WO1994009030A1 - Peptide compound and process for producing the same - Google Patents

Abstract

A peptide compound represented by general formula (I) or a pharmacologically acceptable salt thereof. In said formula, R1 represents aryl which may have one or more suitable substituents; R2 represents optionally protected carboxy(lower)alkyl; R3 represents a carboxamide group; A1 represents lower alkylene; A2 represents -N(R4)-CH2CO- or -NH-(R4)HCO- (wherein R4 represents lower alkyl); A3 represents lower alkylene which may have one or more substituents; m and n may be the same or different from each other and each represents 0 or 1, both being usable as a glycoprotein IIb/IIIa antagonist, a platelet aggregation inhibitor, and so on.

Description

 Specification

 Peptide compounds and their preparation ''

 "Technical field" · "Background technology J"

The present invention relates to a novel peptide compound and a salt thereof. More specifically, the present invention relates to a novel peptide compound which is a glycoprotein IIb ZIIIa antagonist and a platelet aggregation inhibitor, and a salt thereof. These compounds may be used for thrombotic diseases [eg, arterial thrombosis, arteriosclerosis, ischemic heart disease, [eg, angina (stable angina, unstable angina including urgent infarction, etc.), myocardial infarction ( Acute myocardial infarction, etc.), coronary artery thrombosis, etc., ischemic brain disease {cerebral infarction (cerebral thrombosis (cerebral thrombosis in acute phase, etc.), cerebral infarction, etc.), transient cerebral ischemia, cerebral vasospasm after hemorrhage (spider) Vasospasm after subarachnoid hemorrhage), pulmonary vascular disorders (pulmonary thrombosis, pulmonary infarction, etc.), peripheral circulatory disorders {eg, obstructive arteriosclerosis, obstructive thromboangitis, Bajaja disease, Reino disease , Diabetic complications (eg, diabetic vasculopathy), venous thrombosis (eg, deep vein thrombosis, etc.), etc.) and restenosis and Z or reocclusion (eg, , PTCA (percutane ous transluminal coronary angioplasty), restenosis and Z or reocclusion after Z and T or TPA (tissue plasminogen activator) administration, etc.) as prophylactic and / or therapeutic agents for Z or thrombolysis In combination with anti-coagulants (eg, heparin), prophylactic and / or therapeutic agents for thrombus formation in vascular surgery, valve replacement, etc., during extracorporeal circulation Prophylactic and / or therapeutic agent for thrombus formation (eg, surgery, hemodialysis, etc.), prophylactic and / or therapeutic agent for thrombus formation during transplantation, Han-type vascular coagulation (DIC;), thrombotic thrombocytopenia As a preventive and / or therapeutic agent for purpura, essential thrombocythemia, inflammation (for example, nephritis), an inhibitor of cancer metastasis, a preventive and / or therapeutic agent for immune diseases, etc. It is a use. The peptide compounds of the present invention and salts thereof are also expected to be useful as cell adhesion inhibitors, and are used as prophylactic and / or therapeutic agents for inflammation (eg, nephritis), cancer metastasis inhibitors, and immune disease preventive agents. It is expected to be useful as a therapeutic agent. Accordingly, one object of the present invention is to provide a useful novel peptide compound or a salt thereof as described above.

 Another object of the present invention is to provide a method for producing the novel peptide compound or a salt thereof.

 A further object of the present invention is to provide a pharmaceutical composition comprising the above-mentioned peptide compound or a salt thereof as an active ingredient.

 Still another object of the present invention is to provide a method of using the above-mentioned peptide compound or a salt thereof for prevention and / or treatment of the above-mentioned diseases in humans and animals.

 "Disclosure of the invention"

 The peptide compound which is the target compound of the present invention has the following formula (I):

R ²

 I

R ¹ Ten ^{0 A 1 - CO - A 2} -hr- NHCHCO-NH -A 3 - R 3 (I)

[Wherein, R ¹ represents aryl optionally having one or more suitable substituents, R ² represents carboxy (lower) alkyl or protected carboxy (lower) alkyl, and R ³ represents amidated A ¹ is a lower alkylene, A ² is a group of the formula:

R ⁴

-N-CH _z C0-

(Wherein R ⁴ represents lower alkyl) or a formula:

-NH-CHC0-

Wherein R ⁴ is as defined above, A ³ is a lower alkylene which may have one or more substituents, m and n are the same or different, Which represents 0 or 1].

 The target compound (I) or a salt thereof can be produced by the following method, Method 1.

R ²

Tens 0 A ^ COOH + H tens A ² h ^ NHCHCO -NH-A ³ -R ³

 (II) (III) or at the carboxy group or at the amino group

 Reactive derivatives, reactive derivatives,

 Or their salts or their salts

R ²

10 _A i_ co -e A ² ^ r- NHLCO-NH— A ³ — R ³

 (I) or its salt

Method 2

R ²

R ¹ 'ten 0 Α ¹ — CO ten A ² ^ r NHCHCO-NH-A ³ — R ³ (la)

Or its salt, the protecting group of amidino

Elimination reaction _Rlfc o ^ _Al — _C0 + NH0HC0-NH-A ³ -R ³ (lb) or salt

Method 3

Tens 0 ^ ΪΓ Α ¹ — CO tens A ² NHCHC0— NH— Α ³ — R ³ (Ic) or its salt

Elimination reaction of carboxy protecting group

R ¹ dozen ^{0 A 1 -! CO-- e A} 2 r NHCHCO -NH- A 3 - R 3 (Id)

Or its salt

Method 4

R ¹ Ten ◦ A ¹ - CO tens ^{A 2 † ^ NHCHCO - NH -} A 3 a - R 3 (Ie) or a salt thereof Carboxy protecting group

 Elimination reaction

R ¹ Ten 0 Alpha ¹ CO tens ^{A 2 † ^ NHCHCO -NH-A} 3 b - R 3 (If)

Or its salt

Method 5

R ¹ Ten 0 CO A ² tens ^{NH CHC0-NH - A 3 -R} 3 dg) or a salt thereof

Carboxy group

 Esterification reaction

^{R 1 - (- 0 - r} A 1 - CO - A 2 - - NHCHCO- NH- A 3 - R = or a salt thereof

Method 6

R ' _b -0 A ¹ — CO ten A ² -hr NHCHCO -NH- A ³ — R ³ (lb) Or its salt

Amidino protecting group

 Introduction reaction

R ¹ , 10 0 A ¹ — CO 10 A ² -r NHCHCO-NH-A ³ — R ³ (la) or its salt

(In the formula, R ¹ , R ² , R ³ , A ¹ , A ² , A ³ , m and n are as defined above,!? ¹ is an aryl having a protected amidino group, Ri is an amidino An aryl having a group, K ² , is a protected carboxy (lower) alkyl, R or carboxy (lower) alkyl, A ³ , is a lower alkylene having a protected carboxy, A ³ _b is R ² _C represents carboxy (lower) alkyl, and R represents esterified carboxy (lower) alkyl.

 There are novel compounds among the starting compounds (II) and (III). These compounds can be produced from a known compound by a method conventionally known in the art or by a method similar to Production Examples and Z or Examples described later in this specification.

Suitable and pharmacologically acceptable salts of the target compound (I) are conventional non-toxic salts. For example, metal salts such as alkali metal salts (sodium salt, potassium salt, etc.), alkaline earth metal salts (calcium salt, magnesium salt, etc.), ammonium salts, organic base salts (trimethylamine salt, triethylamine salt, pyridine salt, etc.) Picoline salts, dicyclohexylamine salts, N, N-dibenzylethylenediamine salts, etc.), organic acid addition salts (formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, Benzenesulfonate, toluenesulfonate, etc.), inorganic acid addition salts (hydrochloride, hydrobromide, hydroiodide, sulfate, phosphorus) Acid salts), and salts with amino acids (alginate, aspartate, glutarate, etc.).

 As used herein, definitions in formulas are explained, and suitable examples are given in detail.

 “Lower” means 1 to 6 carbon atoms unless otherwise specified.

 Suitable "aryls" are phenyl, naphthyl (1-naphthyl, 2-naphthyl, etc.), anthryl (1-anthryl, 2-anthryl, 9-1 anthryl, etc.), preferably phenyl.

 “Aryl” may be substituted with one or more (preferably 1 to 3) suitable substituents such as amidino-protected amidino.

 Suitable protecting groups in the above-mentioned “protected amidino j” are aralkyl in which the alkyl moiety is lower alkyl, such as ar (lower) alkyl, for example, mono (or di or tri) phenyl (lower) alkyl [benzyl, phenethyl , 1-phenylethyl, benzidyl, trityl, etc.]

 Suitable "acyl" includes aliphatic acyl derived from carboxylic acid, carbonic acid, carbamic acid, sulfonic acid, etc., aromatic acyl, aryl aliphatic aliphatic, heterocyclic mono aliphatic aliphatic. Can be

Suitable examples of the acyl groups described above include lower alkanoyl (formyl, acetyl, propionyl, hexanoyl, vivaloyl, etc.), mono (or di or tri) halo (lower) where the alkyl moiety is a lower alkyl. Grade) alkanol (chloroacetyl, trifluoroacetyl, etc.), lower alkoxycarbonyl (methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, hexyloxycarbonyl, etc.), alkylene moiety (Or di or tri) halo (lower) alkoxycarbonyl wherein is a lower alkylene haloalkoxycarbonyl (such as chloromethoxycarbonyl, dichloroethoxycarbonyl, trichloroethoxyquincarbonyl), Alaroyl (benzoyl, toluoyl, xyloyl, naphthoyl, etc.), alarkanol in which the alkylene moiety is lower alkylene, al (lower) alkanoyl, even For example, phenyl (lower) alkanols (phenylacetyl, phenyl, propionyl, etc.), aryloxycarbonyl (phenyloxycarbonyl, naphthyloxycarbonyl, etc.), aryloxy alkano in which the alkyl part is lower alkyl Aryloxy (lower) alkanols such as phenoxy (lower) alkanols (such as phenoxyacetyl and phenoxypropionyl), arylglycoxyloyl (such as phenylglyoxyloyl and naphthylglyoxyloyl), and lower alkylene moieties And alalkoxycarbonyl, which is alalkylene, and lower (lower) alkoxycarbonyl.

 Further, the acyl group may have a suitable substituent. Suitable substituents include phenyl (lower) alkoxycarbonyl (benzyloxycarbonyl, phenethyloxycarbonyl, P-nitrobenzyloxycarbonyl, P-nitrophenyl) which may be substituted by a nitro group or a lower alkoxy group. -Methoxybenzyloxycarbonyl, etc.) Chenyl acetyl, imidazolyl acetyl, furyl acetyl, tetrazoyl acetyl, triazolyl acetyl, thiadia zolyl acetyl, thienyl propionyl, thiadia zolyl propionyl, lower alkylsulfonyl (methylsulfonyl, methyl sulfonyl) Tylsulfonyl, propylsulfonyl, isopropylsulfonyl, pentylsulfonyl, butylsulfonyl, etc.), arylsulfonyl (phenylsulfonyl, trisulfonyl, xylylsulfonyl, naphthyl) Sulfonyl, etc.), alalkylsulfonyl in which the alkylene moiety is a lower alkylene, such as aralkylsulfonyl, such as phenyl (lower) alkylsulfonyl (benzylsulfonyl, phenethylsulfonyl, benzhydrylsulfonyl, etc.), etc. Are mentioned.

Preferred "protected amidino J is N- ar (lower) alkoxycarbonyl amidino, more preferred are N- phenyl (lower) alkoxycarbonyl amidino, preferred to further the N- phenyl (C i one C ₄₎ alkoxycarbonyl amidino, most Preferred is N-benzyloxycarbonylamidino.

A suitable “lower alkyl” may be straight or branched, for example, methyl, ethyl, isopropyl, propyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, hexyl and the like. Preferred lower alkyls are C 1, C ₄ alkyl. Reference may be made to “lower alkyl” as described above for a suitable “lower alkyl” moiety in “carboxy (lower) alkyl”.

 Specific examples of suitable "carboxy (lower) alkyl" include carboxymethyl,

Examples thereof include 1-carboxyethyl, 2-carboxypropyl, 2-carboxypropyl, 3-carboxybutyl, 2-carboxy-1,1-dimethylethyl, 5-carboxypentyl, and 6-carboxyhexyl. Among them, carboxy (C i one C ₄₎ alkyl, more preferably an carboxymethylation.

A suitable “protected carboxyl J moiety” in “protected carboxy (lower) alkyl” is an esterified carboxy group. Specific examples of the ester moiety in the esterified carboxy group include: Examples include lower alkyl esters (methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, hexyl ester, 1-cyclopropylethyl ester, etc.). May be substituted with appropriate substituents, for example, lower alkanoyloxy (lower) alkyl esters (acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester , Pi Lower alkane sulfonyl, such as propyloxymethyl ester, 1-acetoxethyl ester, 1-propionylethyl ester, bivaloyloxymethyl ester, 2-propionyloxymethyl ester, and hexanoyloxymethyl ester. Lower) alkyl esters (such as 2-mesylethyl ester), mono (or di or tri) halo (lower) alkyl esters (such as 2-odoethyl ester, 2,2,2-trichloromethyl ester) , Lower alkenyl esters (vinyl esters, aryl esters, etc.), lower alkynyl esters (ethynyl esters, propynyl esters, etc.), alkenyl (lower) alkyl esters (benzyl esters, 4-methoxy) which may have appropriate substituents Benzyl ester, 4 12-trobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis (methoxyphenyl) methyl ester, 3,4-dimethoxy Cibenzyl ester, 4-hydroxy-3,5-di-tert-butylbe: ^-zyl ester, etc., aryl ester optionally having a substituent (phenyl ester, 4-monophenyl ester, tolyl ester, 4-t-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, etc.). Among them preferred are mono- (or di- some les, tri) phenyl (C -! C ₄₎ alkyl esters, most preferred are base Njiruesuteru.

 As a suitable “lower alkyl” moiety in “protected carboxy (lower) alkyl”, “lower alkyl” described above can be referred to.

Suitable examples of said "protected carboxy (lower) alkyl", phenyl (lower) alkoxycarbonyl (lower) alkyl, Fuweniru as preferred (C i - C ₄₎ alkoxycarbonyl (C, - C ₄₎ alkyl However, more preferred is benzyloxycarbonylmethyl.

 Suitable "protected carboxy" includes those mentioned in the "protected carboxy" portion of "protected carboxy (lower) alkyl".

Suitable “amidated carboxyls” include carbamoyl, N- (lower) alkyl carbamoyl [N-methylcarbamoyl, N-ethylcarbamoyl, N-isopropyl pyramubayl, N-butylcarbamoyl, N-pentylcarbamoyl , carboxymethyl-carbamoyl, N-t-butylcarbamoyl to N one, N-2, 2-Jimechirupu port pills force Rubamoiru, N-2, 2-dimethyl-butylcarbamoyl, and among others, N-(d one C ₅₎ Alkali rubamoyl is preferred, N-isopropylcarbamoyl, Nt-butylcarbamoyl, N-2,2-dimethylpropyl rubamoyl is more preferred], N — [(lower) alkoxy (lower) alkyl] power rubamoyl [N— Methoxybutylcarbamoyl, N-Methoxymethylcarbamoyl, N- (2-Methoxymethoxy ) Power Lubamoyl, N— (2-Methoxypropyl) Power Lubamoyl, N— (2-Ethoxyshetyl) Power Lubamoyl, N— (1-propoxypropyl) Power Lubamoyl, N— (4-t-butoxybutyl) Power Lubamoyl, N— (2-pentyloxypentyl) force Lubamoyl, N— (6-hexyloxyhexyl) force Lubamoyl, etc., among which N—! : (C! One C ₄ ) alkoxy (Ci—C ₄ ) alkyl] Lubamoyl is preferred, N— (2- / toxityl) lubamoyl and N— (2-ethoxyxyl) lubamoyl are more preferred, and N- (higher) alkyl lubamoyl (N— to Petit carbamoyl, N- (2-menu Chiruhepuchiru) force Rubamoiru, N- Noni carbamoyl, N- Dekanirukarubamo I le, N- tricyclo [3. 3.1.1 ^3.7] de crab carbamoyl, N- © down Dekani Rucarbamoyl, N- (bicyclo [4.3.2.] Pendenyl) carbamoyl, N-dodecanylcarbamoyl, N-tridecanylcarbamoyl, N-tetradecanylcarbamoyl, N-pendecanylcarbamoyl, N-Hexadeforce Nilcarbamoyl, N-Heptadecanylcarbamoyl, N-Octadecanylcarbamoyl, N-Nonadeforce Nilcarbamoyl , N-icosanolcarbamoyl, etc.), N, N-di (lower) alkyl radicals (N, N-dimethylcarbamoyl, N, N-getylcarbamoyl, N-methyl-ethylethylcarbamoyl, N, N-di) Propyl rubamoyl, N, N-di (t-butyl) rubumoyl, N-pentyl-N-hexylcarbamoyl, etc., N-lower alkyl-N-al (lower) alkylcarbamoyl (N-methyl-N-benzylcarbamoyl) And cycloalkylcarbamoyl (such as cyclohexylcarbamoyl) with the formula:

(Wherein, R _N is a heterocycle Jomoto 1 or 2 or more to be a good nitrogen containing comprise suitable substituents, the heterocyclic group R _N nitrogen containing hetero to others, such as oxygen or Iou Atom may be included on the ring), and the formula:

N N-COCHs

\ _ / And formula:

And the like.

 “Higher” refers to seven or eight or more (preferably seven to twenty) carbon atoms unless otherwise specified.

Suitable "nitrogen-containing heterocyclic groups" are saturated or unsaturated monocyclic or polycyclic groups. For example, an unsaturated 3- to 8-membered ring (preferably a 5- to 7-membered ring) heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, azepinyl (such as 1H-azepinyl)], pyrrolylyl , Pyrrolylinyl, imidabril, pyrazolyl, pyridyl and its N-oxide, dihydropyridyl, pyrimidinyl, pyridazinyl, triazolyl (4H-1,2,4-triazolyl, 1H-1,2,3— Triazolyl, 2 H—1,2,3-triazolyl and the like, tetrazolyl (1H—tetrabryl, 2 H—tetrazolyl, and the like), and a saturated 3- to 8-membered ring containing 1-4 nitrogen atoms (more preferably 5 Heteromonocyclic group such as piperidyl, perhydroazepinyl (perhydro-1H-azepinyl, etc.), pyrrolidinyl, imidazolidinyl, piperazinyl ), An unsaturated fused heterocyclic ring containing 1-4 nitrogens, such as indolyl, isoindolyl, indazolyl, benzotriabril, a saturated fused heterocyclic ring containing 1-4 nitrogens, for example, 7-azabicyclo [2.2.1] heptyl, 3-azabicyclo [3.3.2] nonanyl, an unsaturated 3- to 8-membered ring containing one or two oxygen atoms and one to three nitrogen atoms (more preferably Is a 5- to 7-membered ring) heteromonocyclic group, for example, oxazolyl, isoxazolyl, oxdiazolyl (such as 2,4-oxdiazolyl, 1,3,4 monooxaziazolyl), one or two oxygen atoms and one to three oxygen atoms Saturated 3- to 8-membered (more preferably 5- to 7-membered) heterocyclic groups containing nitrogen atoms, such as morpholinyl and sydnonyl, one or two oxygens Unsaturated fused heterocyclic rings containing 1 to 3 nitrogen atoms, such as benzoxazolyl, benzoxadiazolyl, 1 or 2 zeo atoms and 1 to 3 nitrogen atoms Unsaturated 3- to 8-membered ring (more preferably 5- to 7-membered ring) heteromonocyclic group, for example, thiazolyl, isothiabril, thiadiazolyl (1,2,3-thiadiazolyl, 1,2,4-thiadiabryl, 1,3 , 4-ch Asiazoril, 1,2,5—thiadiazolyl), dihydrothiazinyl, 1 or 2 or more saturated 3- or 8-membered rings (more preferably 5- to 7-membered rings) containing 2 atoms and 1 to 3 nitrogen atoms A) heteromonocyclic groups such as thiazolidinyl, thiomorpholinyl, groups having an unsaturated fused heterocyclic ring containing 1 or 2 zeo atoms and 1 to 3 nitrogen atoms, such as benzothiazolyl, benzothiadiazolyl, A group having a saturated condensed heterocyclic ring containing 1 to 4 nitrogen atoms, and a saturated 3- to 8-membered heteromonocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms, etc. Is mentioned. Among them, saturated 3- to 8-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, saturated 3- to 8-membered heteromonocycles containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms Cyclic groups, and saturated 3-8 membered heteromonocyclic groups containing 1 or 2 iodo atoms and 1-3 nitrogen atoms are preferred.

As the group R _N , a saturated 5- to 7-membered heteromonocyclic group containing 1 to 4 nitrogen atoms, a saturated 5 to 7-membered ring containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms, Preferred are 5-membered heteromonocyclic groups containing 1 or 2 zeo atoms and 1 to 3 nitrogen atoms, or piperidino, 1-piperazinyl, morpholino and 4- Thiomorpholinyl is more preferred. The “nitrogen-containing heterocyclic group” may contain one or more (preferably 1 to 3) suitable substituents. Examples of the substituent include lower alkyl, oxo, carboxyl, protected carboxyl (such as methoxycarboxyl), sulfonyl, and lower alkane sulfonyl (such as methanesulfonyl) as described above.

Suitable "lower alkylene" refers to those having one to six carbon atoms. Examples include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylmethylene, ethylmethylene, propylmethylene, isopropylmethylene, ybutylmethylene, sec-butylmethylene, n-butylmethylene, t-butylmethylene and the like. Can be Among these (C, one C ₅₎ laid alkylene preferred, methylene, trimethylene, tetramethylene and pentamethylene are more favorable preferable. Suitable "lower alkylene" moieties in "lower alkylene optionally having one or more suitable substituents" include those described above. Among them, (d—C ₅ ) alkylene is preferable, and methylmethylene, isopropylmethylene, isobutylmethylene and sec-butylmethylene are more preferable.

 One or more (preferably 1 to 3) suitable substituents of the “lower alkylene” include aryl or carboxy, which may have one or more suitable substituents described below, carboxy, Carboxy, cycloalkyl and the like can be mentioned.

 Suitable "aryl" of the above "lower alkylene" includes those described above. Of these, phenyl is preferred.

The "aryl" may contain one or more (preferably 1-3) suitable substituents. As substituents, e.g., lower alkoxy (main butoxy, ethoxy alkoxy, Purobokishi, butoxy, t-butoxy, Penchiruokishi, Kishiruokishi, etc. to) and the like, among others (C, one C ₄₎ alkoxy are preferred, main butoxy Is more preferred.

 The method for producing the target compound of the present invention will be described in detail below.

Method 1

 The target compound (I) or a salt thereof is a compound (11) or a derivative having a carboxy group or a salt thereof, and a compound (111) or a derivative or a salt thereof having an amino group with a reactivity. It can be produced by reacting.

Suitable derivatives of compound (II) reactive at the carboxy group include acid halides, acid anhydrides, active amides, active esters and the like. Suitable specific examples of the reactive derivative include mixed acid anhydrides with acids such as acid chloride, acid azide, and substituted phosphoric acid (dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated halides). Phosphoric acid, etc., dialkyl phosphite, sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid (such as methanesulfonic acid), aliphatic carboxylic acid (acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, valeric acid, iso) Valeric acid, 2-ethyl butyric Acids, trichloroacetic acid, etc.) and aromatic carboxylic acids (benzoic acid ^ '), symmetric acid anhydrides, imidaburu-activated amides, 4-substituted imidazoles, dimethyl pyrazole, triazole, tetrazole and 1-hydroxy-1 H-benzotriazole, and active esters (cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [(CH ₃ ) ₂ N + = CH-] ester, vinyl ester, propargyl ester, p-nitrophenyl) Ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenylthioester, p-nitrophenylthioester, P-cresylthioester, carboxy Methylchoe Ter, bilanyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc.) and esters with N-hydroxy compounds (N, N-dimethylhydroxyamine, 1-hydroxy-2- (1H) monopyridone, N-hydroxysuccinimide, N-hydroxyfuryl imide, 1-hydroxy-1H-benzotriabule, etc. Suitable reactive derivatives may be selected according to the type of compound (II) used. It can be appropriately selected from the above compounds.

 As for the suitable salt of the compound (II) and the reactive derivative thereof, those mentioned for the compound (I) can be referred to.

 As a derivative reactive at the amino group of the compound (III), a Schiff salt-type imino formed by the reaction of the compound (III) with a carbonyl compound such as an aldehyde / ketone, or an enamine-type tautomer thereof, a compound ( III) with bis (trimethylsilyl) acetoamide, mono (trimethylsilyl) adetoamide, bis (trimethylsilyl) urea, and other silyl derivatives formed by the reaction of compound (III) with trichloride diphosphogen phosphite. Derivatives formed by the reaction are exemplified.

 Suitable salts of the compound (II) and its reactive derivative can be referred to those exemplified for the compound (I).

The reaction is usually performed in water or a common solvent such as alcohol (methanol, ethanol This is carried out in acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine or other organic solvents which do not adversely affect the reaction. These ordinary solvents may be used by mixing with water.

 When the compound (II) is used in the form of a free acid or salt in this reaction, the reaction is preferably carried out in the presence of a commonly used condensing agent. Examples of the condensing agent include N, N'-dicyclohexylcarpoimide, N-cyclohexyl-1-N'-morpholinoethylcarpoimide, N-cyclohexyl-N '-(4-J N-N-N-N-N-N-N-N-N-N-N-Ethyl-N-N-N-N-N-N-N-N-N-N-N-Ethyl-N-N-N-N-N-N-N-N-N-N-N-N-N-N-N 1-carbonylbis (2-methylimidazole), pentamethyleneketene-1N-cyclohexylimine, diphenylketene-1N-cyclohexylimine, ethoxyacetylene, 1 alkoxyl 1-chloroethylene, trialkyl phosphite, Polyethyl phosphate, polyisopropyl phosphate, oxycyclophosphite (phosphoryl chloride), trisalt Phosphorus, thionyl chloride, oxalyl chloride, lower alkyl esters of haloformic acid (ethyl ethyl chloroformate, isopropyl chloroformate, etc.), triphenylphosphine, 2-ethyl-7-hydroxybenzisoxoxazolium salt, 2-ethyl-5- (M-sulfophenyl) isoxazolyl hydroxide hydroxide inner salt, 11- (P-chlorobenzenesulfonyloxy) -16-chloro-1H-benzotriazole, so-called Vilsmeier reagent, which is N, N-dimethyl And those obtained by the reaction of formamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride and methanesulfonyl chloride.

 The reaction is carried out using alkali metal carbonate, alkali metal bicarbonate, tri (lower) alkylamine, pyridine, N- (lower) alkylmorpholine, N, N-di (lower) alkylbenzylamine, etc. The reaction may be performed in the presence of an inorganic or organic base. Although the reaction temperature is not particularly limited, it is usually carried out under cooling to heating.

Method 2 The target compound (lb) or a salt thereof can be produced by an elimination reaction of a group protecting the compound (la) or its salt for amidino.

 This reaction is performed according to conventional methods such as hydrolysis or reduction.

 The hydrolysis is preferably performed in the presence of a base or an acid such as a Lewis acid. Suitable bases include inorganic bases and organic bases, such as alkali metals (such as sodium and potassium), alkaline earth metals (such as magnesium and calcium), hydroxides and carbonates, and bicarbonates thereof. , Trialkylamines (trimethylamine, triethylamine, etc.), picoline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] pendase 7-ene and the like.

 Suitable acids include organic acids (such as formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid), and inorganic acids (such as hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, and hydrogen bromide).

 The elimination reaction using a Lewis acid such as trihaloacetic acid (trichloroacetic acid, trifluoroacetic acid, etc.) is preferably performed in the presence of a cation capture agent (anitool, phenol, etc.).

 The reaction is usually carried out in water or a solvent such as an alcohol (methanol, ethanol, etc.), methylene chloride, tetrahydrofuran, a mixture thereof or other solvents which do not adversely influence the reaction. Liquid bases and acids can also be used as solvents.

 Although the reaction temperature is not particularly limited, it is usually carried out under cooling to heating.

 Reduction methods applicable to the elimination reaction of the present invention include chemical reduction and catalytic reduction.

 Suitable reducing agents used for chemical reduction include metals (tin, zinc, iron) and metal compounds (chromium chloride, chromium acetate, etc.) and organic or inorganic acids (formic acid, acetic acid, propionic acid, trifluoroacetic acid, P- It is a mixture with toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.).

Suitable catalysts for use in catalytic reduction are conventional, for example, platinum catalysts ( Platinum plate, Platinum sponge, Platinum black, Colloidal platinum, Platinum oxide, Platinum ring ^: etc.), Palladium catalyst (Palladium sponge, Palladium black, Palladium oxide, Palladium monocarbon, Colloidal palladium, Palladium-barium sulfate , Palladium-barium carbonate, etc.) nickel catalyst (reduced nickel, nickel oxide, Raney nickel, etc.), cobalt catalyst (reduced cobalt, Raney cobalt, etc.), iron catalyst (reduced iron, Raney iron, etc.), copper catalyst (reduced copper, Raney copper, Ullman copper, etc.). The reaction is usually carried out in water or a conventional solvent that does not adversely influence the reaction, for example, methanol, ethanol, propanol, N, N-dimethylformamide, or a mixture thereof.

 When the above-mentioned acids used in chemical reduction are liquid, they can also be used as a solvent. Further, suitable solvents to be used in the catalytic reduction include the above-mentioned solvents, common solvents such as getyl ether, dioxane and tetrahydrofuran, and mixtures thereof.

 Although the reaction temperature of this reduction is not particularly limited, it is usually carried out under cooling to heating.

When the protected carboxy (lower) alkyl of R ² is converted to carboxy (lower) alkyl and when the lower alkylene with protected carboxy of A ³ is converted to lower alkylene with carboxy, Within the scope of the present invention.

Method 3

 The target compound (Ib) or a salt thereof can be produced by elimination of a group protecting carboxy of the compound (Ic) or a salt thereof.

 This reaction can be performed in the same manner as in the above method 2. Therefore, for the reaction method and reaction conditions (base, acid, catalyst, solvent, reaction temperature, etc.) of this reaction, the description in Method 2 can be referred to.

The present invention also applies when an aryl with a protected amidino of R ¹ is converted to an aryl with an amidino, and when a lower alkylene with a protected carboxy of A ³ is converted to a lower alkylene with a carboxy. Within the scope of the invention. Method 4 _r

 The target compound (If) or a salt thereof can be produced by elimination of a carboxyl protecting group of the compound (Ie) or a salt thereof.

 This reaction can be performed in the same manner as in the above method 2. Therefore, for the reaction method and reaction conditions (base, acid, catalyst, solvent, reaction temperature, etc.) of this reaction, the description in Method 2 can be referred to.

Method 5

 The target compound (Ih) or a salt thereof can be produced by subjecting a carboxyl of the compound (Ig) or a salt thereof to an esterification reaction.

 Suitable salts of the compound (Ig) also include the acid addition salts exemplified for the compound (I). The esterification reaction involves the reaction of compound (Ig) or a salt thereof with a conventional esterifying agent such as, for example, a compound of the formula: R—OH, where R is lower alkyl or ar (lower) alkyl, and the presence of an acid. The reaction can be carried out under the following conditions. In this reaction, the above-mentioned esterifying agent usually also serves as a solvent, but a solvent which does not adversely influence the reaction may be used. Although the reaction temperature is not particularly limited, it is usually carried out at normal temperature or under heating.

Method 6

 The target compound (la) or a salt thereof can be produced by introducing a protecting group into the amidino group of the compound (lb) or a salt thereof.

Examples of the amidino-protecting group-introducing agent used in this reaction include, for example, a compound represented by the formula: R represented by X [wherein, R ⁵ represents ar (lower) alkyl or acyl; And a leaving group such as halogen].

 This reaction can be performed in the same manner as in the above method 1. Therefore, for the reaction method and reaction conditions (base, acid, catalyst, solvent, reaction temperature, etc.) of this reaction, the description in Method 1 can be referred to.

When an aryl with a protected amidino of R ¹ is converted to an aryl with an amidino, and the protected carboxy (lower) alkyl of R ² is carboxy Conversion to (lower) alkyl is also within the scope of the invention.

 The target compound (I) obtained by the above-mentioned method is in a free state, which can be converted into a salt by a conventional method. On the other hand, when the target compound (I) thus obtained is in the form of a salt, it can be converted to a free state or to another salt by a conventional method.

 The target compound (I) also includes a stereoisomer resulting from an asymmetric carbon.

 In order to show the usefulness of the target compound (I), the following shows a pharmacological test of a representative compound (I) of the present invention.

 Test 1: Inhibition of ex vivo ADP aggregation in dogs

Test compound

 (1) Compound of Example 13

Test method

 — Using an approximately 8 kg beagle dog (male, fit) that was fasted overnight, blood was collected from the forelimb vein before and 1 hour after oral administration of the compound, and the blood was collected from a 3.8% sodium citrate solution (PH 7.4). ) (9: 1, volume ratio of blood to sodium citrate). Whole blood (10 Og) was centrifuged for 10 minutes to prepare platelet-rich plasma (PRP). The blood (2000 g) after removing the PRP was further centrifuged for 10 minutes to prepare ischemic platelet plasma (PPP).

 The ADP aggregation suppression effect was measured using a 4-channel HEMATRACER-1 (manufactured by NKK JAPAN) as an aggregometer, with the light transmittance of PPP being 100%.

 After incubating PRP (250〃 ^) at 37 ° C for 2 minutes, ADP (500 M, 5 i) was added as flocculant and the light transmission was recorded. The inhibition rate was determined from the maximum value of aggregation.

Dosage 1 OmgZk g Test results

The pharmaceutical composition of the present invention comprises the target compound (I) or a pharmacologically acceptable salt thereof as an active ingredient, and is administered from the rectum, lungs (recruitment or sublingual inhalation), nose, eyes (topical). Or a pharmaceutical formulation with an organic or inorganic carrier or excipient to make it suitable for oral or parenteral (eg, subcutaneous, intravenous, intramuscular) dosing or inhalation, such as solid, semi-solid or It can be used in liquid form. The active ingredient is mixed, for example, with the usual non-toxic pharmacologically acceptable carriers, tablets, pellets, troches, capsules, suppositories, creams, ointments, aerosols, powders for inhalants, solutions, emulsions , Suspensions and other forms suitable for use. If necessary, auxiliary, stabilizing, sizing, coloring and perfuming agents may be used.

 The target compound (I) or a pharmacologically acceptable salt thereof is contained in the pharmaceutical composition in an amount sufficient to produce a desired effect in a disease process or condition. The pharmaceutical compositions of the present invention can be manufactured by conventional methods in the art. If necessary, techniques commonly used in the art can be applied to the pharmaceutical compositions of the present invention to increase the bioavailability of the drug. When the composition of the present invention is applied to humans or animals, intravenous (eg, intravenous infusion), intramuscular or oral administration is preferred. In particular, oral administration is most preferred.

The therapeutically effective dose of the target compound (I) varies depending on the individual age and condition of the patient being treated. Intramuscular administration of the target compound (I) at a dose of 0.0001 to 100 mg, the target compound (I) was added to 0.01 kg of human or animal per day on a daily basis. 10 O mg dosage, oral administration: 1 kg human or animal daily A dose of 0.001 to 20 Omg of the compound of interest (I) is usually given for the prevention and / or treatment of the above-mentioned diseases in chicks or animals.

 "Best mode for carrying out the invention J

 Hereinafter, the present invention will be described in detail based on examples.

Production Example 1

 4-cyanophenol (5.96 g), 5-ethyl valerate (11.5 g) and potassium carbonate (7.6 g) were added to N, N-dimethylformamide (6Om ^). This was stirred at room temperature for 14 hours.

 The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium bicarbonate, then with water, and finally with an aqueous solution of sodium chloride, and dried over magnesium sulfate. After filtration, the filtrate was distilled under vacuum, and the precipitate was washed with getyl ether to obtain ethyl 5- (4-cyanophenoxy) valerate (11.21 g).

 Melting point: 55-57 ° C

IR (Nujol): 2200. 1725, 1600, 1500 cm " ¹

NMR (DMS0-d ₆ , δ) 1.18 (3Η, t, J = 7Hz) .1.4-1.88 (4H, m),

 2.37 (2H, t, J = 7Hz), 3.8-4.13 (4H, m).

 7.1 (2H, d, J = 8.9Hz), 7.76 (2H, d, J = 8.9Hz)

 MASS (M / Z): 247 (M +)

Production Example 2

 In the same manner as in Production Example 1, 4- (4-cyanophenoxy) butyric acid ethyl ester was obtained from 4-cyanophenol (1.8.77 g) and 4-propynylbutyric acid ethyl ester (23.60 m).

 Yield: 23.97 g

 Melting point: 56-57 ° C

IR (Nujol): 2220, 1735, 1610, 1510 cm— ¹

 NMR (DMSO-de.δ) 1.18 (3H, t, J = 4.7Hz),

 2.00 (2H, m), 2.7 (2H, t, J = 4.8Hz), 4.07 (4H, m),

7.09 (2H, d, J = 4.6Hz), 7.76 (2H, d, J = 4.6Hz) MASS (M / Z): 233 (M +),

Production Example 3

 In the same manner as in Production Example 1, 6- (4-cyanophenoxy) hexyl hexanoate was obtained from 4-cyanophenol (191 g) and 6-bromoethyl hexanoate (24.54 g).

 Yield: 27 g

 Melting point: 45-46'C

IR (Nujol): 2200, 1720, 1590, 1565 cm ^-1

Image (DMS0-d ₆ , δ: 1.18 (3Η, t, J = 7.1Hz),

 1.3-1.83 (6H, m), 2.31 (2H, t, J = 7.1Hz),

 3.9-4.2 (4H, m), 7.09 (2H, d, J = 8.9Hz),

 7.75 (2H, d, J = 8.9Hz)

MASS (M / Z): 261 (M ⁺ )

Production Example 4

 Hydrogen chloride was blown into a solution of ethyl 5- (4-cyanophenoxy) valerate (24.7 g) obtained in Production Example 1 in ethanol (250 m) for 4 hours while cooling with ice water. After confirming the completion of the reaction by thin layer chromatography (TLC), nitrogen was blown in at room temperature and distillation was performed in vacuo. The obtained precipitate was washed with getyl ether to give 5- [4- {1- (ethoxy) iminomethyl} phenoxy] ethyl valerate hydrochloride (28.26 g).

 Melting point: 110 ° C (dec.)

IR (Nujol): 1720, 1635, 1600 cm " ¹

Hidden (D S0-d ₆ , <5): 1.18 (3H, t, J = 7.1Hz),

 I.47 (3H, t, J = 7Hz), 1.5-1.9 (4H, m),

 2.38 (2H, t.J = 7.lHz), 4.05 (2H, q.J = 7.1Hz), 4.12 (2H, t, J = 5.8Hz), 4.61 (2H, q, J = 7Hz), 7.16 ( 2H, d, J = 9Hz), 8.14 (2H, d, J = 9Hz).

II.54 (1H, br s) MASS (/ Z): 293 ( ⁺ ) free,

Production Example 5

 In the same manner as in Production Example 4, from 4-ethyl 4-ethyl (2-3.0 g) butyrate (23.0 g) obtained in Production Example 2, 4- [1- {1- (ethoxy) iminomethyl} Noxy] Ethyl butyrate hydrochloride was obtained.

 Yield: 31.84 g

 Melting point: 102-104 ° C

IR (Nujol): 3420, 1735, 1610 cm ' ¹

 NMR (DMSO-de.δ: 1.18 (3H, t, J = 4.7Hz),

 1.47 (3H, t, J = 4.6Hz), 2.01 (2H, m).

 2.48 (2H, t, J = 4.8Hz), 4.09 (4H, m),

 4.60 (2H, q, J = 4.6Hz), 7.16 (2H, d, J = 4.6Hz).

 8.15 (2H, d, J = 4.6Hz)

Production Example 6

 In the same manner as in Production Example 4, from 6- (4-cyanophenoxy) hexyl oxalate (26 g) obtained in Production Example 3, 6- [4-1- (1- (ethoxy) iminomethyl} phenoxy] hexane Obtained acid ethyl hydrochloride.

 Yield: 27.18 g

 Melting point: 107 ° C (dec.)

IR (Nujol): 1720, 1600, 1580, 1510 cm ' ¹

 NMR (DMSO-de, δ): 1.17 (3H, t, J = 7.1Hz),

 1.3-1.84 (6H, m), 1.47 (3H, t, J = 7Hz),

 2.31 (2H, t, J = 7.1Hz), 3.92-4.2 (4H, m),

 4.61 (2H, q, J = 7Hz), 7.16 (2H, d, J = 9Hz),

 8.14 (2H, d, J = 9Hz). 11.54 (1H, br s)

MASS (M / Z): 307 (M ⁺ ) free

Production Example 7

5- (4- {1- (ethokin) iminomethyl} phenoxy) obtained in Production Example 4 Ethyl valerate hydrochloride (28. 2 g), ammonium chloride (4. g) and ammonia (42 m) in ethanol solution were added to ethanol (30 Om ^), and stirred for 15 hours. Perfused. The reaction mixture was cooled to room temperature and filtered. The filtrate was distilled in vacuum. The obtained precipitate was washed with getyl ether to obtain 5- (4-amidino fuoxy) ethyl valerate, hydrochloride (27.28 g).

 Melting point: 150-155 ° C (dec.)

IR (Nujol): 3350, 1710, 1660, 1490 cm " ¹

NMR (D S0-d ₆ , 6): 1.18 (3H, t, J = 7. LHz),

 1.5-1.85 (4H, m), 2.38 (2H, t, J-7.1Hz),

 4.05 (2H, q, J = 7.1Hz), 4.1 (2H, t, J = 5.8Hz), 7.15 (2H, d, J = 8.9Hz), 7.85 (2H, d, J = 8.9Hz), 8.65 ( 4H, br)

MASS (/ Z): 264 ( ⁺ ) free

Production Example 8

 In the same manner as in Production Example 7, 4- (4- {1- (ethoxy) iminomethyl} phosphonyl) ethyl ethyl butyrate hydrochloride (31.7 g) obtained in Production Example 5 was converted to 4- (4-α Midinofuyunoxy) Ethyl butyrate hydrochloride was obtained.

 Yield: 29.88 g

 Melting point: 81-84 ° C (dec.)

IR (Nujol): 3420, 3250, 3100, 1720, 1670, 1600 cm- ¹ NMR (DMSO-de, δ): 1.18 (3H, t, J = 7.1Hz),

 1.9-2.1 (2H, m), 2.47 (2H, t, J = 7.3Hz),

 3.95-4.23 (4H, m), 7.14 (2H, d, J = 8.9Hz).

 7.88 (2H, d, J = 8.9Hz), 8.93 (4H, br s)

 MASS (M / Z): 250 (M +) free

Production Example 9

In the same manner as in Production Example 7, 6- [4- {1- (ethoxy) iminomethyl} phenoxy] hexyl hexanoate hydrochloride (27 s) obtained in Production Example 6 was converted to 6— (4— Amidinophenoxy) ethyl hexanoate hydrochloride was obtained.

 Yield: 27.88 g

 Melting point: 135 ° C (dec.)

IR (Nujol): 3420, 3260 , 3100, 1720, 1660, 1600 cm one ^{1 NMR (DMSO-de, δ} ): 1.17 (3H, t, J = 7.1Hz),

 1.31-1.85 (6H, m), 2.32 (2H.t.J = 7.1Hz),

 3.95-4.2 (4H, m) .7.14 (2H, d, J = 8.9Hz),

 7.89 (2H, d, J = 8.9Hz), 8.69 (4H, br)

 MASS (M / Z): 278 (M +) free

Production Example 10

 To a mixture of tetrahydrofuran (15 Om) and IN sodium hydroxide was added 5-((4-amidinofinoxy) -ethyl valerate hydrochloride (14.6 g) obtained in Preparation Example 7, and ice water was added thereto. While cooling with, benzyloxycarbonyl chloride (10.4 m ^) was added over 1 hour. The resulting mixture was stirred at 10 ° C. for 2 hours while maintaining the pH at about 10 with 1 N sodium hydroxide. The reaction mixture was poured into ethyl acetate (300 mL), the separated organic layer was washed with aqueous sodium chloride solution, dried over magnesium sulfate, filtered, the filtrate was distilled in vacuo, and the precipitate was washed with getyl ether. Thus, 5- [4- (N-benzyloxycarbonylamidino) phenoxy] ethyl ester valerate (17.48 g) was obtained.

 Melting point: 88-90 ° C

IR (Nujol): 3420, 3280, 1715, 1660, 1590, 1560 cm ^-1 NMR (DMSO-de, 5): 1.17 (3H, t, J = 7.1Hz),

 1.55-1.85 (4H, m), 2.37 (2H, t, J = 7Hz),

 4.04 (2H, q. J = 7Hz), 4.05 (2H, t, J = 5.8Hz).

 5.1 (2H, s), 7.0 (2H, d. J = 8.9Hz).

 7.24-7.46 (5H, m). 7.98 (2H, d, J = 8.9Hz),

 9.11 (2H.br s)

MASS (M / Z): 398 (M ⁺ ) Preparation Example 11 _{r In the same} manner as in Preparation Example 10, the 4- (4-amidinov X-nonoxy) ethyl ethyl butyrate hydrochloride (29.5 g) obtained in Preparation Example 8 was converted to 4- [4-N —Benzyloxycarbonylamidino) phenoxy] butyrate was obtained.

 Yield: 32.15 g

 Melting point: 110-112

IR (Nujol): 3430, 3290, 1720, 1655, 1595, 1565 cm " ¹ NMR (D SO-de, 5): 1.18 (3H.t, J = 7.1Hz),

 1.84-2.1 (2H, m), 2.46 (2H, t, J = 7.1Hz),

 3.9-4.19 (4H. N0, 5.12 (2H, s),

 7.01 (2H, d, J = 8.9Hz), 7.23-7.5 (5H, m),

 7.97 (2H, d, J = 8.9Hz), 9.31 (2H, br s)

MASS (/ Z): 384 (M ⁺ )

Production example 1 2

 In the same manner as in Production Example 10, 6- (4-amidinophenoxy) hexyl hexate hydrochloride (27.7 g) obtained in Production Example 9 was used to give 6- [4- (N-base [Ndyloxycarbonylamidino) phenoxy] hexanoate was obtained.

 Yield: 30.72 g

 Melting point: 96-99 ° C

IR (Nujol): 3430, 3300 , 1725, 1660, 1600, 1570, 1490 cm "1 NMR (DMS0-d 6 <5.): 1.17 (. 3H t, J = 7.1Hz).

 1.3-1.85 (6H, m), 2.31 (2H, t, J = 7.1Hz).

 3.92-4.16 (4H, m), 5.1 (2H, s),

 7.0 (2H, d, J = 8.9Hz), 7.25-7.5 (5H, m),

 7.99 (2H, d, J = 8.9Hz), 9.12 (2H, br s)

MASS (M / Z): 412 ( ⁺ )

Production example 1 3

A 10% aqueous solution of hydrochloric acid (150m) and acetic acid (10Om ^) was obtained in Production Example 10 The 5- [4 one (N- benzyl O alkoxycarbonyl amidinophenyl) Fe carboxymethyl] valerate Echiru and the mixture was stirred for 1.5 hours at which 5 0 ^e C. After cooling the reaction mixture to room temperature, the pH was adjusted to about 4 with 4 N sodium hydroxide. The resulting precipitate was collected by filtration to give 5- [4- (N-benzyloxycarbonylamidino) phenoxy] valeric acid (1.487 g).

 Melting point: 103 ° C (dec.)

IR (Nujol): 3300, 1735, 1640, 1600, 1560. 1510 cm ^-1 NMR (DMSO-de, 6): 1.53-1,85 (4H, m),

 2.29 (2H, t, J = 7.2Hz), 4.06 (2H, t, J = 5.8Hz), 5.16 (2H, s), 7.04 (2H, d.J = 8.9Hz).

 7.3-7.5 (5H, m), 7.95 (2H, d, J = 8.9Hz).

 9.54 (1H, br). 12.07 (1H, br)

 MASS (M / Z): 370 (M +)

Production example 1 4

 In the same manner as in Production Example 13, the 4- (4- (N-benzyloxycarbonylamidino) phenoxy] ethyl butyrate (32 g) obtained in Production Example 11 was converted to 4- (4-N-benzyl). Roxycarbonylamidino) phenoxy] butyric acid was obtained.

 Yield: 17.38 g

 Melting point: 110 ° C (dec.)

IR (Nujol): 3280, 1730, 1630, 1600, 1565, 1500 cm ^-1 NMR (solid-d ₆ , δ): 1.83-2.14 (2H, m),

 2.39 (2H, t, J = 7.3Hz),

 4.06 (2H, t, J = 6.4Hz),

 5.10 (2H, s) .7.01 (2H, d, J = 8.9Hz), 7.2-7.5 (5H, m), 7.98 (2H, d, J = 8.9Hz), 9.08 (1H, br s),

 12.08 (1H, br s)

Production example 1 5

In the same manner as in Production Example 13, 6- [4- (N-benzylo) obtained in Production Example 12 was obtained. 61- [41- (N-benzyloxycarbonylamidino) phenoxy] hexanoic acid was obtained from (oxycarbonylamidino) phenoxy] hexyl hexate (30., 5 g).

 Yield: 25 g

Melting point: 143 ^e C (dec.)

IR (Nujol): 1730. 1600. 1560 cm " ¹

NMR (DMS0-d ₆ , <5): 1.3-1.8 (6H, m). 2.24 (2H, t, J = 7Hz),

 4.03 (2H, t, J = 6.4Hz) .5.11 (2H, s),

 7.0 (2H, d, J = 8.9Hz), 7.2-7.55 (5H, m),

 7.98 (2H, d, J = 8.9Hz), 9.22 (1H, br), 12.02 (1H, br) Production example 1 6

 A suspension of 60% sodium hydride (7.92 g) in tetrahydrofuran (10 Om ^) was stirred at 110 ° C under a nitrogen gas atmosphere. 5-Diethoxyphosphorol 3-ethylpentenoate (49.61 g) was poured into the reaction mixture, and the mixture was stirred at 110 ° C for 1 hour. A solution of p-cyanobenzaldehyde (20.00 g) in tetrahydrofuran (5 Om ^) was poured into the reaction mixture, and the mixture was stirred at 0 for 3 hours. The reaction mixture was poured into a mixture of saturated saline and ethyl acetate. The separated organic layer was dried over magnesium sulfate and treated with activated charcoal. After filtration, the filtrate was distilled under vacuum. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate Zn-hexane (1: 4 by volume). The fractions containing the target compound were collected and distilled under vacuum to obtain 5- (4-cyanophenyl) -2,4-pentylethyl ester (10.04 g).

IR (Nujol): 2250, 1720, 1630. 1250 cm ' ¹

 NMR (D SO-de, δ): 1.24 (3Η, t, J = 7. LHz),

 4.16 (2H, q, J = 7. LHz). 6.18 (1H, d, J = 12.5Hz),

 7.13-7,49 (3H, m) .7,74 (2H, d, J = 8.5Hz),

 7.85 (2H.d.J = 8.5Hz)

MASS (M / Z): 227 (M ⁺ ) EI MASS Production example 1 7 _r

 In the same manner as in Production Example 4, 5— (4-cyanophenyl) -1,2,4-pentyl ethenoate (16.50 g) obtained in Production Example 16 was used to give 5 -— (4-I {1- (Ethoxy) iminomethyl} phenyl] 1,2,4-pentylethyl ethyl 'hydrochloride was obtained.

 Yield: 22.35 g

IR (Nujol): 3400, 1720, 1620, 1250 cm " ¹

 NMR (DMSO-de.δ): 1.25 (3Η, t, J = 7.1Hz),

 1.49 (3H, t, J = 7.0Hz), 4.16 (2H, q. J = 7.1Hz),

 4.63 (2H, q, J = 7.0Hz), 6.20 (1H, d, J = 14.2Hz), 7.17-7.46 (3H, m). 7.84 (2H, d, J = 8.5Hz),

 8.15 (2H, d, J = 8.5Hz)

MASS (M / Z): 273 (M ⁺ ) free EI MASS

Production example 1 8

 5- (4- (1- (ethoxy) iminomethyl} phenyl) -1,2,4-pentylethyl ethylate obtained in Production Example 17 'hydrochloride (22.00 g) in ethanol (2 2 Om ^ ) A solution of ammonia (19.7 ml) in 9 N ethanol was poured into the solution, and the mixture was perfused for 15 hours. The reaction mixture was cooled to room temperature, distilled in vacuo, and the obtained precipitate was washed with diisopropyl ether, and 5_ (4-amidinophenyl) -1,2,4-pentylethyl ethyl hydrochloride (20.1 5 g) were obtained.

IR (Nujol): 3400. 1720, 1630, 1250 cm " ¹

 NMR (DMSO-de.δ): 1.25 (3Η, t, J = 7.1Hz),

 4.17 (2H, q, J = 7.lHz), 6.18 (1H, d.J = 14.4Hz), 7.15-7.51 (3H, m), 7,78 (2H, d, J = 8.5Hz),

 7.89 (2H, d, J = 8.5Hz), 9.30 (2H, s), 9.48 (2H, s)

MASS (M / Z): 244 (M ⁺ ) free EI MASS

Production example 1 9

Ethanol (50%) of a mixture of 5- (4-amidinophenyl) -1,2,4-pentylethyl ethyl chloride hydrochloride (20.0 g) and 10% Pd—C (5.0 g) 0 m £) The solution was stirred at room temperature for 3 hours under a hydrogen gas atmosphere. After filtration, the liquid was distilled under vacuum. The obtained precipitate was washed with getyl ether to give ethyl 5-ethyl 4-amidinophenyl) pentanoate hydrochloride (19.42 g).

IR (Nujol): 3400, 3100, 1730, 1660 cm " ¹

NMR (DMS0-d ₆ , δ): 1.16 (3Η, t, J = 7.1 Hz),

 1.52-1.61 (4H, m), 2.32 (2H, t, J = 6.9Hz),

 2.66 (2H, t, J = 7.0Hz), 4.04 (2H, q, J = 7.1Hz), 7.45 (2H, d, J = 8.3Hz). 7.78 (2H, d. J = 8.3Hz).

 9.21 (2H, s), 9.26 (2H, s)

MASS (M / Z): 248 (M ⁺ ) free EI MASS

Production Example 20

 In the same manner as in Production Example 10, 5- (4-amidinofenyl) pentanoic acid ethyl chloride hydrochloride (17.0 g) obtained in Production Example 19 was converted to 5- [4- (N-benzyl) Ethoxycarbonylamidino) phenyl] pentanoate.

 Yield: 22.85 g

IR (Nujol): 3450. 3300, 1730, 1600, 1250 cm " ¹

 NMR (DMSO-de, δ): 1.16 (3H, t, J = 7.1Hz),

 1.56-1.58 (4H, m), 2.31 (2H, t, J = 6.9Hz).

 2.64 (2H.t, J = 7.0Hz), 4.03 (2H, q, J = 7.lHz).

 5.11 (2H, s), 7.23-7.40 (7H, m),

 7.90 (2H.d 'J = 8.3Hz), 9.23 (2H, br s)

Production Example 2 1

A concentrated hydrochloric acid solution of 5- [4- (N-benzyloxycarbonylamidino) phenyl] pentyl pentanoate (22.00 g) obtained in Production Example 20 was stirred at room temperature for 3 hours. The reaction mixture was filtered and the precipitate was dissolved in an aqueous solution of ethyl acetate. The pH of the solution was adjusted to 10.5 with an aqueous solution of sodium hydroxide. The separated aqueous layer was adjusted to pH 4.50 with 10% hydrochloric acid, extracted with ethyl acetate, and the separated organic layer was washed with saturated saline and then dried over magnesium sulfate. After filtration, remove the filtrate under vacuum After distillation, the precipitate was triturated with diisopropyl ether to obtain 5- [4 (N-benzyloxycarbonylamidino) phenyl] pentanoic acid (12.00 g).

IR (Nujol): 3350, 3200 , 1700, 1660, 1620, 1250 cm "1 anonymous _{(DMS0-d 6, δ)} : 1.50-1.60 (4Η, ra),

 2.23 (2H, t, J = 6.9Hz), 2.64 (2H, t, J = 7.0Hz).

 5.10 (2H.s). 7.27-7.42 (7H, m),

 7.90 (2H, d, J = 8.3Hz) .9.11 (2H, br s),

 12.01 (1H, br s)

 MASS (/ Z): 355 (M ++ 1) EI MASS

Production Example 2 2

 A mixture of p-cyanophenol (20.0 g), t-butyl bromoacetate (29.8 mi) and potassium carbonate (25.5 g) in N, N-dimethylformamide (200 ml The mixture was stirred for 85 minutes at 80-90 ° C. The reaction mixture was allowed to cool to room temperature and extracted with ethyl acetate.The separated organic layer was separated from a saturated aqueous solution of sodium hydrogencarbonate, water and then saturated saline. Washed continually with water, dried over magnesium sulfate and treated with activated charcoal After filtration, the filtrate was distilled under vacuum to give an oily t-butyl 1- (4-cyanopanoxy) acetate (48.1 g) I got

IR (Nujol): 2250, 1750, 1615, 1580, 1515 cm " ¹

 Rise (CDCh. Δ): 1.49 (9Η. S). 4.58 (2H, s),

6.94 (2H, d, J = 8.9Hz), 7.62 (2H, d. J = 8.9Hz) MASS (M / Z): 233 (M ⁺ )

Production example 2 3

Hydrogen sulfide was added to a mixture of t-butyl (10.0 g) acetate (10.0 g) obtained in Production Example 22 and pyridine (130 m ^) and triethylamine (26 m ^) at room temperature. For 8 hours and left overnight. After the reaction mixture was poured into water, the pH was adjusted to 4.2 with a 10% aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The separated organic layer was washed with diluted hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate, water and saturated saline in this order, dried over magnesium sulfate, and treated with activated charcoal. After filtration, vacuum the filtrate Distilled under, 1- (4-thiocarbamoylphenoxy) t-butyl acetate 9.4

5 g) were obtained. '

 IR (Nujol): 3350. 3270, 3150, 1750, 1630, 1600, 1580,

1510 cm " ¹

 N R (DMSO-ds.δ): 1.43 (9Η, s), 4,74 (2H, s),

 6.92 (2H, d, J = 8.9Hz), 7.93 (2H, d, J = 8.9Hz) 9.35 (1H, br s), 9.68 (1H, br s)

Production Example 24

 Mixture of t-butyl 1- (4-thiocarbamoylphenoxy) acetate (8.36 g), methyl iodide (2.14m ^) and acetone (30 Om ^) obtained in Production Example 23 Was stirred and perfused for 17 hours. The reaction mixture was allowed to cool to room temperature and distilled under vacuum. Ammonium acetate (3.62 g) and methanol (30 Om ^) were added to the obtained mixture, and the mixture was perfused with stirring for 6.5 hours. The reaction mixture was allowed to cool to room temperature, distilled under vacuum, the precipitate was washed with diisopropyl ether, and t-butyl- (4-amidinophenoxy) hydrochloride (10. 1 2 g) was obtained.

 Hidden (DMSO-de, δ): 1.44 (9Η, s), 4.84 (2H, s),

 7.15 (2H, d, J = 8.9Hz), 7.80 (2H, d, J = 8.9Hz) 8.98 (4H, br s),

MASS (M / Z): 251 (M ⁺ +1) free

Production Example 25

Sodium methoxide (0.07) was added to the mixture of t-butyl (1-amidinophenoxy) acetate (0.50 g) and methylene chloride (1 Om ^) obtained in Production Example 24. g) was added at room temperature, and the mixture was stirred at room temperature for 50 minutes. Triethylamine (0.86m ^) and benzyloxycarbonyl chloride (0.88m £) were added to the obtained reaction mixture, and the mixture was stirred at room temperature for 17 hours. The reaction mixture was poured into an aqueous methylene chloride solution, and the separated organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, water, and a saturated saline solution, and dried over magnesium sulfate. After filtration, the filtrate is Distilled. Anisole (0.5m ^) and trifluoroacetic acid (2m) were added to the resulting mixture while cooling with ice, and the mixture was stirred at room temperature for 50 minutes. The reaction mixture was poured into an aqueous solution of ethyl acetate, and the pH was adjusted to 11 with a 4N aqueous sodium hydroxide solution. The separated aqueous layer was extracted with ethyl acetate, adjusted to pH 3.5 with a 10% aqueous hydrochloric acid solution, and extracted with a mixture of methanol and chloroform. The separated organic layer was dried with magnesium sulfate. After filtration, the filtrate was distilled under vacuum, and the resulting mixture was triturated with diisopropyl ether to obtain 1.1- (4-benzyloxycarbonylamidinofenoxy) acetic acid (0.34 g).

 IR (Nujol): 3450, 3300, 1660. 1600, 1570,

1500 cm " ¹

 NMR (DMSO-de, δ): 4.14 (2Η.s), 5.09 (2H, s),

 6.81 (2H, d, J = 8.9Hz), 7.2-7.5 (5H.m),

 7.93 (2H, d, J = 8.9Hz), 9.19 (2H, br s).

Production Example 26

 Oc, N-dimethylformamide of Boc-Val-OH (3.00 g), morpholine (1.20 mί) and 1-hydroxyl 1Η-benzotriazole (2.11 g) To the solution was added 11- (3-dimethylaminopropyl) -13-ethylcarbodiimide (2.52m) at 0 ° C and mixed at room temperature for 6 hours. The reaction mixture was poured into an aqueous solution of ethyl acetate and adjusted to pH10 with a saturated aqueous solution of potassium carbonate. The separated organic layer was washed with a 0.5 N aqueous solution of hydrochloride, then with a saturated aqueous solution of sodium hydrogen carbonate, water, and saturated saline, and dried over magnesium sulfate. After filtration, the filtrate was distilled under vacuum to obtain the compound shown in Table 1 (4.04 g).

 NMR (DMSO-de, δ: 0.83 (6Η, d, J = 6.7Hz), 1.37 (9H.s),

 1.87-1.94 (1H, m), 3.43-3.56 (8H, m)

 4.08-4.20 (1H, m). 6.83 (1H, d, J = 8.7Hz)

Production Example 27

To the compound of Production Example 26 (4.00 g) was added 4N hydrogen chloride solution of 1,4-dioxane (16 mi) at 0, and the mixture was stirred at room temperature for 3 hours. The reaction mixture under vacuum After distillation, the resulting mixture was washed with n-hexane to obtain the compounds shown in Table 1 (3.01 g).

 Hidden (DMSO-de, 5): 0.92 (3H, d. J = 6.9Hz),

 0.98 (3H, d J = 6.9Hz), 1.96-2.09 (1H, m).

 3.41-3.67 (8H.m), 4.23 (1H, m),

 8.28 (3H, br s)

Production Example 28

 In the same manner as in Production Example 26, the compound shown in Table 1 was obtained from the compound of Production Example 27 (2.9 g) and Boc-Asp (OBzl) -0H by (4.21 g).

 Yield: 5.91 g

 Hidden (DMSO-de, δ): 0.81 (3Η, d, J = 6.6Hz),

 0.84 (3H, d. J = 6.5Hz), 1.38 (9H, s),

 1.90-1.99 (1H, m), 2.58-2.85 (2H, m).

 3.47-3.53 (8H, m), 4.29-4.40 (1H, m)

 4.53-4.61 (1H, m), 5.09 (2H, s),

 7.31-7.36 (6H, m), 7.69 (1H, d, J = 8.8Hz)

Production Example 29

 In the same manner as in Production Example 27, the compounds shown in Table 1 were obtained from the compound of Production Example 28 (5.70 g).

 Yield: 5.15 g

 NMR (DMSO-de, δ): 0.88 (6H, d, J = 6.6Hz),

 1.94-2.04 (1H, m), 2.91-2.95 (2H, m),

 3.46-3.57 (8H, m), 4.25 (1H, m),

 4.57 (1H, m), 5.14 (2H, s),

 7.34-7.41 (5H, m), 8.55 (3H, br s),

 8.70 (1H, d, J = 8.5Hz)

 Table 1 shows the formulas of the compounds obtained in Production Examples 26 to 29.

Further, Table 2 shows the formulas of the starting compound and the target compound in Example 133. You. ,

In the formula, Am (z) is N-benzyloxycarbonylamidino, Ara is amidino, Asp is L-aspartic acid, Val is L-valine, Sar is sarcosine, Leu is-mouth is Bzl Is benzyl,] Pro is isopropyl, ^T Bu is t-butyl, lie is L-isoleucine, Tyr is L-tyrosine, Ala is L-alanine, and TFA is trifluoroacetic acid.

Production Example 26

 Compound Boc-Val-N 0

Production Example 27

Compound HClHVal-N 0

Production Example 28

Compound Boc-Asp (0Bzl) -Val-N 0

Production Example 2

Compound HCl-HAsp (0Bz1) -Val-N 0

Table 2

荬 Example 1

Starting compound (la) HCl. H- -Asp (0Bzl) -Val-NH ₂ Preparation example 14 Compound of Am (ZH ^ O> ~ ⁰ "f ^CH2 ^ ~ ^{C00H Target} compound (1) .0-iCti fr C0 -Asp (0Bzl) -Val-NH ₂

Example 2

Starting compound (2 a) HCl-H- ■ Asp (0Bzl) Val-NH-'Pro Preparation Example 14

Target compound (2) Am (Z) / 0 0-fCH ₂ i-5- CO-Asp (OBzl) -Val -NH- ¹ Pro

Example 3

Starting compound (3 a) HCl · H- Asp (0Bz1) Val-N (CH ₂ JzOCHa

 H

Production Example 14 Compound of Am (Z), O) ~ 0 ~ fCH ₂ T ~ C00H Target compound (3)

^{Am (Z) -) 0 -fCHai} - C0-Asp (0Bzl) -Val-NH (CH 2) 2 0CH 3 Example 4

Starting compound (4 a) HCl. H-Asp (0Bzl) -Tyr (CH ₃ ) -NH- (CH ₂ ) ₂ -0C ₂ H ₅ Preparation example 14 Compound Am (Z)-

Compound of Production Example 14

Target compound (8) Am (Z)-O -0-fCH2-C0-Asp (OBzl) -Val-N

 \ / ヽ — /, Example 9

Starting compound (9a) HCl · H-Asp (0Bz1) -Va1-N- ^T Bu Preparation Example 14

Target compound (9)

Am (Z)-(O ⁰ `` f H ₂ --C0-Asp (0Bzl) -Val-N- ^T Bu

 \ / H Example 10

The starting compound (1 0 a) HCl · H -Asp (0Bzl) -Val-N-CH 2 -C (CH 3) 3

 H

Compound of Production Example 14

The object compound (1 0) C0-Asp ( 0Bzl) -Va1-NH CH 2 -C (CH 3)

Example 1 1

The starting compound (1 1 a) HCl · H -Sar-Asp (0Bzl) -Tyr (CH 3) -NH 2 compound Am (Z) -CQ Production Example 2 5) -0-CH2-C00H object compound (1 1 )

Am (Z) ~ O) ~ 0-CH ₂ -C0-Sar-Asp (0Bzl) -Tyr (CH ₃ ) -NH ₂ Example 1 2

The starting compound (1 2 a) HCl - H -Ala-Asp (0Bzl) -Tyr (CH 3) -NH 2

Example l 8

Starting compound (18)

Am (Z))-0 -fCH ₂ -r- C0-Asp (0Bzl) -Va1-NH Target compound (18) Am-O o-fCHz- -CO-Asp-Val- H / <-TFA Example 1 9

Starting compound (19)

Am (Z))-0 -fCH ₂ -b- C0-Asp (0Bz1) -Val-NH

Target compound (19)

· TFA

Example 20

Starting compound (20)

_{0-fCH 2 - - C0-} Asp (OBzl) -Tyr (CH 3) -NH

Target compound (20)

Am O> ~ 0- CH2 C0_Asp- Tyr (CH ₃ )-NH / \ ^ 0 Η ₅ -TFA Example 2 1

Starting compound (2 1)

Am (Z))-0-CHz r- CO-Asp (OBzl) -Tyr (CH ₃ ) -NH ₂ Target compound (2 1) Am)-0-(CHa ^ T- CO-Asp-Tyr (CH ₃ ) -NH ₂ · HCl example 2 2

Starting compound (2 2)

Am (Z))-0 -fCH ₂ -tr- CO-Asp (OBzl) -Asp (0Bzl) -NH ₂ Target compound (2 2) 0 -fCH ₂ ^ r-C0-Asp-Asp-NH ₂ -TFA Example 23 (By-product of Example 22)

 丫 Rem () Am () 0 -f CH2- r-CO-Asp-Asp-OH · TFA Example 24

 Starting compound (24)

Am (Z)-() -0-CH ₂ -C0-Sar-Asp (0B2l) -Tyr (CH ₃ ) -NH ₂ target compound (24)

Am base 0-CH ₂ -C0-Sar-Asp-Tyr (CH ₃ ) -NH ₂ -TFA Example 25

Starting compound (25)

Am (Z) → (〇 0-CH ₂ -C0-Ala-Asp (0Bzl) -Tyr (CH ₃ ) -NH _; target compound (25)

Am base 0-CH ₂ -CO-Ala-Asp-Tyr (CH ₃ )-NH ₂ -TFA Example 26 (By-product of Example 25)

Compound _{Am - (0-CH 2 -C0} -Ala-Asp-Tyr (CH 3) -0H - TFA Example 2 7

Production Example 13 Compound of Am (Z) 0-CH ₂ -r- C00H Starting compound (27 a) HC1-H-Asp- (0Bz1) -Va1-N 0 Target compound (27 a) ΑΠΙ (Ζ) ^{Η (OV 0 -i c H2- †} r- CO-Asp (OBzl) -Va1-N 0 target compound (2 7 b) Am Baie 〇 0 ~ (CHr † C0-Asp_Va Bok N 0 - TFA Example 28

Compound Am of Preparation 1 5 (Z) - (Q -0-fCH 2 i-C00H starting compound (28 a) HCl · H- Asp (0Bzl) -Val-N 0

\ I Target compound (28 a) Am (Z) ~ 〇 ~ 0 "tCH ₂ i" C0-Asp (0Bzl) -Va NJ) Target compound (28 b) _Am .TFA

Example 29

Compound of Production Example 14

Starting compound (2 9 a) HCl-H- -Asp (0Bzl) -Leu-N 0 Target compound (2 9 a) "CH b" C0_Asp (0Bzl) -Sh eu -N 0

Target compound (29b)

 "·” Person 0 -fCHar-CO-Asp-Leu-N 0 Example 30

Production Example 14 Compound of Am (ZH Starting Compound (30 a) HClH-Asp (0Bz1) -Ile-N 0 Target Compound (30a) Am (Z) CO-Asp (OBzl) -Ile-N 0

The object compound (3 0 b) 0- (CH 2 i ^ C0-Asp-Ile-N 0 - TFA Example 3 1

Production Example 21 Compound Am (Z) fCH ₂ 1r- C00H Starting compound (3 la) HCl. H-Asp (0Bz1) -Val-N 0

Θ曰ό tiίι 1 Rejimu sweet i IW¾nJ * 3 1丄ao Ri AtniZ) - (^)) - "tCH 2 -h- C0-ASD (0BZ1) -Val-N 0

Target compound (3 1b) Am ~ ^ 〇 ~ CH ₂ "CO-Asp-Va to N 0 Example 32

Compound Am of Preparation 1 4 (Z) - o> -. 0 ~ fCH 2 T- C00H starting compound (3 2 a) HCl H- Asp (0Bzl) -Val-N S0 2 The object compound (32 a)

Am (Z) - QV- 0 - (CH 2 - CO-Asp (OBzl) -Val-N S0 2

The object compound (32 b) Am CO-Asp -Val-N S0 2 · TFA

Example 3 3

Preparation Example 14 Compound of Am (Z) Yn 0 -fCH ₂ r- C00H Starting compound (33 a) HCl. H-Asp (0Bzl) -Val-N N-CH3 Target compound (33 a)

Am (Z) -IO ⁰ -fCH ₂ ir C0-Asp (0Bzl) -Va1- N-CH3

Target compound (33b)

Am-(O-0 -fCH ₂ ii- CO-Asp-Val-N N-CH3 2TFA Example 1,

 The starting compound (la) (2.0 g), the 4- (4- (N-benzyloxycarbonylamidino) phenoxy] butyric acid (1.99 g) obtained in Production Example 14 and 1. Hydroxy- 1 H-benzotriazole (0.86 £) in 1 ^ !, N-dimethylformamide (2Om ^) solution, 1- (3-dimethylaminopropyl) -13-ethyl Carbodimid (1.02m) was added at -20 ° C and stirred at room temperature for 3 hours. The reaction mixture was poured into an aqueous solution of ethyl acetate, and the pH was adjusted to 10.5 with a saturated aqueous solution of carbon dioxide lime. The obtained precipitate was filtered to obtain the desired compound (1) (2.45 g).

IR (Nujol): 3400, 3270, 1730, 1630, 1250 cm " ¹

NR (D S0-d ₆ , δ): 0.77 (3Η, d, J = 6.8Hz),

 0.81 (3H.d, J = 6.8Hz), 1.91-2.01 (3H.m),

 2.29 (2H, t, J = 7.2Hz), 2.56-2.89 (2H, m),

 4.00-4.14 (3H, m), 4.67-4.79 (1H, m) .5.07 (2H, s), 5.10 (2H.s), 6.99 (2H, d, J = 8.9Hz), 7.10 (1H, s) ,

 7.29-7.41 (11H.m), 7.57 (1H, d, J = 9.0Hz).

 7.98 (2H, d, J = 8.9Hz), 8.39 (1H, d, J = 7.9Hz), 9.10 (2H, br s)

MASS (M / Z): 660 (M + + 1) FAB MASS

Example 2

 In the same manner as in Example 1, the target compound (2) was obtained from the starting compound (2a) (3.20 g) and the compound of Production Example 14 (2.85 g).

 Yield: 2.30 g

IR (Nujol): 3300, 1740. 1630, 1250 cm " ¹

 NMR (DMSO-de, δ): 0.77 (3H, d, J = 6.4Hz),

 0.79 (3H, d, J = 6.4Hz), 1.01 (3H.d, J = 6.5Hz), 1.04 (3H.d, J = 6.5Hz), 1.85-1.98 (3H, m),

2.29 (2H, t.J = 7.0Hz), 2.56-2.93 (2H, m). 3.77-3.84 (1H, m), 4.01-4.11 (3H.m),

 4.66-4.73 (1H, m), 5.07 (2H, s),

 5.10 (2H, s), 6.99 (2H, d, J = 8.9Hz),

 7.31-7.40 (10H, ra), 7.59 (1H, d, J = 9.0Hz), 7.81 (1H, d, J = 7.6Hz), 7.99 (2H, d, J = 8.9Hz),

 8.40 (1H, d, J = 7.9Hz), 9.13 (2H, br s)

MASS (M / Z): 702 (M + + 1) FAB MASS

Example 3

 In the same manner as in Example 1, the target compound (3) was obtained from the starting compound (3a) (2.5 O g) and the compound of Production Example 14 (2.14 g).

 Yield: 4.62 g

IR (Nujol): 3250, 1720, 1630, 1250 cm " ¹

 NlilR (D SO-de, δ) ： 0.79 (3Η, d, J = 6.8Hz),

 0.81 (3H, d, J = 6.8Hz), 1.94-1.99 (3H, m),

 2.30 (2H, m), 2.64-2.94 (2H, m), 3.16-3.31 (4H, m), 3.46 (3H, s), 4.05 (2H, t, J = 6.5Hz),

 4.11-4.19 (1H, m) .4.72-4.76 (1H, m), 5.08 (2H, s), 5.12 (2H, s) .7.01 (2H, d, J = 8.9Hz).

 7.35-7.39 (10H, m), 7.70 (1H, d, J = 8.8Hz), 8.02-8.12 (3H, m). 8.52 (1H, d, J = 7.8Hz),

 9.19 (2H, br s)

MASS (M / Z): 718 (M + + 1) FAB MASS

Example 4

 In the same manner as in Example 1, the target compound (4) was obtained from the starting compound (4a) (2.54 g) and the compound of Production Example 14 (1.8 g).

 Yield: 3.7 g

 mp: 126-130 ° C

IR (Nujol): 3250, 1715, 1640-1600 (broad) cm " ¹ NMR (DMSO-de.δ): 1.09 (3H. T. J = 7Hz). 1.94-2.02 ^ (2H, m), 2.24-2.31 (2H, m), 2.63-2.96 (4H, m),

 3.10-3.5 (6H, m), 3.79 (3H, s), 4.03 (2H, m),

 4.40 (1H, m). 4.65 (1H, m), 5.12 (2H, s),

 5.21 (2H, s), 6.79 (2H, d, J = 8.8Hz),

 7.02 (2H, d, J = 8.8Hz). 7.10 (2H, d, J = 8.8Hz), 7.35-7.53 (10H, m), 7.85 (1H.d, J = 8Hz),

 8.01 (2H, d, J = 8.8Hz), 8.29 (1H, d, J = 7.9Hz), 9.13 (1H, m)

Example 5

 5- [4- (N-benzyloxycarbonylamidino) phenoxy] obtained in Production Example 13 Valeric acid (1 g), starting compound (5a) (1.18 g) and 1-hydroxy To a solution of xy-1H-benzotriazole (0.41 g) in N, N-dimethylformamide (10 m) was added 1- (3-dimethylaminopropyl) -13-ethylcarbodiimide (0. 49m ^) and stirred at room temperature for 3 hours.

 The reaction mixture was poured into water (100 m_ί), and ρΗ was adjusted to 10 with a 4% aqueous sodium hydroxide solution. The resulting precipitate was collected by filtration, washed with water, and dried under pressure to obtain the target compound (5) (1.55 g).

 Melting point: 152 ° C (dec.)

IR (Nujol): 3270, 1720, 1635, 1600 cm- ¹

 NMR (DMSO-de, 5): 1.51-1,8 (4H, m), 2.13 (2H, t like), 2.5-3.0 (4H.m). 3.68 (3H, s), 4.01 (2H, t like) ),

 4.34 (1H, m), 4.64 (1H, m), 5.06 (2H, s),

 5.1 (2H, s), 6.79 (2H.d, J = 8.6Hz),

 6.99 (2H, d.J = 8.9Hz), 7.09 (2H, d, J = 8.6Hz).

7.1 (1H, s), 7.24-7.51 (12H, m). 7.79 (1H, d, J = 8.lHz), 7.98 (2H, d, J = 8.8Hz), 8.20 (1H, d, J = 7.9 Hz), 9.12 (1H, br) Example 6,

 In the same manner as in Example 5, the target compound (6) was obtained from the starting compound (6a) (0.75 g) and the compound of Production Example 13 (0.60 g).

 Yield: 1.08 g

Melting point: 119-125 ^e C (decorap.)

IR (Nujol): 3250 (br), 1720, 1610 cm " ¹

 N R (D SO-de.δ): 1.67 (4H, brs), 2.17 (2H, brs),

 2.5-3.1 (4H, m) .4.0 (2H, m), 4.60 (2H, m), 5.07 (2H, s), 5.08 (2H.s), 5.10 (2H, s),

 6.98 (2H, d, J = 8.8Hz), 7.1-7.5 (17H, m),

 7.98 (2H, d, J = 8.8Hz), 8.22 (1H, d, J = 8.3Hz).

 8.28 (1H, d, J = 7.7Hz)

Example 7

 Starting compound (7a) (2.50 g), 4- (N-benzyloxycarbonylamidino) phenoxy] butyric acid (2.08 g) and 1-hydroxy-1H-benzotriazole (0. In a solution of 9 ^) in 1 ^, N-dimethylformamide (2Om ^), 120. C was added with 11- (3-dimethylaminopropyl) -3-ethylcarboimide (1.07 m ^), and the mixture was stirred at room temperature for 3 hours.

 The reaction mixture was poured into an aqueous solution of ethyl acetate, and the pH was adjusted to 10.5 with a saturated aqueous solution of carbonated lime. The separated organic layer was washed with water and a saturated saline solution, and dried with magnesium sulfate. After filtration, the filtrate was distilled under vacuum to obtain the target compound (7).

 Oki (D SO-de, δ: 0.78 (3Η, d, J = 6.7Hz),

 0.81 (3H, d, J = 6.7Hz), 1.94-1.99 (3H, m),

 2.28 (2H, t.J = 7.2Hz), 2.54-2.88 (2H, m),

 3.46-3.51 (8H, m), 3.98-4.07 (2H, m), 4.53 (1H, m), 4.69 (1H, m), 5.07 (2H, s), 5.10 (2H, s),

 6.95 (2H, d, J = 8.9Hz), 7.28-7.40 (10H, m),

 7.84 (1H, d, J = 8.7Hz), 7.98 (2H.d.J = 8.9Hz).

4 g 8.35 (1H.d, J = 7.9Hz), 9,15 (2H, br s)

MASS (M / Z): 730 (M + + 1) FAB MASS

Example 8

 In the same manner as in Example 7, the target compound (8) was obtained from the starting compound (8a) (4.00 g) and the compound of Production Example 14 (3.35 g).

 Yield: 5.80 g

IR (Nujol): 3300, 1740, 1620, 1250 cm ' ¹

 N R (D SO-de, δ) ： 0.79 (3Η, d, J = 6.9Hz),

 0.82 (3H, d, J = 6.9Hz), 1.42-1.53 (6H, m), 1.86-2.08 (3H, m), 2.33 (2H, t, J = 6.9Hz), 2.59-2.94 (2H, m) . 3.41-3.43 (4H, m),

 4.06 (2H, t, J = 6.1Hz), 4.61 (1H.m), 4.75 (1H, m),

 5.08 (2H, s) .5.12 (2H, s) .7.01 (2H, d, J = 8.9Hz),

 7.31-7.44 (10H, m), 7.77 (1H, d, J = 8.8Hz).

 8.03 (2H, d, J = 8.9Hz), 8.40 (1H, d, J = 8.4Hz),

 9.18 (2H, br s)

MASS (M / Z): 728 ( ⁺ + 1) FAB MASS

Example 9

 In the same manner as in Example 7, the target compound (9) was obtained from the starting compound (9a) (3.50 g) and the compound of Production Example 14 (3.01 g).

 Yield: 5.69 g

IR (Nujol): 3300, 1740, 1640, 1250 cm " ¹

 NMR (DMSO-de, δ): 0.79 (3H, d, J = 6.9Hz).

 0.82 (3H, d, J = 6.9Hz), 1.26 (9H, s),

 1.88-2.02 (3H, m), 2.33 (1H, t, J = 6.9Hz),

 2.60-2.95 (2H, m), 4.06 (2H, t, J = 6.lHz).

4.08-4.19 C1H, m), 4.70-4.81 (1H, m), 5.09 (2H, s), 5.13 (2H, s), 7.01 (2H, d, J = 8.9Hz), 7.29-7.44 (10H, m), 7.56-7.59 (2H, m), _r

 8.03 (2H.d, J = 8.9Hz), 8.45 (1H, d, J = 8.1Hz),

 9.16 (2H, br s)

MASS (/ Z): 716 ( M + + 1) FAB MASS

Example 10

 In the same manner as in Example 7, the target compound (10) was obtained from the starting compound (10a) (1.7 Og) and the compound of Production Example 14 (1.42 g).

 Yield: 2.70 g

_{NMR (DMS0-d 6, δ} ): 0.82 (. 15H m), 1.91-1.97 (3H, m).

 2.29 (2H, t, J = 7.2Hz), 2.63-3.00 (4H, m),

 4.04 (2H.t, J = 6.2Hz), 4.20-4.24 (1H, m),

 4.67-4.78 (1H, m) .5.07 (2H, s). 5.10 (2H.s),

 6.99 (2H, d, J = 8.9Hz), 7.34-7.47 (10H, m), 7.65 (1H, d, J-8.9Hz), 7.82 (1H, t, J = 6.2Hz), 7.99 (2H, d , J = 8.9Hz). 8.39 (1H, d, J = 7.9Hz), 9.08 (2H, br s)

MASS (M / Z): 730 (M + + 1) FAB MASS

Example 1 1

 2- [4- (N-benzyloxycarbonylamidino) phenoxy] acetic acid (0.73 g) obtained in Production Example 25, starting compound (11a) (1.2 g) and 1-hydroxy To the solution of 1 H-benzotriazole (0.34 g) in ON, N-dimethylformamide (15 m £) solution, add 1- (3-dimethylaminopropyl) -13-ethylethyl carboximidide (0.4 lm ^) was added and the mixture was stirred at room temperature for 5 hours and 15 minutes.

 The reaction mixture was poured into an aqueous solution of ethyl acetate, and the pH was adjusted to 10 with a saturated aqueous solution of carbonated lime. The precipitate was collected by filtration, washed with a saturated aqueous solution of sodium hydroxide, then with water ^, and dried under pressure to obtain the target compound (11) (4 Og).

Melting point: 127-130 ° C IR (Nujol): 3260, 1650, 1610, 1500 cm— ¹ ,

 NMR (DMSO-de.δ): 2.4-3.2 (7H.m). 3.69 (3H, s),

 3.9-4.2 (2H, m), 4.35 (1H, m), 4.63 (1H, m),

4.8- 5.2 (6H.m), 6.79 (2H, d, J = 7.1Hz),

 6.9- 7.2 (4H.m), 7.2-7.4 (12H, m),

 7.96 (2H, d, J = 8.8Hz)

Example 1 2

 In the same manner as in Example 11, the target compound (12) was obtained from the starting compound (12a) (1.33 g) and the compound of Production Example 12 (0.81 g).

 Melting point: 112-114'C

IR (Nujol): 3250 '1720, 1630, 1590 cm " ¹

_{NMR (DMS0-d 6 δ.} ):. 1.28 (3H, d, J = 7.0Hz) 2.3-3.4 (4H, m),

 3.70 (3H, s). 4.2-4.8 (7H, m), 5.10 (2H, s), 6.79 (2H, d, J = 8.5Hz), 7.06 (4H, m), 7.1-7.5 (12H.m) , 7.99 (2H, d, J = 8.8Hz), 8.36 (1H, m), 8.76 (1H, br s), 9.14 (1H, br s)

Example 13

 Starting compound (13) (compound obtained in Example 7) (1.00 g), 11 ^ hydrochloric acid (1.61 m ^) of l O ^ P dZ C (0.60) and tetrahydrofuran ( 20m ^) was stirred at room temperature under a hydrogen gas atmosphere for 3 hours. After filtration, the filtrate was distilled under vacuum and purified by preparative HPLC to obtain the desired compound (13).

 HPLC conditions

 Column: Y C-PACK R-ODS-15 S-15 120A0DS

 500 X250 recitation

Eluent: 19% CH ₃ CN in 0.1% TFA aqueous solution

 Flow rate: 118 ml / min

 Retention time: 9.55 minutes

Melting point: 174- 176 ^e C IR (Nujol): 3320, 1670, 1610, 1270. 1190 cm " ¹ ,

 NMR (D SO-de. Δ: 0.78 (3H, d, J = 6.9Hz),

 0.81 (3H, d, J = 6.9Hz), 1.92-1.99 (3H, m), 2.30 (2H, t, J = 7.2Hz), 2.63-2.74 (2H, m), 3.79 (8H, m), 4.10 (2H, t, J = 6.4Hz).

 4.49-4.60 (2H, m), 7.14 (2H, d, J = 8.9Hz), 7.74-7.83 (3H, m), 8.32 (1H, d, J = 7.9Hz),

 8.97 (2H, s), 9.14 (2H, s)

MASS (/ Z): 506 ( M + + 1) free FAB MASS

Example 14

 In the same manner as in Example 13, the target compound (14) was obtained from the starting compound (14) (the compound of Example 8) (5.0 g).

 Yield: 3.06 g

 HPLC conditions

 Column: Amazing-PACK R-ODS-15 S-15 120A0DS

 500 X250 door

Eluent: 25% CH ₃ CN in 0.1¾ TFA aqueous solution

 Flow rate: 118 ml / min

 Retention time: 6.79 minutes

 Melting point: 153-156 ° C

IR (Nujol): 3350, 3100, 1660, 1200 cm " ¹

_{NMR (DMS0-d 6 δ.} ): 0.76 (3H, d, J = 6.9Hz),

 0.81 (3H, d, J = 6.9Hz), 1.38-1.72 (6H, m),

 1.85-2.01 (3H, m), 2.32 (2H, t, J = 6.9Hz), 2.42-2.54 (2H, m), 3.43 (4H, m),

 4.11 (2H, t, J = 6.3Hz). 4.54-4.65 (2H, m), 7.15 (2H, d, J = 8.9Hz), 7.65 (1H, d, J = 8.8Hz),

7.82 (2H, d, J = 8.9Hz). 8.35 (1H, d, J = 7.9Hz), 9.16 (2H, s), 9.18 (2H, s)

MASS (M / Z): 504 (+ + 1) free FAB MASS

Example 15

 In the same manner as in Example 13, the target compound (15) was obtained from the starting compound (15) (the compound of Example 1) (2.40 g).

 Yield: 0.78 g

 HPLC conditions

 Column: YMC-PACK R-ODS-15 S-15 120A0DS

 500 X250 mm

Eluent: 17% CH ₃ CN in 0.1% TFA aqueous solution

 Flow rate: 118 ml / min

 Retention time: 6.30 minutes

 Melting point: 211-212 ° C

IR (Nujol): 3250, 1700, 1640, 1270, 1200 cm " ¹

_{NMR (DMS0-d 6, δ} ): 0.78 (3Η, d, J = 6.8Hz),

 0.81 (3H.d, J = 6.8Hz), 1.96 (3H, m),

 2.30 (2H, m), 2.50-2.75 (2H, m),

 4.09-4.13 (3H, m), 4.61 (1H.m),

 7.12-7.17 (3H, m). 7.38 (1H, s),

 7.51 (1H, d.J = 9.0Hz), 7.81 (2H, d.J = 8.9Hz), 8.35 (1H, d, J = 7.6Hz), 9.06 (2H, s),

 9.13 (2H, s), 12.35 (1H, s)

 MASS (M / Z): 436 (M ++ 1) free FAB MASS

Example 16

 In the same manner as in Example 13, the target compound (16) was obtained from the starting compound (16) (the compound of Example 2) (2.80 g).

 Yield: 1.67 g

HPLC conditions Column: YMC-PACK R-ODS-15 S-15 120A0DS _r

 500 X250 mm

 Eluent: 22% CHsCN in 0.1% TFA aqueous solution

 Flow rate: 118 ml / min

 Retention time: 5.94 minutes

 Melting point: 204-206 ° C

IR (Nujol): 3400, 3100, 1670. 1640, 1200 cm— ¹

 NMR (DMSO-de, δ: 0.77 (2Η, d, J = 6. Hz),

 0.80 (2H, d, J = 6.4Hz), 1.02 (2H, d, J = 6.5Hz).

 1.04 (2H, d, J = 6.5Hz), 1.86-2.00 (3H, m),

 2.31 (2H, t, J = 7,0Hz), 2.42-2.78 (2H, m),

 3.74-3.90 (1H, m), 4.03-4.14 (3H, m),

 4.56-4.66 (1H, m), 7.15 (2H, d, J = 8.9Hz),

 7.51 (1H, d, J = 9.0Hz), 7.76-7.84 (3H, m).

 8.36 (1H, d, J = 7.8Hz), 9.11 (2H, s),

 9.15 (2H, s)

MASS (M / Z): 478 (M + + 1) free FAB MASS

Example 17

 In the same manner as in Example 13, the target compound (17) was obtained from the starting compound (17) (the compound of Example 9) (5.50 g).

 Yield: 3.02 g

 HPCL conditions

 Column: YMC-PACK R-ODS-15 S-15 120A0DS

 500 X250 mm

Eluent: 25% CH ₃ CN in 0.1% TFA aqueous solution

 Flow rate: 118 ml / min

 Retention time: 6.95 minutes

Melting point: 210-213 ^e C IR (Nujol): 3350, 3100, 1670, 1200 cm " ¹ ,

 NMR (DMSO-de, <5): 0.77 (3H, d, J = 6.9Hz),

 0.80 (3H, d, J = 6.9Hz), 1.24 (9H, s),

 1.86-2.01 (3H, m), 2.32 (2H.t, J = 6.9Hz),

 2.43-2.79 (2H, m), 4.11-4.14 (3H, m),

 4.56-4.66 (1H, m), 7.15 (2H, d. J = 8.9Hz), 7.43-7.51 (2H, m), 7.83 (2H, d, J = 8.9Hz),

 8.40 (1H, d, J = 7.7Hz), 9.16 (2H, s).

 9.24 (2H.s)

MASS (M / Z): 492 (M + + 1) free FAB MASS

Example 18

 In the same manner as in Example 13, the target compound (18) was obtained from the starting compound (18) (the compound of Example 10) (200 g).

 Yield: 1.11 g

 HPLC conditions

 Column: YMC-PACK R-ODS-15 S-15 120A0DS

 500 X250 Yield

Eluent: 32% CH ₃ CN in 0.1% TFA aqueous solution

 Flow rate: 118 ml / min

 Retention time: 5.34 minutes

 Melting point: 183-186 ° C

IR (Nujol): 3300. 3100. 1670, 1650, 1270, 1200 cm " ¹ NMR (D S0-d _6. δ): 0.83 (15H, m). 1.94-2.00 (3H, m), 2.31 (2H, t, J = 7.1Hz), 2.45-3.04 (4H.m), 4.10 (2H, t, J = 6.3Hz) .4.16-4.23 (1H, m), 4.56-4.63 (1H, m), 7.14 (2H , d, J = 8.9Hz), 7.57 (1H, d.J = 8.9Hz), 7.81 (3H, m).

8.36 (1H, d, J = 7.8Hz), 9.04 (2H, s). 9.14 (2H.s),

MASS (M / Z): 506 (+ + 1) free FAB MASS

Example 19

 In the same manner as in Example 13, the target compound (19) was obtained from the starting compound (19) (the compound of Example 3) (4.30 g).

 Yield: 2.65 g

 HPLC conditions

 Column: YMC-PACK R-ODS-15 S-15 120A0DS

 500 X250 mm

Eluent: 19% CH ₃ CN in 0.1% TFA aqueous solution

 Flow rate: 118 ml / min

 Retention time: 5.98 minutes

 Melting point: 203-205

IR (Nujol): 3400, 3100, 1680, 1280, 1200 cm " ¹

 NMR (DMSO-de, δ): 0.77 (3Η, d, J = 6.8Hz),

 0.81 (3H, d, J = 6.8Hz), 1.88-2.01 (3H, m),

 2.32 (2H.t, J = 7.2Hz), 2.56-2.78 (2H, m),

 3.16-3.57 (4H, m). 3.83 (3H, s), 4.08-4.15 (3H, m),

 4.57-4.68 (1H, m), 7.14 (2H, d, J = 8.9Hz),

 7.58 (1H, d, J = 8.8Hz), 7.82 (2H, d, J = 8.9Hz), 8.05 (1H, m), 8.39 (1H, d, J = 7.8Hz),

 9.12 (2H, s), 9.18 (2H, s)

MASS (M / Z): 494 (M + + 1) free FAB MASS

Example 20

 In the same manner as in Example 13, the target compound (20) was obtained from the starting compound (20) (the compound of Example 4) (3.35 g).

 Yield: 1.66 g

HPLC conditions Column: YMC-PACK R-ODS-15 S-15 120A0DS,

 500 250 votes

 Eluent: 0.1% TFA aqueous solution, 28% CHsCN

 Flow rate: 118 ml / min

 Retention time: 5.90 minutes

 Melting point: 222-223 ° C

IR (Nujol): 3300, 1670, 1640, 1270, 1210 cm ' ¹

 NMR (DMSO-de, δ): 1.10 (3Η, t, J = 7. OHz),

 1.92-1.98 (2H, m), 2.27 C2H, t, J = 7.1Hz),

 2.63-2.90 (2H, m), 3.12-3.46 (8H, m), 3.69 (3H, s).

 4.08 (2H, t, J = 6.5Hz), 4.37 (1H, m), 4.54 (1H, m),

 6.79 (2H, d.J = 8.6Hz), 7.08 (2H, d, J = 8.9Hz),

7.14 (2H, d, J = 8.9Hz), 7.74-7.85 (3H, m).

 7.94 (1H, t, J = 5.5Hz). 8.24 (1H.d, J = 7.7Hz).

 9.15 (2H, s), 9.17 (2H, s), 12.38 (1H, s)

MASS (M / Z): 586 (M + + 1) free FAB MASS

Example 2 1

 In the same manner as in Example 13, the target compound (21) was obtained from the starting compound (21) (the compound of Example 5) (1.5 g).

 Yield: 462 mg

 Melting point: 182-184 ° C (dec.)

IR (Nujol): 3275, 1635. 1600, 1505 cm " ¹

 NMR (DMSO-de, δ): 1.54-1.8 (4H, m), 2.15 (2H, t like), 2.3-3.04 (4H, m). 3.69 (3H, s), 4.07 (2H, t like).

 4.31 (1H.m), 4.55 (1H, in), 6.78 (2H, d, J = 8.6Hz).

 7.04-7.42 (6H, m), 7.76-7.9 (3H, m),

 8.15 (1H, d, J = 7.3Hz), 9.14 (3H, s)

MASS (M / Z): 528 (M ⁺¹ ) free Example 22

 In the same manner as in Example 13, the target compound (22) was obtained from the starting compound (22) (the compound of Example 6).

 HPLC conditions

 Column: Thunder-PACK R-ODS-15 S-15 120A0DS

 500 X250 body

Eluent: 0.1% TFA aqueous solution, 12 CH ₃ CN

 Flow rate: 118 ml / min

 Retention time: 8.1 minutes

 Melting point: 138-144 ° C (dec.)

IR (Nujol): 3250, 1660. 1620. 1540 cm- ¹

NMR (D S0-d ₆ .δ): 1.70 (4H, br s), 2.19 (2H, m),

 2.4-2.8 (4H, m), 4.08 (2H, m), 4.46 (2H, m), 7.0-7.2 (4H.m), 7.80 (2H, d, J = 8.9Hz),

 8.10 (1H, d. J = 8.1Hz), 8.24 (1H, d, J = 7.3Hz), 8.90, 9.13 (4H, each s)

MASS (M / Z): 466 (+ + 1) free

Example 23

 In Example 22, compound (23) was obtained as a by-product.

 Retention time: 10.7 minutes

 Melting point: 85-93 ° C

IR (Nujol): 3270. 1650, 1620, 1535 cm " ¹

 NMR (DMSO-ds .: 1.70 (4H, brs), 2.17 (2H, m).

 2.4-2.8 (4H, m), 4.08 (2H, ra), 4.4-4.7 (2H, m),

 7.15 (2H, d, J = 8.8Hz), 7.80 (2H, d, J = 8.8Hz), 8.07 (1H, d, J = 8.2Hz), 8.16 (1H, d, J = 8.0Hz), 8.89, 9.13 (4H, each s)

MASS (M / Z): 467 (M + + 1) free Example 24,

 Starting compound (24) (the compound of Example 11) and 10% Pd—C (0.18 g) were added to a mixture of 10% hydrochloric acid (30m ^) and tetrahydrofuran (30m ^), and hydrogen gas was added. The mixture was stirred at room temperature for 8 hours under an atmosphere. After filtration, the filtrate was distilled under vacuum. The reaction mixture was purified by preparative HP LC to obtain the desired compound (24).

 Yield: 0.52 g.

 HPLC conditions

 Column: Y C-PACK R-ODS-15 S-15 120 A0DS

 500 X250 recitation

Eluent: CH ₃ CN (20:80) in 0.1% TFA aqueous solution

 Flow rate: 118 ml / min

 Retention time: 7.0 minutes

Melting point: 195-199 ^e C

IR (Nujol): 1660, 1640 cm " ¹

 瞧 (DMSO-de, <5): 2.4-3.1 (7H.m). 3.69 (3H, s),

 3.97, 4.02 (3Η, each singlet), 4.30 (1H, m), 4.6 (1H, m). 4.93, 5.10 (2H, each singlet), 6.80 (2H, d.J = 6.7Hz) .7.0-7.2 ( 6H, m),

 7.79 (2H, d, J = 8.8Hz) .9.00 (2H, s), 9.19 (2H, s) Example 25

 In the same manner as in Example 24, the target compound (25) was obtained from the starting compound (25) (the compound of Example 12).

 HPLC conditions

 Column: YMC-PACK R-ODS-15 S-15 120 A0DS

 500 X250 瞧

Eluent: 20% CH ₃ CN in 0.1 TFA aqueous solution

 Flow rate: 118 ml / min

Retention time: 7.1 minutes Melting point: 190-197 ° C,

IR (Nujol): 3250 (br), 1640, 1610, 1510 cm " ¹

 N R (DMSO-de, δ): 1.20 (3H, d, J = 7.0Hz), 2.3-3.2 (4H, m),

3.70 (3H, s), 4.1-4.7 (3H, m), 4.69 (2H, s), 6.79 (2H, d, J = 8.6Hz), 7.0-7.4 (5H, m),

 7.7-8.0 (2H, m), 8.2-8.5 (2H, m).

 8.97, 9.20 (4H, each s)

MASS (/ Z): 557 ( M + + 1)

Example 26

 In Example 25, compound (26) was obtained as a by-product.

 Retention time: 13.3 minutes

 Melting point: 200-205 ° C (decomp.)

IR (Nujol): 3250, 1640, 1540 cm ^-1

 NMR (D SO-de, 6): 1.22 (3H, d, J = 6.9Hz), 2.3-3.1 (4H, m),

3.71 (3H, s), 4.2-4.7 (3H, m), 4.69 (2H, s), 6.82 (2H, d, J = 8.5Hz), 7.0-7.3 (4H, m),

 7.6-7.9 (3H, m) .8.2-8.4 (2H, m),

 9.07, 9.16 (4H, each s)

MASS (M / Z): 558 (M + + 1)

Example 2 7

 The compound of Production Example 13 and the starting compound (27a) were reacted in the same manner as in Example 7 to obtain the desired compound (27a), which was reacted in the same manner as in Example 13 to obtain the desired compound (2 b) was obtained.

 HPLC conditions

Eluent: 0.1% in TFA aqueous solution, 20% CH ₃ CN

 Retention time: 9.21 minutes

IR (Nujol): 3325, 3100, 1665. 1610, 1490 cm " ¹

_{NMR (DMS0-d 6, δ} ): 0.79 (. 3Η d, J = 6.7Hz), 0.82 (3H.d, J = 6.7Hz), 1.71 (4H, m), 1.94 (1H, m),

 2.2 (2H, t like), 2.37-2.8 (2H, m), 3.53 (8H, m),

 4.08 (2H, t like), 4.57 (2H, m),

 7.14 (2H, d, J = 8.8Hz), 7.71 (1H, d, J = 8.8Hz),

 7.82 (2H.d, J = 8.8Hz), 8.27 (1H, d, J = 7.9Hz),

 9.08 (2H.s), 9.14 (2H.s)

Example 28

 In the same manner as in Example 27, the target compound (28b) was obtained from the compound of Production Example 15 and the starting compound (28a) via the target compound (28a).

 HPLC conditions

Eluent: 0.1% in TFA aqueous solution, 22% CH ₃ CN

 Retention time: 10.99 minutes

IR (Nujol): 3320, 3090. 1660. 1605, 1490 cm " ¹

賺_{(DMS0-d s δ:.} 0,79 (3Η, d, J = 6.8Hz),

 0.82 (3H, d, J = 6.8Hz) .1.3-1.85 (6H.m).

 1.94 (1H, m), 2.15 (2H, t like), 2.36-2.8 (2H, m),

 3.53 (8H, m), 4.07 (2H, t like). 4.57 (2H, m),

 7.14 (2H, d, J = 8.9Hz), 7.68 (1H, d, J = 8.8Hz), 7.81 (2H, d, J = 8.9Hz), 8.25 (1H, d.J = 7.9Hz), 9.07 ( 2H, s). 9.14 (2H, s)

Example 29

 In the same manner as in Example 27, the target compound (29b) was obtained from the compound of Production Example 14 and the starting compound (29a) via the target compound (29a).

 HPLC conditions

Eluent: 0.1% TFA aqueous solution, 21% CH ₃ CN

 Retention time: 12.26 minutes

IR (Nujol): 3300, 1660, 1630, 1520 cm " ¹

NMR (DMSO-de.δ): 0.84 (3Η, d, J = 6.4Hz), 0.85 (3H, d, J = 6.4Hz), 1.42 (2H, m), 1.54 (1H, m),

 1.96 (2H, t like), 2.3 (2H 't like),

 2.3-2.76 (2H, m), 3.55 (8H, m), 4.1 (2H, t like),

 4.58 (1H, m), 4.68 (1H, m). 7.15 (2H, d, J = 8.9Hz),

 7.82 (2H.d, J = 8.9Hz), 7.95 (1H, d, J = 8.3Hz).

 8.24 (1H, d, J = 7.9Hz), 9.05 (2H, s), 9.14 (2H, s) Example 30

 In the same manner as in Example 27, the target compound (30b) was obtained from the compound of Production Example 14 and the starting compound (30a) via the target compound (30a).

 HPLC conditions

 Eluent: 0.1% TFA aqueous solution, 21% CHsCN

 Retention time: 11.68 minutes

IR (Nujol): 3275, 3100, 1655, 1630, 1520 cm " ¹

 Hiki (D SO-de. (5): 0.78 (6H, m), 1.02 (1H, m),.

 1.4 (1H, m), 1.71 (1H.m), 1.96 (2H, t like), 2.3 (2H, t like), 2.36-2.8 (2H, m) .3.53 (8H, m),

 4.1 (2H, m), 4.56 (2H, m). 7.15 (2H, d.J-8.9Hz),

 7.79 (1H, d, J = 8.3Hz), 7.81 (2H, d. J = 8.9Hz), 8.29 (1H, d, J = 7.9Hz) .9.03 (2H, s), 9.14 (2H, s) Example 3 1

 In the same manner as in Example 27, the target compound (31b) was obtained from the compound of Production Example 21 and the starting compound (31a) via the target compound (31a).

 HPLC conditions

Eluent: 0.1% TFA aqueous solution, 21% CH ₃ CN

 Retention time: 9.59 minutes

IR (Nujol): 3320, 3080, 1660. 1525 cm " ¹

Anonymous _{(DMS0-d 6 δ.)} : 0.77 (3Η, d, J = 6.8Hz),

0.81 (3H, d, J = 6.8Hz) .1.53 (4H, m), 1.92 (1H.ra), 2.18 (2H, t like) .2.3-2.8 (4H.m) .3.53 (8H m),

 4.56 (2H.m), 7.44 (2H, d.J = 8.3Hz).

 7.69 (1H, d. J = 8.8Hz), 7.74 (2H, d, J = 8.3Hz),

 8.23 (1H, d, J = 7.8Hz), 9.16 (2H, s), 9.24 (2H, s) Example 32

 In the same manner as in Example 27, the target compound (32b) was obtained from the compound of Production Example 14, the starting compound, and (32a) via the target compound (32a).

IR (Nujol): 3320, 1670, 1270, 1190, 1130 cm " ¹

 Nozomi (DMSO-de, (5): 0.84 (6H, ra), 1.93-2.03 (3H, m)

 2.31 (2H.t.J = 7.0Hz), 2.42-2.75 (2H, ra), 3.11 (4H, m), 3.56 (1H, t, J = 10.7Hz). 3.78 (1H, t, J = 9.1Hz) ),

 4.07- 4.13 (4H, m), 4.52-4.67 (2H, m).

 7.14 (2H, d, J = 8.9Hz), 7.82 (2H, d, J = 8.9Hz), 7.97 (1H, d, J = 8.2Hz), 8.31 (IE d, J = 7.8Hz), 9.13 (4H , d, J = 4.6Hz)

 MASS (M / Z): 554 (M ++ 1) free

Example 3 3

 In the same manner as in Example 27, the target compound (33b) was obtained from the compound of Production Example 14 and the starting compound (33a) via the target compound (33a).

 HPLC conditions

Eluent: 0.1% TFA aqueous solution, 13% CH ₃ CN

 Retention time: 9.78 minutes

IR (Nujol): 3300, 1650, 1610 cm " ¹

 Hidden (DMSO-ds, 5): 0.81 (6H, d, J = 6.9Hz), 1.75-2.1 (3H, m),

2.32 (2H.t.J = 7.1Hz) .2.35-2.8 (2H.m). 2.82 (3H, s),

2.8- 4.9 (12H, m), 7.14 (2H, d, J = 8.9Hz),

 7.82 (2H, d, J = 8.9Hz). 7, 83 (1H. D. J = 8.5Hz).

8.34 CIH.d, J = 7.6Hz), 9.15 (4H, s) The formulas of the starting compound and the target compound of Example 3 4-45 are shown in Table 3 as _c.

Table 3 Example 3 4

Starting compound (3 4) HC1 · H-Asp- (OBzl)-eu-N S0 ₂ Target compound (3 4)

Am (Z) -Guo 0 "fCH ₂ †" -C0-Asp- (0Bz1) -Leu-N S0 ₂ Example 35

Starting compound (35) HC1 · H-Asp- (OBzl) -Val-N S0 ₂ Target compound (35)

Am (Z)--C0-Asp- (0Bz1) -Val-N S0 ₂ Example 3 6

Starting compound (36) HC1 · H-Asp- (OBzl) -I1e-N SO2 Target compound (36)

Am (Z) _→ -CO-Asp-(OBzl)-lie-N S0 ₂ Example 3 7

 1 ^

The starting compound (3 7) HC1 · H- Asp- (OBzl) - N People CO - N S0 ₂

 u n 'target compound (3 7)

 Am ^ J— <CO Asp-(OBzl)-N CO-N SO2

 H, ~ 'Example 3 8

The starting compound (3 8) HC1 - H- Asp- (OBzl) - N say yes CO - N S0 ₂

H ^N ~ ' Target compound (38)

Am (Z) - (O 0 "fCH 2 Wa one C0-Asp- (0Bzl) -N ^ CO-N SO:

 H: Example 3 9

Starting compound (39) HC1-H-Asp- (0Bzl) -N ^ CO- 0

 H

Target compound (39)

0 -fCH ₂ † r- C0-Asp- (0Bzl) ι--ΝN people CO-fj 0

Example 40

Starting compound (40) HC1. H-Asp- (0Bz1 J-N ^ CO-N 6

 H

Target compound (40)

Am (Z)-〇 _0 ~ (CH ₂ `` h ~ CO-Asp- (OBzl) -N people CO- 0

 H… 卖 Example 4 1

Starting compound (4 ^HC1 -H-Asp- (0Bz1

Target compound (4 1)

 Am (Z) → (-0- (CH2 † T— CO-Asp- (OBzl) N-containing C0-N 0 Example 4 2

Starting compound (4 2) HC1H-Asp- (0BzL) -Val-N) -C00Me Target compound (4 2)

Am (Z)-/ O ⁰ " ^CH 2" h ~ "C0-Asp- (0BzL) -Va1-N} -C00Me Example 4 3 starting compound (4 3) HC1 - H- Asp- • (OBzl) -Val-N NS0 2 CH 3 The object compound (4 3)

Am (Z)--C0-Asp- (0Bzl) -Val-N NS0 ₂ CH ₃ Example 4 4

 Starting compound (44) HC1 · H-Asp- (OBzl) -Val-N Target compound (44)

 Δ m f,! ~ \ \ n _i "H», ■■■

C) / "Shi ^{M z} 1 ^{3 S} U ASP IUD 1 j V a 1 IN Example 4 5

Starting compound (45) HC1H-Asp- (OBzl) -ν3ΐ-Ν-H Target compound (45)

 Am (Z) →-C0-Asp- (0Bzl) -Val

H

Example 3 4,

 In the same manner as in Example 7, the target compound (34) was obtained from the starting compound (34) (1.5 O g) and the compound of Production Example 14 (1.09 g).

 Yield: 2.01 g

 (DMSO-ds.δ: 0.85 (6Η, m), 1.45-1.54 (3H, m), 1.82-1.90 (2H, m), 2.27 (2H, d, J = 7.lHz), 2.51-2.62 ( 2H, m), 2.66-3.20 (4H, m),

 3.45 i 3.57 (1H, m), 3.75 (1H, m),

 3.98-1 4.08 (4H, m), 4.68 (2H, m), 5.10 (2H, s).

 5.14 (2H, s), 6.99 (2H, d, J = 8.9Hz).

 7.31-7.42 (10H, m), 7.99 (2H.d, J = 8.9Hz), 8.20-8.31 (2H, m), 9.10 (2H, brs)

Example 3 5

 In the same manner as in Example 7, the target compound (10) was obtained from the starting compound (35) (2.00 g) and the compound of Production Example 14 (1.50 g).

 Yield: 3.37 g

IR (Nujol): 3300, 2150, 1930, 1650, 1250 cm " ¹

_{NMR (DMS0-d 6 δ:} . 0.75 - 0.82 (6Η, m),

 1.12-1.21 (1H, m), 1.97 (2H.m),

 2.24-2.33 (2H.m), 2.60-2.80 (2H, ra),

 3.00-3.22 (4H, m), 3.48-3.59 (1H, m),

 3.77-3.81 (1H, m). 4.04 (2H, t, J = 5.3Hz).

 4.11-4.20 (2H, m), 4.56 (1H, m). 4.75 (1H, m).

 5.07 (2H, s), 5.11 (2H, s), 7.00 (2H, d, J = 8.9Hz),

 7.35 1 7.40 (10H, ra), 7.96-8.09 (3H, m), 8.34 (1H, d, J = 7.9Hz). 9.12 (2H, brs)

MASS (/ Z): 778 ( M + + 1) FAB MASS

Example 3 6 Starting compound (36) (1.50 g), compound of Production Example 14 (1 „09 g) and N, N-dimethylformamide of 1-hydroxy-1H-benzotriazole Triethylamine was added to the solution, and the mixture was stirred for 30 minutes at 120 ° C. To this, 11- (3-dimethylaminopropyl) -13-ethylcarboimide / hydrochloride was added at 120 ° C. and room temperature was added. The reaction mixture was poured into an aqueous solution of ethyl acetate, and the pH was adjusted to 0.50 with a saturated aqueous solution of potassium carbonate.The separated organic layer was washed with water and saturated saline, and dried over magnesium sulfate. After filtration, the filtrate was distilled under vacuum to obtain the target compound (36).

 Yield: 2.25 g

讀_{(DMS0-d 6 δ.)} : 0.80 (. 6Η m), 1.05 (1H, m),

 1.17 (1H, ra), 1.46 (1H, m). 1.77 (2H, t, J = 7.4Hz),

 1.97 (2H, t, J = 6.7Hz) .2.51-2.73 (2H, m), 2.99-3.25 (3H, m), 3.49 (1H, ra), 3.81 (1H, m),

 4.04 (3H.m), 4.23 (1H, m), 4.58 (1H, m),

 4.70 (1H, m), 5.07 (2H, s), 5.10 (2H, s),

 6.99 (2H, d, J = 8.9Hz), 7.32-7.41 (mouse m), 7.99 (2H, d.J = 8.9Hz), 8.11 (1H.d, J = 8.1Hz).

 8.31 (1H.d, J = 7.9Hz). 9.10 (2H, brs)

MASS (M / Z): 792 (M + + 1) FAB MASS

Example 3 7

 In the same manner as in Example 36, the target compound (37) was obtained from the starting compound (37) (3.00 g) and the compound of Production Example 14 (2.25 g).

 Yield: 5.32 g

 N R (DMSO-de, δ): 0.80-0.87 (3Η, m).

 1.14-1.28 (2H, m), 1.50-1.59 (2H, m),

 1.83-1.91 (2H, m). 2.29 (2H, t, J = 7.0Hz), 2.55-2.89 (2H, m), 3.00-3.19 (4H.m),

3.55 (2H, m) .3.74 (2H, m) .4.01 one 4.07 (2H, m), 4.08 (2H.m), 5.01 (2H, s), 5.08 (2H, m), _r

 7.00 (2H, d 'J = 8.9Hz) .7.31-7.40 (10H, m), 8.00 (2H.d, J = 8.9Hz), 8.21 (1H, d, J = 7.6Hz).

 8.31 (1H, d, J = 8.1Hz), 9.12 (1H, brs)

MASS (M / Z): 778 (M ⁺ "+1") FAB MASS

Example 3 8

 In the same manner as in Example 36, the target compound (38) was obtained from the starting compound (38) (2.50 g) and the compound of Production Example 14 (1.93 g).

 Yield: 4.44 g

 NMR (DMSO-de, <5): 0.82 (3H, t, J = 7.3Hz),

 1.12-1.21 (2H, m), 1.55 (2H, t, J = 7.3Hz).

 2.30 (2H, t.J = 6.7Hz), 2.56-2.89 (2H, m), 2.99-3.98 (7H, m), 4.05 (2H, m), 4.22 (1H, m).

 4.63-4.78 (2H, m), 5.08 (2H, s), 5.11 (2H, s),

 7.00 (2H, d.J = 8.9Hz), 7.31-7.40 (10H, m), 8.00 (2H, d, J = 8.9Hz), 8.20 (1H, d, J = 7.6Hz), 8.33 (1H, d , J = 8.0Hz), 9.13 (2H, brs)

MASS (M / Z): 764 (M + + 1) FAB MASS

Example 3 9

 In the same manner as in Example 36, the target compound (39) was obtained from the starting compound (39) (5.00 g) and the compound of Production Example 14 (4.17 g).

 Yield: 7.33 g

 NMR (DMSO-de.δ): 0.79-0.86 (3Η, m).

 1.14-1.29 (2H, m), 1.33-1.56 (2H.m), 1.95 (2H, m), 2.29 (2H, t, J = 7.OHz),

 2.55-2.89 (2H, m). 3.50 (8H, m), 4.05 (2H, m),

 4.67 (2H, m), 5.01 (2H, s), 5.07 (2H, s),

7.00 (2H, d, J = 8.9Hz), 7.30-7.41 (10H, m), 7.84 (3H, m), 8.30 (1H, d, J = 8.0Hz). 9.15 (1H, brs) MASS (M / Z): 730 (M ⁺ + 1) FAB MASS

Example 40

 In the same manner as in Example 36, the target compound (40) was obtained from the starting compound (40) (4.OOg) and the compound of Production Example 14 (3.44 g).

 Yield: 5.43 g

 NMR (DMSO-ds. Δ): 0.76-0.83 (3Η, m),

 1.41-1.55 (1H, m), 1.60-1.73 (1H, m),

1.96 (2H, m), 2.31 (2H, t, J = 6.9Hz).

 2.57-2.95 (2H, m), 3.50 (8H, m),

 4.05 (2H, t.J = 7.0Hz), 4.56-4.60 (1H, m).

 4.63-4.77 (1H, m), 5.08 (2H, s), 5.12 (2H, s),

 7.01 (2H, d, J = 8.9Hz), 7.35-7.44 (10H, m), 7.90 (1H, m), 8.01 (2H, d, J = 8.9Hz),

 8.33 (1H.d, J = 8.0Hz), 9.18 (1H, brs)

MASS (M / Z): 716 ( ⁺ + 1) FAB MASS

Example 4 1

 In the same manner as in Example 7, the target compound (41) was obtained from the starting compound (41) (2.50 g) and the compound of Production Example 14 (1.85 g).

 Yield: 4.09 g

IR (Nujol): 3350, 2100, 1720, 1640. 1250 cm— ¹

NMR (DMS0-d ₆ , 5): 0.81 (2H, m), 1.12-1.21 (5H, m), 1.39-1.42 (2H, in), 1.58-1.78 (5H.m),

 1.99 (2H, t, J = 5.7Hz), 2.30 (2H, t, J = 6.7Hz),

 2.56-2.82 (2H, m), 3.47-3.98 (7H, m),

 4.02 (3H, m), 4.76 (2H.m), 5.08 (2H, s),

 5.12 (2H, s), 7.01 (2H, d 'J = 8.9Hz),

7.32-7.40 (10H, m). 7.96-8.06 (3H.m), 8.30 (1H, d, J = 8.0Hz), 9.15 (2H, brs),

MASS (M / Z): 784 (M + + 1) FAB MASS

Example 4 2

 In the same manner as in Example 36, the target compound (42) was obtained from the starting compound (42) (2.75 g) and the compound of Production Example 14 (2.02 g).

 Yield: 4.20 g

 NMR (DMSO-de, δ) 0.79 (6Η, m), 1.09-1.21 (2H, m), 1.83-1.99 (5H, πθ '2.29 (2H, t, J = 7.OHz), 2.55-2.89 (2H , m), 3.11 (1H, m), 3.0 (2H, m).

 3.59 (3H, d, J = 4.4Hz). 3.92 (1H, m),

 4.04 (2H, t, J = 5.5Hz), 4.22 (1H, m),

 4.57 (1H, t, J = 7.4Hz), 4.69 (1H.m) .5.07 (2H, s),

 5.10 (2H, s), 6.99 (2H, d, J = 8.9Hz),

 7.29-7.40 (10H.m), 7.99 (2H, d, J = 8.9Hz), 8.36 (1H, d, J = 8.1Hz), 9.15 (1H, brs)

MASS (M / Z): 786 (M + + 1) FAB MASS

Example 4 3

 In the same manner as in Example 36, the target compound (43) was obtained from the starting compound (43) (1.50 g) and the compound of Production Example 14 (1.06 g).

 Yield: 2.24 g

 NMR (DMSO-de.δ): 0.77-0.84 (6Η, m), 1.94 (3H, m),

 2.30 (2H, t, J = 7.0Hz), 2.56-2.82 (2H, ra), 2.88 (3H, s), 3.35 (4H.m), 3.54 (1H, m),

 3.62 (3H.m), 4.05 (2H, m), 4.55 (1H, m),

 4.70 (1H, m), 5.10 (2H, s), 5.20 (2H, s),

 6.99 (2H, d, J = 8.9Hz), 7.29-7.42 (10H, m).

7.83 (1H, d, J = 8.8Hz), 7.99 (2H, d, J = 8.9Hz), 8.36 (1H, d, J = 7.9Hz). 9.11 (2H, brs) MASS (M / Z): 807 (M ⁺ + 1) FAB MASS _r

Example 4 4

 In the same manner as in Example 7, the target compound (44) was obtained from the starting compound (44) (3.00 g) and the compound of Production Example 14 (2.58 g).

 Yield: 4.23 g

IR (Nujol): 3300, 1730, 1620, 1250 cm " ¹

 N R (D SO-de, δ) ： 0.81 (6Η, m), 0.99 (3H.t, J = 7.0Hz).

 1.10 (3H, t, J = 7.0Hz) .1.84-1.99 (3H.m), 2.31 (2H, t, J = 7.0Hz) .2.57-3.16 (2H, m), 3.35-1.49 (4H, m) , 4.01 (2H.t, J = 7.1Hz), 4.48 (1H, m) .4.72 (1H, in) .5.08 (2H, s),

 5.14 (2H, s), 6.95 (2H, d, J = 8.9Hz),

 7.27-7.8 (10H, m), 7.75 (1H, d, J = 9.0Hz).

 8.01 (2H, d, J = 8.9Hz), 8.35 (1H, d, J = 8.0Hz),

 9.14 (2H, brs)

MASS (M / Z): 716 ( ⁺ + 1) FAB MASS

Example 4 5

 In the same manner as in Example 7, the target compound (45) was obtained from the starting compound (45) (4.00 g) and the compound of Production Example 14 (3.36 g).

 Yield: 5.35 g

IR (Nujol): 3380 '3280, 1740, 1630, 1250 cm " ¹

NMR (D S0-d ₆ , δ): 0.78 (3H.d, J = 6.7Hz),

 0.99 (3H, d, J = 6.7Hz), 1.10-1.20 (6H, m), 1.47-1.63 (5H, m), 1.96 (2H, t, J = 6.6Hz), 2.33 (2H, t, J = 7.0Hz), 2.49-2.59 (2H, m).

 3.51 (1H, m), 4.05 (2H, t, J = 6.2Hz), 4.35 (1H, m),

 4.50 (2H, s), 5.10 (2H.s). 5.20 (1H, m),

7.00 (2H, d, J = 8.9Hz), 7.18-7.42 (11H, m). 8.00 (2H, d, J = 8.9 Hz), 8.88 (1H, d, J = 6.8 Hz), 9.14 (2H, brs)

MASS (M / Z): 742 (M + + 1) FAB MASS

Table 4 shows the formula of the target compound of Examples 46-57.

Table 4

Example 4 6

Am--0-(ΟΗΣ Τ- CO-Asp-Leu-N S0 ₂ .

_{Am- - 0 -fCH 2 - r- CO} -Asp-Val-N S0 2 - TFA treasure β

_{Am- -0-fCH 2 -h-C0} -Asp-Ile-N S0 2 · TFA

Am ― 0 -fCH ₂ iT- CO-1 Asp-1 N CO- "~ S0 ₂ • TFA 夹 Example 5 0

Am -0 "fCHr ~ C0-Asp-NERA CO-N S0 ₂ -TFA Example 5 1

 Am ― 0 ~ f CHr ~ C0-Asp-N CO-N ~ 0. TFA premature TtEiyj O Δ

(o> — 0 "tCH ₂ CO-One Asp-One NERA CO-One N 0 'TFA

Am (> -0-fCH ₂ iT-CO-Asp-N-^ CO-N ~ 0TFA Example 5 4

Am (>-0 -fCH ₂ ir- CO-Asp-Val-N) —COOMe • TFA Example 5 5

Am_ <〇: 0- CH ₂ iT-CO-Asp-Val-N NSO2CH3 TFA

\ I

Example 5 7

Example 4 6 ^

 Compound of Example 34 (1.98 g). 10% wet PdZC and ammonium formate were added to an aqueous methanol solution, and the mixture was stirred at room temperature for 3 hours. After filtration, the filtrate was distilled in vacuo. The obtained mixture was purified by preparative HP LC to obtain the desired compound (46) (1.33 g).

 HPLC conditions

 Column: Lightning-PACK R-ODS-15 S-15 120 A ODS

 500 X250 images

Eluent: CH ₃ CN I 0.1¾ TFA aqueous solution = 25¾

 Flow rate: 118 ml / min

 Retention time: 5.44 minutes

mp: 133-136 ^e C

IR (Nujol): 3300. 1650, 1300, 1180 cm " ¹

Hidden (D S0-d ₆ , δ): 0.84 (6Η.in), 1.45-1.53 (3H, m), 1.95 (2H, t, J = 6.5Hz), 2.29 (2H, t, J = 7.2Hz) , 2.40-2.74 (2H, in). 3.20 (5H, m), 3.58 (1H, in).

 3.76 (1H, m), 3.93 (1H, m), 4.10 (2H, t, J = 6.3Hz).

 4.57 (1H, m), 4.70 (1H, m), 7.14 (2H, d, J = 8.9Hz).

 7.81 (2H, d, J = 8.9Hz), 8.13 (1H, d 'J = 8.0Hz), 8.23 (1H, d, J = 7.9Hz). 8.98 (2H, s), 9.14 (2H, s)

MASS (M / Z): 568 (M + + 1) free FAB MASS

Example 4 7

 The target compound (47) was obtained from the compound of Example 35 (3.00 g) in the same manner as in Example 46.

 Yield: 1.94 g

 Melting point: 138-140 ° C

IR (Nujol): 3350, 1670, 1270, 1190 cm " ¹

NMR (D SO-de. Δ): 0.82-0.86 (6H, m), 1.93-2.03 (3H.m), 2.31 (2H, t, J = 7.0Hz), _r

 2.42-2.75 (2H, m), 3.11 (3H, ra),

 3.25-3.29 (1H, m), 3.51-3.61 (1H, m), 3.71-3.82 (1H, m), 4.07-4.13 (4H, m),

4.52-4.67 (2H, m), 7.14 (2H, d, J = 8.9Hz), 7.82 (2H, d, J = 8.9Hz), 7.97 (1H, d. J = 8.2Hz),

 8.31 (1H.d, J = 7.8Hz), 9.13 (2H, s), 9.15 (2H, s)

MASS (M / Z): 554 (M + + 1) free FAB MASS

Example 4 8

 In the same manner as in Example 46, the target compound (48) was obtained from the compound of Example 36 (2.10 g).

 Yield: 1.49 g

Melting point: 167-169 ^e C

IR (Nujol): 3300, 1660. 1640. 1270, 1180 cm " ¹

 N R (D SO-de.δ): 0.80 (6H, m), 1.08 (ΙΗ 'm),

 1.45 (1H, m), 1.73 (1H.m), 1.95 (2H, t, J = 6.5Hz),

 2.29 (2H, t, J = 7.0Hz), 2.41-2.72 (2H, m), 3.13-3.30 (3H, m), 3.53 (1H, m), 3.77 (1H, m),

 4.10 (2H, t.J = 6.4Hz), 4.19 (3H, m),

 4.53-4.61 (2H, m), 7.14 (2H, d, J = 8.9Hz), 7.81 (2H, d, J = 8.9Hz) .8.01 (1H, d, J = 8.2Hz),

 8.26 (1H, d, J = 7.8Hz), 8.99 (2H, s), 9.13 (2H, s)

MASS (M / Z): 568 (M + + 1) free FAB MASS

Example 4 9

 In the same manner as in Example 46, the target compound (49) was obtained from the compound of Example 37 (5.25 g).

 Yield: 2.46 g

Melting point: 125-127 ° C IR (Nujol): 3300, 3100, 1660, 1260, 1180 cm— ¹ ,

 NMR CDMSO-de.6): 0.84 (3H.t, J = 7.3Hz).

 1.23-1.31 (2H, m). 1.45-1.59 (2H, m),

 1.95 (2H, t, J = 6.6Hz), 2.29 (2H, t, J = 7.0Hz),

 2.41-2.74 (2H, m), 3.15 (4H, m), 3.57 (2H, m).

 3.75 (2H, m), 4.10 (2H, t 'J = 6.3Hz),

 4.54-4.69 (2H.m), 7.14 (2H, d, J = 8.9Hz),

7.81 (2H, d, J = 8.9Hz), 8.12 (1H, d, J = 7.7Hz),

 8.25 (1H, d, J = 7.9Hz). 9.02 (2H, s), 9.14 (2H, s)

 MASS (M / Z): 554 (M ++ 1) free FAB MASS

Example 5 0

 In the same manner as in Example 46, the target compound (50) was obtained from the compound of Example 38 (4.30 g).

 Yield: 2.06 g

 Melting point: 119-122V

IR (Nujol): 3300, 3100, 1670, 1210, 1180 cm " ¹

NMR (DMS0-d ₆ , 5): 0.81 (3H, t, J = 7.1Hz),

 1.50-1.68 (2H, m), 1.96 (2H, m),

 2.30 (2H, t, J-6.7Hz), 2.41-2.74 (2H, m), 3.15 (4H.m), 3.57 (1H.m), 3.74 (1H.m), 3.99 (1H, m), 4.09 (3H, m) .4.62 (2H, m), 7.14 (2H, d, J = 8.9Hz) .7.82 (2H, d, J = 8.9Hz),

 8.12 (1H, d, J = 7.7Hz), 8.27 (1H, d, J = 7.7Hz),

 9.09 (2H, s), 9.15 (2H.s)

MASS (M / Z): 540 (M + + 1) free FAB MASS

Example 5 1

In the same manner as in Example 46, the target compound (51) was obtained from the compound of Example 39 (7.20 g). Yield: 3.14 g _r

 Melting point: 157-160 ° C

IR (Nujol): 3300, 3100, 1670, 1270, 1210 cm " ¹

 NMR (D SO-de, δ) ： 0.84 (3H, t, J = 7.4Hz),

 1.15-1.36 (2H, m), 1.40-1.63 (2H, m), 1.98 (2H.t, J = 6.7Hz). 2.32 (2H, t, J = 7.0Hz).

 2.43-2.76 (2H.ηθ, 3.52 (8H, m),

 4.11 (2H, t, J = 6.4Hz), 4.54-4.71 (2H, m), 7.15 (2H, d, J = 8.9Hz), 7.84 (2H, d, J = 8.9Hz),

 7.94 (1H, d, J = 8.1Hz), 8.29 (1H, d. J = 7.9Hz),

 9.17 (2H, s), 9.22 (2H, s)

MASS (M / Z): 506 (M + + 1) free FAB MASS

Example 5 2

 In the same manner as in Example 46, the target compound (52) was obtained from the compound of Example 40 (5.20 g).

 Yield: 1.92 g

 Melting point: 138-UVC

IR (Nujol): 3300, 3100, 1670, 1270, 1210 cm ' ¹

 NMR (D SO-de, δ: 0.79 (3Η, t, J = 7.4Hz).

 1.31-1.40 (1H.m), 1.43-1.54 (1H, m),

 1.70 (2H, t, J = 7.6Hz), 1.97 (2H, t, J = 6.7Hz),

 2.42-2.75 (2H.m), 3.46-3.54 (8H, m), 4.10 (2H.t, J = 6.4Hz), 4.55-4.65 (2H, m), 7.15 (2H, d, J = 8.9Hz) , 7.82 (2H, d, J = 8.9Hz),

 7.92 (1H, d. J = 7.8Hz), 8.28 (1H, d. J = 7.8Hz),

 9.12 (2H, s), 9.15 (2H, s)

 MASS (M / Z): 492 (M ++ 1) free FAB MASS

Example 5 3 In the same manner as in Example 46, the target compound (53) was obtained from the compound of Example 41 (4.00 g).

 Yield: 1.61 g

 Melting point: 193-195 ° C

IR (Nujol): 3280, 1660 '1640, 1260, 1180 cm " ¹

 Hidden (D SO-de.δ): 0.85 (2H, m), 1.11 (4H, m).

 1.41 (2H, t, J = 6.8Hz), 1.59-1.77 (5H.m), 1.96 (2H, t, J = 6.8Hz), 2.30 (2H, t, J = 7.0Hz),

 2.39-2.74 (2H, m), 3.47-3.54 (9H, m),

4.10 (2H.t, J = 6.4Hz), 4.57 (1H, m),

 4.71 (1H, m), 7.14 (2H, d. J-8.9Hz),

 7.82 (2H, d, J = 8.9Hz), 7.93 (1H, d, J = 8.3Hz),

 8.23 (2H, d, J = 7.9Hz), 9.07 (2H, s), 9.14 (2H, s)

MASS (M / Z): 560 (M + + 1) free FAB MASS

Example 5 4

 In the same manner as in Example 46, the target compound (54) was obtained from the compound of Example 42 (4.00 g).

 Yield: 1.49 g

Melting point: 136-139 ^e C

IR (Nujol): 3300, 3100, 1660. 1270, 1210 cm " ¹

 NMR (DMSO-de, δ): 0.76-0.83 (6Η. M),

 1.33-1.49 (2H, m), 1.85-2.01 (5H, m).

 2.32 (2H.t, J = 7.0Hz) .2.42-2.82 (2H.ra),

3.13 (1H, t, J = 11.6Hz), 3.61 (3H, s), 3.91 (2H, m),

 4.11 (2H.t, J = 6.3Hz). 4.24-4.61 (6H, m), 7.15 (2H, d, J = 8.9Hz). 7.70 (1H, t, J = 9.6Hz).

 7.83 (2H. D. J = 8.9Hz). 8.35 (1H, d. J = 6.5Hz).

9.11 (2H, s). 9.16 (2H.s) MASS (M / Z): 562 (M + + 1) free FAB MASS,

Example 5 5

 In the same manner as in Example 46, the target compound (55) was obtained from the compound of Example 43 (2.20 g).

 Yield: 1.27 g

 Melting point: 120-122V

IR (Nujol): 3350, 1670, 1270, 1180, 1150 cm " ¹

_{NMR 0.76 (DMS0-d 6 δ} .) - 0.84 (6Η, m),

 1.96-2.00 (3H, m), 2.31 (2H, t, J = 7.1Ηζ), 2.41-2.76 (2H, m), 2.89 (3H, s), 3.09 (4H, m),

 3.51 (1H, m), 3.64 (3H, m), 4.10 (2H, t.J = 6.3Hz),

 4.51-4.61 (2H, m), 7.14 (2H, d, J = 8.9Hz),

7.75-7.84 (3H, m), 8.33 (1H, d, J = 7.8Hz),

8.97 (2H, s), 9.14 (2H, s)

MASS (M / Z): 583 (M + + 1) free FAB MASS

Example 5 6

 In the same manner as in Example 46, the target compound (56) was obtained from the compound of Example 44 (4.00 g).

 Yield: 0.75 g

 Melting point: 149-152 ° C

IR (Nujol): 3300. 1660, 1260, 1200 cm " ¹

NMR (鹏 0-d ₆ ,: 0.81 (6H, m), 1.00 (3H, d, J = 7.0Hz), 1.12 (3H, d. J = 7.0Hz), 1.86-2.01 (3H, m), 2.33 (2H, t. J = 6.9Hz). 2.43-2.75 (2H, m), 3.05 (1H, m), 3.35-3.49 (3H.m),

 4.12 (2H, t.J = 6.3Hz), 4.49 (1H, m). 4.60 (1H, m),

7.15 (2H, d, J = 8.9Hz), 7.64 (1H, d, J = 9.0Hz), 7.84 (2H, d, J = 8.9Hz), 8.35 (1H, d. J = 7.8Hz), 9.18 (2H, s), 9.33 (2H, s),

MASS (M / Z): 492 (M + + 1) free FAB MASS

Example 5 7

 In the same manner as in Example 46, the target compound (57) was obtained from the compound of Example 45 (4.00 g).

 Yield: 0.33 g

 Melting point: 192-195 ° C

IR (Nujol): 3250, 3100, 1660, 1620, 1180 cm— ¹

 NMR (DMSO-de, δ): 0.79 (6Η, m), 1.02-1.39 (5H, m), 1.22-1.56 (5H, m), 1.66-1.89 (3H, m),

 1.97 (2H, t, J = 9.4Hz), 2.09-2.77 (2H, m), 3.46 (1H, m), 4.05-4.13 (4H, m),

 4.60 (1H, m), 7.14 (2H, d, J = 8.9Hz).

 7.51 (1H, d, J = 9.0Hz). 7.78 (3H, in).

 8.37 (1H, d, J = 7.8Hz), 9.10 (2H.s), 9.19 (2H.s)

MASS (M / Z): 518 (M + + 1) free FAB MASS

The formulas of the starting compounds, intermediates and target compounds of Examples 58-67 are shown in Table 5.

Table 5

Example 58

Starting compound (58) HClH-Asp- (0Bz1) -Val intermediate (D8)

Am (^. J- <) ~ 0 -fCH ₂ fj— C0-Asp- (0Bz1) va 1-N U2 Target compound (58)

0-fCH ₂ † r- CO-Asp-Val-N _ SO 2

Example 59

Mountain 3¾i / Mn Γϊ Η ΠΠ 1, * Η Π-Α / Λς ^ η- f ^ ΠΜ 11 C 1 J f α 1 -N O2

1 J 3)

 A-/ "7, / \ 0 -fCHz r- CO-Asp- (OMe) -Val -N 5O2 Target compound (59)

0-fCH ₂ i-CO-Asp- (OMe) -Val -N SO 2

\ 1

Example 6 0

1 U product WJ (60 W ai) HCl · H-Asp-(OBzl) -Val SO2

 'Subtle' ¾ ^ shim thing t (Ro ί) "h

Am (Z) ^ 〇 ~ 0-CH ₂ -C0-Sar-0H

Intermediate (60)

Am (Z) Baie _{〇> ~ 0- -CH 2 -C0-Sar} -Asp- (0Bz1) -Val -N SO2 desired compound (6 0)

O-CHz-CO-Sar- Asp-Val - - N S0 2 · TFA

1

Example 6 4

Starting compound (64) HC1H-Asp- (0Bzl) -tertLeu-N0 intermediate (64)

Am (Z,) - 0 - CH 2 "- C0-Asp (0Bzl) -tertLeu- N 0 desired compound (6 4)

Am be o> -o-fCH ₂ --CO-Asp-tert. Eu-N ^ 0 • TFA Example 65

Starting compound (65) £. Π H-Asp- (0Bzl) -Ile-N N -CH ₃ intermediate (65)

 Am (Z) -UΠ2) 3C0-Asp (0Bzl) -Ile-N ^ N-CH3 target compound (65)

 No

_{Am- / o> -0-fCH 2} iT- CO-Asp-Ile-N N-CH 3 · 2TFA Example 6 6

Starting compound (66) 2HC1. H-Asp- (0Bzl) -Va1-N N-Et Intermediate (66)

Am (Z)-/ o -o-cH ₂ --C0-Asp (0Bz1) -Va1- ^ N -Et Target compound (66)

-0-fCH _2- † T-CO-Asp-Val-N ^ N-Et.2TFA Example 67

The starting compound (6 7) 2HC1. H- Asp- (0Bz1) -Val-N N-CH 3 Intermediate (67)

Am (Z)-<0

CO-Asp (0Bzl)-Val-N N-CH3 Target compound (67)

ο>-0 -fCH _2- "CO-Asp-Val-N N-CH3 2TFA

Example 5 8

 The target compound (58) was obtained as follows.

 First, using the starting compound (58) (62.83 g) and the compound of Production Example 14 (42.77 g), the intermediate (58) (81 4 g) was obtained.

 Next, the reaction mixture was mixed with 10 weight Pd—C (16.2 g), ammonium formate and an aqueous methanol solution, and stirred at room temperature for 2 hours. After filtration, the filtrate was distilled in vacuo. The residue was dissolved in water, and ethanol was added thereto. The resulting mixture was stirred at room temperature for 15 hours. The precipitate was collected by filtration, washed with ethanol, and dried under reduced pressure to obtain the target compound (58).

 Yield: 33.84 g

IR (Nujol): 3275, 1625, 1540 cm " ¹

 N R (DMSO-de, δ): 0.85 (6Η.d, J = 6.4Hz),

 1.75-2.15 (3H, m), 2.1-2.55 (4H, m),

 2.8-4.4 (10H, m), 4.45-4.73 (2H.m),

 7.06 (2H, d.J = 8.8Hz), 7.68 (2H.d.J = 8.8Hz).

 8.11 (1H, d, J = 8.1Hz), 8.19 (1H, d, J = 7.5Hz)

 In the same manner as in Example 58, the starting compound (59) (0.88 g) and the compound of Production Example 14 (0.71 g) were converted to the target compound (5 9) was obtained.

 Yield: 0.5 g

IR (Nujol): 3300, 3100, 1720, 1650. 1600, 1530 cm " ¹

NMR (DMSO-de.δ): 0.83 (6H.d, J = 6.5Hz),

 1.8-2.1 (3H, m), 2.30 (2H, t like),

 2.5-2.85 (2H, m), 2.9-4.3 (8H, m),

 3.57 (3H, s), 4.09 (2H, t like), 4.4-4.75 (2H, m),

7.14 (2H, d, J = 8.9Hz), 7.82 (2H, d, J = 8.9Hz), 8.06 (1H.d, J = 8.2Hz), 8.33 (1H.d.J = 7.8Hz) 9.05 (2H.s). 9.15 (2H, s)

MASS (/ Z): 568 (M ⁺ 11) free FAB MASS

Example 6 0

In the same manner as in Example 58, the starting compound (60a) (2.62 g) and the starting compound (6Ob) (2 g) were converted to the target compound (60) via the intermediate (60). 60% yield of _c : 2.02 g

IR (Nujol): 3300 '1660-1630 (br), 1520 cm' ¹

 Original (D SO-de.δ) ： 0.84 (6Η, d, J = 5.4Hz). 1.99 (1H, m), 2.4-2.8 (2H, m), 2.79, 3.0 (3H, each s), 2.9- 4.0 (8H, m), 3.9-4.2 (2H, m),

 4.4-4.8 (2H, m). 4.94, 5.05 (2H. Each s).

 7.12 (2H, d, J = 8.7Hz). 7.78 (2H, d, J = 7.3Hz), 7.99, 8.16 (1H, each d, J = 8.2Hz, 7.9Hz),

 8.32, 8.62 (1H, each d, J = 7.8Hz, 7.9Hz),

 9.02 (2H, s), 9.13 (2H.s)

MASS (M / Z): 596 (+ + 1) free FAB MASS

Example 6 1

 In the same manner as in Example 58, the desired compound (61) was obtained from the starting compound (61) (8.7 g) and the compound (5 g) of Production Example 14 via the intermediate (61). Was.

 Yield: 4.45 g

IR (Nujol): 3250, 1620, 1600, 1560-1520 (br) cnr ¹

_{NMR (DMS0-d 6, δ} ): 0.80 (3H, d, J = 6.4Hz),

 0.83 (3H, d, J = 6.4Hz), 1.73-2.2 (3H, m),

 2.0-2.55 (4H, m), 3.53 (8H.s), 3.9-4.2 (2H, m),

 4.37-4.7 (2H, m). 7.06 (2H, d. J = 8.8Hz),

 7.66 (2H, d, J = 8.8Hz), 7.85 (1H, d, J = 8.8Hz),

8.21 (1H, d, J = 7.6Hz) Example 6 2 _r

 In the same manner as in Example 58, the desired compound (62) was obtained from the starting compound (62) (1 g) and the compound (0.81 g) of Production Example 14 via the intermediate (62). Was.

 Yield: 0.75 g

IR (Nujol): 3280, 3100, 1660, 1630, 1605, 1530 cm " ¹ NMR (D SO-de, δ): 0.82 (3H, m), 1.20 (4H, ra),

 1.2-1.75 (2H, m), 1.96 (2H.t like).

 2.30 (2H, t like), 2.3-2.8 (2H, m),

 3.3-3.7 (8H, m), 4.10 (2H, t like), 4.60 (2H, m), 7.15 (2H, d, J = 8.9Hz), 7.82 (2H, d, J = 8.9Hz),

7.92 (1H, d, J = 8.1Hz), 8.26 (1H.d, J = 7.9Hz), 9.07 (2H, s), 9.14 (2H, s)

Example 6 3

 In the same manner as in Example 58, starting compound (63a) (1.4 g) and starting compound (68b) (0.9 g) were converted to intermediate compound (6) via intermediate (63). 3) was obtained.

 Yield: 0.8 g

IR (Nujol): 3300, 1660-1630, 1520 cm- ¹

NMR (DMS0-d ₆ , δ): 0.81 (6Η, m), 1.96 (ΙΗ 'm),

 2.4-2.8 (2Η, m), 2.8, 3.0 (3H, each s), 3.47 (8H.m), 3.9-4.15 (2H, m), 4.51 (1H, m).

 4.63 (1H, m), 4.95, 5.06 (2H, each s),

 7.13 (2H, d.J = 8.8Hz). 7.78 (2H, d, J = 8Hz), 7.78, 7.95 (1H, each d, J = 8.6Hz),

 8.33, 8.62 (1H, each d, J = 8Hz, 7.8Hz),

 9.0 (2H, s), 9.14 (2H.s)

 MASS (/ Z): 549 (M ++ 1) free FAB MASS

Example 64 In the same manner as in Example 58, the starting compound (64) (0.38 g) and the compound of Production Example 14 (0.31 g) were converted to the target compound (64) via the intermediate (64). Obtained.

 Yield: 118 mg

IR (Nujol): 3320, 3100 , 1660, 1610, 1520 cm one ¹

NMR (DMS0-d ₆ , δ): 0.89 (9Η, s), 1.95 (2H, ra),

 2.31 (2H, t like), 2.35-2.9 (2H, m),

 3.5 (8H, ra), 4.11 (2H. T like). 4.5-4.8 (2H, m).

 7.14 (2H, d, J = 8.8Hz), 7.54 (1H, d, J = 9.2Hz).

 7.82 (2H, d, J = 8.8Hz), 8.43 (1H, d, J = 7.7Hz),

9.08 (2H, s), 9.14 (2H, s)

Example 65

 In the same manner as in Example 58, the desired compound (65) was obtained from the starting compound (65) (1.27 g) and the compound of Production Example 14 (0.84 g) via the intermediate (65). .

 Yield: 0.62 g

IR (Nujol): 3280, 1650-1630 (br), 1600, 1530 cm " ¹

 NMR (recommended 0-ds, δ): 0.81 (6Η, m). 0.8-1.6 (2H, m).

 1.74 (ΙΗ 'm), 1.96 (2H, t like) .2.31 (2H, t like),

 2.4-2.85 (2H, m), 2.6-3.6 (8H, m), 2.82 (3H, s), 4.10 (2H, t like), 4.57 (2H, m),

 7.14 (2H, d, J = 8.9Hz). 7.83 (2H, d, J = 8.9Hz).

 7.89 (1H, d, J = 8.9Hz), 8.33 (1H, d, J = 7.4Hz), 9.17 (2H, s), 9.23 (2H, s)

 MASS (M / Z): 533 (M + + 1) Free FAB MASS

Example 6 6

In the same manner as in Example 58, the starting compound (66) (1.7 g) and the compound of Preparation Example 14 (1.12 g) were converted to the target compound (66) via the intermediate (66). ). Yield: 1.3 g _r

IR (Nujol): 3300, 1650 cm " ¹

 NMR (DMSO-ds, 6): 0.80 (3H, d, J = 6.4Hz),

 0.83 (3H, d.J = 6.3Hz), 1.22 (3H.t.J = 7.2Hz),

1.97 (3H, m), 2.32 (2H, t like), 2.3-2.9 (2H, m),

2.6-3.6 (8H, m), 4.10 (2H, t like),

 4.1-4.7 (6H, m), 7.14 (2H, d 'J = 8.9Hz),

 7.83 (2H, d, J = 8.9Hz). 7.83 (1H, d),

 8.35 (1H, d, J = 7.2Hz), 9.16 (2H, s). 9.19 (2H, s),

 10.24 (1H, br)

MASS (M / Z): 533 (M + + 1) free FAB MASS

Example 6 7

 In the same manner as in Example 58, the starting compound (67) (1.43 g) and the compound of Production Example 14 (1.07 g) were converted to the target compound (6 7) was obtained.

 Yield: 0.94 g

IR (Nujol): 3300. 1650 cm " ¹

 NMR (DMSO-de.δ): 0.80 (3H, d, J = 6.9Hz),

 0.83 (3H, d, J = 6.9Hz). 1.97 (3H, m),

 2.32 (2H, t like), 2.4-2.8 (2H, m), 2.82 (3H, s), 2.75-3.8 (8H, m), 4.10 (2H, t like),

 4.57 (2H, m), 7.14 (2H, d, J = 8.9Hz),

 7.82 (2H, d, J = 8.9Hz), 7.82 (1H, d),

 8.34 (1H, d, J = 7.6Hz), 9.15 (4H, s)

Production Example 30

In the same manner as in Production Example 10, 4- (4- (N-methoxycarbonylamidino) phenoxy] butyric acid was obtained from 4- (4-amidinophenoxy) butyric acid · hydrochloride. NMR (DMS0-d ₆ , δ: 1.18 (3H, t, J = 7.lHz) .1.92-2.06 (2H, m) 2.43-2.51 (2H, m), 3.61 (3H, s), 4.02-4.13 ( 4H.m), 7.01 (2H, d, J = 8.9Hz), 7.97 (2H, d, J = 8.9Hz), 9.06 (2H, br s)

Production example 3 1

 A concentrated hydrochloric acid solution of the compound obtained in Production Example 30 was stirred at 50 ° C. for 5 hours. The reaction mixture was distilled under vacuum, and the obtained precipitate was washed with getyl ether to obtain the compounds shown in Table 6.

NMR (DMS0-d ₆ , δ): 1.90-2.04 (2Η, m), 2.42 (2H, t, J = 7.1 Hz), 3.88 (3H, s), 4.13 (2H, t, J = 6.3 Hz),

 7.15 (2H, d, J = 8.9Hz), 7.86 (2H, d, J = 8.9Hz).

 10.35 (1H, br s)

MASS (M / Z): 281 (M + + 1)

Production Example 32

 In the same manner as in Production Example 26, t-butoxycarbonyl-Va-trithiomorpholine amide was obtained from t-butoxycarbonyl-Val.

 NMR (DMSO-de, δ): 0.83 (6Η, d, J = 6.6Hz), 1.38 (9H, s),

1.88-1.99 (1H, m), 2.49-2.73 (4H, m), 3.55-3.59 (1H, m), 3.66-3.76 (1H.m), 3.87-3.98 (2H, in), 4.08-4.19 (1H , m), 6.88 (1H, d, J = 8.8Hz)

Production example 3 3

A solution of the compound (2.85 g) obtained in Production Example 32 in dichloromethane (4 Om) was stirred at 0 ° C, and m-chloroperbenzoic acid (3.90 g) was added thereto. Stir for 3 hours. The reaction mixture was poured into a saturated aqueous solution of potassium carbonate. The separated organic layer is washed with a saturated aqueous solution of sodium iodide, a saturated aqueous solution of sodium thiosulfate, a saturated aqueous solution of potassium carbonate, water, and then with a saturated saline solution, dried over magnesium sulfate, and the filtrate is distilled in vacuo. -Butoxycarbonyl-Val-thiomorpholine-1,1-dioxyamide was obtained. IR (Nujol): 3400, 1700, 1630, 1310, 1160, 1120 cm; ¹

 NMR (DMSO-ds, 6): 0.83 (3H, d, J = 4.2Hz),

 0.87 (3H, d, J = 4.2Hz), 1.38 (9H, s), 1.85-2.02 (1H, m), 2.98 (1H, m), 3.16 (2H, m), 3.31 (2H, m), 3.52 (1H, m). 3.79 (1H, m), 4.11-4.25 (2H, m), 7.07 (1H, d, J = 8.2Hz) Production example 3 4

 In the same manner as in Production Example 27, Val-thiomorpholine-1-1,1-dioxamide / hydrochloride was obtained from the compound obtained in Production Example 33.

 NMR (DMSO-de.δ): 0.96 (6Η.d, J = 6.8Hz), 1.95-2.08 (1H, m).

 3.05-3.24 (2H, m), 3.28-3.39 (2H, m), 3.57-3.70 (1H, m), 3.77-3.88 (1H, m), 4.30 (1H, d, J = 6.1Hz),

 4.40-4.53 (2H, m). 8.51 (3H, s)

MASS (/ Z): 440 ( M + + 1) free FAB MASS

Production example 3 5

 In the same manner as in Production Example 28, t-butoxycarbonyl-Asp (0Bzl) Vatrithiomorpholine-1.1-dioxyamide was obtained from the compound obtained in Production Example 34.

 NMR (DMSO-de, δ): 0.81 (6Η, d, J = 10.9Hz), 1.38 (9H, s),

 1.89-2.03 (1H, m). 2,55-2.68 (2H, m), 2.77-3.13 (4H, m), 3.23-3.33 (1H, m), 3.50-3.61 (1H, m), 3.98-4.17 (2H, m), 4.31-4.42 (1H, m), 4.56-4.64 (1H, m), 5.09 (2H, s), 7.28 (1H, d. J = 8.2Hz), 7.35-7.39 (5H, m ),

 7.89 (1H, d, J = 8.2Hz)

Production example 3 6

 The compounds shown in Table 6 were obtained from the compounds obtained in Production Example 35 in the same manner as in Production Example 29 except for using ethyl acetate instead of dioxane.

IR (Nujol): 3300, 1740, 1630, 1280, 1120 cm " ¹

 NMR (DMSO-de, δ: 0.89 (3Η, d, J = 6.8Hz),

0.93 (3H, d, J = 6.8Hz), 1.91-2.05 (1H, m), 2.96 (2H, d, J = 6.1Hz), 3.14-3.21 (3H, m),,

 3.33- 3.44 (2H, m), 3.51-3.61 (2H, m), 3.81-3.84 (1H, ra), 4.20-4.26 (1H, m), 4.58-4.66 (1H, m), 5.13 (2H.s ),

7.34- 7.50 (5H, ra), 8.68 (3H, br s), 8.84 (1H, d, J = 7.9Hz) Production example 3 7

 In the same manner as in Production Example 26, t-butoxycarbonyl-ILe-thiomorpholine amide was obtained from t-butoxycarbonyl-ILe.

IR (Nujol): 3300, 1680, 1620, 1500, 1240 cm ^-1

_{NMR (DMS0-d 6 δ.} ): 0.79 (.. 3Η d J = 6.7Hz),

 0.83 (3H, d, J = 7.4Hz), 1.38 (9H, s), 1.43-1.51 (2H, m), 1.69-1.74 (1H, m), 2.51-2.74 (4H.m), 3.53-3.60 ( 1H, m), 3.68-3.78 (1H, m). 3.89 (2H, m), 4.15-4.23 (1H, m), 6.93 (1H, d. J = 8.8Hz)

Production Example 38

 In the same manner as in Production Example 32, from the compound obtained in Production Example 37, t-butoxycarbonyl-ILe-thiomorpholine-11,11-diquinamide was obtained.

Yomi (圆 -d ₆ , ： 0.80 (3H, d, J = 7.0Hz).

 0.83 (3H.d, J = 7.4Hz), 0.98-1.16 (1H, m), 1.38 (9H, s), 1.44-1.53 (1H, m) .1.70-1.74 (1H.m), 2.95-3.00 ( 1H, m), 3.13-3.18 (3H, m), 3.46-3.57 (1H, m), 3.73-3.85 (1H, m), 4.13-4.28 (3H, m), 7.13 (1H, d, J = 8.2 Hz)

Production example 39

 In the same manner as in Production Example 27, ILe-thiomorpholin-1,1,1-dioxamide, hydrochloride was obtained from the compound obtained in Production Example 38.

 NMR (DMSO-de, δ): 0.84 (3Η, d, J = 7.3Hz),

 0.91 (3H, d, J = 7.0Hz), 1.02-1.20 (1H, m),

 1.47-1.76 (1H, m). 1.76-1.79 (1H.m), 3.07-3.47 (4H, m),

3.58-3.82 (2H, m), 4.29-4.32 (2H, m), 4.44-4.51 (1H, m), 8.43 (3H, br s) _r

Production Example 4 0

 In the same manner as in Production Example 28, t-butoxycarbonyl-Asp (OBzl) ILe-thiomorpholine-11,1-dioxyamide was obtained from the compound obtained in Production Example 39.

 NMR (DMSO-de.δ): 0.81 (6Η, m), 1.02-1.17 (1H, m),

 1.38 (9H, s), 1.48 (1H, m), 1.73-1.78 (1H, m).

 2.51-2.76 (2H, m), 2.81-3.27 (4H, m), 3.47-3.58 (1H, m). 3.76 (1H.m), 4.13-4.29 (2H, m), 4.33-4.40 (1H, m ), 4.57-4.65 (1H, m), 5.09 (2H, s), 7.25 (1H, d, J = 8.0Hz), 7.31-7.36 (5H, m). 7.93 (1H, d, J = 8.2Hz)

Production example 4 1

 The compounds shown in Table 6 were obtained from the compounds obtained in Production Example 40 in the same manner as in Production Example 35.

 Hidden (DMSO-de, δ: 0.81-0.87 (6Η, m), 1.13-1.20 (1H, m),

 1.50-1.54 (1H.m) .1.75-1.79 (1H, m),

 2.94 (2H, d, J = 6.2Hz) .3.03 (1H, m), 3.14-3.21 (3H, m), 3.46-3.56 (2H, m), 3.79 (1H, m), 4.17-4.29 (2H, m), 4.61-4.69 (1H.m) .5.13 (2H, s), 7.34-7.42 (5H, m), 8.55 (3H, br s), 8.83 (1H, d, J = 8.0Hz)

 Table 6 shows the formula of the compound obtained in Production Example 30.36.41.

Further, Table 6 shows the formulas of the starting compound and the target compound in Examples 68-85.

Table 6

Production Example 30-(CH ₂ -C00H compound

HC1 in Production Example 3 6 • H-Asp (OBzl ) -Val-N S0 2 Compound Production Example 4 1 of HCl • H- Asp (OBzl) - ILe- N S0 2 Compound

Table 7

Example 6 8

Starting compound (68) HCl-HAsp (0Bzl) Val-N N-C0-CH ₃

 N

Target compound (68)

_{Am (Z) 0- (CH z} ) 3 -C0-Asp (0Bzl) Val-N N-CO-CH3 Example 6 9

Starting compound (69) HCl · HAsp (0Bzl) Val-N VNAc

 H

The target compound (69),,

Am (Z) base) ~ 0- (CH ₂ ) 3 -CO-Asp (OBzl) Val -N -NAc

 H Example 7 0

Target compound (70) Am- ^ OV0- (CH ₂ ) 3-C0-AspVal- N-CO-CH3TFA

Example 7 1 Target compound (71)

V-0- (CH ₂ ) 3-C0-AspVal -N -N-CO-CH3 TFA

 H Example 7 2

The starting compound (7 2 a) Am (Z ) ~ 0CH 2 C0Sar0H starting compound (7 2 b) HC Les HAsp (OBzl) - Leu-N S0 2 The object compound (7 2 a) Am (Z ; 0CH 2 C0Sar-Asp (0Bzl) Leu-N S0 ₂ The object compound (7 2 b) 'TFA

Example Ί 8

 ΗΝ

The starting compound _{(7 8) 0 (CH 2} ) 3 C0-Asp (0Bzl) Val-N SO:

 CHaOCO-N ヽ

 H

HN

The object compound (7 8) OV 0 (CH 2) aCO-AspVal -N_J0 2 - TFA

 CHaOCO-N

 H Example 7 9

 HN

Starting compound (79 a) 0 (CH ₂ ) ₃ C00H

 CHsOCO-N

 H Starting compound (79 b) HCl-HAsp (OBzl) Val-N SO: target compound (79)

 HN

_{0 (CH 2) 3 -C0Asp (} 0BZl) Val-N S0 2 - 2TFA

 H Example 8 0

 HN

The starting compound (8 0 a) 0 (CH 2) 3 C00H

Starting compound (8 O b) HCl-HAsp (0Me) ValN SO

Target compound (80)

 HN

OV- ° ( ^CH 2) 3C0Asp (0Me) ValN S02 ₂ TFA

Example 8 1

Starting compound (8 1) Am ^ 0 (CH ₂ ) ₃ C0AspValN S0 ₂

No

Target compound (8 1) Am- <0 (CH ₂ ) ₃ C0Asp (0Et) Val SO2

Starting compound (8 2) Am -0 (CH ₂ ) ₃ C0AspVal 0-TFA Target compound (82) Am be 0 (CH ₂ ) 3C0Asp (0Et) Val ^ 0 TFA Example 8 3

Starting compound (83) Am ^ 0 (CH ₂ ) ₃ C0AspValN 0-TFA Target compound (83) Am be 0 (CH ₂ ) ₃ C0Asp (0Bzl) Val ^ 0 TFA Example 8 4

The starting compound (8 4) Am ^ 0- ( CH 2) 3 -C0AspValN S0 2 · TFA

_Λ /

Desired compound (8 4) Am- / 0- ( CH 2) 3 -C0Asp (0Bzl) Val N ^ SO EXAMPLE 8 5

Starting compound (85) Am- ^ 0 (CH ₂ ) ₃ C0AspValN S0 ₂ Target compound (85) Am (Z)) ₃ C0AspValN S0 ₂

Example 6 8 _r

 In the same manner as in Example 36, the starting compound (68) (0.75 g) and the compound of Preparation Example 14 (0.57 g) were converted to the target compound (68) (1.36 g). I got

 Hidden (D SO-de, δ): 0.81 (6H, t, J = 6.4Hz), 1.09-1.21 (1H, m), 1.91-2.00 (2H, m), 2.12 (3H, s). 2.22-2.33 (2H, m), 2.55-2.89 (2H, m), 3.12-3.19 (1H, m), 3.23-3.35 (7H, m), 4.05 (2H, m), 4.56 (1H, m), 4.70 (1H , m), 5.06 (2H, s), 5..10 (2H, s), 7.00 (2H, d, J = 8.9Hz). 7.29-7.42 (10H, m). 7.86 (1H, t, J = 8.3Hz), 7.99 (2H, d, J = 8.9Hz),

 8.35 (1H.d, J = 7.2Hz), 9.09 (2H, br s)

MASS (M / Z): 771 (M ⁺ + 1) FAB MASS

Example 6 9

 In the same manner as in Example 36, from the starting compound (69) (0.90 g) and the compound of Production Example 14 (0.66 g), the target compound (69) (1.38 g) was obtained. I got

 Hidden (DMSO-de, δ): 0.75-0.85 (6Η, m), 0.99-1.13 (4H, m),

 1.15-1.21 (2H, m), 2.27-2.34 (2H, t, J = 6.9Hz),

 2.57-2.89 (6H.m), 3.05-3.20 (1H, m), 3.61-3.79 (2H, m), 3.95-4.05 (2H, t, J = 7.1Hz), 4.08-4.18 (1H, ra),

 4.59 (1H, t, J = 6.7Hz), 4.72 (1H, m), 5.07 (2H.s),

 5.11 (2H, s), 7.00 (2H, d, J = 8.9Hz), 7.35-7.50 (10H, m), 7.69-7.88 (2H, m). 8.00 (2H, d, J = 8.9Hz), 8.40 (1H, m), 9.15 (2H, br s)

MASS (M / Z): 785 (M + + 1) FAB MASS

Example Ί 0

 In the same manner as in Example 53, the desired compound (70) (0.71 g) was obtained from the compound (1.30 g) obtained in Example 68.

 HPLC conditions,

Column: YMC-PACK R-ODS-15 S-15 120A0DS 500 x 250 mm,

Eluent: CH ₃ CN / 0.1¾ TFA aqueous solution = 20%

 Flow rate: 118 ml / min

 Retention time: 7.14 minutes

 Melting point: 157-159 ° C

IR (Nujol): 3300, 1660, 1640, 1610. 1270, 1210 cm " ¹ NMR (DMSO-de, 5): 0.81 (6H.t, J = 6.8Hz), 1.94-1.97 (3H, m), 2.02 (3H, s), 2.31 (2H, t, J = 6.9Hz), 2.42-2.76 (2H, m), 3.40-3.52 (8H, m), 4.11 (2H, t, J = 6.3Hz), 4.52- 4.65 (2H, m), 7.15 (2H, d, J = 8.9Hz), 7.82 (3H, m), 8.34 (1H, d, J = 7.7Hz), 9.14 (2H.s), 9.16 (2H.s )

MASS (M / Z): 547 (M + + 1) free FAB MASS

Example 7 1

 In the same manner as in Example 53, the desired compound (71) (0.47 g) was obtained from the compound (1.20 g) obtained in Example 69.

 HPLC conditions

 Column: YMC-PACK R-ODS-15 S-15 120A0DS

 500 X250 images

Eluent: CH ₃ CN / 0.1¾ TFA aqueous solution = 20%

 Flow rate: 118 ml / min

 Retention time: 8.76 minutes

 Melting point: 92-95 ° C

 NMR (DMSO-de.δ): 0.75-0.85 (6Η, in), 1.24 (2H, m).

 1.80 (6H, m), 1.91-2.01 (2H, m), 2.32 (2H, t, J = 6.7Hz), 2.42-2.52 (2H, m), 2.67-2.84 (2H.m), 3.08-3.20 ( 1H, m), 3.77-3.94 (2H, m), 4.11 (2H, t, J = 6.2Hz), 4.23 (1H, m), 4.59 (2H.m), 7.15 (2H.d, J = 8.9Hz) ), 7.69 (1H.m),

7.85 (3H, m), 8.36 (1H, m), 9.06 (2H, s), 9.15 (2H, s) MASS (M / Z): 561 (M ⁺ + 1) free FAB MASS,

Example 72

 In the same manner as in Example 60, the desired compound (72a) (1.75 g) was obtained from the starting compound (72a) (1) and the starting compound (72b) (1.35 g). Purification by HP LC gave the desired compound (72b) (1.08 g).

 The data of the target compound (72b) are shown.

Hidden (DMS0-d _e , <5): 0.83 (3H, d, J = 3.6Hz),

 0.86 (3H, d, J = 3.5Hz), 1.3-1.7 (3H, m). 2.4-2.8 (2H, m), 2.79, 3.00 (3H, each s), 2.8-4.0 (8H, m),

 3.97, 4.05 (2H, each s), 4.93, 5.04 (2H, each s),

 7.12 (2H, d, J = 8.7Hz). 7.78 (2H, d, J = 7.7Hz), 8.30 (1H, d, J = 7.9Hz),

 8.13, 8.60 (1H, each d, J = 7.8Hz, 7.9Hz),

 9.03 (2H, s), 9.14 (2H, s)

MASS (M / Z): 611 (M + + 1) free FAB MASS

 HPLC conditions

Eluent: 20% CH ₃ 1% TFA aqueous solution

 Retention time: 10.47 minutes

Example 73

 From the starting compound (73a) (0.5 g) and the starting compound (73b) (0.61 g), the target compound (73a) (0.84 g) was obtained in the same manner as in Example 60. The obtained compound was purified by preparative HPLC to obtain the desired compound (73b) (0.36 g).

 The data of the target compound (73b) are shown.

IR (Nujol): 3300. 1640, 1520 cm " ¹

_{NMR (DMS0-d 6 δ.} ): 0.82 (6Η, m), 1.41 (. 2H m), 1.54 (1H, m).

 2.35-2.8 (2H, m), 2.80, 3.0 (3H, each s),

3.2-3.7 (8H, m), 3.98, 4.06 (2H, each s), 4.63 (2H.m), 4.94, 5.05 (2H, each s), 7.13 (2H, d, J = 8.9Hz), 7.78 (2H, d, J = 8.7Hz).,

 7.95. 8.13 (1H, each d. J = 8.2Hz. 8.1Hz),

 8.27.8.57 (1H, each d, J = 8.lHz, 7.9Hz),

 9.02 (2H, s). 9.13 (2H, s)

MASS (M / Z): 563 (M + + 1) free FAB MASS

 HPLC conditions

 Eluent: 20% CHsCN / 0.1% TFA aqueous solution

 Retention time: 9.87 minutes

Example 74

 In the same manner as in Example 13, the target compound (74) (2.68 g) was obtained from the starting compound (74) (3.9 g).

 IR (Nujol): 3275, 3100, 1720, 1665, 1635. 1610. 1540.

 1510 cnr

NMR (DMS0-d ₆ , δ): 1.96 (2Η, m). 2.29 (2H, t like),

 2.3-2.95 (2H, in) .3.1-3.6 (10H, m), 3.70 (3H, s),

 4.09 (2H, t like), 4.57 (1H, nO, 4.81 (1H.m),

 6.81 (2H, d, J = 8.6Hz), 7.09 (2H, d, J = 8.6Hz), 7.14 (2H, d, J = 8.9Hz), 7.81 (2H, d, J = 8.9Hz),

8.03 (1H, d, J = 7.8Hz), 8.21 (1H.d, J = 7.9Hz),

9.07 (2H, s), 9.14 (2H, s)

Example 7 5

 In the same manner as in Example 13, the starting compound (75) (2 g) was obtained, and the target compound (75) (0.95 g) was obtained.

IR (Nujol): 3280, 3080, 1720, 1660. 1635, 1540, 1510 cm " ¹ NMR (D S0-d ₆ , δ): 1.52 (4Η, m). 2.13 (2H, t like),

 2.3-2.9 (6H, m), 3.0-3.6 (8H.m), 3.71 (3H.s),

 4.55 (1H, m), 4.80 (1H, m), 6.80 (2H, d, J = 8.6Hz),

7.08 (2H, d, J = 8.6Hz) .7.44 (2H, d, J = 8.3Hz), 7.73 (2H.d, J = 8.3Hz), 7.98 (1H, d, J = 7.8Hz) 8.13 (1H, d, J = 7.9Hz), 9.22 (2H, s), 9.24 (2H, s)

 HPLC conditions

 Eluent: 24¾ CHsCN / 0.1¾ TFA aqueous solution

 Retention time: 12.66 minutes

Example 7 6

 In the same manner as in Example 13, the target compound (76) (1.13 g) was obtained from the starting compound (76) (2 g).

IR (Nujol): 3275, 3100. 1665, 1640, 1535, 1510 cm " ¹

NMR (D S0-d ₆ , δ: 1.10 (3H, t, J = 7Hz), 1.52 (4H.m),

 2.11 (2H, t like), 2.25-3.0 (6H, m), 3.05-3.4 (4H, m), 3.40 (2H, q, J = 7Hz), 3.70 (3H, s). 4.36 (1H, m) ,

 4.52 (1H, m), 6.78 (2H, d, J = 8.6Hz),

 7.07 (2H, d, J = 8.6Hz), 7.44 (2H, d, J = 8.3Hz),

7.74 (2H, d, J = 8.3Hz). 7.74 (1H, m), 7.95 (1H, t like), 8.16 (1H, d, J = 7.8Hz). 9.24 (4H, s)

 HPLC conditions

Eluent: 27% CH ₃ CN / 0.1¾ TFA aqueous solution

 Retention time: 9.41 minutes

Example 7 7

In the same manner as in Example 58, starting compound (77) (2.07 g) was converted to target compound (77 b) (2 g) via target compound (77 a) (3.3 g). . shows data 3 5 g) to _c objective compound was obtained (7 7 b).

IR (Nujol): 3280, 3090, 1665, 1645, 1610, 1530 cm " ¹

NMR (D S0-d _6. δ): 0.97 (3Η, d, J = 6.5Hz),

 1.03 (3H, d, J = 6.5Hz), 1.27 (3H, t, J = 6.9Hz),

1.95 (2H, m). 2.28 (2H, t like). 2.3-3.0 (4H, m),

3.78 (1H, m), 3.94 (2H, q, J = 6.9Hz), 4.09 (2H, t like), 4.30 (1H, m), 4.53 (1H, m), 6.77 (2H, d, J = 8,5Hz),

7.05 (2H, d, J = 8.5Hz), 7.15 (2H, d, J = 8.9Hz),

 7.62 (1H, d, J = 7.7Hz). 7.74 (1H, d, J = 8.2Hz),

 7.81 (2H, d, J = 8.9Hz). 8.26 (1H.d.J = 7.7Hz),

 9.06 (2H, s), 9.14 (2H, s), 12.37 (1H, s)

 HPLC conditions

 Eluent: 30¾ CHsCN / 0.1% TFA aqueous solution

 Retention time: 9.42 minutes

Example 7 8

 In the same manner as in Example 53, the target compound (78) (1.03 g) was obtained from the starting compound (78) (2.5 O g).

 HPLC conditions

 Column: YMC-PACK R-ODS-15 S-15 120A0DS

 500 X 250 recitation

 Eluent: CHsCN / 0.1¾ TFA aqueous solution = 21%

 Flow rate: 118 m £ / min

 Retention time: 7.32 minutes

 Melting point: 89-91 ° C

 NMR (DMSO-ds.δ): 0.83 (3Η, d, J = 6.5Hz),

 0.85 (3H.d.J = 6.5Hz) .1.94-2.04 (3H.m).

 2.32 (2H, d, J = 6.9Hz), 2.43-2.76 (2H, m), 3.11 (3H, m),

3.29 (1H, m), 3.57 (1H.m), 3.75 (1H, m). 3.89 (3H, s),

4.12 (2H, t.J = 6.0Hz), 4.25 (2H, m), 4.53-4.68 (2H, m),

7.15 (2H.d, J = 8.9Hz). 7.81 (2H.d, J = 8.9Hz),

 7.97 (1H, d, J = 8.2Hz), 8.34 (1H, d, J = 7.7Hz),

 10.39 (2H.br s)

MASS (M / Z): 612 (M + + 1) free FAB MASS

Example 7 9 AspCOBzDVal- thiomorpholine-1,1-dioxy amide salt (starting compound (79b)) (1.27 g), 4- (N-methoxycarbonylamidino) phenoxy Valeric acid [Starting compound (79a)] (0.75 g) and N, N-dimethylformamide (20%) of 1-hydroxyl 1H-benzotriazole (0.40 g) m ^) solution was added dropwise with triethylamine (0.45 m_g), and the mixture was stirred at -20 ° C for 30 minutes, and then added with 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The salt was added at 120 ° C and stirred at room temperature for 3 hours. The reaction mixture was poured into an aqueous solution of ethyl acetate, and the pH was adjusted to about 10.5 with a saturated aqueous solution of potassium carbonate. The separated organic layer was washed with 0.5N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate, water, and then with brine, and dried over magnesium sulfate. After filtration, the filtrate was distilled in vacuo and purified by preparative HPLC to obtain the desired compound (79).

 HPLC conditions

 Column: Lightning-PACK R-ODS-15 S-15 120A0DS

 500 X250 mm

Eluent: CH ₃ CN / 0.1% TFA aqueous solution = 40%

 Flow rate: 118 ml / min

 Retention time: 5.80 minutes

 Melting point: 68-70. C

 NMR (DMSO-de, δ: 0.84 (6Η, d, J = 6.6Hz), 1.98 (3H, m), 2.29 (2H, t, J = 6.9Hz), 2.56-2.69 (2H, m),

 2.77-2.99 (5H, m), 3.13 (1H, m), 3.53 (1H, m).

 3.76 (1H.m), 3.89 (3H.s), 4.10 (2H, d, J = 6.3Hz),

 4.20 (2H, m), 4.56 (1H, m), 4.72 (1H, m), 5.08 (2H, s), 7.14 (2H, d, J = 8.9Hz), 7.31-7.37 (5H, m),

 7.81 (2H, d, J = 8.9Hz), 8.09 (1H, d, J = 8.2Hz).

 8.38 (1H, d, J = 7.9Hz)

 MASS (M / Z): 702 (M ++ 1) Free FAB MASS

Example 8 0 In the same manner as in Example 79, starting compound (80) (0.28 g) and starting compound (8Ob) (0.44 g) were converted to target compound (80) (0.285). g) was obtained.

IR (Nujol): 3275, 1720, 1630, 1595, 1500 cm " ¹

 Haze (DMSO-de, δ): 0.84 (6Η, d, J = 6.6Hz), 1.96 (2H, m), 1.99 (1H.m), 2.30 (2H, t like), 2.5-2.85 (2H, m ),

 2.9-4.3 (8H, m), 3.88 (3H, s), 4.10 (2H, t like),

 4.55 (1H, m). 4.66 (1H, m) .7.14 (2H, d, J = 8.9Hz),

 7.81 (2H.d.J = 8.9Hz), 8.06 (1H, d, J = 8.2Hz), 8.33 (1H, d, J = 7.9Hz), 10.36 (1H, s)

MASS (M / Z): 626 (M + + 1) free FAB MASS

 HPLC conditions

Eluent: 25¾ CH ₃ CN / 0.1% TFA aqueous solution

 Retention time: 6.95 minutes

Example 8 1

 A solution of the starting compound (81) (0.5 g) in ethanol (5πι £) -6N hydrochloric acid (1 m ^) was stirred at room temperature for 15 hours. The reaction mixture was distilled under vacuum and purified by preparative HPLC to obtain the desired compound (81) (0.4 g).

IR (Nujol): 3300, 3100, 1720 (), 1660, 1640, 1610, 1525 cm " ¹ NMR (D SO-de, δ): 0.83 (6Η, d 'J = 6.5 Hz),

 1.54 (3H, t, J = 7.1Hz), 1.8-2.1 (3H, m),

 2.30 (2H, t like), 2.4-2.8 (2H.m), 2.85-4.4 (12H.in),

4.55 (1H, m), 4.67 (1H, ra), 7.14 (2H, d, J = 8.8Hz),

 7.82 (2H, d, J = 8.8Hz), 8.05 (1H, d, J = 8.1Hz), 8.33 (1H, d. J = 7.9Hz), 9.10 (2H, s), 9.15 (2H, s)

MASS (M / Z): 582 (M ⁺ + 1) FAB MASS

 HPLC conditions

Eluent: 25% CH ₃ CN / 0.1¾ TFA aqueous solution

Retention time: 9.06 minutes Example 8 2,

 In the same manner as in Example 81, the target compound (82) (0.34 g) was obtained from the starting compound (82) (0.5 g).

IR (Nujol): 3300, 3090 , 1710, 1660, 1630, 1610, 1520 cm NMR (D S0-d 6, δ): 0.79 (. 3Η d, J = 6.6Hz),

 0.82 (3H, d.J = 6.6Hz). 1.15 (3H, t, J = 7.1Hz), 1.96 (3H, m), 2.31 (2H, t like), 2.4-2.85 (2H, m),

 3.53 (8H, m), 3.9-4.2 (4H, m), 4.4-4.8 (2H, m),

 7.14 (2H, d, J = 8.9Hz) .7.81 (2H, d, J = 8.9Hz), 7.81 (1H, d), 8.34 (1H, d, J = 8Hz), 9.02 (2H, s),

 9.14 (2H, s)

MASS (M / Z): 534 (M ⁺ + 1) FAB MASS

 HPLC conditions

Eluent: 25% CH ₃ CN / 0.1¾ TFA aqueous solution

 Retention time: 8.36 minutes

Example 8 3

 The target compound (83) (0.26 g) was obtained from the starting compound (83) (0.5 g) in the same manner as in Example 81 except that benzyl alcohol was used instead of ethanol.

 IR (Nujol): 3300, 3100. 1710, 1660, 1630, 1520 cm

 NMR (DMSO-de, δ): 0.8 (6Η, t, J = 6.7Hz), 1.95 (3H, m),

 2.29 (2H, m) .2.55-2.9 (2H, m), 3.51 (8H, m), 4.09 (2H, t like), 4.53 (1H, ra), 4.69 (1H, m),

 5.07 (2H, s), 7.14 (2H, d, J = 8.9Hz), 7.34 (5H, s like), 7.82 (2H, d, J = 8.9Hz). 7.86 (1H, d), 8.38 (1H, d, J = 8Hz),

9.08 (2H, s), 9.15 (2H, s)

MASS (M / Z): 596 (M + + 1) free FAB MASS

HPLC conditions Eluent: 33 CH ₃ CN / 0.1¾ TFA aqueous solution,

 Retention time: 10.98 minutes

Example 84

In the same manner as in Example 83, the target compound (84) was obtained from the starting compound (84). _C NMR (D SO-de.δ): 0.83 (6Η, d, J = 6.5 Hz), 1.8-2.0 (3H , In).

 2.8 (2H, m), 2.6—4.4 (16H, m), 4.5 (1H, m). 4.7 (1H, m), 5.07 (2H, s), 7.13 (2H, d. J-8.7Hz), 7.35 (5H, s),

 7.82 (2H, d, J = 8.7Hz) .8.07 (1H, d, J = 8.1Hz), 8.36 (1H, d, J = 8.lHz), 9.12 (4H, br s)

MASS (M / Z): 644 (M + 1) ⁺ , 666 (+ Na) ⁺ FAB MASS

 HPLC conditions

 Eluent: 20¾ CHsCN / 0.1¾ aqueous solution

 Retention time: 23.5 minutes

Example 85

 To a solution of the starting compound (85) (1) in IN sodium hydroxide, benzyloxycarbonyl chloride (0.34 g) was added dropwise over 5 minutes while cooling with ice water. The reaction mixture was stirred at 10 ° C for 30 minutes, poured into water, and extracted with ethyl acetate (2 Om ^). The extract was washed with brine and dried over magnesium sulfate. After filtration, the filtrate was distilled under vacuum, and the obtained precipitate was washed with getyl ether to obtain the desired compound (85) (0.825 g).

IR (Nujol): 3300, 1710 (w), 1635, 1500 cm ' ¹

 NMR (DMSO-de, δ): 0.82 (3Η, d, J = 6.6Hz),

 0.83 (3H, d, J = 6.6Hz), 1.8-2.1 (3H, m). 2.29 (2H, t like), 2.35-2.8 (2H, m), 2.9-4.3 (8H.m), 4.05 (2H , m),

 4.57 (2H, m), 5.10 (2H, s) .7.0 (2H, d.J = 8.9Hz),

 7.39 (5H, in), 7.98 (2H, d, J = 8.9Hz), 7.99 (1H, d like), 8.29 (1H.d, J = 7.8Hz), 9.1 (2H, br s)

MASS (M / Z): 688 (M ⁺ 1) FAB MASS

Claims

The scope of the claims

 1. Formula (I):

R ²

 I

R'-f 0 ^ -s- A ¹ -CO-A ² ^ -H— NHCHCO -NH-A ³ -R ³ (I)

Wherein R ¹ is aryl which may have one or more suitable substituents; R ² is carboxy (lower) alkyl or protected carboxy (lower) alkyl; and R ³ is amidated. A ¹ is a lower alkylene, A ² is a formula

I

 -N-CHzCO-

(Wherein R ⁴ represents lower alkyl) or a formula:

-NH-CHC0-

Wherein R ⁴ is as defined above, A ³ is lower alkylene which may have one or more substituents, m and n may be the same or different, 0 or 1] or a pharmacologically acceptable salt thereof.

2. R ¹ is phenyl optionally having 1 to 3 suitable substituents selected from the group consisting of amidino and protected midino groups, and R ³ is carbamoyl, N — (lower) Alkyl Lubamoyl, N—C (lower) Alkoxy— (lower) Alkyl] Lumbamoyl, or Formula:

(Wherein, R _N is piperidino, morpholino, 1-piperazinyl or 4-Chiomo Rufuo Riniru shows a) a group, these are 1-3 suitable substituents selected herds or et consisting of lower alkyl and Okiso A ³ is a (lower) alkylene which may have 1 to 3 phenyl (lower) alkyl which may have 1 to 3 (lower) alkoxy, and n is 0 2. The compound according to claim 1, which is:

3. R ¹ is amidino or a phenyl with a protected amidino, and R ³ is a group of the formula:

-COR _N

(Wherein, R _N is piperidino, morpholino, 1 Piperajiniru or 4 Chiomo Rufuo Riniru) a group having 1 to 3 suitable substituents selected herds or et consisting of lower alkyl and Okiso ^3. The compound according to claim 2, wherein A ³ is lower alkylene.

4. R ¹ is phenyl with an amidino, and R ³ is of the formula:

(Wherein, R _N is morpholino or thiomorpholine 1, 1 one Jiokishido - shows the 4 one I le) group of compounds ranging third claim of claim m is 1.

5. R ′ is phenyl with amidino and R ³ is of the formula:

(Wherein, R _N represents a Morufuorino) group of compounds ranging third claimed according m is 0.

6. Formula (I) by any of the following steps (i) to (iV): R ² '

R ¹ Ten ^{0 A 1 - CO - A 2} - r- NHCHCO -NH-A 3 -R 3 (I)

Wherein R ¹ is aryl which may have one or more suitable substituents; R ² is carboxy (lower) alkyl or protected carboxy (lower) alkyl; and R ³ is amidated. A ¹ is a lower alkylene, A ² is a formula

I

-N-CH ₂ C0-

(Wherein R ⁴ represents lower alkyl) or a formula:

R ⁴

 -NH-CHC0-

Wherein R ⁴ is as defined above, A ³ is lower alkylene which may have one or more substituents, m and n may be the same or different, 0 or 1].

 (i) Formula:

K ¹ dozen 0 A'-COOH

(Wherein R ¹ , A ¹ and m are as defined above), a derivative thereof reactive at the carboxy group, or a salt thereof;

R ²

^H — A ² ~~ HNCHC0- ΝΗ- A ³ — R ³

(Wherein R ² , R ³ , A ² , A ³ and n are as defined above), Reacting its derivatives or their salts in

 (i expression:

R ²

^R i10 0-s- A ¹ — CO10 A ² "r NHCHCO-NH-A ³ — R ³

(Wherein, R ² , R ³ , A ¹ , A ² , A ³ , m and n are as defined above, and Ri represents an aryl having a protected amidino) or a salt thereof. The elimination reaction of the protecting group of mizino gives the formula:

R ²

R ten 0-r A ¹ — CO ten A ² -r NHCHCO-NH-A ³ — R ³

Wherein R ² , R ³ , A ¹ , A ² , A ³ , m and n have the same meanings as described above, and represents an aryl having an amidino, or a salt thereof. (Iii) formula:

R ² ,

RH 0 j-sp A ¹ — CO-- A ² r NHLCO-NH-A ³ -R ³

Wherein R ¹ , R ³ , A ¹ , A ² , A ³ , m and n are as defined above, and R ^Z , represents a protected carboxy (lower) alkyl. The carboxy (lower) alkyl protecting group of the salt is subjected to an elimination reaction to obtain the formula:

RI

R ¹ † 0 A ¹ -C0- (A ² ) ~ i ~ NHCHC0— NH— A ³ — R ³

^{(Wherein, R 1, R 3, A} 1, A 2, A 3, m and n is a same meaning as defined above, R ^z _b is carboxy (lower) alkyl) to give a compound or a salt thereof of the methods , Or (iV) equation:

R ²

^R1 Ten 0 A ¹ - CO tens ^{A 2 "r NHCHC0-NH-} A 3, - R 3

(Wherein R ¹ R ² R ³ A ¹ A ² m and n are as defined above, and A ³ , represents a lower alkylene having a protected carboxy) or a carboquine salt thereof. The elimination reaction of the protecting group gives the formula:

R ²

 I

R ¹ Ten 0 A ¹ - CO tens _{^{A 2 "NHCHCO- NH- A 3 B}} - R 3

The method of obtaining ^{(wherein, R 1 R 2 R 3 A} 'A 2 m and n is a same meaning as defined above, A ³ _b is a lower alkylene having carboxy) compound, or a salt thereof,

 Equation (V):

I

R ¹ Ten ^{0 A 1 - co ~ A 2} - r- NHCHCO -NH - A 3 -R 3

^{(Wherein, R 1 R 3 A 1 A} 2 m and n is a same meaning as defined above, R ² c is Cal Bokishi (lower) alkyl) compounds, or S. etherification reaction of the carboxy group of a salt thereof By the formula:

_R1 Ten ^{_{0 CO - A 2 -hr- ΝΗΑΗΟΟ- NH-}} A 3 - R 3

Wherein R ¹ R ³ A ¹ A ² m and n have the same meanings as described above, and each represents an esterified carboxy (lower) alkyl, or a salt thereof. (V i)

R ²

R ten 0-r A ¹ — CO ten A ² NH0HC0-NH-A ³ — R ³

(Wherein R ¹ , R ³ , A ¹ , A ² , m and n are the same as defined above), or a salt thereof, into the compound represented by the formula:

Kit 0 A ¹ — CO ten A ² ^ TT NHCHC0— NH-A ³ — R ³

Wherein R ¹ , Ri, R ³ , A ¹ , A ² , m and n are as defined above, or a salt thereof.

 7. Pharmaceutical composition containing the compound according to claim 1 as an active ingredient and a pharmacologically acceptable carrier or excipient.

 8. Use of the compound according to claim 1 for the manufacture of a medicament.

 9. A compound according to claim 1 for use in medicine.

 10. A thrombotic disorder, restenosis and Z or reocclusion, vascular surgery or valve replacement, extracorporeal circulation, transplantation, which comprises administering the compound according to claim 1 to a human or animal. Prevention and treatment of thrombosis, Han-like vascular coagulation (DIC), thrombotic thrombocytopenic purpura, essential thrombocythemia, inflammation, immune disease, or thrombolytic, anticoagulant How to use together.