3,5-disubstituted 1,2,4-thiadiazole compounds and methods of binding of thiols

 

(57) Abstract:

Describes a new method of binding of thiols with turning them Tilney group disulfide group, which includes the interaction of compounds containing Tilney group, 1,2,4-thiadiazolyl connection with structural group of formula (I) or its pharmaceutically acceptable salts, where R1, R2, R3, R4independently represent hydrogen, lower alkyl, halogen, the nitro-group, a lower CNS group or a group having the formula R NR'r", OC(O)R', NH(CO) OR' in which R' and R" independently represent hydrogen, lower alkyl, and Y is selected from compounds having the formula (II) in which R7has a wide range of values specified in paragraph 1 of the formula. Also describes 3,5-disubstituted 1,2,4-thiadiazole compounds that can be used in diagnostic methods for trapping organic mercaptans or as diagnostic reagents. The technical result is simplification and improvement of the way the capture of thiols. 3 C. and 120 C.p. f-crystals, 5 Il.

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The invention relates to chemical trapping methods thiols and selective transformation tylnej compounds to disulfide compounds. It t is the quality of the agents, catching thiol, selective reaction with thiols, turning them into disulfides.

BACKGROUND OF THE INVENTION

Tirinya compounds exist in many chemical and biochemical systems, and in many cases are undesirable or harmful compounds that require selective removal from the system or chemical transformations. Compounds containing Tilney group SH (also known as the mercaptan group or sulfhydryl group), often have a strong unpleasant smell. Minerals such as mineral fuels (e.g. oil, natural gas and coal), often have as impurities tirinya connection with a strong unpleasant odor. The gaseous environment in the extraction and processing of crude oil, coal gasification and natural gas production are often contaminated with thiols, and to meet the requirements of the standards for the protection of the environment requires their removal.

Production of some pharmaceutical products, for example, cimetidine, ranitidine and nizatidine, includes the use of sulfur-containing reagents, and getting methylmercaptane by-products. Currently used method of disposal of these products is about to rain." In this context, also an improvement of the method of capture of thiols.

Agents, catching thiol, can be used in diagnostic methods for trapping organic mercaptans. In addition, they can be used as diagnostic reagents, for example, in the determination of sulfhydryl groups of proteins.

Of particular interest in connection with the present invention is a capture biochemical tylnej compounds, such as enzymes. Many enzymes contain an active tirinya group, derivatives of cysteine residues. Reversible or irreversible selective inhibition of the activity of such enzymes in biological systems, by reaction, modifying their tirinya group may, therefore, form the basis for therapeutic treatment. Examples of such enzymes are cathepsin B, papain, H+/K+ATPase, the enzyme that converts interleukin 1-, protein disulfide dry isomerase (HIV).

Cathepsin b and L are involved in several diseases, including progressive degradation of cartilage and bone that is associated with arthritis. Inhibitors of these cathepsins cause a reduction in inflammation and destruction of joints in animal models of arthritis. Calcium is associated is in (M Mullican et al., Bioorganic & Medicinal Chem. Lett., 1994, 2359), is a key target in drug discovery, as it plays a key role in the release of inflammatory protein, interleukin-1, and so on. Excessive levels of interleukin-1 is involved in a wide range of diseases, including rheumatoid arthritis, psoriasis, inflammatory bowel disease and insulin-dependent diabetes. As in the case of tylnej proteases, its mechanism of action is due to the presence of cysteine residues in the active center.

The proposed reversible inhibitors of these enzymes include peptidergic, NITRILES, Methocarbamol connection. The proposed irreversible inhibitors include peptidoglycansynthethase, diazomethylene, acyloxymethyl, salt kilometerscalgary, epoxides and vinylsulfonic. Although these compounds are known as inhibitors tylnej proteases, none of these structural types have not found serious applications as candidates for drugs.

The enzyme proton pump of the gastric Hs+/K+-ATPase, also known as proton pump involved in the development of peptic ulcers in mammals. This enzyme also contains active tirinya group, otnosiasciesia. Agents, catching thiol, can be used for inhibition of the enzyme H+/K+-ATPase. An example of such a connection is omeprazole.

SUMMARY OF THE INVENTION

The present invention provides a new method for trapping tylnej compounds, which is in interaction with some thiadiazole. Some of thiadiazolo used in the present invention are new chemical compounds. Others are known compounds, but are not available previously for this application. Compounds used in the present invention are characterized by the presence of 1,2,4-thiadiazole ring structure, substituted at the 3 position, but not substituted at position N-2.

One group of compounds used in the method of the present invention, represents a 1,2,4-thiadiazolo-[4,5-a] benzimidazole, corresponding to the following formula I:

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or their pharmaceutically acceptable salts, in which:

R1, R2R3, R4independently represent hydrogen, lower alkyl, halogen, nitro-, amino-, hydroxy-, lower alkoxy-, lower alkylamino-, lower dialkylamino group, R NR'r", OC(O)R', OC(O)OR', OC(O)R NR'r", NR'(COR'), NHC(O)NR'r R" or R' and R" NR'r R" form together with the N-atom a five or six-membered heterocyclic ring, those having the formula:

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in which n is 4 or 5, a Y is selected from:

(1) groups of compounds having the formula:

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in which R7represents hydrogen, hydroxyl group, lower alkyl, lower cycloalkyl, low CNS group, lower alkenyl, lower quinil, aryl, lower arylalkyl, heterocyclic group, heterocyclic, heterocyclic lowest alkylen, group R NR'r" where R' and R" are independently selected from hydrogen, lower alkyl, aryl or lower arylalkyl, or R' and R" taken together form with the N-atom a five or six-membered heterocyclic ring N(CH2)nwhere n is 4 or 5; and group ANR'R", AOR, where A represents an amino acid residue or a peptide of 2-3 amino acid residues and R' and R" have the same definition as above;

(2) heterocyclyl, lower alkylene-heterocyclyl, lower alkyl-lower alkylene heterocyclisation group, a lower alkylene-amino-heterocyclyl or aminoheterocycles, and a heterocyclic ring attached via any heteroatom or carbon atom that results in the creation of a stable structure, and heterocyclic rings, optionally substituted by 1-3 substituents selected from lower alkyl; hydroxyl group; nitro-alkyl, substituted by 1-3 substituents selected from hydroxyl group, a lower alkylcarboxylic group, phenyl, halogenfree, heterocyclyl, carboxyl and lower alkylcarboxylic groups; lower acyl; lower alkoxycarbonyl group; lower alkylsulfonyl groups; amide groups; allyl; benzyl; phenyl, optionally substituted amino group, halogenosilanes group, lower CNS group, a lower alkyl, lower alkylamino group or di-lower alkylamino group; heterocyclyl, optionally substituted by 1-3 substituents selected from nitro group, hydroxyl group, lower CNS group, lower alkyl, amino group, halogen, lower alkylamino group, di-lower alkylamino-group; with the proviso that the heterocyclic group Y is not 1-imidazolyl or substituted 1-imidazolyl;

(3) R NR'r" or-CH2-R NR'r", where R', R" have the same definition as described above;

(4) ANR'R", AOR, where A is an amino acid residue or a peptide of 2-3 amino acid residues and R', R" have the same definition as described above;

(5) the lower 2-(alkoxycarbonyl)alkyl;

(6) halogen;

(7) groups of the formula R8-CHOH-, where R8represents hydrogen, nessecities ring, attached at any heteroatom or carbon atom that results in the creation of a stable structure;

(8) groups of the formula R9-C(=NOR10), where R10represents hydrogen, lower alkyl or lower arylalkyl, a R9represents lower alkyl, aryl, lower arylalkyl, lower cycloalkyl, lower alkenyl, lower quinil or heterocyclyl, and the heterocyclic ring may be attached to any carbon atom that results in the creation of a stable structure;

(9) lower CNS group, lower arylalkenes group, lower cycloalkene group, lower heterocyclisation or heterocyclic group;

(10) lower alkylsulfonyl, lower alkylsulfonyl, arylsulfonyl, arylsulfonyl, lower arylalkylamine, lower arylalkylamine, heterocyclization, geterotsiklicheskikh, optionally substituted with 1-2 substituents selected from lower alkyl, halogen, nitro, hydroxyl group, lower CNS group or groups of the formula R NR'r", OC(O)R', OC(O)OR', OC(O)R NR'r", NR'(COR'), NHC(O)R NR'r", NHC(O)OR', where R' and R" have the meanings mentioned above;

(11) groups of formula-C(=NOH)COOR", where R11represents lower alkyl;

(12) hydrogen, zameshennomu 1-2 substituents, selected from halogen, nitro, amino, hydroxyl group, lower CNS group, a lower alkylamino group, a lower dialkylamino group, R NR'r", OC(O)R', OC(O)OR', OC(O)R NR'r", NR'(COR'), NHC(O)R NR'r", NHC(O)OR', where R' and R" have the meanings specified above.

The second class of compounds used in the method of the present invention, presents bicyclic compounds, namely, imidazo[1,2-d]-1,2,4-thiadiazole following formula II:

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in which R5and R6can have the same meanings as R1, R2, R3and R4in formula I, above, a Y has the values listed above.

The third class of compounds used in the present invention, the 3-substituted, N-2-unsubstituted thiadiazole General formula III

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where Y has the meanings indicated above, and T represents

(a) a lower alkyl group, lower alcylaryl group, secondary or tertiary amino group, amino acid residue or heterocyclic group selected from azole, pyridine, piperidine, piperazine and research; or

(b) group-M[-AMA-] L, where M is a chemical spacer elements group associated with thiadiazolyl the nucleus and is selected from

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L is N-terminal protecting group s 'or a peptide residue -[NH-CHA'-CO] -n, where1is any of the known substituents of amino acids, and n is an integer from 1 to 3; or

(c) -NHPh or diphenylguanidine group of the formula,

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in which Ph represents a phenyl, optionally substituted hydroxyl group, lower CNS group or amino group.

New monocyclic compounds used in the present invention are 3-substituted, N-2-unsubstituted thiadiazole General formula IIIa,

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in which Y' represents a lower alkyl, lower CNS group, amino group, carboxyl group, lower alkoxycarbonyl group or 1-piperazinil, optionally substituted in the 4 position by lower alkyl; lower alkyl substituted with one or two substituents selected from a hydroxyl group, a lower alkylcarboxylic group, phenyl, halogenfree, heterocyclyl, carboxy and lower alkoxycarbonyl groups; benzyl; phenyl, optionally substituted amino group, a halogen, a hydroxyl group, a lower CNS group, a lower alkyl, lower alkylamino group or a di(lower alkyl)amino group; heterocyclyl, optionally substituted by 1-3 substituents selected from nitro group, amino group, ISSI alkyl)amino group; 1,1-diphenylmethyl, in which both phenyl rings are optionally substituted with halogen, amino group, hydroxyl group or lower CNS group, 2-pyridyl, in which peregrinae ring optionally substituted by 1-3 substituents selected from nitro group, amino group, halogen, a hydroxyl group, a lower CNS group, lower alkyl, lower alkylamino group or a di(lower alkyl)amino group; or a group-CH2-CO-NH-lower alkyl;

and Q represents a

(a) group-T[-AMA-] L, where L is a chemical spacer elements group associated with thiadiazolyl the nucleus and is selected from

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L represents an N-terminal protective group of the peptide or end group-OR', NR'r R",

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where R' and R" have the meanings mentioned above; -AMA - is an amino acid or peptide residue -[NH-CHA1-CO]-nwhere A1is any of the known substituents of amino acids, and n is an integer from 1 to 3; provided that when Q is NHPh, then Y' is not CNS group, dialkylamino group, hydroxyethylamino group, a di(hydroxyalkyl)amino group; and when Y' is 4-substituted piperazinil, then Q is not a group-T-[AMA]-L.

Another aspect of the brew is lalibala Tilney group in the reaction tylnej compounds through the formation of disulfide compounds. Reactions involving tylnej compounds occur in solution, for example, in the aquatic environment, such as body fluids at temperatures and other relevant conditions for maintaining liquid solutions or suspensions reagents.

BRIEF DESCRIPTION OF DRAWINGS

Fig. 1 is an illustration of the chemical interaction between the thiol compounds and 3-substituted 1,2,4-thiadiazole compounds in accordance with the present invention;

Fig. 2 is an illustration of a synthetic sequence to obtain the most preferred compounds for use in the method of the present invention;

Fig. 3 is a graphical representation of the results of example 41 below.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

Preferred compounds used in the pharmaceutical methods, i.e. the inhibition of the enzyme proton pump, through interaction with its mercaptane groups have specificity against mercaptan functional group, which is manifested in the fact that imidazo[1,2-d] -thiadiazoline the core of these compounds shows a limited reactivity or does not show at all in relation to the other well is Emax, in particular, the heterocyclic ring 1,2,4-thiadiazolo[4,5-a] benzimidazole is directionspanel in relation to these nucleophiles.

Especially preferred compounds of formulas I and II for use in the methods in accordance with this invention are such compounds in which R5and R6represent hydrogen, a Y is an R7CO in which R7is lower alkyl, aryl, hydrogen or 2-pyridium, optionally substituted by 1-3 substituents selected from methyl and methoxy.

Especially interesting and preferred group of compounds in accordance with the present invention are compounds having in the side chain residue of an amino acid or peptide. In accordance with this invention, these compounds can be mono-, di - or tricyclic compounds. Side chains of amino acid or peptide residues can join bicyclic or tricyclic core 3 position thiadiazole ring (group Y). In monocyclic compounds such side chains can join 3 or 5 position.

The application of amino acid or peptide residues as side chains of monocyclic which enables the selection of the appropriate of the group, showing affinity binding to the enzyme, which is inhibited by the connection. In addition, the affinity of the binding can be adjusted by appropriate selection of such a side chain to the connection associated with the enzyme at the location of the protein chain enzyme adjacent to Tilney group of enzyme that attacks the connection. As described below and illustrated in Fig. 1 of the accompanying drawings, it-S-N= C grouping, the compounds of the present invention, activated respectively selected by a group Y, is the key when attacking Colnago connection with the formation of disulfide. The presence of the respectively selected binding or recognizing the enzyme group as a side chain connections at the position remote from the groups-S-N=C, allows the connection to find and associate the selected enzyme and enhance chemical attack on Tilney group of the enzyme. Compounds of this nature in this invention are highly selective when attacking specific selected enzyme and are much less reactive towards other thiols with whom they can meet, due to the sensing side of the group.


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This group is the recognition sequence for cathepsin b and papain in position adjacent to them-SH groups. Accordingly, such a connection as 3-methoxy-5-amino-1,2,4-thiadiazole in which this lateral group is associated with the 5-amino group, is a good inhibitor of cathepsin L, cathepsin b and papain.

Peptide recognition sequence for cathepsins b and L can be determined as follows (shown attached to the 5-position of the 1,2,4-thiadiazole of the present invention):

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where Y is as defined previously;

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in each case represents the amino acid residue so that A1is any of the groups known amino acids, PG is a N-protecting group selected from geterotsiklicheskikh, benzoyl, carbobenzoxy, tributoxy; B2is hydrogen, lower alkyl, optionally substituted amino group, guanidino or N,N-di(lower alkyl)guanidino, and n is 1 or 2.

The same group can be used in bi - and tricyclic compounds in accordance with the present invention. A preferred group of the formula-NH-CHA1-CO is latil. A preferred group B1-NH)nis a dipeptide, i.e. phenylalanyl-alanyl.

For inhibition of the enzyme that converts interleukin-1, which recognizes a side chain represented by the compounds of the present invention, preferably is a Tripeptide, for example, the side group having the General formula:

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where (CO-CHA1-NH)nis valinol-alanyl-aspartyl, and PG is carbobenzoxy group, preferably attached to a position remote from the groups-S-N= C-, for example, to the position of a monocyclic 5 thiadiazole of the present invention.

Accordingly, additional specific preferred compounds of formula III to the present invention include compounds in which T represents an amino acid or peptide residue, for example compounds having the formula:

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formula:

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formula:

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if Y = OCH3it is particularly compounds having the formula:

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compounds in which W is an amino acid or peptide residue with formula AOR' or ANR'R", for example, the compounds of formula:

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and the compounds of formula:

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All compounds used in the method of the present invention are characterized by the structure of calcualtion connection S-N in positions 1, 2. While maintaining these characteristics, the diversity of the groups and substituents in position 4 and 5 thiadiazoline kernel can be very wide without significant impact on a substantial chemical reactivity of these compounds.

Hereinafter in this description is used:

the term "lower" as applied, for example, the lower alkyl means a chain of from 1 to 8 carbon atoms.

The term "aryl" alone or in combination, means a radical of phenyl or naphthyl, optionally having one or more substituents selected from alkyl, CNS group, halogen, hydroxyl group, amino group, etc. such as phenyl, p-tolyl, 4-methoxyphenyl, 4-(tert-butoxy)phenyl, 4-forfinal, 4-chlorophenyl, 4-hydroxyphenyl, 1-naphthyl, 2-naphthyl, etc.

The term "arylethoxysilanes" separately or in combination, means a radical (formula-C(O)-O-arylalkyl in which the term "arylalkyl" has the meaning given above. An example of radical arylethoxysilanes is benzyloxycarbonyl.

The term "arylalkyl" means an alkyl radical in which one hydrogen atom is substituted by an aryl radical, such as benzyl, phenylethyl, etc.

The term "cycloalkylcarbonyl" means acyl grapnel, cyclohexanecarbonyl, adamantanecarbonyl, etc. or from benzododecinium monocyclic cycloalkylcarbonyl acid optionally substituted, for example, alkylamino groups, such as 1,2,3,4-tetrahydro-2-naphtol, 2-acetamido-1,2,3,4-tetrahydro-2-naphtol.

The term "arylalkyl" means an acyl radical derived from an aryl-substituted alkenylboronic acid, such as phenylacetyl, 3-phenylpropionyl, hydrocinnamic, 4-phenylbutyl, (2-naphthyl)acetyl, 4-longitutinal, 4-aminohydrocinnamic, 4-methoxycinnamyl etc.

The term "aroyl" means an acyl radical derived from an aromatic carboxylic acid. Such radicals include, for example, the radical of an aromatic carboxylic acid, optionally substituted benzoic or naphthoic acids, such as benzoyl, 4-chlorobenzoyl, 4-carboxybenzoyl, 4-(benzyloxycarbonyl)benzoyl, 1-naphtol, 2-naphtol, 6-carboxy-2-naphtol, 6-[(benzyloxy)carbonyl] -2-naphtol, 3-benzyloxy-2-naphtol, 3-hydroxy-2-naphtol, 3-[(benzyloxy)formamido]-2-naphtol etc.

The term "heterocyclyl" used in this description, except noted, represents a stable 5 to 7-membered mono - or bicyclic or stable 7-10 membered shall consists of carbon atoms and from 1 to 3 heteroatoms, selected from the group consisting of N, O, S, and where the heteroatoms nitrogen and sulfur may be optionally oxidized, and the nitrogen atom may be optionally quaternity, and includes any bicyclic group in which any of videopreteen heterocyclic ring condensed with the benzene ring. The heterocyclic ring can be attached to any heteroatom or carbon atom, joining which leads to the creation of a stable structure. Examples of such heterocyclic elements, commonly known as heterocyclyl include piperidinyl, piperazinil, 2-oxopiperidine, 2-oxopiperidine, 2-oxopiperidine, 2-oxopyrrolidin, 2-oxoazetidin, azepine, pyrrolyl, 4-piperidinyl, pyrrolidinyl, pyrazolyl, pyrazolidine, imidazole, imidazoline, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,

oxazolidinyl, isoxazolyl, isoxazolidine, morpholine, thiazolyl, diazolidinyl, isothiazolin, hinokitiol, isothiazolinones, indolyl, chinoline, ethenolysis, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothiazyl, tetrahydropyranyl (e.g. 1,2,3,4-tetrahydro-2-hee is bolini, 2-benzofuranyl, thiomorpholine, thiomorpholine sulfoxide, thiomorpholine sulfon, oxadiazolyl, etc., the Heterocycle may be substituted by one or more atoms of carbon or the heteroatom with the formation of a stable structure.

The term "amino acid residues" means any of the naturally occurring-and-aminocarbonyl acids, including D and L optical isomers and racemic mixtures, and N-lower alkyl - N-phenyl lower alkyl derivatives of these amino acids. Amino acid residue is attached via the nitrogen atom of the amino acids. Naturally occurring amino acids that can be included in the present invention include, but are not limited to, alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, ornithine, phenylalanine, Proline, serine, threonine, thyroxine, tryptophane, tyrosine, valine, alanine, and-aminobutyric acid.

Preferred amino acid residues include Proline, leucine, phenylalanine, isoleucine, alanine, -aminobutyric acid, valine, glycine and phenylglycine.

All amino acids, except glycine, contain at least one asimmetricheskie racemic mixtures. Accordingly, some compounds of the present invention can be obtained in optically active form or as racemic mixtures of the claimed compounds.

The term "A", in which A is an amino acid or peptide of 2-3 amino acid residues, refers to an amino acid or peptide to diradical beginning with HN-radical on the left side of A, and ending with-C(O) radical on the right side. For example, the abbreviation of the amino acid glycine is HAOH, where A is HN-CH2-C(O).

The term "aryloxyalkanoic" denotes the acyl radical of the formula aryl-O-alkanoyl.

The term "heterocalixarenes" means an acyl group derived from heterocyclic-O-CO-, in which heterocyclyl defined above.

The term "heterocyclisation" means an acyl radical derived from heterocyclyl-substituted alkenylboronic acid, in which heterocyclyl has the value given above.

The term "geterotsiklicheskikh" means an acyl radical derived from heterocyclyl-substituted alkyl-O-COOH, in which heterocyclyl has the value given above.

The term "aminoalkyl" means an acyl radical derived from amino-Thames containing substituents, selected from hydrogen and alkyl, aryl, kalkilya, cycloalkyl, cycloalkenyl radicals, etc.

The term "pharmaceutically acceptable, nontoxic salts" refers to pharmaceutically acceptable salts of the compounds of the present invention that retain the biological activity of compounds from which they are derived, and are not junk in a biological or other relationship (e.g., salt should be stable). The compounds of this invention can form salts of two types: (1) salts of inorganic and organic bases of the compounds of formula I which have a functional group carboxylic acid; (2) salts of acid accession can be formed with a functional amino group of many compounds of this invention.

Pharmaceutically acceptable salts derived from inorganic bases include salts of sodium, potassium, lithium, ammonium, calcium, magnesium, iron (II), zinc, copper, manganese (II), aluminium, iron (III), manganese (III), etc. are Particularly preferred salts are the ammonium, potassium, sodium, calcium and magnesium. Pharmaceutically acceptable, nontoxic salts derived from organic bases include salts of primary, secondary and tertiary tars. Examples of such bases can be, for example, Isopropylamine, trimethylamine, diethylamine, triethylamine, Tripropylamine, ethanolamine, 2-dimethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, Hydrobromic, choline, betaine, Ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polianinova resin, etc. are Particularly preferred non-toxic organic bases are Isopropylamine, diethylamine, ethanolamine, piperidine, tromethamine, dicyclohexylamine, choline and caffeine.

Pharmaceutically acceptable salts of the acid accession are formed with inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonate acid, econsultancy acid, p-toluensulfonate CIAM animals particularly mammals (e.g., dogs, cats, horses, cattle, pigs, and so on), reptiles, fish, insects and worms.

Below are some specific preferred compounds used in the methods of the present invention:

3-(1-oxoethyl)-1,2,4-thiadiazolo[4,5-a] benzimidazole, which has the following chemical formula:

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3-(oxoferryl)-1,2,4-thiadiazolo[4,5-a] benzimidazole, which has the following chemical formula:

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3-(2-pyridyl)-1,2,4-thiadiazolo[4,5-a] benzimidazole, which has the following chemical formula:

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3-(4-methyl-1-piperazinil)-1,2,4-thiadiazolo[4,5-a] benzimidazole, which has the following chemical formula:

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3-(4-morpholinyl)-1,2,4-thiadiazolo[4,5-a] benzimidazole, which has the following chemical formula:

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3-(1-pyrrolidinyl)-1,2,4-thiadiazolo[4,5-a] benzimidazole, which has the following chemical formula:

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3-bromo-1,2,4-thiadiazolo[4,5-a] benzimidazole, which has the following chemical formula:

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3-[(4-methoxy-3,5-dimethyl-2-pyridyl)oxoethyl] -1,2,4-thiadiazolo[4,5-a] benzimidazole, which has the following chemical formula:

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3-carboxy-1,2,4-thiadiazolo[4,5-a] benzylmethyl] -1,2,4-thiadiazolo[4,5-a]benzimidazole, which has the following chemical formula:

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3-(4-methylphenylsulfonyl)-1,2,4-thiadiazolo[4,5-a] benzimidazole, which has the following chemical formula:

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3-(1-oxoethyl)imidazo[1,2-d] -1,2,4-thiadiazole, which has the following chemical formula:

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3-(oxoferryl)imidazo[1,2-d] -1,2,4-thiadiazole, which has the following chemical formula:

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3-(4-acetyl-1-piperazinil)-1,2,4-thiadiazolo[4,5-a] benzimidazole, which has the following chemical formula:

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3-[4-(3-amino-2-pyridyl)piperazinil] -1,2,4-thiadiazolo[4,5-a] benzimidazole, which has the following chemical formula:

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3-[4-(2-pyridyl)piperazinil] -1,2,4-thiadiazolo[4,5-a] benzimidazole, which has the following chemical formula:

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3-[4-(3-amino-2-pyridyl)piperazinil-methyl] -1,2,4-thiadiazolo[4,5-a] benzimidazole, which has the following chemical formula:

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3-[4-(2-pyridyl)piperazinil-methyl] -1,2,4-thiadiazolo[4,5-a]benzimidazole, which has the following chemical formula:

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3-{ [4-(1-(4-chlorophenyl)-1-phenylmethyl)piperazinil] methyl}-1,2,4-thiadiazolo[4,5-a]benzimidazole, which has the following chemical formula:

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(3-Methoxy-1,2,4-thiadiazole-5-yl)carbarnoyl-L-leucyl isoamylase, which has the following homemeet the following chemical formula:

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The present invention provides synthetic methods for producing compounds of the present invention. Some of these methods include the conversion of one compound into another, different from such connection. The choice of the method depends strongly on the selected group Y, i.e., the substituent in the 3 position of the final product.

In imidazole[1,2-d]thiadiazole compounds and compounds of formula IV, described in these methods, X and Z are R5, R6or, taken together, represent a benzene ring condensed with the imidazole ring, and optionally substituted R1, R2, R3and R4.

In the first method, applied to bi - or tri-cyclic compounds, the corresponding 3-oxo compound of formula V (see below), having in the 2 position as a substituent of lower alkyl or lower arylalkyl interacts with YCN in an inert solvent. This method is suitable for compounds in which Y is lower alkyl, aryl, arylalkyl, cycloalkyl, 1-halogenation, 1,1-dehalogenation, heterocyclyl, lower alkylsulfonyl or arylsulfonyl. This reaction can be represented as follows:

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The appropriate bat is 1,1-dehalogenated, lower alkylsulfonyl, arylsulfonyl or heterocyclic, for the most part are commercially available, e.g., from Aldrich Chemical Co. Alternatively, they may be obtained by methods known in the art (see e.g. , Chapter 17 in Organic Functional Group Preparations, Vol. I by Sandler and Karo, Academic Press, 1983). Acetonitrile, benzonitrile, 2-cyanopyridine, cyclopentadiene, dibromoacetonitrile, 6-Canouan and p-toluensulfonyl cyanide are some typical examples. This reaction usually proceeds at elevated temperatures from 70 to 140oC in an inert solvent, such as toluene, dimethylformamide over a period of 6 to 24 hours, preferably 16 hours. In some cases, YCN is used as the solvent. The product distinguish using traditional means.

Compounds of formulas I and II, i.e., bicyclic and tricyclic compounds in which Y is amino, lower alkylamino, lower dialkylamino, thioalkyl, can also be obtained from compounds of formula YCN, in which Y is amino, lower alkylamino, lower dialkylamino or lower thioalkyl. Examples YCN in this category are the cyanamide, 1-piperidinecarbonitrile, metallicana, which is commercially available.

2-Alkyl-1,2,4-thiadiazolo[4,5-a]benzimidazole-3(2H)-ones of formula V is obtained from alkylsulfonate and 2-mercaptobenzimidazole in accordance with the method of Martin et al., Tetrahedron, 1983, 39, 231 1. 2-Alkylimidazole[1,2-d]-1,2,4-thiadiazole-3(2H)-ones of formula V is obtained from alkylsulfonate and 2-mercaptoimidazole in accordance with the methodology Tittlebach et aL, J. Prakt Chem. 1988, 330, 338 - 348. 2-Mercaptobenzimidazole or are commercially available or can be obtained using methods well known in this area or easily accessible from literature data. Commercially available 2-mercaptobenzimidazole include 5-methyl-2-mercaptobenzimidazole, 5-methoxy-2-mercaptobenzimidazole, 5-chloro-2-mercaptobenzimidazole. The corresponding 2-Mercaptobenzimidazole that are not commercially available, can be obtained using known methods. Preparative method involves the way Billeter et al., Ber., 1887, 20, 231, Org. Synth., Coll. Vol. 4,569, Futaki et al., J. Pharm. Soc. Jpn., 1954, 74, 1365, Bucknall et al., Nature 1967, 213, 1099.

Secondly, similar to the method used to obtain the bicyclic and tricyclic compounds in which the group Y in the final connection is R7-C=O, a, R7represents lower alkyl, aryl, NISS and a heterocyclic ring attached via any heteroatom or carbon atom, joining which leads to the creation of a stable structure, R NR'r", ANR'R", AOR', where A is an amino acid residue or a peptide of 2-3 amino acid residues, a, R', R" have the same definition as above, the compound of General formula:

< / BR>
interact with the corresponding 3-oxo compound, bearing in the second position as a substituent of lower alkyl or lower arylalkyl, i.e. the compound of formula V used in the first method described above, namely:

< / BR>
This reaction can be carried out in an inert solvent, such as dichloromethane, tetrahydrofuran or dimethylformamide. The reaction proceeds at room temperature over a period of 3 to 48 hours, usually about 6 hours. The resulting solid is then allocate using conventional methods.

The majority of derivative cyanomethane, canoeiro formula VI are commercially available. Derivatives cyanomethane used in this invention are either commercially available or can be obtained using methods known in this field. Commercially available cyanomethane include benzylcyanide, acetylene, methoxycarbonylamino. A list of commercially available cyan is either cyanomethane, cyanoethyl that are not commercially available, can be easily obtained using methods known in this field, such as the methods described in Mathieu et al., Formation of C-C Bonds, Vol I, p. 456-457, George Thieme Verlag, 1973, Stuttgart. Other suitable methods include methods Koenig et al., Tet. Lett., 1974, 2275 and Ando et al., Synthesis, 1983, 637. These methods include the interaction of the acid chloride with copper cyanide or potassium cyanide.

Alternative compounds of formula I in which Y is R7-C=O, a, R7has the same definition as described above, can be obtained by hydrolysis of compounds of formula I in which Y is R7-C(Hal)2and where Hal is a halogen. Such hydrolysis can be carried out in a strongly acidic medium or in an aqueous solution of silver nitrate, and can be represented as follows:

< / BR>
The third way to obtain imidazole and benzimidazole products with a Y group as in the second method described above includes, as a final stage, the interaction of 2-chiefindianlung the compounds of formula VI with m-chloroperbenzoic acid (MCPBA) in an inert solvent, resulting in cyclization with the formation of 1,2,4-thiadiazole ring, and may be represented by the following about what imidazole (VIII) in the presence of a base, with the formation of the compounds of formula VI. Examples of such bases are sodium hydroxide or potassium hydroxide. The reaction proceeds in a mixture of water and alcohol at room temperature for about 1 to 16 hours, preferably 8 hours, the product compound VI distinguish using traditional methods.

Compound VI interacts with m-chloroperbenzoic acid in an inert solvent such as dichloromethane or 1,2-dichloroethane, with the formation of the compounds of formula I in which Y is R7-C=O. the Reaction proceeds at room temperature for about 3 to 8 hours, preferably 3 hours. The product distinguish using traditional methods.

Prometriumoccidental (VII) derived in turn is produced by the interaction of the compounds of formula X with N-bromosuccinimide in an inert solvent such as carbon tetrachloride.

In the fourth way as the original substance is used as a compound of the formula IA and modify it with the formation of compounds of formula I in which Y is CHOH-R7(formula IB) or C=NOH-R7(formula IC), or COOH (formula ID), as follows;

< / BR>
The compounds of formula IB can be obtained by in what cyanoborohydride sodium in alcohol. The compound of formula IB distinguish using traditional methods.

The compounds of formula IC can be obtained by reacting the compounds of formula I in which Y is R7-C=O, with derivatives of hydroxylamine. Examples of hydroxylamines are hydroxylamine, methoxylamine, amoxillin, benzylacrylamide. The conversion of the ketone to an oxime is well known in the art (see , for example, Sandler and Karo, Organic Functional Group Preparations, 1989, Vol. III, Chapter II).

The compounds of formula ID, in which R7is a hydroxyl group, can be obtained by basic hydrolysis of compounds of formula I in which Y is R7-C=O, a, R7is lower CNS group. The reaction is carried out in the 1M sodium hydroxide at room temperature in a mixture of water and an organic solvent, such as methanol, ethanol, 1,4-dioxane or acetonitrile. The product distinguish using conventional methods after the neutralization of the base with dilute acid.

In the fifth method used to produce compounds of formulas I and II in accordance with this invention in which Y represents halogen, use the same source compound of formula V, as in the first and second methods, which vzaimodeystviya produce using conventional methods.

In the sixth way as the original substances using compounds of formulas I and II where Y is a halogen, i.e., compounds obtained in accordance with the fifth method described above, which interact with the primary or secondary amine, or alcohol, with formation of compounds of formula I in which Y represents R NR'r", AOR', ANR'R, OR', R', R" have the same definition as above. This process flows better, if Y in the original substance is bromine. It can be represented thus:

< / BR>
Nucleophiles, such as lower alkoxides, aryloxides, lower arillashiga, lower cycloalkane, ammonia, lower alkylamines followed, the lowest dialkylamino, heterocyclic amines, HNR'R", HANR'R", HAOR', where A is an amino acid residue or a peptide of 2-3 amino acid residues that interact with the compounds of the formula I, where Y = bromide, in an inert solvent, with the formation of compounds of formula I, where Y represents lower alkoxy, aryloxy, lower Allakaket, lower cycloalkane, amino, lower alkylamino, lower dialkylamino, R NR'r", ANR'R", AOR', where A is an amino acid residue or a peptide of 2-3 amino acid residues.

In the seventh method as starting substances is obtained on the fourth way, described above), and they interact with the amine, with the formation of the compounds of formula I, where Y is a CO-R7where R7is R NR'r", AOR', ANR'R", as follows:

< / BR>
Thus, the compounds of formulas I and II, in which Y is R7-C=O, a, R7is R NR'r", AOR', ANR'R" can be obtained by reacting compounds of carboxylic acids of the formula I, where Y is COOH, amidon amino acids HANR'R", or amines HNR'R", or ether amino acids HAOR', in the presence of a dehydrating agent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCl) and hydroxybenzotriazole in an inert solvent, such as tetrahydrofuran, dimethylformamide or dichloromethane.

The eighth method used to produce compounds in which Y represents a lower alkylsulfonyl, arylsulfonyl, heterocyclization, lower arylalkylamines, lower alkylsulfonyl, arylsulfonyl, heterocyclisation or lower arylalkylamines, includes the interaction of the thioester compounds with a predefined amount of oxidizing agent, as follows:

< / BR>
where n = 1 or 2. The preferred oxidizing agent for use in this process is m>One of the preferred methods accordingly this invention is the inhibition of enzymes in vitro or in vivo, and especially enzyme inhibition of the proton pump H+/K+-ATPase, for the treatment of stomach ulcers in humans. The main achievement in the treatment of peptic ulcers consists in the introduction of inhibitors of H+/K+- ATPase. The enzyme H+/K+-ATPase, is well known as a proton pump, is located in the membrane of parietal cells of the stomach and is responsible for proton transport from the blood to the cavity cells, reducing the pH of gastric contents, which leads to the aggravation of ulcers. The effectiveness of the method of the present invention, consisting in the capture of this enzyme, and therefore, provides a means of treating peptic ulcers, is demonstrated in several examples below. However, the methods of the present invention can be applied in a wide range of other chemical systems, catching thiol, as in the biochemical (enzyme), and industrial, as evidenced below in connection with their reactivity towards penetrometry.

As thiadiazoline connection catch tiradera compounds through the formation of S-S connection, they can reveal the s label in chemical modification of cysteine residues, or enzyme. Because these compounds can function as affinity labels for enzymes containing cysteine residues, they are useful inhibitors of many physiological enzymes, such as cathepsin, papain, an enzyme that converts interleukin-1 and protein the disulfide isomerase (HIV), and H+/K+-ATPase. Because metabolic pathway enzymes are involved in several physiological and pathological States of the compounds of this invention have many potential therapeutic applications.

Alternative agents, catching thiol, can interact with the cysteine residue on the enzymes or proteins, and thereby to change the biochemical properties of the enzyme. Agents that absorb thiol, can be useful agents, stabilizing and improving enzymes containing cysteine residues. Examples of some of these therapeutically important enzymes are PCl convertase, furin (see O Rabilly S. et al. New England Journal of Medicine, 1995, 23, 1386-1390). PCl is convertases responsible for the processing of proglucagon in the peptide GLP-1. Regulators GLP-1 may be useful therapeutic agents in the treatment of diabetes and obesity. The compounds of this invention are agents, absorbing SS="ptx2">

The reactivity of these compounds in the method of this invention can be illustrated by their interaction with penicillata. It is widely illustrated in Fig. 1 tilenum reagent, R group which is a phenethyl. In addition, according to previous studies (Im et al., J. Biol. Chem., 1985, 260, 4591; Strum et al., J. Org. Chem., 1987, 52, 4573; Lorentzon et al., Biochim. Biophys. Acta, 1985, 817, 25), penicillata can be used as a model of H+/K+-ATPase to determine the reactivity of compounds in relation to tilenum groups of this enzyme. It was found that the compounds of formula I interact with penicillata (RSH = PhCH2CH2SH, Fig. 1) in an inert solvent with the formation of the compounds of formula XI. The compound of formula XI interacts with an additional mole of penicillata with the formation of compounds of formula XII, which decomposes with formation of compounds of formulas XIII and XIV.

Requires at least two mol of penicillata on 1 mol of the substrate in order to open the ring, 1,2,4-thiadiazolo[4,5-a]benzimidazole with the formation of compounds of formula XII. Usually, the reaction disclosing the ring slowly with two moles of penicillata. The speed of this reaction C is but the compounds used in the present invention, to quickly interact with penicillata in accordance with the method shown in Fig. 1. The disulfide can not be selected, because it was discovered that he quickly communicates with the second mercaptan with the formation of disulfide penicillata and represents an intermediate connection. This decay is captured Colnago intermediate compounds with the formation of disulfide observed in the chemical model H+/K+-ATPase (Lindberg et al., J. Med. Chem., 1986, 29, 1329). Noteworthy is the fact that in the real enzyme the second stage, including attack another Tilney group does not hold, due to spatial factors hindering the approach of the two enzymes, or leads to the formation of disulfide bonds in the case, if there is another nearby Tolna group. In both cases, this leads to inhibition of the enzyme.

In accordance with the present invention it was found that such a connection as 3-methoxy-5-amino-1,2,4-thiadiazole interact with benzylmercaptan in an organic solvent, such as methanol, to form a 3-thiocarbamoylation:

< / BR>
Other 1,2,4-thiadiazoles, do not interact with benzylmercaptan under similar conditions. Chemical reactivity monocyclic 1,2,4-thiadiazole, as agent, catching thiol depends on the substituent in the 5 and 5-position of the cyclic system.

Derivatives of 1,2,4-thiadiazolo[4,5-a]benzimidazole enter into a similar reaction with mercaptans:

< / BR>
If RSH is thiophenols, the resulting dimer Ph-S-Ph can be selected. This reaction is common for a number of 1,2,4-bicyclic and tricyclic 1,2,4-thiadiazolo with different substituents in the 3-position of the heterocycle.

Preferred compounds used in the methods of this invention are heterocyclic compounds with molecular weight less than 440. Range of log P of these molecules, i.e., the distribution coefficient between octanol and water, varies from 0.5 to 4.0, which covers the interval lipophilicity of the most well-known drugs. This is an important factor in the development of therapeutic drugs and reflects the fact that the individual analogs may have potential use as therapeutic agents for diseases in which the inhibition diastereomer enzymes is a possible solution in the treatment of disease.

One specific preferred compound for use in the methods in accordance with the present invention is 7-methoxy-3-[(4-methoxy-3,5-dimethyl-2-pyridyl)oxoethyl] -1,2,4-thiadiazolo[4,5-a] benzimidazole. This molecule carries an electron-acceptor group in the 3 position of the heterocyclic ring. It has limited solubility in water. The structure of this compound proved by x-ray crystallography.1H and13C NMR, IR, mass spectrometry and elemental analysis provide additional evidence of the chemical identity of the compound. Next, the individual parts of its receipt, characterization, and properties shown in the specific examples below. The connection is active in the suppression of gastric acid in animal models.

To ensure the, surface application or parenterally in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvant and environment for drugs. The term parenteral as used in this application, includes subcutaneous injection, or infusion techniques. In addition to the treatment of warm-blooded animals, such as mice, rats, horses, cattle, sheep, dogs, cats and so on, the compounds of this invention can be effectively used in the treatment of the person.

The compositions can be used in conventional non-toxic solid carriers, including, for example, mannitol, lactose, starch, magnesium stearate, saccharin sodium, talc, cellulose, glucose, sucrose, magnesium carbonate, etc. with pharmaceutical purity. The active compound, as defined above, formuliruetsya as liquid pharmaceutical compositions for administration may, for example, be obtained by dissolving, dispersing, etc. an active compound, as definitely above and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, etc., with education through this solution or suspecion additives, such as moisturizing or emulsifying agents, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, the triethanolamine oleate, etc., Existing methods for such dosage forms are known, or will be obvious to specialists in this area: for example, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa, 15th Edition, 1975. The composition is prepared for administration in any case contains the active compound(I) in an amount effective to alleviate symptoms of the patient.

Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, in the form of tablets, wafers, cakes, aqueous or oil suspensions dispersed powders or granules, emulsions, hard or soft capsules, or syrups, or Alexiou. Compositions intended for oral use can be obtained in accordance with any known method for the production of pharmaceutical compositions and such compositions contain one or more agents from the group consisting of sweetening agents, fragrances, dyes and preservatives to obtain pharmaceutically elegant and palatable preparations. Tablets contain activata tablets. The excipients can be, for example, inert solvents, such as calcium phosphate or sodium phosphate; granulating or dezintegriruetsja agents, for example corn starch or alginic acid; binding agents, for example starch, gelatin or gum Arabic, and lubricating agents, e.g. magnesium stearate, stearic acid or talc. Tablets may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide actions for a long period. This approach can be applied to monostearate and distearate glycerin.

Ready-made forms for oral administration may be presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, for example, from coconut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active substance in a mixture with excipients acceptable for the manufacture of aqueous suspensions. Such excipients are suspendresume agents, aprilrain, resin and gum Arabic; dispersing or moisturizing agents, namely, natural phosphate, for example, lecithin, or condensation products of halcinonide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, heptadecanol-epoxiconazole, or condensation products of ethylene oxide with partial esters derived from fatty acids and anhydrides hexitol, for example, monooleate polyethylenimine. Aqueous solutions may also contain one or more preservatives, for example ethyl or n-propyl, n-hydroxybenzoate, one or more coloring agents, such as sucrose or saccharin.

Oil suspensions can be prepared by suspension of the active ingredient in a vegetable oil, such as peanut oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweeteners, such as those mentioned above, and perfumes can be added to obtain a palatable preparation for oral administration. These compositions can EROSKI and granules to obtain an aqueous suspension by adding water contain the active ingredient mixed with dispersing or wetting agent, suspendium agent, or one or more preservatives. Examples of suitable dispersing or wetting agents and suspendida agents mentioned above. Can also be additional recipients, for example, sweetening, flavouring and tinted agents.

The pharmaceutical compositions of this invention can also be in the form of emulsions of oil-in-water. The oil phase may be a vegetable oil such as olive or peanut oil, or mineral oil, for example, liquid paraffin, or mixtures thereof. Suitable emulsifying agents may be natural phosphates, esters from fatty acids and anhydrides hexitol, for example, monooleate sorbitan, and the condensation products mentioned partial esters with ethylene oxide, for example, monooleate of polyoxyethylenesorbitan. The emulsions may also contain sweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for example, glycerin, propylene glycol, sorbitol or sucrose. Such compositions may also contain painkillers, preservatives, fragrances and dyes. Pharmaceutical compositions mullaney and suspendida agents, which were mentioned above. Sterile injectable preparations may also be a sterile solution or suspension for injection in a non-toxic parenterally acceptable diluent or solvent, for example, in the form of a solution in 1,3-butanediol. To an acceptable environments for drugs and solvents that may be used include water, solutions of ringer's solution and isotonic sodium chloride solution. In addition, as a solvent or suspension medium is usually used hardened oil. For this purpose, can be used any soft hardened oils, including synthetic mono - or diglyceride. In addition, in the production of drugs for injection have been used fatty acids such as oleic acid.

Parenteral administration typically involves the injection, as subcutaneous, intramuscular, and intravenous. Preparations for injection can be obtained in traditional forms, such as in the form of liquid solutions or suspensions in a liquid for injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol, etc., in Addition, optionally, the pharmaceutical compositions intended for insertion, and emulsifying agents, support pH agents, etc., such as, for example, sodium acetate, monolaurate sorbitan, triethanolamine oleate, etc.

The amount of active ingredient that may be combined with substances-carriers to obtain a single dosage form may vary depending on the patient, the route of administration and may contain from 0.5 mg to 5 g of active agent, combined with relevant and appropriate number of media, which may vary from about 5% to 95% of the total composition. Dosage unit forms usually contain from about 1 mg to 500 mg of active ingredient.

It is clear, however, that the specific dose level for each individual patient depends on a number of factors including the activity of the applied compound, the age, body weight, General health, sex, diet, time of administration, combination of drugs and the severity of the particular disease undergoing therapy.

Hereinafter the invention is described and illustrated by the following specific examples.

A SEPARATE DESCRIPTION OF THE PREFERRED EMBODIMENTS

Example 1

Getting bromo(2-pyridyl)acetonitrile

To a solution of (2-pyridyl)acetonitrile (12,0 round. The mixture is refluxed for 1.5 hours, the Resulting precipitate removed by filtration, and the solvent is removed under reduced pressure with the formation of the crude product, which is recrystallized from hexane, getting to 18.6 g (94%) of the compound indicated in the title, in the form of red crystals: I. pl. 62-64oC;1H NMR (DMCO-d6) : 8.67 (d, 1H), 7.97 (t, 1H), 7.70 (d, 1H), 7.51 (td, 1H), 5.60 (p, 1H) ppm; IR (KBr): 3064, 2972, 1712, 1587, 1470, 1439, 1051, 993 cm-1); MC m/z 196, 198 (M+, 117 (M+-Br); HRMS calculated for C7H5BrN2195.9630 found 195.9645.

In the same way get the following connection: bromo(4-methoxy-3,5-dimethyl-2-pyridyl)acetonitrile:

so PL 56-57oC;1H NMR (CDCl3) : 8.31 (s, 1H), 5.67 (s, 1H), 3.81 (s, 3H), 2.37 (s, 3H), 2.30 (s, 3H) ppm;13C NMR (CDCl3) : 164.84, 150.19, 149.56, 128.28, 125.59, 115.49, 60.135, 27.99, 13.51, 11.05 ppm; IR (KBr): 3415, 2988, 2210, 1568, 1472, 1255, 997, 791 cm-1MC m/z 255, 257 (MH+), 175 (M+- Br).

Example 2

Synthesis of [(2-benzimidazolyl)thio](2-pyridyl)acetonitrile

A mixture of 2-mercaptobenzimidazole (0,30 g, 3.0 mmol), bromo(2-pyridyl)acetonitrile (0,59 g, 3.0 mmol) and potassium carbonate (0,37 g, 3.0 mmol) in 50 ml of dry N, N-dimethylformamide is heated at 60oC for 6 hours, the Solvent is evaporated. The residue is dissolved in these the blockhead magnesium and evaporated, getting solid. The crude product is then purified by the method of column chromatography on silica gel (100% ethyl acetate) to give 66 mg (10%) specified in the connection header in the form of a solid substance; so pl. 166-167oC;1H NMR (DMSO-d6) : 9.3 (m, 1H), 8.65 (m, 2H), 8.32 (m, 1H), 7.78 (br s, 4H), 4.81 (br s, 2H) ppm; IR: 2206, 1512, 1465, 1432, 1357, 1179, 740 cm-1.

Similarly, by replacing 2-mercaptobenzimidazole 2-mercaptoimidazole receive the following connection:

[(2-imidazolyl)thio](2-pyridyl)acetonitrile:

so pl. 203-204oC (Razlog.);1H NMR (CDCl3) : 8.51 (d, 1H), 7.65 (t, 1H), 7.36 (d, 2H), 7.12 (d, 1H), 7.03 (dd, 1H), 6.33 (br s, 2H) ppm.13C NMR (CDCl3) : 154.08, 148.23, 145.76, 136.84, 134.95, 134.43, 119.15, 118.40, 109.32, 96.15 ppm; IR (KBr) 3344, 3225, 2202, 1643, 1493, 1485, 1427 cm-1;

Example 3

Synthesis of [(5-methoxy-2-benzimidazolyl)thio](4-methoxy-3,5 - dimethyl-2-pyridyl)acetonitrile

To a solution of 2-mercapto-5-methoxybenzimidazole (15,1 g of 0.14 mol) in 40 ml of 8.4% sodium hydroxide add 170 ml of methanol, and then bromine(4-methoxy-3,5-dimethyl-2-pyridyl) acetonitrile (21,4 g of 0.11 mole) at room temperature. The mixture is heated under reflux for 1 h in nitrogen atmosphere. The resulting precipitate is removed by filtration, and the methanol evaporated. The resulting residue is extracted with chlorine is accidenly product is recrystallized from diethyl ether, getting to 22.6 g (90%) indicated in the title compound as yellowish crystals: I. pl. 193-197oC;1H NMR (CDCl3) : 8.25 (s, 1H), 7.65 (dd, 1H), 7.30 (m, 1H), 6.90 (m, 1H), 6.30 (br s, 2H), 3.95 (s, 3H), 3.75 (s, 3H), 2.50 (s, 3H), 2.20 (s, 3H) ppm.

Example 4

Synthesis of 3-[oxo-(2-pyridyl)methyl]imidazo[1,2-d]-1,2,4-thiadiazole

To a solution of [(2-imidazolyl)thio] (2-pyridyl)acetonitrile (30 mg, of 0.14 mmole) in 5 ml of chloroform, portions add 0.12 g of 60% m-chloroperbenzoic acid (0,42 mmole). The mixture is stirred for 10 h at room temperature. The resulting mixture was washed with water and saturated sodium bicarbonate solution. The organic phase is treated with charcoal and filtered, obtaining the crude product. After chromatography on silica gel (100% ethyl acetate) to obtain 22 mg (84%) indicated in the title compound as a yellowish solid: so pl. 147-148oC;1H NMR (CDCl3) : 8.87 (d, 1H), 8.30 (m, 2H), 7.95 (m, 1H), 7.57 (m, 1H), 7.52 (m, 1H) ppm; IR (KBr) 1700, 1660 cm-1; MC m/z 230 (M+); HRMS calcd for C10H6N4OS 230.0262 found: 230.0257.

Example 5

Synthesis of 7-methoxy-3-[(4-methoxy-3,5-dimethyl-2 - pyridyl)oxoethyl] -1,2,4-thiadiazolo[4,5-a] benzimidazole and 6-methoxy-3-[(4-methoxy-3,5-dimethyl-2-pyridyl)oxoethyl]-1,2,4 - thiadiazolo[4,5-a]benzimidazole

To a solution of [(5 by dropwise 60% m-chloroperbenzoic acid (8,62 g, 30 mmol), dissolved in 100 ml of chloroform at 0-5oC for 1 h After the addition finished, the reaction mixture was stirred 1 h at room temperature. The resulting mixture was washed with water and dried over magnesium sulfate. The solvent is evaporated, obtaining the crude product. After chromatography on silica gel (ethyl acetate: hexane 1:1) get 0.828 g (10%) 7-methoxy-3-[(4-methoxy-3,5-dimethyl-2-pyridyl)oxoethyl]-1,2,4 - thiadiazolo[4,5-a]benzimidazole in the form of a yellowish solid substance and 0.828 g (10%) 6-methoxy-3-[(4-methoxy-3,5-dimethyl-2 - pyridyl)oxoethyl]-1,2,4-thiadiazolo[4,5-a]benzimidazole in the form of solids.

7-methoxy-3-[(4-methoxy-3,5-dimethyl-2-pyridyl)oxoethyl] - 1,2,4-thiadiazolo[4,5-a]benzimidazole: so pl. 170-171oC;1H NMR (DMSO-d6) : 8.34 (s, 1H), 7.86 (d, 1H), 7.29 (d, 1H), 6.93 (dd, 1H), 3.84 (s, 6H), 2.42 (s, 3H), 2.31 (s, 3H) ppm; IR (KBr): 1684, 1654 cm-1; MS m/z 369 (M++1).

6-methoxy-3-[(4-methoxy-3,5-dimethyl-2-pyridyl)oxoethyl] - 1,2,4-thiadiazolo[4,5-a]benzimidazole:

so pl. 196-197oC;1H NMR (DMSO-d6) : 8.34 (s, 1H), 7.67 (d, 1H), 7.34 (d, 1H), 7.10 (dd, 1H), 3.84 (s, 3H), 3.74 (s, 3H), 2.44 (s, 3H), 2.31 (s, 3H) ppm; IR (KBr): 1684 cm-1; MC m/z 369 (M++1).

Example 6

Synthesis of dibromo(2-pyridyl)acetonitrile

To a solution of (2-pyridyl)acetonitrile is the temperature. The resulting mixture was heated under reflux for 22 hours After cooling, the precipitate is filtered off. Carbon tetrachloride is evaporated, getting 13.5 g (96%) of bromo(2-pyridyl)acetonitrile in the form of a dark brown solid: so pl. 59-61oC;1H NMR (CDCl3) : to 8.62 (d, 1H), to 7.93 (d, 1H), 7,86 (dt, 1H), 7,35 (dt, 1H) ppm;13C NMR (CDCl3) : 155,23, 148,94, 138,24, 125,38, 120,55, 115,81, 30,81 ppm; MCBP calculated for C7H4N2Br2: 273,8741 found: 273,8730.

Example 7

Synthesis of 2-butyl-1,2,4-thiadiazolo[4,5-a]benzimidazole-3(2H)-it

A mixture of 2-mercaptobenzimidazole (29,30 g, of € 0.195 mole) and utilizationof (48,3 ml of 0.33 mol) in 500 ml round bottom flask equipped with a condenser, heated to 130-140oC on an oil bath for 45 minutes and Then the reaction mixture is cooled to room temperature, the solid is filtered off, washed with hexane, and dried under vacuum, obtaining 43,48 g (89%) of 1-(butylcarbamoyl)-1,3-dehydrobenzperidol-2-tion in the form of white crystals: I. pl. 179-180oC.

To a solution of 1-(butylcarbamoyl)-1,3-dehydrobenzperidol-2-thione (39,89 g of 0.16 mol) in 250 ml of chloroform, add 25,57 g (0,16 mol) of bromine in 110 ml of chloroform at 0oC. After adding to the reaction mixture was added stirred at room temperature for 14 hours The resulting mixture was washed with water and then with 10% solution of sodium sulfate. The organic layer is dried over magnesium sulfate and evaporated, obtaining the crude product. After re-crystallization from methanol receive 27,10 g (69%) of 2-butyl-1,2,4-thiadiazolo[4,5-a]benzimidazole-3(2H)-it is in the form of colorless crystals: I. pl. 153-154oC (lit. data: 156-157oC, Martin etal. Tetrahedron 1983, 39, 2311).

Similarly, substituting n-utilitzant other alkylsulfonate receive the following connections:

2-ethyl-1,2,4-thiadiazolo[4,5-a]benzimidazole-3(2H)-he

2-isopropyl-1,2,4-thiadiazolo[4,5-a]benzimidazole-3(2H)-he

2-methyl-1,2,4-thiadiazolo[4,5-a]benzimidazole-3(2H)-he

2-phenyl-1,2,4-thiadiazolo[4,5-a]benzimidazole-3(2H)-he

2-benzyl-1,2,4-thiadiazolo[4,5-a]benzimidazole-3(2H)-he

Example 8

Synthesis of 3-[bromo(2-pyridyl)methyl]-1,2,4-thiadiazolo[4,5-a]benzimidazole

A mixture of 2-butyl-1,2,4-thiadiazolo[4,5-a]benzimidazole-3(2H)-she (2.0 g, 8.1 mmol) and dibromo(2-pyridyl)acetonitrile (4,91 g, 17.8 mmol) in 50 ml of dichloromethane is heated under reflux for 16 hours After cooling to room temperature, the precipitate is filtered, washed with dichloromethane and dried, obtaining 2.76 g (80%) of the compound indicated in the title, in the form of a light brown solid fuel is;13C NMR (CDCl3) : 166,08, 157,95, 150,34, 148,28, 147,71, 138,31, 128,76, 124,79, 124,58, 122,94, 121,68, 119,49, 113,97, 54,37 ppm; MCBP calculated for C14H8Br2N4S: 421,8836 found: 421,8850.

Example 9

Synthesis of 3-(oxoferryl)-1,2,4-thiadiazolo[4,5-a]benzimidazole

A mixture of 2-butyl-1,2,4-thiadiazolo[4,5-a]benzimidazole-3(2H)-she (6.0 g, 24.3 mmol) and benzylcyanide (6,36 g, 48.5 mmol) in 80 ml of dichloromethane is stirred at room temperature for 24 hours the Precipitate is filtered and washed with dichloromethane. The crude product is recrystallized from acetone, getting 6,48 g (96%) of 3-(oxoferryl)-1,2,4-thiadiazolo[4,5-a]benzimidazole in the form of yellow crystals: I. pl. 190-191oC;1H NMR (CDCl3) : 8,35 (d, 3H), of 7.82 (d, 1H), 7,73 (t, 1H), to 7.59 (t, 2H), 7,50 (t, 1H), was 7.36 (t, 1H) ppm;13C NMR (CDCl3) : 180,86, 163,69, 150,82, 146,70, 134,79, 134,34, 131,22 (2C), 129,46 (2C), 128,74, 125,82, 122,27, 119,49, 115,23 ppm; IR (KBr): 1671 cm-1; MCBP calculated for C15H9N3OS: 279,0466 found: 279,0475. Analytically calculated for C15H9N3OS: C, 64,50; H, 3,25; N, 15,04. Found: C, 63,93; H, 3,10; N, 14,53.

Similarly, replacing benzylcyanide provoditsya receive the following connections:

3-(1-oxoethyl)-1,2,4-thiadiazolo[4,5-a] benzimidazole: so pl. 180-181oC;1H NMR (CDCl3) : 8.70 (d, 1H), 7.80 (d, >1. MCBP calculated for C10H7N3OS: 217,0310 found: 217,0318. Analytically calculated for C10H7N3OS: C, 55,29; H, 3,25; N, 19,34. Found: C, 55,31; H, 3,29; N, 19,46.

Similarly, replacing benzylcyanide other cyanides, receive the following connections:

3-(1-oxopropyl)-1,2,4-thiadiazolo[4,5-a]benzimidazole

3-(1-oxobutyl)-1,2,4-thiadiazolo[4,5-a]benzimidazole

3-(1-oxo-2-phenylethyl)-1,2,4-thiadiazolo[4,5-a]benzimidazole

3-(cyclopentylacetyl)-1,2,4-thiadiazolo[4,5-a]benzimidazole

3-(1-oxo-2-phthalimidomethyl)-1,2,4-thiadiazolo[4,5-a]benzimidazole

Example 10

Synthesis of 3-methyl-1,2,4-thiadiazolo[4,5-15A]benzimidazole

2-Butyl-1,2,4-thiadiazolo[4,5-a] benzimidazole-3(2H)-he (1,00 g of 4.04 mmol) is heated under reflux in 100 ml of acetonitrile for 18 hours the Solvent is then evaporated and the residue recrystallized from methanol, getting 0.671 g (88%) of the compound indicated in the title: so pl. 192-193oC;1H NMR (CDCl3) : 7,81 (dm, 2H), 7,47 (td, 1H), 7,34 (td, 1H), 2,92 (s, 3H) ppm; IR (KBr): 1564, 1481, 1453, 1430, 1304, 1208, 756, 745 cm-1; MS m/z 189 (M+), 148 (M+-CH3CN).

Similarly, replacing the acetonitrile with other alkyllithium receive the following connections:

3-ethyl-1,2,4-thiadiazolo[4,5-a]benzyl

Example 11

Synthesis of 3-([4-(methoxycarbonyl)phenyl] )-1,2,4-thiadiazolo[4,5-a] benzimidazole

A mixture of 2-butyl-1,2,4-thiadiazolo[4,5-a]benzimidazole-3(2H)-she (0.3 g, 1.2 mmol) and methyl-4-cyanobenzoate (0,41 g, 2.5 mmol) in 7 ml of dichloromethane is heated under reflux for 20 hours the Precipitate is filtered and washed with dichloromethane, getting 0.16 g(48%) 3-([4-(methoxycarbonyl)]phenyl-1,2,4-thiadiazolo [4,5-<] benzimidazole in the form of a solid white color: so pl. 204-206oC; 1H NMR (CDCl3) : 8,33 (d, 2H), 7,98 (d, 2H), 7,83 (d, 1H), 7,49 (m, 2H), 7,20 (t, 1H), was 4.02 (s, 3H) ppm;13C NMR(CDCl3) : 165,96, 165,30, 151,08, 149,10, 133,16, 132,55, 130,24 (2C), 128,69 (3C), 125,34, 121,58, 119,96, 112,01, 52,56 ppm; IR(KBr): 1729, 1508, 1448, 1275, 733 cm-1; MCPB calculated for C16H11N3O2S, 309,0572 found 309,05719.

Example 12

Synthesis of 3-(4-methylphenylsulfonyl)-1,2,4-thiadiazolo[4,5-a]benzimidazol

A mixture of 2-butyl-1,2,4-thiadiazolo[4,5-a] benzimidazole-3(2H)-she (10.0 g, 40.4 mmol) and p-toluensulfonate (14,7 g, 81.0 mmol) in 120 ml of dichloromethane was stirred at room temperature for 20 hours the Precipitate is filtered and washed with dichloromethane, receiving 12.2 g (91%) of 3-(4-methylphenylsulfonyl)- 1,2,4-thiadiazolo[4,5-a]benzimidazole as a white powder: so pl. 231-234oC;1H NMR (CDCl3) : 8,534, 123,06, 119,70, 114,67, 21,93 ppm; IR (KBr): 1592, 1525, 1444, 1337, 1151, 1081, 735 cm-1; MCBP calculated for C15H11N3O2S2: 329,0293 found: 329,0300. Analytically calculated for C15H11N3O2S2: C, 54,70; H, 3,37; N, OF 12.76. Found: C, 54,29; H, 3,14; N, 14,59.

Example 13

Synthesis of 3-(methoxycarbonyl)-1,2,4-thiadiazolo [4,5-a] benzimidazole

A mixture of 2-butyl-1,2,4-thiadiazolo[4,5-a]benzimidazole-3(2H)-she (4.0 g, 16.2 mmol) and medicinepharmacy (2,75 g, 32.4 mmol) in 30 ml of dichloromethane is stirred at room temperature for 21 hours the Precipitate is filtered and washed with dichloromethane getting to 3.36 g (84%) of 3-(methoxycarbonyl)-1,2,4-thiadiazolo[4,5-a] benzimidazole as colourless solids: I. pl. 208-209oC;1H NMR (CDCl3) : 8,61 (d, 1H), 7,82 (d, 1H), 7,51 (t, 1H), 7,31 (t, 1H), 4,17 (s, 3H) ppm;13C NMR (CDCl3) : 164,02, 156,51, 150,67, 140,89, 129,34, 125,93, 122,41, 119,48, 115,41, 54,04 ppm; IR(KBr): 1733 cm-1; MCBP calculated for C10H7N3O2S 233,0259 found 233,0262. Analytically calculated for C10H7N3O2S: C, 51,50; H, TO 3.02; N, 18,02. Found: C, 51,41; H, 2,89; N, 18,16.

Similarly, replacing medicinepharmacy other cyanoformate receive the following connections:

3-(etoxycarbonyl)-1,2,4-thiadiazolo[4,5-a]azolo[4,5-a]benzimidazole

3-[(benzyloxy)carbonyl]-1,2,4-thiadiazolo[4,5-a]benzimidazole

3-[(cyclopentyloxy)carbonyl]-1,2,4-thiadiazolo[4,5-a]benzimidazole.

Example 14

Synthesis of 3-(2-pyridyl)-1,2,4-thiadiazolo[4,5-a]benzimidazole

A mixture of 2-butyl-1,2,4-thiadiazolo[4,5-a] benzimidazole-3(2H)-she (15.0 g), 60.7 mmol) and 2-cyanopyridine (13.3 g, of 0.13 mol) in 150 ml of dichloromethane is stirred at room temperature for 72 hours the Precipitate is filtered and washed with dichloromethane, getting 10.4 g (68%) of 3-(2-pyridyl)-1,2,4-thiadiazolo[4,5-a] benzimidazole in the form of a solid substance white: so pl. 173-174oC;1H NMR (CDCl3) : of 8.90 (d, 1H), to 8.70 (d, 1H), 8.30 to (d, 1H), 7,99 (t, 1H), 7,80 (d, 1H), EUR 7.57 (t, 1H), 7,47 (t, 1H), 7,37 (t, 1H) ppm; 13C NMR (CDCl3) : 166,10, 151,09, 150,11, 148,74, 147,73, 137,38, 130,50, 125,85, 125,24, 124,52, 121,41, 119,11, 116,33 ppm; IR(KBr): 3419, 3054, 1611, 1587, 1501, 1463, 1446, 727 cm-1. MCBP calculated for C13H8N4S 252,0470 found 252,0882. Analytically calculated for C13H8N4S: C, 61,89; H, 3,20; N, 22,21. Found: C, 61.48 Mass; H, 3,30; N, 22,24.

Example 15

Synthesis of 3-amino-1,2,4-thiadiazolo[4,5-a]benzimidazole

To a chilled solution of 2-butyl-1,2,4-thiadiazolo[4,5-a] benzimidazole - 3(2H)-she (2.00 g, of 8.08 mmol) in 25 ml dichloromethane, add one portion of the cyanamide (0,728 g, 16.2 mmol) and the mixture is stirred for 48 what chlormethine, receiving 1.01 g (66%) of 3-amino-1,2,4-thiadiazolo[4,5-a] benzimidazole as colourless crystals: I. pl. 255-256oC;1H NMR (DMSO-d6) : 8,23 (d, 1H), 7,71 (d, 1H), 7,43 (t, 1H), 7,54 (s, 2H), 7,32 (t, 1H) ppm; IR (KBr): 3302, 3151, 1661, 1577, 1487, 1473, 1251, 1207, 810 cm-1; MCBP calculated for C8H6N4S 190,0313 found 190,0293. Analytically calculated for C8H6N4S: C, 50,51; H, 3,18; N, 29,45. Found: C, 50,26; H, 3,26; N, 29,38.

Example 16

Synthesis of 3-bromo-1,2,4-thiadiazolo[4,5-a]benzimidazole

A mixture of 2-butyl-1,2,4-thiadiazolo[4,5-a] benzimidazole-3(2H)-she (5.0 g, 20.2 mmol) and cyanogenmod (4,28 g, 40.4 mmol) in 100 ml dichloromethane was stirred at room temperature for 26 hours the Precipitate is filtered and washed with dichloromethane, getting 4,18 g (81%) of 3-bromo-1,2,4-thiadiazolo[4,5-a] benzimidazole as a white powder: so pl. 189-190oC;1H NMR (CDCl3) : 8,23 (d, 1H), 7,82 (d, 1H), 7,52 (t, 1H), 7,42 (d, 1H) ppm;13C NMR (1: 1 CDCl3:DMSO-d6) : 162,78, 149,67, 129,22, 125,53, 122,25, 119,48, 117,25, 111,27 ppm; IR(KBr): 3025, 2925, 1601, 1493, 1451, 1028, 757, 701 cm-1; MCBP calculated for C8H4N3SBr 252,9309 found 252,9307. Analytically calculated for C8H4N3SBr: C, 37,81; H, 1,59; N, 16,54. Found: C, 37,44; H, 1,33, N, 16,57.

Similarly, replacing cyanogenmod other CYANOGEN ha the olo[4,5-a]benzimidazole

Example 17

Synthesis of 3-[oxo(2-pyridyl)methyl]-1,2,4-thiadiazolo[4,5-a]benzimidazole

To a solution of 3-[bromo(2-pyridyl)methyl]-1,2,4-thiadiazolo[4,5-a] benzimidazole (2,02 g, 4.76 mmol) in 75 ml of tetrahydrofuran, add a solution of silver nitrate (0,890 g of 5.24 mmol) in 75 ml of water. The suspension is stirred for 2 days and then alkalinized to pH 6 aqueous solution of sodium bicarbonate. After adding 1 ml of saturated solution of sodium chloride, the mixture is filtered on celite celite and washed with ethyl acetate. After extraction with water, the ethyl acetate is dried and evaporated, obtaining the crude residue, which was purified by the method of flash chromatography using a mixture of chloroform/methanol 10:0.1 as eluent. Get 1,05 g (78%) of the compound indicated in the heading in the form of a solid yellow: so pl. 182-186oC (decomp.);1H NMR (CDCl3) : cent to 8.85 (m, 1H), 8,31 (dt, 1H), 8,19 (d, 1H), 8,01 (td, 1H), 7,83 (d, 1H), 7,63 (ddd, 1H), 7,50 (ddd, 1H), 7,35 (ddd, 1H) ppm; IR (film) 1673, 1511, 1444, 1235, 1057, 879, 733 cm-1; MS m/z 280 (M+), 148 (M+-(2-pyridyl)C(O)CN).

Example 18

Synthesis of 3-[bis(etoxycarbonyl)methyl]-1,2,4-thiadiazolo[4,5-a]benzimidazole

A mixture of 3-bromo-1,2,4-thiadiazolo[4,5-a]benzimidazole (0.2 g, 0.78 mmol), diethylmalonate (0.15 g, 0.94 mmol) and triethylamine (of 0.13 ml, 0.94 mmol) silaceata, washed with water and 10% aqueous solution of sodium sulfate. The organic layer is dried over magnesium sulfate, receiving the crude product that is purified by the method of flash chromatography (35% ethyl acetate: 65% hexane), with the formation of 0.14 g (54%) of the compound indicated in the title, in the form of a yellow oil:1H NMR (CDCl3) : 9,48 (s, 1H), of 8.06 (d, 1H), 7,63 (d, 1H), 7,34-7,31 (m, 2H), 4,39 (q, 4H), of 1.35 (t, 6H) ppm; IR (film) 1748 cm-1. MCBP calculated for C15H15N3O4S 333,0783 found 333,0794.

Example 19

Synthesis of 3-methoxy-1,2,4-thiadiazolo[4,5-a] benzimidazole

To a cooled mixture of 3-bromo-1,2,4-thiadiazolo[4,5-a]benzimidazole (4,55 g, 17.9 mmol) in 50 ml of methanol, add one portion of sodium methoxide (0,967 g, 17.9 mmol) and stirred for 4 h at room temperature. The reaction mixture is evaporated to dryness under vacuum, the residue is placed in ethyl acetate and washed with water. The organic layer is dried with sodium sulfate, filtered and evaporated, receiving of 3.64 g (94%) of 3-methoxy-1,2,4 - thiadiazolo[4,5-a]benzimidazole as colourless crystals: I. pl. 172-175oC;1H NMR (CDCl3) : 7,83 (d, 1H), of 7.75 (d, 1H), 7,42 (t, 1H), 7,27 (t, 1H), 4,32 (s, 3H) ppm;13C NMR (CDCl3) : 163,2, 150,2, 148,1, 128,2, 124,9, 121,8, 119,2, 111,7, 57,5 ppm; IR(KBr): 3418, 2942, 1595, 1492, 1404, 1275, 1255, 1206, 1083, 755 cm-1. And Similarly, replacing the sodium methoxide other alkylamide metals, receive the following connections:

3 ethoxy-1,2,4-thiadiazolo[4,5-a]benzimidazole

3-propoxy-1,2,4-thiadiazolo[4,5-a]benzimidazole

3 isopropoxy-1,2,4-thiadiazolo[4,5-a]benzimidazole

3 butoxy-1,2,4-thiadiazolo[4,5-a]benzimidazole

3-tert-butoxy-1,2,4-thiadiazolo[4,5-a]benzimidazole

3-(cyclopentyloxy)-1,2,4-thiadiazolo[4,5-a]benzimidazole

Example 20

Synthesis of 3-(dimethylamino)-1,2,4-thiadiazolo[4,5-a]benzimidazole

To a cooled mixture of 3-bromo-1,2,4-thiadiazolo[4,5 - a]benzimidazole (15,44 g, 0,0603 mol) in 100 ml of dichloromethane, is added dropwise dimethylamine (40% solution in water) (5,44 g, 0,121 mol). The reaction mixture was left to mix for 16 h at room temperature. Then it was diluted with dichloromethane, washed with water, dried with sodium sulfate and evaporated under vacuum, obtaining of 10.47 g (80%) of 3-(dimethylamino)-1,2,4-thiadiazolo[4,5-a]benzimidazole as colourless crystals: I. pl. 102-104oC;1H NMR (CDCl3) : 7,74 (t, 2H), 7,41 (t, 1H), 7,27 (t, 1H), 3,06 (s, 6H) ppm. Analytically calculated for C10H10N4S: C, 55,03; H, TO 4.62; N, 25,69. Found: C, 54,53; H, The 4.90; N, Is 25.50.

Similarly, substituting dimethylamine other amines, receive the following connections:
m, 2H), the 7.65 (d, 1H), 7,43 (t, 1H), 7,21 (t, 1H) 3,68 (q, 2H), 1,45 (t, 3H) ppm.

3-(1-pyrrolyl)-1,2,4-thiadiazolo[4,5-a]benzimidazole:

so pl. 118-119oC;1H NMR (CDCl3) : to 7.77 (t, 2H), 7,43 (t,1H), 7,28 (t, 1H), 3,71 (m, 4H), 2,07 (m, 4H) ppm.

3-(4-morpholinyl)-1,2,4-thiadiazolo[4,5-a]benzimidazole:

so pl. 140-142oC;1H NMR (CDCl3) : for 7.78 (d, 1H), 7,60 (d, 1H), 7,45 (t, 1H), 7,32 (t, 1H), 3,99 (m, 4H), of 3.48 (m, 4H) ppm.

3-(1-piperazinil)-1,2,4-thiadiazolo[4,5-a]benzimidazole:

so pl. 116-118oC; 1H NMR (CDCl3) : 7,76 (d, 1H), 7,63 (d, 1H), 7,42 (t, 1H), 7,30 (t, 1H), 3,41 (m, 4H), 3.15 in (t, 4H), from 2.00 (br s, 1H) ppm.

3-(4-methyl-1-piperazinil)-1,2,4-thiadiazolo[4,5-a]benzimidazole:

so pl. 158-158.5oC;1H NMR (CDCl3) : to 7.77 (d, 1H), to 7.64 (d, 1H), 7,42 (t, 1H), 7,32 (t, 1H), 3,49 (m, 4H), 2,70 (m, 4H), 2,43 (s, 3H) ppm.

3-[[2-(methoxycarbonyl)methyl] amino] -1,2,4-thiadiazolo[4,5 - a]benzimidazole:

so pl. 196-197oC. Analytical calculated for C11H10N4O2S: C, 50,37; H, A-3.84; N, 21,36. Found: C, 50,13; H, Of 3.96; N, 21,26.

Similarly, substituting dimethylamine other nucleophilic amines, get the following connection:

3-(methylamino)-1,2,4-thiadiazolo [4,5-a]benzimidazole

Example 21

Synthesis of 3-[(hydroxyimino)phenylmethyl]-1,2,4-thiadiazolo[4,5 - a]benzimidazole

To a solution of 0.5 g (1.79 mmol) of 3-(oxopentanoate hydroxylamine. The mixture is heated under reflux during the night. The precipitate is collected by filtration and washed with methanol and dichloromethane, receiving the crude product which is recrystallized from methanol, getting to 0.47 g (89%) of the compound indicated in the title, in the form of white crystals, so pl. 247oC;1H NMR (DMSO-d6) : 11,89 (s, 1H), 7,81 (d, 1H), 7,73 (dd, 2H), 7,45-7,53 (m, 5H), 7,32 (t, 1H) ppm;13C NMR (CDCl3) : 168,25, 155,24, 150,52, 147,95, 136,94, 135,67, 134,30 (2C), 133,03, 131,52 (2C), 130,35, 127,26, 124,28, 116,91 ppm; IR(KBr): 2731, 1549, 1475, 1450, 1251, 1194, 983, 753, 736 cm-1. MCBP calculated for C15H10N4OS 294,0575 found 294,0583.

Example 22

Synthesis of 3-(1-hydroxyethyl)-1,2,4-thiadiazolo[4,5-a]benzimidazole

To a suspension of 3-(1-oxoethyl)-1,2,4-thiadiazolo[4,5-a]benzimidazole (729 mg, 3.36 mmol) in 200 ml of methanol is added sodium borohydride (140 mg, at 3.69 mmol). The mixture is stirred for 30 min and add 0.1 ml of water. The methanol is evaporated and the residue distributed between ethyl acetate and 0.1 M hydrochloric acid. The aqueous phase is extracted with ethyl acetate. The combined organic phases are washed twice with saturated saline solution, dried and evaporated. The crude residue purified by chromatography using chloroform/methanol, getting 3-(1-hydroxyethyl)-1,2,4-thiadiazolo[4,5-a] Benzema is, 478, 1451, 1374, 1250, 1200, 1123, 1103, 1093, 752, 729, 711 cm-1; MS m/z 219 (M+), 148 (M+- CH3CH(OH)CH).

Example 23

Synthesis of 3-carboxy-1,2,4-thiadiazolo[4,5-a]benzimidazole

To 6 ml of 1N NaOH added 3-(methoxycarbonyl)-1,2,4-thiadiazolo[4,5-a]benzimidazole (1.0 g, 4.3 mmol) in 6 ml of dioxane. The reaction mixture was stirred at room temperature until completion of the reaction. The resulting mixture was then acidified with 3N HCl to pH ~2,0, and stirred at room temperature for another 0.5 hours, the Solid is filtered off, washed with water and dried under vacuum at 60oC for 24 h, receiving 0.74 g (78%) of the compound indicated in the title, in the form of colorless solids: I. pl. 184-185oC (decomp);1H NMR (DMSO-d6) : 13,79 (br s, 1H), 8,59 (d, 1H), 7,78 (d, 1H), 7,51 (t, 1H), 7,40 (t, 1H); IR (KBr): 3435, 1705 cm-1; MS m/z 193 (M+- OH), 175 (M+- CO2).

Example 24

Synthesis of sodium 3-carboxylato-1,2,4-thiadiazolo[4,5-a 30-a]benzimidazole

To a suspension of 3-carboxy-1,2,4-thiadiazolo[4,5-a] benzimidazole (10,00 g, 45,62 mmol) in methanol (150 ml) and water (100 ml), add 1M NaOH (45,6 ml) within 1 h After 4 h, the solution becomes transparent and the methanol removed under reduced pressure. The aqueous solution is extracted with chloroform, the aqueous phase lyophilizer, receiving R (DMSO-d6) : to 7.68 (d, 1H), 7,05 (d, 1H), 6,95 (t, 1H), 5,80 (t, 1H) ppm; 13C NMR (DMSO-d6) : 167,20, 161,76, 149,68, 148,84, 129,52, 126,23, 122,74, 118,37, 116,06 ppm; IR(KBr): 3395, 3243, 1663, 1641, 1522, 1443, 1334, 827, 729 cm-1.

Example 25

Getting the dihydrochloride of 3-(4-methyl-1-piperazinil)-1,2,4 - thiadiazolo[4,5-a]benzimidazole

A transparent solution of 3-(4-methyl-1-piperazinil)-1,2,4 - thiadiazolo[4,5-a] benzimidazole (6,07 g, 22,21 mmol) in 100 ml of dichloromethane, bubbled with gaseous hydrogen chloride for 40 minutes With time, the solution becomes turbid. The suspension is filtered and dried under vacuum, obtaining mentioned in the title compound as a fine white powder (7,60 g (99%)), I. pl. 252oC (decomp.);1H NMR (DMSO-d6& D2O) : a 7.85 (d, 2H), 7,60 (t, 1H), 7,51 (t, 1H), 3,86 (m, 2H), of 3.56 (m, 6H), 2.91 in (s, 3H) ppm; 13C NMR (DMSO-d6& D2O) : 164,39, 148,80, 144,27, 126,92, 126,12, 123,41, 117,08, 113,20, 51,19, 45,87, 42,32 ppm; IR(KBr): 3420, 1606, 1571, 1475, 1461, 1225, 981, 761 cm-1.

Example 26

Getting 2-butylimido[1,2-d]-1,2,4-thiadiazole-3(2H)-it

2-Mercaptoimidazole (24,39 g, 0,244 mol) and utilizationa (48,3 g, 0,487 mole) are combined in a round bottom flask and heated to 50oC for 30 min or until until the reaction is complete, which is determined using TLC. Then the reaction mixture is cooled to the color filter, washed with a minimum amount of hexane and dried under reduced pressure, getting 44,96 g (93%) of 1-(butylcarbamoyl)-1,3-dihydroimidazole-2-tion in the form of beige crystals: I. pl. 66-68oC.

To a solution containing 1-(butylcarbamoyl)-1,3-dihydroimidazole-2-tion (4,73 g, 23.7 mmol), suspended in 15 ml of dichloromethane, cooled to 0oC, in nitrogen atmosphere is added dropwise bromine (3,79 g, 23.7 mmol), dissolved in 15 ml of dichloromethane. When you are finished adding added triethylamine (4,81 g, 47.5 mmol), dissolved in 15 ml of dichloromethane, so that the temperature of the reaction mixture did not exceed 0oC. the Reaction mixture was kept at 0oC for another 2 h and then stirred for 16 h at room temperature. Then it is diluted with 150 ml dichloromethane and washed twice with water and once with saturated solution of sodium chloride. The organic layer is then dried over magnesium sulfate and evaporated to dryness, obtaining 4,30 g (92%) 2-butylimido[1,2-d]-1,2,4-thiadiazole-3(2H)-he as not quite white powder: so pl. 142-143oC;1H NMR (CDCl3) : 7,40 (d, 1H), 7,20 (d, 1H), 3,79 (t, 2H), 1,73 (m, 2H), 1,40 (m, 2H), 0,957 (t, 3H) ppm; IR (KBr): 1702 cm-1.

Similarly, replacing utilitzant other selected isocyanatomethyl-3(2H)-he

2 propylimidazol[1,2-d]-1,2,4-thiadiazole-3(2H)-he

2 isopropylimidazole[1,2-d]-1,2,4-thiadiazole-3(2H)-he

2 intimidat[1,2-d]-1,2,4-thiadiazole-3(2H)-he

2 hexylamino[1,2-d]-1,2,4-thiadiazole-3(2H)-he

2 cycloheximide[1,2-d]-1,2,4-thiadiazole-3(2H)-he

2 benzimidazo[1,2-d]-1,2,4-thiadiazole-3(2H)-he

Example 27

Synthesis of 3-(1-oxoethyl)imidazo(1,2-d]-1,2,4-thiadiazole-3(2H)-it

To a cooled solution of 2-butylimido[1,2-d]-1,2,4-thiadiazole-3(2H)-she (2,49 g, 12.6 mmol) in 5 ml of dichloromethane, is added dropwise piovanetti (1,74 g, 25.2 mmol) and allowed to mix for 24 hours and Then the precipitate is collected by filtration, washed with dichloromethane and evaporated under reduced pressure, getting to 0.662 g (31%) of 3-(1-oxoethyl)imidazo[1,2-d]-1,2,4-thiadiazole-3(2H)he as yellow-green crystals: I. pl. 142-144oC;1H NMR (CDCl3) : 8,23 (s, 1H), 7,51 (s, 1H), 2,78 (s, 3H) ppm; IR(KBr): 3436, 3168, 3106, 1516, 1408, 1363, 1229, 1136, 730 cm-1. Analytically calculated for C6H5N3SO: C, 43,11; H, A 3.01; N, 25,13. Found: C, 43,11; H, 2.91 In; N, 25,27.

Similarly, replacing proventral benzylcyanide was obtained the following compound:

3-(oxoferryl)imidazo[1,2-d]-1,2,4-thiadiazole-3(2H)-it:

so pl. 166-168oC;1H NMR (CDCl3) : 8.44 (d, 2H), 8.40 (s, 1H), 7.70 (d, 1H), 7.58 (t, 3H) ppm.

Podchinenija:

3-(1-oxopropyl)imidazo[1,2-d]-1,2,4-thiadiazole-3(2H)-he

3-(1-oxobutyl)imidazo[1,2-d]-1,2,4-thiadiazole-3(2H)-he

3-(1-oxobutyl)imidazo[1,2-d]-1,2,4-thiadiazole-3(2H)-he

3-(1-oxohexyl)imidazo[1,2-d]-1,2,4-thiadiazole-3(2H)-he

3-(cyclopentylacetyl)imidazo[1,2-d]-1,2,4-thiadiazole-3(2H)-he

3-(1-oxo-2-phthalimidomethyl)imidazo[1,2-d]-1,2,4-thiadiazole-3(2H)-he

Example 28

Synthesis of 3-(methoxycarbonyl)imidazo[1,2-d]-1,2,4-thiadiazole

To a cooled solution of 2-butylimido[1,2-d]-1,2,4 - thiadiazole-3(2H)-she (2,95 g, 15.0 mmol) in 25 ml of dichloromethane, is added dropwise medicinepharmacy (2,54 g, 30 mmol) and the mixture stirred for 16 h at room temperature. The precipitate is filtered off, then washed with dichloromethane, getting to 2.18 g (80%) of 3-(methoxycarbonyl)imidazo[1,2-d]-1,2,4-thiadiazole in the form of colorless crystals: I. pl. 164.5-165oC;1H NMR(CDCl3) : 8,13 (s, 1H), 7,51 (s, 1H), 4,11 (s, 3H) ppm; IR(KBr) 3440, 1737, 1527, 1253, 1071 cm-1. Analytically calculated for C6H5N3O2S: C, TO 39.34; H, 2,75; N, 22,94. Found: C, 39,41; H, Of 2.51; N, 22,94.

Similarly, replacing metallooprokat other cyanoformate receive the following connections:

3-(etoxycarbonyl)imidazo[1,2-d]-1,2,4-thiadiazole

3-(propoxycarbonyl)imidazo[1,2-d]-1,2,4-thiadiazole

3-(buta) - Rev. XI)cabonyl]imidazo[1,2-d]-1,2,4-thiadiazole

3-[(cyclopentyloxy)carbonyl]imidazo[1,2-d]-1,2,4-thiadiazole

3-[(benzyloxy)carbonyl]imidazo[1,2-d]-1,2,4-thiadiazole

Example 29

Synthesis of 3-bromoimidazo[1,2-d]-1,2,4-thiadiazole

To a cooled solution of 2-butylimido[1,2-d]-1,2,4 - thiadiazole-3(2H)-she (4,78 g, 0,0242 mole) in 25 ml dichloromethane, add one portion of cyanogenmod (5,13 g, 0,0482 mol) and the mixture stirred for 16 h at room temperature. The precipitate is filtered off, suspended in 10 ml of methanol and then washed with dichloromethane, receiving of 4.45 g (90%) 3-bromoimidazo[1,2-d]-1,2,4-thiadiazole in the form of a colorless powder: so pl. 220oC (decomp.); MS m/z 205, 203 (M+). Analytically calculated for C4H2SBr: 1/2 H2O: C, 22,55; H, 1,42; N, Of 19.72; O 3,75; S 15,02; Br, 37,50. Found: C, 22,79; H, 1,41; N, 19,42; O, 2,67; S, 14,61; Br, 38,20.

Similarly, replacing cyanogenmod other cyanophthalide receive the following connections:

3 itemids[1,2-d]-1,2,4-thiadiazole

3 chloroimidazo[1,2-d]-1,2,4-thiadiazole

Example 30

Synthesis of 3-methylsulphonyl-1,2,4-thiadiazolo[4,5-a] benzimidazole

To a solution of 3-methylthio-1,2,4-thiadiazolo[4,5-a]benzimidazole (100 mg, 0.45 mmol) in 10 ml of dichloromethane added m-chloroperbenzoic acid (287 mg, 0.95 mmol). The mixture is stirred at room temperature and ishodnogo. The solvent is then evaporated and the residue purified by chromatography using chloroform/methanol 10:0.1 as eluent, the result is 50 mg (44%) 3-methylsulphonyl-1,2,4-thiadiazolo[4,5-a] benzimidazole as a white solid substance: so pl. 203-207oC (decomp. );1H NMR (CDCl3) : 8,31 (d, 1H), to 7.84 (d, 1H), 7,54 (ddd, 1H), 7,43 (td, 1H), 3,63 (s, 3H) ppm; IR(KBr): 1530, 1487, 1444, 1324, 1315, 1193, 1147, 1141, 735 cm-1MS m/z 253 (M+), 174 (M+- CH3SO2), 148 (M+-CH3SO2CN).

Example 31

Synthesis of 3-[4-(2-pyridyl)piperazinil]-1,2,4-thiadiazolo[4,5-a]benzimidazole

To a chilled solution of 3-bromo-1,2,4-thiadiazolo[4,5-a] benzimidazole (0,30 g, 1.17 mmol) in 10 ml of dichloromethane is added dropwise 2-pyridineboronic (0.54 ml, 3,51 mmol) and the mixture is left to mix for 16 hours, the Reaction mixture is diluted with 100 ml dichloromethane and washed with water (2 x 30 ml) and then saturated saline solution (g ml). The organic layer is dried over sodium sulfate and evaporated, receiving a yellow oil which is purified by the method of column chromatography (40% EtOAc; 60% hexane) to give a solid white color (0.27 g, 68.5 per cent);1H NMR (CDCl3) : to 3.58 (m, 4H, 2CH2), 3,82 (m, 4H, 2CH2), to 6.75 (m, 2H, Rog-H), 7,30 (t, 1H, ArH), 7,44 (t, 1H, ArH), 7,55 (m, 1H, Rog-H), to 7.68 (d, 1H, ArH), 7,79 (d, what odnymi piperazine, receive the following connections:

3-[4-ethylpiperazine]-1,2,4-thiadiazolo[4,5-a]benzimidazole

1H NMR (CDCl3) : to 1.15 (t, 3H, CH3), to 2.55 (q, 2H, CH2, 2,70 (br, s, 4H, 2CH2), 3,49 (br, s, 4H, 2CH2), 7,25 (m, 1H, ArH), 7,40 (m, 1H, ArH), the 7.65 (d, 1H, ArH), 7,79 (d, 1H, ArH); so pl. 153-154,5oC.

3-[4-propylpiperazine]-1,2,4-thiadiazolo[4,5-a]benzimidazole

1H NMR (CDCl3) : to 0.96 (t, 3H, CH3), was 1.58 (m, 2H, CH2), a 2.45 (t, 2H, CH2), is 2.74 (br, s, 4H, 2CH2), 3,49 (br, s, 4H, 2CH2), 7,26 (t, 1H, ArH), 7,30 (t, 1H, ArH), to 7.64 (d, 1H, ArH), to 7.77 (d, 1H, ArH); so pl. 137-138oC.

3-[4-(2-hydroxyethyl)piperazinil]-1,2,4-thiadiazolo[4,5-a]benzimidazole

1H NMR (CDCl3) : to 2.65 (s, 1H, OH), of 2.72 (t, 2H, CH2), 2,84 (s, 4H, 2CH2), 3,51 (s, 4H, 2CH2), 3,70 (t, 2H, CH2), 7,31 (t, 1H, ArH), was 7.45 (t, 1H, ArH), 7,66 (d, 1H, ArH), 7,80 (d, 1H, ArH); so pl. 160-161,5oC.

3-[4-(3-chlorophenylpiperazine)-1,2,4-thiadiazolo[4,5-a]benzimidazole

1H NMR (CDCl3) : 3,37 (m, 6H, 3CH2), of 3.54 (m, 4H, 2CH2), to 6.88 (d, 1H, ArH),? 7.04 baby mortality (dd, 1H, ArH), 7,10 (br, s, 1H, ArH), 7,29 (t, 1H, ArH), 7,41 (t, 1H, ArH), to 7.50 (t, 1H, ArH), 7,78 (d, 1H, ArH), of 7.82 (d, 1H, ArH); so pl. 218,5-to 219.5oC.

3-[4-benzylpiperazine]-1,2-4-thiadiazolo[4,5-a]benzimidazole

1H NMR (CDCl3) : was 2.76 (br, s, 4H, 2CH2), 3,49 (br,s, 4H, 2CH2), 3,66 (s, 2H, CH2), 7,30-to 7.50 (m, 8H, ArH), to 7.64 (d, 1H, ArH), 7,78 (d, 1H, ArH); so pl. 110-112,5o, CH2), 3,32 (d, 2H, CH2), 3,51 (s, 4H, 2CH2), 6,27-6,36 (m, 1H, CH), 6,60 (d, 1H, CH), 7.23 percent - 7,46 (m, 7H, ArH), the 7.65 (d, 1H, ArH), 7,79 (d, 1H, ArH); so pl. 120-121.5oC.

3-[4-(3-amino-2-pyridyl)piperazinil]1,2,4-thiadiazolo[4,5-a]benzimidazole

1H NMR (CDCl3) : of 3.42 (m, 4H, 2CH2), 3,55 (m, 4H, 2CH2), 3,88 (s, 2H, NH2), 6,92 (dd, J= 4,74 Hz, of 7.69 Hz, 1H, PIR H-4), 7,02 (dd, J = 1.57 in Hz, of 7.69 Hz, 1H, PIR H-3), 7,30 (d, 1H), ArH), 7,44 (d, 1H, ArH), 7,76 (apparent br t, 2H, ArH), 7,86 (dd, J = 1,57 Hz, 4,78 Hz, 1H, PIR-H); so pl. 176-177,5oC.

3-[4-(1-(4-chlorophenyl)-1-phenylmethyl)piperazinil]-1,2,4 - thiadiazolo[4,5-a] benzimidazole

1H NMR (CDCl3) : of 2.68 (br,s, 4H, 2CH2), 3,49 (br, s, 4H, 2CH2), 4,35 (s, 1H, CH), 7,2-7,5 (m, 11H, ArH), to 7.59 (d, 1H, ArH), 7,79 (d, 1H, ArH); so pl. 172,5-174oC.

Example 32

Synthesis of 3-[2-pyridylamino]-1,2,4-thiadiazolo[4,5-a]benzimidazole

To a chilled solution of 3-bromo-1,2,4-thiadiazolo[4,5-a] benzimidazole (0,30 g, 1.17 mmol) in 15 ml of dichloromethane is added dropwise 2-aminopyridine (0,276 g, 2.93 mmol) and the mixture is left to mix for 48 hours the Reaction mixture is diluted with 100 ml dichloromethane, washed with water (2 x 30 ml) and then saturated saline solution (g ml). The organic layer is dried over magnesium sulfate and evaporated, getting solid yellow (0.26 g, 83%).1H NMR (CDCl3) : 6,59 (EV, 5, 1H CLASS="ptx2">

Similarly, replacing 2-aminopyridine other amino-derivatives are given the following connections:

3-[3-pyridylamino] -1,2,4-thiadiazolo[4,5-a] benzimidazole.1H NMR (CDCl3) : 7,41 (t, 1H, ArH), of 7.48 (t, 1H, ArH), a 7.62 (dd, 1H, PIR H) of 7.75 (d, 1H, ArH), to 8.34 (d, 1H, ArH), 8,44 (m, 2H, PIR H), of 9.02 (d, 1H, PIR-H); so pl. 175-176oC.

3-[2-pyridylmethylamine]-1,2,4-thiadiazolo[4,5-a]benzimidazole

1H NMR (CDCl3) : 2,02 (s, 1H, NH), 4,84 (d, 2H, CH2), 7,22-7,56 (M, 4H, 2ArH & Pyr-H), to 7.75 (m, 2H, ArH & PIR-H), a 7.85 (d, 1H, ArH), 8,66 (d, 1H, PIR-H); so pl. 155,5-157oC.

3-[N-methyl-(2-pyridylethyl)amino]-1,2,4-thiadiazolo[4,5-a]benzimidazole

1H NMR (CDCl3) : 3,11 (s, 3H, CH3), 3,18 (t, 2H, CH2), a 3.87 (t, 2H, CH2),? 7.04 baby mortality-7,11 (m, 2H, PIR-H), 7,26 (m, 1H, Ar-H), 7,40 (t, 1H, ArH), 7,52 (m, 1H, PIR-H), 7,63 (d, 1H, ArH), 7,74 (1H, d, ArH), to 8.41 (d, 1H, PIR-H); so pl. 105-107oC.

Example 33

Synthesis of 3-brosiomethyl-1,2,4-thiadiazolo [4,5-a]benzimidazole

A solution of 2-butyl-1,2,4-thiadiazolo[4,5-a] benzimidazole-3(2H)-it (15 g, 60,65 mmol) and bromoacetonitrile (18,19 g, USD 151.6 mmol) in dichloromethane (150 ml) is stirred for 48 hours a white precipitate is Formed and the insoluble solid is filtered off, getting 12,50 g (77%) of the connection specified in the header:

1H NMR (CDCl3) : rate 4.79 (s, 2H, CH2, 7,42 (t, 1H, ArH), 7,51 (t, 1H, ArH), to 7.84 (d, 1H, ArH), 7,94 (d, 1H, ArH); so pl. 242R> 1-Ethylpiperazin (0,732 ml, 6,03 mmol) are added to a suspension of 3-methyl bromide-1,2,4-thiadiazolo[4,5-a] benzimidazole (704 mg, 2,62 mmol) in dichloromethane (20 ml). The mixture is allowed to mix at room temperature for 26 hours Then diluted with dichloromethane (150 ml), washed with water (15 ml) and saturated brine (15 ml). The organic layer is dried over sodium sulfate and evaporated, receiving solid, which is recrystallized from acetonitrile (600 g, the output 75,9%).

1H NMR (CDCl3) : of 1.06 (t, 3H, CH3), 2,39 (q, 2H, CH2), is 2.44 (m, 4H, 2CH2), 2,70 (m, 4H, 2CH2), 3,90 (s, 2H, CH3), 7,31 (t, 1H, ArH), the 7.43 (t, 1H, ArH), 7,78 (d, 1H, ArH), 7,92 (d, 1H, ArH); so pl. 140-141,5oC.

Similarly, substituting 1-ethylpiperazin with piperazine derivatives have the following connections:

-{[4-propylpiperazine]methyl}-1,2,4-thiadiazolo[4,5-a]benzimidazole

1H NMR (CDCl, ) : to 0.89 (t, 3H, CH3) and 1.51 (m, 2H, CH3), is 2.30 (t, 2H, CH2), 2,50 (br, s, 4H, 2CH2), 2,70 (s, 4H, 2CH2), to 3.99 (s, 2H, CH2), to 7.32 (t, 1H, ArH), was 7.45 (t, 1H, ArH), 7,80 (d, 1H, ArH), to 7.95 (d, 1H, ArH); so pl. 108-110oC.

3-{ [4-(2-hydroxyethyl)piperazinil]methyl}-1,2,4 - thiadiazolo[4,5-a]benzimidazole

1H NMR (CDCl3) : TO 2.55 (M, 6H, 2CH2piperazine, CH2), 2,70 (m, 4H, 2CH2), 3,61 (m, 2H, Snipering]methyl}-1,2,4-thiadiazolo[4,5-a]benzimidazole

1H NMR (CDCl3) : 2,80 (m, 4H, 2CH2), 3,20 (m, 4H, 2CH2), of 4.00 (s, 2H, CH2), of 6.90 (m, 3H, ArH), 7,25 (t, 4H, ArH), to 7.50 (t, 1H, ArH), 7,80 (d, 1H, ArH), of 8.00 (d, 1H, ArH); so pl. 197-197,5oC.

3-{ [4-(4-amino)phenylpiperazine] methyl} -1,2,4-thiadiazolo[4,5 - a]benzimidazole

1H NMR (CDCl3) : 2,82 (m, 4H, 2CH2), to 3.00 (m, 4H, 2CH2), and 3.31 (s, 2H, NH2, to 4.01 (s, 2H, CH2), 6,63 (d, 2H, ArH), is 6.78 (d, 2H, ArH), 7,32 (t, 1H, ArH), was 7.45 (t, 1H, ArH), 7,80 (d, 1H, ArH), 7,98 (d, 1H, ArH); so pl. 199,5-200,5oC.

3-{[4-benzylpiperazine]methyl}-1,2,4-thiadiazolo[4,5-a]benzimidazole

1H NMR (CDCl3) : 2,50 (br, s, 4H, 2CH2), 2,68 (br, s, 4H, 2CH2), to 3.49 (s, 2H, CH2), 3,98 (S, 2h, chb2), 7,30 (t, 6H, ArH), 7,46 (t, 1H, ArH), 7,79 (d, 1H, ArH), 7,94 (d, 1H, ArH); so pl. of 120.5-122oC.

3-{[4-cinnamylpiperazine]methyl}-1,2,4-thiadiazolo[4,5-a]benzimidazole

1H NMR (CDCl3) : a 2.71 (m, 4H, 2CH2), to 2.55 (m, 4H, 2CH2), 3,14 (d, 2H, CH2), 3,98 (s, 2H, CH2), 6,27 (d, 1H, CH), of 6.49 (d, 1H, CH), 7,30-7,37 (m, 6H, ArH), 7,46 (t, 1H, ArH), to 7.77 (d, 1H, ArH), to 7.93 (d, 1H, ArH); so pl. 162-163oC.

3-{[4-(2-pyridyl)piperazinil]methyl}-1,2,4-thiadiazolo[4,5-a]benzimidazole

1H NMR (CDCl3) : 2,80 (m, 4H, 2CH2), of 3.60 (m, 4H, 2CH2), of 4.00 (s, 2H, CH2), 6,60 (m, 2H, PIR-H), 7,31 (t, 1H, ArH), was 7.45 (t, 2H, ArH), 7,80 (d, 1H, ArH); 7,98 (d, 1H, PIR-H), 8,18 (m, 1H, PIR-H); so pl. 214-214,5oC.

3-{ 4-(3-amino-2-pyridyl)UB>2), 3,79 (s, 2H, NH2), 4,07 (s, 1H, CH2), at 6.84 (m, 1H, PIR H) 6,94 (m, 1H, PIR-H), 7,30 (m, 1H, ArH), to 7.50 (m, 1H, ArH), 7,79 (m, 2H, PIR H, ArH), and 8.0 (d, 1H, ArH); so pl. 214-215,5oC.

3-{ [4-(4-methoxyphenyl)piperazinil] methyl} -1,2,4-thiadiazolo[4,5-a] benzimidazole

1H NMR (CDCl3) : 2,80 (m, 4H, 2CH2), 3,10 (m, 4H, 2CH2), of 3.80 (s, 3H, OCH3), 4,10 (s, 2H, CH2), to 6.80 (m, 4H, ArH), 7,30 (t, 1H, ArH), to 7.50 (t, 1H, ArH), 7,80 (d, 1H, ArH), of 8.00 (d, 1H, ArH); so pl. 202-204,5oC.

3-{ [4-(1-(4-chlorophenyl)-1-phenylmethyl)piperazinil] methyl} -1,2,4 - thiadiazolo[4,5-a]benzimidazole

1H NMR (CDCl3) : 2,44 (br, s, 4H, 2CH2), 2,68 (br,s, 4H, 2CH2), to 3.99 (s, 2H, CH2), 4,18 (s, 1H, CH), 7,20-7,40 (m, 10H, ArH), to 7.50 (t, 1H, ArH), 7,79 (d, 1H, ArH), to $ 7.91 (d, 1H, ArH); so pl. 82-84oC.

Example 35

Synthesis of 3-dipropylamino-1,2,4-thiadiazolo[4,5-a]benzimidazole

To a suspension of 3-methyl bromide-1,2,4-thiadiazolo[4,5-a] benzimidazole (0.5 g, of 1.87 mmol) in dichloromethane (40 ml) add dipropylamine (0,64 ml of 4.67 mmol). The mixture is allowed to mix at room temperature for 26 hours Then diluted with dichloromethane (100 ml), washed with water (3 x 40 ml) and 10% solution of sodium sulfate (15 ml). The organic layer is dried over magnesium sulfate and evaporated, receiving solid, which is recrystallized from acetonitrile (370 mg, 69% vychod (t, 1H, ArH), 7,78 (d, 1H, ArH), 8,03 (d, 1H, ArH); so pl. 70,5-72,5oC.

Similarly, replacing dipropylamine other amine derivatives, receive the following connections:

3-dimethylaminomethyl-1,2,4-thiadiazolo[4,5-a]benzimidazole

1H NMR (CDCl3) : to 2.41 (s, 6H, 2CH3), 3,90 (s, 2H, CH3), to 7.32 (t, 1H, ArH), 7,44 (t, 1H, ArH), 7,76 (d, 1H, ArH), to 7.99 (d, 1H, ArH); so pl. 134-135,5oC.

3-diethylaminomethyl-1,2,4-thiadiazolo[4,5-a]benzimidazole

1H NMR (CDCl3) with 1.07 (t, 6H, 2CH3), 2,73 (q, 4H, 2CH2), 4,08 (s, 2H, CH2, 7,30 (m, 1H, ArH), 7,43 (m, 1H, ArH), to 7.77 (d, 1H, ArH), of 8.04 (d, 1H, ArH); so pl. 109-110,5oC.

3-dibutylamino-1,2,4-thiadiazolo[4,5-a]benzimidazole

1H NMR (CDCl3) : of 0.85 (t, 6H, 2CH3), of 1.26 (m, 4H, 2CH2), was 1.43 (m, 4H, 2CH2), to 2.65 (m, 4H, 2CH2), 4,10 (s, 2H, CH2), 7,27 (t, 1H, ArH), was 7.45 (t, 1H, ArH), 7,78 (d, 1H, ArH), 8,02 (d, 1H, ArH); so pl. 72-72,5oC.

3-(morpholinomethyl)-1,2,4-thiadiazolo[4,5-a]benzimidazole

1H NMR (CDCl3) : of 2.66 (m, 4H, 2CH2), 3,71 (m, 4H, 2CH2), to 3.99 (s, 2H, CH2) 7,33 (t, 1H, ArH), was 7.45 (t, 1H, ArH), 7,80 (d, 1H, ArH), to $ 7.91 (d, 1H, ArH); so pl. 145-147oC.

3-(imidazolylalkyl)-1,2,4-thiadiazolo[4,5-a]benzimidazole

1H NMR (CDCl3) : 6.35mm (s, 2H, CH2), of 7.48 (t, 1H, ArH), 7,54 (t, 1H, ArH), 7,72 (d, 1H, ArH), to 7.84 (m, 2H, ArH, IPD-H) to 8.14 (d, 1H, ArH), 9,12 (d, 1H, ArH); so pl. 226-227 of theoC.

oC.

Example 36

Synthesis of 3-(2-pyrazinyl)-1,2,4-thiadiazolo[4,5-a]benzimidazole

A mixture of 2-butyl-1,2,4-thiadiazolo[4,5-a] benzimidazole-3(2H)-she (300 mg, 1,213 mmol) and pyrazinecarboxamide (319 mg, 3.03 mmol) in 8 ml of dichloromethane is stirred at room temperature for 36 hours the Precipitate is filtered and washed with dichloromethane, getting 0.28 g (91%) of 3-(2-pyrazinyl)-1,2,4-thiadiazolo[4,5-a]benzimidazole in the form of a solid white color.

1H NMR (CDCl3) : to 7.32 (t, 1H, ArH), to 7.50 (t, 1H, ArH), 7,83 (d, 1H, ArH), 8,67 (d, 1H, ArH), 8,87 (br d, 2H, PIR-H), 9,59 (s, 1H, PIR-H); so pl. 255-256,5oC.

Example 37

Synthesis of 4-(2-pyridyl)piperazinylcarbonyl-1,2,4-thiadiazolo[4,5-a]benzimidazole

1-Carbonyldiimidazole (0,355 g, 2.19 mmol) are added to a solution of 2-carboxy-1,2,4-thiadiazolo[4,5-a] benzimidazole (0.3 g, 1.37 mmol) in DMF (10 ml). The resulting solution was stirred at 40oC for 2 h, the Reaction mixture in the form of a white suspension gradually becomes yellow solution. To the reaction mixture of N-(2-pyridyl)piperazine (0,268 g, 1.64 mmol). The resulting mixture was stirred at 40oC for 3 h and cooled. Then it was diluted with dichloromethane (100 ml), promienie, specified in the header, in the form of a solid (0.2 g, 40% yield).

1H NMR (CDCl3) : of 3.69 (m, 2H, CH2), with 3.79 (m, 2H, CH2), of 4.05 (m, 4H, 2CH2), 6,70 (m, 2H, PIR-H), 7,30 (t, 1H, ArH), 7,40-of 7.60 (m, 2H, ArH and PIR-H), 7,80 (d, 1H, ArH), of 8.00 (d, 1H, ArH), 8,23 (m, 1H, PIR-H); so pl. 222-223,5oC.

Similarly, by replacing 4-(2-pyridyl)piperazine other amino-derivatives are given the following connections:

3-{4-(benzyl)piperazinylcarbonyl}-1,2,4-thiadiazolo[4,5-a]benzimidazole

1H NMR (CDCl3) : of 2.72 (m, 4H, 2CH2), of 3.60 (s, 2H, CH2), 3,92 (m, 4H, 2CH2), 7,31 (t, 7H, ArH), 7,46 (t, 1H, ArH), 7,80 (d, 1H, ArH), 7,98 (d, 1H, ArH); so pl. of 230.5-231,5oC.

3-{4-methylpiperazine}-1,2,4-thiadiazolo[4,5-a] benzimidazole

1H NMR (CDCl3) : is 2.37 (s, 3H, CH3), of 2.51 (t, 2H, CH2), 2,60 (t, 2H, CH2), 3,90 (t, 2H, CH2), of 3.96 (t, 2H, CH2), 7,33 (t, 1H, ArH), 7,73 (t, 1H, ArH), 7,80 (d, 1H, ArH), 7,98 (d, 1H, ArH).

Example 38

Synthesis of 3-(4-butylpiperazine)-1,2,4-thiadiazolo[4,5-a]benzimidazole

A mixture of potassium carbonate (700 mg, of 5.06 mmol), butylbromide (of 0.43 ml, 0.4 mmol), 3-piperazinil-1,2,4-thiadiazolo[4,5-a] benzimidazole (798 mg, 3.07 mmol) in THF (15 ml) and DMSO (2 ml) is heated under reflux for 16 hours the Solution is evaporated to dryness, the residue partitioned between dichloromethane and water. aslo mixed with acetonitrile, the resulting insoluble solid is filtered off (595 mg). The solid is purified by chromatography, getting mentioned in the title compound, which is recrystallized from hexane (5:95) (440 mg, 41%).

1H NMR (CDCl3) : of 0.95 (t, 3H, CH3), of 1.30 (m, 2H, CH2), 1,50 (m, 2H, CH2), is 2.40 (t, 2H, CH2), and 2.7 (m, 4H, 2CH2), and 3.5 (m, 4H, 2CH2), and 7.3 (t, 1H, ArH), and 7.4 (t, 1H, ArH), the 7.65 (d, 1H, ArH), and 7.8 (d, 1H, ArH); so pl. 121-122,5oC.

Example 39

Synthesis of 2-mercapto-5-(tert-butoxycarbonyl)amino-benzimidazole

A. a Mixture of 2-mercapto-5-nitrobenzimidazole (10.0 g, 1.23 mmol) and iron filings (8.0 g, 143,24 mmol) in ethanol (80 ml) and water (10 ml) heated under reflux. Then added dropwise concentrated HCl (1.2 ml) 12 minutes Received a dark brown mixture was heated under reflux for a further 1.5 h, then cooled on ice and neutralized with saturated sodium bicarbonate solution to pH 7.0. The mixture is diluted with EtOH (50 ml), suspended with telicom (0.82 g) and filtered through a substrate from celite. The filtered substance was washed with EtOH (g ml). The combined filtrate was concentrated in vacuo, obtaining 9.2 grams light brown substance. After crystallization from hot water to obtain 2-mercapto-5-aminobenzamide is for 6.81-6,85 (d, J= 9,0 Hz, 1H, ArH), 12,06 (br, s, 1H).13C NMR (DMSO) : 165,9 (CS), 144,9, 133,4, 123,6, 109,8, 94,4 IR (KBr, cm-1): 3362, 3295, 3173, 1637, 1622, 1507.

C. a Solution of 2-mercapto-5-aminobenzimidazole (22,0 g, 133,2 mmol) and di-tert-BUTYLCARBAMATE (30,52 g, 139,86 mmol) in anhydrous THF (200 ml) was stirred at room temperature for 16 h under nitrogen atmosphere. THF is removed by evaporation under reduced pressure and the residue crystallized from acetonitrile, getting mentioned in the title compound (28,7 g, 80%) as a pale yellow solid.

1H NMR (DMSO) : a 1.50 (s, 9H), 7,00 (d, J=8,6 Hz, 1H, ArH), 7,11 (dd, J= 8,6 and 1.8 Hz, 1H, ArH), 7,53 (s, 1H, ArH), 9,41 (br, s, 1H), 12,41 (br, s, 2H).13C NMR (DMSO) : 167,9 (CS), 152,9 (C=O), 134,9, 134,9, 132,5, 127,5, 113,3, 109,3, 99,5, 79,0 (C-0), 28,2 IR (KBr, cm-1): 3300, 3127, 1724, 1706, 1623, 1530. So pl. 217,1-217,7oC. the results of elemental analysis (found),%: C 54,32 (54,32); H 5,70 (5,71) and N 15,84 (15,85).

Example 40

Synthesis of 5'-(tert-butoxycarbonyl)amino-2-butyl-3-oxo-2,3-dihydro - 1,2,4-thiadiazolo-[4,5-a] benzimidazole and 6'-(tert-butoxycarbonyl)amino - 2-butyl-3-oxo-2,3-dihydro-1,2,4-thiadiazolo-[4,5-a]benzimidazole

A. To a suspension of 2-mercapto-5-(tert-butoxycarbonyl)aminobenzimidazole (11,46 g, 43,19 mmol) in o-xylene (50 ml) pre-heated to 100oC add n-utilizationa (7.3 ml, 64,79 mmol and diluted with hexane (200 ml). The solid is collected by filtration with suction and dried under vacuum, obtaining 1-butylcarbamoyl-2-mercapto-5-(tert-butoxycarbonyl)amino-benzimidazole (14,19 g, 95%).

1H NMR (DMSO) : 0,94 (t, J= 7,2 Hz, 3H), 1,20-1,60 (m, 4H, 2CH2) and 1.51 (s, 9H), 3,37-of 3.43 (m, 2H, CH2N), 7,19-of 7.23 (dd, J=9,0 and 1.9 Hz, 1H, Ar-H), to 7.64 (s, 1H), of 7.96 (d, J=9,0 Hz, 1H, ArH), 9,59 (s, 1H), 10,22 (t, J=5,4 Hz, 1H, NHCH2). The calculated data of the elemental analysis (found), %: C 56,0 (55,8); H 6,6 (5,7) and N 15,4 (15,3).

C. Suspension 1-butylcarbamoyl-2-mercapto-5-(tert-butoxycarbonyl)aminobenzimidazole (12,90 g, 34,50 mmol) in chloroform (50 ml) is cooled to -5oC and add triethylamine (9,9 ml, 70,79 mmol) in one portion. The obtained clear solution was stirred at 0oC for 45 min, then added dropwise bromine (1,82 ml, 35.4 mmol) in chloroform (40 ml) 1.5 hours After stirring for a further 15 min at 0oC, the mixture is left to warm to room temperature, then diluted with chloroform (1,25 L). The organic phase is washed with saturated brine (2 x 100 ml), dried over sodium sulfate, filtered and concentrated in vacuo. The residue is suspended in methanol (100 ml) and filtered. Gather not quite white solid and dried under vacuum, obtaining mentioned the situation of the spectrum, the proton NMR, it is useful to identify peaks in the aromatic region corresponding to the 2 isomers.

Isomer 1:1H NMR (DMSO) : of 0.95 (t, J=7,2 Hz, 3H), 1,36 was 1.43 (q, J=6,8 Hz, 2H, CH2N) of 1.53 (S, 3H), 1,65-of 1.73 (m, 2H, CH2), to 3.73-of 3.78 (t, J=6,8 Hz, 2H, CH2, N), 7,38 (d, J=8,7 Hz, 1H, ArH), 7,80 (d, J=8,6 Hz, 1H, ArH), 7,98 (s, 1H, ArH), at 9.53 (s, 1H)

Isomer 2:1H NMR (DMSO) : of 0.95 (t, J=7,2 Hz, 3H), 1,36 was 1.43 (q, J=7,4 Hz, 2H, CH2CH3), of 1.53 (S, 9H), 1,65-of 1.73 (m, 2H, CH2), to 3.73-of 3.78 (t, J=6,8 Hz, 2H, CH2N), 7,38 (d, J=8,7 Hz, 1H, ArH), 7,63 (d, J=8,6 Hz, 1H, ArH), to 8.34 (s, 1H, ArH), 9,60 (s, 1H).

Example 41

Synthesis of 5 amino-[3-(2-pyridyl)] -1,2,4-thiadiazolo[4,5-a] benzimidazole and 6'-amino-[3-(2-pyridyl)]-1,2,4-thiadiazolo[4,5-a]benzimidazole

A. To a suspension products obtained in Example 40, part b (1.0 g, 2.76 mmol) in chloroform (5.0 ml) is added 2-cyanopyridine (0,575 g, 5,52 mmol) in one portion. The resulting mixture was heated under reflux for 5 h, then stirred at room temperature for 16 hours, the Chloroform is removed under reduced pressure, the residue suspended in diethyl ether (10 ml) and filtered. Gather not quite white solid and dried under vacuum. In the end you get to 0.68 g (67%) of 5'-(tert-butoxycarbonyl)amino-[3-(2-pyridyl)]-1,2,4-thiadiazolo[4,5-a]benzimidazole and 6'-(tert-butoxycarbonyl)amino-[3-(2-pyridyl)] -1,2,4-thiadiazolo[4,5-a] of gasoline, ,66-7,69 (d, J=8,7 Hz, 0.5 H, ArH), 7,79 (d, J= 1,9 Hz, 0.5 H, ArH), to 7.93-7,98 (t, J=8,0 Hz, 1H, PIR-H), 8,28-8,32 (m, 1H, PIR H) 8,64 (d, J=9,0 Hz, 0.5 H, ArH), 8,86-8,89 (dd, J=4,8 and 0.9 Hz, 0.5 H, PIR-H), 8,98 (br, d, J=4,8 Hz, 0.5 H, PIR H) and 9.20 (br s, 0.5 H).

C. a Suspension of the compounds obtained in Example 41, part a, (1.0 g, 2.72 mmol) in a solution of HCl in MeOH (25 ml) was stirred at room temperature for 4.5 hours Add another 25 ml of HCl in MeOH and the volatiles removed under vacuum. The residue is suspended in diethyl ether and filtered, obtaining the compound indicated in the title, in the form of their HCl salts pale yellow (0,99 g, 96.6 percent), as a mixture of isomers 1:1 (determined using HPLC: 20 mM ammonium acetate/acetonitrile 80/20; C18 column). IR (KBr, cm-1): 3419, 1611, 1551, 1527. Elemental analysis: expect. (found),%: C 41,5 (41,0); H 3.2 (3.5), and N 18,6 (18,3).

Example 42

Synthesis of 1,2,4-thiadiazolo[4,5-a]benzimidazole-3-yl-L-leucyl isomerase.

Potassium carbonate (544 mg, 3.94 mmol) are added to a solution of L-leucyl of isoamylamine (0,788 g, 3.94 mmol) and 3-bromo-1,2,4-thiadiazolo[4,5-a]benzimidazole (1.0 g, 3.94 mmol) in THF (15 ml). The mixture is stirred at room temperature for 16 h and then heated under reflux for a further 8 hours, the Solvent is evaporated to dryness and the residue distributed between ethyl acetate (125 ml) and water (15 ml). Organic fatwa, which is then purified by the method of column chromatography (10% MeOH:CHCl3), getting mentioned in the title compound (715 mg).

1H NMR (CDCl3) : to 0.92 (d, 6H, 2CH3), 0,92-1,10 (dd, 6H, 2CH3), 1,40-of 1.52 (m, 2H), 1,54-of 1.78 (m, 2H), 1,80-2,00 (m, 2H, CH2, 3,34 is-3.45 (m, 2H, CH2NH), 4,48-4,58 (m, 1H, -CH leucine), 6,56 (t, J=5,6 Hz, 1H, NHCH2, 6,60 (d, J=8,3 Hz, 1H, NHCH), to 7.15 (t, 1H, J=7,4 Hz, ArH), 7,34 (t, 1H, J=8,2 Hz, ArH), to 7.64 (d, 1H, J= 8,2 Hz, ArH), to 7.77 (d, 1H, J=8,1 Hz, ArH)/13C NMR (CDCl3) : 172,5 (CO-CH), 164,4 (C-S), 150,4, 145,0, 127,8, 124,5, 121,3, 119,1, 110,2, 55,4 (CH-CO), 41,7, 38,4, 38,2, 25,8, 24,9, 23,0, 22,4, 22,1. IR (thin film, cm-1): 3241 (NH), 1660 (C=O), 1574. So pl. 105-107oC. Elemental analysis: expect. (found), %: C 61,10 (61,30), H 7,29 (7,05), N 18,75 (18,43).

Example 43

Synthesis of { 1,2,4-thiadiazolo[4,5-a)benzimidazol-3-yl}-carbonyl-L-allisoniraheta

1,1-Carbonyldiimidazole (1.30 grams, 8,03 mmol) are added to a suspension of 3-carboxy-1,2,4-thiadiazolo[4,5-a] benzimidazole (1.10 g, 5,02 mmol) in DMF (30 ml). The mixture is heated at 45oC for 2 h, during which time the mixture turned into a yellow solution. The solution is cooled to 0oC add allisonville (1,21 g of 6.02 mmol) and DMF (5 ml) and the resulting mixture stirred for 16 h at room temperature. The mixture is diluted with ether (400 ml), the ether layer washed with 0.5 M HCl (25 ml), water (3 x 25 ml) and us. so g), which is further purified by column chromatography, with the formation of 1.33 g of the target substance.

1H NMR (CDCl3) : of 0.90 (d, 6H, J=6,5 Hz, 2CH3), of 1.05 (dd, 6H, 2CH3), to 1.38 to 1.48 (m, 2H), 1,54 by 1.68 (m, 1H), 1,72-of 1.85 (m, 3H), 3,22-to 3.38 (m, 2H, CH2NH), 4,62-4,78 (m, 1H, CHCO), 6,30 (t, 1H, NH), 7,32 (t, 1H, J=7,3 Hz, ArH), was 7.45 (t, 1H, J=7,4 Hz, ArH), of 7.75 (d, 1H, J=8,0 Hz, ArH), to 7.93 (d, 1H, J=8,4 Hz, ArH), 8,73 (d, 1H, J=8,3 Hz, NH).13C NMR (CDCl3) : 170,8 (COCH), 164,4 (CS), 155,4, 150,5, 144,1, 129,4, 125,8, 122,2, 119,1, 116,3, 52,6 (CHCO), 41,4, 38,3, 38,2, 25,8, 24,9, 22,9, 22,4, 22,1. IR (KBr, cm-1): 3295 (NH), 1651 (C=O), 1527. So pl. 164-167oC.

Example 44

Synthesis of 5-amino-3-methoxy-1,2,4-thiadiazole

This substance receive in accordance with the method of J. Goeredeler et al, Chem. Ber., 1955, 88, 843. The cyanamide (5,77 g, 13.78 mmol) is added slowly to a solution of HCl (5,77 g) in methanol (100 ml). The resulting mixture was stirred at room temperature for 3 days. The residue is evaporated under reduced pressure, obtaining hydrochloride methylisoleucine (15,16 g). A solution of sodium hypochlorite (0,769 M, 149 ml) is added dropwise to a solution of hydrochloride methylisoleucine (12,63 g, 0,114 mol) in water (75 ml) at 0oC for 30 minutes in 1.5 h, the solution is saturated with sodium chloride and extracted with ether (3 x 700 ml). The combined ether layers are dried over sodium sulfate and evaporated, obtaining N-chlorpyrifos KSCN (9,19 g, 94.5 mmol). After 16 hours, the insoluble residue

is filtered off and then washed with methanol. The combined filtrates evaporated, receiving solid, which is purified by column chromatography (eluting gradient: from 5 to 7% MeOH: CHCl3). The selected solid is recrystallized from toluene, getting mentioned in the title compound (3,14 g).

Example 45

Synthesis of 5-{3-methoxy-1,2,4-thiadiazolyl}carbarnoyl-isolationalism

A solution of 5-amino-3-methoxy-1,2,4-thiadiazole (1.0 g, to 7.67 mmol) in THF (20 ml) is added dropwise to a solution of triphosgene (0,837 g, 2.82 mmol) and dipropylamine (1.08 g, 8,35 mmol) in 15oC and the resulting mixture was stirred at room temperature for 1 h the Solution allisoniraheta (1,53 g, 7.62 mmol) in dichloromethane (15 ml) added dropwise within 15 minutes After 2 h the solvent is removed under reduced pressure and the residue diluted with EtOAc (500 ml). Then wash it with a solution of ammonium sulfate (10%, 50 ml) and saturated saline (50 ml). The organic layer is dried over sodium sulfate and evaporated, receiving the oil, which is purified by column chromatography (1.5% MeOH: CHCl3), with the formation specified in the title compound (469 mg, yield 17%).

2isoamyl), 3,17-to 3.33 (m, 2H, CH2NH), 4,10 (s, 3H, OCH3), to 6.58 (t, J=5,4 Hz, 1H, NHCH2), 6,70 (d, J= 8,6 Hz, 1H, NHCH), 12,60 (br, s, 1H, NHCO).13C NMR (CDCl3) : 178,1 , 171,7 , 166,0 , 153,9 , 56,6 , 52,7 , 41,9, 38,2, 38,0, 25,8, 24,7, 22,8, 22,4, 22,3, 22,2. IR (KBr, cm-1): 3359 (NH), 1701 (C=O), 1680, 1645, 1554. So pl. 169-172oC.

Example 46

Synthesis of 5-{ benzyloxycarbonyl-1-i.e. phenylalanyl-1-alanine} -3-methoxy-1,2,4-thiadiazole

EDCI (300 mg, of 1.62 mmol) are added to a solution of HOBt (131 mg, 0.97 mmol) and carbobenzoxy-L-i.e. phenylalanyl-L-alanine (300 mg, 0.81 mmol) in DMF (2 ml) at 0oC. After 25 min add 5-amino-3-methoxy-1,2,4-thiadiazole (140 mg, 1.05 mmol) and the solution stirred at room temperature for 2 days. The reaction mixture is evaporated to dryness and extracted with ethyl acetate. The organic layer is dried over sodium sulfate and evaporated, obtaining oil, which is subjected to chromatography (10% MeOH:CH2Cl2) to give 90 mg of a solid product. The solid is further purified by thin layer chromatography (5% MeOH:CH2Cl2), receiving 30 mg specified in the connection header.

1H NMR (MeOD) : to 1.42 (d, 3H, CH3), 2,80-2,95 (dd, 1H, CH2phenyl), is 3.08-3,18 (dd, 1H, CH2phenyl), to 3.99 (s, 3H, CH3O) of 4.45 (dd, 1H, -CH of phenyl), 4,58 (q, 1H, -CH ala), of 5.05 (s, 2H, OCH2), 7,10-7,40 (m, 10H, ArH).2), AND 57.6 (CHCH2), TO 57.1 (CH3O) 39,0 (CH2CH), 17,2 (CH3CH).

Example 47

Synthesis of N-[3-(4-methylpiperazine-yl)-[1,2,4] thiadiazole-5-yl]-N-ferbenstein

5-Cyanimide-4,5-dihydro-3,4-diphenyl-1,2,4-diphenyl-1,2,4 - thiadiazole get by the method of H. Sonnenschein et al., Liebigs Ann. Chem., 1992, 287-289. 1-Methylpiperazine (0,152 ml, 1,375 mmol) are added to a solution of 5-cyanimide-4,5-dihydro-3,4-diphenyl - 1,2,4-thiadiazole (153 mg, 0.55 mmol) in dioxane (3 ml). The mixture is stirred at room temperature for 3 days. Using TLC (35% EtOAc:hexane) to determine completeness of the reaction. The resulting white solid is filtered off and then recrystallized from a mixture of dichloromethane:hexane (1:9). The result is 97 mg specified in the title compound, which was further purified by column chromatography (10% MeOH:CH2Cl2).

1H NMR (CDCl3) : 2,3 (s, 3H, OMe), 2,4 (m, 4H, 2CH2), and 3.5 (m, 4H, 2CH2), 7,15-7,25 (m, 10H, ArH), 8,51 (s, 1H, NH). So pl. = 152,5-152,7oC.

Example 48

Acid stability of 7-methoxy-3-[(4-methoxy-3,5-dimethyl-2-pyridyl)oxoethyl]-1,2,4-thiadiazolo[4,5-a]benzimidazole

To determine the acid stability of a secure connection, it is dissolved in a minimal volume of methanol and Poluchenie stable in acid and fully regenerated after stirring for 48 hours at room temperature. On the other hand, omeprazole undergoes complete decomposition within a few minutes under the above conditions. 1,2,4-thiadiazoline derivatives superior to omeprazole as an agent, directly detecting thiol in an acidic environment, as they are stable in acid.

Example 49

The reaction of 3-[(4-methoxy-3,5-dimethyl-2-pyridyl)oxoethyl] - 1,2,4-thiadiazolo[4,5-a)benzimidazole 3-mercaptopropionic acid

To a suspension of 250 mg of 3-[(4-methoxy-3,5-dimethyl-2 - pyridyl)oxoethyl]-1,2,4-thiadiazolo[4,5-a]benzimidazole in 125 ml of methanol and 38 ml of 0.1 M hydrochloric acid is added 161 μl of 3-mercaptopropionic acid. After complete decomposition of the educt mixture is neutralized to pH 6 with aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The ethyl acetate is dried with anhydrous magnesium sulfate and evaporated. The crude product was then purified using chromatography, receiving 93 mg of 2-imino-2-(2-mercapto-1-benzimidazolyl)-1-(4-methoxy-3,5-dimethyl-2 - pyridyl)ethanone, 65 mg of 2-mercaptobenzimidazole and 61 mg of methyl 2-(4-methoxy-3,5-dimethyl-2-pyridyl)-2-oxoacetate. 2-imino-2-(2-mercapto-1-benzimidazolyl)-1-(4-methoxy-3,5-dimethyl-2-pyridyl)Manon: 1H NMR (CDCl3) : 10,55 (br s, 1H, NH or SH), 10,35 (br, s, 1H, NH or SH), 8,10 (d, 1H, J = 7 Hz, ArH), 7,80 (s, 1H, H6 PIR, 1635, 1502, 1458, 1396, 1328, 1272, 1247, 1004, 746 cm-1; MS (electrospray) m/z 341 (MH+), 191 (MN+- 2-mercaptobenzimidazole). 2-Mercaptobenzimidazole: this substance is identical to the authentic, obtained from Aldrich Chemical Co., that detected using the1H NMR, IR and TLC. Methyl 2-(4-methoxy-3,5-dimethyl-2-pyridyl)-2-oxoacetate: 1H NMR (CDCl3) : to 8.45 (s, 1H, ArH), 4,1 (s, 3H, OCH3), 3,85 (s, 3H, OCH3), to 2.65 (s, 3H, ArCH3), and 2.4 (s, 3H, ArCH3) ppm; IR (KBr): 1747, 1703, 1468, 1394, 1310, 1242, 1206, 1120, 1004, 740 cm-1; MC m/z 224 (M++H), 164(M+-CO2Me), 136 (M+-CO2Me-CO).

Example 50

The reaction of 3-(dimethylamino)-1,2,4-thiadiazolo[4,5-a]benzimidazole with penicillata

To a solution of 23 mg of 3-(dimethylamino)-1,2,4-thiadiazolo[4,5-a]benzimidazole in 10 ml of methanol, add 360 ál of penicillata after 1 min the reaction is finished. The solvent is evaporated the crude substance is purified using chromatography, receiving 15 mg of N',N'-dimethyl-2-mercapto-1-benzimidazolinone.

1H NMR (DMSO-d6) : 7,3-7,0 (m, 4H, 4ArH), the 3.35 (br, s, 2H, NH, SH), is 2.88 (s, 6H, 2 NCH3) ppm; IR (KBr): 3210, 1641, 1475, 1452, 1407, 1319 cm-1MC m/z 220 (M+), 150 (M+-Me2NC=NH).

Example 51

The reaction of 3-bromo-1,2,4-thiadiazolo[4,5-a]benzimidazole with penicillata

To a suspension of 500 mg quickly dissolves. After completion of the reaction the solvent is evaporated and the residue purified by chromatography, getting 296 mg of 2-mercapto-1-benzenedicarbonitrile.

1H NMR (DMSO-d6) : is 12.85 (br, s, 1H, SH), and 7.5 to 7.2 (m, 4H, 4 ArH) ppm; IR (KBr): 2259, 1509, 1459, 1303, 1189, 752 cm-1; MC m/z 175 (M+), 150 (M+-CN).

Example 52

Reaction of 3-methoxy-1,2,4-thiadiazolo[4,5-a] benzimidazole with penicillata

To a solution of 23 mg of 3-methoxy-1,2,4-thiadiazolo[4,5-a]benzimidazole in 10 ml of methanol add 376 μl of penicillata. The reaction is completed within 1 minute of Methyl 2-mercapto-1-benzimidazolecarboxylate identified as the main reaction product.

1H NMR (DMSO-d6) : 13,45 (br, s, 1H, SH or NH), and 9.8 (s, 1H, NH or SH), and 7.7 (d, 1H, J = 8 Hz, ArH), 7,35 to 7.2 (m, 3H, 3ArH), of 3.95 (s, 3H, OCH3) ppm; IR (KBr): 3437, 3095, 1679, 1450, 1440, 1376, 1193, 735 cm-1; MC m/z = 207 (M+), 150 (M+- MeOC-NH).

Example 53

The reaction of 3-(oxoferryl)-1,2,4-thiadiazolo[4,5-a] benzimidazole with penicillata

To a suspension of 26 mg of 3-(oxoferryl)-1,2,4-thiadiazolo[4,5-a]benzimidazole in 10 ml of methanol, add 31 μl of penicillata. The substrate undergoes a complete transformation in 2-mercaptobenzimidazole that detected when compared with an authentic sample of 2-mercaptobenzimidazole, poluchennaya[4,5-a]benzimidazole with penicillata

To a suspension of 25 mg of 3-[hydroxy(4-methoxy-3,5-dimethyl-2 - pyridyl)methyl]-1,2,4-thiadiazolo[4,5-a] benzimidazole in 10 ml of methanol, add 250 ál of penicillata. The substrate undergoes a complete transformation in 2-mercaptobenzimidazole that detected when compared with an authentic sample of 2-mercaptobenzimidazole, obtained from Aldrich Chemical Co.

Example 55

The reaction of 3-[(4-were)sulfonyl]-1,2,4-thiadiazole,5 - a]benzimidazole with penicillata

To a suspension of 31 mg of 3-[(4-were)sulfonyl]-1,2,4 - thiadiazolo[4,5-a] benzimidazole in 10 ml of methanol add 313 ál penicillata. The substrate undergoes a complete transformation in 2-mercaptobenzimidazole that detected when compared with an authentic sample of 2-mercaptobenzimidazole, obtained from Aldrich Chemical Co.

Example 56

The reaction of 5-amino-3-methoxy-1,2,4-thiadiazole with penicillata

To a solution of 250 mg of 5-amino-3-methoxy-1,2,4-thiadiazole in 10 ml of methanol, add 1.3 ml of penicillata. After completion of the reaction the solvent evaporated. The crude substance is purified using chromatography, getting 236 mg 3-carbamoylation. The structure of this compound was confirmed by x-ray crystallography:

1H NMR (CDCl3) : 10 (br s, the Vuh tautomeric forms 1-thiocarbamoylation, with the formation of 1 NH2and 2 NH in the NMR spectrum; IR (KBr): 3420, 3282, 3266, 3169, 1626, 1601, 1519, 1465, 1411, 1380, 1098 cm-1; MC m/z 133 (M+), 117 (M+- NH2), 100 (M+-SH).

Example 57

The reaction of 3-[(4-methoxy-3,5-dimethyl-2-pyridyl)oxoethyl] - 1,2,4-thiadiazolo[4,5-a]benzimidazole with penicillata

Penicillata (120 μl, 0.90 mmol) is added to a suspension of 3-[(4-4-methoxy-3,5-dimethyl-2-pyridyl)oxoethyl]-1,2,4-thiadiazolo[4,5-a]benzimidazole (300 mg, 0,887 mmol) in methanol (150 ml) and 0.1 M hydrochloric acid (38 ml). After stirring the mixture at room temperature for 51 h, it is neutralized to pH 6 with aqueous solution of sodium bicarbonate and extracted with ethyl ether. The ether layer is dried over sodium sulfate and evaporated. The crude substance is purified by chromatography (eluting gradient: from 10% EtOAc: hexane to 30% EtOAc:hexane) to give 110 mg definitel disulfide (92% yield on penetrometry), 63 mg of methyl ester of 2-oxo-2-(4-methoxy-3,5-dimethyl-2-pyridyl)acetic acid (37.6% of output spent on the connection specified in the header, 1,2,4-thiadiazolo[4,5-a]benzimidazole), 44 mg of 3-[(4-methoxy-3,5-dimethyl-2-pyridyl)oxoethyl]-1,2,4-thiadiazolo[4,5-a]benzimidazole (14,6% recycled source materials) and 2-mercaptobenzimidazole is-2-(4-methoxy-3,5-dimethyl-2-pyridyl)acetate:

1H NMR (CDCl3) : to 8.45 (s, 1H, ArH), 4,1 (s, 3H, OCH3), 3,85 (s, 3H, OCH3), to 2.65 (s, 3H, ArCH3), and 2.4(s, 3H, ArCH3) ppm; IR(KBr): 1747, 1703, 1468, 1394, 1310, 1242, 1205, 1120, 1004, 740 cm-1; MC m/z 224 (M++ H), 164 (M+- CO2Me), 136 (M+- CO2Me - CO). 2-Mercaptobenzimidazole: methods1H NMR, IR, and TLC was established that the substance is identical to the authentic sample obtained from Aldirich Chemical Co. Definitionwhat: 1H NMR (CDCl3) : 3,03 (m, 8H, 2CH2CH2), 7,27 (m, 6H, ArH), 7,30 (m, 4H, ArH).13C NMR (CDCl3): 35,79, 40,27, 126,46, 128,57, 128,67, 140,08.

Example 58

The reaction of 3-(4-methylpiperazine)-1,2,4-thiadiazolo[4,5-a] benzimidazole with thiophenols

The solution of the dihydrochloride of 3-(4-methylpiperazine)-1,2,4 - thiadiazolo[4,5-a] benzimidazole (1,494 g. 4.31 mmol) and thiophenol (1,43 ml, 12,94 mmol) in methanol (400 ml) and 1N HCl (120 ml) was stirred at room temperature for 3.5 days. The reaction mixture is evaporated, obtaining a solid residue, which was partitioned between ether (3 x 103 ml) and water (20 ml). The ether layer is dried over sodium sulfate and evaporated, getting 753 mg diphenyldisulfide (53,31% yield). The aqueous layer was neutralized by adding dropwise 2N NaOH at 0oC and then extracted with dichloromethane (3 x 100 ml). The dichloromethane layer is dried over Sul the substance (1.13 g, 95,1% yield).

1H NMR (DMSO): 2,19 (s, 3H, N-Me), 2,33 (br, s, 4H, 2CH2CH2-), 3,24 (br, s, 4H, 2CH2CH2-), 7,14-of 7.23 (m, 4H, ArH).13C NMR (DMSO): 44,81, 45,11, 53,59, 109,52, 110,42, 123,09, 123,89, 131,47, 131,57, 149,34 (C=NH), 166,89 (CSH).

Example 59

The reaction of 3-benzoyl-1,2,4-thiadiazolo[4,5-a]benzimidazole with thiophenols

The solution thiophenol (1.08 ml of 10.47 mmol), 3-benzoyl-1,2,4-thiadiazolo [4,5-a]benzimidazole (975 mg, 3.49 mmol) in methanol (400 ml) and 1N HCl solution (120 ml) was stirred at room temperature for 16 hours the Solution is evaporated under reduced pressure to remove methanol; the aqueous mixture is neutralized to pH 7.0 with sodium bicarbonate solution and extracted with CH2Cl2. The organic layer is dried over sodium sulfate and evaporated, obtaining a solid substance. This substance was purified by column chromatography, obtaining the following connections: Diphenyldisulfide (700 mg solids; R1= 0,69, 10% EtoAc: hexane), which is identical to diphenyldisulfide from Aldrich Chemical according to NMR analysis.1H NMR (CDCl3): 7,3-7,35 (m, 2H, ArH), 7,35-7,45 (m, 4H, ArH), 7,63-to 7.68 (m, 4H, ArH). 13C NMR (CDCl3): 127,326, 127,703, 129,241, 137,219.

2-mercaptobenzimidazole (180 mg, 34,3% yield; R1= 0.46,20% EtOAc:hexane), which is identical to 2-mercaptobenzimidazole from Aldrich Chemical agreement is diversifolia from Aldrich Chemical according to NMR analysis.1H NMR (CDCl3): 52,67, 128,86, 130,03, 132,44, 134,89, 164,01 (C=O), 185,98 (C=O). IR: 1740, 1687, cm-1.

Example 60

Reaction derived 1,2,4-thiadiazolo[4,5-a] benzimidazole with 2-mercaptoethanol. The determination of the values of t1/2< / BR>
The calculated number derived 1,2,4-thiadiazolo[4,5-a]benzimidazole (end strength solution = 510-3M) and phenol (118 mg, the ultimate power solution = 510-3M) dissolved in methanol (250 ml) in a volumetric flask. 100 ml of solution is transferred into a clean volumetric flask and the resulting solution was stirred at room temperature. 100 μl of 2-mercaptoethanol (the ultimate power solution = 1,1510-2M) added dropwise within 60 seconds with the tip of a needle introduced into the solution. The course of the reaction is controlled by using HPLC (Hewlett Packard. Model 1100) with PE express 3.3 cm, C18 column and UV detector set at 254 nm. Substance elute with a mixture of 70% 50 mm ammonium acetate; 30% acetonitrile as mobile phase. The completion of the reaction, in percent, calculated as follows.

At time 0, 100% of the original substance remains unreacted. At time t, % percentage of unreacted educt = { hsample/hEXT.articlein the IOM. BP t} /{hsample/hEXT.articlein the IOM. BP 0}100%. Build a graph of% arereasonable the original substance. Reaction of tricyclic 1,2,4-thiadiazole with mercaptoethanol is carried out at pH 7.0

< / BR>
Group Y - t1/2at pH 7.0

MeO - 0,31 h

Me2N - 1.5 h

morpholine - 2,4 h

4-methylpiperazine - 6,7 h

phenyl - 45 h

methyl - 59 h

2-pyridyl - 134 h

acetyl - 110 h

morpholinomethyl - 98 h

dimethylaminoethyl - 64 h

Example 61

The effect of compounds of the formula I on the secretion of gastric acid in rats

Hungry adults (140-240 g) male Sprague-Dawley rats were suspended for 24 hours from food, but not from water, and then subjected to forced feeding through a tube portions from 1 ml to 1.5 ml total volume containing compound of the formula I (300 ámol/kg) in different days. Two hours later the rats were shot by a combination of phenobarbital and thiopental, the abdominal cavity was opened, the pylorus is preserved was bandaged and installed cannula into the tracheal, gastrointestinal and peripheral veins. The stomachs were washed in 10 ml of 0.9% physiologic solution every 10 minutes for 30 minutes and gastro-intestinal aspirates were collected in containers to determine the basal secretion of acid. The release of acid defined in each flush by reverse titration to pH 7.0 with 0.02 M NaOH. Next, 5 ml of 8% peptone broth (pH 5.5) was injected into the stomachs were mixed and patony broth, using back titration to pH 5.5 with 0.02 M NaOH.

In the control experiment with placebo (n = 6), the release of acid-stimulated 8% peptone was determined at 160 mmol/30 min after 1 hour, whereas rats that received 7-methoxy-3-[(4-methoxy-3,5-dimethyl-2-pyridyl)oxoethyl] -1,2,4-thiadiazolo[4,5-a] benzimidazole, observed a significant (p<0.05) inhibition of stimulated broth secretion of acid at doses of 300 µmol/kg

Example 62

The effect of compounds of the formula I on the secretion of gastric acid in rats (Study of dose-response relationships)

Hungry adults (140-240 g), male Sprague-Dawley rats were suspended for 24 hours from food, but not from water, and then subjected to forced feeding through a tube portions from 1 ml to 1.5 ml total volume of 4 different doses (0,3, 3.30, and 300 µmol/kg) of each compound in different days. Two hours later the rats were shot by a combination of phenobarbital and thiopental, the abdomen was opened, the pylorus is preserved was bandaged and installed cannula into the tracheal, gastrointestinal and peripheral veins. The stomachs were washed in 10 ml of 0.9% physiologic solution every 10 minutes for 30 minutes and gastro-intestinal aspirates were collected in containers. The release of acid defined in each flush by reverse titration to pH 7.0 with Uchenie 2 hours. The release of acid defined in each flush by reverse titration to pH 7.0 with 0.02 M NaOH. After measuring the basal release of acid for at least 30 minutes, the release of acid then measured within 2 hours of intravenous injection of histamine (5 mg/kg).

In Fig. 3 shows the release of gastric acid (mmol/min) after placebo and after administration of 4 doses of 7-methoxy-3-[(4 - methoxy-3,5-dimethyl-2-pyridyl) oxoethyl] -1,2,4-thiadiazolo[4,5-a] benzimidazole(of 0.3, 3, 30 and 300 µmol/kg) shot in rats.

7-methoxy-3-[(4-methoxy-3,5-dimethyl-2-pyridyl)oxoethyl] -1,2,4-thiadiazolo[4,5-a] benzimidazole demonstrates a significant (p less than 0.05) inhibition of histamine-stimulated acid secretion at doses of 3, 30 and 300 µmol/kg)

Example 63

In Vitro inhibition of the secretion of food acid 3-(4-methyl-1-piperazinil)-1,2,4-thiadiazolo[4,5-a]benzimidazole dihydrochloride a

Secretion of acid is measured indirectly by the accumulation of weak bases14C-aminopyridine in isolated digestive glands of mice. The test is carried out in polypropylene tubes type Eppendorf containing 0.5 ml resuspending digestive glands of mice. In addition, the tubes containing the test substance, with the N. The reaction is stopped by centrifugation of the suspension glands for 5 minutes at 1500 g. The precipitate is washed extensively and digested overnight in 1 ml Protocol (Amersham). After neutralization with acetic acid and add scintillation fluid, and the radioactivity is counted in a beta counter (Beckman). The amount of radioactivity trapped in the sediments, directly corresponds to the number screenoverlay acid. Each experimental point consists of three repetitions. In each experiment is independent of the energy consumption was calculated with 0.1 mm dinitrophenol and basal acid secretion in the absence of stimulants acid. These values were then subtracted from the corresponding results in order to calculate basal or secretagent-stimulated secretion of acid.

Mouse cancer respond to various known secretory post-receptor mediators, but not gastrin. The maximum stimulation of acid secretion is achieved with 1 mm camp, 0.1 mm histamine, 0.1 mm VMH, 10 μm carbachol, 10 μm of Forskolin, 10 μm calcium ionophore And 23187, 1 μm thapsigargin. Each experiment was repeated several times and all the results were expressed in percentage of maximal stimulation. In order to compare potnah post-receptor/camp 3-(4-methyl-1-piperazinil)-1,2,4-thiadiazolo [4,5-a]benzimidazole dihydrochloride a response and ranitidine, which inhibits mediated by histamine secretion of acid.

3-(4-methyl-1-piperazinil)-1,2,4-thiadiazolo[4,5-a] benzimidazole the dihydrochloride inhibited camp and histamine-stimulated secretion of acid at 100 μm. Using the above procedure, the value of U50this connection was found 50 microns.

Example 64

Inhibition of cathepsin B, cathepsin L and papain 1,2,4-thiadiazole and 1,2,4-thiadiazolo[4,5-a] benzimidazole derivatives: enzyme assay and kinetic experiments

Conditions for the above experiments can be found in the following references: R. Menard et. al. Biochemistry 1990, 29, 6706-6713; Fox, T. et. al. Biochemistry 1992, 31, 12571-12576; Cannona E. et. al. Biochemistry 1996, 35, 8149-8157.

A typical experiment consisted of a selection of such concentration of inhibitor at which the maximum inhibition can be achieved in less two hours, when tracking fully during the process (for example, fluorescence from time to time) and the data analysis. The analysis gave two parameters: % inhibition when it reaches a stationary state and the rate constant, which represents the speed at which this stationary state is achieved. Typically, the enzymatic activity of the RNA state), when the enzymatic activity remains constant. From that moment on, as significant levels of activity can be registered at the steady state (e.g. the inhibition is not complete, the data is described by equation (1), which is typically used for slow-binding reversible inhibitors.

< / BR>
% inhibition = (1-vi/v0)100 (2)

In this equation, [R] represents the concentration of the product (obtained from fluorescence data), kabsis the rate constant of the first order achieve steady state, v0is the initial velocity that corresponds to the speed in the absence of inhibitor, and viis the speed of inhibited enzyme at a stationary state. The percentage inhibition obtained using equation (2) where the speed is measured in the absence of inhibitor, is used as v0. An example of a simple mechanism for this process is given below:

< / BR>
For this mechanism, the value of kabsdetermined experimentally, will match:

kobs= kon[inh] + koff< / BR>
The value of kabsvaries with the concentration of the inhibitor. Often koffmuch slower than k
3-(4-methyl-1-piperazinil)-1,2,4-thiadiazolo[4,5-a] benzimidazole of cathepsin L: 98% inhibition at 200 µm

[inhibitor]; kobs/[inh] = 24M-1s-1.

cathepsin B: 68% inhibition at 200 µm [inhibitor]; kobs/[inh] = 19 M-1s-1.

papain 99% inhibition at 200 µm [inhibitor]; kobs/[inh] = 28 M-1s-1.

1,2,4-thiadiazolo[4,5-a]benzimidazole-3-yl carboxylic acid sodium salt cathepsin L: 98% inhibition at 50 μm

[inhibitor]; kobs/[inh] = 184 M-1s-1< / BR>
cathepsin B: 85% inhibition at 200 µm [inhibitor]; kobs/[inh] = 34 M-1s-1.

papain 99.6% inhibition at 200 µm [inhibitor]; kobs/[inh] = 131 M-1s-1.

3-[2-pyridylcarbonyl]-1,2,4-thiadiazolo[4,5-a]benzimidazole

cathepsin L: 99% inhibition at 200 µm

[inhibitor]; kobs/[inh] = 68 M-1s-1.

cathepsin B: 58% inhibition at 200 µm [inhibitor]; kobs/[inh] = 15 M-1s-1.

papain 79% inhibition at 1 μm [inhibitor]; kobs/[inh] = 2479 M-1s-1.

3-[N-morpholinomethyl]-1,2,4-thiadiazolo [4,5-a]benzimidazole

cathepsin L: 80% inhibition at 200 µm
ibator]; kobs/[inh] = 8 M-1s-1.

papain 92% inhibition at 200 µm [inhibitor] ; kobs/[inh] = 7 M-1s-1.

1,2,4-thiadiazolo [4,5-a]benzimidazole-3-yl-L-Proline methyl ester

cathepsin L: 99% inhibition at 10 μm [inhibitor]; kobs/[inh] = 1050 M-1s-1.

cathepsin B: 88% inhibition at 10 μm [inhibitor]; kobs/[inh] = 626 M-1s-1.

papain 97% inhibition of 0.26 μm [inhibitor]; kobs/[inh] = 356 M-1s-1.

3-[2-(N-morpholino)ethoxy]-1,2,4-thiadiazolo [4,5-a]benzimidazole

cathepsin L: 99% inhibition at 25 μm

[inhibitor]; kobs/[inh] = 356 M-1s-1.

cathepsin B: 91% inhibition at 50 μm [inhibitor]; kobs/[inh] = 107 M-1s-1.

papain 99.6% inhibition at 0.66 ám [inhibitor]; kobs/[inh] = 5560 M-1s-1.

{1,2,4-thiadiazolo[4,5-a]benzimidazole-3-yl}-carbonyl-L-leucyl isoamylase

cathepsin L: 93% inhibition at 5 µm

[inhibitor]; kobs/[inh] = 307 M-1s-1.

papain 95% inhibition at 5 μm [inhibitor] ; kobs/[inh] = 500 M-1s-1.

5-{3-methoxy-1,2,4-thiadiazolyl}-carbamoyl-Isak-1.

cathepsin B: 56% inhibition at 5 μm [inhibitor]; kobs/[inh] = 1062 M-1s-1.

papain 97% inhibition at 1 μm [inhibitor]; kobs/[inh] = 3896 M-1s-1.

Example 65

Crystallographic determination of the enzyme complex with the inhibitor 5-{ 3-methoxy-1,2,4-thiadiazolyl}- carbamoyl-isoleucyl of isoamylamine (TAA) with papain and aktinidin: TEA/papirovy complex and TEA/activitiesy complex

Purified papain was obtained commercially and olweny aktinidin was obtained by water extraction of homogenised kiwi, followed by fractionation with ammonium sulfate and ion-exchange DEAE-chromatography. Aktinidin/TEA and papain/TAA reactions were carried out according to the same Protocol. Mercaptopurine were selected beta mercaptoethanol-activated affinity chromatography on mercury-agarose. Proteins were suirvey as mercury derivative. Mercury-mercapto-proteins, 0.1% weight/volume, were incubated with 8 fold molar excess TEA and EDTA at pH 7.5. Papal/TAA was prerestore the 2.5% weight/volume in 67% 2:1 methanol/ethanol, 76 mm NaCl, and 1 mm A100-73.

Crystals papain TEA were grown by evaporation diffusion sitting drop. An aliquot SUP>o
C. Large single crystals grew within 4 to 6 weeks.

Aktinidin/TEA complex was prerestore at 0.5% weight/volume in 20 mm MES buffer, pH 6.0, and 0.5 mm TEA. Aktinidin TEA crystals were grown by the method of evaporation hanging drops. 1:1 mixture aktinidin TEA solution in the tank containing 20 mm MES buffer, pH 6.0 and 1.4 M ammonium sulfate, were incubated over capacity at 4oC. Large single crystals were grown for 7 to 10 days.

The crystals were placed in a wax-coated capillary tubes containing mother liquor. Data were collected on a Siemens Multi-wire detector mounted on Ridaku RU200 X-ray generator. Three groups of data were obtained on the same papain/TEA crystal and two groups of data were obtained on two aktinidin TEA crystals. XDS was used to reduce the data and the corresponding group data were normalized together. Protein crystals had the following dimensions;

For papain/TAA : a = 42,9 A, b = a 49.9 A, c = 95,7 A, =b= = 90.

For aktinidin/TAA: a = 3.9 a, b = 77,9 A, c = 81,4 A, =b= = 90.

Both crystal size group P212121. For papain/TAA normalized group data were fully consistent with the resolution of 2.2 A (60% patterns for razrusheniyu 2.7 And General Rsym= 10%. XPLOR used for structural refinement. 65 water molecules were modeled in papain TAA structure. For papain TAU, Rcryct= 18.4% and Rfree= 20,4%. For aktinidin TAU, Rcryst= 20,5% and Rfree= 24,4%.

Maps of the electron density for papain/TEA and aktinidin TEA complexes show broad electron density, which are located near their respective catalytic cysteine residues (Cys). This demonstrates that TEA reacts covalently with papain and actinidin with the formation of complexes of protein/inhibitor. TEA was fully modeled in the active site of papain, whereas partial model TAA was fully modeled in the active site of papain, whereas partial model TAA in the active centre of actinidin was received.

Kinetic data showed a complete inhibition of the enzymatic activity in the sample aktinidin TEA and re-dissolved crystals aktinidin TEA.

Example 66

Inhibitory test food ATPase

Used the enzyme was pork H+/K+-ATPase (Sachs, et al. J. Biol. Chem. 251:7690-7698, 1976). Used a modified procedure Yoda A. and HokinL.E., Biochem. Res. Commun., 1970, 800-884. Measured cal is Ogadenia H+/K+-ATPase.

Differences in activity in the presence of Mg2+and in the presence of Mg2+and K+taken as enzymatic activity. TO+ionophor nigericin was also present in the ( + )+the incubation mixture to provide an excess of K+inside the vesicles. Hydrolytic activity is measured quantitatively in complex with phosphomolybdate. This complex has a maximum optical density at 320 nm. Pricheska density of many drugs used for inhibition of+/K+-ATPase overlaps the wavelength. Thus, was used modification analysis Fiske-Subero the use of a reducing agent (1-amino-2-naphthol-4-sulfonic acid plus sodium sulfite). This shifts the optical density at 320 nm for the oxidized form phosphomolybdate complex to 600-700 nm. This modification has the advantage in automatic mode, when the analysis of many samples simultaneously. In this modification, the optical density of the samples is recorded at 700 nm.

The basal level of Mg++was determined in the medium with 2 ml MgCl2when 2 mm Na2ATP, 40 mm PIPES-TRIS, pH 6, 10, 20 mm KCl and 10 μg/ml of nigericin were added to determine the amount of Kee was added to initiate the reaction. The final volume of the sample was 200 ál. The Protocol for these tests are given in table. 1.

To reduce the number of additives, salt solutions and water can be combined in one Supplement. Additional reduction in the number of additives can be achieved using the enzyme with nigericin (final concentration after addition of enzyme, 10 μg/ml). The APR must be placed in an ice bath of distilled water immediately after adding. The enzyme should be attan and diluted immediately before adding.

Zero samples (control water) and phosphate standards (200 μl) was added to the appropriate standards: 0.005, 0.01, 0,25, 0,050, 0,075, 0,1...0,5 mm. Order supplements mainly followed the Protocol above. In addition, it may be preferable to add or enzyme before ATF, if it is important to time preincubation with the tested compounds. The time of addition of the last reagent is used to provide a standard time of analysis.

The reaction was carried out in the interval from 30 minutes to one hour. The reaction was stopped by adding 50 μl of a solution prepared by adding 4 volumes of 2.5 M sulfuric acid plus one volume of 1.25% (weight/volume) reagent Fiske-Subari at 700 nm. In the case where there is a white precipitate, net supernatant (after mixing and settling) could be used to determine the enzymatic activity.

3-[4-methylpiperazine] -1,2,4-thiadiazolo[4,5-a] benzimidazole EC50=210-6M

3-[piperazinil]-1,2,4-thiadiazolo [4,5-a]benzimidazole EC50= 110-6M

3-[N-morpholinomethyl]-1,2,4-thiadiazolo[4,5-a]benzimidazole EC50=210-7M

3-[2-(N-morpholino)ethylamino] -1,2,4-thiadiazolo[4,5-a]benzimidazole EC50= 210-7M

Summary of results of studies of biological activity and toxicity

Example 67

A single study of dose-response relationships to estimate the effect of the compounds of formula I when administered orally on the secretion of gastric acid in rats

The purpose of this study was to establish the antisecretory action of experimental compounds in comparison with Omeprazole. Omeprazole is a proton pump inhibitor and antisecretory drug for the treatment of ulcers.

The group of rats albino line Sprague-Dawley was obtained from ACE Animals, Inc., Boyertown, PA. Animals were placed one by one in suspended cells from the stainless Ely. The temperature in the room with the animals was monitored and the cycle of light/dark was 12 hours. The animals were given feed Purina Rodent Chow #5012 and supplied filtered tap water ad libitum via an automatic system for water distribution.

After an adaptation period of duration of 8 days, the animals were subjected to fasting for about 24 hours by removing food from their cells. After a period of starvation for testing selected male rats, based on the state of health and body weight.

Individual doses were calculated based on body weight after a period of starvation. Test or reference product was administered to each animal by oral intubation using a needle with a spherical tip is made from stainless steel, is connected to its corresponding syringe. The concentration of the test product and the control product were selected so that each animal received 10 ml/kg of the test mixture or carboxymethylcellulose (CMC).

Two hours after the introduction of the corresponding preparation all animals were anestesiologi short-acting General anesthetic actions (Methchexital Sodium). Abdominal region recorded the clips, did midline incision, the Incision was sutured and the animal was returned to its cage without access to food or water.

All rats were subjected to euthanasia after about two hours after ligation of the pylorus is preserved using excessive dose of pentobarbital sodium. Sewed up the intact esophagus and the stomach was removed and opened along the line with the greatest curvature. Stomach contents were collected in a plastic Cup and was transferred into a conical tube with a volume of 15 ml of stomach Contents were centrifuged for about ten minutes.

Centrifuged supernatant decantation and counting the amount constituting at least a tenth of a milliliter. A sample of the supernatant volume of 1.0 ml was transferred by pipette 4.0 ml of distilled water and titrated with 0.1 N sodium hydroxide to pH 7.0. If the volume of the supernatant was between 0.5 and 1.0 ml, 0.5 ml of sample was transferred into a 2.0 ml distilled water and titrated. Acidity was determined by titration and calculated the total acid output (see table. 2).

All compounds tested showed antisecretory activity, leading to inhibition of total acid output, when administered orally in a dose of 8 mg/kg In this study, omeprazole (known antiulcer drug) was used as a standard for comparison.

Example 68

The study of acid in rats (Fig. 4)

The purpose of this study was to assess antisecretory actions of the five experimental compounds.

The group of rats albino line Sprague-Dawley was obtained from ACE Animals, Inc. , Boyertown, PA. Animals were placed one by one in suspended cages with stainless steel wire mesh floors. Paper for garbage collection was placed on the bottom of the cells and changed at least three times per week. The temperature in the room with the animals was monitored and the cycle of light/dark was 12 hours. The animals were given feed Purina Rodent Chow #5012 and supplied filtered tap water ad libitum via an automatic system for water distribution. After an adaptation period of duration of 7 days 212 animals were subjected to fasting for about 24 hours by removing food from their cells. After a period of starvation for testing selected male rats, based on the state of health and body weight.

Individual doses were calculated based on body weight after a period of starvation. Test products and pantoprazole were prepared as solutions in 0.9% normal saline solution. The concentration of the test product and the control product were selected so that each animal received 1 ml/kg of the test was smetanasaal short-acting General anesthetic actions (ether). Abdominal region were fixed with clamps, making the middle section and exhibited duodenal stomach. Suture ligature was placed around the pylorus is preserved and tightly tied. The incision was sutured and the animal was returned to its cage without access to food or water. All rats were subjected to euthanasia after about three hours after ligation of the pylorus is preserved using excessive dose of pentobarbital sodium. Sewed up the intact esophagus and the stomach was removed and opened along the line with the greatest curvature. Stomach contents were collected in a plastic Cup and was transferred into a conical tube with a volume of 15 ml of stomach Contents were centrifuged for about ten minutes. Centrifuged supernatant decantation and counting the amount constituting at least a tenth of a milliliter. A sample of the supernatant volume of 1.0 ml was transferred by pipette 4.0 ml of distilled water and titrated in 0.01 N sodium hydroxide to pH 7.0. If the volume of the supernatant was between 0.5 and 1.0 ml, 0.5 ml of sample was transferred into a 2.0 ml distilled water and titrated. Acidity was determined by titration and calculated the total acid output.

Example 69

Study of dose-response relationships to estimate the secretion of gastric acid in the mental connections in comparison with omeprazole.

The group of rats albino line Sprague-Dawley was obtained from ACE Animals, Inc., Boyertown, PA. Animals were placed one by one in suspended cages with stainless steel wire mesh floors. Paper for garbage collection was placed on the bottom of the cells and changed at least three times per week. The temperature in the room with the animals was monitored and the cycle of light/dark was 12 hours. The animals were given feed Purina Rodent Chow # 5012 and supplied filtered tap water ad libibum with automatic water distribution system.

After an adaptation period of duration of 7 days 180 animals were subjected to fasting for about 24 hours by removing food from their cells. After a period of starvation for testing are selected 178 male rats, based on the state of health and body weight.

Individual doses were calculated based on body weight after a period of starvation. Test products and omeprazole were prepared in the form of a suspension in 1% carboxymethylcellulose (CMC). The concentration of the test product and the control product were selected so that each animal received 10 ml/kg of the test mixture or mixture control.

Two hours after the introduction of the corresponding preparation all animals were anestesiologi mimami, did the middle section and exhibited duodenal stomach. Suture ligature was placed around the pylorus is preserved and tightly tied. The incision was sutured and the animal was returned to its cage without access to food or water. All rats were subjected to euthanasia after about two hours after ligation of the pylorus is preserved using excessive dose of pentobarbital sodium. Sewed up the intact esophagus and the stomach was removed and opened along the line with the greatest curvature. Stomach contents were collected in a plastic Cup and was transferred into a conical tube with a volume of 15 ml of stomach Contents were centrifuged for about ten minutes. Centrifuged supernatant decantation and counting the amount constituting at least a tenth of a milliliter. A sample of the supernatant volume of 1.0 ml was transferred by pipette 4.0 ml of distilled water and titrated in 0.01 N sodium hydroxide to pH 7.0. If the volume of the supernatant was between 0.5 and 1.0 ml, 0.5 ml of sample was transferred into a 2.0 ml distilled water and titrated. Acidity was determined by titration and calculated the total acid output.

Example 70

Study of acute toxicity when administered orally in rats

For information about the health threat is Dawley was obtained from ACE Animals, Inc., Boyertown, PA. Animals were placed one by one in suspended cages with stainless steel wire mesh floors. Paper for garbage collection was placed on the bottom of the cells and changed at least three times per week. The temperature in the room with the animals was monitored and the cycle of light/dark was 12 hours. The animals were given feed Purina Rodent Chow #5012 and supplied filtered tap water ad libitum via an automatic system for water distribution.

After a period of adaptation to the laboratory the animals were subjected to fasting for about 18-19 hours by removing food from their cells. After a period of starvation for testing down to 50 healthy rats, and equally distributed in each of the following five dose groups (5 males and 5 females/group) (see table. 3).

Individual doses were calculated based on initial body weight. The desired concentration of APO 199. xHCl was prepared in 0.9% saline solution. For dosage control group used a 30% propylene glycol in 0.9% saline solution. Each animal received the appropriate amount of test substance, as described above, by oral intubation using a needle with a spherical tip, stainless steel, preribosomal three hours after the dose. Observed mortality of animals, poisoning symptoms and changes in behavior after 1 and 3 hours after a dose and at least once a day for 14 days. Body weight was recorded before initiation and after (Day 14). All rats were euthanized by inhalation of CO2on the 14th day. All animals were dissected and their tissues and organs of the thoracic and abdominal cavities were examined. Animals in all groups survived and increased weight during the study. These animals were not observed signs of poisoning, adverse pharmacological effects or abnormal behavior. No significant anomalies were observed also after opening at the expiration of the 14-day observation period. A single toxic dose when administered orally ID50for APO 199 xHCl and APO 121 xHCl was more than 500 mg/kg of body weight.

The chemical structures of the compounds of examples A-E are presented in table. 4.

1. The method of binding of thiols with turning them Tilney group disulfide group, which includes the interaction of compounds containing Tilney group, 1,2,4-thiadiazolyl connection with structural group of the formula

< / BR>
or its pharmaceutically acceptable the lågen, the nitrogroup, low CNS group or a group having the formula R NR'r", OC(O)R', NH(CO)OR' in which R' and R" independently represent hydrogen, lower alkyl;

Y is selected from compounds having the formula

< / BR>
in which R7represents hydrogen, hydroxyl group, lower alkyl, lower CNS group, lower alkenyl, phenyl, pyridyl, lower phenylalkyl, piperazinil, benzyl, pentyloxy, cyclopentyloxy, benzyloxy, group R NR'r" where R' and R", such as defined above, and groups ANR'R", AOR', where A represents an amino acid residue or a peptide of 2 to 3 amino acid residues and R' and R" have the same definition as above, with any heterocyclic group, and optionally substituted lower CNS group lower alkyl, amino group: piperazinil, pyridyl, lower alkylene-pyridyl, lower alkylene-piperazinil, amino pyridyl, amino piperazinil, amino-lower alkylene-pyridyl, morpholinyl, piperazinil, pyrrolidinyl or hydroxy-lower-alkylene-pyridyl, hydroxy-lower-alkylene-piperazinil, and a heterocyclic ring attached to the N-atom or carbon atom that results in the creation of a stable structure and a heterocyclic ring, optionally substituted by 1-3 zamestitelyami and pyridyl, optionally substituted by 1-3 substituents, independently selected from lower alkyl, hydroxyl groups, CNS group, and lower alkyl optionally substituted by 1-3 substituents, independently selected from hydroxyl group, a lower alkylcarboxylic group, phenyl, halogenfree, carboxyl and lower alkylcarboxylic group, lower acyl, lower alkoxycarbonyl group, lower alkylsulfonyl group, amide group, allyl, benzyl, phenyl, optionally substituted amino group, a halogen, a hydroxyl group, a lower CNS group, a lower alkyl, di-lower alkylamino; R NR'r" where R' and R", such as defined above; ANR'R", AOR', where a represents an amino acid residue or a peptide of 2-3 amino acid residues, and R and R" have the same definition as described above, the lower 2-(alkoxycarbonyl) alkyl; halogen; groups of formula R8-CHOH-, where R8represents hydrogen, lower alkyl, phenyl, pyridyl, piperazinil, benzyl and heterocyclic ring attached via any heteroatom or carbon atom that results in the creation of a stable structure; groups of the formula R9-C(=NOR10), where R10represents hydrogen, R9presented the t to the creation of a stable structure; lower CNS group, optionally substituted di(lower alkyl) amino group, a morpholine or 4-alkylpiperazine; lower alkylsulfonyl, lower alkylsulfonyl, phenylsulfonyl, phenylsulfinyl, lower phenylalkylamine, lower alkylresorcinol, optionally substituted with 1-2 substituents selected from lower alkyl, groups of formula-C(= NOH)COOR11where R11represents hydrogen, lower alkyl, phenyl, lower pyridinoline, piperidinyl, each group optionally substituted with 1-2 substituents selected from halogen, amino, hydroxyl group, lower CNS group, lower alkylamino, R NR'r", NR'(COR'), NHC(O)R NR'r", NHC(O)OR', where R' and R" have the meanings specified above.

2. The method according to p. 1, characterized in that use such thiadiazoline connection, in which each R1, R2, R3and R4represent hydrogen or CNS group.

3. The method according to p. 2, characterized in that use such thiadiazoline connection, in which each R1, R3and R4represent hydrogen, and R2is either hydrogen, or metaxylene group.

4. The method according to p. 3, characterized in that use is employed, an alkyl, lowest phenylalkyl.

5. The method according to p. 4, characterized in that use such thiadiazole compounds in which R7represents an optionally substituted heterocyclyl.

6. The method according to p. 5, characterized in that use such thiadiazole compounds in which R7represents 2-pyridyl, or unsubstituted or is substituted by 1-3 substituents selected from methyl and metaxylene group.

7. The method according to p. 6, characterized in that use such thiadiazole compounds in which R7represents 3,5-dimethyl-4-methoxy-2-pyridyl.

8. The method according to p. 7, characterized in that used thiadiazole compound is 7-methoxy-3-[(4-methoxy-3,5-dimethyl-2-pyridyl)oxoethyl]-1,2,4-thiadiazolo[4,5-a]benzimidazole.

9. The method according to p. 7, characterized in that used thiadiazole compound is 3-[(4-methoxy-3,5-dimethyl-2-pyridyl)oxoethyl]-1,2,4-thiadiazolo[4,5-a]benzimidazole.

10. The method according to p. 4, characterized in that use such thiadiazole compounds in which R7represents an optionally substituted piperazine.

11. The method according to p. 1, characterized in that used thiadiazoline soedarsono represent lower alkyl, hydrogen, lower CNS group; G is alkyl (C1-C6), optionally substituted by not more than three substituents selected from a hydroxyl group, phenyl, halogenfree, pyridyl, benzyl, cinnamyl, pyrimidyl.

12. The method according to p. 11, characterized in that use such thiadiazole compounds in which G is a 4-methylpiperazine.

13. The method according to p. 11, characterized in that used thiadiazole compound is 3-(4-methylpiperazine)-1,2,4-thiadiazolo[4,5-a] benzimidazole.

14. Connection on p. 11, characterized in that used thiadiazole connection R1is a G, which in turn represents 4-(2-pyridyl)piperazinil.

15. The method according to p. 14, characterized in that used thiadiazole compound is 3-(4-(2-methylpiperidino)-1,2,4-thiadiazolo[4,5-a] benzimidazole.

16. The method according to p. 4, characterized in that use thiadiazole compounds in which R7represents optionally substituted phenyl.

17. The method according to p. 16, characterized in that use thiadiazole compounds in which R7represents phenyl.

19. The method according to p. 11, characterized in that used thiadiazole compound is 3-(4-(benzyl)piperazinylcarbonyl)-1,2,4-thiadiazolo[4,5-a]benzimidazole.

20. The method according to p. 4, characterized in that use thiadiazole compounds in which R7represents a hydroxyl group.

21. The method according to p. 20, characterized in that used thiadiazole compound is 3-carboxy-1,2,4-thiadiazolo[4,5-a]benzimidazole.

22. The method according to p. 3, characterized in that use thiadiazole compounds in which Y is an optionally substituted heterocyclic group, directly linked to the heterocyclic ring.

23. The method according to p. 22, characterized in that use thiadiazole compounds in which the heterocyclic fragment group Y is selected from pyridyl, piperazinil, morpholinyl, pyrrolidinyl and pyrazinyl.

24. The method according to p. 23, characterized in that used thiadiazole compound is 3-(2-pyridyl)-1,2,4-thiadiazolo[4,5-a]benzimidazole.

25. The method according to p. 23, characterized in that used thiadiazole compound is 3-(4-morpholinyl)-1,2,4-thiadiazolo[4,5-a]benzimidazole.

26. The method according to p. 23,intimidation.

27. The method according to p. 23, characterized in that used thiadiazole compound is 3-(2-pyrazinyl)-1,2,4-thiadiazolo[4,5-a]benzimidazole.

28. The method according to p. 2, characterized in that the compound containing Tilney group, is an enzyme.

29. The method according to p. 1, characterized in that used thiadiazole compounds are compounds of General formula

< / BR>
where R1, R2, R3, R4independently represent lower alkyl, hydrogen, lower CNS group; G is a (C1-C6) alkyl, optionally substituted by not more than three substituents selected from a hydroxyl group, phenyl, halogenfree, carboxyl group, allyl, acetyl, benzyl; phenyl, optionally substituted amino, halogen, lower alkyl; pyridyl, cinnamyl, optionally substituted by not more than three substituents selected from lower CNS group, lower alkyl, amino, lower alkylamino.

30. The method according to p. 29, characterized in that use thiadiazoline connection, in which G represents an optionally substituted lower alkyl.

31. The method according to p. 30, characterized in that toad is in p. 30, characterized in that used thiadiazole compound is 3-(4-ethyl-1-piperazinil)-1,2,4-thiadiazolo[4,5-a]benzimidazole.

33. The method according to p. 30, characterized in that used thiadiazole compound is 3-(4-propyl-1-piperazinil)-1,2,4-thiadiazolo[4,5-a]benzimidazole.

34. The method according to p. 30, characterized in that used thiadiazole compound is 3-(4-butyl-1-piperazinil)-1,2,4-thiadiazolo[4,5-a]benzimidazole.

35. The method according to p. 29, characterized in that used thiadiazole compound is 3-(4-(2-hydroxyethyl)-1-piperazinil)-1,2,4-thiadiazolo[4,5-a]benzimidazole.

36. The method according to p. 29, characterized in that use thiadiazoline connection, in which G represents optionally substituted phenyl.

37. The method according to p. 36, characterized in that used thiadiazole compound is 3-(4-phenylpiperazine)-1,2,4-thiadiazolo[4,5-a]benzimidazole

38. The method according to p. 36, characterized in that used thiadiazole compound is 3-(4-(4-methoxyphenyl)piperazinil)-1,2,4-thiadiazolo[4,5-a]benzimidazole.

39. The method according to p. 36, characterized in that used thiadiazole compound is 3-(4-phenylpiperazine connection, in which G represents benzyl.

41. The method according to p. 40, characterized in that used thiadiazole compound is 3-(4-benzylpiperazine)-1,2,4-thiadiazolo[4,5-a]benzimidazole.

42. The method according to p. 29, characterized in that use thiadiazoline connection, in which G represents cinnamyl.

43. The method according to p. 42, characterized in that used thiadiazole compound is 3-(4-cinnamylpiperazine)-1,2,4-thiadiazolo[4,5-a]benzimidazole.

44. The method according to p. 29, characterized in that use thiadiazole compound in which G is a 2-pyridyl.

45. The method according to p. 44, characterized in that used thiadiazole compound is 3-(4-(2-pyridyl)piperazinil)-1,2,4-thiadiazolo[4,5-a]benzimidazole.

46. The method according to p. 29, characterized in that use thiadiazoline connection, in which G represents 3-amino-2-pyridyl.

47. The method according to p. 46, characterized in that used thiadiazole compound is 3-(4-(3-amino-2-pyridyl)piperazinil)-1,2,4-thiadiazolo[4,5-a]benzimidazole.

48. The method according to p. 29, characterized in that use thiadiazole compound in which G is a 2-pyrimidyl.

50. The method according to p. 29, characterized in that use thiadiazoline connection, in which G represents (1-(4-chlorophenyl)-1-phenylmethyl).

51. The method according to p. 50, characterized in that the connection is thiadiazoline 3-(4-(1-(4-chlorophenyl)-1-phenylmethyl)piperazinil)-1,2,4-thiadiazolo[4,5-a]benzimidazole.

52. The method according to p. 29, characterized in that used thiadiazole compound is 3-(4-acetyl-1-piperazinil)-1,2,4-thiadiazolo[4,5-a]benzimidazole.

53. The method according to p. 1, characterized in that used thiadiazoline the compound is General formula

< / BR>
where R1, R2, R3, R4independently represent lower alkyl, hydrogen, lower CNS group;

G is a (C1-C6) alkyl, optionally substituted by not more than three substituents selected from a hydroxyl group, phenyl, halogenfree, allyl, cinnamyl, benzyl; phenyl, optionally substituted by amino, lower CNS group, the lower alkyl; pirimidinom, pyridium, optionally substituted by not more than three substituents selected from a hydroxyl group, a lower CNS group, lower alkyl, amino.

54. the sory substituted lower alkyl.

55. The method according to p. 54, characterized in that used thiadiazole compound is 3-((4-ethylpiperazin)methyl)-1,2,4-thiadiazolo[4,5-a]benzimidazole.

56. The method according to p. 54, characterized in that used thiadiazole compound is 3-((4-propyl-1-piperazinil)methyl)-1,2,4-thiadiazolo[4,5-a]benzimidazole.

57. The method according to p. 54, characterized in that used thiadiazole compound is 3-((4-butylpiperazine)methyl)-1,2,4-thiadiazolo[4,5-a] benzimidazole.

58. The method according to p. 54, characterized in that used thiadiazole compound is 3-((4-(2-hydroxyethyl)piperazinil)methyl)-1,2,4-thiadiazolo[4,5-a]benzimidazole.

59. The method according to p. 53, characterized in that use thiadiazoline connection, in which G represents optionally substituted phenyl.

60. The method according to p. 59, characterized in that used thiadiazole compound is 3-((4-phenylpiperazine)methyl)-1,2,4-thiadiazolo[4,5-a] benzimidazole.

61. The method according to p. 59, characterized in that used thiadiazole compound is 3-((4-(4-methoxyphenyl)piperazinil)methyl)-1,2,4-thiadiazolo[4,5-a]benzimidazole.

62. The method according to p. 59, characterized in that the TIA">

63. The method according to p. 53, characterized in that use thiadiazoline connection, in which G represents benzyl.

64. The method according to p. 63, characterized in that used thiadiazole compound is 3-((4-benzylpiperazine)methyl)-1,2,4-thiadiazolo[4,5-a] benzimidazole.

65. The method according to p. 53, characterized in that use thiadiazoline connection, in which G represents cinnamyl.

66. The method according to p. 65, characterized in that the compound is 3-((4-cinnamylpiperazine)methyl)-1,2,4-thiadiazolo[4,5-a]benzimidazole.

67. The method according to n.53, characterized in that use thiadiazole compound in which G is a 2-pyridyl.

68. The method according to p. 67, characterized in that used thiadiazole compound is 3-((4-(2-pyridyl)piperazinil)methyl)-1,2,4-thiadiazolo[4,5-a]benzimidazole.

69. The method according to p. 53, characterized in that use thiadiazoline connection, in which G represents 3-amino-2-pyridyl.

70. The method according to p. 69, characterized in that used thiadiazole compound is 3-((4-(3-amino-2-pyridyl)piperazinil)methyl)-1,2,4-thiadiazolo[4,5-a]benzimidazole.

71. The method according to p. 53, characterized is by p. 71, characterized in that used thiadiazole compound is 3-((4-(2-pyrimidyl)piperazinil)methyl)-1,2,4-thiadiazolo[4,5-a]benzimidazole.

73. The method according to p. 53, characterized in that use thiadiazoline connection, in which G represents (1-(4-chlorophenyl)-1-phenylmethyl).

74. The method according to p. 73, characterized in that the connection is thiadiazoline 3-((4-(1-(4-chlorophenyl)-1-phenylmethyl)piperazinil)methyl)-1,2,4-thiadiazolo[4,5-a]benzimidazole.

75. The method according to p. 3, characterized in that use thiadiazole compound in which Y is a halogen.

76. The method according to p. 75, characterized in that use thiadiazole compound in which Y is bromine.

77. The method according to p. 76, characterized in that used thiadiazole compound is 3-bromo-1,2,4-thiadiazolo[4,5-a]benzimidazole.

78. The method according to p. 3, characterized in that use thiadiazole compound in which Y is halogenation.

79. The method according to p. 78, characterized in that used thiadiazole compound is 3-methyl bromide-1,2,4-thiadiazolo[4,5-a]benzimidazole.

80. The method according to p. 3, characterized in that used thiadiazoline the connection, what used thiadiazoline the compound is General formula

< / BR>
where R1, R2, R3, R4independently represent lower alkyl, hydrogen, amino, CNS group; R' and R" are independently selected from lower alkyl, benzyl, phenyl, and lower alkyl substituted with hydroxyl group, amino group, or R' and R" together with N group to which they are attached form a optionally substituted saturated heterocyclic group selected from pyridyl, piperidinyl, shed, morpholinyl, pyrrolidinyl, phenyl.

82. The method according to p. 81, characterized in that use thiadiazoline connection, in which R' and R" are both lower alkyl.

83. The method according to p. 82, characterized in that used thiadiazole compound is 3-dimethylaminomethyl-1,2,4-thiadiazolo[4,5-a] benzimidazole.

84. The method according to p. 82, characterized in that used thiadiazole compound is 3-diethylaminomethyl-1,2,4-thiadiazolo[4,5-a]benzimidazole.

85. The method according to p. 82, characterized in that used thiadiazole compound is 3-dipropylamino-1,2,4-thiadiazolo[4,5-a]benzimidazole.

86. The method according to p. 82, characterized in that the TIA is about p. 81, characterized in that use thiadiazoline connection, in which R' and R" with N-atom to which they are attached, form morpholino a cyclic structure.

88. The method according to p. 87, characterized in that used thiadiazole compound is 3-morpholinomethyl-1,2,4-thiadiazolo[4,5-a]benzimidazole.

89. The method according to p. 1, characterized in that use thiadiazole compound in which Y represents a phenyl, optionally substituted by 1-3 substituents selected from lower alkyl, hydroxyl group, nitro group, amino group, lower alkylamino, di-lower alkylamino and lower CNS group.

90. The method according to p. 89, characterized in that used thiadiazole compound is 3-phenyl-1,2,4-thiadiazolo[4,5-a]benzimidazole.

91. The method according to p. 89, characterized in that used thiadiazole compound is 3-(2-nitrophenyl)-1,2,4-thiadiazolo[4,5-a]benzimidazole.

92. The method according to p. 89, characterized in that used thiadiazole compound is 6-amino-3-phenyl-1,2,4-thiadiazolo[4,5-a]benzimidazole.

93. The method according to p. 89, characterized in that used thiadiazole compound is 7-amino-3-phenyl-1,2,4-tadena, in which Y represents 2-pyridyl, optionally substituted by 1-3 substituents selected from lower alkyl, hydroxyl group, nitro group, amino group, lower alkylamino, di-lower alkylamino and lower CNS group.

95. The method according to p. 94, characterized in that used thiadiazole compound is 3-(2-pyridyl)-1,2,4-thiadiazolo[4,5-a]benzimidazole.

96. The method according to p. 1, characterized in that use thiadiazole compound in which Y represents a 2-pyrazinyl, optionally substituted by 1-3 substituents selected from lower alkyl, hydroxyl group, nitro group, amino group, lower alkylamino, di-lower alkylamino and lower CNS group.

97. The method according to p. 96, characterized in that used thiadiazole compound is 3-(2-pyrazinyl)-1,2,4-thiadiazolo[4,5-a]benzimidazole.

98. The method according to p. 1, characterized in that use thiadiazole compound in which Y represents an optionally substituted aminopyridin.

99. The method according to p. 98, characterized in that used thiadiazole compound is 3-(2-pyridylamino)-1,2,4-thiadiazolo[4,5-a]benzimidazole.

100. Sposa[4,5-a]benzimidazole.

101. The method according to p. 1, characterized in that use thiadiazole compound in which Y is optionally substituted lower alkylene-aminopyridin.

102. The method according to p. 101, characterized in that used thiadiazole compound is 3-[2-pyridylmethylamine]-1,2,4-thiadiazolo[4,5-a]benzimidazole.

103. The method according to p. 101, characterized in that used thiadiazole compound is 3-[N-methyl-(2-pyridylethyl)amino]-1,2,4-thiadiazolo[4,5-a] benzimidazole.

104. The method according to p. 1, characterized in that use thiadiazole compound in which Y represents imidazolylalkyl.

105. The method according to p. 104, characterized in that used thiadiazole compound is 3-(imidazolylalkyl)-1,2,4-thiadiazolo[4,5-a]benzimidazole.

106. The method according to p. 1, characterized in that use thiadiazole compound in which Y represents a 1,2,4-triazolylmethyl.

107. The method according to p. 106, characterized in that used thiadiazole compound is 3-(1,2,4-triazolylmethyl)-1,2,4-thiadiazolo[4,5-a]benzimidazole.

108. The method according to p. 3, characterized in that the thiadiazole is 3-(4-methylphenylsulfonyl)-1,2,4-thiadiazolo[4,5-a]Ben is a group of the formula

< / BR>
where R7is a group ANR'R", in which a is amino acid residue.

110. The method according to p. 109, characterized in that the link represents a leucine residue.

111. The method according to p. 110, wherein in the compound R' is H and R" is lower alkyl.

112. The method according to p. 111, characterized in that the compound has the formula

< / BR>
113. The mode of interaction of the compounds containing Tilney group with turning them Tilney group disulfide group, which includes the interaction of compounds containing Tilney group, a thiadiazole of the General formula III

< / BR>
or its pharmaceutically acceptable salts,

in which R5and R6independently selected from hydrogen and lower alkyl, OC(O)R', OC(O)NR'r R', NH(CO)R', NHC(O)R NR'r" where R' and R" independently have the meanings given in paragraph 1 or NR'r R" represents a five - or six-membered ring consisting of N(CH2)nwhere n = 4 or 5;

Y are such as defined in paragraph 1.

114. The method according to p. 113, characterized in that use thiadiazole compounds in which R5and R6both represent hydrogen.

115. FPIC is/BR> a R7is lower alkyl, lower CNS group or aryl.

116. The method according to p. 114, characterized in that used thiadiazole compound is 3-acetylimidazole[1,2-d]-1,2,4-thiadiazole.

117. The method according to p. 114, characterized in that used thiadiazole compound is 3-benzoimidazol[1,2-d]-1,2,4-thiadiazole.

118. 3,5-Disubstituted 1,2,4-thiadiazole compounds corresponding to the General formula

< / BR>
in which Q represents a group-T[AMA]L, where T is a chemical spacer elements group associated with thiadiazolyl the nucleus and is selected from

< / BR>
< / BR>
L is the terminal protecting group of the peptide, end group

< / BR>
or-OR', NR'r R", where R' and R" are such as listed below for group Y and-AMA - is an amino acid or peptide residue -[NH-CHA'-CO]n - where a' is any of the known substituents of amino acids, and n is an integer from 1 to 3,

Y' represents a lower alkyl, lower CNS group, amino group, 1-piperazinil, optionally substituted in the 4 position by lower alkyl; lower alkyl substituted with 1 or 2 substituents selected from a hydroxyl group, benzyl, phenyl, optionally substituted by 1-3 substituents selected from the second ring optionally substituted by 1-3 substituents, selected from amino group, hydroxyl group, lower CNS group, lower alkyl, lower alkylamino, or a group-CH2-CO-NH - lower alkyl, provided that when Q is NHPh, Y' cannot be CNS group, dialkylamino, hydroxyethylamino, di(hydroxyalkyl)amino group, and when Y' is 4-substituted piperazinil, Q must not be group-T-[AMA]-L.

119. Connection p. 118, in which Q represents an amino acid residue of the formula:

< / BR>
< / BR>
< / BR>
< / BR>
where PG is a N-protecting group selected from geterotsiklicheskikh, benzoyl, carbobenzoxy, tributoxy;

B2is hydrogen, lower alkyl, optionally substituted amino group, guanidino or N,N-di(lower alkyl)guanidino;

n = 1 or 2;

A1is lower alkyl.

120. Connection p. 119, characterized in that the group Y' is selected from lower alkyl, lower CNS group, amino group.

121. Connection on p. 118, which is a

< / BR>
122. Connection on p. 118, which is a

< / BR>
123. Connection on p. 118, which is a



 

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The invention relates to novel condensed polycyclic heterocyclic compounds of the formula I and the way they are received

The invention relates to methods of producing derivatives of 10-propenylbenzene that can be used in the production of stabilized polymer compositions for various purposes

The invention relates to the production of products of oligomerization, which can be used in the manufacture of the stabilized polymer compositions of different directions

The invention relates to compounds of formula (I):

< / BR>
where

-A= B-C= D - represents-CH=CH-CH=CH-group, in which 1 or 2 CH may be replaced by nitrogen;

Ar denotes phenyl or naphthyl, unsubstituted or one-, two - or three-fold substituted with H, Gal, Q, alkenyl with the number of C-atoms up to 6, Ph, OPh, NO2, NR4R5, NHCOR4, CF3, OCF3CN, OR4, COOR4, (CH2)nCOOR4, (CH2)nNR4R5, -N=C=O or NHCONR4R5phenyl or naphthyl;

R1, R2, R3each independently from each other, are absent or represent H, Gal, Q, CF3, NO2, NR4R5, CN, COOR4or CHCOR4;

R4, R5each independently of one another denote H or Q, or together also denote-CH2-(CH2)N-CH2-;

Q denotes alkyl with 1-6 C-atoms;

Ph denotes phenyl;

X denotes O or S;

Gal denotes F, Cl, Br or I;

"n" represents 1, 2 or 3;

and their salts, except 4-methyl-N-(2,1,3-benzothiadiazole - 5-yl)benzosulfimide, 4-nitro-N-(2,1,3-benzothiadiazole-5-yl)- benzosulfimide and 4-amino-N-(2,1,3-benzothiadiazole-5-yl)- benzolsulfonat

The invention relates to the field of production of new heterocyclic O-dicarbonitriles, which can be used to achieve different hexatriene, useful as active media of liquid and solid lasers, scintillators, for the transformation of shortwave radiation in the long wavelength in the transmission of information through fiber-optic communication lines and so on

The invention relates to medicine and relates to a method of inhibiting tyrosine kinase receptor, epidermal growth factor, for example, Erb-b2, Erb-b3, or Erb-b4, by introducing to a mammal in need, an effective amount of nitrogen-containing heterocyclic compounds, which is that as the nitrogen-containing heterocyclic compounds used as a compound of formula I, where R1-R9are specified in the claims value, or its pharmaceutically acceptable salt, or hydrate, thereof the pharmaceutical composition and the contraceptive composition based on them

The invention relates to new 1,4-benzothiazepine-1,1-dioxides of the formula II, where R1, R2are primocane C1-6alkyl group; R4represents unsubstituted phenyl; R5and R8represent hydrogen; R6represents methoxy or bromo; R7arepresents methoxy, hydroxy or trifluoromethyl; R9and R10represent hydrogen, salts, solvate or physiologically functional derivatives, and method of production thereof

The invention relates to compounds of the following formula I which inhibit the enzyme glycinamide ribonucleotide the formyl transferase (GARFT)

The invention relates to new heterocyclic compounds with biological activity, more specifically, to the derivatives of benzothiophene, benzofuran, indoltiazepinone, oxazepines and diazepinone, the pharmaceutical composition having inhibitory cell adhesion or HIV activity, method of inhibition of leukocyte adhesion to endothelial cells in the treatment of diseases caused by it and the method of treating mammals infected with HIV

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to oxazolo- and thiazolo-[4,5-c]-quinoline-4-amines of the general formula (I)

wherein R1 is taken among group consisting of oxygen and sulfur atoms; R2 is taken among hydrogen atom, alkyl, alkyl-OH (hydroxyalkyl), alkyl-X-alkyl, alkyl-O-C(O)-N(R5)2, morpholinyl, pyrrolidinyl, alkyl-X-aryl radical, alkenyl-X-aryl radical; each substitute R3 and R4 represents hydrogen atom or substitutes R3 and R4 taken in common form the condensed aromatic or [1,5]-naphthiridine system; X represents -O- or a single bond; R5 represents hydrogen atom. Also, invention describes intermediate compounds, pharmaceutical composition and a method for stimulating biosynthesis of cytokinins (cytokines) based on these compounds. Invention provides preparing new compounds eliciting valuable biological properties.

EFFECT: valuable properties of compounds.

21 cl, 2 tbl, 64 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzodiazepine. Invention describes a derivative of benzodiazepine of the formula (I): wherein dotted lines show the possible presence of a double bond; R1, R2, R3, R4 and R5 are given in the invention claim; n represents 0, 1, 2, 3 or 4; X represents sulfur atom (S) or -NT wherein T is give in the invention claim; A represents hydrogen atom, (C6-C18)-aryl group substituted optionally with one or more substitutes Su (as given in the invention claim) or (C1-C12)-alkyl; or in alternative variant R4 and R5 form in common the group -CR6=CR7 wherein CR6 is bound with X and wherein R6 and R7 are given in the invention claim, and their pharmaceutically acceptable salts with acids or bases. It is implied that compounds corresponding to one of points (a)-(e) enumerated in the invention claim are excluded from the invention text. Also, invention describes methods for preparing compounds of the formula (I) and a pharmaceutical composition eliciting the hypolipidemic activity. Invention provides preparing new compounds eliciting the useful biological properties.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

20 cl, 6 tbl, 192 ex

FIELD: organic chemistry, madicine.

SUBSTANCE: tricyclic benzodiazepines of formula I as well as their pharmaceutical acceptable salts, pharmaceutical composition containing the same and methods for hypertension treatment are disclosed. In formula A is -C(O)-; Y is CH2 or CH as olefinic site; X is CH2 or CH as olefinic site S, O or NR3 (R3 is C1-C8-alkyl) with the proviso that when Y is CH, X also is CH; Z is N or CH; R1 is hydrogen, C1-C8-alkyl, C1-C8-alkoxy or halogen; R2 is NR4COAr (R4 is hydrogen; Ar is phenyl optionally substituted with 1-3 substitutes independently selected from C1-C8-alkyl, halogen, hydroxyl, fluorinated C1-C8-alkylthio and another phenyl optionally substituted with substitute selected from C1-C4-alkyl, halogen, and hydroxyl); R5 is hydrogen, C1-C4-alkyl, C1-C4-alkoxy, fluorine, chlorine, hydroxyl or di-(C1-C4)-alkylamino.

EFFECT: improved pharmaceutical composition for hypertension treatment.

12 cl, 5 tbl, 52 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to methods for treatment of diseases or syndromes associated with metabolism of fatty acids and glucose and to new compounds and their pharmaceutically acceptable salts. Invention relates to applying new compounds and pharmaceutical compositions for treatment of cardiovascular diseases, diabetes mellitus, cancer diseases, acidosis and obesity by inhibition of activity of enzyme malonyl-CoA-decarboxylase. Indicated compounds correspond to formulae (I) and (II) wherein Y, C, R1, R2, R6 and R7 have values given in the invention claim.

EFFECT: valuable medicinal and biochemical properties of azoles.

27 cl, 8 tbl

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to applying compounds of the general formula (1):

as inhibitors of caspase-3 that allows their applying as "molecular tools" and as active medicinal substances inhibiting selectively the scheduling cellular death (apoptosis). Also, invention relates to pharmaceutical compositions based on compounds of the formula (1), to a method for their preparing and a method for treatment or prophylaxis of diseases associated with enhanced activation of apoptosis. Also, invention relates to new groups of compounds of the formula 91), in particular, to compounds of the formulae (1.1):

and (1.2):

. In indicated structural formulae R1 represents inert substitute; R2, R3 and R4 represent independently of one another hydrogen atom, fluorine atom (F), chlorine atom (Cl), bromine atom (Br), iodine atom (J). CF3, inert substitute, nitro-group (NO2), CN, COOH, optionally substituted sulfamoyl group, optionally substituted carbamide group, optionally substituted carboxy-(C1-C6)-alkyl group; R5 represents oxygen atom or carbon atom included in optionally condensed, optionally substituted and optionally comprising one or some heteroatoms; R6 represents hydrogen atom or inert substitute; X represents sulfur atom or oxygen atom.

EFFECT: improved preparing and applying methods, valuable medicinal and biochemical properties of compounds.

3 cl, 1 dwg, 2 tbl, 1 sch, 8 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to substituted pyridines and pyridazines with angiogenesis inhibition activity of general formula I

(I)1, wherein ring containing A, B, D, E, and L represents phenyl or nitrogen-containing heterocycle; X and Y are various linkage groups; R1 and R2 are identical or different and represent specific substituents or together form linkage ring; ring J represents aryl, pyridyl or cycloalkyl; and G's represent various specific substituents. Also disclosed are pharmaceutical composition containing claimed compounds, as well as method for treating of mammalian with abnormal angiogenesis or treating of increased penetrability using the same.

EFFECT: new pyridine and pyridazine derivatives with angiogenesis inhibition activity.

26 cl, 6 tbl, 114 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to novel heterocyclic compounds comprising 2-aminopyridin-3-sulfonic fragment of the general formula (1) or their pharmaceutically acceptable salts, N-oxides or hydrates possessing properties of antagonists of glutamate-induced calcium ions transport, in particular, neuroprotective effect. Also, invention relates to the focused library for the search of biologically active leader-compounds comprising at least one heterocyclic compound of the general formula (1) and to pharmaceutical composition if form of tablets, capsules or injections placed into pharmaceutically acceptable package containing compounds of invention as an active substance. In compound of the general formula (1) R1 represents hydrogen atom; R2 represents chlorine atom, optionally substituted hydroxyl group, optionally substituted amino-group, optionally substituted azaheterocyclyl; or R1 and R2 in common with nitrogen and sulfur atoms to which they are bound form optionally substituted and optionally condensed with other cycles 1,1-dioxo-4H-pyrido[2,3-e][1,2,4]thiadiazine or optionally substituted and optionally condensed with other cycles 5,5-dioxo-5,6,7,9-tetrahydro-5-thia-1,6,9-triazabenzocyclohepten-8-one. Also, invention discloses methods for preparing different compounds of the general formula (1).

EFFECT: improved preparing methods, valuable medicinal properties of compounds.

10 cl, 4 sch, 4 tbl, 9 ex

FIELD: organic chemistry, medicine, hematology.

SUBSTANCE: invention elates to new compounds that inhibit activated blood coagulating factor X (Fxa factor) eliciting the strong anti-coagulating effect. Invention proposes compound of the formula (1): Q1-Q2-C(=C)-N-(R1)-Q3-N(R2)-T1-Q4(1) wherein R1, R2, Q1, Q2, Q4 and T1 have corresponding values, and Q2 represents the group of the formula: wherein R9, R10 and Q5 have corresponding values also, or its salt, solvate or N-oxide. Invention provides the development of a novel compound possessing strong Fxa-inhibiting effect and showing the rapid, significant and stable anti-thrombosis effectin oral administration.

EFFECT: valuable medicinal properties of compounds.

13 cl, 1 tbl, 195 ex

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