RU2103276C1 - Peptide derivatives or their pharmaceutically acceptable salts, methods of their synthesis, pharmaceutical composition, method of prophylaxis and elimination of thrombosis - Google Patents

Abstract

FIELD: organic chemistry, peptides. SUBSTANCE: product: peptide derivatives of the general formula (I):

where: R¹ - aryl that can contain 1-3 substituents taken from amidino- and protected amidine group; R² - carboxy(lower)alkyl or protected carboxy(lower)alkyl; R³ - carboxy or protected carboxy-group; A¹ - alkylene that can contain 1-3 substituents taken from amino- and protected amino-group; A² - -N(R⁴)CH₂CO- where R⁴ - lower alkyl; or group A²: -NHCH₂CH₂CO-; A³ - lower alkylene containing 1-3 substituents taken from: lower alkyl, mono-, di- or triphenyl(lower)alkyl containing 1-3 substituents taken from the group: hydroxy, lower alkoxy, protected hydroxy, hydroxy(lower)alkyl, protected hydroxy(lower)alkyl, [cyclo(lower)alkyl]-(lower)alkyl, pyridyl(lower)alkyl; l, m and n are similar or different and mean whole number 0 or 1 at condition that A² can not be group -NHCH₂CH₂CO- if l = 0, or pharmaceutical salts. Peptides can be synthesized by two ways: a) by interaction of compounds of the formula (II):

or their reactive derivatives with compounds of the formula (III):

and protected groups were split off from the condensation product; or b) by interaction of compounds of the formula (IV):

with compounds of the formula (V): H₂NCHR²CONHA³R³, or their reactive derivatives by amino-group. Pharmaceutical composition has peptide derivatives of the formula (I) as an active component taken at effective amount. The synthesized compounds were used in medicine for prophylaxis and elimination of thrombosis in mammals by administration of derivatives of the formula (I) at daily dose 0.001-200 mg/kg mass for 2-4 doses. EFFECT: improved method of synthesis. 12 cl, 3 tbl

Description

The invention relates to a new peptide compound and its salt. More specifically, it relates to a new peptide compound and its salt, which is a glycoperothein IIb / IIa antagonist and platelet aggregation inhibitor and is used as
medicine for the prevention or treatment of diseases caused by blood clots, such as arterial thrombosis; atherosclerosis; coronary heart disease (for example, angina pectoris (for example, persistent angina pectoris, unstable angina pectoris, including the threat of heart attack, etc.), myocardial infarction (for example, acute myocardial infarction, etc.), coronary thrombosis, etc.); cerebral ischemic diseases (for example, cerebral infarction {for example, cerebral thrombosis (for example, acute cerebral thrombosis, etc.), cerebral embolism, etc.}, transient cerebral ischemia, cerebrovascular spasm after arachnoid bleeding, etc.), etc. .; pulmonary vascular disease (e.g., pulmonary thrombosis, pulmonary embolism, etc.); peripheral circulatory disorders (e.g., arteriosclerosis obliterans, thromboangiitis obliterans (i.e., Buerger's disease), Raynaud's disease, diabetes complications (e.g., diabetic angiopathy, etc.), phlebothrombosis (e.g., deep vein thrombosis, etc.), etc. P.;
a medicine for the prevention or treatment of restenosis and / or reocclusion, such as, for example, restenosis and / or reocclusion after subcutaneous transluminal coronary angioplasty (PTCA), restenosis and / or reocclusion after administration of tissue plasminogen activator (TPA), etc .;
medicine for adjunctive therapy in the treatment of thrombolytic agents (for example, TPA, etc.) or an anticoagulant (for example, heparin, etc.);
a medicine for the prevention and / or treatment of disseminated intravascular coagulation (DIC), thrombotic thrombocytopenia, underlying thrombosis, inflammatory diseases (e.g., nephritis, etc.), the immune system of diseases, etc .;
medicine for the prevention and / or treatment of blood clots in case of vascular surgery, valve replacement, extracorporeal circulation (eg, hemodialysis, etc.), transplantation, etc .;
a medicine to suppress the development of metastases; etc.

 The peptide compound of this invention is expected to be useful as an inhibitor of cell adhesion and, therefore, a medicament for the prevention and / or baking of disseminated intravascular coagulation of blood (DIC), thrombotic thrombopenia, major thrombosis, inflammation (e.g., nephritis, etc.), diseases of the immune system, etc .; drugs to suppress metastases, etc.

 In accordance with this, one of the objectives of the invention is to provide a new peptide compound or its salt, which can be used as indicated above.

 Another objective of the invention is the provision of methods for obtaining the specified new peptide compounds or its salts.

 The aim of the invention is further the provision of a pharmaceutical composition comprising, as an active ingredient, said peptide compound or its salt.

 Further, the aim of the invention is the development of methods for using the specified peptide compound or its salt for the prevention and / or treatment of the above diseases of a human being or animal.

где R¹ это арил, который может нести один или более подходящих заместителей;
R² это карбокси/низший/алкил или защищенный карбокси/низший/алкил,
R³ это карбоксил или защищенный карбоксил,
A¹ это алкилен, который может иметь один или более подходящих заместителей,
A² это группа формулы:

где R⁴ это низший алкил или группа формулы:
-NHCH₂CH₂CO-,
A³ это низший алкилен, который может иметь один или более подходящих заместителей,
l, m и n каждый, одинаковый или различный, представляет собой целое от 0 до 1,
при условии, что A² не представляет собой группу формулы:
-NHCH₂CH₂CO-,
когда l это целое, равное 0.The target peptide compound of this invention can be represented by the following formula (I):

where R ¹ is aryl, which may bear one or more suitable substituents;
R ² is carboxy / lower / alkyl or protected carboxy / lower / alkyl,
R ³ is a carboxyl or protected carboxyl,
A ¹ is alkylene, which may have one or more suitable substituents,
A ² is a group of the formula:

where R ⁴ is lower alkyl or a group of the formula:
-NHCH ₂ CH ₂ CO-,
A ³ is lower alkylene, which may have one or more suitable substituents,
l, m and n each, the same or different, is an integer from 0 to 1,
provided that A ^{2 is} not a group of the formula:
-NHCH ₂ CH ₂ CO-,
when l is an integer equal to 0.

 The target compound (I) or its salt can be obtained in the following ways.

где R¹, R², R³, A¹, A³, l, m и n каждая как определено выше,
R $\genfrac{}{}{0ex}{}{\text{1}}{\text{a}}$ это арил, несущий защищенную амидино-группу,
R $\genfrac{}{}{0ex}{}{\text{1}}{\text{b}}$ это арил, несущий амидино-группу,
R $\genfrac{}{}{0ex}{}{\text{1}}{\text{c}}$ это арил, несущий тиокарбамоил,
R $\genfrac{}{}{0ex}{}{\text{2}}{\text{a}}$ это защищенный карбокси(низший)алкил,
R $\genfrac{}{}{0ex}{}{\text{2}}{\text{b}}$ это карбокси(низший)алкил,
R $\genfrac{}{}{0ex}{}{\text{3}}{\text{a}}$ это защищенная карбокси-группа,
R $\genfrac{}{}{0ex}{}{\text{3}}{\text{b}}$ это карбокси-группа,
A $\genfrac{}{}{0ex}{}{\text{3}}{\text{a}}$ это низший алкилен, имеющий защищенный гидрокси /низший/алкил или низший алкилен, имеющий /защищенный гидрокси/-ар/низший/алкил,
A $\genfrac{}{}{0ex}{}{\text{3}}{\text{b}}$ это низший алкилен, имеющий гидрокси/низший/алкил или низший алкилен, имеющий /гидрокси/-ар/низший/алкил.

where R ¹ , R ² , R ³ , A ¹ , A ³ , l, m and n are each as defined above,
R $\genfrac{}{}{0ex}{}{\text{1}}{\text{a}}$ this is aryl bearing a protected amidino group,
R $\genfrac{}{}{0ex}{}{\text{1}}{\text{b}}$ it’s an aryl carrying an amidino group,
R $\genfrac{}{}{0ex}{}{\text{1}}{\text{c}}$ this is aryl bearing thiocarbamoyl,
R $\genfrac{}{}{0ex}{}{\text{2}}{\text{a}}$ it is a protected carboxy (lower) alkyl,
R $\genfrac{}{}{0ex}{}{\text{2}}{\text{b}}$ this is carboxy (lower) alkyl,
R $\genfrac{}{}{0ex}{}{\text{3}}{\text{a}}$ it’s a protected carboxy group,
R $\genfrac{}{}{0ex}{}{\text{3}}{\text{b}}$ this is a carboxy group,
A $\genfrac{}{}{0ex}{}{\text{3}}{\text{a}}$ it is lower alkylene having protected hydroxy / lower / alkyl or lower alkylene having / protected hydroxy / ar / lower / alkyl,
A $\genfrac{}{}{0ex}{}{\text{3}}{\text{b}}$ it is lower alkylene having hydroxy / lower / alkyl or lower alkylene having / hydroxy / ar / lower / alkyl.

 Among the starting compounds (II), (III), (IV), (V) and (VI), there are new compounds. They can be obtained from known compounds by methods conventional in the art or by methods similar to those described in the Preparations and / or Examples sections of this description.

 Suitable pharmaceutically acceptable salts of the target compound (I) are conventional non-toxic salts, including metal salts such as alkali metal salts (e.g. sodium, potassium salt and so on) and alkaline earth metal salts (e.g. calcium salt, magnesium salt and the like ), an ammonium salt, an organic base salt (for example, a trimethylamine salt, a triethylamine salt, a pyridine salt, a picoline salt, a dicyclohexylamine salt, an N, N-dibenzylethylenediamine salt, etc.), an organic acid addition salt (for example, formate, ac ethyl acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzyl sulfonate, toluenesulfonate, etc.), an inorganic acid addition salt (e.g., hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, etc.), amino acid salt (e.g., arginine salt , aspartic acid salt, glutamic acid salt, etc.), etc.

 In describing the invention, examples of various definitions are understood in detail as follows.

 The term "lower" is used to mean 1 to 6 carbon atoms, unless otherwise indicated.

 Suitable “aryl” may include phenyl, naphthyl (eg, 1-naphthyl, 2-naphthyl), anthril (eg, 1-antryl, 2-antryl, 9-antryl, etc.) and the like, with preferred aryl being phenyl.

 This “aryl” may have one or more (preferably 1 to 3) suitable substituents, such as an amidino, protected amidino group and the like.

 A suitable protecting group in a "protected amidino group" may include ar (lower) alkyl, such as mono- or di- or triphenyl (lower) alkyl (e.g. benzyl, phenethyl, 1-phenylethyl, benzhydryl, trityl, etc. p.), acyl, as will be shown below, and others.

 Suitable acyl can be aliphatic acyl, aromatic acyl, arylaliphatic acyl and hetero-cycloaliphatic acyl, which are derivatives of carboxylic acid, carbonic acid, carbamic acid, sulfonic acid and the like.

 As an example of the acyl group, in accordance with this explanation, lower alkanoyl (e.g., formyl, acetyl, propionyl, hexanoyl, pivaloyl, etc.), mono (or di, or three) -halo (lower) alkanoyl (e.g., chloroacetyl, trifluoroacetyl and others), lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, tert-pentyoxycarbonyl, hexyloxycarbonyl, etc.), mono (or di or three) -halo (lower) alkoxycarbonyl (e.g. chloromethoxycarbonyl, d trichloroethoxycarbonyl and others), aroyl (nap imer, benzoyl, toluoyl, xyloyl, naphthoyl, etc.), ar (lower) alkanoyl, such as phenyl (lower) alkanoyl (e.g. phenylacetyl, phenylpropionyl, etc.), aryloxycarbonyl (e.g. phenyloxycarbonyl, naphthyloxycarbonyl, etc.), aryloxy (lower) alkanoyl, such as phenoxy (lower) alkanoyl (e.g. phenoxyacetyl, phenoxypropionyl, etc.), arylglyoxyloyl (e.g. phenylglyoxyloyl, naphthylglyoxyloyl, etc.), aryl (lower) alkoxycarbonyl, which may have suitable substituents like phenyl (lower) alkoxycarbonyl, which may include neither a ro- or lower alkoxy group (for example, benzyloxycarbonyl, phenyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, etc.), thienylacetyl, imidazolylacetyl, furylacetyl, tetrazolylacetyl, thiazylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenylphenonephenyl , propylsulfonyl, isopropiosulfonyl, pentylsulfonyl, butylsulfonyl, etc.), arylsulfonyl (e.g. phenylsulfonyl, tolyl sulfonyl, xylylsulfonyl, naphthylsulfonyl, etc.), aryl / lower / alkyl ulfonil such as phenyl / lower / alkylsulfonyl (e.g., benzylsulfonyl, phenethylsulfonyl, benzgidrilsulfonil et al.), etc.

A preferred example of a “protected amidino group” may be N-aryl / lower / alkoxycarbonylamidino, more preferred may be N-phenyl / lower / alkoxycarbonyl-amidino, much more preferred may be N-phenyl / C ₁ -C ₄ / alkoxycarbonylamidino is a group, and the most preferred example is an N-benzyloxycarbonylamidino group.

Suitable "lower alkyls" may be straight or branched chain alkyls such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, and the like, preferred of which may be / C ₁ -C ₄ / alkyl, and a suitable lower alkyl radical in carboxy (lower) alkyl may refer to said lower alkyl.

Suitable examples of “carboxy (lower) alkyl” may include carboxymethyl, 1-carboxyethyl, 2-carboxyethyl, 2-carboxypropyl, 3-carboxybutyl, 2-carboxy-1,1-dimethylethyl, 5-carboxypentyl, 6-carboxyhexyl and the like ., preferred among which may be carboxy / C ₁ -C ₄ / alkyl and more preferred carboxymethyl or 2-carboxyethyl.

A suitable residue of a “protected carboxy group” in a “protected carboxy (lower) alkyl" group may be an esterified carboxy group and the like, and specific examples of the ester residue in said esterified carboxy group may be such as lower alkyl ester (e.g. methyl ether, ethyl ether, propyl ether, isopropyl ether, butyl ether, isobutyl ether, tert-butyl ether, pentyl ether, hexyl ether, 1-cyclopropylethyl ether, etc.), which may contain suitable substituents, for example lower alkanoyloxy / lower / alkyl ester / e.g., acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, 1-atsetiloksietilovy ether, 1-propioniloksietilovy ester, pivaloyloxymethyl ester, 2-propioniloksietilovy ester, hexanoyloxymethyl ester and others /, lower alkanesulfonyl / lower / alkyl ether / for example, 2-mesylethyl ether and others /, or mono / or di, or tri / halogen / lower / alkyl ether / for example, 2-iodoethyl ether, 2 , 2,2-trichloroethyl ether, and others. /; lower alkenyl ether (for example, vinyl ether, allyl ether, etc.); lower alkynyl ether (for example, ethynyl ether, propynyl ether, etc.); aryl / lower / alkyl ether, which may contain suitable substituents (e.g. benzyl ether, 4-methoxybenzyl ether, 4-nitrobenzyl ether, phenethyl ether, trityl ether, benzhydryl ether, bis (methoxyphenyl) methyl ether, 3,4-dimethoxybenzyl ether , 4-hydroxy-3,5-di-tert-butyl-benzyl ether, etc.); aryl ether, which may contain suitable substituents (for example, phenyl ether, 4-chlorophenyl ether, tolyl ether, 4-tert-butylphenyl ether, xylyl ether, mesityl ether, cumenyl ether, etc.); or the like, among which mono- or di- or triphenyl / C ₁ -C ₄ / alkyl ether may be preferred, and benzyl ether may be most preferred.

 A suitable “lower alkyl” residue in “protected carboxy / lower / alkyl” may refer to the above “lower alkyl”.

As a suitable example of said "protected carboxy / lower / alkyl", phenyl / lower / alkoxycarbonyl / lower / alkyls may be mentioned, among which / C ₁ -C ₄ / alkoxycarbonyl / C ₁ -C ₄ alkyl may be preferred, and more preferred benzyloxycarbonylmethyl or 2-benzyloxycarbonylethyl.

 Suitable "protected carboxy" groups include those exemplified by the "protected carboxy" protected carboxy / lower / alkyl radicals.

Suitable examples of “protected carboxy” include phenyl / lower / alkoxycarbonyl, phenyl / C ₁ -C ₄ / alkoxycarbonyl may be preferred, and benzyloxycarbonyl is more preferred; or lower alkoxycarbonyl, of which / C ₁ -C ₄ / alkoxycarbonyl may be preferred, and more preferably methoxycarbonyl or ethoxycarbonyl.

Suitable "alkylene" can be alkylene containing from 1 to 12 carbon atoms, such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene, decamethylene, undecamethylene, dodecamethylene, etc. may be preferred. (C ₁ -C ₁₀ / -alkylene and more preferred methylene, ethylene, trimethylene, tetramethylene, pentamethylene or heptamethylene.

 Such “alkylene” may contain one or more (preferably 1 to 3) suitable substituents, such as amino, protected amino, and the like.

 Suitable protecting groups in said "protected amino" include those exemplified by a "protected amidino group".

A preferred example of a “protected amino” may be lower alkylamino or lower alkoxycarbonylamino, where / C ₁ -C ₄ / alkanoylamino or / C ₁ -C ₄ / alkoxycarbonylamino and most preferred acetylamino or tert-butoxycarbonylamino may be more preferred.

Suitable "lower alkylenes" may include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene and the like, where / C ₁ -C ₄ / alkylene may be preferable, and more preferably methylene or trimethylene.

 Such a “lower alkylene” may contain one or more (preferably 1 to 3) suitable substituents, such as the aforementioned lower alkyl; aryl / lower / alkyl, which may contain one or more suitable substituents, the meanings of which will be explained below; hydroxy (lower) alkyl / e.g. hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxybutyl, 1,1-dimethyl-2-hydroxyethyl, 5-hydroxypentyl, 6-hydroxyhexyl, etc. /; protected hydroxy / lower / alkyl, the meaning of which will be explained later; / cyclo / lower / alkyl / - / lower / alkyl (e.g. cyclopropylmethyl, cyclobutylmethyl, cyclohexylmethyl, 2-cyclopentylethyl, 1-cyclohexylethyl, 3-cyclopentylpropyl, 2-cyclohexylbutyl, 1,1-dimethyl-2-cyclopropylethyl, 5-cyclobutyl , 6-cyclohexylethyl and others); heterocycle / lower / alkyl, the meaning of which will be given later, etc.

Suitable "aryl / lower / alkyl" or "lower alkylene" described above may include mono / or di, or tri / -phenyl / lower / alkyl, such as benzyl, phenethyl, 2-phenylpropyl, 4-phenylbutyl, 1, 1-dimethyl-2-phenylethyl, 5-phenylpentyl, 6-phenylhexyl, diphenylmethyl, 1,2-diphenylethyl, trityl, 1,2,3-triphenylpropyl, etc., where phenyl- / C ₁ -C may be preferred ₄ / alkyl, and more preferred benzyl.

Such "aryl / lower / alkyl" may contain one or more (preferably 1 to 3) suitable substituents, such as hydroxy; protected hydroxy (for example, aryl / lower / -alkyloxy, where the "aryl / lower / alkyl residue" may refer to the above as examples; acyloxy, where the "acyl residue may refer to the above, etc.); lower alkoxy group (e.g. methoxy, ethoxy, propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, etc.); and the like, where the preferred group may be hydroxy, phenyl / C ₁ -C ₄ / alkyloxy or / C ₁ -C ₄ / alkoxy, and more preferred hydroxy, benzyloxy, methoxy or ethoxy.

 Suitable "protected hydroxy / lower / alkyls" may include aryl / lower / alkyloxy / lower / alkyl, acyloxy / lower / alkyl and the like, where the aryl / lower / alkyl residue, the acyl residue and the "/ lower / alkyl "may refer to the above.

Preferred "protected hydroxy / lower / alkyl" may be phenyl / C ₁ -C ₄ / alkyloxy / C ₁ -C ₄ / alkyl, and more preferred is benzyloxymethyl or 1-benzyloxyethyl.

A suitable "heterocyclic" residue in "heterocyclo- / lower / alkyl" means a saturated or unsaturated, monocyclic or polycyclic heterocyclic group containing at least one heteroatom such as oxygen, sulfur, nitrogen and the like. And a particularly preferred heterocyclic group may be such as an unsaturated 3-8 membered heterocyclic group containing from 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N-oxide, pyrimidyl, pyrazinyl, pyridazinyl, 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 other), dihydrotriazinyl (e.g. 4,5-dihydro-1,2,4-triazinyl, 2,5-dihydro-1,2,4-triazinyl, etc.) and the like;
saturated 3-8-membered heteromonocyclic group containing from 1 to 4 nitrogen atoms, for example, pyrrolidinyl, imidazolidinyl, piperidyl (e.g. piperadino, etc.), piperazinyl, etc .;
unsaturated condensed heterocyclic group containing from 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolisinyl, benzylimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridyl, tetrazolopyridinium (for example, tetrazolo-1,5-others). ;
unsaturated 3-8 membered heteromonocyclic group containing from 1 to 2 oxygen atoms and from 1 to 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 3-8 membered heteromonocyclic group containing from 1 to 2 oxygen atoms and from 1 to 3 nitrogen atoms, for example, morpholinyl, oxazolidinyl (for example, 1,3-oxazolidinyl, etc.), etc .;
unsaturated condensed heterocyclic group containing from 1 to 2 oxygen atoms and from 1 to 3 nitrogen atoms, for example, benzoxazolyl, benzoxadiazolyl and others;
unsaturated 3-8 membered heteromonocyclic group containing from 1 to 2 sulfur atoms and from 1 to 3 nitrogen atoms, for example, 1,3-thiazolyl, 1,2-thiazolyl, thiazolinyl, thiadiazolyl (for example, 1,2,4- thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-thiadiazolyl) and the like;
saturated 3-8-membered heteromonocyclic group containing from 1 to 2 sulfur atoms and from 1 to 3 nitrogen atoms, for example, thiazolidinyl, etc .;
unsaturated 3-8 membered heteromonocyclic group containing from 1 to 2 sulfur atoms and from 1 to 3 nitrogen atoms, for example, benzothiazolyl, benzothiadiazolyl and others;
an unsaturated 3-8 membered heteromonocyclic group containing from 1 to 2 oxygen atoms, for example, furyl, pyranyl, dioxolyl, etc .;
saturated 3-8-membered heteromonocyclic group containing from 1 to 2 oxygen atoms, for example, oxolanyl, tetrahydropyranyl (for example, tetrahydro-2H-pyran-2-yl, etc.), dioxolanyl, etc .;
unsaturated condensed heterocyclic group containing from 1 to 2 oxygen atoms, e.g. and others) and others; etc.

 A preferred “heterocyclic” residue may be a 3-8 membered heteromonocyclic group containing from 1 to 4 nitrogen atoms, more preferably pyridyl.

Among the suitable lower alkylene substituents, / C ₁ -C ₄ / alkyl may be preferred; phenyl / C ₁ -C ₄ / alkyl, which may include 1 to 3 hydroxy, phenyl / C ₁ -C ₄ / alkyloxy or / C ₁ -C ₄ / alkoxy groups; hydroxy / C ₁ -C ₄ / alkyl; phenyl- (C ₁ -C ₄ / alkyloxy / C ₁ -C ₄ / alkyl; cyclo / C ₅ -C ₆ / alkyl / C ₁ -C ₄ / alkyl; or pyridyl / C ₁ -C ₄ / alkyl, and more preferred may be methyl, ethyl, propyl, isopropyl, butyl, 1-methylpropyl, 2-methylpropyl, tert-butyl, benzyl, / 4-hydroxyphenyl / methyl, / 4- benzyloxyphenyl / methyl, / 4-methoxyphenyl / methyl, / 4-ethoxyphenyl / methyl, hydroxymethyl, 1-hydroxyethyl, benzyloxymethyl, 1-benzyloxyethyl, cyclohexylmethyl or 2-pyridylmethyl.

 The term "/ hydroxy / aryl / lower / alkyl" means an aryl / lower / alkyl containing a hydroxy group.

 The term "/ protected hydroxy / aryl / lower / alkyl" means an aryl / lower / alkyl containing a protected hydroxy group.

 The following is a detailed explanation of the methods for preparing the target compounds of this invention.

Method 1
The target compound (I) or its salt can be obtained by the reaction of the compound (II), or its reactive derivative at the carboxy group, or its salt with the compound (III), or with its reactive derivative at the amino group, or with its salt .

 Suitable reactive carboxy group derivatives of compound (II) may include acid halide, acid anhydride, activated amide, activated ester, and the like.

Suitable examples of reactive derivatives include chloro anhydride; acid azide; mixed anhydride with an acid, such as substituted phosphoric acid (e.g., dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.), dialkylphosphoric acid, sulfuric acid, thiosulfuric acid, sulfuric acid, for example sulfones , methanesulfonic acid, etc.), aliphatic carboxylic acid (for example, acetic acid, propionic acid, butyric acid, isobutyric acid, trimethylacetic acid, valerianic acid that, isovalerianic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.) or aromatic carboxylic acid (for example, benzoic acid, etc.); asymmetric acid anhydride; activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole, tetrazole or 1-hydroxy-1H-benzotriazole; or an activated ester (e.g., cyanomethyl ether, methoxymethyl ether, dimethyliminomethyl ether, methoxymethyl ether, dimethyliminomethyl ether / (CH ₃ ) ₂ N ⁺ = CH- /, vinyl ether, propargyl ether, p-nitrophenyl ether, 2,4- dinitrophenyl ether, trichlorophenyl ether, pentachlorophenyl ether, mesylphenyl ether, phenylazophenyl ether, phenyl thioether, p-nitrophenyl thioether, p-cresyl thioester, carboxymethyl thioether ether, pyridylpyridyl pyridyl ether pyridyl pyridyl ether ether with an N-hydroxy compound (e.g., N, N-dimethylhydroxylamine, 1-hydroxy-2- (1H) -pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole, etc.), and t. .P. These reactive derivatives can be arbitrarily selected from the above, in accordance with the type of compound (II).

 Suitable salts of compound (II) and its reactive derivative can be considered those examples of which are given for compound (I).

 Suitable reactive amino group derivatives of compound (III) may include a Schiff base amine or its tautomeric enamine type isomer obtained by reacting compound (III) with a carbonyl compound such as an aldehyde, ketone or the like; a silyl derivative obtained by the reaction of compound (III) with a silyl compound such as bis / trimethylsilyl / acetamide, mono / trimethylsilyl / acetamide, bis / trimethylsilyl / urea and the like; a derivative obtained by the reaction of compound (II) with phosphorus trichloride or with phosgene, etc.

 Suitable salts of compound (III) and its reactive derivatives can be attributed to examples of compound (I).

 The reaction is usually carried out in a common solvent, such as water, alcohol (e.g. methanol, ethanol, etc.), acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine or any other organic solvent that does not adversely affect the progress of the reaction. These traditional solvents can also be used in a mixture with water.

 In the case where the compound (II) is used in the form of a free acid or in the form of its salt, it is advisable to carry out the reaction in the presence of a traditional condensing agent, such as N, N'-dicyclohexylcarbodiimide; N-cyclohexyl-N'-morpholinoethylcarbodiimide; N-cyclohexyl-N '- / 4-diethylamino-cyclohexyl / carbodiimide; N, N'-diethylcarbodiimide, N, N'-diisopropylcarbodiimide; N-ethyl-N ' - / 3-dimethylaminopropyl / carbodiimide; N, N'-carbonyl-bis- (2-methylimidazole); pentamethylene ketone-N-cyclohexylimine; diphenylketone-N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-1-chloroethylene, trialkylphosphite; ethyl polyphosphate; isopropyl polyphosphate; trivalent phosphorus oxychloride (phosphoryl chloride); phosphorus trichloride; thionyl chloride; oxalyl chloride; lower alkyl haloformate (e.g., ethyl chloroformate, isopropyl chloroformate, etc.); triphenylphosphine; 2-ethyl-7-hydroxybenzyloxazolinium salt; intramolecular salt of 2-ethyl-5- / m-sulfophenyl / isoxazolinium hydroxide; 1- (p-chlorobenzenesulfonyloxy) -6-chloro-1H-benzotriazole; the so-called Vilsmeier reagent obtained by the reaction of N, N-dimethylformamide with thionyl chloride, phosgene, trichloromethyl formate, phosphorus oxychloride, methanesulfonyl chloride, etc .; etc.

 The reaction can also be carried out in the presence of an inorganic or organic base such as an alkali metal carbonate, alkali metal bicarbonate, tri / lower / alkyl amine, pyridine, N- / lower / alkylmorpholine, N, N-di / lower / -alkylbenzylamine and t .P.

 The reaction temperature is not a critical factor, and usually the reaction is carried out under various conditions, from “in the cold” to “when heated”.

Method 2
The target compound (Ia) or its salt can be obtained by the reaction of the compound (IV), or its reactive derivative at the carboxy group, or its salt with the compound (V), or with its reactive derivative at the amino group, or with its salt .

 This reaction can be carried out similarly to the above Method 1, and therefore, the type and conditions of the reaction (for example, reactive derivatives, solvent, reaction temperature, etc.) correspond to those described in Method 1.

Method 3
The target compound (Ic) or its salt can be obtained by introducing the compound (Ib) or its salt in the reaction of removing the amidino-protecting group.

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

 Hydrolysis is usually carried out in the presence of a base or acid, including Lewis acid. Suitable bases may include inorganic bases and organic bases, such as an alkali metal (e.g., sodium, potassium, etc.), alkaline earth metal (e.g., magnesium, calcium, etc.), their hydroxide, or carbonate, or bicarbonate, trialkylamine (e.g. , trimethylamine, triethylamine, etc.), picolin, 1,5-diazabicyclo / 4.3.0 / non-5-ene, 1,4-diazabicyclo / 2.2.2 / octane, 1,8-diazabicyclo / 5.4.0 / undec -7-en, etc.

 Suitable acids may include organic acid (e.g., formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.) and mineral acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, etc. )

 The deletion reaction using Lewis acid, such as trihaloacetic acid (e.g. trichloroacetic acid, trifluoroacetic acid, etc.), is preferably carried out in the presence of cationic binding agents (e.g., anisole, phenol, etc.).

 The reaction is usually carried out in a solvent such as water, alcohol (for example, methanol, ethanol, etc.), methylene chloride, tetrahydrofuran, a mixture 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 factor, and the reaction is usually carried out under conditions from “in the cold” to “when heated”.

 The reduction method applicable to the removal reaction may include chemical reduction or catalytic reduction.

 Suitable reducing agents for use in this reaction are a combination of a metal (e.g., tin, zinc, iron, etc.) or a compound of a metal (e.g., chromium chloride, chromium acetate, etc.) and an organic or mineral acid (e.g., formic acid, acetic acid) , propionic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.).

 Catalysts suitable for use in catalytic reduction are conventional catalysts such as platinum (e.g., platinum plate, platinum sponge, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalysts (e.g. palladium sponge, palladium black, palladium oxide, palladium-on-charcoal, colloidal palladium, palladium-on-barium sulfate, palladium-on-barium carbonate, etc.), nickel catalysts (for example, reduced nickel, nickel oxide, nor Raney’s cell, etc.), cobalt catalysts (for example, reduced cobalt, Raney’s cobalt, etc.), iron catalysts (for example, reduced iron, Raney’s iron, etc.), copper catalysts (for example, reduced copper, Raney’s copper, Ulman’s copper etc.), etc.

 Recovery is usually carried out in a traditional solvent, which does not adversely affect the progress of the reaction, such as water, methanol, ethanol, propanol, N, N-dimethylformamide or a mixture thereof. In addition, in the case where the aforementioned acids used for chemical reduction are liquids, they can also be used as solvents. Further, a suitable solvent for catalytic reduction may be the aforementioned solvent, as well as other conventional solvents such as diethyl ether, dioxane, tetrahydrofuran, etc., or mixtures thereof.

 The reaction temperature of such a reduction is not a critical parameter, and the reaction is usually carried out under conditions from “in the cold” to “when heated”.

The scope of the present invention includes the case where the protected carboxy / lower / alkyl in R ^{2 is} transformed into a carboxy / lower / alkyl, the case where the protected carboxy group in R ^{3 is} converted to a carboxy group, as well as the case when lower alkylene containing protected hydroxy / lower / alkyl, or lower alkylene containing / protected hydroxy / aryl- / lower / alkyl in A ^{3 is} converted to lower alkylene containing hydroxy / lower / alkyl, or lower alkylene containing / hydroxy / aryl / lower / alkyl.

Method 4
The target compound (Ie) or its salt can be obtained by subjecting the compound (Id) or its salt to a carboxy protecting group deprotection reaction.

 This reaction can be carried out similarly to the reaction of Method 3 discussed above, so that the mode and conditions of the reaction (for example, base, acid, catalyst, solvent, reaction temperature, etc.) correspond to those specified in Method 3.

This invention includes the case where an aryl containing a protected amidino group in R ¹ is converted to an aryl containing an amidino group, a case where a protected carboxy protected group in R ^{3 is} converted to a carboxy group, and also a case where lower alkylene containing protected hydroxy / lower / alkyl or lower alkylene containing / protected hydroxy / aryl / lower / alkyl in A ³ is converted to lower alkylene containing hydroxy / lower / alkyl or lower alkylene containing / hydroxy / aryl / lower / alkyl.

Method 5
The target compound (Ig) or its salt can be obtained by subjecting the compound (If) or its salt to a hydroxy-protecting group removal reaction.

 This reaction can be carried out similarly to the reaction of the above Method 3, so that the mode and conditions of the reaction (for example, base, acid, catalyst, solvent, reaction temperature, etc.) correspond to those discussed in Method 3.

This invention includes the case where an aryl having a protected amidino group in R ¹ is converted to an aryl having an amidino group, a case where the protected carboxy / lower / alkyl to R ² is converted to carboxy / lower / alkyl, and the case when the protected carboxy group in R ^{3 is} converted to a carboxy group.

Method 6
The target compound (Ii) or its salt can be obtained by subjecting the compound (Ih) or its salt to a carboxy protecting group deprotection reaction.

 This reaction can be carried out similarly to the reaction of the aforementioned Method 3, and therefore, the mode and conditions of the reaction (for example, base, acid, catalyst, solvent, reaction temperature, etc.) correspond to those described in the description of Method 3.

It is within the scope of the present invention that an aryl having a protected amidino group in R ¹ is converted to an aryl containing an amidino group, a case where a protected carboxy / lower / alkyl is converted into R ² carboxy / lower / alkyl, and a case when lower alkylene containing protected hydroxy / lower / alkyl, or lower alkylene containing / protected hydroxy / aryl / lower / alkyl in A ³ is converted to lower alkylene having hydroxy / lower / alkyl, or lower alkylene having (hydroxy) aryl (lower) alkyl.

Method 7
The target compound (Ij) or its salt can be obtained by the reaction of converting the thiocarbamoyl group of compound (VI) or its salt into an amidino group.

 Suitable salts of compounds (Ij) and (VI) can be considered as examples given in the description of compound (I).

 This reaction can be carried out as a reaction of the compound (VI) or its salt with an alkylating agent such as an alkyl halide (e.g. methyl iodide, ethyl bromide, etc.) and the like, in a suitable solvent such as acetone dioxane, tetrahydrofuran, etc. item, at room temperature, in heat or under heating, and then as the interaction of the obtained intermediate product, with or without isolation, with ammonia or a derivative thereof, such as ammonium acetate, ammonium halide (e.g., ammonium chloride, etc.), a suitable solvent such as alcohol (e.g. methanol, ethanol, etc.), N, N-dimethylformamide, etc., in heat or when heated.

 In cases where the compound (I) obtained by the above methods is in free form, it can be converted into a salt by conventional methods. On the other hand, when the target compound (I) thus obtained is a salt, it can be converted to the free state or to another salt form by also known methods.

 It should be noted that the target compound (I) may include stereoisomers due to the presence of an asymmetric carbon atom (s).

 Further, in order to demonstrate the usefulness of the target compound (I), some pharmacological test data of representatives of the compound (I) according to this invention will be given.

Test 1: Effect on platelet adhesion caused by alenosine diphosphate (ADR) Test compound: (I) target compound (7) of Example 7
Test method
Platelet-rich plasma (PRP) containing 3 x 10 ⁸ platelets / ml was prepared from human blood. 25 μl of the drug solution was added to 225 μl of PRP, and then stirred for 2 min at 37 ^° C. 5 μl of ADR (finally 2.5 μM) was added to the solution as an agglutination initiator. The degree of agglutination was determined using an agglutination measuring instrument (NKK HEMA-TPACEP I). Inhibitor activity (test compound) was expressed as an IC ₅₀ value, i.e. the dose required to suppress platelet adhesion by 50%.

Drug solution ^x — test compound was dissolved in dimethyl sulfoxide.

Test results
Test compound IC ₅₀ / M /
(I) 1.0 • 10 ^-7
Test 2: Binding of Fibrinogen to Platelets
Test compound
the same compound (I) as in Test 1
Test Methodology
Washed human platelets were obtained from platelet-rich plasma by gel filtration. The washed platelets were activated with 20 μM ADR for 10 minutes, and then fixed for 30 minutes with 0.8% paraformaldehyde. Then, platelets were washed by centrifugation and a suspension was prepared in HEPES-Tyrodes buffer containing 2 mM CaCl ₂ and 1 mM MgCl ₂ .

350 μl of platelets were thermostated at a final concentration of 2 × 10 ⁸ / ml with 100 μg / ml of ¹²⁵ 1-fibronogen and the test compound. The reaction continued for 30 minutes at room temperature. Then, 20% sucrose was coated with a layer of three portions of 100 μl each and a platelet cake was obtained by centrifugation at 10,000 rpm for 5 minutes. The pellet was separated by cutting off the tip of the tube with a blade and counted on a gamma counter.

Specific binding was calculated by subtracting the binding in the presence of a 50-fold excess of unlabeled fibrinogen. The results were expressed as IC ₅₀ values, i.e. as the dose required to inhibit binding by 50%.

Test results
Test compound IC ₅₀
(I) 2.9 • 10 ^-8
Test 3: Test to increase the thrombolytic activity of TPA in modeling thrombosis in guinea pigs
Test compound
(I) the target compound (13) of Example 13
Test procedure
Hartley male guinea pigs (500-800 g) underwent anesthesia with urethane (1.25 g / kg ip). The carotid artery and cervical vein were carefully examined after an incision was made in the middle of the neck. A polyethylene catheter cannula (PE50; Becton Dikinson, USA) was injected into a vein to inject and infuse the drug. A pulse Dopplar flow probe was placed around the carotid artery to record blood flow velocity in order to observe blood clots and thrombolysis. Carotid artery thrombosis was caused by FeCl ₃ according to the following procedure:
a square (1 mm x 1 mm) filter paper of the ADVANTEC N 2 type, impregnated with 20% FeCl ₃ , was placed on the carotid artery, which was blocked by a thrombus.

 When the blood flow rate dropped to zero, the filter paper was removed from the vessel and the carotid artery was washed more than 4 times with saline. 3 minutes after washing, the test compound or saline was administered, and after 3 minutes, g-TPA (trademark Actilyse, Bochringer Ingelheim Ltd.) was poured over 60 minutes.

 The animals were divided into the following groups.

 Group 1 (5 animals): Saline and t-TPA at 0.30 mg / kg intravenous bead + 1.0 mg / kg / h intravenous infusion.

 Group 2 (5 animals): Test compound at 0.32 mg / kg intravenous bead and t-TPA at 0.30 mg / kg intravenous bead + 1.0 mg / kg / hour intravenous infusion.

 Reperfusion was defined as a 50% restoration of the flow rate of blood in the carotid artery compared with the initial value. Blood flow was restored in 90 minutes.

Test results
The number of animals in which reperfusion was observed in each group was as follows.

Group - The number of animals in which reperfusion was observed
eleven
2 - 5
The pharmaceutical composition according to this invention can be used in the form of a pharmaceutical preparation, for example, in the form of a solid, semi-solid or liquid finished form, which contains the target compound (I) or its pharmaceutically acceptable salt as an active ingredient mixed with an organic or inorganic carrier or excipient, suitable for administration or injection rectally, into the lungs (nasal or buccal inhalations), into the nose, into the eyes, externally (topically), orally or parenterally (including subcutaneously, intravenously and intramuscular).

 The active ingredient can be mixed, for example, with conventional non-toxic, pharmaceutically acceptable carriers for tablets, pills, troches, capsules, suppositories, creams, ointments, aerosols, injectable powders, solutions, emulsions, suspensions, as well as any other suitable for use finished form. And, if necessary, can be used, in addition, stabilizing, auxiliary additives, thickeners and dyes, as well as perfumes.

 The target compound (I) or a pharmaceutically acceptable salt thereof is included / included in the pharmaceutical composition in an amount sufficient to create the desired effect on the development or condition of the disease.

 The pharmaceutical composition of this invention can be prepared by methods conventional in the art. If necessary, the methodology commonly used to increase the bioavailability of a drug can be applied to the pharmaceutical composition of this invention.

 To administer the composition to a human being or animal, it is preferable to use the intravenous route (including intravenous infusion), intramuscular, pulmonary or oral administration or injection, including aerosols, using a metered dose inhaler, nebulizer or dry powder inhaler.

 Although the dosage of a therapeutically effective amount of the target compound (I) varies and depends on the age and condition of each individual patient, for the prevention and / or treatment of the above diseases in humans and animals is usually given in case of intravenous administration: daily dose of 0.001-100 mg of the target compound (I) per kg body weight of a human or animal, in case of intramuscular administration, daily dose of 0.001-100 mg of the target compound (I) per kg body weight of human or animal, in case of intramuscular administration, daily dose of 0.001-100 mg of target of compound (I) per kg weight of human or animal body, in the case of oral administration, a daily dose of 0.001-200 mg of the object compound (I) per kg weight of human being or animals.

 Examples of pharmaceutical compositions.

 Dry capsules containing 100 mg of the compounds of example 7.

 Ingredient - Amount of mg per capsule.

The compound of example 7 - 100
Lactose - 45.8
Magnesium Stearate - 4.2
- 150
The ingredients are pulverized to a predetermined particle size, mixed for about 10 minutes and placed in dry gelatin capsules.

Tablets
Ingredient - mg per tablet
The compound of example 13 - 100
Pregelatinized Corn Starch - 72
Microcrystalline Cellulose - 77
Magnesium Stearate - 1
- 250
The compound is finely ground and mixed with the ground inert ingredients according to the recipe, and then compressed into tablets according to the standard procedure on a tablet compression machine.

 Production Method 1.

 A mixture of 4-cyanophenol (5.95 g), ethyl 5-bromovalerate (11.5 g), potassium carbonate (7.6 g) in N, N-dimethylformamide (60 ml) was stirred at room temperature for 14 hours.

The reaction mixture was poured into water and the resulting mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium bicarbonate, water and an aqueous solution of sodium chloride, and then dried over magnesium sulfate. After filtration, the filtrate was dried under vacuum, and the resulting precipitate was washed with diethyl ether to obtain ethyl 5- (4-cyanophenoxy) valerate (11.21 g)
mp: 55-57 ^o C
IR (nujol): 2200, 1725, 1600, 15 cm ^-1
NMR (DMSO-d ₆ , δ): 1.18 (3H, triplet, J = 7 Hz), 1.4-1.88 (4H, multiplet, 2.37 (2H, triplet, J = 7 Hz), 3.8-4.13 (4H, multiplet), 7.1 (2H, doublet, J = 8.9 Hz), 7.76 (2H, doublet, J = 8.9 Hz)
MS (M / Z)): 247 (M ⁺ )
The following compounds (Production Methods 2 and 3) were obtained analogously to Production Method 1.

Production Method 2
Ethyl 4- (4-cyanophenoxy) butyrate
mp: 56-57 ^o C
IR (nujol): 2220, 1735, 1610, 1510 cm ^-1
NMR (DMSO-d ₆ , δ): 1.18 (3H, triplet, J = 4.7 Hz), 2.00 (2H, multiplet), 2.47 (2H, triplet, J = 4.8 Hz) , 4.07 (4H, multiplet), 7.09 (2H, doublet, J = 4.6 Hz), 7.76 (2H, doublet, J = 4.6 Hz)
MS (M / Z): 233 (M ⁺ )
Production Method 3
Ethyl 6- (4-cyanophenoxy) hexanoate
mp: 45-46 ^o C
IR Nujol): 2220, 1720, 1590, 1565 cm ^-1
NMR (DMSO-d ₆ , δ): 1.18 (3H, triplet, J = 7.1 Hz), 1.3-1.83 (6H, multiplet), 2.31 (2H, triplet, J = 7 , 1 Hz), 3.9-4.2 (4H, multiplet), 7.09 (2H, doublet, J = 8.9 Hz), 7.75 (2H, doublet, J = 8.9 Hz)
MS (M / Z): 261 (M ⁺ )
Production Method 4
Hydrogen chloride was bubbled through a solution of ethyl 5- (4-cyanophenoxy) valerate (2.47 g) in ethanol (250 ml) while cooling with ice water for 4 hours. After the completion of the reaction was determined by thin-layer chromatography, nitrogen was bubbled at room temperature, the resulting mixture was evaporated in vacuo and the resulting precipitate was washed with diethyl ether to give ethyl 5- / 4- (1- (ethoxy) iminomethyl) phenoxy / valerate hydrochloride (28.26 g).

mp: 110 ^o C (decomp.)
IR (nujol): 1720, 1635, 1600 cm ^-1
NMR (DMSO-d ₆ , δ): 1.18 (3H, triplet, J = 7.1 Hz), 1.47 (3H, triplet, J = 7 Hz), 1.5-1.9 (4H, multiplet), 2.38 (2H, triplet, J = 7 Hz), 4.05 (2H, quartet, J = 7.1 Hz), 4.12 (2H, triplet, J = 5.8 Hz), 4 61 (2H, quartet, J = 7 Hz), 7.16 (2H, doublet, J = 9 Hz), 8.14 (2H, doublet, J = 9 Hz), 11.54 (1H, wide singlet)
MS (M / Z): 293 (M ⁺ free)
The following compounds (production methods 5 and 6) were obtained analogously to Production method 4.

Production Method 5
Ethyl 4- / 4- (1- (ethoxy) iminomethyl) phenoxy / butyrate hydrochloride.

so pl. 102-104 ^o C
IR (nujol): 3420, 1735, 1610 cm ^-1
NMR (DMSO-d ₆ , δ): 1.18 (3H, triplet, J = 4.7 Hz), 1.47 (3H, triplet, J = 4.6 Hz), 2.01 (2H, multiplet) 2.48 (2H, triplet, J = 4.8 Hz), 4.09 (4H, multiplet), 4.60 (2H, J = 4.6 Hz), 7.16 (2H, doublet, J = 4.6 Hz), 8.15 (2H, doublet, J = 4.6 Hz)
Production Method 6
Ethyl 6- / 4- (1- (ethoxy) iminomethyl) phenoxy) hexanoate hydrochloride
mp: 107 ^o C (decomp.)
IR (nujol): 1720, 1600, 1580, 1510 cm ^-1
NMR (DMSO-d ₆ , δ): 1.17 (3H, triplet, J = 7 Hz), 1.3-1.84 (6H, multiplet), 1.47 (3H, triplet, J = 7 Hz) 2.31 (2H, triplet, J = 7.1 Hz), 3.92-4.2 (4H, multiplet), 4.61 (2H, quartet, J = 7 Hz), 7.16 (2H, doublet, J = 9 Hz), 8.14 (2H, doublet, J = 9 Hz), 11.54 (1H, broad singlet)
MS (M / Z): 307 (M ⁺ free)
Production Method 7
A mixture of ethyl 5- / 4- (1- (ethoxy) iminomethyl) phenoxy / valerate hydrochloride (28.2 g), ammonium chloride (4.8 g), an ethanolic solution of ammonia (42 ml) in ethanol (300 ml) was stirred and refluxed for 15 hours. After cooling to room temperature, the mixture was filtered, the filtrate was evaporated in vacuo and the resulting precipitate was washed with diethyl ether to obtain ethyl 5- (4-amidinophenoxy) valerate hydrochloride (27.28 g).

mp: 150-155 ^o C (decomp.)
IR (nujol): 3350, 1710, 1660, 1490 cm ^-1
NMR (DMSO-d ₆ , δ): 1.18 (3H, triplet, J = 7.1 Hz), 1.5-1.85 (4H, multiplet), 2.38 (2H, triplet, J = 7 , 1 Hz), 4.05 (2H, quartet, J = 7.1 Hz), 4.1 (2H, triplet, J = 5.8 Hz), 7.15 (2H, doublet, J = 8.9 Hz), 7.85 (2H, doublet, J = 8.9 Hz), 8.65 (4H, broad)
MS (M / Z): 264 (M ⁺ - free)
The following compounds (Production Methods 8 and 9) were obtained analogously to Production Method 7.

Production Method 8
Ethyl 4- (4-amidinophenoxy) butyrate hydrochloride
mp: 81-84 ^o C (decomp.)
IR (nujol): 3420, 3250, 3100, 1720, 1670, 1600 cm ^-1
NMR (DMSO-d ₆ , δ): 1.18 (3H, triplet, J = 7.1 Hz), 1.9-2.1 (2H, multiplet), 2.47 (2H, triplet, J = 7 , 3 Hz), 3.95-4.23 (4H, multiplet), 7.14 (2H, doublet, J = 8.9 Hz), 7.88 (2H, doublet, J = 8.9 Hz), 8.93 (4H, broad singlet)
MS (M / Z): 250 (M ⁺ free)
Production Method 9
Ethyl 6- (4-amidinophenoxy) hexanoate hydrochloride
mp: ≈ 135 ^o C (decomp.)
IR (nujol): 3420, 3260, 3100, 1720, 1660, 1600 cm ^-1
NMR (DMSO-d ₆ , δ): 1.17 (3H, triplet, J = 7.1 Hz), 1.31-1.85 (6H, multiplet), 2.32 (2H, triplet, J = 7 , 1 Hz), 3.95-4.2 (4H, multiplet), 7.14 (2H, doublet, J = 8.9 Hz), 7.89 (2H, doublet, J = 8.9 Hz), 8.69 (4H, broad)
MS (M / Z-; 278 (M ⁺ free)
Production Method 10
To a mixture of ethyl 5- (4-amidinophenoxy) valerate hydrochloride (14.6 g) in a mixture of tetrahydrofuran (150 ml) and 1 N. benzyloxycarbonyl chloride (10.4 ml) was added while cooling with ice water for 1 hour. The mixture was stirred for 2 hours at 10 ^° C., maintaining pH = 10 with 1N. sodium hydroxide solution. The reaction mixture was poured into ethyl acetate (300 ml), and the separated organic layer was washed with an aqueous solution of sodium chloride and dried over magnesium sulfate. The filtrate obtained after filtration was evaporated in vacuo and the resulting precipitate was washed with diethyl ether to obtain ethyl 5- / 4- (N-benzyloxycarbonylamidino) phenoxy / valerate (17.48 g).

mp: 88-90 ^o C
IR (nujol): 3420, 3280, 1715, 1660, 1590, 1560 cm ^-1
NMR (DMSO-d ₆ , δ): 1.17 (3H, triplet, J = 7.1 Hz), 1.55-1.85 (4H, multiplet), 2.37 (2H, triplet, J = 7 Hz), 4.04 (2H, quartet, J = 7 Hz), 4.05 (2H, triplet, J = 5.8 Hz), 5.1 (2H, singlet), 7.0 (2H, doublet, J = 8.9 Hz), 7.24 - 7.46 (5H, multiplet), 7.98 (2H, doublet, J = 8.9 Hz), 9.11 (2H, broad singlet)
MS (M / Z): 398 (M ⁺ )
The following compounds (production methods 11 and 12) were obtained analogously to Production method 10.

The method of obtaining 11
Ethyl 4- / 4- (N-benzyloxycarbonylamidino) phenoxy / butyrate
mp: 110-112 ^o C
IR (nujol): 3430, 3290, 1720, 1655, 1595, 1565 cm ^-1
NMR (DMSO-d ₆ , δ): 1.18 (3H, triplet, J = 7.1 Hz), 1.84-2.1 (2H, multiplet), 2.46 (2H, triplet, J = 7 , 1 Hz), 3.9-4.19 (4H, multiplet), 5.12 (2H, singlet), 7.01 (2H, doublet, J = 8.9 Hz), 7.23-7.5 (5H, multiplet), 7.97 (2H, doublet, J = 8.9 Hz), 9.31 (2H, broad singlet)
MS (M / Z): 384 (M ⁺ )
production method 12
Ethyl 6- / 4- (N-benzyloxycarbonylamidino) phenoxy / hexanoate
mp: 96-99 ^o C
IR (nujol): 3430, 3300, 1725, 1660, 1600, 1570, 1490 cm ^-1
NMR (DMSO-d ₆ , δ): 1.17 (3H, triplet, J = 7.1 Hz), 1.3-1.84 (6H, multiplet), 2.31 (2H, triplet, J = 7 , 1 Hz), 3.92-4.16 (4H, multiplet), 5.1 (2H, singlet), 7.0 (2H, doublet, J = 8.9 Hz), 7.25-7.5 (5H, multiplet), 7.99 (2H, doublet, J = 8.9 Hz), 9.12 (2H, broad singlet)
MS (M / Z): 412 (M ⁺ )
Production Method 13
A mixture of ethyl 5- / 4- (N-benzylcarbonylamidino) phenoxy / valerate (17.4 g) in 10% hydrochloric acid (150 ml) and acetic acid (100 ml) was stirred at 50 ^° C. for 1.5 hours After cooling to room temperature, the reaction mixture was adjusted to pH 4.0 with 4N. sodium hydroxide solution. The precipitate formed was collected and 5- / 4- (N-benzyloxycarbonylamidino) phenoxy / valeric acid (14.87 g) was obtained.

mp: ≈ 103 ^o C (decomp.)
IR (nujol): 3300, 1735, 1640, 1600, 1560, 1510 cm ^-1
NMR (DMSO-d ₆ , δ): 1.53-1.85 (4H, multiplet), 2.29 (2H, triplet, J = 7.2 Hz), 4.06 (2H, triplet, J = 5 , 8 Hz), 5.16 (2H, singlet), 7.04 (2H, doublet, J = 8.9 Hz), 7.3-7.5 (5H, multiplet), 7.95 (2H, doublet , J = 8.9 Hz), 9.54 (1H, broad), 12.07 (1H, broad)
MS (M / Z): 370 (M ⁺ )
The following compounds (Production Methods 14 and 15) were obtained analogously to the method of Production Method 13.

Production Method 14
4- / 4- (N-Benzyloxycarbonylamidino) phenoxy / butyric acid
mp: ≈ 143 ^o C (decomp.)
IR (nujol): 1730, 1600, 1560 cm ^-1
NMR (DMSO-d ₆ , δ): 1.3-1.8 (6H, multiplet), 2.24 (2H, triplet, J = 7 Hz), 4.03 (2H, triplet, J = 6.4 Hz), 5.11 (2H, singlet), 7.0 (2H, doublet, J = 8.9 Hz), 7.2-7.55 (5H, multiplet), 7.98 (2H, doublet, J = 8.9 Hz), 9.22 (1H, broad), 12.02 (1H, broad)
The formulas of the starting compounds, as well as the target compounds presented in the following Examples are given in table 1
In the formulas given in Table 1, A _m (Z) is N-benzyloxycarbonylamidino, A _m is amidino, Asp is Z-aspartic acid, VaI is Z-valine, Sar is sarcosine, Leu is L-leucine, BZI is benzyl and ^t Bu means tert-butyl.

Example 1
To a mixture of 5- / 4- (N-benzyloxycarbonylamidino) phenoxy / valerianic acid (0.5 g), starting compound (I) (0.61 g) and 1-hydroxy-1H-benzotriazole (0.21 g) in N , N-dimethylformamide (5 ml) was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (0.25 ml) and the mixture was stirred at room temperature for 2 hours.

 The reaction mixture was poured into a mixture of water (50 ml) and ethyl acetate (30 ml) and the pH was adjusted to 9.5 with 4N. sodium hydroxide solution. The separated organic layer was washed with saturated sodium hydrogen carbonate solution, water and an aqueous solution of sodium chloride and dried over magnesium sulfate. The filtrate obtained after filtration was evaporated in vacuo to give the target compound (I) (1.08 g) as an oil.

NMR (DMSO-d ₆ , δ): 0.83 (6H, doublet, J = 6.7 Hz), 1.53-1.8 (4H, multiplet), 2.16 (2H, multiplet), 2, 5-2.85 (2H, multiplet), 4.01 (2H, triplet type), 4.15-4.28 (1H, multiplet), 5.0-5.23 (7H, multiplet), 6.99 (2H, doublet, J = 8.9 Hz), 7.2-7.5 (15H, multiplet), 7.98 (2H, doublet, J = 8.9 Hz), 8.15 (1H, doublet, J = 8.2 Hz), 8.25 (1H, doublet, J = 8.1 Hz), 9.1 (1H, broad)
Example 2
The target compound (2) was obtained from the starting compound (2A) and the starting compound (28) according to the procedure similar to that described in Example 1.

NMR (DMSO-d ₆ , δ): 0.84 (6H, doublet, J = 6.7 Hz), 1.8-2.2 (3H, multiplet), 2.25 (2H, triplet type), 2 5-2.9 (2H, multiplet), 4.01 (2H, triplet type), 4.20 (1H, multiplet), 4.76 (1H, multiplet), 5.0-5.2 (1H, multiplet), 5.07 (2H, singlet), 5.10 (2H, singlet), 5.11 (2H, singlet), 6.99 (2H, doublet, J = 8.9 Hz), 7.24- 7.53 (15H, multiplet), 7.98 (2H, doublet, J = 9 Hz), 8.16 (1H, doublet, J = 8 Hz), 8.30 (1H, doublet, J = 7.9 ) 9.11 (1H, broad)
Example 3
The target compound (3) was obtained from the starting compound (3A) and the starting compound (3B) in accordance with a procedure similar to that described in Example 1.

IR (nujol): 3300, 1730, 1650, 1600 cm ^-1
NMR (DMSO-d ₆ , δ): 0.83 (6H, doublet, J = 6.7 Hz), 1.3-1.8 (6H, multiplet), 1.9-2.2 (3H, multiplet ), 2.5-2.9 (2H, multiplet), 4.01 (2H, triplet type), 4.13-4.25 (1H, multiplet), 4.66-4.83 (1H, multiplet) 5.0-5.15 (2H, multiplet), 6.98 (2H, doublet, J = 8.9 Hz), 7.2-7.52 (15H, multiplet), 7.98 (2H, doublet , J = 8.9 Hz), 8.05-8.3 (2H, multiplet), 9.1 (1H, broad)
Example 4
The target compound (4) was obtained from the starting compound (4A) and the starting compound (4B) according to a procedure similar to that of Example 1.

mp: 45-50 ^o C
IR (nujol): 3200 (br), 1640, 1600 cm ^-1
NMR (DMSO-d ₆ , δ): 1.84 (6H, doublet, J = 6.7 Hz), 2.05 (1H, multiplet), 2.6-2.9 (4N, multiplet), 2, 78 and 2.97 (3H, each singlet), 3.96 and 4.03 (2H, each singlet), 4.18 (1H, multiplet), 4.84 (1H, broad singlet), 5.0- 5.1 (8H, multiplet), 6.99 (2H, doublet, J = 8.9 Hz), 7.2-7.5 (15H, multiplet), 7.96 (2H, doublet, J = 9, 8 Hz), 8.13 and 8.60 (1H, each is a doublet, J = 8.0 Hz, 7.9 Hz), 8.34 (1H, multiplet), 9.11 (2H, wide singlet)
Example 5
A mixture of starting compound (5) (1 g) and 10% Pd-C (0.6 g) in a mixture of 1 N. hydrochloric acid (5 ml) and tetrahydrofuran (10 ml) was stirred in an atmosphere of gaseous H ₂ at room temperature for 6 hours

 The filtrate obtained after filtration was evaporated in vacuo. The resulting material was subjected to preparative HPLC to obtain the desired compound (5) (0.374 g).

HPLC conditions
column: UMS-RASK R-ODS-15S-15 S-15 120A ODS 50 φ x 250 mm
elution: CH ₃ CN: 0.1% trifluoroacetic acid aqueous solution = 1: 4
flow: 118 ml / min
retention time: 8 min
mp: ≈ 147 ^o C
IR (nujol): 3300, 3080, 1660, 1600, 1530 cm ^-1
NMR (DMSO-d ₆ , δ): 0.84 (6H, doublet, J = 6.7 Hz), 1.54-1.84 (4H, multiplet), 2.03 (1H, multiplet), 2, 19 (2H, triplet type), 2.36-2.78 (2H, multiplet), 3.97-4.2 (3H, multiplet), 4.65 (1H, multiplet), 7.15 (2H, doublet , J = 8.9 Hz), 7.76 (1H, doublet, J = 7.8 Hz), 7.81 (2H, doublet, J = 8.9 Hz), 8.25 (1H, doublet, J = 7.8 Hz), 9.05 (2H, singlet), 9.14 (2H, singlet)
MS (M / Z): 451 (M + 1 free)
Example 6
The target compound (6) was obtained from the starting compound (6) by a method similar to Example 5.

HPLC conditions
column: UMS-RASK R-ODS-15 S-15 120A ODS 50 φ x 250 mm
elution: CH ₃ CN: 0.1% trifluoroacetic acid aqueous solution = 17: 83
flow: 118 ml / min
retention time: 7.355 min
mp: ≈ 195 ^o C (decomp.)
IR (nujol): 3320, 3100, 1655, 1610, 1540, 1490 cm ^-1
NMR (DMSO-d ₆ , δ): 0.84 (6H, doublet, J = 6.7 Hz), 1.8-2.16 (3H, multiplet), 2.3 (2H, triplet, J = 7 , 3 Hz), 2.3-2.8 (2H, multiplet), 3.98-4.2 (3H, multiplet), 4.65 (1H, multiplet), 7.14 (2H, doublet, J = 8.9 Hz), 7.79 (1H, doublet, J = 8.5 Hz), 7.82 (2H, doublet, J = 8.9 Hz), 8.30 (1H, doublet, J = 7, 7 Hz), 9.03 (2H, singlet), 9.14 (2H, singlet)
Example 7
The target compound (7) was obtained from the starting compound (7) by a method similar to Example 5.

HPLC conditions
column: UMS-RASK R-ODS-15 S-15 120A ODS: 50 φ x 250 mm
elution: CH ₃ CN: 0.1% trifluoroacetic acid aqueous solution = 1.1: 4.4
flow: 118 ml / min
retention time: 9.784 min
mp: ≈ 190 ^o C (decomp.)
IR (nujol): 3320, 3100, 1670, 1610, 1540, 1490 cm ^-1
NMR (DMSO-d ₆ , δ): 0.84 (6H, doublet, J = 5.7 Hz), 1.3-1.85 (6H, multiplet), 1.93-2.25 (3H, multiplet ), 2.36-2.79 (2H, multiplet), 3.97-4.21 (3H, multiplet), 4.5-4.76 (1H, multiplet), 7.14 (2H, doublet, J) = 8.9 Hz), 7.72 (1H, doublet, J = 8.6 Hz), 7.81 (2H, doublet, J = 8.9 Hz), 8.23 (1H, doublet, J = 7 , 8 Hz), 9.0 (2H, singlet), 9.14 (2H, singlet)
MS (M / Z): 465 (M + 1 free)
Example 8
The target compound (8) was obtained from the starting compound (8) by a method similar to Example 5.

HPLC conditions
elution: CH ₃ CH: 0.1% trifluoroacetic acid aqueous solution = 15: 85
retention time: 8.0 minutes
(column and flow are the same as in Example 5)
mp: 62-68 ^o C
IR (nujol): 3200 (br), 1640 cm ^-1
NMR (DMSO-d ₆ , δ): 0.86 (6H, doublet, J = 6.8 Hz), 2.04 (1H, multiplet), 2.4-2.8 (2H, multiplet), 2, 80 and 3.00 (3H, each singlet), 3.8-4.2 (3H, multiplet), 4.68 (1H, multiplet), 4.94 and 5.05 (2H, each singlet), 7, 13 (2H, doublet, J = 8.9 Hz), 7.98 (2H, doublet, J = 8.9 Hz), 7.9 and 8.00 (1H, each doublet, J = 7.0, 8 5 Hz), 8.30 and 8.59 (1H, each doublet, J = 8.0, 7.9 Hz), 9.03 (2H, singlet), 9.13 (2H, singlet)
Example 9
(1) The starting compound (9B) was obtained from 2- / 4- (N-benzyloxycarbonylamidino) phenoxy / acetic acid and from the starting compound (9A) according to a procedure similar to Example 1.

 A mixture of the starting compound (9B) thus obtained, anisole (20 ml) and trifluoroacetic acid (80 ml) was stirred for 2 hours and 45 minutes.

 Trifluoroacetic acid was removed under reduced pressure, and the residue was triturated with diethyl ether to give the starting compound (9C) (19.49 g).

mp: 152-156 ^o C
IR (nujol): 1630, 1600, 1560, 1500 cm ^-1
NMR (DMSO-d ₆ , δ): 2.84 and 3.06 (3H, each singlet), 4.01 and 4.19 (2H, each singlet), 4.91 and 5.09 (2H, each singlet) ), 5.34 (2H, singlet), 7.06 and 7.08 (2H, each doublet, J = 8.8 Hz), 7.3-7.6 (5H, multiplet), 7.78 (2H doublet, J = 8.8 Hz)
(2) The target compound (9A) was obtained from the thus obtained starting compound (9C) and from the starting compound (9D) according to a procedure similar to that described in Example 1.

 The protective groups of the target compound (9A) were removed in the same manner as in Example 5 and the target compound (9B) was obtained.

mp: 41-45 ^o C
IR (nujol): 3250, 1630, 1610 cm ^-1
NMR (DMSO-d ₆ , δ): 0.7-1.0 (6H, multiplet), 1.3-1.7 (3H, multiplet), 2.3-2.8 (2H, multiplet), 2 80 and 3.00 (3H, each singlet), 3.97 and 4.04 (2H, each singlet), 4.18 (1H, multiplet), 4.67 (1H, multiplet), 5.93 and 5 05 (2H, each singlet), 7.13 (2H, doublet, J = 8.7 Hz), 7.77 (2H, doublet, J = 8.7 Hz), 7.98 and 8.17 (1H each doublet, J = 7.9 Hz), 8.24 and 8.55 (1H, each doublet, J = 7.9 Hz), 8.55 and 9.13 (4H, each singlet)
MS (M / Z): 494 (M + 1)
HPLC conditions
elution: CH ₃ CN: 0.1% trifluoroacetic acid aqueous solution = 17:83
retention time: 11.0 minutes
(column and flow are the same as in Example 5)
The following compounds (Examples 10 to 12) were prepared from the corresponding trifluoroacetic acid salts in a conventional manner.

Example 10
Target Compound (10)
IR (nujol): 3420, 3270, 1690, 1635, 1600, 1540, 1480 cm ^-1
NMR (DMSO-d ₆ , δ): 0.84 (6H, doublet, J = 6.3 Hz), 1.8-2.2 (3H, multiplet), 2.3 (2H, triplet J = 7, 3 Hz), 2.3-2.8 (2H, multiplet), 3.96-4.2 (3H, multiplet), 4.65 (1H, multiplet), 7.14 (2H, doublet, J = 8 , 9 Hz), 7.8 (1H, doublet, J = 8.5 Hz), 7.85 (2H, doublet, J = 8.9 Hz), 8.35 (1H, doublet, J = 7.7 Hz), 9.04 (2H, singlet, 9.24 (2H, singlet), 12.51 (1H, broad singlet)
Elemental analysis
C ₂₀ H ₂₈ N ₄ O ₇ • HCl • H ₂ O
Calculated: C 48.93; H 6.36; N, 11.41; Cl 7.22
Found: C, 48.77; H 6.52; N, 11.22; Cl 6.98
mp: 198 ^o C (decomp.)
Example 11
Target Compound (11)
mp: 163 ^o C (decomp.)
IR (nujol): 3270, 1700, 1665, 1630, 1605, 1535, 1480 cm ^-1
NMR (DMSO-d ₆ , δ): 0.84 (6H, doublet, J = 6.1 Hz), 1.29-1.85 (6H, multiplet), 1.91-2.23 (3H, multiplet ), 2.35-2.78 (2H, multiplet), 3.98-4.2 (3H, multiplet), 4.55-4.73 (1H, multiplet), 7.14 (2H, doublet, J) = 8.9 Hz), 7.72 (1H, doublet, J = 8.7 Hz), 7.83 (2H, doublet, J = 8.9 Hz), 8.25 (1H, doublet, J = 7 , 7 Hz), 8.94 (2H, singlet), 9.20 (2H, singlet)
Example 12
Target Compound (12)
mp: 133 140 ^o C
IR (nujol): 3000-3300 (wide singlet), 1710 (shoulder), 1630 (wide brs singlet) cm ^-1
NMR (DMSO-d ₆ , δ): 0.86 (6H, doublet, J = 6.8 Hz), 2.05 (1H, multiplet), 2.80 and 3.01 (3H, each singlet), 2 4-2.8 (2H, multiplet), 3.8-4.2 (3H, multiplet), 4.68 (1H, multiplet), 4.94 and 5.06 (2H, each singlet), 7, 13 (2H, doublet, J = 8.8 Hz), 7.80 (2H, doublet, J = 8.8 Hz), 7.8 and 8.0 (1H, each doublet, J = 7.0 and 8 5 Hz), 8.37 and 8.68 (1H, each doublet, J = 8.0 and 7.9 Hz), 9.05 (2H, singlet), 9.24 (2H, singlet)
MS (M / Z): 480 (M ⁺ + 1)
HPLC conditions
column: UMS-RASK R-ODS-15 S-15 120A ODS 50 φ x 250 mm
elution: CH ₃ CN: 0.1% trifluoroacetic acid aqueous solution = 15:85
flow: 1 ml / min
retention time: 8.1 min
The formulas of the starting and target compounds in the following Example 13 can be represented as follows.

(Am, Asr и VaI каждое как определено выше)
Пример 13
Раствор исходного соединения (13) (79 г) в 0,02 М буфере пиридин-уксусная кислота (pH 5) (1 л) подвергли колоночной хроматографии на ионообменной смоле (2 л), элюируя 0,5 М буфером пиридин-уксусная кислота.

(Am, Asr and VaI each as defined above)
Example 13
A solution of the starting compound (13) (79 g) in 0.02 M pyridine-acetic acid buffer (pH 5) (1 L) was subjected to column chromatography on an ion-exchange resin (2 L), eluting with 0.5 M pyridine-acetic acid buffer.

 Fractions containing the target compound were combined and concentrated under reduced pressure to obtain the target compound (13) (62.54 g).

Метод получения 16
Смесь DL-4-циано-N-ацетилфенилаланина (114,0 г), хлорида кобальта (11) (0,63 г) и ацилазы Amano 15000 (торговая марка) (6,27 г) в 1 н. водном растворе гидроксида натрия (492 мл) довели до pH 7,5, добавляя 0,1 н. хлористоводородную кислоту и 0,1 н. водный раствор хлорида натрия, а затем перемешивали при 33-36^oC в течение 20 ч. Реакционную смесь довели до pH 1 с помощью 10% хлористоводородной кислоты, а затем промыли этилацетатом и собрали фильтрацией образовавшийся осадок. Осадок промыли 10% хлористоводородной кислотой и водой, получив 4-циано-N-ацетил-D-фенилаланин (32,00 г).mp: 171 ^o C (decomp.)
IR (nujol): 3310, 1650, 1600, 1520 cm ^-1
NMR (DMSO-d ₆ , δ): 0.80 (6H, doublet, J = 6.8 Hz), 1.8-2.73 (7H, multiplet), 3.8-4.25 (3H, multiplet ), 4.56 (1H, multiplet), 7.10 (2H, doublet, J = 8.8 Hz), 7.44 (1H, doublet, J = 8.1 Hz), 7.74 (2H, doublet , J = 8.7 Hz), 8.39 (1H, doublet, J = 7.6 Hz), 8.75 (1.5H, singlet), 11.25 (1.5H, singlet)
MS (M / Z): 437 (M ⁺ +1)
Elemental analysis
C ₂₀ H ₂₈ N ₄ O ₇ • 1.2H ₂ O

The method of obtaining 16
A mixture of DL-4-cyano-N-acetylphenylalanine (114.0 g), cobalt chloride (11) (0.63 g) and Amano 15000 acylase (trademark) (6.27 g) in 1 N. an aqueous solution of sodium hydroxide (492 ml) was adjusted to pH 7.5 by adding 0.1 n. hydrochloric acid and 0.1 N. an aqueous solution of sodium chloride, and then stirred at 33-36 ^o C for 20 hours. The reaction mixture was adjusted to pH 1 with 10% hydrochloric acid, and then washed with ethyl acetate and the precipitate formed was collected by filtration. The precipitate was washed with 10% hydrochloric acid and water to give 4-cyano-N-acetyl-D-phenylalanine (32.00 g).

mp: 173-175 ^o C
(α) _D (C = 1, MeOH) = - 12.9 ^°
IR (nujol): 2210, 1715, 1600, 1520 cm ^-1
NMR (DMSO-d ₆ , δ): 1.78 (3H, singlet), 2.92 (1H, doublet of doublets, J = 13.8, 9.8 Hz), 3.15 (1H, doublet of doublets, J = 13.8 Hz, 4.9 Hz), 4.48 (1H, multiplet), 7.44 (2H, doublet, J = 8.2 Hz), 7.76 (2H, doublet, J = 8.2 Hz), 8.25 (1H, doublet, J = 8.2 Hz)
The acidic aqueous layer was adjusted to pH 7.5 by adding an aqueous solution of sodium hydroxide, triethylamine (32.2 ml) and di-tert-butyl dicarbonate (83.59 g) were added and stirred at room temperature for 5 days. The reaction mixture was adjusted to pH 6.0 with 10% hydrochloric acid and extracted with ethyl acetate. The separated organic layer was washed with water and brine and dried over magnesium sulfate. After evaporation in vacuo, the precipitate was washed with n-hexane to give 4-cyano-N-tert-butoxycarbonyl-L-phenylalanine (43.50 g)
mp: 149-150 ^o C
(α) _D (C = 1, MeOH) = + 6.1 ^°
IR (nujol): 3350, 3180, 2240, 1730, 1680, 1600, 1505 cm ^-1
NMR (DMSO-d ₆ , δ): 1.31 (9H, singlet), 2.91 (1H, doublet of doublets, J = 13.7 Hz, 10.9 Hz), 3.14 (1H, doublet of doublets, J = 13.7 Hz, J = 10.9 Hz), 4.18 (1H, multiplet), 7.20 (1H, doublet, J = 8.6 Hz), 7.46 (2H, doublet, J = 8.1 Hz), 7.76 (2H, doublet, J = 8.1 Hz)
Elemental analysis
Calculated: C 62.05; H 6.24; N, 9.24
Found: C, 62.38; H 6.32; N 9.55
Production Method 17
A solution of 4-cyano-N-tert-butoxycarbonyl-L-phenylalanine (31.50 g) in pyridine (400 ml) and triethylamine (190 ml) was bubbled at room temperature for 2 hours, and the mixture was left at room temperature for the night. The reaction mixture was diluted with water and ethyl acetate and adjusted to pH 4.5 by adding concentrated hydrochloric acid and extracted with ethyl acetate. The separated organic layer was washed with dilute hydrochloric acid and water and dried over magnesium sulfate. After evaporation in vacuo, the precipitate was collected by filtration and washed with n-hexane to give 4-thiocarbamoyl-N-tert-butoxycarbonyl-L-phenylalanine (30.31 g).

mp: 254-256 ^o C (decomp.)
(α) _D (MeOH, C = 1) = +29.40 ^°
IR (nujol): 3280, 3110, 1670, 1605, 1510 cm ^-1
NMR (DMSO-d ₆ , δ): 1.32 (9H, singlet), 2.87 (1H, doublet of doublets, J = 13.7 Hz, J = 10.3 Hz), 3.05 (1H, double doublet, J = 13.7 Hz, J = 4.5 Hz), 4.12 (1H, multiplet), 7.15 (1H, doublet, J = 8.4 Hz), 7.28 (2H, doublet, J = 8.2 Hz), 7.83 (2H, doublet, J = 8.2 Hz), 9.43 (1H, broad singlet), 9.80 (1H, broad singlet)
Elemental analysis
Found: C, 55.19; H, 6.32; S, 9.99; N, 8.38
Calculated: C 55.53, H 6.21, S 9.88 N 8.63
The method of obtaining 18
A solution of 4-thiocarbamoyl-N-tert-butoxycarbonyl-L-phenylalanine (30.06 g) and methyl iodide (63.5 ml) in acetone (300 ml) was stirred and refluxed for 40 minutes, after which the solvent was removed under a vacuum. The resulting material was dissolved in methanol (300 ml), ammonium acetate (10.71 g) was added, and then the mixture was heated under reflux with stirring for 4 hours and 30 minutes. The reaction mixture was cooled and the precipitate formed was filtered. The filtrate was evaporated in vacuo, the resulting material was triturated with ethanol and diethyl ether and washed with diethyl ether to give 4-amidino-N-tert-butoxycarbonyl-L-phenylalanine hydroiodide (13.83 g).

mp: 184-188 ^o C (decomp.)
IR (nujol): 1670, 1600, 1560 cm ^-1
NMR (DMSO-d ₆ , δ): 1.33 (9H, singlet), 2.7-3.2 (2H, multiplet), 3.97 (1H, multiplet), 7.23 (2H, doublet, J = 8.0 Hz), 7.4-8.0 (6H, multiplet)
MS (m / z): 308 (M ⁺ +1)
Production Method 19
To a mixture of 4-amidino-N-tert-butoxycarbonyl-L-phenylalanine hydroiodide (1.00 g), in 4 N. an aqueous solution of sodium hydroxide (1.15 ml), tetrahydrofuran (2 ml) and water (10 ml) was added a solution of benzyloxycarbonyl chloride in tetrahydrofuran (2 ml), the pH of which was adjusted to 12≈12.5 with 4N. an aqueous solution of sodium hydroxide. The reaction mixture was diluted with water and diethyl ether, the separated aqueous layer was neutralized with 10% hydrochloric acid, extracted with ethyl acetate, washed with water and brine, and dried over magnesium sulfate. The precipitate obtained after evaporation in vacuo was collected by filtration and washed with diethyl ether to give 4- (N-benzyloxycarbonylamidino) -N-tert-butoxycarbonyl-L-phenylalanine (0.53 g).

mp: 112-115 ^o C
IR (Nujol): 3300, 1680, 1620, 1560, 1500 cm ^-1
NMR (DMSO-d ₆ , δ): 1.31 (9H, singlet), 2.8-3.2 (2H, multiplet), 4.12 (1H, multiplet), 5.11 (1H, singlet), 7.12 (1H, doublet, J = 8.3 Hz), 7.3-7.5 (7H, multiplet), 7.91 (2H, doublet, J = 8.3 Hz), 9.14 (wide singlet)
Production Method 20
4- (N-Benzyloxycarbonylamidino) -N-acetyl-D-phenylalanine was obtained from 4-cyano-N-acetyl-D-phenylalanine by a method similar to that of Production Methods 17, 18 and 19.

mp: 140-145 ^o C (decomposition).

IR (nujol): 3250 (wide singlet), 1740, 1605 cm ^-1
NMR (DMSO-d ₆ , δ): 1.77 (3H, singlet), 2.90 (1H, doublet of doublets, J = 13.8, 10.0 Hz), 3.16 (1H, doublet of doublets, J = 13.8, 4.5 Hz), 4.46 (1H, multiplet), 5.27 (2H, singlet), 7.2-7.5 (7H, multiplet), 7.80 (2H, doublet, J = 8.2 Hz), 8.32 (1H, doublet, J = 8.2 Hz)
Production Method 21
A mixture of ethyl 5- (4-amidinophenyl) -2,4-pentadienoate hydrochloride (20.00 g) and 10% Pd-C (5.00 g) in ethanol (500 ml) was stirred in an atmosphere of gaseous H ₂ at room temperature within 3 hours. After filtration, the filtrate was evaporated in vacuo. The resulting precipitate was washed with diethyl ether and 5- / 4-amidinophenyl / pentanoate hydrochloride (19.32 g) was obtained.

IR / Nujol /: 3400, 3100, 1730, 1660 cm ^-1
NMR (DMSO-d ₆ , δ): 1.16 / 3H, triplet, J = 7.1 Hz /, 1.52-1.61 / 4H, multiplet /, 2.32 (2H, triplet, J = 6 9 Hz /, 2.66 / 2H, triplet, J = 7.0 Hz /, 4.04 / 2H, quartet, J = 7.1 Hz /, 7.45 / 2H, doublet, J = 8.8 Hz /, 7.78 / 2H, doublet, J = 8.3 Hz /, 9.21 / 2H, singlet /, 9.26 / 2H, singlet /
MS / m / z /: 248 / M ⁺ /
The method of obtaining 22
Ethyl 3- / 4-amidinophenyl / propionate hydrochloride was prepared according to a procedure similar to Example 21.

IR / Nujol /: 3350, 3150, 1720, 1670, 1210 cm ^-1
NMR (DMSO-d ₆ , δ): 1.16 / 3H, triplet, J = 7.1 /, 2.69 / 2H, triplet, J = 7.4 Hz /, 2.95 / 2H, doublet, J = 8.3 Hz /, 4.09 / 2H, quartet, J = 7.1 Hz /, 7.48 / 2H, doublet, J = 8.3 Hz /, 7.82 / 2H, doublet, J = 8 , 3 Hz /, 8.94 / 4H, wide singlet /
MS / m / z /: 220 / M ⁺ /
The following compounds (Production Methods 23 to 25) were obtained analogously to the method of Production Method 10.

Production Method 23
Ethyl 3- / 4- (N-benzyloxycarbonylamidino) phenyl / propionate
NMR (DMSO-d ₆ , δ): 1.15 / 3H, triplet, J = 7.1 Hz /, 2.65 / 2H, triplet, J = 7.4 Hz /, 2.91 / 2H, triplet, J = 7.4 Hz /, 4.03 / 2H, quartet, J = 7.1 Hz /, 5.10 / 2H, singlet /, 7.31-7.41 / 7H, multiplet /, 7.90 / 2H, doublet, J = 8.3 Hz /, 9.13 / 2H, broad singlet /
MS (m / z): 354 / M ⁺ /
The method of obtaining 24
Ethyl 5- / 4- (N-benzyloxycarbonylamidino) phenyl / pentanoate
IR (nujol /: 3450, 3300, 1730, 1600, 1250 cm ^-1
NMR (DMSO-d ₆ , δ): 1.16 / 3H, triplet, J = 7.1 Hz /, 1.56-1.58 / 4H, multiplet /, 2.31 / 2H, triplet, J = 6 9 Hz /, 2.64 / 2H, triplet, J = 7.0 Hz /, 4.03 / 2H, quartet, J = 7.1 Hz /, 5.11 / 2H, singlet /, 7.23- 7.40 / 7H, multiplet /, 7.90 / 2H, doublet, J = 8.3 Hz /, 9.23 / 2H, wide singlet /
Production Method 25
Ethyl 8- / 4- (N-benzyloxycarbonylamidino) phenoxy / octanoate
mp: 93-95 ^o C
IR / Nujol /: 3420, 3290, 1720, 1650, 1590, 1560, 480 cm ^-1
NMR (DMSO-d ₆ , δ): 1.17 / 3H, triplet, J = 7.1 /, 1.15-1.83 / 10H, multiplet /, 2.27 / 2H, triplet, J = 7, 2 /, 4.01 / 2H, triplet type /, 4.04 / 2H, quartet, J = 7.1 Hz /, 5.10 / 2H, singlet /, 7.0 / 2H, doublet, J = 8, 9 Hz /, 7.36 / 5H, multiplet /, 7.98 / 2H, doublet, J = 8.9 Hz /, 9.09 / 2H, wide singlet /
Production Method 26
Ethyl 5- / 4- (N-benzyloxycarbonylamidinophenyl) / pentanoate (22.00 g) in concentrated hydrochloric acid (220 ml) was stirred at room temperature for 3 weeks. The reaction mixture was filtered and the filtered precipitate was dissolved in a mixture of water and ethyl acetate, the pH was adjusted to 10.50 by adding an aqueous solution of sodium hydroxide, the pH of the separated aqueous layer was adjusted to 4.5 by adding 10% hydrochloric acid and extracted with ethyl acetate, and the separated organic layer washed with brine and dried over magnesium sulfate, the filtrate obtained after filtration was evaporated in vacuo, and the precipitate formed was triturated with diisopropyl ether to give 5- [4- (N-benzyloxycarbonylamidinophenyl)] - pentanoic acid (12 , 0 g).

IR (nujol): 3350, 3200, 1700, 1660, 1620, 1250 cm ^-1
NMR (DMSO-d ₆ , δ): 1.50-1.60 (4H, multiplet), 2.23 (2H, triplet, J = 6.9 Hz), 2.64 (2H, triplet, J = 7 , 0 Hz), 5.10 (2H, singlet), 7.27-7.42 (7H, multiplet), 7.90 (2H, doublet, J = 8.3 Hz), 9.11 (2H, broad singlet), 12.01 (1H, broad singlet)
MS (m / z): 355 (M ⁺ +1)
The method of obtaining 27
3- / 4 (N-Benzyloxycarbonylamidino) phenyl / propionic acid was prepared according to a procedure similar to that described in Production Method 26.

NMR (DMSO-d ₆ , δ): 2.56 (2H, triplet, J = 7.4 Hz), 2.88 (2H, triplet, J = 7.4 Hz), 5.10 (2H, singlet) 7.32 - 7.38 (8H, multiplet), 7.90 (2H, doublet, J = 8.3 Hz), 9.08 (1H, broad singlet)
The method of obtaining 28
8- / 4 (N-Benzyloxycarbonylamidino) phenoxy / octanoic acid was obtained analogously to Production Method 13.

mp: 130 ^o C (decomp.)
IR (nujol): 1760, 1700, 1600 cm ^-1
NMR (DMSO-d ₆ , δ): 1.15-1.8 (10H, multiplet), 2.20 (2H, triplet, J = 7.2 Hz), 4.07 (2H, triplet, J = 6 , 4 Hz), 5.27 (2H, singlet), 7.09 (2H, doublet, J = 8.9 Hz), 10.0 (1H, broad), 12.0 (1H, broad)
Production Method 29
A mixture of ethyl 4- (4-cyanophenoxy) butyrate (4.7 g) in tetrahydrofuran (23.5 ml) and 1 N. sodium hydroxide solution (40.2 ml) was heated under reflux for 2 hours with stirring. The reaction mixture was adjusted to pH 2.0 by adding 10% hydrochloric acid, and the precipitate formed was collected by filtration to obtain 4- (4-cyanophenoxy) butyric acid (4.06 g).

mp: 210 ^o C
IR (nujol): 3175, 2220, 1730, 1600, 1510 cm ^-1
NMR (DMSO-d ₆ , δ): 1.96 (2H, multiplet), 2.39 (2H, multiplet), 4.08 (2H, multiplet), 7.08 (2H, doublet, J = 8.9 Hz), 7.76 (2H, doublet, J = 8.9 Hz), 12.18 (1H, singlet)
Production Method 30
5- (4-Cyanophenoxy) pentanoic acid was obtained according to a procedure similar to that described in Production Method 29.

mp: 160 ^o C
IR (nujol): 3200, 2225, 1720, 1600, 1560, 1505 cm ^-1
NMR (DMSO-d ₆ , δ): 1.5-1.85 (4H, multiplet), 2.29 (2H, triplet-like), 4.05 (2H, multiplet), 7.09 (2H, doublet, J = 6.9 Hz), 7.76 (2H, doublet, J = 6.9 Hz)
Production Method 31
A mixture of 4- (4-cyanophenoxy) butyric acid (1 g), triethylamine (0.75 ml) and diphenylphosphoryl azide (1.16 ml) in tetrahydrofuran (10 ml) was heated under reflux for 6 hours with stirring. The starting compound (P-31) (2.4 g) was added to the resulting mixture at room temperature, and the mixture was stirred under the same conditions for 15 hours. The reaction mixture was poured into a mixture of ethyl acetate (30 ml) and water (100 ml) and adjusted to pH 10 by adding 4 n. sodium hydroxide solution. The separated organic layer was washed with dilute hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine, dried over magnesium sulfate and evaporated in vacuo to give the desired compound (P-31) (1.7 g).

mp: 106-109 ^o C
IR (nujol): 3360, 3300, 3270, 2225, 1725, 1630, 1600 cm ^-1
NMR (DMSO-d ₆ , δ): 0.82 (6H, doublet, J = 5.6 Hz), 1.83 (2H, triplet, J = 6.3 Hz), 2.05 (1H, multiplet) 2.4-2.8 (2H, multiplet), 3.15 (2H, multiplet), 4.05 (2H, triplet, J = 6.2 Hz), 4.23 (1H, multiplet), 4, 61 (1H, multiplet), 5.05 (2H, singlet), 5.10 (2H, singlet), 6.22-6.4 (2H, multiplet), 7.08 (2H, doublet, J = 8, 9 Hz), 7.35 (10H, multiplet), 7.75 (2H, doublet, J = 8.9 Hz), 8.15 (1H, doublet, J = 8.3 Hz)
FAB-MASS: 615 (M ⁺ +1)
Production Method 32
The target compound (P-32) was obtained by a method similar to Production Method 31.

mp: 115-122 ^o C
IR (nujol): 3300, 2220, 1730, 1625, 1600, 1540 cm ^-1
NMR (DMSO-d ₆ , δ): 0.83 (6H, doublet, J = 6.7 Hz), 1.52 (2H, multiplet), 1.69 (2H, multiplet), 2.06 (1H, multiplet), 2.5-2.8 (2H, multiplet), 3.05 (2H, multiplet), 4.05 (2H, triplet, J = 6.2 Hz), 4.23 (1H, multiplet), 4.63 (1H, multiplet), 5.06 (2H, singlet), 5.11 (2H, singlet), 6.2-6.4 (2H, multiplet), 7.08 (2H, doublet, J = 8.9 Hz), 7.35 (10H, multiplet), 7.74 (2H, doublet, J = 8.9 Hz), 8.16 (1H, doublet, J = 8.3 Hz)
The following compounds (methods of obtaining 33 and 34) were obtained by a method similar to Method of obtaining 17.

Production Method 33
Target Compound (P-33)
mp: 139 ^o C
IR (nujol): 3430, 3320, 3200, 1730, 1715, 1630, 1540 cm ^-1
NMR (DMSO-d ₆ , δ): 0.83 (6H, doublet, J = 6.5 Hz), 1.93 (2H, triple-like), 2.05 (1H, multiplet), 2.4-2, 8 (2H, multiplet), 3.15 (2H, multiplet), 4.03 (2H, triple-like), 4.23 (1H, multiplet), 4.62 (1H, multiplet), 5.06 (2H, singlet) ), 5.11 (2H, singlet), 6.2-6.42 (2H, multiplet), 6.93 (2H, doublet, J = 8.8 Hz), 7.34 (10H, multiplet), 7 95 (2H, doublet, J = 8.8 Hz), 8.15 (1H, doublet, J = 8.2 Hz), 9.32 (1H, singlet), 9.64 (1H, singlet)
Production Method 34
Target Compound (P-34)
mp: 130 ^o C
NMR (DMSO-d ₆ , δ): 0.83 (6H, doublet, J = 5.8 Hz), 1.52 (2H, multiplet), 1.69 (2H, multiplet), 2.06 (2H, multiplet), 2.4-2.8 (2H, multiplet), 3.05 (2H, multiplet), 4.01 (2H, triplet, J = 6.0 Hz), 4.23 (1H, multiplet), 4.62 (1H, multiplet), 5.06 (2H, singlet), 5.11 (2H, singlet), 6.2-6.4 (2H, multiplet), 6.93 (2H, doublet, J = 8.9 Hz), 7.35 (10H, multiplet), 7.95 (2H, doublet, J = 8.9 Hz), 8.15 (1H, doublet, J = 8.3 Hz), 9.32 (1H, singlet), 9.64 (1H, singlet)
In the above Preparation Methods 31-34, the formulas of the starting and target compounds have the following form shown in Table 2 (in the formulas Asp, VaI and BZI, each as explained in Table 2).

The method of obtaining 35
A mixture of 60% sodium hydride (7.92 g) in tetrahydrofuran (100 ml) was stirred at -10 ^o C in an atmosphere of gaseous nitrogen. Ethyl 5-diethoxyphosphoryl-3-pentenoate (49.61 g) was poured into the reaction mixture and stirred for 1 h at -10 ^° C. P-cyanobenzaldehyde (20.00 g) in tetrahydrofuran (50 ml) was poured into the reaction mixture. and stirred for 3 hours at 0 ^° C. The reaction mixture was poured into a mixture of brine and ethyl acetate. The separated organic layer was dried over magnesium sulfate and treated with activated carbon. After filtration, the filtrate was evaporated in vacuo. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate / n-hexane = 1: 4. Fractions containing the target compound were combined and evaporated in vacuo to give 5- (4-cyanophenyl) -2,4-pentadienoate (10.04 g).

IR (nujol): 2250, 1720, 1630, 1250 cm ^-1
NMR (DMSO-d ₆ , δ): 1.24 (3H, triplet, J = 7.1 Hz), 4.16 (2H, quartet, J = 7.1 Hz), 6.18 (1H, doublet, J = 12.5 Hz), 7.13-7.49 (3H, multiplet), 7.74 (2H, doublet, J = 8.5 Hz), 7.85 (2H, doublet, J = 8.5 Hz)
MS (m / z): 227 (M ⁺ )
The following compounds (production methods 36 and 37) were obtained by a method similar to Production method 4.

Production Method 36
Ethyl 3- / 4- (1- (ethoxy) iminomethyl) phenyl / acrylate hydrochloride
IR (nujol): 1720, 1640, 1320, 1180 cm ^-1
NMR (DMSO-d ₆ , δ): 1.28 (3H, triplet, J = 7.1 Hz), 1.49 (3H, triplet, J = 7.0 Hz), 4.21 (2H, quartet, J = 7.1 Hz), 4.66 (2H, quartet, J = 7.0 Hz), 6.86 (1H, doublet, J = 16.0 Hz), 7.59 (1H, doublet, J = 16.0 Hz), 7.79 (2H, doublet, J = 8.7 Hz), 8.18 (2H, doublet, J = 8.7 Hz)
MS (m / z): 247 (M ⁺ )
The method of obtaining 37
Ethyl 5- / 4- (1- (ethoxy) iminomethyl) phenyl / -2,4-pentadienoate hydrochloride
IR (nujol): 3400, 1720, 1620, 1250 cm ^-1
NMR (DMSO-d ₆ , δ): 1.25 (3H, triplet, J = 7.1 Hz), 1.49 (3H, triplet, J = 7.0 Hz), 4.16 (2H, quartet, J = 7.1 Hz), 4.63 (2H, quartet, J = 7.0 Hz), 6.20 (1H, doublet, J = 14.2 Hz), 7.17-7.46 (3H, multiplet), 7.84 (2H, doublet, J = 8.5 Hz), 8.15 (2H, doublet, J = 8.5 Hz)
MS (m / z): 273 (M ⁺ )
Production Method 38
To a mixture of ethyl 5- / 4 - ((1-ethoxy) iminomethyl) phenyl / -2,4-pentadienoate hydrochloride (22.00 g) in ethanol (220 ml) was poured. a solution of ammonia in ethanol (19.7 ml) and heated under reflux for 15 h. After cooling to room temperature, the reaction mixture was evaporated in vacuo, the precipitate was washed with diisopropyl ether and ethyl 5- (4-amidinophenyl) -2.4 was obtained pentadienoate hydrochloride (20.15 g).

IR (nujol): 3400, 1720, 1630, 1250 cm ^-1
NMR (DMSO-d ₆ , δ): 1.25 (3H, triplet, J = 7.1 Hz), 4.17 (2H, quartet, J = 7.1 Hz), 6.18 (1H, doublet, J = 14.4 Hz), 7.15-7.51 (3H, multiplet), 7.78 (2H, doublet, J = 8.5 Hz), 7.89 (2H, doublet, J = 8.5 Hz), 9.30 (2H, singlet), 9.48 (2H, singlet)
MS (m / z): 244 (M ⁺ )
Production Method 39
Ethyl 3- (4-amidinophenyl) acrylate hydrochloride was obtained analogously to Production Method 7.

IR (nujol): 3400, 1720, 1320, 1200 cm ^-1
NMR (DMSO-d ₆ , δ): 1.28 (3H, triplet, J = 7.1 Hz), 4.22 (2H, quartet, J = 7.1 Hz), 6.86 (1H, doublet, J = 16.1 Hz), 7.73 (1H, doublet, J = 16.1 Hz), 7.91 (2H, doublet, J = 8.5 Hz), 7.98 (2H, doublet, J = 8.5 Hz), 8.76 (4H wide singlet)
MS (m / z): 218 (M ⁺ )
Production Method 40
3- / 4- (N-Benzyloxycarbonylamino) phenyl / propionic acid was prepared according to a procedure similar to Production Method 26.

NMR (DMSO-d ₆ , δ): 2.56 (2H, triplet, J = 7.4 Hz), 2.88 (2H, triplet, J = 7.4 Hz), 5.10 (2H, singlet) 7.32 - 7.38 (8H, multiplet), 7.90 (2H, doublet, J = 8.3 Hz), 9.08 (1H, broad singlet)
The formulas of the starting and target compounds in the following Examples are shown in table.3.

 In the formulas given in table. 3 Am / Z /, Am, Bzl, Asp, Val, Sar and Leu each correspond to the definitions given above, Tyr means 1-tyrosine, Ser means L-serine, Gly means glycine, Ala means L-alanine, β Ala means β -alanine, Phe means L-phenylalanine, D-VaI means D-valine, Thr means L-threonine, Ile means L-isoleucine, Nle means L-norleucine, Glu means L-glutamic acid, Me means methyl, Et means ethyl, Ac is acetyl and Boc is tert-butoxycarbonyl.

 The following compounds (examples 14 to 20) were obtained by a method similar to that of Example 1.

Example 14
Target Compound (14)
mp: 95-100 ^o C
IR (nujol): 3300, 1730, 1710, 1650, 1625, 1530 cm ^-1
NMR (DMSO-d ₆ , δ): 0.82 (6H, doublet, J = 6.6 Hz), 1.34-1.68 (4H, multiplet), 1.92-2.22 (3H, multiplet ), 2.4-2.85 (4H, multiplet), 4.1-4.29 (1H, multiplet), 4.65-5.84 (1H, multiplet), 4.1-4.29 (1H multiplet), 4.65-4.84 (1H, multiplet), 5.05 (2H, singlet), 5.1 (4H, singlet), 7.1-7.52 (17H, multiplet), 7, 9 (2H, doublet, J = 8.1 Hz), 8.11 (1H, doublet, J = 8.2 Hz), 8.22 (1H, doublet, J = 7.9 Hz), 9.12 ( 2H, wide singlet)
Example 15
Target Compound (15)
mp: ≈125 ^o C / decomp. /
IR (nujol): 3300, 1725, 1650, 1605, 1490 cm ^-1
NMR (DMSO-d ₆ , δ): 1.5-1.85 (4H, multiplet), 2.14 (2H, triplet type), 2.5-3.01 (4H, multiplet), 3.56 ( 3H, singlet), 4.01 (2H, multiplet), 4.36 (1H, multiplet), 4.73 (1H, multiplet), 5.07 (2H, singlet), 5.1 (2H, singlet), 6.65 (2H, doublet, J = 8.4 Hz), 6.9-7.1 (4H, multiplet), 7.24-7.5 (12H, multiplet), 7.98 (2H, doublet, J = 8.9 Hz), 8.17 (2H, doublet, J = 6.7 Hz), 8.95-9.37 (2H, broad)
Example 16
Target Compound (16)
mp: ≈128 ^o C / decomp. /
IR (nujol): 3300, 1730, 1640, 1600, 1530 cm ^-1
NMR (DMSO-d ₆ , δ): 1.5-1.83 (4H, multiplet), 2.14 (2H, triplet type), 2.5-3.05 (4H, multiplet), 3.58 ( 3H, singlet), 3.69 (3H, singlet), 4.01 (2H, triplet type), 4.40 (1H, multiplet), 4.72 (1H, multiplet), 5.07 (2H, singlet) 5.10 (2H, singlet), 6.82 (2H, doublet, J = 8.6 Hz), 6.99 (2H, doublet, J = 8.9 Hz), 7.10 (2H, doublet, J = 8.6 Hz), 7.22-7.50 (12H, multiplet), 7.99 (2H, doublet, J = 8.8 Hz), 8.1-8.29 (2H, multiplet), 9.14 (1H, broad singlet)
Example 17
Target Compound (17)
mp: 120 ^o C / decomp. /
IR (nujol): 3300, 1730, 1640, 1605, 1500 cm ^-1
NMR (DMSO-d ₆ , δ): 1.48-1.8 (4H, multiplet), 2.13 (2H, triplet type), 2.4-3.06 (4H, multiplet), 3.69 ( 3H, singlet), 4.00 (2H, triplet type), 4.46 (1H, multiplet), 4.73 (1H, multiplet), 5.05 (4H, singlet), 5.10 (2H, singlet) 6.79 (2H, doublet, J = 8.6 Hz), 6.98 (2H, doublet, J = 8.9 Hz), 7.08 (2H, doublet, J = 8.6 Hz), 7 , 17-7.5 (15H, multiplet), 7.98 (2H, doublet, J = 8.9 Hz), 8.16 (1H, doublet, J = 8.1 Hz), 8.29 (1H, doublet, J = 7.4 Hz), 9.16 (1H, broad singlet)
Example 18
Target Compound (18)
mp: 86-90 ^o C
IR (nujol): 3300, 1720, 1610, 1595 cm ^-1
NMR (DMSO-d ₆ , δ): 1.71 (4H, broad singlet), 2.22 (2H, broad singlet), 2.67 (1H, doublet of doublets, J = 17.4 Hz, J = 5, 9 Hz), 3.05 (1H, doublet of doublets, J = 17.7 Hz, J = 9.2 Hz), 3.7-4.2 (4H, multiplet), 4.52 (4H, broad singlet) 5.0-5.2 (6H, multiplet), 7.00 (2H, doublet, J = 8.3 Hz), 7.2-7.6 / 21H /, 7.99 / 2H, doublet, J = 8.4 Hz /, 8.69 / 1H, doublet, J = 7.4 Hz)
Example 19
Target compound / 19 /
mp: 55-60 ^o C
IR (nujol): 3260, 1725, 1645, 1600 cm ^-1
NMR (DMSO-d ₆ , δ): 2.6-3.1 / 4H, multiplet /, 2.77 and 2.96 / 3H, each singlet /, 3.56 / 3H, singlet /, 3.69 / 3H, singlet /, 3.97 and 4.01 / 2H, each singlet /, 4.4 / 1H, multiplet /, 4.7-5.3 / 7H, multiplet /, 6.80 / 2H, multiplet /, 6.95-7.2 / 4H, multiplet /, 7.35 / 10H, multiplet /, 7.97 / 2H, doublet, J = 7.9 Hz /, 8.2-8.3 / 1H, multiplet / 8.4-8.6 / 1H, multiplet /
Example 20
Target connection / 20 /
mp: 50-55 ^o C
IR (nujol): 3250 / expanded /, 1720, 1640, 1600 cm ^-1
NMR (DMSO-d ₆ , δ): 2.4-3.1 / 4H, multiplet /, 2.76 and 2.95 / 3H, each singlet /, 3.68 and 3.69 / 3H, each singlet / 3.95 and 3.99 / 2H, each singlet /, 4.43 / 1H, multiplet /, 4.6-5.3 / 9H, multiplet /, 6.79 / 2H, multiplet /, 6.99 / 2H, doublet, J = 8.9 Hz /, 7.08 / 2H, doublet, J = 8.9 Hz /, 7.1-7.5 / 15H, multiplet /, 7.95 / 2H, doublet, J = 7.9 Hz /, 8.32 / 1H, multiplet /, 8.53 / 1H, multiplet /
Example 21
The target compound / 21-A / was obtained by a method similar to that of Example 1.

 Trifluoroacetic acid / 4 ml / was added to the mixture of the crude starting compound / 21-A / 0.787 mmol / and anisole / 1 ml at room temperature and the mixture was stirred at room temperature for 1 h. After evaporation, a mixture of 4 N was added to the obtained substance. . hydrochloric acid / dioxa / 5 ml /, then the mixture was evaporated in vacuo and the resulting material was triturated with diethyl ether, washed with diethyl ether, and the target compound (21-B) / 0.58 g / was obtained.

mp: 105-110 ^o C
IR (nujol): 1730, 1650 cm ^-1
NMR (DMSO-d ₆ , δ): 0.80 / 6H, multiplet /, 2.05 / 1H, multiplet /, 2.65 and 2.75 / 3H, each singlet /, 2.6-2.9 / 2H, multiplet /, 3.19 / 2H, multiplet /, 3.6-4.4 / 3H, multiplet /, 4.5-4.8 / 2H, multiplet /, 5.09 / 4H, singlet /, 5 , 33 / 2H, singlet /, 7.2-7.6 / 17H, multiplet /, 7.80 / 2H, doublet, J = 8.0 Hz /, 8.17 and 8.36 / 1H, each doublet, J = 8.1 Hz /, 8.2-8.8 / 4H, multiplet /
Example 22
To a mixture of 4- (4- (N-benzyloxycarbonylamidino) phenoxy / butyric acid / 1.18 g /, the starting compound / 22 / / 2.00 g / and 1-hydroxy-1H-benzothiazole / 0.51 g / v N, N-dimethylformamide / 30 ml / at -20 ^° C was added 1- / 3-dimethylaminopropyl / -3-ethylcarbodiimide / 0.61 ml / and the mixture was stirred at room temperature for 6 hours. The reaction mixture was poured into a mixture of water / 300 ml / and ethyl acetate / 200 ml /, the pH was adjusted to 10.50 with a sodium hydroxide solution. The separated organic layer was washed with 0.5 n. hydrochloric acid, saturated sodium bicarbonate, water and brine and dried over magnesium sulfate. The filtrate obtained after filtration was evaporated in vacuo, the precipitate was washed with diisopropyl ether and the target compound (22) (2.04 g) was obtained.

IR (nujol): 3300, 1730, 1650, 1600 cm ^-1
NMR (DMSO-d ₆ , δ): 1.92 / 2H, multiplet /, 2.25 / 2H, triplet, J = 6.4 Hz /, 2.54-2.78 / 2H, multiplet /, 2, 85-2.93 / 2H, multiplet /, 4.01 / 2H, triplet, J = 6.8 Hz /, 4.42 (1H, multiplet /, 4.70 / 1H, multiplet /, 4.99 / 2H singlet /, 5.03 / 2H, singlet /, 5.05 / 2H, singlet /, 5.10 / 2H, singlet /, 6.87 / 2H, doublet, J = 8.9 Hz /, 6.98 / 2H, doublet, J = 8.6 Hz /, 7.08 / 2H, doublet, J = 8.6 Hz /, 7.24-7.39 / 20H, multiplet /, 7.98 / 2H, doublet, J = 8.9 Hz /, 8.22 / 1H, doublet, J = 8.1 Hz /, 8.31 / 1H, doublet, J = 7.4 Hz /, 9.11 / 2H, wide singlet /
MS (m / z): 905 / M ⁺ /
The following compounds / Examples 23 to 36 / were obtained by a method similar to that of Example 22.

Example 23
Target connection / 23 /
IR (nujol): 3400, 1740, 1620, 1250 cm ^-1
NMR (DMSO-d ₆ , δ): 1.92 / 2H, multiplet /, 2.25 / 2H, triplet, J = 6.4 Hz /, 2.54-2.78 / 2H, multiplet /, 2, 88-2.95 / 2H, multiplet /, 3.60 / 3H, singlet /, 4.01 / 2H, triplet, J = 6.8 Hz /, 4.45 / 1H, multiplet /, 4.73 / 1H multiplet /, 4.79 / 2H, singlet /, 4.94 / 2H, singlet /, 5.10 / 2H, singlet /, 6.79 / 2H, doublet, J = 8.9 Hz /, 7.04 / 2H, doublet, J = 8.6 Hz /, 7.08 / 2H, doublet, J = 8.6 Hz /, 7.23-7.42 / 15H, multiplet /, 7.99 / 2H, doublet, J = 8.9 Hz /, 8.22 / 1H, doublet, J = 8.1 Hz /, 8.31 / 1H, doublet, J = 7.4 Hz /, 9.10 / 2H, wide singlet /,
MS (m / z): 829 / M ⁺ + 1 /
Example 24
Target connection / 24 /
IR (nujol): 3400, 3300, 1730, 1700, 1650, 1250 cm ^-1
NMR (DMSO-d ₆ , δ): 1.40-1.50 / 4H, multiplet / 2.08 / 2H, triplet type /, 2.57 / 2H, triplet type /, 2.66-2.76 / 2H, multiplet /, 2.89 - 2.93 / 2H, multiplet /, 3.69 / 3H, singlet /, 4.45 / 1H, multiplet /, 4.41 / 1H, multiplet /, 5.04 / 2H , singlet /, 5.10 / 2H, singlet /, 5.20 / 2H, singlet /, 6.78 / 2H, doublet, J = 8.9 Hz /, 7.07 / 2H, doublet, J = 8, 6 Hz /, 7.23-7.40 / 17H, multiplet /, 7.91 / 2H, doublet, J = 8.9 Hz /, 8.13 / 1H, doublet, J = 8.1 Hz /, 8 26 / 1H, doublet, J = 7.4 Hz /, 9.12 / 2H, wide singlet /
Example 25
Target connection / 25 /
IR (nujol): 3300, 1740, 1700, 1650, 1600, 1250 cm ^-1
NMR (DMSO-d ₆ , δ): 1.06-1.35 / 4H, multiplet /, 1.39-1.51 / 2H, multiplet /, 2.06 / 2H triplet, J = 6.9 Hz / 2.49-2.77 / 2H, multiplet /, 2.85-2.93 / 2H, multiplet /, 3.70 / 3H, singlet /, 3.99 / 2H, triplet, J = 6.4 Hz /, 4.44 / 1H, multiplet /, 4.71 / 1H, multiplet /, 4.99 / 2H, singlet /, 5.01 / 2H, singlet /, 5.09 / 2H, singlet /, 6.78 / 2H, doublet, J = 8.9 Hz /, 6.98 / 2H, doublet, J = 8.6 Hz /, 7.07 / 2H, doublet, J = 8.6 Hz /, 7.24-7 , 89 / 15H, multiplet /, 7.97 / 2H, doublet, J = 8.9 Hz /, 8.12 / 1H, doublet, J = 8.1 Hz /, 8.25 / 1H, doublet, J = 7.4 Hz /, 9.10 / 2H, wide singlet /
MS (m / z): 857 / M ⁺ + 1 /
Example 26
Target connection / 26 /
NMR (DMSO-d ₆ , δ): 0.80 / 3H, doublet, J = 6.0 Hz /, 0.85 / 3H, doublet, J = 6.0 Hz /, 1.40-1.71 / 7H, multiplet /, 1.99 / 2H, type of triplet /, 2.56-2.78 / 4H, multiplet /, 4.30 / 1H, multiplet /, 4.71 / 1H, multiplet /, 5.04 / 2H, singlet /, 5.09 / 2H, singlet /, 5.10 / 2H, singlet /, 7.26-7.49 / 17H, multiplet /, 7.91 / 2H, doublet, J = 8.9 Hz /, 8.15 / 1H, doublet, J = 8.1 Hz /, 8.30 / 1H, doublet, J = 7.6 Hz /, 9.12 / 2H, wide singlet /
MS (m / z): 763 / M ⁺ + 1 /
Example 27
Target connection / 27 /
IR (nujol): 3380, 3300, 1740, 1630, 1250 cm ^-1
NMR (DMSO-d ₆ , δ): 1.87-2.02 / 2H, multiplet /, 2.28 / 2H, triplet, J = 7.0 Hz /, 2.64-2.83 / 2H, multiplet /, 3.87 / 2H, doublet, J = 6.5 Hz /, 4.02 / 2H, triplet, J = 6.4 Hz /, 4.73 / 1H, multiplet /, 5.06 / 2H, singlet /, 5.10 / 2H, singlet /, 5.11 / 2H, singlet /, 6.99 / 2H, doublet, J = 8.9 Hz /, 7.31-7.37 / 15H, multiplet /, 7 , 98 / 2H, doublet, J = 8.9 Hz /, 8.27-8.34 / 2H, multiplet /, 9.07 / 2H, wide singlet /
MS (m / z): 709 / M ⁺ + 1 /
Example 28
Target connection / 28 /
NMR (DMSO-d ₆ , δ): 1.29 / 3H, doublet, J = 7.3 Hz /, 1.92 / 2H, multiplet /, 2.27 / 2H, triplet, J = 7.3 Hz / , 2.55-2.78 / 2H, multiplet /, 4.02 / 2H, triplet, J = 6.3 Hz /, 4.31 / 1H, multiplet /, 4.72 / 1H, multiplet /, 5, 05 / 2H, singlet /, 5.06 / 2H, singlet /, 5.10 / 2H, singlet /, 6.99 / 2H, doublet, J = 8.9 Hz /, 7.34-7.40 / 15H multiplet /, 7.98 / 2H, doublet, J = 8.9 Hz /, 8.24 / 1H, doublet, J = 8.2 Hz /, 8.43 / 1H, doublet, J = 7.2 Hz /, 9.10 / 2H, broad singlet /
Example 29
Target connection / 29 /
IR (nujol): 3300, 1740, 1650, 1600, 1250 cm ^-1
NMR (DMSO-d ₆ , δ): 1.88-1.99 / 2H, multiplet /, 2.25 / 2H, triplet, J = 7.1 Hz /, 2.52-2.60 / 2H, multiplet /, 2.97-3.07 / 2H, multiplet /, 4.03 / 2H, triplet, J = 6.4 Hz /, 4.52 / 1H, multiplet /, 4.73 / 1H, multiplet /, 4 97 / 2H, singlet /, 4.99 / 2H, singlet /, 5.11 / 2H, singlet /, 6.99 / 2H, doublet, J = 8.9 Hz /, 7.18-7.40 / 20H, multiplet /, 8.00 / 2H, doublet, J = 8.9 Hz /, 8.22 / 1H, doublet, J = 8.1 Hz /, 8.36 / 1H, doublet, J = 7.4 Hz /, 9.16 / 2H, wide singlet /
MS (m / z): 799 / M ⁺ + 1 /
Example 30
Target connection / 30 /
IR (nujol): 3300, 1740, 1650, 1600, 1250 cm ^-1
NMR (DMSO-d ₆ , δ): 1.12 / 3H, triplet, J = 7.1 Hz /, 1.56-1.64 / 2H, multiplet /, 1.90-1.97 / 2H, multiplet /, 2.18-2.30 / 4H, multiplet /, 2.57-2.79 / 4H, multiplet /, 3.90-4.06 / 5H, multiplet /, 4.64 / 1H, multiplet /, 5.06 / 2H, singlet /, 5.11 / 2H, singlet /, 7.00 / 2H, doublet, J = 8.9 Hz /, 7.14-7.40 / 15H, multiplet /, 7.68 / 1H, doublet, J = 7.9 Hz /, 8.00 / 2H, doublet, J = 8.9 Hz /, 8.16 / 1H, doublet, J = 8.1 Hz /, 9.12 / 2H wide singlet /
MS (m / z): 765 / M ⁺ + 1 /
Example 31
Target connection / 31 /
NMR (DMSO-d ₆ , δ): 0.68-0.95 / 2H, multiplet /, 1.01-1.35 / 5H, multiplet /, 1.39-1.61 / 10H, multiplet /, 2 11 / 2H, type of triplet /, 2.60-2.75 / 4H, multiplet /, 4.31 / 1H, multiplet /, 4.71 / 1H, multiplet /, 5.04 / 2H, singlet /, 5 , 07 / 2H, singlet /, 5.09 / 2H, singlet /, 7.26-7.37 / 15H, multiplet /, 7.90 / 2H, doublet, J = 8.9 Hz /, 8.15 / 1H, doublet, J = 8.1 Hz /, 8.27 / 1H, doublet, J = 7.4 Hz /, 9.11 / 2H, wide singlet /
MS (m / z): 803 / M ⁺ /
Example 32
Target connection / 32 /
NMR (DMSO-d ₆ , δ): 0.84 / 3H, triplet, J = 7.4 Hz /, 1.60-1.67 / 2H, multiplet /, 1.95 / 2H, multiplet /, 2, 27 / 2H, triplet, J = 6.4 Hz /, 2.57-2.80 / 2H, multiplet /, 4.02 / 2H, triplet, J = 6.8 Hz /, 4.20 / 1H, multiplet /, 4.76 / 1H, multiplet /, 5.00 / 2H, singlet /, 5.06 / 2H, singlet /, 5.07 / 2H, singlet /, 6.99 / 2H, doublet, J = 8, 9 Hz /, 7.24-7.44 / 15H, multiplet /, 7.99 / 2H, doublet, J = 8.9 Hz /, 8.25-8.29 / 2H, multiplet /, 9.12 / 2H, wide singlet /,
MS (m / z): 737 / M ⁺ + 1 /
Example 33
Target connection / 33 /
NMR (DMSO-d ₆ , δ): 0.82 / 3H, triplet, J = 7.3 Hz /, 1.23-1.34 / 2H, multiplet /, 1.64 / 2H, multiplet /, 1, 92-2.10 / 2H, multiplet /, 2.24 / 2H, triplet, J = 6.4 Hz /, 2.56-2.78 / 2H, multiplet /, 4.05 / 2H, triplet, J = 6.8 Hz /, 4.25 / 1H, multiplet /, 4.72 / 1H, multiplet /, 5.05 / 2H, singlet /, 5.06 / 2H, singlet /, 5.09 / 2H, singlet / 6.99 / 2H, doublet, J = 8.9 Hz /, 7.31-7.40 / 15H, multiplet /, 7.98 / 2H, doublet, J = 8.9 Hz /, 8.25 / 1H, doublet, J = 8.0 Hz /, 8.32 / 1H, doublet, J = 7.4 Hz /, 9.10 / 2H, wide singlet /
Example 34
Target connection / 34 /
NMR (DMSO-d ₆ , δ): 0.62-0.97 / 2H, multiplet /, 1.01-1.18 / 5H, multiplet /, 1.42-1.69 / 6H, multiplet /, 1 94 / 2H, multiplet /, 2.24 / 2H, triplet, J = 6.4 Hz /, 2.56-2.76 / 2H, multiplet /, 4.02 / 2H, triplet, J = 6.8 Hz /, 4.32 / 1H, multiplet /, 4.72 / 1H, multiplet /, 5.05 / 2H, singlet /, 5.06 / 2H, singlet /, 5.08 / 2H, singlet /, 6, 98 / 2H, doublet, J = 8.9 Hz /, 7.23-7.39 / 15H, multiplet /, 7.98 / 2H, doublet, J = 8.9 Hz /, 8.23-8.38 / 2H, multiplet /, 9.13 / 2H, wide singlet /
MS (m / z): 805 / M ⁺ + 1 /
Example 35
Target connection / 35 /
NMR (DMSO-d ₆ , δ): 2.52-2.98 / 3H, multiplet /, 2.90 / 3H, singlet /, 3.70 / 3H, singlet /, 3.92 / 2H, multiplet /, 4.43 / 1H, multiplet /, 4.72 / 1H, multiplet /, 5.04 / 2H, singlet /, 5.07 / 2H, singlet /, 5.10 / 2H, singlet /, 6.77 / 1H multiplet /, 7.09 / 2H, multiplet /, 7.26-7.37 / 19H, multiplet /, 7.82-7.95 / 1H, multiplet /, 8.22-8.56 / 1H, multiplet /, 9.18 / 2H, broad singlet /
Example 36
Target connection / 36 /
NMR (DMSO-d ₆ , δ): 0.72-0.98 / 2H, multiplet /, 1.01-1.38 / 5H, multiplet /, 1.41-1.68 / 6H, multiplet /, 2 , 60-2.88 / 2H, multiplet /, 2.77 / 3H, singlet /, 3.98 / 2H, multiplet /, 4.29 / 1H, multiplet /, 4.80 / 1H, multiplet /, 5, 05 / 2H, singlet /, 5.06 / 2H, singlet /, 5.06 / 2H, singlet /, 5.09 / 2H, singlet /, 6.99 / 2H, doublet, J = 8.9 Hz /, 7.33-7.37 / 15H, multiplet /, 7.95 / 2H, doublet, J = 8.9 Hz /, 8.28-8.33 / 1H, multiplet /, 8.46-8.60 / 1H, multiplet /, 9.12 / 2H, wide singlet /
MS (m / z): 848 / M ⁺ + 1 /
Example 37
A mixture of the starting compound / 37 / / 1.70 g / and 10% Pd-C / 0.80 g / in a mixture of 1N hydrochloric acid / 2.25 ml / and tetrahydrofuran / 20 ml / was stirred in an atmosphere of H ₂ at room temperature in for 6 hours. After filtration, the filtrate was evaporated in vacuo. The final substance was washed with an isotonic sodium chloride solution and the target compound (37) (0.60 g) was isolated.

mp: 180-183 ^o C
IR (nujol): 3250, 1670, 1640, 1600, 1260 cm ^-1
NMR (DMSO-d ₆ , δ): 1.94 / 2H, multiplet (2.27 / 2H, triplet type), 2.63-2.72 / 2H, multiplet (2.80-2.87 / 2H, multiplet /, 4.08 / 2H, type of triplet /, 4.30 / 1H, multiplet /, 4.62 / 1H, multiplet /, 6.66 / 2H, doublet, J = 8.9 Hz /, 6 97 / 2H, doublet, J = 8.6 Hz /, 7.14 / 2H, doublet, J = 8.6 Hz /, 7.85 / 3H, multiplet /, 8.25 / 1H, doublet, J = 7.4 Hz /, 9.05 / 2H, singlet /, 9.25 / 3H, multiplet /, 12.51 / 2H, wide singlet /
MS (m / z): 501 / M ⁺ /
The following compounds / Examples 38 to 41 / were obtained by a method similar to that described in Example 37.

Example 38
Target connection / 38 /
mp: 204-206 ^o C
IR (nujol): 3350, 3300, 1670, 1640, 1540, 1260 cm ^-1
NMR (DMSO-d ₆ , δ): 1.94 / 2H, multiplet /, 2.31 / 2H, triplet, J = 6.4 Hz /, 2.45-2.62 / 2H, multiplet /, 2, 79-2.96 / 2H, multiplet /, 3.70 / 3H, singlet /, 4.08 / 2H, triplet, J = 6.8 Hz /, 4.35 / 1H, multiplet /, 4.61 / 1H multiplet /, 6.81 / 2H, doublet, J = 8.9 Hz /, 7.10-7.16 / 4H, multiplet /, 7.84-7.93 / 3H, multiplet /, 8.26 / 1H, doublet, J = 7.8 Hz /, 9.09 / 2H, singlet /, 9.27 / 2H, singlet /, 12.00 / 2H, wide singlet /
MS (m / z): 515 / M ⁺ /
Example 39
Target Compound / 39 /
mp: 163 ^o C / decomp. /
IR (nujol): 3270, 1700, 1665, 1630, 1605, 1535, 1480 cm ^-1
NMR (DMSO-d ₆ , δ): 0.84 / 6H, doublet, J = 6.1 Hz /, 1.29-1.85 / 6H, multiplet /, 1.91-2.23 / 3H, multiplet /, 2.35-2.78 / 2H, multiplet /, 3.98-4.2 / 3H, multiplet /, 4.55-4.73 / 1H, multiplet /, 7.14 / 2H, doublet, J = 8.9 Hz /, 7.72 / 1H, doublet, J = 8.7 Hz /, 7.83 / 2H, doublet, J = 8.9 Hz /, 8.25 / 1H, doublet, J = 7 7 Hz /, 8.94 / 2H, singlet /, 9.20 / 2H, singlet /
Elemental analysis of C ₂₂ H ₃₂ N ₄ O ₇ • HCl • 1H ₂ O
Calculated: C 50.91, H 6.79, N 10.79, Cl 6.83
Found: C, 51.14; H, 6.81; N, 10.74; Cl, 6.37
Example 40
Target connection / 40 /
IR (nujol): 3300, / wide /, 1720, 1650 cm ^-1
NMR (DMSO-d ₆ , δ): 0.83 / 6H, doublet, J = 6.7 Hz /, 1.35-1.7 / 4H, multiplet /, 1.9-2.25 / 3H, multiplet /, 2.33-2.8 / 4H, multiplet /, 4.03-4.2 / 1H, multiplet /, 4.5-4.7 / 1H, multiplet /, 7.44 / 2H, doublet, J = 8.2 Hz /, 7.75 / 1H, doublet, J = 8.3 Hz /, 7.77 / 2H, doublet, J = 8.2 Hz /, 8.28 / 1H, doublet, = 7, 7 Hz /, 9.16 / 2H, singlet /, 9.34 / 2H, singlet /,
Example 41
Target compound / 41 /
mp: 87-90 ^o C
IR (nujol): 3200 / wide /, 1640, 1595, 1530 cm ^-1
NMR (DMSO-d ₆ , δ): 2.4-3.1 / 4H, multiplet /, 2.77 and 2.97 / 3H, each singlet /, 3.69 and 3.70 / 3H, each singlet / 3.96 and 4.02 / 2H, each singlet /, 4.33 / 1H, multiplet /, 4.65 / 1H, multiplet /, 4.93 and 5.06 / 2H, each singlet /, 6.82 / 2H, multiplet /, 7.12 / 4H, doublet, J = 8.8 Hz /, 7.80 / 2H, doublet, J = 8.8 Hz /, 7.95 and 8.17 / 1H, each doublet each J = 7.7 Hz /, 8.28 and 8.59 / 1H, each doublet, each J = 8.2 Hz /, 9.02 and 9.22 / 4H, each singlet /
MS (m / z): 558 / M ⁺ + 1 /
The following compounds / Examples 42 to 58 / were obtained by the method similar to that described in Example 5
Example 42
Target connection / 42 /
mp: 200-202 ^o C
IR (nujol): 3300, 1640, 1270 cm ^-1
NMR (DMSO-d ₆ , δ): 1.06-1.35 / 4H, multiplet /, 1.39-1.51 / 2H, multiplet /, 2.06 / 2H, triplet, J = 6.9 Hz /, 2.49-2.77 / 2H, multiplet /, 2.84-2.94 / 2H, multiplet /, 3.70 / 3H, singlet /, 4.04 / 2H, triplet, J = 6.4 Hz /, 4.38 / 1H, multiplet /, 4.62 / 1H, multiplet /, 6.80 / 2H, doublet, J = 8.9 Hz /, 7.05-7.20 / 4H, multiplet /, 7.76 / 2H, multiplet /, 8.15 / 1H, doublet, J = 7.4 Hz /, 8.91-9.80 / 1H, wide singlet /, 9.10-9.21 / 2H, wide singlet /
MS (M / z): 543 / M ⁺ + 1 /
Example 43
Target connection / 43 /
mp: 205-207 ^o C
IR (nujol): 3280, 1640, 1550, 1210 cm ^-1
NMR (DMSO-d ₆ , δ): 1.39-1.62 / 4H, multiplet /, 2.10 / 2H, triplet, J = 6.5 Hz /, 2.40-2.62 / 2H, multiplet /, 2.64 / 2H, triplet-like /, 2.77-2.97 / 2H, multiplet /, 3.71 / 3H, singlet /, 4.39 / 1H, multiplet /, 4.58 / 1H, multiplet / 6.80 / 2H, doublet, J = 8.9 Hz /, 7.10 / 2H, doublet, J = 8.6 Hz /, 7.43 / 2H, doublet, J = 8.8 Hz /, 7 , 73 / 2H, doublet, J = 8.9 Hz /, 7.83 / 1H, doublet, J = 7.7 Hz /, 8.10 / 1H, doublet, J = 8.0 Hz /, 9.18 / 2H, singlet /, 9.23 / 2H, singlet /, 12.54 / 2H, broad singlet /
MS (m / z): 513 / M ⁺ + 1 /
Example 44
Target connection / 44 /
mp: ≈150 ^o C / decomp. /
IR (nujol): 3300, 3100, 1720, 1670, 1610, 1540 cm ^-1
NMR (DMSO-d ₆ , δ): 1.51-1.84 / 4H, multiplet /, 2.16 / 2H, triplet-like /, 2.31-3.0 / 4H, multiplet /, 3.58 / 3H singlet /, 4.08 / 2H, triplet-like /, 4.35 / 1H, multiplet /, 4.61 / 1H, multiplet /, 6.66 / 2H, doublet, J = 8.4 Hz /, 6.97 / 2H, doublet, J = 8.4 Hz /, 7.15 / 2H, doublet, J = 8.9 Hz /, 7.82 / 2H, doublet, J = 8.8 Hz /, 8.06 / 1H doublet, J = 7.4 Hz /, 8.13 / 1H, doublet, J = 7.9 Hz /, 9.08 / 2H, singlet /, 9.14 / 2H, singlet /
MS (m / z): 529 / M ⁺ + 1 /
Example 45
Target connection / 45 /
mp: 208 ^o C / decomp. /
IR (nujol): 3280, 3090, 1730, 1705, 1660, 1640, 1605, 1540 cm ^-1
NMR (DMSO-d ₆ , δ): 1.51-1.96 / 4H, multiplet /, 2.15 / 2H, triplet-like /, 2.32-3.0 / 4H, multiplet /, 3.58 / 3H , singlet /, 3.70 / 3H, singlet /, 4.07 / 2H, triplet-like /, 4.38 / 1H, multiplet /, 4.60 / 1H, multiplet /, 6.82 / 2H, doublet, J = 8.6 Hz /, 7.10 / 2H, doublet, J = 8.6 Hz /, 7.15 / 2H, doublet, J = 8.9 Hz /, 7.81 / 2H, doublet, J = 8, 9 Hz /, 8.11 / 2H, multiplet /, 9.04 / 2H, singlet /, 9.14 / 2H, singlet /
MS (m / z): 543 / M ⁺ + 1 /
Example 46
Target connection / 46 /
mp: 173 ^o C / decomp. /
IR (nujol): 3275, 1680, 1620, 1600, 1540 cm ^-1
NMR (DMSO-d ₆ + TFA, δ): 1.5-1.8 / 4H, multiplet /, 2.14 / 2H, triplet-like /, 2.25-3.10 / 4H, multiplet /, 3.69 / 3H, singlet /, 4.05 / 2H, triplet-like /, 4.32 / 1H, multiplet /, 4.59 / 1H, multiplet /, 6.80 / 2H, doublet, J = 8.6 Hz /, 7 , 09 / 2H, doublet, J = 8.6 Hz /, 7.13 / 2H, doublet, J = 8.9 Hz /, 7.79 / 2H, doublet, J = 8.9 Hz /, 7.85 / 1H, doublet, J = 7.7 Hz /, 8.11 / 1H, doublet, J = 7.9 Hz /, 8.90 / 2H, singlet /, 9.11 / 2H, singlet /
MS (m / z): 529 / M ⁺ + 1 /
Example 47
Target connection / 47 /
mp: 162-164 ^o C
IR (nujol): 3300, 3100, 1660, 1270, 1200 cm ^-1
NMR (DMSO-d ₆ , δ): 1.93-2.00 / 2H, multiplet /, 2.31 / 2H, triplet, J = 7.1 Hz /, 2.64-2.75 / 2H, multiplet /, 3.73 / 2H, doublet, J = 5.7 Hz /, 4.10 / 2H, triplet, J = 6.5 Hz /, 4.64 / 1H, multiplet /, 7.15 / 2H, doublet , J = 8.9 Hz /, 7.81 / 2H, doublet, J = 8.9 Hz /, 8.10 / 1H, triplet, J = 5.7 Hz /, 8.23 / 1H, doublet, J = 8.1 Hz /, 9.01 / 2H, singlet /, 9.14 / 2H, singlet /
MS (m / z): 395 / M ⁺ + 1 /
Example 48
Target connection / 48 /
mp: 160-162 ^o C
IR (nujol): 3300, 1670, 1600, 1270, 1200 cm ^-1
NMR (DMSO-d ₆ , δ): 1.25 / 3H, doublet, J = 7.3 Hz /, 1.95 / 2H, multiplet /, 2.29 / 2H, triplet, J = 7.1 Hz / 2.42-2.72 / 2H, multiplet /, 4.09 / 2H, triplet, J = 6.4 Hz /, 4.14 / 1H, multiplet /, 4.62 / 1H, multiplet /, 7, 15 / 2H, doublet, J = 8.9 Hz /, 7.81 / 2H, doublet, J = 8.9 Hz /, 8.12 / 1H, doublet, J = 7.3 Hz /, 8.19 / 1H, doublet, J = 7.9 Hz /, 8.99 / 2H, singlet /, 9.14 / 2H, singlet /
MS (m / z): 409 / M ⁺ + 1 /
Example 49
Target connection / 49 /
mp: 118-120 ^o C
IR (nujol): 3280, 1650, 1600, 1540 cm ^-1
NMR (DMSO-d ₆ , δ): 1.70 / 4H, broad singlet /, 2.19 / 2H, multiplet /, 2.2-2.6 / 1H, multiplet /, 2.70 / 1H, doublet of doublets , J = 16.6 Hz, J = 5.0 Hz /, 3.67 / 2H, multiplet /, 4.08 / 2H, wide singlet /, 4.22 / 1H, multiplet /, 4.65 / 1H, multiplet /, 7.15 / 2H, doublet, J = 8.9 Hz /, 7.7-7.9 / 3H, multiplet /, 8.19 / 1H, doublet, J = 7.8 Hz /, 9, 00 and 9.14 / 4H, each singlet /
MS (M / z): 439 / M ⁺ + 1 /
Example 50
Target connection / 50 /
mp: 207-209 ^o C
IR (nujol): 3300, 1720, 1640, 1270, 1200 cm ^-1
NMR (DMSO-d ₆ , δ): 1.83-2.02 / 2H, multiplet /, 2.25 / 2H, triplet, J = 7.0 Hz /, 2.34-2.68 / 2H, multiplet /, 2.92-3.02 / 2H, multiplet /, 4.07 / 2H, triplet, J = 6.3 Hz /, 4.38 / 1H, multiplet /, 4.62 / 1H, multiplet /, 7 , 12-7.26 / 7H, multiplet /, 7.80 / 2H, doublet, J = 8.9 Hz /, 7.94 / 1H, doublet, J = 7.6 Hz /, 8.17 / 1H, doublet, J = 7.9 Hz /, 8.90 / 2H, singlet /, 9.12 / 2H, singlet /, 12.55 / 2H, wide singlet /
MS (m / z): 485 / M ⁺ + 1 /
Example 51
Target connection / 51 /
mp: 172-175 ^o C
IR (nujol): 3300, 3100, 1660, 1550, 1200 cm ^-1
NMR (DMSO-d ₆ , δ): 0.80 / 3H, doublet, J = 6.2 Hz /, 0.85 / 3H, doublet, J = 6.2 Hz /, 1.41-1.65 / 7H, multiplet /, 2.13 / 2H, triplet, J = 6.2 Hz /, 2.40-2.71 / 4H, multiplet /, 4.16 / 1H, multiplet /, 4.58 / 1H, multiplet /, 7.44 / 2H, doublet, J = 8.9 Hz /, 7.74 / 2H, doublet, J = 8.9 Hz /, 7.97 / 1H, doublet, J = 8.0 Hz /, 8.11 / 1H, doublet, J = 7.9 Hz /, 9.13 / 2H, singlet /, 9.23 / 2H, singlet /
MS (M / z): 449 / M ⁺ + 1 /
Example 52
Target connection / 52 /
mp: 177-180 ^o C
NMR (nujol): 0.84 / 3H, triplet, J = 7.4 Hz /, 1.26-1.34 / 2H, multiplet /, 1.57-1.65 / 2H, multiplet /, 1.90 -2.10 / 2H, multiplet /, 2.27 / 2H, triplet, J = 6.5 Hz /, 2.51-2.70 / 2H, multiplet /, 4.06-4.16 / 3H, multiplet /, 4.63 / 1H, multiplet /, 7.14 / 2H, doublet, J = 8.9 Hz /, 7.80 / 2H, doublet, J = 8.9 Hz /, 7.99 / 1H, doublet , J = 7.8 Hz /, 8.20 / 1H, doublet, J = 7.9 Hz /, 8.87 / 2H, singlet /, 9.13 / 2H, singlet /, 12.4 / 2H, wide singlet /
MS (m / z): 437 / M ⁺ + 1 /
Example 53
Target connection / 53 /
mp: 217-219 ^o C
NMR (DMSO-d ₆ , δ): 0.71-0.98 / 2H, multiplet /, 1.01-1.39 / 5H, multiplet /, 1.47-1.71 / 6H, multiplet /, 1 97 / 2H, multiplet /, 2.25 / 2H, triplet, J = 6.4 /, 2.62-2.70 / 2H, multiplet /, 4.09 / 2H, triplet, J = 6.8 Hz /, 4.21 / 1H, multiplet / 4.62 / 1H, multiplet /, 7.14 / 2H, doublet, J = 8.9 Hz /, 7.80 / 2H, doublet, J = 8.9 Hz / 7.99 / 1H, doublet, J = 7.9 Hz /, 8.20 / 1H, doublet, J = 7.9 Hz /, 8.95 / 2H, singlet /, 9.13 / 2H, singlet / 12.43 / 2H, broad singlet /
MS (m / z): 491 / M ⁺ + 1 /
Example 54
Target connection / 54 /
mp: 220-221 ^o C
IR (nujol): 3300, 1670, 1650, 1250, cm ^-1
NMR (DMSO-d ₆ , δ): 1.45-1.79 / 2H, multiplet /, 1.92-2.01 / 2H, multiplet /, 2.10-2.29 / 4H, multiplet /, 2 , 37-2.68 / 4H, multiplet /, 3.88 / 1H, multiplet /, 4.09 / 2H, triplet, J = 6.4 Hz /, 4.52 / 1H, multiplet /, 7.12- 7.24 / 7H, multiplet /, 7.71 / 1H, doublet, J = 8.5 Hz /, 7.81 / 2H, doublet, J = 8.9 Hz /, 8.09 / 1H, doublet, J = 7.9 Hz /, 8.99 / 2H, singlet /, 9.13 / 2H, singlet /, 12.13 / 2H, wide singlet /
MS (m / z): 513 / M ⁺ + 1 /
Example 55
mp: 186-188 ^o C
IR (nujol): 3300, 1670, 1210 cm ^-1
NMR (DMSO-d ₆ , δ): 0.72-0.98 / 2H, multiplet /, 1.05-1.18 / 5H, multiplet /, 1.39-1.71 / 10H, multiplet /, 2 13 / 2H, type of triplet /, 2.61-2.71 / 4H, multiplet /, 4.19 / 1H, multiplet /, 4.59 / 1H, multiplet /, 7.44 / 2H, doublet, J = 8.9 Hz /, 7.73 / 2H, doublet, J = 8.9 Hz /, 7.95 / 1H, doublet, J = 7.9 Hz /, 8.11 / 1H, doublet, J = 7, 9 Hz /, 9.07 / 2H, singlet /, 9.23 / 2H, singlet /, 12.43 / 2H, wide singlet /
MS (m / z): 489 / M ⁺ + 1 /
Example 56
Target connection / 56 /
mp: 65-73 ^o C
IR (nujol): 3270 / wide /, 1650, 1610, 1510 cm ^-1
NMR (DMSO-d ₆ , δ): 2.3-3.1 / 4H, multiplet /, 2.78 and 2.98 / 3H, each singlet /, 3.56 / 3H, singlet /, 3.70 / 3H, singlet / 3.96 and 4.02 / 2H, each singlet /, 4.37 / 1H, multiplet /, 4.65 / 1H, multiplet /, 4.93 and 5.05 / 2H, each singlet /, 6.82 / 2H, multiplet /, 7.12 / 4H, multiplet /, 7.77 / 2H, doublet, J = 8.3 Hz /, 8.14 and 8.23 / 1H, each doublet, J = 7 , 3 Hz (by 8.14), J = 8.0 Hz / by 8.23), 8.37 and 8.53 / 1H, each doublet, J = 7.6 Hz (by 8.37), J = 8.0 Hz (by 8.53), 9.00 and 9.13 / 4H, each singlet /
Example 57
Target connection / 57 /
mp: 90-92 ^o C / decomp. /
IR (nujol): 1650, 1300, 1250 cm ^-1
NMR (DMSO-d ₆ , δ): 2.58-2.98 / 8H, multiplet /, 2.75 / 3H, singlet /, 3.71 / 3H, singlet /, 3.94 / 2H, multiplet /, 4.32 / 1H, multiplet /, 4.62 / 1H, multiplet /, 6.81 / 2H, multiplet /, 7.12 / 2H, multiplet /, 7.47 / 2H, multiplet /, 7.71 / 2H multiplet /, 7.90-8.18 / 1H, multiplet /, 8.07-8.32 / 1H, multiplet /, 9.94 / 2H, singlet /, 9.22 / 2H, singlet /
MS (m / z): 556 / M ⁺ + 1 /
Example 58
Target connection / 58 /
mp: 95-98 ^o C
IR (nujol): 3300, 1650, 1250 cm ^-1
NMR (DMSO-d ₆ , δ): 0.73-1.00 / 2H, multiplet /, 1.01-1.39 / 5H, multiplet /, 1.42-1.69 / 6H, multiplet /, 2 63-3.02 / 2H, multiplet /, 2.79 / 3H, singlet /, 4.00 / 1H, singlet /, 4.04 / 1H, singlet /, 4.22 / 1H, multiplet /, 4, 65 / 1H, multiplet /, 4.94 / 1H, singlet /, 5.04 / 1H, singlet /, 7.13 / 2H, doublet, J = 8.9 Hz /, 7.77 / 2H, doublet, J = 8.9 Hz /, 8.00-8.18 / 1H, multiplet /, 8.19-8.56 / 1H, multiplet /, 8.86 / 2H, singlet /, 9.12 / 2H, singlet /
MS (m / z): 534 / M ⁺ + 1 /
Example 59
The target compound / 59-A / was obtained analogously to the method of Example 5.

 Lyophilized a mixture of this target compound / 59-A / and 1 N. hydrochloric acid / 200 ml /. The resulting powder was dried, which gave the target compound / 59-B / / 5.33 g /.

mp: 198 ^o C / decomp. /
IR (nujol): 3270, 1690, 1635, 1600, 1540 cm ^-1
NMR (DMSO-d ₆ , δ): 0.84 / 6H, doublet, J = 6.4 Hz /, 1.8-2.05 / 3H, multiplet /, 2.3 / 2H, triplet, J = 7 Hz /, 2.3-2.8 / 2H, multiplet /, 3.97-4.22 / 3H, multiplet /, 4.65 / 1H, multiplet /, 7.14 / 2H, doublet, J = 8, 9 Hz /, 7.8 / 1H, doublet, J = 8.5 Hz /, 7.85 / 2H, doublet, J = 8.9 Hz /, 8.35 / 1H, doublet, J = 7.7 Hz /, 9.04 / 2H, singlet /, 9.24 / 2H, singlet /, 12.51 / 1H, wide singlet /
Elemental analysis: C ₂₀ H ₂₈ N ₄ O ₇ • HCl • 1H ₂ O
Calculated: C 48.93 H 6.36 N 11.41 Cl 7.22
Found: C, 48.77; H, 6.52; N, 11.22; Cl, 6.98.
Example 60
A mixture of the starting compound / 60 / / 0.7 g / in tetrahydrofuran / 3.5 ml / and 1 N. an aqueous solution of sodium hydroxide / 3.49 ml / was stirred at room temperature for 2 hours. The reaction mixture was adjusted to pH 5.0 by adding 10% hydrochloric acid, and the precipitate formed was collected by filtration to obtain the desired compound / 60 / / 0.5 g /.

mp: 220 ^o C / decomp. /
IR (nujol): 3280, 1650, 1605, 1550, 1490 cm ^-1
NMR (DMSO-d ₆ + TFA, δ): 1.5-1.85 / 4H, multiplet /, 2.19 / 2H, triplet-like /, 2.3-3.0 / 4H, multiplet /, 4.08 / 2H, triplet-like /, 4.31 / 1H, multiplet /, 4.61 / 1H, multiplet /, 6.65 / 2H, doublet, J = 8.4 Hz /, 6.97 / 2H, doublet, J = 8.4 Hz /, 7.15 / 2H, doublet, J = 8.9 Hz /, 7.81 / 2H, doublet, J = 8.8 Hz /, 7.83 / 1H, doublet, J = 7, 8 Hz /, 8.15 / 1H, doublet, J = 8 Hz /, 8.98 / 2H, singlet /, 9.13 / 2H, singlet /
MS / m / z /: 515 / M ⁺ + 1 /
Elemental analysis: C ₂₅ H ₃₀ N ₄ O ₈ • 2H ₂ O
Calculated: C 54.53 H 6.22 N 10.17
Found: C 54.32 H 6.04 N 10.08
Example 61
To a solution of the starting compound / 61 / / 0.53 g / and triethylamine / 0.20 ml / in methylene chloride / 5 ml / was added acetic anhydride / 0.066 ml / under ice-cooling, and the mixture was stirred at room temperature for 4 hours. the mixture was diluted with water and extracted with ethyl acetate, the separated organic layer was washed with dilute hydrochloric acid, saturated aqueous sodium bicarbonate, water and brine, dried over magnesium sulfate and evaporated in vacuo to give the desired compound / 61-A / / crude / / this compound not isolated.

 From the specified compound / 61-A /, the following target compound / 61-B / was obtained by a method similar to that of Example 5.

mp: 86-94 ^o C
IR (nujol): 1640 / wide singlet /, 1530 cm ^-1
NMR (DMSO-d ₆ , δ): 0.86 / 6H, multiplet /, 1.71 and 1.76 / 3H, each singlet /, 2.04 / 1H, multiplet /, 2.80 and 3.03 / 3H, each singlet /, 2.4-3.2 / 4H, multiplet /, 3.8-5.1 / 5H, multiplet /, 7.49 / 2H, multiplet /, 7.72 / 2H, multiplet /, 7.6-8.6 / 3H, multiplet /, 9.15 and 9.26 / 4H, each singlet /
MS (m / z): 535 / M ⁺ + 1 /
HPLC conditions
column: MS-RASK P-ODS-15 S-15 120A ODS 50 φ x 250
elution: CH ₃ CN: 0.1% trifluoroacetic acid / 15: 85 /
flow: 118 ml / min
retention time: 7.6 minutes
Example 62
The target compound / 62 / was obtained from the starting compound / 62 / by a method similar to that of Examples 37 and 13,
mp: 175-177 ^o C / decomp. /
IR (nujol): 3300, 1640, 1600, 1260 cm ^-1
NMR (DMSO-d ₆ , δ): 0.75 / 3H, triplet, J = 7.2 Hz /, 1.60-1.72 / 2H, multiplet /, 1.94 / 2H, multiplet /, 2, 31 / 2H, triplet-like /, 2.60-2.68 / 2H, multiplet /, 3.90 / 1H, multiplet, 4.07 / 2H, triplet-like /, 4.56 / 1H, multiplet /, 7.09 / 2H, doublet, J = 8.9 Hz /, 7.56 / 1H, doublet, J = 6.6 Hz /, 7.72 / 2H, doublet, J = 8.9 Hz /, 8.38 / 1H, doublet, J = 7.6 Hz /, 8.75 / 2H, wide singlet /, 11.18 / 2H, wide singlet /
MS (m / z): 423 / M ⁺ + 1 /
Example 63
The target compound / 63 / was obtained from the starting compounds / 63-A / and / 63-B / according to a method similar to that of Example 22.

IR (nujol): 3300, 1720, 1640, 1250 cm ^-1
NMR (DMSO-d ₆ , δ): 1.91 / 2H, multiplet /, 2.24 / 2H, triplet, J = 7.1 Hz /, 2.73-2.96 / 2H, multiplet /, 3, 11-3.15 / 2H, multiplet /, 3.57 / 3H, singlet /, 3.98-4.04 / 3H, multiplet /, 4.65-4.72 / 1H, multiplet /, 5.06 / 2H, singlet /, 5.11 / 2H, singlet /, 6.99 / 2H, doublet, J = 8.9 Hz /, 7.18-7.26 / 2H, multiplet /, 7.34-7.40 / 10H, multiplet /, 7.64-7.72 / 1H, multiplet /, 7.99 / 2H, doublet, J = 8.9 Hz /, 8.24 / 1H, doublet, J = 8.1 Hz / 8.37 / 1H, doublet, J = 7.6 Hz /, 8.46 / 1H, doublet, J = 4.0 Hz /, 9.15 / 2H, wide singlet /
MS (m / z): 724 / M ⁺ + 1 /
Example 64
The target compound / 64 / was obtained analogously to the method of Example 5.

mp: 120-125 ^o C
IR (nujol): 3300, 1740, 1660, 1200 cm ^-1
NMR (DMSO-d ₆ , δ): 1.91 / 2H, multiplet /, 2.28 / 2H, triplet, J = 7.2 Hz /, 2.53-2.67 / 2H, multiplet /, 3, 20-3.33 / 2H, multiplet /, 3.60 / 3H, singlet /, 4.07 / 2H, triplet, J = 6.4 Hz /, 4.55 / 1H, multiplet /, 4.72 / 1H multiplet /, 7.14 / 21, doublet, J = 8.9 Hz /, 7.55 / 2H, doublet, J = 7.8 Hz /, 7.82 / 2H, doublet, J = 8.9 Hz /, 8.02 / 1H, multiplet /, 8.19 / 1H, doublet, J = 7.8 Hz /, 8.40 / 1H, doublet, J = 7.8 Hz /, 8.63 / 1H, doublet , J = 4.9 Hz /, 9.13 / 2H, singlet /, 9.16 / 2H, singlet /
MS (m / z): 500 / M ⁺ +1
Example 65
The target compound (65-A) was obtained from the starting compound (65-A) and the starting compound (65-B) according to the procedure similar to that described in Example 1.

 The target compound (65-B) was obtained from the thus obtained target compound (65-A) according to a procedure similar to that described in Example 5.

mp: 50-54 ^o C (decomp.)
IR (nujol): 1640 (br), 1520 cm ^-1
NMR (DMSO-d ₆ , δ): 0.84 (6H, multiplet), 2.07 (1H, multiplet), 2.4-2.8 (2H, multiplet), 2.79 and 3.00 (each - singlet), 3.8-4.2 (3H, multiplet), 4.7 (1H, multiplet), 4.94 and 5.06) (2H, each singlet), 7.13 (2H, doublet, J = 7.4 Hz), 7.78 (2H, doublet, J = 7.4 Hz), 7.78 and 8.05 (1H, each doublet, each J = 8.8 Hz), 8.27 and 8.57 (1H, each doublet, each J = 8.0 Hz), 9.00 and 9.13 (4H, each singlet).

Example 66
The target compound (66-A) was obtained from the starting compound (66-A) and the starting compound (66-B) according to the procedure similar to that described in Example 1.

 The target compound (66-B) was obtained from the thus obtained target compound (66-A) according to a procedure similar to that described in Example 5.

mp: 67-72 ^o C
IR (nujol): 1640 (br), 1530 cm ^-1
NMR (DMSO-d ₆ , δ): 0.86 (6H, multiplet), 2.05 (1H, multiplet), 2.3-2.8 (2H, multiplet), 2.82 and 3.03 (3H each singlet), 3.74 and 3.89 (2H, each singlet), 3.8-4.2 (3H, multiplet), 4.68 (1H, multiplet), 7.4 (2H, multiplet), 7.7 (2H, multiplet), 7.8 and 7.97 (1H, multiplet and doublet (J = 8.5 Hz)), 8.3 and 8.52 (1H, each doublet, J = 7.9 Hz), 9.24 and 9.28 (4H, each singlet)
MS (m / z): 464 (M ⁺ + 1 /
Example 67
The target compound (67-A) was obtained from the starting compound (67-A) and the starting compound (67-B) according to the procedure similar to that described in Example 1.

 The target compound (67-B) was obtained from the thus obtained target compound (67-A) according to a procedure similar to that described in Example 5.

mp: 52-56 ^o C
IR (nujol): 1660 (br), 1540 cm ^-1
NMR (DMSO-d ₆ , δ): 0.85 (6H, multiplet), 2.05 (1H, multiplet), 2.4-3.0 (6H, multiplet), 2.78 and 2.96 (3H each is a singlet), 3.9-4.2 (3H, multiplet), 4.66 (1H, multiplet), 7.48 (2H, multiplet), 7.71 (2H, multiplet), 7.7 and 7.92 (1H, multiplet and doublet (J = 8.56 Hz), 8.28 and 8.46 (1H, each doublet, J = 7.9 Hz)), 9.15 and 9.24 (4H every singlet)
MS (m / z): 478 (M ⁺ +1)
Example 68
The target compound (68-A) was obtained from the starting compound (68-A) and the starting compound (68-B) according to the procedure similar to that described in Example 1.

 The target compound (68-B) was obtained from the thus obtained target compound (68-A) according to the procedure similar to that described in Example 5.

mp: 88-94 ^o C
IR (nujol): 1610 (wide singlet), 1510 cm ^-1
NMR (DMSO-d ₆ , δ): 0.85 (6H, multiplet), 1.71 and 1.76 (3H, each singlet), 2.08 (1H, multiplet), 2.80 and 3.03 ( 3H, each singlet), 2.4-3.2 (4H, multiplet), 3.8-5.1 (5H, multiplet), 7.49 (2H, multiplet), 7.72 (2H, multiplet), 7.6-8.6 (3H, multiplet), 9.18 and 9.26 (4H, each singlet)
MS (m / z): 535 (M ⁺ +1)
Example 69
The target compound (69-A) was obtained from the starting compound (69-A) and the starting compound (69-B) according to a procedure similar to that described in Example 1.

 The target compound (69-B) was obtained from the thus obtained target compound (69-A) according to a procedure similar to that described in Example 5.

mp: 84-91 ^o C
IR (nujol): 1650 (expanded), 1610, 1490 cm ^-1
NMR (DMSO-d ₆ , δ): 1.05 (3H, doublet, J = 6.1 Hz), 2.4-2.8 / 3H, multiplet /, 2.80 and 3.01 / 3H, each singlet /, 3.9-4.2 / 3H, multiplet /, 4.7 / 1H, multiplet /, 4.95 and 5.06 / 2H, each singlet /, 7.13 / 2H, doublet, J = 8 , 9 Hz /, 7.58 and 7.74 / 1H, doublet, (J = 8.5 Hz) and multiplet /, 7.78 / 2H, doublet, J = 8.9 Hz /, 8.38 and 8 70 / 1H, each doublet, J = 8.1 Hz /, 9.0-9.3 / 4H, multiplet /
MS / m / z /: 482 / M ⁺ + 1 /
Example 70
The target compound / 70-A / was obtained from the starting compound / 70-A / and the starting compound / 70-B / according to a procedure similar to that described in Example 1.

The target compound / 70-B / was obtained from the target compound / 70-A / according to the procedure described in Example 5
mp: ≈170 ^o C / decomp. /
IR (nujol): 3300, 3100, 1725, 1660, 1640, 1610, 1540, 1490 cm ^-1
NMR (DMSO-d ₆ , δ): 0.85 / 6H, doublet, J = 6.7 Hz /, 1.8-2.1 / 3H, multiplet /, 2.29 / 2H, triplet type /, 2 3-2.76 / 2H, multiplet /, 3.63 / 3H, singlet /, 4.0-4.2 / 3H, multiplet /, 4.65 / 1H, multiplet /, 7.14 / 2H, doublet , J = 8.8 Hz /, 7.81 / 2H, doublet, J = 8.8 Hz /, 8.03 / 1H, doublet, J = 8.2 Hz /, 8.27 / 1H, doublet, J = 7.7 Hz /, 9.04 / 2H, singlet /, 9.14 / 2H, singlet /
FAB-MC: 451 / M ⁺ + 1 /
Example 71
The target compound / 71-A / was obtained from the starting compound / 71-A / and the starting compound / 71-B / according to a procedure similar to that described in Example 1.

 The target compound / 71-B / was obtained from the target compound / 71-A /, thus obtained by a method similar to that described in Example 5.

mp: ≈169 ^o C / decomp. /
IR (nujol): 3280, 3100, 1710, 1660, 1600, 1540, 1490 cm ^-1
NMR (DMSO-d ₆ , δ): 0.84 (6H, doublet, J = 6.8 Hz), 1.16-1.8 (10H, multiplet), 1.94-2.2 (3H, multiplet ), 2.33-2.8 (2H, multiplet), 3.9-4.25 (3H, multiplet), 4.65 (1H, multiplet), 7.15 (2H, doublet, J = 8.9 Hz), 7.70 (1H, doublet, J = 8.7 Hz), 7.81 (2H, doublet, J = 8.9 Hz), 8.21 (1H, doublet, J = 7.8 Hz, 8.97 (2H, singlet)), 9.13 2H, singlet.

Example 72
The target compound (72-A) was obtained from the starting compound (72-A) and the starting compound (72-B) according to a procedure similar to that described in Example 1.

 The target compound (72-B) was obtained from the thus obtained target compound (72-A) according to a procedure similar to that described in Example 5.

mp: ≈210 ^o C / decomp. /
IR (nujol): 3300, 3080, 1660, 1630, 1540, 1510 cm ^-1
NMR (DMSO-d ₆ , δ): 1.3 (3H, triplet, J = 6.9 Hz), 1.51 (4H, multiplet), 2.1 (2H, triplet type), 2.3-3 , 1 (6H, multiplet), 3.97 (2H, quartet J = 6.9 Hz), 4.34 (1H, multiplet), 4.59 (1H, multiplet), 6.79 (2H, doublet, J = 8.6 Hz), 7.08 (2H, doublet, J = 8.8 Hz), 7.43 (2H, doublet, J = 8.3 Hz), 7.74 (2H, doublet, J = 8 , 3 Hz), 7.83 (1H, doublet, J = 7.7 Hz), 8.11 (1H, doublet, J = 7.9 Hz), 9.24 (4H, singlet)
Example 73
The target compound / 73-A / was obtained from the starting compound / 73-A / and the starting compound / 73-B / according to a procedure similar to that described in Example 1.

 The target compound / 73-B / was obtained from the target compound / 73-A /, thus obtained by the method similar to that described in Example 5.

mp: 145 ^o C / decomp. /
IR (nujol): 3320, 3100, 1660, 1610, 1530, 1490 cm ^-1
NMR (DMSO-d ₆ , δ): 1.02 (3H, doublet, J = 6.3 Hz), 1.97 (2H, multiplet), 2.31 (2H, triplet type), 2.35-2 8 (2H, multiplet), 3.95-4.25 (4H, multiplet), 4.68 (1H, multiplet), 7.15 (2H, doublet, J = 8.9 Hz), 7.55 ( 1H, doublet, J = 8.6 Hz), 7.81 (2H, doublet, J = 8.9 Hz), 8.34 (1H, doublet, J = 7.9 Hz), 8.98 (2H, singlet), 9.13 (2H, singlet)
Example 74
The target compound / 74-A / was obtained from the starting compound / 74-A / and the starting compound / 74-B / according to a procedure similar to that described in Example 1.

 The target compound / 74-B / was obtained from the thus obtained target compound / 74-A / according to a procedure similar to that described in Example 5.

mp: 136 ^o C / decomp. /
IR (nujol): 3300, 3100, 1720, 1670, 1540, 1490 cm ^-1
NMR (DMSO-d ₆ , δ): 1.02 (3H, doublet, J = 6.3 Hz), 1.53 (4H, multiplet), 2.15 (2H, triplet type), 2.35-2 9 (4H, multiplet), 4.0-4.2 (2H, multiplet), 4.65 (1H, multiplet), 7.45 (2H, doublet, J = 8.3 Hz), 7.51 ( 1H, doublet, J = 8.6 Hz), 7.74 (2H, doublet, J = 8.3 Hz), 8.24 (1H, doublet, J = 7.9 Hz), 9.15 (2H, singlet), 9.23 (2H, singlet)
Example 75
The target compound / 75-A / was obtained from the starting compound / 75-A / and the starting compound / 75-B / according to the procedure similar to that described in Example 1.

 The target compound / 75-B / was obtained from the thus obtained target compound / 75-A / according to the procedure similar to that described in Example 5.

mp: 198 ^o C / decomp.
IR (nujol): 3280, 1630, 1600, 1540, 1480 cm ^-1
NMR (DMSO-d ₆ , δ): 0.84 (6H, multiplet), 1.34-1.72 (3H, multiplet), 1.97 (2H, multiplet), 2.15-2.8 (4H multiplet), 3.9-4.27 (3H, multiplet), 4.57 (1H, multiplet), 7.11 (2H, doublet, J = 8.8 Hz), 7.68 (1H, doublet, J = 7.8 Hz), 7.75 (2H, doublet, J = 8.7 Hz), 8.29 (1H, doublet, J = 7.8 Hz), 8.82 (1.5H, singlet) , 10.9 (1.5H, singlet)
Example 76
The target compound / 76-A / was obtained from the starting compound / 76-A / and the starting compound / 76-B / according to a procedure similar to that described in Example 1.

 The target compound / 76-B / was obtained from the target compound / 76-A /, thus obtained by a method similar to that described in Example 5.

mp: 204 ^o C / decomp. /
IR (nujol): 3275, 1625, 1535, 1490 cm ^-1
NMR (DMSO-d ₆ , δ): 0.7-1.0 (6H, multiplet), 1.0-1.57 (2H, multiplet), 1.74 (1H, multiplet), 1.98 / 2H multiplet /, 2.34 (2H, triplet type), 2.3-2.8 (2H, multiplet), 3.97 (1H, multiplet), 4.09 (2H, triplet type), 4.56 ( 1H, multiplet), 7.10 (2H, doublet, J = 8.8 Hz), 7.48 (2H, doublet, J = 7.8 Hz), 7.73 (2H, doublet, J = 8.6 Hz), 8.39 (1H, doublet, J = 7.6 Hz), 8.73 (1.5H, singlet), 11.29 (1.5H, singlet)
Example 77
The target compound / 77-A / is obtained from the starting compound / 77-A / and the starting compound / 77-B / according to a procedure similar to that described in Example 1.

 The target compound / 77-B / obtained from the target compound / 77-A /, thus obtained by the method similar to that described in Example 5.

IR (nujol): 3275, 3080, 1700, 1630, 1600, 1540, 1480 cm ^-1
NMR (DMSO-d ₆ , δ): 0.7-1.0 (6H, multiplet), 1.0-1.51 (2H, multiplet), 1.7 (5H, multiplet), 2.19 (2H triplet type), 2.25-2.79 (2H, multiplet), 3.97-4.25 (3H, multiplet), 4.63 (1H, multiplet), 7.14 (2H, doublet, J = 8.9 Hz), 7.76 (1H, doublet, J = 9.5 Hz), 7.80 (2H, doublet, J = 8.9 Hz), 8.24 (1H, doublet, J = 7, 7 Hz), 9.02 (2H, singlet), 9.13 (2H, singlet), 12.52 (1.5H, singlet)
Example 78
The target compound / 78-A / was obtained from the starting compound / 78-A / and the starting compound according to the procedure similar to that described in Example 1.

 The target compound / 78-B / was obtained from the target compound / 78-A /, thus obtained by a method similar to that described in Example 5.

mp: ≈118 ^o C / decomp. /
IR (nujol): 3300, 3080, 1655, 1600, 1530, 1480 cm ^-1
NMR (DMSO-d ₆ , δ): 0.7-0.92 (6H, multiplet), 1.0-1.8 (9H, multiplet), 2.14 (2H, triplet type), 2.35- 2.77 (2H, multiplet), 3.94 - 4.27 (3H, multiplet), 4.63 (1H, multiplet), 7.14 (2H, doublet, J = 8.9 Hz), 7.73 (1H, doublet, J = 8.5 Hz), 7.80 (2H, doublet, J = 8.9 Hz), 8.12 (1H, doublet, J = 7.7 Hz), 8.83 (2H singlet), 9.13 (2H, singlet)
Example 79
The target compound / 79-A / was obtained from the starting compound / 79-A / and the starting compound / 79-B / according to a procedure similar to that described in Example 1.

 The target compound / 79-B / was obtained from the target compound / 79-A /, thus obtained by a method similar to that described in Example 5.

mp: 196-200 ^o C
IR (nujol): 3300, 1710, 1640, 1615, 1540, 1490 cm ^-1
NMR (DMSO-d ₆ , δ): 0.83 (3H, broad singlet), 1.22 (4H, multiplet), 1.62 (2H, multiplet), 1.96 (2H, multiplet), 2.29 (2H, multiplet), 2.2-2.8 (2H, multiplet), 4.09 (3H, multiplet), 4.62 (1H, multiplet), 7.13 (2H, doublet, J = 8.5 Hz), 7.81 (2H, doublet, J = 8.5 Hz), 7.80 (1H, multiplet), 8.24 (1H, multiplet), 9.10 and 9.40 (4H, each singlet)
Example 80
The target compound / 80-A / was obtained from the starting compound / 80-A / and the starting compound / 80-B / according to the procedure similar to that described in Example 1.

 The target compound / 80-B / was obtained from the target compound / 80-A /, thus obtained by the method similar to that described in Example 5.

mp: 216 ^o C / decomp. /
IR (nujol): 3275, 1680, 1630, 1600, 1540, 1480 cm ^-1
NMR (DMSO-d ₆ , δ): 0.81 (3H, triplet type), 1.19 (4H, multiplet), 1.4-1.8 (2H, multiplet), 1.85-2.1 ( 2H, multiplet), 2.2-2.9 (4H, multiplet), 3.93 (1H, multiplet), 4.08 (2H, multiplet), 4.56 (1H, multiplet), 7.09 (2H doublet, J = 8.9 Hz), 7.57 (1H, doublet, J = 6.9 Hz), 7.72 2H, doublet, J = 8.8 Hz), 8.37 (1H, doublet, J = 7.9 Hz), 8.75 (2H, singlet), 11.19 (2H, singlet)
Example 81
The target compound / 81-A / was obtained from the starting compound / 81-A / and the starting compound / 81-B / according to a procedure similar to that described in Example 1.

 The target compound / 81-B / was obtained from the target compound / 81-A /, thus obtained by a method similar to that described in Example 5.

mp: ≈175 ^o C / decomp. /
IR (nujol): 3300, 3100, 1660, 1600, 1530, 1480 cm ^-1
NMR (DMSO-d ₆ , δ): 0.87 (9H, singlet), 1.45-1.71 (2H, multiplet), 1.94 (2H, multiplet), 2.27 (2H, triplet type) 2.3-2.8 (2H, multiplet), 4.09 (2H, triplet type), 4.21 (1H, multiplet), 4.59 (1H, multiplet), 7.14 (2H, doublet, J = 8.9 Hz), 7.82 (2H, doublet, J = 8.9 Hz), 8.02 (1H, doublet, J = 8.2 Hz), 8.16 (1H, doublet, J = 8.0 Hz), 9.06 (2H, singlet), 9.14 (2H, singlet)
Example 82
The target compound / 82-A / was obtained from the starting compound / 82-A / and the starting compound / 82-B / according to a procedure similar to that described in Example 1.

 The target compound / 82-B / was obtained from the target compound / 82-A /, thus obtained by the method similar to that described in Example 5.

mp: ≈202 ^o C / decomp. /
IR (nujol): 3270, 3075, 1690, 1640, 1600, 1530, 1490 cm ^-1
NMR (DMSO-d ₆ , δ): 1.68 (4H, multiplet), 2.15 (2H, triplet type), 2.3-2.75 (2H, multiplet), 2.78-3.15 ( 2H, multiplet), 4.07 (2H, triplet type), 4.39 (1H, multiplet), 4.6 (1H, multiplet), 7.05-7.37 (7H, multiplet), 7.81 ( 2H, doublet, J = 8.9 Hz), 7.92 (1H, doublet, J = 7.7 Hz), 8.13 (1H, doublet, J = 8 Hz), 9.1 (2H, singlet) 9.14 (2H, singlet), 12.58 (1H, singlet)
FAB-MC: 499 / M ⁺ + 1 /
Example 83
The target compound / 83-A / was obtained from the starting compound / 83-A / and the starting compound / 83-B / according to a procedure similar to that described in Example 1.

 The target compound / 83-B / was obtained from the target compound / 83-A /, thus obtained by the method similar to that described in Example 5.

mp: 168-170 ^o C / decomp. /
IR (nujol): 3300, 1670, 1200 cm ^-1
NMR (DMSO-d ₆ , δ): 0.83 (3H, triplet, J = 7.4 Hz), 1.21-1.38 (2H, multiplet), 1.40-1.68 (4H, multiplet ), 2.12 (2H, triplet type), 2.63-2.71 (6H, multiplet), 4.15 (1H, multiplet), 4.61 (1H, multiplet), 7.44 (2H, doublet, J = 8.9 Hz), 7.73 (2H, doublet, J = 8.9 Hz), 7.92 (1H, doublet, J = 7.9 Hz), 8.11 (1H, doublet, J = 7.8 Hz), 9.01 (2H, singlet), 9.22 (2H, singlet), 12.41 2H, broad singlet)
MS (m / z): 435 / M ⁺ + 1 /
Example 84
The target compound / 84-A / was obtained from the starting compound / 84-A / and the starting compound / 84-B / according to a procedure similar to that described in Example 1.

 The target compound / 84-B / was obtained from the target compound / 84-A /, thus obtained by a method similar to that described in Example 5.

IR (nujol): 3280, 3100, 1650, 1605, 1530, 1490 cm ^-1
NMR (DMSO-d ₆ , δ): 0.88 (6H, doublet, J = 6.8 Hz), 1.6-2.44 (9H, multiplet), 3.9-4.2 (3H, multiplet ), 4.38 (1H, multiplet), 7.14 (2H, doublet, J = 8.9 Hz), 7.81 (2H, doublet, J = 8.9 Hz), 7.95 (1H, doublet , J = 8.3 Hz), 8.08 (1H, doublet, J = 8, Hz), 9.05 (2H, singlet), 9.14 (2H, singlet)
Example 85
The target compound / 85-A / was obtained from the starting compound / 85-A / and the starting compound / 85-B / according to a procedure similar to that described in Example 1.

 The target compound / 85, B / was obtained from the target compound / 85-A /, thus obtained by a method similar to that described in Example 5.

mp: ≈199 ^o C / decomp. /
IR (nujol): 3320, 3100, 1700, 1660, 1610, 1530, 1490 cm ^-1
NMR (DMSO-d ₆ , δ): 0.85 (6H, doublet, J = 6.6 Hz), 2.05 (1H, multiplet), 2.5-2.8 (2H, multiplet), 4, 12 (1H, multiplet), 4.68 (2H, singlet), 4.74 (1H, multiplet), 7.15 (2H, doublet, J = 8.9 Hz), 7.81 (2H, doublet, J = 8.9 Hz), 7.96 (1H, doublet, J = 9.5 Hz), 8.48 (1H, doublet, J = 8, Hz), 9.04 (2H, singlet), 9.16 (2H, singlet), 12.54 (1H, singlet)
Example 86
The target compound / 86-A / was obtained from the starting compound / 86-A / and the starting compound / 86-B / according to a procedure similar to that described in Example 1.

 The target compound / 86-B / was obtained from the target compound / 86-A /, thus obtained by the method similar to that described in Example 5.

mp: ≈150 ^o C / decomp. /
IR (nujol): 3300, 3100, 1660, 1610, 1540, 1490 cm ^-1
NMR (DMSO-d ₆ , δ): 0.82 (3H, doublet, J = 6.2 Hz), 0.87 (3H, doublet, J = 6.2 Hz), 1.25-1.85 ( 9H, multiplet), 2.13 (2H, triplet type), 2.3-2.75 (2H, multiplet), 4.07 (2H, triplet type), 4.19 (1H, multiplet), 4.61 (1H, multiplet), 7.14 (2H, doublet, J = 8.9 Hz), 7.81 (2H, doublet, J = 8.9 Hz), 7.95 (1H, doublet, J = 8, 0 Hz), 8.11 (1H, doublet, J = 8.0 Hz), 8.96 (2H, singlet), 9.13 (2H, singlet)
Example 87
The target compound / 87-A / was obtained from the starting compound / 87-A / and the starting compound / 87-B / according to a procedure similar to that described in Example 1.

 The target compound / 87-B / was obtained from the target compound / 87-A /, thus obtained by the method similar to that described in Example 5.

mp: 189-191 ^o C
IR (nujol): 1665, 1615, 1525, 1495 cm ^-1
NMR (DMSO-d ₆ , δ): 0.91 (9H, singlet), 1.97 (2H, multiplet), 2.2-2.6 (3H, multiplet), 2.70 (1H, doublet of doublets, J = 16.7 Hz, J = 5.9 Hz), 4.0-4.2 (3H, multiplet), 4.66 (1H, multiplet), 7.14 (2H, doublet, J = 8.9 Hz), 7.66 (1H, doublet, J = 9.2 Hz), 7.83 (2H, doublet, J = 8.9 Hz), 8.40 (1H, doublet, J = 7.6 Hz) 9.16 and 9.21 (4H, each singlet)
MS (m / z): 451.2 / M ⁺ + 1 /
Example 88
The target compound / 88-A / is obtained from the starting compound / 88-A / and the starting compound / 88-B / according to a procedure similar to that described in Example 1.

 The target compound / 88-B / was obtained from the target compound / 88-A /, thus obtained by the method similar to that described in Example 5.

mp: 76-82 ^o C
IR (nujol): 1640, 1520 cm ^-1
NMR (DMSO-d ₆ , δ): 0.92 and 0.93 (9H, each singlet), 2.3-2.8 (2H, multiplet), 2.80 and 3.00 (3H, each singlet) 3.8-4.2 (3H, multiplet), 4.73 (1H, multiplet), 4.94 and 5.06 (2H, each singlet), 7.13 (2H, doublet, J = 8.9 Hz), 7.78 (2H, doublet, J = 8.9 Hz), 7.6-8.0 (1H, multiplet), 8.37 and 8.65 (1H, each doublet, J = 7.8 Hz and 7.7 Hz), 9.08 and 9.14 (4H, each singlet)
MS (m / z): 494 / M ⁺ + 1 /
Example 89
The target compound / 89-A / was obtained from the starting compound / 89-A / and the starting compound / 89-B / according to a procedure similar to that described in Example 1.

 The target compound / 89-B / was obtained from the target compound / 89-A /, thus obtained by a method similar to that described in Example 5.

mp: ≈170 ^o C / decomp. /
IR (nujol): 3320, 1700, 1660, 1610, 1540, 1480 cm ^-1
NMR (DMSO-d ₆ , δ): 0.87 (6H, doublet, J = 6.7 Hz), 2.05 (1H, multiplet), 2.34 (2H, triplet type), 2.35-2 8 (2H, multiplet), 3.34 (2H, multiplet), 4.12 (1H, multiplet), 4.61 (2H, singlet), 4.64 (1H, multiplet), 7.15 (2H, doublet, J = 8.9 Hz), 7.81 (2H, doublet, J = 8.9 Hz), 7.82 (1H, doublet, J = 8.5 Hz, 8.2 (1H, triplet type) ), 8.32 (1H, doublet, J = 7.7 Hz), 9.03 (2H, singlet), 9.16 (2H, singlet)
Example 90
The target compound / 90 / was obtained from the starting compound / 90 / according to a procedure similar to that described in Production Method 18.

mp: ≈210 ^o C / decomp. /
IR (nujol): 3300, 1730, 1650, 1600, 1550 cm ^-1
NMR (DMSO-d ₆ , δ): 0.83 (6H, doublet, J = 6.4 Hz), 1.82 (2H, triplet type), 2.05 (1H, multiplet), 2.4-2 8 (2H, multiplet), 3.14 (2H, multiplet), 4.05 (2H, triplet type), 4.23 (1H, multiplet), 4.6 (1H, multiplet), 5.06 (2H singlet), 5.10, (2H, singlet), 6.25-6.4 (2H, multiplet), 7.13 (2H, doublet, J = 8.9 Hz), 7.34 (10H, multiplet ), 7.79 (2H, doublet, J = 8.9 Hz), 8.16 (1H, doublet, J = 8.3 Hz),
FAB-MC: 632 / M + 1 /
Example 91
The target compound / 91 / was obtained from the starting compound / 91 / according to a procedure similar to that described in Production Method 18
mp: 190 ^o C / decomp. /
IR (nujol): 3300, 3100, 1725, 1670, 1630, 1610, 1550, 1490 cm ^-1
NMR (DMSO-d ₆ , δ): 0.83 (6H, doublet, J = 5.7 Hz), 1.53 (2H, multiplet), 1.71 (2H, multiplet), 2.06 (1H, multiplet), 2.4-2.8 (2H, multiplet), 3.06 (2H, multiplet), 4.07 (2H, triplet, J = 6.1 Hz), 4.22 (1H, multiplet), 4.62 (1H, multiplet), 5.06 (2H, singlet), 5.11 (2H, singlet), 6.2-6.4 (2H, multiplet), 7.14 (2H, doublet, J = 8.9 Hz), 7.35 (10H, multiplet), 7.81 (2H, doublet, J = 8.9 Hz), 8.16 (1H, doublet, J = 8.3 Hz), 9.03 (2H, singlet), 9.14 (2H, singlet)
The following compounds / Examples 92 and 93 / were obtained by the method similar to that described in Example 5.

Example 92
Target connection / 92 /
mp: ≈188 ^o C / decomp. /
IR (nujol): 3300, 1710, 1650, 1600, 1550 cm ^-1
NMR (DMSO-d ₆ , δ): 0.84 (6H, doublet, J = 5.4 Hz), 1.85 (2H, triplet, J = 6.4 Hz), 1.9-2.28 ( 1H, multiplet), 2.35 - 2.72 (2H, multiplet), 3.17 (2H, multiplet), 4.05 (1H, multiplet), 4.10 (2H, triplet type), 4.49 ( 1H, multiplet), 6.42 (2H, multiplet), 7.15 (2H, doublet, J = 8.8 Hz), 7.75 (1H, doublet, J = 8.8 Hz), 7.84 ( 2H, doublet, J = 8.8 Hz), 9.0 / 2H, singlet /, 9.23 / 2H, singlet /
MS: 452 / M + 1 /
Example 93
Target connection / 93 /
mp: ≈183 ^o C / decomp. /
IR (nujol): 3310, 1700, 1650, 1635, 1600, 1560, 1540, 1480 cm ^-1
NMR (DMSO-d ₆ , δ): 0.84 / 6H, doublet, J = 5.7 Hz /, 1.4-1.8 / 4H, multiplet /, 2.04 / 1H, multiplet /, 2, 3-2.5 / 2H, multiplet /, 3.07 / 2H, multiplet /, 4.0-4.2 / 3H, multiplet /, 4.48 / 1H, multiplet /, 6.2-6.45 / 2H, multiplet /, 7.14 / 2H, doublet, J = 8.8 Hz /, 7.73 / 1H, doublet, J = 8.9 Hz /, 7.81 / 2H, doublet, J = 8.8 Hz /, 9.02 / 2H, singlet /, 9.14 / 2H, singlet /, 12.51 / 1H, wide singlet /
Example 94
The original compound / 94 / / 6.89 g / was dissolved in 1N hydrochloric acid / 116 ml / and the resulting solution was lyophilized. The resulting powder was dried and isolated the target compound / 94 / / 4.34 g /.

mp: 133-140 ^o C.

IR (nujol): 1620-1660 / wide /, 1530 cm ^-1
NMR (DMSO-d ₆ , δ): 0.86 / 6H, doublet, J = 6.8 Hz /, 2.04 / 1H, multiplet /, 2.2-2.8 / 2H, multiplet /, 2, 80 and 3.0 / 3H, each singlet /, 3.8-4.2 / 3H, multiplet /, 4.6 / 1H, multiplet /, 5.06 and 5.41 / 2H, each singlet /, 7, 13 / 2H, doublet, J = 8.8 Hz /, 8.00 / 2H, doublet, J = 8.8 Hz /, 7.80-8.20 / 1H, multiplet /, 8.27 and 8.68 / 1H, each doublet, J = 7.8 Hz /, 9.05 and 9.25 / 4H, each singlet /
MS (m / z): 480 / M ⁺ + 1 /
Example 95
A mixture of the starting compound / 95 / / 19.61 g / and water / 50 ml / was adjusted to pH 6.05 with aqueous ammonia and the mixture was lyophilized. The resulting powder was dried and isolated the target compound / 95 / / 19.17 g /.

Mp: 167-170 ^o C
IR (nujol): 3260, 1640 wide /, 1540, 1485 cm ^-1
NMR (DMSO-d ₆ , δ): 0.80 / 6H, doublet, J = 4.9 Hz /, 2.03 / 1H, multiplet /, 2.2-2.8 / 2H, multiplet /, 2, 80 and 3.03 / 3H, each singlet /, 3.8-4.7 / 4H, multiplet /, 4.94 and 5.04 / 2H, each singlet /, 7.10 / 2H, doublet, J = 8 , 2 Hz /, 7.59 / 1H, multiplet /, 7.73 / 2H, multiplet /, 8.45 and 8.72 / 1H, multiplet /
MS (m / z): 480 / M ⁺ + 1 /

Claims (12)

1. Derivatives of the peptides of General formula I

where R ^{1 is} aryl, which may contain from 1 to 3 substituents selected from the group consisting of amidino and protected amidino;
R ² carboxy (lower) alkyl or protected carboxy (lower) alkyl;
R ^{3 is a} carboxy or protected carboxy group;
A ¹ alkylene, which may contain from 1 to 3 substituents selected from amino and protected amino groups;
A ² group of the formula

where R ⁴ lower alkyl, or A ² group of the formula —NH — CH ₂ —CH ₂ —CO—;
A ³ lower alkylene, which may contain 1 3 suitable substituents selected from lower alkyl, mono- or di-, or triphenyl (lower) alkyl, containing 1 3 substituents selected from the group consisting of hydroxy, lower alkoxy and protected hydroxy hydroxy (lower) alkyl, protected hydroxy (lower) alkyl, (cyclo) lower (alkyl) (lower) alkyl, pyridyl (lower) alkyl;
l, m and n are the same or different, an integer 0 or 1, provided that A ^{2 is} not a group of the formula
-NHCH ₂ CH ₂ CO-,
if l is an integer equal to 0,
or pharmaceutically acceptable salts thereof.  2. The derivatives of claim 1, where l 1. 3. The derivatives of claim 2, wherein R ^{1 is} aryl, which may contain 1 to 3 substituents selected from the group consisting of amidino, N-phenyl (lower) alkoxycarbonylamidino, A ¹ alkylene, which may contain 1 to 7 atoms carbon, A ³ lower alkylene, which may contain from 1 to 3 suitable substituents selected from the group consisting of lower alkyl, phenyl (lower) alkyl, which may contain 1 to 3 suitable substituents selected from the group consisting of hydroxy, phenyl ( lower) alkoxy and lower alkoxy groups, hydroxy (lower) alkyl, protected guide hydroxy (lower) alkyl, (cyclo) lower (alkyl) (lower) alkyl and pyridyl (lower) alkyl.  4. The derivatives of claim 3, where m n 0. 5. The derivatives of claim 4, wherein A ^{3 is} lower alkylene, which may contain a substituent selected from the group consisting of lower alkyl, phenyl (lower) alkyl, which may contain a hydroxy, phenyl (lower) alkoxy or lower alkoxy group, and [cyclo (lower) alkyl] (lower) alkyl. 6. The derivatives of claim 5, wherein R ^{1 is} phenyl containing an amidino group, R ^{2 is a} carboxy (lower) alkyl, R ^{3 is a} carboxy group, and A ³ is lower alkylene containing lower alkyl as a substituent. 7. The derivatives of claim 6, wherein R ^{1 is} 4-amidinophenyl, R ² is carboxymethyl, A ^{1 is} trimethylene, and A is methylene containing isopropyl as a substituent.  8. Derivatives of the peptides of general formula I according to claim 1 or their pharmaceutically acceptable salts having thrombosis inhibitory activity. 9. The method of obtaining derivatives of peptides of General formula I

or their pharmaceutically acceptable salts, the meanings of the radicals are indicated in paragraph 1, wherein the compounds of general formula II

where R ¹ , A ¹ , l and m have the indicated meanings,
or their reactive derivatives at the carboxy group,
or their salts are reacted with compounds of the general formula III

where R ² R ³ , A ² , A ³ and n have the indicated meanings,
or their salts and from the derivatives of formula I obtained in this case, where R ¹ aryl containing an amidino group, the amidino-protecting group is cleaved, or from the obtained derivative of formula I, where R ^{2 is a} protected carboxy (lower) alkyl group, the carboxy-protecting group is cleaved to give compounds of general formula I where R ^{2 is} carboxy (lower) acyl, or from the obtained compounds of formula I, where A ^{3 is} lower alkylene containing mono (or di- or tri-) (protected hydroxy) phenyl (lower) alkyl, or salts, or the obtained compounds of formula I, wherein R ³ is protected carboxy, or both salts of carboxy protecting group is cleaved off to give compounds of formula I, wherein R ^3, carboxy, or salts thereof. 10. The method of obtaining derivatives of peptides of General formula I

where the values of the radicals are indicated in paragraph 1,
or their pharmaceutically acceptable salts, characterized in that the compounds of formula IV
R ¹ - (O) _l -A ¹ - (NH) _m -CO-A ² - OH,
where R ¹ , A ¹ , A ² , l, m have the meanings indicated in paragraph 1,
or their salts are reacted with compounds of formula V

where R ² , R ³ and A ³ have the meanings indicated in paragraph 1,
or with their amino-reactive derivatives, or their salts.  11. A pharmaceutical composition having thrombotic inhibitory activity, characterized in that it contains, as an active ingredient, derivatives of the peptides of formula I according to claim 1 in an effective amount.  12. A method for preventing and eliminating thrombosis in a mammal by administering a substance having an inhibitory activity against thrombosis, characterized in that the derivatives of formula I according to claim 1 are administered in a daily dose of 0.001,200 mg / kg weight in 1 4 doses.

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