Derivatives pyrrolidine and their pharmaceutically acceptable salts, method of production thereof, and pharmaceutical composition

 

(57) Abstract:

The essence of the invention. The proposed derivatives pyrrolidine formula (I), where R1- heteryl(lower)alkyl, (C1-C12) alkyl and optionally substituted phenyl(lower)alkyl; R2Is H, phenyl(lower)alkoxycarbonyl or optionally substituted phenylsulfonyl; R3- carboxy(lower)alkyl, esterified carboxy lower alkyl, carboxyphenyl or esterified carboxyphenyl; and its pharmaceutically acceptable salts, which is produced by interaction of the compounds of formula (II) with the compound of the formula (XIV) or its salt. The proposed farmcampsite, which has antagonistic activity against thromboxane A2(TXA2and inhibiting TXA2synthase, based on the compounds of formula (I). 3 s and 5 C.p. f-crystals.

I

2 the Invention relates to new derivatives of pyrrolidine and their pharmaceutically acceptable salts.

In particular, the invention relates to new derivatives of pyrrolidine and their pharmaceutically acceptable salts, having the antagonism of thromboxane A2(TXA2), as well as activity, inhibitory TXA2-synthetase, which can be used for the treatment and/or preduprejdat, unstable angina, myocardial infarction, failure of the peripheral circulation, bleeding in the brain, unstable angina, myocardial infarction, failure of the peripheral circulation, blood clot after percutaneous plastic surgery on vessels, generalized thrombohemorrhagic syndrome, etc., allergic diseases such as asthma or similar jade; peptic ulcers; migraine; diabetic neuropathy; diabetic angiopathy; restenosis after plastic operations on vessels; respiratory distress syndrome in adults; shock; hepatitis; cerebral vasospasm after subarachnoid hemorrhage; hypertension; atherosclerosis; metastasis of malignant tumors; the formation of a blood clot in performi; the formation of a blood clot in transplantation; and so on, as well as to reduce the nephrotoxicity caused by immunosuppressants, such as cyclosporine in kidney transplantation; these derivatives pyrrolidine or their pharmaceutically acceptable salts can also be used in combination with fibrinolytic agents in order to enhance the fibrinolytic action of these agents.

Derivatives pyrrolidine of the present invention m is can be suitable Deputy (deputies); or heterocyclic(lower)alkyl;

R2is hydrogen or acyl group; and

R3is carboxy(lower)alkyl; protected carboxy(lower)alkyl, carboxyaniline or protected by carboxyaniline.

In accordance with the invention is new derivatives of pyrrolidine (I) get in the way I options 1-5 are listed at the end of

where

R1, R2and R3are the same as defined above;

X is halogen;

R3aprotected carboxy(lower)alkyl or protected carboxyethyl

R3incarboxy(lower)alkyl or carboxyethyl;

R8hydrogen, (C1-C4)alkyl; aryl, which may have an appropriate substituent (s), ar(C1-C5)alkyl, which may have an appropriate substituent(s), heterocyclic group, or heterocyclic (C1-C5)alkyl;

R2a1acyl group;

R1aar(lower)alkyl having protected amino group;

R1inar(lower)alkyl, with the amino group.

The original compound (II) can be obtained by methods a and b, given in the end of the description.

where

R2, R2
X1halogen;

M is alkali metal; and

R7aryl

Below explains in detail the terminology used in the description of the invention and the examples illustrating the invention.

The term "lower" means having 1-6 carbon atoms and preferably 1-4 carbon atoms, if it is not specifically mentioned.

The term "alkyl" means that the corresponding alkyl straight or branched chain contains 1 to 15 carbon atoms, examples of the specified alkyl can serve as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, t-pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, or etc.

Suitable "lower alkyl" and part of (lower) alkyl", indicated by the terms "heterocyclic(lower)alkyl", "carboxy(lower)alkyl" and "protected carboxy(lower)alkyl" is an alkyl straight or branched chain having 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, t-pentyl, hexyl, or similar and preferably having 1-4 carbon atoms.

The corresponding part of the lower alkyl" defined the term "ar(lower)alkyl", is alkv carbon.

The relevant "aryl" and "aryl part, indicated by the terms "ar(lower)alkyl", carboxyethyl" protected carboxyethyl" and "ar(C1-C5)alkyl" may be phenyl, naphthyl, etc.

The appropriate "substitute" designated by the terms "ar(lower)alkyl which may have an appropriate substituent(s)", "aryl which may have an appropriate substituent(s), and ar(C1-C5alkyl, which may have an appropriate substituent(s) "may be cyano, hydroxy, halogen (e.g. chlorine, bromine, fluorine and iodine), lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, t-pentyl, hexyl, etc.,), the lowest alkoxygroup (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, t-butoxy, petroczi, t-pentyloxy, hexyloxy and etc.), aryl (e.g. phenyl, naphthyl, etc.) amino group, di(lower amino group (for example, dimethylamino, diethylamino, dipropylamino, dibutylamino, diphenhydamine, digoxigenin and so on), a protected amino group, etc.

The corresponding protected amino group may be an acyl-amino group or the like.

Appropriate "(C1-C5)alkyl part, marked or branched chain, having 1-5 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, t-pentyl etc.

The relevant "(C1-C14)alkyl" may be alkyl straight or branched chain, having 1 to 14 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, t-Pentin, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, diradical or etc.

The corresponding "heterocyclic group" and "heterocyclic part, indicated by the terms "heterocyclic lower alkyl" and "heterocyclic (C1-C5)alkyl" may be saturated or unsaturated, monocyclic or polycyclic heterocyclic group containing at least one hetero-atom such as oxygen atom, sulfur, nitrogen, etc., Particularly preferred are heterocyclic groups, such as:

unsaturated consisting of 3-8 members (more preferably 5-6 members) heterocyclic group having 1-4 nitrogen atom, for example, pyrrolyl, pyrrolidyl, imidazolyl, pyrazolyl, pyridyl, and its N-oxide, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1, 2,4-triazolyl, 1H-1,2,3-triazo is 4,5-dihydro-1,2,4-triazinyl, 2,5-dihydro-1,2,4-triazinyl and so on), etc.

ninasimone consisting of 3-8 members (more preferably 5-6 members) heterophilically group containing 1-4 nitrogen atoms, for example, pyrrolidino, piperidino, piperazinil etc.

unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, hinely, ethanolic, indazoles, benzotriazolyl, tetrasulphides, tetrachloropyridine (for example, tetrazolo/a 1.5-in/pyridazinyl, etc.) dihydrotriazines, I. p.

unsaturated consisting of 3-8 members, more preferably 5-6 members) heterophilically group containing 1-2 oxygen atoms and 1-3 nitrogen atom, for example oxazolyl, isoxazolyl, oxadiazolyl (for example, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, and so on), etc.

rich, consisting of 3-8 members (more preferably 5-6 members) heterophilically group containing 1-2 oxygen atoms and 1-3 nitrogen atom, for example, morpholinyl etc.

unsaturated condensed heterocyclic group containing 1-2 oxygen atoms and 1-3 nitrogen atom, for example benzoxazolyl, benzoxadiazole etc.

nanosys the Ohm sulfur and 1 to 3 nitrogen atom, for example thiazolyl, 1,2-thiazolyl, thiazolyl, thiadiazolyl (e.g., 1,2, 4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl), etc.

rich, consisting of 3-8 members (more preferably 5-6 members) heterophilically group containing 1-2 sulfur atom and 1 to 3 nitrogen atom, such as diazolidinyl etc.

unsaturated, comprising from 3 to 9 atoms (more preferably 5-6 members) heterophilically group containing a sulfur atom, such as thienyl etc.

unsaturated consisting of 3-8 members (more preferably, 5 to 6 members), heterophilically group containing an oxygen atom, such as furyl, etc.

unsaturated condensed heterocyclic group containing 1-2 sulfur atom and 1 to 3 nitrogen atom, for example benzothiazolyl, benzothiadiazole etc.

The corresponding "acyl" and "acyl part, denoted by the term "acylamino" may be lower alkanoyl (for example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl and so on), low alkoxycarbonyl (such as methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, pentyloxybenzoyl, t-pentyloxybenzoyl, g is isopropylmalonic, butylsulfonyl, t-butylsulfonyl, peterculter, t-PENTACARBONYL, lexicology, and so on), arylsulfonyl (for example, phenylsulfonyl, nuptiality, and so on), aroyl (for example benzoyl, Naftoli, etc. ar(lower) alkanoyl, (for example phenylacetyl, phenylpropionyl and so on), cyclo(lower)alkyl(lower alkanoyl (such as cyclohexylethyl, cyclopentylacetyl and so on), ar(lower) alkoxycarbonyl (for example, benzyloxycarbonyl, ventilatsioonil, and so on), arylcarbamoyl (for example, phenylcarbamoyl, afterburner, and so on), heterocyclic sulfonyl, such as heteroscedasticity sulfonyl (for example, thienyl-sulfonyl, fullcolor, pyridylsulfonyl, and so on), etc.

these acyl groups may be substituted by 1-3 appropriate substituents, such as halogen, for example chlorine, fluorine, bromine and iodine, lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, t-pentyl, hexyl, etc.), lower alkoxy group (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentox, t-pentox, hexyloxy and so on), a nitro group, mono - or di-, or tri - halo(lower)alkyl (e.g., chloromethyl, bromomethyl, chloropropyl, 1,2-dichloroethyl, 1,2-dibromoethyl, 2,2-dichloroethyl, three the military terms "protected lower alkyl" and "protected carboxyethyl", can be carbarnoyl; arylcarbamoyl, such as lower alkylsulfonyl (for example, methylsulfonylamino, ethylsulfonyl, propylsulfonyl, isopropylaminocarbonyl, butylcarbamoyl, t-butylcarbamoyl, vexillological etc.) arylcarbamoyl (for example, phenylsulfonylacetate, mattersalternative, etc. or etc., esterified carboxyl group, in which the specified ester may be one of the following compounds: complex lower alkilany ester (e.g. methyl ester, complex ethyl ester, complex propyl ether complex isopropyl ether complex butyl ether, complex isobutyl ether, complex t-butyl ether, complex pentalogy ether complex t-pentalogy ester, hexyl ester, etc.); complex lower alkenilovyh ether (for example, a complex atinlay ether complex propenyloxy ether, etc.,); complex mono(or di-or tri -) halo(lower)alkilany ether (for example, a complex 2-iodoethylene ether complex 2,2,2-trichlorethylene ether, etc.) complex alkanoyloxy(lower)alkilany ether (for example, a complex acetoxymethyl ether complex propionylacetate ether complex 1-acetoxypropionyl ether, closetotray ether, complex 2-propionylacetate ether complex 1-isobutyrylacetate ether, and so on), complex lower alkanesulfonyl(lower)alkilany ether (for example, a complex methylotrophy ether complex 2-mutilative ether, and so on). complex ar(lower)alkilany ether, for example, a complex phenyl lower alkilany ether, which may be substituted by one or more appropriate substituents (for example, a complex benzyl ether complex 4-methoxybenzyloxy ether complex 4-nitrobenzyloxy ether complex finitely ether complex trailovic ether complex diphenylmethylene ether complex biotoxins methyl ether complex of 3,4-dimethoxybenzyl ether complex 4-hydroxy-3,5-discretionarily ether, and so on), complex lower alkoxycarbonyl(lower)alkilany ether (for example, a complex methoxycarbonylmethylene ether, complex ethoxycarbonylmethylene ether complex ethoxycarbonylmethylene ether, and so on), complex urologic(lower)alkilany ether (for example, a complex benzoyloxymethyl ether complex benzoylacetone ether complex teleologically ether, and so on), complex arrowy ester which may have one or more appropriate Deputy or acceptable substituents such as phenyl complex EPE is R, complex comenjoy ether, etc.

The corresponding "halogen may be chlorine, bromine, fluorine, and iodine.

The corresponding "imino-protective group" may be mentioned acyl group, etc.

The corresponding "alkali metal may be sodium, potassium, etc.

Appropriate pharmaceutically acceptable salts of the target compound (I) are the standard non-toxic salts, and metal salts such as the alkali metal salt (e.g. sodium salt, potassium salt, etc. and salts of alkaline-earth metal such as calcium salt, magnesium salt, etc.,), ammonium salt, salt with organic bases (for example, triethylamine salt, dimethylamino salt, pyridine salt, picolina salt, dicyclohexylamine salt, N, N-dibenzylethylenediamine salt, etc), salt of organic acid (for example, acetate, maleate, tartrate, methanesulfonate, bansilalpet, format, toluensulfonate, triptorelin and so on), salt of an inorganic acid (e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.,), salt, formed by the amino acid (for example, agrinine, aspartic acid, glutamic acid, lysine, etc.,), etc.

Preferred target compound (I) is the l in which heterophilically group contains 1-4 nitrogen atoms, more preferred are pyridyl(lower)alkyl, pyrazinyl(lower)alkyl pyrrolyl(lower)alkyl or imidazolyl(lower)alkyl, most preferred: pyridyl (C1-C4)alkyl, pyrazinyl(C1-C4)alkyl, pyrrolyl(C1-C4)alkyl or imidazolyl(C1-C4)alkyl,

unsaturated condensed heterobicyclic(lower)alkyl, in which heterobicyclic group contains 1-4 nitrogen atom, more preferable is: hinely(lower)alkyl, most preferred, chinolin(C1-C4)alkyl,

unsaturated condensed heterobicyclic(lower)alkyl, in which heterobicyclic group contains 1-2 oxygen atoms and 1-3 nitrogen atom, more preferred is benzoxazolyl(lower)alkyl, most preferred is benzoxazolyl C1-C4alkyl,

unsaturated consisting of 5-6 atoms heterophilically(lower)alkyl, in which heterophilically group contains 1-2 sulfur atom and 1 to 3 nitrogen atom, the more preferred is thiazolyl(lower)alkyl, most preferred is thiazolyl(lower)alkyl, most preferred is ISSI)alkyl, in which heterophilically group contains a sulfur atom /is preferred thienyl(lower)alkyl, most preferred thienyl(C1-C4)alkyl/,

unsaturated, consisting of 5-6 members heterophilically(lower)alkyl, in which heterophilically group contains an oxygen atom, more preferred is furyl(lower)alkyl, most preferred furyl(C1-C4)alkyl/,

unsaturated condensed heterobicyclic(lower)alkyl, in which heterobicyclic group contains 1-2 sulfur atom and 1 to 3 nitrogen atom, the more preferred is benzothiazolyl(lower)alkyl, most preferred benzothiazolyl C1-C4alkyl/,

C1-C15-alkyl, more preferred is C1-C12alkyl

phenyl(lower)alkyl which may have 1-3 substituent selected from the group consisting of: cyano, hydroxy, halogen, lower alkyl, lower alkoxy groups, aryl, amino, di(lower)alkylamino and protected amino groups, more preferred are a phenyl(lower)alkyl which may have 1--2 substituent selected from the group consisting of cyano, hydroxy, halogen, lower alkyl, lower alkoxy(lower)alkyl, cyanophenyl(lower)alkyl, hydroxyphenyl (lower) alkyl, mono (or di-) halophenol(lower)alkyl, phenyl(lower)alkyl, diphenyl(lower)alkyl, AMINOPHENYL(lower)alkyl, di(lower)alkyl amino-phenyl(lower)alkyl, or lower alkanolamine(lower)alkyl or naphthyl(lower)alkyl;

R2hydrogen, ar(lower)alkoxycarbonyl, more preferred is a phenyl lower alkoxycarbonyl, or arylsulfonyl, which may have 1-3 substituent selected from the group consisting of halogen, lower alkyl, lower alkoxy groups and mono (or di-or tri-) halo( lower)alkyl, more preferred is phenylsulfonyl, which may have 1-2 substituent selected from the group containing halogen, lower alkyl, lower alkoxy and mono (or di - or tri-) halo(lower)alkyl, most preferred is phenylsulfonyl, which may contain a halogen, lower alkyl, lower alkoxy group or a mono (or di-or tri-) halo(lower)alkyl;

R3carboxy(lower)alkyl, protected carboxy(lower)alkyl, more preferred is esterified carboxy(lower)alkyl, most preferably, lower alkoxycarbonyl lower alkyl, carboxyphenyl or protected carboxyphenyl, more predoc.

Below describes the options of the way to obtain the target compound (I) and the starting compound (II) according to the invention.

Option 1.

The compound (Ib) or its salt can be obtained by using the reactions of elimination carboxyl protective group, which is subjected to the compound (Ia) or its salt.

The above reaction is carried out in accordance with standard methods, such as hydrolysis, recovery, etc.

If the protective group is a complex ether, specified protective group can be removed by hydrolysis. The hydrolysis is carried out preferably in the presence of a base or acid such as a Lewis acid. Appropriate base can be an inorganic base and organic base, such as alkali metals (e.g. sodium, potassium, etc.,) alkaline-earth metals (e.g. magnesium, calcium, etc), their hydroxides, carbonates or bicarbonates; trialkylamine (for example, trimethylamine, triethylamine, etc.,) or the like.

The corresponding acid may be an organic acid (e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, triperoxonane, sulfuric acid, etc.,).

The reaction of recovery is used, preferably, for the removal of the protective group, such as for example, 4-nitrobenzyl, 2-iodoethyl; 2,2,2-trichloroethyl or the like. This method of recovery, be applied for the implementation of the elimination reaction may be performed, for example, by using a combination of metal (e.g. zinc, zinc amalgam, etc., or salts of compounds of chromium, for example, chromium chloride, chromium acetate, etc., and organic or inorganic acid (e.g. acetic acid, propionic acid, hydrochloric acid, etc.,); and when using standard catalytic reduction in the presence of a metal catalyst (e.g. palladium carbon, etc).

This reaction usually proceeds in a solvent such as water, alcohol (e.g. methanol, ethanol, etc.,) methylenchlorid, tetrahydrofuran, a mixture thereof or any other solvent which doesn't have any undesirable effect on the reaction. The solvent can be also used liquid base or acid. The reaction temperature is not critical and the reaction usually proceeds in the mode from cooling to on the AI between the compound (II) or its salt and the compound (XIV) or its salt.

This reaction may proceed in the presence of a reducing agent, such as cyanoborohydride alkali metal (for example, cyanoborohydride sodium), borohydride alkali metal (for example, borohydride sodium, etc.) DIBORANE, etc.

This reaction usually proceeds in a solvent such as alcohol (e.g. methanol, ethanol, etc.,) methylene chloride, tetrahydrofuran, chloroform, a mixture thereof or any other solvent which doesn't have any undesirable effect on the reaction. The reaction temperature is not critical and the reaction usually proceeds in the mode from cooling to heating.

Option 3.

The compound (Ie) or its salt can be obtained by using the reaction gazillionare, which is subjected to compound (Id) or its salt.

The above reaction is carried out in accordance with standard methods, such as hydrolysis, repair, or etc.

This reaction is performed in a manner similar to described in method B , and therefore, the reaction conditions correspond to the reaction conditions described in the specified Way B .

Option 4.

The compound (Ig) or its salt can be obtained by using the reaction laminirovaniya in accordance with standard methods, such as hydrolysis, repair, or etc.

This reaction is performed in a manner similar to described in method B , and therefore, the reaction conditions correspond to the reaction conditions described in the specified Way B .

Option 5.

Compound (Id) or its salt can be obtained by using the reaction of the compound (Ie) or its salt with allermuir agent.

Allermuir agent may be an organic acid (i.e., R2aOH, where R2aacyl group) or its reactive derivative, or its salt.

The corresponding reactive derivative of an organic acid may be a standard connection, such as an acid halide, e.g. acid chloride, acid bromide, etc., acid azide, acid anhydride, activated amide, an activated ester, isocyanate, for example, arylisocyanate, for example, phenylisocyanate etc.

If Alliluyeva agent uses free acid, the acylation reaction is preferably conducted in the presence of standard condensing agent such as N, N'-dicyclohexylcarbodiimide or similar.

The above reaction is preferably carried out in presets the Ktsia usually proceeds in a solvent, 't have unwanted effects on the reaction, such as methanol, ethanol, propanol, dichloromethane, tetrahydrofuran, chloroform, etc.

The reaction temperature is not critical and the reaction can occur under from cooling to heating.

Method A .

The compound (VI) or its salt can be obtained by using the reaction of the compound (IV) or its salt with the compound (V).

This reaction usually proceeds in a standard solvent, such as dichloromethane, or any other solvent that do not have undesirable effects on the reaction.

The above reaction is preferably carried out in the presence of inorganic or organic bases, as shown in Method B .

Method A .

The compound (VIII) or its salt can be obtained by using the reaction of compound (VI) or its salt with the compound (VII).

This reaction usually proceeds in a standard solvent such as dimethylsulfoxide or any other solvent that do not have undesirable effects on the reaction.

The reaction temperature is not critical and the reaction usually proceeds in Rio salt can be obtained through hydrogenation reactions, which is subjected to the compound (VIII) or its salt. The above reaction is usually carried out in the presence of a catalyst such as palladium carbon or the like.

This reaction usually proceeds in a standard solvent such as an alcohol, e.g. methanol, ethanol, etc. or any other solvent that do not have undesirable effects on the reaction.

The reaction temperature is not critical and the reaction can occur under from cooling to heating.

Method A .

The compound (Xa) or its salt can be obtained by using the reaction of compound (IX) or its salt with allermuir agent.

The above reaction is carried out a method basically similar to the method described in method 6, and therefore the conditions of this reaction correspond to the reaction conditions described in the specified way 6.

Method A .

The compound (XIa) or its salt can be obtained by recovering the compound (Xa) or its salt.

The reduction generally proceeds in the presence of a reducing agent, such as di(lower)alkylhalogenide (for example, diisobutylaluminium and so on), aluminohydrides alkaline metah">

This reaction usually proceeds in a standard solvent, such as toluene, tetrahydrofuran or any other solvent that do not have undesirable effects on the reaction.

The reaction temperature is not critical and the reaction can occur under cooling or at room temperature.

Method B .

The compound (XIII) or its salt can be obtained by using the reaction of compound (XI) or its salt with a solvent (XII) or its salt.

This reaction usually proceeds in a standard solvent, such as acetone, dioxane, acetonitrile, chloroform, methylene chloride, telengard, tetrahydrofuran, ethyl acetate, N, N'-dimethylformamide, dimethylsulfoxide, or any other solvent that do not have undesirable effects on the reaction.

The reaction temperature is not critical and the reaction usually takes place in conditions of from cooling to heating.

Method B .

The compound (II) or its salt can be obtained by using the reactions of elimination imino-protective group, which is subjected to the compound (XIII) or its salt.

The above elimination reaction is carried out by standard who you are or bases, etc. These methods can be selected depending on the type of the deleted group.

Among the standard methods, the hydrolysis is conducted using acid, is one of the most famous and preferred methods for removal of the protective group such as substituted or unsubstituted alkoxycarbonyl (for example, t-pentyloxybenzoyl, t-butoxycarbonyl and so on ), alkanoyl (for example, formyl, etc.,), cycloalkylcarbonyl, substituted or unsubstituted arelaxation (for example, benzyloxycarbonyl, substituted benzyloxycarbonyl and so on), or the like.

The corresponding acid may be organic or inorganic acid, for example formic acid, triperoxonane acid, benzolsulfonat acid, p-toluensulfonate acid, hydrochloric acid, etc. and the preferred acid is formic acid, triperoxonane acid, hydrochloric acid, etc., Acid, acceptable for a given reaction can be selected in accordance with a disposable protective group. If the reaction is carried out using acid, it can take place in a solvent or without solvent. An appropriate solvent may be a standard organic rustie base preferably used to remove the acyl group, for example, haloalkane (for example, dichloracetyl, divorcethe and so on), etc.

Appropriate base can be, for example, inorganic base such as alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.,) the hydroxide of alkaline-earth metal (e.g. magnesium hydroxide, calcium hydroxide, etc.,), a carbonate of an alkali metal (e.g. sodium carbonate, potassium carbonate, sodium carbonate, etc.,), carbonate of alkaline-earth metal (e.g. magnesium carbonate, calcium carbonate, etc.,), bicarbonate of an alkali metal (e.g. sodium bicarbonate, potassium bicarbonate, etc.,), the alkali metal acetate (e.g. sodium acetate, potassium acetate, etc ), phosphate, alkaline-earth metal (e.g. magnesium phosphate, calcium phosphate, etc.) acid phosphate of alkali metals (for example, secondary acid phosphate of alkali metals (for example, secondary acidic sodium phosphate, secondary acid phosphate and potassium etc.), etc. and an organic base, such as trialkylamine (for example, triethylamine, trimethylamine, etc.,) or the like. The hydrolysis using a base is often carried out in water, a standard organic solvent or mixtures thereof. If the acyl group is hallym metal, such as copper, zinc or the like.

Reductive elimination is usually carried out in order to remove the protective group, for example, Gloucestershire (for example, trichlorocarbanilide and etc.), substituted or unsubstituted arylcarbamoyl (for example, benzyloxycarbonyl, substituted benzyloxycarbonyl and so on) or the like. The corresponding reaction recovery may occur, for example, in the presence of alkali metal borohydride (e.g. sodium borohydride, etc.,), etc.

The reaction temperature is not critical and may be selected in accordance with the form of the imino-protective group and the above-described method of elimination. The above reaction is preferably carried out in mild conditions, for example, cooling, room temperature or slightly elevated temperature.

The target compound (I) and its pharmaceutically acceptable salts are antagonists of thromboxane A2(TXA2) and inhibitors TXA2synthetase.

For purposes of illustration, below are some biological data of the target compound (I).

In the following test used 9,11-metanoiax PCH2(I) pharmacologically, harmoko connection (see for example, the Journal of Pharmacology and Experimental Therapeut: cs Vol. 234, ppm 435-441).

Test the connection.

(2S, 4R)-2-[(Z)-5-carboxy-1-pentenyl] -4-/4-course-sulfonylamino/-1-(3-pyridylmethyl pyrrolidin /the connection specified hereinafter referred to as compound (1)/.

Test 1.

Inhibition of TXA2synthetase.

(a) Method of testing:

Treated with aspirin microsome human platelet (APM, Ran Biochem, Is real) was used as a source TXA2synthetase. APM suspended in 50 mm Tris/100 mm NaCl buffer (pH 7.5). Then, 90 μl of the suspension APM was added 10 μl of a solution of the test compound and the resulting mixture was incubated for 3 min at 25oC. And then the mixture was added 2 μl of PGH2(10 ág/ml in acetone, Ran Biochem). After 3 minutes of incubation the reaction was stopped by adding 10 μl of a solution of FeCl2(25 mm H2O) and left at room temperature for 15 min, and then cooled with ice. The reaction mixture was centrifuged at 10,000 rpm for 5 min at 4oC. TXB2in the supernatant was measured using a radioimmunoassay analysis. IC50(dose, most TXB2-generate 50%) was determined graphically.

(C) test Result:

IC50

(a) Method of testing:

Human blood was taken from healthy donors-men and was mixed with 3.8 wt. /about. sodium citrate in the ratio of 9:1. From blood treated with citrate by centrifugation at 150 x g for 15 min, got the plasma rich in platelets (PRP). Platelet aggregation in PRP was studied photometrically using aggregometer (NKK HAEMAT-PACEP 1). Then to 225 μl of PRP was added 25 μl of a solution of the test compound and stirred at 1000 rpm for 2 min at 37oC. To this solution as an aggregation inducer was added 5 μl I (final quantity of 1.0 μm).

(C) test Result:

IC50test connections 1 2,710-7M

The target compound (1) or its pharmaceutically acceptable salt can be introduced mammals, including humans, in the form of a standard pharmaceutical composition, such as capsule, microcapsule, tablet, granule, powder, toffee, cheese, aerosol medication for inhalation solution drug for injection, suspension, emulsion, suppository, salve, nose drops, eye drops or the like.

The pharmaceutical composition according to the invention can contain various organic or reorganize the oz, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, calcium carbonate, etc.,), binding agent (e.g., cellulose, methylcellulose, hydroxypropylcellulose, polipropilenglicol, gelatin, Arabic gum, polyethylene glycol, sucrose, starch, etc.,), a disintegrator (e.g. starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, oxypropylated starch, sodium-glycol-starch, sodium bicarbonate, calcium phosphate, calcium citrate, etc.,), a lubricant (for example, sodium stearate, talc, sodium lauryl sulfate, etc.,), flavoring agent (such as citric acid, menthol, glycine, orange powder, etc.) protecting agent (e.g., sodium benzoate, sodium bisulfite, methylparaben, propylparaben, etc.,), a stabilizer (for example, citric acid, sodium citrate, acetic acid, etc.,), suspendisse agent (for example, methylcellulose, polyvinylpyrrolidine, aluminum stearate, etc.,), dispersing agent, a diluent (e.g. water), a wax medium (for example, cocoa butter, polyethylene glycol, white petrolatum, etc.,).

The active ingredient can be entered 1-4 times per day in a single dose of 0.01 mg/kg to 50 mg/kg, However, this dose can the P CLASS="ptx2">

Example 1. (1) a Solution of (2S, 4R)-4-(4-chlorophenylsulfonyl)-2- [(Z)-5-methyloxycarbonyl-1-pentenyl] -1-(3-pyridylmethyl) pyrrolidine (670 mg) in a mixture of methanol (5 ml) and 1N. aqueous sodium hydroxide (3 ml) was stirred for 4 h at room temperature. the pH of the solution was brought to 5 with 10% hydrochloric acid and then the solution was extracted with chloroform. The organic solution was washed with salt solution. The solution was dried over magnesium sulfate, and the solvent evaporated in vacuum. The residue was chromatographically on a column of silica gel (20 g), elwira with a mixture of chloroform and methanol (20: 1), resulting in the received connection (2S, 4R-2-[(Z)-5-carboxy-1-pentenyl] -4-(4-course-sulfonylamino)-1-(3-pyridyl)methyl pyrrolidine (408 mg) as an amorphous substance pale yellow color.

1H-NMR (CDCI3) million dollars. 1,6-of 1.75 (2H, m), 1,8-1,9 (2H, m), from 2.1 to 2.25 (2H, m), of 2.38 (2H, m), of 3.13 (1H, DD, J=7,5, 10 Hz) to 3.41 (1H, d, J=13.5 Hz), to 3.67 (1H, sq J=8 Hz), 3,82 (1H, m), 3,9 (1H, d, J=13.5 Hz), are 5.36 (1H, t, J= 10Hz), 5,62 (1H, dt, J=10, and 11.5 Hz), 7,34 (1H, m), 7, 42 (2H, d, J=8.5 Hz), 7,74 (1H, m), 7,76 (2H, d, J=8.5 Hz), 8,45-8,55 (2H, m).

The following compounds were obtained by the method similar to that described in example 1 (1).

(2) (2S, 4R)-2-[(Z)-5-carboxy-1-pentenyl] -4- (4-chlorophenylsulfonyl)-1-(2-pyridylmethyl)pin.

(4) (2S, 4R)-2-[(Z)-2-(4-carboxyphenyl)vinyl]-4- (4-chlorophenylsulfonyl)-1-(3-pyridylmethyl pyrrolidin.

1H-NMR (DMCO-d6) (d) mln: 1,80 (2H, t, J=6.5 Hz), 1,90 (1H, t, J=8,5 Hz), and 2.83 (1H, t, J=8.5 Hz), 3,12 (1H, d, J=13.5 Hz), 3,35-the 3.65 (3H, m), 3,68 (1H, d, J=13.5 Hz), 5,62 (1H, DD, J=11.5 Hz), 6,62 (1H, d, J=11.5 Hz), from 7.24 (1H, DD, J= 4.5 Hz), 7,31 (2H, d, J=7.5 Hz), 7,44 (1H, d, J=4.5 Hz), 7,31 (2H, d, J=7.5 Hz), 7,44 (1H, d, J=7.5 Hz), a 7.62 (2H, d, J=8.5 Hz), 7,88 (2H, d, J=8.5 Hz), 7,94 (2H, d, J=7.5 Hz), 8,03 (1H, m), of 8.28 (1H, s), 8,39 (1H, d, J=4.5 Hz).

(5) (2S, 4R)-2-[(Z)-2-(3-carboxyphenyl)vinyl]-4- (4-chlorophenylsulfonyl)-1-(3-pyridylmethyl)pyrrolidine.

1H-NMR (D-16d million dollars. of 1.78 (2H, t, J=6.5 Hz), 1,90 (1H, t, J=8.5 Hz), 2,72 (1H, t, J=8.5 Hz), 3,13 (1H, d, J=13.5 Hz), 3,3-3,6 (2H, m), and 3.72 (1H, d, J= 13.5 Hz), the ceiling of 5.60 (1H, DD, J=11,5,9 Hz), 6,62 (1H, d, J=11.5 Hz), 7,20 (1H, DD, J=4,7,5 Hz), 7,4-7,6 (3H, m), of 7.64 (1H, d, J=8 Hz), 7,75-7,9 (4H, m), of 8.06 (1H, d, J=7.5 Hz), of 8.27 (1H, m), scored 8.38 (1H, m).

Example 2. (1) To a mixture of (2S, 4R)-4-(4-chlorophenylsulfonyl)-2- [(Z)-5-methoxycarbonyl-1-pentenyl] pyrrolidine (356 mg) and nicotinamide (98,6 mg) in methanol (5 ml) was added acetic acid (0.1 ml) and cyanoborohydride sodium (58 mg) and the resulting mixture was stirred for 3 h at room temperature. Then to this solution was added saturated aqueous sodium carbonate (20 ml) and the resulting aqueous solution was extracted with chloroform (50 ml). Org is Ali in vacuum, and the residue was chromatographically on a column of silica gel (10 g), elwira with a mixture of chloroform and methanol (99:1), resulting in the received connection (2S, 4R)-4-(4-chlorophenylsulfonyl)-2- [(Z)-5-methoxycarbonyl-1-pentenyl] -1-(3-pyridylmethyl)pyrrolidine (340 mg).

The following compounds were obtained in a manner analogous to that described in example 2 (1).

(2) (2S, 4R)-1-benzyl-4-(4-chlorophenylsulfonyl)- 2[(Z)-5-methoxycarbonyl-1-pentenyl]pyrrolidin.

1H-NMR (CDCI3d million dollars. 1,2-2,0 (5H, m) 2,07 (2H, q, J=6.5 Hz), 2,31 (2H, t, J=6.5 Hz), to 3.0-3.2 (2H, m) to 3.33 (1H, q, J=8.5 Hz), 3,68 (3H, s), 3,63 (1H, m), 3,86 (1H, d, J=12,5 Hz), 4,96 (1H, d, J=8.5 Hz), 5,31 (1H, DD, J= 9,5,10,5 Hz), of 5.53 (1H, dt, J=10.5 Hz), 7,1-7,3 5H, m), 7,44 (2H, d, J=8.5 Hz), to 7.77 (2H, d, J=8,5 Hz).

(3)(2S, 4R)-1-(4-chlorophenylacetyl)-4-(4-chlorophenylsulfonyl) -2-[(Z)-5-methoxycarbonyl-1-pentenyl]-pyrrolidin.

1H-NMR (CDCI3d million dollars. 1,6-2,0 (5H, m), of 2.08 (1H, m), 2,28 (2H, t, J= 7.0 Hz), totaling 3.04 (2H, m), 3,32 (1H, q, J=7 Hz), 3,68 (1H, m), of 3.69 (3H, s) is 3.82 (1H, d, J=12,5 Hz), a 4.83 (1H, d, J=7.5 Hz), from 5.29 (1H, t, J=10 Hz), of 5.50 (1H, dt, J=10,8 Hz), 7,12 (2H, d, J=8 Hz), 7,32 (2H, d, J=8 Hz), of 7.48 (2H, d, J=8.5 Hz), 7,79 (2H, d, J=8,5 Hz).

(4)(2S, 4R)-4-(4-chlorophenylsulfonyl)-2- [(Z)-5-methoxycarbonyl-1-pentenyl]-1-(4-methylphenylethyl)-pyrrolidin.

1H-NMR (CDCI3d million dollars. 1,6-1,8 (4H, m), 1,8-2,0 is), 5,52 (1H, d, J=11,7,5 Hz), 7,0-to 7.15 (4H, m), 7,54 (1H, d, J=9 Hz), 7,76 (2H, d, J=9 Hz).

(5)(2S, 4R)-4-(4-chlorophenylsulfonyl)-2- [(Z)-5-methoxycarbonyl-1-pentenyl]-1-(4-methoxyphenethyl)-pyrrolidin.

1H-NMR (CDCI3d million dollars. 1,6-1,9 (5H, m), 2.05 is-of 2.15 (2H, m), is 2.30 (2H, t, J=7.5 Hz), 3,00 (1H, d, J=13 Hz), 3,06 (1H, DD, J=10, 7.5 Hz), 3,29 (1H, q, J= 9 Hz), of 3.69 (3H, s), 3,7-of 3.85 (2H, m), of 3.80 (3H, s), 4,84 (1H, d, J= 7.5 Hz), and 5.30 (1H, t, J=10 Hz), 5,52 (1H, dt, J=10, 7.5 Hz), for 6.81 (2H, d, J= 9 Hz), to 7.09 (2H, d, J=9 Hz), was 7.45 (2H, d, J=9 Hz), to 7.77(2H, d, J=9 Hz).

(6)(2S, 4R)-4-(4-chlorophenylsulfonyl)-1- (3,4-dichlorophenylethyl)-2-[(Z)-5-methoxycarbonyl-1-pentenyl]pyrrolidin.

1H-NMR (CDCI3d million dollars. 1,6-2,0 (5H, m), a 2.0 to 2.15 (2H, m), is 2.30 (2H, t, J= 7 Hz), 3.04 from (1H, d, J=14 Hz), to 3.09 (1H, DD, J=7,5, 10 Hz), the 3.35 (1H, q, J= 10 Hz) to 3.67 (3H, s), of 3.73 (1H, m), 3,80 (1H, d, J=14 Hz), 4,80 (1H, d, J=7.5 Hz), 5,27 (1H, d, J=11 Hz), of 5.53 (1H, dt, J=11, 7.5 Hz), 7,02 (1H, DD, J= 3, 10 Hz), 7,2-7,4 (2H, m), 7,47 (2H, d, J=9 Hz), 7,78 (2H, d, J=9 Hz).

(7) (2S, 4R)-4-(4-chlorophenylsulfonyl)-2- [(Z)-5-methoxycarbonyl-1-pentenyl]-1-(4-phenylphenolate)-pyrrolidin.

1H-NMR (CDCI3d million dollars. of 1.6-1.8 (3H, m), of 1.95 (1H, m), of 2.08 (2H, m), 2,31 (1H, t, J=7.5 Hz), 3,11 (1H, d, J=14 Hz) and 3.15 (1H, t, J=7 Hz), to 3.36 (1H, q, J=7.5 Hz), 3,71 (1H, s), 3,85 (1H, m), 3,91 (1H, d, J=14 Hz), 4,80 (1H, d, J=7.5 Hz), of 5.34 (1H, t, J=10 Hz), of 5.55 (1H, dt, J=10, 7.5 Hz), 7,19 (2H, d, J=9 Hz), 7.3 to the 7.65 (9H, m), 7,83 (2H, d, J=9 Hz).

(8)(2S, 4R)-4-(4-chlorophenyl>d million dollars. 1.55V and 1.80 (4H, m), 1,9-of 2.15 (3H, m), is 2.30 (2H, t, J= 7.5 Hz), is 3.08 (1H, m) and 3.15 (1H, d, J=14 Hz), to 3.38 (1H, q, J=9 Hz), of 3.69 (3H, s), 3,76 (1H, m), 3,92 (1H, d, J=14 Hz), 5,00 (1H, m), 5.25-inch (1H, DD, J= 10, GC), of 5.53 (1H, dt, J=10, 7.5 Hz), 7,32 (2H, d, J=9 Hz), 7,46 (2H, d, J=9 Hz), to 7.59 (2H, d, J=9 Hz), 7,78 (2H, d, J= 9 Hz).

(9)(2S, 4R)-4-(4-chlorophenylsulfonyl)-1-(2-hydroxyphenylethyl)-2-[(Z)-5-methoxycarbonyl-1-pentenyl]-pyrrolidin.

1H-NMR (CDCI3d million dollars. 1,6-of 1.75 (2H, m) to 1.87 (2H, m), is 2.05 (2H, d, J= 7 Hz), of 2.16 (1H, m), 2,28 (2H, t, J=7 Hz), 3,23 (1H, d, J=13 Hz) at 3.25 (1H, DD, J=6, 11 Hz), 3,52 (1H, q, J=7.5 Hz), and 3.72 (1H, s), 3,81 (1H, m), to 4.17 (1H, d, J=13 Hz), 5,32 (1H, t, J=10 Hz), 5,61 (1H, dt, J=6, 7.5 Hz), 6,77 (2H, d, J=9 Hz), 6,91 (1H, d, J=7 Hz), 7,14 (1H, dt, J=7, 1 Hz), 7,47 (2H, d, J=9 Hz), 7,78 (2H, d, J=9 Hz).

(10) (2S, 4R)-4-(4-chlorophenylsulfonyl)-2- [(Z)-5-methoxycarbonyl-1-pentenyl]-1-1(2-thienylmethyl)pyrrolidin.

1H-NMR (CDCI3d million dollars. 1,6-1,9 (4H, m), 2.05 is-of 2.15 (3H, m), is 2.30 (2H, t, J=7.5 Hz), 3,9 (1H, DD, J=7.5 Hz), 10 Hz), 3,39 (1H, q, J=7.5 Hz), 3,47 (1H, d, J=15 Hz), 482 (1H, Shir. C), and 5.30 (1H, t, J=10 Hz), 5,54 (1H, dt, J= 10, 7.5 Hz), to 6.80 (1H, DD, J=1, 5 Hz), 7,56 (2H, d, J=9 Hz), 7,78 (2H, d, J= 9 Hz).

(11) (2S, 4R)-4-(4-chlorophenylsulfonyl)-1-(2 - furylmethyl)-2-[(Z)-5-methoxycarbonyl-1-pentenyl]-pyrrolidin.

1H-NMR (CDCI3d million dollars. 1,6-of 1.95 (5H, m), a 2.0 to 2.15 (2H, m), is 2.30 (2H, t, J= 7.5 Hz), 3,15 and 3.4 (3H, m), 3,68 (3H, s), of 3.78 (1H, d, J=15 Hz), 3,81 (1H, m), 4,82 (1H, d, J=9 Hz), 5,27 (1H, t, is sulfonylamino)-2- [(Z)-5-methoxycarbonyl-1-pentenyl]-1-(2-perineometer)-pyrrolidin.

1H-NMR (CDCI3d million dollars. 1,6-1,9 (4H, m), is 2.05 (2H, m), and 2.26 (1H, m), 2,28 (2H, t, J=6.5 Hz) at 3.25 (1H, DD, J=10, 7.5 Hz), 3,51 (1H, d, J=14 Hz), 3,53 (1H, m), 3,68 (3H, s), a-3.84 (1H, m), was 4.02 (1H, d, J=14 Hz), 5,2 to 5.35 (2H, m) 5,52 (1H, dt, J=10, 7 Hz), 7,47 (2H, d, J=8.5 Hz), 7,78 (2H, d, J= 8.5 Hz), 8,45-8,55 (3H, m).

(13) (2S, 4R)-4-(4-chlorophenylsulfonyl)-1-hexyl)-2- [(Z)-5-methoxycarbonyl-1-pentenyl]pyrrolidin.

1H-NMR (CDCI3d million dollars. of 0.87 (3H, t, J=7 Hz), 1,2-1,4 (8H, m), 1,6-1,8 (4H, m), 1,9-2,1 (4H, m), is 2.30 (2H, t, J=7 Hz), 2,59 (1H, dt, J=7, 13 Hz), 3,17 (1H, q, J=8 Hz), to 3.36 (1H, DD, J=7,5, 10 Hz), 3,70 (3H, s), of 3.80 (1H, m), a 4.86 (1H, Shir,), 5,20 (1H, DD, J=10, 11 Hz), vs. 5.47 (1H, dt, J=11, 7.5 Hz), to 7.50 (2H, d, J=9 Hz), 7,81 (2H, d, J=9 Hz).

(14) (2S, 4R)-4-(4-chlorophenylsulfonyl)-2- [(Z)-5-methoxycarbonyl-1-pentenyl]-1-(2-phenylethyl) pyrrolidin.

1H-NMR (CDCI3d million dollars. 1,6-of 1.85 (4H, m), 2,0-2,1 (3H, m), 2,25-2,4 (3H, m), 2,6-of 2.75 (2H, m), 2,85 (1H, DD, J=10, 13 Hz), to 3.38 (1H, q, J=8 Hz), 3,43 (1H, DD, J=10, 7.5 Hz), the 3.65 (3H, s), 3,81 (1H, m), of 4.95 (1H, d, J= 7.5 Hz), to 5.21 (1H, t, J=10 Hz), of 5.48 (1H, dt, J=10, 7.5 Hz), 7,05-to 7.35 (5H, m) to 7.50 (2H, d, J=9 Hz), 7,71 (2H, d, J=9 Hz).

(15) (2S, 4R)-4-(4-chlorophenylsulfonyl)-2- [(Z)-5-methoxy-carbonyl-1-pentenyl]-1-(3-phenylpropyl)pyrrolidine.

1H-NMR (CDCI3d million dollars. 1,6-of 1.85 (6H, m), are 1.95 and 2.1 (4H, m), 2,28 (2H, t, J= 7.5 Hz), 2,5-2,7 (3H, m), 3,19 (1H, q, J=9 Hz), 3,37 (1H, J=10, 7.5 Hz), 3,68 (3H, s), 3,80 (1H, m), 5,20 (1H, t, J=10 Hz), 5,46 (1H, DD, J=7.5 to 12 Hz), 7,1-7,3 (5H, m), 7,(3-pyridylmethyl)pyrrolidine.

1H-NMR (CDCI3d million dollars. 1,7-1,9 (2H, m), from 2.00 (1H, m), 2.3 to 2.4 (4H, m), is 3.08 (1H, DD, J=6,10 Hz), 3,13 (1H, d, J=14 Hz), 3,42 (1H, q, J=Hz), 3,66 (3H, s), of 3.78 (1H, m), 3,35 (1H, d, J=14 Hz), 5,24 (1H, d, J=7.5 Hz), 5,28 (1H, t, J= 10 Hz), a 5.4 to 5.6 (1H, m), 7,22 (1H, DD, J=5, 7.5 Hz), was 7.45 (2H, d, J=9 Hz), 7,56 (1H, m), 7,78 (2H, d, J=9 Hz), 8,4-8,6 (2H, m).

Example 3. A solution of (2S, 4R)-1-benzyl-4-(4-chlorophenylsulfonyl)-2- [(Z)-5-methoxycarbonyl-1-pentenyl] -pyrrolidine (320 mg) in a mixture of methanol (5 ml) and 1 n sodium hydroxide (3 ml) was stirred for 3 hours at room temperature, and the volatile solvent evaporated in vacuum. To the residue was added water (20 ml) and the pH of the aqueous solution was brought to a value of 7 using 1N. of hydrochloric acid. The precipitated solid was collected by filtration and dried under vacuum, resulting in the received connection (2S, 4R)-1-benzyl-2-[(Z)-5-methoxycarbonyl-1-pentenyl] -4- (4-chlorophenylsulfonyl)-pyrrolidine (176 mg).

So pl. 87-91oC.

1H-NMR (CDCI3d million dollars. 1,71 (2H, m), 2,02 (2H, m), 2,17 (2H, m), and 2.26 (2H, t, J=6.5 Hz), 2,46 (1H, DD, J=11 Hz), 3,10 (1H, DD, J=6,5, 11 Hz), the 3.65 (1H, d, J=12,5 Hz), 3,9-4,0 (2H, m), 4,11 (1H, m), the 5.45 (1H, t, J=10 Hz), 5,73 (1H, dt, J=10, 7.5 Hz), 7.23 percent (5H, s), 7,38 (2H, d, J=8.5 Hz), 7,76 (2H, d, J=8,5 Hz).

Example 4. The following compounds were obtained by methods similar to the methods described in Primera.

1H-NMR (CDCI3d million dollars. 1,6-of 1.75 (2H, m), 2.05 is-with 2.2 (4H, m), 2.3 to 2.4 (2H, m), of 2.92 (1H, m), of 3.54 (1H, m), a 4.03 (1H, m), of 4.12 (1H, d, J=14 Hz), and 4.40 (1H, d, J= 14 Hz), 4,48 (1H, m), 5.5 to 5.7 (2H, m), 7,35 (2H, d, J=8.5 Hz), 7,5-a 7.85 (6H, m), 8,07 (1H, d, J=8.5 Hz), 8,18 (1H, d, J=8,5 Hz).

(2) (2S, 4R)-1-(2-benzoxazolyl)-2- [(Z)-5-carboxy-1-pentenyl]-4-(4-chlorophenylsulfonyl)pyrrolidin.

1H-NMR (CDCI3d million dollars. of 1.55 to 1.7 (2H, m), 1,75-of 2.05 (4H, m), and 2.26 (2H, t, J= 7 Hz), 2,58 (1H, DD, J=2, 10 Hz), 3,44 (1H, DD, J=7, 10 Hz), 3,85-of 4.05 (2H, m), of 3.97 (1H, d, J=16 Hz), 4,12 (1H, d, J=16 Hz), 5,28 (1H, t, J=10 Hz), of 5.53 (1H, dt, J=10, 7 Hz), 7,3 was 7.45 (4H, m), 7,52 (1H, m), 7,78 (1H, d, J=8.5 Hz), 7,80 (1H, m).

(3) (2S, 4R)--2-[(Z)-5-carboxy-1-pentenyl]-4- (4-chlorophenylsulfonyl)-1-(2-personality)pyrrolidin.

1H-NMR (CDCI3d million dollars. of 1.66 (2H, m) to 1.87 (2H, m), 2,10 (2H, m), 2,3-2,4 (3H, m), 3,21 (1H, m), 3,57 (1H, d, J=14 Hz), 3,68 (1H, m), 3,85 (1H, m), was 4.02 (1H, d, J=14 Hz), and 5.30 (1H, t, J=10 Hz), 5,54 (1H, dt, J=10, 7 Hz)that was 7.45 (2H, d, J=8.5 Hz), 7,78 (2H, d, J=8.5 Hz), 8,5-8,55 (2H, m), 8,58 (1H, m).

(4) (2S, 4R)-2[(Z)-4-carboxy-1-butenyl]-4- (4-chlorophenylsulfonyl)-1-(3-pyridylmethyl)pyrrolidine.

1H-NMR (CDCI3d million dollars. of 1.85 (2H, m), 2,3-2,5 (4H, m), 3,05 (1H, DD, J= 10, 7 Hz), or 3.28 (1H, d, J=13 Hz), the 3.65 (1H, q, J=9 Hz), 3,70 (1H, m), 3,82 (1H, d, J=13 Hz), 6,30 (1H, t, J=10 Hz), to 5.58 (1H, m), 7,27 (1H, m), 7,41 (2H, d, J=9 Hz), 7,53 (1H, d, J=7.5 Hz), 7,76 (2H, d, J=9 Hz), 8,35 to 8.5 (2H, m).

(5) (2S, 4R)-2[(Z)-5-carboxy-1-p is(2H, m) of 1.85 (2H, m), and 2.14 (2H, m), 2,2-2,4 (3H, m), of 3.12 (1H, DD, J=7, 9 Hz), to 3.41 (1H, d, J=13.5 Hz), 3,68 (1H, m), 3,85 (1H, m), of 3.96 (1H, d, J=13.5 Hz), are 5.36 (1H, t, J=10 Hz), the ceiling of 5.60 (1H, dt, J= 10, 7 Hz), 7,30 (1H, DD, J=5, 7 Hz), 7,4-of 7.55 (3H, m), 7,7-7,8 (3H, m), and 8.4 to 8.5 (2H, m).

(6) (2S, 4R)-[(Z)-5-carboxy-1-pentenyl]-1-(4-chlorophenylacetyl)- 4-(4-chlorophenylsulfonyl)-pyrrolidin.

So pl. 84-86oC.

1H-NMR (CDCI3d million dollars. was 1.69 (2H, m) to 1.98 (2H, m), of 2.15 (2H, m), 2,28 (2H, m), 2,43 (2H, DD, J=5,11 Hz), and 3.16 (1H, m), 3,57 (1H, d, J=12,5 Hz), 3,85 of 4.1 (3H, m), 5,43 (1H, t, J=10 Hz), of 5.68 (1H, m), 7,15-of 7.25 (4H, m), 7,42 (2H, d, J=8.5 Hz), to 7.77 (2H, d, J=8,5 Hz).

(7) (2S, 4R)-2-[(Z)-5-carboxy-1-pentenyl]-4- (4-chlorophenylsulfonyl)-1-(4-methylphenylethyl)-pyrrolidin.

1H-NMR (CDCI3d million dollars. 1,6-1,8 (2H, m), 1,9-2,1 (2H, m), of 2.1-2.4 (4H, m), 2,31 (3H, m), 2,43 (1H, DD, J=5, 11 Hz), 3,05 (1H, DD, J=7, 11 Hz), to 3.64 (1H, d, J=13 Hz), 3,93 (1H, d, J=13 Hz), of 3.95 (1H, m), of 4.12 (1H, m), the 5.45 (1H, t, J=10 Hz), 5,74 (1H, dt, J=10, 7.5 Hz), was 7.08 (2H, d, J=7 Hz), to 7.15 (2H, d, J=7 Hz), 7,40 (2H, d, J=9 Hz), of 7.75 (2H, d, J=9 Hz).

(8) (2S, 4R)-2-[(Z)-5-carboxy-1-pentenyl]-4- (4-chlorophenylsulfonyl)-1-(4-methoxyphenethyl)-pyrrolidin.

1H-NMR (CDCI3d million dollars. 1,6-1,8 (2H, m), from 2.00 (2H, m), 2,15-2,3 (4H, m), of 2.45 (1H, DD, J=5, 12 Hz), is 3.08 (1H, DD, J=7,5, 12 Hz), 3, 59 (1H, d, J= 13 Hz), of 3.78 (3H, s), 3,82 (1H, d, J=13 Hz), of 3.95 (1H, m) 4,06 (1H, q, J= 7.5 Hz), 5,42 (1H, t, J=10 Hz), 5,72 (1H, dt, J=10, 7.5 Hz), to 6.80 (2H, d, J= 9 Hz), 7,16 (2H, d, J=9 Hz), 7,40 (2H, l, J is lmutil)-pyrrolidin.

1H-NMR (CDCI3d million dollars. 1,6-of 1.75 (2H, m), 1,9-of 2.05 (2H, m), from 2.1 to 2.25 (2H, m), 2,3 at 2.45 (3H, m), 3,17 (1H, m), 3,42 (1H, m), 3.75 to 4,0 (3H, m), 5,42 (1H, t, J=10 Hz), 5,67 (1H, dt, J=10, 7 Hz), and 7.1 to 7.4 (3H, m), 7,46 (2H, d, J=9 Hz), 7,78 (2H, d, J=9 Hz).

(10) (2S, 4R)-2-[(Z)-5-carboxy-1-pentenyl]-4 - (chlorophenylsulfonyl)-1-(4-phenylphenolate)-pyrrolidin.

1H-NMR (CDCI3d million dollars. 1,55-1,8 (2H, m), 1.85 to a 2.0 (2H, m), 2,15-2,3 (2H, m), 2.3 to 2.4 (2H, m), 3,11 (1H, DD, J=7.5 to 12 Hz), 3,52 (1H, d, J=13 Hz), 3,8-4,0 (3H, m), of 5.40 (1H, t, J=12 Hz), 5,69 (1H, dt, J=12, 7.5 Hz), to 7.15 (2H, d, J=9 Hz), 7,35 and 7.6 (9H, m), 7,83 (2H, d, J=9 Hz).

(11) (2S, 4R)-2-[(Z)-5-carboxy-1-pentenyl]-4- (4-chlorophenylsulfonyl)-1-(4-cyanovinylene)-pyrrolidin.

1H-NMR (CDCI3d million dollars. to 1.67 (2H, m), a 1.88 (2H, m), by 2.0-2.4 (5H, m), 3,10 (1H, m) to 3.36 (1H, d J=14 Hz), 3,37 (1H, m), 3,70 (1H, m), 3,85 (1H, m), 3,95 (1H, d J=14 Hz), to 5.35 (1H, t, J=10 Hz), 5,62 (1H, dt, J=10, 7.5 Hz), 7,37 (2H, d, J=9 Hz), the 7.43 (2H, d, J=9 Hz), 7,56 (2H, d, J=9 Hz), 7,78 (2H, l, J=9 Hz).

(12) (2S, 4R)-2-[(Z)-5-carboxy-1-pentenyl]-4- (4-chlorophenylsulfonyl)-1-(2-hydroxyphenylethyl)-pyrrolidin.

1H-NMR (CDCI3+ CD3OD) d million dollars. 1,6-of 1.75 (2H, m), of 2.0-2.2 (4H, m), of 2.33 (2H, t, J=6.5 Hz), 2,70 (1H, DD, J=5,5, 11 Hz), to 3.41 (1H, DD, J=6,5, 11 Hz), to 3.64 (1H, d, J=13 Hz), 3,85-of 4.05 (2H, m), of 4.77 (1H, d, J=13 Hz), vs. 5.47 (1H, t, J=10 Hz), 5,73 (1H, dt, 110, 7.5 Hz), for 6.81 (2H, d, J=7.5 Hz), 7,10 (1H, DD, J= 7,5, 10 Hz), 7,21 (1H, dt, J=1, 7.5 Hz), of 7.48 (1H, d, J=9 Hz), 7,78 (1H, d, J=9 Hz).

(14) (2S, 4R)-2-[(Z)-5-carboxy-1-pentenyl]-4 - (chlorophenylsulfonyl)-1-(2-furylmethyl)pyrrolidin.

1H-NMR (CDCI3d million dollars. 1,6-of 1.75 (2H, m), 1,8-2,95 (2H, m), 2.1 a and 2.1 (2H, m), 2,25-2,4 (2H, m), 3,20 (1H, DD, J=11, 7.5 Hz), 3,51 (1H, d, J=14 Hz), 3.6 and 4.0 (3H, m), 5,32 (1H, t, J=10 Hz), the 5.65 (1H, dt, J=10, 7.5 Hz), to 6.19 (1H, d, J=3 Hz), 6,30 (1H, DD, J=3, 1.5 Hz), 7,32 (1H, d, J=1.5 Hz), the 7.43 (2H, d, J=9 Hz), 7,8 (2H, d, J=9 Hz).

(15) (2S, 4R)-2-[(Z)-5-carboxy-1-pentenyl]-4- (4-chlorophenylsulfonyl)-1-hexyl-pyrrolidin.

1H-NMR (CDCI3d million dollars. of 0.83 (3H, t, J=7 Hz), 1,15-1,35 (8H, m), 1,5-1,8 (4H, m), 2.05 is a 2.3 (5H, m), 2,73 (1H, m), 3,06 (1H, DD, J=4, 13 Hz), to 3.38 (1H, DD, J= 7, 10 Hz), 4.09 to (1H, m), 4,35 (1H, m), of 5.40 (1H, t, J=10 Hz), 5,79 (1H, dt, J=10, 7.5 Hz), 7,49 (1H, d, J=9 Hz), the 7.85 (1H, d, J=9 Hz).

(16) (2S, 4R)-2-[(Z)-5-carboxy-1-pentenyl] -4- (4-chlorophenylsulfonyl)-1-(2-phenetyl)pyrrolidin.

1H-NMR (CDCI3d million dollars. 1,55-1,8 (2H, m), of 2.0 to 2.35 (5H, m), 2,48 (1H, m), 2,8-3,1 (4H, m), 3,3-3,6 (2H, m), is 4.15 (1H, m), 4,37 (1H, m), 5,41 (1H, t, J=10 Hz) 5,72 (1H, m), 4,37 (1H, m), 5,41 (1H, t, J=10 Hz), 5,72 (1H, dt, J=10, 7.5 Hz), 7,0 is 7.3 (5H, m), 7,45 (2H, d, J=9 Hz), 7,81 (2H, d, J=9 Hz).

(17) (2S, 4R)(CDCI3d million dollars. 1,5-1,8 (2H, m), 1,92,3 (7H, m), 2,55-to 2.65 (3H, m), 2.91 in (2H, m), 3,18 (1H, d, J=13 Hz), 3,63 (1H, m), 4,08 (1H, m), 4,48 (1H, m), 5 (1H, t, J=10 Hz), 5,79 (1H, dt, J=10, 7.5 Hz), 7,0 is 7.3 (5H, m), 7,41 (2H, d, J=9 Hz), 7,81 (2H, d, J=9 Hz).

(18) (2S, 4R)-1-/(2-beautiesroomates)-2-[(Z)-5-carboxy-1-pentenyl] -4-(4-chlorophenylsulfonyl)-pyrrolidin.

Example 5. (2S, 4R)-1-(2-benzothiazolylthio)-2- [(Z)-5-methoxycarbonyl-1-pentenyl] -4-(4-chlorophenylsulfonyl) pyrrolidine was dissolved in 1 n sodium hydroxide and the solution was injected into the column Diai on 20 HP. The column was washed with water and suirable 70% aqueous methanol. The desired fractions were collected, and the volatile solvent evaporated in vacuum. The resulting aqueous solution was liofilizovane to obtain the sodium salt of compound (2S, 4R)-1-(2-benzothiazolylthio)-2- [(Z)-5-carboxy-1-pentenyl] -4-(4-chlorophenylsulfonyl)pyrrolidin.

1H-NMR (D2O) d million dollars. to 1.45 (2H, m) to 1.70 (2H, t, J=7 Hz), 1,9-2,1 (5H, m), of 2.81 (1H, m), 3,4-3,6 (2H, m), 3,1 (1H, d, J=14 Hz), 4,00 (1H, d, J= 14 Hz), 5,1 (1H, t, J=10 Hz), 5,42(1H, dt, J=10, 7 Hz), 7,2 (2H, d, J=8.5 Hz), 7,25 was 7.45 (2H, d, J=8.5 Hz), 7,81 (2H, d, J=8,5 Hz).

Example 6. The following compounds were obtained in a manner analogous to the method described in example 2 (1).

(1) (2S, 4R)-4-(4-chlorophenylsulfonyl)-2- [(Z)-5-methoxycarbonyl-1-pentenyl]-1-(3-pinolillo is, ,30 (1H, d, J=13.5 Hz), 3,43 (1H, q, J=9 Hz), 3,68 (3H, s), of 3.77 (1H, m), of 4.05 (1H, d, J=13.5 Hz), 4,91 (1H, d, J=7.5 Hz), to 5.35 (1H, t, J=10 Hz), to 5.58 (1H, dt, J=10, 7.5 Hz), 7,42 (2H, d, J=8,5 Hz), at 7.55 (1H, m), 7,65 one-7.8 (4H, m), of 7.96 (1H, m), 8,10 (1H, d, J=8 Hz), 8,81 (1H, d, J=1.5 Hz).

(2) (2S, 4R)-4-(4-chlorophenylsulfonyl)-2- [(Z)-5-methoxycarbonyl-1-pentenyl]-1-(1-naphthylmethyl)-pyrrolidin.

1H-NMR (CDCI3d million dollars. 1,6-2,0 (4H, m) to 2.18 (2H, m), of 2.33 (2H, t, J=7.5 Hz), only 2.91 (1H, DD, J=6, 10 Hz), 3,30 (1H, d, J=12,5 Hz), 3,44 (1H, q, J= 10 Hz), b (3H, s), and 4.40 (1H, d, J=l Hz), of 4.95 (1H, dir, C), 5,46 (1H, DD, J= 10, 9 Hz), 5,63 (1H, dt, J=10, 7.5 Hz), and 7.1 to 7.9 (10H, m), 8,15 (1H, m).

(3) (2S, 4R)-4-(4-chlorophenylsulfonyl)-2- [(Z)-5-methoxycarbonyl-1-pentenyl]-1-(2-naphthylmethyl)-pyrrolidin.

1H-NMR (CDCI3d million dollars. 1,66-2,03 (4H, m), 2,10 (2H, q, J=7.5 Hz), 2,30 (2H, t, J= 7.5 Hz), is 3.08 (1H, DD, J=10, 7.5 Hz), 3,21 (1H, d, J=12,5 Hz), 3,39 (1H, DD, J=7.5 Hz), 3,68 (3H, in), 3.75 (1H, m), was 4.02 (1H, d, J= 12,5 Hz), to 4.92 (1H, Shir. C) are 5.36 (1H, DD, J=10, 11 Hz), to 5.56 (1H, dt, J=11, 7.5 Hz), 7,3-7,5 (5H, m), 7,60 (1H, Shir.C) to 7.67-of 7.90 (5H, m).

(4) (2S, 4R)-1-[(4-acetamidophenyl)methyl]-4- (4-chlorophenylsulfonyl)-2-[(Z)-5-methoxycarbonyl-1-pentenyl] pyrrolidin.

1H-NMR (CDCI3d million dollars. 1,55-of 1.95 (4H, m), of 2.08 (2H, m) of 2.16 (3H, s), is 2.30 (2H, t, J=7.5 Hz), 2.95 and-3,10 (2H, m), 3,30 (2H, q, J=7.5 Hz), 3,68 (3H, in), 3.75 (1H, m), and 3.8 (1H, d, J=12 Hz), and 5.30 (1H, m), of 5.50 (1H, dt, J= 10, 7.5 Hz), 7,10 (2H, d, J=9.5 Hz) 7,41 (2H, d, J=9.5 Hz), was 7.45 (2H, d, J= 10 Gcarbon-1-pentenyl]pyrrolidin.

1H-NMR (CDCI3d million dollars. 1,60-of 2.20 (8H, m), is 2.30 (2H, t, J=7.5 Hz), to 3.02 (1H, d, J=12 Hz), to 3.09 (1H, DD, J=7,5, 10 Hz) and 3.31 (1H, q, J=7.5 Hz), of 3.69 (3H, s), 3,70 (1H, m), 3,80 (1H, d, J=12 Hz), 5,33 (1H, t, J=10 Hz), 5,54 (1H, dt, J=10, 7.5 Hz), only 6.64 (2H, d, J=10 Hz), 7,00 (2H, d, J=10 Hz), 7,44 (2H, d, J=10 Hz), of 7.75 (2H, d, J=10 Hz).

(6) (2S, 4R)-4-(4-chlorophenylsulfonyl)-1- (4-dimethylaminophenyl methyl)-2-[(Z)-5-methoxycarbonyl-1-pentenyl]pyrrolidin.

1H-NMR (CDCI3d million dollars. 1,60-of 1.95 (4H, m), 2,10 (2H, q, J=7.5 Hz), 2,30 (2H, t, J=7.5 Hz), 2,95 (6H, s), 2,90-3,10 (2H, m), with 3.27 (1H, q, J=7.5 Hz), of 3.69 (3H, s), and 3.72 (1H, m), of 3.78 (1H, d, J=12 Hz), 4,80 (1H, Shir.C.), 5,32 (1H, t, J=10 Hz), the 5.51 (1H, dt, J=10, 7.5 Hz), 6,60 (2H, d, J=10 Hz), 7,01 (2H, d, J=10 Hz), was 7.45 (2H, d, J=10 Hz), of 7.75 (2H, d, J=10 Hz).

(7) (2S, 4R)-4-(4-chlorophenylsulfonyl-2- [(Z)-5-methoxycarbonyl-1-pentenyl]-1-(2-pyrrolidinyl)pyrrolidin.

1H-NMR (CDCI3d million dollars. 1,60-of 1.85 (4H, m), 1,95-2,15 (2H, m), is 2.30 (2H, t, J=7.5 Hz), 3,10 (1H, DD, J=7,0, 10 Hz), 3,20 (1H, d, J=12 Hz), 3,32 (1H, q, J=7.5 Hz), of 3.69 (3H, s) to 3.33 (1H, m), of 3.78 (1H, d, J=12 Hz), 5,10 (1H, Shir. C),5,25 (1H, t, J=10 Hz), of 5.50 (1H, dt, J=10, 7,0 Hz), of 5.92 (1H, m) 6,09 (1H, DD, J=2,5,5,0 Hz), 6,69 (1H, DD, J=3,0 5,0 Hz), 7,46 (2H, d, J=10 Hz), 7,78 (2H, d, J=10 Hz), 8,40 (1H, Shir.S.).

(8) (2S, 4R)-1-[(2-course)methyl]-4- (4-chlorophenylsulfonyl)-2-[(Z)-5-methoxycarbonyl-1-pentenyl] pyrrolidin.

1H-NMR (CDCI3d million dollars. 1,60-1,90 (4H, m), 2,10 (3H, m), is 2.30 (2H, t, J=7.5 Hz (2H, d, J=10 Hz), 7,76 (2H, d, J=10 Hz).

(9) (2S, 4R)-4-(4-chlorophenylsulfonyl)-1-ethyl-2- [(Z)-5-methoxycarbonyl-1-pentenyl]pyrrolidin.

1H-NMR (CDCI3d million dollars. to 1.00 (3H, t, J=7.0 Hz), 1.56 to of 1.85 (4H, m), 1,87-of 2.15 (4H, m), is 2.30 (2H, t, J=7.5 Hz), 2,71 (1H, m), 3,20 (1H, m), 3,40 (1H, DD, J=7,5, 10 Hz), of 3.69 (3H, s), 3,81 (1H, m), 5,20 (1H, t, J=10 Hz), 5,49 (1H, dt, J=10, 7.5 Hz), to 7.50 (2H, d, J=10 Hz), 7,81 (2H, d, J=10 Hz).

(10) (2S, 4R)-4-(4-chlorophenylsulfonyl)-1-dodecyl-2- [(Z)-5-methoxycarbonyl-1-pentenyl]pyrrolidin.

1H-NMR (CDCI3d million dollars. to 0.88 (3H, t, J 7.5 Hz), 1,15-of 1.40 (20H, m), 1.55V and 1.80 (4H, m), 1.85 to to 2.15 (4H, m), is 2.30 (2H, t, J=7.5 Hz), 2,60 (1H, dt, J= 7,5, 13 Hz), 3,18 (1H, q, J=7.5 Hz), 3,37 (1H, DD, J=8,0, 10 Hz), 3,70 (3H, s), of 3.80 (1H, m), 4,88 (1H, m), 5,20 (1H, t, J=10 Hz), vs. 5.47 (1H, dt, J= 10, 7.5 Hz), to 7.50 (2H, d, J=10 Hz), 7,82 (2H, d, J=10 Hz).

(11) (2S, 4R)-4-(4-chlorophenylsulfonyl)-2- [(Z)-5-methoxycarbonyl-1-pentenyl]-1-(5-fenilpentil)pyrrolidin.

1H-NMR (CDCI3d million dollars. 1,20-of 1.45(4H, m), 1,50-1,80 (6H, m), 1.85 to 2,10 (4H, m) to 2.29 (2H, t, J=7.5 Hz), 2,58 (1H, m), 2,58 (2H, t, J=8.0 Hz) and 3.15 (1H, q, J= 8.0 Hz), to 3.36 (1H, DD, J=7,5, 10 Hz), 3,68 (3H, s), 3,80 (1H, Shir. C) equal to 4.97 (1H, Shir. C), by 5.18 (1H, t, J=10 Hz), 5,46 (1H, dt, J=10, 7.5 Hz), 7,10-to 7.35 (5H, m) to 7.50 (2H, d, J=10 Hz), 7,82 (2H, d, J=10 Hz)

(12) (2S, 4R)-4-(4-chlorophenylsulfonyl)-2- [(Z)-5-methoxycarbonyl-1-pentenyl]-1-(4-phenylbutyl)pyrrolidin.

1H-NMR (CDCI3d million dollars. of 1.30 and 1.80 =10 Hz), 5,46 (1H, dt, J=10, 7.5 Hz), 7,10-7,34 (5H, m), 7,49 (2H, d, J=10 Hz), 7,80 (2H, d, J=10 Hz).

(13) (2S, 4R)-4-(4-chlorophenylsulfonyl)-2- [(Z)-5-methoxycarbonyl-1-pentenyl]-1-[2-(3-pyridyl)ethyl]-pyrrolidin.

1H-NMR (CDCI3d million dollars. 1,6-1,9 (4H, m), of 2.0-2.2 (3H, m), 2,2-2,4 (3H, m), 2,68 (2H, t, J=6 Hz), 2,84 (1H, m), 3,29 (1H, q, J=8.5 Hz), 3,44 (1H, DD, J=6, 9.5 Hz), 3,63 (3H, s), 3,80 (1H, m), of 5.05-5,20 (2H, m), vs. 5.47 (1H, dt, J=7,5 11 Hz), 7,17 (1H, DD, J=5, 7.5 Hz), 7,45 (1H, m), of 7.48(2H, d, J=8 Hz), 7,80 (2H, d, J=8 Hz), 8,42 (2H, m).

(14) (2S, 4R)-4-(4-chlorophenylsulfonyl-1-[2-(1-imidazolyl)ethyl]-2- [(Z)-5-methoxycarbonyl-1-pentenyl]-pyrrolidin.

1H-NMR (CDCI3d million dollars. 1,6-1,8 (4H, m), of 2.0-2.2 (3H, m) to 2.29 (2H, t, J= 6.5 Hz), 2,50 (1H, m) to 2.94 (1H, m), 3,25-3,4 (2H, m), 3,68 (3H, s), of 3.78 (1H, m), of 3.94 (2H, t, J=6 Hz), 5,07 (1H, t, J=10 Hz), vs. 5.47 (dt, J=10, 7.5 Hz), of 5.68 (1H, Shir. D. J=7 Hz), to 6.88 (1H, s) to 7.0 (1H, s), 7,49 (2H, d, J=8 Hz), to 7.50 (1H, s), 7,78 (2H, d, J=8 Hz).

(15) (2S, 4R)-4-(4-chlorophenylsulfonyl)-2- [(Z)-6-methoxycarbonyl-1-hexenyl]-1-(3-pyridylmethyl)pyrrolidine.

1H-NMR (CDCI3d million dollars. from 1.3 to 1.45 (2H, m), 1,55-1,7 (2H, m) of 1.76 (1H, m), of 1.85 (1H, m), are 1.95 and 2.1 (3H, m), of 2.33 (2H, t, J=7 Hz), is 3.08 (1H, m), 3,11 (1H, d, J= 13.5 Hz), to 3.36 (1H, q, J=8.5 Hz), the 3.65 (3H, in), 3.75 (1H, m), 3,88 (1H, d, J=13.5 Hz), of 5.24 (1H, t, J=8 Hz), 5,54 (1H, dt, J=8, 11 Hz), 7.23 percent (1H, DD, J=4.5 to 7.5 Hz), 7,46 (2H, d, J=8 Hz), 7,54 (1H, m), 7,78 (2H, d, J=8 Hz), and 8.4 to 8.5 (2H, m).

(16) (2S, 4R)-2-[(Z)-5-methoxycarbonyl-1-pentenyl]-1-(3-PIR is -1,90 (4H, m), a 2.0 to 2.15 (3H, m), 2,32 (2H, t, J= 6.5 Hz), 3,10 (1H, m), 3,13 (1H, d, J=13 Hz), 3,40 (1H, q, J=8 Hz), of 3.69 (3H, s), with 3.27 (1H, m) to 3.38 (1H, d, J=13 Hz), 5,2 to 5.35 (2H, m), of 5.55 (1H, dt, J=11, 7 Hz), 7,22 (1H, DD, J=4,5, 7.5 Hz), 7,53 (1H, d, J=7.5 Hz), to 7.77 (2H, d, J=8 Hz), 7,98 (2H, d, J=8 Hz), and 8.4 to 8.5 (2H, m).

(17) (2S, 4R)-2-[(Z)-5-methoxycarbonyl-1-pentenyl]-1 - phenylmethyl-4[4-(trifluoromethyl)phenylcarbonylamino]-pyrrolidin.

1H-NMR (CDCI3d million dollars. of 1.65 and 1.80 (4H, m), 1,80-of 1.95 (2H, m), 2.00 in to 2.15 (2H, m) to 2.29 (2H, t, J=7.5 Hz), 3,05 (1H, d, J=12 Hz), to 3.09 (1H, t, J= 8.0 Hz), 3,30 (1H, m) to 3.67 (3H, in), 3.75 (1H, m), 3,86 (1H, d, J=12 Hz), 5,00 (1H, m), and 5.30 (1H, t, J=10 Hz), of 5.53 (1H, dt, J=10, 7.5 Hz), 7,10-7,40 (5H, m), 7,73 (2H, d, J=9.0 Hz), 795 (2H, d, J=9.0 Hz).

(18) (2S, 4R)-4-benzyloxycarbonylamino-2- [(Z)-5-methoxycarbonyl-1-pentenyl]-1-(phenylmethyl)pyrrolidin.

1H-NMR (CDCI3d million dollars. 1,60-1,80 (4H, m), 1,90-of 2.20 (4H, m), of 2.33 (2H, t, J=8 Hz), 3,12 (1H, d, J=12,5 Hz), 3,30 (2H, m), the 3.65 (3H, s), of 3.94 (1H, d, J=12,5 Hz), 4,18 (1H, m), is 4.85 (1H, m), 5,07 (2H, s), and 5.30-ceiling of 5.60 (2H, m), 7,20-to 7.35 (5H, m).

(19) (2S, 4R)-2-[(Z)-5-carboxy-1-pentenyl] -4- (4-chlorophenylsulfonyl)-1-(3-pyridylmethyl)pyrrolidine hydrochloride.

1H-NMR (D2O-DCI) d million dollars. 1,5-of 1.65 (2H, m), 1,95-2,15 (4H, m), 2,24 (2H, t, J=6.5 Hz), 3,18 (1H, DD, J=5,5, 12,5 Hz), 3,60 (1H, DD, J=7,5 12,5 Hz), was 4.02 (1H, m), 4,5-4,7 (2H, m), 5,33 (1H, t, J=8 Hz), of 5.83 (1H, dt, J= 10, and 11.5 Hz), 7,51 (2H, d, J=8 Hz), 7,83 (2H, d, J=8 Hz), 8,08 (1H, DD, J= 5.5 Hz), 8,63 (1H, m), 8,82 (1H, d, J=5.5 Hz), of 8.90 (1H, s).

1H-NMR (CDCI3d million dollars. 1,6-1,8 (2H, m), 1.85 to 1,95 (2H, m), 2,15 was 2.25 (2H, m), 2,25-2,4 (3H, m), and 3.16 (1H, DD, J=7,5, 9 Hz), 3,55 (1H, d, J=13.5 Hz), 3,65-3-9 (2H, m), 4,08 (1H, d, J=13.5 Hz), of 5.40 (1H, t, J=10 Hz), 5,62 (1H, dt, J=10, 7.5 Hz), 7,34 (2H, d, J=8.5 Hz), 7,52 (1H, m), 7,7-7,8 (4H, m), with 8.05 (1H, m), 8,81 (1H, d, J=1.5 Hz).

(2) (2S, 4R)-2-[(Z)-5-carboxy-1-pentenyl]-4- (4-chlorophenylsulfonyl)-1-(4-triazolylmethyl)-pyrrolidin.

1H-NMR (CDCI3d million dollars. 1,6-1,8 (2H, m), 1,95-of 2.05 (2H, m), 2.1 to a 2.2 (2H, m), of 2.25 to 2.35 (2H, m), 2,65 (1H, DD, J=4,5, 11 Hz), to 3.34 (1H, DD, J=6, 11 Hz), 3,85-of 3.95 (2H, m), 4,05-to 4.15 (2H, m), the 5.45 (1H, t, J=10 Hz), of 5.68 (1H, dt, J=10, 7.5 Hz), 7,42 (1H, m), the 7.43 (2H, d, J=8 Hz), to 7.77 (2H, d, J=8 Hz), 8,80 (1H, d, J=1.5 Hz).

(3) (2S, 4R)-2-[(Z)-5-carboxy-1-pentenyl]-4- (4-chlorophenylsulfonyl)-1-(5-triazolylmethyl)pyrrolidin.

1H-NMR (CDCI3d million dollars. of 1.65 to 1.9 (4H, m), from 2.1 to 2.25 (3H, m), 2,32 (2H, t, J=7 Hz), 3,19 (1H, DD, J=7.9 Hz), 3,55 (1H, q, J=9 Hz), the 3.65 (2H, d, J= 14 Hz), 3,81 (1H, m), a 4.03 (1H, d, J=14 Hz), from 5.29 (1H, t, J=10 Hz), to 5.58 (1H, dt, J=10, 7.5 Hz), was 7.45 (2H, d, J=8.5 Hz), 7,68 (1H, s), to 7.77 (1H, s), 8,80 (1H, s).

(4) (2S, 4R)-2-[(Z)-5-carboxy-1-pentenyl]-4- (4-chlorophenylsulfonyl)-1-[2-(3-pyridyl)ethyl]-pyrrolidin.

1H-NMR (CDCI3d million dollars. 1,55-1,75 (2H, m), 1,9-2,0 (2H, m), 2.05 is-with 2.2 (2H, m) to 2.29 (2H, t, J=6 Hz), 2,6-2,7 (2H, m), 2.8 to 3.0 (3H, m), 3,50 (1H, m), 3,8-R)-2-[(Z)-5-carboxy-1-pentenyl]-4- (4-chlorophenylsulfonyl)-1-[2-(1-imidazolyl)ethyl]-pyrrolidin.

1H-NMR (CDCI3+ SD3OD) d million dollars. of 1.5-1.7 (4H, m), a 2.0 to 2.15 (3H, m), of 2.23 (2H, t, J=7 Hz), 2,50 (1H, m), of 2.92 (1H, m), 3,2-3,4 (2H, m), 3,70 (1H, m), of 3.95 (2H, t, J=6 Hz), 5,10 (1H, t, J=10 Hz), the 5.45 (1H, dt, J=7,5, 10 Hz), of 6.96 (2H, s), was 7.45 (2H, d, J=8 Hz), 7,63 (1H, s), to 7.77 (2H, d, J=8 Hz).

(6) (2S, 4R)-2-[(Z)-6-carboxy-1-pentenyl]-4- (4-chlorophenylsulfonyl)-1-(3-pyridylmethyl)-pyrrolidin.

1H-NMR (CDCI3+ CD3OD) d million dollars. 1,35-1,45 (2H, m), 1,6-1,65 (2H, m), 1,65-of 1.85 (2H, m), a 2.0 to 2.15 (3H, m), is 2.30 (2H, t, J=8 Hz), totaling 3.04 (1H, DD, J= 7,5, 10 Hz), 3,13 (1H, d, J=13.5 Hz), 3,37 (1H, q, J=7.5 Hz), 3,23 (1H, m), 3,90 (1H, d, J=13.5 Hz), with 5.22 (1H, t, J=8 Hz), to 5.58 (1H, dt, J=10,5, 8 Hz), 7,29 (1H, DD, J=4.5 to 8 Hz), 7,46 (2H, d, J=8 Hz), 7,63 (1H, dt, J=7,5, 1.5 Hz), to 7.77 (1H, d, J=8 Hz), 8,35-to 8.45 (2H, m).

(7) (2S, 4R)-2-[(Z)-5-carboxy-1-pentenyl] -1- (3-pyridylmethyl)-4-[4-(trifluoromethyl)phenylcarbonylamino]-pyrrolidin.

1H-NMR (CDCI3d million dollars. 1,6-1,7 (2H, m), 1,8-1,9 (2H, m), from 2.1 to 2.25 (3H, m), 2.3 to 2.4 (2H, m), 3,10 (1H, DD, J=6,5, 10 Hz), 3,32 (1H, d, J=13 Hz), 3,62 (1H, q, J=8 Hz), 3,81 (1H, m), 3,92 (1H, d, J=13 Hz), and 5.30 (1H, t, J= 10 Hz), 5,59 (1H, dt, J=10, 7.5 Hz), 7,30 (1H, DD, J=5, 8 Hz), the 7.65 to 7.75 (3H, m), of 7.97 (2H, d, J=8 Hz), 8,45-8,55 (2H, m).

(8) (2S, 4R)-2-[(Z)-5-carboxy-1-pentenyl]-4- (4-chlorophenylsulfonyl)-1-(3-pyridylmethyl)pyrrolidine.

1H-NMR (D2O-DC1d million dollars. 1,5-of 1.65 (2H, m), 1,95-2,15 (4H, m), 2,24 (2H, t, J=6.5 Hz), 3,18 (1H, DD, J=5,5, 12,5 Hz), 3,60 (1H, DD, J=7,5, 12,5 Hz), was 4.02 (1H, m), 4,5-4,7 (2S="ptx2">

(9) (2S, 4R)-2-[(Z)-5-carboxy-1-pentenyl]-4- (4-chlorophenylsulfonyl)-1-(1-naphthylmethyl)pyrrolidin.

1H-NMR (CDCI3d million dollars. by 1.68 (2H, m), 1,90 (2H, m), of 2.15 (2H, m), is 2.30 (2H, t, J=7 Hz), 2,96 (1H, DD, J=7,5, 10 Hz) and 3.59 (1H, d, J=12,5 Hz in), 3.75 (2H, m), 4,60 (1H, d, J=12,5 Hz), 5,49 (1H, t, J=10 Hz), of 5.68 (1H, dt, J=a 10.6 Hz), 7,20-of 7.55 (6H, m), 7,60-of 7.90 (4H, m), 8,00-of 8.15 (1H, m).

(10) (2S, 4R)-2-[(Z)-5-carboxy-1-pentenyl]-4- (4-chlorophenylsulfonyl)-1-(2-naphthylmethyl)pyrrolidin.

1H-NMR (CDCI3d million dollars. of 1.65 (2H, m), 1,90 (2H, m) to 2.13 (2H, m), 2,28 (2H, m), 3,10 (1H, DD, J=9,0 10 Hz) to 3.56 (1H, d, J=13 Hz), 3,91 (1H, m) 4,00 (1H, d, J=13 Hz), of 5.39 (1H, t, d, 10 Hz), 5,64 (1H, dt, J=10, 8.0 Hz), 7,20-of 7.90 (11H, m).

(11) (2S, 4R)-1-[(4-acetylaminophenol/methyl]-2- [(Z)-5-carboxy-1-pentenyl]-4-(4-chlorophenylsulfonyl)- pyrrolidin.

1H-NMR (DMCO-d6d million dollars. B is 1.70 (4H, m), 1,75 is 2.10 (2H, m), from 2.00 (3H, s), 2,19 (2H, t, J=7.5 Hz), and 2.79 (1H, m), 2,96 (1H, d, J=12 Hz), 3,70 (1H, d, J= 12 Hz), with 5.22 (1H, m), of 5.48 (1H, m),? 7.04 baby mortality (2H, d, J=10 Hz), of 7.48 (2H, d, J=10 Hz), 7,63 (2H, d, J=9 Hz), 7,76 (2H, d, J=9 Hz), 7,98 (1H, Shir. C).

(12) (2S, 4R)-2-[(Z)-5-carboxy-1-pentenyl]-4- (4-chlorophenylsulfonyl)-1-[(4-hydroxyphenyl)methyl]pyrrolidin.

1H-NMR (DMCO-d6d million dollars. 1,50-1,75 (4H, m), is 2.09 (2H, m), of 2.20 (2H, t, J=7.5 Hz), 2,86 (1H, Shir. C) of 5.26 (1H, m), of 5.50 (1H, m), to 6.67 (2H, d, J= 9.0 Hz), to 6.95 (2H, d, J=9.0 Hz), 7,60 (2H, d, J=10 Hz), 7,78 (2H, d, J=10 Hz), 7,95 (1H, Shir. C), which 9.22 methyl] pyrrolidin.

1H-NMR (DMCO-d6d million dollars. a 1.45-1.77 in (4H, m) to 2.06 (2H, m), of 2.20 (2H, t, J= 7.5 Hz), is 2.88 (6H, s), and 5.30 (1H, m), of 5.53 (1H, m), only 6.64 (2H, d, J=10 Hz), 6,97 (2H, m), the 7.65 (2H, d, J=10 Hz), 7,79 (2H, d, J=10 Hz).

(14) (2S, 4R)-2-[(Z)-5-carboxy-1-pentenyl]-4- (4-chlorophenylsulfonyl)-1-(2-pyrrolidinyl)pyrrolidin.

1H-NMR (DMCO-d6d million dollars. of 1.37 (2H, m) to 1.48 (2H, m) to 1.86 (2H, m) 2,00 (2H, t, J=7.5 Hz), 2.70 height of 3.75 (6H, m), 5,12 (1H, t, J=10 Hz), to 5.35 (1H, dt, J=10, 7.5 Hz), 5,63 (1H, Shir. C) of 5.75 (1H, Shir. C) of 6.45 (1H, Shir. C) 7,46 (2H, d, J=10 Hz), 7,60 (2H, d, J=10 Hz), to 7.93 (1H, Shir. C).

(15) (2S, 4R)-2-[(Z)-5-carboxy-1-pentenyl]-1- [(2-chloro/phenyl)methyl]-4-(4-chlorophenylsulfonyl)-pyrrolidin.

1H-NMR (CDCI3d million dollars. to 1.70 (2H, m), 1,90 (2H, m) of 2.16 (2H, m), is 2.30 (2H, m), 3,11 (1H, m), 3,50 (1H, m), 3,85 (2H, m), 3,85 (2H, m), of 3.97 (1H, d, J=12 Hz), 4,78 (1H, s) 5,38 (1H, t, J=10 Hz), 5,62 (1H, dt, J=10, 8.0 Hz), 7,11-of 7.55 (6H, m), 7,76 (2H, d, J=10 Hz).

(16) (2S, 4R)-2-[(Z)-5-carboxy-1-pentenyl]-4- (4-chlorophenylsulfonyl)-1-(diphenylmethyl)pyrrolidin.

1H-NMR (CDCI1d million dollars. 1,4-of 1.65 (4H, m), 1,9-of 2.05 (2H, m), 2,1-2,2 (3H, m), 2,32 (1H, m), 2,90 (1H, m), 3,9-4,1 (2H, m), to 4.73 (1H, S), 5,35-of 5.45 (2H, m), 7,2-7,4 (12H, m), 7,74 (2H, d, J=8 Hz).

(17) (2S, 4R)-2-[(Z)-5-carboxy-1-pentenyl] -4- (4-chlorophenylsulfonyl)-1-ethylpyrrolidin.

1H-NMR (DMCO-d6d million dollars. of 1.05 (3H, m) of 1.50 (4H, m), from 2.00 (4H, m) to 2.18 (2H, m), 5,2-5,7 (2H, m), 7,69 (2H, m), 7,8x2">

1H-NMR (CDCI1d million dollars. to 0.88 (3H, t, J=7.5 Hz), 1,14-1,36 (20H, m), 1,36-of 1.55 (2H, m), 1,55-of 1.74 (2H, m), 1,86-of 2.15 (4H, m), of 2.20 (2H, m), of 2.56 (1H, m), 2,85 (1H, m) and 3.15 (1H, m), a 4.03 (1H, m), 5,24 (1H, m), of 5.68 (1H, m), 7,47 (2H, d, J=10 Hz), the 7.85 (2H, d, J=10 Hz).

(19) (2S, 4R)-2-[(Z)-5-carboxy-1-pentenyl] -4- (4-chlorophenylsulfonyl)-1-(5-fenilpentil)pyrrolidin.

1H-NMR (CDCI3d million dollars. 1,10-1,40 (2H, m), of 1.40 and 1.80 (6H, m), 1,95-of 2.30 (6H, m) of 2.50 (2H, t, J=7.5 Hz), 2,90 (2H, m), 3,18 (1H, m), 3,70 (1H, m), 4,10 (1H, m), 4,50 (1H, m), of 5.15 (1H, t, J=10 Hz), of 5.81 (1H, dt, J=10, 7,0 Hz), 7,05-7,30 (5H, m), 7,45 (2H, d, J=10 Hz), 7,86 (2H, d, J=10 Hz).

(20) (2S, 4R)-2-[(Z)-5-carboxy-1-pentenyl] -4- (4-chlorophenylsulfonyl)-1-(4-phenylbutyl)pyrrolidin.

1H-NMR (CDCI3d million dollars. the 1.4 and 1.8 (6H, m), of 2.08 (4H, m), of 2.20 (2H, m) to 2.55 (2H, m), 2,78 (2H, m), 3,05(1H, m) to 3.38 (1H, m), of 4.05 (1H, m, to 4.33 (1H, m), of 5.40 (1H, t, J=10 Hz), of 5.75 (1H, d, J=10 Hz), 7.5 Hz), 7,00-7,34 (5H, m)that was 7.45 (2H, d, J=10 Hz), to 7.84 (2H, d, J=10 Hz).

(21) (2S, 4R)-2-[(Z)-5-carboxy-1-pentenyl] -1 - phenylmethyl-4-(4-trifluoromethyl, phenylcarbonylamino)-pyrrolidin.

1H-NMR (CDCI3d million dollars. 1,40-of 1.85 (2H, m), 2,10-to 2.40 (6H, m), 2,85 (1H, DD, J=5,0 11 Hz), 3,10-of 3.45 (1H, m), of 3.94 (1H, d, J=12 Hz), of 4.05 (1H, m), 4,13 (1H, d, J=12 Hz), 4,48 (1H, q, J=7.5 Hz), 5,63 (1H, t, J=10 Hz), of 5.82 (1H, d, J=10, 7.5 Hz), 7,20-7,40 (5H, m, of 7.70 (2H, d, J=9.0 Hz), of 7.96 (2H, d, J=9.0 Hz).

(22) (2S, 4R)-2-[(Z)-5-carboxy-1-pentenyl] -4- (4-methylphenylsulfonyl)-1-(penile,64 (1H, DD, J=5.0 and 11 Hz), 3,20 (1H, DD, J= 7,5, 10 Hz) of 3.78 (1H, d, J=12 Hz), of 4.00 (1H, m), Android 4.04 (1H, d, J=12 Hz), 4,25 (1H, dt, J=7,5: 7.5 Hz), to 5.57 (1H, t, J=10 Hz), 5,78 (1H, dt, J= 10, 7.5 Hz), 7,20-7,40 (7H, m), 7,74 (2H, d, J=10 Hz).

(23) (2S, 4R)-2-[(Z)-5-carboxy-1-pentenyl] -4- (4-methoxyphenylacetylene)-1-(phenylmethyl)pyrrolidin.

1H-NMR (CDCI3d million dollars. was 1.69 (2H, m) to 1.98 (2H, m), 2,17 (2H, m), is 2.30 (2H, t, J=7.5 Hz), 2,50 (1H, DD, J=5.0 and 10 Hz), 3,14 (1H, DD, J=7,5, 10 Hz), 3,61 (1H, d, J=12 Hz), 3,85 (3H, s), 4,00 (1H, d, J=12 Hz), 4,10 (2H, m), 5,49 (1H, t, J=10 Hz), 5,72 (1H, dt, J=10, 7.5 Hz), 6,91 (2H, d, J=9 Hz), 7,28 (5H, Shir. C) 7,76 (2H, d, J=9 Hz).

Example 8. A solution of (2S, 4R)-1-[(4-acetylaminophenol)-methyl]-2/ [(Z)-5-carboxy-1-pentenyl] -4-(4-chlorophenylsulfonyl)pyrrolidine (200 mg) in 6 n hydrochloric acid (5 ml) was heated in a flask under reflux for 4 h, the mixture was cooled in an ice bath, the pH was brought to a value of 7 using IR. of sodium hydroxide. Sozdannoe solid substance was collected by filtration resulting in the received connection (2S, 4R)-1-[(4-aminophenethyl)-2-[(Z)-5-carboxy-1-pentenyl] -4- (4-chlorophenylsulfonyl) pyrrolidine (95 mg).

1H-NMR (DMCO-O6d million dollars. to 1.45 (2H, process,78 (2H, the process of 1.97 (2H, m), 2,11 (2H, t, J=7.5 Hz), of 2.54 (1H, Shir.C) the 3.65 (1H, Shir. C) of 3.84 (1H, d, J=12 Hz), 4.09 to (1H, Shir. C) 5,44 (1H, t, J=10 Hz), 5,61 (1H, dt, J= 10, 7.5 Hz), 6,40 (2H, (2H, d, J=10 Hz), 6,86 (2H, d, J=10 Hz), 7,55 Boxing-1-pentenyl] -1-(phenylmethyl)-pyrrolidine (700 mg) and 30% of Pomodoro in acetic acid (2 ml) was stirred for 2 h at room temperature, and then the solvent is evaporated under vacuum, resulting in the received connection (2S, 4R)-4-amino-2- [(Z)-5-methoxycarbonyl-1-pentenyl]-1-(phenylmethyl)-pyrrolidine (800 mg) as an oily substance.

Example 10. To a solution of (2S, 4R)-4-amino-2- [(Z)-5-methoxycarbonyl-1-pentenyl] -1-(phenylmethyl)pyrrolidine hydrobromide (371 mg) in dichloromethane (4 ml) was added triethylamine (of 0.67 ml) and p-toluensulfonate (200 mg) at 0oC and the resulting mixture stirred for 1.5 h at the same temperature. Then the solution is then washed with water and brine, and dried over magnesium sulfate. The solvent is evaporated in vacuo, and the residue was chromatographically on a column of silica gel, elwira a mixture of ethyl acetate and n-hexane (1:2), resulting in the received connection (2S, 4R)-2-[(Z)-5-methoxycarbonyl-1-pentenyl] -4- (4-methylphenylsulfonyl)-1-(phenylmethyl) pyrrolidine (249 mg) as an oily substance.

1H-NMR (CDCI3d million dollars. 1,40-2,00 (4H, m), is 2.09 (2H, m), is 2.30 (2H, t, J= 7.5 Hz), is 2.41 (3H, s), 3.04 from (1H, d, J=12 Hz), is 3.08 (1H, t, J=8 Hz), and 3.31 (1H, q, J=7.5 Hz), 3,70 (3H, s), 3,88 (1H, d, J=12 Hz), 4,78 (1H, d, J=8.0 Hz), 5,31 (1H, t, J=10 Hz), of 5.50 (1H, dt, J=10, 7.5 Hz), 7,14-to 7.35 (7H, m), of 7.70 (2H, d, J=10 Hz).

Example 11. The following compounds were obtained in a manner analogous to opisannyj)pyrrolidin

1H-NMR (CDCI3d million dollars. 1,60-of 1.95 (4H, m), 2,10 (2H, m), is 2.30 (2H, t, J= 7.5 Hz), 3,05 (1H, d, J=12 Hz), of 3.07 (2H, m), 3,30 (1H, q, J=7.5 Hz), of 3.69 (3H, s), 3,71 (1H, m), 3,86 (3H, s), a 3.87 (1H, d, J=12 Hz), 4.72 in (1H, d, J=9.0 Hz), and 5.30 (1H, t, J=10 Hz), of 5.50 (1H, dt, J=10, 7.5 Hz), 6,93 (2H, d, J=10 Hz), 7,11-7,33 (5H, m), of 7.75 (2H, d, J=10 Hz).

(2) (2S, 4R)-2-[(Z)-5-carboxy-1-pentenyl]-4- (4-chlorophenylsulfonyl)-1-(3-pyridylmethyl)pyrrolidine hydrochloride.

1H-NMR (D2O-DCI) d million dollars. 1,5-of 1.65 (2H, m), 1,95-2,15 (4H, m), 2,24 (2H, t, J= 6.5 Hz), 3,18 (1H, DD, J=5,5, 12,5 Hz), 3,60 (1H, DD, J=7,5, 12 Hz), was 4.02 (1H, m), 4,5-4,7 (2H, m), 5,33 (1H, t, J=10 Hz), of 5.83 (1H, dt, J= 10, and 11.5 Hz), 7,51 (2H, d, J=8 Hz), 7,83 (2H, d, J=8 Hz), 8,08 (1H, DD, J= 5,5, 8 Hz), 8,63 (1H, m), 8,82 (1H, d, J=5.5 Hz), of 8.90 (1H, s).

Derivatives pyrrolidine General formula I

< / BR>
in which R1pyridyl(lower)alkyl, pyrazinyl(lower)alkyl, pyrrolyl(lower)alkyl, imidazolyl(lower)alkyl, chinolin(lower)alkyl, benzoxazolyl(lower)alkyl, thiazolyl(lower)alkyl, thienyl(lower)alkyl, furyl(lower)alkyl or benzothiazolyl(lower)alkyl, (C1- C12)alkyl, phenyl(lower)alkyl which may have one or two substituent selected from a range that includes a cyano, a hydroxy-group, halogen, lower alkyl, lower alkoxy, phenyl, amino, di(lower)alkylamino, lower alkanolamines and the t to have one or two substituent, selected from the group comprising halogen, lower alkyl, lower alkoxy and mono-(or di-, or three)halogen(lower)alkyl;

R3carboxy(lower)alkyl, esterified carboxy(lower)alkyl, carboxyphenyl or esterified carboxyphenyl,

and their pharmaceutically acceptable salts.

2. Connection on p. 1, in which

R1pyridyl (C1WITH1)alkyl, pyrazinyl(C1- C4)alkyl, pyrrolyl(C1WITH4)alkyl, imidazolyl(C1- C4)alkyl, chinolin(C1WITH4)alkyl, benzoxazolyl(C1WITH4)alkyl, thiazolyl(C1WITH4)alkyl, thienyl(C1- C4)alkyl, furyl(C1WITH4)alkyl, benzothiazolyl(C1- C4)alkyl, (C1WITH12)alkyl, phenyl(lower)alkyl, cyanophenyl(lower)alkyl, hydroxyphenyl(lower)alkyl, mono (or di)haloethanol(lower)alkylphenyl(lower)alkyl, lower alkoxyphenyl(lower)alkyl, phenylphenyl(lower)alkyl, diphenyl(lower)alkyl, AMINOPHENYL(lower)alkyl, di(lower alkyl)AMINOPHENYL(lower)alkyl, lower alkanolamines(lower)alkyl or naphthyl(lower)alkyl;

R2hydrogen, phenyl(lower)alkoxycarbonyl, or phenylsulfonyl, which may have one or two substituent, viil;

R3carboxy(lower)alkyl, lower alkoxycarbonyl(lower)alkyl, carboxyphenyl or lower alkoxycarbonylmethyl.

3. Connection on p. 2, in which R1pyridyl(C1-C4)alkyl, pyrazinyl(C1WITH4)alkyl, pyrrolyl(C1- C4)alkyl, imidazolyl(C1WITH4)alkyl, chinolin (C1- C4)alkyl, benzoxazolyl(C1WITH4)alkyl, thiazolyl(C1-C4)alkyl, thienyl(C1WITH4)alkyl, furyl(C1- C4)alkyl, benzothiazolyl(C1WITH4)alkyl, (C1- C12)alkyl, phenyl(C1WITH5)alkyl, cyanophenyl(C1WITH5)alkyl, hydroxyphenyl(C1- C5)alkyl, mono- (or di-haloethanol(C1WITH5)alkyl, C1WITH4-alkylphenyl(C1WITH5)alkyl, (C1- C4)alkoxyphenyl(C1WITH5)alkyl, phenylphenyl(C1- C5)alkyl, diphenyl(C1WITH5)alkyl, AMINOPHENYL(C1- C5)alkyl, di(C1WITH4)-alkyl)AMINOPHENYL(C1- C5)alkyl, (C1WITH4-alkanolamines(C1- C5)alkyl or naphthyl(C1WITH5)alkyl; R2hydrogen, phenyl(C1-C4)alkoxycarbonyl, or phenylsulfonyl, which can be4)alkoxy or mono- (or di-, or three)halogen(C1WITH4)alkyl, R3- carboxy(C1WITH4)alkyl, (C1- C4)alkoxycarbonyl(C1WITH4)alkyl, carboxyphenyl or (C1< / BR>
WITH4)alkoxycarbonylmethyl.

4. Connection on p. 3 in which R1pyridyl(C1- C4)alkyl, R2phenylsulfonyl, which may have one or two substituent selected from a range that contains halogen, (C1- C4)alkyl, (C1-C4)alkoxy or mono- (or di-, or three)halogen(C1WITH4)alkyl, and R3carboxy(C1- C4)alkyl.

5. Connection on p. 4, a (2S, 4R) 2-[(Z)-5-carboxy-1-pentenyl] -4- (4-chlorophenylsulfonyl)-1-(3-pyridylmethyl)-pyrrolidin or its hydrochloride.

6. The method of obtaining compounds of General formula I under item 1, in which R2and R3matter under item 1, R1the group R8-CH2where R8hydrogen, pyridyl, pyrazinyl, pyrrolyl, imidazolyl, hinely, benzoxazolyl, thiazolyl, thienyl, furyl, benzothiazolyl, pyridyl(C1WITH5)alkyl, pyrazinyl(C1WITH5)alkyl, pyrrolyl(C1WITH5)alkyl, imidazolyl(C1WITH5)alkyl, chinolin(C1WITH5)alkyl, furyl(C1WITH5)alkyl, benzothiazolyl(C1- C5)alkyl, (C1WITH11)alkyl, phenyl which may contain 1 or 2 substituent selected from the group of cyano, hydroxyl, halogen, lower alkyl, lower alkoxy, phenyl, amino, di(lower)alkylamino, and (lower)alkanolamines, phenyl(C1- C5)alkyl which may have one or two substituent selected from the group vkluchaya a cyano, hydroxyl, halogen, lower alkyl, lower alkoxy, phenyl, amino, di(lower)alkylamino and (lower)alkanolamines, naphthyl or naphthyl(C1WITH5)alkyl, and salts thereof, characterized in that the compound of General formula II

< / BR>
where R2and R3have the specified values,

subjected to interaction with the compound of General formula XIV

< / BR>
where R8has the specified values,

or its salt to obtain the desired product.

7. Pharmaceutical composition having an antagonistic action against thromboxane A2(TX-A2and inhibiting TX A2- synthetase comprising the active principle and the target additives, characterized in that the active agent it contains effectieve pharmaceutically acceptable salt, having the properties of an antagonist of the thromboxane A2and/or synthetase inhibitor of thromboxane A2.

Priority points and features: 31.10.88 on PP.1 and 7, R1- pyridyl(lower)alkyl, pyrazinyl(lower)alkyl, pyrrolyl(lower)alkyl, imidazolyl(lower)alkyl, chinolin(lower)alkyl, benzoxazolyl(lower)alkyl, thiazolyl(lower)alkyl, thienyl(lower)alkyl, furyl(lower)alkyl and benzothiazolyl(lower)alkyl, R2phenyl(lower)alkoxycarbonyl or phenylsulfonyl, which may have one or two substituent selected from the group comprising halogen, lower alkyl, lower alkoxy and mono(or di-, or three)halogen(lower)alkyl, R3carboxy(lower)alkyl, esterified carboxy(lower)alkyl, carboxyphenyl and the esterified carboxyphenyl.

13.04.89 on PP. 1, 6 and 7, R1(C1WITH6)alkyl, phenyl(lower)alkyl which may have one or two substituent selected from the group comprising a cyano, a hydroxy-group, halogen, lower alkyl, lower alkoxy, phenyl, amino, di(lower)alkylamino and allmenalp, or naphthyl(lower)alkyl, R8pyridyl, pyrazinyl, pyrrolyl, imidazolyl, hinely, benzoxazolyl, thiazolyl, thienyl, furyl, benzothiazolyl, pyridyl ( - C5)alkyl, chinolin(C1WITH5)alkyl, benzoxazolyl(C1WITH5)alkyl, thiazolyl(C1WITH5)alkyl, thienyl(C1- C5)alkyl, furyl(C1WITH5)Alcide, benzothiazolyl(C1- C5)alkyl, hydrogen, (C1WITH5)alkyl, phenyl, which may contain one or two substituent selected from the group comprising a cyano, a hydroxy-group, halogen, lower alkyl, lower alkoxy, phenyl, amino, di(lower)alkylamino and allmenalp, phenyl(C1- C5)alkyl, which may contain one or two substituent selected from the group comprising a cyano, a hydroxy-group, halogen, lower alkyl, lower alkoxy, phenyl, amino, di(lower)alkylamino and allmenalp, naphthyl or naphthyl(C1WITH5)alkyl.

 

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,

in which n is an integer from 1 to 5; each of R1and R2which may be identical or different, is hydrogen, halogen, -CN, -NO2C1-C4the alkyl, or a group:, R3is hydrogen, halogen, -CN or-NO2

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The invention relates to new derivatives of aryl - and heteroarylboronic, to the way they are received, to contain their pharmaceutical compositions and to their use as therapeutic agents

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as a highly effective protective means in cardiogenic shock and toxic stress

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FIELD: medicine.

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

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

3 cl, 5 dwg

FIELD: medicine.

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

EFFECT: enhanced effectiveness of treatment.

4 cl

FIELD: medicine.

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

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

4 cl

FIELD: medicine.

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

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

3 cl, 3 dwg

FIELD: medicine.

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

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

2 cl

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

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

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

EFFECT: valuable medicinal properties of compounds.

5 cl, 1 tbl, 1 ex

FIELD: medicine, cardiology.

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

EFFECT: higher efficiency of therapy.

3 ex

FIELD: medicine.

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

EFFECT: reduced risk of metastasizing.

4 cl, 13 dwg

FIELD: medicine.

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

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

6 cl

FIELD: medicine.

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

EFFECT: enhanced effectiveness of treatment in early postoperative period.

FIELD: organic chemistry.

SUBSTANCE: invention relates to method for production of N,N,1-trimethyl-2-(3,4-fullero[60])pyrrolidine amine of formula 1 .

Claimed method includes reaction of fullerene[60] (C60) with N,N,N,N-tetramethylmethane diamine of general formula (CH3)2-N-CH2-N-(CH3)2 in C60:(CH3)2-N-CH2-N-(CH3)2 molar ratio of 0.01:(0.01-0.011) in presence of Cp2TiCl2 as catalyst in amount of 15-25 mol.% based on fullerene in argon atmosphere in toluene medium as solvent at 140-160°C for 2-4 hours. Yield of target product is 79-89 %.

EFFECT: compound useful as complexing agents, sorbents, biologically active materials and in production of materials with desired electronic, magnetic and optical characteristics.

1 tbl, 1 ex

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