2-sharinglretirement carboxylates or acid additive salts of these compounds are the main character or main-additive salts of these compounds are acidic in nature, and pharmaceutical composition inhibiting activity of proteolytic enzymes

 

(57) Abstract:

Usage: in the chemistry of heterocyclic compounds, inhibiting the activity of proteolytic enzymes. The inventive product: 2-sharinglretirement carboxylates of the formula I

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where Het is a 5-or 6-membered monocyclic heterocycle or a 9-membered ring of the bicyclic heterocycle containing 1-2 heteroatom selected from: oxygen, sulfur or nitrogen, or the same heterocycle, substituted by 1-3 identical or different members of the group, including: lower alkyl, oxo group, phenyl, halogen and-O-/C2-C10-alkylen/-N = B, where N = B is di/lower alkyl/amino or 4-morpholinyl, R4- H, lower alkyl or alkoxy, benzyloxy, lower alkoxycarbonyl, hydroxyl or phenyl; R5- H or one or two substituent in any of the 5-, 6 - or 7-positions selected from lower alkyl or alkoxy, or their salts, and pharmaceutical compositions on their basis, inhibiting activity of proteolytic enzymes. 2 C. and 18 h.p. f-crystals, 2 ill., 10 table.

The invention relates to new 2-sharonlee heterocyclic carboxylates, inhibiting the enzymatic activity of proteolytic enzymes, containing compositions, with the="ptx2">

Inhibition of proteolytic enzymes, non-toxic reagents applicable to the treatment of various disorders, such as emphysema, rheumatoid arthritis and pancreatic, an essential element of which is proteolysis. 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 cleaved peptide bond at the site where the amino acid residue side carboxyl, usually represented by Ala, Dal, 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 organi 72/00419 revealed a number of 2-RZ-methylcholine, which, as indicated, are characterized by strong activity against pyricularia rice, rizoctonia rice, leaf spot of rice (Helminthosporium) and damage to the leaves in the 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, fenoxaprop (or fenoxaprop substituted by chlorine, stands, nitro - or methylthioribose), phenylthiourea, chlorophenylthio, menzilcioglu (or chlorobenzylthio, acetochlor, dichloracetate, benzyloxy (or benzyloxy substituted by chlorine or nitro-group), acetylthiourea, dichloroacetylene, chlorobenzothiazole, methyl - or ethylcarboxylate, dimethylcarbamoyl, phenylcarbamoyloxy, acylcarnitine, phenylcarbonylamino, dimethylthiocarbamate, editiontype, ethoxycarbonylethyl, toxiciology and ethylthioxanthone.

In the work Sunkel and other J. Med. Chem. 31, 1886-1890 (1988) described a number of 2-swesty and antithrombotic activity.

In U.S. patent 4263393 (Chen) discloses various 2-kolmetoaline applicable as photographic elements and film elements.

In U.S. patent 4195023 (Mulvey and others ) revealed R1-2-R2CO-1,2-benzisothiazol-3-ones, where 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-sacharine, 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) described N-acylcholine, where acyl is represented by purola, tenolol, benzoyl, cyclopropanol, ethylbutyryl and acryloyl, with activity on the inhibition of serine protease.

In the work Chiyomapu and other Chemical Abstracis 81, 22249n described 4-were-2-shorinjiryukata, kharakterizujuschie which are inhibitors of the serine protease. For example, in U.S. patent 4659855 (Powers) discloses derivatives of arylsulfonate applicable as inhibitors of elastase. In U.S. patent 4546371 and 4623645 (Doherytu 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 leukocyte-elastase, porcine pancreatic elastase, cathepsin G, and bovine chymotrypsin Aain the presence of 4-Mitrofanovich esters and thioesters of N-crittercontrol.com, 2-substituted 4H-3,1-benzoxazin-4-ones, 2-substituted 4-khinazolinov and 2-substituted 4-chlorination.

In the work of the Cha, Biochem. Pnarmacol, 24, 2177-2185 (1975) discusses the kinetic approach to study the binding of 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, trifloromethyl, N,N-dialkylammonium, cryptomaterial, cryptomaterial, triftormetilfullerenov and triptoreline, or pyridyl substituted as R is represented by phenyl, except that the pyridyl may be substituted 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 C, proteases I and II mast cells rat chymase human skin and chymotrypsin AaN-forolaherencia and N-(2,4-dicyanovinyl) saccharin.

In the work Svohoda and other Coll Checz 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 4350752 and 4363865 (Reczek and others) and U.S. patent 4410618 (Vanmeter and other) related to the reagents for pictures (Reczek 4350762 and Vanmeter and others) and pigments for pictures (Reczek 4363865), discloses various 2-substituted sa is Mitilini blocking group (Reczek 4350752), diffusing through the media pigments for pictures related to the nitrogen atom of Amida through 1,1-alkylenes group (Reczek 4363865) and N-arylmethylidene, characterized as blocked reagents for pictures and with the remainder of the organic reagent for pictures containing a heteroatom through which the reagent is associated with a blocking group (Vanmeter).

In U.S. patent 3314960 (G CCO and others) disclosed are 2-(1,1,3-trioxo-1,3-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-TRANS-chrysanthemate 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 useful as inhibitors of proteolytic enzymes.

The present invention relates to 4-R4-R5-2-sharonlee (aryl, aryloxy)acetates and 4,5,6,7-tetrahydro-2-sharonlee(aryl, aryloxy)acetates having inhibitory activity against pranie relates to compositions for the treatment reborn diseases, containing a pharmaceutical carrier and an effective inhibition of the proteolytic enzyme number 4-R4-R5-2-sharonlee(aryl, aryloxy) acetate or 4,6,5,7-tetrahydro-2-sharonlee(aryl or aryloxy)acetate.

The invention also relates to a method of applying the above 2-sharonlee(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 or aryloxy) acetates and 4,5,6,7-tetrahydro-2-sharonlee (heterocycle)carboxylates, which consists in the reaction of: (1) 2-peloidoterapija with a heterocyclic carboxylic acid in the presence of an acid acceptor, or (2) reaction of the alkali metal salt of the appropriate acid with the appropriate galoidoproizvodnykh.

More specifically, the invention relates to R4-R5-2-sharonlee (heterocycle)carboxy is azikliceski a heterocycle, containing 1-2 heteroatom selected from: oxygen, nitrogen and sulfur, or the heterocycles substituted with one to three same or different members of the group, including: lower alkyl, PERFLUORO(lower)alkyl, lower alkyl, oxoprop, phenyl, halogen and-O-(C2-C10-alkylen)-N= B, where N=B is di(lower alkyl) amino group, 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl, 1-piperazinil or 4-(lower alkyl)-1-piperazinil;

R4represents hydrogen, halogen, lower alkyl, PERFLUORO(lower)alkyl, perchloro(lower)alkyl, lower alkenyl, lower quinil, cyan, carboxamido, amino group, lower alkylamino, 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, hydroxyethyl, 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 katela or acetal, SR, -SOR, -SO2R, -OCOR, -O-(C1-C10-alkylene)-COOR, -O-(C2-C10-alkylen)-N= B', where R represents lower alkyl, phenyl, benzyl or naphthyl, or phenyl or naphthyl substituted by one or two substituents selected from: lower alkyl, lower alkoxygroup or halogen and where N=B' in each case represents an amino group, a lower alkylamino, 1-azetidine, 1-pyrrolidinyl, 1-piperidinyl, 4-morpholinyl, di(lower alkyl) amino group, 1-piperazinil, 4-(lower alkyl)-1-piperazinil, 4-benzyl-1-piperazinil, 1-imidazolyl or carboxy(lower alkyl)amino group; or R5represents 5 - or 6-membered saturated cycle, condensed at 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 formed by addition of acids ZOLOTOGO nature, provided that when R4and R5are both hydrogen, then Het cannot be dihydropyridines.

Recommended for those compounds of the above formula 1, in which:

R4represents hydrogen, lower alkyl or lower alkoxygroup and R5represents hydrogen, lower alkoxygroup, methylendioxy, cycloalkylation, hydroxy(lower)alkoxygroup, polyhydroxyalkane or ketal or acetal, -O-(C1-C10-alkylene)-COOR or-O-(C2-C10-alkylen)-N=B'.

Especially recommended for those compounds of the above formula 1, in which:

Het substituted or unsubstituted pyridinyl, preferably 4-pyridinyl, 3,5-dichloro-4-pyridinyl, 2,4-dimethyl-3-pyridinyl, or 3,5-dichloro-2-/0-(C2-C10-alkylen)- N= B/-4-pyridinyl, in particular: 3,5-dichloro-2-/2-(4-morpholinyl)ethoxy/-4-pyridinyl or 3,5-dichloro-2-/2-(dimethylamino)ethoxy/-4-pyridinyl;

R4hydrogen or lower alkyl, preferably hydrogen or isopropyl, and

R5hydrogen, lower alkoxygroup or polyalkoxyalkyl, preferably hydrogen or methoxy group.

Other featured compounds of the above formula I include those compounds in which:

Het thienyl, oxazolyl, or isoxazolyl, substituted lower alkyl, most preferably thienyl, matiltan, chloranil, 3-methyl-5-isoxazolyl or 3,5-dimethyl-4-isoxazolyl;

R4lower alkyl and

R5lowest alkoxygroup or polyalkylacrylate.

Especially recommended for those compounds in which Het represents thienyl, matiltan, chloranil, 3-methyl-5-isoxazolyl or 3,5-dimethyl-4-isoxazolyl, R4isopropyl and R5-methoxy group.

Other featured compounds of the above formula 1 are those compounds in which:

Het pyrrolyl or pyrrolidinyl, unsubstituted or substituted lower alkyl, PERFLUORO(lower)alkyl, lower alkoxygroup, exography or halogen, pyrazolyl and imidazolyl, unsubstituted or substituted lower alkyl, PERFLUORO(lower)alkyl, lower alkoxygroup, phenyl or halogen.

It is additionally recommended to compounds of formula 1 include those compounds in which Het is a 9-or 10-membered bicyclic a heterocycle, preferably indolyl, unsubstituted or substituted lower alkyl, lower alkoxygroup, PERFLUORO(lower)alkyl or halogen.

The invention relates to 4,5,6,7-tetrahydro the sludge;

R6hydrogen or primary lower alkyl, or R4aand R6together form spirocyclopropane and

R7hydrogen or lower alkoxygroup, and Het takes on the values specified for formula 1.

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

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where a represents a methylene, ethylene or dimethylmethylene,

Het takes on the values specified for formula 1.

You must specify that the connection meets the General structural formula 1, in the chemical literature usually referred to as 1,2-benzothiazol-3(2H)-one-1,1-dioxides. However, for brevity, such compounds are 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 with one to ten carbon atoms. So lower alkyl (or lower alkanoyl)a fragment of such groups include, for example: methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, and-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 out-buildings 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 lower alkylen in the lower alkilinity means a divalent saturated radicals, including those radicals out-buildings 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, i.e., includes 2-hydroxyethoxy 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 out-buildings with two to ten carbon atoms, and thus includes: 1-ethylene, 1-(2-propylene), 1-(2-butenyl), 1-(1-methyl-2-propylene),1-(4-methyl-2-pentenyl), 4,4,6-trimethyl-2-heptenyl, 1-ethinyl, 1-(2-PROPYNYL), 1-(2-butenyl), 1-(1-methyl-2-PROPYNYL), 1-(4-methyl-2-pentenyl), etc.

As used here, the value of the term C2-C10-alkylene means a divalent saturated radical, including the radical out-buildings with two to ten carbon atoms and free is-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 thus includes: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Compounds of the present invention inhibit the activity of serine-prosthesis, in particular, human leukocytosis 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 heterocyclic acid (HetCOOHin the presence of an acid acceptor, such as a carbonate of an alkali metal or three(lower alkyl)amine. Or alkali metal salt, especially a salt of cesium heterocyclic carboxylic acid (HetCOO-M+) (obtained by reaction of the same conducting this reaction in the presence of tetrabutylammonium (TBAB). The reaction can be carried out in an inert organic solvent, such as xylene, acetonitrile, methylenechloride (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 by the following diagram, where X is chlorine, bromine or iodine.

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Required to obtain compounds of the formula I 4-R4-R5-2-haloalkaline can be synthesized by the methods described in the works: D AIeIio and other J. MacromoI. Sci-Chem, A3(5), 941 (1969) and Saari, etc. J. Het. Chem. 23, 1253 (1986), according to scheme 1, where AIk 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 proizvoditeli 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 sulfuricacid in an inert organic solvent, for example: methylenechloride (YFC), ethylene dichloride (ejh) or carbon tetrachloride at a temperature of 0-30oC. 4-R4-R5-2-phenyldimethylsilane in turn is produced by reaction of the 4-R4-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 cakovice potassium.

Sacharine formula can also be in one stage turned into chlorotriazine formula IV (X-CI) 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 VII.

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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 molar equivalent of (lower)alkyl (alkali)metal, such as lower alkyl lithium, 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 (-50) to (-80)oC and then the reaction obtained sulfonate alkali metal with hydroxylamine-O-sulfonic kastam 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 with 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 R4, 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 compounds of formula II, where R4primary lower alkyl, synthesized by the reaction of 4-methyl-R5-saccharin (formula II, R4-CH3) with two molar equivalents of the lower alkylate in an inert organic solvent, for example THF, followed by reaction of the floor is the temperature value in the interval from (-50) to (-80)oC.

The compounds of formula II, where R4primary lower alkyl and R5different 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 molar equivalent of a 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 molar equivalent of a lower alkylamine at a temperature in the range from (-50) to (-80)oC. the Obtained 2-(primary or secondary lower alkyl)-R5-N, N-di(lower alkyl)benzamid then converted into the compounds of formula II, where R4< / BR>
primary or secondary alkyl, the same above sequence of reactions, i.e., by the reaction of 2-(primary or secondary lower alkyl)-R5-N,N-di(lower alkyl)benzamide with one molar equivalent of a 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 ammonia, and cicley 2-(lower alkyl)group in the original 2-(lower alkyl)-R5-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 ISO-structure depending on what was used for the alkylation alkylated normal or ISO-structure. 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 R5hydrogen 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 benzyl anion using alkylate or preferably, dialkylamino lithium (DAL) in an inert solvent, preferably THF and processing of acceptable chlorotriethylsilane, preferably by chlorotrimethylsilane. Saccharin synthesize the Oia in DMF or Tetra-n-butylammonium fluoride and 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 R5-7-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 molar 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-2-he, the oxidation of which one molar equivalent of nagkalat, such as: natantia acid or 3-chlormadinone acid to obtain 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-benzothiazol-2H-3-one-1-oxide. If desired 7-hydroxy-group can then be used in the reaction with the lowest alkylamidoamines 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 in the manner and one molar 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:

< / BR>
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 the alternative scheme of cyclohexanone:

< / BR>
2-Cyclohexanone enter into reaction with the corresponding cuprate - (R4)2CuZ, where Z is Li or Mg(X')2and X1is chloride, bromide or iodide, then medicinetramadol and hexamethylphosphoramide (HMPA) by the method of Winkler and (Tet. Lett. 1987, 1051 and J. Org Chem. 54, 4491 (1989). Pecaut 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 2.

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, the processing of which the above method are the target 4,4-dialkyl-4,5,6,7-tetrahydrocanabinol.

Heterocyclic carboxylic acid (HetCOOH) used to obtain the final products f which may 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 against human leukocyte-elastase (CLA), resulting in compounds applicable to the treatment reborn diseases, such as emphysema, rheumatoid arthritis, cystic fibrosis degeneration, chronic bronchitis, respiratory distress cynipsea.

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 an 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 organic base, such as alkyl - dialkyl - or trialkylamine, and acid can be separated from their salts by treatment of aqueous acids.

The pharmacological activity of the compounds of the invention may be detected in a useful form for pharmaceutical purposes by applying themselves of the free bases or free acids or the use of salts formed with pharmaceutically acceptable animal with effective doses of the salts, therefore 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 is recommended, of course, 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 area, however, 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 these salts can be used for characterizing or identifying derivatives of the free acids or free bases or in the methods for the extraction or purification. Like all salts such operations 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-Sharonville(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 or oil solutions or emulsions of the type oil-in-water so as this is done in the manufacture of conventional medicines.

The percentage of active ingredient in these compositions may vary in order to obtain an acceptable dosage. Dosage entered a particular patient varies hung the Oia, 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, however, do not restrict it. All melting points given inoC and not adjusted.

Obtaining parent compounds

Preparative example 1

Powdered potassium hydroxide (7.4 g, 0,132 mol) is mixed with dimethylsulfoxide (DMSO) (100 ml) and the mixture is stirred for 5 minutes Then added to the mixture of 6-methylanthranilic acid (10 g, of 0.066 mol), and then added dropwise to itmean (4.52 ml, 0,073 mol). The reaction mixture was stirred 30 min at room temperature, then diluted with 250 ml of ether, PR is the appropriate fields 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, which immediately add 100 ml of cooled ice ammonium hydroxide and stirred for about a day at room 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 cal 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 2 hours under stirring 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 above in preparative example 1, 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 4,22 g (78%) of methyl ester of 6-chlorantraniliprole acid.

4-Hariharan get on the technique to obtain 4-methylcholine 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 salt diagonal, which is added to 1,93 g (to 0.011 mol) chloride dihydrate, copper (II) and 6.5 g of sulfur dioxide in 30 ml oxypropane conditions 150 ml of ammonium hydroxide and receive of 3.07 g (62%) 4-hariharan in the form of a pale yellow substance 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 subsequent reactions. The rest (205 mg) is subjected to pressure chromatography on silica gel with elution with 40% ether in pentane 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 addition on niewy the solution is stirred under 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 30 min, 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 ammonium chloride, 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 and 1 g of resin AmberliteR-15 (room and Xaac) boil for 20 h in chloroform, the mixture is treated with an additional amount of resin (1.5 g) and heated for another 4 hours and Then the mixture is 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 and 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-chlorbenzoyl acid, which is dissolved in 10 ml of THF and to the solution while cooling in a bath of ice in acetone add 25 ml of concentrated ammonium hydroxide solution. The reaction mixture was extracted with YFC, the organic phase is discarded, and the aqueous layer was acidified with concentrated hydrochloric acid to pH 1 and extracted with YFC. From organic extracts, after 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-fenisay 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 mmol). 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 (3x50 ml), water (2 × 50 ml), brine (1x50 ml) and dried (Na2SO4). Removal of solvent in vacuo and purification by distillation in the apparatus Cuellar (bath temperature 100 to 150oC at 0.3 mm) to obtain 4.7 g (88%) of methyl ester of 2-(1,1-dimethylethyl)-cyclohexane-6-noncarbonate acid.

Cyclohexanone (4.6 g, 0.22 mol) is mixed with benzylmercaptan (2,95 g 0,024 mol) and acidic montmorillonite clay KG (7.5 g) in anhydrous toluene (7.5 ml). The mixture is boiled for 6 hours in an atmosphere of nitrogen with azeotropic removal in the United 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 and 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 (17.5 g, 0.77 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-dimethylethyl)benzoic acid.

Entitiesthat (1.3 g, of 0.0004 mol) is dissolved in YFC (5 ml), diluted with acetic acid (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 Ki is the bath of acetone with ice. After stirring 16 h at room temperature the reaction mixture was concentrated in vacuo and acidified with 2 N. 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.

Preparative example 4

The mixture 3,22 g (0.012 mol) of 4-brachina (Japanese patent publication 58/79034; S. A. 100, 773w(1984)), 1.63 g (0.015 mol) of tert-butoxide potassium, 0.39 g (0,0012 mol) TBAB and 3 ml of chlorocarbonylsulfenyl boil in a nitrogen atmosphere, and then stirred at room temperature for about 16 hours Then the reaction mixture was diluted with ethyl acetate, the organic layer is washed with dilute potassium carbonate solution, water and brine, dried over sulfate m (84%) 4-bromo-2-phenyldimethylsilane, so pl. of 174.5-178oC.

To a solution of the latter (with 3.27 g, 0,0085 mol) in 85 ml of YFC added dropwise and stirring of 1.02 ml (0,0127 mol) of sulfurylchloride. The mixture is stirred for 1.5 h 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 2-methoxy-N,N-diethylbenzamide in 150 ml of THF, maintaining the temperature at -60oC or below. After stirring 20 min at a temperature below -50oC through the reaction mixture propulsive sulfur dioxide until the reaction scheme 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 the 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% conduct boiling 6.5 h in glacial acetic acid.

By the method similar to that shown in preparative example 4, 1,14 g (0,053 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-butoxide potassium and 174 mg (0,00054 mol) of tetrabutylammonium and gain of 1.23 g (69% ) 4-methoxy-2-phenyldimethylsilane, so of 152.5 square-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-methoxyindole 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 to -78oC and treated to 34.9 ml (0,031 mol) of 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 chromatographic on silica gel with elution with 10% ethyl acetate in hexane produced in the form of a yellow oil 2.86 g (43%) 2-sec-butyl-N,N-diethylbenzamide.

By the method similar to that shown in preparative example 5, the obtained product (10,45 g, 0.045 mol) is dissolved in 70 ml of THF 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 further 0.5 h 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 water and added with stirring to a cold solution of 15.2 g (0,134 mol) of hydroxylamine-O-sulfonic acid and 15.4 ml (0,134 mol) of 35% aqueous hydroxide is e (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 6V

By the method similar to the method of preparative example 6A, conduct the reaction of 9.2 g (32,9 mmol) of 3,4-dimethoxy-2-propyl-N,N-diethylbenzamide with sulfur dioxide and 5.6 g (49.4 mmol) of hydroxylamine-O-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) 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 is the atur 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 1H after treatment. 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), 2,5 N. n-utility in hexane. The reaction mixture is heated to 0oC, allowed to stand for 1 h, cooled to -70oC and add 9 ml (71,2 mmol) diethylcarbamazine. The reaction mixture was left to warm to room temperature 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 Huck is tion of example 5 and glorious 3 equivalents of sulfurylchloride with obtaining with access to 85% of 2-chloromethyl-5-dimethoxy-4-isopropylaniline, so pl. 117-119oC from a mixture of ethyl acetate-hexane.

Target benzamide obtained from 2,3-dimethoxy-a-methylbenzoate his bromirovanii with subsequent carbamylcholine as well as in preparative example 6, to obtain 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 was left to warm to room temperature and stirred for 18 h with removal of SO2. At 0oC add 10 ml of sulfurylchloride and the reaction mixture otparivat. Sulfurylchloride extracted in a mixture of E10Ac-ether, washed with water, dried and otparivat. The residue is dissolved in 80 ml of THF and at 0oC add 17 ml of concentrated NH4OH. The reaction mixture is briefly stirred at room temperature otparivat and rinsing 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 relax the Il-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 1.5 h 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 by elution with 10% ethyl acetate in hexane get 3,23 g (25%) of 2-(3-pentyl)-N,N-diethylbenzamide in the form of a yellow oil.

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 sodium salt of hydroxylamine-0-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 to the P>C.

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-(3-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. The obtained 2,4-dimethoxybenzoate dissolved in 150 ml of YFC and at 0oC is treated with a solution of 68 ml (48 g, 0.66 mol) of 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) tetramethylethylenediamine (0.13 mol) of sodium salt of hydroxylamine-0-sulfonic acid and get compared to 8.26 g of 2-aminosulfonyl-4,6-dimethoxy-N,N-diethylbenzamide, 7 g (0,022 mol) cycleroute 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 the treatment of 3.23 g (0,0019 mol) of sulfurylchloride in 100 ml of YFC form 4,63 g (100%) 2-chloromethyl-4,6-dimethoxycoumarin, so pl. 185-187oC.

Preparative examples 9A-9C

By the method similar to the method preparting of example 5, but using instead 2-methoxy-N,N-diethylbenzamide the corresponding 2-R4-R5-substituted N, N-diethylbenzamide synthesize listed in the table. And 2-kaleidotile-4R4-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/solvent" and "Exit" below the melting temperature (0oC) and exit. In all cases, the intermediate 2-finaltime.

(b) 2-unsubstituted saccharin obtained by cyclization of dimethyl-3-aminosulphonylphenyl in the presence of a molar equivalent of sodium methoxide in methanol. Ether phthalic acid obtained by diazotization dimethyl-3-aminophthalate, the decomposition of diazonium salts with sulfur dioxide in the presence of copper chloride (II)and reaction of the resulting dimethyl-2-chlorosulfonylphenyl with ammonia (total yield 84% ).

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) was 63.8 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) ethoxide thallium, the mixture is left for 1 h at room temperature, cooled to about 16 hours, the precipitate 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 about 1 the YFC and filtration to remove salts waist. 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 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 (92%) of methyl ester of 2-hydroxy-5-(1,1,3,3-TETRAMETHYLBUTYL)benzoic acid.

The resulting ester was dissolved in 250 ml of DMF and treated first of 40.4 g (0.36 mol) of 1,4-dusabimana 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 (14%) methyl ester-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 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 extracts obtain 6.8 g (78% ) matilovo ether 2-chlorosulfonyl-5-(1,1,3,3-TETRAMETHYLBUTYL)benzoic acid.

Total 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/a 2.2.2/octane in DMF and obtain 22.1 g (96%) of ethyl ester of 2-(N, N-dimethylthiocarbamate)-6-methylbenzoic acid, which is heated for about 10 hours at 220oC. Purification of the product LTI)-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 minutes propulsive chlorine. The reaction vessel is evacuated to remove excess chlorine and YFC, 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-panelbeater-4-methylcholine.

Reaction of the latter (6.7 g, 0,021 mol) with Sulfuryl chloride 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 mol of thionyl chloride and catalytic amounts of pyridine is stirred for about 24 h and then evaporated doukharina 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 pereshivayut 2 h at 40-45oC, cooled, the precipitate is separated, washed with water and after drying obtain 59 g (84%) of N,N'-dibenzylhydroxylamine, 3,3-dithiobisnitrobenzoic acid, so pl. 162 to 165 of theoC.

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 ultrasonic processing 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 e is a Solution 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) under the conditions 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 g (0,0062 mol) of prduct 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 boiled for 8 h, then cooled and transferred into ice-cold water. The precipitation was separated, washed with water and after drying obtain 0.5 g (33%) 2-phenylthiomethyl-4,7-dimethoxyethan the EPA 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 14V

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 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-horned-benzoic 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-pentultimate-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) with the reparative 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-(methoxyethoxy)ethylbromide in the methyl-etelecare 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 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-hydroxymethylcytosine in 25 ml YFC at -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 CommVault water, dried over magnesium sulfate and after evaporation to dryness obtain 2.2 g of the 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) under the conditions. 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 etecetera. 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 domiciliaria.

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 anywayt. Evaporation of the following 20 fractions obtain 0.07 g of product, mainly consisting of 2-phenylthiomethyl-4,7-dimethylalanine that 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 (0,051 mol) 4-methylcholine in THF (86 ml (0.1 mol) of 1.8 M solution of second-bucilly 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 form a crude mixture from which the pressure chromatography on silica gel isolated in the form of oil 2-phenylthiomethyl-4-propylalanine, 1.8 g (0,0052 mol) in the reaction with 1.25 ml (0,016 mol) of sulfurylchloride 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 mol) N,N,2-triethylbenzene in THF (50 ml) at -78oC add the solution is then cooled to -78oC dry ice in acetone. At -78oC in its pure form is added TMSCl (6,34 ml, 50 mmol) and after one hour the reaction mixture is heated to room temperature. The reaction mixture was neutralized with saturated solution of NH4Cl and extracted with ether (2x100 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 excess O2in 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) hydroaxe sodium (0.36 g, 9 mmol) and hydroxylamine-O-sulfonic acid (1 g, 9 mmol) in H2O. the Reaction mixture was stirred 4 h at room temperature, xtraceroute EtOA 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)Atila/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 is silyl)ethyl/saccharin, so pl. 123-125oC.

To trimethylsilylmethylamine (0.25 g, 0.7 mmol) in DMF (9 ml) at room temperature add H2O (1 ml) and cesium fluoride (0.75 g, 4,94 mmol, 7 equivalents). After 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-chloromethyl-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, rastrapathi 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 a simultaneous increase in temperature and then neutralized with a saturated solution of ammonium chloride. Aqueous and organic layers separated, 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. 128-129oC/0,2-0,3 mm

By the method similar to 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. The resulting lithium salt is introduced into the first reaction with 50 ml of sulfur dioxide and then with 0,181 mol of sodium salt of hydroxylamine-O-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 ethyl acetate-hexane), 11 g (0,034 mol) which cyclist 200 ml for the 5oC.

The reaction of the salts (0.03 mol) from 6.14 ml (7,25 g, 0.046 mol) of chlorocarbonylsulfenyl in the presence of 0.98 g (of 0.003 mol) TBAB in 250 ml of toluene gain of 10.1 g (88%) 2-phenylthiomethyl-4-isopropyl-6-methoxycoumarin 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. Those who powdery precipitate of sulfinate argillite). After addition of chilled bath removed and the reaction mixture was stirred 2 h at room temperature. Then the solution is cooled to -5oC and to it under stirring for 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.

oC under vacuum for 18 h and recrystallization from a mixture of ethyl acetate-hexane get 303 g (91%) of 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 18C

By the method of preparative example 18A 5 g of 2-bromo-N,N-dimethylaniline turn in 3.5 g of N,N-diethyl-2-dimethylaminobenzene. Amide is introduced into the reaction as Metodi-4-diethylaminocoumarin (see, preparative example 23V).

Preparative example 19

To a solution of 1 g (to 0.0039 mol) of 4-isopropyl-6-methoxycoumarin in 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 is acidified to pH 1. Extraction of the mixture ethyl acetate-diethyl ether (8:2) drying of the organic extracts and removal of the solvent and vacuum get 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 3-4 h at 60o. After the OHL is 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, 1,76 g which 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 18A

We believe that the use of a technique similar to the technique of preparative example 19, but replacing 4-isopropyl-6-methoxycoumarin 4-methoxycoumarin can be synthesized 2-chloromethyl-4-hydroxycoumarin.

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) Cl2CO3. The mixture is stirred for 3-4 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) chlorocarbonylsulfenyl. Stir the mixture is heated for 12 h at 70-75oC, cooled, treated with ice water and extracted with 600 ml of a mixture of ethyl acetate-ether (4:1). Organic is jut pressure chromatography with elution with 20% ethyl acetate in YFC. Obtain 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) 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 nitrogen atmosphere and at room temperature for about a day. The formed precipitate is filtered off and washed with YFC (50 ml). The combined filtrate is evaporated almost to dryness, and the residue is distributed between ethyl acetate (300 ml) and a saturated solution of NaHCO3(100 ml). The layers separated, and the organic phase is washed with a saturated solution of NaHCO3(2x100 ml), brine (1x100 ml) and dried. Removal of solvent in vacuo get 10 g (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 of reaction who I sucked off, washed with water (I ml), hexane, and after drying in the air get in the form of a colorless solid of 4.6 g (45%) of 5-chloro-2-benzyl-4-isothiazolin-3(2H)-one-1,1-di-oxide.

Dioxide (1.2 g, 4.7 mmol) is mixed with 2.02 g (11 mmol) of 2-trimethylsilyloxy-5-methylhexane-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 ml) and treated with 2 N. HCl (10 ml). After stirring 20 min in nitrogen atmosphere and at room temperature add 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-oxitetraciclina in the form of a pale yellow foam.

Tetrahydrofuran (0,59 g, 1.7 mmol what nnuu the mixture boil 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 United filters obtained as a pale yellow solid 0,63 g (99%) of 2-benzyl-4-isopropyl-6-dimethylamino-(4,5)-dehydroalanine.

To a solution of dihydrocoumarin (to 0.63 g, 1.7 mmol) in boiling chloroform (50 ml) in portions over 4 h added activated manganese dioxide (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 eluate 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%) of 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 e billaut 0.25 ml of glacial acetic acid, stirred for 5 min and evaporation in vacuum is obtained as colorless foam 0.25 g (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, which is treated with sulfurylchloride (of 1.86 ml, 0,31 M solution, 0.6 mmol) and obtain 0.15 g of a yellow resin containing 25% (according to NMR) 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 (e is the 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 sulfurylchloride with the subsequent removal of the solvent and rinsing with hexane obtain 0.3 g of 2-chloromethyl-6,7-dimethoxy-4-isopropylaniline.

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'-methylethylbenzene. 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-benzodioxin example 22A obtain 700 mg of 4-isopropyl-6,7-dimethylethoxysilane, 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-triftorperasin acid with thionyl chloride receive 2-cryptomathematical, which in reaction with diethylamine 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-O-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-trichlorosilane, 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 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 second-butyllithium with subsequent reaction of the obtained lithium salt with sulfur dioxide and then with a sodium salt of hydroxylamine-O-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.

Diaset the accordance 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. The oxidation of 6-methylthiopurine and 6-triftormetilfosfinov two molar equivalents of 3-chlormadinone acid are respectively 6-methylsulfonylamino and 6-triftormetilfosfinov.

Hydrolysis of 6-cyanoalanine by heating with aqueous sodium hydroxide receive saccharin-6-carboxylic acid. 11-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 holdem is benzamid. 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-cryptomaterial.

The reaction by trichloromethylbenzene acid with thionyl chloride receive a 4-trichlorocarbanilide, 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-ethylbenzoyl acid with thionyl chloride receive 2-ethenylbenzene, which in reaction with diethylamine forms a 2-ethinyl-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 KIS is Brazul 4-itinerarary.

The reaction of 2-ethinyl-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-ethnischen.

The reaction of the ethyl ester of 2-aminobenzoic acid with two molar equivalents of benzylchloride in acetone in the presence of potassium carbonate receive 2-(N, N-dibenzylamino) benzoic acid ethyl ester, which upon 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 diethylamine 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, catalytic dibenzylammonium ketorolaco one molar 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 by the reaction of 2-benzyl-6-hydroxy-4-isopropylaniline with N,N-diethylthiocarbamate in DMF by the method of preparative example 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 of the latter with one or two molar equivalents of 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 salts of the PR-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-methoxybenzylidene, 4-chlorpheniram, 1-mercapto-4-methylnaphthalene or 1-mercaptoethanol by heating the reagents in DMF are respectively 4-isopropyl-6-penaltyshall, 4-isopropyl-6-(4-methylphenylthio) saccharin, 4-isopropyl-6-(4-methoxybenzylthio)saccharin, 4-isopropyl-6-(4-chlorophenylthio)saccharin, 4-isopropyl-6-(4-methyl-1-naphthylthio)saccharin and 4-isopropyl-6-(1-naphthylthio)saccharin, the oxidation of which in each case one or two molar equivalents of 3-chlormadinone acid leads to 4-isopropyl-6-vinylsulfonylacetamido, 4-isopropyl-6-vinylsulfonylacetamido, 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 saccharine, 4-isopropyl-6-(4-chlorophenylsulfonyl)the saccharin, 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.

By heating 4-isopropyl-6-forsharing in DMF with azetidinol, pyrrolidine, piperidine, morpholine, 1-benzylpiperazine, 1-methylpiperazine, imidazole, tert-butyl-alpha-aminoacetate or ammonia, respectively, received 4-isopropyl-6-(1-azetidine)saccharin, 4-isopropyl-6-(1-pyrrolidinyl)saccharin, 4-isopropyl-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-piperidinyl)saccharin.

Hydrolysis of 4-isopropyl-6-(tert-butoxycarbonyl-methylamino)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 molar equivalent of acetylchloride get 4-isopropyl-6-acetaminoohen.

The saponification of 4-Melisa, the conversion of acid into the corresponding acid chloride by reaction of the acid with thionyl chloride and reaction of chloranhydride with ammonia receive saccharin-4-carbox-amide.

Reaction of each of the thus obtained 4-R4-R5-saccharin with paraformaldehyde and chlorotrimethylsilane in the presence of chloride tin (IV) dichloride receive a 4-R4-R5-2-chlorotriazine formula IV listed in table B, where in each case XCI.

Preparative example 23K

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-tetrahydrobenzaldehyde. 4-Oxoproline enter into reaction with methyltriphenylphosphonium in the standard conditions of the Wittig reaction and carrying out the reaction of Simmens-Smith in the received 4-methylandrosta injected methylene and receive 6,7-dihydrospiro/benzisothiazol-4(5H), 1'- cyclopropane/, oxidation of which with hydrogen peroxide in acetic acid leads to 6,7-dihydrospiro/3-oxopentanoate-4(5H), 1'-cyclopropane/-1,1-dioxide (4-spirocyclopentane-4,5,6,7-tetrahydrofuran.

Preparative example 23B1

2-Benzyl-4-isopropyl-6-oxitetraciclina (preparative example 21) restore the sodium borohydride and was identified in idestam the stands in the presence of sodium hydride to obtain 2-benzyl-4-isopropyl-6-methoxytryptamine. Dibenzylammonium and chlorotoluene product by the method of preparative example 21 get 2-chloromethyl-4-isopropyl-6-methoxy-4,5,6,7-tetrahydrofuran.

Preparative example 24

The method is essentially the same technique CaIe and other J. Med. Chem. 1989, 32, 2178) synthesize 3,5-dichloro-4-pyridylcarbonyl acid, white crystals, so pl. 231-235oC (decomposition).

Preparative example 25

In 100 ml of THF under nitrogen atmosphere suspended 97% sodium hydride (2,72 g, 0.11 mol) and the suspension portions add a solution of N-(2-hydroxyethyl) the research in THF (15 ml). After cessation of hydrogen evolution with speed, providing a small boil, add a solution of 2,3,5-trichloropyridine (18.2 g, 0.1 mol) in THF (25 ml). The reaction mixture is boiled for 2 h followed by removal of solvent in vacuo. The residue is transferred with a mixture of water-CH2Cl2, the organic layer is separated and removal of solvent in vacuo receive in the form of crystal is, ,06 mol) in THF (100 ml) under nitrogen atmosphere cooled to -70oC and syringe add a solution of 3,5-dichloro-2-/2-(4-morpholinyl)ethoxy/pyridine (13 g, 0,047 mol) in THF (10 ml). Yellow-red solution is stirred for 30 min at -70oC and then slowly warmed to room temperature. The mixture is transferred into a mixture of crushed dry ice with THF and after evaporation of the dry ice is used, the solvent is removed in vacuum. The residue is transferred to a dilute solution of ammonium hydroxide and extracted with chloroform (2X). The organic layer is separated and concentrated in vacuo get 6 g of unreacted raw product. The aqueous layer was concentrated in vacuo and to the residue add 3 N. HCl. The solution is cooled, and the precipitate is filtered off. By recrystallization of the solid product from the water get in the form of a white substance with a 71% yield (taking into account the extracted source product) hydrochloride, 3,5-dichloro-2-/-(4-morpholinyl)ethoxy/pyridine-4-carboxylic acid, so pl. 230-231oC (decomposition).

Believe, using essentially the same method of 2,3,5-trichloropyridine and the corresponding derivative N-(2-hydroxyethyl)amine can be obtained 3,5-dichloro-2-/2-(pyrrolidinyl)ethoxy/pyridine, 3,5-dichloro-2-/2-(pyrrolidinyl)ethoxy/R is hydroxy/pyridine-4-carboxylic acid, hydrochloride, 3,5-dichloro-2-/2-(piperazinil)ethoxy/pyridine, 3,5-dichloro-2/2-(piperazinil)ethoxy/pyridine-4-carboxylic acid, hydrochloride, 3,5-dichloro-2-/2-(4-methylpiperazine)ethoxy/pyridine and 3,5-dichloro-2-/-(4-methylpiperazine)ethoxy/pyridine-4-carboxylic acid, hydrochloride.

Preparative example 26

The method is basically similar to the method of preparative example 25, exit 36% synthesized 3,5-dichloro-2-/2-(dimethylamino)ethoxy/pyridine and 1,3% hydrochloride 3,5-dichloro-2-/2-(dimethylamino)ethoxy/pyridine-4-karbonovy acid, so pl. 184-186oC (decomposition) by recrystallization from water.

Preparative example 27

To ethyl-2,4-dioxooleana (of 177.8 g, 1.1 mol) is added concentrated HCl (450 ml) and then hydroxylamine hydrochloride (103,7 g, 1,68 mol). The reaction mixture is stirred for 7 h and then left for 60 hours the Solvent is removed in vacuum and the residue is cooled on ice. The formed precipitate is filtered and washed with cold water. The solid product was dissolved in THF (1 l), the solution is filtered and the solvent is removed in vacuum. Form a suspension of the residue in ethyl acetate (200 ml), which was filtered. Concentration of the filtrate to about 30 ml to get the second batch of the product. Both parties unite and ASS="ptx2">

The final product

Example 1

A mixture of isonicotinic acid (0,98 g 0,008 mol), 2-bromoethylamine (2,11 g 0,008 mol), triethylamine (0,81 g 0,008 mol) and xylene (25 ml) was boiled for 1 h the Solvent is removed in vacuo and the residue partitioned between water and methylene chloride. The organic layer is separated and the solvent is removed in vacuum. By recrystallization of the solid residue of CH3CN obtain 0.9 g (37%) 2-Sakhalinenergo ether pyridine-4-carboxylic acid, so pl. 145-146oC (yellow substance).

Example 2

The method is basically similar to the method of example 1, but using 3,5-dichloro-4-pyridineboronic acid instead of isonicotinic acid with a yield of 29% receive 2-sharinaletisha ester of 3,5-dichloropyridine-4-carboxylic acid, so pl. 159-160oC.

Example 3

A solution of 3,5-dichloro-2-/2-(4-morpholinyl)ethoxy/pyridine-4-carboxylic acid hydrochloride in the form of the free base (3.6 g, 0.01 mol) and cesium carbonate (4,85 g, 0.015 mol) in methanol (50 ml) is stirred for 30 minutes, the Methanol is removed in vacuo and the residue is dissolved in DMF (50 ml). Then add 2-chloromethyl-4-(isopropyl)saccharin (3 g, 0.01 mol) and the reaction mixture is heated 3 hours at 80oC. DMF is removed in vacuo, the residue transferring the t in tert-butyl methyl ether and the solution is filtered. The solvent is removed in vacuo, and the residue is treated with ethereal HCl solution. Finally obtained resin CH3CN obtained as white matter 0.5 g (9%) 4-(isopropyl-)-2-Sakhalinenergo ester of 3,5-dichloro-2-/2-(4-morpholinyl)ethoxy/pyridine-4-carboxylic acid, so pl. 120-140oC.

Example 4

A mixture of 3,5-dichloro-4-pyridineboronic acid (0,42 g, 0.002 mol), cesium carbonate (0.36 g, 0.001 mol) and methanol (10 ml) is stirred for 30 minutes the Solvent is removed in vacuo and to the residue is added 2-chloromethyl-4-isopropylaniline (0.55 g, 0.002 mol) in DMF (10 ml). The mixture is heated to 75oC and stirred for several hours. The solvent is removed in vacuo and the residue partitioned between water and methylenechloride. The organic layer is separated, dried over anhydrous MgSO4and concentrated in vacuo. The residue is treated with ethereal HCl solution and get a white resinous substance which rinse Et2O and then with acetone. The obtained white substance is filtered off and after drying in high vacuum to obtain 0.14 g (15%) 4-isopropyl-2-sharonlee-3,5-dichloropyridine-4-carboxylate, T. pl. 93-95oC.

Example 5

A mixture of the hydrochloride 3,5-dichloro-2-/2-(dimethylamino) ethoxy/pyridine-4-karbonovy acid (2.65 g, 0,0084 donkey which is added 2-chloromethyl-4-isopropyl-6-methoxycoumarin (82,4 g, 0,0084 mol). The mixture is heated to 80oC and stirred for 1 h the Solvent is removed in vacuo and the residue partitioned between water and methylenechloride. The organic layer was separated, washed with water, dried over anhydrous MgSO4and concentrated in vacuo. The residue is dissolved in ethyl acetate and filtered through a small layer of silicon oxide. To the filtrate is added an ethereal solution of HCl and the solvent is removed in vacuum. The residue is washed with ether (50 ml), treated with a saturated solution of NaHCO3and extracted with methylenechloride. The solvent is removed in vacuum, the residue is rinsed with methanol and the snow-white solid filtered off. Drying the product under high vacuum, get 0,096 g (2,1%) of 1-isopropyl-6-methoxy-2-sharonlee-3,5-dichloro-2-/2-(dimethylamino)ethoxy/pyridine-4-carboxylate, T. pl. 155-156oC (decomposition).

We believe that essentially the same method from 2-chloro-methyl-4-isopropyl-6-methoxycoumarin and the corresponding carboxylic acid derivative can be obtained 4-isopropyl-6-methoxy-2-sharonlee-3,5-dichloro-2-/2-(pyrrolidinyl)ethoxy/pyridine-4 - carboxylate, 4-isopropyl-6-methoxy-2-sharonlee-3,5-dichloro-2-/2-(piperidinyl) ethoxy/pyridine-4-carboxylate, 4-isopropyl-6-methoxy-2-saharonim-(4-methylpiperazine)ethoxy/pyridine-4 - carboxylate, 4-isopropyl-6-methoxy-2-sharonlee-2-triptorelin-4-carboxylate and 4-isopropyl-6-methoxy-2-sharonlee-2-methoxypyridine-4-carboxylate.

Example 6

A mixture of 3-thiophencarboxylic acid (0.6 g, 2 mmol), K2CO3(0.28 g, 2 mmol) and DMF(4 ml) is stirred for 1 h and Then added 2-chloromethyl-4-isopropyl-6-methoxycoumarin (0,61 g, 2 mmol) and the mixture is stirred for 24 hours To the reaction mixture are added water (20 ml) and the solution extracted with ether (2x40 ml). The organic layer was separated, washed with water, then brine and dried over anhydrous Na2SO4. The solvent is removed in vacuo and recrystallization of the solid residue from a mixture of toluene-hexane receive in the form of a white powder, 0.5 g(65% ) of 4-isopropyl-6-methoxy-2-saharanamerican-3-carboxylate, so pl. 125-127oC.

We believe that essentially the same method of 2-chloromethyl-4-isopropyl-6-methoxycoumarin and 4-methoxy-3-thiophencarboxylic acid can be obtained 4-isopropyl-6-methoxy-2-sharonlee-4-methoxythiophene-3-carboxylate.

Example 7

The method is essentially similar to the method of example 6, but using 3-methyl-2-thiophencarboxylic acid instead of 3-thiophencarboxylic acid with a yield of 78% gain in the form of a white powder 4-isop codice, essentially similar to the method of example 6, but replacing 3-thiophencarboxylic acid 2-thiencarbazone acid is obtained with a yield of 62% in the form of white crystals of 4-isopropyl-6-methoxy-2-saharanamerican-2-carboxylate, T. pl. 139-141oC.

Example 9

The method is essentially similar to the method of example 6, but using 3-chloro-2-thiophencarboxylic acid instead of 3-thiophencarboxylic acid get in the form of a snow-white powder with a yield of 65% 4-isopropyl-6-methoxy-2-sharonlee-3-chlorothiophene-3-carboxylate, T. pl. 138-140oC.

Example 10

A mixture of 3-methylisoxazol-5-carboxylic acid (0,63 g, 5 mmol), cesium carbonate (0.8 g, 2.45 mmol) and methanol is stirred for 30 minutes the Solvent is removed in vacuum and the residue is dried for 1 h in high vacuum. Then the residue is suspended in DMF (30 ml) and to the suspension is added 2-chloromethyl-4-isopropyl-6-methoxycoumarin (1 g, 3.3 mmol). The mixture is stirred for 19 h at room temperature and transferred into the water. The resulting mixture was extracted with a mixture of ethyl acetate-ether (4:1, 300 ml), the organic layer separated, washed with water and brine. The solvent is removed in vacuo and purification of the residue pressure chromatography (30% ethyl acetate in hexane) are obtained in the form of a white powder (1.1 g (86 11

A mixture of 2-pyrrolidone-5-carboxylic acid (0,85 g, 6.6 mmol), cesium carbonate (1.07 g, 3.3 mmol) and methanol is stirred for 30 minutes the Solvent is removed in vacuum and the residue is dried for 1 h in high vacuum. Then the residue is suspended in DMF (30 ml) and to the suspension was added 1 g (3.3 mmol) of 2-chloromethyl-4-isopropyl-6-methoxycoumarin. The mixture is stirred for 24 h at room temperature and transferred into the water. The resulting mixture was extracted with ethyl acetate-ether (4: 1), the organic layer separated, washed with water and brine. The solvent is removed in vacuo and purification of the residue pressure chromatography (CH2Cl2then 2% methanol in CH2Cl2) obtain 0.56 g (53%) of 4-isopropyl-6-methoxy-2-sharonlee-2-oxopyrrolidin-5-carboxylate, T. pl. 159-160oC.

Example 12

To 3,5-dimethyl-isoxazol-4-carboxylic acid (0.21 g, 1.5 mmol) is added acetonitrile (3 ml) and then of 0.26 ml (1.5 mmol) of N,N-diisopropylethylamine. The mixture is stirred for 5 minutes and then add 2-chloromethyl-4-isopropyl-6-methoxycoumarin (0.3 g, 1 mmol). The reaction mixture was stirred 18 h at room temperature, diluted with ethyl acetate (75 ml) and washed with saturated solution of NaHCO3. The organic layer is dried over anhydrous Na2SO4, filtered and conc(100%) was obtained as white matter 0,041 g (10% ) 4-isopropyl-6-methoxy-2-sharonlee-3,5-dimethyloxazole-4-carboxylate, so pl. 136,8-139,1oC.

Example 13

To 3,5-dimethyl-1-phenylpyrazol-4-carboxylic acid (0,44 g, 2 mmol) added acetonitrile (3 ml) and then of 0.26 ml (1.5 mmol) of N,N-diisopropylethylamine. The mixture is stirred for 5 min and add 2-chloromethyl-4-isopropyl-6-methoxycoumarin (0.3 g, 1 mmol). The reaction mixture is stirred for 35 h at room temperature, then 1 h at 80oC. the Mixture is diluted with ethyl acetate (75 ml), washed with saturated solution of NaHCO3and the organic layer dried over Na2SO4. The solvent is removed in vacuo and recrystallization of the residue from ethanol as yellow substances 0.31 g (64%) of 4-isopropyl-6-methoxy-2-sharonlee-3,5-dimethyl - 1-phenylpyrazol-4-carboxylate, T. pl. 167,3-169,4oC.

Example 14

To 2,4-dimethyl-3-pyridineboronic acid (5.1 g, 33 mmol) add acetonitrile (20 ml) and then 5.8 ml (33 mmol) N,N-diisopropylethylamine. The mixture is stirred for 5 min and add 2-chloromethyl-4-isopropyl-6-methoxycoumarin (4.3 g, 14 mmol). The reaction mixture is stirred for 47 hours at room temperature, then 1 h at 80oC. the Mixture is diluted with ethyl acetate (100 ml), washed with saturated solution of NaHCO3and the organic layer dried over Na2SO4. The solvent is removed in vacuum and peracre is celata, so pl. 132,1-133,5oC.

Example 15

The method is essentially similar to the method of example 11, but using 1,3-dimethyl-5-Clorinda-2-carboxylic acid (obtained standard indole synthesis Fisher of the hydrochloride of 4-chlorophenylhydrazone and alpha ketomalonate acid with subsequent N-methylation of the obtained ethyl ester 3-methyl-5-Clorinda-2-carboxylic acid and saponification of the ester instead of 2-pyrrolidone-2-carboxylic acid obtained as white crystals with a yield of 38% 4-isopropyl-6-methoxy-2-sharonlee-1,3 - dimethyl-5-Clorinda-2-carboxylate, T. pl. 183-184oC by recrystallization from ethyl acetate-hexane.

Example 16

We believe that the method is substantially similar to the method of example 11, but using furan-3-carboxylic acid, pyrrole-2-carboxylic acid, 1-methylpyrrole-2-carboxylic acid, pyrazole-4-carboxylic acid, pyrrolidine-2-carboxylic acid isoxazol-5-carboxylic acid or imidazole-2-carboxylic acid instead of 2-pyrrolidin-5-carboxylic acid can be obtained 4-isopropyl-6-methoxy-2-shrinemaiden-3-carboxylate, 4-isopropyl-6-methoxy-2-sharonelementary-2-carboxylate, 4-isopropyl-6-methoxy-2-sharonlee-1-methylpyrrole-2-carboxyl is n-2-carboxylate, 4-isopropyl-6-methoxy-2-sharinaletisha-5-carboxylate and 4-isopropyl-6-methoxy-2-sharinglretirement-2-carboxylate.

Example 17

The reaction of the corresponding 4-R4-R5-2-peloidoterapija formula IV with the appropriate heterocalixarenes acid using methods substantially similar to the method of examples 1, 3 and 5, can be obtained, as we believe, the compounds listed in table. 1.

Example 17CQ

We believe that the method is essentially similar to the method of example 17, 2-chloromethyl-4-spirocyclopropane-4,5,6,7-tetrahydrofuran (preparative example 23BI) can be connected with 2,4-dimethyl-3 - pyridineboronic acid with the formation of 4-spirocyclopropane-4,5,6,7-tetrahydro-2-sharonlee-2,4-dimethylpyridin-3-carboxylate.

An example of a 17cr

We believe that the method is essentially similar to the method of example 17, 2-chloromethyl-4-isopropyl-6-methoxy-4,5,6,7-tetrahydrochloride (preparative example 23C) can be connected with 2,4-dimethyl-3 - pyridineboronic acid with the formation of 4-isopropyl-6-methoxy-4,5,6,7-tetrahydro-2-sharonlee-2,4-dimethylpyridin-3-carboxylate.

Example 18A.

We believe that 6 ethoxy-4-isopropyl-2-chainmail-3,5-dihl the-4-carboxylate with triphenylphosphine and diethylazodicarboxylate in the presence of ethanol.

We believe that the method is essentially similar to the method of example 18, from 6-hydroxy-4 - isopropyl-2-sharonlee-3,5-dichloropyridine-4-carboxylate and the corresponding alcohol can be synthesized compounds from table. 2.

Glycerin, which can be used in the synthesis of example 18F, 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-benzylglycine in a small amount of THF, the mixture is stirred for 1 h at room temperature and add 18,72 g (0,132 mol) of iodomethane, when immediately a white precipitate is formed. 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 and 9.1 (79%) of 1-benzyloxy-2,3-dimethoxypropane.

A solution of 8.8 g (0,042 mol) of the obtained product in 200 ml of MeOH hydronaut in the presence of 1.1 g of 10% Po-C under a pressure of 50 psi (3.5 kg/cm2). Removing the catalyst by filtration and removal of solvent under reduced pressure to obtain 4.4 g (87%) the second example 19) with the release of 85% receive 6 ethoxy-4-isopropyl-2-phenyldimethylsilane (so pl. 111,5-112,5oC) by the method of preparative example 18A turn with the release of 91% in 2-chloromethyl-6-ethoxy-4-isopropylaniline, so pl. 127-128oC

Example R.

We believe that the method is essentially similar to the method of example 18A, benzyl alcohol 4-hydroxy-2 - sharonlee-3,5-dichloropyridine-4-carboxylate can be obtained 4-benzyloxy-2-sharonlee-3,5-dichloropyridine-4-carboxylate.

Example 19. We believe that 6-hydroxy-4-isopropyl-2-sharonlee-3,5-dichloropyridine-4-carboxylate may be processed anhydride triftormetilfullerenov acid and the presence of triethylamine with the formation of 4-isopropyl-6-triftoratsetilatsetonom-3,5 - dichloropyridine-4-carboxylate.

Triftorbyenzola can then be treated with a 1-methyl-2-trimethylaniline, tetrakis (triphenylphosphine) palladium (O), lithium chloride and 2,6-di-tert-butyl-4-METHYLPHENOL and p-dioxane with the formation of 4-isopropyl-6-/2/1-methyl/pyrrolyl/sharonlee/-3.5 dichloropyridine-4-carboxylate.

Example 20.

We believe that the treatment triftoratsetata example 19 dimethylamine will lead to 4-isopropyl-6-dimethylaminomethyl-3,5-dichloropyridine-4-carboxylate.

pyridin-4-carboxylate and di(fluorine-butoxymethyl)methylamine will lead to the formation of 2-(3,5-dichloro-4-pyridylcarboxylic)-4-isopropyl-8-methyl-2,3,7,8-tetrahydro-N-/1,3/oxazino/6,5-about/benzisothiazol-3-one-1,1-dioxide.

Example 22.

We believe that the processing of isopropylidene example 18C (PL. 2) monohydrate p-toluenesulfonic acid in a mixture of methanol-chloroform will lead to 6-(2,3-dihydroxypropane)-4 - isopropylaminomethyl-3,5-dichloropyridine-4-carboxylate.

Example 23.

We believe that the treatment of 6-hydroxy-4-sharonlee-3,5-dichloropyridine-4-carboxylate tert-butylbromide and K2CO3acetone will cause 6-(2-tert-butoxy-2-oksidoksi)-4-isopropyl-2-sharonlee-3,5-dichloropyridine-4 - carboxylate.

In a similar way by using benzylbromide can be obtained 6-(2-benzyloxy-2-oksidoksi)-4-isopropyl - 2-sharonlee-3,5-dichloropyridine-4-carboxylate.

Example 24A.

To fresh the cyclopentadiene at 0oC add 4-bromo-2-(tert-butyl)isothiazol-3(2H)one-1,1-dioxide (Heiv. Chim. Acta, 72, 1416, 1989) (7.9 g, 0.03 mol) and after stirring 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) and then with 20% ethyl acetate in hexane (500 ml). Concentration in vacuo last eluates gain of 9.8 g (100%) norbornene adduct - 3A-bromo-2-tert-butyl-3A,4,7,7-tetrahydro-4,7-methane-1,2-b is the Etat, containing 5% Pd on CaCO3(0.2 g) is stirred for 4 hours at one atmosphere of hydrogen and the reaction mixture is filtered through a layer of silica gel with elution by ethyl acetate (100 ml). The concentration of the eluates 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 (25 ml) at 0oC add diazabicyclo (1,37 g to 0.011 mol) in toluene (10 ml) and after stirring 20 min at 0oC to the reaction mixture add silica gel (25 g). The obtained suspension is transferred into the upper part of the layer of silica gel in 15 cm and elute with 20% ethyl acetate in hexane (800 ml). The concentration of the eluates in vacuo receive in the form of a white solid substance 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 triperoxonane acid (30 ml) 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(1x50 ml). The layers separated, the aqueous phase is acidified with 2 N. HCl to pH 1 and extrahieren bicyclo/2.2.1/saccharin as a white solid.

A mixture of bicyclo derivative/2.2.1/saccharin (0.9 g, 5 mmol), chlorocarbonylsulfenyl (0.07 g, 1 mmol) and tetrabutylammonium (0.36 g, 0.16 mmol) in toluene (50 ml) is boiled for 16 hours under nitrogen atmosphere 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 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 solution of NaHCO3, dried and concentrated in vacuo. Purification of the residue pressure chromatography on silica gel (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 the treatment according to the method similar to the method of example 17, 2-chloromethylphosphonic 3,5-dichloro-4-pyridineboronic acid, 3-methyl-2-thiophencarboxylic acid, furan-3-carboxylic acid, 2-trifluoromethyl-4-pyridineboronic acid, 2-methoxy-4-pyridineboronic acid or 3,5-dichloro-2-/2-(4-morpholinyl)ethoxy/pyridine - 4-carboxylic acid leads to the formation of 2-(3,5-dichloro-4-pyridinecarboxamide-4,7-methane-1,2-benzisothiazol-3(2H)-one-1,1-dioxide, 2-(3-uranilkarbonatov)-4,5,6,7-tetrahydro - 4,7-methane-1,2-benzisothiazol-3(2H)-one-1,1-dioxide, 2-(2-trifluoromethyl-4 - pyridinecarboxamide)-4,5,6,7-tetrahydro-4,7-methane-1,2-benzisothiazol-3(2H)-one-1,1-dioxide, 2-(2-methoxy-4-pyridinyl-carbonylmethyl)-4,5,6,7-tetrahydro-4,7-methane-1,2-benzisothiazol-3(2H)-one-1,1-dioxide or 2-(3,5-dichloro-2-/2-(4-morpholinyl)ethoxy/-4-pyridinecarboxamide)- 4,5,6,7-tetrahydro-4,7-methane-1,2-benzisothiazol-3(2H)-one-1,1-dioxide.

Examples 24B and 24C

We believe that in a manner analogous to the method of example 24A, cyclohexadiene and 1,1-dimethylcyclopentane can be transformed, respectively, in 2-chloromethyl-4,5,6,7-tetrahydro-4,7-ethano-1,2-benzisothiazol-3(2H)-one-1,1-dioxide and 2-chloromethyl-8,8-dimethyl-4,5,6,7-tetrahydro-4,7-methane-1,2-benzisothiazol-3(2H)-one-1,1-dioxide, which in turn can be processed by the method similar to the method of example 17, the corresponding heterocyclic carboxylic acid with the formation of 2-(3-methylisobutylcarbinol)-4,5,6,7 - tetrahydro-4,7-ethano-1,2-benzisothiazol-3(2H)-one-1,1-dioxide, 2-(1,3-dimethyl-5-chloro-2-indolinecarboxylic)-4,5,6,7-tetrahydro-4,7-ethano-1,2-benzisothiazol-3(2H)-one-1,1-dioxide, 2-(2-imidazolecarboxamide)-4,5,6,7-tetrahydro-4,7-ethano-1,2-benzisothiazol-3(2H)-one-1,1 - is 1,1-dioxide, 2-(3,5-dimethyl-1-phenyl-4 - pyrazolecarboxylate)-8,8-dimethyl-4,5,6,7-tetrahydro-4,7-methane-1,2-benzisothiazol-3(2H)-one-1,1-dioxide or 2-(1-methyl-2-pyrrolidinedione)-8,8-dimethyl-4,5,6,7-tetrahydro-4,7-methane-1,2-benzisothiazol-3(2H)-one-1,1-dioxide.

Examples 25A-25I

A General method of obtaining methyl-2-alkylcyclohexane-6-noncarboxylic. To a suspension of anhydrous CuJ (10 mmol) in anhydrous THF (100 ml) add Me2(100 mmol) and the resulting solution cooled to -78oC. for 15 minutes, add the appropriate alkyllithium reagent (20 mmol). After stirring one hour at -78oC add a solution of cyclohexanone (10 mmol) in THF and stirring is continued for another 15 minutes To the resulting mixture add GTFA (5 ml), after 15 minutes add medicinepharmacy (30 mmol) in THF (20 ml), the reaction mixture is heated to room temperature and stirred for about a day. Then the reaction mixture is neutralized 2 N. HCl (50 ml), the layers separated and the aqueous phase extracted with Et2O (1x100 ml). Obyedinenie organic extracts washed with a saturated solution of NH4Cl (3x50 ml), water (I ml), brine (g ml) and dried (Na2SO4). Removal of solvent in vacuo and purification of the residue or by distillation in the apparatus Cuellar, whether the

A General method of obtaining methyl-2-benzylthio-6-alkyl-cyclohex-2-enecarboxylate and methyl-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 (1.5 times the weight of the methyl-2-alkylcyclohexane-6-noncarboxylic) in anhydrous toluene (50-100 ml), boiled for 12-14 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% Na2CO3water, 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-alkylcyclohexane-2-enecarboxylate and methyl 2-benzylthio-6-alkylcyclohexane-1 enecarboxylate (PL. D), which is used in the next stage without separation of components.

A General method of obtaining 4-alkyltetrahydrofuranes. A solution of methyl-2-benzylthio-6-alkylcyclohexane-2-enecarboxylate and methyl-2-benzylthio-6-alkylcyclohexane-1 enecarboxylate (1-10 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 it pronunciat gazoo is a mixture of methyl 2-chloro-sulfonyl-6-alkylcyclohexane-2-enecarboxylate and methyl-2-chlorosulfonyl-6-alkylcyclohexane-1 enecarboxylate, which is dissolved in 10 ml of THF and cooled in a bath of dry ice in acetone was added 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 a freshly prepared solution of sodium methoxide (10-50 mmol) and stirred for 12 h at room temperature. The reaction mixture was concentrated in vacuo, diluted with water and extracted with ether. The organic phase is discarded, and the aqueous phase is acidified with concentrated HCl to pH 1 and extracted with YFC. From organic extracts, after washing with brine, drying and evaporation to dryness receive a 4-alkyl-4,5,6,7-tetrahydrobenzoic-3-one-1,1-dioxide or 4-alkyltetrahydrofuranes (PL. E).

A mixture of 4-alkyl-4,5,6,7-tetrahydrobenzoic-3-one-1,1-dioxide (4-alkyldiethanolamine) (1 EQ.), chlorocarbonylsulfenyl (1.5 EQ.) and tetrabutylammonium (0.2 EQ.) in toluene (25 mg/g of saccharin) boil for 16-24 h at residue on silica gel with elution by the mixture hexane-YFC (1:1 1:3) to obtain the corresponding 2-phenylthiomethyl-4-alkyl-4,5,6,7-tetrahydrobenzoic-3-one-1,1-dioxide or 2-phenylthiomethyl-4-alkyltetrahydrofuranes (PL. F).

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 heterocyclic carboxylic acid, anhydrous potassium carbonate and tetrabutylammonium in DMF with formation of the corresponding 4-alkyl-4,5,6,7-tetrahydro-2-sharonlee(heterocycle)carboxylate (PL. G).

Example 26

Methyl-2,2-dimethylcyclohexane-6-noncarboxylic. To a suspension of anhydrous C1 (70 g, and 0.37 mol) in absolute ether (500 ml) at 0oC not containing added Gallica motility (520 ml, 1.4 M solution in ether, 0.73 mol). 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 (25 ml), after 15 min medicinepharmacy (45 g, of 0.53 mol), the reaction mixture is heated to room temperature and stirred for 3 hours, the Reaction mixture is neutralized 2 N. HCI (50 ml). The layers are separated and the aqueous phase extracted with Et2O (1 x 500 ml). The combined organic extracts washed the tion of the solvent in vacuo and purification by distillation in the apparatus Cuellar obtain 34 g (99%) of methyl 2,2-dimethylcyclohexane-6-noncarboxylic, so pl. 80-84oC/0.6 mm

According to the method described above for examples 25A-25L obtained cyclohexanone can be converted to 4,4-dimethyl-4,5,6,7-tetrahydro-2-sharonlee-3,5-dichloropyridine-4-carboxylate.

You must specify that the above methods are equally applicable for various 4-R4-R5-2-sharonlee or 4,5,6,7-tetrahydro-2-sharonlee-(heterocycle)carboxylates. For example, the processing of the corresponding derivative 4-R4-R5-2-peloidoterapija or 4,5,6,7-tetrahydro-2-peloidoterapija corresponding derivatives of heterocyclic carboxylic acids will lead to target-derived 4-R4-R5-2-sharonlee or 4,5,6,7-tetrahydro-2-sharonlee(heterocycle)carboxylate, which in turn can undergo transformations on the functional group of the type described in the examples 18A-R, with the formation of other derivatives of 4-R4-R5-2-sharonlee or 4,5,6,7-tetrahydro-2-sharonlee(heterocycle)carboxylate.

Determination of the inhibition constants (Kand) complex CLS-inhibitor described for a truly reversible inhibition constants, usually related to competitive inhibitors (Cha, Biochem. PharmacoI. 24, W some extent consumed by the enzyme. So instead of defining aandcalculate the value of K*and, which is defined as the ratio of kd/kDeux, i.e. the degree of reactivation of the enzyme to the degree of deactivation of the enzyme. Determine the values of Kdand KDeuxon the basis of which count K*andu.

The degree of decontamination (kDeux) enzymatic activity determined for the tested compounds by measuring the enzymatic activity of aliquots of the appropriate enzyme, as a function of time after addition of test compounds. Development of a schedule I0enzymatic activity with respect to time obtain the observed degree of decontamination (kneb), which can be represented as kneb1,2/I1/2where I1/2the time required for the drop of the enzymatic activity by 50% Then the degree of decontamination is determined by the following expression:

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where (I) the concentration of inhibitory compounds.

Similarly define a constant reactivation (kd), and then calculate the inhibition constant (K*and) based on the following relationships:

K*and= kd/kDeux< / BR>
Received C what toroi compounds are represented by the numbers of examples, above that describe their receipt.

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. The ingredients are mixed for about 10 min and placed in a dry gelatin capsule No. 1.

Tablets

Ingredient Amount mg per pill

Connection 100

Pregelatinized corn starch 60

Microcrystalline cellulose 36

Magnesium stearate 4

Total 200

The connection is finely pulverized and mixed with a powdered inert ingredients according to the recipe, and then pressed into tablets using standard hardware.

1. 2-Sharinglretirement carboxylates of the formula I

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where Het is 5 - or 6-membered monocyclic heterocycle or a 9-membered ring of the bicyclic heterocycle containing 1 to 2 heteroatoms selected from oxygen, sulfur or nitrogen, or such heterocycles, substituted by one to three identical or razlichnymi, where N In di(lower alkyl) amino or 4-morpholinyl;

R4hydrogen, lower alkyl or lower alkoxy, benzyloxy, lower alkoxycarbonyl, hydroxyl or phenyl;

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

or acid additive salts of these compounds are the main character or main-additive salts of these compounds are acidic in nature, provided that when R4and R5hydrogen, Het cannot be dihydropyridines.

2. Connection on p. 1, where R4hydrogen, lower alkali or lower alkoxy and R5hydrogen or lower alkoxy.

3. Connection on p. 1 where Het is 5 - or 6-membered monocyclic heterocycle.

4. Connection on p. 3, where Het pyridinyl or substituted pyridinyl, R4hydrogen, lower alkyl or lower alkoxy and R5hydrogen or lower alkoxy.

5. Connection on p. 4, where Het is 4-pyridinyl, 3,5-dichloropyridine, 2,4-dimethyl-3 - pyridinyl, or 3,5-dichloro-2- [O-(C2- C10-alkylen)- N=]-4 - pyridinyl, R4hydrogen or lower alkyl and R5hydrogen or lower alkoxy.

6. Connection on p. 5, where Het is 4-pyridinyl, 3,5-dichloro-4 - pyridinyl, 2,4-dimethyl-UP>4hydrogen or isopropyl and R5hydrogen or a methoxy group.

7. Connection on p. 3, where the Het thienyl or thienyl substituted by one or two identical or different members of the group comprising lower alkyl and halogen.

8. Connection on p. 7, where the Het thienyl, (lower alkyl)thienyl or haloethanol, R4hydrogen, lower alkyl or lower alkoxy and R5hydrogen or lower alkoxy.

9. Connection on p. 8, where R4lower alkyl and R5lower alkoxy.

10. Connection on p. 9, where the Het thienyl, methylthieno or chloranil, R4isopropyl and R5the methoxy group.

11. Connection on p. 3, where Het isoxazolyl or isoxazolyl substituted by one or two identical or different members of the group comprising lower alkyl and halogen.

12. Connection on p. 11, where Het isoxazolyl or isoxazolyl, substituted lower alkyl, R4hydrogen, lower alkyl or lower alkoxy and R5hydrogen or lower alkoxy.

13. Connection on p. 12, where R4lower alkyl and R5- lower alkoxy.

14. Connection on p. 13, where Het is 3-methyl-5-isoxazolyl or 3,5-dimethyl-4 - isoxazolyl, R4isopropyl and R5the methoxy group.

15. Connected is passed or different members of the group, including lower alkyl, oxoprop and halogen.

16. Connection on p. 3, where Het pyrazolyl, imidazolyl or the same heterocycle substituted by one or two identical or different members of the group comprising lower alkyl, phenyl and halogen.

17. Connection on p. 1 where Het 9-membered ring of the bicyclic heterocycle.

18. Connection on p. 17, where Het indolyl or indolyl substituted by one or two identical or different members of the group comprising lower alkyl and halogen.

19. Connection on p. 1, the inhibitory activity of proteolytic enzymes.

20. 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.

 

Same patents:

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),

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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 aminoven derivatives, processes for their production and insecticide containing as selective compounds listed derivatives

Derivative amide // 2037493

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

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)

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where a group

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where m and n are independent of each other represent 1 or 2,

Q group of formulae

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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

The invention relates to new derivatives of arylalkylamines, as well as containing their farbkomposition, which can find application in pathological conditions involving the system of neurokinin

The invention relates to the field of animal husbandry, in particular to a method of preventing technological stress in cattle

- carbolines, which or their salts with organic or inorganic acids, exhibiting antimicrobial activity" target="_blank">

The invention relates to the field of new biologically active compounds - derivatives of 3,4, -dihydro - or 1,2,3,4-tetrahydro-b-carbolines, which and their salts have antibacterial properties, so that they can be used as drugs in medical practice
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