Derivatives pyrrolidine, the retrieval method (variants), pharmaceutical composition, method of separating the enantiomers and the chiral phase for the separation of enantiomers

 

(57) Abstract:

The invention relates to the derivatives of pyrrolidine formula (I) in which either R is methylene, ethyleneglycol, >SO, >SO2group or a sulfur atom; R1means pyridinyl, furyl, thienyl, optionally substituted by one or more alkyl groups, naphthyl, indolyl or phenyl, optionally substituted by one or more substituents selected from halogen atoms, alkyl-, alkoxy-, hydroxy - and dialkylamino; R5means a hydrogen atom; or R is methylene, R1is a hydrogen atom and R5means phenyl; or R is a group > CHR6, R1and R5mean a hydrogen atom; R2means alkoxycarbonyl, cycloalkyl-alkyloxy-carbonyl -, etc., R3means indolyl - or phenylaminopropyl, the phenyl nucleus of which is substituted by one or more substituents selected from a range that contains the halogen atom, the alkyl-, alkoxy-, alkylthio group and others; R4means a hydrogen atom and alkylaryl; R6means phenyl radical in the form of iamiceli mixture or enantiomers and their salts. Obtain compounds of General formula (I) or by active interaction produced by carbs is either by reacting compounds of General formula (II) with phenylisocyanate, or by reacting compounds of General formula (IV) with an acid HOOC-CH (R4)-NH-CO-R3or with a reactive derivative of this acid. Method of separating enantiomers of compounds of formula (I) consists in the fact that they are carrying out chromatography on chiral phase. Pharmaceutical composition having activity for receptor cholecystokinin and gastrin, containing the active principle and pharmaceutical additives and compound of formula (I) as the active agent in an effective amount. 8 C. and 4 h.p - ly, 1 table. ;

The invention relates to the synthesis of new biologically active compounds of group pyrrolidine, in particular to new derivatives of pyrrolidine, to the way they are received in the form of salts or enantiomers, to a method for separation of enantiomers using a chiral phase, and to the use of new compounds in pharmaceutical compositions.

The new compounds correspond to General formula I

< / BR>
where or

R - methylene-, ethylene radical, SO, SO2, CHOH or sulfur, R1- pyridyl radical optionally substituted by one or more alkyl-, furilazole, optionally substituted by one or more alkyl-, tinidazole, optionally substituted some what irradically, optionally substituted by one or more alkyl-, intrinsically, optionally substituted by one or more alkyl - or phenylsalicylate, optionally substituted by one or more substituents selected from halogen atoms and alkyl-, alkoxy-, hydroxy-, nitro-, amino-, monoalkylamines, dialkylamines, alkoxycarbonyl-, -CO-NR7R8-, -NH-CO-CH3-, trifluoromethyl - or triptoreline-radicals, and R5is hydrogen;

or

R - metroradio, and R1is hydrogen, and R5- terratial;

or

R - CHR6, R1and R5each hydrogen;

R2- alkoxycarbonyl, cycloalkylcarbonyl, cycloalkylcarbonyl-, -CONR9R10or phenyl radical, optionally substituted by one or more substituents selected from alkyl, alkoxy or hydroxy radicals;

R3- terratial (optionally substituted by one or more substituents selected from halogen atoms and alkyl-, alkoxy-, or alkylthiomethyl), naphthyl-, indolyl-, chinolin or phenylaminopropyl, the phenyl nucleus of which is optionally substituted by one or more substituents selected from halogen atoms or Alki mail-, carbarnoyl, hydroxyarylalkyl, alkoxyalkyl, hydroxymelatonin, alkoxyimino-, tetrazolyl-5-, tetrazolyl-5 alkyl, driftor, methylsulfonylamino, alkylsulfonyl-, mono - or polyhydroxylated, sulfo-, -ALK-O-CO-ALK-, -ALK-COOX-, -O-ALK-COOX-, -CH=CH-COOX-, -CO-COOX-, -ALK - SO3H-, in the form of a salt, -CH=CH-ALK'-, -C(=NOH)-COOX-, -S-ALK-COOX, -O-CH2-ALK'-COOX-, -CX=N-O-ALK-COOX, -ALK-N(OH)-CO-ALK radical or dimethyl-2,2 km dioxo-4,6 dioxane-1,3-yl-5;

R4is hydrogen or alkylaryl;

R6- terratial;

R7is hydrogen or alkyl, phenylalkyl or terratial, optionally substituted by one or more substituents selected from halogen atoms and alkyl-, alkoxy - and alkylthiomethyl;

R8- alkyl-, phenylalkyl or terratial, optionally substituted by one or more substituents selected from halogen atoms and alkyl-, alkoxy - and alkylthiomethyl;

or

R7and R8form together with the nitrogen atom to which they are connected, one saturated or unsaturated mono - or politicheskii a heterocycle containing 4 to 9 carbon atoms or one or more heteroatoms (O, N) and optionally substituted by one or more alkyl radicals;

R9is hydrogen or al is alkemi substituents, selected from halogen atoms or alkyl-, alkoxy - or alkylthiomethyl;

R10- alkyl-, cycloalkenyl, cycloalkyl, phenylalkyl or terratial, optionally substituted by one or more substituents selected from halogen atoms or alkyl-, alkoxy - or alkylthiomethyl;

or

R9and R10form together with the nitrogen atom to which they are connected, one saturated or unsaturated mono - or politicheskii a heterocycle containing 4 to 9 carbon atoms or one or more heteroatoms (O, N, S) and optionally substituted by one or more alkyl radicals;

X is hydrogen, alkyl - or phenylalkyl radical;

Ala - alkyl - or alkylene radical;

Ala' - hydroxyalkyl, hydroxyalkyl, alkoxyalkyl or alkoxyalkyl radical.

In the previous and the following definitions, unless otherwise indicated, the alkyl-, alkylene and alkoxyalkyl and lots of alkyl, alkylene and alkoxy contain 1 to 4 carbon atoms, straight or branched-chain radicals and lots of alkyl containing 2 to 4 carbon atoms, and radicals and lots of cycloalkyl contain 3 to 6 carbon atoms.

When R7and R8form together with the nitrogen atom to which they are bound, a heterocycle, what adically of alkyl or tetrahydro-1,2,3,4 hinolinovy cycle.

When R9and R10form together with the nitrogen atom to which they are bound, a heterocycle, the latter is preferably piperidino-, 1-peligrosamente-, 1,2,3,6-tetrahydro 1-pyridyl, 1,2,3,4-tetrahydro 1-chinolin-, 1-pyrrolidinyl-, 1,2,3,4-tetrahydro 2-isoquinolin, thiomorpholine - or 1-indolyl-cycles, which may optionally be substituted by at least one alkyl radical.

The compounds of formula I containing one or more asymmetric centers are in the form of isomers. The racemates and enantiomers of these compounds are also part of the invention.

The compounds of formula I, where R denotes a methylene, ethylene, CHOH, CHR6radical or sulfur, and R3- phenylamino-radical, where the phenyl nucleus is optionally substituted, can be prepared by exposure of the active derivative carbamino acid obtained if necessary "in situ" by exposure to active derivative of carbonic acid, selected from N, N'-imidazolidinyl, phosgene, diphosgene and chloroformiate p-nitrophenyl, on a derivative of formula II

< / BR>
where

R - methylene-, ethylene-, CHOH-, CHR6radical or sulfur, and R1, R2, R3, R4, R5and R6have the same labels, Thu the representatives, selected from halogen atoms and alkyl-, alkoxy-, alkylthio-, trifluoromethyl-, carboxy-, alkoxycarbonyl-, hydroxy-, nitro-, amino-, acyl-, cyano-, sulfamoyl-, carbarnoyl, hydroxyarylalkyl, alkoxyalkyl, hydroxyaminobuteroyl, alkoxyamino-carbonyl, 5-tetrazolyl-, 5-tetrazolyl, triftormetilfullerenov, alkylsulfonyl-, mono - or polyhydroxylated, sulfo-, -ALK-O-CO-ALK, -ALK-COOX-, -ALK-O-ALK-, -ALK'-COOX-, -O-ALK-COOX-, -CH= CH-COOX, -CO-COOX-, -ALK-SO3H-, -CH=CH-ALK'-, -C(=NOH)-COOX, -- S-ALK-COOX, -O-CH2-ALK'-COOX-, -CX=N-O-ALK-COOX or-ALK-N(OH)-CO-ALK radical or dimethyl-2,2 km dioxo-4,6 dioxane-1,3-yl-5.

This reaction is carried out usually in an inert solvent, such as tetrahydrofuran, dimethylformamide, charcterize solvent (e.g. chloroform, sodium dichloro-1,2 ethane), at a temperature in the range of 20oC to the boiling point of the solvent.

The active derivative of carbamino acid can be obtained under the same environmental conditions and temperature.

Derivatives of formula II can be obtained by removing the protection of a derivative of formula III

< / BR>
where

R is methylene, ethylene, CHOH-, -CHR6radical or sulfur, and R1, R2, R4, R5and R6have the same signs as in the second solvent, such as a chlorinated solvent (e.g. chloroform, 1,2-dichloroethane) at 15 - 40oC.

Derivatives of the formula (III) can be obtained by exposure of a derivative of formula IV

< / BR>
where

R - methylene-, ethylene-, CHOH-, CHR6radical or sulfur, and R1, R2, R5and R6have the same signs as in formula I, the acid of formula V

< / BR>
where

R4defined as in formula I.

This reaction is carried out in an inert solvent, such as acetonitrile, tetrahydrofuran or a chlorinated solvent, in the presence of the thickener used in the chemistry of peptides, such as carbodiimide (for example, N, N'-DICYCLOHEXYL-carbodiimide) or alkyl-chloroformiate, at 10 - 40oC.

Derivatives of the formula V can be obtained by conventional methods of protection of amino acids.

Derivatives of the formula V can be prepared by applying or adapting the methods described in the literature, or methods described above.

Derivative of formula V, where R2denotes alkoxycarbonyl, cycloalkylcarbonyl or cycloalkylcarbonyl radical, can be obtained by esterification of the acid of formula VI

< / BR>
where

R - methylene-, ethylene-LASS="ptx2">

Etherification is carried out, usually with alcohol R13OH, where R13denotes alkyl-, cycloalkyl or cycloalkenyl-radical, in an acid medium at the boiling temperature of the reaction mixture. For the compounds of formula IV, where R2denotes tert-butoxycarbonyl radical, conduct the reaction of isobutylene with product form VI in an inert solvent such as a chlorinated solvent, in the presence of acid, such as sulfuric acid, at a temperature of approximately 20oC.

Derivative of formula VI, where R means metallugical, and R1and R5defined as in formula I, can be obtained by applying or adapting known method (H. Gerchon et coll., J. Org. Chem., 26, 2347, 1961).

Derivative of formula VI, where R means CHR6and R1, R5and R6defined as in formula I, can be obtained by using or adapting known method (J. K. Thottathil et coll., Tetrahedron Letters, 26, 151, 1986, and D. R. Kronenthal et coll., Tetrahedron Letters, 31, 1241, 1990).

Derivative of formula VI, where R is a methylene radical, R1is hydrogen, and R5- terratial can be obtained by using or adapting known method (Y. N. Belokon et coll., J. Chem. Soc. Perkin Trans, 1, 2075, 1988, and J. Rivier et G. R. Marshall, Peptides, Chemistry, Structure and bilogy, Proceed sulfur, R1defined as in formula I, and R5hydrogen can be obtained by reaction of a derivative of formula VII

< / BR>
where

R5is hydrogen, with an aldehyde of formula VIII

R1- CHO

where

R1has the same meaning as in the formula I

This reaction is carried out preferably in alcohol at the boiling temperature of the reaction medium.

Derivative of formula VI, where R denotes an ethylene radical, R1defined as in formula I, and R5is hydrogen, can be obtained by recovering derivatives of the formula IX

< / BR>
where

R1has the same meaning as in formula I.

The reduction is usually performed using hydrogen in an inert solvent, such as alcohol, in the presence of a catalyst such as platinum oxide, at 20 - 100oC, optionally under pressure, or by using sodium borohydride and potassium carbonate in aqueous-alcoholic medium (preferably ethanol) at 0 - 20oC.

Derivative of formula IX can be obtained by reaction of alkyl-acetamidomalonate with a derivative of formula X

< / BR>
where

R1has the same meaning as in formula I,

followed by hydrolysis, decarboxylation and d is malonate with the product of formula X is carried out in ethanol in the presence of a base, such as an alcoholate of an alkali metal, at the boiling temperature of the solvent.

Derivative of formula X can be obtained using or adapting known method (M. T> Vills et coll., J. Org. Chem., 45 (12), 2495, 1980).

Derivatives of formula IV can also be obtained by removing the protection of a derivative of formula VI

< / BR>
where

R - methylene-, ethylene-, CHOH-, CHR6radical or a sulphur atom;

R1, R2, R5and R6have the same signs as in formula I;

X - alkyl and, preferably, tert.butyl radical, if R2means tert-butoxycarbonyl radical, Z cannot be the stands or ethyl.

This reaction is carried out in an inert solvent such as a chlorinated solvent, with the help of idolisation at a temperature of from 15oC to the boiling temperature of the reaction medium.

Derivative of formula XI, where R is a methylene radical, R1- phenyl-, optionally substituted 2-thienyl-, optionally substituted 2-furyl - or optionally substituted 3-indolyl radical, R2- alkoxycarbonyl, cycloalkylcarbonyl, cycloalkylcarbonyl-radicals, and R5is hydrogen, can be obtained by reaction priori necessary, substituted 2-furyl - or, optionally substituted 3-indolyl radical, with a derivative of formula VIII

< / BR>
where

R is a methylene radical;

R2and R5have the above meanings;

R11- alkoxy radical containing 1 or 2 carbon atoms;

Z is an alkyl radical.

This reaction is carried out usually in the presence of a strong acid, such as p-toluensulfonate acid, or Lewis acid, such as trichloride aluminum, optionally in an inert solvent such as an aromatic solvent, at a temperature of 20oC to the boiling temperature of the reaction medium.

Derivatives of formula XIII can be obtained by using or adapting known method (T. Shono et coll., J. Am. Chem. Soc., 104, 6697, 1982).

Derivative of formula XI, where R2means alkoxycarbonyl, cycloalkylcarbonyl, cycloalkylcarbonyl radical, Z - tert.butyl radical, can be obtained by esterification of the acid of formula XIV

< / BR>
where

R - methylene-, ethylene-, CHOH-, CHR6radical or sulfur;

R1, R5and R6have the same signs as in formula I.

Etherification is carried out in the conditions described above for the esterification of acids of formula VI, or with the help of dicret-BUTYLCARBAMATE acid of formula VI.

This reaction is carried out in an inert solvent, such as water, dioxane or a mixture of these solvents, in the presence of a carbonate of an alkali metal, at a temperature of approximately 20oC.

Derivative of formula XI, where R2means balance-CONR9R10and Z - tert. butyl radical, can be obtained by reaction of the acid of formula XIV or active derivative of this acid to amine of formula XV

HNR9R10< / BR>
where

R9and R10have the same meanings as in formula I.

When using acids act in the presence of a condensing agent used in the chemistry of peptides, such as carbodiimide (for example, N,N'-dicyclohexylcarbodiimide) or N,N'-diimidazole carbonyl, in an inert solvent such as ether (e.g. tetrahydrofuran, dioxane), an amide (dimethylformamide) or a chlorinated solvent (e.g. methylene chloride, 1,2-dichloroethane, chloroform) at a temperature of from 0oC to the temperature of phlegmy reaction solution.

When using active derivative acid is possible to conduct the reaction of the anhydride, a mixed anhydride or ester (which you can choose from the activated or unactivated esters acid).

Derivatives of the formula IV, where R is a methylene radical, R1defined as in General formula I, with the exception of radicals or substituents, which may be modified during recovery (e.g., chinolin-radical or nitro-Deputy), R2is a phenyl radical, optionally substituted by one or more radicals selected from alkyl, alkoxy and hydroxy radicals, and R5is hydrogen, can be obtained by using or adapting known methods (C. G. Overberger et coll., J. Amer. Chem. Soc., 91 887, 1969). This method uses the restoration of pyrrole, which can be retrieved using or adapting known methods (Synthesis, 613, 1991; Tetrahedron Letters, 4407-4410, 1986).

Derivatives of the formula IV, where R is a methylene radical, R1- phenyl radical, with Kalou, R2is a phenyl radical, optionally selected from alkyl, alkoxy and hydroxy radicals, R5is hydrogen, can be obtained by the reaction of ethylene derivative of the formula XVI

R1-CH=N-CH2-R2< / BR>
where

R1and R22have designations listed above.

Ethylene can be formed in situ by decomposition of tetrahydrofuran in the presence of a base, such as utility, when 0-25oC. you Can add ethylene in the presence of diisopropylamide lithium in tetrahydrofuran at a temperature of approximately 20oC.

Derivative of formula XVI can be obtained by exposure of the aldehyde of formula VIII, where R1has the values given above for the amine of formula XVII

R2-CH2-NH2< / BR>
where

R2has the values listed above.

This reaction is carried out usually in an inert solvent such as a hydrocarbon (e.g. benzene, toluene), chlorinated solvent (e.g. dichloromethane, chloroform), optionally in the presence of p-toluensulfonate acid, at the boiling temperature of the reaction mixture.

The compounds of formula IV, where R is a methylene radical or CHOH, R1- alkoxycarbonyl-, cinacalcet substituents, selected from alkyl-, alkoxy - or hydroxy radicals, R5is hydrogen, can be obtained by reduction of a derivative of formula XVIII

< / BR>
where

R, R1and R2have the values specified above.

This reaction is carried out preferably using hydrogen in the presence of a catalyst such as platinum oxide, in an inert solvent, such as ethanol, at a temperature of approximately 20oC, or by using sodium borohydride and potassium carbonate in a water-alcohol mixture (preferably ethanol), at 0 - 20oC.

Derivative of formula XVIII can be obtained by using or adapting known methods (A. Mkairi et J. Hamelin, Tetrahedron Letters, 28 1397, 1987; A. Vander Werf et R. M. Kellogg, Tetrahedron Letters, 32 3727, 1991; E. Kato et coll., Chemm. Pharm. Bull, 33 4836, 1985; J. Ackermann et coll., Helv. Chim. Acta, 73 122, 1990).

Derivative of formula XVIII can be obtained by removing the protection and dehydration of the derived formulas XIX and XX

< / BR>
< / BR>
where

R, R1and R2have the meanings specified above,

or mixtures of these derivatives.

The reaction unprotect and dehydration are carried out, generally, by using triperoxonane acid or idolisation in an inert solvent, such as chlorinated races XIX and XX can be obtained by exposure of a derivative of formula XXI

R1- M

where

R1has the values listed above;

and

R1- M means magyarkanizsa, organolithium derivative or cuprate, carbonyl-containing derivative of formula XXII

< / BR>
where

R and R2have the same values as above.

This reaction is carried out in an inert solvent, such as tetrahydrofuran, at (-78) - 20oC.

Derivatives of formula XXII can be obtained by using or adapting known methods (J. Ackermann et coll., Helv. Chim. Acta, 73, 122, 1990; T. Ohta, Chem. Lett., 2091, 1987, and T. Ohta et coll., Tetrahedron Letters, 29 329, 1988). Preferably, carried out the reaction of bicarbonate dicret-butyl with a derivative of formula XXIII

< / BR>
where

R and R2have the same values as before.

This reaction is carried out usually in the presence of triethylamine and 4-dimethylaminopyridine in a chlorinated solvent such as dichloromethane, at a temperature of approximately 20oC.

Derivatives of formula XXII can be obtained by using or adapting known methods (T. Kolasa et coll., J. Org. Chem., 55, 1711, 1990; A. L. Johnson et coll., J. Med. Chem., 28, 1596, 1985 and B. Rigo et coll., J. Het. Chie. 25, 49, 1988; R. W. Rosenmund and P. Engels, Arch. Parm., 284 16, 1951; C. F. Koelsch and C. H. Stratton, J. Am. Chem. Soc., 66 1883, 1944; S. Sidequist, ArK. Kemi. Mimeral., Geil., where R is a methylene radical, R1- pyridyl-, chinolin-, naphthyl - or terratial, optionally substituted by one or more substituents selected from halogen atoms and alkyl-, alkoxy-, hydroxy-, amino-, monoalkylamines, dialkylamino-, alkoxy-carbonyl radical, -CO-NH7R8or-NH-CO-CH3and R2- alkoxycarbonyl, cycloalkylcarbonyl or cycloalkylcarbonyl radical, and R5hydrogen can also be obtained by recovering the derivative of formula XXIV

< / BR>
This reaction is carried out usually by using amalgam mercury-sodium in the presence of sodium dihydrophosphate or hydrogen phosphate of sodium in a solvent such as alcohol (e.g. methanol, tetrahydrofuran, water or a mixture of these solvents, at (-10) - 40oC, or with magnesium in an inert solvent, such as alcohol (e.g. methanol) at a temperature of 20oC and the boiling temperature of the reaction medium.

Derivatives of formula XXIV can be obtained by reaction of a derivative of formula XVI, where R1and R2shall have the same meaning as above, and phenylenesulfonyl.

This reaction is carried out usually in the presence of a metal salt, such as lithium bromide or silver acetate, and trilce 20oC.

Derivatives of the formula IV, where R is sulfur, R1defined as in formula I, R2the phenyl radical, and R5is hydrogen, can be obtained by reaction of a derivative of formula VIII and 2-amino-2-phenylethanol, the phenyl nucleus of which is optionally substituted by one or more substituents selected from alkyl-, alkoxy-, hydroxy-radicals.

This reaction is carried out usually in an inert solvent, such as ethanol, at the boiling temperature of the reaction medium.

2-amino-2-phenylethanol, the phenyl nucleus of which is optionally substituted, can be prepared by using or adapting known method (JP patent 197447), using 2-amino-2-phenylethanol, which are prepared by using or adapting known methods (Z. L. Kis and J. Morly, EP 258191, J. Pless, CH 590 820, S. Miyamoto et coll., EP 432661, J. Suzuki et coll., EP 345775).

Derivatives of the formula IV, where R2means phenyl optionally substituted by one or more substituents selected from alkyl-, alkoxy - or hydroxy radicals, R is a methylene radical, R1is hydrogen, and R5the phenyl radical can be obtained by using or adapting known methods (W. H. Pearson et coll., J. Am. Chem. Soc., 1141329, 1992; O. Tsuge et cool.,s and related pyrroline, using and adapting known methods (C. G. Overberger et coll., J. Am. Chem. Soc., 91687, 1969).

These peroli and pyrroline can be retrieved using or adapting known methods (Onno M. et coll., Tetrahedron Letters, 325093, 1991; S. C. Cherkofsky US 4267184, S. C. Cherkofsky u G. A. Boswell, Jr., EP 25884, O. Tsuge et coll., Bull. Chem. Soc. Japan, 591809, 1986).

Derivatives of the formula IV, where R is an ethylene radical, R2is phenyl, optionally substituted by one or more substituents selected from alkyl-, alkoxy - or hydroxy radicals, R5is hydrogen, and R1has the same meaning as in formula I, can be obtained by using or adapting known methods (C. G. Overberger et coll., J. Am. Chem. Soc., 796430, 1957; J. Thesing et H. Meyer, Ann. 60946, 1957; D. Y. Jackson u P. G. Schultz, J. Am. Chem. Soc. , 1132319, 1991; C. G. Overberger U L. P. Herin, J. Org. Chem., 272423, 1962).

Some of these methods use the response recovery piperidinol, which can also be obtained using or adapting known methods (H. Quast u B. Miller, Chem. Ber., 1163931, 1983; R. Weil u N. Collignon, C. Rend. Acad. Ser. C., 275299, 1972 and Bull. Soc. Chim. Fr., 258, 1974).

Derivatives of the formula IV, where R2means phenyl optionally substituted by one or more substituents selected from alkyl-, alkoxy - or hydroxy radicals, R - CHR6, R1and R5each, in Chem. Soc., 692271, 1947; W. H. Pearson et coll., J. Am. Chem. Soc. , 1141329, 1992; O. Tsuge et coll., Bull. Soc. Japan, 592537, 1986; M. Carriou et coll., Can. J. Chem., 612359, 1983; E. Brewer et, D. Melumad, J. Org. Chem., 373949, 1972).

In some of these methods are reduction reaction of pirrello and pyrroline, which can be retrieved using or adapting known methods (C. F. H. Allen et, C. V. Wilson, Org. Synth. Coll. Vol., 111358, 1955; W. Savey et D. J. Tivey, J. Chem. Soc., 2276, 1958; W. Chen et coll., Chin. Chem. Lett, 2439, 1991; S. M. Blomm et P. P Gorcia, US, 3883555 and US, 3691161).

Derivatives of the formula III, where R2means alkoxycarbonyl, cycloalkylcarbonyl or cycloalkylcarbonyl radical, can also be obtained by esterification of the acid of formula XXV

< / BR>
where

R, R1, R4, R5and R6have the same values as in formula I.

This reaction is carried out preferably under the same conditions as previously described for the esterification of compounds of formula V.

Acid of formula XXV can be obtained by hydrolysis of the methyl or ethyl esters corresponding to formula III.

The hydrolysis is carried out usually in an inert solvent, such as water, dioxane or a mixture of these solvents, using a base such as a hydroxide of alkaline metal (sodium hydroxide, GI is the ethene-radical, R1- pyridyl-, chinolin-, naphthyl - or phenyl radical, optionally substituted by one or more substituents selected from halogen atoms or alkyl-, alkoxy-, hydroxy-, amino-, monoalkylamines, dialkylamino-, alkoxy-carbonyl radical, -CO-NR7R8or-NH-CO-CH3and R2- alkoxycarbonyl, cycloalkylcarbonyl or cycloalkylcarbonyl radical, and R5hydrogen can also be obtained by recovering the derived formula XXVI

< / BR>
where

Z1- tert-butoxycarbonyl radical or a radical CO-CH(R4)-NH-COOC (CH3)3;

R1and R2have the same values as before;

R4has the same meaning as in formula I.

This reaction is carried out under the same conditions as previously described for the reduction reaction of the derivatives of formula XXIV.

Derivatives of formula XXVI can be obtained by acid of formula V or di-carbonate di-tert.butyl, XXIV.

These reactions are carried out in an inert solvent, such as acetonitrile, tetrahydrofuran or a chlorinated solvent, in the presence of a condensing agent used in the chemistry of peridot, such as carbodiimide (for example, N,N'-dice amennye commercially available or can be obtained, using or adapting known methods (R. Schroeter, Methods der organischen Chemie, Houben Weil, Band XI/I, p. 360; G. J. Esselen et coll. , J. Am. Chem. Soc., 36, 322, 1914; G. Adriant et coll., Bull. Soc. Chim. Fr. 1511, 1970; W. A. Jacobs et coll., J. Am. Chem. Soc., 39, 2438, 1917 and J. Am. Chem. Soc., 39, 1438, 1917).

The compounds of formula I, in which R means a radical methylene, ethylene, CHOH, CHR6or sulfur, R3radical, phenylamino, the phenyl nucleus of which can be substituted by one or more substituents selected from halogen atoms and the radicals alkyl, alkoxy, alkylthio, trifluoromethyl, nitro, acyl, cyano, sulfamoyl, alkoxycarbonyl, ALK-O-ALK, triftormetilfullerenov, Ala-SO3H radicals in the form of a salt, ALK-COOX or ALK'-COOX, where X is not hydrogen, can be obtained by the interaction of the derivative of formula II with phenylisocyanate, the phenyl nucleus of which can be substituted by one or more substituents selected from halogen atoms and the radicals alkyl, alkoxy, alkylthio, trifluoromethyl, nitro, acyl, cyano, sulfamoyl, alkoxycarbonyl, ALK-O-ALK, triftormetilfullerenov or ALK-SO3H, in salt form.

This reaction is carried out usually in an inert solvent, such as tetrahydrofuran, dimethylformamide, a chlorinated solvent (chloroform, 1,2-dichloroethane) is La.

Phenylisocyanate can be found on sale or can be obtained by adaptation or application of known methods (R. Richter and others, The chemistry of Cyanate and their thio derivatives, S. Patal, part 2, Wiley, New York, 1977).

The compounds of formula I, where R is methylene, ethylene, CHOH-, CHR6radical or sulfur, and R3radical, phenylamino, the phenyl nucleus of which is substituted by carboxy, Ala-COOH-, -O-ALK-COOH, -,- ALK'-COOH-, -CH=CH-COOH-, -CO-COOH-, -S-ALK-COOH-, -C(=NOH)-COOH, OCH2ALK COOH or CX=N-O-ALK-COOH, and R1, R2, R5and R6defined as in formula I, can also be obtained by hydrolysis or, if necessary, the hydrogenolysis reaction of the corresponding esters.

When using esters of alkyl or phenylalkyl to better hydrolysis using a base such as sodium hydroxide, potassium hydroxide or lithium hydroxide, in an inert solvent, such as tetrahydrofuran, dioxane, water or a mixture of these solvents, at 20 - 40oC. When using a complex ester trimethylsilylmethyl, it is better to work in an inert solvent, such as tetrahydrofuran, using a fluoride such as tetrabutylammonium fluoride, 10 to 40oC. When using esters of phenylalkyl also better to carry out hydro is the solvent, such as methanol or ethyl acetate.

Esters of trimethylsilylmethyl can be obtained by using or adapting the method described in the examples.

The compounds of formula I, where R denotes a methylene, ethylene, CHOH-, CHR6radical or sulfur, and R3radical, phenylamino, the phenyl nucleus of which is optionally substituted hydroxyalkyl or alkoxyalkyl-radical, R1, R2, R5and R6defined as the formula I can also be obtained by reaction of the corresponding alkylated derivative and derivative of formula XXVII

H2N - OR12< / BR>
where

R12is hydrogen or alkyl radical.

This reaction is conducted usually in an inert solvent, such as alcohol (e.g. methanol, ethanol), water or a mixture of these solvents, at the boiling temperature of the solvent, and optionally in the presence of a base, such as pyridine.

The compounds of formula I, where R denotes a methylene, ethylene, CHOH-, CHR6radical or sulfur, and R3radical, phenylamino, the phenyl nucleus of which is optionally substituted more substituents selected from halogen atoms and alkyl-, alkoxy-, alkylthio-, trifluoromethyl-, nitro-, acyl-, cyano-, sulfa what volume of hydrogen, and R1, R2, R5and R6defined as in formula I, can also be obtained by reaction of a derivative of formula IV to the acid of formula XXVIII

< / BR>
where

R3have the above values, or an active derivative of this acid, and R4has the same meaning as in formula I.

This reaction is conducted preferably in the presence of a condensing agent used in the chemistry of peptides, such as carbodiimide, in a solvent such as acetonitrile, tetrahydrofuran or a chlorinated solvent, or with thionyl chloride in dichloromethane at a temperature from 10oC to the boiling point of the solvent.

Acid of formula XXVIII can be obtained by using or adapting known method (J. R. Johnson et coll., J. Am. Chem. Soc., 69, 2370, 1947), or compounds, where R3denotes phenylaminopropyl, optionally substituted by reaction of phenylisocyanate, the phenyl nucleus of which is optionally substituted by one or more substituents selected from halogen atoms and alkyl-, alkoxy-, alkylthio-, trifluoromethyl-, nitro - acyl-, cyano-, sulfamoyl, alkoxycarbonyl-, -ALK-O-ALK, -ALK-COOX or-ALK'-COOX radicals, where X is not hydrogen, or triftormetilfullerenov, and the reaction is carried out, typically, in an aqueous solvent in the presence of a base, such as a bicarbonate of an alkali metal or in aqueous dioxane, at a temperature of about 20oC.

The compounds of formula I, where R denotes SO or SO2, R1, R2and R5defined as in General formula I, can be obtained by oxidation of the corresponding compounds of formula I, where R denotes sulfur, while the other radicals and the other substituents are chosen so that they were not sensitive to the reaction conditions.

This oxidation reaction is carried out usually using oxoneR(peroxymonosulfate potassium), produced "Aldrich" in alcohol, such as methanol or a mixture of methanol-water at a temperature of about 25oC.

To implement the methods of the invention described above, it is sometimes necessary to introduce a protection group, amino-, hydroxy-, carboxy-functions in order to avoid secondary reactions. Amino functions can, for example, be blocked in the form of carbamates tert.-butyl or methyl, then regenerated using idolisation or carbamates of benzyl, then regenerated by hydrogenation after the implementation of the method described in the invention. Hydroxypoly can, for example, be blocked invention.

The enantiomers of compounds of formula I containing at least one asymmetric center can be obtained by separation of the racemates, for example by chromatography on a chiral column or by synthesis from chiral precursors.

As chiral phase used is preferably phase, chiral selector which, which is preferably a 33.5-dinitro-benzoyl-D-phenylglycine, removed from the silica using aminoalkylindole link containing 3 to 14 carbon atoms, fixed on the amino functions of siliconindia and whose free silanol combined with caffeine-function blocked trialkylsilyl-radicals.

This chiral phase, which is also an object of the invention may be defined by the following structure XXX

< / BR>
where

R' is identical or different;

R" are identical or different alkyl radicals containing 01 to 10 carbon atoms;

G1- electro-acceptor group;

n = 3 - 13.

Preferably one of the symbols R' denotes alkylaryl containing 7 to 10 carbon atoms, and the other two denote an alkyl radical containing 1 to 2 carbon atoms, and preferably methyl radical, the symbols R are identical and represent methyl - or ethyl-radium radicals, nitro-, such as 3,5-dinitro-benzoyl radical, and n = 10.

New chiral phase described in the invention can be obtained by reaction of silico-aminopropyl anhydride aminoalkanoic acid containing 3 to 14 carbon atoms, amino function of which is protected by a protective group, such as tert.butoxycarbonyl radical, followed by blocking part of the silanol combined with caffeine-functions with Si(R')3radicals, as defined above, then, after removal of the protective groups of the amino-funcity, carry out the amidation using D-phenylglycine, amino function is protected by a group of electro-akatinol G1defined above, and finally, carry out a lock of residual silanol combined with caffeine-functions with Si(R")3radicals defined above.

As a rule, the reaction of the anhydride of the protected aminoalkanoic acid, silico-aminopropyl, is carried out in an anhydrous organic solvent, such as dimethylformamide, at a temperature of about 20oC.

Lock silanol combined with caffeine-functions with Si(R)3groups defined above, is carried out by reaction of halogennitroalkane with silico-aminopropyl inoculated via aminoalcohol residue in an organic solvent, such as metranil alkanoyl residues is usually done, if the protective group is tert. butoxycarbonyl radical, reaction triperoxonane acid in an organic solvent such as methylene chloride.

The amidation using D-phenylglycine-protected amine function is carried out in the presence of a condensing agent such as N-etoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, in an anhydrous organic solvent such as dimethylformamide.

Lock residual silanol combined with caffeine functions Si(R")3the radicals defined above, is carried out usually using trialkylsilanes in an organic solvent such as methylene chloride.

The compounds of formula I can be purified well-known and commonly used methods, for example, crystallization, chromatography or extraction.

The compounds of formula I can be, if necessary, be converted into additive salts with inorganic or organic acids by the reaction of this acid in an organic solvent, such as alcohol, ketone, ether or a chlorinated solvent.

The compounds of formula I containing a carboxy, sulfo - or ALK-SO3The H-function, can also be converted into metal salts or additive with the Alla (for example, alkali or alkaline earth, ammonia, amine or salt of the organic acid with the compound of the formula I in the solvent. The resulting salt is separated by conventional methods.

These salts form part of the invention.

As examples of pharmaceutically acceptable salts can lead additive salts with inorganic or organic acids (such as acetate, propionate, succinate, benzoate, fumarate, maleate, oxalate, methanesulfonate, isetionate, theophyllinate, salicylate, methylene-bis - xinafoate, hydrochloride, sulfate, nitrate and phosphate), the salts with alkali metals (sodium, potassium, lithium) or with alkaline earth metals (calcium, magic), ammonium salt, salts of nitrogenous bases (ethanolamine, trimethylamine, methylamine, benzylamine, N-benzyl - phenethylamine, choline, arginine, leucine, lysine, N-methyl glucamine).

The compounds of formula I possess interesting from a pharmacological point of view properties. These compounds have high affinity with the receptor cholecystokinin (CCK) and gastrin and, thus, are used in the treatment or prevention of disorders associated with HCP and gastrinom at the level of the Central nervous system and gastrointestinal tract.

Thus, Eton, slow dyskinesia, a syndrome irritable colon, acute pancreatitis, ulcers, disorders of intestinal motility, some types of neoplasms (tumors), sensitive to CCK, as well as for the regulation of appetite.

These compounds have the effect of potentialization analgesic activity of narcotic and non-narcotic medication. In addition, they have an analgesic effect.

In addition, compounds having a high affinity with the CCK receptors, modify, remember. In consequence, these compounds may be effective in disorders of memory.

The affinity of the compounds of formula I of CCK receptors was determined by the method based on method A. Saito et coll., (J. Neuro. Chem., 7, 483 - 490, 1981), at the level of brain and pancreas.

The results of these tests showed that CI50compounds of the formula I, typically, less than or equal to 1000 nm.

In addition, it is known that the products, which "recognize" the Central CCK receptors have the same specific properties in relation to gastrin receptors in the gastrointestinal tract (Bock et coll., J. Med. Chem., 32, 16-23, 1989; Reyfeld et coll., Am. J. Physiol., 240, G255-266, 1981; Beinfeld e above 40 mg/kg after subcutaneous administration in mice.

Of particular interest are the compounds of formula I, where R is a methylene radical, sulfur or SO-radical, R1is a phenyl radical, optionally substituted, R2- phenyl - or alkoxycarbonyl radical, R4and R5is hydrogen, R3radical, phenylamino, the phenyl nucleus of which is substituted by carboxy, -ALK-COOH, -S-ALK-COOH, hydroxyalkyl-, ALK'-COOH or Ala SO-3hydroxyarylalkyl-radical. In particular, interesting products of the formula I, where R1and R2are in the position of Cys one against another.

Of special interest are the following compounds:

1-(2-(3-(3-(1-hydroxy-ethyl-(RS)phenyl)ureido)acetyl)5-phenyl prolinate have been obtained tert-butyl-(2RS, 5SR);

2-(3-(3-(2-(2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl (2S,5R))2-oxo-ethyl)ureido)phenyl)propionic acid (form B);

(3-3-(2-(2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl) 2-oxo-ethyl)ureido)phenylthio) acetic acid(2RS, 5SR) acid;

3-(3-((4-tert-butoxycarbonyl-2-(2-fluoro-3-thiazolidine) 2-oxo-ethyl)ureido)phenylacetic-(2R, 4R) acid;

2-(3-(3-(2-(2-tert-butoxycarbonyl-2-(2-fluoro-phenyl)-3 - thiazolidine-(2R, 4R))-2-oxo-ethyl)ureido)phenyl) propionic- (2R, 4R) acid (form B);

1-(3-(3-(2-(4-tert-butoxycarbonyl-2-phenyl-3-thiazolidine (2R, 4R)2-oxo-ethyl)ureido)FOXO-ethyl)ureido)phenyl)econsultant potassium (RS);

3-(3-(2-(2-tertbutoxycarbonyl-5-phenyl-1-pyrrolidinyl) 2-oxo-ethyl)ureido)1-phenyl-methanesulfonate potassium(2S, 5R);

3-(3-(2-(2-tert-butoxycarbonyl 5-phenyl 1-pyrrolidinyl)2 - oxo-ethyl)ureido) benzoic acid- (2S, 5R) acid;

3-(3-(2-(2-tert-butoxycarbonyl-5)2-fluoro-phenyl)1 - pyrrolidinyl 2-oxo-ethyl)ureido) benzoic-(2RS, 5SR) acid

3-(3-(2-(2,5-diphenyl 1-pyrrolidinyl) 2-oxo-ethyl)ureido benzoic-(CIS) acid;

3-(2-(2-(2-hydroxy-phenyl)-5-phenyl-1-pyrrolidinyl 2 - oxo-ureido) phenylacetic- (2RS, 5SR) acid;

3-(3-(2-(4-tert-butoxycarbonyl-2-phenyl-3-thiazolidine) 2-oxo-ethyl)ureido) phenylacetic- (2R, 4R) acid;

3-(3-(2-(4-tert-butoxycarbonyl 2-phenyl 3-thiazolidine) 2-oxo-ethyl)ureido) benzoic-(2R, 4R)acid;

2-(3-(3-(2-(4-tert-butoxycarbonyl 2-(2-fluoro-phenyl)-1 - oxide 3-thiazolidine-(1RS, 2R, 4R)) 2-oxo-ethyl)ureido)phenyl) propionic acid (form A);

3-(3-(4-tert-butoxycarbonyl 2-(2,3-debtor-phenyl) 3-thiazolidine) 2-oxo-ethyl)ureido)phenylacetic-(2R, 4R) acid;

1-(2-(3-(3-(1-hydroxyimino-ethyl) - phenyl-(E))ureido) acetyl)5-phenyl prolinate have been obtained tert-butyl-(RS, 5SR).

Example 1. To a suspension of 3.1 g of tert.butyl-5-phenyl-prolinate have been obtained (2RS, 5SR) and 2.6 g of 2-(3(3-methyl-phenyl-ureido)acetic acid in 100 cm3anhydrous 1,2-dichloroethane, heated to temperate fridge for 15 min, then cooled to 50oC and neutralized to pH 7 to 8 by adding 10% aqueous solution of acid sodium carbonate. The organic phase is washed with 3 times 50 cm3water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The resulting product was then purified by chromatography on silica (eluent: dichloromethane-methanol (98/2 volumes)). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and a temperature of approximately 45oC. After recrystallization in acetonitrile get 1 g 1 (2-(3-(3-were)ureido)acetyl)-5-phenyl-tert. butyl of prolinate have been obtained (2RS, 5SR), melting at 156oC.

A) 2-(3-(3-Were)ureido) acetic acid can be obtained in the following way: to a solution of 30 g of glycine and 53 g of acid sodium carbonate in 600 cm3water is added within 15 min of 53.2 g of 3-methylphenothiazine. The reaction mixture is stirred for 4 hours at a temperature of approximately 25oC, then washed with 200 cm3ethyl acetate and acidified to pH 1 using 200 cm3aqueous solution of 4N hydrochloric acid. The insoluble product is separated by filtration, washed with three times 80 cm3water and dried in air. Poluchila (2RS, 5SR) can be obtained in the following way: a suspension of 45 g of the hydrochloride of 5-phenylpropane-(2RS, 5SR) 500 cm3anhydrous chloroform is stirred and cooled to a temperature of approximately 5oC. was added dropwise 5.5 cm3concentrated sulfuric acid, then the reaction mixture is saturated with isobutene for 2 h while stirring and maintaining the temperature at 5oC. After heating to a temperature of approximately 20oC stirring is carried out for 20 hours Then the reaction mixture is brought to pH 8 with 4N aqueous sodium hydroxide solution. The organic phase is decanted, washed with 3 times 100 cm3water, dried over magnesium sulfate and concentrated to dryness under reduced pressure and a temperature of approximately 40oC. Thus obtain 40 g of tert.butyl-5-phenylpropionate-(2RS, 5SR) as an orange oil, used in the subsequent synthesis.

Hydrochloride 5-phenylpropane-(2RS, 5SR) can be obtained by known methods (H. WHO and A. SCALA, J. Org. Chem., 26, 2347-50, 1961).

Example 2. To a solution of 2 g of 1-(2-aminoacetyl) 5-phenyl-tert.butylmalonate (2RS, 5SR) 20 cm3anhydrous tetrahydrofuran (THF) add 0.9 cm33-methoxyphenylalanine. The reaction mixture is stirred for 20 h at tempera is sustained fashion 45oC received the original product was then purified by chromatography on silica (eluent: dichloromethane-methanol (95/5 by vol.). The fractions containing the desired product are pooled, then concentrated to dryness under reduced pressure. After recrystallization in acetonitrile get 1.9 grams 1-(2-(3-(3-methoxyphenyl)ureido)acetyl) 5-phenyl - tert.butylmalonate (2RS, 5SR), melting at 174oC.

A) 1-(2-Amino-acetyl) 5-phenyl-tert.butylmalonate (2RS, 5SR) can be obtained as follows: to a solution of 16 g of 1-(2-tert.butoxycarbonylamino-acetyl) 5-phenyl-tert.butylmalonate (2SR, 5SR) 150 cm3chloroform was added dropwise 5.6 cm3attributively at a temperature of approximately 25oC. the Reaction mixture was stirred for 20 h at this temperature, then concentrated to dryness under reduced pressure and a temperature of approximately 45oC. the initial product was then purified by chromatography on silica (eluent: dichloromethane-methanol (90/10 vol.)). The fractions containing the desired product are pooled, then concentrated to dryness under reduced pressure. Get 10 g of 1-(2-aminoacetyl) 5-phenyl-tert.butylphosphonate (2RS, 5SR) in the form of a white amorphous product used in the subsequent synthesis.

NMR IS2-CH2), 2,7, 3,25, of 3.45 and 3.6 (bd, 2H, AB, CH2CO2), 4,3 (bt, 1H, CH), of 5.05 (bm, 1H, CH), 7,2-7,8 (m, 5H, aromatic).

B) 1-(2-Tert-butoxycarbonylamino-acetyl) 5-phenyl-tert.butoxy prolinate have been obtained (2RS, 5SR) can be prepared as follows: to a solution of 11.5 g of 5-phenyl-tert. butoxy of prolinate have been obtained (2RS, 5SR) and 8.2 g of 2-tert-butoxycarbonylamino acid in 150 cm3anhydrous acetonitrile, maintained at a temperature of approximately 0oC add 30 min a solution of 9.6 g of N,N'-dicyclohexylcarbodiimide 50 cm3anhydrous acetonitrile. The reaction mixture is stirred for 16 hours at a temperature of approximately 25oC, then the insoluble product is separated by filtration and washed three times in 30 cm3dichloromethane. The filtrate is concentrated to dryness under reduced pressure and a temperature of approximately 45oC. After recrystallization in pentane obtain 16 g of 1-(2-tert-butoxycarbonylamino-acetyl) 5-phenyl-tert.butoxy of prolinate have been obtained (2RS, 5SR), melting at +112oC.

Example 3. To a solution of 1.8 g of N,N'-diimidazole-carbonyl 50 cm31,2-dichloroethane waterless, add slowly a solution of 3.1 g of 1-(2-amino-acetyl) 5-phenyl-tert.butyl-prolinate have been obtained (2RS, 5SR) 50 cm31,2-dichloroethane anhydrous. The reaction is ethanol (RS). The reaction mixture is heated under reflux with stirring for 4 h, After cooling, the mixture is washed with 3 times 50 cm3water, the organic phase is dried over magnesium sulfate, and the solvent is evaporated to dryness under reduced pressure and a temperature of 45oC. the Obtained oily residue is purified by chromatography on silica (eluent: dichloromethane-methanol (95/5 by vol. )), and fractions containing the desired product are pooled, then concentrated to dryness under reduced pressure, after recrystallization in acetonitrile get 1.8 g 1-/2-(3-(3-(1-hydroxyethyl-(RS))phenyl)ureido)acetyl) 5-phenyl-tert.butyl of prolinate have been obtained (2RS,5SR), melting at 160oC.

Example 4. According to the method described in example 3, but from 1.8 g of N,N'-diimidazole-carbonyl, 3.1 g of 1-(2-amino-acetyl) 5-phenyl-tert.butyl-prolinate have been obtained (2RS, 5SR) dissolved in 100 cm31,2-dichloroethane anhydrous, and from 1.3 cm33-methylthio-aniline is obtained after recrystallization in acetonitrile 1.8 g 1-(2-(3-(3-methylthio-phenyl)ureido)acetyl) 5-phenyl-tert. butyl of prolinate have been obtained (2RS, 5SR), melting at 163oC.

Example 5. According to the method described in example 3, but from 1.8 g of N,N'-diimidazole, 3.1 g of 1-(2-amino-acetyl) 5-phenyl-tert.butyl-prolinate have been obtained the recrystallization in acetonitrile 1.8 g of 1-(2-(3-hydroxymethyl-phenyl)ureido)acetyl)-5-phenyl-tert. butyl - prolinate have been obtained (2RS, 5SR), melting at 163oC.

Example 6. According to the method described in example 3, but from 1.8 g of N,N'-diimidazole-carbonyl, 3.1 g of 1-(2-amino-acetyl)-5-phenyl - tert.butyl of prolinate have been obtained (2RS, 5SR) dissolved in 100 cm31,2-dichloroethane anhydrous, and 1.5 g of 3-amino-acetophenone is obtained after recrystallization in a mixture of cyclohexane-methanol (9/1 volume) 1.1 g 1-(2-(3-(3-acetyl-phenyl)ureido)acetyl) 5-phenyl-tert.butyl-prolinate have been obtained (2RS, 5SR), melting at 122oC.

Example 7. To a solution of 3 g 1-(2-(3-(3-acetyl-phenyl)ureido)acetyl) 5-phenyl-tert.butyl-prolinate have been obtained (2RS, 5SR) 12 cm3methanol and 6 cm3pyridine add 0.5 g of hydroxylamine hydrochloride dissolved in 6 cm3water. The reaction mixture is heated under reflux for 2 hours After evaporation of the solvents under reduced pressure and a temperature of approximately 45oC, the residue is extracted with 100 cm3ethyl acetate, and the organic phase is washed with 3 times 50 cm3water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The resulting crude product was then purified by chromatography on silica (eluent: dichloromethane-methanol (95/5 by vol.). The fraction containing the target product, cristallization in acetonitrile obtain 1.1 g 1-(2-(-3(3-(1-hydroximino-ethylphenyl)ureido)acetyl) 5-phenyl-tert. butyl-prolinate have been obtained (2RS, 5SR), melting at 118 oC.

Example 8. According to the method described in example 3, but from 12.5 g of N, N'-diimidazole-carbonyl, 21,3 g of 1-(2-amino-acetyl) 5-phenyl-tert.butyl-prolinate have been obtained (2RS, 5SR) dissolved in 400 cm31,2-anhydrous dichloroethane, and from 10.5 cm33-amino-ethylbenzoic obtain 24.8 g 1-(2-(3-(3-etoxycarbonyl - phenyl)ureido)acetyl)-5-phenyl-tert. butyl-prolinate have been obtained (2RS, 5SR) in the form of air mass of white.

Proton NMR (250 MHz, DNSO D6in ppm), 2 rotamer at room temperature, coalescence lines at 120oC, General description of suitable for other series products: of 1.35 (t, 3H, CH3ethyl), 1,50 (bs, 9H, (CH3)3), 1,90-2,5 (m, 4H, H at 3 and 4 pyrrolidine), of 3.9 and 3.5 (ABX, 2H, CH2N), a 4.3 (q, 2H, CH2O), 4,5 (vbdd, 1H, H in 2 pyrrolidine), of 5.15 (dd, 1H, H in the 5 pyrrolidine), 6,2 (bdd, 1H, NH), 7,2-7,6 (m, 8H, aromatic), 8 (bs, 1H, H in 2 prilocaine), and 8.7 (bs, 1H, NH).

Infrared spectrum (KBr), characteristic bands in cm-1: 3375, 3150, 3090, 3065, 3030, 2980, 2930, 2870, 1720, 1635, 1610, 1596, 1555, 1490, 1450, 1430, 1390, 1365, 1300, 1285, 1235, 1180, 1150, 1105, 1030, 860, 840, 755, 700, 685.

Example 9. To a solution of 8 g 1-(2-(3-(3-etoxycarbonyl-phenyl)ureido)acetyl-5-phenyl-tert. butyl-prolinate have been obtained (2RS, 5SR) 120 cm3methanol is added 0.9 g of potassium hydroxide dissolved in 60 cm3>, then concentrated to 50 cm3under reduced pressure. The resulting solution was diluted with 30 cm3water, washed with 2 times 50 cm3ethyl acetate, acidified to pH 2 with aqueous solution of 4N hydrochloric acid and extracted with 3 times 100 cm3dichloromethane. The combined organic phases are washed 2 times in 50 cm3water, dried over magnesium sulfate and concentrated to dryness under reduced pressure and a temperature of approximately 40oC. the initial product was then purified by chromatography on silica (eluent: dichloromethane-methanol (90/10 vol.). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure. After recrystallization in ethyl acetate to obtain 4.5 g 3(3-(2-(2-tert-butoxycarbonyl 5-phenyl 1-pyrrolidinyl) 2-oxoethyl) ureido) benzoic acid (2RS, 5SR), melting at 236oC.

Example 10. According to the method described in example 3, but from 1.8 g of N, N'-diimidazole, 3.1 g of 1-(2-aminoacetyl) 5-Finestrat.butyl-prolinate have been obtained (2RS, 5SR) dissolved in 100 cm3anhydrous 1,2-dichloroethane, and 1.4 g of 2-(3-amino-phenyl)ethanol obtained after recrystallization in acetonitrile, 1.5 g 1-(2-(3-(3-(2-hydroxyethyl)phenyl)ureido)acetyl) 5-phenyl-tert. butyl-prolinate have been obtained (2RS, 5S is oru 15 g of 2-(3-nitro-phenyl)ethanol in 250 cm3ethanol add 0.75 g of 5% palladium on coal. The suspension is stirred for 2 hours at a temperature of approximately 25oC in an atmosphere of hydrogen (130 kPa). The catalyst is separated by filtration, and the filtrate is concentrated to dryness under reduced pressure at 45oC. Thus, obtain 12 g of 2-(3-amino-phenyl)ethanol in the form of an orange oil, used in the subsequent synthesis.

Example 11. In the manner similar to that described in example 3, but from 3.6 g of N,N'-diimidazole-carbonyl, 6.2 g of 1-(2-amino-acetyl) 5-phenyl-tert.butyl-prolinate have been obtained (2RS, 5SR) dissolved in 150 cm3anhydrous 1,2-dichloroethane, and of 3.9 g of 3-amino-ethylcinnamate -(E) are obtained 4.8 g 3-(3-(2-(2-tert. butoxycarbonyl-5-phenyl-1-pyrrolidinyl- (2 RS, 5SR)) 2-oxo-ethyl)ureido)ethylcinnamate -(E).

Proton NMR (250 MHz, DMCO D6in ppm, J in Hz), 2 rotamer at room temperature, coalescence lines at 120oC: 1,3 (t, 3H, CH3), and 1.5 (bs, 9H, (CH3)3), of 4.25 (q, 2H, CH2O) to 6.4 (d, 1H, J = 15, CH=TRANS.), 7,10-of 7.70 (m, 10H, aromatic CH=TRANS).

Infrared spectrum (KBr), characteristic bands in cm-1: 3375, 3150, 3070, 3035, 2980, 2940, 2880, 1740, 1700, 1640, 1610, 1590, 1560, 1495, 1490, 1455, 1430, 1395, 1370, 1310, 1270, 1220, 1180, 1160, 1040, 990, 860, 840, 790, 760, 705, 685.

3-amino-ethyl-Cinna the training, described in example 9, but on the basis of 3.7 g 3-(3-(2-(2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl- (2 RS, 5SR)) 2-oxo-ethyl)ureido)-ethylcinnamate (E) dissolved in 60 cm3of methanol, and 0.4 g of potassium hydroxide dissolved in 20 cm3water, after treatment, get 1 g 3-(3-(2-(2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl)- (2 RS, 5SR)) 2-oxo-ethyl)ureido)cinnamon (E) acid.

Proton NMR (250 MHz, DMCO D6ppm, J in Hz), 2 rotamers at room temperature, a description of the prevailing rotamer, General description of suitable for other series products: a 1.5 (bs, 9H, (CH3)3), to 1.9 and 2.2 (2 m, 4H, H 3, and 4 on pyrrolidine), a 3.2 and 3.9 (ABX, 2H, CH2N), 4,35 (dd, 1H, H in 2 pyrrolidine), 5,20 (dd, 1H, H in the 5 pyrrolidine), 6,30 (dd, 1H, NH), 6,4 (bd, 1H, J = 15, CH = TRANS.), of 7.1 to 7.7 (m, 10H, aromatic CH = TRANS.), of 8.7 (s, 1H, NH).

Infrared spectrum (KBr), characteristic bands in cm-1: 3380, 3075, 3030, 3700-2250 with a maximum at 2745, 2980, 2935, 2875, 1735, 1705, 1695, 1640, 1610, 1590, 1560, 1495, 1450, 1430, 1395, 1370, 1315, 1250, 1225, 1155, 985, 910, 890, 860, 840, 790, 760, 705, 685.

Example 13. According to the method described in example 3, but from 3.6 g of N, N'-diimidazole-carbonyl, 6.2 g of 1-(2-amino-acetyl) 5-phenyl-tert.butyl of prolinate have been obtained (2RS, 5SR) dissolved in 125 cm3anhydrous 1,2-dichloroethane, and of 3.9 g of 3-(3-amino-phenyl) ethylpropane get after Outil)ureido)-3-phenylethyl propionate (2RS, 5SR), melting at 96oC.

3-(3-Amino-phenyl)ethylpropane can be obtained in the manner similar to that described in example 10, A, but according to 16.8 g of 3-nitro-ethylcinnamate (E), dissolved in 500 cm3ethanol and 0.9 g of 5% palladium on coal. Thus, the gain of 14.2 g of 3-(3-amino-phenyl)ethyl-propionate in the form of oils used in the subsequent synthesis.

3-Nitro-ethylcinnamate (E) can be obtained in the following way: a solution of 31 g of 3-nitro-cinnamic-(E) acid in 300 cm3ethanol add 5 cm3pure sulfuric acid. The reaction mixture is stirred under reflux for 3 hours After cooling and adding 59 cm3water the solution is concentrated to a volume of approximately 60 cm3under reduced pressure and the 49oC. Add 250 cm3ethyl acetate, then the organic phase is washed successively with 2 times 100 cm3aqueous sodium hydroxide solution (2N, 2 times 100 cm3water, then dried over magnesium sulfate and concentrated to dryness under reduced pressure and at 40oC. Thus, obtain 32 g of 3-nitro-ethylcinnamate (E), melting at 70oC.

3-Nitro-cinnamic-(E) acid can be obtained in the following way: a mixture 30,2 g 3-NITR the nickname within 1 hour After cooling, add 50 cm3water, and the insoluble product is separated by filtration, washed 3 times in 50 cm3water and dried in air. So, get 31 g of 3-nitro-cinnamic-(E) of acid, melting at 205oC.

Example 14. According to the method described in example 9, but on the basis of 3,9 g 3-(3-(2-(2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl) 2-oxoethyl)ureido)3-phenyl-ethylpropylamine (2RS, 5SR) dissolved in 60 cm3methanol and 0.45 g of potassium hydroxide dissolved in 20 cm3water, after treatment get 2.1 g 3-(3-(2-(2-tertbutoxycarbonyl-5 - phenyl-1-pyrrolidinyl) 2-oxo-ethyl)ureido) 3-phenyl-propionic-(2RS, 5SR)acid.

Proton NMR (250 MHz, DMCO D6in ppm), 2 rotamer at room temperature, coalescence lines at 120oC: of 1.5 (bs, 9H, (CH3)3), and 2.5 (t, 2H, CH2), 2.8 (t, 2H, CH2), 6,8-7,60) (m, 9H, aromatic).

Infrared spectrum (KBr), characteristic bands in cm-1: 3380, 3700-2250 with maximum 2625, 3160, 3060, 3030, 2980, 2930, 2880, 1735, 1610, 1595, 1560, 1495, 1450, 1440, 1395, 1370, 1310, 1225, 1155, 905, 890, 865, 840, 790, 760, 705.

Example 15. In the manner similar to that described in example 3, but from 2.9 g of N, N'-carbonyl-diimidazole, 5 g of 1-(2-amino-acetyl) 5-phenyl-tert.butyl of prolinate have been obtained (2RS, 5SR) dissolved in 1 is carbonyl-5-phenyl-1-pyrrolidinyl)2-oxo-ethyl)ureido) phenoxyacetate (2RS, 5SR).

Proton NMR (200 MHz, DMCO D6in ppm), 2 rotamer at room temperature, a description of the prevailing rotamer: 1,15 (bt, 3H, CH3ethyl), 1,50 (bs, 9H, (CH3)3) and 4.2 (q, 2H, CH2ethyl), and 4.5 (bs, 2H, OCH2CO), 6,4 (bd, 1H, H in the 6 prilocaine), 6,8 to 7.75 (m, 8H, aromatic).

Infrared spectrum (KBR), characteristic bands in cm-1: 3375, 3150, 3090, 3060, 3030, 2980, 2930, 2875, 1758, 1735, 1700, 1638, 1600, 1550, 1495, 1450, 1430, 1390, 1365, 1295, 1220, 1190, 1155, 1085, 1030, 860, 840, 760, 700, 690.

3-Amino-phenoxyethylacrylate can be obtained as described in example 10, A, but on the basis of 18 g of 3-nitro-phenoxyethylamine dissolved in 250 cm3ethanol, and 0.2 g of 5% palladium on coal. Thus, 15 g of 3-amino-phenoxyethylamine in the form of oils used in the subsequent synthesis.

3-Nitro-phenoxyethylacrylate can be obtained in the following way: a solution of 13.9 g of 3-nitro-phenol in 125 cm3anhydrous dimethylformamide added dropwise within 20 min 4.8 g of oily suspension (50% by weight) of sodium hydride. The resulting mixture was stirred at a temperature of approximately 25oC for 30 min, then added dropwise within 10 min 10.8 cm3ethylchloride. The reaction mixture is stirred for 20 hours at a temperature of approximately 20oC, saevissima over magnesium sulfate and concentrated to dryness under reduced pressure, and the temperature of the 35oC. Obtain 18 g of 3-nitro-phenoxyethylamine in the form of an orange oil, used in the subsequent synthesis.

Example 16. In the manner similar to that described in example 9, but on the basis of 3.7 g of 3-(2-(2-tert. butoxycarbonyl-5-phenyl-1-pyrrolidinyl) 2-oxo-ethyl)ureido)phenoxyacetate (2RS, 5SR) dissolved in 80 cm3of methanol, and 0.4 g of potassium hydroxide dissolved in 40 cm3water. After treatment and recrystallization in isopropylacetate obtain 1.4 g 3-(3-(2-(2-tert-butoxycarbonyl-5 - phenyl-1-pyrrolidinyl) 2-oxo-ethyl)ureido)Phenoxyethanol-(2RS, 5SR) of acid, melting at 192oC.

Example 17. According to the method described in example 3, but from 3.6 g of N, N'-diimidazole-carbonyl, 6.2 g of 1-(2-amino-acetyl)-5-phenyl-tert.butyl of prolinate have been obtained (2RS, 5SR) dissolved in 150 cm3anhydrous 1,2-dichloroethane, and from 4.2 g (3 aminophenylthio) of ethyl acetate to obtain 4.9 g 3-(3-(2-(2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl)2-oxo-ethyl)ureido) phenylthio) ethyl acetate (2RS,5SR).

Proton Yarm (300 MHz, DMCO D6in g/m), 2 rotamer at room temperature, a description of the prevailing rotamer: 1,2 (t, 3H, CH3ethyl), and 1.5 (bs, 9H, (CH3)3), and 3.8 (bs, 2H, CH2) and 4.2 (q, 2H, CH2O ethyl) and 6.9 to 7.7 (m, 9H, aromatic).

In, 1395, 1365, 1305, 1295, 1275 1220, 1150, 1030, 885, 865, 840, 780, 760, 700, 690.

(3 Aminophenylthio)acetate can be obtained in the following way: a solution of 12.5 g of 3-amino-thiophenol 200 cm3ethanol is added dropwise within 5 min 16.7 g of ethylbromoacetate. The mixture is stirred at a temperature of approximately 20oC for 3, then concentrated to dryness under reduced pressure and at 40oC. the Obtained product is dissolved in 100 cm3ethyl acetate and washed with 100 cm3aqueous sodium hydroxide solution 1N. The organic phase is separated, washed with 2 times 50 cm3water, dried over magnesium sulfate and concentrated to dryness under reduced pressure. The resulting product was then purified by chromatography on silica (eluent: ethyl acetate-cyclohexane (about 70/30.)). The fractions containing the desired product are combined and concentrated to dryness under reduced pressure and at 40oC. Thus, obtain 13 g of (3-aminophenylthio) acetic acid ethyl ester in the form of oils used in the subsequent synthesis.

Example 18. According to the method described in example 9, but on the basis of 4 g of 3-(3-2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl)2-oxoethyl)ureido) phenylethylamine (2RS, 5SR) dissolved in 80 cm3methanol and 0.45 g of potassium hydroxide, rastvorennogo 2 g 3-(3-(2-(2-tertbutoxycarbonyl-5-phenyl-1-pyrrolidinyl)2-oxoethyl)ureido) phenylthiourea-(2RS, 5SR) of acid, melting at 136oC.

Example 19. In the manner similar to that described in example 3, but from 3.6 g of N,N'-diimidazole-carbonyl, 6.2 g of 1-(2-aminoacetyl) 5-phenyl-tert.butylmalonate (2RS, 5SR) dissolved in 150 cm3anhydrous 1,2-dichloroethane and 3.7 g of 5-amino-ethyl musk, obtain 3.1 g 5-(3-(2-(2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl)2-oxoethyl)ureido) ethylsilicate (2RS, 5SR), melting at 150oC.

5-Amino-utililities may be prepared in a manner similar to that described in example 10, A, but on the basis of 10 g of 5-nitroanisole dissolved in 200 cm3ethanol, and 0.5 g of 5% palladium on coal. Obtain 8.5 g of 5-amino-ethylsilicate in the form of an orange oil, used in the subsequent syntheses.

5-Nitro-utililities can be obtained by the following method: to a solution of 10 g of 5-nitrosalicylic acid in 250 cm3ethanol add 3 cm3concentrated sulfuric acid. The reaction mixture is stirred under reflux for 70 hours, After cooling and adding 50 cm3water, the solution is concentrated up to approximately 60 cm3under reduced pressure and at 40oC. Add 250 cm3ethyl acetate, then the organic Pasha under reduced pressure. The resulting crude product was then purified by chromatography on silica (eluent: dichloromethane). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and the 40oC. Thus obtain 10 g of 5-nitro-ethylsilicate, melting at 96oC.

Example 20. According to the method described in example 9, but on the basis of 4.7 grams 5-(3-(2-(2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl)2-oxoethyl)ureido) ethylsilicate (2RS, 5SR) dissolved in 80 cm3methanol, and 1.04 g of potassium hydroxide dissolved in 40 cm3water, after treatment receive 2.3 g 5-(3-(2-(2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl)2-oxoethyl)ureido) salicylic acid (2RS, 5SR) of acid, melting at 190oC.

Example 21. In the manner similar to that described in example 2, but from 6.2 g of 1-(2-amino-acetyl)5-phenyl-tert.butylmalonate (2RS, 5SR) dissolved in 150 cm3anhydrous tetrahydrofuran, and from 4.2 g of 3-isocyanate of phenylethylamine receive 6 g 3-(3-(2-(2-tert - butoxycarbonyl-5-phenyl-1-pyrrolidinyl)2-oxoethyl)ureido)phenylethylamine (2SR, 5SR).

Proton NMR (200 MHz, DMCO D6in ppm), 2 rotamer at room temperature, coalescence lines at 120oC: 1,5 (s, 9H, (CH3)3), and 3.6 (s, 2H, CH2CO), the 3.65 (s, 3H, 55, 3110, 3090, 3060, 3030, 2975, 2950, 2930, 2875, 1738, 1700, 1650, 1610, 1595, 1560, 1495, 1435, 1395, 1365, 1315, 1250, 1220, 1155, 1-15, 905, 890, 860, 845, 780, 760, 700.

3-Isocyanatomethyl prepared as follows: to a suspension of 1 g of coal and 6 cm3diphosgene 70 cm3toluene was added when the temperature is approximately -20oC in an argon atmosphere of 8.25 g of 3-aminophenylacetic dissolved in 100 cm3of toluene. The reaction mixture is stirred and maintained at -20oC for 15 min, then after heating to a temperature of approximately 20oC heated under reflux for 2 hours 30 minutes the Mixture Tegaserod by ozonation of argon for 30 min, filtered over celite, washed with 50 cm3dichloromethane and concentrated under reduced pressure and a temperature of about 50oC. Thus, the gain of 9.30 g of 3-isocyanatomethyl in the form of a yellow liquid contained in the argon atmosphere and used in the subsequent synthesis.

3-Aminophenylacetate can be obtained by a method similar to that described in example 10, A, but according to 37.1 g of 3-nitrophenylacetate dissolved in 550 cm3of methanol, and 2 g of palladium on coal. Thus, the gain of 28.2 g of 3-aminophenylacetate in the can be obtained by a known method (SEGERS and A. BRUYLANTS, Bull.Soc.Chim.Belg.64, 87, 1955).

Example 22. In the manner similar to that described in example 9, but on the basis of 4.9 g of 3-(2-(2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl) 2-oxoethyl)ureido)phenylethylamine (2SR, 5SR) dissolved in 80 cm3methanol and 0.56 g of potassium hydroxide dissolved in 40 cm3water, after treatment, get 1 g 3-(3-(2-(2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl)2-oxoethyl)ureido) phenylacetic acid (2RS, 5SR) acid.

Proton Yarm (200 MHz, DMCO D6in ppm), 2 rotamer at room temperature, coalescence lines at 120oC: of 1.5 (bs, 9H,(CH3)3), and 3.5 (s, 2H, CH2CO), of 6.8 to 7.7 (m, 9H, aromatic).

Infrared spectrum (KBr), characteristic bands in cm-1: 3380, 3700-2250 with maximum 2625, 3155, 3110, 3090, 3030, 2975, 2930, 2880, 1735, 1635, 1610, 1595, 1560, 1495, 1450, 1395, 1365, 1310, 1225, 1155, 905, 890, 980, 840, 780, 760, 705.

Example 23. According to the method described in example 1, but from 2.2 g of 5-phenylethylamine (2RS, 5SR), 2.1 g of 2-(3-(3-were)ureido) acetic acid in suspension in 50 cm3anhydrous 1,2-dichloroethane and to 0.72 cm3sulphonylchloride obtained after recrystallization in acetonitrile 1.2 g 1-(2-(3-(3-were)ureido)acetyl)5-phenylethylamine (2RS, 5SR), melting at 115oC.

5-phenylethylamine (2RS, 5SR) koreanamerican described in example 3, but from 4.1 g of N,N'-diimidazole-carbonyl, 7 g of 1-(2-aminoacetyl)-5-phenylethylamine (2RS, 5SR) dissolved in 135 cm3anhydrous 1,2-dichloroethane, and 4.1 g of 3-aminomethylbenzoic get 1.5 g of 1-(2-(3-ethoxycarbonylphenyl)ureido)acetyl) 5-phenylethylamine 2RS, 5SR), melting at 136oC.

1-(2-Aminoacetyl)-5-phenylethylamine (2RS, 5SR) can be obtained in the manner similar to that described in example 2, A, but on the basis of 11.1 g of 1-(2-tert-butoxycarbonylamino) 5-phenylethylamine (2RS, 5SR) and from 4.3 cm3attributively dissolved in 150 cm3anhydrous chloroform. So, get 7 g of 1-(2-aminoacetyl)-5-phenylethylamine (2RS, 5SR) used in the subsequent synthesis.

1-(2-Tert. butoxycarbonylamino)-5-phenylethylamine (2RS, 5SR) can be obtained as described in example 2 B, but on the basis of the solution containing 7 g of 5-phenylethylamine (2RS, 5SR), 5.6 g of 2-tert.butoxycarbonylamino acid and 6.6 g of N,N'-dicyclohexylcarbodimide 65 cm3anhydrous acetonitrile. Thus, the gain of 11.1 g of 1-(2-tert.butoxycarbonylamino-acetyl)-5-phenylethylamine (2RS, 5SR) in the form of an orange oil, used in the subsequent synthesis.

Example 25. According to the method described you in suspension in 50 cm3anhydrous 1,2-dichloroethane and 0.6 cm3sulphonylchloride obtained after recrystallization in acetonitrile, 1.1 g 1-(2-(3-(3-were)ureido)acetyl)- 5-phenylcyclopropanecarboxylic (2RS, 5RS), melting at 130oC.

A) 5-Phenylcyclopropanecarboxylic (2RS, 5RS) can be obtained in the following way: a solution of 3.5 g of 1-(tert.butoxycarbonyl) 5-phenylcyclopropanecarboxylic (2RS, 5RS) 50 cm3anhydrous chloroform was added dropwise 1.5 cm3idolisation. The reaction mixture is stirred for 20 hours at a temperature of approximately 25oC, then concentrated to dryness under reduced pressure and a temperature of 45oC. the resulting crude product was then purified by chromatography on silica (eluent: dichloromethane (97/3 by vol.). The fractions containing the desired product are pooled, then concentrated to dryness under reduced pressure. Thus, receive 2 g of 5-phenylcyclopropanecarboxylic (2RS, 5RS) in the form of an orange oil, used in the subsequent synthesis.

B) 1-(tert. butoxycarbonyl)-5-phenylcyclopropanecarboxylic (2RS, 5RS) can be obtained in the following way: a solution of 7 g of 1-(tert-butoxycarbonyl)-5-phenylpropane-(2RS, 5RS) and 4.6 g of paratoluenesulfonyl 403oC. After returning to a temperature of 20oC stirring is continued for 20 h, then extracted with 3 times 100 cm3ethyl acetate. The combined organic phases are washed with 2 times 100 cm32 times in 100 cm3aqueous solution of 1N hydrochloric acid, 2 times 100 cm3aqueous solution of 1N sodium hydroxide, then 3 times with 100 cm3water, dried over magnesium sulfate and concentrated to dryness under reduced pressure and a temperature of approximately 45oC. the resulting crude product was then purified by chromatography on silica (eluent: dichloromethane-methanol (97/3 by vol.). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and a temperature of approximately 45oC. Thus, obtain 3.6 g of 1-(tert.butoxycarbonyl)-5-phenylcyclopropanecarboxylic (2RS, 5SR) in the form of an orange oil, used in the subsequent synthesis.

1-(tert. butoxycarbonyl)-5-phenylpropan-(2RS, 5SR) can be obtained in the following way: a solution of 22.8 g of the hydrochloride of 5-phenylpropene (2RS, 5SR) and 22 g of sodium carbonate in 160 cm3water was added dropwise, with stirring, 21.8 g of bicarbonate dicret-butyl, dissolved in 120 cm3dioxane. The reaction mixture is stirred for 20 hours at temperature is 3 ethyl acetate and acidified to pH in an aqueous solution of 4N hydrochloric acid. The aqueous acidic phase is extracted with 3 times 150 cm3dichloromethane. The combined organic extracts are washed with 2 times 50 cm3water, dried over magnesium sulfate and concentrated to dryness under reduced pressure and a temperature of approximately 40oC. After recrystallization in acetonitrile obtain 24 g of 1-(tert.butoxycarbonyl) 5-phenylpropane-(2RS, 5SR), melting at 170oC.

Example 26. According to the method described in example 1, but on the basis of 3 g of 5-phenylisopropylamine (2RS, 5SR), 2.7 g of 2-/3-(3-were)ureido/acetic acid in suspension in 75 cm3anhydrous 1,2-dichloroethane and 1 cm3sulphonylchloride get after cleaning 1.2 g 1-(2-(3-(3-were)ureido)acetyl)-5-phenylisopropylamine (2RS, 5SR).

Proton NMR (200 MHz, CDCl3) in ppm), 2 rotamer at room temperature, a description of the prevailing rotamer: 1,1 (d, 6H, (CH3)2), of 1.7 - 2.5 (m, 4H, H at 3 and 4 pyrrolidine), of 2.15 (s, 3H, CH3), 3 and 4.1 (2bd, 2H, CH2N), 4,4 (bt, 1H, H in 2 pyrrolidine), 4,9 (m, 2H, CH of isopropyl and H in 5 pyrrolidine), 6,6 - 7,5 (m, 9H, aromatic).

Infrared spectrum (KBr), characteristic bands in cm-1: 3365, 3150, 3060, 3030, 2980, 2935, 2875, 1738, 1700, 1645, 1615, 1595, 1560, but as follows, similar to that described in example 25, A, but starting from 5 g of 1-(tert.butoxycarbonyl)-5-phenylisopropylamine (2RS, 5SR) and 2.4 cm3attributively in solution in 50 cm3anhydrous chloroform. Thus, get 3 g of 5-phenylisopropylamine (2RS, 5SR) in the form of a yellow oil, used in the subsequent synthesis.

1-(Tert. butoxycarbonyl)-5-phenylisopropylamine (2RS, 5SR) can be obtained as described in example 25, B, but according to 5.85 g of 1-(tert.butoxycarbonyl)-5-phenylpropane-(2RS, 5SR), 3,85 g paratoluenesulfonyl and 1.6 g of 2-propanol in 30 cm3anhydrous pyridine. After treatment, get 5 g of 1-(tert. butoxycarbonyl)-5-phenylisopropylamine (2RS, 5SR) in the form of a yellow oil, used in the subsequent synthesis.

Example 27. Enantiomers 1-(2-(3-(3-were)ureido)acetyl) 5-phenyl-tert. butylmalonate (2RS, 5SR) share a high-speed liquid chromatography on chiral phase type PIRCKLE using 400 g of (E)-N-3,5-dinitrobenzonitrile, grafted on siliconindia as a stationary phase that is loaded into the column with the length of 200 mm and a diameter of 80 mm, using as mobile phase a mixture of hexane-2 propanol-methylene chloride (87/7, 5/7,5). Based on 1 g of the racemate get 0,48 g 1-(2-(3-(3-� = +33,40,9(C = 1, methanol), proton NMR (300 MHz, DMCO D6in ppm), 2 rotamer at room temperature, a description of the prevailing rotamer: 1,5 (s, 9H, (CH3)3)), and 1.9 and 2.2 (2m, 4H, H at 3 and 4 pyrrolidine) and 2.2 (s, 3H, CH3), a 3.2 and 3.9 (ABX, 2H, CH2N), 4,35 (dd, 1H, H in 2 pyrrolidine), 5,20 (dd, 1H, H in the 5 pyrrolidine), 6,30 (dd, 1H, NH), 6,70 (bd, 1H, H at 4 prilocaine); and 7.1 to 7.7 (m, 8H, aromatic), and 8.7 (s, 1H, NH); 0,48 g 1-(2-(3-(3-were)ureido)acetyl)- 5-Finestrat.butylmalonate (2R, 5S), melting at 79oC, //2D0= -31,60,8(C = 1, methanol).

The carrier can be prepared as follows:

In a 6-liter three-neck flask suspension 600 g siliconefree ( -10 μm - NH2, Macherey - Nagel) in 2 l of dimethylformamide. Add 95 g of the anhydride of N-tert-butoxycarbonylamino-11-undecanoic acid and stirred the reaction mixture for 18 h at a temperature of about 20oC. the silica is filtered off, washed successively with 2 times 1500 cm3dichloromethane, then 2 times in 1500 cm3of dimethylformamide. The washed silica again suspension in 2 l of dimethylformamide and added to 95 g of the anhydride of N-tert-butoxycarbonylamino-11-undecanoic acid, then stirred in tecia 600 cm3dichloromethane, twice in 600 cm3of tetrahydrofuran, twice in 600 cm3methanol and twice in 600 cm3diethyl ether, then dried under reduced pressure and a temperature of about 20oC. Thus, receive 610 g of silicon dioxide, having the name "BOC-C11- C3silicon dioxide, in the form of a white powder, the structure of which is confirmed by infrared spectrum and elemental analysis: C% = 8,8, H% = 1,7, N% = 1,2.

In a 6-liter three-neck flask suspension 607 g of silicon dioxide "BOC-C11- C3silicon dioxide" in 2 l of dichloromethane and 68 cm3pyridine. Added dropwise 530 cm3dimethylchlorosilane and stirred the reaction mixture for 16 h at a temperature of about 20oC. the Obtained solid is filtered off and washed successively with two times 1 l of dichloromethane, with two times 1 l of methanol, 2 times in 1 l of tetrahydrofuran, two times 1 l of dichloromethane and twice in 1 l of diethyl ether, then dried under reduced pressure and a temperature of about 20oC. Thus, receive 712 g of silicon dioxide, having the name "VOS-C11-C3-silica-O-Si(CH3)2(CH2)7CH3"in the form of a white powder, the structure to the>/P>In a 6-liter three-neck flask suspension 711 g of silicon dioxide "VOS-C11-C3-silica-O-Si(CH3)2(CH2)7CH3" at 2200 cm36% (in volume terms) solution triptocaine acid in dichloromethane. The reaction mixture was stirred for 5 h at a temperature of about 20oC. the silica is filtered and washed successively with two times 1 l of dichloromethane, with two times 1 l of a mixture of dichloromethane-diisopropylethylamine (about 70/30.), in 1 l of dichloromethane, with two times 1 l of tetrahydrofuran, two times 1 l of methanol and two times 1 l of diethyl ether, then dried under reduced pressure and a temperature of about 50oC. the Washed and dried silica again suspension in 2 l of 6% (in volume terms) solution triperoxonane acid in dichloromethane. The reaction mixture is stirred for 16 hours at a temperature of about 20oC. the silica is filtered and washed successively twice with 1.5 l of dichloromethane, with two times 1 l of a mixture of dichloromethane-diisopropylethylamine (about 70/30. ), 1.5 l of dichloromethane, twice in 2 l of tetrahydrofuran, twice in 2 l of methanol and two times in 2 l of diethyl ether, then dried under reduced pressure and a temperature of about 50oC. So N>2(CH2)7CH3"in the form of a white powder, the structure of which is confirmed by infrared spectrum and elemental analysis which gives: C% = 8,8, H% = 1,7, N% = 1,3.

In a 4-liter three-neck flask suspension 400 g of silicon dioxide "C11-C3-silica-O-Si(CH3)2(CH2)7CH3" in 1800 cm3of dimethylformamide. Added 42 g of 3,5-dinitrobenzoyl-D-phenylglycine and 30 g of 2-ethoxy-1-etoxycarbonyl-1,2-dihydroquinoline and the reaction mixture stirred for 16 h at a temperature of about 20oC. the silica is filtered and washed successively with two times 1 l of dichloromethane, with two times 1 l of tetrahydrofuran, twice in 1 l of methanol and two times 1 l of diethyl ether. Silica, washed thus, again suspended in 2 l of dimethylformamide and add 30 g of 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline and 42 g of 3,5-dinitrobenzoyl-D-phenylglycine, then the reaction mixture was stirred for 5 h at a temperature of about 20oC. the silica is filtered off, washed successively with two times 1 l of dimethylformamide, two times 1 l of dichloromethane, with two times 1 l of tetrahydrofuran, twice in 1 l of methanol and two times 1 l of diethyl ether, then vysushila is the fact that the name "DNB-D-Phg - C11-C3-silica-O-Si(CH3)2(CH2)7CH3"in the form of a white powder, the structure of which is confirmed by infrared spectrum and elemental analysis which gives: C% = 12,3, H% = 1,8, N% = 2,1.

In a 4-liter three-neck flask suspension 434 g of silicon dioxide "DNB-D-Phg-C11-C3-silica-O-Si(CH3)2(CH2)7CH3" in 1.3 l of dichloromethane and add 100 cm3dimethylethoxysilane, then the reaction mixture is stirred for 54 hours at a temperature of about 20oC. the silica is filtered off, washed successively with two times 1 l of dichloromethane, with two times 1 l of methanol, twice in 1 l of tetrahydrofuran and two times 1 l of dichloromethane, then dried under reduced pressure at a temperature of about 140oC. Thus, get 425 g of silicon dioxide, having the name "DNB-D-Phg-C11-C3-silicon dioxide-OSi(CH3)2(CH2)7CH3reactionary", in the form of a white powder, the structure of which is confirmed by infrared spectrum and elemental analysis which gives: C% = 12,7, H% = 1,9, N% = 2,0.

In a 4-liter three-neck flask suspension 425 g of silicon dioxide "DNB-D-Phg-C11-C3the silicon dioxide is trimethylsilylimidazole and the reaction mixture stirred for 15 h at a temperature of about 20oC. the resulting solid product is separated by filtration and washed successively with two times 1 l of tetrahydrofuran, twice in 1 of methanol, twice in 1 l of acetone and twice in 1 l of dichloromethane, then dried under reduced pressure and a temperature of about 20oC. Thus, receive 431 g of silicon dioxide, having the name "DNB-D-Phg-C11-C3-silicon dioxide-/OSi(CH3)2(CH2)7CH3/- /O-Si(CH3)3/ "in the form of a white powder, the structure of which is confirmed by infrared spectrum and elemental analysis which gives: C% = 13,7, H% = 2,2, N% = 2,0.

The anhydride of N-tert. butoxycarbonylamino-11-undecanoic acid can be obtained in the following way: a solution of 30.1 g of N-tert-butoxycarbonylamino-11 undecanoic acid in 480 cm3ethyl acetate, keeping the temperature about 5oC added dropwise within 10 min the solution 10,63 g N,N'-dicyclohexylcarbodiimide 120 cm3ethyl acetate. The reaction mixture was stirred for 1 h at a temperature of about 5oC, then for 16 h at a temperature of about 20oC. the precipitation is filtered off and washed with 30 cm3ethyl acetate. The filtrate is concentrated under reduced pressure and at 30oC. the Obtained solid productsonline-11 undecanoic acid, melting at 58oC.

N-tert-butoxycarbonylamino-11-undecanoate acid can be obtained by a known method (I. T. Sparrow, J. Org. Chem., 41, 1350, 1976).

Example 28. In a solution of 0.08 g of 1-(2-amino-acetyl)-5-Finestrat.butylmalonate (2S, 5R), 10 cm3anhydrous tetrahydrofuran, add to 0.05 cm3isocyanate 3-methylphenyl. The reaction mixture is stirred for 3 hours at a temperature of about 25oC, then the solvent is evaporated under reduced pressure at 45oC. the resulting crude product was then purified by chromatography on silica (eluent: dichloromethane-methanol (98/2 about.). The fractions containing the desired product are combined and concentrated to dryness under reduced pressure. Thus, the gain of 0.04 g 1-(2-(3-(3-were)ureido)acetyl) 5-Finestrat. butyrophilin-(2S, 5R), analytical data analytical data correspond clockwise rotating enantiomer obtained by chromatography on chiral stationary phase of the racemate, //2D0= +35,60,8(C = 0,11%, MeOH).

1-(2-Aminoacetyl)-5-Finestrat. butylmalonate (2S,5R) can be obtained in the following way: a solution of 0.08 g of 1-(2-tert.butoxycarbonylamino)-5-phenyl-2-pyrrolidinecarbonyl -(2S,5R) is islote. The reaction medium is saturated with isobutylene in the next 2 hours, stirring and keeping the temperature at 5oC. After increasing the temperature to about 20oC, continue stirring for 20 h the Solution was adjusted to pH 8 by adding 10% aqueous sodium bicarbonate solution and the aqueous phase is separated and then extracted 3 times with 30 cm3the chloroform. The combined organic phases are washed with 2 times 10 cm3water, dried over magnesium sulfate and concentrated to dryness under reduced pressure and at 40oC. Thus, obtain 0.08 g of 1-(2-aminoacetyl)-5-Finestrat.butylmalonate (2S,5R) in the form of a yellow color, used in the subsequent synthesis.

1-(2-Tert. butoxycarbonylamino) 5-phenyl-2 - pyrrolidinecarbonyl-(2S, 5R) acid can be obtained in the following way: cooled to 5oC a solution of 0.16 g of 1-(2-tert.butoxycarbonylamino) 5-phenylethylamine (2S, 5R) 15 cm3a mixture of dioxane-water (70/30 vol.) add 0.5 cm3aqueous sodium hydroxide solution 1N. After increasing the temperature to about 20oC continue stirring for 12 h, then add again 0.5 cm3aqueous 1 N sodium hydroxide. After 3 h stirring at temperature is aballea 20 cm3an aqueous solution of 0.1 N hydrochloric acid. The reaction mixture is extracted 3 times with 40 cm3ethyl acetate. The combined organic phases are dried over magnesium sulfate and concentrated to dryness under reduced pressure and the 35oC. Thus, obtain 0.09 g of 1-(2-tert.butoxycarbonylamino)-5-phenyl-2-pyrrolidinecarbonyl (2S,5R) acid as a colourless resin, which is used in further synthesis.

1-(2-Tert.butoxycarbonylamino)-5-phenylethylamine (2S,5R) can be obtained in the following way: a solution of 0.1 g of 5-phenylethylamine-(2S, 5R) and 0.1 g of 2-tert.butoxycarbonylamino acid in 10 cm3anhydrous acetonitrile, aged at a temperature of about 0oC, immediately add 0.12 g of N, N'-dicyclohexylcarbodiimide. The reaction mixture is stirred for 16 hours at a temperature of about 25oC, then the insoluble product is filtered and washed three times in 5 cm3dichloromethane. The filtrate is concentrated to dryness under reduced pressure and at 40oC. the Obtained oily residue is purified by chromatography on silica (eluent: ethylacetoacetate (30/70 vol.). The fractions containing the desired product are pooled and concentrated to dryness in phenylpropionate(2S, 5R) as a colourless oil, used in the subsequent synthesis.

5-Phenylethylamine (2S,5R) can be obtained as follows: to a solution of 0.6 g of 1-methoxycarbonyl-5-phenylethylamine (2S,5R) 15 cm3chloroform was added dropwise to 0.45 cm3attributively at a temperature of approximately 25oC. the Mixture is heated under reflux for 18 hours, After cooling to a temperature of about 25oC add 20 cm2water. The aqueous phase is separated, then extracted with 2 times 20 cm2the chloroform. The combined organic phases are washed 2 times in 10 cm3water, dried over magnesium sulfate and concentrated to dryness under reduced pressure and at 40oC. the mixture of the two diastereoisomers purify by chromatography on silica (eluent: ethylacetoacetate (30/70 vol.)). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and at 40oC. are Thus obtained 0.12 g of 5-phenylethylamine (2S,5R) in the form of oils used in the subsequent synthesis.

1-Methoxycarbonyl-5-phenylethylamine (2S,5R) can be obtained in the following way: a solution of 5.1 g of 5-methoxy-1-methoxycarbonylmethylene (2S, 5RS) 400 cm3benzene, a cooling gap for 12 h at a temperature of approximately 25oC, then add 50 cm3saturated aqueous sodium bicarbonate solution. The aluminum hydroxide is filtered off and washed with 2 times 20 cm3of methylene chloride. The combined organic phases are washed with 2 times 50 cm3water, dried over magnesium sulfate and concentrated to dryness under reduced pressure and at 40oC. the resulting oil residue purified by chromatography on silica (eluent: ethylacetoacetate (20/80 vol.)). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and at 40oC. Thus, obtain 0.6 g of 1-methoxycarbonyl-5-phenylethylamine-(2S, 5RS) in the form of oil is light yellow in color, the mixture (40/60 weight.) isomers of (2S,5R) and (2S,5S) used in the subsequent synthesis.

5-Methoxy-1-methoxycarbonylmethylene (2S,5RS) can be obtained by a known method (T. Shono et coll., J. Am. Chem. Soc., 104, 6697, 1982).

Example 29. Enantiomers 3-(3-(2-(2-tert.butoxycarbonyl-5-phenyl - 1-pyrrolidinyl)2-oxo-ethyl)ureido)benzoic-((2RS, 5SR) acid is separated by high-speed liquid chromatography on chiral phase type PIRCKLE using 400 g (D)-N-3,5-dinitrobenzonitrile, grafted on siliconindia, as a stationary phase chromatog triperoxonane acid (80/20/0,05 vol.). On the basis of 3.5 g of racemate get:

0,72 g 3-(3-(2-(2-tert.butoxycarbonyl-5-phenyl-1-pyrrolidinyl) 2-oxoethyl)ureido)benzoic-((2S,5R) acid, melting at 204oC, //2D0= +32,30,7(C = 1,08, methanol);

0,54 g 3-(3-(2-(2-tert.butoxycarbonyl-5-phenyl-1-pyrrolidinyl) 2-oxoethyl)ureido)benzoic-((2SR,5RS) of acid, melting at 240oC, //2D0= -33,10,8(C = of 1.03, methanol).

Example 30. According to the method described in example 2, but from 2 g of 1-(2-aminoacetyl)-2,5-diphenyl-pyrrolidine-(Cys) and 0.9 cm3isocyanate 3-METHYLPHENOL in solution in 25 cm3anhydrous tetrahydrofuran is obtained after recrystallization in 2-propanol 1.4 g 1-/2-(2,5-diphenyl-1-pyrrolidinyl)2-oxoethyl/-3-(3-were) urea((2RS,5SR), melting at 168oC.

1-(2-Aminoacetyl)-2,5-diphenylpyrrolidine-(CIS) can be obtained in the manner similar to that described in example 2, but on the basis of 6.6 g of 1-(2-tert. butoxycarbonylamino)-2,5-diphenylpyrrolidine-(Cys) and 2.5 cm3attributively dissolved in 70 cm3anhydrous chloroform. Thus obtained 4.8 g of 1-(2-aminoacetyl)-2,5-diphenylpyrrolidine-(CIS) in the form of an orange oil, ispolzuemogo: 1,8-2,4 (bm, 4H, CH2-CH2), of 2.7 and 3.3 (bd, 2H, AB, CH2CO2, 5,0 (bm, 1H, CH), 5,2 (bm, 1H, CHN), 7,2-7,5 (m, 10H, aromatic).

Mass (electron impact, 70 eV, m/z), 280 (M+), 263 (M+-NH2), 222 (M+-COCH2NH2), 91 (C6H5CH+2).

1-(2-Tert.butoxycarbonylamino)-2,5-diphenylpyrrolidine- (CIS) can be obtained as described in example 2 B, but on the basis of a solution of 6.6 g of 2,5-diphenylpyrrolidine (mixture of isomers CIS-TRANS), and 5.2 g of 2-(tert.butoxycarbonylamino)acetic acid and 6.1 g of N,N'-dicyclohexylcarbodiimide 50 cm3anhydrous acetonitrile. Get after separation by chromatography on silica (eluent: dichloromethane-methanol (98/2 about.)) 3.6 g of 1-(2-tert.butoxycarbonylamino)-2,5-diphenylpyrrolidine-(CIS) in the form of an orange oil, used in the subsequent synthesis.

2,5-Diphenylpyrrolidine (mixture of isomers CIS-TRANS) can be obtained by a known method (C. G. Overberger, M. Valentine et J.-P. Anselme, J. Amer. Chem. Soc., 91, 687-94, 1969).

Example 31. According to the method described in example 9, but based on 3 g 3-(3-(2-(2,5-diphenyl-1-pyrrolidinyl)-2-oxo-ethyl)ureido)ethylbenzoic -(CIS), dissolved in 50 cm3of methanol, and 0.7 g of potassium hydroxide dissolved in 20 cm3water, after treatment and ry, melting at 255oC.

3-(3-(2-(2,5-Diphenyl-1-pyrrolidinyl)-2-oxo-ethyl)ureido)- ethylbenzoic-(CIS) can be obtained in a way similar to that described in example 3, but from 3.4 g of 1-(2-aminoacetyl)-2,5-diphenyl - pyrrolidine)-(CIS), 2.2 g of N, N'-diimidazole dissolved in 75 cm3anhydrous 1,2-dichloroethane and 2 g of 3-aminomethylbenzoic. After cleaning they receive 3 g 3-(3-(2-(2,5-diphenyl-1-pyrrolidinyl)-2-oxo-ethyl)ureido)ethylbenzoic (CIS) in the form of air mass of the white colors used in the subsequent synthesis.

Example 32. In the manner similar to that described in example 2, but from 1.8 g of 1-(2-aminoacetyl)-6-phenyl-2-piperidine - tert.BUTYLCARBAMATE (2RS, 5SR) dissolved in 30 cm3anhydrous tetrahydrofuran, add 0.7 cm3isocyanate 3-methylphenyl. Obtained after recrystallization in oxide diisopropyl 0.7 g 1-(2-(3-(3-were)ureido)acetyl)-6-phenyl-2-piperidine - tert. BUTYLCARBAMATE (2RS,5SR), melting at 123oC.

1-(2-Aminoacetyl)-6-phenyl-2-piperidine. butylcarbamoyl (2RS, 5SR) can be obtained in the manner similar to that described in example 2, but from 5.9 g of 1-(2-tert. butoxycarbonylamino)-6-phenyl-2-piperidine. BUTYLCARBAMATE (2RS,5SR) and 2 cm3ITRI-phenyl-2-piperidine - tert.butylcarbamoyl (2RS,5SR) in the form of an orange oil, used in the subsequent synthesis.

Mass (electron impact, 70 eV, m/z), 318 (M+), 159 (M+-COCH2NH2and-CO2tert.butyl).

1-(2-Tert. butoxycarbonylamino)-6-phenyl-2-piperidine - tert.butylcarbamoyl-(2RS,5SR) can be obtained as described in example 2 B, but based on the solution of 5.1 g of 6-phenyl-2-piperidine-tert.BUTYLCARBAMATE-(2RS,5SR), 3.4 g of 2-(tert.butoxycarbonylamino) acetic acid and 4 g of N,N'-dicyclohexylcarbodiimide dissolved in 90 cm3anhydrous acetonitrile. Obtain 5.9 g of 1-(2-tert. butoxycarbonylamino)6-phenyl-2-piperidine - tert.BUTYLCARBAMATE (2RS,5SR) in the form of an orange oil, used in the subsequent synthesis.

6-Phenyl-2-piperidine. butylcarbamoyl-(2RS, 5SR) can be obtained by a method similar to that described in example 1 B, but based on 14 g of the hydrochloride of 6-phenyl-2-piperidinecarbonitrile-(2RS, 5SR) acid in suspension in a mixture of 5 cm3concentrated sulfuric acid in 250 cm3anhydrous chloroform. The mixture is saturated with isobutylene. After processing gain of 5.2 g of 6-phenyl-2-piperidinecarboxylate tert-butyl-(2RS, 5SR), melting at 68oC.

The hydrochloride of 6-phenyl-2-piperidinecarbonitrile-(2RS, 5SR) acid can be poluchenii 200 cm3ethanol is stirred for 3 hours at a temperature of about 20oC in an atmosphere of hydrogen (130 kPa). The catalyst is filtered off and the filtrate is concentrated to dryness under reduced pressure and at 45oC. After recrystallization in acetonitrile obtain 14 g of the hydrochloride of 6-phenyl-2-piperidinecarbonitrile-(2RS, 5SR) of acid, melting at 184oC.

The hydrochloride of 6-phenyl-2,3,4,5-tetrahydro-2-pyridineboronic acid can be obtained in the following way: a solution of ateleta sodium obtained from 4.1 g of sodium in 180 cm3anhydrous ethanol, add to 38.3 g of ethyl-acetamidomalonate. After 1 h stirring at a temperature of about 20oC poured onto 40 g of 2-(3-chlorpropyl)-2-phenyl-1,3-dioxolane and 2.1 g of potassium iodide. The reaction mixture is heated under reflux for 24 h, then concentrated to dryness under reduced pressure and a temperature of approximately 45oC. the Pasty residue is extracted with 400 cm3dichloromethane, washed with 3 times 100 cm3water, dried over magnesium sulfate and concentrated to dryness under reduced pressure. The crude product is purified by chromatography on silica (eluent: dichloromethane). The fractions containing the desired product are pooled and concentrated to dryness under ponii 102 cm312 N hydrochloric acid. The reaction mixture is heated under reflux, stirring, for 5 hours After cooling the acid solution is washed with 3 times 100 cm3diethyl ether, then concentrated to dryness under reduced pressure and a temperature of about 50oC. After recrystallization in acetonitrile obtain 14 g of the hydrochloride of 6-phenyl-2,3,4,5-tetrahydro-2-pyridineboronic acid, melting at 146oC.

2-(3-Chlorpropyl)-2-phenyl-1,3-dioxolane can be obtained by a known method (M. T. WILLS, J. E. WILLS, L. Von DOLLEN, B. L. BUTLER et J. PORTER, J, Org. Chem., 45(12), 2495, 1980).

Example 33. In a suspension of 0.5 g of 5-(2-furyl) tert.butylmalonate (2S, 5R) and of 0.48 g 2/3-(3-were)ureido/acetic acid 50 cm3mixture of anhydrous acetonitrile/-1,2-dichloroethane (80/20 by vol.), supported at a temperature of about 0oC add 10 min a solution of 0.48 g of N,N'-dicyclohexylcarbodiimide 10 cm3anhydrous acetonitrile. The reaction mixture is stirred for 16 hours at a temperature of about 25oC, then the insoluble product is filtered and washed three times in 5 cm3dichloromethane. The filtrate is concentrated to dryness under reduced pressure and at 40oC. the Oily residue is purified by chromatography on silica (eluana under reduced pressure and at 40oC. Thus, obtained after recrystallization in a mixture of ethylacetoacetate (about 50/50.) 0.15 g of 5-(2-furyl)-1- (2-(3-(3-were)ureido)acetyl)tert. butylmalonate (2S, 5R), melting at 144oC, //2D0= +4,80,8(C = 0,51%, MeOH).

Proton NMR (250 MHz, DMCO D6in ppm), 2 rotamer at room temperature, coalescence at 120oC, description 120oC: 1,50 (bs, 9H, (CH3)3), 2,10 (bm, 2H, CH2), 2,30 (bm, 2H, CH2), is 2.30 (s, 3H, CH3), and 3.8 and 4.0 (ABX, 2H, CH2N) 4,45 (bt, 1H, NCHCOO), 5,20 (bdd, 1H, NCHC), 6,15 (bt, 1H, NH), 6,40 (bdd, 1H, C4H4O at position 4), 6,50 (bd, 1H, C4H4O at position 3), 6,70 (bd, 1H, N-C6H4C at position 4), 7,15 - 7,25 (m, 3H, aromatic), to 7.50 (bs, 1H, C4H4O in position 5), to 8.40 (bs, 1H, NH).

Infrared spectrum (KBr), characteristic bands in cm-1: 3365, 2975, 2930, 2850, 1735, 1640, 1615, 1595, 1560, 1490, 1390, 1365, 1150, 780, 745, 695.

5-(2-Furyl)tert. BodyPaint-(2S, 5R) can be obtained in the following way: a solution of 3.8 g of 1-tert.butoxycarbonyl-5-(2-furyl)tert.butylmalonate (2S, 5RS) 50 cm3chloroform was added dropwise 1,77 cm3attributively at a temperature of approximately 25oC. Mixing produce for 30 min, then add 20 cm3water. Wednesdayevening 30 cm3saturated aqueous solution of acid sodium carbonate and twice in 30 cm3water, then dried over magnesium sulfate and concentrated to dryness under reduced pressure and at 40oC. the resulting mixture of both diastereoisomers separated by chromatography on silica (eluent: ethylacetoacetate (20/80 vol.)). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and at 40oC. Thus, obtain 0.50 g of 5-(2-furyl)tert.butylmalonate-(2S, 5R) in the form of butter yellow-orange color used in the subsequent reactions of synthesis.

1-Tert-butoxycarbonyl-5-(2-furyl)tert. butyl prolinate have been obtained (2S, 5RS) can be obtained in the following way: a solution of 9.6 g of 1-tert.butoxycarbonyl-5-methoxide. butyl of prolinate have been obtained (2S, 5RS) 100 cm3furan add 0,42 g paratoluenesulfonyl acid. The reaction mixture is stirred for 24 hours at a temperature of about 25oC, then add 1 g of acid sodium carbonate. Heterogeneous environment concentrated to dryness under reduced pressure and a temperature of about 30oC. the resulting residue is extracted with 250 cm3ethyl acetate and washed with 2 times 50 cm3water. The organic phase is dried over magnesium sulfate and concentrate silica (eluent: ethyl acetate-cyclohexane (about 5/95. )). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and the 35oC. Thus, obtain 3.8 g of 1-tert-butoxycarbonyl-5-(2-furyl)tert. butylmalonate (2S, 5RS), melting at 70oC, mixture of isomers (30/70 by weight) of (2S, 5R) and (2S, 5S) used in subsequent reactions of synthesis.

1-Tert-butoxycarbonyl-5-methoxide. butylmalonate (2S, 5RS) can be obtained by a known method (T. SHONO et coll., J. Am. Chem. Soc., 104, 6697, 1982), but on the basis of 1-tert-butoxycarbonyl tert-butyl of prolinate have been obtained (2S).

1-Tert. butoxycarbonyl tert. butylmalonate (2S) can be obtained by a known method (S. YOSHIFUJI et coll. , Chem. Pharm. Bull., 34, 3873, 1986).

Example 34. To a solution of 2.0 g of 3-(2-aminoacetyl)-2-phenyl-4-thiazolidin tert. BUTYLCARBAMATE (2R, 4R) 25 cm3anhydrous tetrahydrofuran, add 0.8 cm3isocyanate 3-methylphenyl. The reaction mixture is stirred for 12 hours at a temperature of about 25oC, then diluted with 100 cm3ethyl acetate. The organic phase is washed 2 times in 40 cm3water, dried over magnesium sulfate and concentrated to dryness under reduced pressure and at 40oC. the resulting crude product was then purified by chromatography on silica (eluent: methylindene and at 40oC. Thus, obtained after shaking in heptane 0.5 g 3-(2-(3-(3-methyl-phenyl)ureido)acetyl)-2-phenyl-4-thiazolidine. BUTYLCARBAMATE (2R, 4R) in the form of an amorphous white powder, //2D0= +70,01,3(C = 1,02%, CHCl3).

Proton NMR (200 MHz, CDCl3in ppm), 2 rotamer at room temperature, a description of the prevailing rotamer at 25oC: 1,45 (bs, 9H, (CH3)3) and 2.2 (s, 3H, CH3), 3,2 (A2X, 2H, CH2S) of 3.2 and 4.3 (ABX, 2H, CH2N) to 4.9 (t, 1H, CHN), 6,1 (bdd, 1H, NH), and 6.2 (s, 1H, SCHN), of 6.8 to 7.7 (m, 9H, aromatic).

Infrared spectrum (KBr), characteristic bands in cm-1: 3375, 2975, 2930, 1735, 1650, 1610, 1595, 1490, 1455, 1370, 1150, 780, 730, 695.

A) 3-(2-Aminoacetyl)-2-phenyl-4-thiazolidine.butylcarbamoyl (2R, 4R) can be obtained in the following way: a solution of 2.5 g of 3-(2-tert.butoxycarbonylamino)-2-phenyl-4 - thiazolidine.butoxycarboxim (2R, 4R) 15 cm3chloroform was added dropwise 0.9 cm3attributively at a temperature of approximately 25oC. the Reaction mixture was stirred for 1 h at a temperature of approximately 25oC, then add 15 cm3water. The aqueous phase is separated, then extracted with 2 times 10 cm3the chloroform. The combined organic phases are washed PEFC is SUP> water, then dried over magnesium sulfate and concentrated to dryness under reduced pressure and at 40oC. Thus, receive 2 g of 3-(2-amino-acetyl)-2-phenyl - 4-thiazolidin-tert.BUTYLCARBAMATE (2R, 4R) in the form of oil is light yellow in color, used in subsequent reactions of synthesis.

Proton NMR (200 MHz, DMCO D6in ppm), 2 rotamer at room temperature of 1.5 (s, 9H, C(CH3)3), 2,9-4,4 (vbm, 4H, 2CH2), 4,8-5,4 (2m, 1H, NCHCO), 6,2-6,55 (2s, 1H, NCHS), 7,2-7,8 (m, 5H, aromatic), 8,3 (vbs, 1H, NH+3).

B) 3-(2-Tert.butoxycarbonylamino)-2-phenyl-4-thiazolidin - tert.butylcarbamoyl (2R, 4R) can be obtained in the following way: a solution with 37.4 g of 2-phenyl-4-thiazolidin-tert.BUTYLCARBAMATE (2RS, 4R) and 24.7 g of 2-tert.butoxycarbonylamino acid in 150 cm3anhydrous acetonitrile, keeping the temperature at 0oC add 30 min a solution of 29.1 g of N,N'-dicyclohexylcarbodiimide 80 cm3anhydrous acetonitrile. The reaction mixture is stirred for 16 hours at a temperature of about 25oC, then the insoluble product is filtered and washed three times in 20 cm3acetonitrile. The filtrate is concentrated to dryness under reduced pressure and at 45oC. the Crude product is purified the TPC, are combined and concentrated to dryness under reduced pressure. So, get to 39.6 g of 3-(2-tert.butoxycarbonylamino)-2-phenyl-4 - thiazolidine.BUTYLCARBAMATE (2R, 4R) in the form of a viscous yellow oil, which was used in subsequent reactions of the synthesis //2D0= +60,31,1(C = 0,98%, CHCl3).

A) 2-Phenyl-4-thiazolidine.butylcarbamoyl (2RS, 4R) can be obtained in the following way: a suspension of 53.7 g of 2-phenyl-4-thiazolidinediones-(2RS, 4R) acid 590 cm3chloroform, cooled to a temperature of about 5oC, was added dropwise 15 cm3concentrated sulfuric acid. The reaction medium is saturated with isobutylene in air for 5 hours while stirring and maintaining the temperature at 5oC. After increasing the temperature to about 20oC, the stirring is continued for 20 hours the Solution was adjusted to pH 8 by adding saturated aqueous solution of acid sodium carbonate, and then the aqueous phase is separated and extracted 2 times with 300 cm3the chloroform. The combined organic phases are washed with 2 times 300 cm3water, dried over magnesium sulfate and concentrated to dryness under reduced pressure and at 40oC. the resulting oil residue purified, hrot, unite, then concentrated to dryness under reduced pressure. So, get 42.8 g of 2-phenyl-4-thiazolidine. BUTYLCARBAMATE (2RS, 4R) in the form of oil is light yellow in color, the mixture (40/60 weight. ) isomers (2R, 4R) and (2S, 4R) used in subsequent reactions of synthesis.

G) 2-phenyl-4-thiazolidinedione-(2RS, 4R) acid can be obtained in the following way: a suspension of 2.4 g of L-cysteine in 35 cm3ethanol was added dropwise at a temperature of about 50oC 2.3 cm3benzaldehyde. The reaction medium is heated under reflux for 2 hours, After cooling to a temperature of about 25oC insoluble product is filtered and washed sequentially in 20 cm3ethanol and 20 cm3diethyl ether. Thus, the gain of 3.7 g of 2-phenyl-4-thiazolidinediones- (2RS, 4R) acid, melting at 190oC, which is used for subsequent reactions of synthesis.

Example 35. Working analogously to example 34, but on the basis of 0.3 g of 3-(2-aminoacetyl)-2-phenyl-4-thiazolidine. BUTYLCARBAMATE (2S, 4S) and 0,12 cm33-methylphenothiazine. Get after shaking in cyclohexane 0.16 g 3(2-(3(3-were)ureido)acetyl)- 2-phenyl-4-thiazolidine.BUTYLCARBAMATE (2S, 4S) as amorphous bled the Mr proton (250 MHz, DMCO D6in ppm), 2 rotamer at room temperature, coalescence bands at 120oC; General description indeed to other products of the group of thiazolidine (at 120oC): 1,50 (bc, 9H, (CH3)3), and 2.3 (s, 3H, CH3) at 3.25 and 3.5 (ABX, 2H, CH2S), 3.7 and 4,05 (ABX, 2H, CH2N, 5,0 (bdd, 1H, CHN), 6,2 (bds, 1H, NH), of 6.4 (bs, 1H, SCHN), 6,7 (bd, 1H, N-C6H4-C in position 4 or 6), 7,05 to 7.2 (m, 3H, N-C6H4-C in position 2, 4 and 5), 7,35 (m, 3H, C6H5), the 7.65 (bd, 2H, C6H5), 8,35 (bs, 1H, NH).

Range IR (KBr), characteristic bands in cm-1: 3380, 2990, 2940, 2860, 1745, 1650, 1615, 1600, 1560, 1495, 1460, 1375, 1155, 785, 735, 700).

3-(2-Aminoacetyl)-2-phenyl-4-thiazolidin-tert. butylcarbamoyl (2S, 4S) can be obtained as in example 34, A, but according to 0.53 g of 3-(2-tert.butoxycarbonylamino)-2-phenyl-4-thiazolidin - tert.BUTYLCARBAMATE (2S, 4S) and from 0,18 cm3attributively. Obtain 0.31 g of 3-(2-aminoacetyl)-2-phenyl-4-thiazolidin - tert. BUTYLCARBAMATE (2S, 4S) in the form of a pale yellow oil, used in the subsequent syntheses.

3-(2-Tert.butoxycarbonylamino)-2-phenyl-4-thiazolidin - tert.butylcarbamoyl (2S, 4S) can be obtained as described in example 34, B, but on the basis of 0.75 g of 2-phenyl-4-thiazolidine. BUTYLCARBAMATE (2RS, 4S), of 0.53 g of 2-tert-butoxycarbonylamino)-2-phenyl-4-thiazolidin tert. BUTYLCARBAMATE-(2S, 4S) as amorphous powder beige color, which is used for subsequent reactions of the synthesis //2D0= -52,41,1(C = 0,01%, CHCl3).

2-Phenyl-4-thiazolidine. butylcarbamoyl (2RS, 4S) can be obtained as described in example 34, but on the basis of 4.5 g of 2-phenyl-4-thiazolidinediones-(2RS, 4S) acid, 1.3 cm3concentrated sulphuric acid and an excess of isobutene. So, get 1.5 grams of 2-phenyl-4-thiazolidinone.butyl carboxylate (2RS, 4S) in the form of oil is light yellow in color, blend (50/50 wt.) isomers (2R, 4S) and (2S, 4S) used in subsequent reactions of synthesis.

2-Phenyl-4-thiazolidinedione-(2RS, 4S) acid can be obtained, as in example 34, G, but on the basis of 3.0 g L-cysteine and 2.85 cm3benzaldehyde. Thus, the gain of 4.5 g of 2-phenyl-4-thiazolidinediones- (2RS, 4S) acid, melting at 190oC, which is used for subsequent reactions of synthesis.

Example 36. To a solution of 1.1 g of N,N'-diimidazole-carbonyl 30 cm3chloroform add a solution of 0.97 g of 3-aminomethylbenzoic 10 cm3the chloroform. The reaction mixture is stirred for 6 hours at a temperature of about 25oC, then add 1.3 g of 3-(2-aminoacid the camping stirred for 24 h at a temperature of approximately 25oC, then washed sequentially in 50 cm3water, 40 cm3aqueous solution of 0.5 N hydrochloric acid and 50 cm3water. The organic phase is separated, dried over magnesium sulfate and concentrated to dryness under reduced pressure and at 40oC. the resulting oil residue purified by chromatography on silica (eluent: ethyl acetate-cyclohexane (about 35/65. )), and fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and the 40oC. Thus, obtained after shaking in heptane and 1.0 g 3-(2-(3-(3-ethoxycarbonylphenyl)ureido)acetyl)-2-phenyl-4-thiazolidine. BUTYLCARBAMATE (2R, 4R) in the form of an amorphous white powder, melting at 85oC, //2D0= +61,51,2(C = 0,97%, CHCl3).

Proton NMR (200 MHz, DMCO D6in ppm), 2 rotamer at room temperature, coalescence lines at 120oC, characteristic chemical shifts at 120oC: 1,3 (s, 3H, CH3), a 4.3 (q, 2H, CH2O) of 7.3 to 7.7 (m, 8H, aromatic), and 8.0 (bs, 1H, N-C6H4-C at position 2).

Infrared spectrum (KBr), characteristic bands in cm-1: 3375, 2980, 2930, 1720, 1655, 1610, 1600, 1560, 1460, 1370, 1240, 1155, 760,735, 700, 690.

Example 37. In a solution of 0.6 g of N,N'what.BUTYLCARBAMATE-(2R, 4R) 10 cm3the chloroform. The reaction mixture was stirred for 2 h at a temperature of approximately 25oC, then add to 0.44 g of 2-(3-AMINOPHENYL)-ethanol dissolved in 5 cm3the chloroform. The reaction mixture is stirred for 12 hours at a temperature of about 25oC, then concentrated to dryness under reduced pressure and at 40oC. the resulting oil residue purified by chromatography on silica (eluent: ethyl acetate), and the fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and at 40oC. Thus, obtained after recrystallization in acetonitrile 0.18 g 3(-2(3-(3-(2-hydroxyethyl) phenyl)ureido)acetyl)-2-phenyl-4-thiazolidine.BUTYLCARBAMATE- (2R, 4R) in the form of white crystals, melting at 164oC, //2D0= +59,61,8(C = 0,50%, D MF).

Proton NMR (300 MHz, DMCO D6, / h/m), 2 rotamer at room temperature, coalescence lines at 120oC, characteristic chemical shifts at 120oC: 2,7-3,60 (2t, 4H, CH2CH2O), 6,8 (6d, 1H, N-C6H4-C at position 4 or 6), 7,05-7,20 (m, 3H, N-C6H4-C at position 2.5 and 6), and 7.3 (m, 3H, C6H5), and 7.6 (d, 2H, C6H5).

Infrared SP is

Example 38. In a solution of 1.3 g of N,N'-diimidazole-carbonyl 15 cm3anhydrous tetrahydrofuran (THF) added over 2 h a solution of 2.6 g (3-(2-aminoacetyl) 2-phenyl-4-thiazolidine. BUTYLCARBAMATE (2R, 4R) 15 cm of anhydrous tetrahydrofuran. The reaction mixture is stirred at a temperature of approximately 25oC for 12 h, then concentrated to dryness under reduced pressure and the 40oC. the resulting oil residue purified by chromatography on silica (eluent: ethyl acetate). A solution of 2.8 g of 3-/2-(1-imidazolecarboxamide)acetyl/2-phenyl-4-thiazolidine. BUTYLCARBAMATE -(2R, 4R) thus obtained, and 2.7 g of 3-aminophenylacetate 100 cm3toluene is heated under reflux for 4 hours After cooling at a temperature of approximately 25oC, the reaction mixture is washed successively with 50 cm3water, 50 cm3aqueous solution of 1N hydrochloric acid and 2 times 50 cm3water. The organic phase is separated, dried over magnesium sulfate and concentrated to dryness under reduced pressure and the 40oC. the resulting oil residue purified by chromatography on silica (eluent: ethyl acetate-cyclohexane (50/50 by vol.). The fractions containing the desired product are pooled, then concentrated to dryness with onigen the-2-phenyl-3-thiazolidine) 2-oxo - ethyl)ureido)phenylethylamine-(2R, 4R) in the form of powder light beige color, melting at 69oC, //2D0= +59,11,2(C = 0,55%, CHCl3).

Proton NMR (200 MHz, DMCO D6in ppm), 2 rotamer at room temperature, coalescence lines at 120oC, characteristic chemical shifts at 120oC TO 3.7 (2S, 5H, CH2CO2CH3), 6,8 (d, 1H, N-C6H4-C at position 4 or 6), and 7.1 to 7.7 (m, 8H, aromatic).

Infrared spectrum (KBr), characteristic bands in cm-1: 3370, 2980, 2950, 2930, 1740, 1650, 1610, 1595, 1560, 1495, 1370, 1240, 1155, 780, 735, 700.

Example 39. In a solution of 1.2 g 3-(3-(2-(4-tert-butoxycarbonyl-2 - phenyl-3-thiazolidine)2-oxo-ethyl)ureido) phenylethylamine-(2R, 4R) 25 cm3a mixture of water-tetrahydrofuran (30/70 vol.) add at a temperature of about 5oC 0.1 g of lithium hydroxide. The reaction mixture is stirred for 12 hours at a temperature of about 25oC, then concentrated to a volume of 5 cm3under reduced pressure and the 40oC. the resulting solution was diluted with 50 cm3water, washed with 2 times 30 cm3ethyl ether, then acidified to pH 2 with 2.8 cm3aqueous solution of 1N hydrochloric acid. The insoluble product is filtered off, washed 3 times in 10 cm3water-oxo-ethyl)ureido) phenylacetic-(2R, 4R) acid, melting at 140oC, //2D0= +62,61,6(C = 0,64%, DMF).

Proton NMR (200 MHz, DMCO D6in h/million), 2 rotamer at room temperature, coalescence bands at 120oC, characteristic chemical shifts at 120oC: of 3.60 (bs, 2H, CH2CO2H) to 6.8 (bd, 1H, N-C6H4-C at position 6), 7,15 - 7,80 (m, 8H, aromatic).

Infrared spectrum (KBr), characteristic bands in cm-1: 3385, 2985, 2945, 2625, 1735, 1650, 1615, 1600, 1560, 1500, 1375, 1240, 1155, 785, 735, 705.

Example 40. According to the method described in example 33, but on the basis of 3.5 g of 2-(2-forfinal)-4-thiazolidine. BUTYLCARBAMATE-(2RS, 4R), 2.3 g of 2-(3-(3-were)ureido)acetic acid and 2.3 g of N,N'-dicyclohexylcarbodiimide. So, get after stirring in heptane 1,05 g 3-(2-(3-(3-were)ureido)acetyl)-2-(2-forfinal)-4-thiazolidine. BUTYLCARBAMATE-(2R, 4R) as a white solid, melting at 107oC, //2D0= +61,81,5(C = 0,66%. DMF).

Proton NMR (200 MHz, DMCO D6in ppm), 2 rotamer at room temperature, coalescence lines at 120oC: 2,2 (bs, 3H, CH3), 6,7 (bd, 1H, N-C6H4-C at position 4 or 6), 7,1 - 7,40 (m, 6H aromaticheski>1: 3370, 2975, 2925, 1735, 1645, 1615, 1560, 1490, 1460, 1370, 1150, 775, 760, 690.

2-(2-Fluoro-phenyl)-4-thiazolidine. butylcarbamoyl-(2RS, 4R) can be obtained as described in example 34, B, but on the basis of 5.7 g of 2-(2-forfinal)-4-thiazolidinones-(2RS, 4H) acid, dissolved in 60 cm3chloroform, 1.5 cm3concentrated sulphuric acid and an excess of isobutene. Thus, the gain of 5.8 g of 2-(2-fluoro-phenyl)-4-thiazolidine.BUTYLCARBAMATE-(2RS, 4R) in the form of a yellow oil, a mixture (50/50 weight) of isomers (2R, 4R) and (2S, 4R), which is used for subsequent reactions of synthesis.

2-(2-Forfinal)-4-thiazolidinedione-(2RS, 4R) acid may be obtained as described in example 34, G, but according to 21.2 g of L-cysteine and 19.2 cm32-fluoro-benzaldehyde. Thus, the gain of 28.2 g of 2-(2-forfinal)-4-thiazolidinones-(2RS, 4R) acid, melting at 147oC, which is used for subsequent reactions of synthesis.

Example 41. In a solution of 4.2 g 3-(3-(2-(4-tert.butoxycarbonyl-2- (3-methoxyphenyl)-3-thiazolidine) 2-oxo-ethyl)ureido)-2 - trimethylsilylimidazole (2R, 4R) 80 cm3the tetrahydrofuran was added when the temperature is approximately 25oC 13,7 cm3solution of 1M tetrabutylammonium fluoride in tetrahydrofuran. The reaction mixture peremeshennoi acid. After extracting 3 times with 50 cm3ethyl acetate, the combined organic phases are washed with 60 cm3water, then extracted with 2 times 20 cm3aqueous solution of 1N sodium hydroxide. The aqueous phase was separated, washed 2 times in 40 cm3diethyl ether, acidified to pH 4 aqueous solution of 4N sulfuric acid and extracted with 3 times 50 cm3diethyl ether. The combined organic phases, dried over magnesium sulfate and concentrated to dryness under reduced pressure and at 30oC. the Obtained solid is dissolved in 10 cm3an aqueous solution of 0.5 N sodium hydroxide. The resulting solution is filtered and acidified by adding 5 cm3aqueous solution of 1N hydrochloric acid. The insoluble product is filtered 2 times in 5 cm3water and dried in air. Thus, receive 1.48 g of 3-(3-2-(4-tert. butoxycarbonyl-2-(3-methoxyphenyl)-3-thiazolidine) -2-oxo-ethyl)ureido) benzoic-(2R, 4R) acid, melting at 125oC, //2D0= +742(C = 0,32, DMF).

Proton NMR (200 MHz, DMCO D6in ppm), 2 rotamer at room temperature, coalescence lines at 120oC, characteristic chemical shifts at 120oC: of 3.8 (s, 3H, OCH3) 6,85 (bd, 1H, O-CACLs spectrum (KBr), characteristic bands in cm-1: 3380, 2975, 2930, 2830, 2600, 1715, 1690, 1655, 1600, 1555, 1490, 1370, 1230, 1150, 1050, 755, 690, 680.

A) 3-(3-(2-(4-Tert.butoxycarbonyl-2-(3-methoxyphenyl)-3-thiazolidine)-2 - oxo-ethyl)ureido)-2-trimethylsilylethynyl -(2R, 4R) can be obtained as follows: to a solution of 3.5 g of 2-(3-methoxyphenyl)-4-thiazolidine.BUTYLCARBAMATE (2RS, 4R) and 4.0 g 2-(3-(3-(2-trimethylsilylethynyl)phenyl)ureido) acetic acid in 20 cm3anhydrous tetrahydrofuran, cooled to a temperature of about 5oC add 10 minutes a solution of 2.45 g of N, N'-dicyclohexylcarbodiimide 10 cm3anhydrous tetrahydrofuran. The reaction mixture is stirred for 16 hours at a temperature of about 25oC. the Insoluble product is filtered and washed with 2 times 10 cm3tetrahydrofuran (THF). The filtrate is concentrated to dryness under reduced pressure and the 40oC. the resulting oil residue purified by chromatography on silica (eluent: ethyl acetate-cyclohexane (30/70 about. )). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and the 40oC. Thus, get 4,85 g 3-(3-(2-(4-tert.butoxycarbonyl-2-(3-(methoxyphenyl)-3-thiazolidine) -2-oxo-ethyl)ureido-2-trimethylsilylimidazole-(2R, +67,21,3(C = 0,52%, CHCl3).

B) 2-(3-methoxyphenyl)-4-thiazolidine.butylcarbamoyl (2RS, 4R) can be obtained in the manner similar to that described in example 34, B, but on the basis of 14.0 g of 2-(3-methoxyphenyl)-4-thiazolidinones-(2RS, 4R) acid, 3.0 cm3concentrated sulphuric acid and an excess of isobutene. The resulting crude product is purified by chromatography on silica (eluent: ethyl acetate-cyclohexane (30/70 about. )). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and the 40oC. are Thus obtained 11 g of 2-(3-methoxyphenyl)-4-thiazolidine.BUTYLCARBAMATE (2RS, 4R) in the form of a yellow oil, a mixture (40/60 weight.) isomers (2R, 4R) and (2S, 4R), which is used in the subsequent synthesis.

A) 2-(3-Methoxyphenyl)-4-thiazolidinedione-(2RS, 4R) acid may be obtained as described in example 34, G, but according to 21.2 g of L-cysteine and 23 cm33-methoxybenzaldehyde. So, get 38 g of 2-(3-methoxyphenyl)-4-thiazolidinones-(2RS, 4R) acid, melting at 171oC, which is used for subsequent synthesis.

G) 2-(3-(3-(2-Trimethylsilylethynyl(phenyl)ureido)acetic acid can be obtained in the following way: make a solution of 4.45 g of potassium hydroxide in 160 cm3. The reaction mixture is stirred for 12 hours at a temperature of about 25oC, then concentrated to 150 cm3under reduced pressure and at 40oC. the resulting solution was diluted with 200 cm3water, washed with 2 times 50 cm3ethyl acetate, acidified with 68 cm3aqueous solution of 1N hydrochloric acid and extracted with 3 times 100 cm3diethyl ether. The combined organic phases, dried over magnesium sulfate and concentrated to dryness under reduced pressure. Obtained after crystallization in oxide diisopropyl 17,2 g 2-(3-(3-(2-trimethylsilylethynyl)phenyl)ureido) acetic acid, melting at 173oC.

D) 3-(3-Ethoxycarbonylmethylene)-2-trimethylsilylethynyl can be obtained in the following way: a solution of 29.5 g of 2-(1-imidazolecarboxamide)-acetic acid ethyl ester and 36.2 g of 3-amino-2-trimethylsilylimidazole 1000 cm3toluene is stirred under reflux for 3 hours After cooling to a temperature of about 25oC the reaction mixture is washed with 3 times 50 cm3water, dried over magnesium sulfate and concentrated to dryness under reduced pressure and the 40oC. the resulting oil residue purified by chromatography on silica (eluent: ethyl is hinnon pressure and 40oC. Thus, the gain of 24.7 g of 3-(3-ethoxycarbonylmethylene)-2-trimethylsilylimidazole in the form of a viscous yellow oil, used in the subsequent synthesis.

E) 2-(1-Imidazolecarboxamide)-acetic acid ethyl ester can be obtained in the following way: a solution of 50.0 g of N,N'-diimidazole-carbonyl and 43 cm3of triethylamine in 800 cm3anhydrous tetrahydrofuran added dropwise within 2 h of 42.3 g of the hydrochloride of 2-amino-ethyl acetate. The mixture is stirred for 24 hours at a temperature of about 25oC, then the insoluble product is filtered and washed with 2 times 50 cm3tetrahydrofuran (THF). The filtrate is concentrated to dryness under reduced pressure and the 40oC. the resulting oil residue purified by chromatography on silica (eluent: ethyl acetate). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure. So, get to 36.7 g of 2-(1-imidazolecarboxamide)-acetic acid ethyl ester, melting at +103oC.

G) 3-Amino-2-trimethylsilylethynyl can be obtained in the following way: a solution of 42.7 g of 3-nitro-2-trimethylsilyl-ethylbenzoic 600 cm3ethanol is added 2.1 g of 5% palladium on soot. The suspension is stirred for 2 hours at a temperature of the at reduced pressure and 40oC. Thus, receive and 36.2 g of 3-amino-2-trimethylsilyl-ethylbenzoic in the form of oils used in the subsequent synthesis.

C) 3-Nitro-2-trimethylsilyl-ethylbenzoic can be obtained in the following way: a solution to 66.0 g of 3-nitro-benzoyl chloride in 1000 cm31,2 dichloroethane, cooled to 5oC, add a solution of 41.8 g of 2-(trimethylsilyl)-ethanol in 200 cm31,2-dichloroethane and 51 cm3of triethylamine. The reaction mixture is stirred for 12 hours at a temperature of about 25oC, then the insoluble product is filtered and washed with 2 times 50 cm31,2-dichloroethane. The filtrate is concentrated to dryness under reduced pressure and the 40oC. the resulting oil residue is purified by chromatography on silica (eluent: ethyl acetate-cyclohexane (30/70 vol.)). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and the 40oC. Thus, get 76.9 g of 3-nitro-2-trimethylsilyl-ethylbenzoic in the form of oils used in the subsequent synthesis.

Example 42. According to the method described in example 41, but on the basis of 2.3 g 3-(3-(2-(4-tert-butoxycarbonyl-2-(2-fluoro-phenyl)-3 - thiazolidine)2-oxo-ethyl)ureido)2-trimethylsilyl-ethylbenzoic- (2R, 4R) and 7.6 cm31M solution ftol (90/10 vol.)). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and the 40oC. Thus, obtained after shaking in oxide diisopropyl: 0.4 g 3-(3-(2-(4-tert-butoxycarbonyl-2-(2-fluoro-phenyl)-3-thiazolidine)-1 - oxo-ethyl)ureido)benzoic-(2R, 4R)-acid as an amorphous solid, //2D0= +68,31,8(C = 0,57%, CHCl3).

Proton NMR (200 MHz, DMCO D6in ppm), 2 rotamer at room temperature, coalescence lines at 120oC, characteristic chemical shifts at 120oC: 7,2-7,6 (m, 6H aromatic), 7,9 (bt, 1H, F-C6H4in position 3, JHF= 9 Hz), and 8.0 (bs, 1H, N-C6H4in position 2).

Infrared spectrum (KBr), characteristic bands in cm-1: 3380, 2980, 2930, 2600, 1735, 1690, 1655: 1610, 1590, 1555, 1490, 1455, 1370, 1230, 1150, 760, 680.

3-(3-(2-(4-Tert-butoxycarbonyl-2-(2-fluoro-phenyl)-3 - thiazolidine)-2-oxo-ethyl)ureido)2-trimethylsilyl-ethylbenzoic-(2R, 4R) can be obtained by the method similar to that described in example 41, but on the basis of the 3.35 g of 2-(2-fluoro-phenyl)-4-thiazolidine. BUTYLCARBAMATE-(2RS, 4R), 4.0 g 2-(3-(3-(2-trimethylsilyl-etoxycarbonyl)phenyl)ureido)acetic acid and 2.45 g of N, N'-dicyclohexylcarbodimide. The crude product PTS is th product are combined and concentrated to dryness under reduced pressure and the 40oC. Thus, obtain 2.4 g 3-(3-(2-(4-tert-butoxycarbonyl-2-(2-fluoro-phenyl)-3-thiazolidine)-2 - oxoethyl)ureido-2-trimethylsilyl-ethylbenzoic-(2R, 4R) as amorphous solids beige colors used in subsequent synthesis, //2D0= +50,21,6(C = 0,38%, CHCl3).

Example 43. According to the method described in example 41, but on the basis of 1.6 g 3-(3-(2-(4-tert. butoxycarbonyl-2-(3-fluoro-phenyl)-3-thiazolidine)-2 - oxo-ethyl)ureido-2-trimethylsilyl-ethylbenzoic-(2R, 4R) and 5.3 cm31M solution of floridatestimonials. The crude product is purified by chromatography on silica (eluent: ethyl acetate methanol (90/10 vol.)). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and the 40oC. Thus, obtained after shaking in oxide diisopropyl, 0,22 g 3-(3-(2-(4-tert. butoxycarbonyl-2-(3-fluoro-phenyl)-3-thiazolidine)-2 - oxo-ethyl)ureido) benzoic acid (2R, 4R) acid as an amorphous solid, //2D0= +79,02,0(C = 0,43%, CHCl3).

Proton NMR (250 MHz, DMCO D6in ppm), 2 rotamer at room temperature, the nature of the>4in position 2).

Infrared spectrum (KBr), characteristic bands in cm-1: 3380, 2975, 2930, 2600, 1715, 1695, 1650, 1610, 1590, 1560, 1490, 1450, 1370, 1240, 1150, 780, 755, 685.

3-(3-(2-(4-Tert. butoxycarbonyl-2-(3-fluoro-phenyl)-3 - thiazolidine)-2-oxo-ethyl)ureido)2-trimethylsilyl-ethylbenzoic (2R, 4R) can be obtained by a method similar to that described in example 41, but on the basis of 1.68 g of 2-(3-fluoro-phenyl)-4-thiazolidine. BUTYLCARBAMATE-(2RS, 4R), 2.0 g 2-(3-(3-(2-trimethylsilyl-etoxycarbonyl)phenyl)ureido)acetic acid and 1.23 g of N, N'-dicyclohexylcarbodiimide. The crude product is purified by chromatography on silica (eluent: ethyl acetate-cyclohexane (30/70 vol.)). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and the 40oC. Thus, obtain 1.6 g 3-(3-(2-(4-tert.butoxycarbonyl-2-(3-fluoro-phenyl)-3 - thiazolidine)-2-oxo-ethyl)-ureido)2-trimethylsilyl-ethylbenzoic-(2R, 4R) as amorphous solids beige colors used in subsequent synthesis, //2D0= +45,71,5(C = 0,53%, CHCl3).

2-(3-Fluoro-phenyl)-4-thiazolidine.BUTYLCARBAMATE-(2RS, 4R) can be obtained by a method similar to that described in example 34, but on the basis of 11.4 g of 2-(3-fluoro-f the new sulphuric acid and an excess of isobutene. The resulting crude product was then purified by chromatography on silica (eluent: ethyl acetate-cyclohexane (30/70 vol.)). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and the 40oC. Thus, obtain 10.3 g of 2-(3-fluoro-phenyl)-4-thiazolidine.BUTYLCARBAMATE-(2RS, 4R) in the form of a yellow oil, a mixture (30/70 wt.) isomers (2R, 4R) and (2S, 4R), which is used for subsequent synthesis.

2-(3-Fluoro-phenyl)-4-thiazolidinedione-(2RS, 4R) acid may be obtained as described in example 34, G, but according to 21.2 g of L-cysteine and 20 cm33-fluoro-benzaldehyde. So, get up from 30.2 g of 2-(3-fluoro-phenyl)-4-thiazolidinones-(2RS, 4R) acid, melting at 178oC used in the subsequent synthesis.

Example 44. According to the method described in example 41, but on the basis of 2.0 g 3-(3-(2-(4-tert. butoxycarbonyl-2-(4-fluoro-phenyl)-3-thiazolidine)2-oxo-ethyl) ureido)-2-trimethylsilyl-ethylbenzoic (2R, 4R) and 6.6 cm31M solution of tetrabutylammonium fluoride. The crude product is purified by chromatography on silica (eluent: ethyl acetate). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and the 40oC. Thus, obtained after shaking the Neu-(2R, 4R) acid, melting at 154oC, //2D0= +49,71,3(C = 0,46%, DMF).

Proton NMR (250 MHz, DMSO D6in h/min), 2 rotamer at room temperature, characteristic chemical shifts at 25oC: of 1.5 (bs, 9H, (CH3)3), a 7.1 to 7.8 (m, 7H, aromatic), and 8.0 (bs, 1H, N-C6H4in position 2).

Infrared spectrum (KBr), characteristic bands in cm-1: 3380, 2985, 2945, 2625 ,1695, 1650, 1610, 1560, 1510, 1490, 1375, 1235, 1155, 800, 760, 685.

3-(3-(2-(4-Tert.butoxycarbonyl-2-(4-fluoro-phenyl)-3-thiazolidine)- 2-oxo-ethyl)ureido)-2-trimethylsilyl-ethylbenzoic (2R, 4R) can be obtained by a method similar to that described in example 41, A, but on the basis of 1.68 g of 2-(4-fluoro-phenyl)-4-thiazolidine. BUTYLCARBAMATE-(2RS, 4R), 2.0 g 2-(3-(3-(2-trimethylsilyl-etoxycarbonyl) phenyl) ureido) of acetic acid and of 1.23 g of N, N'-dicyclohexylcarbodiimide. The crude product is purified by chromatography on silica (eluent: ethyl acetate-cyclohexane (30/70 vol.). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and the 40oC. Thus, obtain 2.0 g 3-(3-(2-(4-tert.butoxycarbonyl-2-(4-fluoro-phenyl)-3-thiazolidine)-2-oxoethyl) ureido-2-trimethylsilyl-ethylbenzoic (2R, 4R) in the form of Amorin1(C = 0,50%, CHCl3).

2-(4-Fluoro-phenyl)-4-thiazolidine. butylcarbamoyl-(2RS, 4R) can be obtained by a method similar to that described in example 34, B, but on the basis of 11.4 g 2(4-fluoro-phenyl)-4-thiazolidinones-(2RS, 4R) acid, 3.0 cm3concentrated sulphuric acid and an excess of isobutene. The resulting crude product was then purified by chromatography on silica gel (eluent: ethyl acetate-cyclohexane (30/70 vol.)). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and the 40oC. Thus, obtain 10.0 g of 2-(4-fluoro-phenyl)-4-thiazolidine. BUTYLCARBAMATE-(2RS, 4R) in the form of a yellow oil, a mixture (40/60 weight.) isomers (2R, 4R) and (2S, 4R), which is used in the subsequent synthesis.

2-(4-Fluoro-phenyl)-4-thiazolidinedione-(2RS, 4R) acid may be obtained as described in example 34, G, but according to 21.2 g of L-cysteine and 20 cm34-fluoro-benzaldehyde. So, get to 34.3 g of 2-(4-fluoro-phenyl)-4-thiazolidinones-(2RS, 4R) acid, melting at 186oC used in the subsequent synthesis.

Example 45. According to the method described in example 41, but on the basis of 2.0 g 3-(3-(2-(4-tert. butoxycarbonyl-2-(2-chloro-phenyl)-3-thiazolidine) 2-oxo-ethyl)ureido)-2-trimethylsily the th on silica (eluent: ethyl acetate-methanol (90/10 vol.)). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and the 40oC. Thus, obtained after shaking in the oxide diisopropyl, 0.65 g 3-(3-(2-(4-tert.butoxycarbonyl-2-(2-chloro-phenyl)-3-thiazolidine) 2-oxo-ethyl) ureido) benzoic-(2R, 4R) acid as an amorphous solid, //2D0= +882(C = 0,39%, CHCl3).

Proton NMR (200 MHz, DMSO D6in ppm), 2 rotamer at room temperature, coalescence lines at 120oC, characteristic chemical shifts at 120oC: of 7.3 and 7.6 (m, 7H, aromatic), 7,95 (bs, 1H, N-C6H4in position 2).

Infrared spectrum (KBr), characteristic bands in cm-1: 3390, 2985, 2940, 2600, 1735, 1660, 1610, 1595, 1560, 1375, 1240, 1155, 755, 685.

3-(3-(2-(4-Tert. butoxycarbonyl-2-(2-chloro-phenyl)-3 - thiazolidine) 2-oxo-ethyl) ureido)-2-trimethylsilyl-ethylbenzoic-(2R, 4R) can be obtained by a method similar to that described in example 41, A, but on the basis of 1.6 g of 2-(2-chloro-phenyl)-4-thiazolidine. BUTYLCARBAMATE-(2RS, 4R), 2.0 g 2-(3-(3-(2-trimethylsilyl-etoxycarbonyl)-phenyl)ureido) of acetic acid and of 1.23 g of N, N'-dicyclohexylcarbodiimide. The crude product is purified by chromatography on silica (eluent: etelaat the pressure and the 40oC. Thus, obtain 2.0 g 3-(3-(2-(4-tert.butoxycarbonyl-2-(2-chloro-phenyl)-3-thiazolidine)-2 - oxoethyl)ureido)-2-trimethylsilyl-ethylbenzoic-(2R, 4R) as amorphous solids beige colors used in subsequent synthesis, //2D0= +87,02,0(C = 0,46%, CHCl3).

2-(2-Chloro-phenyl)-4-thiazolidine. butylcarbamoyl-(2RS, 4R) can be obtained by a method similar to that described in example 34, B, but on the basis of 12.2 g of 2-(2-chloro-phenyl)-4-thiazolidinones-(2RS, 4R) acid, 3.0 cm3concentrated sulphuric acid and an excess of isobutene. The resulting crude product was then purified by chromatography on silica (eluent: ethyl acetate-cyclohexane (30/70 about. )). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and the 40oC. Thus, the gain of 11.0 g of 2-(2-chloro-phenyl)-4-thiazolidine. BUTYLCARBAMATE (2RS, 4R) in the form of a yellow oil, a mixture (40/60 weight.) isomers (2R, 4R) and (2S, 4R), which is used in the subsequent synthesis.

2-(2-Chloro-phenyl)-4-thiazolidinedione-(2RS, 4R) acid can be obtained, as in example 34, G, but according to 21.2 g of L-cysteine and 25.8 g of 2-chloro-benzaldehyde. Thus, to 21.9 g of 2-(2-chorus-phenyl)-4-thiazolidine is On the way described in example 41, but on the basis of 4.0 g 3-(3-(2-(4-tert. butoxycarbonyl-2-(3-hydroxy-phenyl)-3 - thiazolidine)-2-oxo-ethyl)ureido)-2-trimethylsilyl-ethylbenzoic (2R, 4R) and 11.8 cm31M solution of tetrabutylammonium chloride. The crude product is purified by chromatography on silica (eluent: ethyl acetate). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and the 40oC. the Solid residue is dissolved in 8.0 cm3an aqueous solution of sodium hydroxide of 0.5 N. the Solution is filtered and acidified with 4.1 cm3aqueous solution of 1N hydrochloric acid. The insoluble product is filtered, washed with 2 times 5 cm3water and dried in air. Thus, the gain of 0.65 g 3-(3-(2-(4-tert.butoxycarbonyl-2-(3-hydroxyphenyl)-3-thiazolidine)-2 - oxo-ethyl)ureido)benzoic acid (2R, 4R) acid, melting at 150oC. //2D0= +622(C = 0,28, DMF).

Proton NMR (200 MHz, DMCO D6in ppm), 2 rotamer at room temperature, coalescence lines at 120oC: 6,8 (bd, 1H, O-C6H4-C at position 4), of 7.0 and 7.6 (m, 6H aromatic), and 8.0 (bs, 1H, N-C6H4in position 2).

Infrared spectrum (KBr), characteristic bands in cm-1: 3380 is diazolidinyl) 2-oxo-ethyl)ureido)-2-trimethylsilyl-ethylbenzoic- (2R, 4R) can be obtained by a method similar to that described in example 41, but on the basis of 1.66 g of 2-(3-hydroxy-phenyl)-4 - thiazolidine.BUTYLCARBAMATE-(2RS, 4R), 2.0 g 2-(3-(3-(2-trimethylsilyl-etoxycarbonyl)phenyl)ureido) of acetic acid and of 1.33 g of N, N'-dicyclohexylcarbodiimide. Thus, gain 4.0 g 3-(3-(2-(4-tert. butoxycarbonyl-2-(3-hydroxy - phenyl)-3-thiazolidine)-2-oxo-ethyl)ureido-2-trimethylsilyl - ethylbenzoic (2R, 4R) as amorphous yellow powder used in the subsequent synthesis.

2-(3-Hydroxy-phenyl)-4-tizanidine. butylcarbamoyl-(2RS, 4R) can be obtained by a method similar to that described in example 34, B, but on the basis of 11.3 g of 2-(3-hydroxy-phenyl)-4-thiazolidinones- (2RS, 4R) acid, dissolved in 200 cm3chloroform, 3.0 cm3concentrated sulphuric acid and an excess of isobutene. The resulting crude product was then purified by chromatography on silica (eluent: ethyl acetate/cyclohexane (30/70 by vol.). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and the 40oC. Thus, obtain 4.5 g of 2-(3-hydroxy-phenyl)-4-thiazolidine. BUTYLCARBAMATE (2RS, 4R) in the form of a yellow oil, a mixture (50/50 wt.) isomers (2R, 4R) and (2S, 4R), which is used when posl example 34, G, but according to 21.2 g of L-cysteine and 22.8 g of 3-hydroxybenzaldehyde. Thus receive 37.5 g of 2-(3-hydroxy-phenyl)-4-thiazolidinones-(2RS, 4R) acid, melting at 207oC used in the subsequent synthesis.

Example 47. According to the method described in example 41, but on the basis of 1.3 g 3-(3-(2-(4-tert. butoxycarbonyl-2-phenyl-3-thiazolidine) 2-oxo-ethyl)ureido)-2-trimethylsilyl-ethylbenzoic (2R, 4R) and 4.5 cm3molar solution of tetrabutylammonium fluoride. The crude product is purified by chromatography on silica (eluent: ethyl acetate-methanol (95/5 by vol.). The fractions containing the desired product are combined and concentrated to dryness under reduced pressure and the 40oC. the Solid residue is dissolved in 4.0 cm30.5 N aqueous solution of sodium hydroxide. The solution is filtered and acidified with 2.1 cm31N aqueous solution of hydrochloric acid. The insoluble product is filtered, washed with 2 times 5 cm3water and dried in air. Thus, the gain of 0.33 g 3-(3-(2-(4- tert. butoxycarbonyl-2-phenyl-3-thiazolidine) 2-oxo-ethyl)ureido) benzoic-(2R, 4R) acid, melting at 134oC. //2D0= +853(C = 0,40%, CHCl3).

Proton NMR (250 MHz, DMCO D6in ppm), 2 the 120oC: of 7.3 to 7.7 (m, 8H, aromatic), and 8.0 (bs, 1H, N-C6H4-C at position 2).

Infrared spectrum (KBr), characteristic bands in cm-1: 3380, 2980, 2930, 2600, 1690, 1650, 1610, 1590, 1555, 1490, 1370, 1235, 1150, 760, 730, 700, 680.

3-(3-(2-(4-Tert. butoxycarbonyl-2-phenyl-3-thiazolidine) 2-oxoethyl)ureido)-2-trimethylsilyl-ethylbenzoic-(2R, 4R) can be obtained by a method similar to that described in example 38, but from 1.7 g of 3-(2-(1-imidazolyl-carboxamide)acetyl)-2-phenyl-4 - thiazolidine.BUTYLCARBAMATE-(2R, 4R) and 12 g of 3-amino-2 - trimethylsilyl-ethylbenzoic. The crude product is purified by chromatography on silica (eluent: ethyl acetate-cyclohexane (30/70 about. )). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and the 40oC. Thus, obtain 1.3 g 3-(3-(2-(4-tert. butoxycarbonyl-2-phenyl-3-thiazolidine) 2-oxo-ethyl)ureido) 2-trimethylsilyl-ethylbenzoic-(2R, 4R) in the form of an orange oil, used in the subsequent synthesis.

Example 48. According to the method described in example 41, but on the basis of 4.0 g 3-(3-(2-(4-tert. butoxycarbonyl-2-(4-dimethylamino-phenyl)-3 - thiazolidine)-2-oxo-ethyl)ureido)-2-trimethylsilyl-ethylbenzoic (2R, 4R) and 4.2 cm31M solution of tetrabutylammonium fluoride. The crude product is purified which are combined and concentrated to dryness under reduced pressure and the 40oC. Thus, after shaking in oxide diisopropyl obtain 0.35 g 2-(3-(2-(4-tert. butoxycarbonyl-2-(4-dimethylamine-phenyl)-3 - thiazolidine (2-oxo-ethyl)ureido) benzoic-(2R, 4R) as amorphous solid product, //2D0= +1383(C = 0,37%, CHCl3).

Proton NMR (200 MHz, DMCO D6in ppm), 2 rotamer at room temperature, coalescence lines at 120oC, characteristic chemical shifts at 120oC: 6,7 (bd, 2H, (Me)2) N-C6H4in positions 3 and 5), and 7.3 and 7.6 (m, 5H, aromatic), and 8.0 (bs, 1H, N-C6H4in position 2).

Infrared spectrum (KBr), characteristic bands in cm-1: 3380, 2975, 2930, 2805, 2600, 1715, 1690, 1650, 1610, 1555, 1520, 1485, 1365, 1230, 1150, 815, 760, 685.

And) 3-(3-(2-(4-Tert. butoxycarbonyl-2-(4-dimethylamine-phenyl)- 3-thiazolidine)-2-oxo-ethyl)ureido)-2-trimethylsilyl-ethylbenzoic (2R, 4R) can be obtained by a method similar to that described in example 41, A, but on the basis of 1.66 g of 2-(4-dimethylaminophenyl)-4 - thiazolidine.BUTYLCARBAMATE (2RS, 4R), 2.0 g 2-(3-(3-(2-trimethylsilylethynyl)phenyl)ureido)of acetic acid and of 1.23 g of N,N'-dicyclohexylcarbodiimide. The crude product is purified by chromatography on silica (eluent: ethyl acetate-cyclohexane (30/70 vol.). the thus, the get 1.3 g 3-(3-(2-(4-tert.butoxycarbonyl-2- (4-dimethylamine-phenyl)-3-thiazolidine)-2-oxo-ethyl)ureido)-2 - trimethylsilyl-ethylbenzoic-(2R, 4R) as amorphous solids beige colors used in subsequent synthesis, //2D0= +932(C = 0,49%, CHCl3).

B) 2-(4-dimethylaminophenyl)-4-thiazolidine.butylcarbamoyl- (2RS, 4R) can be obtained in the following way: a solution of 8.1 g of 3-tert.butoxycarbonyl-2-(4-dimethylaminophenyl)-4 - thiazolidine.BUTYLCARBAMATE (2RS, 4R) 100 cm3chloroform was added dropwise 2,95 cm3attributively at a temperature of approximately 25oC. the Reaction mixture was stirred for 18 h at this temperature, then add 50 cm3water. The organic phase is separated, washed with 2 times 30 cm3saturated aqueous solution of acid sodium carbonate and 2 times 30 cm3water, then extracted 3 times with 30 cm3a water solution of hydrochloric acid 1N. The aqueous phase unite, washed with 2 times 20 cm3dichloromethane, adjusted to pH 7 aqueous solution of 4N sodium hydroxide and extracted 3 times with 30 cm3dichloromethane. The combined organic phases are dried over magnesium sulfate and concentrated dorene (eluent: oxide of diisopropyl). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure. Thus, the gain of 2.3 g of 2-(4-dimethylaminophenyl)-4-thiazolidin - tert. BUTYLCARBAMATE-(2RS, 4R), melting at 142oC, the mixture (50/50 wt.) isomers (2R, 4R) and (2S, 4R) used in the subsequent synthesis.

C) 3-tert.butoxycarbonyl-2-(4-dimethylaminophenyl)-4 - thiazolidine.butylcarbamoyl (2RS, 4R) can be obtained in the following way: a solution of 14.8 g of 3-tert. butoxycarbonyl-2- (4-dimethylaminophenyl)-4-thiazolidinones-(2RS, 4R) acid and 16.0 g of paratoluenesulfonyl 70 cm3anhydrous pyridine, cooled to a temperature of approximately 0oC, enter 3.1 g of tert. butanol. After returning to a temperature of 20oC is stirred for 20 h, then the mixture is poured into 200 cm3water and extracted with 3 times 100 cm3ethyl acetate. The combined organic phases are washed successively with 2 times 100 cm3water, 2 times 100 cm3an aqueous solution of sodium hydroxide 1N and 2 times 100 cm3water, then dried over magnesium sulfate and concentrated to dryness under reduced pressure and at 40oC. the resulting crude product was then purified by chromatography on silica (eluent: oxide of Diisopropylamine approximately 45oC. Thus, the gain of 8.1 g of 3-tert. butoxycarbonyl-2- (4-dimethylaminophenyl)-4-thiazolidine.butyl carboxylate (2RS, 4R) in the form of an orange oil, which is used for subsequent synthesis.

G), 2-Tert. butoxycarbonyl-2-(4-dimethylaminophenyl)-4 - thiazolidinedione-(2RS, 4R) acid can be obtained in the following way: a solution of 12.6 g of 2-(4-dimethylaminophenyl)-4 - thiazolidinones-(2RS, 4R) acid, a 5.25 g of sodium carbonate in 100 cm3water was added dropwise, with stirring, to 10.9 g dicarbonate dicret. butyl dissolved in 50 cm3dioxane. The reaction mixture is stirred for 20 hours at a temperature of about 20oC, then the resulting precipitate is filtered off. The filtrate is washed with 2 times 100 cm3ethyl acetate, acidified to pH 4 aqueous solution of 4N hydrochloric acid, then extracted with 3 times 100 cm3ethyl acetate. Combine the organic phases are washed with 2 times 50 cm3, dried over magnesium sulfate and concentrated to dryness under reduced pressure and the 40oC. Thus, obtained after crystallization in oxide diisopropyl, 14.8 g of 3-tert.butoxycarbonyl-2-(4-dimethylaminophenyl)-4-thiazolidinones- (2RS, 4R) acid, melting at 175oC.

2-(4-Dimethylaminophenyl)-4-dimethylaminobenzaldehyde. So, get 41.5 g of 2-(4-dimethylaminophenyl)-4-thiazolidinones-(2RS, 4R) acid, melting at 184oC used in the subsequent synthesis.

Example 49. According to the method described in example 41, but on the basis of 0.95 g 3-(3-(2-(4-tert. butoxycarbonyl-2-(3-pyridyl)-3 - thiazolidine)-2-oxo-ethyl)ureido)-2-trimethylsilyl-ethylbenzoic- (2R, 4R) and 3.2 cm31M solution of tetrabutylammonium fluoride. The crude product is purified by chromatography on silica (eluent: ethyl acetate). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and the 40oC. Thus, get, after shaking in oxide diisopropyl, 0.36g 3-(3-(2-(4-tert.butoxycarbonyl-2-(3-pyridyl)-3-thiazolidine)-2 - oxo-ethyl)ureido)benzoic-(2R, 4R) acid, melting at 147oC, //2D0= +51,11,7(C = 0,49%, DMF).

Proton NMR (200 MHz, DMCO D6in ppm), 2 rotamer at room temperature, coalescence line at 120oC, characteristic chemical shifts at 120o: to 7.3 and 7.6 (m, 5H, aromatic), and 8.0 (bs, 1H, N-C6H4-C at position 2), and 8.5 (bs, 1H, H in position 6 of pyridil).

Infrared spectrum (KBr), characteristic bands in cm-1: 3385, 2975, 2930, 260- 2-oxo-ethyl)ureido)-2-trimethylsilyl-ethylbenzoic-(2R, 4R) can be obtained by a method similar to that described in example 41, A, but on the basis of 2.0 g of 2-(3-pyridyl)-4-thiazolidine.BUTYLCARBAMATE-(2RS, 4R), 2.5 g 2-(3-(3-(2-trimethylsilyl-etoxycarbonyl)phenyl)ureido) acetic acid and 1.8 g of N,N'-dicyclohexylcarbodiimide. The crude product is purified by chromatography on silica (eluent: ethyl acetate-cyclohexane (40/60 vol.)). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and the 40oC. Thus, obtain 1.0 g 3-(3-(2-(4-tert.butoxycarbonyl-2-(3-pyridyl)-3-thiazolidine)- 2-oxo-ethyl)ureido)-2-trimethylsilyl-ethylbenzoic (2R, 4R) in the form of a yellow oil, used in the subsequent synthesis.

2-(3-Pyridyl)-4-thiazolidine.butylcarbamoyl (2RS, 4R) can be obtained by a method similar to that described in example 43, B, but on the basis of 3.4 g of 3-tert. butoxycarbonyl-2-(3-pyridyl)-4 - thiazolidine. BUTYLCARBAMATE (2RS, 4R) and 1.7 cm3attributively. Thus, the gain of 2.1 g of 2-(3-pyridyl)-4-thiazolidine. BUTYLCARBAMATE-(2RS, 4R) in the form of a yellow oil, used in the subsequent synthesis.

3-Tert. butoxycarbonyl-2-(3-pyridyl)-4 - thiazolidine.butylcarbamoyl (2RS, 4R) can be obtained in a manner analogous to the description of the 7 g paratoluenesulfonyl and 2.2 g of tert-butanol. The resulting crude product was then purified by chromatography on silica (eluent: ethyl acetate-cyclohexane (50/50 by vol.). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and the 40oC. Thus, earn 1.25 g of 3-tert.butoxycarbonyl-2-(3-pyridyl)-4-thiazolidine. BUTYLCARBAMATE (2RS, 4R) in the form of an orange oil, used in the subsequent synthesis.

3-Tert. butoxycarbonyl-2-(3-pyridyl)-4-thiazolidinedione- (2RS, 4R) acid can be obtained by a method similar to that described in example 48, G, but on the basis of 26.5 g of 2-(3-pyridyl)-4 - thiazolidinones-(2RS, 4R) acid, 130 cm31N sodium hydroxide solution and 28.4 g of dicarbonate dicret.butyl. Thus, the gain of 31.6 g of 3-tert.butoxycarbonyl-2-(3-pyridyl)-4 - thiazolidinones-(2RS, 4R) acid in the form of an amorphous yellow powder, used in the subsequent synthesis.

2-(3-Pyridyl)-4-thiazolidinedione-(2RS, 4R) acid can be obtained, as in example 34, G, but according to 25.0 g of L-cysteine and 22 cm3nicotinanilide. Thus, the gain of 26.6 g of 2-(3-pyridyl)-4-thiazolidinones-(2RS, 4R) acid, melting at 149oC used in the subsequent synthesis.

Example 50. By the way, op is enyl)ethylpropane-(2R, 4R) and 0.2 g of lithium hydroxide. The crude product is purified by chromatography on silica (eluent: ethyl acetate-methanol (90/10 vol.)). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and at 40oC. Thus, obtain 0.25 g 3-(3-(3-(2- (4-tert.butoxycarbonyl-2-phenyl-3-thiazolidine)-2 - oxo-ethyl)ureido)phenyl)ethylpropane-(2R, 4R) acid as an amorphous solid beige color, //2D0= +58,41,6(C = 0,61%, CHCl3).

Proton NMR (200 MHz, DMCO D6in ppm), 2 rotamer at room temperature, characteristic chemical shifts at 25oC: of 1.5 (bs, 9H, (CH3)3), 2,5 (bt, 2H, CH2), 2,8 (bt, 2H, CH2), 6,8 (bd, 1H, N-C6H4-C at position 4), 7,1 - 7,5 (m, 7H, aromatic) and 7.7 (bd, 2H, aromatic).

Infrared spectrum (KBr), characteristic bands in cm-1: 3380, 2975, 2930, 2620, 1730, 1645, 1610, 1590, 1555, 1490, 1370, 1235, 1150, 785, 730, 695.

3-(3-(3-(2-(4-Tert.butoxycarbonyl-2-phenyl-3-thiazolidine)- 2-oxo-ethyl)ureido)phenyl)ethylpropane-(2R, 4R) can be obtained by a method similar to that described in example 38, but from 3.75 g of 3-(2-(1-imidazolyl-carboxamide)acetyl)-2-phenyl-4 - thiazolidine.BUTYLCARBAMATE-(2R, 4R) and 3.5 g of 3-(3-what the ethyl acetate-cyclohexane (30/70 about. )). The fractions containing the desired product are pooled, then concentrated to dryness under reduced pressure and the 40oC. Thus, obtain 2.5 g 3-(3-(2-(4-tert.butoxycarbonyl-2-)- phenyl-3-thiazolidine)-2-oxo-ethyl)ureido)phenyl)ethylpropylamine (2R, 4R) in the form of oils used in the subsequent synthesis.

Example 51. According to the method described in example 39, but on the basis of 2.4 g 3-(3-(2-(4-tert.butoxycarbonyl-2-phenyl-3-thiazolidine)-2-oxo - ethyl)ureido)phenoxyethylamine-(2R, 4R) and 0.2 g of hydrocity lithium. The crude product is purified by chromatography on silica (eluent: ethyl acetate). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and the 40oC. Thus, get, after shaking in oxide diisopropyl, 1.3 g 3-(3-(2-(4-tert.butoxycarbonyl-2-phenyl-3-thiazolidine) -2-oxo-ethyl)ureido)Phenoxyethanol -(2R, 4R) acid as an amorphous solid, //2D0= +63,71,2(C = 0,96%, CHCl3).

Proton NMR (200 MHz, DMCO D6in ppm), 2 rotamer at room temperature, coalescence lines at 120oC, characteristic chemical shifts at 120oC: 4,5 (bs, 2H, OCH2CO2), 6,5 (ddd, 1H, N-C6H4-C at position 4), 6,9 (d -1: 3380, 2975, 2930, 2630, 2550, 1735, 1640, 1600, 1555, 1490, 1370, 1240, 1150, 770, 730, 695.

3-(3-(2-(4-Tert. butoxycarbonyl-2-phenyl-3-thiazolidine)- 2-oxoethyl)ureido)phenoxyacetate (2R, 4R) can be obtained by a method similar to that described in example 38, but from 4.4 g of 3-(2-(1-imidazolyl-carboxamide)acetyl)-2-phenyl - 4-thiazolidine.BUTYLCARBAMATE (2R, 4R) and 4.1 g of 3-aminophenoxy acetate. The obtained oily residue is purified by chromatography on silica (eluent: ethyl acetate-cyclohexane (about 35/65.)). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and the 40oC. Thus, obtain 2.5 g 3-(3-(2-(4-tert.butoxycarbonyl-2-phenyl - 3-thiazolidine)2-oxo-ethyl)ureido)phenoxyethylamine-(2R, 4R) as amorphous powder beige colors used in subsequent synthesis.

Example 52. In a solution of 2.5 g 3-(2-(3-(3-acetyl-phenyl)ureido)acetyl) - 2-phenyl-4-thiazolidine. BUTYLCARBAMATE-(2R, 4R) 10 cm3methanol and 5 cm3pyridine add 0.4 g of the hydrochloride hydroxylamine dissolved in 5 cm3water. The reaction mixture is stirred under reflux for 2 hours After evaporation of the solvents under reduced pressure and at 45oC, the residue is extracted with 100 cmCentricut to dryness under reduced pressure. The resulting crude product was then purified by chromatography on silica (eluent: ethyl acetate/cyclohexane (50/50 by vol.). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and the 40oC. Receive, after shaking in oxide diisopropyl, 0.5 g 3-(2-(3-(3-(1-hydroxyimino-ethyl) - phenyl-(E)/ureido)acetyl)-2-phenyl 4-thiazolidine. BUTYLCARBAMATE-(2R, 4R) as an amorphous solid, //2D0= +541,5(C = 0,61%, CHCl3).

Proton NMR (300 MHz, DMCO D6, / h/m), 2 rotamer at room temperature, coalescence lines at 120oC, characteristic chemical shifts at 120oC: 2,1 (s, 3H, CH3), 7,2-7,6 (m, 8H, aromatic), and 7.7 (bs, 1H, N-C6H4-C at position 2), and 10.8 (bs, 1H, NOH). The NOE effect was observed between stands with and 2.1 ppm and the oxime NOH when 10,8 h/million

Infrared spectrum (KBr), characteristic bands in cm-1: 3350, 2975, 2930, 1740, 1650, 1610, 1590, 1560, 1370, 1240, 1150, 1005, 790, 730, 695.

3-(2-(3-(3-Acetyl-phenyl)ureido)acetyl)-2-phenyl-4-thiazolidine.butylcarbamoyl (2R, 4R) can be obtained by a method similar to that described in example 38, but from 3.75 g of 3-(2-(1-imidazolyl-carboxamide)acetyl)-2-phenyl-4-thiazolidine. BUTYLCARBAMATE (2R, 4R) elzett-cyclohexane (50/50 by vol.). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and the 40oC. Thus, obtain 2.5 g 3-(2-(3-(3-acetyl-phenyl)ureido)acetyl)-2-phenyl-4-thiazolidine. butyl carboxylate (2R, 4R) as amorphous yellow powder used in the subsequent synthesis.

Example 53. According to the method described in example 38, but from 2.3 g of 3-(2-(1-imidazolyl-carboxamide)acetyl)-2-phenyl-4-thiazolidine. BUTYLCARBAMATE (2R, 4R) and 4.7 g of 3-amino-benzylmalonate Tetra-n-butyl-ammonium. The resulting crude product was dissolved in 20 cm3acetone and add a solution of 1.86 g nonattributable of potassium in 20 cm3of acetone. The reaction medium is stirred for 18 hours at a temperature of about 25oC, then add 80 cm3oxide diisopropyl. The insoluble product is filtered off, washed 2 times in 3 cm3mixture of acetone and nitric oxide in diisopropyl (30/70 vol.). So, get after shaking in acetonitrile, 0.75 g 3-(3-(2-(4-tert.butoxycarbonyl-2-phenyl-3-thiazolidine) 2-oxo-ethyl)uridine)benzylmalonate potassium(2R, 4R), melting at 185oC, //2D0= +37,31,4(C = 0,38%, CHCl3).

Proton NMR (300 MHz, DMCO D6, their shifts at 120oC: 3,7 (AB, 2H, CH2SO3), 6,9 (bd, 1H, N-C6H4-C at position 6), a 7.1 to 7.6 (m, 8H, aromatic).

Infrared spectrum (KBr), characteristic bands in cm-1: 3400, 2980, 2945, 1740, 1660, 1615, 1600, 1560, 1500, 1375, 1220, 1200, 1160, 1050, 800, 735, 700.

3-Amino-bansilalpet Tetra-n-butyl ammonium can be obtained by a method similar to that described in example 41, W, but on the basis of 11.6 g of 3-nitrobenzenesulfonate Tetra-n-butylamine and 0.3 g of a 5% palladium on soot. So, get 10,5 g 3-aminobenzenesulfonate Tetra-n-butylamine in the form of oils used in the subsequent synthesis.

3-Nitro-bansilalpet Tetra-n-butylamine can be obtained in the following way: to 800 cm3an aqueous solution of hydrogenphosphate potassium 0.5 M type of 6.9 g of 3-nitrobenzenesulfonate sodium, then 9,9 g acid, sulfonate, Tetra-n-butylamine. The mixture is extracted with 500 cm3of methylene chloride. The organic phase is dried over magnesium sulfate and concentrated to dryness under slight pressure and the 40oC. Thus, obtain 13 g of 3-nitrobenzenesulfonate Tetra-n-butylamine in the form of oils used in the subsequent synthesis.

3-Nitro-bansilalpet sodium can be obtained by a known method (P. ethoxycarbonyl-2-phenyl-3-thiazolidine-(2R, 4R)) 2-oxo-ethyl)uredo)phenyl)methylpropionate-(RS) and 0.11 g of lithium hydroxide. The crude product is purified by chromatography on silica (eluent: ethyl acetate). The fractions containing the desired product, after shaking in oxide diisopropyl, 0.25 g 2-(3-(3- (4-tert.butoxycarbonyl-2-phenyl-3-thiazolidine-(2R, 4R)2-oxo-ethyl) ureido)phenyl)propionic-(RS) acid as an amorphous solid.

Proton NMR (200 MHz, DMCO D6in ppm), 2 rotamer at room temperature, coalescence lines at 120oC, characteristic chemical shifts at 120oC: 1,4 (d, 3H, CH3), and 3.5 (bm, 1H, Ph-CH-CO2), 6,9 (bd, 1H, N-C6H4-C at position 4), and 7.1 to 7.4 (m, 6H aromatic), and 7.7 (bd, 2H, aromatic).

Infrared spectrum (KBr), characteristic bands in cm-1: 3385, 2975, 2935, 1735, 1650, 1610, 1560, 1495, 1455, 1370, 1240, 1155, 785, 730, 700.

2-(3-(3-(2-(4-Tert. butoxycarbonyl-2-phenyl-3-thiazolidine- (2R, 4R))-2-oxo-ethyl)ureido)phenyl)methylpropionate-(RS) can be obtained by a method similar to that described in example 38, but from 3.75 g of 3-(2-(1-imidazolyl-carboxamide)acetyl)-2-phenyl-4 - thiazolidine. BUTYLCARBAMATE-(2R, 4R) and 3.22 g of 2-(3-AMINOPHENYL)methylpropionate (RS). The resulting oil residue clean chromatogr is dried under reduced pressure and the 40oC. Thus, obtain 3.1 g 2-(3-(3-(2-(4-tert.butoxycarbonyl-2-phenyl-3-thiazolidine- (2R, 4R) 2-oxo-ethyl)ureido)phenylethylamine(RS) in the form of amorphous powder beige color, which is used for subsequent synthesis.

2-(3-Amino-phenyl)methylpropionate-(RS) can be obtained by a method similar to that described in example 41, W, but on the basis of 4 g of 3-(3-nitro-phenyl)methylpropionate-(RS) and 0.3 g of 5% palladium on soot. Thus, the gain of 3.3 g of 2-(3-amino-phenyl)methylpropionate-(RS) in the form of oils used in the subsequent synthesis.

3-(3-Nitro-phenyl)methylpropionate-(RS) can be obtained in the following way: within 3 h bubbled gaseous hydrochloric acid in a solution of 5 g of 2-(3-nitro-phenyl)propionitrile-(RS) 40 cm3of methanol. The resulting mixture was stirred under reflux for 30 min, the insoluble product is filtered. The filtrate is concentrated to dryness under reduced pressure and the 40oC. the Crude product is purified by chromatography on silica (eluent: petroleum ether-ethyl acetate (80/20 by vol.). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and at 40oC. Thus, get 4 g of 3-(3-nitro-phenyl)-methylpropionate-(RS) in the form mastectomy method (E. Felder et coll., J. Med. Chem., 13, 559, 1970).

Example 55. According to the method described in example 41, but on the basis of 1.7 g of 2-(4-fluoro-phenyl) 4-thiazolidin-tert.BUTYLCARBAMATE-(2R, 4R) dissolved in 20 cm3anhydrous acetonitrile, 1.24 g of N,N'-dicyclohexylcarbodiimide and 1.3 g of 2-(2-indolyl-carboxamido)-acetic acid in a mixture of 40 cm3anhydrous acetonitrile and 40 cm3dichloromethane, after crystallization in oxide diisopropyl, 1.7 g of 2-(4-fluoro-phenyl)-3-(2-(2-indolyl-carboxamide)acetyl/4 - thiazolidine.BUTYLCARBAMATE-(2R, 4R), melting at 176oC.

2-(2-Indolyl-carboxamido)acetic acid can be obtained by a known method (J. R. Johnson et coll., J. Am. Chem. Soc., 69, 2370, 1947).

Example 56. According to the method described in example 1, but from 1.2 g of N-methyl-N-phenyl-5-phenyl-prolinamide-(2RS, 4SR), of 0.94 g of 2-(3-(3-methyl-phenyl)ureido)acetic acid in suspension with 25 cm31,2-dichloro-ethane and 0.33 cm3sulphonylchloride, obtained after recrystallization in acetonitrile, 1 g of N-methyl-1-(3-(3-methyl-phenyl)weidacher)-N-phenyl-5-phenylpropanamide- (2RS, 4SR), melting at 210oC.

N-methyl-N-phenyl-5-phenylpropanamide-(2RS, 5SR) can be obtained by a method similar to that described in example 25, but on the basis of 2.2 g of 1-(tert.butoxycarbonyl)-PA. Obtain 1.2 g of N-methyl-N-phenyl-5-phenylpropanamide-(2RS, 5SR) in the form of an orange oil, used in the subsequent synthesis.

A) 1-(tert. butoxycarbonyl)-N-methyl-N-phenyl-5-phenylpropanamide- (2RS, 5SR) can be obtained in the following way: a suspension of 2.9 g of 1-(tert.butoxycarbonyl)-5-phenylpropanamide-(2RS, 5SR) and 1.1 cm3N-methylaniline 25 cm3anhydrous acetonitrile was added dropwise at a temperature of about 0oC a solution of 2.1 g of N,N'-dicyclohexylcarbodiimide 15 cm3anhydrous acetonitrile. The reaction medium is stirred for 30 minutes at a temperature of about 0oC, then for 20 h at a temperature of about 20oC. Then the insoluble product is filtered and washed with 2 times 20 cm3dichloromethane. The filtrate is concentrated to dryness under reduced pressure and a temperature of approximately 40oC. the resulting crude product was then purified by chromatography on silica (eluent: dichloromethane-methanol (99/1 in solution)). The fractions containing the desired product are pooled, then concentrated to dryness under reduced pressure. Thus, obtained after crystallization in pentane, 2.2 g of 1-(tert.butoxycarbonyl)-N-methyl-N-phenyl-5 - phenylpropanamine-(2RS, 5SR), melting at 132oC.

Example 57. For SPO 2-(3-(3-methyl-phenyl)ureido)acetic acid in suspension with 100 cm31,2-dichloroethane and 0.7 cm3sulphonylchloride, obtained after recrystallization in acetonitrile, 1.5 g 1-(2-(3-(3-methyl-phenyl)ureido)acetyl)-5-phenyl-(1,2,3,4 - tetrahydro-1-chinolin)-2-carbonitriding-(2RS, 5SR), melting at 158oC.

5-Phenyl-(1,2,3,4-tetrahydro-1-quinoline)-2-carbonyliron (2RS, 5SR) can be obtained by a method similar to that described in example 25, but on the basis of 4.1 g of 1-(tert.butoxycarbonyl)- 5-phenyl-(1,2,3,4-tetrahydro-1-quinoline)-2-carbonitriding (2RS, 5SR) 50 cm3anhydrous chloroform and 1.4 cm3idolisation. Get 3 g of 5-phenyl-(1,2,3,4-tetrahydro-1-quinoline)-2-carbonitriding- (2RS, 5SR) in the form of an orange oil, used in the subsequent synthesis.

1-(Tert. butoxycarbonyl)-5-phenyl-(1,2,3,4-tetrahydro-1 - chinolin)-2-carbonitriding-(2RS, 5SR) can be obtained by a method similar to that described in example 56, but on the basis of 8.7 g of 1-(tert.butoxycarbonyl)-5-phenylpropane-(2RS, 5SR), 3.8 cm31,2,3,4-tetrahydroquinoline 75 cm3anhydrous acetonitrile and 6.2 g of N,N'-dicyclohexylcarbodiimide 45 cm3anhydrous acetonitrile. Obtained after crystallization in hexane 4.1 g of 1-(tert.butoxycarbonyl)-5-phenyl-(1,2,3,4-tetrahydro-1-chinolin) -2-carbonitriding-(2RS, 5SR), PL is peridine)-2-carbonyl-5-phenylpyrrolidine-(2RS, 5SR), 1.3 g of 2-(3-(3-methyl-phenyl)ureido)acetic acid in 75 cm31,2-dichloroethane and 0.5 cm3sulphonylchloride, obtained after recrystallization in acetonitrile, 0.7 g (3,3-dimethylpiperidino)-2-carbonyl-1-(2-(3-methyl-phenyl)ureido) acetyl) 5-phenylpyrrolidine-(2RS, 5SR), melting at 150oC.

(3,3-Dimethylpiperidino)-2-carbonyl-5-phenyl-pyrrolidin- (2RS, 5SR) can be obtained in the manner similar to that described in example 25, but on the basis of 5.0 g of 1-(tert.butoxycarbonyl)-(3,3-dimethylpiperidino)- -2-carbonyl-5-phenylpyrrolidine-(2RS, 5SR) 50 cm3anhydrous chloroform and 1.9 cm3idolisation. Receive the crystallization of the oxide diisopropyl 1.8 g (3,3-dimethylpiperidino)-2-carbonyl-5-phenylpyrrolidine- (2RS, 5SR), melting at 163oC.

1-(Tert. butoxycarbonyl)-(3,3-dimethylpiperidino)- -2-carbonyl-5-phenylpyrrolidine-(2RS, 5SR) can be obtained by a method similar to that described in example 56, but on the basis of 5.8 g of 1-(tert.butoxycarbonyl)-5-phenylpropane-(2RS, 5SR), 2.6 cm33.3 dimethylpiperidine 50 cm3anhydrous acetonitrile and 4.1 g of N,N'-dicyclohexylcarbodiimide 30 cm3anhydrous acetonitrile. Obtained after crystallization in hexane 4 g 1 - (tert.butoxycarbonyl)-(3,3-dimethylpiperidino)-2-carbonyl - 5-is based on the 1.9 g of 1-(2-amino-acetyl)-5-phenyl-N-tert. butyl-prolinamide-(2RS, 5SR) dissolved in 20 cm3anhydrous tetrahydrofuran (THF) and 0.82 cm3isocyanate methyl 3-phenyl, obtained after recrystallization in acetonitrile, 0.7 g of N-tert.butyl-1-(3-(3-were)weidacher)-5-phenylpropanamide- (2SR, 5SR), melting at 169oC.

1-(2-Amino-acetyl)-5-phenyl-N-tert.butyl-prolinamide-(2RS, 5SR) can be obtained by a method similar to that described in example 2, A, but on the basis of 2.7 g of 1-(2-tert. butoxycarbonylamino-acetyl)-N-tert. -butyl-5-phenylpropanamide- (2RS, 5SR) dissolved in 50 cm3anhydrous chloroform and 0.95 cm3attributively. Gain of 1.9 g of 1-(2-aminoacetyl)-5-phenyl-N-tert.butyl-prolinamide-(2RS, 5SR) in the form of amorphous powder used in the subsequent synthesis.

Proton Yarm (250 M Hz, DMCO D6in ppm), 2 rotamer at room temperature, of 1.35 (s, 9H, C(CH3)3, 1,8-2,4 (bm, 4H, CH2-CH2), 2,7, 3,25 and 3.8 (d, 2H, AB, CH2CO2), 4,45 (bm, 1H, CHN), 5,1 (bm, 1H, CHN), 7,2-8 (m, 6H, aromatic and NH).

1-(2-Tert. butoxycarbonylamino-acetyl)N-tert-butyl-5 - phenylpropanamide can be obtained by a method similar to that described in example 2B, but from 1.8 g of N-tert.butyl-5-phenylpropanamide-(2RS, 5SR), 1.28 g of 2-tert.butoxy-carbonyloxy acid in 50 and. Obtained after crystallization in petrolina air 2.7 g of 1-(2-tert.butoxycarbonylamino)-N-tert.butyl-5-phenylpropanamide, melting at 117oC.

N-tert. butyl-5-phenylpropanamide-(2RS, 5SR) can be obtained by a method similar to that described in example 25, A, but on the basis of 3.5 g of 1-(tert.butoxycarbonyl)-N-tert. butyl-5-phenylpropanamide-(2RS, 5SR) 50 cm3anhydrous chloroform and 2.1 cm3attributively. Obtain 1.8 g of N-tert.butyl-5-phenylpropanamide-(2RS, 5SR) in the form of a yellow oil, used in the subsequent synthesis.

1-(Tert.butoxycarbonyl)-N-tert.butyl-5-phenylpropanamide-(2RS, 5SR) can be obtained in the following way: a solution of 2.9 g of 1-tert.butoxycarbonyl-5-phenylpropane-(2RS, 5SR) 50 cm31,2-dichloroethane was added when the temperature of about 20oC 1.8 g of N,N'-diimidazole. The reaction medium is stirred for 2 hours at a temperature of about 20oC, then add 1 cm3tert.of butylamine and heated under reflux for 5 hours, stirring. After cooling, the reaction mixture is diluted with 100 cm3dichloromethane and washed successively with 2 times 50 cm3standard aqueous solution of hydrochloric acid, then 3 times in 50 cm3water. Organic f is imaut chromatography on silica (eluent: dichloro-methanol (a 97.5/2.5 to about. )), and fractions containing the desired product are pooled and concentrated to dryness under reduced pressure. Thus, get 3 g of 1-(tert.butoxycarbonyl)-N-tert. butyl-5-phenylpropanamide-(2RS, 5SR) in the form of a yellow oil, used in the subsequent synthesis.

Example 60. According to the method described in example 9, but on the basis of 10.6 g 3-(3-(2-(2,5-diphenyl-1-pyrrolidinyl) 2 oxo-ethyl)ureido)phenyl-acetate-(CIS), dissolved in 150 cm3methanol and 1.7 g of potassium hydroxide dissolved in 30 cm3water, and after treatment and recrystallization in ethanol 1.2 g 3-(3-(2-(2,5-diphenyl-1-pyrrolidinyl)2-oxo-ethyl)ureido) phenylacetic acid (CIS) acid, melting at 152oC.

3-(3-(2-(2,5-Diphenyl-1-pyrrolidinyl)2-oxo-ethyl)ureido) feniletilamin-(CIS) can be obtained by a method similar to that described in example 41, A, but on the basis of of 4.45 g of 2,5-diphenylpyrrolidine-(CIS), 5.32 g of 2-(3-(3-methoxycarbonylmethyl-phenyl)ureido)-acetic acid and 4.2 g of N,N'-dicyclohexylcarbodiimide 40 cm3acetonitrile. After processing gain of 10.6 g 3-(3-(2-(2,5-diphenyl-1-pyrrolidinyl) 2-oxo-ethyl)ureido)phenylethylamine-(CIS) in the form of oils used in the subsequent synthesis.

2-(3-(3-Methoxycarbonylmethyl-phenyl)ureido) ukusnog potassium carbonate in 220 cm3water and 24 g of 3-isocyanate-phenylethylamine dissolved in 170 cm31,4-dioxane. After treatment and recrystallization in ethyl acetate receive 46,85 g of 2-(3-(3-methoxycarbonylmethyl-phenyl)ureido) acetic acid, melting at 136oC.

Example 61. In the manner similar to that described in example 9, but on the basis of 4.8 g 3-(3-(2-(2,5-diphenyl-2-pyrrolidinyl) 2-oxo-ethyl)ureido)-phenyl)ethylpropane-(CIS), dissolved in 25 cm3methanol and 0.25 g of potassium hydroxide dissolved in 5 cm3water and after treatment receive 0.9 g(3-(3-(3-(2-(2,5-diphenyl-1-pyrrolidinyl) 2(oxo-ethyl)ureido)phenyl)propionic-(CIS) acid, melting at 170oC.

3-(3-(3-(2-(2,5-Diphenyl-1-pyrrolidinyl)2-oxo-ethyl)ureido)phenyl) ethylpropane-(CIS) can be obtained by a method similar to that described in example 41, A, but according to 0.68 g of 2,5-diphenylpyrrolidine-(CIS), 0.9 g 2-(3-(3-(2-etoxycarbonyl-ethyl)ureido)phenyl)acetic acid and 0.63 g of N,N'-dicyclohexylcarbodiimide 6 cm3acetonitrile. After processing gain of 1.8 g 3-(3-(3-(2,5-diphenyl-1-pyrrolidinyl)- 2-oxo-ethyl)ureido)phenyl)ethylpropylamine (CIS) in the form of oils used in the subsequent synthesis.

2-(3-(3-(2-Etoxycarbonyl-ethyl)ureido)phenyl)acetic acid can be UP> water and 1.3 g of 3-(3-isocyanate-phenyl) ethylpropane dissolved in 8 cm31,4-dioxane. After processing receive 0.9 g 2-(3-(3-(2-etoxycarbonyl-ethyl)ureido)phenyl) acetic acid as an amorphous body used in the subsequent synthesis.

3-(3-Isocyanate-phenyl) ethylpropane can be obtained in the following way: a suspension of 0.45 g of coal in 3 g of 3-(3-amino-phenyl) aterproof dissolved in 60 cm3toluene, are added dropwise within 30 minutes at a temperature of about -20oC solution of 2.36 g of carbonate bis-trichloromethyl 20 cm3of toluene. The reaction mixture is heated to 110oC for 2 h 30 min, cooled to a temperature of about 20oC, filtered on celite and concentrate under reduced pressure. So, get 3.5 g of 3-(3-isocyanate-phenyl)ethylpropane in the form of oils used in the subsequent synthesis.

Example 62. According to the method described in example 9, but on the basis of 1.2 g 3-(3-(2-(2-(2-methoxy-phenyl) 5-phenyl-1-pyrrolidinyl) 2-oxo-ethyl)ureido)phenylethylamine-(2RS, 5SR) dissolved in 20 cm3methanol and to 0.19 g of potassium hydroxide dissolved in 4 cm3water, after treatment and crystallization in diethyl ether to obtain 0.6 g 3-(3-(2-(2-(2-methoxy-phenyl) 5-phenyl-1-pyrrolidinyl) 2-oxo-ethyl)Ureines) 2-oxoethyl)ureido)feniletilamin (2RS, 5SR) can be obtained by a method similar to that described in example 41, A, but based on 0,57 g 2-(2-methoxy-phenyl) 5-phenylpyrrolidine-(2RS, 5SR), 0.6 g of 2-(3-(3-methoxycarbonylmethyl-phenyl)ureido)acetic acid and 0.46 g of N,N'-dicyclohexylcarbodiimide 4.5 cm3acetonitrile. After processing receive 1.2 g 3-(3-(2-(2-(2-methoxy-phenyl 5-phenyl-1-pyrrolidinyl)-2-oxo-ethyl) ureido)phenylethylamine-(2RS, 5SR) in the form of oils used in the subsequent synthesis.

A) 2-(2-methoxy-phenyl) 5-phenylpyrrolidine-(2RS, 5SR) can be obtained in the following way: a solution of 2.25 g of N-benzyl-o-methoxybenzylamine 20 cm3of tetrahydrofuran was added dropwise, with stirring, 12,8 cm3a 1.6 M solution of utility in hexane at a temperature of about -78oC. After increasing the temperature to about 20oC continue to stir for 40 h, then the reaction mixture is poured into 100 cm3saturated aqueous solution of ammonium chloride and the product extracted with 50 cm3then 2 times 25 cm3oxide diisopropyl. The combined organic phases are dried over magnesium sulfate and concentrated to dryness under reduced pressure and a temperature of approximately 35oC. the Residue is dissolved in 25 cm3standard aqueous solution solenoidal 20oC the solution is washed three times in 25 cm3oxide diisopropyl, then the pH is brought to 9 by addition of 1N aqueous solution of sodium hydroxide and the product extracted with 3 times 25 cm3oxide diisopropyl. The organic extracts are combined, washed twice in 25 cm3water, dried over magnesium sulfate and concentrated to dryness under reduced pressure and a temperature of approximately 35oC. the resulting product was then purified by chromatography on silica (eluent: petroleum ether oxide of diisopropyl (50/50 by vol.). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and a temperature of approximately 45oC. Thus, obtain 0.9 g of 2-(2-methoxy-phenyl) 5-phenylpyrrolidine-(2RS, 5SR) in the form of amorphous body used in the subsequent synthesis.

B) N-benzyl-o-methoxybenzylidene can be obtained in the following way: a solution of 60 cm3archaeoseismological, 55 cm3benzylamine and 50 mg paratoluenesulfonyl 150 cm3toluene is heated for 3 h under reflux, collecting the water formed by means of a device, Dean-stark. After returning to a temperature of approximately 20oC the organic phase is washed with 100 cm3saturated water RES reduced pressure. After distillation of 57.3 g of N-benzyl-o-methoxybenzylamine, warded off with 155 - 159oC at 130 PA.

Example 63. According to the method described in example 9, but based on 0,46 g 3-(3-(2-(2-(3-hydroxy-phenyl) 5-phenyl-1-pyrrolidinyl) 2-oxo-ethyl)ureido) phenylethylamine-(2RS, 5SR) dissolved in 10 cm3methanol and 0.1 g of hydrocity potassium, dissolved in 2 cm3water, and after treatment and recrystallization in ethanol 0.2 g 3-(3-(2-(2-(3-hydroxy-phenyl) 5-phenyl-1-pyrrolidinyl) 2-oxo-ethyl)ureido) phenylacetic-(2RS, 5SR) of acid, melting at 166oC.

3-(3-(2-(2-(3-Hydroxy-phenyl) 5-phenyl-1-pyrrolidinyl) 2-oxoethyl)ureido) feniletilamin-(2RS, 5SP) can be obtained by a method similar to that described in example 41, A, but according to 0.48 g of 2-(3-hydroxy-phenyl) 5-phenylpyrrolidine-(2RS, 5SR), 0.54 g of 2-(3-(3-methoxycarbonylmethyl-phenyl)ureido)acetic acid and 0.42 g of N, N'-dicyclohexylcarbodiimide 5 cm3acetonitrile. After processing, you will receive 0,.73 g 3-(3-(2-(2-(3-hydroxy-phenyl) 5-phenyl-1-pyrrolidinyl)-2-oxo-ethyl)ureido)phenylethylamine-(2RS, 5SR) in the form of air masses used in the subsequent synthesis.

2-(3-Hydroxy-phenyl) 5-phenylpyrrolidine-(2RS, 5SR) can be obtained by a method similar to that described in example 62, A but and the 5 M solution of utility in hexane. After processing gain of 3.3 g of 2-(3-hydroxy-phenyl) 5-phenylpyrrolidine-(2RS, 5SR) in the form of oils used in the subsequent synthesis.

N-benzyl-m-hydroxybenzaldehyde can be obtained by a method similar to that described in example 62, A, but based on 61,1 g of 3-hydroxy-benzaldehyde and 55 cm3benzylamine 450 cm3of toluene. After processing get to 100.3 g of N-benzyl-m-hydroxybenzaldehyde, melting at 151oC.

Example 64. According to the method described in example 9, but on the basis of 4 g 4-(3-(2-(2,5-diphenyl-1-pyrrolidinyl) 2-oxo-ethyl)ureido)phenylbenzoate-(CIS), dissolved in 65 cm3methanol, and 0.61 g of potassium hydroxide dissolved in 12 cm3water, after treatment get 1.8 g 4-(3-(2-(2,5-diphenyl-1-pyrrolidinyl) 2-oxo-ethyl)ureido)phenylacetic-(CIS) acid, melting at 221oC.

Proton NMR (200 MHz, DMCO D6in h/m), 1,4 - 2,4 (m, 4H, CH2-CH2), and 3.3 (s, 2H, CH2CO2), 3,2 - 3,8 (ABX, 2H, CH2NH), 5,1 (m, 2H, 2 CHN), or 6.1 (t, 1H exchange, NH) and 6.9 (d, 2H, aromatic in the "pair"), and 7.1 to 7.4 (m, 12H, aromatic), or 8.6 (s, 1H, exchangeable, NH).

Infrared spectrum (KBr), characteristic bands in cm-1: 3375, 3095, 3070, 3035, 2980, 2880, 1735, 1700, 1630, 1610, 1515, 1450, 1560, 805, 760, 705).

4-(3-(2-(2,5-Diphenyl-1-pyrrolidinyl) 2-on the basis of 1.7 g of 2,5-diphenylpyrrolidine-(Cys), 2.6 g of 2-(3-(4-benzyloxycarbonylamino-phenyl)ureido)of acetic acid and 1.6 g of N, N'-dicyclohexylcarbodiimide 15 cm3acetonitrile. After processing receive 4 g 4-(3-(2-(2,5-diphenyl-1-pyrrolidinyl) 2-oxo-ethyl)ureido)phenylbenzoate-(CIS) in the form of air masses used in the subsequent synthesis.

2-(3-(4-Benzyloxycarbonylamino-phenyl)ureido)acetic acid can be obtained by a method similar to that described in example 1 A, but based on 3,68 g glycine, 4.1 g of acid sodium carbonate in 150 cm3water and 13 g of 4-isocyanato-phenylbenzoate dissolved in 60 cm31,4-dioxane. After processing gain of 5.2 g of 2-(3-(4-benzyloxycarbonylamino-phenyl)ureido)-acetic acid, melting at 192oC.

A) 4-Isocyanatobenzene can be obtained in the following way: a suspension of 1 g of coal in a mixture of 5.9 cm3chloroformiate of trichloromethyl and 50 cm3toluene added dropwise within 15 min at a temperature of about -25oC, a solution of 11.8 g of 4-aminophenylacetate 150 cm3torwald. The reaction mixture is stirred at a temperature of approximately 25oC for 2 h, then heated to 110oC for 2 h, After cooling to a temperature of approximately 25oC, the reaction medium of money and the temperature is about 52oC. Thus, the gain of 15.4 g of 4-isocyanate-vinylbenzyl acetate in the form of oils used in the subsequent synthesis.

4-Amin-phenylbenzoate can be obtained by a known method (E. ZURABY et coll, lzv Akad Nauk SSSR, Ser. Khim. (II) 2036, 1964).

Example 65. According to the method described in example 9, but on the basis of 3.5 g 3-(3-(2-(2-(2-methyl-phenyl) 5-phenyl-1-pyrrolidin 2-oxoethyl)ureido) phenylethylamine-(2RS, 5SR) dissolved in 60 cm3methanol and 0.56 g of potassium hydroxide dissolved in 11 cm3water, after treatment and recrystallization in ethyl acetate to obtain 2.2 g 3-(3-(2-(2-(2-methyl-phenyl) 5-phenyl-1-pyrrolidinyl) 2-oxo-ethyl)-ureido)phenylacetic acid(2RS, 5SR), melting at 133oC.

3-(3-(2-(2-(2-Methyl-phenyl) 5-phenyl-1-pyrrolidinyl) 2-oxo-ethyl) -ureido)feniletilamin-(2RS, 5SR) can be obtained by a method similar to that described in example 41, but on the basis of 1.6 g of 2-(2-methyl-phenyl) 5-phenylpyrrolidine-(2RS, 5SR), 1.8 g of 2-(3-(3-methoxycarbonylmethyl-phenyl)ureido)acetic acid and 1.4 g of N,N'-dicyclohexylcarbodiimide 15 cm3acetonitrile. After processing receive 3.5 g 3-(3-(2-(2-(2-methyl-phenyl) 5-phenyl-1-pyrrolidin) 2-oxo-ethyl)ureido)phenylethylamine-(2RS, 5SR) in the form of air masses used in the subsequent synthesis.

is based on 4,18 g of N-benzyl-o-methylbenzylamine, dissolved in 40 cm3tetrahydrofuran (THF), and 25.6 cm3a 2.5 M solution of utility in hexane. After processing gain of 1.7 g of 2-(2-methyl-phenyl) 5-phenylpyrrolidine-(2RS, 5SR) in the form of oils used in the subsequent synthesis.

N-Benzyl-o-methylbenzylidene can be obtained by well-known methods (A. PADVA et coll., J. Amer. Chem. Soc., 91 2653, 1969).

Example 66. According to the method described in example 9, but on the basis of 1.8 g 3-(3-(2-(2-(3-hydroxy-phenyl)-5-(3-methoxy-phenyl)-1-pyrrolidinyl) 2-oxo-ethyl)ureido)ethylbenzoic-(2RS, 5SR) dissolved in 30 cm3methanol, and 0.29 grams of potassium hydroxide dissolved in 6 cm3water, after treatment and crystallization in diethyl ether to obtain 1 g 3-(3-(2-(2-(3-hydroxy-phenyl)-5-(3-methoxy-phenyl) 1-pyrrolidinyl 2-oxo-ethyl)ureido)benzoic-(2R*, 5S*) acid, melting at 172oC.

3-(3-(2-(2-(3-Hydroxy-phenyl)-5-(3-methoxy-phenyl)-1-pyrrolidinyl) 2-oxo-ethyl)ureido)ethylbenzoic-(2RS, 5SR) can be obtained by a method similar to that described in example 41, but on the basis of 1.3 g of 2-(3-hydroxy-phenyl)-5-(3-methoxy-phenyl)-pyrrolidine-(2RS, 5SR), 1.3 g of 2-(3-(3-etoxycarbonyl-phenyl)ureido) acetic acid and 1 g of N,N'-dicyclohexylcarbodiimide 11 cm3acetonitrile. After processing gain of 1.8 g 3-(3-(2-(2-(3-hydroc the emnd in the subsequent synthesis.

2-(3-Hydroxy-phenyl)-5-(3-methoxy-phenyl)-pyrrolidin-(2RS, 5SR) can be obtained by a method similar to that described in example 62, but on the basis of 7.2 g of N-/(3-hydroxy-phenyl)methylene/-(3-methoxy-phenyl)-methylamine 60 cm3tetrahydrofuran (THF) and 50.4 cm3a 2.5 M solution of utility in hexane. After processing receive 4.5 g of 2-(3-hydroxy-phenyl)-5-(3-methoxy-phenyl)pyrrolidine-(2RS, 5SR) in the form of oils used in the subsequent synthesis. N-/(3-hydroxy-phenyl)methylene/-(3-methoxy-phenyl)methylamine can be obtained by a method similar to that described in example 62, B, but according to 13.2 g of 3-hydroxybenzaldehyde and 13.7 g m-methoxybenzylamine 90 cm3toluene after treatment receive 20.7 g of N-/(3-hydroxy-phenyl)methylene/- (3-methoxyphenyl)methylamine, melting at 103oC.

2-/3-(3-Etoxycarbonyl-phenyl)ureido/Oksana acid may be obtained as described in example 1, but based on 9,85 g glycine, 11 g of acid sodium carbonate dissolved in 150 cm3water, and 25 g of 3-isocyanate of ethylbenzoic. After processing gain of 16 g of 2-(3-(3-etoxycarbonyl-phenyl)ureido)acetic acid, melting at 174oC.

Example 67. According to the method described in example 9, but on the basis of 1.8 g 4-(3-(2-(2-(3-hydroxy-phenyl)-5-phenyl-1-pyrrolidinyl)2-oxo-etil 6 cm3water, after treatment and crystallization in diethyl ether to obtain 0.5 g 4-(3-(2-(2-(3-hydroxy-phenyl)-5-phenyl-1-pyrrolidinyl) 2-oxo-ethyl)-ureido)phenylacetic-(2RS, 5SR) of acid, melting at 260oC.

4-(3-(2-(2-(3-Hydroxy-phenyl)-5-phenyl-1-pyrrolidinyl)2-oxoethyl) ureido)phenylbenzoate-(2RS, 5SR) can be obtained by a method similar to that described in example 41, but on the basis of 1.4 g of 2-(3-hydroxy-phenyl)-5-phenylpyrrolidine-(2RS, 5SR), 2.0 g of 2-(3-(3-methoxycarbonylmethyl-phenyl)ureido)acetic acid and 1.2 g of N,N'-dicyclohexylcarbodiimide 11 cm3acetonitrile. After processing gain of 1.8 g 4-(3-(2-(2-(3-hydroxy-phenyl)-5-phenyl-1-pyrrolidinyl)-2 - oxo-ethyl)ureido)phenylbenzoate-(2RS, 5SR) in the form of air masses used in the subsequent synthesis.

Example 68. According to the method described in example 9, but on the basis of 1.3 g(4-(3-(2-(2,5-diphenyl-1-pyrrolidinyl)2-oxo-ethyl)ureido)-phenylthio) tert. butyl acetate-(CIS), dissolved in 20 cm3methanol, and 0.17 g of potassium hydroxide dissolved in 4 cm3water, after treatment receive 0.5 g(4-(3-(2-(2,5-diphenyl-1-pyrrolidinyl)2-oxo-ethyl)ureido)phenylthio) acetic acid(CIS) acid, melting at 200oC.

Proton NMR (200 MHz, DMCO D6in h/m), 1,8-2,4 (m, 4H, CH2-CH2), prekrasny spectrum (KBr), characteristic bands in cm-1: 3400, 3090, 3060, 3030, 2975, 2875, 1640, 1595, 1540, 1495, 1450, 1400, 825, 760, 700.

(4-(3-(2-(2,5-diphenyl-1-pyrrolidinyl)2-oxo-ethyl)ureido) phenylthio)tert-butyl acetate-(CIS) can be obtained by a method similar to that described in example 41, but on the basis of 0,46 g 2,5-diphenylpyrrolidine, 0.7 g of 2-(3-(4-tert. butoxycarbonylamino-phenyl)ureido)-acetic acid and 0.42 g of N,N'-dicyclohexylcarbodiimide 5 cm3acetonitrile. After processing gain of 1.3 g(4-(3-(2-(2,5-diphenyl-1-pyrrolidinyl)2 - oxo-ethyl)ureido)phenylthio)-tert.butyl acetate-(CIS) in the form of air masses used in the subsequent synthesis.

2-(3-(4-Tert.butoxycarbonylamino-phenyl)ureido)acetic acid can be obtained by a method similar to that described in example 1, but on the basis of 0.65 g of glycine, 2.4 g of potassium carbonate in 15 cm3water and 2.3 g of (4-isocyanatophenyl)tert-butyl acetate, dissolved in 12 cm31,4-dioxane. After processing gain of 1.7 g of 2-(3-(4-tert.butoxycarbonylamino-phenyl)ureido)acetic acid in the form of air masses used in the subsequent synthesis.

(4-Isocyanate-phenylthio)tert.butyl acetate can be obtained by a method similar to that described in example 64, but on the basis of 3.1 g (4 aminophenylthio)tre is and. After processing gain of 2.3 g of (4-isocyanate-phenylthio)tert. butyl acetate in the form of oils used in the subsequent synthesis.

(4-Amino-phenylthio)tert. butyl acetate can be obtained by a method similar to that described in example 17 to obtain (3-amino-phenylthio)ethyl acetate, but starting from 5 g of 4-amino-thiophenol and 6.4 cm3bromoacetate tert.butyl 80 cm3of ethanol. So, get 7,45 g (4-Amin-phenylthio)acetate tert. butyl in the form of oils used in the subsequent synthesis.

Example 69. According to the method described in example 9, but on the basis of 0.8 g 3-(3-(2-(2-(2-hydroxy-phenyl) 5-phenyl-1-pyrrolidinyl)-2-oxo-ethyl(ureido) ethylbenzoic-(2RS, 5SR) dissolved in 15 cm3methanol, and 0.27 g of potassium hydroxide dissolved in 3 cm3water, after treatment and crystallization in oxide diisopropyl obtain 0.21 g 3-(3-(2-(2-(2-hydroxy-phenyl) 5-phenyl-1-pyrrolidinyl) 2-oxo-ethyl)ureido) benzoic-(2RS, 5R) acid, melting at 160oC.

Proton NMR (200 MHz, DMCO D6in h/m), 1,8-2,5 (2m, 4H, CH2-CH2), 3.3 and 4 (ABX, 2H, CH2N), and 5.2 (m, 2H, 2CHN), of 6.7 to 7.4 (m, 13H, aromatic), 6,8 (bt), 9(s), or 9.8(bs), 12,8(vbs) (4H exchange, 1 OH, 1 CO2H and 2NH).

Infrared spectrum (KBr), characteristic bands in cm-1: 3400, 3070, 2980,-(2RS, 5SR) can be obtained by a method similar to that described in example 41, A, but based on 0.5 g of 2-(2-hydroxy-phenyl) 5-phenylpyrrolidine-(2RS, 5SR), 0.56 g of 2-(3-(3-etoxycarbonyl-phenyl)ureido)acetic acid and 0.43 g of N,N'-dicyclohexylcarbodiimide 7.5 cm3acetonitrile. After processing gain of 0.85 g 3-(3-(2-(2-(2-hydroxy-phenyl) 5 phenyl-1-pyrrolidinyl)-2-oxo-ethyl)ureido) ethylbenzoic-(2RS, 5SR) in the form of air masses used in the subsequent synthesis.

2-(2-Hydroxy-phenyl) 5-phenylpyrrolidine-(2RS, 5SR) can be obtained in the following way: a solution of 8.6 cm3Diisopropylamine 60 cm3tetrahydrofuran (THF) added over 10 min at a temperature of about -78oC, 24 cm3a 2.5 M solution of utility. Then the reaction medium is stirred at a temperature of about 20oC for 15 min, then cooled to a temperature of approximately -70oC. Add 5 minutes at a temperature of about -70oC solution of 4.2 g of N-benzyl-o-hydroxybenzylidene 5 cm3tetrahydrofuran (THF). The solution is stirred for 10 min at a temperature of about -70oC, then leave to raise the temperature to 20oC. Then the reaction medium is saturated by bubbling ethylene for 40 h, then poured into 150 cm3saturated vodno the combined organic phases are dried over magnesium sulfate and concentrated to dryness under reduced pressure and a temperature of approximately 35oC. the Residue is dissolved in 150 cm3normal aqueous solution of hydrochloric acid and the solution heated under reflux for 1 min. After cooling to a temperature of about 20oC the solution was washed three times in 100 cm3diethyl ether, then pH adjusted to 11 using a 4N aqueous solution of sodium hydroxide and the solution extracted three times with 75 cm3diethyl ether. The organic extracts are combined, washed twice in 50 cm3water, dried over magnesium sulfate and concentrated to dryness under reduced pressure and a temperature of approximately 35oC. the resulting product was then purified by chromatography on silica (eluent: dichloromethane, then dichloromethane-methanol (95-5 by vol.). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and a temperature of approximately 45oC. Thus, obtain 0.5 g of 2-(2-hydroxy-phenyl) 5-phenylpyrrolidine-(2RS, 5SR) in the form of oils used in the subsequent synthesis.

N-benzyl-o-hydroxybenzylidene can be obtained by a method similar to that described in example 62, B, but on the basis of 21.2 cm32-hydroxybenzaldehyde and 22 cm3benzylamine 180 cm3of toluene. After processing gain of 38.2 g of N-benzyl-o-hydroc is conducted in example 9, but on the basis of 1.4 g 3-(3-(2-(2-(2-hydroxy-phenyl) 5-phenyl-1-pyrrolidinyl) 2-oxoethyl)ureido)phenylethylamine-(2RS, 5SR) dissolved in 30 cm3methanol, and 0.49 g of potassium hydroxide dissolved in 6 cm3water, after treatment and crystallization in oxide diisopropyl obtain 0.45 g 3-(2-(-2-(2-(2-hydroxy-phenyl) 5-phenyl-1-pyrrolidin) 2-oxo-ethyl)-ureido)phenylacetic-(2RS, 5SR) of acid, melting at 165oC.

3-(3-(2-(2-(2-hydroxy-phenyl) 5-phenyl-1-pyrrolidinyl) 2-oxoethyl(ureido) feniletilamin-(2RS, 5SR) can be obtained by a method similar to that described in example 41, A, but on the basis of 1.8 g of 2-(3-hydroxy-phenyl)-5-phenylpyrrolidine-(2RS, 5SR), 2 g of 2-(3-(3-methoxycarbonylmethyl-phenyl)ureido) acetic acid and 1.55 g of N,N'-dicyclohexylcarbodiimide 30 cm3acetonitrile. After processing gain of 1.4 g 3-(3-(2-(2-(2-hydroxy-phenyl) 5-phenyl-1-pyrrolidinyl)-2-oxo-ethyl)ureido) phenylethylamine-(2RS, 5SR) in the form of air masses used in the subsequent synthesis.

Example 71. According to the method described in example 41, but on the basis of 0.2 g 3-(3-(2-(2-tert. butoxycarbonyl-5-(3-indolyl)-1 - pyrrolidinyl)2-oxo-ethyl)ureido)2-trimethylsilyl-ethylbenzoic-(2S, 5R) and 1.0 cm31M solution of tetrabutylammonium fluoride. The crude product is dissolved in 25 cm3utilizable 1N aqueous solution of hydrochloric acid. Precipitated precipitated product is filtered off, washed with 2 times 5 cm3distilled water and dried in air. So, get 0.12 g 3-(3-(2-(2-tert. butoxycarbonyl-5-(3-indolyl)-1-pyrrolidinyl) 2-oxo-ethyl)ureido) benzoic acid-(2S, 5R) acid in the form of a solid, melting at 160oC, //2D0= +10,71,1(C = 0.43 PERCENT, CH3OH).

Proton NMR (300 MHz, DMCO D6in ppm, J in Hz), and 1.5 (S, 9H, -C(CH3)3), 1,8-2,5 (m, 4H, -CH2-CH2-), 3.6 and 4.1 (2dd, J is 17.5 and 5.1, 2H, N-CO-CH2N), 4.26 deaths (dd, J=9 and 8, 1H, N-CH-COO-), 5,52 (d,J=8,5, 1H, N-CH-Ar), 6,38 (t, J= 5,1 H, -NH-CO-), of 7.0 to 7.7 (m, 7H, aromatic), 7,68 (s, 1H, N-CH= ), 8(bs, 1H, in position 2, NH-Ph-COO -), 9,03 (array, 1H, Ph-NH-CO-), 11,05 (array, 1H, -NH-), the NOE effect was observed between N-CH= indolyl and the proton at position 5 of pyrrolidine).

Infrared spectrum (KBr), characteristic bands in cm-1: 3380, 2980, 2935, 2700-2250 (wide band), 1720-1695 (wide band), 1635, 1595, 1560, 1490, 1460, 1370, 1155, 745, 685.

3-(3-(2-(2-Tert. butoxycarbonyl-5-(3-indolyl)-1-pyrrolidinyl)- 2-oxo-ethyl) ureido)2-trimethylsilyl-ethylbenzoic-(2S, 5R) can be obtained by a method similar to that described in example 41, A, but on the basis of 0.5 g (5-(3-indolyl)-2-pyrrolidine. BUTYLCARBAMATE-(2S, 5RS), 0,59 g 2-(3-(3-(2-trimethylsilyloxy Omnia (eluent: ethyl acetate-cyclohexane (about 40-60.)). Fractions containing a mixture of diastereoisomers, concentrated to dryness under reduced pressure and at 40oC, the obtained residue is purified second chromatography on silica (eluent: ethyl acetate-cyclohexane (with a gradient of ethyl acetate)). The fractions containing each two diastereoisomer, are combined and concentrated to dryness under reduced pressure and at 40oC. Thus, obtain 0.20 g 3-(3-(2-(4-tert.butoxycarbonyl-5-(3-indolyl)-1-pyrrolidinyl) 2-oxo-ethyl)ureido)2-trimethylsilyl-ethylbenzoic-(2S, 5R) (first product elution) and 0.26 g 3-(3-(2-(4-tert. butoxycarbonyl-5-(3-indenyl)-1-pyrrolidinyl) 2-oxo-ethyl)ureido 2-(trimethylsilyl)-ethylbenzoic-(2S, 5S) (second product elution).

5-(3-Indolyl)-2-pyrrolidine. butylcarbamoyl-(2S, 5SR) can be obtained by a method similar to that described in example 48, B, but on the basis of 0.7 g of 1-tert-butoxycarbonyl-5-(3-indolyl)-2-pyrrolidine. BUTYLCARBAMATE- (2S, 5R) and 0.25 cm3attributively. Thus, the gain of 0.50 g of 5-(3-indolyl)-5-pyrrolidine. BUTYLCARBAMATE-(2S, 5RS) in the form of oils used in the subsequent synthesis.

1-Tert. butoxycarbonyl-5-(3-indolyl)-2-pyrrolidine. butylcarbamoyl (2S, 5R) can be obtained in the following way: in rastvory 100 cm3anhydrous methylene chloride, cooled to a temperature of about 5oC, add a solution of 3.5 g of indole in 30 cm3of methylene chloride. At the end of the addition the temperature of the reaction medium is brought to approximately 25oC, stirred for 2 h at this temperature, and then hydrolyzing the addition of 40 cm3saturated aqueous solution of acid sodium carbonate. The organic phase is decanted, the aqueous phase is extracted with 2 times 50 cm3of methylene chloride. The combined organic phases, dried over magnesium sulfate and concentrated to dryness under reduced pressure and at 30oC. the resulting residue is purified by chromatography on silica (eluent: ethyl acetate-cyclohexane (about 10/90.)). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and the 35oC. Thus, obtained after stirring in the oxide diisopropyl 1.2 g of 1-tert.butoxycarbonyl-5-(3-indolyl)-2-pyrrolidin-tert. BUTYLCARBAMATE-(2S, 5R) (first product elution), melting at 214oC, and 0.8 g of I-tert.butoxycarbonyl-5-(3-indolyl)-2 - pyrrolidine. BUTYLCARBAMATE-(2S, 5S) (second product elution), melting at 194oC.

Example 72. According to the method described in example 41, but is of enzoate-(2S, 5S) and 1.5 cm31M solution of tetrabutylammonium fluoride. The crude product is dissolved in 25 cm3ethyl acetate and extracted with 2 times 10 cm3a 0.1 N aqueous solution of sodium hydroxide. The aqueous phase is brought to pH 2 add 1N aqueous solution of hydrochloric acid. Precipitated precipitated product is filtered off, washed with 2 times 5 cm3distilled water and dried in air. So, get 0.09g 3-(3-(2-(2-tert. butoxycarbonyl-5-(3-indolyl)-1-pyrrolidinyl) 2-oxo-ethyl)ureido) benzoic acid-(2S, 5S) acid in the form of an amorphous product, //2D0= -42,91,5(C = 0,503%, CH3OH).

Proton NMR (300 MHz, DMCO D6), in ppm), J in Hz) of 1.44 (S, 9H, -C(CH3)3, of 1.7 - 2.4 (m, 4H, -CH2-CH2-), 3,59, and 3,99 (2 dd, J = 18 and 6, 2H, N-CO-CH2-N) 4,55 (d, J = 9 Hz, 1H, N-CH-COO-), of 5.53 (d, J = 8, 1H, N-CH-Ar), and 6.3 (t, J = 6,1 Hz, 1H, -NH-CO-), 6,9 - 7,6 (m, 7H, aromatic), to 7.15 (bs, 1H, N-CH=), 7,94 (s broad, 1H at position 2 in NH-Ph-COO -), 8,95 (array, 1H, Ph-NH-CO), 11,02 (array, 1H, -NH-), was 12.75 (array, 1H, COOH).

Were awarded two of the NOE effect between N-CH= indole and protons in positions 2 and 5 pyrrolidine.

Infrared spectrum (KBr), characteristic bands in cm-1: 3385, 2975, 2930, 2700-2250 (wide band), 1730, 1630, 1640, 1560, 1490, 1460, 1395, 1370, 1155, 740, 685.

Example 73. In so BUTYLCARBAMATE-(2R, 4R) and cent to 8.85 g of 1-(3-AMINOPHENYL)-econsultant Tetra-n-butylamine-(RS). In the obtained crude product in the form of salts of Tetra-n-butylamine dissolved in 20 cm3acetone, add a solution of 2.5 g nonattributable potassium in 15 cm3of acetone. After 2 h stirring at a temperature of approximately 25oC add 220 cm3oxide diisopropyl. The insoluble product is filtered off, washed 2 times in 3 cm3mixture of acetone and nitric oxide in diisopropyl (about 30/70. ) and purified by chromatography on dboxii silica (eluent: ethyl acetate-methanol (85/15)). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and the 40oC. Thus, obtained after shaking in acetonitrile 0.40 g 1-(3-(3-(2-(4-tert.butoxycarbonyl-2-phenyl-3-thiazolidine-(2R, 4R)) 2-oxo-ethyl)ureido)phenyl) econsultant potassium(RS) (mixture of forms A and B), melting at 240oC, solid, //2D0= +50,11,5(C = 0.57 PERCENT, CH3OH).

Proton NMR (200 MHz, DMCO D6+ a few drops CD3COOD, ppm, J in Hz) 2 rotamer at room temperature, coalescence lines at 120oC, characteristic shifts at 120oC: is 1.51 (m, 12H, -C(CH3)3) J = 6, 1H, N-CH-COO), to 6.4 (s, 1H, S-CH-N), 6,98 (d broad, J = 8, 1H, in position 4 on CO-NH-Ph), was 7.08 (t, J = 8, 1H, in position 5 in CO-NH-Ph), 7,2 - 7,5 (m, 5H, aromatic), to 7.64 (bd, J = 8, 2H, aromatic).

Infrared spectrum (KBr), characteristic bands in cm-1: 3370, 2970, 2920, 2870, 1725, 1655, 1610, 1590, 1555, 1490, 1450, 1365, 1205, 1150, 1025, 725, 695).

1-(3-AMINOPHENYL)econsultant Tetra-n-butylamine-(RS) can be obtained by a method similar to that described in example 41, W, but on the basis of a total of 22.4 g of 1-(3-nitro-phenyl) econsultant Tetra-n-butylamine-(RS) and 0.8 g of 5% palladium on soot. Thus, the gain of 20.7 g of 1-(3-amino-phenyl) econsultant Tetra-n-butylamine in the form of oils used in the subsequent synthesis.

1-(3-Nitro-phenyl) econsultant Tetra-n-butylamine-(RS) can be obtained in the following way: a solution of 9.45 g of sodium sulfite in 125 cm3distilled water is added to 11.5 g 3-(1-bromacil) nitrobenzene-(5). The reaction medium is heated for 3 hours at a temperature of about 70oC, cooled to a temperature of approximately 25oC, then pour in 1450 cm3a 0.5 M aqueous solution of hydrogenphosphate potassium. Then add 17.8 g of acid sulfate Tetra-n-butylamine and extracted with a mixture with 300 cm3of methylene chloride. The organic phase promyvayut over magnesium sulfate and concentrated to dryness under reduced pressure and the 40oC. Thus, the gain of 22.4 g of 1-(3-nitro-phenyl) econsultant Tetra-n-butylamine-(RS) in the form of oils used in the subsequent synthesis.

3-(1-Bromo-ethyl) - nitrobenzene-(RS) can be obtained by a known method (E. FELDER et coll., J. Med. Cheh., 13, 559, 1970).

Example 74. According to the method described in example 38, but from 2,42 g 3-(2-(1-imidazolyl-carboxamide)acetyl/-2-phenyl-4-thiazolidin - tert. BUTYLCARBAMATE-(2R, 4R) and 1.4 g of 1-(3-amino-phenyl)- ethanol. The crude product is purified by chromatography on silica (eluent: ethyl acetate-cyclohexane (about 75/25. )). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure. Thus, obtained after recrystallization in acetonitrile 0,62 g 3-(2-(3-(3-(1-hydroxy-ethyl) - phenyl-(RS)/ureido)acetyl)-2-phenyl-4 - thiazolidine. butyl-carboxylate-(2R, 4R) (a mixture of forms A and B), melting at 160oC //2D0= +60,71,3(C = 0,51%, DMF).

Proton NMR (200 MHz, plus a few drops CD3COOD, ppm, J in Hz), 2 rotamer at room temperature, coalescence lines at 120oC, characteristic chemical shift at 120oC: of 1.35 (d, J = 6,5, 3H, -CH3), and 1.5 (s, 9H, -C(CH3)3), 3,29 and 3.45 (2dd, J = 12.5 and 6, 2H, S-CH2-), 3 is I J = 8, 1H, in position 4 on CO-NH-Ph), 7,14 (t, J = 8, 1H, in position 5 in CO-NH-Ph), 7,22 (dd, J = 3 and 2.5, 1H, in position 2, CO-NH-Ph), 7,2-7,5 (m, 4H, aromatic), to 7.64 (bd, J = 8, 2H, aromatic).

Infrared spectrum (KBr), characteristic bands in cm-1: 3350, 2975, 2930, 1740, 1660, 1615, 1590, 1560, 1480, 1445, 1365, 1155, 1060, 730, 705, 700.

Example 75. According to the method described in example 34, but on the basis of 2.0 g of 3-(2-amino-acetyl)-2-phenyl-4-thiazolidine.BUTYLCARBAMATE -(2R, 4R) and 1.6 g of isocyanate 4-chloro-3-triptoreline. The resulting crude product was then purified by chromatography on silica (eluent: ethyl acetate/cyclohexane (30/70 about. )). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and the 40oC. Thus, obtained after shaking at 20 cm3hexane 0.7 g 3-(2-(3-(4-chloro-3-trifluoromethyl-phenyl)ureido)-acetyl)2 - phenyl-4-thiazolidine. BUTYLCARBAMATE (2R, 4R) in the form of amorphous powder, //2D0= +58,21,3(C = 0,49%, CH3CH).

Proton NMR (250 MHz, DMCO D6in ppm, J in Hz), 2 rotamer at room temperature, coalescence lines at 130oC, characteristic chemical shifts at 130oC: of 1.53 (s, 9H, -C(CH3)3), 3,29 and 3,47 (2dd, J = 12.5 and about 6.5, 2H, S-CH2-), of 3.73 (array, 1H, N-COCH2

Infrared spectrum (KBr), characteristic bands in cm-1: 3375, 2980, 2930, 2875, 1740, 1640, 1595, 1550, 1485, 1455, 1370, 1325, 1175, 1150, 895, 730, 695).

Example 76. According to the method described in example 41, but according to 1.37 g 3-(3-(2-(4-tert. butoxycarbonyl(2-(2-methyl-phenyl)-3 - thiazolidine)2-oxo-ethyl)ureido)-2-trimethylsilyl-ethylbenzoic-(2R, 4R) and 4.6 cm31M solution of tetrabutylammonium fluoride. The crude product is dissolved in 25 cm3a saturated solution of acidic sodium carbonate and washed with 25 cm3ethyl acetate. The aqueous phase is brought to pH 2 by addition of an aqueous solution of hydrochloric acid 4N. Precipitated precipitated product is filtered off, washed with distilled water until neutrality of wash water and dried in air. So, get 0,89 g 3-(3-(2-(4-tert.butoxycarbonyl-2-(2-methyl-phenyl)-3-thiazolidine)2 - oxo-ethyl)ureido)benzoic-(2R, 4R) acid in the form of a solid, melting at 152oC, //2D0= +70,31,9(C = 0,53%, DMF).

Proton NMR (200 MHz, DMCO D6plus a few drops CD3COOD, ppm, J in Hz), 2 rotamer at room temperature, coalescence lines at 110oC, characteristic chemical change, -COCH2-N) of 4.05 (d, J = 17,5, 1H, the other H of N-COCH2-N, to 4.98 (t, J = 6,5, 1H, N-CH-COO), 6,24 (array, 1H, -NH-CO), 6,46 (S, 1H, S-CH-N), 7,10-the 7.65 (m, 5H, aromatic), 7,33 (t, J = 8, 1H, in position: CO-NHPh), 7,94 (array, 1H, in position 6 on S-CH-Ph), and 8.0 (dd, J = 2 and 3, 1H, in position 2, CO-NH-Ph), 8,67 (array, 1H, -CO-NH-Ph).

Infrared spectrum (KBr), characteristic bands in cm-1: 3380, 2980, 2935, 2700-2250 (wide band), 1715-1695 (wide band), 1655, 1610, 1595, 1560, 1490, 1370, 1155, 760, 745, 685.

3-(3-(2-(4-Tert. butoxycarbonyl-2-(2-methyl-phenyl)-3-thiazolidine 2-oxo-ethyl)ureido)2-trimethylsilyl-ethylbenzoic-(2R, 4R) can be obtained by a method similar to that described in example 41, but on the basis of 2.1 g of 2-(2-methyl-phenyl)-4-thiazolidine. BUTYLCARBAMATE-(2RS, 4R), 2.5 g 2-(3-(3-(2-trimethylsilylethynyl)phenyl)ureido)of acetic acid and 1.6 g of N,N'-dicyclohexylcarbodiimide. The crude product is purified by chromatography on silica (eluent: ethyl acetate/cyclohexane (40/60 vol.)). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and the 40oC. Thus, obtain 1.7 g 3-(3-(2-(4-tert.butoxycarbonyl-2-(2-methyl-phenyl)-3-thiazolyl)-1 - oxo-ethyl)ureido)2-trimethylsilyl-ethylbenzoic-(2R, 4R) as amorphous solids used in the subsequent synthesis.

2-(is the example 34, In, but on the basis of 10.0 g of 2-(2-methyl-phenyl)-4-thiazolidinones-(2RS, 4R) acid dissolved in 130 cm3chloroform, 3.0 cm3concentrated sulphuric acid and an excess of isobutene. The resulting crude product was then purified by chromatography on silica (eluent: ethyl acetate-cyclohexane (about 10/90.)). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and the 40oC. Thus, obtain 3.8 g of 2-(2-methyl-phenyl)-4-thiazolidine.BUTYLCARBAMATE-(2RS, 4R) in the form of oils used in the subsequent synthesis.

2-(2-Methyl-phenyl)-4-thiazolidinedione-(2RS, 4R) acid can be obtained, as in example 34, G, but on the basis of 12.5 g of L-cysteine and 12.0 cm32-methyl-benzaldehyde. Thus, the gain of 18.4 g of 2-(2-methyl-phenyl)-4-thiazolidinones-(2RS, 4R) acid, melting at a subsequent synthesis.

Example 77. In the solution 0,95 3-(3-(2-(4-tert.butoxycarbonyl-2-(2-fluoro-phenyl)-3-thiazolidine) 2-oxo-ethyl)ureido)phenylethylamine-(2R, 4R) 6 cm3a mixture of water-methanol (30/70 vol.) add at a temperature of approximately 25oC, 0.12 g of potassium hydroxide. The reaction mixture is stirred for 3 hours at a temperature of about 25oC, then concentrated to approximately half volume when Panera, then brought to pH 2 by addition of 2.1 cm31N aqueous solution of sulfuric acid. The insoluble product is filtered off and purified by chromatography on silica (eluent: ethylacetate (90/10 vol.)). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and the 40oC. the thus Obtained amorphous product (0.26 g) was dissolved in 1N aqueous solution of sodium hydroxide. This solution is filtered, then acidified by addition of 1N aqueous solution of sulfuric acid. Precipitated precipitated product is filtered off, washed 3 times in 10 cm3water, then dried in air. Thus, the gain of 0.26 g 3-(3-(2-(4-tert. butoxycarbonyl-2-(2 - fluoro-phenyl)-3-thiazolidine)-2-oxo-ethyl)ureido)phenylacetic-(2R, 4R) acid, melting at 110oC, //2D0= +51,11,6(C = 0,528%, DMF).

Proton NMR (200 MHz, DMCO D6plus a few drops CD3COOD, ppm, J in Hz), 2 rotamer at room temperature, coalescence lines at 120oC, characteristic chemical shifts at 120oC: of 1.55 (s, 9H, -C(CH3)3), 3,34 and 3,52 (2dd, J = 12.5 and about 6.5, 2H, S-CH2-), 3,51 (S, 2H, Ar CH2COO-), 3,8 and 4,07 (2d, J = 17,5, 2H, N-COCH2-N) 5,02 (t, J = 6,5, 1H, N-CH-COO), 6,55 (s, 1H, S-CH-N), 6,85 spectrum (KBr), the characteristic bands in cm-1: 3380, 2980, 2930, 2700 - 2250 (wide band), 1735, 1650, 1615, 1595, 1560, 1490, 1460, 1370, 1230, 1155, 760, 705.

3-(3-(2-(4-Tert. butoxycarbonyl-2-(2-fluoro-phenyl)-3 - thiazolidine)-2-oxo-ethyl)ureido)feniletilamin-(2R, 4R) can be obtained by a method similar to that described in example 41, A, but based on a 1.46 g of 2-(2-fluoro-phenyl)-4-thiazolidine. BUTYLCARBAMATE-(2RS, 4R), of 1.37 g of 2-(3-(3-(methoxycarbonylmethyl)phenyl)ureido)acetic acid and 1.15 g of N,N'-dicyclohexylcarbodimide. The crude product is purified by chromatography on silica (eluent: ethyl acetate-cyclohexane (50//50.)). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and the 40oC. Thus, obtain 0.95 g 3-(3-(2-(4-tert.butoxycarbonyl-2- (2-fluoro-phenyl)-3-thiazolidine)-2-oxo-ethyl)ureido)phenylethylamine- (2R, 4R) in the form of a solid amorphous product used in the subsequent synthesis.

Example 78. According to the method described in example 77, but on the basis of 0,76 g 3-(3-(2-(4-tert. butoxycarbonyl-2-(2-methoxy-phenyl)-3 - thiazolidine)-2-oxo-ethyl)ureido)phenylethylamine-(2R, 4R) 6 cm3a mixture of water-methanol (30/70 about. ) and 0.09 g of potassium hydroxide. The crude product (0.45 g) was dissolved in 7.5 cm3a 0.1 N aqueous solution of hydroxide and sodium. Pol sulfuric acid, then extracted 2 times with 20 cm3ethyl acetate. The combined organic phases, dried over magnesium sulfate and concentrated to dryness under reduced pressure and the 40oC. Thus, obtained after shaking in aminobutiramida, 0.25 g 3-(3-(2-(4-tert.butoxycarbonyl-2-(2-methoxy-phenyl)-3 - thiazolidine)2-oxo-ethyl)ureido)phenyl-acetic acid(2S, 4R) acid in the form of an amorphous product, //2D0= +6,41,0(C = 0,466%, CHCl3).

Proton NMR (200 MHz, DMCO D6plus a few drops CD3COOD, ppm (J in Hz), 2 rotamer at room temperature, coalescence lines at 120oC, characteristic chemical shifts at 120oC: of 1.55 (s, 9H, -C(CH3)3), up 3.22 and 3.45 (2dd, J = 12.5 and 7, 2H, S-CH2-), 3,51 (s, 2H, ArCH2COO-), the 3.65 (bd, 1H, N-COCH2-N) 3,93 (s, 3H, -OCH3), of 4.05 (d, J = 17,5, 1H, the other H of N-COCH2-N), 4,91 (t, J = 7, 1H, N-CH-COO), and 6.5 (s, 1H, N-CH-N), 6,85 (bd, J = 8, 1H, in position 4 on CO-NH-Ph), of 6.9 to 7.4 (m, 6H, aromatic), 7,9 (bd, J = 8, 1H, in position 6 on S-CH-Ph).

Infrared spectrum (KBr), characteristic bands in cm-1: 3390, 2975, 2930, 2840, 2700 - 2250 (wide band), 1735, 1645, 1610, 1600, 1595, 1560, 1370, 1245, 1155, 1025, 760, 705.

3-(3-(2-(4-Tert. butoxycarbonyl-2-(2-methoxy-phenyl)-3 - thiazolidine)2-oxo-ethyl)ureido)phenylmethyl who yl)-4-thiazolecarboxamide- (2RS, 4R), 1.73 g of 2-(3-(3-methoxycarbonylmethyl-phenyl)ureido)acetic acid and 1.4 g of N,N'-dicyclohexylcarbodiimide. The crude product is purified by chromatography on silica (eluent: ethyl acetate-cyclohexane (50/50 by vol. )). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and the 40oC. Thus, receive 1.5 g 3-(3-(2- (4-tert.butoxycarbonyl-2-(2-methoxy-phenyl)-3-thiazolidine)2-oxoethyl)ureido)-phenylethylamine-(2R, 4R) as an amorphous white solid product used in the subsequent synthesis.

2-(2-Methoxy-phenyl)-4-thiazolidine. butylcarbamoyl-(2RS, 4R) can be obtained by a method similar to that described in example 34, but on the basis of 3.5 g of 2-(2-methoxy-phenyl)-4-thiazolidinones-(2RS, 4R) acid dissolved in 50 cm3chloroform, 1.0 cm3concentrated sulphuric acid and an excess of isobutene. The initial product was then purified by chromatography on silica (eluent: ethyl acetate-cyclohexane (30/70 vol.)). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and the 40oC. Thus, obtain 2.0 g of 2-(2-methoxy-phenyl)- 4-thiazolidine. BUTYLCARBAMATE-(2RS, 4R) in the form of oil, a mixture of isomers (2R, 4R) and (2S, 4R) using the may be obtained, as in example 34, G, but based on 7,26 g of L-cysteine and 8.9 g of 2-methoxy-benzaldehyde. Thus, the gain of 3.7 g of 2-(2-methoxy-phenyl)-4-thiazolidinones-(2RS, 4R) acid, melting at 170oC used in the subsequent synthesis.

Example 79. In manner analogous to example 77, but on the basis of 0,70 g 3-(3-(2-(4-tert. butoxycarbonyl-2-(2-fluoro-phenyl)-3 - thiazolidin-(2R, 4R)2-oxo-ethyl)ureido)-methylmandelic-(RS) 7 cm3a mixture of water-methanol (30/70 vol.) and 0.08 g of potassium hydroxide. The crude product (0.45 g) was dissolved in 8.5 cm3a 0.1 N aqueous solution of sodium hydroxide. The resulting solution is washed with 2 times 25 cm3ethyl acetate, filtered and acidified to pH 2 by addition of 1N aqueous solution of hydrochloric acid. Precipitated precipitated product is filtered off, washed with 2 times 10 cm3water and dried in air. Thus, the gain of 0.15 g 3-(3-(2-(4-tert.butoxycarbonyl-2-(2-fluoro-phenyl)-3 - thiazolidine (2R, 4R)/2-oxo-ethyl)ureido)Mendeley-(RS) acid in the form of a white product, melting at 135oC.

Proton NMR (200 MHz, DMCO D6plus a few drops CD3COOD, ppm (J in Hz), 2 rotamer at room temperature, coalescence lines at 110oC, characteristic chemical shifts at 110oC: of 1.55 (s, 9H, -C(CHs, 2H, in the aggregate, respectively, N-CH-COO -, and Ar-CH-), 6,2 (mass, 1H, -NHCO-), is 6.54 (s, 1H, S-CH-N), 7,02 (bd, J = 7,5, 1H, in position 4 on CO-NH-Ph), 7,1 - 7,5 (m, 6H, aromatic) 7,94 (dd, J = 7.5 and 9, 1H, in position 6 on S-CH-Ph), 8,5 (mass), -CONH-Ar).

Infrared spectrum (KBr), characteristic bands in cm-1: 3390, 2980, 2930, 2840, 2700 - 2250 (wide band), 1735, 1650, 1610, 1560, 1490, 1455, 1370, 1230, 1150, 1060, 790, 760, 700.

3-(3-(2-(4-Tert. butoxycarbonyl-2-(2-fluoro-phenyl)-3 - thiazolidin-(2R, 4R)/2-oxo-ethyl)ureido)-methylmandelic-(2R, 4R) can be obtained in the manner similar to that described in example 38, but from 3.2 g of 3-(2-(1-imidazolyl-carboxamide)acetyl-2- (2-forfinal)-4-thiazolidine. BUTYLCARBAMATE-(2R, 4R) and 2.7 g of 3-aminomethylenemalonate-(RS). The crude product is purified by two successive chromatography on silica (eluent: methylene chloride-methanol (95/5 by vol.) for the first chromatography, eluent: ethyl acetate for the second chromatography). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure. Thus, the gain of 1.6 g 3-(3-(2-(4-tert. butoxycarbonyl-2- (2-forfinal)-3-thiazolidine-(2R, 4R)/2-oxo-ethyl)ureido)methylmandelic- (R, S) in the form of air mass used for further synthesis.

3-(2-(1-Imidazolyl-carboxamide)acetyl)-2-(2-fluoro-phenyl)-2-(2-fluoro-phenyl) 4-thiazolidine.BUTYLCARBAMATE-(2R, 4R) 100 cm3anhydrous tetrahydrofuran (THF) is added slowly at a temperature of approximately 25oC, a solution of 4.8 g of N,N'-diimidazole-carbonyl 50 cm3anhydrous tetrahydrofuran. The reaction medium is stirred for 12 h at this temperature, then concentrated to dryness under reduced pressure and the 40oC. the resulting residue is dissolved in 200 cm3ethyl acetate and washed with 2 times 50 cm3water. The organic phase is dried over magnesium sulfate and evaporated to dryness under reduced pressure and the 40oC. Thus, obtain 8.7 g of 3-(2-(1-imidazolyl-carboxamide)acetyl/-2- (2-fluoro-phenyl)-4-thiazolidine. BUTYLCARBAMATE (2R, 4R) in the form of oils used in the subsequent synthesis.

3-(2-Amino-acetyl)-2-(2-fluoro-phenyl)-4 - thiazolidine. butylcarbamoyl-(2R, 4R) can be obtained by a method similar to that described in example 34, but on the basis of 15.0 g of 3-(2-tert.butoxycarbonylamino)-2-(2-fluoro-phenyl)-4 - thiazolidine. BUTYLCARBAMATE-(2R, 4R) and 5.34 g of idolisation. So, get 10 g of 3-(2-amino-acetyl)-2- (2-fluoro-phenyl)-4-thiazolidine. BUTYLCARBAMATE-(2R, 4R) in the form of oils used in the subsequent synthesis.

3-(2-Tert. butoxycarbonylamino-acetyl)-2-(2-fluoro-phenyl)- 4-thiazole out of 25.0 g of 2-(2-fluoro-phenyl)-4-thiazolidine. BUTYLCARBAMATE-(2RS, 4R), 15.5 g of 2-tert.butoxycarbonylamino-acetic acid and 18.2 g of N,N'-dicyclohexylcarbodiimide. The crude product is purified by chromatography on silica (eluent: ethyl acetate-cyclohexane (30/70 vol.)). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure. Thus, the gain of 25.0 g of 3-(2-tert. butoxycarbonylamino-acetyl)-2-(2-fluoro-phenyl)- 4-thiazolidin-tert. BUTYLCARBAMATE-(2R, 4R) in the form of oils used in the subsequent synthesis.

3-Amino-methylmandelic-(RS) can be obtained in the following way: a solution of 15 g of 3-nitromethylene-(RS) 150 cm3ethanol is added 0.5 g of 5% palladium on coal. The suspension is stirred for 2 hours at a temperature of about 25oC in hydrogen atmosphere (100 kPa). Then the catalyst is filtered off and the filtrate is concentrated to dryness under reduced pressure and the 40oC. Thus, the gain of 13.1 g of 3-aminomethylenemalonate-(RS) in the form of oils used in the subsequent synthesis.

3-Nitromethylene (RS) can be obtained by a known method (L. S. FOSDICK et J. C. CALANDRA, J. Am. Chem. Soc.,63,1101,1941).

Example 80. According to the method similar to example 38, but from 2.17 g of 3-(2-(1-imidazolyl-carboxamide)acetyl)-2-(2-fluoro-phenyl)-the tion chromatography on silica (eluent: methylene chloride-methanol (95/5 by vol.) for the first chromatography eluent: ethyl acetate - for the second chromatography). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure. Thus, receive 0.5 g 3-(2-(3-(2-hydroxy-ethyl)phenyl)ureido) acetyl)-2-(2-fluoro-phenyl)-4-thiazolidine. BUTYLCARBAMATE-(2R, 4R) in the form of an amorphous product, //2D0= +69,02,0(C = 0,48%, CHCl3).

Proton NMR (200 MHz, DMCO D6plus a few drops CD3COOD, ppm, J in Hz), 2 rotamer at room temperature, coalescence lines at 110oC, characteristic chemical shift at 110oC, of 1.55 (s, 9H, -C(CH3)3), of 2.72 (t, J = 7, 2H, Ar CH2), 3,31 and 3,52 (2dd, J = 12 and 6, 2H, S-CH2), to 3.67 (t, J = 7, 2H, -CH2O-), 4,1 (d, J = 17, 1H, the other H of N-COCH2-N), 3,8 (bd, 1H, N-COCH2-N), free 5.01 (t, J = 6, 1H, N-CH-COO), 6,2 (array, 1H, - NHCO-), is 6.54 (s, 1H, S-CH-N), for 6.81 (bd, J = 7,5, 1H, in position 4 on CO-NH-Ph-), 7,05 was 7.45 (m, 6H, aromatic), to 7.93 (bt, J = 8,5, 1H, in position 6 on S-CH-Ph), at 8.36 array, 1H, Ar NHCO-).

Infrared spectrum (KBr), characteristic bands in cm-1: 3380, 2975, 2930, 2875, 1740, 1655, 1610, 1590, 1560, 1490, 1460, 1370, 1230, 1150, 1050, 760, 700.

2-(3-Amino-phenyl) ethanol can be obtained by a known method (B. CARNMALM et coll., Acta Pharm Suecica, 11,33,1974).

Example 81. According to the method described in example 41, n the Lil-ethylbenzoic (2R, 4R) and 4.3 cm31M solution of tetrabutylammonium fluoride. The crude product is dissolved in 10 cm30.5 M aqueous solution of sodium hydroxide and washed with 2 times 20 cm3ethyl acetate. The aqueous phase is brought to pH 2 by addition of 1N aqueous solution of sulfuric acid. Precipitated precipitated product is filtered off, washed with 2 times 5 cm3distilled water and dried in air. So, get 0.12 g 3-(3-(2-(4-tert. butoxycarbonyl-2- (2-chloro-6-forfinal)-3-thiazolidine)-2-oxo-ethyl)ureido) benzoic-(2R, 4R) acid, melting at 148oC //2D0= +3,10,8C = 0,518%, DMF).

Proton NMR (250 MHz, DMCO D6in ppm, J in Hz), 2 rotamer at room temperature, coalescence lines at 120oC, characteristic chemical shifts at 120oC: 1,5 (s, 9H, -C(CH3)3), of 3.48 (dd, J = 12.5 and about 6.5, 1H, S-CH2), 3,62 (dd, J = 12.5 and 5, 1H, the other H N-CH2-) of 3.96 (dd, J = 17.5 and 5, 1H, N-COCH2-N) 4,18 (dd, J = 17.5 and a 5.5, 1H, the other H of N-COCH2-N), 5,11 (dd, J = 6.5 and 5, N-CH-COO), 6,24 (array, 1H, -NHCO-), 6,01 (S, 1H, S-CH-N), 7,05-the 7.65 (m, 6H, aromatic), 7,98 (bs, 1H, in position 2, CO-NH-Ph), 8,66 (array, 1H, Ar NHCO-).

Infrared spectrum (KBr), [characteristic bands in cm-1: 3380, 2980, 2930, 2700-2250 (wide band), 1715, 1695, 1655, 1605, 1590, Wed) 2-trimethylsilyl-ethylbenzoic (2R, 4R) can be obtained by a method similar to that described in example 34, but on the basis of 1.40 g of 3-(2-amino-acetyl)-2-(2-chloro-6-forfinal)-4 - thiazolidine.BUTYLCARBAMATE-(2R, 4R) and 1.4 g of 3-isocyanatobenzene 2-(trimethylsilyl)-ethylene. The resulting crude product was then purified by chromatography on silica (eluent: ethylacetoacetate (about 30/70. )). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and the 40oC. Thus, obtain 1.44 g 3-(3-(2-(4- tert.butoxycarbonyl-2-(2-chloro-6-forfinal)-3-thiazolidin) 2-oxo-ethyl)ureido)-2-trimethylsilyl-ethylbenzoic- (2R, 4R) in the form of air masses used in the subsequent synthesis.

3-(2-Amino-acetyl)-2-(2-chloro-6-forfinal)-4-thiazolidin - tert.butylcarbamoyl-(2R, 4R) can be obtained in a manner similar to described in example 34, A, but on the basis of 1.86 g of 3-(2-tert.butoxycarbonylamino-acetyl)-2-(2-chloro-6-forfinal)-4 - thiazolidine. BUTYLCARBAMATE-(2R, 4R) and 0.67 cm3idolisation. Thus, the gain of 1.4 g of 3-(2 - amino-acetyl)-2-(2-chloro-6-forfinal)-4 - thiazolidine. BUTYLCARBAMATE-(2R, 4R) in paste form, used in the subsequent synthesis.

3-(2-Tert.butoxycarbonylamino)-2-(2-chloro-6-forfinal) -4-thiazolidin-tert. butilka who yl)-4-thiazolidin-tert.BUTYLCARBAMATE (2RS, 4R), 1.22 g of 2-tert.butoxycarbonylamino acid and 1.45 g of N,N'-dicyclohexylcarbodiimide. The crude product is purified by chromatography on silica (eluent: methylene chloride-methanol (98/2 by vol.). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure. Obtain 1.56 g of 3(2-tert.butoxycarbonylamino)-2-(2-chloro-6-forfinal)-4 - thiazolidine.BUTYLCARBAMATE (2R, 4R) in the form of a solid substance used in the subsequent syntheses.

2-(2-Chloro-6-forfinal)-4-thiazolidine.butylcarbamoyl (2RS, 4R) can be obtained by a method similar to that described in example 34, but according to 6.1 g of 2-(2-chloro-6-forfinal)-4-thiazolidinones- (2R, 4R) acid, dissolved in 60 cm3chloroform, 1,4 cm3concentrated sulphuric acid and an excess of isobutene. The resulting crude product was then purified by chromatography on silica (eluent: ethyl acetate-cyclohexane (25/75% by vol.). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and the 40oC. Thus, obtain 4.4 g of 2-(2-chloro-6-forfinal)-4-thiazolidine. BUTYLCARBAMATE-(2RS, 4R) in the form of oils used in the subsequent synthesis.

2-(2-chloro-6-forfinal)-4-thiazolidinedione solidarnosci- (2RS, 4R) acid, melting at 148oC used in the subsequent synthesis.

3-Isocyanate-benzoate 2-(trimethylsilyl)-ethyl can be obtained as in example 21, but on the basis of 2.37 g of 3-amino-benzoate 2-(trimethylsilyl)-ethyl, 1,32 cm3chloroformiate of trichloromethyl and 0.21 g of coal. Thus, the gain of 21.6 g of 3-isocyanate-benzoate 2-(trimethylsilyl)-ethyl, in the form of oils used in the subsequent synthesis.

Example 82. According to the method described in example 77, but on the basis of 0,38 g 3-(3-(1-(4-tert. butoxycarbonyl-2-(2-fluoro-methyl)-3 - thiazolidine-(2R, 4R)) 1-oxo-2-propyl-(2S)ureido)phenylethylamine 6 cm3a mixture of water-methanol (30/70 about. ) and 0.05 g of potassium hydroxide. The crude product is dissolved in 3.5 cm3a 0.1 N aqueous solution of sodium hydroxide. The resulting solution is washed with 2 times 10 cm3ethyl acetate, filtered and brought to pH 2 by addition of 1N aqueous solution of sulfuric acid. Precipitated precipitated product is filtered off, washed with 2 times 5 cm3water and dried in air. Thus, the gain of 0.13 g 3-(3-(1-(4-tert.butoxycarbonyl-2-(2-fluoro-phenyl)-3-thiazolidine- (2R, 4R))1-oxo-2-propyl-(2S))ureido)phenylacetic acid, melting at 110oC, //2D0= +1034(C = 0,244%, DMF).

o
C, characteristic chemical shifts at 120oC: of 1.05 (d, J = 7, 3H, -CH3), of 1.55 (s, 9H, -C(CH3)3) at 3.25 (dd, J = 12.5 and 7,1 H, S-CH2): to 3.52 (dd, J = 12.5 and 6, 1H, the other H S-CH2-), 3,53 (s, 2H, ArCH2COO), 4,4 (m, 1H, N-COCH-N), a 4.86 (dd, J = 7 and 6, N-CH-COO), and 6.3 (d, J = 8, 1H, N-HCO-), 6,83 (s, 1H, S-CH-N), 6,89 (bd, J = 8, 1H, in position 4 on CO-NH-Ph), 7,10-7,5 (m, 6H, aromatic), 8.0 a (bt, J = 8,5, 1H, in position 6 on S-CH-Ph), 8,29 (array, 1H, Ar NHCO-).

Infrared spectrum (KBr), characteristic bands in cm-1: 3380, 2980, 2935, 2700-2250 (wide band),1735, 1640, 1615, 1595, 1560, 1490, 1460, 1370, 1235, 1155, 760, 705.

3-(3-(1-(4-Tert. butoxycarbonyl-2-(2-fluoro-phenyl)-3-thiazolidine- (2R, 4R))1-oxo-2-propyl-(2S))ureido)feniletilamin can be obtained by a method similar to that described in example 34, but on the basis of 0.85 grams of 3-(2-amino-propionyl(2S))-2-(2-fluoro-phenyl)-4 - thiazolidine.BUTYLCARBAMATE(2R, 4R) and of 0.53 g of 3-isocyanate-phenylethylamine. The resulting crude product was then purified by chromatography on silica (eluent: ethylacetoacetate (about 30/70. )). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and the 40oC. Thus, the gain of 0.38 g 3-(3-(1-(4-tert.butoxycarbonyl-2-(2-fluoro-phenyl)-3-thiazolidine- (2R, 4R))1-oxo-2-propyl-(2S))ureido)phenylethylamine in the form of oils used R, 4R) can be obtained by a method similar to that described in example 34, but on the basis of 1.0 g of 3-(2-tert.butoxycarbonylamino-(2S))-2-(2-fluoro-phenyl)-4 - thiazolidine.butylcarbamoyl-(2R, 4R) and 0.39 cm3idolisation. Thus, the gain of 0.85 g of 3-(2-amino-propionyl(2S))-2-(2-fluoro-phenyl)-4 - thiazolidine.BUTYLCARBAMATE-(2R, 4R) in the form of oils used in the subsequent synthesis.

3-(2-Tert.butoxycarbonylamino-(2S))-2-(2-fluoro-phenyl)-4 - thiazolidine. butylcarbamoyl-(2R, 4R) can be obtained by a method similar to that described in example 34, B, but on the basis of 2.0 g of 2-(2-fluoro-phenyl)-4-thiazolidine. BUTYLCARBAMATE-(2RS, 4R), of 1.36 g of N-tert.butoxycarbonyl-L-alanine and 1.47 g of N,N'-dicyclohexylcarbodiimide. The crude product is purified by chromatography on silica (eluent: ethyl acetate-cyclohexane (15/85 by vol.). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure. Thus, gain of 1.0 g of 3-(2-tert.butoxycarbonylamino-propionyl(2S))-2-(2-fluoro-phenyl)-4 - thiazolidine. BUTYLCARBAMATE-(2R, 4R) in the form of oil used in the last synthesis.

Example 83. Operate according to the method described in example 77, but on the basis of 0,48 g 3-(3-(1-(4-tert.butoxycarbonyl-2-(2-fluoro-phenyl) 3-thiazolidine-(2R, 4R))1-scientists after filtration on silica product (eluent: ethyl acetate-methanol (90/10 vol.)) dissolved in 7.0 cm3a 0.1 N aqueous solution of sodium hydroxide. The resulting solution is filtered and brought to pH 2 by addition of 1N aqueous solution of sulfuric acid. Precipitated precipitated product is filtered off, washed with 2 times 5 cm3water and dried in air. Thus, 0.25 g get 3-(3-(1-(4-tert.butoxycarbonyl-2-(2-fluoro-phenyl)-3-thiazolidine- (2R, 4R))1-oxo-2-propyl)ureido-(2R)) phenylacetic acid, melting at 200oC, //2D0= +832,0(C = 0,48%, DMF).

Proton NMR (250 MHz, DMCO6in ppm, J in Hz), 2 rotamer at room temperature, coalescence lines at 120oC, characteristic chemical shifts at 120oC: of 1.27 (d, J = 7,5, 3H, -CH3), and 1.54 (s, 9H, -C(CH3)3, 3,40, and of 3.56 (2dd, J = 12.5 and about 6.5, 2H, S-CH2-), 3,50 (s, 2H, -CH2COO-), 4,50 (m, 1H, N-COCH-N), the 5.45 (mass, 1H, N-CH-COO), and 6.3 (d, J = 8,5, 1H, -NHCO-), of 6.50 (s, 1H, S-CH-N), 6,9 (bd, J = 8, 1H, in position 4 on CO-NH-Ph), 7,0-7,415 (m, 6H, aromatic), 7,9 (bt, J = 8,5, 1H, at position 6 in S-CH-Ph), 8,3 (array, 1H, ArNHCO-).

Infrared spectrum (KBr), characteristic bands in cm-1: 3380, 2975, 2930, 2700-2250 (wide band), 1730, 1640, 1610, 1595, 1555, 1490, 1455, 1365, 1230, 1150, 755, 700.

(3-(3-(1-(4-Tert. butoxycarbonyl-2-(2-fluoro-phenyl)-3-thiazolidine-(2R, 4R)) 1-oxa-2-propyl-(2R)) ureido) phenylmethyl acetate could yl)-4-thiazolidine.BUTYLCARBAMATE -(2R, 4R) and 0.37 g of 3-isocynate of phenylethylamine. The resulting crude product was then purified by chromatography on silica (eluent: ethyl acetate-cyclohexane (40/60 in about. )). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and the 40oC. Thus, the gain of 0.48 g 3-(3-(1-(4-tert. butoxycarbonyl-2-(2-fluoro-phenyl)-3-thiazolidine-(2R, 4R)) 1-oxo-2-propyl-(2R))ureido) phenylethylamine in the form of an amorphous product used in the subsequent synthesis.

3-(2-Amino-propionyl(2R))-2-(2-fluoro-phenyl)-4-thiazolidin-tert. butylcarbamoyl -(2R, 4R) can be obtained by a method similar to that described in example 34, A, but on the basis of 0.8 g of 3-(2-tert.butoxycarbonylamino-propionyl (2R))-2-(2-fluoro-phenyl)-4-thiazolidine. BUTYLCARBAMATE-(2R, 4R) and 0.30 cm3idolisation. Thus, the gain of 0.55 g of 3-(2-amino-propionyl(2R)-2-(2-fluoro-phenyl)-4-thiazolidine. BUTYLCARBAMATE -(2R, 4R) in the form of oils used in the subsequent synthesis.

3-(2-Tert. butoxycarbonylamino-propionyl(2R))-2-(2-forfinal)- 4-thiazolidin-tert. butylcarbamoyl can be obtained by a method similar to that described in example 34, B, but on the basis of 2.0 g of 2-(2-fluoro-phenyl)-4-thiazolidine. BUTYLCARBAMATE- (2RS, 4R), of 1.36 g of N-tert.butoxycarbonyl the eluent: ethyl acetate-cyclohexane (15/85 by vol.). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure. Thus, gain of 1.0 g of 3-(2-tert.butoxycarbonyl-amino-propionyl(2R))-2-(2-forfinal)-4-thiazolidine. BUTYLCARBAMATE-(2R, 4R) in the form of oils used in the subsequent synthesis.

Example 84. In a solution of 0.35 g 2-(3-(3-(2-(4-tert.butoxycarbonyl-2-(2-forfinal)-3-thiazolidine-(2R, 4R)) 2-oxo-ethyl)ureido)phenylbenzyl)propionate (form B) 40 cm3ethyl acetate added 0.1 g of 10% palladium on coal. The suspension is stirred for 48 hours at a temperature of about 25oC in hydrogen atmosphere (100 kPa). Then the catalyst is filtered off and the filtrate is concentrated to dryness under reduced pressure and the 40oC. the resulting residue is dissolved in 10 cm3a 0.1 N aqueous solution of sodium hydroxide and washed twice in 10 cm3diethyl ether. The aqueous phase is brought to pH 2 by addition of 1N aqueous solution of sulfuric acid. Precipitated precipitated product is filtered off, washed with 2 times 10 cm3water and dried in air. So, get 0.12 g 2-(3-(3-(2-(4-tert.butoxycarbonyl-2-(2-fluoro-phenyl) 3-thiazolidine-(2R, 4R)) 2-oxoethyl)ureido)phenyl)propionic acid (form B), melting at 126oC //2D0=PEL SD3SOOD, h/m, J in Hz), 2 rotamer at room temperature, coalescence lines at 120oC, characteristic chemical shifts at 120oC: 1,4 (d, J = 7,5, 3H, -CH3), and 1.54 (s, 9H, -C(CH3)3), of 3.32 (dd, J = 12 and 6.5, 1H, S - CH2), 3,52 (dd, J = 12 and 7, 1H, the other H S-CH2-), 3,62 (q, J = 7,5, 1H, Ar-CO-COOO), 3,78 (bd, 1H, N-COCH2-N) 4,07 (d, J = 17, 1H, the other H of N-COCH2-N, 5,0 (dd, J = 7 and 6.5, 1H, N-CH-COO), 6,17 (array, 1H, -NHCO-), 6,53 (s, 1H, S-CH-N) 6,86 (bd, J = 8, 1H, in position 4 on CO-NH-Ph-), 7,10-7,5 (m, 6H, aromatic), 7,92 (bt, J = 8,5, 1H, at position 6 in S-CH-Ph), 8,43 (array, 1H, ArNHCO-).

Infrared spectrum (KBr), characteristic bands in cm-1: 3380, 2975, 2930, 2650-2250 (wide band), 1735 1650, 1610, 1595, 1560, 1490, 1455, 1370, 1230, 1150, 760, 700.

And) 2-(3-(3-(2-(4-Tert. butoxycarbonyl-2-(2-fluoro-phenyl)-3 - diazolidinyl-(2R, 4R)) 2-oxo-ethyl)ureido)phenyl)benzoylpropionate (form B) can be obtained in the following way: similar to that described in example 34, but on the basis of 1,02 g of 3-(2-aminoacetyl-2-(2-fluoro-phenyl)-4-thiazolidine.BUTYLCARBAMATE-(2R, 4R) and 0,89 g (2-(3-isocyanate-phenyl) benzoylpropionate (form B). The crude product is purified by chromatography on silica (eluent: ethyl acetate-cyclohexane (50/50 by vol.). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and the 40oC. Such benzoylpropionate (form B) in paste form yellow, used in the subsequent synthesis.

B) 2-(3-Isocyanate-phenyl)benzoylpropionate (form B) can be obtained as in example 21, but on the basis of 2.85 g of (+)-2-(3-AMINOPHENYL)benzoylpropionate 1,48 cm3chloroformiate of trichloromethyl and 0.24 g of coal. Thus, the gain of 3.1 g of 2-(3-isocyanatophenyl)benzoylpropionate (form B) in the form of an orange oil, used in the subsequent synthesis.

In) (+)-2-(3-amino-phenyl)benzoylpropionate can be obtained in the following way: a mixture of 8.0 g of (+)-2-(3-nitro-phenyl)benzoylpropionate 35 cm3methanol and 300 cm3water, add 75 g of ammonium chloride and 37,0 zinc powder. The reaction medium is heated under reflux for 1 h, then cooled to 0oC. the Insoluble salts are filtered off and the filtrate is extracted with 3 times 200 cm3diethyl ether. The collected organic phases are washed successively with 100 cm3water and 100 cm3saturated aqueous solution of sodium chloride. Thus, get, after drying over magnesium sulfate and concentration to dryness under reduced pressure and the 40oC, 6.7 g of (+)-2-(3-amino-phenyl)benzoylpropionate in the form of a yellow oil, used in the subsequent synthesis.

G) (+)-2-(3-nitro-phenyl) - Rev. acid and 0.5 cm3of dimethylformamide at 100 cm31,2-dichloroethane, add slowly 4,72 cm3oxalidaceae. The reaction medium is stirred for 3 hours at a temperature of about 25oC, then add in for 12 h at this temperature, then the reaction mixture is washed successively with 2 times 200 cm3saturated aqueous solution of acid sodium carbonate, 100 cm3water and 100 cm3saturated aqueous solution of sodium chloride. The combined organic phases are dried over magnesium sulfate and concentrated to dryness under reduced pressure and the 40oC. the resulting residue is purified by chromatography on silica (eluent: ethyl acetate-cyclohexane (30/70 vol.)). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and the 40oC. Thus, the gain of 11.5 g of (+)-2-(3-nitro-phenyl)benzoylpropionate in the form of a yellow oil, used in the subsequent synthesis.

D) (+)-2-(3-nitro-phenyl) propionic acid can be obtained in the following way: 21,5 g of 2-(3-nitro-phenyl)-N-(2-hydroxy-1-phenyl-ethyl-(R)-propionamide (form B), dissolved in a mixture of 450 cm3dioxane, and 450 cm34N aqueous solution of hydrochloric acid, is heated at a temperature of approximately 80who tryout half by evaporation under reduced pressure and the 40oC, diluted by adding 500 cm3water and extracted 2 times with 500 cm3diethyl ether. The collected organic phases are washed successively 3 times with 250 cm3water and 250 cm3saturated aqueous solution of sodium chloride. Thus, get, after drying over magnesium sulfate and concentrated to dryness under reduced pressure and the 40oC, 14 d (+)-2-(3-nitro-phenyl)propionic acid (form B) in the form of creamy product that is used in the subsequent synthesis.

E) 2-(3-Nitro-phenyl)-N-(2-hydroxy-1-phenyl-ethyl-(R) - propionamide (form B) can be obtained in the following way: a mixture containing of 39.0 g of 2-(3-nitro-phenyl)propionic-(RS) acid and 0.5 cm3of dimethylformamide 400 cm31,2-dichloro-ethane, add slowly 17,2 cm3oxalidaceae. The reaction medium is stirred for 3 hours at a temperature of about 25oC, then concentrated to dryness under reduced pressure and the 40oC. the resulting residue is dissolved in 150 cm31,2-dichloroethane. The resulting solution of acid chloride of acid added to a solution of 27.4 G. of 2-phenyl-Galitzine (2R), maintaining the temperature of the reaction medium below 10oC. After the addition the mixture is stirred for 12 h at a temperature what olaney acid, two times in 500 cm3water and once with 500 cm3saturated aqueous solution of sodium chloride. The collected organic phases are dried over magnesium sulfate and concentrated to dryness under reduced pressure and the 40oC. the Obtained two diastereoisomers separated by chromatography on silica (eluent: methylene chloride-ethyl acetate (70/30 by vol.). The fractions containing each two diastereoisomer, are combined and concentrated to dryness under reduced pressure and the 40oC. Thus have to 21.0 g of 2-(3-nitro-phenyl)-N-(2-hydroxy-1-phenyl-ethyl-(R)-propionamide (form A) (the first product elution), melting at 135oC, and 19.0 g of 2-(3-nitro-phenyl)-N-(2-hydroxy-phenyl-ethyl-(R)/-propionamide (form B) (the second product elution), melting at 150oC.

Example 85. Operate according to the method described in example 84, but on the basis of 3.8 g 2-(3-(3-(2-(4-tert.butoxycarbonyl-2-(2-forfinal) 3-thiazolidine-(2R, 4R) 2-oxo-ethyl)ureido)phenyl)benzoylpropionate (form A) and 0.8 g of 10% palladium on coal. Thus, get 2-(3-(3-(2-(4-tert.butoxycarbonyl-2-(2-fluoro-phenyl) 3-thiazolidine-(2R, 4R) 20 oxo-ethyl)ureido)phenyl) propionic acid (form A), melting at 145oC. //2D0= +20,01,1(C = 0,539%, DMF).

oC, characteristic chemical shifts at 120oC:1,4 (d, J = 3, 3H, -CH3), of 1.53 (s, 9H, -C(CH3)3), 3.3% of 3.48 (dd, J = 12.5 and 6, 2H, S-CH2), and 3.6 (q, J = 7, 1H, Ar-CH-COO), of 3.77 and of 4.05 (2 dd, J = 17.5 and 5,5, 2H, N-COCH2-N, 5,0 (t, J = 6, 1H, N-CH-COO), 6,17 (t, J = 5,5 1H, -NHCO-), 6,53 (s, 1H, S-CH-N), 6,85 (bd, J = 7,5, 1H, in position 4 on CO-NH-Ph-), 7,05 was 7.45 (m, 6H, aromatic), to $ 7.91 (dt, J = 8 and 1, 1H, at position 6 in S-CH-Ph), 8,43 (mass, 1H, Ar NHCO-).

Infrared spectrum (KBr), characteristic bands in cm-1: 3380, 3100 - 300, 2975, 2930, 2875, 2750 - 2350 (wide band), 1735, 1650, 1615, 1595, 1555, 1490, 1490, 1460, 1420, 1395, 1370, 1155, 760, 700.

2-(3-(3-(2-(4-Tert.butoxycarbonyl-2-(2-fluoro-phenyl)-3-thiazolidine- (2R, 4R)) 2-oxo-ethyl)ureido)phenyl)benzoylpropionate (form A) can be obtained by the method described in example 34, but on the basis of 4.0 g of 3-(2-amino-acetyl)-2-(2-fluoro-phenyl) 4-thiazolidine.butylcarbamoyl-(2R, 4R) and 4.0 g of 2-(3-isocyanate-phenyl)benzoylpropionate (form A). The crude product is purified by chromatography on silica (eluent: ethyl acetate-cyclohexane (40/60 vol.)). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and the 40oC. Thus, obtain 3.8 g 2-(3-(3-(2-(4-tert. butoxycarbonyl-2-(2-fluoro-phenyl)-3-thiazolidine -(2R, 4R)) 2-oxo-ethyl)ureido)phenyl)benzyl propionate (form A) in amorphous form is et to be obtained, as described in example 21, but on the basis of 4.0 g of (-)-2-(3-amino-phenyl) benzoylpropionate 2.1 cm3chloroformiate of trichloromethyl and 0.33 g of coal. Thus, the gain of 4.7 g of 2-(3-isocyanatophenyl)-benzoylpropionate (form A) in the form of an orange oil, used in the subsequent synthesis.

(-)-2-(3-Amino-phenyl)benzoylpropionate can be obtained by the method described in example 84, B, but on the basis of 5.3 g of (-)-2-(3-nitro-phenyl)benzoylpropionate, 50 g of ammonium chloride and 24.8 g of zinc powder. Thus, get 4,2 (-)-2-(3-AMINOPHENYL)benzoylpropionate in the form of a yellow oil, used in the subsequent synthesis.

(-)-2-(3-Nitro-phenyl)benzoylpropionate can be obtained by the method described in example 84, G, but on the basis of of 4.45 g of 2-(3-nitro-phenyl)propionic (-)-acid, 0.3 cm3of dimethylformamide and 2.15 cm3oxalidaceae. The crude product is purified by chromatography on silica (eluent: ethyl acetate-cyclohexane (30/70 vol.)). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and the 40oC. Thus, obtain 5.6 g of (-)-2-(3-nitro-phenyl)benzoylpropionate in the form of a yellow oil, used in the subsequent synthesis.

2-(3-Nitro-phenyl) propionic (-)-acid can be floor-(R)/-propionamide (form A), dissolved in a mixture of 200 cm3dioxane and 200 cm34N aqueous solution of hydrochloric acid. Thus, the gain of 5.85 g of 2-(3-nitro-phenyl) propionic (-)-acid in the form of creamy product that is used in the subsequent synthesis.

Example 86. Acting in the manner similar to that described in example 77, but based on 0,68 g 3-(3-(2-(4-tert.butoxycarbonyl-2- (2,3-debtor-phenyl) 3-thiazolidine) 2-oxo-ethyl(ureido)phenyl-acetate-(2R, 4R) 6 cm3a mixture of water-methanol (30/70 vol.) and 0.08 g of potassium hydroxide. The crude product (0.45 g) was dissolved in 7.5 cm3a 0.1 N aqueous solution of sodium hydroxide. The resulting solution was washed with 2 x 10 cm3diethyl ether was adjusted to pH 2 by addition of 1N aqueous solution of sulfuric acid, then extracted with 2 times 20 cm3ethyl acetate. The combined organic phases, dried over magnesium sulfate and concentrated to dryness under reduced pressure and the 40oC. the product Obtained by chromatography on silica (eluent: methylene chloride-methanol (80/20 by vol.). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and the 40oC. are Thus obtained 0.05 g 3-(3-(2-(4-tert. butoxycarbonyl-2-(2,3-debtor-phenyl) 3-thiazolidine) 2-oxo-ethyl)ureed the>SUP>
(C = 0,557%, CHCl3).

Proton NMR (200 MHz, DMCO D6plus a few drops CD3COOD, ppm, J in Hz), 2 rotamer at room temperature, coalescence lines at 120oC, characteristic chemical shift at 120oC: of 1.52 (s, 9H, -C(CH3)3), 3,31 and 3,51 (2dd, J = 12.5 and 6, 2H, S-CH2), of 3.46 (s, 2H, Ar-CH2-COO), 3,82 (bd, 1H, COCH2-N) of 4.05 (d, J = 17, 1H, the other H of N-COCH2-N, 5,0 (t, J = 6, 1H, N-CO-COO), 6,15 (array, 1H, -NHCO-), and 6.5 (s, 1H, S-CH=N), PC 6.82 (bd, J = 7,5, 1H, in position 4 on CO-NH-Ph-), 7,05 was 7.45 (m, 5H, aromatic), 7,86 (bt, J = 8, 1H, in position 6 on S-CH-Ph), 8,7 (array, 1H, ArNHCO-).

Infrared spectrum (KBr), characteristic bands in cm-1: 3380, 3100-3000, 2975, 2930, 2750-2350 (wide band), 1735, 1655, 1615, 1595, 1560, 1490, 1405, 1370, 1150, 775, 745.

3-(3-(2-(4-Tert. butoxycarbonyl-2-(2.3-debtor-phenyl)3 - thiazolidine)2-oxo-ethyl)ureido)feniletilamin-(2R, 4R) can be obtained by the method described in example 41, but on the basis of 1.5 g of 2-(2,3-debtor-phenyl)-4-thiazolidine. BUTYLCARBAMATE-(2R, 4R), 1,33 g of 2-(3-(3-methoxycarbonylmethyl-phenyl)ureido)acetic acid and 1.0 g of N,N'-dicyclohexylcarbodiimide. The crude product is purified by chromatography on silica: (eluent: ethyl acetate-cyclohexane (40/60 about. )). The fractions containing the desired product are pooled and concentrated to dryness p is diazolidinyl) 2-oxo-ethyl)ureido)phenylethylamine-(2R, 4R) as a colourless oil, used in the subsequent synthesis.

2-(2,3-Debtor-phenyl)-4-thiazolidine. butylcarbamoyl (2RS, 4R) can be obtained by the method described in example 34, but on the basis of 14.3 g of 2-(2,3-debtor-phenyl)4-thiazolidinediones-(2RS, 4R) acid dissolved in 50 cm3chloroform, 3.5 cm3concentrated sulphuric acid and an excess of isobutene. The resulting crude product was then purified by chromatography on silica (eluent: ethyl acetate-cyclohexane (about 10/90.)). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and the 40oC. Thus, obtain 14.0 g of 2-(2,3-dichlorophenyl)4-thiazolidine.BUTYLCARBAMATE-(2RS, 4R) as a thick yellow oil mixture of isomers (2R, 4R) and (2S, 4R) used in the subsequent synthesis.

2-(2,3-debtor-phenyl)4-thiazolidinedione-(2RS, 4R) acid can be obtained, as in example 34, G, but on the basis of 8.5 g of L-cysteine and 10.1 g of 2,3-debtor-benzaldehyde. Thus, the gain of 3.7 g of 2-(2,3-debtor-phenyl)4-thiazolidinediones-(2RS, 4R)acid, melting at 120oC used in the subsequent synthesis.

Example 87. According to the method described in example 41, but on the basis of 1.2 g of 2,4-diphenylthiazole(2RS, 4R), 1.04 g of 2-(3-(3-Abadi, get 0.9 g 1-(2-(3-(3-methyl-phenyl)ureido)acetyl)2,4-diphenylthiazole-(2RS, 4R) air masses.

Mass (chemical ionization with ammonia, 70 eV, m/z), 432 (M+).

Infrared spectrum (KBr), characteristic bands in cm-1: 3340, 3085, 3060, 3030, 2920, 2920, 1635, 1610, 1490, 1450, 1560, 780, 765, 695.

2,4-Diphenylthiazole-(2RS, 4R) can be obtained as in example 34, G, but on the basis of the 1.9 g of the hydrochloride of 2-amino-2-phenyl-ethandiol-(R), 2,75 cm3diethylamine and 1.15 cm3benzaldehyde in 25 cm3of ethanol. So get to 1.15 g of 2,4-diphenyl-thiazolidin-(2RS, 4R), melting at 120oC.

2-Amino 2-phenyl-ethandiol-(R) can be obtained by a known method (patent application JP 57193447, C. A. 98, 17894r).

Example 88. According to the method described in example 9, but on the basis of 1.35 g 3-(3-(2-(2-(2-fluoro-phenyl)-4-phenyl-3-thiazolidine) 2-oxoethyl)ureido) phenylethylamine-(2RS, 4R) dissolved in 25 cm3methanol and 0.22 g of potassium hydroxide dissolved in 5 cm3water, after treatment receive 0.45 g 3-(3-(2-(2-(2-fluoro-phenyl)-4-phenyl-3-thiazolidine)2-oxo-ethyl)ureido) phenylacetic-(2RS, 4R)acid, in the form of air masses.

Mass (chemical ionization with ammonia, 70 eV, m/z), 494 (M+), 343.

Infrared spectrum (KBr), hanil)-4-phenyl-3-thiazolidine)2-oxo-ethyl) ureido)feniletilamin-(2RS, 4R) can be obtained as described in example 41, but on the basis of 1.3 g 2-2-forfinal)4-phenyl-thiazolidin-(2RS, 4R), 1,33 g of 2-(3-(3-methoxycarbonylmethyl-phenyl)ureido)acetic acid and 1.03 g of N,N'-dicyclohexylcarbodiimide 15 cm3acetonitrile. After treatment receiving 1.5 g

3-(3-(-(2-(2-(2-forfinal)4-phenyl-3-diazolidinyl/2-oxo-ethyl) ureido)phenylethylamine-(2RS, 4R) in the form of oils used in the subsequent synthesis.

2-(2-fluoro-phenyl)4-phenyl-3-thiazolidine-(2RS, 4R) can be obtained as in example 34, G, but on the basis of the 1.9 g of the hydrochloride of 2-amino-2-phenyl-ethandiol-R), 2,75 cm3of triethylamine and of 1.37 g of 2-fluoro-benzaldehyde in 25 cm3of ethanol. So, get 1.5 g of 2-(2-fluoro-phenyl)4-phenyl-3-thiazolidine-(2RS, 4R) in the form of oils used in the subsequent synthesis.

Example 89. Operate according to the method described in example 9, but based on 0.9 g 1-(2-(3-(3-ethoxycarbonyl-phenyl)ureido)acetyl)-5- (2-were)tert. butylmalonate-(2RS, 5SR) dissolved in 30 cm3methanol and 0.1 g of potassium hydroxide dissolved in 15 cm3water. After treatment and crystallization in a mixture of oxide diisopropyl-acetaminophena (9-1 volumes) obtain 0.35 g 3-(3-(-(2-(2-tert. butoxycarbonyl 5-(2-methyl-phenyl)1-pyrrolidinyl) 2-oxo-ethyl)ureido)benzoic-(2RS is et.butylmalonate-(2RS, 5SR) can be obtained as described in example 41, but on the basis of 1.3 g of 5-(2-methyl-phenyl)tert.butylmalonate-(2RS, 5SR), 1,32 g of 2-(3-(3-etoxycarbonyl-phenyl)ureido)acetic acid and 1.03 g of N,N'-dicyclohexylcarbodiimide 50 cm3tetrahydrofuran (THF). After processing gain of 1.9 g 1-(2-(3-(3-etoxycarbonyl-phenyl)ureido)acetyl)5-(2-methyl-phenyl) tert.butylmalonate-(2RS, 5SR) in the form of air masses used in the subsequent synthesis.

5-(2-Methyl-phenyl)tert. butylmalonate-(2RS, 5SR) can be obtained in the following way: a suspension of 3 g of magnesium and a solution of 4 g of a mixture of two epimeres in position 4 5-(2-methyl-phenyl)-4-phenylsulfonyl-tert. butylmalonate-(2RS, 5SR) 200 cm3methanol is stirred for 3 hours at a temperature of about 20oC. the Reaction mixture was then poured into 20 cm3normal aqueous solution of hydrochloric acid, then extracted with three times 200 cm3dichloromethane. The organic extracts are combined, washed twice in 100 cm3saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrate under reduced pressure. The remainder chromatographic on silica (eluent: cyclohexane-ethyl acetate (70/30 by vol.). The fractions containing the desired product are pooled and conc is used in the subsequent synthesis.

A) 5-(2-methyl-phenyl)4-phenolsulfonate.BodyPaint-(2RS, 5SR) can be obtained in the following way: a suspension of 5 g of silver acetate in a solution of 3.4 g of phenylenesulfonyl and 4.7 N-(automaticbuilder)-tert.butilhioscina 150 cm3acetonitrile, was added dropwise 2.8 cm3of triethylamine at a temperature of about 20oC. the Reaction mixture is stirred for 2 hours at a temperature of about 20oC, then poured into 200 cm3saturated aqueous solution of ammonium chloride. The aqueous phase is filtered and extracted with three times 100 cm3dichloromethane. The organic extracts are combined, washed in 100 cm3saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrate under reduced pressure. Thus, obtained after crystallization in diethyl ether, 5 g of 5-(2-methyl-phenyl) 4-phenylsulfonyl-tert.butylmalonate-(2RS, 5SR), (mixture of two epimeres 4), melting at 180oC.

B) N-(automaticbuilder)-tert. butyllithium can be obtained in the following way: a suspension of 3 g of molecular sieve solution to 3.35 g of the hydrochloride tert.butilhioscina 2.4 cm3orthotoluidine and 50 cm3dichloromethane, was added dropwise 2.8 cm3of triethylamine at a temperature of the center under reduced pressure. The residue is extracted with 250 cm3diethyl ether, filtered and concentrate under reduced pressure. Thus, the gain of 4.7 g of N-(automaticbuilder)-tert.-butilhioscina in the form of oils used in the subsequent synthesis.

Example 90. Operate according to the method described in example 9, but from 1.1 g 1-(2-(3-(3-etoxycarbonyl-phenyl)ureido-)acetyl) 5-(2-forfinal) of tert-butylmalonate (2RS, 5SR) dissolved in 30 cm3methanol and 0.12 g of potassium hydroxide dissolved in 15 cm3water. After processing and crystallization of oxide diisopropyl obtain 0.4 g 3-(3-(2-(2-tert.butoxycarbonyl 5-(2-fluoro-phenyl) 1-pyrrolidinyl) 2-oxo-ethyl)ureido)benzoic-(2RS, 5SR) of acid, melting at 180oC.

1-(2-(3-(3-etoxycarbonyl-phenyl)ureido)acetyl)-5-(ftor-phenyl)- tert.butylmalonate (2RS, 5SR) can be obtained as described in example 41, A, but on the basis of 0.8 g of 5-(2-fluoro-phenyl)tert.butylmalonate (2RS, 5SR), 0.8 g of 2-(3-(3-(etoxycarbonyl-phenyl)ureido) acetic acid and 0.62 g of N, N'-dicyclohexylcarbodiimide 30 cm3tetrahydrofuran (THF). After processing, receive 1.5 g 1-(2-(3-(3-ethoxycarbonylphenyl)ureido)acetyl)-5-(2-fluoro-phenyl) tert. butylmalonate (2RS, 5SR) in the form of air masses used in the subsequent synthesis.

A) 5-(2-Fo phosphate and 7.7 g of amalgam with 6% sodium (mercury) in solution 4,06 g of a mixture of two epimeres in position 4 5-(2-fluoro-phenyl)-4-phenylsulfonyl - tert. butylmalonate-(2RS, 5RS) 150 cm3methanol, stirred for 20 h at a temperature of about 20oC. Then the reaction mixture is poured into 200 cm3water and mercury is separated by decantation. The aqueous phase is extracted with three times 100 cm3ethyl acetate. The organic extracts are combined, washed twice in 100 cm3water, dried over magnesium sulfate and concentrate under reduced pressure. The residue is subjected to chromatography on silica (eluent: cyclohexane-ethyl acetate (70/30 about. )). The fractions containing the desired product are pooled and concentrated under reduced pressure. Thus, the gain of 0.4 g of 5-(2-fluoro-phenyl) tert. butylmalonate (2RS, 5SR) in the form of oils used in the subsequent synthesis.

5-(2-Fluoro-phenyl)-4-phenylsulfonyl. BodyPaint-(2RS, 5RS) can be obtained as described in example 89, A, but on the basis of 4.8 g of N-(orthoferrosilite)-tert. butylglycol, 5 g of silver acetate, 3.4 g of phenylenesulfonyl and 2.8 cm3of triethylamine. After treatment and crystallization in diethyl ether to obtain 8 g of 5-(2-fluoro-phenyl)-4 - phenylsulfonyl.butylmalonate (2RS, 5RS), a mixture of two epimeres in position 4), melting at 200oC.

N-(orthoferrosilite) tert. butylglycol m tert.butylglycol, 2.8 cm3of triethylamine and 3 g of molecular sieve 50 cm3dichloromethane. After processing gain of 4.8 g of N-(orthoferrosilite)-tert. butilhioscina in the form of oils used in the subsequent synthesis.

Example 91. Operate according to the method described in example 2, but on the basis of 1.12 g of 1-(2-amino-acetyl)-5-phenyl-tert.butyl(2RS, 5SR) and 1.3 cm3isocyanate of parachlorophenyl 50 cm3tetrahydrofuran (THF). After processing receive 1.2 g 1-(2-(3-(4-chloro-phenyl)ureido) acetyl)5-phenyl-tert.butylmalonate-(2RS, 5SR) in the form of an amorphous product.

Proton NMR (250 MHz, DMCO D6in ppm) of 1.50 (s, 9H, (CH3)3), of 1.85 (m, 2H, CH2) of 2.2 and 2.4 (2m, 2H, CH2), 3,25 and 3.85 (ABX, 2H, CH2), 4,30 (dd, 1H, CHN), 5,20 (dd, 1H, CHN), and 6.3 (t, 1H exchangeable, NH), 7,2 - 7,6 (m, 9H, aromatic), 9 (s, 1H exchangeable, NH).

Infrared spectrum (KBr), characteristic bands in cm-1: 3370, 3065, 3030, 2980, 2930, 2875, 1735, 1555, 1490, 1450, 1445, 1365, 1150, 830, 760, 700.

Example 92. Acting according to the method similar to example 3, but from 3,05 g of 1-(2-amino-acetyl)-5-phenyl-tert.butylmalonate (2RS, 5SR), 1.78 g of N, N'-diimidazole-carbonyl and 4.5 g of 1-(3-AMINOPHENYL)econsultant tetrabutylammonium-(RS) 100 cm31,2-dichloroethane. After processing gain of 0.6 g 1-(3-(3-(2-(2-tert.butoxycarbonyl-5-phenyl-1-pirta.

Proton NMR (200 MHz, DMCO D6in h/m), 1,6 (s + d, 12H, CCH3and (CH3)3), 1,8-2,4 (m, 4H, 2CH2), and 3.5 (m, 1H, CHSO3), a 3.1 and 3.8 (ABX, 2H, CH2N) to 4.2 (dd, 1H, CHN), 5,1 (dd, 1HCHN) and 6.2 (t, 1H exchangeable, NH), of 6.8 to 7.6 (m, 9H, aromatic), and 8.7 (bs, 1H exchangeable, NH).

Infrared spectrum (KBr), characteristic bands in cm-1: 3380, 3060, 3025, 2975, 2930, 2875, 1730, 1555, 1490, 1445, 1390, 1360, 1215, 1115, 1030, 790, 755, 700.

Example 93.

Acting in the same way as in example 41, A, but on the basis of of 4.95 g of 5-phenyl-tert. butylmalonate (2RS, 5SR), 5,04 g of 2-(3-(3-methoxycarbonyl-phenyl)ureido) acetic acid and 4.12 g of N,N'-dicyclohexylcarbodiimide 75 cm3tetrahydrofuran (THF). After treatment and crystallization in a mixture of oxide Diisopropylamine of isopropyl (90 - 10 vol.) receive 1.2 g 1-(2-(3-(3-methoxycarbonyl-phenyl)ureido)acetyl) 5-phenyl-tert. butylmalonate (2RS, 5SR), melting at 141oC.

2-(3-(3-Methoxycarbonyl-phenyl)ureido)acetic acid may be obtained as described in example 1 A, but on the basis of 7.5 g of glycine, and 8.4 g of acid sodium carbonate in 150 cm3water and 17.7 g of 3-isocyanatobenzene. After processing gain of 14.5 g of 2-(3-(3-methoxycarbonyl-phenyl)ureido)acetic acid, melting at 215oC.

Example 94. Are on the way, an is-(2S, 5R) ,dissolved in 40 cm3methanol, and 0.33 g of potassium hydroxide dissolved in 20 cm3water. After processing gain of 1.8 g 3-(3-(2-(2-tert. butoxycarbonyl-5-phenyl-1-pyrrolidinyl) 2-oxo-ethyl)ureido benzoic acid-(2S, 5R) acid, analytical data which correspond to the analytical data clockwise rotating enantiomer obtained by chromatography on chiral stationary phase racemic product.

1-(2-(3-(3-Etoxycarbonyl-phenyl)ureido)acetyl) 5-phenyl-tert. BodyPaint-(2S, 5R) can be obtained in the following way: coming from 6.6 g 1-(2-(3-(3-etoxycarbonyl-phenyl)ureido) acetyl) 5-phenyl-tert.butylmalonate-(2RS, 5SR) separates the high-speed liquid chromatography on 400 g of substrate, method of manufacture of which is described below, contained in a column with a length of 26 cm and a diameter of 6 cm using a mixture of hexane-ethanol (70 to 30 vol.) as mobile phase with a flow rate of 70 cm3/min, through sequential elution: 2.9 g 1-(2-(3-(3-etoxycarbonyl-phenyl)ureido)acetyl) 5-phenyl-tert. butylmalonate-(2S, 5R) with rotational ability //2D0= +300,8(C = 0,922, methanol); 2.8 g 1-(2-(3-(3-etoxycarbonyl-phenyl)ureido)acetyl)5-phenyl - tert. butylmalonate-(2R, 5S) from rotating with setout on the way, described in example 9, but on the basis of 3.5 g 1-(2-(3-(3-methoxycarbonyl-phenyl)ureido)acetyl)- 5-phenyl-tert. butylmalonate-(2S, 5R) dissolved in 60 cm3methanol and 0.45 g of potassium hydroxide dissolved in 30 cm3water. After processing receive 2.0 g 3-(3-(2-(2-tert. butoxycarbonyl-5-phenyl-1-pyrrolidinyl) 2-oxo-ethyl)ureido) benzoic acid-(2S, 5R) acid, analytical data which correspond to the analytical data clockwise rotating enantiomer obtained by chromatography on chiral stationary phase of the racemate.

1-(2-(3-(3-Methoxycarbonyl-phenyl)ureido)acetyl)-5-phenyl - tert. BodyPaint-(2S, 5R) can be obtained as described in example 41, A, but on the basis of 0.1 g of 5-phenyl-tert.butylmalonate-(2S, 5R), 0.1 g of 2-(3-(3-methoxycarbonyl-phenyl)ureido)acetic acid and 0.08 g of N,N'-dicyclohexylcarbodiimide 5 cm3tetrahydrofuran (THF). After processing receive 0.1 g 1-(2-(3-(3-methoxycarbonyl-phenyl)ureido)acetyl) 5-phenyl-tert. butylmalonate (2S, 5R), analytical data analytical data correspond clockwise rotating enantiomer obtained by chromatography on chiral stationary phase of the racemate.

5-Phenyl-tert.BodyPaint-(2S, 5R) can be obtained in the following way: in the emulsion of 0.83 g of 5-phenyl- - -5-Pierre is the temperature about 2oC solution of 0.14 g of sodium borohydride and 0.07 g of potassium carbonate in 0.8 cm3water. The reaction medium is stirred for 20 hours at a temperature of about 20oC, then add a solution of 0.14 g of sodium borohydride and 0.07 g of potassium carbonate in 0.8 cm3water. The reaction mixture is again stirred for 70 hours at a temperature of about 20oC, then diluted with 25 cm3water and extracted three times with 20 cm3dichloromethane. The organic extracts are combined, washed in 10 cm3water, dried over magnesium sulfate and concentrated to dryness under reduced pressure and 50oC. the Residue is purified by chromatography on silica (eluent: dichloromethane). The fractions containing the desired product are pooled and concentrated under reduced pressure. Thus, gain of 0.1 g of 5-phenylpropionate tert-butyl-(2S, 5R) in the form of oils used in the subsequent synthesis.

5-phenyl- -5-pyrrolin-2-tert. butylcarbamoyl-(S) can be obtained in the following way: a solution of 1.8 g of 2-tert.butoxycarbonylamino-5-oxo-5-phenyl-tert-butyl-(S)-pentanoate 25 cm3dichloromethane was added when the temperature of about 20oC 2.3 cm3triperoxonane acid. The reaction mixture is stirred for 6 hours at a temperature of definition phase is separated by decantation, washed in 20 cm3distilled water, dried over magnesium sulfate and concentrate under reduced pressure. Thus, the gain of 0.9 g of 5-phenyl- - -5-pyrrolin-2-tert.butyl-(S)-carboxylate in the form of oils used in the subsequent synthesis.

2-Tert. butoxycarbonylamino-5-oxo-5-Finestrat.butyl (S)pentanoate can be obtained in the following way: a suspension to 0.72 g of magnesium in 20 cm3of tetrahydrofuran added dropwise within 35 min at 20 - 30oC a solution of 2.8 cm3bromine benzol 60 cm3tetrahydrofuran (THF). Reaction medium was again stirred at a temperature of approximately 24oC for 145 min, then injected for 20 min in a solution of 5.7 g of 1-tert.butoxycarbonyl-5-oxopyrrolidin-2-tert.BUTYLCARBAMATE (S) 80 cm3tetrahydrofuran (THF), supported at a temperature of about -75oC. the Reaction medium is again stirred for 3 hours at a temperature of about -70oC, then heated to a temperature of about -15oC. Added dropwise within 15 min 100 cm310% aqueous solution of ammonium chloride. The aqueous phase is separated by decantation and extracted three times with 100 cm3diethyl ether. The organic phases are combined and washed twice with 25 cm3water, dried crystallization of 20 cm3pentane. Thus, receive 2.5 g of 2-tert.butoxycarbonylamino 5-oxo-5-phenyl-tert. butyl(S) of pentanoate, melting at 107oC. This product may be in the form of 1-tert. butoxycarbonyl-5-hydroxy-5-phenyl-pyrrolidin-2 - tert-BUTYLCARBAMATE (2S, 5RS), melting at 85oC.

1-Tert. butoxycarbonyl-5-oxo-pyrrolidin-2-tert. butyl-(S) carboxylate can be obtained by a known method (J. ACKERMANN et M. MATTHES, Helv. Chim. Acta, 73, 122 - 132, 1990).

1-(2-(3-(3-Methoxycarbonyl-phenyl)ureido)acetyl)-5-phenyl-tert. butylmalonate (2S, 5R) can be obtained in the following way: coming of 7.8 g 1-(2-(3-(3-methoxycarbonyl-phenyl)ureido)acetyl) 5-phenyl-tert. butylmalonate (2RS, 5SR) separates the high-speed liquid chromatography on 400 g of substrate, method of production described in the previous example, in column a length of 26 cm and a diameter of 6 cm using a mixture of hexane-ethanol (70 - 30. ) as mobile phase with a flow rate of 70 cm3/min consistently elwira 3.7 g 1-(2-(3-(3-methoxycarbonyl-phenyl)ureido)acetyl)-5 - phenyl tert. butylmalonate-(2S, 5R) with rotational ability //2D0= +31,41,2(C = 0,579, methanol), 3.6 g 1-(2-(3-(3-methoxycarbonyl-phenyl)ureido)acetyl) 5-phenyl-tert.the bout is 49, methanol).

Example 96. Operate according to the method described in example 9, but on the basis of 2.6 g 1-(2-(3-(3-etoxycarbonyl-phenyl)ureido)acetyl)- 5-phenyl tert-butylmalonate-(2R, 5S) dissolved in 60 cm3of methanol, and 0.3 g of potassium hydroxide dissolved in 40 cm3water. After processing gain of 1.3 g 3-(3-(2-(2-tert.butoxycarbonyl 5-phenyl-1-pyrrolidinyl)2-oxo-ethyl)ureido)benzoic-(2R, 5S) acid, analytical data which correspond to the analytical data such as enantiomer obtained by chromatography on chiral stationary phase of the racemate.

Example 97. Operate according to the method described in example 9, but according to 3.38 g 1-(2-(3-(3-methoxycarbonyl-phenyl)ureido)acetyl) 5-phenyl-tert. butylmalonate-(2R, 5S) dissolved in 60 cm3methanol and 0.45 g of potassium hydroxide dissolved in 20 cm3water. After processing receive 2.0 g 3-(3-(2-(2-tert.butoxycarbonyl-5 - phenyl-1-pyrrolidinyl)2-oxo-ethyl)ureido)benzoic-(2R, 5S) acid, analytical data which correspond to the analytical data such as enantiomer obtained by chromatography on chiral stationary phase of the racemate.

Example 98. Act as in example 9, but on the basis of 1.9 grams 3-(3-(2-(2-tert.butoxycarbonyl-5-phenyl-1-pyrrole, dissolved in 30 cm3water. After processing receive 0.65 g 3-(3-(2-(2-tert.butoxycarbonyl-5-phenyl-1-pyrrolidinyl) 2-oxo-ethyl)ureido) phenylacetic acid-(2S, 5R) acid, melting at 112oC, //2D0= +30,60,8(C = 1, methanol).

3-(3-(2-(2-Tert. butoxycarbonyl-5-phenyl-1-pyrrolidinyl) 2-oxo-ethyl)ureido) feniletilamin-(2S, 5R) can be obtained as described in example 41, A, but on the basis of 1.2 g of 5-phenyl-tert.butylmalonate-(2S, 5R), 1.29 g of 2-(3-(3-methoxycarbonylmethyl-phenyl) ureido) acetic acid and 1 g of N,N'-dicyclohexylcarbodiimide 50 cm3acetonitrile. After processing gain of 1.9 g 3-(3-(2-(2-tert. butoxycarbonyl-5-phenyl-1-pyrrolidinyl) 2-oxo-ethyl)ureido) phenylethylamine-(2S, 5R) in the form of air masses used in the subsequent synthesis.

5-Finestrat. BodyPaint-(2S, 5R) can be obtained in the following way: a solution of 1.25 g of 5-phenyl- - -5-pyrrolin-2-tert. BUTYLCARBAMATE (S) 50 cm3ethanol is injected 0.02 g of platinum oxide. The suspension is stirred for 3 hours at a temperature of about 20oC in an atmosphere of hydrogen (130 kPa). The catalyst is filtered off and the filtrate is concentrated to dryness under reduced pressure at 45oC. the Residue is purified by chromatography on duobus the comfort to dryness under reduced pressure. Thus, the gain of 1.2 g of 5-Finestrat.butylmalonate (2S, 5R) in the form of oils used in the subsequent synthesis.

2-Phenyl -- 5-pyrrolin-2-tert. butylcarbamoyl (S) can be obtained in the following way: a solution of 3.65 g of 2-tert.butoxycarbonylamino-5-oxo-5-Finestrat. butylperbenzoate (S) 50 cm3dichloromethane was added when the temperature of about 20oC 1.4 cm3idolisation. The reaction mixture is stirred for 20 hours at a temperature of about 20oC, then add 50 cm3saturated aqueous solution of acid sodium carbonate. The organic phase is separated by decantation, washed with 20 cm3distilled water, dried over magnesium sulfate and concentrate under reduced pressure. Thus, the gain of 2.0 g of 5-phenyl -- 5-pyrrolin-2-tert.BUTYLCARBAMATE (S) in the form of oils used in the subsequent synthesis.

Example 99. Operate according to the method described in example 2, but from 1,93 g of 1-(2-amino-acetyl) 5-Finestrat. butylmalonate (2RS, 5SR) and 3,61 g 3-isocyanatobenzene 50 cm3tetrahydrofuran (THF). After processing receive 1 g 1-(2-(3-(3-benzyloxycarbonyl-phenyl)ureido)acetyl) 5-Finestrat.butylmalonate-(2RS, 5SR), melting at 75oC.

3 Isoci is Tata 200 cm3toluene, 14,4 cm3of triethylamine, 2 g of charcoal and 12.5 cm3chloroformiate of trichloromethyl 200 cm3of toluene. After processing receive 27 g of 3-isocyanatobenzene in the form of oils used in the subsequent synthesis.

3-aminomethylbenzoic can be obtained by a known method (H. A. SHONLE et coll., J. Am. Chem. Soc., 43, 361, 1921).

Example 100. To a solution of 1.7 g 1-(2-(3-(3-benzyloxycarbonyl-phenyl) ureido)-acetyl 5-phenylethylamine-(2RS, 5SR) 100 cm3ethanol is added 0.5 g of 5% palladium on coal. The suspension is stirred for 20 hours at a temperature of about 25oC in an atmosphere of hydrogen (130 kPa). The catalyst is filtered off and the filtrate is concentrated to dryness under reduced pressure. The remainder will recrystallized 80 cm3of ethanol. Thus, the gain of 0.7 g of 3-(2-(2-etoxycarbonyl-5 - phenyl-1-pyrrolidinyl) 2-oxo-ethyl)ureido) benzoic-(2RS, 5SR) of acid, melting at 240oC.

1-(2-/3-(3-Benzyloxycarbonyl-phenyl)ureido/acetyl-5-phenyl-etherprint-(2RS, 5SP) can be obtained as described in example 41, A, but from 2 g of 5-phenyl of etherprint-(2RS, 5SR), 2,99 g of 2-(3-(3-benzyloxycarbonyl - phenyl)ureido)acetic acid and 2.07 g of N,N'-dicyclohexylcarbodiimide 180 cm3tetrahydrofuran (THF). After processing receive 1,95 my subsequent synthesis.

2-(3-(3-Benzyloxycarbonyl-phenyl)ureido)acetic acid may be obtained as described in example 1 A, but on the basis of of 3.97 g of glycine and 14,62 g of potassium carbonate dissolved in 90 cm3water, and 13.4 g of 3-isocyanatobenzene, dissolved in 80 cm31,4-dioxane. After processing, 13 g of 2-(3-(3-benzyloxycarbonyl-phenyl)ureido) acetic acid used in the subsequent synthesis.

5-Phenylethylamine- (2RS, 5SR) can be obtained in the following way: a solution of 5.5 g of 5-phenylpropane-(2RS, 5SR) 50 cm3ethanol was added dropwise 0.5 cm3concentrated sulfuric acid. Then the reaction mixture is stirred at a temperature of approximately 80oC and concentrate for 5 h, then cooled to a temperature of about 20oC and concentrated under reduced pressure. The residue is extracted with 50 cm3water, brought to a pH of about 9 by addition of a normal aqueous solution of sodium hydroxide and extracted with three times 100 cm3ethyl acetate. The combined organic extracts are washed with 50 cm3saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue is subjected to chromatography on silica (eluent: cyclohexa is I. Thus, the gain of 2.16 g of 5-phenylethylamine-(2RS, 5SR) in the form of oils used in the subsequent synthesis.

Example 101. Operate according to the method described in example 100, but on the basis of 10.2 g 1-(2-(3-(3-benzyloxycarbonyl-phenyl)ureido/acetyl) 5-Finestrat.butylmalonate-(2RS, 5SR) and 1 g of 5% palladium on coal 300 cm3of ethanol. After processing gain of 7.1 g 3-(3-(2-(2-tert. butoxycarbonyl-5-phenyl-1-pyrrolidinyl) 2-oxo-ethyl)ureido)benzoic acid (2RS, 5SR) of acid, melting at 236oC.

Example 102. Operate according to the method described in example 100, but on the basis of 0.8 g (2-(3-(3-benzyloxycarbonyl-phenyl)ureido)acetyl)-5- (3-methyl-phenyl) tert. butylmalonate-(2RS, 5SR) dissolved in 50 cm3ethyl acetate, and 0.1 g of 5% palladium on coal. After processing receive 0.45 g 3-(3-(2-(2-tert.butoxycarbonyl-5-(3-methyl-phenyl)-1 - pyrrolidinyl) 2-oxo-ethyl)ureido) benzoic-(2RS, 5SR) of acid, melting at 208oC.

1-(2-(3-(3-Benzyloxycarbonyl-phenyl)ureido)acetyl)-5-(3-methyl - phenyl) tert. BodyPaint-(2RS, 5SR) can be obtained as described in example 41, A, but on the basis of 0.4 g of 5-(3-methyl-phenyl)-tert. butylmalonate-(2RS, 5SR), 0.5 g of 2-(3-(3-benzyloxycarbonylamino) ureido)acetic acid and 0.31 g of N,N'-dicyclohexylcarbodiimide 20 cm3acetonitrile. After the s, 5SR) in the form of air masses used in the subsequent synthesis.

5-(3-Methyl-phenyl) tert.BodyPaint-(2RS, 5SR) can be obtained as in example 2, A, but on the basis of 1 g of 1-tert.butoxycarbonyl - 5-(3-methyl-phenyl) tert. butylmalonate-(2RS, 5SR) and 0.4 cm3idolisation 40 cm3the chloroform. After treatment, obtain 0.4 g of 5-(3-methyl-phenyl) tert.butylmalonate-(2RS, 5SR) in the form of oils used in the subsequent synthesis.

1-Tert. butoxycarbonyl-5-(3-methyl-phenyl) tert.butyl-prolinate have been obtained (2RS, 5SR) can be obtained as described in example 90, A, but on the basis of 2.4 g one-deputizing of sodium phosphate and 7,63 g amalgam with 6% sodium (mercury) in a solution of 2.5 g of a mixture of two epimeres in position 4 1-tert.butoxycarbonyl-5-(3-methyl-phenyl)-4-phenylsulfonyl tert.butylmalonate (2RS, 5RS) in a mixture of 20 cm3methanol 40 cm3tetrahydrofuran (THF). After processing receive 1 g of 1-tert.butoxycarbonyl-5-(3-methyl-phenyl) tert.butylmalonate-(2RS, 5SR) in the form of oils used in the subsequent synthesis.

1-Tert. butoxycarbonyl-5-(3-methyl-phenyl) 4-phenolsulfonate. butylmalonate (2RS, 5RS) can be obtained in the following way: a solution for 2.01 g of a mixture of two epimeres in position 4 5-(3-methyl-phenyl) 4-phenylsulfonyl tert. butylmalonate-(2RS, 5R dicret-butyl 20 cm3dichloromethane. The reaction mixture was stirred for 72 h at a temperature of about 20oC, then add 50 cm3water. The organic phase is separated by decantation, dried over magnesium sulfate and concentrated to dryness under reduced pressure. Thus, gain of 2.5 g of 1-tert.butoxycarbonyl-5- (3-methyl-phenyl)-4-phenylsulfonyl. butylmalonate-(2RS, 5R), a mixture of two epimeres 4) in the form of oils used in the subsequent synthesis.

5-(3-Methyl-phenyl)-4-phenylsulfonyl tert. BodyPaint-(2RS, 5RS) can be obtained as described in example 89, A, but on the basis of 4.7 g of N-(metamotivation)-tert.butylglycol, 5 g of silver acetate, 3.4 g of phenylenesulfonyl and 2.8 cm3of triethylamine. After processing gain of 6.1 g of 5-(3-methyl-phenyl) 4-phenolsulfonate. butylmalonate- (2RS, 5RS), a mixture of two epimeres 4, melting at 139oC.

N-(metamotivation) tert. butyllithium can be obtained as described in example 89, B, but on the basis of 2.4 cm3metatoluidine, at 3.35 g of the hydrochloride tert-butylglycol, 2.8 cm3of triethylamine and 3 g of molecular sieve 30 cm3dichloromethane, after processing, obtain 4.7 g of N-(metamotivation) -tert-butylglycol in the form of oil, used prii 1-(2-(3-(3-etoxycarbonyl-phenyl)ureido)-acetyl) 3-Finestrat.butylmalonate-(2RS, 3SR) and -(2RS, 3RS) 85/15 by weight, dissolved in 30 cm3tetrahydrofuran (THF), and 2.4 cm3normal sodium hydroxide solution, diluted in 15 cm3water. After treatment receive a mixture of 0.7 g 3-(3-(2- (2-tert. butoxycarbonyl-3-phenyl-1-pyrrolidinyl) 2-oxo-ethyl)ureido) benzoic acid (2RS, 3SR) - and -(2RS, 3RS) 85/15 by weight, melting at 225oC.

1-(2-(3-(3-Ethoxycarbonylphenyl)ureido)acetyl) 3-phenyl - tert. BodyPaint-(2RS, 3SR) can be obtained as described in example 41, A, but on the basis of 1 g of a mixture of 3-Finestrat.butylmalonate (2RS, 3SR) - and -(2RS, 3RS) 85/15 by weight, 1.1 g of 2-(3-3 - ethoxycarbonylphenyl)ureido) of acetic acid and of 0.83 g of N, N'- dicyclohexylcarbodiimide 30 cm3tetrahydrofuran (THF). After treatment receive a mixture of 1.2 g 1-(2-(3-(3-etoxycarbonyl-phenyl) ureido)acetyl) 3-Finestrat. butylmalonate-(2RS, 3SR) - and -(2RS, 3RS) 85/15 weight., melting at 154oC.

3-Finestrat. BodyPaint-(2RS, 3SR) and 3-Finestrat.BodyPaint -(2RS, 3RS) can be obtained as described in example 1 B, but on the basis of 10 g of a mixture of 3-phenylpropene (2RS, 5SP) and -(2RS, 5RS), isobutylene and 3 cm3sulfuric acid in 200 cm3the chloroform. After treatment and chromatography on silica (eluent: cyclohexane-ethyl acetate (50 - 50.)) receive 1 g of a mixture of 3-Finestrat.butylmalonate-(2RS, 3RS)- and(2RS, 3SR) 85.15 weight. in the form of oils used in the subsequent synthesis.

3-Phenylpropan-(2RS, 5SR)- and(2RS, 5RS) can be obtained by known methods (Y. N BELOKON et coll., J. Chem. Soc., Perkin. Trans., 1, 2075, 1988, and J. RIVIER., G. R. MARSHALL Peptides, Chemistry, Structure and Biology, Proceedings of the Eleventh American Peptide Symposium. July 9 - 14 1989, La Jolla, California, USA, ESCOM, Leiden, 1990).

Example 104. Operate according to the method described in example 9, but based on 2.5 g of the mixture 1-(2-(3-(3-etoxycarbonyl-phenyl)ureido)acetyl) 3-Finestrat.butylmalonate-(2RS, 3RS)- and(2RS, 3SR) 80/20 weight. dissolved in 30 cm3of tetrahydrofuran and 5 cm3normal sodium hydroxide solution, diluted in 15 cm3water. After treatment receive a mixture of 1 g 3-(3-(2-(2-tert. butoxycarbonyl-3-phenyl-1-pyrrolidinyl)2-oxo-ethyl) ureido)benzoic- (2RS, 3RS)- and(2RS, 3SR) acids (90-10 wt.), melting at 200oC.

1-(2-(3-(3-Etoxycarbonyl-phenyl)ureido)acetyl) 3-phenyl tert-butylphenol-(2RS, 3RS) can be obtained as described in example 41, but on the basis of 2.5 g of a mixture of 3-Finestrat.butylphosphonate-(2RS, 3RS)- and(2RS, 3SR)(90/10 weight. ), 2.7 g of 2-(3-(3-ethoxycarbonylphenyl)ureido)acetic acid and 2.1 g of N, N'-dicyclohexylcarbodiimide 50 cm3tetrahydrofuran (THF). After treatment receive a mixture of 1.2 g 1-(2-(3-(3-ethoxycarbonyl-phenyl)ureido)acetyl) 3-Finestrat. b is isonomy in example 9, but on the basis of 2.1 g 1-(2-(3-(3-methoxycarbonyl-phenyl)ureido)acetyl)-4-phenyl - tert.butylmalonate-(2S, 4S) dissolved in 30 cm3of methanol, and 0.5 g of potassium hydroxide dissolved in 15 cm3water. After treatment and crystallization in a mixture of nitric-oxide diisopropylate of isopropyl (about 90-10.), obtain 0.65 g 3-(3-(2-(2-tert. butoxycarbonyl-4-phenyl-1-pyrrolidinyl) 2-oxo-ethyl)ureido)benzoic acid-(2S, 4S) acid, melting at 144oC.

1-(2-(3-(3-Methoxycarbonyl-phenyl)ureido)acetyl) 4-phenyl-tert. BodyPaint-(2S, 4S) can be obtained as described in example 41, but on the basis of 1.2 g of 4-Finestrat.butylmalonate-(2S, 4S), 1.2 g of 2-(3-(3-methoxycarbonyl-phenyl) ureido)acetic acid and 1 g of N, N'-dicyclohexylcarbodiimide 30 cm3acetonitrile. After processing gain of 2.1 g 1-(2-(3-(3-methoxycarbonyl-phenyl)ureido)-acetyl) - 4 Finestrat. butylmalonate-(2S, 4S) in the form of air masses used in the subsequent synthesis.

4-Finestrat. BodyPaint-(2S, 4S) can be obtained as described in example 1 B, but on the basis of 3.4 g of 4-phenylpropene-(2S, 4S), isobutylene and 1.5 cm3sulfuric acid in 150 cm3the chloroform. After processing gain of 1.2 g of 4-phenyl-tert. butylmalonate-(2S, 4S) in the form of air masses used in the subsequent synthesis.

Example 106. Operate in the manner similar to that described in example 9, but on the basis of 1.8 g 1-(2-(3-(3-methoxycarbonyl-phenyl)ureido) acetyl)-4 Finestrat. butylmalonate-(2S, 4S) dissolved in 30 cm3methanol, and 0.21 g of potassium hydroxide dissolved in 15 cm3water. After treatment and crystallization in a mixture of nitric-oxide diisopropyl-isopropyl acetate (90-10 about.) obtain 0.55 g 3-(3-(2-(2-tert. butoxycarbonyl-4-phenyl-1-pyrrolidinyl) 2-oxo-ethyl)ureido) benzoic acid -(2S, 4R) acid, melting at 140oC.

1-(2-(3-(3-Methoxycarbonyl-phenyl)ureido)acetyl) 4-phenyl-tert. BodyPaint-(2S, 4R) can be obtained as described in example 41. But on the basis of 1 g of 4-Finestrat. butylmalonate-(2S, 4R), 1 g of 2-(3-(3-methoxycarbonyl-phenyl)ureido)- acetic acid and 0.85 grams N, N'-dicyclohexylcarbodiimide 30 cm3acetonitrile. After processing gain of 1.8 g 1-(2-(3-(3-methoxycarbonyl-phenyl)ureido)acetyl-4-Finestrat, butylmalonate-(2S, 4R) in the form of air masses used in the subsequent synthesis.

4-Finestrat. BodyPaint-(2S, 4R) can be obtained as described in example 1 B, but on the basis of 4.4 g of 4-phenylpropene-(2S, 4R), isobutylene and 1.5 cm3sulfuric acid in 150 cm3the chloroform. After processing receive 1 g 4 what about the known methods (J. K. THOTTATHIL et J. L. MONIOT Tetrahedron Lett., 27, 151, 1986, and D. R. KRONENTHAL et coll.,Tetrahedron Lett, 31, 1241, 1990).

Example 107. Operate in the manner similar to that described in example 9, but on the basis of 0.55 g 1-(2-(3-(3-benzyloxycarbonyl-phenyl)ureido)acetyl) 5-(2-pyridyl)tert. butylmalonate-(2RS, 5SR) dissolved in 20 cm3of methanol, and 10 cm3a 0.1 N aqueous solution of potassium hydroxide. After processing receive 0.17 g 3-(3- (2-(2-tert.butoxycarbonyl 5-(2-pyridine) 1-pyrrolidinyl) 2-oxoethyl)ureido)benzoic -(2RS, 5SR) of acid, melting at 174oC.

1-(2-(3-(3-Benzyloxycarbonyl-phenyl)ureido)acetyl)-5-(2-pericytic. BodyPaint-(2RS, 5SR) can be obtained as described in example 2, but based on 0.5 g of 1-(2-amino-acetyl)-5-(2-pyridine)of tert-butylmalonate-(2RS, 5SR) and 0.45 g of 3-isocyanatobenzene 25 cm3tetrahydrofuran (THF). After processing gain of 0.7 g 1-(2-(3-(3-benzyloxycarbonyl-phenyl)ureido) acetyl)-5-(2-pyridyl)-tert. butylmalonate-(2RS, 5SR) in the form of air masses used in the subsequent synthesis.

1-(2-Amino-acetyl)-5-(2-pyridine)tert.BodyPaint-(2RS, 5SR) can be obtained as described in example 2, but on the basis of 0.7 g of 1-(2-tert.butoxycarbonylamino-acetyl)-5-(2-pyridyl)tert. butylmalonate) -(2RS, 5SR) and 0.25 cm3editamerica 30 cm3CHL is althemore subsequent synthesis.

1-(2-Tert. butoxycarbonylamino-acetyl)-5-(2-pyridyl)-tert.BodyPaint -(2RS, 5SR) can be obtained as described in example 90, but on the basis of 4.8 g one-deputizing phosphate and 15.3 g of amalgam with 6% sodium (mercury) in a solution of 5.5 g of a mixture of two epimeres in position 4 1-(2-tert-butoxycarbonylamino-acetyl)-4-phenylsulfonyl-5- (2-pericytic.butylmalonate-(2RS, 5RS) in a mixture of 20 cm3methanol and 60 cm3tetrahydrofuran (THF). After processing gain of 0.7 g of 1-(2-tert. butoxycarbonylamino-acetyl)-5-(2-pyridyl) tert. butylmalonate (2RS, 5SR) in the form of oils used in the subsequent synthesis.

1-(2-Tert. butoxycarbonylamino-acetyl)-4-phenylsulfonyl-5-(2-pyridyl) tert. BodyPaint-(2RS, 5RS) can be obtained in the following way: a solution of 2.7 g of 2-tert. butoxycarbonylamino-acetic acid in a mixture of 2.2 cm3of triethylamine and 100 cm3dichloromethane, maintained at a temperature of about 0oC add 1.5 cm3ethyl ester harpalinae acid. The reaction medium is stirred for 30 minutes at a temperature of about 0oC, then add a solution of 6 g of 4-phenylsulfonyl-5-(2-pyridyl)tert.butylmalonate-(2RS, 5RS) 50 cm3dichloromethane. The reaction mixture is stirred for 20 hours at a temperature of SUP>3water, dried over magnesium sulfate and concentrate under reduced pressure. The residue is purified by chromatography on silica (eluent: cyclohexen-ethyl acetate (50/50 by vol.). The fractions containing the desired product are pooled and concentrated under reduced pressure. So, get 5.6 g of 1-(2-tert.butoxycarbonylamino-acetyl)-4-phenylsulfonyl-5-(2-pyridyl) tert.butylmalonate-(2RS, 5RS), a mixture of two epimeres 4) in the form of oils used in the subsequent synthesis.

4-Phenylsulfonyl-5-(2-pyridyl-tert. butylbromide (2RS, 5RS) can be obtained as described in example 89, but on the basis of 4.4 g of N-/(2-pyridyl)methylene-tert. butylglycol, 5 g of silver acetate, 3.4 g of phenylenesulfonyl and 2.8 cm3of triethylamine in 200 cm3acetonitrile. After processing receive 6 g of 4-phenylsulfonyl-5-(2-pyridyl)tert. butylmalonate-(2RS, 5R), a mixture of two epimeres 4) in the form of oils used in the subsequent synthesis.

N-/(2-pyridyl)methylene/tert.butyllithium can be obtained as described in example 89, B, but on the basis of 1.4 cm32-pyridylcarboxylic, at 3.35 g of the hydrochloride tert. butylglycol, 2.8 cm3of triethylamine and 3 g of molecular sieve 30 cm3dichloromethane. After processing gain of 4.8 g of N-(2-pyridi is the target of 0.65 g 2-(3-(3-(2-(4-tert.butoxycarbonyl - 2-(2-fluoro-phenyl)-3-thiazolidine-(2R, 4R) 2-oxo-ethyl)ureido)phenyl) propionic acid (form A) 6 cm3methanol add 1.3 g OksanaPdissolved in 8 cm3of distilled water. The reaction medium is stirred for 12 hours at a temperature of about 25oC, then concentrated under reduced pressure and the 40oC. the resulting product was then purified by chromatography on silica (eluent: methylene chloride-methanol (90/10 about. )). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and the 40oC. are Thus obtained 0.4 g 2-(3-(3-(2-(4- tert.butoxycarbonyl-2-(2-fluoro-phenyl) 1-oxide-3-thiazolidine-(1RS, 2R, 4R) / 2-oxo-ethyl)ureido)phenyl) propionic acid (form A) in the form of an amorphous product.

Proton NMR (200 MHz, DMCO D6in ppm, J in Hz) at 120oC there is a mixture of two diastereoisomers in proportion 85-15, characteristic chemical shifts at 120oC: 1,32 (d, J = 7,5, 3H, -CH3), of 1.50 and 1.58 (2S, 9H in total, -C(CH3)3highest isomer, then the lowest isomer to 2.85 (t, J = 12,5, 0,85 H, 1H, S-CH2for most of isomers) 3,4 - 4,4 (m, 6,15 H, -CH-COO, the other H - S-CH2for the greatest isomer, -S-CH2lowest isomer and N-COCH2-N) to 4.8 (t, J = 8, 0,15 H, S-CH-N least-isomer), equal to 4.97 (dd, J 8 (bd, J = 8, 1H, in position 4 on CO-NH-Ph-), of 7.0 and 7.6 (m, 6H, aromatic), to 7.77 and 8,10 (t, J = 8, 0,15 H and 0,85 H, in position 6 on S-CH-Ph - smallest and largest isomers), 8,84 and 8,96 (2S, 0,85 H and 0.15 H, ArNHCO in the smallest and largest isomers).

Infrared spectrum (KBr), characteristic bands in cm-1: 3390, 3100-3000, 2975, 2930, 2875, 2750-2300 (wide band), 1735, 1670, 1615, 1595, 1555, 1490, 1460, 1400, 1395, 1370, 1150, 760, 700.

Example 109. Operate according to the method described in example 41, but on the basis of 1.85 g 3-(3-(2-(4-tert.butoxycarbonyl-2-(1-naphthyl)-3 - thiazolidine) 2-oxo-ethyl)ureido)trimethylsilylmethylamine (2R, 4R) and 5.82 cm31M solution of tetrabutylammonium fluoride. Thus, the gain of 0.47 g 3-(3-(2-(4-tert. butoxycarbonyl-2-(1-naphthyl) 3-thiazolidine) 2-oxo-ethyl)ureido)benzoic-(2R, 4R) acid in a solid beige color, melting at 210oC. //2D0= +222 5 (C = 0.5%, CHCl3).

Proton NMR (200 MHz, DMCO D6plus a few drops CD3COOD, ppm, J in Hz), 2 rotamer at room temperature, characteristic chemical shifts at 120oC: of 1.53 (s, 9H, -C(CH3)3) at 3.25 (dd, J = 12 and 7, 1H, 1H, S-CH2), to 3.49 (dd, J = 12 and 6.5, 1H, the other H S-CH2), 3,7 (bd, J = 17,5 1H N-COCH2-N) 4,08 (d, J = 17,5 1H, the other H of N-COCH2-N) 5,02 (dd, J = 7,0 and 6.5, 1H, N-CH-COO), was 7.08 (S, 1H, S-CH-100-3000, 2975, 2930, 1735, 1655, 1595, 1555, 1510, 1485, 1400, 1150, 785, 770.

3-(3-(2-(4-Tert. butoxycarbonyl-2-(1-naphthyl)-3-thiazolidine)-2 - oxo-ethyl)ureido) 2-trimethylsilyl-ethylbenzoic-(2R, 4R) can be obtained by a method similar to that described in example 34, but on the basis of 2.4 g of 3-(2-amino-acetyl)-2-(1-naphthyl)-4-thiazolidine. BUTYLCARBAMATE-(2R, 4R) and 2.1 g of 3-isocyanate-2-trimethylsilyl - ethylbenzoic. The crude product is purified by chromatography on silica (eluent: ethyl acetate-cyclohexane (30/70 vol.). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and the 40oC. Thus, obtain 1.85 g 3-(3-(2-(4-tert.butoxycarbonyl-2-(1-naphthyl)-3-thiazolidine) 2-oxoethyl) ureido) 2 trimethylsilylmethyl-(4R) (form A) in the form of a beige paste used in the subsequent synthesis.

3-(2-Amino-acetyl)-2-(1-naphthyl)-4-thiazolidine. butylcarbamoyl-(2R, 4R) can be obtained by the method similar to that described in example 34, but on the basis of the 3.65 g of 3-(2-tert. butoxycarbonylamino)- 2-(1-naphthyl)-4-thiazolidine. BUTYLCARBAMATE-(2R, 4R) and 1.13 cm3attributively. So, get 2,43 g 3-(2-amino-acetyl)-2-(2-naphthyl)-4-thiazolidine. BUTYLCARBAMATE-(2R, 4R) as a yellow solid product, which is used when the placenta is-(2R, 4R) can be obtained by a method similar to that described in example 34, B, but based on the rate of 7.54 g of 2-(1-naphthyl)-4-thiazolidine. BUTYLCARBAMATE-(2RS, 4R), to 4.23 and 2-tert.butoxycarbonylamino acid and to 4.98 g of N,N'-dicyclohexylcarbodiimide. The crude product is purified by chromatography on silica (eluent: ethyl acetate-cyclohexane (30/70 vol.)). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure. Thus, the gain of 13.9 g of 3-(2-tert.butoxycarbonylamino-acetyl)-2-(1-naphthyl)-4-thiazolidine. BUTYLCARBAMATE-(2R, 4R) as an orange oil, used in the subsequent synthesis.

2-(1-Naphthyl)-4 - thiazolidine.butylcarbamoyl-(2RS, 4R) can be obtained by a method similar to that described in example 34, but according to 20.0 g of 2-(1-naphthyl)-4-thiazolidinones-(2RS, 4R) acid dissolved in 300 cm3chloroform, 5.8 cm3concentrated sulphuric acid and an excess of isobutene. The resulting crude product was then purified by chromatography on Dookie silica (eluent: ethylacetoacetate (about 30/70. )). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and the 40oC. Thus, get 10,15 g 2-(1-naphthyl)-4 - thiazolidine.BUTYLCARBAMATE the P CLASS="ptx2">

2-(1-Naphthyl)-4-thiazolidinedione-(2RS, 4R) acid can be obtained, as in example 34, G, but according to 20.0 g of L-cysteine and 28.5 g of 1-aftercollege. Thus, the gain of 36.3 g of 2-(1-naphthyl)-4-thiazolidinones-(2RS, 4R) acid, melting at 208oC used in the subsequent synthesis.

Example 110. Operate according to the method described in example 41, but on the basis of 0.12 g 3-(3-(2-(4-tert.butoxycarbonyl-2-(5-methyl-2-thienyl) 3-thiazolidine) 2-oxo-ethyl) ureido) 2-trimethylsilyl-ethylbenzoic-(4R) (form A) and 0.4 cm31M solution of fluoride tetrabutylammonium. Thus, 0.08 g 3-(3-(2-(4-tert. butoxycarbonyl-2-(5-methyl-2-thienyl) 3-thiazolidine) 2-(oxo-ethyl) ureido) benzoic-(4R) acid (form A) as an orange solid, melting at 85 - 90oC.

Proton NMR (300 MHz, DMCO D6plus a few drops CD3COOD, ppm, J in Hz), 2 rotamer at room temperature, characteristic chemical shifts at 120oC: 1,5 (s, 9H, -C(CH3)3, THE 2.46 (S, 3H, -CH3), 3,4 and 3,52 (2dd, J = 12 and 6.5, 1H each, - S-CH2), of 3.96 (d, J = 17,5 1H, 1H, N-COOH2-N) of 4.05 (d, J = 17,5, 1H, the other H of N-COCH2-N), 4,96 (t, J = 6,5, 1H, OOC-CH-N), Of 6.65 (S, 1H, S-CH-N), of 6.65 (d, J = 4 1H, H at position 4 in Fienile), 7,12 (d, J = 4, 1H, H at position 3 in Fienile), 7,55 and 7.62 (2dd, J = 8 and 2. Each 1H, H in poosy in cm-1: 3390, 3100-3000, 2975, 2930, 2830, 2750-2300 (wide band), 1750, 1695, 1650, 1615, 1595, 1560, 1490, 1425, 1395, 1370, 1150, 800, 785, 755.

3-(3-(2-(4-Tert. butoxycarbonyl-2-(5-methyl-2-thienyl) 3-thiazolidine) 2-oxo-ethyl)ureido) 2-trimethylsilyl-ethylbenzene (4R) (form A) can be obtained by a method similar to that described in example 41, A, but according to 0.38 g of 2-(5-methyl-2-thienyl) 4-thiazolidine.BUTYLCARBAMATE-(2RS, 4R), 0.45 g 2-(3-(3-(2-trimethylsilyl-etoxycarbonyl) phenyl)ureido) acetic acid and 0.30 g of N, N'-dicyclohexylcarbodiimide. The crude product is purified by chromatography on silica (eluent: ethylacetoacetate (30/70 vol.)). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and the 40oC. Thus, obtain 0.12 g 3-(3-(2-(4-tert.butoxycarbonyl-2-(5-methyl-2-thienyl)-3-thiazolidin) 2-oxo-ethyl)ureido)-2-trimethylsilyl-ethylbenzoic-(4R) (form A) as a yellow-orange body, used in the subsequent synthesis.

2-(5-Methyl-2-thienyl)-4-thiazolidine. butylcarbamoyl-(2RS, 4R) can be obtained by a method similar to that described in example 48, B, but on the basis of 1.0 g of 3-tert.butoxycarbonyl-2-(5-methyl-2-thienyl) 4-thiazolidine.BUTYLCARBAMATE-(4R) (form A) and 0.38 cm3idolisation. Thus, polucau subsequent synthesis.

3-Tert.butoxycarbonyl-2-(5-methyl-2-thienyl)-4-thiazolidine. butoxycarbonyl-(4R) (form A) can be obtained by a method similar to that described in example 48, but on the basis of 2,97 g of 3-tert.butoxycarbonyl-2-(5-methyl-2-thienyl)-4-thiazolidinones-(4R) acid (form A), 1,72 g paratoluenesulfonyl and 0.67 g of tert. butanol. The resulting crude product was then purified by chromatography on silica (eluent: ethyl acetate-cyclohexane (30/70 vol.)). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and the 40oC. Thus, obtain 1.0 g of 3-tert.butoxycarbonyl-2-(5-methyl-2-thienyl)-4-thiazolidine. BUTYLCARBAMATE-(4R) (form A) as an orange oil, used in the subsequent synthesis.

3-Tert. butoxycarbonyl-2-(5-methyl-2-thienyl)-4-thiazolidinedione-(4R) acid (form A) can be obtained by a method similar to that described in example 48, G, but on the basis of 2.7 g of 2-(5-methyl-2-thienyl) -4-thiazolidinones-(2RS, 4R) acid, 11,9 cm3aqueous 1N solution of sodium hydroxide and 2.6 g of dicarbonate dicret.butyl. Thus, the gain of 3.0 g of 3-tert. butoxycarbonyl-2-(5-methyl-2-thienyl)-4-thiazolidinones-(4R) acid (form A) in the form of a yellow product that is used posleduyushe 34, G, but on the basis of 10.0 g of L-cysteine and 11.3 g of (5-methyl-2-Tieni l) carboxaldehyde. So, get 7,86 g of 2-(5-methyl-2-thienyl)-4-thiazolidinones-(2RS, 4R) acid, melting at 178oC used in the subsequent synthesis.

Example 111. Operates according to the method described in example 84, but on the basis of 0.88 g 2-(3-(3-(2-(2-tert.butoxycarbonyl-5-phenyl-1-pyrrolidinyl (2S, 5R))-2-oxo-ethyl)ureido)phenyl) benzoylpropionate (form C), dissolved in 50 cm3ethyl acetate, and 0.22 g of 10% palladium on coal. After processing receive 0.5 g 2-(3-(3-(2-(2-tert. butoxycarbonyl-5-phenyl-1-pyrrolidinyl-(2S, 5R)) 2-oxo-ethyl)ureido)phenyl) propionic acid (form), melting at 120oC, //2D0= +49,80,8(C = 0,53, methanol).

2-(3-(3-(2-(2-Tert. butoxycarbonyl-5-phenyl-1-pyrrolidinyl-2S, 5R)) 2-oxo-ethyl)ureido)phenyl)benzoylpropionate (form C) can be obtained in the manner similar to that described in example 2, but from 0,79 g 1(2-amino-acetyl)-5-Finestrat. butylmalonate-(2S, 5R) and 0.8 g of 2-(3-isocyanato-phenyl)benzoylpropionate (form C) 40 cm3tetrahydrofuran (THF). After processing receive 0.9 g 2-(3-(3-(2-(2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl- (2S, 5R))-2-oxo-ethyl)ureido)phenyl) benzoylpropionate, lavaderos the logical described in example 2A, but on the basis of 1.22 g of 1-(2-tert.butoxycarbonyl-aminoacetyl) 5-Finestrat. butylmalonate-(2S, 5R), 0,45 cm3idolisation dissolved in 30 cm3anhydrous chloroform. Thus, the gain of 0.79 g 1-2(amino-acetyl)-5-phenyl-tert.butylmalonate-(2S, 5R) in the form of oils used in the subsequent synthesis.

1-(2-Tert.butoxycarbonyl-amino-acetyl) 5-phenyl-tert. BodyPaint-(2S, 5R) can be obtained as described in example 2B, but from a solution containing 8 g of 5-phenyltrichlorosilane- (2-S, 5R), 5.7 g of 2-tert.butoxycarbonylamino acid and 6.7 g of N, N'-dicyclohexylcarbodiimide 75 cm3anhydrous acetonitrile. Thus, the gain of 10.5 g of 1-(2-tert.butoxycarbonylamino-acetyl) 5-phenyl-tert.butylmalonate-(2S, 5R), melting at 136oC, //2D0= +19,10,8(C = 0,64, methanol).

Example 112. Operate according to the method described in example 2, but from 2.5 g of 1-(2-amino-acetyl)-5-Finestrat. butylmalonate (2S, 5R), 5 g of 1-(3-isocyanate-phenyl)econsultant tetrabutylammonium (RS) 60 cm3tetrahydrofuran (THF). After processing gain of 0.23 g 1-(3-(3-(2-(2-tert.butoxycarbonyl-5-phenyl-1-pyrrolidinyl) 2-oxoethyl)ureido)phenyl)econsultant potassium(2S, 5R) (a mixture of both EPI the/SUP>0,9(C = 0,55, methanol).

1-(3-Isocyanate-phenyl) econsultant tetrabutylammonium (RS) can be obtained as described in example 21, but on the basis of 4.5 g of 1-(3-amino-phenyl) econsultant tetrabutylammonium (RS) 40 cm6toluene, 0.2 g of coal and of 1.21 cm3chloroformiate trifloromethyl. After processing receive 5 g of 1-(3-isocyanatophenyl) ethane-sulfonate of tetrabutylammonium (RS) in the form of oils used in the subsequent synthesis.

Example 113. Operate in the manner similar to that described in example 2, but from 2.6 g of 1-(2-amino-acetyl) 5-phenyl-tert.butyl-prolinate have been obtained (2S, 5R), 4.8 g (3-isocyanate-phenylmethanesulfonyl tetrabutylammonium 60 cm3tetrahydrofuran (THF). After processing gain of 0.21 g(1-(3-(3-(2-(2-tert.butoxycarbonyl-5-phenyl-1-pyrrolidinyl) 2-oxo-ethyl)ureido)phenyl) methansulfonate potassium(2S, 5R) solid beige color, //2D0= +18,70,8(C = 0,63, methanol).

(3-Isocyanate-phenyl)methane - sulfonate tetrabutylammonium can be obtained as described in example 21, but on the basis of (3-amino-phenyl)methansulfonate tetrabutylammonium-(RS) 80 cm3toluene, 0,49 g coal and 2.85 g of chloroformiate of trichloromethyl. After processing gain 11 g (3-isocyanate-FeNi is 114. Into the flask containing 1,38 g 2-(3-(3-(2-(4-tert.butoxycarbonyl-2-(2,3-debtor-phenyl) 3-thiazolidine-(2R, 4R)) 2-oxo-ethyl)ureido)phenyl)benzoylpropionate (form B), 0.85 grams of ammonium formate and 1.38 g of 10% palladium on charcoal, is added slowly in an inert atmosphere of 20 cm3of methanol. The reaction medium is heated under reflux for 1 h, then cooled to a temperature of about 25oC. Then the catalyst is filtered off and the filtrate is concentrated to dryness under reduced pressure and the 40oC. the resulting residue is dissolved in 20 cm3a 0.1 N aqueous solution of sodium hydroxide and washed twice in 10 cm3diethyl ether. The aqueous phase is brought to pH 2 by adding 1 N aqueous solution of sulfuric acid. Precipitated precipitated product is filtered off, washed with 2 times 10 cm3water and dried in air. Thus, gain 1.0 g 2-(3-(3-(2-(4-tert.butoxy-carbonyl-2-(2,3-debtor-phenyl) 3-thiazolidine-(2R, 4R)) 2-oxo-ethyl)ureido)phenyl)propionic acid (form B), melting at 130oC, //2D0= +822(C = 0,707%, DMF).

2-(3-(3-(2-(4-tert-butoxycarbonyl-2-(2,3-debtor-phenyl) 3-thiazolidine-(2R, 4R)) 2-oxo-ethyl)ureido)phenyl)benzoylpropionate (form B) can be obtained according to the method, similar to the one (2R, 4R) and 1.96 g of 2-(3-isocyanate-phenyl) benzoylpropionate (form B). The crude product is purified by chromatography on silica (eluent: ethyl acetate-cyclohexane (40/60 vol.)). The fractions containing the product are combined and concentrated to dryness under reduced pressure and the 40oC. Thus, obtain 1.8 g 2-(3-(3-(2-(4-tert.butoxycarbonyl-2- (2,3-debtor-phenyl) 3-thiazolidine-(2R, 4R)) 2-oxo-ethyl)ureido)phenyl benzoylpropionate (form B) in the form of an amorphous product used in the subsequent synthesis.

Example 115. A solution of 2.1 g(3-(3-(2-(2,5-diphenyl-1-pyrrolidinyl)2-oxo-ethyl)ureido)phenyl) methylenedioxyaniline tert.butyl-(CIS), dissolved in 10 cm3triperoxonane acid, stirred for two hours at a temperature of about 20oC, then the reaction medium was concentrated to dryness under reduced pressure and a temperature of approximately 40oC. the Residue is crystallized in 50 cm3water, filtered, washed three times in 15 cm3water and dried at a temperature of about 20oC. the resulting product was then purified by chromatography on silica (eluent: dichloromethane-methanol (95/5 by vol.). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and a temperature of approximately 35oC. Thus, renominations-(CIS) acid, melting at 194oC.

(3-(3-(2-(2,5-Diphenyl-1-pyrrolidinyl)-2-oxo-ethyl)ureido)phenyl) methylenedioxyaniline tert-butyl-(CIS) can be obtained by a method similar to that described in example 3, but judging from 4.2 g of 1-(2-amino-acetyl) 2,5-diphenylpyrrolidine-(CIS), 1.8 g of N, N-diimidazole-carbonyl and 2.5 g of (3-amino-phenyl)methylenedioxyaniline tert.butyl 60 cm31,2-dichloroethane. After processing gain of 2.1 g(3-(3-(2-(2,5-diphenyl-1-pyrrolidinyl) 2-oxo-ethyl)ureido)phenyl) methylenedioxyaniline tert-butyl-(CIS) in the form of an amorphous beige product.

(3-amino-phenyl)methylenedioxyaniline tert-butyl can be obtained in the following way: a solution of 7.5 g (3-nitro-phenyl)methylenedioxyaniline tert. butyl 100 cm3ethanol add 0.75 g of platinum oxide. The suspension is stirred for 1 h at a temperature of about 20oC in an atmosphere of hydrogen (130 kPa). The catalyst is filtered off and the filtrate is concentrated to dryness under reduced pressure at 45oC. the Residue is dissolved in 50 cm3ethyl acetate, and the organic phase is washed with 50 cm3water, dried over magnesium sulfate and concentrate under reduced pressure. So, get 6.2 g of (3-AMINOPHENYL)methylenedioxyaniline tert. Buti is butyl can be obtained in the following way: a solution of 4.3 g of 60% sodium hydride in vaseline degreased, washing two times in 50 cm3hexane. Then add 100 cm3of tetrahydrofuran, and then the suspension is cooled to a temperature of about 5oC and added dropwise a solution to 4.98 g of 3-nitro-benzaldoxime 20 cm3tetrahydrofuran (THF). The reaction mixture was stirred for 1 h at a temperature of approximately 25oC, add a solution of 6 g of tert. butylbromide 5 cm3of tetrahydrofuran and stirred for 1 h at a temperature of approximately 25oC. Then the reaction medium is poured into a mixture of 200 cm3water and 100 cm3ethyl acetate. The organic phase is separated by decantation, dried over magnesium sulfate and concentrated under reduced pressure and a temperature of approximately 40oC. Thus, the gain of 7.5 g (3-nitro-phenyl)methylenedioxyaniline tert.butyl, melting at 120oC.

3-Nitro-benzaldoxime can be obtained by well-known methods (T. M. Oprishko et coll. . Izv. Vyssh Uchebn Zaved. Khim Khim. Tekhnol., 31, 53 (1988)).

Example 116. Act as described in example 108, but based on 0.5 g 2-(3-(3-(2-(4-tert.butoxycarbonyl-2-(2-fluoro-phenyl)-3-thiazolidine-(2R, 4R)) 2-oxo-ethyl)ureido)phenyl) propionic acid (form B) and 1.0 g OksanaP. The resulting crude product was then purified by chromatography on silica (eluent: methylene is low pressure and the 40oC. Thus, obtain 0.2 g 2-(3-(3-(2-(4-tert.butoxycarbonyl-2- (2-fluoro-phenyl) 1-oxide-3-thiazolidine-(1RS, 2R, 4R)) 2-oxo-ethyl)ureido)phenyl) propionic acid (form B) in the form of an amorphous product. Fractions 9 to 14 are combined and concentrated to dryness under reduced pressure and the 40oC. Thus, obtain 0.1 g of the mixture 2-(3-(3-(2-(4-tert.butoxycarbonyl-2-(2-fluoro-phenyl) 1-oxide-3-thiazolidine-(1RS, 2R, 4R) 2-oxo-ethyl)ureido)phenyl) propionic acid (form B) and 2-(3-(3-(2-(4-tert.butoxycarbonyl-2-(2-fluoro-phenyl) 1-dioxide-3-thiazolidine-(2R, 4R)) 2-oxo-ethyl)ureido)phenyl)propionic acid (form B).

Proton NMR (200 MHz, DMSO-D6in ppm, J in Hz) at 120oC there is a mixture of two diasteroisomers in proportion 88-12, characteristic chemical shifts at 120oC: 1,32 (d, J = 7,5, 3H, -CH3), of 1.50 and 1.58 (2s, 9H, in the aggregate, -C(CH3)3highest isomer, then the lowest isomer), 2,85 (t, J = 12,5, 0,88 H, 1H, d - S-CH2the greatest isomer), 3,4 - 4,4 (m, 6,12 H, -CH-COO, the other H-S-CH2most of the isomer, -S-CH2lowest isomer and N-COOH2-N) to 4.8 (t, J = 8, 0,12 H, S-CH-N least-isomer), 4,96 (dd, J = 12.5, 5,0, 0,88 H, S-CH-N greatest isomer), 6,3 - of 6.45 (m, 1H, -NHCO-), 6,5-6,6 (2S, 0,12 H and 0.88 H, S-CH-N smallest and largest isomer), 6,8 (bd, J = 8, 1H, in position 4 on CO-NH), 8,84 and 8,96 (2s, 0,88 H and 0.12 H, ArNHCO for the highest and lowest isomers).

Infrared spectrum (KBr), characteristic bands in cm-1: 3380, 2975, 2930, 2650-2250 (wide band), 1735, 1650, 1610, 1595, 1560, 1490, 1455, 1370, 1230, 1150, 1050, 760, 700.

2-(3-(3-(2-(4-tert. butoxycarbonyl-2-(2-fluoro-phenyl) 1-dioxide-3-thiazolidine-(2R-, 4R) 2-oxo-ethyl)ureido)phenyl) propionic acid (form B) was isolated from a mixture of 2-(3-(3-(2-(4-tert.butoxycarbonyl-2-(2-fluoro-phenyl)-1-oxide-3 - thiazolidine-(1RS, 2R, 4R)) 2-oxo-ethyl)ureido)phenyl) propionic acid (form B) and 2-(3-(3-(2-(4-tert.butoxycarbonyl-2-(2-fluoro-phenyl)1-dioxide-3 - thiazolidine-(2R, 4R)) 2-oxo-ethyl)ureido)phenyl propionic acid (form B) by chromatography on silica (eluent: ethyl acetate-methanol (95/5 by vol. ). The fractions containing the desired product are pooled and concentrated to dryness under reduced pressure and 30oC. Thus, obtain 0.02 g 2-(3-(3-(2-(4-tert.butoxycarbonyl-2-(2-fluoro-phenyl) 1-dioxide-3-thiazolidine-(2R, 4R) 2-oxo-ethyl)ureido)phenyl)propionic acid (form B) as an amorphous substance.

Proton NMR (200 MHz, DMCO D6in ppm): 11,3 (d, 3H, -CH3), and 1.5 (s, 9H, -CH3)3), and 3.6 (m, 2H, CH2- SO2), 4,0-4,3 (m, 3H, Ar-CH-COO and N-COCH2-N), 4,8 (bt, 1H, N-CH-COO), 6,4 (bt, 1H, -N-HCO-), and 6.5 (S, 1H, S-CH-N), 6,8 (bd,th spectrum (KBr, characteristic bands in cm-1; 3380, 2975, 2930, 2650-2250 (wide band), 1735, 1650, 1610, 1595, 1560, 1490, 1455, 1370, 1345, 1230, 1150, 760, 700, 550.

Example 117. Operating according to example 3, get 5[3[3[2(2-tert.butoxycarbonyl-5-phenyl-1-pyrrolidinyl)-2-oxo-ethyl]phenyl] tetrazol-(2S, 5R).

The rotational ability2D0= +27,6 (k = 1,024% MeOH).

The invention relates also to farmatsevticheskii compositions, which contain as active principle at least one compound of the formula I, in free form or in the form of additive salts with a pharmaceutically acceptable acid, in combination with other pharmaceutically compatible ingredient, which can be inert or physiologically active. These compositions can be applied oral, parenteral, rectal or topical way.

As solid compositions for oral administration may be tablets, pills, powders (gelatin capsules, pills or granules.

In these compositions, the active principle described in the invention which have one or more inert diluents, such as starch, cellulose, sucrose, lactose or silica, in a stream of argon. These compositions can also contain the at magnesium or talc, dye, protective shell (draize) or floor.

As liquid compositions for oral route of administration can be applied pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or liquid paraffin. These compositions may contain substances that are not diluents, for example wetting, sweetening, gelatinous, flavouring agents or stabilizers.

Sterile compositions for parenteral administration are preferably in the form of aqueous or non-aqueous solutions, suspensions or emulsions. As a solvent or carrier, you can use water, propylene glycol, polyethylene glycol, vegetable oils, in particular olive, organic esters for injection, for example, ethyl oleate or other suitable organic solvents. These compositions may also contain additional substances, in particular wetting, isotonicity, emulsifiers, dispersing agents, stabilizers. Sterilization can be accomplished in several ways, for example by aseptic filtration, by entering into the composition of Stari is nazizi, directly before use, dissolve in water or any other sterile environment, suitable for injection.

Compositions for rectal injection is presented in the form of suppositories or rectal capsules which contain, in addition to the active product, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.

Compositions for topical (local) application can be produced, for example, in the form of creams, lotions, eye drops, medicines for the mucous membrane of the throat and mouth, nose drops or sprays.

In human therapy described in the invention compounds are used in particular for the treatment and prevention of disorders associated with CCK and gastrinom at the level of the Central nervous system and gastrointestinal tract. These compounds can be used in the treatment and prevention of psychosis, restlessness, Parkinson's disease, late dyskinesia syndrome excitable membranes ulcer, acute pancreatitis, ulcers, disorders of intestinal motility, some types of neoplasms (tumors), sensitive to CCK, memory disorders, as analgesic means, means for increasing analgesic activity is the stimulation of appetite.

Doses depend on the desired effect, the duration of treatment and route of administration, typically 0.05 to 1 g per day in oral introduction for adults, a single dose of 10-500 mg of active substance.

Typically, the physician should determine the appropriate patologicheskoi (daily) dose depending on the age, weight and other individual characteristics of the patient.

Example A. the usual procedure is made gelatin capsules with a dose of the active substance 50 mg) having the following composition, mg:

3-(3-(2-(2-Tert. butoxycarbonyl-5-phenyl-1-pyrrolidinyl)-2-oxo - ethyl)ureido)-3-phenyl-benzoic acid-(2R, 5SR) acid - 50

Cellulose - 18

Lactose - 55

Kolodny silicon dioxide - 1

Sodium carboximetilkrahmal - 10

Talc - 10

Magnesium stearate - 1

Example b In the usual manner to produce tablets with a dose of the active substance 50 mg) having the following composition, mg:

3-((3-(2-(2-Tert. butoxycarbonyl-5-phenyl-1-pyrrolidinyl)-2-oxo - ethyl)-ureido)-benzoic acid-(2R, 5S) acid - 50

Cellulose - 40

Lactose - 104

Polyvidone - 10 g

Sodium carboximetilkrahmal - 23

Talc - 10

Colloidal silicon dioxide - 2

Magnesium stearate - 2

The mixture hydroxyesters for injection, containing 10 mg of active substance and having the following composition, mg:

3-((3-(2-(4-Tert. butoxycarbonyl-2-phenyl-3-thiazolidine)-2 - oxo-ethyl)ureido)-phenylacetic-(2R, 4R) acid - 10

Benzoic acid - 80

Benzyl alcohol - 0,06

Sodium benzoate - 80

95% ethanol - 0.4 cm3< / BR>
Sodium hydroxide - 24

Propylene glycol - 1.6 cm3< / BR>
Water - Up to 4 cm3< / BR>
Were conducted biological studies of new compounds to determine their affinity for receptor cholecystokinin and gastrin using known methods (A. Saito et coll., J. Neuro. Chem., 37 483-490, 1981).

Studies were performed on membrane preparations of the pancreas and of the cerebral cortex of the mouse in the presence of investigated compounds and receptors SCQ.

The results are expressed as the minimum concentration of the investigated compounds, inhibiting by 50% the relationship cholecystokinin with its receptor, and is listed in the table.

1 1. Derivatives pyrrolidine General formula I 6 1 in which either R methylene-, ethyleneglycol, group, or sulfur; 4 R1- pyridinethiol, furilazole, titillation optionally substituted by one or more alkyl groups, naphthyridines, indolylacetic lagena, alkyl-, alkoxy-, hydroxy - and dialkylamino; 4 R5is hydrogen, 2 or R - metroradio; 4 R1is hydrogen; 4 R5- terratial; 2 or R - group 4 R1and R5each is hydrogen; 4 R2- alkoxycarbonyl, cycloalkyl-alkyloxy-carbonyl-, -CONR9R10or terratial, optionally substituted by one or more substituents selected from alkyl-, alkoxy - or hydroxy-group; 4 R3- indolyl - or phenylaminopropyl, the phenyl nucleus of which is optionally substituted by one or more substituents selected from a range that contains the halogen atom, the alkyl-, alkoxy-, alkylthio-, trifluoromethyl-, carboxy-, alkoxycarbonyl-, hydroxy-, acyl-, hydroxyimino-alkyl-, tetrazolyl-5, mono - or polyhydroxyalkanoate, the group-ALK-COOX, -AQL'-COOX, -O-ALK-COOX, -CH=CH-COOX, -ALK-SO3H in salt form, -S-ALK-COOX, -CX= NO-ALK-COOX; 4 R4is hydrogen or alkylaryl; 4 R6- terratial; 4 R9is hydrogen or alkyl; 4 R10is alkyl or terratial, 4 or R9- R10form together with the nitrogen atom to which they relate, 1,2,3,4-tetrahydroquinolin or piperidinylmethyl, optionally substituted by one or more alkyl radicals; 4 X alkylation, hydrogen Elnya and alkoxyalkyl radicals and alkyl and CNS parts contain 1 - 4 carbon atoms in straight or branched chain acyl radicals or acyl portion contains 2 to 4 carbon atoms and cycloalkyl radicals and cycloalkyl parts contain 3 to 6 carbon atoms, 1 in the form of racemic mixtures or enantiomers in the presence of at least one asymmetric centre, and also their salts. 2 2. The compound of formula I under item 1, where R is metroradio, sulphur or the radical R1- optionally substituted terratial, R2- phenyl - or alkoxycarbonylmethyl, R4and R5is hydrogen, R3Veniaminovna, the phenyl nucleus of which is substituted by carboxy-, ALK-COOH, -S-ALK-COOH, hydroxyalkyl-ALK'-COOH or-ALK-SOR3-radical. 2 3. The compounds of formula I on p. 1 the following: 2 1-{2-{3-[3-(1-hydroxyethyl-(RS))phenyl] -ureido} -acetyl}-5-phenyl - prolinate have been obtained tert-butyl-(2RS, 5SR), 2 2-{ 3-{3-[2-(2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl(2S,5R)) 2-oxo-ethyl] ureido} phenyl} propionic acid (form B), 2 {3-{3-[2-(2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl-2-oxo - ethyl] ureido} phenylthio} acetic acid(2RS, 5SR) acid, 2 3-{3-[4-tert-butoxycarbonyl-2-(2-fluoro-3-thiazolidine)- 2-oxo-ethyl] ureido} phenylacetic-(2R,4R) acid, 2 2-{3-{ 3-[2-(2-tert-butoxycarbonyl-2-(2-fluoro-phenyl)-3-thiazolidine-(2R,4R))-2-oxo-ethyl] ureido} phenyl} propionanilide potassium (RS), a mixture of forms A and B, 2 1-{3-{3-[2-(2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl-(2RS, 5SR) -2-oxo-ethyl]ureido} phenyl} econsultant potassium(RS), 2 3-{3-[2-(2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl)-2-oxo - ethyl]ureido}1-phenylmethanesulfonyl potassium(2S,5R), 2 3-{3-[2-(2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl)-2-oxo - ethyl] ureido} benzoic acid-(2S, 5R) acid, 2 3-{3-[2-(2-tert-butoxycarbonyl-5-(2-fluoro-phenyl)-1-pyrrolidinyl)-2-oxo - ethyl] ureido} benzoic acid-(2RS, 5SR) acid, 2 3-{3-[2-(2,5-diphenyl-1-pyrrolidinyl)-2-oxo-ethyl]ureido}-benzoic acid -(CIS) acid, 2 3-{2-[2(2-hydroxy-phenyl)5-phenyl-1-pyrrolidinyl] -2-occoured} phenylacetic-(2RS, 5SR) acid, 2 3-{3-[2-(4-tert-butoxycarbonyl-2-phenyl-3-thiazolidine)-2-oxo - ethyl]ureido}phenylacetic-(2R, 4R) acid, 2 3-{3-[2-(4-tert-butoxycarbonyl-2-phenyl-3-thiazolidine)-2-oxo - ethyl]ureido}benzoic-(2R,4R) acid, 2 2-{3-{3-[2-(4-tert-butoxycarbonyl-2-(2-fluoro-phenyl)-1-oxide - 3-thiazolidine-(1RS, 2R, 4R))-2-oxo-ethyl] ureido} phenyl} propionic acid (form A), 2 3-{{3-[4-tert-butoxycarbonyl-2-(2,3-debtor-phenyl)-3-thiazolidine] - 2-oxo-ethyl] ureido} phenylacetic-(2R, 4R) acid, 2 1-{2-{3-[3-(1-hydroxyimino-ethyl)-phenyl-(E)] ureido-acetyl} -5-phenyl-prolinate have been obtained tert-butyl-(2RS,5SR). 2 4. The method of obtaining compounds of General formula I according to one of paragraphs.1 to 3, where R is the IFRC substituted by one or more substituents on the PP.1 - 3, or its salts, characterized in that the active derivative carbamino acid obtained if necessary in situ by exposure to N,N-diaminotoluene on a derivative of General formula II 6 1 where R has the above meanings; 4 R1, R2, R4and R5have values for PP.1 - 3, 1 is subjected to interaction with aniline, phenyl nucleus of which is optionally substituted by one or more substituents specified in the description of the radical R3with subsequent isolation of the target product in free form or in salt form. 2 5. The method according to p. 4, characterized in that the reaction is carried out in an inert organic solvent at a temperature of from 20C to the boiling point of the solvent. 2 6. The method of obtaining compounds of General formula I on PP. 1 to 3, where R is methylene, ethylene, radical or sulfur, and R3- phenylaminopropyl, the phenyl nucleus of which can be substituted by one or more substituents selected from a range that contains halogen atom, alkyl, alkoxyalkyl-, trifluoromethyl-, acyl-, alkoxycarbonyl and ALK-SO3H in the form of salts, and their salts, characterized in that the compound of General formula II 6 1 where R, R1, R2, R4and R5have the specified values, alkemi substituents, selected from the row containing the halogen atom, the alkyl-, alkoxy-, alkylthio-, trifluoromethyl-, acyl-, alkoxycarbonyl and-ALK-SO3H in the form of a salt, with subsequent isolation of the target product, and optionally converting it into salt. 2 7. The method according to p. 6, characterized in that the interaction is carried out in an inert organic solvent at a temperature from 10C up to the boiling point of the solvent. 2 8. The method of obtaining compounds of General formula I on PP.1 to 3, where R is methylene, ethylene, radical or sulfur, and R3- phenylaminopropyl, the phenyl nucleus of which is substituted by a group selected from a range that contains carboxypropyl, -ALK-COOH, -O-ALK-COOH, -ALK'-COOH, -CH=CH-COOH, -S-ALK-COOH or CX=N-O-ALK-COOH, and their salts, characterized in that conduct hydrolysis or hydrogenolysis of the corresponding complex ether, followed by separation of the target product, and optionally converting it into salt. 2 9. The method of obtaining compounds of General formula I on PP.1 to 3, where R is methylene, ethylene, radical or sulfur, and R3- indolyl - or phenylaminopropyl, the phenyl nucleus of which is optionally substituted by one or more substituents selected from the group consisting of halogen atom, alkyl, alkoxyalkyl-, trifluoromethyl-, acetyl-, alcox who spend the interaction of compounds of General formula (IV) 6 1 where R, R1, R2and R5defined above, 1 with the acid of General formula 6 1 where R3and R4have the specified values; 1, or with a reactive derivative of this acid, followed by separation of the target product, and optionally converting it into salt. 2 10. Pharmaceutical composition having activity for receptor cholecystokinin and gastrin, containing the active principle and pharmaceutical additives, characterized in that the active agent contains at least one connection on the PP.1 to 3 in an effective amount. 2 11. Method of separating enantiomers of compounds of formula I according to one of paragraphs.1 to 3, characterized in that the conducting chromatography on chiral phase, having the structure 6 1 where G1group 3,5-dinitrobenzene. 2 12. Chiral phase for the separation of enantiomers of compounds of General formula I on PP.1 to 3, representing a modified silicon dioxide having a structural fragments, as described in paragraph 11.

 

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