JP2001064166A - Cataplasm - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a cataplasm useful as a blood coagulation inhibitor or prophylactic/therapeutic agent for thrombosis by making the cataplasm include a medicament reserve layer comprising a specific aromatic amidine derivative or the like and a percutaneous absorption promoter so as to improve the percutaneous absorbability of the above aromatic amidine derivative or the like. SOLUTION: This cataplasm is obtained by including a medicament reserve layer comprising (A) an aromatic amidine derivative of formula I [R1 is H or a lower alkoxyl; R2 is H, a lower alkyl or the like; R3 is H, carboxyl or the like; R4 is H, a halogen or the like; n is 0-4; A is a 1-4 alkylene or the like optionally substituted with 1-2 carboxyl(s) or the like; X is a single bond, O, S or the like; Y is a (substituted) five- to six-membered heterocyclic ring or the like; a group of formula II is indolyl, naphthyl or the like], a salt thereof, solvent thereof or solvate of a salt thereof and (B) a percutaneous absorption promoter in the weight ratio B/A or pref. 0.01-100.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a patch of an aromatic amidine derivative which is useful as a blood coagulation inhibitor and a prophylactic / therapeutic agent for thrombus.

[0002]

BACKGROUND OF THE INVENTION A compound having an aromatic amidine structure in its chemical structure inhibits blood coagulation factor X and is useful as a blood coagulation inhibitor and a prophylactic / therapeutic agent for thrombus. Are described in JP-A-5-208946 and International Publication WO96 / 16940. Heretofore, intravenous administration and oral administration have generally been used as administration forms of these drugs acting on the blood coagulation system, and other administration forms have hardly been studied. Accordingly, an object of the present invention is to provide a new administration form of the aromatic amidine derivatives.

[0003]

The inventors of the present invention have conducted various studies on the absorbability of the above aromatic amidine derivatives by transdermal administration, and found that the patch was prepared by using this compound in combination with a transdermal absorption enhancer. If so, it was found that this compound was efficiently absorbed from the skin, and the effective blood concentration was maintained for a long time, and the present invention was completed.

That is, the present invention provides a compound represented by the general formula (1):

[0005]

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[Wherein, R ¹ represents a hydrogen atom or a lower alkoxyl group, and R ² represents a hydrogen atom, a lower alkyl group, a lower alkoxyl group, a carboxyl group, an alkoxycarbonyl group, a carboxyalkyl group or an alkoxycarbonylalkyl group. , R ³ is a hydrogen atom, a carboxyl group, an alkoxycarbonyl group, a carboxyalkyl group,
R ⁴ represents a hydrogen atom, a halogen atom, an amino group, a cyano group, a nitro group, a hydroxyl group, a lower alkyl group or a lower alkoxyl group, and n represents 0 to 5; an alkoxycarbonylalkyl group, a carboxyalkoxyl group or an alkoxycarbonylalkoxyl group; 4 represents the number, A is 1-2
Hydroxyalkyl group, carboxyl group, alkoxycarbonyl group, carboxyalkyl group or alkoxycarbonylalkyl group optionally having 1 to 4 carbon atoms,

[0007]

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In the formula, E represents a lower alkylene group or a carbonyl group, and R ⁵ is a hydrogen atom or a group represented by the formula —D—W—R ⁶ (where D is a group represented by the formula

[0009]

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Wherein Z represents an oxygen atom or a sulfur atom;

[0011]

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[0012] represents a group or a sulfonyl group represented by, W is a single bond or -NR ⁷ - in group represented by (wherein, R ⁷ is a hydrogen atom, a carbamoyl group, a lower alkoxycarbonyl group, mono- - or di - lower It represents an alkylaminocarbonyl group, a lower alkylsulfonyl group, a mono- or di-lower alkylaminothiocarbonyl group, a lower alkyl group which may have a substituent or a lower alkanoyl group which may have a substituent. ) And R
Reference numeral ⁶ represents a hydroxyl group, a lower alkoxyl group, a lower alkyl group which may have a substituent, an aryl group which may have a substituent, or a heteroaryl group which may have a substituent. ) Represents X, X represents a single bond, an oxygen atom, a sulfur atom or a carbonyl group, and Y represents a saturated or unsaturated 5- or 6-membered heterocyclic group or cyclic hydrocarbon which may have a substituent. Group, an amino group which may have a substituent or an aminoalkyl group which may have a substituent,

[0013]

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The group represented by represents a group selected from indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, naphthyl, tetrahydronaphthyl and indanyl.
The present invention provides a patch having a drug storage layer containing an aromatic amidine derivative represented by the following formula, a salt of the derivative, a solvate of the derivative or a solvate of a salt of the derivative, and a transdermal absorption enhancer. .

[0015]

BEST MODE FOR CARRYING OUT THE INVENTION The aromatic amidine derivative (1), a salt of the derivative, a solvate of the derivative or a solvate of a salt of the derivative used in the patch of the present invention is used as described above for blood coagulation. It is known that it inhibits factor X and is useful as a blood coagulation inhibitor and a prophylactic / therapeutic agent for blood clots (JP-A-5-208946 and WO 96/16940).

In the above general formula (1), the lower alkyl group may be any of a linear, branched or cyclic alkyl group having 1 to 6 carbon atoms, and a specific example is a methyl group. , Ethyl, propyl, isopropyl, butyl, secondary butyl, tertiary butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

The lower alkyl group may have a substituent. Examples of the group which can be substituted with the lower alkyl group include a halogen atom, a carboxyl group, a carbamoyl group, an amino group, a cyano group, a nitro group, a lower alkanoyl group, Lower alkoxyl group, lower alkoxycarbonyl group, mono- or di-lower alkylamino group, aryl group, aralkyloxy group, aryloxy group, mercapto group, lower alkylthio group, lower alkylthiocarbonyl group, hydroxyl group, carbamoyl group, mono- Or a di-lower alkylaminocarbonyl group.

The lower alkoxyl group may have 1 to 1 carbon atoms.
6, and specific examples include a methoxyl group, an ethoxyl group, a propoxyl group, an isopropoxyl group, a butoxyl group, a secondary butoxyl group and a tertiary butoxyl group. Examples of the alkoxycarbonyl group include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, a butoxycarbonyl group, and the like. Examples of the carboxyalkyl group include a carboxymethyl group, a carboxyethyl group, a carboxypropyl group, and the like.

Examples of the alkoxycarbonylalkyl group include a methoxycarbonylmethyl group, an ethoxycarbonylmethyl group, a propoxycarbonylmethyl group, a methoxycarbonylethyl group, an ethoxycarbonylethyl group, a methoxycarbonylpropyl group and an ethoxycarbonylpropyl group. Examples of the carboxyalkoxyl group include a carboxymethoxyl group, a carboxyethoxyl group, and a carboxypropoxyl group.Examples of the alkoxycarbonylalkoxyl group include a methoxycarbonylmethoxyl group, an ethoxycarbonylmethoxyl group,
Examples include a propoxycarbonylmethoxyl group, a methoxycarbonylethoxyl group, and an ethoxycarbonylethoxyl group. Examples of the hydroxyalkyl group include a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, and a hydroxybutyl group. C 1-4
Examples of the alkylene group include a methylene group, an ethylene group, a trimethylene group, and a tetramethylene group.

As the mono- or di-lower alkylaminocarbonyl group, mono-lower alkylaminocarbonyl groups such as methylaminocarbonyl group, ethylaminocarbonyl group, propylaminocarbonyl group, isopropylaminocarbonyl group, butylaminocarbonyl group, Examples include an isobutylaminocarbonyl group, a pentylaminocarbonyl group, an isopentylaminocarbonyl group, a hexylaminocarbonyl group, and an isohexylaminocarbonyl group. Further, as the dialkylaminocarbonyl group, a dimethylaminocarbonyl group, a diethylaminocarbonyl group, a dipropylaminocarbonyl group, a diisopropylaminocarbonyl group, a dibutylaminocarbonyl group, a symmetric type di-substituted with a lower alkyl group such as dipentylaminocarbonyl group. Dialkylaminocarbonyl group, and different lower alkyl groups such as ethylmethylaminocarbonyl group, methylpropylaminocarbonyl group, ethylpropylaminocarbonyl group, butylmethylaminocarbonyl group, butylethylaminocarbonyl group, butylpropylaminocarbonyl group, etc. And a disubstituted asymmetric dialkylaminocarbonyl group.

The lower alkylsulfonyl group includes methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, pentylsulfonyl,
Examples include an isopentylsulfonyl group, a hexylpropyl group, and an isohexylpropyl group.

Mono- or di-lower alkylaminothiocarbonyl groups include mono-lower alkylaminothiocarbonyl groups such as methylaminothiocarbonyl group, ethylaminothiocarbonyl group, propylaminothiocarbonyl group and isopropylaminothiocarbonyl group. Butylaminothiocarbonyl group, isobutylaminothiocarbonyl group, pentylaminothiocarbonyl group,
Examples include an isopentylaminothiocarbonyl group, a hexylaminothiocarbonyl group, and an isohexylaminothiocarbonyl group. Further, as a dialkylaminothiocarbonyl group, a dimethylaminothiocarbonyl group, a diethylaminothiocarbonyl group, a dipropylaminothiocarbonyl group, a diisopropylaminothiocarbonyl group,
A symmetric dialkylaminothiocarbonyl group di-substituted with a lower alkyl group such as a dibutylaminothiocarbonyl group or a dipentylaminothiocarbonyl group; and an ethylmethylaminothiocarbonyl group, a methylpropylaminothiocarbonyl group, an ethylpropylaminothio group. Asymmetric dialkylaminothiocarbonyl groups disubstituted with different lower alkyl groups such as carbonyl group, butylmethylaminothiocarbonyl group, butylethylaminothiocarbonyl group, and butylpropylaminothiocarbonyl group are exemplified.

The lower alkanoyl group includes formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group, hexanoyl group, etc., preferably acetyl group, propionyl group, butyryl group. And more preferably an acetyl group or a propionyl group. The lower alkanoyl group may have a substituent. In addition, as a group that can be substituted with a lower alkanoyl group, a halogen atom, a carboxyl group, a carbamoyl group, an amino group, a cyano group,
Nitro group, lower alkanoyl group, lower alkoxyl group,
Lower alkoxycarbonyl group, mono- or di-lower alkylamino group, aryl group, aralkyloxy group,
Examples include an aryloxy group, a mercapto group, a lower alkylthio group, a lower alkylthiocarbonyl group, a hydroxyl group, a carbamoyl group, and a mono- or di-lower alkylaminocarbonyl group.

Examples of the aryl group include a phenyl group, a naphthyl group, a biphenyl group and an anthryl group, and the aryl group may have a substituent. As a heteroaryl group, a furyl group, a thienyl group, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, an isothiazolyl group, an isoxazolyl group, a pyridyl group, a pyrimidinyl group, a quinolyl group,
Isoquinolyl, quinazolinyl, quinolizinyl, quinoxalinyl, cinnolinyl, benzimidazolyl, imidazopyridyl, benzofuranyl, naphthyridinyl, 1,2-benzoisoxazolyl, benzoxazolyl, benzothiazolyl, oxa Zolopyridyl group, isothiazolopyridyl group, benzothienyl group, etc., preferably, furyl group, thienyl group, pyrrolyl group, imidazolyl group, pyridyl group, etc., and the heteroaryl group has a substituent. Is also good.

The groups which can be substituted on these aryl groups or heteroaryl groups include halogen atoms, carboxyl groups, amino groups, cyano groups, nitro groups, hydroxyl groups,
Examples include a lower alkoxy group, a lower alkoxycarbonyl group, a mono- or di-lower alkylamino group, a lower alkanoyl group, and a lower alkyl group which may have a substituent.

The saturated or unsaturated 5- or 6-membered heterocyclic group is preferably a heterocyclic group containing one or two nitrogen or oxygen atoms as a hetero atom. Specific examples of such heterocycles include pyrrolidine, piperidine,
Examples thereof include imidazoline, piperazine, tetrahydrofuran, hexahydropyrimidine, pyrrole, imidazole, pyrazine, pyrrolidinone, piperidinone, and morpholine. Of these, pyrrolidine and piperidine are particularly preferable. Examples of the saturated or unsaturated cyclic hydrocarbon group include a cyclopentyl group and a cyclohexyl group. Examples of the aminoalkyl group include an aminomethyl group, an aminoethyl group, an aminopropyl group, and the like.

The heterocyclic group or cyclic hydrocarbon group may have a substituent. Examples of the group which can be substituted on the heterocyclic group or cyclic hydrocarbon group include a lower alkyl group, a lower alkanoyl group and a carbamoyl group. Group, monoalkylcarbamoyl group, dialkylcarbamoyl group, formimidoyl group, alkanoimidoyl group, benzimidoyl group, carboxyl group, alkoxycarbonyl group, carboxyalkyl group, alkylcarbonylalkyl group, aminoalkyl group, alkanoylamino group, alkanoylamino Examples include an alkyl group, an imino group, and an alkoxycarbonylimino group.

The group which can be substituted on the amino group of the amino group or the aminoalkyl group includes a lower alkyl group,
Examples include a pyrrolidinyl group, a pyrazyl group, a carbamoyl group, a monoalkylcarbamoyl group, a dialkylcarbamoyl group, a lower alkanoyl group, a formimidoyl group, an alkanoimidoyl group, a benzimidoyl group, and an alkoxycarbonyl group.

The alkyl group, alkoxyl group, alkanoyl group and the like, and the alkyl, alkoxyl and alkanoyl groups in each substituent preferably have 1 to 6 carbon atoms.

[0030]

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As the group represented by benzofuranyl,
Particularly preferred are groups selected from benzimidazolyl, indolyl, benzothienyl, benzothiazolyl, naphthyl and tetrahydronaphthyl.

The aromatic amidine derivative represented by the general formula (1), a salt of the derivative, a solvate of the derivative or a solvate of a salt of the derivative according to the present invention has an asymmetric carbon atom. In such a case, optical isomers or stereoisomers based on asymmetric carbon atoms exist, and all of these optical isomers, stereoisomers, and mixtures thereof are included in the present invention.

In the present invention, among the above-mentioned aromatic amidine derivatives (1), salts of the derivatives, solvates of the derivatives or solvates of the salts of the derivatives, the following compounds,
The salts or solvates thereof are preferred. 2- [4-
[((3S) -1-acetimidoyl-3-pyrrolidinyl) oxy] phenyl] -3- (7-amidino-2-naphthyl) propionic acid, (+)-2- [4-[((3
S) -1-Acetimidoyl-3-pyrrolidinyl) oxy] phenyl] -3- (7-amidino-2-naphthyl)
Propionic acid, (2S) -2- [4-[((3S) -1
-Acetimidoyl-3-pyrrolidinyl) oxy] phenyl] -3- (7-amidino-2-naphthyl) propionic acid, (2R) -2- [4-[((3R) -1-acetimidoyl-3 -Pyrrolidinyl) oxy] phenyl]-
3- (7-amidino-2-naphthyl) propionic acid, 2
-[4-[(1-acetimidoyl-4-piperidyl)
Oxy] phenyl] -3- (7-amidino-2-naphthyl) propionic acid, (+)-2- [4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl] -3
-(7-amidino-2-naphthyl) propionic acid, 2-
[4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl] -3- (5-amidinobenzo [b] thien-2-yl) propionic acid, 2- [4-[((2
S) -1-Acetimidoyl-2-pyrrolidinyl) meloxy] phenyl] -3- (5-amidinobenzo [b] thien-2-yl) propionic acid, (+)-2- [4-
[((2S) -1-acetimidoyl-2-pyrrolidinyl) methoxy] phenyl] -3- (5-amidinobenzo [b] thien-2-yl) propionic acid, 3- [4-
[((3S) -1-acetimidoyl-3-pyrrolidinyl) oxy] phenyl] -4- (5-amidinobenzo [b] thien-2-yl) butyric acid, 2- [4-[((3
S) -1-Acetimidoyl-3-pyrrolidinyl) oxy] phenyl] -3- (6-amidino-1-ethyl-2
-Indolyl) propionic acid, 2- [4-[((3R)
-1-acetimidoyl-3-pyrrolidinyl) oxy]
Phenyl] -3- (6-amidino-1-ethyl-2-indolyl) propionic acid, 2- [4-[(1-acetimidoyl-4-piperidinyl) oxy] phenyl] -3
-(6-amidino-1-ethyl-2-indolyl) propionic acid, N- [4-[(1-acetimidoyl-4-
Piperidyl) oxy] phenyl] -N-[(7-amidino-2-naphthyl) methyl] -N'-methylsulfamide, ethyl N- [N-4-[(1-acetimidoyl-4-piperidyl) [Oxy] phenyl] -N-[(7-
Amidino-2-naphthyl) methyl] sulfamoyl] carbamate, 4- [N-4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl] -N-[(7-
Amidino-2-naphthyl) methyl] sulfamoyl] benzoic acid, N- [4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl] -N-
[(7-Amidino-2-naphthyl) methyl] sulfamoylacetic acid, ethyl N- [N- [4-
[(1-acetimidoyl-4-piperidyl) oxy]
Phenyl] -N-[(7-amidino-2-naphthyl) methyl] sulfamoyl] glycinate, N- [N-4-
[(1-acetimidoyl-4-piperidyl) oxy]
Phenyl] -N-[(7-amidino-2-naphthyl) methyl] sulfamoyl] -N-ethoxycarbonylglycine and N- [N-4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl] -N-[(7-
Amidino-2-naphthyl) methyl] sulfamoyl] glycine.

Particularly preferred is (2S) -2- [4
-[((3S) -1-acetimidoyl-3-pyrrolidinyl) oxy] phenyl] -3- (7-amidino-2-
Naphthyl) propionic acid, (+)-2- [4-[(1-
Acetimidyl-4-piperidyl) oxy] phenyl] -3- (7-amidino-2-naphthyl) propionic acid, (+)-2- [4-[((2S) -1-acetimidoyl-2-) Pyrrolidinyl) methoxy] phenyl] -3
-(5-amidinobenzo [b] thien-2-yl) propionic acid, ethyl N- [N- [4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl] -N-
[(7-Amidino-2-naphthyl) methyl] sulfamoyl] glycinate, N- [N-4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl] -N-
[(7-Amidino-2-naphthyl) methyl] sulfamoyl] glycine and N- [4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl] -N-
[(7-amidino-2-naphthyl) methyl] sulfamoylacetic acid, a salt thereof, a solvate thereof, or a solvate of these salts.

Further, (2S) -2- [4-[((3
S) -1-Acetimidoyl-3-pyrrolidinyl) oxy] phenyl] -3- (7-amidino-2-naphthyl)
Propionic acid hydrochloride pentahydrate, (+)-2- [4-
[(1-acetimidoyl-4-piperidyl) oxy]
Phenyl] -3- (7-amidino-2-naphthyl) propionic acid dihydrochloride, (+)-2- [4-[((2S)
-1-acetimidoyl-2-pyrrolidinyl) methoxy] phenyl] -3- (5-amidinobenzo [b] thien-2-yl) propionic acid dihydrochloride, ethyl N-
[N- [4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl] -N-[(7-amidino-2-
Naphthyl) methyl] sulfamoyl] glycinate 2
Hydrochloride, N- [N-4-[(1-acetimidoyl-4
-Piperidyl) oxy] phenyl] -N-[(7-amidino-2-naphthyl) methyl] sulfamoyl] glycine dihydrochloride and N- [4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl ] -N-[(7
-Amidino-2-naphthyl) methyl] sulfamoylatic acid dihydrochloride is preferred.

The substance (transdermal absorption enhancer) which promotes the percutaneous absorption of the above-mentioned amidine derivative (1), the salt of the derivative, the solvate of the derivative or the solvate of the salt of the derivative is alcohol. , Polyhydric alcohols, higher alkanes, higher fatty acids, higher fatty acid esters, terpenes, alkyl sulfates, alkylamine oxides, carboxybetaines, polyoxyalkylene alkyl ethers, sulfoxides, amides and oxycarboxylic acids One or two or more selected from Among them, alcohols, polyhydric alcohols, higher fatty acids, higher fatty acid esters, terpenes, alkyl sulfates, alkylamine oxides, carboxybetaines, polyoxyalkylene alkyl ethers, amides and oxycarboxylic acids are selected. One or more of these are more preferred.

Among the above-mentioned percutaneous absorption enhancers, the alcohol is preferably a saturated aliphatic alcohol having 2 to 18 carbon atoms or an arylalkanol having 7 to 14 carbon atoms, and specific examples thereof include those having 2 carbon atoms such as ethanol and isopropanol. ~
Alcohol having 4 to 7 carbon atoms such as benzyl alcohol
2, aryl alcohol, 1-octanol, 1-nonanol, 1-decanol, 1-dodecanol, stearyl alcohol and the like.

Examples of the polyhydric alcohol include alkylene glycols having 2 to 4 carbon atoms, glycerin, polyethylene glycol, polypropylene glycol, polyglycerin,
Sorbitan and the like, specific examples of which include ethylene glycol, propylene glycol, butylene glycol,
Glycerin, polyethylene glycol, sorbitan and the like can be mentioned. As the higher alkane, an alkane having 6 to 12 carbon atoms is preferable, and specific examples are n-heptane and n-heptane.
-Nonane, n-dodecane and the like. As the higher fatty acid, a saturated or unsaturated fatty acid having 6 to 24 carbon atoms is preferable, and among them, a saturated or unsaturated fatty acid having 6 to 16 carbon atoms is more preferable. Specific examples of higher fatty acids include caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, and oleic acid.

As the higher fatty acid esters, esters of a monohydric alcohol or a polyhydric alcohol with a fatty acid having 6 to 24 carbon atoms are preferable.
Esters with a fatty acid having from 24 to 24 are more preferred, and esters with a polyhydric alcohol and a fatty acid having from 6 to 16 carbon atoms are still more preferred. Here, examples of the polyhydric alcohol include ethylene glycol, polyethylene glycol, propylene glycol, polypropylene glycol, glycerin, polyglycerin, and sorbitan. Examples of fatty acids that form esters with these polyhydric alcohols include caproic acid, caprylic acid, capric acid, lauric acid, and myristic acid. Among these polyhydric alcohol fatty acid esters, polyhydric alcohol monofatty acid esters are preferable, and polyhydric alcohol mono-C ₆ -C
₁₆ fatty acid esters are more preferable, glycerin mono fatty acid ester is further preferable, and glycerin mono C ₆ -C
₁₆ fatty acid esters are particularly preferred. Specific examples of the glycerin monofatty acid ester include glycerin monocaproate, glyceryl monocaprylate, and glycerin monocaprate. Of these, glyceryl monocaprylate is particularly preferred.

Examples of terpenes include monoterpenes and sesquiterpenes, and specific examples include cineol,
l-menthol, menthone, d-limonene, nerolidol and the like. As alkyl sulfates,
Alkyl sulfate salts having 6 to 24 carbon atoms are preferred,
Examples thereof include decyl sulfate, lauryl sulfate, and tetradecyl sulfate. Of these, alkali metal lauryl sulfate is more preferred, and sodium lauryl sulfate is particularly preferred. As the alkylamine oxides, alkyldimethylamine oxides are preferable, and alkyldimethylamine oxides having 6 to 24 carbon atoms are more preferable. Specific examples include decyldimethylamine oxide, lauryldimethylamineoxide, and tetradecyldimethylamineoxide. No. As carboxybetaines,
Alkyl dimethylaminoacetic acids are preferred, and have 6 to 6 carbon atoms.
24 alkyldimethylaminoacetic acids are more preferred. Specific examples thereof include decyldimethylaminoacetic acid, dodecyldimethylaminoacetic acid, and tetradecyldimethylaminoacetic acid. Oxycarboxylic acids include those having 2 carbon atoms.
And those of -10 are preferred, and specific examples of the oxycarboxylic acid include lactic acid, citric acid, glyceric acid, tartaric acid, tropic acid, and benzyl acid, and lactic acid is particularly preferred.

Examples of the polyoxyalkylene alkyl ethers include polyoxyethylene alkyl ether and polyoxypropylene alkyl ether.
Polyoxyethylene alkyl ethers are preferred, and polyoxyethylene C ₆ -C _{2 4} alkyl ether. Sulfoxides include dialkyl sulfoxides, for example, dimethyl sulfoxide. As amides, N, N-dialkylformamide,
N, N-dialkylacetamide, N, N-dialkyltoluamide, N-hydroxyalkyl lactamide, pyrrolidone, N-alkylpyrrolidone and the like,
More specifically, N, N-dimethylformamide, N, N
-Dimethylacetamide, N, N-diethyltoluamide, N-hydroxyethyl lactamide, 2-pyrrolidone, N-octyl-2-pyrrolidone and the like.

Among the above-mentioned percutaneous absorption enhancers, C_Two-C_FourA
Lucor, C₇-C₁₂Aryl alkanol, C₆-C₁₈
Saturated aliphatic alcohol, polyhydric alcohol, C₆-C₁₆Fat
Fatty acids, monoterpenes, sesquiterpenes, polyhydric alcohols
Product C₆-C₁₆Fatty acid ester, C₆-C_{twenty four}Alkyl sulfate
Ester salt, C₆-C_{twenty four}Alkyl dimethylamine oxy
C₆-C_{twenty four}Alkyl dimethylaminoacetic acid, polyethylene
Len glycol C₆-C _{twenty four}Alkyl ether, pyrrolide
, N-alkylpyrrolidone, N, N-dialkylform
Muamide, N, N-dialkyltoluamide and lactic acid
One or a combination of two or more selected from the above is preferable.

Further, ethanol, isopropanol,
Benzyl alcohol, ethylene glycol, propylene glycol, glycerin, 1-nonanol, 1-decanol, stearyl alcohol, caproic acid, caprylic acid, capric acid, d-limonene, cineol, propylene glycol monocaprylate, glyceryl monocaprylate, monocaprin Glycerin acid, lauryl dimethylamine oxide, dodecyl N, N-dimethylaminoacetic acid, sodium lauryl sulfate, polyoxyethylene lauryl ether, N, N-diethyltoluamide, 2-pyrrolidone, N-octyl-2-pyrrolidone and lactic acid One or a combination of two or more of these is more preferable.

Furthermore, C_Two-C_FourAlcohol, C₇−
C₁₂Aryl alkanol, C₆-C ₁₈Saturated aliphatic al
Cole, C₆-C₁₆Fatty acids, monoterpenes, pyrrolidone
And one selected from N-alkylpyrrolidone or
A combination of two or more is preferred. More specifically,
Knol, capric acid, benzyl alcohol, 1-nonano
, N-octyl-2-pyrrolidone and d-limone
One or a combination of two or more selected from
More preferably, 1 to 4 combinations are more preferable. here
5 to 90% by weight of ethanol, 0.1 to 1 of capric acid
0% by weight, benzyl alcohol is 0.1 to 30% by weight,
1-nonanol is 0.1 to 10% by weight, N-octyl 2
-Pyrrolidone is preferably 0.1-20% by weight
No. Examples of combinations of two or more of these include ethanol
And capric acid; benzyl alcohol and capric acid;
Benzyl alcohol and d-limonene; ethanol and cap
Phosphoric acid and 1-nonanol; ethanol and capric acid and d
-Limonene; ethanol, benzyl alcohol and 1-no
Nanol; ethanol, benzyl alcohol and d-limo
Nene; ethanol, N-octyl-2-pyrrolidone and
Prulinic acid; ethanol, benzyl alcohol and 1-nona
Nol and capric acid; capric acid and benzyl alcohol
And d-limonene and ethanol; capric acid and benzyl acetate
Rucol, d-limonene, 1-nonanol and ethanol
Each combination. This composition is transdermal
Excellent and also good in terms of skin irritation and drug stability
Excellent percutaneous absorption promoting composition that can be used in transdermal preparations
Things.

The compounding ratio of the aromatic amidine derivative (1), the salt of the derivative, the solvate of the derivative or the solvate of the salt of the derivative and the transdermal absorption enhancer in the drug storage layer of the patch of the present invention. Is not particularly limited, but a transdermal absorption enhancer is used in a weight ratio of 0.01 to the aromatic amidine derivative (1), a salt of the derivative, a solvate of the derivative or a solvate of the salt of the derivative. It is preferably from 100 to 100 times, more preferably from 0.1 to 10 times, particularly preferably from 0.2 to 5 times. The amount of the aromatic amidine derivative (1), the salt of the derivative, the solvate of the derivative or the solvate of the salt of the derivative in the drug storage layer is preferably 0.0001 to 60% by weight,
0.001 to 50% by weight is more preferable, and 0.1 to 30% by weight.
% By weight is particularly preferred. The total amount of the transdermal absorption enhancer is preferably 0.0001 to 60% by weight.
001 to 50% by weight is more preferable, and 0.1 to 50% by weight is particularly preferable. In addition, when two or more transdermal absorption enhancers are combined and compounded, the compounding ratio is not particularly limited,
It is preferable that the weight ratio be 1/50 to 50/1.

The drug storage layer is in a liquid or semi-solid state. In preparing these layers, various known pharmaceutically acceptable carriers (additives) may be added as necessary. it can. Examples of such additives include a base for external use, an emulsifier, a suspending agent, a preservative, a stabilizer, a thickener, a gelling agent, and water.

The patch of the present invention basically comprises a backing material layer,
A patch comprising a drug storage layer, an adhesive layer, and a drug release film. The drug release film is present between the drug storage layer and the adapted skin surface, and is used to control the release of a drug or an accelerator from the drug storage layer. Further, an adhesive layer may or may not be provided between the drug releasing film and the applied skin surface, and the drug that has passed through the drug releasing film may be directly distributed to the skin, or may be distributed to the skin via the adhesive layer. Or any of them. Here, as the drug release film, an ethylene-vinyl acetate copolymer is the most common, but in the present invention, one or more polymer films selected from polycarbonate, polypropylene, polyethylene, polyurethane and polyethylene terephthalate are used. Is more preferable since the release property of the medicinal component from the drug storage layer to the skin is good.
The drug release film may be a single layer or a laminate of two or more layers. The drug release film may be non-porous or porous, but preferably has good porosity, and preferably has a pore size of 0.001 to 100 μm.

The drug storage layer resides in the space formed by the outer backing layer and the drug release membrane. Here, it is desirable that the film serving as the backing layer can be easily bonded to the drug release film. Specifically, aluminum, ethylene-vinyl acetate copolymer, cellulose, cellulose acetate, nylon, polyester, polyethylene,
Materials such as polyvinylidene chloride, polyvinyl chloride, and polypropylene can be used. These materials may be laminated as necessary to adjust the flexibility as a film, the adhesiveness with a drug release film, and the barrier property to a drug component.

Further, the adhesive layer needs to have an adhesive property for fixing the patch to the skin surface, and it is desirable that the adhesive layer has excellent skin safety. The adhesive layer may be provided by any method as long as it can be fixed to the skin, and may be used in any method such as a method of providing the entire surface of the patch-applied surface, a part thereof (discontinuous, mesh-like, or the like), or a method of providing only the peripheral portion. be able to. Specifically, acrylate copolymer, sodium carboxymethylcellulose, styrene-isoprene-styrene block copolymer, natural rubber, vinyl ether copolymer, sodium polyacrylate, polydimethylsiloxane, methacrylate polymer, etc. A pressure-sensitive adhesive as a base polymer may be mentioned, and well-known additives can be blended as needed for adjusting the adhesiveness and safety.

In the patch of the present invention, a release liner can be provided on the adhesive layer, and a known material can be used for the film to be the release liner layer. Specific examples include aluminum, cellulose, polyester, and the like. Polyethylene, polypropylene and the like are preferable, and these films may be laminated as necessary. In addition, the surface can be treated with silicone, a surfactant or a fluorocarbon, or a known additive can be added to the release liner material, or the release liner surface can be made uneven to remove the pressure-sensitive adhesive. The peelability at the time of peeling may be adjusted.

The patch of the present invention preferably has a shape such as a circle, an ellipse, and a polygon. The size of the patch was 2 to 200 as the area of the surface releasing the drug.
It is preferably in the range of cm ² .

[0052]

Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

Test Example 1 (in vivo via drug release membrane)
(tro skin permeability test) Each drug-releasing membrane was placed on the stratum corneum side of the excised skin, sandwiched between horizontal cells, and each donor solution or suspension was applied to the drug-releasing membrane side, and (2S) -2- [4-[((3S) -1-
Cumulative permeation of acetimidoyl-3-pyrrolidinyl) oxy] phenyl] -3- (7-amidino-2-naphthyl) propionic acid hydrochloride pentahydrate (hereinafter referred to as compound A) at 48 hours per unit area Quantity Q (μg / cm ² )
Was calculated, and skin permeability through the drug release membrane was compared (n = 3). The experimental conditions are as follows.

<Experimental conditions> Skin: skin extirpated from the back of Yucatan minipig (5 months old) Apparatus: horizontal cell capacity 0.8 mL, effective area 0.2827 cm
² (37 ° C) Donor side: Compound A 50 mg / mL or suspension (saline solution)
Liquid containing various percutaneous absorption enhancers on the receiver side; 0.05 mol / L phosphate buffer (pH 6.8) containing 0.01% benzalkonium chloride solution Preparation of sample solution: Receiver solution at regular intervals Sample 0.3 mL. 0.15 each sample solution
Take a mL of the solution, accurately add 0.15 mL of a methanol solution of methyl p-hydroxybenzoate as a sample solution, and measure the amount of Compound A permeated through the skin using HPLC. Table 1 shows the obtained results. The abbreviations in Table 1 are as follows. CA: capric acid, NA: nonanol, EtOH: ethanol, BA: benzyl alcohol, DL: d-limonene, OP: N-octyl-2-pyrrolidone Saline: saline (0.1% polyoxyethylene sorbitan monolaurate) % And benzalkonium chloride 0.01%) EVA film: ethylene-vinyl acetate copolymer film EVOH film: ethylene-vinyl alcohol copolymer resin film PC film: polycarbonate film PP film: polypropylene film PE film: polyethylene film PET Film: polyethylene terephthalate film

[0055]

[Table 1]

Test Example 2 Each sample composition shown in Table 2 was added to a container (backing material layer) made of a polyester or polypropylene film, each drug release film was superimposed thereon, and the sample liquid was sealed by heat sealing, followed by attachment. An agent was prepared. Using this patch, 4 per unit area of Compound A from each preparation was used.
The accumulated permeation amount Q (μg / cm ² ) at the 8th hour was calculated, and the permeabilities were compared (n = 3).

<Experimental conditions> Skin: skin extirpated from the back of Yucatan mini-pig (5 months old). Applicable area of 0.95 cm ^{2 in} Table 2 is a Franz diffusion cell. Apparatus: Applicable area of 1.5 cm ^{2 in} Table 2. For 2.0 cm ² , 6 well cells: cell volume 1.2 mL (37 ° C.) Receiver side: Same as Test Example 1. Preparation of sample solution: Same as in Test Example 1. Tables 2 to 4 show the obtained results. The abbreviations in Tables 2 to 4 are the same as in Table 1.

[0058]

[Table 2]

[0059]

[Table 3]

[0060]

[Table 4]

From Tables 1 to 4, it can be seen that the patch of the present invention has better skin permeability than the matrix patch. Furthermore, when a polymer film of polypropylene, polyethylene, polycarbonate or polyethylene terephthalate is used as the drug release film, it shows higher permeability than when an ethylene-vinyl acetate copolymer film is used. It turns out that it is especially preferable.

[0062]

According to the present invention, a patch with improved percutaneous absorbability of aromatic amidine conductors can be obtained.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) A61K 31/4535 A61K 31/4535 31/454 31/454 47/10 47/10 47/12 47/12 47 / 14 47/14 47/16 47/16 47/20 47/20 A61P 7/02 A61P 7/02 C07D 207/12 C07D 207/12 211/46 211/46 // C07D 401/06 401/06 403 / 06 403/06 409/06 409/06 (72) Inventor Yoshiki Sugizaki 8-1, Minamisakaemachi, Kasukabe City, Saitama Prefecture Saitama Daiichi Pharmaceutical Co., Ltd. (72) Inventor Hideo Mizu 8-1, Minamisakaemachi Kasukabe City, Saitama Saitama Daiichi Pharmaceutical Co., Ltd.

Claims (25)

[Claims] 1. A compound of the general formula (1) Wherein, R ¹ represents a hydrogen atom or a lower alkoxyl group, R ² represents a hydrogen atom, a lower alkyl group, lower alkoxyl group, a carboxyl group, an alkoxycarbonyl group, carboxyalkyl group or alkoxycarbonylalkyl group, R ³ Represents a hydrogen atom, a carboxyl group, an alkoxycarbonyl group, a carboxyalkyl group, an alkoxycarbonylalkyl group, a carboxyalkoxyl group or an alkoxycarbonylalkoxyl group, and R ⁴ represents a hydrogen atom, a halogen atom, an amino group, a cyano group, a nitro group, a hydroxyl group Represents a lower alkyl group or a lower alkoxyl group, n represents a number of 0 to 4, A represents 1 to 2 hydroxyalkyl groups, carboxyl groups, alkoxycarbonyl groups, carboxyalkyl groups or alkoxycarbonylalkyl groups. Alkylene group or a group represented by the formula of 1 to 4 carbon atoms which may be embedded image In the formula, E represents a lower alkylene group or a carbonyl group, and R ⁵ represents a hydrogen atom or a formula -D-W-
A group represented by R ⁶ , wherein D is a group represented by the formula: (Wherein Z represents an oxygen atom or a sulfur atom), a compound represented by the formula: And W represents a single bond or a group represented by —NR ⁷ — (wherein R ⁷ is a hydrogen atom, a carbamoyl group, a lower alkoxycarbonyl group, a mono- or di-lower alkylaminocarbonyl) A lower alkylsulfonyl group, a mono- or di-lower alkylaminothiocarbonyl group, a lower alkyl group which may have a substituent or a lower alkanoyl group which may have a substituent.) And R ⁶ represent a hydroxyl group, a lower alkoxyl group, a lower alkyl group which may have a substituent, an aryl group which may have a substituent, or a heteroaryl group which may have a substituent. ) Represents X, X represents a single bond, an oxygen atom, a sulfur atom or a carbonyl group, and Y represents a saturated or unsaturated 5- or 6-membered heterocyclic group or cyclic hydrocarbon which may have a substituent. A group, an amino group which may have a substituent or an aminoalkyl group which may have a substituent; Represents a group selected from indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, naphthyl, tetrahydronaphthyl and indanyl), an aromatic amidine derivative represented by the formula: A patch having a drug storage layer containing a solvate of a derivative or a solvate of a salt of the derivative and a transdermal absorption enhancer. 2. The transdermal absorption enhancer comprises alcohols, polyhydric alcohols, higher alkanes, higher fatty acids, higher fatty acid esters, terpenes, alkyl sulfates, alkylamine oxides, carboxybetaines, polyoxyalkylenes. Alkyl ethers, sulfoxides,
The patch according to claim 1, wherein the patch is one or more selected from amides and oxycarboxylic acids. 3. The method according to claim 1, wherein the drug release film between the drug storage layer and the applied skin surface is made of polycarbonate, polypropylene,
The patch according to claim 1 or 2, which is one or more polymer films selected from polyethylene, polyurethane and polyethylene terephthalate. 4. The patch according to claim 2, wherein the alcohol is a saturated aliphatic alcohol having 2 to 18 carbon atoms or an arylalkanol having 7 to 14 carbon atoms. 5. The patch according to claim 2, wherein the polyhydric alcohol is selected from alkylene glycols having 2 to 4 carbon atoms, glycerin, polyethylene glycol, polypropylene glycol, polyglycerin and sorbitan. 6. The patch according to claim 2, wherein the higher alkane is an alkane having 6 to 12 carbon atoms. 7. The patch according to claim 2, wherein the higher fatty acid is a saturated or unsaturated fatty acid having 6 to 24 carbon atoms. 8. The patch according to claim 2, wherein the higher fatty acid ester is an ester of a polyhydric alcohol and a fatty acid having 6 to 24 carbon atoms. 9. The patch according to claim 2, wherein the terpene is selected from cineol, 1-menthol, menthone, d-limonene and nerolidol. 10. An alkyl sulfate having 6 carbon atoms.
The patch according to claim 2, wherein the patch is an alkyl sulfate salt of (a) to (d). 11. The patch according to claim 2, wherein the alkylamine oxide is an alkyldimethylamine oxide having 6 to 24 carbon atoms. 12. A carboxybetaine having 6 to 6 carbon atoms.
The patch according to claim 2 or 3, which is 24 alkyldimethylaminoacetic acids. 13. The patch according to claim 2, wherein the polyoxyalkylene alkyl ether is a polyoxyethylene alkyl ether. 14. The patch according to claim 2, wherein the sulfoxide is a dialkyl sulfoxide. 15. The amide according to claim 2 or 3, wherein the amide is N, N-dialkylformamide, N, N-dialkylacetamide, N, N-dialkyltoluamide, N-hydroxyalkyllactoamide, pyrrolidone or N-alkylpyrrolidone. The patch as described in the above. 16. The oxycarboxylic acid has 2 to 10 carbon atoms.
The patch according to claim 2 or 3, which is an oxycarboxylic acid. 17. The transdermal absorption enhancer comprises C_Two-C_FourAlcow
Le, C₇-C₁₂Aryl alkanol, C₆-C₁₈Saturated fat
Fatty alcohol, polyhydric alcohol, C₆-C ₁₆fatty acid,
Monoterpene, sesquiterpene, polyhydric alcohol mono-C
₆-C₁₆Fatty acid ester, C₆-C_{twenty four}Alkyl sulfate esthetic
Le salt, C₆-C_{twenty four}Alkyldimethylamine oxide, C₆
-C_{twenty four}Alkyl dimethylaminoacetic acid, polyethylene glycol
Call C₆-C_{twenty four}Alkyl ether, pyrrolidone, N-
Alkylpyrrolidone, N, N-dialkylformamid
Selected from N, N, N-dialkyltoluamide and lactic acid
Claim 2 or a combination of two or more kinds
Is the patch of item 3. 18. The transdermal absorption enhancer is ethanol, isopropanol, benzyl alcohol, ethylene glycol, propylene glycol, glycerin, 1-nonanol, 1-decanol, stearyl alcohol, caproic acid, caprylic acid, capric acid, d-limonene. , Cineol, propylene glycol monocaprylate, glyceryl monocaprylate, glyceryl monocaprate, lauryl dimethylamine oxide, dodecyl N, N-dimethylaminoacetic acid, sodium lauryl sulfate, polyoxyethylene lauryl ether, N, N-diethyltoluamide , 2
3. One or a combination of two or more selected from -pyrrolidone and N-octyl-2-pyrrolidone.
Or the patch of item 3. 19. The transdermal absorption enhancer comprises C ₂ -C ₄ alcohol, C ₇ -C ₁₂ arylalkanol, C ₆ -C ₁₈ saturated aliphatic alcohol, C ₆ -C ₁₆ fatty acid, monoterpene, pyrrolidone and N 1 selected from alkylpyrrolidone
The patch according to claim 2 or 3, which is a kind or a combination of two or more kinds. 20. The transdermal absorption enhancer is one or a combination of two or more selected from ethanol, benzyl alcohol, 1-nonanol, capric acid, d-limonene and N-octyl-2-pyrrolidone. The patch according to 2 or 3. 21. In the general formula (1), Is a group represented by benzofuranyl, benzimidazolyl, indolyl, benzothienyl, benzothiazolyl,
The patch according to any one of claims 1 to 20, which is a group selected from naphthyl and tetrahydronaphthyl. 22. In the general formula (1), the saturated or unsaturated 5- or 6-membered heterocyclic group is a group containing one or two nitrogen atoms or oxygen atoms as hetero atoms. ~ 2
The patch according to any one of claims 1 to 7. 23. The patch according to claim 1, wherein in the general formula (1), the saturated or unsaturated 5- to 6-membered heterocyclic group is a pyrrolidinyl group or a piperidyl group. . 24. The aromatic amidine derivative, a salt of the derivative, a solvate of the derivative or a solvate of a salt of the derivative is a compound selected from the following group, a salt thereof, or a solvate thereof. The patch according to any one of claims 1 to 20. 2- [4-[((3S) -1-acetimidoyl-3-pyrrolidinyl) oxy] phenyl] -3- (7
-Amidino-2-naphthyl) propionic acid, (+)-2
-[4-[((3S) -1-acetimidoyl-3-pyrrolidinyl) oxy] phenyl] -3- (7-amidino-2-naphthyl) propionic acid, (2S) -2- [4-
[((3S) -1-acetimidoyl-3-pyrrolidinyl) oxy] phenyl] -3- (7-amidino-2-naphthyl) propionic acid, (2R) -2- [4-[((3
R) -1-acetimidoyl-3-pyrrolidinyl) oxy] phenyl] -3- (7-amidino-2-naphthyl)
Propionic acid, 2- [4-[(1-acetimidoyl-
4-piperidyl) oxy] phenyl] -3- (7-amidino-2-naphthyl) propionic acid, (+)-2- [4
-[(1-acetimidoyl-4-piperidyl) oxy] phenyl] -3- (7-amidino-2-naphthyl)
Propionic acid, 2- [4-[(1-acetimidoyl-
4-piperidyl) oxy] phenyl] -3- (5-amidinobenzo [b] thien-2-yl) propionic acid, 2
-[4-[((2S) -1-acetimidoyl-2-pyrrolidinyl) methoxy] phenyl] -3- (5-amidinobenzo [b] thien-2-yl) propionic acid,
(+)-2- [4-[((2S) -1-acetimidoyl-2-pyrrolidinyl) methoxy] phenyl] -3-
(5-amidinobenzo [b] thien-2-yl) propionic acid, 3- [4-[((3S) -1-acetimidoyl-3-pyrrolidinyl) oxy] phenyl] -4- (5
-Amidinobenzo [b] thien-2-yl) butyric acid, 2-
[4-[((3S) -1-acetimidoyl-3-pyrrolidinyl) oxy] phenyl] -3- (6-amidino-
1-ethyl-2-indolyl) propionic acid, 2- [4
-[((3R) -1-acetimidoyl-3-pyrrolidinyl) oxy] phenyl] -3- (6-amidino-1-
Ethyl-2-indolyl) propionic acid, 2- [4-
[(1-acetimidoyl-4-piperidyl) oxy]
Phenyl] -3- (6-amidino-1-ethyl-2-indolyl) propionic acid, N- [4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl] -N-
[(7-amidino-2-naphthyl) methyl] -N'-methylsulfamide, ethyl N- [N-4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl]
-N-[(7-amidino-2-naphthyl) methyl] sulfamoyl] carbamate, 4- [N-4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl]
-N-[(7-amidino-2-naphthyl) methyl] sulfamoyl] benzoic acid, N- [4-[(1
-Acetimidoyl-4-piperidyl) oxy] phenyl] -N-[(7-amidino-2-naphthyl) methyl]
Sulfamoyl acetate acid, ethyl N-
[N- [4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl] -N-[(7-amidino-2-
Naphthyl) methyl] sulfamoyl] glycinate, N
-[N-4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl] -N-[(7-amidino-2-
Naphthyl) methyl] sulfamoyl] -N-ethoxycarbonylglycine, and N- [N-4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl]-
N-[(7-Amidino-2-naphthyl) methyl] sulfamoyl] glycine. 25. The aromatic amidine derivative, a salt of the derivative, a solvate of the derivative, or a solvate of a salt of the derivative is selected from the following group: The patch according to Item. (2S) -2- [4-
[((3S) -1-acetimidoyl-3-pyrrolidinyl) oxy] phenyl] -3- (7-amidino-2-naphthyl) propionic acid hydrochloride pentahydrate, (+)-2
-[4-[(1-acetimidoyl-4-piperidyl)
Oxy] phenyl] -3- (7-amidino-2-naphthyl) propionic acid dihydrochloride, (+)-2- [4-
[((2S) -1-acetimidoyl-2-pyrrolidinyl) methoxy] phenyl] -3- (5-amidinobenzo [b] thien-2-yl) propionic acid dihydrochloride, ethyl N- [N- [ 4-[(1-acetimidoyl-4
-Piperidyl) oxy] phenyl] -N-[(7-amidino-2-naphthyl) methyl] sulfamoyl] glycinate dihydrochloride, N- [N-4-[(1-acetimidoyl-4-piperidyl) oxy] Phenyl] -N-
[(7-Amidino-2-naphthyl) methyl] sulfamoyl] glycine dihydrochloride and N- [4-[(1-acetimidoyl-4-piperidyl) oxy] phenyl]
-N-[(7-amidino-2-naphthyl) methyl] sulfamoylacetic acid dihydrochloride.