2-sharonlee(aryl or aryloxy) acetates, or their salts formed by addition of acids to these compounds, the main character, or their salts, formed by adding bases to these compounds acidic character, and a pharmaceutical composition inhibiting the activity of proteolytic enzymes

 

(57) Abstract:

Usage: in the chemistry of heterocyclic compounds, inhibiting the activity of proteolytic enzymes. The inventive Product: 2-sharonlee/aryl or aryloxy/acetates of formula I listed in the description, where m = 0 or 1, n = 0 or 1 and the sum of m + n = 0 or 1, R1-H or lower alkyl; R2-H or lower alkyl; R3is phenyl or phenyl substituted 1 to 3 same or different halogen; R4-H, lower alkyl or lower alkoxy, R5-H or 1 - 2 substituent in any of the 5-, 6 - or 7-position selected from lower alkyl, lower alkoxy, hydroxy/lower/alkyl, hydroxy/lower/alkoxy, or their salts, and pharmaceutical composition on the basis of these compounds, inhibiting the activity of proteolytic enzymes. 2 S. and 11 C.p. f-crystals, 12 tab.

The invention relates to new 2-saharinen-methyl(aryl or aryloxy)acetates, inhibiting the enzymatic activity of proteolytic enzymes, containing compositions, to a method of their use for the treatment reborn diseases and the way they are received.

Inhibition of proteolytic enzymes, non-toxic reagents applicable to the treatment reborn bre is Z. The protease inhibitors are widely used in biochemical research. Serine proteases are the most widespread class of proteolytic enzymes. Some serine proteases are characterized as chymotrypsinogen or anastasopoulou depending on the specificity of their substrate.

Chymotrypsin and chymotrypsinogen enzymes usually break down the peptide bonds in proteins by site, in which amino acid residue from carboxyl usually presents Trp, Tyr, Phe, Met, Leu, or other amino acid residue containing the aromatics or large alkyl side chains. Elastase or anastasopoulou enzymes usually you unhook the peptide bond at the site where the amino acid residue side carboxyl, usually represented by Ala, Val, Ser, Leu, or other similar amino acid of small size. As chymotrypsinogen and anastasopoulos enzymes are found in leukocytes, mast cells and pancreatic fluid of higher organisms and are secreted by bacteria, yeasts and parasites of many types.

In patent publication Japan 72/00419 revealed a number of 2-RZ-methylcholine, which, as indicated, are characterized by strong activity in relation to the result of bacterial diseases, where RZ is lower alkoxygroup, butoxyethoxy, ethylthioethyl, di(lower alkyl)aminoethoxy, ethylthiourea, 2-chlorethoxyfos, 1-(2-propenyl)oxygraph, 1-(2-PROPYNYL)oxygraph, 2-sharinaletisha, fenoxaprop (or fenoxaprop substituted by chlorine, stands, nitro - or methylthioribose), phenylthiourea, chlorophenylthio, menzilcioglu (or chlorobenzylthio), acetochlor, dichloracetate, benzoyloxy (or benzoyloxy substituted by chlorine or nitro-group), acetylthiourea, dichloroacetylene, chlorobenzothiazole, methyl - or ethylcarboxylate, dimethylcarbamoyl, phenylcarbamoyloxy, acylcarnitine, phenylcarbonylamino, dimethylcarbamoyl, editiontype, ethoxycarbonylethyl, toxiciology and ethylthioxanthone.

In the work Sunkel and other J. Med. Shem. 31, 1886 1890 (1988) described a number of 2-saharinen(lower)alkyl-1-dihydropyridine-3-carboxylates having inhibiting platelet aggregation activity, and antithrombotic activity.

In U.S. patent 4263393 (Chen) discloses various 2-roulettecasino applicable as photographic elements, laid down the de R1represents halogen, alkoxygroup, alkylamino, dialkylamino, alkoxycarbonyl, an amino group, a nitro-group or hydrogen benzenoids cycle and R2represents hydrogen, alkyl, alkenyl, quinil, cycloalkyl, haloethanol, heteroaryl or substituted heteroaryl, and R1-2-A-CO-charity, where R1accepts the same values as the substituents in BENZENOID cycle 1,2-benzisothiazol-3-ones and a represents alkyl, alkenyl, quinil, cycloalkyl, forfinal, heteroaryl or substituted heteroaryl. Indicated that the compounds have activity in inhibiting elastase and applicable for the treatment of emphysema.

In the work of Zimmerman and others J. Biol. Chem. 255 (20), 9848-9851 (1980) describes N-acyl-sacharine, where acyl is represented by purola, tenolol, benzoyl, cyclopropanol, ethylbutyryl and acryloyl with activity inhibition of series-protease.

In the work Chiyomaru and other Chemical Abstracts 81, 22249, described 4-were-2-shorinjiryukata, which, as indicated, bactericidal and fungicidal activity.

It is known that some connection types are inhibitors of the serine protease. For example, in U.S. patent 4659855 (Powers) discloses derivatives of arylsulfonate, primenen and 4623645 (Doherty and others) are disclosed respectively sulfones and sulfoxidov of cyclosporine, which, as indicated, powerful inhibitors of elastase, applicable for the treatment of inflammatory conditions, especially arthritis and emphysema.

In the work Teshima and other J. Biol. Chem. 257(9), 5085-5091 (1982) the results of studies serine-proteases (human leukocytosis, porcine pancreatic elastase, cathepsin G, and bovine chymotrypsin Aandin the presence of 4-Mitrofanovich esters and thioesters of N-crittercontrol.com, 2-substituted 4H-3,1-benzoxazin-4-ones, 2-substituted 4-hinazolinam and 2-substituted 4-chlorination.

In the work of the Cha, Biochem. Pharmacol. 24, 2177-2185 (1975) discusses the kinetic approach to radiation binding inhibitors with macromolecules, such as enzymes, and methods for determining parameters such as the inhibition constants, speed of reaction and the concentration of bound and unbound enzyme.

In U.S. patent 4276298 (Jones and others) disclosed are 2-R-1,2-benzisothiazolinone-1,1-dioxides, where R is phenyl, substituted by fluorine, dinitropropane, trifluoromethyl, cyan, alkoxycarbonyl, alkylcarboxylic, carboxyla, carbamoyl, alkylsilanes, alkylsulfonyl, N,N-dialkylamino, cryptomaterial, cryptomaterial, triftormetilfullerenov and triform can also be replaced by manontroppo. Indicates that the compounds possess inhibitory activity against the enzymes are proteases, in particular activity by inhibition of elastase, and can be used to treat emphysema, rheumatoid arthritis and other inflammatory diseases.

In the work of Powers and other Biochem. 24, 2048-2058 (1985) described a study of the inhibition of four chymotrypsinogen enzymes, cathepsin G protease I and II mast cells rat chymase human skin and chymotrypsin ANDaN-forolaherencia and N-(2,4-dicyanovinyl)saccharin.

In the work of Svoboda and other Coll. Czech. Chem. Commun, 51, 1133-1139 (1986) describes the obtaining of 4-hydroxy-2H-1,2-benzothiazin-3-carboxylates intramolecular condensation Beckmann esters 2H-1,2-benzisothiazol-3-one-2-acetate-1,1-dioxide.

In U.S. patent 435072 and 4363865 (Reczek and others) and U.S. patent 4410618 (Vanmeter and other) related to the reagents for pictures (Reczek 4350752 and Vanmete and others ) and pigments for pictures (Reczek 4363865), discloses various 2-substituted sacharine applicable in these areas, for example, reagents for pictures that are related through the heteroatom with iminomethylene blocking group (Reczek 4350752), diffusing through the media pigments for pictures related to the nitrogen atom of Amida through 1,1-alkylene the surrounding remnant organic reagent for pictures, containing a heteroatom through which the reagent is associated with a blocking group (Vanmeter).

In U.S. patent 3314960 (Freed and others) disclosed are 2-(1,1,3-trioxo-1,2-benzisothiazol-2-yl)glutarimide, which, as indicated, applicable as sedatives.

In French patent 1451417 disclosed 2-chlorotriazine as an intermediate product for the synthesis of N-metalshark-d,1-transliterate used as an insecticide, and in U.S. patent 3002884 (Lo) disclosed are 2-chloro-, 2-bromo - and 2-iodotoluene applicable as fungicidal funds.

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

The present invention relates to 4-R4-R5-2-chainmail(aryl, aryloxy) acetates and 4,5,6,7-tetrahydro-2-sharonlee (aryl, aryloxy) acetates having inhibitory activity against proteolytic enzymes and applicable to the treatment reborn diseases.

In addition, the invention relates to compositions for the treatment reborn diseases, containing a pharmaceutical carrier and an effective inhibition of the proteolytic enzyme colic or aryloxy)acetate.

The invention also relates to a method of applying the above 2-scapinelli(aryl, aryloxy)acetates in the treatment reborn diseases, which consists in the introduction in need of such treatment a patient medication containing an effective inhibition of the proteolytic enzyme number 4-R4-R5-2-sharonlee(aryl or aryloxy)acetate or 4,5,6,7-tetrahydro-2-sharonlee(aryl or aryloxy)-acetate.

The invention relates also to method of obtaining the above 4-R4-R5-2-sharonlee(aryl, aryloxy)acetates and 4,5,6,7-tetrahydro-2-sharonlee(aryl, aryloxy) acetates, which consists in the reaction of 2-peloidoterapija with aryl - or aryloxyalkanoic acid in the presence of an acid acceptor.

More specifically, the invention relates to 4-R4-R5-2-sharonlee (aryl, aryloxy)acetates of the formula:

< / BR>
where m is either zero or one, n is zero or one and the sum of m+n is zero or one;

R1hydrogen or lower alkyl;

R2hydrogen or lower alkyl;

R3represents phenyl or phenyl substituted with one to three same or different members of the group which includes lower alkyl, PERFLUORO(lower)alkyl, lower alkoxide)alkyl, lower alkenyl, lower quinil, cyan, carboxamido, the amino group, the lower alkyl, the amino group, di(lower alkyl)amino group, a lower alkoxygroup, benzyloxy, lower alkoxycarbonyl, hydroxyl or phenyl; and

R5represents hydrogen or one or two substituent in any of the 5-, 6 - or 7-position selected from halogen, cyanide, nitro, N=B, (lower alkyl)-2-pyrrolyl, low alkylsulfonamides, polyflor(lower alkyl)sulfonylamino, polychlor(lower alkyl)sulfonylamino, aminosulfonyl, lower alkyl, polyflor(lower)alkyl, polychlor(lower)alkyl, cycloalkyl, low alkoxygroup, hydroxyl, carboxyl, carboxamido, hydroxy(lower)alkyl, methylenedioxy, cycloalkylcarbonyl, formyl, aminomethyl, polyflor(lower alkyl)sulfonyl, polychlor(lower alkyl)sulfonyl, (lower alkyl)sulfonylmethane, (lower alkoxygroup)carbonyl(lower alkyl)amino, (lower alkyl)carbylamine, di(lower alkyl)phosphoroscope, (lower alkoxygroup)poly(lower alkylene)actigraphy, hydroxy(lower)alkoxygroup, polyhydroxyalkanoate or her Catala or acetal, polyalkoxyalkyl, SR, SOR, SO2R, -OCOR, -O-(C1-C105represents 5 - or 6-teleny saturated cycle condensed in positions 5, 6 or 6, 7 - cycle saccharin, and this cycle contains two heteroatoms selected from the group comprising nitrogen, oxygen and sulfur or a methylated derivative of this loop;

or educated by the addition of acid salts of these compounds, the main character, or formed by the addition of bases, the salts of these compounds are acidic in nature.

Recommended for those compounds of the above formula I, in which:

R4represents hydrogen, halogen, lower alkyl or lower alkoxygroup and R5represents hydrogen, lower alkoxygroup, methylendioxy, cycloalkylation, hydroxy(lower)alkoxygroup, polyhydroxyalkane or her ketal or acetal, polyalkoxyalkyl, -O-(in the above formula I, where:

R1hydrogen or methyl;

R2hydrogen or methyl;

R3phenyl or phenyl substituted by chlorine;

R4hydrogen or lower alkyl; and

R5hydrogen, lower alkoxygroup or polyalkoxyalkyl.

If n is 0 and m is 0, then R4preferably hydrogen or lower alkyl, most preferably hydrogen or isopropyl, R5hydrogen, lower alkoxygroup, polyalkoxyalkyl, most preferably hydrogen, R1methyl, R2methyl and R3phenyl.

If n is 0 and m 1, then R4preferably hydrogen or lower alkyl, most preferably isopropyl, R5hydrogen, lower alkoxygroup or polyalkoxyalkyl, most preferably hydrogen or methoxy group, R1hydrogen or methyl, R2hydrogen or methyl and R3phenyl.

If n is 1 and m is 0, then R4preferably hydrogen or lower alkyl, most preferably hydrogen or isopropyl, R5hydrogen, lower alkoxygroup or polyalkoxyalkyl, preferably hydrogen, R1methyl, R2methyl, R3phenyl or phenyl substituted by chlorine.

The invention relates to 4,5,6,7-tetrahydro-2-CA>hydrogen or primary lower alkyl, or R4aand R6together form spirocyclopropane; R7hydrogen or lower alkoxygroup, m, n, R1, R2and R3take the values specified for formula I.

Tetrahydrofuran may include a 4.7-Allenby bridge, due to which the invention relates also to compounds of the formula:

< / BR>
where A represents A methylene, ethylene or dimethylmethylene, m, n, R1, R2and R3take the values specified for formula I.

You must specify that the connection meets the General structural formula I, in the chemical literature usually referred to as 1,2-benzisothiazol-3 (2H)-one-1,1-dioxides. However, for short connections, often referred to as derivatives of saccharin and this nomenclature will be used below in the description of the compounds of the invention and their biological properties.

As used here, the value of the terms lower alkyl, lower alkoxygroup and lower alkane indicated monovalent aliphatic radicals, including those radicals branched chain of one to ten carbon atoms. So lower alkyl (or lower alkanoyl) a fragment of such groups include, for example, methyl, et is Teal, n-hexyl, 1-methylpentyl, 3-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 2-hexyl, 3-hexyl, 1,1,3,3-TETRAMETHYLBUTYL, 1,1-dimethyloctyl etc.

As used here, the value of the term C1-C10-alkylen refers to divalent saturated radicals, including those radicals, isotrate with one to ten carbon atoms with free valences on the same or different carbon atoms, including, therefore, the methylene, 1,2-ethylene, ethylidene, 1,3-propylene, propylidene etc.

As used here, the value of the term (lower alkoxygroup)poly(lower)accelerograph denotes such radicals in which the lowest alkoxygroup accepts the above values, poly means 2 4 and the lower alkylen in the lower alkilinity means a divalent saturated radicals, including those radicals, isotrate with two to five carbon atoms. Thus, the term covered by the radicals of formula: CH3(OCH2CH2)p-O-CH3CH2[OCH2CH(CH3)]p-O-, where p 2 4 etc.

As used here, the value of the term hydroxy(lower)alkoxygroup means lower alkoxygroup according to the definition above, substituted by hydroxyl, but not at the carbon atom C-1, so the group refers to a group, in which alkoxides presents monovalent aliphatic radical with two to five carbon atoms, substituted with two to four hydroxyl, none of which is attached to the same or the C-1 carbon atom, including, thus, 2,3-dihydroxypropyl, 2,3,4,5-tetrahydroxypregna etc.

As used here, the value of the term polyalkoxyalkyl refers to monovalent aliphatic alkoxylation with three to five carbon atoms, substituted with two to four methoxy - or ethoxypropane, none of which are attached to the same or the C-1 carbon atom.

As used here, the value of the term halogen or halogen means fluorine, chlorine, bromine and iodine.

As used here, the meaning of terms of lower alkenyl and lower quinil means a monovalent unsaturated radicals, including those radicals, isotrate with two to ten carbon atoms, and include 1-ethynyl, 1-(2 propenyl), 1-(2-butenyl), 1-(1-methyl-2-propenyl), 1-(4-methyl-2-pentenyl), 4,4,6 - trimethyl-2-heptenyl, 1-ethinyl, 1-(2-PROPYNYL), 1-(2-butynyl), 1-(1-methyl-2 - PROPYNYL), 1-(4-methyl-2-pentenyl), etc.

As used here, the value of the term C2-C10-alkylen means divalent natami on different carbon atoms and include 1,2-ethylene, 1,3-propylene, 1,4-butylene, 1-methyl-1,2-ethylene, 1,8-octile etc.

As used here, the value of the term cycloalkyl means a saturated monocyclic hydrocarbon, C3-C7-balance and includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Compounds of the invention inhibit the activity of serine proteases, in particular, human leukocytes and chymotrypsinogen enzymes, therefore suitable for the treatment of symptoms reborn diseases such as emphysema, rheumatoid arthritis, pancreatic, cystic degeneration, chronic bronchitis, respiratory distress syndrome of adults, inflammatory bowel disease, bullous drug of dyskeratosis and alpha-1-antitrypsin failure.

The compounds of formula I and the compounds of formula VI can be obtained by the reaction of 2-peloidoterapija or 2-kaleidotile-4,5,6,7-tetrahydrofuran with the appropriate aryl - or aryloxyalkanoic acid in the presence of acid acceptors, such as carbonate of an alkali metal or three(lower alkyl)amine. Or alkali metal salt, especially a salt of cesium aryl - or aryloxyalkanoic acid (obtained by reaction of the acid with the carbonate of the alkaline the functions in the presence of tetrabutylammonium (TBAB). The reaction can be carried out in an inert organic solvent, such as xylene, acetonitrile, methylene chloride (methylenchlorid YFC), N-methyl-2-pyrrolidinone or dimethylformamide (DMF) in the temperature interval from room temperature to the boiling point of the employed solvent. The reaction is illustrated in scheme A, where X is chlorine, bromine or iodine.

Required to obtain compounds of the formula I 4-R4-R5-2-haloalkaline can be synthesized by the methods described in the works: D Alelio and other J. Macromol, Sci-Chem. A3(5), 941 (1969) and Saari, etc. J. Het. Chem. 23, 1253 (1986), according to scheme B, where Alk is a lower alkyl.

According to the method described Saari, conventional methods of substituted Anthranilic acids get the ether, which is then diazotised. Sol, page introduced into reaction with sulfur dioxide and chloride of copper (II) with the formation of sulphonylchloride, by reaction with concentrated ammonium hydroxide receive substituted derivatives of saccharin of formula II. The last in the reaction with formaldehyde in the lower alkanol as solvent gives 4-R4-R5-2-hydroxymitragynine formula III, which in reaction with toniguy.com or trihalogen phosphorus form the corresponding derivatives of the crystals IV, where R4, R5and X agree to the above values, can also be obtained by reaction of the corresponding 4-R4-R5-2-phenyldimethylsilane with sulfurylation in an inert organic solvent, such as methylenechloride (YFC), ethylene dichloride (ejh) or carbon tetrachloride at a temperature of 0 30oC. 4-R4-R5-2-phenyldimethylsilane, in turn, is obtained by reaction of 4-R5-R5-saccharin of formula II with peloidodistillatum in an inert organic solvent such as toluene, xylene, DMF and YFC, in the temperature interval from room temperature to the boiling point of the employed solvent. The reaction can be carried out by the interaction of haloelitesrule or tallic salt derived saccharin of formula II is obtained by reaction of a derivative of saccharin with a lower alkoxide of thallium in the lower alkanol), or di(lower alkyl)ammonium salt derived saccharin (receipt see below) in the presence of Tetra(lower alkyl)ammoniated, such as tetrabutylammonium (hereinafter TBAB) or saccharin derivative of formula II as such in the presence of Tetra(lower alkyl)ammoniated or saccharin derivative of formula II as taxed potassium.

Sacharine formula can also be in one stage turned into chlorotriazine formula IV (X Cl) reaction of an excess of formaldehyde or equivalent of formaldehyde, such as paraform and 1,3,5-trioxane and CHLOROSILANES, preferably of chlorotrimethylsilane in the presence of a Lewis acid, preferably catalytic amounts of tin chloride (IV) in an inert solvent, preferably 1,2-dichloroethane (ethylene dichloride ejh).

It is obvious that all the transformations sharenow formula II 2-chlorotriazine formula IV are equally applicable for the conversion tetrahydrocanabinol formula VII in a 2-chloromethylfluorescein formula VIII.

< / BR>
The compounds of formula II, in addition, can be synthesized by the reaction of 2-R4-R5-N, N-di(lower alkyl)benzamide of formula V with one modernim equivalent (lower)alkyl(alkali) metal, such as lower alkylate, possibly in the presence of Tetra(lower alkyl)ethylene diamine in an inert organic solvent, for example THF, followed by reaction of the obtained alkali metal salt either with sulfur dioxide at a temperature in the range from -50oC to -80oC and then the reaction obtained sulfonate alkali metal with hydroxylamine-O-sulfona the s involving sulfur dioxide hydroxylamine-O-sulfonic acid is particularly recommended to neutralize the hydroxylamine-O-sulfonic acid base, preferably equivalent of sodium hydroxide before adding sulfonate alkali metal. The obtained 2-R4-R5-6-aminosulfonyl-N,N-di(lower alkyl)benzamid then heated in an acid environment with its cyclization and the formation of di(lower alkyl)ammonium salt of the target 4-R4-R5-saccharin of formula II, which can be used as such in subsequent reactions or can be hydrolyzed in dilute acid with evolution of free saccharin. The method is illustrated by the following diagram, where R$, R5and Alk agree to the above values. The cyclization recommended in boiling glacial acetic acid.

< / BR>
The compounds of formula II, where R4primary or secondary lower alkyl, which can be used as intermediates in obtaining the compounds of formula I by the methods described above will receive one of the following ways. The compound of formula II, where R4primary lower alkyl, synthesized by the reaction of 4-methyl-R5-saccharin (formula II, R4-CH3with two malernee equivalents lowest alkylate in an inert organic solvent, for example THF, followed by reaction of the resulting litative -50oC to -80oC.

The compounds of formula II, where R4primary alkyl and R5is different from hydrogen, or R4secondary lower alkyl, and R5takes on the values specified for formula I, are synthesized by the reaction of 2-(primary lower alkyl)-R5-N,N-di(lower alkyl)benzamide (formula V, R4- primary lower alkyl) with one modernim equivalent lower alkylate or di(lower alkyl)amide, lithium, possibly in the presence of Tetra(lower alkyl)ethylene diamine in an inert organic solvent, for example THF, and reaction of the obtained lithium salt with one modernim equivalent lower alkylamine at a temperature in the range from -50oC to -80oC). Obtained 2-(primary or secondary lower alkyl)-R5-N,N-di(lower alkyl)-benzamid then converted into the compounds of formula II, where R4primary or secondary alkyl, the same above sequence reaction, i.e. the reaction of 2-(primary or secondary lower alkyl)-R5-N,N-di(lower alkyl)benzamide with one modernim equivalent lower alkylate; reaction of the obtained lithium salt either with sulfur dioxide and then with hydroxylamine-O-sulfonic acid in the presence of base, or with sulfanilamides and then with ammiano the s II. If 2-(lower alkyl)group in the original 2-(lower alkyl)-5-N,N-di(lower alkyl)benzamide presents the stands, in this case, the alkylation obtain compounds in which the 2-(lower alkyl)group is normal or izotropnye depending on what was used for the alkylation alkylated normal or isotrate, on the other hand, if - 2-(lower alkyl)group the original product has more than one carbon atom, in this case, the alkylation occurs on the carbon atom adjacent to the benzene cycle, with the formation of products having the second-(lower)alkyl in the 2-position.

A particularly useful method of obtaining compounds of formula II, where R4-n-(lower)alkyl and R5-hydrogen is the protection of the benzyl protons in the initial compound of formula V trialkylsilyl group, which might result in the introduction of lithium in the 6-position and education sulfonamida the above method.

< / BR>
2-n-(lower)alkylbenzene, where R8lower alkyl, similarbut education tensile anion using alkylate or preferably, dialkylamino lithium (DAL) in an inert solvent, preferably THF, and processing of acceptable chlorotriethylsilane, PR is the source of floridayou, preferably perelom cesium in DMF or Tetra-n-butylammonium in an inert solvent.

The synthesis of specific target intermediates in some cases requires two cycles to obtain the kernel of saccharin. Thus, to obtain sharenow, where R4lowest alkoxygroup and R57 - hydroxy-group, or tetrahydrofurane, where R7lowest alkoxygroup may be used in the following synthesis scheme:

< / BR>
Reaction with thionyl chloride 3,3-dithiobisbenzothiazole acid is converted into its acid chloride and bischloromethyl, then injected into the reaction with two malernee equivalents of benzylamine obtaining bis-N-benzylamine. The last in the reaction with sulfurylchloride in an organic solvent, such as YFC, ejh or carbon tetrachloride, forms a 5-chloro-2-benzyl-2H-isothiazol-3-one, the oxidation of which one modernim equivalent of nagkalat, such as natantia acid or 3-chlormadinone acid, receive 5-chloro-2-benzyl-2H-isothiazol-3-one-1-oxide. The latter when heated under pressure with 2-(lower alkoxygroup)furan in an organic solvent such as benzene, toluene or xylene, forms a 4-(lower alkoxygroup)-7-hydroxy-2-benzyl-1,2-bennitt is m or (lower alkyl)-O-lower alkylene)p-halide, where the halide is chloride, bromide or iodide, with the formation of the corresponding 4,7-di(lower alkoxygroup) or 4-(lower alkoxygroup)-7-[(lower alkyl)-O-lower alkylene)p-O] -2-benzyl-1,2-benzisothiazol-2H-3-one-1-oxide. Subsequent oxidation of the product of the above method one modernim equivalent of nagkalat and then catalytic dibenzylammonium by hydrogenation with transfer receive the corresponding 4-(lower alkoxygroup)-7-hydroxycoumarin.

If you want to get tetrahydrofuran, use the following modification of the method(see diagram).

5-Chloro-2-benzyl-2H-isothiazol-3-one-1-oxide can be oxidized acceptable oxidizing agent, preferably hydrogen peroxide in acetic acid 1,1-dioxide, which is then in typical conditions of the Diels-alder condensation with acceptable diene and after recovery get 2-benzylacrylamide, hydrogenolysis of which the above method are tetrahydrofuran.

The compounds of formula II, where R4lower alkyl or phenyl and R5hydrogen can be synthesized by an alternative scheme G of cyclohexanone.

2-Cyclohexanone enter into reaction with the appropriate buy-hexamethylphosphoramide (HMPA) by the method of Winkler and others [Tet. Lett. 1987, 1051 and J. Org. Chem. 54, 4491 (1989)] Received-ketoester enter into reaction with benzylmercaptan in the presence of an acidic Montmorillonite clay KSF and get a mixture of regioisomers benzylideneamino simple ether. A mixture of flavored processing dichlorodicyanoquinone (DDH) and oxidized with gaseous chlorine in aqueous acid to obtain a complex ester sulphonylchloride, which can then be converted to the above method an intermediate compound of formula II.

4,5,6,7-Tetrahydrofurane, which is the starting products for producing compounds of formula VI, where R7hydrogen, synthesized according to scheme D.

3-Alkyl-2-cyclohexene enter into reaction with the corresponding alkyllithium in ethereal solvent, preferably diethyl ether, at temperatures from 50 to + 20oC, preferably about 0oC, and the resulting adduct is treated in situ medicinetramadol and hexamethylphosphoramide. The resulting 6,6-dialkyl-2-oxocyclohexanecarboxylate introduced into the reaction in the above conditions with benzylmercaptan and a mixture of 2-(benzylthio)cyclohexanecarboxylate oxidative glorious in the above conditions with the mixture chlorosulfonated esters, op> Aryl - and aryloxyalkyl acid used to obtain the final products of formula I are either selling products or are members of known classes of compounds which can be obtained by conventional methods of synthesis.

Simple chemical transformations which are conventional and well known to chemists, can be used to make changes in the functional groups of the compounds of the invention. For example, catalytic nitrogroup reduction receive aminosilane derivatives by acylation aminosilane connections receive the corresponding amides, oxidation of sulfides or sulfoxidov receive respectively the sulfoxidov or sulfones, saponification of esters obtain the corresponding carboxylic acid by the catalytic dibenzylammonium phenolic ethers or benzylamino receive the corresponding phenols or dibenzylamine amines, or by the reaction of phenol with an alkylating means in the presence of a base receive ethers.

The standard methods of biological testing for representative examples of compounds of the invention found inhibitory activity from the s diseases, such as emphysema, rheumatoid arthritis, cystic fibrosis degeneration, chronic bronchitis, respiratory distress syndrome adults, inflammatory bowel disease, psoriasis, bullous drug of dyskeratosis and deficiency of alpha-1-antitrypsin deficiency.

Compounds of the invention with the basic functions can be converted into a salt with an acid by the interaction of the base with acid. Similarly, the free base can be isolated in the usual way from salt with the acid, i.e. the processing of cold salt of a weak aqueous bases, such as carbonates and bicarbonates of alkali metals. Isolated from the base can be introduced into the reaction again with the same acid or other acid with the formation of the same or another salt with the acid. Thus, bases and their salts with acids are easily interconvertible.

Likewise, compounds of the invention with the acid function, for example carboxylic acids, can be converted into a salt by reaction of the acid with a base, such as hydroxides of alkali metals and ammonium, or an organic base, such as alkyl-, dialkyl - or trialkylamine, and acid can be separated from their salts by treatment of aqueous acids.

what their goals by applying themselves of the free bases or free acids or the use of salts, formed with pharmaceutically acceptable acids and bases, i.e acids or bases, anions or cations which are harmless to the animal organism in effective doses of the salts, whereby the beneficial properties inherent in the free bases or free acids, are not reduced to no side effects attributed to the anions or cations.

To use this pharmacological activity of the salt it is recommended to use pharmaceutically acceptable salts. Although the insolubility in water, high toxicity, or lack of crystallinity and can make a certain type of salt is unsuitable or less desirable for use as such in a given pharmaceutical field, however, the water-insoluble or toxic salts can be converted into the corresponding pharmaceutically acceptable bases by decomposition of salts aqueous base or aqueous acid in the above conditions or such salts can be converted into any target pharmaceutically acceptable salt in the reaction of double decomposition with the participation of the anion or cation, for example, ion-exchange methods.

Moreover, in addition to the use of such salts in the field of pharmacy's these grounds or in the methods for the extraction or purification. Like all salts such characterized or purified derivative salts can be optionally used for the regeneration of the pharmaceutically acceptable free bases or free acids by reaction of the salts with aqueous base or aqueous acid or they may be converted into a pharmaceutically acceptable salt, for example, ion-exchange methods.

New characteristic compounds, thus, due to the General structure of 2-sharonlee(aryl - or aryloxy)acetates, and not in any particular acid or the main part, any acid anion or cation Foundation, associated with the salt forms of the compounds.

Compounds of the invention can be prepared for pharmaceutical use their introduction in unit dosage forms such as tablets or capsules for oral administration either in pure form or in combination with acceptable adjuvants such as calcium carbonate, starch, lactose, talc, magnesium stearate, gum acacia, etc. moreover, the compounds can be introduced into the compositions for parenteral, oral administration or administration by aerosol inhalation or in aqueous solutions of water-soluble salts of the compounds or in aqueous alcohol, glycol iSky drugs.

The percentage of active ingredient in these compositions may vary in order to obtain an acceptable dosage. Dosage, introduced specific to the patient varies depending on the decision of the attending physician, based on criteria, such as route of administration, duration of treatment, weight and physical condition of the patient, the effectiveness of the active component and the patient's response to it. Effective dosage amounts of the active component, thus, can easily be determined by the attending physician after consideration of all factors with the adoption of the most favorable decisions for the patient.

Molecular structure of compounds of the invention was determined on the basis of study of their infrared and NMR spectra. The structure was confirmed by comparison of calculated and found values of elemental analysis for items or analysis of mass spectra of high resolution.

Further, the invention is disclosed with reference to the following examples which do not limit it. All melting points given inoC and not adjusted.

Getting the initial connection.

Preparative example 1. Powdered potassium hydroxide (7.4 g, 0,132 mol) smeww acid (10 g, of 0.066 mol), and then added dropwise logmean (4.52 ml, 0,073 mol). The reaction mixture was stirred 30 min at room temperature, then diluted with 250 ml of ether, washed with water (3 x 100 ml), dried over magnesium sulfate and concentrated. The crude product is filtered through a layer of silica gel for chromatography (32-63) and elution with a mixture of ether-hexane (1:9) get to 4.23 g (39%) of methyl ester of 6-methylanthranilic acid in the form of butter.

The obtained methyl ester 6-methylanthranilic acid (to 4.23 g, 0,026 mol) is dissolved in 25 ml of acetic acid and the solution is cooled to 0oC. After the addition of concentrated hydrochloric acid (45 ml) suspension is formed tan. With stirring, added dropwise a solution of 1.89 g (or 0.027 mol) of sodium nitrite in 8 ml of water, the resulting orange solution is stirred 1 h at 0oC and then 6 portions at 0oC is added to a mixture of 2.18 g (0,013 mol) chloride dihydrate, copper (II) and sulfur dioxide (6.3 g) in 33 ml of acetic acid and 6 ml of water. The dark green solution is stirred for about a day at room temperature, transferred into 300 ml ice water, the precipitate is separated and after drying with suction gain of 1.11 g of methyl ester of 2-chlorosulfonyl-6-methylbenzoic acid, to atoi temperature. The solution is acidified with concentrated hydrochloric acid to pH 1, the formed precipitate was separated and after drying in the air getting 729 mg (12%) 4-methylcholine, so pl. 224-226oC.

A mixture of 1 g (0,005 mol) 4-methylcholine 0.33 g (0.001 mol) of TBAB and 1.2 g (0,0075 mol) of chlorocarbonylsulfenyl in 25 ml of toluene is boiled for about sixteen hours, then cooled, diluted with ethyl acetate and the solution washed with aqueous bicarbonate and water. The organic layer is dried and after evaporation to dryness obtain 0.74 g of 2-phenylthiomethyl-4-methylcholine.

The obtained compound (0.74 g, 0.002 mol) is dissolved in 25 ml of YFC and the solution is treated with added dropwise over about two hours while stirring the solution of 0.47 g (of 0.003 mol) of sulfurylchloride in YFC and the reaction mixture is evaporated to dryness. The yellow solid residue is rinsed with hexane, filtered and after drying obtained as a pale yellow solid and 0.46 g of 2-chloromethyl-4-methylcholine.

Preparative example 2. According to the method described in preparative example 1, 5 g (0,029 mol) 6-chlorantraniliprole acid and 2.75 ml (0,044 mol) of iodomethane interact in the presence 4,08 g (0,073 mol) of powdered potassium hydroxide with the formation in the form of oil 422 g (78%) of metalina use 4,22 g (is 0.023 mol) of methyl ester of 6-chlorantraniliprole acid in 22 ml of acetic acid and 40 ml of concentrated hydrochloric acid, and 1.68 g (0,024 mol) of sodium nitrite in 7 ml of water to obtain diazonium salts, which add to 1,93 g (to 0.011 mol) chloride dihydrate, copper (II) and 6.5 g of sulfur dioxide in 30 ml of acetic acid and 5 ml of water. The obtained methyl ester 2-chlorosulfonyl-6-chlorbenzoyl acid is treated in the above conditions 150 ml of ammonium hydroxide and receive of 3.07 g (62%) 4-hariharan in the form of a pale yellow substance with so pl. 245 246oC.

2-Hydroxymethyl-4-hariharan obtained by heating the solution of 1 g (0,0046 mol) 4-hariharan and 3.22 ml of aqueous 37% formaldehyde solution in ethanol. All attempts at crystallization viscous oily product lead to its decomposition to the original connection, so the product is used in the next stage without his characteristics.

The resulting crude 2-hydroxymethyl-4-hariharan (609 mg, 0,0025 mol) is mixed with 5 ml of diethyl ether and then add 3 ml of thionyl chloride. The resulting mixture is heated to dissolve, mix about a day at room temperature, diluted with 20 ml of ether and filtered through a layer of celite, covered with sand, with elution with ether. Removal of solvent obtain 430 mg of crude chloromethylphosphonic, part of which (225 mg) leave for posleduyuschye and obtain 137 mg of 2-chloromethyl-4-hariharan, so pl. 135 136oC.

Preparative example 3A.

To a suspension of 6 g (0.03 mol) of copper iodide (I) in 100 ml of THF, add 25 ml of dimethyl sulfide, the resulting yellow solution is cooled to -78oC and treated with dropwise addition of a solution of 23 ml (0.06 mol) of 3 M solution of phenylmagnesium in diethyl ether. The obtained pale yellow-orange solution was stirred in nitrogen atmosphere for 1 h at -78oC and then treated to 3.02 g (0.03 mol) of 2-cyclohexenone in 10 ml of THF. The mixture is left for 2 h to warm to 0oC, again cooled to -78oC, treated with 15 ml hexamethylphosphoramide, stirred for thirty minutes, treated with 8 g (0.09 mol) of medicinepharmacy and leave about a day to warm to room temperature. The reaction mixture was transferred into a 100 ml 2 N. hydrochloric acid, the organic phase is separated and the aqueous phase is extracted with YFC. The combined organic extracts evaporated under vacuum to dryness, the residue rinsed with saturated ammonia, then with water and finally with brine and after repeated evaporation in vacuo to dryness receive in the form of oil, 3.2 g of methyl ester of 2-phenylcyclohexane-6-noncarbonate acid.

Received ketoester (3 g, of 0.013 mol), 4.8 g (0,039 mol) benzylmercaptan the amount of resin (1.5 g) and heated for another 4 hours The mixture is then cooled to room temperature, filtered, the filtrate evaporated in vacuum to dryness, the residue rinsed with hexane and after filtration gain of 0.85 g (19%) of a mixture of methyl ester of 2-benzylthio-6-phenylcyclohexyl-2-inkarbaeva acid and methyl ester of 2-benzylthio-6-phenylcyclohexane-1-inkarbaeva acid, 0.6 g (0,0018 mol) is heated for 24 h under nitrogen atmosphere and under stirring with 2 g of 2,3-dichloro-5,6-dicyanobenzoquinone in 25 ml of toluene. The mixture is filtered through a layer of silica gel with elution with a mixture of YFC-hexane (2 1) and evaporation of the eluate to dryness obtain 0.3 g (67%) of methyl ester of 2-benzylthio-6-vinylbenzoic acid.

The resulting ester (0.52 g, 0,0016 mol) is dissolved in 10 ml of YFC, diluted with 20 ml of acetic acid and 5 ml of water, the mixture is cooled to -10oC and through it propulsive gaseous chlorine until the termination of the exothermic reaction. The mixture is then stirred for 10 min and after evaporation in vacuo to dryness receive 0,41 g (85%) of methyl ester of 2-chlorosulfonyl-6-vinylbenzoic acid, which is dissolved in 10 ml of THF and to the solution while cooling in a bath of ice acetone add 25 ml of concentrated ammonium hydroxide solution. The reaction mixture was extracted with YFC, the organic phase is discarded, and the water lyrics by the washing with brine, drying and evaporation to dryness obtain 0.33 g (97%) 4-fenilalanina.

By the method similar to the method of preparative example, 1,4-phenylalanin (0.33 g, 0,0012 mol) is introduced into reaction with 0.3 g (0,0019 mol) of chlorocarbonylsulfenyl in 15 ml of toluene in the presence of 0.08 g (0,0025 mol) TBAB and processing of the received 2-phenylthiomethyl-4-phenylalanine (0,48 g, 100%) sulfurylchloride in YFC obtain 0.36 g (95%) of 2-chloromethyl-4-fenilalanina.

Preparative example 3B. To a suspension of anhydrous CuCN (2.16 g, 0,025 mol) in absolute ether (100 ml) at -78oC add tert-utility 29 ml of 1.7 M solution in pentane (0.05 mol). After stirring 1 h at -78oC and 30 min at -45oC, the reaction mixture was again cooled to -78oC. Add a solution of cyclohexenone (2.4 g, 0,025 mol) in ether (25 ml) and stirring is continued for 15 min at -78oC and 30 min at -45oC. the resulting mixture was again cooled to -78oC and then add HMPA (10 ml) in ether (25 ml). After 5 min add medicinepharmacy (2.55 g, 0.03 mol) in ether (25 ml) and the reaction mixture is heated for 2 h to 0oC. the Resulting mixture is neutralized 2 N. HCl (100 ml), the layers separated and the organic phase washed with a saturated solution of NH4Cl (3 x 50 ml), water (2 x 50 ml), brine (1 x 50 ml) and wicosuta baths 100 - 115oC at 0.6 mm) to obtain 4.7 g (88%) of methyl ester of 2-(1,1-dimethylethyl)cyclohexane-6-noncarbonate acid.

Cyclohexanone (4.6 g, of 0.022 mol) is mixed with benzylmercaptan (2,95 g 0,024 mol) and acidic montmorillonite clay KSF (7.5 g) in anhydrous toluene (7.5 ml). The mixture is boiled for 6 h and nitrogen atmosphere with isotropy by the removal of water, cooled to room temperature and left overnight. The precipitate is filtered and washed with ether. The combined filtrate washed with 10% Na2CO3, water, brine and dried. Removal of solvent in vacuo and purification of the residue pressure chromatography on silica gel (10% ether in hexane) to obtain 4.4 g (66%) of a mixture of methyl ester of 2-benzylthio-6-(1,1-dimethylethyl)cyclohex-2-inkarbaeva acid and methyl ester of 2-benzylthio-6-(1,1-dimethylethyl)cyclohex-1-inkarbaeva acid, which is mixed with DDH (18,5 g 0,077 mol) in toluene (50 ml) 16 hours the Reaction mixture is red filtered through a layer of silica gel in 15 cm with elution by the mixture hexane-YFC-ether (6: 3:1) (1000 ml). Eluate washed with 10% NaOH solution, water, brine and dried. Removal of solvent in vacuo and purification by chromatography on silica gel (5% ether in hexane) to obtain 1.6 g (40%) of the methyl ester of 2-benzylthio-6-(1,1-dimethyl)ethylbenzo is (25 ml) and water (2 ml), the mixture is cooled to -10oC and then propulsive gaseous chlorine until the end of the exothermic reaction. The mixture is stirred for 10 min and evaporated in vacuum to dryness. Purification of the residue pressure chromatography on silica gel (hexane-YFC, 1:1) to obtain 0.8 g (67% ) of methyl ester of 2-chlorosulfonyl-6-(1,1-dimethylethyl)benzoic acid, which was dissolved in THF (5 ml) and added to concentrated ammonia solution (25 ml) under cooling in a bath of acetone with ice. After stirring 16 h at room temperature the reaction mixture was concentrated in vacuo and acidified with 2n. HCl to pH 1. The precipitation is filtered off and crystallization from ether to obtain 0.64 g (95%) of 4-(1,1-dimethylethyl)saccharin, so pl. 185 187oC.

In 25 ml of toluene is mixed with 4-(1,1-dimethylethyl)saccharin (0.025 g, 1 mmol) with chlorocarbonylsulfenyl (0.25 g, 1.5 mmol) and tetrabutylammonium (0.2 g, 0.6 mmol) and heated in a nitrogen atmosphere for 16 hours the mixture is cooled to room temperature, evaporated to dryness and after purification by chromatography on silica gel (80% YFC in hexane) to obtain 0.35 g (98%) 2-phenylthiomethyl-4-1,1-dimethylethyl)saccharin, treatment of which with sulfurylchloride (0.25 g, 1.8 mmol) in YFC obtain 0.21 g (75%) of 2-chloromethyl-4(1,1-dimethylethyl)saccharin.

oC.

To a solution of the latter (with 3.27 g, 0,0085 mol) in 85 ml of YFC added dropwise and stirred 1,02 ml (0,0127 mol) of sulfurylchloride. The mixture is stirred for half hour at room temperature, concentrated in vacuo, the residue is rinsed and after filtration receive 2,61 g crude product by recrystallization from a mixture of toluene with hexane obtain 2.24 g (85%) of 2-chloromethyl-4-bronchain, so pl. 157 159oC.

Preparative example 5. To a solution of 8 ml (0,053 mol) of tetramethylethylenediamine (TMEDA) in 350 ml of THF was added at -70oC 42 ml (by 0.055 mol) of 1.3 M solution of sec-utility in cyclohexane and the mixture is stirred for 15 minutes To the solution dropwise and stirring was added a solution of 10,36 g (0.05 mol) of 20 min at a temperature below -50oC through the reaction mixture propulsive sulfur dioxide until the reaction mixture shows the acid reaction on litmus paper. The mixture is stirred for 2 h at room temperature, diluted with 450 ml of hexane, the precipitate is separated, dissolved in 200 ml of water and the resulting mixture is treated by adding portions and with stirring, 65 g of sodium acetate and 2.15 g (to 0.19 mol) of hydroxylamine-0-sulfonic acid. Precipitated white precipitate was separated and after drying receive? 7.04 baby mortality g (49%) 2-aminosulfonyl-6-methoxy-N-N-diethylbenzamide, so pl. 190-194,5oC.

A mixture of the obtained product (4.3 g, 0.015 mol) in 75 ml of dioxane and 25 ml of concentrated hydrochloric acid is heated to 70 hours on a water bath, then cooled, concentrated in vacuo, diluted with water with ice and add a concentrated solution of sodium hydroxide create a strong alkaline reaction. The mixture was washed with YFC, the aqueous layer was acidified with diluted hydrochloric acid and extracted with YFC. The extracts are dried over magnesium sulfate and after evaporation to dryness obtain 1.29 g (40%) 4-methoxycoumarin. The alternative recommended method cyclization of 2-aminosulfonyl-6-methoxy-N,N-diethylbenzamide 4-methoxycoumarin exit 65% Provo is effected in preparative example 4, 1,14 g (0,0053 mol) of the obtained product is introduced into a reaction from 1.31 ml (0,0097 mol) of chlorocarbonylsulfenyl in toluene in the presence 0,72 g (0,0064 mol) of tert-butoxy potassium and 174 mg (0,00054 mol) of tetrabutylammonium and gain of 1.23 g (69% ) 4-methoxy-2-phenyldimethylsilane, so pl. 152,5 154,5oC (from a mixture of ethyl acetate-hexane), processing (1,02 g of 0.003 mol) of 0.36 ml (0,0045 mol) of sulfurylchloride in YFC obtain 282 mg (36%) of 2-chloromethyl-4-methoxycoumarin, so pl. 169 174oC.

Preparative example 6A. To a solution 4,74 ml (0,031 mol) of tetramethylethylenediamine in 300 ml of THF (before using passed through alumina) is added 5.8 g (0.03 mol) 2-ethyl-N-N-diethylbenzamide. The solution is cooled -78oC and treated to 34.9 ml (0,031 mol) 0.9 M solution of sec-utility in cyclohexane. Upon completion of addition, the mixture is stirred for 20 min and then treated with a solution of 3.2 ml (0.04 mol) of ethyliodide, maintaining the temperature at -78oC. the Temperature is left to rise to room temperature, the mixture is stirred for about 16 h and then transferred into the water. The resulting oil is separated and chromatography on silica gel with elution with 10% ethyl acetate in hexane receive in the form of a yellow oil 2.86 g (43%) of 2-fluoro-butyl-N,N-deterpenated.

According to the method of the F. and at -78oC are added to a solution of 39.2 ml (0,047 mol) of sec-utility (1.2 M solution in cyclohexane) and 7.1 ml (0,047 mol) of tetramethylethylenediamine in 250 ml of THF. Upon completion of addition, the mixture is stirred for another half hour at -78oC, then at -70oC is treated with sulphur dioxide, and then left to warm to room temperature. The mixture is evaporated to dryness in vacuo, the residue is dissolved in the form and add with stirring to a cold solution of 15.2 g (0,134 mol) of hydroxylamine-0-sulfonic acid and 15.4 ml (0,134 mol) of 35% aqueous sodium hydroxide solution to obtain 10.1 g (72%) 2-aminosulfonyl-6-sec-butyl-N, N-diethylbenzamide.

The compound obtained (6,83 g, 0.22 mol) is dissolved in 100 ml of glacial acetic acid, the solution boiled for 13 h and then evaporated to dryness. The residue is rinsed with diethyl ether and after filtration obtain 5.7 g (83%) diethylammonium salt 4-second-Boticaria.

The reaction of the obtained salt (3 g, 0,0096 mol) of 1.13 ml (0.012 mol) of chlorocarbonylsulfenyl in toluene receive 3,47 g (100%) 2-phenylthiomethyl-4-second-Boticaria.

Reaction of the latter (3.2 g, 0,0097 mol) with 2.3 ml (0,029 mol) of sulfurylchloride in 20 ml of YFC obtain 2.4 g (87%) of 2-chloromethyl-4-second-Boticaria.

Preparative example 6B. On N-diethylbenzamide with sulfur dioxide and 5.6 g (49.4 mmol) of hydroxylamine-0-sulfonic acid and get 7,4 g (63%) of 2-aminosulfonyl-4,5-dimethoxy-6-propyl-N, N-diethylbenzamide that cyclist with a quantitative yield of acetic acid and penultimately with of 1.42 ml (15 mmol) of chlorocarbonylsulfenyl obtaining 4,07 g of 5,6-dimethoxy-2-phenylthio-4-propylalanine. Reaction 3,59 g (8,8 mmol) phenylthiourea with a 2.12 ml (26,4 mmol) sulfurylchloride get 2,84 g (97%) of 2-chloromethyl-5,6-dimethoxy-4-propylalanine.

3,4-Dimethoxy-2-propyl-N, N-diethylbenzamide receive according to the following procedure.

To a solution of 0,216 mol n-butile in 250 ml of ether at room temperature is added dropwise 138,2 g (0,216 mol) of veratrole in 100 ml of ether and 32.6 ml (0,216 mol) TMEDA. The reaction mixture was stirred 14 h at room temperature, for 1 h at room temperature add to 21.9 ml (0,225 mol) of n-propyl and after treatment 1 N. aqueous HCl get 14 g (36%) of 2,3-dimethoxybenzoate, bromirovanii which 14,52 g (81,6 mmol) of N-bromosuccinimide 36 g Kieselgel in 400 ml of CCl4according to the method Hisatoshi and others [Bull. Chem. Soc. Jap. 32, 591 593 (1989)] gain of 19.6 g (98%) of 6-bromo-2,3-dimethoxybenzamide.

Brobinson (14.2 g, of 54.8 mmol) was dissolved in 200 ml of ether, cooled to -78oC and add to 25.2 ml (63 mmol) of 2.5 n n-utility in hexane. The reaction mixture is heated to 0oC, allowed to stand for 1 h, cooled to -70oC and Dury and neutralized with a saturated solution of ammonium chloride. After extraction and drying crystallization of the product from hexane obtain 9.5 g (62%) of 3,4-dimethoxy-2-propyl-N,N-diethylbenzamide, so pl. 65 67oC.

Preparative example 6C. In a manner analogous to the preparative method of example 6B, cyclist of 10.75 g (30 mmol) 2-aminosulfonyl-4,5-dimethoxy-6-isopropyl-N, N-diethylbenzamide and get to 6.43 g of 5,6-dimethoxy-4-isopropylaniline (so pl. 186 188oC from a mixture of ether and hexane), 5 g (17.5 mmol) which will penultimately 2,48 ml (26,3 mmol) phenyldimethylsilane by the method of preparative example 5 and glorious 3 equivalents of sulfurylchloride with obtaining with access to 85% of 2-chloromethyl-5,6-dimethoxy-4-isopropylaniline, so pl. 117 119oC from a mixture of ethyl acetate-hexane.

Target benzamide obtained from 2,3-dimethoxy - methylbenzoate his bromirovanii with subsequent carbamylcholine as well as in preparative example 6B, with the intermediate 3,4-dimethoxy-2-isopropyl-N,N-diethylbenzamide. To 16,1 g (57.6 mmol) benzamide in 400 ml of THF at -78oC in nitrogen atmosphere add a solution of 66 ml of 0.96 M Deut-utility. After stirring 2 h, the orange solution of the anion through the cannula at -60oC add to excess sulfur dioxide. The reaction mixture is left to warm to room for the operating mixture otparivat. Sulphonylchloride extracted in a mixture of EtOAc-ether, washed with water, dried and otparivat. The residue is dissolved in 80 ml of THF and at 0oC add 17 ml conc. NH4OH. The reaction mixture is briefly stirred at room temperature otparivat and rinsed with a mixture of ether-hexane (2 1), receive 12,89 g (62%) 2-aminosulfonyl-4,5-dimethoxy-6-isopropyl-N,N-diethylbenzamide, so pl. 138 140oC.

Preparative example 7. To a solution of 9.3 ml (0,058 mol) of tetramethylethylenediamine in 340 ml of THF at -78oC added 52 ml of a 1.1 M solution (0,057 mol) of sec-utility in cyclohexane. Then the solution is treated with a solution 11,37 g (0,052 mol) of 2-propyl - N,N-diethylbenzamide in 75 ml of THF at -78oC, stirred for 15 min and then treated with a solution of 8.3 ml (0.104 g mol) ethyliodide in THF. The solution is stirred for half hour at -78oC, then neutralized by adding dropwise at -78oC saturated solution of ammonium chloride. Then, the mixture is left to warm to room temperature, diluted with diethyl ether, washed first with dilute hydrochloric acid, then water, then a saturated solution and finally brine, drying and evaporation to dryness receive 12,91 g crude product by chromatography on the silica gel with Elya is 2">

By the method similar to the method of preparative example 5, the obtained compound (3,05 g, 0,0115 mol) in THF is injected into reaction with 10.5 ml (0,126 mol) 1.2 M solution of sec-utility in cyclohexane in the presence of 2.1 ml (0.014 mol) of tetramethylaniline. The obtained lithium salt is introduced into the first reaction with sulfur dioxide and then with a sodium salt of hydroxylamine-O-sulfonic acid and gain of 1.97 g (52%) of 2-aminosulfonyl-6-(3-pentyl)-N,N-diethylbenzamide in the form of pale yellow crystals with so pl. 118 120oC (softening at 102oC) cyclization of (1.84 g, 0,0056 mol) in 22 ml of boiling glacial acetic acid to obtain 1.28 g (70%) diethylammonium salt of 4-(3-pentyl)-saccharin, so pl. 107,5 109,5oC.

The reaction of the salts from 0.74 ml (0,0055 mol) of chlorocarbonylsulfenyl in the presence of 116 mg (of 0.0004 mol) TBAB in 45 ml of toluene obtained as a pale yellow oil of 1.93 g of 2-phenylthiomethyl-4-(3-pentyl)saccharin, reaction (1,93 g, 0,0037 mol) of 0.59 ml (0,0073 mol) of sulfurylchloride in 37 ml YFC receive in the form of a pale yellow oil 1.2 g of 2-chloromethyl-4-(pentyl)saccharin.

Preparative example 8. A solution of 50 g (0.27 mol) of 2,4-dimethoxybenzoic acid in 60 ml (98 g, 0.82 mol) of thionyl chloride are boiled for 3 h, then cooled and the excess thionyl chloride is distilled off. Pmol) diethylamine in 500 ml of YFC. Upon completion of addition, the mixture is stirred for 15 min at room temperature, then washed with saturated sodium bicarbonate solution, water and brine, evaporated to dryness and after distillation of the residue in vacuum get 44,78 g (69%) of 2,4-dimethoxy-N,N-diethylbenzamide, so Kip. 155 163oC/0,4 mm

By the method similar to the method of preparative example 5, are obtained reaction product (10 g, 0,042 mol) in 250 ml of THF with 40,57 ml of a 1.1 M solution storage capacity (0.044 mol) of sec-utility in cyclohexane and 6.35 ml (0,042 mol) of tetramethylethylenediamine in THF. The obtained lithium salt is introduced into the reaction first with about 40 ml of sulfur dioxide and then with an aqueous solution (0.13 mol) of sodium salt of hydroxylamine-O-sulfonic acid and get compared to 8.26 g of 2-aminosulfonyl-4,6-dimethoxy-N, N-diethylbenzamide, 7 g (0,022 mol) cyclist in 80 ml of boiling glacial acetic acid and obtain 6.6 g (94%) diethylammonium salt of 4,6-dimethoxyaniline, which is used as such in the next stage without further purification.

The resulting product (6 g, 0.019 mol) in the reaction with 3,82 ml (0,028 mol) of chlorocarbonylsulfenyl in the presence 0,611 g (0,0019 mol) TBAB in 200 ml of toluene forms 6.2 g (89%) 2-phenylthiomethyl-4,6-dimethoxycoumarin, of 5.82 g (to 0.016 mol) in processing 3,23 CLASS="ptx2">

Preparative examples 9A-9G. By the method similar to the method of preparative example 5, but using instead 2-methoxy-N,N-diethylbenzamide the corresponding 2-R4-R5-substituted N,N-diethylbenzamide, synthesize listed in the table. 1 2-kaleidotile-4-R4-R5-sacharine through the intermediate formation of the corresponding 2-phenyldimethylsilane. Where such information is available, for each 2-unsubstituted saccharin, 2-phenyldimethylsilane and 2-chlorotriazine in the columns entitled "So pl./p-ritel" and "Exit" below the melting temperature (oC) and exit. In all cases, the intermediate 2-phenyldimethylsilane used directly in the next stage without further characterization or purification.

Preparative example 10. By the method similar to the method of preparative example 2, reaction of 18.3 g (0.1 mol) of saccharin with 70 ml of 37% formalin in ethanol 3.58 g (70%) 2-hydroxymethylamino, the processing of which (25 g, 0,117 mol) and 63.3 g (0,234 mol) trichromate phosphorus in diethyl ether get to 29.8 g (92%) 2-bromoethylamine, so pl. 155 157oC.

Preparative example 11. To a solution of 4 g (0,0175 mol) of 6-nitrosourea in 240 ml of ethanol is added 4.4 g (0,0175 mol the dock is filtered off and after drying obtain 7.6 g (100%) tallic salt of 6-nitrosourea. Salt is suspended in 50 ml of DMF and the mixture is treated of 3.07 g (0,0194 mol) of chlorocarbonylsulfenyl, the mixture is heated 5 h at about 63oC, leave for about 16 h at room temperature and then transferred into the water. Obtained by filtering the crude product is stirred in YFC and filtration to remove salts thallium. From the filtrate to remove the solvent, the obtained pale-yellow solid is treated with ultrasound in warm ethanol and after repeated filtration and drying obtain 4.6 g (75%) of 6-nitro-2-phenyldimethylsilane, so pl. 161 163oC. the Last in the reaction with sulfurylchloride in YFC by the method of preparative example 4 forms of 3.7 g of 2-chloromethyl-6-nitrosourea.

Preparative example 12. A solution of 49.8 g (0,199 mol) of 2-hydroxy-5-(1,1,3,3-TETRAMETHYLBUTYL)benzoic acid in 200 ml of methanol is heated to 50oC and then treated with dropwise addition of approximately 80 g of sulfuric acid with such a rate as to maintain the boiling reaction mixture. The reaction mixture is boiled for a further 11 h, then cooled and distributed between ethyl acetate and water. The organic layer was washed with saturated sodium bicarbonate solution, then brine, dried over sodium sulfate and after evaporation to dryness get to 48.6 g is Aut in 250 ml of DMF and treated first of 40.4 g (0.36 mol) of 1,4-diazabicyclo[2,2,2]octane then of 33.4 g (0.27 mol) of N,N-dimethylthiocarbamate and 100 ml of DMF. The reaction mixture is heated for approximately 8 h at 45oC, cooled, transferred into ice water and concentrated hydrochloric acid and extracted with ethyl acetate. The combined organic extracts washed with diluted hydrochloric acid, then with sodium bicarbonate solution and finally brine, drying and evaporation to dryness receive 48,2 g (76%) of methyl ester of 2-(N, N-dimethylthiocarbamate)-5-(1,1,3,3-TETRAMETHYLBUTYL)benzoic acid, which is heated for 15 h at 220oC, then cooled, dissolved in toluene and chromatography on silica with elution with a mixture of ethyl acetate-toluene (1: 9) to obtain 3.6 g 814%) methyl ester of 2-(N,N-dimethylcarbamate)-5-(1,1,3,3-TETRAMETHYLBUTYL)benzoic acid.

The last solution (0,025 mol) in 40 ml of YFC is treated with stirring, 80 ml of glacial acetic acid and then 16 ml of water. The reaction mixture was cooled to 0oC and through it for 5 min at a temperature of 5 - 24oC propulsive chlorine gas. The mixture is stirred for another 30 min, concentrated in vacuo and the residual liquid is transferred into ice-cold water. Extraction of the mixture with ethyl acetate and the release of product from the combined organic extract of the scientists of the product (9 g, 0,026 mol) is dissolved in THF and cooled in a bath of ice is added to 100 ml of concentrated ammonium hydroxide. The resulting solution was stirred for about 16 h, then concentrated in vacuo and the concentrated solution is acidified with concentrated hydrochloric acid to pH 3. The mixture is stirred for several hours, the precipitated precipitate was separated, washed with water and after drying obtain 9 g of 5-(1,1,3,3-TETRAMETHYLBUTYL)saccharin, so pl. 213 215oC.

By the method similar to the method of preparative example 11, are obtained reaction product (9 g, 0.3 mol) ethoxide thallium in ethanol and the resulting salt of thallium is injected into reaction with 3.33 g (0,021 mol) of chlorocarbonylsulfenyl in DMF and get 5,76 g (66%) 2-phenylthiomethyl-5-(1,1,3,3-TETRAMETHYLBUTYL)saccharin, 3.3 grams (0,007 mol) which is treated 0,944 g sulfurylchloride in YFC and get 1 g (41%) of 2-chloromethyl-5-(1,1,3,3-TETRAMETHYLBUTYL)saccharin.

Preparative example 13. By the method similar to the method of preparative example 12, conduct the reaction 15.5 g (0,086 mol) ethyl ester of 2-hydroxy-6-methylbenzoic acid with 15.9 g (0,129 mol) of N,N-dimethylthiocarbamate in the presence of 19.3 g (0,172 mol) of 1,4-diazabicyclo[2,2,2]octane in DMF and obtain 22.1 g (96%) of ethyl ester of 2-(N,N-dimethyl what matography on silica gel in YFC receive in the form of a red-brown oil ethyl ester of 2-(N,N-dimethylcarbamate)-6-methylbenzoic acid.

The last solution (22,6 g, 0,0844 mol) in 170 ml of YFC process when cooled in a bath of acetone with ice 340 ml of glacial acetic acid and 68 ml of water and through the reaction mixture for 10 - 15 min propulsive chlorine. The reaction vessel is evacuated to remove excess chlorine and DMH, the mixture is transferred into water and partitioned between YFC and water. From the organic layer after drying and evaporation to dryness obtain 19 g of ethyl ester of 2-chlorosulfonyl-6-methylbenzoic acid, 5 g (0.019 mol) which enter into reaction with concentrated ammonium hydroxide in THF and get 6,1 g (67) 4-methylcholine.

By the method similar to the method of preparative example 11, the resulting product (10.1 g, 0,0512 mol) in the reaction with 12.8 g (0,0512 mol) ethoxide thallium in ethanol converted into the salt of thallium and the resulting salt is introduced into reaction with 6.7 g (0,0427 mol) of chlorocarbonylsulfenyl in DMF and get 6.85 g (50%) 2-phenylthiomethyl-4-methylcholine.

Reaction of the latter (6.7 g, 0,021 mol) sulfurylchloride in YFC obtain 4.9 g (95%) of 2-chloromethyl-4-methylcholine.

Preparative example 14A.

A mixture of 75 g (0.36 mol) of 3,3-dithiobisnitrobenzoic acid, 102 ml of thionyl chloride and catalytic amounts of pyridine is stirred for about 24 h and then evaporated virigina obtain 87 g (98% ) of the corresponding beschorneria, with 44.8 g (0.18 mol) is dissolved in THF and added dropwise to a solution of 77,16 g (to 0.72 mol) of benzylamine in THF. The mixture is stirred for 2 h at 40 45oC, cooled, the precipitate is separated, washed with water and after drying obtain 59 g (84%) of N, N'-dibenzoylperoxide 3,3-dithiobisnitrobenzoic acid, so pl. 162 165oC.

Reaction 7 g (0.018 mol) of the amide from 10.25 g (0,076 mol) of sulfurylchloride in YFC receive a mixture of 2-benzyl-2H-isothiazol-3-one and 5-chloro-2-benzyl-2H-isothiazol-3-one, which is almost completely separated into components by sonication in YFC (with translation in the solution the greater part of the first component). The insoluble product is filtered and chromatographic on silica gel with YFC. The result is 5-chloro-2-benzyl-2H-isothiazol-3-one, so pl. 58 68oC.

A solution of 10 g (0,044 mol) of the obtained product in YFC cooled to 0oC, treated with 7.6 g (0,044 mol) 3-chlormadinone acid, stirred for 10 min and then treated with a second portion of 7.6 g adventurou acid. The reaction mixture is filtered, the filter washed with YFC, and the filtrate washed with saturated sodium bicarbonate solution, then brine, dried over sodium sulfate, evaporated to dryness and chromatography of the residue in YFC on silica gel with AluI is the target of 1.1 g (0,0045 mol) of the latter in 8 ml of benzene is treated with 0.55 g (0,0051 mol) of 2-methoxyfuran, heat 1-1/2 hours at 70oC in a vessel to work under pressure, cooled, the precipitate was separated, washed with benzene and after drying receive 2-benzyl-7-hydroxy-4-methoxybenzothiazole-3-one-1-oxide, so pl. 235 237oC.

A mixture of the obtained product (1.85 g, 0,006 mol), 2,48 g (0.018 mol) of potassium carbonate and 1.7 g (0.012 mol) of methyliodide in acetone boil for 1 1/2 hours, then cooled and transferred into the water. The precipitation is filtered off, washed with water and after drying obtain 1.7 g (89%) of 2-benzyl-4,7-dimethoxybenzoate-3-one-1-oxide, 1.13 g (0,0035 mol) which oxidizes 1.2 g (to 0.007 mol) 3-chlormadinone acid according to the aforementioned method and gain of 1.03 g (88%) of 2-benzyl-4,7-dimethoxycoumarin.

The mixture 2,07 (0,0062 mol) of product of 1.37 g (0.02 mol) of monitorate and 1.5 g of catalyst 10% palladium on coal in 80 ml of methanol is boiled for 1 h, then cooled and filtered, the filtrate is evaporated to dryness and receive 0,92 g (57%) ammonium salt of 4,7-dimethoxycoumarin.

To a solution of 1.11 g (0,0042 mol) ammonium salt in DMF type of 0.67 g (0,0042 mol) of chlorocarbonylsulfenyl, the solution boils 8 h, then cooled and transferred into ice-cold water. The precipitation was separated, washed with water and after drying earn 0.5 (33%) 2-phenylthiomethyl-4,7-dimethoxycoumarin. 4 get 0,22 g (58%) of 2-chloromethyl-4,7-dimethoxycoumarin.

Preparative examples 14B and 14C. By the method similar to the method of preparative example 14A, received other derivatives of 2-chlorotriazine as follows.

Preparative example 14C. Reaction of 5.8 g (0,024 mol) 5-chloro-2-benzyl-2H-isothiazol-3-one-1-oxide from 3.76 g (0,0335 mol) of 2-toxiferine get 3,05 g (40%) of 2-benzyl-4-ethoxy-7-hydroxybenzotriazol-3-one-1-oxide, 5.7 g which enter into reaction with 3.6 g (0,0197 mol) of 2-(2-methoxyethoxy)ethylbromide in the presence of 4.95 g (0,0358 mol) potassium carbonate in 125 ml of methyl ethyl ketone and 25 ml of DMF, and get 7 g (93%) of 2-benzyl - 4-ethoxy-7-[2-(2-methoxyethoxy)ethoxy] benzisothiazol-3-one-1-oxide, the oxidation of which the above conditions for 3-chlormadinone acid in YFC get 2-benzyl-4-ethoxy-7-[2-(2-methoxyethoxy)ethoxy] saccharin. Dibenzylammonium last (6.6 g, 0.015 mol) 3,34 g (0,053 mol) of monitorate in the presence as catalyst 10% palladium on coal in methanol receive the ammonium salt of 4-ethoxy-7-[2-(2-methoxyethoxy)ethoxy] saccharin, the reaction of which with of 2.38 g (0.015 mol) of chlorocarbonylsulfenyl in 100 ml of DMF gain of 1.46 g (21%) 2-phenylthiomethyl-4-ethoxy-7-[2-(2-methoxyethoxy)ethoxy]saccharin, so pl. 73 75oC (from isopropanol). The processing of 1.4 g(0,0029 mol) of product of 0.4 g (0,0029 mol) Sulfuryl the first example 14C. Reaction 3.03 g (0.01 mol) of 2-benzyl-7-hydroxy-4-methoxybenzothiazole-3-one-1-oxide (preparative example 14A) with a 2.01 g (to 0.011 mol) of 2-(2-methoxyethoxy)ethylbromide in methyl ethyl ketone in the presence of 2 g (0.015 mol) of carbonate obtain 2.58 g (64%) of 2-benzyl-4-methoxy-7-[2-(2-methoxyethoxy)ethoxy]benzisothiazol-3-one-1-oxide, oxidation of which 1.1 g (0,0063 mol) 3-chlormadinone acid in YFC get 2-benzyl-4-methoxy-7-[2-(2-methoxyethoxy)-ethoxy] saccharin. Dibenzylammonium product (0.25 g, 0,0006 mol) of 0.13 g (0,0021 mol) of monitorate in methanol in the presence of 0.25 g of 10% palladium on coal obtain 0.21 g (100%) of the ammonium salt of 4-methoxy-7-[2-(2-methoxyethoxy)-ethoxy] saccharin. The reaction of 1, 4 g (0,004 mol) ammonium salt from 0.63 g (0,004 mol) of chlorocarbonylsulfenyl in DMF receive 2-phenylthiomethyl-4-methoxy-7-[2-(2-methoxyethoxy)-ethoxy] saccharin, reaction of which with sulfurylchloride in YFC gain of 0.53 g (35%) of 2-chloromethyl-4-methoxy-7-[2-(2-methoxyethoxy)ethoxy]saccharin.

Preparative example 15. To a suspension of 2.13 g (0.01 mol) 2-hydroxymitragynine in 25 ml of YFC, with 78oC add a solution of 1.89 g (to 0.011 mol) of diethylaminoacetate (will GIVE) in 20 ml of YFC. The reaction mixture was stirred 1 h at -78oC, the temperature is left to slowly rise to room temperature is over magnesium sulfate and after evaporation to dryness obtain 2.2 g of product, by recrystallization from ethyl acetate obtain 1.6 g (74%) 2-hermeticaly, so pl. 96-98oC.

Preparative example 16A. To a solution of 0.5 g (0,0025 mol) 4-methylcholine cooled to -78oC in a bath of dry ice in acetone, are added dropwise with stirring, a solution of 5.2 ml of 1.3 M solution of sec-utility in cyclohexane. The mixture is stirred for another hour at -78oC and then treated by adding for 1-1/2 hours and 0.16 ml (0,025 mol) of methyliodide. The reaction mixture was stirred 1 h and 45 min, neutralize 25 ml of 1 N. hydrochloric acid, produce an alkaline reaction, the aqueous phase is extracted with chloroform, then acidified and extracted with ethyl acetate. The combined organic extracts are washed with 10% sodium thiosulfate solution, then brine, dried over sodium sulfate and after evaporation to dryness receive the product, the PMR spectrum which showed the presence of a mixture consisting of 74% of 4-acylcholine and 21% of 4.7 dimethylalanine.

By the method similar to the method of preparative example 4, the crude mixture of 0.47 g, 0,0022 mol) are introduced into a reaction from 0.24 ml (0,0028 mol) of chlorocarbonylsulfenyl in toluene in the presence of Tetramethylammonium and product chromatographic on silica gel with elution YFC and selection Festina consisting of 2-phenylthiomethyl-4,7-dimethylalanine, which lay. From next 25 fractions gain of 0.37 g of 2-phenylthiomethyl-4-acylcholine, which enter into reaction with sulfurylchloride in YFC and get to 0.19 g (66%) of 2-chloromethyl-4-acylcholine.

Preparative example 16B. By the method similar to the method of preparative example 16A, conduct the reaction of 10 g (0.51 mol) of 4-methylcholine in THF (86 ml (0.1 mol) of 1.18 M solution of sec-utility in cyclohexane and the resulting solution is treated with 4.5 ml (0.05 mol) of ethyliodide obtaining 10,15 g (89% ) of 4-propylalanine, which in reaction with 5,32 ml (0,056 mol) of chlorocarbonylsulfenyl in toluene in the presence of Tetramethylammonium forms a crude mixture from which the pressure chromatography on silica gel isolated in the form of oil 2-phenylthiomethyl-4-profilesharing, 1.8 g (0,0052 mol) in YFC give 0,94 g (66%) of 2-chloromethyl-4-propylalanine.

Preparative example 16C. Recommended alternative preparative example 16A is as follows.

To a solution 5,13 g (25 mmol) of N,N,2-triethylbenzene in THF (50 ml) at -78oC add a solution of LDA (Aldrich, 2 M, 15,63 ml, 31.25 mmol). The solution is heated to -10oC, allowed to stand for 1 h at -10oC in ice water, then cooled to -78oC dry ice in acetone. At -78oC is actionnow the mixture is neutralized with saturated solution of NH4Cl and extracted with ether (2100 ml), dried over MgSO4, evaporated and the distillation residue in the apparatus Cuellar (130-140oC, 0.65 mm) receive 6,51 g (94%) of N, N-diethyl-2-[1-(trimethylsilyl)ethyl]benzamide.

To a solution of sec-BuLi (0,97 M, 5.1 ml, 4,96 mmol), TMEDA (0.75 ml, 4,96 mmol) in THF added at -78oC obtained amide (1.25 g, 4.5 mmol). Quickly add at -78oC an excess of SO2in THF and then warmed to room temperature. THF is removed in vacuo and the residue at 0oC enter into a reaction with two equivalents of a solution of a mixture (1: 1) of sodium hydroxide (0.36 g, 9 mmol) and hydroxylamine-0-sulfonic acid (1 g, 9 mmol) in H2O. the Reaction mixture was stirred 4 h at room temperature, extracted with EtOAc, and pressure chromatography on silica gel with elution with 20% ethyl acetate in hexane gain of 0.62 g (47%) 2-aminosulfonyl-N, N-diethyl-6-[1-(trimethylsilyl)ethyl] benzamide. The resulting benzamide (0.95 g, of 2.66 mmol) is boiled for 18 h in glacial acetic acid (20 ml), evaporated to dryness, then rinsed with hot cyclohexane (30 ml) and traces of EtOAc (3 ml), cooled at scratching and filtered. As a result 0,81 g(85%) 4-[1-(trimethylsilyl)ethyl]saccharin, so pl. 123-125oC.

To trimethylsilylmethylamine (0.25 g, 0.7 mmol) in DM is I 7 h, the reaction mixture was transferred into a 5% solution of NaOH and extracted with EtOAc. The aqueous layer was acidified with 12 N. HCl and extracted with Et2O-EtOAc (1: 1), dried over Na2SO4, filtered and after evaporation of the get with quantitative yield colourless solid, recrystallization of which from 5% Et2O in hexane get 0,091 g (64%) 4-acylcholine, so pl. 183-185oC.

Preparative example 17. A sample of the product (0.07 g), obtained from the first fractions of the chromatographic separation described in preparative example 16A and consisting mainly of 2-phenylthiomethyl-4,7-dimethylalanine, enter into reaction with 0.05 ml of sulfurylchloride in YFC and recrystallization of the product from a mixture of cyclohexane-ethyl acetate to obtain 20 mg (51%) of 2-chloro-methyl-4,7-dimethylalanine, so pl. 107 108oC.

Preparative example 18A. To a solution of 40 g (0,174 mol) of 2-isopropyl-4-methoxypropanol in 600 ml of diethyl ether at 0oC add 103,68 ml (0,175 mol) 1,69 M solution of utility in diethyl ether. Upon completion of addition, the solution is cooled to 0o1 h, 5 h and stirred at room temperature, then cooled to -78oC and treated with a solution 23,68 g (0,175 mol) of N,N-diethylcarbamoyl in 80 ml of diethyl ether. The resulting solution was stirred for about 12 h with simultaneous povysheniya, the aqueous layer was extracted with ethyl acetate, the combined organic extracts washed once with brine, then dried and evaporation of solvent to dryness get the crude product, pressure chromatography with elution 30% ethyl acetate in hexane obtain 34.4 g (79%) of 2-isopropyl-4-methoxy-N,N-diethylbenzamide in the form of oil, which is used as such in the next stage without additional purification. If desired, the oil can be distilled, so Kip. 123-129oC /0,2 0,3 mm

By the method of preparative example 5, the obtained oil (15 g, 0.06 mol) is introduced into reaction with 77,8 ml (0,784 mol) 1.2 M solution of sec-utility in cyclohexane in the presence 6,98 g (0.06 mol) of tetramethylethylenediamine. Obrazovavshuyusya salt of lithium is introduced into the first reaction with 50 ml of sulfur dioxide and then with 0,181 mol of sodium salt of hydroxylamine-0-sulfonic acid and obtain 11.6 g (59%) 2-aminosulfonyl-6-isopropyl-4-methoxy-N,N-diethylbenzamide, so pl. 103 105oC (from a mixture of ethylacetate), 11 g (0,034 mol) which cyclist in 200 ml of boiling glacial acetic acid and obtain 10.3 g diethylammonium salt of 4-isopropyl-6-methoxycoumarin, so pl. 132 135oC.

The reaction of the salts (0.03 mol) from 6.14 ml (7,25 g, 0.046 mol) of chlorocarbonylsulfenyl in the form of oil, 9.7 g (0,026 mol) in the reaction with 3.1 ml (a total of 5.21 g, 0,039 mol) of sulfurylchloride in YFC form of 6.9 g (88%) of 2-chloromethyl-4-isopropyl-6-methoxycoumarin, so pl. 151 - 152oC.

Preparative example 18V. An alternative method consists in the following.

To a solution of 300 ml of N,N,N',N'-tetramethylethylenediamine (TMEDA) (1,99 mol) in 4 l of anhydrous ether is added 1550 ml of sec-BuLi (1.3 M) and the system under nitrogen atmosphere cooled to -70oC. for 30 min added dropwise N, N-diethylbenzamide (1.82 mol) in 300 ml anhydrous ether (during the addition the temperature of the support at -60oC or below). Upon completion of addition the reaction mixture was stirred 1 h at -70oC and then allowed to warm to -50oC. After incubation for 30 min at -50oC the mixture is again cooled to -70oC. To stir the solution for 20 min through a tube in the form of a cannula was added a solution of 200 g of SO2in 200 ml of dry ether, pre-cooled to -40oC under positive nitrogen pressure. The temperature of the reaction mixture during the addition of support below -40oC. (Almost immediately formed a white powdery precipitate of sulfinate argillite). After addition the cooling bath removed and the reaction mixture was perenia 15 min added dropwise 190 ml (2.36 mol) of sulfurylchloride, maintaining the temperature during addition below 10oC. After stirring for further 30 minutes at 0-5oC white insoluble precipitate is filtered off and washed with 2 l of anhydrous ether. Removal of solvent under atmospheric pressure to obtain crude sulphonylchloride in the form of a dark oil. The resulting crude sulphonylchloride dissolved in 1.4 liters of THF, cooled to -10oC and for 15 min portions added to 540 ml of concentrated (28%) solution of NH4OH (during the addition the temperature of the support at the 15oC or below). After stirring 15 min at room temperature THF and excess ammonia is removed under vacuum and get a dark oil, which was diluted with 6 l of water and acidified with 3 N. HCl to pH 1. Light yellow precipitate is filtered off and washed with 800 ml of water. Drying the obtained material in vacuum at 60oC and recrystallization from a mixture of 800 ml of ethyl acetate and 3 l of hexane receive 429 g (72%) 2-aminosulfonyl-6-isopropyl-4-methoxy-N,N-diethylbenzamide, so pl. 122 - 125oC.

The solution 429,6 g diethylbenzamide (1,31 mol) in 1.5 l of acetic acid is boiled for 20 hours Then cooled to room temperature and the solvent is removed in vacuum. The oily residue is dissolved in 6 l of water and acidified with 6 N. hydrochloric acid to pH 1 the recrystallization from a mixture of ethyl acetate-hexane get 303 g (91%) receive a 4-isopropyl-6-methoxycoumarin, so pl. 188oC.

To a suspension of 24 g (0.8 mol) of paraformaldehyde and 86.4 g (1.6 mol) of chlorotrimethylsilane in 200 ml of 1,2-dichloroethane add 0.8 ml of anhydrous tin chloride (IV) and the resulting solution was stirred for 1 h in a water bath. By the end of this period to a transparent solution was added 51 g (0.2 mol) of 4-isopropyl-6-methoxycoumarin and the reaction mixture is boiled for 18 hours Then cooled to room temperature, transferred into water, the organic layer is separated and washed with 50 ml of 2 n sodium hydroxide solution. The organic layer is dried over anhydrous magnesium sulfate and concentrated in vacuum to get crude product by crystallization from a mixture of ethyl acetate-hexane obtain 57 g (87% ) of 2-chloromethyl-4-isopropyl-6-methoxycoumarin, so pl. 151oC.

Preparative example 19. To a solution of 1 g (to 0.0039 mol) of 4-isopropyl-6-methoxycoumarin you 15 ml YFC at room temperature add 1.28 g (5,12 ml) of 1 M solution trichromate boron in YFC. Upon completion of addition, the reaction mixture is boiled for about 5 h, cooled, evaporated in vacuum to dryness and the residue is treated with ice and saturated sodium bicarbonate solution. The aqueous solution once extracted with ethyl acetate and then concentrated hydrochloric acid acidified D. the receiving of the solvent in vacuo receive in the form of a white crystalline substance 0.9 g (96%) of 6-hydroxy-4-isopropylaniline, which is used as such in the next stage.

Used as an alternative method. To a stirred suspension 62,74 g (0.47 mol) AlCl3in 500 ml of chloroform at 0oC add 43,9 g (0.7 mol) of ethanthiol. Within a few minutes formed a clear solution. To the resulting solution for 30 min add 20 g (0,078 mol) of 4-isopropyl-6-methoxycoumarin. The solution is allowed to warm to room temperature and stirred for 3 to 4 h at 60oC. After cooling, the mixture is transferred into ice water and acidified with diluted HCl. The precipitation is filtered off, washed with water and after drying gain of 18.4 g (97%) of 6-hydroxy-4-isopropylaniline.

By the method similar to the method of preparative example 4, are obtained reaction product (0,004 mol) and 0.61 ml (0,0046 mol) of chlorocarbonylsulfenyl in toluene in the presence of 0.133 g (0,004 mol) TBAB and obtain 0.32 g (21% ) of 4-isopropyl-6-hydroxy-2-phenyldimethylsilane, so pl. 127 129,5oC, 1.78 g of which the process of 0.43 ml (0.73 g) sulfurylchloride in YFC and receive 1.2 g (84%) of 2-chloromethyl-4-isopropyl-6-hydroxycoumarin.

Preparative example 19A. We believe that the use of a technique similar to the technique of preparative example 19, Noreen.

Preparative example 20. In 150 ml of methanol is dissolved 5 g (0,0207 mol) of 6-hydroxy-4-isopropylaniline and to the solution was added 3.4 g (0,0104 mol) Cs2CO3. The mixture is stirred for 3 to 4 h at room temperature. The excess methanol is removed under reduced pressure, and the residue is dried for 2 hours in high vacuum. Then the residue is dissolved in 110 ml of DMF and to the solution was added 0.32 g (0,0209 mol) of chlorocarbonylsulfenyl. Stir the mixture is heated for 12 h at 70 75oC, cooled, treated with ice water and extracted with 600 mo mixture ethylacetate (4: 1). The organic layer was washed with saturated NaCl solution, dried and the solvent is removed under reduced pressure. The residue is purified displacement chromatography with elution with 20% ethyl acetate in YFC. Obtained 4.5 g (60% ) of 6-hydroxy-4-isopropyl-2-phenyldimethylsilane (so pl. 150 151,5oC) that in the reaction with sulfurylchloride by the method of preparative example 19 forms a 2-chloromethyl-6-hydroxy-4-isopropylaniline.

Preparative example 21. To a solution of 5-chloro-2-benzyl-4-isothiazolin-3-one (J. Het. Chem. 8, 571, 1971) (9.4 g, 0.04 mol) in YFC (100 ml) in one portion add 80-85% 3-chlormadinone acid (10.8 g, 0.06 mol) and the resulting mixture was stirred in the atmosphere and at room temperature, PR is acti dry, and the residue is distributed between ethyl acetate (300 ml) and a saturated solution of NaHCO3(100 ml). The layers are separated and the organic phase is washed with a saturated solution of NaHCO3(2 x 100 ml), brine (1 x 100 ml) and dried. Removal of solvent in vacuo get 10 grams (99 ) 5-chloro-2-benzyl-4-isothiazolin-3(2H)-one-1-oxide as a pale yellow oil.

1-Oxide (10 g, 0.04 mol) in glacial acetic acid (200 ml) is treated with 30% H2O2(100 ml, 0.88 mol) and heated for 2 h on a water bath with the addition during this time another 30 ml (0.26 mol) of 30% H2O2. After heating on a water bath for another hour, the reaction mixture was cooled to room temperature, transferred into ice water (1 l) and stirred. The formed precipitate is filtered off, washed with water (2 x 100 ml), hexane, and after drying in air obtained as colorless solids 4.8 g (45%) of 5-chloro-2-benzyl-4-isothiazolin-3(2H)-one-1,1-dioxide.

Dioxide (1.2 g, 4.7 mmol) is mixed with 2.02 g (11 mmol) of 2-trimethylsiloxy-5-methylhexan-1,3-diene (obtained from 5-metrex-3-ene by the method of E. J. Corey and others Tet. Lett. 495, 1984) in toluene and heated in a nitrogen atmosphere for 20 hours the mixture is cooled to room temperature and concentrated in vacuo. The residue is dissolved in THF (25 Mut ether (100 ml) and the layers separated. The organic phase is washed with water, brine, dried and evaporation to dryness get a pale yellow foam. The foam was dissolved in toluene (30 ml), added DBN (1,5 ml) and stirred for 2 h at room temperature. Add YFC (100 ml) and 2 N. HCl (50 ml) and stirring is continued for 5 minutes, the Layers separated and the organic phase washed with water, brine and dried. Removal of solvent in vacuo and purification of the residue pressure chromatography on silica gel (hexane-YFC-ether, 5:4:1) to obtain 0.6 g (39%) of 2-benzyl-4-isopropyl-6-oxo-tetrahydrofuran in the form of a pale yellow foam.

Tetrahydrofuran (0,59 g, 1.7 mmol) dissolved in toluene (50 ml) and to the solution was added dimethylamine hydrochloride (1.5 g, 18 mmol) and sieves (2 g). The resulting mixture was boiled for 96 h with azeotropic removal of water. It is necessary during these 96 h every 12 h add dimethylamine hydrochloride (0.8 g, 10 mmol) and sieves , and at the end of this period the reaction mixture is cooled to room temperature and filtered. The filter cake was washed with diethyl ether (100 ml) and concentration in vacuo of the combined filtrates obtained as a pale yellow solid 0,63 g (99%) of 2-benzyl-4-isopropyl-6-dimethylamino-(4,5)-dehydroalanine.

To a solution of digitrakker is a (4.3 g, a 49.5 mmol). After adding the last portion of the manganese dioxide, the reaction mixture is boiled for another hour, cooled to room temperature and filtered through a layer of Super-Zell with elution by ethyl acetate. United eluant concentrated in vacuo and purification of the residue pressure chromatography on silica gel (hexane-YFC-ether, 5: 4: 1) obtained as colorless solids 0.32 g (50) 2-benzyl-4-isopropyl-6-diethylaminocoumarin.

2-Bensisahar-(0.32 g, 0.9 mmol) in methanol (20 ml) is treated with ammonitrates (0.24 g, 3.8 mmol) and 10% Pd on charcoal, boiled for 1 h, cooled to room temperature and filtered through a layer of Super-Zell with elution with methanol (100 ml). United eluate concentrated in vacuo. The residue is dissolved in YFC (10 ml), add 0.25 ml of glacial acetic acid, stirred for 5 min and evaporation in vacuo to dryness obtained as colorless foam 0,25 (100%) 4-isopropyl-6-diethylaminocoumarin.

By the method similar to the method of preparative example 1, a mixture of 4-isopropyl-6-diethylaminocoumarin (0.27 g, 1 mmol), chlorocarbonylsulfenyl (0.32 g, 2 mmol) and tetrabutylammonium (0.1 g, 0.2 mmol) in toluene turn of 0.22 g (56%) 2-phenylthiomethyl-4-isopropyl-6-diethylaminocoumarin that obrm NMR) of 2-chloromethyl-4-isopropyl-6-dimethylamino-7-hariharan.

Preparative example 22A. 31 g of 4-Isopropyl-1,2-dimethoxybenzene treated by the method of preparative example 6B N-bromosuccinimide, then butyllithium and diethylcarbamazine and obtain 15.2 g of 2-isopropyl-4,5-dimethoxy-N,N-diethylbenzamide in the form of a viscous oil. Benzamid treated by the method of preparative example 18B by butyllithium and sulfur dioxide, then sulfurylchloride and finally ammonia and receive 4.5 g sulfonamida, so pl. 181 182oC from the ether. The cyclization sulfonamida in acetic acid by the method of preparative example 18B obtain 2.86 g of 6,7-dimethoxy-4-isopropylaniline, so pl. 210 212oC (ETHYLACETYLENE).

To a solution of 0.5 g of 4-isopropyl-6,7-dimethoxycoumarin in 3 ml of DMF at room temperature, add 0.5 ml of diisopropylethylamine. After 15 minutes add 0.35 g of chlorocarbonylsulfenyl and the mixture is heated for 16 h at 80oC. the Reaction mixture was transferred into EtOAc and washed with aqueous solution of Na2CO3water 2 N. HCl and saturated aqueous NaCl. The organic layer is dried over Na2SO4and the solvents removed. Chromatography with YFC obtain 0.35 g of the target product. Processing of 0.35 g of the sample phenyldimethylsilane in 3 ml of YFC for 30 min at 20oC, 0.1 ml of sulfurylchloride.

Preparative example 22B. To a solution of 5.7 g of methylpiperidine in 20 ml of dry ether at 0oC for 20 min was added 30 ml of 3 M solution methylacrylamide in the air. The mixture is stirred for 20 h, then diluted with 200 ml of ether and washed with water. The organic layer is dried over Na2SO4and after evaporation of the solvent to obtain 5.6 g of crude 3,4-dimethoxy-(1'-hydroxy-1'-methylethyl)benzene. Received the product immediately treated with 50 ml of acetic acid and 1 g of 10% Pd/C for 20 h under hydrogen pressure of 50 psi (3.5 kg/cm2). Filtration to remove the catalyst and evaporation of the solvent to obtain 4.5 g of 5-isopropyl-1,3-benzodioxole. Bromirovanii, amidation, sulfonation and cyclization of isopropylthiazole by the method of preparative example 22A obtain 700 mg of 4-isopropyl-6,7-methylenedioxyaniline, so pl. 226 228oC (from ethyl acetate-hexane). Chlorotoluene 500 mg of saccharin by the method of preparative example 22A receive 300 mg of 2-chloromethyl-4-isopropyl-6,7-methylenedioxyaniline, so pl. 174 176oC.

Other 4-R1-R2-R3-sacharine formula II, used as intermediate products for the synthesis of compounds of formula I can be obtained as follows.

The reaction of 2-trif is an amine gives 2-trifluoromethyl-N, N-diethylbenzamide. By the method similar to the method of preparative example 5, reaction of the latter with second-butyllithium and reaction of the obtained lithium salt with sulfur dioxide and then with a sodium salt of hydroxylamine-0-sulfonic acid to obtain 2-trifluoromethyl-6-aminosulfonyl--N,N-diethylbenzamide, which when heated in glacial acetic acid forms a 4-cryptomaterial.

Similarly, the reaction of 2-trichloromethylbenzene acid with thionyl chloride receive 2-trichloromethylbenzene, which in reaction with diethylamine forms a 2-trichloromethyl-N, N-diethylbenzamide. By the method similar to the method of preparative example 5, reaction of the latter with second-butyllithium and reaction of the obtained lithium salt with sulfur dioxide and then with a sodium salt of hydroxylamine-0-sulfonic acid get 2 trichloromethyl-6-aminosulfonyl-N,N-diethylbenzamide, which when heated in glacial acetic acid forms a 4-trichlorotriazine.

The reaction of 4-cyclohexylbenzene acid with thionyl chloride receive a 4-cyclohexylbenzothiazole, which in reaction with diethylamine forms 4-cyclohexyl-N,N-diethylbenzamide. By the method similar to the method of preparative example 5, the last in the reaction with sec-butyl is-0-sulfonic acid forms a 4-cyclohexyl-2-aminosulfonyl-N,N-diethylbenzamide, which when heated in glacial acetic acid gives 6-cyclohexylaniline.

Benzylalkonium 6-nitrosourea get 2-benzyl-6-nitrofuran that when restoring chloride tin (II) and aqueous hydrochloric acid to form 2-benzyl-6-aminocoumarin. Reaction of the latter with methanesulfonamido, triftormetilfullerenov or trichlorocarbanilide in YFC in the presence of pyridine, followed by hydrogenolysis in the presence of transition metal 2-benzyl protective groups are, respectively, 6-methylsulfonylmethane, 6-triftormetilfullerenov or 6-trichlorotrifluoroethane.

The diazotization of 6-aminocoumarin nitrous acid in acidic medium and decomposition of the resulting diazonium salts in the presence of copper cyanide (II) or copper chloride (II) and sulfur dioxide or chloride copper (II) and alkali-metal salt of methylmercaptan or triftoratsetata are respectively 6-cyanoalanine, 6-chlorosulfonylphenyl, 6-methylcoumarin or 6-cryptomaterial. The reaction of 6-chlorotriphenylmethane in situ with ammonia or methanesulfonamido are respectively 6-aminosulphonylphenyl and 6-methanesulfonylaminoethyl. Ociety are respectively 6-methylsulfonylamino and 6-triftormetilfosfinov.

Hydrolysis of 6-cyanoalanine by heating with aqueous sodium hydroxide receive saccharin-6-carboxylic acid. N-Benzilidene 6-cyanoalanine get 2-benzyl-6-cyanoalanine. Alkaline hydrolysis of the latter is obtained 2-bensisahar-6-carboxylic acid, which upon conversion into the acid chloride 2-bensisahar-6-carboxylic acid in the reaction with thionyl chloride, followed by exhaustive hydrogenation in the presence of palladium on coal forms a 6-hydroxymitragynine. Oxidation of the latter complex pyridine-chromium trioxide (2:1) (Collins reagent) in YFC get 6-formicary, by reductive amination of which ammonia receive 6-aminotetralin.

The reaction of 4-triftorperasin acid with thionyl chloride receive the acid chloride 4-triftorperasin acid, which in reaction with diethylamine forms 4-trifluoromethyl-N,N-diethylbenzamide. By the method similar to the method of preparative example 5, the reaction of the amide with second-butyllithium and reaction of the obtained lithium salt with sulfur dioxide and then with a sodium salt of hydroxylamine-O-sulfonic acid to obtain 4-trifluoromethyl-2-aminosulfonyl-N,N-diethylbenzamide, which when heated in glacial acetic acid forms a 6-titelbezeichnet, which in reaction with diethylamine forms a 4-trichloromethyl-N, N-diethylbenzamide. By the method similar to the method of preparative example 5, reaction of the latter with second-butyllithium and reaction of the obtained lithium salt with sulfur dioxide and then with a sodium salt of hydroxylamine-O-sulfonic acid to obtain 4-trichloromethyl-2-aminosulfonyl-N,N-diethylbenzamide, which when heated in glacial acetic acid forms a 6-trichlorotriazine.

The reaction of 2-ethanbentley acid with thionyl chloride receive 2-ethenylbenzene, which in reaction with diethylamine forms a 2-ethynyl-N,N-diethylbenzamide. Reaction of the latter with second-butyllithium and reaction of the obtained lithium salt with sulfur dioxide and then with a sodium salt of hydroxylamine-O-sulfonic acid to obtain 2-ethynyl-6-aminosulfonyl-N,N-diethylbenzamide, which when heated in glacial acetic acid forms a 4-itinerarary.

The reaction of 2-ethynyl-6-aminosulfonyl-N,N-diethylbenzamide with bromine receive 2-(1,2-dibromoethyl)-6-aminosulfonyl-N, N-diethylbenzamide, which in reaction with Amida sodium in ammonia forms a 2-ethinyl-6-aminosulfonyl-N,N-diethylbenzamide, heated in glacial acetic acid is obtained 4-atinnisfail.

R the presence of potassium carbonate receive 2-(N,N-dibenzylamino)benzoic acid ethyl ester, when saponification in aqueous-ethanolic solution of potassium hydroxide with the release of the product from a neutral environment receive 2-(N-N-dibenzylamino)benzoic acid.

Reaction of the latter with thionyl chloride receive 2-(N, N-dibenzylamino)benzoyl chloride, which in reaction with citramonum forms a 2-(N,N-dibenzylamino)-N-N-diethylbenzamide. The reaction of the amide obtained with second-butyllithium and reaction of the resulting lithium salt with sulfur dioxide and then with a sodium salt of hydroxylamine-O-sulfonic acid to obtain 2-(N,N-dibenzylamino)-6-aminosulfonyl-N, N-diethylbenzamide, which when heated in glacial acetic acid forms a 4-(N-N-dibenzylamino)saccharin, kataliticheskim dibenzylammonium which hydrogen in the presence of palladium on coal receive a 4-aminocoumarin. Reductive alkylation last one modernim equivalent of formaldehyde in formic acid is obtained 4-methylaminoethanol. The diazotization of 4-aminocoumarin nitrous acid in acidic medium and decomposition of the obtained diazonium salts in the presence of copper cyanide (II) receive a 4-cyanoalanine.

Selective N-benzilidene cesium salt of 6-hydroxy-4-isopropylaniline (preparative example 19) benzylbromide and response the EPA 12 get 2-benzyl-4-isopropyl-6-(N,N-diethylthiocarbamate)saccharin, which when heated programmirovaniya 2-benzyl-4-isopropyl-6-(N, N-diethylcarbamyl)saccharin. Last alkaline hydrolysis is converted into 2-benzyl-4-isopropyl-6-mercaptopurin, which in reaction with methyliodide with subsequent hydrogenolysis forms 4-isopropyl-6-methylcoumarin. Oxidation last one or two malernee equivalently 3-chlormadinone acid get 4-isopropyl-6-methylsulfonylamino and 4-isopropyl-6-methylsulfonylamino.

The reaction of 2-isopropyl-4-fermenting acid with thionyl chloride receive 2-isopropyl-4-perbenzoate, which in reaction with diethylamine forms 2-isopropyl-4-fluoro-N, N-diethylbenzamide. Reaction of the latter with second-butyllithium and reaction of the obtained lithium salt with sulfur dioxide and then with a sodium salt of hydroxylamine-O-sulfonic acid to obtain 2-isopropyl-4-fluoro-2-aminosulfonyl-N, N-diethylbenzamide, which when heated in glacial acetic acid forms 4-isopropyl-6-forsharing.

Reaction of the latter with thiophenols, 4-methylphenylimino, 4-chlorpheniram, 1-mercapto-4-methylnaphthalene or 1-mercaptoethanol by heating the reagents in DMF are respectively 4-isopropyl-6-penaltyshall, 4-isopropyl-6-the saw-6-(4-methyl-1-naphthylthio)saccharin, 4-isopropyl-6-(1-naphthylthio)saccharin, oxidation which in each case one or two malernee equivalents of 3-chlormadinone acid lead to 4-isopropyl-6-vinylsulfonylacetamido, 4-isopropyl-6-phenyl-sulfonylamino, 4-isopropyl-6-(4-methylphenylsulfonyl)the saccharin, 4-isopropyl-6-(4-methylphenylsulfonyl)the saccharin, 4-isopropyl-6-(4-methoxybenzenesulfonyl)the saccharin, 4-isopropyl-6-(4-methoxybenzenesulfonyl)the saccharin, 4-isopropyl-6-(4-chlorophenylsulfonyl)the saccharine, 4-isopropyl-6-(4-chlorophenylsulfonyl)the saccharin, 4-isopropyl-6-(4-methyl-1-naphthylmethyl)the saccharin, 4-isopropyl-6-(4-methyl-1-naphthylmethyl)the saccharin, 4-isopropyl-6-(1-naphthylmethyl)the saccharin, 4-isopropyl-6-(1-naphthylmethyl)the saccharine.

The reaction of 2-benzyl-6-hydroxy-4-isopropylaniline with one modernim equivalent of acetic anhydride, benzoyl chloride or acid chloride of 1-naftilaminom acid, followed by hydrogenolysis in each case are respectively 4-isopropyl-6-acetoxyacetyl, 4-isopropyl-6-benzoyloxymethyl and 4-isopropyl-6-(1-niftycorners)saccharin.

By heating 4-isopropyl-6-forsharing in DMF with azetidinol, pyrrolidine, piperidine, morpholine, 1-benzylpiperazine, 1-methylpiperazine, imidazole, tert-butyl-alpha-aminoacetate or AMIA is l-6-(1-piperidinyl)saccharin, 4-isopropyl-6-(4-morpholinyl)saccharin, 4-isopropyl-6-(4-benzyl-1-piperazinil)saccharin, 4-isopropyl-6-(4-methyl-1-piperazinil)saccharin, 4-isopropyl-6-(1-1H-imidazolyl)saccharin, 4-isopropyl-6-(tert-butoxycarbonylmethylene)saccharin, 4-isopropyl-6-aminocoumarin.

Catalytic dibenzylammonium 4-isopropyl-6-(4-benzyl-1-piperazinil)saccharin hydrogen in the presence of palladium on coal receive a 4-isopropyl-6-(1-piperazinil)saccharin.

Hydrolysis of 4-isopropyl-6-(tert-butoxycarbonylmethyl-amino)saccharin diluted hydrochloric acid and isolation of the product from a neutral environment receive a 4-isopropyl-6-carboxymethylaminomethyl.

The reaction of 4-isopropyl-6-aminocoumarin with one modernim equivalent of acetylchloride get 4-isopropyl-6-acetaminoohen.

The saponification of 4-methoxycarbonylamino (preparative example 9D) in the appropriate saccharin-4-carboxylic acid by alkaline hydrolysis, conversion of the acid into the corresponding acid chloride by reaction of the acid with thionyl chloride and reaction of the acid chloride with ammonia receive saccharin-4-carboxamide.

Reaction of each of the thus obtained 4-R4-R5-saccharin with paraformaldehyde and chlorotrimethylsilane in prisutstvie table. 2, where in each case X=Cl.

Preparative example 23BK. Reaction isothiazol-5-carboxaldehyde with lithium-3-(triphenylphosphonio)propanoate in a standard reaction conditions of the Wittig receive a 4-(5-isothiazole)-3-butenova acid, which restores and cyclist in the presence of aluminum chloride to obtain 4-oxo-4,5,6,7-tetrahydroindazole. 4-Oxoproline enter into reaction with methyltriphenylphosphonium in the standard conditions of the Wittig reaction and carrying out the reaction of the Simmons-Smith in the received 4-methylandrosta injected methylene and receive 6,7-dihydrospiro[benzisothiazol-4(5H), 1'-cyclopropane] oxidation which hydrogen peroxide in acetic acid leads to 6,7-dihydrospiro[3-oxopentanoate-4(5H), 1'- cyclopropane] -1,1-dioxide (4-spirocyclopropane). Chlorotoluene product by the method of preparative example 1A receive 2-chloromethyl-4-spirocyclopropane-4,5,6,7-tetrahydrofuran.

Preparative example 23BL. 2-Benzyl-4-isopropyl-6-oxitetraciclina (see preparative example 21) restore the borohydride sodium and iodide was identified in the stands in the presence of sodium hydride to obtain 2-benzyl-4-isopropyl-6-methoxytryptamine. Dibenzylammonium-4,5,6,7-tetrahydrofuran.

The final products.

Example 1.

A General method. The mixture of excess N,N-diisopropylethylamine acceptable solvent and excess of the corresponding derived akriluksusnoy acid or aryloxyalkanoic acid is stirred for about 5 minutes, then add one equivalent of the appropriately substituted derivative 2-chlorotriazine. The mixture is then stirred for 1 to 24 h at the same temperature. The reaction mixture was extracted with ethyl acetate, the organic layer was washed with a saturated solution of NaHCO3and dried over anhydrous Na2SO4. Removal of solvent in vacuo and purification of the residue by chromatography or recrystallization, if necessary, to obtain the compounds of formula I, are given in table. 3. In the case of examples 1A, 1B and 1C of the original product is 2-bremershaven. In examples 1D 1H reference compound is 2-chloromethyl-4-isopropylaniline, as in examples 1I 1K starting compound is 2-chloromethyl-4-isopropyl-6-methoxycoumarin.

We believe that the reaction of the corresponding 4-R4-R5-2-peloidoterapija formula IV with an acceptable aryl - or aryloxyalkanoic acid by the method substantially similar to the method of example 1, can be 2 2-chloromethyl-4 - spirocyclopropane-4,5,6,7-tetrahydrofuran (see preparative example V) can be connected with-methoxyphenylacetic acid with the formation of 4 - spirocyclopropane-4,5,6,7-tetrahydro-2 - sharonlee-a-methoxyphenylacetate.

Example 2CS. We believe that by the method of example 2, 2-chloromethyl-4 - isopropyl-6-methoxy-4,5,6,7-tetrahydrofuran (see preparative example 23BJ) can be connected to the a-methoxyphenylacetic acid with the formation of 4 - isopropyl-6-methoxy-4,5,6,7-tetrahydro-2-sharonlee-a-methoxyphenylacetate.

Example 3A. Believes that 6-ethoxy-4-isopropyl-2 - sharonlee-alpha methoxyphenylacetate can be obtained by treatment of 6-hydroxy-4 - isopropyl-2-sharonlee-a-methoxyphenylacetate with triphenylphosphine and diethylazodicarboxylate in the presence of ethanol.

We believe that the method is essentially similar to the method of example 3A, on the basis of 6 hydroxy-4-isopropyl-2 - sharonlee-a-methoxyphenylacetate and the corresponding alcohol can be synthesized compounds are given in table. 5.

Glycerin, which can be used in the synthesis of example 3F was obtained as follows.

To a suspension 15,38 g (0,137 mol) of tert-butoxide potassium in 300 ml of THF added a solution of 10 g (by 0.055 mol of DL-alpha-O-benzylglycine in nebulite. The reaction mixture was stirred for 10 h at room temperature, cooled, carefully dilute with sodium chloride solution and extracted with ether. The organic layer is washed with water, 5% HCl, water, saturated NaCl solution and dried. The solvent is removed and purification of the residue pressure chromatography receive in the form of oil 9,16 g (79%) of 1-benzyloxy-2,3-dimethoxypropane.

A solution of 8.8 g (0.42 mol) of the obtained product in 200 ml of MeOH hydronaut in the presence of 1.1 g of 10% Pd-C at 50 psi; (3.5 kg/cm2). The catalyst is filtered off and removal of solvent under reduced pressure to obtain 4.4 g (87%) of 2,3-dimethoxy-1-propanol.

Example 3 0. According to the method of example 3A from 6-hydroxyanisole (preparative example 19) are obtained with a yield of 85% 6 ethoxy-4 - isopropyl-2 - phenyldimethylsilane (so pl. 111,5 112,5oC) by the method of preparative example 18A with the release of 91% turn 2-chloromethyl-6-ethoxy-4-isopropylaniline (so pl. 127 128oC).

Example 3P. We believe that the method is essentially similar to the method of example 3A, 4-benzyloxy-2-sharonlee-a - methoxyphenylacetic can be obtained from benzyl alcohol and 4-hydroxy-2-sharonlee - alpha methoxyphenylacetate.

Example 4. We believe that 6-hydroxy-4 - of the acid with the formation of 4-isopropyl-6 - triftoratsetilatsetonom-alpha methoxyphenylacetate.

Received triftorbyenzola can then be heated in the presence of 1-methyl-2-trimethylaniline, tetrakis(triphenylphosphine)palladium (0), lithium chloride, 2,6-di-tert-butyl-4 - METHYLPHENOL and p-dioxane with the formation of 4-isopropyl-6[2-[1-methyl]pyrrolyl]sharonlee-alpha methoxyphenylacetate.

Example 5. We believe that treatment triftoratsetata example 4 dimethylamine should lead to the formation of 4-isopropyl-6-dimethylaminocarbonylmethyl-alpha methoxyphenylacetate.

Example 6. We believe that heating a mixture of 4-isopropyl-6 - hydroxy-2-sharonlee-alpha methoxyphenylacetate and di(sec-butoxymethyl)of methylamine in toluene should lead to the formation of 2-(alpha - methoxyphenylacetylene)-4-isopropyl-8-methyl-2,3,7,8-tetrahydro-9H-[1,3]oxazino/6,5-g/benzisothiazol-3-one-1,1-dioxide.

Example 7. We believe that the processing of isopropylidene example 3C (table. 3) monohydrate p-toluenesulfonic acid in methanol will cause 6-(2,3-dihydroxypropane) -4 - isopropylaminomethyl-alpha methoxyphenylacetate.

Example 8. We believe that the treatment of 6-hydroxy-4-isopropyl-2-sharonlee-alpha methoxyphenylacetate tert-butylbromide and K2CO3acetone will give 6-(2-tert-bout what Lovanium of benzylbromide can be obtained 6-(2-benzyloxy-2-oksidoksi)-4-isopropyl-2-chainmail-alpha methoxyphenylacetate.

Example 9A. To fresh the cyclopentadiene (25 ml) at 0oC added 7.9 g (0.03 mol) of 4-bromo-2-(tert-butyl)isothiazol-3(2H)-one-1,1-dioxide (Helv. Chim. Acta, 72, 1416, 1989). After peremesheniya 16 h at 0oC in nitrogen atmosphere the mixture was concentrated in vacuo. The residue is purified by filtration through silica gel with elution with hexane (500 ml), then 20% ethyl acetate in hexane (500 ml). Concentration in vacuo of the later eluate obtained as white solids of 9.8 g (100%) normalinogo adduct 3A-bromo-2-tert-butyl-3A, 4,7,7-tetrahydro-4,7-methane-1,2-benzisothiazol - 3(2H)-one-1,1-dioxide.

Adduct (0.4 g, 1.2 mmol) in 25 ml of ethyl acetate in the presence of 5% Pd on CaCO3(0.2 g) is stirred for 4 h under hydrogen pressure at one atmosphere and then the reaction mixture was filtered through a layer of silica gel with elution by ethyl acetate (100 ml). Eluate concentrated in vacuo and crystallization of the residue from hexane receive in the form of a white crystalline substance of 0.4 g (100%) of bromobutane.

To a solution of bromobutane (3.7 g, to 0.011 mol) in toluene (10 ml) at 0oC add diazabicyclo (1,37 g to 0.011 mol) in toluene (10 ml). After stirring 20 min at 0oC to the reaction mixture add silica gel (25 g). The obtained suspension per the ATA in vacuum obtained as white solids 2.8 g (100%) dehydrobrominated derived.

2-Tert-butyl-4,5,6,7-tetrahydro-4,7-methane-1,2-benzisothiazol -3(2H)-one-1,1-dioxide (2.8 g, to 0.011 mol) in 30 ml triperoxonane acid is boiled for 48 h and left for 4 days at room temperature. The resulting mixture was concentrated in vacuo, treated with methanol (20 ml) and evaporated to dryness. The residue is transferred in ether (100 ml) and washed with saturated solution of NaHCO3(G ml). The layers separated, the aqueous phase is acidified with 2 N. HCl to pH 1 and extracted with YFC (g ml). The combined organic extracts dried and concentrated in vacuo receive in the form of a white solid substance 0.9 g (42%) bicyclo derivative/2.2.1/saccharin.

A mixture of bicyclo derivative/2.2.1/saccharin (0.9 g, 5 mmol), chlorocarbonylsulfenyl (0.07 g, 7 mmol) and 0.36 g (0.16 mmol) of tetrabutylammonium in toluene (50 ml) is boiled for 16 hours under nitrogen atmosphere, cooled to room temperature and evaporated in vacuum to dryness. Purification of the residue pressure chromatography on silica gel (100 g) using as eluent 100% YFC receive in the form of a viscous oil of 1.05 g (72%) of the sulfide.

Sulfide (of 1.05 g, 3 mmol) in dichloromethane (100 ml) is treated with sulfurylchloride (0.66 g, 5 mmol) and stirred for 2 h the Resulting yellow solution was diluted with YFC (100 ml), washed with saturated of rest the Le (33% YFC in hexane) to obtain 0.66 g (81%) of 2-chloromethyl-4,5,6,7-tetrahydro-4,7-methane-1,2-benzisothiazol-3(2H)-one-1,1-dioxide.

We believe that treatment of 2-chloromethylphosphonic by the method similar to the method of example 2, a-methoxyphenylacetic acid, 2-phenyl-2 - methylpropionic acid, 2-(4-chlorophenoxy) -2 - methylpropionic acid, 4-trifluoromethyl-phenylacetic acid, 4-methoxyphenylacetic acid or 4-methylphenylacetic acid will lead respectively to 2-( a - methoxyphenylacetylene) -4,5,6,7-tetrahydro-4,7-methane-1,2-benzisothiazol-3(2H)-one-1,1-dioxide, 2-( a, -dimethylphenylethylamine)-4,5,6,7-tetrahydro-4,7 methane-1,2-benzisothiazol -3(2H)-one-1,1-dioxide, 2-(a, a-dimethyl-4 - chlorophenoxyacetate)-4,5,7-tetrahydro-4,7-methane-1,2-benzisothiazol-3(2H)-one-1,1-dioxide, 2-(4-triftormetilfullerenov)-4,5,6,7-tetrahydro-4,7-methane - 1,2-benzisothiazol 3(2H)-one-1,1-dioxide, 2 -(4-methoxyphenylacetylene)-4,5,6,7 tetrahydro - 4,7-methane-1,2-benzisothiazol -3(2H)-one-1,1-dioxide or 2-(4 - methylphenylacetonitrile)-4,5,6,7-tetrahydro-4,7-methane-1,2-benzisothiazol -3(2H)-one-1,1 dioxide.

Examples 9B and 9C. We believe that the same way of example 9A, cyclohexadiene and 1,1-dimethylcyclopentane can be transformed, respectively, in 2 chloromethyl-4,5,6,7-tetrahydro-4,7 km ethano-1,2 - benzisothiazol-3(2H)-one-1,1-dioxide and 2-chlormethyl-8,8-dimethyl-4,5,6, is there to be processed corresponding aryl - or aryloxyalkanoic acid with the formation of 2-( a-methoxyphenylacetylene)

4,5,6,7-tetrahydro-4,7-ethano-1,2-benzisothiazol-3(2H) one-1,1 dioxide, 2-(4 - triftormetilfullerenov)-4,5,6,7-tetrahydro-4,7-ethano - 1,2-benzisothiazol 3(2H)-one-1,1 - dioxide, 2-( a, -dimethylphenylcarbamate) 4,5,6,7 tetrahydro-4,7-ethano-1,2 - benzisothiazol-3(2H)-one-1,1-dioxide, 2-(4 methoxyphenylacetylene)-8,8 - dimethyl-4,5,6,7-tetrahydro-4,7-methane-1,2-benzisothiazol - 3(2H)-one-1,1-dioxide, 2-( a, a-dimethyl-4-chlorophenoxyacetate) - 8,8-dimethyl 4,5,6,7-tetrahydro-4,7-methane-1,2-benzisothiazol-3(2H)-one-1,1 - dioxide or 2-(4 - methylphenylacetonitrile)-8,8-dimethyl-4,5,6,7-tetrahydro-4,7 - methane-1,2-benzisothiazol -3(2H)-1,1-dioxide.

Examples 10A-10L. A General method of obtaining methyl-2-alkylcyclohexane-6-noncarboxylic. To a suspension of anhydrous Cu1 (10 mmol) in anhydrous THF (100 ml) add Me2S (100 mmol) and the resulting solution cooled to -78oC. for 15 minutes, add the appropriate alkyllithium reagent and after stirring 1 h at -78oC add a solution of cyclohexanone (10 mmol) in THF and stirring is continued for another 15 minutes To the mixture add HMPA (5 ml), after 15 min add metilo day. Then the reaction mixture is neutralized 2n. HCL (50 ml). The layers are separated and the aqueous phase extracted with Et2O (1 x 100 ml). The combined organic extracts washed with a saturated solution of NH4Cl (3 x 50 ml), water (2 x 50 ml), brine (1 x 50 ml) and dried (PA2SO4). Removal of solvent in vacuo and purification of the residue or by distillation in unit Cuellar or pressure chromatography receive targeted methyl-2-alkylcyclohexane-6-noncarboxylic (PL. 6).

A General method of obtaining 2-benzylthio-6 - alkylcyclohexane-2-enecarboxylate and 2 benzylthio-6-alkylcyclohexane-1 enecarboxylate. A mixture of methyl-2-alkylcyclohexane-6-noncarboxylic (1 EQ.), benzylmercaptan (1.1 EQ.) and acidic montmorillonite clay KSF (one and a half times by weight methyl-2 - alkylcyclohexane-6-noncarboxylic) in anhydrous toluene (50 to 100 ml) is boiled for 12 to 14 h in an atmosphere of nitrogen with azeotropic removal of water, and then cooled to room temperature. The precipitate is filtered and washed with ether. The combined filtrate washed with 10% solution of Na2CO3, water, brine and dried. Removal of solvent in vacuo and purification of the residue pressure chromatography on silica gel (10% ether in hexane) to obtain a mixture of methyl-2 - benzylthio-6-alkyltin is Tadei used without separation of the components.

A General method of obtaining 4-alkyltetrahydrofuranes.

A solution of methyl-2-benzothia-6 - alkylcyclohexane-2 - enecarboxylate and methyl-2-benzylthio-6-alkylcyclohexane-1 enecarboxylate (1 to 10 mmol of the mixture) in 10 ml of YFC diluted 20 50 ml of glacial acetic acid and 1 5 ml of water, the mixture is cooled to -10oC and through a mixture propulsive gaseous chlorine to stop the heat. The mixture is then stirred for 10 min and evaporation to dryness receive a mixture of methyl-2 - chlorosulfonyl-6-alkylcyclohexane-2 - enecarboxylate and methyl-2-chlorosulfonyl-6-alkylcyclohexane-1 enecarboxylate, which is dissolved in 10 ml of THF and added dropwise while cooling with dry ice in acetone to 25 ml of concentrated solution of ammonium hydroxide. After stirring 2 h, the reaction mixture was concentrated in vacuo, the residue is transferred into water, acidified with 2 N. HCl to pH 1 and extracted with YFC. The organic phase is dried and concentrated in vacuum to obtain a mixture of methyl-2 - aminosulfonyl-6-alkylcyclohexane-2 - enecarboxylate and methyl-2-aminosulfonyl-6-alkylcyclohexane-1 enecarboxylate. The mixture is dissolved in methanol and added to the freshly prepared sodium methoxide (10 50 mmol), stirred for 12 h at room temperature. The reaction mixture was concentrated in vacuo, Rabbi HCl to pH 1 and extracted with YFC. From organic extracts, after washing with brine, drying and evaporation receive a 4-alkyl-45,6,7-tetrahydrobenzoic-3-one-1,1-dioxide or 4-alkyltetrahydrofuranes (PL. 8).

A mixture of 4-alkyl-4,5,6,7 tetrahedralization-3-one-1,1-dioxide (4-alkyldiethanolamine) (1 EQ. ), chlorocarbonylsulfenyl (1.5 EQ.) and tetrabutylammonium (0.2 EQ.) in toluene (25 ml/g of saccharin) is boiled under nitrogen atmosphere for 16 to 24 hours and then cooled to room temperature. The resulting mixture is evaporated to dryness and chromatography of the residue on silica gel with elution by the mixture hexane YFC (1 1 1 3) receive the corresponding 2-phenylthiomethyl-4 - alkyl-4,5,6,7-tetrahydrobenzoic-3-one-1,1-dioxide or 2-phenylthiomethyl-4 - alkyltetrahydrofuranes (PL. 9).

A solution of 2-phenylthiomethyl-4 - alkyldiethanolamine (1 EQ.) treated with sulfurylchloride (1.5 EQ.) and stirred for 2 hours Evaporation to dryness the resulting yellow solution obtain 2-chloromethyl-4 - alkyltetrahydrofuranes. We believe that this derivative can be heated with an appropriate derivative of an aryl - or akriluksusnoy acid, anhydrous potassium carbonate and tetrabutylammonium in DMF with formation of the corresponding 4 alkyl-4,5,6,7-tetrahydro-2-shrinelike anhydrous CuI (70 g, of 0.37 mol) in absolute ether (500 ml) at 0oC type not containing halide motility (520 ml, 1.4 M solution in ether, 0.73 mmol). After stirring 15 min at 0oC add a solution of 3-methyl-2-cyclohexenone (20 g, 0.18 mol) in ether (50 ml) and stirring is continued for another 1 hour To the resulting mixture is added THF (50 ml) and HMPA 825 ml) after 5 min medicinepharmacy (45 g, of 0.53 mol) in THF (20 ml), the reaction mixture is heated to room temperature and stirred for 3 h Then the reaction mixture is neutralized 2 N. HCl (50 ml). The layers are separated and the aqueous phase extracted with Et2O (1x500 ml). The combined organic extracts washed with a saturated solution of NH4Cl (g ml), water (2 x 50 ml), brine (1 x 50 ml) and dried (Na2SO4). Removal of solvent in vacuo and purification distillation equipment Cuellar obtain 34 g (99%) of methyl 2,2-dimethylcyclohexane-6-noncarboxylic, so Kip. 80 84oC/0.6 mm

According to the method described for examples 10A-10L, cyclohexanone can be converted into 4,4-dimethyl 4,5,6,7-tetrahydro-2-sharonlee-alpha methoxyphenylacetate.

It should be stated that the above methods are equally applicable to the synthesis of various other typical 4-R4-R5-2 - sharonlee or the CSOs 4-R4-R5-2-peloidoterapija or 4,5,6,7-tetrahydro-2-peloidoterapija acceptable derivative of an aryl - or aryloxyalkanoic acid should lead to the formation of target-derived 4-R4-R5-2-sharonlee or 4,5,6,7-tetrahydro-2 - sharinaletisha or aryloxyacetic, which, in turn, may change according to the functional groups of the type described in examples 3A-3P, with the formation of other 4-R4-R5-2-sharonlee or 4,5,6,7-tetrahydro-2-sharinaletisha or aryloxyacetic.

Determination of the inhibition constants (Kandfor complex LA-inhibitor described for a truly reversible inhibition constants, usually related to design inhibitors [Cha, Biochem, Pharmacol, 24, 2177 - 2185 (1975)] However, compounds of the present invention do not form a truly reversible complexes inhibition, but to some extent consumed by the enzyme. So instead of defining Kandcalculate the value of K*andwhich is defined as the ratio of the kd/kDeux, i.e. the degree of reactivation of the enzyme to the degree of deactivation of the enzyme. Values of kdand kDeuxdefine, then calculate the value of K*and< / BR>
The degree of de is effective activity of aliquots of the appropriate enzyme as a function of time after addition of test compounds. Building plot of log enzymatic activity from time to time get the value of the observed degree of decontamination (kOBS), which can be represented as kOBSIn2t1/2where t1/2the time required for 50% fall in enzyme activity. The degree of decontamination is then expressed by the following equation:

< / BR>
where [In] the concentration of inhibitory compounds.

Similarly define a constant reactivation (kd, and then calculate K*and< / BR>
K*and=kd/kDeux< / BR>
The obtained values of kDeuxand K*andfor typical substituted saccharin derivatives are given in table. 11, where connections are specified under the numbers of the examples described their reception.

Typical examples of the composition.

Dry capsules containing 100 mg of the compound of example 1.

Ingredient Amount mg capsule

Connection 100

Lactose 149

Magnesium stearate 1

Capsule (N 1) 250

The connection is crushed into powder to the specified particle size and magnesium stearate and lactose are passed through the filter cloth with the same pore size directly on the powder. Ingredients Malchut and also mixed with crushed inert ingredients according to the recipe, and then pressed into tablets using standard hardware.

1. 2-Sharonlee(aryl or aryloxy) acetates of the formula I

< / BR>
where m is 0 or 1;

n is 0 or 1;

m + n is 0 or 1;

R1hydrogen or lower alkyl;

R2hydrogen or lower alkyl;

R3phenyl or phenyl substituted with one to three same or different Halogens;

R4hydrogen, lower alkyl or lower alkoxy;

R5hydrogen, or one substituent in any of the 5-, 6 - or 7-positions selected from lower alkyl, lower alkoxy, hydroxy(lower)alkyl, hydroxy(lower)alkoxy,

or their salts formed by addition of acids to these compounds, the main character, or their salts, formed by adding bases to these compounds acidic character.

2. Connection on p. 1, where R4hydrogen, lower alkyl or lower alkoxy and R5hydrogen, lower alkoxy or hydroxy(lower)alkoxy.

3. Connection PP. 1 and 2, where R1hydrogen or methyl, R2hydrogen or methyl, R3phenyl or substituted phenyl, R4is hydrogen or lower alkyl; R5hydrogen or lower alkoxy.

4. Connection on p. 2, where n 0.

5. Connection on p. 4, where m 0; R4Il; R2methyl; R3phenyl; R4hydrogen or isopropyl; R5the hydrogen.

7. Connection on p. 4, where m is 1; R4hydrogen or lower alkyl; R5hydrogen or lower alkoxy.

8. Connection on p. 7, where R1hydrogen or methyl; R2is isopropyl; R5hydrogen or methoxy.

9. Connection on p. 2, where m is 0 and n is 1.

10. Connection on p. 9, where R4hydrogen or lower alkyl; R5hydrogen or lower alkoxy.

11. Connection on p. 10, where R1methyl; R2methyl; R3phenyl or phenyl substituted by chlorine; R4hydrogen or isopropyl; R5the hydrogen.

12. Connection on p. 1, the inhibitory activity of the proteolytic enzyme.

13. The pharmaceutical composition inhibiting activity of proteolytic enzymes, containing the active ingredient and pharmaceutically acceptable carrier, wherein the active ingredient contains a compound of formula I under item 1 in an effective amount.

 

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

< / BR>
where X is oxygen or sulfur;

Y is carbon or nitrogen;

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

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

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

R5and R6independent from each other and denote hydrogen or methyl;

n is 0,1 or 2,

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

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

The invention relates to new 2-sharonlee heterocyclic carboxylates, inhibiting the enzymatic activity of proteolytic enzymes, containing compositions, to a method of their use for the treatment of diseases associated with degeneration of the tissues, and to a method of production thereof

The invention relates to new benzanilide derivatives, processes for their preparation and the pharmaceutical compositions

The invention relates to organic chemistry, and more specifically to new connections - hydrochloridum 2-aminoimidazole and 2-aminothiazole General formula (1),

< / BR>
aryl, the substituent in position 4 and a disulfide bridge in the position 5, where X is alkylamino, for example, methylamino, and R1-R2is hydrogen; X-methylaminopropyl, and R1-alkyl, for example methyl and R2is hydrogen; X-methylaminopropyl, and R1-alkoxygroup, for example, methoxy and R2is hydrogen; X-methylaminopropyl, and R1-ethoxypropan and R2is hydrogen; X-methylaminopropyl, and R1halogen, for example chlorine and RF2is hydrogen; X-methylaminopropyl, and R1-R2-alkoxygroup, for example, methoxy; X-atramentaria, and R1-alkoxygroup, for example, methoxy and R2is hydrogen; X is sulfur, and R1-alkoxygroup, for example, methoxy and R2is hydrogen; X is sulfur, and R1-R2-alkoxygroup, for example, methoxy; X is sulfur, and R1halogen, for example fluorine and R2-hydrogen

The invention relates to new heterocyclic derivatives of substituted 2-acylamino-5-thiazolo exhibiting affinity to the receptor cholecystokinin and gastrin to a method for producing such compounds and to pharmaceutical compositions based on

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

The invention relates to new 2-sharonlee heterocyclic carboxylates, inhibiting the enzymatic activity of proteolytic enzymes, containing compositions, to a method of their use for the treatment of diseases associated with degeneration of the tissues, and to a method of production thereof

The invention relates to the production of heterocyclic compounds containing two cyclic selftimer grouping in a single aromatic nucleus such as diimide 4,6-Desulfovibrio acid (dithio-m-bisharin), formulas

HNNH,

which can be used as a monomer for the synthesis of new geterotsiklicheskikh heat-resistant polymers, new polymers with a system of conjugate relations, as well as new reactive oligomers

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The invention relates to a series of new piperidyl - occaisonally and khinuklidinilbenzilata derivatives that can be used in the treatment and prevention of various disorders, especially senile dementia / including disease of Alzheimer/

The invention relates to pharmaceutical industry and relates to a method of controlled selection of the active substance

The invention relates to new biologically active compounds, in particular to new pyridone derivative exhibiting analgesic activity

The invention relates to new 2-sharonlee heterocyclic carboxylates, inhibiting the enzymatic activity of proteolytic enzymes, containing compositions, to a method of their use for the treatment of diseases associated with degeneration of the tissues, and to a method of production thereof

The invention relates to 3,4,4-triple-substituted piperidinyl-N-alkylcarboxylic and to methods of their use as peripheral opioid antagonists

The invention relates to new esters of carboxylic acids with valuable properties, in particular the esters taylorbow acids and aminoalcohols of General formula (I)

< / BR>
where a group

< / BR>
where m and n are independent of each other represent 1 or 2,

Q group of formulae

< / BR>
Q' группаNR, where R denotes hydrogen or alkyl with 1 to 4 carbon atoms, unsubstituted or substituted with halogen or hydroxyl, or a group NRR', where R' is alkyl with 1 to 4 carbon atoms, or R and R' together form alkylene with 4 to 6 carbon atoms, and in the case of the fourth connection to the positive charge of the nitrogen atom is the equivalent of the anion (X),,

R1thienyl, phenyl, furyl, cyclopentyl and cyclohexyl, unsubstituted or substituted stands, and thienyl and phenyl may be substituted by fluorine or chlorine,

R2hydrogen, alkoxy 1 to 4 carbon atoms or alkyl with 1 to 4 carbon atoms,

Rahydrogen, fluorine, chlorine or methyl, provided that when a represents 3-tropanol, R1hydroxyl and R

The invention relates to agriculture, particularly livestock, and can be used to reduce losses of meat production and maintaining (improving) its qualitative characteristics of young cattle, due to technological stress factors when growing, fattening and implementation
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