Substituted ariliawitiers, the retrieval method, the drug and the method of obtaining the drug.

 

(57) Abstract:

Substituted ariliawitiers formula I, where R1-R4denotes hydrogen, R5is hydrogen, (C1-C4)alkyl or (C1-C4)alkoxy, R6denotes substituted with R8and R9the cycle which are selected from the group consisting of benzene, thiazole, imidazole, triazole, tetrazole, thiadiazole, pyridine, pyridine-N-oxide, pyrimidine, and benzimidazole; R7, R9, R11, R12is hydrogen or (C1-C4)alkyl; R8is hydrogen, NH2group or (C1-C4)alkyl, possibly substituted R10, m = 2-4; n, p, q = 0, and their salts are effective against Helicobacter-bacteria. 4 C. and 6 C.p. f-crystals, 2 PL.

(I)

The invention relates to compounds that should be applied in the pharmaceutical industry as biologically active substances to obtain drugs.

Prior art

In European patent application 150586 closed 2-(pyridylmethyl-, respectively, sulfinil) benzimidazole, in which the pyridine part of the molecule in position 4, among others, can be substituted for alkylthio or killiecrankie. For embedded described patent application WIPO-89/03830 describes the same and similar in structure connections shall be suitable for the treatment of osteoporosis.

In international patent application WIPO -92/12976 describes a certain way of substituted 2-(pyridylmethyl-, respectively, sulfinil) benzimidazole, which should be effective against Helicobacter bacteria, and next to them revealed that they must be suitable for the prevention and treatment of several diseases of the stomach.

Description of the invention

The subject invention are compounds of formula I (see attached formula sheet), where

R1 denotes hydrogen, (C1-C4)-alkyl or (C1-C4-alkoxyl;

R2 denotes hydrogen, (C1-C4)-alkyl, (C1-C4-alkoxy, halogen, trifluoromethyl, completely or predominantly substituted by fluorine, (C1-C4-alkoxyl, chloroformate group, 2-chloro-1,1,2-triptoreline group or, together with R3, if desired, means wholly or partly replaced by fluorine (C1-C2)-alkylenedioxy or chlorotrifluorethylene-group;

R3 denotes hydrogen, completely or predominantly substituted by fluorine, (C1-C4-alkoxyl, chloroformate group, 2-chloro-1,1,2-tripterocalyx or chlorotrifluorethylene-group;

R4 denotes hydrogen, (C1-C4)-alkyl;

R5 denotes hydrogen, (C1-C4)-alkyl or (C1-C4- alkoxyl;

R6 represents substituted with R8 and R9 cycle or Bicycle, which selects from the group consisting of benzene, furan, thiophene, pyrrole, oxazole, isoxazol, thiazole, thiazoline, isothiazole, imidazole, imidazoline, pyrazole, triazole, tetrazole, thiadiazole, oxadiazole, pyridine, pyridine-N-oxide, pyrimidine, and benzimidazole;

R7 denotes hydrogen, (C1-C4)-alkyl or (C1-C4-alkoxyl;

R8 denotes hydrogen, (C1-C4)-alkyl, hydroxyl, (C1-C4-alkoxyl, halogen, nitro group, carboxyl, (C1-C4-alkoxycarbonyl, guanidino group substituted with R10 (C1-C4)-alkyl or-N(R11)R12;

R9 denotes hydrogen, (C1-C4)-alkyl, (C1-C4-alkoxy, fluorine or trifluoromethyl;

R10 denotes hydroxyl, (C1-C4-alkoxyl, carboxyl, (C1-C4-alkoxycarbonyl or-N(R11)R12, and

R11 denotes hydrogen, (C1-C4)-alkyl or-CO - R13, and

R12 denotes hydrogen or (C1-C4)-alkyl, or with

R11 and R12 together and with inclusion of the nitrogen atom to which both the>)-alkyl or (C1-C4-alkoxyl;

"m" denotes the number of 2 - 7;

"n" denotes the number 0 or 1;

"p" denotes the number 0 or 1 and

"q" denotes the number 0 or 1 and their salts;

(C1-C4)-alkyl denotes a linear or branched alkyl residues with 1-4 C-atoms. As an example, should be called boutigny, isobutylene, Deut. -boutigny, tert. -boutigny, sawn, ISO-propyl, ethyl and methyl residue.

(C1-C4-alkoxy represents a residue that, together with the oxygen atom contains one of the above (C1-C4)-alkyl residues. As an example, should be called methoxy -, ethoxy-balance.

Halogen within the meaning of the present invention is bromine, chlorine and fluorine.

As completely or predominantly substituted by fluorine, (C1-C4)-alkoxyl should be called, for example, 1,2,2-triptoreline-, 2,2,3,3,3-pentafluoropropane, perforators - and in particular the 1,1,2,2,-tetrafluoroethoxy, triptoreline-, 2,2,2-triptoreline and deformedarse-balance.

As wholly or partly replaced by fluorine (C1-C2)-alkylenedioxy group should, for example, to call methylendioxy- (-O-CH2-O-), Ethylenedioxy(F2-O-) and especially diversitronics-(-O-CF2-O-) balance.

If R2 and R3 optionally together represent wholly or partly replaced by fluorine (C1-C2)-alkylenedioxy or chlorotrifluorethylene-balance, the substituents R2 and R3 in adjacent positions, preferably in positions 5 and 6 is linked with the benzene part of the benzimidazole ring.

The group-S(O)qlinked to the carbon atom of the corresponding loop, respectively Bicycle R6, so that the residues R6, for example, should be called the remains of: phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 3-pyrrolyl, 2-oxazoline, 4-oxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 3-isothiazole, 2-imidazolyl, 3-pyrazolyl, 4-pyrazolyl, 1,2,3-triazole-4-yl, 1,2,5-thiadiazole-4-yl, 1,2,4-triazole-3-yl, tetrazol-5-yl, 1,3,4-thiadiazole-2-yl, 1,2,3-thiadiazole-4-yl, 1,3,4-oxadiazol-2-yl, 2-pyridyl, 4-pyridyl, 2-pyrimidinyl and 2-benzimidazolyl.

The substituents R8 and, if necessary, R9 in cycles, respectively, bicyclo R6 can be linked to any possible position. As, for example, substituted residues R6 should be called: 4-were 3-dimethylaminomethylphenol, 3-piperidinemethanol, 3-carboxymethyl, 2-dimethylaminomethyl-5-methyl-3-furyl, 1-metile is-yl, 1-methyl-imidazol-2-yl, 1-methyl-pyrazole-3-yl, 1-(2-dimethylaminoethyl)-pyrazole-3-yl, 5-methyl-1,3,4-oxadiazol-2-yl, 1-methyl-1,2,3-triazole-4-yl, 1-methyl-1,2,4-triazole-3-yl, 1-(2-dimethylaminoethyl)-1,2,3-triazole-4-yl, 1-methyl-tetrazol-5-yl, 1-(2-dimethylaminoethyl)-tetrazol-5-yl, 1-carboxymethyl-tetrazol-5-yl, 5-methyl-1,3,4-thiadiazole-2-yl, 5-trifluoromethyl-1,3,4-thiadiazol-2-yl, 1-(2-hydroxyethyl)-tetrazol-5-yl, 2-amino-1,3,4-thiadiazole-2-yl, 3-amino-1,2,4-triazole-5-yl, 4-methyl-5-trifluoromethyl-1,2,4-triazole-3-yl and 4-amino-pyrimidine-2-yl.

As residue-CmH2mthat are substituted with R6-S(O)q- take into account linear or branched residues. As an example, should be called Gately, isoheptyl (2-methyl-sexily), sexily, isohexyl (2-methyl-pentelenyi), neohexyl (2,2-dimethylbutyryl), pentelenyi, isopentyl (3-methyl-botilony), neopentyl (2,2-dimethylpropylene), boutigny, isobutylene, Deut.-boutigny, tert.-boutigny, sawn, ISO-propyl and ethyl residue. As, for example, residues R6-S(O)q-CmH2mshould be called:

phenylthiomethyl; phenylthiomethyl; paneltoplevel; phenylthiomethyl; 4-methyl-phenylthiomethyl; 4-methyl-phenylthiomethyl; 3-dimethylaminomethyl-phenyl-thioethyl; 3-dimetho-methyl-phenyl-dibutyl; 1-methyl-pyrrole-3-thioethyl; 4,5-dimethyloxazole-methyl-phenyl-dibutyl; 1-methyl-pyrrole-3-thioethyl; 4,5-dimethyloxazole-2-thiopropyl; 3,5-dimethyl-isoxazol-5-thioethyl; 3,5-dimethyl-isoxazol-5-thiopropyl; thiazol-2-thioethyl; thiazol-2-thiopropyl; thiazol-2-dibutyl; 4-methyl-5-carboxymethyl-thiazol-2-thiopropyl; 1-methyl-imidazol-2-thioethyl; 1-Mei-2-thiopropyl; 1-Mei-2-dibutyl; imidazol-2-thioethyl; imidazol-2-thiopropyl; pyrazole-3-thiopropyl; 1-(2-dimethylaminoethyl)-pyrazole-2-thioethyl; 1,3,4-oxadiazol-2-thioethyl; 1,3,4-oxadiazol-2-thiopropyl; 1,2,3-triazole-4-thioethyl; 1,2,3-triazole-thiopropyl; 1,2,3-triazole-4-dibutyl; 1-methyl-1,2,3-triazole-4-thioethyl; 1-methyl-1,2,3-triazole-4-thiopropyl; 1,2,3-triazole-4-thioethyl; 1,2,4-triazole-3-thiopropyl; 3-amino-1,2,4-triazole-5-thioethyl; 3-amino-1,2,4-triazole-5-thiopropyl; 4-methyl-5-trifluoromethyl-1,264-triazole-3-thioethyl; 4-methyl-5-trifluoromethyl-1,2,4-triazole-3-thiopropyl; 1-methyl-1,2,4-triazole-3-thioethyl; 1-methyl-1,2,4-triazole-3-thiopropyl; 1-methyl 1,2,4-triazole-3-dibutyl; tetrazol-5-thioethyl; tetrazol-5-thiopropyl; tetrazol-5-dibutyl; 1-methyl-tetrazol-5-thioethyl; 1-methyl-tetrazol-5-thiopropyl; 1-methyl-tetrazol-5-dibutyl; 1-(2-dimethylaminoethyl)-tetrazol-5-thioethyl; 1-(2-dimethylaminoethyl)-tetrazol-5-thiopropyl; 1-(2-hydroxyethyl)-tetrazol-5-thioethyl; 1-(2-hydroxyethyl)-tetrazol-2-thiopropyl; 5-methyl-1,3,4-thiadiazole-2-dibutyl; 5-trifluoromethyl-1,3,4-thiadiazole-2-thioethyl; 5-trifluoromethyl-1,3,4-thiadiazole-2-thiopropyl; 1,2,3-thia-diazol-4-thioethyl; 1,2,3-thiadiazole-4-thiopropyl; 1-carboxymethyl-tetrazol-5-thioethyl; 1-carboxymethyl-tetrazol-5-thiopropyl; 2-pyridyl-thioethyl; 2-pyridyl-thiopropyl; 2-pyridyl-dibutyl; 4-pyridyl-thioethyl; 4-pyridyl-thiopropyl; 4-pyridyl-dibutyl; 2-pyrimidine-thioethyl; 2-pyrimidine-thiopropyl; 2-pyrimidine-dibutyl; 4-amino-pyrimidine-2-thioethyl; 4-amino-pyrimidine-2-thiopropyl; 2-benzimidazole-thioethyl; 2-benzimidazole-thiopropyl; 4-methyl-thiazole-5-thioethyl; 4-methyl-thiazole-5-thiopropyl; 4-methyl-thiazole-5-dibutyl; 1-methoxycarbonylmethylene-5-thioethyl; 1-methoxycarbonylmethylene-5-thiopropyl; 1-methoxycarbonylmethylene-5-dibutyl; 5-nitroimidazol-1-thioethyl; 5-nitroimidazol-1-thiopropyl; 5-nitroimidazol-1-dibutyl; 2-methyl-5-nitroimidazol-1-thioethyl; 2-methyl-5-nitroimidazol-1-thiopropyl and 2-methyl-5-nitroimidazol-1-libutil.

As salts of the compounds of formula (I), where "n" denotes a number equal to zero, taking into account any salt accession acids. Special mention should be made of the pharmacologically acceptable salt is usually used in galenical industrial inorganic and organic kisloid according to the invention compounds on an industrial scale as technology products, using a well-known specialist methods translate into pharmacologically acceptable salts. As such suitable water-soluble and water-insoluble salt of joining acids, such as hydrochloric acid, bromatologia acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2-(4-hydroxybenzoyl) benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, albanova acid, stearic acid, toluensulfonate, methanesulfonate or 3-hydroxy-2-naphthoic acid, moreover, depending on whether it is about one - or polybasic acid and depending on which acid is desired, the acid upon receipt of salts used in equimolar or deviating from it proportions.

For compounds of formula (I), where "n" denotes a number equal to 1, as salts take into account also the salts with bases. As examples of basic salts should be mentioned salts of lithium, sodium, potassium, calcium, aluminum, magnesium, titanium, ammonium,canauxrama from him proportions.

Preferred compounds of formula (I) are those in which:

R1 denotes hydrogen;

R2 denotes hydrogen, halogen or methoxy group;

R3 represents hydrogen; R4 represents hydrogen;

R5 denotes hydrogen, (C1-C4)-alkyl or (C1-C4-alkoxyl;

R6 represents substituted with R8 and R9 cycle which are selected from the group consisting of benzene, isoxazol, thiazole, imidazole, triazole, tetrazole, thiadiazole, pyridine, pyridine-N-oxide, pyrimidine, and benzimidazole;

R7 denotes hydrogen or (C1-C4)-alkyl;

R8 denotes hydrogen, (C1-C4)-alkyl, hydroxyl, nitro, guanidino group, carboxyl, (C1-C4-alkoxycarbonyl substituted with R10 (C1-C4)-alkyl or amino group;

R9 denotes hydrogen or (C1-C4)-alkyl;

R10 denotes hydroxyl, carboxyl, (C1-C4-alkoxycarbonyl or-N(R11) R12, and

R11 denotes hydrogen, (C1-C4)-alkyl or-CO-R13; and

R12 denotes hydrogen or (C1-C4)-alkyl or with

R11 and R12 together and with inclusion of the nitrogen atom to which both are bound, represent piperidinyl the rest;

R13 denotes hydrogen, (C1-C "p" denotes the number 0, and

"q" denotes the number 0;

and their salts.

Especially preferred compounds of formula (I) are those in which

R1 denotes hydrogen;

R2 denotes hydrogen, fluorine or methoxy group;

R3 denotes hydrogen;

R4 denotes hydrogen;

R5 denotes (C1-C4)-alkyl or (C1-C4-alkoxyl;

R6 represents substituted with R8 and R9 cycle which are selected from the group consisting of benzene, thiazole, imidazole, triazole, tetrazole, thiadiazole, pyridine, pyrimidine, and benzimidazole;

R7 denotes hydrogen;

R8 denotes hydrogen, (C1-C4)-alkyl, hydroxyl, nitro, guanidino group, carboxyl, (C1-C4-alkoxycarbonyl or substituted with R10 methyl or ethyl;

R9 denotes hydrogen or (C1-C4)-alkyl;

R10 denotes hydroxyl, carboxyl or-N(R11)R12,

and

R11 denotes a (C1-C4)-alkyl and

R12 denotes a (C1-C4)-alkyl, or with

R11 and R12 together and with inclusion of the nitrogen atom to which both are bound, represent piperidinyl the rest;

"m" denotes the number of 2-4;

"n" means the number equal to 0;

"p" denotes a number equal to 0;

R1 denotes hydrogen;

R2 denotes hydrogen or fluorine;

R3 denotes hydrogen;

R4 denotes hydrogen;

R5 denotes (C1-C4)-alkyl or (C1-C4-alkoxyl;

R6 represents substituted with R8 and R9 cycle which are selected from the group consisting of benzene, thiazole, imidazole, triazole, tetrazole, thiadiazole, pyridine, pyrimidine, and benzimidazole;

R7 denotes hydrogen;

R8 denotes hydrogen, methyl, nitro group, (C1-C4-alkoxycarbonyl or substituted with R10 methyl or ethyl;

R9 denotes hydrogen;

R10 denotes hydroxyl, carboxyl or - N(R11)R12, and

R11 represents methyl and

R12 represents methyl, or with

R11 and R12 together and with inclusion of the nitrogen atom to which both are bound, represent piperidinyl the rest;

"m" denotes the number of 2-4;

"n" means the number equal to 0;

"p" denotes a number equal to 0;

"q" denotes a number of 0

and their salts.

Other especially preferred compounds of formula (I) are those in which

R1 denotes hydrogen;

R2 denotes hydrogen;

R3 denotes hydrogen;

R4 denotes hydrogen;

R5 denotes (C1is beraut from the group consisting of benzene, thiazole, imidazole, triazole, tetrazole, thiadiazole, pyridine, pyrimidine;

R7 denotes hydrogen;

R8 denotes hydrogen, methyl or substituted with R10 is methyl or ethyl;

R9 denotes hydrogen;

R10 denotes carboxyl or-N(R11) R12, and

R11 represents methyl;

R12 represents methyl;

"m" denotes the number of 2-4;

"n" means the number equal to 0;

"p" denotes a number equal to 0; and

"q" denotes a number of 0

and their salts.

Proposed according to the invention cited as examples of the compounds shown in Table 1 (at the end of the description), and the substituent R1 is in position 5, 6 respectively, and Deputy R2 is in position 6, 5 respectively (due to the tautomerism in the benzimidazole ring in case R4=H positions 5 and 6 do not differ).

Another object of the invention is a method of obtaining compounds of formula (I), where R1, R2, R3, and R4, R5, R6, R7, "m", "n", "p" and "q" have the above meanings, and their salts.

The method differs in that

a) mercaptobenzimidazole formula (II (see attached formula sheet), where R1, R2, R3 and R4 have the above values, enter into interaction with picolinate derived formulas is th fit the group that you want; or

b) the compounds of formula (IV) (see attached formula sheet), where R1, R2, R3, R4, R5, R7 and m have the above significance, "n" and "p" denote the number of 0, and Y represents a suitable a group to delete, enter into interaction with thiols R6 - SH; and (in the case of compounds of formula (I) with n=1, respectively, "p" = 1 and/or q= 1 represent the desired target products) is then obtained by PP (a) or (b) compounds with n = 0 and/or p = 0 and/or "o" = 0 oxidize;

and/or the compounds obtained, if desired, then transferred to salt;

and/or the salts, if desired, then transferred to a loose connection.

When the above interaction of the parent compound can be applied as such or, if necessary, in the form of their salts.

As deleted suitable groups X, respectively Y, for example, include halogen atoms, especially chlorine, or activated by esterification to complex ether (for example, using n-toluenesulfonic acid) hydroxyl group.

The interaction of the compounds of formula (II) with the compound of the formula (III) is carried out in a suitable, preferably polar proton or an aprotic solvent (such as methanol, ethanol, isopropanol, demetia do for example, in the presence of a proton acceptor. As such suitable hydroxides of alkaline metals such as sodium hydroxide; carbonates of alkali metals such as potassium carbonate; tertiary amines as pyridine, triethyl amines or ethyldiethanolamine. Alternatively, the interaction can also be achieved without the acceptor of protons, and - depending on the kind of source compounds, if necessary, first of all can stand salt accession acids in a particularly pure form. The reaction temperature may range 0-150oC, and in the presence of acceptors of protons preferred temperature in the range 20-80oC, and without acceptors of protons 60-120oC, in particular the boiling point of the used solvent. Reaction times are about 0.5-30 hours.

The interaction of compounds of the formula (IV) with thiols R6-SH carried out in a similar way as the interaction of compounds of the formula (II) with compounds of the formula (III).

The oxidation of the sulfide (compound of formula (I) with n=0) to sulfoxidov (the compounds of formula (I) with n = 1) is carried out in conditions that are known to the specialist for oxidation of sulfides to sulfoxidov (see this, for example, J. Drabowicz and M. Mikolajczyk, Organic preparations and proced who blackace, 1980). As oxidizing agents take into account all conventionally used for oxidation of sulfides to sulfoxidov reagents, especially nagkalat, as, for example, peracetic acid, CRYPTOMAGAZINE acid, 3,5-dinitro-adventia acid, nadalina acid, perceptual magnesium or preferably m-chloro-adventia acid.

The reaction temperature (depending on the reactivity of the oxidizing agent and the degree of dilution) is from -70oC to the boiling point of the employed solvent, preferably, however, -30oC to +20oC. also preferred is the oxidation with Halogens, respectively, using hypogalactia (for example, using an aqueous solution of sodium hypochlorite), which is expediently carried out at temperatures from 0 to 50oC. the Reaction should be better carried out in inert solvents such as aromatic or chlorinated hydrocarbons as benzene, toluene, dichloromethane or chloroform, preferably in a complex or simple esters as ethyl acetate, isopropylacetate or dioxane, or alcohols, preferably isopropanol.

Proposed according to the invention the sulfoxidov are say chirality. The invention therefore includes both enantiomers and diastereomers and their mixtures and racemates. Enantiomers itself in a known manner (for example by preparation and separation of the respective diastereoisomeric compounds) can be divided (see, for example, WIPO-92/08716).

The compounds of formula (II) are known, for example, of the WIPO-86/02646, European patent 134400 or European patent 127763. The compounds of formula (III) with p = 0, q = 0 can be obtained, for example, as described in the following examples.

To obtain compounds of the formula (III) with p = 1, respectively, q = 1, the corresponding 2-hydroxy-methyl-4-mercaptopyridine pyridine, for example, oxidized using m-chlormadinone acid to sulfoxidov and then glorious, for example, using thionyl chloride. Interaction with 2-mercaptobenzimidazole gives the compounds of formula (1) with p = 1 and q = 1.

Depending on the kind of substituents R6 sulfoxidov with q = 1 are also in the oxidation to sulfoxidov with "n" = 1. However, the corresponding sulfides, respectively sulfoxidov, can be obtained by selecting suitable starting compounds, respectively, due to the use of selective oxidants.

Necessary for for the breaking of compounds similar to J. Med. Chem. 14 (1971) 349.

The following examples explain more the invention without limiting its scope. Proposed according to the invention the connection and the source connection can be obtained in a similar way, as described in the examples.

EXAMPLES

Target products

1. 2-{ /[3-Methyl-4-(3-(5-methyl-1,3,4-thiadiazole-2-yl-thio)propylthio)-2-pyridinyl]methyl/thio}-1H-benzimidazole

To a solution of 5-methyl-1,3,4-thiadiazole-2-thiol (0.16 g; 1.2 mmol) in 10 ml of ethanol and 1.4 ml of 1N. the sodium hydroxide solution add 2-{/[4-(3-chlorpropyl)-3-methyl-2-pyridinyl] methyl/thio}-1H-benzimidazole (36 g, 1.0 mol) and refluxed for 20-30 hours. Was added dropwise 12 ml of H2O, leave to cool, filtered segregated solid, washed with water and dried in vacuum at 50oC. Gain of 0.38 g (83% of theory) of the target compound as colorless solids with so pl. 76-77oC.

2. 2-{ /[3-Methyl-4-(3-(4-methyl-1,2,3-triazole-3-yl-thio)propylthio)-2-pyridinyl]methyl/thio}-1H-benzimidazole

As specified in example 1 methods by reacting 4-methyl-1,2,4-triazole-3-thiol (0,19 g; 1.6 mmol) with 2-{/[4-(3-chlorine-propylthio)-3-methyl-2-pyridinyl] methyl/thio} -1H - benzimidazole (0.36 g, 1.0 mmol) and 1.7 mmol 1H. Rast is the art of ethyl acetate with diisopropyl ether obtain the target compound as colorless solids with so pl. 98-99oC (yield 58% of theory).

3. 2-{ /[3-Methyl-4-(3-(1-Mei-2-yl-thio)propylthio)-2-pyridinyl] methyl/thio}-1H-benzimidazole

According to this example 1 method, by reacting 2-mercapto-1-methylimidazole with 2-{ /[4-(3-chlorpropyl)-3 - methyl-2-pyridinyl] methyl/thio}-1H-benzimidazole and NaOH, after crystallization from ethyl acetate with diisopropyl ether obtain the target compound (68% of theory) as a colorless solid with so pl. 97-99oC.

4. 2-{/[4[3-(3-Amino-1,2,4-triazole-5-yl-thio)propylthio)-3 - methyl-2-pyridinyl]methyl/thio}-1H-benzimidazole

According to this example 1 method, by reacting 3-amino-5-mercapto-1,2,4-triazole with 2-{/[4-(3-chlorpropyl)-3-methyl-2 - pyridinyl] methyl/thio}-1H-benzimidazole and NaOH obtain the target compound (82% of theory) as a colorless solid with so pl. 94-96oC.

5. 2-{/[4[3-(5-Amino-1,3,4-thiadiazole - 2-yl-thio)propylthio]-3-methyl-2-pyridinyl]methyl/thio}-1H-benzimidazole

According to this example 1 method, by reacting 2-amino-5-mercapto-1,3,4-thiadiazole with 2-{/[4-(3- chlorpropyl)-3-methyl-2-pyridinyl] methyl/thio}-1H - benzimidazole and NaOH get the crude target compound in the form of oil. By dissolving in isoprop the rubbing with acetone obtain the target compound in the form of trihydrochloride; colorless solid; 105oC-gassing; above 240oC decomposition.

6. 2-{ /[4-(3-Imidazol-2-yl-thio-propylthio)-3-methyl-2 - pyridinyl] methyl/thio}-1H-benzimidazole

According to this example 1 method, by reacting 2-mercaptoimidazole with 2-{ /[4-(3- chlorpropyl)-3-methyl-2-pyridinyl]methyl/thio}-1H - benzimidazole and NaOH, after crystallization from a mixture of methanol with toluene obtain the target compound (62% of theory); colourless solid with so pl. 195oC (decomposition).

7. 2-{/[3-Methyl-4-(3-(3-1,2,4-triazole-3-yl-thio)propylthio)-2-pyridinyl] methyl/thio}-1H-benzimidazole

As specified in example 1 methods by means of interaction of 3-mercapto-1,2,4-triazole with 2-{ /[4-(3-chlorpropyl)-3-methyl-2-pyridinyl] methyl/thio} -1H - benzimidazole and NaOH, get the target connection (76% of theory); colourless solid with so pl. 80-82oC.

8.2-{ /[3-Methyl-4-(3-(1-methyl-tetrazol-5-yl-thio)propylthio)-2-pyridinyl] methyl/thio}-1H-benzimidazole

As specified in example 1 methods by means of interaction of 1 methyl-5-mercapto-tetrazole with 2-{ /[4-(3- chlorpropyl)-3-methyl-2-pyridinyl]methyl/thio} -1H - benzimidazole and NaOH obtain the target compound (68% of theory); colourless solid with so pl. 99-glasno specified in example 1, method by reacting 2 with mercaptothiazole 2-{ /[4-(3-chlorpropyl)-3 - methyl-2-pyridinyl]methyl/thio}-1H-benzimidazole and NaOH obtain the target compound (63% of theory); colourless solid with so pl. 121-123oC.

10. 2-{ /[3-Methyl-4-(3-(pyridin-2-yl-thio)propylthio)-2-pyridinyl] methyl/thio}-1H-benzimidazole

According to this example 1 method, by reacting 2 with mercaptopyridine 2-{ /[4-(3-chlorpropyl)-3-methyl-2-pyridinyl]methyl/thio}-1H-benzimidazole and NaOH obtain the target compound (87% of theory); colourless solid with so pl. 97-99oC.

11. 2-{/[3-Methyl-4-(3-(pyrimidine-2-yl-thio)propylthio)-2-pyridinyl]methyl/ thio}-1H-benzimidazole

According to this example 1 method, by reacting 2 with mercaptopyrimidine 2-{/[4-(3-chlorpropyl)-3-methyl-2-pyridinyl]methyl/thio}-1H-benzimidazole and NaOH obtain the target compound in the form of monohydrate (92% of theory); colourless solid with so pl. 118-119oC.

12. 2-{ /[4-/(3-the Benzimidazole-2-yl thio)propylthio/-3-methyl-2-pyridinyl] methyl/thio}-1H-benzimidazole

According to this example 1 method, by reacting 2 with mercaptobenzimidazole 2-{ /[4-(3-chlorpropyl)-3-methyl-2 - pyridinyl] methyl/thio} -1H-benzimidazole and NaOH receive the target is l-4-(3-phenylthio-propylthio)-2-pyridinyl] methyl/thio} -1H - benzimidazole

According to this example 1 method, by interaction with thiophenol 2-{/[4-(3-chlorpropyl)-3-methyl-2 - pyridinyl]methyl/thio}-1H-benzimidazole and NaOH obtain the target compound (95% of theory); colourless solid with so pl. 141-143oC.

14. 2-{/[3-Methyl-4-(3-(pyridine-1-oxo-2-yl-thio)propylthio)-2-pyridinyl] methyl/thio} -1H-benzimidazole-dihydrochloride

According to this example 1 method, by reacting 2-mercaptopyridine-N-oxide with 2-{/[4-(3- chlorpropyl)-3-methyl-2-pyridinyl]methyl/thio} -1H - benzimidazole and NaOH obtain the target compound in the form of a viscous oil. Extracted with dichloromethane, dried over potassium carbonate, fully concentrate (dry), the residue is dissolved in isopropanol, mixed with 3 equivalents of concentrated hydrochloric acid and distilled. The formed solid is filtered off and dried in vacuum over KOH. Get the target compound (66% of theory); colourless solid with so pl. 71-73oC (decomposition).

15. 2-{/[3-Methyl-4-(2-(pyridin-2-yl-thio)ethylthio)-2-pyridinyl] methyl/thio} -1H-benzimidazole

According to this example 1 method, by reacting 2-mercaptopyridine with 2-{/[4-(2- chloroethylthio)-3-methyl-2-pyridinyl/methyl/thio}-1H - benzimidazole and is) as colorless solids with so pl. 145-147oC.

16. 2-{ /[3-Methyl-4-(3-(4-methyl-pyrimidine-2-yl-thio)propylthio)- 2-pyridinyl]methyl/thio}-1H-benzimidazole

According to this example 1 method, by reacting 2-mercapto-4-methylpyrimidine, get the target connection; beige solid; T. pl. 70-72oC; yield = 77% of theory.

17. 2-{/[4/3-(1-(2-Dimethylaminoethyl)tetrazol-5-yl-thio)propylthio)-3 - methyl-2-pyridinyl]methyl/thio}-1H-benzimidazole-trihydrochloride

As described in examples 14 and 1 technique, by reacting 1-(2-dimethylamino)-2-mercaptotetrazole, get the target connection with so pl. 131-133oC (decomposition); yield = 40% of theory.

18. 2-{/[3-Methyl-4-(3-(1,3,4-thiadiazole-2-yl-thio)propylthio)-2-pyridinyl] methyl/thio}-1H-benzimidazole-trihydrochloride

As described in examples 14 and 1 technique, by reacting 2-mercapto-1,3,4-thiadiazole, get the target connection with so pl. 167-170oC; output is 53% of theory.

19. 2-{ /[3-Methyl-4-(3-(pyridin-4-yl-thio)propylthio)-2-pyridinyl] methyl/ thio}-1H-benzimidazol

As described in example 1 method, by reacting with 4-mercaptopyridine, get the target connection; colourless powder; so pl. 164-166; yield = 92% of theory.


As described in examples 14 and 1 methods by means of interaction 2-{ /[4-(3-chlorpropyl)-3-methoxy-2-pyridinyl] methyl/thio}-1H-benzimidazole with 1-methyl-5-mercaptotetrazole, get the target compound in the form of colorless kristalliset; so pl. 135oC (decomposition); yield 84% of theory.

21. 2-{/[3-Methoxy-4-(3-(pyrimidine-2-yl-thio)propylthio)-2-pyridinyl]methyl/ thio}-1H-benzimidazole

As described in example 1 method, by reacting 2-mercaptopyrimidine with 2-{/[4-(3-chlorpropyl)-3 methoxy-2-pyridinyl]methyl/thio} -1H-benzimidazole, get the target compound in the form of a beige powder; so pl. 88-90oC; yield = 77% of theory.

22. 5-{5-/2-(1H-Benzimidazole-2-yl-thiomethyl)-3-methyl-4 - pyridinyl/-1.5-dithia-Penta-1-yl}-tetrazol-1-sodium acetate

As described in example 1 method, by reacting 2-mercaptotetrazole-1-acetic acid, and sodium hydroxide solution, after precipitation with acetone and recrystallization from a mixture of methanol with diisopropyl ether, to obtain the target compound; beige powder; so pl.: starting from 180oC decomposition; yield = 34% of theory.

23. 2-{ /[3-Methyl-4-(2-(1-methyl-tetrazol-5-yl-thio)ethylthio)-2-pyridinyl] methyl/thio}-1H-benzimidazole

Sigmatel-2-pyridinyl/methyl/thio}-1H-benzimidazole and NaOH, get the target compound (82% of theory) as a colorless solid. So pl. 204-208oC.

24. 2-{/[3-Methyl-4-(4-(1-methyl-tetrazol-5-yl-thio)butylthio)-2-pyridinyl] methyl/thio} -1H-benzimidazole

According to this example 1 method, by reacting 1-methyl-5-mercaptotetrazole with 2-{ /[4-(4-chlorpropyl)-3-methyl-2-pyridinyl] methyl/thio} -1H-benzimidazole and NaOH, get the target connection (48% of theory) as a colorless solid. So pl. 208-210oC.

The source connection

And 1. 2-{/[4-(3-chlorpropyl)-3 methyl-2-pyridinyl]methyl/thio} -1H-benzimidazole

To a solution of 2-mercapto-1H-benzimidazole (1.5 g/10 mmol) in 40 ml of ethanol and 21 ml of 1N. the sodium hydroxide solution for 20 minutes at 40oC pin one equivalent of 2-chloromethyl-4-(3-chlorpropyl)-23-methylpyridin-hydrochloride (dissolved in 10 ml of water). Then stirred for 2-3 hours at 50-60oC and the following 3-4 hours at room temperature, distilled ethanol on a rotary evaporator (1 kPa/40oC), extracted 3 times with 20 ml dichloromethane, washed with 0.1 G. of sodium hydroxide solution, dried over potassium carbonate and concentrated in vacuo to dryness. For purification the crude product is chromatografic on siliciecation with toluene. Output: 2.67 g (74%) of target compound as colorless solids with so pl. 112-114oC.

And 2. 2-Chloromethyl-4-(3-chlorpropyl)-3-methylpyridine hydrochloride

a) 2,3-Dimethyl-4-(3-hydroxypropyl)pyridine-N-oxide

To 50 ml of anhydrous (dried) N-methylpyrrolidone (N) portions add 6 g (60%) NaH, stirred for 15 minutes, within 20 minutes add 9.5 g (0.11 mol) of 3-hydroxypropionate and again stirred for 30 minutes until gas evolution stops. Then within 20 minutes was added dropwise a solution of 14.4 g (0.1 mol) 4-chloro-2,3-dimethylpyridine-N-oxide in 100 ml NM, the reaction mixture is stirred for 1 hour at room temperature, then for 1 hour at 70oC and then for 1 hour at 100oC.

At the end of the interaction is allowed to cool, diluted with 500 ml of water and extracted 4 times with 300 ml of dichloromethane. The combined organic phases are washed with water, dried over magnesium sulfate and concentrated. Oily residue [10.0 g of crude 2,3-dimethyl-4-(3-hydroxypropyl)- pyridine-N-oxide] directly used in the next stage.

b) 2-Hydroxymethyl-4-(3-hydroxypropyl)-3-methyl-pyridine

Obtained in paragraph (a) of the yellow oil is dissolved in 100 ml in the first color oily residue is distilled in the apparatus for distillation, includes hose with ball extension, and enter into interaction without further purification.

The oily distillate in 100 ml of 2 n sodium hydroxide solution and 100 ml of isopropanol is refluxed with stirring for 2 hours. The isopropanol is distilled off, the residue is extracted with 3 times 100 ml of dichloromethane, the combined organic phases are washed with water, dried over potassium carbonate and concentrated in vacuo. Receive 5.0 g of 2-hydroxymethyl-4-(3-hydroxypropyl)-3-methylpyridine, which without treatment is injected into the interaction further.

a) 2-Chloromethyl-4-(3-chlorpropyl)-3-methyl-pyridine hydrochloride

5.0 g of the oil from example b) was dissolved in dichloromethane (100 ml) was added dropwise to the obtained solution of 4 equivalents of thionyl chloride and stirred for 20 hours at room temperature. Fully concentrate and obtain 4.5 g of target compound in the form of oily, gradually crystallising the residue, which is desirable in the case can also be applied in the form of a solution in ethanol directly for introduction into the interaction, if necessary, with substituted 2-mercaptobenzimidazole.

B 1. 2-{/[4-(2-Chloroethylthio)-3-methyl-2-pyridinyl]methyl/thio}-1H-benzimidazole

According to indicated the pyridine hydrochloride and NaOH, after crystallization from ethyl acetate, to obtain the target compound (62% of theory) as a colorless solid with so pl. 178-180oC.

B 2. 4-(2-Chloroethylthio)-2-chloromethyl-3-methylpyridine hydrochloride

a) 2,3-Dimethyl-4-(2-hydroxyethylthio)pyridine-N-oxide

According to that indicated in example 2.a) the method by reacting 4-chloro-2,3-dimethyl-pyridine-N-oxide with 2-mercaptoethanol and sodium hydride, to obtain the target compound in the form of an oily residue, which without further purification used in the next stage.

b) 4(2-hydroxyethylthio)-2-hydroxymethyl-3-methylpyridin

According to that indicated in example 2.b) the method by interaction obtained in paragraph (a) of the oil with acetic anhydride and subsequent saponification with NaOH, get the target compound in the form of an oily residue, which without further purification used in the next stage.

b) 4-(2-Chloroethylthio)-2-chloromethyl-3-methylpyridine hydrochloride

According to that indicated in example 2.C) the method by interaction obtained in paragraph (b) of the oil with thionyl chloride, to obtain the target compound in the form of an oily residue, which is in the form of a solution in ethanol is used directly for introduction into interaction with 2-mercapto specified in example A1 method by reacting 2-mercapto-1H-benzimidazole with 4-(4-chloroethylthio)-2-chloromethyl-3 - methyl-pyridine hydrochloride and NaOH, after crystallization and mixtures of ethyl acetate with diisopropyl ether, to obtain the target compound (82% of theory) in the form of slightly yellow solid with so pl. 151-153oC.

2. 4-(4-Chloroethylthio)-2-chloromethyl-3-methylpyridine hydrochloride

a) 2,3-Dimethyl-4-(4-hydroxyethylthio)pyridine-N-oxide

According to that indicated in example 2.a) the method by reacting 4-chloro-2,3-dimethyl-pyridine-N-oxide (4-mercaptoethanol and sodium hydride, to obtain the target compound in the form of an oily residue, which without further purification used in the next stage.

b) 4-(4-Hydroxyethylthio)-2-hydroxymethyl-3-methylpyridin

According to that indicated in example 2.b) the method by interaction obtained in paragraph (a) of the oil with acetic anhydride and subsequent saponification with NaOH, get the target compound in the form of an oily residue, which without further purification used in the next stage.

b) 4-(2-Chloroethylthio)-2-chloromethyl-3-methylpyridine hydrochloride

According to that indicated in example 2.C) the method by interaction obtained in paragraph (b) of the oil with thionyl chloride, for injection into an interaction with 2-mercaptobenzimidazole.

G1. 2-{/[4-(3-Chlorpropyl)-3-methoxy-2-pyridinyl]methyl/thio}- 1H-benzimidazole-dihydrochloride

2-Mercapto-1H-benzimidazole (10 g) and 2-chloromethyl-4-(3-chlorpropyl)-3-methoxypyridine hydrochloride (1 equivalent) in 150 ml of isopropanol and 15 ml of water is stirred for 5 hours at 80oC, cooled, filtered separated solid and recrystallized from a mixture of isopropanol with water. Get the target compound in the form of powder light brown; T. pl. 117-119oC (decomposition). Yield = 67% of theory.

G 2. 2-Chloromethyl-4-(3-chlorpropyl)-3-methoxy-pyridine hydrochloride

As described in example 2 a), b) and C) way of working, based on 4-chloro-3-methoxy-2-methylpyridine-N-oxide, obtain the target compound in the form of a slowly crystallizing oil, which is directly used further.

Industrial applicability

Excellent efficacy of compounds of formula (1) and their salts against Helicobacter bacteria allows their use in medicine as biologically active substances for the treatment of diseases which are based on the effect of Helicobacter bacteria.

Another object of the invention therefore is a method of treating mammals, particularly humans, which article is womam is administered a therapeutically effective and pharmacologically acceptable amount of one or more compounds of formula (1) and/or their pharmacologically acceptable salts.

The subject invention also include compounds of formula (I) and their pharmacologically acceptable salts for use in the treatment of diseases which are based on the effect of Helicobacter bacteria.

The invention also encompasses the use of compounds of formula (I) and their pharmacologically acceptable salts in the preparation of pharmaceuticals that are used to control such diseases, which are based on the effect of Helicobacter bacteria.

The next subject of the invention are drugs to combat Helicobacter-bacteria, which contain one or more compounds of General formula (I) and/or their pharmacologically acceptable salts.

From Helicobacter-strains, against which the compounds of formula (I) to be effective, should especially be mentioned the strain of Helicobacter pylori.

Medicines get itself known, affordable professional ways. As drugs pharmacologically active compounds of the formula (I) and their salts (=biologically active substances) are used either as such or preferably in combination with suitable pharmaceutical auxiliaries, for example, in the form of tasta preferably is 0.1 - 95%.

What excipients suitable for the desired formulations of medicines, known specialist on the basis of his expert knowledge. Besides solvents, gel-forming agents, auxiliary substances for the manufacture of tablets and other carriers of biologically active substances can be applied, for example, antioxidants, dispersants, emulsifiers, antispyware; substances corrective unpleasant taste, medicaments, preservatives, agents, dissolution, dyes or promoters permeability and complexing agents (e.g. cyclodextrins).

The biologically active substance can be entered, for example, parenteral (e.g. intravenous) or especially orally.

In General, in medicine biologically active substance is administered in a daily dose of about 0.2 to 50, preferably 1-30 mg/kg of body weight, if necessary in the form of several, preferably 2-6, single doses, to achieve the desired result.

In this regard, as significant according to the invention of aspect, especially need to mention that the compounds of formula (I), in which "n" represents the number of 0 in relation to Helicobacter-bacteria is La achieve sufficient for therapeutic purposes suppress excretion of acid gastric juice.

The compounds of formula (I), where "n" denotes a number equal to 1, along with its efficacy against Helicobacter bacteria also have a clear, overwhelming the acid secretion of gastric juice action. Accordingly, these compounds are used for the treatment of such diseases, which are based on the increased acid secretion of gastric juice.

Proposed according to the invention compounds can be administered in fixed or free combination with neutralizing the acid of the gastric juice and/or overwhelming secretion of gastric acid substance and/or substance suitable for classic fight against Helicobacter pylori.

As neutralizing the acid of the gastric juice substances, for example, should be called sodium bicarbonate or other antacid (aluminum hydroxide, magnesium aluminate or magaldrate). As suppressing the secretion of gastric acid substances should be called, for example, H2-blocking means (for example, cimetidine, ranitidine), H+/K+ATP - inhibitors (e.g., lansoprazole, omeprazole, or especially pantoprazole), as well as the so-called peripheral anticholinergics (for example, ernesti should be called antimicrobe/effective substances, as, for example, penicillin G, gentamicin, erythromycin, nitrofurazone, tinidazole, nitrofurantoin, furazolidone, metronidazole and especially amoxicillin, or, however, also salts of bismuth such as bismuth citrate.

Biological studies

The compounds of formula (I) are examined with respect to their activity (efficacy against Helicobacter pylori, the following described Tomoyuki Iwahi and others (Antimicrobial Agents and Chemotherapy, 1991, 490-496) method when using Columbia agar (oxide), and when the growth period of 4 days. For the studied compounds thus obtained are listed in the following table 2 approximate MIC 50 values (the numbers of connections coincide with the numbers of the compounds in the description).

1. Substituted ariliawitiers formula I

< / BR>
where R1, R2, R3, R4each denotes hydrogen;

R5denotes hydrogen, (C1-C4)alkyl or (C1-C4)alkoxyl;

R6denotes substituted with R8and R9the cycle which are selected from the group consisting of benzene, thiazole, imidazole, triazole, tetrazole, thiadiazole, pyridine, pyridine-N-oxide, pyrimidine and benzimidazole,

R7denotes hydrogen or (C1-C4)alkyl;
R>
R9denotes hydrogen or (C1-C4)alkyl; R10denotes carboxyl or-N(R11R12and R11denotes hydrogen or (C1-C4)alkyl and

R12denotes hydrogen or (C1-C4)alkyl,

m = 2 to 4; n = 0; p =0; q =0;

and their salts.

2. Ariliawitiers formula I under item 1, in which R5means (C1-C4)alkyl or (C1-C4)alkoxy, R6is substituted with R8and R9the cycle which are selected from the group consisting of benzene, thiazole, triazole, tetrazole, thiadiazole or pyridine, R7is hydrogen, R8is hydrogen, (C1-C4)alkyl or substituted with R10methyl or ethyl, R10- carboxyl or-N(R11R12and R11and R12each denotes a (C1-C4)alkyl, and m denotes the number 2 or 3, and their salts.

3. Ariliawitiers formula I under item 1, in which R5means (C1-C4)alkyl or (C1-C4)alkoxy, R6is substituted with R8and R9the cycle which are selected from the group consisting of benzene, thiazole, imidazole, triazole, tetrazole, thiadiazole, pyridine, pyrimidine and benzimidazole, R7is hydrogen, forces, or-N(R11R12and R11means (C1-C4)alkyl and R12means (C1-C4)alkyl, and their salts.

4. Ariliawitiers formula I under item 1, in which R5means (C1-C4)alkyl or (C1-C4)alkoxy, R6is substituted with R8and R9the cycle which are selected from the group consisting of benzene, thiazole, triazole, tetrazole, thiadiazole and pyridine, R7is hydrogen, R8is hydrogen, methyl or substituted with R10methyl or ethyl.

5. Ariliawitiers formula I under item 1, in which R5means (C1-C4)alkyl or (C1-C4)alkoxy, R6is substituted with R8and R9the cycle which are selected from the group consisting of benzene, thiazole, imidazole, triazole, tetrazole, thiadiazole, pyridine, pyrimidine and benzimidazole, R7is hydrogen, R8is hydrogen, methyl or substituted with R10methyl or ethyl, R9is hydrogen, R10- carboxyl or-N(R11R12and R11and R12each represents methyl, and their salts.

6. Ariliawitiers formula I under item 1, in which R5means (C1-C4)alkyl or (C1-C4) the ash, thiazole, imidazole, triazole, tetrazole, thiadiazole, pyridine, and pyrimidine; R7is hydrogen; R8is hydrogen, methyl or substituted with R10methyl or ethyl; R9is hydrogen; R10- carboxyl or-N(R11R12and R11and R12each represents methyl, and their salts.

7. The method of obtaining compounds of formula I on p. 1, where R1, R2, R3, R4, R5, R6, R7, m, n, p, q are specified in paragraph 1 values, and their salts, characterized in that mercaptobenzimidazole formula II

< / BR>
where R1, R2, R3and R4are specified in paragraph 1 values, enter into interaction with picolinafen derivative of the formula III:

< / BR>
where R5, R6, R7, m and q are specified in paragraph 1 values;

X denotes a suitable delete group

and/or the salts, if desired, transferred to a loose connection.

8. Drug to combat Helicobacter-bacteria containing the active substance and conventional additives, characterized in that the active substance using one or more compounds of the formula I under item 1 and/or their pharmacologically acceptable salt in an effective amount.

9. The compound of formula I is 2">

10. The method of obtaining medicines to combat Helicobacter-bacteria, characterized in that the take effective amount of the compounds of formula I and/or its pharmacologically acceptable salt and translate in herbal form.

 

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