Derivatives of benzimidazole and method of production thereof

 

(57) Abstract:

Usage: as an inhibitor of the secretion of gastric juice. The inventive product of General formula:

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where X Is-S - or-SO-; R1-R4that may be the same or different and represent hydrogen, alkyl containing 1 to 8, especially 1 to 6 carbon atoms, alkoxy containing from 1 to 8, especially 1 to 6 carbon atoms, alkoxy containing from 1 to 8, especially 1 to 6, carbon atoms, alkoxyalkyl containing 1-3 carbon atoms in each alkyl part, D is a group of the formula:

< / BR>
R5represents a group of the formula

< / BR>
where Vice phenyl group is in the meta or in the para-position;

< / BR>
R6represents hydrogen, alkyl containing 1 to 8, especially 1 to 6, carbon atoms, R8represents hydrogen, alkyl containing 1 to 8, especially 1 to 6, carbon atoms, R7represents alkoxy containing 1 to 7 carbon atoms And represents a straight or branched /1-8C/alkylen; /3-7C/cycloalkyl; /4-9C/alkylene containing cycloalkenyl group; Z1is, Z2is-NRd(Rq)v, Ra, Rb, Rdand Rqbenzyl, m is an integer from 0 to 8; p is 1-4; q is 1 to 4; r is 0 to 8; t is 0 or 1, and group D, when it contains a phosphorus-containing group, may be in the form of mono-, di-, tri - or tetragonal salt containing a physiologically acceptable anion, and when it contains aminopentyl, it can be in the form of ammonium salt (v = 1) with a physiologically acceptable cation, or in the form of a free amine (v = 0)provided that A is a /3-7C/cycloalkyl or /4-9C/alkylene containing cycloalkenyl group, when both the following conditions are met: R5is a group ; Rais a /1-3C/alkyl, Rbis a /1-3C/alkyl, v is 0, or Rqis hydrogen, and v - 1. Reagent 1: compound of General formula:

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where R1-R8and X have the above meanings and Z represents a halogen, such as chlorine. Reagent II: R5- CO2M;

< / BR>
< / BR>
< / BR>
where R5b, Raand Rehave the meanings given above, Rprepresents a protective group, M represents a cation, and then, if necessary, the protective groups are removed. The selection of the target product in free form or in salt form. 2 C. and 16 h. p. F.-ly, 4 PL.

The present invention relates to the use of compounds of the invention, especially their therapeutically acceptable salts, for inhibiting gastric secretion in mammals and man In a more General sense, the compounds of the invention can be used for the prevention and treatment of gastrointestinal inflammatory diseases and diseases associated with gastric juice mammals and humans, such as gastritis, gastric ulcer, duodenal ulcer and peptic esophagitis. In addition, the compounds of the invention can be used for treatment of other gastrointestinal disorders or disorders in which desirable gastric antisecretory effect, for example, in patients with ulcerogenic adenomas of the pancreas in patients with acute upper gastrointestinal bleeding. They can also be used in cases of intensive care patients and in DOI postoperative period to prevent acid aspiration and stress ulcers. This invention yoke therapeutically acceptable salt as an active ingredient. The following aspect of this invention relates to methods of producing such novel compounds, to new intermediate products for preparing compounds of the invention and to the use of active compounds for pharmaceutical compositions for the above medical use.

Derivatives of benzimidazole, intended for inhibiting the secretion of gastric juice, are described in numerous patent documents. Among them may be mentioned patents GB N 1500043, GB N 1525958, US N 4182766, EP N 0005129 and VE N 890024. Derivatives of benzimidazole, proposed for use in the treatment or prevention of a special gastro-intestinal inflammatory diseases, are described in EP-A-0045200, N-substituted 2-/pyridylacetonitrile/benzimidazole described in EP-A-0176308.

For some forms of pharmaceutical use, there is a great need for high water solubility which connection to use. For example, in the case of ready-made forms for intravenous and intramuscular injection dose of the drug should be dissolved in a small volume of the water environment. This, of course, requires a high solubility in water. However, the solubility in water is often a large preoedinte typically have low solubility in water, which makes it impossible to produce such highly concentrated aqueous solutions, which are necessary for intravenous and intramuscular injection. For example, the compounds presented in the published European patent application N 0176308, which are disclosed N-substituted benzimidazole derivatives have a low solubility in water and thus are not suitable for the above parenteral use.

It was found that the compounds of the following formula 1 are effective as inhibitors of gastric juice in mammals and humans, and that these compounds 1 have unexpectedly high solubility in water compared with the compounds of the prior art.

The compounds of this invention in which X represents SO usually exhibit higher chemical stability in aqueous solutions at a pH at which they find optimal stability compared with the corresponding compounds without the N-1 substitution, at the same pH value, some of the compounds of the invention find extremely high chemical stability in solution. The compounds of formula 1 are, therefore, especially suitable for Himicheskaya stability also makes the compounds of the invention suitable for other methods of assigning, such as, for example, oral and rectal fashion destination.

Compounds of the invention are compounds of the following formula 1:

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and their physiologically acceptable salts, where X is an S - or-SO-;

R1, R2, R3and R4that are the same or different, represent

/a/ H,

/b/ alkyl containing 1 to 8, especially 1 to 6 carbon atoms,

/c/ alkoxy containing from 1 to 8, especially 1 to 6 carbon atoms,

/d/ alkoxyalkyl containing 1-3 carbon atoms in each alkyl part,

/e/ alkoxyalkane containing 1-3 carbon atoms in each alkyl part,

/f/ halogen,

/g/ -SP,

/h/ CF3,

/i/ NO2,

/j/ COR10,

// alkylthio containing 1-6 carbon atoms in the alkyl part,

/l/ alkylsulfonyl containing 1-7 carbon atoms in the alkyl part,

/m/ aryl-thio, -sulfinil, sulfonyl, sulfonyloxy, -oxycarbonyl, sulphonamido or aminosulfonyl, with each aryl group is optionally substituted by 1-3 substituents, same or different and selected from halogen, trifloromethyl, /1-5C/alkyl and /1-5C/alkoxy,

/n/ arylalkyl or Allakaket containing 1-6 carbon atoms in the alkyl and Allie different and selected from halogen, trifloromethyl, /1-5C/alkyl and /1-5C/alkoxy,

/o/ aryl or aryloxy, with each aryl group is optionally substituted by 1-3 substituents, same or different and selected from halogen, trifloromethyl, /1-5C/alkyl and /1-5C/alkoxy,

/p/ haloalkoxy containing 1-6 carbon atoms and 1-11, especially 1 to 6 atoms of halogen,

/q/ hydroxyalkyl containing 1-6 carbon atoms,

/r/ R1and R2, R2and R3or R3and R4together with the neighboring carbon atoms in the benzimidazole ring form one or more 5-, 6 - or 7-membered rings, each of which may be saturated or unsaturated and may contain 0-3 hetero-atom selected from nitrogen, sulfur and oxygen, and each ring may be optionally substituted by 1-10, appropriately 1-6 or 1-4 substituents selected from alkyl groups with 1-3 carbon atoms and halogen, or two or four of the mentioned substituents together form one or two oxo groups , in this case, if R1and R2, R2and R3or R3and R4together with the neighboring carbon atoms in the benzimidazole ring form two rings, the rings may be condensed with each other;

D represents a group of the formula:

< / BR>
where the substituent in the phenyl group is in the meta or in the para-position

< / BR>
< / BR>
< / BR>
< / BR>
/i/ mono - or dicarboxy-substituted 2-, 3 - or 4-pyridinyl or mono - or dicarboxy-substituted 2-, 3-, or 4-pyridyloxy,

j)

R6represents a

/a/ H,

/b/ alkyl containing 1 to 8, especially 1 to 6 carbon atoms,

/s/ alkoxy containing from 1 to 8, especially 1 to 6 carbon atoms,

/d/ halogen,

R8represents a

/a/ H,

/b/ alkyl containing 1 to 8, especially 1 to 6 carbon atoms,

/c/ alkoxy containing from 1 to 8, especially 1 to 6 carbon atoms,

/d/ halogen,

/e/ arylalkyl containing 1-4 carbon atoms in the alkyl part,

R7represents a

/a/ H,

/b/ alkyl containing 1-7 carbon atoms,

/c/ alkoxy containing 1 to 7 carbon atoms,

/d/ alkoxyalkyl containing 1-3 carbon atoms in each alkyl part,

/e/ alkoxyalkane containing 1-3 carbon atoms in each alkyl part,

/f/ aryloxy, while aryl group optionally substituted by 1 or 2 substituents, same or different and selected from halogen, trifloromethyl, /1-3S/alkyl or /1-3S/alkoxy,

/g/ arylalkyl or Allakaket containing 1-7 atoms by uglerodnymi, the same or different and selected from halogen, trifloromethyl, /1-3C/alkyl and /l-3P/alkoxy,

/h/ alkenylacyl containing 1-7 carbon atoms in alkenylphenol part,

/i/ alkyloxy containing 1-7 carbon atoms in alkenylphenol part,

/j/ alkylthio containing 1-7, preferably 1-3 carbon atoms in the alkyl part,

/k/ aaltio or arylalkyl containing 1-3, preferably 1 carbon atom in the alkyl part,

/l/ dialkylamino containing 1-7, preferably 1-3 carbon atoms in each alkyl parts,

/m/ morpholino,

/n/ piperidino,

/e/ N-methylpiperazine,

/p/ pyrrolidino,

/q/ feralcode containing 2-5 carbon atoms and 1-9 of fluorine atoms

or R6and R7or R7and R8together with the neighboring carbon atom in the pyridine ring form a 5 - or 6-membered, saturated or unsaturated ring, which may optionally contain an oxygen atom, a sulfur, or optional alkilirovanny nitrogen atom;

R9represents a

/a/ H

/b/ alkyl containing 1-4 carbon atom,

R10represents a

/a/ alkyl containing 1-6 carbon atoms,

/b/ alkoxy containing 1-6 carbon atoms,

/c/ aryl;

A represents the speaker cycloalkenyl group;

B is a

/a/ -/CH2/m-< / BR>
< / BR>
E is a

/a/ -O- /6/- NH-; is ; is a (a)- (CH2-, (b) -NRd(Rq)v-;; /c/ S, /d/ -O-;

Ra, Rb, Rc, Rdand Rqare the same or different and selected from: a/a H /b/1-6C/alkyl; represents /a/H/ /b/1-6/alkyl /c/ aryl /0-3S/ alkyl, with the aryl group is optionally substituted by 1-3 substituents, same or different and selected from halogen, trifloromethyl, nitro/1-5C/ alkyl and /1-5C/ alkoxy;

Rfrepresents the side chain of amino acids;

m represents an integer 0, 1, 2, 3, 4, 5, 6, 7 or 8; p represents the integer 1, 2, 3 or 4;

q is an integer 1, 2, 3 or 4;

r is an integer 0, 1, 2, 3, 4, 5, 6, 7, 8;

s represents an integer 0 or 1;

t represents an integer 0 or 1

u is an integer 1 or 2;

v represents an integer 0 or 1;

and group d, when it contains one or two carbon-acid group or a phosphorus-containing group, preferably is in the form of mono-, di-, tri - or Tetra-ionic salt containing a physiologically acceptable counter-cation is th physiologically acceptable counter anion, or in the form of a free amine /v 0/. In the case when R5represents the side chain of aspartic acid /u 1/ or glutamic acid /u 2/, h/, R5can also be in zwitter-ionic form; provided that:

/1/ A is a /3-7C/cycloalkyl or /4-9C/alkylene containing cycloalkenyl group, when both the following conditions are met:

/a/ R5represents a group

< / BR>
/b/ R2represents H, /1-3C/alkyl,

/c/ R6represents H, /1-3C/alkyl,

/d/ v represents 0, or Rqrepresents H and v represents 1,

/2/ either or both of R6and R8represents a halogen when R7represents dialkylamino, morpholino, piperidino, N-methyl-piperazine derivatives or pyrrolidino.

It should be understood that the expression "alkyl" and "alkoxy" includes straight, branched and cyclic structures, including respectively cycloalkenyl, cycloalkylation, cycloalkylation.

The number of atoms in this radical in this description or clearly specified, or given in an abbreviated form in brackets, as, for example, /1-3C/alkyl.

Compounds of the invention are sulfoxidov, emautou/, or if they contain one or more asymmetric carbon atoms, these compounds have two or more diastereomeric forms, each of which exists in two enantiomeric forms.

The scope of the present invention are covered as pure enantiomers, racemic mixtures of /50% of each enantiomer/ and unequal mixtures of two enantiomers. It should be understood that all diastereomeric forms that are possible /pure enantiomers or racemic mixtures/ are covered by the scope of the invention.

Compounds of the invention, which are sulfides /X=S/, can be asymmetric due to one or more asymmetric carbon atoms, as described above. Various possible diastereomeric forms, as well as pure enantiomers and racemic mixtures of the compounds are within the scope of this invention.

Preferred groups of compounds of formula 1 are:

1. Compounds in which X represents-SO,

2. Compounds in which X represents-S-,

3. Compounds in which R1, R2, R3and R4are the same or different and selected from hydrogen, /1-4S/alkyl, /5-6S/cycloalkyl, /1-4S/alkoxy, /1-2C/alkoxy/1-2C/alkyl, /1-2C/alkoxy/1-2C/alkaloid /1-4S/alkoxy, hydroxy/1-4S/alkyl, /2-4C/alkanol/1-LC/ alkyl, or where R2and R3together with the ring atoms form a 5 - or 6-membered saturated, oxygen-containing or carbocyclic ring, optionally substituted by 1-6 substituents, same or different and selected from halogen, /1-20C/alkyl, or two substituents together form an oxo-group /keto-group/.

4. Compounds in which R1, R2, R3and R4are the same or different and selected from hydrogen, /1-4S/alkyl, /1-4S/alkoxy, /1-2C/alkoxy/1-2C/alkyl, fluorine, trifloromethyl, /2-4C/alkanoyl, /1-2C/alkoxycarbonyl, fluorine/1-4S/alkoxy, hydroxy/1-4S/alkyl, or in which R2and R3form a group-OCH2O, -OCF2O, -OCF2-HF-, or-C/CH3/2COC/CH3/2-.

5. Compounds in which R1, R2, R3and R4are the same or different and selected from hydrogen, methyl, ethyl, isopropyl, tert-butyl, methoxy, ethoxy, methoxymethyl, ethoxymethyl, fluorine, triptoreline, tetrafluoroethoxy, hydroxymethyl, or where R2and R3form a group-OCF2O-, -C/CH3/2COC/CH3/2or OCH2O-.

6. Compounds in which R1, R2

7. Compounds in which R1and R4are H, and R2and R3selected from tert-butyl, methoxy, methoxymethyl, fluorine, triptoreline, hydroxymethyl and hydroxyethyl.

8. Compounds in which R1, R2, R3and R4represent H, alkyl containing 1-6 carbon atoms, or alkoxy containing 1-6 carbon atoms.

9. Compounds in which R1and R4are H, and R2and R3both represent alkoxy containing 1-3 carbon atoms.

10. Compounds in which R1, R2, R3and R4all represent hydrogen.

11. Compounds in which R1and R4represent alkoxy containing 1-3 carbon atoms, and R2and R3represent hydrogen or hydroxyalkyl containing 1-3 carbon atoms.

12. Compounds in which R1, R3and R4represent hydrogen, and R2represents methoxy.

13. Compounds in which R1, R2and R4represent hydrogen, and R3represents the property is Yes, alkoxy containing 1-6 carbon atoms.

15. Compounds in which R7represents aryloxy or Allakaket, optionally substituted.

16. Compounds in which R7represents alkoxy containing 1-6 carbon atoms.

17. Compounds in which R3represents hydrogen or methyl, especially hydrogen.

18. Preferred substituents in the position I benzimidazole nucleus are substitutes, in which R9represents hydrogen, and D is such, as illustrated by the examples in table. 1, is presented below.

19. Compounds in which D represents .

20. Compounds in which D is a group , especially their acid additive salt.

21. Compounds in which D is a group , or , especially their acid additive salt.

22. Compounds in which D represents , especially their alkali metal salts.

23. Compounds in which D represents , especially their alkali metal salts.

24. Compounds in which D represents , especially their alkali metal salts.

25. Compounds in which D represents , especially their alkali with the tion, in which D represents , especially their alkali metal salts.

28. Compounds in which D represents , especially their alkali metal salts.

29. Compounds in which D represents , especially their alkali metal salts.

30. Compounds in which D represents , especially their alkali metal salts.

31. Compounds in which Rerepresents an optionally substituted aryl group.

32. Preferred benzimidazole structures are unsubstituted, 5-methoxy and 6-methoxy-substituted.

33. Preferred of pyridine fragments are: 3,5-dimethyl-4-methoxy-, 3-methyl-4-methoxy-, 5-ethyl-4-methoxy-, 4-methoxy, 4-ethoxy-, 4-isopropoxy-, 3,5-dimethyl-, 3,4-dimethyl-, 4,5-dimethyl-, 3-methyl-4-/2,2,2-trifter/ethoxy-, 3,4-dimethoxy, 4,5-dimethoxy-, 3-methyl-4-ethylthio-, 3-methyl-4,5-dimethoxy-, 3,4,5-trimethyl-, 3-ethyl-4-methoxy-, 3-n-propyl-4-methoxy-, 3-isopropyl-4-methoxy-, 3-tert-butyl-4-methoxy-substituted.

34. Especially preferred pyridine fragments are: 3,5-dimethyl-4-methoxy-, 3-methyl-4-methoxy-, 3-ethyl-4-methoxy-, 3-isopropyl-4-methoxy-, 4-methoxy-, 4-ethoxy - and 4-isopropoxy-substituted, especially 3,5-dimethyl-4-methoxy-substituted.

35. Additionally all of the radicals X and R1R10as indicated in groups 1-34 above.

36. Preferred from pyridinylmethyl-benzimidazole fragments are:

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< / BR>
< / BR>
37. Preferred groups of the radicals R6and R8are H, methyl, ethyl, n-propyl, ISO-propyl and tert-butyl.

38. The most preferred compounds of the invention are:

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39. Other preferred compounds of the invention are:

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Illustrative examples of the various radicals in the formula 1 are radicals which follow. These illustrative examples are applicable to various radicals depending on the number of carbon atoms prescribed for each radical.

The alkyl group in the definitions of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, Ra, Rb, Rc, Rd, Re, Rqillustrated examples methyl, ethyl. n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentile, n-hexyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl, cyclopentylamine and cyclohexylamine. Particularly preferred lower alkyl groups containing 1-4 carbon atoms.

8and R10are methoxy, ethoxy, n-propoxy, ISO-propoxy, n-butoxy, out-butoxy, sec-butoxy, tert-butoxy, n-pentox, out-pentox, n-hexose, cyclopropane, cyclopentane, cyclohexane, cyclopropylmethoxy, cyclopentyloxy, cyclopentyloxy, cyclohexylmethoxy. Preferred lower alkoxy groups, particularly groups containing 1-4 carbon atoms, preferably a lower alkoxy group having particularly preferably 1-3 carbon atoms, e.g. methoxy, ethoxy, n-propoxy or isopropoxy. Halogen in the definitions of R1, R2, R3, R4, R5, R6and R8represents chlorine, bromine, fluorine and iodine, preferably chlorine, bromine and fluorine.

When determining R1, R2, R3, R4and R7when they represent alkylthio or alkylsulfonyl, in which the alkyl is preferably lower alkyl, with particularly preferably 1-4 carbon atoms, typical representatives are, for example, methylthio, methylsulfinyl, ethylthio, ethylsulfinyl, isopropylthio, n-butylsulfonyl or isobutyric.

The aryl group, when it is present in R1, R2, R3, R4, R7, R10and Rcthat site has the th group.

R1, R2, R3R4, R7representing aryloxy or aaltio group have preferably up to 10 carbon atoms, particularly preferably up to 6 carbon atoms and represents, for example, Benxi or phenylthio group.

Group arylalkyl, Allakaket, arylalkyl when they are present in the definition of R1, R2, R3, R4, R7, R8and Rchave preferably up to 10 carbon atoms in the aryl group. Especially preferred are the group with 6 carbon atoms in the aryl group and 1 to 3 carbon atoms in the alkyl group or alkoxy group, respectively, for example, phenylmethyl, phenylethyl, phenylmethoxy, phenylpropyl, phenylisopropyl, feniletilic, feniletilic.

Group/4-9C/alkylene containing cycloalkenyl group" when it is present And is particularly

< / BR>
Examples R1, R2, R3, R4and R7representing alkoxy-alkyl or alkoxyalkyl group are methoxymethyl, methoxyethyl, methoxypropyl, ethoxypropan, ethoxyethyl, propoxyethyl, methoxyethoxy, ethoxyethoxy, methoxypropane, ethoxyethoxy, propositons.

R7represen the ode, and it is, for example, allyloxy, propargyloxy, 2-butenyloxy and 2 butenyloxy.

Illustrative examples of ring structures formed by groups of R1and R2, R2and R3and R3and R4are-CH2CH2CH2-, -CH2CH2CH2CH2-, CH2C/CH3/2CH2-, /CH2/5-, -CH= CH-CH= CH-, -CH2COCH2-, -OCH2O-, -OCH2CH2O-,

-OCH2CH2CH2O-, -OCH2CH2-, -CH2CH2NH-, -CH=CH-CH=N-, -COCH2CO-, -SCH2CH2-,

-SCH2S-, -SCH2CH2S-, -C/CH3/2-CO-C-/CH3/2-, OCF2O-, -OCF2CHFO-, -OCF2CF2O - and-OCF2CFClO-.

R6and R7or R7and R8that represents a 5 - or 6-membered saturated or unsaturated ring, preferably is a saturated carbocyclic ring or a saturated ring containing an oxygen atom or sulfur in the 4-position of the pyridine ring, for example, -CH2CH2CH2-, -CH2CH2CH2CH2-, -0-CH2CH2-, -0-CH2CH2CH2-, -SCH2CH2or-SCH2CH2CH2-.

The group R1, R2, R3and R4when the elegance is lower feralcode or perchlorate group, for example, OCF3, OCHF3, OCF2CHF2, OCF2CF3, OCF2Cl, OCH2CF3.

R7when he is feralcode, illustrated by the example OCH2CF3, OCH2CF2CF3and OCH2CF2CHF2.

R1, R2, R3and R4representing hydroxyalkyl, illustrated by the example of CH2OH, CH2CH2OH, CH2CH2CH2OH and /CH2/4HE.

The group R7when it is dialkylamino group is preferably-N/CH3/2or-N/C2H5/2.

Rfthat represents the side chain of amino acids is, for example, CH3originating from alanine, or /CH2/2COOH, derived glutamic acid.

For the compound of General formula 1, containing an asymmetric center, the scope of the present invention are covered as pure enantiomers and racemic mixtures.

Additional illustrative examples of the radicals in the formula 1 are given in the examples and lists specific compounds, data elsewhere in this specification.

It is believed that the compounds of formula 1 are metabolized before Gasolina core. In addition, the compounds of the invention in which X represents sulphur are considered, show their protivozachatocnuu activity after metabolism in relation to compounds in which X represents a group SO.

Receive.

The compound of formula 1, in which D represents COO, can be obtained by using:

A. Interaction of compounds of formula II

< / BR>
where R1, R2, R3, R4, R5, R6, R7, R8, R9and X have the meanings defined for formula 1, with a compound of formula III

R5COOH III or its activated derivative, where R5has the values defined for formula 1 above.

The reaction of the compound of formula II with the compound of the formula III in a suitable manner is carried out directly or in the presence of dicyclohexylcarbodiimide and, if necessary, in the presence of N,N-dimethylaminopyridine /DMAP/ or activated form of the compound III, such as galoyanized acid or a mixed anhydride, or carbonate. Suitable solvents are hydrocarbons, such as toluene and benzene, or halogenated hydrocarbons such as methylene chloride and chloroform, or polar solvents, the compounds of formulas II and III can be carried out at a temperature between -15oC and the boiling point of the reaction mixture.

C. To obtain the compounds of formula I in which R3represents hydrogen, through reaction of compounds of formula IV

< / BR>
where R1, R2, R3, R4, R6, R7, R8and X have the meanings given for formula I and Z represents a halogen, such as chlorine, bromine or iodine, or a functionally equivalent group, with a compound of formula V, VI, VII, VIII, IX, X, XI, XII or XIII:

< / BR>
< / BR>
< / BR>
where S, R5and Rehave the meanings defined for formula 1 above, Rprepresents a suitable protective group, such as cyanoethyl, benzyl or p-nitrophenyl, and M represents a counter-ion, such as PA+TO+Ad+or trialkylamine. When used protective group, this protective group is removed after the reaction combinations /see paragraph E, below).

C. Oxidation of the compounds of formula I

< / BR>
where X represents sulfur, S, R1, R2, R3, R4, R6, R7, R8, R9and D have the above values, to obtain compounds of the same formula 1 in which X represents S0. This oxidation can be carried out using okikawa /or perepelov/, ozone, tetrakis dinitrogen, iodosobenzene, N-gallodactylidae, 1-chlorobenzotriazole, tert-butylhypochlorite, diazabicyclo-/2,2,2/-octane bromine complex, metaperiodate sodium, selenium dioxide, manganese dioxide, chromic acid, nitrate of cereomony, bromine, chlorine and sulfurylchloride. Oxidation usually occurs in some abundance in relation to oxidize the product.

The oxidation can also be carried out by enzymatic when using oxidizing enzyme or microbiocides by using a suitable microorganism.

D. Effect of the compounds of formula IIA

< / BR>
where R1, R2, R3, R4, R6, R7, R8and X have the meanings given for formula I, and Mais a or a cation of a metal, such as PA+TO+Li+or Ag+or Quaternary ammonium ion, such as Tetramethylammonium, with the compound of the formula:

< / BR>
where D and R9have the meanings given for formula I, and Y represents a halogen such as CI, BZ, or I, or a functionally equivalent group.

The reaction of compounds of formula IIA with a compound of formula XII in a suitable manner is carried out in an atmosphere of C is, the halogenated hydrocarbons such as methylene chloride and chloroform.

The reaction of compounds of formula IIA and XII can be carried out at a temperature between ambient temperature and the boiling temperature of the reaction mixture.

That is, the Removal of the protective group in D the Deputy, which is carried out using methods well known in the art. For example, the phosphates can be protected in the form of dibenzylamine or diphenyl esters, which can be split using alkaline hydrolysis with base/. Complex dibenzylamine esters can also be broken down sodium iodide in acetone. Cyanoethylene protective group can be removed by treatment with base, such as sodium hydroxide.

Depending on the process conditions and starting materials, the final products of formula I are obtained, or in neutral form or in salt form. In the scope of the invention are included as neutral compounds, and salts of these end products. Thus, the salt can be obtained as well as Hemi, mono, Sesqui, or polyhydrate.

Acid additive salts of amino-containing compounds can, in a manner which is itself known, be transformed by the free base can then be transformed into salts with organic or inorganic acids. Upon receipt of acid additive salts are used preferably such acids which form suitable therapeutically acceptable salt. Examples of such acids are kaleidostone acid, acid, phosphoric acid, nitric acid, Perlina acid; aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, such as formic acid, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric acid, ascorbic, maleic, hydroxymaleimide, pyruvic, phenylacetic, benzoic, p-aminobenzoic acid, p-hydroxybenzoic acid, salicylic acid or p-aminosalicylic acid, albanova acid, methanesulfonate, econsultation, hydroxyeicosatetraenoic, halodendron-acid, toluensulfonate, aftershocked or sulfanilic acid, methionine, tryptophan, lysine or arginine.

Additive salts of the bases and carboxylic acid or phosphorus-containing compounds can accordingly be converted to the acid form, and then to turn into a therapeutically suitable salt, such as sodium and potassium salts.

implementation of the optically active solvent.

In the case of the diastereomeric mixtures /racemate mix/ they can be divided into stereoisomeric /diastereomers/ pure racemates using chromatography or fractional crystallization.

The source materials used in methods a-E, are in some cases new. These new raw materials, however, may be obtained according to processes which are in themselves known.

Educt of the formula II are obtained through reaction of the corresponding benzimidazole compounds bearing N in the N-1 position with an aldehyde R9SNO.

Starting materials of formula IV are new and form part of this invention. The compounds of formula IV, which represents CL, obtained from the reactions of compounds of formula II with gloriouse agent such as Sl2in the presence of a suitable base, such as triethylamine, in a suitable solvent such as CH2CL2, toluene, acetonitrile, tetrahydrofuran or mixtures thereof. To obtain compounds of the formula IV, in which Z represents a VG go I used similar methods, which apply the appropriate reagents, bromine, such as BBr3or iodine. Examples of these prolgue X S, used in Method C can be obtained according to Method a or Method C.

According to further aspect this invention relates to the use as a means to increase water solubility benzimidazole derivatives, inhibiting gastric juice, the radical of the formula

< / BR>
where D and R9have the meanings given for the formula I, as Deputy in the N-I benzimidazole nucleus.

This invention also relates to inhibiting gastric juice benzimidazole derivative having in position N-1 animetitle kernel radical of the formula D-CH/R9/ - a, where D and R9have the meanings defined for formula 1.

The preferred values of D and R9are such as listed here in this description.

This invention relates also to the use as an agent attached to the position N-1 benzimidazole kernel to increase the water solubility of benzimidazole derivatives, having the effect of inhibiting gastric acid, the compounds of formula

where D, R9and Y have the values defined in this specification.

For clinical use of the compounds of the invention do another assignment method. Especially it is preferable to convert the compounds of the invention in pharmaceutical forms for parenteral purposes. Pharmaceutical finished formulation form contains a compound of the invention in combination with a pharmaceutically acceptable carrier. The carrier may be in the form of solid, semi-solid or liquid diluent or in the form of a capsule. These pharmaceutical preparations comprise a further object of the present invention. Usually the number of active compounds is between 0.1-95% by weight of the drug, between 0.2-20% by weight in preparations for parenteral use and between 1 and 50% by weight in preparations for oral purposes.

In the preparation of pharmaceutical finished preparative forms containing the compound of the present invention in the form of dosage units for oral destination, the selected compound may be mixed with a powdered solid carrier such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or other suitable media, as well as with lubricating agents such as magnesium stearate, calcium stearate, sodium fumarate and polietilenglikolya waxes. The mixture was then processed in hypocrities, which protects the active compound from the acid catalyzed decomposition over a period of time until the dosage form remains in the stomach. Small bowel or enterically coating is selected among the pharmaceutically acceptable enterically coating materials, for example, beeswax, shellac or anionic film-forming polymers, such as phthalate cellulose acetate, phthalate hydroxypropyl-methyl cellulose, polymers partially slozhnoefirnoi the stands of methacrylic acid and similar, if preferred, in combination with a suitable plasticizer. To this coverage can be added a variety of dyes to distinguish between tablets or granules with different active compounds or with different amounts of present active compounds.

Soft gelatin capsules may be prepared with capsules containing a mixture of active compound or compounds of the invention, vegetable oil, fat or other suitable media for soft gelatin capsules. Soft gelatin capsules may also be enterically coating, as described above. Hard gelatin capsules may contain granules or pellets with antirecessionary in combination with a powdered solid carrier, such as lactose, saccharose, sorbitol, mannitol, potato starch, amylopectin, cellulose derivatives or gelatin. Hard gelatin capsules may be a finely-enteric coating, as described above.

Dosage unit forms for rectal application can be prepared in the form of medical candles, which contain the active substance is mixed with a neutral fat base, or they can be prepared in the form of a gelatine rectal capsule which contains the active substance in a mixture with a vegetable oil, paraffin oil or other suitable media for gelatin rectal capsules, or they can be prepared in the form of easily manufactured, or in the form of ready-made micro enema, or they can be in the form of a dry micro-cosmoboy ready preparative form, intended for preparation in a suitable solvent immediately before the appointment.

Liquid preparation for oral destination may be in the form of syrups or suspensions, e.g. solutions or suspensions containing from 0.2% to 20% by weight of active ingredient, and the rest is sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and politicing and carboxymethylcellulose or other thickening agents. Liquid preparations for oral assignments can also be prepared in the form of a dry powder, designed to compile a finished product with a suitable solvent before use.

Solutions for parenteral purposes can be prepared in the form of a solution of the compound of the invention in a pharmaceutically acceptable solvent, preferably in a concentration of from 0.1% to 10% by weight. These solutions may also contain stabilizing agents and/or buferiruemoi agents and can be produced in various dosage ampoules or vials. Solutions for parenteral destination can also be prepared in the form of a dry product intended to obtain a finished product with a suitable solvent before use.

A typical daily dose of the active substance varies in a wide range and depends on various factors, such as, for example, an individual need of each patient, the mode of appointment and disease. Usually oral and parenteral dosages are in the range from 5 to 500 mg per day of the active substance.

The invention is illustrated by the following examples.

Example 1

Obtaining bromide Sol-1-yl] methyl ether complex.

(Method A).

To a stirred mixture of 4-carboxy-N-methyl-piperidine /1,8 g of 0.01 mol/ acetone /75 ml/ add the triethylamine /1.5 g, of 0.015 mol/ and isobutylparaben /1,93 ml of 0.015 mol/. The mixture is stirred for 15 min at room temperature. Dropwise added [2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl] sulfinil] -1H-benzimidazole-1-yl] methanol /0,01 mol/ dissolved in pyridine /15 ml/. Once added, the mixture stirred for 2 h at room temperature. Inorganic salts were removed by filtration. The filtrate was supariwala, and the residue was dissolved in dichloromethane /100 ml. The dichloromethane solution was washed 3 times with 0.5 M sodium hydroxide solution /10 ml/, and then once with water /25 ml/. Drying of the organic phase, filtering and evaporation of the solvent gave the desired product. /Yield: 0.4 g /8.5 percent/. Hydrobromide salt /target connection/ were prepared from the free base using conventional methods.

Example 2

Obtaining [2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl] - sulfinil]-1H-benzimidazole-1-yl] methyl ether complex p-N,N-dimethylaminomethylphenol acid

(The way IN)

p-N,N-Dimethylaminomethylphenol acid /50 mg of 0.28 mmole) and triethylamine /60 mg, 0.6 mmole/ RA is ffinal] -IH-benzimidazole /100 mg, a 0.27 mmole/ methylene chloride /5 ml/. After exposure for 10 h at room temperature methylenchloride the solution was washed with 0.5 M sodium hydroxide /5 ml and saline /5 ml/. The organic base was dried over sodium sulfate, filtered and evaporated under reduced pressure. The balance is an essentially pure target compound. Yield: 56 mg /40%/.

Example 3

The compound of this example is identified in the table. 1 and it turned out according to the Method as illustrated in Example 1.

Example 10

Obtaining sodium salt complex benzyl-[2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinil]-1H-benzimidazole-1-yl methyl diapir phosphoric acid (Method E).

Dibenzyl-[2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinil]-1H-benzimidazole-1-yl] methyl triavir phosphoric acid /90 mg, 0.15 mmole/ dissolved in a mixture of methanol/water /2 ml, 1:1/. Was added sodium bicarbonate /58 mg, 0.7 mmole) and the mixture was heated under reflux for 2 h on a water bath. Concentrating the mixture under reduced pressure and chromatography of the residue on silica gel /ethyl acetate-methanol-water, 20:4:3/ gave essentially pure target compound.

Output: 30 mg /37%/.

Example 14

Getting Hydrobromic salt [2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl] sulfinil] -1H-benzimidazole -1--yl] methyl(1-methyl-4-piperidinyl)carbonate (Method A)

n-Nitrophenylphosphate /3.1 g, 15 mmol/ were dissolved in toluene /75 ml/. Under stirring for 5 min at room temperature was added a solution of 4-hydroxy-1-methylpiperidin /1,75 g, 15 mmol) and triethylamine in toluene /75 ml/. After 5 min at room temperature the reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The oily residue was taken in methylene chloride /50 ml and added to a solution of 2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl/sulfinil-1H-benzimidazole-1-yl] methanol /10 mmol/ triethylamine /1 g, 10 mmol/ methylene chloride /50 ml/. Methylene chloride was distilled, and the residue was heated on a water bath for 5 min at 70oC. After cooling to room temperature was added a methylene chloride /100 ml, and the solution was extracted with sodium hydroxide /1 M, 16 ml/ were washed with saline and dried over anhydrous sodium sulfate. Filtration and evaporation of the solvent from the filtrate gave an oil residue, which by adding ethyl acetate-diethylamine mixture crystallized free /2,22, 2,25, 2,30, 3,70, 4,96, 6,52, 7,40, 7,74, 8,14.

Hydrobromic salt /target connection/ were prepared from the free base using conventional methods.

Example 23

Getting iodide, 1,1-dimethyl-4-[2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl] sulfinil] -1H-benzimidazole-1-yl/ methoxycarbonylamino-piperazinil.

The target compound is obtained by alkylation [2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinil]1H-benzimidazole-1-yl]methyl-3-(1-methyl-piperazine-4-yl)propyl-carbonate iodine stands using conventional methods.

Example 29 and 32

a/ Obtaining a mixture of di-sodium salt of [6-methoxy-[2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl] sulfinil] -1H-benzimidazol-1-yl] methyl ester of phosphoric acid and disodium salt [5-methoxy-[2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl] sulfinil] -1H-benzimidazole-1-yl] methyl ester of phosphoric acid, 2:1 (Way In).

Tributylamine /14 ml, 0,059 mol/ was added with stirring to a solution of phosphoric acid, 85% /2 ml, 0,030 mol/ ethanol /10 ml/. The solvent was evaporated, and the residue was taken in methylene chloride /25 ml/. The organic phase was dried over sodium sulfate, filtered and perivolas. A mixture of 1-[[(4 - methoxy-3,5-dimethyl-2-pyridinyl)methyl sulfinil-1H-benzimidazole, 2: 1 /1.0 g, 0,0025 mol/ and tributylammonium copy phosphonic acid, prepared above, was dissolved in methylene chloride /50 ml/. Methylene chloride was distilled, and the residue was heated on a water bath for 5 min at 60oC. the Residue was dissolved in methylene chloride /50 ml/, and again the methylene chloride was distilled and the mixture of the oil product was heated on a water bath for 5 min at 60oC. This procedure was repeated four times as long as the reaction was not completed. The residue was dissolved in methylene chloride and washed with three portions of water. The organic layer was dried, filtered and evaporated. The crude mixture tributylammonium salts were dissolved in methylene chloride /25 ml and was added to water /10 ml/. With stirring was added a solution of sodium hydroxide, and the pH of the aqueous layer was carefully adjusted. When the pH value reached 9,0-9,5 in the aqueous phase /added 0,005 mol Paon/, and the mixture was centrifugals. Water sing were washed with three portions /25 ml of methylene chloride, and then dried by freezing, giving 760 mg, 61% of the target compounds. An NMR spectrum of the mixture is consistent with the spectrum of pure isomers, the data in the table. 2.

b/ Receiving disodium salt [5-methoxy-[2-[[(4-methoxy,5-dimethyl-2-pyridinyl)IU the s salts, obtained in stage a/ above, was tributylammonium salt [5-methoxy-[2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl] sulfinil] -1H-benzimidazole-1-yl] -methyl ester of phosphoric acid by chromatography on a column of reversed phase, elyuirovaniya 15% acetonitrile in water. After freeze-drying, the compound was dissolved in methylene chloride, the acid was treated with sodium hydroxide as described above. Pure disodium salt of [5-methoxy-[2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl] sulfinil]-1H-benzimidazole-1-yl] methyl ester of phosphoric acid was obtained with a yield of about 1% of an NMR Spectrum is given in table. 2.

with/ Get disodium salt [6-methoxy-[2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinil]-1H-benzimidazol-yl)] methyl ether phosphoric acid. (The way IN)

The target compound was prepared as described in stage a/ above for isomeric mixture, on the basis of pure 1-chloromethyl-6 - methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl] sulfinil] -1H-benzimidazole /1,9 g, 0,0048 mol/, phosphoric acid, 85% /4 ml, 0,070 mol/, tributylamine /28 ml, amount of 0.118 mol/ 100 ml of methylene chloride. The product was crystallized from a mixture of ethanol and water, giving 0,85 g, 35% is an NMR Spectrum of compound identity was Anatel-6 - methoxy-[2-[[(4-methoxy-3,5-dimethyl-2-pyridine)methyl] sulfinil] -1H-benzimidazole-1-yl methyl ester of phosphoric acid was added to the solution Paon /0,30 g, 0,0075 mol/ dissolved in water /25 ml/. After heating the mixture on a water bath /60oWith/ within 15 min, it was filtered twice with methylene chloride /25 ml/ perivolas to dryness, yielding the desired compound /0.25 g/. The identity of the product was confirmed by NMR data.

Output: 22%

Example 33

Obtaining the sodium salt of [6-methoxy-[2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl] sulfinil] -1H-benzimidazole-1-yl methyl diapir phosphoric acid

Pure 1-chloromethyl[6-methoxy[2-[(4-methoxy-b-dimethyl-2-pyridinyl) methyl]sulfinil]-1H-benzimidazole /0.3 g, 0,00076 mol/ and mono-triethylammonium salt monoethylene ether phosphoric acid /0,5, 0,0022 mol/ mixed with triethylamine /0.3 ml/ methylene chloride /10 ml/. The solvent was evaporated, and the residue was heated on a water bath at 60oC for 5 minutes was Added to the methylene chloride was distilled, and the product was again heated for 5 min at 60oC. This procedure was repeated four times as long as the reaction was not completed. The crude material was purified using chromatography on a column of reversed phase using a mixture of water and acetonitrile 90: 10 as eluent. Pure fractions were combined, evaporated, and added one equivale is the identified data NMR.

Examples 34 and 35

A mixture of 4-methyl-g-oxo[/5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl] sulfinil] 1H-benzimidazole-1-yl methyl ether 1-piperazineethanol acid and 4-methyl-1-g-oxo-[6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl] sulfinil] -1H-benzimidazole-1-yl methyl ether 1-piperazine-butane acid 1:2 (Method A).

Anhydride butandione acid /4 g of 0.04 mol/ N-methylpiperazin /4 g of 0.04 mol/ and triethylamine /4 g of 0.04 mol/ added to dichloromethane /250 ml/. The mixture was mixed for 10 min at room temperature. The mixture was cooled to -15oWith, and added methylchloroform /of 3.78 g of 0.04 mol/. Isomeric mixture of 1-hydroxymethyl-(5-methoxy)- and -(5-methoxy)-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinil]-1H-benzimidazole /15 g of 0.04 mol/ triethylamine (4 g, a 0.04 mol) was dissolved in dichloromethane /75 ml/, and then was added dropwise to the mixed anhydride solution. Then added dimethylaminopyridine /0,49 g of 0.04 mol/, and the temperature was raised and the mixture is stirred at room temperature for 90 minutes the Solution was washed twice with water /150 ml/, and then twice with sodium hydroxide /50 ml, 0.5 M/, and the phases were separated and the dichloromethane phase was dried, filtered and supariwala /80 ml/, yielding 12.2 g, 56% of the target compounds in the form of an isomer mixture in the ratio 1:2.

Example 45

Obtaining the sodium salt of p-nitrophenyl-[2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl] sulfinil]-1H-benzimidazol-yl methyl diapir phosphoric acid

1-Chloromethyl-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl] sulfinil]-1H-benzimidazole /0,22 g, 0.60 mmole/, disodium-nitrophenylphosphate, 6H2O /2.4 g, 6.4 mmole/ were dissolved in 15 ml of acetonitrile containing 10 ml of water. The solution was heated under reflux for 1 h the Solvents were then removed in vacuo, and the residue was dissolved in water. The aqueous layer was rinsed with methylene chloride, and then supariwala. The crude material was purified using instant chromatography on silica using a mixture of ethyl acetate-methanol-water /20: 4: 3/ as eluent, yielding 32 mg /10%/ pure target compound.

Example 54

Obtaining the sodium salt of ethyl-[2-[[(4-(2,2,2-triptoreline)-3-methyl-2-pyridinyl)methyl] sulfinil] -1H-benzimidazole-1-yl] methyl diapir phosphoric acid

1-Chloromethyl-2-[[(4-(2,2,2-triptoreline)-3-methyl-2-pyridinyl)methyl] sulfinil]-1H-benzimidazole /40.5 mg, 0.1 mmole/ and tributylammonium salt of mono-ethyl ester of phosphoric acid /198 the very, and the residue was heated on a water bath at 60oC for 5 minutes was Added to the methylene chloride was distilled, and the product was again heated for 5 min at 60oC. This procedure was repeated four times as long as the reaction was not completed. The residue was dissolved in methylene chloride and washed with three portions of water. Organic plant were dried, filtered and supariwala. The crude mixture tributylammonium salts were dissolved in methylene chloride, and water was added. Was added a solution of sodium hydroxide until then, until the pH value was not equal to 10. The mixture was centrifugals, and the aqueous layer was washed with three portions of methylene chloride. Drying by freezing gave the pure target compound, which was identified by NMR data /table. 2/.

Examples 57 and 58

Obtaining a mixture of Pikalevo salt [6-methoxy-[2-[[(4-isopropoxy-2-pyridinyl)methyl]sulfinil]-1H-benzimidazol-yl] methyl ester of phosphoric acid and Pikalevo salt [5-methoxy-[2-[[(4-isopropoxy-2-pyridinyl)methyl] sulfinil]-1H-benzimidazole-1-yl] methyl ester of phosphoric acid.

The target compounds were obtained as described in examples 29 and 32, but using potassium hydroxide instead of sodium hydroxide.

Examples of thenil] -1H-benzimidazole-1-yl] methyl diapir phosphoric acid and sodium salt of methyl-[5-methoxy-[2-[[(4-isopentane-3,5-dimethyl-2-pyridinyl)methyl] sulfinil]-1H-benzimidazole-1-yl] methyl diapir phosphoric acid.

The target compounds were obtained as described in example 54, but using di-tributylammonium salt nanometrology ester of phosphoric acid.

Example 67

This connection is identified in Table 1, and got it on the way In, as shown in examples 63 and 64, except that instead of sodium hydroxide was used potassium hydroxide.

Examples 75 and 76

These compounds are identified in the table. 1 and they were prepared as shown in example 54, except that instead of sodium hydroxide was used potassium hydroxide.

The production of intermediate products

[2-[[(4-Methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinil]-1H-benzimidazole-1-yl] methanol

[2-[[(4-Methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinil] -1H-benzimidazole /a 3.15 g, 10 mmol/ and N,N-dimethylaminopyridine /120 mg, 1 mmol/ was dissolved in methylene chloride /50 ml/. Was added a solution of formaldehyde /5 M, 10 ml, 50 mmole/ and the mixture was strongly stirred for 2 minutes, the Phases were separated and the methylene chloride was dried /sodium sulfate/, filtered and supariwala dry. Slightly reddish residue was the target compound in the form of essentially pure oil. NMR /500 MHz, Dl3/: 2,15; 2,27; 3,70: 4,89; 5,89; 7,methyl]sulfinil]-1H-benzimidazole.

5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl] - sulfinil] -1H-benzimidazole /34,5 g of 0.1 mol/ was dissolved in methylene chloride /500 ml/. Was added a solution of formaldehyde /5 M, 100 ml of 0.5 mol/ and the mixture is vigorously stirred for 2 minutes, the Phases were separated, and the solution of methylene chloride were dried /sodium sulfate/, filtered and supariwala to dryness at low temperature / 30oWith/. The reddish residue was isomeric mixture /ratio 1:2/ target connection and essentially pure oil. This oil was used without purification in subsequent reactions.

Example 1 12

1-Chloromethyl-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl] sulfinil]-1H-benzimidazole

[2-[[(4-Methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinil] -1H-benzimidazole-1-yl] methanol /4.8 g, 14 mmol) and triethylamine /1.6 g, 15 mmol/ was dissolved in methylene chloride /100 ml. Was added a solution of thionyl chloride /1.8 g, 15 mmol/ methylene chloride /10 ml/ with such speed, that the reaction mixture is gently boiled under reflux. After 10 minutes of finding at room temperature, methylene chloride was distilled under reduced pressure, and the residue was taken into ethyl acetate /100 ml and water /50 ml/. The phases were separated, and an ethyl acetate phase was dried over sodium sulfate and viparivartate in a mixture of ethyl acetate and diethyl ether. So pl. 140-141oC. Yield: 1.5 g /27%/.

Compounds according to examples 1 1- 1 11, 1 13 1 20, 1 23 1 39 were prepared according to the method illustrated in example 1, 12.

Examples 1 21 1 22

1-Chloromethyl-(5-methoxy) and (6-methoxy)-2-[[(4-methoxy-3,5 - dimethyl-2-pyridinyl)-methyl]sulfonyl]-1H-benzimidazole.

1-Hydroxymethyl-(5-methoxy)- (6-methoxy)-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl] sulfinil] -1H-benzimidazole to 30 g of 0.08 mol /ratio 1:2/ were dissolved in toluene /500 ml, and the solution was cooled to -30oC. dropwise at -30oC was added a solution of thionyl chloride /19 g of 0.15 mol/ toluene /100 ml, and the mixture was mixed for 10 min at -30oC. Then was added dropwise a solution of triethylamine /45 g of 0.45 mol/ toluene /200 ml/. After the addition the temperature rose, and the mixture is stirred at room temperature for 30 minutes the Mixture was evaporated, and the residue /120 g/ chromatographically on silica gel /ethyl acetate-methylene chloride 50-50/, giving the target compound in the form of an isomeric mixture /ratio 1:3/.

Output: 11,9,

NMR /500 MHz, DCl3/ 2.23, 2.25, 2.26, 3.72, 3.87, 3,92, 4.88, 4.95, 4.96, 6.17, 6.18, 6.54, 6.57, 6.95, 7.01, 7.19, 7.26, 7.43, 7.67, 8.17. If desired, pure 1-chloromethyl-6-methoxy-2-[[(4-methoxy,5-dimethyl-2-pyridinyl)mate the Mr /500 MHz, DCl3/ 2.23, 2.25, 3.72, 3.92, 4.88, 4.96, 6.17, 6,57, 6.95, 7.P1, 7.67, 8.17.

Getting triethylammonium salt cyanoethyl-6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl] sulfinil] -1H-benzimidazole-1-yl] methyl diapir phosphoric acid.

1-Chloromethyl-6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl] sulfinil] -1H-benzimidazole /0,90 g, 0,0023 mol/ was added with stirring to a solution of mono-triethylammonium salt cyanoethylated ether phosphoric acid /0,70 g, 0,0028 mol/ triethylamine /0.65 g, 0,0064 mol/ methylene chloride /20 ml/. The mixture was heated under reflux over night. Methylene chloride was distilled, and the residue was heated on a water bath for 10 min at 60oWith, and then was used without further purification in subsequent reactions.

Getting dibenzyl-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl] sulfinil]-1H-benzimidazole-1-yl methyl Trevira phosphoric acid

1-Chloromethyl-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl] -sulfinil] -IH-benzimidazole /1.29 g, 3.5 mmole/ and a silver salt of dimensional ether phosphoric acid /1,79 g, 4.6 mmole/ splenderous in dry toluene. The mixture was heated on a water bath at 90oC for 3 h, after which the toluene was distilled under reduced is and gave a mixture of the oily product, which was chromatographically on silica gel /ethyl acetate/. Yield: 0.9 g /42%/ essentially pure target compound in the form of oil. NMR /500 MHz, CDCl3/ d: 2.20 /double singlet /D. C./, 6N/, 3.65 /s, ZN/, 4.8-5.0 (multiplet (m), 6N), 6.25-6.3 (m, 1H), 6.45-6.5 /m 1H/, 7.15-7.40 /m, N/, 7.65 /doublet /d/, 1H/, 7.80 /l, 1H/, 8.1 /C, 1N/.

Isomeric forms

Isomeric identity pure compound of example 29 was required when using the RLP techniques NMR on its synthetic precursor N 1 22. All other isomers benzimidazole structurally identified when the ratio of their NMR spectra to spectra of compound example No. 29.

Getting predecessors N 1 21 1 22 results in the formation of isomeric mixture in the ratio 1:2. As a consequence, the target compound N 32 and 29 are formed in the form of isomers with the same ratio of 1:2. In other examples, the isomeric ratio is sometimes different from the 1:2 and depend on the substituents, especially of the substituents in the benzimidazole core.

Brief information about the compounds of examples is given in table. 1 below.

Pharmaceutical preparations containing the compound of the invention as the active ingredient, are illustrated in the following examples ready preparative participating ingredients:

The compound according to example 29 1.0 g

Sugar, powder 30.0 g

Saccharin 0.6 grams

Glycerin 5.0 g

Taste or flavoring agent 0.05 g

Ethanol 96% 5,0 g

Distilled water as needed until a final volume of 100 ml

Sugar and saccharin were dissolved in 60 g of warm water. After cooling, the active compound was added to the sugar solution, and was added to the glycerol solution, flavoring agents, dissolved in ethanol. The mixture was diluted with water to a final volume of 100 ml.

Tablets with enterococci coating

Tablet with enterococci /small bowel/ coating containing 20 mg of active compound, was prepared from the following ingredients:

The compound according to Example 1 200 grams

Lactose 700 g

The methylcellulose 6 grams

Polyvinylpyrrolidone cross-linked 50 g

Magnesium stearate 15 g

Sodium carbonate 6 g

Distilled water as needed

Phthalate cellulose acetate 200 grams

Cetyl alcohol 15 g

Isopropanol 2000

Methylene chloride 2000

1. The compound according to example 5, the powder was mixed with lactose and granulated with a water solution of methyl cellulose and sodium carbonate. The wet mass was dented through a sieve, and the granules were put into a pill /10000 tablets/, each tablet contained 20 mg of the active substance, in teletrauma machine using the pressing stamp /punch/ diameter 6 mm

II. The solution phthalate cellulose acetate and cetyl alcohol in a mixture of isopropanol and methylene chloride was sprayed on the tablet 1 by using the equipment for coating was Obtained a final tablet weight of 110 mg.

Solution for intravenous destination

Parenteral ready preparative form for intravenous use, containing 4 mg of active compound per ml, were prepared from the following ingredients:

The compound according to example 1 to 4 grams

Sterile water to a final volume of 1000 ml

The active compound was dissolved in water to obtain a final volume of 1000 ml, the Solution was filtered through a 0.22 μm filter and immediately poured into 10 ml of sterile ampoules. The ampoule was sealed.

Tablets

Tablets containing 30 mg of active compound, was prepared from the following ingredients:

The compound according to example 33 in table. 1 300 g

Lactose 700 g

The methylcellulose 6 grams

Polyvinylpyrrolidone cross-linked /VP-XL/ 62 g

Secondary acid phosphate of sodium, 2 grams

Magnesium stearate were controlled with a solution of methylcellulose and secondary acid phosphate. The wet mass was dented through a sieve and dried in a fluidized bed dryer. After addition of magnesium stearate and the balance V-XL and mixing the mixture of the drug was merged into tablets with an average weight of 110 mg, each tablet containing 30 mg of active compound.

Tablets with small bowel or enterococci coating

500 g of tablets obtained above was covered enterococci coating. The solution of the composition below was sprayed on the tablet and the device in the fluidized bed using coating technologies

Solution coverage:

Phthalate cellulose acetate 40 g

Cetyl alcohol 2 g

Isopropanol 400 g

Dichloromethane 400 g

The final tablet coated weighed 117 mg

Medical candles

Medical candles or suppositories were prepared from the following ingredients using the procedure of welding. Each suppository contained 40 mg of active compound.

The compound according to example 3 in table. 1 to 4 grams

Witepsol N-15 180 grams

An active connection is homogeneous mixed with Witepsol N-15 at a temperature of 41oC. the Molten mass was filled into the pre-made packaging for a suppository is mg of active compound.

Syrup

Syrup, contains 1% of the active substance was prepared from the following ingredients:

The compound according to example 33 in table. 1 1.0 g

Sugar, powder 30.0 g

Saccharin 0.6 grams

Flavoring agent 0.05 g

Ethanol 96% 5,0 g

Purified water as needed

Sugar and saccharin were dissolved in 60 g of warm water. After cooling, the active compound was added to the sugar solution, and was added to a solution of flavoring agents dissolved in ethanol. The mixture was diluted with water to a final volume of 100 ml.

Solution for intravenous or intramuscular injection

The compound according to example 29 in table. 1 60g

Water for injection to a final volume of 1000 ml

The active compound was dissolved in water to a final volume of 1000 ml, the Solution was filtered through a sterile 0.22 μm filter and filled under aseptic conditions in 1 ml of sterile ampoules. The ampoule was sealed.

Preparative form for intravenous infusion

Sterile connection according to example 29 in table. 1 60 mg

Sterile vials for injection solutions and tubes.

Sterile active connection 60 mg was filled into 10 ml sterile vials for injection solutions. Puzyrkah in conditions of sterile production areas with vertical laminar flow.

Directly before use, the active compound dissolved in 10 ml of sterile water, transferred to 100 ml of normal saline solution for injection /infusion/, to give a total volume of approximately 110 ml of the Solution is administered in the form of intravenous infusion over a period of time of about 30 minutes

Biological tests

The effect of inhibition in vivo in relation to the secretion of gastric acid in conscious dogs.

Test method

Used dogs with chronic gastric fistula. These dogs surgically introduced gastric fistula into the stomach and duodenum, and the dogs were used to directly assign them intraduodenal by the test compounds. After 4 weeks of recovery after surgery, each dog was tested once a week. For 18 h before each test food and water were removed.

The secretion of gastric acid was induced continuous 4-hour infusion of histamine in the individual doses 400-600 nmol/kg / hour intravenously /centuries/, which has resulted in approximately 90% of the maximum secretion of gastric acid. After stimulation with histamine, y saline or intraduodenal /media 0,5% MetozelR, 90 G 15000, Dau Whom. Bldg./ with the help of a catheter through the duodenal fistula. Gastric juice was collected in a free flow from the gastric cannula in successive 30 min samples during infusion of histamine. The samples were titrated to pH 7.0 using 0.1 M or 1.0 M of sodium hydroxide using an automatic titrator, and was calculated output acids. The release of acid during the periods after the appointment of the test compounds or media was expressed in fraction form release /output/ during the period prior to these appointments, and the percentage of inhibition of acid secretion was calculated when comparing each dog fractional reaction caused by the test compound, with fractional responses caused by the media.

The results of the test, the data in the table. 3 below, represent inhibition within 2 h after dosing of the drug.

Solubility

Measured the solubility at room temperature of the compounds according to examples 3 /NVG salt/ 29 /disodium salt/, and it has been shown that it is higher than 60 mg per ml. For comparison, the sodium salt of omeprazole, 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-pyridinyl)methyl] sulfinil] -1H-benzimidazole, has a solubility stabilnosti

Chemical stability of various compounds of the invention were studied kinetically at low concentrations at 37oWith in aqueous buffer solution at different pH values: es. The results shown in the table. 4, below, illustrate that the compounds of the invention have a high chemical stability. TTT TTT TTT TTT TTT TTT TTT TTT TTT TTT TTT

1. Derivatives of benzimidazole of General formula I

< / BR>
where X S - or-SO-;

R1R4identical or different, are hydrogen, alkyl containing 1 to 8, especially 1 to 6 carbon atoms. alkoxy containing 1 to 8, especially 1 to 6 carbon atoms, alkoxyalkyl containing 1 to 3 carbon atoms in each alkyl part;

D group of the General formula

< / BR>
< / BR>
< / BR>
where R5group in General formula

< / BR>
< / BR>
< / BR>
where Vice phenyl group is in the meta - or para-position;

< / BR>
R6hydrogen, alkyl containing 1 to 8, especially 1 to 6, carbon atoms;

R8hydrogen, alkyl containing 1 to 8, especially 1 to 6, carbon atoms;

R7alkoxy containing 1 to 7 carbon atoms;

And straight or branched C1C8-alkylene, C3- C7-cycloalkyl, C4WITH9-alkylene containing the, NRd(Rq)v;

Ra, Rb, Rdand Rqthe same or different, - C1C6-alkyl;

Rehydrogen, ClC6-alkyl, benzyl;

m 0 8;

p 1 4;

q 1 4;

r 0 8;

t is 0 or 1;

v is 0 or 1,

moreover, group D, when it contains a phosphorus-containing group, may be in the form of mono-, di-, tri - or tetragonal salt containing a physiologically acceptable anion, and when it contains aminopentyl, it may be in the form of ammonium salt (v 1) with a physiologically acceptable cation, or in the form of a free amine (v 0), provided that A CC- C7cycloalkyl or C4C9-alkylene containing cycloalkenyl group, when both the following conditions are met: R5group

< / BR>
RaC1C3-alkyl, RbC1- C3-alkyl, Rv 0 or Rqhydrogen, and v 1,

or their physiologically acceptable salts.

2. Derivatives under item 1, where X IS SO.

3. Derivatives under item 1, where X s

4. Derivatives under item 1, where R1R4the same or different, hydrogen, C1C4-alkyl, C1C4-alkoxy, alkoxyalkyl containing 1-2 carbon atoms in each alkyl part.

P CLASS="ptx2">

6. Derivatives under item 1, where R1R4the hydrogen.

7. Derivatives under item 1, where R1, R3and R4hydrogen, R2OCH3or R1, R2and R4hydrogen, R3OCH3.

8. Derivatives under item 1, where R7C1C6-alkoxy.

9. Derivatives under item 1, where D R5where R5has the values specified in paragraph 1.

10. Derivatives under item 1, where

< / BR>
or their alkali metal salts, where Rematter specified in paragraph 1.

11. Derivatives under item 1, where the substituent in position 1 benzimidazole nucleus is

< / BR>
or their alkali metal salts.

12. Derivatives under item 1, where the substituent in position 1 benzimidazole nucleus is

< / BR>
or its alkali metal salts.

13. Derivatives under item 1, where D is selected from

< / BR>
< / BR>
< / BR>
14. Derivatives under item 1, where the pyridine fragment is 3,5-dimethyl-4-methoxy-.

15. Derivatives under item 1, where X SO that R1R4have the values specified in paragraph 4, D has the values specified in paragraph (11, R6and R8is methyl and R7methoxy.

16. Derivatives under item 1, where pyridineacetonitrile fragments are

< / BR>
< / BR>
2hydrogen, R3OCH3or R2- OCH3, R3the hydrogen.

18. The method of obtaining derivatives of benzimidazole of General formula I on p. 1, characterized in that the compound of General formula II

< / BR>
where R1R8and X have the above meanings;

Z is halogen, such as chlorine,

subjected to interaction with the compound of the General formula R5-CO2M;

< / BR>
,

,

,

,

,

where R5, Raand Rehave the specified values; M is a cation; Rpprotective group,

then, if necessary, the protective group is removed and the compound of formula I thus obtained, if necessary, transformed into a salt or optical isomer.

Priority signs:

21.11.86 when X is-S - or-SO-, R1R4identical or different, are hydrogen, alkyl containing 1 to 8, especially 1 to 6, carbon atoms, alkoxyalkyl containing 1 to 3 carbon atoms in each alkyl part, D group in General formula

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
where Vice phenyl group is in the meta - or para-position,

< / BR>
R6hydrogen, alkyl containing 1 to 8, especially 1 to 6, carbon atoms, R8hydrogen, alkyl containing 1 to 8, especially 1 to 6, atoms angle is 3C7-cycloalkyl, C4C9-alkylene containing cycloalkenyl group , Zr-, -CH2, NRd(Rq)v, Ra, Rb, Rd, Rqthe same or different, C1- C6-alkyl. Rehydrogen, benzyl, m 0 8, R 1 4, q 1 4, r 0 8, t is 0 or 1, v is 0 or 1, and group D, when it contains a phosphorus-containing group, may be in the form of mono-, di-, tri - or tetragonal salt containing a physiologically acceptable anion, and when it contains aminopentyl, it can be in the form of ammonium salt (v 1) with a physiologically acceptable cation, or in the form of a free amine (v 0), provided what is A C3C7-cycloalkyl or C4C9-Allenova group, when both the following conditions are met:

Raand RbC1C3-alkyl, v is 0 or Rqhydrogen, v is 1.

23.12.86 when

< / BR>
16.10.87 when ReC1C6-alkyl.

 

Same patents:

The invention relates to new 3[2H]-pyridazinone derived, as well as to receive them, containing their insecticidal acaricide, nematocide, fungicidal compositions for use in agriculture and horticulture; compositions for removing ticks from animals, where these compositions contain these derivatives as the active ingredient

The invention relates to new derivatives of 3(2H)-pyridazinone and to their pharmaceutically acceptable salts, possessing inhibitory activity against the aggregation of platelets, cardiotonic activity, vasodilating activity, anti-SRS-A activity, to processes for their preparation and to pharmaceutical compositions containing them as active ingredient

The invention relates to new biologically active compounds, namely, the derivative of 4-aminophenol of the formula I

XNROR1where R1represents a group WITH/ABOUT/УZ;

Y represents a single bond, 0, NR7or; Z represents hydrogen, pyridyl; phenyl which may be substituted with halogen, nitro, lower alkoxy or carboxy; lower alkyl which may be substituted by hydroxy, lower acyloxy, carboxy, lower alkoxycarbonyl, CONR8R9, phenyl/lower/ alkoxy, phenyl, halogen, cyano or NR10R11;

R2, R3, R5and R6that may be the same or different, represent hydrogen, lower alkyl or alkenyl, lower alkoxy or halogen;

R4and R7that may be the same or different, represent hydrogen or lower alkyl;

X 4.5-dihydropyrazolo or pyrazolyl, which may be substituted WITH3-C6-cycloalkyl or phenyl which can be substituted by trihalomethyl;

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The invention relates to the production of new proizvodnyh of thiazolidine that are used in pharmaceutical compositions

The invention relates to chemical-pharmaceutical industry, namely to new biologically active substances on the basis of which can be created drugs with hypotensive and analepticheskih activity

The invention relates to chemical compounds with valuable properties, in particular derivatives of 2,3-dihydropyrano[2,3-b] pyridine of General formula

< / BR>
(I) where a lower alkylene;

R is a hydrogen atom or a group

A< / BR>
or their salts

The invention relates to novel condensed heterocyclic compounds or their salts, and their intermediate compounds, method of their production and the fungicide on their basis for the processing of agricultural and horticultural crops

The invention relates to new pyridine containing heterocyclic compounds, in particular new 1,3-dioxane-5-silt derived alkenovich acids containing pyridyloxy residue attached to position 4 of the 1,3-dioxane ring

The invention relates to new derivatives of glycerol General formula

where k=1 or 0;

Lower alkyl or arylalkyl;

R1acetyl, 2-alkoxybenzyl or aryl;

n=0 or an integer from 1 to 3;

The group G formula< / BR>
orX-

A is selected from groups of formula:

(1) -NH-(CH2)where R2, R3and R4lowest alkoxygroup;

(2) -NH-(CH2)SO2-NH-R5where R5hydrogen, alkyl, or CHp=1 or 2;

(3) -NX-R6where the X group is-CH - or a nitrogen atom; R6group-СОR7where R7alkyl or alkoxy, or a group-0-C0-NH-R8where R8alkyl;

(4) -NH< / BR>
(5) -NH-(CH2)3-OR10where R10alkyl;

(6) -NH-(CH2)10-NH-CO-NR11R12where R11and R12lower alkyl;

(7) -NH-CHNO

(9) -NH-(CH2)5-0-(CH2)5-0-(CH2)5-H

(10) -NH-(CH2)3-0-CO-NH-R14where R14alkyl;

(11) -NH-CH< / BR>
(12)CHwhere m=0 or from 1 to 6; R9, R15and R16the same or different and represent hydrogen or alkoxygroup, provided that when k=0, group a sure formula

FIELD: chemistry.

SUBSTANCE: invention relates to novel derivatives of bis-(4-alkylaminopiridinium-1)alkanes of formula (1) where X stands for lipophilic anion from the following group: triiodide I3, iodate IO3, perchlorate ClO4; Y stands for either linear or branched alkylene group, which contains 4 to 18 carbon atoms; R stands for either linear or branched alkyl, cycloalkyl or arylalkyl group, which contains 5 to 18 carbon atoms, to methods of preparation thereof and application thereof as antibacterial and antiviral substances.

EFFECT: new substances show useful biological properties.

10 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to production of bis(4-alkylaminopyridine-1) alkanes of formula I where R1 -s linear or branched alkyl, cycloalkyl or arylalkyl groups having from 4 to 18 carbons, preferably from 8 to 12 carbons, ideally - normal octyl, R2 - linear or branched alkylene groups having from 4 to 18 carbons, preferably from 8 to 14 carbons, ideally - 1,10 decandyl, X1, X2 - halogenanions (identical or diverse): fluoride-, chloride-, bromide-, iodideanions, ideally - chlorideanions through interreacting of 4-alkylaminopyridine of formula II with disubstituted alkylene of formula III X1-R2-X2 in a solvent at increased temperature with mole ratio of formula II compound to formula III compound equals 2:1, the process is carried out in anoxic environment, acetic acid or its mixture with water is used as a solvent, meanwhile the compound of formula II is treated with the compound of formula III in gradual and continuous way or portionwise, ensuring the reaction at temperature ranging from 90° to 130°C, ideally from 100 to 105°C.

EFFECT: preparation of bis(4-alkylaminopyridine-1) alkanes of high quality with higher yield at essential saving of expandable materials.

6 cl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing HIV protease inhibitor atazanavir sulphate in form of Form A crystals, which involves reacting a solution of a free base of atazanavir in an organic solvent in which atazanavir sulphate is virtually insoluble, at temperature ranging from 35°C to 55°C with a first portion of concentrated sulphuric acid in an amount sufficient for reaction with less than approximately 15 wt % free base of atazanavir, addition of nucleating centres of Form A atazanavir sulphate crystals, addition of an additional amount of concentrated sulphuric acid in several steps, where the acid is added at increasing rate to form atazanavir sulphate crystals and drying the atazanavir sulphate to form Form A crystals. A method of producing atazanavir sulphate in form of Form C crystals is also proposed.

EFFECT: improved method.

20 cl, 11 dwg, 6 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I , where R2 is selected from a group consisting of (1) phenyl, which is substituted with R2a, R2b and R2c, (2) furanyl, (3) C3-6 cycloalkyl; R2a, R2b and R2c are independently selected from a group consisting of (1) hydrogen, (2) halogen, (3) C1-6 alkyl, which is unsubstituted or substituted with (a) 1-6 halogen atoms, (4) -NR10R11, where R10 and R11 are hydrogen; R3 is C1-6 alkyl or C3-6 cycloalkyl, which is independently unsubstituted or substituted with 1-6 halogen atoms; R4 and R5 are hydrogen and m equals zero, R2 is directly bonded to a carbonyl; and to pharmaceutically acceptable salts thereof. The invention also pertains to compounds which are selected from the group, as well as a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds which are active as glycine transporter GlyT1 inhibitors.

10 cl, 14 ex, 1 tbl

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