EP0535081A1 - Benzimidazoles substitues, procede de preparation et utilisation pharmaceutique de ceux-ci - Google Patents
Benzimidazoles substitues, procede de preparation et utilisation pharmaceutique de ceux-ciInfo
- Publication number
- EP0535081A1 EP0535081A1 EP91911659A EP91911659A EP0535081A1 EP 0535081 A1 EP0535081 A1 EP 0535081A1 EP 91911659 A EP91911659 A EP 91911659A EP 91911659 A EP91911659 A EP 91911659A EP 0535081 A1 EP0535081 A1 EP 0535081A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- methyl
- compound
- formula
- pyridinyl
- dimethoxy
- 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.)
- Withdrawn
Links
Classifications
-
- 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
- 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
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
Definitions
- the object of the present invention is to provide novel compounds, which inhibit exogenously or endogenously stimulated gastric acid secretion and thus can be used in the prevention and treatment of peptic ulcer.
- the present invention also relates to the use of the compounds of the invention for inhibiting gastric acid secretion in mammals including man.
- the compounds of the invention may be used for prevention and treatment of gastrointestinal inflammatory diseases, and gastric acid-related diseases in mammals including man, such as gastritis, gastric ulcer, duodenal ulcer, reflux esophagitis, and Zollinger-Ellison syndrome.
- the compounds may be used for treatment of other gastrointestinal disorders where gastric
- antisecretory effect is desirable e.g. in patients with gastrinomas, and in patients with acute upper
- the compounds of the invention may also be used for treatment or prophylaxis of inflammatory disorders
- the invention also relates to pharmaceutical compositions containing the compounds of the invention, as active ingredient. In a further aspect, the invention relates to processes for preparation of such new compounds and to the use of the active compounds for the preparation of pharmaceutical compositions for the medical use indicated above.
- the compounds of the invention will also exhibit good
- the compounds of the invention will not block the uptake of iodine into the thyroid gland. It has earlier been disclosed in several lectures from the company, where the inventors are working that thyroid toxicity depends on if the compounds are lipophilic or not. The inventors have now unexpectedly found that it is not the lipophilicity that is the critical parameter.
- the claimed compounds which include rather hydrophilic compounds, do not give any thyroid toxic effect and have at the same time high acid secretion inhibitory effect, good bioavailability and stability.
- Benzimidazole derivatives intended for inhibiting gastric acid secretion are disclosed in numerous patent documents. Among these can be mentioned GB 1 500 043, GB 1 525 958, US 4 182 766, US 4 255 431, US 4 599 347, BE 898 880, EP 124 495, EP 208 452, EP 221 041, EP 279 149, EP 176 308 and Derwent abstract 87-294449/42.
- the compounds of the invention exhibit a high chemical stability in solution at neutral and acidic pH.
- the high chemical stability also at acidic pH makes the compounds useful for non-enteric coated peroral formulations.
- the compounds of the invention are of the following formula I:
- R 1 and R 2 which are different, is each H, alkyl
- R 1 or R 2 is always selected from the group -C(O)-R 6 ;
- R 6 is alkyl containing 1-4 carbon atoms or alkoxy
- R 3 is the group -CH 2 OCCOR 7 , wherein R 7 is alkyl containing
- R 4 and R 5 are the same or different and selected from
- R 4 and R 5 form together with the adjacent oxygen atoms attached to the pyridine ring and the carbon atoms in the pyridine ring a ring, wherein the part constituted by R 4 and R 5 is -CH 2 CH 2 CH 2 -, -CH 2 CH 2 - or -CH 2 -.
- alkyl and “alkoxy” include straight and branched structures.
- the compounds of the invention of the formula I have an asymmetric centre in the sulfur atom, i.e. exists as two optical isomers (enantiomers) or if they also contain one or more asymmetric carbon atoms, the compounds have two or more diastereomeric forms, each existing in the two enantiomeric forms.
- Both the pure enantiomers, racemic mixtures (50% of each enantiomer) and unequal mixtures of the two are within the scope of the present invention. It should also be understood that all the diastereomeric forms possible (pure enantiomers or racemic mixtures) are within the scope of the invention.
- Preferred groups of compounds of the formula I are: 1. Compounds, wherein R 3 is -CH 2 OCOOCH 2 CH 3 .
- R 1 and R 2 are selected from H, methyl or -C(O)-R 6 , wherein R 6 is alkyl containing 1-
- Benzimidazole structures are:
- the compounds of the invention may be prepared according to the following methods: a) Reacting a compound of the formula II
- R 1 , R 2 , R 4 and R 5 are as definedw under formula I, and Z, is either a metal cation such as Na+, K+, Li+ or Ag+ or a quaternary ammonium ion, such as tetrabutylammonium with alkyl chloromethyl carbonate or benzyl chloromethyl carbonate.
- the reactions according to a) and b) are suitably carried out under protective gas in absence of water.
- Suitable solvents are hydrocarbons such as toluene or benzene or halogenated hydrocarbons such as methylene chloride or chloroform, or acetone, acetonitrile or dimethyIformamide.
- the reactions may be carried out at a temperature between the ambient temperature and the boiling temperature of the reaction mixture.
- R 1 , R 2 , R 3 , R 4 and R 5 are as defined under formula I.
- This oxidation may be carried out by using an oxidizing agent such as nitric acid, hydrogen peroxide, (optionally in the presence of vanadium compounds), peracids, peresters, ozone, dinitrogentetraoxide, iodosobenzene, Nhalosuccinimide, 1-chlorobenzotriazole, tbutylhypochlorite, diazabicyclo-[2,2,2]-octane bromine complex, sodium metaperiodate, selenium dioxide, manganese dioxide, chromic acid, cericammonium nitrate, bromine, chlorine, and sulfuryl chloride.
- the oxidation usually takes place in a solvent such as halogenated hydrocarbons, alcohols, ethers, ketones.
- the oxidation may also be carried out enzymatically by using an oxidizing enzyme or microbiotically by using a suitable microorganism.
- the structural isomers obtained may be separated by means of crystallization or
- Racemates obtained can be separated according to known methods, e.g. recrystallization from an optically active solvent. In the case of racemic diastereomeric mixtures these may be separated into diastereomeric pure enantiomers by means of chromatography or fractional crystallization.
- the starting materials utilized in the methods a)-c) are in some cases unknown. These unknown starting materials may, be obtained according to processes known per se.
- Alkyl chloromethyl carbonate and benzyl chloromethyl carbonate may be obtained from the pertinent alcohol by treatment with chloromethyl chloroformate in the presence of pyridine.
- Starting materials of the formula III may be obtained by known methods, e.g. from an alcohol HOR 7 by treatment with phosgene or 1,1 1 -carbonyldiimidazole or p-nitrophenyl chloroformate.
- a compound of the invention is formulated into pharmaceutical formulations for oral, rectal, or other modes of administration.
- the pharmaceutical formulation contains a compound of the invention normally in combinatio with a pharmaceutically acceptable carrier.
- the carrier may be in the form of a solid, semi-solid or liquid diluent, or a capsule.
- a compound selected may be mixed with a solid, powdered carrier, such as lactose, saccharose, sorbitol, mannitol, starch,
- the mixture is then processed into granules or pressed into tablets.
- Granules and tablets may be coated with an enteric coating which protects the active compound from acid catalyzed degradation as long as the dosage form remains in the stomach.
- the enteric coating is chosen among pharmaceutically acceptable enteric-coating materials e.g.
- soft gelatine capsules vegetable oil, fat, or other suitable vehicle for soft gelatine capsules.
- Soft gelatine capsules may also be enteric-coated as described above.
- Hard gelatine capsules may contain granules or enteric-coated granules of the active compound.
- Hard gelatine capsules may also contain the active compound in combination with a solid powdered carrier such as lactose, saccharose, sorbitol, mannitol, potato starch, amylopection, cellulose
- Dosage units for rectal administration may be prepared in the form of suppositories which contain an active substance mixed with a neutral fat base, or they may be prepared in the form of a gelatine rectal capsule which contains the active substance in a mixture with a vegetable oil, paraffin oil or other suitable vehicle for gelatine rectal capsules, or they may be prepared in the form of a ready-made micro enema, or they may be prepared in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.
- Liquid preparation for oral administration may be prepared in the form of syrups or suspensions, e.g. solutions or suspensions containing from 0.2% to 20% by weight of the active ingredient and the remainder consisting of sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and/or polyethylene glycol. If desired, such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethyl cellulose or other thickening agents.
- Liquid preparations for oral administration may also be prepared in the form of a dry powder to be reconstituted with a suitable solvent prior to use.
- the typical daily dose of the active substance will depend on various factors such as for example the individual requirement of each patient, the route of administration and the disease. In general, oral dosages will be in the range of 5 to 500 mg per day of active substance.
- Example 1 Preparation of 5-carbomethoxy-6-methyl-2-[[(3,4- dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole-1- ylmethyl ethyl carbonate and 6-carbomethoxy-5-methyl-2- [[(3,4-dimethoxy-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole-1-ylmethyl ethyl carbonate, as an isomeric mixture.
- the title compound was isolated from the isomeric mixture given in example 3 by chromatography on a silica column with methylene chloride - acetonitrile (ratio 6:4) as eluent. The title compound was crystallized from ethanol.
- the title compound was isolated from the isomeric mixture given in example 3 by chromatography on a silica column with methylene chloride-acetonitrile (ratio 6:4) as eluent. The title compound was crystallized from ethanol.
- a syrup containing 1% (weight per volume) of active substance was prepared from the following ingredients:
- a compound according to Example 4 1. 0 g Sugar, powder 30. 0 g Saccharine 0.6 g Glycerol 5. 0 g Tween 1.0 g
- Tablets A tablet containing 50 mg of active compound was prepared from the following ingredients:
- Capsules containing 30 mg of active compound were prepared from the following ingredients:
- the active compound mixture was mixed with the dry ingredients and granulated with a solution of disodium hydrogen phosphate.
- the wet mass was forced through an extruder and spheronized and dried in a fluidized bed dryer.
- 500 g of the pellets above were first coated with a solution of hydroxypropyl methylcellulose, 30 g, in water, 600 g, using a fluidized bed coater. After drying, the pellets were coated with a second coating as given below: Coating solution:
- the final coated pellets were filled into capsules.
- Suppositories Suppositories were prepared from the following ingredients using a welding procedure. Each suppository contained 40 mg of active compound.
- the active compound mixture was homogenously mixed with Witepsol H-15 at a temperature of 41°C.
- the molten mass was volume filled into pre-fabricated suppository packages to a net weight of 1.84 g. After cooling the packages were heat sealed.
- Each suppository contained 40 mg of active compound.
- Bioavailability is assessed by calculating the quotient between the areas under plasma concentration (AUC) curve of a compound of the formula I wherein R 3 is hydrogen
- compound A (herein defined as compound A), following 1) intraduodenal (id) or oral (po) administration of the corresponding compound according to the invention and 2) intravenous
- the potency for inhibition of acid secretion is measured in the female rat orally and in the dog both
- the effect of a compound within the invention of the formula I on the uptake of iodine into the thyroid gland is measured as an effect on the accumulation of 125 I in the thyroid gland of the corresponding compound of the formula I, wherein R 3 is hydrogen, that is a metabolized compound of the formula I.
- the samples were frozen as soon as possible until analysis of the test compound.
- the area under the blood concentration vs time curve, AUC, for the compound A, determined by the linear trapezoidal rule and extrapolated to infinity by dividing the last determined blood concentration by the elimination rate constant in the terminal phase.
- Harrier dogs of either sex were used. They were equipped with a duodenal fistula for the administration of test compounds or vehicle and a cannulated gastric fistula or a Heidenhain-pouch for the collection of gastric secretions. Before secretory tests the animals were fasted for about 18 h but water was freely allowed. Gastric acid secretion was stimulated by a 4 h infusion of histamine
- test substance or vehicle was given orally, id or iv 1 h after starting the histamine infusion, in a volume of 0.5 ml/kg body weight.
- test compound is administered to the acid secreting main stomach of the Heidenhain-pouch dog.
- the acidity of the gastric juice samples were determined by titration to pH 7.0, and the acid output calculated. The acid output in the collection periods after
- Percentage inhibition was calculated from fractional responses elicited by test compound and vehicle. ED 50 -values were obtained by graphical interpolation on log dose - response curves, or estimated from single-dose experiments under the assumption of the same slope of the dose-response curve for all test compounds. All results reported are based on acid output 2 h after dosing.
- methocel were administerd by oral gavage in a volume of 5 ml/kg body weight. After 1 hour, 125 I (300kBq/kg, 3ml/kg) was administered by intraperitoneal injection. Four hours after 125I-administration, the animals were killed by
- Table 4 and 5 give a sumnary of the test data available for the compounds of the invention.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyridine Compounds (AREA)
Abstract
On décrit les nouveaux composés de formule (I), où R1 et R2, qui sont différents, représentent chacun H, un alkyle contenant de 1 à 4 atomes de carbone ou -C(O)-R6; l'un d'entre R1 et R2 est toujours choisi dans le groupe -C(O)-R6; où R6 représente un alkyle contenant de 1 à 4 atomes de carbone ou un alcoxy contenant de 1 à 4 atomes de carbone, R3 représente le groupe -CH2OCOOR7, où R7 représente un alkyle contenant de 1 à 6 atomes de carbone ou un benzyle; R4 et R5 sont les mêmes ou différents et choisis à partir de -CH3, -C2H5, (a), (b) et -CH2CH2OCH3, ou R4 et R5 forment un cycle avec les atomes d'oxygène contigus rattachés au cycle pyridique et les atomes de carbone dans le cycle pyridique, où la partie composée de R4 et R5 représente -CH2CH2CH2-, -CH2CH2- ou -CH2-. On décrit aussi des compositions pharmaceutiques contenant de tels composés comme ingrédient actif et l'utilisation de ces composés dans le domaine médical.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
SE9002206A SE9002206D0 (sv) | 1990-06-20 | 1990-06-20 | New compounds |
SE9002206 | 1990-06-20 |
Publications (1)
Publication Number | Publication Date |
---|---|
EP0535081A1 true EP0535081A1 (fr) | 1993-04-07 |
Family
ID=20379831
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP91911659A Withdrawn EP0535081A1 (fr) | 1990-06-20 | 1991-06-11 | Benzimidazoles substitues, procede de preparation et utilisation pharmaceutique de ceux-ci |
Country Status (27)
Country | Link |
---|---|
EP (1) | EP0535081A1 (fr) |
JP (1) | JPH05507713A (fr) |
CN (1) | CN1058212A (fr) |
AP (1) | AP215A (fr) |
AU (1) | AU649453B2 (fr) |
BG (1) | BG97200A (fr) |
CA (1) | CA2083714A1 (fr) |
CZ (1) | CZ279772B6 (fr) |
FI (1) | FI925766A0 (fr) |
HU (1) | HUT62881A (fr) |
IE (1) | IE912025A1 (fr) |
IL (1) | IL98470A0 (fr) |
IS (1) | IS3721A7 (fr) |
LT (2) | LT3952B (fr) |
LV (1) | LV10953A (fr) |
MA (1) | MA22199A1 (fr) |
NO (1) | NO924775L (fr) |
NZ (1) | NZ238546A (fr) |
OA (1) | OA09682A (fr) |
PT (1) | PT98035A (fr) |
RO (1) | RO110493B1 (fr) |
SE (1) | SE9002206D0 (fr) |
TN (1) | TNSN91049A1 (fr) |
TW (1) | TW216418B (fr) |
WO (1) | WO1991019711A1 (fr) |
YU (1) | YU104191A (fr) |
ZA (2) | ZA914296B (fr) |
Families Citing this family (29)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SE9002043D0 (sv) * | 1990-06-07 | 1990-06-07 | Astra Ab | Improved method for synthesis |
SE9103776D0 (sv) * | 1991-12-19 | 1991-12-19 | Astra Ab | New compounds |
IS4232A (is) * | 1993-12-06 | 1995-06-07 | Astra Aktiebolag | Súbstitúerað bensimidasól, aðferðir við framleiðslu þess og lyfjafræðileg notkun |
SE9500422D0 (sv) * | 1995-02-06 | 1995-02-06 | Astra Ab | New oral pharmaceutical dosage forms |
SE9500478D0 (sv) * | 1995-02-09 | 1995-02-09 | Astra Ab | New pharmaceutical formulation and process |
SE9600070D0 (sv) | 1996-01-08 | 1996-01-08 | Astra Ab | New oral pharmaceutical dosage forms |
WO2001062248A1 (fr) | 2000-02-24 | 2001-08-30 | Kopran Research Laboratories Limited | Derives de benzimidazole antiulcereux a acidite stable administrables oralement |
SE0101379D0 (sv) | 2001-04-18 | 2001-04-18 | Diabact Ab | Komposition som hämmar utsöndring av magsyra |
US8206741B2 (en) | 2001-06-01 | 2012-06-26 | Pozen Inc. | Pharmaceutical compositions for the coordinated delivery of NSAIDs |
PT1492511E (pt) | 2002-04-09 | 2009-04-09 | Flamel Tech Sa | Formulação farmacêutica oral na forma de suspensão aquosa de microcápsulas para libertação modificada de princípio(s) activo(s) |
SE0203065D0 (sv) | 2002-10-16 | 2002-10-16 | Diabact Ab | Gastric acid secretion inhibiting composition |
MXPA06003450A (es) | 2003-09-26 | 2006-08-31 | Johnson & Johnson | Recubrimiento de farmaco que proporciona alta carga del farmaco y metodos para proporcionar el mismo. |
TW200606163A (en) | 2004-04-22 | 2006-02-16 | Eisai Co Ltd | Imidazopyridine compound |
US8541026B2 (en) | 2004-09-24 | 2013-09-24 | Abbvie Inc. | Sustained release formulations of opioid and nonopioid analgesics |
US20070015782A1 (en) | 2005-04-15 | 2007-01-18 | Eisai Co., Ltd. | Benzimidazole compound |
US9040564B2 (en) | 2005-04-28 | 2015-05-26 | Eisai R&D Management Co., Ltd. | Stabilized composition |
US7981908B2 (en) | 2005-05-11 | 2011-07-19 | Vecta, Ltd. | Compositions and methods for inhibiting gastric acid secretion |
US7803817B2 (en) | 2005-05-11 | 2010-09-28 | Vecta, Ltd. | Composition and methods for inhibiting gastric acid secretion |
WO2007122686A1 (fr) * | 2006-04-14 | 2007-11-01 | Eisai R & D Management Co., Ltd. | Composes benzimidazole |
EP2046334B1 (fr) | 2006-07-25 | 2014-05-21 | Vecta Ltd. | Compositions et procédés d'inhibition de sécrétion d'acide gastrique utilisant des dérivés de petits acides dicarboxyliques combinés á un ipp |
JP5492417B2 (ja) * | 2006-10-13 | 2014-05-14 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | 胃酸分泌抑制作用を有するベンズイミダゾール化合物 |
AU2009290712A1 (en) | 2008-09-09 | 2010-03-18 | Astrazeneca Ab | Method for delivering a pharmaceutical composition to patient in need thereof |
AU2010263304A1 (en) | 2009-06-25 | 2012-02-02 | Astrazeneca Ab | Method for treating a patient at risk for developing an NSAID-associated ulcer |
WO2011080501A2 (fr) | 2009-12-29 | 2011-07-07 | Orexo Ab | Nouvelle forme pharmaceutique destinée au traitement de troubles liés à l'acide gastrique |
WO2011080500A2 (fr) | 2009-12-29 | 2011-07-07 | Orexo Ab | Nouvelle forme pharmaceutique destinée au traitement de troubles liés à l'acide gastrique |
WO2011080502A2 (fr) | 2009-12-29 | 2011-07-07 | Orexo Ab | Nouvelle forme pharmaceutique destinée au traitement de troubles liés à l'acide gastrique |
EP2601947A1 (fr) | 2011-12-05 | 2013-06-12 | Abo Bakr Mohammed Ali Al-Mehdar | Combinaison à dose fixe pour le traitement de maladies associées à Hélicobacter pylori |
CA2860231A1 (fr) | 2011-12-28 | 2013-07-04 | Pozen Inc. | Compositions et procedes d'administration d'omeprazole plus acide acetylsalicylique ameliores |
EP3512840B1 (fr) * | 2016-09-14 | 2024-03-06 | Yufeng Jane Tseng | Nouveaux dérivés de benzimidazole substitués utilisés en tant qu'inhibiteurs de la d-amino-acide oxydase (daao) |
Family Cites Families (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SE418966B (sv) | 1974-02-18 | 1981-07-06 | Haessle Ab | Analogiforfarande for framstellning av foreningar med magsyrasekretionsinhiberande verkan |
SE416649B (sv) | 1974-05-16 | 1981-01-26 | Haessle Ab | Forfarande for framstellning av foreningar som paverkar magsyrasekretionen |
IN148930B (fr) | 1977-09-19 | 1981-07-25 | Hoffmann La Roche | |
SE7804231L (sv) | 1978-04-14 | 1979-10-15 | Haessle Ab | Magsyrasekretionsmedel |
US4359465A (en) | 1980-07-28 | 1982-11-16 | The Upjohn Company | Methods for treating gastrointestinal inflammation |
CH644116A5 (de) | 1980-08-21 | 1984-07-13 | Hoffmann La Roche | Imidazolderivate. |
SE8300736D0 (sv) | 1983-02-11 | 1983-02-11 | Haessle Ab | Novel pharmacologically active compounds |
SE8301182D0 (sv) | 1983-03-04 | 1983-03-04 | Haessle Ab | Novel compounds |
IL75400A (en) * | 1984-06-16 | 1988-10-31 | Byk Gulden Lomberg Chem Fab | Dialkoxypyridine methyl(sulfinyl or sulfonyl)benzimidazoles,processes for the preparation thereof and pharmaceutical compositions containing the same |
AU568441B2 (en) * | 1984-09-24 | 1987-12-24 | Upjohn Company, The | 2-(pyridylalkenesulfinyl) benzimidazole derivatives |
IL76839A (en) * | 1984-10-31 | 1988-08-31 | Byk Gulden Lomberg Chem Fab | Picoline derivatives,processes for the preparation thereof and pharmaceutical compositions containing the same |
US4738975A (en) | 1985-07-02 | 1988-04-19 | Takeda Chemical Industries, Ltd. | Pyridine derivatives, and use as anti-ulcer agents |
SE8505112D0 (sv) * | 1985-10-29 | 1985-10-29 | Haessle Ab | Novel pharmacological compounds |
NZ234564A (en) | 1986-11-21 | 1991-04-26 | Haessle Ab | 1-substituted benzimidazoles and pharmaceutical compositions |
DE3722810A1 (de) * | 1987-07-10 | 1989-01-19 | Hoechst Ag | Substituierte benzimidazole, verfahren zu deren herstellung, diese enthaltende pharmazeutische zubereitungen und deren verwendung |
JPH02501930A (ja) * | 1987-10-30 | 1990-06-28 | アクチエボラゲツト・ヘツスレ | 薬学的化合物のための新規な用途 |
EP0390842A1 (fr) * | 1987-12-11 | 1990-10-10 | Byk Gulden Lomberg Chemische Fabrik GmbH | Nouveaux derives benzoglyoxaline |
AU3690289A (en) * | 1988-05-25 | 1989-12-12 | Byk Gulden Lomberg Chemische Fabrik Gmbh | New fluoralkoxy compounds |
-
1990
- 1990-06-20 SE SE9002206A patent/SE9002206D0/xx unknown
-
1991
- 1991-06-05 ZA ZA914296A patent/ZA914296B/xx unknown
- 1991-06-05 ZA ZA914297A patent/ZA914297B/xx unknown
- 1991-06-11 EP EP91911659A patent/EP0535081A1/fr not_active Withdrawn
- 1991-06-11 CA CA002083714A patent/CA2083714A1/fr not_active Abandoned
- 1991-06-11 RO RO92-01581A patent/RO110493B1/ro unknown
- 1991-06-11 JP JP91511435A patent/JPH05507713A/ja active Pending
- 1991-06-11 HU HU924033A patent/HUT62881A/hu unknown
- 1991-06-11 AU AU80097/91A patent/AU649453B2/en not_active Ceased
- 1991-06-11 WO PCT/SE1991/000415 patent/WO1991019711A1/fr not_active Application Discontinuation
- 1991-06-12 IL IL98470A patent/IL98470A0/xx unknown
- 1991-06-12 TW TW080104582A patent/TW216418B/zh active
- 1991-06-12 YU YU104191A patent/YU104191A/sh unknown
- 1991-06-14 NZ NZ238546A patent/NZ238546A/en unknown
- 1991-06-14 IE IE202591A patent/IE912025A1/en unknown
- 1991-06-18 MA MA22462A patent/MA22199A1/fr unknown
- 1991-06-19 PT PT98035A patent/PT98035A/pt not_active Application Discontinuation
- 1991-06-19 AP APAP/P/1991/000285A patent/AP215A/en active
- 1991-06-19 TN TNTNSN91049A patent/TNSN91049A1/fr unknown
- 1991-06-20 CZ CS911894A patent/CZ279772B6/cs unknown
- 1991-06-20 CN CN91105024A patent/CN1058212A/zh active Pending
- 1991-06-20 IS IS3721A patent/IS3721A7/is unknown
-
1992
- 1992-11-27 OA OA60306A patent/OA09682A/en unknown
- 1992-12-10 NO NO92924775A patent/NO924775L/no unknown
- 1992-12-18 BG BG097200A patent/BG97200A/bg unknown
- 1992-12-18 FI FI925766A patent/FI925766A0/fi not_active Application Discontinuation
-
1993
- 1993-08-27 LV LV931045A patent/LV10953A/xx unknown
- 1993-12-30 LT LTIP1712A patent/LT3952B/lt not_active IP Right Cessation
- 1993-12-30 LT LTIP1713A patent/LT3977B/lt not_active IP Right Cessation
Non-Patent Citations (1)
Title |
---|
See references of WO9119711A1 * |
Also Published As
Publication number | Publication date |
---|---|
NZ238546A (en) | 1994-03-25 |
MA22199A1 (fr) | 1992-04-01 |
SE9002206D0 (sv) | 1990-06-20 |
LT3977B (en) | 1996-06-25 |
AP9100285A0 (en) | 1991-07-31 |
HU9204033D0 (en) | 1993-03-29 |
CS189491A3 (en) | 1992-04-15 |
BG97200A (bg) | 1993-12-24 |
IS3721A7 (is) | 1991-12-21 |
AU8009791A (en) | 1992-01-07 |
AP215A (en) | 1992-09-02 |
IL98470A0 (en) | 1992-07-15 |
AU649453B2 (en) | 1994-05-26 |
LTIP1713A (en) | 1995-08-25 |
RO110493B1 (ro) | 1996-01-30 |
NO924775D0 (no) | 1992-12-10 |
JPH05507713A (ja) | 1993-11-04 |
IE912025A1 (en) | 1992-01-01 |
LV10953A (lv) | 1995-12-20 |
LTIP1712A (en) | 1995-08-25 |
WO1991019711A1 (fr) | 1991-12-26 |
OA09682A (en) | 1993-05-15 |
TW216418B (fr) | 1993-11-21 |
ZA914297B (en) | 1992-03-25 |
CN1058212A (zh) | 1992-01-29 |
ZA914296B (en) | 1992-03-25 |
HUT62881A (en) | 1993-06-28 |
CZ279772B6 (cs) | 1995-06-14 |
PT98035A (pt) | 1992-03-31 |
YU104191A (sh) | 1994-01-20 |
LT3952B (en) | 1996-05-27 |
CA2083714A1 (fr) | 1991-12-21 |
TNSN91049A1 (fr) | 1992-10-25 |
FI925766A (fi) | 1992-12-18 |
NO924775L (no) | 1992-12-10 |
FI925766A0 (fi) | 1992-12-18 |
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