IE59587B1 - Substituted toluidines, a process for their preparation, pharmaceutical formulations containing them, and their use as inhibitors of gastric acid secretion - Google Patents
Substituted toluidines, a process for their preparation, pharmaceutical formulations containing them, and their use as inhibitors of gastric acid secretionInfo
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- IE59587B1 IE59587B1 IE225886A IE225886A IE59587B1 IE 59587 B1 IE59587 B1 IE 59587B1 IE 225886 A IE225886 A IE 225886A IE 225886 A IE225886 A IE 225886A IE 59587 B1 IE59587 B1 IE 59587B1
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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
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
- C07D235/28—Sulfur atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
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Abstract
o-Toluidine derivatives of the formula I in which A denotes S, SO or SO2 and R<1>, R<2>, R<3>, R<4>, R<5>, R<6>, R<7>, R<8>, R<1><3>, R<1><4> and R<1><5> represent hydrogen and/or defined substituents.
Description
Substituted toluidines, a process for their preparation, pharmaceutical formulations containing them, and their use as inhibitors of gastric acid secretion • Benzimidazole derivatives having an analgesic action are disclosed in DE-A-2,246,429, and those having an inhibi- v tory action on gastric acid secretion are disclosed in, for example, DE-A-2,548,340, EP-A-5,129, DE-A-3,240,248 and DE-A-3,333,314. Further benzimidazole derivatives have been proposed in German Patent Application P 35 09 333.1.
DE-A-3,531,487 (published on: March 13, 1986), EP-A-174,717 (published on: March 19, 1986) and EP-A-0,204,215 (published on: December 10, 1986) likewise relate to benzimidazole derivatives.
EP-A-0,045,200 and EP-A-0,074,341 propose for the treatment of inflammatory gastrointestinal disorders and for the inhibition of gastric acid secretion, respectively, benzimidazole derivatives composed of 3 important structural elements: a substituted benzimidazole ring, a substituted heterocycle or benzene nucleus, and a sulfurcontaining chain between the two aromatic moieties.
Animal experimental studies of the activity of similar compounds such as omeprazole, picoprazole and their derivatives have been published in Scand. J. Gastroenterol 1985; 20 (suppl 108):15-22. They led to the recognition that all three abovementioned structural elements are of equally essential importance for the pharmacological activity of the benzimidazole derivatives and that, based on omeprazole as reference, modifications on the pyridine ring or attempts to replace one of the abovementioned structural elements by another led in all cases to a biological activity which was usually crucially less.
The present invention is therefore based on the object of providing another substance which has, measured by known substances, at least the same or better biological activity in the abovementioned sense. It has now been found, surprisingly, that certain substituted toluidines are highly active inhibitors of gastric acid secretion.
The present invention relates to o-toluidine derivatives of the formula I (I) in which A represents -S- or -SO-, R1 denotes (CX-CJ-alkyl, preferably methyl or ethyl, R2, R7, R® and R15 each denote hydrogen, R3, R4, R5 and R6 are identical or different and denote hydrogen, (Cj-CJ-alkyl or methoxy, or R4 and R5 together represent -CH=CH-CH=CH-, R13 and R14 are identical or different and denote (Ci-CJalkoxy, and their physiologically tolerated salts.
Compounds of the formula I in which A represents -SO-, and their physiologically tolerated salts, are preferred.
Compounds of the formula I in which R3, R4, R5 and R6 each represent hydrogen, and their physiologically tolerated salts, are particularly preferred.
Compounds of the formula I in which R13 and R14 are located in the 5 position and 6 position of the benzimidazole system, are identical or different, and denote methoxy or ethoxy, preferably methoxy, and R1 denotes ethyl, and their tolerated salts, are furthermore preferred.
Particular attention may furthermore be drawn to compounds of the formula I in which one or two radicals R3, R4, R5 and R6 represents (represent) (Ci-CJ-alkyl, and their physiologically tolerated salts. 2- (2-ethylaminobenzylsulfinyl) -5,6-dimethoxybenzimidazole and its physiologically tolerated salts is very particularly preferred.
Any chiral carbon or sulfur atoms which are present may occur both in the R and in the S configuration. In such cases, compounds of the formula 1 exist in the form of the pure enantiomers or as a mixture of stereoisomers (such as a mixture of enantiomers and a mixture of diastereomers).
Suitable salts are, in particular, alkali metal and alkaline earth metal salts, and salts of inorganic or organic acids such as, for example, HCl, HBr, H2SO4, methanesulfonic acid, amidosulfonic acid and p-toluenesulfonic acid.
Alkyl and alkoxy can be straight-chain or branched.
The invention also relates to a process for the preparation of a compound of the formula I, which comprises a) reaction of a compound of the formula II in which R13, R14 and R15 are as defined above, and Q1 denotes i. a leaving group or ii. -SH, -S- or SO2-, with a compound of the formula III (III) above, and Q2 denotes, in the abovementioned case i., -SH, -S- or -SO2- and, in the abovementioned case ii., a leaving group, b) reaction of a compound of the formula IV NH.
NH. 4 (IV) in which R13 and R1* are as defined above, with a compound of the formula V B A - COOR (V) in which R1, R2, R3, R4, R5, R6, R7, R8 and A are as defined above, and R16 represent an esterifying group, or c) for the preparation of a compound of the formula I in which R1 and R2 each denote hydrogen, reduction of a compound of the formula VI R I C (VI) in which R3, R4, R5, R6, R7, R8, R13, R14 and R15 are as defined above, and A represent a sulfur atom, oxidation, in the compounds of the formula I which have been obtained according to a), b) or c) and in which A represents -S- or -SO-, and/or R3 to R6 and/or R13 and R14 represent radicals containing -S- or -SO-, to the corresponding -SO- or -SO2- group, alkylation or acylation of a compound of the formula I in which R1 and/or R2 represents hydrogen, subjection of a compound of the formula I in which R1 and/or R2 represents acyl to deacylating hydrolysis or hydrogenolysis, and conversion of a compound of the formula I, thus obtained, where appropriate into its physiologically tolerated salt.
When, in accordance with process variant a), which is preferred here, compounds of the formula II are reacted with compounds of the formula III, then Q1 or Q2 represents a leaving group which can be detached nucleophilically, such as Cl, Br, I, -OSO2CH3, -O-SO2CF3 or -O-SO2C6H4pCH3.
The reaction of a compound of the formula II with a compound of the formula III or its salts takes place in an inert solvent such as, for example, water, methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, 1,2dimethoxyethane, methylene chloride, acetone, ethyl acetate, dimethylformamide, acetonitrile, dimethylacetamide, dimethyl sulfoxide, or mixtures of these solvents. The reaction can be carried out in the presence or absence of an inorganic or organic base, it being possible to use sodium or potassium hydroxide, carbonate, alkoxide, hydride or amide, ammonia, triethylamine, tributylamine or pyridine. The reaction temperature is between -20 and +150*C, preferably at 0 to 80°C.
Compounds of the formula II are known from the literature ϊ 5 or can be prepared in analogy to known processes, for example by ring closure of appropriately substituted o-phenylenediamines with carbon disulfide (for example DE-A-3,132,167).
The o-phenylenediamines required for this purpose are 10 likewise known from the literature and are obtained by, for example, catalytic reduction of appropriately substituted o-nitroanilines.
Compounds of the formula III are likewise known from the literature or can be prepared in analogy to known proces15 ses.
In the esters of the formula V, used in process variant b), R16 represents an esterifying group, preferably (Ci-Cg)-alkyl or benzyl. The transesterification of the compounds of the formula IV with compounds of the formula V is carried out in analogy to the procedures described in Preston et al., Benzimidazoles and Congeneric Tricyclic Compounds, Part 1, New York, pages 10-13.
Tin(II) salts such as SnCl2 have proved to be particularly suitable reducing agents for compounds of the formula VI.
The reduction is particularly preferably carried out in aqueous medium or in mixtures of an aqueous phase with polar organic solvents under strongly acid conditions, for example in concentrated hydrochloric acid between 0 and 100°C, preferably between 20 and 80°C. The working up and isolation of the substance is preferably carried out under alkaline conditions in a manner known per se from the literature.
V The 2-(2-nitrobenzylthio)benzimidazole derivatives used as starting materials are obtained in accordance with procedure a) ii. in a manner known per se by reaction of a 2-mercaptobenzimidazole of the formula II with a 2-nitrobenzyl halide, preferably with a 2-nitrobenzyl chloride or bromide derivative of the formula VII (Hal = Cl or Br).
(VII) The compounds of the formula I which are thus obtained and in which A represents -S- can, where R3 denotes hydrogen, be converted into physiologically tolerated salts with bases.
Compounds of the formula I with A= -S- can furthermore be converted into those with A= -SO- or -SO2- with suitable oxidizing agents.
This reaction is carried out in a suitable inert solvent such as, for example, methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, toluene, ethyl acetate, acetic acid, trifluoroacetic acid, water, methanol, ethanol or mixtures thereof, at -20°C to +150®C, preferably at -10®C to +40®C.
Examples of suitable oxidizing agents are: hydrogen peroxide, peracids and peresters such as peracetic acid, trifluoroperacetic acid, monoperphthalic acid, m-chloroperbenzoic acid and its esters, ozone, dinitrogen tetroxide, iodosobenzene, N-chlorosuccinimide, 1-chlorobenzotriazole, sodium hypochlorite, potassium peroxodisulfate, t-butyl hypochlorite, tetrabutylammonium periodate or permanganate, sodium metaperiodate, selenium dioxide or manganese dioxide, ceric ammonium nitrate, chromic acid, chlorine, bromine, diazabicyclo[2.2.2]octane-bromine complex, dioxane dibromide and pyridinium perbromide.
It is likewise possible to use isolated, where appropriate immobilized, oxidizing enzymes or microorganisms as oxidizing agents.
For oxidation to A= -SO- the oxidizing agents are used in equimolar amounts, and where appropriate in a slight excess of 5-10 mol-%, or when oxidation to A= -S02- is desired they are used in greater excess and/or at a higher reaction temperature.
Compounds according to the invention which may be mentioned are: R7, R8, R15 = H A = S R1 R2 R3 R4 Rs Re R" R14 Me H H Me H H OMe OMe Me H H H Me H OMe OMe Me H H H OMe Me OMe OMe Me H Me H OMe H OMe OMe Me H Me H H H •OMe OMe Me H H Me H H OMe OMe Me H H H Me H OMe OMe Me H Et H H H OMe OMe Me H H Et H H OMe OMe Me H H H Et H OMe OMe R’ R2 R3 R4 R5 Re R’3 R’4 Me H H H H Me OMe OMe Et H H H OMe Me OMe OMe Et H Me H OMe H OMe OMe Et H Me H H H OMe OMe Et H H Me H H OMe OMe Et H H H Me H OMe OMe Et H Et H H H OMe OMe Et H H Et H H OMe OMe Et H H H Et H OMe OMe Et H H H H Me OMe OMe Et H OMe H H H OMe OMe Et H H H OMe H OMe OMe Et H Me H Me H OMe OMe Et H Me Me H H OMe OMe Et H H Me Me H OMe OMe Me H H OMe H H OMe OMe Me H H H OMe H OMe OMe Me H Me H Me H OMe OMe Me H Me Me H H OMe OMe Me H H Me Me H OMe OMe Me H H Me Me Me OMe OMe Me H H OMe Me Me OMe OMe Me H H Me OMe Me OMe OMe R7, Re, R15 = H A = SO R’ R2 R3 R4 R5 R’ R" R14 Et H Me H Me H OMe OMe Et H Me Me H H OMe OMe Et H H Me Me H OMe OMe R1 R2 R3 R* R® R® R'3 R Me H H Me H H OMe OMe Me H H H Me H OMe OMe Me H Me H OMe H OMe OMe Me H Me H H H OMe OMe Me H H Me H H OMe OMe Me H H H Me H OMe OMe Me H Et H H H OMe OMe Me H H Et H H OMe OMe Me H H H Et H OMe OMe Me H H H H Me OMe OMe Me H OMe H H H OMe OMe Et H H H OMe Me OMe OMe Et H Me H OMe H OMe OMe Et H Me H H H OMe OMe Et H H Me H H OMe OMe Et H H H Me H OMe OMe Et H Et H H H OMe OMe Et H H Et H H OMe OMe Et H H H Et H OMe OMe Et H H H H Me OMe OMe Et H OMe H H H OMe OMe Et H H OMe H H OMe OMe Et H H H OMe H OMe OMe Me H H OMe H H OMe OMe Me H H H OMe H OMe OMe Me H Me H Me H OMe OMe Me H Me Me H H OMe OMe Me H H Me Me H OMe OMe Me H H Me Me Me OMe OMe Me H H OMe Me Me OMe OMe Me H H Me OMe Me OMe OMe Abbreviations: Me Methyl Et Ethyl The new compounds of the formula I and their salts have valuable pharmacological properties.
They markedly inhibit gastric acid secretion and, furthermore, exhibit an excellent gastrointestinal protective action.
Gastrointestinal protection in this connection is understood to be the prevention and treatment of gastrointestinal disorders, in particular inflammatory gastrointestinal disorders and lesions (such as, for example, gastric ulcer, duodenal ulcer, gastritis, hyperacid or drug-related functional gastropathy, which may be caused by, for example, microorganisms, bacterial toxins, drugs (for example anti-inflammatory and antirheumatic agents), chemicals (for example ethanol), gastric acid or stress situations.
Because of their excellent properties, the compounds of the formula I and their pharmacologically tolerated salts are outstandingly suitable for use in human and veterinary medicine, being used, in particular, for the treatment and prophylaxis of gastrointestinal disorders and those disorders based on excessive gastric acid secretion.
Thus the invention also relates to the compounds of the formula I, according to the invention, for use for the treatment and prophylaxis of the abovementioned disorders .
Likewise, the invention embraces the use of the compounds according to the invention for the preparation of medicaments which are used for the treatment and prophylaxis of the abovementioned disorders.
The invention furthermore relates to medicaments which contain one or more compound(s) of the general formula I and/or their pharmacologically tolerated salts.
The medicaments are prepared by processes which are known per se and are familiar to those skilled in the art. The pharmacologically effective compounds (- active compounds) according to the invention are used as medicaments either as such or, preferably, in combination with suitable pharmaceutical auxiliaries, in the form of tablets, coated tablets, capsules, suppositories, emulsions, suspensions or solutions, the content of active compound advantageously being between 0.1 and 96%.
The particular auxiliaries suitable for the desired medicament formulation are familiar to those skilled in the art on the basis of their knowledge. Apart from solvents, gel-forming agents, suppository bases, tabletting auxiliaries and other vehicles for active compounds, it is possible to use, for example, antioxidants, dis20 persing agents, emulsifiers, defoaming agents, flavor corrigents, preservatives, solubilizers or colorants.
The active compounds can be administered orally or parenterally, oral administration being preferred.
In general, it has proved advantageous in human medicine to administer the active compound(s) in a daily dose on oral administration from about 0.01 to about 20 mg/kg of body weight, where appropriate in the form of several, preferably 1 to 4, individual administrations, to achieve the desired result. It is possible on parenteral treatment for similar or (especially on intravenous administration of the active compounds) as a rule lower doses to be used. The establishment of the optimal dosage and mode of administration of the active compounds which are necessary in each case can easily be carried out by all those skilled in the art on the basis of their expert knowledge.
If the compounds according to the invention and/or their salts are to be used for the treatment of the abovementioned disorders, it is possible for the pharmaceutical formulations also to contain one or more pharmacologically active constituents of other medicament groups, such as antacids, for example aluminum hydroxide and magnesium aluminate; tranquilizers such as benzodiazepines, for example diazepam; spasmolytics such as, for example, bietamiverine and camylofin; anticholinergics such as, for example, oxyphency limine and phenearbamide; local anesthetics such as, for example, tetracaine and procaine; and, where appropriate, enzymes, vitamins or amino acids.
For an oral administration form, the active compounds are mixed with the additives customary for this purpose, such as vehicles, stabilizers or inert diluents, and are converted by customary methods into suitable administration forms, such as tablets, coated tablets, hard gelatin capsules, or aqueous, alcoholic or oily solutions. Examples of inert vehicles which can be used are gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose or starch, in particular corn starch. This can entail the formulation being carried out either as dry or wet granules. Examples of suitable oily vehicles or solvents are vegetable and animal oils, such as sunflower oil or fish liver oil.
For subcutaneous or intravenous administration, the active compounds or their physiologically tolerated salts are converted into a solution, suspension or emulsion, if desired with the substances customary for this purpose, such as solubilizers, emulsifiers or other auxiliaries.
Examples of suitable solvents for the new active compounds and the corresponding physiologically tolerated salts are: water, physiological saline solutions or alcohols, for example ethanol, propanol or glycerol, as well as sugar solutions, such as glucose or mannitol solutions, or a mixture of the various solvents mentioned.
The examples which follow are intended to illustrate the procedures according to the invention.
Example 1: 2-(2-Ethvlaminobenzvlthio)-5.6-dimethoxybenzimidazole .5 g of 5,6-dimethoxy-2-mercaptobenzimidazole are suspended in 250 ml of THF, and 15 g of 2-ethylaminobenzyl bromide hydrobromide are added in portions. The mixture is stirred at room temperature for 6 hours, and then the precipitate is filtered off with suction, washed with THF and petroleum ether and dried under reduced pressure at about 80°C.
The resulting hydrobromide is introduced into 400 ml of 1% strength aqueous sodium hydroxide solution, and the mixture is then stirred at room temperature for 2 hours. The free base is filtered off with suction, washed with water and dried. Melting point 162°C (decomposition).
Example 2: 2- f 2-Ethvlaminobenzvlsulfinvl) -5.6-dimethoxvbenz imidazole 2.0 g of 85% m-chloroperbenzoic acid, dissolved in 70 ml of methylene chloride, are added dropwise at room temperature, within 10 minutes, to 3.4 g of 2-(2ethylaminobenzylthio)-5,6-dimethoxybenzimidazole in 100 ml of methylene chloride, with stirring. The mixture is then stirred for 20 minutes, excess two-normal aqueous ammonia solution is added, and the organic phase is separated off. After drying over sodium sulfate, it is evaporated in a rotary evaporator, and the residue is stirred with a little acetone, filtered off with suction, recrystallized from acetone and dried. Melting point 168°C (decomposition).
Example 3: General procedure for the preparation of the free benzoimidazole derivatives from the benzimidazole sodium salts A mixture of equal parts of tetrahydrofuran and saturated 10 NaHCO3 solution is suitable for converting the sodium salts into the free sulfinylbenzimidazoles of the general formula I. The organic phase is concentrated, and the crystalline product is washed with diisopropyl ether.
The following compounds of the formula I are prepared in 15 an analogous procedure: 'j Table Ex- ample R1 R2 R3 R* R5 R6 R7 Re A r’3 melting point (°C) 1 R 5 V 4 C2H5 H ch3 H H H H H S <3 H 3 .OCH 5 och3 88 5 c2h5 H ch3 H H H H H SO .och3 och3 151 (decomp.) 6 c2h5 H H H H ch3 H H S it .och3 276 κ ΪΙ IT H 1 ^och3 7 c2h5 H H H H ch3 H H SO M Sxoch3 136 H •J1 OCHj (decomp.) Table - Continuation Ex- ample R1 R2 R3 R* R5 R6 R7 R8 A R,J 1 p * 4 R15 R melting point (°C) 8 ch3 H H H H H H H S H- II II 1 x 2 Η B r H 254 (decomp.) 9 ch3 H H H H H H H S N-ΐίΎ'1 •^nA-^OCHj H 230 (decomp.) 10 ch3 H H H R H H H SO H-[Ργ0<:Η3 ^nA^A0CHj H 140 (decomp.) 11 c2h5 H H H H H H H S H- OC,H, H 130 (decomp.) τ») #· » * Table - Continuation Ex- ample R1 R2 R3 R* R5 R6 R7 R8 A R13 melting point (°C) 1 r'5 12 c2h5 H H H H H H H SO XO FT H ^oc2h5soc2h5 about 156 (decomp.) I
Claims (14)
1. A compound of the formula I in which A represents -S- or -S0R 1 denotes (C x -C 4 )-alkyl, preferably methyl or ethyl, R 2 , R 7 , R 8 and R 15 each denote hydrogen, R 3 , R 4 , R 5 and R 6 are identical or different and denote hydrogen, (Cx-C*)-alkyl or methoxy, or R 4 and R 5 together represent -CH=CH-CH=CH-, R 13 and R 14 are identical or different and denote (Cx-Cj -alkoxy, and their physiologically tolerated salts.
2. A compound of the formula I as claimed in claim 1, in which A represents -SO-, and its physiologically tolerated salts.
3. A compound of the formula I as claimed in claim 1 or 2, in which R 3 , R 4 , R 5 and R 6 each represent hydrogen, and its physiologically tolerated salts.
4. A compound of the formula I as claimed in one of claims 1 to 3, in which R 13 and R 14 are located in the 5 position and 6 position of the benzimidazole system, are identical or different, and denote * methoxy or ethoxy, preferably methoxy, and R 1 denotes ethyl, and its physiologically tolerated salts. '
5. 2-(2-Ethylaminobenzylsulfinyl)-5,6-dimethoxybenzimidazole and its physiologically tolerated salts.
6. A compound of the formula I as claimed in one of claims 1 to 4, in which one or two of the radicals R 3 , R*, R 5 represents (represent) (Cx-C 4 )-alkyl, and its physiologically tolerated salts.
7. A process for the preparation of a compound of the formula I as claimed in one of claims 1 to 6, which comprises a) reaction of a compound of the formula II (II) in which R 13 , R 1 * and R 15 are as defined in claim 1, and Q 1 denotes i. a leaving group or ii -SH, -S' or -S0 2 with a compound of the formula III (HI) defined in claim 1, and Q 2 denotes, in the abovementioned case 1., -SH, -S' or -S0 2 , and, in the abovementioned case ii., an approaching group, b) reaction of a compound of the formula IV F 13 ^2 1' (IV) HH 2 in which R 13 and R 14 are as pound of the formula V defined above, with a com(V) in which R 1 , R*, R 3 , R', R 3 , R“, R', R° and A are as defined above, and R 16 represents and esterifying group, or c) for the preparation of a compound of the formula I in which R 1 and R 2 each denote hydrogen, reduction of a compound of the formula VI (VI) in which R 3 , R 4 , R s , R 6 , R 7 , R e , R 13 , R 14 and R X3 are as defined in claim 1, and A represents a sulfur atom, oxidation, in the compounds of the formula I which have been been obtained according to a), b) or c) and in which A represents -S- or SO-, and/or R 3 to R 6 and/or R 13 and R 14 represent radicals containing -Sor -SO-, to the corresponding -SO- or -S0 2 - group, alkylation or acylation of a compound of the formula I in which R 1 and/or R 2 represents hydrogen, subjection of a compound of the formula I in which R 1 and/or R 2 represents acyl to deacylating hydrolysis or hydrogenolysis, and conversion of a compound of the formula I, thus obtained, where appropriate into its physiologically tolerated salt.
8. A compound as claimed in one of claims 1 to 6, for use as medicine.
9. A compound as claimed in one of claims 1 to 6, for use as inhibitor of gastric acid secretion.
10. A pharmaceutical agents containing a compound as claimed in one of claims 1 to 6.
11. A compound of the formula I given and defined in claim 1 or a physiologically tolerated salt thereof, substantially as hereinbefore described with particular reference to the accompanying Examples.
12. A process for the preparation of a compound of the formula I given and defined in claim 1 or a physiologically tolerated salt thereof, substantially as hereinbefore described with particular reference to the accompanying Examples.
13. A compound of the formula I given and defined in claim 1 or a physiologically tolerated salt thereof, whenever prepared by a process claimed in claim 7 or 12
14. A pharmaceutical agent according to claim 10, substantially as hereinbefore described.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19853530342 DE3530342A1 (en) | 1985-08-24 | 1985-08-24 | Substituted toluidines, processes for their preparation, pharmaceutical preparations containing them and their use as gastric acid secretion inhibitors |
| DE19863610609 DE3610609A1 (en) | 1986-03-29 | 1986-03-29 | Substituted toluidines, processes for their preparation, pharmaceutical preparations containing them and their use as gastric secretion inhibitors |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| IE59587B1 true IE59587B1 (en) | 1994-03-09 |
Family
ID=25835350
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE225886A IE59587B1 (en) | 1985-08-24 | 1986-08-22 | Substituted toluidines, a process for their preparation, pharmaceutical formulations containing them, and their use as inhibitors of gastric acid secretion |
Country Status (17)
| Country | Link |
|---|---|
| EP (1) | EP0213474B1 (en) |
| JP (1) | JPH0791276B2 (en) |
| KR (1) | KR940005020B1 (en) |
| AR (1) | AR243167A1 (en) |
| AT (1) | ATE85328T1 (en) |
| DE (1) | DE3687675D1 (en) |
| DK (1) | DK401586A (en) |
| ES (1) | ES2001389A6 (en) |
| FI (1) | FI89910C (en) |
| GR (1) | GR862180B (en) |
| HU (1) | HU199126B (en) |
| IE (1) | IE59587B1 (en) |
| IL (1) | IL79813A0 (en) |
| NO (1) | NO169169C (en) |
| NZ (1) | NZ217322A (en) |
| PH (1) | PH24073A (en) |
| PT (1) | PT83240B (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0239129B1 (en) | 1986-03-28 | 1991-09-25 | Otsuka Pharmaceutical Co., Ltd. | Hydroquinoline compounds, compositions containing same and processes for preparing same |
| EP0251536A1 (en) * | 1986-06-24 | 1988-01-07 | FISONS plc | Benzimidazoles, their production, formulation and use as gastric acid secretion inhibitors |
| IT1222412B (en) * | 1987-07-31 | 1990-09-05 | Chiesi Farma Spa | THYOMETHYL AND SULFINYL METHYL DERIVED WITH ANTI-SECRET ACID GASTRIC ACTION, THEIR PREPARATION PROCEDURE AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| EP0318085A3 (en) * | 1987-11-25 | 1990-03-14 | Merck Frosst Canada Inc. | Heterazole dialkanoic acids |
| CA1322005C (en) * | 1987-11-25 | 1993-09-07 | Robert N. Young | Benzoheterazoles |
| JP2564162B2 (en) * | 1988-02-12 | 1996-12-18 | 日本ケミファ株式会社 | Quaternary salts of benzimidazole derivatives |
| ES2047451B1 (en) * | 1992-07-10 | 1994-10-01 | Sint Quimica Sa | PROCEDURE FOR THE PREPARATION OF A STABLE ORAL PHARMACEUTICAL COMPOSITION. |
| KR20040028815A (en) * | 2004-01-07 | 2004-04-03 | 화인고무(주) | Synthetic Leather that injection and heat adhension is available without using cement |
| CN115433167B (en) * | 2022-11-10 | 2023-03-24 | 中国药科大学 | Benzo-heterocyclic compound with Snail inhibitory activity, preparation method thereof, pharmaceutical composition and medical application |
Family Cites Families (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE332167C (en) | 1918-08-09 | 1921-01-26 | Chem Fab Vorm Goldenberg | Glycerine substitute |
| BE788805A (en) | 1971-09-22 | 1973-01-02 | Lafon Victor | NEW ANTALGIC DERIVATIVES FROM THE SULFUR ARYLAMINE SERIES |
| SE416649B (en) | 1974-05-16 | 1981-01-26 | Haessle Ab | PROCEDURE FOR THE PREPARATION OF SUBSTANCES WHICH PREVENT Gastric acid secretion |
| SE7804231L (en) | 1978-04-14 | 1979-10-15 | Haessle Ab | Gastric acid secretion |
| US4359465A (en) * | 1980-07-28 | 1982-11-16 | The Upjohn Company | Methods for treating gastrointestinal inflammation |
| ZA825106B (en) * | 1981-08-13 | 1983-04-27 | Haessle Ab | Novel pharmaceutical compositions |
| US4472409A (en) | 1981-11-05 | 1984-09-18 | Byk Gulden Lomberg Chemische Fabrik Gesellschaft Mit Beschrankter Haftung | 2-Pyridylmethyl thio(sulfinyl)benzimidazoles with gastric acid secretion inhibiting effects |
| DE3333314A1 (en) | 1983-09-15 | 1985-03-28 | Hoechst Ag, 6230 Frankfurt | SUBSTITUTED PYRIDO (1,2-C) IMIDAZO (1,2-A) BENZIMIDAZOLES, METHOD FOR THE PRODUCTION THEREOF, THEIR USE AND PHARMACEUTICAL PREPARATIONS BASED ON THESE COMPOUNDS |
| GB8417271D0 (en) * | 1984-07-06 | 1984-08-08 | Fisons Plc | Biologically active nitrogen heterocycles |
| DE3585252D1 (en) | 1984-07-06 | 1992-03-05 | Fisons Plc | BENZIMIDAZOLES, AND METHOD FOR THE PRODUCTION THEREOF, THE FORMULATION AND USE THEREOF AS ANCIENT ANTI-ACIDIC COMPETITION. |
| AU4640985A (en) | 1984-08-31 | 1986-03-06 | Nippon Chemiphar Co. Ltd. | Benzimidazole derivatives |
| DE3509333A1 (en) | 1985-03-15 | 1986-09-18 | Hoechst Ag, 6230 Frankfurt | SUBSTITUTED BENZIMIDAZOLE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, PHARMACEUTICAL PREPARATIONS CONTAINING THEM AND THEIR USE AS AN INGESTIC ACID INHIBITOR |
| AU5768886A (en) * | 1985-05-24 | 1986-11-27 | G.D. Searle & Co. | 2-((1-h-benzimidazol-2-ylsulfinyl)methyl)benzenamines |
| WO1987001114A2 (en) * | 1985-08-21 | 1987-02-26 | Byk Gulden Lomberg Chemische Fabrik Gmbh | New amines, process for their manufacture, their use and medicines containing them |
-
1986
- 1986-08-01 AR AR86305006A patent/AR243167A1/en active
- 1986-08-12 AT AT86111104T patent/ATE85328T1/en not_active IP Right Cessation
- 1986-08-12 EP EP86111104A patent/EP0213474B1/en not_active Expired - Lifetime
- 1986-08-12 DE DE8686111104T patent/DE3687675D1/en not_active Expired - Fee Related
- 1986-08-21 FI FI863382A patent/FI89910C/en not_active IP Right Cessation
- 1986-08-22 IE IE225886A patent/IE59587B1/en not_active IP Right Cessation
- 1986-08-22 PH PH34172A patent/PH24073A/en unknown
- 1986-08-22 DK DK401586A patent/DK401586A/en not_active Application Discontinuation
- 1986-08-22 NZ NZ217322A patent/NZ217322A/en unknown
- 1986-08-22 ES ES8601270A patent/ES2001389A6/en not_active Expired
- 1986-08-22 PT PT83240A patent/PT83240B/en not_active IP Right Cessation
- 1986-08-22 IL IL79813A patent/IL79813A0/en unknown
- 1986-08-22 JP JP61195738A patent/JPH0791276B2/en not_active Expired - Lifetime
- 1986-08-22 KR KR1019860006949A patent/KR940005020B1/en not_active IP Right Cessation
- 1986-08-22 NO NO863389A patent/NO169169C/en unknown
- 1986-08-22 GR GR862180A patent/GR862180B/en unknown
- 1986-08-22 HU HU863659A patent/HU199126B/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| FI89910B (en) | 1993-08-31 |
| FI89910C (en) | 1993-12-10 |
| ATE85328T1 (en) | 1993-02-15 |
| IL79813A0 (en) | 1986-11-30 |
| EP0213474B1 (en) | 1993-02-03 |
| DK401586A (en) | 1987-02-25 |
| NO169169B (en) | 1992-02-10 |
| DK401586D0 (en) | 1986-08-22 |
| NZ217322A (en) | 1990-02-26 |
| HU199126B (en) | 1990-01-29 |
| ES2001389A6 (en) | 1988-05-16 |
| EP0213474A2 (en) | 1987-03-11 |
| JPH0791276B2 (en) | 1995-10-04 |
| NO863389L (en) | 1987-02-25 |
| GR862180B (en) | 1986-12-23 |
| NO863389D0 (en) | 1986-08-22 |
| FI863382A (en) | 1987-02-25 |
| KR870002087A (en) | 1987-03-30 |
| KR940005020B1 (en) | 1994-06-09 |
| NO169169C (en) | 1992-05-20 |
| AU6174586A (en) | 1987-02-26 |
| DE3687675D1 (en) | 1993-03-18 |
| JPS6251671A (en) | 1987-03-06 |
| PH24073A (en) | 1990-03-05 |
| HUT44242A (en) | 1988-02-29 |
| PT83240A (en) | 1986-09-01 |
| AR243167A1 (en) | 1993-07-30 |
| EP0213474A3 (en) | 1987-05-20 |
| FI863382A0 (en) | 1986-08-21 |
| PT83240B (en) | 1989-03-30 |
| AU595231B2 (en) | 1990-03-29 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM4A | Patent lapsed |