CN110179821A - The composition and method and its application for promoting hair growth and/or color development to thicken - Google Patents

The composition and method and its application for promoting hair growth and/or color development to thicken Download PDF

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CN110179821A
CN110179821A CN201910412196.8A CN201910412196A CN110179821A CN 110179821 A CN110179821 A CN 110179821A CN 201910412196 A CN201910412196 A CN 201910412196A CN 110179821 A CN110179821 A CN 110179821A
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alkyl
fullerene
composition
acid salt
hair
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宋艳丽
闫淑梅
邹德双
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Jiaxing Juetou Technology Co Ltd
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Jiaxing Juetou Technology Co Ltd
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    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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Abstract

The present invention provides a kind of promotion hair growth and/or the composition that thickens of color development and method and its application, belongs to hair therapy and health care technology field, comprising: 1) aromatic amides shown in formula (I)；With the pharmaceutically acceptable acid-addition salts and 3 of 2) 1- (5- (tert-butyl) isoxazole -3- base) -3- (4- ((4- (3- morpholino propoxyl group) phenyl) acetenyl) phenyl) urea) water-soluble fullerene；

Description

The composition and method and its application for promoting hair growth and/or color development to thicken
Technical field
The invention belongs to hair therapies and health care technology field, specifically a kind of that hair growth and/or color development is promoted to thicken Composition and method and its application.
Background technique
Alopecia (alopecia) is clinical common trichonosis, with the improvement of living standards, people want cosmetology It asks and is increasingly urgent to, modern medicine and traditional medicine are also increasingly taken seriously to this research.Though alopecia does not belong to serious disease, But large effect is generated to the spirit of people, psychology.With the improvement of living standards, requirement of the people to cosmetology is increasingly Urgently, modern medicine and traditional medicine also increasingly pay attention to the research to alopecia.Clinical common alopecia has following several at present: 1, androgenetic alopecia (AGA) has family history, is the hereditary alopecia disease of androgen-dependent, pathological characteristic is growth period hair follicle 5:1 is reduced to by normal 12:1 with the ratio of stand-down hair follicle, hair follicle is gradually reduced and follicle population is by normal adult 326/cm2, it is reduced to 278/cm2.2, alopecia areata (alopecia areata) a kind of functional disease, can betide body suddenly The limitation plaque-like alopecia at any position of body, nerve problems is key factor.3, alopecia seborrheica is also referred to as early bald, main Want pathogenesis and heredity, androgen, seborrhea etc. related.Since head fat secretion is excessive, hair is greasy, so as to cause Scalp humidity is greasy, and the dust in air mixes with dandruff, and several days very dirty without washing hair, and gives an offensive smell.
Currently, can substantially be divided into synthetic drug, Chinese medicine and confection in the market there are many drugs of hair growth, it is existing Hair growth product due to its preparation cost is high, in terms of formula for growing hair reasonability it is defective, can not quickly promote head The effect got instant result is not achieved in the growth of hair.Some also has certain curative effect when the drug is used, but patient once stops Medicine, the state of an illness will recur.Formula is only related to the one aspect or two aspects of phalacrosis prevention and hair generation mostly, and phalacrosis prevention and hair generation is desirable Various collective effects could generate good effect, be not merely that the active material of several energy hair tonics is added together energy It generates.
Summary of the invention
The purpose of the present invention is to provide a kind of promotion hair growth and/or the composition that thickens of color development and method and its Using the composition can remarkably promote hair growth and effectively inhibiting 5α-reductase active and/or color development thickens, together When can also prevent and treat the symptoms such as alopecia areata, trichomadesis, baldness as caused by associated disease or boundary's factor.
The technical solution that the present invention is taken to achieve the above object are as follows:
[1] a kind of composition for promoting hair growth and/or color development to thicken, comprising:
1) aromatic amides shown in formula (I)；With
2) 1- (5- (tert-butyl) isoxazole -3- base) -3- (4- ((4- (3- morpholino propoxyl group) phenyl) acetenyl) benzene Base) urea pharmaceutically acceptable acid-addition salts, and
3) water-soluble fullerene；
Component 1 in the composition) in aromatic amides shown in formula (I), the R1And R2It is each independently hydrogen Atom, hydroxyl, C1-6Alkyl, C1-6Hydroxy alkyl, C1-6Carboxyalkyl, C1-6Mercaptoalkyl, C1-6Alkoxyalkyl, C2-6Alkenyl, C2-6Alkynyl ,-C (O) OC1-6Alkyl ,-C (O) NHC1-6Alkyl, C1-6Aralkyl, cyano, nitro, halogen or amino, the C1-6Alkane Base, C1-6Hydroxy alkyl, C1-6Carboxyalkyl, C1-6Mercaptoalkyl, C1-6Alkoxyalkyl, C2-6Alkenyl, C2-6Alkynyl ,-C (O) OC1-6Alkyl ,-C (O) NHC1-6Alkyl or C1-6Aralkyl is optionally replaced by more than one halogen atom；
In formula (I), the R3、R4And R5It is each independently hydrogen atom, hydroxyl, C1-6Alkyl, C1-6Hydroxy alkyl, C1-6Alkane Oxygroup alkyl, C2-6Alkenyl, C2-6Alkynyl, C1-6Aralkyl, cyano, nitro, halogen or amino；
In formula (I), the R6It independently is C1-6Alkylidene, C1-6Hydroxy alkylidene, C1-6Carboxyalkylene, C1-6Alkoxy Alkylidene, C6-10Arlydene ,-C (O) O- ,-C (O) OC1-3Alkylidene ,-C (O) NH- or-C (O) NHC1-3Alkylidene；
In formula (I), the R7It independently is hydrogen atom, C1-6Alkyl, C1-6Hydroxy alkyl, C1-6Carboxyalkyl, C1-6Sulfydryl Alkyl, C1-6Alkoxyalkyl, C2-6Alkenyl, C2-6Alkynyl ,-C (O) OC1-6Alkyl ,-C (O) NHC1-6Alkyl, C1-6Aralkyl, cyanogen Base, nitro, halogen or amino, the C1-6Alkyl, C1-6Hydroxy alkyl, C1-6Carboxyalkyl, C1-6Mercaptoalkyl, C1-6Alkoxy Alkyl, C2-6Alkenyl, C2-6Alkynyl ,-C (O) OC1-6Alkyl ,-C (O) NHC1-6Alkyl or C1-6Aralkyl is optionally by more than one Halogen atom replace；
In formula (I), the X independently is carbon atom or nitrogen-atoms；With
In formula (I), the Y independently is carbon atom, nitrogen-atoms, oxygen atom or sulphur atom；
In formula (I), the m and n are 0,1,2 or 3 each independently respectively, and 6 > m+n > 0.
Component 2 in the composition) 1- (5- (tert-butyl) isoxazole -3- base) -3- (4- ((4- (third oxygen of 3- morpholino Base) phenyl) acetenyl) phenyl) urea pharmaceutically acceptable acid-addition salts in 1- (5- (tert-butyl) isoxazole -3- base) - 3- (4- ((4- (3- morpholino propoxyl group) phenyl) acetenyl) phenyl) urea is compound shown in following formula (a):
Described 1- (5- (tert-butyl) isoxazole -3- base) -3- (4- ((4- (3- morpholino propoxyl group) phenyl) acetenyl) benzene Base) urea pharmaceutically acceptable acid-addition salts be inorganic acid salt or acylate.
The inorganic acid salt is hydrochloride, hydrobromate, hydrofluoride, hydriodate, perchlorate, chlorate, secondary chlorine Hydrochlorate, hypobromite, bromate, hypoiodite, iodate, periodate, carbonate, bicarbonate, nitrate, nitrous acid Salt, nitroxylate, borate, metaborate, borous acid salt, metasilicate, silicate, sulfate, disulfate, sulfurous acid Salt, bisulfites, pyrosulfate, persulfate, Hemisulphate, bisulphate, rhodanate, peroxydisulfate, even two sulphur Hydrochlorate, thiosulfate, thio salt sulfate, metaphosphate, metaphosphite, phosphite, pyrophosphite, hypophosphorous acid Salt, dibasic alkaliine, dihydric phosphate, phosphate, pyrophosphate, metaphosphate, manganate, permanganate, molybdate, wolframic acid Salt or their any combination；Preferably nitric acid, phosphoric acid, metaphosphate, sulfuric acid, silicate, molybdate or their any group It closes.
The acylate be formates, acetate, propionate, butyrate, benzoate, malonate, succinate, Acetonate, esilate, propane sulfonic acid salt, citrate, benzene sulfonate, tosilate, L MALIC ACID salt, methanesulfonic acid Salt, propiolate, vinylacetate, L-TARTARIC ACID salt, fumarate, lactate, Lactobionate, lactobionate, gala Glycuronate, cyclopentyl propionate, lauryl sulfate, acrylates, cyclopentane propionate, glycerophosphate, methoxyl group Benzoate, digluconate, gluconate, enanthate, embonate, salicylate, galactosaccharic acid salt, Portugal heptan Sugar lime, mandelate, naphthalene sulfonate, beta-naphthalenesulfonic-acid salt, oxalates, maleate, tartrate, trifluoroacetate, trifluoro Mesylate, caproate, pivalate, glucuronate, laruate, phthalate, lauryl sulfate, cigarette Hydrochlorate, cinnamate, oleate, palmitate, pamoate, pectate, Phthalate, caprylate, pelargonate, cyclamic acid Salt, phthalate, CYSTEAMINE HCL hydrochlorate, sorbate, pa not hydrochlorate, mucate, glycine hydrochloride salt, napadisilate, poly- Vinyl sulfonate, sulfosalicylate, adipate, suberate, sebacate, fourth hydroxyl acetate, alginates, Vitamin C Hydrochlorate, erythorbate, aspartate, glutamate, acetoacetate, borate, chloro-benzoate, camphoric acid Salt, itaconate, l-camphor sulfonic acid salt, methyl benzoic acid salt, dinitro-benzoate, sulfamate, glutarate, hydroxyl Base maleate, hydroxy benzoate, phenylacetate, isobutyrate, Pivalate, picrate, stearate, acylated amino group Hydrochlorate, alginate or their any combination；Preferably citrate, naphthalene sulfonate, beta-naphthalenesulfonic-acid salt, L-TARTARIC ACID salt, Tosilate, mesylate, maleate, tartrate or their any combination.
Component 3 in the composition) water-soluble fullerene is fullerene-hyaluronic acid polymer, i.e., water-soluble fowler Alkene, it is to react on the basis of original fullerene is by purification process with aminating agent, and fullerene surface connection is upper anti- After answering the stronger amino of activity, then react with hyaluronic acid, generation fullerene-hyaluronic acid polymer.
Fullerene in the fullerene-hyaluronic acid polymer as water-soluble fullerene is empty fullerene, gold Belong to one or more of in fullerene, heterocycle fullerene and embedded fullerene；Including but not limited to fullerene C2n、M@C2n、M2@C2n、 MA@C2n、M3N@C2n、M2C2@C2n、M2S@C2n、M2O@C2n、MxA3-xN@C2nAny one of, the M and A are metallic element, And it is selected from any one in Sc, Y and lanthanide element；10≤n≤60,0≤x≤3.
In preferred embodiment of the invention, the optional C28, C36 of the fullerene, C50, C60, C72, C76, C78, One or more kinds of mixtures of C80 and C84 and its derivative.
In the fullerene-hyaluronic acid polymer, the mass content ratio of hyaluronic acid and fullerene is 0.32-0.38: 1, preferably 0.35-0.36:1.
In preferred embodiment of the invention, R described in formula (I)1And R2Be each independently hydrogen atom, optionally by The more than one substituted or unsubstituted C of halogen atom1-6Alkyl, C1-6Alkoxyalkyl ,-C (O) OC1-6Alkyl ,-C (O) NHC1-6Alkyl, cyano, nitro or amino, more preferably R1And R2It is each independently hydrogen atom, cyano, nitro or a by 1-3 The C that halogen atom replaces1-4Alkyl or C1-4Alkoxyalkyl, more preferably R1And R2It is each independently by 1-3 halogen atom Substituted C1-4Alkyl.
In preferred embodiment of the invention, R described in formula (I)3、R4And R5Be each independently hydrogen atom, hydroxyl, C1-6Alkyl, C1-6Alkoxyalkyl or halogen, the more preferably described R3、R4And R5It is each independently hydrogen atom, hydroxyl, C1-4Alkane Base or halogen, the more preferably described R3、R4And R5It is each independently hydroxyl, ethyl or halogen.
In preferred embodiment of the invention, R described in formula (I)6It independently is C1-6Alkoxyalkylene ,-C (O) O-、-C(O)OC1-3Alkylidene ,-C (O) NH- or-C (O) NHC1-3Alkylidene, the more preferably described R6It independently is-C (O) OC1-3 Alkylidene or-C (O) NHC1-3Alkylidene, the more preferably described R6It independently is-C (O) OCH2Or-C (O) NHCH2-。
In preferred embodiment of the invention, R described in formula (I)7It independently is hydrogen atom, halogen, by 1-3 halogen The substituted or unsubstituted C of atom1-4Alkyl, C1-4Carboxyalkyl, C1-4Mercaptoalkyl ,-C (O) OC1-3Alkyl or-C (O) NHC1-3Alkane Base, the more preferably described R7It independently is by the substituted or unsubstituted C of 1-3 halogen atom1-4Alkyl, C1-4Mercaptoalkyl ,-C (O)OC1-3Alkyl or-C (O) NHC1-3Alkyl, the more preferably described R7It independently is trifluoromethyl ,-CH2CH2SH、-C(O) NHCH3。
In preferred embodiment of the invention, X described in formula (I) is nitrogen-atoms, and the Y independently is nitrogen-atoms or sulphur Atom, the more preferably described Y are nitrogen-atoms.
In preferred embodiment of the invention, m and n described in formula (I) is 1 or 2 each independently respectively, more preferably It is 2 or m be 2, n is 1 that the m, which is 1, n, and the more preferably described m and n is 2.
In preferred embodiment of the invention, aromatic amides of the present invention have shown in the following general formula (II) Structure:
Wherein, R1、R2、R3、R4、R5、R6And R7Meaning limited respectively with above-mentioned definition it is identical.
In preferred embodiment of the invention, aromatic amides of the present invention
With structure shown in the following general formula (III):
Wherein, R1、R2、R3、R4、R5、R6And R7Meaning limited respectively with above-mentioned definition it is identical.
In preferred embodiment of the invention, aromatic amides of the present invention have shown in the following general formula (IV) Structure:
Wherein, R1、R2、R3、R4、R5、R6And R7Meaning limited respectively with above-mentioned definition it is identical.
There is chiral atom in above-mentioned logical formula (I), (II), (III) or (IV) molecule, in the present invention the compounds of this invention It can be raceme, left-handed (R configuration) and/or dextrorotation (S configuration).Therefore, the invention also includes aromatic amides shown in logical formula (I) The stereoisomer of compound or its pharmaceutically acceptable salt, i.e. the left-handed of them, dextrorotation and/or raceme.
In preferred embodiment of the invention, general formula I compound represented of the present invention is preferably following aromatic amides Close object and its pharmaceutically acceptable salt:
The invention also includes aromatic amides shown in general formula I, its pharmaceutically acceptable salt or its alloisomerisms The hydrate of body, internal level-one and/or secondary metabolism object and prodrug.
The invention further relates to the method for compound shown in the formula that is used to prepare (I), at least one included the following steps:
(i) amorphous compound shown in formula (I) is prepared；
(ii) in organic solvent by amorphous compound dissolution；
(iii) make solution supersaturated, to cause the generation of crystal；And
(iv) crystal is separated, such as by filtering crystals, by the way that liquid to be decanted off coming from crystal, or passed through any other Suitable isolation technics.In some embodiments, preparation further includes the crystal of washing filtering, such as with solvent or non-solvent liquid Body washing.In some embodiments, preparation further includes drying, is preferably such as dried under the vacuum pressures under reduced pressure.
In preferred embodiment of the invention, amorphous compound shown in the formula (I) be soluble in selected from acetonitrile, Acetone, ether, isopropyl ether, ethyl alcohol, ethyl acetate, heptane, isopropyl acetate, methanol, methyl tertiary butyl ether(MTBE), tetrahydrofuran, first In the organic solvent of benzene, dimethylbenzene or any combination thereof.In preferred embodiment of the invention, without fixed shown in the formula (I) Shape compound be preferably soluble in ethyl alcohol, acetone, or combinations thereof in.In some preferred embodiments, the formula (I) Shown amorphous compound is most preferably soluble in toluene.
In preferred embodiment of the invention, it is described make solution supersaturation include addition anti-solvent, such as not with it is described The miscible another liquid of organic solvent allows solution cooling, reduces volume of solution or any combination thereof.In certain embodiment party In formula, making solution supersaturation includes adding anti-solvent, solution being made to be cooled to environment temperature or volume that is lower and reducing solution, Such as by evaporating solvent from solution.In some embodiments, allow solution cooling to can be passively, for example allow molten Liquid is stood at ambient temperature or active, such as the cooling solution in the ice bath or freezer unit.
In preferred embodiment of the invention, the induction crystallization includes secondary nucleation, wherein being nucleated depositing in crystal seed It is lower or with occur under environmental interaction.
Rationally, reaction condition is mild for the synthetic route design of the compounds of this invention, and each yield that walks is high, easy to operate, is suitble to Industrialized production.
Compound 1- shown in formula (a) of the present invention (5- (tert-butyl) isoxazole -3- base) -3- (4- ((4- (3- morpholino Propoxyl group) phenyl) acetenyl) phenyl) urea specific synthetic method referring to patent CN105272930A (patent application publication number) In embodiment.
The invention further relates to be used to prepare component 2) 1- (5- (tert-butyl) isoxazole -3- base) -3- (4- ((4- (3- morpholine For propoxyl group) phenyl) acetenyl) phenyl) urea pharmaceutically acceptable acid-addition salts method, the free alkali (similarly hereinafter) is 1- (5- (tert-butyl) isoxazole -3- base) -3- (4- ((4- (3- morpholino propoxyl group) phenyl) acetenyl) phenyl) urea, i.e. formula (Ia) compound shown in, at least one included the following steps:
1) free alkali is added in a solvent and is completely dissolved at a temperature of 78 DEG C by room temperature,
2) solvent solution of the solvent solution of the acid or the hydrate of the acid is added dropwise, or is added dropwise described sour and molten Agent, room temperature or insulation reaction and but to room temperature,
3) it filters, filter cake is drying to obtain after being washed with the solvent.
In preferred embodiment of the invention, the amount of the free alkali is 0.1~2.1mmol, and the amount of the solvent is 3 ~100mL.
In preferred embodiment of the invention, in the dropwise addition object, the amount of the hydrate of the acid or the acid is 0.2 ~25mmol, the solvent are 0.5~10mL.
In preferred embodiment of the invention, a solvent is selected from acetone, methanol, ethyl alcohol, isopropanol, acetic acid second Ester, toluene, dimethylbenzene, preferably acetone.
In preferred embodiment of the invention, the reaction time is 10min~48h.
In preferred embodiment of the invention, the drying can be to be dried under reduced pressure preferably to do under the vacuum pressures It is dry.
The invention further relates to be used to prepare component 3) method of water-soluble fullerene, at least one included the following steps:
1) 5~20mL aminating agent and the mixing of 1~3g sodium hydroxide, add the ethyl alcohol of 60~100mL75~95%, stir After uniformly, the parallel aminating reaction of organic solution 50mL containing fullerene is added dropwise；
2) organic solvent for removing upper layer, is evaporated off water and ethyl alcohol, then with ethyl alcohol or methanol filtering and washing, is dried in vacuo to obtain ammonia Base fullerene；
3) according to weight ratio 1:1~2:3~5:3~4 ratio by above-mentioned amino fullerene, hyaluronic acid, 1- ethyl- (3- dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate and n-hydroxysuccinimide 500~1000 equivalents formamide or Parallel polymerization reaction is uniformly mixed in N,N-dimethylformamide；
4) ethyl alcohol or acetone filtering and washing are used, unreacted impurity is removed, is dried in vacuo to obtain fullerene-hyaluronic acid polymerization Object, i.e. water-soluble fullerene.
The aminating agent is ethylenediamine, 1,3- propane diamine, 1,6- hexamethylene diamine, one in 2,4,6- trimethylbenzene sulfonamide Kind.
The fullerene is one or more of in empty fullerene, metal fullerene, heterocycle fullerene and embedded fullerene； Including but not limited to fullerene C2n、M@C2n、M2@C2n、MA@C2n、M3N@C2n、M2C2@C2n、M2S@C2n、M2O@C2n、MxA3-xN@C2n Any one of, the M and A are metallic element, and any one being selected from Sc, Y and lanthanide element；10≤n The optional section of≤60, n include but is not limited to 10≤n≤15,10≤n≤20,10≤n≤25,10≤n≤30,10≤n≤ 35、10≤n≤40、10≤n≤45、10≤n≤50、10≤n≤55、10≤n≤60、15≤n≤25、15≤n≤30、15≤ n≤35、15≤n≤40、15≤n≤45、15≤n≤50、15≤n≤55、15≤n≤60、20≤n≤25、20≤n≤30、 20≤n≤35、20≤n≤40、20≤n≤45、20≤n≤50、20≤n≤55、20≤n≤60、25≤n≤30、25≤n≤ 35,5≤n≤40,25≤n≤45,25≤n≤50,25≤n≤55,25≤n≤60；0≤x≤3.
In preferred embodiment of the invention, the optional C28, C36 of the fullerene, C50, C60, C72, C76, C78, One or more kinds of mixtures of C80 and C84 and its derivative.
The organic solution containing fullerene is made of fullerene and organic solvent, containing richness in the organic solution of every 1mL Strangle 0.1~1mg of alkene.
The organic solvent is one or more of 1,2- dichloro-benzenes, carbon disulfide, meta-xylene, toluene, benzene Mixture.
The aminating reaction is to be stirred to react 1~7d at 40~50 DEG C, 260~300r/min.
The polymerization reaction is stirred to react 48~96h at 20~25 DEG C, 60~80r/min.
In the fullerene-hyaluronic acid polymer, the mass content ratio of hyaluronic acid and fullerene is 0.32~0.38: 1, preferably 0.35~0.36:1.
Applicant have surprisingly discovered that carrying out aminating reaction under selection high temperature, high revolving speed, it is polymerize under low temperature, the slow-speed of revolution After reaction, can largely the low leading amination for improving fullerene it is horizontal, show to connect upper reactivity in fullerene Polymerization reaction occurred after the strong and biggish amino of content, then with hyaluronic acid, helps to promote target product richness significantly Strangle the content of the hyaluronic acid in alkene-hyaluronic acid polymer, hyaluronic acid and richness in the fullerene-hyaluronic acid polymer The raising that the mass content ratio of alkene may be significantly up to 0.32~0.38:1, the dissolubility of water-soluble fullerene is strangled, and Uniform particle sizes, deliquescent raising also accordingly enhance its medicine to the composition for promoting hair growth and/or color development to thicken Active cooperation and contribution of science are suitably applied it relatively in the composition and play promote hair growth, promote hair The dense effect of discoloration；In addition, fullerene can reduce the activity of MMP-9 in skin (collagen catabolic enzyme), to avoid skin The decomposition of middle collagen (basilar memebrane) is lost, and fullerene can also restore bowl structure caused by pore recess etc., restores skin State, fullerene are affine for the height of free radical, make it have extremely strong inoxidizability, have to the active oxygen in skin clear It except effect, weakens skin and generates the substances such as melanocyte-stimulating hormone, interleukins, and then inhibit melanocyte, subtract Tyrosine reduces color spot coloration to the conversion of melanin in slow melanocyte, promotes skin-whitening.
In the composition of the present invention for promoting hair growth and/or color development to thicken, 1) aromatic amides shown in the formula (I) Compound and 2) 1- (5- (tert-butyl) isoxazole -3- base) -3- (4- ((4- (3- morpholino propoxyl group) phenyl) acetenyl) benzene Base) urea pharmaceutically acceptable acid-addition salts and 3) weight ratio of water-soluble fullerene can for 0.1~100:0.1~ 1000:1。
It is of the present invention to include aromatic amides, 1- (5- (tert-butyl) isoxazole -3- base) -3- (4- shown in formula (I) ((4- (3- morpholino propoxyl group) phenyl) acetenyl) phenyl) urea pharmaceutically acceptable acid-addition salts and water-soluble fowler The composition of alkene is positive to promoting hair growth to have the function of, three kinds of effectiveness ingredients in the composition cooperate, and lead to The drug class preparation for effectively inhibiting and the 5α-reductase activity of alopecia being induced to can be used as preventing hair loss and/or promoting hair tonic is crossed, The composition is to the inhibiting effect of I type 5α-reductase up to IC50About 15nmol/L, even better than traditional benzo quinoline promise Ketone derivatives class compound (its IC to I type 5α-reductase50About 17nmol/L), the composition is in 2.5mg/mL concentration It is to the inhibiting rate of I type 5α-reductase up to 91.55%, therefore there is significant inhibiting effect to I type 5α-reductase.Therefore Composition of the present invention is applied to the disease with alopecia, the related hair disorders such as hypotrichosis, hair is soft, hair color is light Suffer from, hair growth and color development can be promoted active and effectively to thicken.
[2] method for promoting hair growth and/or color development to thicken comprising apply safety to the required position of required individual A effective amount of item [1] composition.
In some preferred embodiments, the method for stimulating hair growth include to patient dermal administration it is effective Item [1] described composition according to previously described any embodiment of amount, wherein application increases hair growth, composition It can be applied to scalp, can at least apply composition once a day.
In some preferred embodiments, described to the item [1] of the required position of required individual application safe and effective amount The method of composition can be with are as follows: the required position of individual needed for being applied to the composition and following substance after miscible:
A) at least one monohydric alcohol of total amount 0-99.99wt% is accounted for, and/or
B) at least one dihydric alcohol of total amount 0-99.99wt% is accounted for, and/or
C) distilled water of total amount 0-99.99wt% is accounted for.
The monohydric alcohol is selected from ethyl alcohol, propyl alcohol and isopropanol, and the dihydric alcohol is selected from propylene glycol, butanediol and pentanediol.
[3] item [1] application for promoting composition comprising
The hair growth and/or color development that the composition can be applied to the required position of individual needed for promoting thicken；With/ Or
The composition can be applied to the scalp of individual needed for being applied to for preventing and/or treating selected from by with the following group At group symptom: alopecia areata, telogen effluvim, growth period alopecia, Cicatricial baldness, alopecia cicatrisata；Hair Shaft Abnormalities, nodositas Trichorrhexis disease, the loose syndrome of anagen hair, trichologia, traction property baldness；Infectious hair disorders, favus of the scalp, seborrheica skin Scorching, scalp hair follicles inflammation and androgenetic alopecia；And/or
The composition can be applied to be applied to due to the fact that and the scalp of the required individual that undergoes trichomadesis Reach the purpose for the treatment of trichomadesis: chemotherapy, hormone imbalances, scalp fungal infection with one or both of eyebrow, Anticoagulant is used for gout, depression, hypertension and cardiopathic drug.
In some embodiments, composition is applied to scalp for preventing and/or treating selected from being made up of The symptom of group: alopecia areata, telogen effluvim, growth period alopecia, Cicatricial baldness, alopecia cicatrisata；Hair Shaft Abnormalities, Clastothrix Disease, the loose syndrome of anagen hair, trichologia, traction property baldness；Infectious hair disorders, favus of the scalp, seborrhea, head Fur capsulitis and androgenetic alopecia.In some embodiments, wherein composition is applied to due to the fact that and undergoing One or both of scalp and eyebrow of the patient of trichomadesis treat the purpose of trichomadesis: chemotherapy to reach, and swash Plain unbalance, scalp fungal infection, anticoagulant are used for gout, depression, hypertension and cardiopathic drug.
[4] a kind of pharmaceutical composition comprising item [1] described composition of safe and effective amount；Described pharmaceutical composition can The hair growth and color development at the required position of individual needed for promoting thicken；The composition can be applied to a needed for being applied to The scalp of body is used to prevent and/or treat the symptom of group selected from being made up of: alopecia areata, telogen effluvim, growth period alopecia, Cicatricial baldness, alopecia cicatrisata；Hair Shaft Abnormalities, clastothrix, anagen hair loose syndrome, are led at trichologia Drawing property baldness；Infectious hair disorders, favus of the scalp, seborrhea, scalp hair follicles inflammation and androgenetic alopecia；The composition is also It can be applied to be applied to due to the fact that and one of undergoing scalp and the eyebrow of the required individual of trichomadesis or two Kind with reach treatment trichomadesis purpose: chemotherapy, hormone imbalances, scalp fungal infection, anticoagulant, for gout, Depression, hypertension and cardiopathic drug.
The invention has the benefit that
1) of the present invention to include aromatic amides, 1- (5- (tert-butyl) isoxazole -3- base) -3- shown in formula (I) The pharmaceutically acceptable acid-addition salts and water solubility of (4- ((4- (3- morpholino propoxyl group) phenyl) acetenyl) phenyl) urea The composition of fullerene is positive to promoting hair growth to have the function of, three kinds of effectiveness ingredients in the composition are mutually assisted Make, the 5α-reductase activity by effectively inhibiting induction alopecia can be applied to alopecia, hypotrichosis, hair are soft, The sufferer of the light equal related hair disorders of hair color, can promote active and effectively hair growth and color development to thicken；
2) composition of the present invention and/or the pharmaceutical composition comprising composition of the present invention can be applied to scalp For preventing and/or treating the symptom selected from the group being made up of: alopecia areata, telogen effluvim, growth period alopecia, cicatricial are bald Hair, alopecia cicatrisata；The loose syndrome of Hair Shaft Abnormalities, clastothrix, anagen hair, trichologia, traction property baldness； Infectious hair disorders, favus of the scalp, seborrhea, scalp hair follicles inflammation and androgenetic alopecia；
3) composition of the present invention and/or the pharmaceutical composition comprising composition of the present invention can be applied to due to Following reason and one or both of scalp and eyebrow of the patient that undergoes trichomadesis are to reach treatment trichomadesis illness Purpose: chemotherapy, hormone imbalances, scalp fungal infection, anticoagulant, be used for gout, depression, hypertension and heart disease Drug；
4) it when preparing water-soluble fullerene, selects to carry out aminating reaction under high temperature, high revolving speed, be carried out under low temperature, the slow-speed of revolution After polymerization reaction, the content of the hyaluronic acid in target product fullerene-hyaluronic acid polymer is promoted with can dramatically, it is water-soluble The raising that the dissolubility of property fullerene may be significantly, and uniform particle sizes, deliquescent raising also accordingly enhance it Cooperation and contribution to the pharmacological activity for the composition for promoting hair growth and/or color development to thicken, are suitably applied it relatively In the composition and play the effect of promoting hair growth, color development is promoted to thicken.
Present invention employs above-mentioned technical proposals to provide model essay, compensates for the deficiencies in the prior art, design is reasonable, operation side Just.
Detailed description of the invention
Fig. 1 is the structural formula schematic diagram of aromatic amides of the invention；
Fig. 2 is 1- (5- (tert-butyl) isoxazole -3- base) -3- (4- ((4- (3- morpholino propoxyl group) phenyl) of the invention Acetenyl) phenyl) urea structural formula schematic diagram；
Fig. 3 is that the composition in various embodiments of the present invention counts schematic diagram to the active inhibiting rate of I type 5α-reductase.
Specific embodiment
Unless otherwise defined, technical and scientific term used herein has ordinary skill of the art The identical meaning that personnel are generally understood.The present invention uses method described herein and material；But as is generally known in the art Other suitable methods and material can also be used.Material, method and example described herein are merely illustrative, It is not intended for limiting.All publications, patent application case, Patent Case, Provisional Application, data base entries and herein Other bibliography referred to etc., entirety is incorporated herein as reference.It include being defined as with this specification if there is conflict It is quasi-.
By following detailed description, attached drawing and claim, other features and advantages of the present invention be will become apparent.
Composition of the invention may include element, step and limitation as described herein, or by element as described herein, step And it limitation composition or is substantially made of and any of the present invention additional element as described herein, step and limitation Or optional compositions, component or limitation.
The term as used herein " include (and its phraseological modification) " with " having " or " comprising " include meaning rather than It is used with the exclusive meaning of " only including ".The term as used herein "an" and " described " be construed as covering plural form with And singular.
Unless otherwise specified, all percentages, number and ratio are based on the total weight of the present composition.It removes Non- otherwise indicated, otherwise all such weight relevant to ingredients listed are based on the content of active material, therefore not including can It can include the carrier or by-product in marketable material.
Term " growth " used herein about hair refers to the growth or regeneration of hair.It is raw accordingly, with respect to hair is made It is long or about for making the active material of hair growth term " growth " and " regeneration " be used interchangeably.It is as used herein to close Refer in the term " thickening " of hair and the growth of hair or regeneration and hair thickens close, hair color is deeper.
The term as used herein " safe and effective amount " refers in the reasonable determination range of technical staff, such as local application or The compound or composition of systemic administration active material etc is enough significantly to induce positive beneficial effect (such as hair growth And/or color development thickens) but down to being enough to avoid the amount of serious side effects, that is, the amount of reasonable effective hazard ratio is provided.
The substance that can be used as pharmaceutically acceptable carrier includes but is not limited to ion-exchanger；Aluminium；Aluminum stearate；Ovum Phosphatide；Haemocyanin, such as human albumin；Buffer substance such as phosphate；Glycine；Sorbic acid；Potassium sorbate；It is saturated vegetable butter The partial glyceride mixtures of fat acid；Water；Salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, chlorination Sodium, zinc salt；Colloidal silicon；Magnesium trisilicate；Polyvinylpyrrolidone；Polyacrylate；Wax；Polyethylene-polyoxypropylene-blocking polymerization Body；Lanolin；Sugar, such as lactose, dextrose and saccharose；Starch such as cornstarch and potato starch；The derivative of cellulose and it Such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate；Gum powder；Malt；Gelatin；Talcum powder；Auxiliary material such as cocoa bean Rouge and suppository wax；Oil such as peanut oil, cotton seed oil, safflower oil, sesame oil, olive oil, corn oil and soya-bean oil；Glycols chemical combination Object, such as propylene glycol and polyethylene glycol；Esters such as ethyl oleate and ethyl laurate；Agar；Buffer such as magnesium hydroxide and Aluminium hydroxide；Alginic acid；Pyrogen-free water；Isotonic salt；Lin Ge (family name) solution；Ethyl alcohol；Phosphate buffer solution；It is nontoxic with other Suitable lubricant such as Sodium Laurylsulfate and magnesium stearate；Colorant；Releasing agent；Coating agents；Sweetener；Flavoring agent；Fragrance； Preservative and antioxidant.
The term as used herein " compound ", refer to including all stereoisomers, geometric isomer, tautomer and The isotope of described structure.It is herein the compound packet of a specific tautomeric form with title or structural identification Other tautomeric forms are included, unless otherwise prescribed.All compounds and its pharmaceutically acceptable salt can contain other objects Matter, such as water and solvent (for example, hydrate and solvate).
The term as used herein " Cx-yAlkyl " refers to substituted or unsubstituted saturated hydrocarbyl, including in chain containing from x to The straight chained alkyl and branched alkyl group of y carbon atom.For example, C1-6Alkyl refers to that having includes entire scope carbon atom number (that is, 1 to 6 carbon atom) and all subgroups are (for example, 1-6,2-6,1-5,3-6,2-5,3-4,1,2,3,4,5 and 6 Carbon atom).
The term as used herein " Cx-yAlkenyl " refers to substituted or unsubstituted unsaturated alkyl, including contains in chain from x To the straight-chain alkenyl and branched alkenyl group of y carbon atom.
The term as used herein " Cx-yAlkynyl " refers to substituted or unsubstituted unsaturated alkyl, including contains in chain from x To the straight-chain alkynyl and branched alkynyl group of y carbon atom.
The term as used herein " alkoxy " refers to the C with oxygen connected to it1-4Alkyl, including methoxyl group, ethoxy Base, propoxyl group and tert-butoxy.
The term as used herein " Cx-yAlkoxyalkyl " refers to the C replaced by " alkoxy "x-yAlkyl, as front is determined Justice.For example, term " C1-6Alkoxyalkyl " refers to the C replaced by alkoxy1-6Alkyl forms ether whereby.
The term as used herein " Cx-yHydroxy alkyl " refers to the C replaced with hydroxylx-yAlkyl, it is as defined above.For example, Term " C1-6Hydroxy alkyl " refers to the C replaced by a hydroxyl1-6Alkyl.
The term as used herein " Cx-yCarboxyalkyl " refers to the C replaced with carboxylx-yAlkyl, it is as defined above.For example, Term " C1-6Carboxyalkyl " refers to the C replaced by a carboxyl1-6Alkyl.
The term as used herein " Cx-yMercaptoalkyl " refers to the C replaced with carbonylx-yAlkyl, it is as defined above.For example, Term " C1-6Mercaptoalkyl " refers to the C replaced by a sulfydryl1-6Alkyl.
The term as used herein " Cx-yAlkylidene " is as defined above a, hydrogen of alkyl from alkyl derivative Atom is removed.Such as term " C1-6Alkylidene " refers to the C for removing a hydrogen atom1-6Alkyl.Moreover, used herein Term " C1-6Hydroxy alkylidene ", " C1-6Carboxyalkylene ", " C1-6Alkoxyalkylene " is all as defined above.Such as example Term " C1-6Carboxyalkylene " refers to the C for removing a hydrogen atom1-6Carboxyalkyl, remaining is not repeated one by one.
The term as used herein " Cx-yArlydene " is derived by aromatic hydrocarbon (aromatic hydrocarbons), two ring carbons of aromatic hydrocarbon Respectively there is a hydrogen atom to be removed in atom.Such as term " C6-10Arlydene " refers to C6-10In two ring carbon atoms of aromatic hydrocarbons Respectively there is a hydrogen atom to be removed, including but not limited to as described in following formula:
Embodiment 1:
The present embodiment provides the following termss.
[1] a kind of composition for promoting hair growth and/or color development to thicken, comprising:
1) aromatic amides shown in formula (1)；With
2) 1- (5- (tert-butyl) isoxazole -3- base) -3- (4- ((4- (3- morpholino propoxyl group) phenyl) acetenyl) benzene Base) urea pharmaceutically acceptable acid-addition salts, and
3) water-soluble fullerene.
Described 1- (5- (tert-butyl) isoxazole -3- base) -3- (4- ((4- (3- morpholino propoxyl group) phenyl) acetenyl) benzene Base) urea pharmaceutically acceptable acid-addition salts be tosilate, 1- (5- (tert-butyl) isoxazole -3- the base) -3- (4- ((4- (3- morpholino propoxyl group) phenyl) acetenyl) phenyl) urea (lower referred to as free alkali) p-methyl benzenesulfonic acid addition salts Preparation process are as follows:
1) at room temperature, 2mmol free alkali is added in 60mL acetone, is stirred at room temperature；
2) acetone soln that 12mL contains 2.5mmol p-methyl benzenesulfonic acid monohydrate is added dropwise, room temperature reaction is for 24 hours；
3) it filters, a small amount of acetone washing of filter cake, 40 DEG C are dried in vacuo to obtain the final product.
The water-soluble fullerene is fullerene-hyaluronic acid polymer, and wherein the quality of hyaluronic acid and fullerene contains Amount is than being 0.36:1, the preparation process of the water-soluble fullerene are as follows:
1) 5mL aminating agent and 1g sodium hydroxide are mixed, add 60mL95% ethyl alcohol, after mixing evenly, dropwise plus Enter the parallel aminating reaction of organic solution 50mL containing fullerene；
2) organic solvent for removing upper layer, is evaporated off water and ethyl alcohol, then with ethyl alcohol or methanol filtering and washing, is dried in vacuo to obtain ammonia Base fullerene；
3) according to the ratio of weight ratio 1:2:5:4 by above-mentioned amino fullerene, hyaluronic acid, 1- ethyl-(3- dimethylamino Base propyl) phosphinylidyne diimmonium salt hydrochlorate and n-hydroxysuccinimide 1000 equivalents formamide or N,N-dimethylformamide In be uniformly mixed parallel polymerization reaction；
4) ethyl alcohol or acetone filtering and washing are used, unreacted impurity is removed, is dried in vacuo to obtain fullerene-hyaluronic acid polymerization Object, i.e. water-soluble fullerene.
The aminating agent is 2,4,6- trimethylbenzene sulfonamide；The fullerene is C60；It is described to contain fullerene C60's In organic solution, the C containing 0.5mg in every 1mL toluene solution60；The aminating reaction is to stir instead at 50 DEG C, 300r/min Answer 4d；The polymerization reaction is stirred to react 96h at 22 DEG C, 80r/min.
Polymerization reaction can largely low raising fullerene under aminating reaction and low temperature, the slow-speed of revolution under high temperature, high revolving speed Leading amination it is horizontal, after fullerene shows to connect upper reactivity compared with the strong and biggish amino of content, then with hyalomitome Polymerization reaction occurred for acid, helped to be promoted the hyaluronic acid in target product fullerene-hyaluronic acid polymer significantly Content, in the fullerene-hyaluronic acid polymer mass content of hyaluronic acid and fullerene ratio up to 0.32~0.38:1, The raising that the dissolubility of water-soluble fullerene may be significantly, and uniform particle sizes, deliquescent raising also corresponding enhancing Its cooperation and contribution to the pharmacological activity for the composition for promoting hair growth and/or color development to thicken, makes it relatively be suitble to answer For in the composition and the effect of playing promotion hair growth, color development promoted to thicken；In addition, fullerene can reduce skin The activity of middle MMP-9 (collagen catabolic enzyme), so that the decomposition of collagen in skin (basilar memebrane) is avoided to be lost, fullerene It can also restore bowl structure caused by pore recess etc., restore skin state, fullerene is affine for the height of free radical, makes it With extremely strong inoxidizability, there is scavenging effect to the active oxygen in skin, reduction skin generate melanocyte-stimulating hormone, The substances such as interleukins, and then melanocyte is inhibited, slow down conversion of the tyrosine to melanin, drop in melanocyte Low color spot coloration promotes skin-whitening.
In the composition that promotion hair growth and/or color development thicken described in the present embodiment, aromatic amides shown in the formula (1) Compound and 1- (5- (tert-butyl) isoxazole -3- base) -3- (4- ((4- (3- morpholino propoxyl group) phenyl) acetenyl) phenyl) The toluenesulfonic acid addition salt of urea and the weight ratio of water-soluble fullerene can be 100:1000:1.
Include aromatic amides, 1- (5- (tert-butyl) isoxazole -3- base) -3- shown in formula (1) described in the present embodiment The toluenesulfonic acid addition salt of (4- ((4- (3- morpholino propoxyl group) phenyl) acetenyl) phenyl) urea and water-soluble fullerene Composition is positive to promoting hair growth to have the function of, three kinds of effectiveness ingredients in the composition cooperate, by having The 5α-reductase activity of effect ground inhibition induction alopecia can be used as preventing hair loss and/or promoting the drug class preparation of hair tonic, described Composition is about 15nmolL up to IC50 to the inhibiting effect of I type 5α-reductase, even better than traditional benzo quinolone Derivatives quasi-compound (it is about 17nmolL to the IC50 of I type 5α-reductase), therefore composition of the present invention is applied For the sufferer with alopecia, the related hair disorders such as hypotrichosis, hair is soft, hair color is light, can promote active and effectively Hair growth and color development thicken.
[2] method for promoting hair growth and/or color development to thicken comprising apply safety to the required position of required individual A effective amount of item [1] composition.
In some preferred embodiments, the method for stimulating hair growth include to patient dermal administration it is effective Amount according to previously described item [1] described composition, wherein application increases hair growth.Composition can be applied to head Skin.Composition can at least be applied once a day.
[3] item [1] application for promoting composition comprising
The hair growth and/or color development that the composition can be applied to the required position of individual needed for promoting thicken；With/ Or
The composition can be applied to the scalp of individual needed for being applied to for preventing and/or treating selected from by with the following group At group symptom: alopecia areata, telogen effluvim, growth period alopecia, Cicatricial baldness, alopecia cicatrisata；Hair Shaft Abnormalities, nodositas Trichorrhexis disease, the loose syndrome of anagen hair, trichologia, traction property baldness；Infectious hair disorders, favus of the scalp, seborrheica skin Scorching, scalp hair follicles inflammation and androgenetic alopecia；And/or
The composition can be applied to be applied to due to the fact that and the scalp of the required individual that undergoes trichomadesis Reach the purpose for the treatment of trichomadesis: chemotherapy, hormone imbalances, scalp fungal infection with one or both of eyebrow, Anticoagulant is used for gout, depression, hypertension and cardiopathic drug.
[4] a kind of pharmaceutical composition comprising item [1] described composition of safe and effective amount；Described pharmaceutical composition can The hair growth and color development at the required position of individual needed for promoting thicken；The composition can be applied to a needed for being applied to The scalp of body is used to prevent and/or treat the symptom of group selected from being made up of: alopecia areata, telogen effluvim, growth period alopecia, Cicatricial baldness, alopecia cicatrisata；Hair Shaft Abnormalities, clastothrix, anagen hair loose syndrome, are led at trichologia Drawing property baldness；Infectious hair disorders, favus of the scalp, seborrhea, scalp hair follicles inflammation and androgenetic alopecia；The composition is also It can be applied to be applied to due to the fact that and one of undergoing scalp and the eyebrow of the required individual of trichomadesis or two Kind with reach treatment trichomadesis purpose: chemotherapy, hormone imbalances, scalp fungal infection, anticoagulant, for gout, Depression, hypertension and cardiopathic drug.
Embodiment 2:
The present embodiment provides a kind of preparation methods of water-soluble fullerene, comprising the following steps:
1) 5mL ethylenediamine and the mixing of 1g sodium hydroxide, add 60mL75% ethyl alcohol, after mixing evenly, are added dropwise and contain There is the organic solution 50mL of fullerene, the aminating reaction 5d at 40 DEG C, 280r/min；
2) organic solvent for removing upper layer, is evaporated off water and ethyl alcohol, then with ethyl alcohol or methanol filtering and washing, is dried in vacuo to obtain ammonia Base fullerene；
3) according to the ratio of weight ratio 1:2:3:4 by above-mentioned amino fullerene, hyaluronic acid, 1- ethyl-(3- dimethylamino Base propyl) phosphinylidyne diimmonium salt hydrochlorate and n-hydroxysuccinimide be uniformly mixed in the formamide of 600 equivalents.20 DEG C, Polymerization reaction 48h under 70r/min；
4) ethyl alcohol or acetone filtering and washing are used, unreacted impurity is removed, is dried in vacuo to obtain fullerene-hyaluronic acid polymerization Object, i.e. water-soluble fullerene.
The organic solution containing fullerene is by fullerene C60It is formed with carbon disulfide solvent, the carbon disulfide of every 1mL The C of fullerene containing 0.5mg in solution60。
Embodiment 3:
The present embodiment provides a kind of preparation methods of water-soluble fullerene, comprising the following steps:
1) 10mL aminating agent 1,6- hexamethylene diamine and the mixing of 2g sodium hydroxide, add 70mL80% ethyl alcohol, stir evenly Afterwards, the organic solution 50mL containing fullerene is added dropwise, the aminating reaction 2d at 45 DEG C, 280r/min；
2) organic solvent for removing upper layer, is evaporated off water and ethyl alcohol, then with ethyl alcohol or methanol filtering and washing, is dried in vacuo to obtain ammonia Base fullerene；
3) according to the ratio of weight ratio 1:2:5:4 by above-mentioned amino fullerene, hyaluronic acid, 1- ethyl-(3- dimethylamino Base propyl) phosphinylidyne diimmonium salt hydrochlorate and n-hydroxysuccinimide be uniformly mixed in the formamide of 600 equivalents.25 DEG C, Polymerization reaction 48h under 60r/min；
4) ethyl alcohol or acetone filtering and washing are used, unreacted impurity is removed, is dried in vacuo to obtain fullerene-hyaluronic acid polymerization Object, i.e. water-soluble fullerene.
The organic solution containing fullerene is by fullerene C60It is formed with 1,2- dichloro-benzenes, 1, the 2- dichloro-benzenes of every 1mL The C of fullerene containing 1mg in solution60。
Embodiment 4:
The present embodiment provides a kind of preparation methods of water-soluble fullerene, comprising the following steps:
1) 20mL aminating agent 2,4,6- trimethylbenzene sulfonamides and the mixing of 2g sodium hydroxide, add 100mL80% second The organic solution 50mL containing fullerene is added dropwise after mixing evenly in alcohol, the aminating reaction 7d at 50 DEG C, 270r/min；
2) organic solvent for removing upper layer, is evaporated off water and ethyl alcohol, then with ethyl alcohol or methanol filtering and washing, is dried in vacuo to obtain ammonia Base fullerene；
3) according to the ratio of weight ratio 1:1:5:4 by above-mentioned amino fullerene, hyaluronic acid, 1- ethyl-(3- dimethylamino Base propyl) phosphinylidyne diimmonium salt hydrochlorate and n-hydroxysuccinimide mix in the N,N-dimethylformamide of 800 equivalents It is even.The polymerization reaction 72h at 22 DEG C, 60r/min；
4) ethyl alcohol or acetone filtering and washing are used, unreacted impurity is removed, is dried in vacuo to obtain fullerene-hyaluronic acid polymerization Object, i.e. water-soluble fullerene.
The organic solution containing fullerene is by fullerene C70It is formed with meta-xylene, the meta-xylene solution of every 1mL In the C of fullerene containing 0.5mg70。
Embodiment 5:
The present embodiment provides a kind of preparation methods of water-soluble fullerene, comprising the following steps:
1) 15mL aminating agent 2,4,6- trimethylbenzene sulfonamides and the mixing of 1g sodium hydroxide, add 80mL90% second The organic solution 50mL containing fullerene is added dropwise after mixing evenly in alcohol, the aminating reaction 4d at 48 DEG C, 300r/min；
2) organic solvent for removing upper layer, is evaporated off water and ethyl alcohol, then with ethyl alcohol or methanol filtering and washing, is dried in vacuo to obtain ammonia Base fullerene；
3) according to the ratio of weight ratio 1:2:5:4 by above-mentioned amino fullerene, hyaluronic acid, 1- ethyl-(3- dimethylamino Base propyl) phosphinylidyne diimmonium salt hydrochlorate and n-hydroxysuccinimide be uniformly mixed in the formamide of 600 equivalents.20 DEG C, Polymerization reaction 48h under 80r/min；
4) ethyl alcohol or acetone filtering and washing are used, unreacted impurity is removed, is dried in vacuo to obtain fullerene-hyaluronic acid polymerization Object, i.e. water-soluble fullerene.
The organic solution containing fullerene is by fullerene C60It is formed with toluene, it is rich containing 0.5mg in every 1mL toluene solution Strangle alkene C60。
Embodiment 6:
The present embodiment provides a kind of preparation methods of water-soluble fullerene, comprising the following steps:
1) 15mL aminating agent 1,3- propane diamine and 1g sodium hydroxide mixing, then plus 75mL95% ethyl alcohol, after mixing evenly, The organic solution 50mL containing fullerene is added dropwise, the aminating reaction 6d at 48 DEG C, 290r/min；
2) organic solvent for removing upper layer, is evaporated off water and ethyl alcohol, then with ethyl alcohol or methanol filtering and washing, is dried in vacuo to obtain ammonia Base fullerene；
3) according to the ratio of weight ratio 1:2:5:3 by above-mentioned amino fullerene, hyaluronic acid, 1- ethyl-(3- dimethylamino Base propyl) phosphinylidyne diimmonium salt hydrochlorate and n-hydroxysuccinimide be uniformly mixed in the formamide of 800 equivalents.24 DEG C, Polymerization reaction 60h under 60r/min；
4) ethyl alcohol or acetone filtering and washing are used, unreacted impurity is removed, is dried in vacuo to obtain fullerene-hyaluronic acid polymerization Object, i.e. water-soluble fullerene.
The organic solution containing fullerene is by fullerene C70It is formed with carbon disulfide, the carbon disulfide solution of every 1mL In the C of fullerene containing 1mg70。
Embodiment 7:
The present embodiment provides a kind of preparation methods of water-soluble fullerene, comprising the following steps:
1) 18mL aminating agent 1,3- propane diamine and the mixing of 2g sodium hydroxide, add 100mL85% ethyl alcohol, stir evenly Afterwards, the organic solution 50mL containing fullerene is added dropwise, the aminating reaction 3d at 46 DEG C, 300r/min；
2) organic solvent for removing upper layer, is evaporated off water and ethyl alcohol, then with ethyl alcohol or methanol filtering and washing, is dried in vacuo to obtain ammonia Base fullerene；
3) according to the ratio of weight ratio 1:2:5:4 by above-mentioned amino fullerene, hyaluronic acid, 1- ethyl-(3- dimethylamino Base propyl) phosphinylidyne diimmonium salt hydrochlorate and n-hydroxysuccinimide be uniformly mixed in the formamide of 900 equivalents.21 DEG C, Polymerization reaction 96h under 65r/min；
4) ethyl alcohol or acetone filtering and washing are used, unreacted impurity is removed, is dried in vacuo to obtain fullerene-hyaluronic acid polymerization Object, i.e. water-soluble fullerene.
The organic solution containing fullerene is by fullerene C60It is formed with toluene, 0.6mg is contained in the toluene solution of every 1mL Fullerene C60。
Embodiment 8:
The present embodiment provides a kind of preparation methods of water-soluble fullerene, comprising the following steps:
1) 20mL aminating agent 2,4,6- trimethylbenzene sulfonamides and the mixing of 2g sodium hydroxide, add 100mL95% second The organic solution 50mL containing fullerene is added dropwise after mixing evenly in alcohol, the aminating reaction 6d at 25 DEG C, 150r/min；
2) organic solvent for removing upper layer, is evaporated off water and ethyl alcohol, then with ethyl alcohol or methanol filtering and washing, is dried in vacuo to obtain ammonia Base fullerene；
3) according to the ratio of weight ratio 1:2:4:4 by above-mentioned amino fullerene, hyaluronic acid, 1- ethyl-(3- dimethylamino Base propyl) phosphinylidyne diimmonium salt hydrochlorate and n-hydroxysuccinimide mix in the N,N-dimethylformamide of 1000 equivalents It is even.The polymerization reaction 60h at 45 DEG C, 280r/min；
4) ethyl alcohol or acetone filtering and washing are used, unreacted impurity is removed, is dried in vacuo to obtain fullerene-hyaluronic acid polymerization Object, i.e. water-soluble fullerene.
The organic solution containing fullerene is by fullerene C60It is formed with 1,2- dichloro-benzenes, 1, the 2- dichloro-benzenes of every 1mL The C of fullerene containing 1mg in solution60。
Embodiment 9:
The present embodiment provides a kind of preparation methods of water-soluble fullerene, comprising the following steps:
1) 18mL aminating agent 1,6- hexamethylene diamine and the mixing of 2g sodium hydroxide, add 80mL80% ethyl alcohol, stir evenly Afterwards, the organic solution 50mL containing fullerene is added dropwise, the aminating reaction 5d at 20 DEG C, 120r/min；
2) organic solvent for removing upper layer, is evaporated off water and ethyl alcohol, then with ethyl alcohol or methanol filtering and washing, is dried in vacuo to obtain ammonia Base fullerene；
3) according to the ratio of weight ratio 1:1:3:4 by above-mentioned amino fullerene, hyaluronic acid, 1- ethyl-(3- dimethylamino Base propyl) phosphinylidyne diimmonium salt hydrochlorate and n-hydroxysuccinimide be uniformly mixed in the formamide of 800 equivalents.50 DEG C, Polymerization reaction 72h under 260r/min；
4) ethyl alcohol or acetone filtering and washing are used, unreacted impurity is removed, is dried in vacuo to obtain fullerene-hyaluronic acid polymerization Object, i.e. water-soluble fullerene.
The organic solution containing fullerene is by fullerene C60It is formed with carbon disulfide, the carbon disulfide solution of every 1mL In the C of fullerene containing 1mg60。
Embodiment 10:
The present embodiment provides a kind of preparation methods of water-soluble fullerene, comprising the following steps:
1) 14mL aminating agent 2,4,6- trimethylbenzene sulfonamides and the mixing of 1.5g sodium hydroxide, add 70mL90% second The organic solution 50mL containing fullerene is added dropwise after mixing evenly in alcohol, the aminating reaction 4d at 22 DEG C, 180r/min；
2) organic solvent for removing upper layer, is evaporated off water and ethyl alcohol, then with ethyl alcohol or methanol filtering and washing, is dried in vacuo to obtain ammonia Base fullerene；
3) according to the ratio of weight ratio 1:1:4:3 by above-mentioned amino fullerene, hyaluronic acid, 1- ethyl-(3- dimethylamino Base propyl) phosphinylidyne diimmonium salt hydrochlorate and n-hydroxysuccinimide be uniformly mixed in the formamide of 700 equivalents.48 DEG C, Polymerization reaction 48h under 300r/min；
4) ethyl alcohol filtering and washing is used, unreacted impurity is removed, is dried in vacuo to obtain fullerene-hyaluronic acid polymer, i.e., Water-soluble fullerene.
The organic solution containing fullerene is by fullerene C60It is formed with toluene, 0.8mg is contained in the toluene solution of every 1mL Fullerene C60。
Test case 1:
Mass ratio through hyaluronic acid and fullerene in the water-soluble fullerene in analytical control Examples 1 to 10 can be with Find out (table 1), polymerization reaction can largely low raising fowler under aminating reaction and low temperature, the slow-speed of revolution under high temperature, high revolving speed The leading amination of alkene is horizontal, after fullerene shows to connect upper reactivity compared with the strong and biggish amino of content, then with it is transparent Polymerization reaction occurred for matter acid, helped to promote the hyaluronic acid in target product fullerene-hyaluronic acid polymer significantly Content, the mass content of hyaluronic acid and fullerene ratio is up to 0.32~0.38 in the fullerene-hyaluronic acid polymer: 1, the raising that the dissolubility of water-soluble fullerene may be significantly, and uniform particle sizes, deliquescent raising is also corresponding to be increased Its strong cooperation and contribution to the pharmacological activity for the composition for promoting hair growth and/or color development to thicken.
The mass content of hyaluronic acid and fullerene ratio in water-soluble fullerene under the conditions of 1 differential responses of table
Embodiment 11~24:
Embodiment 11~24 provides the combination that the promotion hair growth and/or color development of the present invention of a variety of proportions thicken Object, details are as shown in list 2.
The composition for promoting hair growth and/or color development to thicken of 2 embodiment of table 11~24
Note:*It indicates not containing the component.
Test case 1:
A, the preparation of 5α-reductase and quantitative:
The preparation of A1, II type 5α-reductase: taking male SD rat 10, puts to death after being deprived of food but not water overnight, takes liver rapidly Dirty and epididymis (removing adipose tissue), weighing in shredding on ice pan, obtains sample.Then it is added and is equivalent to 3 times of matter of sample quality The pre-cooling homogenate of amount is homogenized in glass homogenizer.Homogenate system is centrifuged 2 times at 4 DEG C with the revolving speed of 3500rpm, Each 10min, takes supernatant.Then with the relative centrifugal force 50min of 10000g, supernatant, i.e. 5α-reductase are taken again Extracting solution includes II type 5α-reductase in the 5α-reductase extracting solution.It is into 5α-reductase extracting solution plus a certain amount of sweet Oil, obtaining spare II type 5α-reductase sample, (wherein, the volumetric concentration of glycerol is in spare II type 5α-reductase sample 10%) it, dispenses, is stored in -80 DEG C of ultra low temperature freezers, it is spare.Wherein, the pre-cooling homogenate is by 100uL100mmol/L's DTT, 1mL glycerol of PMSF, 100uL100mmol/L are dissolved in the Tris-HCL buffer that the PH of 1mol/L is 5.5, and are added Tris-HCL buffer is calmly molten to be prepared to obtain to 10mL.
The preparation of A2, I type 5α-reductase: taking male SD rat 20, dislocates and puts to death after being deprived of food but not water overnight, rapidly Liver is taken, weighs, in shredding on ice pan, obtains sample.In addition to the PH of Tris-HCL buffer used is 6.8, subsequent step is equal The step of with II type 5α-reductase of preparation, is identical, finally obtains I spare type 5α-reductase sample.
A3, testosterone chromatographic condition is determined:
A31, chromatographic condition are as follows:
Chromatographic column: DiamonsilTMC18 column (250mm × 4.6mm, 5 μm)；
Mobile phase: methanol-water (volume ratio 70:30)；
Flow velocity: 1.0mL/min；
Column temperature: room temperature；
Detection wavelength: 242nm；
Sampling volume: 20 μ L.
A32, method is investigated:
The 5α-reductase extracting solution of the accurate testosterone solution for drawing 20 μ L and 20 μ L, NADPH and testosterone are molten respectively The mixed liquor of liquid, and they are injected into liquid chromatograph, spectrogram measurement is carried out under the chromatographic condition described in A31.Described in A31 Chromatographic condition under, testosterone peak occurs in about 12min, and peak type is symmetrical, preferable with the separating degree of other components.This shows Chromatographic condition described in this test case A31 is solid.
Precision weighs testosterone sample 36mg, is configured to the testosterone mother liquor that mass concentration is 5mmol/L with methanol.By solution by Grade dilution, makes its mass concentration be followed successively by 1.44 μ g/mL, 7.2 μ g/mL, 14.4 μ g/mL, 28.8 μ g/mL, 15.2 μ g/mL, 230.4 μ g/mL, 460.8 μ g/mL.Then by chromatographic condition sample introduction described in A31, with testosterone peak area (A) to testosterone mother liquor Mass concentration (X) mapping, draws testosterone standard curve, and obtaining testosterone standard curve is A=0.263X-0.4106, R2= 0.9999.The result shows that testosterone is with peak area within the scope of 1.44-460.8 μ g/mL in good linear pass in its mass concentration System.Testosterone mother liquor is taken, methanol dilution is added, obtains the test solution that concentration is 100 μm of ol/L.According to chromatostrip described in A31 It part continuous sample introduction 6 times, measures testosterone peak area A value and calculates testosterone concentration, the phase for the testosterone concentration that 6 sample introductions are tested It is 1.01% to standard deviation RSD, shows instrument precision height, favorable reproducibility.Testosterone test solution is taken, according to described in A31 Chromatographic condition, sample introduction when 0h, 2h, 6h, 12h, 48h, measurement testosterone peak area A value simultaneously calculate testosterone concentration, it is above-mentioned The relative standard deviation RSD for the testosterone concentration that various time points sample introduction is tested is 1.37%, this shows testosterone test sample Solution is good in 48h internal stability.6 parts of testosterone test solution are taken, distinguishes sample introduction according to chromatographic condition described in A31 respectively, Measurement testosterone peak area A value simultaneously calculates testosterone concentration, the testosterone concentration tested using above-mentioned 6 parts of testosterone test solutions Relative standard deviation RSD be 2.11%, this shows that the repeatability of operating method used by the present embodiment is good.
B, the foundation of 5α-reductase inhibitor external model:
The active measuring method of B1,5α-reductase: setting test sample quality control and control tube, by Tris-HCL buffer, 5 5 alpha-reductases extracting solution, testosterone, composition sample, NADPH (reduced Coenzyme II, i.e. reduced form two nucleoside of nicotinamide adenine Acid phosphoric acid) it sequentially adds in reaction tube, it is uniformly mixed, obtains 5α-reductase reaction system.Then make the reaction system at 37 DEG C Lower reaction 30min, and separately sampled 0.5mL when 0min and 30min, finally plus methanol 1mL stopped reaction, vortex 1min, and It is centrifuged 15min under the revolving speed of 5000rpm, takes supernatant, and using average pore size is 0.22 μm of miillpore filter to the supernatant Liquid is filtered, and carries out high performance liquid chromatography detection to the filtered supernatant.Wherein, sample includes: as empty map Distilled water, the Finasteride as positive control and the composition of the present invention as given the test agent.Inventor is through grinding After studying carefully, determine that the total amount of above-mentioned reaction system is 1000 μ L, as shown in table 3.
3 5α-reductase active reaction system of table
Classification Blank control (μ L) Positive control (μ L) Given the test agent (μ L)
Tris-HCL buffer 300 300 300
5α-reductase extracting solution 500 500 500
Testosterone 50 50 50
Distilled water 50 / /
Composition sample / / 50
Finasteride / 50 /
NADPH 100 100 100
Should be understood as 5α-reductase described in the embodiment of the present invention (extracting solution) can be understood as I type 5α-reductase or II type 5α-reductase of person.
After measured, the optimum reaction condition of the I type 5α-reductase are as follows: substrate testosterone concentration is 1000umol/L, NADPH concentration is 1mmol/L, and the concentration of 5α-reductase extracting solution is 3mg/mL, and reaction temperature is 37 DEG C, and the reaction time is 30min；The optimum reaction condition of the II type 5α-reductase are as follows: substrate testosterone is dense to spend 1000umol/L, and NADPH concentration is 1mmol/L, the concentration of 5α-reductase extracting solution are 0.7mg/mL, and reaction temperature is 37 DEG C, reaction time 30min.
The activity of 5α-reductase is with T umolL-1/ (mg protein30min) is indicated, with reference to Yan Dongmei, Tu Ling Haze, Li Wenjun etc., foundation [J] the Pharmaceutical Analysis magazine 2008 of RP-HPLC method in-vitro screening 5α-reductase inhibitor model, 07:1046-1049。
When testosterone conversion ratio %=(testosterone concentration measured value when testosterone concentration measured value -30min when 0min)/0min Testosterone concentration measured value * 100%.
5α-reductase maximum inhibition %=(testosterone inversion quantity-plus suppression when unchecked dose of reaction system 30min Testosterone inversion quantity when the reaction system 30min of preparation)/unchecked dose of reaction system 30min when testosterone inversion quantity * 100%.
The composition for taking embodiment 1 of the present invention, the different ratio of embodiment 11~24, is made dense using distilled water Degree is respectively the drug solution of 50mg/mL, 10mg/mL and 2mg/mL, and drug solution is added in above-mentioned reaction system and is diluted After 20 times, then the reaction density of composition of the present invention is respectively 2.5mg/mL, 0.5mg/mL and 0.1mg/mL.
C, Finasteride is on the active influence of 5α-reductase:
Specificity, which is added, in reaction system described in positive control tube into table 3 inhibits II type 5α-reductase active non- That male amine, Finasteride concentration is followed successively by 0.1 μm of ol/L, 0.5 μm of ol/L, 1 μm of ol/L, by the active survey of above-mentioned 5α-reductase Determine method and carry out enzymatic reaction, obtain Finasteride to the active inhibiting rate of 5α-reductase and IC50, and the mould is evaluated with this The reliability of type.
Finasteride can be up to 82.16% in 5 alpha-reductase of dose-dependent inhibition activity, inhibiting rate as the result is shown, IC50 is 209nmol/L, with document (Mitamura K, Ogasawara C, Shiozawa A, etal.Determination method for steroid 5alpha-reductase activity using liquid chromatography/ atmospheric pressure chemical ionization-mass spectrometry[J].Anal Sci.2005Oct；21 (10): 1241-1244.) report Finasteride IC50It is close for 237nmol/L.This shows this implementation Example has specificity using the 5α-reductase activity determination method that the measurement of HPLC method is established, and the model is reliable, stablizes, and can be used for 5 The screening of alpha-reductase inhibitors.
D, composition of the present invention is on the I active influence of type 5α-reductase:
The composition given the test agent solution of embodiment 1 of the present invention, the different ratio of embodiment 11~24 is taken respectively, Enzymatic reaction is carried out by the above-mentioned active measuring method of 5α-reductase, obtains promotion hair growth and/or hair of the present invention The dense composition of discoloration is to the I active inhibiting rate of type 5α-reductase, and experimental result is as shown in Figure 3.From the figure 3, it may be seen that with the present invention The blank control group of the composition for promoting hair growth and/or color development to thicken is compared, and concentration is the present invention of 0.1mg/mL The composition has no remarkable effect to the I active inhibiting effect of type 5α-reductase, and when external dosage is greater than 0.1mg/mL When, the composition of the present invention for promoting hair growth and/or color development to thicken inhibits I type 5α-reductase activity in which can dramatically, Inhibiting rate is up to 91.55%, shows of the present invention to inhibiting I type 5α-reductase activity, hair regeneration, color development is promoted to thicken All have positive effect.
Test case 2:
The composition that promotion hair growth of the present invention and/or color development thicken is promoted about induction and promotes growth The experiment of the effect of phase (that is, hair tonic period) utilizes 7 week old mouse being widely used in assessment growth period induced activity (C57BL/6, female) Lai Jinhang.Firstly, removing the hair of mouse drosal part using electric hair cutter.The weight of each mouse is weighed, and will All mice groups, each group has 5 mouse, so that mouse weight is uniformly distributed.Excipient, control are respectively coated to cropping area Group and test sample of the present invention, sample of the present invention includes embodiment 1, the totally 15 groups of compositions of embodiment 11~24.Wherein The excipient is 95% ethyl alcohol, and control group is 2% minoxidil, and test used herein is final with sample of the present invention Diluted 95% ethyl alcohol of use that concentration is 5mg/mL includes embodiment 1, the totally 15 groups of compositions of embodiment 11~24.It uses Above each test sample is well coated with to the drosal part of each mouse by brush, once a day.
Total treatment effect is determined and is assessed with four kinds of levels, and four kinds of levels are respectively about after experiment 20d and to using Compared before test sample, hair growth, recovery and hair color whether significantly improve (+++), improve (++), slightly improve (+) or Constant (-).
The assessment result that the composition of the present invention of table 4 induces growth period mouse hair and promotes
As listed by above-mentioned table 4, it can learn to apply in the preferred embodiment of the present invention 1,11~15 can promote hair The mouse for the composition that growth and/or color development thicken shows rapid hair growth in its cropping area and hair color thickens, table Composition in bright the application thicken for hair growth, color development have the function of it is positive.
The prior art of routine techniques dawn known to those skilled in the art in above-described embodiment, therefore herein no longer in detail It repeats.
Above said content is only the basic explanation under present inventive concept, and is appointed made by technical solution according to the present invention What equivalent transformation, is within the scope of protection of the invention.
In the description of this specification, reference term " one embodiment ", " some embodiments ", " example ", " specifically show The description of example " or " some examples " etc. means specific features, structure, material or spy described in conjunction with this embodiment or example Point is included at least one embodiment or example of the invention.In the present specification, schematic expression of the above terms are not It must be directed to identical embodiment or example.Moreover, particular features, structures, materials, or characteristics described can be in office It can be combined in any suitable manner in one or more embodiment or examples.In addition, without conflicting with each other, the skill of this field Art personnel can tie the feature of different embodiments or examples described in this specification and different embodiments or examples It closes and combines.
Although above-mentioned specific embodiment has shown that, is described and pointed out novel feature applied to various embodiments, It, can form and details to illustrated device or method it should be understood that under the premise of not departing from the spirit of present disclosure Carry out various omissions, substitutions and changes.In addition, above-mentioned various features and method can be used independently of each other, or can be with various sides Formula combination.All possible combination and sub-portfolio are intended to and fall within the scope of the present disclosure.Above-mentioned many embodiment packets Similar component is included, and therefore, these similar components are interchangeable in different implementation scenarios.Although in certain realities Apply scheme and embodiment it is disclosed in the context that the present invention, it is understood by one skilled in the art that the present invention can be beyond specific Disclosed embodiment extends to other alternate embodiments and/or application and its apparent modification and equivalent.Therefore, The present invention is not intended to be limited by the specific disclosure of this paper preferred embodiment.

Claims (10)

1. a kind of composition for promoting hair growth and/or color development to thicken, characterized by comprising:
1) aromatic amides shown in formula (I)；With
2) 1- (5- (tert-butyl) isoxazole -3- base) -3- (4- ((4- (3- morpholino propoxyl group) phenyl) acetenyl) phenyl) urea Pharmaceutically acceptable acid-addition salts, and
3) water-soluble fullerene；
Component 1 in the composition) in aromatic amides shown in formula (I), the R1And R2It is each independently hydrogen original Son, hydroxyl, C1-6Alkyl, C1-6Hydroxy alkyl, C1-6Carboxyalkyl, C1-6Mercaptoalkyl, C1-6Alkoxyalkyl, C2-6Alkenyl, C2-6 Alkynyl ,-C (O) OC1-6Alkyl ,-C (O) NHC1-6Alkyl, C1-6Aralkyl, cyano, nitro, halogen or amino, the C1-6Alkyl, C1-6Hydroxy alkyl, C1-6Carboxyalkyl, C1-6Mercaptoalkyl, C1-6Alkoxyalkyl, C2-6Alkenyl, C2-6Alkynyl ,-C (O) OC1-6Alkane Base ,-C (O) NHC1-6Alkyl or C1-6Aralkyl is optionally replaced by more than one halogen atom；
In formula (I), the R3、R4And R5It is each independently hydrogen atom, hydroxyl, C1-6Alkyl, C1-6Hydroxy alkyl, C1-6Alkoxy Alkyl, C2-6Alkenyl, C2-6Alkynyl, C1-6Aralkyl, cyano, nitro, halogen or amino；
In formula (I), the R6It independently is C1-6Alkylidene, C1-6Hydroxy alkylidene, C1-6Carboxyalkylene, C1-6Alkoxy alkylene Base, C6-10Arlydene ,-C (O) O- ,-C (O) OC1-3Alkylidene ,-C (O) NH- or-C (O) NHC1-3Alkylidene；
In formula (I), the R7It independently is hydrogen atom, C1-6Alkyl, C1-6Hydroxy alkyl, C1-6Carboxyalkyl, C1-6Mercaptoalkyl, C1-6Alkoxyalkyl, C2-6Alkenyl, C2-6Alkynyl ,-C (O) OC1-6Alkyl ,-C (O) NHC1-6Alkyl, C1-6Aralkyl, cyano, nitre Base, halogen or amino, the C1-6Alkyl, C1-6Hydroxy alkyl, C1-6Carboxyalkyl, C1-6Mercaptoalkyl, C1-6Alkoxyalkyl, C2-6Alkenyl, C2-6Alkynyl ,-C (O) OC1-6Alkyl ,-C (O) NHC1-6Alkyl or C1-6Aralkyl is optionally by more than one halogen Atom replaces；
In formula (I), the X independently is carbon atom or nitrogen-atoms；With
In formula (I), the Y independently is carbon atom, nitrogen-atoms, oxygen atom or sulphur atom；
In formula (I), the m and n are 0,1,2 or 3 each independently respectively, and 6 > m+n > 0.
2. composition according to claim 1, it is characterised in that:
The R1And R2It is each independently hydrogen atom, optionally by the substituted or unsubstituted C of more than one halogen atom1-6Alkane Base, C1-6Alkoxyalkyl ,-C (O) OC1-6Alkyl ,-C (O) NHC1-6Alkyl, cyano, nitro or amino；
The R3、R4And R5It is each independently hydrogen atom, hydroxyl, C1-6Alkyl, C1-6Alkoxyalkyl or halogen；
The R6It independently is C1-6Alkoxyalkylene ,-C (O) O- ,-C (O) OC1-3Alkylidene ,-C (O) NH- or-C (O) NHC1-3 Alkylidene；
The R7It independently is hydrogen atom, halogen, by the substituted or unsubstituted C of 1-3 halogen atom1-4Alkyl, C1-4Carboxyl alkane Base, C1-4Mercaptoalkyl ,-C (O) OC1-3Alkyl or-C (O) NHC1-3Alkyl；
The X is nitrogen-atoms, and the Y independently is nitrogen-atoms or sulphur atom；
The m and n is 1 or 2 each independently respectively.
3. composition according to claim 1 or 2, it is characterised in that: the 1- (5- (tert-butyl) isoxazole -3- base) - The pharmaceutically acceptable acid-addition salts of 3- (4- ((4- (3- morpholino propoxyl group) phenyl) acetenyl) phenyl) urea are inorganic acid Salt or acylate.
4. composition according to claim 3, it is characterised in that: the inorganic acid salt is hydrochloride, hydrobromate, hydrogen fluorine Hydrochlorate, hydriodate, perchlorate, chlorate, hypochlorite, hypobromite, bromate, hypoiodite, iodate, periodic acid Salt, carbonate, bicarbonate, nitrate, nitrite, nitroxylate, borate, metaborate, borous acid salt, metasilicic acid Salt, silicate, sulfate, disulfate, sulphite, bisulfites, pyrosulfate, persulfate, Hemisulphate, weight sulphur Hydrochlorate, rhodanate, peroxydisulfate, dithionate, thiosulfate, thio salt sulfate, metaphosphate, metaphosphorous acid Salt, phosphite, pyrophosphite, hypophosphites, dibasic alkaliine, dihydric phosphate, phosphate, pyrophosphate, metaphosphoric acid Salt, manganate, permanganate, molybdate, tungstates or their any combination.
5. composition according to claim 3, it is characterised in that: the acylate is formates, acetate, propionic acid Salt, butyrate, benzoate, malonate, succinate, acetonate, esilate, propane sulfonic acid salt, citrate, benzene sulphur Hydrochlorate, tosilate, L MALIC ACID salt, mesylate, propiolate, vinylacetate, L-TARTARIC ACID salt, fumaric acid Salt, lactate, Lactobionate, lactobionate, galacturonic hydrochlorate, cyclopentyl propionate, lauryl sulfate, acrylic acid Salt, cyclopentane propionate, glycerophosphate, methoxy benzoic acid salt, digluconate, gluconate, enanthate, double hydroxyls Naphthoate, salicylate, galactosaccharic acid salt, gluceptate, mandelate, naphthalene sulfonate, beta-naphthalenesulfonic-acid salt, oxalates, Maleate, tartrate, trifluoroacetate, fluoroform sulphonate, caproate, pivalate, glucuronate, laurel Hydrochlorate, phthalate, lauryl sulfate, nicotinate, cinnamate, oleate, palmitate, pamoate, pectic acid Salt, Phthalate, caprylate, pelargonate, cyclamate, phthalate, CYSTEAMINE HCL hydrochlorate, sorbate, pa not hydrochlorate, Mucate, glycine hydrochloride salt, napadisilate, polyvinyl sulfonate, sulfosalicylate, adipate, suberate, the last of the ten Heavenly stems Diacid salt, fourth hydroxyl acetate, alginates, ascorbate, erythorbate, aspartate, glutamate, acetyl second Hydrochlorate, borate, chloro-benzoate, camphor hydrochlorate, itaconate, l-camphor sulfonic acid salt, methyl benzoic acid salt, dinitro Benzoate, sulfamate, glutarate, hydroxymaleic acid salt, hydroxy benzoate, phenylacetate, isobutyrate, new penta Hydrochlorate, picrate, stearate, acylated amino group hydrochlorate, alginate or their any combination.
6. according to claim 1, composition described in 4 or 5, it is characterised in that: the component 3 in the composition) it is water-soluble rich Le alkene is fullerene-hyaluronic acid polymer.
7. composition according to claim 6, it is characterised in that: the preparation method of the water-soluble fullerene includes following At least one of step:
1) 5~20mL aminating agent and the mixing of 1~3g sodium hydroxide, add the ethyl alcohol of 60~100mL75~95%, stir evenly Afterwards, the parallel aminating reaction of organic solution 50mL containing fullerene is added dropwise；
2) organic solvent for removing upper layer, is evaporated off water and ethyl alcohol, then uses ethyl alcohol or methanol filtering and washing, is dried in vacuo to obtain amino richness Strangle alkene；
3) according to weight ratio 1:1~2:3~5:3~4 ratio by above-mentioned amino fullerene, hyaluronic acid, 1- ethyl-(3- bis- Dimethylaminopropyl) formamide or N of phosphinylidyne diimmonium salt hydrochlorate and n-hydroxysuccinimide in 500~1000 equivalents, N- Parallel polymerization reaction is uniformly mixed in dimethylformamide；
4) ethyl alcohol or acetone filtering and washing are used, unreacted impurity is removed, is dried in vacuo to obtain fullerene-hyaluronic acid polymer, That is water-soluble fullerene.
8. the method for promoting hair growth and/or color development to thicken comprising safe and effective to the application of the required position of required individual Any one of the claim 1~7 of the amount composition.
9. the application for promoting composition of any one of claim 1~7, it is characterised in that including
The hair growth and/or color development that the composition can be applied to the required position of individual needed for promoting thicken；And/or
The scalp of individual needed for the composition can be applied to be applied to is used to preventing and/or treat selected from being made up of The symptom of group: alopecia areata, telogen effluvim, growth period alopecia, Cicatricial baldness, alopecia cicatrisata；Hair Shaft Abnormalities, Clastothrix Disease, the loose syndrome of anagen hair, trichologia, traction property baldness；Infectious hair disorders, favus of the scalp, seborrhea, head Fur capsulitis and androgenetic alopecia；And/or
The composition can be applied to be applied to due to the fact that and the scalp and eyebrow of the required individual that undergoes trichomadesis Hair one or both of with reach treatment trichomadesis purpose: chemotherapy, hormone imbalances, scalp fungal infection, it is anticoagulant Blood agent is used for gout, depression, hypertension and cardiopathic drug.
10. a kind of pharmaceutical composition, it is characterised in that any one of claim 1~7 including safe and effective amount composition.
CN201910412196.8A 2019-05-17 2019-05-17 The composition and method and its application for promoting hair growth and/or color development to thicken Withdrawn CN110179821A (en)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113599307A (en) * 2021-08-17 2021-11-05 北京福纳康生物技术有限公司 Fullerene composition for hair care

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998022432A1 (en) * 1996-11-18 1998-05-28 Yamanouchi Pharmaceutical Co., Ltd. Novel acylamino-substituted acylanilide derivatives or pharmaceutical composition comprising the same
CN108558760A (en) * 2018-05-29 2018-09-21 杨国宏 A kind of aromatic amides and its preparation method and application

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998022432A1 (en) * 1996-11-18 1998-05-28 Yamanouchi Pharmaceutical Co., Ltd. Novel acylamino-substituted acylanilide derivatives or pharmaceutical composition comprising the same
CN108558760A (en) * 2018-05-29 2018-09-21 杨国宏 A kind of aromatic amides and its preparation method and application

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
刘静媛等: "新型长链芳香酰胺聚合物的合成", 《合成化学》 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113599307A (en) * 2021-08-17 2021-11-05 北京福纳康生物技术有限公司 Fullerene composition for hair care

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