JPS62201818A - External preparation comprising cyclopentenone or such as active ingredient - Google Patents

Abstract

PURPOSE:An external preparation having improved antiviral action, antimicrobial action, etc., comprising a cyclopentenone as an active ingredient. CONSTITUTION:An external preparation comprising a compound [e.g. 2-chloro-4- butyl-5-(6-carbocyhexylidene)-2-cyclopentenone, etc.] shown by the formula (Ra is 1-12C aliphatic hydrocarbon or phenyl; Rb is 1-12C aliphatic hydrocarbon; X is halogen or H) as an active ingredient. An ointment, cream, lotion, solution, etc., may be cited as a dosage form, endermic administration has the same or higher remedying effects as those of oral administration or injection administration and merits of long duration time. The compound shown by the formula is effective especially to viral diseases (e.g. skin diseases such as herpes, wart, hand-foot-and-mouth disease, melanoma, etc., and infectious disease such as candidiasis, etc.) in the skin. EFFECT:Since a drug is locally administrated, an action site is limited and a pharmaceutical action appears at a specific site.

Description

DETAILED DESCRIPTION OF THE INVENTION <Industrial Application Field> The present invention relates to a topical drug containing cyclobentenones as an active ingredient. More specifically, mK relates to a topical drug suitable for local administration that contains cyclobentenones as an active ingredient and has excellent antiviral and antibacterial effects.

<Conventional technology> Prostaglandin has an inhibitory effect on platelet aggregation.

It is a chemical compound that has unique biological activities such as blood pressure lowering effects, and is a useful natural product that has recently been used as a peripheral circulation treatment drug in the medical field.

Among boostaglandins, prostaglandin A is known to have a double bond in its cyclopentane ring.
Prostaglandin AWA strongly inhibits synthesis.
has been reported to have potential as an antitumor agent [Biochemical and Biophysical Research Communication (Biochem, Biophys, R
eg, Commun,) 87t795.1979;
ProstaglandinsRelat, Lip
idgl+2e365-8 (1982)].

On the other hand, research on the effects of prostaglandins on viruses is also active, and Sendai virus (5endai V
It has been reported that the PGA series suppresses the proliferation of S. irus [Science (5science) 2
G 9 @ l pages 032-1034.

1980]. Furthermore, it has been reported that PGE suppresses the proliferation of encephalomyocarditis virus [Brosiedendus op the Society for Experimental Biology and Medicine (Pr.
oceedings of th@5ocietyfo
r Experimental ljiology a
nd Medicine 170, pp. 925-28, 1982].

On the other hand, as a derivative of prostaglandin A,
5-Alkylidene-chloro-4-substituted-2,-cyclobentenones having a 221LIIj bond at the 221LIIj position are known, and such compounds have excellent antitumor activity as well as antiviral permeation activity. It is an extremely useful compound as a medicine (European Publication No. Na013144
1). 5-Alkylidene-2- to 〇-4-11-2-
As a method of administering cyclobentenones, oral, rectal, subcutaneous, intramuscular, and intravenous parenteral administration are known (European Publication Publication Oni 0131441).

However, in the case of such administration, it is difficult to administer the drug because its pharmacological action is systemic and limited locally. Furthermore, subcutaneous, intramuscular, and intravenous administration have the disadvantage of causing skin pain.

<Problem that the invention seeks to solve> The inventors have discovered that it is an excellent anti-viral, anti-inflammatory drug.

To develop a simple administration form that eliminates the side effects that occur when 5-alkylidene-4-substituted-2-cyclobentenones having antibacterial effects are administered orally, and eliminates the pain caused by subcutaneous, intramuscular, etc. administration. I have done extensive research with this in mind.

5-Alkylidene-2-no-1--4-substituted-2-cyclobentenones have excellent transdermal absorption and exhibit favorable pharmacological effects.
The inventors have discovered that this is a preferable dosage form of -substituted-2-cyclobentenone and have arrived at the present invention.

Means for Solving the Problems> The present invention is an external drug containing 5-alkylidene-4-substituted-2-cyclobentenones represented by the following formula (I) as an active ingredient.

Ra in formula (I) is substituted or unsubstituted with 1 to 1 carbon atoms;
Rh represents a substituted or unsubstituted aliphatic hydrocarbon group having 1 to 12 carbon atoms, or a substituted or unsubstituted phenyl group.

The aliphatic hydrocarbon group having 1 to 12 carbon atoms in Ra + Rb may be linear, 9-branched, or cyclic, and may contain a double bond or triple bond. Preferred aliphatic hydrocarbon groups include, for example, linear or branched furkyl groups having 1 to 12 carbon atoms, alkenyl groups, or alkynyl groups, or dichlorofurkyl groups having 3 to 8 carbon atoms.

Straight-chain or branched carbon Xml~12 alkyl groups include, for example, methyl, ethyl, n-propyl + j8
0-propyl, n 7'thyl, formula -butyl + ter
t-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, 3.7-dimethyloctyl, n-nonyl+n-decyl.

Examples include n-undecyl and n-dodecyl.

Straight-chain or branched alkenyl groups having 1 to 12 carbon atoms include 1 such as edenyl, l-pen-1-yl,
2-ben-1-yl.

1-buten-1-yl, 1,3-butadien-1-yl, 2-buten-1-yl, 1-penten-1-yl, 2
-penten-1-yl, l-hexen-1-yl, 2-
Hexen-1-yl.

1,5-hexadien-1-yl, 2,5-hexaxen-1-yl, 3-hexen-1-yl.

1-hept-7-1-yl, 1-octen-1-yl, 1
．． 7-octacyen-1-yl, 3+7-cymethyl-6
-Octen-1-yl, l-nonen-1-yl, 1-decen-1-yl, l-undecen-1-yl, 1-dodecen-1-yl, etc.Zo Straight chain or branched carbon Examples of the alkynyl group having numbers 1 to 12 include ethynyl, l-purvin-1-yl,
2-propyn-1-yl.

l-butyn-1-yl, 3-buten-1-yn-1-yl, 2-butyn-1-yl, 1-pentyn-1-yl,
2-pentyn-1-yl, 1-hexyn-1-yl, 2
-Hexen-1-yl, 5-hexen-1-yn-1-
yl, 3-hexy7-1-yl, l-heptyn-1-yl.

1-octyn-1-yl, 7-octen-1-yn-1
-yl, 1-nonyn-1-yl, 1-decyn-1-yl, ! -undecin-1-yl.

Examples include 1-dobsin-1-yl.

As a cycloalkyl crystal having 3 to 8 carbon atoms, 9'A e? Examples include cyclopropyl, cyclopentyl, cyclohexyl, cyclooctyl, and cyclohexenyl.

Ra + Rb aliphatic hydrocarbon group having 1 to 12 carbon atoms.

Alternatively, the phenyl group of Ra may have a substituent,
Examples of the substituent include the following groups.

For example -〇〇〇R'(R'' is a hydrogen atom, carbon number 1-1
0 alkyl group or -equivalent cation)
; -OR"(R" is a water bulky atom; an alkyl group having 1 to 6 carbon atoms which may be substituted with a halogen atom; 1 carbon number
~70 carboacyl group; halogen atom.

represents a furkyl group having 1 to 4 carbon atoms which may be substituted with a halogen atom, or a phenyl group which may be substituted with a furfoxy group having 1 to 4 carbon atoms); halogen atom, alkyl having 1 to 4 carbon atoms 1-4σ carbon atoms which may be substituted with a group or a carboacyl crystal having 1-7 carbon atoms
Phenyl group optionally substituted with noalfoxy group: cycloalkyl group having 3 to 8 carbon atoms optionally substituted with alkyl group having 1 to 4 carbon atoms; -CONR'E''(R'
, R'' each represents a hydrogen atom or a fulkyl group having carbons a1-6); -COC, oH; or an oxo group.

Examples of the alkyl group having 1 to 10 carbon atoms in -cout include the alkyl group like I!II mentioned -'', and the -equivalent canon includes M such as NL+I tetramethylammonium, monomethylammonium, Ammonium cations such as dimethylammonium, trimethylammonium, benzylammonium, 7enethylammonium, morpholinium cation, monoethanolammonium, piperazinium cation: Na+,
Alkali metal cations such as Li+, Ni+; 1/2C
Examples include divalent or trivalent metal cations such as at++ 172Mg"+ 1/2Zn"+ and 1/3 to 10.

-〇W is a hydroxyl group: methoxy, ethogish! C1-C6 flukoxy groups such as n-propoxy, impropoxy, n-butoxy, n-pentyloxy, n-hexyloxy: acetoxy, putupionyloxy, n-butyryloxy.

C1-70 carbo7-siloquine groups such as inbutyryloxy, n-valeryloxy, invaleryloxy, cab-yloxy, enantyloxy, and benzoyloxy; phenoxy groups; and the like. -OR" is an alkoxy group having 1 to 6 carbon atoms, promethoxy, dichloromethoxy.

May be substituted with (/%q) gene atom, such as trifluoromethoxy.

10 When W is a phenoxy group, a chlorine atom, a fluorine atom,
Halogen atoms such as bromine atoms; methyl.

Trifluoro p-methyl! An alkyl group having 1 to 4 carbon atoms which may be substituted with a halogen atom such as ethyl t-propyl diptyl; an alkyl group having 1 to 4 carbon atoms such as methoxy, nidoxy, propoxy, butoxy, etc., which is substituted with tIt. Good too.

When the substituent of the aliphatic hydrocarbon group having 1 to 12 carbon atoms in la+lζb or the phenyl group in haRa is a phenyl group, the phenyl group is a chlorine atom or a bromine atom.

A halogen atom such as a fluorine atom; an alkyl group having 4 to 4 carbon atoms such as methyl, ethyl, propyl, butyl; methoxy, ethoxy, propoxy.

1-70 carbon atoms such as 1-methoxycarbonylethoxy
It may be substituted with an alkoxy group having 1 to 4 carbon atoms, which may be substituted with a carbo7yl group, or the like.

RatRb is an aliphatic hydrocarbon group having 1 to 12 carbon atoms.

Alternatively, when the substituent of the phenyl group of Ra is a dichlorofurkyl group having 3 to 8 carbon atoms, the cycloalkyl group may be substituted with an alkyl group having 1 to 4 carbon atoms (such cycloalkyl groups include, for example, Examples include cyclopentyl, cyclohexyl, 3-methylcyclopentyl, 4-methylcyclohexyl, 3,3-dimethylcyclopentyl, 3-methylcyclopentyl, and the like.

Ra, Rh is an aliphatic hydrocarbon group having 1 to 12 carbon atoms.

Or, when the substituent of the phenyl group of Ra is -CONR'R', such a substituent includes, for example, amine carbonyl, N,N-dimethylami/carbonyl.

Examples include N,N-diethyl 7-minocarbonyl and N-methyl 7-minocarbonyl.

X in the formula (1+ represents a halogen atom such as a chlorine atom, a bromine atom, a fluorine atom, or a hydrogen atom).

Among the 5-alkylidene-4-@substituted-2-cyclobentenones of formula (11), the following formula fl+-1 is the same.

5-fulkylidene-4-substituted-2-cyclrho represented by
Bentenones are preferred.

Formula (1)-10W represents a hydrogen atom or a substituted or unsubstituted aliphatic hydrocarbon group having 1 to 10 carbon atoms. Such aliphatic hydrocarbons having 1 to 10 carbon atoms: the A group may be linear, 9-branched, or cyclic (and may contain a double bond; aliphatic hydrocarbons having 1 to 10 carbon atoms) The hydrocarbon group is preferably a linear or branched alkyl group, an alkenyl group, or a cycloalkyl group having 3 to 8 carbon atoms.

Examples of alkyl groups having 1 to 10 carbon atoms include methyl,
Ethyl, n-propyl wiso-pvyl+n-butyl, 5ac-butyl+tart-butyl 9n-pentyl, n-hexyl, n-heptyl.

Examples include n-octyl, n-nonyl, n-decyl, and the like.

Examples of alkenyl groups having 1 to 10 carbon atoms include ethynylg1-propen-1-yl, 2-propen-1-yl,
3-buten-1-yl, 1-butyn-1-yl, 4-penten-1-yl.

5-mugicen-1-yl, 6-penten-1-yl, 7
-octen-1-yl, 8-nonen-1-yl, 9-decen-1-yl, etc., among which 1-pudiben-1-yl, 2-7'lopen-1-yl, 3-butene-1-yl, etc.
1-yl, 4-penten-1-yl, 5-hexene-1
-yl is preferred.

As a cycloalkyl group having 3 to 8 carbon atoms.

The same ones as mentioned above can be mentioned.

When R1 is an aliphatic hydrocarbon group having 1 to 10 carbon atoms, the substituent is Ra+Rbf)l of the formula (1) described above.
The same substituents as ik substituents can be mentioned.

The symbol φ in formula (1)-1 represents a single bond, double bond, or triple bond.

Among the 5-alkylidene-4-substituted-2-cyclobentenones represented by the formula +11-1, the following formula (11-
A compound of prostaglandin Affi, represented by 2,
Alternatively, a prostaglandin D type compound represented by the following formula 111-3 is preferable.

R in formula (1)-2 represents a hydrogen atom or a methyl group. Formulas (1)-2 and (1)-30 represent a hydrogen atom or a substituted or unsubstituted aliphatic hydrocarbon group having 1 to 9 carbon atoms. Examples of such aliphatic hydrocarbon groups having 1 to 9 carbon atoms include methyl.

Ethyl, n-propyl + 1ao-propyl + n-butyl, 5ee-dutyl, t-butyl, n-pentyl, n-
hexyl, 2-methyl-1-hexyl.

Straight-chain or branched alkyl groups such as 2-methyl-2-hexyl, n-hephthyl, n-octyl; dichlorofurkyl groups having 3 to 8 carbon atoms as described above; and the like. As substituents for aliphatic hydrocarbon groups having 1 to 9 carbon atoms,
Halogen atom; -01c'; Halogen atom, IR,
an alkyl group having a prime number of 1 to 4, or a phenyl group optionally substituted with an alkoxy group having 1 to 4 carbon atoms, which may be substituted with a carboacyl group having 1 to 70 carbon atoms; a phenyl group having 1 to 4 carbon atoms;
3 to 8 carbon atoms, optionally substituted with ~4 alkyl groups
Examples include cycloalkyl groups. Specific examples of these substituents are the same as those for rl in Ra + Rb described above.

R3 in formula fil-2 represents a hydrogen atom, a hydroxyl group, or protected water #&. As a protective crystal for protected hydroxyl groups)! j (C, ~, hydrocarbon) silyl group.

There is a group that forms a 7-cetal bond with the oxygen atom of the hydroxyl group. Examples of triCC+-s hydrocarbon) silyl groups include tri(C1-4 alkyl)silyl groups such as trimethylsilyl, triethylsilyl, and t-butyldimethylsilyl; diphenyl CC such as t-7'tyldiphenylsilyl;
,,,alkyl)silyl; tribenzylsilyl and the like.

Examples of groups that form an acetal bond with the Mt elementary atom of the water group include methoxymethyl, 1-ethoxyethyl, and 2-methoxy-2-propyl.

2-ethoxy-2-propyl, (2-methoxyethoxy)methyl, benzyloxymethyl, 2-tetrahydropyranyl, 2-tetrahydrofuranyl, 616-cymethyl-3-oxa-2-oquin-bicycloC3,1,0)-
Hex-4-yl, among others, 2-tetrahydropyranyl, 2-tetrahydrofuranyl, 1-ethoxyethyl, 2-methoxy-2-propyl.

(2-methoxyethoxy)methyl, 6,6-dimethyl-3-oxa-2-oquine-bicyclo(3,1,0)hex-4-yl are preferred.

The notation \ in the formulas fi+-2 and fi+-3 represents a single bond or a double bond. The symbol ♂ in formula (11-2, (1)-3) represents a single bond, a 21 bond, or a 321 bond.

The definition of X in the formulas ill+ -2 and +II -3 is the formula ill
K is the same.

Next, 5-alkylidene-4-1flle-2 of the present invention
-Specific examples of cyclobentenones are given.

(1) Compound (100) of formula (11-2) 2-chloro-4-butyl-5-(6-
carboxyhexylidene)-2-cyclobentenone (102) 2-chloro-4-ctyl-5-(6-
Carboxyhexylidene)-2-cyclobentenone (104) 2-couro-4-(1-octenyl)-
5-(6-carboxyhexylidene)-2-cyclobentenone (106) 2-chloroa-4(3-hydoxy-1-
octenyl)-5-(6-carboxylitene)-2-cyclobentenone (108) 2-promo-4-(3-hydroxy-3
-cyclohexyl-1-propenyl)-5-(6-carboxyhexylidene)-2-cyclobentenone (110) 2-curo-4-(3-hydroxy-3
-cyclopentyl-1-propenyl)-5-(6-carboxyhexylidene)-2-cyclobentenone (112) 2-promo 4-(2-propenyl)-
5-(6-carboxyhexylidene)-2-cyclobentenone (114) 2-riaa-4(3-hydroxy-5-
Methyl-1-nonenyl)-5-(6-carboxyhexylidene)-2-cyclobentenone (116) 2-paa-4-(3-hydroxy-3
-phenyl-1-propenyl)-5-(6-carboxyhexylidene)-2-cyclobentenone (118) 2-chloro-4-(1-hydroxy-3
-phenyl-1-propenyl)-5-(6-carboxyhexylidene)-2-cyclobentenone (120) 2-promo 4-(3-hydroxy-3
-Methyl-1-propenyl)-5-(6-carboxyhexylidene)-2-cyclobentenone (122) 2-promo 4-(3-hydroxy-5
,5-dimethyl-1-octenyl)-5-(6-carboxyhexylidene)-2-cyclobentenone (124) 2-fluor+=-4-(3-hydroxy-4-phenoxy-1-butenyl) -5-(6-carboxyhexylidene)-2-cyclobentenone (126) 2-chloro-4-butyl-5-(6-carpoxy-2-hexylidene)-2-cyclobentenone (128) 2-promo 4-Butyl-5-(6-carboxy-2-hexylidene)-2-cyclobentenone (13G) 2-chloro-4-butyl-5-(6-carboxy-5-hexylidene)-2-cyclobentene Non(132) 2-ria a -4-octenyl-5-
(6-carboxy-2-hexylidene)-2-cyclobentenone (134) 2-riρa -4-ctenyl-5-(
6-carpoxy-2-hexylidene)-2-cyclobentenone (136) 2-chloro-4-(3-hydroxy-1
-octenyl)-5-(6-carboxy-2-hexynylidene)-2-cyclobentenone (13 g) 2-promo 4-(3-hydroxy-3
-cyclopentyl-1-propenyl)-5-(6-carboxy-2-hexenylidene)-2-cyclobentenone (140) 2-bromo-4-(3-hydroxy-3
-cyclohexyl-1-propenyl)-5-(6-carboxy-2-hexynylidene)-2-cyclobentenone (142) 2-fluoro-4-butyl-5-(2-
methylpropylidene)-2-cyclobentenone (144), 2-chloro-4-dimethyl-5- (2
,2-dimethylpurpylidene)-2-cyclobentenone (146) 2-chloro-4-(3-hydroxy-1
-: ter-yyl)-5-butylidene-2-cyclobentenone (148) 2-chloroa -4-butyl-5-(3-
phenyl-2-propylidene)-2-cyclobentenone (150) 2-promo4-octyl-5-(2-
Methylpropylidene)-2-cyclobenzonone (152) 2-lycl+-4-(1-octenyl)-5-(6-carboxy-2-hexenylidene)-2
-Cyclobenzonone (154) 2-Fluor-4-butyl-5-hebutylidene-2-cyclobenzonone (156) 2-dichloro-4-ctyl-5-hebutylidene-2-cyclobentenone (158) 2-chloro-4-(3-hydroxy-1
-octenyl)-5-hebutylidene-2-cyclobenzonone (160) 2-bromo-4-butyl-5-(7-hydroxyhebutylidene)-2-cyclobenzonone (162) 2-riσ-4-octyl 5-(7-
hydroxyhebutylidene)-2-cyclobenzonone (164) 2-ri-0-4-(3-hydroxy-
1-octenyl)-5-(7-hydroxyhebutylidene)-2-cyclobentenone (166) 2-bromo 4-(1-octenyl)-
5-(7-hydroxyhebutylidene)-2-cyclobentenone (168) 2-chloro-4-(3-hydroxy-4
-m-fluorophenoxy)-5-(6-carboxyhexylidene)-2-cyclobentenone (170) 2-furomo-4-(3-hydroxy-4
-m-trifluoromethylphenyl)-5-(6-carboxyhexylidene)-2-cyclobentenone (172) 2-fluoro-4-(1-octyl)-
5-(6-carboxyhexylidene)-2-cyclobenzonone (174) 2-chloro-4-(6-ri a a -3
,7-dimethyloctyl')-5-(6-medoxycarpoxyhexylidene)-2-cyclobentenone (176) 2-chlorol'-4-(3,7-cymethyl-6-octen-1-yl )-5-(6-carboxyhexylidene)-2-cyclopente/(178) 2-
Chloro-4-(3-hydroxy-1-octenyl) -
5-Cm -(methoxycarbonylethoxy)phenylmethylidenecou 2-cyclobentenone (180) 2-dichloro4-(1-octenyl)(
204) 2-Chloa-4-(6-carboxy-2
,5-hexagenyl)-5-(3-(3-furobylcyclopentyl)-2-penylidene]-2-cyclobentenone (206) 2-I: Ity -4-(6-carboxyhexyl) -5-(2-octenyritene)-2-cyclobentenone (208) 2-chloro-4-(6-carboxyhexyl)-5-(3-phenoxy-2-propylidene)-
The present invention The 5-alkylidene-4-substituted-2-cyclobentenones can be prepared by methods such as those described in European Publication No. Na0131441.

When 5-alkylidene-4-substituted-2-cyclobentenones are administered transdermally, they exhibit favorable pharmacological effects. When 5-alkylidene-4-substituted-2-cyclobentenones are administered transdermally, they exhibit antiviral, anti-111&), and antibacterial effects that are equivalent to or greater than oral administration or injection administration,
It has the advantage of long duration. In addition, since it is possible to administer locally with limited pharmacological action, transdermal administration of 5-alkylidene-4-substituted-2-cyclobentenones is particularly effective against viral diseases on the skin.
For example, herpes disease.

Warts, foot and mouth disease, skin cancers such as melanoma, and skin infections such as candidiasis! It is effective against staphylococcal infections.

Dosage forms of external drugs containing 5-fulkyritene-4-substituted-2-cyclobentenones as active ingredients include ointments, creams, o-jones, and liquid preparations.

Bases for ointments include 1 fatty oils such as castor oil, olive oil, sesame oil, safflower oil; lanolin; white, yellow or hydrophilic petrolatum; wax; oleyl alcohol;
Higher alcohols such as instearyl alcohol, octyldodecanol, hexyldecanol; glycerin.

Examples include glyfurs such as diglycerin, ethylene glycol, propylene glycol, nrubitol, and 193-//tanediol.

Ethanol, dimethyl sulfoxide, polyethylene glycol, etc. may also be used as a solubilizer for 7-thi-7 prostaglandin E and the like. Must see again! Depending on paraoxybenzoic acid ester.

Sodium benzoate, salicylic compound #! ! Preservatives such as boric acid: antioxidants such as butylhydroxyanine and dibutylhydroxytoluene may also be used.

In order to promote transdermal absorption of 5-furkylidef-4-substituted-2-cyclobentenones, absorption enhancers such as diisopropyl adipate, diethyl sebacate, ethyl caproate, and ethyl laurate may be added. Also, 5-
5-alkylidene-4-substituted-
2-cyclobentenones are converted into α-cyclodextrin, β
It can also be used as an inclusion compound of cyclodextrin such as -cyclodextrin Ir-cyclodextrin; methylated cyclodextrin such as α-methylated cyclodextrin and β-methylated cyclodextrin/etc.

Ointments can be manufactured by conventional methods.

As the cream, an oil-in-water cream is preferred in terms of stabilizing the 5-alkylidene-4-substituted-2-cyclobentenone. Also, as a base, fatty oil as mentioned above, etc. j Quaternary alcohols, glycols, etc. are used, and diethylene glycol,
Bubbin glycol, sorbita monofatty acid ester 9
Polysorbate 80. An emulsifier such as lauryl (jIm natritum) is used.Furthermore, the above-mentioned preservatives, antioxidants, etc. may be added as necessary.Furthermore, as in the case of the softening agent, 5-alkylidene-4-substituted -2-Cyclobentenones can also be used as inclusion compounds of cyclodextrin methylated cyclodextrin.Creams can be produced by conventional methods.

As a lotion, suspension ffi, emulsion shop, solution -
-tion agents. Suspension lotions are obtained using a suspending agent such as sodium alginate or sodium tragantracarboxymethylcellulose, and optionally adding an antioxidant, preservative, etc.

The emulsion lotion can be obtained by a conventional method using an emulsifier such as sorbitan monofatty acid ester, Polyne lupee 80, sodium lauryl sulfate, or the like.

Solution-type p-john agent is alcohol! &S! Lotions are preferably obtained in conventional manner using alcohols such as ethanol.

Examples of liquid preparations include those obtained by dissolving 5-alkylidene-4-substituted-2-cyclobentenones in an alcohol solution such as ethanol, and adding antioxidants, preservatives, etc. according to the required fiK.

In addition to these dosage forms, there are also pasta preparations and bag preparations.

Examples include dosage forms such as aerosols. Such formulations can be manufactured by conventional methods.

The dosage of 5-fulkyritene-4-fit-2-cyclobentenones varies depending on the type of compound, pathological condition, etc., but is usually administered in an amount of about 1 # to about xol/kl body weight. Therefore, the amount of 5-alkylidene-4-substituted-2-cyclopentenes to be included in a drug for transdermal administration is determined by the dosage.

<Effects of the Invention> As mentioned above, since the topical drug containing 5-alkylidene-4-ill-2-cyclobentenone as an active ingredient is administered locally to the skin, the site of action is limited. It is possible to express conditioning effects such as antiviral, anti-km, and antibacterial effects only in specific areas.

In addition, when administered transdermally, the duration of the therapeutic action is long;
It also has the advantage of exhibiting strong rational action.

<Example> Hereinafter, the present invention will be explained in detail by way of examples.

Example 1 Adipic acid diimpyl pvir 18H9 to 2-p-rho 4-
(3,7-dimethyl-6-octenyl)-5-(6-carbomethoxyhexylidene)-2-cyclobentenone 1
Dissolve 0M9 in bath and add white petrolatum 7219 to it (mix to make a uniform ointment).

When examining the stability of the drug during such soft decomposition, the drug was not decomposed even after 40 days.

Example 2 2-rep-4-(3,7-dimethyl-6-octenyl)-5-(6-carbomethoxyhexylidene)-2-cyclobentenone 2119 was taken and converted into a hydrophilic Vaseline, stearyl alcohol, propylene glycol, sodium lauryl sulfate, ethyl roseoxybenzoate, ) (bouvil laoxybenzoate) 100■ Toyo (
The mixture was kneaded to make a uniform ointment.

Example 3 2-riq p-4-(3+7-dimethyl-6-octenyl)-5-(6-carbomethoxyhexylidene)-2-
Take 111v of cyclobentenone and mix it with cold cream (rough infusion, purified water, borax)
In addition to 50 dah, it was kneaded to obtain a uniform cream.

Example 4 The hair on the right dorsal abdomen of a 6-week-old Balb/c female mouse was clipped with clippers, and a hair removal cream was applied. After 10 minutes, the hair removal cream was washed away with water, and the next day, HS V -I Ha was applied to the center of the mouse.
yaghida strain 10" p.f.u. was inoculated intradermally.

Three days later, where a lesion appeared locally at the inoculation site, 10% 2-po-4-(L7-dimethyl-6-octenyl)-5-octenyl)-5-(6-carbomethoxy) prepared in Example 1 was applied. xylidene)-2-cyclobentenone soft 1' was applied every 12 hours in an amount ranging from 0.1 to IM9 to completely cover the lesion. The degree of the lesion is localized lesions 2 degrees, 1 dotted lesions 6 degrees, FJ
The following results were obtained, with 8 degrees of severe zonal lesions and 10 degrees of severe band-like lesions. 10 of base alone and acyclovir as control drugs.
A preparatory ointment was prepared and administered using the same administration method and frequency.

The results are shown in Table m1 and Table 2.

Mouse 1 Table Number of days for treatment

Claims (1)

[Claims] 1. The following formula (I) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I) [In the formula, Ra is a substituted or unsubstituted aliphatic hydrocarbon group having 1 to 12 carbon atoms, or It represents a substituted or unsubstituted phenyl group, Rb represents a substituted or unsubstituted aliphatic hydrocarbon group having 1 to 12 carbon atoms, and X represents a halogen atom or a hydrogen atom. ] An external drug containing a 5-alkylidene-4-substituted-2-cyclopentenone represented by the following as an active ingredient. 2,5-Alkylidene-4-substituted-2-cyclopentenones have the following formula (I)-2 ▲There are numerical formulas, chemical formulas, tables, etc.▼(I)-2 [In the formula, R^2 is a hydrogen atom, Represents an alkyl group having 1 to 10 carbon atoms or a one-equivalent cation, R^6 represents a hydrogen atom or a methyl group, R^
7 is a hydrogen atom, or substituted or unsubstituted carbon number 1-
9 represents an aliphatic hydrocarbon group, R^5 represents a hydrogen atom, a hydroxyl group, or a protected hydroxyl group, the symbol ■ represents a single bond or a double bond, and the symbol ■ represents a single bond, a double bond, or represents a triple bond. ] The external medicine according to claim 1, which is a compound represented by: 3. The external medicine according to claim 1 or 2, which is in the form of an ointment, cream, lotion, or liquid.