, ibuprofen, naproxen, flurbiprofen, fenoprofen and ketoprofen. Other members of this group include, for example, fenbufen, pirprofen, oxaprozin, indoprofen and tiaprofenic acid.
  • Still other NSAIDs are piroxicam, ampiroxicam, oxicam derivatives
  • NSAIDs include etodolac and nabumentone.
  • NSAIDs and selective COX-2 inhibitors are described more fully in the literature, such as in Goodman and Gilman, The Pharmacological Basis of Therapeutics (8th Edition), McGraw-Hill, pages 617-657 (1993); Merck Index on CD-ROM, Twelfth Edition, Version 12:1, (1996); STN Express, file phar and file registry, the disclosures of which are incorporated by reference herein in their entirety.
  • Other NSAIDs and selective COX-2 inhibitors that can be used in the present invention include those described in U. S. Patent No. 5,703,073, and co- pending Application Serial No. 09/441,891 and 60/171,623, the disclosures of which are incorporated by reference herein in their entirety.
  • Another embodiment of the present invention provides methods to treat Helicobacter pylori by administering one or more acid-degradable antibacterial compounds in combination with at least one proton pump inhibitor that is substituted with at least one NO and /or N0 2 group, and, optionally, a therapeutically effective amount of at least one compound that donates, transfers or releases nitric oxide and /or stimulates endogenous production of NO o; EDRF in vivo.
  • this embodiment provides administering one or more acid-degradable antibacterial compounds in combination with at least one proton pump inhibitor, and, a therapeutically effective amount of at least one compound that donates, transfers or releases nitric oxide and /or stimulates endogenous production of NO or EDRF in vivo.
  • Patent Nos. 5,629,305 and 5,599,794 disclose treating or preventing gastrointestinal disorders resulting from Helicobacter pylori by administering proton pump inhibitors in combination with antibacterial compounds.
  • the proton pump inhibitors increase the intra-gastric pH in the stomach, thereby increasing the bioavailability of the acid-labile antibacterial compound.
  • the antibacterial compound(s), proton pump inhibitor(s), optionally substituted with at least one NO and/or N0 2 group, and/or nitric oxide donor(s) can be administered separately, or as components of the same composition.
  • the compounds and/or compositions can also be provided in the form of a kit.
  • the proton pump inhibitors that are optionally substituted with at least one NO group and nitric oxide donors are described herein.
  • the antibacterial compounds contemplated for use in this embodiment of the invention include any acid-degradable antibacterial compound that is known in the art, including, for example antibiotics, such as, for example, amoxycillin, penicillin, benzylpenicillin, erythromycin base, clarithromycin, and the like.
  • Yet another embodiment of the present invention provides methods to treat viral infections by administering at least one proton pump inhibitor that is substituted with at least one NO and /or N0 2 group, and, optionally, a therapeutically effective amount of at least one compound that donates, transfers or releases nitric oxide and /or stimulates endogenous production of NO or EDRF in vivo.
  • this embodiment provides administering at least one proton pump inhibitor, and, a therapeutically effective amount of at least one compound that donates, transfers or releases nitric oxide and /or stimulates endogenous production of NO or EDRF in vivo.
  • 5,945,4205 discloses treating viral infections by administering proton pump inhibitors.
  • the proton pump inhibitor(s), optionally substituted with at least one NO and/or N0 2 group, and /or nitric oxide donor(s) can be administered separately, or as components of the same composition.
  • the compounds and/or compositions can also be provided in the form of a kit.
  • the proton pump inhibitors that are optionally substituted with at least one NO group and nitric oxide donors are described herein.
  • compositions of the present invention can be administered by any available and effective delivery system including, but not limited to, orally, bucally, parenterally, by inhalation spray, by topical application, by injection, transdermally, or rectally (e.g., by the use of suppositories) in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles, as desired.
  • Parenteral includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques.
  • Transdermal compound administration involves the delivery of pharmaceutical compounds via percutaneous passage of the compound into the systemic circulation of the patient.
  • Topical administration can also involve the use of transdermal administration such as transdermal patches or iontophoresis devices.
  • Other components can be incorporated into the transdermal patches as well.
  • compositions and/or transdermal patches can be formulated with one or more preservatives or bacteriostatic agents including, but not limited to, methyl hydroxybenzoate, propyl hydroxybenzoate, chlorocresol, benzalkonium chloride, and the like.
  • Dosage forms for topical administration of the compounds and compositions can include creams, sprays, lotions, gels, ointments, eye drops, nose drops, ear drops, and the like.
  • the compositions of the invention can be mixed to form white, smooth, homogeneous, opaque cream or lotion with, for example, benzyl alcohol 1% or 2% (wt/wt) as a preservative, emulsifying wax, glycerin, isopropyl palmitate, lactic acid, purified water and sorbitol solution.
  • the compositions can contain polyethylene glycol 400.
  • compositions can be mixed to form ointments with, for example, benzyl alcohol 2% (wt/wt) as preservative, white petrolatum, emulsifying wax, and tenox II (butylated hydroxyanisole, propyl gallate, citric acid, propylene glycol).
  • Woven pads or rolls of bandaging material e.g., gauze, can be impregnated with the compositions in solution, lotion, cream, ointment or other such form can also be used for topical application.
  • the compositions can also be applied topically using a transdermal system, such as one of an acrylic-based polymer adhesive with a resinous crosslinking agent impregnated with the composition and laminated to an impermeable backing.
  • Solid dosage forms for oral administration can include capsules, tablets, effervescent tablets, chewable tablets, pills, powders, sachets, granules and gels.
  • the active compounds can be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms can also comprise, as in normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate.
  • the dosage forms can also comprise buffering agents.
  • Soft gelatin capsules can be prepared to contain a mixture of the active compounds or compositions of the present invention and vegetable oil.
  • Hard gelatin capsules can contain granules of the active compound in combination with a solid, pulverulent carrier such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives of gelatin. Tablets and pills can be prepared with enteric coatings.
  • a solid, pulverulent carrier such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives of gelatin.
  • Tablets and pills can be prepared with enteric coatings.
  • Liquid dosage forms for oral administration can include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water.
  • Such compositions can also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
  • Suppositories for vaginal or rectal administration of the compounds and compositions of the invention can be prepared by mixing the compounds or compositions with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at room temperature but liquid at body temperature, such that they will melt and release the drug.
  • sterile injectable preparations for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing agents, wetting agents and/or suspending agents.
  • the sterile injectable preparation can also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution.
  • Sterile fixed oils are also conventionally used as a solvent or suspending medium.
  • compositions of this invention can further include conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral application which do not deleteriously react with the active compounds.
  • suitable pharmaceutically acceptable carriers include, for example, water, salt solutions, alcohol, vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, surfactants, silicic acid, viscous paraffin, perfume oil, fatty acid monoglycerides and diglycerides, petroethral fatty acid esters, hydroxymethyl-cellulose, polyvinylpyrrolidone, and the like.
  • the pharmaceutical preparations can be sterilized and if desired, mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavoring and /or aromatic substances and the like which do not deleteriously react with the active compounds.
  • auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavoring and /or aromatic substances and the like which do not deleteriously react with the active compounds.
  • auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavoring and /or aromatic substances and the like which do not deleteriously react with the active compounds.
  • particularly suitable vehicles
  • the composition can also contain minor amounts of wetting agents, emulsifying agents and /or pH buffering agents.
  • the composition can be a liquid solution, suspension, emulsion, tablet, pill, capsule, sustained release formulation, or powder.
  • the composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides.
  • Oral formulations can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, and the like.
  • Various delivery systems are known and can be used to administer the compounds or compositions of the present invention, including, for example, encapsulation in liposomes, microbubbles, emulsions, microparticles, microcapsules and the like.
  • the required dosage can be administered as a single unit or in a sustained release form
  • compositions can be enhanced by micronization of the formulations using conventional techniques such as grinding, milling, spray drying and the like in the presence of suitable excipients or agents such as phospholipids or surfactants.
  • suitable excipients or agents such as phospholipids or surfactants.
  • the compounds and compositions of the present invention can be formulated as pharmaceutically acceptable salts.
  • Pharmaceutically acceptable salts include, for example, alkali metal salts and addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically- acceptable. Suitable pharmaceutically-acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid.
  • organic acids include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, nitrous (nitrite salt), nitric (nitrate salt), carbonic, sulfuric, phosphoric acid, and the like.
  • Appropriate organic acids include, but are not limited to, aliphatic, cycloaliphatic, aromatic, heterocyclic, carboxylic and sulfonic classes of organic acids, such as, for example, formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, p- hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothe
  • Suitable pharmaceutically-acceptable base addition salts include, but are not limited to, metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from primary, secondary and tertiary amines, cyclic amines, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine and the like. All of these salts may be prepared by conventional means from the corresponding compound by reacting, for example, the appropriate acid or base with the compound.
  • “Therapeutically effective amount” refers to the amount of the proton pump inhibitor, that is optionally substituted with at least one NO and /or N0 2 group, nitric oxide donor, antacid, bismuth-complex, NSAID, selective COX-2 inhibitor and /or acid-degradable antibacterial compound, that is effective to achieve its intended purpose. While individual patient needs may vary, determination of optimal ranges for effective amounts of each of the compounds and compositions is within the skill of the art. Generally, the dosage required to provide an effective amount of the composition, and which can be adjusted by one of ordinary skill in the art will vary, depending on the age, health, physical condition, sex, weight, extent of the dysfunction of the recipient, frequency of treatment and the nature and scope of the dysfunction or disease.
  • the amount of a given proton pump inhibitor, that is optionally substituted with at least one NO and /or N0 2 group, which will be effective in the treatment of a particular disorder or condition will depend on the nature of the disorder or condition, and can be determined by standard clinical techniques, including reference to Goodman and Gilman, supra; The Physician's Desk Reference, Medical Economics Company, Inc., Oradell, N.J., 1995; and Drug Facts and Comparisons, Inc., St. Louis, MO, 1993. The precise dose to be used in the formulation will also depend on the route of administration, and the seriousness of the disease or disorder, and should be decided by the physician and the patient's circumstances.
  • the amount of nitric oxide donor in a pharmaceutical composition can be in amounts of about 0.1 to about 10 times the molar equivalent of the proton pump inhibitor.
  • the usual daily doses of proton pump inhibitors are about 10 mg to about 400 mg per day and the doses of nitric oxide donors in the pharmaceutical composition can be in amounts of about 1 to about 500 mg/kg of body weight daily, preferably about 1 to about 50 mg/kg of body weight daily.
  • Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems and are in the same ranges or less than as described for the commercially available compounds in the Physician's Desk Reference, supra.
  • the present invention also provides pharmaceutical kits comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compounds and /or compositions of the present invention, including, at least, one or more of the proton pump inhibitors, that are optionally substituted with at least one NO moiety, and one or more of the NO donors described herein.
  • kits can also include, for example, other compounds and/or compositions (e.g., NSAIDs, antacids and/or antibacterial compounds), a device(s) for administering the compounds and/or compositions, and written instructions in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which instructions can also reflect approval by the agency of manufacture, use or sale for human administration.
  • other compounds and/or compositions e.g., NSAIDs, antacids and/or antibacterial compounds
  • a device(s) for administering the compounds and/or compositions e.g., a device(s) for administering the compounds and/or compositions
  • written instructions in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which instructions can also reflect approval by the agency of manufacture, use or sale for human administration.
  • Example lc (0.65 g, 2 mol), 4-(N-N-dimethylamino)pyridine (10 mg) and dicyclohexylcarbodiimide (IM in dichloromethane, 4 ml, 4 mmol). After stirring at room temperature for 3 hours, the reaction was concentrated under vacuum and the residue was purified by flash column chromatography (ethyl acetate /hexane, 4:1 to 7:1) to afford the title compound (0.65 g, 54.7%) as a green foam.
  • Example 2 ⁇ 2-( ⁇ [3-methyl-4-(2,2,2-trifluoroethyl)-2-pyridyl]methyl ⁇ sulfinyl) benzimidazolyl]-methyl-3- ⁇ N-[2-methyl-2-(nitrosothio)-propyl]-N- benzylcarbamoyljpropanoate
  • Example Id The procedure described in Example Id was repeated using lansoprozole (0.739 g, 2 mmol) instead of timoprazole.
  • the title compound (0.82 g, 59.4%) was obtained as a green foam.
  • Example 3b 4.1 g, 24.1 mmol
  • anhydrous dichloromethane 40 mL
  • lithium aluminum hydride (1 M solution in THF) (40 mL) was added dropwise over a period of 20 minutes.
  • the reaction mixture was stirred at 0 °C for further 15 minutes and then at room temperature for 30 minutes.
  • the excess LiAlH4 was destroyed by the addition of ethyl acetate.
  • the reaction mixture was then poured over ice cold water, acidified with 1 N HCl and extracted with dichloromethane (2 x 200 mL).
  • Example 3c To a 0 °C cooled solution of Example 3c (1.06 g, 5 mmol) in anhydrous dichloromethane (40 mL) was added t-butyl nitrite (7.5 mmol, 890 ⁇ L). The reaction mixture was stirred at 0 °C for 30 minutes and then at room temperature for 30 minutes. The solvent was removed at reduced pressure and product was recrystallized from ethyl ether/hexane to give 1.2 g ( 80% yield) of the title compound as a green crystalline solid, mp 77-79 °C; H NMR (CDCI3): ⁇ 1.7-1.74
  • Example 1 compares the gastric lesion activity of vehicle alone, lanzoprazole in vehicle and Example 2 (nitrosylated lanzoprazole) in vehicle.
  • Ethanol /HCl mixture produced gastric lesion in the control rats treated with vehicle (0.5% Methocel).
  • Lanzoprazole at a dose of 200 ⁇ mol /kg failed to significantly inhibit the formation of gastric lesions.
  • Example 2 at 200 ⁇ mol/kg, significantly inhibited the formation of gastric lesions produced by the ethanol /HCl mixture.

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Abstract

L'invention concerne des composés inhibiteurs de la pompe à proton nitrosés et/ou nitrosylés, et des compositions nouvelles comprenant au moins un composé inhibiteur de la pompe à proton, éventuellement substitué par au moins un groupe NO et/ou NO2, et éventuellement au moins un composé qui donne, transfère ou dégage de l'oxyde nitrique, stimule la synthèse endogène de l'oxyde nitrique, élève les niveaux endogènes de facteur de relaxation dérivé de l'endothélium ou constitue un substrat pour la synthase d'oxyde nitrique, et/ou au moins un médicament anti-inflammatoire non-stéroïdien, un inhibiteur de COX-2 sélectif, un anti-acide, un réactif contenant du bismuth, un composé antibactérien dégradable par l'acide et des mélanges de ceux-ci. L'invention porte également sur des procédés pour traiter et/ou prévenir les troubles gastro-intestinaux ; faciliter la cicatrisation des ulcères ; réduire la récurrence des ulcères ; améliorer les propriétés de protection gastrique, les propriétés anti-helicobacter pylori ou les propriétés anti-acides des inhibiteurs de la pompe à proton ; diminuer ou supprimer la toxicité gastro-intestinale associée à l'utilisation de composés anti-inflammatoires non-stéroïdiens ; traiter les infections à helicobacter pylori et les infections virales. Les composés et/ou les compositions de l'invention peuvent également se présenter sous la forme d'un kit pharmaceutique.
PCT/US2000/002524 1999-02-26 2000-02-25 Inhibiteurs de la pompe a proton nitroses et nitrosyles, compositions et procedes d'utilisation WO2000050037A1 (fr)

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JP2000600648A JP2002537336A (ja) 1999-02-26 2000-02-25 ニトロソ化およびニトロシル化されたプロトンポンプ阻害剤、組成物および使用方法
AU32196/00A AU781133B2 (en) 1999-02-26 2000-02-25 Nitrosated and nitrosylated proton pump inhibitors, compositions and methods of use
CA2362930A CA2362930C (fr) 1999-02-26 2000-02-25 Inhibiteurs de la pompe a proton nitroses et nitrosyles, compositions et procedes d'utilisation
EP00910039A EP1154771A4 (fr) 1999-02-26 2000-02-25 Inhibiteurs de la pompe a proton nitroses et nitrosyles, compositions et procedes d'utilisation
AU2005202553A AU2005202553A1 (en) 1999-02-26 2005-06-10 Nitrosated and nitrosylated proton pump inhibitors, compositions and methods of use

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US60/122,111 1999-02-26

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WO2003043614A2 (fr) * 2001-11-19 2003-05-30 Altana Pharma Ag Agents utiles pour le traitement des troubles des voies aeriennes
WO2003061704A2 (fr) * 2002-01-23 2003-07-31 Pharmacia & Upjohn Company Traitement combine d'infections bacteriennes
WO2003075926A1 (fr) * 2002-03-14 2003-09-18 Altana Pharma Ag Utilisation d'inhibiteurs de la pompe a protons pour traiter des troubles des voies respiratoires
WO2003082854A1 (fr) * 2002-03-29 2003-10-09 Zeria Pharmaceutical Co., Ltd. Derives 1-n-aminobenzimidazole
US6673819B2 (en) 2000-06-30 2004-01-06 Astrazeneca Ab Compounds useful as antibacterial agents
FR2845917A1 (fr) * 2002-10-21 2004-04-23 Negma Gild Composition pharmaceutique associant le tenatoprazole et un anti-inflammatoire
WO2004037255A1 (fr) * 2002-10-21 2004-05-06 Sidem Pharma Utilisation du tenatoprazole pour le traitement du reflux gastro-oesophagien
EP1497268A2 (fr) * 2002-04-05 2005-01-19 Nitromed, Inc. Donneurs de monoxyde d'azote, compositions et procedes d'utilisation, applications correspondantes
EP1534278A2 (fr) * 2002-08-01 2005-06-01 Nitromed, Inc. Inhibiteurs nitroses de la pompe a protons, compositions et procedes d'utilisation
WO2005103049A1 (fr) 2004-04-22 2005-11-03 Eisai R & D Management Co., Ltd. Composé imidazopyridine
WO2005076987A3 (fr) * 2004-02-10 2006-06-08 Santarus Inc Combinaison d'un inhibiteur de la pompe a protons, d'un tampon et d'un medicament anti-inflammatoire non steroidien
WO2007016677A2 (fr) 2005-08-02 2007-02-08 Nitromed, Inc. Composes antimicrobiens promoteurs d'oxyde nitrique, compositions et procedes d'utilisation
US7425634B2 (en) 2005-04-15 2008-09-16 Eisai R&D Management Co., Ltd. Benzimidazole compound
US9040564B2 (en) 2005-04-28 2015-05-26 Eisai R&D Management Co., Ltd. Stabilized composition
US9243300B2 (en) 2011-01-07 2016-01-26 Snowden Kabushikikaisha Lactic acid bacterium for inhibiting production of gastric acid and gastrin
CN115252610A (zh) * 2020-02-26 2022-11-01 上海科技大学 质子泵抑制剂在抗冠状病毒中的应用

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Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6673819B2 (en) 2000-06-30 2004-01-06 Astrazeneca Ab Compounds useful as antibacterial agents
WO2003043614A3 (fr) * 2001-11-19 2004-03-11 Altana Pharma Ag Agents utiles pour le traitement des troubles des voies aeriennes
WO2003043614A2 (fr) * 2001-11-19 2003-05-30 Altana Pharma Ag Agents utiles pour le traitement des troubles des voies aeriennes
WO2003061704A2 (fr) * 2002-01-23 2003-07-31 Pharmacia & Upjohn Company Traitement combine d'infections bacteriennes
WO2003061704A3 (fr) * 2002-01-23 2003-12-18 Upjohn Co Traitement combine d'infections bacteriennes
WO2003075926A1 (fr) * 2002-03-14 2003-09-18 Altana Pharma Ag Utilisation d'inhibiteurs de la pompe a protons pour traiter des troubles des voies respiratoires
WO2003082854A1 (fr) * 2002-03-29 2003-10-09 Zeria Pharmaceutical Co., Ltd. Derives 1-n-aminobenzimidazole
EP1497268A2 (fr) * 2002-04-05 2005-01-19 Nitromed, Inc. Donneurs de monoxyde d'azote, compositions et procedes d'utilisation, applications correspondantes
EP1497268A4 (fr) * 2002-04-05 2006-01-18 Nitromed Inc Donneurs de monoxyde d'azote, compositions et procedes d'utilisation, applications correspondantes
EP1534278A4 (fr) * 2002-08-01 2006-09-06 Nitromed Inc Inhibiteurs nitroses de la pompe a protons, compositions et procedes d'utilisation
JP4634144B2 (ja) * 2002-08-01 2011-02-16 ニコックス エスエー ニトロソ化プロトンポンプ阻害剤、組成物および使用方法
EP1534278A2 (fr) * 2002-08-01 2005-06-01 Nitromed, Inc. Inhibiteurs nitroses de la pompe a protons, compositions et procedes d'utilisation
US7211590B2 (en) 2002-08-01 2007-05-01 Nitromed, Inc. Nitrosated proton pump inhibitors, compositions and methods of use
JP2005539013A (ja) * 2002-08-01 2005-12-22 ニトロメッド インコーポレーティッド ニトロソ化プロトンポンプ阻害剤、組成物および使用方法
FR2845917A1 (fr) * 2002-10-21 2004-04-23 Negma Gild Composition pharmaceutique associant le tenatoprazole et un anti-inflammatoire
WO2004037255A1 (fr) * 2002-10-21 2004-05-06 Sidem Pharma Utilisation du tenatoprazole pour le traitement du reflux gastro-oesophagien
CN102920705A (zh) * 2002-10-21 2013-02-13 希德姆制药 泰妥拉唑在制造治疗胃食管反流性疾病的药物中的应用
EP2014290A3 (fr) * 2002-10-21 2009-03-04 Sidem Pharma SA Utilisation du ténatoprazole pour le traitment du reflux gastro-oesophagien
WO2005076987A3 (fr) * 2004-02-10 2006-06-08 Santarus Inc Combinaison d'un inhibiteur de la pompe a protons, d'un tampon et d'un medicament anti-inflammatoire non steroidien
WO2005103049A1 (fr) 2004-04-22 2005-11-03 Eisai R & D Management Co., Ltd. Composé imidazopyridine
US7781452B2 (en) 2004-04-22 2010-08-24 Eisai R&D Management Co., Ltd. Imidazopyridine compound
US7425634B2 (en) 2005-04-15 2008-09-16 Eisai R&D Management Co., Ltd. Benzimidazole compound
US8124780B2 (en) 2005-04-15 2012-02-28 Eisai R&D Management Co., Ltd. Benzimidazole compound
US9040564B2 (en) 2005-04-28 2015-05-26 Eisai R&D Management Co., Ltd. Stabilized composition
WO2007016677A2 (fr) 2005-08-02 2007-02-08 Nitromed, Inc. Composes antimicrobiens promoteurs d'oxyde nitrique, compositions et procedes d'utilisation
US9243300B2 (en) 2011-01-07 2016-01-26 Snowden Kabushikikaisha Lactic acid bacterium for inhibiting production of gastric acid and gastrin
CN115252610A (zh) * 2020-02-26 2022-11-01 上海科技大学 质子泵抑制剂在抗冠状病毒中的应用
CN115252610B (zh) * 2020-02-26 2024-03-26 上海科技大学 质子泵抑制剂在抗冠状病毒中的应用

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AU3219600A (en) 2000-09-14
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AU781133B2 (en) 2005-05-05
CA2362930A1 (fr) 2000-08-31
CA2362930C (fr) 2010-10-05
AU2005202553A1 (en) 2005-07-07
EP1154771A1 (fr) 2001-11-21

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