Wool composition for hair regeneration containing 2,2-dimethylpropanediol compound and use thereof

专利摘要:
A hair composition for regenerating hair containing a dimethylpropanediol derivative of Formula 1, and a method for preventing hair loss promoting, hair growth stimulation, or hair loss in a mammal using the hair composition for regenerating hair are disclosed. Also disclosed is the use of compound (I) of formula (1) in the preparation of a wool composition for hair regeneration. Therefore, the present invention can provide excellent means for preventing hair regeneration or hair loss in mammals. [Meal, R 1 and R 2 each independently represent a C 1-30 hydrocarbon group which may be substituted or a 5 or 6 membered heterocycle containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen atoms. Clicker, R 3 is a hydrogen atom, a substituted alkyl group, an acyl group, an alkoxycarbonyl group, a phenoxycarbonyl group, or a substituted carbamoyl group, and a and b are each independently 0 or 1.]
公开号:KR19980018485A
申请号:KR1019970037782
申请日:1997-08-07
公开日:1998-06-05
发明作者:쓰나오 마가라；마사히로 다지마；고오지 고바야시；히로따다 후꾸니시；마사즈미 와따나베
申请人:겐마 아끼라；가부시끼가이샤 시세이도；다까데 구니오；다께다 야꾸힝 고오교 가부시끼가이샤；
IPC主号:

专利说明:

Wool composition for hair regeneration containing 2,2-dimethylpropanediol compound and use thereof
The present invention relates to the use of the novel 2,2-dimethylpropanediol derivatives used for mammalian hair regeneration, in particular for hair regeneration purposes.
Usually, hair revitalizing tonic compositions containing various vitamins, amino acids, female hormones, and various components such as plant extracts having vasodilating or anti-inflammatory effects are used to prevent and treat hair loss or to prevent hair loss. It has been used for the prevention or treatment of loss. Moreover, various other compounds have also been proposed for use as active ingredients, but they are not always satisfactory in terms of efficacy. On the other hand, a number of 2-substituted glycerol derivatives having anti-allergic and anti-inflammatory effects have been synthesized (see, for example, Japanese translation of PCT International Publication No. 501612 / '91), and much attention is paid to their excellent effects. This was concentrated.
However, there is still a continuing need for better hair composition for hair regeneration. It is therefore an object of the present invention to provide a wool composition for hair regeneration comprising a chemically synthesized compound having a hair growth promoting or stimulating effect, and the use of such a compound in a method of hair regeneration.
The present inventors synthesized various compounds and investigated their hair growth promoting effect. As a result, it has now been found that the novel dimethylpropanediol derivatives having two methyl groups in the 2-position have an excellent hair growth promoting effect.
Accordingly, the present invention is directed to hair regeneration comprising an effective amount of a novel 2,2-dimethylpropanediol derivative of formula (1) or a salt thereof for the hair regeneration of a mammal together with a pharmaceutically or cosmetically acceptable excipient or other component. To provide a wool composition:
[Formula 1]
[Meal,
R ¹ and R ² each independently represent a C _1-30 hydrocarbon group which may be substituted or a 5 or 6 membered heterocycle containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen atoms. Is a click group, R ³ is a hydrogen atom, a substituted alkyl group, an acyl group, an alkoxycarbonyl group, a phenoxycarbonyl group, or a substituted carbamoyl group, and a and b are each independently 0 or 1.]
According to still another aspect of the present invention, there is provided a method for regenerating hair of a mammal, characterized by topically applying the compound of formula (1) or a pharmaceutically or cosmetically acceptable salt thereof to the skin or hair of the mammal.
It is also to provide a use of the compound of formula (1) used in the preparation of the wool composition for hair regeneration as described above.
The compound represented by the formula (1) or a salt thereof not only exhibits an excellent hair growth promoting effect, but also exhibits a hair loss prevention effect and an effect of inhibiting dandruff and itchy scalp. Thus, the term hair regeneration or hair regeneration action as used herein refers to one or more of the effects described above.
Compounds of formula 1 are more specifically described below.
The C _1-30 hydrocarbon represented by R ¹ and R ² in Formula 1 may be, for example, a C _1-30 alkyl group, C _3-8 cycloalkyl group, C _2-10 alkenyl group, C _2-10 alkynyl group, C _{3 -10} cycloalkenyl groups, C _6-14 aryl groups and C _7-16 aralkyl groups.
Examples of C _1-30 alkyl groups include methyl, ethyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, Linear alkyl groups such as nonadecyl, ecosil, henicosil, docosyl, tricosyl, tetracosyl, pentacosyl, hexacosyl, heptacosyl, octacosyl, nonacosyl and triacontyl; And isopropyl, isobutyl, sec-butyl, tert-butyl, 2-methylpentyl, 3-methylpentyl, 4-isocapryl, 4-ethylpentyl, 6-methyldecyl, 9-methyldecyl, 6-ethylnonyl , 5-propyloctyl, 11-methyldodecyl, 12-methyldodecyl, 4-methyltetradecyl, 13-methyltetradecyl, 14-ethylhexadecyl, 10-methyloctadecyl, 15-ethylpentadecyl, 10- Methyl docosyl, 2-pentyloctadecyl, 22-methyl tricosyl, 12-hexyl octadecyl, 6-methyltetracosyl, 24-methylheptacosyl, 2-decylhexadecyl, 2-nonyloctadecyl, 2-dodec Side chain alkyl groups such as ciloctadecyl, 3-methyltetracosyl and 3-methyltricosyl are included.
Preferred examples of the groups represented by R ¹ and R ² are a straight or branched C _6-22 alkyl group which may be substituted, and more preferred examples thereof are a straight or branched C _8-20 alkyl group.
Examples of C _3-8 cycloalkyl groups include cyclopropyl, cyclopentyl and cyclohexyl. Examples of C _2-10 alkenyl groups include vinyl, allyl, 2-methylallyl, 2-butenyl, 3-butenyl, 3-octenyl, 2-nonenyl and 4-decenyl. Examples of C _2-10 alkynyl groups include ethynyl, 2-propynyl and 3-hexylyl.
Examples of C _3-10 cycloalkenyl groups include cyclopropenyl, cyclopentenyl and cyclohexenyl. Examples of C _6-14 aryl groups include phenyl and naphthyl. Examples of C _7-16 aralkyl groups include benzyl, phenylethyl and naphthylethyl.
The preceding group represented by R ¹ and R ² may have one or more (eg 1 to 5) substituents at any substitutable position or positions of the carbon chain or carbocyclic ring. Specific examples of substituents include halogen atoms (e.g., fluorine, chlorine, bromine and iodine) and C _3-8 cycloalkyl, hydroxy, mercapto, oxo, thioxo, cyano, carbamoyl, carboxyl, C _1-4 alkoxycarbonyl (eg methoxycarbonyl and ethoxycarbonyl), sulfonyl, C _1-4 alkoxy (eg methoxy, ethoxy, propoxy, isopropoxy, butoxy , Isobutoxy, sec-butoxy and tert-butoxy), phenoxy, halogenophenoxy (eg o-, m- or p-chlorophenoxy and o-, m- or p-bromophenoxy C), lower (C _1-4 ) alkylthio (eg, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio and tert-butylthio), phenylthio, C _1-4 Alkylsulfinyl (eg, methylsulfinyl and ethylsulfinyl), C _1-4 alkylsulfonyl (eg, methylsulfonyl and ethylsulfonyl) and C _1-10 haloalkyl groups (eg, di Fluoromethyl, triple In Oro methyl, trifluoromethyl include ethyl acetate and trichloroethane). Other specific examples of the substituent for the hydrocarbon group include amino; Substituted amino such as C _1-6 acylamino (eg, acetylamino and propionylamino), C _1-30 alkylamino (eg, methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, s-butylamino, t-butylamino, pentylamino, hexylamino, heptylamino, octylamino, nonylamino, decylamino, undecylamino, dodecylamino, tridecylamino, tetra Decylamino, pentadecylamino, hexadecylamino, heptadecylamino, octadecylamino, nonadecylamino, isosylamino, henicosylamino, docosylamino, tricosylamino, tetracosylamino, pentacosylamino, hexacosylamino , Heptacosylamino, octacosylamino, nonacosylamino and triacontylamino), di-C _1-4 alkylamino (eg, dimethylamino, diethylamino, N-methyl-N-ethylamino and N- Til -N- propylamino); C _1-5 acyl (eg C _1-5 alkanoyl such as formyl, acetyl and propionyl); And benzoyl groups.
More specific examples of substituents for hydrocarbon groups include pyrrolidyl, piperidyl, morpholino, thiomorpholino, 2- or 3-thienyl, 2- or 3-furyl, 3-, 4- or 5- Pyrazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2 -, 4- or 5-imidazolyl, 1,2,3- or 1,2,4-triazolyl, 1H- or 2H-tetrazolyl, 2-, 3- or 4-pyridyl, 2-, 4 Or may contain substituted one to four heteroatoms selected from oxygen, sulfur and nitrogen atoms, such as 5-pyrimidyl, 3- or 4-pyridazinyl, quinolyl, imidazoquinolyl and indolyl 5- and 6-membered heterocyclic groups are included. The heterocyclic group is generally linked to a C _1-2 hydrocarbon group. The heterocyclic group may have 1 to 4 substituents. Specific examples of the substituents include halogen atoms (eg fluorine, chlorine and bromine), C _1-4 alkyl groups (eg methyl, ethyl, propyl and isopropyl) and halogenophenoxy groups (eg o -, m- or p-chlorophenoxy and o-, m- or p-bromophenoxy).
Preferred substituents for the above-mentioned cycloalkyl, cycloalkenyl, aryl and aralkyl groups include C _1-4 alkyl groups such as methyl, ethyl, propyl, isopropyl and butyl, and they are 1 to 1 selected from said alkyl group. It may have four substituents. When the above-mentioned alkyl group is substituted with a C _3-8 cycloalkyl group or groups, it may be preferable that the alkyl group is a straight C _6-14 alkyl group.
Examples of the heterocyclic group represented by R ¹ and R ^2, R ^1, and the same containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen atoms, such as those mentioned above as substituents for groups hydrocarbon group represented by R ² 5- and 6-membered heterocyclic groups are included. Preferred examples of heterocyclic groups represented by R ¹ and R ² are 5- or 6-membered aromatic heterocyclics such as 2-, 3- or 4-pyridyl and 2-, 3- or 4-piperidyl Groups and alicyclic heterocyclic groups are included. The heterocyclic group may be preferably substituted with 1 to 4 substituents selected from a halogen atom and a C _1-4 alkyl group.
A particularly preferred compound, wherein R ¹ and R ² lifter, R ¹ is a C _1-30 hydrocarbon group and a C _1-30 hydrocarbon group or a salt thereof is substituted by an amino group in the R ² may be substituted. In particular, R ² is represented by the following formula:
In the formula, R ⁴ and R ⁵ are each independently a hydrogen atom or a C _1-5 alkyl group which may be substituted, and n is an integer of 1 to 10. A compound or a salt thereof is preferable. It may be desirable for R ⁴ and R ⁵ to represent a C _1-3 alkyl group which may be the same or different.
Useful substituents for C _1-5 alkyl groups include, for example, hydroxyl groups. The C _1-5 alkyl group may further have 1 to 3 substituents.
Wherein R ⁴ and R ⁵ may be bonded to the nitrogen atom to which they are linked to form a nitrogen-containing heterocyclic ring. Specifically, R ⁴ and R ⁵ may combine to form tetramethylene or pentamethylene chains. Alternatively, R ⁴ and R ⁵ may form a 5- or 6-membered heterocyclic ring through linkage with adjacent nitrogen atoms and one or more other heteroatoms (eg, oxygen, nitrogen and / or sulfur atoms). .
In the formula, examples of the alkyl group represented by R ³ include C _1-5 alkyl groups such as methyl, ethyl, propyl, butyl and pentyl. The alkyl group is, for example, carboxyl and lower (C _1-5 ) alkoxycarbonyl (eg methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl or pentoxycarbonyl It may be substituted with 1 to 4 substituents selected from the group. Examples of acyl groups represented by R ³ include lower (C _1-5 ) alkanoyl (eg, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl and isovaleryl) and benzoyl groups . Examples of the alkoxycarbonyl group represented by R ³ include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and pentoxycarbonyl. As shown by R ³ , examples of carbamoyl groups which may be substituted include carbamoyl, lower (C _1-5 ) alkylcarbamoyl (eg, methylcarbamoyl, ethylcarbamoyl, propylcarb) Barmoyl and butylcarbamoyl), di-lower (C _1-5 ) alkylcarbamoyl (eg dimethylcarbamoyl, methylethylcarbamoyl, diethylcarbamoyl and methylpropylcarbamoyl) , 3- to 7-membered cyclic aminocarbonyl [eg, (aziridin-1-yl) carbonyl, (azetidin-1-yl) carbonyl, (pyrrolidin-1-yl) carbonyl , Piperidinocarbonyl, (piperazin-1-yl) carbonyl, morpholinocarbonyl and thiomorpholinocarbonyl].
The alkyl group represented by R ³ may combine with R ⁴ or R ⁵ to form an alkenylene or alkylene bridge. Specific examples of alkenylene or alkylene bridges include lower (C _1-4 ) alkenylene and alkylene groups such as methylene, ethylene, trimethylene, tetramethylene, vinylene and propenylene. The groups may have one or two substituents (eg, oxo) at substitutable positions or positions. Examples of substituted alkylene and alkenylene groups include 1-oxoethylene, 3-oxopropenylene and 1,2-dioxoethylene. In this case, specific examples of the group formed by bonding R ³ to R ⁴ or R ⁵ together with an adjacent nitrogen atom include groups of the following formula:
And
Preferably, R ³ is hydrogen or lower alkanoyl. More preferably, R ³ is hydrogen.
When both a and b are 0, the compound of formula 1 is as if R ¹ and R ² are each bonded via an ether linkage. When both a and b are 1, R ¹ and R ² are bonded via an oxycarbamoyl linkage (-OCONH-) and -OCONR ^3-, respectively. Compounds in which one of a and b are 0 and the other is 1 are also within the range of formula (1).
When the compound of formula 1 has an asymmetric carbon atom in R ¹ or R ² , the compound may be an optically active form or a mixture of optically active forms. In addition, the compounds of formula 1 may or may not be a hydrate.
When the compound of formula 1 has a basic group such as an amino or imino group, the compound of formula 1 may be an acid addition salt thereof. Such salts include pharmaceutically or cosmetically acceptable inorganic acid salts such as hydrohalogenides (eg hydrochloride and hydrobromide), sulfates, nitrates and phosphates; And acetate, propionate, hydroxyacetate, 2-hydroxypropionate, 2-oxopropionate, ethanedicarboxylate, propanedicarboxylate, butanedicarboxylate, methanesulfonate, ethanesulfo Pharmaceutically or cosmetically acceptable organic acid salts such as nitrate, benzenesulfonate, 4-methylbenzenesulfonate and 2-hydroxybenzoate. When the compound of formula 1 has a carboxyl group, it is also used as an ammonium salt, an alkali metal salt (eg lithium, sodium and potassium salts), or a salt with an organic base (eg amino acids such as arginine and lysine). Can be.
The compound of formula (1) or a salt thereof (hereinafter sometimes referred to as compound (I) comprising compound (I) and salts thereof) can be produced, for example, by the following method.
A) Compound (I) can be obtained by reacting Compound (II) of Formula 2 with an amine (III) of Formula 3 which may be substituted:
[Wherein Y is a C _1-30 alkylene group which may be substituted and Q ¹ is a group that can be easily replaced with nitrogen [eg halogen (eg chlorine, bromine or iodine), O-tosyl or O Mesyl], other markers as previously defined]
NHR ⁴ R ⁵
Wherein the marker is as previously defined.
The reaction can be carried out by adding an equal or excess of compound (III) to compound (II) and reacting the mixture at a temperature of 0 to 200 ° C. for about 0.5 to 48 hours in the presence or absence of a solvent. Useful solvents include toluene, benzene, ether, dioxane, tetrahydrofuran and the like, and compound (III) itself can be used as the solvent. Under heating conditions, the reaction can be carried out in a sealed tube.
B) Compound (I) can be obtained by reacting Compound (IV) of Formula 4 with Compound (V) of Formula 5:
[Formula 4]
Wherein Q ² is a group capable of activating a carbonyl group [eg, halogen (eg, chlorine) or phenoxy] or an atom (hereinafter simply referred to as a group), and the other markers are as previously defined]
[Formula 5]
HN (R ³ ) -R ²
[Wherein R ² is a typical group -WZ as defined above, wherein W is a single bond or a lower alkylene group and Z is a mono- or di-substituted amino group, or when W is a single bond, 5- Or a 6-membered nitrogen-containing heterocyclic group is bonded to a carbon atom) and the other markers are as previously defined].
Examples of mono- or di-substituted amino groups represented by Z include the same as those described for the substituted amino group as a substituent for the hydrocarbon group represented by R ¹ and R ² . The reaction of compound (IV) with compound (V) can be carried out for about 0.5 to 48 hours at a temperature of -10 to 150 ° C in the presence or absence of a solvent. Useful solvents include toluene, benzene, ether, dioxane, tetrahydrofuran, chloroform and the like. To accelerate the reaction, a base such as triethylamine or pyridine can be added. It is also possible to react compound (V) with sodium hydride, n-butyllinium or the like in any of the above-mentioned solvents to convert it to a metal salt thereof, and then to react the metal salt with compound (IV).
C) Compound (I) can be obtained by reacting Compound (VI) of Formula 6 with Compound (VII) of Formula 7:
Wherein the marker is as previously defined],
Q ² -CO-N (R ³ ) -R ²
Wherein the label is as defined before.
In formula (7), R ² comprises a group -WZ, wherein the label is as defined above.
The reaction of compound (VI) with compound (VII) can be carried out in substantially the same manner as described for the reaction of compound (IV) with compound (V) in B).
D) A compound of formula 1 wherein b is 0 and R ² is-(CH ₂ ) _n NR ⁴ R ⁵ is obtained by reacting compound (VIII) of formula 8 with compound (III) of formula 3 Can be:
Wherein the marker is as previously defined]
[Formula 3]
NHR ⁴ R ⁵
Wherein R ⁴ and R ⁵ are as previously defined.
The reaction can be carried out in substantially the same manner as described for the reaction of compound (II) with compound (III) in A).
E) Compound (I) can be obtained by reacting Compound (IX) of Formula 9 with Compound (VI) of Formula 6:
R ² NCO
Wherein the marker is as previously defined.
The reaction may be carried out for about 0.5 to 48 hours at a temperature of -10 to 150 ℃ in the presence or absence of a solvent. Useful solvents include toluene, benzene, ether, dioxane, tetrahydrofuran, chloroform and the like. To accelerate the reaction, a base such as triethylamine, pyridine or 4-dimethylaminopyridine can be added.
Compound (IX) is a compound of Formula 10 (X) for about 0.5 to 12 hours in the absence of solvent or in an inert solvent such as methylene chloride, chloroform, benzene or tetrahydrofuran at a temperature of -20 to 120 ° C. ) Is reacted with diphosgene or in a solvent such as chloroform, toluene, benzene, dichloromethane or tetrahydrofuran in the presence of a tertiary amine such as triethylamine or tributylamine, at a temperature of from 0 to 150 ° C. By reacting compound (XI) of formula (11) with diphenyl phosphoryl azide (DPPA) for 0.5-48 hours, and then at a temperature of 0-150 ° C. for about 0.5-48 hours in the presence of a tertiary amine such as pyridine. It can be easily synthesized.
R ² NH ₂
Wherein the marker is as previously defined]
R ² COOH
Wherein the marker is as previously defined.
Compounds of formula (I) in which the nitrogen atom contained in the R ² substituent is secondary or tertiary can be obtained by reacting a compound of formula (I) in which the nitrogen atom included in the R ² substituent is primary or secondary, for example, an alkyl halide. The reaction can be carried out in a solvent such as ether, chloroform, tetrahydrofuran, benzene or toluene, in the presence of the same or excess alkyl halide at a temperature of 0-150 ° C. for about 0.5-60 hours.
Synthetic intermediates (VIII) can be obtained, for example, by reacting compound (VI) of formula 6 with dihaloalkane of formula 12:
[Formula 6]
Wherein the marker is as defined previously
Hal (CH ₂ ) _n Hal
Wherein Hal represents a halogen atom such as chlorine and bromine, and other labels are as defined above.
The reaction is preferably in the absence of solvent or in a suitable solvent (eg benzene, toluene, hexane, dioxane or tetrahydrofuran) in the presence of a strong base (eg sodium hydroxide, potassium hydroxide or an aqueous solution thereof) and is preferred. Preferably, under conditions containing water, in the presence of a phase-transfer catalyst (eg cetyltrimethylammonium chloride or benzyltrimethylammonium chloride) at a temperature of -20 to 150 ° C and preferably 20 to + 100 ° C. At a temperature of about 0.5 to 60 hours.
Starting compounds (VI) can be prepared according to the following schemes:
Wherein the marker is as previously defined.
The reaction of compound (XIII) with alkyl isocyanate (XIV) can be carried out for about 0.5 to 48 hours at a temperature of -10 to +150 ° C in the presence or absence of a solvent. Useful solvents include toluene, benzene, ether, dioxane, tetrahydrofuran, chloroform and the like. To accelerate the reaction, a base such as triethylamine, pyridine or 4-dimethylaminopyridine can be added. The reaction of compound (XIII) with alkyl halide (XV) can be carried out in substantially the same manner as described for the reaction of compound (VI) with compound (XII).
In this reaction, compound (XVI) of formula (16) can be obtained by reacting 1 mole of starting compound (XIII) with at least 2 moles of compound (XIV) or (XV):
Wherein the label is as defined previously (ie, a compound of formula 1 wherein R ¹ and R ² are the same, a and b are the same, and R ³ is a hydrogen atom);
Starting compound (IV) can be produced by reacting compound (VI) with phenyl halogenocarbonate (eg phenyl chlorocarbonate) according to similar reaction conditions as described in method E).
In each of the above-mentioned reactions, when the starting compounds and the intermediate compounds have amino groups, carboxyl groups or hydroxyl groups as substituents, they may have protecting groups generally used in peptide chemistry. After completion of the reaction, the desired compound can be obtained by removing the protecting group if necessary.
Examples of amino-protecting groups include optionally substituted C _1-6 alkyl carbonyl (eg formyl, methyl carbonyl and ethyl carbonyl), phenyl carbonyl, C _1-6 alkyl-oxycarbonyl (eg Methoxycarbonyl and ethoxycarbonyl), phenyloxycarbonyl (eg benzoxycarbonyl), C _7-10 aralkyloxycarbonyl (eg benzyloxycarbonyl), trityl And phthaloyl. Examples of the substituents among them include halogen atoms (e.g., fluorine, chlorine, bromine and iodine), C _1-6 alkyl-carbonyl (e.g., methylcarbonyl, ethylcarbonyl and butylcarbonyl) and nitro A group is contained and the number of substituents is about 1-3 ranges.
Examples of carboxyl-protecting groups include C _1-6 alkyl (eg methyl, ethyl, n-propyl, i-propyl, n-butyl and tert-butyl), phenyl, trityl and silyl. Examples of the substituents among them include halogen atoms (e.g., fluorine, chlorine, bromine and iodine), C _1-6 alkylcarbonyl (formyl, methylcarbonyl, ethylcarbonyl and butylcarbonyl) and nitro groups And the number of substituents is about 1-3 ranges.
Examples of hydroxy-protecting groups include optionally substituted C _1-6 alkyl (eg, methyl, ethyl, n-propyl, i-propyl, n-butyl and tert-butyl), phenyl, C _7-10 aralkyl (Eg benzyl), C _1-6 alkylcarbonyl (eg formyl, methylcarbonyl and ethylcarbonyl), phenyloxycarbonyl, C _7-10 aralkyloxycarbonyl (eg , Benzyloxycarbonyl), pyranyl, furanyl and silyl. As the above-mentioned substituents, halogen atoms (eg, fluorine, chlorine, bromine and iodine), C _1-6 alkyl, phenyl, C _7-10 aralkyl and nitro groups are used. The number of substituents is in the range of about 1-4.
And protecting groups can be introduced and removed by methods known to date or similar (e.g., I. F.W. McOmie et al., PROTECTIVE GROUPS IN ORGANIC CHEMISTRY, Plenum Press). More specifically, the protecting groups are removed by, for example, acid, base, reduction, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutyl ammonium fluoride or palladium acetate.
Compound (I) produced by the above-mentioned method can be separated and purified by conventional separation methods such as recrystallization, distillation and chromatography. If the obtained compound (I) is in free form, it can be converted into a salt by a method known to date or a similar method (for example, a neutralization method). In contrast, when compound (I) is obtained in the form of a salt, it may be converted into the free form or any other salt by methods known to date or similar thereto.
Although some typical methods for the preparation of compound (I) have been described above, compound (I) may also be prepared according to variations of the above methods.
In the hair regeneration wool composition of the present invention, various pharmaceutically or cosmetically acceptable excipients and other components usable in the hair regeneration wool composition may also be mixed to such an extent that they do not adversely affect the hair growth promoting effect of Compound 1. . They contain the active ingredients and auxiliaries which are believed to have the hair producing effect in themselves. Examples thereof include plant extracts such as Swertia herb extract and ginseng extract; Vitamins such as vitamin B ₆ , vitamin E and derivatives thereof; And biotin; Pantothenic Acid and Derivatives thereof, Glycyrrhizinic Acid and Derivatives thereof (e.g., Monoammonium Glycyrrhizinate), Glycyrrhetinic Acid and Derivatives thereof, Nicotinic Acid Ester (e.g. Benzyl Nicotinate), Cyclosporine, Carr Hair-generating agents and hair-generating aids such as pronium chloride, ceparantin, oxedolone, diazoxide, minoxidil and ethynylestradiol; Antibacterial agents such as hinokithiol, hexachlorophene, phenol, isopropylmethylphenol, benzalkonium chloride, cetylpyridinium chloride, undecylenic acid, trichlorocarvanilide and bithionol; Coolants such as menthol and eucalyptus oil; Agents such as salicylic acid, zinc and derivatives thereof, and lactic acid and alkyl esters thereof; Organic acids such as citric acid, succinic acid and malic acid; Amino acids such as arginine; Silicone oils, olive oils, squalene, petrolatum, liquid paraffin, isopropyl myristate, isocetyl octanoate, higher fatty acids such as stearic acid and higher alcohols such as cetanol, cetostearyl alcohol ingredient; Polyhydric alcohols such as glycerin, propylene glycol, 1,3-butylene glycol, dipropylene glycol and polyethylene glycol; Esters of polyhydric alcohols such as glyceryl monostearate; Alkyl sulfates, polyoxyethylene hydrogenated castor oil, cocoacyl N-methyltaurate, polyoxyethylene alkyl ethers, fatty acid diethanolamides, ethylene glycol fatty acid esters, alkyltrimethylammonium chlorides, sorbitan monooleates and amine oxides Such surfactants; High molecular compounds such as carboxymethyl cellulose; Blocking agents such as hexametaphosphate and disodium edate; Spices; Antioxidants; Ultraviolet absorbers; dyes; ethanol; water; Wetting agents; Thickeners; And preservatives such as alkylparabens. In particular, the aforementioned antibacterial agents are preferably used in combination with compound (I).
The hair composition for regenerating hair of the present invention may be prepared in any dosage form that can be applied to the epidermis, such as liquids, emulsions, ointments, creams, gels or aerosols, tonics, conditioners and scalp treatments; Shampoo liquid; And rinse liquids.
In order to prepare the wool composition for hair regeneration, any apparatus and method conventionally used in the art that can be used for mixing various components, solubilizing or kneading the mixture can be used.
Since the compound of Formula 1 has very low toxicity to humans, the hair composition for regenerating hair containing the compound according to the present invention can be administered transdermally by being applied directly to the skin or hair or sprayed directly onto the skin or hair. have. The dosage of the wool composition for hair regeneration may not be accurately determined because it may vary according to age, individuality, severity of symptoms, and the like. However, for humans, compound (I) is generally administered at a dosage of 0.01 to 100 mg, preferably 0.1 to 50 mg per day, per kg of body weight. The dosage may be administered once a day or in two to four portions.
The action and effects of the hair composition for hair regeneration of the present invention are evaluated for the hair regeneration effect of each compound or composition, in particular in the same manner as in the hair growth test described below, and if necessary, the results obtained It can be verified on the basis of its actual use.
Therefore, the present invention is directed to a wool composition for hair regeneration for mammals (including humans) in need of hair regeneration or hair loss prevention treatment, more specifically to promote hair growth, to stimulate hair growth, to prevent hair loss, to prevent scalp itch. And it provides a wool composition for hair regeneration very effective in the prevention of dandruff and a method for applying the hair composition for hair regeneration to such mammals.
The invention is explained in more detail with reference to the following synthesis examples and examples.
Synthesis Example 1
2,2-dimethyl-3- (octadecylcarbamoyloxy) -1-propanol
5.91 g (20.00 mmol) in a stirred methylene chloride solution (15 ml) containing 2.08 g (20.00 mmol) of 2,2-dimethyl-1,3-propanediol and 2.12 g of (21.00 mmol) triethylamine Oxadecyl isocyanate is added dropwise at room temperature and then stirred at room temperature for 21 hours. The reaction mixture is diluted with chloroform (15 ml) and filtered to remove insoluble matters. The filtrate is washed with 1 N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the filtrate is concentrated under reduced pressure. The resulting residue is separated and purified by silica gel (250 ml) column chromatography (chloroform: methanol = 50: 1 to 20: 1) to give 6.56 g of the title compound (82% yield).
Example 1
2,2-dimethyl-3-[(3'-dimethylaminopropyl) carbamoyloxy] -1- (octadecylcarbamoyloxy) propane
2.40 in a stirred methylene chloride solution (35 ml) containing 6.12 g (15.31 mmol) of 2,2-dimethyl-3- (octadecylcarbamoyloxy) -1-propanol and 2.42 g (15.31 mmol) pyridine g (30.62 mmol) of phenyl chlorocarbonate is added dropwise under ice cooling, followed by stirring at room temperature for 1.5 hours. The reaction mixture is washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. To the resulting residue is added 1.56 g (15.31 mmol) of N, N-dimethyl-1,3-propanediamine and then stirred at 70 ° C. for 5 hours. The reaction mixture is separated and purified by silica gel (200 ml) column chromatography (chloroform: methanol = 100: 1 to 10: 1) to give 7.57 g of the title compound (yield 94%). The compound (470 mg) was dissolved by applying heat to a solvent mixture consisting of 0.5 ml of acetone and 3 ml of hexane, and the resulting solution was recrystallized by standing at 0 ° C. for 6 hours. 220 mg of purified product (purity of 98.4% expressed in percent HPLC area) are then obtained.
Melting Point: 53.2∼ 53.8 ℃
¹ H-NMR (CDCl ₃ ) δ:
0.88 (3H, t, J = 6.8 Hz)
0.93 (6H, s)
1.25 (30H, m)
1.48 (2H, m)
1.66 (2H, m)
2.23 (6H, s)
2.35 (2H, t, J = 6.8 Hz)
3.15 (2H, m)
3.24 (2H, dt, J = 6.1, 6.3 Hz)
3.86 (4H, m)
4.69 (1H, brs)
5.49 (1H, brs)
Example 2
2,2-dimethyl-3-{(3'-dimethylaminopropyl) carbamoyloxy} -1- (octadecylcarbamoyloxy) propane hydrochloride
Stirred ethyl acetate solution containing 5.96 g (11.29 mmol) of 2,2-dimethyl-3-{(3'-dimethylaminopropyl) carbamoyloxy} -1- (octadecylcarbamoyloxy) propane ( 40 ml) is added dropwise 2.96 ml (11.86 mmol) of a 4 N hydrogen chloride solution in ethyl acetate under ice-cooling, followed by stirring for 0.5 h under ice-cooling. The resulting precipitate is filtered off and washed with ethyl acetate to give 6.05 g of the title compound (yield 95%). Recrystallization of the compound from the solvent mixture consisting of ethanol and ethyl acetate was repeated four times to give 2.51 g of purified product (purity 99.0% expressed in HPLC area percent).
Melting Point: 83.0-84.0 ℃
¹ H-NMR (CDCl ₃ ) δ:
0.88 (3H, t, J = 6.9 Hz)
0.94 (6H, s)
1.25 (30H, m)
1.49 (2H, m)
2.09 (2H, dt, J = 6.5, 7.0 Hz)
2.81 (3H, s)
2.82 (3H, s)
3.10-3.17 (4H, m)
3.37 (2H, dt, J = 5.9, 6.1 Hz)
3.86 (4H, m)
4.81 (1H, brs)
5.72 (1H, brs)
Evaluation method (hair growth test method)
The wool composition for hair regeneration according to the present invention to be described later can be evaluated according to the following hair growth test method.
Using C3H / HeNCrJ mice whose hair cycles are resting, hair growth tests are performed on the samples according to the method of Ogawa et al. [M. Seiji and I. A. Bernstein (ed.), Normal and Abnormal Epidermal Differentiation (Todai Shuppan, 1982), pp. 159-170].
Specifically, the mouse is shaved with a haircutting machine and a razor and used in the group of 10. In the test group, 0.1 ml of each sample is applied to the mice once a day, and no sample is applied in the control group. The hair production effect of the sample is evaluated by measuring the area of the hair-producing area in the back of the mouse and expressing it as a percentage. The number of days required for 50% hair growth rate is recorded and the data obtained as samples are compared with those obtained in comparison with the comparative composition, if necessary. Measurements are taken on days 18, 24, 30, 37 and 43.
Example 3 (hair growth test)
Using the following compositions 1 and 2, hair growth tests were carried out according to the methods described above.
The results obtained in this manner are shown in Table 1.
Preparation of Composition 1
0.1 g of the compound obtained in Example 1, 70.0 g of 95% ethanol, and 29.9 g of ion-exchanged water are mixed, and the mixture is stirred to obtain a solution composition.
Preparation of Composition 2
0.1 g of the compound obtained in Example 2, 70.0 g of 95% ethanol, and 29.9 g of ion-exchanged water are mixed, and the mixture is stirred to obtain a solution composition.
Preparation of Comparative Composition
0.1 g of soybean oil, 70.0 g of 95% ethanol and 29.9 g of ion-exchanged water are mixed and the mixture is stirred to obtain a solution composition.
A composition without addition of compound or soybean oil is used as Control 2.
CompositionComposition 1Composition 2Comparative composition (soybean oil)Contrast 1 (not applicable)Contrast 2 (not applicable) 50% number of days needed for hair growthLess than 18 daysLess than 18 days19-37 daysMore than 150 days19-37 days
Example 4 (Formulation Example)
Formulation Example 1
A lotion having the following composition is prepared.
95% Ethanol 50.0 Weight%
0.1% by weight of monoammonium glycyrginate
1.0% by weight of compound obtained in Example 1
Sodium Lauryl Sulfate 0.1% by weight
Hydrogenated Castor Oil Ethylene Oxide (40 mol) Addition 0.5% by weight
Succinic acid
Spices and dyes
Purified Water Balance
(Production method)
Hydrogenated castor oil ethylene oxide (40 moles) adduct and flavorings are dissolved in 95% ethanol and then purified water is added. Then other ingredients are added and dissolved therein under stirring to obtain a clear liquid lotion.
Formulation Example 2
A lotion having the following composition is prepared.
95% Ethanol 50.0 Weight%
Vitamin E Acetate 0.05% by weight
0.01% by weight of compound obtained in Example 2
Sodium Lauryl Sulfate 0.06 wt%
Propylene glycol 0.1% by weight
Hydrogenated Castor Oil Ethylene Oxide (40 mol) Addition 0.5% by weight
Lactic acid
Sodium Lactate Proper
Spices and dyes
Purified Water Balance
(Production method)
Hydrogenated castor oil ethylene oxide (40 moles) adduct and flavorings are dissolved in 95% ethanol and then purified water is added. Thereafter, the other ingredients are added and stirred and dissolved therein with stirring to obtain a clear liquid lotion.
The hair composition for hair regeneration obtained in Formulation Examples 1 and 2 has excellent hair loss prevention and hair regeneration effect, and further excellent anti dandruff and itchy scalp effect.
Formulation Example 3
A hair tonic having the following composition is prepared.
0.1% by weight of compound obtained in Example 2
Hinokithiol 1.0 wt%
Vitamin B ₆ 0.2 wt%
Vitamin E Acetate 0.02 wt%
Menthol 0.2% by weight
Svertia Herb Extract 1.0% by weight
Salicylic Acid 0.1% by weight
Propylene Glycol 2.0 wt%
Polyoxyethylene (10 mol) monostearate 2.0% by weight
75% ethanol balance
(Production method)
Various components are added successively to 75% ethanol and dissolved in there under stirring to obtain a hair tonic.
Formulation Example 4
A hair tonic having the following composition is prepared.
0.5% by weight of compound obtained in Example 1
0.1% by weight of compound obtained in Example 2
Hinokithiol 1.0 wt%
Vitamin B ₆ 0.2 wt%
Vitamin E 0.02 wt%
Menthol 0.2% by weight
Salicylic Acid 0.1% by weight
Propylene Glycol 2.0 wt%
Sodium hyaluronate 0.01% by weight
Polyoxyethylene (10 mol) monostearate 2.0% by weight
70% Ethanol Balance
(Production method)
Various components are added successively to 70% ethanol and dissolved in there under stirring to obtain a hair tonic.
Formulation Example 5
An O / W emulsion having the following composition was prepared.
(Phase A)
Hydrogenated castor oil polyoxyethylene (60 mol) Addition product 2.0 wt%
Glycerin 10.0 wt%
Dipropylene glycol 10.0% by weight
1,3-butylene glycol 4.0% by weight
0.1% by weight of compound obtained in Example 2
Polyethylene glycol 1500 5.0% by weight
(Phase B)
Isocetyl octanoate 10.0% by weight
Squalane 5.0 wt%
Vaseline 2.0% by weight
Propylparaben 2.0 wt%
(Phase C)
30.0% by weight of 1% aqueous solution of carboxyvinyl polymer
Sodium hexametaphosphate 0.03 wt%
8.35% by weight of ion exchange water
(Phase D)
4.5% by weight of ion-exchanged water
(Phase E)
KOH 0.12 weight%
Ion exchange water balance
(Production method)
Phases A and B are heated at 60 ° C. to dissolve individually and mixed with a homogeneous mixer to obtain a gel. Phase D is then slowly added to the gel and dispersed in it with a homogeneous mixer.
Then, pre-dissolved phase C is added to the gel dispersion described above, and pre-dissolved phase E is added. This mixture is emulsified with a homogeneous mixer to obtain an O / W emulsion.
Formulation Example 6
A cream having the following composition is prepared.
(Phase A)
Dimethylhexylpolyoxyethylene (5 mol) amine oxide 2.5% by weight
Liquid Paraffin 5.0 wt%
Cetostearyl alcohol 5.5% by weight
Glyceryl Monostearate 3.0% by weight
EO (20 mol) 2-octyldodecyl ether 3.0 wt%
Propylparaben 0.3 wt%
Perfume 0.1% by weight
(Phase B)
1.0% by weight of compound obtained in Example 2
Glycerin 8.0% by weight
Dipropylene glycol 20.0 wt%
Polyethylene Glycol 4000 5.0 wt%
Sodium hexametaphosphate 0.005% by weight
Ion exchange water balance
(Production method)
Phases A and B are heated to dissolve, mixed together and then emulsified with a homogeneous mixer to obtain a cream.
Formulation Example 7
An aerosol spray having the following composition is prepared.
(Pharmaceutical Formulation)
95% Ethanol 50.0 Weight%
0.1% by weight of glycyrheptic acid
0.5% by weight of compound obtained in Example 1
Swetia Herb Extract 0.1% by weight
Sodium Lauryl Sulfate 0.1% by weight
Hydrogenated Castor Oil Ethylene Oxide (40 mol) Addition 0.5% by weight
Lactic acid
Sodium Lactate Proper
Spices
Ion exchange water balance
(Packing formulation)
Pharmaceutical 50.0% by weight
Liquefied Petroleum Gas 50.0 wt%
Manufacturing method
The pharmaceutical solution is prepared according to the formulation and packaged in a container. After installing the valve, fill the gas to create an aerosol spray.
Formulation Example 8
A shampoo having the following composition is prepared.
(1) Cocoylmethyltaurine Sodium 2.0% by weight
(2) 2.0% by weight of polyoxyethylene (8 mol) oleyl alcohol ether
(3) 4.0% by weight of lauric acid diethanolamide
(4) 1.0% by weight of ethylene glycol fatty acid ester
(5) 0.2% by weight glycerin
(6) menthol 0.1 wt%
(7) 0.1 wt% of the compound obtained in Example 2
(8) 0.1% by weight of disodium edetate
(9) appropriate amount of spices
(10) Purified Water Balance
Manufacturing method
After heating purified water to 70 degreeC, components (1)-(9) are added continuously, it melts, stirring in it, and cools to obtain a shampoo.
Formulation Example 9
A rinse having the following composition is prepared.
(1) Stearyltrimethylammonium chloride 1.5% by weight
(2) Dimethylpolysiloxane (20 cs) 3.0 wt%
(3) 1.0% by weight of polyoxyethylene (10 mol) oleyl alcohol ether
(4) glycerin 5.0% by weight
(5) 0.5 wt% of the compound obtained in Example 1
(6) preservative appropriate amount
(7) 4-t-butyl-4'-methoxybenzoylmethane appropriate amount
(10) Purified Water Balance
Manufacturing method
Components (1), (3) and (4) are added to purified water and this mixture is heated at 70 ° C. to obtain an aqueous phase. The other components are heated and melted at 70 ° C. to obtain an oily phase. The oil phase is added to the aqueous phase, mixed with the emulsifier and then cooled to obtain a rinse.
Formulation Example 10
A scalp treatment agent having the following composition is prepared.
(Pharmaceutical Formulation)
(1) 27.0% by weight of liquid paraffin
(2) 5.0% by weight stearic acid
(3) cetanol 5.0% by weight
(4) sorbitan mono-oleate 2.0 wt%
(5) polyoxyethylene sorbitan mono-oleate 3.0 wt%
(6) 0.1 wt% of the compound obtained in Example 2
(7) 1,3-butylene glycol 5.0% by weight
(8) Preservative appropriate amount
(9) purified water balance
(Packing formulation)
Pharmaceutical 50.0% by weight
Liquefied Petroleum Gas 50.0 wt%
Components (5) and (6) are dissolved in components (1)-(4) and the mixture is heated at 80 ° C. until a homogeneous solution is obtained. The resulting solution is cooled to 30 ° C. and mixed with components (7) to (9) to prepare a pharmaceutical solution. The pharmaceutical solution thus prepared is filled into a container together with a propellant to form a scalp treatment agent.
Formulation Example 11
A scalp treatment agent having the following composition is prepared.
(Pharmaceutical Formulation)
(1) 0.1% by weight of hinokithiol
(2) 1.0% by weight Swertia herb extract
(3) Vitamin B ₆ 0.1 wt%
(4) 0.01% by weight of vitamin E
(5) menthol 0.1 wt%
(6) salicylic acid 0.001% by weight
(7) 0.1 wt% of the compound obtained in Example 1
(8) 0.1 weight% polyoxyethylene sorbitan mono-oleate
(9) propylene glycol 2.0% by weight
10. 75% Ethanol Balance
(Packing formulation)
Pharmaceutical 50.0% by weight
Dimethyl Ether 50.0 wt%
Manufacturing method
A scalp treatment is prepared in the same manner as in Formulation Example 10.
Therefore, the present invention relates to a wool composition for hair regeneration for mammals (including humans) in need of hair regeneration or hair loss prevention treatment, more specifically to promote hair growth, to stimulate hair growth, to prevent hair loss, to prevent scalp itch. And a hair composition for regenerating hair which is very effective in preventing dandruff and a method for applying the hair composition for regenerating hair to such mammals.

权利要求:
Claims (9)
[1" claim-type="Currently amended] A wool composition for hair regeneration comprising an effective amount of Compound (I) or a salt thereof for hair regeneration in a mammal, together with a pharmaceutically or cosmetically acceptable excipient or other component:
[Formula 1]
[Meal,
R ¹ and R ² each independently represent a C _1-30 hydrocarbon group which may be substituted or a 5 or 6 membered heterocycle containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen atoms. Clicker,
R ³ is a hydrogen atom, a substituted alkyl group, an acyl group, an alkoxycarbonyl group, a phenoxycarbonyl group, or a substituted carbamoyl group, and
a and b are each independently 0 or 1.] [2" claim-type="Currently amended] The wool composition for hair regeneration according to claim 1, wherein R ¹ is a C _1-30 hydrocarbon group.
[3" claim-type="Currently amended] The wool composition for hair regeneration according to claim 1 or 2, wherein R ² is a C _1-30 hydrocarbon group substituted by an amino group which may be substituted.
[4" claim-type="Currently amended] The wool composition for hair regeneration according to claim 3, wherein R ² is a group of the formula

[Wherein, R ⁴ and R ⁵ are each independently a hydrogen atom or a C _1-5 alkyl group which may be substituted, and n is an integer of 1 to 10.] [5" claim-type="Currently amended] 5. The wool composition for hair regeneration according to claim 4, wherein R ⁴ and R ⁵ are each independently a C _1-3 alkyl group.
[6" claim-type="Currently amended] The compound of formula (I) according to claim 1, wherein the compound (I) of formula (1) Wool composition for hair regeneration which is a salt.
[7" claim-type="Currently amended] The wool composition of claim 1, wherein the hair regeneration is to promote or stimulate hair growth or to prevent hair loss.
[8" claim-type="Currently amended] The hair composition of claim 1 in the form of a composition suitable for topical application to the skin or hair of a mammal.
[9" claim-type="Currently amended] Compound (I) of the general formula (I) as an active ingredient, comprising the step of mixing or homogenizing a pharmaceutically or cosmetically acceptable excipient or component with a compound of formula (I) Method for producing a wool composition for hair regeneration containing a salt thereof:
[Formula 1]
[Meal,
R ¹ and R ² each independently represent a C _1-30 hydrocarbon group which may be substituted or a 5 or 6 membered heterocycle containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen atoms. Clicker,
R ³ is a hydrogen atom, a substituted alkyl group, an acyl group, an alkoxycarbonyl group, a phenoxycarbonyl group, or a substituted carbamoyl group, and
a and b are each independently 0 or 1.]

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同族专利:

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公开号 | 公开日

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EP0823251A3|2000-02-09|

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CA2212443A1|1998-02-09|

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EP0823251A2|1998-02-11|

引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

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法律状态:
1996-08-09|Priority to JP22613996

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1996-08-09|Priority to JP96-226,139

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1997-08-07|Application filed by 겐마 아끼라, 가부시끼가이샤 시세이도, 다까데 구니오, 다께다 야꾸힝 고오교 가부시끼가이샤

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1998-06-05|Publication of KR19980018485A

优先权:

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申请号 | 申请日 | 专利标题

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JP22613996|1996-08-09|

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JP96-226,139|1996-08-09|