Derived saccharin or its pharmaceutically acceptable salt, a method thereof, derivatives of saccharin, inhibiting the activity of proteolytic enzymes, pharmaceutical composition active inhibitor of proteolytic enzyme

 

(57) Abstract:

Usage: in the chemistry of heterocyclic compounds, inhibiting the enzymatic activity of proteolytic enzymes. The inventive derived saccharin of formula I:

< / BR>
where R1- H or lower alkyl; R2is hydrogen, lower alkoxygroup, hydroxyl, hydroxy(lower)alkoxygroup, phenyl(lower)alkoxycarbonyl(lower)alkoxygroup; X is H, halogen, lower alkyl, phenyl, phenyl (lower) alkyl, phenylcarbamoyl, lower alkanoyl, lower alkoxycarbonyl, B=N, B=N - (lower) alkyl, fenoxaprop, where B=N - 1-piperidinyl or 4-morpholinyl;

Y IS -(CH2)m-, -(CH2)m-O-, -CHR-O-, -(CH2)m-N(R')-, -C(R')=C(R')-O-, -C(R')= C(R')-N(R')-, -C(=O)-C(R")=C(R")-, -C(Z')=C(Z')-, -C(Z')=C(Z')-O-, -C(Z')=C(Z')-S-, -C(Z')=C(Z')-N(R')-, -N(Z)-C(Z)=N - or-N=C(Z)-N(Z') -,

where m = 1, 2, 3, or 4, R, R', R", Z' and Z" have the meanings specified in paragraph 1. A method of producing compounds of formula I and pharmaceutical compositions on their basis, inhibiting activity of proteolytic enzymes. 4 C. and 5 C.p. f-crystals, 4 PL.

The invention relates to the derivatives of saccharin, inhibiting the enzymatic activity of proteolytic enzymes, methods of producing such derivatives, method for their primeneniya proteolytic enzymes applicable in the treatment of those diseases, in which the essential element is proteolysis. Serine protease form a group of the most common proteolytic enzymes. Individual serine protease described as chymotrypsinogen or anastasopoulou, depending on the specificity of the substrate on which they are directed. Chymotrypsin and chymotrypsinogen enzymes usually break down the peptide bonds in the protein in the center, in which the amino acid side of the carbonyl presents Trp, Tyr, Phe, Met, Leu, or other amino acid containing an aromatic or more alkyl side chain. Elastase and anastasopoulos enzymes usually break down the peptide bond at the site where the amino acid residue on the carbonyl side of the link represented by Ala, Val, Ser, Leu or another small amino acid. As chymotrypsinogen and lastsavedby enzymes can be detected in leukocytes, mastoid cells, and pancreatic fluid of higher organisms, and in addition are secreted by many types of bacteria, yeast and parasites.

In PCT application WO 90/13549 (Dunlap and others) revealed a series of 2-substituted saccharin derivatives applicable as inhibitors of proteolytic enzymes.

According to the present invention is given th) alkyl, perchloro (lower) alkyl, lower alkenyl, lower quinil, cyan, amino group, lower alkylamino, di (lower alkyl) amino group, a lower alkoxygroup, benzyloxy, lower alkoxycarbonyl or phenyl and

R2is one to three substituent in any or all of the 5-, 6 - and 7-position selected from the group Lucaya : hydrogen, lower alkyl, cycloalkyl, amino (lower) alkyl, (lower alkyl) amino (lower) alkyl, di (lower alkyl) amino(lower) alkyl, hydroxy (lower) alkyl, (lower alkoxygroup) (lower) alkyl, PERFLUORO (lower) alkyl, perchloro (lower) alkyl, formyl, cyan, carboxyl, aminocarbonyl, R-oxycarbonyl, B = N 1-(lower) alkyl-2-pyrrolyl, lower alkylsulfonamides, a nitrogroup, hydroxyl, R-carbonyloxy, lower alkoxygroup, cycloalkylation, PERFLUORO (lower) alkylsulfonamides, perchloro (lower) alkylsulfonamides, B = N -(lower) alkoxygroup, hydroxy (lower)-alkoxygroup, polyhydroxy (lower) alkoxygroup or their ketals or acetals, (lower alkoxy) (lower) alkoxygroup, poly (lower alkoxy) (lower) alkoxygroup, hydroxy-poly(lower) alkylen/oxygraph, (lower alkoxy) poly (lower)-accelerograph, B = N-carbonyloxy, carboxy (lower) Alu, R-togroup, R-sulfinil, R-sulfonyl, PERFLUORO (lower) alkylsulfonyl, perchloro (lower) alkylsulfonyl, aminosulfonyl, lower alkylaminocarbonyl, di (lower) alkylaminocarbonyl and halogen, where R is lower alkyl, phenyl or phenyl (lower) alkyl, and phenyl has one to three substituent selected from the group comprising lower alkyl, B = N-carbonyl, B = N, the lower alkoxygroup, B = N -(lower)-alkoxygroup and halogen.

B = N represents an amino group, a lower alkylamino di(lower)alkylamino, carboxy(lower)alkylamino, 1-pyrrolidine, 1-piperidinyl, 1-azetidinol, 4-morpholinyl, 1-piperazinil, 4-(lower) alkyl-1-piperazinil, 4-benzyl-1-piperazinil or 1-imidazolyl.

R3is hydrogen, lower alkyl or phenyl.

X is hydrogen, a nitro-group, a lower alkyl, PERFLUORO (lower) alkyl, perchloro (lower) alkyl, phenyl, phenyl (lower) alkyl, phenylcarbinol, pyridyl (lower) alkyl, formyl, lower alkanoyl, carboxyl, lower alkoxycarbonyl, aminocarbonyl, lower alkylaminocarbonyl, di (lower) - alkylaminocarbonyl, cyan, B = N, B = N -(lower) alkyl, B = N - (lower) alkanoyl, B = N -(lower) alkoxycarbonyl, hydroxyl, lower alkoxygroup, fenoxaprop, B = N -(lower) -alkoxygroup, lower Alky who has one to three substituent, selected from the group comprising lower alkyl, lower alkoxygroup or halogen and B = N takes values above.

-Y represents the remaining atoms of the monocyclic or bicyclic, substituted or unsubstituted, carbocyclic or heterocyclic system;

or pharmaceutically acceptable salts formed by addition of acids, if the compound has a basic functional group, or pharmaceutically acceptable salts formed by addition of acids, if the compound has an acidic functional group.

The compounds of formula 1 inhibit the enzymatic activity of proteolytic enzymes and applicable to the treatment of diseases associated with degeneration of the tissues.

Featured aspect of the invention provides compounds of formula 1, where-Y - is ((CH2)m-, -C(= O)-, -CH2)m-O-, -CHR-O-, -CR2-O-, -C[(CH2)n] -O-, -C (CH2CH2N(R)CH2CH2] -O-, -(CH2)m-N(R')-, CHR-N(R')-, -CR2-N(R')-, -C(R')= C(R')-O-, C(R')= C(R')= C(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-or-N=C(Z)-N(Z') -,

where m = 1,2,3 or 4; n = 3,4 or 5; R is the same or different and represented by the lower alkyl, phenyl or phenyl (lower) alkyl; R' is H or R; R" is H or R, Il the volumes of carbon to which they are attached, form a benzo-, furano-, pyrido-, pyrimidine or pyridazinone, and Z" is a group together with the carbon atoms or nitrogen to which they are attached, form a pyrido-, pyrimidine or pyridazinone, where phenyl, benzo-, furano, pyrido-, pyrimidine or pyridazinone may have one to three substituent selected from the group comprising lower alkyl, B=N-carbonyl, B=N, the lower alkoxygroup, B=N -(lower) alkoxygroup and gasoil, and B=N takes values above.

Given the method of obtaining the compounds of formula 1, which consists in the condensation of the corresponding compounds of formula II

< / BR>
where Q represents chlorine or bromine, with a corresponding compound of formula III

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

Given the application of the formula I to obtain medication intended for treatment of diseases associated with regenerated tissues from patients in need of such treatment.

Provides a pharmaceutical composition for the treatment of these diseases, containing proteolytic enzyme inhibitory concentration of the compounds of formula I in a pharmaceutical carrier.

The connection part is Oia formula III below, as meeting the formula: H-O-z -

Saccharin is 1,2-benzisothiazol-(1H)-3-one-1,1-dioxide, and the compounds of formula I called 2-[Z-O-CH(R3)]-4-R1-(5,6 and/or 7)-R2-1,2-benzisothiazol-(1H)-3-one-1,1-dioxides can be designated respectively as 2-[Z-O-CH(R3)]-4-R1-(5,6 and/or 7)-R2-sacharine.

For the compounds of formula I-III "corresponding" means that the received definitions of the variables in one of the formulas have the same definition in another formula.

The connection part in the carbon chain has one to ten carbon atoms, preferably one to four carbon atoms, and branched chain or neravetla in the following radicals: lower alkyl, PERFLUORO (lower) alkyl, perchloro (lower)-alkyl, lower alkoxycarbonyl lowest alkylamino, di-(lower alkyl) amino group, a lower alkoxygroup, lower alkylamino part (lower alkyl) amino (lower) alkyl, lower alkylamino part of the di (lower alkyl) amino (lower) alkyl, lower alkoxy-part (lower alkoxygroup) (lower) of alkyl, carboxy (lower) alkylamino, 4-(lower) alkyl-1-piperazinil, 1-(lower) alkyl-2-pyrrolyl lowest alkylsulfonamides, PERFLUORO (lower) alkylsulfonamides, perchloro (lower) alkoxy-part poly (lower) alkoxy(lower)alkoxygroup, lower alkoxy-part (lower) alkoxyl(lower)accelerometry, R-oxycarbonyl (lower) alkoxygroup, PERFLUORO-(lower) alkylsulfonyl, perchloro (lower) alkylsulfonyl, lower alkylaminocarbonyl, di(lower alkyl)aminosulfonyl, phenyl(lower)alkyl, pyridyl (lower)alkyl, lower alkylaminocarbonyl, di(lower alkyl)aminocarbonyl lowest allylthiourea and carboxy(lower) alkylamino.

The following radicals pierogarnia part has two to ten carbon atoms, preferably two to four carbon atoms, these radicals are branched or nerasvetlena: lower alkenyl, lower quinil, amino (lower)-alkyl, the lower alkyl part of the (lower alkyl) amino(lower) alkyl, lower alkyl part of the di(lower alkyl)amino(lower)alkyl, hydroxy (lower)alkyl, lower alkyl part of the (lower alkoxygroup) (lower) alkyl, lower alkoxy-part B=N -(lower) alkoxygroup, hydroxy (lower) alkoxygroup, polyhydroxy (lower) alkoxygroup, the second lower alkoxy-part (lower alkoxygroup) (lower) alkoxygroup, the second lower alkoxy-part poly (lower alkoxygroup) (lower) alkoxygroup, alkylene-part hydroxypoly (lower)accelerometry, alkylene-part (the lower SSI) alkoxycarbonyl. Alkylene preferably presents 1,2-alkylene. Cycloalkyl and cycloalkanes preferably are in a cycle of three to six carbon atoms and can be substituted by one or more lower alkilani. The halogen represented by fluorine, chlorine, bromine or iodine.

R1preferably represents a primary or secondary alkyl of two to four carbon atoms or lower alkoxygroup.

R2preferably represents hydrogen, hydroxyl, lower alkoxygroup, cycloalkanes, B= N -(lower)-alkoxygroup, hydroxy (lower) alkoxygroup, polyhydroxy (lower) alkoxygroup or their ketals or acetals, (lower alkoxygroup) (lower) alkoxygroup, poly (lower alkoxygroup) (lower) alkoxygroup, hydroxypoly (lower) accelerograph, (lower alkoxygroup) poly (lower) accelerograph, B=N-carbonyloxy, carboxy (lower) alkoxygroup, R-oxycarbonyl (lower) alkoxygroup, methylendioxy or di(lower alkyl) phosphoryloxy that (except methylendioxy) are preferably in the 6-position. Methylendioxy can be located in 5 and 6 or 6 and 7-positions.

Especially recommended connection formulation, halogen, lower alkyl, phenyl, phenyl (lower) alkyl, phenylcarbamoyl, lower alkanoyl, B=N, B=N -(lower) alkyl or fenoxaprop.

Especially preferred compounds of formula 1 in which R1is isopropyl, R2is hydrogen or 6-methoxy group and X represents hydrogen, chlorine, methyl, phenyl, phenylmethyl, phenylcarbinol, acetyl, 1-piperidinyl, 4-morpholinylmethyl or fenoxaprop.

Upon receipt of the compounds of formula 1 from the corresponding compounds of formula II and the corresponding compounds of formula III in the presence of a base, the base can be any base that is not a reagent under the reaction conditions, preferably a carbonate of an alkali metal, an alkali metal alkoxide, three(lower alkyl)-amine, lower alkoxide of thallium (1), 1,8-diazabicyclo[5.4.0] undec-7-ene or 7-methyl-1,5,7-diazabicyclo[4.4.0] Dec-5-ene. Under the reaction conditions, the base can form a basic salt of the compounds of formula III, which then reacts with the compound of the formula II. The basic salt of the compounds of formula II may also be formed separately and then condensed with the compound of the formula II, and such salt preferably is a salt of an alkali metal, especially the cesium salt or waist (I). The condensation is carried out in the region, methylethylketone, acetonitrile, tetrahydrofuran, diethyl ether, dimethylformamide, N-organic, dichloromethane, xylene, toluene or lower alkanol or their mixtures in the temperature range from room temperature to the boiling point of the solvent or solvent mixture.

Compounds of formulas II and III are known or they get known methods or in the following methods.

The compound of formula II in which R3is hydrogen, can be synthesized by diazotization of the corresponding (lower alkyl)-2-amino-3(4 or 5)-R2-R2-6-R1-properties of the ether, chlorosulfonylphenyl obtained 2-diazonium salt lower Olkiluoto ether 3(4 or 5)-5-R2-6-R1benzoic acid, sulfur dioxide and chloride of copper (I) and cyclization of the obtained lower Olkiluoto ether 2-chlorosulfonyl-3(4 or 5)-R2-6-R1benzoic acid in the presence of ammonia with formation of the corresponding compounds of formula IV

< / BR>
hydroxymethylpropane which formaldehyde receive the corresponding 2-hydroxymethyl-4-R1-(5,6 or 7)-R2- saccharin, replace in which hydroxyl by chlorine or bromine, for example, by the action of chloride of tonila, bromide tonila, trichloroethene formula II, in which R3is hydrogen and Q is chlorine, can be obtained in one stage from the corresponding compounds of formula IV chlorotoluene paraformal and chloromethylstyrene in the presence of a Lewis acid such as tin chloride (IV).

The compound of formula II in which R3is lower alkyl and Q is chlorine, can be synthesized by waniliowym respective Association of the formula IV corresponding substituted or unsubstituted vinyl ether lowest alanovoy acid in the presence of dinitrophenylhydrazine with subsequent treatment of the obtained 2-(substituted or unsubstituted vinyl)-4-R1-(5,6 or 7)-R2-saccharin chloride hydrogen. The use of unsubstituted vinyl acetate gives, for example, an appropriate compound of the formula I, in which R3is methyl.

The compound of formula II in which R3is hydrogen or phenyl, can be obtained phenylthio-R3-methylation of the corresponding compounds of formula IV or basic salts of the corresponding phenyl-R3-chloromethylation with the formation of the corresponding 2-(phenylthio-R3-methyl)-4-R1-(5,6 or 7)-R2-saccharin, which then phenylthiourea replace chlorine or bromine, for example chlorestol in the corresponding 2-R1-3 (4 or 5)-R2-N, N-di(lower alkyl) benzamid processing lower alkyllithium, aminosulphonylphenyl obtained 2-R1-3(4 or 5)-R2-6-litio-N, N-di (lower alkyl) benzamide sulfur dioxide, then hydroxylamine-O-sulfonic acid or sulfurylchloride with subsequent treatment with ammonia and cyclization of the obtained 2-R1-3(4 or 5)-R52-aminosulfonyl-N,N-di (lower alkyl) benzamide in boiling acetic acid.

The compound of formula IV in which R1represents a primary or secondary alkyl of two to four carbon atoms, can be obtained by introducing lithium into the corresponding compound of formula IV in which R1is methyl, by treatment with two molar equivalents of the lower alkylate in an inert solvent, such as tetrahydrofuran and obtained by alkylation of 4-Sociometer-5(6 or 7)-R2-saccharin appropriate alkylhalides. Both reactions are carried out in the temperature range from -80 to -50oC. the Above-mentioned 2-R1-3(4Or 5)-R2-N,N-di (lower alkyl) benzamid, where R1represents a primary or secondary alkyl of two to four carbon atoms, can be obtained by using the same sequence of liceali-alkylation on the basis sotomura IV, in which R1represents a primary or secondary alkyl of two to four carbon atoms, can also be obtained by introducing the R1at earlier stages of the synthesis. Joint adding the appropriate R1-cuprate to 2-cyclohexanone and methoxycarbonylamino received enolate copper medicinetramadol by the method of Winkler et al (Tetrahendron, page 1051, 1987; Jornal of Organic Chemistry, 54 so, 4491 S., 1989) gives the corresponding 2-methoxycarbonyl-3-R1-cyclohexanone, enol esterification of which benzylthio and acidic clay get a mixture of methyl ester of 6-R1-2-benzylthio-1-cyclohexanecarboxylic acid methyl ester 6-R1-2-benzylthio-3-cyclohexanecarbonyl acid, a mixture of flavored dichlorodicyanoquinone with the formation of the corresponding methyl ester 2-R1-6-sensitivetony acid, ether oxidize-glorious-dibenzyline chlorine in aqueous acetic acid to obtain methyl ester 2-R1-6-chlorosulfonylbenzoic acid, cyclization of which, in the presence of ammonia to obtain the corresponding 4-R1-saccharin of formula IV.

The synthesis of certain compounds of formula IV require building it in both cycles. For example, to obtain the compounds of formula abucay chloride tiomila in bischloromethyl, which in reaction with benzylamine turn in bisbenzimide, cyclization which, in the presence of chloride Sulfuryl get 5-chloro-2-benzyl-3H-isothiazol-3-one. The oxidation of one oil equivalent of nagkalat get 5-chloro-2-benzyl - 2H-isothiazol-3-one-1-oxide, which is heated under pressure in the presence of 2-(lower alkoxygroup) furan and receive a 4-(lower alkoxygroup)-7-hydroxy-2-benzyl-1,2-benzisothiazol-2H-3-one - 1-oxide, the oxidation of which one molar equivalent of nagkalat receive the corresponding 4-(lower alkoxygroup)-7-hydroxy-2 - benzyl-1,2-benzisothiazol-2H-3-one-1,1-dioxide, which is then dibenzyline catalytic hydrogenation and receive the corresponding 4-(lower alkoxygroup)-7-hydroxycoumarin formula IV.

Similarly, alkylation of 4-(lower alkoxygroup)-7-hydroxy - 2-benzyl-1,2-benzisothiazol-2H-3-one-1-oxide lower alkylhalides or correspondingly substituted lower alkylhalides with subsequent oxidation and dibenzylammonium receive the corresponding 4-(lower alkoxygroup)-7-R2-saccharin of formula IV in which R2is lower alkoxygroup, cycloalkanes, B = N -(lower) alkoxygroup, hydroxy (lower alkoxygroup), polyhydroxy (alkoxygroup) (lower) alkoxygroup, hydroxypoly(lower) accelerograph or (lower alkoxygroup) poly (lower) accelerograph.

Pharmaceutically acceptable salt formed by the addition of acid or base may be any salt formed by the addition of acid or base, but preferably salt normal anion, for example, hyrochloride or conventional cation, such as sodium or potassium, respectively. If the salt with normal anion or cation unacceptable because of its cristallinity or insufficient solubility, or hygroscopicity, in this case, accordingly, apply salt with less conventional anion, for example, methanesulfonate or less conventional cation, such as, salt diethylamine. In any case, the salt formed by the addition of acid or base and intended for a mammal, must be non-toxic and should not affect the inhibitory effect on elastase compounds of formula I in the form respectively of a free base or free acid.

In the preparative examples, working examples below, the conclusion about the structure of the products made on the basis of the structure of the parent compounds and expected path preparative reactions. Confirmation of purity and PTS the population (I. p.), optical rotation, elemental analysis, infrared spectral analysis, ultraviolet spectral analysis, mass spectral analysis, spectral analysis, nuclear magnetic resonance, gas chromatography, column chromatography, liquid chromatography high pressure liquid chromatography moderate pressure and/or thin-layer chromatography.

Example 1. Obtaining parent compounds

(a) Obtain 2-chloromethyl-4-isopropylaniline

(P; R1=ISO-Pr, R2=H, R3=H, Q = Cl)

To a solution of 2-isopropylphenol in anhydrous ether (500 ml) under stirring in nitrogen atmosphere at 0-5oC for ten minutes, add n-utility (2.5 M, 100 ml). The mixture is left to warm to room temperature, stirred at room temperature for six hours and cooled to -60oC. for 20 min. at a temperature below -50oC was added a solution of diethylcarbamazine (34g) in anhydrous ether (50 ml). The temperature is left to rise to room temperature during one hour and then add water (100 ml). The ether layer was washed with saturated aqueous sodium chloride (200 ml), dried over magnesium sulfate and the ether otparivat. Pereg is N,N',N'-tetramethylethylenediamine (25,5 g) in anhydrous ether (600 ml) add second-utility (1.3 M, 170 ml) and the mixture in the atmosphere of nitrogen to -70oC. is added dropwise within 20 min was added a solution of 2-isopropyl-N,N-diethylbenzamide (44 g) in anhydrous ether (300 ml), maintaining the temperature during addition below -60oC. After the addition the mixture is stirred for 30 min at -70oC, left for 30 min to warm to -50oC, incubated 10 min at -50oC, then re-cooled to -70oC. Through a tube in the form of a cannula under positive pressure of nitrogen for 10 min was added a solution of sulfur dioxide (50 g) in anhydrous ether (50 ml) pre-cooled to -60oC. the Temperature during the addition of support below -50oC. Almost immediately formed a white powdery precipitate of allitaliana. The temperature is left to rise for one hour to room temperature. For 15 min with continuous stirring, added dropwise chloride Sulfuryl (54 g). After additional stirring for 30 min at 0-5oC white residue is filtered off and washed with anhydrous ether (2 l). Removal of solvent under vacuum to obtain a pale yellow oil, which was dissolved in tetrahydrofuran (150 ml). The solution is cooled to 0oC and for 15 min servings add concentrated stirring 15 min at ambient temperature, the tetrahydrofuran and excess ammonia are removed, and the residue acidified with hydrochloric acid (2 BC) to pH 1. The resulting white solid was separated, washed with soda (200 ml) and hexane (200 ml) and after drying receive 2-aminosulfonyl-6-isopropyl-N, N-diethylbenzamide (54 g, yield 90%).

A solution of 2-aminosulfonyl-6-isopropyl-N,N-diethylbenzamide (60 g) in acetic acid 9400 ml) is boiled for 24 h, then cooled to room temperature. The solvent is removed under vacuum, the oily residue is dissolved in water (500 ml) and add 2 N. hydrochloric acid to establish a pH of 1. The crude product is filtered off, washed with water (300 ml), dried for 18 hours under vacuum at 60oC after recrystallization of isostasy ether-ether-hexane receive a 4-isopropylaniline (40 g, yield 90%, so pl. 177oC) (IV; R1= ISO-Pr, R2= H).

A mixture of 4-isopropylaniline (of 37.9 g) phenylcarbylamine (33.3 g), tetrabutylammonium (5,4 g) and toluene (200 ml), boiled for 24 h, after which the volatile components otparivat. Column chromatography of the residue on silica gel (485 g) with elution first with hexane, then hexane-dichloromethane (1:1) and finally dichloromethane get hexane-dichloromethane eluate 2-phenylthiomethyl-4-isopropylaniline in the form of a pale yellow oil (53,5 g, yield 92%).

2-FeNi is the temperature and stirring. The mixture undergoes a weakly exothermic reaction, after which it is left for 17 h at room temperature and then volatile components otparivat. The residue is crystallized from hexane three factions (33,65 g, so pl. 101-102oC; of 3.45 g, so pl. 100-101oC; 0.45 g, so pl. 99-100oC; just 38,55 g, yield 91%) three fractions are combined and by recrystallization from a mixture of isopropyl alcohol (30 ml)-cyclohexane (270 ml) to obtain 2-chloromethyl-4-isopropylaniline in the form of two fractions (33,5 g, I. p. 101-102,5oC; 2.65 g, I. p. 100-101oC).

(b) Obtain 2-chloromethyl-4-isopropyl-6-methoxycoumarin

(P; R1= ISO-Pr, R2= 6-OMe, R3= H, Q = Cl)

To a solution of N,N,N',N'-tetramethylethylenediamine (300 ml) in anhydrous ether (4 l) add second-utility (1.3 M, 4 l) and the mixture under nitrogen atmosphere cooled to -70oC. and Then added dropwise within 30 minutes, add a solution of 2-isopropyl-4-methoxy - N, N-diethylbenzamide (454,2 g) in anhydrous ether (300 ml), maintaining during the addition the temperature at -60oC or below. Upon completion of addition, the mixture is stirred for one hour at -70oC, allowed to warm to -50oC, incubated 30 min at -50oC, then re-cooled to -70oC. Through a tube in the form of a cannula over 20 min at a positive Tao -40oC. the Temperature of the reaction mixture during the addition of support below -40oC. Almost immediately formed a white powdery precipitate of allitaliana. Upon completion of addition, the cooling bath removed and the mixture is stirred for two hours at ambient temperature, then cooled to -5oC. for 15 min with continuous stirring and at a temperature below 10oC added dropwise chloride Sulfuryl (190 ml). After additional stirring for further 30 minutes at 0-5oC white precipitate is filtered and washed with anhydrous ether (2 l). Removal of solvent under atmospheric pressure to obtain a dark oil, which was dissolved in tetrahydrofuran (1.4 l). The solution is cooled to -10oC and for 15 min portions was added concentrated aqueous ammonia (28%, 540 ml). The temperature during the addition to maintain the 15oC or below. After stirring 15 min at ambient temperature, the tetrahydrofuran and excess ammonia is removed under vacuum to obtain a dark oil, which was diluted with water (6 l) and acidified with hydrochloric acid (3 BC) to pH I. the Obtained light yellow solid is filtered off, washed with water (800 ml), dried for 18 hours under vacuum at 60oC is ethylbenzamide (429 g, yield 72%, I. p. 122-125oC).

A solution of 2-aminosulfonyl-6-isopropyl-4-methoxy-N, N-diethylbenzamide (429,6 g) in acetic acid (1.5 l) boiled for 20 hours, then cooled to room temperature.

The solvent is removed under vacuum, the oily residue is dissolved in water (6 l) and the addition of hydrochloric acid (6 BC) set pH I. the crude product is filtered off, washed with water (2 l), dried for 18 hours under vacuum at 60oC and recrystallization from a mixture of ethyl acetate-hexane get 4-isopropyl-6-methoxycoumarin.

(IV; R1= ISO-Pr, R2= 6-OMe) (303 g, yield 91%, so pl. 188oC).

To a suspension of paraform (24 g) and chlorotrimethylsilane (86,4 g) in 1,2-dichloroethane (200 ml) add dry chloride tin (IV) (0, 8 ml) and the resulting solution was stirred for one hour in an ice bath. To the clear solution add 4-isopropyl-6-methoxy-saccharin (51,5 g), the mixture is boiled for 18 h, cooled to room temperature and transferred into the water. The organic layer was separated, washed with an aqueous solution of sodium hydroxide (2 N., 50 ml), dried over magnesium sulfate and concentrated in vacuo. By recrystallization of the residue from a mixture of ethyl acetate-hexane get 2-chloromethyl-4-isopropyl-6-methoxycoumarin (57 g, yield 87%, so pl. 151oC).


To a suspension of sodium hydride (60% dispersion in mineral oil, 0.1 g) in dimethylformamide (4 ml) in a nitrogen atmosphere under stirring and cooling in a bath of ice was added a solution of tetronic acid (0,22 g) in dimethylformamide (5 ml). Bath ice is removed, and stirring is continued for 15 minutes, added dropwise a solution of 2-chloromethyl-4-isopropylaniline (0,547) in dimethylformamide (10 ml), stirring is continued for two and a half days, after which the mixture is transferred into the water. The resulting mixture was extracted with ethyl acetate. An ethyl acetate layer is dried over magnesium sulfate and the ethyl acetate otparivat. By recrystallization of the obtained colorless solid (0.6 g) from ethyl acetate to obtain the title compound (0.34 g, yield 51%, I. p. 174-175oC).

Examples 1B-1W. According to the method similar to the above method of example 1A from 2-chloromethyl-4-isopropylaniline or 2-chloromethyl-4 - isopropyl-6-methoxycoumarin and the corresponding compounds of formula III (H-O-Z), the compounds listed in table. 1.

Example 2. 2-(1-Methylcarbamoyl-4-yl)oxymethyl-4-isopropyl-6-methoxycoumarin

< / BR>
To a suspension of sodium hydride (60% dispersion in mineral oil, 0.36 g) in dimethylformamide was added with stirring 4-hidrock half an hour at room temperature is treated with ultrasound. Add 2-chloromethyl-4-isopropyl-6-methoxycoumarin (1,83 g). The resulting mixture is heated for two hours at 100oC and continuous stirring, and then transferred into water (300 ml). Add hydrochloric acid (1 N., 25 ml) and the mixture extracted with chloroform. The chloroform extract is dried over sodium sulfate and the chloroform otparivat. Displacement chromatography of the obtained solid product (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, yield 28%) of ethanol (90%) receive the title compound as a yellow substance (0.39 g, yield 15%, I. p. 198-200oC.

Example 3A. 2-(1-Phenyl-3-acetylcarnosine-4-yl)oxymethyl-4-isopropyl-6-methoxycoumarin

< / BR>
A mixture of 3-acetyl-4-hydroxy-1-vinylcarbazole (0.52 g), potassium carbonate (0.28 g), and dimethylformamide (7 ml) is stirred for half an hour at room temperature. Add 2-chloromethyl-4-isopropyl-6-methoxycoumarin (0.71 g), the mixture is treated for one hour with ultrasound at 40oC and stirred for 16 h at room temperature. Additional sonication does not change the degree of conversion in the reaction, which was determined by thin-layer chromatography. The reaction mixture is transferred into the water and raffia moderate pressure 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 title compound (0.24 g, yield 24%, I. p. 210-212oC).

Example 3B. 2-(1-Methyl-3-acetylcarnosine-4-yl)oxymethyl-4 - isopropyl-6-methoxycoumarin

< / BR>
According to the method similar to the above method of example 3A, 3-acetyl-4-hydroxy-1-methylcarbamoyl (0,63 g) condenses with 2-chloromethyl - 4-isopropyl-6-methoxycoumarin (1.1 g) and purification of the product from methanol-ether to obtain the title compound (0.28 g, yield 20% I. p. 194 - 196oC).

Example 4A. 2-(2,5-dihydro-2-oxo-3-phenylfuro-4-yl)oxymethyl-4 - isopropyl-6-methoxycoumarin

< / BR>
To a solution of 3-phenyl-2(5H)-furanone (0.88 g) in methanol (15 ml) is added cesium carbonate of 0.82 g), the mixture is stirred for one hour at room temperature and the methanol otparivat. To a solution of the residue in dimethylformamide (15 ml) is added 2-chloromethyl-4-isopropyl-6-methoxycoumarin (1.52 g) and the mixture is stirred two days at room temperature. Add silica gel (4.4 g), volatile components are removed under vacuum and the solid product is subjected to pressure chromatography on silica gel using as eluent a mixture of ethyl acetate-hexane (3: 7). By recrystallization of the product from a mixture of ethanol-ether to obtain the title compound in the form of a colorless substance (0.45 g, yield 20% colorless substance (0.45 g, yield 20%, I. p. 180-yl-4-isopropyl-6-methoxycoumarin and the corresponding compounds of formula III (H-O-Z) of the obtained compound, are given in table.2.

Example 4J.

< / BR>
In accordance with the procedure described in example 4A was obtained 0.71 g (62,8% ) 2-[4-oxo-4H-pyrido[1,2-pyrimidine-2-yl]oxymethyl-4-isopropyl-6- (benzyloxycarbonyloxy)saccharin, melting point 69 - 71oC, when used as starting compounds 2-chloromethyl-4-isopropyl-6- (benzyloxycarbonyloxy)saccharin (0,876 g), cesium carbonate (0,326 g), methanol, 2-hydroxypyridine[1,2-a] pyrimidine-4-it (0,324 g) and N, N-dimethylformamide. The reaction mixture was poured into a mixture of ice water and was extracted with ethyl acetate, the organic layer was separated and washed with brine, and then dried over Na2SO4.

Example 4K.

< / BR>
In accordance with the procedure described in example 4A was obtained 0,267 g (58%)of 2-[4-oxo-4-H-pyrido[1,2-a] pyrimidine-2-yl]oxymethyl-4-sec-butyl-6-methoxycoumarin, melting point 160 - 185oC, when used as starting compounds 2-chloromethyl-4-sec-butyl-6-methoxycoumarin (0,318 g, 1.0 mmol), 2-hydroxypyridine[1,2-a]pyrimidine-4-it (0.18 g, 1.1 to 1 mmole), cesium carbonate (0.18 g, of 0.56 mmole), methanol (5 ml) and N, N-dimethylformamide. The reaction mixture was poured into a saturated solution of ammonium chloride and was extracted with ethyl acetate, the body of silica gel, producing elution with a mixture of 50% ethyl acetate and hexane, and then with a mixture of 5% methanol and ethyl acetate.

Example 5. 2-[3-(4-morpholinylmethyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-ID] oxymethyl-4-isopropyl-6-methoxycoumarin

< / BR>
A mixture of 3-(4-morpholinylmethyl) pyrido [1,2-a]pyrimidine-2,4-dione, hydrochloride (0.6 g) and tert-butoxide potassium (0,49 g) in dimethylformamide (20 ml) is stirred for five minutes at room temperature. Add 2-chloromethyl-4-isopropyl-6-methoxycoumarin (0,61 g) and stirring is continued for another hour at room temperature. The reaction mixture was diluted with water (50 ml) and extracted with dichloromethane (3 x 200 ml). The dichloromethane extract is dried over sodium sulfate and the volatile components otparivat at a high vacuum. The crude product (780 mg) combined with the product from another experience (0.65 g), conducted in the same scale by the use of sodium hydride (60% dispersion in mineral oil, 0,19 g) instead of tert-butoxide potassium, and purified column chromatography on silica gel using as eluent a mixture of dichloromethane (95: 5) to give the title compound (500 mg, yield 23%), partially recrystallized from ethanol (I. p. 177-180oC).

Example 6. 2-(3,5,6-trimethyl-1,4-dioxo-2,5-cyclohexadien-is ultrasonication (0.18 g) in acetonitrile (20 ml) at room temperature and stirring 2-chloromethyl-4-isopropyl-6-methoxycoumarin (0.34 g). Stirring at room temperature continued for 24 h and the solution with a dark color poured into ice water containing few drops of hydrochloric acid. The obtained brown solid is first purified column chromatography on silica gel and then recrystallized from hot ethanol and receive the title compound (60 mg, yield of 12.7% I. p. 164-166oC).

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

< / BR>
To a solution of 4,7-dimethoxy-5-acetyl-6-hydroxybenzophenone (0.39 g) and methyltriethoxysilane (0.28 g) in acetonitrile (20 ml) is added at room temperature and stirring 2-chloromethyl-4-isopropyl-6-methoxycoumarin (0.5 g). The mixture is stirred for about a day at room temperature. Because thin-layer chromatography revealed the presence of unreacted 4,7-dimethoxy-5-acetyl-6-hydroxybenzophenone additionally added 2-chloromethyl-4-isopropyl-6-methoxycoumarin with a drop base, stirring is continued for a total of 24 h and the reaction mixture was transferred into ice water containing hydrochloric acid. Received Golden solid partially purified using as eluent dechlorinate. the partially purified product from the first reaction unite and purification of column chromatography on silica gel get 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) added dropwise a solution of tricheditaligncenter (0,98 g) in water (3 ml). The mixture is stirred for 15 min at room temperature and transferred into ice-cold water. The obtained solid Golden color cleanse fast chromatography on silica gel using as eluent a mixture of dichloromethane-ether (95:5) and crystallization with sonication from ethanol gain of 0.13 g of product (yield 46.6 per cent, I. p. 193-195oC, with decomposition).

Example 8.

< / BR>
A mixture of 3-chloro-4-hydroxy-6-methyl-2H-Piran-2-it(0,493 g of 3.07 mmole), N, N-dimethylformamide and K2CO3(0,467 g, to 3.38 mmole) was stirred at room temperature under a layer of nitrogen for 0.5 h, and then in one portion was added 2-chloromethyl-4-isopropyl-6-methoxycoumarin (0,978 g, up 3.22 mmole). The resulting mixture was stirred at room temperature for 3 h, and then at a temperature of 75oC for another 3 hours, the Reaction mixture was poured into water and was extracted with ethyl acetate, the organic layer was washed with brine and was dried, the solvent was removed under vacuum and the residue was purified by chromatogra is Holocene 0.25 g (18,1%) of 2-(3-chloro-6-methyl-2-oxo-2H-Piran-4-yl)oxymethyl-4-isopropyl-6-methoxycoumarin, melting point 182,5-183,5oC, after recrystallization from a mixture of simple ether and hexane.

Examples 9A-9J. Compounds shown in table III were obtained by following General procedure.

A mixture of the corresponding compounds of formula III (H-O-Z), 1.0 to 1.5 equivalent of the required base and suitable solvent was stirred at room temperature for about 0-60 min, then was added a 1.0-1.2 equivalents of the appropriate 2-chloromethyl-4-isopropyl-6-R2-saccharin. The reaction mixture was stirred at a temperature of from room temperature up to 90oC for 1-48 h, and then subjected to the next process. Method 1: the reaction mixture was poured into a mixture of ice water and either (a) were extracted acceptable solvent (e.g. ethyl acetate, chloroform or methylene chloride), organic layer was separated, dried over Na2SO4was filtered and concentrated, and the thus obtained residue was purified as described in table. 3; or (b) the product precipitated from the mixture with ice water, collected by filtration and washed as described in table. III. Method 2: solvent was removed under vacuum and the residue was purified as described in table. 3.

Example 11.

< / BR>
To a mixture of tert-butoxide potassium (0,37 g, 3.3 mmole) in tetrahydrofuran (20 ml) was added ethyl-5-oxo-2-(pyrimidinyl-2-yl)- 2,5-dihydroisoxazole-4-carboxylate (0,70 g, 3.0 mmole) and for 0.5 h and stirred under a layer of nitrogen at 40oC. the Solvent was removed under vacuum and the residue was dried in high vacuum. The residue was mixed with N,N-dimethylformamide (20 ml) and was treated with 2-chloromethyl-4-isopropyl-6-methoxycoumarin (0,91 g, 3.0 mmole) in N, N-dimethylformamide (5 ml). The reaction mixture was stirred at room temperature for 3 days, poured into a mixture of ice water and e is the conditions of vacuum, the residue was purified by chromatography on columns of silica gel, producing elution with a mixture of 5% MeOH and EtOAc, which allowed us to obtain 0.18 g(12%) 2-[3-(etoxycarbonyl)-4-oxo-4H-Piramida[1,2-a] pyrimidine-2-yl] oxymethyl-4-isopropyl-6-methoxycoumarin, melting point 189-191oC, after recrystallization from a mixture of toluene and hexane.

Example 12.

< / BR>
A mixture of the product obtained in accordance with example 9G( 1.35 g) with ethyl acetate (200 ml), methanol (5 ml) and 10% palladium carbon (0.5 g) for 3 h were hydrogenosomal under pressure of 3.5 atmospheres in hydrogenator Parra. After adding an additional amount of palladium carbon (0.5 g), the mixture was hydrogenosomal another 8-9 hours, the Reaction mixture was filtered, the filtrate was concentrated under vacuum and the residue was purified by chromatography on columns of silica gel, spending Ilyasova with ethyl acetate, which allowed us to get to 0.89 g of 2-[4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a] -pyrimidine-2-yl] oxymethyl-4-isopropyl-6-(2-hydroxyethoxy)saccharin as a white foam.

Example 14.

< / BR>
To a suspension of the compound obtained in accordance with example N, (0,76 g) in methanol (30 ml) was added tetrahydrofuran, and then 2 HCl solution (20-30 ml). The floor is followed by a session during the night. The solvent was removed under vacuum, the residue was diluted with tetrahydrofuran and treated with concentrated HCl (2 ml). After stirring for 5-6 h, the solvent was removed under vacuum and the residue was extracted with ethyl acetate. The organic layer was washed with water, brine and was dried, the solvent was removed under vacuum and the residue was purified by chromatography on columns of silica gel, producing elution with a mixture of 80% ethyl acetate and hexane, which allowed us to obtain of 0.43 g of 2-[3-chloro-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-yl]oxymethyl-4-isopropyl - 6-[2-hydroxyethoxy]saccharin, melting point 214,5-215,5oC.

Example 15A.

In the procedure described in example 9D, but using the corresponding compounds of formula III (H-O-Z) we can obtain the following compound of the formula I

< / BR>
where Z

< / BR>
Example 16.

< / BR>
It was established that in the procedure described in example 6, we can obtain 2-[3-chloro-4-oxo-4H-pyrido[1,2-a] pyrimidine-2-yl]oxymethyl-6-hydroxy-4-isopropylaniline, using as starting substances 3 chloropyrid[1,2-a] pyrimidine-2,4-dione (2 equivalent), methyltriethoxysilane (2 equivalents), N, N-dimethylformamide and the Jn - 2-yl]oxymethyl-4-isopropyl-6-[1-(5-dimethylaminomethyl-2-furanyl) methoxy]saccharin can be obtained in the processing solution of 2-[3 - chloro-4-oxo-4H-pyrido[1,2-a] pyrimidine-2-yl] -oxymethyl-6-hydroxy-4-isopropylaniline in N,N-dimethylformamide by means of triphenylphosphine, 5-dimethylaminomethyl-2-hydroxymethylpropane and diethylazodicarboxylate.

Example 17.

< / BR>
The mixture of compounds obtained in accordance with example 4C (0.3 g, 0,708 mmole), ethyl acetate (14 ml) and 10% palladium carbon (0.3 g) for 7 h were hydrogenosomal and hydrogenization Parra under pressure of 3.5 ATM. The reaction mixture was filtered through celite, the filtrate was concentrated under vacuum and the residue was purified by chromatography on columns of silica gel, producing elution mixtures from 50% ethyl acetate and hexane to 70% ethyl acetate and hexane, which allowed us to obtain 0,165 g (54%) 2[4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a] pyrimidine-2-yl] oxymethyl-4 - isopropyl-6-methoxycoumarin, melting point 183,5-185,5oC, after recrystallization from a mixture of ethyl acetate and hexane.

Example 18.

< / BR>
To a mixture of 2-hydroxy-3-chloropyrid[1,2-a] pyrimidine-4-it (0,324 g) and methyltriethoxysilane (of 0.24 ml) in N,N-dimethylformamide (15 ml) was added 2-bremershaven (0,414 g). The resulting mixture was stirred overnight and poured into water. The precipitate was collected by filtration and recrystallized from N,N-dimethylformamide education 0,371 g (65%O 2-[3-chloro-4-oxo-4H-pyrido[1,2-a]pyrido[1,2-a]pyrimidine-2-yl] the n-4-it (6,29 g) and methyltriethoxysilane (0,22 ml) in N,N-dimethylformamide (12 ml) was added 2-chloromethyl-4-second-balilihan (0.39 g). The reaction mixture was stirred for 8 h, then poured into water and the precipitate was collected by filtration. The solid residue was purified by chromatography on columns of silica gel, producing elution by the mixture hexane ratio (2/1) to (1/1), which allowed us to obtain 0,284 (46.7% of 2-[chloro-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-yl] oxymethyl-4-second-Boticaria (example 19a), melting point 211-212oC, after recrystallization from ethyl acetate; and 0.027 g of 2-[3-chloro-2-oxo-2H-pyrido[1,2-a] pyrimidine-4-yl] oxymethyl-4-second-Boticaria (example 19b), melting point 268-271oC (decomposition) after recrystallization from CH2Cl2.

Can be examples of reception and other compounds of the formula I, in which Z represents any of the fragments described above in examples 1-7, and where R1represents hydrogen, methyl, ethyl, n-propyl, 2-butyl, dimethylaminopropyl, a methoxy group, ethoxypropan or isopropoxy, R2is hydrogen, 7-methyl, 6-(4-methyl-1-piperazinil), 6-(1-methyl-2-pyrrolyl), 6-dimethylaminopropyl, 5-nitrogroup, 6-nitro-group, 6-hydroxy-group, 7-hydroxy-group, 5-methoxy group, 7-metacarpo, 5,6-dimethoxypropane, 5,7-dimethoxypropane, 6,7-dimethoxypropane, 6-taksigrup is, 6[(2,3-propylenediene)-propoxy]group 6[2,3-dimethoxypropane] group, 6-[2-(2-methoxyethoxy)-ethoxy]group, 7-[2-(2-methoxyethoxy)ethoxy] group 7-carboxymethoxy, 6-ethoxycarbonylmethoxy, 6-(tert-butoxycarbonyl)methoxy group, 6-benzyloxycarbonyloxy, 7-(tert-butoxycarbonyl)methoxy group, 7-dimethylaminocarbonylmethyl, 6,7-methylenedioxy, 6-fluoro, 7-chloro, 6-(n-propyl)-7-methoxy group, 6-methyl-5,7-dimethoxypropane, 5-hydroxy-6-methoxy group or 6-dimethylamino-7-chloro.

As indicated above, the compounds of formula I inhibit the enzymatic activity proteoliticheskikh enzymes, and applicable to the treatment reborn diseases. More specifically, the compounds inhibit human leukocyte-elastase and chymotrypsinogen enzymes useful in the treatment of emphysema, rheumatoid arthritis, pancreatica, cystic degeneration, chronic bronchitis, respiratory distress syndrome of adults, inflammatory bowel disease, psoriasis, bullous of Desperados and deficiency of alpha-1-antitrypsin deficiency.

Determination of the inhibition constants (Kandset of inhibitor of human leukocyte-elastase described (Cha, Biochemical Pharmacology, T. 24, pp. 2177-2185, 1975) for itinerant truly reversible inhibitor complexes, but rather in some 28 degrees consumed by the enzyme. Therefore, instead of Kanddefine K*and, which is expressed as the degree of reactivation of the enzyme divided by the degree of deactivation of the enzyme (kd/kDeux).

Determine the values of kdand kDeuxthen calculate K*and.

The value of kDeuxdetermined by measuring the enzymatic activity of aliquots of the enzyme as a function of time after addition of the test compound (inhibitor). Plotting the Log of the enzymatic activity with respect to time are set to the observed degree of decontamination (knebaccording to the equation:

kneb= ln 2/t1/2,

where

t1/2the time required to reduce enzyme activity by 50%. Then calculate the kDeuxaccording to the equation: kDeux= kneb(I) where (I) the concentration of the inhibitor. Similarly determine the value of kdthen get the value of K*andaccording to the equation: K*and= kd/kDeux.

Are given in table. 4 the results obtained for compounds of formula I of examples.

Inhibition of the proteolytic enzyme, the amount of compounds of formula additionally, this number may vary depending on the physical condition of the patient, route of administration, duration of treatment and patient response. An effective dose of a compound of formula I, thus, can only be determined by the attending physician after consideration of all appropriate assessments of the best ways of treatment of the patient.

The compound of the formula I can be prepared for pharmaceutical use by introducing the compound in the pharmaceutical composition for oral, parenteral administration or administration in the form of aerosol inhalation. The composition may be solid or liquid dosage forms, including tablets, capsules, solutions, suspensions and emulsions, and may include one or more adjuvants. Recommended for solid dosage forms in the form of tablets or capsules for oral administration. Adjuvant for this purpose can be, for example: calcium carbonate, starch, lactose, talc, stearate magnet and gum acacia or their mixture. The compositions have a conventional pharmaceutical methods.

1. Derived saccharin of formula I

< / BR>
where R1is hydrogen or lower alkyl;

R2is hydrogen, lower alkoxygroup, hydroxyl, hydroxy(lower) alkoxygroup or phenyl(lower) alkoxycarbonyl(lower) alkoxygroup;

R3is hydrogen;
carbonyl, B = N, B = N-(lower alkyl, fenoxaprop, where B = N represents 1-piperidinyl or 4-morpholinyl;

Y is

-(CH2)m-, -(CH2)m-O-, -CHR-O-, -(CH2)m-N(R')-, -C(R')=C(R')-O-, -C(R')= C(R')-N(R')-, -C(=O)-C(R")=C(R")-, -C(Z')=C(Z')-, -C(Z')=C(Z')-O-, -C(Z')= C(Z')-S-, -C(Z')=C(Z')-N(R')-, -N(Z)-C(Z)=N - or-N=C(Z)-N(Z') -, where m = 1, 2, 3, or 4

R is identical or different and represent lower alkyl, phenyl or phenyl(lower)alkyl;

R' is H or R;

R" is H or R, or R"groups taken together with the carbon atoms to which they are attached, form farinograph;

Z' groups taken together with the carbon atoms to which they are attached, form anthropo;

Z groups taken together with the carbon atoms and the nitrogen to which they are attached, form a pyrido - pyrimidine-, pyridazino-, thiazolyl, piperazine derivatives or piperidinium where periodogram can be replaced by B=N-carbonyl or B=N-(lower)alkoxygroup, where B=N-pyrrolidinyl or 4-(lower) alkyl-1-piperazinil,

or its pharmaceutically acceptable salt, formed by the addition of acid, if the compound has a basic functional group, or its pharmaceutically acceptable salt, formed by adding the base, if the compound has an acidic functional group.B>)mN(R')-, -C(R')=C(R')-O-, -C(R')= C(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 - or-N=C(Z)-N(Z")-

where m = 1, 2, 3 or 4;

R is identical or different and represent lower alkyl, phenyl or phenyl(lower)alkyl;

R' is H or R, R" is H or R, or R" groups taken together with the carbon atoms to which they are attached, form farinograph;

Z' groups taken together with the carbon atoms to which they are attached, form anthropo;

Z groups taken together with the carbon atoms and the nitrogen to which they are attached, form a pyrido-, pyrimidine or pyridazinone where periodogram can be replaced by B=N-carbonyl or B=N-(lower) alkoxygroup, where B=N-pyrrolidinyl or 4-(lower)alkyl-1-piperazinil.

3. Connection on p. 2, where R1is lower alkyl, R2is hydrogen or lower alkoxygroup, R3is hydrogen, X is hydrogen, halogen, lower alkyl, phenyl, phenyl(lower) alkyl, phenylcarbamoyl, lower alkanoyl, B= N, B=N-(lower)alkyl or fenoxaprop, where B=N represents 1-piperidinyl or 4-morpholinyl.

4. Connection on p. 3, where R1is isopropyl, R2is hydrogen or 6-methoxy and X is hydrogen, chlorine, methyl, phenyl, phenylmethyl, phenylcarbinol, acetyl, 1-Piperi - hydrogen or a 6-methoxy group, R3is hydrogen, and the group

< / BR>
meets one of the following formulas:

< / BR>
< / BR>
< / BR>
6. The method of obtaining saccharin derivatives of the formula I on p. 1, characterized in that carry out the condensation of the corresponding compounds of formula II

< / BR>
where R1, R2, R3have the values listed in paragraph 1;

Q is chlorine or bromine,

with the appropriate compound of formula III

< / BR>
where X and Y have the values listed in paragraph 1,

in the presence of base or with a corresponding basic salt of the compounds of formula III.

7. The method according to p. 6, characterized in that Y represents a group of formula-C(=O)-C(R")=C(R")- R" group, taken with the carbon atoms to which they are attached, form pornograpy, and X represents a lower alkanoyl, and consisting in the oxidation of the corresponding 2-(4,7-dimethoxy-5-(lower) alkanolamine-6-yl) oxy R3-methyl-4-R1-5(6 and 7)-R2-saccharin salt of cerium (IV).

8. The pharmaceutical composition active ingitor proteolytic enzyme, comprising an effective amount of the active ingredient and pharmaceutically acceptable additives, wherein as the active ingredient Codecasa enzymes.

 

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