WO1999045004A1 - Nitrate salt of anti-ulcer medicine - Google Patents

Nitrate salt of anti-ulcer medicine Download PDF

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Publication number
WO1999045004A1
WO1999045004A1 PCT/EP1999/001226 EP9901226W WO9945004A1 WO 1999045004 A1 WO1999045004 A1 WO 1999045004A1 EP 9901226 W EP9901226 W EP 9901226W WO 9945004 A1 WO9945004 A1 WO 9945004A1
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WO
WIPO (PCT)
Prior art keywords
salt
residue
salts
nitrate
free valence
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP1999/001226
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English (en)
French (fr)
Inventor
Piero Del Soldato
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nicox SA
Original Assignee
Nicox SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Nicox SA filed Critical Nicox SA
Priority to CA002322493A priority Critical patent/CA2322493A1/en
Priority to IL13772199A priority patent/IL137721A0/xx
Priority to SI9930655T priority patent/SI1068196T1/xx
Priority to KR1020007009693A priority patent/KR20010041522A/ko
Priority to EP99911708A priority patent/EP1068196B1/en
Priority to BR9908428-7A priority patent/BR9908428A/pt
Priority to JP2000534547A priority patent/JP2002505328A/ja
Priority to AU30303/99A priority patent/AU752919B2/en
Priority to HU0100853A priority patent/HUP0100853A3/hu
Priority to AT99911708T priority patent/ATE273297T1/de
Priority to US09/622,068 priority patent/US6503929B1/en
Priority to DE69919341T priority patent/DE69919341T2/de
Publication of WO1999045004A1 publication Critical patent/WO1999045004A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • 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
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/425—Thiazoles
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/28—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/48—Acylated amino or imino radicals by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof, e.g. carbonylguanidines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • 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

Definitions

  • the present invention relates to compositions to be used in the therapy and in the prevention of the ulcer relapses and, in general, of dyspepsias. More particularly it relates to compositions having an improved gastroprotective activity combined with a high acid secretion inhibition activity.
  • Products known in the art and those commercialized and used in the ulcer therapy are compounds which perform an anti- secretory activity (acid secretion inhibition) . See for instance " New Guide to Medicine & Drugs" Brit. Medical Assoc. Editor, 1997, pagg. 108-109.
  • Known products having higher therapeutic efficacy show a high anti-secretory activity and are used, both in the acute and in long-therm (six months and more) therapies.
  • the drawback of these products is that they have a poor gastroprotectve activity, when present. From a practical point of view this means that the gastric protection is not optimal and causes inconveniences above all in the long-term therapy. In this case the presence of frequent relapses due to the enfeeblement of gastric mucosa is noticed.
  • prostaglandins e.g.
  • compositions active in the ulcer and gastric dyspepsia treatment having improved therapeutic characteristic and tolerability, general and local, in particular having an improved gastroprotective activity combined to a high anti-secretion activity.
  • the Applicant has unexpectedly and surprisingly found pharmaceutical anti-ulcer compositions having the above mentioned desired properties.
  • compositions comprising as essential components nitrate salts of one or more components selected from the following classes of compounds :
  • R x s H, -NH-CH 3 , NH 2 ;
  • N AI and C* 11 mean, respectively, the nitrogen and carbon atom in 1 and 2 position of the pyridine ring of formula A and C B2 and N B3 the carbon and nitrogen atom, respectively, in 2 and 3 position of the imydazole ring (1 position of the imydazole ring is that of the proton nitrogen) .
  • R x 4 is a free valence and forms with R 1 ⁇ a double bond
  • R ⁇ 2 H
  • n l
  • R I S H
  • Z (VII A )
  • compositions according to the present invention also isomers of the compounds belonging to (A) and (B) classes may be used.
  • the compound salts of above classes contain at least one mole of nitrate ion/mole of compounds .
  • the ratio between the nitrate ion moles and the precursor is equal to one. Salts having a higher molar ratio are obtained when in the molecule other amino groups basic enough to be salified are present.
  • Salt precursors belonging to the above mentioned classes are prepared according to the methods described in "The Merck Index I2 a Ed.” (1996) , herein completely incorporated by reference .
  • the salts of the present invention may be prepared accor- ding to one of the following methods.
  • the salt is prepared by dissolving the substance in the solvent at a concentration preferably equal or higher than 10% w/v, by adding the amount of concentrated nitric acid corresponding to the moles of salifiable aminic groups present in the compound.
  • the nitric acid is preferably diluted in the same solvent.
  • the mixture is cooled to temperatures in the range 20°-0°C.
  • the product is generally recovered by filtration and washed with the solvent.
  • the corresponding mixtures with hydroxylated solvents may be used.
  • solvents are methyl alcohol, ethyl alcohol and water.
  • the precipitation can be quickened by diluting then the so obtained mixture, after the addition of nitric acid, with an apolar solvent.
  • the starting product is salified with hydrochloric acid it is possible to prepare the salt with nitric acid directing adding silver nitrate to the compound solution. After filtering silver chloride, the solution is concentrated and cooled to recover the nitrate salt.
  • the starting product is a salt
  • the base is then extracted by a suitable organic solvent (e.g. halogenated solvents, esters, ethers) which is then dried.
  • the organic solution is evaporated and then one proceeds according to the preceding preparation methods, by dissolving the base in acetonitrile or in the other above mentioned solvents .
  • compositions of the present invention allow to improve, compared with the known above mentioned combinations, the comprehensive pharma- co-toxicological situation of precursors, increasing the therapeutic efficacy and their general and local tolerability in the ulcer and gastric dyspepsia treatment with an improved gastroprotective activity.
  • compositions of the present invention are formulated in the corresponding pharmaceutical compositions according to well known techniques in this field together with the common excipients; see for example the volume “Remington's Pharmaceutical Sciences 15a Ed.”
  • the invention salt dosages are the conventional ones of their precursors of (A) and (B) classes.
  • compositions obtainable combining one or more nitrate salts of the compounds of (A) and (B) classes, or their pharmaceutical compositions, with conventional gastroprotectives .
  • prostaglandines As examples, prostaglandines, bismuth salts, active antibiotics towards pathogenic microorganisms in the gastrointestinal mucosa
  • gastroprotective activity of the invention compositions is very high. This makes it possible to avoid the undesirable effects of known gastroprotectives when they are used in combination with compounds or formulation of the invention. It has indeed been found that the amount of known gastroprotectives, in the combination of the invention, is lower compared with those known and does not cause undesirable effects. The skilled in this field is able to easily determine the maximum amount of conventional gastroprotectives to be combined with the pharmaceutical compositions of the invention since this corresponds to the absence of typical side effects of known gastroprotectives . In any case the amount of conventional gastroprotectives to be used in the combination is lower than that used in the combinations described in the art .
  • ranitidine hydrochloride 5 g of ranitidine hydrochloride are dissolved in a 140 ml acetonitrile/methyl alcohol 6 : 1 mixture at + 20°C. 4,2 g of powder silver nitrate are added. The silver chloride precipitate is filtered, the precipitate is washed with an acetonitrile/methyl alcohol 6 : l solution, the organic phases are put together, dried and treated to obtain a dry residue. 3,5 g of an amorphous solid corresponding to the ranitidine mono- nitrate salt are obtained.
  • a single dose equal to 100 mg/Kg respectively of cimeti-
  • Anti-ulcer activity is evaluated according to the experimental model described in the paper of A. Robert e Al . "Cytoprotection by prostaglandins in rats. Prevention of gastric necrosis produced by alcohol, HC1, NaOH, hypertonic NaCl and thermal injury" Gastroenterology 77, 433-43 1979.
  • ranitidine nitrate corresponding to 60 mg/Kg of ranitidine
  • carboxymethylcellulose aqueous suspension 2% 60 mg/Kg of ranitidine nitrate (corresponding to 60 mg/Kg of ranitidine) in 5 ml/Kg of carboxymethylcellulose aqueous suspension 2%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Furan Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
PCT/EP1999/001226 1998-03-05 1999-02-25 Nitrate salt of anti-ulcer medicine Ceased WO1999045004A1 (en)

Priority Applications (12)

Application Number Priority Date Filing Date Title
CA002322493A CA2322493A1 (en) 1998-03-05 1999-02-25 Nitrate salt of anti-ulcer medicine
IL13772199A IL137721A0 (en) 1998-03-05 1999-02-25 Nitrate salt of anti-ulcer medicine
SI9930655T SI1068196T1 (en) 1998-03-05 1999-02-25 Nitrate salt of anti-ulcer medicine
KR1020007009693A KR20010041522A (ko) 1998-03-05 1999-02-25 항-궤양의 질산염 약제
EP99911708A EP1068196B1 (en) 1998-03-05 1999-02-25 Nitrate salt of anti-ulcer medicine
BR9908428-7A BR9908428A (pt) 1998-03-05 1999-02-25 Sais de nitrato, composições, uso de sal e composição, e, processo para preparação de sais de nitrato
JP2000534547A JP2002505328A (ja) 1998-03-05 1999-02-25 抗潰瘍医薬の硝酸塩
AU30303/99A AU752919B2 (en) 1998-03-05 1999-02-25 Nitrate salt of anti-ulcer medicine
HU0100853A HUP0100853A3 (en) 1998-03-05 1999-02-25 Nitrate salt of anti-ulcer medicine and pharmaceutical compositions containing the same compounds
AT99911708T ATE273297T1 (de) 1998-03-05 1999-02-25 Salpetersäuresalz von antiulcus arzneimitteln
US09/622,068 US6503929B1 (en) 1998-03-05 1999-02-25 Nitrate salt of anti-ulcer medicine
DE69919341T DE69919341T2 (de) 1998-03-05 1999-02-25 Salpetersäuresalz von antiulcus arzneimitteln

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI98A000442 1998-03-05
IT98MI000442A IT1299198B1 (it) 1998-03-05 1998-03-05 Sali nitrati di farmaci antiulcera

Publications (1)

Publication Number Publication Date
WO1999045004A1 true WO1999045004A1 (en) 1999-09-10

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ID=11379185

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1999/001226 Ceased WO1999045004A1 (en) 1998-03-05 1999-02-25 Nitrate salt of anti-ulcer medicine

Country Status (19)

Country Link
US (1) US6503929B1 (https=)
EP (1) EP1068196B1 (https=)
JP (1) JP2002505328A (https=)
KR (1) KR20010041522A (https=)
CN (1) CN1249053C (https=)
AT (1) ATE273297T1 (https=)
AU (1) AU752919B2 (https=)
BR (1) BR9908428A (https=)
CA (1) CA2322493A1 (https=)
DE (1) DE69919341T2 (https=)
DK (1) DK1068196T3 (https=)
ES (1) ES2226357T3 (https=)
HU (1) HUP0100853A3 (https=)
IL (1) IL137721A0 (https=)
IT (1) IT1299198B1 (https=)
PT (1) PT1068196E (https=)
RU (1) RU2228331C2 (https=)
SI (1) SI1068196T1 (https=)
WO (1) WO1999045004A1 (https=)

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6552047B2 (en) 1998-11-17 2003-04-22 Nitromed, Inc. H2 receptor antagonist compounds in combination with nitric oxide donors, compositions and methods of use
US6649629B2 (en) 1999-12-23 2003-11-18 Nitromed, Inc. Nitrosated and nitrosylated cyclooxygenase-2 inhibitors, compositions and methods of use
US6673819B2 (en) 2000-06-30 2004-01-06 Astrazeneca Ab Compounds useful as antibacterial agents
US6780882B2 (en) 1996-01-04 2004-08-24 The Curators Of The University Of Missouri Substituted benzimidazole dosage forms and method of using same
US6825185B2 (en) 2000-12-21 2004-11-30 Nitromed, Inc. Substituted aryl compounds as novel cyclooxygenase-2 selective inhibitors, compositions and methods of use
US6852739B1 (en) 1999-02-26 2005-02-08 Nitromed Inc. Methods using proton pump inhibitors and nitric oxide donors
US7163958B2 (en) 2002-07-03 2007-01-16 Nitromed Inc. Nitrosated nonsteroidal antiinflammatory compounds, compositions and methods of use
US7211590B2 (en) 2002-08-01 2007-05-01 Nitromed, Inc. Nitrosated proton pump inhibitors, compositions and methods of use
US7211598B2 (en) 2002-06-28 2007-05-01 Nitromed, Inc. Oxime and/or hydrozone containing nitrosated and/or nitrosylated cyclooxygenase-2 selective inhibitors, compositions and methods of use
US7220749B2 (en) 2002-06-11 2007-05-22 Nitromed, Inc. Nitrosated and/or nitrosylated cyclooxygenase-2 selective inhibitors, compositions and methods of use
US7244753B2 (en) 2002-07-29 2007-07-17 Nitromed, Inc. Cyclooxygenase-2 selective inhibitors, compositions and methods of use
USRE45198E1 (en) 1996-01-04 2014-10-14 The Curators Of The University Of Missouri Omeprazole solution and method for using same
US8906940B2 (en) 2004-05-25 2014-12-09 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US8993599B2 (en) 2003-07-18 2015-03-31 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1317735B1 (it) * 2000-01-26 2003-07-15 Nicox Sa Sali di agenti antimicrobici.
US7129161B2 (en) * 2001-07-19 2006-10-31 Trikon Holdings Limited Depositing a tantalum film
RU2304967C2 (ru) * 2005-05-26 2007-08-27 Государственное общеобразовательное учреждение высшего профессионального образования Казанский государственный медицинский университет Способ лечения язвенной болезни желудка и двенадцатиперстной кишки

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DE2344779A1 (de) * 1972-09-05 1974-03-14 Smith Kline French Lab Cyanguanidine, ihre salze, verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneimittel
EP0005129A1 (en) * 1978-04-14 1979-10-31 Aktiebolaget Hässle Substituted pyridylsulfinylbenzimidazoles having gastric acid secretion properties, pharmaceutical preparations containing same, and intermediates for their preparation
EP0049618A1 (en) * 1980-10-02 1982-04-14 Eli Lilly And Company Improvements in or relating to 2,4-disubstituted thiazole derivatives
EP0224612A1 (de) * 1985-12-05 1987-06-10 HEUMANN PHARMA GMBH & CO Verfahren zur Herstellung von N-Cyano-N'-methyl-N"[2-[[(5-methyl-1H-imidazol-4-yl)methyl]thio]ethyl]guanidin
EP0285681A1 (de) * 1987-04-06 1988-10-12 HEUMANN PHARMA GMBH & CO Verfahren zur Herstellung von Nitroethenderivaten

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TW205041B (https=) * 1989-08-07 1993-05-01 Fujisawa Pharmaceutical Co

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2344779A1 (de) * 1972-09-05 1974-03-14 Smith Kline French Lab Cyanguanidine, ihre salze, verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneimittel
EP0005129A1 (en) * 1978-04-14 1979-10-31 Aktiebolaget Hässle Substituted pyridylsulfinylbenzimidazoles having gastric acid secretion properties, pharmaceutical preparations containing same, and intermediates for their preparation
EP0049618A1 (en) * 1980-10-02 1982-04-14 Eli Lilly And Company Improvements in or relating to 2,4-disubstituted thiazole derivatives
EP0224612A1 (de) * 1985-12-05 1987-06-10 HEUMANN PHARMA GMBH & CO Verfahren zur Herstellung von N-Cyano-N'-methyl-N"[2-[[(5-methyl-1H-imidazol-4-yl)methyl]thio]ethyl]guanidin
EP0285681A1 (de) * 1987-04-06 1988-10-12 HEUMANN PHARMA GMBH & CO Verfahren zur Herstellung von Nitroethenderivaten

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6780882B2 (en) 1996-01-04 2004-08-24 The Curators Of The University Of Missouri Substituted benzimidazole dosage forms and method of using same
USRE45198E1 (en) 1996-01-04 2014-10-14 The Curators Of The University Of Missouri Omeprazole solution and method for using same
US6936627B2 (en) 1998-11-17 2005-08-30 Nitromed, Inc. Nitrosated and nitrosylated H2 receptor antagonist compounds, compositions and methods of use
US7256205B2 (en) 1998-11-17 2007-08-14 Nitromed, Inc. Nitrosated and nitrosylated H2 receptor antagonist compounds, compositions and methods of use
US7129251B2 (en) 1998-11-17 2006-10-31 Nitromed, Inc. Nitrosated and nitrosylated H2 receptor antagonist compounds, compositions and methods of use
US6552047B2 (en) 1998-11-17 2003-04-22 Nitromed, Inc. H2 receptor antagonist compounds in combination with nitric oxide donors, compositions and methods of use
US6852739B1 (en) 1999-02-26 2005-02-08 Nitromed Inc. Methods using proton pump inhibitors and nitric oxide donors
US7332505B2 (en) 1999-02-26 2008-02-19 Nitromed, Inc. Nitrosated and nitrosylated proton pump inhibitors, compositions and methods of use
US6649629B2 (en) 1999-12-23 2003-11-18 Nitromed, Inc. Nitrosated and nitrosylated cyclooxygenase-2 inhibitors, compositions and methods of use
US7166618B2 (en) 1999-12-23 2007-01-23 Nitromed, Inc. Nitrosated and nitrosylated cyclooxygenase-2 inhibitors, compositions and methods of use
US7432285B2 (en) 1999-12-23 2008-10-07 Nitromed, Inc. Nitrosated and nitrosylated cyclooxygenase-2 inhibitors, compositions and methods of use
US6673819B2 (en) 2000-06-30 2004-01-06 Astrazeneca Ab Compounds useful as antibacterial agents
US6825185B2 (en) 2000-12-21 2004-11-30 Nitromed, Inc. Substituted aryl compounds as novel cyclooxygenase-2 selective inhibitors, compositions and methods of use
US7220749B2 (en) 2002-06-11 2007-05-22 Nitromed, Inc. Nitrosated and/or nitrosylated cyclooxygenase-2 selective inhibitors, compositions and methods of use
US7589124B2 (en) 2002-06-11 2009-09-15 Nicox, S.A. Nitrosated and/or nitrosylated cyclooxygenase-2 selective inhibitors, compositions and methods of use
US7211598B2 (en) 2002-06-28 2007-05-01 Nitromed, Inc. Oxime and/or hydrozone containing nitrosated and/or nitrosylated cyclooxygenase-2 selective inhibitors, compositions and methods of use
US7883714B2 (en) 2002-07-03 2011-02-08 Nicox S.A. Nitrosated nonsteroidal antiinflammatory compounds, compositions and methods of use
US8088762B2 (en) 2002-07-03 2012-01-03 Nicox S.A. Nitrosated nonsteroidal antiinflammatory compounds, compositions and methods of use
US8222277B2 (en) 2002-07-03 2012-07-17 Nicox S.A. Nitrosated nonsteroidal antiinflammatory compounds, compositions and methods of use
US8304409B2 (en) 2002-07-03 2012-11-06 Nicox S.A. Nitrosated nonsteroidal antiinflammatory compounds, compositions and methods of use
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HUP0100853A3 (en) 2003-01-28
JP2002505328A (ja) 2002-02-19
DE69919341T2 (de) 2005-09-08
HUP0100853A2 (hu) 2001-10-28
CN1291982A (zh) 2001-04-18
CN1249053C (zh) 2006-04-05
RU2228331C2 (ru) 2004-05-10
IL137721A0 (en) 2001-10-31
DK1068196T3 (da) 2004-11-29
AU752919B2 (en) 2002-10-03
CA2322493A1 (en) 1999-09-10
PT1068196E (pt) 2004-10-29
ATE273297T1 (de) 2004-08-15
EP1068196A1 (en) 2001-01-17
SI1068196T1 (en) 2004-12-31
US6503929B1 (en) 2003-01-07
DE69919341D1 (de) 2004-09-16
ES2226357T3 (es) 2005-03-16
IT1299198B1 (it) 2000-02-29
EP1068196B1 (en) 2004-08-11
BR9908428A (pt) 2000-10-31
AU3030399A (en) 1999-09-20
ITMI980442A1 (it) 1999-09-05
KR20010041522A (ko) 2001-05-25

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