Derivatives of saccharin or their pharmaceutically acceptable additive salt of the acid or base, the pharmaceutical composition active elastase inhibitor

 

(57) Abstract:

The invention relates to the derivatives of saccharin General formula 1, where L denotes 0 or N; when L is 0, R1- 2,6-dichloro-3-[2-(4-morpholinyl)ethoxy] benzoyl, when L is N, then L together with R1represents a 4,5-di(tert-butylsulfonyl)-1,2,3-triazole-1-yl, R2primary or secondary alkyl of 2-4 carbon atoms, R3- lower alkoxy at any of the 5-, 6 - or 7-positions, or their pharmaceutically acceptable additive salts of acids or bases, which inhibit the activity of proteolytic enzymes. Also disclosed pharmaceutical composition based on compounds 1, active inhibitor of elastase. 2 S. and 2 C.p. f-crystals, 1 PL.

the

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

Inhibitors of proteolytic enzymes used in the treatment of such degenerative diseases as emphysema, rheumatoid arthritis, and pancreatitis, in which proteolysis is an essential element. The most is teasy characterized as chymotrypsinogen or lastsavedby on the basis of their specific substrate. Chymotrypsin and chymotrypsinogen enzymes usually break down the peptide bonds of the protein where the amino acid residue on the carbonyl side represents Trp, Tyr, Phe, Met, Leu or another amino acid that contains an aromatic or more alkyl side chain. Elastase and lastsavedby enzymes usually break down the peptide bond at the place, where the remainder of the amino acid on the carbonyl side of the link represents Ala, Val, Ser, Leu, or another small amino acid. And chymotrypsin-like and lastsavedby enzymes contained in the cells, the cells of the mammary glands and the secretions of the pancreas higher organisms and secreted by many types of bacteria, yeast and parasites.

Mulvey other U.S. patent N 4195023, describes methods of inhibiting elastase and treatment of emphysema using 4, 5, 6 - or 7-R1-2-R2CO-1,2-benzisothiazolinone-1,1-dioxide(4,5,6 or 7-R1-2-R2CO-saccharin), where R1- halogen, alkoxy, alkylamino, dialkylamino, alkoxycarbonyl, amino, nitro or especially hydrogen and R2is hydrogen, alkyl, alkenyl, quinil, cycloalkyl, halophenol, heteroaryl or substituted heteroaryl, for example, 2-(2-furoyl) saccharin, and their pharmaceutical compositions.

Chen, U.S. patent N 4263393, Addendum, how 12,2-[(p-perbenzoic)methyl] saccharin used in photographic elements, film and producing electrons for immobilization of compounds, which should take at least one electron before release is able to diffuse the dye or photographic reagent.

Jones and others , U.S. patent N 4276298, describes 2-R-1,2 - benzisothiazolinone-1,1-dioxides (2-R-saccharin), where R is phenyl or pyridyl, substituted 1-5 fluorine, nitro, except mononitro, when R is phenyl, trifluoromethyl, cyano, alkoxycarbonyl, alkylcarboxylic, carboxyla, carbamoyl, alkylsilane, alkylsulfonyl, N,N-dialkylamino, triptoreline, triptoreline, triftormetilfullerenov and triptoreline used in methods of inhibiting proteases, particularly elastase and treatment of emphysema, rheumatoid arthritis and other inflammatory diseases.

Reczek, etc. in U.S. patent N 4350752 describes 2- (heterocyclyl) sacharine, substituted or unsubstituted on heterocyclyl and some saccharine core, including, for example, the connection of 28.2-[(1 - ventilation-5-yl)thiomethyl] saccharin in the form of a blocked photographic reagents used in photographic elementov as inhibitors of proteolytic enzymes with structural formula

< / BR>
where

L represents-O-, -S-, -SO-, or-SO2-;

m and n are each independently 0 or 1;

R1halogen, lower alkanoyl, 1-oxo-phenalenyl, phenyl (or phenyl substituted by halogen, lower alkyl, lower alkoxy, nitro, amino, lower alkylamino or dialkylamino) or heterocyclyl selected from 1H-(5-tetrazolyl), 5-oxo-1-tetrazolyl, 5-thioxo-1-tetrazolyl (when R2as described below, is not phenylthio), pyrimidinyl, 2-benzo-casalilla, 2-benzothiazolyl, 2-phthalimide, 2-(1,3,4-thia-diazole), 5-(1,2,4-thiadiazolyl), 5-thioxo-3-(1,2,4-thiadiazolyl), 4-(5-oxo-1,3,4-thiadiazolyl), 4,5-dioxo-1,3-4-thiadiazolyl), 3-(1,2,4-triazolyl), 4-(1,2, 4-triazolyl), (1,2,3-triazolyl), 2-imidazolyl or 3-(1,2,4-triazolo-[4,3-a] pyridinyl), or from such heterocyclyl groups substituted on any available nitrogen atom by lower alkyl, hydroxy lower alkyl, cyclo-alkyl, 2-, 3 - or 4-pyridinyl, carboxy lower alkyl, lower alkoxycarbonyl lower alkyl, aminocarbonyl lower alkyl, lower alkylamino-carbonyl lower alkyl, di-lower alkylamino-carbonyl-lower-alkyl, amino-lower-alkyl, lower-alkylamino-lower alkyl, di-lower-alkylamino-lower-alkyl, 4-morpholinyl-lower-alkyl, 1-piperidinyl-lower-alkyl, 1-pyrrolidino, N-lower-alkyl-lower-alcanada, carboxy-lower-alcanada, carboxy, Carbo-lower-alkoxy, lower-alkoxy or halogen), or such heterocyclyl groups substituted on any available carbon atom, nitro, lower alkyl, amino, lower alkylamino, di-lower alkylamino, cyclooctylamine, mercapto, lower alkylthio, amino-lower-alkylthio, low-alkylamino-lowest-alkylthio, di-lower-alkylamino-lowest-alkylthio, 4-morpholinyl-lowest-alkylthio, 1-piperidinyl-lowest-alkylthio, 1-pyrrolidinyl-lowest - alkylthio, Carbo-lower alkoxy or phenyl (or phenyl, substituted amino, lower-alkyl-amino, di-lower-alkylamino, low-alcanada, N-lower-alkyl-lower-alcanada, lower alkyl, lower alkoxy or halogen).

R2is hydrogen, Carbo-lower-alkoxy, phenyl or phenylthio;

R3is hydrogen, halogen, primary or secondary lower alkyl, lower alkoxy, Carbo-lower-alkoxy, phenyl, fluoro-lower-alkyl, lower alkenyl or cyano;

R4is hydrogen or 1 to 2 substituent selected from halogen, cyano, nitro, amino, lower alcanada, phenyl-lower-alcanada, diphenyl-lower-alcanada, lower alkylsulfonate, polyflor-lowest-alkylsulfonamides, aminosulfonyl, lower and is of proximately, of formyl, aminomethyl, lower-alkyl-sulfonyl, polyhalo-lower-alkyl-sulfonyl, lower-alkyl-sulfonyl-amino-sulfonyl and lower-alkoxy-polnischer-alkylene; and CHR2group attached either to the heteroatom L-half, as described above, or a heteroatom R1-half, with reservations, that

(I) when m and n are 0, and R2, R3and R4all are hydrogens, R1may not be halogen;

(II) when m is 0, n-1, L-S, and R2, R3and R4- each is hydrogen, R1there can be 1-phenyl-1H-(5-tetrazolyl);

(III) when m is 0, n is 1, L is-O-or-S-, and R2, R3and R4all are hydrogens, R1may not be the lowest alkanoyl;

(IV) when m is 0, n-1, L-O, -S-, or-SO-, and R2, R3and R4are all hydrogens, or when m is 0, n-1, L-S, and R2and R4are hydrogens and R3is halogen, or when m is 0, n is 1, L is-SO - or-SO2-, R2- carbonize alkoxy, and R3and R4both hydrogen, R1cannot be phenyl or substituted phenyl.

In accordance with one aspect of the present invention features a compound having the structural formula

< / BR>
in which L represents O or N, when L ASN is UP> represents a 4,5-di(tert-butylsulfonyl)-1,2,3-triazole-1-yl,

R2primary or secondary alkyl of 2 to 4 carbon atoms,

R3- lower alkoxy at any of 5, 6 - or 7-positions, or their pharmaceutically acceptable additive salt of the acid, if the compound has a basic functional group, or their pharmaceutically acceptable additive salt of the base, if the compound has an acidic functional group.

The compounds of formula I inhibit the enzymatic activity of proteolytic enzymes and are used in the treatment of degenerative diseases.

In another aspect of the invention provides a method of obtaining the compounds of formula I, which comprises condensation of the corresponding compounds of structural formula II

< / BR>
where X is chlorine or bromine, with a corresponding compound of the formula: H-L'-R1in the presence of base or with a corresponding basic salt of the compound of the formula: H-L'-R1where L'Is N or O, to obtain the corresponding compound of formula I, where L Is N or O.

Another aspect of the invention provides a method of obtaining the compounds of formula I, which comprises condensation of the corresponding compounds of formula X-CH2-L'-R, where X is chlorine or or basic salt to obtain the compounds of formula I, where L Is N or O.

Another aspect of the invention encompasses a method of obtaining the compounds of formula I, where L is R1is substituted or unsubstituted 1,2,3-triazole-1-yl, comprising condensation of the corresponding compounds of formula II with an alkali metal azide, and then the process cycloaddition obtained 2-azidomethyl-4-R2-5,6 or 7-R3-saccharin with the corresponding substituted or unsubstituted acetylene.

In another aspect of the invention provides the use of compounds of formula I to obtain medicines for the treatment of patients with degenerative disease in case of need of such treatment.

Finally, the invention provides a pharmaceutical composition for treating degenerative diseases containing a compound of formula I in a pharmaceutical carrier, the concentration inhibiting the proteolytic activity of the enzyme.

Saccharin is 1,2-benzisothiazol-(2H)-3-one-1,1-dioxide, and the compounds of formula I, which are 2-(R1-L-CH2)-4-R2-(5,6 and/or 7)-R3-1,2-benzisothiazol-(2H)-3-one-1,1-dioxide, 2-(R1-L-CH2)-4-R2-(5,6 and/or 7)-R3-sacharine.

In the compounds of formulas I - IV "appropriate" or> When L-N, N together with R1is a N-heterocyclyl, i.e., N is part of the heterocyclic ring and the atom through which the heterocyclic ring is connected with the CH2. N-heterocyclyl is preferably monocyclic or bicyclic, substituted or unsubstituted, aromatic or hydroaromatic N-heterocyclyl, and preferably monocyclic, substituted, aromatic N-heterocyclyl, for example, 4,5-di(t-butylsulfonyl)-1,2, 3-triazole-1-yl.

When L Is O, the bond between L and R1is an ester or similar communication or broadcasting or etiopathology communication. If it is an ester or similar relationship, R1preferably an acyl, where acyl is lower alkanoyl or acyl amino acid or peptide or cycloalkylcarbonyl; monocyclic, bicyclic or tricyclic aryl-lower-alkanoyl, unsubstituted or substituted on alkanoyl hydroxy or lower alkoxy; monocyclic or bicyclic, substituted or unsubstituted, aromatic or hydroaromatic C-heterocalixarenes; monocyclic substituted or unsubstituted, aryloxy-2-lower-alkanoyl, or more preferably monotonicity substituted or unsubstituted, aroyl.

In conducting the process of obtaining the compounds of formula I from the corresponding compounds of formula II and the corresponding connection H-L'-R1or the corresponding compounds of formula III and the corresponding connection X-CH2-L'-R1in the presence of a base, the base can be any base that is not a reactant in this reaction, and preferably is a carbonate of an alkali metal, an alkoxide of an alkali metal, three or lowest alkylamino, lower alkoxide of thallium, 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 H-L'-R1or the compounds of formula III, which then reacts with the compound of the formula I, or X-CH2-L'-R1respectively. The main Sol H-L'-R1or the compounds of formula III can also be obtained separately and then be condensed with the compound of the formula II or X-CH2-L'-R1accordingly and preferably represents an alkali metal, especially cesium or tallic salt. The condensation is carried out in an organic solvent or mixture of organic solvents inert under the conditions of this reaction, for example, acetone, methylethylketone, ACE is Awale, lower alkanol or their mixtures in the temperature range from t environment to t the boiling point of the solvent or solvent mixture.

In obtaining the compounds of formula I, where L is R1substituted or unsubstituted 1,2,3-triazole-1-yl, azide of an alkali metal is preferably, Asit sodium. Condensation of the corresponding compounds of formula II with an alkali metal azide is carried out with heating or cooling, or without, preferably at room temperature, in an inert solvent, for example benzene, toluene or dimethylformamide, with the possible use of a crown ether such as 18-crown-6 ether. Cyclization of the obtained 2-azidomethyl-4-R2-5,6 or 7-R3- saccharin with the corresponding substituted or unsubstituted acetylene is carried out, preferably, in the same inert solvent with heating.

Compounds of formulas II, III, and formula (H-L-R1and X-CH2-L-R1known or obtained by known methods or by methods described below.

The compound of formula III can be obtained by diazotization of the corresponding lower alkyl 2-amino-3,4 or of ester 5-R3-6-R4-benzoate, chlorosulfonylisocyanate obtained from salts of 2-page low-Alki lower-alkyl 2-chlorosulfonyl-3,4 or of ester 5-R3-6-R4-benzoate of ammonia. Hydroxymethylpropane the compounds of formula III formaldehyde gives the corresponding hydroxy compound. Substitution of hydroxyl in the received connection chloride or bromide using, for example, thionyl chloride, tiniversity, trichloride phosphorus or tribromide phosphorus, gives the corresponding compound of formula II.

The compound of the formula II can also be obtained by phenyldimethylsilane the corresponding compounds of formula III or its underlying salt phenylcarbonylamino and substitution penalty in the resulting 2-phenylthiomethyl-4-R2-5,6 or 7-R3-saccharin chloride or bromide using, for example, Sulfuryl bromide or chloride.

The compound of formula II, where X is chlorine, can also be obtained in one step from the corresponding compounds of formula III chlorotoluene with paraformaldehyde and chlorotrimethylsilane in the presence of chloride of tin.

The compound of the formula III can also be obtained by otherovarian the corresponding 2-R2-3,4 or 5-R3-N, N-di-lower-alkyl-benzamide lower-alkyl-lithium, aminosulphonylphenyl obtained 2-R2-3,4 or 5-R3-6-litio-N,N-di-lower-alkylbenzene sulfur dioxide gas, and then hydro is 5-R3-6 - aminosulfonyl-N,N-di-lower-alkylbenzene in heated under reflux with acetic acid.

The compound of formula III in which R2primary or secondary alkyl of 2-4 carbon atoms, can be obtained by litrownik the corresponding 4-methyl-5,6 or 7-R3-saccharin two molar equivalents of a lower alkyl lithium in an inert solvent, e.g. tetrahydrofuran (THF) and obtained by alkylation of 4-Sociometer-5,6 or 7-R3-saccharin appropriate alkylhalides. Both reactions are conducted at temperatures in the range of -80 to -50oC. the Above 2-R2-3,4 or 5-R2-N,N-di-lower-alkylbenzene, in which R2primary or secondary alkyl of 2 to 4 carbon atoms, can be obtained in a similar sequence litrovaya-alkylation, starting from the corresponding 2-methyl, ethyl or propyl-3,4 or 5-R3-N,N-di-lower alkylbenzene.

The compound of formula III, where R2primary or secondary alkyl of 2 to 4 carbon atoms, can also be obtained by the introduction of R2earlier in the synthesis. Conjugate addition of a suitable R2-cuprate to 2-cyclohexenone and methoxycarbonylamino received enolate copper medicinetramadol Yes clay gives a mixture of the corresponding methyl ester 6-R2-2-benzylthio-1-cyclo-hexensabbat acid methyl ester 6-R2-2-benzyl-thio-3-cyclohexenecarboxylic acid, aromatization which dichlorodicyanoquinone gives the corresponding methyl ester 2-R2-6-sensitivetony acid. Oxidation-chlorination-dibenzylamine it with chlorine in aqueous acetic acid gives the methyl ester of 2-R2-6-chlorosulfonylbenzoic acid, cyclization with ammonia gives the corresponding 4-R2-saccharin of formula III.

Upon receipt of the compounds of formula I, where L is R1substituted or unsubstituted 1,2,3-triazole-1-yl, from the corresponding 2-azidomethyl-4-R2-5,6 or 7-R3-saccharin, condensation of the corresponding compounds of formula II with an alkali metal azide, preferably sodium azide, is carried out in an inert solvent, for example benzene or toluene, at 0 - 150oC. Without separation, the obtained 2-azidomethyl-4-R2-5,6 or 7-R3-saccharin undergoes cyclization with the corresponding substituted or unsubstituted acetylene in the same solvent at 0 - 150oC to obtain the compounds of formula I.

Pharmaceutically acceptable additive salt of the acid or base may be any pharmaceutically an prinaple, hydrochloric salt, or common cation, e.g. sodium or potassium, respectively. If the salt having a common anion or cation unacceptable because of its cristallinity or insufficient solubility or hygroscopicity, you can use salt with less common anion, for example, methanesulfonate, or less common cation, such as salt diethylamine. Anyway, as applied to mammals salt of the acid or basic accession should be non-toxic and should not interfere with the action of elastase inhibition in free base form or acid compounds of formula I.

pKk-values of the compounds of the formula H-L-R1known or can be determined using any of several known methods, for example, as described Adrien Albert and E. P. Serjeant, The Determination of Ionization Constans, A. Laboratory Manual, Third Edition, Chapman and Hall, London and New York, 1984) titration in water (chapters 2 and 3) or UV spectrometric determination in water (Chapter 4), or can be calculated from known or thus certain values of the pKkloved ones connections. CRC Handbook of Chemistry and Phisics (72nd Edition, CRC Press, Inc., Boca Raton Ann Arbor Boston, 1991, S. 8 - 39 8 - 40) gives the dissociation constants and the values of pK (pK< 1961) gives the dissociation constants 1056 organic acids.

In the processes of production and the examples described below, it is assumed that the structures of products of famous structures of starting materials and reactions. Purification or purity and confirmation of the structure of the starting materials and products were determined or measured by the temperature range of melting (D. p.), optical rotation, elemental analysis, infrared spectral analysis, ultraviolet spectral analysis, mass spectral analysis, NMR spectral analysis, gas chromatography, column chromatography, high performance liquid chromatography, liquid chromatography medium pressure and/or thin-layer chromatography (ie, x).

The following examples illustrate the invention, but in any case not be considered as limiting its scope.

Example 1. Obtaining the starting material 2-chloromethyl-4-isopropyl-6-methoxycoumarin [II; R2= i-Pr, R3= 6-MeO, X=Cl]

(a) 2 - aminosulfonyl 6-isopropyl-4-methoxy-N,N-diethyl - benzamide

To a solution of 300 ml of N, N, N', N'- tetramethylethylenediamine (1,99 mol) in 4 l of anhydrous ether was added 1550 ml of sec-BuLi (1.3 M) and the mixture was cooled to -70oC in nitrogen atmosphere. Dropwise within 30 min was added to the solution 454,2 g 2-isopr is alas at or below -60oC:. After the addition the mixture is stirred at -70oC for 1 h, vestibules until heated to -50oC, was maintained at -50oC for 30 min and then was cooled to -70oC. using kanulau tube was added a solution of 200 g of SO2in 200 ml of dry ether, cooled beforehand to -40oC under positive nitrogen pressure over a period of 20 minutes the Temperature of the reaction mixture during the addition was maintained below -40oC. a White powdery precipitate of sulfinate aryl-lithium stood out almost immediately.

After addition the cooling bath was removed and the mixture stirred at ambient temperature for 2 h, then was cooled to -5oC. With stirring dropwise within 15 min was added 190 ml of chloride Sulfuryl, the temperature during the addition was maintained below 10oC. After further stirring for 30 min at 0 - 5oC, white insoluble precipitate was filtered off and washed with 2 l of anhydrous ether. Removal of the solvent at atmospheric pressure gave the received sulphonylchloride (crude dark oil, which was dissolved in 1.4 l of THF. The solution was cooled to -10oC and it was added by portions in techer>C or below in the continuation of add. After 15 min stirring at ambient temperature THF and excess ammonia were removed under vacuum, which gave a dark oil, which was diluted to 6.0 water and Pocillos to pH 1 3NHCl. The obtained solid yellow were collected by filtration, were washed with 800 ml of water, dried at 60oC under vacuum for 18 h were precrystallization from a mixture of 800 ml of ethyl acetate and 3 l of hexane to yield 429,6 g (72%) 2-aminosulfonyl-6-isopropyl-4-methoxy-N,N-diethylbenzamide, so pl. 122 - 125oC.

(b) 4-isopropyl 6-methoxycoumarin

The solution 429,6 g diethylbenzamide (1,31 mol) in 1.5 l of acetic acid was heated under reflux for 20 h, then was cooled to room temperature. The solvent was removed under vacuum. The oily residue was dissolved in 6 l of water and the pH was brought to 1 with 6NHCl. The crude product was collected by filtration, were washed with 2 l of water, dried at 60oC in vacuum for 18 h and was precrystallizer from ethyl acetate/hexane to yield 303 g (91%) of 4-isopropyl-6-methoxycoumarin, so pl. 188oC.

(C) 2-chloromethyl-4-isopropyl-6-methoxycoumarin

To a suspension of 24 g of paraformaldehyde (0.8 mol) and 86.4 g of chlorotrimethylsilane (1.6 mol) in 200 ml of 1,2-dichloroethane is th solution was added 4-isopropyl-6-methoxycoumarin (51,4 g, 0.2 mol) and the mixture was heated under reflux for 18 h, cooled to room temperature and poured into water. The organic layer was separated, washed with 50 ml of 2N sodium hydroxide solution, dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was purified by crystallization from ethyl acetate/hexane to yield 57 g (87%) of 2-chloromethyl-4-isopropyl-6-methoxy-saccharin, so pl. 151oC.

Obtaining compounds of formula I

2-(4,5-di(t-butylsulfonyl)- 1,2,3-triazole-1-yl] methyl-4-isopropyl-6-methoxycoumarin

[I; R2= iPr, R3= 6-MeO, L-R1= 4,5-di(t-BuSO2-1,2,3-triazole-1-yl)]

A solution of 18-crown-6 ether (0,60 g) and benzene (60 ml) was heated under reflux with a water separator for 1 h, then was cooled to room temperature. Was added 2-chloromethyl-4-isopropyl-6-methoxycoumarin (3.03 g) and sodium azide (0.65 g) and the mixture stirred for 1 week at room temperature, then was chromatographically on silikagelevye column (silica gel 60, 83 g) using benzene as eluent. The fractions containing the product, a certain T. S. H., were combined and concentrated, giving 2-azidomethyl-4-isopropyl-6-methoxycoumarin in the form of a solution in benzene (250 ml).

oC, the output of both stages 26%) were precrystallization twice from ethyl acetate, giving 2-[4,5-di(t-butyl-sulfonyl)-1,2,3-triazole-1-yl] methyl-4-isopropyl-6-methoxy-saccharin in the form of a pale yellow elongated prisms (0.15 g, so pl. 207,5 - 209oC).

Titration in water values pKk1,2,3-triazole-4,5-dinitrile and dimethyl ether of 1,2,3-triazole-4,5-dicarboxylic acid were found as 1.6 and 4.4, respectively. Ultraviolet spectrophotometric determination in water is pKk1,2,3-triazole-4,5-dicarboxamide been found as of 5.3. By comparing these values pKkthe value of the pKk4,5-di(t-butylsulfonyl)-1,2,3-triazole was estimated equal to 2 or less.

Example 2.

2-{ 2, b-dichloro-3-[2-(4-morpholinoethoxy)] benzoyloxymethyl}-4-isopropyl-6-methoxycoumarin

[I; R2= iPr, R3= 6-MeO, L = O, R1oC for 1.5 h, cooled to room temperature and poured into water (400 ml). The precipitate was collected by filtration were washed with water (200 ml) and hexane (200 ml) and dried, yielding 2-{2,6-dichloro-3-[2-(4-morpholinoethoxy)] benzoyloxymethyl}-4-isopropyl-6-methoxycoumarin (6,1 g; theory, 5.50 g).

Such condensation of 2-chloromethyl-4-isopropyl-6-methoxycoumarin and 2,6-dichloro-3-[2-(4-morpholinoethoxy)] benzoic acid with potassium carbonate in N-organic at room temperature and recrystallization of the product from ethanol gave 2-{2,6-dichloro-3-[2-(4-morpholinoethoxy)]benzoyloxymethyl}-4-isopropyl-6-methoxycoumarin with the release of 69% (so pl. 146oC).

Saturated ethereal hydrogen chloride was added to a solution of 2-{2,6-dichloro-3-[2-(4-morpholinoethoxy)] benzoyloxymethyl} -4-isopropyl-6 - methoxycoumarin (4.6 g of the above-described first of its receipt) in ether-dichloromethane (9: 1, 100 ml). The precipitate was collected by filtration, rinsed with ether and cyclohexane and dried, yielding hydrochloric salt of 2-{2,6-dichloro-3-[2-(4-morpholinoethoxy)] benzoyloxymethyl}-4-isopropyl-6-methoxycoumarin (3,9 g, the output of both stages is giving pKk2,6-sodium dichloro-3-[2- (4-morpholinoethoxy)]benzoic acid estimated from 2 to 3.

Example 3.

2-(1-phenyltetrazol-5-yl)thiomethyl-4-isopropyl-6-methoxycoumarin

[I; R2= iPr, R3= 6-MeO, L = S, R1= 1 - phenyltetrazol-5-yl]

A mixture of 2-chloromethyl-4-isopropyl-6-methoxycoumarin (0.25 g) and sodium salt of 1-phenyltetrazol-5-linking with mottolino (0,173 g) in dimethylformamide (10 ml) was heated at 60 - 80oC 8 h, then was poured into ice water containing saturated aqueous sodium bicarbonate. The resulting mixture was extracted with ether. The ether extract was washed with water and saturated aqueous sodium chloride, was passed through silica gel and was freed from ether, yielding 2-(1 - phenyltetrazol-5-yl)thiomethyl-4-isopropyl-6-methoxycoumarin in the form of foam (0.3 g, 83%).

Ultraviolet spectrophotometric determination in water is pKk1-phenyltetrazol-5-thiol was defined as 2,9.

Example 4.

2-(1-phenyltetrazol-5-yl)sulfanilyl-4-isopropyl-6-methoxycoumarin

[I; R2= iPr, R3= 6-MeO, L = SO, R1= 1 - phenyltetrazol-5-yl]

Oxidation of 2-(1-phenyltetrazol-5-yl)thiomethyl-4-isopropyl-6-methoxycoumarin one molar equivalent of m-perbenzoic acid in an inert solvent gives terazol-5-yl)sulfanilyl-4-isopropyl-6-methoxycoumarin

[I; R2= iPr, R3= 6-MeO, L = SO2, R1= 1 - phenyltetrazol-5-yl]

Oxidation of 2-(1-phenyltetrazol-5-yl)sulfanilyl-4-isopropyl - 6-methoxycoumarin one molar equivalent of m-perbenzoic acid in an inert solvent gives 2-(1-phenyltetrazol-5-yl) sulfanilyl-4-isopropyl-6-methoxy-saccharin.

Example 6.

2-(4-phenyl-5-thiono-4,5-dihydrotetrazolo-1 - yl)methyl-4-isopropyl-6-methoxycoumarin

[I; R2= iPr, R3= 6-MeO, L-P1= -N-N=N-N (Ph)-C(=S)-, where the first N attached to C]

The condensation of the sodium salt of 4-isopropyl-6-methoxycoumarin with 2-chloromethyl-4-phenyl-5-thiono-4,5-dihydrotetrazolo in dimethylformamide with heating gives 2-(4-phenyl-5-thiono-4,5-dihydrotetrazolo-1-yl)methyl-4-isopropyl-6-methoxycoumarin.

Example 7.

2-acetoxymethyl-4-isopropyl-6-methoxycoumarin

[I; R2= ipr, R3= 6-MeO, L = O, R1= CH3CO]

The condensation of 4-isopropyl-6-methoxycoumarin with aqueous formaldehyde in ethanol gives 2-hydroxymethyl-4-isopropyl-6-methoxycoumarin, acetylation with acetic anhydride and a catalytic amount of sulfuric acid gives 2-acetoxymethyl-4-isopropyl-6-methoxycoumarin.

Additional examples of compounds of formula I were poliah variables R3, R2and L-R1.

Were obtained the compounds of formula I in which R2- ethyl, n-propyl, isopropyl, 2-butyl, dimethylamino, methoxy, ethoxy, and isopropoxy.

Were obtained the compounds of formula I in which R3is hydrogen, 7-methyl, 6-(4-methyl-1-piperazinil), 6-(1-methyl-2-pyrrolyl), 6-dimethylamino, 5-nitro, 6-nitro, 6-hydroxy, 7-hydroxy, 5-methoxy, 6-methoxy, 7-methoxy, 5,6-dimethoxy, 5,7-dimethoxy, 6,7-dimethoxy, 6-ethoxy, 6-isopropoxy, 6-cyclobutylamine, 6-[2-(4-morpholinyl)ethoxy], 6-[(2,3-dihydroxy)-propoxy], 6-[(2,3-propylenediene)propoxy] , 6-[2,3-dimethoxypropane] , 6-[2-(2-methoxyethoxy)ethoxy] , 7-[2-(2- methoxyethoxy)ethoxy], 7 carboxymethoxy, 6-ethoxycarbonylmethoxy, 6-(t-butoxycarbonyl) methoxy, 6-benzyloxycarbonyloxy, 7-(t - butoxycarbonyl)methoxy, 7-dimethylaminoethyl-hydroxy, 6,7 - methylenedioxy, 6 fluorescent, 7-chloro, 6-(n-propyl)-7-methoxy, 6-methyl-5,7-dimethoxy, 5-hydroxy-6-methoxy and 6-dimethylamino-7-chloro.

Were obtained the compounds of formula I, where L-N and N taken together with R1forms N-heterocyclyl, where N is heterocyclyl: 4,5-di(t-butylsulfonyl)-1,2,3-triazole-1-yl, 4-phenyl-5-thiono-4,5-dihydrotetrazolo-1-yl, 4-(3-pyridyl)-5-thiono-4,5-dihydrotetrazolo-1-yl, 1,1,3-triakistetrahedron-1,2,5-thiadiazole-2-yl, 4,5-di(methoxy) - Rev.,2,3-triazole-1-yl, 4-phenyl-5-etoxycarbonyl-1,2,3-triazole-1-yl, 4-etoxycarbonyl-5-phenyl-1,2,3-triazole-1-yl, 4-carboxy-1,2,3-triazole-1-yl, 4-(trimethylsilyl)-5-phenylsulfonyl-1,2,3-triazole-1-yl, 5-phenylsulfonyl-1,2,3-triazole-1-yl, 4-phenylsulfonyl-5-isopropyl-1,2,3-triazine-1-yl, 4-isopropyl-5-phenylsulfonyl-1,2,3-triazole-1-yl, 4,5-di(aminocarbonyl)-1,2,3-triazole-1-yl, 4,5-dicarboxy-1,2,3 - triazole-1-yl and salt monolatry, 4-trimethylsilyl-5-dimethylaminomethyl-1,2,3-triazole-1-yl, 2-thiono-2,3-dihydro-5-(2-pyridyl)-1,3,4-thiadiazole-3-yl, 4-(t-butyl)-5 - dimethylaminomethyl-1,2,3-triazole-1-yl, 4-dimethyl-aminosulfonyl-5-(t-butyl)-1,2,3-triazole-1-yl, 4-trimethylsilyl-1,2,3-triazole-1-yl, 4,5-dicyano-1,2,3-triazole-1-yl, 4,5-di(1-piperidinylcarbonyl)-1,2,3-triazole-1-yl, 4,5-di (trifluoromethyl)-1,2,3-triazole-1-yl, 4,5-di(1-piperidinylcarbonyl)-1,2,3-triazole-2-yl, 3-benzyloxy-4,5-dihydro-5-oxo-1,2, 4-oxadiazol-4-yl and 4,5-dicyano-1,2,3-triazole-2-yl.

There was obtained compound of formula I, where L Is O, and R1lowest alkanoyl, where the lowest alkanoyl - 2,2-dimethylpropanoyl.

There was obtained compound of formula I, where L Is O, and R1- acyl amino acid or peptide, where the acyl peptide - (N-benzoylglycine)- i.e. phenylalanyl.

There was obtained compound of formula I, where L Is O, and R1- cycloalkylcarbonyl where cycloalkylcarbonyl is, unsubstituted or substituted by hydroxy or lower alkoxy, where the substituted or unsubstituted aryl-lower-alkanoyl: 2 - methyl-2-phenylpropanol, 2-methyl-2-(4-chlorophenyl)propanol, 2-(2-chlorophenyl)propanol, 2-hydroxy-2-phenylacetyl, 2-methoxy-2-phenylacetyl or 2-hydroxy-2-phenyl-propanol.

Were obtained the compounds of formula I, where L Is Oh, and R1- monocyclic, substituted or unsubstituted, aromatic or hydroaromatic-heterocalixarenes, where C is heterocalixarenes : 3, 5-dichloropyridine-4-carbonyl, 3,5-dichloro-2-[2-(4-morpholinyl) ethoxy] pyridyl-4-carbonyl, 3,5-dichloro-2-[2-(dimethylamino)ethoxy] pyridyl-4-carbonyl, thiophene-3-carbonyl, 3-methylthiophene-2-carbonyl, thiophene-2-carbonyl, 3-chlorothiophene-2-carbonyl, 2-oxopyrrolidin-5-carbonyl, 3,5-dimethyl-isoxazol-4-carbonyl, 2,4-dimethylpyridin-3 - carbonyl and 1-phenyl-3,5-dimethylpyrazol-4-carbonyl.

There was obtained compound of formula I, where L Is Oh, and R1- substituted monocyclic aryloxy-2-lower alkanoyl, where aryloxy-2 - lower-alkanoyl: 2-methyl-2-(4-chlorphenoxy)propionyl.

There was obtained compound of formula I, where L is 0,and R1- bicyclic or tricyclic unsubstituted aroyl where aroyl: 2 - naphtol or 4-anthranol.

Were obtained soedineny or unsubstituted, aroyl: 2,6-dichloro-3-[2-(4-morpholinyl) ethoxy] benzoyl, benzoyl, 2,6-dichlorobenzoyl, 2, 6-dichloro-3-(4-morpholinylcarbonyl) benzoyl, 2,6-dichloro-3-(4-methyl-1-piperazinil sulfonyl)benzoyl, 2, 6-dichloro-3-(carboxymethylaminomethyl)benzoyl, 2,6-dichloro-3-[N-(4-isopropyl-2-sharonlee)-N-(benzyloxycarbonyl)aminosulfonyl benzoyl, 2,6-dichloro-3-(1-piperazinil sulfonyl)benzoyl, 2,6-dichloro-3-[N-(2-dimethylaminoethyl)-N-(methyl) aminosulfonyl benzoyl, 2,6-dichloro-3-hydroxybenzoyl, 2,6-dichloro-3-benzyloxybenzyl, 3-benzyloxybenzyl, 2,6-dichloro-3-(4-benzyl-1-piperazinylcarbonyl) benzoyl, 2, 6-dichloro-3-carboxy - methoxybenzyl, 2,6-dichloro-3-methoxybenzoyl, 2,6-dichloro-4-methoxybenzoyl, 2,6-dichloro-3-[2-(dimethylamino)ethoxy] benzoyl, 2,6-dichloro-3-[N-(3-dimethylaminopropyl)-N-(methyl) aminosulfonyl]benzoyl, 2,6-debtor-3-(4-methyl-1-piperazinylcarbonyl) benzoyl, 2,4,6-trichlorobenzoyl, 2,6-differentail, 2,6-dimethylbenzoyl, 2,4-dichlorobenzoyl, 2,6-dichloro-4-[2-(4-morpholinyl)-ethoxy]benzoyl, 2,6-dichloro-3-[2- (1-pyrrolidinyloxy] benzoyl, 2, 6-dichloro-3-[2-(1-piperidinyl)ethoxy] benzoyl, 2,6-dichloro-3-[2-(diethylamino)ethoxy]benzoyl, 2,6-debtor-4-methoxybenzyl, 2,6-dimethoxy-4-benzyloxybenzyl, 2,4,6-trimethoxybenzoyl, 2,6-dichloro-4-etoxycarbonyl-benzoyl, 2-isopropylphenol, 2,6-dimethoxy-4-acetylaminobenzoic, 2, 6-dimethyl-4-benzyloxybenzyl, 2,6-dime ethoxybenzoyl.

There was obtained compound of formula I, where L Is Oh, and R1- aryl-lower-alkylaminocarbonyl, where aryl-lower-alkylaminocarbonyl: phenylmethylaminopropanes.

There was obtained compound of formula I, where L Is Oh, and R1- (mono or di-lower-alkyl, phenyl or lower alkoxyphenyl) phosphinyl, where (mono or di-lower alkyl, phenyl or lower alkoxyphenyl) phosphinyl diphenylphosphinyl.

There was obtained compound of formula I, where L Is Oh, and R1- (mono or di-lower-alkyl, phenyl or phenyl-lower-alkyl) phosphono, where (mono or di-lower-alkyl, phenyl or phenyl-lower-alkyl) phosphono: diethylphosphino.

Were obtained the compounds of formula I, where L Is Oh, and R1-C-heterocyclyl, where C is heterocyclyl: 2-methyl-4-pyrone-3-yl, 6 - hydroxymethyl-4-pyrone-3-yl, 3,4-dichloropyridazin-2-yl, 3-anilkumar-7-yl, 4-anilkumar-7-yl, 6-chloro-4-Cryptor-methylcoumarin-7-yl, 4-methylcoumarin-7-yl, 3-(benzothiazol-2-yl) coumarin-7-yl, saccharin-6-yl, 4-(4-morpholinyl)-1,2,5-thiadiazole-3-yl, 5-phenyl-1,3,4-thiadiazole-2-yl, 5-phenyl-1,3,4-oxadiazol-2-yl, 3-methylthio-6-methyl-1,2,4 - triazine-5-yl, 4-ethoxycarbonylmethoxy-5-yl, 1,2,5-thiadiazole-3-yl, 2, 5-dioxopiperidin-1-yl, 2-methyl-4,5-di(hydroxymethyl)-3-pyridyl, 5-methoxycarbonylamino-3-yl and 1-methyl-2-ethoxycarbonylmethyl-3-yl.

Was and 3,4-dihydro-3-oxo-5-phenylpyrazol-4-imino.

There was obtained compound of formula I, where L Is Oh, and R1- tricyclic substituted aryl, where the tricyclic substituted aryl: 1-oxo-7-phenalenyl.

Were obtained the compounds of formula I, where L Is Oh, and R1- substituted monocyclic aryl, monocyclic where substituted aryl: 2.5-debtor-4-(4-morpholinylcarbonyl)phenyl, 2,4-dichloro-3-[2-(4-morpholinyl)etoxycarbonyl)]phenyl, 2,4-dichlorophenyl, 2,4,6-trichlorophenyl, 2,4-dichloro-3- (4-methylpiperazine)phenyl, 2,4-dichloro-3-carboxyphenyl, 3-[2-(4-morpholinyl)etoxycarbonyl)] phenyl, 3-(4 - methylpiperazine)phenyl, 2,4-dichloro-3-[2-(4-morpholinyl) ethylaminomethyl] phenyl, 4-(4-morpholinylcarbonyl)phenyl, 2,4-dichloro-6-(4-morpholinylcarbonyl)phenyl, 2-chloro-4-(4 - morpholinylcarbonyl)phenyl, 2-methoxycarbonyl-5-methoxyphenyl, 2-fluoro-4-(4-morphophysiology)phenyl, 2-chloro-4-(4 - tumorgenicity)phenyl, 2-chloro-4-(4,4-dioxy-4 - tumorgenicity)phenyl, 2,6-debtor-4-(4-morpholinylcarbonyl) phenyl, 2,4-debtor-6-(4-morpholinylcarbonyl)phenyl, 3,4-debtor-6-(4-morpholinylcarbonyl)phenyl, 2-(4-morpholinylcarbonyl)-4-forfinal, 4-[2-(4-morpholinyl)ethylaminomethyl] phenyl, pentafluorophenyl, 3-(4-metilprednisolone) phenyl, 3-(4-morpholinyl-ethoxy) phenyl, 3-[2-(dimethylamino ethyl)methylaminomethyl] phenyl, gidroksosoli-2-yl)phenyl, 3,5-debtor-4-(4-morpholinylcarbonyl)phenyl, 3,5-differenl, 2.5-debtor-4-(4-metilprednisolone)phenyl, 2,6-debtor-4-(4-metilprednisolone) phenyl, 3,5-debtor-4-(4 - morpholinylcarbonyl) phenyl, 2,6-dichloro-4-ethoxycarbonylphenyl, 1 - oxocyclopent-2-yl and 3,5,6-trimethylene-2-yl.

There was obtained compound of formula I, where L Is Oh, and R1- substituted monocyclic hydroaromatics 3-exacerbation-1-enyl, where 3-exacerbation-1-enyl; 2-methyl-3-oxo-1-cyclopentenyl.

There was obtained compound of formula I, where L Is O, and R1- substituted aromatic monocyclic 3-oxo-C-hetero-cycle-1-enyl, where 3-oxo-C-heterocycle-1-enyl: 6-methyl-1-pyrone-4-yl.

Were obtained the compounds of formula I, where L-S, and R1is cyano, benzoyl and toxicogenomic.

Were obtained the compounds of formula I, where L IS S, SO2or SO, and R1- substituted monocyclic aryl, monocyclic where substituted aryl: 2-fluoro-4-(4-morpholinylcarbonyl)phenyl.

Were obtained the compounds of formula I, where L-S, and R1- substituted monocyclic aromatic C-heterocycle, where the substituted monocyclic aromatic C-heterocycle; 1-phenyltetrazol-5-yl, 1-[2-(4-morpholinyl)ethyl]tetrazol-5-yl, 1-(dimethylaminocarbonylmethyl)diazol-2-yl, 1-(4-morpholinylmethyl)- tetrazol-5-yl, 5-[2-(4-morpholinyl)ethylthio] -1,3,4-thiadiazole-2-yl, 5-[2-(1-piperidinyl)ethylthio]-1,3,4-thiadiazole-2-yl, 5-(2-diethylaminoethyl)-1,3,4-thiadiazole-yl, 5-(2-di methylaminomethyl)-1,3,4-thiadiazole-yl, 5-[2-(4-morpholinyl)ethyl] -1,3,4-thiadiazole-2 - yl, 5-[2-(1-piperidinyl)ethyl]-1,3,4-thiadiazole-2-yl, 5-phenyl-1,3,4-oxadiazol-2-yl, 5-(2-furyl)-1,3,4-oxadiazol-2-yl, 1-(3-succinylamino)tetrazol-5-yl, 5-benzyl-1,3,4-oxadiazol-2-yl, 5 - hydroxy-6-methyl-6,7-dihydro-1H-1,2,4-triazolo[3,4-b] [1,3] thiazin-3-yl, 5-(3-pyridyl)-1,3,4-oxadiazol-2-yl, 1-methyl-5-ethoxy-1,3,4-triazole-2-yl, 5-(4-triptoreline)-1,3,4-oxadiazol-2-yl, 5-(4-methoxyphenyl)-1,3,4-oxalyl-2-yl, 5-(4-piridin)-1,3,4-oxadiazol-2-yl, 5-(4-biphenylyl)-1,3,4-oxadiazol-2-yl, 5-(2-pyrazinyl)-1,3,4-oxadiazol-2-yl, 4-(ethoxycarbonylmethyl) -thiazol-2-yl, 5-(2-pyridyl)-1,3,4-oxadiazol-2-yl, 5-(3-furyl)-1,3,4-oxadiazol-2-yl, 4-etoxycarbonyl-5-methylthiazole-2-yl, 4-phenylthiazol-2-yl, 4,5-dimethylthiazol-2-yl, 4-(4-morpholinyl)-1,2,5-thiadiazole-2-yl, 3-phenyl-2-thiono-2,3-dihydro-1,3,4-thiadiazole-5-yl, 4-methyl-5-oxo-6-hydroxy-4,5-dihydro-1,2,4-triazine-3-yl, 5-[4-(n-pentyloxy)phenyl]-1,3,4-oxadiazol-2-yl, 5-{4-[2-(2-methoxyethoxy)ethoxy] phenyl} -1,3,4-oxadiazol-2-yl, 5-(3,4-methylenedioxyphenyl)-1,3,4-oxadiazol-2-yl, 5-(2,5-acid)-1,3,4-oxadiazol-2-yl, 5-(2-methoxyphenyl)-1,3,4-oxadiazole proteolytic enzymes and are used in the treatment of degenerative diseases. More specifically, they inhibit the human leukocyte elastase and chymotrypsinogen enzymes and is used in the treatment of emphysema, rheumatoid arthritis, pancreatitis, cystic fibrosa, chronic bronchitis, respiratory diseases among adults, inflammatory bowel disease, psoriasis, bubble of pemphigoid and alpha-1-antitrypsin failure. Their use was demonstrated by testing in vitro inhibition of the compounds of formula 1 against human leukocyte elastase.

Measurement of the inhibition constants (Kandcomplex of inhibitor of human leukocyte elastase described (Cha, Biochemical Pharmacology, vol 24, S. 2177 - 2185, 1975) constants for reversible reversible inhibition relative to competing inhibitors. The compounds of formula I do not quite form complexes reversible inhibitor, but is consumed by the enzyme to some extent. Therefore, instead of such quantities were determined K*and, which was defined as the rate of reactivation of the enzyme divided by the rate of inactivation of the enzyme (Koff/on). Measured values of Koff and Kon, and then calculated the K*and.

The value of Kon was determined by measuring the enzyme activity of aliquots of the enzyme armenta and depending on the time using the equation KOBS.= 1n2/t1/2was obtained the observed rate of inactivation (KOBS.), the equation t1/2the time required to reduce the activity of the enzyme by 50%. Was then the obtained value of Kon using equation Kon = KOBS./[1] where [1] is the concentration of the inhibitor. Likewise determined the value of Koff, and then using equation K*and= Koff/Kon was obtained K*and.

The results shown in the table were obtained for compounds of formula I of examples 1 to 3.

Table. Inhibition of human leukocyte elastase

The compound of formula I Example - K*and(NM)

1 - 0,024

2 - 0,014

3 - 0,27

Other examples of compounds of formula 1 have K*andvalues in the range from 1000 M to 0.01 M. the Inhibitory amount of a proteolytic enzyme, the compounds of formula I can be determined from the test results of the inhibition of human leukocyte elastase and additionally change for a particular patient depending on his physical condition, type of destination, duration of treatment and the response of the patient. Therefore, an effective dose of a compound of the formula I can be determined only by a physician taking into account all criteria and Riem him in the pharmaceutical composition for oral, parenteral or aerosol application for inhalation. This can be in solid or liquid dosing form, including tablets, capsules, solutions, suspensions and emulsions, which may contain one or more fillers. Preferred solid dosage in the form of tablets or capsules for oral purposes. For this purpose, the filler can be one or more of the following substances: calcium carbonate, starch, lactose, talc, magnesium stearate and the Arabian gum. Compositions are prepared with conventional pharmaceutical technology.

The following are examples of pharmaceutical compositions.

Example 8. Tablets are a common example)

Ingredients - % in/in

Connection examples 1-7 - 32 - 62

Disintegrity agent - 28 - 36

The binding agent is 10 - 20

Lubricating agent is 0.1 - 0.5

Other expediency - 2 - 5

Note; as disintegrator use different starch as a binding agent - various cellulose, as a lubricating agent is talc, silica and magnesium stearate.

Example 9. (Pill)

Ingredients mg/tablet

Connection example 1 - 150

Monohydrate lactose - 100

Hydroxypropylcellulose - 50

Polyvinylidene 3 - 140

The rest of the ingredients as in example 9b

1. Derivatives of saccharin of formula I

< / BR>
where L Is O or N, when L is O, R1means 2,6-dichloro-3-[2-(4-morpholinyl)ethoxy]benzoyl, when L is N, then L together with R1represents a 4,5-di(tert-butylsulfonyl)-1,2,3-triazole-1-yl,

R2primary or secondary alkyl of 2 to 4 carbon atoms;

R3- lower alkoxy at any of the 5-, 6 - or 7-positions,

or their pharmaceutically acceptable additive salt of the acid, if the compound has a basic functional group, or their pharmaceutically acceptable additive salt of the base, if the compound has an acidic functional group.

2. Derived under item 1, where R2is isopropyl, and R3- lower alkoxy.

3. Derived under item 1, where R3- 6-methoxy.

4. The pharmaceutical composition active elastase inhibitor comprising an effective amount of the active ingredient is a derivative of the saccharide and pharmaceutically acceptable additives, wherein the active ingredient contains a compound of the formula I on p. 1.

 

Same patents:

The invention relates to branched amino-thiazole, methods for their preparation and the pharmaceutical compositions

The invention relates to the chemistry of heterocyclic compounds exhibiting inhibitory activity against elastase

The invention relates to racemic mixtures and (S)-4-[(2-benzothiazolyl)methylamino]--[(3,4-differience)methyl]-1-piperazineethanol, which can be represented by formula

< / BR>
and its pharmaceutically acceptable acid additive salts (salts of acid incorporation)

The invention relates to new derivatives of sulfamethoxypyrazine and herbicides containing them as active ingredients

The invention relates to new benzothiophen-2-carboxamide-S,S-dioxides having valuable properties, in particular to derive benzothiophen-2-carboxamide - S,S-dioxide of the General formula I

< / BR>
where

R1unbranched or branched alkyl with 1 to 20 carbon atoms, unbranched or branched halogenated, cianelli, oxyalkyl, alkoxyalkyl or alkoxycarbonyl with 1 to 8 carbon atoms in each alkyl part, unbranched or branched alkenyl with 2 to 12 carbon atoms, unbranched or branched quinil with 2 to 12 carbon atoms or unsubstituted or once to six times substituted by alkyl cyclohexyl or cyclohexylmethyl, unsubstituted or once to fivefold substituted in the phenyl part of the same or different substituents phenyl, phenylalkyl or phenylalkyl with 1 to 12 carbon atoms in each unbranched or branched alkyl or alkenylphenol part, moreover, as substituents of the phenyl can be called a halogen atom, hydroxyl, cyano, formylamino, unbranched or branched alkyl, alkoxygroup with 1 to 4 carbon atoms, unbranched or branched girsvetlana or branched, dialkylamino, alkylsulphonyl, alkylcarboxylic, alkoxycarbonyl, aminocarbonyl, N-alkylaminocarbonyl, N,N-dialkylaminoalkyl, formylamino, alifornian;

R2a hydrogen atom or an unbranched or branched alkyl with 1 to 18 carbon atoms, unsubstituted or singly or multiply substituted by identical or different substituents from the group comprising hydroxyl group, a halogen atom, a cyano;

R1and R2together with the nitrogen atom to which they relate, signify unsubstituted or singly or multiply substituted, saturated five - to semicolony a heterocycle, which may contain in addition to the nitrogen atom, an oxygen atom and a Deputy may be alkoxycarbonyl with 1 to 4 carbon atoms;

R3, R4, R5and R6independently from each other mean a hydrogen atom, halogen atom, alkoxygroup with 1 to 6 carbon atoms

The invention relates to optically active derivative of carboxamides with a strong analgezirutuyu activity and low toxicity, or their pharmacologically suitable salts

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The invention relates to novel condensed heterocyclic compounds or their salts

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