JP2000239188A - Hair growing and restoring agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To prepare a hair growing and restoring agent capable of attaining the enhancement and normalization, or the like, of functions of scalp and hair of head and excellent trichogenous effect and depilation inhibiting one by including a prostaglandin I2(PGI2) agonist not having a prostanoic acid skeleton. SOLUTION: This agent contains a PGI2 agonist not having a prostanoic acid skeleton. The PGI2 agonist is preferably a (condensed) benzene oxyacetate derivative and is e.g. a compound of formula I wherein, R1 is H or a 1-4C alkyl; R2 and R3 are each phenyl, a 4-7C cycloalkyl, a 4-7 membered monocyclic heterocyclic group containing one nitrogen; the part of formula II is a bivalent group of formula III [wherein, B is (CH2)p; (p) is 1-4], or the like; the part of formula IV is a trivalent group of formula V, or the like}. When therapeutically used for enhancing the growth of hair, a solution, a lotion, cream and the like each containing preferably from about 0.01 (w/v)% to a few (w/v)% effective ingredient can be prepared.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a hair restorer having effects such as promoting hair regeneration and suppressing hair loss.

[0002]

2. Description of the Related Art Prostaglandins (hereinafter sometimes abbreviated as "PG") are synthesized in animal tissues from eicosapolyenoic acid such as arachidonic acid, and are a group of physiological activities showing various activities in vivo. The substance is structurally characterized by having prostanoic acid as a basic skeleton. PG
Are classified according to the difference between the oxygen atom and the double bond bonded to the five-membered ring part and the difference in the number of double bonds present in the side chain, each showing a structure-specific physiological activity It is known. For example, prostaglandin F has effects such as blood pressure increase, intestinal hypertension, uterine contraction, bronchoconstriction, and prostaglandin E exhibits blood pressure lowering, vasodilation, suppression of gastric acid secretion, diuretic effect and the like. Therefore, it has been applied as a medicament for promoting labor and delivery and as an agent for improving skin ulcer.

[0003] Prostaglandin I2 (hereinafter PGI2)
May be abbreviated to have the effect of dilating blood vessels to lower blood pressure and the effect of suppressing platelet aggregation, and further have the effect of suppressing the action of thromboxane A2 that causes platelet aggregation. Application to is expected. However, the epoxide moiety contained in the chemical structure is extremely unstable, and its half-life in a neutral aqueous solution at 37 ° C. is extremely short, about 5 minutes. The development of PGI2 derivatives has been desired. Further, PGI2 has a basic structure of prostanoic acid, and has a structure similar to PGE1 or PGE2. Therefore, it is also a problem that it is difficult to dissociate PGE2 from the side effects observed in PGE and the like.

Recently, PGI present in human platelet membrane fraction
Although it has high affinity for the two receptors, it is structurally PGI
A series of compounds that are completely different from 2 have been discovered. Furthermore, these compounds show a platelet aggregation inhibitory action,
It was also found to have two agonistic effects. For example,
As PGI2 agonists, JP-A-6-87811, JP-A-6-25074, JP-A-7-145057 and JP-A-6-72978 describe condensed benzeneoxyacetic acid derivatives or non-toxic salts thereof. JP-A-6-56744 describes a non-condensed benzeneoxyacetic acid derivative or a non-toxic salt thereof.

More specifically, for example, Japanese Patent Laid-Open No. 6-87
No. 811 discloses [5- [2-] represented by the formula (a).
[1-Phenyl-1- (3-pyridyl) methylideneaminooxy] ethyl] -7,8-dihydronaphthalene-1
-Yloxy] acetic acid (compound 1) is disclosed, and JP-A-6-25074 discloses [2- (2-diphenylmethyloxyiminopropyl) represented by the formula (b).
-1,2,3,4-tetrahydronaphth-5-yloxy] acetic acid (compound 2), [2- (3
-Diphenylmethyloxyiminopropyl) -1,2,2
3,4-tetrahydronaphth-5-yloxy] acetic acid (compound 3) and [2- [2- [1
-Phenyl-1- (3-pyridyl) methyloxyimino] propyl] -1,2,3,4-tetrahydronaphth-5-yloxy] acetic acid (Compound 4) is disclosed. Japanese Patent Application Laid-Open No. H7-145057 discloses that [2- (4- (diphenylmethyl) pyrazol-1-yl) methyl-3,4-dihydronaphthalen-5-yloxy] acetic acid represented by the formula (e): Compound 5) is disclosed, and JP-A-6-56744 discloses 3- [3- (5-diphenylmethylisoxazol-3-yl) propyl] phenoxyacetic acid (compound 6) is disclosed. These publications show that the above compounds are useful for prevention and treatment of thrombosis, arteriosclerosis, ischemic heart disease, gastric ulcer, and hypertension.

[0006]

Embedded image (In the above formulas (a) to (f), Ph represents a phenyl group.)

On the other hand, hair loss is a common problem for humankind. In particular, recently, the number of adult men suffering from thinning hair and hair loss has increased due to changes in the social environment and stress, changes in eating habits, and various other causes. This trend has also been observed in women. For example, alopecia areata induced by stress or the like, and male pattern baldness in which men lose their hair as they age, are well-known phenomena, but the onset mechanism of male pattern baldness is often unclear. Hair follicles continually cycle from anagen to catagen and telogen, forming a so-called hair cycle.In male pattern baldness, at least the proportion of telogen follicles increases, and the dwarfing of these hair follicles further progresses I do. As other changes, it is known that the hair changes from hard to soft as the alopecia progresses. Research on hair growth agents has been carried out for these phenomena for a long time, but most of the conventional hair growth agents aim at nutritional supplementation, improvement of blood circulation promotion, moisturizing action, and insufficient effect. That is what everyone acknowledges. Therefore, the birth of a more effective hair restorer has been desired.

[0008]

SUMMARY OF THE INVENTION An object of the present invention is to achieve the enhancement and normalization of the scalp and hair, and to exhibit excellent effects in promoting hair growth and suppressing hair loss. An object of the present invention is to provide a hair restorer. The present inventors have conducted intensive research to solve the above problems,
It has been found that a compound having an agonistic action on the PGI2 receptor, in particular, a PGI2 agonist having a non-prostanoic acid skeleton has a desired hair growth promoting and hair loss suppressing effect and is extremely useful as an active ingredient of a hair restorer. The present invention has been completed based on these findings.

[0009] That is, the present invention provides a hair restorer containing, as an active ingredient, a PGI2 agonist having no prostanic acid skeleton. According to a preferred embodiment of the present invention, the hair restorer wherein the PGI2 agonist is a condensed or non-condensed benzeneoxyacetic acid derivative or a physiologically acceptable salt thereof; and the PGI2 agonist has the following formula (I):

Embedded image Wherein R ¹ represents a hydrogen atom or a C _1-4 alkyl group;
² and R ³ each independently represent a phenyl group, a C _4-7 cycloalkyl group, a 4- to 7-membered monocyclic heterocyclic group containing one nitrogen atom, or a phenyl group,
A C _1-4 alkyl group having a substituent selected from the group consisting of a _4-7 cycloalkyl group and a 4- to 7-membered monocyclic heterocyclic group containing one nitrogen atom; , Cycloalkyl group, or a monocyclic heterocyclic group on the ring C _1-4 alkyl group, C _1-4 alkoxy group, halogen atom, nitro group, and a group consisting of C _1-4 halogenated alkyl group 1 to 3 selected substituents may be present,

Embedded image Is the following formula:

Embedded image [Wherein, B represents a group represented by-(CH ₂ ) _p- (wherein _p represents an integer of 1 to 4), and in the group represented by the above formula (1), B represents the a-position. Or binds to the b-position], a divalent group selected from the group consisting of:

Embedded image Is the following formula:

Embedded image [Wherein R ⁴ represents a hydrogen atom or a C _1-6 alkyl group;
et represents a 5-membered monocyclic heterocyclic group containing two nitrogen atoms, or a 5-membered heterocyclic group containing one nitrogen atom and one oxygen atom.
A monovalent heterocyclic group (wherein the ring may be substituted with one or two C _1-4 alkyl groups). Or a physiologically acceptable salt thereof.

From another viewpoint, a PGI2 agonist having no prostanoic acid skeleton, preferably a condensed or non-condensed benzeneoxyacetic acid derivative or a physiologically acceptable salt thereof, more preferably represented by the above formula (I) Use of a compound or a physiologically acceptable salt thereof for the production of the above hair restorer; and a hair restorer, comprising a PGI2 agonist having no prostanic acid skeleton, preferably a condensed or non-condensed benzeneoxyacetic acid derivative or a physiologic derivative Administering an effective amount of a physiologically acceptable salt thereof, more preferably a compound represented by the above formula (I), or a physiologically acceptable salt thereof, preferably a topical administration to the scalp and / or hair. Are provided.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION The hair restorer of the present invention is characterized by containing a PGI2 agonist having no prostanic acid skeleton as an active ingredient. The active ingredient of the hair restorer of the present invention is not particularly limited as long as it has an agonistic action on the PGI2 receptor and does not have a prostanoic acid skeleton. The human PGI2 receptor is described, for example, in International Publication WO95 / 21863,
Whether it acts as an agonist on 2 receptors
For example, according to the method described in JP-A-6-87811, (i) binding ability to PGI2 receptor and / or (i)
i) Those skilled in the art can easily carry out an assay using a biological action such as a platelet aggregation inhibitory action as an index.

The degree of action of the active ingredient of the hair restorer of the present invention as a PGI2 agonist is not particularly limited, but it is desirable to use a compound having an action as strong as possible as an agonist. Further, the above-mentioned active ingredient may have a physiological activity other than the agonistic action on the PGI2 receptor. Examples of the compound having no prostanoic acid skeleton acting as a PGI2 agonist include, for example,
No. 87811, JP-A-6-25074, JP-A-7-145057, JP-A-6-72978, or JP-A-6-56744, condensed or non-condensed benzeneoxyacetic acid derivatives, etc. Can be mentioned. Among these, the compound represented by the above formula (I) can be particularly suitably used as an active ingredient of the hair restorer of the present invention.

In the present specification, the alkyl moiety of an alkyl group or a substituent containing an alkyl moiety (eg, an alkoxy group, a halogenated alkyl group, etc.) may be straight-chain or branched. A C _1-4 alkyl group represented by R ¹ , R ² or R ³ (means an alkyl group having 1 to 4 carbon atoms).
The same applies to other similar expressions.)
For example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, an isobutyl group, or a tert-butyl group can be given.
As the C _1-6 alkyl group represented by R ⁴ , in addition to the alkyl group specifically described for the above C _1-4 alkyl group, n-
A pentyl group, an n-hexyl group and the like can be used.

The C _4-7 cycloalkyl group represented by R ² and R ³ includes a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and a cycloheptyl group.
4 to 7 containing one nitrogen atom represented by R ² and R ³
The membered monocyclic heterocyclic group may be, for example, any of a heterocyclic aryl group or a partially or wholly saturated ring residue. More specifically, azete, pyrrole,
Pyroline, pyrrolidine, pyridine, piperidine or azepine ring residues can be used. Preferably, a residue of a heterocyclic aryl group can be used,
More preferred are residues of pyrrole, pyridine, or azepine, and residues of pyridine, ie, a 2-pyridinyl group, 3-
A pyridinyl group or a 4-pyridinyl group is particularly preferred.

On the ring of a phenyl group, a cycloalkyl group or a heterocyclic group represented by R ² and R ³ or an alkyl group having a substituent selected from the group consisting of a phenyl group, a cycloalkyl group and a heterocyclic group A phenyl group, a cycloalkyl group, or a C _1-4 alkyl group, a C _1-4 alkoxy group, a halogen atom, a nitro group, and a C _1-4 halogenated alkyl group at any position on the ring of the heterocyclic group And 1 to 3 substituents selected from the group consisting of: C
_1-4 alkoxy groups include a methoxy group, an ethoxy group,
n-propoxy group, isopropoxy group, n-butoxy group, sec-butoxy group, isobutoxy group, or ter
A t-butoxy group can be used. As the halogen atom, any of a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom may be used. Examples of the halogenated alkyl group include a C _1-4 alkyl group having one or more identical or different halogen atoms, preferably a trihalomethyl group, more preferably a trifluoromethyl group. Can be.

The group represented by B is bonded to either the a-position or the b-position with respect to the group represented by (1). (2)
In the group represented by or the group represented by (3), the group represented by B may be present at any position of the ring to which it is bonded. Further, the divalent oxygen atom bonded to the group represented by (1) to (3) may be present at an arbitrary position on the benzene ring. In the group containing A, a wavy line in the group represented by 1) or 2) indicates that the oxime group is either one of two kinds of stereoisomers or a mixture of both. Het in the group represented by 3) represents a 5-membered monocyclic heterocyclic group containing two nitrogen atoms or one nitrogen atom and one oxygen atom. The group or a part or all of the group may be a saturated ring residue. Examples of the heterocycle containing two nitrogen atoms include, for example, residues of pyrazole, imidazole, pyrazoline, imidazoline, pyrazolidine, and imidazolidine. The heterocycle containing one nitrogen atom and one oxygen atom can be mentioned. As a ring, for example, oxazole,
Isoxazole, oxazoline, isoxazoline,
Oxazolidine or ioxoxazolidine residues can be mentioned. Preferable examples include a pyrazole or isoxazole residue. One or two C _1-4 alkyl groups may be present at any position on the ring of the heterocyclic group.

The compound which is an active ingredient of the hair restorer of the present invention is described in, for example, JP-A-6-87811 and JP-A-6-87811.
JP-A-25074, JP-A-7-145057, JP-A-6-72978, or JP-A-6-56744
It can be easily produced according to the method described in Japanese Patent Application Laid-Open Publication No. H10-260, or a method analogous thereto. The compounds specifically disclosed in these publications can be suitably used as the active ingredient of the hair restorer of the present invention. When the compound as an active ingredient of the hair restorer of the present invention has one or more asymmetric carbons, stereoisomers such as optically active isomers and diastereoisomers based on the asymmetric carbons are available. Isomers may be present.
As the active ingredient of the hair restorer of the present invention, not only stereoisomers in a pure form, but also any mixture of the isomers, racemates and the like may be used.

As an active ingredient of the hair restorer of the present invention, a physiologically acceptable salt may be used. For example, acid addition salts (for example, mineral acid salts such as hydrochloride and sulfate, organic acid salts such as p-toluenesulfonic acid salt and maleate), base addition salts (for example, sodium salt, potassium salt, calcium salt) Metal salts, ammonium salts, organic amine salts such as triethylamine salts), amino acid salts (glycine salts) and the like, as well as internal salts (so-called Zwitter ions). Further, as the active ingredient of the hair restorer of the present invention, any hydrate or solvate of the above compound may be used.

The hair restorer of the present invention has effects such as promoting hair growth and suppressing hair loss, and treats and / or prevents various alopecia including male pattern alopecia and alopecia areata. Can be used for As used herein, the term "hair restorer" refers to a drug that is used therapeutically and / or prophylactically against alopecia, including the inhibition of hair growth, as well as hair growth. It should be interpreted in the broadest sense to include any drug that can be used as a quasi-drug in addition to the drugs specified in the above. As the active ingredient of the hair restorer of the present invention, one or more of the above compounds can be used.

The method of applying the hair restorer of the present invention is not particularly limited. However, when it is used therapeutically to promote hair growth, it is preferably about 0.01% to several% (w / v). Liquid preparations, lotions, and creams containing the active ingredient can be prepared, and approximately 0.1 ml to 1 ml per day may be applied to the hair loss area to be treated. It is also possible to perform an intradermal injection in order to achieve a reliable intradermal administration. When used prophylactically for the purpose of suppressing hair loss, etc., the amount of the active ingredient should be 0.05%.
% (W / v), and 0.1%
It is preferable to apply about 1 ml to about 1 ml. The form of the hair restorer of the present invention is not particularly limited, but a liquid agent or the like that can achieve rapid skin penetration is desirable.

In the hair restorer of the present invention, various pharmaceutical ingredients or pharmaceutical additives are added to the hair restorer of the present invention for the purpose of enhancing the action of the active ingredient PGI2 agonist, enhancing the feeling of use and refreshing. It can be added to a hair restorer.
For example, it is possible to mix components of a hair restorer that has been certified as a quasi drug or a pharmaceutical. Examples include mild bactericides such as benzalkonium chloride, benzethonium chloride, and phenol sugar, estradiol, other ovarian hormones, antihistamines such as diphenhydramine chloride, chlorpheniramine maleate, photosensitizers, chlorophyllin derivatives, cholesterol, and salicylic acid. , Cystine and various amino acids and derivatives thereof, pantothenyl ethyl ether, tocopherol acetate, pepper tincture, tincture tincture, benzyl nicotinate, dL-menthol, L-menthol, peppermint oil, calcium pantothenate, pantothenyl alcohol, castor oil , Hinokitiol, prednisolone, hydrocortisone, pyridoxine hydrochloride, resorcinol, thymol, ethanol, vitamins, olive oil, squalane, liquid paraffin,
Examples include isopropyl myristate, higher fatty acids, higher alcohols, lactic acid, various surfactants, fragrances, antioxidants, ultraviolet absorbers, carpronium chloride having a vasodilator effect, and minoxidil which is a potassium channel opener.

[0022]

EXAMPLES Hereinafter, the present invention will be described more specifically with reference to Examples, but the scope of the present invention is not limited to the following Examples. In the examples, compound 1 is described in JP-A-6-8781.
Compound 2 described in Example 2 (g) of JP-A No. 1; Compound 2 is a compound described in Example 6 of JP-A-6-25074; Compound 5 is described in Example 22 of JP-A No. 7-145057. Compound 6: Compound 6 is disclosed in JP-A-6-56744.
The compound is described in Example 19 of the publication, and the respective structural formulas are shown in the section of the prior art in this specification.

Example 1: Formulation Example <Formulation Example 1> Active ingredient 0.05% (W / V) Ethyl alcohol 45.0% 0.02M Phosphate buffer 54.95% <Formulation example 2> Active ingredient 0.05% (W / V) Ethyl alcohol 30.0% Propylene glycol 50.0% Sterile water 19.95% <Formulation example 3> Active ingredient 0.05% (W / V) Ethyl alcohol 50.0% Glycerin 2.0% Propylene glycol 30.0% Hinokitiol 0.1% Sterile water 17.85%

Example 2: Mouse hair growth effect test C3H / HenCrj mice (SPF, male, Charles Nippon
After purchasing River Co., Ltd. (42-43 days old), the animals were preliminarily reared for about 7 days for acclimation (including shaving). Three days before the start of the test (47-48 days old), the entire back of the mouse was shaved using an electric clipper (National Skical ER554P-A). Further, using Kanebo Epirat depilatory foam, the whole of the back of the cut mouse was sprayed. After leaving at room temperature for about 3 minutes, the mouse was promptly and thoroughly washed with hot water at 37 ° C., and water droplets attached to the mouse were removed using Kim towel. About 24 hours after the hair removal treatment, the weight of the mice was measured, and individuals with no abnormal skin were selected and divided into groups so that the weight of each group was almost uniform. Thereafter, each of the samples (compounds 1, 2, 5, and 6) prepared in Formulation Example 1 described in Example 1 and a control sample containing only the solvent were administered once a day, 7 days a week, 1 day per animal. Times 0.
1 ml was applied.

The hair growth effect was determined by determining the area ratio of hair growth 13 days after the start of application and the area ratio at which skin color change (change from skin color to black) was induced prior to hair growth, using only the solvent. The comparison was performed with the control group. The area of hair growth and the rate of change in pigmentation of the skin are photographed of the test area,
The percentage of the area of hair growth on the entire back part subjected to the hair removal treatment or the percentage of change in pigment of the skin was measured by image analysis. As a control, a group containing only the solvent was provided, and the effect of the hair restorer according to the present invention was compared by comparing with the group. The results are shown in FIGS. Compound 1 compared to the solvent-only sample
2, 5, and 6 markedly improved the hair growth area ratio (FIG. 1) and the pigment change rate (FIG. 2).

[0026]

Industrial Applicability The hair restorer of the present invention can achieve the function enhancement and normalization of the scalp and hair, and has extremely excellent hair regeneration promoting effects and hair loss suppressing effects. In addition, it has a feature of high safety and storage stability.

[Brief description of the drawings]

FIG. 1 is a view showing the effect of improving the area ratio of hair growth of a hair growth agent of the present invention.

FIG. 2 is a graph showing the effect of the hair restorer of the present invention on improving pigment change.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) // A61K 7/06 A61K 7/06

Claims (5)

[Claims] 1. A hair restorer comprising, as an active ingredient, a PGI2 agonist having no prostanic acid skeleton. 2. The hair restorer according to claim 1, wherein the PGI2 agonist is a condensed or non-condensed benzeneoxyacetic acid derivative or a physiologically acceptable salt thereof. 3. The method of claim 1, wherein the PGI2 agonist has the following formula (I): Wherein R ¹ represents a hydrogen atom or a C _1-4 alkyl group;
² and R ³ each independently represent a phenyl group, a C _4-7 cycloalkyl group, a 4- to 7-membered monocyclic heterocyclic group containing one nitrogen atom, or a phenyl group,
A C _1-4 alkyl group having a substituent selected from the group consisting of a _4-7 cycloalkyl group and a 4- to 7-membered monocyclic heterocyclic group containing one nitrogen atom; , Cycloalkyl group, or a monocyclic heterocyclic group on the ring C _1-4 alkyl group, C _1-4 alkoxy group, halogen atom, nitro group, and a group consisting of C _1-4 halogenated alkyl group One to three selected substituents may be present, Is the following formula: [Wherein, B represents a group represented by-(CH ₂ ) _p- (wherein _p represents an integer of 1 to 4), and in the group represented by the above formula (1), B represents the a-position. Or a divalent group selected from the group consisting of groups represented by the following formula: Is the following formula: [Wherein R ⁴ represents a hydrogen atom or a C _1-6 alkyl group;
et represents a 5-membered monocyclic heterocyclic group containing two nitrogen atoms or a 5-membered heterocyclic group containing one nitrogen atom and one oxygen atom.
A monovalent heterocyclic group (wherein the ring may be substituted with one or two C _1-4 alkyl groups). The hair restorer according to claim 1, which is a compound represented by the following formula: or a physiologically acceptable salt thereof. 4. The method according to claim 1, wherein the PGI2 agonist is [5- [2-
[1-Phenyl-1- (3-pyridyl) methylideneaminooxy] ethyl] -7,8-dihydronaphthalene-1
-Yloxy] acetic acid, [2- (2-diphenylmethyloxyiminopropyl) -1,2,3,4-tetrahydronaphth-5-yloxy] acetic acid, [2- (3-diphenylmethyloxyiminopropyl) -1, 2,3,4-tetrahydronaphth-5-yloxy] acetic acid, [2- [2
-[1-Phenyl-1- (3-pyridyl) methyloxyimino] propyl] -1,2,3,4-tetrahydronaphth-5-yloxy] acetic acid, [2- (4- (diphenylmethyl) pyrazole-1) -Yl) methyl-3,4-dihydronaphthalen-5-yloxy] acetic acid, and 3-
[3- (5-diphenylmethylisoxazole-3-
The hair restorer according to claim 1, which is a compound selected from the group consisting of yl) propyl] phenoxyacetic acid or a physiologically acceptable salt thereof. 5. The hair restorer according to claim 1, which is in the form of a liquid preparation.