Derived saccharin or its pharmaceutically acceptable salt, pharmaceutical composition for the inhibition of proteolytic enzymes in the treatment of degenerative diseases

 

(57) Abstract:

Derived saccharin General formula I where R1is lower alkyl; R2- B = N-(CH2)pC(O)O(CH2)p, -O-, -O-(CH2)p-(5-((CH2)p), -B= N-2-furanyl), R is hydroxy(lower)alkyloxy, where B = N-di(lower)alkylamino; R is phenyl(lower)alkyl; p and p' is a whole number 1 or 2; R3Is H; X is H or halogen; Y is a group-N= C(Z') -, or-N=C(R')-N(R')-, where the group R"' together with the carbon atoms or nitrogen to which they are attached, represent a group -(CH2)4-, and Z", combined with the carbon atoms or nitrogen atoms to which they are attached, form peridogram, or its pharmaceutically acceptable salt as inhibitors of proteolytic enzymes useful in the treatment of degenerative disorders such as emphysema, rheumatoid arthritis, and pancreatitis. 2 s and 5 C.p. f-crystals, 5 PL.

The invention relates to the derivatives of saccharin, which inhibit the enzymatic activity of proteolytic (breaks down proteins), enzymes, methods for their preparation and methods for their use in the treatment of degenerative diseases and containing pharmaceutical compositions.

Inhibitors of proteolytic enzymes useful in the treatment of which is the splitting of proteins. The most widespread class of proteolytic proteins are semipretioase. Some semipretioase can be characterized based on their specificity towards certain substrates, such as chymotrypsin-like or elastase similar. Chymotrypsin and chymotrypsinogen enzymes usually break down the peptide bonds in the protein where the amino acid side of the carbonyl group is Trp, Tyr, Phe, Met, Leu or another amino acid, which contains the aromatic fragment or more alkyl side chain, Elastase and elastase such enzymes are usually cleaved the peptide bond at the place, where amino acid residue with the carbonyl side of the peptide bond is Ala, Val, Ser, Leu, or other small amino acids. As the chymotrypsin like and elastase such enzymes are found in leukocytes, the cells of the mammary glands and the secretions of the pancreas and may be released by many types of bacteria, yeast and parasites.

Dunlap et al. in the International application WO 90/13549 describe a series of 2-substituted saccharin derivatives which are useful as inhibitors of proteolytic enzymes.

Barber et al. in U.S. Patent 2855401 lead connection formulas

< / BR>
n denotes an integer from 5 to 9;

R3is a group selected from methanesulfonamido group, benzosulfimide group and o-sulfonanilide group. Indicates that these compounds are useful in the treatment of bilharziasis.

Brown et al. in U.S. Patent 3220940 report the use of acidic Nickel baths compounds of the formula

< / BR>
or Nickel, sodium, cobalt, potassium, lithium, magnesium, etc. sulphonate salts, where

A is chosen from the group comprising benzene, biphenylene and naphthalene rings,

R is chosen from the group comprising a hydrogen atom, hydroxyl, chlorine atom, bromine, SO3H and methyl,

n is an integer from 1 to 4, inclusive,

n1is 0 or 1, n2is 0, 1 or 2, if n2zero, and n1zero.

Sunket et al. in the European patent 253092 describe 2-saharinen-(lower alkyl)-1,4-dihydropyridines-3-carboxylates, which prevent the aggregation of platelets and have antithrombotic activity. A very similar description can also be found in Sunket et al., J. Med Chem., 1886-1890 (1988).

Mylvey et al. in U.S. Patent 4195023 lead R1-2-R2CO-1,2-benzisothiazol-3-ones, where R1indicates the APG, nitro group or a hydrogen atom in BENZENOID ring, and R2denotes a hydrogen atom, alkyl, alkenyl, quinil, cycloalkyl, halogenfree, heteroaryl or substituted heteroaryl, R1-2-A-CO sacharine, where R1has the same meaning as the substituents in BENZENOID ring 1,2-benzisothiazol-3-ones, and A denotes alkyl, alkenyl, quinil, cycloalkyl, forfinal, heteroaryl or substituted heteroaryl. Indicates that the described compounds have inhibitory activity against elastase and useful in the treatment of emphysema. A similar description can be found in French Patent 2321288.

Dunlap et al, European patent application 483928 A1 discloses 4-R4-R52-sharinglretirement and 4,5,6,7-tetrahydro-2-sharinglretirement, which, as indicated, have inhibitory activity against the enzyme protease and are useful in the treatment of degenerative diseases. A similar description can be found in U.S. Patent 5128339 (authors Dunlap et al.).

Jones et al. in U.S. Patent 4276298 lead 2-R-1,2-benzisothiazolinone-1,1-dioxides, where: R is phenyl, substituted by a fluorine atom, dinitro-group triptorelin group, cyano group, alkoxycarbonyl group, Onlineu group, N,N-dialkylaminoalkyl group, triptoreline group, triptoreline group, triftormetilfullerenov group and triftormetilfullerenov group or pyridium, substituted as R in the case when R stands for phenyl, except that the pyridyl may be mononitrotoluenes. Indicate that these compounds possess inhibitory activity against the enzyme protease and are useful in the treatment of emphysema, rheumatoid arthritis and other inflammatory diseases.

In the present invention claimed compound having the following structural formula:

< / BR>
where R1denotes a hydrogen atom, halogen atom, lower alkyl, perversioni lower alkyl, perchloromethyl lower alkyl, lower alkenyl, lower quinil, cyano, amino, lower alkylamino, di(lower alkyl) amino group, a lower alkoxygroup, benzyloxy, lower alkoxycarbonyl group or phenyl;

R2means from one to three substituents on any or all of the 5-, 6 - or 7-positions selected from the group including a group B=N-(CH2)pC(O)O(CH2)p'-O-, a group-O-(CH2)p-(5-((CH2)p'-B=N-2-furanyl) and R is hydroxy(lower)alkyloxy, where p and p' aldergate from one to three substituents, selected from the group comprising lower alkyl, B=N-carbonyl, group B=N, the lower alkoxygroup, B=N-(lower) alkoxygroup and halogen atom, and B=N denotes an amino group, a lower alkylamino, di(lower)alkylamino, carboxy(lower)alkylamino. 1-pyrrolidinyl group, 1-piperidinyl group, 1-azetidinol group, 4-morpholinyl group, 1-piperazinyl group, 4-(lower)alkyl-1-piperazinilnom group, 4-benzyl-1-piperazinilnom group or 1-imidazolidinyl group;

R3denotes a hydrogen atom, lower alkyl or phenyl;

X denotes a hydrogen atom, a nitro-group, halogen atom, lower alkyl, perversioni lower alkyl, perchloromethyl lower alkyl, phenyl, phenyl(lower)alkyl, fantaboulous group, pyridyl(lower)alkyl, formyl group, lower alkanoyloxy group, carboxyl group, lower alkoxycarbonyl group, aminocarbonyl group, lower alkylaminocarbonyl group, di(lower)alkylaminocarbonyl group, a cyano group B=N, B=N-(lower) alkyl, B=N-(lower) alkanoyloxy group, B=N-(lower)alkoxycarbonyl group, hydroxyl group, lower alkoxygroup, fenoxaprop, B=N-(lower)alkoxygroup, lower allylthiourea, fenit phenyl is unsubstituted or contains one to three substituents, selected from the group comprising lower alkyl, lower alkoxygroup and halogen atom and group B=N has the above meaning;

Y denotes the remaining atoms of the monocyclic or bicyclic, substituted or unsubstituted carbocyclic or heterocyclic ring system; or its pharmaceutically acceptable acid additive salt in that case, if the compound has a basic functional group, or its pharmaceutically acceptable base - additive salt, if the compound has an acidic functional group.

In the invention hereinafter claimed is a method of obtaining the compounds of formula I, which consists in condensing the corresponding compound having the structural formula II:

< / BR>
where O denotes a chlorine atom or aroma,

with a corresponding compound having the structural formula III:

< / BR>
in the presence of base or with a corresponding basic salt of the compounds of formula III.

Another objective of the present invention is a pharmaceutical composition for the treatment of degenerative diseases, which contains a compound of formula I with a concentration sufficient for inhibition of proteolytic enzyme in the pharmaceutical carry the I in number, sufficient for inhibition of proteolytic enzyme in the production of drugs for the treatment of degerativnye disease in a patient in need of such treatment.

The compound of formula I inhibits the enzymatic activity of proteolytic enzymes and are useful in the treatment of degenerative diseases.

Part of the compounds of formula I having structural formula

< / BR>
below is described further by the formula - Z. Similarly, the compound of formula III is described further by the formula H-O-z -

Saccharin is 1,2-benzisothiazol-(1H)-3-one-1,1-di-oxide; compounds of the formula I, which are 2-[Z-O-CH(R3)]-4-R1-(5,6 and/or 7)-R2-1,2-benzisothiazol-(1H)-3-one-1,1-dioxides are the corresponding 2-[Z-O-CH(R3]-4-R1-(5,6 and/or 7)-R2-sharename.

In compounds according to formulas I-III expression "corresponding" means that the defined variable in one formula has the same meaning in a different formula.

Carbon chain, representing the portion of these compounds contains from one to ten carbon atoms, predominantly from one to four carbon atoms and is branched or unbranched in the following graphgraph, lowest alkylamino, di-(lower)alkylamino lowest alkoxygroup, carboxy (lower) alkylamino, 4-(lower alkyl)-1-piperazinilnom group, phenyl(lower)alkyl, pyridyl(lower)alkyl, lower alkylaminocarbonyl group, lower allylthiourea and carboxy (lower) alkylamino.

The following groups of these compounds, consisting of a carbon chain contains from two to ten carbon atoms, predominantly from two to four carbon atoms and is branched or unbranched: lower alkenyl, lower quinil, amino(lower)alkyl, lower CNS part of the group: B=N-(lower)alkoxycarbonyl group, lower alcoolica group, B=N-(lower) alkyl, B=N-(lower)alcoolica group and B= N-(lower)alkoxycarbonyl group. Halogen denotes fluorine atom, chlorine, bromine or iodine.

In the compounds of the formula I R1mainly refers to primary or secondary alkyl having from two to four carbon atoms, or lower alkoxygroup, and R2mainly attached at position 6 and most predominantly is the group B= N-(CH2)pC(O)O(CH2)p'-O - or R is hydroxy(lower)alkoxyl. Next-Y - advantage is-C (CH2CH2N(R)CH2CH2]c-O-,

-(CH2)m-N(R')-, CHR-N(R')-, -CR2-N(R')-, -C(R')=(R')-O-, -C(R')=(R')-N(R'), -C(=O)-C(R")=C(R")-, -C(Z')=C(Z')-, -C(Z')=-C(Z')-O-, -C(Z')=C(Z')-N(R')-, -N(Z)-C (Z)=N-, -N=C(Z)-N-(Z)-, C(Z)=C(Z)-S, N=C(R) NC(R') -, or-C(R"=C(L)-N(L),

where groups: Z",together with the carbon atoms to which they are attached, denote anthropo;

group R"' together with the carbon atoms or nitrogen atoms to which they are attached, denote a group -(C2)n'-, -(CH2)qN(R*) (CH2)q'or titlegroup, group L, together with the carbon atoms or nitrogen atoms to which they are attached, denote peridogram; n1is an integer from 3 to 5; R*denotes a hydrogen atom, phenyl, phenyl(lower)alkyl or lower alkyl; q is 1 or 2, q1is 1 or 2; R '" represents a hydrogen atom, a cyano group CO2L' SO2L" or a nitro-group; L' represents a hydrogen atom, lower alkyl or di(lower)alkylamino, L" denotes a hydrogen atom, a lower alkoxygroup, or di(lower)alkylamino or triptorelin group; m is 1, 2, 3 or 4; n is 3, 4 or 5, R represents the same or different lower alkyl, phenyl or phenyl(lower)alkyl; R' denotes a hydrogen atom or a group R, R" denotes atnam pornograpy,

the group Z' is combined with the carbon atoms to which they are attached, form anthropou, pornograpy, periodogram, pyrimidinone or pyridazino-group and

Z" combined with the carbon atom or the nitrogen atom to which they are attached, form a pyrido group, pyrimidinone or pyridazinone, in which phenyl, anthropo, farinograph, periodogram, pyrimidinone or pyridazinone can contain from one to three substituents selected from the group comprising lower alkyl, B=N-carbonyl group, group B=N, a lower alkoxy group, B=N-(lower)alkoxygroup and halogen atom, and the group value In the= above.

Preferred compounds of the present invention are, in particular, those in which n' is 4, R*denotes a hydrogen atom; q is 1; q' is 2; R"" represents hydrogen atom, cyano, a group of CO2L' or SO2L"; L' is lower alkyl, L is a di(lower)alkylamino, in particular, if R1is lower alkyl; R2is a group di(lower)alkylamino-(CH2)pC(O)O(CH2)p'-O -, or phenyl (lower) alkyloxy(lower)alkoxygroup; R3denotes a hydrogen atom, and X is a group (B=N, B=N-(lower) alkyl, fenoxaprop or lower alkoxycarbonyl group.

The most preferred compounds are those in which R1denotes ISO-sawn group; R2is a group of 6 dimethylamino-CH2(C(O)O(CH2)2-O - or 6-benzyloxyethanol, and X is a hydrogen atom, in particular those in which Z denotes one of the following structural formulas

< / BR>
Upon receipt of the compounds of formula I from the corresponding compounds of formula I and the corresponding compounds of formula III in the presence of a base may be any base, which itself does not react under the conditions of its implementation, and is preferably a hydride of an alkali metal, a carbonate of an alkali metal, an alkali metal alkoxide, three(lower)alkylamino, tall lower alkoxide, 1,8-diazabicyclo 5,4,0 cndac-7-Yong or 7-methyl-1,5,7-diazabicyclo 4,4,0 Oct-5-Yong. In the reaction conditions, the base can form a salt with the compound of the formula III, which interacts with the compound of the formula II.

The basic salt of the compounds of formula III can also be obtained separately, and then be condensed with the compound of the formula II and provocat in an organic solvent or mixture of organic solvents, which are inert under the reaction conditions, for example, acetone, methyl ethyl ketone, acetonitrile, tetrahydrofuran, diethyl ether, dimethylformamide, N-organic, dichloromethane, xylene, toluene or lower alkanol or a mixture of these solvents, in the range from room temperature to the boiling point of the solvent or solvent mixture.

The compounds of formula II and formula III are known or can be obtained by known methods, described below.

The compound of formula II in which R3denotes a hydrogen atom, can be obtained by diazotization of the corresponding (lower) alkyl 2-amino-3,4 or 5-R2-6-R1-properties of the ether, chlorosulfonylisocyanate obtained 2-diazonium salt (lower)alkyl 3,4 or 5-P2-6-R1-properties of the ether with sulfur dioxide in the presence of copper chloride (II) and cyclization of the obtained (lower)Olkiluoto ether 2-chlorosulfonyl-3, 4, or 5 R2-6-R1-benzoate of ammonia with formation of the corresponding compounds having structural formula IV:

< / BR>
hydroxymethylpropane which use formaldehyde can be obtained the corresponding 2-hydroxymethyl-4-R1-(5,6 or 7)-R2-saccharin, substitution of hydroxyl SFOR or trichromacy phosphorus, you can obtain the corresponding compound of formula II.

The compound of formula II in which R3denotes a hydrogen atom, and Q represents a chlorine atom, can be obtained in one stage from the corresponding compounds of formula IV chlorotoluene formaldehyde and chlorotrimethylsilane in the presence of a Lewis acid, for example, chloride of tin.

The compound of formula II in which R3denotes lower alkyl, and Q represents a chlorine atom, can be obtained by waniliowym the corresponding compounds of formula IV corresponding substituted or unsubstituted vinyl ether or lower alanovoy acid in the presence of disodium salt of palladium tetrachloride, processing then obtained 2-(substituted or unsubstituted vinyl)-4-R1-(5,6 or 7)-R2-saccharin chloride hydrogen. Using, for example, the unsubstituted vinyl acetate, it is possible to obtain the corresponding compound of formula II in which R3denotes methyl.

The compound of formula II in which R3denotes a hydrogen atom or phenyl, can be obtained by the reaction of phenylthio-R3methylation of the corresponding compounds of formula IV or its basic salts with the corresponding phenyl-R3- chloromethylation with obrazovanieto groups in it, a chlorine atom or bromine, using, for example, chloride Sulfuryl or bromide Sulfuryl.

The compound of formula IV can be obtained by treatment of the corresponding 2-R1-3, 4, or 5 R2-N, N-di(lower)alkylbenzene lower alkyllithium and aminosulphonylphenyl obtained 2-R1-3, 4, or 5 R2-Li-N,N-di(lower)alkylbenzene sulfur dioxide, followed by treatment of the hydroxylamine-O-sulfonic acid or chloride sulfuricum and amercom, and then cyclize obtained 2-R1-3, 4, or 5 R2-3, 4, or 5 R2-6-aminosulfonyl-N,N-di(lower)alkylbenzene by boiling under reflux in acetic acid.

The compound of formula IV in which R1indicates primary or secondary alkyl containing from two to four carbon atoms, can be obtained by metallation of the corresponding compounds of formula IV in which R1denotes methyl, two molar equivalents of the lower alkylate in an inert solvent, e.g. tetrahydrofuran, and alteromonas obtained 4-Latimer 5, 6 or 7-R2-saccharin appropriate alkyl halide. Both these reactions are carried out in the temperature range from -80oC to -50oC. above 2-R1-3, 4, or 5 R2-N,N-di (nissimov carbon can be obtained by the same sequence of transformations metallation-alkylation, starting from the corresponding 2-methyl, ethyl or propyl-3, 4, or 5 R2-N,N-di(lower) alkylbenzene.

The compound of formula IV in which R1indicates primary or secondary alkyl containing from two to four carbon atoms, can also be obtained by introduction of the group R1in the earlier stages of the synthesis. Paired attachment of a corresponding R1-cuprate to 2-cyclohexanone and subsequent methoxycarbonylamino received enolate copper using medicinepharmacy according to the method of Winkler et al., (Tetrapedron Letters, p. 1051, 1987; Journal of Organic Chemistry, Vol. 54, R. 4491, 1989) receive the corresponding 2-methoxycarbonyl-3-R1-cyclohexanone, enol esterification of which benzylthio in the presence of an acidic clay get a mixture of the corresponding methyl ester 6-R1-2-benzylthio-1-cyclohexanecarbonyl acid methyl ester 6-R1-2-benzylthio-3-cyclohexenecarboxylic acid, aromatization which dichlorodicyanoquinone allows to obtain the corresponding methyl ester 2-R1-6-sensitivetony acid; sequential oxidation-chlorination-dibenzylammonium Polo acid, the cyclization using ammonia are appropriate 4R1-saccharin of formula IV.

The preparation of some compounds of formula IV requires binding of both rings. For example, to obtain the compounds of formula IV in which R1is the lowest alkoxygroup, and R2is hydroxyl, 3,3-thiobisphenol acid with chloride tiomila transferred to the bis-acid chloride of the acid, which is then using benzylamine transferred to bis-benzylated, cyclization is chloride Sulfuryl allows to obtain 5-chloro-2-benzyl-2H-isothiazol-3-one. Oxidation with one molar equivalent of nagkalat get 5-chloro-2-benzyl-2H-isothiazol-3-one-1-oxide, by heating under pressure with 2-(lower)alkoxyphenyl receive a 4-(lower)alkoxy-7-hydroxy-2-benzyl-1,2-benzisothiazol-2H-3-one-1 - oxide, and the oxidation of one molar equivalent of nagkalat receive the corresponding 4-(lower)alkoxy-7-hydroxy-2-benzyl-1,2-benzisothiazol-2H-3-one-1-di - oxide. Catalytic hydrogenation then get the corresponding 4-(lower)alkoxy-7-hydroxycoumarin formula IV.

Similarly, alkylation obtained in this way 4-(lower)alkoxy-7-hydroxy-2 is loadnum by alkyl with subsequent oxidation and dibenzylammonium receive the corresponding 4-(lower)alkoxy-R2-Cacharel formula IV in which R2is the lowest alkoxygroup, cycloalexie, B=N-(lower) alkoxygroup, hydroxy (lower) alkoxygroup, polyhydroxy (lower) alkoxygroup or its acetal or Cetelem, (lower)alkoxy(lower) alkoxygroup, poly(lower)alkoxy (lower)alkoxygroup, hydroxypoly(lower)accelerograph or (lower)alkoxyl(lower)accelerographs.

Simple chemical transformations which are conventional and well known to experts in the field of chemistry can be made for changes in functional groups in the compounds of the present invention. For example, by catalytic regeneration of the heterocyclic system with formation of the corresponding partially saturated heterocyclic system, catalytic dibenzylammonium benzyl ethers with formation of the corresponding alcohols, the condensation of alcohols with acids in the presence of a condensing agent with formation of the corresponding esters, disilylgermane cyrilovich ethers with formation of the corresponding alcohols.

Pharmaceutically acceptable acid - or basic-salt additive can be any pharmaceutically acceptable kislotno salt, or a cation, for example, is sodium or potassium salt, respectively. If the salt containing a simple anion or cation, is unacceptable because it is not crystalline or does not have sufficient solubility or absorption, then you can use salt with a complex anion, for example, methanesulfonate, or complex cation, for example, diethylammonium salt, respectively. In any case, when used for the treatment of human acidic or basic additive salt should be non-toxic and should not interfere with the inhibitory effect on elastase free basic or acid forms of the compounds of formula I.

The following methods of preparation and examples of products derived from known materials used and the expected paths of reactions in the synthesis process. Clean or clean and confirmation of the structure of the parent compounds and reaction products was performed or measured by measuring the interval melting point, optical rotation, elemental analysis, infrared spectral analysis, ultraviolet spectral analysis, mass spectral analysis, spectroscopy, nuclear magnetic resonance, gas chromatography, pressure and/or thin-layer chromatography.

The invention is further illustrated by the following examples, which in no way limit the present invention.

Example 1.

Obtaining parent compounds

a) Obtain 2-chloromethyl-4-ISO-propylalanine

(II, R1= i-Pr, R2= H, R3= H, Q = C1) n-Utility (2.5 M, 10 ml) is added over 10 minutes under stirring in a stream of nitrogen at a temperature of 0-5oC to a solution of 2-ISO-propylbromide in anhydrous ether (500 ml). Allow the mixture to warm to room temperature, stirred at room temperature for six hours and cooled to -60oC. for 20 min, keeping the temperature no higher than -50oC add a solution of diethylcarbamazine (34 g) in anhydrous ether (50 ml). Within one hour give the temperature of the mixture to rise to room. Add water (100 ml). The ether layer is separated, washed with saturated aqueous salt solution (200 ml), dried over magnesium sulfate and the ether distilled off. The residue is distilled (80-90o/0.1 mm RT.CT.) and get 2-isopropyl - N,N-diethylbenzamide (44 g, yield 80%).

To a solution of N, N, N', N'-tetramethylethylenediamine (25,5 g) in anhydrous ether (600 ml) was added S-utility (1.3 M, 170 ml) and the mixture cooled in a stream of nitrogen to -70oC. dropwise adding keep the temperature as low as -60oC or below. Upon completion of the transaction, the mixture is stirred at -70oC for 30 min, then for 30 min, allowed to warm to a temperature of -50oC, kept at this temperature for 10 min and again cooled to -70oC. With excess pressure of nitrogen for 10 minutes serves through a tube pre-cooled to -60oC solution of sulfur dioxide (50 g) in anhydrous ether (50 ml). The temperature of the reaction mixture in the process of adding support at the level of -50oC. Almost instantly falls white powdery precipitate of sulfinate argillite. Give the temperature for one hour to rise to room temperature. Dropwise within 15 min under continuous stirring chloride Sulfuryl (54 g). Stirred at 0-5oC for 30 minutes, a white precipitate is filtered and washed with anhydrous ether (2 liters). The solvent is removed in vacuum and get a pale yellow oil, which was dissolved in tetrahydrofuran (150 ml). The resulting solution was cooled to 0oC and portions over 15 minutes servings add concentrated aqueous ammonia solution (28%, 60 ml). During this operation, keep the temperature no higher than 10oC. After permissum hydrochloric acid (2N solution) to pH 1. The obtained solid white color separated, washed with water (200 ml) and hexane (200 ml) and dried, obtaining 2-aminosulfonyl-6,-ISO-propyl-N,N-diethylbenzamide (54 g, yield 90%).

A solution of 2-aminosulfonyl-6, -ISO-propyl-N, N-diethylbenzamide (60 g) in acetic acid (400 ml) is refluxed for 24 h, and then cooled to room temperature. The solvent is removed in vacuum. The oily residue is dissolved in water (500 ml) and the pH adjusted to 1 with 2 hydrochloric acid. The crude product is separated by filtration, washed with water (300 ml), dried in vacuum at 60oC for 18 h and recrystallized from a mixture of ether - hexane, obtaining 4-ISO-profilesharing (40 g, yield 90%, so pl. 177oC). (IV; R1= i - Pr; R2= H).

A mixture of 4-ISO-propylalanine (of 37.9 g), phenylcarbylamine (33,3 g), tetrabutylammonium (5,4 g) and toluene (200 ml) is refluxed for 24 h, and then the volatile matter is distilled, and column chromatography on silica gel (485 g), elwira first with hexane, then with a mixture of hexane-dichloromethane (1:1) and then dichloromethane obtained from hexane-dichloromethane suita 2-phenylthiomethyl-4-isopropylaniline in the form of oil, pale yellow (53,5 g, yield 92%).

the room temperature. Starts weak exothermic reaction and the mixture is left at room temperature for 17 h and then the volatiles evaporated. The residue is recrystallized from hexane and get three servings (33,55 g, So pl. 101-102oC; 3,45, So pl. 100-101oC; 0.45 g, So pl. 99-100oC; just 38,55 g, yield 91%). All three portions are combined and recrystallized from a mixture of ISO-propyl alcohol (30 ml)-hexane (270 ml) and receive 2-chloromethyl-4-ISO-profileshare in two portions (33,5, So pl. 101-102,5oC; 2.65 g, So pl. 100-101oC).

b) Obtain 2-chloromethyl-4-ISO-propyl-6-methoxycoumarin

(II, R1= i-Pr, R2= 6-OMe, R3= H, Q = C1)

To a solution of N, N, N', N'-tetramethylethylenediamine (300 ml) in anhydrous ether (4 l) add second-utility (1.3 M solution, 4 l) and the mixture is cooled in a stream of nitrogen to -70oC. is added dropwise within 30 minutes, add a solution of 2-ISO-propyl-4-methoxy-N, N-diethylbenzamide (454,2 g) in anhydrous ether (300 ml). During this operation the temperature of the support below -60oC. Upon completion of addition the mixture is stirred at -70oC for one hour, allowed to warm to a temperature of -50oC, kept at this temperature for 30 min and again cooled to -70oC. With excess pressure, AZ) in anhydrous ether (200 ml). The temperature of the reaction mixture in the process of adding support level -40oC. Almost instantly falls white powdery precipitate of sulfinate argillite. At the end of the addition the cooling bath is removed and stirred the mixture at room temperature for two hours, and then cooled to -5oC. is added dropwise within 15 min under continuous stirring chloride Sulfuryl (190 g), keeping the temperature no higher than 10oC. Stirred at 0-5oC for 30 minutes, a white precipitate is filtered and washed with anhydrous ether (2 l). The solvent is removed under normal pressure and get a dark oil, which was dissolved in tetrahydrofuran (1.4 l). The resulting solution was cooled to -10oC and portions over 15 min add concentrated aqueous ammonia solution (28%, 540 ml). During this operation, keep the temperature not higher than the 15oC. After stirring for 15 minutes at room temperature, the tetrahydrofuran and excess ammonia is removed in vacuum, obtaining a dark oil, which was diluted with water (6.0 l) and acidified with hydrochloric acid (3 solution) to pH 1. The obtained solid light yellow color is separated by filtration, washed with water (800 ml), dried with 6 noalter-6-ISO-propyl-4-methoxy-N, N-diethylbenzamide (429 g, yield 72%, So pl. 122-125oC).

A solution of 2-aminosulfonyl-6-ISO-propyl-4-methoxy-N, N-diethylbenzamide (429,6 g) in acetic acid (1.5 l) is refluxed for 20 h, and then cooled to room temperature. The solvent is removed in vacuum. The oily residue is dissolved in water (6 l) and the pH adjusted to 1 with hydrochloric acid. The crude product is separated by filtration, washed with water (2 l), dried in vacuum at 60oC for 18 h and recrystallized from a mixture of ethyl acetate - hexane, obtaining 4-ISO-propyl-6-methoxycoumarin (303 g, yield 91%, So pl. 188). (IV; R1= i-Pr, R2= 6-OMe).

To a suspension of paraformaldehyde (24 g) and chlorotrimethylsilane (86,4 g) in 1,2-dichloroethane (200 ml) was added anhydrous tin chloride (IV) (0.8 ml) and the resulting solution is stirred while heating on the steam bath for one hour. To the resulting clear solution was added 4-ISO-propyl-6-methoxycoumarin (51,4 g) and boil the mixture for 18 h, cooled to room temperature and poured into water. The organic layer is separated, washed with aqueous sodium hydroxide solution (2N, 50 ml), dried over magnesium sulfate and evaporated in vacuum. The residue is recrystallized from a mixture of ethyl acetate - g the e 2-chloromethyl-4-isopropyl-6 - 2-(benzyloxy) ethoxy saccharin

(II, R1= i-Pr, R2= 6-OCH2CH2OCH2Ph, R3= H, Q = Cl)

To a solution of 1.0 g (to 0.0039 mol) of 4-ISO-propyl-6-methoxycoumarin in 15 ml of methylene chloride at room temperature is added 1.28 g (5,122 ml), 1 M solution trichromate boron in methylene chloride. After adding the reagent mixture is refluxed for five hours, cooled, evaporated to dryness in vacuo and to the residue add ice and saturated aqueous sodium bicarbonate solution. The aqueous solution once extracted with ethyl acetate, and then acidified to pH 1 using concentrated hydrochloric acid. After extraction with a mixture of ethyl acetate/diethyl ether (8:2), drying of the organic extract and removal of solvent in vacuo obtain 0.9 g (96%) of 6-hydroxy-4-ISO-propylalanine (IV, R1= i-Pr, R2= 6-OH) in the form of a crystalline substance of white color, which without further purification used in the next stage.

Also use an alternative methodology. To a stirred suspension 62,74 g (0.47 mol) of aluminum chloride (III) in 500 ml of chloroform at 0oC add 43,9 g (0.7 mol) of ethanthiol. Within one minute formed a clear solution. To the resulting solution for 30 min add solution 20,ri 60oC for 3-4 hours After cooling, the mixture was poured into ice water and acidified with diluted hydrochloric acid. The residue is separated by filtration, washed with water and dried, obtaining of 18.4 g (970) 6-hydroxy-4-ISO-propylalanine.

6-Hydroxy-4-ISO-propylalanine (30.0 g, 0.12 mol) in methanol is treated with cesium carbonate (to 20.28 g, 0,062 mol). Stir the mixture at room temperature for 3-4 h, the excess methanol is removed under reduced pressure and the residue is dried in vacuum. It is dissolved in DMF and added chloromethylthiazole (21,72 g, 0.14 mol). Heat the mixture to 70 to 80oC for 24 h, cooled, poured into ice water and extracted with a mixture of ethyl acetate/ether. The organic extracts washed with water, saturated salt solution and dried. The solvent is removed in vacuo and the residue purified column chromatography on silica gel, elwira a mixture of ethyl acetate/hexane, and obtain 30.5 g (67%) of 4-ISO-propyl-6-hydroxy-2-phenyldimethylsilane.

To a solution of 4-ISO-propyl-6-hydroxy-2-phenyldimethylsilane (2.0 g, 5.5 mmol) in THF (40 ml) add tributylphosphine (1,46, to 5.56 mmol), 2-benzyloxyethanol (0.87 g, 5,71 mmol) and diethylazodicarboxylate (0,99 g of 5.68 mmol). The mixture is stirred at room temperature, elwira 20% solution of ethyl acetate in hexane, and obtain 2.1 g (77%) of 4-ISO-propyl-6-2-(benzyloxy)ethoxy 2-phenyldimethylsilane with So pl. 98-99oC.

To a solution of the obtained compound (2.1 g, 4,22 mmol) in methylene chloride at room temperature add chloride Sulfuryl (0,37 ml and 4.65 mmol) and the mixture is stirred for 3 hours the Solvent is removed in vacuo, the residue triturated with hexane, the resulting solid is separated by filtration and receive a rate of 1.67 g (93%) of 2-chloromethyl-4-ISO-propyl-6 - 2-(benzyloxy)ethoxy saccharin with So pl. 101-102oC.

g) Obtaining 2-chloromethyl-4-isopropyl-6 - 2-(tri-isopropylidene)ethoxy saccharin

(II, R1= i-Pr, R2= 6-OCH2CH2OSi(i-Pr)3, R3= H, Q = CI)

To a solution of 4-ISO-propyl-6-hydroxy-2-phenyldimethylsilane (2.0 g, 5,509 mmol) in THF (35 ml) containing triphenylphosphine (1,59 g, the 6.06 mol) and 2-(tri-ISO-propylsilane)ethanol (1.13 g, 6.0 mmol) at room temperature add diethylazodicarboxylate (1,04 ml, 6.6 mmol). The mixture is left to mix overnight (16 h), the solvent is removed in vacuo and the residue purified column chromatography on silica gel, elwira 10% solution of ethyl acetate in hexane, and obtain 2.66 g (86%) of 4-ISO-propyl-6 - 2-(tri-and(2.6 g, to 4.62 mmol) in methylene chloride is treated with chloride sulfuricum (0.65 g, 4,51 mmol) and stirred the mixture for 3 hours. The solvent is removed in vacuo, the residue triturated with hexane. The product is separated by filtration and obtain 1.73 g (76%) of 2-chloromethyl-4-ISO-propyl-6 - 2- (tri-isopropylethylene)ethoxy saccharin with So pl. 85-86oC.

d) 2-chloromethyl-4-isopropyl-6-(benzyloxycarbonyloxy)saccharin

(II, R1= i-Pr, R2= 6-OCH2(CO)OCH2Ph), R3= H, Q = CI)

A mixture of 4-isopropyl-6-hydroxy-2-phenyldimethylsilane (3.5 g, 9,63 mmol), acetone (25 ml) and potassium carbonate (2.66 g, (Jn 19: 26 mmol) is stirred in a stream of nitrogen for 2 min, and then add benzylbromide (2.4 ml, accounted for 14.45 mmol). The mixture is stirred for 6 h, filtered and the filtrate evaporated in vacuum. The residue is purified liquid chromatography medium pressure elwira 20% solution of ethyl acetate in hexane, and receive of 4.67 g (100) 4-ISO-propyl-6-(benzyloxycarbonyloxy)- 2-phenylmethylnitramine.

To a solution of the obtained compound (0.5 g, 1,043 mmol) in methylene chloride (5 ml) at room temperature add chloride Sulfuryl. The mixture is stirred for 4 h, the solvent is distilled off in vacuum and the residue Ocimum solution of ethyl acetate in hexane, and get 0,37 g (81%) of 2-chloromethyl-4-isopropyl-6-(benzyloxycarbonyloxy)saccharin.

e) Obtain 2-chloromethyl-4-isopropyl-6-hydroxycoumarin

(II, R1= i-Pr, R2= 6-OH, R3= H, Q = CI)

4-isopropyl-6-hydroxy-2-phenyldimethylsilane (1.78 g) in methylene chloride is treated with chloride sulfuricum (of 0.43 ml, 0.73 g) and obtain 1.2 g (84%) of 2-chloromethyl-4-isopropyl-6-hydroxycoumarin with So pl. 149-150oC.

f) Obtaining 2-chloromethyl-4-sec-butyl-6-methoxycoumarin

(II, R1= Deut.-Bu, R2= 6-OMe, R3= H, Q = CI)

To a mixture of diethylamine (89,1 ml), triethylamine (120,2 ml) and methylene chloride (500 ml), cooled in a bath of ice, dropwise during 40 min type p-antillarum (133,8 g). The reaction mixture was stirred at room temperature for 40 min, filtered off, washed with ether and the solvent is removed in vacuum. Add ether and then water, the organic layer is separated and washed with 5% sodium hydroxide solution, then with hydrochloric acid, a saturated salt solution and dried over sodium sulfate. The solvent is removed in vacuum and the residue is distilled on a column Kugelrohr at a temperature of 140-180oC in high vacuum and get 164, 8mm g of 4-methoxy-, -diethylbenzamide with So pl. 40-42oC for 70 min and within 35 min add ethyliodide (26,63 g, 333 mmole). Heated the reaction mixture to room temperature and stirred for 1.5 hours. The reaction is interrupted by adding a saturated solution of ammonium chloride (100 ml). The organic layer is separated, dried over sodium sulfate and evaporated in vacuum. The residue is purified by Kugelrohr distillation over the column at a temperature of 190-210oC in high vacuum and get to 58.1 g of 2-ethyl-4-methoxy-N,N-diethylbenzamide.

To a mixture of di-Isopropylamine (40,7 ml, 290 mmol) in THF (800 ml) at -78oC add n-utility (100 ml, 2.15 M solution). The mixture is stirred for 1/4 hour and then at -78oC add 2-ethyl-4-methoxy-N,N-diethylbenzamide (235,3 g) in THF (300 ml). The resulting mixture was stirred at -78oC for 2.5 h, and then for 1 h at a temperature of 0oC and for 10 min at -78oC add ethyliodide (23,2 ml) in THF (150 ml). The reaction is interrupted by the addition of saturated solution of ammonium chloride (100 ml) and the solvent is removed in vacuum. To the residue is added ether (500 ml), the ether layer is washed with saturated sodium bicarbonate solution (50 ml), 1N hydrochloric calme. The residue is purified by distillation under vacuum (2 mm RT.CT.) and get with 46.6 g (76%) of 2-sec-butyl-4-methoxy-N,N-diethylbenzamide.

To a solution of tetramethylethylenediamine (31 ml) in THF (500 ml) at -78oC add second-utility (170 ml, 1.1 M solution), and then 2-sec-butyl-4-methoxy-N, N-diethylbenzamide (45 g) in THF (150 ml). The mixture was stirred at -78oC for 15 min; then for 30 min at a temperature of 0oC and the mixture at -78oC condense sulfur dioxide (50 ml). Heat the mixture to -10oC add chloride Sulfuryl (17 ml), the mixture is slowly heated with stirring to room temperature and left to mix overnight. The reaction mixture was added to a solution of ammonium hydroxide (94 ml) in THF (200 ml), the mixture is filtered through a layer silicate spruce/sodium sulfate/sand and get 51.8 g of 2-aminosulfonyl-6-sec-butyl-4-methoxy-N,N-diethylbenzamide.

A mixture of acetic acid (200 ml) and 2-aminosulfonyl-6-sec-butyl-4-methoxy-N, N-diethylbenzamide (51,7 g) leave overnight to boil under reflux. Acetic acid is removed by distillation, the residue is poured into a mixture of ice and 2 M solution of caustic (80 ml). The aqueous layer was washed with methylene chloride, acidified with concentrated hydrochloric acid and CLASS="ptx2">

A mixture of 4-sec-butyl-6-methoxycoumarin (3 g), toluene, tertbutoxide potassium (1.4 g) and tetrabutylammonium (0.4 g) is heated to boiling and contribute phenylbarbituric (1.8 ml). The resulting mixture is refluxed for approximately 27 hours, the solvent is removed in vacuum, the residue is extracted with ethyl acetate, washed with saturated salt solution and dried over sodium sulfate. The solvent is removed in vacuo and the residue purified column chromatography on silica gel, elwira 10% solution of ethyl acetate in hexane, and get 2,63 g (60%) 2-phenylthiomethyl-4-sec-butyl-6-methoxycoumarin.

To a solution of 2-phenylthiomethyl-4-sec-butyl-6-methoxycoumarin (2.6 g) in methylene chloride (20 ml) is added chloride Sulfuryl (0.7 ml). The mixture is left at room temperature to mix overnight, then the solvent evaporated in vacuum. The residue is treated with hexane and the mixture is treated with ultrasound for 6 hours the Resulting precipitate was separated by filtration and gain of 1.33 g of 2-chloromethyl-4-sec-butyl-6-methoxycoumarin.

C) Obtain 2-chloromethyl-4-second-Boticaria

(II, R1= verbatim, R2=H, R3=H, Q=CI)

To a solution 4,74 ml (0,031 mol) of tetramethylethylenediamine in 300 ml of THF (pastor cooled to -78oC and treated to 34.9 ml (0,031 mol) 0.9 M solution of utility in cyclohexane. When you are finished adding stirred the mixture for 20 min, and then treated with a solution of 3.2 ml (0.04 mol) of ethyliodide, maintaining the temperature at -78oC. Allow the mixture to warm to room temperature, stirred for 16 h and poured into water. The resulting oil is separated and chromatographic on silica gel, elwira 19% solution of ethyl acetate in hexane, and get 2,86 (43%) 2-sec-butyl-N,N-diethylbenzamide in the form of a yellow oil.

The resulting substance (10,45 g, 0.045 mol) is dissolved in 70 ml of THF and added dropwise to a mixture of 39.2 ml (0,047 mol) 1.2 M solution of sec-utility in cyclohexane and 7.1 ml (0,047 mol) of tetramethylethylenediamine in 250 ml of THF, while maintaining the temperature at -78oC. Upon completion of addition the mixture is stirred for another hour at -78oC, and then treated at -70oC-sulfur dioxide and allowed to warm to room temperature. The mixture is evaporated to dryness in vacuo, the residue is dissolved in water and added with stirring to a cold solution of 15.2 g (0,134 mol) hydroxylamine-O-sulfonic acid and 15.4 ml (0,134 mol) of 35% aqueous sodium hydroxide solution, getting the 10.1 g (72%) 2-aminosulfonyl-6-sec-butyl-N,N-diethyla the resulting solution under reflux for thirteen hours, and then evaporated to dryness. The residue is treated with diethyl ether and the product is separated by filtration, gaining 5.7 g (83%) diethylammonium salt 4-second-Boticaria.

The resulting material (3.0 g, 0,0096 mol) after interaction with 1.13 ml (0.012 mol) of chlorocarbonylsulfenyl in toluene gives 3,47 g (100%) 2-phenylthiomethyl-4-second-Boticaria.

The interaction of the obtained compound (3.2 g, 0,00097 mol) with 2.3 ml (0,029 mol) chloride Sulfuryl in 20 ml of methylene chloride obtain 2.4 g (87%) of 2-chloromethyl-4-second-Boticaria.

Get the targeted products

Example 1A 2-(2,5-dihydro-5-oxo-3-furanyl)oxymethyl-4-isopropyl-saccharin

< / BR>
The solution of tetronic acid (0,22 g) in dimethylformamide (5 ml) are added to a suspension of sodium hydride (60% dispersion in mineral oil, 0.10 g) in dimethylformamide (4 ml) in a stream of nitrogen is stirred in a bath with ice. Bath ice is removed and stirring is continued for another 15 min and then added dropwise a solution of 2-chloromethyl-4-isopropylaniline (0,547 g) in dimethylformamide (10 ml), stirred for two and a half days, and then poured into water. The resulting mixture was extracted with ethyl acetate, the ethyl acetate layer is dried over magnesium sulfate and the ethyl acetate removed. Lane is e (0.34 g, yield 51%, So pl. 174-175o< / BR>
Examples 1B-1

According to the methods similar to the above in Example 1A from 2-chloromethyl-4-isopropylaniline or 2-chloromethyl-4-isopropyl-6-methoxycoumarin and the corresponding compounds of formula III (H-O-Z) are obtained compounds indicated in Table 1.

(a) the Product before recrystallization of the purified column chromatography on silica gel, elwira methylene chloride, and then changing the ratio of components solutions of ethyl acetate in hexane.

(b) the Product is purified column chromatography on silica gel, elwira methylene chloride, and then changing the ratio of components solutions of ethyl acetate in hexane.

(c) the Product is purified column chromatography (2 x) on silica gel, elwira methylene chloride, and then changing the ratio of components solutions of ethyl acetate in hexane.

(d) the Product is purified column chromatography on silica gel, elwira mixtures of ethyl acetate/hexane (1/3 to 1/2).

In addition to the compounds according to Example 1M, with 38% give 2-(1-methyl-2,6-chlorides)methyl-4-isopropyl-6-methoxycoumarin (So pl. 159,5-161,5oC, from ethyl acetate).

Example 2

2-(1-methylcarbamic stirring to a suspension of sodium hydride (60% dispersion in mineral oil, 0.36 g) in dimethylformamide. The mixture within 3/4 hour with continuous stirring, heated to a temperature of 100oC, and then treated at room temperature by ultrasound within half an hour. Add 2-chloro-4-isopropyl-6-methoxycoumarin (1,83 g). Obtained mixture under stirring for 2 h, heated to a temperature of 100oC, and then poured into water (300 ml). Add hydrochloric acid (1N solution, 25 ml) and extracted with chloroform. The chloroform extract is dried with sodium sulfate and the chloroform evaporated. Thin-layer chromatography evaporative obtained solid (3.3 g) on silica gel, using as eluent a mixture of ethyl acetate - hexane (1:1) and recrystallization of the obtained solid (0.7 g, 2Q%) of ethanol (90%) get the target compound in the form of solid yellow (0.39 g, yield 15%, So pl. 198 - 200oC).

Example 3A

2-(1-phenyl-3-acetylcarnosine-4-yl)oxymethyl-4 - isopropyl-6-methoxycoumarin

< / BR>
A mixture of 3-acetoxy-4-hydroxy-1-vinylcarbazole (0.52 g), potassium carbonate (0.28 g) and dimethylformamide (7 ml) was stirred at room temperature for half an hour. Add 2-chloromethyl-4-ISO-propyl-6-methoxycoumarin (0.71 g) and the mixture is treated with ultrasound at what Ultrazvuk does not affect the degree of completeness of the reaction, as shown by thin layer chromatography. The reaction mixture was poured into water and extracted with ethyl acetate. The organic extract is dried and the solvent evaporated. Liquid medium pressure chromatography of the residue (0.5 g) on silica gel, using as eluent a mixture of ethyl acetate - hexane (3:7), and recrystallization of the product from methanol to obtain the target compound (0.24 g, yield 24%, So pl. 210-212oC).

Example 3B

2-(1-methyl-3-acetylcarnosine-4-yl)oxymethyl-4 - isopropyl-6-methoxycoumarin

< / BR>
According to the method described above in Example 3A, condense 3-acetyl-4-hydroxy-1-methylcarbamoyl (0,63 g) with 2-chloromethyl-4-isopropyl-6-methoxycoumarin (1.10 g) and purify the product by recrystallization from methanol - ether, obtaining the target compound as white powder (0.28 g, yield 20%. So pl. 194-196oC).

Example 4A

2-(2,5-dihydro-2-oxo-3-phenylfuro-4-yl)oxymethyl-4 - ISO-propyl-6-methoxycoumarin

< / BR>
To a solution of 3-phenyl-2(5H)-furanone (0.88 g) in methanol (15 ml) is added cesium carbonate (0,82 g) and the resulting mixture was stirred at room temperature for one hour, and then the methanol is removed. The residue is dissolved in dimethylformamide (15 ml), add to it 2-chloro-4-isoplast silica gel (4.4 g), volatile matter is distilled off in vacuum and the resulting solid is subjected to evaporative chromatography on silica gel using a mixture of ethyl acetate - hexane (3:7) as eluent. By recrystallization of the product from a mixture of ethanol - ether to obtain the target compound as a colourless solid (0.45 g, yield 20%, So pl. 180-182oC).

Examples 4B-41

According to the methods similar to the above in Example 4A, 2-chloromethyl-4-isopropyl-6-methoxycoumarin and the corresponding compounds of formula III (H-O-Z) are obtained compounds indicated in table II.

(a) the Reaction mixture is treated, pouring iced water, extragere W with ethyl acetate, washing the organic layer with 5% sodium hydroxide solution, 1N hydrochloric acid, water, then saturated salt solution and removing the solvent in vacuo. Then the rest before crystallization of pre-purified column chromatography on silica gel, elwira 40% solution of ethyl acetate in hexane.

(b) the Reaction mixture is treated, pouring in water, adding 5% sodium hydroxide solution and extragere a mixture of ethyl acetate - methylene chloride. The organic extracts are combined, washed, and dried by sodium sulfate. The solvent ughele, gradient elwira, starting with a 25% solution of ethyl acetate in hexane and ending with pure ethyl acetate.

Example 4J 2-4-oxo-4H--pyrido 1,2-a pyrimidine-2-Il oxymethyl-4-isopropyl-6-(benzyloxycarbonyloxy)saccharin

< / BR>
Using a methodology similar to that shown in Example 4A, obtain 0.71 g (62,8%) of target compound with So pl. 69-71oC, on the basis of 2-chloromethyl-4-ISO-propyl-6-(benzyloxycarbonyloxy)saccharin (0,876 g), cesium carbonate (0,326 g), methanol, 2-hydroxypyridine - 1,2-a pyrimidine-4-it (0,324 g) and DMF (5 ml). The reaction mixture is developing, pouring it into ice water, extragere with ethyl acetate and separating the organic layer, which is washed with saturated salt solution and dried over sodium sulfate.

Example 4K

2-4-oxo-4H--pyrido 1,2 a pyrimidine-2-Il oxymethyl-4-sec-butyl-6-methoxycoumarin

< / BR>
Using a methodology similar to that shown in Example 4A, get 0,267 g (58%) of target compound with So pl. 160-185oC, on the basis of 2-chloromethyl-4-sec-butyl-6-methoxycoumarin (0,318 g, 1.0 mmol), cesium carbonate (0.18 g, 0,56 mmol), methanol (5 ml), 2-hydroxypyridine - 1,2-a pyrimidine-4-it (0.18 g, 1.11 mmol) and DMF. The reaction mixture is developing, pouring it into a saturated solution of ammonium chloride, extragere etiracetam first 50% solution of ethyl acetate in hexane, and then a 5% solution of methanol in ethyl acetate.

Example 5

2-3-(4-morpholinylmethyl)-4-oxo-4h-pyrido[1,2-a] pyrimidine-2-Il oxymethyl-4-isopropyl-6-methoxycoumarin

< / BR>
A mixture of the hydrochloride of 3-(4-morpholinylmethyl)pyrido 1,2-and pyrimidine-2,4-dione (0.6 g) and tert-butoxide potassium (0,49 g) in dimethylformamide (20 ml) was stirred at room temperature for five minutes. Add 2-chloromethyl-4-isopropyl-6-methoxycoumarin (0,61 g) and stirring at room temperature continued for hours. Dilute the reaction mixture with water (50 ml) and extracted with dichloromethane (3 x 200 ml). The organic extracts are combined, dried over sodium sulfate and the volatile matter is distilled off, and then dried in high vacuum. The crude product (780 mg) combined with 0.65 g of the product obtained in another experiment with the same loading of the parent compounds, but when using sodium hydride (60% dispersion in oil, 0,19 g) instead of tert-butoxide potassium, and purified column chromatography on silica gel, elwira a mixture dichloromethane (95:5), and obtain the target compound (500 mg, yield 23%), part of which is recrystallized from ethanol (So pl. 177-180oC).

Example 6

2 - 3,5,6-trimethyl-1,4-dioxo-2,5-cyclohexa the keys 2-chloromethyl-4-isopropyl-6-methoxycoumarin (0.34 g) to a solution of 2-hydroxy-3,5-trimethyl-1,4-hydroquinone (of 0.182 g) and methyltriethoxysilane (0.18 g) in acetonitrile (20 ml). Stirring at room temperature continued for 24 h and the resulting dark colored solution was poured into ice-cold water containing a few drops of hydrochloric acid. The obtained solid brown cleanse first column chromatography on silica gel, and then by recrystallization from burning ethanol and obtain the target compound (60 ml, the yield of 12.7%. So pl. 164-166oC).

Example 7

2 - 5-acetyl-4,7-dihydro-4,7-dioxobenzo-6-yl) oxymethyl-4-isopropyl-6-methoxycoumarin

< / BR>
Under stirring at room temperature is added 2-chloromethyl-4-isopropyl-6-methoxycoumarin (0.5 g) to a solution of 4,7-dimethoxy-5-acetyl-6-hydroxybenzophenone (0.39 g) and methyltriethoxysilane (0.28 g) in acetonitrile (20 ml). The resulting mixture was left overnight to mix at room temperature. Because thin-layer chromatography shows the presence of unreacted 4,7-dimethoxy-5-acetyl-6-hydroxybenzophenone, then add some more 2-chloromethyl-4-isopropyl-6-methoxycoumarin and one drop Foundation, and the stirring is continued for another 24 h, and then the mixture is poured into ice water containing hydrochloric acid. The obtained solid Golden color h is room temperature, and at a temperature of 35-40oC. Product and partially purified product from the first synthesis are combined and purified column chromatography on silica gel, receiving 2-(4,7-dimethoxy-5-acetylbenzoate-6-yl)oxymethyl-4 - isopropyl-6-methoxycoumarin (0.4 g, yield 24%).

To a solution of 2-(4,7-dimethoxy-5-acetylbenzoate-6-yl)oxymethyl-4-isopropyl-6-methoxycoumarin (0.3 g) in acetonitrile (5 ml) is added dropwise a solution triarylamine-hexanitrate (0,98 g) in water (3 ml). The resulting mixture was stirred at room temperature for 15 min and poured into ice water. The obtained solid Golden color cleanse fast chromatography on silica gel, elwira a mixture of dichloromethane - ether (95:5) and recrystallized simultaneous processing of ultrasound from ethanol, obtaining the target compound (0,13 g, yield 46.6 per cent, So pl. 193-195oC, with decomposition).

Example 8

2-(3-chloro-6-methyl-2-oxo-2H-Piran-4-yl)oxymethyl - 4-isopropyl-6-methoxycoumarin

< / BR>
A mixture of 3-chloro-4-hydroxy-6-methyl-2H-Piran-2-it (0,493 g of 3.07 mmol), DMF and potassium carbonate (0,467 g, to 3.38 mmol) was stirred at room temperature in a stream of nitrogen for 0.5 h, and then in one portion add 2-chloromethyl-4-isopropyl-6-methoxycoumarin (0,978 g, 3,22 m/SUP>C. was Poured into water, extracted with ethyl acetate and the organic extracts washed with saturated salt solution and dried. The solvent is removed in vacuo and the residue purified column chromatography on silica gel, elwira 30% solution of ethyl acetate in hexane, and after recrystallization from a mixture of ether - hexane obtain 0.25 g (18,1%) of target compound with So pl. 182,5-183,5oC.

Examples 9A-9J

The compounds listed in the following Table III, receive according to the following procedure.

A mixture of suitable compounds of formula III (H-O-Z), approximately 1.0 to 1.5 equivalents of a suitable base and a suitable solvent is stirred at room temperature for about 0-60 min, and then add approximately 1.0-1.2 equivalents of the appropriate 2-chloromethyl-4-isopropyl-6-P2-saccharin. The mixture is stirred at a temperature close to the room temperature, or when heated to a temperature of approximately 90oC for 1-48 h, and then develop as follows.

Method 1: the reaction mixture is poured into water with ice and either (a) is extracted with a suitable solvent (in particular, ethyl acetate, chloroform or methylene chloride), the organic layer is separated, dried over sodium sulfate, the indicate of a mixture of ice water and separated by filtration, and then cleaned as specified in Table III.

Method 2: solvent is removed in vacuo and the residue purified as described in Table III.

(a) the Product is distilled before the crystallization method column chromatography on silica gel, elwira 5% solution of methanol in chloroform.

(b) the Product before the final recrystallization purified by recrystallization from acetonitrile, and then column chromatography on silica gel, elwira 5% solution of ethyl acetate in methylene chloride.

(c) Before the formation of cleaners containing hydrochloride salt by treatment of 4,6 N solution of hydrogen chloride in ethanol free base is purified column chromatography on silica gel, elwira a mixture of 65% ethyl acetate/ 30% methanol/ 5% triethylamine.

(d) the Product before crystallization purified by the method of column chromatography on silica gel, gradient elwira a mixture of hexane/ethyl acetate (3/1 to 2/1).

(e) the Product is purified column chromatography on silica gel, elwira 60% solution of ethyl acetate in hexane.

(f) the Product was then purified column chromatography on silica gel, elwira 60% solution of ethyl acetate in hexane.

(g) the Product before crystallization LASS="ptx2">

Example 10

< / BR>
The mixture of compounds according to Example 4H (0,359 g, 0,834 mmol), ethyl acetate (35 ml) and palladium on coal hydronaut under a pressure of 50 pounds/inch2in the apparatus Parr hydrogenation for 1 and 3/4 hours Add an additional amount of palladium on coal (0.16 g) and the reaction continued for another 2 hours, the Catalyst was removed by filtration and the filtrate evaporated in vacuum. The crude product is purified column chromatography on silica gel, elwira a mixture of ethyl acetate/methanol/triethylamine (88,5/7,5/4) and get 0,132 g (36,5%) of the desired product as the free base, which was dissolved in ethanol and treated with a solution of citric acid in methanol, getting 0,142 g of the product in the form of the citrate salt So pl. 198-200oC.

Example 11

2 - 3-(etoxycarbonyl)-4-oxo-4H-pyrido 1,2-and pyrimidine-Il oxymethyl-4-isopropyl-6-methoxycoumarin

< / BR>
To a mixture of tert-butoxide potassium (0,37 g, 3.3 mmol) in THF (20 ml) is added ethyl 5-oxo-2-(pyrimidinyl-2-yl)-2,5-dihydroisoxazole-4-carboxylate (0,70 g, 3.0 mmol) and stirred the mixture in a stream of nitrogen at a temperature of 40oC for 0.5 h the Solvent is removed in vacuo and the residue dried in high vacuum. The crude product is mixed with DMF (20 ml) and add 2-chloromethyl-4-isopropyl-6-metoc for 23 days poured into ice water and extracted with ethyl acetate. The organic layer is separated, dried over sodium sulfate and evaporated in vacuum. The residue is purified column chromatography on silica gel, elwira 5% solution of methanol in ethyl acetate, and after recrystallization from a mixture of talwalkars, obtain 0.17 g (12%) of target compound with So pl. 189-191oC.

Example 12

2 - 4-oxo-6,7,8,9-tetrahydro-4H-pyrido 1,2-and pyrimidine-Il oxymethyl-4-isopropyl-6-(2-hydroxyethoxy)saccharin

< / BR>
Mixture of product Example 9G (1.35 g) in ethyl acetate (200 ml) and methanol (5 ml) and 10% palladium on coal (0.5 g) hydronaut in the Parr apparatus under a pressure of 50 pounds/inch2within 3 hours Add an additional amount of palladium on coal (0.5 g) and the mixture hydronaut for 8-9 hours is Filtered off and the filtrate evaporated in vacuo, and the residue is purified column chromatography on silica gel, elwira with ethyl acetate, and get to 0.89 g of the target product as a foamy substance.

Example 13

2 - 4-oxo-6,7,8,9-tetrahydro-4H-pyrido 1,2-and pyrimidine-2-Il oxymethyl-4-isopropyl-6 - 2-(dimethylaminoethylacrylate)ethoxy saccharin

< / BR>
Into a solution of the compound from Example 12 (0.8 g, 1,72 mmol) in methylene chloride (25 ml) containing 1,3-is 1,72 mmol). The resulting mixture was stirred at room temperature for 2 h, the solvent is removed in vacuo and the residue purified column chromatography on silica gel, elwira 10% solution of methanol in ethyl acetate, and obtain 0.64 g (68%) of target compound in the form of a foamy substance.

Example 14

2 - 3-chloro-4-oxo-4H-pyrido 1,2-and pyrimidine-2-Il oxymethyl-4-isopropyl-6-2-hydroxyethoxy saccharin

< / BR>
To a suspension of the compound from Example 9H (0,76 g) in methanol (30 ml) is added THF, and then 2 a solution of hydrochloric acid (20-30 ml). The mixture is stirred for 4-5 h, add additional quantity 2 hydrochloric acid and the mixture is left to mix overnight. The solvent is removed in vacuo, the residue diluted with tetrahydrofuran and treated with concentrated hydrochloric acid (2 ml). After stirring for 5-6 h, the solvent is removed in vacuum and the residue extracted with ethyl acetate. The organic layer is washed with water, saturated salt solution and dried. The solvent is removed in vacuo and the residue purified column chromatography on silica gel, elwira 80% solution of ethyl acetate in hexane, and gain of 0.43 g of target compound with So pl. 214-215,5oC.

Examples 15A-15C

Predpolagaetsya formula III (H-O-Z), you can obtain the following connections:

< / BR>
< / BR>
< / BR>
< / BR>
Example 16

(a) 2 - 3-chloro-4-oxo-4H-pyrido 1,2-and pyrimidine-2-Il oxymethyl-6-hydroxy-4-isopropylaniline

< / BR>
It is assumed that using a methodology similar to that shown in Example 6, it is possible to obtain the target compound 3-chloro-pyrido 1,2-and pyrimidine-2,4-dione (2 equivalent), methyltriethoxysilane (2 equivalent), DMF and 2-chloromethyl-4-isopropyl-6-hydroxycoumarin.

(b) 2 - 3-chloro-4-oxo-4H-pyrido 1,2-and pyrimidine-2-Il oxymethyl-4-isopropyl-6 - 1-(5-dimethylaminomethyl-2-furanyl)methoxy saccharin

< / BR>
It is assumed that the target compound can be obtained by treatment of a solution of 2 - to 3-chloro-4-oxo-4H-pyrido 1,2-and pyrimidine-2-Il oxymethyl-6-hydroxy-4-isopropylaniline in DMF with triphenylphosphine, 5-dimethylaminomethyl-2-hydroxymethylfurfural and diethylazodicarboxylate.

Example 17

2 - 4-oxo-6,7,8,9-tetrahydro-4H-pyrido 1,2-and pyrimidine-2-Il oxymethyl-4-isopropyl-6-methoxycoumarin

< / BR>
The mixture of compounds from Example 4C (0.3 g, 0,708 mmol), ethyl acetate (14 ml) and 10% palladium on coal (0.3 g) hydronaut in the Parr apparatus under a pressure of 50 pounds/inch2within 7 hours, the Reaction mixture was filtered through celite, the filtrate evaporated in Westboro and ending with 70% solution of ethyl acetate in hexane, and get after recrystallization from a mixture of ethyl acetate - hexane 0,165 g (54%) of target compound with So pl. 183,5-185,5oC.

Example 18

2 - 3-chloro-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-yl]oksimetildifenil

< / BR>
To a mixture of 2-hydroxy-Z-chloropyrid 1,2-pyrimidine-4-it (0,324 g) and methyltriethoxysilane (of 0.24 ml) in DMF (15 ml) is added 2-bremershaven (0,414 g). The mixture is left to mix overnight, poured into water and the resulting precipitates are filtered and recrystallized from DMF, getting 0,371 g (65%) of target compound.

Example 19a

2 - 3-chloro-4-oxo-4H-pyrido 1,2-and pyrimidine-Il oxymethyl-4-second-balilihan Example 19(b)

2 - 3-chloro-4-oxo-4H-pyrido 1,2-and pyrimidine-4-Il oxymethyl-4-second-balilihan

< / BR>
< / BR>
< / BR>
To a mixture of 2-hydroxy-3-chloropyrid 1,2-and pyrimidine-4-it (0.29 grams) and methyltriethoxysilane (0,22 ml) in DMF (12 ml) is added 2-chloromethyl-4-second-balilihan (0.39 g). The mixture is stirred for 8 hours, poured into water and the resulting precipitates are filtered. The resulting crude product was then purified column chromatography on silica gel with a gradient elution with mixtures of ethyl acetate - hexane (from 2/1 to 1/1 and and get after recrystallization from ethyl acetate 0,284 g (46,7%) target soyedineniya in Example 19a with So pl. 268-271oC (decomposition).

Examples preparative forms of the pharmaceutical composition

Example 20

Tablet

Ingredients Quantity (mg

The compound of Example 96 - 50,0

Mannitol, USP - 223,75

Sodium crosscarmellose - 6,0

Corn starch - 15,0

The hypromellose, USP was 2.25

Magnesium stearate - 3,0

Example 21

Capsule

Ingredients Quantity (mg

The compound of Example 13 - 10,0

Mannitol, USP - 448,5

Sodium crosscarmellose - 15,0

Magnesium stearate and 1.5

Example 22

Injection

Ingredients Quantity (mg/sec

The compound of Example 16b - 2,0

Dextrose - 39,5

Sterile water for injection To 1 ml

As mentioned previously, the compounds of formula 1 inhibit the enzymatic activity of proteolytic enzymes and are useful in the treatment of degenerative diseases. In particular, they inhibit the elastase of human leukocytes and chymotrypsin like enzymes and are useful in the treatment of emphysema, rheumatoid arthritis, pacreatitis, kitayskogo fibrosis, chronic bronchitis, respiratory distress syndrome in adults, inflammatory bowel disease, psoriasis, bubble of pemphigoid and alpha-1-antitrypsine not the leukocytes of man.

Measurement of the inhibition constants (Ki) leukocyte elastase person ingibiruet complex described (Cha, Biochemical Pharmacology, vol. 24, p. 2177-2185, 1975) for the true reverse the inhibition constant Ki, usually in relation to competitive inhibitors. The compounds of formula I do not give a true reversible inhibitory complexes, but rather can be considered as a kind of enzymes. For this reason, calculate the value of Ki*which is defined as the ratio of the rate of reactivation of the enzyme and speed inaktivirovanie enzyme (Koff/Kon). Measured values (Koffand Konand calculate the Ki*.

The value of Kondetermined by measuring the enzymatic activity of aliquots of the enzyme as a function of time elapsed after addition of the test compound (inhibitor). Building a graph logarithmic values of enzyme activity with respect to time, determine the observed rate inaktivirovanie by the equation Kobs=ln 2/t1/2where t1/2indicates the time during which the enzyme activity is reduced by 50%. Then calculate the value of Konby the equation Kon= Kobs[I] where [I] denotes the concentration of the inhibitor. The value of Koffset the ATA, in table IV were obtained for the compounds of formula 1, are given in the examples.

Inhibitory activity of compounds represented relative to the elastase of human leukocytes was also demonstrated in the following test:

The test compound (inhibitor) dissolved in DMSO in the test tube, receiving the original solution with a concentration in the range of 200-1000 mm. The original solution of the inhibitor was diluted (1:4, 1:16 and 1:64) in test tubes for analysis (tubes 1, 2 and 3, respectively) containing 2.4 ml of buffer solution (50 mm N-2-hydroxyethyl] piperazine-N'[econsultancy] acid/NaOH, 500 mm sodium chloride, pH 7.8 at 25oC), and add DMSO so that the total amount of liquid in each tube was 3.2 ml of 70 µl 35 µl and 25 µl of inhibitor from a test tube for analysis 1 is placed in the first four cells of the microlithic plate with 96 cells and bring the volume of each cell to 90 µl using a mixture of 25% DMSO/buffer solution. With the inhibitor of the tubes 2 and 3 do the same and placed in a cell 5-12, respectively, receiving 12 different concentrations of the inhibitor. Similarly, quality control prepare four cells (cell 13-16), containing 90 μl of a mixture of 25% DMSO/buffer solution without added inhibitor. Satata elastase of human leukocytes MeOSuc-Ala-Ala-Pro-Val-pNA (18,7 mm in DMSO) to a 19.5 ml of buffer solution) and the solution in each cell is thoroughly mixed.

Plate with 96 cells are placed in a spectrophotometer Microplate Reader # 89815A and in each of the 16 cells simultaneously add 110 μl of an enzyme solution (obtained as follows: a mixture of 20 ml of buffer solution and 20 mg of bovine serum albumin gently shaken in a vessel for holding scintillation measurements) and 5 ál of a solution of leukocyte elastase (1 mg/ml in deionized water). Each of the solutions in the cells are thoroughly mixed and get the values of absorption depending on the time at 410 nm as long as the analysis is completed. It should be noted that although the analysis can be carried out manually, however, it is preferable to automated analysis using work for the microanalysis of the company "Hewlett Packard".

Obtained in this way a plot of the absorption time allows to obtain the curves of progression, the slope of which determines the final equilibrium velocity (VFUsing the program ENZFITTER (software company "Elsevier"), progression curves for the four samples (a[I] = 0) agree on the method of linear regression and get the values of the reaction rate of the enzyme in the absence of inhibitor (V0
< / BR>
which allows to obtain a linear relationship, where

< / BR>
[S] denotes the substrate concentration,

Mmthe Michaelis constant.

The following table V summarizes the results obtained when testing the presented compounds according to the invention by the method described above.

A number of compounds of the formula I, inhibition of proteolytic enzymes can be identified from the test results on the inhibition of elastase of human leukocytes and may optionally be changed for a particular patient depending on the physical condition of the patient, method of administration, duration of treatment and the patient's response. The effective dose of the compounds of formula I can be determined only by a physician after evaluation of all the required criteria and should be optimal for the patient.

The compound of the formula I can be prepared for pharmaceutical use by its inclusion in a pharmaceutical composition for oral and parenteral administration or inhalation of an aerosol and may be in solid or liquid dosage form, including tablets, capsules, solutions, suspensions and emulsions, and may also contain suitable auxiliary DoB. With this purpose as one or more additives can be used, for example, calcium carbonate, starch, lactose, talc, magnesium stearate and gum. The compositions have the usual methods customary in the pharmaceutical practice.

1. Derived saccharin General formula I

< / BR>
where R1- lower alkyl,

R2the substituent in the 5-, 6 - or 7-positions selected from the group consisting of:

B = N-(CH2)pC(O)O(CH2)p, -O-,

-O-(CH2)p-(5-((CH2)p, -B = N-2-furanyl)

and R is hydroxy(lower)alkoxy, where B = N-di(lower)alkylamino,

R is phenyl(lower)alkyl,

p and p' are integers 1 or 2,

R3is a hydrogen atom,

X is a hydrogen atom or halogen,

Y represents a group-N=C(Z)-N(Z")- or-N=C(R')-N(R')-, where the group R"' together with the carbon atoms or nitrogen to which they are attached, represent a group -(CH2)4-, and Z", combined with the carbon atoms or nitrogen atoms to which they are attached, form peridogram,

or its pharmaceutically acceptable basic additive salt, if the compound has an acidic functional group, or its pharmaceutically acceptable acid additive salt, if the connection has the basic functionality is UB>C(O)O(CH2)p, -O - and R is hydroxy(lower)alkyloxy.

3. Connection on p. 1, in which R1is isopropyl; R2is a group of 6-dimethylamino-CH2C(O)O(CH2)2-O - or 6-benzyloxyethyl group; and X is hydrogen.

4. Connection on p. 3 having the structural formula

< / BR>
where R2is dimethylamino-CH2C(O)O(CH2)2-O - or benzylacetone group, and Z represents the following structural formula:

< / BR>
< / BR>
5. Pharmaceutical composition for the inhibition of proteolytic enzymes in the treatment of degenerative diseases, characterized in that it comprises a compound of formula 1 according to any one of paragraphs.1 to 4 in an effective dose and a pharmaceutically acceptable carrier.

6. The compound according to any one of paragraphs.1 to 4, characterized in that it is useful to prepare medicines for the treatment of a patient suffering from degenerative diseases.

7. The pharmaceutical composition according to p. 5, characterized in that it is useful to prepare medicines for the treatment of a patient suffering from degenerative diseases.

 

Same patents:

The invention relates to new compounds having pharmacological activity, to a method of their preparation and use as pharmaceuticals

The invention relates to new chemical substances, which have valuable pharmacological properties, more particularly to a nitrogen-containing heterocyclic compounds of General formula I

< / BR>
where X is oxygen or sulfur;

Y is carbon or nitrogen;

Z is carbon or nitrogen, and Y and Z are not simultaneously mean nitrogen;

R1and R2independent from each other and denote hydrogen, alkyl with 1 to 6 carbon atoms, halogen, trifluoromethyl, nitrile, alkoxy with 1 to 6 carbon atoms, a group of CO2R7where R7means hydrogen or alkyl with 1 to 6 carbon atoms, group-C(O)NR8R9where R8and R9not dependent from each other and denote hydrogen, alkyl with 1 to 3 carbon atoms, methoxy or together with the nitrogen form a morpholine, pyrrolidine or piperidine-NR10R11where R10and R11denote hydrogen or alkyl with 1 to 6 carbon atoms, group-C(O)R12where R12means alkyl with 1 to 6 carbon atoms, group-SO2R12where R12has the specified value, -NHC(O)R12where R12has the specified value, -NHSO2R12where R12has a specified value, and-SO2NR13R14where R13and R142R12where R12has the specified value, -NHC(O)R12where R12has the specified value, -NHSO2R12where R12has the specified value, -SO2NR13R14where R13and R14have a specified value, a nitrogroup, 1-piperidinyl, 2-, 3 - or 4-pyridine, morpholine, thiomorpholine, pyrrolidine, imidazole, unsubstituted or substituted at the nitrogen by alkyl with 1 to 4 carbon atoms, 2-thiazole, 2-methyl-4-thiazole, dialkylamino with 1 to 4 carbon atoms in each alkyl group, or alkilany ether with 1 to 4 carbon atoms;

R4an ester of formula-CO2R16where R16means alkyl with 1 to 4 carbon atoms, the amide of formula C(O)NR17R18where R17and R18independent from each other and denote hydrogen, alkyl with 1 to 2 carbon atoms, methoxy or together with the nitrogen form a morpholine, piperidine or pyrrolidine, phenyl, unsubstituted or substituted by residues from the group comprising halogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, 3-methyl-1,2,4-oxadiazol-5-yl, 2 - or 3-thienyl, 2-, 3 - or 4-pyridyl, 4-pyrazolylborate 4 stands, the ketone of the formula C(O)R19'where R19means alkyl with 1 to 3 carbon atoms, phenyl or 1-Mei-2-yl, a simple ester of the formula-CH2OR20where R20means alkyl with 1 to 3 carbon atoms, thioether formula-CH2SR20where R20has the specified value, the group CH2SO2CH3amines of the formula-CH2N(R20)2where R20has the specified value, the remainder of the formula-CH2NHC(O)R21where R21means methyl, amino or methylamino - group-CH2NHSO2Me2where Me denotes methyl carbamate of the formula CH2OC(O)NHCH3;

R5and R6independent from each other and denote hydrogen or methyl;

n is 0,1 or 2,

Provided that the substituents are not simultaneously have the following meanings: Y and Z is carbon, R1or R2hydrogen, halogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, cyano, nitro, trifluoromethyl, R3unsubstituted phenyl and R4group-C(O)OR16'where R16'means hydrogen, alkyl, alkenyl or quinil, group-C(O)N(R18')(R19'), where R18'and R19'denote hydrogen, alkyl with 1 to 6 carbon atoms, phenyl, alkoxy or together with the nitrogen form pyrrolidine, piperidine or morpholine, cyanotic, unsubstituted phenyl and 4-imidazole,

in the form of a racemate or an individual enantiomers and their salts, are inhibitors of leukotriene biosynthesis

The invention relates to new cephalosporins, namely to derive 1-zetia-diazaphosphorines General formula 1:

(I)

where the wavy line represents a CIS - or TRANS-configuration; R1-C1-C4alkyl, if necessary, replaced by carboxypropyl;

R2-tetrazol-5-yl, if necessary, replaced by stands, methylthiourea or dihydroxyphenylethylamine, thiadiazole-2-yl, if necessary, replaced by stands, methylthio-, amino-, pyridylcarbonyl-, 3,4-diacetoxybiphenyl - carbonylmethyl - or 1-methylprednisolone - amino group of the purine-6-yl, 1,2,3-triazole-5-yl, 1,2,4-triazolyl, if necessary, replaced by stands and trifluoromethyl, thiazolo (5,4-C) pyridin-2-yl or 5,6-dioxo-1,2,4-triazinyl, replaced by chlorpropamide, cooa group COOH or R2-1 methylpyridine, sooa-radical soo-that may find application as antibacterial substances in medicine

The invention relates to new biologically active chemical compounds, specifically to derived dihydropyrimidine formula I

where R1- C1-C6-alkoxy or phenylaminopropyl,

R2- C1-C6-alkyl or phenyl,

R3is a hydrogen atom or a C1-C6-alkyl,

R4- C1-C6-alkyl or phenyl which may be substituted by one or more identical or different substituents from the group halogen, nitro, C1-C6-dialkylamino,1-C6-alkyl, C1-C6-alkoxy and hydroxy-group, or their therapeutically acceptable salts accession acid with protivominniy and anti-inflammatory activity

The invention relates to the first new derivatives of 1,2,5-thiadiazolo[3,4-h] quinoline General formula 1

NNAlK where Alk is methyl or ethyl, with improved anthelminthic activity

The invention relates to new compounds of the formula

< / BR>
to pharmaceutically acceptable additive salts of the acid and stereoisomers of these compounds, which are used as antagonists of mediators and have a high activity against Central nervous system

The invention relates to new heterocyclic substances exhibiting antagonist against angiotensin II action

The invention relates to certain condensed to errorcorrection that selectively associated with GABA receptors

The invention relates to a method for 3-{ 2-[4-(6-toranzo[d]isoxazol-3-yl) piperidine-1-yl] ethyl} -2-methyl-6,7,8,9-tetrahydro-4H-pyrido-[1,2-a] pyrimidine-4-it (I) interaction of 3-(2-amino-ethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a] pyrimidine-4-it (II) isoxazol derivative of the formula (III)where Y and Z represent the deleted group, such as halogen or alkyl - or arylsulfonate, in the presence of a suitable solvent and base

The invention relates to new derivatives hinolincarbonova acids of the formula I, their pharmaceutically acceptable salts and their hydrates
Up!