Derivatives isoindoline in the form (3 ar, 7 ar)- or (3 Árs, 7 Árs)-forms or their mixtures or their hydrochloride, which are antagonists of substance p

 

(57) Abstract:

Usage: the antagonist of substance P in therapy. The essence of the invention: derivatives isoindoline General formula 1, where each R is hydrogen or together form a bond, both R - phenyl, which may be substituted in position 2 or 3 halogen or stands, R is phenyl which may be substituted, if necessary, by one or more radicals such as halogen, hydroxyl, alkyl (which may be substituted with halogen, amine or alkylamine), alkoxy, alkylthio (which may be substituted by hydroxyl, dialkylamino or 4-methylpiperazine), Amin, alkylamino, dialkylamino, 1-pyrrolidinyl, cyclohexanediyl, naphthyl, thienyl, dithienyl, pyridil and indolyl, R is hydrogen, halogen, hydroxyl, alkyl, aminoalkyl, alkoxy, acyloxy, carboxy, allyloxycarbonyl, benzyloxycarbonyl, amino or acylamino, X is an oxygen atom or a radical NR5where R5is a hydrogen atom, alkyl containing from 1 to 12 carbon atoms, optionally substituted by one or two radicals, such as carboxy radical, dialkylamino, acylamino, allyloxycarbonyl, allyloxycarbonyl, carbamyl, allylcarbamate, diallylbarbital (and the alkyl portions of these radicals can be the, naphthyl, thienyl, furyl, pyridinyl or imidazolyl, or dialkylamino (and the alkyl and acyl radicals mentioned above, unless otherwise indicated, are acceptable or branched and contain from 1 to 4 carbon atoms) in the form (3R, 7R) or (3RS, 7RS) - forms or their mixtures, or their hydrochloride. Reagent 1: reactive derivative of the acid of General formula R3R4CHCOOH . Reagent 2: derivatives isoindoline. Reaction conditions: subsequent modification. table 2.

The invention relates to the chemistry of indole derivatives, specifically to the new derived isoindoline General formula I

NR3where both R1is hydrogen or together form a bond;

both R2is phenyl which may be substituted in position 2 or 3 halogen or stands;

R3is phenyl which may be substituted, if necessary, by one or more radicals such as halogen, hydroxyl, alkyl (which may be substituted with halogen, amine or alkylamine), alkoxy, alkylthio (which may be substituted by hydroxyl, dialkylamino or 4-methylpiperazine), Amin, alkylamino, dialkylamino, 1-pyrrolidinyl or morpholino; cyclohexadienyl; naphthyl; thienyl; dithienyl; pyridyl or indolyl,

X - atom color is bademosi substituted by one or two radicals, such as a carboxy radical, dialkylamino, acylamino, allyloxycarbonyl, allyloxycarbonyl, carbamyl, allylcarbamate, diallylbarbital (and the alkyl portions of these radicals can be dialkylamino or phenyl substituent), phenyl, halogen, alkyl, alkyloxy or dialkylaminomethyl phenyl, naphthyl, thienyl, furyl, pyridinyl or imidazolyl, or dialkylamino, and alkyl and acyl radicals mentioned above, unless otherwise indicated, are straight or branched and contain from 1 to 4 carbon atoms, in the form of (3R, 7aR) - or (3RS, 7aRS)-forms or their mixtures or their hydrochloride, which are antagonists of substance P, which can find use in therapy.

Known isoindole derivatives of General formula

NR which have opioid activity [1] .

However, these products do not have activity against substance P.

Up to the present time despite studies [2] have not been designed products, acting specifically on substance P and having ones structure.

The aim of the invention is the development of new indole derivatives which are antagonists of substance P.

This goal is achieved offer the Idov, which can be obtained by the action of the acid of General formula II

R3--COOH or a reactive derivative of this acid, where R3and R4defined as above, on the isoindole derivative of General formula III

NH in which the symbols R1and R2defined as above, followed, if necessary, the transformation of the amide obtained in thioamide or amidin, for which X represents the radical N-R5where R5corresponds to the definition given above.

Assume that the radicals of amino, alkylamino - or carboxy-contained in R3and/or R4are mainly pre-reserved. Protection is accomplished through any suitable group, the introduction and the removal of which does not affect the rest of the molecule. As a rule, carry out reaction according to described methods [3, 4] .

As an example, amino - or alkylamino can be protected by radicals methoxycarbonyl, taxicab - nilnil, tert-butoxycarbonyl, allyloxycarbonyl, vinyloxycarbonyl, trichlorocarbanilide, trichloroethylene, trifluoracetyl, chloroacetyl, tritely, benzhydryl, benzil the groups can be protected by methyl radicals, ethyl, tert-botilinum, benzyl, substituted benzyl or benzhydryl.

In addition, when R3is hydroxyacyl, preferably in advance to protect this radical. Protection is carried out by radical acetoxy-, trialkylsilyl, benzyl or in the form of carbonate radical-Ra, where Ra is alkyl or benzyl radical.

When carry out the condensation product with the General formula (II) in its acid form (which, if necessary, the Vice-amino-, alkylamino-, carboxy - and/or hydroxy-pre-protected), the reaction is carried out usually in the presence of a condensing agent such as carbodiimide (for example, dicyclohexylcarbodiimide, or 1-(3-dimethylamino-propyl)-3-ethylcarbodiimide), N, N'-carbonyldiimidazole or 2-ethoxy-1-etoxycarbonyl-1,2-dihydroquinoline, in such an organic solvent, as a chlorinated solvent (dichloromethane, dichloroethane, chloroform, for example), an ether (e.g. tetrahydrofuran, dioxane), esters (ethyl acetate, for example), an amide (for example, dimethylacetamide, dimethylformamide), a nitrile(acetonitrile for example), a ketone (acetone, for example), or in an aromatic hydrocarbon such as toluene, at a temperature, Zack is Dean and remove, if necessary, protecting groups.

When conducting the condensation of a reactive derivative of the acid of General formula (II), the reaction is carried out at a temperature that is between -40 and +40aboutC, in an organic solvent such as a chlorinated solvent (e.g. dichloromethane, dichloroethane, chloroform), an ether (e.g. tetrahydrofuran, dioxane), an amide (for example, dimethylacetamide, dimethylformamide) or a ketone (acetone, for example), or in mixtures of these solvents, in the presence of an acid acceptor such as nitrated organic base, such as pyridine, dimethylaminopyridine, N-methylmorpholine or trialkylamine (especially triethylamine), or such as epoxide (propylene oxide, for example) or carbodiimide, or in aqueous organic medium in the presence of an alkaline condensing agent, for example, sodium bicarbonate, and then, if necessary, converts the obtained amide in thioamide or amidin, as indicated above.

The transformation of the amide with the General formula (I) in thioamide is carried out by any method of tonirovania, which does not change the rest of the molecule.

The reaction is carried out usually under the action of Lawesson's reagent [bis-2,4-(4-methoxyphenyl)-2,4-dicicco-1,2,3,4-dithiodi - Tsvetan] or under the influence of PE, Iksan), aromatic hydrocarbons (toluene, for example), at a temperature that is between the 0aboutAnd temperature phlegmy reaction mixture.

The transformation of the amide with the General formula (I) in amidin for which X is a radical N-R4. is carried out either directly or through appropriate thioamide, getting derived isoindole with the General formula IV

N in which R1, R2, R3and R4defined as above and Y or represents a chlorine atom, a methoxy radical or ethoxy-, and Z-is a chloride ion, tetrafluoroborate, persulphate, triftormetilfullerenov, methyl sulfate or ethyl sulfate, or Y represents a chlorine atom or a radical methylthio, ethylthio, benzylthio or allyloxycarbonyl-, and Z is defined as above, or represents the ion iodide or bromide, and then affect the amine with the General formula V

R4-NH2where is defined as above.

Derivatization isoindole with the General formula IV in which Y is a chlorine atom or a methoxy radical or ethoxy is carried out under the action of this reagent as phosgene, phosphorus oxychloride, pentachloride phosphorus, thionyl chloride, oxalyl the l- ( or ethyl-) persulfonic, or methyl-(or ethyl-) sulfate. Derivatization isoindole with the General formula IV in which Y is a chlorine atom, a radical of methyl- (or ethyl) thio-, benzylthio or allyloxycarbonyl-is derived from isoindoline with the General formula I, in which X is a sulfur atom, under the action of the bromide or iodide of methyl, ethyl or benzyl. The reaction is carried out in a chlorinated solvent (e.g. dichloromethane, dichloroethane) or an aromatic hydrocarbon (toluene, for example) at a temperature that is between the 0aboutAnd temperature phlegmy the reaction mixture. When conducting the reaction on the basis of thioamide with the General formula I, it is also possible to use solvents such as ethers, ketones, esters or NITRILES. The action of the amine with the General formula V is derived from the General formula IV is carried out in an anhydrous organic solvent such as a chlorinated solvent (e.g. dichloromethane, dichloroethane), in a mixture perchloromethyl solvent, an ether (tetrahydrofuran, for example), in a complex ester (ethyl acetate, for example), in an aromatic solvent (toluene, for example), or in mixtures of these solvents at a temperature that is between -20aboutAnd those who indole with the General formula IV, to enter it in the response.

According to the invention derived isoindoline with the General formula I, in which R3and R4defined as above, except when they are or substituted groups, hydroxy-, amino-, alkylamino, dialkylamino - or carboxy-, and R1, R2, R3, R4and X are defined as above, can also be derived from cyclohexanone with the General formula VI

in which R1and R2defined as above, under the action of 1,3,5-titrimetrically-1,3,5-triazine and foramerica acid with the General formula VII

R3--COF in which R3and R4defined as above, followed, if necessary, the transformation of the amide obtained in thioamide or amidin, in which X represents a radical N-R5defined as above. The reaction is carried out usually in an organic solvent such as a chlorinated solvent (e.g. dichloroethane, trichloroethane) or aromatic hydrocarbons (e.g. toluene, xylene) at a temperature that is between 80aboutAnd temperature phlegmy reaction medium.

The transformation of the amide in thioamide or amidin is ACC the nd IX, in which R3is alkyloxyalkyl radical, the alkyl part of which is substituted or not, and the symbol R4different from hydroxyalkyl, can also be derived from the isoindole derivative with the General formula I, in which R3is a radical hydroxyproline, under the action of the primary environment of the corresponding halogenated derivative of General formula VIII

Hal - R6in which l is a halogen atom, and R6are the alkyl radical, substituted if necessary by hydroxyradicals, or dialkylamino-whose alkyl portions may, if necessary, to form with the nitrogen atom to which they are bound, a heterocycle is the same as defined in General formula I.

The reaction is carried out usually in the presence of a base such as a hydride, alkali metal hydroxide, an alcoholate of an alkali metal or carbonate of an alkali metal, in an organic solvent such as an amide (dimethylformamide, for example), aromatic hydrocarbons (toluene, for example) ketone (butanone, for example), or in mixtures of these solvents at a temperature that is between the 20aboutAnd temperature phlegmy reaction mixture.

When the radical R6iAUDIO radical is carried out in accordance with the methods above.

According to the invention derived isoindoline with the General formula I, in which X is a radical N-R5can also be obtained on the basis of the derived isoindoline with the General formula III, under the action of the product with the General formula IX

R3- C if necessary in the form of salts, in which R3, R4and R5defined as above, and R7is alkyloxyalkyl containing 1-4 carbon atoms in a straight or razvetvlennye, or radical methyltin, ethylthio, benzylthio or allyloxycarbonyl, or, if R5different from hydrogen, then R7is acyloxyacyl containing 1-4 carbon atoms or a chlorine atom.

The reaction is carried out by means of a derivative with the General formula IX obtained, if necessary, in situ, in an organic solvent such as a chlorinated solvent (e.g. dichloromethane, dichloroethane), an ether (tetrahydrofuran, for example), aromatic hydrocarbons (toluene, for example) or a nitrile (acetonitrile for example), at a temperature that is between the 0aboutAnd temperature phlegmy reaction mixture.

It is understood that in case of necessity, when the radicals Rduring the reaction, the latter must be pre-reserved.

Acid with the General formula II can be obtained in accordance with the methods described below in the examples or in analogy to these methods.

Derived isoindole with the General formula III can be obtained on the basis of the corresponding derivative with the General formula X

N-R8in which R1and R2defined as above, and R8represents an allyl radical or a radical of structure - CRaRbRcwhere Raand Rbare hydrogen atoms or phenyl radicals, substituted if necessary (atoms, halogen, a radical, alkyl, alkyloxy - or nitro), and Rcdefined as Raand Rb. or represents alkyl or alkyloxyalkyl radical, and at least one of the radicals Ra, Rband Rcis a phenyl radical, substituted or not, and alkyl radicals contain from 1 to 4 carbon atoms in straight or branched chain, by any known method which does not affect the rest of the molecule.

Typically, when R1is a hydrogen atom, and when R7different from allyl radical, RaboutWITH

When R8is benzhydryl or tritely radical, the cleavage can be carried out by treatment in an acidic environment, conducting the reaction at a temperature that is between the 0aboutAnd temperature phlegmy reaction mixture, alcohol, simple ester in water or directly in acetic acid, formic acid or triperoxonane acid. The group R8can also be derived under the action of vinylnorbornene, 1-chloroethylphosphonic or phenylcarbamate passing through the intermediate product with the General formula XI

N-COOR9in which R1and R2defined as above, and R9is a radical of the vinyl, 1-chlorethylene or phenyl, with subsequent cleavage of the radical R9when acid treatment. The effect of chloroformiate is usually performed in an organic solvent such as a chlorinated solvent (e.g. dichloromethane, dichloroethane, chloroform), an ether (tetrahydrofuran, for example), or a ketone (acetone, for example), or in mixtures of these solvents through the reaction when the temperature is9provided by treatment in an acidic environment, such as acid triperoxonane, formic, methanesulfonates, p-toluensulfonate, chloroethanol or pomodorini in a solvent such as alcohol, simple ester, ester, nitrile, in a mixture of these solvents or in water at a temperature that is between the 0aboutAnd temperature phlegmy reaction mixture.

Under these conditions, removal of the radicals R9derived isoindoline with the General formula III is obtained in the form of salt used acid, which can directly used in the next stage.

Derived isoindoline with the General formula X can be obtained in the cycloaddition reaction under the action of silyl derivative with the General formula XII

R Ni in which R8defined as above, (Ro)3are alkyl radicals or alkyl and phenyl radicals, and Roois a radical of alkyloxy-, cyano - or phenylthio-derived cyclohexenone with the General formula VI.

The reaction is carried out in the presence of catalytic amount of acid that is selected from among triperoxonane acid, acetic acid, methanesulfonate or acids mentioned in the literature is harmatan, dichloroethane), aromatic hydrocarbon, a nitrile (acetonitrile) or a simple ether, at a temperature that is between the 0aboutAnd temperature phlegmy reaction mixture.

Silyl derivative with the General formula XII can be obtained according to the methods described in the - y Tarao et coll. , Chem. Pharm. Bull. , 33, 2762 (1985); A. Hosomi et coll. , Chem. Lett. 1117 (1984); A. Padwa et coll. , Chem. Ber. , 119, 813 (1986) or Tetrahedron, 41, 3529 (1985).

Assume that derivatives isoindoline with the General formula III and X represent several stereoisomeric forms. When you want to obtain a product with the General formula I in the form (3R, 7aR), the separation of isomeric forms is carried out mainly at the level of the derivative with the General formula III. The separation is carried out in accordance with any known method suitable for the molecule.

As an example, the separation can be carried out by obtaining the optically active salts under the action of almond acid L(+) or D(-) or dibenzoyltartaric acid, followed by separation of the isomers by crystallization. The desired isomer is released from its salt in a basic environment.

New derivatives of isoindoline with the General formula (I) can be purified, if necessary, such Fizicheskii formula I, in which the symbols R3and/or R4contain amino or alkilaminometilen and/or X is a radical NR5can be converted into a salt accession with acids. As examples of salts of joining with acids (salts) are pharmaceutically acceptable, you can specify salts formed with inorganic acids (chlorhydrate, bromhidrosis, sulfates, nitrates, phosphates) or with organic acids (succinate, fumarate, tartratami, acetates, propionate, maleate, citrates, methanesulphonate, p-toluensulfonate, isethionate, or substituted derivatives of these compounds).

New derivatives of isoindoline with the General formula I, if necessary, when R4is carboxylation, can be converted into metal salts or salts of joining with nitrided bases in accordance with known methods. These salts can be obtained by the action of bases metals (e.g. alkali or alkaline-earth), ammonia or amines in the product according to the invention in a suitable solvent, such as alcohol, simple ester or water, or by exchange reaction with a salt of an organic acid. Educated salt after a possible concentration of precipitates and the development of pharmaceutically acceptable salts, you can specify salts of alkali metals (sodium, potassium, lithium) or alkaline-earth metals (magnesium, calcium), ammonium salt, salt nitrided bases (ethanolamine, diethanolamine, trimethylamine, triethylamine, methylamine, Propylamine, Diisopropylamine, N, N-dimethylethanolamine, benzylamine, dicyclohexylamine, N-benzyl-pentylamine, N, N'-dibenziletilendiaminom, diphenylethylamine, benzhydrylamine, quinine, choline, angelina, lysine, leucine, dibenzylamine.

New derivatives of isoindoline according to the invention, which counteract the effects of substance P, can be used as an analgesic for the treatment of inflammation, asthma, Allergy, Central nervous system, cardiovascular system, as antispasmodics, or for the immune system, as well as in promoting lacrimal secretion.

Indeed, the products according to the invention show affinity to receptors substance P in doses of prisoners between 5 and 2000 nm in accordance with the method described in S. M. Lee et col. , Mol. Rharmacd, 23, 563-69 (1983).

Moreover, it was shown that we are talking about the effect of counteracting substance P through different products. In the method described by S. Rasell et coll. , Substance P , Ed. by B. Pernow, New York, 1977, S. 83-88, studied products okazivaete pathological areas;

- Agonists and antagonists of substance P. A. S. Dutta Drugs of the future, 12 (8), 782 (1987);

- Substance P and pain : an updating, J. L. Henry, TINS, 3 (4), 97 (1980);

- Substance p in inflammatory, reactions and pain, S. Rosell, Actual. Chim. Ther. , 12 eme serie, 249 (1985);

- Effects of Neuropeptides on Production of Inflammatory Cytokines by Human Monocytes, M. Lotz et coll. Science, 241, 1218 (1988);

- Neuropeptides and the pathogenesis of allergy, Allergy, 42, 1 a 11 (1987);

- Sybstance P in Human Essenntial Hypertension, J. Cardiocascular Pharmaco-logy, 10 (suppl. 12), 5172 (1987).

It was emphasized in the study of many products that new derivatives isoindoline show boletos - tion activity in method E. Siegmund et coll. , Proc. Soc. Exp Biol 18 Med. , 95, 729 (1957).

The study of many derivatives isoindoline with the General formula (I) in method A. Saria et coll. , Arch. Pharmacol, 324, 212-218 (1983) revealed rats slowing down (inhibitory) effect of increasing capillary permeability caused by substance P, which demonstrates anti-inflammatory activity Was also shown with the help of many products that new derivatives isoindoline operate at the level of the Central nervous system: they counteract the effects caused by the agonist substance P (cepteam), introduced by intrathecal rat, in the method of R. E. Rodriques et coll. Neuropharmacol. 22 (2), 173-176 (1983);

Introduction substance P animal causes poiut in rat effect of combating against this hypotonia. Especially the product of example 60, administered intravenously per minute with a dose of 0.2 mg/kg, calls for 5 min, the antagonism about 50% of hypotonia caused by the intravenous injection of 250 micrograms of septica.

Substance P plays a role in modulation of immune processes (J. P. Mc. Gillus et coll. , Fed. Proc. , 46, E1), 196 to 199 (1987). Substance P is connected with receptors on human cells in cultures: lymphoblasts offspring IM 9/D. G. Payan et coll. , V. of Immu nol. , 133 (6), 3260-5 (1984). The products according to the invention displace substance P from these provisions.

Finally, the methodology G. Rosell, Substunce P. p. 83-88, Raven Press, New York (1977) carried out to identify the effect of countermeasures in relation to substance P, also shows the counteracting activity in relation to spasms caused by substance P or agonist substance P.

On the other hand, derivatives isoindoline according to the invention do not exhibit toxicity, they are non-toxic to mice at a subcutaneous injection with a dose of 40 mg/kg or oral administration with a dose of 100 mg/kg

The following examples are given as non-limiting, illustrate the present invention.

In the examples below, it is understood that, except for special mention, range and m e R 1. To a solution containing of 1.34 g of phenylacetic acid in 30 cm3anhydrous dichloromethane, cooled to 5aboutTo give 1.7 g of N, N-carbonyldiimidazole. Stirred for 1 h at 5aboutWith, then add a solution containing of 3.27 g of the hydrochloride of 7,7-diphenyl-4-perhydrosqualene and 1.7 cm3of triethylamine in 30 cm3dichloromethane. The reaction mixture was stirred 1 h at 5aboutC, then 1 h at 20aboutC. Then the reaction mixture is washed with 50 cm3saturated aqueous solution of acid sodium carbonate, dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue crystallizes 15 cm3acetonitrile. The crystals are centrifuged (press), washed with 10 cm3isopropoxide and dried. Obtain 2.7 g of 7,7-diphenyl-2-(phenylacetyl)-4-perhydrosqualene-(3RS, 7aRS), melting at 216aboutC.

Hydrochloride 7,7-diphenyl-4-perhydrosqualene-(3aRS, 7aRS) can be obtained according to one of the following methods:

a) To 15 g of palladium with 10% carbon added 150 g of 2-benzyl-7,7-diphenyl-4-perhydrosqualene-(3RS, 7aRS), 1500 cm3methanol and 450 cm31 N. chloroethanol acid, the reaction mixture hydronaut under stirring, at room temperature, and so is the comfort, then concentrated to dryness under reduced pressure (2.7 kPa); the residue is crystallized at 200 cm3ethanol, the crystals are centrifuged, washed with 50 cm3ethanol and dried. Obtain 110 g of the hydrochloride of 7,7-diphenyl-4-perhydrosqualene-(3RS, 7aRS), melting at 270aboutWith decomposition.

An NMR spectrum of the proton:

2,03 (MT, 1H, 1H from N in 5 or 6); 2,3 (MT, 1H, 1H from N in 5 or 6); 2,48 (DD, hidden part, from 1H-CH2- 1); 2,69 (DD, 1H, 1H from-CH2- 1); 2,8 (MT, 2H, -CH2- 6 or 5); to 3.34 (DD, hidden part, 1H,- CH2- 3); 3,5 (MT, 1H, -CH - 3A); is 3.82 (DD, 1H, 1H from-CH23); of 3.95 (MT, 1H, -CH - 7a); 7,15 to 7.65 (MT, 10H, aromatic); 9,43 (MT, 2H, -NH2-Cl).

The characteristic bands of the infrared spectrum (KBR) in cm-1:

3600-3300, 3100-3000, 3000-2850, 3100-2400, 1715, 195, 1580, 1495, 1470, 1445, 775, 750, 705.

To the solution containing 193 g of 2-benzyl-7,7-diphenyl-4-peligrosidad - on - (3RS, 7aRS) 1225 cm31,2-dichloroethane cooled to 5aboutWith added drop by drop within 10 min 56 cm3vinylnorbornene. After 30 minutes of mixing between 10 and 20aboutWith the reaction mixture is heated to education phlegmy for 90 min, then cooled and concentrated to dryness under reduced pressure (2.7 kPa, then 1 kPa). P is obtained crystals are centrifuged, washed with 2 times 100 cm3isopropoxide and dried. Get 177 g of 7,7-diphenyl-2-vinyloxycarbonyl-4-perhydrosqualene-(3aRS, 7aRS), melting at 178aboutC.

Handle 177 g of 7,7-diphenyl-2-vinyloxycarbonyl-4-perhydrosqualene-(3RS, 7aRS) by 100 cm35,7-called solution chloroethanol acid in dry dioxane for 30 min at 20aboutC. the Solution is concentrated to dryness under reduced pressure (2.7 kPa) and the residue is extracted by 500 cm3ethanol; the resulting mixture was stirred at 60aboutC for 30 min, then cooled to +5aboutC. the resulting crystals are centrifuged, washed with 50 cm3ethanol and dried. Obtain 130 g of hydrochloride, 7,7-diphenyl-4-perhydrosqualene-(3RS, 7aRS), melting at 270aboutC.

2-Benzyl-7,7-diphenyl-4-peligroso - indolo-(3RS, 7aRS) can be obtained as follows.

To a solution containing 155 g of 4,4-diphenyl-2-cyclohexen-1-she and 202 cm3N-butoxymethyl-N-trimethylsilylmethylamine - amine 1000 cm3anhydrous dichloromethane, was added 5 drops triperoxonane acid and heated the reaction mixture to form phlegmy for 45 minutes Add 50 cm3N-butoxymethyl-N-trimethylsilylmethylamine 25 cm3N-butoxymethyl-N-trimethylsilylmethylamine 3 drops triperoxonane acid. The reaction mixture was stirred under irrigation by phlegm 45 min, then treated with 50 g of potassium carbonate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is dissolved in 200 cm3isopropoxide and the solution is cooled at 0aboutC for 1 h the resulting crystals are centrifuged, washed 2 times 15 cm3isopropoxide and dried, resulting in a gain of 193 g of 2-benzyl-7,7-diphenyl-4-perhydrosqualene-(3aRS, 7aRS) in the form of white crystals, melting at 132aboutC.

N-Butoxymethyl-N-trimethylsilyl - deventilation can be obtained in accordance with the method of Y. Tarao et coll. Chem. Pharm. Bull. , 33, 2762 (1985).

P R I m m e R 2. To a solution containing 10 g of the hydrochloride of 7,7-diphenyl-4-perhydrosqualene-(3R, 7aR) 80 cm3anhydrous dichloromethane, cooled to 5aboutTo add drop by drop a solution containing 4 cm3phenylacetylide and 8.6 cm3of triethylamine in 10 cm3dichloromethane. The reaction mixture was stirred 2 h at 5aboutC, followed by 20 h at 20aboutC. Then the reaction mixture is treated with 30 cm3saturated aqueous solution of acid sodium carbonate; organic tatsuha under reduced pressure (2.7 kPa). The residue is crystallized in 15 cm3acetonitrile. The obtained crystals are centrifuged, washed with 10 cm3acetonitrile, 10 cm3isopropoxide and dried. Obtain 5.7 g of 7,7-diphenyl-2-(phenylacetyl)-4-peligroso - indolene - (3R, 7aR), melting at 173aboutC.

()D20= -282about(C = 1, methanol).

Hydrochloride 7,7-diphenyl-4-perhydrosqualene-(3R, 7aR) can be obtained in the following way:

To a suspension consisting of 200 g of the hydrochloride of 7,7-diphenyl-4-perhydrosqualene - (3RS, 7aRS) in 2000 cm3ethyl acetate is added slowly with stirring to 500 cm34h. aqueous sodium hydroxide solution; stirring is continued until dissolution of the original product. The organic solution was washed with 250 cm3distilled water, 250 cm3saturated aqueous solution of sodium chloride, dried on magnesium sulfate and filtered. To the thus obtained solution was added with stirring a solution containing 92,8 g almond acid L-(+) 1000 cm3ethyl acetate, after 4 hours of stirring the obtained crystals are centrifuged, washed with 250 cm3ethyl acetate (2 times) and dried. Then the crystals extracted by 2000 cm3distilled water, the mixture promyvayut 100 cm3distilled water (2 times) and dried. They precrystallization from a mixture of 1100 cm3acetonitrile and 500 cm3distilled water; the resulting crystals are centrifuged, washed with 40 cm3acetonitrile (3 times) and dried. Get 80 g of 7,7-diphenyl-4-peligrosidad-(3R, 7aR) - mandelate-(L).

()D20= -164about(C = 1, methanol).

To 80 g of 7,7-diphenyl-4-peligrosidad-(3R, 7aR)-mandelate-(L) add 400 cm31 N. aqueous solution of hydroxicut sodium and 600 cm3ethyl acetate; the mixture is stirred at room temperature until dissolution of the original product; the organic solution is washed with 250 cm3distilled water, 250 cm3saturated aqueous solution of sodium chloride, dried on magnesium sulfate and filtered; then it is acidified under stirring by addition of 30 cm39 N. solution chloroethanol acid; the resulting crystals are centrifuged, washed with 50 cm3ethyl acetate (2 times), 50 cm3isopropoxide and dried. Get the 52.3 g of the hydrochloride of 7,7-diphenyl-4-perhydrosqualene-(3R, 7aR), melting at 270aboutWith decomposition.

()D20= -282about(C = 0.5 in methanol).

P R I m e R 3. To the solution, the content is 5 g of bis-2,4-(4-methoxyphenyl)-2,4-dicicco-1,2,3,4-dithiadiphosphetane; the reaction mixture is left under stirring for 20 h at room temperature. Then it is treated with 10 cm320% aqueous ammonia solution and 30 cm3distilled water, followed by extraction by 150 cm3ethyl acetate (2 times); the combined organic phases are washed with 200 cm3distilled water (2 times), 100 cm3saturated aqueous solution of calcium chloride, dried on magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The remainder chromatographic on a column of silica gel (0.06 to 0.2 mm, diameter 3 cm, height 30 cm) and elution with a mixture of cyclohexane and ethyl acetate (50/50 by volume), collecting fractions of 25 cm3. Fractions 1 to 6 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The resulting crystals are washed with 20 cm3isopropylated, centrifuged and dried. Get 1.5 g of 7,7-diphenyl - 2-(2-phenylthiazol)-4-perhydrosqualene-(3RS, 7aRS), melting at 221aboutC.

P R I m e R 4. To a solution containing 20 g of 7,7-diphenyl-2-phenylacetyl-4-perhydrosqualene-(3RS, 7aRS), 50 cm3dichloromethane is added 10,45 g tetrafluoroborate triethyloxonium. The reaction mixture is left under stirring for 20 h at room is SUP> anhydrous ether and dried, to obtain 11.1 g of tetrafluoroborate 2-[(1-ethoxy-2-phenyl)-ethylidene] -4-oxo-7,7-diphenyl-purged - Rosendale - (3RS, 7aRS) in the form of a white powder used in this state for subsequent operations.

To a stirred and cooled to -20aboutWith a suspension consisting of 3.75 g of tetrafluoroborate 2-[(1-ethoxy-2-phenyl)-ethylidene] -4-oxo-7,7-diphenyl-peligrosos - Leah-(3RS, 7aRS) 30 cm3anhydrous dichloromethane, was added 8.8 cm30,8 n solution of ammonia in dichloromethane. Give the temperature of the reaction mixture to rise to room temperature and continue stirring for 5 hours the Reaction mixture is treated with 30 cm310% aqueous potassium carbonate solution. The precipitate is removed by filtration, and then the organic phase is washed with 15 cm3distilled water, 15 cm3saturated aqueous solution of sodium chloride, dried on magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is recrystallized from 22 cm3acetonitrile. The obtained crystals are centrifuged and dried. Obtain 1.3 g of 2-(-aminophenethyl)-7,7-diphenyl-4-purged - roseingrave-(3RS, 7aRS), melting at 202aboutC.

P R I m e R 5. To the stirred suspension, with the i.i.d. according to example 4, 5 cm3anhydrous dichloromethane, was added 0,43 cm3of methylamine. The reaction mixture is left under stirring for 3 h at room temperature, then diluted with 40 cm3dichloromethane and treated with 15 cm3an aqueous solution containing 22 g of potassium carbonate. The precipitate is removed by filtration, and then the organic phase is washed with 15 cm3distilled water, 10 cm3saturated aqueous solution of sodium chloride, dried on magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The remainder chromatographic on a column of neutral alumoweld echiney SVT 1 (diameter 3 cm, height 23.5 cm) by elution through 750 cm3a mixture of cyclohexane and ethyl acetate (10/90 by volume), 250 cm3ethyl acetate and 500 cm3a mixture of ethyl acetate and methanol (95/5 by volume), taking fractions of 25 cm3. Fractions 41 to 65 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in 0.5 cm3acetonitrile, and the resulting crystals are centrifuged, washed with 0.5 cm3acetonitrile and dried. Obtain 0.5 g of 2-(-methylaminomethyl)-7,7-diphenyl-4-lane - hydroisoquinoline-(3RS, 7aRS), melting at 110aboutC.

P R I m e R 6. To stir is-(3aRS, 7aRS), prepared according to example 4, 5 cm3anhydrous dichloromethane, was added 0.3 cm3ethylamine. The reaction mixture is left under stirring for 20 h at room temperature. The precipitate centrifuged, washed with 30 cm3ethyl ether and dried. Then it is dissolved in 40 cm3dichloromethane, and the solution was washed with 15 cm3an aqueous solution containing 44 g of potassium carbonate, 30 cm3distilled water and 15 cm3saturated aqueous solution of sodium chloride, then the solution is dried on magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is recrystallized from 15 cm3isopropanol, and the resulting crystals are centrifuged and dried. Get to 1.15 g of 2-( -ethylenevinyl)-7,7-diphenyl-4-perhydrosqualene-(3aRS, 7aRS), melting at IaboutC.

P R I m e R 7. To a stirred and cooled to +5aboutWith a suspension consisting of 3.5 g of tetrafluoroborate 2-[(1-ethoxy-2-phenyl)-ethylidene] -4-oxo-7,7-diphenyl-purged - Rosendale-(3RS, 7aRS), obtained according to example 4, 30 cm3anhydrous dichloromethane, was added 0.6 cm3Propylamine. The reaction mixture is left under stirring for 20 hours at komnatok removed by filtration, then the organic phase is washed with 15 cm3distilled water, 15 cm3saturated aqueous solution of sodium chloride, dried on magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is recrystallized from 5 cm3acetonitrile. The obtained crystals are centrifuged and dried. Obtain 0.5 g of 2-(-drunk - aminophenethyl)-7,7-diphenyl-4-perhydro - isoindoline-(3RS, 7aRS), melting at 86aboutC.

P R I m e R 8. To a stirred and cooled to +5aboutWith a suspension consisting of 3.75 g of tetrafluoroborate 2-[(1-ethoxy-2-phenyl)-ethylidene] -4-oxo-7,7-diphenyl-purged - Rosendale-(3RS, 7aRS), obtained according to example 4, 30 cm3anhydrous dichloromethane, was added 0,77 cm32-N, N-diethylaminoethylamine. The reaction mixture is left under stirring for 20 h at room temperature, then treated with 30 cm310% aqueous potassium carbonate solution. The precipitate is removed by filtration, and then the organic phase is washed with 15 cm3distilled water, 15 cm3saturated aqueous solution of sodium chloride, dried on magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in 5 cm3astrila. The obtained crystals are centrifuged and dried. Obtain 1.6 g of 2-[-(2-N, N-diethylaminoethylamine)-Fe - Neil] -7,7-diphenyl-4-peligrosidad-on-(3RS, 7aRS), melting at 134aboutC.

P R I m e R 9. To a suspension consisting of 2.1 g of tetrafluoroborate 2-[(1-ethoxy-2-phenyl)-ethylidene] -4-oxo-7,7-diphenyl-purged - Rosendale-(3aRS, 7aRS), 15 cm3anhydrous dichloromethane, was added to 0.63 g of 6-acetylaminofluorene. The reaction mixture was stirred for 16 h at 20aboutC, then diluted with 50 cm320% aqueous potassium carbonate solution and 50 cm3dichloromethane, stirred and filtered. The organic phase is washed with 50 cm3a saturated solution of sodium chloride, dried on magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The remainder chromatographic on a column of aluminum oxide SVT 1 (diameter 3 cm, height 24 cm) with elution 1 l of ethyl acetate at a pressure of 0.5 bar, then a mixture of 1,2-dichloroethane and ethanol (90/10 by volume) at the same pressure, collecting the fraction at 75 cm3. Faction with about 15 23 collected and concentrated to dryness under reduced pressure (2.7 kPa), resulting in a gain of 1.2 g of 2-[(6-acetamido-1-hexyl)-1-amino-2-phenyl - ethyl] -7,7-diphenyl-4-perhydrosqualene-(3RS, 7aRS) in the white matter of the Sabbath. -CH2-CH2-CH2-CH2-NHAc); to 1.32 (m, 4H, = N-CH2-CH2-CH2-CH2-CH2-CH2-NHAc); 1,8 (c, 3H, -PINES3); of 1.95-2.30 (m, 2H, -CH25); by 2.55 to 2.95 (m, 4H, -CH26 and 1); 2,96 (m, 2H, -CH2-NHAc); 3,05 (t, J = 7, N-CH2-); 3,24 (m, 1H, H in 3A); to 3.34 (DD, J = 11 and 6, 1H, 1H in 3); 3,69 (AB, 2H, Agsn2); 4 (m, 1H, H-7a); 4,12 (d, J = 11, 1H, 1H in 3); 7 to 7.7 (m, 15 NM, aromatic); 7,8 (t, J = 5, 1H, -NHAc).

Infrared spectrum (characteristic bands in cm-1):

3290, 3100-3000, 3000-2825, 1715, 1655, 1600, 1580, 1495, 1550, 750, 700.

P R I m e R 10. To a solution containing 20 g of 7,7-diphenyl-2-(2-phenylthiazol)-4-perhydrosqualene-(3RS, 7aRS) 150 cm3acetone is added a solution containing 20 g of iodomethane 200 cm3of acetone. The reaction mixture is stirred at +50aboutWith over 20 hours the precipitate centrifuged, washed with isopropoxide and dried. Obtain 23.7 g of iodide 2-[(1-methylthio-2-phenyl)-ethylidene] -4-oxo-7,7-diphenyl - peligrosamente-(3aRS, 7aRS) in a solid white color.

To a solution containing 5 g of iodide 2-[(1-methylthio-2-phenyl)-ethylidene] -4-oxo-7,7-diphenyl-peligrosamente-(3a S, 7aRS) 50 cm3anhydrous tetrahydrofuran, are added dropwise at room temperature a solution containing 0.65 g sobouti the Noah temperature. The precipitate centrifuged and dried. Obtain 4.3 g of oggidata 7,7-diphenyl-2-[(isobutylamino)-phenethyl] -4-perhydrosqualene-(3aRS, 7aRS) in the form of white crystals, melting at 241aboutC.

P R I m e R 11. To a suspension consisting of 2.1 g of tetrafluoroborate 2-[(1-ethoxy-2-phenyl)-ethylidene] -4-oxo-7,7-diphenyl-purged - Rosendale-(3aRS, 7aRS) 15 cm3anhydrous dichloromethane, was added to 0.63 g of 6-acetylaminofluorene. The reaction mixture was stirred for 16 h at 20aboutC, then diluted with 50 cm320% aqueous solution of carbonate ka lia and 50 cm3dichloromethane, stirred and filtered. The organic phase is washed with 50 cm3a saturated solution of sodium chloride, dried on magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The remainder chromatographic on a column of aluminum oxide SVT 1 (diameter 3 cm, height 24 cm) with elution at a reduced pressure of 0.5 bar by 1 liter of ethyl acetate, then with a mixture of 1,2-dichloroethane and ethanol (90/10), collecting fractions of 75 cm3. Fractions 15 to 23 are combined and concentrated to dryness under reduced pressure (2.7 kPa), resulting in a gain of 1.2 g of 2-[(6-acetamido-1-hexyl)-1-imino-2-phenyl - ethyl] -7,7-diphenyl-4-perhydrosqualene-(3RS, 7aRS) 4H, = N-CH2-CH2-CH2-CH2-CH2-CH2-NHAc); to 1.32 (m, 4H, = N-CH2-CH2-CH2-CH2-CH2-CH2-NHAc); 1,8 (c, 3H, PINES3); of 1.95-2.30 (m, 2H, -CH25); by 2.55 to 2.95 (m, 4H, -CH26 and 1); 2,96 (m, 2H, -CH2-NHAc); 3,05 (t, J = 7, = N-CH2-); 3,24 (m, 1H, H in 3A); to 3.34 (DD, J = 11 and 6, 1H, 1H in 3); 3,69 (AB, 2H, Agsn2-); 4 (m, 1H, H-7a); 4,12 (d, J = 11, 1H, 1 H 3); 7 to 7.7 (m, 15 NM, aromatic); 7,8 (t, J = 5, 1H, -NHAc).

Infrared spectrum (characteristic bands in cm-1):

3290, 3100-3000, 3000-2825, 1715, 1655, 1615, 1600, 1580, 1495, 1550, 750, 700.

P R I m e R 12. To a solution containing 1.2 g of the hydrochloride of methylglycine 40 cm3anhydrous dichloromethane, was added 1.2 cm3of triethylamine, and then 5 g of tetrafluoroborate 2-[(1-ethoxy-2-phenyl)-ethylidene] -4-oxo-7,7-diphenyl-peligrosamente -(3RS, 7aRS), obtained according to example 4. The reaction mixture is left under stirring for 20 h at room temperature; then it was washed with 50 cm3distilled water (2 times), dried on magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The remainder chromatographic on a column of neutral alumoweld Pechiney SVT 1 (diameter 3 cm, height 23.5 cm) with elution with a mixture of cyclohexane and ethyl acetate (30/70 by volume)7 kPa). Obtain 0.4 g of 2-( -methoxycarbonylaminophenyl)-7,7-diphenyl-4 - perhydrosqualene-(3RS, 7aRS), melting at 147aboutC.

P R I m e p 13. To a stirred suspension consisting of 6.5 g of tetrafluoroborate 2-[(1-ethoxy-2-phenyl)-ethylidene] -4-oxo-7,7-diphenylpiperazine-(3RS, 7aRS), obtained according to example 4, 25 cm3anhydrous dichloromethane, was added 1.3 cm3benzylamine. The reaction mixture is left under stirring for 20 h at room temperature, it was diluted with 30 cm3dichloromethane and treated with 30 cm3an aqueous solution containing 44 g of potassium carbonate. The precipitate is removed by filtration, and then the organic phase is washed with 30 cm3distilled water (2 times), 30 cm3saturated aqueous solution of sodium chloride, dried on magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The remainder chromatographic on a column of neutral alumoweld Pechiney SVT 1 (diameter 4.5 cm, height 28 cm) with elution by ethyl acetate, collecting fractions of 60 cm3. Fractions 2 through 4 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in 10 cm3acetonitrile, and the resulting crystals are centrifuged, washed with 5 cmaboutC.

P R I m e R 14. To a stirred and cooled to 5aboutWith a suspension consisting of 3.75 g of tetrafluoroborate 2-[(1-ethoxy-2-phenyl)-ethylidene] -4-oxo-7,7-diphenyl-purged - Rosendale-(3RS, 7aRS), obtained according to example 4, 40 cm3anhydrous dichloromethane, was added 0.9 cm3phenethylamine. The reaction mixture is left under stirring for 20 h at room temperature, then treated with 30 cm310% aqueous potassium carbonate solution. The precipitate is removed by filtration, and then the organic phase is washed with 15 cm3distilled water, 10 cm3saturated aqueous solution of sodium chloride, dried on magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is recrystallized from 100 cm3acetonitrile. The obtained crystals are centrifuged and dried. Gain of 2.05 g of 2-(-penetrometer)-7,7-diphenyl-4-perhydrosqualene- -(3RS, 7aRS), melting at 188aboutC.

P R I m e R 15. To a stirred and cooled to 5aboutWith a suspension consisting of the 5.25 g tetrafluoroborate 2-[(1-ethoxy-2-phenyl)-ethylidene] -4-oxo-7,7-diphenyl-purged - Rosendale-(3aRS, 7aRS), obtained according to example 4, 30 cm3anhydrous dichloromethane, pribavliaet stirring for 20 hours The reaction mixture is treated with 20 cm310% aqueous potassium carbonate solution. The precipitate is removed by filtration, and then the organic phase is washed with 25 cm3distilled water, 25 cm3saturated aqueous solution of sodium chloride, dried on magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in 5 cm3acetonitrile. The obtained crystals are centrifuged and dried. They precrystallization of 15 cm3acetonitrile, and the resulting crystals are centrifuged and dried. Gain of 1.9 g of 2-[-(3-phenylpropylamine)-phenethyl] -7,7-diphenyl-4-peligroso - indolene-(3aRS, 7aRS), melting at 144aboutC.

P R I m e R 16. To a stirred suspension consisting of 5 g of tetrafluoroborate 2-[(1-ethoxy-2-phenyl)-ethylidene] -4-oxo-7,7-diphenylpiperazine-(3aRS, 7aRS), obtained according to example 4 in 10 cm3anhydrous dichloromethane, was added 1.7 cm3aminodiphenylamine. The reaction mixture is left under stirring for 20 h at room temperature, then treated with 20 cm3saturated aqueous potassium carbonate solution. The precipitate is removed by filtration, and then the organic phase is dried on magnesium sulfate and concentrate the W 1 (diameter 3.4 cm, height 28 cm) with elution 1,2-dichloroethane, collecting fractions of 60 cm3. Fractions 8 to 10 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in 2 cm3acetonitrile, the resulting crystals are centrifuged, washed with 2 cm3acetonitrile and dried. Obtain 0.17 g of 2-(-diphenylethylenediamine)-7,7-diphenyl-4-perhydro - isoindoline-(3RS, 7aRS), melting at 172aboutC.

P R I m e R 17. To a stirred suspension consisting of 4.5 g of tetrafluoroborate 2-[(1-ethoxy-2-phenyl)-ethylidene] -4-oxo-7,7-diphenylpiperazine-(3aRS, 7aRS), obtained according to example 4 in 10 cm3anhydrous dichloromethane, was added 1 cm3(2-fluoro)-benzylamine. The reaction mixture is left under stirring for 20 h at room temperature, then diluted with 20 cm3dichloromethane and treated with 20 cm3saturated aqueous potassium carbonate solution. The precipitate is removed by filtration, and then the organic phase is dried on magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in a mixture of 10 cm3acetonitrile and 5 cm3isopropoxide; the resulting crystals are centrifuged, washed with 5 cm3acetonitrile and dried. is the atur 160aboutC.

P R I m e R 18. To a stirred suspension consisting of 4,2 g tetrafluoroborate 2-[(1-ethoxy-2-phenyl)-ethylidene] -4-oxo-7,7-diphenylpiperazine-(3aRS, 7aRS), obtained according to example 4 in 10 cm3anhydrous dichloromethane, was added 0.95 cm3(3-fluoro)-benzylamine. The reaction mixture is left under stirring for 20 h at room temperature, then diluted with 20 cm3dichloromethane and treated with 20 cm3saturated aqueous potassium carbonate solution. The precipitate is removed by filtration, and then the organic phase is dried on magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in 10 cm3acetonitrile, and the resulting crystals are centrifuged, washed with 5 cm3acetonitrile and dried. Obtain 1.7 g of 2-[-(3-terbisil)-aminopentyl] -7,7-diphenyl-4-lane - hydroisoquinoline-(3RS, 7aRS), melting at 156aboutC.

P R I m e R 19. To a stirred suspension consisting of 4,2 g tetrafluoroborate 2-[(1-ethoxy-2-phenyl)-ethylidene] -4-oxo-7,7-diphenylpiperazine-(3RS, 7aRS), obtained according to example 4 in 10 cm3anhydrous dichloromethane, was added 0.95 cm3(4-fluoro)-benzylamine. The reaction mixture is left at paramashiva3saturated aqueous potassium carbonate solution. The precipitate is removed by filtration, and then the organic phase is dried on magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in 10 cm3acetonitrile, and the resulting crystals centrifugeuse, washed with a 5 cm3acetonitrile and dried. Obtain 2.7 g of 2-[ -(4-terbisil)-aminopentyl] -7,7-diphenyl-4-peligrosos - Dolon-(3RS, 7aRS), melting at 180aboutC.

P R I m e R 20. To a stirred suspension consisting of 5 g of tetrafluoroborate 2-[(1-ethoxy-2-phenyl)-ethylidene] -4-oxo-7,7-diphenylpiperazine-(3aRS, 7aRS), obtained according to example 4 in 10 cm3anhydrous dichloromethane, was added 1.2 cm3(2-chloro)-benzylamine. The reaction mixture is left under stirring for 20 h at room temperature, then treated with 20 cm3on-Semenovo aqueous solution of potassium carbonate. The precipitate is removed by filtration, and then the organic phase is dried on magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in 5 cm3acetonitrile, the resulting crystals are centrifuged, washed with 5 cm3, acetonitrile, and dried. Obtain 2.2 g of 2-[-(2-Horm e R 21. To a stirred suspension consisting of 5 g of tetrafluoroborate 2-[(1-ethoxy-2-phenyl)-ethylidene] -4-oxo-7,7-diphenylpiperazine-(3RS, 7aRS), obtained according to example 4 in 10 cm3anhydrous dichloromethane, was added 1.2 cm3(4-chloro)-benzylamine. The reaction mixture is left under stirring for 20 h at room temperature, then treated with 20 cm3saturated aqueous potassium carbonate solution. The resulting residue is removed by filtration, and then the organic phase is dried on magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in 20 cm3acetonitrile, and the resulting crystals are centrifuged, washed with 10 cm3acetonitrile and dried. Obtain 2.9 g of 2-[ -(4-chlorbenzyl)-aminopentyl] -7,7-diphenyl-4-perhydrosqualene-(3RS, 7aRS), melting at 198aboutC.

P R I m e R 22. To a stirred suspension consisting of 4.1 g of tetrafluoroborate 2-[(1-ethoxy-2-phenyl)-ethylidene] -4-oxo-7,7-diphenylpiperazine-(3RS, 7aRS), obtained according to example 4 in 10 cm3anhydrous dichloromethane, was added 1 cm3(2-methoxy)-benzylamine. The reaction mixture is left under stirring for 20 h at room temperature; then it was diluted with 20 with the tank removed by filtration, then the organic phase is dried on magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in a mixture of 5 cm3acetonitrile and 10 cm3isopropoxide; the resulting crystals are centrifuged, washed with 5 cm3acetonitrile and dried. Obtain 1.6 g of 2-[ -(2-methoxybenzyl)-aminopentyl] -7,7-diphenyl-4-perhydrosqualene-(3aRS, 7aRS), melting at 146aboutC.

P R I m e R 23. To a stirred suspension consisting of 4.1 g of tetrafluoroborate 2-[(1-ethoxy-2-phenyl)-ethylidene] -4-oxo-7,7-diphenylpiperazine-(3RS, 7aRS), obtained according to example 4 in 10 cm3anhydrous dichloromethane, was added 1 cm3(3-methoxy)-benzylamine. The reaction mixture is left under stirring for 20 h at room temperature; then it was diluted with 20 cm3dichloromethane and treated with 20 cm3saturated aqueous potassium carbonate solution. The precipitate is removed by filtration, and then the organic phase is dried on magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue crystallizes 15 cm3acetonitrile, and the resulting crystals are centrifuged, washed with 5 cm3acetonitrile and dried. Obtain 2.7 g of 2-[ -(3-methoxybenzyl)-AMINOPHENYL stirred suspension, consisting of 4.5 g of tetrafluoroborate 2-[(1-ethoxy-2-phenyl)-ethylidene] -4-oxo-7,7-diphenyl-peligrosamente-(3aRS 7aRS), obtained according to example 4 in 10 cm3anhydrous dichloromethane, was added 1.1 cm3(4-methoxy)-benzylamine. The reaction mixture is left under stirring for 20 h at room temperature; then it was diluted with 20 cm3dichloromethane and treated with 20 cm3saturated aqueous potassium carbonate solution. The precipitate is removed by filtration, and then the organic phase is dried on magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in 15 cm3acetonitrile, and the resulting crystals are centrifuged, washed with 5 cm3acetonitrile and dried. Obtain 2.7 g of 2-[ -(4-methoxybenzyl)-aminopentyl] -7,7-diphenyl-4-peligroso - indolene-(3RS, 7aRS), melting at 158aboutC.

P R I m e R 25. To a stirred suspension consisting of 5 g, tetrafluoroborate 2-[(1-ethoxy-2-phenyl)-ethylidene] -4-oxo-7,7-diphenyl-peligrosamente-(3RS 7aRS), obtained according to example 4 in 10 cm3anhydrous dichloromethane, was added 1.4 g of 4-dimethylaminobenzylidene. The reaction mixture is left under stirring for 20 h at room temperature, then its volume, then the organic phase is dried on magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in 5 cm3acetonitrile, and the resulting crystals are centrifuged, washed with 5 cm3acetonitrile and dried, to obtain 3.5 g of 2-[ -(4-dimethylaminobenzylidene)-phenethyl] -7,7-diphenyl-4-perhydro - isoindoline-(3aRS, 7aRS), melting at 186aboutC.

P R I m e R 26. To a stirred suspension consisting of 5 g of tetrafluoroborate 2-[(1-ethoxy-2-phenyl)-ethylidene] -4-oxo-7,7-diphenylpiperazine-(3aRS, 7aRS), obtained according to example 4 in 10 cm3anhydrous dichloromethane, was added 1.4 cm31-aminomethylation. The reaction mixture is left under stirring for 20 h at room temperature, then treated with 20 cm3saturated aqueous potassium carbonate solution. The precipitate is removed by filtration, and then the organic phase is dried on magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in 15 cm3acetonitrile, the resulting crystals are centrifuged, washed with 10 cm3acetonitrile and dried. Obtain 3.2 g of 2-[ -(1-naphthylmethyl)-aminopentyl] -7,7-diphenyl-4-peligroso - indolene-(3aRS, 7aRS), melting at enyl)-ethylidene] -4-oxo-7,7 - diphenylpiperazine-(3RS, 7aRS), obtained according to example 4 in 10 cm3anhydrous dichloromethane, was added 1 cm32-aminomethylation. The reaction mixture is left under stirring for 20 h at room temperature, then treated with 20 cm3saturated aqueous potassium carbonate solution. The precipitate is removed by filtration, and then the organic phase is dried on magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in 5 cm3acetonitrile, and the resulting crystals are centrifuged, washed with 5 cm3acetonitrile and dried. Obtain 2.5 g of 7,7-diphenyl-2 - [(2-thienylmethyl(-aminophenethyl)-4-perhydrosqualene-(3aRS, 7aRS), melting at 114aboutC.

P R I m e R 28. To a stirred suspension consisting of 5 g of tetrafluoroborate 2-[(1-ethoxy-2-phenyl)ethylidene] -4-oxo-7,7-diphenylpiperazine-(3aRS, 7aRS), obtained according to example 4 in 10 cm3anhydrous dichloromethane, was added 0,85 cm3furfurylamine. The reaction mixture is left under stirring for 20 h at room temperature, then treated with 20 cm3saturated aqueous potassium carbonate solution. The precipitate is removed by filtration, and then the organic phase is dried on sulfating ether, the obtained crystals are centrifuged and dried. These crystals are recrystallized from 10 cm3acetonitrile, the resulting crystals are centrifuged, washed with 10 cm3acetonitrile and dried. Obtain 1.7 g of 2-[ -(2-furylmethyl)-aminophenethyl)-7,7-diphenyl-4-perhydrosqualene-(3RS, 7aRS), melting at 128aboutC.

P R I m e R 29. To a stirred suspension consisting of 4.5 g of tetrafluoroborate 2-[(1-ethoxy-2-phenyl)-4-oxo-7,7-diphenyl-peligrosamente-(3RS, 7aRS), obtained according to example 4 in 10 cm3anhydrous dichloromethane, was added 0.9 cm32-aminomethylpyridine. The reaction mixture is left under stirring for 20 h at room temperature, then treated with 20 cm3saturated aqueous potassium carbonate solution. The precipitate is removed by filtration, and then the organic phase is dried on magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in a mixture of 3 cm3acetonitrile and 5 cm3isopropoxide obtained crystals are centrifuged, washed with 5 cm3acetonitrile and dried. Receive 2 g of 2-[ -(2-pyridylmethyl)-aminophenethyl)-7,7-dif - Neil-4-perhydrosqualene-(3RS, 7aRS), melting at 180aboutC.

P R I m e R 30. To praisingly-(3aRS, 7aRS), obtained according to example 4 in 10 cm3anhydrous dichloromethane, was added 0.9 cm33-aminomethylpyridine. The reaction mixture is left under stirring for 20 h at room temperature, then treated with 20 cm3saturated aqueous potassium carbonate solution. The precipitate is removed by filtration, and then the organic phase is dried on magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in a mixture of 3 cm3acetonitrile and 5 cm3isopropoxide obtained crystals are centrifuged, washed with 5 cm3acetonitrile and dried. Obtain 1.7 g of 2-[-(3-pyridylmethyl)-aminopentyl] -7,7-diphenyl-4-perhydrosqualene-(3aRS 7aRS), melting at 102aboutC.

P R I m e R 31. To a stirred suspension consisting of 4.5 g of tetrafluoroborate 2-[(1-ethoxy-2-phenyl)-ethylidene] -4-oxo-7,7-diphenyl-peligrosamente-(3aRS 7aRS), obtained according to example 4, 20 cm3anhydrous dichloromethane, was added 0.9 cm34-aminomethylpyridine. The reaction mixture is left under stirring for 20 h at room temperature, then treated with 20 cm3saturated aqueous potassium carbonate solution. The precipitate is removed filter is. the STATCOM is crystallized in a mixture of 5 cm3acetonitrile and 5 cm3isopropoxide obtained crystals are centrifuged, washed with 5 cm3acetonitrile and dried. Their recrystallized from 5 cm3acetonitrile. The obtained crystals are centrifuged and dried. Obtain 2.3 g of 2-[-(4-pyridylmethyl)-aminopentyl] -7,7-diphenyl-4-peligrosos - Dolon-(3aRS, 7aRS), melting at 150aboutC.

P R I m e R 32. To a stirred suspension consisting of 3.75 g of tetrafluoroborate 2-[(1-ethoxy-2-phenyl)-ethylidene] -4-oxo-7,7-diphenyl-peligrosamente-(3aRS 7aRS), obtained according to example 4, 40 cm3anhydrous dichloromethane, cooled to 5aboutWith added 0.53 cm3N, N-dimethylhydrazine. The reaction mixture was stirred for 1 h at 5aboutWith, then for 20 h at room temperature, then it is treated with 30 cm3saturated aqueous potassium carbonate solution. The precipitate is removed by filtration, and then the organic phase is washed with 30 cm3distilled water, dried on magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The remainder chromatographic on a column of neutral alumoweld Pechiney CBT 1 (diameter 3 cm, height 30 cm) with elution with a mixture of cyclohexane and the attachment (2.7 kPa). The residue is crystallized in 10 cm3acetonitrile, and the resulting crystals are centrifuged. Water of crystallization concentrated to dryness under reduced pressure (2.7 kPa); the residue is crystallized in 5 cm3isopropoxide obtained crystals are centrifuged and dried. Get 0,22 g of 2-[(N, N-dimethyl - 1-hydrazino-2-phenyl)-ethyl] -7,7-diphenyl-4 - perhydrosqualene-(3aRS, 7aRS), melting at 142aboutC.

P R I m e R 33. To a solution containing 1.08 g of 2-florfenicol acid in 30 cm3anhydrous dichloromethane and cooled to 5aboutC, add to 1.14 g of N, N'-carbonyldiimidazole. Stirred for 20 min at 5aboutWith, then add a solution containing 2.3 g of hydrochloride, 7,7-diphenyl-4-perhydrosqualene-(3RS, 7aRS), and to 1.98 cm3of triethylamine in 20 cm3dichloromethane. The reaction mixture is stirred at 20aboutC for 72 h, then washed with 150 cm3water (2 times), dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The obtained solid is crystallized in a mixture of 30 cm3acetonitrile and 50 cm3isopropoxide. The crystals are centrifuged, washed with isopropoxide and dried. Gain of 1.53 g of 2-[ (2-forfinal)-acetyl] -7,7-diphenyl-4-peligroso is 4. To a cooled to 5aboutWith the solution containing 1.08 g of 2-(4-forfinal)-acetic acid in 30 cm3anhydrous dichloromethane was added 1.13 g of N, N'-carbonyldiimidazole. Stirred for 1 h at 5aboutWith, then add a solution containing 2.3 g of the hydrochloride of 7,7-diphenyl-4-perhydrosqualene and 0.98 cm3of triethylamine in 40 cm3dichloromethane. The reaction mixture was stirred for 1 h at 5aboutWith, then for 16 h at 20aboutC. the Reaction mixture is washed with 50 cm3distilled water (3 times), dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is recrystallized from 5 cm3acetonitrile. The obtained crystals are centrifuged, washed with 10 cm3isopropoxide and dried. Receive 2 g of 2-[(4-forfinal)-acetyl] -7,7-diphenyl-4-perhydrosqualene-(3aRS, 7aRS), melting at 210aboutC.

P R I m e R 35. To a cooled to 5aboutWith the solution containing 1.2 g of 2-(2,6-differenl)-acetic acid in 30 cm3anhydrous dichloromethane, was added 1.13 g of N, N'-carbonyldiimidazole. Stirred for 45 min at 5aboutWith, then add a solution containing 2.3 g of the hydrochloride of 7,7-diphenyl-4-perhydrosqualene-(3aRS, 7aRS), and 0.98 cm3toimivat 50 cm3distilled water (2 times), dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in 10 cm3ethyl acetate. The obtained crystals are centrifuged, washed with 10 cm3isopropoxide and dried. Obtain 2.1 g of 2-[(2,6 - differenl)-acetyl] -7,7-diphenyl-4-perhydrosqualene-(3aRS, 7aRS), melting at 218aboutC.

P R I m e R 36. To a cooled to 5aboutWith the solution containing 1.19 g of 2-chlorophenylalanine acid in 30 cm3anhydrous dichloromethane, was added 1.13 g of N, N'-carbonyldiimidazole. Stirred for 15 min at 5aboutWith, then add a solution containing 2.28 g of the hydrochloride of 7,7-diphenyl-4-perhydrosqualene (3aRS, 7aRS) and 1.96 cm3of triethylamine in 20 cm3dichloromethane. The reaction mixture is stirred at 20aboutC for 2.5 h, then washed with 150 cm3water (2 times), dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The obtained solid is crystallized in a mixture of 25 cm3acetonitrile and 25 cm3isopropoxide. The crystals are centrifuged, washed with isopropoxide and dried. Gain of 1.9 g of 2-(2-chlorophenyl)-acetyl-7,7-diphenyl-4-perhydrosqualene-(3RS, 7aRS) crew, containing 1.19 g of 3-chlorophenylalanine acid in 30 cm3anhydrous dichloromethane, was added 1.13 g of N, N'-carbonyldiimidazole. Mix for 15 minutes with 5aboutWith, then add a solution containing 2.28 g of the hydrochloride of 7,7-diphenyl-4-perhydrosqualene-(3RS, 7aRS), and 1.96 cm3of triethylamine in 20 cm3dichloromethane. The reaction mixture is stirred at 20aboutC for 16 h, then washed with 150 cm3water (2 times), dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The resulting substance with the consistency of type "meringue" is crystallized in a mixture of 30 cm3acetonitrile and 100 cm3isopropoxide. The crystals are centrifuged, washed with isopropoxide and dried. Obtain 2.2 g of 2-[(3-chlorophenyl)-acetyl] -7,7-diphenyl-4-lane - hydroisoquinoline-(3aRS, 7aRS) in the form of white crystals, melting at 179aboutC.

P R I m e R 38. To a cooled to 5aboutWith the solution containing of 1.36 g of 2-(4-chlorophenyl)-acetic acid in 30 cm3anhydrous dichloromethane, was added 1.3 g of N, N'-carbonyldiimidazole. Stirred for 1 h at 5aboutWith, then add a solution containing 2,62 g of the hydrochloride of 7,7-diphenyl-4-perhydrosqualene-(3RS, 7aRS) and 1.12 cm3of triethylamine in 20 cmATEM her washed with 50 cm3distilled water (3 times), dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in a mixture of 5 cm3acetonitrile and 10 cm3isopropoxide. The obtained crystals are centrifuged, and then dried. The remainder precrystallization 40 cm3acetonitrile. The obtained crystals centrifugeuse, washed with 10 cm3isopropoxide and dried. Obtain 2.4 g of 2-[(4-chlorophenyl)-acetyl] -7,7-diphenyl-4-lane - hydroisoquinoline-(3RS, 7aRS), melting at 213aboutC.

P R I m e R 39. To a cooled to 5aboutWith the solution containing 1,43 g of 2-(2,6-dichlorophenyl)-acetic acid in 30 cm3anhydrous dichloromethane, was added 1.13 g of N, N'-carbonyldiimidazole. Stirred for 30 min at 5aboutWith, then add a solution containing 2.3 g of the hydrochloride of 7,7-diphenyl-4-perhydrosqualene-(3RS, 7aRS) and 0.98 cm3of triethylamine in 40 cm3dichloromethane. The reaction mixture is stirred at 20aboutC for 20 h, then washed with 50 cm3distilled water (3 times), dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in a mixture of 5 cm3acetonitrile and 4 cm3isopro is 2-[(2,6-dichlorophenyl)-acetyl] -7,7-diphenyl-4-perhydrosqualene-(3RS, 7aRS), melting at 201aboutC.

P R I m e R 40. To a cooled to 5aboutWith the solution containing 1.5 g of 2-(2-bromophenyl)-acetic acid in 30 cm3anhydrous dichloromethane, was added 1.13 g of N, N'-carbonyldiimidazole. Stirred for 45 min at 5aboutWith, then add a solution containing 2.3 g of the hydrochloride of 7,7-diphenyl-4-perhydrosqualene-(3RS, 7aRS) and 0.98 cm3of triethylamine in 40 cm3dichloromethane. The reaction mixture was stirred for 4 h at 20aboutC. the Reaction mixture is washed with 50 cm3distilled water (3 times), dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is recrystallized in 74 cm3acetonitrile. The crystals are centrifuged, washed with 10 cm3isopropoxide and dried. Get 2,04 g of 2-[(2-bromophenyl)-acetyl] -7,7-diphenyl-4-perhydrosqualene-(3RS, 7aRS), melting at 217aboutC.

P R I m e R 41. To a cooled to 5aboutWith the solution containing 1.06 g of 2-hydroxyphenylacetic acid in 30 cm3anhydrous dichloromethane, was added to 1.14 g of N, N'-carbonyldiimidazole. Stirred for 30 min at 5aboutWith, then add a solution containing of 2.23 g of the hydrochloride of 7,7-diphenyl-4-perhydrosqualene-(3 for 16 h, then washed with 100 cm3water (2 times), dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The remainder chromatographic on a column of silica gel (0,2-0,063 mm, diameter 4 cm, height 40 cm) with elution with a mixture of cyclohexane and ethyl acetate (70/30 by volume) under a nitrogen pressure of 0.7 bar, collecting fractions of 125 cm3. Fractions 4 to 11 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in a mixture of 15 cm3acetonitrile and 30 cm3isopropoxide. The crystals are centrifuged, washed with isopropoxide and dried. Obtain 0.8 g of 2-[(2-hydroxy - phenyl)-acetyl] -7,7-diphenyl-4-peligroso - indolene-(3aRS, 7aRS) in the form of white crystals, melting at 232aboutC.

P R I m e R 42. To a cooled to 5aboutWith the solution containing of 1.05 g of 2-(2-were)-acetic acid in 30 cm3anhydrous dichloromethane, was added 1.13 g of N, N'-carbonyldiimidazole. Stirred for 40 min at 5aboutWith, then add a solution containing 2.3 g of the hydrochloride of 7,7-diphenyl-4-perhydrosqualene-(3aRS, 7aRS) and 0.98 cm3of triethylamine in 20 cm3dichloromethane. The reaction mixture is stirred at 20aboutC for 16 h, then washed with 50 cm3distiller is). The remainder chromatographic on a column of silica gel (0,2-0,063 mm, diameter 2 cm, height 16 cm) with elution by ethyl acetate, collecting fractions of 45 cm3. Fractions 2 through 4 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is recrystallized in a mixture of 8 cm3acetonitrile and 7.5 cm3isopropoxide. The crystals are centrifuged, washed with 10 cm3isopropoxide and dried. Earn 1.25 g of 2-[(2-were)-acetyl] -7,7-diphenyl-4 - perhydrosqualene-(3aRS, 7aRS), melting at 196aboutC.

P R I m e R 43. To a cooled to 5aboutWith the solution containing of 1.05 g of 2-(3-were)-acetic acid in 30 cm3anhydrous dichloromethane, was added 1.13 g of N, N'-carbonyldiimidazole. Stirred for 35 min at 5aboutWith, then add a solution containing 2.3 g of the hydrochloride of 7,7-diphenyl-4-perhydrosqualene-(3aRS, 7aRS) and 0.98 cm3of triethylamine in 20 cm3dichloromethane. The reaction mixture is stirred at 20aboutC for 16 h, then washed with 50 cm3distilled water (2 times), dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized by dissolving in 10 cm3boiling ethyl acetate. Crystals centrifuger is centrifuged, washed with 10 cm3isopropoxide and dried. Get to 1.37 g of 2-[(3-were)-acetyl] -7,7-diphenyl-4 - perhydrosqualene-(3aRS, 7aRS), melting at 184aboutC.

P R I m e R 44. To a cooled to 5aboutWith the solution containing 1,43 g 3-triftormetilfullerenov acid in 30 cm3anhydrous dichloromethane, was added 1.13 g of N, N'-carbonyldiimidazole. Stirred for 15 min at 5aboutWith, then add a solution containing 2.28 g of the hydrochloride of 7,7-diphenyl-4-perhydrosqualene-(3aRS, 7aRS) and 1.96 cm3of triethylamine in 20 cm3dichloromethane. The reaction mixture is stirred at 20aboutC for 2 h, then washed with 150 cm3water (2 times), dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The resulting substance with the consistency of type "meringue" is crystallized in a mixture of 30 cm3acetonitrile and 30 cm3isopropoxide. The crystals are centrifuged, washed with isopropoxide and dried. Receive 2 g 2[(3-triptoreline)-acetyl] -7,7-dif - Neil-4-perhydrosqualene-(3RS, 7aRS) in the form of white crystals, melting at 184aboutC.

P R I m e R 45. To a cooled to 5aboutWith the solution containing 1.42 g of 2-(2-triptoreline)-acetic acid in 30 cm3With, then add a solution containing 2.3 g of the hydrochloride of 7,7-diphenyl-4-perhydrosqualene-(3RS, 7aRS) and 0.98 cm3of triethylamine in 40 cm3dichloromethane. The reaction mixture is stirred at 20aboutC for 18 h, then washed with 50 cm3distilled water (3 times), dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in 10 cm3acetonitrile. The obtained crystals are centrifuged, washed with 10 cm3isopropoxide and dried. Obtain 1.68 g of 7,7-diphenyl-2-[(2-triptoreline)-acetyl] -4-perhydro - isoindoline-(3RS, 7aRS), melting at 207aboutC.

P R I m e R 46. To a cooled to 5aboutWith the solution containing 0.6 g of 2-(tert-butoxycarbonylmethylene)-acetic acid in 20 cm3anhydrous dichloromethane, was added and 0.37 g of N, N'-carbonyldiimidazole. Stirred for 30 min at 5aboutWith, then add a solution containing 0.75 g of the hydrochloride of 7,7-diphenyl-4-perhydrosqualene-(3RS, 7aRS) and 0.6 cm3of triethylamine in 20 cm3dichloromethane. The reaction mixture is stirred at 20aboutC for 16 h, then washed with 100 cm3water (2 times), dried on magnesium sulfate, filtered and concentrated to dryness under pengenalan-(3aRS, 7aRS) in the form of a substance of white color with the consistency of type "meringue".

Treated with 1 g of 2-[(2-tert-butoxycarbonylmethylene)-acetyl] -7,7-diphenyl-4-perhydro indolene-(3aRS, 7aRS) by 10 cm35,7-called solution chloroethanol acid in anhydrous dioxane at 20aboutC for 16 hours the Reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) and the residue is compacted by friction in the presence of isopropoxide, and then again precipitated by cooling the solution to 20 cm3boiling acetonitrile. The solid is centrifuged, washed with isopropoxide and dried. The solid is dissolved in water, the solution is filtered, alkalinized to pH 10 by adding decinormal of sodium hydroxide solution and extracted with ethyl acetate. The organic phase is dried on magnesium sulfate, filtered and treated with 1 cm33 N. of a solution chloroethanol acid in dioxane. The precipitate centrifuged, washed with isopropoxide and dried. Obtain 0.5 g of the hydrochloride of 2-[(2-aminomethylphenol)-acetyl] -7,7-diphenyl-4-perhydro - isoindoline-(3RS, 7aRS) in the form of solid white.

An NMR spectrum of the proton:

At room temperature see a mixture of rotational isomers:

2 to 2.35 (MT, 2 is 7, - N-CO-CH2- and-CH2N); 7,05 to 7.7 (MT, 14N, aromatic).

Characteristic bands (cm-1) infrared spectrum (KBR):

3600-3250, 3100-3000, 3000-2800, 2750-2250, 1715, 1620, 1600, 1580, 1495, 1475, 1445, 1440, 755, 703.

(2-Tert-butoxycarbonylamino-phenyl)-acetic acid is obtained in accordance with the method described in Japanese patent application 74 24 975.

P R I m e R 47. To a cooled to 5aboutWith the solution containing of 1.16 g of 2-methoxyphenylacetic acid in 30 cm3anhydrous dichloromethane, was added 1.13 g of N, N'-carbonyldiimidazole. Stirred for 15 min at 5aboutWith, then add a solution containing 2.28 g of the hydrochloride of 7,7-diphenyl-4-perhydrosqualene-(3RS, 7aRS) and 1.96 cm3of triethylamine in 20 cm3dichloromethane. The reaction mixture is stirred at 20aboutC for 16 h, then washed with 150 cm3water (2 times), dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The resulting substance with the consistency of type "meringue" is crystallized in a mixture of 30 cm3acetonitrile and 30 cm3isopropoxide. Crystals centrifuging, washed with 25 cm3isopropoxide and dried. Receive 2 g of 2-[(2-methoxyphenyl)-acetyl] -7,7-diphenyl-4-perhydrosqualene-is the overarching 5 g of 2-[(2-methoxyphenyl)-acetyl-(-7,7-diphenyl-4-perhydrosqualene-(3RS, 7aRS ) in 10 cm3dichloromethane, was added 2.35 tetrafluoroborate triethyloxonium. The reaction mixture is left under stirring for 20 h at room temperature, then treated with 100 cm3ether, semi-obtained precipitate is centrifuged, washed with 100 cm3ether and dried. Get 5.75 g of tetrafluoroborate 2-[1-ethoxy-2-(2-methoxyphenyl)-ethylidene] -4-oxo-7,7-diphenyl-purged - Rosendale-(3RS, 7aRS) in the form of a yellow powder used in this form for further manipulation.

To a stirred and cooled to -10aboutWith a suspension consisting of 5.7 g of tetrafluoroborate 2-[1-ethoxy-2-(2-methoxyphenyl)-ethylidene] -4-oxo-7,7-diphenyl-peligrosamente FL-(3aRS, 7aRS) 15 cm3anhydrous dichloromethane, was added 1.3 cm35,4 N. ethanolic ammonia solution. Then allow the reaction mixture to return to room temperature and continue stirring for 20 hours the Reaction mixture is diluted with 20 cm3dichloromethane and treated with 20 cm310% aqueous potassium carbonate solution. The precipitate is removed by filtration, and then the organic phase is washed with 25 cm3distilled water, 25 cm3saturated aqueous solution of sodium chloride, dried on magnesium sulfate and the concentrate is of Tallaght centrifuged, washed with 10 cm3acetonitrile and dried. Receive 1 g of 2-[1-imino-2-(2-methoxyphenyl)-ethyl] -7,7-diphenyl-4-perhydrosqualene-(3RS 7aRS), melting at a temperature above 260aboutC.

in which l is a halogen atom, and R6 are alkyl radical, substituted if necessary by hydroxyradicals, or dialkylamino-whose alkyl portions may, if necessary, to form with the nitrogen atom to which they are bound, a heterocycle is the same as defined in General formula I.

The reaction is carried out usually in the presence of a base such as a hydride, alkali metal hydroxide, an alcoholate of an alkali metal or carbonate of an alkali metal, in an organic solvent such as an amide (dimethylformamide, for example), aromatic hydrocarbons (toluene, for example, ketone (butanone, for example), or in mixtures of these solvents at a temperature that is between 20 ° C and temperature phlegmy reaction mixture.

When the radical R6 has hydroxysultaine, it is assumed that the last pre-reserved. Protection and removal of the protecting radical is carried out in accordance with the methods described above.

According to the invention derived from the th isoindoline with the General formula III, under the action of the product with the General formula IX@NO INDENTATION = 10 cm3acetonitrile. The obtained crystals are centrifuged, washed with 10 cm3acetonitrile and dried. Receive 1 g of 2-[1-imino-2-(2-methoxyphenyl)-ethyl] -7,7-diphenyl-4-perhydrosqualene-(3RS 7aRS), melting at a temperature above 260aboutC.

P R I m e R 49. To a cooled to 5aboutWith the solution containing 1 g of 2-methoxyphenylacetic acid in 30 cm3anhydrous dichloromethane, was added 1 g of N, N'-carbonyldiimidazole. Stirred for 40 min at 5aboutWith, then add a solution containing 2 g of the hydrochloride of 7,7-diphenyl-4-perhydrosqualene-(3RS, 7aRS) and 1.7 cm3of triethylamine in 40 cm3dichloromethane. The reaction mixture is stirred at 20aboutC for 16 h, then washed with 50 cm3water (2 times), dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The remainder chromatographic on a column of silica gel (0,2-0,063 mm, diameter 1.8 cm, height 13 cm) with elution by ethyl acetate, collecting fractions of 25 cm3. Fractions 3 through 5 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in a mixture of 5 cm3acetonitrile and 10 cm3isopropoxide. Kristallgitter-4-perhydrosqualene-(3R, 7aR) in the form of white crystals, melting at 200aboutC.

()D20= -274about(C = 0,49, acetic acid).

P R I m e R 50. To a solution containing 7.7 g of 2-[(2-methoxyphenyl)-acetyl] -7,7-diphenyl-4-perhydrosqualene-(3R, 7aR) 13 cm3anhydrous dichloromethane, was added 4 g of tetrafluoroborate triethyloxonium. The reaction mixture is left under stirring for 20 h at room temperature, then the mixture is cooled to -15aboutWith and add 2.6 cm35,4 N. ethanolic ammonia solution. Allow the reaction mixture to return to room temperature and continue stirring for five and a half hours. The reaction mixture is treated with 20 cm310% aqueous potassium carbonate solution, the formed precipitate is centrifuged and washed with 10 cm3dichloromethane. The combined organic phases are dried on magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in 10 cm3acetonitrile, the resulting crystals are centrifuged, washed with 5 cm3acetonitrile, 10 cm3isopropoxide and dried. Then chromatografic on a column of neutral alumoweld Pechiney SVT 1 (diameter 4.5 cm, height 28 cm) with elution by 200 is collecting fractions at 25 cm3. Fractions 8 through 31 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in 10 cm3acetonitrile, and the resulting crystals are centrifuged and dried. Obtain 1.6 g of 2-[1-imino-2-(2-method xifei)-ethyl] -7,7-diphenyl-4-perhydro - isoindoline-(3aR, 7aR), melting at 190aboutC.

( )D20= -254about(C = 1, methanol).

P R I m e R 51. To a cooled to 5aboutWith the solution containing of 1.16 g of 2-methoxyphenylacetic acid in 30 cm3anhydrous dichloromethane, was added 1.13 g of N, N'-carbonyldiimidazole. Stirred for 15 min at 5aboutWith, then add a solution containing 2.28 g of the hydrochloride of 7,7-diphenyl-4-perhydrosqualene-(3RS, 7aRS) and and 1.96 cm3of triethylamine in 20 cm3dichloromethane. The reaction mixture is stirred at 20aboutC for 16 h, then washed with 150 cm3water (2 times), dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The resulting substance with the consistency of type "meringue" is crystallized in a mixture of 30 cm3acetonitrile and 80 cm3isopropoxide. The crystals are centrifuged, washed with isopropoxide and dried. Receive 2 g of 2-[(2-methoxyphenyl)-acetyl] -7,7-diphenyl-4-perhydrosqualene-(3aRS, AAMU to 5aboutWith the solution containing 0,63 g of 2-(2,6-acid) acetic acid in 20 cm3anhydrous dichloromethane, was added 0.52 g of N, N'-carbonyldiimidazole. Stirred for 35 minutes with 5aboutWith, then add a solution containing of 1.05 g of the hydrochloride of 7,7-diphenyl-4-perhydrosqualene-(3RS, 7aRS) and 0.44 cm3of triethylamine in 25 cm3dichloromethane. The reaction mixture is stirred at 20aboutC for 16 h, then washed with 50 cm3distilled water (2 times), dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in a mixture of 16 cm3acetonitrile and 15 cm3isopropoxide. The crystals are centrifuged, washed with 10 cm3isopropoxide and dried. Get to 0.89 g of 2-[(2,6-acid)-acetyl] -7,7-diphenyl-4 - perhydrosqualene-(3aRS, 7aRS), melting at 224aboutC.

2-(2,6-Acid) acetic acid can be obtained in the following way:

The mixture is 2.88 g of N-[2-(2,6-acid)-thioacetic] -the research and 40 cm310% aqueous solution of potassium hydroxide, heated to education phlegmy within 12 hours After cooling to room temperature the reaction mixture is extracted with 100 cm3ethyl acetate, trout 100 cm3ethyl acetate (2 times). The combined organic phases are washed with 100 cm3distilled water (3 times), dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is recrystallized from a mixture of 20 cm3cyclohexane and 10 cm3ethyl acetate. The obtained crystals are centrifuged, washed with 15 cm3(2 times) isopropoxide and dried. Get to 0.63 g of 2-(2,6-acid)-acetic acid, melting at 156aboutC.

N-[2-(2,6-Acid)-thioacetic] - morpholine can be obtained in the following way.

A mixture consisting of 39.5 g of 2,6-dimethoxyacetophenone, 19 cm3the research and 7 g of sulfur are heated to education phlegmy under stirring for 24 hours After reaching room temperature, the reaction mixture was poured on ice. The mixture is extracted with 100 cm3ethyl acetate, the organic solution was washed with 100 cm3distilled water (3 times), dried on magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The remainder chromatographic on a column of silica gel (0,2-0,063 mm, diameter 4.3 cm, height 48 cm) with elution with a mixture of cyclohexane and ethyl acetate (90/10 by volume), collecting fractions of 100 cm3. Fractions from 61 to 72 of the volume of orfelina, used in raw form for subsequent syntheses.

P R I m e R 53. To a cooled to 5aboutWith the solution containing of 1.34 g of 2,5-dimethoxyphenylacetic acid in 30 cm3anhydrous dichloromethane, was added to 1.14 g of N, N'-carbonyldiimidazole. Stirred for 30 min at 5aboutWith, then add a solution containing 2.28 g of the hydrochloride of 7,7-diphenyl-4-perhydrosqualene-(3RS, 7aRS) and 1.96 cm3 of triethylamine in 20 cm3dichloromethane. The reaction mixture is stirred at 20aboutC for 16 h, then washed with 200 cm3water (2 times), dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The resulting substance with the consistency of type "meringue" is crystallized in a mixture of 20 cm3acetonitrile and 80 cm3isopropoxide. The crystals are centrifuged, washed with 25 cm3isopropoxide and dried. Obtain 1.5 g of 2-[(2,5-acid)-acetyl] -7,7-diphenyl-4-perhydrosqualene-(3aRS, 7aRS) in the form of white crystals, melting at 209aboutC.

P R I m e R 54. To a cooled to 5aboutWith the solution containing 0.87 g of 2-methyldiphenylamine acid in 30 cm3anhydrous dichloromethane, was added of 0.77 g of N, N'-carbonyldiimidazole. Stirred for 15 min at 5about<3 of triethylamine in 30 cm3dichloromethane. The reaction mixture is stirred at 20aboutC for 3.5 hours, then washed with 100 cm3water (3 times), dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The remainder chromatographic on a column of silica gel (0.04 to 0,063 mm, diameter 5 cm, height 50 cm) with elution with a mixture of cyclohexane and ethyl acetate (60/40 by volume) under a nitrogen pressure of 0.5 bar, collecting fractions of 50 cm3. Fractions 1 to 14 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The obtained solid is recrystallized in 5 cm3acetonitrile, the crystals are centrifuged, washed with isopropoxide and dried. Obtain 1.29 g of 2-[(2-methylthiophenyl)-acetyl] -7,7-diphenyl-4-lane - hydroisoquinoline-(3RS, 7aRS) in the form of crystals of pale yellow color, melting at 188aboutC.

2-Methyldiphenylamine acid obtained according to G. Compa et SJ. Weckman, V. Prak. Chem. , (2), 138, 123 (1933).

P R I m e R 55. To a cooled to 5aboutWith the solution containing of 2.51 g (2-tert-butoxycarbonylamino)-acetic acid in anhydrous dichloromethane is added of 1.62 g of N, N'-carbonyldiimidazole. Stirred for 45 min at 5aboutWith, then add a solution, soderman. The reaction mixture is stirred at 20aboutC for 16 h, then washed with 100 cm3water (3 times), dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The remainder chromatographic on a column of silica gel (0,2-0,063 mm, diameter 4 cm, height 40 cm) with elution with a mixture of cyclohexane and ethyl acetate (60/40 by volume) under a nitrogen pressure of 0.7 bar, collecting fractions of 125 cm3. Fractions 22 to 34 are combined and concentrated to dryness under reduced pressure (2.7 kPa), resulting in a gain of 1.5 g of 2-[(2-tert-butoxycarbonylamino)-acetyl] -7,7-dif - Neil-4-perhydrosqualene-(3aRS, 7aRS) in the form of a yellow substance with the consistency of type "meringue".

Treated with 1.5 g of 2-[(2-tert-butoxycarbonylamino)-acetyl] -7,7-dif - Neil-4-perhydrosqualene-(3aRS, 7aRS) by 15 cm35,7-called solution chloroethanol acid in anhydrous dioxane at 20aboutC for 4 h, the Reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) and the residue is purified by dissolution in 20 cm3acetonitrile and deposition of 30 cm3isopropoxide. The solid is centrifuged, washed with isopropoxide and dried. Obtain 1.1 g of the hydrochloride of 2-[(2-AMINOPHENYL)-acetyl] -7,7-diphenyl-4-ambrosia At room temperature see a mixture of two rotational isomers.

2,1 to 2.27 (2MT, respectively 1H each, -CH2- a 5 or 6); 2.65 to to 3.35 (MT, 4H, -CH26 or 5 and CH2- 1); 3,4 up to 3.75 (MT, 1H,- CH2- 3 and CH - 3A); 3,55 to 3,84 (2C, -N-CO-CH2-); of 3.9 to 4.2 (MT-SN - 7a); 4,15 to 4.4 (MT, 1H from-CH2- 3); 7 to 7.7 (MT, 14N, aromatic).

Characteristic bands (cm-1) infra-red spectrum (KBR):

3430, 3085, 3055, 3025, 3000-1900, 2965, 2880, 1715, 1630-1520, 1625, 1595, 1580, 1492, 1455, 755, 703.

(2-Tert-butoxycarbonylamino)-acetic acid may be obtained in the following way:

The solution containing 18,1 g (2-nitrophenyl)-acetic acid in 120 cm31 n sodium hydroxide solution, hydronaut in an autoclave at a pressure of 5 bar for 2.5 h at 20aboutIn the presence of 1.5 g of palladium with 3% carbon black. The resulting solution of sodium salt of (2-AMINOPHENYL)-acetic acid cooled to 5aboutC, then treated with a solution containing 26,16 g of di-tert-BUTYLCARBAMATE 100 cm3tetrahydrofuran (THF), and then 80 cm31 n sodium hydroxide solution. The reaction mixture is stirred at 20aboutC for 80 h, partially concentrated under reduced pressure (2.7 kPa), diluted with 200 cm3water and washed 3 times with 200 cm3ethyl ether. The aqueous phase is acidified with the organic phase are combined and washed with 150 cm3water (2 times), dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). Get 25 g of (2-tert-butoxycarbonylamino)-acetic acid in the form of solid white.

P R I m e R 56. To a cooled to 5aboutWith the solution containing 1.85 g (N-tert-butoxycarbonyl-N-methyl-2-AMINOPHENYL)-vinegar - Noah acid in 30 cm3anhydrous dichloromethane, was added 1.13 g of N, N'-carbonyldiimidazole. Stirred for 30 min at 5aboutWith, then add a solution containing to 2.29 g of the hydrochloride of 7,7-diphenyl-4-perhydrosqualene-(3RS, 7aRS) and 1.9 cm3of triethylamine in 20 cm3dichloromethane. The reaction mixture is stirred at 20aboutC for 2 h, then washed with 200 cm3water (2 times), dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The remainder chromatographic on a column of silica gel (0,2-0,063 mm, diameter 4 cm, height 50 cm) with elution with a mixture of cyclohexane and ethyl acetate (30/70 by volume) under a nitrogen pressure of 0.7 bar, collecting fractions of 125 cm3. Fractions 22 to 34 are combined and concentrated to dryness under reduced pressure (2.7 kPa), resulting in a gain of 2.8 g of 2-[(N-tert-butoxycarbonyl-N-methyl-2-AMINOPHENYL)-AC is">

Treated with 2.8 g of 2-[(N-tert-butoxycarbonyl-N-methyl-2-AMINOPHENYL)-acetyl] -7,7-diphenyl-4-Perg kosongkan-(3RS, 7aRS) by 30 cm35,7-called solution chloroethanol acid in anhydrous dioxane at 20aboutC for 4 h Add 100 cm3isopropoxide, the solid is centrifuged, washed with isopropoxide and dried. Obtain 2.1 g of the hydrochloride of 2-[(2-methylaminophenol)-acetyl] -7,7-diphenyl - 4-perhydrosqualene-(3aRS, 7aRS) in a solid white color.

An NMR spectrum of the proton:

At room temperature, see the mixture of two rotational isomers.

2,1 to 2.27 (2MT, respectively 1H each, -CH2- a 5 or 6); 2.65 to to 3.35 (MT, -CH26 or 5 and CH2- 1); 2,82 are 2.87 (2C, -NCH3); 3,4 up to 3.75 (MT, 1H from-CH2- 3 and CH - 3A); 3,55 and 3.85 (2S, -N-CO-CH2-); of 3.9 to 4.2 (MT-SN - 7a); 4.15 to 4,45 (MT, 1H from-CH26 or 5); 7 to 7.7 (MT, 14N, aromatic).

Characteristic bands (cm-1) infra-red spectrum (KBR):

3600-3300, 3100-3000, 3000-2850, 3100-2200, 1712, 1640-1610, 1595, 1495, 1475-1410, 1445, 755, 702.

(N-Tert-butoxycarbonyl-N-methyl-2 - AMINOPHENYL)-acetic acid may be obtained in the following way:

A solution containing 3.5 g (N-tert-butoxycarbonyl-N-methyl-2-AMINOPHENYL)-mechanie 4 hours The reaction mixture was concentrated under reduced pressure (2.7 kPa). The remainder is absorbed by 100 cm3water, and the solution was acidified to pH 1 by adding 4 N. chloroethanol acid, extracted with 100 cm3ethyl acetate (2 times). The combined organic phases are dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa), resulting in a gain 2.85 g (N-tert-butoxycarbonyl-N-methyl-2-AMINOPHENYL)-acetic acid in a solid white color.

(N-Tert-butoxycarbonyl-N-methyl-2 - AMINOPHENYL)-acetate can be obtained in the following way:

A solution containing 5 g of (2-tert-butoxycarbonylamino-phenyl)-acetic acid in 50 cm3anhydrous dimethylformamide is added to a suspension consisting of 1.2 g of sodium hydride, (80% dispersion in liquid oil) in 20 cm3anhydrous DMF (dimethylformamide). The reaction mixture is heated for 2 h at 80about, Then cooled to 20aboutC. Type of 2.51 cm3under the conditions, and stirred at 20aboutC for 16 hours Diluted with 200 cm3water and extracted with ethyl acetate (2 x 200 cm3). The combined organic phases are washed with 100 cm3water, dried on magnesium sulfate, filtered and the con is, iameter 4 cm, height 48 cm) with elution with a mixture of cyclohexane and ethyl acetate (90/10 by volume) under a nitrogen pressure of 0.7 bar, collecting fractions of 125 cm3. Fractions 9 to 17 are combined and concentrated to dryness under reduced pressure (2.7 kPa), resulting in a gain of 3.5 g (N-tert-butoxycarbonyl-N-methyl-2-AMINOPHENYL)-acetate in the form of liquid oil yellow.

P R I m e R 57. To a cooled to 5aboutWith the solution containing 1.4 g (N-tert-butoxycarbonyl-N-ethyl-2-AMINOPHENYL)-acetic acid in 30 cm3anhydrous dichloromethane, was added 0,81 g N, N'-carbonyldiimidazole. Stirred for 30 min at 5aboutWith, then add a solution containing 1.63 g of the hydrochloride of 7,7-diphenyl-4-perhydrosqualene-(3aRS, 7aRS) and 1.4 cm3of triethylamine in 20 cm3dichloromethane. The reaction mixture is stirred at 20aboutC for 16 h, then washed with 100 cm3water (2 times), dried on magnesium sulfate and concentrate (after filtering) to dryness under reduced pressure (2.7 kPa). The remainder chromatographic on a column of silica gel (0,2-0,063 mm, diameter 4 cm, height 35 cm) with elution with a mixture of cyclohexane and ethyl acetate (60/40 by volume) under a nitrogen pressure of 0.7 bar, collecting fractions of 125 cm3. Fractions 19 to 29 joint is arbonyl-N-ethyl-2-amino - phenyl)-acetyl] -7,7-diphenyl-4-perhydrosqualene-(3RS, 7aRS) in the form of a substance of white color with the consistency of type "meringue".

Treated with 1.8 g of 2-[(N-tert-butoxycarbonyl-N-ethyl-2-AMINOPHENYL)-acetyl] -7, 7-diphenyl-4-perhydrosqualene-(3RS, 7aRS) by 18 cm35,7-called solution chloroethanol acid in anhydrous dioxane at 20aboutC for 4 h the Reaction mixture was contentresult to dryness under reduced pressure (2.7 kPa), the solid is stirred with 100 cm3isopropoxide, centrifuged, washed with isopropoxide and dried. Obtain 1.54 g of the hydrochloride of 2-[(2-ethylaminomethyl)-acetyl] -7,7-diphenyl-4-perhydrosqualene-(3RS, 7aRS), which is then stirred with a mixture of 40 cm31 n sodium hydroxide solution and 30 cm3ethyl acetate. The solid is centrifuged and washed with 2 times 10 cm3water and 3 times with 10 cm3ethyl acetate and dried. Gain of 0.85 g of 2-[(2-ethylaminomethyl)-acetyl] -7,7-diphenyl-4-peligrosos - Dolon-(3aRS, 7aRS) in a solid white color.

An NMR spectrum of the proton:

At room temperature, see the mixture of two rotational isomers.

OF 1.16 (T, 3H, -CH3from ethylamino-); 2.05 and 2,23 (2MT, respectively 1H each, -CH2- a 5 or 6); 2.6 to 3.6V (MT, -CH26 or 5, -CH2- 1, -NCH2-ethyl, -NCOCH2

Characteristic bands (cm-1) infra-red spectrum (KBR):

3600-3300, 3465, 3105-3000, 3000-2870, 1715, 1625, 1595, 1525, 1495, 1475, 1445, 1410, 755, 705.

(N-Tert-butoxycarbonyl-N-ethyl-2-AMI - nofinal)-acetic acid may be obtained in the following way:

The solution containing 4.7 g (N-tert-butoxycarbonyl-N-ethyl-2-AMINOPHENYL)-ethyl - acetate in 50 cm3ethanol, treated with 20 cm31 n sodium hydroxide solution for 4 h under irrigation by phlegm. The reaction mixture was concentrated under reduced pressure (2.7 kPa). The residue is extracted by 50 cm3water and 50 cm3ethyl acetate, the aqueous phase is washed with 2 times 100 cm3ethyl acetate, then acidified to pH 1 by adding 4 N. hydrochloric acid and extracted with 100 cm3ethyl acetate (2 times). The combined organic phases are dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa), resulting in a gain of 4 g (N-tert-butoxycarbonyl-N-ethyl-2-amino - phenyl)-acetic acid in the form of liquid oil yellow.

(N-Tert-butoxycarbonyl-N-ethyl-2-AMI - nofinal)-acetic acid ethyl ester can be obtained in the following way:

A solution containing 5 g of (2-tert-butoxycarbonylamino)-acetic acid in 50 cmcom oil) in 20 cm3anhydrous DMF (dimethylformamide). The reaction mixture is heated at 80aboutC for 2 h, then cooled to 20aboutC. Add 3,25 cm3ethyliodide and stirred at 20aboutC for 16 hours Diluted with 200 cm3water and extracted with ethyl acetate (2 x 200 cm3). The combined organic phases are washed with 100 cm3water, dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The remainder chromatographic on a column of silica gel (0,2-0,063 mm, diameter 4 cm, height 40 cm) with elution with a mixture of cyclohexane and ethyl acetate (80/20 by volume) under a nitrogen pressure of 0.7 bar, collecting fractions of 125 cm3. Fractions 5 to 7 are combined and concentrated to dryness under reduced pressure (2.7 kPa), resulting in a gain of 4.7 g (N-tert-butoxycarbonyl-N-ethyl-2-AMINOPHENYL)-acetic acid ethyl ester in the form of liquid oil yellow.

P R I m e R 58. To a cooled to 5aboutWith the solution containing 0.9 g (N-tert-butoxycarbonyl-N-propyl-2-AMINOPHENYL)-uksusnoi acid in 25 cm3anhydrous dichloromethane, was added 0.5 g of N, N'-carbonyldiimidazole. Stirred for 30 min at 5aboutWith, then add a solution containing 1 g of the hydrochloride of 7,7-diphenyl-4-perhydrosqualene-(3aRS, Uchenie 3 h, then diluted with water (75 cm3) and ethyl acetate (50 cm3). The organic phase is washed with 50 cm3water and 75 cm3a saturated solution of sodium chloride, dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The remainder chromatographic on a column of silica gel (0,2-0,063 mm, diameter 2.2 cm, height 25 cm) with elution with a mixture of cyclohexane and ethyl acetate (50/50 by volume), collecting fractions of 50 cm3. Fractions 5 to 10 are combined and concentrated to dryness under reduced pressure (2.7 kPa), resulting in a gain of 1.4 g of 2-[(N-tert-butoxycarbonyl-N-propyl-2-AMINOPHENYL)-acetyl] -7,7-diphenyl-4 - perhydrosqualene-(3RS, 7aRS) in the form of liquid oil yellow.

Treated with 1.4 g of 2-[(N-tert-butoxycarbonyl-N-propyl-2-AMINOPHENYL)-ACE - Tyl] -7,7-diphenyl-4-peligrosidad - on-(3aRS, 7aRS) by 15 cm35,7-called solution chloroethanol acid in anhydrous dioxane at 20aboutC for 4 h, the Reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) and the residue dissolved in a mixture of 50 cm3ethyl acetate and 50 cm3water. Formed crystals are centrifuged, washed with 15 cm3water, 25 cm3ethyl acetate and 2 times 50 cm3isopropoxide and sushi is low white, melting at 238aboutC.

(N-Tert-butoxycarbonyl-N-propyl-2-AMINOPHENYL)-acetic acid may be obtained in the following way:

A solution containing 1.1 g (N-tert-butoxycarbonyl-N-propyl-2-AMINOPHENYL)- propyl 25 cm3ethanol, treated with 3.3 cm31 n sodium hydroxide solution for 3 hours under irrigation by phlegm. The reaction mixture was concentrated under reduced pressure (2.7 kPa). The residue is extracted by 50 cm3water and 50 cm3ethyl acetate and acidified to pH 14 chloroethanol acid, the aqueous phase is extracted with 50 cm3ethyl acetate (2 times). The combined organic phases are washed with 50 cm3water and 50 cm3a saturated solution of sodium chloride, dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa), resulting in a gain of 0.9 g (N-tert-butoxycarbonyl-N-propyl-2-AMINOPHENYL)- acetic acid in the form of liquid oil yellow.

(N-Tert-butoxycarbonyl-N-propyl-2-AMINOPHENYL)-propyl can be obtained the following way.

A solution containing 3 g of (2-tert-butoxycarbonylamino)-acetic acid in 30 cm3anhydrous dimethylformamide is added to a suspension consisting of n heated at 80aboutC for 2 h, then cooled to 20aboutC. Type of 2.33 cm3propyliodide and stirred at 20aboutWith over 20 hours is Diluted by adding 100 cm3water and extracted with ethyl acetate (2 times 1000 cm3). The combined organic phases are washed with 100 cm3water (2 times) and 100 cm3a saturated solution of sodium chloride, dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The remainder chromatographic on a column of silica gel (0,2-0,063 mm, diameter 2.6 cm, height 27 cm) with elution with a mixture of cyclohexane and ethyl acetate (97/3 by volume) under a nitrogen pressure of 0.5 bar, collecting fractions of 35 cm3. Fractions 10 to 20 are combined and concentrated to dryness under reduced pressure (2.7 kPa), resulting in a gain of 1.1 g (N-tert-butoxycarbonyl-N-propyl-2-AMINOPHENYL)-propyl in the form of liquid oil yellow.

P R I m e R 59. To a cooled to 5aboutWith the solution containing 1.1 g of 2-dimethylaminopropanol acid in 30 cm3anhydrous dichloromethane, was added 1 g of N, N'- carbonyldiimidazole. Stirred for 30 min at 5aboutWith, then add a solution containing 2,03 g of the hydrochloride of 7,7-diphenyl-4-perhydrosqualene-(3RS, 7aRS) and 1,68 cm3raybaut 200 cm of water (3 times), dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The remainder chromatographic on a column of silica gel (0,2-0,063 mm, diameter 3 cm, height 25 cm) with elution with a mixture of cyclohexane and ethyl acetate (40/60 by volume) under a nitrogen pressure of 0.7 bar, collecting fractions of 125 cm3. Fractions 8 to 26 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized at 40 cm3isopropoxide. The crystals are centrifuged, washed with isopropoxide and dried. Obtain 0.9 g of 2-[(2-dimethylaminophenyl)-acetyl] -7,7-di - phenyl-4-perhydrosqualene-(3aRS, 7aRS) in the form of white crystals, melting at 150aboutC.

2-Dimethylaminopropoxy acid can be obtained according to the method of D. U, Lee, K. K. Mayer, W. Wiegrebe, Arch. Pharm. (Weinheim), 321, 303 (1988).

P R I m e R 60. To a cooled to 5aboutWith the solution containing 2,68 g 2-dimethylaminopropanol acid in 50 cm3anhydrous dichloromethane, was added 2,43 g N, N'-carbonyldiimidazole. Stirred for 90 min at 5aboutWith, then add a solution containing 4.9 g of the hydrochloride of 7,7-diphenyl-4-perhydrosqualene-(3R, 7aR) and 4.2 cm3of triethylamine in 50 cm3dichloromethane. The reaction mixture is stirred at 20about the comfort to dryness under reduced pressure (2.7 kPa). The remainder chromatographic on a column of silica gel (0,2-0,063 mm, diameter 5 cm, height 50 cm) with elution with a mixture of cyclohexane and ethyl acetate (40/60 by volume) under a nitrogen pressure of 0.7 bar, collecting fractions of 125 cm3. Fractions 5 to 20 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in a mixture of 40 cm3acetonitrile and 200 cm3isopropoxide. The crystals are centrifuged, washed with isopropoxide and dried. Obtain 2.58 g of 7,7-diphenyl-2-[(2-dimethylaminophenyl)-acetyl] -4-lane - hydroisoquinoline-(3R, 7aR) in the form of white crystals, melting at 190aboutC.

()D20= -242about(C = 1,18, chloroform).

P R I m e R 61. To a cooled to 5aboutWith the solution containing 1.1 g of 2-diethylaminopentane acid in 30 cm3anhydrous dichloromethane, was added 0,86 g N, N'-carbonyldiimidazole. Stirred for 30 min at 5aboutWith, then add a solution containing 1.73 g of the hydrochloride of 7,7-diphenyl-4-perhydrosqualene-(3RS, 7aRS) 1.48 cm3of triethylamine in 40 cm3dichloromethane. The reaction mixture is stirred at 20aboutC for 24 h, then washed with 150 cm3water (2 times), dried on magnesium sulfate, filtered and concentrated to dryness under PSM) with elution with a mixture of cyclohexane and ethyl acetate (30/80 by volume) under a nitrogen pressure of 0.7 bar, collecting fractions of 125 cm3. Fractions 12 to 20 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in a mixture of 15 cm3acetonitrile and 50 cm3isopropoxide. The crystals are centrifuged, washed with isopropoxide and dried. Obtain 1.6 g of 2-[(2-diethylaminophenyl)-acetyl] -7,7-diphenyl-4-perhydrosqualene -/3aRS, 7aRS/ in the form of white crystals, melting at 160aboutC.

2-Diethylaminopentane acid is obtained by hydrogenation of a suspension consisting of 9 g of 2-nitrophenylacetic acid at 40 cm3ethanol, at a pressure of 7 bar for 4 h at 25aboutIn the presence of 7 cm3acetaldehyde and 1 g of palladium with 10% carbon black. The reaction mixture was filtered, concentrated to dryness under reduced pressure (2.7 kPa) and the residue chromatographic on a column of silica (0,2-0,063 mm, diameter 5 cm, height 50 cm) with elution with a mixture of cyclohexane and ethyl acetate (70/30 by volume) under a nitrogen pressure of 0.7 bar, collecting fractions of 125 cm3. Fractions 38 48 concentrated to dryness under reduced pressure (2.7 kPa), resulting in a gain of 1.1 g of 2-diethylaminopropylamine acid in the form of liquid oil yellow.

P R I m e R 62. To ohlazhdennim dichloromethane, gain of 1.62 g of N, N'-carbonyldiimidazole. Stirred for 90 min at 5aboutWith, then add a solution containing of 3.27 g of the hydrochloride of 7,7-diphenyl-4-perhydrosqualene-(3aRS, 7aRS) and 2.8 cm3of triethylamine in 50 cm3dichloromethane. The reaction mixture is stirred at 20aboutC for 16 h, then washed with 100 cm3water (2 times), dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The remainder chromatographic on a column of silica gel (grain size distribution of 0.04-0.06 mm, diameter 4 cm, height 25 cm) with elution with a mixture of cyclohexane and ethyl acetate (70/30 by volume) under a nitrogen pressure of 0.5 bar, collecting fractions of 50 cm3. Fractions 6 to 19 are combined and concentrated to dryness under reduced pressure. The residue is ground to powder in ethyl ether. The crystals are centrifuged and dried. Obtain 3.6 g of 2-[(2-dimethylamino-6-forfinal)-acetyl] -7,7-diphenyl-4-peligroso - indolene-(3RS, 7aRS) in the form of white crystals, melting at 210aboutC.

(2-Dimethylamino-6-forfinal)-acetic acid is obtained as follows.

In the autoclave of 250 cm3a solution containing 10 g (6-fluoro-2-nitrophenyl)-acetic acid and 25 cm337% aqueous Rast is by providing hydrogen at 30 bar and stirred at room temperature for 45 minutes Next, the reaction mixture was filtered and concentrated to dryness under reduced pressure (2.7 kPa). The remainder chromatographic on a column of Merck silica gel (grain size distribution 0.06 to 0.04 mm, diameter 4.0 cm, height 40 cm) with elution with a mixture of cyclohexane and ethyl acetate (75/25 by volume), collecting fractions of 60 cm3. Fractions 11 to 25 are combined and concentrated to dryness under reduced pressure (2.7 kPa). Obtain 7.0 g (2-dimethylamino-6-forfinal)-acetic acid as white crystals, melting at 94aboutC.

(6-fluoro-2-nitrophenyl)-acetic acid is obtained according to the method described in the patent CS 194005.

P R I m e R 63. To a cooled to 5aboutWith the solution containing 2 g of (2-dimethylamino-4-forfinal)-acetic acid in 50 cm3anhydrous dichloromethane, was added 1.64 g of N, N'-carbonyldiimidazole. Stirred for 90 min at 5aboutWith, then add a solution containing 3.3 grams of the hydrochloride of 7,7-diphenyl-4-perhydrosqualene-(3aRS, 7aRS) and 2.8 cm3of triethylamine in 50 cm3dichloromethane. The reaction mixture is stirred at 20aboutC for 16 h, then washed with 100 cm3water (2 times), dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The remainder of the chromium is cyclohexane and ethyl acetate (50/50 by volume) under a nitrogen pressure of 0.4 bar, collecting fractions of 50 cm3. Fractions 5 to 12 are combined and concentrated to dryness under reduced pressure. The residue is ground to powder in ethyl ether. The crystals are centrifuged and dried. Obtain 3.1 g of 2-[(2-dimethylamino-4-forfinal)-acetyl] -7,7-diphenyl-4-peligroso - indolene-(3aRS, 7aRS) in the form of white crystals, melting at 164aboutC.

(2-Dimethyl-amino-4-forfinal)-vinegar - Naya acid obtained as follows.

In the autoclave of 250 cm3the solution containing 5.5 g of (4-fluoro-2-nitrophenyl)-acetic acid and 15 cm337% aqueous formaldehyde solution in 130 cm3ethanol was added 0.6 g of palladium with 10% carbon, then put the autoclave under a hydrogen pressure in bar 47 and stirred at room temperature for 48 hours the Reaction mixture was then filtered and concentrated to dryness under reduced pressure (2.7 kPa). The remainder chromatographic on a column of Merck silica gel (grain size distribution 0.06 to 0.04 mm, the diameter of 4.2 cm, height 50 cm) with elution with a mixture of cyclohexane and ethyl acetate (80/20 by volume), collecting fractions of 50 cm3. Fractions 9 to 23 are combined and concentrated to dryness under reduced pressure (2.7 kPa). Gain of 3.9 g (2-dimethylamino-4-forfeits according to the method described in the patent CS 194005.

P R I m e R 64. To a cooled to 5aboutWith the solution containing 1.42 g of 2-[2-(pyrrolidinyl-1)-phenyl] -acetic acid in 30 cm3anhydrous dichloromethane, was added 1.13 g of N, N'-carbonyldiimidazole. Stirred for 40 min at 5aboutWith, then add a solution containing 2.8 g of the hydrochloride of 7,7-diphenyl-4-peligrosidad-on-(3RS, 7aRS) and 0.98 cm3of triethylamine in 20 cm3dichloromethane. The reaction mixture was stirred for 1 h at 5aboutC, then for 1 h at 20aboutC. Further, it is washed with 20 cm3distilled water (2 times), dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The remainder chromatographic on a column of silica gel (0,2-0,063 mm, diameter 2 cm, height 25 cm) with elution with a mixture of ethyl acetate and cyclohexane (70/30 by volume), collecting fractions of 100 cm3. Fractions 3 to 8 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is recrystallized in a mixture of 5 cm3acetonitrile and 5 cm3isopropoxide. The crystals are centrifuged, washed with 10 cm3of ethylene oxide and dried. Obtain 2.2 g of 7,7-diphenyl-2-{ 2-[2-(1-pyrrolidinyl)-phenyl] -acetyl} -4-lane - hydroisoquinoline-(3aRS, 7aRS), melting the ins and 1.66 g of copper acetate, heated with stirring for 2 h at 90aboutAfter returning to room temperature the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The remainder chromatographic on a column of silica gel (0,2-0,063 mm, diameter 5 cm, height 55 cm) with elution at first through 1000 cm31,2-dichloroethane, and then the mixtures of 1,2-dichloroethane and methanol (volume ratio): 1000 cm3(98/2), 2000 cm3(97/3), 1000 cm3(96/4) and 1000 (95/5), collecting fractions of 250 cm3. Fractions 21 to 29 are combined and concentrated to dryness under reduced pressure (2.7 kPa). Receive 2 g of 2-[2-(1-pyrrolidinyl)-phenyl] -acetic acid in the form of liquid oil orange.

P R I m e R 65. To a cooled to 5aboutWith the solution containing of 0.48 g of 2-[2-(4-morpholinyl)-phenyl] -acetic acid in 25 cm3anhydrous dichloromethane, was added 0.35 g of N, N'-carbonyldiimidazole. Stirred for 75 min at 5aboutWith, then add a solution containing 0.71 g of the hydrochloride of 7,7-diphenyl-4-perhydrosqualene-(3RS, 7aRS) and 0.6 cm3of triethylamine in 20 cm3dichloromethane. The reaction mixture was stirred for 1 h at 5aboutWith, then for 8 h at 20aboutC. Next, it was washed with 100 cm3distilled water (3 is to dryness under reduced pressure (2.7 kPa). The remainder chromatographic on a column of silica gel (0.04 to 0,063 mm, diameter 2.2 cm, height 12 cm) with elution with a mixture of ethyl acetate and cyclohexane (70/30 by volume) under a nitrogen pressure of 0.7 bar, collecting fractions of 50 cm3. Fractions 4 and 5 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is recrystallized in 2 cm3of ethylene oxide. The crystals are centrifuged, washed with 1 cm3isopropoxide and dried. Obtain 0.27 g of 7,7-diphenyl-2-{ 2-[2-(4-morpholinyl)-phenyl] -acetyl} -4-peroxid - roseingrave-(3aRS, 7aRS), melting at 167aboutC.

2-[2-(4-Morpholinyl)-phenyl] -acetic acid may be obtained as follows.

The solution containing 2,78 g of N-[2-(4-morpholinyl)-phenylthiomethyl] -the research in a mixture of 25 cm3acetic acid and 25 cm337% chloroethanol acid, heated under irrigation phlegm for 8 h, then concentrated to dryness under reduced pressure (2.7 kPa). The residue is extracted by 20 cm3ethyl acetate and 20 cm31 n sodium hydroxide solution. The aqueous phase is acidified to pH 5 by addition of acetic acid, then extracted with 20 cm3ethyl acetate. The organic phase is washed with water (2 x 4 cm3), dried on Scasny acid, melting at 128aboutC.

N-[2-(4-Morpholinyl)-phenylthiomethyl] -morpholine can be obtained as follows.

A mixture of 4.6 g of 2-(4-morpholinyl)-acetophenone, 3.9 cm3the research and 1.79 g of sulfur is heated under irrigation phlegm for 5 h with stirring, then the hot reaction mixture is diluted with 17 cm3boiling ethanol. After cooling, the solid is centrifuged and chromatographic on a column of silica gel (0.04 to 0,063 mm, the diameter of 3.9 cm, height 30 cm) with elution with a mixture of cyclohexane and ethyl acetate (60/40 by volume) under a nitrogen pressure of 0.6 bar, collecting fractions of 100 cm3. Fractions 7 to 28 are combined and concentrated to dryness under reduced pressure (2.7 kPa), resulting in a gain 3,82 g of N-[2-(4-morpholinyl)-phenylthiomethyl] -the research, melting at 140aboutC.

2-(4-Morpholino)-acetophenone can be obtained as follows.

A mixture of 19.9 g of 2-fortetienne, 21 cm3the research and 27.6 g of potassium carbonate in 32 cm3dimethyl sulfoxide is heated at 110aboutC for 30 h, the Reaction mixture is diluted with 100 cm3water and extracted with 4 times 100 cm3ethyl acetate; the organic solution is washed with 100 cm3distilled is alance silica gel (0.04 to 0,063 mm, diameter 9 cm, height 40 cm) with elution with a mixture of cyclohexane and ethyl acetate (80/20 by volume), collecting fractions of 250 cm3. Fractions 24 to 44 are combined and concentrated to dryness under reduced pressure (2.7 kPa). Get 4,72 g of 2-(4-morpholinyl)-acetophenone used in this form for subsequent syntheses.

P R I m e R 66. To a cooled to 5aboutWith the solution containing 1.3 g of 2-(1-naphthyl)-acetic acid in 30 cm3anhydrous dichloromethane was added 1.13 g of N, N'-carbonyldiimidazole. Stirred for 25 min at 5aboutWith, then add a solution containing 2.3 g of the hydrochloride of 7,7-diphenyl-4-perhydrosqualene-(3RS, 7aRS) and 0.98 cm3of triethylamine in 40 cm3dichloromethane. The reaction mixture is stirred at 20aboutC for 4 h, then washed with 50 cm3distilled water (2 times), dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The remainder chromatographic on a column of silica gel (0,2-0,063 mm, diameter 1.8 cm, height 19 cm) with elution dichloromethane, collecting fractions at 30 cm3. Fractions 3 to 8 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in 14 cm3acetonitrile. The crystals are centrifuged, p(3RS, 7aRS), melting at 207aboutC.

P R I m e R 67. To a cooled to 5aboutWith the solution containing 0.71 g of 2-(2-thienyl)-acetic acid, add 0,81 g N, N'-carbonyldiimidazole. Stirred for 1 h at 5aboutWith, then add a solution containing 1.6 g of the hydrochloride of 7,7-diphenyl-4-perhydrosqualene and 0.7 cm3of triethylamine in 20 cm3dichloromethane. The reaction mixture was stirred for 2 h at 5aboutWith, then for 16 h at 20aboutC, then washed with 50 cm3distilled water (3 times), dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is recrystallized in 10 cm3acetonitrile. The crystals are centrifuged, washed with 10 cm3isopropoxide and dried. Obtain 1.5 g of 2-[(2-thienyl)-acetyl] -7,7-diphenyl-4-perhydrosqualene-(3RS, 7aRS), melting at 206aboutC.

P R I m e R 68. To a cooled to 5aboutWith the solution containing 0,99 g of 2-(3-thienyl)-acetic acid in 30 cm3anhydrous dichloromethane, was added 1.13 g of N, N'-carbonyldiimidazole. Stirred for 15 min at 5aboutWith, then add a solution containing 2.24 g of the hydrochloride of 7,7-diphenyl-4-perhydrosqualene-(3RS, 7aRS) and 1.96 cm3of triethylamine in 20 CMP> distilled water (3 times), dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is recrystallized in a mixture of 30 cm3acetonitrile and 40 cm3isopropoxide. The crystals are centrifuged, washed with isopropoxide and dried. Obtain 2.2 g of 2-[2-(3-thienyl)-acetyl] -7,7-diphenyl-4-perhydrosqualene-(3RS, 7aRS), melting at 224aboutC.

P R I m e R 69. To a cooled to 5aboutWith the solution containing 1.23 g of 2-(1,3-dithiin-5-yl)-acetic acid in 30 cm3anhydrous dichloromethane, was added 1.13 g of N, N'-carbonyldiimidazole. Stirred for 20 min at 5aboutWith, then add a solution containing 2.3 g of the hydrochloride of 7,7-diphenyl-4-perhydrosqualene-(3RS, 7aRS) and 0.98 cm3of triethylamine in 40 cm3dichloromethane. The reaction mixture was stirred for 16 h at 20aboutC. Then the reaction mixture is washed with 50 cm3distilled water (3 times), dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized at 80 cm3acetonitrile. The crystals are centrifuged, washed with 10 cm3isopropoxide and dried. Gain of 1.94 g of 2-[2-(1,3-dithiin-5)-acetyl] -7,7-diphenyl-4-peligrosamente(2-pyridyl)-acetic acid in 30 cm3anhydrous dichloromethane, was added 1.4 cm3of triethylamine. The solution is cooled to 5aboutSince then processed of 1.62 g of N, N'-carbonyldiimidazole. Stirred for 15 min at 5aboutWith, then add a solution containing of 3.27 g of the hydrochloride of 7,7-diphenyl-4-perhydrosqualene-(3RS, 7aRS) and 2.8 cm3of triethylamine in 20 cm3dichloromethane. The reaction mixture is stirred at 20aboutC for 2 h, then concentrated to dryness under reduced pressure (2.7 kPa). The residue is extracted by a mixture of 100 cm3ethyl acetate and 75 cm3water. The organic phase is washed with 50 cm3water, dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is recrystallized in a mixture of 30 cm3acetonitrile and 30 cm3isopropoxide. Obtain 1.6 g of 2-[2-(2-pyridyl)-acetyl] -7,7-diphenyl-4-lane - hydroisoquinoline-(3RS, 7aRS) in the form of white crystals, melting at 195aboutC.

P R I m e R 71. To a cooled to 5aboutWith the solution containing 0,685 g of 2-(3-pyridyl)-acetic acid in 15 cm3anhydrous dichloromethane, was added 0,81 g N, N'-carbonyldiimidazole. Stirred for 30 min at 5aboutWith, then add a solution containing 1.6 g of the hydrochloride mesh stirred at 20aboutC for 16 h, then concentrated to dryness under reduced pressure (2.7 kPa). The residue is extracted by a mixture of 100 cm3ethyl acetate and 75 cm3water. The organic phase is washed with 50 cm3a saturated solution of sodium chloride, dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The remainder chromatographic on column alumoweld main character (diameter 2 cm, height 15 cm) with elution by ethyl acetate, collecting fractions of 50 cm3. Fractions 4 through 24 are concentrated to dryness under reduced pressure (2.7 kPa). The obtained crystals are recrystallized in 15 cm3acetonitrile, resulting in a gain of 0.9 g of 7,7-diphenyl-2-[2-(3-pyridyl)-acetyl] -4-peligrosos - Dolon-(3aRS, 7aRS) in the form of white crystals, melting at 208aboutC.

P R I m e R 72. To a cooled to 5aboutWith the solution containing 4,37 g of 2-(3-indolyl)-acetic acid in 100 cm3anhydrous dichloromethane, was added of 4.05 g of N, N'-carbonyldiimidazole. Stirred for 1 h at 5aboutWith, then add to 7.3 g of 7,7-diphenyl-4-perhydrosqualene-(3RS, 7aRS). The reaction mixture is stirred at 20aboutC for 20 h, then washed with 50 cm3distilled water (omatography on a column of silica gel (0,2-0,063 mm, diameter 7 cm, height 40 cm) with elution with a mixture of ethyl acetate and cyclohexane (70/30 by volume), collecting fractions of 100 cm3. Fractions 6 to 11 are concentrated to dryness under reduced pressure (2.7 kPa). The residue is recrystallized in 50 cm3acetonitrile. The obtained crystals are centrifuged, washed with 10 cm3isopropyl - oxide and dried. Get 5 g of 2-[2-(3-indolyl)-acetyl] -7,7-diphenyl-4-perhydrosqualene-(3RS, 7aRS), melting at 250aboutC.

To a solution containing 16.6 g of the hydrochloride of 7,7-diphenyl-4-perhydrosqualene-(3RS, 7aRS), 250 cm3dichloromethane is added with stirring 100 cm34 N. aqueous sodium hydroxide, the organic phase is dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (4 kPa). 13 g of 7,7-diphenyl-4-perhydrosqualene-(3RS, 7aRS) in the form of a substance of white color with the consistency of type "meringue".

An NMR spectrum of protons: 2,15 and 2.4 (2MT, respectively 1H each, -CH2- a 5 or 6); to 2.75 (MT, 4H, -CH26 or 5); and 3.3 to 3.6 (MT, 2H, 1H-CH2- 3 and CH - 3A); 3,95 to 4.2 (MT, 2H, 1H-CH2- 3 and CH - 7a); 7 to 7.5 (MT, 10H, aromatic).

Characteristic bands (cm-1) infra-red spectrum (ADHD3):

3350, 3100-3000, 3000-2800, EU based on 1 g of the acid according to the method described S. Hamman et coll. , V. Fluorine Chem. , 37, 85/1987) 20 cm3dichloromethane was added at 0aboutWith a solution containing a 2.12 g of the hydrochloride of 7,7-diphenyl - 4-perhydrosqualene-(3R, 7aR), 0.9 cm3of triethylamine and 0.5 cm3pyridine in 30 cm3dichloromethane. The reaction mixture is stirred for 2 hours, brought to room temperature, then concentrated to dryness under reduced pressure (2.7 kPa). The residue is extracted by 100 cm3ethyl acetate. The solution is washed with 2 times 100 cm3water, then 50 cm3a saturated solution of sodium bicarbonate and 50 cm3a saturated solution of sodium chloride, dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The remainder chromatographic on a column of silica gel (grain size distribution of 0.2-0,063 mm, diameter 3 cm, height 40 cm) with elution by ethyl acetate under a nitrogen pressure of 0.7 bar, collecting fractions of 100 cm3, resulting in a gain of 1 g of 2-( -perforater-(S) (-7,7-diphenyl-4-perhydrosqualene-(3R, 7aR) in the form of a substance of white color with the consistency of type "meringue".

An NMR spectrum of the proton (DMSO-d6).

At ordinary temperature see a mixture of two rotational isomers.

2 to 2.4 (m, 2H, -CH25); 2,45 up to 3 , N 3); 5,90 and 6,28 (2D, J = 47, 1H, -F); 7 to 7.7 (m, 15 NM, aromatic).

Infrared spectrum (characteristic bands in cm-1): 3100-2875, 1715, 1655, 1600, 1580, 1495, 1450, 750, 700.

P R I m e R 74. To a cooled to 5aboutWith the solution containing 0.62 g of 2-phenylpropionate-(S) acid in 30 cm3anhydrous dichloromethane, was added 0.66 g of N, N-carbonyldiimidazole. Stirred for 40 min at 5aboutWith, then add a solution containing 1.35 g of the hydrochloride of 7,7-diphenyl-4-perhydrosqualene-(3R, 7aR) and 0.57 cm3of triethylamine in 40 cm3dichloromethane. The reaction mixture is stirred at 20aboutC for 16 h, then washed with 50 cm3distilled water (2 times), dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The remainder chromatographic on a column of silica gel (0,2-0,063 mm, diameter 1.8 cm, height 15 cm) with elution by ethyl acetate, collecting fractions 15 cm3. The first fraction is concentrated to dryness under reduced pressure (2.7 kPa). Receive 1 g of 2-(2-phenylpropionyl-(S)-7,7-diphenyl-4-perhydrosqualene-(3R, 7aR) in the form of a substance of white color with the consistency of type "meringue".

()D20= -231about(C = 1, methanol).

An NMR spectrum of the proton:

When to is; ,95 to 2.3 (MT, 2H, -CH2- a 5 or 6); to 2.65 to 2.9 (MT, 4H, -CH26 or 5 and CH2- 1); 3,05 up to 3.35 (MT, 2H, 1H-CH2- 3 and CH - 3A); 3.4 and 3.8 to 4 (MT, -N-CO-CH - and-CH - 7a); of 4.2 to 4.4 (MT, 1H, 1H from-CH23); of 6.9 to 7.6 (MT, 15 NM, aromatic).

Characteristic bands (cm-1) infra-red spectrum (KBR):

3600-3300, 3100-3000, 3000-2870, 1715, 1640, 1600, 1580, 1495, 1455, 1445, 1420, 1370, 755, 700. P R I m e R 75. To a cooled to 5aboutWith the solution containing 0.62 g of 2-phenylpropionate-(R) acid in 30 cm3anhydrous dichloromethane, was added 0.66 g of N, N'-carbonyldiimidazole. Stirred for 30 min at 5aboutWith, then add a solution containing 1.35 g of the hydrochloride of 7,7-diphenyl-4-perhydrosqualene-(3R, 7aR) and 0.57 cm3of triethylamine in 40 cm3dichloromethane. The reaction mixture is stirred at 20aboutC for 16 h, then concentrated to dryness under reduced pressure (2.7 kPa). The residue is dissolved in 100 cm3ethyl acetate and the solution washed with 50 cm3water (2 times), dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (4 kPa). The remainder chromatographic on a column of silica gel (0.2 to 0.04 mm, diameter 2.8 cm, height 15 cm) with elution with a mixture of cyclohexane and ethyl acetate (60/40 by volume) under a pressure of azo is what Tata obtain 1.4 g of 2-(2-phenylpropionyl-(R)-7,7-diphenyl-4-perhydrosqualene-(3R, 7aR) in the form of a substance of white color with the consistency of type "meringue", infra-red spectrum of which is identical to the spectrum of the product from example 68.

()D20= -278o(c = 1, methanol).

An NMR spectrum of the proton:

1,2 and 1.28 (2D, 3H, CH3); and 1.9 to 2.3 (MT, 2H, -CH2-a 5 or 6); 2,50 to 3.15 (MT, 4H, -CH26 or 5 and CH2- 1); 3,15 to 4.05 (MT-SN - 3A, 1N-CH2- 3, -N-CO-CH-, -CH - 7a); 4 to 4,21 (MT, 1H from-CH2- 3); 6,85 to 7.7 (MT, 15 NM, aromatic).

P R I m e R 76. To a solution containing 0.75 g of 2-(2-methoxyphenyl)-propionic-(S) acid with 84% optical purity, semi - Chennai according to 58, 340 (1985), 15 cm3anhydrous DMF (dimethylformamide), gain of 0.59 g of 1-hydroxybenzotriazole, then cooled the solution to 0aboutC. Further gain of 0.91 g of N, N-dicyclohexylcarbodiimide, stirred for 1 hour at this temperature, then add a solution containing 1.44 g of the hydrochloride of 7,7-diphenyl-4-perhydrosqualene-(3R, 7aR) and 0,76 cm3N, N-diisopropylethylamine 10 cm3of dimethylformamide. The reaction mixture is stirred at 20aboutC for 16 h, diluted with 100 cm3ethyl acetate and concentrated to dryness under reduced pressure (2.7 kPa) after filtration of the precipitate. The rest of chromatographica (50/50 by volume), under a nitrogen pressure of 0.7 bar, collecting fractions of 125 cm3. Fractions 4 through 7 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by dissolving in 60 cm3boiling isopropoxide with the addition of 30 cm3hexane. The cooled solution is filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa), resulting in a gain of 1.2 g of 7,7-diphenyl-2-[2-(2-methoxyphenyl)-propionyl(S)] -4-perhydrosqualene-(3R 7aR) in the form of a substance of white color with the consistency of type "meringue", containing 10% 7,7-diphenyl-2-[2-(2-methoxyphenyl)-propionyl R)] -4-perhydrosqualene- (3aR, 7aR).

()D20= -181o(c = 0,81, chloroform).

An NMR spectrum of the proton:

At room temperature, see the mixture of two rotational isomers of each of the two diastereoisomers. Two diastereoisomer are in the ratio of 90/10.

of 1.10 and 1.20 (2MT, 3H, CH3); and 1.9 to 2.4 (MT, 2H, -CH2- a 5 or 6); by 2.55 to 2.95 (MT, -CH2- in 1-CH26 or 5); 2,95 to 3.4 (MT, 1H from-CH2- 3 and CH - 3A); 3,20-3,32-3,50 and 3,83 (4C, -och3); 3,65 to 4.3 (MT-SN - 7a-N-CO-CH-, 1H-CH2- 3); 6,7 to 7.65 (MT, 14N, aromatic).

Characteristic bands (cm-1) infra-red spectrum (KBR):

3430, 310 the oru, containing 1 g of 2-(2-dimethylaminophenyl)-propionic-(RS) acid in 30 cm3dichloromethane is added to 0.85 g of N, N-carbonyldiimidazole, then stirred for 30 min at this temperature. Next, add a solution containing 1.7 g of the hydrochloride of 7,7-diphenyl-4-perhydrosqualene-(3R, 7aR), and 1.4 cm3of triethylamine in 30 cm3dichloromethane. The reaction mixture is stirred at 20aboutC for 16 h, washed with 2 times 100 cm3water, dried on magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The remainder chromatographic on a column of silica gel (0,2-0,063 mm, diameter 3 cm, height 50 cm) with elution of ethyl acetate under a nitrogen pressure of 0.5 bar, collecting fractions of 125 cm3. Fractions 4 to 6 are combined and concentrated to dryness under reduced pressure (2.7 kPa), resulting in a gain of 1.4 g of 2-[2-(2-dimethylaminophenyl)-propionyl(RS)] -7,7-diphenyl-4-peligrosidad -(3R, 7aR) in the form of a substance of white color with the consistency of type "meringue".

An NMR spectrum of the protons.

At ordinary temperature see a mixture of two rotational isomers of each of the two diastereoisomers.

of 1.15 to 1.35 (MT, 3H, -CH3); and 1.9 to 2.4 (MT, -CH2- a 5 or 6); 2,1-2,19-2,62-2,64 (45, -N(CH3)2); 2,55 to 3.4 (MT, -CH2

Characteristic bands (cm-1) infra-red spectrum (KBR):

3600-3300, 3100-3000, 3000-2780, 1715, 1640, 1595, 1580, 1490, 1460, 1445, 1410, 750, 702.

A solution containing 1.8 g of 2-(2-dimethylaminophenyl)-acetic acid in 10 cm3anhydrous tetrahydrofuran, are added at 10aboutWith the solution diisopropylamide lithium (obtained by the action of 2.6 cm31.6 M solution of utility in hexane to a solution containing 2.8 g of Diisopropylamine 30 cm3anhydrous tetrahydrofuran, at 10aboutC). The reaction mixture was stirred for 30 min at 20aboutC, then for 30 min at 35aboutC. After cooling to 20aboutTo add 0,63 cm3under the conditions and heated for 1 h at 35aboutC. Then cooled, diluted with 20 cm3water and 100 cm3ethyl acetate. The aqueous phase is washed with 100 cm3ethyl acetate, acidified to pH 5 by adding chloroethanol acid and extracted with 2 times 100 cm3ethyl acetate. The organic phase is washed with water, dried on magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa), resulting in a gain of 1 g of 2-(2-dimethylaminophenyl)-propionic-(RS) acid in the form of liquid oil yellow.

P R I m e R 78. To the cooling gap is Ana, gain of 0.49 g of N, N'-carbonyldiimidazole. Stirred for 30 min at 5aboutWith, then add a solution containing 0,98 g of the hydrochloride of 7,7-diphenyl-4-perhydrosqualene-(3R, 7aR) and 0.42 cm3of triethylamine in 20 cm3dichloromethane. The reaction mixture is stirred at 20aboutC for 16 h, then washed with 50 cm3distilled water (2 times), dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The remainder chromatographic on a column of silica gel (0,2-0,063 mm, diameter 1.6 cm, height of 9.7 cm) with elution with a mixture of ethyl acetate and cyclohexane (80/20 by volume), collecting fractions at 30 cm3. The first fraction is concentrated to dryness under reduced pressure (2.7 kPa). The residue is again chromatographic on a column of silica gel (0,2-0,063 mm, diameter 1.3 cm, height 14.5 cm) with elution with a mixture of cyclohexane and ethyl acetate (70/30 by volume), collecting fractions of 50 cm3. Fractions 1 through 3 are combined and concentrated to dryness under reduced pressure (2.7 kPa). Gain of 0.54 g of 7,7-diphenyl-2-(2-phenylbutyric-(S)] -4-lane-hydroisoquinoline-(3R, 7aR) in the form of a substance of white color with the consistency of type "meringue".

()D20= -216about(C = 1, methanol).

An NMR spectrum of the proton:

Prla); 1.4 to 2 (MT, -CH2- ethyl); and 1.9 to 2.3 (MT, 2H, -CH2in ili 6); 2,8 (MT, 4H, -CH26 or 5 and CH2- 1); 3,05 up to 3.35 (MT, -CH, - 3A, -N-CO-CH - and 1H-CH2- 3); 3,75 to 4.1 (MT, 1H, -CH - 7a); 4.2 to 4,45 (MT, 1H, 1H from-CH2- 3); 6,9 to 7.65 (MT, 15 NM, aromatic).

Characteristic bands (cm-1) infra-red spectrum (KBR):

3600-3300, 3100-3000, 3000-2830, 1715, 1640, 1600, 1580, 1492, 1450, 1445, 1420, 1375, 755 and 700.

P R I m e R 79. To a cooled to 5aboutWith the solution containing 0,79 g of 3-tert-butoxycarbonylamino-2-phenyl-propionic-(S) acid in 20 cm3anhydrous dichloromethane, was added 0.5 N, N'-carbonyldiimidazole. Stirred for 1 h 15 min at 5aboutWith, then add a solution containing 1 g of the hydrochloride of 7,7-diphenyl-4-perhydrosqualene-(3R, 3. aR) and 0.4 cm3of triethylamine in 25 cm3dichloromethane. The reaction mixture was stirred for 15 min at 5aboutWith, then add 16 h at 20aboutC. the Reaction mixture was washed with 100 cm3distilled water (3 times), dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The remainder chromatographic on a column of silica gel (0.2 to 0.06 mm, diameter 3 cm, height 30 cm) with elution with a mixture of cyclohexane and ethyl acetate (50/50 by volume is(2.7 kPa). Obtain 1.2 g of 2-[2-tert-butoxycarbonylamino-2 - phenyl-acetyl-(S)] -7,7-diphenyl-4-purged - rotondella-(3R, 7aR) in the form of a substance of white color with the consistency of type "meringue".

Treated with 1 g of 2-[2-tert-butoxycarbonylamino-2-phenyl-acetyl-(S)] -7,7-diphenyl-4-ambrosia roseingrave-(3R, 7aR) by 10 cm35,7-called solution chloroethanol acid in anhydrous dioxane for 2 h at 5aboutWith, then for 3 h at 20aboutC. the Reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa); the residue is crystallized in 5 cm3acetonitrile. The obtained crystals are centrifuged, washed with 0.5 cm3acetonitrile and dried. Get 0,76 g of the hydrochloride of 2-[(2-aminomethyl-2-phenyl)-acetyl-(S)] -7,7-diphenyl-4-perhydrosqualene-(3A , 7aR), melting at 220aboutC.

()D20= -199about(C = 0,2, methanol).

To a suspension consisting of 8 g of 3-amino-2-phenyl-propionic-(S) acid in a mixture of 55 cm3water and 10 cm3dioxane is added with stirring 10.3 g of sodium carbonate, then poured the solution containing of 12.6 g of di-tert-BUTYLCARBAMATE 16 cm3dioxane. The reaction mixture is stirred for 20 h at room temperature, filtered and concentrate DM3ethyl acetate; the mixture is cooled to 5aboutC, then acidified by addition of 4 n solution chloroethanol acid to pH = 1, i.e. 35 cm3. The organic phase is washed with 100 cm3distilled water (3 times), dried on magnesium sulfate, then concentrated to dryness under reduced pressure (2.7 kPa). Obtain 11.3 g of 3-tert-butoxycarbonylamino-2-phenyl-propionic-(S) of acid, melting at 138aboutC.

()D20= +94about(C = 0.25, methanol).

3-Amino-2-phenyl-propionic-(S) acid can be obtained according to the method described by J. A. Catbarino, J. Chem. Soc. Perkin 1, 906 (1981).

P R I m e R 80. To a cooled to 5aboutWith the solution containing 1.23 g L-methoxyphenylacetic acid (S) 20 cm3anhydrous dimethylformamide, are added 1 g of hydroxybenzotriazole, monohydrate; continue stirring for 15 min, then add 1,53 g N, N'-dicyclohexylcarbodiimide. Stirred for 1 h at 5aboutWith, then add a solution containing 2,43 g of the hydrochloride of 7,7-diphenyl-4-perhydrosqualene-(3ap, ar) and 1.28 cm3diisopropylethylamine 10 cm3anhydrous DMF (dimethylformamide). The reaction mixture is stirred at 5aboutC for 2 h, then at room temperature during which SUP>3
distilled water (2 times), dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The remainder chromatographic on a column of silica gel (diameter 2.2 cm, height 27 cm) with elution with a mixture of cyclohexane and ethyl acetate (80/20 by volume), collecting fractions of 20 cm3. Faction 68 through 177 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in 15 cm3isopropoxide; the resulting crystals are centrifuged, and then dried. Obtain 1.3 g of 7,7-diphenyl-2-[2-methoxy-2-phenyl-acetyl-(S)] -4-peligroso - indolene-(3R, 7aR) in the form of white crystals, melting at 130aboutC.

()D20= -230about(C = 1, methanol).

P R I m e R 81. To a cooled to 5aboutWith the solution containing 1.55 g of o-acetylindole-(S)-(+) acid in 60 cm3anhydrous dichloromethane, was added 1.3 g of N, N'-carbonyldiimidazole. Stirred for 90 min at 5aboutWith, then add a solution containing 2.6 g of the hydrochloride of 7,7-diphenyl-4-perhydrosqualene-(3R, 7aR) and 1.12 cm3of triethylamine in 80 cm3dichloromethane. The reaction mixture was stirred for 16 h at 20aboutWith concentrate to dryness under reduced pressure (2.7 kPa). Ostadi, then 50 cm3a saturated solution of sodium chloride, dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The remainder chromatographic on a column of silica gel (0,4-0,063 mm, diameter 4 cm, height 23 cm) with elution with a mixture of cyclohexane and ethyl acetate (50/50 by volume) under a nitrogen pressure of 0.5 bar, collecting fractions of 60 cm3. Fractions 13 to 19 are combined and concentrated to dryness under reduced pressure (2.7 kPa), resulting in a gain of 2.9 g of 2-(2-acetoxy-2-phenyl-acetyl-(S)] -7,7-diphenyl-4-peligroso - indolene-(3R, 7aR) in the form of a substance of white color with the consistency of type "meringue".

()D20= -186,4o(c = 0.1, methanol).

An NMR spectrum of the protons.

At room temperature, see the mixture of two rotational isomers.

2 and 2,05 (2C, -ASON3); and 1.9 to 2.3 (MT, -CH2- a 5 or 6); 2.6-3 (MT, 4H, -CH26 or 5 and CH2- 1); 3,05 to 3.4 (MT, 2H, 1H-CH2- 3 or-CH2in 3A); 3,75 to 4.1 (MT, 1H, -CH - 7a); 4.15 to 4.5 m (MT, 1H, 1H from-CH26 or 5); 5,65 and 6.14 (2S, 1H, N-CO-CH-); 7,05 to 7.6 (MT, 15 NM, aromatic).

Characteristic bands (cm-1) infra-red spectrum (KBR):

3090-3065, 2980-2880, 1735, 1720, 1660, 1600, 1585, 1495, 1460, 1445, 1435, 1375, 1240, 700.

An NMR spectrum of the proton:

At room temperature, see the mixture of two rotational isomers.

of 1.95 to 2.45 (MT, 2H, -CH2- a 5 or 6); 2.6-3 (MT, 4H, -CH26 or 5 and CH2- 1); 3.8 to 4 (MT, 1H, -CH - 7a); 4,10 to 4.35 (MT, 1H, 1H from-CH2- 3); 4,90 and 5.25 (2D, J = 6, not exchangeable, 1H, N-CO-CH-O-/; 5,47 and 5.6/2D, I= 6, exchanged, IH, IT); 7 to 7.7 (MT, 15 NM, aromatic).

Characteristic bands (cm-1) infra-red spectrum (KBR):

3410, 3100-3000, 3000-2870, 1715, 1640, 1600, 1580, 1492, 1460, 1445, 1380, 1065, 755 and 700. 2-[2-Acetoxy-2-phenyl-acetyl-(S)] -7,7-diphenyl-4-peligrosidad-(3R, 7aR) can be floor is 40,5 g monobenzyl ether phenylmalonate acid at 810 cm3anhydrous dichloromethane, was added 24.3 g of N, N'-carbonyldiimidazole. Stirred for 25 min at 5aboutWith, then add a solution containing 49,1 g of the hydrochloride of 7,7-diphenyl-4-perhydrosqualene-(3aRS, 7aRS) and 21 cm3of triethylamine in 1000 cm3dichloromethane. The reaction mixture is stirred at 20aboutC for 16 h, then washed with 1000 cm3distilled water (3 times), dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The remainder chromatographic on a column of silica gel (0,2-0,063 mm, diameter 5.8 cm, height 63 cm) with elution with a mixture of ethyl acetate and cyclohexane (90/10 by volume), collecting fractions of 200 cm3. Fractions 14 to 17 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized at 400 cm3isopropoxide; the resulting crystals are centrifuged, washed with 40 cm3isopropoxide and dried. Then 5 g of a 35.6 g of the obtained crystals chromatographic on a column of silica gel (0,2-0,063 mm, the diameter of 4.6 cm, height 30 cm) with elution with a mixture of cyclohexane and ethyl acetate (60/40 by volume), collecting fractions of 100 cm3. Fractions 4 to 10 are combined and concentrated to dryness under reduced pressure (2.7 kPa); the residue Perekrest is xida and dried. Obtain 1.6 g of 2-(2-benzyloxycarbonyl-2-phenyl-acetyl)-7,7-diphenyl-4-peligroso - indolene-(3RS, 7aRS), melting at 210aboutC.

P R I m e R 84. To a suspension consisting of 5 g of 2-(2-benzyloxycarbonyl-2-phenyl-acetyl)-7,7-diphenyl-4-peligrosidad - on-(3RS, 7aRS) 50 cm3methanol is added with stirring 1 g of palladium with 5% carbon. The reaction mixture hydronaut at atmospheric pressure and room temperature for 3.5 h, then filtered and concentrated to dryness under reduced pressure (2.7 kPa); the residue is treated with 5 cm31 N. aqueous sodium hydroxide solution, cooled to 5aboutC, then 40 cm3distilled water and 40 cm3ethyl acetate. The aqueous solution is extracted with 40 cm3ethyl acetate; the organic solutions are combined to a cooled to 5aboutC and acidified by addition of 4 cm34 N. solution chloroethanol acid; the precipitate is dissolved in 50 cm3ethyl acetate and the organic solution washed with 40 cm3distilled water (3 times), dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is extracted by 5 cm3isopropoxide, centrifuged and dried. Receive 2 g of 2-[(2-carboxy-is xianbei-2-phenyl-acetyl)-7,7-diphenyl-4-peligrosidad- (3RS, 7aRS) can be obtained, as described previously in example 83.

P R I m e R 85. Carrying out the reaction as described previously in example 83, but on the basis of the methyl ether of phenylmalonate acid, gain of 0.53 g of 2-[(2-methoxycarbonyl-2-phenyl)-acetyl] -7,7-diphenyl-4-peligroso - indolene-(3RS, 7aRS) in the form of a substance of white color with the consistency of type "meringue".

An NMR spectrum of the proton:

At room temperature, see the mixture of two rotational isomers of each of the two diastereoisomers. of 1.85 to 2.3 (MT, 2H, -CH2- a 5 or 6); of 2.6 to 3.2 (MT, 4H, -CH26 or 5 and CH2- 1); 3 to 3.5 (MT, 2H, 1H-CH2- 3 and CH - 3A); 3,48-to 3.58-3.6 and 3,62 (4S, 3H in total, SOON3); 3,65 to 4.42 (MT-SN - 7a and 1H from-CH2- 3); 4,6-4.63 to-5 and 5.08 (4S, 1H, N-COCH-COO-); 6,9 to 7.65 (MT, 15 NM, aromatic).

Characteristic bands (cm-1) infra-red spectrum (KBR):

3600-3300, 3100-3000, 3000-2800, 1745, 1715, 1650, 1600, 1580, 1495, 1475, 1445, 1195, 755, 700.

P R I m e R 86. To a cooled to 5aboutWith the solution containing 1,53 g (L)-N - tert-butoxycarbonyl-phenylglycine 25 cm3anhydrous dimethylformamide, was added 0,825 g of 1-hydroxybenzotriazole, followed by 1.25 g of N, N'-dicyclohexylcarbodiimide; after stirring for 1 h at the same temperature, add rest is 10 cm3of dimethylformamide. The reaction mixture was stirred for 2 h at 5aboutC and 1.5 h at 20aboutC, then diluted with 250 cm3ethyl acetate and after filtration of the precipitate, washed with 100 cm3water (2 times) and 100 cm3a saturated solution of sodium chloride and dried on magnesium sulfate. After concentration to dryness under reduced pressure (2.7 kPa), the residue chromatographic on a column of silica gel (0,2-0,063 mm, diameter 3.8 cm, height 31 cm) with elution with a mixture of tigogenin and ethyl acetate (75/25 by volume) under a nitrogen pressure of 0.5 bar, collecting fractions of 25 cm3. Fractions 9 to 20 are combined and concentrated to dryness under reduced pressure (2.7 kPa), resulting in a gain of 5.3 g of 2-[2-tert-butoxycarbonylamino-2-phenyl-acetyl-(S)] -7,7-diphenyl-4-perhydro - isoindoline-(3R , 7aR) in the form of a substance of white color with the consistency of type "meringue".

Treated with 5 g of 2-[2-tert-butoxycarbonylamino-2-phenylacetyl-(S)] -7,7-dif-Neil-4-perhydro indolene-(3R, 7aR) by 50 cm35,7-called solution chloroethanol acid in anhydrous dioxane for 30 min in 5aboutC, then for 1 h at 20aboutC. the Reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) and the residue is dissolved in 50 cm3water and profilesint. The solid is extracted by 25 cm3water and the suspension is again concentrated to dryness under reduced pressure (2.7 kPa). The solid is ground to powder in 10 cm3acetone, centrifuged, washed 2 times 2.5 cm3acetone and dried. Get 2,53 g of the hydrochloride of 7,7-diphenyl-2-[(L)--phenylglycyl] -4-perhydrosqualene-(3R, 7aR) in a solid white color, partially hydrated.

()D20= -234about(C = 0.3, and water).

An NMR spectrum of the proton:

At room temperature, see the mixture of two rotational isomers.

of 1.75 to 2.35 (MT, 2H, -CH2- a 5 or 6); 2.6-3 (MT, 4H, -CH2- 6 or 5 and CH2- 1); 3.25 to to 3.45 (MT, partially hidden, 1H from-CH2- 3 and CH - 3A); 3,85 to 4.15 (MT, 1H, -CH2in 7a); 4,25 to 4,45 (MT, 1H, 1H from-CH2- 3); 5.02 and 5,4 (2S, 1H, N-CO-CH-N-); 6,95 to 7.65 (MT, 14N, aromatic); 8,65 (M, 3H, -NH3+Cl-).

Characteristic bands (cm-1) infra-red spectrum (KBR):

3600-3300, 3100-3000, 3000-2850, 3150-2500, 1715, 1655, 1595, 1580, 1495, 1475, 1445, 1440, 755, 700.

P R I m e R 87. Conducting the reaction in the same manner as in example 86, but on the basis of (L)-N-acetyl-phenylglycine, receive and 0.37 g of 2-[2-acetylamino-2-phenyl-acetyl-(S)] -7,7-diphenyl-4-ptx2">

P R I m e R 88. To a cooled to 5aboutWith the solution containing 2.35 g (1,4-cyclohexadiene-1-yl)-acetic acid in 50 cm3anhydrous dichloromethane, was added 3.6 g of N, N'-carbonyldiimidazole. Stirred for 30 min at 5aboutWith, then add a solution containing 6,55 g of the hydrochloride of 7,7-diphenyl-4-perhydrosqualene and 5.6 cm3of triethylamine in 30 cm3dichloromethane. The reaction mixture was stirred for 1 h at 5aboutWith, then for 16 h at 20aboutC and washed with 150 cm31 N. solution chloroethanol acid and 150 cm3saturated aqueous solution of sodium chloride. The organic phase is dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The remainder chromatographic on a column of silica gel (grain size distribution of 0.2-0,063 mm, diameter 6 cm, height 30 cm) with elution under a nitrogen pressure of 0.5 bar first 3 liters of a mixture of cyclohexane and ethyl acetate (50/50 by volume), and then 2 liters of ethyl acetate, collecting fractions of 100 cm3. Fractions 10 through 48 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is recrystallized in 15 cm3acetonitrile. The crystals are centrifuged, washed with 5 cm3acetonitrile and 25 cm3isopropylate is at 186aboutC.

P R I m e R 89. A solution containing 3.7 g (1,4-cyclohexadiene-1-yl)-2-acetyl-7,7-diphenyl-4-perhydrosqualene-(3RS, 7aRS) 20 cm3anhydrous dichloromethane, treated by 1.9 grams of tetrafluoroborate triethyloxonium and stirred for 22 hours at 20aboutC. the Formed crystals are centrifuged, washed with 10 cm3dichloromethane and dried, resulting in a gain of 2 g of tetrafluoroborate 2-[1-ethoxy-2-(1,4-cyclohexadiene-1-yl)-ethylidene] -4-oxo- -7,7-diphenyl-peligrosamente-(3RS, 7aRS) in the form of a white powder that is used in the crude state for the next stage.

To a stirred and cooled to -15aboutWith a suspension consisting of 2 g of Tetra-perborate 2-[1-ethoxy-2-(1,4-cyclohexadiene-1-yl)-ethylidene)-4-oxo-7,7-diphenyl-purged isoindole-(3RS, 7aRS) 30 cm3anhydrous dichloromethane, was added 0.7 cm3solution of 5.4 N ammonia in ethanol. After returning to room temperature, the reaction mixture was stirred for 20 h, then washed 2 times 35 cm320% aqueous potassium carbonate solution. The organic phase is dried on magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in 5 cm3acetonitrile. The obtained crystal is enyl-4-peligrosidad(3RS, 7aRS) in the form of white crystals, melting at 190aboutC.

P R I m e R 90. To a cooled to 5aboutWith the solution containing 2 g of the hydrochloride of 7,7-diphenyl-2,3,3 a, 4,7,7-hexahydro-1H-ISO - indolene-4 and 1.7 cm3of triethylamine in 20 cm3anhydrous dichloromethane, was added 0,82 cm3phenylacetylide. The reaction mixture was stirred for 1 h at 5aboutC and for 1 h at room temperature; then it was washed with 20 cm3distilled water (2 times); dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in 15 cm3acetonitrile. The crystals are centrifuged, washed with 10 cm3isopropoxide, dried, then recrystallized in 20 cm3acetonitrile. The obtained crystals are centrifuged and dried. Obtain 2.7 g of 7,7-diphenyl-2-(phenylacetyl)-2,3,3 a, 4,7,7-hexahydro-1H-ISO - indolene-4-(3RS, 7aRS), melting at 188aboutC.

Hydrochloride 7,7-diphenyl-2,3,3 a, 4,7,7-hexahydro-1H-isoindole-4 can be obtained as follows.

A mixture of 3.4 g of 2-benzyl-7,7-diphenyl-2,3,3 a, 4,7,7-hexahydro-1H-ISO-indolene-4 and 0.92 cm3vinylnorbornene 80 cm31,2-dichloroethane, heating is 7 kPa). The residue is crystallized in 20 cm3ethyl ether. Obtain 2.6 g of 7,7-diphenyl-2-vinyloxycarbonyl-2,3,3 a, 4,7,7-hexahydro-1H-ISO - indolene-4, melting at 162aboutC.

Mix 2.6 g of 7,7-diphenyl-2-vinyloxycarbonyl-2,3,3 a, 4,7,7-hexahydro - 1H-isoindole-4 30 cm33 N. of a solution chloroethanol acid in dioxane at room temperature for 30 min; then the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is extracted by 50 cm3ethanol and heated under irrigation phlegm for 30 min; the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in 20 cm3ethyl ether; the resulting crystals are centrifuged and dried. Receive 2 g of the hydrochloride of 7,7-diphenyl-2,3,3 a, 4,7,7-hexahydro-1H-isoindole-4, melting at a temperature above 260aboutC.

2-Benzyl-7,7-diphenyl-2,3,3 a, 4,7,7 and-Huck - sagita-1H-isoindole-4-(3aRS, 7aRS) can be obtained as follows.

To a solution containing 7.7 g of 4,4-diphenyl-2,5-cyclohexadiene-1-she and 11 cm3N-butoxymethyl-N-trimethylsilylmethylamine - amine in 80 cm3anhydrous dichloromethane, was added 2 drops triperoxonane acid and heat the mixture under irrigation plegine, and 2 drops triperoxonane acid and the reaction mixture is heated for one and a half hours Then the reaction mixture is processed with 3 g of potassium carbonate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in 15 cm3isopropoxide. The obtained crystals are centrifuged, washed with 5 cm3isopropoxide (2 times) and dried; obtain 4.4 g of 2-benzyl-7,7-diphenyl-2,3,3 a, 4,7,7-hexahydro-1H-isoindole - on-4-(3RS, 7aRS), melting at 132aboutC.

4,4-Diphenyl-2,5-cyclohexadiene-1-it can be obtained according to the method described by H. E. Zimmerman, D. I. Schuster, J. Am. Chem. Soc. , 84, 527 (1962).

P R I m e R 91. Cooled to 4aboutWith a suspension consisting of 1.5 g of the hydrochloride of bis-7,7-(3-forfinal)-4-peligrosos - Lona 30 cm3dichloromethane, is treated first 1,15 cm3of triethylamine, then 0,63 g phenylacetylide. The reaction mixture was stirred for 5 h at 25aboutC, then washed with 3 times 100 cm3water. The organic phase is dried on magnesium sulfate, filtered to dryness under reduced pressure (2.7 kPa). The remainder chromatographic on a column of silica gel (grain size distribution of 0.04-0,063 mm, diameter 2.3 cm, height 25 cm) with elution under a nitrogen pressure of 0.5 bar with a mixture of cyclo is allsouth adding 10 cm3isopropoxide. The crystals are centrifuged, washed with isopropoxide and dried. Get 0,76 g bis-7,7-(3-forfinal)-2-(phenylacetyl)-4-perhydrosqualene-(3RS, 7aRS), melting at 108aboutC.

The hydrochloride of bis-7,7-(3-forfinal)-4-peligrosidad can be obtained as follows.

A solution containing of 92.2 g of 2-benzyl-bis-7,7-(3-forfinal)-4-peligrosos - Lona-(3RS, 7aRS) at 860 cm31,2-dichloroethane is processed with 26,3 cm3vinylnorbornene and heated for 3 h under irrigation with phlegm, then concentrate under reduced pressure (2.7 kPa). The remainder chromatographic (for two times) on silica gel (grain size distribution of 0.04-0,063 mm column with a diameter of 8 cm and a height of 35 cm) with elution under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (75/25). The resulting substance with the consistency of type "meringue" crystallized in isopropoxide, resulting in a gain 50,3 g bis-7,7-(3-forfinal)-2-vinyloxycarbonyl-4-perhydrosqualene-(3RS, 7aRS), melting at 152aboutC.

Process of 64.5 g of bis-7,7-(3-forfinal)-2-vinyloxycarbonyl-4-peligroso - indolene-(3RS, 7aRS) through 330 cm36 N. solution chloroethanol acid in dioxane for 30 min at 25aboutC. the Solution is the end is heated at 60aboutC for 6 h and stirred for 16 h at 25aboutWith, then concentrated to half under reduced pressure (2.7 kPa) and the formed crystals are centrifuged and washed with isopropoxide, and then dried. Get to 48.7 g of the hydrochloride of bis-7,7-(3-forfinal)-4-peligrosos - Lona, melting at 264aboutC.

2-Benzyl-bis-7,7-(3-forfinal)-4-lane - hydrocondone (3RS, 7aRS) can be obtained in the following way:

To a solution containing of 90.3 g of bis-4,4-(3-forfinal)-cyclohexanone and 123 cm3N-butoxymethyl-N-trimethylsilylmethyl - Salamina 1000 cm3anhydrous dichloromethane. Add 3 cm3triperoxonane acid. The reaction mixture is brought to the education of phlegmy, then stirred for 2 h, returning to a temperature of 25aboutWith, and after addition of 60 g of potassium carbonate is stirred for further 15 minutes After filtration and concentration to dryness under reduced pressure (2.7 kPa) and the residue is crystallized destroy isopropoxide, centrifuged, washed and recrystallized 300 cm3cyclohexane. The crystals are centrifuged, washed 2 times 15 cm3cyclohexane and dried, resulting in a gain of 92 g of 2-benzyl-bis-7,7-(3-forfinal)-4-perhydrosqualene-/3aRS, 7aRS/ is to be obtained in the following way:

To a solution containing 144,5 g bis-/3-forfinal/-acetaldehyde 500 cm3ethyl ether is added 50,4 cm3button, then after cooling to 0aboutWith added dropwise a solution containing a 13.9 g of potassium hydroxide in 89 cm3of ethanol. The reaction mixture was stirred for 2 h at 0aboutSince then for 16 h at 25aboutC, diluted with 300 cm3ethyl acetate and 500 cm3water. The aqueous phase is washed with 300 cm3ethyl acetate. The combined organic phases are washed with 500 cm3a saturated solution of sodium chloride, dried on magnesium sulfate and concentrate under reduced pressure (2.7 kPa). The remainder chromatographic (for two times) on silica gel (grain size distribution of 0.04-0,063 mm column with a diameter of 8.5 cm and a height of 34 cm) with elution under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (90/10). Get to 90.3 g of bis-4,4-(3-forfinal)-cyclohexanone in the form of white crystals, melting at 95aboutC.

Bis-(3-forfinal)-acetaldehyde can be obtained as follows.

The solution containing 156,7 g of bis-1,1-(3-forfinal)-2-methoxyethanol (obtained by the reaction of 3-performancebased with 2 ethoxyethylacetate in THF) in 160 cm3formic acid is heated in those who of rbonate sodium and 500 cm3ethyl acetate. The organic phase is washed with 2 times 500 cm3water and 500 cm3a saturated solution of sodium chloride, then dried and concentrated to dryness under reduced pressure (2.7 kPa), resulting in a gain of 144, 5 g of bis-(3-forfinal)-acetaldehyde in the form of liquid oil yellow.

P R I m e R 92. The solution containing 0.46 g of (2-methoxyphenyl)-acetic acid in 15 cm3anhydrous dichloromethane, cooled to 0aboutWith, then processed 0.45 g of N, N'-carbonyldiimidazole and stirred for 1 h at 0aboutC. Add one drop of solution containing 1 g of the hydrochloride of bis 7,7-(3-forfinal)-4-perhydrosqualene and 0,76 cm3of triethylamine in 20 cm3dichloromethane. The reaction mixture was stirred for 3 h at 25aboutC, then washed with 50 cm3water and 50 cm3a saturated solution of sodium chloride. The organic phase is dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The remainder chromatographic on a column of silica gel (grain size distribution of 0.04-0,063 mm, diameter 2.2 cm, height 23 cm) with elution under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (70/30), collecting fractions 15 cm3. Fractions 4 to 9 are combined and concentrated to dryness PR is Giroud, wash out isopropoxide and dried. Get 0,76 g bis-7,7-(3-forfinal)-2-(phenylacetyl)-4-perhydrosqualene- (3RS, 7aRS) melting at 194aboutC.

P R I m e R 93. To a cooled to 4aboutWith the solution containing 0.65 g (2-dimethylaminophenyl)-acetic acid in 20 cm3anhydrous dichloromethane, was added 0,59 g N, N'-carbonyldiimidazole. The mixture is stirred for 90 min at 25aboutWith, then add drop by drop a solution containing 1.3 g of the hydrochloride of bis-7,7-(3-forfinal)-4-perhydrosqualene and 1,02 cm3of triethylamine in 25 cm3anhydrous dichloromethane. The reaction mixture was stirred for 16 h at 25aboutC and washed 2 times with 250 cm3water and 250 cm3a saturated solution of sodium chloride. The organic phase is dried on magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The remainder chromatographic on a column of silica gel (grain size distribution of 0.04-0,063 mm, diameter 2.3 cm, height 23 cm) with elution under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (55/45), collecting fractions 15 cm3. Fractions 6 to 18 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is compacted by isopropoxide, resulting in a gain of 0.6 g of bis-7,7-(3-forfe the attachment 1 cm3ethyl acetate and adding 3 n solution chloroethanol acid isopropoxide. The precipitate centrifuged, washed with isopropoxide and dried. Get to 0.48 g of the hydrochloride of bis-7,7-(3-forfinal)-(2-dimethylaminophenyl)-2-acetyl-4-peligroso-indolene (3RS, 7aRS) in a solid white color.

An NMR spectrum of the protons.

At ordinary temperature see a mixture of two rotational isomers,

2 to 2,32 (m, 2H, -CH25); 2,37 and 2.6 (2s, 3H each, -N(CH3)2); 2.65 to 3 (m, 4H, -CH26 and CH2- 1); 3,15 to 3.3 (m, 1H, H in 3A); 3,35 and 3,47 (2m, 1H, 1H in 3); 3,35 and 3.5 (2D, J = 15, Agsn2WITH one rotational isomer); to 3.67 (s, ArCH2CO other rotational isomer); 4 (m, 1H, H-7a); 4.2 and 4.25 in (2m, J = 11, 1H, 1H in 3); and 6.9-7.7 (m, M, aromatic).

Infra-red spectrum (characteristic bands in cm-1):

3500-3150, 3100-3000, 3000-2850, 1712, 1650, 1615, 1595, 1580, 1495, 1445, 1535, 755, 700.

P R I m e R 94. To a cooled to 4aboutWith the solution containing 0,49 g (2-dimethylaminophenyl)-acetic acid in 20 cm3anhydrous dichloromethane, was added to 0.44 g of N, N'-carbonyldiimidazole. The mixture was stirred for 1 h at 25aboutWith, then add drop by drop a solution containing 1 g of the hydrochloride of bis-7,7-(2-forfinal)-4-purged is more for 20 h at 25aboutC and washed with 2 times 100 cm3water and 100 cm3a saturated solution of sodium chloride. The organic phase is dried on magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The remainder chromatographic in column (grain size distribution of 0.04-0,063 mm, diameter 2 cm, height 23 cm) with elution under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (50/50), collecting fractions of 10 cm3. Fractions 14 to 36 are combined and concentrated to dryness under reduced pressure (2.7 kPa), resulting in a gain of 1 g of bis-7,7-(2-forfinal)-(2-dimethylaminophenyl)-2-acetyl-4-peligrosidad-3RS, 7aRS) from which to obtain the hydrochloride by dissolving in 2 cm3ethyl acetate and adding 3 n solution chloroethanol acid isopropoxide. The precipitate centrifuged and dried. Obtain 0.87 g of the hydrochloride of bis-7,7-(2-forfinal)-(2-dimethylaminophenyl)-2-acetyl-4-peligroso-indolene (3RS, 7aRS) in a solid white color.

An NMR spectrum of the proton (DMSO-d6The MES 90/10):

At room temperature, see the mixture of two rotational isomers.

of 2.1 to 2.35 (m, 2H, -CH25); 2.8 to 3.4 (m, 10H, -CH21 and 6, -N(CH3)2); at 3.7 and 3.5 (d broad, 1H, H in 3A); and 3.8 (DD broad, 1H, 1H in 3); of 4.05 (broad, 2H, -Spertini)-4-perhydrosqualene-(3RS, 7aRS) can be obtained in the following way.

A solution containing of 2.34 g of 2-benzyl-bis-7,7-(2-forfinal)-4-peligrosos - Lona-(3RS, 7aRS) 100 cm3methanol with the addition of 6.2 cm31H. hydrochloric acid hydronaut at atmospheric pressure in the presence of 0.4 g of palladium with 10% carbon, within 5 h at 25aboutC. the Reaction mixture was filtered and concentrated to dryness under reduced pressure (2.7 kPa), resulting in a gain of 2 g of the hydrochloride of bis-7,7-(2-forfinal)-4-peligrosos - Lona-(3RS, 7aRS) in a solid white color.

An NMR spectrum of the proton (DMSO-d6):

2 to 2.4 (m, 2H, -CH25); 2.7 to 3 (m, 4H, -CH21 and 6); 3,5 (DD broad, 1H, 1H in 3); 3,7 (DD broad, 1H, H in 3A); 3,9 (d broad, 1H, 1H in 3); 4,2 (m, 1H, H-7a); 7.1 to 8 (m, 8H, aromatic).

2-Benzyl-bis-7,7-(2-forfinal)-4-lane - hydrocondone-(3RS, 7aRS) can be obtained as follows.

To a solution containing 4.3 g of bis-4,4-(2-forfinal)-cyclohexanone and 5.8 cm3N-butoxymethyl-N-trimethylsilylmethylamine 30 cm3anhydrous dichloromethane, was added 3 drops triperoxonane acid. The reaction mixture is brought to the education of phlegmy, then stirred for 16 h after establishing a temperature of 25you and stirred for 3 h under irrigation by phlegm. The reaction mixture is treated with 3 g of potassium carbonate and stirred for 15 minutes After filtration and concentration to dryness under reduced pressure (2.7 kPa), the residue chromatographic on a column of silica gel (grain size distribution of 0.04-0,063 mm, diameter 4 cm, height 32 cm) with elution under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (85/15), collecting fractions of 20 cm3. Fractions 13 to 22 are combined and concentrated to dryness under reduced pressure (2.7 kPa), resulting in a gain of 2.28 g of 2-benzyl-bis-7,3-(2-forfinal)-4-perhydrosqualene-(3RS, 7aRS), melting at 138aboutC.

Bis-(2-forfinal)-4,4-cyclohexene can be obtained as follows.

To a solution containing 30,8 g bis-(2-forfinal)-acetaldehyde in 135 cm31,2-dimethoxyethane, add to 26.9 g of potassium carbonate, and then after cooling to -50aboutTo add a drop of 19.9 cm3butanone. The reaction mixture was stirred for 12 h at -50aboutWith, then for 6 h at 25aboutC, diluted with 250 cm3ethyl acetate and 200 cm3water. The organic phase is washed 3 times with 200 cm3water, then 200 cm3a saturated solution of sodium chloride, dried on magnesium sulfate and concentrate under reduced pressure (2,7 what the chromatography under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (90/10). Get 9 g of bis-2,2-(2-forfinal)-5-oxo-hexanal in the form of liquid oil yellow. A solution of 6.65 g of this compound in 100 cm3toluene containing 1.5 g of para-toluenesulfonic acid, heated under irrigation phlegm for 3 hours, washed with 2 times 100 cm3water, then 100 cm3a saturated solution of sodium chloride, dried on magnesium sulfate and concentrate under reduced pressure (2.7 kPa). The remainder chromatographic on a column of silica gel (grain size distribution of 0.04-0,063 mm, diameter 4 cm, height 30 cm) with elution under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (90/10), collecting fractions 15 cm3. Fractions 21 to 26 are combined and concentrated to dryness under reduced pressure (2.7 kPa), resulting in a gain of 2.83 g of bis-4,4-(2-forfinal)-cyclohexanone in the form of liquid oil yellow.

An NMR spectrum of the proton (DMSO-d6):

2, 6 (m, 2H, -CH25); 2,8 (DD broad, 2H, -CH26); 6,2 (d, 1H, H in 2); of 6.9 to 7.4 (m, aromatic 98 and H 3).

Bis-(2-forfinal)-acetaldehyde can be obtained as follows.

To a solution containing 26,3 g bis-1,2-(2-forfinal)-ethylene oxide 500 cm3toluene, was added dropwise 7 cm3the ether extracts of boron TRIFLUORIDE and stirred during the After drying on magnesium sulfate and concentrating to dryness under reduced pressure (2.7 kPa) get 25 g of bis-(2-forfinal)-acetaldehyde in the form of liquid oil yellow.

Bis-1,2-(2-forfinal)-ethylene oxide can be obtained according to the method described by V. Mark, J. Am. Chem. Soc. , 85, 1884 (1963).

P R I m e R 95. To a cooled to 4aboutWith the solution containing 1.06 g of the hydrochloride of bis-7,7-(2-chlorophenyl)-4-peligrosos - Lona 20 cm3dichloromethane is added to 0.45 cm3of triethylamine, then 0,49 g phenylacetylide. The reaction mixture was stirred for 2 h at 25aboutC, then washed with 3 times 30 cm3water and 3 times 30 cm3a saturated solution of sodium chloride. The organic phase is dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The remainder chromatographic on a column of silica gel (grain size distribution of 0.04-0,063 mm, diameter 2.2 cm, height 23 cm) with elution under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (55/45 by volume), collecting fractions 15 cm3. Fractions 7 through 18 are concentrated to dryness under reduced pressure (2.7 kPa) and the residue crystallized in acetonitrile. The crystals are centrifuged, washed with isopropoxide and dried. Obtain 0.21 g of bis-7,7-(3-chlorophenyl)-2-(phenylacetyl)-4-peligrosos-Lona-(3RS, 7aRS), melting at 160aboutC.

The hydrochloride of bis-7,7-(3-chlorophenyl)-4-perhydrosqualene may be PNA-(3aRS, 7aRS) 250 cm31,2-dichloroethane, process 2.8 cm3vinylnorbornene and heated for 16 h under irrigation with phlegm, then concentrate under reduced pressure (2.7 kPa). The remainder chromatographic on a column of silica gel (grain size distribution of 0.04-0,063 mm, diameter 6 cm, height 32 cm) with elution under pressure azta 0.5 bar with a mixture of cyclohexane and ethyl acetate (80/20), collecting fractions of 25 cm3. Fractions 19 to 27 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The resulting substance with the consistency of type "meringue" condense in isopropoxide and the precipitate centrifuged, washed with isopropoxide and dried, resulting in a gain of 6.7 g of bis-7,7-(3-chlorophenyl)-2-vinyloxycarbonyl-4-perhydrophenanthrene-(3RS, 7aRS) in a solid white color.

An NMR spectrum of the proton (DMSO-d6):

2.1 and 2.3 (2 DD broad, 2H, -CH25); 2.7 to 3 (m, 4H, -CH21 and 6); 3,3 (m, 1H, H in 3A); of 3.45 (DD broad, 1H, 1H in 3); to 4.1 (m, 2H, H at 7a, 1H in 3); 4,45 and 4,70 (2D broad, 2H, -CH2from vinyl); 7,05 (DD, 1H, och = vinyl); of 7.2 to 7.7 (m, 8H, aromatic).

Treated with 1.5 g of bis-7,7-(3-chlorophenyl)-2-vinyloxycarbonyl-4-peligroso - indolene-(3RS, 7aRS) by 7.4 cm36 N. solution chloroethanol acid in dioxane is t for 1 hour in a solution of ethanol at 60aboutC, then stirred for 6 h at 25aboutC. the Solution is concentrated to dryness under reduced pressure (2.7 kPa) and the resulting substance with the consistency of type "meringue" condense in isopropoxide. The precipitate centrifuged and washed with isopropoxide, resulting in getting (after drying) 1 g of the hydrochloride of bis-7,7-(3-chlorophenyl)-4-perhydrosqualene.

An NMR spectrum of the proton (DMSO-d6):

2 to 2.4 (m, 2H, -CH25); by 2.55 to 2.9 (m, 2H, -CH26); 3,3 (DD broad, 1H, 1H in 3); 3,5 (m, 1H, H in 3A); 3,85 (d broad, 1H, H-3); 3,95 (m, 1H, H-7a); 7,1 to 7.76 (m, 8H, aromatic).

2-Benzyl-bis-7,7-(3-chlorophenyl)-4-peligrosidad-(3RS, 7aRS) can be obtained as follows.

To a solution containing 26,8 g of bis-4,4-(3-chlorophenyl)-cyclohexanone and 33 cm3N-butoxymethyl-N-trimethylsilylmethylamine 200 cm3anhydrous dichloromethane, was added 15 drops triperoxonane acid. The reaction mixture is brought to the education of phlegmy, then after setting temperature 25aboutWith stirred for 16 h, and after adding 16 g of potassium carbonate is stirred for 15 more minutes After filtration and concentration to dryness under reduced pressure (2.7 kPa), the residue chromatographic on the column with the Yu of cyclohexane and ethyl acetate (75/25 by volume), collecting fractions of 500 cm3. Fractions 12 to 18 are combined and concentrated to dryness under reduced pressure (2.7 kPa), resulting in a gain of 16.2 g of 2-benzyl-bis-7,7-(3-chlorophenyl)-4-perhydro - isoindoline-(3RS, 7aRS) in the form of liquid oil yellow.

An NMR spectrum of the proton (DMSO-d6):

of 1.75 (DDD, 1H) and 2.1 to 2.45 (m, 3H: -CH25 and 6); the 2.7 to 2.9 (m, 4H: CH21 and 3); 3,1 (m, 1H, H in 3A); 3,5 (AB, 2H, -CH2- benzyl); and 3.8 (DD broad, 1H, H-7a); 7.1 to 7.5 (m, 13H, aromatic).

Bis-4,4-(3-chlorophenyl)-cyclohexanone can be obtained as follows.

To a solution containing ratio of 36.9 g of bis-(3-chlorophenyl)-acetaldehyde 200 cm3ethyl ether is added to 11.3 cm3button, then after cooling to 0aboutWith drop by drop add the solution containing 3.1 g of potassium hydroxide in 20 cm3of ethanol. The reaction mixture was stirred for 2 h at 0aboutWith, then for 16 h at 25aboutC, diluted with 100 cm3ethyl acetate and 200 cm3. The aqueous phase is washed with 100 cm3ethyl acetate. The combined organic phases are washed with 3 times 100 cm3a saturated solution of sodium chloride, dried on magnesium sulfate and concentrate under reduced pressure (2.7 kPa). The remainder chromatographic n is nitrogen with a mixture of cyclohexane and ethyl acetate (90/10 by volume). Get to 27.7 g of bis-4,4-(3-chlorophenyl)-cyclohexanone in the form of liquid oil yellow.

An NMR spectrum of the proton (DMSO-d6):

2,3 (DD broad, 2H, -CH25); and 2.7 (DD broad, 2H, -CH26); 6,2 (d, 1H, H in 2); of 7.2 to 7.4 (m, 8H, aromatic); and 7.6 (d, 1H, H-3).

Bis-(3-chlorophenyl)-acetaldehyde can be obtained as follows.

The solution containing 47 g of bis-1,1-(3-chlorophenyl)-2-methoxyethanol (obtained in the reaction of 3-chlorpheniramine with 2 ethoxyethylacetate in tetrahydrofuran) in 44 cm3formic acid, heated for 5 h under irrigation phlegm, cooled and poured to a mixture of 500 cm3a saturated solution of sodium carbonate and 300 cm3ethyl acetate. The organic phase is washed with 3 times 250 cm3water and 200 cm3a saturated solution of sodium chloride, then dried and concentrated under reduced pressure (2.7 kPa), resulting in a gain ratio of 36.9 g of bis-(3-chlorophenyl)-acetaldehyde in the form of liquid oil yellow.

P R I m e R 96. To a cooled to 4aboutWith the solution containing of 2.45 g of the hydrochloride of bis-7,7-(3-chlorophenyl)-4-peligrosos - womb 50 cm3anhydrous dichloromethane, was added 1.1 g (2-dimethylaminophenyl)-acetic acid and 0.09 g of 1-hydroxybenzotriazole - diimide 100 cm3anhydrous dichloromethane. The reaction mixture was stirred for 5 h at 0aboutWith, then for 16 h at 25aboutC and washed 2 times with 250 cm3water and 250 cm3a saturated solution of sodium chloride. The organic phase is dried on magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The remainder chromatographic on a column of silica gel (grain size distribution of 0.04-0,063 mm, diameter 3 cm, height 22 cm) with elution under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (55/45 by volume), collecting fractions of 20 cm3. Fractions 13 to 24 are combined and concentrated to dryness under reduced pressure (2.7 kPa), resulting in a gain of 2.3 g of bis-7,7-(3-chlorophenyl)-2-(2-dimethylaminophenyl)-acetyl-4-purged - roseingrave-(3RS , 7aRS), from which the hydrochloride by dissolving in 2 cm3ethyl acetate and adding 3 n hydrochloric acid solution in isopropoxide. The precipitate centrifuged, washed with isopropoxide and dried. Gain of 1.94 g of the hydrochloride of bis-7,7-(3-chlorophenyl)-2-(2-dimethylaminophenyl)-ACE-Tyl-4-perhydrosqualene (3aRS, 7aRS) in a solid white color.

An NMR spectrum of the proton (DMSO-d6/MES 90/10).

At room temperature, see the mixture of two BP>and H in 3A); 3,7 (m, 1H, 1H in 3); 4 (m, 3H, H-7a and-CH2CO); and 4,4 4,2 (2D, 1H, 1H in 3); and 7.1 to 7.8 (m, N aromatic).

P R I m e R 97. Cooled to 4aboutWith a suspension consisting of 1.5 g of the hydrochloride of bis-7,7-(3-tolyl)-4-perhydrosqualene- (3RS, 7aRS) 30 cm3dichloromethane, is treated first 1,15 cm3of triethylamine, then 0,63 g phenylacetylide. The reaction mixture was stirred for 5 h at 25aboutC, then washed with 3 times 100 cm3water. The organic phase is dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized 2 times in acetonitrile, resulting in a gain of 0.36 g of bis-7,7-(3-tolyl)-2-(phenylacetyl)-4-peligroso - indolene-(3RS, 7aRS), melting at 207aboutC.

The hydrochloride of bis-7,7-(3-tolyl)-4-peligrosidad can be obtained as follows.

A solution containing of 13.7 g of 2-benzyl-bis-7,7-(3-tolyl)-4-perhydrosqualene- (3RS, 7aRS) 150 cm31,2-dichloroethane, processed 3,7 cm3vinylchloride and heated for 3 h under irrigation with phlegm, then concentrated under pony leaders introduce pressure (2.7 kPa). The remainder chromatographic on silica gel (grain size distribution of 0.04-0,063 mm column with a diameter of 5.4 cm and a height of 39 cm) when eleirovania is described to dryness under reduced pressure (2.7 kPa), resulting in a gain of 7.4 g of bis-7,7-(3-tolyl)-2-vinyloxycarbonyl-4-peligroso - indolene-(3RS, 7aRS) in the form of a substance of white color with the consistency of type "meringue".

An NMR spectrum of the proton (DMSO-d6/MES 90/10).

At ordinary temperature see a mixture of 2 rotational isomers.

of 1.95 to 2.4 (m, 2H, -CH25); 2,27 and 2,32 (2C, 6N, ArCH3); 2,4 to 2.95 (m, 4H, -CH21 and 6); 3.2 to 3.5 (m, 2H, H in 3A and 1H in 3); a 4.03 (m, 1H, H-7a); 4.09 to and 4,16 (2D broad, 1H, H-3); 4,35 to 4,85 (4D broad, 2H, -CH2from vinyl); 6.9-7.5 (m, N, aromatic and base - from vinyl).

Treated with 7.4 g of bis-7,7-(3-tolyl)-2-vinyloxycarbonyl-4-perhydrosqualene-(3RS, 7aRS) through 39 cm36 N. RAS down chloroethanol acid in dioxane for 30 min at 25aboutC. the Solution is concentrated to dryness under reduced pressure (2.7 kPa) and the residue is extracted by 100 cm3of ethanol. The solution was heated at 60aboutWith over 2 hours and stirred for 16 h at 25aboutWith, then concentrated to dryness under reduced pressure (2.7 kPa). The residue is compacted by isopropoxide, the solid is washed, centrifuged and dried. Get 6,36 g of the hydrochloride of bis-7,7-(3-tolyl)-4-perhydrosqualene in the form of solid substances is - 5); 2,24 and 2.3 (2C, 6N, Agsn3); 2.4 to 2.9 (m, -CH26 and 1); 3,3 (DD broad, 1H, 1H in 3); of 3.48 (m, 1H, H in 3A); 3,85 (d broad, 1H, 1H in 3); 3,90 (m, 1H, H-7a); of 6.9 to 7.4 (m, 8H, aromatic).

2-Benzyl-bis-7,7-(3-tolyl)-4-perhydro - isoindole-(3RS, 7aRS) can be obtained as follows.

To a solution containing 16.7 g of bis-4,4-(3-tolyl)-cyclohexanone and 18.7 cm3N-butoxymethyl-N-trimethylsilylmethylamine 150 cm3anhydrous dichloromethane, add 12 drops triperoxonane acid. The reaction mixture is brought to the education of phlegmy, then stirred for 3 h, returning to a temperature of 25aboutFrom and after addition of 12 g of potassium carbonate is stirred for another 10 minutes After filtration and concentration to dryness under reduced pressure (2.7 kPa), the residue chromatographically on a column of silica gel (grain size distribution of 0.04-0,063 mm, diameter 5 cm, height 50 cm) with elution under nitrogen pressure of 0.7 bar with a mixture of cyclohexane and ethyl acetate (85/15 by volume), collecting fractions of 25 cm3. Fractions 14 to 30 are combined and concentrated to dryness under reduced pressure (2.7 kPa), resulting in a gain of 13.9 g of 2-benzyl-bis-7,7-(3-tolyl)-4-perhydrosqualene-(3RS, 7aRS) in the form of white crystals (in the form of colorless idcon, ArCH3); 2.5 to 3,05 (m, 4H, -CH21 and 3); 3,2 (m, 1H, H in 3A); 3,45 & 3.65 (AB, 2H, -CH2-, Ar); 3,7 (m, 1H, H-7a); of 6.9 to 7.4 (mm, 13H, aromatic).

Bis-4,4-(3-tolyl)-cyclohexene can be obtained as follows.

To a solution containing 20.4 g of bis-(3-tolyl)-acetaldehyde 110 cm3ethyl ether is added of 7.23 cm3button, then after cooling to 0aboutWith added dropwise a solution containing 2 g of potassium hydroxide in 12.7 cm3of ethanol. The reaction mixture was stirred for 2 h at 0aboutWith, then for 16 h at 25aboutC, diluted with 200 cm3ethyl acetate and 200 cm3water. The aqueous phase is washed 2 times with 250 cm3ethyl acetate. The combined organic phases are washed 2 times with 250 cm3water, then 250 cm3a saturated solution of sodium chloride, dried on magnesium sulfate and concentrated under reduced pressure (2.7 kPa). The remainder chromatographies on silica gel (grain size distribution of 0.04 - 0,063 mm column with a diameter of 5.4 cm and height 40 cm) with elution under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (85/15 by volume). Obtain 16.7 g of bis-4,4-(3-tolyl)-cyclohexanone in the form of liquid oil yellow.

Bis-(3-tolyl)-acetaldehyde can byt the reaction of 3-wellmannered with 2 ethoxyethylacetate in tetrahydrofuran) in 30 cm3formic acid is heated for 12 h under irrigation phlegm, cooled and prilisaetsa to a mixture of 400 cm3a saturated solution of sodium carbonate and 400 cm3ethyl acetate. The organic phase is washed 3 times with 300 cm3water and 300 cm3a saturated solution of sodium chloride, then dried and concentrated to dryness under reduced pressure (2.7 kPa), resulting in a gain 20,45 g of bis-(3-tolyl)-acetaldehyde in the form of liquid oil yellow.

P R I m e R 98. A solution containing 25 g of 4,4-diphenyl-2-cyclohexen-1-she of 1.65 g of Tris-1,3,5-trimethylsilylmethyl-1,3,5-triazine 17 cm31,1,2-trichloroethane, is treated with a solution containing 1.8 g phenylacetylglutamine 5 cm31,1,2-trichloroethane, and then heated at 120aboutC for 22 hours, the Reaction mixture is diluted with 100 cm3dichloromethane, washed with 100 cm3a saturated solution of sodium bicarbonate and 100 cm3a saturated solution of sodium chloride, dried on magnesium sulfate, then concentrated to dryness under reduced pressure (2.7 kPa). The remainder chromatographically on a column of silica gel (0,2-0,063 mm, diameter 3 cm, height 27 cm) with elution with a mixture of cyclohexane and ethyl acetate (90/10 by volume), collecting fractions of 35 cmaboutC.

Tris-1,3,5-trimethylsilylmethyl-1,3,5-tri - Azin can be obtained according to the method described by T. Morimoto, Y. Meru et K. Achiwa, Chem. Pharm. Bull. , 33, 4596 (1985).

Phenylacetylene can be obtained by the method of G. Olah. , S. Kuhn et S. Beke, Chem. Ber. , 89, 862 (1956).

P R I m e R 99. To a solution containing 1.3 g of 2-[(2-hydroxyphenyl)-acetyl] -7,7-diphenyl-4-perhydrosqualene-(3RS, 7aRS) 26 cm3butanone and 1.3 cm3of dimethylformamide, are added to 0.34 cm3isopropylidene and 0,89 g of potassium carbonate. Heated for 6 h under irrigation with phlegm, then cooled to room temperature. The solid is removed by filtration and washed with 2 times 10 cm3butanone. The organic fractions are collected, dried on magnesium sulfate and concentrated under reduced pressure. The remainder chromatographically on a column of 150 g of silica gel with elution with a mixture of cyclohexane and ethyl acetate (80/20 by volume). The residue is extracted by 5 cm3of methylene chloride and 5 cm3water. The organic phase is decanted, washed with 2 times 5 cm, dried on magnesium sulfate and evaporated under reduced pressure. The residue is crystallized in 50 cm3petroleum ether (CTF. 4 is 2[(2-isopropoxyphenyl)-acetyl] -7,7-diphenyl-4-peligrosos - Dolon-(3RS, 7aRS) in the form of white crystals, melting at 177aboutC.

P R I m e R 100. To a suspension consisting of 0.26 g of sodium hydride (50% dispersion in liquid oil) in 3 cm3toluene, was added 2.1 g of 2-[(2-hydroxyphenyl)-acetyl] -7,7-diphenyl-4-perhydrosqualene-(3RS, 7aRS) and stirred for 30 min at 50aboutC. Cooled to 25aboutThe solution is treated with a solution of N, N-dimethyl-2-chloroethylamine 4 cm3anhydrous toluene (obtained by decomposition of 2.16 g of the corresponding hydrochloride by the action of potassium hydroxide). The reaction mixture is heated for 21 h under irrigation with phlegm, then processed 0,35 cm3acetic acid, diluted with 20 cm3water and 20 cm3ethyl acetate. The organic phase is extracted 2 times 30 cm30,2 N. solution chloroethanol acid. The aqueous phase with an acidic washed with ethyl acetate, podslushivaet addition of 25 cm31 n sodium hydroxide solution and again extracted with ethyl acetate. The organic phase is washed with water until neutral, dried on magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). After chromatography was carried out on a column of 100 g of silica gel (0.2 to 0,045 mm), while elution with a mixture of tone ether and dried. Get to 0.47 g of 2-[2-(2-dimethylaminoethoxy)-phenylacetyl] -7,7-diphenyl-4-perhydrosqualene - 3aRS, 7aRS), melting at 90aboutC.

P R I m e R 101. To a solution containing 2.1 g of 2-[(2-hydroxyphenyl)-acetyl] -7,7-diphenyl-4-perhydrosqualene-(3RS, 7aRS) 20 cm3toluene, was added 0.18 g of sodium hydride (80% dispersion in liquid oil) and stirred for 30 min at 20aboutC. the Suspension is treated with a solution of N, N-dimethyl-3-chloropropylamine. 20 cm3anhydrous toluene (obtained by decomposition of 2.3 g of the corresponding hydrochloride by the action of potassium hydroxide). The reaction mixture is heated for 16 hours under irrigation with phlegm, then treated with 0.5 cm3acetic acid, diluted with 20 cm3water and 50 cm3ethyl acetate. The organic phase is extracted 2 times 25 cm30,2 N. solution chloroethanol acid. The aqueous phase, having an acid reaction, washed with ethyl acetate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is dissolved in 20 cm3ethyl acetate and treated with 1.2 cm33M solution chloroethanol acid in anhydrous dioxane. The expected product precipitates in the form of contaminated hydrochloride. This solid Westem 0.1 N. the sodium hydroxide solution and extracted with ethyl acetate. The aqueous phase is extracted with ethyl acetate. The resulting organic phase is dried on magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The product obtained in the form of the base, is converted into hydrochloride by dissolving in 10 cm3ethyl acetate at 0.5 cm3solution (SM) chloroethanol acid in anhydrous dioxane.

Obtain 0.45 g of the hydrochloride of 2-[2-(3-dimethylaminopropoxy)-phenyl-acetyl] -7,7-diphenyl-4-peligrosidad and-(3RS, 7aRS) in a solid yellow color.

An NMR spectrum of the proton:

of 2.0 to 2.35 (MT, 4H, -CH2- a 5 or 6 and CH2the Central 3-dimethylaminopropoxy); 2.65 to 3 (MT, -CH26 or 5 and CH2- 1); and 2.83 (s, -N(CH3)2); the 3.2 to 3.4 (MT, 3H, -CH - 3A-N-CH2-); 3,4, the 3.65 (MT, 3H, -N-CO-CH2- and 1H-CH23); of 3.9 to 4.5 (MT, 3H, -CH, - 7a,- O-CH2-); to 4.28 (D, J = 11 HZ, 1H, 1H from-CH2- 3); 6,8 to 7.65 (MT, 14N, aromatic).

Characteristic bands (cm-1) infra-red spectrum (KBR):

3600-3250, 3100-3000, 3000-2850, 2750, 2250, 1715, 1640, 1600, 1495, 1475, 1455, 1440, 1245, 1050, 755, 705.

P R I m e R 102. To a suspension consisting of 0.32 g of sodium hydride (50% dispersion in liquid oil) in 10 cm the 25aboutTo add a solution of 1-(4-methyl-1-piperazinil)-2-chlorethane 10 cm3anhydrous toluene (obtained by the decomposition of 1.14 g of the corresponding dichlorhydrate under the action of potassium hydroxide). The reaction mixture is heated for 18 h under irrigation with phlegm, then processed 20 cm3water and 30 cm3ethyl acetate. The aqueous phase is extracted with 10 cm3ethyl acetate and the combined organic phases are washed with water until neutral, dried on sodium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is washed with petroleum ether, then dissolved in a mixture of ethyl acetate and diluted methansulfonate (pH 2). The organic phase is washed with water, aqueous phase, having an acid reaction, are combined and are washed with ethyl acetate, neutralized by adding 1 n sodium hydroxide solution. The extraction is carried out with ethyl acetate, then washed the organic phase with water, dried on sodium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). After chromatography was carried out on a column of 50 g of silica gel (0.2 to 0,045 m) for elution with a mixture of toluene and diethylamine (90/10 by volume) allocate 0.6 g of the expected product, which is pounded into a powder in 15 cmabout
C.

Hydrochloride of 1-(4-methyl-1-piperazinil)-2-chlorethane receive according to G. Emptoz et coll. , Chim. Ther. , 4 (4), 283 (1969).

P R I m e R 103. Carrying out the reaction as in example 102, but on the basis of 7,7-diphenyl-2-(2-hydroxyphenylacetic)-4-peligrosos - Dolon-(3aRS, 7aRS) and 1-benzyloxy-2-chlorethane receive 0.5 g of 7,7-diphenyl-2-{ 2-[2-(2-hydroxyethoxy)-phenyl] -2-acetyl} -4-peligrosidad and-(3RS, 7aRS) in the form of white crystals, melting at 150aboutC.

P R I m e R 104. To a stirred suspension consisting of 1.6 g of the hydrochloride of 7,7-diphenyl-4-perhydrosqualene-(3RS, 7aRS) 40 cm31,2-dichloroethane, was added 1.2 g of bromhidrosis of phenylacetamide ethyl and 1.4 cm3of triethylamine. The reaction mixture was stirred for 20 h at room temperature, then for 6 h under irrigation by phlegm. After returning to room temperature, the reaction mixture is treated with 50 cm3saturated aqueous potassium carbonate solution; the organic phase is dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in 20 cm3acetonitrile. The obtained crystals centrifugeuse and dried. Obtain 0.9 g of 2-(-aminophenethyl)-7,7-diphenyl-4-lane - gel obtained according to the method described by D. J. Morgan, Chem. and Ind. 854 (1959).

P R I m e R 105. To a stirred suspension consisting of 6.6 g of 2-(2-methoxyphenyl)-ndimethylacetamide 20 cm3anhydrous dichloromethane, was added to 8.4 g of tetrafluoroborate triethyloxonium. The reaction mixture was stirred for 20 h at room temperature. It is cooled to 5aboutWith, then add a solution containing 9.8 g of the hydrochloride of 7,7-diphenyl-4-perhydrosqualene-(3RS, 7aRS) and 10.4 cm3of triethylamine in 60 cm3dichloromethane. After returning to room temperature, the reaction mixture is heated for 4 h under irrigation by phlegm. She further processed (after returning to room temperature) 40 cm310% aqueous potassium carbonate solution. The organic phase is washed with 20 cm3distilled water, dried on magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in 20 cm3acetonitrile, and the resulting crystals centrifugeuse, washed with 5 cm3acetonitrile, 10 cm3isopropoxide and dried. Crystals precrystallization 45 cm3acetonitrile, and the resulting crystals centrifugeuse and dried. Obtain 3.8 g of 2-[1-imino-2-(2-methoxyphenyl)-ethyl] -7,7-diphenyl-4-lane is CLASS="ptx2">

2-(2-Methoxyphenyl)-ndimethylacetamide can be obtained according to the method described by V. S. Seh. , S. S. Desnapande, J. Indian Chem. Soc. , 27, 429 (1950).

P R I m e R 106. Suspension consisting of 0.9 g (2-methoxyphenyl)-ndimethylacetamide 3 cm3anhydrous dichloromethane is treated 1,14 g tetrafluoroborate triethyloxonium and the resulting solution was stirred for 20 h at 25aboutC. After cooling to 0aboutTo add to the reaction medium solution containing 1.5 g of the hydrochloride of bis-7,7-(3-forfinal)-4-perhydrosqualene and 1.4 cm3of triethylamine in 9 cm3dichloromethane. The reaction mixture was stirred for 30 min at 25aboutC, then heated under irrigation by phlegm for 5 hours and finally stirred for 16 h at 25aboutC. Add 50 cm3saturated solution of potassium bicarbonate, stirred, filtered and the organic phase is washed with 2 times 50 cm3water. After drying on magnesium sulfate, filtering and concentrating to dryness under reduced pressure (2.7 kPa), the residue chromatographically on column alumoweld (diameter 2.6 cm, height 24 cm) with elution under a nitrogen pressure of 0.5 bar with a mixture of 1,2-dichloroethane and methanol (95/5 by volume), collecting fractions 15 cm3. Fractions 7 to 25 are combined and conco-2-(2-methoxyphenyl)-ethyl] -4-peligrosamente she is(3RS, 7aRS) in the form of substances pale yellow color with a consistency of type "meringue".

An NMR spectrum of protons (l3):

of 2.20 and 2.45 (2m, 2H, -CH25); 2,8 (m, 2H, -CH26); is 3.08 (m, 2H, -CH2- 1); 3,23 (m, 1H, H in 3A). of 3.53 (DD, J = 11 and 6.5, 1H, 1H from-CH2- 3); and 3.6 (s, 2H, -CH2-Ar); and 3.8 (m, 1H, H-7a); and 3.8 (s, 3H, och3); 4,43 (d, J = 11, 1H, 1H from-CH2- 3); 6.8 to 7.5 (m, 14N, aromatic).

Infra-red spectrum (characteristic bands):

3425, 3100-3000, 3000-2850, 2835, 1715, 1592, 1610, 1595, 1460, 1250, 1030, 780, 755, 695.

P R I m e R 107. To a stirred suspension consisting of the 5.4 g of 2-[2-methoxyphenyl)-propionamide-(RS) 60 cm3anhydrous dichloromethane, was added 6,34 g tetrafluoroborate triethyloxonium. The reaction mixture is stirred for 20 hours Add a solution containing of 6.65 g of the hydrochloride of 7,7-diphenyl-4-perhydrosqualene-(3RS, 7aRS) and 2.8 cm3of triethylamine in 30 cm3dichloromethane. The reaction mixture is heated for 5 hours under irrigation by phlegm. Then it is cooled to 5aboutWith and handled by 20 cm310% aqueous potassium carbonate solution. After filtration the organic phase is washed with 20 cm3distilled water, dried on magnesium sulfate and concentrated to dryness under reduced davleniya the elution with a mixture of cyclohexane and ethyl acetate (50/50), collecting fractions of 250 cm3. The first fraction is concentrated to dryness under reduced pressure (2.7 kPa). The remainder chromatographically on a column of silica gel (0.04 mm - 0.06 mm, diameter 2 cm, height 35 cm) with elution with a mixture of n-butanol (acetic acid) pyridine/water (90/4/4/2 by volume), collecting fractions of 20 cm3. Fractions 14 to 19 are concentrated to dryness under reduced pressure (0,13 kPa). The residue is extracted by 40 cm3dichloroethane and washed with 10 cm3an aqueous solution of potassium carbonate. The organic phase is dried on magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue crystallizes in diisopropoxide. Crystals centrifugeuse, dried under reduced pressure (0,13 kPa).

Obtain 0.12 g of 2-[1-imino-2-(2-methoxyphenyl)-2-methyl-ethyl] -7,7-diphenyl-4-lane - hydroisoquinoline-(3aR, 7aR) form And in the form of a substance of white color with the consistency of type "meringue".

An NMR spectrum of protons (Cl3, 323 K):

of 1.34 (D, J = 7, 3H); 2.05 is to 2.45 (m, 2H, 2H 5); 2.7 to 3 (m, 4H, 2H, 6 and 2N 1); 3,2 (m, 1H, 1H in 3); to 3.58 (DD, J = 11 and 7, 1H from-CH2- 3); 3,7 (S, 3H, -och3); of 3.75 (m, 1H, H-7a); Android 4.04 (Q, J = 7, 1H, Ar-CH-CH3); 4,37 (D, J = 11, 1H, 1H from-CH23); of 6.7 to 7.6 (m, 14N, aromatic).

ptx2">

P R I m e R 108. Carrying out the reaction as described in example 107 to receive the form, And receive, from the United khromatograficheskikh fractions from 21 to 30, 0.1 g of 2-[1-imino-2-(2-methoxyphenyl)-2-methylethyl] -7,7-diphenyl-4-peligrosidad -(3R, 7aR) form, in the form of a substance of white color with the consistency of type "meringue".

An NMR spectrum of protons (l3, 333 K):

of 2.20 (m, 1H, 1H from-CH25); of 2.45 (m, 1H, 1H from-CH25); 2,8 (m, 2H, -CH26); is 3.08 (m, 2H, -CH2" 1); 3,23 (m, 1H, 1H in 3); of 3.53 (DD, J = 11 and 6.5, 1H, 1H from-CH2- 3); and 3.6 (S, 3H, -och3); 4,43 (D, J = 11, 1H, 1H in 7a/; 3,8/C, 3H, -OCH3/; 4,43 /D, I= 11, 1H,- CH2- 3); 6,78 to 7.5 (m, 14N, aromatic).

Infra-red spectrum: bands of identical bands form A.

2-(2-Methoxyphenyl)-propionamide-(RS) can be obtained as follows.

To a cooled to 5aboutWith the solution containing 17.5 g of 2-(2-methoxyphenyl)-propionic acid in 200 cm3anhydrous dichloromethane, was added 16.2 g of N, N'-carbonyldiimidazole. Stirred for 30 min at 5aboutWith, then passed through a solution of a stream of ammonia for 1 h, maintaining the same temperature. The reaction mixture after stirring for 2 h at 20about(C) washed with 200 cm3water, dried on propylamide, crystals centrifugeuse, dried under reduced pressure (2.7 kPa). Get to 12.1 g of 2-(2-methoxyphenyl)-propionamide (RS) in a solid white color, melting at 138aboutC.

2-(2-Methoxyphenyl)-propionic acid (RS) can be obtained as follows.

To a cooled to 10aboutWith the solution containing 45,5 cm3Diisopropylamine 250 cm3tetrahydrofuran (THF) was added over 20 min 20 cm3a 1.6 M solution of n-utility in tetrahydrofuran. After stirring for 10 min the mixture is brought to 0aboutWith and added over 20 min a solution of 2-(2-methoxyphenyl)-acetic acid in 100 cm3tetrahydrofuran (THF). After 30 min at 35aboutTo add 10 cm3under the conditions and stirred for 1 h at 35aboutC. the Reaction mixture is added to 150 cm3water, diluted with ethyl acetate. The aqueous phase is separated, acidified adding 4 n solution chloroethanol acid, then extracted 2 times with 100 cm3ethyl acetate. The organic phase is dried on magnesium sulfate, concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in 100 cm3isopropoxide, crystals centrifugeuse, dried under reduced pressure (2.7 kPa).

aboutC.

P R I m e R 109. To mix the solution containing 5.2 g of N-(2-thienyl)-methyl-2-(2-methoxyphenyl)-ndimethylacetamide 50 cm3anhydrous dichloromethane, was added 4 g of tetrafluoroborate triethyloxonium. The reaction mixture was stirred for 7 h at room temperature. It is cooled to 5aboutWith, then add a solution containing 4.6 g of the hydrochloride of 7,7-diphenyl-4-perhydrosqualene-(3R, 7aR) and 5 cm3of triethylamine in 50 cm3dichloromethane. Next, the reaction mixture was stirred at room temperature for 20 h, then heated for 1 h under irrigation by phlegm. She further processed (after returning to room temperature) 100 cm310% aqueous potassium carbonate solution; the organic phase is washed with 40 cm3distilled water, dried on magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The remainder chromatographically on a column of neutral alumoweld Pechiney SVT 1 (diameter 5 cm, height 40 cm) with elution with a mixture of cyclohexane and ethyl acetate (50/50 by volume), collecting fractions of 100 cm3. Fractions 4 to 13 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized in 20 cm3isopropyl 2-[2-(2-methoxyphenyl)-(2-thienylmethyl)-1-aminoethyl] -7,7-diphenyl-4-perhydro indolene-(3R, 7aR), melting at 88aboutC.

()D20= -170about(C = 1, methanol).

N-(2-Thienyl)-methyl-2-(2-methoxyphenyl)-ndimethylacetamide can be obtained in the following way:

To a stirred and cooled to 5aboutWith the solution containing of 8.3 g of 2-(2-methoxyphenyl)-acetic acid in 80 cm3anhydrous dichloromethane, was added 8.1 g of N, N'-carbonyldiimidazole; the reaction mixture is stirred for one and a half hours, then add 5.1 cm3(2-thienyl)-methylamine. The reaction mixture was stirred for 1 h at 5aboutC, then for 2 h at room temperature. She then washed with 40 cm3distilled water (2 times); the organic solution is dried on magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The obtained solid residue is washed with 30 cm3isopropoxide, centrifuged and dried. Receive a 10.5 g of N-(2-thienyl)-methyl-2-(2-methoxyphenyl)-ndimethylacetamide, melting at 84aboutC.

P R I m e R s 110-136. Carrying out the reaction as described above in example 4, on the basis of 7,7-diphenyl-2-phenylacetyl-4-peligrosamente-(3RS, 7aRS) or (3aR, 7aR), 7,7-diphenyl-(2-forfinal)-2-acetyl-4-purged - roseingrave-(3RS, 7aRS) or 7,7-diphenyl-(2-methoxyphenyl)-2-acetyl-4-perger the m e R 137. Carrying out the reaction as described in example 104 based on the hydrochloride 7,7-diphenyl-4-perhydrosqualene-(3R, 7aR) receive 7,7-diphenyl-2-[1-imino-2-(2-dimethylaminophenyl)-ethyl] -4-peligroso - indolo-(3R, 7aR), melting at 188aboutWith the release of 55% .

The invention also concerns pharmaceutical compositions (formulations), formed by the product with the General formula (1) or salt, when they exist, if necessary in combination with any other pharmaceutically acceptable product, which can be inert or physiologically active. Compositions according to the invention can be used for parenteral, oral, rectal, or local path.

Sterile compositions for parenteral administration, which can especially be applied in the form of injections (injections) are predominantly aqueous or nonaqueous solutions, suspensions or emulsions. As a solvent or carrier, you can use water, propylene glycol, polyethylene glycol, liquid vegetable oils, especially olive oil, capable of injection of organic esters, for example etiloleat, or other suitable organic solvents. These compositions can also contain additives, especially Simachev the change in several ways, for example, by filtration under aseptic conditions, the introduction into the composition of sterilizing agents, training or heating. They can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in sterile injectable medium.

Compositions for rectal injection are candles or rectal capsules, which in addition to the active product contain indifferent substances such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.

As solid compositions for oral administration may be tablets, pills, powders or granules. In these compositions, the active product according to the invention (if necessary in combination with other pharmaceutically acceptable product) is mixed with one or more diluents or inert additives, such as sucrose, lactose or starch. These compositions can also comprise substances other than diluents, for example, a lubricating substance, such as magnesium stearate.

As liquid compositions for oral administration, can be used pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs, soderjaschihsya from diluents, for example wetting, sweetening or flavouring products.

Compositions for topical application may be, for example, creams, lipstick or lotions.

In human therapy, the products according to the invention can be particularly useful in the treatment of traumatic pain, after surgery, menstrual cramps, brain origin, in the treatment of anxiety, psychoses, Parkinson's disease, schizophrenia, Alzeimer disease, in the treatment of muscle relaxants in the treatment spasmodically, painful and inflammatory manifestations of the digestive tract (colitis, ulcerative syndrome irritation of the colon, Crohn's disease), urinary tract (cystitis) and respiratory tract (asthma, rhinitis) or in gynecology and in the treatment of migraine headaches. New derivatives of isoindoline also useful in the treatment of rheumatic arthritis and disorders caused by disorders of the immune system in the treatment of inflammation in dermatology, such as psoriasis, herpes, nettle fever, eczema, photo, and in the treatment of eye and dental inflammation.

The products according to the invention may also find application in the treatment of cardiovascular disorders such as hypotension.

Doses depend on the study aprimo.

In General, the physician will determine the dosage which he deems most appropriate, depending on age, weight and all other factors peculiar to the subject of treatment.

The following example is given as a non-limiting, illustrates a composition according to the invention.

P R I m e R 138. Prepared in accordance with the usual technique of tablets of active product having the following composition mg:

2-[1-Imino-2-(2-methoxy-

phenyl)-ethyl] -7,7-diphenyl-

4-peligrosidad- (3R, 7aR) 25 Starch 83 Silica 30 magnesium Stearate 3

Derivatives isoindoline General formula

NR3< / BR>
where both R1is hydrogen or together form a bond;

both R2is phenyl which may be substituted in position 2 or 3 halogen or stands;

R3is phenyl which may be substituted, if necessary, by one or more radicals such as halogen, hydroxyl, alkyl (which may be substituted with halogen, amine or alkylamine), alkoxy, alkylthio (which may be substituted by hydroxyl, dialkylamino or 4-methylpiperazine), Amin, alkylamino, dialkylamino, 1-pyrrolidinyl, cyclohexadienyl, naphthyl, thienyl, dithienyl, pyridyl or indolyl;

R
X is oxygen, sulfur or a radical NR5where R5is hydrogen, C1- C12-alkyl optionally substituted by one or two radicals, such as carboxy, dialkylamino, acylamino, allyloxycarbonyl, allyloxycarbonyl, carbamyl, allylcarbamate, diallylbarbital (and the alkyl portions of these radicals can be dialkylamino or phenyl substituent), phenyl, halogen, alkyl, alkyloxy or dialkylaminomethyl phenyl, naphthyl, thienyl, furyl, pyridinyl or imidazolyl, or dialkylamino,

moreover, these alkyl and acyl radicals, if not otherwise indicated, are straight or branched and contain 1 to 4 carbon atoms,

in the form (3R, 7R) or (3RS, 7RS)-forms or their mixtures or their hydrochloride, which are antagonists of substance P.

 

Same patents:

The invention relates to the chemistry of condensed heterocyclic systems and specifically relates to new compounds - 4-acetyl-3-benzyl-2-methylthiopyridine(4,5-b)indole of the formula I

< / BR>
Through the study of its biological activity is established that it has the property to protect the liver from carbon tetrachloride poisoning

The invention relates to new derivatives of 2-(21-cyano-31-dialkylamino-21- enylidene)indolinone-3 of the General formula I

(I) where R= R1= CH3(Ia),

R + R1= (CH2)5(IB) having antihypertensive activity

The invention relates to medicine, namely to obstetrics

FIELD: medicine.

SUBSTANCE: method involves introducing 0.1-0.3 ml of photosensitizing gel preliminarily activated with laser radiation, after having removed neovascular membrane. The photosensitizing gel is based on a viscoelastic of hyaluronic acid containing khlorin, selected from group containing photolon, radachlorine or photoditazine in the amount of 0.1-2% by mass. The photosensitizing gel is in vitro activated with laser radiation having wavelength of 661-666 nm during 3-10 min with total radiation dose being equal to 100-600 J/cm2. The gel is introduced immediately after being activated. To compress the retina, vitreous cavity is filled with perfluororganic compound or air to be further substituted with silicon oil. The operation is ended with placing sutures on sclerotomy and conjunctiva areas. Compounds like chealon, viscoate or hyatulon are used as viscoelastic based on hyaluronic acid. Perfluormetylcyclohexylperidin, perfluortributylamine or perfluorpolyester or like are used as the perfluororganic compound for filling vitreous cavity.

EFFECT: excluded recurrences of surgically removed neovascular membrane and development of proliferative retinopathy and retina detachment; retained vision function.

3 cl, 5 dwg

FIELD: medicine.

SUBSTANCE: method involves making incision in conjunctiva and Tenon's capsule of 3-4 mm in size in choroid hemangioma projection to sclera 3-4 mm far from limb. Tunnel is built between sclera and Tenon's capsule to extrasclerally introduce flexible polymer magnetolaser implant through the tunnel to the place, the choroid hemangioma is localized, after performing transscleral diaphanoscopic adjustment of choroid hemangioma localization and size, under visual control using guidance beam. The implant has permanent ring-shaped magnet in the center of which a short focus scattering lens of laser radiator is fixed. The lens is connected to light guide in soft flexible envelope. The permanent implant magnet is axially magnetized and produces permanent magnetic field of 2-3 mTesla units intensity. It is arranged with its north pole turned towards the choroid hemangioma so that extrascleral implant laser radiator disposition. The other end of the implant is sutured to sclera 5-6 mm far from the limb with two interrupted sutures through prefabricated openings. The implant is covered with conjunctiva and relaxation sutures are placed over it. Light guide outlet is attached to temple using any known method. 0.1-1% khlorin solution is injected in intravenous bolus dose of 0.8-1.1 mg/kg as photosensitizer and visual control of choroid hemangioma cells fluorescence and fluorescent diagnosis methods are applied. After saturating choroid hemangioma with the photosensitizer to maximum level, transscleral choroid hemangioma laser radiation treatment is carried out via laser light guide and implant lens using divergent laser radiation at wavelength of 661-666 nm with total radiation dose being equal to 30-120 J/cm2. The flexible polymer magnetolaser implant is removed and sutures are placed on conjunctiva. Permanent magnet of the flexible polymer magnetolaser implant is manufactured from samarium-cobalt, samarium-iron-nitrogen or neodymium-iron-boron system material. The photosensitizer is repeatedly intravenously introduced at the same dose in 2-3 days after the first laser radiation treatment. Visual intraocular neoplasm cells fluorescence control is carried out using fluorescent diagnosis techniques. Maximum level of saturation with the photosensitizer being achieved in the intraocular neoplasm, repeated laser irradiation of the choroid hemangioma is carried out with radiation dose of 30-60 J/cm2.

EFFECT: enhanced effectiveness of treatment.

4 cl

FIELD: medicine.

SUBSTANCE: method involves creating tunnel between sclera and Tenon's capsule in intraocular neoplasm projection. Intraocular neoplasm localization and size is adjusted by applying transscleral diaphanoscopic examination method. 0.1-0.3 ml of photosensitizing gel based on viscoelastic of hyaluronic acid, selected from group containing chealon, viscoate or hyatulon, is transsclerally introduced into intraocular neoplasm structure using special purpose needle in dosed manner. The photosensitizing gel contains khlorin, selected from group containing photolon, radachlorine or photoditazine in the amount of 0.1-1% by mass. Flexible polymer magnetolaser implant is extrasclerally introduced into the built tunnel in intraocular neoplasm projection zone under visual control using guidance beam. The implant has permanent ring-shaped magnet axially magnetized and producing permanent magnetic field of 3-4 mTesla units intensity, in the center of which a short focus scattering lens of laser radiator is fixed. The lens is connected to light guide in soft flexible envelope. The implant is arranged with its north pole turned towards the intraocular neoplasm so that implant laser radiator lens is extrasclerally arranged in intraocular neoplasm projection zone. The implant light guide is sutured to sclera 5-6 mm far from the limb with single interrupted suture. The implant is covered with conjunctiva and relaxation sutures are placed over it. Light guide outlet is attached to temple using any known method. Visual control of intraocular neoplasm cells is carried out by applying fluorescence and fluorescent diagnosis methods. After saturating the intraocular neoplasm with the photosensitizer to maximum saturation level, transscleral intraocular neoplasm laser radiation treatment is carried out via laser light guide and implant lens using divergent laser radiation at wavelength of 661-666 nm. The treatment course being over, the flexible polymer magnetolaser implant is removed and sutures are placed on conjunctiva. Permanent magnet of the flexible polymer magnetolaser implant is manufactured from samarium-cobalt, neodymium-iron-boron or samarium-iron-nitrogen. 0.1-1% khlorin solution as photosensitizer, selected from group containing photolon, radachlorine or photoditazine, is additionally intravenously introduced in 2-3 days at a dose of 0.8-1.1 mg/kg and repeated laser irradiation of the intraocular neoplasm is carried out with radiation dose of 30-45 J/cm2 15-20 min later during 30-90 s.

EFFECT: complete destruction of neoplasm; excluded its further growth.

4 cl

FIELD: medicine.

SUBSTANCE: method involves applying transscleral diaphanoscopic examination method for adjusting intraocular neoplasm localization and size. Rectangular scleral pocket is built 2/3 times as large as sclera thickness which base is turned from the limb. Several electrodes manufactured from a metal of platinum group are introduced into intraocular neoplasm structure via the built scleral pocket. Next to it, intraocular neoplasm electrochemical destruction is carried out in changing electrodes polarity with current intensity of 100 mA during 1-10 min, and the electrodes are removed. Superficial scleral flap is returned to its place and fixed with interrupted sutures. 0.1-2% aqueous solution of khlorin as photosensitizer, selected from group containing photolon, radachlorine or photoditazine, is intravenously introduced at a dose of 0.8-1.1 mg/kg. Visual control of intraocular neoplasm cells is carried out by applying fluorescence and fluorescent diagnosis methods. After saturating the intraocular neoplasm with the photosensitizer to maximum saturation level, transpupillary laser radiation of 661-666 nm large wavelength is applied at a dose of 30-120 J/cm2. the operation is ended with placing sutures on conjunctiva. Platinum, iridium or rhodium are used as the metals of platinum group. The number of electrodes is equal to 4-8. 0.1-1% khlorin solution, selected from group containing photolon, radachlorine or photoditazine, is additionally repeatedly intravenously introduced in 2-3 days at a dose of 0.8-1.1 mg/kg. Visual control of intraocular neoplasm cells is carried out by applying fluorescence and fluorescent diagnosis methods. After saturating the intraocular neoplasm with the photosensitizer to maximum saturation level, repeated laser irradiation of the intraocular neoplasm is carried out with radiation dose of 30-45 J/cm2.

EFFECT: complete destruction of neoplasm; excluded tumor recurrence; reduced risk of tumor cells dissemination.

3 cl, 3 dwg

FIELD: medicine.

SUBSTANCE: method involves intravenously administering 0.1-1% aqueous solution of khlorin, selected from group containing photolon, radachlorine or photoditazine at a dose of 0.2-0.5 mg/kg or 0.2-1% aqueous solution of porphyrin like photogem at a dose of 0.2-1 mg/kg. Laser irradiation of blood is carried out 5-15 min later after beginning photosensitizer injection into cubital vein of one arm via laser light guide set in advance in the cubital vein of the other arm during 10-40 min at wavelength of 661-666 nm and power of 20-50 mW one session per day during 3-10 days with the aqueous solution of khlorin used as the photosensitizer, or laser irradiation of blood with wavelength equal to 630-633 nm during 10-45 min with power of 20-50 mW one session per day with the aqueous solution of porphyrin used as the photosensitizer. Repeated intravenous administration of photosensitizer is carried out 1-3 months later combined with repeated laser irradiation of blood.

EFFECT: reduced risk of tumor cells dissemination and metastasis development.

2 cl

FIELD: organic chemistry, medicine, chemical-pharmaceutical industry, pharmacology, pharmacy.

SUBSTANCE: invention relates to a medicinal agent used for prophylaxis and treatment of diseases and disorders associated with dysfunction of benzodiazepine receptors. This medicinal agent comprises compound of the formula (I)

. Compound of the formula (I) elicits high cardioprotective, neurotrophic, renoprotective activity and enhanced bioavailability.

EFFECT: valuable medicinal properties of compounds.

5 cl, 1 tbl, 1 ex

FIELD: medicine, cardiology.

SUBSTANCE: the suggested method should be performed at the background of medicinal therapy with preparations out of statins group, tevetene, polyoxidonium and conducting seances of plasmapheresis by removing 800 ml plasma twice weekly with N 5 due to additional intramuscular injection of immunophan 0.005%-1.0 with N 10 and fluimucyl 300 mg intravenously daily with N 5-10, total course of therapy lasts for 2 mo. The method provides modulation of leukocytic functional activity, moreover, due to altered cytokine profile and, thus, through disintegration of protein-lipid complexes participating in the development of atherosclerotic platelets.

EFFECT: higher efficiency of therapy.

3 ex

FIELD: medicine.

SUBSTANCE: method involves intravitreously introducing two electrodes into intraocular neoplasm after carrying out vitrectomy and retinotomy to expose the intraocular neoplasm. The electrodes are manufactured from platinum group metal. Electrochemical destruction is carried out with current intensity of 100 mA during 1-10 min or 10 mA during 10 min in changing electrodes polarity and their position in the intraocular neoplasm space, and the electrodes are removed. 0.1-1% aqueous solution of khlorin as photosensitizer, selected from group containing photolon, radachlorine or photoditazine, is intravenously introduced at a dose of 0.8-1.1 mg/kg. Visual control of intraocular neoplasm cells fluorescence is carried out by applying fluorescent diagnosis methods. After saturating the intraocular neoplasm with the photosensitizer to maximum saturation level, intravitreous laser radiation is carried out in parallel light beam of wavelength equal to 661-666 nm is applied at a dose of 30-120 J/cm2.The transformed retina and tumor destruction products are intravitreally removed. Boundary-making endolasercoagulation of retinotomy area is carried out after having smoothed and compressed retina with perfluororganic compound. The operation is finished with placing sutures on sclerotomy and conjunctiva. Platinum, iridium or rhodium are used as the platinum group metals. Another embodiment of the invention involves adjusting position and size of the intraocular neoplasm in trans-scleral diaphanoscopic way. Rectangular scleral pocket is built above the intraocular neoplasm to 2/3 of sclera thickness with its base turned away from limb. Several electrodes are introduced into intraocular neoplasm structure via the built bed. The electrodes are manufactured from platinum group metal. Electrochemical destruction is carried out with the same current intensity in changing electrodes polarity and their position in the intraocular neoplasm space, and the electrodes are removed. Superficial scleral flat is returned to its place and fixed with interrupted sutures. 0.1-1% aqueous solution of khlorin as photosensitizer, selected from group containing photolon, radachlorine or photoditazine, is intravenously introduced at a dose of 0.8-1.1 mg/kg after having carried out vitrectomy and retinotomy. Visual control of intraocular neoplasm cells fluorescence is carried out by applying fluorescent diagnosis methods. After saturating the intraocular neoplasm with the photosensitizer to maximum saturation level, intravitreous laser radiation is carried out in parallel light beam of wavelength equal to 661-666 nm is applied at a dose of 30-120 J/cm2. The transformed retina and tumor destruction products are intravitreally removed using vitreotome. Boundary-making endolasercoagulation of retinotomy area is carried out after having smoothed and compressed retina with perfluororganic compound. The operation is finished with placing sutures on sclerotomy and conjunctiva. Platinum, iridium or rhodium are used as the platinum group metals. The number of electrodes is equal to 4-8.

EFFECT: reduced risk of metastasizing.

4 cl, 13 dwg

FIELD: medicine.

SUBSTANCE: method involves building tunnel to posterior eyeball pole in inferoexterior and superexterior quadrants. The tunnel is used for implanting flexible polymer magnetolaser implant to the place, the subretinal neovascular membrane is localized. The implant has a permanent magnet shaped as a cut ring and is provided with drug delivery system and a short focus scattering lens of laser radiator connected to light guide. The permanent implant magnet is axially magnetized and produces permanent magnetic field of 5-7 mTesla units intensity. It is arranged with its north pole turned towards sclera at the place of the subretinal neovascular membrane projection with extrascleral arrangement of laser radiator lens membrane being provided in the subretinal neovascular membrane projection area. The other implant end is sutured to sclera 5-6 mm far from the limb via holes made in advance. The implant is covered with conjunctiva and retention sutures are placed thereon. Light guide and drug supply system lead is attached to temple with any known method applied. Drugs are supplied via the implant drug supply system in retrobulbary way in any order. Triombrast is given in the amount of 0,4-0,6 ml and dexamethasone or dexone in the amount of 0,4-0,6 ml during 3-4 days every 12 h. 0.1-1% aqueous solution of khlorin is intravenously introduced at the third-fourth day after setting the implant as photosensitizer, selected from group containing photolon, radachlorine or photoditazine, at a bolus dose of 0.8-1.1 mg/kg. Visual control of subretinal neovascular membrane cells fluorescence is carried out by applying fluorescent diagnosis methods. After saturating the subretinal neovascular membrane with the photosensitizer to maximum saturation level, intravitreous, transretinal laser radiation of 661-666 nm large wavelength is applied at general dose of 30-120 J/cm2. The flexible polymer magnetolaser implant is removed and sutures are placed on conjunctiva. Permanent magnet of the flexible polymer magnetolaser implant is manufactured from samarium-cobalt, samarium-iron-nitrogen or neodymium-iron-boron system material. The photosensitizer is repeatedly intravenously introduced at the same dose in 2-3 days after the first laser radiation treatment. Visual intraocular neoplasm cells fluorescence control is carried out using fluorescent diagnosis techniques. Maximum level of saturation with the photosensitizer being achieved in the subretinal neovascular membrane via laser light guide and implant lens, repeated laser irradiation of the subretinal neovascular membrane is carried out with radiation dose of 30-60 J/cm2.

EFFECT: accelerated subretinal edema and hemorrhages resorption; regression and obliteration of the subretinal neovascular membrane; prolonged vision function stabilization.

6 cl

FIELD: medicine.

SUBSTANCE: method involves administering Noliprelum in postoperative period for reducing left ventricle hypertrophy.

EFFECT: enhanced effectiveness of treatment in early postoperative period.

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing aminoxyl ethers, for example, N-hydrocarbyloxy-derivatives of steric hindranced amines that can be used as light- and/or thermostabilizing organic materials and/or a regulator in the polymerization reaction. Invention describes a method for preparing aminoxyl ethers by interaction of the corresponding N-oxyl derivative with hydrocarbon organic solvent in the presence of organic peroxide and a catalyst representing copper or copper compound, preferably, inorganic compound Cu (I) or Cu (II) as a solution in suitable solvent chosen in the catalytically effective amount. Method provides preparing the end product with the high yield by simplified technological schedule and without using high temperatures.

EFFECT: improved method of synthesis.

15 cl, 2 tbl, 27 ex

Compounds // 2327690

FIELD: chemistry.

SUBSTANCE: description is given of compounds with formula (I) in which A and B represent -(CH2)m- and -(CH2)n- groups respectively; R1 represents hydrogen or C1-6 alkyl; R2 represents hydrogen, C1-6alkyl, C1-6alkoxy, -S-C1-6alkyl, -(CH2)pNR5R6 optionally substituted aryl, heteroaryl or optionally substituted heterocyclyl; R3 represents optionally substituted aryl or optionally substituted heteroaryl; R4 represents hydrogen, C1-6alkyl or halogen; R5 and R6 each independently represents hydrogen or C1-6akyl; Z represents -(CH2)rX-, in which the -(CH2)r- group is bonded to R3 radical, or -X(CH2)r-, in which X is bonded to R3 radical; X represents oxygen, -NR7 group or -CH2- group; R7 represents hydrogen or C1-6alkyl; m and n independently represent an integer, chosen from 1 and 2; p represents 0; r independently represents an integer, chosen from 0 and 1. The invention also relates to use of the given compounds in therapy, in particular, as antipsychotic agents. The result is achieved when using serotonin receptors 5-HT2c, 5-HT2A and 5-HT6.

EFFECT: given compounds have antagonist affinity to serotonin receptors.

12 cl, 9 tbl, 265 ex

FIELD: chemistry.

SUBSTANCE: invention concerns malonamide derivatives of the formulae (IA) or (IB) , and pharmaceutically acceptable acid additive salts of them, where R1, R1',(R2)1,2,3, R3, R4, R14, L, and are such as described in this invention. Also the invention concerns a medicine with inhibition effect on γ-secretase, which can be applied in treatment of Alzheimer's disease.

EFFECT: obtaining new malonamide derivatives with beneficial biological properties.

17 cl, 188 ex

FIELD: chemistry.

SUBSTANCE: described are compounds of formula I in form of free base or acid-additive salt, method of their obtaining, pharmaceutical composition based on them and their application s antagonists of metabotropic glutamate receptors (mGluR5). The invention can be applied in the treatment of the illnesses connected with the disorder of glutamatic signal transfer and the disorder of nervous system partially or completety mediate mGluR5. In general formula T represents 0 or 1, A represents hydroxy, X represents hydrogen, Y represents hydrogen or A forms simple bond with X or Y; ring methylene group directly bound with CH(X)-, can be dimethylated; R0 represents hydrogen, C1-C4alkyl, C1-C4alkoxy, halogen, cyano, and R represents -COR3, -COOR3 or -SO2R6,where R3 represents C1-C4alkyl, C3-C7cycloakyl, and R6 represents C1-C4alkyl, C3-C7cycloakyl, or R represents -C(O)R3, where R3 represents furanyl, trifluoromethyl, pyridinyl, morpholinyl or methylpiperasinyl; or -C(O)OR3, where R3 represents tetrahydrofuranyl, R' represents hydrogen, C1-C4alkyl or 4-methoxybenzyl, and R" represents hydrogen or C1-C4alkyl, or R' and R" together form group -CH2-(CH2)p-, where p represents 0, 1 or 2, one of symbols n and p does not represent 0, on condition that R0 does not represent hydrogen, trifluoromethyl and methoxy, when m represents 1, n represents 0, A represents hydroxy, X and Y both represent hydrogen, R represents COOEt and R' and R" together form group -(CH2)2-.

EFFECT: efficient application of compounds for treatment of diseases caused by disturbance of transduction of glutamatergic signal and diseases of nervous system.

8 cl, 11 ex

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