Derivatives of 4-chinoline with antihelicobacterial activity, the method of production thereof, pharmaceutical composition containing them, and method of reception

 

(57) Abstract:

The invention relates to new quinoline derivatives having anti - Helicobacter activity of the formula I, their pharmaceutically acceptable salts with acids, their stereochemical isomeric forms, Quaternary forms and their N-oxides, where-A - is a bivalent radical of formula: -N=CH-CH=CH- (a), -CH= N-CH= CH- (b)- N=N-CH=CH- (c), -N=CH-N=CH- (d), -N=CH-CH=N- (e)- CH= N-N=CH- (f)- N=N-N=CH- (g)- N=N-CH=N- (h), -CH=CH-CH=CH- (i), R1, R2, R3, R4, R5and R6each independently of one another represent hydrogen, halogen, hydroxy, C1- C4- alkyloxy, C1- C4-alkyl, trifluoromethyl, amino, mono - or di(C1- C4-alkyl)amino or nitro, or their pharmaceutically acceptable salts with acids, stereochemical isomeric forms, Quaternary forms or N-oxide, provided that, if one Deputy from the phenyl group is a nitro-group, the other substituents have the above-mentioned phenyl groups other than nitro. Describes compositions comprising the aforementioned compounds; methods of obtaining the above-mentioned compounds and compositions and methods of treatment of subjects suffering from disorders or injuries associated with infection Helicobacter

< / BR>
their pharmaceutically acceptable salts with acids, from a stereochemical isomeric forms, Quaternary forms and their N-oxides, where-A - is a bivalent radical of the formula

-N=CH-CH=CH- (a)

-CH=N-CH=CH- (b),

-N=N-CH=CH- (c),

-N=CH-N=CH- (d),

-N=CH-CH=N- (e),

-CH=N-N=CH- (f),

-N=N-N=CH- (g),

-N=N-CH=N- (h), or

-CH=CH-CH=CH- (i);

means hydrogen, halogen, hydroxy, C1-4alkyloxy, C1-4alkyl, trifluoromethyl, amino, mono - or di(C1-4alkyl)amino or nitro, provided that when one Deputy phenyl group is a nitro group, the other substituents of this phenyl group is other than nitro, and which are strong anti-Helicobacter agents that can be used for monotherapy for destruction Helicobacter pylori and related species.

The present invention relates also to method of obtaining new compounds of formula I, pharmaceutical compositions and method of its receipt.

Known (1H-azole-1-yl-methyl)substituted derivatives of quinoline /EP N 0371564/ suppressing plasma allocation retinol-carboxylic acid.

It is known that diseases of the gastrointestinal tract are widely distributed and their treatment is difficult, in private the, duodenal ulcer and relapse of duodenal ulcers. Dual therapy for destruction Helicobacter, including the introduction of two antibiotics, is still unsatisfactory due to one or more of the following reasons: low speed destruction, numerous side effects and development of resistance of Helicobacter.

Triple therapy, including the introduction of two antibiotics and bismuth compounds, effective, but very demanding for patients and also complicated side effects.

The present invention is the creation of new derivatives of 4-quinoline with antihelicobacterial activity, which can be used in pharmaceutical compositions suitable for treatment of diseases associated with Helicobacter.

This object is achieved by the new compounds of General formula mentioned above.

Used in the preceding and subsequent terms refer to compounds: halogen means fluorine, chlorine, bromine, and iodine; C1-4alkyl means straight or branched saturated hydrocarbon radical having from 1 to 4 atoms of carbon, such as, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-here previously, determines the form of a therapeutically active non-toxic salts with acids, which can form compounds of formula (I). The compounds of formula (I) have basic properties can be transformed into the corresponding therapeutically active form and non-toxic salts with acids during processing of free bases are suitable amount of the appropriate acid after following the usual methods. Examples of appropriate acids are inorganic acids, such as halogen acid, i.e. hydrochloric, Hydrobromic and other similar acid, sulfuric acid, nitric acid, phosphoric acid and other like; or organic acids, such as, for example, acetic, propanoic, hydroxyestra, 2-hydroxypropanoic, 2-oxopropanoic, atindimubona, perpendicularly, butandikislota, (Z)-2-butandikislota, (E)-2-butandikislota, 2-hydroxybutyrophenone, 2,3-dihydroxybutanedioate, 2-hydroxy-1,2,3-propanetricarboxylate, methansulfonate, econsultation, benzosulfimide, 4-methylbenzenesulfonate, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and other similar acids.

The term pharmaceuticae hydrates, the alcoholate and the like.

The term stereochemical isomeric forms reflect such compounds that have the same molecular formula but different arrangement of atoms in space. Unless otherwise indicated, the chemical designation of compounds describes the mixture of all possible stereochemical isomeric forms, and these mixtures contain the same ratio of all diastereomers and enantiomers of basic molecular structure. A mixture containing equal amounts of the enantiomers is called a "racemic mixture". Enantiomerically pure form or a mixture containing unequal ratio of enantiomers can be characterized by optical activity. Optically active substance is described as a clockwise rotating or such and is denoted as (+)- or (-)-isomer, respectively. All stereochemical isomeric forms of the compounds of formula (I) in pure form and in the form of a mixture are assumed to be included in the scope of the present invention.

From the formula (I) shows that the compounds of this invention have at least one asymmetric carbon atom in its structure, namely the carbon atom having a quinoline, phenyl and azole Deputy. The absolute is e compounds of the present invention may exist in different tautomeric forms, and all tautomeric forms are to be included in the scope of the present invention.

As described above, the invention also includes Quaternary forms of the compounds of formula (I), and the above-mentioned Quaternary forms are expressed by the formula

< / BR>
where A, R1, R2, R3, R4, R5, R6and R7previously defined and R8represents a C1-4alkyl, which is linked to the nitrogen atom of bivalent radical-A-. Thus, the positive charge is localized on the nitrogen R8the Deputy. X-is an organic or inorganic anion, and preferably represents a hydroxide, an alkoxide, or an anion of an acid, such as hydrofluoric acid, hydrochloric acid, Hydrobromic acid, uudistoodetena acid, sulfuric acid, nitric acid, Chlorophyta acid, perchloric acid, phosphoric acid, dialkylphosphorous acid, 4-methylbenzenesulfonate, benzosulfimide, methansulfonate, triftormetilfullerenov, acetic acid, triperoxonane acid, benzoic acid, Chloroacetic acid, phthalic acid, maleic acid, malonic acid, citric acid and the like.

In addition, the invention also applies to the N-oxides of compounds of formula (I). These N-oxides are in the (+) and (-) formal charges. Preferably oxidized may be a nitrogen atom forming part of the system quinoline ring.

R1is suitably hydrogen, C1-4the alkyl, especially ethyl or stands; hydroxy; C1-4alkyloxy, especially ethoxy or methoxy; nitro; amino; mono - or di(C1-4alkyl)amino. R2means suitable hydrogen; halogen, especially bromine, chlorine or fluorine; trifluoromethyl; hydroxy; or C1-4alkoxy, especially methoxy. R3and R4is suitable hydrogen; halogen; trifluoromethyl; hydroxy; or C1-4alkyloxy. R5is suitable hydrogen; halogen; hydroxy; C1-4the alkyl, especially stands; or (C1-4alkoxy. R6and R7each independently from each other suitable means hydrogen; halogen; predominantly fluorine, chlorine, bromine; hydroxy; C1-4alkyloxy, mainly methoxy, or trifluoromethyl.

Interesting compounds are those compounds of formula (I), where A denotes a bivalent radical of formula-N=CH-CH=CH- (a) or-CH=N-CH=CH- (b). Also interesting compounds are those compounds of formula (I), where A denotes a bivalent radical of formula-N=N-CH=CH- (c), -N=CH-N=CH- (d)-N=CH-CH=N- (e)- CH=N-N=CH- (f).

private radical of the formula-N=N-N=CH (g) - or-N=N-CH=N- (h).

An additional group of interesting compounds are those of formula (I), where-A - is a bivalent radical of formula-CH=CH-CH=CH- (i).

Another group of interesting compounds are those compounds of formula (I), where R5, R6and R7mean hydrogen.

Particular compounds are those compounds of formula (I), where R1represents hydrogen.

Another group of preferred compounds are those compounds of formula (I), where R2and R3mean hydrogen and R4is halogen, especially chlorine or fluorine, preferably R4is substituted in the 3-position of the phenyl part.

Another special group of compounds are those compounds of formula (I), where R5and R6each independently from each other are hydrogen or halogen and R7represents hydrogen or halogen, especially chlorine or fluorine, preferably R7is a substituted 5 - or 8-position of the quinoline part.

The preferred compounds are those compounds of formula (I), where R1means hydrogen, C1-4alkyl, hydroxy, C1-4alkoxy, nitro, amino or mono - or di(C1-4alkyl)amino; R is droxy or C1-4alkoxy;

R5means hydrogen, halogen, hydroxy or C1-4alkoxy;

R6and R7each independently of one another are hydrogen, halogen, hydroxy, C1-4alkoxy or trifluoromethyl.

The most preferred compounds are those preferred compounds wherein R1, R2, R3, R5and R6means hydrogen and R4and R7each independently from each other represents a hydrogen or halogen.

Even more preferred compounds are those preferred compounds where-A - is a bivalent radical of formula-N=N-CH=CH- (c), or-N=CH-N=CH- (d) and R4means 3 is halogen.

The most preferred compounds are 4-[(3-chlorophenyl) (1H-1,2,4-triazole-1-yl)methyl] quinoline, its pharmaceutically acceptable salt of the acid, its stereochemical isomeric forms, its Quaternary form or its N-oxide.

The compounds of formula (I) can be obtained by N-alkylation of asola formula (II) an intermediate product of the formula (III).

< / BR>
In the formula (III) and then W means corresponding to the deleted group, such as, for example, halogen, for example chlorine, bromine, iodine, and other similar; the mud.

The above reaction of N-alkylation may be carried out in an inert solvent, such as, for example, aromatic hydrocarbons such as benzene, methylbenzol, xylene and so on; alcohols, e.g. methanol, ethanol, 1-butanol, and so on; ketones, such as 2-propanone, 4-methyl-2-pentanon etc., ethers, such as tetrahydrofuran, 1,4-dioxane, 1,1-oxybis-ethane, 1,1-oxybis-(12-methoxyethane), etc.; dipolar aprotic solvents, such as N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, nitrobenzene, 1-methyl-2-pyrrolidinone, acetonitrile and other like; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and other like; or a mixture of such solvents. To bind the acid that is released during the reaction, add a suitable base, such as, for example, carbonate, bicarbonate, alcoholate, hydride, amide, hydroxide or oxide of an alkaline or alkaline-earth metal, for example, sodium carbonate, sodium bicarbonate, potassium carbonate, sodium methylate, sodium ethylate, tetrabutyl sodium, sodium hydride, sodium amide, calcium carbonate, sodium hydroxide, calcium hydroxide, calcium oxide and other like; or organic bases, such as amines, e.g. N, the STN adding iodide, preferably the iodide of an alkali metal. The reaction rate may increase partly elevated temperature and mixing. In some cases it may be useful to utilize excess asola (II) or initial turning it into a suitable salt, such as, for example, salt of alkali or alkaline earth metal, by means of reaction (II) with a suitable base as defined previously, and the subsequent use of this salt in the reaction with the alkylating agent of formula (III). Additionally it may be useful to carry out the above-mentioned reaction of N-alkylation in an inert atmosphere, such as, for example, free oxygen argon or nitrogen. Alternatively, the N-alkylation may be carried out under the conditions known from previous works, phase transfer catalysis reactions.

In these and the following methods, the reaction products can be isolated from the environment and, if necessary, further purified according to methodologies, mainly known from previous works, such as, for example, extraction, crystallization and chromatography.

Alternatively, the compounds of formula (I) can be obtained by N-alkylation of the nitrogen of the formula (II) an intermediate product of the formula (IV) in an inert solvent as defined previously, and preferably in the group, for example, triphenylphosphine and diethylazodicarboxylate.

< / BR>
In addition, the compounds of formula (I), where A is a radical of the formula (i), these compounds are represented by formula (I-b) can be obtained by reaction of the intermediate product of the formula (V) with a reagent of formula (VI), where W1is the reaction removable group, for example, C1-4alkyloxy, optionally in the presence of acid, for example acetic acid.

< / BR>
The compounds of formula (I), where A is a radical of formula (f) and R1means hydroxy, these connections are indicated by the formula (I-c) can be obtained by reaction of the intermediate product of the formula (VII) with methanimidamide or its derivative in an inert solvent, for example ethanol.

< / BR>
Quaternary forms of the compounds of formula (I-a) can be conveniently obtained by the reaction of the compounds of formula (I) with a reagent of formula R8-W (VIII), where R8and W have the meanings previously defined; thus receiving these Quaternary compounds of the formula (I-a), as described previously, where X=W. the Reaction (I) to (VIII) is preferably carried out in a suitable solvent, such as, for example, hydrocarbons, such as heptane, benzene, methylbenzol, xylene, and other such; spirtual, 1,4-dioxane, and other such; a ketone, e.g. 2-propanone, 2-butanone and other like; halogenated hydrocarbons such as carbon tetrachloride, trichloromethane, dichloromethane and other like; dipolar aprotic solvent, e.g. N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, acetonitrile and the like. In some cases the reaction can be conducted at elevated temperatures. If required, the anion W in the product obtained by the above method, may be exchanged for another anion with other Quaternary salts of the formula (I-a). This reaction exchange anion may conveniently be carried out by the following known methods, for example, using an anion exchange column or by turning the Quaternary salt to the corresponding hydroxide with the main anionoobmennika with subsequent interaction of the above-mentioned hydroxide with the corresponding acid.

N-oxides of compounds of formula (I) can be conveniently obtained N-oxidation of compounds of formula (I). The above reaction of N-oxidation for the most part can be carried out by reaction of the starting material of the formula (I) with an appropriate organic or inorganic peroxide. Relevant neorganic the emer, the sodium peroxide, potassium peroxide, barium peroxide, and other similar; appropriate organic peroxides may include peroxyacids, such as, for example, natantia acid or halogen-substituted natantia acid, such as 3-chlormadinone acid and other similar phenoxyalkanoic acid, such as peracetic acid and other similar, alkylhydroperoxide, for example, butylhydroperoxide and other similar. If desirable, the above-mentioned N-oxidation may be carried out in a suitable solvent, such as, for example, water, lower alcohol, e.g. methanol, ethanol, propanol, butanol and other like; hydrocarbons, such as benzene, methylbenzol, xylene, and other such; a ketone, e.g. 2-propanone, 2-butanone, and other similar and mixtures of such solvents. In order to increase the speed of reaction the reaction mixture is suitably heated.

Enantiomerically pure forms of compounds of formula (I) can be obtained by transformation of a racemic mixture of compounds of formula (I) with the separating reagent, such as, for example, chiral acid, such as, wine, Apple and almond acid to a mixture of diastereomeric salts; physical separation of the above-mentioned mixture with haze separated diastereomeric salts into the corresponding enantiomers of the compounds of formula (I) by hydrolysis in a basic aqueous medium, optionally at elevated temperature.

Alternatively, enantiomerically pure form can be conveniently obtained from enantiomerically pure isomeric forms of the appropriate starting material, provided that the subsequent reactions are stereospetsifichno.

As a further alternative, the enantiomers may be separated liquid chromatography using a chiral stationary phase.

The compounds of formula (I) may also be transformed into each other by the following known from previous work methods of transformation of functional groups.

A number of intermediates and starting materials in the above methods are known compounds which can be obtained by known methods of obtaining for the above or similar compounds. Methods of obtaining some intermediate products will be described later in more detail.

Intermediates of formula (III) can be obtained by transformation of the corresponding alcohols of formula (IV) with a reagent capable of converting an alcohol functional group corresponding to the group that you want, for example, thionyl chloride, phosphorus oxychloride, trichromatism privedennaya reaction conversion can be performed in a suitable inert solvent, such as for example a halogenated hydrocarbon, e.g. dichloromethane, trichloromethane and other similar. Optional added an appropriate base, such as, for example, tertiary amine, e.g. N,N-diethylethanamine, N,N-di(1-methylethyl)ethanamine and other such.

Alcohols of formula (IV) can be obtained by reaction of the intermediate product of formula (IX) with magnesium in an inert reaction solvent such as an ether, for example, 1,1'-oxy-bis-ethane, tetrahydrofuran and the like, in the presence of a catalyst, for example 1,2-dibromethane, iodine and the like, and then the subsequent interaction of the resulting compounds with Grignard reagent of formula (X).

< / BR>
The technique of synthesis of chinainternational described at length in "Quinolines (Part III)" (G. Jones ed). The Chemistry of Heterocyclic Compounds (Vol. 32), Wiley & Sons, Chichester (1990). In particular, intermediates of formula (X) can be obtained by oxidation of the intermediate product of formula (X) in an inert solvent such as an aromatic hydrocarbon, e.g. benzene, methylbenzol, chlorobenzene, bramasol and other such.

< / BR>
Appropriate oxidizing agent in the above reaction is, for example, selenium dioxide, chloride promila and other Vuwsa carboxylic acids of the formula (XII).

< / BR>
Intermediates of formula (XII) and methods for their production are known in previous works, for example in (1977). The above work also describes getting 4-methylinosine formula (XI).

For example, 4-methylinosine formula (XI) can be obtained by reaction of the intermediate product of formula (XIII) with a reagent of formula (XIV-a) or (XIV-b) in an inert solvent in the presence of acid.

< / BR>
The above reaction is preferably performed in the presence of acid, preferably a Lewis acid such as zinc chloride, iron chloride (III), aluminium oxide, aluminium chloride and the like, or mixture of Lewis acids. Suitable inert reaction solvent in the above reaction is, for example, an alcohol, e.g. ethanol, methanol and the like.

Instead reagents (XIV-a) or (XIV-b) can also be used reagent of the formula

< / BR>
where Z represents hydroxy, halogen, C1-4alkyloxy or di(C1-4alkyl)amino and R9and R10mean C1-4alkyl, or R9R10together represent a C2-6ascandilwy radical.

Intermediates of formula (IV) can also be obtained from corresponding to the e ketones are usually formed by the reaction of carboxylic acids of the formula (XII) with a suitable phenyllithium reagent of the formula (XVIII).

< / BR>
Intermediates of formula (V) and (VII) can be obtained by the following reactions:

< / BR>
< / BR>
< / BR>
Oxidation of (IV) to (XIX) may be carried out using suitable oxidizing reagent, such as Jones reagent or potassium permanganate, preferably in the presence of a base, for example, Tris-(2-(2-methoxyethoxy)ethyl)amine and the like. The intermediate ketone of formula (XIX) can be further transformed into amine of formula (V) by reductive amination. When using formamide and formic acid intermediate amide of formula (XX) can be selected. The intermediate product (XX) is then transformed into an intermediate product (V) in the presence of acid in a suitable solvent, for example, using hydrochloric acid in 2-propanol. Reaction (V) to (XXI) and (XXII) to (VII) is usually conducted in an inert solvent, such as tetrahydrofuran.

In addition, intermediates of formula (IV) can be transformed into each other by the following known from previous work methods of transformation of functional groups.

For example, intermediates of formula (IV), where R5is halogen, C1-4alkyloxy, amino or mono - or di(C1-4alkyl)amino, machale above the corresponding compounds of formula (IV), where R5is hydroxy, are oxidized to carbonyl compounds of the formula (XIX); where R5is hydroxy. These carbonyl compounds of the formula (XIX), where R5is hydroxy, then treated with suitable palodiruyut reagent, such as phosphorus oxychloride, 2,4,6-cryptorchidism and other similar before formation of the intermediate products of the formula (XIX), where R5is a halogen. In order to obtain intermediate products (XIX), where R5is C1-4alkoxy, the above-described halogenated derivatives react with C1-4alkyl-O-M, where M is a cation of an alkali metal, e.g. sodium, potassium, etc. in the appropriate alcohol, for example, sodium methylate in methanol. In order to obtain intermediates of formula (XIX), where R5is amino or mono - or di(C1-4alkyl)amino, halogen derivatives react with ammonia or mono - or di(C1-4alkyl)amino in an inert solvent, for example acetonitrile. Carbonyl compounds of the formula (XIX) can then be restored to the corresponding hydroxy intermediates of formula (IV) using a suitable reducing agent, e.g. sodium borohydride, in an inert solvent, for example methanol.

Especially important in this regard is to establish that these compounds show inhibitory activity against the growth of Helicobacter as well as bactericidal activity in vitro against the above bacteria. A bactericidal effect on Helicobacter defined in suspension culture according to the method described in Antimicrob. Agents Chemother., 1991, v. 35, p. 869 - 872.

An interesting feature of these compounds is related to their highly specific activity against Helicobacter. The compounds of formula (I) exhibit inhibitory activity against any of the following species: Campylobacter jejuni, Campylobacter coli, Campylobacter fetus, Campylobacter sputorum. Vibrio pp. , Staphylococcus aureus and Escherichia coli, in tests up to concentrations of up to 10-5M

Important valuable as these compounds is their activity against H. pylori, continuing at a pH below the normal neutral pH. Activity at low pH in vitro may indicate that the compounds do not affect negatively the acid environment of the stomach in vivo.

Sledai warm-blooded animals, especially humans suffering from diseases and lesions associated with Helicobacter. Examples of the above-mentioned diseases and lesions are gastritis, gastric ulcers and duodenal ulcers and stomach cancer.

Because of their suitable anti-Helicobacter properties, these compounds can be formulated into various pharmaceutical forms of application for the introduction. To obtain pharmaceutical compositions of this invention, an effective amount of individual compounds in the form of a base or salt of acid as the active ingredient is combined in intimate mixture with a pharmaceutically acceptable carrier, which can take a wide variety of forms depending on the form of application required for injection. These pharmaceutical compositions are good in empirical dosage form suitable, preferably, for oral, rectal, injection or parenteral administration. For example, upon receipt of the compositions for oral administration, any of the usual pharmaceutical media may be used, such as, for example, water, glycols, oils, alcohols and the like, liquid forms for oral administration such as suspensions, syrups, elixirs and solutions; or solid carriers, such as the, in the case of powders, pellet, capsules and tablets. Because of the ease of introduction of tablets and capsules are the most preferred form for oral administration and in this case obviously used solid pharmaceutical carriers. For parenteral compositions, the carrier will typically include sterile water, at least for the most part, although there may be other ingredients, for example, to increase the solubility. Solutions for injection can be obtained, for example, when used as a carrier salt solution, a glucose solution or a mixture of solutions of salt and glucose. Suspension for injection can also be obtained in this case can be used appropriate liquid carriers, suspendresume agents and the like.

If the pharmaceutical compositions are in the form of an aqueous solution, such compounds of formula (I), which have low solubility, can be formulated in the form of a salt or may be added miscible with water, physiologically acceptable co-solvent, such as dimethylsulfoxide and the like, or compounds of formula (I) can solubilisate with a suitable carrier, for example, cyclodextrin (CD) or, in particular,97571 (15 October 1986), US-4535152 or WO 90/12035 (18 October 1990). Typically, these derivatives include the_, or CD, where one or more hydroxyl groups substituted C1-6the alkyl, in particular, stands, ethyl or isopropyl; hydraxis1-6the alkyl, particularly hydroxyethyl, hydroxypropyl or hydroxybutyl; carboxyl1-6the alkyl, in particular carboxymethyl or carboxyethyl; C1-6alkylcarboxylic, particularly acetyl; C1-6allyloxycarbonyl1-6by alkyl; carboxy1-6alkalosis1-6the alkyl, especially carboxyphenoxypropane or carboxitherapy; or C1-6alkylcarboxylic1-6the alkyl, in particular 12-acetylaminophenol. Especially deserves attention as complexants and/or solubilization-CD, 2,6-dimethyl --CD and, in particular 2-hydroxypropyl --CD, 2-hydroxyethyl--CD, 2-hydroxyethyl--CD, 2-hydroxypropyl--DM and (2 carboxymethoxy)propyl--CD. For the above-mentioned derivatives of cyclodextrin DS (degree of substitution, i.e. the average number of substituted hydroxy functional groups per glucose) is preferably range from 0.125 to 3, in particular from 0.2 to 2, or from 0.2 to 1.5. More preferably DS varies from about 0.2 to about 0.7, in particular from p is the degree of substitution, i.e., the average number of moles of the substituting agent per unit of glucose) is the range from 0.125 to 10, in particular from 0.3 to 3, or from 0.3 to 1.5. More preferably MS changed about 0.3 to about 0.8, in particular from about 0.35 to about 0.5 and most especially is approximately 0.4. The most preferred cyclodextrin derivative for use in the compositions of the present invention is hydroxypropyl--cyclodextrin with MS in the range of from 0.35 to 0.50, and containing less than 1.5% unsubstituted-cyclodextrin. The amount of cyclodextrin or its ether derivative in the final position usually varies from about 1% to about 40%, in particular from 2.5% to 25% and most likely from 5% to 20%.

Especially useful to formulate the above pharmaceutical composition in the form of a unit dose for ease of injection and constant dose. The term "form of a unit dose" as used here in the description and the claims, refers to physically discrete units suitable as unit dosages, each unit contains a predetermined quantity of active ingredient calculated to obtain the desired therapeutic effect in connection with the required tabletki), capsules, pilley, packaging, powder, pills, solutions or suspensions for injection or the like, and the separated components.

Due to the suitability of these compounds for the treatment of diseases associated with Helicobacter, the above-mentioned compounds can be used as drugs for disorders caused by Helicobacter. Compounds of the present invention used in the method of treating warm-blooded animals, in particular humans, suffering from diseases caused by Helicobacter, and the method includes the systematic introduction of pharmaceutically effective amounts of compounds of formula (I), its pharmaceutically acceptable salt with an acid, its Quaternary form or its N-oxide in a mixture with a pharmaceutical carrier. In General it is assumed that the effective daily amount is from 0.05 mg/kg to 100 mg/kg body weight, preferably from 0.1 mg/kg to 50 mg/kg body weight and more preferably from 0.5 mg/kg to 5 mg/kg of body weight. It is obvious that the above-mentioned effective daily amount may be reduced or increased depending on the patient's response and/or depending on the decision of the physician prescribing the compounds of the present invention. Therefore, the above series of effective stenia to any degree.

Optional in combination with the quinoline compounds of the present invention can be administered with other active compounds, used for destruction Helicobacter. The introduction can be carried out separately (i.e., at the same time, matching or sequentially) or different drugs can be combined in a single dosage form. The preferred compounds for combination therapy are compounds of bismuth, for example, citrate of bismuth (III), salicylate of bismuth (III) and other similar, proton pump inhibitors, e.g. omeprazole, lansoprazole and other such.

Experimental part

A. Obtaining an intermediate product

Example 1

A mixture of monohydrochloride 2,3-dichlorobenzamide (0.308 mol), iron chloride (III) (0.52 moles) and zinc chloride (0.0308 mol) in ethanol (800 ml) is heated at 65oC for 30 minutes, then for 1 hour at 65oC is added dropwise 3-butene (0.308 mol) in ethanol (200 ml), stirred, boiled over night, cooled to room temperature and evaporated. The residue is treated with water, alkalinized NH4OH, filtered and extracted with ethyl acetate. The organic layer is extracted with 3 N HCl. The aqueous layer was alkalinized NH4OH and extragere. 1).

Similarly also receive:

5,8-dichloro-4-methylinosine (InterMedia. 2); and

4-methyl-8-(trifluoromethyl)quinoline (InterMedia. 3).

Example 2

A mixture of intermediate (1) (forms 0.141 moles) and selenium oxide (IV) (0.28 moles) in bromobenzene (300 ml) is stirred and boiled for 2 hours, filtered, the filtrate evaporated, the residue is treated with cyclohexane. The precipitation is filtered off, dried in air and obtain 23 g (71%) of 7,8-dichloro-4-chinainternational (InterMedia. 4).

Similarly also get:

6-bromo-4-hyalinobatrachium (InterMedia. 5);

5,8-dichloro-4-hyalinobatrachium (InterMedia. 6);

6-(trifluoromethyl)-4-hyalinobatrachium (InterMedia. 7); and

8-(trifluoromethyl)-4-hyalinobatrachium (InterMedia. 8).

Example 3

To a mixture of magnesium (0.15 moles) of 1,1'-oxy-bis-ethane (100 ml) for 20 minutes, added dropwise 1-bromo-3-chlorobenzene (0.15 mol), stirred for 30 minutes at room temperature, cooled to 0oC, are added dropwise within 1 hour intermediate product (4) (0.075 moles) in tetrahydrofuran (200 ml). The mixture was poured into ice-cold water with NH4Cl, extracted with ethyl acetate. The organic layer is dried (MgSO4) and evaporated. The residue is crystallized from 1,1'-oxy-bis-ethane/etilize is unity, presented in table. 1 at the end of the description.

Example 4

To a mixture of intermediate (9) (0,05 moles) in dichloromethane (200 ml) at 0 - 5oC added dropwise thionyl chloride (17 ml), stirred the mixture overnight at room temperature and evaporated in vacuum. The residue is treated with dichloromethane, washed with aqueous sodium bicarbonate solution. The organic layer is dried (MgSO4), evaporated and obtain 17.8 g (99.7%) ()-7,8-dichloro-4-[chloro(3-chlorophenyl)methyl] quinoline (InterMedia. 29).

Similarly also get a connection, are presented in table. 2 at the end of the description.

Example 5

To a mixture of intermediate (18) (0,026 mol) and N,N-diethylethanamine (0.065 moles) in dichloromethane (70 ml) at 0oC in nitrogen atmosphere is added dropwise methansulfonate, stirred for 4 hours at 0oC add at this temperature, a saturated aqueous solution of sodium bicarbonate and extracted with dichloromethane. The organic layer is dried (MgSO4), evaporated and get 13 g methansulfonate () -(4-methoxyphenyl)-4-kinalimutan (ether) (InterMedia. 52), the product is used without further purification.

Example 6

a) a Mixture of intermediate (19) (amount of 0.118 moles) in 2-propanol (350 ml) cooled to 0oC, Dobb over night at room temperature, alkalinized with potassium carbonate (powder). The precipitation is filtered off, washed with water. The precipitate is extracted with a mixture of dichloromethane and acetic acid and the filtrate evaporated. The residue is treated with a solution of NaHCO3, filtered, washed with water. The precipitate is filtered off, dried in air and obtain 21.6 g (64%) of 4-(3-chlorobenzoyl)-2(1H)-quinoline (InterMedia. 55).

b) a Mixture of intermediate (55) (0.07 moles) in phosphorus oxychloride (60 ml) is stirred for 4 hours at 60oC, evaporated, the residue is treated with a solution of NaHCO3. The precipitation is filtered off, washed with water, the residue is filtered, air-dried and receive a 20 g (94%) of (3-[chlorophenyl)-2-(2-chloro-4-chinoline)methanol (InterMedia. 56).

c) a Mixture of intermediate (56) in dimethylamine (150 ml) and acetonitrile (100 ml) is stirred for 24 hours at 50oC, evaporated in vacuum. The residue is treated with water, extracted with a mixture of dichloromethane/ethyl acetate. The organic layer is extracted with 3 N HCl. The aqueous layer was alkalinized with NaOH and extracted with a mixture of dichloromethane/ethyl acetate. The organic layer is dried (MgSO4), evaporated and obtain 10.5 g (84%) (3-chlorophenyl)-[2-(dimethylamino)-4-chinoline]methanol (InterMedia. 57).

d) To a solution of intermediate (57) (0.032 moles) is based temperature poured into ice water and filtered. The precipitate is washed with water, dried in air and get 9.27 g(92%) ()--(3-chlorophenyl)-2-(dimethylamino)-4-kinalimutan (intermediate 58), the product is used without further purification.

Similarly get: ()--/ (3-chlorophenyl)-2-methoxy-4-kinalimutan (InterMedia. 59); and (a)--(3-chlorophenyl)-2-fluoro-4-kinalimutan (InterMedia. 60).

Example 7

To a solution of intermediate (56) (0.033 moles) in methanol (100 ml) at room temperature is added sodium methylate (0.152 mol), stirred, boiled for 24 hours and evaporated in vacuum. The residue is treated with ethyl acetate. The organic layer is dried (MgSO4), filtered and evaporated. The residue was purified through column chromatography with silica gel (eluent: cyclohexane/dichloromethane 50/50) (35 - 75 microns). Pure fractions are collected, evaporated and obtain 6.8 g (69%) (3-chlorophenyl) (2-methoxy-4-chinoline) methanol (InterMedia. 62).

Example 8

The intermediate product (55) (0.0423 mol) and 2,4,6-Cryptor-1,3,5-triazine (0.0634 mol) are heated in an autoclave for 2 hours at 175oC, the mixture is evaporated, the residue treated with ethyl acetate, filtered, the filtrate washed with 3 N NAOH and the product extracted with ethyl acetate, the organic layer is dried (MgSO4), filtered, action collect, evaporated, the product is recrystallized from 1,1'-oxy-bis-ethane and obtain 1.4 g (12%) (3-chlorophenyl)(2-fluoro-4-chinoline)methanone; so pl. 93,2oC (InterMedia. 63).

Example 9

a) a Mixture of intermediate (10) (0.02595 mol), Tris(2-(2-methoxyethoxy)ethyl)amine (0.0009 moles) and potassium permanganate (0.02076 moles) in dichloromethane (200 ml) was stirred for 12 hours at room temperature, filtered through celite, the solvent evaporated in vacuum, the residue is recrystallized from 2,2'-oxy-bis-propane/cyclohexane and receive 6 g (87%) (3-chlorophenyl)(4-chinoline)methanone; so pl. 92.7oC (InterMedia. 64).

b) a Mixture of intermediate (64) (0.029 mol) and formamide (0.15 moles) in formic acid (16 ml) is heated for 24 hours at 130oC, cooled to room temperature, poured into water and extracted with ethyl acetate. An ethyl acetate layer is extracted with 3 N HCl. The aqueous layer was alkalinized NH4OH, extracted with ethyl acetate. The organic layer is dried (MgSO4) and evaporated, the residue is purified on a chromatographic column with silica gel (eluent: CH2Cl2/CH3OH 98/2) 70 - 200 microns). Pure fractions are collected, evaporated, the residue (6 g) is crystallized from ethyl acetate/2,2'-oxy-bis-propane and receive 2,7 (30%) ()-N-[(3-chlorophenyl)-4-hyalinella the 6 N (250 ml) and 2-propanol (400 ml) is stirred and boiled for night, cooled to room temperature, poured into ice water, alkalinized NH4OH, extracted with ethyl acetate. The organic layer was washed with water, dried (MgSO4) and evaporated. The residue is converted into the salt ethicalmoney acid (2 : 3) and recrystallized from 2-propanol and obtain 2.5 g of the hemihydrate of candiota(2 : 3) ()--(3-chlorophenyl)-4-kinalimutan; so pl. 196,1oC (InterMedia. 66).

d) To a solution of the base of the intermediate product (66) (0.0857 mol) in tetrahydrofuran at room temperature was added 1,1'-carbonyl-bis-1H-imidazole (0.257 mol) in tetrahydrofuran, stirred for 1 hour and receive a 25 g(99%) ()-4-[(3-chlorophenyl)isocyanatomethyl]quinoline (InterMedia. 67).

e) To a solution of intermediate (67) in tetrahydrofuran at room temperature was added hydrazine (0.428 mol) in tetrahydrofuran, stirred for 1 hour, evaporated in vacuum. The residue is treated with dichloromethane, washed with saturated aqueous NaCl. The organic layer is dried (MgSO4) filtered, evaporated, the residue is purified on a chromatographic column with silica gel (eluent: CH2Cl/CH3OH/NH4OH 96/4/0.2). Pure fractions are collected, evaporated, the residue is recrystallized from dichloromethane/methanol/ethyl acetate and receive 1 is the group of target compounds

Example 10

A mixture of intermediate (30) (0.0427 mol) of 1,2,4-triazole (0.217 moles) and potassium carbonate (0.214 mol) in acetonitrile (200 ml) is stirred, boiled for 12 hours, the solvent evaporated, the crude residue is stirred in water, the mixture extracted with dichloromethane. The organic layer is separated, dried (MgSO4), filtered, the solvent evaporated, the residue (15 g) is purified on a chromatographic column with silica gel (300 g; 70 - 200 μm; eluent: CH2Cl/CH3OH 98/2), collected 2 required fraction. The first fraction is evaporated, the residue (4.8 g) turn in salt ethicalmoney acid (1 : 1) and the salt is recrystallized from a mixture of methanol, 2-propanone and 1,1'-oxy-bis-ethane. The crystals are filtered and dried, yielding 3.1 g (17.7%) of candiota(1 : 1) 4-[3-chlorophenyl) (1H-1,2,4-triazole-1-yl)methyl]quinoline, so pl. 165.8oC (Conn. 1).

The second collected from the column fraction evaporated, the residue is crystallized from 2-propanone and 2,2'-oxy-bis-propane. The crystals are filtered and dried, yielding 0.9 g(6.6%) 4-[(3-chlorophenyl) (4H-1,2,4-triazole-4-yl)methyl]quinoline; so pl. 203.3oC (Conn. 2).

Example 11

A mixture of intermediate (34) (0.018 mol), 1H-imidazole (0.092 moles) and potassium carbonate (0.05 moles) of 1,1'-oxy-bis-[2-methoxyethane] (80 ml) var is practical layer is separated, dried (MgSO4), evaporated, the residue is purified on a chromatographic column with silica gel (eluent: CH2Cl2and then CH2Cl2/CH3OH 98/2) (35 to 70 μm). Pure fractions are collected, evaporated, the residue is crystallized from 2-butanone and receive 1.2 g(21%) ()-4-[(3-forfinal)(1H-imidazol-1-yl)methyl] quinoline; so pl. 140.3oC (Conn. 48).

Example 12

A mixture of intermediate (33) (0.033 mol), 1H-imidazole (0.16 moles of 1,1'-oxy-bis-[2-methoxyethane] (130 ml) is boiled for 4 hours, cooled to room temperature, poured into water and extracted with ethyl acetate. The organic layer is dried (MgSO4) and evaporated. The residue is purified on a chromatographic column with silica gel (eluent: CH2Cl2/ CH3OH 98/2) (33 - 70 microns). Pure fractions are collected, evaporated. The residue (7.2 g) crystallized from 2-butanone and obtain 2.9 g(30%) ()-4-[(1H-imidazol-1-yl)-phenylmethyl]quinoline; so pl. 143.0oC (Conn. 59).

Example 13

To N,N-dimethylformamide was added in portions dispersion of sodium hydride 80% (0.1 mol) is added dropwise at 0oC 1H-1,2,3,4-tetrazole (0.1 mol) in N, N-dimethylformamide, stirred for 15 minutes at room temperature, at room temperature make dropwise intermediate product 30 (0.034 moles) in N,N-dimetil the Loy extracted with 3 N HCl. The acid layer is alkalinized NH4OH, extracted with ethyl acetate. The organic layer is dried (MgSO4) and evaporated. The residue is purified on a chromatographic column with silica gel (eluent: CH2Cl2-/2-propanol 98/2) (35 to 70 μm). Pure fractions are collected, evaporated, fraction 1 (2.2 g) crystallized from 2-propanol and (C2H5)2O and gain of 2.26 g of candiota(1 : 1) ()-4-[(3-chlorophenyl)(2H-tetrazol-2-yl)methyl] quinoline(1 : 1) (20%); 181.8oC (Conn. 65).

Fraction 2 (4.3 g) is crystallized from (C2H5)2O and obtain 3.47 g ()-4-[(3-chlorophenyl)(1H-tetrazol-1-yl)methyl] quinoline (31%); so pl. 131.5oC (Conn. 66).

Example 14

A mixture of intermediate (30) (0.02 mol), 1H-pyrazole (0.1 mole) and potassium carbonate (0.06 moles) and N,N-dimethylformamide (60 ml) is heated for 2 days at 80oC, cooled to room temperature, poured into water and extracted with ethyl acetate. The organic layer is dried (MgSO4), evaporated, the residue is purified on a chromatographic column with silica gel (eluent: CH2Cl2-/2-propanol 98/2) (35 to 70 μm). Pure fractions are collected and evaporated, the residue (2.3 g) turn in salt ethicalmoney acid (1 : 1), crystallized from 2-propanone and obtain 1.4 g (21%) of candiota(1 : 1) ()-4-[(3-chlorophenyl)- 1H-pgct (66) (0.0186 mol) in acetic acid (50 ml) was added dropwise at room temperature 2.5-dimethoxytetrahydrofuran (0.0214 mol), boil 10 minutes, evaporated, the residue treated with ethyl acetate, washed with a solution of K2CO3. The organic layer is dried (MgSO4), filtered, evaporated to dryness. The residue is purified on a chromatographic column with silica gel (eluent: CH2Cl2/CH3OH 98.5/1.5) (15 - 40 µm). Pure fractions are collected, evaporated, the product is transformed into a salt ethicalmoney acid (1 : 1), crystallized from 2-propanone and obtain 2.5 g (33%) of candiota(1 : 1) ()-4-[(3-chlorophenyl)-1H-pyrrol-1-yl-methyl]quinoline; so pl. 177.4oC (Conn. 79).

Example 16

To a solution of intermediate (60) (0.0169 moles) of 1,2,4-triazole (0.0174 moles) and triphenylphosphine (0.0174 moles) in tetrahydrofuran (70 ml) was added at 0oC diethylazodicarboxylate (0.0174 moles) in tetrahydrofuran (15 ml), stirred for 4 hours at room temperature, evaporated in vacuo, the residue is treated with ethyl acetate, washed with a solution of K2CO3. The organic layer is dried (MgSO4), filtered, evaporated to dryness, the residue is purified on a chromatographic column with silica gel (eluent: CH2Cl2/CH3OH 98/2) (15 - 40 µm). Pure fractions are collected, evaporated, the residue (1.9 g) is crystallized from 1,1'-oxy-bis-ethane and obtain 1.35 g(23%) ()-4-[(3-chlorophenyl)-1H-1,2,4-triazole-1 - I moles), in ethanol (100 ml) at room temperature was added acetate methanimidamide (0.0918 mol), boiled for 3 hours, evaporated in vacuo, the residue is treated with dichloromethane, washed with saturated aqueous NaCl. The organic layer is dried (MgSO4), filtered, evaporated, the residue is purified on a chromatographic column with silica gel (eluent: CH2Cl2/CH3OH/NH4OH 97/3/0.1) Pure fractions are collected, evaporated, the residue is recrystallized from 2 propanone/1,1'-oxy-bis-ethane and get 1.25 g(16%) ()-4-[(3-chlorophenyl)-4-hyalinella]-2,4-dihydro-3H-1,2,4-triazole-3-one; so pl. 244.3oC (Conn. 82).

Example 18

A mixture of compound (49) (0.00625 mol) and methyl iodide (0.01375 moles) in 2-propanone (30 ml) is stirred overnight at room temperature, the precipitate is filtered off, washed with 2-propanone, air-dried and obtain 2.2 g of the iodide ()-1-[(3-chlorophenyl)-4-hyalinella]-3-methyl-niridazole (76.4%); so pl. 231.3oC (Conn. 68).

Example 19

Connection (1) (0.0012 moles) release in the water with NH4OH. The product is extracted with dichloromethane. The organic layer is dried, filtered, evaporated. The residue is purified on Chiracell OD (eluent: hexane/C2H5OH 60/40). Suitable fractions are collected, evaporated. Fraction 1 again clean n the t and obtain 0.16 g(+)-4-[(3-chlorophenyl)(1H-1,2,4-triazole-1-yl)methyl]quinoline; []D= 100.35o(c = 0.114 in methanol) (Conn. 70). Fraction 2 purified again on a glass filter with silica gel (eluent: CH2Cl2/CH3OH 95/5). Pure fractions are collected, evaporated and get 0.073 g(-)-4-[(3-chlorophenyl)(1H-1,2,4-triazole-1-yl)methyl]quinoline; (Conn. 69).

Example 20

To a mixture of compound (49) (0.03127 moles) in dichloromethane (200 ml) was added in portions during 10 minutes 3-chlormadinone acid (0.06254 mol), stirred for 4 hours at room temperature, add saturated aqueous solution of NaHCO3, extracted with dichloromethane. The organic layer is dried (MgSO4), and evaporated. The residue is purified on a chromatographic column with silica gel (eluent: CH2Cl2/CH3OH 96/4) Pure fractions are collected, evaporated. The residue is crystallized from 2-butanol and 1,1'-oxy-bis-ethane and obtain 1.4 g (64%) of N-oxide ()-4-[(3-chlorophenyl)(1H-imidazol-1-yl)methyl]quinoline; so pl. 184.1oC (Conn. 83).

All compounds listed in tables 3 and 4 receive the methods described in examples 10 to 20, as shown in column (PL. 3 and 4, see the end of the description).

C. Pharmacological examples

Anti-Helicobacter activity of these compounds is assessed using the following in vitro tests.

The activity of testerone andartes series 5 strains of H. pylori, obtained from clinical material. The minimum inhibiting concentrations (MICs) determined by measurement of the activity of the urease of H. pylori after treatment of a growing culture of bacteria antimicrobial drugs.

Test compounds dissolved in DMSO to a concentration of 10-3M Also preparing a dilution up to 10-4M in DMSO, 10 µl. The volumes of these solutions contributed by pipette into wells Repli-Dish (Sterilin). As a control using wells containing only DMSO, which are included in each tablet Repli-Dish. In each group of tests are included as reference compounds ampicillin (trihydrate(+)-6-[(2-amino-2-phenylacetyl)amino]-3,3-dimethyl-7 - oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid) and metronidazole (2-methyl-5-nitro-1H-imidazole-1-ethanol). (These compounds are tested at final concentrations of 10-5, 10-6, 10-7and 10-8M). Test tablets stored until use at 4oC.

Five isolates of H. pylori keep using subculture 10% blood agar every 2 or 3 days. Bacteria grow at 37oC microaerophilic atmosphere containing 5% oxygen, 10% CO2and 85% nitrogen. Suspension for Helicobacter inoculum is prepared broth extract the brain, the heart and regulate UP>oC, was added to 1 ml volumes into the wells of the test tablet, thus diluting the test connection up to 10-5and 10-6M Wednesday, leave to cool, then make the pipette 10 ál volumes of bacterial suspension on the surface of the agar. Board incubated for 48 hours at 37oC microaerophilic atmosphere, as described earlier. For ease of reading with the cards and to ensure that any growth on the environment is exactly H. pylori, use vysokozhirnuyu urease activity, unique to this species. After 48 hours of incubation, each well Repli-Dish gently add 1 ml volume urease broth and incubated card at 37oC for 2 hours. 100 μl samples of fluid from each well make then pipette into the wells of 96-local Board for microrasbora. Staining in the purple color is evaluated as growth, yellow-orange as the lack of growth of H. pylori. Using this method, you clearly get the endpoint from which the inhibiting effects. All connections that were active when any of the two tested concentrations, test again with additional dilution, including the assessment of the MIC and using a wide range of species of bacteria as Televisi of the present invention (see at the end of the description).

D. Examples of songs

The term "active ingredient (A. I.)" used in these examples relates to a compound of formula (I), its pharmaceutically acceptable salt with an acid or its stereochemical isomeric form.

Examples 21: Drops for oral administration

200 g of A. I. dissolved in 0.5 l of 2-hydroxypropanoic acid and 1.5 l of the polyethylene glycol at 60-80oC, cooled to 30-40oC, then make 35 l of polyethylene glycol and the mixture is mixed well, then add a solution of 1750 g of saccharin sodium in 2.5 l of purified water and while stirring to make 2.5 l of coconut perfumes and polyethylene glycol to a volume of 50 l, obtaining the solution drops for oral administration containing 10 mg/ml A. I. the Resulting solution fill the appropriate containers.

Example 22: Capsules

A mixture of 20 g A. I., 6 g of lauryl sodium, 56 g of starch, 56 g of lactose, 0.8 g of colloidal silicon dioxide, and 1.2 g of magnesium stearate vigorously stirred. Next, the resulting mixture fill 1000 suitable hard gelatin capsules, each containing 20 mg of active ingredient.

Example 23: film-Coated tablets

A mixture of 100 g A. I., 570 g lactose and 200 g starch is mixed well, then HC is shaped mixture is sifted, dry, sift again, then make 100 g microcrystalline cellulose and 15 g hydrogenated vegetable oil, mix well, pressed into tablets, receiving 10,000 tablets, each of which contains 10 mg of active ingredient.

Floor

To a solution of 10 g of methyl cellulose in 75 ml of denatured ethanol is added a solution of 5 g of ethyl cellulose in 150 ml of dichloromethane, then make 75 ml of dichloromethane and 2.5 ml 1,2,3-propanetriol. 10 g of polyethylene Glycol is melted and dissolved in 75 ml of dichloromethane. The resulting solution is added to previously obtained, contribute 2.5 g of octadecanoate magnesium, 5 g of polyvinylpyrrolidone and 30 ml of concentrated colour suspension, everything is homogenized. Based tablet cover thus obtained mixture in a special apparatus for the coating.

Example 24: Solution for injection

1.8 g of Methyl-4-hydroxybenzoate and 0.2 g of propyl-4-hydroxybenzoate dissolved in about 0.5 l of boiling water for injection, cooled to about 50oC, was added while stirring 4 g lactic acid, 0.05 grams propylene glycol and 4 g of A. I. the Solution is cooled to room temperature, add water for injection to 1 l, thus obtaining a solution containing 4 mg/ml A. I. Rest the A. I. dissolved in a solution of 3 g of 2,3-dihydroxybutanedioate acid in 25 ml of polyethylene glycol 400. 12 g of Surfactants and triglycerides in a quantity sufficient to 300 g, melted together. Formed mixture is well mixed with the resulting solution, and pour the resulting mixture into molds at a temperature of 37 - 38oC and get 100 suppositories each containing 30 mg/ml A. I.

Example 26: the Form of application containing cyclodextrin

100 ml of Propylene glycol process 3.76 ml of concentrated HCl, stirred, slowly heat up, make 10 g of A. I. and continuously stirred to obtain a homogeneous mass. In a separate vessel, 400 g of hydroxypropyl --cyclodextrin is dissolved in 400 ml of distilled water. Slowly add to cyclodextrine solution with stirring, a solution of the active ingredient, contribute sorbitol solution (190 ml) and stirred until a homogeneous mass. To this mixture add saccharin sodium (0.6 g) in 50 ml of distilled water, making perfumes, bring the pH of the mixture (about 1.7) adding a solution of 10 N NaOH to pH 2.00.1. The resulting solution was diluted with distilled water to a final volume of 1 L. the Pharmaceutical dosage form is received filtrowanie covers.

1. Derivatives of 4-chinoline General formula I

< / BR>
where A represents a bivalent radical of the formula

-N=CH - CH=CH- (a)

-CH=N - CH=CH- (b)

-N=N - CH=CH- (c)

-N=CH - N=CH- (d)

-N=CH - CH=N- (e)

-CH=N - N=CH- (f)

-N=N - N=CH- (g)

-N=N - CH=N- (h)

-CH=CH - CH=CH- (i)

R1, R2, R3, R4, R5and R6each independently of one another represent hydrogen, halogen, hydroxy, C1-4-alkoxy, C1-4-alkyl, trifluoromethyl, amino, mono - or di(C1-4-alkyl)amino or nitro,

or their pharmaceutically acceptable salts with acids, stereochemical isomeric forms, Quaternary forms or N-oxide, provided that, if one Deputy from the phenyl group is a nitro-group, the other substituents have the above-mentioned phenyl groups other than the nitro group.

2. The compound of General formula I under item 1, in which R1is hydrogen, C1-4-alkyl, nitro, amino, or mono-or di(C1-4-alkyl)amino; R2and R3each independently of one another denote hydrogen, halogen, trifluoromethyl, hydroxy or C1-4-alkoxy, R4is hydrogen, halogen, hydroxy or C1-4-alkoxy; R5and R6each independently of one another represent hydrogen, halogen are hydrogen, and R3and R6each independently of one another represent hydrogen or halogen.

4. Connection on p. 3, in which - A represents a bivalent radical of formula-N=CH - N=CH- (d) and R3- 3-halogen.

5. Connection on p. 4, which is selected from the group consisting of 4-[(3-chlorophenyl)-(1H-1,2,4-triazole-1-yl)methyl] quinoline, its pharmaceutically acceptable salts with acids, it stereochemical isomeric forms, its Quaternary form and its N-salts.

6. Pharmaceutical composition having activity against Helicobacter pylori, comprising an active component and a pharmaceutically acceptable carrier, wherein the active component is used as a compound according to any one of paragraphs.1 to 5 in an effective amount.

7. A method of obtaining a pharmaceutical composition having activity against Helicobacter pylori, wherein therapeutically effective amount of the active ingredient is thoroughly mixed with a pharmaceutically acceptable carrier.

8. Connection on p. 1, having inhibitory activity against the growth of Helicobacter.

9. The method of obtaining derivatives of 4-chinoline according to any one of paragraphs.1 to 5, characterized in that the azole
< / BR>
where R1- R6are specified in paragraph 1 values;

W is a reactive delete group

with the selection of target products in a free form in the form of their pharmaceutically acceptable salts with acids, stereochemical isomeric forms, Quaternary forms or their N-oxides.

Priority signs:

20.10.92 when A is a bivalent radical of the formula

-N=CH - CH=CH- (a)

-CH=N - CH=CH- (b)

-N=N - CH=CH- (c)

-N=CH - N=CH- (d)

-N=CH - CH=N- (e)

-CH=N - N=CH- (f)

-N=N - N=CH- (g)

-N=N - CH=N- (h)

R1, R2, R3, R4, R5, R6each independently represents hydrogen, halogen, hydroxy, C1-4-alkoxy, C1-4-alkyl, trifluoromethyl, amino, mono - or di(C1-4-alkyl)amino or nitro, provided that when one Deputy phenyl group is a nitro-group, the other substituents are different;

01.06.93 when A is - CH = CH - CH = CH (i).

 

Same patents:

The invention relates to novel 1,2,4-substituted piperidines formula 1, where R1is unsubstituted or substituted with halogen and/or trifluoromethyl phenyl or diphenyl-C1-C4-alkyl, ; 9-fluorenyl, pyridil-C1-C4-alkyl; chinolin-C1-C4-alkyl; 5-chloro-2-[1H-1,2,4-triazolyl-1-yl]-phenoxy-C1-C4-alkyl, unsubstituted or substituted C1-C4-alkyl, C1-C4-alkoxyl, hydroxyl, halogen, trifluoromethyl, di-C1-C4-alkylamino-group and/or cyano benzoyl; naphtol; 2-fluorenyl; phenyl - or diphenyl-C2-C4-alkanoyl; naphthyl-C2-C4-alkanoyl; dimethylcyclohexanols; hinolincarbonova; pyridyl-C2-C4-alkanoyl; benzyloxycarbonyl, unsubstituted or substituted by acetyl or 4-carboxymethylation phenylalanine or phenylcarbamoyl; 2,3,4,9-tetrahydro-1H-pyrido[3,4-b] indol-3-yl-carbonyl; R2is unsubstituted or substituted with halogen phenyl or naphthyl; R3is hydrogen, C1-C4-alkyl, cyclohexyl or phenylcarbamoyl, or 3-aminocarbonylmethyl; R4- if necessary substituted C1-C4-alkyl or C1-C4-alkoxyl phenyl, naphthyl, benzyl, pyridyl, if necessary, C-Zam the sludge; if necessary substituted C1-C4the alkyl benzothiophenes, dihydrobenzofuranyl or aniline group, X1- simple bond, methylene, hydroxymethylene or carbonyl, X2- a simple link, X3- simple bond, methylene, ethylene, benzylidene or carbonyl or their salts

The invention relates to new indolinone derived formula, method of production thereof and to pharmaceutical compositions based on

The invention relates to new derivatives of arylsulfonamides having, in particular, valuable pharmacological properties, more particularly to a derivative of arylsulfonamides General formula (I)

< / BR>
where R1benzyl, thienyl, chloranil, tetramethylene pentamethylbenzyl, phenyl, unsubstituted or monosubstituted by a halogen atom, a nitro-group, stands, metaxylem or trifluoromethyl, phenyl, disubstituted by chlorine atoms or methoxypropane,

R2a hydrogen atom, methyl,

R3pyridyl,

R4and R5hydrogen atoms or together denote a carbon-uglerodnoi communication,

R6hydroxyl, methoxyl,

A group of the formula

< / BR>
where R7and R8a hydrogen atom or together denote a methylene or ethylene group

X N-methyl-aminogroup or sulfur atom, and the group-CHR7associated with the group-NR2-,

B a carbon-carbon bond or unbranched Allenova group with 2-4 carbon atoms,

their mixtures, isomers or individual isomers and physiologically tolerated additive salts with bases, if R6means hydroxyl, which

The invention relates to novel condensed heterocyclic compounds or their salts

The invention relates to 5,6-disubstituted-3 - pyridylmethylamine compounds of the formula I

< / BR>
where Z is hydrogen, halogen;

Z1represents hydrogen, halogen, cyano and nitro;

X represents Cl, Br, J, or R3SO3;

R3represents C1-C4-alkyl or phenyl, are not necessarily substituted with one to three C1-C4-alkoxygroup, C1-C4- alkyl groups, nitro groups: cyano groups or halogen atoms;

Y and Y1each independently represents OR4, NR4R5or, if they are taken together, YY1represent-O-, -S - or;

R4and R5are each independently hydrogen, C1-C4-alkyl, does not necessarily substituted C1-C4- alkoxygroup, or phenyl, does not necessarily substituted with one to three C1-C4-alkyl groups, C1-C4- alkoxygroup or halogen atoms; or phenyl, does not necessarily substituted with one to three C1-C4-alkyl groups, C1-C4- alkoxygroup atoms or halogen;

R6represents hydrogen or C1- C4- alkyl;

Q is

The invention relates to new derivatives of 5-amino-8-methyl-7-pyrrolidineethanol-3-carboxylic acids and their stereoisomers and their pharmacologically acceptable salts, have excellent antibacterial activity, and to methods for their preparation

The invention relates to new compounds of formula I, where b and E are independently selected from CH or N; R4is hydrogen, halogen, hydroxy; G represents the compounds of formula II (a, b, c) and their optical and geometric isomers; and nontoxic pharmaceutically acceptable acid salt additive

The invention relates to biologically active compounds, namely cyclohexylamino chinoline[2,1-b]hinzelin-12-he-5-carboxylic acid formula

< / BR>
with antireverse activity, suggesting the possibility of its use in medicine as a drug for the treatment of tick-borne encephalitis

The invention relates to a 6,9-bis(aminosilane) benzo(g)isoquinoline-5,10-diones and, more specifically, to those 6,9-substituents which are (aminoalkyl)aminosalicylate

The invention relates to 5-nitrofurfurylidene 2-chloro-5,6,7,8-tetrahydroquinolin-4-carboxylic acid with bacteriostatic activity against Staphylococcus aureus with MIC of 1 µg/l and E. coli was 3.9 µg/ml at LD50more than 500 MK/kg

The invention relates to crystals containing water of crystallization (hereinafter referred to as hydrated form or simply hydrate), and the crystals without water of crystallization (hereinafter referred to as the anhydrous form or simply anhydrous), to a method for selective receipt of these crystals and, in addition, to pharmaceutical preparations containing such crystalline form

The invention relates to unknown compounds useful in the treatment of humans and animals, their pharmaceutically acceptable salts, to their bioapatite derivatives, methods of producing these new compounds, pharmaceutical compositions containing the new compounds, to dosage units of the compositions and to methods of treating patients using these compositions and unit dosages
Up!