RU2095346C1 - Pyrrolidine derivatives and pharmaceutically acceptable salts thereof - Google Patents

Abstract

FIELD: pharmaceutical industry. SUBSTANCE: present invention describes pyrrolidine derivatives of formula 1:

wherein R¹ is heteryl(lower)alkyl, (C₁-C₁₂) alkyl and optionally substituted phenyl (lower) alkyl; R² is H, phenyl (lower)alkoxycarbonyl or optionally substituted phenylsulphonyl; R³ is carboxy (lower) alkyl, etherified carboxylower alkyl, carboxyphenyl or etherified carboxyphenyl and pharmaceutically acceptable salts thereof. Said salts are prepared by reacting compound of formula II:

with compound of formula XIV:

or salt thereof. Present invention describes pharmaceutical composition which has antagonistic activity against thromboxane A₂(TXA₂) and inhibits TXA₂ synthase based on compound I. EFFECT: improved properties of the pharmaceutical composition. 9 cl

Description

2 The invention relates to new derivatives of pyrrolidine and their pharmaceutically acceptable salts.

In particular, the invention relates to novel pyrrolidine derivatives and their pharmaceutically acceptable salts having thromboxane A ₂ antagonism (TXA ₂ ), as well as TXA ₂ synthetase inhibiting activity that can be used to treat and / or prevent thrombotic diseases, such as a transient disturbance of cerebral circulation, cerebral hemorrhage, unstable angina, myocardial infarction, peripheral circulatory failure, cerebral hemorrhage, unstable angina, myocardial infarction tatochnost peripheral circulation, thrombus formation after percutaneous transluminal angioplasty, generalized trombogemorragichesky syndrome, etc. allergic diseases such as asthma or the like. jade; peptic ulcers; migraine; diabetic neuropathy; diabetic angiopathy; restenosis after plastic surgery on the vessels; respiratory distress syndrome in adults; shock; hepatitis A; cerebral vasospasm after subarachnoid hemorrhage; hypertension atherosclerosis; cancer metastasis; blood clots with perfuria; blood clot during transplantation; etc. and also to reduce the nephrotoxicity caused by immunosuppressants, such as cyclosporine during kidney transplantation; said pyrrolidine derivatives or pharmaceutically acceptable salts thereof may also be used in combination with fibrinolytic agents to enhance the action of said fibrinolytic agents.

где
R¹ является алкилом; ар(низший)алкилом, который может иметь подходящий заместитель (заместители); или гетероциклическим(низшим)алкилом;
R² является водородом или ацильной группой; и
R³ является карбокси(низший)алкилом; защищенным карбокси(низший)алкилом, карбоксиарилом или защищенным карбоксиарилом.Derivatives of pyrrolidine of the present invention can be represented by formula (I)

Where
R ¹ is alkyl; ar (lower) alkyl, which may have suitable substituent (s); or heterocyclic (lower) alkyl;
R ² is hydrogen or an acyl group; and
R ³ is carboxy (lower) alkyl; protected carboxy (lower) alkyl, carboxyaryl or protected carboxyaryl.

In accordance with the invention, new pyrrolidine derivatives (I) are prepared according to method I options 1-5 at the end of the description
Where
R ¹ , R ² and R ³ are as defined above;
X is halogen;
R $\genfrac{}{}{0ex}{}{\text{3}}{\text{a}}$ protected carboxy (lower) alkyl or protected carboxyaryl
R $\genfrac{}{}{0ex}{}{\text{3}}{\text{in}}$ carboxy (lower) alkyl or carboxyaryl;
R ^{8 is} hydrogen, (C ₁ -C ₄ ) alkyl; aryl, which may have the corresponding substituent (s), ap (C ₁ -C ₅ ) alkyl, which may have the corresponding substituent (s), a heterocyclic group, or heterocyclic (C ₁ -C ₅ ) alkyl;
R $\genfrac{}{}{0ex}{}{\text{2}}{\text{a1}}$ acyl group;
R $\genfrac{}{}{0ex}{}{\text{one}}{\text{a}}$ ap (lower) alkyl having a protected amino group;
R $\genfrac{}{}{0ex}{}{\text{one}}{\text{in}}$ ar (lower) alkyl having an amino group.

 The starting compound (II) can be prepared by methods A and B at the end of the description.

Where
R ² , R ² a, R ^{3 are as} defined above,
R ^{4 an} imino protecting group;
R ⁵ lower alkyl;
R ⁶ lower alkyl;
X ^{1 is} halogen;
M alkali metal; and
R ⁷ aryl
The terminology used in the description of the invention and examples illustrating the invention are explained in detail below.

 The term "lower" means having 1-6 carbon atoms, and preferably 1-4 carbon atoms, unless otherwise specified.

 The term “alkyl” means that the corresponding straight or branched chain alkyl contains 1-15 carbon atoms, examples of said alkyl are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, t- pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, petadecyl, or the like.

 The corresponding "lower alkyl" and part of the (lower) alkyl, designated by the terms "heterocyclic (lower) alkyl", "carboxy (lower) alkyl" and "protected carboxy (lower) alkyl", is a straight or branched chain alkyl having 1 -6 carbon atoms, for example, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, t-pentyl, hexyl, or the like, and preferably having 1-4 carbon atoms.

 The corresponding “lower alkyl moiety” designated by the term “ar (lower) alkyl" is straight or branched chain alkyl having, as mentioned above, 1 to 6 carbon atoms, preferably 1 to 5 carbon atoms.

The corresponding “aryl” and “aryl moiety” designated by the terms “ar (lower) alkyl”, carboxyaryl, protected carboxyaryl and “ar (C ₁ -C ₅ ) alkyl" may be phenyl, naphthyl, and the like.

The corresponding “substituent”, denoted by the terms “ar (lower) alkyl, which may have the corresponding substituent (s)”, “aryl, which may have the corresponding substituent (s)”, and “ar (C ₁ -C ₅ alkyl, which may have the 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 and the like), lower alkoxy group (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-bottle and, t-butoxy, peethyloxy, t-pentyloxy, hexyloxy, etc.), aryl (e.g. phenyl, naphthyl, etc.) amino group, di (lower amino group (e.g. dimethylamino, diethylamino, dipropylamino, dibutylamino, dipentylamino, dihexylamino, etc.), a protected amino group, and the like.

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

The corresponding “(C ₁ -C ₅ ) alkyl moiety”, denoted by the terms “ar (C ₁ -C ₅ ) alkyl” and “heterocyclic (C ₁ -C ₅ ) alkyl,” may be straight or branched chain alkyl having 1 -5 carbon atoms, for example, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, t-pentyl and the like.

The corresponding "(C ₁ -C ₁₄ ) alkyl" may be straight or branched chain alkyl having 1-14 carbon atoms, for example, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t- butyl, pentyl, t-pentin, hexyl, heptyl, octyl, nonyl, decyl, undecel, dodecyl, tridecyl, tctradecyl or the like.

The corresponding “heterocyclic group” and “heterocyclic moiety” designated by the terms “heterocyclic lower alkyl” and “heterocyclic (C ₁ -C ₅ ) alkyl” may be a saturated or unsaturated, monocyclic or polycyclic heterocyclic group containing at least one hetero atom such as an oxygen, sulfur, nitrogen atom and the like. Particularly preferred are heterocyclic groups such as:
unsaturated, consisting of 3-8 members (more preferably 5-6 members), a heterocyclic group having 1-4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, and its N-oxide, pyrimidyl, pyrazinyl, pyridazimyl, triazolyl (e.g. 4H-1, 2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.) tetrazolyl (e.g. 1H-tetrazolyl, 2H- tetrazolyl and the like dihydrotriazinyl (e.g. 4,5-dihydro-1,2,4-trasinyl, 2,5-dihydro-1,2,4-triazinyl and the like), etc.

 unsaturated, consisting of 3-8 members (more preferably 5-6 members), a heteromonocyclic group containing 1-4 nitrogen atoms, for example, pyrrolidinyl, piperidino, piperazinyl and the like.

 unsaturated condensed heterocyclic group containing 1-5 nitrogen atoms, for example, indolyl, isoindolyl, indolisinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridyl, tetrazolopyridazinyl (e.g. tetrazolo / 1,5-pazyl, etc. ) dihydrotriazolopyridazinyl, I.P.

 unsaturated, consisting of 3-8 members, more preferably 5-6 members) a heteromonocyclic group containing 1-2 oxygen atoms and 1-3 nitrogen atoms, for example oxazolyl, isoxazolyl, oxadiazolyl (for example, 1,2,4-oxadiazolyl, 1, 3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.) and the like.

 saturated, consisting of 3-8 members (more preferably 5-6 members), a heteromonocyclic group containing 1-2 oxygen atoms and 1-3 nitrogen atoms, for example, morpholinyl and the like.

 unsaturated condensed heterocyclic group containing 1-2 oxygen atoms and 1-3 nitrogen atoms, for example benzoxazolyl, benzoxadiazolyl and the like.

 unsaturated, consisting of 3-8 members (more preferably 5-6 members), a heteromonocyclic group containing 1-2 sulfur atoms and 1-3 nitrogen atoms, for example thiazolyl, 1,2-thiazolyl, thiazolinyl, thiadiazolyl (e.g. 1, 2, 4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl), and the like.

 saturated, consisting of 3-8 members (more preferably 5-6 members), a heteromonocyclic group containing 1-2 sulfur atoms and 1-3 nitrogen atoms, for example thiazolidinyl, and the like.

 unsaturated, consisting of 3-9 atoms (more preferably 5-6 members), a heteromonocyclic group containing a sulfur atom, for example thienyl, etc.

 unsaturated, consisting of 3-8 members (more preferably 5-6 members), a heteromonocyclic group containing an oxygen atom, for example furyl, and the like.

 unsaturated condensed heterocyclic group containing 1-2 sulfur atoms and 1-3 nitrogen atoms, for example benzothiazolyl, benzothiadiazolyl, etc.

 The corresponding “acyl” and “acyl moiety” designated by the term “acylamino” may be lower alkanoyl (eg, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivanoyl, etc.), lower alkoxycarbonyl (eg methoxycarbonyl , ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, t-butoxycarbonyl, pentyloxycarbonyl, t-pentyloxycarbonyl, hexyloxycarbonyl, etc.), lower alkylsulfonyl (e.g. methylsulfonyl, ethylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonyl bonyl, pentylsulfonyl, t-pentisulfonyl, hexisulfonyl, etc.), arylsulfonyl (e.g. phenylsulfonyl, naphthisulfonyl, etc.), aroyl (e.g. benzoyl, naphthoyl, etc. ar (lower) alkanoyl, (e.g. phenylacetyl, phenylpropionyl, etc.), cyclo (lower) alkyl (lower alkanoyl (e.g. cyclohexylacetyl, cyclopentylacetyl, etc.), ar (lower) alkoxycarbonyl (e.g. benzyloxycarbonyl, phenethyloxycarbonyl, etc.) , arylcarbamoyl (e.g. phenylcarbamoyl, naphthylcarbamoyl, etc.), heterocyclic sulfonyl, such as heteromonocyclic sulfon phonyl (e.g., thienyl-sulfonyl, furylsulfonyl, pyridylsulfonyl, etc.), and the like.

 these acyl groups can be substituted by 1-3 corresponding substituents, such as halogen, for example, chlorine, fluorine, bromine and iodine, lower alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t- butyl, pentyl, t-pentyl, hexyl, and the like), lower alkoxy group (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy, pentoxy, t-pentoxy, hexyloxy, etc. ), nitro group, mono- or di-, or trihalo (lower) alkyl (e.g. chloromethyl, bromomethyl, chloropropyl, 1,2-dichloroethyl, 1,2-dibromethyl, 2,2-dichloroethyl, trifluoromethyl, 1 , 2,2-trichloroethyl and the like) and the like.

 The corresponding “protected carboxy moiety”, denoted by the terms “protected lower alkyl” and “protected carboxyaryl”, may be carbamoyl; atsilkarbamoil such as lower alkilsulfonilkarbamoil (e.g. metilsulfonilkarbamoil, etilsulfonilkarbamoil, propilsulfonilkarbamoil, izopropilsulfonilkarbamoil, butilsulfonilkarbamoil, t-butilsulfonilkarbamoil, geksilsulfonilkarbamoil etc.) arilsulfonilkarbamoil (e.g. fenilsulfonilkarbamoil, naftilsulfonilkarbamoil, etc.) or the like an esterified carboxyl group in which said ester can be one of the following compounds: lower alkyl ester (e.g. methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t- butyl ether, pentyl ester, t-pentyl ester, hexyl ester, etc.); lower alkenyl ester (for example, ethinyl ester, propynyl ester, etc.); mono (or di- or three-) - halo (lower) alkyl ester (e.g., 2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.) alkanoyloxy (lower) alkyl ester ( for example, acetoxymethyl ester, propionyloxymethyl ester, 1-acetoxypropyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester, 1-acetoxyethyl ester, 2-propionyloxyethyl ester, 1-ester, etc. ), complex lower alkanesulfonyl (lower) alkyl ester (e.g. mesyl methyl ester, 2-mesylethyl ester, etc.). ar (lower) alkyl ester, e.g. phenyl lower alkyl ester, which may be substituted with one or more suitable substituents (e.g., benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester ether, diphenylmethyl ester, bismethoxyphenyl methyl ester, 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-ditretiaryrylbutylbenzyl ester, etc.), lower alkoxycarbonyloxy (lower) alkyl ester (e.g., with methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, ethoxycarbonyloxyethyl ester, etc.), aryloxy (lower) alkyl ester (e.g., benzoyloxymethyl ester, benzoyloxyethyl ester, toluoroxyethyl ester, etc.) an ester which may have one or more acceptable substituent or acceptable substituents, for example phenyl ester, tolyl ester, tert-butylphenyl ester, xylyl ester, mesityl ester ether, cumenyl ester, etc.

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

 The corresponding "imino-protective group" may be the acyl group and the like.

 The corresponding “alkali metal” may be sodium, potassium, and the like.

 Suitable pharmaceutically acceptable salts of the target compound (I) are standard non-toxic salts, as well as metal salts, such as an alkali metal salt (e.g., sodium salt, potassium salt, etc.) and an alkaline earth metal salt, e.g., calcium salt , magnesium salt, etc.), ammonium salt, salt of organic bases (e.g. triethylamine salt, thimethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N, N-dibenzylethylenediamine salt and the like), organic acid salt (e.g. acetate, maleate, tartrate, methanesulfonate, benzenesulfonate, format, toluenesulfonate, trifluoroacetate and the like), an inorganic acid salt (e.g. hydrochloride, hydrobromide, sulfate, phosphate and the like), a salt formed by an amino acid (e.g. agrinine, aspartic acid, glutamic acid, lysine, etc.), etc.

A preferred target compound (I) is a compound in which:
R ¹ unsaturated 5-6-member hetero monocyclic (lower) alkyl in which the hetero monocyclic 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 (C ₁ -C ₄ ) alkyl, pyrazinyl (C ₁ -C ₄ ) alkyl, pyrrolyl (C ₁ -C ₄ ) alkyl or imidazolyl (C ₁ -C ₄ ) alkyl,
unsaturated condensed heterobicyclic (lower) alkyl, in which the heterobicyclic group contains 1-4 nitrogen atoms, more preferred is quinolyl (lower) alkyl, most preferred is quinolyl (C ₁ -C ₄ ) alkyl,
unsaturated condensed heterobicyclic (lower) alkyl, in which the heterobicyclic group contains 1-2 oxygen atoms and 1-3 nitrogen atoms, benzoxazolyl (lower) alkyl is more preferred, benzoxazolyl C ₁ -C ₄ alkyl is most preferred,
unsaturated 5-6 atom heteromonocyclic (lower) alkyl, in which the heteromonocyclic group contains 1-2 sulfur atoms and 1-3 nitrogen atoms / thiazolyl (lower) alkyl is more preferred, thiazolyl (lower) alkyl is most preferred, most preferred thiazolyl (C ₁ -C ₄ ) alkyl /,
5-6-member unsaturated heteromonocyclic (lower) alkyl in which the heteromonocyclic group contains a sulfur atom / more preferred is thienyl (lower) alkyl, most preferred is thienyl (C ₁ -C ₄ ) alkyl /,
a 5-6-member unsaturated heteromonocyclic (lower) alkyl group in which the heteromonocyclic group contains an oxygen atom / furyl (lower) alkyl is more preferred, furyl (C ₁ -C ₄ ) alkyl is most preferred /,
unsaturated condensed heterobicyclic (lower) alkyl, in which the heterobicyclic group contains 1-2 sulfur atoms and 1-3 nitrogen atoms / more preferred is benzothiazolyl (lower) alkyl, most preferred benzothiazolyl C ₁ -C ₄ alkyl /,
C ₁ -C ₁₅ alkyl, more preferred is C ₁ -C ₁₂ alkyl
phenyl (lower) alkyl, which may have 1-3 substituents selected from the group consisting of: cyano, hydroxy, halogen, lower alkyl, lower alkoxy group, aryl, amino group, di (lower) alkylamino and protected amino group, more preferred are phenyl (lower) alkyl, which may have 1-2 substituents selected from the group consisting of cyano, hydroxy, halogen, lower alkyl, lower alkoxy groups, phenyl, amino, di lower alkylamino groups and acylamino groups, most phenyl (lower) alkyl, cyanophenyl (lower) are preferred ) alkyl, hydroxyphenyl (lower) alkyl, mono (or di-) halophenyl (lower) alkyl, phenyl (lower) alkyl, diphenyl (lower) alkyl, aminophenyl (lower) alkyl, di (lower) alkyl amino-phenyl (lower) alkyl, or lower alkanoylaminophenyl (lower) alkyl, or naphthyl (lower) alkyl;
R ^{2 is} hydrogen, ap (lower) alkoxycarbonyl, phenyl lower alkoxycarbonyl, or arylsulfonyl, which may have 1-3 substituents selected from the group consisting of halogen, lower alkyl, lower alkoxy and mono (or di-, or tri-) halo (lower) alkyl, phenylsulfonyl is more preferred, which may have 1-2 substituents selected from the group consisting of halogen, lower alkyl, lower alkoxy and mono (or di- or tri-) halo (lower) alkyl, most preferred is phenylsulfonyl, which may t contain halogen, lower alkyl, lower alkoxy group or mono (or di- or tri-) halo (lower) alkyl;
R ³ carboxy (lower) alkyl, protected carboxy (lower) alkyl, esterified carboxy (lower) alkyl is more preferred, lower alkoxycarbonyl lower alkyl, carboxyphenyl or protected carboxyphenyl is most preferred, esterified carboxyphenyl is most preferred, lower alkoxycarbonylphenyl is most preferred.

 Variants of the method for preparing the target compound (I) and the starting compound (II) according to the invention are described in detail below.

 Option 1.

 Compound (Ib) or a salt thereof can be obtained by eliminating a carboxy protecting group to which compound (Ia) or a salt thereof is subjected.

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

 In case the protecting group is an ester, said protecting group may be removed by a hydrolysis reaction. The hydrolysis is preferably carried out in the presence of a base or an acid, for example a Lewis acid. A suitable base may be an inorganic base and an organic base, such as alkali metals (e.g., sodium, potassium, etc.), alkaline earth metals (e.g., magnesium, calcium, etc.), their hydroxides, carbonates or bicarbonates ; trialkylamines (e.g. trimethylamine, triethylamine, etc.) or the like.

 The corresponding acid can be organic acid (e.g., formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.), and inorganic acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, etc.) .

 The reduction reaction is used, preferably, to remove a protective group, such as, for example, 4-nitrobenzyl, 2-iodoethyl; 2,2,2-trichloroethyl or the like. Said reduction method used to carry out the elimination reaction can be performed, for example, using a combination of a metal (e.g. zinc, zinc amalgam, etc.) or a salt of a chromium compound, e.g., chromium chloride, chromium acetate, etc. . ) and an organic or inorganic acid (e.g., acetic acid, propionic acid, hydrochloric acid, etc.); as well as using standard catalytic reduction in the presence of a standard metal catalyst (e.g. palladium carbon, etc.).

 This reaction usually takes place in a solvent, such as water, alcohol (e.g. methanol, ethanol, etc.), methylene chloride, tetrahydrofuran, mixtures thereof or any other solvent that does not adversely affect the reaction. A liquid base or acid may also be used as a solvent. The reaction temperature is not a critical parameter and the reaction usually proceeds from cooling to heating.

 Option 2

 Compound (Ic) or a salt can be obtained by carrying out the reaction between compound (II) or its salt and compound (XIV) or its salt.

 Said reaction can proceed in the presence of a reducing agent, such as an alkali metal cyanoborohydride (e.g., sodium cyanoborohydride), an alkali metal borohydride (e.g., sodium borohydride, etc.), diborane, and the like.

 This reaction usually takes place in a solvent, such as alcohol (e.g. methanol, ethanol, etc.), methylene chloride, tetrahydrofuran, chloroform, a mixture thereof, or any other solvent that does not adversely affect the reaction. The reaction temperature is not a critical parameter, and the reaction usually proceeds from cooling to heating.

 Option 3

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

 This reaction is carried out in accordance with standard methods, such as hydrolysis, reduction, or the like.

, а следовательно, условия реакции соответствуют условиям реакции, описанным в указанном Способе B

.This reaction is carried out in a manner similar to that described in method B

and therefore, the reaction conditions correspond to the reaction conditions described in the specified Method B

.

 Option 4

 The compound (Ig) or its salt can be obtained by the elimination reaction of the amino protecting group to which the compound (If) or its salt is subjected.

 This reaction is carried out in accordance with standard methods, such as hydrolysis, reduction, or the like.

, а следовательно, условия реакции соответствуют условиям реакции, описанным в указанном Способе B .This reaction is carried out in a manner similar to that described in method B

and therefore, the reaction conditions correspond to the reaction conditions described in the specified Method B .

 Option 5

 The compound (Id) or its salt can be obtained by reacting the compound (Ie) or its salt with an acylating agent.

The acylating agent may be an organic acid (i.e., R $\genfrac{}{}{0ex}{}{\text{2}}{\text{a}}$ OH where R $\genfrac{}{}{0ex}{}{\text{2}}{\text{a}}$ an acyl group) or a reactive derivative thereof, or a salt thereof.

 The corresponding reactive organic acid derivative may be a standard compound, such as an acid halide, for example an acid chloride, an acid bromide, and the like. acid azide, acid anhydride, activated amide, activated ester, isocyanate, for example, aryl isocyanate, for example, phenyl isocyanate, and the like.

 If free acid is used as the acylating agent, the acylation reaction is preferably carried out in the presence of a standard condensing agent, such as N, N'-dicyclohexylcarbodiimide or the like.

.The specified reaction is preferably carried out in the presence of inorganic or organic bases, which are described in Method B

.

 Said reaction usually proceeds in a solvent which does not adversely affect the reaction, for example, such as methanol, ethanol, propanol, dichloromethane, tetrahydrofuran, chloroform and the like.

 The reaction temperature is not a critical parameter, and the reaction can proceed under conditions from cooling to heating.

.Method A

.

 Compound (VI) or a salt thereof can be prepared by reacting a compound (IV) or a salt thereof with a compound (V).

 This reaction usually takes place in a standard solvent, such as dichloromethane, or any other solvent which does not adversely affect the reaction.

.The specified reaction is preferably carried out in the presence of an inorganic or organic base, as shown in the Description of Method B

.

.Method A

.

 Compound (VIII) or a salt thereof can be prepared by reacting a compound (VI) or a salt thereof with a compound (VII).

 This reaction usually takes place in a standard solvent, such as dimethyl sulfoxide or any other solvent that does not adversely affect the reaction.

 The reaction temperature is not a critical parameter, and the reaction usually proceeds from a slight increase in temperature to heating.

.Method A

.

 Compound (IX) or a salt thereof can be prepared by the hydrogenation reaction to which compound (VIII) or a salt thereof is subjected. Said reaction is usually carried out in the presence of a catalyst, such as palladium carbon or the like.

 Said reaction usually proceeds in a standard solvent, such as an alcohol, for example methanol, ethanol and the like. or any other solvent that does not adversely affect the reaction.

 The reaction temperature is not a critical parameter, and the reaction can proceed under conditions from cooling to heating.

.Method A

.

 Compound (Xa) or a salt thereof can be prepared by reacting a compound (IX) or a salt thereof with an acylating agent.

 The specified reaction is carried out by a method essentially similar to the method described in method 6 and therefore the conditions of this reaction correspond to the reaction conditions described in the specified method 6.

.Method A

.

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

 The reduction reaction usually proceeds in the presence of a reducing agent, such as di (lower) alkylaluminium hydride (e.g. diisobutylaluminum hydride, etc.), alkali metal hydride (e.g. lithium aluminum hydride, sodium aluminum hydride, potassium aluminum hydride, etc.) or like that.

 This reaction usually takes place in a standard solvent, such as toluene, tetrahydrofuran or any other solvent that does not adversely affect the reaction.

 The reaction temperature is not a critical parameter, and the reaction can proceed under cooling conditions or at room temperature.

.Method B

.

 Compound (XIII) or a salt thereof can be prepared by reacting a compound (XI) or a salt thereof with a solvent (XII) or a salt thereof.

 This reaction usually takes place in a standard solvent, such as acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N'-dimethylformamide, dimethyl sulfoxide, or any other solvent that does not adversely affect the reaction.

 The reaction temperature is not a critical parameter, and the reaction usually proceeds from cooling to heating.

.Method B

.

 Compound (II) or its salt can be obtained by eliminating the imino-protective group to which compound (XIII) or its salt is subjected.

 Said elimination reaction is carried out in a standard manner, such as hydrolysis, reduction, and the like. Hydrolysis can be carried out using an acid or a base and the like. These methods can be selected depending on the type of group to be deleted.

 Among standard methods, acid hydrolysis is one of the best known and preferred methods for removing a protecting group, such as substituted or unsubstituted alkoxycarbonyl (e.g. t-pentyloxycarbonyl, t-butoxycarbonyl, etc.), alkanoyl (e.g. , formyl and the like), cycloalkoxycarbonyl, substituted or unsubstituted aralkoxycarbonyl (e.g. benzyloxycarbonyl, substituted benzyloxycarbonyl and the like), or the like.

 The corresponding acid may be an organic or inorganic acid, for example, formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, and the like. and the preferred acid is formic acid, trifluoroacetic acid, hydrochloric acid, and the like. Acid suitable for the reaction may be selected according to the type of protecting group to be removed. If this reaction is carried out using an acid, then it can proceed in a solvent or without a solvent. The appropriate solvent may be a standard organic solvent (e.g., methanol, ethanol, tetrahydrofuran, etc.), water, or a mixture thereof.

 Hydrolysis in the presence of a base is preferably used to remove an acyl group, for example, a haloalkanoyl (e.g., dichloroacetyl, difluoroacetyl, etc.) and the like.

 A suitable base may be, for example, an inorganic base such as an alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.) an alkaline earth metal hydroxide (e.g. magnesium hydroxide, calcium hydroxide, etc.), alkali metal carbonate (e.g. sodium carbonate, potassium carbonate, carbonate, etc.), alkaline earth metal carbonate (e.g. magnesium carbonate, calcium carbonate, etc.), alkali metal bicarbonate (e.g. sodium bicarbonate, bicarbonate potassium, etc.), alkali metal acetate (e.g. sodium acetate, potassium acetate, etc.), alkaline earth metal phosphate (e.g. magnesium phosphate, calcium phosphate, etc.) alkali metal acid phosphate (e.g. alkali metal secondary acid phosphate (e.g. sodium hydrogen phosphate, potassium hydrogen phosphate and the like) and the like and an organic base such as trialkylamine (eg triethylamine, trimethylamine, etc.) or the like. in water, a standard organic solvent, or mixtures thereof. In case the acyl group is halogen-substituted alkoxycarbonyl or 8-quinolyloxycarbonyl, elimination is carried out by treatment with a heavy metal such as copper, zinc or the like.

 Reductive elimination is usually carried out in order to remove a protective group, for example, haloalkoxycarbonyl (e.g. trichloroethoxycarbonyl, etc.), substituted or unsubstituted aralkoxycarbonyl (e.g. benzyloxycarbonyl, substituted benzyloxycarbonyl, etc.) or the like. An appropriate reduction reaction can proceed, for example, in the presence of an alkali metal borohydride (e.g. sodium borohydride, etc.), and the like.

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

The target compound (I) and its pharmaceutically acceptable salts are thromboxane A ₂ antagonists (TXA ₂ ) and TXA ₂ synthetase inhibitors.

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

In the test described below, the 9,11-methanoepoxy PCH ₂ (I46619) used is pharmacologically characterized as a TXA ₂ mimetic agent and is widely used to evaluate the TXA ₂ antagonism of a test compound (see, for example, Journal of Pharmacology and Experimental Therapeut: cs Vol. 234 ppm 435-441).

 Test compound.

 (2S, 4R) -2 - [(Z) -5-carboxy-1-pentenyl] -4- / 4-chlorophenyl-sulfonylamino / -1- (3-pyridylmethyl pyrrolidine / this compound is hereinafter referred to as compound (1) /.

 Test 1.

Inhibition of TXA ₂ synthetase.

(a) Test method:
An aspirin-treated human platelet microsome (APM, Ran Biochem, Is real) was used as a source of TXA ₂ synthetase. APMs were suspended in 50 mM Tris / 100 mM NaCl buffer (pH 7.5). Then, 10 μl of the test compound solution was added to 90 μl of the APM suspension, and the resulting mixture was incubated for 3 min at 25 ^° C. And then 2 μl of PGH ₂ (10 μg / ml in acetone, Ran Biochem) was added to this mixture. After 3 minutes of incubation, the reaction was stopped by adding 10 μl of a solution of FeCl ₂ (25 mm H ₂ O) 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 4 ^° C. TXB ₂ in the supernatant was measured by radioimmunoassay. IC ₅₀ (dose that suppresses TXB ₂ generation by 50%) was determined graphically.

(c) Test result:
IC _{50 of the} test compound (1) 4.6 • 10 ^-8 M
Test 2.

 Inhibition of human platelet aggregation induced by I46619.

(a) Test method:
Human blood was taken from healthy male donors and mixed with 3.8 wt. /about. sodium citrate in a ratio of 9: 1. From blood treated with citrate, by centrifugation at 150 x g for 15 min, platelet rich plasma (PRP) was obtained. Platelet aggregation in PRP was studied photometrically using an aggregometer (NKK HAEMAT-PACEP 1). Then, 25 μl of a solution of the test compound was added to 225 μl of PRP and stirred at 1000 rpm for 2 min at 37 ^° C. To this solution, 5 μl of I46619 (final amount of 1.0 μM) was added as an aggregation inductor.

(c) Test result:
IC _{50 of} test compound 1 2.7 • 10 ^-7 M.

 The target compound (1) or its pharmaceutically acceptable salts can be administered to mammals, including humans, in the form of a pharmaceutical standard composition such as a capsule, microcapsule, tablet, granule, powder, troche, syrup, aerosol, inhalation preparation, solution, preparation for injection, suspension, emulsion, suppository, ointment, nasal drops, eye drops or the like.

 The pharmaceutical composition of the invention may contain various organic or inorganic carriers commonly used for pharmaceutical purposes, such as an inert excipient (e.g. sucrose, starch, mannitol, sorbitol, lactose, glucose, cellulose, talc, calcium phosphate, calcium carbonate, etc. p.), a binding agent (e.g. cellulose, methyl cellulose, hydroxypropyl cellulose, polypropyl pyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose, starch, etc.), a disintegrant (e.g. starch, carboxymethyl cellulose vine, carboxymethyl cellulose calcium salt, hydroxypropyl starch, sodium glycol starch, sodium bicarbonate, calcium phosphate, calcium citrate, etc.), a sizing agent (e.g. sodium stearate, talc, sodium lauryl sulfate, etc.), flavoring agent (e.g. citric acid, menthol, glycine, orange powders, etc.), a preservative agent (e.g. sodium benzoate, sodium bisulfite, methyl paraben, propyl paraben, etc.), a stabilizer (e.g. citric acid, sodium citrate, acetic acid and the like), a suspending agent (e.g. tylcellulose, polyvinylpyrrolidine, aluminum stearate, etc.), a dispersing agent, a diluent (e.g. water), a wax carrier (e.g. cocoa butter, polyethylene glycol, white petrolatum, etc.).

 The active ingredient can be administered 1-4 times a day with a single dose of from 0.01 mg / kg to 50 mg / kg. However, the indicated dose can be increased and decreased in accordance with the increase in weight, the condition of the patient or the route of administration.

 Example 1. (1) A solution of (2S, 4R) -4- (4-chlorophenylsulfonylamino) -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 hours at room temperature. The pH of the solution was adjusted to 5 with 10% hydrochloric acid, and then the solution was extracted with chloroform. The organic solution was washed with brine. The solution was dried over magnesium sulfate, and the solvent was evaporated in vacuo. The residue was chromatographed on a silica gel column (20 g), eluting with a mixture of chloroform and methanol (20: 1), whereby the compound (2S, 4R-2 - [(Z) -5-carboxy-1-pentenyl] -4- (4-Chlorophenyl-sulfonylamino) -1- (3-pyridyl) methyl pyrrolidine (408 mg) as a pale yellow amorphous substance.

¹ H-NMR (CDCI ₃ ) δ ppm. 1.6-1.75 (2H, m), 1.8-1.9 (2H, m), 2.1-2.25 (2H, m), 2.38 (2H, m), 3, 13 (1H, dd, J = 7.5, 10 Hz), 3.41 (1H, d, J = 13.5 Hz), 3.67 (1H, q, J = 8 Hz), 3.82 ( 1H, m), 3.9 (1H, d, J = 13.5 Hz), 5.36 (1H, t, J = 10Hz), 5.62 (1H, dt, J = 10, 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 a method similar to that described in example 1 (1).

 (2) (2S, 4R) -2 - [(Z) -5-carboxy-1-pentenyl] -4- (4-chlorophenylsulfonylamino) -1- (2-pyridylmethio) pyrrolidine.

 (3) (2S, 4R) -2 - [(Z) -5-carboxy-1-pentenyl] -4- (4-chlorophenylsulfonylamino) -1- (4-pyridylmethio) pyrrolidine.

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

¹ H-NMR (DMCO-d ₆ ) d ppm: 1.80 (2H, t, J = 6.5 Hz), 1.90 (1H, t, J = 8.5 Hz), 2.83 (1H, t, J = 8.5 Hz), 3.12 (1H, d, J = 13.5 Hz), 3.35-3.65 (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), 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), 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), 8.28 (1H, s), 8.39 (1H, d, J = 4.5 Hz )

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

¹ H-NMR (DMSO-1 ₆ ) d ppm 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), 3.72 (1H, d, J = 13.5 Hz), 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), 7.64 (1H, d, J = 8 Hz), 7.75-7.9 (4H, m), 8.06 (1H, d, J = 7.5 Hz) 8.27 (1H, m); 8.38 (1H, m).

 Example 2. (1) To a mixture of (2S, 4R) -4- (4-chlorophenylsulfonylamino) -2- [(Z) -5-methoxycarbonyl-1-pentenyl] pyrrolidine (356 mg) and nicotinaldehyde (98.6 mg) in methanol (5 ml) was added acetic acid (0.1 ml) and sodium cyanoborohydride (58 mg) and the resulting mixture was stirred for 3 hours at room temperature. Then, saturated aqueous sodium carbonate (20 ml) was added to this solution, and the resulting aqueous solution was extracted with chloroform (50 ml). The organic layer was washed with brine and dried in the presence of magnesium sulfate. The solvent was evaporated in vacuo, and the residue was chromatographed on a silica gel column (10 g), eluting with a mixture of chloroform and methanol (99: 1), whereby the compound (2S, 4R) -4- (4-chlorophenylsulfonylamino) -2- [ (Z) -5-methoxycarbonyl-1-pentenyl] -1- (3-pyridimethyl) pyrrolidine (340 mg).

 The following compounds were obtained by a method similar to that described in example 2 (1).

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

¹ H-NMR (CDCI ₃ ) d ppm 1.2-2.0 (5H, m), 2.07 (2H, q, J = 6.5 Hz), 2.31 (2H, t, J = 6.5 Hz), 3.0-3 , 2 (2H, m), 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), 5.53 (1H, dt, J = 10.5 Hz), 7.1-7.3 5H, m), 7.44 (2H, d, J = 8.5 Hz), 7.77 (2H, d, J = 8, 5 Hz).

 (3) (2S, 4R) -1- (4-chlorophenylmethyl) -4- (4-chlorophenylsulfonylamino) -2 - [(Z) -5-methoxycarbonyl-1-pentenyl] pyrrolidine.

¹ H-NMR (CDCI ₃ ) d ppm 1.6-2.0 (5H, m), 2.08 (1H, m), 2.28 (2H, t, J = 7.0 Hz), 3.04 (2H, m), 3.32 (1H, q, J = 7 Hz), 3.68 (1H, m), 3.69 (3H, s) 3.82 (1H, d, J = 12.5 Hz), 4.83 (1H, d, J = 7.5 Hz), 5.29 (1H, t, J = 10 Hz), 5.50 (1H, dt, J = 10.8 Hz), 7.12 (2H, d, J = 8 Hz), 7.32 (2H, d, J = 8 Hz), 7.48 (2H, d, J = 8.5 Hz), 7.79 (2H, d, J = 8.5 Hz).

 (4) (2S, 4R) -4- (4-chlorophenylsulfonylamino) -2- [(Z) -5-methoxycarbonyl-1-pentenyl] -1- (4-methylphenylmethyl) pyrrolidine.

¹ H-NMR (CDCI ₃ ) d ppm 1.6-1.8 (4H, m), 1.8-2.0 (2H, m), 2.0-2.2 (2H, m), 2.1-2.4 (3H, m ), 2.34 (3H, m), 2.9-3.1 (2H, m), 3.29 (1H, q, J = 9 Hz), 3.68 (3H, s), 3.10 (1H, m), 3.82 (1H, d, J = 13 Hz), 4.85 (1H, m), 5.32 (1H, d, J = 10 Hz), 5.52 (1H, di , J = 11.7.5 Hz), 7.0-7.15 (4H, m), 7.54 (1H, d, J = 9 Hz), 7.76 (2H, d, J = 9 Hz )

 (5) (2S, 4R) -4- (4-chlorophenylsulfonylamino) -2- [(Z) -5-methoxycarbonyl-1-pentenyl] -1- (4-methoxyphenylmethyl) pyrrolidine.

¹ H-NMR (CDCI ₃ ) d ppm 1.6-1.9 (5H, m), 2.05-2.15 (2H, m), 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), 3.69 (3H, s), 3.7 -3.85 (2H, m), 3.80 (3H, s), 4.84 (1H, d, J = 7.5 Hz), 5.30 (1H, t, J = 10 Hz), 5 52 (1H, dt, J = 10.7.5 Hz), 6.81 (2H, d, J = 9 Hz), 7.09 (2H, d, J = 9 Hz), 7.45 (2H d, J = 9 Hz), 7.77 (2H, d, J = 9 Hz).

 (6) (2S, 4R) -4- (4-chlorophenylsulfonylamino) -1- (3,4-dichlorophenylmethyl) -2 - [(Z) -5-methoxycarbonyl-1-pentenyl] pyrrolidine.

¹ H-NMR (CDCI ₃ ) d ppm 1.6-2.0 (5H, m), 2.0-2.15 (2H, m), 2.30 (2H, t, J = 7 Hz), 3.04 (1H, d, J = 14 Hz), 3.09 (1H, dd, J = 7.5, 10 Hz), 3.35 (1H, q, J = 10 Hz), 3.67 (3H, s), 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), 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-chlorophenylsulfonylamino) -2- [(Z) -5-methoxycarbonyl-1-pentenyl] -1- (4-phenylphenylmethyl) pyrrolidine.

¹ H-NMR (CDCI ₃ ) d ppm 1.6-1.8 (3H, m), 1.95 (1H, m), 2.08 (2H, m), 2.31 (1H, t, J = 7.5 Hz), 3.11 (1H, d, J = 14 Hz), 3.15 (1H, t, J = 7 Hz), 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), 5.34 (1H, t, J = 10 Hz), 5.55 (1H, dt, J = 10, 7.5 Hz), 7.19 (2H, d, J = 9 Hz), 7.3-7.65 (9H, m), 7, 83 (2H, d, J = 9 Hz).

 (8) (2S, 4R) -4- (4-chlorophenylsulfonylamino) -1- (4-cyanophenylmethyl) -2- [(Z) -5-methoxycarbonyl-1-pentenyl] pyrrolidine.

¹ H-NMR (CDCI ₃ ) d ppm 1.55-1.80 (4H, m), 1.9-2.15 (3H, m), 2.30 (2H, t, J = 7.5 Hz), 3.08 (1H, m) , 3.15 (1H, d, J = 14 Hz), 3.38 (1H, q, J = 9 Hz), 3.69 (3H, s), 3.76 (1H, m), 3.92 (1H, d, J = 14 Hz), 5.00 (1H, m), 5.25 (1H, dd, J = 10, 11 Hz), 5.53 (1H, dt, J = 10, 7.5 Hz), 7.32 (2H, d, J = 9 Hz), 7.46 (2H, d, J = 9 Hz), 7.59 (2H, d, J = 9 Hz), 7.78 (2H , d, J = 9 Hz).

 (9) (2S, 4R) -4- (4-chlorophenylsulfonylamino) -1- (2-hydroxyphenylmethyl) -2 - [(Z) -5-methoxycarbonyl-1-pentenyl] pyrrolidine.

¹ H-NMR (CDCI ₃ ) d ppm 1.6-1.75 (2H, m), 1.87 (2H, m), 2.05 (2H, d, J = 7 Hz), 2.16 (1H, m), 2.28 (2H , t, J = 7 Hz), 3.23 (1H, d, J = 13 Hz), 3.25 (1H, dd, J = 6, 11 Hz), 3.52 (1H, q, J = 7 5 Hz), 3.72 (1H, s), 3.81 (1H, m), 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-chlorophenylsulfonylamino) -2- [(Z) -5-methoxycarbonyl-1-pentenyl] -1-1 (2-thienylmethio) pyrrolidine.

¹ H-NMR (CDCI ₃ ) d ppm 1.6-1.9 (4H, m), 2.05-2.15 (3H, m), 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, br s) , 5.30 (1H, t, J = 10 Hz), 5.54 (1H, dt, J = 10, 7.5 Hz), 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-chlorophenylsulfonylamino) -1- (2-furylmethyl) -2 - [(Z) -5-methoxycarbonyl-1-pentenyl] pyrrolidine.

¹ H-NMR (CDCI ₃ ) d ppm 1.6-1.95 (5H, m), 2.0-2.15 (2H, m), 2.30 (2H, t, J = 7.5 Hz), 3.15-3.4 ( 3H, m), 3.68 (3H, s), 3.78 (1H, d, J = 15 Hz), 3.81 (1H, m), 4.82 (1H, d, J = 9 Hz) , 5.27 (1H, t, J = 10 Hz), 5.52 (1H, dt, J = 10, 7.5 Hz), 6.11 (1H, s), 6.30 (1H, s) 7.34 (1H, s), 7.47 (2H, d, J = 9 Hz), 7.78 (2H, d, J = 9 Hz).

 (12) (2S, 4R) -4- (4-chlorophenylsulfonylamino) -2- [(Z) -5-methoxycarbonyl-1-pentenyl] -1- (2-pyraziniolmethyl) pyrrolidine.

¹ H-NMR (CDCI ₃ ) d ppm 1.6-1.9 (4H, m), 2.05 (2H, m), 2.26 (1H, m), 2.28 (2H, t, J = 6.5 Hz), 3.25 (1H, dd, J = 10, 7.5 Hz), 3.51 (1H, d, J = 14 Hz), 3.53 (1H, m), 3.68 (3H, s), 3.84 (1H, m), 4.02 (1H, d, J = 14 Hz), 5.2-5.35 (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-chlorophenylsulfonylamino) -1-hexyl) -2- [(Z) -5-methoxycarbonyl-1-pentenyl] pyrrolidine.

¹ H-NMR (CDCI ₃ ) d ppm 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), 2.30 (2H, t, J = 7 Hz), 2.59 (1H, dt, J = 7, 13 Hz), 3.17 (1H, q, J = 8 Hz), 3.36 (1H, dd, J = 7.5, 10 Hz), 3.70 (3H, s), 3.80 (1H, m), 4.86 (1H, br,), 5.20 (1H, dd , J = 10, 11 Hz), 5.47 (1H, dt, J = 11, 7.5 Hz), 7.50 (2H, d, J = 9 Hz), 7.81 (2H, d, J = 9 Hz).

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

¹ H-NMR (CDCI ₃ ) d ppm 1.6-1.85 (4H, m), 2.0-2.1 (3H, m), 2.25-2.4 (3H, m), 2.6-2.75 (2H, m) ), 2.85 (1H, dd, J = 10, 13 Hz), 3.38 (1H, q, J = 8 Hz), 3.43 (1H, dd, J = 10, 7.5 Hz), 3.65 (3H, s), 3.81 (1H, m), 4.95 (1H, d, J = 7.5 Hz), 5.21 (1H, t, J = 10 Hz), 5, 48 (1H, dt, J = 10, 7.5 Hz), 7.05-7.35 (5H, m), 7.50 (2H, d, J = 9 Hz), 7.71 (2H, d , J = 9 Hz).

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

¹ H-NMR (CDCI ₃ ) d ppm 1.6-1.85 (6H, m), 1.95-2.1 (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 = 7.5-12 Hz), 7.1-7.3 (5H, m), 7.50 (2H, d, J = 9 Hz), 7.80 (2H, d, J = 9 Hz).

 (16) (2S, 4R) -4- (4-chlorophenylsulfonylamino) -2- [(Z) -4-methoxycarbonyl-1-butenyl] -1- (3-pyridylmethyl) pyrrolidine.

¹ H-NMR (CDCI ₃ ) d ppm 1.7-1.9 (2H, m), 2.00 (1H, m), 2.3-2.4 (4H, m), 3.08 (1H, dd, J = 6.10 Hz) , 3.13 (1H, d, J = 14 Hz), 3.42 (1H, q, J = 9 Hz), 3.66 (3H, s), 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), 5.4-5.6 (1H, m), 7.22 (1H, dd, J = 5, 7.5 Hz), 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-chlorophenylsulfonylamino) -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 was evaporated in vacuo. Water (20 ml) was added to the residue, and the pH of the aqueous solution was adjusted to a value of 7 with 1N. of hydrochloric acid. The precipitated solid was collected by filtration and dried in vacuo to give the compound (2S, 4R) -1-benzyl-2 - [(Z) -5-methoxycarbonyl-1-pentenyl] -4- (4-chlorophenylsulfonylamino) - pyrrolidine (176 mg).

Mp 87-91 ^o C.

¹ H-NMR (CDCI ₃ ) d ppm 1.71 (2H, m), 2.02 (2H, m), 2.17 (2H, m), 2.26 (2H, t, J = 6.5 Hz), 2.46 (1H, dd , J = 11 Hz), 3.10 (1H, dd, J = 6.5, 11 Hz), 3.65 (1H, d, J = 12.5 Hz), 3.9-4.0 (2H , m), 4.11 (1H, m), 5.45 (1H, t, J = 10 Hz), 5.73 (1H, dt, J = 10, 7.5 Hz), 7.23 (5H c), 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 examples 1 (1) and 3.

 (1) (2S, 4R) -2 - [(Z) -5-carboxy-1-pentenyl] -4- (4-chlorophenylsulfonylamino) -1- (2-quinolylmethyl) pyrrolidine.

¹ H-NMR (CDCI ₃ ) d ppm 1.6-1.75 (2H, m), 2.05-2.2 (4H, m), 2.3-2.4 (2H, m), 2.92 (1H, m), 3, 54 (1H, m), 4.03 (1H, m), 4.12 (1H, d, J = 14 Hz), 4.40 (1H, d, J = 14 Hz), 4.48 (1H, m), 5.5-5.7 (2H, m), 7.35 (2H, d, J = 8.5 Hz), 7.5-7.85 (6H, m), 8.07 (1H d, J = 8.5 Hz), 8.18 (1H, d, J = 8.5 Hz).

 (2) (2S, 4R) -1- (2-benzoxazolylmethyl) -2- [(Z) -5-carboxy-1-pentenyl] -4- (4-chlorophenylsulfonylamino) pyrrolidine.

¹ H-NMR (CDCI ₃ ) d ppm 1.55-1.7 (2H, m), 1.75-2.05 (4H, m), 2.26 (2H, t, J = 7 Hz), 2.58 (1H, dd, J = 2, 10 Hz), 3.44 (1H, dd, J = 7.10 Hz), 3.85-4.05 (2H, m), 3.97 (1H, d, J = 16 Hz), 4 12 (1H, d, J = 16 Hz), 5.28 (1H, t, J = 10 Hz), 5.53 (1H, dt, J = 10, 7 Hz), 7.3-7.45 (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-chlorophenylsulfonylamino) -1- (2-pyrazinylmethyl) pyrrolidine.

¹ H-NMR (CDCI ₃ ) d ppm 1.66 (2H, m), 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), 4.02 (1H, d, J = 14 Hz), 5.30 (1H , t, J = 10 Hz), 5.54 (1H, dt, J = 10, 7 Hz), 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-chlorophenylsulfonylamino) -1- (3-pyridylmethyl) pyrrolidine.

¹ H-NMR (CDCI ₃ ) d ppm 1.85 (2H, m), 2.3-2.5 (4H, m), 3.05 (1H, dd, J = 10.7 Hz), 3.28 (1H, d, J = 13 Hz ), 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), 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); 8.35-8.5 (2H, m).

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

¹ H-NMR (CDCI ₃ ) d ppm 1.54 (2H, m), 1.85 (2H, m), 2.14 (2H, m), 2.2-2.4 (3H, m), 3.12 (1H, dd, J = 7.9 Hz), 3.41 (1H, d, J = 13.5 Hz), 3.68 (1H, m), 3.85 (1H, m), 3.96 (1H, d, J = 13.5 Hz), 5.36 (1H, t, J = 10 Hz), 5.60 (1H, dt, J = 10, 7 Hz), 7.30 (1H, dd, J = 5.7 Hz ), 7.4-7.55 (3H, m), 7.7-7.8 (3H, m), 8.4-8.5 (2H, m).

 (6) (2S, 4R) - [(Z) -5-carboxy-1-pentenyl] -1- (4-chlorophenylmethyl) - 4- (4-chlorophenylsulfonylamino) pyrrolidine.

Mp 84-86 ^o C.

¹ H-NMR (CDCI ₃ ) d ppm 1.69 (2H, m), 1.98 (2H, m), 2.15 (2H, m), 2.28 (2H, m), 2.43 (2H, dd, J = 5.11 Hz ), 3.16 (1H, m), 3.57 (1H, d, J = 12.5 Hz), 3.85-4.1 (3H, m), 5.43 (1H, t, J = 10 Hz), 5.68 (1H, m), 7.15-7.25 (4H, m), 7.42 (2H, d, J = 8.5 Hz), 7.77 (2H, d, J = 8.5 Hz).

 (7) (2S, 4R) -2 - [(Z) -5-carboxy-1-pentenyl] -4- (4-chlorophenylsulfonylamino) -1- (4-methylphenylmethyl) pyrrolidine.

¹ H-NMR (CDCI ₃ ) d ppm 1.6-1.8 (2H, m), 1.9-2.1 (2H, m), 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), 3.64 (1H, d, J = 13 Hz), 3.93 (1H, d, J = 13 Hz), 3.95 (1H, m), 4.12 (1H, m), 5.45 (1H, t, J = 10 Hz), 5.74 (1H, dt, J = 10, 7.5 Hz), 7.08 (2H, d, J = 7 Hz), 7.15 (2H, d, J = 7 Hz), 7.40 (2H, d, J = 9 Hz), 7.75 (2H, d, J = 9 Hz).

 (8) (2S, 4R) -2 - [(Z) -5-carboxy-1-pentenyl] -4- (4-chlorophenylsulfonylamino) -1- (4-methoxyphenylmethyl) pyrrolidine.

¹ H-NMR (CDCI ₃ ) d ppm 1.6-1.8 (2H, m), 2.00 (2H, m), 2.15-2.3 (4H, m), 2.45 (1H, dd, J = 5, 12 Hz) , 3.08 (1H, dd, J = 7.5, 12 Hz), 3, 59 (1H, d, J = 13 Hz), 3.78 (3H, s), 3.82 (1H, d, J = 13 Hz), 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), 6.80 (2H, d, J = 9 Hz), 7.16 (2H, d, J = 9 Hz), 7.40 (2H, l, J = 9 Hz), 7.77 (2H, d, J = 9 Hz).

 (9) (2S, 4R) -2 - [(Z) -5-carboxy-1-pentenyl] -4- (4-chlorophenylsulfonylamino) -1- (3,4-dichlorophenylmethyl) pyrrolidine.

¹ H-NMR (CDCI ₃ ) d ppm 1.6-1.75 (2H, m), 1.9-2.05 (2H, m), 2.1-2.25 (2H, m), 2.3-2.45 (3H, m) ), 3.17 (1H, m), 3.42 (1H, m), 3.75-4.0 (3H, m), 5.42 (1H, t, J = 10 Hz), 5.67 (1H, dt, J = 10.7 Hz), 7.1-7.4 (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- (-chlorophenylsulfonylamino) -1- (4-phenylphenylmethyl) pyrrolidine.

¹ H-NMR (CDCI ₃ ) d ppm 1.55-1.8 (2H, m), 1.85-2.0 (2H, m), 2.15-2.3 (2H, m), 2.3-2.4 (2H, m) ), 3.11 (1H, dd, J = 7.5-12 Hz), 3.52 (1H, d, J = 13 Hz), 3.8-4.0 (3H, m), 5.40 ( 1H, t, J = 12 Hz), 5.69 (1H, dt, J = 12, 7.5 Hz), 7.15 (2H, d, J = 9 Hz), 7.35-7.6 ( 9H, m), 7.83 (2H, d, J = 9 Hz).

 (11) (2S, 4R) -2 - [(Z) -5-carboxy-1-pentenyl] -4- (4-chlorophenylsulfonylamino) -1- (4-cyanophenylmethyl) pyrrolidine.

¹ H-NMR (CDCI ₃ ) d ppm 1.67 (2H, m), 1.88 (2H, m), 2.0-2.4 (5H, m), 3.10 (1H, m), 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), 5.35 (1H , t, J = 10 Hz), 5.62 (1H, dt, J = 10, 7.5 Hz), 7.37 (2H, d, J = 9 Hz), 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-chlorophenylsulfonylamino) -1- (2-hydroxyphenylmethyl) pyrrolidine.

¹ H-NMR (CDCI ₃ + CD ₃ OD) d ppm 1.6-1.75 (2H, m), 2.0-2.2 (4H, m), 2.33 (2H, t, J = 6.5 Hz), 2.70 (1H, dd, J = 5.5, 11 Hz), 3.41 (1H, dd, J = 6.5, 11 Hz), 3.64 (1H, d, J = 13 Hz), 3.85-4.05 ( 2H, m), 4.77 (1H, d, J = 13 Hz), 5.47 (1H, t, J = 10 Hz), 5.73 (1H, dt, 110, 7.5 Hz), 6 81 (2H, d, J = 7.5 Hz), 7.10 (1H, dd, J = 7.5, 10 Hz), 7.21 (1H, td, J = 1, 7.5 Hz) 7.48 (1H, d, J = 9 Hz); 7.78 (1H, d, J = 9 Hz).

 (13) (2S, 4R) -2 - [(Z) -5-carboxy-1-pentenyl] -4- (4-chlorophenylsulfonylamino) -1- (2-thienylmethyl) pyrrolidine.

¹ H-NMR (CDCI ₃ ) d ppm 1.6-1.85 (2H, m), 1.9-2.05 (2H, m), 2.1-2.25 (2H, m), 2.34 (2H, t, J = 7 Hz), 2.48 (1H, dd, J = 5, 11 Hz), 3.21 (1H, dd, J = 7.5, 11 Hz), 3.85 (1H, d, J = 15 Hz) 3.85-3.95 (2H, m), 4.08 (1H, d, J = 15 Hz), 5.44 (1H, t, J = 10 Hz), 5.70 (1H, dt, J = 10, 7.5 Hz), 6.93 (2H, m), 7.23 (1H, dd, J = 2.4 Hz), 7.42 (2H, d, J = 9 Hz), 7 78 (2H, d, J = 9 Hz).

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

¹ H-NMR (CDCI ₃ ) d ppm 1.6-1.75 (2H, m), 1.8-2.95 (2H, m), 2.1-2.1 (2H, m), 2.25-2.4 (2H, m) ), 3.20 (1H, dd, J = 11.7.5 Hz), 3.51 (1H, d, J = 14 Hz), 3.6-4.0 (3H, m), 5.32 (1H, t, J = 10 Hz), 5.65 (1H, dt, J = 10, 7.5 Hz), 6.19 (1H, d, J = 3 Hz), 6.30 (1H, dd , J = 3, 1.5 Hz), 7.32 (1H, d, J = 1.5 Hz), 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-chlorophenylsulfonylamino) -1-hexyl-pyrrolidine.

¹ H-NMR (CDCI ₃ ) d ppm 0.83 (3H, t, J = 7 Hz), 1.15-1.35 (8H, m), 1.5-1.8 (4H, m), 2.05-2.3 (5H, m), 2.73 (1H, m), 3.06 (1H, dd, J = 4, 13 Hz), 3.38 (1H, dd, J = 7, 10 Hz), 4.09 (1H, m), 4.35 (1H, m), 5.40 (1H, t, J = 10 Hz), 5.79 (1H, dt, J = 10, 7.5 Hz), 7.49 (1H, d, J = 9 Hz), 7.85 (1H, d, J = 9 Hz).

 (16) (2S, 4R) -2 - [(Z) -5-carboxy-1-pentenyl] -4- (4-chlorophenylsulfonylamino) -1- (2-phenethyl) pyrrolidine.

¹ H-NMR (CDCI ₃ ) d ppm 1.55-1.8 (2H, m), 2.0-2.35 (5H, m), 2.48 (1H, m), 2.8-3.1 (4H, m), 3, 3-3.6 (2H, m), 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), 7.0-7.3 ( 5H, m), 7.45 (2H, d, J = 9 Hz), 7.81 (2H, d, J = 9 Hz).

 (17) (2S, 4R) -2 - [(Z) -5-carboxy-1-pentenyl] -4- (4-chlorophenylsulfonylamino) -1- (3-phenylpropyl) pyrrolidine.

¹ H-NMR (CDCI ₃ ) d ppm 1.5-1.8 (2H, m), 1.92.3 (7H, m), 2.55-2.65 (3H, m), 2.91 (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), 7.0-7.3 (5H, m), 7.41 (2H, d, J = 9 Hz), 7.81 (2H, d, J = 9 Hz).

 (18) (2S, 4R) -1 - / (2-beneothiazolimethyl) -2 - [(Z) -5-carboxy-1-pentenyl] -4- (4-chlorophenylsulfonylamino) pyrrolidine.

 Example 5. (2S, 4R) -1- (2-benzothiazolylmethyl) -2- [(Z) -5-methoxycarbonyl-1-pentenyl] -4- (4-chlorophenylsulfonylamino) pyrrolidine was dissolved in 1-n-sodium hydroxide and the solution was introduced into a Diai on HP 20 column. The column was washed with water and eluted with 70% aqueous methanol. The desired fractions were collected and the volatile solvent was evaporated in vacuo. The resulting aqueous solution was lyophilized to obtain the sodium salt of the compound (2S, 4R) -1- (2-benzothiazolylmethyl) -2- [(Z) -5-carboxy-1-pentenyl] -4- (4-chlorophenylsulfonylamino) pyrrolidine.

¹ H-NMR (D ₂ O) d ppm 1.45 (2H, m), 1.70 (2H, t, J = 7 Hz), 1.9-2.1 (5H, m), 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), 7.25-7.45 (2H, d, J = 8.5 Hz ), 7.81 (2H, d, J = 8.5 Hz).

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

 (1) (2S, 4R) -4- (4-chlorophenylsulfonylamino) -2- [(Z) -5-methoxycarbonyl-1-pentenyl] -1- (3-quinolylmethyl) pyrrolidine.

¹ H-NMR (CDCI ₃ ) d ppm 1.65-1.9 (4H, m), 2.0-2.2 (3H, m), 2.33 (2H, t, J = 7 Hz), 3.15 (1H, dd, J = 7, 10 Hz), 3.30 (1H, d, J = 13.5 Hz), 3.43 (1H, q, J = 9 Hz), 3.68 (3H, s), 3.77 (1H , m), 4.05 (1H, d, J = 13.5 Hz), 4.91 (1H, d, J = 7.5 Hz), 5.35 (1H, t, J = 10 Hz), 5.58 (1H, dt, J = 10.7.5 Hz), 7.42 (2H, d, J = 8.5 Hz), 7.55 (1H, m), 7.65-7.8 (4H, m), 7.96 (1H, m), 8.10 (1H, d, J = 8 Hz), 8.81 (1H, d, J = 1.5 Hz).

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

¹ H-NMR (CDCI ₃ ) d ppm 1.6-2.0 (4H, m), 2.18 (2H, m), 2.33 (2H, t, J = 7.5 Hz), 2.91 (1H, dd, J = 6, 10 Hz), 3.30 (1H, d, J = 12.5 Hz), 3.44 (1H, q, J = 10 Hz), 3b68 (3H, s), 4.40 (1H, d, J = 12b5 Hz), 4.95 (1H, broad, s), 5.46 (1H, dd, J = 10, 9 Hz), 5.63 (1H, dt, J = 10, 7.5 Hz), 7.1-7.9 (10H, m); 8.15 (1H, m).

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

¹ H-NMR (CDCI ₃ ) d ppm 1.66-2.03 (4H, m), 2.10 (2H, q, J = 7.5 Hz), 2.30 (2H, t, J = 7.5 Hz), 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 , s), 3.75 (1H, m), 4.02 (1H, d, J = 12.5 Hz), 4.92 (1H, br s), 5.36 (1H, dd, J = 10, 11 Hz), 5.56 (1H, dt, J = 11.7.5 Hz), 7.3-7.5 (5H, m), 7.60 (1H, br s), 7, 67-7.90 (5H, m).

 (4) (2S, 4R) -1 - [(4-acetylaminophenyl) methyl] -4- (4-chlorophenylsulfonylamino) -2 - [(Z) -5-methoxycarbonyl-1-pentenyl] pyrrolidine.

¹ H-NMR (CDCI ₃ ) d ppm 1.55-1.95 (4H, m), 2.08 (2H, m), 2.16 (3H, s), 2.30 (2H, t, J = 7.5 Hz), 2.95 -3.10 (2H, m), 3.30 (2H, q, J = 7.5 Hz), 3.68 (3H, s), 3.75 (1H, m), 3.8 (1H, d, J = 12 Hz), 5.30 (1H, m), 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), 7.45 (2H, d, J = 10 Hz), 7.58 (1H, br C), 7.76 (2H, d, J = 10 Hz).

 (5) (2S, 4R) -4- (4-chlorophenylsulfonylamino) -1- (4-hydroxyphenylmethyl) -2 - [(Z) -5-methoxycarbonyl-1-pentenyl] pyrrolidine.

¹ H-NMR (CDCI ₃ ) d ppm 1.60-2.20 (8H, m), 2.30 (2H, t, J = 7.5 Hz), 3.02 (1H, d, J = 12 Hz), 3.09 (1H, dd , J = 7.5, 10 Hz), 3.31 (1H, q, J = 7.5 Hz), 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), 6.64 (2H, d, J = 10 Hz), 7.00 (2H, d, J = 10 Hz), 7.44 (2H, d, J = 10 Hz), 7.75 (2H, d, J = 10 Hz).

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

¹ H-NMR (CDCI ₃ ) d ppm 1.60-1.95 (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), 3.27 (1H, q, J = 7.5 Hz), 3.69 (3H, s), 3.72 (1H, m) , 3.78 (1H, d, J = 12 Hz), 4.80 (1H, br.s), 5.32 (1H, t, J = 10 Hz), 5.51 (1H, dt, J = 10, 7.5 Hz), 6.60 (2H, d, J = 10 Hz), 7.01 (2H, d, J = 10 Hz), 7.45 (2H, d, J = 10 Hz) 7.75 (2H, d, J = 10 Hz).

 (7) (2S, 4R) -4- (4-chlorophenylsulfonylamino-2- [(Z) -5-methoxycarbonyl-1-pentenyl] -1- (2-pyrrolimethyl) pyrrolidine.

¹ H-NMR (CDCI ₃ ) d ppm 1.60-1.85 (4H, m), 1.95-2.15 (2H, m), 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), 3.69 (3H, s), 3 , 33 (1H, m), 3.78 (1H, d, J = 12 Hz), 5.10 (1H, br s), 5.25 (1H, t, J = 10 Hz), 5.50 (1H, dt, J = 10, 7.0 Hz), 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, br s .).

 (8) (2S, 4R) -1 - [(2-chlorophenyl) methyl] -4- (4-chlorophenylsulfonylamino) -2 - [(Z) -5-methoxycarbonyl-1-pentenyl] pyrrolidine.

¹ H-NMR (CDCI ₃ ) d ppm 1.60-1.90 (4H, m), 2.10 (3H, m), 2.30 (2H, t, J = 7.5 Hz), 3.12 (1H, dd, J = 10, 7.5 Hz), 3.30 (1H, l, J = 12 Hz), 3.43 (1H, q, J = 7.5 Hz), 3.70 (3H, s), 3.80 (1H , m), 3.88 (1H, d, J = 12 Hz), 4.80 (1H, br s), 5.33 (1H, d, J = 10 Hz), 5.52 (2H, d , J = 10 Hz), 7.76 (2H, d, J = 10 Hz).

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

¹ H-NMR (CDCI ₃ ) d ppm 1.00 (3H, t, J = 7.0 Hz), 1.56-1.85 (4H, m), 1.87-2.15 (4H, m), 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), 3.69 (3H, s), 3.81 (1H, m), 5.20 (1H, t, J = 10 Hz), 5.49 (1H, dt, J = 10, 7.5 Hz), 7.50 (2H, d, J = 10 Hz), 7.81 (2H, d, J = 10 Hz).

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

¹ H-NMR (CDCI ₃ ) d ppm 0.88 (3H, t, J 7.5 Hz), 1.15-1.40 (20H, m), 1.55-1.80 (4H, m), 1.85-2.15 (4H , m), 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), 3.80 (1H, m), 4.88 (1H, m), 5 , 20 (1H, t, J = 10 Hz), 5.47 (1H, dt, J = 10, 7.5 Hz), 7.50 (2H, d, J = 10 Hz), 7.82 (2H , d, J = 10 Hz).

 (11) (2S, 4R) -4- (4-chlorophenylsulfonylamino) -2- [(Z) -5-methoxycarbonyl-1-pentenyl] -1- (5-phenylpentyl) pyrrolidine.

¹ H-NMR (CDCI ₃ ) d ppm 1.20-1.45 (4H, m), 1.50-1.80 (6H, m), 1.85-2.10 (4H, m), 2.29 (2H, t, J = 7 5 Hz), 2.58 (1H, m), 2.58 (2H, t, J = 8.0 Hz), 3.15 (1H, q, J = 8.0 Hz), 3.36 ( 1H, dd, J = 7.5, 10 Hz), 3.68 (3H, s), 3.80 (1H, br s), 4.97 (1H, br s), 5.18 (1H , t, J = 10 Hz), 5.46 (1H, dt, J = 10, 7.5 Hz), 7.10-7.35 (5H, m), 7.50 (2H, d, J = 10 Hz), 7.82 (2H, d, J = 10 Hz)
(12) (2S, 4R) -4- (4-chlorophenylsulfonylamino) -2- [(Z) -5-methoxycarbonyl-1-pentenyl] -1- (4-phenylbutyl) pyrrolidine.

¹ H-NMR (CDCI ₃ ) d ppm 1.30-1.80 (6H, m), 1.83-2.12 (4H, m), 2.28 (2H, t, J = 7.5 Hz), 2.50-2.70 ( 4H, m), 3.16 (1H, q, J = 7.5 Hz), 3.34 (1H, dd, J = 7.5, 10 Hz), 3.67 (3H, s), 3, 80 (1H, m), 4.98 (1H, m), 5.17 (1H, t, J = 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-chlorophenylsulfonylamino) -2- [(Z) -5-methoxycarbonyl-1-pentenyl] -1- [2- (3-pyridyl) ethyl] pyrrolidine.

¹ H-NMR (CDCI ₃ ) d ppm 1.6-1.9 (4H, m), 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), 5.05-5.20 (2H, m), 5.47 (1H, dt, J = 7.5 11 Hz), 7.17 (1H, dd, J = 5, 7.5 Hz), 7.45 (1H, m), 7.48 (2H, d, J = 8 Hz), 7.80 (2H, d, J = 8 Hz), 8 42 (2H, m).

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

¹ H-NMR (CDCI ₃ ) d ppm 1.6-1.8 (4H, m), 2.0-2.2 (3H, m), 2.29 (2H, t, J = 6.5 Hz), 2.50 (1H, m) 2.94 (1H, m), 3.25-3.4 (2H, m), 3.68 (3H, s), 3.78 (1H, m), 3.94 (2H, t, J = 6 Hz), 5.07 (1H, t, J = 10 Hz), 5.47 (dt, J = 10, 7.5 Hz), 5.68 (1H, wide d.J = 7 Hz) 6.88 (1H, s), 7.0 (1H, s), 7.49 (2H, d, J = 8 Hz), 7.50 (1H, s), 7.78 (2H, d, J = 8 Hz).

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

¹ H-NMR (CDCI ₃ ) d ppm 1.3-1.45 (2H, m), 1.55-1.7 (2H, m), 1.76 (1H, m), 1.85 (1H, m), 1.95-2, 1 (3H, m), 2.33 (2H, t, J = 7 Hz), 3.08 (1H, m), 3.11 (1H, d, J = 13.5 Hz), 3.36 ( 1H, q, J = 8.5 Hz), 3.65 (3H, s), 3.75 (1H, m), 3.88 (1H, d, J = 13.5 Hz), 5.24 ( 1H, t, J = 8 Hz), 5.54 (1H, dt, J = 8, 11 Hz), 7.23 (1H, dd, J = 4.5 7.5 Hz), 7.46 (2H d, J = 8 Hz), 7.54 (1H, m), 7.78 (2H, d, J = 8 Hz), 8.4-8.5 (2H, m).

 (16) (2S, 4R) -2 - [(Z) -5-methoxycarbonyl-1-pentenyl] -1- (3-pyridylmethyl-4- [4- (trifluoromethyl) phenylsulfonylamino] pyrrolidine.

¹ H-NMR (CDCI ₃ ) d ppm 1.65-1.90 (4H, m), 2.0-2.15 (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), 3.69 (3H, s), 3.27 (1H, m), 3.38 (1H, d, J = 13 Hz), 5.2-5.35 (2H, m), 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), 7.77 (2H, d, J = 8 Hz), 7.98 (2H, d, J = 8 Hz), 8.4-8.5 (2H, m).

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

¹ H-NMR (CDCI ₃ ) d ppm 1.65-1.80 (4H, m), 1.80-1.95 (2H, m), 2.00-2.15 (2H, m), 2.29 (2H, t, J = 7 5 Hz), 3.05 (1H, d, J = 12 Hz), 3.09 (1H, t, J = 8.0 Hz), 3.30 (1H, m), 3.67 (3H, s), 3.75 (1H, m), 3.86 (1H, d, J = 12 Hz), 5.00 (1H, m), 5.30 (1H, t, J = 10 Hz), 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) pyrrolidine.

¹ H-NMR (CDCI ₃ ) d ppm 1.60-1.80 (4H, m), 1.90-2.20 (4H, m), 2.33 (2H, t, J = 8 Hz), 3.12 (1H, d, J = 12.5 Hz), 3.30 (2H, m), 3.65 (3H, s), 3.94 (1H, d, J = 12.5 Hz), 4.18 (1H, m), 4 85 (1H, m), 5.07 (2H, s), 5.30-5.60 (2H, m), 7.20-7.35 (5H, m).

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

¹ H-NMR (D ₂ O-DCI) d ppm 1.5-1.65 (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), 4.02 (1H, m), 4.5-4.7 (2H, m), 5.33 (1H, t, J = 8 Hz), 5.83 (1H, dt, J = 10, 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), 8.90 (1H, s).

 Example 7. The following compounds were obtained by the methods described in examples 1 (1) and 3.

 (1) (2S, 4R) -2 - [(Z) -5-carboxy-1-pentenyl] -4- (4-chlorophenylsulfonylamino) -1- (3-quinolylmethyl) pyrrolidine.

¹ H-NMR (CDCI ₃ ) d ppm 1.6-1.8 (2H, m), 1.85-1.95 (2H, m), 2.15-2.25 (2H, m), 2.25-2.4 (3H, m) ), 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), 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), 8.05 (1H, m), 8.81 (1H, d, J = 1.5 Hz).

 (2) (2S, 4R) -2 - [(Z) -5-carboxy-1-pentenyl] -4- (4-chlorophenylsulfonylamino) -1- (4-thiazolylmethyl) pyrrolidine.

¹ H-NMR (CDCI ₃ ) d ppm 1.6-1.8 (2H, m), 1.95-2.05 (2H, m), 2.1-2.2 (2H, m), 2.25-2.35 (2H, m ), 2.65 (1H, dd, J = 4.5, 11 Hz), 3.34 (1H, dd, J = 6, 11 Hz), 3.85-3.95 (2H, m), 4 05-4.15 (2H, m), 5.45 (1H, t, J = 10 Hz), 5.68 (1H, dt, J = 10, 7.5 Hz), 7.42 (1H, m), 7.43 (2H, d, J = 8 Hz), 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-chlorophenylsulfonylamino) -1- (5-thiazolylmethyl) pyrrolidine.

¹ H-NMR (CDCI ₃ ) d ppm 1.65-1.9 (4H, m), 2.1-2.25 (3H, m), 2.32 (2H, t, J = 7 Hz), 3.19 (1H, dd, J = 7.9 Hz), 3.55 (1H, q, J = 9 Hz), 3.65 (2H, d, J = 14 Hz), 3.81 (1H, m), 4.03 (1H, d , J = 14 Hz), 5.29 (1H, t, J = 10 Hz), 5.58 (1H, dt, J = 10, 7.5 Hz), 7.45 (2H, d, J = 8 5 Hz), 7.68 (1H, s), 7.77 (1H, s), 8.80 (1H, s).

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

¹ H-NMR (CDCI ₃ ) d ppm 1.55-1.75 (2H, m), 1.9-2.0 (2H, m), 2.05-2.2 (2H, m), 2.29 (2H, t, J = 6 Hz), 2.6-2.7 (2H, m), 2.8-3.0 (3H, m), 3.50 (1H, m), 3.8-4.0 (2H, m) , 5.31 (1H, t, J = 10 Hz), 5.62 (1H, dt, J = 7.5, 11 Hz), 7.03 (1H, m), 7.45 (2H, d, J = 8 Hz), 7.55 (1H, m), 7.83 (2H, d, J = 8 Hz), 8.44 (2H, m).

 (5) (2S, 4R) -2 - [(Z) -5-carboxy-1-pentenyl] -4- (4-chlorophenylsulfonylamino) -1- [2- (1-imidazolyl) ethyl] pyrodiline.

¹ H-NMR (CDCI ₃ + CD ₃ OD) d mln. 1.5-1.7 (4H, m), 2.0-2.15 (3H, m), 2.23 (2H, t, J = 7 Hz), 2.50 (1H, m), 2 92 (1H, m), 3.2-3.4 (2H, m), 3.70 (1H, m), 3.95 (2H, t, J = 6 Hz), 5.10 (1H, t, J = 10 Hz), 5.45 (1H, dt, J = 7.5, 10 Hz), 6.96 (2H, s), 7.45 (2H, d, J = 8 Hz), 7 63 (1H, s); 7.77 (2H, d, J = 8 Hz).

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

¹ H-NMR (CDCI ₃ + CD ₃ OD) d ppm 1.35-1.45 (2H, m), 1.6-1.65 (2H, m), 1.65-1.85 (2H, m), 2.0-2.15 (3H, m) ), 2.30 (2H, t, J = 8 Hz), 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), 5.22 (1H, t, J = 8 Hz), 5.58 (1H, dt, J = 10.5, 8 Hz), 7.29 (1H, dd, J = 4.5-8 Hz), 7.46 (2H, d, J = 8 Hz), 7.63 (1H, dt, J = 7.5, 1.5 Hz), 7.77 (1H, d, J = 8 Hz), 8.35-8.45 (2H, m) .

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

¹ H-NMR (CDCI ₃ ) d ppm 1.6-1.7 (2H, m), 1.8-1.9 (2H, m), 2.1-2.25 (3H, m), 2.3-2.4 (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), 5.30 (1H, t, J = 10 Hz), 5.59 (1H, dt, J = 10, 7.5 Hz), 7.30 (1H, dd, J = 5.8 Hz), 7.65-7.75 (3H, m), 7.97 (2H, d, J = 8 Hz), 8.45- 8.55 (2H, m).

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

¹ H-NMR (D ₂ O-DC ₁ ) d ppm 1.5-1.65 (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), 4.02 (1H, m), 4.5-4.7 (2H , m), 5.33 (1H, t, J = 10 Hz), 5.83 (1H, dt, J = 10, 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, d, J = 5.5 Hz), 8, 90 (1H, s).

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

¹ H-NMR (CDCI ₃ ) d ppm 1.68 (2H, m), 1.90 (2H, m), 2.15 (2H, m), 2.30 (2H, t, J = 7 Hz), 2.96 (1H, dd, J = 7.5, 10 Hz), 3.59 (1H, d, J = 12.5 Hz), 3.75 (2H, m), 4.60 (1H, d, J = 12.5 Hz), 5.49 (1H, t, J = 10 Hz), 5.68 (1H, dt, J = 10.6 Hz), 7.20-7.55 (6H, m), 7.60-7.90 (4H, m), 8.00-8.15 (1H, m).

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

¹ H-NMR (CDCI ₃ ) d ppm 1.65 (2H, m), 1.90 (2H, m), 2.13 (2H, m), 2.28 (2H, m), 3.10 (1H, dd, J = 9.0 10 Hz), 3.56 (1H, d, J = 13 Hz), 3.91 (1H, m), 4.00 (1H, d, J = 13 Hz), 5.39 (1H, t, d, 10 Hz), 5.64 (1H, dt, J = 10.8.0 Hz), 7.20-7.90 (11H, m).

 (11) (2S, 4R) -1 - [(4) -acetylaminophenyl / methyl] -2- [(Z) -5-carboxy-1-pentenyl] -4- (4-chlorophenylsulfonylamino) pyrrolidine.

¹ H-NMR (DMCO-d ₆ ) d ppm 1B43-1.70 (4H, m), 1.75-2.10 (2H, m), 2.00 (3H, s), 2.19 (2H, t, J = 7.5 Hz), 2 79 (1H, m), 2.96 (1H, d, J = 12 Hz), 3.70 (1H, d, J = 12 Hz), 5.22 (1H, m), 5.48 (1H , m), 7.04 (2H, d, J = 10 Hz), 7.48 (2H, d, J = 10 Hz), 7.63 (2H, d, J = 9 Hz), 7.76 ( 2H, d, J = 9 Hz), 7.98 (1H, br s).

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

¹ H-NMR (DMCO-d ₆ ) d ppm 1.50-1.75 (4H, m), 2.09 (2H, m), 2.20 (2H, t, J = 7.5 Hz), 2.86 (1H, br s) 5, 26 (1H, m), 5.50 (1H, m), 6.67 (2H, d, J = 9.0 Hz), 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, br s), 9.22 (1H, br s).

 (13) (2S, 4R) -2 - [(Z) -5-carboxy-1-pentenyl] -4- (4-chlorophenylsulfonylamino) -1 - [{4- (dimethylamino) phenyl} methyl] pyrrolidine.

¹ H-NMR (DMCO-d ₆ ) d ppm 1.45-1.77 (4H, m), 2.06 (2H, m), 2.20 (2H, t, J = 7.5 Hz), 2.88 (6H, s), 5.30 (1H, m), 5.53 (1H, m), 6.64 (2H, d, J = 10 Hz), 6.97 (2H, m), 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-chlorophenylsulfonylamino) -1- (2-pyrrolylmethyl) pyrrolidine.

¹ H-NMR (DMCO-d ₆ ) d ppm 1.37 (2H, m), 1.48 (2H, m), 1.86 (2H, m), 2.00 (2H, t, J = 7.5 Hz), 2.70-3.75 (6H, m), 5.12 (1H, t, J = 10 Hz), 5.35 (1H, dt, J = 10, 7.5 Hz), 5.63 (1H, br s), 5 75 (1H, br s), 6.45 (1H, br s), 7.46 (2H, d, J = 10 Hz), 7.60 (2H, d, J = 10 Hz), 7 93 (1H, br s).

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

¹ H-NMR (CDCI ₃ ) d ppm 1.70 (2H, m), 1.90 (2H, m), 2.16 (2H, m), 2.30 (2H, m), 3.11 (1H, m), 3.50 (1H , m), 3.85 (2H, m), 3.85 (2H, m), 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), 7.11-7.55 (6H, m), 7.76 (2H, d, J = 10 Hz).

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

¹ H-NMR (CDCI ₁ ) d ppm 1.4-1.65 (4H, m), 1.9-2.05 (2H, m), 2.1-2.2 (3H, m), 2.32 (1H, m), 2, 90 (1H, m), 3.9-4.1 (2H, m), 4.73 (1H, C), 5.35-5.45 (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-chlorophenylsulfonylamino) -1-ethylpyrrolidine.

¹ H-NMR (DMCO-d ₆ ) d ppm 1.05 (3H, m), 1.50 (4H, m), 2.00 (4H, m), 2.18 (2H, m), 5.2-5.7 (2H, m), 7 69 (2H, m); 7.85 (2H, m).

 (18) (2S, 4R) -2 - [(Z) -5-carboxy-1-pentenyl] -4- (4-chlorophenylsulfonylamino) -1-dodecylpyrrolidine.

¹ H-NMR (CDCI ₁ ) d ppm 0.88 (3H, t, J = 7.5 Hz), 1.14-1.36 (20H, m), 1.36-1.55 (2H, m), 1.55-1.74 ( 2H, m), 1.86-2.15 (4H, m), 2.20 (2H, m), 2.56 (1H, m), 2.85 (1H, m), 3.15 (1H , m), 4.03 (1H, m), 5.24 (1H, m), 5.68 (1H, m), 7.47 (2H, d, J = 10 Hz), 7.85 (2H , d, J = 10 Hz).

 (19) (2S, 4R) -2 - [(Z) -5-carboxy-1-pentenyl] -4- (4-chlorophenylsulfonylamino) -1- (5-phenylpentyl) pyrrolidine.

¹ H-NMR (CDCI ₃ ) d ppm 1.10-1.40 (2H, m), 1.40-1.80 (6H, m), 1.95-2.30 (6H, m), 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), 5.15 (1H, t, J = 10 Hz), 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-chlorophenylsulfonylamino) -1- (4-phenylbutyl) pyrrolidine.

¹ H-NMR (CDCI ₃ ) d ppm 1.4-1.8 (6H, m), 2.08 (4H, m), 2.20 (2H, m), 2.55 (2H, m), 2.78 (2H, m), 3 05 (1H, m), 3.38 (1H, m), 4.05 (1H, m, 4.33 (1H, m), 5.40 (1H, t, J = 10 Hz), 5, 75 (1H, d, J = 10 Hz), 7.5 Hz), 7.00-7.34 (5H, m), 7.45 (2H, d, J = 10 Hz), 7.84 (2H , d, J = 10 Hz).

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

¹ H-NMR (CDCI ₃ ) d ppm 1.40-1.85 (2H, m), 2.10-2.40 (6H, m), 2.85 (1H, dd, J = 5.0 11 Hz), 3.10-3.45 (1H, m), 3.94 (1H, d, J = 12 Hz), 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), 5.82 (1H, d, J = 10, 7.5 Hz), 7.20-7.40 (5H m, 7.70 (2H, d, J = 9.0 Hz), 7.96 (2H, d, J = 9.0 Hz).

 (22) (2S, 4R) -2 - [(Z) -5-carboxy-1-pentenyl] -4- (4-methylphenylsulfonylamino) -1- (phenylmethyl) pyrrolidine.

¹ H-NMR (CDCI ₃ ) d ppm 1.71 (2H, m), 2.07 (2H, m), 2.20 (2H, m), 2.34 (2H, t, J = 7.5 Hz), 2.40 (3H, s ), 2.64 (1H, dd, J = 5.0, 11 Hz), 3.20 (1H, dd, J = 7.5, 10 Hz), 3.78 (1H, d, J = 12 Hz ), 4.00 (1H, m), 4.04 (1H, d, J = 12 Hz), 4.25 (1H, dt, J = 7.5: 7.5 Hz), 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-methaxiphenylsulfonylamino) -1- (phenylmethyl) pyrrolidine.

¹ H-NMR (CDCI ₃ ) d ppm 1.69 (2H, m), 1.98 (2H, m), 2.17 (2H, m), 2.30 (2H, t, J = 7.5 Hz), 2.50 (1H, dd , J = 5.0, 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, br s), 7.76 (2H, d, J = 9 Hz).

 Example 8. A solution of (2S, 4R) -1 - [(4) -acetylaminophenyl) methyl] -2 / [(Z) -5-carboxy-1-pentenyl] -4- (4-chlorophenylsulfonylamino) pyrrolidine (200 mg ) in 6-hydrochloric acid (5 ml) was heated in a flask under reflux for 4 hours, the mixture was cooled in an ice bath, the pH was adjusted to 7 with In. sodium hydroxide. The precipitated solid was collected by filtration to obtain the compound (2S, 4R) -1 - [(4) -aminophenylmethyl) -2 - [(Z) -5-carboxy-1-pentenyl] -4- (4-chlorophenylsulfonylamino) pyrrolidine (95 mg).

¹ H-NMR (DMCO-O ₆ ) d ppm 1.45 (2H, process 1.78 (2H, process 1.97 (2H, m), 2.11 (2H, t, J = 7.5 Hz), 2.54 (1H, br s), 3 65 (1H, br s), 3.84 (1H, d, J = 12 Hz), 4.09 (1H, br s), 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 (2H, d, J = 10 Hz), 7.71 (2H, d, J = 10 Hz), 8, o43 (1H, br s).

 Example 9. A solution of (2S, 4R) -4-benzyloxycarbonylamino-2- [(Z) -5-carboxy-1-pentenyl] -1- (phenylmethyl) pyrrolidine (700 mg) and 30% hydrogen bromide in acetic acid (2 ml) was stirred for 2 hours at room temperature, and then the solvent was evaporated in vacuo to give the compound (2S, 4R) -4-amino-2- [(Z) -5-methaxicarbonyl-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 (0.67 ml) and p-toluenesulfonyl chloride (200 mg) at 0 ^° C. and the resulting mixture was stirred for 1.5 hours at the same temperature. Then, the solution was washed successively with water and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo, and the residue was chromatographed on a silica gel column, eluting with a mixture of ethyl acetate and n-hexane (1: 2), whereby the compound (2S, 4R) -2 - [(Z) -5-methoxycarbonyl-1- was obtained pentenyl] -4- (4-methylphenylsulfonylamino) -1- (phenylmethyl) pyrrolidine (249 mg) as an oily substance.

¹ H-NMR (CDCI ₃ ) d ppm 1.40-2.00 (4H, m), 2.09 (2H, m), 2.30 (2H, t, J = 7.5 Hz), 2.41 (3H, s), 3.04 (1H, d, J = 12 Hz), 3.08 (1H, t, J = 8 Hz), 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), 5.50 (1H, dt, J = 10.7.5 Hz), 7.14-7.35 (7H, m), 7.70 (2H, d, J = 10 Hz).

 Example 11. The following compounds were obtained by a method similar to that described in example 10.

(1) (2S, 4R) -2 - [(Z) -5-methoxycarbonyl-1-pentenyl] -4- (4-methoxyphenylsulfonylamino) -1- (phenylmethyl) prirrolidine
¹ H-NMR (CDCI ₃ ) d ppm 1.60-1.95 (4H, m), 2.10 (2H, m), 2.30 (2H, t, J = 7.5 Hz), 3.05 (1H, d, J = 12 Hz ), 3.07 (2H, m), 3.30 (1H, q, J = 7.5 Hz), 3.69 (3H, s), 3.71 (1H, m), 3.86 (3H , s), 3.87 (1H, d, J = 12 Hz), 4.72 (1H, d, J = 9.0 Hz), 5.30 (1H, t, J = 10 Hz), 5, 50 (1H, dt, J = 10, 7.5 Hz), 6.93 (2H, d, J = 10 Hz), 7.11-7.33 (5H, m), 7.75 (2H, d , J = 10 Hz).

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

¹ H-NMR (D ₂ O-DCI) d mln. 1.5-1.65 (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), 4.02 (1H, m), 4.5-4.7 (2H, m ), 5.33 (1H, t, J = 10 Hz), 5.83 (1H, dt, J = 10, 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), 8.90 (1H, s).

Claims (9)

Pyrrolidine derivatives of the general formula I

in which R ¹ pyridyl (lower) alkyl, pyrazinyl (lower) alkyl, pyrrolyl (lower) alkyl, imidazolyl (lower) alkyl, quinolyl (lower) alkyl, benzoxazolyl (lower) alkyl, thiazolyl (lower) alkyl, thienyl (lower) alkyl, furyl (lower) alkyl or benzothiazolyl (lower) alkyl, (C ₁ - C _{1 2} ) alkyl, phenyl (lower) alkyl, which may have one or two substituents selected from the group consisting of cyano, hydroxy, halogen, lower alkyl, lower alkoxyl, phenyl, amino, di (lower) alkylamino, lower alkanoylamino or naphthyl (lower) alkyl;
R ^{2 is} hydrogen, phenyl (lower) alkoxycarbonyl or phenylsulfonyl, which may have one or two substituents selected from the group consisting of halogen, lower alkyl, lower alkoxyl and mono- (or di- or tri) halogen (lower) alkyl;
R ³ carboxy (lower) alkyl, esterified carboxy (lower) alkyl, carboxyphenyl or esterified carboxyphenyl,
and their pharmaceutically acceptable salts. 2. The compound according to claim 1, in which
R ¹ pyridyl (C ₁ C ₁ ) alkyl, pyrazinyl (C ₁ - C ₄ ) alkyl, pyrrolyl (C ₁ C ₄ ) alkyl, imidazolyl (C ₁ - C ₄ ) alkyl, quinolyl (C ₁ C ₄ ) alkyl, benzoxazolyl (C ₁ C ₄ ) alkyl, thiazolyl (C ₁ C ₄ ) alkyl, thienyl (C ₁ - C ₄ ) alkyl, furyl (C ₁ C ₄ ) alkyl, benzothiazolyl (C ₁ - C ₄ ) alkyl, (C ₁ C _{1 2} ) alkyl, phenyl (lower) alkyl, cyanophenyl (lower) alkyl, hydroxyphenyl (lower) alkyl, mono- (or di) halo-phenyl (lower) alkylphenyl (lower) alkyl, lower alkoxyphenyl (lower) alkyl, phenylphenyl (lower) alkyl, diphenyl (lower) alkyl, aminophenyl (lower) alkyl, di (lower alkyl) aminophenyl (lower) alkyl, lower alkanoylamino enyl (lower) alkyl or naphthyl (lower) alkyl;
R ^{2 is} hydrogen, phenyl (lower) alkoxycarbonyl, or phenylsulfonyl, which may have one or two substituents selected from the group consisting of halogen, lower alkyl, lower alkoxyl or mono (or di- or tri) halogen (lower) alkyl;
R ^{3 is} carboxy (lower) alkyl, lower alkoxycarbonyl (lower) alkyl, carboxyphenyl or lower alkoxycarbonylphenyl. 3. The compound according to claim 2, in which R ¹ pyridyl (C ₁ -C ₄ ) alkyl, pyrazinyl (C ₁ C ₄ ) alkyl, pyrrolyl (C ₁ - C ₄ ) alkyl, imidazolyl (C ₁ C ₄ ) alkyl, quinolyl (C ₁ - C ₄ ) alkyl, benzoxazolyl (C ₁ C ₄ ) alkyl, thiazolyl (C ₁ -C ₄ ) alkyl, thienyl (C ₁ C ₄ ) alkyl, furyl (C ₁ - C ₄ ) alkyl, benzothiazolyl ( C ₁ C ₄ ) alkyl, (C ₁ - C _{1 2} ) alkyl, phenyl (C ₁ C ₅ ) alkyl, cyanophenyl (C ₁ C ₅ ) alkyl, hydroxyphenyl (C ₁ - C ₅ ) alkyl, mono- (or di -halo phenyl (C ₁ C ₅ ) alkyl, C ₁ C ₄ -alkylphenyl (C ₁ C ₅ ) alkyl, (C ₁ - C ₄ ) alkoxyphenyl (C ₁ C ₅ ) alkyl, phenylphenyl (C ₁ - C ₅ ) alkyl, diphenyl (C ₁ C ₅ ) alkyl, aminophenyl (C ₁ - C ₅ ) alkyl, di (C ₁ C ₄ ) -alkyl) aminophenyl (C ₁ - C ₅ ) alkyl, (C ₁ C ₄ ) -alkanoylaminophenyl (C ₁ - C ₅ ) alkyl, or naphthyl (C ₁ C ₅ ) alkyl; R ^{2 is} hydrogen, phenyl (C ₁ -C ₄ ) alkoxycarbonyl, or phenylsulfonyl, which may have one or two substituents selected from the group consisting of halogen, (C ₁ C ₄ ) alkyl, (C ₁ C ₄ ) alkoxy or mono (or di- or tri-) halogen (C ₁ C ₄ ) alkyl, R ³ - carboxy (C ₁ C ₄ ) alkyl, (C ₁ - C ₄ ) alkoxycarbonyl (C ₁ C ₄ ) alkyl, carboxyphenyl or (C ₁
C ₄ ) alkoxycarbonylphenyl. 4. The compound according to claim 3, in which R ¹ pyridyl (C ₁ - C ₄ ) alkyl, R ² phenylsulfonyl, which may have one or two substituents selected from the series containing halogen, (C ₁ - C ₄ ) alkyl, (C ₁ -C ₄ ) alkoxyl or mono- (or di- or tri-) halogen (C ₁ C ₄ ) alkyl; and R ³ carboxy (C ₁ -C ₄ ) alkyl.  5. The compound according to claim 4, which is (2S, 4R) 2 - [(Z) -5-carboxy -1-pentenyl] -4- (4-chlorophenylsulfonylamino) -1- (3-pyridylmethyl) -pyrrolidine or its hydrochloride. 6. The method of obtaining compounds of General formula I according to claim 1, in which R ² and R ³ have the meanings according to claim 1, R ¹ group R ⁸ -CH ₂ where R ^{8 is} hydrogen, pyridyl, pyrazinyl, pyrrolyl, imidazolyl, quinolyl , benzoxazolyl, thiazolyl, thienyl, furyl, benzothiazolyl, pyridyl (C ₁ C ₅ ) alkyl, pyrazinyl (C ₁ C ₅ ) alkyl, pyrrolyl (C ₁ C ₅ ) alkyl, imidazolyl (C ₁ C ₅ ) alkyl, quinolyl (C ₁ C ₅ ) alkyl, benzoxazolyl (C ₁ - C ₅ ) alkyl, thiazolyl (C ₁ C ₅ ) alkyl, thienyl (C ₁ - C ₅ ) alkyl, furyl (C ₁ C ₅ ) alkyl, benzothiazolyl (C ₁ - C ₅₎ alkyl, (C _{1 1} C ₁₎ alkyl, phenyl which may have 1 or 2 substituents selected from the group consisting of it cyano, hydroxyl, halogen, lower alkyl, lower alkoxy, phenyl, amino, di (lower) alkinaminogruppu and (lower) alkanoylamino, phenyl (C ₁ - C ₅₎ alkyl which may have one or two substituents selected from the group including cyano group, hydroxyl, halogen, lower alkyl, lower alkoxyl, phenyl, amino group, di (lower) alkylamino group and (lower) alkanoylamino group, naphthyl or naphthyl (C ₁ C ₅ ) alkyl, and its salts, characterized in that the compound is common formula II

where R ² and R ³ have the indicated meanings,
reacted with a compound of general formula XIV

where R ⁸ has the indicated meanings,
or its salt to obtain the desired product. 7. A pharmaceutical composition that has an antagonistic effect on thromboxane A ₂ (TX A ₂ ) and inhibits TX A ₂ synthetase, comprising an active principle and target additives, characterized in that as an active principle it contains an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof. 8. The compound according to claim 1 or its pharmaceutically acceptable salt having the properties of a thromboxane A ₂ antagonist and / or thromboxane A ₂ synthetase inhibitor. The priority according to points and signs: 10.31.88 according to claims 1 and 7, R ¹ - pyridyl (lower) alkyl, pyrazinyl (lower) alkyl, pyrrolyl (lower) alkyl, imidazolyl (lower) alkyl, quinolyl (lower) alkyl, benzoxazolyl (lower) alkyl, thiazolyl (lower) alkyl, thienyl (lower) alkyl, furyl (lower) alkyl and benzothiazolyl (lower) alkyl, R ² phenyl (lower) alkoxycarbonyl or phenylsulfonyl, which may have one or two substituents selected from the group including halogen, lower alkyl, lower alkoxyl and mono (or di- or three) halogen (lower) alkyl, R ³ carboxy (lower) alkyl, esterified to arboxy (lower) alkyl, carboxyphenyl and esterified carboxyphenyl. 04.13.89 PP 1, 6 and 7, R ¹ (C ₁ C ₆ ) alkyl, phenyl (lower) alkyl, which may have one or two substituents selected from the group consisting of cyano, hydroxy, halogen, lower alkyl, lower alkoxyl, phenyl, amino , di (lower) alkylamino group and acylamino group, or naphthyl (lower) alkyl, R ⁸ pyridyl, pyrazinyl, pyrrolyl, imidazolyl, quinolyl, benzoxazolyl, thiazolyl, thienyl, furyl, benzothiazolyl, pyridyl (C ₁ C ₅ ) alkyl, pyraz ₁ - C ₅ ) alkyl, pyrrolyl (C ₁ C ₅ ) alkyl, imidazolyl (C ₁ - C ₅ ) alkyl, quinolyl (C ₁ C ₅ ) alkyl, benzoxazolyl (C ₁ C ₅ ) alkyl, thiazolyl (C ₁ C ₅ ) alkyl thienyl (C ₁ - C ₅ ) alkyl, furyl (C ₁ C ₅ ) alkyd, benzothiazolyl (C ₁ - C ₅ ) alkyl, hydrogen, (C ₁ C ₅ ) alkyl, phenyl, which may contain one or two substituents, selected from the group consisting of cyano, hydroxy, halogen, lower alkyl, lower alkoxyl, phenyl, amino, di (lower) alkylamino and acylamino, phenyl (C ₁ - C ₅ ) alkyl, which may contain one or two substituents selected from the groups including a cyano group, hydroxy group, halogen, lower alkyl, lower alkoxyl, phenyl, amino group, di (lower) alkylamino group and acylamino uppu, naphthyl or naphthyl (C ₁ C ₅ ) alkyl.