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WO1996003403A1 - Benzylimidazopyridines - Google Patents

Benzylimidazopyridines Download PDF

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Publication number
WO1996003403A1
WO1996003403A1 PCT/EP1995/002952 EP9502952W WO9603403A1 WO 1996003403 A1 WO1996003403 A1 WO 1996003403A1 EP 9502952 W EP9502952 W EP 9502952W WO 9603403 A1 WO9603403 A1 WO 9603403A1
Authority
WO
WIPO (PCT)
Prior art keywords
compounds
formula
methyl
hydrogen
salts
Prior art date
Application number
PCT/EP1995/002952
Other languages
German (de)
English (en)
Inventor
Georg Rainer
Jörg Senn-Bilfinger
Gerhard Grundler
Richard Riedel
Stefan Postius
Wolfgang-Alexander Simon
Original Assignee
Byk Gulden Lomberg Chemische Fabrik Gmbh
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 Byk Gulden Lomberg Chemische Fabrik Gmbh filed Critical Byk Gulden Lomberg Chemische Fabrik Gmbh
Priority to NZ290818A priority Critical patent/NZ290818A/xx
Priority to JP8505480A priority patent/JPH10505331A/ja
Priority to EP95927725A priority patent/EP0773944A1/fr
Priority to AU31660/95A priority patent/AU700737B2/en
Publication of WO1996003403A1 publication Critical patent/WO1996003403A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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

Definitions

  • the invention relates to new benzylimidazopyridines which are to be used in the pharmaceutical industry as active ingredients for the production of medicaments.
  • European patent application EP-A-0033094 describes imidazo [1,2-a] pyridines which carry an aryl substituent in the 8-position which preferably has a phenyl, thienyl, pyridyl or chlorine, fluorine, Methyl, tert-butyl, trifluoromethyl, methoxy or cyano-substituted phenyl radical.
  • the invention relates to compounds of the formula I (see attached formula sheet), in which R0 is methyl or hydroxymethyl,
  • R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, halogen or trifluoromethyl,
  • R4 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, halogen or trifluoromethyl,
  • R5 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy or halogen and
  • A denotes 0 (oxygen) or NH, where R4 and R5 do not simultaneously denote hydrogen if R2 denotes 1-4C-alkyl, and their salts.
  • 1-4C-Alkyl stands for straight-chain or branched alkyl radicals with 1 to 4 carbon atoms. Examples include the butyl, iso-butyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and especially the methyl radical.
  • 1-4C-Alkoxy stands for an oxygen atom to which one of the 1-4C-alkyl radicals mentioned above is bound.
  • the methoxy radical is preferred.
  • Halogen in the sense of the invention is bromine, fluorine and especially chlorine.
  • Suitable salts for compounds of the formula I are preferably all acid addition salts. Particular mention should be made of the pharmacologically tolerable salts of the inorganic and organic acids usually used in galenics. Pharmacologically incompatible salts, which may initially be obtained as process products in the preparation of the compounds according to the invention on an industrial scale, are converted into pharmacologically acceptable salts by processes known to the person skilled in the art.
  • Suitable as such are water-soluble and water-insoluble acid addition salts with acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2- (4-hydroxybenzoyl) benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, maleic acid Lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, ebonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid, the acids in the salt production - depending on whether it is a or multi-base acid and, depending on which salt is desired, be used in an equimolar or a different ratio.
  • acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid
  • R2 is hydrogen, 1-4C-alkyl, 1-4C-alkoxy, chlorine or fluorine,
  • R4 is hydrogen, 1-4C-alkyl or 1-4C-alkoxy
  • A is 0 (oxygen) or NH, where R4 is not hydrogen if R2 is 1-4C-alkyl, and their salts.
  • R4 is hydrogen
  • the invention further relates to a process for the preparation of the compounds of the formula I and their salts.
  • the method is characterized in that a) for the preparation of compounds of the formula I in which RO is hydroxymethyl, compounds of the formula II (see the enclosed formula sheet), in which R1, R2, R3, R4, R5 and A have the meanings given above , reduced, or that one
  • the compounds I obtained according to a), b) or c) are subsequently converted into their salts, or if desired the compounds I are subsequently released from the salts of the compounds I obtained.
  • the compounds II are reduced in a manner known per se to the person skilled in the art. It takes place in inert solvents, e.g. nie ⁇ their aliphatic alcohols, e.g. using suitable hydrides, such as sodium borohydride, if necessary with the addition of water.
  • inert solvents e.g. nie ⁇ their aliphatic alcohols
  • suitable hydrides such as sodium borohydride
  • reaction of the compounds III with the compounds IV is carried out in a manner known per se to the person skilled in the art, for example using methods analogous to those described in European patent applications EP-A-0268989 or EP-A-0308917.
  • a suitable leaving group is, for example, a halogen atom (preferably chlorine or bromine) or a methanesulfonyloxy group.
  • a base for example an inorganic hydroxide, such as sodium hydroxide, or an inorganic carbonate, such as potassium carbonate, or an organic nitrogen base, such as triethylamine, pyridine, collidine or 4-dimethylaminopyridine
  • catalysts such as Alkali iodide or tetrabutylammonium bromide
  • Y halogen
  • the reaction is advantageously carried out in the presence of an acid-binding agent (proton acceptor).
  • proton acceptors are alkali metal carbonates (such as potassium carbonate) or hydrogen carbonates (such as sodium hydrogen carbonate), or tertiary amines (such as triethylamine).
  • the substances according to the invention are isolated and purified in a manner known per se, e.g. such that the solvent is distilled off in vacuo and the residue obtained is recrystallized from a suitable solvent or subjected to one of the customary purification methods, such as, for example, column chromatography on a suitable support material.
  • Acid addition salts are obtained by dissolving the free base in a suitable solvent, e.g. in water, in a chlorinated hydrocarbon, such as methylene chloride or chloroform, a lower aliphatic alcohol (ethanol, isopropanol), a ketone, such as acetone, or an ether, such as THF or diisopropyl ether, which contains the desired acid, or which contains the desired acid Acid is then added.
  • a chlorinated hydrocarbon such as methylene chloride or chloroform
  • a lower aliphatic alcohol ethanol, isopropanol
  • a ketone such as acetone
  • an ether such as THF or diisopropyl ether
  • the salts are obtained by filtration, reprecipitation, precipitation with a non-solvent for the addition salt or by evaporation of the solvent. Salts obtained can by alkalization, for example with aqueous ammonia solution, are converted into the free bases, which in turn can be converted into acid addition salts. In this way, pharmacologically unacceptable acid addition salts can be converted into pharmacologically acceptable acid addition salts.
  • the starting compounds II can be prepared in a manner known per se, for example by reacting the compounds VII with the compounds IV (see attached formula sheet), in which R1, R2, R3, R4, R5 and A have the meanings indicated above and X has one suitable leaving group, e.g. represents a halogen atom (preferably chlorine or bromine), or using methods analogous to those described, for example, in European patent applications EP-A-0 268989 or EP-A-0308917.
  • R1, R2, R3, R4, R5 and A have the meanings indicated above
  • X has one suitable leaving group, e.g. represents a halogen atom (preferably chlorine or bromine), or using methods analogous to those described, for example, in European patent applications EP-A-0 268989 or EP-A-0308917.
  • the starting compounds III are known from European patent application EP-A-0299470, the starting compounds IV can be prepared in an analogous manner to that described in European patent application EP-A-0308917.
  • the starting compounds V can be prepared in a manner known per se from the corresponding nitro compounds by reduction or by hydrolysis of suitable N-acyl derivatives.
  • the nitro compounds in turn can be prepared from the compounds III and corresponding nitro compounds corresponding to the compounds IV.
  • Examples 2-10 are prepared in an analogous manner, the amount of solvent and the temperature being able to be reduced in the case of more readily soluble derivatives.
  • the mixture is filtered while hot and a solution of 0.7 g of fumaric acid in 70 ml of acetone is added to the filtrate.
  • the mixture is left to crystallize for 5 hours with stirring and cooling and the hemifumarate of the title compound (mp. 191-192'C, dec.) Is separated off.
  • Example II By reacting the above compound analogously to Example Ec, after concentration on a rotary evaporator, the title compound is obtained as a crude product which is used directly in Example Ie.
  • the compounds of the formula I and their salts have valuable pharmacological properties which make them commercially usable. In particular, they have a pronounced inhibition of gastric acid secretion and an excellent gastric and intestinal protective effect in warm-blooded animals.
  • the compounds according to the invention are distinguished here by a high degree of selectivity of action, a comparatively long duration of action, good enteral activity, the absence of essential side effects and a large therapeutic breadth.
  • “Stomach and intestinal protection” in this context means the prevention and treatment of gastrointestinal diseases, in particular gastrointestinal inflammatory diseases and lesions (such as, for example, ulcer ventriculi, duodenal ulcer, gastritis, hyperacid or drug-induced irritable stomach), which are caused, for example, by microorganisms (eg Helicobacter pylori), bacterial toxins, medications (eg certain anti-inflammatory drugs and anti-rheumatic drugs), chemicals (eg ethanol), gastric acid or stressful situations.
  • the compounds of the invention also have an intrinsic activity against the Helicobacter pylori germ.
  • the compounds according to the invention surprisingly prove to be clearly superior to the compounds known from the prior art on various models in which the antiulcerogenic and the antisecretory properties are determined.
  • the compounds of the formula I and their pharmacologically acceptable salts are outstandingly suitable for use in human and veterinary medicine, and are used in particular for the treatment and / or prophylaxis of diseases of the stomach and / or intestine.
  • the invention therefore furthermore relates to the compounds according to the invention for use in the treatment and / or prophylaxis of the abovementioned diseases.
  • the invention also includes the use of the compounds according to the invention for the production of medicaments which are used for the treatment and / or prophylaxis of the abovementioned diseases.
  • the invention further comprises the use of the compounds according to the invention for the treatment and / or prophylaxis of the abovementioned diseases.
  • the invention further relates to medicaments which contain one or more compounds of the formula I and / or their pharmacologically tolerable salts.
  • the pharmaceuticals are produced by methods known per se and familiar to the person skilled in the art.
  • auxiliaries and excipients suitable for the desired pharmaceutical formulations on the basis of his specialist knowledge.
  • active substance carriers for example antioxidants, dispersants, emulsifiers, defoamers, taste correctives, preservatives, solubilizers, colorants or in particular performance promoters and complexing agents (e.g. cyclodextrins) can be used.
  • the active ingredients can be administered orally, parenterally or percutaneously.
  • the active ingredient (s) when administered orally in a daily dose of about 0.01 up to about 20, preferably 0.05 to 5, in particular 0.1 to 1.5 mg / kg of body weight, optionally in the form of several, preferably 1 to 4, individual doses to achieve the desired result.
  • a daily dose of about 0.01 up to about 20, preferably 0.05 to 5, in particular 0.1 to 1.5 mg / kg of body weight, optionally in the form of several, preferably 1 to 4, individual doses to achieve the desired result.
  • parenteral treatment similar or (in particular when the active compounds are administered intravenously) generally lower doses can be used. Any person skilled in the art can easily determine the optimum dosage and mode of application of the active ingredients required on the basis of his or her specialist knowledge.
  • the pharmaceutical preparations can also comprise one or more pharmacologically active constituents of other groups of medicaments, such as antacids, for example aluminum hydroxide, magnesium aluminate; Tranquilizers, such as benzodiazepines, for example diazepam; Antispasmodics, e.g. Bieta iverin, Camylofin, Anticholinergica, such as e.g. Oxyphencycl i in, phencarbamide; Local anesthetics, e.g. Tetracaine, procaine; optionally also contain ferments, vitamins or amino acids.
  • antacids for example aluminum hydroxide, magnesium aluminate
  • Tranquilizers such as benzodiazepines, for example diazepam
  • Antispasmodics e.g. Bieta iverin, Camylofin
  • Anticholinergica such as e.g. Oxyphencycl i in, phencarbamide
  • the combination of the compounds according to the invention with Phar aka which inhibit acid secretion such as, for example, H 2 blockers (for example cimetidine, ranitidine), H + / K + -ATPase inhibitors (for example omeprazole, pantoprazole), or should be emphasized in particular furthermore with so-called peripheral anticholinergics (eg Pirenzepin, Telenzepin) and with gastrin antagonists with the aim of strengthening the main effect in an additive or superadditive sense and / or eliminating or reducing the side effects, or furthermore the combination with antibacterial effective substances (such as cephalosporins, tetracyclines, nalidixic acid, penicillins or bismuth salts) for combating Helicobacter pylori. pharmacology
  • H 2 blockers for example cimetidine, ranitidine
  • H + / K + -ATPase inhibitors for example omeprazole, pantoprazole
  • gastrin antagonists
  • the excellent gastric protective effect and the gastric acid secretion-inhibiting effect of the compounds according to the invention can be demonstrated in studies on animal experimental models.
  • the compounds according to the invention investigated in the model listed below have been given numbers which correspond to the numbers of these compounds in the examples.
  • Table A below shows the influence of the compounds according to the invention after intravenous administration on the acid secretion of the perfused rat stomach stimulated by pentagastrin in vivo.
  • anesthetized rats (CD rat, female, 200-250 g; 1.5 g / kg in urethane) were opened by a median upper abdominal incision and a PVC catheter transorally in the esophagus and a white ⁇ fixed via pylorus in such a way that the tube ends just protruded into the stomach lumen.
  • the catheter leading out of the pylorus led outwards through a lateral opening in the right abdominal wall.
  • warm physiological NaCl solution was continuously passed through (0.5 ml / min, pH 6.8-6.9; Braun-Unita I).
  • Dosimat 665 Metrohm 0.01 N NaOH to pH 7
  • the body temperature of the animals was kept at a constant 37.8-38 * C by infrared radiation and heating pad (automatic, stepless regulation via rectal temperature sensor).
  • the table shows the dose which led to a maximum inhibition of acid secretion by approximately 100%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention a pour objet des composés de formule (I), dans laquelle les substituants et les symboles ont les significations données dans la description, et leur application thérapeutique pour le traitement de maladies gastro-intestinales.
PCT/EP1995/002952 1994-07-28 1995-07-26 Benzylimidazopyridines WO1996003403A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
NZ290818A NZ290818A (en) 1994-07-28 1995-07-26 Benzyl-imidazopyridines
JP8505480A JPH10505331A (ja) 1994-07-28 1995-07-26 ベンジルイミダゾピリジン
EP95927725A EP0773944A1 (fr) 1994-07-28 1995-07-26 Benzylimidazopyridines
AU31660/95A AU700737B2 (en) 1994-07-28 1995-07-26 Benzylimidazopyridines

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CH2389/94-0 1994-07-28
CH238994 1994-07-28

Publications (1)

Publication Number Publication Date
WO1996003403A1 true WO1996003403A1 (fr) 1996-02-08

Family

ID=4232645

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1995/002952 WO1996003403A1 (fr) 1994-07-28 1995-07-26 Benzylimidazopyridines

Country Status (6)

Country Link
EP (1) EP0773944A1 (fr)
JP (1) JPH10505331A (fr)
AU (1) AU700737B2 (fr)
CA (1) CA2196077A1 (fr)
NZ (1) NZ290818A (fr)
WO (1) WO1996003403A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997027192A1 (fr) * 1996-01-26 1997-07-31 Byk Gulden Lomberg Chemische Fabrik Gmbh 3-methylimidazopyridines
US6051570A (en) * 1997-05-30 2000-04-18 Dr. Reddy's Research Foundation Benzimidazole derivatives as antiulcer agents, process for their preparation and pharmaceutical compositions containing them
WO2000011000A3 (fr) * 1998-08-21 2000-06-15 Astrazeneca Ab Nouveaux composes

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0268989A1 (fr) * 1986-11-26 1988-06-01 Fujisawa Pharmaceutical Co., Ltd. Composés d'imidazopyridine et leurs procédés de préparation
EP0308917A2 (fr) * 1987-09-24 1989-03-29 Fujisawa Pharmaceutical Co., Ltd. Composés d'imidazopyridine, procédé pour leur préparation et compositions pharmaceutiques les contenant
WO1994018199A1 (fr) * 1993-02-15 1994-08-18 Byk Gulden Lomberg Chemische Fabrik Gmbh Imidazopyridines et leur utilisation pour traiter des maladies gastro-intestinales

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0266890A1 (fr) * 1986-10-07 1988-05-11 Yamanouchi Pharmaceutical Co. Ltd. Dérivés d'imidazopyridine, leur production et compositions pharmaceutiques les contenant
CA2196076A1 (fr) * 1994-07-28 1996-02-08 Gerhard Grundler Acylimidazopyridines

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0268989A1 (fr) * 1986-11-26 1988-06-01 Fujisawa Pharmaceutical Co., Ltd. Composés d'imidazopyridine et leurs procédés de préparation
EP0308917A2 (fr) * 1987-09-24 1989-03-29 Fujisawa Pharmaceutical Co., Ltd. Composés d'imidazopyridine, procédé pour leur préparation et compositions pharmaceutiques les contenant
WO1994018199A1 (fr) * 1993-02-15 1994-08-18 Byk Gulden Lomberg Chemische Fabrik Gmbh Imidazopyridines et leur utilisation pour traiter des maladies gastro-intestinales

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997027192A1 (fr) * 1996-01-26 1997-07-31 Byk Gulden Lomberg Chemische Fabrik Gmbh 3-methylimidazopyridines
US6051570A (en) * 1997-05-30 2000-04-18 Dr. Reddy's Research Foundation Benzimidazole derivatives as antiulcer agents, process for their preparation and pharmaceutical compositions containing them
WO2000011000A3 (fr) * 1998-08-21 2000-06-15 Astrazeneca Ab Nouveaux composes
US6579884B1 (en) 1998-08-21 2003-06-17 Astrazeneca Ab Compounds
EP1411056A3 (fr) * 1998-08-21 2004-04-28 AstraZeneca AB Dérivés de l'imidazo[1,2-a]pyridine qui inhibent la sécrétion acide gastrique, compositions pharmaceutiques qui les contiennent et procédés pour leur préparation
US6790960B2 (en) 1998-08-21 2004-09-14 Astrazeneca Ab Compounds

Also Published As

Publication number Publication date
AU3166095A (en) 1996-02-22
JPH10505331A (ja) 1998-05-26
AU700737B2 (en) 1999-01-14
NZ290818A (en) 1998-10-28
EP0773944A1 (fr) 1997-05-21
CA2196077A1 (fr) 1996-02-08

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