JP2990042B2 - Novel fused ring carboxylic acid derivative or salt thereof, and pharmaceutical use thereof - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel fused ring carboxylic acid derivative or a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof, and a pharmaceutical use thereof. More specifically, a novel fused ring carboxylic acid derivative or a pharmacologically acceptable salt thereof that is useful for the prevention and treatment of thrombotic diseases and the like, the prevention and treatment of thrombus formation during surgery and extracorporeal circulation, and the like. , Its pharmaceutical compositions, and its pharmaceutical uses.

[0002]

BACKGROUND OF THE INVENTION Platelet membrane
Glycoprotein GPIIb / IIIa (hereinafter abbreviated as GPIIb / IIIa)
Receptors involved in cell-cell and cell-substrate adhesion
Belonging to the integrin family
Ca on the surface⁺⁺Form a heterodimer in the presence
, Α _IIbβ_ThreeAlso called. Platelets at the site of vascular injury
By sticking, furthermore, adenosine 5'-
Is stimulated by acid (ADP), thrombin, etc.
This GPIIb / IIIa changes its steric structure,
RGD such as brinogen and von Willebrand factors
Riga containing the sequence (L-Gly-Aspartic acid)
(GPIIb / II in unstimulated state)
Ia does not bind to these ligands), through these
Platelet aggregation is triggered, the last step in stimulus transmission. So
Therefore, binding of these ligands to this GPIIb / IIIa
Inhibitors (GPIIb / IIIa antagonists) are excellent antiplatelets
It can be an agent.

From this viewpoint, [[4-[(p-amidino-N-methylbenzamide) acetyl] -o-phenylene] dioxy] diacetate (Ro43-8857),
[[1- [N- (p-amidinobenzoyl) -L-tyrosyl] -4-piperidinyl] oxy] acetic acid (Ro44-
9883) (Leo Alig et al., Journal of Medicinal C
hemistry 1992, Vol. 35 (No. 23), 4393-4407), N- (n-butanesulfonyl) -O- (4- (4
-Piperidinyl) -butyl)-(S) -tyrosine (L-70
0,462; MK-383) (GDHartmans et al., Journal of Me
dicinal Chemistry 1992, Vol. 35 (No. 24), 4640-4642
), (3S, 5S) -5- (4'-amidino-4
-Biphenyl) oxymethyl-3-[(methoxycarbonyl) methyl] -2-pyrrolidinone (BIBU-52)
(See JP-A-4-264068), 4-amidino-4 '-[(4-carboxycyclohexyl) aminocarbonyl] biphenyl hydrochloride (JP-A-4-33435)
No. 1) is known.

However, all of these are not always satisfactory in terms of efficacy, sustained efficacy, side effects, difficulty in oral administration, and the like.

Accordingly, it is an object of the present invention to provide a novel compound having better GPIIb / IIIa antagonism, a pharmaceutical composition thereof, and a GPIIb / IIIa antagonist.

[0006]

Means for Solving the Problems The inventors of the present invention have made various studies to achieve the above-mentioned object, and found that a fused ring carboxylic acid derivative having a specific structure has an excellent GPIIb / II
The inventors have found that they have Ia antagonism and low toxicity, and have completed the present invention.

That is, the present invention provides a compound of the formula (I)

[0008]

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[Wherein A is the formula (1)

[0010]

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Wherein E is hydrogen, alkyl, or a protecting group for amidino, guanidino or amino;

[0012]

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Wherein E is as defined above,
Or a formula (3) E-NH- (CH ₂ ) _c − (3) (wherein E is as defined above, and c represents 1, 2 or 3)
And B is a group represented by the formula (4)

[0014]

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In the formula, D is the formula (i)

[0016]

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Wherein R ⁵ is hydrogen, alkyl, cycloalkyl or aralkyl, and Q is -O-, -S- or -NR ^6- (R ⁶ is hydrogen, alkyl, cycloalkyl, aralkyl, alkyl Sulfonyl, aralkylsulfonyl, arylsulfonyl, acyl or-(C
H ₂ ) _d -COOR ⁷ (R ⁷ represents hydrogen, alkyl, cycloalkyl or aralkyl, d represents 1, 2 or 3); G represents hydrogen, a hydroxyl group, alkyl, cycloalkyl, phenyl, Biphenylyl, pyridyl, aralkyl or E ¹ —NR ⁸ — (E ¹ represents a protecting group for hydrogen, alkyl or amino, and R ⁸ represents hydrogen, alkyl, cycloalkyl or aralkyl),
p and r are each independently 0 or 1, q is 0,
1, 2 or 3 is indicated. Provided that when p ≠ 0, at least one of q and r is a group represented by non-０, W is ＣＨCH— or ＮN—, and R ³ and R ⁴ may be the same or different; Each represents hydrogen, alkyl, halogen, acyl or alkoxy; e represents 1 or 2;

[0018]

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Wherein D is as defined above,
Equation (6)

[0020]

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(Wherein, J and T may be the same or different and each represents -CH <or -N <.
Represents a group represented by the formula (i), and when T represents -N <, p = 0. R ³ has the same meaning as described above, and f represents 1, 2 or 3), a group represented by the formula (7)

[0022]

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(Wherein E ² represents a protecting group for hydrogen, alkyl or amino, g represents 1, 2, 3 or 4;
D and R ³ are the same as defined above, or a group represented by the formula (8)

[0024]

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Wherein D, E ² , R ³ and g are as defined above, and L is —O—, —NR ⁹ —.
(R ⁹ represents hydrogen, alkyl, cycloalkyl, aralkyl or acyl), -S-, -SO _2- or-
CH ₂ —, M represents —NR ¹⁰ — (R ¹⁰ represents hydrogen, alkyl, cycloalkyl or aralkyl), —O
-Or -S-, wherein R ¹ and R ² may be the same or different and each represents hydrogen, hydroxyl, alkyl,
Represents halogen, amino, acyl or alkoxy, a
Represents 0 or 1, and b represents 0, 1, 2 or 3.
However, when a = 0, b = 0, B represents a group represented by the formula (5) or (6) (where J is -N <), and a = 1 and b = 0 In some cases, B represents a group represented by Formula (4), Formula (6) (where J is -CH <), Formula (7) or Formula (8). Or a pharmacologically acceptable salt thereof.

The present invention also provides the above fused ring carboxylic acid derivative wherein B is a group represented by the formula (4) or the formula (6) in the formula (I), or a pharmaceutically acceptable salt thereof; In the formula (I), a = 1 and b = 0, B is a group represented by the formula (4) or (6) (where J is -CH <), and In D represented p
+ Q + r ≦ 3, or the above-mentioned fused ring carboxylic acid derivative or a pharmaceutically acceptable salt thereof;
= 1 and b = 0, and B is the formula (4) or the formula (6)
(Where J is -CH <, f = 2), and in D represented by the formula (i), p + q + r = 2
Or a pharmacologically acceptable salt thereof, wherein L is -O-,-
NR ⁹ - (R ⁹ is as defined above) or -S- in which the fused ring carboxylic acid derivative or a pharmacologically acceptable salt thereof; In formula (I), the condensed ring L is -O- It relates to a carboxylic acid derivative or a pharmacologically acceptable salt thereof.

Further, the present invention provides a compound of the formula (I ′)

[0028]

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Wherein R ⁵ is hydrogen, alkyl, cycloalkyl or aralkyl, and Q is —O—, —S—
Or -NR ^6- (R ⁶ is hydrogen, alkyl, cycloalkyl, aralkyl, alkylsulfonyl, aralkylsulfonyl, arylsulfonyl, acyl or-
(CH ₂ ) _d —COOR ⁷ (R ⁷ represents hydrogen, alkyl, cycloalkyl or aralkyl, d represents 1, 2 or 3), and L represents —O—, —NR ⁹ —.
(R ⁹ represents hydrogen, alkyl, cycloalkyl, aralkyl or acyl), -S-, -SO _2- or-
CH ₂ —, M represents —NR ¹⁰ — (R ¹⁰ represents hydrogen, alkyl, cycloalkyl or aralkyl), —O
-Or -S-, wherein R ¹ and R ² may be the same or different and each represents hydrogen, hydroxyl, alkyl,
Represents halogen, amino, acyl or alkoxy. ]
(Hereinafter also referred to as compound (I ′)) or a salt thereof, and a cyclodextrin or a derivative thereof.

The present invention also provides a pharmaceutical composition comprising the compound represented by the above formula (I) [hereinafter also referred to as compound (I)] or a pharmaceutically acceptable salt thereof, Pharmaceutical compositions comprising the same, and their pharmaceutical uses, especially GPIIb / II
Ia antagonist, prevention of diseases caused by platelet thrombus formation
Related to therapeutic agents.

The symbols used in the present specification are described below. The alkyl in R ^{1 to} R ¹⁰ , E, E ¹ , E ² , and G is lower alkyl having 1 to 6 carbon atoms, and may be linear or branched. Specifically, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, n-hexyl,
2-methylpropyl, 1,1-dimethylpropyl, 1,
2,2-trimethylpropyl and the like. Preferred are methyl, ethyl, propyl, isopropyl, n-butyl and the like. This alkyl may be substituted with a hydroxyl group or the like. The halogen in R ^{1 to} R ⁴ means fluorine, chlorine, bromine and iodine.

The acyl represented by R ^{1 to} R ⁴ , R ⁶ and R ⁹ includes alkanoyl, alalkanoyl, aroyl,
Heteroarylcarbonyl is mentioned. In particular,
The alkanoyl is a lower alkanoyl having 1 to 6 carbon atoms and may be linear or branched, and examples thereof include formyl, acetyl, propionyl, butyryl, valeryl, pivaloyl, and hexanoyl. The alkanoyl moiety of the alkanoyl is the same as described above, and examples thereof include phenylacetyl, 3-phenylpropionyl, and 4-phenylbutyryl. Examples of aroyl include benzoyl, toluoyl, xyloyl, salicyloyl, cinnamoyl, naphthoyl and the like. Heteroarylcarbonyl includes, for example, furoyl, nicotinoyl, isonicotinoyl, tenoyl and the like. Preferred are acetyl, propionyl, butyryl, phenylacetyl, 3-phenylpropionyl, benzoyl, p-toluoyl and the like.

As the alkoxy in R ^{1 to} R ⁴ ,
It is a lower alkoxy having 1 to 6 carbon atoms and may be linear or branched. Specifically, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy,
t-butoxy, pentyloxy, hexyloxy and the like. Preferred are methoxy, ethoxy, propoxy, isopropoxy and the like.

The cycloalkyl in R ^{5 to} R ¹⁰ and G preferably has 3 to 8 carbon atoms.
Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. The cycloalkyl may be substituted with an alkyl (as described above), a hydroxyl group or the like.

As the aralkyl for R ^{5 to} R ¹⁰ and G, the alkyl portion is the same as described above, and specifically, benzyl, phenethyl, 3-phenylpropyl,
-Phenylbutyl, benzhydryl, trityl and the like. The aralkyl may be substituted with alkyl (as described above), halogen (as described above), nitro, cyano, alkoxy (as described above) and the like.

In the alkylsulfonyl for R ⁶ , the alkyl portion is the same as described above, and specific examples include methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, pentylsulfonyl, hexylsulfonyl and the like. In the aralkylsulfonyl for R ⁶ , the aralkyl moiety is the same as described above, and specific examples thereof include benzylsulfonyl, phenethylsulfonyl, 3-phenylpropylsulfonyl, 4-phenylbutylsulfonyl, benzhydrylsulfonyl, and tritylsulfonyl. Is mentioned. In the arylsulfonyl for R ⁶ , the aryl moiety includes phenyl, tolyl, xylyl, naphthyl and the like, and specific examples include phenylsulfonyl and naphthylsulfonyl. This arylsulfonyl is
It may be substituted with alkyl (as described above), halogen (as described above), nitro, cyano, alkoxy (as described above) and the like.

The phenyl, biphenylyl and pyridyl in G may be substituted with alkyl (as described above), halogen (as described above), nitro, cyano, alkoxy (as described above) and the like.

As a protecting group for amidino, guanidino or amino in E, E ¹ and E ² , aralkyl which may have a substituent (for example, benzyl, p
-Chlorobenzyl, p-fluorobenzyl, m-trifluoromethylbenzyl, phenethyl, 1-phenylethyl, benzhydryl, trityl and the like, alkanoyl (for example, formyl, acetyl, propionyl, butyryl,
Valeryl, pivaloyl, hexanoyl, etc.), haloalkanoyl (eg, chloroacetyl, trifluoroacetyl, etc.), piperidinyloxyalkanoyl (eg, 4
-Piperidinyloxyacetyl, etc.), alkenyloxycarbonyl (eg, allyloxycarbonyl, etc.), alkoxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, hexyloxycarbonyl, etc.), acyloxyalkoxycarbonyl (eg, acetoxy) Methyloxycarbonyl,
(1-acetoxyethyl) oxycarbonyl, propionyloxymethyloxycarbonyl, pivaloyloxymethyloxycarbonyl, butyryloxymethyloxycarbonyl, isobutyryloxymethyloxycarbonyl, etc.), haloalkoxycarbonyl (for example, chloromethoxycarbonyl, Trichloroethoxycarbonyl, etc.), optionally substituted aroyl (eg, benzoyl, toluoyl, xyloyl, naphthoyl, phthaloyl, etc.), optionally substituted phenylalkanoyl (eg, phenylacetyl, 3- Phenylpropionyl, 3- (p-methoxyphenyl) propionyl, 3- (p-chlorophenyl) propionyl and the like), and an optionally substituted heteroarylcarbonyl (for example, nicotinoyl, Nicotinoyl, 6-chloro nicotinoyl, furoyl, thenoyl, etc.), heteroaryl alkanoyl (e.g., thienylacetyl, imidazolylmethyl acetyl, furyl acetyl, triazolyl acetyl,
Thiadiazolylpropionyl, etc.), optionally substituted aryloxycarbonyl (eg, phenoxycarbonyl, naphthyloxycarbonyl, etc.), optionally substituted phenoxyalkanoyl (eg, phenoxyacetyl, phenoxypropionyl) Etc.), optionally substituted arylglyoxyloyl (eg, phenylglyoxyloyl, naphthylglyoxyloyl, etc.), optionally substituted phenylalkoxycarbonyl (eg, benzyloxycarbonyl, Phenethyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, etc., alkylsulfonyl (for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, pentyls) Honiru etc.), haloalkylsulfonyl (e.g., trifluoromethylsulfonyl, etc.),
Optionally substituted aralkylsulfonyl (eg, benzylsulfonyl, p-chlorobenzylsulfonyl, phenethylsulfonyl, benzhydrylsulfonyl, etc.), optionally substituted arylsulfonyl (eg, phenylsulfonyl) , P-chlorophenylsulfonyl, tolylsulfonyl, xylylsulfonyl, naphthylsulfonyl, etc.). The alkyl, alkanoyl, alkoxy, and acyl moieties in each group include lower ones having 1 to 6 carbon atoms, and the alkenyl moieties include lower ones having 2 to 6 carbon atoms.

Preferred are phenylalkoxycarbonyl, alkoxycarbonyl, acyloxyalkoxycarbonyl, alkanoyl, phenylalkanoyl, haloalkanoyl, aralkyl, alkylsulfonyl, aralkylsulfonyl, arylsulfonyl, etc.
More preferably, benzyloxycarbonyl, t-butoxycarbonyl, acetoxymethyloxycarbonyl, pivaloyloxymethyloxycarbonyl, n-valeryl, n-hexanoyl, 3-phenylpropionyl, trifluoroacetyl, benzyl, phenethyl, trityl, n -Butylsulfonyl, n-hexylsulfonyl, benzylsulfonyl, phenylsulfonyl, p-tolylsulfonyl and the like.

Substitution in aralkyl, aroyl, phenylalkanoyl, heteroarylcarbonyl, aryloxycarbonyl, phenoxyalkanoyl, arylglyoxyloyl, phenylalkoxycarbonyl, aralkylsulfonyl, and arylsulfonyl which may have a substituent. Examples of the group include nitro, trifluoromethyl, alkyl (as described above), phenyl, alkoxy (as described above), halogen (as described above), alkanoyl (as described above), and the like.

The pharmacologically acceptable salts of compound (I) include inorganic acid addition salts (eg, hydrochloric acid, hydrobromic acid,
Salts with hydroiodic acid, sulfuric acid, phosphoric acid, etc., salts with amino acids (eg, salts with glutamic acid, aspartic acid, etc.), and organic acid addition salts (eg, methanesulfonic acid, benzenesulfonic acid, p-toluene) Sulfonic acid, formic acid, acetic acid, trifluoroacetic acid, oxalic acid, citric acid, malonic acid, fumaric acid, glutaric acid, adipic acid, maleic acid,
Salts with tartaric acid, succinic acid, mandelic acid, malic acid and the like).

When the compound (I) has a free carboxyl group, the pharmacologically acceptable salts include alkali metal salts (eg, salts with sodium, potassium, etc.) and alkaline earth metal salts (eg, , Calcium, magnesium, etc.), salts with organic bases (eg, salts with methylamine, trimethylamine, ethylamine, diethylamine, triethylamine, dicyclohexylamine, pyridine, picoline, ethylenediamine, etc.), ammonium salts and the like.

Further, when compound (I) or a salt thereof has various isomers (for example, cis and trans isomers and optical isomers based on asymmetric carbon), these are also within the scope of the present invention.

Of the compounds (I) of the present invention, those of the formula (I) wherein B is a group represented by the formula (4) or (6) are preferred. In the formula (I), a = 1 and b = 0, B is a group represented by the formula (4) or (6) (where J is -CH <), and the formula (i) A compound represented by the formula (D) wherein p + q + r ≦ 3 is more preferable. Further, in the formula (I), a = 1 and b =
0, B is a group represented by formula (4) or formula (6) (where J is -CH <, f = 2), and formula (i)
Compounds in which D + p + q = r = 2 are particularly preferred.

[0045] Among the present compounds (I), In the formula (I), L is ^{-O -, - NR 9 - (} R 9 is as defined above) are preferred or -S-, compound, L is −
Compounds that are O- are more preferred. Further, in the formula (I), M is -NR ^10- (R ¹⁰ is as defined above) or-
Compounds that are O- are preferred.

The bonding position of each substituent in the formula (I) is not particularly limited, but may be -CO- (M) _a- (C
It is preferred that the group represented by H ₂ ) _b -B is 2-position to L, and the group represented by A is 5- or 6-position to L.

The compound (I) can be synthesized by the following method or the like.

[0048]

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[In the formula, A ′ has the same meaning as the above A, or represents halogen, cyano or amino which may be protected, and R ¹ , R ² , A, B, L, M, a And b
Is as defined above. ]

That is, the compound (I) is prepared by reacting a carboxylic acid represented by the formula (II) (hereinafter also referred to as a carboxylic acid (II)) or a reactive derivative of the carboxylic acid (II) with a compound represented by the formula (III) The compound can be synthesized directly or via a precursor thereof by a condensation reaction with a compound represented by the formula (hereinafter, also referred to as compound (III)). The charged amounts of the carboxylic acid (II) or its reactive derivative and the compound (III) may be usually equimolar, but if necessary, one of them may be replaced with the other 1.1.
It may be used up to three times.

When carboxylic acid (II) is used as it is, 2-chloro-4,6-dimethoxy-1,3,5-triazine, o-benzotriazol-1-yl-N,
N, N ', N'-tetramethyluronium hexafluorophosphate, PyBOP (benzotriazole-1
-Yl-oxy-tris (pyrrolidino) phosphonium hexafluorophosphate), BOP (benzotriazol-1-yl-oxy-tris (dimethylamino) phosphonium hexafluorophosphate), PyBro
P (bromo-tris (pyrrolidino) phosphonium hexafluorophosphate), N, N-dicyclohexylcarbodiimide, N, N-diisopropylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide methiodide, 1-ethyl- The reaction is carried out in the presence of a condensing agent such as 3- (3-dimethylaminopropyl) carbodiimide hydrochloride, N-cyclohexyl-N '-(2-morpholinoethyl) carbodiimide meth-p-toluenesulfonate.

The carboxylic acid (II) may be converted to a reactive derivative such as an acid anhydride, an active ester or an acid halide by a conventional method. As the acid anhydride, for example,
An anhydride with pivalic acid, an anhydride with isobutyl carbonate and the like are used. Examples of the active ester include, for example, p
-Nitrophenyl ester, 2,4,5-trichlorophenyl ester, N-hydroxysuccinimide ester, N-hydroxyphthalimide ester, N-hydroxy-5-norbornene-2,3-dicarboximide ester and the like are used. As the acid halide, for example, carboxylic acid chloride, carboxylic acid bromide and the like are used.

In the compound (III), the group represented by B in the compound (III) contains a free carboxyl group or an ester group thereof. It is desirable that

As a reaction solvent, in any case, N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulfoxide, hexamethylphosphoric triamide, pyridine, dioxane, tetrahydrofuran, acetonitrile, chloroform, methylene chloride , Dimethoxyethane, benzene, ethyl acetate, sulfolane, etc., or a mixed solvent thereof is used. Preferred solvents include N, N-dimethylformamide,
Examples include methylene chloride, tetrahydrofuran, and acetonitrile.

Usually, the reaction temperature is about 0-100 ° C.
The reaction time is several hours to three days.

In the above reaction, when a condensing agent or an active ester of carboxylic acid (II) is used, N-methylmorpholine, 1-hydroxybenzotriazole,
A reaction aid such as 4-dimethylaminopyridine can be used. When an acid anhydride of carboxylic acid (II) is used, a reaction assistant such as 4-dimethylaminopyridine and 1-hydroxybenzotriazole can be used. When an acid halide of carboxylic acid (II) is used, the reaction is preferably performed in the presence of a hydrogen halide scavenger such as triethylamine, pyridine, picoline, sodium hydrogen carbonate, or the like.

In the carboxylic acid (II) or a reactive derivative thereof, A ′ halogen, cyano or optionally protected amino can be converted at an appropriate stage of the synthesis to amidino, guanidino, A of formula (I). , Is converted to protected amidino or protected guanidino. The amidino, guanidino and amino protecting groups are as described above. Further, the protecting groups for amidino, guanidino and amino can be deprotected if necessary. As the deprotection method,
Examples include hydrogenation, acid decomposition, base decomposition, and hydrolysis, which may be performed by a conventional method.

In the following, at the stage of the product after the reaction of the compound (III) with the carboxylic acid (II) or a reactive derivative thereof, or at the stage of the carboxylic acid (II) before the reaction, the above-mentioned A ′
The conversion method from to A is described. In the latter case, the conversion can be carried out as it is as the carboxylic acid (II), or it can be converted after the alkyl ester is formed to protect the carboxyl group. The converted amidino or guanidino may be protected if necessary, or, if it is converted to its carboxylic acid (II) when its alkyl ester is used to protect the carboxyl group, the compound (III)
With the reaction. The carboxylic acid (I
As described above, I) may be subjected to a reaction with the compound (III) after being converted into a reactive derivative thereof as required.

Method 1 This is a method for converting the halogen, amino and cyano of A 'to the amidino of A.

[0060]

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[0061] wherein, X is a halogen (same as above) or an amino, Y is formula _{(ii) -CO- (M) a} - (CH 2) b -B (ii) ( wherein, B, M, a and b are as defined above, or a group represented by the formula (iii) -COOR ¹¹ (iii) (wherein R ¹¹ is hydrogen or alkyl (as defined above)) , L, R ¹ and R ² are as defined above. ]

First, cyanation will be described. When X is a halogen in the above formula, a nitrile compound is obtained by a substitution reaction using a metal cyanide compound. As a metal cyanide,
Cuprous cyanide, potassium cyanide, sodium cyanide, or the like is used. The reaction solvent is 1,3-dimethyl-2-imidazolidinone, N, N-dimethylformamide, N-
Methyl-2-pyrrolidone or the like is used. Reaction temperature is from room temperature
At about 250 ° C, the reaction time is several hours to 3 days, preferably at about 80 to 230 ° C for several hours to 1 day.

When X is amino, the conversion to cyano is Sand
Performed by meyer reaction. A salt of an amine compound as a raw material such as hydrochloric acid or sulfuric acid is diazotized with sodium nitrite to form a diazonium salt, to which a metal cyanide compound is added to obtain a nitrile compound.
As the metal cyanide compound, cuprous cyanide, potassium cyanide, sodium cyanide and the like are preferably used, but complexes of potassium cyanide with nickel cyanide, nickel sulfate, nickel chloride and the like can also be used. The reaction solvent is preferably water, but if necessary, tetrahydrofuran, dioxane, ethanol or the like may be used together with water. In order to prevent the generation of hydrogen cyanide, neutralization with sodium carbonate or the use of a sodium carbonate buffer of the metal cyanide is performed before adding the metal cyanide. The reaction temperature is lower than room temperature, preferably under ice cooling, and the reaction time is about 0.5 to 5 hours. Finally, the reaction is terminated by heating at about 40 to 60 ° C. for about 0.5 to 1 hour.

Next, amidination will be described. This can be performed according to a known method via an imidate form or a thiocarbamoyl form (Organic Functional G
roupPreparations, III, Academic, Chaper 6, or L
eo Alig et al., Journal of Medicinal Chemistry 199
2, Vol. 35 (No. 23), 4393-4407).

In the method using an imidate form, a nitrile form is added to a nitrile form in the presence of hydrogen halide such as hydrogen chloride or hydrogen bromide.
An imidate form is obtained by reacting an equivalent to a large excess of an alcohol such as methanol, ethanol, propanol, or butanol. If necessary, an aliphatic ether such as diethyl ether, a halogenated hydrocarbon such as chloroform or methylene chloride, or an aprotic solvent such as benzene may be used. The reaction temperature is about -10 to + 30 ° C, and the reaction time is several hours to 2 days. It is preferably for about 8 to 15 hours under ice cooling to room temperature. Next, an amidine compound is obtained by reacting the obtained imidate compound with ammonia. Examples of the solvent include alcohols such as methanol, ethanol and propanol, aliphatic ethers such as diethyl ether, halogenated hydrocarbons such as chloroform and methylene chloride, aprotic solvents such as benzene, N, N-dimethylformamide, dimethyl sulfoxide and the like. Used. It is preferable that ammonium chloride coexist in the reaction with ammonia. The reaction temperature is about -10 to + 100 ° C, and the reaction time is several hours to 20 hours. About 50 to 8 preferably in a methanol, ethanol or propanol solvent.
Perform the reaction at 0 ° C. for several hours.

In the method involving the thiocarbamoyl form, the nitrile form is reacted with hydrogen sulfide in a solvent such as pyridine, triethylamine, N, N-dimethylformamide, or a mixed solvent thereof to obtain a thiocarbamoyl form.
The reaction temperature is under ice cooling to room temperature, and the reaction time is about 5 hours to 1 day, preferably about 10 to 20 hours at room temperature. next,
The resulting thiocarbamoyl compound is reacted with an alkyl halide such as methyl iodide or ethyl bromide in a solvent such as acetone, dioxane, or tetrahydrofuran. The reaction temperature is about 50-100 ° C, and the reaction time is about 0.5-10 hours. The intermediate thus obtained is isolated or not isolated, and ammonia or an ammonia derivative such as ammonium acetate or ammonium chloride is reacted to obtain an amidine derivative. As a solvent, an alcohol such as methanol, ethanol, or propanol, N, N-dimethylformamide, or the like is used. The reaction is preferably carried out by reacting with ammonium acetate in a methanol or ethanol solvent. The reaction temperature is about 50 to 100 ° C, and the reaction time is several hours to 10 hours.

Method 2 This is a method for converting the optionally protected amino of A 'to the guanidino of A.

[0068]

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[In the formula, E 'represents an amino-protecting group (as defined above), and L, Y, R ¹ and R ² are as defined above. ]

First, deprotection of the amino protecting group can be carried out by a conventional method as described above.

The next conversion to guanidino is cyanamide,
It can be carried out according to a known method using formamidine sulfinic acid or aminoiminomethanesulfonic acid (T. Nakayama et al., Chem. Pharm. Bull. V
ol. 41 (1), 117-125 (1993), or AE Miller et a
l., Synthesis 1986, 777-779). For example, when a guanidino form is obtained by reacting a cyanamide with a salt of a raw material such as hydrochloric acid or sulfuric acid of an amine form, methanol,
Use alcohol such as ethanol. Reaction temperature is about 60
The reaction time is from several hours to one day.

In the above-mentioned production method, protection and deprotection of the amino group, esterification of the carboxylic acid and hydrolysis of the ester can be carried out by a conventional method, if necessary.

The starting compound carboxylic acid (II)
And a reactive derivative thereof and compound (III) can be produced by a conventionally known method, and benzofurancarboxylic acid having a cyano group on a phenyl nucleus, indolecarboxylic acid, benzo [ b]
Thiophenecarboxylic acid and indenecarboxylic acid can be synthesized according to the method described in the literature (O. Dann et al., Liebigs
Ann. Chem. 1982, 1836-1869, O. Dann et al., Liebi
gs Ann. Chem. 1986, 438-455, AJBridgeset al., T
etrahedron Letters, Vol.33 (No.49), 7499-7502 (199
2), see JP-A-5-208946).

Compound (I) of the present invention thus synthesized
Can be collected at any purity by appropriately performing known separation and purification means, for example, means such as concentration, extraction, chromatography, reprecipitation, and recrystallization.

Further, a pharmacologically acceptable salt of the compound (I) can be produced by a known method. further,
Various isomers of the compound (I) can also be produced by a known method.

Specific examples of the compound (I) of the present invention are shown below, but it should not be construed that the invention is limited thereto. 1. A compound represented by the following formula (Ia) [in the formula (I), a = 1, b = 0, B = a compound represented by the formula (4)]

[0077]

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Wherein each symbol is as defined above. Compound (I) wherein L = —O— Compound (1) 4-[[5- (t-Butoxycarbonylamidino) -2-benzofuranyl] carbonyl amino]
Methyl phenoxyacetate Compound (2) 4-[[5- (acetoxymethyloxycarbonylamidino) -2-benzofuranyl] carbonylamino] Ethyl phenoxyacetate Compound (3) 4-[[5- (methoxycarbonylamidino) -2-benzofuranyl ] Carbonylamino] ethyl phenoxyacetate compound (4) 4-[[5- (pivaloyloxymethyloxycarbonylamidino) -2-benzofuranyl] carbonylamino] ethyl phenoxyacetate compound (5) 4-[[6- (pi Valoyloxymethyloxycarbonylamidino) -2-benzofuranyl] carbonylamino] ethyl phenoxyacetate compound (6) 4-[(5-benzylamidino-2-benzofuranyl) carbonylamino] ethyl phenoxyacetate compound (7) 4-[[ 5- (benzyloxyca Rubonylamidino) -2-benzofuranyl] carbonylamino] ethyl phenoxyacetate compound (8) 4-[[5- (benzyloxycarbonylamidino) -2-benzofuranyl] carbonylamino] t-butyl phenoxyacetate compound (9) 4- [ [5- (acetoxymethyloxycarbonylamidino) -2-benzofuranyl] carbonylamino] phenoxyacetic acid compound (10) 4-[[5- (benzyloxycarbonylamidino) -2-benzofuranyl] carbonylamino] phenoxyacetic acid

Compound (11) 4-[(5-Benzylamidino-2-benzofuranyl) carbonylamino] phenoxyacetic acid compound (12) 4-[(6-Benzylamidino-2-benzofuranyl) carbonylamino] phenoxyacetic acid compound (13) ) 4-[(5-Amidino-2-benzofuranyl) carbonylamino] methyl phenoxyacetate compound (14) 4-[(5-Amidino-2-benzofuranyl) carbonylamino] ethyl phenoxyacetate compound (15) 4-[(6 -Amidino-2-benzofuranyl) carbonylamino] ethyl phenoxyacetate compound (16) 4-[(6-amidino-3-benzofuranyl) carbonylamino] ethyl phenoxyacetate compound (17) 4-[(5-amidino-2-benzofuranyl) ) Carbonylamino] phenoxyacetic acid t-butyl compound 18) 4-[(6-Amidino-2-benzofuranyl) carbonylamino] t-butyl phenoxyacetate compound (19) 4-[(5-Amidino-2-benzofuranyl) carbonylamino] cyclohexyl phenoxyacetate compound (20) 4- [(6-Amidino-2-benzofuranyl) carbonylamino] cyclohexyl phenoxyacetate

Compound (21) 4-[(5-amidino-2
-Benzofuranyl) carbonylamino] benzyl phenoxyacetate Compound (22) 4-[(5-amidino-2-benzofuranyl) carbonylamino] phenoxyacetic acid compound (23) 4-[(5-amidino-3-benzofuranyl) carbonylamino] phenoxy Acetic acid compound (24) 4-[(6-Amidino-2-benzofuranyl) carbonylamino] phenoxyacetic acid compound (25) 4-[(6-amidino-3-benzofuranyl) carbonylamino] phenoxyacetic acid compound (26) 4- [ (5-amidino-3-methyl-2
-Benzofuranyl) carbonylamino] t-butyl phenoxyacetate compound (27) 4-[(5-amidino-3-chloro-2
-Benzofuranyl) carbonylamino] phenoxyacetic acid compound (28) 4-[(5-amidino-3-hydroxy-2-benzofuranyl) carbonylamino] phenoxyacetic acid compound (29) 4-[(5-amidino-3-methyl-2)
-Benzofuranyl) carbonylamino] phenoxyacetic acid compound (30) 4-[(6-amidino-3-methyl-2)
-Benzofuranyl) carbonylamino] phenoxyacetic acid

Compound (31) 4-[(5-amidino-3
-Methoxy-2-benzofuranyl) carbonylamino]
Phenoxyacetic acid compound (32) 4-[(5-amidino-7-chloro-2)
-Benzofuranyl) carbonylamino] phenoxyacetic acid compound (33) 4-[(5-amidino-7-methoxy-
2-benzofuranyl) carbonylamino] phenoxyacetic acid compound (34) 4-[[5- (acetoxymethyloxycarbonylamidino) -2-benzofuranyl] carbonyl-N-methylamino] ethyl phenoxyacetate compound (35) 4-[[5 -(Benzyloxycarbonylamidino) -2-benzofuranyl] carbonyl-N-
Methylamino] t-butyl phenoxyacetate Compound (36) 4-[(5-benzylamidino-2-benzofuranyl) carbonyl-N-methylamino] phenoxyacetic acid compound (37) 4-[(5-amidino-2-benzofuranyl) Ethyl carbonyl-N-methylamino] phenoxyacetate (38) 4-[(6-Amidino-2-benzofuranyl) carbonyl-N-methylamino] ethyl phenoxyacetate (39) 4-[(5-amidino-2- Benzofuranyl) carbonyl-N-methylamino] t-butyl phenoxyacetate Compound (40) 4-[(5-amidino-2-benzofuranyl) carbonyl-N-methylamino] phenoxyacetic acid

Compound (41) 4-[(6-amidino-2)
-Benzofuranyl) carbonyl-N-methylamino] phenoxyacetic acid compound (42) 4-[(5-amidino-2-benzofuranyl) carbonyl-N-propylamino] phenoxyacetic acid compound (43) 4-[(5-amidino-2 -Benzofuranyl) carbonyl-N-benzylamino] phenoxyacetic acid compound (44) 4-[(5-amidino-2-benzofuranyl) carbonylamino] -2-benzoylphenoxyacetic acid compound (45) 4-[(5-amidino-2 -Benzofuranyl) carbonylamino] -2-n-butylphenoxyacetic acid compound (46) 4-[(5-amidino-2-benzofuranyl) carbonylamino] -2,6-difluorophenoxyacetic acid compound (47) [[4- [ [5- (t-butoxycarbonylamidino) -2-benzofuranyl] carbonylamino] o-Phenylene] dioxy] dimethyl diacetate compound (48) [[4-[[5- (acetoxymethyloxycarbonylamidino) -2-benzofuranyl] carbonylamino] -o-phenylene] dioxy] diethyl diacetate compound (49) [[4-[[5- (benzyloxycarbonylamidino) -2-benzofuranyl] carbonylamino] -o-phenylene] dioxy] di-t-butyl diacetate Compound (50) [[4-[(5-benzylamidino- 2
-Benzofuranyl) carbonylamino] -o-phenylene] dioxy] diethyl diacetate

Compound (51) [[4-[[5- (pivaloyloxymethyloxycarbonylamidino) -2-benzofuranyl] carbonylamino] -o-phenylene]
Dioxy] diethyl diacetate compound (52) [[4-[[5- (acetoxymethyloxycarbonylamidino) -2-benzofuranyl] carbonylamino] -o-phenylene] dioxy] diacetate compound (53) [[4- [ [5- (benzyloxycarbonylamidino) -2-benzofuranyl] carbonylamino] -o-phenylene] dioxy] diacetate compound (54) [[4-[(5-benzylamidino-2)
-Benzofuranyl) carbonylamino] -o-phenylene] dioxy] diacetate compound (55) [[4-[[6- (pivaloyloxymethyloxycarbonylamidino) -2-benzofuranyl] carbonylamino] -o-phenylene] Dioxy]
Diacetic acid compound (56) [[4-[(5-Amidino-2-benzofuranyl) carbonylamino] -o-phenylene] dioxy] diethyl diacetate compound (57) [[4-[(5-amidino-2-benzofuranyl) ) Carbonylamino] -o-phenylene] dioxy] di-tert-butyl diacetate compound (58) [[4-[(5-Amidino-2-benzofuranyl) carbonylamino] -o-phenylene] dioxy] dibenzyl diacetate compound ( 59) [[4-[(5-Amidino-2-benzofuranyl) carbonylamino] -o-phenylene] dioxy] diacetate compound (60) [[4-[(6-Amidino-2-benzofuranyl) carbonylamino]- o-phenylene] dioxy] diacetic acid

Compound (61) [[4-[(5-Amidino-3-benzofuranyl) carbonylamino] -o-phenylene] dioxy] diacetate Compound (62) [[4-[(6-Amidino-3-benzofuranyl) ) Carbonylamino] -o-phenylene] dioxy] diacetate compound (63) [[4-[(5-Amidino-3-methyl-2-benzofuranyl) carbonylamino] -o-phenylene] dioxy] di-t-diacetate Butyl compound (64) [[4-[(5-Amidino-3-methyl-2-benzofuranyl) carbonylamino] -o-phenylene] dioxy] diacetate compound (65) [[4-[(5-amidino-7) -Methyl-2-benzofuranyl) carbonylamino] -o-phenylene] dioxy] diacetate compound (66) [[4-[(5-Amidino-7-methoxy-2-benzofuranyl) carbo] [Amino] -o-phenylene] dioxy] diacetate Compound (67) [[4-[[5- (acetoxymethyloxycarbonylamidino) -2-benzofuranyl] carbonyl-N-methylamino] -o-phenylene] dioxy] di Dimethyl acetate compound (68) [[4-[[5- (benzyloxycarbonylamidino) -2-benzofuranyl] carbonyl-
N-methylamino] -o-phenylene] dioxy] di-t-butyl diacetate compound (69) [[4-[(5-amidino-2-benzofuranyl) carbonyl-N-methylamino] -o-phenylene] dioxy] Diethyl diacetate Compound (70) [[4-[(5-Amidino-2-benzofuranyl) carbonyl-N-methylamino] -o-phenylene] dioxy] di-t-butyl diacetate

Compound (71) [[4-[(5-Amidino-2-benzofuranyl) carbonyl-N-methylamino] -o-phenylene] dioxy] diacetate Compound (72) [[4-[(6-amidino) -2-benzofuranyl) carbonyl-N-methylamino] -o-phenylene] dioxy] diacetate compound (73) [[4-[(5-amidino-3-methyl-2-benzofuranyl) carbonyl-N-methylamino] -O-phenylene] dioxy] diacetate compound (74) 3- [4-[[5- (acetoxymethyloxycarbonylamidino) -2-benzofuranyl] carbonylamino] phenyl] ethyl propionate compound (75) 3- [4 -[[5- (benzyloxycarbonylamidino) -2-benzofuranyl] carbonylamino] phenyl] ethyl propionate Compound (76) 3- [4 -[[5- (benzyloxycarbonylamidino) -2-benzofuranyl] carbonylamino] phenyl] benzylpropionate compound (77) 3- [4-[(5-benzylamidino-
2-benzofuranyl) carbonylamino] phenyl] ethyl propionate compound (78) 3- [4-[[5- (Acetoxymethyloxycarbonylamidino) -2-benzofuranyl] carbonylamino] phenyl] propionic acid compound (79) 3- [4-[[5- (allyloxycarbonylamidino) -2-benzofuranyl] carbonylamino] phenyl] propionic acid compound (80) 3- [4-[[5- (benzyloxycarbonylamidino) -2-benzofuranyl] carbonyl Amino] phenyl] propionic acid

Compound (81) 3- [4-[(5-benzylamidino-2-benzofuranyl) carbonylamino]
Phenyl] propionic acid compound (82) 3- [4-[(5-Amidino-2-benzofuranyl) carbonylamino] phenyl] methyl propionate compound (83) 3- [4-[(5-amidino-2-benzofuranyl) Carbonylamino] phenyl] ethyl propionate compound (84) 3- [4-[(5-Amidino-2-benzofuranyl) carbonylamino] phenyl] benzylpropionate compound (85) 3- [4-[(5-amidino- 2-benzofuranyl) carbonylamino] phenyl] propionic acid compound (86) 3- [4-[(6-amidino-2-benzofuranyl) carbonylamino] phenyl] propionic acid compound (87) 3- [4-[(5- Amidino-3-benzofuranyl) carbonylamino] phenyl] propionic acid compound (88) 3- [4-[(6-amidino -3-benzofuranyl) carbonylamino] phenyl] propionic acid compound (89) 3- [4-[(5-Amidino-3-methyl-2-benzofuranyl) carbonylamino] phenyl] propionic acid compound (90) 3- [4 -[(7-acetoxy-5-amidino-2-benzofuranyl) carbonylamino] phenyl] propionic acid

Compound (91) 3- [4-[(5-Amidino-3-benzofuranyl) carbonyl-N-methylamino] phenyl] propionic acid Compound (92) 3- [4-[(5-benzylamidino-
2-benzofuranyl) carbonylamino] phenyl]-
2- (n-butylsulfonylamino) propionic acid compound (93) 3- [4-[(5-amidino-2-benzofuranyl) carbonylamino] phenyl] -2- (n
-Butylsulfonylamino) propionate methyl compound (94) (S) -3- [4-[(5-amidino-
2-benzofuranyl) carbonylamino] phenyl]-
Ethyl 2- (n-butylsulfonylamino) propionate Compound (95) (S) -3- [4-[(5-amidino-
2-benzofuranyl) carbonylamino] phenyl]-
Ethyl 2- (benzyloxycarbonylamino) propionate Compound (96) (S) -3- [4-[(5-amidino-
2-benzofuranyl) carbonylamino] phenyl]-
Ethyl 2- [3- (4-methoxyphenyl) propionylamino] propionate Compound (97) (S) -3- [4-[(5-amidino-
2-benzofuranyl) carbonylamino] phenyl]-
Ethyl 2-[(4-piperidinyloxy) acetylamino] propionate Compound (98) (S) -3- [4-[(5-amidino-
2-benzofuranyl) carbonylamino] phenyl]-
Ethyl 2-aminopropionate Compound (99) (S) -3- [4-[(5-amidino-
2-benzofuranyl) carbonylamino] phenyl]-
2-Aminopropionic acid compound (100) 3- [4-[(5-Amidino-2-benzofuranyl) carbonylamino] phenyl] -2- (methylsulfonylamino) propionic acid

Compound (101) 3- [4-[(5-Amidino-2-benzofuranyl) carbonylamino] phenyl] -2- (n-butylsulfonylamino) propionic acid Compound (102) (S) -3- [ 4-[(5-amidino-
2-benzofuranyl) carbonylamino] phenyl]-
2- (n-butylsulfonylamino) propionic acid compound (103) (R) -3- [4-[(5-amidino-
2-benzofuranyl) carbonylamino] phenyl]-
2- (n-butylsulfonylamino) propionic acid compound (104) 3- [4-[(6-amidino-2-benzofuranyl) carbonylamino] phenyl] -2- (n
-Butylsulfonylamino) propionic acid compound (105) 3- [4-[(5-Amidino-2-benzofuranyl) carbonylamino] phenyl] -2- (n
-Butylsulfonyl-N-methylamino) propionic acid compound (106) 3- [4-[(5-Amidino-2-benzofuranyl) carbonylamino] phenyl] -2- (benzylsulfonylamino) propionic acid compound (107) ( S) -3- [4-[(5-amidino-
2-benzofuranyl) carbonylamino] phenyl]-
2- (benzylsulfonylamino) propionic acid compound (108) (R) -3- [4-[(5-amidino-
2-benzofuranyl) carbonylamino] phenyl]-
2- (benzylsulfonylamino) propionic acid compound (109) 3- [4-[(6-Amidino-2-benzofuranyl) carbonylamino] phenyl] -2- (benzylsulfonylamino) propionic acid compound (110) 3- [ 4-[(5-amidino-2-benzofuranyl) carbonylamino] phenyl] -2- (4
-Chlorobenzylsulfonylamino) propionic acid

Compound (111) 3- [4-[(6-Amidino-2-benzofuranyl) carbonylamino] phenyl] -2- (phenethylsulfonylamino) propionic acid Compound (112) 3- [4-[(5- Amidino-2-benzofuranyl) carbonylamino] phenyl] -2- (phenylsulfonylamino) propionic acid compound (113) 3- [4-[(5-Amidino-2-benzofuranyl) carbonylamino] phenyl] -2- (p
-Tolylsulfonylamino) propionic acid compound (114) 3- [4-[(5-Amidino-2-benzofuranyl) carbonylamino] phenyl] -2- (4
-Methoxybenzenesulfonylamino) propionic acid compound (115) (S) -3- [4-[(5-amidino-
2-benzofuranyl) carbonylamino] phenyl]-
Ethyl 2- (trifluoromethylsulfonylamino) propionate Compound (116) (S) -3- [4-[(5-amidino-
2-benzofuranyl) carbonylamino] phenyl]-
2- (trifluoromethylsulfonylamino) propionic acid compound (117) (S) -3- [4-[(5-amidino-
2-benzofuranyl) carbonylamino] phenyl]-
2-[(4-piperidinyloxy) acetylamino] propionic acid compound (118) 2-acetylamino-3- [4-[(5
-Amidino-2-benzofuranyl) carbonylamino]
Phenyl] propionic acid compound (119) 2- (acetyl-N-benzylamino)
-3- [4-[(5-amidino-2-benzofuranyl)
Carbonylamino] phenyl] propionic acid compound (120) 3- [4-[(5-Amidino-2-benzofuranyl) carbonylamino] phenyl] -2- (n
-Hexanoylamino) propionic acid

Compound (121) (S) -3- [4-[(5
-Amidino-2-benzofuranyl) carbonylamino]
Phenyl] -2- (n-hexanoylamino) propionic acid compound (122) (R) -3- [4-[(5-amidino-
2-benzofuranyl) carbonylamino] phenyl]-
2- (n-hexanoylamino) propionic acid compound (123) 3- [4-[(6-amidino-2-benzofuranyl) carbonylamino] phenyl] -2- (n
-Hexanoylamino) propionic acid compound (124) 3- [4-[(5-Amidino-2-benzofuranyl) carbonylamino] phenyl] -2- (n
-Hexanoyl-N-methylamino) propionic acid compound (125) 3- [4-[(5-Amidino-2-benzofuranyl) carbonylamino] phenyl] -2- (2
-Phenylacetylamino) propionic acid compound (126) 3- [4-[(5-Amidino-2-benzofuranyl) carbonylamino] phenyl] -2- (3
-Phenylpropionylamino) propionic acid compound (127) 3- [4-[(5-Amidino-2-benzofuranyl) carbonylamino] phenyl] -2- [3
-(4-Chlorophenyl) propionylamino] propionic acid compound (128) (S) -3- [4-[(5-amidino-
2-benzofuranyl) carbonylamino] phenyl]-
2- [3- (4-methoxyphenyl) propionylamino] propionic acid compound (129) 3- [4-[(5-amidino-2-benzofuranyl) carbonylamino] phenyl] -2- (2
-Naphthanoylamino) propionic acid compound (130) 3- [4-[(5-Amidino-2-benzofuranyl) carbonylamino] phenyl] -2- (4
-Biphenylacetylamino) propionic acid

Compound (131) 3- [4-[(5-Amidino-2-benzofuranyl) carbonylamino] phenyl] -2- (benzyloxycarbonylamino) propionic acid Compound (132) 3- [4-[(5 -Amidino-2-benzofuranyl) carbonylamino] phenyl] -2- (t
-Butoxycarbonylamino) propionic acid compound (133) 3- [4-[(5-Amidino-2-benzofuranyl) carbonylamino] phenyl] -2- (benzylamino) propionic acid compound (134) 3- [4- [ (5-amidino-2-benzofuranyl) carbonylamino] phenyl] -2- (4
-Chlorobenzylamino) propionic acid compound (135) 3- [4-[(5-Amidino-2-benzofuranyl) carbonylamino] phenyl] -2- (4
-Methoxybenzylamino) propionic acid compound (136) 3- [4-[(5-Amidino-2-benzofuranyl) carbonylamino] phenyl] -2- (phenethylamino) propionic acid compound (137) 3- [4- [ (5-amidino-2-benzofuranyl) carbonylamino] phenyl] -2- (methylamino) propionic acid compound (138) 3- [4-[(5-amidino-2-benzofuranyl) carbonylamino] phenyl] -2- (N
-Pentylamino) propionic acid compound (139) [4-[(5-Amidino-2-benzofuranyl) carbonylamino] -N- (n-valeryl) anilino] ethyl acetate compound (140) [4-[[5- ( [Benzyloxycarbonylamidino) -2-benzofuranyl] carbonylamino] -N- (benzyloxycarbonyl) anilino] ethyl acetate

Compound (141) [4-[(5-amidino-
2-benzofuranyl) carbonylamino] anilino] acetic acid compound (142) [4-[(5-amidino-2-benzofuranyl) carbonylamino] -N-methylanilino] acetic acid compound (143) [4-[(5-amidino-2) -Benzofuranyl) carbonylamino] -N-benzylanilino]
Acetic acid compound (144) [4-[(5-Amidino-2-benzofuranyl) carbonylamino] -N- (n-butylsulfonyl) anilino] acetic acid compound (145) [4-[(5-amidino-2-benzofuranyl)] Carbonylamino] -N- (n-valeryl) anilino] acetic acid compound (146) [4-[(5-amidino-2-benzofuranyl) carbonylamino] phenylthio] acetic acid compound (147) 4-[[5- (acetoxymethyl) Oxycarbonylamidino) -2-benzofuranyl] carbonyloxy] ethyl phenoxyacetate compound (148) 4-[[5-[(1-acetoxyethyl) oxycarbonylamidino] -2-benzofuranyl] carbonyloxy] ethyl phenoxyacetate compound (149 ) 4-[(5-Benzylamidino-2-benzofuranyl) carbonyloxy] phenoxyacetic acid Compound (150) 4-[(5-amidino-2-benzofuranyl) carbonyloxy] ethyl phenoxyacetate

Compound (151) 4-[(5-amidino-2
-Benzofuranyl) carbonyloxy] phenoxyacetic acid compound (152) 4-[(6-amidino-2-benzofuranyl) carbonyloxy] phenoxyacetic acid compound (153) [[4-[[5- (acetoxymethyloxycarbonylamidino) -2] -Benzofuranyl] carbonyloxy] -o-phenylene] dioxy] diethyl diacetate compound (154) [[4-[(5-amidino-2-benzofuranyl) carbonyloxy] -o-phenylene] dioxy] diethyl diacetate compound (155 ) [[4-[(5-Amidino-2-benzofuranyl) carbonyloxy] -o-phenylene] dioxy] di-tert-butyl diacetate Compound (156) [[4-[(5-Amidino-2-benzofuranyl) carbonyl] [Oxy] -o-phenylene] dioxy] diacetate compound (157) [[4-[(6-amidino-2-benzofura) Nyl) carbonyloxy] -o-phenylene] dioxy] diacetate compound (158) 3- [4-[[5- (acetoxymethyloxycarbonylamidino) -2-benzofuranyl] carbonyloxy] phenyl] ethyl propionate compound (159 ) 3- [4-[(5-benzylamidino-
2-benzofuranyl) carbonyloxy] phenyl] propionic acid compound (160) 3- [4-[(5-amidino-2-benzofuranyl) carbonyloxy] phenyl] propionic acid

Compound (161) 3- [4-[(5-Amidino-2-benzofuranyl) carbonyloxy] phenyl] -2- (n-butylsulfonylamino) propionic acid Compound (162) (S) -3- [ 4-[(5-amidino-
2-benzofuranyl) carbonyloxy] phenyl]-
2- (n-butylsulfonylamino) propionic acid compound (163) (R) -3- [4-[(5-amidino-
2-benzofuranyl) carbonyloxy] phenyl]-
2- (n-butylsulfonylamino) propionic acid compound (164) 3- [4-[(6-Amidino-2-benzofuranyl) carbonyloxy] phenyl] propionic acid compound (165) 4-[[5- (acetoxymethyl Oxycarbonylguanidino) -2-benzofuranyl] carbonylamino] ethyl phenoxyacetate Compound (166) 4-[(5-benzylguanidino-2-
Benzofuranyl) carbonylamino] ethyl phenoxyacetate compound (167) 4-[[5- (benzyloxycarbonylguanidino) -2-benzofuranyl] carbonylamino] t-butyl phenoxyacetate compound (168) 4-[(5-guanidino-2 -Benzofuranyl) carbonylamino] t-butyl phenoxyacetate compound (169) 4-[(5-guanidino-2-benzofuranyl) carbonylamino] phenoxyacetic acid compound (170) 4-[(6-guanidino-2-benzofuranyl) carbonylamino ] Phenoxyacetic acid

Compound (171) [[4-[[5- (Acetoxymethyloxycarbonylguanidino) -2-benzofuranyl] carbonylamino] -o-phenylene] dioxy] diacetic acid diethyl compound (172) [[4-[[ 5- (benzyloxycarbonylguanidino) -2-benzofuranyl] carbonylamino] -o-phenylene] dioxy] di-t-butyl diacetate Compound (173) [[4-[(5-guanidino-2-benzofuranyl) carbonylamino] -O-phenylene] dioxy] diacetate compound (174) [[4-[(6-guanidino-2-benzofuranyl) carbonylamino] -o-phenylene] dioxy] diacetate compound (175) [[4-[(5 -Guanidino-3-methyl-2-benzofuranyl) carbonylamino] -o-phenylene] dioxy] diacetate compound (176) 3- [4-[( -Guanidino-2-benzofuranyl) carbonylamino] phenyl] ethyl propionate compound (177) 3- [4-[(5-Guanidino-2-benzofuranyl) carbonylamino] phenyl] propionic acid compound (178) 3- [4- [(6-Guanidino-2-benzofuranyl) carbonylamino] phenyl] propionic acid compound (179) 2- (n-butylsulfonylamino)-
3- [4-[(5-guanidino-2-benzofuranyl)
Carbonylamino] phenyl] propionic acid compound (180) 3- [4-[(5-guanidino-2-benzofuranyl) carbonylamino] phenyl] -2-
(N-hexanoylamino) propionic acid

Compound (181) 4-[(5-Benzylaminomethyl-2-benzofuranyl) carbonylamino] ethyl phenoxyacetate Compound (182) 4-[(5-Aminomethyl-2-benzofuranyl) carbonylamino] phenoxyacetic acid compound (183) 4-[(6-aminomethyl-2-benzofuranyl) carbonylamino] phenoxyacetic acid compound (184) 4-[(5-aminoethyl-2-benzofuranyl) carbonylamino] phenoxyacetic acid compound (185) [[4 -[(5-aminoethyl-2-benzofuranyl) carbonylamino] -o-phenylene]
Dioxy] diacetate compound (186) 3- [4-[(5-aminomethyl-2-
Benzofuranyl) carbonylamino] phenyl] propionic acid compound (187) 3- [4-[(6-aminomethyl-2-
Benzofuranyl) carbonylamino] phenyl] propionic acid

[0097] formula ^{(Ia) L = -NR 9 -} (R 9
Is the same as defined above) Compound (188) 4-[[5-[(1-Acetoxyethyl) oxycarbonylamidino] -2-indolyl] carbonylamino] ethyl phenoxyacetate Compound (189) 4-[[5- (Methoxycarbonylamidino) -2-indolyl] carbonylamino] ethyl phenoxyacetate compound (190) 4-[[6- (acetoxymethyloxycarbonylamidino) -2-indolyl] carbonylamino] ethyl phenoxyacetate compound (191) 4- [[6- (Pivaloyloxymethyloxycarbonylamidino) -2-indolyl] carbonylamino] ethyl phenoxyacetate compound (192) 4-[(6-benzylamidino-2-indolyl) carbonylamino] cyclohexyl phenoxyacetate compound ( 193) 4-[[6- (benzyloxycarbonylamido) No.)-2-Indolyl] carbonylamino] phenoxyacetic acid compound (194) 4-[(6-benzylamidino-2-indolyl) carbonylamino] phenoxyacetic acid compound (195) 4-[(5-amidino-2-indolyl) Carbonylamino] methyl phenoxyacetate Compound (196) 4-[(5-Amidino-2-indolyl) carbonylamino] ethyl phenoxyacetate Compound (197) 4-[(6-Amidino-2-indolyl) carbonylamino] ethyl phenoxyacetate Compound (198) 4-[(6-Amidino-2-indolyl) carbonylamino] t-butyl phenoxyacetate compound (199) 4-[(6-Amidino-2-indolyl) carbonylamino] cyclohexyl phenoxyacetate compound (200) 4-[(6-amidino-3-indolyl) carbonylamino] phenoxy vinegar Cyclohexyl

Compound (201) 4-[(5-amidino-2
-Indolyl) carbonylamino] phenoxyacetic acid compound (202) 4-[(6-amidino-2-indolyl) carbonylamino] phenoxyacetic acid compound (203) 4-[(5-amidino-3-indolyl) carbonylamino] phenoxyacetic acid Compound (204) 4-[(6-Amidino-3-indolyl) carbonylamino] phenoxyacetic acid compound (205) 4-[(6-Benzylamidino-3-methyl-2-indolyl) carbonylamino] phenoxyacetic acid compound (206 ) 4-[(6-amidino-3-methyl-2
-Indolyl) carbonylamino] ethyl phenoxyacetate compound (207) 4-[(6-amidino-3-chloro-2)
-Indolyl) carbonylamino] phenoxyacetic acid compound (208) 4-[(6-amidino-3-hydroxy-2-indolyl) carbonylamino] phenoxyacetic acid compound (209) 4-[(5-amidino-3-methyl-2)
-Indolyl) carbonylamino] phenoxyacetic acid compound (210) 4-[(6-amidino-3-methyl-2)
-Indolyl) carbonylamino] phenoxyacetic acid

Compound (211) 4-[(6-amidino-2
-Indolyl) carbonyl-N-methylamino] phenoxyacetic acid compound (212) 4-[(6-amidino-2-indolyl) carbonylamino] -2,6-difluorophenoxyacetic acid compound (213) [[4-[[6 -(Pivaloyloxymethyloxycarbonylamidino) -2-indolyl] carbonylamino] -o-phenylene] dioxy] diacetic acid diethyl compound (214) [[4-[(6-benzylamidino-2)]
-Indolyl) carbonylamino] -o-phenylene]
Dioxy] diacetate compound (215) [[4-[(5-Amidino-2-indolyl) carbonylamino] -o-phenylene] dioxy] diethyldiacetate compound (216) [[4-[(6-amidino-2) -Indolyl) carbonylamino] -o-phenylene] dioxy] diethyl diacetate compound (217) [[4-[(6-amidino-2-indolyl) carbonylamino] -o-phenylene] dioxy] di-t-butyl diacetate Compound (218) [[4-[(5-Amidino-2-indolyl) carbonylamino] -o-phenylene] dioxy] diacetate Compound (219) [[4-[(6-Amidino-2-indolyl) carbonylamino] ] -O-phenylene] dioxy] diacetate compound (220) [[4-[(5-amidino-3-indolyl) carbonylamino] -o-phenylene] dioxy] diacetate

Compound (221) [[4-[(6-Amidino-3-indolyl) carbonylamino] -o-phenylene] dioxy] diacetate Compound (222) [[4-[(6-Amidino-3-methyl) -2-Indolyl) carbonylamino] -o-phenylene] dioxy] diacetate compound (223) 3- [4-[[6- (Isobutyryloxymethyloxycarbonylamidino) -2-indolyl] carbonylamino] phenyl] Ethyl propionate compound (224) 3- [4-[(6-benzylamidino-
2-Indolyl) carbonylamino] phenyl] ethyl propionate compound (225) 3- [4-[[6- (allyloxycarbonylamidino) -2-indolyl] carbonylamino] phenyl] propionic acid compound (226) 3- [ 4-[(6-benzylamidino-
2-Indolyl) carbonylamino] phenyl] propionic acid compound (227) 3- [4-[(5-Amidino-2-indolyl) carbonylamino] phenyl] ethyl propionate compound (228) 3- [4-[(6 -Amidino-2-indolyl) carbonylamino] phenyl] ethyl propionate compound (229) 3- [4-[(6-Amidino-2-indolyl) carbonylamino] phenyl] benzyl propionate compound (230) 3- [4 -[(6-amidino-3-methyl-2-indolyl) carbonylamino] phenyl] benzyl propionate

Compound (231) 3- [4-[(5-Amidino-2-indolyl) carbonylamino] phenyl] propionic acid Compound (232) 3- [4-[(6-Amidino-2-indolyl) carbonylamino ] Phenyl] propionic acid compound (233) 3- [4-[(5-amidino-3-indolyl) carbonylamino] phenyl] propionic acid compound (234) 3- [4-[(6-amidino-3-indolyl) Carbonylamino] phenyl] propionic acid compound (235) 3- [4-[(6-Amidino-3-methyl-2-indolyl) carbonylamino] phenyl] propionic acid compound (236) 3- [4-[(6- Amidino-3-chloro-2-indolyl) carbonylamino] phenyl] propionic acid compound (237) 3- [4-[(6-benzylamidino-
2-indolyl) carbonylamino] phenyl] -2-
(N-butylsulfonylamino) propionic acid compound (238) methyl 3- [4-[(6-amidino-2-indolyl) carbonylamino] phenyl] -2- (n-butylsulfonylamino) propionate (239) 3- [4-[(6-Amidino-2-indolyl) carbonylamino] phenyl] -2-aminopropionic acid compound (240) 3- [4-[(5-Amidino-2-indolyl) carbonylamino] phenyl] -2- (n-butylsulfonylamino) propionic acid

Compound (241) 3- [4-[(6-Amidino-2-indolyl) carbonylamino] phenyl]-
2- (n-butylsulfonylamino) propionic acid compound (242) (S) -3- [4-[(6-amidino-
2-indolyl) carbonylamino] phenyl] -2-
(N-butylsulfonylamino) propionic acid compound (243) (R) -3- [4-[(6-amidino-
2-indolyl) carbonylamino] phenyl] -2-
(N-Butylsulfonylamino) propionic acid compound (244) 3- [4-[(6-Amidino-3-indolyl) carbonylamino] phenyl] -2- (n-butylsulfonylamino) propionic acid compound (245) 3 -[4-[(6-amidino-3-methyl-2-indolyl) carbonylamino] phenyl]-
2- (n-butylsulfonylamino) propionic acid compound (246) 3- [4-[(6-Amidino-2-indolyl) carbonylamino] phenyl] -2- (phenylsulfonylamino) propionic acid compound (247) 3 -[4-[(6-amidino-2-indolyl) carbonylamino] phenyl] -2- (p-tolylsulfonylamino) propionic acid compound (248) 3- [4-[(6-amidino-2-indolyl) Carbonylamino] phenyl] -2- (4-chlorobenzylsulfonylamino) propionic acid compound (249) (S) -3- [4-[(6-amidino-
2-indolyl) carbonylamino] phenyl] -2-
(4-chlorobenzylsulfonylamino) propionic acid compound (250) (R) -3- [4-[(6-amidino-
2-indolyl) carbonylamino] phenyl] -2-
(4-chlorobenzylsulfonylamino) propionic acid

Compound (251) 3- [4-[(6-amidino-2-indolyl) carbonylamino] phenyl]-
2- (benzylsulfonyl-N-methylamino) propionic acid compound (252) 3- [4-[(6-amidino-2-indolyl) carbonylamino] phenyl] -2- (n-valerylamino) propionic acid compound (253 ) 3- [4-[(6-Amidino-2-indolyl) carbonylamino] phenyl] -2- (n-hexanoylamino) propionic acid compound (254) 3- [4-[(6-amidino-2- Indolyl) carbonylamino] phenyl] -2- (4-phenylbutyrylamino) propionic acid compound (255) 3- [4-[(6-Amidino-2-indolyl) carbonylamino] phenyl] -2-methylpropionic acid Compound (256) 4-[(6-amidino-2-indolyl) carbonyloxy] phenoxyacetic acid Compound (257) 3- [4-[(6-amidino-3-hydro) [Xy-2-indolyl) carbonylamino] cyclohexyl] propionic acid compound (258) [4-[(6-amidino-2-indolyl) carbonylamino] phenylthio] acetic acid compound (259) 4-[[5- (acetoxymethyloxy) Carbonylguanidino) -2-indolyl] carbonylamino] methyl phenoxyacetate Compound (260) 4-[(5-benzylguanidino-2-
Indolyl) carbonylamino] ethyl phenoxyacetate

Compound (261) 4-[(5-guanidino-
2- (indolyl) carbonylamino] ethyl phenoxyacetate compound (262) 4-[(6-guanidino-2-indolyl) carbonylamino] ethyl phenoxyacetate compound (263) 4-[(5-guanidino-2-indolyl) carbonylamino ] Phenoxyacetic acid compound (264) 4-[(6-guanidino-2-indolyl) carbonylamino] phenoxyacetic acid compound (265) [[4-[(5-guanidino-2-indolyl) carbonylamino] -o-phenylene] Dioxy] diacetate compound (266) [[4-[(6-Guanidino-2-indolyl) carbonylamino] -o-phenylene] dioxy] diacetate compound (267) 3- [4-[(5-guanidino-2) -Indolyl) carbonylamino] phenyl] propionic acid compound (268) 3- [4-[(6-guanidino-2-indolyl) ca Bonylamino] phenyl] propionic acid compound (269) 4-[[5- (t-butoxycarbonylamidino) -1-methyl-2-indolyl] carbonylamino] ethyl phenoxyacetate compound (270) 4-[[1-methyl- 6- (pivaloyloxymethyloxycarbonylamidino) -2-indolyl] carbonylamino] ethyl phenoxyacetate

Compound (271) 4-[[6- (benzyloxycarbonylamidino) -1-methyl-2-indolyl] carbonylamino] t-butyl phenoxyacetate Compound (272) 4-[(6-benzylamidino-1) -Methyl-2-indolyl) carbonylamino] phenoxyacetic acid compound (273) 4-[(5-amidino-1-methyl-2)
-Indolyl) carbonylamino] ethyl phenoxyacetate Compound (274) 4-[(6-amidino-1-methyl-2)
-Indolyl) carbonylamino] ethyl phenoxyacetate compound (275) 4-[(6-amidino-1-methyl-2)
-Indolyl) carbonylamino] phenoxyacetic acid t-
Butyl compound (276) 4-[(5-amidino-1-methyl-2
-Indolyl) carbonylamino] cyclohexyl phenoxyacetate compound (277) 4-[(5-amidino-1-methyl-2)
-Indolyl) carbonylamino] phenoxyacetic acid compound (278) 4-[(6-amidino-1-methyl-2)
-Indolyl) carbonylamino] phenoxyacetic acid compound (279) 4-[(6-amidino-1-ethyl-2)
-Indolyl) carbonylamino] phenoxyacetic acid compound (280) 4-[(6-amidino-1-methyl-3)
-Indolyl) carbonylamino] phenoxyacetic acid

Compound (281) 4-[(6-amidino-3
-Chloro-1-methyl-2-indolyl) carbonylamino] phenoxyacetic acid compound (282) 4-[(6-amidino-1,3-dimethyl-2-indolyl) carbonylamino] phenoxyacetic acid compound (283) 4- [ (3-acetoxy-6-amidino-1-methyl-2-indolyl) carbonylamino] phenoxyacetic acid compound (284) 4-[(1-acetyl-6-acetylamidino-2-indolyl) carbonylamino] phenoxyacetic acid compound ( 285) 4-[(1-acetyl-6-amidino-
2-Indolyl) carbonylamino] phenoxyacetic acid compound (286) [[4-[(5-Amidino-1-methyl-2-indolyl) carbonylamino] -o-phenylene] dioxy] diacetate compound (287) [[4 -[(6-amidino-1-methyl-2-indolyl) carbonylamino] -o-phenylene] dioxy] diacetate compound (288) [[4-[(1-acetyl-6-amidino-2-indolyl) carbonyl] Amino] -o-phenylene] dioxy] diacetate compound (289) 3- [4-[(6-benzylamidino-
1-methyl-2-indolyl) carbonylamino] phenyl] propionic acid compound (290) 3- [4-[(5-Amidino-1-methyl-2-indolyl) carbonylamino] phenyl] propionic acid

Compound (291) 3- [4-[(6-Amidino-1-methyl-2-indolyl) carbonylamino]
Phenyl] propionic acid compound (292) 3- [4-[(6-Amidino-1-methyl-2-indolyl) carbonylamino] phenyl]-
Methyl 2- (n-butylsulfonylamino) propionate Compound (293) 3- [4-[(6-Amidino-1-methyl-2-indolyl) carbonylamino] phenyl]-
2- (n-butylsulfonylamino) propionic acid compound (294) (S) -3- [4-[(6-amidino-
1-methyl-2-indolyl) carbonylamino] phenyl] -2- (n-butylsulfonylamino) propionic acid compound (295) (R) -3- [4-[(6-amidino-
1-methyl-2-indolyl) carbonylamino] phenyl] -2- (n-butylsulfonylamino) propionic acid compound (296) [4-[(6-amidino-1-methyl-
2-Indolyl) carbonylamino] -N-methylanilino] acetic acid compound (297) [4-[(6-amidino-1-methyl-
2-Indolyl) carbonylamino] phenylthio] acetic acid compound (298) 4-[[5- (acetoxymethyloxycarbonylguanidino) -1-methyl-2-indolyl] carbonylamino] ethyl phenoxyacetate compound (299) 4-[[ 6- (methoxycarbonylguanidino) -1-methyl-2-indolyl] carbonylamino] ethyl phenoxyacetate compound (300) 4-[(5-benzylguanidino-1-
Methyl-2-indolyl) carbonylamino] phenoxyacetic acid

Compound (301) 4-[(5-guanidino-
1-methyl-2-indolyl) carbonylamino] ethyl phenoxyacetate Compound (302) 4-[(6-guanidino-1-methyl-
2-Indolyl) carbonylamino] ethyl phenoxyacetate Compound (303) 4-[(5-guanidino-1-methyl-
2-Indolyl) carbonylamino] phenoxyacetic acid compound (304) 4-[(6-guanidino-1-methyl-
2-Indolyl) carbonylamino] phenoxyacetic acid compound (305) [[4-[[1-Methyl-6- (pivaloyloxymethyloxycarbonylguanidino) -2-
Indolyl] carbonylamino] -o-phenylene] dioxy] diethyl diacetate compound (306) [[4-[(5-guanidino-1-methyl-2-indolyl) carbonylamino] -o-phenylene] dioxy] diacetate compound (307) [[4-[(6-Guanidino-1-methyl-2-indolyl) carbonylamino] -o-phenylene] dioxy] diacetate compound (308) 3- [4-[(5-guanidino-1- Methyl-2-indolyl) carbonylamino] phenyl]
Propionic acid compound (309) 3- [4-[(6-Guanidino-1-methyl-2-indolyl) carbonylamino] phenyl]
Propionic acid compound (310) 3- [4-[(5-guanidino-1,3
-Dimethyl-2-indolyl) carbonylamino] phenyl] propionic acid

Compound (311) 2- (n-butylsulfonylamino) -3- [4-[(6-guanidino-1-methyl-2-indolyl) carbonylamino] phenyl] propionic acid compound (312) 4- [ [6-[(Isobutyryloxymethyloxycarbonylamino) methyl] -2-indolyl] carbonylamino] ethyl phenoxyacetate compound (313) 4-[(6-aminomethyl-2-indolyl) carbonylamino] phenoxyacetic acid compound (314) 4-[(5-aminomethyl-1-methyl-2-indolyl) carbonylamino] phenoxyacetic acid compound (315) 3- [4-[(5-aminomethyl-2-
Indolyl) carbonylamino] phenyl] propionic acid

Compound (316) 4-[[6- (acetoxymethyloxycarbonylamidino) benzo [b] thien-2-yl] wherein L = —S— in formula (Ia)
Ethyl carbonylamino] phenoxyacetate Compound (317) 4-[[6- (allyloxycarbonylamidino) benzo [b] thien-2-yl] carbonylamino] ethyl phenoxyacetate Compound (318) 4-[[5- (benzyl Oxycarbonylamidino) benzo [b] thien-2-yl] carbonylamino] ethyl phenoxyacetate Compound (319) 4-[[6- (pivaloyloxymethyloxycarbonylamidino) benzo [b] thien-2-
Yl] carbonylamino] ethyl phenoxyacetate compound (320) 4-[[5- (n-butyryloxymethyloxycarbonylamidino) benzo [b] thien-2
-Yl] carbonylamino] phenoxyacetic acid

Compound (321) 4-[[6- (Methoxycarbonylamidino) benzo [b] thien-2-yl] carbonylamino] phenoxyacetic acid Compound (322) 4-[(6-benzylamidinobenzo)
[b] thien-2-yl) carbonylamino] phenoxyacetic acid compound (323) 4-[(5-amidinobenzo [b] thien-2-yl) carbonylamino] ethyl phenoxyacetate compound (324) 4-[(6 -Amidinobenzo [b] thien-2-yl) carbonylamino] ethyl phenoxyacetate compound (325) 4-[(5-amidinobenzo [b] thien-2-yl) carbonylamino] phenoxyacetic acid t-
Butyl compound (326) 4-[(6-amidinobenzo [b] thien-2-yl) carbonylamino] phenoxyacetic acid t-
Butyl compound (327) 4-[(6-amidinobenzo [b] thien-2-yl) carbonylamino] cyclohexyl phenoxyacetate compound (328) 4-[(5-amidinobenzo [b] thien-2-yl) carbonyl Amino] phenoxyacetic acid compound (329) 4-[(6-amidinobenzo [b] thien-2-yl) carbonylamino] phenoxyacetic acid compound (330) 4-[(5-amidinobenzo [b] thien-3-yl ) Carbonylamino] phenoxyacetic acid

Compound (331) 4-[(6-Amidinobenzo [b] thien-3-yl) carbonylamino] phenoxyacetic acid Compound (332) 4-[(6-Amidino-3-methylbenzo [b] thien-2 -Yl) carbonylamino] ethyl phenoxyacetate compound (333) 4-[(6-amidino-3-chlorobenzo [b] thien-2-yl) carbonylamino] phenoxyacetic acid compound (334) 4-[(6-amidino- 3-Methylbenzo [b] thien-2-yl) carbonylamino] phenoxyacetic acid compound (335) 4-[(6-amidinobenzo [b] thien-2-yl) carbonylamino] -2,5-difluorophenoxyacetic acid compound (336) [[4-[[6- (acetoxymethyloxycarbonylamidino) benzo [b] thien-2-yl] carbonylamino] -o-phenylene] dioxy Shi]
Diethyl diacetate compound (337) [[4-[(6-benzylamidinobenzo [b] thien-2-yl) carbonylamino] -o-
[Phenylene] dioxy] diethyl diacetate compound (338) [[4-[(6-amidinobenzo [b]
Thien-2-yl) carbonylamino] -o-phenylene] dioxy] diethyl diacetate compound (339) [[4-[(5-amidinobenzo [b])
Thien-2-yl) carbonylamino] -o-phenylene] dioxy] diacetate compound (340) [[4-[(6-amidinobenzo [b])
Thien-2-yl) carbonylamino] -o-phenylene] dioxy] diacetate

Compound (341) [[4-[(5-Amidinobenzo [b] thien-3-yl) carbonylamino]-
o-phenylene] dioxy] diacetate compound (342) [[4-[(6-amidinobenzo [b]
Thien-3-yl) carbonylamino] -o-phenylene] dioxy] diacetate compound (343) 3- [4-[(6-benzylamidinobenzo [b] thien-2-yl) carbonylamino] phenyl] propionic acid Compound (344) 3- [4-[(6-amidinobenzo
[b] thien-2-yl) carbonylamino] phenyl]
Ethyl propionate compound (345) 3- [4-[(6-amidinobenzo
[b] thien-2-yl) carbonylamino] phenyl]
Cyclohexyl propionate compound (346) 3- [4-[(5-amidinobenzo)
[b] thien-2-yl) carbonylamino] phenyl]
Propionic acid compound (347) 3- [4-[(6-amidinobenzo
[b] thien-2-yl) carbonylamino] phenyl]
Propionic acid compound (348) 3- [4-[(5-amidinobenzo
[b] thien-3-yl) carbonylamino] phenyl]
Propionic acid compound (349) 3- [4-[(6-amidinobenzo
[b] thien-3-yl) carbonylamino] phenyl]
Propionic acid compound (350) 3- [4-[(6-benzylamidinobenzo [b] thien-2-yl) carbonylamino] phenyl] -2- (n-butylsulfonylamino) propionic acid

Compound (351) 3- [4-[(6-Amidinobenzo [b] thien-2-yl) carbonylamino]
Phenyl] -2- (n-butylsulfonylamino) propionic acid methyl compound (352) 3- [4-[(6-amidinobenzo)
[b] thien-2-yl) carbonylamino] phenyl]
-2- (n-butylsulfonylamino) propionic acid compound (353) (S) -3- [4-[(6-amidinobenzo [b] thien-2-yl) carbonylamino] phenyl] -2- (n -Butylsulfonylamino) propionic acid compound (354) (R) -3- [4-[(6-Amidinobenzo [b] thien-2-yl) carbonylamino] phenyl] -2- (n-butylsulfonylamino) Propionic acid compound (355) 3- [4-[(6-amidinobenzo
[b] thien-2-yl) carbonylamino] phenyl]
-2- (benzylsulfonylamino) propionic acid compound (356) 3- [4-[(6-amidinobenzo)
[b] thien-2-yl) carbonylamino] phenyl]
-2- (phenethylsulfonylamino) propionic acid compound (357) 3- [4-[(6-amidinobenzo
[b] thien-2-yl) carbonylamino] phenyl]
-2- (n-Hexanoylamino) propionic acid compound (358) (S) -3- [4-[(6-Amidinobenzo [b] thien-2-yl) carbonylamino] phenyl] -2- (n -Hexanoylamino) propionic acid compound (359) (R) -3- [4-[(6-Amidinobenzo [b] thien-2-yl) carbonylamino] phenyl] -2- (n-hexanoylamino) Propionic acid compound (360) 3- [4-[(6-amidinobenzo
[b] thien-2-yl) carbonylamino] phenyl]
-2- (acetylamino) propionic acid

Compound (361) 3- [4-[(6-Amidinobenzo [b] thien-2-yl) carbonylamino]
Phenyl] -2- (n-pentylamino) propionic acid compound (362) 3- [4-[(6-amidinobenzo)
[b] thien-2-yl) carbonylamino] phenyl]
-2- (benzylamino) propionic acid compound (363) [4-[(6-amidinobenzo [b] thien-2-yl) carbonylamino] phenylthio] acetic acid compound (364) 4-[[5- (benzyloxy Carbonylguanidino) benzo [b] thien-2-yl] carbonylamino] t-butyl phenoxyacetate Compound (365) 4-[(6-benzylguanidinobenzo)
[b] thien-2-yl) carbonylamino] phenoxyacetic acid compound (366) 4-[(5-guanidinobenzo [b] thien-2-yl) carbonylamino] ethyl phenoxyacetate compound (367) 4-[(6 -Guanidinobenzo [b] thien-2-yl) carbonylamino] cyclohexyl phenoxyacetate compound (368) 4-[(5-guanidinobenzo [b] thien-2-yl) carbonylamino] phenoxyacetic acid compound (369) 4- [(6-guanidinobenzo [b] thien-2-yl) carbonylamino] phenoxyacetic acid compound (370) [[4-[(6-guanidinobenzo
[b] thien-2-yl) carbonylamino] -o-phenylene] dioxy] diethyl diacetate

Compound (371) [[4-[(5-guanidinobenzo [b] thien-2-yl) carbonylamino]
-O-phenylene] dioxy] diacetate compound (372) [[4-[(6-guanidinobenzo)
[b] thien-2-yl) carbonylamino] -o-phenylene] dioxy] diacetate compound (373) 3- [4-[(5-guanidinobenzo)
[b] thien-2-yl) carbonylamino] phenyl]
Propionic acid compound (374) 3- [4-[(6-guanidinobenzo
[b] thien-2-yl) carbonylamino] phenyl]
Propionic acid compound (375) 3- [4-[(5-guanidinobenzo
[b] thien-2-yl) carbonyloxy] phenyl]
Propionic acid compound (376) 3- [4-[(6-guanidinobenzo
[b] thien-2-yl) carbonyloxy] phenyl]
Propionic acid compound (377) 4-[[5- (aminomethyl) benzo
[b] thien-2-yl] carbonylamino] ethyl phenoxyacetate compound (378) 4-[[5- (aminomethyl) benzo
[b] thien-2-yl] carbonylamino] phenoxyacetic acid compound (379) 4-[[6- (aminomethyl) benzo]
[b] thien-2-yl] carbonylamino] phenoxyacetic acid

Compound (380) 4-[[5- (acetoxymethyloxycarbonylamidino) -2-indenyl] carbonylamino] ethyl phenoxyacetate (381) 4 wherein L = —CH ₂ — in formula (Ia) -[[6- (acetoxymethyloxycarbonylamidino) -2-indenyl] carbonylamino] ethyl phenoxyacetate compound (382) 4-[[6- (t-Butoxycarbonylamidino) -2-indenyl] carbonylamino] phenoxyacetic acid Compound (383) 4-[(5-benzylamidino-2-indenyl) carbonylamino] phenoxyacetic acid compound (384) 4-[(5-amidino-2-indenyl) carbonylamino] ethyl phenoxyacetate compound (385) 4- [(5-amidino-2-indenyl) carbonylamino] t-butyl phenoxyacetate Compound (386) 4-[(6-Amidino-2-indenyl) carbonylamino] t-butyl phenoxyacetate compound (387) 4-[(5-Amidino-2-indenyl) carbonylamino] cyclohexyl phenoxyacetate compound (388) 4-[(5-amidino-2-indenyl) carbonylamino] phenoxyacetic acid compound (389) 4-[(6-amidino-2-indenyl) carbonylamino] phenoxyacetic acid compound (390) 4-[(5-amidino- 2-indenyl) carbonyloxy] phenoxyacetic acid

Compound (391) 4-[(6-amidino-2)
-Indenyl) carbonyloxy] phenoxyacetic acid compound (392) [[4-[(6-benzylamidino-2)
-Indenyl) carbonylamino] -o-phenylene]
Dioxy] diacetate compound (393) [[4-[(5-Amidino-2-indenyl) carbonylamino] -o-phenylene] dioxy] di-t-butyldiacetate compound (394) [[4-[(6- Amidino-2-indenyl) carbonylamino] -o-phenylene] dioxy] di-tert-butyl diacetate Compound (395) [[4-[(5-Amidino-2-indenyl) carbonylamino] -o-phenylene] dioxy] Diacetate compound (396) [[4-[(6-Amidino-2-indenyl) carbonylamino] -o-phenylene] dioxy] diacetate compound (397) 3- [4-[[5- (acetoxymethyloxycarbonyl) Amidino) -2-indenyl] carbonylamino] phenyl] ethyl propionate Compound (398) 3- [4-[[5- (n-propionyloxymethyloxycarbonylamidino) -2 -Indenyl] carbonylamino] phenyl] ethyl propionate compound (399) 3- [4-[(5-benzylamidino-
2- (indenyl) carbonylamino] phenyl] ethyl propionate compound (400) 3- [4-[(5-Amidino-2-indenyl) carbonylamino] phenyl] ethyl propionate

Compound (401) Ethyl 3- [4-[(6-amidino-2-indenyl) carbonylamino] phenyl] propionate Compound (402) 3- [4-[(5-Amidino-2-indenyl) carbonyl Amino] phenyl] propionic acid compound (403) 3- [4-[(6-Amidino-2-indenyl) carbonylamino] phenyl] propionic acid compound (404) 3- [4-[(5-amidino-2-indenyl) ) Carbonylamino] phenyl] -2- (n-butylsulfonylamino) propionic acid compound (405) (S) -3- [4-[(5-amidino-
2-indenyl) carbonylamino] phenyl] -2-
(N-butylsulfonylamino) propionic acid compound (406) (R) -3- [4-[(5-amidino-
2-indenyl) carbonylamino] phenyl] -2-
(N-Butylsulfonylamino) propionic acid compound (407) 3- [4-[(6-Amidino-2-indenyl) carbonylamino] phenyl] -2- (n-butylsulfonylamino) propionic acid compound (408) 3 -[4-[(5-amidino-2-indenyl) carbonylamino] phenyl] -2- (n-hexanoylamino) propionic acid compound (409) (S) -3- [4-[(5-amidino-
2-indenyl) carbonylamino] phenyl] -2-
(N-Hexanoylamino) propionic acid compound (410) (R) -3- [4-[(5-amidino-
2-indenyl) carbonylamino] phenyl] -2-
(N-hexanoylamino) propionic acid

Compound (411) 3- [4-[(6-amidino-2-indenyl) carbonylamino] phenyl]-
2- (n-hexanoylamino) propionic acid compound (412) 4-[(5-guanidino-2-indenyl) carbonylamino] phenoxyacetic acid compound (413) 4-[(6-guanidino-2-indenyl) carbonylamino ] Phenoxyacetic acid compound (414) [[4-[(5-benzylguanidino-
2-Indenyl) carbonylamino] -o-phenylene] dioxy] diacetate compound (415) [[4-[(5-Guanidino-2-indenyl) carbonylamino] -o-phenylene] dioxy] diacetate compound (416) [[4-[(6-Guanidino-2-indenyl) carbonylamino] -o-phenylene] dioxy] diacetate compound (417) 3- [4-[(5-guanidino-2-indenyl) carbonylamino] phenyl] Propionic acid compound (418) 3- [4-[(6-Guanidino-2-indenyl) carbonylamino] phenyl] propionic acid compound (419) [4-[(6-Amidino-2-indenyl) carbonylamino] phenylthio] Acetic acid compound (420) 4-[(5-aminomethyl-2-indenyl) carbonylamino] phenoxyacetic acid

Compound (421) 4-[(6-Aminomethyl-2-indenyl) carbonylamino] phenoxyacetic acid compound (422) 4-[(5-Aminoethyl-2-indenyl) carbonylamino] phenoxyacetic acid compound (423 ) 4-[(6-Aminoethyl-2-indenyl) carbonylamino] phenoxyacetic acid compound (424) 3- [4-[(5-aminomethyl-2-
Indenyl) carbonylamino] phenyl] propionic acid compound (425) 3- [4-[(6-aminomethyl-2-
Indenyl) carbonylamino] phenyl] propionic acid

2. A compound represented by the following formula (Ib) [in the formula (I), a = 1, b = 0, B = a group represented by the formula (6), and a compound wherein J = -CH <]

[0123]

Embedded image

Wherein each symbol is as defined above. Compound (Ib) wherein L = —O— Compound (426) 3- [4-[(5-Amidino-2-benzofuranyl) carbonyloxy] cyclohexyl T-butyl propionate compound (427) 3- [4-[(5-Amidino-2-benzofuranyl) carbonyloxy] cyclohexyl] propionic acid compound (428) [4-[(5-amidino-2-benzofuranyl) carbonyl Oxy] cyclohexyloxy] t-butyl acetate compound (429) [4-[(5-amidino-2-benzofuranyl) carbonyloxy] cyclohexyloxy] acetic acid compound (430) 3- [4-[(5-amidino-2- Benzofuranyl) carbonyloxy] piperidino] propionic acid

Compound (431) [4-[(5-amidino-
2-benzofuranyl) carbonyloxy] cyclohexylamino] acetic acid compound (432) 4-[(5-amidino-2-benzofuranyl) carbonylamino] cyclohexylacetic acid compound (433) trans-3- [4-[[5- (benzyloxy) Carbonylamidino) -2-benzofuranyl]
Carbonylamino] cyclohexyl] ethyl propionate compound (434) 3- [4-[[5- (Acetoxymethyloxycarbonylamidino) -2-benzofuranyl] carbonylamino] cyclohexyl] ethyl propionate compound (435) 3- [4- [[5- (methoxycarbonylamidino) -2-benzofuranyl] carbonylamino] cyclohexyl] ethyl propionate compound (436) 3- [4-[(5-benzylamidino-
2-benzofuranyl) carbonylamino] cyclohexyl] ethyl propionate compound (437) 3- [4-[(5-benzylamidino-
2-benzofuranyl) carbonylamino] cyclohexyl] propionic acid compound (438) 3- [4-[(5-Amidino-2-benzofuranyl) carbonylamino] cyclohexyl] methyl propionate compound (439) trans-3- [4- [ (5-amidino-2-benzofuranyl) carbonylamino] cyclohexyl] ethyl propionate compound (440) trans-3- [4-[(5-amidino-2-benzofuranyl) carbonylamino] cyclohexyl] isopropyl propionate

Compound (441) trans-3- [4-
[(5-Amidino-2-benzofuranyl) carbonylamino] cyclohexyl] t-butyl propionate compound (442) trans-3- [4-[(5-Amidino-2-benzofuranyl) carbonylamino] cyclohexyl] cyclohexyl propionate compound (443) trans-3- [4-[(5-amidino-2-benzofuranyl) carbonylamino] cyclohexyl] 2-hydroxyethyl propionate compound (444) trans- [4-[(5-amidino-2)
-Benzofuranyl) carbonylamino] cyclohexyloxy] 2-hydroxyethyl acetate compound (445) 3- [4-[(5-Amidino-2-benzofuranyl) carbonylamino] cyclohexyl] propionic acid compound (446) cis-3- [4 -[(5-amidino-2
-Benzofuranyl) carbonylamino] cyclohexyl] propionic acid compound (447) trans-3- [4-[(5-amidino-2-benzofuranyl) carbonylamino] cyclohexyl] propionic acid compound (448) 3- [4-[(6 -Amidino-2-benzofuranyl) carbonylamino] cyclohexyl] propionic acid compound (449) 3- [4-[(6-Amidino-3-benzofuranyl) carbonylamino] cyclohexyl] propionic acid compound (450) 3- [4- [ (5-amidino-3-chloro-2-benzofuranyl) carbonylamino] cyclohexyl] propionic acid

Compound (451) 3- [4-[(5-Amidino-3-methyl-2-benzofuranyl) carbonylamino] cyclohexyl] propionic acid Compound (452) trans- [4-[[5- (benzyloxycarbonyl) Amidino) -2-benzofuranyl] carbonylamino] cyclohexyloxy] ethyl acetate compound (453) trans- [4-[[5- (benzyloxycarbonylamidino) -2-benzofuranyl] carbonylamino] cyclohexyloxy] t-butyl acetate compound (454) [4-[(5-benzylamidino-2-
Benzofuranyl) carbonylamino] cyclohexyloxy] ethyl acetate compound (455) trans- [4-[(5-benzylamidino-2-benzofuranyl) carbonylamino] cyclohexyloxy] t-butyl acetate compound (456) trans- [4- [ (5-benzylamidino-2-benzofuranyl) carbonylamino] cyclohexyloxy] ethyl acetate compound (457) trans- [4-[[5- (benzyloxycarbonylamidino) -2-benzofuranyl] carbonylamino] cyclohexyloxy] acetic acid compound (458) trans- [4-[(5-benzylamidino-2-benzofuranyl) carbonylamino] cyclohexyloxy] acetic acid compound (459) trans- [4-[(5-amidino-2)
-Benzofuranyl) carbonylamino] cyclohexyloxy] ethyl acetate compound (460) trans- [4-[(5-amidino-2)
-Benzofuranyl) carbonylamino] cyclohexyloxy] n-butyl acetate

Compound (461) trans- [4-[(5-
Amidino-2-benzofuranyl) carbonylamino] cyclohexyloxy] t-butyl acetate compound (462) trans- [4-[(5-amidino-2)
-Benzofuranyl) carbonylamino] cyclohexyloxy] benzyl acetate compound (463) [4-[(5-amidino-2-benzofuranyl) carbonylamino] cyclohexyloxy] acetic acid compound (464) cis- [4-[(5-amidino- 2-benzofuranyl) carbonylamino] cyclohexyloxy] acetic acid compound (465) trans- [4-[(5-amidino-2)
-Benzofuranyl) carbonylamino] cyclohexyloxy] acetic acid compound (466) [4-[(6-amidino-2-benzofuranyl) carbonylamino] cyclohexyloxy] acetic acid compound (467) trans- [4-[(5-amidino-3)
-Methyl-2-benzofuranyl) carbonylamino] cyclohexyloxy] t-butyl acetate compound (468) trans- [4-[(5-amidino-3)
-Methyl-2-benzofuranyl) carbonylamino] cyclohexyloxy] acetic acid compound (469) trans- [4-[(5-amidino-3)
-Methoxy-2-benzofuranyl) carbonylamino]
Cyclohexyloxy] t-butyl acetate compound (470) trans- [4-[(5-amidino-3)
-Methoxy-2-benzofuranyl) carbonylamino]
Cyclohexyloxy] acetic acid

Compound (471) Ethyl 3- [4-[[5- (acetoxymethyloxycarbonylamidino) -2-benzofuranyl] carbonylamino] piperidino] propionate Compound (472) 3- [4-[[5- ( Benzyloxycarbonylamidino) -2-benzofuranyl] carbonylamino] piperidino] ethyl propionate compound (473) 3- [4-[[5- (Methoxycarbonylamidino) -2-benzofuranyl] carbonylamino] piperidino] ethyl propionate compound (474) 3- [4-[(5-benzylamidino-
2-benzofuranyl) carbonylamino] piperidino]
Ethyl propionate compound (475) 3- [4-[[5- (Benzyloxycarbonylamidino) -2-benzofuranyl] carbonylamino] piperidino] propionic acid compound (476) 3- [4-[(5-benzylamidino-
2-benzofuranyl) carbonylamino] piperidino]
Propionic acid compound (477) 3- [4-[(5-Amidino-2-benzofuranyl) carbonylamino] piperidino] ethyl propionate compound (478) 3- [4-[(5-Amidino-2-benzofuranyl) carbonylamino ] Piperidino] t-butyl propionate compound (479) 3- [4-[(5-Amidino-2-benzofuranyl) carbonylamino] piperidino] propionic acid compound (480) 3- [4-[(6-amidino-2) -Benzofuranyl) carbonylamino] piperidino] propionic acid

Compound (481) Ethyl 3- [4-[(5-amidino-2-benzofuranyl) carbonyloxy] piperidino] propionate Compound (482) trans- [4-[(5-amidino-2)
-Benzofuranyl) carbonylamino] cyclohexyl-N- (t-butoxycarbonyl) amino] t-butyl acetate compound (483) trans- [4-[(5-amidino-2)
-Benzofuranyl) carbonylamino] cyclohexylamino] acetic acid compound (484) [4-[(5-amidino-2-benzofuranyl) carbonylamino] cyclohexyl-N-methylamino] acetic acid compound (485) trans- [4-[(5 -Amidino-2
-Benzofuranyl) carbonylamino] cyclohexyl-N-n-butylamino] t-butyl acetate compound (486) trans- [4-[(5-amidino-2)
-Benzofuranyl) carbonylamino] cyclohexyl-N-n-butylamino] acetic acid compound (487) [4-[(5-amidino-2-benzofuranyl) carbonylamino] cyclohexyl-N-benzylamino] acetic acid compound (488) [4 -[(5-amidino-2-benzofuranyl) carbonylamino] cyclohexyl-N- (n
-Butylsulfonyl) amino] acetic acid compound (489) trans- [4-[[5- (benzyloxycarbonylamidino) -2-benzofuranyl] carbonylamino] cyclohexylamino] di-t-butyl diacetate compound (490) trans- [ 4-[(5-amidino-2
-Benzofuranyl) carbonylamino] cyclohexylamino] diethyl diacetate

Compound (491) trans- [4-[(5-
Amidino-2-benzofuranyl) carbonylamino] cyclohexylamino] di-tert-butyl diacetate compound (492) trans- [4-[(5-amidino-2)
-Benzofuranyl) carbonylamino] cyclohexylamino] diacetate compound (493) cis- [4-[(5-Amidino-2-benzofuranyl) carbonylamino] cyclohexylamino] diacetate compound (494) 3- [4-[(6 -Aminomethyl-2-
Benzofuranyl) carbonylamino] cyclohexyl]
Propionic acid

[0132] formula ^{(Ib) L = -NR 9 -} (R 9
Is the same as defined above) Compound (495) 3- [4-[(6-Amidino-3-methyl-2-indolyl) carbonylamino] cyclohexyl] propionic acid Compound (496) trans- [4-[[6 -(Benzyloxycarbonylamidino) -2-indolyl] carbonylamino] cyclohexyloxy] ethyl acetate compound (497) [4-[[6- (t-butoxycarbonylamidino) -2-indolyl] carbonylamino] cyclohexyloxy] acetic acid Ethyl compound (498) [4-[(6-benzylamidino-2-
Indolyl) carbonylamino] cyclohexyloxy] ethyl acetate compound (499) trans- [4-[[6- (benzyloxycarbonylamidino) -2-indolyl] carbonylamino] cyclohexyloxy] acetic acid compound (500) trans- [4- [(6-benzylamidino-2-indolyl) carbonylamino] cyclohexyloxy] acetic acid

Compound (501) trans- [4-[(6-
Amidino-2-indolyl) carbonylamino] cyclohexyloxy] ethyl acetate compound (502) trans- [4-[(6-amidino-2)
-Indolyl) carbonylamino] cyclohexyloxy] t-butyl acetate compound (503) trans- [4-[(6-amidino-2)
-Indolyl) carbonylamino] cyclohexyloxy] cyclohexyl acetate compound (504) [4-[(5-amidino-2-indolyl) carbonylamino] cyclohexyloxy] acetic acid compound (505) cis- [4-[(5-amidino- 2-indolyl) carbonylamino] cyclohexyloxy]
Acetic acid compound (506) trans- [4-[(5-amidino-2
-Indolyl) carbonylamino] cyclohexyloxy] acetic acid compound (507) trans- [4-[(6-Amidino-2)
-Indolyl) carbonylamino] cyclohexyloxy] acetic acid compound (508) 3- [4-[[6- (benzyloxycarbonylamidino) -2-indolyl] carbonylamino] piperidino] ethyl propionate compound (509) 3- [4 -[[6- (pivaloyloxymethyloxycarbonylamidino) -2-indolyl]
Carbonylamino] piperidino] ethyl propionate Compound (510) 3- [4-[(6-benzylamidino-
2-Indolyl) carbonylamino] piperidino] ethyl propionate

Compound (511) 3- [4-[[6- (benzyloxycarbonylamidino) -2-indolyl] carbonylamino] piperidino] propionic acid Compound (512) 3- [4-[(6-benzylamidino-
2-Indolyl) carbonylamino] piperidino] propionic acid compound (513) 3- [4-[(6-Amidino-2-indolyl) carbonylamino] piperidino] ethyl propionate compound (514) 3- [4-[(5 -Amidino-2-indolyl) carbonylamino] piperidino] propionic acid compound (515) 3- [4-[(6-Amidino-2-indolyl) carbonylamino] piperidino] propionic acid compound (516) trans- [4- [ (6-Amidino-2
-Indolyl) carbonylamino] cyclohexylamino] acetic acid compound (517) trans- [4-[(6-amidino-2)
-Indolyl) carbonylamino] cyclohexyl-N
-Methylamino] acetic acid compound (518) trans- [4-[(6-amidino-2)
-Indolyl) carbonylamino] cyclohexyl-N
-N-butylsulfonylamino] acetic acid compound (519) 3- [4-[[6- (acetoxymethyloxycarbonylamidino) -2-indolyl] carbonylamino] cyclohexyl] ethyl propionate compound (520) 3- [4- [[6- (benzyloxycarbonylamidino) -2-indolyl] carbonylamino] cyclohexyl] ethyl propionate

Compound (521) Ethyl 3- [4-[(6-benzylamidino-2-indolyl) carbonylamino] cyclohexyl] propionate Compound (522) 3- [4-[(6-benzylamidino-
2-indolyl) carbonylamino] cyclohexyl]
Propionic acid compound (523) 3- [4-[(6-Amidino-2-indolyl) carbonylamino] cyclohexyl] ethyl propionate compound (524) 3- [4-[(5-Amidino-2-indolyl) carbonylamino Cyclohexyl] propionic acid compound (525) 3- [4-[(6-Amidino-2-indolyl) carbonylamino] cyclohexyl] propionic acid compound (526) cis-3- [4-[(6-amidino-2)
-Indolyl) carbonylamino] cyclohexyl] propionic acid compound (527) trans-3- [4-[(6-amidino-2-indolyl) carbonylamino] cyclohexyl] propionic acid compound (528) 3- [4-[(6 -Amidino-3-indolyl) carbonylamino] cyclohexyl] propionic acid compound (529) 3- [4-[(6-Amidino-3-chloro-2-indolyl) carbonylamino] cyclohexyl] propionic acid compound (530) 3- [4-[(6-amidino-2-indolyl) carbonyloxy] cyclohexyl] propionic acid

Compound (531) [4-[(6-amidino-
2-Indolyl) carbonyloxy] cyclohexyloxy] acetic acid compound (532) 3- [4-[(6-amidino-2-indolyl) carbonyloxy] piperidino] propionic acid compound (533) 3- [4-[(6- Amidino-1-methyl-2-indolyl) carbonylamino] cyclohexyl] propionic acid compound (534) [4-[(6-amidino-1-methyl-
2-Indolyl) carbonylamino] cyclohexyloxy] acetic acid compound (535) 3- [4-[(6-Amidino-1-methyl-2-indolyl) carbonylamino] piperidino]
Propionic acid compound (536) 3- [4-[(5-aminomethyl-2-
Indolyl) carbonylamino] cyclohexyl] propionic acid

Compound of the formula (Ib) wherein L = —S— Compound (537) 3- [4-[[6- (acetoxymethyloxycarbonylamidino) benzo [b] thien-2-
Yl] carbonylamino] cyclohexyl] ethyl propionate compound (538) 3- [4-[(6-benzylamidinobenzo [b] thien-2-yl) carbonylamino] cyclohexyl] ethyl propionate compound (539) 3- [ 4-[[6- (methoxycarbonylamidino) benzo [b] thien-2-yl] carbonylamino] cyclohexyl] cyclohexylpropionate Compound (540) 3- [4-[(6-benzylamidinobenzo [b] thien- 2-yl) carbonylamino] cyclohexyl] propionic acid

Compound (541) 3- [4-[(5-Amidinobenzo [b] thien-2-yl) carbonylamino]
Cyclohexyl] propionic acid compound (542) 3- [4-[(6-amidinobenzo)
[b] thien-2-yl) carbonylamino] cyclohexyl] ethyl propionate compound (543) 3- [4-[(6-amidinobenzo)
[b] thien-2-yl) carbonylamino] cyclohexyl] propionic acid compound (544) cis-3- [4-[(6-amidinobenzo [b] thien-2-yl) carbonylamino] cyclohexyl] propionic acid compound (545) trans-3- [4-[(6-amidinobenzo [b] thien-2-yl) carbonylamino] cyclohexyl] propionic acid compound (546) 3- [4-[(6-amidinobenzo)
[b] thien-3-yl) carbonylamino] cyclohexyl] propionic acid compound (547) 3- [4-[(6-amidino-3-chlorobenzo [b] thien-2-yl) carbonylamino]
Cyclohexyl] propionic acid compound (548) 3- [4-[(6-Amidino-3-methylbenzo [b] thien-2-yl) carbonylamino]
Cyclohexyl] propionic acid compound (549) trans- [4-[[6- (benzyloxycarbonylamidino) benzo [b] thien-2-yl] carbonylamino] cyclohexyloxy] acetate compound (550) [4-[( 6-benzylamidinobenzo
[b] thien-2-yl) carbonylamino] cyclohexyloxy] ethyl acetate

Compound (551) trans- [4-[(6-
Amidinobenzo [b] thien-2-yl) carbonylamino] cyclohexyloxy] n-hexyl acetate Compound (552) trans- [4-[[6- (benzyloxycarbonylamidino) benzo [b] thien-2-yl] Carbonylamino] cyclohexyloxy] acetic acid compound (553) trans- [4-[(6-benzylamidinobenzo [b] thien-2-yl) carbonylamino] cyclohexyloxy] acetic acid compound (554) trans- [4-[( 6-amidinobenzo [b] thien-2-yl) carbonylamino] cyclohexyloxy] ethyl acetate compound (555) [4-[(5-amidinobenzo [b] thien-2-yl) carbonylamino] cyclohexyloxy] acetic acid Compound (556) [4-[(6-Amidinobenzo [b] thien-2-yl) carbonylamino] cyclohexy Ruoxy] acetic acid compound (557) cis- [4-[(6-amidinobenzo)
[b] thien-2-yl) carbonylamino] cyclohexyloxy] acetic acid compound (558) trans- [4-[(6-amidinobenzo [b] thien-2-yl) carbonylamino] cyclohexyloxy] acetic acid compound (559 ) 3- [4-[[6- (Benzyloxycarbonylamidino) benzo [b] thien-2-yl] carbonylamino] piperidino] ethyl propionate Compound (560) 3- [4-[(6-benzylamidinobenzo) [b] thien-2-yl) carbonylamino] piperidino] ethyl propionate

Compound (561) 3- [4-[[6- (benzyloxycarbonylamidino) benzo [b] thien-
2-yl] carbonylamino] piperidino] propionic acid compound (562) 3- [4-[(6-benzylamidinobenzo [b] thien-2-yl) carbonylamino] piperidino] propionic acid compound (563) 3- [ 4-[(5-amidinobenzo
[b] thien-2-yl) carbonylamino] piperidino] ethyl propionate compound (564) 3- [4-[(6-amidinobenzo)
[b] thien-2-yl) carbonylamino] piperidino] ethyl propionate compound (565) 3- [4-[(5-amidinobenzo)
[b] thien-2-yl) carbonylamino] piperidino] propionic acid compound (566) 3- [4-[(6-amidinobenzo)
[b] thien-2-yl) carbonylamino] piperidino] propionic acid compound (567) [4-[(6-amidinobenzo [b] thien-2-yl) carbonylamino] cyclohexylamino] acetic acid compound (568) 3 -[4-[(6-amidinobenzo
[b] thien-2-yl) carbonyloxy] cyclohexyl] propionic acid compound (569) [4-[(6-amidinobenzo [b] thien-2-yl) carbonyloxy] cyclohexyloxy] acetic acid compound (570) 3 -[4-[(6-benzylamidinobenzo [b] thien-2-yl) carbonyloxy] piperidino] propionic acid compound (571) 3- [4-[[5- (aminomethyl) benzo [b] thien- 2-yl] carbonylamino] cyclohexyl] propionic acid

Compound of the formula (Ib) wherein L = —CH ₂ — Compound (572) Ethyl 3- [4-[[6- (acetoxymethyloxycarbonylamidino) -2-indenyl] carbonylamino] cyclohexyl] propionate Compound (573) 3- [4-[[6- (t-Butoxycarbonylamidino) -2-indenyl] carbonylamino] cyclohexyl] ethyl propionate Compound (574) 3- [4-[(6-benzylamidino-
2-indenyl) carbonylamino] cyclohexyl]
Ethyl propionate compound (575) 3- [4-[(6-benzylamidino-
2-indenyl) carbonylamino] cyclohexyl]
Propionic acid compound (576) 3- [4-[(6-Amidino-2-indenyl) carbonylamino] cyclohexyl] ethyl propionate compound (577) 3- [4-[(5-Amidino-2-indenyl) carbonylamino ] Cyclohexyl] propionic acid compound (578) 3- [4-[(6-Amidino-2-indenyl) carbonylamino] cyclohexyl] propionic acid compound (579) cis-3- [4-[(6-amidino-2)
-Indenyl) carbonylamino] cyclohexyl] propionic acid compound (580) trans-3- [4-[(6-amidino-2-indenyl) carbonylamino] cyclohexyl] propionic acid

Compound (581) trans- [4-[[5-
(Benzyloxycarbonylamidino) -2-indenyl] carbonylamino] cyclohexyloxy] ethyl acetate compound (582) trans- [4-[[5- (benzyloxycarbonylamidino) -2-indenyl] carbonylamino] cyclohexyloxy] acetic acid Compound (583) trans- [4-[(5-amidino-2
-Indenyl) carbonylamino] cyclohexyloxy] ethyl acetate compound (584) trans- [4-[(5-amidino-2)
-Indenyl) carbonylamino] cyclohexyloxy] acetic acid compound (585) [4-[(6-amidino-2-indenyl) carbonylamino] cyclohexyloxy] acetic acid compound (586) 3- [4-[[5- (benzyloxy) Carbonylamidino) -2-indenyl] carbonylamino] piperidino] ethyl propionate compound (587) 3- [4-[[5- (benzyloxycarbonylamidino) -2-indenyl] carbonylamino] piperidino] propionic acid compound (588 ) 3- [4-[(6-benzylamidino-
2-indenyl) carbonylamino] piperidino] propionic acid compound (589) 3- [4-[(5-Amidino-2-indenyl) carbonylamino] piperidino] ethyl propionate compound (590) 3- [4-[(5 -Amidino-2-indenyl) carbonylamino] piperidino] propionic acid

Compound (591) 3- [4-[(6-Amidino-2-indenyl) carbonylamino] piperidino]
Propionic acid compound (592) [4-[(5-Amidino-2-indenyl) carbonylamino] cyclohexylamino] acetic acid compound (593) 3- [4-[(5-Amidino-2-indenyl) carbonyloxy] cyclohexyl] Propionic acid compound (594) [4-[(5-Amidino-2-indenyl) carbonyloxy] cyclohexyloxy] acetic acid compound (595) 3- [4-[(5-Amidino-2-indenyl) carbonyloxy] piperidino] Propionic acid compound (596) 3- [4-[(5-aminomethyl-2-
Indenyl) carbonylamino] cyclohexyl] propionic acid

[0144] 3. Compound represented by the following formula (Ic) [Compound of formula (I) wherein a = 1 and b = 1]

[0145]

Embedded image

Wherein each symbol is as defined above. Compound (597) (3S, 5S) -5-[[5- (benzyloxycarbonylamidino) wherein L = —O— in formula (Ic) -2-benzofuranyl] carbonylamino] methyl] -3-[(t-butoxycarbonyl) methyl] -2-pyrrolidinone compound (598) 5-[[[5- (acetoxymethyloxycarbonylamidino) -2-benzofuranyl] carbonyl Amino] methyl] -3-carboxymethyl-2-pyrrolidinone compound (599) 5-[[(5-benzylamidino-2-
Benzofuranyl) carbonylamino] methyl] -3-carboxymethyl-2-pyrrolidinone compound (600) 5-[[(5-amidino-2-benzofuranyl) carbonylamino] methyl] -3-[(t-butoxycarbonyl) methyl] -2-pyrrolidinone

Compound (601) (3S, 5S) -5- [
[(5-Amidino-2-benzofuranyl) carbonylamino] methyl] -3-carboxymethyl-2-pyrrolidinone compound (602) 5-[[(6-amidino-2-benzofuranyl) carbonylamino] methyl] -3-carboxy Methyl-2-pyrrolidinone compound (603) 5-[[(5-amidino-3-methyl-
2-benzofuranyl) carbonylamino] methyl] -3
-Carboxymethyl-2-pyrrolidinone compound (604) 1-acetyl-5-[[(5-amidino-2-benzofuranyl) carbonylamino] methyl]-
3-carboxymethyl-2-pyrrolidinone compound (605) 1-acetyl-5-[[(6-amidino-2-benzofuranyl) carbonylamino] methyl]-
3-carboxymethyl-2-pyrrolidinone compound (606) 5-[[(5-amidino-2-benzofuranyl) carbonylamino] methyl] -3-carboxymethyl-1-nicotinoyl-2-pyrrolidinone compound (607) 5- [ [(5-amidino-2-benzofuranyl) carbonylamino] methyl] -3-carboxymethyl-1- (3-phenylpropyl) -2-pyrrolidinone compound (608) 5-[[(5-amidino-2-benzofuranyl) Carbonylamino] methyl] -3-carboxymethylpyrrolidine compound (609) 5-[[(6-amidino-2-benzofuranyl) carbonylamino] methyl] -3-carboxymethylpyrrolidine compound (610) 1-acetyl-5- [ [(5-amidino-2-benzofuranyl) carbonylamino] methyl]-
3-carboxymethylpyrrolidine

Compound (611) (3S, 5S) -5- [
[(5-amidino-2-benzofuranyl) carbonyloxy] methyl] -3-[(t-butoxycarbonyl) methyl] -2-pyrrolidinone Compound (612) 5-[[(5-amidino-2-benzofuranyl) carbonyloxy ] Methyl] -3-carboxymethyl-2-pyrrolidinone compound (613) 4-[[(5-amidino-2-benzofuranyl) carbonylamino] methyl] cyclohexylacetic acid compound (614) 4-[[(5-amidino-2 -Benzofuranyl) carbonylamino] methyl] cyclohexanecarboxylic acid compound (615) [4-[[(5-amidino-2-benzofuranyl) carbonylamino] methyl] piperidino] acetic acid compound (616) [4-[[(6-amidino -2-benzofuranyl) carbonylamino] methyl] piperidino] acetic acid

[0149] In the formula ^{(Ic) L = -NR 9 -} (R 9
Is the same as defined above) Compound (617) 5- [[(6-benzylamidino-2-
Indolyl) carbonylamino] methyl] -3-carboxymethyl-2-pyrrolidinone compound (618) 5-[[(5-amidino-2-indolyl) carbonylamino] methyl] -3-carboxymethyl-2-pyrrolidinone compound (619) ) 5-[[(6-Amidino-2-indolyl) carbonylamino] methyl] -3-carboxymethyl-2-pyrrolidinone Compound (620) 5-[[(6-Amidino-2-indolyl) carbonyloxy] methyl] -3-t-butoxycarbonylmethyl-2-pyrrolidinone compound (621) 5-[[(5-amidino-2-indolyl) carbonyloxy] methyl] -3-carboxymethyl-2-pyrrolidinone compound (622) 5- [ [(6-Amidino-2-indolyl) carbonyloxy] methyl] -3-carboxymethyl-2-pyrrolidinone Compound (623) 5-[[((6-amidino-1-methyl-
2-indolyl) carbonylamino] methyl] -3-carboxymethyl-2-pyrrolidinone

Compound of the formula (Ic) wherein L = -S- Compound (624) 5-[[(6-benzylamidinobenzo)
[b] thien-2-yl) carbonylamino] methyl]
-3-Carboxymethyl-2-pyrrolidinone compound (625) 5-[[(6-Amidinobenzo [b] thien-2-yl) carbonylamino] methyl] -3-ethoxycarbonylmethyl-2-pyrrolidinone compound (626) 5-[[(5-amidinobenzo [b] thien-2-yl) carbonylamino] methyl] -3-carboxymethyl-2-pyrrolidinone compound (627) 5-[[(6-amidinobenzo [b] thien- 2-yl) carbonylamino] methyl] -3-carboxymethyl-2-pyrrolidinone compound (628) 5-[[(5-amidinobenzo [b] thien-2-yl) carbonyloxy] methyl] -3-carboxymethyl -2-pyrrolidinone compound (629) 5-[[(6-amidinobenzo [b] thien-2-yl) carbonyloxy] methyl] -3-carboxymethyl-2- Rorijinon

Compound of the formula (Ic) wherein L = —CH ₂ — Compound (630) 5-[[(5-benzylamidino-2-
Indenyl) carbonylamino] methyl] -3-carboxymethyl-2-pyrrolidinone compound (631) 5-[[(5-amidino-2-indenyl) carbonylamino] methyl] -3-carboxymethyl-2-pyrrolidinone compound (632 ) 5-[[(6-Amidino-2-indenyl) carbonylamino] methyl] -3-carboxymethyl-2-pyrrolidinone compound (633) 5-[[(5-amidino-2-indenyl) carbonyloxy] methyl] -3-carboxymethyl-2-pyrrolidinone compound (634) 5-[[(6-amidino-2-indenyl) carbonyloxy] methyl] -3-carboxymethyl-2-pyrrolidinone

4. Other compound Compound (635) 4- [1-[(5-Amidino-2-benzofuranyl) carbonyl] -4-piperidinyl] butyric acid Compound (636) 4- [1-[(5-Amidino-2-benzofuranyl) carbonyl ] -4-piperazinyl] butyric acid compound (637) [1-[(5-Amidino-2-benzofuranyl) carbonyl] -4-piperidinyloxy] methyl acetate compound (638) [1-[(5-amidino-2) -Benzofuranyl) carbonyl] -4-piperidinyloxy] acetic acid compound (639) 1-[(5-amidino-2-benzofuranyl) carbonyl] -4- (2-carboxyethyl) imidazole compound (640) 1-[( 5-amidino-2-benzofuranyl) carbonyl] -4- (2-carboxy-2-hydroxyethyl) imidazole compound (641) 1-[(5-amidino-2-ben Zofuranyl) carbonyl] -4- [2-carboxy-2- (n
-Valerylamino) ethyl] imidazole compound (642) 1-[(5-amidino-2-benzofuranyl) carbonyl] -4- [2-carboxy-2- (n
-Butylsulfonylamino) ethyl] imidazole compound (643) 1-[(6-amidino-2-indolyl) carbonyl] -4- (2-carboxyethyl) imidazole

Of the above compounds, particularly preferred compounds include the following compounds. Compound (22) 4-[(5-Amidino-2-benzofuranyl) carbonylamino] phenoxyacetic acid Compound (59) [[4-[(5-Amidino-2-benzofuranyl) carbonylamino] -o-phenylene] dioxy] 2 Acetic acid compound (101) 3- [4-[(5-Amidino-2-benzofuranyl) carbonylamino] phenyl] -2- (n
-Butylsulfonylamino) propionic acid compound (439) trans-3- [4-[(5-amidino-2-benzofuranyl) carbonylamino] cyclohexyl] ethyl propionate compound (447) trans-3- [4-[(5 -Amidino-2-benzofuranyl) carbonylamino] cyclohexyl] propionic acid compound (459) trans- [4-[(5-amidino-2)
-Benzofuranyl) carbonylamino] cyclohexyloxy] ethyl acetate compound (465) trans- [4-[(5-amidino-2)
-Benzofuranyl) carbonylamino] cyclohexyloxy] acetic acid compound (479) 3- [4-[(5-Amidino-2-benzofuranyl) carbonylamino] piperidino] propionic acid compound (491) trans- [4-[(5-amidino -2
-Benzofuranyl) carbonylamino] cyclohexylamino] di-t-butyl diacetate compound (492) trans- [4-[(5-amidino-2)
-Benzofuranyl) carbonylamino] cyclohexylamino] diacetate compound (558) trans- [4-[(6-Amidinobenzo [b] thien-2-yl) carbonylamino] cyclohexyloxy] acetic acid

The compound (I) of the present invention and a pharmacologically acceptable salt thereof can be used as an excellent GPIIb / IIIa antagonist for mammals (eg, human, mouse, rat, rabbit, dog, cat, etc.). Has an action. In addition, it has low toxicity, can be administered orally, has a long blood life, and has few side effects such as prolonged bleeding time.

Therefore, the compound (I) and a pharmacologically acceptable salt thereof are useful as GPIIb / IIIa antagonists, prevent the formation of thrombus of platelets, and prevent diseases caused by the formation of thrombus of platelets ( For example, it can be used in the prevention and treatment of thrombosis, stroke, heart failure, inflammation and arteriosclerosis).

Specific examples of the disease to which the compound (I) of the present invention or a pharmacologically acceptable salt thereof can be applied include, for example, ischemic heart disease [angina pectoris (unstable, exertional) ), Myocardial infarction, postoperative PTCA (percutaneous transluminal coronary angioplasty), cerebrovascular accident [TIA (transient cerebral ischemic attack), cerebral infarction (thrombosis, embolism), subarachnoid hemorrhage (vascular Spasm)], cardiovascular surgery (valve replacement, AC bypass (prevention of graft occlusion after coronary artery bypass surgery), revascularization,
Arteriovenous shunt, peripheral arterial occlusion (ASO (obstructive arteriosclerosis), Burger's disease), deep venous thrombosis, duct-dependent congenital heart disease), respiratory disease [pulmonary embolism, bronchial asthma, pulmonary edema, ARDS ( Adult respiratory distress syndrome), pulmonary hypertension],
Kidney disease [nephrotic syndrome, glomerulonephritis], collagen disease [S
LE (systemic lupus erythematosus), RA (rheumatoid arthritis), PSS (systemic scleroderma) (Raynaud phenomenon)],
Artificial organs [artificial heart-lung, artificial dialysis], others [essential thrombocythemia, TTP (thrombotic thrombocytopenic purpura), HUS
(Hemolytic uremic syndrome), DIC (disseminated intravascular coagulation), Kawasaki disease, diabetes, organ transplantation, arteriosclerosis, vibration, shock, uterine contraction, peptic ulcer, t-PA (tissue plasminogen activity) , The effect of chemotherapeutic factor), eclampsia] and the like.

Furthermore, the compound (I) and a pharmaceutically acceptable salt thereof inhibit metastasis of tumor cells.
It also promotes wound healing. It can also be used in the treatment of osteoporosis as it prevents bone degradation.

The GPIIb / IIIa antagonism of the compound (I) of the present invention and a pharmaceutically acceptable salt thereof is, for example, as follows:
Platelet ADP (adenosine 5'-
(Diphosphate) Aggregation inhibitory activity, fibrinogen binding inhibitory activity to platelets, etc. are determined by measurement (see the above-mentioned literature by Leo Alig et al., The above-mentioned literature by GDHartmans et al.).

Further, the compound (I ′) or a salt thereof contained in the compound (I) of the present invention can be used as an inclusion complex with cyclodextrin or a derivative thereof in order to further improve the water solubility. . The clathrate is a compound obtained by clathrate compound (I ′) or a salt thereof with cyclodextrin or a derivative thereof.

As the salt of compound (I '), the same as the above-mentioned pharmacologically acceptable salts and the like can be mentioned.

Examples of the cyclodextrin or a derivative thereof that can be used for preparing an inclusion complex include α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, and derivatives thereof, for example, a glucose residue. Ester with hydroxyl group (eg, acetylated product), ether (eg, methylated, hydroxyethylated, hydroxypropylated, etc.), nitrogen-containing (eg, aminomethylcyclodextrin, etc.), sulfur-containing (Eg: cyclodextrin sulfate), acid group-containing (eg:
Carboxymethyl cyclodextrin, etc.), sugar-containing substances (eg, glucosylated form, mantosylated form, etc.) and the like.

The method for preparing the clathrate is not particularly limited, and can be prepared by a method known per se, but the compound (I ')
Alternatively, the mixing ratio of the salt thereof to cyclodextrin or a derivative thereof is preferably from 1: 0.5 to 1:50, particularly preferably from 1: 1 to 1:10.

When the compound (I) of the present invention and its pharmacologically acceptable salt and the above-mentioned clathrate are used as the above-mentioned pharmaceuticals, addition of pharmacologically acceptable carriers, excipients, diluents, etc. Agent, appropriately mixed with pharmaceutically necessary ingredients, powder,
Granules, tablets, capsules, syrups, injections, ointments,
It can be made into a pharmaceutical composition in the form of a cream or the like and administered orally or parenterally. An effective amount of the compound (I) or a pharmacologically acceptable salt thereof is blended in the above preparation.

The dose of the compound (I) and a pharmacologically acceptable salt thereof varies depending on the administration route, patient's condition, body weight, age and the like, and can be appropriately set depending on the purpose of administration. Usually, when administered orally to an adult, 0.01 to 1000 mg / kg body weight / day, preferably 0.05 to 500 mg / kg body weight / day, 1 day
It is preferable to administer the drug in several divided doses.

In the compound (I), the group represented by A has or does not have an amino-protecting group, and the group represented by B has a free carboxyl group or an ester group thereof. However, the above group, the efficacy, persistence of efficacy, toxicity, solubility, stability, considering the absorbability, etc., depending on the form of administration, the type of disease, the purpose of treatment, etc.
They are appropriately selected, and all are useful GPIIb / IIIa antagonists.

[0166]

The present invention will be described more specifically with reference to the following examples, but the present invention is not limited to these examples. In addition, ¹ H-NMR measurement was performed at 200 MHz unless otherwise specified.

Example 1 (1) 13.9 g (100 mmol) of t-butyl 4-aminophenoxyacetate 4-nitrophenol was dissolved in 20 ml of N, N-dimethylformamide.
29.3 g (150 mmol) of butyl and 27.6 g (200 mmo) of potassium carbonate
l) was added and the mixture was stirred at 70 ° C for 4 hours. The reaction solution was diluted with 100 ml of ethyl acetate, washed with water, and the aqueous layer was extracted with ethyl acetate. The extract and the organic layer were combined, washed with water, and dried over anhydrous magnesium sulfate. After filtration, low-boiling substances were distilled off from the filtrate under reduced pressure, and the residue was subjected to silica gel column chromatography (n-hexane / ethyl acetate =
5/1), and further recrystallized from a mixed solvent of ethyl acetate and n-hexane to obtain 21.8 g (86%) of t-butyl 4-nitrophenoxyacetate as pale yellow crystals. IR (KBr): 1740, 1590, 1500, 1330, 1240, 116
^{0 cm -1 1 H-NMR (} DMSO-d 6) δ TMS: 8.21 (d, J = 7.1H
z, 2H), 7.13 (d, J = 7.1Hz, 2H), 4.86 (s, 2H), 1.43 (s, 9H)

Tert-Butyl 4-nitrophenoxyacetate 19.3
g (76.0 mmol) was dissolved in 100 ml of ethanol, and 10%
1.0 g of palladium carbon was added, and the mixture was stirred at room temperature for 18 hours under a hydrogen atmosphere. The reaction solution was filtered, and low-boiling substances were distilled off from the filtrate under reduced pressure to obtain 16.8 g (99%) of t-butyl 4-aminophenoxyacetate as a light brown solid. IR (neat): 3350, 2950, 1740, 1510, 1220, 1
^{150 cm -1 1 H-NMR (} DMSO-d 6) δ TMS: 6.62 (d, J = 6.6H
z, 2H), 6.49 (d, J = 6.6Hz, 2H), 4.63 (s, 2H), 4.43 (s, 2H),
1.41 (s, 9H)

(2) 4-[(5-cyano-2-benzofuranyl) carbonylamino] tert-butyl phenoxyacetate 5-cyano-2-benzofurancarboxylic acid 300 mg (1.60
mmol) and 395 mg of t-butyl 4-aminophenoxyacetate
(1.76 mmol) was dissolved in N, N-dimethylformamide (40 ml).
l) was added and the mixture was stirred at room temperature for 18 hours. 100 ml of water in the reaction solution
And extracted with ethyl acetate. The extract was washed with water and saturated saline and dried over anhydrous magnesium sulfate. After filtration, low-boiling substances were distilled off from the filtrate under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 1/1) to give 4-[(5-cyano-2).
-Benzofuranyl) carbonylamino] 512 mg (82%) of t-butyl phenoxyacetate was obtained as a pale yellow solid. IR (KBr): 2200, 1750, 1680, 1605, 1530, 150
^{5 cm -1 1 H-NMR (} CDCl 3) δ TMS: 8.07 (d, J = 0.8Hz, 1
H), 7.75-7.60 (m, 5H), 6.94 (d, 2H), 4.53 (s, 2H), 1.50
(s, 9H)

(3) 4-[(5-Amidino-2-benzofuranyl) carbonylamino] t-butyl phenoxyacetate (compound (17)) 4-[(5-Cyano-2-benzofuranyl) carbonylamino] phenoxyacetic acid t -Butyl 430mg (1.10 mmol)
Was dissolved in a mixture of 30 ml of pyridine and 7 ml of triethylamine, and hydrogen sulfide gas was blown into the mixture at room temperature for 10 minutes, followed by stirring for 18 hours. Low-boiling substances were distilled off from the reaction solution under reduced pressure, and the residue was dissolved in ethyl acetate. This was washed with a 2N aqueous solution of potassium hydrogen sulfate, water and saturated saline, and dried over anhydrous magnesium sulfate. After filtration, low-boiling substances were distilled off from the filtrate under reduced pressure to give 4-[(5-thiocarbamoyl-2-).
Benzofuranyl) carbonylamino] phenoxyacetic acid t
-Butyl was obtained as a yellow solid. This is acetone 5
The mixture was dissolved in 0 ml, and 2 ml of methyl iodide was added, followed by heating under reflux for 40 minutes. Low-boiling substances were distilled off from the reaction solution under reduced pressure,
[[5-[(1-Methylthio) iminomethyl] -2-benzofuranyl] carbonylamino] phenoxyacetic acid t-
Butyl was obtained as a yellow solid. Add methanol 3
0 ml and ammonium acetate 280 mg (3.64 mmol)
Heated to reflux for an hour. The low-boiling substances were distilled off from the reaction solution under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol = 100/3 to 3/1) to give the hydroiodide salt of compound (17) as a yellow solid. As 596
mg (quantitative in 3 steps). IR (KBr): 3700-2900, 1730 , 1640, 1600 cm -1 1 H-NMR (DMSO-d 6) δ TMS: 8.32 (s, 1H), 8.
00-7.80 (m, 3H), 7.69 (d, 2H), 6.93 (d, 2H), 4.65 (s, 2H),
1.44 (s, 9H)

Example 2: 4-[(5-amidino-2-benzofuranyl) carbonylamino] phenoxyacetic acid (compound (22)) To 537 mg (1.00 mmol) of the hydroiodide salt of compound (17) was added 25 ml of methylene chloride. 8 ml of trifluoroacetic acid was added thereto, and the mixture was stirred at room temperature for 2 hours. 100 ml of diethyl ether was added to the reaction solution, and the mixture was stirred for 10 minutes. The precipitate was collected by filtration and washed with diethyl ether to obtain 380 mg (79%) of hydroiodide as a pale brown solid such as compound (22). Mp:> 250 ℃ IR (KBr) : 1740, 1690, 1610, 1540, 1505 cm -1 1 H-NMR (DMSO-d 6, 500MHz) δ TMS:
10.57 (s, 1H), 9.38 (bs, 2H), 9.11 (bs, 2H), 8.34 (d, J = 1.
7Hz, 1H), 7.97 (d, J = 8.8Hz, 1H), 7.91 (s, 1H), 7.89 (dd, J =
1.7,8.8Hz, 1H), 7.72-7.69 (m, 2H), 6.97-6.93 (m, 2H), 4.
67 (s, 2H)

Example 3: 4-[(5-amidino-3-methyl-2-benzofuranyl) carbonylamino] t-butyl phenoxyacetate (compound (26)) According to the same method as in Example 1 (2), -Cyano-3-
Methyl-2-benzofurancarboxylic acid 427mg (1.86mmo
l) and 500 mg of t-butyl 4-aminophenoxyacetate (2.2
4 mmol), and purified by silica gel column chromatography (n-hexane / ethyl acetate = 7/3) to obtain t-butyl 4-[(5-cyano-3-methyl-2-benzofuranyl) carbonylamino] phenoxyacetate. Was obtained as a colorless solid (562 mg, 74%). IR (KBr): 2450, 1715, 1660, 1610, 1535, 150
^{5, 1210, 1150 cm -1 1} H-NMR (DMSO-d 6) δ TMS: 8.23 (s, 1H), 8.
00-7.99 (m, 1H), 7.72 (dd, J = 1.6,8.6Hz, 1H), 7.63-7.59
(m, 3H), 6.95-6.91 (m, 2H), 4.52 (s, 2H), 2.69 (s, 3H), 1.
50 (s, 9H)

According to the same method as in Example 1 (3), 4-
[(5-cyano-3-methyl-2-benzofuranyl) carbonylamino] tert-butyl phenoxyacetate 550 mg (1.3
(5 mmol) cyano group was converted to an amidino group, and silica gel column chromatography (chloroform / methanol =
95/5 to 85/15) to give 520 mg (70% over 3 steps) of hydroiodide as a light brown solid, as compound (26). ¹ H-NMR (DMSO-d ₆ ) δ _TMS : 9.32 (bs, 4H),
8.33-8.32 (m, 1H), 7.91-7.89 (m, 2H), 7.71 (d, J = 9.1Hz, 2
H), 6.81 (d, J = 9.1Hz, 2H), 4.65 (s, 2H), 2.64 (s, 3H), 1.4
4 (s, 9H)

Example 4: 4-[(5-amidino-3-methyl-2-benzofuranyl) carbonylamino] phenoxyacetic acid (compound (29)) According to the same method as in Example 2, compound (26) was obtained. The hydrochloride (510 mg, 0.925 mmol) was treated with trifluoroacetic acid (6 ml), and the hydroiodide as a compound (29) was converted to a brown solid.
mg (83%). Melting point: 220-228 ° C (decomposition) IR (KBr): 3300, 3100, 1730, 1670, 1610, 153
^{5, 1510, 1205, 1140cm -1} 1 H-NMR (DMSO-d 6, 500MHz) δ TMS:
10.42 (s, 1H), 9.38 (bs, 2H), 9.14 (bs, 2H), 8.34 (d, J = 1.
8Hz, 1H), 7.92 (dd, J = 1.8,8.6Hz, 1H), 7.90 (d, J = 8.6Hz, 1
H), 7.73-7.70 (m, 2H), 6.94-6.91 (m, 2H), 4.67 (s, 2H),
2.64 (s, 3H)

Example 5 (1) t-butyl 4- (methylamino) phenoxyacetate 7.00 g (31.4 mmol) of t-butyl 4-aminophenoxyacetate
l) and 3.11 g (31.4 mmol) of succinimide in ethanol 40
2.55 g of 37% aqueous formaldehyde solution
(31.4 mmol) was added and the mixture was heated under reflux for 4 hours. Low-boiling substances were distilled off from the reaction solution under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate).
8.37 g (84%) of t-butyl (succinimidomethylamino) phenoxyacetate was obtained as a yellow solid. This one 8.3
0 g (26.0 mmol) was dissolved in dimethyl sulfoxide 50 ml, and sodium borohydride 989 mg (26.0 mmol) was added thereto.
And stirred at 100 ° C. for 30 minutes. After cooling, water was poured into the reaction solution, and the mixture was extracted with diethyl ether. The extract was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. After filtration, low-boiling substances were distilled off from the filtrate under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 1/1) to give 4- (methylamino)
3.62 g of t-butyl phenoxyacetate as a yellow oil (59
%)Obtained. ¹ H-NMR (DMSO-d ₆ ) δ _TMS : 6.69 (d, 2H), 6.
45 (d, 2H), 4.51 (s, 2H), 2.61 (d, J = 5.2Hz, 3H), 1.42 (s, 9
H)

(2) 4-[(5-amidino-2-benzofuranyl) carbonyl-N-methylamino] tert-butyl phenoxyacetate (compound (39)) Cyano-2-
300 mg (1.60 mmol) of benzofurancarboxylic acid and 417 mg (1.76 mmol) of t-butyl 4- (methylamino) phenoxyacetate
l), and purified by silica gel column chromatography (chloroform / methanol = 10/1).
4-[(5-cyano-2-benzofuranyl) carbonyl-N-methylamino] 652 mg (quantitative) of t-butyl phenoxyacetate was obtained as a yellow solid. ¹ H-NMR (DMSO-d ₆ ) δ _TMS : 8.15 (s, 1H), 7.
96 (s, 1H), 7.82-7.65 (m, 2H), 7.31 (d, 2H), 6.95 (d, 2H),
4.69 (s, 2H), 3.36 (s, 3H), 1.40 (s, 9H)

According to the same method as in Example 1 (3), 4-
[(5-cyano-2-benzofuranyl) carbonyl-N
-Methylamino] tert-butyl phenoxyacetate 652 mg (1.
60 mmol) of the cyano group to an amidino group, compound (39)
392 mg of hydroiodide as yellow solid (44 in 3 steps)
%) Obtained. ¹ H-NMR (DMSO-d ₆ ) δ _TMS : 8.08 (s, 1H), 7.
76 (s, 2H), 6.46 (bs, 1H), 7.31 (d, 2H), 6.96 (d, 2H), 4.6
9 (s, 2H), 3.37 (s, 3H), 1.42 (s, 9H)

Example 6: 4-[(5-Amidino-2-benzofuranyl) carbonyl-N-methylamino] phenoxyacetic acid (compound (40)) The hydrochloride (390 mg, 0.708 mmol) was treated with trifluoroacetic acid (5 ml) to give hydroiodide as a yellow solid as a compound (40).
mg (80%). Melting point: 185-195 ° C (decomposition) IR (KBr): 3700-2800, 1750, 1690, 1640, 1505
^{cm -1 1 H-NMR (DMSO} -d 6, 500MHz) δ TMS:
13.11 (bs, 1H), 9.26 (bs, 2H), 9.16 (bs, 2H), 8.10 (s, 1
H), 7.76 (s, 2H), 7.32 (d, 2H), 6.97 (d, 2H), 6.43 (bs, 1
H), 4.71 (s, 2H), 3.37 (s, 3H)

Example 7 (1) [(4-amino-o-phenylene) dioxy] 7.95 g (51.3 mmol) of di-tert-butyl 4-nitrocatechol diacetate and 25.0 g (128 mmol) of t-butyl bromoacetate were added to N , N-dimethylformamide in 100 ml, and potassium carbonate 19.7 g (14
3 mmol) and stirred at room temperature for 24 hours. Water was poured into the reaction solution, and the mixture was extracted with diethyl ether. The extract was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. After filtration, low-boiling substances were distilled off from the filtrate under reduced pressure, and the residue was recrystallized from a mixture of n-hexane and ethyl acetate.
[Nitro-o-phenylene) dioxy] 18.10 g (61%) of di-t-butyl diacetate as colorless crystals were obtained. This one 13.
10 g (34.1 mmol) was dissolved in 70 ml of ethyl acetate, and 10%
1.3 g of palladium carbon was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 5 hours. The reaction solution was filtered through celite, and low-boiling substances were distilled off from the filtrate under reduced pressure to give [(4-amino-o-phenylene) dioxy] di-t-butyl diacetate as a colorless oil.
11.81 g (98%) were obtained. IR (KBr): 3350, 3000 , 1740, 1510, 1150 cm -1 1 H-NMR (CDCl 3) δ TMS: 6.79 (m, 1H), 6.27-
6.20 (m, 2H), 4.54 (s, 2H), 4.50 (s, 2H), 1.48 (s, 1H), 1.4
7 (s, 9H)

(2) [[4-[(5-Amidino-2-benzofuranyl) carbonylamino] -o-phenylene]
Dioxy] di-tert-butyl diacetate (compound (57)) According to the same method as in Example 1 (2), 5-cyano-2-
Benzofurancarboxylic acid 200 mg (1.07 mmol) and [(4-
Amino-o-phenylene) dioxy] t-butyl diacetate
415 mg (1.17 mmol) were condensed and subjected to silica gel column chromatography (n-hexane / ethyl acetate = 3/1 to 1).
/ [1-[(5-cyano-2-benzofuranyl) carbonylamino] -o-phenylene]
Dioxy] di-t-butyl diacetate as a colorless solid 473mg
(84%). IR (KBr): 2220, 1740, 1735, 1640, 1275-1215
^{cm -1 1 H-NMR (DMSO} -d 6) δ TMS: 8.07 (s, 1H), 7.
78-7.66 (m, 2H), 7.61 (s, 1H), 7.52 (d, J = 2.4Hz, 1H), 7.15
(dd, J = 8.7,2.4Hz, 1H), 6.90 (d, J = 8.7Hz, 1H), 4.65 (s, 2
H), 4.61 (s, 2H), 1.50 (s, 9H), 1.48 (s, 9H)

According to the same method as in Example 1 (3),
[4-[(5-cyano-2-benzofuranyl) carbonylamino] -o-phenylene] dioxy] di-t-diacetate
The cyano group of 463 mg (0.881 mmol) of butyl was converted to an amidino group, and purified by silica gel column chromatography (chloroform / methanol = 95/5 to 85/15).
244 mg of hydroiodide as a yellow solid as compound (57)
(42% in 3 steps). ¹ H-NMR (DMSO-d ₆ ) δ _TMS : 10.52 (bs, 1H),
9.34 (bs, 4H), 8.33 (s, 1H), 8.00-7.85 (m, 3H), 7.52 (d, J =
2.1Hz, 1H), 7.35 (dd, J = 8.9,2.1Hz, 1H), 6.93 (d, J = 8.9H
z, 1H), 4.66 (s, 4H), 1.45 (s, 9H), 1.44 (s, 9H)

Example 8: [[4-[(5-amidino-2)
-Benzofuranyl) carbonylamino] -o-phenylene] dioxy] diacetic acid (compound (59)) According to the same method as in Example 2, 187 mg (0.280 mmol) of hydroiodide of compound (57) was added to 3 ml of trifluoroacetic acid. To give the hydroiodide salt as a light brown solid as compound (59).
27 mg (82%) were obtained. Mp:> 250 ℃ IR (KBr) : 3300, 1660, 1200, 1135 cm -1 1 H-NMR (DMSO-d 6, 500MHz) δ TMS:
13.01 (bs, 1H), 13.00 (bs, 1H), 10.55 (bs, 1H), 9.38 (s, 2
H), 9.24 (s, 2H), 8.33 (d, J = 1.7Hz, 1H), 7.96 (d, J = 8.8Hz,
1H), 7.89 (dd, J = 1.7,8.8Hz, 1H), 7.89 (s, 1H), 7.43-7.41
(m, 2H), 6.93 (d, J = 9.5Hz, 1H), 4.69 (s, 2H), 4.68 (s, 2H)

Example 9 (1) Methyl 3- (4-aminophenyl) propionate 15.0 g (77.6 mmol) of 4-aminocinnamic acid was added to methanol 250
To a mixed solvent of 150 ml of chloroform and 150 ml of chloroform, 3 ml of sulfuric acid was added, and the mixture was refluxed for 47 hours. The reaction solution was concentrated under reduced pressure, the residue was made weakly alkaline with saturated aqueous sodium hydrogen carbonate, extracted with ethyl acetate, and the extract was washed with water and saturated saline.
It was dried over anhydrous magnesium sulfate. After filtration, low-boiling substances were distilled off from the filtrate under reduced pressure to obtain 7.84 g (72%) of methyl 4-aminocinnamate as a yellow solid. This one 7.80g (44.1
was dissolved in 250 ml of methanol, 780 mg of 10% palladium carbon was added thereto, and the mixture was stirred under a hydrogen atmosphere at room temperature for 19 hours. The reaction solution was filtered through celite, low-boiling substances were distilled off from the filtrate under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 3/1) to give 3- (4-aminophenyl) 5.) Methyl propionate was obtained as a colorless solid, 5.98 g (76%). Melting point: 47-49.5 ° C IR (KBr): 3700-2500, 1710, 1600, 1500, 1425
^{cm -1 1 H-NMR (CDCl} 3) δ TMS: 6.97 (d, 2H), 6.61
(d, 2H), 3.66 (s, 3H), 2.83 (t, J = 6.8Hz, 2H), 2.57 (t, J = 6.
(8Hz, 2H)

(2) 3- [4-[(5-amidino-2-
Benzofuranyl) carbonylamino] phenyl] methyl propionate (compound (82)) According to the same method as in Example 1 (2), 5-cyano-2-
Benzofurancarboxylic acid 200mg (1.07mmol) and 3- (4
-Aminophenyl) methyl propionate 211 mg (1.18 mmo
l) was condensed to obtain 371 mg (quantitative) of methyl 3- [4-[(5-cyano-2-benzofuranyl) carbonylamino] phenyl] propionate as a yellow solid. IR (KBr): 2200, 1735 , 1685, 1600, 1520 cm -1 1 H-NMR (DMSO-d 6) δ TMS: 10.59 (bs, 1H),
8.44 (s, 1H), 7.94 (s, 2H), 7.86 (s, 1H), 7.69 (d, 2H), 7.2
2 (d, 2H), 3.59 (s, 3H), 2.84 (t, J = 7.0Hz, 2H), 2.63 (t, J =
(7.0Hz, 2H)

According to a method similar to that of Example 1 (3), 3-
[4-[(5-Cyan-2-benzofuranyl) carbonylamino] phenyl] methyl propionate 350 mg (1.01
mmol) of the cyano group to an amidino group, followed by silica gel column chromatography (methylene chloride / methanol =
Purification by 100/3 to 5/1) afforded 206 mg (41% over three steps) of hydroiodide as compound (82) as a yellow solid. IR (KBr): 1700, 1645 , 1600, 1535 cm -1 1 H-NMR (DMSO-d 6) δ TMS: 10.59 (bs, 1H),
9.36 (bs, 2H), 8.92 (bs, 2H), 8.33 (s, 1H), 8.01-7.85 (m,
3H), 7.70 (d, 2H), 7.24 (d, 2H), 3.59 (s, 3H), 2.85 (t, J =
7.4Hz, 2H), 2.64 (t, J = 7.4Hz, 2H)

Example 10: 3- [4-[(5-amidino-2-benzofuranyl) carbonylamino] phenyl]
Propionic acid (compound (85)) 162 mg (0.329 mmol) of the hydroiodide salt of compound (82) is suspended in 6 ml of tetrahydrofuran. Stirred. The reaction solution was adjusted to pH 2 with 1N hydrochloric acid and concentrated under reduced pressure. The precipitate was collected by filtration and washed with water to give the hydrochloride of compound (85) as a yellow solid (82 mg, 64%). Melting point:> 250 ° C IR (KBr): 3600-2700, 1700, 1650, 1600, 1535
^{cm -1 1 H-NMR (DMSO} -d 6) δ TMS: 12.11 (bs, 1H),
10.67 (s, 1H), 9.47 (bs, 2H), 9.26 (bs, 2H), 8.37 (d, J = 1.
8Hz, 1H), 8.02 (s, 1H), 7.97 (d, J = 8.8Hz, 1H), 7.91 (dd, J =
1.8,8.8Hz, 1H), 7.73 (d, 2H), 7.23 (d, 2H), 2.82 (t, J = 7.7
Hz, 2H), 2.57 (t, J = 7.7Hz, 2H)

Example 11 (1) Methyl 3- (4-aminophenyl) -2- (n-butylsulfonylamino) propionate 2-Amino-3- (4-nitrophenyl) propionic acid
4.60 g (21.9 mmol) in 100 ml of methanol and chloroform
3 ml of sulfuric acid was added to the mixture, and the mixture was refluxed for 30 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was adjusted to pH 8 to 9 with a 1N aqueous sodium hydroxide solution, extracted with chloroform, and the extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. Dried. After filtration, low-boiling substances were distilled off from the filtrate under reduced pressure to give 2-amino-3-.
4.06 g (83%) of methyl (4-nitrophenyl) propionate was obtained as a yellow oil. 4.00g (17.8mmol) of this
Was dissolved in 56 ml of acetonitrile, and pyridine 1.7 was added thereto.
6 ml (21.4 mmol) and n-butylsulfonyl chloride 2.80 g
(17.8 mmol) were sequentially added, and the mixture was stirred at 70 ° C. for 4.5 hours. After cooling, pour the reaction solution into 70 ml of water, extract with ethyl acetate,
The extract was washed with water and saturated saline and dried over anhydrous magnesium sulfate. After filtration, low-boiling substances were distilled off from the filtrate under reduced pressure to give 2- (n-butylsulfonylamino) -3- (4
4.06 g (66%) of methyl -nitrophenyl) propionate were obtained as an orange oil. 3.40 g (9.88 mmol) of this product was dissolved in 130 ml of acetic acid, 1.5 g of 10% palladium carbon was added thereto, and the mixture was stirred under a hydrogen atmosphere for 3 days. The reaction solution was filtered through celite, and acetic acid was distilled off from the filtrate under reduced pressure.
3.16 g (quantitative) of methyl aminophenyl) -2- (n-butylsulfonylamino) propionate was obtained as a brown solid. ¹ H-NMR (CDCl ₃ ) δ _TMS : 7.50-7.25 (m, 4H),
4.25-4.05 (m, 1H), 3.65 (s, 3H), 3.04 (dd, J = 5.6,13.6Hz,
1H), 2.84 (dd, J = 9.6,13.6Hz, 1H), 2.72 (t, J = 7.4Hz, 2H),
1.60-1.10 (m, 4H), 0.81 (t, J = 7.2Hz, 3H)

(2) 3- [4-[(5-amidino-2-
Benzofuranyl) carbonylamino] phenyl] -2-
Methyl (n-butylsulfonylamino) propionate (Compound (93)) According to the same method as in Example 1 (2), 5-cyano-2-
Benzofurancarboxylic acid 200mg (1.07mmol) and 3- (4
Condensation of 371 mg (1.18 mmol) of methyl -aminophenyl) -2- (n-butylsulfonylamino) propionate,
2- (n-butylsulfonylamino) -3- [4-
[(5-cyano-2-benzofuranyl) carbonylamino] phenyl] methyl propionate as a yellow solid 1
88 mg (36%) were obtained. ¹ H-NMR (DMSO-d ₆ ) δ _TMS : 10.63 (s, 1H),
8.36 (s, 1H), 8.00-7.30 (m, 7H), 4.22-3.97 (m, 1H), 3.66
(s, 3H), 3.00-2.60 (m, 4H), 1.50-1.05 (m, 4H), 0.85-0.65
(m, 3H)

According to a method similar to that of Example 1 (3), 2-
(N-butylsulfonylamino) -3- [4-[(5-
Methyl cyano-2-benzofuranyl) carbonylamino] phenyl] propionate 225 mg (0.466 mmol) of cyano group was converted to amidino group, and purified by silica gel column chromatography (chloroform / methanol = 10/1) to obtain compound (93) Hydroiodide as yellow solid
89 mg (30% over three steps) were obtained. ¹ H-NMR (DMSO-d ₆ ) δ _TMS : 10.62 (s, 1H),
8.33 (s, 1H), 8.20-7.60 (m, 5H), 7.29 (d, 2H), 4.30-4.00
(m, 1H), 3.66 (s, 3H), 3.00-2.60 (m, 4H), 1.50-1.00 (m, 4
H), 0.85-0.70 (m, 3H)

Example 12: 3- [4-[(5-amidino-2-benzofuranyl) carbonylamino] phenyl]
2- (n-butylsulfonylamino) propionic acid (compound (101)) 89 mg (0.14 mmol) of hydroiodide salt of compound (93) was suspended in 2 ml of tetrahydrofuran, and lithium hydroxide (15 m) was added thereto.
g (0.34 mmol) dissolved in 4 ml of water was added.
Stir for 5 hours. The reaction solution was washed with ethyl acetate, the aqueous layer was adjusted to pH 2 with 1N hydrochloric acid, and then concentrated under reduced pressure. The precipitate was collected by filtration and washed with water to give 35 mg (47%) of the hydrochloride of compound (101) as a colorless solid. Melting point:> 250 ° C IR (KBr): 3700-2700, 1740, 1660, 1605, 1540
^{cm -1 1 H-NMR (DMSO} -d 6, 500MHz) δ TMS:
10.67 (bs, 1H), 9.44 (bs, 2H), 9.16 (bs, 2H), 8.00 (s, 1
H), 7.98 (d, J = 8.6Hz, 1H), 7.91 (dd, J = 1.9,8.6Hz, 1H), 7.
75 (d, 2H), 7.60 (d, J = 9.2Hz, 1H), 7.30 (d, 2H), 4.00 (d, J =
5.0Hz, 1H), 3.04 (dd, J = 5.0,13.8Hz, 1H), 2.77 (dd, J = 10.
0,13.8Hz, 1H), 2.64 (t, J = 7.6Hz, 2H), 1.40-1.20 (m, 2H),
1.20-1.15 (m, 2H), 0.76 (t, J = 7.8Hz, 3H)

Example 13 (1) t-butyl 3- (4-aminocyclohexyl) propionate (methoxymethyl) triphenylphosphonium chloride
280 ml of tetrahydrofuran was added to 27.8 g (81.1 mmol), and 50.0 ml (80.0 mmol) of a 1.6 M n-butyllithium n-hexane solution was added dropwise at -40 ° C for 30 minutes, and the mixture was stirred for 1 hour. Then, 4- (benzyloxycarbonylamino) cyclohexanone 20.0 g (81.0 mmol)
Was dissolved in 200 ml of tetrahydrofuran, and the solution was added dropwise over 30 minutes, and then returned to room temperature and stirred for 3.5 hours. The reaction solution was poured into a saturated aqueous solution of ammonium chloride, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The extract and the organic layer were combined, washed with water and saturated saline, and dried over anhydrous magnesium sulfate. After filtration, low-boiling substances were distilled off from the filtrate under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 4/1).
7.02 g (32%) of (benzyloxycarbonylamino) cyclohexylidenemethyl methyl ether as a colorless solid
Obtained. IR (neat): 3600-3100, 2900, 1670, 1530, 13
^{00 cm -1 1 H-NMR (} CDCl 3) δ TMS: 7.33 (m, 5H), 5.77
(s, 1H), 5.10 (s, 2H), 4.69 (bs, 1H), 3.63 (m, 1H), 3.53
(s, 3H), 2.20-1.80 (m, 6H), 1.34-1.05 (m, 2H)

4- (benzyloxycarbonylamino)
Cyclohexylidene methyl methyl ether 7.00 g (25.5
mmol) in 50 ml of tetrahydrofuran.
25 ml of N hydrochloric acid was added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was made weakly alkaline by adding saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The extract was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. After filtration, low-boiling substances are distilled off from the filtrate under reduced pressure to give 4- (benzyloxycarbonylamino) cyclohexylcarbaldehyde as a colorless solid.
6.25 g (94%) were obtained. ¹ H-NMR (CDCl ₃ ) δ _TMS : 9.65,9.61 (each s,
1H), 7.34 (m, 5H), 5.02 (s, 2H), 4.73 (m, 1H), 3.50 (m, 1
H), 2.30-1.10 (m, 9H)

1.17 g (28.9 mmol) of sodium hydride (60%)
Was suspended in 240 ml of tetrahydrofuran, and thereto was added t-butyl diethylphosphonoacetate (95% purity) 6.15 g (25.8 mmol)
Was dissolved in 60 ml of tetrahydrofuran and added dropwise over 15 minutes under ice-cooling. Thereafter, the temperature was returned to room temperature, and the mixture was stirred for 30 minutes. The reaction solution was cooled again with ice, and 4- (benzyloxycarbonylamino) cyclohexylcarbaldehyde was added thereto.
A solution of 6.15 g (23.4 mmol) in 60 ml of tetrahydrofuran was added dropwise over 45 minutes, followed by stirring at room temperature for 1 hour. Low-boiling substances were distilled off from the reaction solution under reduced pressure, and ethyl acetate and saturated saline were added to the residue. The organic layer was separated, washed with water and saturated saline, and dried over anhydrous magnesium sulfate. After filtration, low-boiling substances were distilled off from the filtrate under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 4/1) to give β- [4- (benzyloxycarbonylamino). Cyclohexyl] 7.02 g (32%) of t-butyl acrylate was obtained as a colorless solid. IR (KBr): 3700-3100, 2900, 1710, 1700, 165
^{0, 1510 cm -1 1 H-} NMR (CDCl 3) δ TMS: 7.34 (m, 5H), 6.83
(dd, J = 6.8,15.8Hz, 0.5H), 6.75 (dd, J = 6.8,15.8Hz, 0.5H
H), 5.72 (dd, J = 1.3,15.8Hz, 0.5H), 5.68 (dd, J = 1.3,15.8H
z, 0.5H), 5.08 (s, 2H), 4.85,4.75 (each bs, 1H), 3.81,3.
45 (each bs, 1H), 1.48 (s, 9H), 2.30-1.10 (m, 8H)

Β- [4- (benzyloxycarbonylamino) cyclohexyl] t-butyl acrylate 7.00 g
(19.5 mmol) was dissolved in 200 ml of methanol, and 10%
Add 700 mg of palladium on carbon, and add
Stirred for hours. The reaction solution was filtered, low-boiling substances were distilled off from the filtrate under reduced pressure, the residue was washed with a mixed solution of n-hexane and ethyl acetate, and t-butyl 3- (4-aminocyclohexyl) propionate was colorless. 3.78 g (85%) were obtained as a solid. Mp: 39-40 ℃ IR (KBr): 2900, 1720, 1360, 1160 cm -1 1 H-NMR (CDCl 3) δ TMS: 8.00 (bs, 2H), 2.88
(m, 1H), 2.19 (m, 2H), 1.91 (d, J = 9.9Hz, 2H), 1.73 (d, J = 9.
9Hz, 2H), 1.39 (s, 9H), 1.60-0.80 (m, 8H)

(2) 3- [4-[(5-amidino-2-
Benzofuranyl) carbonylamino] cyclohexyl]
Methyl propionate (compound (438)) According to the same method as in Example 1 (2), 5-cyano-2-
Benzofurancarboxylic acid 203mg (1.08mmol) and 3- (4
-Aminocyclohexyl) t-butyl propionate 295
mg (1.30 mmol) was condensed and purified by silica gel column chromatography (n-hexane / ethyl acetate = 2/1) to give 3- [4-[(5-cyano-2-benzofuranyl) carbonylamino] cyclohexyl] propion 165 mg (38%) of t-butyl acid were obtained as a colorless solid. IR (KBr): 2910, 2210, 1715, 1680, 1595, 150
^{5, 1455, 885 cm -1 1} H-NMR (CDCl 3) δ TMS: 8.04 (s, 1H), 7.71-
7.57 (m, 2H), 7.50 (s, 1H), 6.68,6.42 (each d, J = 8.0Hz, 1
H), 4.29-4.21,3.98-3.90 (each m, 1H), 2.30-1.08 (m, 13
H), 1.45 (s, 9H)

160 mg (0.403 mmol) of t-butyl 3- [4-[(5-cyano-2-benzofuranyl) carbonylamino] cyclohexyl] propionate in 40 ml of methanol
The solution was cooled with ice, hydrogen chloride gas was blown in for 20 minutes, and the mixture was stirred for 3 hours. Low-boiling substances were distilled off from the reaction solution under reduced pressure, 20 ml of chloroform and 20 ml of saturated aqueous sodium hydrogen carbonate were added to the residue, and the mixture was stirred for 30 minutes. The organic layer was separated, the aqueous layer was extracted with chloroform, the extract and the organic layer were combined, washed with water and saturated saline, and dried over anhydrous magnesium sulfate. After filtration, low-boiling substances were distilled off from the filtrate under reduced pressure. To the residue were added 60 mg (1.12 mmol) of ammonium chloride, 10 ml of a methanol solution of ammonia, and 20 ml of methanol, and the mixture was refluxed for 3 hours. Low-boiling substances were distilled off from the reaction solution under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol = 95/5 to 85/15) to give 54 mg of the hydrochloride of compound (438) as a colorless solid.
(33% in two steps). ¹ H-NMR (DMSO-d ₆ , 500 MHz) δ _TMS :
8.66,8.48 (each d, J = 7.6Hz, 1H), 8.33-8.31 (m, 1H), 7.9
2-7.88 (m, 2H), 7.78,7.75 (each s, 1H), 4.09-3.72 (m, 1
H), 3.60,3.59 (each s, 3H), 2.33 (t, J = 8.2Hz, 2H), 1.85-
0.97 (m, 1H)

Example 14: 3- [4-[(5-Amidino-2-benzofuranyl) carbonylamino] cyclohexyl] propionic acid (compound (445)) salt
50 mg (0.12 mmol) of 1N sodium hydroxide aqueous solution 2.0 ml
(2.0 mmol) to give 14 mg (29%) of the hydrochloride of compound (445) as a colorless solid. Melting point:> 250 ° C IR (KBr): 3250, 3050, 2910, 1670, 1635, 159
^{0, 1520, 1450 cm -1 1} H-NMR (DMSO-d 6) δ TMS: 9.41 (bs, 2H),
9.16 (bs, 2H), 8.65,8.50 (each d, J = 8.5Hz, 1H), 7.94-7.
84 (m, 2H), 7.76,7.73 (each s, 1H), 3.93-3.76 (m, 1H), 2.
24 (t, J = 7.5Hz, 2H), 1.88-0.98 (m, 11H)

Example 15: [1-[(5-Amidino-2)
-Benzofuranyl) carbonyl] -4-piperidinyloxy] methyl acetate (compound (637)) 5-cyano-2-
Condensation of 185 mg (0.988 mmol) of benzofurancarboxylic acid and 255 mg (1.18 mmol) of t-butyl 4-piperidinyloxyacetate gives [1-[(5-cyano-2-benzofuranyl) carbonyl] -4-piperidinyloxy. 289 mg (76%) of methyl acetate was obtained as a colorless oil. IR (neat): 2920, 2230, 1745, 1640, 1125 cm
^{-1 1 H-NMR (DMSO-} d 6) δ TMS: 8.01 (d, J = 0.9H
z, 1H), 7.70-7.61 (m, 2H), 7.29 (s, 1H), 4.05 (s, 2H), 4.0
5-3.94 (m, 2H), 3.78-3.61 (m, 3H), 2.04-1.76 (m, 4H), 1.
50 (s, 9H)

[1-[(5-Cyano-2-benzofuranyl) carbonyl] -4-piperidinyloxy] 280 mg (0.728 mmol) of methyl acetate was dissolved in 20 ml of methanol, and the solution was cooled with ice and hydrogen chloride gas was added. Was blown for 5 minutes and then stirred for 4 hours. Low-boiling substances were distilled off under reduced pressure from the reaction solution, and the residue was chloroform 15 ml, saturated aqueous sodium hydrogen carbonate 25
ml was added and stirred for 30 minutes. Separate the organic layer, extract the aqueous layer with chloroform, combine the extract with the organic layer,
The extract was washed with saturated saline and dried over anhydrous magnesium sulfate. After filtration, low-boiling substances were distilled off from the filtrate under reduced pressure. To the residue were added 60 mg (1.12 mmol) of ammonium chloride, 10 ml of a methanol solution of ammonia, and 20 ml of methanol, and the mixture was heated under reflux for 3 hours. Low-boiling substances are distilled off from the reaction solution under reduced pressure,
The residue was purified by silica gel column chromatography (chloroform / methanol = 95/5 to 85/15) to give 62 mg of the hydrochloride of compound (637) as a colorless solid (22
%)Obtained. ¹ H-NMR (DMSO-d ₆ , 500 MHz) δ _TMS :
9.34 (bs, 4H), 8.27 (d, J = 2.0Hz, 1H), 7.92 (d, J = 8.8Hz, 1
H), 7.87 (dd, J = 2.0, 8.8 Hz, 1H), 7.55 (s, 1H), 4.20 (s, 2
H), 3.94-3.92 (m, 2H), 3.66 (s, 3H), 3.73-3.69 (m, 1H),
3.50-3.38 (m, 2H), 1.96-1.92 (m, 2H), 1.57-1.55 (m, 2H)

Example 16: [1-[(5-amidino-2)
-Benzofuranyl) carbonyl] -4-piperidinyloxy] acetic acid (compound (638)) According to a method similar to that in Example 10, hydrochloride of compound (637)
60 mg (0.16 mmol) of 1N sodium hydroxide aqueous solution 1.0 ml
(1.0 mmol) to give 22 mg (37%) of the hydrochloride of compound (638) as a colorless solid. Mp: 217 to 228 ° C. (decomposition) IR (KBr): 3300, 3100, 1730, 1640, 1120 cm -1 1 H-NMR (DMSO-d 6, 500MHz) δ TMS:
9.43 (s, 2H), 9.24 (s, 2H), 8.27 (d, J = 2.0Hz, 1H), 7.93
(d, J = 8.8Hz, 1H), 7.87 (dd, J = 2.0,8.8Hz, 1H), 7.55 (d, J =
0.7Hz, 1H), 4.09 (s, 2H), 3.94-3.91 (m, 2H), 3.72-3.69
(m, 1H), 3.48-3.37 (m, 2H), 1.95-1.91 (m, 2H), 1.57-1.55
(m, 2H)

Example 17 (1) Ethyl 4-aminophenoxyacetate 25.0 g (180 mmol) of 4-nitrophenol and 20.0 ml (180 mmol) of ethyl bromoacetate were mixed with N, N-dimethylformamide.
Dissolve in 40 ml, add potassium carbonate 27.4 g (198 mmol)
Was added, and the mixture was stirred at room temperature for 16 hours under a nitrogen atmosphere. The reaction solution was poured into 100 ml of water, extracted with a mixture of equal amounts of n-hexane and ethyl acetate, and the extract was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. After filtration, low-boiling substances were distilled off from the filtrate under reduced pressure to obtain 40.5 g (quantitative) of ethyl 4-aminophenoxyacetate as a colorless solid. IR (KBr): 3700-2900, 1755 , 1590, 1500 cm -1 1 H-NMR (DMSO-d 6) δ TMS: 8.25-8.16 (m, 2
H), 7.20-7.12 (m, 2H), 4.99 (s, 2H), 4.18 (q, J = 7.1Hz, 2
H), 1.22 (t, J = 7.1Hz, 3H)

(2) Ethyl 5- (benzyloxycarbonylamidino) -2-benzofurancarboxylate 4.0 g of ethyl 5-cyano-2-benzofurancarboxylate
(18.6 mmol) was added with 100 ml of ethanol, and this was cooled with ice,
Hydrogen chloride gas was blown in for 15 minutes, and the mixture was further stirred at room temperature for 14 hours. Low-boiling substances were distilled off from the reaction solution under reduced pressure, the residue was dissolved in 200 ml of chloroform, and 200 ml of saturated aqueous sodium hydrogen carbonate was added.
Stirred for 10 minutes. The organic layer was separated, washed with water and saturated saline, and dried over anhydrous magnesium sulfate. After filtration, low-boiling substances were distilled off from the filtrate under reduced pressure to obtain 4.85 g (quantitative) of ethyl 5-[(1-ethoxy) iminomethyl)]-2-benzofurancarboxylate as a yellow solid. IR (KBr): 3700-3100, 2950, 1710, 1635, 1575
^{cm -1 1 H-NMR (DMSO} -d 6, 500MHz)
δ _TMS ： 8.28 (d, J = 1.8Hz, 1H), 8.04 (dd, J = 1.8,8.8Hz, 1H
H), 7.82 (s, 1H), 7.78 (d, J = 8.8Hz, 1H), 4.38 (q, J = 7.2Hz, 2
H), 4.27 (q, J = 7.1Hz, 2H), 1.40-1.30 (m, 6H)

5-[(1-ethoxy) iminomethyl)]
Ethyl-2-benzofurancarboxylate 4.85 g (18.6 mmol)
1.05 g (19.5 mmol) of ammonium chloride, 14.2 ml of an ammonia-ethanol solution, and 100 ml of ethanol were added to the mixture, and the mixture was refluxed for 2 hours under a nitrogen atmosphere. Low-boiling substances were distilled off from the reaction solution under reduced pressure, and the residue was washed with diethyl ether.
4.85 g (97%) of the hydrochloride of ethyl amidino-2-benzofurancarboxylate were obtained as a pale yellow solid. IR (KBr): 3600-2800, 1710, 1690, 1650, 1610
^{cm -1 1 H-NMR (DMSO} -d 6, 500MHz)
δ _TMS : 10.00-8.40 (bs, 4H), 8.34 (s, 1H), 8.00 (d, J = 8.
9Hz, 1H), 7.97-7.93 (m, 2H), 4.39 (d, J = 7.2Hz, 2H), 1.36
(t, J = 7.2Hz, 3H)

1.00 g (3.72 mmol) of the hydrochloride of ethyl 5-amidino-2-benzofurancarboxylate was mixed with 7.5 ml of tetrahydrofuran and 7.5 ml of a 1N aqueous sodium hydroxide solution (7.5 m
mol) and stirred at room temperature for 1 hour. The reaction solution was concentrated to about 1/2 under reduced pressure, washed with chloroform, and the aqueous layer was adjusted to pH 2-3 with 1N hydrochloric acid. The precipitate is collected by filtration, washed with water, and washed with water.
791 mg (88%) of the hydrochloride salt of amidino-2-benzofurancarboxylic acid as a pale yellow solid. IR (KBr): 3600-2600, 1710, 1690, 1610, 1570
^{cm -1 1 H-NMR (DMSO} -d 6, 500MHz)
δ _TMS ： 9.52 (bs, 2H), 9.38 (bs, 2H), 8.34 (d, J = 1.7Hz, 1
H), 7.97 (d, J = 8.8Hz, 1H), 7.94 (dd, J = 1.7,8.8Hz, 1H), 7.
84 (s, 1H)

To 7.55 g (31.4 mmol) of 5-amidino-2-benzofurancarboxylic acid hydrochloride was added tetrahydrofuran 2
Then, while maintaining the pH at 10 by adding a 1N aqueous sodium hydroxide solution, 6.74 ml (47.0 mmol) of benzyloxycarbonyl chloride was added dropwise over about 15 minutes. Thereafter, the mixture was stirred for 30 minutes as it was and further for 2 hours at room temperature. The reaction solution is concentrated under reduced pressure, and the precipitate is collected by filtration, washed with water, a mixture of equal volumes of n-hexane and ethyl acetate, and 5- (benzyloxycarbonylamidino) -2-benzofurancarboxylic acid is pale yellow. 7.94 g (75%) were obtained as a solid. IR (KBr): 3600-2900, 1650 , 1600, 1560 cm -1 1 H-NMR (DMSO-d 6) δ TMS: 9.23 (bs, 2H),
8.32 (d, J = 1.7Hz, 1H), 7.96 (dd, J = 1.7,8.8Hz, 1H), 7.61
(d, J = 8.8Hz, 1H), 7.45-7.30 (m, 5H), 7.07 (s, 1H), 5.12
(s, 2H)

(3) 4-[[5- (benzyloxycarbonylamidino) -2-benzofuranyl] carbonylamino] ethyl phenoxyacetate (compound (7)) 5- (benzyloxycarbonylamidino) -2-benzofurancarboxylic acid 2.00 g (6.18 mmol) and 1.32 g (6.79 mmol) of ethyl 4-aminophenoxyacetate were dissolved in 100 ml of N, N-dimethylformamide, and 919 mg (6.79 mmol) of 1-hydroxy-1H-benzotriazole and 1
1.30 g (6.79 mmol) of-(3-dimethylaminopropyl) -3-ethylcarbodiimide was added, and the mixture was stirred at room temperature for 14 hours. 250 ml of water was added to the reaction solution, and the precipitate was collected by filtration and washed with water to obtain 2.73 g (91%) of compound (7) as a colorless solid. IR (KBr): 3700-3000, 1750 , 1650, 1605 cm -1 1 H-NMR (DMSO-d 6) δ TMS: 10.51 (bs, 1H),
9.23 (bs, 2H), 8.49 (d, J = 1.4Hz, 1H), 8.11 (dd, J = 1.4,8.
8Hz, 1H), 7.85-7.80 (m, 2H), 7.73-7.65 (m, 2H), 6.99-6.9
2 (m, 2H), 5.13 (s, 2H), 4.77 (s, 2H), 4.17 (q, J = 7.0Hz, 2
H), 1.22 (t, J = 7.0 Hz, 3H) MS (SIMS) (m / z) 5
16 (MH ⁺ )

Example 18: 4-[[5- (Benzyloxycarbonylamidino) -2-benzofuranyl] carbonylamino] phenoxyacetic acid (Compound (10)) In the same manner as in Example 10, 540 mg of compound (7) 1.
05mmol) to give compound (10) as a yellow solid.
93 mg (96%) were obtained. IR (KBr): 3700-2400, 1740 , 1670 cm -1 1 H-NMR (DMSO-d 6) δ TMS: 10.57 (s, 1H),
8.39 (s, 1H), 8.05-7.85 (m, 3H), 7.72-7.66 (m, 2H), 7.47-
7.37 (m, 5H), 6.97-6.90 (m, 2H), 5.29 (s, 2H), 4.67 (s, 2
H)

Example 19: 4-[(5-amidino-2-
Benzofuranyl) carbonylamino] ethylphenoxyacetate (Compound (14)) Compound (7) 2.70 g (5.24 mmol) in tetrahydrofuran 3
After adding 7 ml (7 mmol) of 1N hydrochloric acid and 10% palladium carbon, the mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours. The reaction solution was filtered through celite, low-boiling substances were distilled off from the filtrate under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol = 4/1) to give compound (14).
1.55 g (71%) of the hydrochloride as a pale yellow solid. IR (KBr): 3700-2800, 1740 , 1680, 1650 cm -1 1 H-NMR (DMSO-d 6) δ TMS: 10.70 (bs, 1H),
9.35 (bs, 4H), 8.36 (d, J = 1.0Hz, 1H), 8.00-7.90 (m, 3H),
7.76-7.70 (m, 2H), 6.93-6.70 (m, 2H), 4.77 (s, 2H), 4.17
(q, J = 7.1Hz, 2H), 1.23 (t, J = 7.1Hz, 3H)

Example 20: 4-[(5-benzylamidino-2-benzofuranyl) carbonylamino] ethyl phenoxyacetate (compound (6)) 830 mg (4.43) of 5-cyano-2-benzofurancarboxylic acid
mmol) and 910 mg of ethyl 4-aminophenoxyacetate (4.66
mmol) was dissolved in 40 ml of N, N-dimethylformamide, and 1-hydroxy-1H-benzotriazole was added thereto.
630 mg (4.66 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide 893 mg (4.66 mmol) were added, and the mixture was stirred at room temperature for 13 hours. 100 ml of water was added to the reaction solution, and the precipitate was collected by filtration and washed with water to obtain 1.49 g (92%) of ethyl 4-[(5-cyano-2-benzofuranyl) carbonylamino] phenoxyacetate as a colorless solid. . ¹ H-NMR (DMSO-d ₆ ) δ _TMS : 10.59 (s, 1H),
8.43 (s, 1H), 7.93 (s, 2H), 7.84 (s, 1H), 7.70 (d, J = 9.0H
z, 2H), 6.95 (d, J = 9.0Hz, 2H), 4.18 (q, J = 7.1Hz, 2H), 1.22
(t, J = 7.1Hz, 3H)

1.49 g of ethyl 4-[(5-cyano-2-benzofuranyl) carbonylamino] phenoxyacetate
(4.09 mmol) in 50 ml of pyridine and 5 ml of triethylamine
And a hydrogen sulfide gas was blown into the mixture at room temperature for 10 minutes, followed by stirring for 16 hours. Low-boiling substances were distilled off from the reaction solution under reduced pressure to give 4-[(5-thiocarbamoyl-2).
-Benzofuranyl) carbonylamino] ethyl phenoxyacetate was obtained as a yellow solid. Acetone 100
and 10 ml of iodomethane, and the mixture was heated under reflux for 2 hours.
The reaction solution was returned to room temperature, the precipitate was collected by filtration, and 4-[[5-
[(1-Methylthio) iminomethyl] -2-benzofuranyl] carbonylamino] ethyl phenoxyacetate was obtained as a yellow solid. To this, 50 ml of ethanol and 0.5 ml (4.6 mmol) of benzylamine were added, and the mixture was heated under reflux for 2 hours. The reaction solution was concentrated under reduced pressure to about 10 ml, 40 ml of diethyl ether was added thereto, and the precipitate was collected by filtration.
1.70 g (69% in 3 steps) of the hydroiodide as a yellow solid as in (6) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ _TMS : 10.57 (s, 1H),
9.82-9.55 (m, 3H), 8.31 (d, J = 2.0Hz, 1H), 7.98 (d, J = 9.0H
z, 1H), 7.91 (s, 1H), 7.86 (dd, J = 2.0,9.0Hz, 1H), 7.71 (d,
J = 9.0Hz, 2H), 7.47-7.36 (m, 5H), 6.96 (d, J = 9.0Hz, 2H),
4.78 (s, 2H), 4.71 (s, 2H), 4.18 (q, J = 7.1Hz, 2H), 1.22 (t,
(J = 7.1Hz, 3H)

Example 21: 4-[(5-Benzylamidino-2-benzofuranyl) carbonylamino] phenoxyacetic acid (Compound (11)) According to the same method as that of Example 10, hydriodic acid such as compound (6) Hydrolysis of 502 mg (0.837 mmol) gave 400 mg (quantitative) of the hydrochloride of compound (11) as a colorless solid. ¹ H-NMR (DMSO-d ₆ ) δ _TMS : 10.66 (s, 1H),
10.30-9.30 (m, 3H), 8.34 (s, 1H), 7.97-7.87 (m, 3H), 7.71
(d, J = 9.0Hz, 2H), 7.52-7.32 (m, 5H), 6.90 (d, J = 9.0Hz, 2H
H), 4.75 (s, 2H), 4.58 (s, 2H)

Example 22 (1) 6-amidino-2-benzofurancarboxylic acid The same method as in Example 17 (2) was used. That is, 6
-Ethyl cyano-2-benzofurancarboxylate 135mg
(0.628 mmol) was reacted with ethanol in the presence of hydrogen chloride to give 137 mg of ethyl 6-[(1-ethoxy) iminomethyl)]-2-benzofurancarboxylate as an orange solid.
(84%). ¹ H-NMR (CDCl ₃ ) δ _TMS : 8.03-8.02 (m, 1H),
7.30-7.20 (m, 1H), 7.53 (s, 1H), 4.45 (q, J = 7.1Hz, 2H), 4.
36 (q, J = 7.1Hz, 2H), 1.50-1.40 (m, 6H)

6-[(1-ethoxy) iminomethyl)]
-2-ethyl benzofurancarboxylate 137mg (0.525mmo
l) was reacted with ammonia, and the hydrochloride of ethyl 6-amidino-2-benzofurancarboxylate was converted into a yellow solid as a yellow solid.
mg (94%). ¹ H-NMR (DMSO-d ₆ ) δ _TMS : 9.33 (bs, 4H),
8.26 (s, 1H), 8.01 (d, J = 8.4Hz, 1H), 7.87 (d, J = 1.4Hz, 1
H), 7.76 (dd, J = 1.4,8.6Hz, 1H), 4.38 (q, J = 7.2Hz, 2H), 1.
34 (t, J = 7.2Hz, 3H)

129 mg (0.480 mmol) of ethyl 6-amidino-2-benzofurancarboxylate hydrochloride was hydrolyzed with a 1N aqueous sodium hydroxide solution to give 65 mg of 6-amidino-2-benzofurancarboxylic acid hydrochloride as a brown solid ( 56
%) Obtained. IR (KBr): 3700-2700, 1680 , 1590 cm -1 1 H-NMR (DMSO-d 6) δ TMS: 9.46 (bs, 2H),
9.18 (bs, 2H), 8.24 (s, 1H), 8.02 (d, J = 8.3Hz, 1H), 7.92-
7.74 (m, 2H)

(2) 4-[(6-amidino-2-benzofuranyl) carbonylamino] t-butyl phenoxyacetate (compound (18))
63 mg (0.26 mmol) of 2-benzofurancarboxylic acid hydrochloride
And t-butyl 4-aminophenoxyacetate 66 mg (0.30 mmo
l) was condensed and purified by silica gel column chromatography (chloroform / methanol = 100/3 to 3/1) to obtain 109 mg of a compound (18) hydrochloride as a colorless solid (91%).
%) Obtained. IR (KBr): 1750, 1710 , 1630 cm -1 1 H-NMR (DMSO-d 6) δ TMS: 10.65 (bs, 1H),
8.20 (s, 1H), 8.05 (d, J = 7.8Hz, 1H), 7.90 (s, 1H), 7.80-
7.60 (m, 3H), 6.97-6.90 (m, 2H), 4.65 (m, 2H), 1.44 (s, 9
H)

Example 23: 4-[(6-amidino-2-
[Benzofuranyl) carbonylamino] phenoxyacetic acid (compound (24)) According to the same method as in Example 2, hydrochloride of compound (18)
mg (2.45 mmol) was treated with 2.5 ml of trifluoroacetic acid to obtain 96 mg (quantitative) of a hydrochloride of compound (24) as a pale yellow solid. Melting point:> 250 ° C IR (KBr): 3700-2800, 1730, 1690, 1520, 1505
^{cm -1 1 H-NMR (DMSO} -d 6, 500MHz)
δ _TMS ： 10.63 (bs, 1H), 9.45 (bs, 2H), 9.32 (bs, 2H), 8.
20 (s, 1H), 8.06 (d, J = 8.3Hz, 1H), 7.89 (d, J = 1.6Hz, 1H), 7.
79 (dd, J = 1.6,8.3Hz, 1H), 7.72-7.69 (m, 2H), 6.97-6.93
(m, 2H), 4.67 (s, 2H)

Example 24: (3S, 5S) -5-[[[
5- (benzyloxycarbonylamidino) -2-benzofuranyl] carbonylamino] methyl] -3-[(t
-Butoxycarbonyl) methyl] -2-pyrrolidinone (compound (597)) 5- (benzyloxycarbonylamidino) -2-benzofurancarboxylic acid 37 mg (0.11 mmol) and (3S, 5S)
-25-Aminomethyl-3-[(t-butoxycarbonyl) methyl] -2-pyrrolidinone (25 mg, 0.11 mmol) was dissolved in N, N-dimethylformamide (2 ml).
-Hydroxy-1H-benzotriazole 15 mg (0.11 mm
ol) and 21 mg (0.11 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide were added, and the mixture was stirred at room temperature for 24 hours. 5 ml of water was added to the reaction solution, and extracted with ethyl acetate. The extract was washed with water and saturated saline and dried over anhydrous magnesium sulfate. After filtration, low-boiling substances were distilled off from the filtrate under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride / methanol = 10/1).
39 mg (65%) of compound (597) was obtained as a colorless solid. ¹ H-NMR (CDCl ₃ ) δ _TMS : 7.83 to 7.65 (m, 2H),
7.65-7.48 (m, 2H), 7.48-7.18 (m, 5H), 7.15-7.05 (m, 2H),
5.21 (s, 2H), 4.00-3.85 (m, 1H), 3.68-3.51 (m, 1H), 3.51
-3.48 (m, 1H), 3.00-2.75 (m, 1H), 2.71 (dd, J = 3.4,16.4H
z, 1H), 2.31 (dd, J = 9.0,16.4Hz, 1H), 2.30-1.96 (m, 2H),
1.42 (s, 9H)

Example 25: (3S, 5S) -5- [
[(5-Amidino-2-benzofuranyl) carbonylamino] methyl] -3-carboxymethyl-2-pyrrolidinone (compound (601)) 38 mg (0.069 mmol) of compound (597) was dissolved in 5 ml of ethanol, and 10% 5 mg of palladium carbon was added, and the mixture was heated under reflux in a hydrogen atmosphere for 2 hours. The reaction solution was filtered through celite, and low-boiling substances were distilled off from the filtrate under reduced pressure. Next, 1 ml of methylene chloride and 0.5 ml of trifluoroacetic acid were added to the residue, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, diethyl ether was added, and the precipitate was collected by filtration and washed with diethyl ether to obtain 30 mg (91%) of a trifluoroacetate salt of compound (601) as a colorless solid. ¹ H-NMR (CDCl ₃ , 500 MHz) δ _TMS : 12.
50-12.05 (m, 1H), 9.36 (bs, 2H), 9.22 (bs, 2H), 8.30 (s, 1
H), 7.98-7.83 (m, 3H), 7.73 (s, 1H), 3.75-3.63 (m, 1H),
3.45-3.27 (m, 2H), 2.72-2.61 (m, 1H), 2.57 (dd, J = 4.2,16.
4Hz, 1H), 2.23 (dd, J = 9.3,16.4Hz, 1H), 2.19-2.13 (m, 1H),
1.93-1.83 (m, 1H)

Example 26: (3S, 5S) -5- [
[(5-Amidino-2-benzofuranyl) carbonyloxy] methyl] -3-[(t-butoxycarbonyl) methyl] -2-pyrrolidinone (compound (611)) 5-cyano-2-benzofurancarboxylic acid 200 mg (1.07 m
mol) and 328 mg (1.07 mmol) of (3S, 5S) -5-[(methylsulfonyloxy) methyl] -3-[(t-butoxycarbonyl) methyl] -2-pyrrolidinone in N, N-
It was dissolved in 10 ml of dimethylformamide, 296 mg (2.14 mm01) of potassium carbonate was added thereto, and the mixture was stirred at about 70 ° C. for 7 hours. 10 ml of water was added to the reaction solution, and extracted with ethyl acetate. The extract was washed with water and saturated saline and dried over anhydrous magnesium sulfate. After filtration, low-boiling substances were distilled off from the filtrate under reduced pressure, and the residue was subjected to silica gel column chromatography (n-
The product was purified by hexane / ethyl acetate = 1/2) and further recrystallized from a mixture of methylene chloride and ethyl acetate to give (3
147 mg (34%) of S, 5S) -5-[[(5-cyano-2-benzofuranyl) carbonyloxy] methyl] -3-[(t-butoxycarbonyl) methyl] -2-pyrrolidinone was obtained as colorless crystals. . ¹ H-NMR (CDCl ₃ ) δ _TMS : 8.06 (s, 1H), 7.80-
7.60 (m, 3H), 6.82 (s, 1H), 4.52 (dd, J = 3.9,11.1Hz, 1H),
4.23 (dd, J = 7.1,11.1Hz, 1H), 4.12-3.97 (m, 1H), 3.85-3.
03 (m, 1H), 2.79 (dd, J = 3.8,16.6Hz, 1H), 2.39 (dd, J = 9.1,1
6.6Hz, 1H), 2.50-2.06 (m, 2H), 1.46 (s, 9H)

According to the same method as in Example 1 (3), (3
S, 5S) -5-[[(5-cyano-2-benzofuranyl) carbonyloxy] methyl] -3-[(t-butoxycarbonyl) methyl] -2-pyrrolidinone 145mg (0.
(364 mmol) of the cyano group was converted to an amidino group, and purified by silica gel column chromatography (methylene chloride / methanol = 10/1 to 5/1). (64% in 3 steps)
I got ^{1 H-NMR (DMSO-d} 6, 500MHz)
δ _TMS ： 9.65-9.10 (m, 4H), 8.33 (d, J = 1.8Hz, 1H), 8.07-
7.98 (m, 3H), 7.92 (dd, J = 1.8,10.8Hz, 1H), 4.36 (dd, J = 4.
3,11.0Hz, 1H), 4.29 (dd, J = 6.2,11.0Hz, 1H), 3.90-3.86
(m, 1H), 2.77 (dq, J = 4.2,9.1Hz, 1H), 2.55 (dd, J = 4.2,16.2
(Hz, 1H)

Example 27 (1) trans- (4-aminocyclohexyloxy)
T-butyl acetate trans-4-aminocyclohexanol 5.00 g (43.4 m
mol), N, N-dimethylurea 3.82 g (43.4 mmol), 37%
Formalin 50 ml, N-methylmorpholine 9.54 ml (86.
8 mmol) and dioxane (10 ml) were mixed with toluene (200 ml) and heated for about 5 hours while azeotropically removing water. Low-boiling substances were distilled off from the reaction solution under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride / methanol = 50/1 to 10/1) to obtain trans-5- (4
-Hydroxycyclohexyl) -1,3-dimethylhexahydro-2-oxo-1,3,5-triazine was obtained as a colorless solid, 7.40 g (75%). ¹ H-NMR (CDCl ₃ ) δ _TMS : 4.21 (s, 4H), 3.68-
3.55 (m, 1H), 3.46 (d, J = 4.6Hz, 1H), 2.85 (s, 6H), 2.90-2.
74 (m, 1H), 2.13-1.88 (m, 4H), 1.46-1.23 (m, 4H)

Trans-5- (4-hydroxycyclohexyl) -1,3-dimethylhexahydro-2-oxo-1,3,5-triazine 1.00 g (4.40 mmol) and t-butyl bromoacetate 1.29 g (6.60 mmol) ) Was dissolved in 13 ml of toluene, and tetra-n-butylammonium hydrogen sulfate was added thereto.
5 mg (0.13 mmol) was added, and sodium hydroxide 13.2 g (330 mm
ol) in 13.2 ml of water was added dropwise, and the mixture was stirred at room temperature for 15 hours. The organic layer was separated, washed with water, and dried over anhydrous magnesium sulfate. After filtration, low-boiling substances were distilled off from the filtrate under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride / methanol = 20/1) to obtain trans-5- [4-[(t-butoxycarbonyl). ) Methyloxy] cyclohexyl] -1,3-dimethylhexahydro-2-oxo-1,3,5-triazine was obtained as a colorless solid (680 mg, 45%). ¹ H-NMR (CDCl ₃ ) δ _TMS : 4.20 (s, 4H), 3.98
(s, 2H), 3.49-3.23 (m, 1H), 2.84 (s, 6H), 2.88-2.75 (m, 1
H), 2.18-2.06 (m, 2H), 2.06-1.93 (m, 2H), 1.47 (s, 9H),
1.44-1.16 (m, 4H)

Trans-5- [4-[(t-Butoxycarbonyl) methyloxy] cyclohexyl] -1,3-
Dimethylhexahydro-2-oxo-1,3,5-triazine (300 mg, 0.879 mmol) was dissolved in t-butanol (5 ml), and a saturated ammonium chloride aqueous solution (5 ml) was added thereto.
The mixture was heated under reflux for 2 hours. The reaction solution was adjusted to pH 10 with a 1N aqueous solution of sodium hydroxide and then extracted with benzene. The extract was washed with water and saturated saline and dried over anhydrous sodium sulfate. After filtration, low-boiling substances are distilled off from the filtrate under reduced pressure, and the residue is purified by silica gel column chromatography (methylene chloride / methanol = 10/1 to 5/1) to obtain trans- (4-aminocyclohexyloxy). 130 mg (57%) of t-butyl acetate was obtained as a colorless solid. ¹ H-NMR (CDCl ₃ ) δ _TMS : 3.98 (s, 2H), 4.24-
3.42 (m, 1H), 2.88-2.69 (m, 1H), 2.45-1.82 (m, 6H), 1.47
(s, 9H), 1.50-1.07 (m, 4H)

(2) trans- [4-[[5- (benzyloxycarbonylamidino) -2-benzofuranyl]
Carbonylamino] cyclohexyloxy] t-butyl acetate (compound (453)) According to the same method as in Example 17 (3), 183 mg (0.541 mmol) of 5- (benzyloxycarbonylamidino) -2-benzofurancarboxylic acid and trans- 124 mg (0.541 mmol) of t-butyl (4-aminocyclohexyloxy) acetate
Was purified by silica gel column chromatography (methylene chloride / methanol = 30/1 to 10/1) to obtain 251 mg (84%) of compound (453) as a colorless solid. ¹ H-NMR (CDCl ₃ ) δ _TMS : 8.21 (d, J = 1.3 Hz, 1
H), 7.95 (dd, J = 1.3,8.8Hz, 1H), 7.60-7.27 (m, 7H), 6.45
(d, J = 8.0Hz, 1H), 5.22 (s, 2H), 4.00 (s, 2H), 4.05-3.92
(m, 1H), 3.48-3.30 (m, 1H), 2.25-2.17 (m, 4H), 1.48 (s, 9
H), 1.60-1.24 (m, 4H)

Example 28: trans- [4-[(5-Amidino-2-benzofuranyl) carbonylamino] cyclohexyloxy] acetic acid (compound (465)) Compound (453) 135 mg (0.246 mmol) and t-butanol 13 m
l, 20% of 10% palladium on carbon, and under a hydrogen atmosphere,
The mixture was refluxed for 7 hours. The reaction solution was filtered through celite, and low-boiling substances were distilled off from the filtrate under reduced pressure. Next, 1 ml of trifluoroacetic acid was added to the residue, and the mixture was stirred at room temperature for 1 hour. Diethyl ether was added to the reaction solution, and the precipitate was collected by filtration and washed with diethyl ether to obtain 103 mg (88%) of a trifluoroacetate salt of compound (465) as a colorless solid. ^{1 H-NMR (DMSO-d} 6, 500MHz)
δ _TMS ： 12.90-12.00 (m, 1H), 9.36 (bs, 2H), 9.18 (bs, 2
H), 8.64 (d, J = 8.0Hz, 1H), 8.28 (s, 1H), 7.97-7.82 (m, 2
H), 7.71 (s, 1H), 4.03 (s, 2H), 3.90-3.65 (m, 1H), 3.55-
3.25 (m, 1H), 2.13-1.96 (m, 2H), 1.96-1.81 (m, 2H), 1.57
-1.15 (m, 4H)

Compound (465) trifluoroacetate (100 mg)
(0.211 mmol) was dissolved in 5 ml of acetic acid at 70 ° C.
31 mg (0.317 mmol) was gradually added, and the mixture was stirred as it was for 30 minutes. The reaction solution was returned to room temperature, and diethyl ether (20 ml) was added.
The precipitated precipitate was washed with diethyl ether, collected by filtration,
92 mg (95%) of a sulfate of the compound (465) was obtained as a colorless solid. ¹ H-NMR (DMSO-d ₆ ) δ _TMS : 9.35 (bs, 2H),
8.94 (bs, 2H), 8.64 (d, J = 8.0Hz, 1H), 8.28 (d, J = 1.8Hz, 1
H), 7.92 (d, J = 8.8Hz, 1H), 7.84 (dd, J = 8.8,1.8Hz, 1H), 7.
72 (s, 1H), 4.04 (s, 2H), 3.95-3.65 (m, 1H), 3.45-3.20
(m, 1H), 2.15-1.75 (m, 4H), 1.60-1.15 (m, 4H)

Example 29 (1) 5-guanidino-2-benzofurancarboxylic acid 856 mg (3.54 mmol) of ethyl 5-amino-2-benzofurancarboxylate hydrochloride was added with 30 ml of ethanol and cyanamide.
298 mg (7.09 mmol) was added, and the mixture was heated and stirred at about 50 ° C. for 24 hours. Low-boiling substances are distilled off from the reaction solution under reduced pressure, and the residue is purified by silica gel column chromatography (chloroform / methanol = 100/3 to 3/1) to give the hydrochloride of ethyl 5-guanidino-2-benzofurancarboxylate. Was obtained as a colorless solid (902 mg, 90%). IR (KBr): 2500, 1720, 1670, 1630, 1600, 156
^{0 cm -1 1 H-NMR (} DMSO-d 6) δ TMS: 8.00-7.90 (m, 2
H), 7.68 (d, J = 2.1Hz, 1H), 7.38 (dd, J = 2.1,8.6Hz, 1H), 8.
00-7.00 (bs, 2H), 4.38 (q, J = 7.2Hz, 2H), 1.35 (t, J = 7.2H
(z, 3H)

900 mg (3.18 mmol) of ethyl 5-guanidino-2-benzofurancarboxylate hydrochloride was suspended in 8 ml of tetrahydrofuran, and 8.0 ml (8.0 mmol) of a 1N aqueous sodium hydroxide solution was added thereto, followed by stirring at room temperature for 2 hours. . The reaction solution was adjusted to pH 2 to 3 with 1N hydrochloric acid and then concentrated under reduced pressure. The precipitate is collected by filtration, washed with water, and treated with 5-guanidino-2.
-Hydrochloride of benzofurancarboxylic acid as a colorless solid 3
36 mg (41%) were obtained. IR (KBr): 3700-3000, 2300, 1720, 1685, 1630
^{cm -1 1 H-NMR (DMSO} -d 6) δ TMS: 10.07 (bs, 1H),
7.80-7.30 (bs, 4H), 7.77 (d, J = 8.9Hz, 1H), 7.70-7.65
(m, 2H), 7.37 (dd, J = 2.2,8.9Hz, 1H)

(2) 4-[(5-Guanidino-2-benzofuranyl) carbonylamino] t-butyl phenoxyacetate (Compound (168)) 5-Hydranidino-2-benzofurancarboxylic acid hydrochloride 100 mg (0.391 m
mol) and t-butyl 4-aminophenoxyacetate 96.0 mg
(0.431 mmol) was dissolved in 4 ml of N, N-dimethylformamide, and 58.2 mg (0.431 mmol) of 1-hydroxy-1H-benzotriazole and 54.3 mg (0.431 mmol) of diisopropylcarbodiimide were added thereto. Stirred. The low-boiling substances were distilled off from the reaction solution under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol = 100/3 to 3/1) to give compound (16).
144 mg (80%) of the hydrochloride salt of 8) was obtained as a colorless solid. IR (KBr): 3700-3000, 1740, 1600, 1605, 1510
^{cm -1 1 H-NMR (DMSO} -d 6) δ TMS: 10.53 (bs, 1H),
7.79-7.65 (m, 3H), 7.65-7.40 (bs, 4H), 7.34 (dd, J = 2.1,
9.0Hz, 1H), 6.95-6.87 (m, 2H), 4.64 (s, 2H), 1.44 (s, 9H)

Example 30: 4-[(5-guanidino-2)
-Benzofuranyl) carbonylamino] phenoxyacetic acid (compound (169)) According to the same method as in Example 2, hydrochloride of compound (168) 1
40 mg (0.304 mmol) was treated with 2.8 ml of trifluoroacetic acid,
123 mg (quantitative) of the hydrochloride of the compound (169) was obtained as a pale yellow solid. Mp: 135 to 145 ° C. (decomposition) IR (KBr): 3700-3000, 1670, 1510 cm -1 1 H-NMR (DMSO-d 6, 500MHz)
δ _TMS ： 10.50 (bs, 1H), 9.97 (bs, 1H), 7.79-7.77 (m, 2
H), 7.73-7.70 (m, 3H), 7.65-7.36 (bs, 4H), 7.35 (dd, J = 2.
2,8.9Hz, 1H), 6.95-6.92 (m, 2H), 4.66 (s, 2H)

Example 31: 4-[(6-amidino-2-
Indolyl) carbonylamino] t-butyl phenoxyacetate (compound (198)) 6-cyano-2-
295 mg (1.59 mmol) of indolecarboxylic acid and 386 mg (1.74 mmol) of t-butyl 4-aminophenoxyacetate were condensed and purified by silica gel column chromatography (n-hexane / ethyl acetate = 1/2) to give 4-[( 6-
Cyano-2-indolyl) carbonylamino] 622 mg (quantitative) of t-butyl phenoxyacetate as a light brown solid
Obtained. IR (KBr): 3700-2900, 2200, 1730, 1650, 1540
^{cm -1 1 H-NMR (DMSO} -d 6) δ TMS: 12.23 (bs, 1H),
10.32 (bs, 1H), 8.00-7.85 (m, 2H), 7.68 (d, 2H), 7.55-7.3
5 (m, 2H), 6.94 (d, 2H), 4.64 (s, 2H), 1.44 (s, 9H)

According to a method similar to that of Example 1 (3), 4-
[(6-cyano-2-indolyl) carbonylamino]
The cyano group of 630 mg (1.61 mmol) of t-butyl phenoxyacetate was converted to an amidino group to obtain 891 mg (quantitative in 3 steps) of hydroiodide as a brown viscous oil as compound (198). ¹ H-NMR (DMSO-d ₆ ) δ _TMS : 10.33 (bs, 1H),
7.95-7.86 (m, 2H), 7.69 (d, 2H), 7.51 (s, 1H), 7.43 (d, J =
9.2Hz, 1H), 6.94 (d, 2H), 4.65 (s, 2H), 1.44 (s, 9H)

Example 32: 4-[(6-amidino-2-
Indolyl) carbonylamino] phenoxyacetic acid (compound (202)) According to the same method as in Example 2, 891 mg (1.61 mmol) of hydroiodide like compound (198) was treated with 10 ml of trifluoroacetic acid to give compound (202) As a brown solid
489 mg (63%) were obtained. Mp: 205 to 245 ° C. (decomposition) IR (KBr): 3700-3100, 1660, 1520, 1400 cm -1 1 H-NMR (DMSO-d 6, 500MHz) δ TMS:
10.33 (bs, 1H), 9.27 (bs, 2H), 8.82 (bs, 2H), 7.95 (s, 1
H), 7.91 (d, J = 8.4Hz, 1H), 7.70 (d, 2H), 7.51 (s, 1H), 7.4
5 (dd, J = 1.3,8.4Hz, 1H), 6.95 (d, 2H), 4.67 (s, 2H)

Example 33: 4-[(6-amidino-1-
Methyl-2-indolyl) carbonylamino] t-butyl phenoxyacetate (compound (275)) According to the same method as in Example 1 (2), 6-cyano-1-
52 mg (0.26 mmol) of methyl-2-indolecarboxylic acid and 63 mg (0.29 mmol) of t-butyl 4-aminophenoxyacetate
Was condensed to give 109 mg (quantitative) of 4-[(6-cyano-1-methyl-2-indolyl) carbonylamino] t-butyl phenoxyacetate as a colorless solid. IR (KBr): 3700-3000, 2200 , 1740, 1505 cm -1 1 H-NMR (CDCl 3) δ TMS: 7.85-7.70 (m, 2H),
7.53 (d, 2H), 7.39 (d, J = 9.0Hz, 1H), 7.26 (s, 1H), 6.93
(d, 2H), 4.52 (s, 2H), 4.11 (s, 3H), 1.50 (s, 9H)

According to a method similar to that of Example 1 (3), 4-
[(6-cyano-1-methyl-2-indolyl) carbonylamino] t-butyl phenoxyacetate 105 mg (0.259 m
mol) was converted to an amidino group to obtain 240 mg (quantitative in 3 steps) of hydroiodide as a brown solid, as in compound (275). IR (KBr): 3700-2900, 1640 , 1400 cm -1 1 H-NMR (DMSO-d 6) δ TMS: 10.23 (bs, 1H),
8.18 (s, 1H), 7.91 (d, J = 8.8Hz, 1H), 7.67 (d, 2H), 7.54 (d,
J = 8.8Hz, 1H), 7.36 (s, 1H), 6.92 (d, 2H), 4.64 (s, 2H),
4.09 (s, 3H), 1.44 (s, 9H)

Example 34: 4-[(6-amidino-1-
Methyl-2-indolyl) carbonylamino] phenoxyacetic acid (compound (278)) According to the same method as in Example 2, 240 mg (0.26 mmol) of hydroiodide of compound (275) was treated with 2 ml of trifluoroacetic acid. Compound (278) hydroiodide as yellow solid
128 mg (quantitative) were obtained. Mp:> 250 ℃ IR (KBr) : 3700-2800, 1640, 1505, 1390 cm -1 1 H-NMR (DMSO-d 6, 500MHz) δ TMS:
9.28 (bs, 2H), 8.90 (bs, 2H), 8.19 (s, 1H), 7.92 (d, J = 8.4
Hz, 1H), 7.67 (d, 2H), 7.54 (dd, J = 1.5,8.4Hz, 1H), 7.37
(s, 1H), 6.94 (d, 2H), 4.64 (s, 2H), 4.09 (s, 3H)

Example 35: 4-[(5-amidinobenzo
[b] Thien-2-yl) carbonylamino] t-butyl phenoxyacetate (compound (325)) According to the same method as in Example 1 (2), 5-cyanobenzo
[b] Thiene-2-carboxylic acid (520 mg, 2.56 mmol) and 4
-T-butyl aminophenoxyacetate 632 mg (2.82 mmol)
To give 4-[(5-cyanobenzo [b] thien-2
-Yl) carbonylamino] 888 mg (85%) of t-butyl phenoxyacetate as an orange solid. IR (KBr): 2200, 1740 , 1635, 1600, 1500 cm -1 1 H-NMR (DMSO-d 6) δ TMS: 10.59 (bs, 1H),
8.61 (d, J = 1.5Hz, 1H), 8.40 (s, 1H), 8.30 (d, J = 8.4Hz, 1
H), 7.83 (dd, J = 1.5, 8.4 Hz, 1H), 7.65 (d, 2H), 6.94 (d, 2
H), 4.65 (s, 2H), 1.44 (s, 9H)

According to a method similar to that of Example 1 (3), 4-
[(5-cyanobenzo [b] thien-2-yl) carbonylamino] t-butyl phenoxyacetate 850 mg (2.08 mm
ol) to convert the cyano group to an amidino group, and 469 mg of hydroiodide as a yellow solid as compound (325) (41 steps in 3 steps)
%)Obtained. IR (KBr): 1755, 1640 , 1510, 1230, 1160 cm -1 1 H-NMR (DMSO-d 6) δ TMS: 8.45 (s, 1H), 8.
35-8.26 (m, 1H), 7.84 (d, J = 8.4Hz, 1H), 7.66 (d, 2H), 6.9
3 (d, 2H), 4.63 (s, 2H), 1.45 (s, 9H)

Example 36: 4-[(5-amidinobenzo
[b] thien-2-yl) carbonylamino] phenoxyacetic acid (compound (328)) According to the same method as in Example 2, 459 mg (0.830 mmol) of hydroiodide such as compound (325) was treated with 7 ml of trifluoroacetic acid. Treated with hydroiodide as compound (328) as a brown solid
338 mg (84%) were obtained. Mp:> 210 ° C. (decomposition) IR (KBr): 3700-2700, 1680, 1640, 1510 cm -1 1 H-NMR (DMSO-d 6, 500MHz) δ TMS:
10.58 (bs, 1H), 9.42 (bs, 2H), 9.28 (bs, 2H), 8.42 (m, 2
H), 8.32 (d, J = 8.6Hz, 1H), 7.84 (dd, J = 1.8,8.6Hz, 1H), 7.
68-7.65 (m, 2H), 6.97-6.93 (m, 2H), 4.67 (s, 2H)

Example 37: 4-[(6-amidinobenzo)
[b] Thien-2-yl) carbonylamino] t-butyl phenoxyacetate (compound (326)) According to the same method as in Example 1 (2), 6-cyanobenzo
[b] Thiene-2-carboxylic acid (280 mg, 1.38 mmol) and 4
341 mg (1.52 mmol) of t-butyl-aminophenoxyacetate was condensed and purified by silica gel column chromatography (n-hexane / ethyl acetate = 1/3) to give 4-
[(6-Cyanobenzo [b] thien-2-yl) carbonylamino] 485 mg (90%) of t-butyl phenoxyacetate was obtained as a yellow solid. IR (KBr): 2200, 1740 , 1635, 1500 cm -1 1 H-NMR (DMSO-d 6) δ TMS: 10.6 (s, 1H), 8.
70 (s, 1H), 8.41 (s, 1H), 8.19 (d, J = 8.4Hz, 1H), 7.82 (dd, J
= 1.4,8.4Hz, 1H), 7.65 (d, 2H), 6.93 (d, 2H), 4.65 (s, 2
H), 1.44 (s, 9H)

According to a method similar to that of Example 1 (3), 4-
[(6-cyanobenzo [b] thien-2-yl) carbonylamino] t-butyl phenoxyacetate 475 mg (1.22 mm
ol) to convert the cyano group to an amidino group, and 462 mg of hydroiodide as a yellow solid as compound (326) (68
%) Obtained. IR (KBr): 3700-2700, 1730 , 1635, 1500 cm -1 1 H-NMR (DMSO-d 6) δ TMS: 10.58 (s, 1H), 1
0.0-8.50 (bs, 4H), 8.57 (s, 1H), 8.43 (s, 1H), 8.24 (d, J =
8.5Hz, 1H), 7.81 (d, J = 8.5Hz, 1H), 7.66 (d, 2H), 6.96 (d,
2H), 4.65 (s, 2H), 1.44 (s, 9H)

Example 38: 4-[(6-amidinobenzo)
[b] thien-2-yl) carbonylamino] phenoxyacetic acid (compound (329)) According to the same method as in Example 2, 407 mg (0.736 mmol) of hydroiodide of compound (326) was treated with 7 ml of trifluoroacetic acid. Treatment yielded 345 mg (94%) of the hydroiodide salt as a compound (329) as a reddish brown solid. Melting point:> 250 ° C IR (KBr): 3700-2800, 1740, 1680, 1635, 1500
^{cm -1 1 H-NMR (DMSO} -d 6, 500MHz) δ TMS:
10.59 (s, 1H), 9.41 (bs, 2H), 9.21 (bs, 2H), 8.58 (s, 1H),
8.44 (s, 1H), 8.23 (d, J = 8.5Hz, 1H), 7.81 (dd, J = 1.5,8.5H
z, 1H), 7.67 (d, 2H), 6.95 (d, 2H), 4.67 (s, 2H)

Example 39: trans-3- [4-[[5
-(Benzyloxycarbonylamidino) -2-benzofuranyl] carbonylamino] cyclohexyl] ethyl propionate (compound (433)) According to the same method as in Example 17 (3), 5- (benzyloxycarbonylamidino) -2-benzofuran 3.98 g (11.8 mmol) of carboxylic acid and 3.00 g (14.1 mmol) of ethyl trans-3- (4-aminocyclohexyl) propionate are condensed, and the mixture is subjected to silica gel column chromatography (n-hexane / ethyl acetate = 1/1 to 0 /). 1) Purify by
4.66 g (76%) of compound (433) was obtained as a colorless solid. IR (KBr): 1730, 1640 , 1600, 1530 cm -1 1 H-NMR (CDCl 3, 500MHz) δ TMS: 8.2
3 (d, J = 1.7Hz, 1H), 7.95 (dd, J = 8.8,1.7Hz, 1H), 7.53
(d, J = 8.8Hz, 1H), 7.50-7.25 (m, 6H), 6.47 (d, J = 7.0Hz, 1
H), 5.22 (s, 2H), 4.13 (q, J = 7.1Hz, 2H), 3.93-3.90 (m,
1H), 2.38-2.30 (m, 2H), 2.15-2.05 (m, 2H), 1.86-1.80
(m, 2H), 1.48-1.40 (m, 2H), 1.32-1.22 (m, 5H), 1.15-
1.00 (m, 2H)

Example 40: trans-3- [4-[(5
-Amidino-2-benzofuranyl) carbonylamino]
Cyclohexyl] ethyl propionate (Compound (439)) 2.85 g of Compound (433) in the same manner as in Example 19.
(5.48 mmol) was reduced with hydrogen and purified by silica gel column chromatography (chloroform / methanol = 4/1) to give 2.18 g of the hydrochloride of compound (439) as a colorless solid.
(94%). Mp:> 250 ℃ IR (KBr) : 3700-2600, 1720, 1640, 1520 cm -1 1 H-NMR (DMSO-d 6, 500MHz)
δ _TMS ： 9.31 (bs, 4H), 8.67 (d, J = 8.1Hz, 1H), 8.30
(d, J = 1.8Hz, 1H), 7.90 (d, J = 8.7Hz, 1H), 7.87 (dd, J = 8.
7,1.8Hz, 1H), 7.74 (s, 1H), 4.05 (q, J = 7.1Hz, 2H), 3.78
-3.71 (m, 1H), 2.35-2.26 (m, 2H), 1.88-1.71 (m, 4H),
1.48-1.35 (m, 4H), 1.24-1.13 (m, 4H), 1.07-0.97 (m, 2
H)

Example 41: trans-3- [4-[(5
-Amidino-2-benzofuranyl) carbonylamino]
Cyclohexyl] propionic acid (compound (447)) According to the same method as in Example 10, hydrochloride of compound (439)
1.59 g (3.77 mmol) was hydrolyzed to obtain 1.45 g (67%) of a hydrochloride of compound (447) as a light brown solid. Mp:> 250 ℃ IR (KBr) : 3600-2500, 1700, 1630, 1500 cm -1 1 H-NMR (DMSO-d 6, 500MHz)
δ _TMS ： 9.47 (bs, 2H), 9.20 (bs, 2H), 8.67 (d, J = 8.2H
z, 1H), 8.30 (d, J = 1.4Hz, 1H), 7.94-7.71 (m, 2H), 7.63
(s, 1H), 3.80-3.69 (m, 1H), 2.28-2.19 (m, 2H), 1.89-1.
71 (m, 4H), 1.49-1.20 (m, 4H), 1.20-1.10 (m, 1H), 1.0
7-0.95 (m, 2H)

1.00 g (2.54 mmol) of the hydrochloride of compound (447) was dissolved in 100 ml of acetic acid at 70 ° C., and 2.71 ml of concentrated sulfuric acid (50.7 ml) was added.
(7 mmol) was added slowly, and the mixture was stirred as it was until the precipitated crystals were dissolved again. The reaction solution was returned to room temperature, and 200 ml of diethyl ether was added. The precipitated precipitate was washed with diethyl ether and collected by filtration to obtain 1.15 g (quantitative) of a sulfate of compound (447) as a colorless solid. ¹ H-NMR (DMSO-d ₆ ) δ _TMS : 9.36 (bs, 2H),
8.96 (bs, 2H), 8.63 (d, J = 8.1Hz, 1H), 8.28 (d, J = 1.7H
z, 1H), 7.92 (d, J = 8.8Hz, 1H), 7.84 (dd, J = 8.8,1.7Hz, 1
H), 7.71 (s, 1H), 3.90-3.65 (m, 1H), 2.24 (t, J = 7.5Hz,
2H), 2.00-1.65 (m, 4H), 1.60-0.90 (m, 7H)

Example 42: trans-3- [4-[(5
-Amidino-2-benzofuranyl) carbonylamino]
Cyclohexyl] isopropyl propionate (compound (4
40)) 10 ml of isopropanol was added to 100 mg (0.254 mmol) of the hydrochloride of the compound (447), and hydrogen chloride gas was blown into the mixture for 5 minutes, followed by stirring at room temperature for 14 hours. Low-boiling substances were distilled off from the reaction solution under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol = 97/3) to give 101 mg of the hydrochloride of compound (440) as a colorless solid (9
1%). IR (KBr): 3700-2700, 1720 , 1630, 1520 cm -1 1 H-NMR (DMSO-d 6, 500MHz)
δ _TMS ： 9.46 (bs, 2H), 9.21 (bs, 2H), 8.66 (d, J = 8.2H
z, 1H), 8.30 (d, J = 1.3Hz, 1H), 7.92-7.85 (m, 2H), 7.74
(s, 1H), 4.92-4.85 (m, 1H), 3.77-3.72 (m, 1H), 2.27
(t, J = 7.7Hz, 2H), 1.86-1.73 (m, 4H), 1.48-1.36 (m, 4
H), 1.19-1.17 (m, 7H), 1.17-0.97 (m, 2H)

Example 43: trans-3- [4-[(5
-Amidino-2-benzofuranyl) carbonylamino]
Cyclohexyl] cyclohexyl propionate (compound
(442)) According to a method similar to that in Example 42, hydrochloride of compound (447)
100 mg (0.254 mmol) is reacted with cyclohexanol,
109 mg (90%) of the hydrochloride of compound (442) was obtained as a colorless solid. IR (KBr): 1720, 1635 , 1520 cm -1 1 H-NMR (DMSO-d 6, 500MHz)
δ _TMS ： 9.70-9.00 (bs, 4H), 8.66 (d, J = 8.2Hz, 1H), 8.
30 (d, J = 1.8Hz, 1H), 7.90 (d, J = 8.8Hz, 1H), 7.87 (dd, J =
(8.8,1.8Hz, 1H), 7.73 (s, 1H), 4.68-4.62 (m, 1H), 3.78-
3.71 (m, 1H), 2.29 (t, J = 7.6Hz, 2H), 1.88-1.81 (m, 2H),
1.81-1.70 (m, 4H), 1.70-1.60 (m, 2H), 1.53-1.45 (m,
4H), 1.45-1.30 (m, 5H), 1.30-1.10 (m, 2H), 1.05-0.95
(m, 2H)

Example 44: trans-3- [4-[(5
-Amidino-2-benzofuranyl) carbonylamino]
[Cyclohexyl] 2-hydroxyethyl propionate (compound (443)) To 250 mg (0.635 mmol) of the hydrochloride of compound (447) were added 3 ml of ethylene glycol and 75 mg (0.780 mmol) of methanesulfonic acid, followed by stirring at 100 ° C for 30 minutes. Ethylene glycol was distilled off from the reaction solution (0.5 mmHg / 60 ° C.), and the residue was washed with diethyl ether to obtain 309 mg (95%) of a methanesulfonic acid salt of compound (443) as a colorless solid. Melting point: 206-209 ° C IR (KBr): 3700-3150, 3100, 2900, 2850, 171
0, 1680, 1638, 1595,1527 cm -1 1 H-NMR (DMSO-d 6) δ TMS: 9.37 (bs, 2H),
9.06 (bs, 2H), 8.64 (d, J = 7.9Hz, 1H), 8.29 (s, 1H), 7.
92 (d, J = 8.9Hz, 1H), 7.85 (dd, J = 8.8,1.7Hz, 1H), 7.72
(s, 1H), 4.03 (t, J = 5.1Hz, 2H), 3.90-3.65 (m, 1H), 3.56
(t, J = 5.1Hz, 2H), 2.34 (s, 3H), 2.34 (t, J = 7.7Hz, 2H),
1.95-1.70 (m, 4H), 1.60-0.88 (m, 7H)

Example 45: 2-hydroxyethyl trans- [4-[(5-amidino-2-benzofuranyl) carbonylamino] cyclohexyloxy] acetate (compound
(444)) According to a method similar to that in Example 44, 50 mg (0.106 mmol) of trifluoroacetate of compound (465) was reacted with ethylene glycol, and 42 mg of methanesulfonate of compound (444) was obtained as a colorless solid (78 mg). %)Obtained. Melting point: 212-215 ° C IR (KBr): 3700-2500, 1740, 1690, 1638, 159
^{5, 1535, 1505 cm -1 1} H-NMR (DMSO-d 6) δ TMS: 9.35 (bs, 2H),
9.01 (bs, 2H), 8.64 (d, J = 8.1Hz, 1H), 8.28 (d, J = 1.2H
z, 1H), 7.92 (d, J = 8.8Hz, 1H), 7.84 (dd, J = 8.8,1.7Hz, 1
H), 7.72 (s, 1H), 4.15 (s, 2H), 4.10 (t, J = 5.1Hz, 2H),
3.95-3.65 (m, 1H), 3.58 (t, J = 5.0Hz, 2H), 3.40-3.25
(m, 1H), 2.35 (s, 3H), 2.15-1.80 (m, 4H), 1.60-1.15
(m, 4H)

Example 46: n-butyl trans- [4-[(5-amidino-2-benzofuranyl) carbonylamino] cyclohexyloxy] acetate (compound (460)) The compound (465) was prepared in the same manner as in Example 44. ) Was reacted with n-butanol to obtain 190 mg (88%) of a methanesulfonate of the compound (460) as a colorless solid. ¹ H-NMR (DMSO-d ₆ ) δ _TMS : 9.35 (bs, 2H),
8.98 (bs, 2H), 8.70-8.55 (bd, 1H), 8.28 (d, J = 1.2Hz,
1H), 7.97-7.75 (m, 2H), 7.72 (s, 1H), 4.14 (s, 2H), 4.
10 (q, J = 6.5Hz, 2H), 3.92-3.70 (m, 1H), 3.45-3.20 (m, 1
H), 2.34 (s, 3H), 2.12-1.78 (m, 4H), 1.68-1.15 (m, 8
H), 0.90 (t, J = 7.2Hz, 3H)

Example 47: Ethyl trans- [4-[(5-amidino-2-benzofuranyl) carbonylamino] cyclohexyloxy] acetate (compound (459)) 8 ml and methanesulfonic acid (360 mg, 3.74 mmol) were added, and the mixture was heated under reflux for 1 hour. The reaction solution was concentrated under reduced pressure to about 1/4,
To this, 8 ml of diethyl ether was added, and the precipitated precipitate was washed with diethyl ether to obtain 350 mg (95%) of a methanesulfonate of the compound (459) as a colorless solid. Melting point: 242-245 ° C IR (KBr): 3600-2700, 1745, 1673, 1635, 159
^{0, 1520 cm -1 1 H-} NMR (DMSO-d 6) δ TMS: 9.36 (bs, 2H),
9.06 (bs, 2H), 8.65 (d, J = 8.0Hz, 1H), 8.29 (d, J = 1.0H
z, 1H), 7.95-7.80 (m, 2H), 7.72 (s, 1H), 4.13 (s, 2H),
4.12 (q, J = 7.1Hz, 2H), 3.93-3.68 (m, 1H), 3.50-3.20
(m, 1H), 2.38 (s, 3H), 2.15-1.78 (m, 4H), 1.21 (t, J = 7.
1Hz, 3H), 1.60-1.15 (m, 4H)

Example 48: t-butyl trans- [4-[(5-amidino-3-methyl-2-benzofuranyl) carbonylamino] cyclohexyloxy] acetate (compound (467)) Same as in Example 1 (2) According to the method of 5-cyano-3-
Methyl-2-benzofurancarboxylic acid 312 mg (1.55 mmo
l) and trans- (4-aminocyclohexyloxy)
380 mg (1.66 mmol) of t-butyl acetate was condensed and trans-
[4-[(5-cyano-3-methyl-2-benzofuranyl) carbonylamino] cyclohexyloxy] acetic acid t
534 mg (84%) of -butyl was obtained as a colorless solid. IR (KBr): 3250, 2900, 2200, 1750, 1630, 112
^{0 cm -1 1 H-NMR (} CDCl 3) δ TMS: 7.96 (d, J = 1.5Hz, 1
H), 7.68 (dd, J = 8.6,1.5Hz, 1H), 7.53 (d, J = 8.6Hz, 1H),
6.42 (d, J = 7.9Hz, 1H), 4.01 (s, 2H), 4.07-3.92 (m, 1
H), 3.45-3.34 (m, 1H), 2.63 (s, 3H), 2.17-2.12 (m, 4
H), 1.49 (s, 9H), 1.55-1.26 (m, 4H)

According to a method similar to that of Example 1 (3), trans- [4-[(5-cyano-3-methyl-2-benzofuranyl) carbonylamino] cyclohexyloxy]
The cyano group of 530 mg (1.28 mmol) of t-butyl acetate was converted to an amidino group to obtain 459 mg (64%) of a hydroiodide salt as a light brown solid such as compound (467). IR (KBr): 3250, 2900, 1720, 1640, 1600, 111
^{0 cm -1 1 H-NMR (} DMSO-d 6, 500MHz)
δ _TMS ： 9.33 (bs, 4H), 8.45 (d, J = 8.1Hz, 1H), 8.29
(dJ = 1.9Hz, 1H), 7.88 (dd, J = 8.7,1.9Hz, 1H), 7.83 (d, J
= 8.7Hz, 1H), 4.00 (s, 2H), 3.80-3.78 (m, 1H), 2.58 (s,
3H), 2.62-2.54 (m, 1H), 2.04-2.02 (m, 2H), 1.85-1.82
(m, 2H), 1.43 (s, 9H), 1.56-1.39 (m, 2H), 1.31-1.25
(m, 2H)

Example 49: trans- [4-[(5-Amidino-3-methyl-2-benzofuranyl) carbonylamino] cyclohexyloxy] acetic acid (compound (468)) 435 mg (0.780 mmol) of hydroiodide like 467) was treated with 7 ml of trifluoroacetic acid to give hydroiodide as compound (468) as a yellow solid.
356 mg (91%) were obtained. ^{1 H-NMR (DMSO-d} 6, 500MHz)
δ _TMS ： 12.52 (bs, 1H), 9.36 (s, 2H), 9.17 (s, 2H),
8.46 (d, J = 8.1Hz, 1H), 8.29 (dJ = 1.9Hz, 1H), 7.87 (dd,
J = 8.7,1.9Hz, 1H), 7.83 (d, J = 8.7Hz, 1H), 4.04 (s, 2H),
3.80-3.77 (m, 1H), 3.34-3.29 (m, 1H), 2.57 (s, 3H), 2.
05-2.03 (m, 2H), 1.85-1.83 (m, 2H), 1.49-1.41 (m, 2
H), 1.30-1.25 (m, 2H)

Example 50 (1) 25.6 g of methyl 5-cyano-3-methoxy-2-benzofurancarboxylate 5-bromo-2-hydroxybenzoate (129)
mmol), cuprous cyanide 20.8 g (257 mmol), copper sulfate 200 m
g was added to 250 ml of N-methyl-2-pyrrolidone, and the mixture was refluxed for 2 hours under a nitrogen atmosphere. Bring the reaction to room temperature and add water
The mixture was poured into a mixture of 500 ml and 10 ml of ethylenediamine. After filtration, the filtrate was extracted with ethyl acetate, and the extract was washed with water and saturated saline and dried over anhydrous magnesium sulfate. After filtration, low-boiling substances were distilled off from the filtrate under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / n-hexane = 5/1) to give methyl 5-cyano-2-hydroxybenzoate. 3.35 g (15%) were obtained as a colorless solid. 3.35 g (18.9 mmol) of this and 5.23 g of potassium carbonate (3
7.0 mmol) in 45 ml of N, N-dimethylformamide,
To this, 2.21 ml (19.9 mmol) of ethyl bromoacetate was gradually added, and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction solution, and the mixture was extracted with a mixed solution of an equal amount of ethyl acetate and n-hexane. The extract was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. After filtration, low-boiling substances are distilled off from the filtrate under reduced pressure.
-A crude product of ethyl cyano-2-methoxycarbonylphenoxyacetate was obtained. 3.39 g (19.3 mmol) of this was dissolved in 20 ml of ethanol, and this was dissolved in 622 mg of metal sodium (2
(7.1 mmol) was added slowly to a solution of 50 ml of ethanol, and the mixture was stirred at room temperature for 45 minutes. Low-boiling substances were distilled off from the reaction solution under reduced pressure, and 200 ml of water was added to the residue, and diluted hydrochloric acid was added to adjust the pH to 2-3. The precipitate is collected by filtration and treated with 5-cyano-3
2.98 g (quantitative) of ethyl-hydroxy-2-benzofurancarboxylate was obtained as a colorless solid. IR (KBr): 2200, 1680 , 1620, 1590 cm -1 1 H-NMR (DMSO-d 6, 500MHz)
δ _TMS : 8.38 (s, 1H), 7.91 (d, J = 8.7Hz, 1H), 7.80 (d,
J = 8.7Hz, 1H), 4.33 (q, J = 7.1Hz, 2H), 1.32 (t, J = 7.1Hz, 3
H)

Ethyl 5-cyano-3-hydroxy-2-benzofurancarboxylate 200 mg (0.866 mmol), dimethyl sulfate 131 mg (1.04 mmol), potassium carbonate 132 mg (0.953 mmol)
l) was added to 140 ml of acetone, and the mixture was refluxed for 1.5 hours.
Low-boiling substances were distilled off from the reaction solution under reduced pressure, and 200 ml of water was added to the residue.
Was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline and dried over anhydrous magnesium sulfate. After filtration,
Low-boiling substances were distilled off from the filtrate under reduced pressure to give 5-cyano-3-
193 mg of ethyl methoxy-2-benzofurancarboxylate
(91%). 170 mg (0.694 mmol) of this
Dissolve in 5 ml, add potassium hydroxide 160 mg (2.86 mmol)
Was added and the mixture was heated under reflux for 45 minutes. The low-boiling substances were distilled off from the reaction solution under reduced pressure, 1N hydrochloric acid was added to the residue to adjust the pH to 2-3, and the precipitate was collected by filtration. 123 mg (82%) were obtained. IR (KBr): 2300, 1690 , 1585, 1490 cm -1 1 H-NMR (DMSO-d 6, 500MHz)
δ _TMS ： 8.56 (s, 1H), 7.94 (dd, J = 8.8,1.7Hz, 1H), 7.8
5 (d, J = 8.8Hz, 1H), 4.22 (s, 3H)

(2) t-butyl trans- [4-[(5-amidino-3-methoxy-2-benzofuranyl) carbonylamino] cyclohexyloxy] acetate (compound (4
69)) According to the same method as in Example 1 (2), 5-cyano-3-
Methoxybenzofuran-2-carboxylic acid 220mg (1.01mmo
l) and 3- (4-aminocyclohexyl) propionic acid t
-Butyl-244 mg (1.06 mmol) was condensed to give trans- [4-
[(5-cyano-3-methoxy-2-benzofuranyl)
316 mg (73%) of carbonylamino] cyclohexyloxy] t-butyl acetate was obtained as a colorless solid. IR (KBr): 2200, 1740 , 1640, 1540 cm -1 1 H-NMR (DMSO-d 6, 500MHz)
δ _TMS : 8.48 (d, J = 1.3Hz, 1H), 7.90 (dd, J = 8.6,1.3Hz,
1H), 7.80 (d, J = 8.6Hz, 1H), 4.20 (s, 3H), 3.35-3.25
(m, 1H), 3.82-3.73 (m, 1H), 2.05-1.95 (m, 2H), 1.90-1.
80 (m, 2H), 1.43 (s, 9H), 1.50-1.10 (m, 4H)

According to a method similar to that of Example 1 (3), trans- [4-[(5-cyano-3-methoxy-2-benzofuranyl) carbonylamino] cyclohexyloxy
] 310 mg (0.724 mmol) of t-butyl acetate was converted from a cyano group to an amidino group, and silica gel (Chromatorex, NH type,
Purified by Fuji Silysia Chemical) column chromatography (chloroform / methanol = 30/1 to 1/1)
185 mg (57%) of compound (469) was obtained as a colorless solid. IR (KBr): 1740, 1640 , 1520 cm -1 1 H-NMR (CDCl 3) δ TMS: 8.05 (s, 1H), 7.67
(dd, J = 8.7,1.5Hz, 1H), 7.51 (d, J = 8.7Hz, 1H), 7.79-7.6
0 (m, 1H), 4.29 (s, 3H), 4.10-4.00 (m, 1H), 4.01 (s, 2
H), 3.45-3.35 (m, 1H), 2.20-2.00 (m, 4H), 1.49 (s, 9
H), 1.70-1.30 (m, 4H)

Example 51: trans- [4-[(5-Amidino-3-methoxy-2-benzofuranyl) carbonylamino] cyclohexyloxy] acetic acid (compound (470)) 469) 180mg (0.4
04 mmol) was treated with 2 ml of trifluoroacetic acid to give the compound (47
179 mg (86%) of trifluoroacetate as a colorless solid
Obtained. Mp: 130~131 ℃ IR (KBr): 1720, 1640, 1530 cm -1 1 H-NMR (DMSO-d 6, 500MHz)
δ _TMS ： 12.50 (bs, 1H), 9.38 (bs, 2H), 9.15 (bs, 2H),
8.35 (d, J = 1.8Hz, 1H), 7.98 (d, J = 8.0Hz, 1H), 7.88 (d
d, J = 8.8,1.8Hz, 1H), 7.84 (d, J = 8.8Hz, 1H), 4.27 (s, 3
H), 4.03 (s, 2H), 3.85-3.70 (m, 1H), 3.40-3.30 (m, 1
H), 2.10-2.00 (m, 2H), 1.90-1.80 (m, 2H), 1.50-1.43
(m, 2H), 1.43-1.20 (m, 2H)

Example 52: Trans- [4-[(5-benzylamidino-2-benzofuranyl) carbonylamino] cyclohexyloxy] t-butyl acetate (compound (4
55)) The same method as in Example 20 was followed. That is, 749 mg (4.00 mmol) of 5-cyano-2-benzofurancarboxylic acid and trans- (4-aminocyclohexyloxy) acetic acid t-
917 mg (4.00 mmol) of butyl was condensed and trans- [4-
1.24 g (78%) of [(5-cyano-2-benzofuranyl) carbonylamino] cyclohexyloxy] t-butyl acetate was obtained as a colorless solid. IR (KBr): 3600-3100, 2900, 2200, 1740, 164
^{0, 1562, 1524 cm -1 1} H-NMR (CDCl 3) δ TMS: 8.04 (d, J = 1.4Hz, 1
H), 7.69 (dd, J = 8.6,1.6Hz, 1H), 7.60 (d, J = 8.5Hz, 1H),
7.51 (s, 1H), 6.43 (d, J = 7.9Hz, 1H), 4.02 (s, 2H), 4.1
0-3.85 (m, 1H), 3.50-3.30 (m, 1H), 2.28-2.15 (m, 4H),
1.49 (s, 9H), 1.78-1.20 (m, 4H)

Next, trans- [4-[(5-cyano-
2-benzofuranyl) carbonylamino] cyclohexyloxy] 1.24 g (3.11 mmol) of t-butyl acetate was converted from a cyano group to a benzylamidino group, followed by silica gel column chromatography (chloroform / methanol = 50/1 to 50: 1).
5/1) followed by silica gel (Chromatorex, NH form,
Purification by column chromatography (chloroform / methanol = 100/1 to 20/1) gave 701 mg (44%) of compound (455) as a colorless solid. IR (KBr): 3700-3000, 2920, 1740, 1640, 1590,
^{1525 cm -1 1 H-NMR (} DMSO-d 6) δ TMS: 8.49 (d, 1H),
8.31 (s, 1H), 7.97 (d, J = 8.8Hz, 1H), 7.64 (d, J = 8.8Hz,
1H), 7.57 (s, 1H), 7.50-7.15 (m, 5H), 6.80-6.40 (m, 2
H), 4.38 (s, 2H), 4.00 (s, 2H), 3.90-3.68 (m, 1H), 3.5
0-3.30 (m, 1H), 2.12-1.78 (m, 4H), 1.43 (s, 9H), 1.60-
1.10 (m, 4H)

Example 53: trans- [4-[(5-Benzylamidino-2-benzofuranyl) carbonylamino] cyclohexyloxy] acetic acid (compound (458)) According to the same method as in Example 2, 420 mg of compound (455) (0.8
31 mmol) was treated with 3 ml of trifluoroacetic acid to give the compound (45
8) trifluoroacetate as a colorless solid 395mg (84%)
Obtained. Mp: 102~105 ℃ IR (KBr): 3600-2700, 1640, 1590, 1520 cm -1 1 H-NMR (DMSO-d 6, 500MHz)
δ _TMS ： 10.31 (t, J = 5.2Hz, 1H), 9.64 (s, 1H), 9.24
(s, 1H), 8.66 (d, J = 8.0Hz, 1H), 8.25 (d, J = 1.7Hz, 1H),
7.91 (d, J = 8.8Hz, 1H), 7.83 (dd, J = 8.7,1.8Hz, 1H), 7.71
(s, 1H), 7.50-7.30 (m, 5H), 4.70 (d, J = 5.9Hz, 2H), 4.
04 (s, 2H), 3.85-3.72 (m, 1H), 3.40-3.20 (m, 1H), 2.10
-1.80 (m, 4H), 1.50-1.20 (m, 4H)

Example 54 (1) Ethyl 3- (4-aminopiperidino) propionate 10.0 g (73.7 mmol) of 4-piperidinone and 30.6 of potassium carbonate
g (221 mmol) and N, N-dimethylformamide 100 ml
To this, ethyl 3-bromopropionate 10.0 ml
(78.0 mmol), and the mixture was stirred at 60 ° C for 4.5 hours. The reaction solution was filtered, and the filtrate was added with a saturated aqueous sodium hydrogen carbonate solution (150 ml).
And extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. After filtration, low-boiling substances were distilled off from the filtrate under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform / methanol = 19).
/ 1) to give 9.70 g (66%) of ethyl 3- (4-oxopiperidino) propionate as a pale yellow oil. Next, 1.29 g (6.47 mmol) of ethyl 3- (4-oxopiperidino) propionate and 0.85 ml (7.78 mmol) of benzylamine
mmol) was dissolved in 40 ml of ethanol. To this, 256 mg (4.22 mmol) of sodium cyanoborohydride was added to ethanol 20
solution at room temperature, and add 1 ml of acetic acid
The pH was adjusted to 6-7. This is stirred at room temperature for 18 hours, and concentrated hydrochloric acid 3
ml was added to adjust the pH to 1-2. The precipitate was collected by filtration, adjusted to pH 8 to 9 by adding 150 ml of a saturated aqueous solution of sodium hydrogen carbonate, extracted with ethyl acetate, and the extract was washed with brine and dried over anhydrous magnesium sulfate. After filtration, low-boiling substances were distilled off from the filtrate under reduced pressure, and 1.39 g (74%) of ethyl 3- (4-benzylaminopiperidino) propionate was obtained as a colorless oil.
Obtained. 1.11 g (3.82 mmol) of this product was dissolved in 120 ml of ethanol, 320 mg of 10% palladium on carbon was added thereto, and the mixture was refluxed for 5 hours under a hydrogen atmosphere. The reaction solution was filtered, and low-boiling substances were distilled off from the filtrate under reduced pressure, to give 617 mg (8
1%). IR (neat): 3300, 2900 , 1720, 1600 cm -1 1 H-NMR (CDCl 3) δ TMS: 4.14 (q, J = 7.1Hz, 2
H), 2.87-2.79 (m, 2H), 2.72-2.63 (m, 3H), 2.52-2.44
(m, 2H), 2.05 (td, J = 11.6,2.4Hz, 2H), 1.83-1.77 (m, 2
H), 1.45-1.29 (m, 2H), 1.25 (t, J = 7.1Hz, 3H)

(2) Ethyl 3- [4-[[5- (benzyloxycarbonylamidino) -2-benzofuranyl] carbonylamino] piperidino] propionate (compound
(472)) According to the same method as in Example 17 (3), 1.08 g (3.19 mmol) of 5- (benzyloxycarbonylamidino) -2-benzofurancarboxylic acid and 3- (4-aminopiperidino)
Condensation of 610 mg (3.05 mmol) of ethyl propionate gives the compound
(472) was obtained as a colorless solid (1.10 g, 69%). IR (KBr): 3300, 2930, 1725, 1660, 1635, 152
^{0, 1250 cm -1 1 H-} NMR (CDCl 3) δ TMS: 8.24 (d, J = 1.9Hz, 1
H), 7.96 (dd, J = 8.8,1.9Hz, 1H), 7.55 (d, J = 8.8Hz, 1H),
7.48-7.30 (m, 6H), 6.48 (d, J = 8.3Hz, 1H), 5.23 (s, 2
H), 4.15 (q, J = 7.2Hz, 2H), 4.03-3.99 (m, 1H), 2.93-2.8
7 (m, 2H), 2.73 (t, J = 7.0Hz, 2H), 2.51 (t, J = 7.0Hz, 2H),
2.23 (td, J = 11.5,2.1Hz, 2H), 2.07-2.02 (m, 2H), 1.72-
1.53 (m, 2H), 1.27 (t, J = 7.2Hz, 3H)

Example 55: 3- [4-[(5-Amidino-2-benzofuranyl) carbonylamino] piperidino
Ethyl propionate (compound (477)) 400 mg (0.768 mmol) of compound (472) was dissolved in 100 ml of ethanol, 80 mg of 10% palladium on carbon was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 4 hours. The reaction solution was filtered, and low-boiling substances were distilled off from the filtrate under reduced pressure.
romatorex, NH type, Fuji Silysia Chemical Ltd.) column chromatography (chloroform / methanol = 9/1) to give 246 mg (83%) of compound (477) as a colorless solid.
%) Obtained. IR (KBr): 3240, 2920 , 1725, 1635, 1180 cm -1 1 H-NMR (CDCl 3) δ TMS: 7.93 (d, J = 1.7Hz, 1
H), 7.70 (dd, J = 8.7,1.7Hz, 1H), 7.53 (d, J = 8.7Hz, 1
H), 7.47 (d, J = 0.6Hz, 1H), 6.52 (bs, 1H), 4.31 (bs, 3
H), 4.15 (q, J = 7.2Hz, 2H), 4.06-3.94 (m, 1H), 2.92-2.8
6 (m, 2H), 2.73 (t, J = 6.7Hz, 2H), 2.50 (t, J = 6.7Hz, 2H),
2.28-2.16 (ddd, J = 12.0,11.4,2.2Hz, 2H), 2.07-2.02
(m, 2H), 1.70-1.51 (m, 2H), 1.27 (t, J = 7.2Hz, 3H)

Example 56: 3- [4-[(5-Amidino-2-benzofuranyl) carbonylamino] piperidino
] Propionic acid (compound (479)) According to the same method as in Example 10, compound (477) 142 mg
(0.367 mmol) was hydrolyzed to obtain 150 mg (95%) of a dihydrochloride of the compound (479) as a colorless solid. Mp:> 250 ℃ IR (KBr) : 3250, 1715, 1660, 1195 cm -1 1 H-NMR (DMSO-d 6, 500MHz)
δ _TMS ： 11.10 (bs, 1H), 9.47 (bs, 2H), 9.25 (bs, 2H),
9.06 (d, J = 7.5Hz, 1H), 8.33 (s, 1H), 7.92 (d, J = 8.8Hz,
1H), 7.89 (d, J = 8.8Hz, 1H), 7.85 (s, 1H), 4.10-4.07
(m, 1H), 3.48-3.23 (m, 4H), 3.13-3.06 (m, 2H), 2.86
(t, J = 7.5Hz, 2H), 2.06-2.01 (m, 4H)

Example 57: 3- [4-[[5- (benzyloxycarbonylamidino) -2-benzofuranyl]
Carbonylamino] piperidino] propionic acid (compound
(475)) According to the same method as in Example 10, compound (472) 150 mg
(0.288 mmol) was hydrolyzed, and the residue was purified by column chromatography (chloroform / methanol = 1/1) to give 110 mg of the hydrochloride of compound (475) as a yellow solid (7
8%). IR (KBr): 3600-2500, 1750 , 1570, 1520 cm -1 1 H-NMR (DMSO-d 6, 500MHz)
δ _TMS ： 9.23 (bs, 2H), 8.84 (d, J = 7.7Hz, 1H), 8.45
(d, J = 1.8Hz, 1H), 8.09 (dd, J = 8.9,1.8Hz, 1H), 7.73 (d, J
= 8.9Hz, 1H), 7.71 (s, 1H), 7.45-7.30 (m, 5H), 5.12 (s,
2H), 4.10-3.90 (bs, 1H), 3.60-3.40 (m, 2H), 3.10-2.95
(m, 2H), 2.90-2.70 (m, 2H), 2.00-1.80 (m, 4H)

Example 58 (1) 5- (Methoxycarbonylamidino) -2-benzofurancarboxylic acid To 100 mg (0.372 mmol) of ethyl 5-amidino-2-benzofurancarboxylate hydrochloride was added 2 ml of methylene chloride, and chlorotoluene was added. 30 μl (0.391 mmol) of methyl carbonate, then 0.2
0.391 ml (0.782 mmol) of an N aqueous sodium hydroxide solution was added at room temperature, followed by vigorous stirring for 10 minutes. Methylene chloride 15
Then, the mixture was washed with water and dried over anhydrous magnesium sulfate. After filtration, low-boiling substances were distilled off from the filtrate under reduced pressure.
88.0 mg (82%) of ethyl (methoxycarbonylamidino) -2-benzofurancarboxylate was obtained as a colorless solid. To 73.0 mg (0.252 mmol) of this, 2 ml of tetrahydrofuran,
2 ml of water and 2 ml (2 mmol) of a 1N aqueous sodium hydroxide solution were added, and the mixture was stirred at room temperature for 1 hour. 1N hydrochloric acid was added to the reaction solution
The pH was adjusted to 2-3, and low-boiling substances were distilled off under reduced pressure to obtain 183 mg of 5- (methoxycarbonylamidino) -2-benzofurancarboxylic acid as a yellow solid (including salt). IR (KBr): 1730, 1680 , 1550, 1240 cm -1 1 H-NMR (DMSO-d 6, 500MHz)
δ _TMS ： 10.40 (s, 1H), 9.59 (bs, 1H), 9.46 (bs, 1H),
8.38-8.35 (m, 1H), 7.98-7.93 (m, 2H), 7.89-7.85 (m, 1
H), 3.86 (s, 3H)

(2) Ethyl 3- [4-[[5- (methoxycarbonylamidino) -2-benzofuranyl] carbonylamino] piperidino] propionate (Compound (473)) Ethyl 3- (4-aminopiperidino) propionate 14 ml of N, N-dimethylformamide and 0.57 ml (5.20 mmol) of N-methylmorpholine were added to 567 mg (2.08 mmol) of the dihydrochloride, and the mixture was stirred at 60 ° C. for 20 minutes under a nitrogen atmosphere. This solution was added to 15 ml of N, N-dimethylformamide with 5- (methoxycarbonylamidino) -2-benzofurancarboxylic acid.
364 mg (1.39 mmol), 1-hydroxy-1H-benzotriazole 207 mg (1.54 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide 294 mg (1.54 mmol)
The mixture was added to l) and stirred at room temperature for 18 hours. 100 ml of water was added to the reaction solution, and the mixture was extracted with ethyl acetate. Extract water with water,
The extract was washed with saturated saline and dried over anhydrous magnesium sulfate. After filtration, low-boiling substances were distilled off from the filtrate under reduced pressure, and the residue was purified by column chromatography (chloroform / methanol = 10/1) to obtain 338 mg (55%) of compound (473) as a yellow solid. . IR (KBr): 1700, 1620 , 1490 cm -1 1 H-NMR (DMSO-d 6, 500MHz)
δ _TMS ： 9.15 (bs, 2H), 8.60 (d, J = 8.0Hz, 1H), 8.41
(d, J = 1.7Hz, 1H), 8.06 (dd, J = 8.5,1.7Hz, 1H), 7.73 (d,
J = 8.5Hz, 1H), 7.65 (s, 1H), 4.07 (q, J = 7.1Hz, 2H), 3.82
-3.72 (m, 1H), 2.93-2.75 (m, 2H), 2.60-2.40 (m, 4H),
2.10-1.93 (m, 2H), 1.80-1.70 (m, 2H), 1.65-1.50 (m, 2
H), 1.19 (t, J = 7.1Hz, 3H)

Example 59 (1) 5-benzylamidino-2-benzofurancarboxylic acid 689 mg (3.68 m) of 5-cyano-2-benzofurancarboxylic acid
mol) was added with 30 ml of ethanol, and hydrogen chloride gas was blown into the mixture under ice cooling for 15 minutes, followed by stirring at room temperature for 16 hours. Low-boiling substances are distilled off from the reaction solution under reduced pressure, and the residue is ethanol 25 ml.
And 1.58 g (14.7 mmol) of benzylamine was added thereto under ice cooling, and the mixture was stirred for 1 hour and at room temperature for 2 hours. Low-boiling substances are distilled off from the reaction solution under reduced pressure, and the residue is purified by silica gel column chromatography (chloroform / methanol = 100/3 to 4/1), and hydrochloric acid of ethyl 5-benzylamidino-2-benzofurancarboxylate is added. 361 mg (30%) of the salt was obtained as a colorless solid. ^{1 H-NMR (DMSO-d} 6, 500MHz)
δ _TMS ： 9.75 (s, 1H), 9.45 (s, 1H), 8.37 (s, 1H), 8.0
4-7.99 (m, 1H), 7.98-7.90 (m, 2H), 7.55-7.45 (m, 5H),
4.75 (d, J = 5.8Hz, 2H), 4.40 (q, J = 7.2Hz, 2H), 1.36 (t, J
= 7.2Hz, 3H)

To 325 mg (1.21 mmol) of ethyl 5-benzylamidino-2-benzofurancarboxylate was added 5 ml of tetrahydrofuran.
ml (5 mmol) was added, and the mixture was stirred at room temperature for 45 minutes. 1 in the reaction solution
N hydrochloric acid was added to adjust the pH to 2-3, low-boiling substances were distilled off under reduced pressure, the precipitate was collected by filtration, washed with water, and hydrochloride of 5-benzylamidino-2-benzofurancarboxylic acid was converted into a colorless solid. 213 mg (53%) were obtained. IR (KBr): 1680, 1635 , 1580, 1400 cm -1 1 H-NMR (DMSO-d 6, 500MHz)
δ _TMS : 10.40 (s, 1H), 9.69 (s, 1H), 9.37 (s, 1H), 8.
28 (d, J = 1.6Hz, 1H), 7.97 (d, J = 8.8Hz, 1H), 7.89 (dd, J =
(8.8,1.6Hz, 1H), 7.85 (s, 1H), 7.50-7.30 (m, 5H), 4.73
(d, J = 5.7Hz, 2H)

(2) Ethyl 3- [4-[(5-benzylamidino-2-benzofuranyl) carbonylamino] piperidino] propionate (Compound (474)) Benzylamidino-2-benzofurancarboxylic acid 210mg (0.635mmo
l) was condensed with 173 mg (0.635 mmol) of ethyl 3- (4-aminopiperidino) propionate dihydrochloride to give compound (474)
To give 160 mg (53%) as a yellow solid. IR (KBr): 1695, 1625 , 1580, 1500, 1430 cm -1 1 H-NMR (DMSO-d 6, 500MHz)
δ _TMS ： 8.54 (d, J = 8.0Hz, 1H), 8.20 (s, 1H), 8.00-7.9
0 (m, 1H), 7.64 (d, J = 8.7Hz, 1H), 7.58 (s, 1H), 7.43
(d, J = 7.4Hz, 1H), 7.33 (dd, J = 7.4Hz, 1H), 7.21 (t, J = 7.4
Hz, 1H), 4.37 (s, 2H), 4.06 (q, J = 7.1Hz, 2H), 3.80-3.70
(m, 1H), 3.00-2.80 (m, 2H), 2.60-2.45 (m, 4H), 2.08-
1.97 (t, J = 8.5Hz, 2H), 1.80-1.70 (m, 2H), 1.68-1.57
(m, 2H), 1.19 (t, J = 7.1Hz, 3H)

Example 60: 3- [4-[(5-Benzylamidino-2-benzofuranyl) carbonylamino] piperidino] propionic acid (compound (476)) 140 mg of compound (474) according to the same method as in Example 10.
(0.294 mmol) was hydrolyzed to obtain 150 mg (98%) of a dihydrochloride of the compound (476) as a yellow solid. Mp: 181~184 ℃ IR (KBr): 1710, 1620, 1520 cm -1 1 H-NMR (DMSO-d 6, 500MHz)
δ _TMS : 10.46 (s, 1H), 9.73 (s, 1H), 9.42 (s, 1H), 9.
09 (d, J = 7.5Hz, 1H), 8.31 (s, 1H), 7.90 (d, J = 8.8Hz, 1
H), 7.87 (d, J = 8.7Hz, 1H), 7.83 (s, 1H), 7.49 (d, J = 7.4
Hz, 2H), 7.43 (t, J = 7.4Hz, 2H), 7.35 (t, J = 7.4Hz, 1H),
4.75 (d, J = 5.8Hz, 2H), 4.14-4.00 (m, 1H), 3.55-3.40
(m, 2H), 3.30-3.18 (m, 2H), 3.15-3.05 (m, 2H), 2.89
(t, J = 8.1Hz, 2H), 2.13-1.95 (m, 4H)

Example 61 (1) di-tert-butyl cis- and trans- (4-aminocyclohexylamino) diacetate 24.0 g (210 mmol) of 1,4-diaminocyclohexane (a mixture of cis and trans) and 16.3 ml of triethylamine (117 mm
ol) was dissolved in 400 ml of methylene chloride. 32.5 g (117 mmol) of triphenylmethyl chloride was added to 100 ml of methylene chloride.
Was added dropwise under ice cooling, and the mixture was stirred for 15 minutes at room temperature and for 45 minutes at room temperature. The reaction solution was filtered, low-boiling substances were distilled off from the filtrate under reduced pressure, 100 ml of water was added to the residue, extracted with chloroform, and the extract was dried over anhydrous sodium sulfate.
After filtration, low-boiling substances are distilled off from the filtrate under reduced pressure, and the residue is silica gel (Chromatorex, NH type, Fuji Silysia Chemical)
Purification by column chromatography (chloroform / n-hexane = 5/1 to 10/1) gave 1-amino-4-
18.4 g (25%) of (triphenylmethylamino) cyclohexane was obtained as a pale yellow oil. 18.4 g of 1-amino-4- (triphenylmethylamino) cyclohexane (51.7 m
mol) and 15.0 g (108.6 mmol) of potassium carbonate were added to 250 ml of N, N-dimethylformamide.
20.7 g (106.0 mmol) of butyl was added dropwise under ice cooling, and
And stirred at room temperature for 2.5 hours. Thereafter, 14.8 ml (106 mmol) of triethylamine was added, and the mixture was stirred for 1.5 hours. The reaction solution was filtered, 500 ml of water was added to the filtrate, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, low-boiling substances were distilled off from the filtrate under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 50/1 to 5/1) to obtain trans- [4- (tri Phenylmethylamino) cyclohexylamino] di-t-butyl diacetate as a colorless solid 3.56 g (12%), cis- [4- (Triphenylmethylamino) cyclohexylamino] di-t-butyl diacetate as pale yellow viscous oil 16.23 g (54%).

Trans- [4- (triphenylmethylamino) cyclohexylamino] di-t-butyl diacetate 3.46
g (5.92 mmol) in 100 ml of methanol and add 10%
0.75 g of palladium carbon was added, and the mixture was heated and refluxed for 7 hours under a hydrogen atmosphere. The reaction solution was filtered through celite, low-boiling substances were distilled off from the filtrate under reduced pressure, 30 ml of 1N hydrochloric acid and 50 ml of water were added to the residue, and the mixture was washed with diethyl ether. And extracted with chloroform, and the extract was dried over anhydrous sodium sulfate. After filtration, low-boiling substances are distilled off from the filtrate under reduced pressure, and trans- (4-aminocyclohexylamino) diacetate di-t
2.13 g (quantitative) of -butyl was obtained as a pale yellow oil.

Similarly, di-t-butyl cis- (4-aminocyclohexylamino) diacetate was converted from 135 mg (0.165 mmol) of di-t-butyl cis- [4- (triphenylmethylamino) cyclohexylamino] diacetate. 89 mg (quantitative) were obtained as a colorless oil. Trans IR (CHCl ₃ ): 2910, 1725, 1590, 1480, 1442
^{cm -1 1 H-NMR (CDCl} 3) δ TMS: 3.45 (s, 4H), 2.78
-2.50 (m, 2H), 2.00-1.80 (m, 4H), 1.45 (s, 18H), 1.65-
0.95 (m, 4H) cis IR (neat): 2975, 2925, 2850, 1730, 1670, 1
450, 1390, 1365,1250, 1215, 1150 cm -1 1 H-NMR (CDCl 3) δ TMS: 3.46 (s, 4H), 2.98
-2.68 (m, 2H), 1.85-1.18 (m, 8H), 1.45 (s, 18H)

(2) trans- [4-[[5- (benzyloxycarbonylamidino) -2-benzofuranyl]
Carbonylamino] cyclohexylamino] diacetate dit
-Butyl (compound (489)) According to the same method as in Example 17 (3), 2.04 g (6.04 mmol) of 5- (benzyloxycarbonylamidino) -2-benzofurancarboxylic acid and trans- (4-aminocyclohexylamino) 2.07 g (6.04 mmol) of di-t-butyl diacetate
Was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1/2 to 2/1) to obtain 2.04 g (51%) of compound (489) as a colorless solid. IR (KBr): 3700-3000, 2910, 1722, 1657, 161
^{8, 1587, 1510 cm -1 1} H-NMR (CDCl 3) δ TMS: 8.23 (d, J = 1.5Hz, 1
H), 7.95 (dd, J = 8.8,1.9Hz, 1H), 7.60-7.25 (m, 7H), 6.4
1 (d, J = 8.3Hz, 1H), 5.23 (s, 2H), 4.05-3.80 (m, 1H),
3.47 (s, 4H), 2.95-2.60 (m, 1H), 2.25-1.90 (m, 4H), 1.
46 (s, 18H), 1.60-1.15 (m, 4H)

Example 62: trans- [4-[(5-Amidino-2-benzofuranyl) carbonylamino] cyclohexylamino] di-tert-butyl diacetate (compound (491)) Compound (489) 1.60 g (2.41 mmol) To t-butanol 100 ml
And 0.56 g of 10% palladium carbon was added thereto, and the mixture was heated under reflux in a hydrogen atmosphere for 14 hours. The reaction solution was filtered through celite, low-boiling substances were distilled off from the filtrate under reduced pressure, and the residue was subjected to silica gel (Chromatorex, NH type, Fuji Silysia Chemical) column chromatography (chloroform / methanol =
Purification by 5/1 to 3/1) yielded 1.20 g (94%) of compound (491) as a light brown solid. Melting point: 78-81 ° C IR (KBr): 3700-3000, 2960, 2910, 1725, 163
^{8, 1590, 1570, 1520cm -1} 1 H-NMR (CDCl 3) δ TMS: 7.93 (s, 1H), 7.69
(d, J = 8.3Hz, 1H), 7.52 (d, J = 8.8Hz, 1H), 7.47 (s, 1H),
6.44 (d, J = 6.2Hz, 1H), 4.07-3.85 (m, 1H), 3.47 (s, 4
H), 2.88-2.65 (m, 1H), 2.28-1.95 (m, 4H), 1.46 (s, 18
H), 1.60-1.15 (m, 4H)

Example 63: trans- [4-[(5-Amidino-2-benzofuranyl) carbonylamino] cyclohexylamino] diacetate (Compound (492)) g (2.2
(2 mmol) was treated with 14 ml of trifluoroacetic acid to give compound (492)
1.11 g (77%) of ditrifluoroacetate as a colorless solid
Obtained. IR (KBr): 3700-2500, 1658, 1592, 1528, 1450
^{cm -1 1 H-NMR (DMSO} -d 6) δ TMS: 9.37 (bs, 2H),
9.17 (bs, 2H), 8.69 (d, J = 8.1Hz, 1H), 8.28 (s, 1H), 7.
92 (d, J = 8.7Hz, 1H), 7.85 (dd, J = 8.8,1.7Hz, 1H), 7.71
(s, 1H), 3.81 (s, 4H), 3.10-2.90 (m, 1H), 2.10-1.72
(m, 4H), 1.65-1.30 (m, 4H)

Compound (492) ditrifluoroacetate (200 m)
10 g of acetic acid was added to g (0.310 mmol), and 1.63 g (16.95 mmol) of methanesulfonic acid was added while heating to 70 ° C.
When the reaction solution was transparently dissolved, the temperature was returned to room temperature, 50 ml of diethyl ether was added, and the precipitated precipitate was washed with diethyl ether and tetrahydrofuran in this order, and collected by filtration. As 2
14 mg (quantitative) were obtained. Melting point:> 250 ° C IR (KBr): 3700-2100, 1720, 1680, 1635, 160
^{0, 1585, 1530 cm -1 1} H-NMR (DMSO-d 6, 500MHz)
δ _TMS : 9.36 (s, 2H), 8.98 (s, 2H), 8.74 (d, J = 8.1Hz,
1H), 8.29 (d, J = 1.5Hz, 1H), 7.91 (d, J = 8.8Hz, 1H), 7.86
(dd, J = 8.8,1.8Hz, 1H), 7.72 (s, 1H), 4.18 (s, 4H), 3.9
7-3.85 (m, 1H), 3.48-3.35 (m, 1H), 2.36 (s, 6H), 2.10-
1.90 (m, 4H), 1.80-1.45 (m, 4H)

Example 64 Diethyl trans- [4-[(5-amidino-2-benzofuranyl) carbonylamino] cyclohexylamino] diacetate (Compound (490)) 131 mg (0.216 g) of the dimethanesulfonic acid salt of Compound (492) mmo
l) in ethanol 8ml and methanesulfonic acid 654mg (6.80mm
ol) and heated to reflux for 6 hours. The reaction solution was returned to room temperature, and diethyl ether (40 ml) was added.The precipitated precipitate was washed with diethyl ether and tetrahydrofuran in this order, and collected by filtration to obtain 75 mg (52%) of a dimethanesulfonic acid salt of compound (490) as a colorless solid. Was. Melting point: 100-102 ° C IR (KBr): 3700-2500, 1738, 1640, 1592, 157
^{0, 1525, 1450 cm -1 1} H-NMR (DMSO-d 6) δ TMS: 9.37 (bs, 2H),
9.10 (bs, 2H), 8.76 (d, J = 8.2Hz, 1H), 8.30 (s, 1H), 8.
00-7.80 (m, 2H), 7.73 (s, 1H), 4.26 (s, 4H), 4.24 (q,
J = 7.1Hz, 4H), 3.55-3.40 (m, 1H), 2.37 (s, 6H), 2.12-1.
83 (m, 4H), 1.80-1.35 (m, 4H), 1.26 (t, J = 7.1Hz, 6H)

Example 65: cis- [4-[(5-Amidino-2-benzofuranyl) carbonylamino] cyclohexylamino] diacetate (compound (493)) According to a method similar to that of Example 17 (3), 27.8 mg (0.0822 mmol) of (benzyloxycarbonylamidino) -2-benzofurancarboxylic acid and 27.6 mg (0.0806 mm) of di-t-butyl cis- (4-aminocyclohexylamino) diacetate
ol) was condensed to obtain 34.0 mg (64%) of tert-butyl cis- [4-[[5- (benzyloxycarbonylamidino) -2-benzofuranyl] carbonylamino] cyclohexylamino] diacetate as a colorless oil. . 34.0mg of this
(0.0513 mmol) was reduced by hydrogen in the same manner as in Example 62. mg (quantitative). 0.8m of methylene chloride was added to 28.4mg (0.0513mmol) of this product
l and 0.8 ml of trifluoroacetic acid were added, and the mixture was stirred at room temperature for 3 hours. The low-boiling substances were distilled off from the reaction solution under reduced pressure, and the residue was dissolved in 4 ml of water and freeze-dried to obtain 29.3 mg (89%) of a ditrifluoroacetic acid salt of compound (493) as a colorless solid. IR (KBr): 3350, 1665, 1520, 1450, 1320, 126
^{5, 1195, 1130 cm -1 1} H-NMR (DMSO-d 6, 500MHz)
δ _TMS ： 9.37 (s, 2H), 9.19 (s, 2H), 8.55 (d, J = 7.6Hz,
1H), 8.29 (s, 1H), 7.94 (d, J = 8.8Hz, 1H), 7.86 (dd, J =
8.8,1.8Hz, 1H), 7.78 (s, 1H), 4.09 (s, 1H), 3.84 (s, 4
H), 3.13 (s, 1H), 1.86 (m, 2H), 1.76 (m, 2H), 1.70 (b
s, 2H), 1.61 (m, 2H)

Example 66 (1) trans- [4-aminocyclohexyl-N-
(T-butoxycarbonyl) amino] t-butyl trans-4- (triphenylmethylamino) cyclohexylamine 2.73 g (7.66 mmol) and potassium carbonate 2.22 g (1
6.08 mmol) was added to 100 ml of N, N-dimethylformamide, and 1.57 g (8.04 mmol) of t-butyl bromoacetate was added dropwise under ice-cooling, followed by stirring for 30 minutes at room temperature and 30 minutes at room temperature. The reaction mixture was filtered, 200 ml of water was added to the filtrate, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. After filtration, low-boiling substances are distilled off from the filtrate under reduced pressure, and the residue is subjected to silica gel column chromatography (n-hexane / ethyl acetate = 20/1 to 1/1).
) To give 2.98 g (83%) of t-butyl trans- [4- (triphenylmethylamino) cyclohexylamino] acetate as a colorless solid. 2.40g (5.1
0 mmol), 0.31 g of 4-dimethylaminopyridine (2.55 mmo
l) and 0.81 g (10.20 mmol) of pyridine were dissolved in 40 ml of methylene chloride, and a solution of 1.17 g (5.35 mmol) of di-t-butyl dicarbonate dissolved in 10 ml of methylene chloride was added dropwise thereto under ice-cooling. Stirred for hours. 100 ml of water and 20 ml of 1N hydrochloric acid were added to the reaction solution.
The mixture was added with ml, extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate. After filtration, low-boiling substances were distilled off from the filtrate under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 10/1 to 5/1) to obtain trans- [4- (tri Phenylmethylamino) cyclohexyl-N- (t-butoxycarbonyl)
Amino] t-butyl acetate as a colorless solid 1.82 g (63%)
Obtained. 1.82 g (3.19 mmol) of this product was dissolved in 60 ml of ethanol, 0.40 g of 10% palladium carbon was added thereto, and the mixture was heated under reflux in a hydrogen atmosphere for 16 hours. The reaction solution was filtered through celite, and low-boiling substances were distilled off from the filtrate under reduced pressure.
And 1N hydrochloric acid (10 ml), and the mixture was extracted with diethyl ether. The aqueous layer was made alkaline with saturated aqueous sodium hydrogen carbonate, extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate. After filtration, low-boiling substances were distilled off from the filtrate under reduced pressure.
[4-Aminocyclohexyl-N- (t-butoxycarbonyl) amino] t-butyl acetate was used as a pale yellow solid in 0.1 ml.
67 g (64%) were obtained. IR (KBr): 3400, 2900 , 1738, 1690, 1435 cm -1 1 H-NMR (CDCl 3) δ TMS: 4.15-3.90 (m, 1H),
3.65 (s, 2H), 2.70-2.45 (m, 1H), 2.00-1.70 (m, 4H),
1.46 (s, 9H), 1.44 (s, 9H), 1.55-0.80 (m, 4H)

(2) trans- [4-[(5-amidino-2-benzofuranyl) carbonylamino] cyclohexyl-N- (t-butoxycarbonyl) amino] acetic acid t
-Butyl (compound (482)) According to the same method as in Example 17 (3), 690 mg (2.04 mmol) of 5- (benzyloxycarbonylamidino) -2-benzofurancarboxylic acid and trans- [4-aminocyclohexyl-N- (T-butoxycarbonyl) amino] 670 mg (2.04 mmol) of t-butyl acetate was condensed, and silica gel column chromatography (n-hexane / ethyl acetate =
2/3) and t-butyl trans- [4-[[5- (benzyloxycarbonylamidino) -2-benzofuranyl] carbonylamino] cyclohexyl-N- (t-butoxycarbonyl) amino] acetate was converted to a colorless solid. 493 mg (37%). IR (KBr): 3600-3100, 2910, 1740, 1650, 162
^{0, 1585, 1510, 1438cm -1} 1 H-NMR (CDCl 3) δ TMS: 10.2-9.70 (br, 2
H), 8.21 (d, J = 1.6Hz, 1H), 7.95 (dd, J = 8.8,1.6Hz, 1H),
7.55-7.25 (m, 7H), 6.54 (d, J = 8.3Hz, 1H), 5.22 (s, 2
H), 4.25-4.02 (m, 1H), 4.02-3.75 (m, 1H), 3.68 (s, 2
H), 2.25-1.75 (m, 4H), 1.48 (s, 9H), 1.45 (s, 9H), 1.6
0-0.80 (m, 4H)

Trans- [4-[[5- (benzyloxycarbonylamidino) -2-benzofuranyl] carbonylamino] cyclohexyl-N- (t-butoxycarbonyl) amino] t-butyl acetate 482 mg (0.743 mmol) in ethanol 20 ml Dissolved in 10% palladium on carbon 15
0 mg was added, and the mixture was refluxed for 16 hours under a hydrogen atmosphere. The reaction solution was filtered through celite, low-boiling substances were distilled off from the filtrate under reduced pressure, and the residue was purified by silica gel (Chromatorex, NH type, Fuji Silysia Chemical) column chromatography (chloroform / methanol = 5/1). 328 mg (86%) of compound (482) was obtained as a pale yellow solid. IR (KBr): 3600-3000, 2920, 1735, 1635, 159
^{0, 1520, 1432 cm -1 1} H-NMR (CDCl 3) δ TMS: 7.94 (s, 1H), 7.70
(d, J = 8.9Hz, 1H), 7.52 (m, 1H), 7.45 (s, 1H), 6.75-6.3
0 (m, 1H), 5.20-4.30 (m, 3H), 4.30-4.03 (m, 1H), 4.03-
3.80 (m, 1H), 3.68 (s, 2H), 2.30-1.70 (m, 4H), 1.48
(s, 9H), 1.45 (s, 9H), 1.70-0.80 (m, 4H)

Example 67: trans- [4-[(5-Amidino-2-benzofuranyl) carbonylamino] cyclohexylamino] acetic acid (compound (483)) 216 mg (0.420 mmol) of compound (482) was dissolved in 8 ml of methylene chloride. Then, 4 ml of trifluoroacetic acid was added thereto, and the
Stirred for hours. The reaction solution was concentrated to about 1/3 under reduced pressure, 50 ml of diethyl ether was added, and the deposited precipitate was washed with diethyl ether, collected by filtration, and 219 mg of the ditrifluoroacetic acid salt of compound (483) was obtained as a colorless solid. (89%). IR (KBr): 3600-2600, 1665 , 1530, 1450 cm -1 1 H-NMR (DMSO-d 6, 500MHz)
δ _TMS : 9.37 (bs, 2H), 9.21 (bs, 2H), 8.96 (bs, 2H),
8.74 (d, J = 8.0Hz, 1H), 8.29 (d, J = 1.8Hz, 1H), 7.91 (d, J
= 8.8Hz, 1H), 7.86 (dd, J = 8.8,1.8Hz, 1H), 7.72 (s, 1H),
3.94 (s, 2H), 3.83-3.70 (m, 1H), 3.12-3.00 (m, 1H), 2.
20-2.00 (m, 2H), 2.00-1.88 (m, 2H), 1.56-1.37 (m, 4H)

Compound (483) ditrifluoroacetate (200 m)
g (0.341 mmol) in 10 ml of acetic acid and 148 mg of methanesulfonic acid
(1.54 mmol) was added, and the mixture was stirred at 50 ° C. until the reaction solution was transparently dissolved. The reaction solution is returned to room temperature, and diethyl ether 50
The precipitated precipitate was washed with diethyl ether and collected by filtration.
g (75%). ¹ H-NMR (DMSO-d ₆ ) δ _TMS : 9.36 (bs, 2H),
9.08 (bs, 2H), 8.91 (bs, 2H), 8.75 (d, J = 8.1Hz, 1H),
8.30 (s, 1H), 7.92 (d, J = 8.8Hz, 1H), 7.85 (dd, J = 8.8,
1.7Hz, 1H), 7.73 (s, 1H), 3.94 (bs, 2H), 3.90-3.65 (m,
1H), 3.20-2.95 (m, 1H), 2.36 (s, 6H), 2.27-1.80 (m, 4
H), 1.70-1.30 (m, 4H)

Example 68: (S) -3- [4-[(5-
Ethyl amidino-2-benzofuranyl) carbonylamino] phenyl] -2- (n-butylsulfonylamino) propionate (compound (94)) According to the same method as in Example 17 (3), 5- (benzyloxycarbonyl)- 2-benzofurancarboxylic acid 462
mg (1.36 mmol) and (S) -3- (4-aminophenyl)
448 mg (1.36 mmol) of ethyl-2- (n-butylsulfonylamino) propionate was condensed to give (S) -3- [4-
[[5- (benzyloxycarbonylamidino) -2-
Benzofuranyl] carbonylamino] phenyl] -2-
886 mg (quantitative) of ethyl (n-butylsulfonylamino) propionate was obtained as a colorless solid. 830mg of this
(1.28 mmol) in ethanol 20 ml, chloroform 100 ml, 10
% 260 mg of palladium carbon and 2 ml of 1N hydrochloric acid were added, and the mixture was stirred at room temperature for 30 hours under a hydrogen atmosphere. The reaction solution was filtered, low-boiling substances were distilled off from the filtrate under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform / methanol = 9).
To give 524 mg (74%) of the hydrochloride salt of compound (94) as a colorless solid. ¹ H-NMR (DMSO-d ₆ ) δ _TMS : 10.72 (bs, 1
H), 9.33 (bs, 4H), 8.38 (d, J = 1.5Hz, 1H), 8.03 (s, 1
H), 7.97 (d, J = 10.0Hz, 1H), 7.93 (dd, J = 10,1.5Hz, 1H),
7.78 (d, J = 8.4Hz, 2H), 7.29 (d, J = 8.4Hz, 2H), 4.16-4.05
(m, 3H), 2.97 (dd, J = 13.6,5.9Hz, 1H), 2.85 (dd, J = 13.
6,9.3Hz, 1H), 2.68 (t, J = 6.8Hz, 2H), 1.41-1.13 (m, 7
H), 0.76 (t, J = 7.0Hz, 3H)

Example 69 (1) Ethyl (S) -3- (4-aminophenyl) -2- (benzyloxycarbonylamino) propionate (S) -2-amino-3- (4-nitrophenyl) propion 1.00 g (3.64 mmol) of ethyl acid hydrochloride was added to 10 ml of tetrahydrofuran, 10 ml of water, and a 1N aqueous solution of sodium hydroxide.
Dissolve in 64 ml of a mixture, and add 0.57 ml (3.99 mmol) of benzyloxycarbonyl chloride to 3.5 m of tetrahydrofuran.
solution and 1N aqueous solution of sodium hydroxide 3.64ml
(3.64 mmol) was simultaneously added dropwise under ice-cooling, followed by stirring at room temperature for 4 hours. 30 ml of saturated aqueous layer was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. After filtration, low-boiling substances were distilled off from the filtrate under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 1/1) to give (S) -2- (benzyloxycarbonylamino). ) Ethyl-3- (4-nitrophenyl) propionate as a colorless solid was obtained as 743 mg (55%). 724mg of this
(1.94 mmol) was dissolved in a mixture of 120 ml of ethanol and 30 ml of water, and 6.40 g (97.9 mmol) of zinc and 2.00 of calcium chloride were added thereto.
g (18.0 mmol) was added and the mixture was heated under reflux for 3.5 hours. The reaction solution was returned to room temperature and filtered. The filtrate was concentrated, 100 ml of water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. After filtration, low-boiling substances were distilled off from the filtrate under reduced pressure, and 572 mg (86%) of ethyl (S) -3- (4-aminophenyl) -2- (benzyloxycarbonylamino) propionate was obtained as a pale yellow oil. ) Obtained. IR (neat): 3320, 1710 , 1620, 1510 cm -1 1 H-NMR (CDCl 3) δ TMS: 7.34-7.29 (m, 5H),
6.88 (d, J = 8.4Hz, 2H), 6.58 (d, J = 8.4Hz, 2H), 5.21 (d,
J = 8.0Hz, 1H), 5.09 (s, 2H), 4.62-4.52 (m, 1H), 4.16
(q, J = 7.1Hz, 2H), 2.99 (d, J = 5.7Hz, 2H), 1.24 (t, J = 7.1H
(z, 3H)

(2) (S) -3- [4-[(5-Amidino-2-benzofuranyl) carbonylamino] phenyl
Ethyl 2- (benzyloxycarbonylamino) propionate (Compound (95)) Hydrochloride salt of 5-amidino-2-benzofurancarboxylic acid 38
7 mg (1.61 mmol) and (S) -3- (4-aminophenyl)
550 mg (1.61 mmol) of ethyl-2- (benzyloxycarbonylamino) propionate was added to 20 ml of N, N-dimethylformamide, and diisopropylcarbodiimide was added thereto.
0.30 ml (1.94 mmol) and 260 mg (1.92 mmol) of 1-hydroxy-1H-benzotriazole were added, and the mixture was added at room temperature for 12 hours.
Stirred at 60 ° C. for 4 hours. N, N-dimethylformamide was distilled off from the reaction solution under reduced pressure, and the residue was silica gel (Ch.
romatorex, NH type, Fuji Silysia Chemical) column chromatography (chloroform / methanol = 9/1), to which 10 ml of an ethanol solution of hydrochloric acid was added to form a hydrochloride, and low-boiling substances were distilled off from this solution under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 5/2) to give compound (95)
Afforded 343 mg (38%) of the hydrochloride salt as a pale yellow solid. IR (KBr): 3200, 1710 , 1660, 1600, 1520 cm -1 1 H-NMR (DMSO-d 6) δ TMS: 10.72 (bs, 1
H), 9.40 (bs, 4H), 8.39 (s, 1H), 8.06-7.78 (m, 4H), 7.
75 (d, J = 8.3Hz, 2H), 7.35-7.24 (m, 7H), 5.00 (s, 2H),
4.31-4.19 (m, 1H), 4.09 (q, J = 7.1Hz, 2H), 3.09-2.81
(m, 2H), 1.14 (t, J = 7.1Hz, 3H)

Example 70: (S) -3- [4-[(5-
Amidino-2-benzofuranyl) carbonylamino] phenyl] ethyl 2-aminopropionate (compound (9
8)) 335 mg (0.593 mmol) of the hydrochloride of compound (95) was dissolved in 40 ml of an equal volume mixture of ethanol and methanol, 100 mg of 10% palladium on carbon was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 15 hours. The reaction solution was filtered, and low-boiling substances were distilled off from the filtrate under reduced pressure.
9 mg (94%) were obtained. IR (KBr): 3150, 1720 , 1660, 1600, 1520 cm -1 1 H-NMR (DMSO-d 6) δ TMS: 10.70 (bs, 1
H), 9.33 (bs, 4H), 8.38 (d, J = 1.7Hz, 1H), 8.03 (s, 1
H), 7.98 (d, J = 9.0Hz, 1H), 7.92 (dd, J = 9.0,1.7Hz, 1H),
7.73 (d, J = 8.5Hz, 2H), 7.19 (d, J = 8.5Hz, 2H), 4.04 (q, J
= 7.1Hz, 2H), 3.60-3.53 (m, 1H), 2.85-2.76 (m, 2H), 1.1
4 (t, J = 7.1Hz, 3H)

Example 71: (S) -3- [4-[(5-
Amidino-2-benzofuranyl) carbonylamino] phenyl] -2-aminopropionic acid (compound (99)) According to the same method as in Example 10, monohydrochloride of compound (98)
Hydrolysis of 224 mg (0.520 mmol) gave 103 mg (45%) of the dihydrochloride of compound (99) as a colorless solid. Mp:> 250 ℃ IR (KBr) : 3200, 1680, 1650, 1600, 1520 cm -1 1 H-NMR (DMSO-d 6, 500MHz)
δ _TMS ： 10.76 (s, 1H), 9.37 (bs, 4H), 8.38 (s, 1H),
8.05 (s, 1H), 7.97-7.91 (m, 2H), 7.76 (d, J = 8.6Hz, 2H),
7.29 (d, J = 8.6Hz, 2H), 3.58-3.56 (m, 1H), 3.14 (dd, J =
14.4,4.8Hz, 2H), 2.97 (dd, J = 14.4,2.9Hz, 2H)

Example 72 (1) (S) -3- (4-aminophenyl) -2- [3
-(4-methoxyphenyl) propionylamino] ethyl propionate 1.36 g of 3- (4-hydroxyphenyl) propionic acid
(8.18 mmol) and methyl iodide (1.20 ml, 19.3 mmol) in N, N
-Dissolved in 20 ml of dimethylformamide, and 3.40 g (24.6 mmol) of potassium carbonate was added thereto, followed by stirring at 50 to 60 ° C for 4 hours and further at room temperature for 14 hours. The reaction solution was filtered, the filtrate was added to 100 ml of a saturated saline solution, extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. After filtration, low-boiling substances were distilled off from the filtrate under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 4/1) to give methyl 3- (4-methoxyphenyl) propionate. Was obtained as a colorless solid (1.35 g, 85%). This one 1.30
g (6.69 mmol) was dissolved in tetrahydrofuran (10 ml), 1N aqueous sodium hydroxide solution (7.0 ml, 7.0 mmol) was added thereto, and the mixture was stirred at room temperature for 2 hours. Add 1N hydrochloric acid to the reaction solution and adjust the pH.
The precipitate was collected by filtration, washed with water, and treated with 3- (4-
Methoxyphenyl) propionic acid as a colorless solid 1.11
g (92%).

Next, 330 mg (1.83 mmol) of 3- (4-methoxyphenyl) propionic acid and (S) -2-amino-3-
Hydrochloride of ethyl (4-nitrophenyl) propionate 50
0 mg (1.82 mmol) was dissolved in 30 ml of N, N-dimethylformamide, and 1- (3-dimethylaminopropyl)-
384 mg (2.00 mmol) of 3-ethylcarbodiimide, 270 mg (2.00 mmol) of 1-hydroxy-1H-benzotriazole,
0.25 ml (2.27 mmol) of N-methylmorpholine was added, and the mixture was stirred at room temperature for 21 hours. 100 ml of water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous magnesium sulfate. After filtration, low-boiling substances were distilled off from the filtrate under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 2/1) to give (S) -2- [3- (4 -Methoxyphenyl) propionylamino] -3- (4-nitrophenyl) propionate ethyl ester was obtained as a colorless solid (292 mg, 40%). 280 mg (0.699 mmol) of this was dissolved in 30 ml of ethanol, and 100 mg of 10% palladium on carbon was added thereto.
The mixture was refluxed for 14 hours. The reaction solution was returned to room temperature and filtered. Low-boiling substances were distilled off from the filtrate under reduced pressure, and the residue was subjected to silica gel column chromatography (n-hexane / ethyl acetate = 1).
/ 1 to 3/7) and ethyl (S) -3- (4-aminophenyl) -2- [3- (4-methoxyphenyl) propionylamino] propionate as a colorless solid (171 mg, 66%). Obtained. IR (KBr): 3350, 3300, 3200, 1740, 1640, 151
^{0, 1250 cm -1 1 H-} NMR (CDCl 3) δ TMS: 7.11 (d, J = 8.6Hz, 2
H), 6.82 (d, J = 8.6Hz, 2H), 6.73 (d, J = 8.4Hz, 2H), 6.55
(d, J = 8.4Hz, 2H), 5.80 (d, J = 7.7Hz, 1H), 4.83-4.74 (m,
1H), 4.15 (q, J = 7.1Hz, 2H), 3.78 (s, 3H), 3.59 (bs, 2
H), 2.97-2.85 (m, 4H), 2.49-2.39 (m, 2H), 1.25 (t, J =
(7.1Hz, 3H)

(2) (S) -3- [4-[(5-Amidino-2-benzofuranyl) carbonylamino] phenyl
] -2-Ethyl 3- [3- (4-methoxyphenyl) propionylamino] propionate (Compound (96)) 151 mg (0.447 mmol) of 5- (benzyloxycarbonylamidino) -2-benzofurancarboxylic acid and (S) -3 −
Ethyl (4-aminophenyl) -2- [3- (4-methoxyphenyl) propionylamino] propionate 165m
g (0.445 mmol) was dissolved in N, N-dimethylformamide (10 ml), and PyBOP (benzotriazol-1-yl-oxy-tris (pyrrolidino) phosphonium hexafluorophosphate) (225 mg, 0.490 mmol) and N-methylmorpholine 0.05 ml (0.455 mmol) was added, and the mixture was stirred at room temperature for 15 hours. 20 ml of water was added to the reaction solution, and the precipitate was collected by filtration, washed with water, and treated with (S) -3- [4-[[5- (benzyloxycarbonylamidino) -2-benzofuranyl] carbonylamino] phenyl]-. 271 mg (88%) of ethyl 2- [3- (4-methoxyphenyl) propionylamino] propionate was obtained as a colorless solid. IR (KBr): 3300, 1730, 1650, 1620, 1580, 151
^{0, 1250 cm -1 1 H-} NMR (DMSO-d 6) δ TMS: 10.56 (s, 1H),
9.26 (bs, 2H), 8.30 (d, J = 7.7Hz, 1H), 8.11 (dd, J = 8.9,
1.8Hz, 1H), 7.86 (s, 1H), 7.81 (d, J = 8.9Hz, 1H), 7.71
(d, J = 8.5Hz, 2H), 7.44-7.32 (m, 5H), 7.19 (d, J = 8.5Hz,
2H), 7.06 (d, J = 8.6Hz, 2H), 6.79 (d, J = 8.6Hz, 2H), 5.14
(s, 2H), 4.48-4.40 (m, 1H), 4.06 (q, J = 7.1Hz, 2H), 3.6
9 (s, 3H), 3.00-2.87 (m, 2H), 2.69 (t, J = 7.0Hz, 2H), 2.
35 (t, J = 7.0Hz, 2H), 1.13 (t, J = 7.1Hz, 3H)

According to a method similar to that in Example 19, (S)-
267 mg (0.387 mmol) of ethyl 3- [4-[[5- (benzyloxycarbonylamidino) -2-benzofuranyl] carbonylamino] phenyl] -2- [3- (4-methoxyphenyl) propionylamino] propionate was converted to hydrogen The reduction gave 230 mg (quantitative) of the hydrochloride salt of compound (96). ¹ H-NMR (DMSO-d ₆ ) δ _TMS : 10.84 (s, 1H),
9.60 (bs, 2H), 9.44 (bs, 2H), 8.42 (s, 1H), 8.38 (d, J
= 6.9Hz, 1H), 8.15 (s, 1H), 7.97 (s, 2H), 7.78 (d, J = 8.
5Hz, 2H), 7.20 (d, J = 8.5Hz, 2H), 7.06 (d, J = 8.5Hz, 2H),
6.80 (d, J = 8.5Hz, 2H), 4.48-4.40 (m, 1H), 4.06 (q, J = 7.
1Hz, 2H), 3.69 (s, 3H), 3.11-2.89 (m, 2H), 2.69 (t, J =
7.2Hz, 2H), 2.36 (t, J = 7.2Hz, 2H), 1.13 (t, J = 7.1Hz, 3
H)

Example 73: (S) -3- [4-[(5-
Amidino-2-benzofuranyl) carbonylamino] phenyl] -2- [3- (4-methoxyphenyl) propionylamino] propionic acid (compound (128)) According to the same method as in Example 10, hydrochloride of compound (96) twenty three
Hydrolysis of 0 mg (0.387 mmol) gave 96 mg (44%) of the hydrochloride of compound (128) as a colorless solid. Mp: 187~191 ℃ (decomposition) IR (KBr): 3200, 1710, 1640, 1560, 1510 cm -1 1 H-NMR (DMSO-d 6) δ TMS: 10.70 (s, 1H),
9.74 (bs, 2H), 9.37 (bs, 2H), 8.37 (s, 1H), 8.10 (d, J
= 7.0Hz, 1H), 8.00-7.87 (m, 3H), 7.72 (d, J = 8.5Hz, 2H),
7.20 (d, J = 8.5Hz, 2H), 7.06 (d, J = 8.5Hz, 2H), 6.80 (d,
J = 8.5Hz, 2H), 4.45-4.36 (m, 1H), 3.69 (s, 3H), 3.06 (d
d, J = 12,4.0Hz, 1H), 2.84 (dd, J = 12,8.0Hz, 1H), 2.69 (t,
(J = 7.2Hz, 2H), 2.35 (t, J = 7.2Hz, 2H)

Example 74 (1) (S) -3- (4-aminophenyl) -2- [
(N-benzyloxycarbonyl-4-piperidinyloxy) acetylamino] ethyl propionate tert-butyl 4-piperidinyloxyacetate 521 mg (2.42 mmol
l) and triethylamine 0.40 ml (2.9 mmol) in methylene chloride
Dissolve in 20 ml and add benzyloxycarbonyl chloride to this.
41 mmol (2.9 mmol) was added, and the mixture was stirred at room temperature for 74 hours. To the reaction mixture was added 50 ml of saturated aqueous layer water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous magnesium sulfate. After filtration, low-boiling substances were distilled off from the filtrate under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 2/1) to give [N-benzyloxycarbonyl-4-piperidinium. Nyloxy] acetic acid
710 mg (84%) of -butyl was obtained as a colorless oil. This one
To 692 mg (1.99 mmol), 30 ml of methylene chloride and 10 ml of trifluoroacetic acid were added, and the mixture was stirred at room temperature for 17 hours. Low-boiling substances were distilled off from the reaction solution under reduced pressure, and [N-benzyloxycarbonyl-4-piperidinyloxy] acetic acid was converted to a colorless solid by 55%.
5 mg (96%) were obtained. [N-benzyloxycarbonyl-4-piperidinyloxy] acetic acid 530 mg (1.81 mmol) and (S) -2-amino-3- (4-nitrophenyl) propion were prepared according to the same method as in Example 72 (1). Ethyl acid hydrochloride (500 mg, 1.82 mmol) was condensed to give (S) -2-[(N-
Benzyloxycarbonyl-4-piperidinyloxy)
Acetylamino] -3- (4-nitrophenyl) ethyl propionate was obtained as a yellow oil (707 mg, 76%).

According to a method similar to that in Example 69 (1),
(S) -2-[(N-benzyloxycarbonyl-4-
Ethyl piperidinyloxy) acetylamino] -3- (4-nitrophenyl) propionate 685 mg (1.33 mmol) of the nitro group was converted to an amino group, and (S) -3- (4-aminophenyl) -2- 558 mg (87%) of ethyl [(N-benzyloxycarbonyl-4-piperidinyloxy) acetylamino] propionate was obtained as a pale yellow oil. IR (neat): 3350, 2920, 1735, 1680-1660, 110
^{0 cm -1 1 H-NMR (} CDCl 3) δ TMS: 7.37-7.29 (m, 5H),
6.95 (d, J = 8.0Hz, 1H), 6.86 (d, J = 8.4Hz, 2H), 6.53 (d, J
J = 8.4Hz, 2H), 5.12 (s, 2H), 4.82-4.73 (m, 1H), 4.17
(q, J = 7.2Hz, 2H), 3.93 (s, 2H), 3.68-3.58 (m, 4H), 3,49
-3.42 (m, 1H), 3.29-3.16 (m, 2H), 3.02 (d, J = 5.8Hz, 2
H), 1.78-1.67 (m, 2H), 1.55-1.43 (m, 2H), 1.25 (t, J =
(7.2Hz, 3H)

(2) (S) -3- [4-[(5-Amidino-2-benzofuranyl) carbonylamino] phenyl
] -2- [(4-Piperidinyloxy) acetylamino
Ethyl propionate (compound (97)) According to the same method as in Example 17 (3), 187 mg (0.553 mmol) of 5- (benzyloxycarbonylamidino) -2-benzofurancarboxylic acid and (S) -3- (4 -Aminophenyl) -2-[(N-benzyloxycarbonyl-4
-Piperidinyloxy) acetylamino] ethylpropionate (258 mg, 0.533 mmol) was condensed and the mixture was subjected to silica gel column chromatography (chloroform / methanol = 99/99).
1) and purified by (S) -3- [4-[[5- (benzyloxycarbonylamidino) -2-benzofuranyl].
] Carbonylamino] phenyl] -2-[(N-benzyloxycarbonyl-4-piperidinyloxy) acetylamino] ethyl propionate as a colorless solid 238 mg
(56%). IR (KBr): 3380, 1730, 1680-1660, 1620, 1100
^{cm -1 1 H-NMR (CDCl} 3) δ TMS: 9.07 (bs, 2H), 8.4
5 (bs, 1H), 8.27 (d, J = 1.9Hz, 1H), 7.99 (dd, J = 9.1,1.9H
z, 1H), 7.62-7.56 (m, 4H), 7.48-7.30 (m, 10H), 7.14
(d, J = 8.5Hz, 2H), 7.00 (d, J = 8.1Hz, 1H), 5.24 (s, 2H),
5.11 (s, 2H), 4.92-4.83 (m, 1H), 4.20 (q, J = 5.2Hz, 2H),
3.96 (s, 2H), 3.78-3.63 (m, 2H), 3.53-3.49 (m, 1H),
3.30-3.13 (m, 4H), 1.78-1.71 (m, 2H), 1.57-1.51 (m, 2
H), 1.27 (t, J = 5.2Hz, 3H)

(S) -3- [4-[[5- (Benzyloxycarbonylamidino) -2-benzofuranyl] carbonylamino] phenyl] -2-[(N-benzyloxycarbonyl-4-piperidinyloxy) 230 mg (0.286 mmol) of ethyl [acetylamino] propionate was dissolved in 50 ml of ethanol, and 40 mg of 10% palladium carbon was added thereto, followed by stirring at room temperature for 22 hours under a hydrogen atmosphere. The reaction solution is filtered, low-boiling substances are distilled off from the filtrate under reduced pressure, and the residue is subjected to silica gel (Chromatorex, NH type, Fuji Silysia Chemical) column chromatography (chloroform / methanol =
85/15) to give compound (97) as a colorless solid.
mg (55%). IR (KBr): 3350, 1725 , 1650, 1520, 1090 cm -1 1 H-NMR (CDCl 3) δ TMS: 7.97 (s, 1H), 7.76
-7.55 (m, 5H), 7.16 (d, J = 8.5Hz, 2H), 7.19-7.08 (m, 1
H), 4.95-4.85 (m, 1H), 4.20 (q, J = 7.2Hz, 2H), 3.96 (s,
2H), 3.43-3.34 (m, 1H), 3.16-3.14 (m, 2H), 3.08-2.97
(m, 2H), 2.64-2.52 (m, 2H), 1.87-1.81 (m, 2H), 1.45-1.
32 (m, 2H), 1.27 (t, J = 7.2Hz, 3H)

Example 75: (S) -3- [4-[(5-
Amidino-2-benzofuranyl) carbonylamino] phenyl] -2-[(4-piperidinyloxy) acetylamino] propionic acid (Compound (117)) According to the same method as in Example 10, 83 mg (0.1
55 mmol) was hydrolyzed to obtain 90 mg (quantitative) of a dihydrochloride of the compound (117) as a colorless solid. Mp:> 250 ℃ IR (KBr) : 3350, 1720, 1655, 1530, 1100 cm -1 1 H-NMR (DMSO-d 6, 500MHz)
δ _TMS ： 12.90 (bs, 1H), 10.82 (s, 1H), 9.54 (bs, 2H),
9.34 (bs, 2H), 9.06-8.98 (m, 2H), 8.40 (d, J = 1.7Hz, 1
H), 8.15 (s, 1H), 7.97 (d, J = 8.9Hz, 1H), 7.94 (dd, J = 8.
9,1.7Hz, 1H), 7.80 (d, J = 8.3Hz, 1H), 7.76 (d, J = 8.5Hz,
2H), 7.24 (d, J = 8.5Hz, 2H), 4.55-4.51 (m, 1H), 3.91
(d, J = 15.2Hz, 1H), 3.88 (d, J = 15.2Hz, 1H), 3.55-3.53
(m, 1H), 3.14-3.10 (m, 2H), 3.12 (dd, J = 13.7,4.8Hz, 1
H), 3.01 (dd, J = 13.7,9.0Hz, 1H), 2.96-2.91 (m, 2H), 1.
95-1.89 (m, 2H), 1.76-1.73 (m, 2H)

Example 76 (1) [4-Amino-N- (n-valeryl) anilino]
Under a nitrogen atmosphere, a mixture of ethyl acetate 4-nitroaniline 25.0 g (181 mmol) and ethyl bromoacetate 10.0 ml (90.5 mmol) was added to a mixture of 80 to 90.
Stirred at C for 20 hours. 30 ml of ethyl acetate was added to the reaction solution, and 10
After heating under reflux for 1 minute, the solid was collected by filtration and recrystallized from ethanol to obtain 13.1 g (64%) of ethyl (4-nitroanilino) acetate as a yellow solid. A mixture of 1.00 g (4.46 mmol) of this product and 1.12 g (9.36 mmol) of n-valeryl chloride was stirred at 80 to 90 ° C. for 2 hours under a nitrogen atmosphere. The reaction solution was purified by silica gel column chromatography (n-hexane / ethyl acetate = 1/1), and ethyl [4-nitro-N- (n-valeryl) anilino] acetate was used as a pale yellow solid to give 948 m
g (69%). Dissolve 851 mg (2.76 mmol) of this in a mixture of chloroform 20 ml and ethanol 30 ml, and add 10%
80 mg of palladium carbon was added, and the mixture was stirred at room temperature for 60 hours under a hydrogen atmosphere. After filtration, low-boiling substances were distilled off from the filtrate under reduced pressure to obtain 759 mg (99%) of ethyl [4-amino-N- (n-valeryl) anilino] acetate as a colorless oil. IR (neat): 3600-2300, 1730 cm -1 1 H-NMR (DMSO-d 6) δ TMS: 7.45-7.25 (m,
4H), 4.30 (s, 2H), 4.10 (q, J = 7.1Hz, 2H), 2.08 (t, J =
7.1Hz, 2H), 1.38 (quint, J = 7.4Hz, 2H), 1.30-1.03 (m, 5
H), 0.76 (t, J = 7.1Hz, 3H)

(2) Ethyl [4-[(5-amidino-2-benzofuranyl) carbonylamino] -N- (n-valeryl) anilino] acetate (Compound (139)) A method similar to that in Example 17 (3) Was condensed with 421 mg (1.24 mmol) of 5- (benzyloxycarbonylamidino) -2-benzofurancarboxylic acid and 346 mg (1.24 mmol) of ethyl [4-amino-N- (n-valeryl) anilino] acetate, followed by silica gel column chromatography. Purified by chromatography (n-hexane / ethyl acetate = 3/1 to 1/1),
[4-[[5- (benzyloxycarbonylamidino)
-2-benzofuranyl] carbonylamino] -N- (n
-Valeryl) anilino] ethyl acetate as a pale yellow solid
308 mg (42%) were obtained. IR (KBr): 3600-2700, 1740 , 1610 cm -1 1 H-NMR (CDCl 3) δ TMS: 8.80 (s, 1H), 8.21
(s, 1H), 7.96 (d, J = 9.0Hz, 1H), 7.85-7.75 (m, 2H), 7.6
0-7.18 (m, 4H + 5H), 5.22 (s, 2H), 4.35 (s, 2H), 4.17
(q, J = 7.0Hz, 2H), 2.14 (t, J = 7.2Hz, 2H), 1.54 (quint, J =
7.2Hz, 2H), 1.40-1.10 (m, 5H), 0.78 (t, J = 7.2Hz, 3H)

[4-[[5- (benzyloxycarbonylamidino) -2-benzofuranyl] carbonylamino
] -N- (n-Valeryl) anilino] ethyl acetate 351 g
(0.587 mmol), 25 ml of chloroform and 25 ml of methanol were added, and 30 mg of 10% palladium carbon and 1.2 ml of 1N hydrochloric acid were added thereto.
(1.2 mmol), and the mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. The reaction solution was filtered, low-boiling substances were distilled off from the filtrate under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / methanol = 4/1) to give the compound
281 mg (95%) of the hydrochloride salt of (139) was obtained as a yellow solid. IR (KBr): 3600-2800, 1730 , 1640, 1505 cm -1 1 H-NMR (DMSO-d 6, 500MHz)
δ _TMS : 8.38 (s, 1H), 8.08 (s, 1H), 8.00 (d, J = 5Hz, 1
H), 7.95-7.88 (m, 3H), 7.40-7.35 (m, 2H), 4.32 (s, 2
H), 4.11 (q, J = 7.3Hz, 2H), 2.10 (t, J = 7.3Hz, 2H), 1.43
(quint, J = 7.3Hz, 2H), 1.25-1.12 (m, 5H), 0.77 (t, J = 7.
(3Hz, 3H)

Example 77: [4-[(5-amidino-2)
-Benzofuranyl) carbonylamino] -N- (n-valeryl) anilino] acetic acid (compound (145)) According to the same method as in Example 10, hydrochloride of compound (139)
Hydrolyze 202 mg (0.404 mmol) and reverse phase column (Chroma
torex-ODS DM1020T, Fuji Silysia Chemical) chromatography (water to acetonitrile) to give compound (1
45) was obtained as a yellow solid (60 mg, 28%). Mp: two hundred sixteen to two hundred and thirty ° C. (decomposition) IR (KBr): 3600-2500, 1650, 1600 cm -1 1 H-NMR (DMSO-d 6, 500MHz)
δ _TMS ： 9.41 (bs, 2H), 9.13 (bs, 2H), 8.35 (s, 1H),
8.05-7.85 (m, 5H), 7.45-7.36 (m, 2H), 4.20 (s, 2H), 2.
09 (t, J = 7.5Hz, 2H), 1.50-1.40 (m, 2H), 1.26-1.13 (m, 2
H), 0.83-0.73 (m, 3H)

Example 78 (1) Ethyl [4-amino-N- (benzyloxycarbonyl) anilino] acetate 25.0 g (181 mmol) of 4-nitroaniline and 10.0 ml (90.5 mmol) of ethyl bromoacetate were added in a nitrogen atmosphere under a nitrogen atmosphere. Stirred at ~ 90 ° C for 20 hours. Ethyl acetate (30 ml) was added to the reaction solution, and the mixture was heated under reflux for 10 minutes. The obtained solid was collected by filtration and recrystallized from ethanol to obtain 13.1 g (64%) of ethyl (4-nitroanilino) acetate as a yellow solid. Under a nitrogen atmosphere, 1.00 g (4.46 mmol) of this product and 8 ml of benzyloxycarbonyl chloride were added at 80 to 90.
Stirred at C for 1.5 hours. After adding 20 ml of toluene to the reaction solution, low-boiling substances were distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 5/2) to obtain [4-nitro-N -(Benzyloxycarbonyl) anilino] ethyl acetate was obtained as a yellow oil (962 mg, quantitative). 716mg of this one (2.00m
mol), 100 ml of ethanol and 30 ml of water were added, and 6.55 g (100 mmol) of active zinc and 2.22 g (20.0 mmol) of calcium chloride were added thereto.
Was added and the mixture was heated under reflux for 2 hours. The reaction solution was filtered, low-boiling substances were distilled off from the filtrate under reduced pressure, 100 ml of water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline and dried over anhydrous magnesium sulfate. After filtration, low-boiling substances were distilled off from the filtrate under reduced pressure to obtain 576 mg (88%) of ethyl [4-amino-N- (benzyloxycarbonyl) anilino] acetate as a yellow oil. ^{1 H-NMR (DMSO-d} 6, 500MHz)
δ _TMS : 7.35-7.20 (m, 5H), 6.97-6.91 (m, 2H), 6.53-
6.47 (m, 2H), 5.06 (s, 2H), 4.23 (s, 2H), 4.11 (q, J = 7.
1Hz, 2H), 1.17 (t, J = 7.1Hz, 3H)

(2) [4-[[5- (benzyloxycarbonylamidino) -2-benzofuranyl] carbonylamino] -N- (benzyloxycarbonyl) anilino
Ethyl acetate (compound (140)) According to the same method as in Example 17 (3), 567 mg (1.68 mmol) of 5- (benzyloxycarbonylamidino) -2-benzofurancarboxylic acid and [4-amino-N- (benzyl) Oxycarbonyl) anilino] ethyl acetate 550mg (1.68m
mol) were condensed and purified by silica gel column chromatography (n-hexane / ethyl acetate = 2/1 to 1/1) to obtain 857 mg (82%) of compound (140) as a yellow solid. ^{1 H-NMR (DMSO-d} 6, 500MHz)
δ _TMS ： 8.50 (s, 1H), 8.13-8.11 (m, 1H), 7.88-7.78
(m, 4H), 7.45-7.30 (m, 12H), 5.13 (s, 2H × 2), 4.39 (s,
2H), 4.03 (q, J = 7.1Hz, 2H), 1.19 (t, J = 7.1Hz, 3H)

Example 79: [4-[(5-amidino-2)
-Benzofuranyl) carbonylamino] anilino] acetic acid (compound (141)) According to the same method as in Example 19, 857 mg of compound (140)
(1.32 mmol) by hydrogen reduction, [4-[(5-amidino-2)
-Benzofuranyl) carbonylamino] anilino] acetate, and then hydrolyzed in the same manner as in Example 10, to give the dihydrochloride of compound (141) as a yellow solid in 125 m
g (22%). Mp:> 235 ° C. (decomposition) IR (KBr): 1730, 1650, 1610, 1580 cm -1 1 H-NMR (DMSO-d 6, 500MHz)
δ _TMS ： 10.44 (s, 1H), 9.45 (bs, 2H), 9.20 (bs, 2H),
8.34 (s, 1H), 8.10-7.87 (m, 4H), 7.55-7.53 (m, 2H), 6.
66-6.63 (m, 2H), 3.84 (s, 2H)

Example 80 (1) (4-hydroxycyclohexyloxy) acetic acid t
5.7 g (0.14 mol) of -butyl sodium hydroxide was dissolved in 6 ml of water, and 15.0 g (0.13 mol) of 1,4-cyclohexanediol (cis / trans = 6/4) was added thereto, followed by stirring at room temperature for 30 minutes. . Then, 20.8 g of tetrabutylammonium bromide
(0.065 mol) and 24.5 ml (0.13 mol) of t-butyl bromoacetate were added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. After filtration, low-boiling substances were distilled off from the filtrate under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 5/1 to 2/1) to give (4-hydroxycyclohexyl) acetic acid. t-butyl as a clear oil 2.
13 g (7%) were obtained. IR (KBr): 3400, 2910 , 2850, 1740 cm -1 1 H-NMR (CDCl 3) δ TMS: 3.98, 3.97 (each
s, 2H), 3.85-3.61 (m, 1H), 3.58-3.27 (m, 1H), 2.18-1.1
0 (m, 17H)

(2) [4-[(5-amidino-2-benzofuranyl) carbonyloxy] cyclohexyloxy
] T-butyl acetate (compound (428)) 5-cyano-2-benzofurancarboxylic acid 1.00 g (5.34m
mol) were added to thionyl chloride (8 ml, 110 mmol), and the mixture was refluxed for 30 minutes. Thionyl chloride was distilled off from the reaction solution under reduced pressure,
To this was added 3 ml of toluene, and the mixture was again distilled under reduced pressure to obtain 5-cyano-2-benzofurancarboxylic acid chloride. This was dissolved in 20 ml of toluene, then 0.86 ml of pyridine (10.7
mmol), 131 mg of 4-dimethylaminopyridine (1.07 mmo
l), t-butyl 4-hydroxycyclohexyl acetate 1.35
g (5.88 mmol) was added and the mixture was heated under reflux for 1 hour. Water was added to the reaction solution, extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. After filtration, low-boiling substances were distilled off from the filtrate under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 10/1 to 5/1) to obtain [4-[(5- Cyano-2-benzofuranyl)
1.12 g (52%) of carbonyloxy] cyclohexyloxy] t-butyl acetate was obtained as a colorless solid. IR (KBr): 3400, 2950, 2200, 1740, 1719, 162
^{0, 1580 cm -1 1 H-} NMR (CDCl 3) δ TMS: 8.10-8.02 (m, 1H),
7.78-7.63 (m, 2H), 7.55 (d, J = 2.0Hz, 1H), 5.23-5.00
(m, 1H), 4.02, 4.01 (each s, 2H), 3.53-3.40 (m, 1H),
2.27-1.52 (m, 8H), 1.49 (s, 9H)

According to the same method as in Example 1 (3), [4]
-[(5-cyano-2-benzofuranyl) carbonyloxy] cyclohexyloxy] t-butyl acetate 1.00 g
(2.50 mmol) of the cyano group was converted to an amidino group, and the compound (4
28) 1.00 g (73%) of hydroiodide as light brown solid
Obtained. IR (KBr): 3200, 2950 , 1720, 1670 cm -1 1 H-NMR (CDCl 3) δ TMS: 12.0-8.40 (bs, 4
H), 8.30 (s, 1H), 8.08-7.79 (m, 3H), 5.19-4.90 (m, 1
H), 4.02 (s, 2H), 3.65-3.35 (m, 1H), 2.15-1.25 (m, 17
H)

Example 81: [4-[(5-amidino-2)
-Benzofuranyl) carbonyloxy] cyclohexyloxy] acetic acid (compound (429)) In the same manner as in Example 2, 1.00 g (1.84 mmol) of hydroiodide like compound (428) was treated with 10 ml of trifluoroacetic acid. Hydroiodide as compound (429) as light brown solid
520 mg (58%) were obtained. ¹ H-NMR (DMSO-d ₆ ) δ _TMS : 9.39 (s, 2H),
9.10 (s, 2H), 8.30 (s, 1H), 8.09-7.81 (m, 3H), 5.15-4.
88 (m, 1H), 4.05 (s, 2H), 3.65-3.35 (m, 1H), 2.17-1.3
1 (m, 8H) SIMS m / z: 361 (M + H)

Compound (429) hydroiodide 300 mg (0.6
1 mmol), 10 ml of acetic acid and 12 μl of concentrated sulfuric acid (0.23 mmol) were added, and 90
Stirred at C for 10 minutes. The reaction solution was returned to room temperature, 50 ml of diethyl ether was added, and the precipitated precipitate was washed with diethyl ether and collected by filtration to obtain 220 mg (78%) of a sulfate of compound (429) as a colorless solid. Melting point: 186-188 ° C IR (KBr): 3300, 3120, 2920, 1720, 1670, 161
^{8 cm -1 1 H-NMR (} DMSO-d 6) δ TMS: 9.39 (s, 2H),
9.06 (s, 2H), 8.31 (s, 1H), 8.09-7.81 (m, 3H), 5.15-4.
88 (m, 1H), 4.05 (s, 2H), 3.35-3.65 (s, 1H), 2.17-1.1
2 (m, 8H) (cis / trans is approximately equivalent)

Example 82: 3- [4-[(5-Amidino-2-benzofuranyl) carbonyloxy] piperidino
Ethyl propionate (compound (481)) According to the same method as in Example 80 (2), 5-cyano-2
1.00 g (5.34 mmol) of benzofurancarboxylic acid as the corresponding acid chloride, which was reacted with 1.08 g (5.77 mmol) of ethyl 3- (4-hydroxypiperidino) propionate;
Silica gel column chromatography (chloroform)
To give 733 mg (33%) of ethyl 3- [4-[(5-cyano-2-benzofuranyl) carbonyloxy] piperidino] propionate as a colorless solid. ¹ H-NMR (DMSO-d ₆ ) δ _TMS : 8.37 (s, 1H),
8.00 (d, J = 14.4Hz, 1H), 7.92 (d, J = 14.4Hz, 1H), 7.84
(s, 1H), 5.06-4.92 (m, 1H), 4.07 (q, J = 7.1Hz, 2H), 2.73
-2.58 (m, 6H), 2.52-2.43 (m, 2H), 2.02-1.92 (m, 2H),
1.91 (t, J = 7.1Hz, 3H), 1.75-1.63 (m, 2H),

According to a method similar to that of Example 1 (3), 3-
723 mg of ethyl [4-[(5-cyano-2-benzofuranyl) carbonyloxy] piperidino] propionate
(1.78 mmol) cyano group was converted to amidino group, and column chromatography on silica gel (Chromatorex, NH type, Fuji Silysia Chemical) (chloroform / methanol = 85 /
15) The compound (481) was purified as a colorless solid by 140m
g (20%). ¹ H-NMR (CDCl ₃ ) δ _TMS : 7.96 (s, 1H), 7.72
(d, J = 8.6Hz, 1H), 7.60 (d, J = 8.6Hz, 1H), 7.53 (s, 1H),
5.14-5.04 (m, 1H), 4.62 (bs, 3H), 4.15 (q, J = 7.1Hz, 2
H), 2.82-2.63 (m, 4H), 2.54-2.33 (m, 4H), 2.11-1.80
(m, 4H), 1.27 (t, J = 7.1Hz, 3H)

Example 83: t-butyl trans- [4-[(6-amidino-2-indolyl) carbonylamino] cyclohexyloxy] acetate (compound (502)) In the same manner as in Example 1 (2), 6-cyano-2-
Indolecarboxylic acid 244mg (1.31mmol) and trans-
(4-aminocyclohexyloxy) t-butyl acetate 30
0 mg (1.31 mmol) was condensed and subjected to silica gel column chromatography (chloroform / methanol = 50/1 to 1/1).
) To give trans- [4-[(6-cyano-
465 mg (89%) of 2-indolyl) carbonylamino] cyclohexyloxy] t-butyl acetate were obtained as a brown solid. IR (KBr): 3600-3000, 2900, 2200, 1730, 163
^{0, 1540 cm -1 1 H-} NMR (CDCl 3) δ TMS: 9.96 (bs, 1H), 7.7
9 (s, 1H), 7.71 (d, J = 8.3Hz, 1H), 7.35 (dd, J = 8.3,1.4H
z, 1H), 6.86 (d, J = 1.3Hz, 1H), 6.09 (d, J = 7.9Hz, 1H), 4.
02 (s, 2H), 4.12-3.90 (m, 1H), 3.50-3.30 (m, 1H), 2.2
7-2.05 (m, 4H), 1.49 (s, 9H), 1.75-1.15 (m, 4H)

According to a method similar to that of Example 1 (3), trans- [4-[(6-cyano-2-indolyl) carbonylamino] cyclohexyloxy] t-butyl acetate 46
5 mg (1.17 mmol) of the cyano group was converted to an amidino group, and 343 mg (54
%) Obtained. IR (KBr): 3600-2800, 1725, 1660, 1630, 1530
^{cm -1 1 H-NMR (DMSO} -d 6) δ TMS: 12.23 (bs, 1
H), 9.50-8.45 (br, 4H), 7.89 (s, 1H), 7.84 (d, J = 8.5H
z, 1H), 7.41 (dd, J = 8.4,1.5Hz, 1H), 7.28 (s, 1H), 4.01
(s, 2H), 3.92-3.67 (m, 1H), 2.10-1.80 (m, 4H), 1.43
(s, 9H), 1.55-1.10 (m, 4H)

Example 84: trans- [4-[(6-amidino-2-indolyl) carbonylamino] cyclohexyloxy] acetic acid (compound (507)) 824 mg (1.52 mmol) of the hydrochloride was treated with 6 ml of trifluoroacetic acid, and the hydroiodide as a brown solid was obtained as a compound (507).
1 mg (87%) was obtained. IR (KBr): 3600-2800, 1720, 1670, 1630, 1520
^{cm -1 1 H-NMR (DMSO} -d 6) δ TMS: 12.24 (s, 1H),
9.25 (bs, 2H), 8.89 (bs, 2H), 8.45 (d, J = 7.6Hz, 1H),
7.90 (s, 1H), 7.84 (d, J = 8.5Hz, 1H), 7.41 (dd, J = 8.4,
1.3Hz, 1H), 7.29 (s, 1H), 4.04 (s, 2H), 3.90-3.65 (m, 1
H), 2.20-1.78 (m, 4H), 1.55-1.10 (m, 4H)

Example 85: Trans- [4-[(6-amidino-2-indolyl) carbonylamino] cyclohexyloxy] ethyl acetate (Compound (501)) Ethanol was reacted with 641 mg (1.32 mmol) of hydroiodide to give the methanesulfonate of compound (501) as a pale yellow solid.
5 mg (78%) were obtained. Melting point: 263-266 ° C IR (KBr): 3600-2800, 1745, 1670, 1630, 156
^{0, 1530 cm -1 1 H-} NMR (DMSO-d 6) δ TMS: 12.20 (bs, 1
H), 9.24 (bs, 2H), 8.83 (bs, 2H), 8.42 (d, J = 7.8Hz, 1
H), 7.90 (s, 1H), 7.84 (d, J = 8.4Hz, 1H), 7.41 (dd, J = 8.
5,1.5Hz, 1H), 7.29 (d, J = 1.5Hz, 1H), 4.13 (s, 2H), 4.13
(q, J = 7.1Hz, 2H), 3.90-3.70 (m, 1H), 2.35 (s, 3H), 2.1
5-1.82 (m, 4H), 1.21 (t, J = 7.1Hz, 3H), 1.55-1.15 (m, 4
H)

Example 86: trans- [4-[(6-Amidinobenzo [b] thien-2-yl) carbonylamino] cyclohexyloxy] acetic acid (compound (558)) A method similar to that in Example 1 (2) According to 6-cyanobenzo
[b] Condensation of 400 mg (1.97 mmol) of thien-2-carboxylic acid and 474 mg (2.07 mmol) of t-butyl trans-3- (4-aminocyclohexyl) propionate gave trans- [4
-471 mg (58%) of t-butyl [[6-cyanobenzo [b] thien-2-yl) carbonylamino] cyclohexyloxy] acetate were obtained as an orange solid. IR (KBr): 3700-3000, 2200 , 1730, 1620 cm -1 1 H-NMR (DMSO-d 6) δ TMS: 8.64 (d, J = 1.5
Hz, 1H), 8.20 (s, 1H), 8.12 (d, J = 8.3Hz, 1H), 7.79 (dd,
J = 8.3,1.5Hz, 1H), 3.80-3.70 (m, 1H), 2.08-1.98 (m, 3
H), 1.95-1.85 (m, 2H), 1.43 (s, 9H), 1.45-1.35 (m, 2
H), 1.33-1.23 (m, 2H)

According to a method similar to that of Example 1 (3), trans- [4-[(6-cyanobenzo [b] thien-2-
Yl) carbonylamino] cyclohexyloxy] cyano group of 450 mg (1.09 mmol) of t-butyl acetate was converted to an amidino group, and the mixture was subjected to silica gel (Chromatorex, NH type, Fuji Silysia Chemical) column chromatography (chloroform /
Purified by methanol = 6/1), trans- [4-
About 147 mg of [(6-amidinobenzo [b] thien-2-yl) carbonylamino] cyclohexyloxy] t-butyl acetate was obtained as a yellow solid. This was treated with 2 ml of trifluoroacetic acid in the same manner as in Example 2 to give the compound
104 mg of trifluoroacetate (558) as a yellow solid (2
0%). Mp:> 250 ℃ IR (KBr) : 3700-2700, 1740, 1670, 1600 cm -1 1 H-NMR (DMSO-d 6, 500MHz)
δ _TMS : 9.40 (bs, 2H), 9.18 (bs, 2H), 8.69 (d, J = 7.8H
z, 1H), 8.53 (s, 1H), 8.23 (s, 1H), 8.15 (d, J = 8.5Hz, 1
H), 7.78 (dd, J = 8.5,1.5Hz, 1H), 4.04 (s, 2H), 3.80-3.7
0 (m, 1H), 3.43 (m, 1H), 2.13-2.00 (m, 2H), 1.97-1.85
(m, 2H), 1.45-1.35 (m, 2H), 1.33-1.20 (m, 2H)

Example 87: trans- [4-[(6-Amidinobenzo [b] thien-2-yl) carbonylamino] cyclohexyloxy] ethyl acetate (compound (554)) Ethanol was reacted with 85 mg (0.174 mmol) of the trifluoroacetate salt of compound (558) to obtain 89 mg (quantitative) of a methanesulfonate salt of compound (554) as a colorless solid. ¹ H-NMR (DMSO-d ₆ ) δ _TMS : 9.38 (bs, 2H),
9.01 (bs, 2H), 8.70 (d, J = 8.0Hz, 1H), 8.52 (s, 1H), 8.
23 (s, 1H), 8.16 (d, J = 8.5Hz, 1H), 7.78 (d, J = 8.5Hz, 1
H), 4.13 (s, 2H), 4.12 (q, J = 7.1Hz, 2H), 3.85-3.65 (m,
1H), 2.35 (s, 3H), 2.15-1.85 (m, 4H), 1.21 (t, J = 7.1H
z, 3H), 1.50-1.15 (m, 4H)

Example 88 (1) Ethyl (S) -3- (4-aminophenyl) -2- (trifluoromethylsulfonylamino) propionate (S) -2-amino-3- (4-nitrophenyl) To 4.00 g (14.6 mmol) of the hydrochloride of ethyl propionate was added 100 ml of acetonitrile, and 2.5 ml (23.5 mmol) of trifluoromethylsulfonyl chloride and then 3.2 ml (29.1 mmol) of N-methylmorpholine were added, and the mixture was added at room temperature for 2 hours. Stirred.
100 ml of water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. After filtration, low-boiling substances were distilled off from the filtrate under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform / n-hexane = 2/1) to give (S) -2- (trifluoromethylsulfonylamino). 2.25 g of ethyl 3- (4-nitrophenyl) propionate as a yellow solid
2%). 1.97 g (5.32 mmol) of this product was dissolved in 100 ml of acetic acid, 750 mg of 10% palladium carbon was added thereto, and the mixture was stirred at room temperature under a hydrogen atmosphere for 66 hours. The reaction solution was filtered through celite, acetic acid was distilled off from the filtrate under reduced pressure, the residue was washed with water, and (S) -3- (4-aminophenyl) -2- (trifluoromethylsulfonylamino) propionic acid was removed. 1.81 g (quantitative) of ethyl was obtained as a yellow solid. ¹ H-NMR (CDCl ₃ ) δ _TMS : 6.90 (d, J = 8.4 Hz, 2
H), 6.62 (d, J = 8.4Hz, 2H), 4.72 (bs, 3H), 4.42 (dd, J =
5.9,5.3Hz, 1H), 4.21 (q, J = 7.2Hz, 2H), 3.10 (dd, J = 14.
1,5.3Hz, 1H), 2.98 (dd, J = 14.1,5.9Hz, 1H), 1.27 (t, J =
(7.2Hz, 3H)

(2) (S) -3- [4-[(5-Amidino-2-benzofuranyl) carbonylamino] phenyl
Ethyl 2- (trifluoromethylsulfonylamino) propionate (Compound (115)) According to the same method as in Example 17 (3), 1.02 g (3.01 g) of 5- (benzyloxycarbonylamidino) -2-benzofurancarboxylic acid mmol) and (S) -3- (4-aminophenyl) -2- (trifluoromethylsulfonylamino)
1.03 g (3.03 mmol) of ethyl propionate was condensed and purified by silica gel column chromatography (n-hexane / ethyl acetate = 1/1 to 1/2) to give (S) -3-
[4-[[5- (benzyloxycarbonylamidino)
-2-benzofuranyl] carbonylamino] phenyl]
1.31 g (65%) of ethyl-2- (trifluoromethylsulfonylamino) propionate was obtained as a colorless solid. To 1.30 g (1.97 mmol) of this was added 200 ml of ethanol, 450 mg of 10% palladium on carbon, and 2 ml of 1N hydrochloric acid.
Stirred at room temperature for 2 hours. The reaction solution was filtered, and low-boiling substances were distilled off from the filtrate under reduced pressure to obtain 1.11 g (quantitative) of the hydrochloride of compound (115) as a colorless solid. ¹ H-NMR (DMSO-d ₆ ) δ _TMS : 10.71 (s, 1H),
10.26 (bs, 1H), 9.46 (bs, 2H), 9.18 (bs, 2H), 8.37
(d, J = 1.3Hz, 1H), 8.02 (s, 1H), 7.99 (d, J = 8.6Hz, 1H),
7.90 (dd, J = 8.6,1.3Hz, 1H), 7.78 (d, J = 8.7Hz, 2H), 7.2
9 (d, J = 8.7Hz, 2H), 4.17 (q, J = 7.1Hz, 2H), 3.44 (dd, J = 1
0.1,5.0Hz, 1H), 3.14 (dd, J = 13.8,5.0Hz, 1H), 2.87 (dd,
J = 13.8,10.1Hz, 1H), 1.97 (t, J = 7.1Hz, 3H)

Example 89: (S) -3- [4-[(5-
Amidino-2-benzofuranyl) carbonylamino] phenyl] -2- (trifluoromethylsulfonylamino) propionic acid (compound (116)) To 180 mg (0.320 mmol) of compound (115), 50 ml of 2.5 N hydrochloric acid and 10 ml of acetic acid were added. Heated to reflux for an hour. The reaction solution was concentrated under reduced pressure, and the precipitated solid was washed with water and dilute hydrochloric acid to give the compound (1
30) (18%) of the hydrochloride salt of 16) was obtained as a colorless solid. ¹ H-NMR (DMSO-d ₆ + TFA) δ _TMS : 10.74
(s, 1H), 10.07 (d, J = 8.9Hz, 1H), 9.50 (bs, 2H), 9.29
(bs, 2H), 8.39 (d, J = 1.6Hz, 1H), 8.05 (s, 1H), 7,99 (d,
J = 8.9Hz, 1H), 7.93 (dd, J = 8.9,1.6Hz, 1H), 7.79 (d, J = 8.
5Hz, 2H), 7.30 (d, J = 8.5Hz, 2H), 4.18-4.05 (m, 1H), 3.1
8 (dd, J = 14.0,4.3Hz, 1H), 2.84 (dd, J = 14.0,13.5Hz, 1H)

Example 90: trans- [4-[(5-Amidino-2-benzofuranyl) carbonylamino] cyclohexyloxy] t-butyl acetate (compound (461)) 925 mg (1.68 mmol) of compound (453) was added to t-butyl acetate. Butanol 120ml
, And 200 mg of 10% palladium carbon was added thereto, and the mixture was heated under reflux in a hydrogen atmosphere for 2 hours. The reaction solution was returned to room temperature, filtered through celite, and low-boiling substances were distilled off from the filtrate under reduced pressure.
The residue was purified by silica gel (Chromatorex, NH type, Fuji Silysia Chemical) column chromatography (chloroform / methanol = 20/1 to 3/1) to give compound (4
61) as a colorless solid was obtained in an amount of 665 mg (95%). This thing 400
mg (0.963 mmol) in 24 ml of tetrahydrofuran,
A solution of 93 mg (0.963 mmol) of methanesulfonic acid dissolved in 6 ml of tetrahydrofuran was added dropwise thereto under ice-cooling, and the mixture was stirred for 10 minutes. 30 ml of diethyl ether in the reaction solution
Was added, and the precipitated precipitate was washed with diethyl ether,
The crystals were collected by filtration to give 425 mg (86%) of a methanesulfonate of the compound (461) as a colorless solid. IR (KBr): 3600-2700, 1720, 1670, 1632, 159
^{4, 1525 cm -1 1 H-} NMR (DMSO-d 6) δ TMS: 9.35 (bs, 2H),
8.95 (bs, 2H), 8.62 (d, J = 7.9Hz, 1H), 8.28 (s, 1H), 7.
92 (d, J = 8.6Hz, 1H), 7.84 (dd, J = 8.8,1.7Hz, 1H), 7.71
(s, 1H), 4.00 (s, 2H), 3.90-3.68 (m, 1H), 3.40-3.20
(m, 1H), 2.32 (s, 3H), 2.12-1.80 (m, 4H), 1.43 (s, 9H),
1.60-1.15 (m, 4H)

Example 91 (1) t-butyl trans-3- (4-aminocyclohexyl) propionate β- [4] obtained by the same method as in Example 13 (1)
-(Benzyloxycarbonylamino) cyclohexyl] 60.0 g of t-butyl acrylate was recrystallized from a mixed solvent of n-hexane and ethyl acetate to obtain 23.5 g (39%) of a trans form (cyclohexyl ring). This is methanol
The mixture was dissolved in 150 ml, 250 mg of 10% palladium carbon was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 20 hours. Filter the reaction solution,
Low-boiling substances were distilled off from the filtrate under reduced pressure, and trans-3-
14.9 g (quantitative) of t-butyl (4-aminocyclohexyl) propionate was obtained as a colorless solid. ¹ H-NMR (CDCl ₃ ) δ _TMS : 7.35 (s, 5H), 6.78
(dd, J = 15.7,6.8Hz, 1H), 5.70 (d, J = 15.7Hz, 1H), 5.09
(bs, 1H), 4.59 (bs, 1H), 3.56-3.30 (m, 1H), 2.12-1.95
(m, 3H), 2.87-2.70 (m, 2H), 1.45 (s, 1H), 1.32-1.02
(m, 4H)

(2) trans-3- [4-[(5-Amidino-2-benzofuranyl) carbonylamino] cyclohexyl] t-butyl propionate (compound (441)) According to a method similar to that in Example 17 (3) 3.98 g (11.8 mmol) of 1,5- (benzyloxycarbonylamidino) -2-benzofurancarboxylic acid and 2.70 g (11.8 mmol) of t-butyl trans-3- (4-aminocyclohexyl) propionate
mmol) to give 5.04 g (78%) of trans-3- [4-[[5- (benzyloxycarbonylamidino) -2-benzofuranyl] carbonylamino] cyclohexyl] t-butyl propionate as a colorless solid. . According to the same method as that of Example 90, 4.90 g (8.95 mmol) of this product was reduced with hydrogen to give compound (441) as a colorless solid in 3.52 g (95%
%) And then treated with 0.82 g (8.52 mmol) of methanesulfonic acid in a tetrahydrofuran solvent to obtain 3.82 g (88%) of a methanesulfonic acid salt of the compound (441) as a colorless solid. ¹ H-NMR (DMSO-d ₆ ) δ _TMS : 9.36 (bs, 2H),
9.00 (bs, 2H), 8.64 (d, J = 8.1Hz, 1H), 8.27 (s, 1H), 8.
00-7.80 (m, 2H), 7.71 (s, 1H), 3.90-3.60 (m, 1H), 2.3
2 (s, 3H), 2.25-2.10 (m, 2H), 1.95-1.68 (m, 4H), 1.43
(s, 9H), 1.60-0.85 (m, 7H)

Example 92 (1) trans- (4-aminocyclohexyl-Nn
-Butylamino) t-butyl acetate According to the same method as in Example 61 (1), trans-1,
14.7 g (105 mmol) of 4-diaminocyclohexane was reacted with 14.7 g (52.5 mmol) of triphenylmethyl chloride to give trans-1-amino-4- (triphenylmethylamino).
11.1 g (30%) of cyclohexane was obtained as a colorless solid. 2.00 g (5.61 mmol) of this substance and n-butyraldehyde 400
mg (5.61 mmol) in 70 ml of ethanol.
A solution obtained by suspending sodium cyanoborohydride (220 mg, 3.64 mmol) in ethanol (30 ml) was added dropwise.
The mixture was adjusted to pH 6 to 7 by adding ml and stirred at room temperature for 14 hours. 200 ml of water was added to the reaction solution, concentrated under reduced pressure to 1/3, extracted with chloroform, and the extract was dried over anhydrous sodium sulfate. After filtration, low-boiling substances were distilled off from the filtrate under reduced pressure, and the residue was purified by silica gel (Chromatorex, NH type, Fuji Silysia Chemical) column chromatography (n-hexane / chloroform = 5/1). 1- (n
-Butylamino) -4- (triphenylmethylamino)
1.72 g (74%) of cyclohexane was obtained as a colorless oil. 1.72 g (4.17 mmol) of this product and 1.21 g (8.75 g) of potassium carbonate
mmol) in 80 ml of N, N-dimethylformamide.
To this, 850 mg (4.38 mmol) of t-butyl bromoacetate was added dropwise at room temperature, and the mixture was stirred for 4.5 hours. The reaction solution was filtered, 100 ml of water was added to the filtrate, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. After filtration, low-boiling substances were distilled off from the filtrate under reduced pressure, and the residue was subjected to silica gel column chromatography (n-
Hexane / ethyl acetate = 20/1 to 10/1)
Trans- [4- (triphenylmethylamino) cyclohexyl-Nn-butylamino] 1.88 g (86%) of t-butyl acetate was obtained as a colorless oil. This one 1.74g (3.31
(mmol) was dissolved in 60 ml of ethanol, 520 mg of 10% palladium carbon was added thereto, and the mixture was refluxed for 4 hours under a hydrogen atmosphere. The reaction solution was filtered through celite, low-boiling substances were distilled off under reduced pressure from the filtrate, 30 ml of water and 10 ml of 1N hydrochloric acid were added to the residue, and the mixture was extracted with diethyl ether. And the extract was dried over anhydrous sodium sulfate. After filtration, low-boiling substances were distilled off from the filtrate under reduced pressure to obtain 680 mg (72%) of t-butyl trans- (4-aminocyclohexyl-Nn-butylamino) acetate as a yellow oil. IR (KBr): 3500-3000, 2900, 1730, 1590, 1450
^{cm -1 1 H-NMR (CDCl} 3) δ TMS: 3.20 (s, 2H), 2.75
-2.45 (m, 4H), 2.05-1.70 (m, 4H), 1.45 (s, 9H), 1.60-
1.00 (m, 8H), 0.90 (t, J = 7.0Hz, 3H)

(2) trans- [4-[(5-Amidino-2-benzofuranyl) carbonylamino] cyclohexyl-Nn-butylamino] t-butyl acetate (compound
(485)) According to the same method as in Example 17 (3), 785 mg (2.32 mmol) of 5- (benzyloxycarbonylamidino) -2-benzofurancarboxylic acid and trans- (4-aminocyclohexyl-Nn-butylamino) ) T-butyl acetate 6
80 mg (2.32 mmol) were condensed and subjected to silica gel column chromatography (n-hexane / ethyl acetate = 1/1 to 1/1).
4) and purified by trans- [4-[[5- (benzyloxycarbonylamidino) -2-benzofuranyl]]
[Carbonylamino] cyclohexyl-Nn-butylamino] 1.06 g (75%) of t-butyl acetate was obtained as a colorless solid. IR (KBr): 3600-3000, 2900, 1720, 1635, 151
^{0, 1440 cm -1 1 H-} NMR (CDCl 3) δ TMS: 8.23 (d, J = 1.9Hz, 1
H), 7.95 (dd, J = 8.7,1.9Hz, 1H), 7.60-7.20 (m, 7H), 6.4
3 (d, J = 8.3Hz, 1H), 5.23 (s, 2H), 4.05-3.80 (m, 1H),
3.23 (s, 2H), 2.80-2.45 (m, 3H), 2.30-1.80 (m, 4H), 1.
46 (s, 9H), 1.60-1.15 (m, 8H), 1.05-0.75 (m, 3H)

According to a method similar to that in Example 62, trans- [4-[[5- (benzyloxycarbonylamidino) -2-benzofuranyl] carbonylamino] cyclohexyl-Nn-butylamino] t-butyl acetate 941
mg (1.56 mmol) by hydrogen reduction and silica gel (Chromatore
x, NH type, Fuji Silysia Chemical) column chromatography (chloroform / methanol = 20/1 to 2/1) to give 625 mg of compound (485) as a pale yellow solid
(85%). IR (KBr): 3600-3000, 2900, 1720, 1635, 152
^{0, 1450 cm -1 1 H-} NMR (CDCl 3) δ TMS: 7.94 (s, 1H), 7.80
-7.60 (m, 1H), 7.60-7.35 (m, 2H), 6.60-6.30 (m, 1H),
4.10-3.80 (m, 1H), 3.23 (s, 2H), 2.80-2.40 (m, 3H),
2.30-1.80 (m, 4H), 1.46 (s, 9H), 1.65-1.10 (m, 8H), 1.
00-0.85 (m, 3H)

Example 93: trans- [4-[(5-Amidino-2-benzofuranyl) carbonylamino] cyclohexyl-Nn-butylamino] acetic acid (compound (48
6)) In the same manner as in Example 2, compound (485) 100 mg (0.2
12 mmol) was treated with 10 ml of trifluoroacetic acid to give compound (48
120 mg (8
8%). IR (KBr): 3600-2800, 1665 , 1530, 1450 cm -1 1 H-NMR (DMSO-d 6, 500MHz)
δ _TMS : 9.37 (bs, 2H), 9.29 (bs, 2H), 8.74 (d, J = 8.1H
z, 1H), 8.29 (d, J = 1.9Hz, 1H), 7.91 (d, J = 8.8Hz, 1H), 7.
86 (dd, J = 8.8,1.9Hz, 1H), 7.72 (s, 1H), 4.10 (s, 2H),
3.95-3.80 (m, 1H), 3.40-3.05 (m, 3H), 2.10-1.90 (m, 4
H), 1.78-1.55 (m, 4H), 1.55-1.40 (m, 2H), 1.40-1.25
(m, 2H), 0.92 (t, J = 7.4Hz, 3H)

Example 94: Preparation of inclusion complex of compound (447) with α-cyclodextrin 2.50 g (5.49 mmol) of sulfate of compound (447) and 7.50 g (7.71 mmol) of α-cyclodextrin were added to 300 ml of distilled water. Plus 70
Heated to ℃ to completely dissolve. This solution was filtered, and the filtrate was freeze-dried to obtain 10.00 g of a powder (clathrate). 16 mg of this powder was dissolved in 200 μl of distilled water at room temperature, and no solid matter was deposited even after standing at room temperature for 1 day.

Example 95: Preparation of inclusion complex of compound (465) with 2-hydroxypropyl-β-cyclodextrin 2.50 g (5.46 mmol) of sulfate of compound (465) and 2-hydroxypropyl-β-cyclodextrin (Research Bioch
emicals International, H-107) (10.00 g, 7.49 mmol) was added to distilled water (400 ml), and the mixture was heated to 70 ° C. and completely dissolved.
This solution is filtered, the filtrate is freeze-dried, and powder (inclusion body)
12.50 g was obtained. 50 mg of this powder was dissolved in 1 ml of distilled water at room temperature, and no solid matter was deposited even after standing at room temperature for 1 day.

Experimental Example 1 Measurement of ADP Aggregation Inhibitory Activity of Human Platelets Platelet-rich plasma was prepared by centrifugation from blood collected from a healthy individual in the presence of 0.38% sodium citrate.
Used for measurement. Two minutes after the test compounds described in Table 1 were added to the platelet-rich plasma, ADP (adenosine-5'-diphosphate) at a concentration at which only primary aggregation was observed was 1 to 5 µm.
M was added to evaluate the suppression of ADP aggregation ability by the compound. The inhibitory rate was examined by changing the compound concentration, and the compound concentration (IC ₅₀ value) that inhibited aggregation by 50% was calculated.
It was taken as the activity of the compound. Table 1 shows the results.

[0338]

[Table 1]

Formulation Example 1: Tablet (1) Compound (I) of the present invention 10 mg (2) Fine granules 209 (manufactured by Fuji Chemical Co., Ltd.) 46.6 mg magnesium aluminate metasilicate 20% corn starch 30% lactose 50% (3) crystalline cellulose 24.0 mg (4) carboxymethylcellulose calcium 4.0 mg (5) magnesium stearate 0. Each of 4 mg (1), (3) and (4) is passed through a 100 mesh sieve in advance. These (1), (3), (4) and (2)
Was dried to a constant moisture content, and then mixed at the above weight ratio using a mixer. (5) was added to the mixed powder having a uniform quality and mixed for a short time (30 seconds).
One tablet was 85 mg. This tablet may be used, if necessary, as a gastric-soluble film coating agent (eg, polyvinyl acetal diethylaminoacetate).
Or an edible colorant.

Formulation Example 2: Capsule (1) Compound (I) of the present invention 50 g (2) Lactose 935 g (3) Magnesium stearate 15 g After weighing each of the above components, they are uniformly mixed, and the mixed powder is hard gelatin capsule. Was filled in 200 mg portions.

Formulation Example 3: Injection (1) Hydrochloride of present compound (I) 5 mg (2) Sucrose 100 mg (3) Physiological saline 10 ml The filtrate was aseptically dispensed into vials, filled with nitrogen gas, and sealed to give an intravenous injection.

[0342]

Industrial Applicability The novel fused ring carboxylic acid derivative (I) of the present invention and a pharmaceutically acceptable salt thereof have excellent GPIIb / IIIa antagonism against mammals including humans and are orally administered. It has a long blood life, low toxicity, and few side effects. Therefore, it is very useful for prevention and treatment of thrombotic diseases and the like.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/38 ABG A61K 31/38 ABG ABS ABS ABX ABX ACL ACL ACL ACV ACV ACY ACY ADP ADP ADS ADS ADU A2 ABN ABN ABN ABN A0 C07C 229/42 229/46 229/46 257/18 257/18 271/22 271/22 271/28 271/28 311/06 311/06 C07D 209/42 C07D 209/42 307/84 307/84 333 / 70 333/70 405/12 207 405/12 207 271/84 271/84 (72) Inventor Atsuyuki Ashimori 2- 25-1, Shodai Otani, Hirakata-shi, Osaka Midori Cross Central Research Institute Co., Ltd. (72) Invention Person Tomohiro Yoshida 2- 25-1, Invitation Otani, Hirakata City, Osaka Prefecture Inside the Midori Cross Research Laboratory Co., Ltd. (72) Inventor Masahiro Eda 2 Invitation Otani, Hirakata City, Osaka Prefecture No. 25-1 Inside the Midori Cross Central Research Institute Co., Ltd. (72) Inventor Mori Fumio 2-25-1 Otani, Hirakata City, Osaka Prefecture Inside Midori Cross Central Research Institute Co., Ltd. (72) Inventor Yoshihisa Inoue Hirakata City, Osaka Prefecture 2-25-1, Otani Inside Midori Cross Central Research Institute Co., Ltd. (72) Inventor Mitsuaki Imada 2-25-1, Otani Invitation, Hirakata City, Osaka Prefecture Midori Cross Central Research Institute Co., Ltd. (72) Inventor Ruriko Ikegawa Hirakata, Osaka Prefecture 2-25-1, Otani City, Midori-Cho, Japan Midori Cross Central Research Institute Co., Ltd. (72) Inventor: Wang Feng 2-25-1, Invitation Otani, Hirakata City, Osaka Prefecture, Japan Midori Cross Central Research Institute Co., Ltd. (72) Noriyoshi Nakamura Osaka, Osaka 2-25-1, Ohtani, Hirakata City, Fukushima City Inside Midori Cross Research Laboratory Co., Ltd. (56) References Table 9-507474 (JP, A) US Patent 5,865,525 (US, A) International Publication 95/16687 (WO, A1)

Claims (12)

(57) [Claims] 1. A compound of the formula (I) [Wherein A is the formula (1) (Wherein E represents hydrogen, alkyl, or a protecting group for amidino, guanidino or amino), and a group represented by the formula (2): (Wherein E is as defined above) or a group represented by the formula (3) E-NH- (CH ₂ ) _c − (3) (in the formula, E is as defined above, and c is 1, 2 or 3)
Wherein B is a group represented by the formula (4): Ｄwhere D is the formula (i) Wherein R ⁵ is hydrogen, alkyl, cycloalkyl or aralkyl, and Q is -O-, -S- or -NR ^6-
(R ⁶ is hydrogen, alkyl, cycloalkyl, aralkyl, alkylsulfonyl, aralkylsulfonyl, arylsulfonyl, alkanoyl, alkanoyl,
Aroyl, heteroarylcarbonyl or-(C
H ₂ ) _d -COOR ⁷ (R ⁷ represents hydrogen, alkyl, cycloalkyl or aralkyl, d represents 1, 2 or 3); G represents hydrogen, a hydroxyl group, alkyl, cycloalkyl, phenyl, Biphenylyl, pyridyl, aralkyl or E ¹ —NR ⁸ — (E ¹ represents a protecting group for hydrogen, alkyl or amino, and R ⁸ represents hydrogen, alkyl, cycloalkyl or aralkyl),
p and r are each independently 0 or 1, q is 0,
1, 2 or 3 is indicated. Provided that when p ≠ 0, at least one of q and r is a group represented by non-０, W is ＣＨCH— or ＮN—, and R ³ and R ⁴ may be the same or different; A hydrogen, an alkyl, a halogen, an alkanoyl, an alkanoyl, an aroyl, a heteroarylcarbonyl or an alkoxy, e represents a group represented by｝ representing 1 or 2, and a compound represented by the formula (5): (Wherein D is as defined above), a group represented by the formula (6): (Wherein J and T may be the same or different,
Each represents -CH <or -N <. D represents a group represented by the above formula (i), and when T indicates -N <, p = 0. R ³ has the same meaning as described above, and f represents 1, 2 or 3), a group represented by the formula (7): (Wherein E ² represents a protecting group for hydrogen, alkyl or amino, g represents 1, 2, 3 or 4; D and R ³
Is the same as defined above) or a group represented by the formula (8): (Wherein D, E ² , R ³ and g are as defined above), wherein L is —O—, —NR ⁹ — (R ⁹ is hydrogen, alkyl, cycloalkyl, aralkyl, shown alkanoyl, Al alkanoyl, aroyl or heteroarylcarbonyl), - S -, - SO 2 - or -CH ₂ - indicates, M is -NR ¹⁰ - (R ¹⁰ is hydrogen, alkyl, cycloalkyl or aralkyl R ¹ and R ² may be the same or different and each represents hydrogen, hydroxyl, alkyl, halogen, amino, alkanoyl, alkanoyl, aroyl, heteroarylcarbonyl or alkoxy. A represents 0 or 1, b represents 0, 1, 2 or 3. However, when a = 0, b = 0, and B is given by equation (5).
Or a group represented by the formula (6) (where J is -N <), and when a = 1 and b = 0, B is the formula (4) and the formula (6) (where J is- CH <), a group represented by the formula (7) or the formula (8). Or a pharmacologically acceptable salt thereof. 2. The fused ring carboxylic acid derivative according to claim 1, wherein B in the formula (I) is a group represented by the formula (4) or the formula (6), or a pharmacologically acceptable salt thereof. 3. In the formula (I), a = 1 and b = 0, and B is the formula (4) or the formula (6) (where J is -C
H <), and D represented by the formula (i)
The fused ring carboxylic acid derivative according to claim 1 or 2, wherein p + q + r ≦ 3, or a pharmaceutically acceptable salt thereof. 4. In the formula (I), a = 1 and b = 0, and B is the formula (4) or the formula (6) (where J is -C
4. The fused ring carboxylic acid derivative according to any one of claims 1 to 3, wherein p is a group represented by H <, f = 2), and p + q + r = 2 in D represented by the formula (i). Physically acceptable salts. 5. In the formula (I), L represents —O—, —NR
^9- (R ⁹ is as defined above) or -S-.
5. The condensed ring carboxylic acid derivative or the pharmacologically acceptable salt thereof according to any one of items 1 to 4. 6. The fused ring carboxylic acid derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein L in the formula (I) is —O—. 7. 4-[(5-amidino-2-benzofuranyl) carbonylamino] phenoxyacetic acid,
[(5-amidino-2-benzofuranyl) carbonylamino] -o-phenylene] dioxy] diacetate, 3- [4
-[(5-amidino-2-benzofuranyl) carbonylamino] phenyl] -2- (n-butylsulfonylamino) propionic acid, trans-3- [4-[(5-amidino-2-benzofuranyl) carbonylamino] cyclohexyl Ethyl propionate, trans-3- [4-
[(5-amidino-2-benzofuranyl) carbonylamino] cyclohexyl] propionic acid, trans- [4
-[(5-amidino-2-benzofuranyl) carbonylamino] cyclohexyloxy] ethyl acetate, trans- [4-[(5-amidino-2-benzofuranyl) carbonylamino] cyclohexyloxy] acetic acid, 3- [4
-[(5-amidino-2-benzofuranyl) carbonylamino] piperidino] propionic acid, trans- [4-
[(5-amidino-2-benzofuranyl) carbonylamino] cyclohexylamino] di-t-butyl diacetate, trans- [4-[(5-Amidino-2-benzofuranyl) carbonylamino] cyclohexylamino] diacetate, and trans- [4-[(6-amidinobenzo
[b] Thien-2-yl) carbonylamino] cyclohexyloxy] acetic acid, the fused ring carboxylic acid derivative according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof. 8. The formula (I ′) [Wherein R ⁵ represents hydrogen, alkyl, cycloalkyl or aralkyl, and Q represents -O-, -S- or -NR
⁶ - (R ⁶ is hydrogen, alkyl, cycloalkyl, aralkyl, alkylsulfonyl, aralkyl sulfonyl, arylsulfonyl, alkanoyl, Al alkanoyl, aroyl, heteroarylcarbonyl or -
(CH ₂ ) _d —COOR ⁷ (R ⁷ represents hydrogen, alkyl, cycloalkyl or aralkyl, d represents 1, 2 or 3), and L represents —O—, —NR ⁹ —.
(R ⁹ represents hydrogen, alkyl, cycloalkyl, aralkyl, alkanoyl, alkanoyl, aroyl or heteroarylcarbonyl), —S—, —SO ₂
- or -CH ₂ - indicates, M is -NR ¹⁰ - (R ¹⁰ represents hydrogen, alkyl, cycloalkyl or aralkyl), - O-or -S- are shown, R ¹ and R ² are the same or May be different, each hydrogen, hydroxyl,
Represents alkyl, halogen, amino, alkanoyl, alalkanoyl, aroyl, heteroarylcarbonyl or alkoxy. And a salt thereof, and a cyclodextrin or a derivative thereof. 9. A compound of the formula (I) [Wherein A is the formula (1) (Wherein E is hydrogen, alkyl, or amidino, guanine
Represents a protecting group for dino or amino)
And B is a group represented by the formula (4) : Ｄwhere D is the formula (i) Wherein R ⁵ is hydrogen, alkyl, cycloalkyl or
Aralkyl, Q is -O -, - S- or -NR ⁶ -
(R ⁶ is hydrogen, alkyl, cycloalkyl, alkyl)
, Alkylsulfonyl, aralkylsulfonyl,
Reelsulfonyl , alkanoyl, alkanoyl,
Aroyl, heteroarylcarbonyl or-(C
H ₂ ) _d —COOR ⁷ (R ⁷ is hydrogen, alkyl, cyclo
Alkyl or aralkyl, d is 1, 2 or 3
G) is hydrogen, a hydroxyl group, an alkyl,
Loalkyl, phenyl, biphenylyl, pyridyl, al
Alkyl or E ¹ —NR ⁸ — (E ¹ is hydrogen, alkyl
R or a protecting group for amino, R ⁸ is hydrogen,
Represents a kill, cycloalkyl or aralkyl)
p and r are each independently 0 or 1, q is 0,
1, 2 or 3 is indicated. However, when p ≠ 0, q and
at least one of r is a group represented by｝ which is not 0, and W is
= CH- or = N-, R ³ and R ⁴ are the same or
May be different, each of hydrogen, alkyl, halogen
, Alkanoyl, alalkanoyl, aroyl, hete
E is 1 or 2
Is a group represented by｝ which represents 2, and a compound represented by the formula (5) : (Wherein D is as defined above), a group represented by the formula (6) : (Wherein J and T may be the same or different,
Each represents -CH <or -N <. D is the above formula
Represents a group represented by (i), and when T represents -N <
p = 0. R ³ is as defined above, and f is 1, 2 or
Or 3), a compound represented by the formula (7) : (Wherein E ² is hydrogen, alkyl or amino
G represents 1, 2, 3 or 4; D and R ³
Is the same as defined above) or a group represented by the formula (8) : ( Wherein D, E ² , R ³ and g are as defined above)
A group of the, L is ^{-O -, - NR 9 - (} R 9 is hydrogen, alkyl, consequent
Loalkyl, aralkyl, alkanoyl, aralk
Represents noyl, aroyl or heteroarylcarbonyl
Be), - S -, - SO 2 - or -CH ₂ - indicates, M is -NR ¹⁰ - (R ¹⁰ is hydrogen, alkyl, cycloalkyl
Or -aralkyl), -O- or -S-
Shown, R ¹ and R ² may be the same or different, it
Hydrogen, hydroxyl, alkyl, halogen, amino, al, respectively
Canoyl, alalkanoyl, aroyl, heteroaryl
A represents 0 or 1; b represents 0, 1, 2 or 3
You. However, when a = 0, b = 0, and B is given by equation (5).
Or a group represented by the formula (6) (where J is -N <)
When a = 1 and b = 0, B is expressed by equation (4) and equation
(6) (where J is -CH <), Equation (7) or Equation
The group represented by (8) is shown. GPIIb / IIIa antagonists including fused ring carboxylic acid derivative or a pharmacologically acceptable salt thereof represented by]. 10. GPIIb / containing the clathrate according to claim 8
IIIa antagonists. 11. A compound of the formula (I) [In the formula, A is the formula (1). (Wherein E is hydrogen, alkyl, or amidino, guanine
Represents a protecting group for dino or amino)
B represents a group represented by the formula (4) : Ｄwhere D is the formula (i) Wherein R ⁵ is hydrogen, alkyl, cycloalkyl or
Aralkyl, Q is -O -, - S- or -NR ⁶ -
(R ⁶ is hydrogen, alkyl, cycloalkyl, alkyl)
, Alkylsulfonyl, aralkylsulfonyl,
Reelsulfonyl, alkanoyl, alkanoyl,
Aroyl, heteroarylcarbonyl or-(C
H ₂ ) _d —COOR ⁷ (R ⁷ is hydrogen, alkyl, cyclo
Alkyl or aralkyl, d is 1, 2 or 3
G) is hydrogen, a hydroxyl group, an alkyl,
Loalkyl, phenyl, biphenylyl, pyridyl, al
Alkyl or E ¹ —NR ⁸ — (E ¹ is hydrogen, alkyl
R or a protecting group for amino, R ⁸ is hydrogen,
Represents a kill, cycloalkyl or aralkyl)
p and r are each independently 0 or 1, q is 0,
1, 2 or 3 is indicated. However, when p ≠ 0, q and
at least one of r is a group represented by｝ which is not 0, and W is
= CH- or = N-, R ³ and R ⁴ are the same or
May be different, each of hydrogen, alkyl, halogen
, Alkanoyl, alalkanoyl, aroyl, hete
E is 1 or 2
Is a group represented by｝ which represents 2 and a compound represented by the formula (5) : Wherein D is as defined above, and a group represented by the formula (6) : (Wherein J and T may be the same or different,
Each represents -CH <or -N <. D is the above formula
Represents a group represented by (i), and when T represents -N <
p = 0. R ³ is as defined above, and f is 1, 2 or
Or 3), a compound represented by the formula (7) : (Wherein E ² is hydrogen, alkyl or amino
G represents 1, 2, 3 or 4; D and R ³
Is the same as defined above), or a group represented by the formula (8) : ( Wherein D, E ² , R ³ and g are as defined above)
A group of the, L is ^{-O -, - NR 9 - (} R 9 is hydrogen, alkyl, consequent
Loalkyl, aralkyl, alkanoyl, aralk
Represents noyl, aroyl or heteroarylcarbonyl
Be), - S -, - SO 2 - or -CH ₂ - indicates, M is -NR ¹⁰ - (R ¹⁰ is hydrogen, alkyl, cycloalkyl
Or -aralkyl), -O- or -S-
Shown, R ¹ and R ² may be the same or different, it
Hydrogen, hydroxyl, alkyl, halogen, amino, al, respectively
Canoyl, alalkanoyl, aroyl, heteroaryl
A represents 0 or 1; b represents 0, 1, 2 or 3
You. However, when a = 0, b = 0, and B is given by equation (5).
Or a group represented by the formula (6) (where J is -N <)
When a = 1 and b = 0, B is expressed by equation (4) and equation
(6) (where J is -CH <), Equation (7) or Equation
The group represented by (8) is shown. Agent for the prophylaxis or treatment of diseases caused by thrombus formation of platelets comprise fused rings carboxylic acid derivative or a pharmacologically acceptable salt thereof represented by]. A preventive / therapeutic agent for a disease caused by platelet thrombus formation, comprising the clathrate according to claim 8.