JPH0859467A - Therapeutic agent for dermatopathy - Google Patents

Abstract

PURPOSE: To obtain a medicinal composition, containing a rhodacyanine derivative as an active ingredient, hardly causing side effects and useful for treating dermatopathy such as psoriasis, pemphigus, atopic and contact dermatitises, etc. CONSTITUTION: This therapeutic agent for dermatopathy contains at least one of a compound of the formula [A and B are each a 5- or a 6-membered heterocyclic ring; R is an alkyl or an aryl; L is methine or N; L, together with B, may form a ring; Y is O, S, Se or NR1 ; R1 is an alkyl, an aryl or a heterocyclic ring; Q is an anion; (k) is 1 or 2] and its salt as an active ingredient. The compound of the formula has suppressing actions on proliferation of human keratinocytes and immunosuppressive actions. The therapeutic agent is obtained by suitably blending a usually used medicinal carrier, etc., and formulating the active ingredient into an oral or a parenteral administration form or an external preparation according to a conventional method. The daily dose thereof is 0.1-100mg/kg for oral and parenteral administrations and the dose of the external preparation for an adult is 0.1μg to 10mg at a time.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a therapeutic drug for skin diseases such as psoriasis, pemphigus, atopic dermatitis and contact dermatitis.

[0002]

2. Description of the Related Art Conventionally, for the treatment of psoriasis, oral and external use of corticosteroids, phototherapy with ultraviolet irradiation after oral administration of psoralen, or oral administration of methotrexate, retinoids, cyclosporine, vitamins B2, B6, calcium pantothenate, etc. Has been done. However, all of these treatments have problems. That is, corticosteroids, methotrexate, retinoids, and cyclosporine are limited in their use because of their side effects, and vitamins have no immediate effect and need to be taken for a long time. Immunosuppressive agents such as corticosteroids and cyclosporine have been conventionally used for the treatment of pemphigus. However, their use is limited due to side effects. Further, various chemical transmitter release inhibitors, antihistamines or immunosuppressants are used for the treatment of skin allergies, but their use is limited due to their weak efficacy and side effects.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide a pharmaceutical composition for treating skin diseases, which contains a low-molecular weight compound having minor side effects as an active ingredient. The skin diseases to be treated by the pharmaceutical composition for treating skin diseases of the present invention include psoriasis, pemphigus, atopic dermatitis and contact dermatitis.

[0004]

As a result of searching various compounds, the above object of the present invention can be achieved by a rhodacyanine dye which has been known to be mainly used for producing a photosensitive material. all right. These rhodacyanine dyes have a strong immunosuppressive action and keratinocyte proliferation inhibitory action. In one embodiment,
The present invention provides (A) general formula (I)

[0005]

[Chemical 7]

(In the formula, A and B each independently represent an optionally condensed 5-membered or 6-membered heterocycle, which may be substituted, and R is an alkyl group or Represents an aryl group, L represents an optionally substituted methine group or a nitrogen atom, L may form a ring with B, Y represents O, S, Se, or —NR ₁ —, R ₁ represents an alkyl group, an aryl group or a heterocyclic group, Q represents a pharmaceutically acceptable anion, and k represents 1 or 2), and a rhodacyanine derivative represented by the formula and a pharmaceutically acceptable derivative thereof. There is provided a composition comprising a salt and (B) a pharmaceutically acceptable carrier or diluent.

A preferred embodiment of the present invention includes the above composition, wherein the rhodacyanine compound is a compound selected from the group consisting of compounds of the following general formula (II).

[0008]

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(In the formula, A, B, R, L, Q, and k all have the same meanings as described above.)

A further preferred embodiment of the present invention includes the above composition wherein the rhodacyanine compound is a compound selected from the group consisting of compounds of the following general formula (III):

[0011]

[Chemical 9]

(In the formula, X ₁ and X ₂ each independently represent O, S, Se, —CH═CH—, —CR ₄ R ₅ — or —NR ₆ —, and R ₄ and R _{4 5} each represents an alkyl group, which may be the same or different, and R ₆ is
Represents an alkyl group or an aryl group, R ₂ and R ₃ are
Each independently represents an optionally substituted alkyl group, and Z ₁ and Z ₂ are each independently required to form a 5- or 6-membered ring with other ring members of the ring containing them. Represents a group of atoms, the ring formed may be substituted, m and n each represent 0 or 1, and may be the same or different, and R, L, Q, and k have the same meanings as described above. Have. )

In a further preferred aspect of the present invention, the compound represented by the general formula (III) is represented by the following general formula (IV)

[0014]

[Chemical 10]

(In the formula, R ₇ , R ₈ , R ₉ and R ₁₀ each represent a hydrogen atom, an alkyl group or an aryl group, which may be the same or different, and R ₇ and R ₈ are bonded to each other to form a ring. R ₉ and R ₁₀ may combine to form a ring, and R, R ₂ , R ₃ , X ₁ , L, Q, and k have the same meanings as described above.) And a compound represented by the following general formula (V)

[0016]

[Chemical 11]

(In the formula, R ₁₁ , R ₁₂ , R ₁₃ and R ₁₄ each represent a hydrogen atom, an alkyl group or an aryl group, and may be the same or different, or any one of R ₁₁ to R ₁₄ Two groups may combine to form a 5- or 6-membered ring, and R, R ₂ , R ₃ , X ₁ , X ₂ , L, Q, and k have the same meanings as described above.). Included in the above compositions are the compounds shown. More specifically, the general formula (I) ~
In (V), A is a dihydropyridine ring, a tetrahydropyridine ring, a thiazolidine ring, a thiazoline ring, a tetrahydrobenzothiazoline ring, a benzothiazoline ring, a dihydroquinoline ring, a benzoxazoline ring, a naphthoxazoline ring, a naphthothiazoline ring, a benzoselenazoline ring. And these rings may be substituted, and B is
Thiazoline ring, thiazole ring, pyridine ring, tetrahydrobenzothiazole ring, benzothiazole ring, quinoline ring, benzoxazole ring, naphthoxazole ring, naphthothiazole ring, benzoselenazole ring, dimethylindolenine ring, and these rings are substituted It may have been done.

Y represents an oxygen atom, a sulfur atom, a selenium atom, or --NR _1- , wherein R ₁ is an alkyl group (an unsubstituted or substituted alkyl group such as a linear, branched or cyclic alkyl group). Group), an aryl group (an unsubstituted or substituted aryl group such as a monocyclic or bicyclic aryl group), or a heterocyclic group (which may be saturated or unsaturated, one or more nitrogen atoms, oxygen) Atom, and an unsubstituted or substituted heterocyclic group such as a 5- to 6-membered heterocycle which may contain a sulfur atom).
R, R ₂ and R ₃ each independently represent an alkyl group (a linear, branched or cyclic unsubstituted or substituted alkyl group), and R is further an aryl group (monocyclic or bicyclic). An unsubstituted or substituted aryl group such as a system aryl group) or a heterocyclic group (which may be saturated or unsaturated and may contain one or more nitrogen atoms, oxygen atoms, and sulfur atoms 5 Membered to 6-membered heterocyclic group, such as an unsubstituted or substituted heterocyclic group).

Z ₁ and Z ₂ may be the same or different and each is a 5- or 6-membered ring (containing one or more nitrogen atoms, oxygen atoms, sulfur atoms or selenium atoms as hetero atoms). May be saturated or unsaturated 5
Member or 6-membered ring),
Z ₁ and Z ₂ may each be substituted or fused with another ring such as a saturated or unsaturated ring. L is a methine group (unsubstituted methine group or substituted methine group)
Alternatively, when a nitrogen atom is represented and L is a substituted methine group, L and R ₃ may combine to form a saturated or unsaturated 5- or 6-membered ring.

R ₇ , R ₈ , R ₉ and R ₁₀ each independently represent a hydrogen atom or an alkyl group (an unsubstituted or substituted alkyl group such as a linear, branched or cyclic alkyl group), Further, R ₇ , R ₈ , R ₉ and R ₁₀ represent an aryl group (an unsubstituted or substituted aryl group such as a monocyclic or bicyclic aryl group), or R ₇
And R ₈ and R ₉ and R ₁₀ are bonded to each other to form a 5- or 6-membered ring (a saturated or unsaturated 5-membered ring which may be substituted and may form a condensed ring with another ring or 6-membered ring) may be formed. R ₁₁ , R ₁₂ , R ₁₃ and R
₁₄ each independently represents a hydrogen atom or an alkyl group (an unsubstituted or substituted alkyl group such as a linear, branched or cyclic alkyl group), and further R ₁₁ , R ₁₂ and R ₁₃
And R ₁₄ each represent an aryl group (an unsubstituted or substituted aryl group such as a monocyclic or bicyclic aryl group), and further any one of R ₁₁ , R ₁₂ , R ₁₃ and R ₁₄ Two groups may combine to form a 5-membered or 6-membered ring (an optionally substituted saturated or unsaturated 5-membered or 6-membered ring), and a carbocycle is particularly preferable.
Q represents a pharmaceutically acceptable anion required for charge balance, k represents 1 or 2, and n represents 0 or 1.

More specifically, as mentioned above, R ₂ and R ₃ each independently represent an alkyl group which may be unsubstituted or substituted. Suitable examples of alkyl groups include straight chain, branched and cyclic alkyl groups having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 8 carbon atoms. Specific examples of the alkyl group of R ₂ and R ₃ include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,
Examples thereof include tert-butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclopentyl, cyclohexyl, 2-propenyl, 2-butenyl and 3-hexenyl groups. When R ₂ and R ₃ represent a substituted alkyl group, specific examples of the suitable substituent that may be present on the alkyl group include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, an aryl group and an alkoxy group. , A hydroxyl group, a group represented by the following general formula (VII), and the like.

[0022]

[Chemical 12]

(In the formula, R ₁₅ is an alkyl group having 2 or less carbon atoms, m is 3 or 4, n is 2 or 3.) Unsubstituted and substituted alkyls for R ₂ and R ₃ The group preferably has 1 to 15 carbon atoms, more preferably 1 to 10 carbon atoms, and particularly preferably 1 to 8 carbon atoms. Specific examples of R ₂ and R ₃ substituted with a halogen atom include, for example, trichloroethyl, tetrachloropropyl, pentachloropropyl group and the like.
Further, a preferred specific example of the substituent represented by the general formula (VII) is a 3-methoxyethoxyethoxyethoxy group or a 3-methoxyethoxyethoxyethoxyethoxy group.

As defined above, R represents an alkyl group which may be a linear, branched or cyclic alkyl group and may be substituted. Suitable examples of alkyl groups and their substituents are as described for R ₂ and R ₃ .
The number of carbon atoms of the alkyl group represented by R is 1 to 1.
5, preferably 1 to 10 carbon atoms, more preferably 1 to 8 carbon atoms. The aryl group represented by R may be a monocyclic, bicyclic or tricyclic aryl group such as a phenyl group, a biphenyl group, a naphthyl group or an anthracenyl group, and the aryl group is unsubstituted. It may be present or replaced. Examples of suitable substituents that may be present on the aryl group represented by R include:
Fluoro atom, chlorine atom, bromine atom, iodine atom, alkyl group, alkoxy group, hydroxyl group, nitro group, cyano group, amino group, amino group substituted with alkyl group or aryl group, acylamino group, sulfonylamino group, carbamoyl group , Sulfamoyl group, carboxyl group, alkoxycarbonyl group and the like. The aryl group represented by R has 6 to 20 carbon atoms, preferably 6 to 15 carbon atoms, and more preferably 6 to 8 carbon atoms.

The heterocycle represented by R is a 5- to 6-membered heterocycle containing one or more oxygen atoms, sulfur atoms or nitrogen atoms as heteroatoms. Preferable examples of the hetero ring represented by R include imidazole ring, thiazole ring, pyrrole ring, pyrazole ring, furan ring, thiophene ring, piperidine ring, morpholine ring, piperazine ring, pyrazine ring, pyridine ring, pyrimidine ring and the like. Is mentioned. These heterocycles may be substituted, for example, with the substituents described above for aryl groups for R and may form fused rings with other rings, such as saturated or unsaturated rings. The above R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ and R
_The alkyl group represented by ₁₂ , R ₁₃ and R ₁₄ may be a linear, branched or cyclic alkyl group and has 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably It may have 1 to 8 carbon atoms. R ₇ , R ₈ ,
The alkyl group represented by R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ and R ₁₄ may also be a substituted alkyl group. R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ and R
Specific examples of the alkyl group represented by ₁₄ include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, cyclopropyl,
Cyclopentyl, cyclohexyl, 2-propenyl, 2
Examples include -butenyl and 3-hexenyl groups. R ₇ ,
When R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ and R ₁₄ represent a substituted alkyl group, specific examples of suitable substituents which may be present on the alkyl group include a fluorine atom. , Chlorine atom, bromine atom, iodine atom, aryl group, alkoxy group, hydroxyl group and the like. R ₇ , R ₈ , R ₉ , R ₁₀ , R
_The number of carbon atoms of the unsubstituted and substituted alkyl groups represented by ₁₁ , R ₁₂ , R ₁₃ and R ₁₄ is preferably 1 to 15, preferably 1 to 10 carbon atoms, and more preferably 1 to 10 carbon atoms.
8

R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃
And the aryl group represented by R ₁₄ may be a monocyclic, bicyclic or tricyclic aryl group such as a phenyl group, a biphenyl group, a naphthyl group or an anthracenyl group,
Such an aryl group may be unsubstituted or substituted. Examples of suitable substituents which may be present on the aryl group represented by R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ and R ₁₄ include a fluorine atom, a chlorine atom and a bromine atom. Atom, iodine atom, alkyl group, alkoxy group, hydroxyl group, nitro group, cyano group, amino group, amino group substituted with an alkyl group or aryl group, acylamino group, sulfonylamino group, carbamoyl group, sulfamoyl group, carboxyl group, One or more such as an alkoxycarbonyl group may be mentioned. R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃
And the aryl group represented by R ₁₄ has 6 to 20 carbon atoms, preferably 6 to 15 carbon atoms, and more preferably 6 to 12 carbon atoms.

R ₇ and R ₈ , or R ₉ and R
Examples of the ring formed by combining ₁₀ are a benzene ring,
Examples thereof include a naphthalene ring, a dihydronaphthalene ring, an anthracene ring, and a phenanthrene ring. Examples of the substituent that may be present on such a ring include a hydrogen atom, a mercapto group,
Alkyl group, aryl group, alkoxy group, aryloxy group, halogen atom, alkoxycarbonyl group, acylamino group, sulfonylamino group, acyl group, cyano group,
Nitro group, carbamoyl group, sulfamoyl group, acyloxy group, amino group, alkanesulfonyl group, arenesulfonyl group, alkylthio group, arylthio group, hydroxyl group, carboxyl group or heterocyclic residue (subsequent substituent groups)
GpA). Examples of preferred substituents that may be present on such a ring include a hydrogen atom, a mercapto group,
Alkyl group which may have a substituent (methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, hexyl, heptyl, Octyl, cyclopropyl, cyclopentyl,
Cyclohexyl, trifluoromethyl group, etc.), allyl group, arylalkyl group (benzyl, phenethyl, 3-
(Phenylpropyl group, etc.) group, optionally substituted aryl group (phenyl, 4-methylphenyl, 4-chlorophenyl, naphthyl group, etc.), alkoxy group (methoxy, ethoxy, propoxy, butoxy, pentyloxy group, etc. ), An arylalkyloxy group (benzyloxy,
Phenethyloxy group, etc.), an aryloxy group which may have a substituent (phenoxy, 4-methylphenoxy,
4-chlorophenoxy, naphthyloxy group, etc.), halogen atom (fluorine atom, chlorine atom, bromine atom, iodine atom), alkoxycarbonyl group (methoxycarbonyl,
Ethoxycarbonyl group), arylalkoxycarbonyl group (benzyloxycarbonyl group, etc.), optionally substituted acylamino group (acetylamino, trifluoroacetylamino, propionylamino, benzoylamino group, etc.), sulfonylamino group (Methanesulfonylamino, benzenesulfonylamino group, etc.), acyl group (acetyl, trifluoroacetyl, propionyl,
Benzoyl, p-chlorobenzoyl group, etc.), cyano group,
Nitro group, carbamoyl group (carbamoyl, N, N-dimethylcarbamoyl, morpholinocarbonyl, piperidinocarbonyl, methylpiperidinocarbonyl group, etc.), sulfamoyl group (sulfamoyl, N, N-dimethylsulfamoyl, morpholinosulfamoyl) , Piperidinosulfamoyl group, etc.), acyloxy group (acetyloxy, trifluoroacetyloxy, propionyloxy, benzoyloxy group, etc.), amino group (amino, dimethylamino, diethylamino, piperidino, morpholino, anilino, methylpiperidino group, etc.) , Alkanesulfonyl group (methanesulfonyl, trifluoromethanesulfonyl, ethanesulfonyl group, etc.), arenesulfonyl group (benzenesulfonyl, p-toluenesulfonyl, p
-Chlorobenzenesulfonyl group etc.), alkylthio group (methylthio, ethylthio, propylthio group etc.), arylthio group (phenylthio, p-tolylthio group etc.), hydroxyl group, carboxyl group or heterocyclic residue (pyridyl,
5-methyl-2-pyridyl, thienyl group and the like). More preferable examples of the substituent which may be present on the ring include a chlorine atom, a methoxy group, an ethoxy group, a methyl group, a phenoxy group, a phenyl group and a methoxycarbonyl group.

Further, two groups out of R ₁₁ , R ₁₂ , R ₁₃ and R ₁₄ may combine with each other to form a 5- or 6-membered carbon ring. The preferred number of carbon atoms in the carbocycle is R ₁₁ , R ₁₂ , R
_It is 3 to 15, and preferably 3 to 10, including the substituents on the carbocycle of ₁₃ and R ₁₄ . Typical examples of the 5- or 6-membered carbon ring include a cyclopentane ring, a cyclopentene ring, a cyclohexane ring, a cyclohexene ring and the like. Z ₁ and Z ₂ each represent an atomic group necessary for forming a 5-membered or 6-membered ring (saturated or unsaturated 5-membered or 6-membered ring), and may be the same or different.
Further, the ring formed by Z ₁ and Z ₂ may be substituted with one or more substituents, and may be condensed with other saturated or unsaturated ring such as cyclohexene ring, benzene ring or naphthalene ring. You may have. Preferable examples of the substituent which may be present on the ring formed by Z ₁ and Z ₂ include those shown in the above-mentioned substituent group GpA, and preferable examples of saturated or unsaturated condensed therewith Include a cyclopentene ring, a cyclohexene ring, a benzene ring, a naphthalene ring, an anthracene ring, a phenanthrene ring, a thiophene ring, and a pyridine ring.

Specific examples of the 5- or 6-membered hetero ring formed by Z ₁ include dihydropyridine ring, tetrahydropyridine ring, thiazolidine ring, thiazoline ring, tetrahydrobenzothiazoline ring, benzothiazoline ring and dihydroquinoline ring. , A benzoxazoline ring, a naphthoxazoline ring, a naphthothiazoline ring, and a benzoselenazoline ring, and these rings may be substituted by the substituent group GpA. Preferred are a thiazolidine ring, a thiazoline ring, a benzothiazoline ring and a naphthothiazoline ring. More preferably, it is a thiazoline ring. 5 members or 6 formed by Z ₂
Specific examples of the heterocycle which is a member ring include a thiazoline ring,
Examples thereof include a thiazole ring, a pyridine ring, a tetrahydrobenzothiazole ring, a benzothiazole ring, a quinoline ring, a benzoxazole ring, a naphthoxazole ring, a naphthothiazole ring, a benzoselenazole ring, and a dimethylindolenine ring. It may be replaced by the group GpA. Preferably, a benzothiazole ring,
A naphthothiazole ring is mentioned. More preferably, it is a naphthothiazole ring.

L represents a methine group (unsubstituted methine group or substituted methine group) or a nitrogen atom. When L is a substituted methine group, preferable examples of the substituent include an alkyl group (eg, methyl, ethyl, butyl group, etc.), an aryl group (eg, phenyl, tolyl group, etc.),
Halogen atoms (eg fluorine, chlorine, bromine, iodine),
Alkoxy groups (eg, methoxy, ethoxy groups, etc.) can be mentioned. Suitable rings formed by the bond of L and R ₃ include a 5-membered heterocycle (eg, pyrroline ring) and a 6-membered heterocycle (eg, tetrahydropyridine ring). L is preferably an unsubstituted methine group.
In the above compounds, the term "pharmaceutically acceptable anion" for Q, which is required for charge balance, refers to an ion that is non-toxic when the compound is administered to a recipient and that causes the compound to dissolve in water. Means

Suitable examples of the pharmaceutically acceptable anion represented by Q include halogen ions such as chloride ion, bromide ion, and iodide ion; for example, methanesulfonate ion, trifluoromethanesulfonate ion, p- Sulfonate ion such as aliphatic and aromatic sulfonate ion such as toluene sulfonate ion, naphthalene sulfonate ion, 2-hydroxyethane sulfonate ion; sulfamate ion such as cyclohexanesulfamate ion; methylsulfate ion and ethylsulfate ion Such as sulfate ion; hydrogen sulfate ion; borate ion; alkyl and dialkyl phosphate ion such as diethyl phosphate ion and methyl hydrogen phosphate ion; trimethyl pyrophosphate ion and diethyl hydrogen pyrophosphate ion Pyrophosphate ion; carboxylate ion (carboxylate ions carboxy group and a hydroxyl group is substituted with conveniently used) include and carbonate ions. Preferred examples of pharmaceutically acceptable anions include chloride ion, acetate ion, propionate ion,
Examples include valerate ion, citrate ion, maleate ion, fumarate ion, lactate ion, succinate ion, tartrate ion and benzoate ion. k is 1 or 2, but preferably k is 2. m is 0 or 1
However, preferably m is 0. n is 0 or 1, but preferably n is 0. With respect to the compound represented by the general formula (V), the compound represented by the general formula (VI) is preferable.

[0032]

[Chemical 13]

In the general formula (VI), W is a substituent, which is selected from the above substituent group GpA. A halogen atom, a hydroxyl group, an alkyl group, an alkoxy group, an aryl group, an aryloxy group and an alkoxycarbonyl group are preferable, and a methyl group and a methoxy group are more preferable. p is an integer of 1 to 6, preferably 1 to 3, and more preferably 1. R is as described above, but more preferably a methyl group, an ethyl group or a propyl group. R ₂ and R ₃ are as described above, more preferably a methyl group or an ethyl group, and they may be the same or different. Q is as described above, but more preferably chlorine ion, bromine ion, iodine ion or acetate ion. k is preferably 2.

The compounds of the above general formula (I) are compounds of British Patent Nos. 487, 051 and 489, 335 and US Pat. No. 2,536, 986, 2, 454, 629, 2, 96.
1,318, 2,388,963 and 2,504,46
No. 8, JP-A-6-80,892, JP-A-6-116,5
03, JP-A-6-122,828, Japanese Patent Application No. 4-3057.
No. 69, Japanese Patent Application No. 5-22,811 can be manufactured from a known starting material according to the method disclosed in the present specification. Preferred specific examples of the compound of the present invention are shown below, but the present invention is not limited thereto.

[0035]

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[0036]

[Chemical 15]

[0037]

Embedded image

[0038]

[Chemical 17]

[0039]

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[0040]

[Chemical 19]

[0041]

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[0042]

[Chemical 21]

[0043]

[Chemical formula 22]

The compound used in the present invention has a keratinocyte proliferation inhibitory action and an immunosuppressive action, and is therefore useful for the treatment and prevention of skin diseases such as skin allergy and skin autoimmune disease. The pharmaceutical composition of the present invention contains at least one rhodacyanine dye and a pharmaceutically acceptable salt thereof as an active ingredient, and can be used in the form of a pharmaceutical preparation suitable for oral administration, parenteral administration or external medicine. . It may also be used as a mixture with a generally pharmaceutically acceptable carrier. Typical carriers that can be used include water, glucose, sucrose, lactose,
Glycerin, mannitol, sorbitol, pentaerythritol, ethylene glycol, diethylene glycol, propylene glycol, polyethylene glycol,
Mono-, di- and triglycerides of saturated fatty acids such as trilauric acid glyceride, pectin, acacia gum, tragacanth gum, gelatin, starch, dextran, cyclodextrins, olive oil, corn oil, cottonseed oil, sunflower oil, silicone oil, petrolatum, paraffin, lecithin, Examples thereof include cellulose and its derivatives, calcium or magnesium salts of fatty acids such as calcium stearate, salt and other physiological inorganic salts.

Further, known therapeutic agents for skin allergies and therapeutic agents for skin autoimmune diseases, such as cyclosporin A,
Corticosteroids, methotrexate, retinoids,
It can also be used in combination with vitamins B2, B6, calcium pantothenate and the like. The effective dose of the compound used in the present invention in humans varies greatly depending on the administration route, and is usually 0.1 mg / kg / day to 1 mg orally or parenterally.
00 mg / kg / day, 0.1 per adult for external use
It is appropriately selected from the range of μg to 10 mg. The following examples show synthetic examples and pharmacological test results of the compound represented by the general formula (1) of the present invention.

[0046]

【Example】

Example 1. Synthesis of Compound 30 1) 3-Ethyl-5- (3-methylthiazolidine-2-
Synthesis of ylidene) thiazolidin-4-one-2-thione 2-mercapto-2-thiazoline (11.9 g, 0.1
0 mol), methyl p-toluenesulfonate (55.8 g,
A mixture of 0.30 mol) and ethoxybenzene (30 ml) is heated at 120 ° C for 4 hours and then cooled to room temperature. Acetonitrile (400 ml) is added and the mixture is stirred at room temperature for 15 minutes. Add 3-ethylthiazolidin-4-one-2-thione (16.1 g, 0.10 mol) and cool to 5 ° C. Triethylamine (31 ml, 0.22 mol) was added dropwise to this mixture taking care not to let the reaction temperature exceed 10 ° C. and stirred for 4 hours. The precipitated crystals are suction filtered,
Wash twice with acetonitrile (20 ml) and dry to give 3
-Ethyl-5- (3-methylthiazolidine-2-ylidene) thiazolidin-4-one-2-thione (23.1
g, 89%, yellow crystals) was obtained.

2) Synthesis of 3-ethyl-5- (3-methylthiazolidine-2-ylidene) -2-methylthio-4-oxo-2-thiazolinium = p-toluenesulfonate 3-ethyl-5- (3- Methylthiazolidine-2-ylidene) thiazolidin-4-one-2-thione (20.8
g, 80 mmol), methyl p-toluenesulfonate (6
A mixed solution of 0.8 g, 320 mmol) and dimethylformamide (24 ml) is stirred at 130 ° C. for 2.5 hours. After cooling to 50 ° C, add ethyl acetate (300 ml) and add 3
Stir for 0 minutes. The crystals formed were suction filtered, washed twice with ethyl acetate (20 ml) and dried to give 3-ethyl-5-
(3-Methylthiazolin-2-ylidene) -2-methylthio-4-oxo-2-thiazolinium = p-toluenesulfonate (28.5 g, 80%, yellow crystals) was obtained.

3) Synthesis of Compound 30 2,8-Dimethylnaphtho [1,2-d] thiazoline (5
00 mg, 2.44 mmol) and ethyl p-toluenesulfonate (2.0 ml, 11.7 mmol) at 140 ° C.
And heat and stir for 6 hours. After cooling, acetonitrile (1
ml) and 3-ethyl-5- (3-methylthiazoline-
2-Ylidene) -2-methylthio-4-oxo-2-thiazolinium = p-toluenesulfonate (1088 m
g, 2.44 mmol) is added, triethylamine (1 ml) is added dropwise with good stirring at 70 ° C., and the mixture is stirred for 1 hour.
After cooling, the crystals formed are suction filtered. The crude crystals obtained were mixed with methylene chloride / methanol (1: 1) mixed solvent (2 ml).
Ethyl acetate (50 ml) was added with stirring,
Stir for 15 minutes. The precipitated crystals were suction filtered, washed twice with ethyl acetate (10 ml), and air-dried at room temperature to give compound 3
0 (1293 mg, 83%, orange crystals, mp 256)
C) was obtained.

Example 2 Synthesis of Compound 1 Dissolve Compound 30 (300 mg, 0.48 mmol) in a methylene chloride / methanol (1/1) mixed solution (20 ml),
Ion exchange resin (Mitsubishi Kasei, Diaion PA31
(8, Cl type), and eluted with methanol. After the eluates were collected and filtered, the solvent was distilled off under reduced pressure. The residue is dissolved in a methylene chloride / methanol (1/1) mixed solution (20 ml), ethyl acetate is added to the solution while stirring well, and the mixture is stirred for 15 minutes. The precipitated crystals were filtered by suction, washed twice with ethyl acetate (5 ml) and air-dried at room temperature to give compound 1.
(206 mg, 87%, orange crystal, mp 215 ° C.) was obtained.

Example 3 Synthesis of compound 9 A mixture of 8-methoxy-2-methylnaphtho [1,2-d] thiazoline (500 mg, 2.26 mmol) and ethyl p-toluenesulfonate (2.0 ml, 11.7 mmol). Is heated and stirred at 140 ° C. for 6 hours. After cooling, acetonitrile (1 ml) and 3-ethyl-5- (3-methylthiazolin-2-ylidene) -2-methylthio-4-oxo-2-thiazolinium = p-toluenesulfonate (1
(009 mg, 2.26 mmol) was added, triethylamine (1 ml) was added dropwise at 70 ° C. with good stirring, and the mixture was stirred for 1 hour. After cooling, ethyl acetate (20 ml) was added and the resulting crystals were suction filtered. The obtained crude crystals are dissolved in a mixed solvent (2 ml) of methylene chloride / methanol (1: 1), ethyl acetate (50 ml) is added with stirring and the mixture is stirred for 15 minutes. The precipitated crystals were filtered by suction, washed twice with ethyl acetate (10 ml) and air-dried at room temperature to give paratoluenesulfonate of compound 9 (1160 mg, 78%, orange crystals, mp 269).
C) was obtained. Anion exchange was carried out in the same manner as in Example 2 to obtain compound 9.

Example 4 Human Keratinocyte Growth Inhibition Test 1) Human keratinocytes (HEK) purchased from Kyokuto Pharmaceutical Co., Ltd. were typed using BSL-K100 medium.
2 × 10 ⁴ c on a 96-well plate treated with eI collagen
The cells were collected at a concentration of well / well and cultured at 37 ° C. in air containing 5% CO ₂ . 2) After 6 hours, the sample was added and the cells were cultured at 37 ° C. for 2 days in the air containing 5% CO ₂ . 3) After washing each well with PBS, 100 μl / well of 0.04% crystal violet / 20% methanol was added. Leave at room temperature for 15 minutes, then wash with water and
100 μl / well of 0% acetic acid was added. The absorbance at 565 nm of the dissolved dye was measured with a microplate reader. Based on the case of adding water instead of the sample,
The sample concentration at which the absorbance was halved was defined as IC ₅₀ . The results are shown in Table 1.

Example 5 T Cell Proliferation Inhibition Test Solution or dispersion of compound to be tested (RPMI164
0) 20 μl and antigen (BCG 200 μg / ml, RP
MI1640) (20 μl) was added to a dispersion liquid (5 × 10 ⁶ cells) of human peripheral blood mononuclear cells (PBMC) prepared by a conventional method.
/ Ml, RPMI1640 with 20% FCS) 40 μl
In addition, the cells were cultured in a CO ₂ incubator at 37 ° C. About 72 hours later MTT (5 mg / ml, PBS) 10
μl was added, and the mixture was allowed to stand in a CO ₂ incubator at 37 ° C. After 6 hours, the MTT formazan solution (1
100 μl of 0% SDS, 0 / 01N hydrochloric acid / isopropyl alcohol) was added, and the absorbance at 565 nm was measured. Based on the case where water was added instead of the sample, the concentration of the sample at which the absorbance was halved was taken as IC ₅₀ . The results are shown in Table 1.

[0053]

[Table 1] Table 1 ────────────────────────────────── Keratinocyte proliferation inhibition T cell proliferation inhibition Compound No. IC ₅₀ (μg / ml) IC ₅₀ (μg / ml) ─────────────────────────────────── 10 .15 0.02 2 1.5 0.1 3 5 5 3.0 4>10> 10 5>10> 10 6>10> 10 7>10> 10 8 5 3.0 9 0.6 0.2 0.2 10 >10> 10 11 6 1.0 12 0.5 0.5 0.5 13 3 3.0 14>10> 10 15 3 3.0 16 3 0.2 17 1.5 0.3 18 5 4.0 19>10> 10 20 5 4.0 Comparative Example Cyclosporine A 3 Methotrexate 8 ────────────────────────────────────

Example 6 Delayed Type Hypersensitivity Test 100 μl of 0.5% oxazolone ethanol solution as a sensitizing agent was applied to the abdomen of a mouse, and 4 days after that, 0.5% oxazolone acetone solution as an inducing agent was auricular. 20 μl was applied to each part. The thickness of the pinna was measured 24 hours after the induction. As a control, 5% glucose aqueous solution,
As a sample, 200 μl of 0.5 mg / ml 5% glucose solution of Compound 1 was intravenously administered. The administration was continued every day from the first day of sensitization. As a result, the average thickness of the control auricle was 180 μm, whereas it was 110 μm in the Compound 1 administration group, which was significantly suppressed. As is clear from the above results, the compound of the present invention is effective for suppressing the growth of human keratinocytes and suppressing the immune reaction,
It has been shown to be effective in treating skin diseases such as psoriasis, pemphigus, atopic dermatitis and contact dermatitis.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07D 277/66 277/84 417/14 213 215 233 235 263

Claims (10)

[Claims] 1. A compound of the general formula (I) (In the formula, each of A and B independently represents an optionally condensed 5-membered or 6-membered heterocycle, which may be substituted, and R may be substituted. Represents an alkyl group or an aryl group, L represents an optionally substituted methine group or a nitrogen atom, L may form a ring together with B, Y represents O, S, Se, or —NR ₁
Represents-, R ₁ represents an alkyl group, an aryl group or a heterocyclic group, Q represents a pharmaceutically acceptable anion, and k represents 1 or 2. ) A rhodacyanine derivative represented by the formula (1) and a pharmaceutically acceptable salt thereof are contained as at least one active ingredient, and a pharmaceutical composition for treating a skin disease. 2. At least one compound of the general formula (I) is a compound of the general formula (II): (Wherein A, B, R, L, Q, and k are all defined in claim 1
Has the same meaning as. The composition according to claim 1, which is a compound selected from the group consisting of compounds represented by 3. The compound of the general formula (II) has the following general formula:
(III) [Chemical Formula 3] (In the formula, X ₁ and X ₂ are each independently O, S,
Se, -CH = CH -, - CR 4 R 5 - or -NR _6,
And R ₄ and R ₅ each represent an alkyl group, which may be the same or different, R ₆ represents an alkyl group or an aryl group, and R ₂ and R ₃ are each independently substituted. Represents an optionally substituted alkyl group, Z ₁ and Z ₂ each independently represent an atomic group necessary for forming a 5-membered or 6-membered ring together with other ring members of the ring containing them. The ring provided may be substituted, m and n each represent 0 or 1 and may be the same or different, and R, L, Q and k have the same meanings as in claim 2. The composition according to claim 2, which is a compound represented by the formula (1). 4. In the general formula (III), Z ₁ is a dihydropyridine ring, a tetrahydropyridine ring, a thiazolidine ring, a thiazoline ring, a tetrahydrobenzothiazoline ring, a benzothiazoline ring, a dihydroquinoline ring, a benzoxazoline ring, a naphthoxazoline. Represents an atomic group necessary for forming a ring, a naphthothiazoline ring, and a benzoselenazoline ring, and these rings may be substituted, and Z ₂
Required to form a thiazoline ring, thiazole ring, pyridine ring, tetrahydrobenzothiazole ring, benzothiazole ring, quinoline ring, benzoxazole ring, naphthoxazole ring, naphthothiazole ring, benzoselenazole ring, dimethylindolenine ring 4. The composition according to claim 3, which represents a group of atoms, and represents that these rings may be substituted. 5. The compound of the general formula (III) is represented by the following general formula:
(IV) [Chemical 4] (In the formula, R ₇ , R ₈ , R ₉ , and R ₁₀ are each a hydrogen atom,
Represents an alkyl group or an aryl group, which may be the same or different, R ₇ and R ₈ may combine to form a ring, and R ₉ and R ₁₀ may combine to form a ring;
R, R ₂ , R ₃ , X ₁ , X ₂ , L, Q, and k are defined in claim 3.
Has the same meaning as. The composition of Claim 3 which is a compound shown by these. 6. The compound of the general formula (III) is represented by the following general formula (V): (In the formula, R ₁₁ , R ₁₂ , R ₁₃ , and R ₁₄ each represent a hydrogen atom, an alkyl group, or an aryl group, and may be the same or different, or any two groups of R ₁₁ to R ₁₄ May combine to form a 5- or 6-membered ring,
R, R ₂ , R ₃ , X ₁ , X ₂ , L, Q, and k are defined in claim 3.
Has the same meaning as. The composition of Claim 3 which is a compound shown by these. 7. The compound of the general formula (V) is represented by the following general formula (VI): (In the formula, W represents a substituent, p represents an integer of 1 to 6, and R, R ₂ , R ₃ , Q, and k have the same meanings as in claim 3.) The composition according to claim 6. 8. In the general formula (VI), W represents a halogen atom, a hydroxyl group, an alkyl group, an alkoxy group, an aryl group, an aryloxy group or an alkoxycarbonyl group; p represents an integer of 1 to 6; R Has 1 to 8 carbon atoms
Represents an alkyl group; R ₂ and R ₃ have 1 to ₃ carbon atoms
Represents an alkyl group of, and may be the same or different.
The composition according to claim 6, wherein represents chlorine ion, bromine ion, iodine ion or acetate ion, and k represents 2. 9. In the general formula (VI), W represents a methyl group or a methoxy group; p represents 1; R is a methyl group;
Represents an ethyl group or a propyl group; R ₂ and R ₃ represent a methyl group or an ethyl group, which may be the same or different, Q represents a chlorine ion, bromide ion, iodide ion or acetate ion, and k represents 2 7. The composition of claim 6, which represents. 10. The pharmaceutical composition according to claim 1, wherein the skin disease is one of psoriasis, pemphigus, atopic dermatitis and contact dermatitis.