Pyridylacetate to fight the bacteria helicobacter

 

(57) Abstract:

Describes compounds of formula I

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where the substituents and symbols are listed in the value formula designed to combat the bacteria Helicobacter. These new compounds are produced either by the coupling of compounds of formula II with the compound of the formula III, or the interaction of the compounds of formula IV with the compound of the formula V. the compounds optionally oxidized and/or transferred to salt and/or salt obtained was transferred to a loose connection. 6 C.p. f-crystals, 21 PL.

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H[[Y-CrH2r]t-[Z-CuH2u]v-R4 (V)

The technical field to which the invention relates

The invention relates to compounds intended for use in the pharmaceutical industry as active ingredients in the manufacture of medicines.

Description of the invention

The object of the present invention are the compounds of formula I (see attached sheet with formulas), where

R is hydrogen, C1-C4alkyl, halogen, trifluoromethyl, C1-C4alkoxycarbonyl, carboxy or cyan,

R1 means hydrogen or C1-C4alkyl,

R2 ASN is cocci or halogen,

R4 means a mono - or di-C1-C4allylcarbamate or thiocarbamoyl, N-C1-C4alkyl-N'-cyanamide, 1-N-C1-C4alkylamino-2-nitroethylene, N-2-PROPYNYL-N'-cyanamide, aminosulfonyl, the radical - N(R7)R8 or represents a substituted radicals R9 and R10 cycle or Bicycle selected from the group comprising benzene, naphthalene, furan, thiophene, pyrrole, oxazole, isoxazol, thiazole, thiazoline, isothiazol, imidazole, imidazoline, pyrazole, triazole, tetrazole, thiadiazole, thiadiazole-1-oxide, oxadiazole, pyridine, pyridine-N-oxide, pyrimidine, triazine, pyridone, benzimidazole, imidazopyridine, benzthiazole, benzoxazole and quinoline,

R5 means hydrogen, C1-C4alkyl, C1-C4alkoxy or halogen,

R6 means hydrogen or C1-C4alkyl,

R7 means C1-C7alkyl, C3-C7cycloalkyl or Ar-C1-C4alkyl and

R8 means C1-C7alkyl, C3-C7cycloalkyl or Ar-C1-C4alkyl and

where

Ar denotes phenyl, furyl, naphthyl, tetrahydronaphthyl or substituted by the radicals R11, R12 and R13 phenyl,

or

R7 and R8, together and including the nitrogen atom to which they are both linked, represent an unsubstituted or substituted 5 - and hydrochinon and 1,2,3,4-tetrahydroisoquinoline,

and

- substituted piperidino radical substituted by one, two or three identical or different substituents selected from the group comprising C1-C4alkyl, C1-C4alkoxycarbonyl, hydroxy-C1-C4alkyl, phenyl, substituted by the radicals R11, R12 and R13 phenyl, phenyl-C1-C4alkyl, benzoyl, substituted with halogen benzoyl and carboxy,

- substituted pieperazinove radical in position 2, 3, 5, or 6 may be substituted C1-C4alkyl radical, and in position 4 is substituted by one Deputy, selected from the group comprising C1-C4alkyl, C3-C7cycloalkyl, C3-C7cycloalkyl - C1-C4alkyl, C1-C4alkoxycarbonyl - C1-C4alkyl, carbarnoyl, -CpH(2p-2)-R14 and-CqH2q-R14,

- substituted morpholinyl radical substituted by one or two identical or different C1-C4alkyl radicals,

- substituted indolin-1 silt radical in position 2 and/or 3 may be substituted by a carboxyl group or two identical or different C1-C4alkyl radicals, and benzoic acid fragment may be substituted by one or two identical or different samecnierokvlevit radical substituted by one or two identical or different substituents, selected from the group comprising C1-C4alkyl and halogen,

- substituted 1,2,3,4-tetrahydroisoquinoline radical substituted by one or two identical or different substituents selected from the group comprising C1-C4alkyl, carboxy and phenyl,

R9 means hydrogen, C1-C4alkyl, hydroxy, C1-C4alkoxy, halogen, nitro, guanidino, carboxy, C1-C4alkoxycarbonyl, substituted radical R15 C1-C4alkyl or-N(R16)R17,

R10 denotes hydrogen, C1-C4alkyl, hydroxy, C1-C4alkoxy, halogen or trifluoromethyl,

R11 denotes hydrogen, C1-C4alkyl, hydroxy, C1-C4alkoxy, C1-C4alkylsulphonyl, halogen, C1-C4alkylamino or nitro,

R12 denotes hydrogen, C1-C4alkyl, hydroxy, C1-C4alkoxy, halogen or nitro and

R13 means hydrogen or trifluoromethyl,

R14 represents a substituted radicals R9 and R10 cycle or Bicycle selected from the group comprising benzene, naphthalene, furan, thiophene, pyrrole, oxazole, isoxazol, thiazole, thiazoline, isothiazol, imidazole, imidazoline, pyrazole, triazole, tetrazole, thiadiazole, oxadiazole, pyridine, pyridine-N-oxide, paramilitary or-N(R16)R17, where

R16 denotes hydrogen, C1-C4alkyl or-CO-R18 and

R17 denotes a hydrogen or C1-C4alkyl, or

R16 and R17 together and including the nitrogen atom to which they are both linked, represent piperidinyl or morpholinyl radical,

R18 denotes hydrogen, C1-C4alkyl or C1-C4alkoxy,

W stands for CH or N,

X represents O (oxygen), N-C1-C4alkyl or S,

Y represents O (oxygen), N-C1-C4alkyl, S, SO or SO2,

Z means O (oxygen), N-C1-C4alkyl, S, SO or SO2,

m means a number in the range from 1 to 7,

n represents the number 0, 1 or 2,

r means the number in the interval from 2 to 4,

t means the number 0 or 1,

u represents a number in the range from 0 to 4,

v means the number 0 or 1,

p is a number in the range from 2 to 4 and

q means the number in the interval from 0 to 4,

and their salts,

moreover, t and/or v does not represent the number 1, if m represents the number 1,

Z has no value SO or SO2if u mean the number 0, and

R4 does not represent-N(R7)R8, or linked through N (nitrogen atom) cycle or Bicycle, if Z denotes O, S, SO or SO2, v 1, and u is the number 0.

C1-C4alkyl represents pratcie radicals, as butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl.

Halogen in the context of the present invention represents a bromine, chlorine and fluorine.

C1-C4alkoxy is a radical containing along with the oxygen atom of one of the above C1-C4alkyl radicals. As examples metaxylene and ethoxyline radicals.

C1-C4alkoxycarbonyl represents a radical containing together with the carbonyl group of one of the above C1-C4CNS radicals. As examples of such can be called methoxycarbonyl and etoxycarbonyl.

Mono - or di-C1-C4alkylcarboxylic radicals are carbamoyl radicals (-CO-NH2), substituted by one or two identical or different C1-C4the alkyl radicals of the above. As examples of such radicals include methylcarbamoyl, isopropylcarbamate and dimethylcarbamoyl.

Mono - or di-C1-C4alkyldiethanolamine radicals are thiocarbamoyl radicals (-CS-NH2), substituted by one or two identical or realistically, isopropylaminocarbonyl and dimethylthiocarbamyl radicals.

As N-C1-C4alkyl-N'-cyaniding radical include, for example, primarily N-methyl-N'-tsunamigenesis radical [-C(=NCN)-NH-CH3].

As 1-N-C1-C4alkylamino-2-nitroethylene radical include, for example, primarily 1-N-methylamino-2-nitroethylene radical [-C(NHCH3)= CHNO2] , and the remains - NHCH3and-NO2may be in CIS - or TRANS-position relative to each other.

C1-C7alkyl represents remotemachine or branched alkyl radicals with 1 to 7 carbon atoms. As examples of the radicals: heptyl, isoheptyl (2-etylhexyl), hexyl, isohexyl (2-methylpentyl), neohexyl (2,2-dimethylbutyl), pentyl, isopentyl (3-methylbutyl), neopentyl (2,2-dimethylpropyl), butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl.

C3-C7cycloalkyl is cycloalkyl radicals having 3-7 carbon atoms, i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Ar-C1-C4alkyl represents one of the above, substituted Aryl radical and 1-naphthylmethyl.

Hydroxy-C1-C4alkyl represents one of the above C1-C4alkyl radicals, substituted by a hydroxy-group. As examples of such can be called hydroxymethyl, 2-hydroxyethyl or 3-hydroxypropyl.

C3-C7cycloalkyl-C1-C4alkyl represents one of the above C1-C4alkyl radicals, substituted by one of the above C3-C7cycloalkyl radicals. As examples of such can be called cyclopropylmethyl, cyclohexylmethyl and cyclohexylethyl.

C1-C4alkoxycarbonyl-C1-C4alkyl represents one of the above C1-C4alkyl radicals, substituted one of the above above C1-C4alkoxycarbonyl radicals. As an example of such can be called ethoxycarbonylmethyl.

As examples of substituted radicals R15 C1-C4the alkyl radicals can be called such as 2-methoxycarbonylethyl, 2-ethoxycarbonylethyl, methoxycarbonylmethyl, carboxymethyl, 2-hydroxyethyl, methoxymethyl, 2-methoxyethyl, dimethylaminoethyl and 2-dimethylaminoethyl.

C1-C4alkylsulphonyl of predstavleniya. As an example, can be called acetyl.

As the radical-CmH2m-, -CrH2r-, -CuH2uand CqH2qcan be considered remotemachine or branched radicals. As such it can be called, for example, heptylene, isoheptyl (2-methylhexane), hexylen, isohexane (2-methylpentane), neohexane (2,2-dimethylbutyl), pentile, isopentyl (3-methylbutyl), neopentyl (2,2-dimethylpropylene), butylene, isobutylene, sec-butylene, tert-butylene, propylene, isopropylene, ethylene and methylene.

As the radical-CmH2m- should be called preferably ethylene (-CH2CH2-), butylene (-CH2CH2CH2CH2- and primarily propylene (-CH2CH2CH2-) radicals.

As the radical-CrH2r- preferably include methylene, respectively, in another preferred embodiment, the r means the number 0, so that the notation CrH2rno, respectively, presented in the form of direct communication.

In another preferred embodiment, u is the number 0, so that the notation CuH2umissing is Ianto run t represents the number 1.

In another embodiment, the t represents the number 0, resulting in the designation Y-CrH2rmissing or presented in the form of direct communication.

In another preferred embodiment, the v means the number 0, resulting in the designation Z-CuH2uno, respectively, presented in the form of direct communication.

As the radical-CpH(2p-2)- should be called vinile, 2-butylen, 3-butylen and above all 1-propanole and 2-propanole.

As the radical-CqH2q- preferably include methylene, respectively, in another preferred embodiment, q means the number 0, so that the notation CqH2qno, respectively, presented in the form of direct communication.

The substituents R9 and R10 in cycles, respectively, bicyclo R4 may be connected in any possible position. As examples of substituted radicals R9 and R10 radicals R4 include the following: 4-were 3-dimethylaminomethylphenol, 3-piperidinemethanol, 3-carboxymethyl, 2-dimethylaminomethyl-5-methyl-3-furyl, 1-methylpyrrole-3-yl, 4,5-dimethyloxazole-2-yl, 3,5-dimethylisoxazol-4-yl, 4,5-dimethylthiazol-2-yl, 4-methyl-5-carboxym the-2-yl, 1-methyl-1,2,3-triazole-4-yl, 1-methyl-1,2,4-triazole-3-yl, 1-(2-dimethylamino-ethyl)-1,2,3-triazole-4-yl, 1-methyltetrazol-5-yl, 1-(2-dimethylaminoethyl)tetrazol-5-yl, 1-carboxylesterase-5-yl, 5-methyl-1,3,4-thiadiazole-2-yl, 5-trifluoromethyl-1,3,4-thiadiazole-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, 4-aminopyrimidine-2-yl, 3-methyl-2-furyl, 2-methyl-3-furyl, 5-methyl-2-furyl, 5-ethyl-2-furyl, 3-methoxy-2-furyl, 5-dimethylaminomethyl-2-furyl, 5-N-morpholinomethyl-2-furyl, 5-methoxymethyl-2-furyl, 5-hydroxymethyl-2-furyl, 5-N-piperidinomethyl-2-furyl, 5-chloro-2-furyl, 5-fluoro-2-furyl, 5-methyl-2-thienyl, 5-chloro-2-thienyl, 3-methyl-2-thienyl, 3-amino-2-thienyl, 3-guanidino-2-thienyl, 3-methoxy-2-thienyl, 2-methyl-3-thienyl, 5-dimethylaminomethyl-2-thienyl, 5-N-morpholinomethyl-2-thienyl, 5-methyl-2-pyrrolyl, 2,5-dimethyl-1-pyrrolyl, 1,5-dimethyl-2-pyrrolyl, 1-methyl-2-pyrrolyl, 2-amino-4-thiazolyl, 2-methyl-4-thiazolyl, 2-amino-5-methyl-4-thiazolyl, 4-methyl-5-thiazolyl, 2-dimethylaminomethyl-4-thiazolyl, 2-guanidino-4-thiazolyl, 2-formylamino-4-thiazolyl, 2-N-morpholinomethyl-4-thiazolyl, 4-methyl-5-oxazolyl, 3-guanidino-1-pyrazolyl, 3-guanidino-4-pyrazolyl, 2-methyl-4-imidazolyl, 5-methyl-4-imidazolyl, 2-methyl-1-imidazolyl, 2-methyl-5-nitro-1-imidazolyl, 4,5-dimethyl-2-imidazoline-3-methyl-2-pyridinyl and 3,4-dimethoxypyridine.

As examples of substituted radicals R11, R12 and R13 phenyl radicals include the following: 3,4-dihydroxy-, 3-hydroxy-4-methoxy-, 3,4-dimethoxy-, 2-methoxy-, 2-ethoxy-, 3-methoxy-, 4-methoxy-, 2-hydroxy, 3-hydroxy, 4-hydroxy-, 3,4-dihydroxy-, 4-acetyl, 4-fluoro-, 4-chloro-, 2-chloro-, 3-chloro-, 3,4-dichloro-, 3-trifluoromethyl-, 2-trifluoromethyl-, 2-methyl-, 3-methyl-, 4-methyl-, 2,3-dimethyl-, 2,4-dimethyl-, 3,4-dimethyl-, 2,5-dimethyl-, 4-nitro-, 2,6-dinitro-4-trifluoromethyl - 5-chloro-2-methylaminophenol.

As substituted piperidinovyh radicals include, for example, the following: 2-carboxypeptidase, 2-n-propylpiperidine, 5-ethyl-2-methylpiperidino, 4-hydroxymethyl-4-phenylpiperidine, 4-n-propylpiperidine, 4-(3-phenylpropyl)piperidine, 2,6-dimethylpiperidine, 4-phenyl-4-propylenecarbonate, 4-etoxycarbonyl-4-phenylpiperidine, 4-carboxy-4-phenylpiperidine, 4-carboxypeptidase, 4-(4-perbenzoic)piperidino, 4-(4-chlorbenzoyl)piperidine, 2,3-dicarboximide, 2,4-dicarboximide, 2,6-dicarboximide, 2-ethoxycarbonylpyrimidine, 2-methylpiperidino, 2,6-dimethylpiperidino, 2-hydroxyethylpiperazine, 2-ethylpiperidine, 2-(2-hydroxyethyl)piperidino, 3-ethoxycarbonylpyrimidine and 4-benzylpiperidine.

As substituted PIO, 4-(2,3-dimetilfenil)piperazine derivatives, 4-(2-chlorophenyl)piperazine derivatives, 4-(2-methoxyphenyl)piperazine derivatives, 4-(2-ethoxyphenyl)piperazine derivatives, 4-(3-chlorophenyl)piperazine derivatives, 4-(4-forfinal)piperazine derivatives, 4-(4-chlorophenyl)piperazine derivatives, 4-(4-methoxyphenyl)piperazine derivatives, 4-carbamoylbiphenyl, 3-methyl-4-(4-chlorophenyl)piperazine derivatives, 3-methyl-4-(4-methoxyphenyl)the piperazine derivatives, 3-methyl-4-(4-were)piperazine derivatives, 4-(2,4-dimetilfenil)piperazine derivatives, 4-(3,4-dichlorophenyl)piperazine derivatives, 4-(3,4-dimetilfenil)piperazine derivatives, 3-methyl-4-phenylpiperazine, 3-methyl-4-(3-chlorophenyl)piperazine derivatives, 4-benzylpiperazine, 4-propylpiperazine, 4-(3-were)piperazine derivatives, 4-(3-methoxyphenyl)piperazine derivatives, 4-(4-were)piperazine derivatives, 4-(2,5-dimetilfenil)piperazine derivatives, 4-cyclopropylbenzene, 4-cyclobutylamine, 4-cyclopentenopyridine, 4-cyclohexylpiperazine, 4-cycloheptylamine, 4-n-butylpiperazine, 4-isobutylpyrazine, 4-tert-butylpiperazine, 4-(1-phenylethyl)piperazine derivatives, 4-ethoxycarbonylmethylene, 4-(2-phenylethyl)piperazine derivatives, 4-(2-cyclohexylethyl)piperazine derivatives, 4-(2-hydroxyphenyl)piperazine derivatives, 4-(3,4-acid), piperazine derivatives, 4-isopropylpiperazine, 3-methyl-4-(3-methoxyphenyl)piperazine derivatives, 4-(4-hydroxyphenyl)piperazine derivatives, 3-methyl-4-(3-were)piperazine derivatives, 4-(3-hydroxyphenyl)piperazine derivatives, 4-(2,6-dinitro-4-triptoreline)piperazine derivatives, 4-(4-nil)ethyl]piperazine derivatives.

As an example, substituted morpholino radical can be called, in particular, 3,5-dimethylmorpholine.

As of substituted indolin-1 silt radicals include, for example, the following: 2-carboxy-1-indolinyl, 6-fluoro-1-indolinyl, 5-bromo-1-indolinyl, 2,7-dimethyl-1-indolinyl, 2-methyl-1-indolinyl, 5-bromo-7-nitro-1-indolinyl, 5-nitro-1-indolinyl, 2,3-dimethyl-1-indolinyl and 6-nitro-1-indolinyl.

As substituted 1,2,3,4-tetrahydroquinoline radical include, for example, 2-etoxycarbonyl-1,2,3,4-tetrahydro-1-chinoline, 2-methyl-1,2,3,4-tetrahydro-1-chinoline, 6-methyl-1,2,3,4-tetrahydro-1-chinoline, 6-fluoro-2-methyl-1,2,3,4-tetrahydro-1-chinoline, 4-methyl-1,2,3,4-tetrahydro-1-chinoline and 2-fluoro-6-methyl-1,2,3,4-tetrahydro-1-chinoline.

As substituted 1,2,3,4-tetrahydroisoquinoline radical include, for example, 3-carboxy-1,2,3,4-tetrahydro-2-ethenolysis.

Salts of compounds of formula I in which n represents the number 0, you can include all the acid additive salt. Among these one should mention first of all pharmacologically acceptable salts of inorganic and organic acids commonly used in Galenika. Pharmacologically unacceptable salts formed as pervonachalnym scale, using methods known to the person skilled in the art can be converted into pharmacologically acceptable salts. As such suitable water-soluble and water-insoluble acid additive salts with such acids, such as hydrochloric acid, Hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-Glukhova 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 acid, methansulfonate acid or 3-hydroxy-2-naphthoic acid, and upon receipt of salts, depending on use, whether one - or polybasic acid, and a salt is required to obtain the acid used in equimolar or in some other proportion.

As salts of the compounds of formula I in which n represents the number 1 or 2, and/or compounds with a carboxyl group can be considered also salts with bases. As examples of such basic soia, moreover, in these cases, upon receipt of salts applied Foundation in equimolar or in some other proportion.

Among the compounds of formula I should highlight those that

R is hydrogen, C1-C4alkyl or halogen,

R1 means hydrogen,

R2 means hydrogen or C1-C4alkyl,

R3 means hydrogen, C1-C4alkyl, C1-C4alkoxy or halogen,

R4 means a mono - or di-C1-C4alkylthiomethyl, the radical-N(R7)R8 or represents a substituted radicals R9 and R10 cycle or Bicycle selected from the group comprising benzene, naphthalene, furan, thiophene, pyrrole, oxazole, isoxazol, thiazole, thiazoline, isothiazol, imidazole, imidazoline, pyrazole, triazole, tetrazole, thiadiazole, thiadiazole-1-oxide, oxadiazole, pyridine, pyridine-N-oxide, pyrimidine, triazine, pyridone, benzimidazole, imidazopyridine, benzthiazole, benzoxazole and quinoline,

R5 means hydrogen or C1-C4alkyl,

R6 means hydrogen or C1-C4alkyl,

R7 means C1-C4alkyl and

R8 means Ar-C1-C4alkyl,

where

Ar denotes phenyl, furyl, naphthyl, tetrahydronaphthyl or substituted by the radicals R11, R12 and R13 phenyl,

and

- substituted piperidino radical substituted by one, two or three identical or different substituents selected from the group comprising C1-C4alkyl, phenyl, substituted by the radicals R11, R12 and R13 phenyl and phenyl-C1-C4alkyl,

- substituted pieperazinove radical in position 4 is substituted by one Deputy, selected from the group comprising C1-C4alkyl, C1-C4alkoxycarbonyl-C1-C4alkyl, -CpH(2p-2)-R14 and-CqH2q-R14,

- substituted 1,2,3,4-tetrahydroquinoline radical substituted by one or two identical or different substituents selected from the group comprising C1-C4alkyl and halogen,

- substituted 1,2,3,4-tetrahydroisoquinoline radical substituted by one or two identical or different substituents selected from the group comprising C1-C4alkyl, carboxy and phenyl,

R9 means hydrogen, C1-C4alkyl, halogen, nitro, carboxy, C1-C4alkoxycarbonyl or substituted radical R15 C1-C4alkyl,

R10 denotes hydrogen or C1-C4
R12 denotes hydrogen, C1-C4alkyl, hydroxy, or C1-C4alkoxy,

R13 means hydrogen,

R14 represents a substituted radicals R9 and R10 cycle or Bicycle selected from the group comprising benzene, naphthalene, furan, thiophene, pyrrole, oxazole, isoxazol, thiazole, thiazoline, isothiazol, imidazole, imidazoline, pyrazole, triazole, tetrazole, thiadiazole, oxadiazole, pyridine, pyridine-N-oxide, pyrimidine, benzimidazole and quinoline,

R15 means carboxy, C1-C4alkoxycarbonyl or-N(R16)R17, where

R16 denotes hydrogen or C1-C4alkyl and

R17 means C1-C4alkyl or

R16 and R17 together and including the nitrogen atom to which they are both linked, represent piperidinyl or morpholinyl radical,

W stands for CH or N,

X represents O (oxygen), N-C1-C4alkyl or S,

Z means O (oxygen), N-C1-C4alkyl, S or SO2,

m means a number in the range from 1 to 6,

n represents the number 0,

t means the number 0,

u represents a number in the range from 0 to 4,

v means the number 0 or 1,

p is a number in the range from 2 to 4 and

q means the number in the interval from 0 to 2,

and their salts,

and

v means the number 1, if the focus of a N(R7)R8, or linked through N (nitrogen) cycle or Bicycle, if Z denotes O, S or SO2v means the number 1, and u represents the number 0.

Among the compounds of formula I should highlight any, in which

R means hydrogen or C1-C4alkyl,

R1 means hydrogen,

R2 means hydrogen,

R3 means hydrogen, C1-C4alkyl, C1-C4alkoxy or halogen,

R4 is a mono - or di-C1-C4alkylthiomethyl, the radical-N(R7)R8 or substituted by the radicals R9 and R10 cycle or Bicycle selected from the group comprising benzene, furan, thiophene, thiazole, isothiazol, imidazole, triazole, tetrazole, thiadiazole, pyridine, pyrimidine, benzimidazole and quinoline,

R5 means hydrogen,

R6 means hydrogen or C1-C4alkyl,

R7 means C1-C4alkyl and

R8 means Ar-C1-C4alkyl,

where

Ar denotes phenyl,

or

R7 and R8, together and including the nitrogen atom to which they are linked, represent an unsubstituted or substituted 5 - or 6-membered hetero(bi)cycle selected from the group comprising piperidine, piperazine and 1,2,3,4-tetrahydroisoquinoline,

and

- substituted piperidino radical substituted by one, two or three of the phenyl-C1-C4alkyl,

- substituted pieperazinove radical in position 4 is substituted by one Deputy, selected from the group comprising C1-C4alkyl, C1-C4alkoxycarbonyl-C1-C4alkyl, -CpH(2p-2)-R14 and-CqH2q-R14,

- substituted 1,2,3,4-tetrahydroisoquinoline radical substituted by one or two identical or different substituents selected from the group comprising C1-C4alkyl and carboxy,

R9 means hydrogen, C1-C4alkyl, halogen, nitro, carboxy, C1-C4alkoxycarbonyl or substituted radical R15 C1-C4alkyl,

R10 denotes hydrogen or C1-C4alkyl,

R14 represents a substituted radicals R9 and R10 cycle or Bicycle selected from the group comprising benzene, furan, thiophene, thiazole, isothiazol, imidazole, triazole, tetrazole, thiadiazole, pyridine, pyrimidine, benzimidazole and quinoline,

R15 means carboxy, C1-C4alkoxycarbonyl or-N(R16)R17, where

R16 means C1-C4alkyl and

R17 means C1-C4alkyl, or

R16 and R17 together and including the nitrogen atom to which they are both linked, represent piperidinyl or morpholinyl radical,

W oslislo 0,

t means the number 0,

u represents a number in the interval from 0 to 2,

v means the number 0 or 1,

p is a number in the range from 2 to 4 and

q means the number in the interval from 0 to 2,

and their salts,

and

v means the number 1, if m represents the number 1,

and

R4 does not represent-N(R7)R8, or linked through N (nitrogen atom) cycle or Bicycle, if Z denotes S, v means the number 1, and u represents the number 0.

The most preferred compounds of formula I are those in which

R means hydrogen,

R1 means hydrogen,

R2 means hydrogen,

R3 means hydrogen, C1-C4alkyl or C1-C4alkoxy,

R4 is a CI-C1-C4alkylthiomethyl, the radical-N(R7)R8 or substituted by the radicals R9 and R10 cycle or Bicycle selected from the group comprising benzene, furan, thiophene, thiazole, imidazole, tetrazole, pyridine and benzimidazole,

R5 means hydrogen,

R6 means hydrogen or C1-C4alkyl,

R7 and R8, together and including the nitrogen atom to which they are both linked, represent unsubstituted or substituted pieperazinove or 1,2,3,4-tetrahydroisoquinoline radical,

and

- substituted pieperazinove BR> R9 means hydrogen, C1-C4alkyl, halogen, nitro, carboxy, C1-C4alkoxycarbonyl or substituted radical R15 C1-C4alkyl,

R10 denotes hydrogen or C1-C4alkyl,

R14 represents a substituted radicals R9 and R10 cycle selected from the group comprising benzene and thiophene,

R15 means carboxy,

W stands for CH or N,

X represents S,

Z means S,

m means a number in the range from 1 to 3,

n represents the number 0,

t means the number 0,

u means the number 0, 1 or 2,

v means the number 0 or 1,

p means the number 3 and

q means the number 0 or 1,

and their salts,

and

v means the number 1, if m represents the number 1,

and

R4 does not represent - N(R7)R8, or linked through N (nitrogen atom) cycle or Bicycle, if Z denotes S, v means the number 1, and u represents the number 0.

A modification of the invention (option a) are such connections, respectively, such preferred, particularly preferred and most preferred compounds of formula I in which t represents the number 0, and v means the number 0, as well as their salts.

Another modification of the invention (option b) are such compounds that matched the where t represents the number 0, v means the number 1, and u represents the number 0, as well as their salts.

Another modification of the invention (modification) are such connections, respectively, such preferred, particularly preferred and most preferred compounds of formula I in which t represents the number 0, v means the number 1, and u represents the number 1 or 2, and their salts.

The most preferred compounds according to the invention are presented in tables (see below).

Table 21-40

In these tables presents the compounds of formula I (see attached sheet with formulas), identical specified in tables 1-20, however, with the difference that the pyridine ring is attached in position 4.

Presented in tables 1-40 compounds also include salts of these compounds.

Another object of the invention is a method of obtaining compounds of formula I and their salts.

The method differs in that

a) mercaptoethane formula II (see attached sheet with formulas), where R and W have the above meanings, is subjected to the interaction with derivatives of pyridine of formula III (see attached sheet with formulas), where R1, R2, R3, R4, R5, R6, X, Y, Z, m, r, t, u and v have the above values, and A representation is and), where W, R, R1, R2, R3, R5, R6, X, m and n have the above meanings and A represents an appropriate leaving group, is subjected to the interaction with compounds of formula V (see the attached sheet with formulas), where R4, Y, Z, r, t, u and v have the above values, and

(if the compounds of formula I with n equal to 1 or 2 and/or Y to indicate SO or SO2and/or Z, to indicate SO or SO2are the desired end products), then the obtained compound with n equal to 0 and/or Y, indicating S, and/or Z, meaning S, oxidize and/or the compounds obtained, if necessary, transferred to salt and/or the salts, if necessary, transferred to the free connection.

When carrying out the above reactions starting compound can be used either as such or optionally in the form of their salts.

As appropriate leaving group A can be mentioned, for example, halogen atoms, especially chlorine, or activated by esterification (for example, p-toluensulfonate acid) hydroxyl group.

The interaction of compounds of the formula II with compounds of the formula III is carried out in suitable for this purpose, preferably proton polar or aprotic solvents (such to the water or anhydrous conditions. This reaction is carried out, for example, in the presence of a proton acceptor, optionally with the addition of catalytic amounts of iodide such as sodium iodide. As acceptors of protons suitable hydroxides of alkali metals such as sodium hydroxide, carbonates of alkali metals such as potassium carbonate, or tertiary amines, such as pyridine, triethylamine or ethyldiethanolamine. An alternative to this reaction can be carried out and no acceptor of protons, and depending on the type of source connections, you first may not necessarily be allocated acid additive salt in a particularly pure form. The reaction temperature may be in the range from 0 to 150oC, and in the presence of a proton acceptor preferred temperature range is from 20 to 80oC, and in the absence of acceptors of protons from 60 to 120oC first preferred boiling point of the employed solvent. The reaction time is from 0.5 to 30 hours

The interaction of compounds of the formula IV with compounds of the formula V is carried out by the method similar to when carrying out the reaction between compounds of formula II and compounds of formula III or an alternative to this, [for example, the interaction of compounds IV with the using excess amine as an acceptor of protons and simultaneously as solvent. The reaction temperature in this case is in the range from 60 to 180oC, preferably from 80 to 160oC.

Oxidation of sulfides to sulfoxidov, respectively, to sulfones carried out under conditions known to the expert at carrying out oxidation of sulfides to sulfoxidov, respectively, to sulfones [see, for example, J. Drabowicz and M. Mikolajczyk, Organic preparations and procedures int. 14 (1-2), 45-89 (1982) or E. Block in S. Patai, The Chemistry of Functional Groups, Supplement E. part 1, page 539-608, John. Wiley and Sons (Interscience Publication), 1980] . As oxidants can be used all reagents, usually used for oxidation of sulfides to sulfoxidov, respectively, to sulfones.

The sulfoxidov according to the invention are optically active compounds. Depending on the type of substituents in the molecule may also have other chiral centers. In accordance with this invention includes both enantiomers and diastereomers and their mixtures and racemates. Enantiomers can be separated by known methods (for example, obtaining and sharing their diastereoisomeric connections).

The initial compounds of formulas II, III, IV and V are known or can be obtained by known methods, for example, just as this is ichiwa its volume. Proposed according to the invention compounds as starting compound can be obtained according to methods similar to those described in the examples. Abbreviations mean: CT = temperature, h = h, tPL= melting point, decomp. = decomposition.

Examples

The final products

1. 4-(2-fullerto)-3-methyl-2-[(2-pyridylthio)methyl]pyridine

To a solution of 2-mercaptopyridine (1.12 g/10 mmol) in 40 ml of ethanol and 21 ml of 1N sodium hydroxide for 20 min at 40oC added dropwise 1 equivalent (2,92 g) of the hydrochloride of 2-chloromethyl-4-(2-fullerto)-3-methylpyridine (dissolved in 10 ml of water). Then stirred for 2-3 h at 50-60oC and continue stirring for 3-4 hours at room temperature. Next is sucked off from the precipitated precipitated solids are removed by mixing with aqueous ethanol (1:1) and dried under vacuum. The result is indicated in the title compound in the form of a powder ochre; tPL102-104oC; yield 91% of theory.

2. 4 benzylthio-3-methyl-2-[(2-pyridylthio)methyl]pyridine

According to the method described in example 1, the interaction of 2-mercaptopyridine hydrochloride 4-benzylthio-2-chloromethyl-3-methylpyridine get mentioned in the title is)methyl] pyridine

According to the method described in example 1, the interaction of 2-mercaptopyridine hydrochloride with 2-chloromethyl-4-[2-(4-methyl-5 - thiazolyl)ethylthio]-3-methylpyridine get mentioned in the title compound as a yellow oil. Then extracted with dichloromethane, washed with water, dried over calcium carbonate and concentrated. By crystallization from diisopropyl ether get mentioned in the title compound; tPL67-69oC.

4. The dihydrochloride of 4-(2-fullerto)-3-methoxy-2-[(2 - pyridylthio)methyl]pyridine

According to the method described in example 1, the interaction of 2-mercaptopyridine hydrochloride with 2-chloromethyl-4-(2-fullerto)-3 - methoxypyridine receives a yellow oil. Then extracted with dichloromethane, concentrated, the residue is dissolved in isopropanol and add concentrated hydrochloric acid (2.5 equivalent). Then re-concentrated and crystallized by adding acetone specified in the title compound, which is obtained as colorless solids; tPL148oC (decomposition); yield 74% of theory.

5. 3-methyl-4-[5-(1-methyl-5-tetrazolyl)-1,5-datapanel] -2-[(2 - pyridinylmethyl]pyridine

The dihydrochloride of 4-(3-chlorpropyl)-3-methyl-2-[(2 - pyridylthio)methyl]pyrazolo (2.0 mmole) in ethanol (15 ml) for 24 h at 80oC. and Then slowly added dropwise water, allow to cool to 25oC and filtered off from precipitated in the sludge solids. After drying over P2O5get listed in the title compound in the form of solid light beige; tPL113-114oC; yield 78% of theory.

6. 3-methyl-4-[5-(4-pyridinyl)-1,5-datapanel] -2-[(2 - pyridylthio)methyl]pyridine

According to the method described in example 5, the interaction of the dihydrochloride of 4-(3-chlorpropyl)-3-methyl-2-[(2-pyridylthio)methyl]pyridine with 4-mercaptopyridine and caustic soda receive specified in the header of the connection; tPL99-102oC; yield 67% of theory.

7. Hydrochloric salt of 4-[3-(4-benzyl-1-piperazinil)propylthio]- 3-methyl-2-[(2-pyridylthio)methyl]pyridine

The dihydrochloride of 4-(3-chlorpropyl)-3-methyl-2-[(2 - pyridylthio)methyl] pyridine (0,59 g, 1.5 mmole) are stirred in acetonitrile (10 ml) while adding potassium carbonate (7.5 mmol) and catalytic amounts of sodium iodide with benzylpiperazine (2.0 mmole) for 24 h at 100oC. After adding water, extracted with dichloromethane (2x10 ml), the combined organic extracts washed with water, dried, concentrated and the crude product (yellow oil) chrome who live with 3.5 equivalents of concentrated hydrochloric acid. Then filtered off from precipitated in the sludge solids, washed with diisopropyl ether and dried. This way, get listed in the title compound as colourless crystals; tPL170-172oC; yield 81% of theory.

8. Hydrochloric salt of 3-methyl-4-[3-(4-phenyl-1 - piperazinil)propylthio]-2-[(2-pyridylthio)methyl]pyridine

According to the method described in example 7, the interaction of the dihydrochloride of 4-(3-chlorpropyl)-3-methyl-2-[(2-pyridylthio)methyl]pyridine with 1-phenylpiperazine and potassium carbonate receive specified in the header of the connection; tPL137-140oC (decomposition); yield 46% of theory.

9. 3-methyl-4-[3-(1,2,3,4-tetrahydroisoquinoline-2-yl)propylthio] - 2-[(2-pyridylthio)methyl]pyridine

According to the method described in example 7, the interaction of the dihydrochloride of 4-(3-chlorpropyl)-3-methyl-2-[(2-pyridylthio)methyl]pyridine with 1,2,3,4-tetrahydroisoquinoline and potassium carbonate receive specified in the header of the connection; tPLhygroscopic; above 58oC decomposition; yield 46% of theory.

10. Hydrochloric salt of 3-methyl-4-{ 3-[4-(3-(phenyl-2-propen - 1-yl)piperazine-1-yl]propylthio}-2-[(2-pyridylthio)methyl]pyridine

According to the method described in example 7, the interaction Digi specified in the header of the connection; tPL205-206oC (decomposition); yield 69% of theory.

11. 4-(2-fullerto)-3-methyl-2-[(4-pyridylthio)methyl]pyridine

According to the method described in example 1, the interaction of 4-mercaptopyridine hydrochloride with 2-chloromethyl-4-(2-fullerto)-3-methylpyridine and sodium hydroxide, followed by chromatography on silica gel (ethyl acetate-ethanol) and crystallization from diisopropyl ether get mentioned in the title compound as a colourless powder; tPL126-128oC; yield 89% of theory.

12. 3-methyl-4-[5-(1-methyl-5-tetrazolyl)-1,5-datapanel] -2-[(4 - pyridylthio)methyl]pyridine

According to the method described in example 5, the interaction of 4-(3-chlorpropyl)-3-methyl-2-[(4-pyridylthio)methyl] pyridine with 5-mercapto-1-methyltetrazole and caustic soda receive specified in the title compound in the form of powder beige; tPL95-97oC (decomposition); yield 59% of theory.

13. 4- [3-(4-benzyl-1-piperazinil)propylthio]-3-methyl-2-[(4 - pyridylthio)methyl]pyridine

According to the method described in example 7, the interaction of 4-(3-chlorpropyl)-3-methyl-2-[(4-pyridylthio)methyl] pyridine with 1-benzylpiperazine and potassium carbonate in acetonitrile after chromatography on silica gel and crystallization conc the aqueous solids; tPL79-81oC; yield 57% of theory. Of isopropanol can be obtained aqueous hydrochloride; tPL165oC (decomposition); yield 87% of theory.

14. 3-methyl-2-[(4-pyridylthio)methyl] -4-[5-(4-pyridinyl)-1,5 - datapanel]pyridine

According to the method described in example 5, the interaction of 4-(3-chlorpropyl)-3-methyl-2-[(4-pyridylthio)methyl]pyridine with 4-mercaptopyridine and caustic soda receive specified in the header of the connection; tPL116-118oC; yield 69% of theory.

15. 4-[(3-dimethyldithiocarbamic)propylthio] -3-methyl-2-[(4 - pyridylthio)methyl]pyridine

4-(3-chlorpropyl)-3-methyl-2-[(4-pyridylthio)methyl] pyridine (2 mmole) is stirred with Na-salt dimethyldithiocarbamic acid (Me2NCS2Na) (2.5 mmole) in 25 ml of ethanol for 20 h at 60oC, then cooled and filtered from the resulting solids. This way, get listed in the title compound as a light grey crystalline powder; tPL112-114oC; change color; yield 88% of theory.

16. 4-[3-(4-phenyl-1-piperazinil)propylthio] -2-[(4 - pyridylthio)methyl] pyridine

According to the method described in example 7, the interaction of 4-(3-chlorpropyl)-3-methyl-2-[(4-pyridylthio)methyl] pyridine is isopropylalcohol ether get mentioned in the title compound; tPLfrom 210oC and above (decomposition); yield 79% of theory.

17. 4-[3-(1-imidazolyl)propylthio] -3-methyl-2-[(4 - pyridylthio)methyl] pyridine

According to the method described in example 7, the interaction of 4-(3-chlorpropyl)-3-methyl-2-[(4-pyridylthio)methyl]pyridine with imidazole (2.0 equivalents) and potassium carbonate and subsequent chromatography on silica gel (dichloromethane-acetone-water NH3after crystallization from diisopropyl ether get mentioned in the title compound; tPL117-119oC; yield 32% of theory.

18. 3-methyl-4-[3-(1,2,3,4-tetrahydroisoquinoline-1-yl)propylthio]- 2-[(4-pyridylthio)methyl]pyridine

According to the method described in example 7, the interaction of 4-(3-chlorpropyl)-3-methyl-2-[(4-pyridylthio)methyl] pyridine with 1,2,3,4-tetrahydroisoquinoline, chromatography on silica gel followed by crystallization from isopropanol-diisopropyl ether get mentioned in the title compound; tPL190-192oC; yield 36% of theory.

19. Trihydrochloride 4-{3-[4-(5-chloro-2-thienylmethyl)-1 - piperazinil]propylthio)-3-methyl-2-[(4-pyridylthio)methyl]pyridine

According to the method described in example 7, the interaction of 4-(3-chlorpropyl)-3-methyl-2-[(4-pyridylthio)methyl] pyridine with [1-(5-chlorothiophenol acid get mentioned in the title compound; tPL160-162oC (decomposition); yield 79% of theory.

20. 2-[[[3-methyl-2-[(4-pyridylthio)methyl] -4 - pyridinyl]thiopropyl]thio] -1H-benzimidazole

According to the method described in example 5, the interaction of 4-(3-chlorpropyl)-3-methyl-2-[(4-pyridylthio)methyl] pyridine with 2-mercaptobenzimidazole in the presence of caustic soda after crystallization from dichloromethane-diisopropyl ether get mentioned in the title compound; tPL128-129oC; yield 83% of theory.

21. 4-[[5-(2-ethoxycarbonylphenyl)-1,5-ticipant-1-yl] -3-methyl] - 2-[(4-pyridylthio)methyl]pyridine

4-(3-chlorpropyl)-3-methyl-2-[(4-pyridylthio)methyl] pyridine (2 mmole) is stirred while adding potassium carbonate (10 mmol) with methyl ether 2-mercaptobenzoic acid (2.2 mmole) for 48 h at 25oC in methanol (10 ml), diluted with water, filtered from the precipitated precipitated solids are removed by mixing with aqueous methanol. After drying receive specified in the title compound in the form of powder beige; tPL85-88oC; yield 72% of theory.

22. 3-methyl-4-[3-(2-methyl-5-nitroimidazol-1-yl)propylthio]- 2-[(4-pyridylthio)methyl]pyridine

According to the method described in example 7, from 4-(3-chloropropylamine on silica gel (ethyl acetate-methanol-concentrated ammonia) and crystallization from diisopropyl ether get mentioned in the title compound as a yellow powder; tPL140-142oC; yield 70% of theory.

23. 3-methyl-4-(7-(phenyl-1,5-ditigal-1-yl)-2-[(4 - pyridylthio)methyl] pyridine

According to the method described in example 5, the interaction of 4-(3-chlorpropyl)-3-methyl-2-[(4-pyridylthio)methyl] pyridine with 2-fenilatilmalonamid after chromatography on silica gel and crystallization from diisopropyl ether get mentioned in the title compound as a colourless powder; tPL48-50oC; yield 49% of theory.

24. 4-[6-(5-chlorothiophene-2-yl)-1,5-citiaens-1-yl] -3-methyl-2-[(4 - pyridylthio)methyl]pyridine

According to the method described in example 5, the interaction of 4-(3-chlorpropyl)-3-methyl-2-[(4-pyridylthio)methyl] pyridine with 5-chlorothiophene-2-mercaptan after chromatography on silica gel (ethyl acetate-concentrated ammonia, 100:1) and subsequent crystallization from diisopropyl ether get mentioned in the title compound as a colourless powder; tPL76-77oC; yield 58% of theory.

25. 2-{5-[3-methyl-2-[(4-pyridylthio)methyl]-4-pyridinyl]-1,5 - datapanel}pyridine-3-carboxylic acid

According to the method described in example 21, the interaction of 4-(3-chlorpropyl)-3-methyl-2-[(4-pyridylthio)methyl] pyridine with 2-mercaptonicotinic acid and the latter is a solid substance; tPL219oC (decomposition); yield 57% of theory.

26. Single fumarate 6-methyl-4-[5-(4-pyridinyl)-1,5 - datapanel]-2-[(4-pyridylthio)methyl]pyridine

As described in example 5, the method of interaction dihydrochloride 4-(3-chlorpropyl)-6-methyl-2-[(4-dipyridine)methyl] pyridine with 4-mercaptopyridine and caustic soda after chromatography of the crude product on silica gel (solvent system: acetic ether-methanol-ammonia = 40:1:1) and subsequent crystallization of 1.5 equivalents of fumaric acid from acetone receive specified in the title compound (yield 27% of theory) with tPL150-152oC.

27. Difumarat 4-[3-(4-benzyl-1-piperazinil)propylthio]-6-methyl - 2-[(4-pyridylthio)methyl]pyridine

As described in example 7 the method of interaction dihydrochloride 4-(3-chlorpropyl)-6-methyl-2-[(4-dipyridine)methyl] pyridine with 1-benzylpiperazine, sodium iodide and potassium carbonate in acetonitrile after chromatography of the crude product on silica gel (solvent system: acetic ether - methanol-ammonia = 19:1:1) and subsequent crystallization using two equivalents of fumaric acid from acetone receive specified in the title compound (yield 14% of theory) with tPL171-173oC.

Besando in example 7 the method of interaction dihydrochloride 4-(3-chlorpropyl)-6-methyl-2-[(4-dipyridine)methyl] pyridine with 1-[(5-chlorothiophene-2-yl)methyl] piperazine, the sodium iodide and potassium carbonate in acetonitrile after chromatography of the crude product on silica gel (solvent system: acetic ether-methanol-ammonia = 19:1:1) and subsequent crystallization using two equivalents of fumaric acid from acetone receive specified in the title compound (38% of theory) with tPL148-151oC.

29. The dihydrochloride of 4-[[7-(2-methyl-5-nitroimidazol-1-yl)-1,5 - ditigal-1-yl]-3-methyl]-2-[(4-pyridylthio)methyl]pyridine

According to the method described in example 5, the interaction with 1-(2-mercaptoethyl)-2-methyl-5-nitroimidazole at 25oC after chromatography of the crude product on silica gel and transfer to the hydrochloric salt in acetone-hydrochloric acid get hygroscopic compound indicated in the heading; tPL73-78oC (decomposition); yield 39% of theory.

30. 5-{5-[3-methyl-2-[(4-pyridylthio)methyl]-4-pyridinyl]-1,5 - dicament-1-yl}tetrazol-1-acetic acid

According to the method described in examples 25 and 21 receive specified in the header of the connection; tPL185-187oC; yield 57% of theory.

31. Trihydrochloride 4-[3-(4-benzyl-1-piperazinil)propylthio]-3 - methyl-2-[(2-pyrimidinyl)methyl]pyridine

On the basis of the dihydrochloride of 4-(3-chlorpropyl)-3-methyl-2-[(2 - what are specified in the header of the connection; tPL208oC (decomposition); yield 49% of theory.

32. 3-methyl-4-[3-(2-methyl-5-nitroimidazol-1-yl)propylthio]-2-[(2 - pyrimidinyl)methyl]pyridine

According to the method described in example 22, from 4-(3-chlorpropyl)-3-methyl-2-[(2-pyrimidinyl)methyl] pyridine, get mentioned in the title compound; tPL141-143oC; yield 81% of theory.

33. 3-methyl-4-{[7-(2-methyl-5-nitroimidazol-1-yl)-1,5-ditigal - 1-yl]-3-methyl}-2-[(2-pyrimidinyl)methyl]pyridine

According to the method described in example 5 starting from 4-(3-chlorpropyl)-3-methyl-2-[(2-pyrimidinyl)methyl] pyridine, get mentioned in the title compound as a yellow oil, which when crushed in diethyl ether crystallizes. After filtration and drying over paraffin receive specified in the title compound as a pale yellow solid; tPL83-85oC; yield 62% of theory.

The source connection

A1. The dihydrochloride of 4-(3-chlorpropyl)-3-methyl-2-[(2 - pyridylthio)methyl] pyridine

2-mercaptopyridine (10 mmol) and the hydrochloride of 2-chloromethyl-4-(3-chlorpropyl)-3-methylpyridine (10 mmol) is heated in isopropanol (25 ml) for 4-6 h to a boil. After cooling, is filtered off from precipitated precipitated solid vedennogo the title compound as a colourless solid; tPL112-114oC (decomposition).

A2. Hydrochloride of 2-chloromethyl-4-(3-chlorpropyl)-3-methylpyridine

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

To 50 ml of dry N-methylpyrrolidone (MP) portions add 6 g (60-percent) NaH, stirred for 15 min, for 20 min add 9.5 g (of 0.11 mole) of 3-hydroxypropionate and again stirred for 30 min until the completion of gas evolution. Then within 20 minutes added dropwise a solution of 14.4 g (0.1 mol) of N-oxide of 4-chloro-2,3-dimethylpyridine 100 ml MP, the reaction mixture was stirred for 1 h at RT, after which stirring is continued for 1 h at 70oC and for 1 h at 100oC.

After the completion of the exchange reaction is allowed to cool down, diluted with 500 ml of water and extracted four times with portions of 300 ml of dichloromethane, respectively. The combined organic extracts washed with water, dried over magnesium sulfate, concentrated and crystallized from toluene. After recrystallization from methanol-toluene receive specified in the title compound in the form of solid beige color with tPL106-107oC (lyophilized); yield 68% of theory.

b) 2-hydroxymethyl-4-(3-hydroxypropyl)-3-methylpyridin
100oC. After concentration under vacuum, the brown oily residue is distilled in a tubular ball extension distillation apparatus and used without purification in the subsequent reaction stage.

The oily distillate is heated in 100 ml of 2N sodium hydroxide and 100 ml of isopropanol for 2 h under stirring to a temperature of reflux distilled, then the isopropanol is distilled off, the residue is shaken out three times with 100 ml dichloromethane, respectively, the combined organic extracts washed with water, dried over potassium carbonate and concentrated under vacuum. In this way receive 5.0 g of 2-hydroxymethyl-4-(3-hydroxypropyl)-3-methylpyridine, which is used without purification in the subsequent reaction stage.

From isopropanol using concentrated hydrochloric acid you can get monohydrochloride the connection specified in the header; tPL188-190oC (decomposition).

b) Hydrochloride of 2-chloromethyl-4-(3-chlorpropyl)-3-methylpyridine

5 g of the oil from b) is dissolved in dichloromethane (100 ml), then added dropwise to 4 equivalents of thionyl chloride and stirred for 20 h at RT. Then fully concentrate, resulting in the 4.5 g specified in the header connection is profilepage ether get mentioned in the title compound as a colourless solid; tPL142-144oC (decomposition).

A3. 4-(3-chlorpropyl)-3-methyl-2-[(4-pyridylthio)methyl]pyridine

According to the method described in example A1, the interaction of 4-mercaptopyridine hydrochloride with 2-chloromethyl-4-(3-chlorpropyl)-3-methylpyridine in isopropanol receive hydrochloride is indicated in the title compound as a colourless solid. After dissolution in water establish a pH of 10, twice extracted with dichloromethane, the organic extracts washed with sodium carbonate solution, dried over magnesium sulfate, the solvent was concentrated using a rotary evaporator and crystallized from dichloromethane-diisopropyl ether. This way, get listed in the title compound as a colourless solid; yield 78% of theory; tPL88-91oC.

B1. The hydrochloride of 4-(2-chloroethylthio)-2-chloromethyl-3-methylpyridine

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

According to the method described in example A2.a) interaction of the N-oxide of 4-chloro-2,3-dimethylpyridine with 2-mercaptoethanol and sodium hydride get mentioned in the title compound as an oily residue, which without further purification used at a later stage.

b) 4-(2-is received in a) oil with acetic anhydride and subsequent saponification with NaOH get mentioned in the title compound as an oily residue, which without further purification used at a later stage.

b) Hydrochloride of 4-(2-chloroethylthio)-2-chloromethyl-3-methylpyridine

According to the method described in example A2.in), the interaction obtained in b) oil with thionyl chloride receive specified in the title compound in the form of an oily residue, which is in the form of a solution in ethanol directly used for interaction with 2-mercaptobenzimidazole.

B1. Hydrochloride of 2-chloromethyl-4-(3-chlorpropyl)-3-methoxypyridine

According to the method described in example A2.a)-C), starting from 4-chloro-3-methoxy-2-methylpyridine, engaging first 3-hydroxypropionate, then with acetic anhydride, caustic soda and thionyl chloride receive specified in the title compound as a yellow slowly crystallizing oil, which was directly used for interaction with mercaptopyridine.

G1. The dihydrochloride of 3-chloro-4-[N-(2-chloroethyl)-N-methylamino]-2-[(2 - pyridylthio)methyl]pyridine

According to the method described in example A1, the interaction of the hydrochloride of 3-chloro-4-[N-(2-chloroethyl)-N-methylamino]-2-chlormethyl 4-mercaptopyridine (1 equivalent) in isopropanol receive specified in the header of the connection is drochloric 3-chloro-4-[N-(2-chloroethyl)-N-methylamino-2 - chloromethylpyridine

a) 3-chloro-4-[N-(2-hydroxyethyl)-N-methylamino]-2-hydroxymethylpropane

A mixture of 3,4-dichloro-2-hydroxymethylpropane (Journ. Med. Chem. 1989, 32, 1970) (2.5 g) in 2-methylaminoethanol (30 ml) is heated in a steel autoclave for 2.5 h to 160oC, the excess amine is removed under vacuum and the resulting residue chromatographic on silica gel (dichloromethane-methanol 95:5). Output 2.3 g in the form of a yellowish oil.

b) Hydrochloride of 3-chloro-4-[N-(2-chloroethyl)-N-methylamino] -2 - chloromethylpyridine

A solution of 3-chloro-4-[N-(2-hydroxyethyl)-N-methylamino] -2 - hydroxymethylpropane (2.3 g) in dichloromethane (30 ml) is mixed at 0oC dropwise with a solution of thionyl chloride (4 ml) in dichloromethane (20 ml). Then the temperature is allowed to rise to 20oC (20 min), after which the temperature for 30 min support at the level of the 40oC. After removal of the solvent under vacuum, the resulting residue chromatographic on silica gel (petroleum ether-ethyl acetate mixture 7: 3, containing 1 ml of concentrated aqueous solution of NH3). The output of 2.6 g

1. The dihydrochloride of 4-(3-chlorpropyl)-6-methyl-2-[(4 - dipyridine)methyl] pyridine

4-mercaptopyridine (10.9 mmol) and the hydrochloride of 2-chloromethyl-4-(3-chlorpropyl)-6-methylpyridine (10.9 mmol) is heated in isochronous to dryness and then chromatographic on silica gel (solvent system: acetic ether-methanol-ammonia = 19:1:1). Fractions with Rf= 0,3 concentrate, dissolve in a small amount of acetone and mixed with 2 equivalents of concentrated hydrochloric acid. The residue is sucked off and dried under vacuum. In this way receive 3,55 g (82% of theory) specified in the connection header in the form of a solid beige; tPL194-197oC.

2. Hydrochloride of 2-chloromethyl-4-(3-chlorpropyl)-6-methylpyridine

a) N-oxide 2,6-dimethyl-4-(3-hydroxypropyl)pyridine

To 50 ml of dry N-methylpyrrolidone (MP) portions add 12 g (60%) NaH. Then stirred for 10 min within 30 min add 19 g (0,22 mole) 3-hydroxypropionate and continue stirring until complete selection of gas for 30 minutes Then added dropwise within 30 minutes, add a solution of 28.8 g (0.2 mole) of N-oxide of 4-chloro-2,6-dimethylpyridine in 150 ml of MP, the reaction mixture was stirred for 1 h at RT, then continue stirring for 1 h at 70oC and for a further 1 h at 100 C. After the completion of the exchange reaction is allowed to cool down, diluted with 700 ml of water and extracted first four portions of 300 ml of dichloromethane, respectively, and then another four times portions of 300 ml of dichloromethane-n-butanol (10:1), respectively. Obednoe the title compound is isolated in the form of a solid beige color with tPL117-119oC. Yield of 59% of theory.

b) 2-hydroxymethyl-4-(3-hydroxypropyl)-6-methylpyridin

Obtained in (a) the product is dissolved in 100 ml of acetanhydride and stirred for 2 h at 100oC. After concentration under vacuum, the brown oily residue is distilled in a tubular ball extension distillation apparatus and without further purification used at a later stage.

The oily distillate within 2 hours heated with 100 ml of 2N sodium hydroxide and 100 ml of isopropanol under reflux. Then the isopropanol is distilled off and the residue is extracted four times with 100 ml dichloromethane and four times with 100 ml of a mixture of dichloromethane-n-butanol (10:1). The combined organic extracts washed with water, dried over potassium carbonate and concentrated under vacuum. In this way gain of 4.2 g specified in the connection header in the form of oil, which without further purification used at a later stage.

After chromatography on silica gel (solvent system: acetic ether-methanol = 10: 1) and subsequent crystallization from diisopropyl ether specified in the title compound is isolated in crystalline form; tPL94-96oC.

1H-NMR (DMSO-D6, ppm million): 7,88 (d, 1H), to 7.77 (d, 1H), 5,00 (s, 2H), 3,79 (t, 2H), 3,40 (t, 2H), 2,70 (s, 3H), and 2.14 (m, 2H).

E1. 4-(3-chlorpropyl)-3-methyl-2-[(2-pyrimidinyl)methyl]pyridine

According to the method described in example A3, the interaction with 2-mercaptopyrimidine get mentioned in the title compound; tPL83-85oC; colorless powder; yield 73% of theory.

Industrial applicability

The exceptionally high efficiency of the compounds of formula I and their salts in relation to the bacteria Helicobacter allows them to be used in medicine as active substances for the treatment of diseases, pathogens are bacteria Helicobacter.

Another object of the invention accordingly is a method of treating mammals, especially humans, suffering from diseases caused by the bacteria Helicobacter. The method differs in that ill patient is administered a therapeutically effective and pharmacologically acceptable number is this invention, also, are the compounds of formula I and their pharmacologically acceptable salts for use in the treatment of diseases, pathogens are bacteria Helicobacter.

The invention also includes the use of compounds of the formula I and their pharmacologically acceptable salts in the manufacture of medicines designed to fight disease that is caused by the bacteria Helicobacter.

Another subject of the invention are drugs to fight bacteria Helicobacter containing one or more compounds of General formula I and/or their pharmacologically acceptable salts.

From strains of bacteria Helicobacter, against which the compounds of formula I are highly effective and should be called just before the strain of Helicobacter pylori.

Medications manufactured using known, conventional to a person skilled in the art methods. As drugs pharmacologically effective compounds of formula I and their salts (which are the active ingredients) used either individually or preferably in combination with appropriate pharmaceutical excipients, for example, in the form of Tatianna is from 0.1 to 95%.

What excipients required for drug combinations to choose, to decide the specialist on the basis of their knowledge and experience. Along with solvents, geleobrazovanie, excipients for tablets and other carriers of active substances can also be used, for example, antioxidants, dispersants, emulsifiers, antispyware, korrigentami taste, preservatives, agents, solubility, dyes, or promoters, improving permeability, and complexing agents (in particular, cyclodextrins).

The active substances may be administered, for example, for parenteral (especially intravenous) or primarily for oral administration.

As a rule, in medicine to achieve the desired effect of the active ingredients is administered in a daily dosage of about 0.2 to 50, preferably 1-30 mg/kg of body weight, if necessary, dividing the daily dose into several, preferably 2-6, single doses.

In this regard as essential for the present invention of the aspect should be emphasized that the compounds of formula I in which n represents the number 0, show their effectiveness against the bacteria Helicobacter when the introduction is to assign to suppress secretion of gastric acid.

The compounds of formula I in which n represents the number 1, along with effectiveness against the bacteria Helicobacter also have a pronounced inhibitory action on secretion of gastric acid. In accordance with the above-mentioned compounds can also be used for the treatment of diseases caused by increased secretion of gastric acid.

Proposed according to the invention compounds can also be designated for the introduction of a strict or free combination together with the substance, neutralizing gastric acid and/or suppressing secretion of gastric acid, and/or substance used in traditional methods of fighting bacteria Helicobacter pylori.

As substances to neutralize stomach acid include, for example, sodium bicarbonate or other antacids such as aluminum hydroxide, magnesium aluminate or magaldrate. As substances inhibiting the secretion of gastric acid, can be called, for example, H2a-blocker (in particular, cimetidine, ranitidine), inhibitors of H+/K+-ATP-ases (in particular, lansoprazole, omeprazole, or primarily pantoprazole), as well as the so-called peripheral antialising how to fight with the bacteria Helicobacter pylori, you should call first those that have antimicrobial action, as, for example, penicillin G, gentamicin, erythromycin, nitrofurazone, tinidazole, nitrofurantoin, furazolidone, metronidazole, and primarily amoxillin, or also salts of bismuth such as bismuth citrate.

Biological studies

The compounds of formula I were tested for their efficacy against the bacteria Helicobacter pylori according to the method described Tomoyuki Iwahi and others in Antimicrobial Agents and Chemotherapy, 1991, 490-496, using Columbia agar (oxoid) and a growth period of 4 days. During studies of these compounds were identified approximate values MICK-50, shown in table A (see end of description) (the numbers of the compounds correspond to the numbers of examples in the description).

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H[Y-CrH2r]t-[Z-CuH2u]v-R4 (V)

1. Pyridostigmine General formula I

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where R is hydrogen or C1- C4alkyl;

R1 is hydrogen;

R2 is hydrogen;

R3 is hydrogen, C1- C4alkyl, C1- C4alkoxy or halogen;

R4 is a mono - or di-C1- C4alkylthiomethyl, the radical-N(R7)R8 or substituted imidazol, triazole, tetrazole, thiadiazole, pyridine, pyrimidine, benzimidazole and quinoline;

R5 is hydrogen;

R6 is hydrogen or C1- C4alkyl;

R7 - C1- C7alkyl;

R8 - Ar-C1- C4alkyl, where Ar denotes phenyl,

or R7 and R8 together and including the nitrogen atom to which they are linked, represent an unsubstituted or substituted 5 - or 6-membered hetero(bi)cycle selected from the group comprising piperidine, piperazine and 1,2,3,4-tetrahydroisoquinoline,

and substituted piperidino radical substituted by one, two or three identical or different substituents selected from the group comprising FROM1- C4alkyl, phenyl and phenyl-C1- C4alkyl, substituted pieperazinove radical in position 4 is substituted by one Deputy, selected from the group comprising FROM1- C4alkyl, C1- C4alkoxycarbonyl-C1- C4alkyl, -CpN(2P-2) - R14-sqH2q- R14, substituted 1,2,3,4-tetrahydroisoquinoline radical substituted by one or two identical or different substituents selected from the group comprising FROM1- C4alkyl and carboxy,

R9 is hydrogen, C1- C4alkyl, halogen, nitro, carboxy, C1- C4alkyl;

R14 represents a substituted radicals R9 and R10 cycle or Bicycle selected from the group comprising benzene, furan, thiophene, thiazole, isothiazol, imidazole, triazole, tetrazole, thiadiazole, pyridine, pyrimidine, benzimidazole and quinoline;

R15 is carboxy, WITH1- C4alkoxycarbonyl or-N(R16)R17 where R16 - C1- C4alkyl and R17 means1- C4alkyl,

or

R16 and R17 together and including the nitrogen atom to which they are both linked, represent piperidinyl or morpholinyl radical;

W is CH or N;

X - S;

Z - S;

m means a number in the range from 1 to 5;

n represents the number 0;

t means the number 0;

u represents a number in the interval from 0 to 2;

v means the number 0 or 1;

R means the number in the interval from 2 to 4;

q means the number in the interval from 0 to 2,

and their salts, and v means the number 1, if m represents the number 1, and R4 does not represent-N(R7)R8, or linked through N (nitrogen atom) cycle or Bicycle, if Z denotes S, v means the number 1, and u represents the number 0.

2. The compounds of formula I on p. 1, where R is hydrogen; R1 is hydrogen; R2 is hydrogen; R3 is hydrogen, C1- C4alkyl or C1- C4alkoxy; R4 is a CI-C1- C4Alki is benzene, furan, thiophene, thiazole, imidazole, tetrazole, pyridine and benzimidazole; R5 is hydrogen, R6 is hydrogen or C1- C4alkyl; R7 and R8, together and including the nitrogen atom to which they are both linked, represent unsubstituted or substituted pieperazinove or 1,2,3,4-tetrahydroisoquinoline radical, and substituted pieperazinove radical in position 4 is substituted by one Deputy, selected from the group comprising-CpN(2P-2) - R14-sqH2q- R14; R9 is hydrogen, C1- C4alkyl, halogen, nitro, carboxy, C1- C4alkoxycarbonyl or substituted radical R151- C4alkyl; R10 is hydrogen or C1- C4alkyl; R14 is a substituted radicals R9 and R10 cycle selected from the group comprising benzene and thiophene; R15 is carboxy; W is CH or N; X Is S; Z Is S; m means a number in the range from 1 to 3; n represents the number 0; t means the number 0; u represents a number 0, 1 or 2; v represents the number 0 or 1; p represents the number 3 and q means the number 0 or 1, and their salts, and v means the number 1, if m represents the number 1, and R4 does not represent-N(R7)R8, or linked through N (nitrogen atom) cycle or Bicycle, if Z denotes S, v means the number 1, and u represents the number 0.

3. The compounds of formula I on p. 1, where t represents the number 1, and u represents the number 0, and their salts.

5. The compounds of formula I on p. 1, where t represents the number 0, v means the number 1, and u represents the number 1 or 2, and their salts.

6. The compounds of formula I on p. 1, where pyridine, respectively pyrimidine ring attached in position 2.

7. The compounds of formula I on p. 1, where pyridine, respectively pyrimidine ring is attached in position 4.

 

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