JP2008169155A - Penetration enhancer of medicine for nail and nail-treating agent for external application, containing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a compound imparting a medicine penetration-enhancing effect on a nail. <P>SOLUTION: This penetration enhancer has e.g. a structure expressed by figures [wherein, R<SP>1</SP>to R<SP>3</SP>are each a 1-15C alkyl having hydroxy group at its terminal]. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a drug penetration enhancer for nails and an external nail treatment agent containing the same.

  Although topical administration of drugs to the skin is widely performed by various drugs, drugs with low absorbability cannot fully exhibit their efficacy. The skin is composed of the epidermis, dermis and subcutaneous tissue, and the epidermis can be further divided into a stratum corneum layer, a granule layer, a spiny layer, a basal layer, and four layers in order from the top. Among them, the stratum corneum is made of keratin, fibrous protein, ceramide, and neutral lipid, and prevents foreign substances from entering and moisture from evaporating.

This barrier inherent to the skin is the cause of hindering the percutaneous absorption of the drug, and one way to improve this problem is to use a penetration enhancer.
There have been many reported examples of penetration enhancers, for example, dimethyl sulfoxide, N, N-dimethylformamide, urea, fatty acids such as lauric acid and diethyl sebacate, and esters thereof, Azone. Examples include an azacycloalkane-2-one derivative (Patent Document 1), a dioxolane derivative (Patent Document 2), and a macrocyclic ester (Patent Document 3).

However, these penetration enhancers have problems in stability and skin irritation, and their effects are never sufficient, so that practically effective penetration enhancers are not yet known.
Such a current situation is even more conspicuous with regard to nails. The nail is one of the appendages of the skin and, like the skin, is rich in keratin, whereas the keratin keratin in the skin is soft keratin, whereas the keratin in the nail is hard keratin and contains a lot of cystine, The polypeptide chain has a complex structure in which disulfide bonds are cross-linked. Also, the nail is about 100 times thicker than the skin stratum corneum, and therefore generally has a significantly lower drug permeability than the skin. A typical disease in such nails is onychomycosis.

Nail ringworm, like athlete's foot, is a superficial mycosis caused by the infestation of ringworm fungus, which thickens the nail, makes it opaque, and is sometimes painful. Currently, the main treatment methods for onychomycosis in the dermatology field are methods using oral agents such as griseofulvin and itraconazole, or surgical nail extraction.
The former is forced to take drugs over a long period of time, causing side effects such as liver damage and interaction with other drugs, and the latter is not only severely painful but also causes nails that have become brittle to remain in the affected area. There is a problem such as. Therefore, treatment with a topical external preparation is desired, but since the nail itself prevents the absorption of the drug as a strong barrier as described above, little effect is seen even when applied for a long period of time.

Thus, it is difficult to treat onychomycosis, and a safe and effective treatment method has not been established.
Under such circumstances, many attempts have been made to increase the effect of external therapy. For example, a method of combining an antifungal agent with a fatty acid (Patent Document 4), urea (Patent Document 5), a basic substance (Patent Document 6), or the like is mentioned. The effect on the nail is low, so the effect cannot be expected. Although methods (Patent Documents 7 to 9) using a film forming agent to enhance adhesion to the nail are disclosed, all of these can solve the problem of drug adhesion to the nail to some extent. The drug release from the skin and the permeability to the nail cannot be said to be sufficient, and a satisfactory therapeutic effect cannot be exhibited. To begin with, the nail structure consists of three layers, the upper nail plate layer, the middle nail plate middle layer, and the lower nail plate layer, and the nail plate structure called the nail bed is in contact with the nail plate. Ringworms in onychomycosis are known to have a very high infection rate in the lower nail plate and nail bed. To effectively perform drug treatment with topical agents, the lower nail plate and nail bed It is important to deliver antifungal agents. However, since the nail works as a strong barrier, the drug cannot reach the site where the fungal infection rate is high, which is the cause of the ineffective therapeutic effect.

  Furthermore, it has also been proposed to use an N-alkyl heterocyclic compound in combination with an antifungal compound (Patent Document 10). However, the N-alkyl heterocyclic compound disclosed in Patent Document 10 relates to a compound in which an alkyl group is directly bonded to an N atom of the heterocyclic ring, and has a hydroxyl group at the terminal of the alkyl group. It is not about things. Furthermore, even if the alkyl group is directly bonded to the N atom of the heterocyclic ring, the number of carbon atoms of the alkyl group is limited, and there is no disclosure at all when it has an alkyl group of other carbon number. I have not done it. Moreover, the effect as a penetration enhancer is not examined.

JP 52-1035 A Japanese Patent Laid-Open No. 1-135727 US Pat. No. 5,032,252 JP 58-32818 A JP-A 63-258814 JP 2004-83439 A JP-A-62-155205 JP-A-2-264708 WO96 / 11710 publication Special Table 2000-516928

  As described above, many studies have been made on penetration enhancers to allow the drug to penetrate to the target site in the nail where the permeability of the drug is extremely low. There are problems such as stability, irritation, and feeling of use of the agent itself, and development of a more versatile penetration enhancer is desired. Accordingly, an object of the present invention is to provide a penetration enhancer that is excellent in safety and stability and has a higher effect on the nail, and further provides an external nail treatment agent containing the same.

Therefore, in view of the current situation, the present inventors have recognized the need for an effective penetration enhancer in the nail and conducted extensive studies on this, and as a result, have been promoted drug penetration superior to nitrogen-containing heterocyclic derivatives. It has been found that there is an effect, and the present invention has been completed.
That is, the present invention relates to general formula (I),

(式中、
Zは、窒素原子（-NH-）、酸素原子（-O-）又は硫黄原子（-S-）を示し、
Yは、三級窒素原子（−N=）又は三級炭素原子（-CH=）を示し、
R¹は、C１〜C15の不飽和又は飽和炭化水素基（但し、R¹が、CH₃C_mH_2mで表される飽和炭化水素基（ｍは、5〜14を示す）であり、式中の五員環上の窒素原子と直接結合している場合を除く。）を示し、そして
nは、1〜5を示す。)
で表される化合物又はその薬学的に許容可能な塩からなることを特徴とする浸透促進剤、並びにこれらを含有する外用爪治療剤、若しくは一般式（II）、

(Where
Z represents a nitrogen atom (—NH—), an oxygen atom (—O—) or a sulfur atom (—S—),
Y represents a tertiary nitrogen atom (-N =) or a tertiary carbon atom (-CH =),
R ¹ is a C1-C15 unsaturated or saturated hydrocarbon group (provided that R ¹ is a saturated hydrocarbon group represented by CH ₃ C _m H _2m (m represents 5 to 14), Unless directly bound to the nitrogen atom on the five-membered ring in the middle)
n represents 1 to 5. )
A penetration enhancer characterized by comprising a compound represented by the formula: or a pharmaceutically acceptable salt thereof, as well as an external nail treatment agent containing these, or the general formula (II),

(Where
R ² and R ³ independently represent a C ^{1 to} C 15 saturated or unsaturated hydrocarbon group or a C 1 to C 15 saturated or unsaturated hydrocarbon group bonded through oxygen,
Y represents a tertiary nitrogen atom (-N =) or a tertiary carbon atom (-CH =),
n represents 0-5. )
A penetration enhancer characterized by comprising a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and an external nail treatment agent containing the same.

In the formula (I) or (II) that defines the active ingredient of the present invention, the hydrocarbon group as R ¹ , R ² and R ³ is saturated or has one double bond or one triple bond unsaturated bond. Or it is the hydrocarbon group which has two or more. The number of carbon atoms in the hydrocarbon group is preferably 1 to 15, preferably 2 to 10, more preferably 3 to 8, and an alkyl group or an alkenyl group, particularly an alkyl group. The alkyl group may be linear, branched, or cyclic.
The hydrocarbon group for R ² preferably has 1 to 15 carbon atoms, preferably 2 to 10 carbon atoms, and more preferably 3 to 8 carbon atoms.

The hydrocarbon group in R ³ is preferably a hydrocarbon group having 1 to 15, preferably 2 to 10, more preferably 3 to 8, particularly an alkyl group. R ³ may be an alkoxy group. The range of the alkyl group in that case is the same as that of the alkyl group in R ² . Further, R ³ may have a hydroxyl group at the end of the alkoxy group, and further, an ether bond of a divalent alkylene glycol such as ethylene glycol or propylene glycol may be provided via the hydroxyl group. When alkylene glycol is additionally bonded, the number of moles added is, for example, 1 to 5, preferably about 1 to 3.
The alkyl group may have one or a plurality of substituents, and in the case of having a plurality, the respective substituents may be the same or different.

  Examples of the substituent include a halogen atom (F, Cl, Br, I), a hydroxyl group or a hydroxyl group (—OH), an amino group, an alkoxy group, a carbonyl group, a formyl group, a carboxyl group, a carboxyester group, and a carboxyamide. Preferred examples include a group, a ureido group, a phenyl group, and an aromatic heterocyclic group. In particular, those having a hydroxyl group such as a hydroxyl group, an alkoxy group, a carboxyl group, or a carboxyester group at the terminal carbon atom are preferred. Furthermore, in the case of a five-membered ring containing a nitrogen atom, the hydrocarbon group may or may not be directly bonded to the nitrogen atom. However, when it is a hydrocarbon group having a hydroxyl group as a substituent, those bonded to a nitrogen atom are particularly preferred.

Here, the alkoxy group is a group composed of an oxygen atom and an alkyl group. The range of the alkyl group is as described above. Preferably, as the alkyl group, the number of carbon atoms is 1 to 8, particularly 1 to 5.
The amino group is a group represented by —NR ⁴ R ⁵ , and R ⁴ and R ⁵ are in the same range as a hydrogen atom or the alkyl group.
The carboxyester group is a group represented by —COOR ⁶ , and R ⁶ is in the range defined as the alkyl group.
The carboxamide group is a group represented by —CONR ⁷ R ⁸ . Wherein, R ⁷ and R ⁸ in NR ⁷ R ⁸ is in the same range as the hydrogen atom or the alkyl group.
The ureido group is a group represented by —NR ⁹ CONR ¹⁰ R ¹¹ , and R ⁹ and NR ¹⁰ R ¹¹ are the same as those of the alkyl group and amino group defined above.
The phenyl group may have a substituent, and the substituent is the same as defined above.

As the aromatic heterocyclic group, for example, imidazolyl, triazolyl, pyridyl, pyrrolyl, furyl, thiophenyl and the like may be preferably mentioned, each of which may have a substituent, and the range of the substituent is as defined above. It is the same as what I did.
In the five-membered ring and the six-membered ring, when R ¹ , R ² and R ³ have a hydrocarbon group, the number thereof is 4 or less in the case of a five-membered ring, In the member ring, when the number is 5 or less, other substituents may be substituted at the remaining substitution positions. As such a substituent, for example, a substituent such as a halogen atom, an amino group, a cyano group, a nitro group, a hydroxyl group, and an alkoxy group can be preferably exemplified. The ranges of the halogen atom, amino group, and alkoxy group are the same as those described above as the substituent.

  As the penetration enhancer of the present invention, a compound represented by the following formula is suitable.

  In the above formulas I-1 to I-4, n is an integer of 3 to 10, preferably 5 to 7. This hydroxyl group may be bonded to an alkyl group within the above range to form an alkoxy group.

As the compound represented by the formula II relating to the six-membered ring, those in which the hetero nitrogen atom is at the 2-position, 3-position or 4-position with respect to the substitution position of R ² , particularly at the 4-position are preferred. In R ² , a hydrocarbon group may be directly bonded, or a hydrocarbon group may be bonded via an oxygen atom. In addition, the number showing the position of the substituent of the said compound is for convenience, and the position is not restrict | limited by IUPAC nomenclature.
As such a six-membered ring compound, for example, a compound represented by the following formula is preferable.

In the formula, R ² is preferably an integer of 3 to 10 carbon atoms, preferably 5 to 7 carbon atoms. Particularly preferred are alkyl groups or alkoxy groups having a hydroxyl group at the terminal.

  The compound represented by the above formula I or II is used in an external nail therapeutic agent, for example, in an amount of 0.5 to 80% by mass, preferably 3 to 20% by mass.

  The compound (I) represented by the formula I can be easily produced from known starting materials by those skilled in the art. For example, it can be produced by the following known method.

Step A (for example, for compounds No. 1 to 19 in Table 1 below)

(Wherein R ¹ , Y and Z are as defined in the above formula (I). X represents a halogen atom)

In addition, the compound (I) can be obtained by, for example, the following literature (Sycheva, TP et al., Chem. Heterocycl. Compd. (Engl. Transl.), CODEN: CHCCAL, 8, <1972> 5-7) and It can be produced by the same method (step B) (for example, for compounds No. 20 to 24 in Table 1 below).
Further, the compound (I) of the present invention can be produced by a known method such as synthesis of Paal-Knorr using, for example, γ-diketone (Step C) (for example, Table 1 below). Compound No. 25).

  Specifically, Compound (I) is produced by reacting Compound A and Compound B in Step A in the presence of a base in an inert solvent. Examples of compound A include 8-bromo-1-octanol, 7-bromo-1-heptanol, 6-bromo-1-hexanol, 5-bromo-1-pentanol, bromocycloheptane, etc. Examples of such include imidazole, 2-methylimidazole, 2-undecylimidazole, pyrrole, pyrazole, 1H-1,2,3-triazole, 1H-1,2,4-triazole, etc. Examples thereof include sodium hydride and potassium carbonate, and examples of the reaction solution include dehydrated dimethylformamide and dehydrated tetrahydrofuran. As the reaction conditions, for example, when heated at 60 to 150 ° C. for 3 to 48 hours, compound (I) is obtained, which is purified by a silica gel column. Compound (I) is further purified by distillation as necessary.

The compound represented by the formula II can be easily produced from known starting materials by those skilled in the art. For example, compound (II) (for example, compounds Nos. 26 to 28 in Table 4 below) can be produced by a known method such as hydrogenation after the Wittig reaction.
Compound (II) (for example, compounds Nos. 29 to 37 in Table 4 below) can be produced by a known method such as Williamson's ether synthesis.

  Preferred examples of the medicinal component applied in the present invention include antifungal agents, antibiotics, anti-inflammatory agents, local anesthetics, antiallergic agents, antihistamines, and vitamins. Specific examples of each drug include, for example, nystatin, naphthatin, terbinafine, butenafine, amorolfine, clotrimazole, miconazole, econazole, thioconazole, ketoconazole, lanoconazole, neticonazole, fluconazole, itraconazole, cyclopyrox, Examples include ciclopirox olamine, rilopirox, tolnaftate, griseofulvin, flucytosine, amphotericin B, 5-FU and the like. Antibiotics include, for example, penicillin, methicillin, ampicillin, cephalosporin, cephalexin, streptomycin, gentamicin, kanamycin, tetracycline, minocycline, erythromycin, lincomycin, clindamycin, micamycin,

Examples include vancomycin and chloramphenicol. Anti-inflammatory agents are not limited to steroidal or non-steroidal types. For example, steroidal types include dexamethasone acetate, betamethasone valerate, hydrocortisone butyrate, prednisolone, fluocinoloacetonide, etc. Examples of the system include aspirin, salicylic acid, acetaminophen, ibuprofen, indomethacin, diclofenac, sulindac, colchicine, mefenamic acid, felbinac, fenbufen and the like. Suitable examples of the local anesthetic include lidocaine, dibucaine and procaine. Antiallergic agents include ibudilast, tranilast, cromoglycate sodium and the like. Preferable examples of the antihistamine include diphenhydramine, diphenylpyralin, clemastine fumarate, chlorpheniramine maleate, and mequitazine. Preferred examples of vitamins include vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin C, vitamin D, vitamin E, folic acid, lipoic acid, ubiquinone, and inositol. Other examples include morphine, nicotine, chondroitin sulfate, nitroglycerin and the like.

  These medicinal ingredients are used in an appropriate amount depending on the purpose. For example, when terbinafine, butenafine, amorolfine, or the like is used as an antifungal agent, for example, 0.1 to 30%, preferably 0.5 to 15%, based on the mass of the external nail treatment agent Is preferably blended.

  The penetration enhancer of the present invention is applied to external preparations for nails, and is in the form of nail lacquer, nail polish, liquid, ointment, plaster, gel, cream, patch, patch Agents, aerosol agents and the like. The preparation methods of these preparations can be manufactured by known methods usually performed by those skilled in the art. For example, the 15th revised Japanese Pharmacopoeia Manual (Yodogawa Shoten, issued in June 2006), topical skin application It can be produced by the method described in its preparation and application (Masahiko Takano, Junichi Miyazaki, Nanzando, published on September 20, 1957). In addition, the bases, solvents, solubilizers, film forming agents, fragrances, coloring agents, containers, and the like used in the production of these preparations can be those known by those skilled in the art. However, for example, those described in Pharmaceutical Additives Encyclopedia 2005 (edited by the Japan Pharmaceutical Additives Association, published by Yakuji Nippo, July 12, 2005) can be mentioned.

  As a base, as a specific example of a typical formulation, in the case of a nail lacquer agent, a nail polish agent, etc., if it is normally used, it will not specifically limit, Various bases can be used. Examples of such a base include methacrylic acid ester / methacrylic acid copolymer (for example, EUDRAGIT L100, manufactured by Degussa), methacrylic acid ester copolymers, cellulose derivatives, acrylic acid / styrene copolymers. , Ethylene / vinyl acetate copolymer, alkyd resin, polyester resin, polyvinyl alcohol, soluble nylon, and the like. These may be used alone or in combination of two or more. Moreover, as an organic solvent, a lower alcohol is preferable, for example, ethanol, isopropanol, etc. are mentioned suitably.

Furthermore, preferable examples of the solubilizer, the volatilization retarder, and the plasticizer include ethyl acetate, propyl acetate, butyl acetate, acetone, toluene, triacetin, and menthol.
The base of the ointment is not particularly limited as long as it is usually used. For example, higher fatty acids such as myristic acid, palmitic acid, stearic acid, oleic acid, adipic acid, etc. Esters, waxes, e.g. beeswax, whale wax, higher alcohols, e.g., cetanol, stearyl alcohol, various silicone oils, hydrocarbons, e.g., hydrophilic petrolatum, white petrolatum, purified lanolin In addition, liquid paraffin and the like are preferably mentioned, and as the additive, for example, various surfactants, moisturizers, rash prevention agents and the like are preferably mentioned.

The base of the cream is not particularly limited as long as it is normally used. For example, as higher fatty acid esters, myristic acid ester, palmitic acid ester, etc., as lower alcohol, ethanol, isopropanol, etc. Preferred examples of the polyhydric alcohol include propylene glycol, higher alcohols, cetanol and the like, and carbohydrates such as squalane and liquid paraffin.
Moreover, as an additive, various emulsifiers, antiseptic | preservative, a rash prevention agent, etc. can be mix | blended suitably.

  EXAMPLES Hereinafter, although this invention is demonstrated still in detail, referring an Example, the scope of the present invention is not limited at all by these Examples.

  The structure of the compound (I) represented by the formula I specifically synthesized in the present invention is shown in Table 1 below. In addition, the numbers (1st to 5th) given to the atoms constituting the five-membered ring shown in Table 1 are for convenience to indicate the position, and the position is not limited by the IUPAC nomenclature. Absent.

(In the formula, R ¹ , Y and Z are as defined in the general formula (I).)

The ¹ H NMR spectrum of the above compound is shown in Table 2 below.

(In ¹ H NMR spectrum, signal shape is s (single line), d (double line), t (triple line), q (quadruple line), quint (quintet line), m (multiple line) , Br (broad), etc.)

Example 1
Synthesis of 7-imidazol-1-yl-heptan-1-ol (Compound No. 1) represented by the following formula

To 7-bromo-1-heptanol (2.0 g, 10.3 mmol) was added 30 mL of dehydrated dimethylformamide as a reaction solvent, and imidazole (837 mg, 12.3 mmol) was further added. Sodium hydride (50 to 72%, 451 mg) was added thereto, and the mixture was stirred at room temperature for 30 minutes and then heated and stirred at 125 ° C. for 7 hours. After heating and stirring, 100 mL of purified water was added thereto, and extraction was performed twice with 100 mL of chloroform. The extracts were combined, sodium sulfate was added to this, dried, filtered, and evaporated. After the solvent was distilled off, the residue was purified by silica gel column chromatography (eluted with ethyl acetate and ethyl acetate: methanol = 5: 1) to obtain the title compound (1.76 g, 94.2%) as a pale yellow, transparent liquid.
¹ H-NMR (400MHz: CDCl ₃ ) δ: 1.29-1.37 (6H, m), 1.52-1.57 (2H, m), 1.74-1.81 (2H, m), 3.63 (2H, t, J = 6.6Hz) 3.92 (2H, t, J = 7.1 Hz), 6.90 (1H, s), 7.04 (1H, s), 7.46 (1H, s).

  The structure of compound (II) synthesized in the present invention is shown in Table 3 below. In addition, the numbers (1st to 6th positions) given to the atoms constituting the six-membered ring shown in Table 3 are for convenience to indicate the position, and the position is not limited by the IUPAC nomenclature. .

The ¹ H NMR spectrum of the above compound is shown in Table 4 below.

(In ¹ H NMR spectrum, signal shape is s (single line), d (double line), t (triple line), q (quadruple line), quint (quintet line), m (multiple line) , Br (broad), etc.)

Preparation of formulation using penetration enhancer and evaluation of penetration promotion effect of formulation Hereinafter, formulation examples and penetration promotion effect of the formulation will be described in detail, but the scope of the present invention is not limited to these formulation examples. It is not limited.

Example 2
(Prototype preparation A)
Using 7-imidazol-1-yl-heptan-1-ol (Compound No. 1), a nail lacquer type external therapeutic agent for the treatment of onychomycosis was prepared. Butenafine hydrochloride was used as a medicinal component.

  The composition of the formulation is shown below. The formulation contains 5% (w / v) butenafine hydrochloride as butenafine.

Compound No. 1 0.500 g
Butenafine hydrochloride 0.279 g
EUDRAGIT L100 0.625 g
Butyl acetate 0.250 g
Ethyl acetate 0.750 g
Make absolute ethanol 5 mL

Example 3
(Prototype preparation B)
Using 5- (pyridin-4-yloxy) -pentan-1-ol (Compound No. 33), a nail lacquer type external therapeutic agent for the treatment of onychomycosis was prepared. Butenafine hydrochloride was used as the main drug.

  The composition of the formulation is shown below. The formulation contains 5% (w / v) butenafine hydrochloride as butenafine.

Compound No. 33 0.500 g
Butenafine hydrochloride 0.279 g
EUDRAGIT L100 0.625 g
Butyl acetate 0.250 g
Ethyl acetate 0.750 g
Make absolute ethanol 5 mL

Example 4
(Prototype preparation C)
Using n-heptyloxy-pyridine (Compound No. 29), a nail lacquer type external therapeutic agent for the treatment of onychomycosis was prepared. Butenafine hydrochloride was used as the main drug.

  The composition of the formulation is shown below. The formulation contains 5% (w / v) butenafine hydrochloride as butenafine.

Compound No. 29 0.500 g
Butenafine hydrochloride 0.279 g
EUDRAGIT L100 0.625 g
Butyl acetate 0.250 g
Ethyl acetate 0.750 g
Make absolute ethanol 5 mL

Example 5
(Prototype preparation D)
Using 3-heptyloxy-pyridine (Compound No. 30), a nail lacquer type external therapeutic agent for the treatment of onychomycosis was prepared. Butenafine hydrochloride was used as the main drug. The composition of the formulation is shown below. The formulation contains 5% (w / v) butenafine hydrochloride as butenafine.

Compound No. 30 0.500 g
Butenafine hydrochloride 0.279 g
EUDRAGIT L100 0.625 g
Butyl acetate 0.250 g
Ethyl acetate 0.750 g
Make absolute ethanol 5 mL

Example 6
(Prototype preparation E)
Using 2-heptyloxy-pyridine (Compound No. 31), a nail lacquer type external therapeutic agent for the treatment of onychomycosis was prepared. Butenafine hydrochloride was used as the main drug. The composition of the formulation is shown below. The formulation contains 5% (w / v) butenafine hydrochloride as butenafine.

Compound No. 31 0.500 g
Butenafine hydrochloride 0.279 g
EUDRAGIT L100 0.625 g
Butyl acetate 0.250 g
Ethyl acetate 0.750 g
Make absolute ethanol 5 mL

Example 7
(Prototype preparation F)
Using 7-pyrrol-1-yl-hepten-1-ol (Compound No. 11), a nail lacquer type external therapeutic agent for the treatment of onychomycosis was prepared. Butenafine hydrochloride was used as a medicinal component.

  The composition of the formulation is shown below. The formulation contains 5% (w / v) butenafine hydrochloride as butenafine.

Compound No. 11 0.500 g
Butenafine hydrochloride 0.279 g
EUDRAGIT L100 0.625 g
Butyl acetate 0.250 g
Ethyl acetate 0.750 g
Make absolute ethanol 5 mL

Example 8
(Prototype preparation G)
Using 7-imidazol-1-yl-heptan-1-ol (Compound No. 1), a nail lacquer type external therapeutic agent for the treatment of onychomycosis was prepared. Butenafine hydrochloride was used as a medicinal component. The composition of the formulation is shown below. The formulation contains 15% (w / v) butenafine hydrochloride as butenafine.

Compound No. 1 0.500 g
Butenafine hydrochloride 0.836 g
EUDRAGIT L100 0.625 g
Butyl acetate 0.250 g
Ethyl acetate 0.750 g
Make absolute ethanol 5 mL

Example 9
(Prototype preparation H)
Using 7-imidazol-1-yl-heptan-1-ol (Compound No. 1), a nail lacquer type external therapeutic agent for the treatment of onychomycosis was prepared. Terbinafine hydrochloride was used as a medicinal component. The composition of the formulation is shown below. The formulation contains 15% (w / v) terbinafine hydrochloride as terbinafine.

Compound No. 1 0.500 g
Terbinafine hydrochloride 0.844 g
EUDRAGIT L100 0.625 g
Butyl acetate 0.250 g
Ethyl acetate 0.750 g
Make absolute ethanol 5 mL

Example 10
(Prototype preparation I)
Using 7-imidazol-1-yl-heptan-1-ol (Compound No. 1), a nail lacquer type external therapeutic agent for the treatment of onychomycosis was prepared. As the medicinal component, amorolfine hydrochloride was used.

  The composition of the formulation is shown below. The formulation contains 15% (w / v) amorolfine hydrochloride as amorolfine.

Compound No. 1 0.500 g
Amorolfine hydrochloride 0.836 g
EUDRAGIT L100 0.625 g
Butyl acetate 0.250 g
Ethyl acetate 0.750 g
Make absolute ethanol total volume 5mL

Example 11
Evaluation of penetration promotion effect by formulation using penetration enhancer Hereinafter, the penetration promotion effect of the formulation will be specifically described in detail, but the present invention is not limited thereto.

Evaluation test method
Drug nail permeation amount test method First, add 1% Bacto Agar (Becton Dickinson) to purified water containing 70% propylene glycol to prepare agarose agar, and add it to a vial with a screw cap (inner diameter 24 x high). Was dispensed 1 mL at a time to 55 mm) and solidified to be flat. Next, the human nail is precisely cut into 4 × 4 mm, and a silicone O-ring having an outer diameter of 2.5 mm is adhered to the center of the upper nail with a silicone-based synthetic adhesive, and the preparation prepared above is placed in the O-ring. Was applied in an amount of 5 μL. The nail specimen was placed gently so that the O ring was on the top and the upper nail and O ring were not in contact with agarose agar. After placing the nail specimen at 37 ° C. for 5 days, the nail was taken out, made basic by adding 1N sodium hydroxide aqueous solution to agarose agar, and after extracting the antibacterial agent permeated into the agar twice with ethyl acetate, The amount of the antibacterial agent, which is a medicinal component, was measured by HPLC.

The permeation amounts of butenafine hydrochloride, terbinafine hydrochloride and amorolfine hydrochloride with respect to the nail measured by the above test method are shown in Tables 5, 6, 7 and 8 below.
Nail permeation amount of butenafine hydrochloride in a preparation containing 5% (w / v) butenafine hydrochloride as butenafine (concentration of compound (penetration enhancer) is 10% w / v)

* 1 Formulation of trial preparation A, excluding penetration enhancer only * 2 Quantitative value of butenafine as hydrochloride

Nail permeation of butenafine hydrochloride in a preparation containing 15% (w / v) butenafine hydrochloride as butenafine (concentration of compound (penetration enhancer) is 10% w / v)

※3 試作製剤Gより、浸透促進剤のみを除いた組成の製剤
※4 ブテナフィンの塩酸塩としての定量値

* 3 Formulation with formulation excluding penetration enhancer from trial preparation G * 4 Quantitative value of butenafine as hydrochloride

Nail permeation of terbinafine hydrochloride in a preparation containing 15% (w / v) terbinafine hydrochloride as terbinafine (concentration of compound (permeation enhancer) is 10% w / v)

* 5 Formulation with the composition excluding only penetration enhancer from trial preparation H * 6 Quantitative value of terbinafine as hydrochloride

Nail permeation of amorolfine hydrochloride in a preparation containing 15% (w / v) amorolfine hydrochloride as amorolfine
(Concentration of compound (permeation enhancer) is 10% w / v)

※7 試作製剤Iより、浸透促進剤のみを除いた組成の製剤
※8 アモロルフィンの塩酸塩としての定量値

* 7 Formulation I, excluding only penetration enhancer from trial preparation I * 8 Quantitative value of amorolfine as hydrochloride

  From the above measurement results, various antibacterial preparations blended with the penetration enhancer of the present invention showed a clear penetration promoting effect in the penetration test of the antibacterial agent using a human nail specimen. For example, in the permeation amount test (Table 5) of a preparation system containing 5% (w / v) butenafine hydrochloride as butenafine, when trial preparation A containing 10% of compound No. 1 as a penetration enhancer was used, About 7.9 times the penetration promoting effect of butenafine hydrochloride was observed compared to the placebo a containing no compound No. 1. Similarly, when trial preparation B containing 10% of compound No. 33 was used as a penetration enhancer, a penetration enhancement effect of about 6.6 times was observed compared to the case where placebo a was used.

  The penetration-promoting action of Compound No. 1 is particularly noticeable when the concentration of the antibacterial agent is high. In the permeation amount test of a formulation system containing 15% (w / v) butenafine hydrochloride as butenafine (Table 6) When trial preparation G containing 10% of compound No. 1 was used, the penetration promoting effect of butenafine hydrochloride was about 33 times that of the case where placebo g not containing compound No. 1 was used. Similarly, in the permeation test of the trial preparation H containing 15% (w / v) terbinafine hydrochloride as terbinafine (Table 7), an about 15-fold penetration promoting effect was observed, and 15% (w / v) as amorolfine. In the permeation amount test (Table 8) of the trial preparation I containing amorolfine hydrochloride, about 25 times higher penetration promoting effect was observed. Thus, the compound of the present invention has a penetration-promoting action, which can be expected to be highly useful in the prevention and treatment of nail diseases.

  The present invention provides a novel compound that is useful for the prevention and treatment of pathological conditions such as infectious diseases including inflammation of the skin, inflammation, and allergies, etc. by having a strong penetration promoting effect of the therapeutic agent on the nail. So far, it has been very difficult to treat nail diseases with external medicines, but it is expected that the effectiveness of the treatment with external medicines will be greatly improved by the present invention, and its utility value is considered high.

Claims (6)

Formula (I),

(Where
Z represents a secondary nitrogen atom (—NH—), an oxygen atom (—O—) or a sulfur atom (—S—);
Y represents a tertiary nitrogen atom (-N =) or a tertiary carbon atom (-CH =),
R ¹ is a C1-C15 unsaturated or saturated hydrocarbon group (provided that R ¹ is a saturated hydrocarbon group represented by CH ₃ C _m H _2m (m represents 5 to 14), Unless directly bound to the nitrogen atom on the five-membered ring in the middle)
n represents 1 to 5. )
Or a pharmaceutically acceptable salt thereof. Formula (II),

(Where
R ² and R ³ independently represent a C1-C15 saturated or unsaturated hydrocarbon group or a C1-C15 saturated or unsaturated hydrocarbon group bonded to a six-membered ring via oxygen;
Y represents a tertiary nitrogen atom (-N =) or a tertiary carbon atom (-CH =), and
n represents 0-5. )
Or a pharmaceutically acceptable salt thereof.   An external nail treatment agent comprising the penetration enhancer of claim 1 and a medicinal component.   An external nail treatment agent comprising the penetration enhancer according to claim 2 and a medicinal component.   The nail therapeutic agent for external use according to claim 3, wherein the medicinal component is a medicinal component selected from the group consisting of butenafine, terbinafine and amorolfine.   The nail therapeutic agent for external use according to claim 4, wherein the medicinal component is a medicinal component selected from the group consisting of butenafine, terbinafine and amorolfine.