JPH07138221A - Amidino compound - Google Patents

Abstract

PURPOSE:To obtain a new amidino compound useful as a glycoprotein IIb/IIIa antagonism, an inhibitor of blood platelet agglutination, a preventive and/or therapeutic agent for thrombosis. CONSTITUTION:A compound of formula I [R<1> is amidino or a protected amidino; R<2> is H or a lower alkyl; R<3> is H, an acyl, an acyl (lower) alkoxy, an acyl-(lower) alkyl which may be substituted or an N-ar-(lower) alkyl-N-lower alkanoylamino-(lower) alkyl; m is 1-6] or its salt such as dimethyl[4-(4- amidinophenyloxy)acetylamino-l, 2-phenylenedioxy] diacetate.hydrochloride. The compound is obtained by reacting a compound of formula II with a compound of formula III in the presence of a condensation agent.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to amidino compounds having various pharmacological actions and salts thereof, and is useful in the field of medicine.

The amidino compounds and salts thereof of the present invention are glycoprotein IIb / IIIa antagonists,
Platelet aggregation inhibitor, thrombotic disease [eg, arterial thrombosis; arteriosclerosis; ischemic heart disease {eg, angina (eg, stable angina, unstable angina including urgent infarction, etc.) ,
Myocardial infarction (eg, acute myocardial infarction, etc.), coronary thrombosis,
Etc .; ischemic brain disease {eg, cerebral infarction (eg, cerebral thrombosis (eg, acute cerebral thrombosis, etc.), cerebral embolism, etc.), transient cerebral ischemia, cerebral vasospasm after bleeding (eg, Cerebrovascular spasm after subarachnoid hemorrhage, etc.), etc .; Pulmonary vascular disorders (eg, pulmonary thrombosis, pulmonary embolism, etc.); Peripheral circulatory disorders {eg,
Arteriosclerosis obliterans, thromboangiitis obliterans (Buerger's disease), Raynaud's disease, diabetic complications (eg diabetic angiopathy, etc.), venous thrombosis (eg deep vein thrombosis,
Etc.) etc.}; etc.] and is useful as a prophylactic and / or therapeutic agent, and also for restenosis and / or reocclusion (eg PTCA (percutaneous trans).
luminal coronary angioplas
ty) after restenosis / reocclusion, reocclusion after TPA (tissue plasminogen activator) administration, etc.) useful as a preventive agent, and further, a combination agent with a thrombolytic agent (eg, TPA) A combination agent with an anticoagulant (for example, heparin, etc.); a preventive and / or therapeutic agent for thrombus formation in the area of vascular surgery or valve replacement: during extracorporeal circulation (for example,
Surgery, hemodialysis, etc.) preventive agent for thrombus formation and /
Or a therapeutic agent; a preventive and / or therapeutic agent for thrombus formation during transplantation; disseminated intravascular coagulation (DIC), thrombotic thrombocytopenic purpura, essential thrombocythemia, inflammation (eg, nephritis, etc.), etc. It is useful as a preventive and / or therapeutic agent for cancer metastasis; an agent for suppressing cancer metastasis: a preventive agent and / or therapeutic agent for immune diseases;

Further, the amidino compound and salts thereof of the present invention are expected to be useful as cell adhesion inhibitors, and are prophylactic and / or therapeutic agents for inflammation (eg nephritis);
It is expected to be useful as an agent for suppressing cancer metastasis; a preventive agent and / or a therapeutic agent for immune diseases.

That is, one object of the present invention is to provide compounds and salts thereof which are useful as the above-mentioned various drugs.

Another object of the present invention is to provide a process for producing such compounds or salts thereof.

[0006] Still another object of the present invention is to provide a pharmaceutical composition (formulation) containing the compound or a salt thereof as an active ingredient and serving as the above-mentioned various drugs.

[0007]

The novel object compound of the present invention is represented by the following formula (I). formula: [Wherein R ¹ is an amidino group or a protected amidino group, R ² is hydrogen or a lower alkyl group, R ³ is hydrogen, an acyl group, an acyl (lower) alkoxy group, or a suitable substituent. A good acyl (lower) alkyl group or N-ar (lower) alkyl-N-lower alkanoylamino (lower) alkyl group, R ⁴ may have an acyl group, an acyl (lower) alkoxy group, or a suitable substituent. Good acyl (lower) alkyl group or N-ar (lower) alkyl-N-
Lower alkanoyl (lower) alkyl group, m means an integer of 1 to 6] or a salt thereof.

The object compound (I) or a salt thereof can be produced by the method represented by the following reaction formula. Manufacturing method 1

Manufacturing method 2

Manufacturing method 3 (Wherein R ¹ , R ² , R ³ and R ⁴ have the same meanings as described above, R ¹ _a represents a protected amidino group, R ³ _a and / or
Or R ⁴ _a is a group having a carboxy protecting group, R ⁴ _a
³ _b and / or R ⁴ _b each means a group having a carboxy protecting group).

Suitable pharmaceutically acceptable salts of compound (I) are conventional non-toxic salts, such as salts with inorganic bases such as alkali metal salts (eg sodium salt, potassium salt etc.), alkaline earth salts. Metal salts (eg calcium salt, magnesium salt etc.), ammonium salts; salts with organic bases such as organic amine salts (eg triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N, N'-
Dibenzylethylenediamine salt etc.); Inorganic acid addition salt (eg hydrochloride, hydrobromide, sulfate, phosphate etc.); Organic carboxylic acid addition salt or organic sulfonic acid addition salt (eg formate, acetate) , Trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, etc.); salts with bases such as salts with basic or acidic amino acids (eg arginine, aspartic acid, glutamic acid, etc.) Or it may include acid addition salts.

In the above and subsequent descriptions of the present specification, suitable examples and explanations of various definitions included within the scope of the present invention will be explained in detail below.

The term "lower" means 1 to 6 carbon atoms (preferably 1 to 4 carbon atoms) unless otherwise specified.

"Lower alkyl group" and "acyl (lower) alkyl group", "acyl (lower) alkoxy group",
Suitable "lower alkyl" moiety of "N-ar (lower) alkyl-N-lower alkanoylamino (lower) alkyl group" includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, It means a residue of a linear or branched alkane having 1 to 6 carbon atoms such as neopentyl, hexyl and the like, and a preferable example thereof is a C ₁ -C ₄ alkyl group.

The "lower alkyl group" is, for example, a straight or branched chain having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, neopentyl, hexyl and the like. Alkyl group, and a preferable example thereof is an alkyl group having 1 to 4 carbon atoms.

Suitable "protected amidino group" is an acylamidino group or a conventional protecting group such as an ar (lower) alkyl group which may have a suitable substituent (eg, benzyl group, trityl group, etc.). And an amidino group substituted by. Suitable "acyl" moieties of "acyl group" and "acyl (lower) alkoxy group", "acyl (lower) alkyl group", "acyl amidino group" include carboxy; esterified carboxy; lower alkyl, carboxy lower Carbamoyl optionally substituted with a substituent selected from the group consisting of alkyl, lower alkoxy, lower alkoxycarbonyl lower alkyl, cyclo (lower) alkyl, aryl and hydroxy; lower alkanoyl; heterocyclic carbonyl; lower alkylsulfonyl; Can be mentioned.

Esterified carboxy includes substituted or unsubstituted lower alkoxycarbonyl (eg methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, hexyloxycarbonyl, 2-iodoethoxycarbonyl, 2,2,2-trichloroethoxy). Carbonyl), substituted or unsubstituted aryloxycarbonyl (eg, phenoxycarbonyl, 4-nitrophenoxycarbonyl, 2-naphthyloxycarbonyl, etc.), substituted or unsubstituted ar (lower)
Alkoxycarbonyl (for example, benzyloxycarbonyl, phenethyloxycarbonyl, benzhydryloxycarbonyl, 4-nitrobenzyloxycarbonyl etc.) etc. can be mentioned.

The heterocyclic moiety in the "heterocyclic carbonyl" is 3 to 8 having 1 to 4 nitrogen atoms.
Member, more preferably a 5- or 6-membered unsaturated heteromonocyclic group,
For example, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridyl N-oxide, dihydropyridyl, tetrahydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, triazolyl, tetrazinyl, tetrazolyl; 3 to 8 members having 1 to 4 nitrogen atoms, more preferably Is a 5- to 6-membered saturated heteromonocyclic group,
For example, pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc .; unsaturated fused heterocyclic group having 1 to 5 nitrogen atoms, such as indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl;

A 3- to 8-membered unsaturated heteromonocyclic group having 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isooxazolyl, oxadiazolyl, etc .; 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms. 3 to 8 membered saturated heterocyclic group having 1 to 2 members, such as morpholino, sydnonyl, etc .; unsaturated condensed heterocyclic group having 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, benzoxazolyl, benzoxa Such as diazolyl.

Unsaturated 3- to 8-membered unsaturated heteromonocyclic groups having 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, isothiazolyl, thiadiazolyl; 3 to 8 having 1 oxygen atom. Membered unsaturated heteromonocyclic groups such as furyl; oxygen atom 1 to 2
Unsaturated fused heterocyclic group having a group such as benzofuranyl;

The "suitable substituent" of the acyl (lower) alkyl group which may have a suitable substituent includes lower alkyl (eg methyl, ethyl, propyl, etc.) and lower alkoxy (eg methoxy, ethoxy). , Propoxy, etc.), lower alkylsulfonylamino (eg, methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, butylsulfonylamino, etc.),
Lower alkanoylamino (eg formylamino, acetylamino, propionylamino, butyrylamino, valerylamino, hexanoylamino, pivaloylamino, etc.), carboxy lower alkanoylamino (eg carboxyacetylamino, carboxypropionylamino, carboxybutyrylamino, carboxyvalerylamino) , Carboxyhexanoylamino, carboxypivaloylamino, etc.), lower alkoxycarbonyl lower alkanoylamino (eg, methoxycarbonylacetylamino, ethoxycarbonylacetylamino, propoxycarbonylacetylamino, etc.) and the like.

Suitable "ar (lower) alkyl" moiety of "N-ar (lower) alkyl-N-lower alkanoylamino (lower) alkyl" is phenyl (lower) alkyl (eg benzyl, phenethyl, phenylpropyl, etc.). ), Benzhydryl, trityl, tolylmethyl, xylylmethyl, mesitylmethyl, cumenylmethyl and the like. Among them, preferred is phenyl (lower) alkyl, and most preferred is benzyl.

The method for producing the object compound (I) is described in detail below. Production Method 1 The object compound (I) or a salt thereof is produced by reacting a compound (II) or a reactive derivative thereof at an amino group or a salt thereof with a compound (III) or a reactive derivative thereof at a carboxy group or a salt thereof. can do.

Suitable reaction derivatives of the compound (II) at the amino group include Schiff base type imino compounds formed by the reaction of the compound (II) with carbonyl compounds such as aldehydes and ketones, or tautomeric enamines thereof. Type isomers, silyl derivatives formed by the reaction of compound (II) with a silyl compound such as bis (trimethylsilyl) acetamide, mono (trimethylsilyl) acetamide [eg N- (trimethylsilyl) acetamide], bis (trimethylsilyl) urea, etc. A derivative or the like formed by the reaction of compound (II) with phosphorus trichloride or phosgene.

Preferable examples of the reactive derivative at the carboxy group of the compound (III) include acid halide, acid anhydride, active amide, active ester and the like. Preferable examples thereof include acid chloride; acid azide; substituted phosphoric acid (eg, dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, etc.), dialkyl phosphorous acid, lower alkanesulfonic acid (eg, methanesulfonic acid, Ethanesulfonic acid, etc.), sulfurous acid, thiosulfuric acid, sulfuric acid, aliphatic carboxylic acid (for example, acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, valeric acid, isovaleric acid, 2-ethylbutyric acid, trichloroacetic acid, etc.) or Mixed acid anhydrides with acids such as aromatic carboxylic acids (eg benzoic acid); symmetrical acid anhydrides; active amides with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; or active esters (eg cyanomethyl) ester, methoxymethyl ester, dimethyl imino-methyl _[(CH 3) N ⁺ = CH-] ester, vinyl ester, propargyl ester, p- nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesyl phenyl ester, phenylazophenyl ester, phenyl thioester, p- Nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc.) or N-hydroxy compound (for example, N,
N-dimethylhydroxylamine, 1-hydroxy-2
-(1H) -pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-1
H-benzotriazole etc.) and the like. These reactive derivatives can be appropriately selected from these depending on the type of compound (III) to be used.

The reaction is usually carried out in a conventional manner such as water, alcohol (eg methanol, ethanol, etc.), acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine and the like. It is carried out in a solvent or any other organic solvent that does not adversely influence the reaction. These conventional solvents may be used as a mixture with water.

When the compound (III) is used in this reaction in the form of a free acid or a salt thereof, the reaction is a conventional condensing agent,
For example, N, N'-dicyclohexylcarbodiimide; N
-Cyclohexyl-N'-morpholinoethylcarbodiimide; N-cyclohexyl-N '-(4-diethylaminocyclohexyl) carbodiimide; N, N'-diethylcarbodiimide, N, N'-diisopropylcarbodiimide;N-ethyl-N'-(3 -Dimethylaminopropyl) carbodiimide; N, N'-carbonylbis-
(2-methylimidazole); pentamethylene ketene-
N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-1-chloroethylene; trialkylphosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); phosphorus trichloride; Thionyl chloride; oxalyl chloride; lower alkyl haloformates (eg ethyl chloroformate, isopropyl chloroformate, etc.); triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5- (m-sulfo Phenyl) isoxazolium hydroxide inner salt; 1-
(P-Chlorobenzenesulfonyloxy) -6-chloro-1H-benzotriazole; conventional condensation such as so-called Vilsmeier reagent prepared by reacting N, N-dimethylformamide with thionyl chloride, phosgene, phosphorus oxychloride and the like. It is desirable to carry out in the presence of the agent.

The reaction is carried out in the presence of an inorganic or organic base such as alkali metal hydrogen carbonate, tri (lower) alkylamine, pyridine, N- (lower) alkylmorpholine, N, N-di (lower) alkylbenzylamine. You can also do it. The reaction temperature is not particularly limited and is usually under cooling or heating.

Production Method 2 Compound (Ib) or a salt thereof can be produced by subjecting compound (Ia) or a salt thereof to an elimination reaction of an amidino protecting group. Compounds (Ia) and (Ib)
For the suitable salts of the above, those exemplified for the compound (I) may be referred to. Suitable methods for this elimination reaction include conventional methods such as hydrolysis and reduction.

(I) Hydrolysis Hydrolysis is preferably carried out in the presence of a base or an acid (including a Lewis acid). Suitable bases include, for example, alkali metals such as sodium and potassium, such as magnesium,
Alkaline earth metals such as calcium Hydroxides or carbonates or bicarbonates of these metals, for example trialkylamines such as trimethylamine, triethylamine, picoline, 1,5-diazabicyclo [4.3.0] nona-5
-Ene, 1,4-diazabicyclo [2.2.2] octane, 1,8-diazabicyclo [5.4.0] undeca-
Inorganic and organic bases such as 7-ene and the like can be mentioned.

Suitable acids include organic acids such as formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid and the like, and inorganic acids such as hydrochloric acid, hydrobromic acid, hydrogen chloride, hydrogen bromide and the like. . For example trichloroacetic acid,
The elimination using a Lewis acid such as trihaloacetic acid such as trifluoroacetic acid is preferably carried out in the presence of a cation scavenger such as anisole and phenol. The reaction is usually carried out in a solvent such as water, an alcohol such as methanol and ethanol, methylene chloride, tetrahydrofuran, or a mixture thereof, but the reaction may be carried out in any other solvent as long as it does not adversely influence the reaction. It can be carried out. Liquid bases or acids can also be used as solvents. The reaction temperature is not particularly limited,
Usually, the reaction is carried out under cooling or heating.

(Ii) Reduction Reduction is carried out by a conventional method including chemical reduction and catalytic reduction. Suitable reducing agents used for the chemical reduction are, for example, metals such as tin, zinc and iron or metal compounds such as chromium chloride and chromium acetate, and formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluene. Sulfonic acid,
It is a combination with an organic acid such as hydrochloric acid or hydrobromic acid, or an inorganic acid. Suitable catalysts used for catalytic reduction are, for example, platinum plates, platinum sponges, platinum black, colloidal platinum, platinum oxides, platinum wires, and other platinum catalysts, such as palladium sponge, palladium black, palladium oxide, palladium-carbon, colloids. Palladium, palladium-barium sulfate, palladium-barium carbonate, and other palladium catalysts, such as reduced nickel, nickel oxide, Raney nickel, and other nickel catalysts, such as reduced cobalt, Raney cobalt, and other cobalt catalysts, such as reduced iron, Raney iron, and other iron catalysts. , Conventional copper catalysts such as reduced copper, Raney copper, and Ullmann copper. The reduction is usually carried out in a conventional solvent which does not adversely influence the reaction, such as water, methanol, ethanol, propanol, N, N-dimethylformamide, or a mixture thereof. Furthermore, if the acids used for the chemical reduction are liquids, they can also be used as solvents. Furthermore, suitable solvents used for catalytic reduction include the above-mentioned solvents, as well as other conventional solvents such as diethyl ether, dioxane, tetrahydrofuran and the like, or mixtures thereof. The reaction temperature of this reaction is not particularly limited, but the reaction is usually performed under cooling or heating.

Production Method 3 The object compound (Id) or a salt thereof can be produced by subjecting the compound (Ic) or a salt thereof to a reaction for eliminating a carboxy protecting group. This reaction can be carried out by the method shown in Production method 2 or a method similar thereto.
Suitable salts of the compound (Ic) and the compound (Id) may be the same as those exemplified for the compound (I). The compound obtained by the above-mentioned production method can be isolated and purified by a conventional method such as pulverization, recrystallization, column chromatography or reprecipitation. Target compound (I)
In order to demonstrate the usefulness of the above, the pharmacological test data of a representative compound of the compound (I) is shown below.

Test Test 1: Action on platelet aggregation by adenosine diphosphate (ADP) Test compound (1) Target compound of Example 1 (1) Test method Platelet was prepared from human blood at a concentration of 3 × 10 ⁸ cells / ml. Platelet-rich plasma (PRP) containing was prepared. After adding 25 μl of the drug solution ^* to 225 μl of PRP, the mixture was stirred at 37 ° C. for 2 minutes. To this solution, 5 μl of ADP (2.5 μM) was added as an aggregation inducer. Aggregometer (NKK HEHA-
Aggregation was measured using TRACER1). The activity of the inhibitor (test compound) was expressed as an IC ₅₀ value, that is, a dose required to suppress the platelet aggregation reaction by 50%. Chemical solution ^* ... The test compound was dissolved in dimethyl sulfoxide. Test results Test compound IC ₅₀ (M) (1) 6.0 × 10 ⁻⁷

Example 1 Dimethyl [4- [4- (N-benzyloxycarbonyl) amidinophenyloxy] acetylamino] -1,
A large mixture of 2-phenylenedioxy] diacetate (1.0 g) and 10% palladium-carbon (0.4 g, 50% wet) in 1N hydrochloric acid (2.1 ml), water (10 ml) and tetrahydrofuran (60 ml) was added. Hydrogenate at atmospheric pressure for 1 hour. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure and freeze-dried to obtain dimethyl [4- (4-amidinophenyloxy) acetylamino-1,2-phenylenedioxy].
Diacetate hydrochloride (0.81 g) is obtained. IR (Nujol): 3340, 1735, 1670, 160
0 cm-1 NMR (DMSOd ₆ , δ): 3.69 (3
H, s) 3.70 (3H, s) 4.77 (4H, s)
4.86 (2H, s) 6.91 (1H, d, J = 8.8
Hz) 7.18-7.30 (4H, m) 7.84 (2
H, d, J = 8.8 Hz) 9.06-9.10 (2H,
br) 9.25-9.29 (2H, br) 10.34
(1H, s) Mass (m / z): 466 (M ⁺ free + 1)

Example 2 Dimethyl [4- [2- (4-amidinophenyloxy)]
Acetylamino] -1,2-phenylenedioxy] diacetate hydrochloride (0.26 g) in 10% acetic acid (8 m
l) Reflux the aqueous solution for 6 hours. After cooling to room temperature, the precipitate is collected by filtration to obtain [4- (4-amidinophenyloxy) acetylamino-1,2-phenylenedioxy] diacetic acid / hydrochloride (0.1 g). NMR (DMSOd ₆ , δ): 4.79 (6H, s)
6.77 (1H, d, J = 8.8Hz) 7.11-7.
15 (4H, m) 7.77 (2H, d, J = 8.5H
z) 8.94-9.02 (2H, br) 10.10 (1
H, s) 10.50-11.00 (2H, br) Mass (m / z): 418 (M ⁺ free + 1)

Example 3 The following compound was obtained in the same manner as in Example 1. Methyl [4- (4-amidinophenyloxy) acetylaminophenyloxy] acetate / hydrochloride mp: 190 ° C IR (nujol): 3340, 3200, 1735,
1650, 1600 cm ^-1 NMR (DMSOd ₆ , δ): 369 (3H, s) 4.
76 (2H, s) 4.88 (2H, s) 6.90 (2
H, d, J = 9.1) 7.21 (2H, d, J = 8.
9) 7.56 (2H, d, J = 9.1) 7.87 (2
H, d, J = 8.9) 9.10 (2H, s) 9.29
(2H, s) 10.38 (1H, s)

Example 4 In the same manner as in Example 2, the following compound is obtained. [4- (4-amidinophenyloxy) acetylaminophenyloxy] acetic acid / hydrochloride mp: 2300 ° C. IR (nujol): 3250, 3140, 1650,
1605 cm ^-1 NMR (DMSOd ₆ , δ): 4.66 (2H, s)
4.87 (2H, s) 6.91 (2H, d, J = 9.
1) 7.24 (2H, d, J = 8.9) 7.57 (2
H, d, J = 9.0) 7.86 (2H, d, J = 8.
9)

Example 5 The following compound was obtained in the same manner as in Example 1. Methyl [3- (4-amidinophenyloxy) acetyl
Aminophenyloxy] acetate / hydrochloride mp: 90 ° C. IR (nujol): 3370, 3250, 3070,
1740, 1685 cm^-1  NMR (DMSOd₆, Δ): 3.70 (3H, s)
4.76 (2H, s) 4.92 (2H, s) 6.63-
6.68 (1H, m) 7.19-7.30 (4H, m)
7.34-7.35 (1H, m) 7.88 (2H, d,
J = 8.9) 9.11 (2H, s) 9.31 (2H,
s) 10.55 (1H, s) Mass (m / z): 35
8 (M⁺free)

Example 6 The following compound was obtained in the same manner as in Example 2. [3- (4-amidinophenyloxy) acetylaminophenyloxy] acetic acid / hydrochloride mp: 290 ° C. (dec) IR (nujol): 3280, 1675, 1610
cm ^-1 NMR (DMSOd ₆ , δ): 4.89 (2H, s)
4.99 (2H, s) 6.97 (1H, d, J = 8.
0) 7.18 (1H, d, J = 7.8) 7.30-7.
47 (4H, m) 7.90 (2H, d, J = 8.3) Mass (m / z): 344 (M ⁺ free)

Example 7 The following compound was obtained in the same manner as in Example 1. [4-[(4-amidinophenyloxy) -N-methylacetylamino] -1,2-phenylenedioxy] diacetic acid / hydrochloride mp: 80 ° C IR (nujol): 1730, 1650, 1600
cm ^-1 NMR (DMSOd ₆ , δ): 3.14 (3H, s)
4.57 (2H, s) 4.74 (2H, s) 4.78
(2H, s) 6.92-7.12 (5H, m) 7.79
(2H, d, J = 8.8) 9.05 (2H, s) 9.2
2 (2H, s) Mass (m / z): 432 (M ⁺ free)

Example 8 The following compound was obtained in the same manner as in Example 1. Methyl [4- (4-amidinophenyloxy) acetylamino-2-methoxycarbonylphenyloxy] acetate / hydrochloride IR (nujol): 3300, 1760, 1690,
1660, 1600 cm ^-1 NMR (DMSOd ₆ , δ): 3.69 (3H, s)
3.80 (3H, s) 4.85 (2H, s) 4.91
(2H, s) 7.05 (1H, d, J = 9.1) 7.2
2 (2H, d, J = 8.9) 7.72-7.78 (1
H, m) 7.88 (2H, d, J = 8.8) 8.03
(1H, d, J = 2.6) 9.11 (2H, s) 9.3
0 (2H, s) 10.60 (1H, s) Mass (m / z): 416 (M ⁺ free)

Example 9 The following compound was obtained in the same manner as in Example 2. [4- (4-amidinophenyloxy) acetylamino-2-carboxyphenyloxy] acetic acid trifluoroacetate mp: 275 ° C. (dec) IR (nujol): 3550, 3370, 3300,
1690, 1605 cm ^-1 NMR (DMSOd ₆ , δ): 4.59 (2H, s)
4.86 (2H, s) 7.17-7.29 (3H, m)
7.63-7.69 (1H, m) 7.78-7.82
(3H, m) 9.08-9.16 (2H, br) 9.2
1-9.33 (2H, br) 10.26 (1H, s)

Example 10 The following compound was obtained in the same manner as in Example 1. Methyl 3- [5- (4-amidinophenyloxy) acetylamino-2-methoxycarbonyl-methyloxyphenyl] propionate-hydrochloride NMR (DMSOd ₆ , δ): 2.61 (2H, t, J
= 7.4 Hz) 2.83 (2H, t, J = 7.4 Hz)
3.59 (3H, s) 3.69 (3H, s) 4.82
(2H, s) 4.87 (2H, S) 6.85 (1H,
d, J = 9.2 Hz) 7.20 (2H, d, J = 8.9)
Hz) 7.43 (1H, s) 7.45 (2H, d, J =
8.9 Hz) 8.98-9.12 (2H, br) 9.2
6-9.30 (2H, br) 10.30 (1H, s) Mass (m / z): 444 (M ⁺ +1)

Example 11 In the same manner as in Example 1, the following compound is obtained. Methyl [4- (4-amidinophenyloxy) acetylamino-2- [2- (2-methoxyethylaminocarbonyl) ethyl] phenyloxy] acetate / hydrochloride mp: 91 ° C IR (nujol): 3600, 1740, 1665 ，
1630, 1605 cm ^-1 NMR (DMSOd ₆ , δ): 2.35 (2H, t, J
= 7.6) 2.78 (2H, t, J = 8.1) 3.22
(3H, s) 3.15-3.33 (4H, m) 3.69
(3H, s) 4.81 (2H, s) 4.86 (2H,
s) 6.83 (2H, d, J = 9.6) 7.20 (2
H, d, J = 8.9) 7.42-7.45 (2H, m)
7.84-7.93 (3H, m) 9.09 (2H, s)
9.29 (2H, s) 10.27 (1H, s) Mass (m / z): 487 (M ⁺ free)

Example 12 The following compound was obtained in the same manner as in Example 2. [4- (4-Amidinophenyloxy) acetylamino-2- [2- (2-methoxyethylaminocarbonyl))
Ethyl] phenyloxy] acetic acid trifluoroacetate IR (nujol): 3310, 3250, 3070,
1730, 1665, 1610 cm ^-1 NMR (DMSOd ₆ , δ): 2.35 (2H, t, J
= 7.6) 2.78 (2H, t, J = 8.0) 3.17
-3.32 (4H, m) 3.21 (3H, s) 4.68
(2H, s) 4.83 (2H, s) 6.80 (1H,
d, J = 8.6) 7.20 (2H, d, J = 8.9)
7.38-7.85 (2H, m) 7.80-7.88
(3H, m) 9.05 (2H, s) 9.16 (2H,
s) 10.03 (1H, s) Mass (m / z): 473 (M ⁺ free)

Example 13 The following compound was obtained in the same manner as in Example 1. Methyl [4- (4-amidinophenyloxy) acetylamino-2- (2-morpholinocarbonylethyl) phenyloxy] acetate / hydrochloride IR (nujol): 3350, 1760, 1660c
m ⁻¹ mp: 183 ° C. NMR (DMSOd ₆ , δ): 2.52-2.62 (2
H, m) 2.76-2.84 (2H, m) 3.69 (3
H, s) 3.42-3.48 (8H, m) 4.82 (2
H, s) 4.85 (2H, s) 6.85 (1H, d, J
= 8.9) 7.20 (2H, d, J = 8.9) 7.42
−7.46 (2H, m) 7.85 (2H, d, J = 8.
9) 9.02 (2H, s) 9.24 (2H, s) 10.
06 (1H, s) Mass (m / z): 499 (M ⁺ free)

Example 14 The following compound was obtained in the same manner as in Example 2. [4- (4-amidinophenyloxy) acetylamino-2- (2-morpholinocarbonylethyl) phenyloxy] acetic acid / hydrochloride mp: 255 ° C. (dec) IR (nujol): 3650, 3200, 1720,
1670, 1650, 1600 cm ^-1 NMR (DMSOd ₆ , δ): 2.55-2.62 (2
H, m) 2.71-2.79 (2H, M) 3.00-
3.58 (8H, m) 4.65 (2H, s) 4.84
(2H, s) 6.82 (1H, d, J = 8.6) 7.2
0 (2H, d, J = 8.8) 7.40-7.45 (2
H, m) 7.84 (2H, d, J = 8.8) 9.19
(4H, s) 10.15 (1H, s) Mass (m / z): 485 (M ⁺ free)

Example 15 The following compound was obtained in the same manner as in Example 1. Methyl [4- (4-amidinophenyl) acetylamino-2-morpholinocarbonylphenyloxy] acetate / hydrochloride mp: 143 ° C. IR (nujol): 3280,3050,1750,
1670 cm ^-1 NMR (DMSOd ₆ , δ): 3.40-3.82 (8
H, m) 3.70 (3H, s) 4.86 (2H, s)
4.90 (2H, s) 4.86 (2H, s) 4.90
(2H, s) 6.95 (1H, d, J = 8.9) 7.2
1 (2H, d, J = 8.9) 7.56-7.65 (2
H, m) 7.87 (2H, d, J = 8.9) 9.10
(2H, s) 9.29 (2H, s) 10.56 (1H,
s) Mass (m / z): 471 (M ⁺ free)

Example 16 The following compound was obtained in the same manner as in Example 2. [4- (4-amidinophenyloxy) acetylamino-2-morpholinocarbonylphenyloxy] acetic acid trifluoroacetate mp: 226 ° C. (dec) IR (nujol): 3400, 1650, 1600c
m ^-1 NMR (DMSOd ₆ , δ): 3.10-3.90 (8
H, m) 4.39 (2H, s) 4.84 (2H, s)
6.78 (1H, d, J = 9.0) 7.13 (2H,
d, J = 8.9) 7.43-7.52 (2H, m) 7.
75 (2H, d, J = 8.8) 8.75 (2H, s) 1
0.21 (1H, s) 11.25-11.34 (2H,
br)

Example 17 The following compound was obtained in the same manner as in Example 1. Methyl [4- (4-amidinophenyloxy) acetylamino-2- (2-methoxyethylamino) carbonylphenyloxy] acetate / hydrochloride mp: 175 ° C IR (nujol): 3420, 1740, 1670,
1625, 1600 cm ^-1 NMR (DMSOd ₆ , δ): 3.27 (3H, s)
3.39 (4H, s) 3.75 (3H, s) 4.89
(2H, s) 4.95 (2H, s) 7.10 (1H,
d, J = 9.0) 7.22 (2H, d, J = 8.9)
7.76-7.81 (1H, m) 7.86 (2H, d,
J = 8.9) 8.14 (1H, d, J = 2.7) 8.5
6 (1H, s) 9.08 (2H, s) 9.27 (2H,
s) 10.47 (1H, s) Mass (m / z): 459 (M ⁺ free)

Example 18 Methyl [4- [4- (amidinophenyloxy) acetylamino] -2- (2-methoxyethylaminocarbonyl) phenyloxy] acetate hydrochloride (0.34
A mixture of g) with 1N sodium hydroxide (2.06 ml) in tetrahydrofuran (3.5 ml) and water (3.5 ml) is stirred for 1 hour at room temperature. The mixture was acidified with a 0.1% trifluorioloacetic acid aqueous solution, and the formed precipitate was collected by filtration to give [4- (4-amidinophenyloxy) acetylamino] -2- (2-methoxyethylamino) carbonylphenyloxy. ] Acetic acid trifluoroacetate (0.19 g) is obtained. mp: 282 ° C. (dec) IR (nujol): 3230, 1660, 1630,
1610 cm ^-1 Mass (m / z): 445 (M ⁺ free)

Example 19 The following compound was obtained in the same manner as in Example 1. 3- [5- (4-amidinophenyloxy) acetylamino-2-morpholinocarbonylmethyloxyphenyl] propionic acid / hydrochloride mp: 82 ° C. (dec) IR (nujol): 3350, 3200, 1675,
1640, 1610 cm ^-1 NMR (DMSOd ₆ , δ): 2.42-2.58 (2
H, m) 2.75-2.82 (2H, m) 3.25-
3.70 (8H, m) 4.84 (4H, s) 6.85
(1H, d, J = 8.5) 7.20 (2H, d, J =
8.7) 7.40-7.45 (2H, m) 7.84 (2
H, d, J = 8.7) 8.99 (2H, s) 9.23
(2H, s) 10.15 (1H, s) Mass (m / z): 485 (M ⁺ free)

Example 20 The following compound was obtained in the same manner as in Example 1. Methyl 2- (S) -butylsulfonylamino-3- [4
-(4-amidinophenyloxy) acetylaminophenyl] propionate / hydrochloride mp: 120 ° C IR (nujol): 3200, 1720, 1670,
1600 cm ^-1 NMR (DMSOd ₆ , δ): 0.75 (3H, t, J
= 7.1) 1.06-1.42 (4H, m) 2.60-
2.82 (3H, m) 2.94-3.03 (1H, m)
3.64 (2H, s) 4.01-4.13 (1H, m)
4.91 (2H, s) 7.18-7.25 (4H, m)
7.60 (2H, d, J = 8.5) 7.81-7.90
(3H, m) 9.12 (2H, s) 9.31 (2H,
s) 10.52 (1H, s) Mass (m / z): 491 (M ⁺ free)

Example 21 The following compound was obtained as in Example 18. 2- (S) -butylsulfonylamino-3- [4- (4
-Amidinophenyloxy) acetylaminofemil]
Propionic acid trifluoroacetate IR (nujol): 3320, 3080, 1680,
1605 cm ^-1 NMR (DMSOd ₆ , δ): 0.75 (3H, t, J
= 7.1) 1.06-1.52 (4H, m) 2.58-
2.80 (3H, m) 2.97-3.06 (1H, m)
3.90-4.02 (1H, m) 4.87 (2H, s)
7.22 (4H, t, J = 9.0) 7.54-7.64
(3H, m) 7.83 (2H, d, J = 8.9) 9.1
7 (2H, s) 9.20 (2H, s) 10.24 (1
H, s)

Example 22 The following compound was obtained in the same manner as in Example 1. Methyl 2- (S) -acetylamino-3- [4- (4-
Amidinophenyloxy) acetylaminophenyl] propionate / hydrochloride mp: 130 ° C. IR (nujol): 3300, 1715, 1675,
1650, 1600 cm ^-1 NMR (DMSOd ₆ , δ): 1.79 (3H, s)
2.76-3.02 (2H, m) 3.59 (3H, s)
4.36-4.47 (1H, m) 4.90 (2H, s)
7.19 (4H, t, J = 8.2) 7.56 (2H,
d, J = 8.4) 7.86 (2H, d, J = 8.8)
8.37 (1H, d, J = 7.7) 9.08 (2H,
s) 9.28 (2H, s) 10.4 (1H, s) Mass (m / z): 413 (M ⁺ free)

Example 23 The following compound was obtained in the same manner as in Example 18. 2- (S) -acetylamino-3- [4- (4-amidinophenyloxy) acetylaminophenyl] propionic acid trifluoroacetate mp: 202 ° C IR (nujol): 3380, 3300, 3070,
1680, 1660, 1600 cm ^-1 NMR (DMSOd ₆ , δ): 1.78 (3H, s)
2.73-2.84 (1H, m) 3.00-3.06
(1H, m) 4.31-4.42 (1H, m) 4.87
(2H, s) 7.15-7.22 (4H, m) 7.53
(2H, d, J = 8.3) 7.84 (2H, d, J =
8.8) 8.13 (1H, d, J = 8.0) 9.13-
9.20 (2H, br) 9.44-9.52 (2H, b
r) 10.26 (1H, s) Mass (m / z): 399 (M ⁺ free)

Example 24 The following compound was obtained in the same manner as in Example 1. Methyl 4- (4-amidinophenyloxy) acetylamino-2- (N-benzyl-N-acetylaminomethyl) phenyloxyacetate / hydrochloride mp: 117 ° C. IR (nujol): 1750, 1660, 1630,
1605 cm ^-1 NMR (DMSOd ₆ , δ): 2.12 (3H, s)
3.66 (3H, s) 4.48-4.88 (8H, m)
6.85-6.98 (1H, m) 7.19-7.42
(8H, m) 7.54-7.63 (1H, m) 7.87
(2H, d, J = 8.8) 9.08 (2H, s) 9.2
8 (2H, s) 10.35 (1H, d, J = 7.4) Mass (m / z): 519 (M ⁺ free)

Example 25 Dimethyl (4-amino-1,2-phenylenedioxy)
Diacetate hydrochloride (0.70 g), [4- (N-benzyloxycarbonyl) amidinophenyloxy] acetic acid (0.75 g) and 5-hydroxybenztriazole (0.35 g) in N, N-dimethylformamide ( 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide (0.42 ml) is added to the mixture in 10 ml) at 0 ° C. with stirring. After stirring overnight at room temperature, the mixture is poured into water and extracted with ethyl acetate. The extract is washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from diethyl ether-acetone to give dimethyl [4- [4- (N-benzyloxycarbonyl) amidinophenyloxy] acetylamino-1,2-phenylenedioxy] diacetate (0.6
0 g) is obtained. mp: 162-164 ° C IR (nujol): 3420, 3360, 1740,
1680, 1640, 1610 cm ^-1 NMR (DMSOd ₆ , δ): 3.69 (6H, s)
4.76 (2H, s) 4.77 (4H, s) 5.10
(2H, s) 6.90 (1H, d, J = 8.7Hz)
7.07 (2H, d, J = 8.8Hz) 7.17-7.
40 (7H, m) 8.00 (2H, d, J = 8.8H
z) 9.13-9.19 (1H, br) 10.02 (1
H, s)

Example 26 The following compound was obtained in the same manner as in Example 25. Diphenyl [4- [4- (N-benzyloxycarbonyl) amidinophenyloxy] -N-methylacetylamino-1,2-phenylenedioxy] diacetate mp: 108 ° C IR (nujol): 3380, 3240, 1760,
1745, 1680, 1660, 1630, 1610c
m ^-1 NMR (CDCl ₃ , δ): 3.19 (3H, s) 4.
37 (2H, s) 4.71 (2H, s) 4.73 (2
H, s) 5.18 (2H, s) 5.19 (2H, s)
5.22 (2H, s) 6.71-6.86 (6H, m)
7.26-7.46 (15H, m) 7.78 (2H,
d, J = 8.8) Mass (m / z): 746 (M ⁺ ).

Example 27 The following compound was obtained in the same manner as in Example 25. Methyl [4- [4- (N-benzyloxycarbonyl)
Amidinophenyloxy] acetylaminophenyloxy] acetate mp: 166 ° C. IR (nujol): 3400, 3330, 1760,
1675, 1600 cm ^-1 NMR (CDCl ₃ , δ): 3.81 (3H, s) 4.
63 (2H, s) 4.64 (2H, s) 5.21 (2
H, s) 6.90 (2H, d, J = 6.9) 7.02
(2H, d, J = 9.0) 7.29-7.52 (7H,
m) 7.95 (2H, d, J = 8.9) 8.26 (1
H, s)

Example 28 The following compound was obtained in the same manner as in Example 25. Methyl [4- [4- (N-benzyloxycarbonyl)
Amidinophenyloxy] acetylaminophenyloxy] acetate mp: 146 ° C. IR (nujol): 3340,3190,1735,
1725, 1660, 1600 cm ^-1 NMR (CDCl ₃ , δ): 3.76 (3H, s)
4.49 (2H, s) 4.60 (2H, s) 5.18
(2H, s) 6.64-6.68 (1H, m) 6.87
(2H, d, J = 8.9) 7.06-7.43 (8H,
m) 7.81 (2H, d, J = 8.9) 8.42 (1
H, s)

Example 29 The following compound was obtained in the same manner as in Example 25. Methyl 3- [5- [4- (N-benzyloxycarbonyl) amidinophenyloxy] acetylamino-2-methoxycarbonylmethyloxyphenyl] propionate mp: 149-150 ° C IR (nujol): 3450,3360,1750,
1720, 1670, 1650, 1620 cm ^-1 NMR (DMSOd ₆ , δ): 2.61 (2H, t, J
= 7.3 Hz) 2.84 (2H, t, J = 7.3 Hz)
3.59 (3H, s) 3.69 (3H, s) 4.75
(2H, s) 4.82 (2H, s) 5.10 (2H,
s) 6.85 (1H, d, J = 8.6Hz) 7.08
(2H, d, J = 8.8 Hz) 7.31-7.45 (7
H, m) 7.99 (2H, d, J = 8.8Hz) 9.0
3-9.10 (2H, br) 9.96 (1H, s)

Example 30 The following compound was obtained in the same manner as in Example 25. Methyl [4- [4- (N-benzyloxycarbonyl)
Amidinophenyloxy] acetylamino-2-[(2
-Methoxyethylaminocarbonyl) ethyl] phenyloxy] acetate mp: 160 ° C IR (nujol): 3470, 1720, 1685,
1620, 1605 cm ^-1 NMR (CDCl ₃ , δ): 2.55 (2H, t, J =
7.3) 2.96 (2H, t, J = 7.4) 3.27
(3H, s) 3.31 (4H, s) 3.80 (3H,
s) 4.60 (2H, s) 4.68 (2H, s) 5.2
1 (2H, s) 6.2-6.3 (1H, br) 6.68
(1H, d, J = 8.9) 7.00 (2H, d, J =
6.5) 7.12-7.61 (7H, m) 7.92 (2
H, J = 8.9) 8.18 (1H, s) Mass (m / z): 621 (M ⁺ )

Example 31 The following compound was obtained as in Example 25. Methyl 4- [4- (N-benzyloxycarbonyl) amidinophenyloxy] acetylamino-2- (2-morpholinocarbonylethyl) phenyloxy] acetate mp: 157 ° C IR (nujol): 1745, 1655, 1630c
m ^-1 NMR (CDCl ₃ , δ): 2.67 (2H, t, J =
7.5) 2.97 (2H, t, J = 7.7) 3.46-
3.54 (8H, m) 3.78 (3H, s) 4.61
(2H, s) 4.64 (2H, s) 5.21 (2H,
s) 6.68 (1H, d, J = 8.8) 7.01 (2
H, d, J = 8.9) 7.25-7.53 (7H, m)
7.92 (2H, d, J = 8.9) 8.17 (1H,
s) Mass (m / z): 633 (M ⁺ ).

Example 32 The following compound was obtained in the same manner as in Example 25. Methyl [4- [4- (N-benzyloxycarbonyl)
Amidinophenyloxy] acetylamino-2-methoxycarbonylphenyloxy] acetate mp: 76 ° C. IR (nujol): 3340, 3180, 1750,
1735, 1660, 1620 cm ^-1 NMR (DMSOd ₆ , δ): 3.69 (3H, s)
3.80 (3H, s) 4.80 (2H, s) 4.85
(2H, S) 5.12 (2H, s) 7.08 (3H,
t, J = 10.2) 7.32-7.41 (5H, m)
7.71-7.77 (1H, m) 7.98-8.02
(3H, m) 10.25 (1H, s)

Example 33 The following compound was obtained in the same manner as in Example 25. Methyl [4- [4- (N-benzyloxycarbonyl)
Amidinophenyloxy] acetylamino-2- (2-
Methoxyethylamino) carbonylphenyloxy] acetate mp: 135 ° C. IR (nujol): 3400, 3200, 1750,
1680, 1650, 1620, 1605 cm ^-1 NMR (CDCl ₃ , δ): 3.39 (3H, s)
3.59-3.69 (4H, m) 3.85 (3H, s)
4.61 (2H, s) 4.72 (2H, s) 5.21
(2H, s) 6.81 (1H, d, J = 8.9) 6.9
5 (2H, d, J = 8.9) 7.27-7.47 (5
H, m) 7.87 (2H, d, J = 8.9) 7.96
(1H, d, J = 2.8) 8.06-8.12 (1H, d
m) 8.53 (1H, s) 8.61-8.72 (1H,
m) Mass (m / z): 593 (M ⁺ ).

Example 34 The following compound was obtained in the same manner as in Example 25. Methyl [4- [4- (N-benzyloxycarbonyl)
Amidinophenyloxy] acetylamino-2-morpholinocarbonylphenyloxy] acetate mp: 16
7 ° C IR (nujol): 1750, 1605 cm ^-1 NMR (CDCl ₃ , 8): 3.2-4.0 (8H,
m) 3.77 (3H, s) 4.61 (2H, s) 4.65 (2H, s) 5.21
(2H, s) 6.71 (1H, d, J = 9.0) 6.9
6 (2H, d, J = 8.9) 7.26-7.46 (6
H, m) 7.58-7.63 (1H, m) 7.88 (2
H, d, J = 8.8) 8.37 (1H, s) Mass (m / z): 605 (M ⁺ ).

Example 35 The following compound was obtained in the same manner as in Example 25. Methyl 3- [5- [4- (N-benzyloxycarbonyl) amidinophenyloxy] acetylamino-2-morpholinocarbonylmethyloxyphenyl] propionate IR (film): 3380, 1720, 1640, 1
620 cm ^-1 NMR (CDCl ₃ , δ): 2.61 (2H, t, J =
7.5) 2.93 (2H, t, J = 7.7) 3.65
(3H, s) 3.52-3.70 (8H, m) 4.48
(2H, s) 4.69 (2H, s) 5.20 (2H,
s) 6.81 (1H, d, J = 8.8) 6.97 (2
H, d, J = 9.1) 7.28-7.46 (7H, m)
7.90 (2H, d, J = 8.9) 8.21 (1H,
s)

Example 36 The following compound was obtained as in Example 25. Methyl 2- (S) -butylsulfonylamino-3- [4
-[4- (N-benzyloxycarbonyl) amidinophenyloxy] acetylaminophenyl] propionate mp: 73 ° C IR (nujol): 3300, 1740, 1660,
1610 cm ^-1 NMR (CDCl ₃ , δ): 0.85 (3H, t, J =
7.3) 1.20-1.40 (2H, m) 1.55-
1.69 (2H, m) 2.76-2.87 (2H, m)
2.93-3.16 (2H, m) 3.75 (3H, s)
4.29-4.40 (1H, m) 4.56 (2H, s)
5.02 (1H, d, J = 9.2) 5.20 (2H,
s) 6.95 (2H, d, J = 8.9) 7.15 (2
H, d, J = 8.4) 7.31-7.65 (7H, m)
7.86 (2H, d, J = 8.9) 8.29-8.32.
(1H, m)

Example 37 The following compound was obtained in the same manner as in Example 25. Methyl 2- (S) -acetylamino-3- [4- [4-
(N-benzyloxycarbonyl) amidinophenyloxy] acetylaminophenyl] propionate mp:
181 ° C IR (Nujol): 3420, 3320, 3270,
1740, 1655 cm ^-1 NMR (CDCl ₃ , δ): 1.52 (3H, s) 2.
50-2.74 (2H, M) 3.28 (3H, s) 4.
22 (2H, s) 4.27-4.38 (1H, m) 4.
78 (2H, s) 6.58 (2H, d, J = 8.9)
6.71 (2H, d, J = 8.5) 6.84-7.16
(8H, m) 7.57 (2H, d, J = 8.8) 7.9
8-8.10 (1H-br) 8.86 (1H, s) 9.
00-9.11 (1H, br) Mass (m / z): 547 (M ⁺ ).

Example 38 The following compound was obtained as in Example 25. Methyl 4- [4- (N-benzyloxycarbonyl) amidinophenyloxy] acetylamino-2- (N-benzyl-N-acetylaminomethyl) phenyloxyacetate mp: 75 ° C. IR (nujol): 3280, 1725, 1605c.
m ^-1 NMR (CDCl ₃ , δ): 2.14 (3H, s) 3.
75 (3H, d, J = 4.3) 4.52-4.63 (8
H, m) 5.24 (2H, s) 6.65-6.76 (1
H ,, m) 6.97-7.05 (2H, m) 7.17-
7.43 (11H, m) 7.67 (1H, d, J = 8.
6) 7.78-7.94 (2H, m) 8.25 (1H,
d, J = 7.3) Mass (m / z) 653 (M ⁺ ).

Example 39 The following compound was obtained as in Example 18. 3- [4- (4-amidinophenyloxy) acetylaminophenyl] propionic acid trifluoroacetate mp: 260 ° C. <IR (nujol): 3300, 1685, 1670,
1610 cm ^-1 NMR (DMSOd ₆ , δ): 2.50 (2H, t,
J = 7.3) 2.78 (2H, t, J = 7.4) 4.8
6 (2H, s) 7.15-7.22 (4H, m) 7.5
2 (2H, d, J = 8.5) 7.82 (2H, d, J =
8.9) 9.09 (2H, s) 9.16 (2H, s) 1
0.17 (1H, s) Mass (m / z): 342 (M ⁺ free + 1)

Example 40 The following compound was obtained in the same manner as in Example 18. 2- (S)-[2- (carbetoxy) acetyl [amino-3- {4-[(4-amidinophenyloxy) acetyl] aminophenyl} propionic acid trifluoroacetate mp: 142 ° C. IR (nujol): 3280, 1670, 1650,
1600 cm ^-1 NMR (DMSOd ₆ , δ): 2.78-3.11 (4
H, m) 4.30-4.42 (1H, m) 4.86 (2
H, s) 7.14-7.21 (4H, m) 7.51 (2
H, d, J = 8.0) 7.82 (2H, d, J = 8.
4) 8.38 (1H, d, J = 7.3) 9.01 (2
H, s) 10.25 (3H, s) Mass (m / z) 4
43 (M ⁺ free + 1)

Example 41 N- {N- [5- (4-amidinophenyloxy) acetyl-5-amino-2-[(carbetoxy) methyloxy] benzoyl} glycine (0.2 g) in tetrahydrofuran (20 ml) and To a solution of water (20 ml) 1
N hydrochloric acid (4.5 ml) is added with stirring at room temperature, and the solvent is distilled off under reduced pressure. The precipitate was collected by filtration, and N-{[N- (4-
Amidinophenyloxy) acetyl] -5-amino-2
-[(Carbetoxy) methyloxy] benzoyl} glycine hydrochloride (0.18 g) is obtained. NMR (DMSOd ₆ , δ): 3.97 (2H, d,
J = 5.7) 4.79 (2H, s) 4.87 (2H,
s) 7.06-7.23 (4H, m) 7.75-7.8
4 (3H, m) 8.12-8.13 (1H, m) 9.1
7 (4H, s) 10.34 (1H, s)

Example 42 The following compound was obtained in the same manner as in Example 18. N-{[N- (4-amidinophenyloxy) acetyl] -5-amino-2-[(methoxycarbonyl) methyloxy] benzoyl} glycine mp: 250 ° C (dec) IR (nujol): 3330, 3200, 1740 ，
1660 cm ^-1 NMR (DMSOd ₆ , δ): 3.81 (2H, d, J
= 5.7) 4.44 (2H, s) 4.85 (2H, s)
6.99-7.16 (3H, m) 7.65-7.77
(4H, m) 8.05-8.08 (1H, m) 8.82
(1H, s) 9.95 (1H, s) 10.29 (1H,
s) 11.02 (1H, s)

Example 43 In the same manner as in Example 18, the following compound is obtained. 2- (S) -hexanoylamino-3- [4- (4-amidinophenyloxy) acetylaminophenyl] propionic acid trifluoroacetate mp: 210 ° C. (dec) IR (nujol): 3340, 3300, 3100,
1670, 1600 cm ^-1 NMR (DMSOd ₆ , δ): 0.84 (3H, t, J
= 6.8) 1.13-1.37 (4H, m) 1.40-
1.58 (2H, m) 2.00-2.15 (2H, m)
2.82-3.16 (2H, m) 4.10-4.20
(1H, m) 4.86 (2H, s) 7.05 (2H,
d, J = 8.4) 7.14 (3H, d, J = 8.4)
7.44 (2H, d, J = 8.4) 7.78 (2H,
d, J = 8.7) 10.21 (1H, s) Mass (m / z) 455 (M ⁺ free + 1)

Example 44 N- [4- (4-amidinophenyloxy) acetyl]
A solution of -L-prolyl-β-alanylmethyl ester hydrochloride (0.14 g) in methanol (1.5 ml) and water (1.5 ml) was added to lithium hydroxide monohydrate (43
mg) under stirring at 0 ° C. After stirring at room temperature for 1 hour, the mixture was subjected to HPLC using silica gel, 0.1%
Trifluoroacetic acid aqueous solution-acetonitrile (91: 9)
Elution with a mixed solution of N- [4- (4-amidinophenyloxy) acetyl] -L-prolyl-β-alanine trifluoroacetate (0.09 g). NMR (δ, DMSOd ₆ ): 1.77-2.16 (4
H, m) 2.33-2.45 (2H, m) 3.19-
3.60 (4H, m) 4.21-4.95 (3H, m)
7.06-7.16 (3H, m) 7.79 (2H, d,
J = 8.8) 7.96 and 8.32 (total1)
H, t, J = 5.5) 9.07 (2HS), 9.15
(2H, s) Mass (m / z): 363 (M ⁺ free + 1)

Example 45 In the same manner as in Example 18, the following compound is obtained. 3 {5- [2- (4-amidinophenyloxy) acetylamino] -2- (carboxymethyloxy) phenyl]} propionic acid / hydrochloride NMR (DMSO-d ₆ , δ): 2.57-2.64.
(2H, m) 2.79-2.86 (2H, m) 4.69
(2H, s) 4.85 (2H, s) 6.82 (1H,
d, J = 8.6 Hz) 7.20 (2H, d, J = 8.9)
Hz) 7.41-7.46 (2H, m) 7.84 (2
H, d, J = 8.9 Hz) 9.03 (2H, br) 9.
25 (2H, br) 10.20 (1H, s)

Example 46 In the same manner as in Example 25, the following compound was obtained. Methyl 3-{[4- [4- (N-benzyloxycarbosyl) amidinophenyloxy] acetyl] aminophenyl} propionate mp: 153 ° C IR (nujol): 3300, 1725, 1660,
1645 cm ^-1 NMR (CDCl ₃ , δ) 2.31 (2H, t, J =
7.5) 3.35 (3H, s) 3.56 (2H, s)
4.89 (2H, s) 6.73 (2H, d, J = 8.
9) 6.86 (2H, d, J = 8.4) 6.95-7.
16 (5H, m) 7.23 (2H, d, J = 8.4)
7.71 (2H, d, J = 8.9) 7.99-8.14
(1H, br) 8.77 (1H, s) 9.10-9.2
3 (1H, br) Mass (m / z): 490 (M ⁺ +1)

Example 47 The following compound was obtained in the same manner as in Example 1. Methyl 3-{[4- (4-amidinophenyloxy) acetyl] aminophenyl} propionate / hydrochloride mp: 170 ° C IR (nujol): 3320, 1715, 1665,
1655, 1600 cm ^-1 NMR (DMSOd ₆ , δ): 2.60 (2H, t, J
= 7.2) 2.81 (2H, t, J = 7.2) 3.42
(2H, s) 3.57 (3H, s) 4.91 (2H,
s) 7.19 (4H, t, J = 7.2) 7.57 (2
H, d, J = 8.4) 7.88 (2H, d, J = 8.
9) 9.14-9.27 (1H, br) 9.27-9.
39 (1H, br) 10.49 (1H, s) Mass (m / s): 356 (M ⁺ free + 1)

Example 48 The following compound was obtained in the same manner as in Example 1. N-{[N-[[4- (N-benzyloxycarbonyl
A) amidinophenyloxy] acetyl] -5-amino
-2-[(methoxycarbonyl) methyloxy]] ben
Zoyl} glycine methyl ester mp: 165 ° C. IR (nujol): 3450, 1750, 1735,
1670, 1650, 1625, 1610cm^-1  NMR (DMSOd₆, Δ): 3.66 (3H, s)
3.74 (3H, s) 4.10 (2H, d, J = 5.
8) 4.79 (2H, s) 4.98 (2H, s) 5.1
0 (2H, s) 7.07-7.13 (3H, m) 7.3
1-7.40 (5H, m) 7.82 (1H, dd, J =
2.7, 9.0) 8.00 (2H, d, J = 8.8)
8.13 (1H, d, J = 2.7) 8.88 (1H,
t, J = 5.8) 9.02-9.18 (2H, br) 1
0.21 (1H, s) Mass (m / s): 607 (M⁺1)

Example 49 The following compound was obtained in the same manner as in Example 1. N-{[N-[(4-amidinophenyloxy) acetyl
L] -5-amino-2-[(methoxycarbonyl) meth]
Loxy] benzoyl} glycine methyl ester / hydrochloric acid
Salt mp: 194 ° C IR (nujol): 3350, 3060, 1945,
1660, 1650, 1605 cm^-1  NMR (DMSOd₆, Δ): 3.66 (3H, s)
3.74 (3H, s) 4.09 (2H, d, J = 5.
7) 4.89 (2H, s) 4.98 (2H, s) 7.1
1 (1H, d, J = 9.0) 7.22 (2H, d, J =
8.9) 7.77-7.87 (3H, m) 8.16 (1
H, d, J = 2.7) 8.88 (1H, t, J = 5.
8) 9.04 (2H, s) 9.26 (2H, s) 10.
46 (1H, s) Mass (m / s): 473 (M⁺f
ree + 1)

Example 50 In the same manner as in Example 1, the following compound is obtained. Methyl 2- (S) -hexanoylamino-3- {4-
[(4-amidinophenyloxy) acetyl] aminophenyl} propionate / hydrochloride mp: 135 ° C IR (nujol): 3280, 1735, 1670,
1640, 1605 cm ^-1 NMR (DMSOd ₆ , δ): 0.81 (3H, t, J
= 7.0) 1.08-1.27 (4H, m) 1.33-
1.48 (2H, m) 2.05 (2H, t, J = 7.
3) 2.77-3.03 (2H, m) 3.60 (3H.
s) 4.38-4.49 (1H, m) 4.90 (2H,
s) 7.18 (4H, t, J = 8.0) 7.57 (2
H, d, J = 8.4) 7.87 (2H, d, J = 8.
8) 8.29 (1H, d, J = 7.8) 9.11 (2
H, s) 9.30 (2H, s) 10.47 (1H, s) Mass (m / z): 469 (M ⁺ free + 1)

Example 51 The following compound was obtained as in Example 25. Methyl 2- (S) -hexanoylamino-3-{[4-
[4- (N-benzyloxycarbonyl) amidinophenyloxy] acetyl] aminophenyl} propionate mp: 162 ° C IR (nujol): 3360, 3200, 3120,
3060, 1730, 1690, 1610 cm ^-1 NMR (CDCl ₃ , δ): 0.87 (3H, t, J =
6.7) 1.24-1.30 (4H, m) 1.51-
1.66 (2H, m) 2.16 (2H, t, J = 7.
6) 2.99-3.19 (2H, m) 3.72 (3H,
s) 4.60 (2H, s) 4.87 (1H, q, J =
7.8) 5.21 (2H, s) 5.96 (1H, d, J
= 7.8) 6.98 (2H, d, J = 8.9) 7.07
(2H, d, J = 8.4) 7.26-7.27 (5H,
m) 7.50 (2H, d, J = 8.5) 7.90 (2
H, d, J = 8.9) 8.25 (1H, s) Mass (m / z): 603 (M ⁺⁺ 1)

Example 52 The following compound was obtained in the same manner as in Example 1. Methyl 2- (S)-[2- (ethoxycarbonyl) acetyl] amino-3- {4-[[4- (N-benzyloxycarbonyl) amidinophenyloxy] acetyl] aminophenyl} propionate mp: 100 ° C. IR ( Nujol): 3340, 3190, 1730,
1665, 1655, 1620, 1605 cm ^-1 NMR (CDCl ₃ , δ): 1.26 (3H, t, J =
7.1) 3.00-3.21 (2H, m) 3.21 (2
H, s) 3.72 (3H, s) 4.18 (2H, q, J
= 7.2) 4.59 (2H, s) 4.85 (1H, q,
J = 7.6) 5.21 (2H, s) 6.97 (2H,
d, J = 8.9) 7.11 (2H, d, J = 8.4)
7.27-7.55 (8H, m) 7.88 (2H, d,
J = 8.9) 8.26 (1H, s) Mass (m / z): 619 (M ⁺⁺ 1)

Example 53 In the same manner as in Example 1, the following compound is obtained. Methyl 2- (S)-[2- (ethoxycarbonyl) acetyl] amino-3- {4-[[(4-amidinophenyloxy] acetyl] aminophenyl} propionate.
Hydrochloride mp: 125 ° C. IR (nujol): 3300, 1730, 1665,
1640, 1600 cm ^-1 NMR (DMSOd ₆ , δ): 1.15 (3H, t, J
= 7.1) 2.81-3.04 (2H, m) 3.26
(2H, s) 3.61 (3H.s) 4.04 (2H,
q, J = 7.1) 4.46 (1H, q, J = 5.8)
4.90 (2H, s) 7.18 (4H, t, J = 8.
5) 7.57 (2H, d, J = 8.4) 7.87 (2
H, d, J = 8.9) 8.64 (1H, d, J = 7.
7) 9.08 (2H, s) 9.29 (2H, s) 10.
46 (1H, s) Mass (m / z): 485 (M ⁺ free + 1)

Example 54 L-prolyl-β-alanine methyl ester hydrochloride (1 g), [4- (N-benzyloxycarbonyl) amidinophenyloxy] acetic acid (1.39 g) and 1-
Hydroxybenztriazole (0.63 g) N, N
-To a mixture in dimethylformamide (10 ml) was added triethylamine (0.71 ml) at -10 ° C with stirring and after stirring at -10 ° C for 3 hours, 1-ethyl-3- (3-
Add dimethyl-aminopropyl) carbodiimide hydrochloride (0.89 g). After 3 hours, the mixture is poured into water and extracted with ethyl acetate. The extract is washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was chromatographed on silica gel, eluting with a mixture of chloroform-methanol (20: 1) to give N-[[4- (N-benzyloxycarbonyl) amidinophenyloxy] acetyl] -L-prolyl. -Β-alanine methyl ester (0.34 g) is obtained. IR (Nujol): 1720, 1640, 1605c
_{^{m -1 NMR (CDCl 3, δ}} ): 1.80-2.32 (4
H, m) 2.48 (2H, t, J = 6.3) 3.40-
3.70 (4H, m) 3.64 (3H, s) 4.43-
4.73 (3H, m) 5.21 (2H, s) 6.87-
7.03 (3H, m) 7.27-7.46 (6H, m)
7.85 (2H, d, J = 8.7) Mass (m / z) 511 (M ⁺ +1)

Example 55 The following compound was obtained in the same manner as in Example 1. N- [4- (4-amidinophenyloxy) acetyl]
-L-prolyl-β-alanine methyl ester / hydrochloride mp: 135 ° C IR (nujol): 3200, 1730, 1645,
1605 cm ^-1 NMR (DMSOd ₆ , δ): 1.76-2.14 (4
H, m) 2.44 (2H, t, J = 6.9) 3.21-
3.71 (4H, m) 3.58 (3H, s) 4.01-
4.97 (3H, m) 6.94-7.18 (2H, m)
7.83 (2H, d, J = 8.8) 8.07 and 8.4
5 (total1H, t, J = 5.6) 9.09 (2
H, s) 9.28 (2H, s) Mass (m / z): 377 (M ⁺ free + 1)

Claims (2)

[Claims] 1. A formula: [Wherein R ¹ is an amidino group or a protected amidino group, R ² is hydrogen or a lower alkyl group, R ³ is hydrogen, an acyl group, an acyl (lower) alkoxy group, or a suitable substituent. A good acyl (lower) alkyl group or N-ar (lower) alkyl-N-lower alkanoylamino (lower) alkyl group, R ⁴ may have an acyl group, an acyl (lower) alkoxy group, or a suitable substituent. Good acyl (lower) alkyl group or N-ar (lower) alkyl-N-
Lower alkanoyl (lower) alkyl group, m means an integer of 1 to 6] or a salt thereof. 2. A pharmaceutical composition containing the compound according to claim 1 or a salt thereof as an active ingredient.