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    • 专利摘要:
    The present invention discloses a novel dimethylpropanediol compound of formula (1) or a salt thereof having a hair regeneration action in a mammal and useful for promoting hair growth, stimulating hair growth, or preventing hair loss. [Formula 1] Wherein R 1 and R 2 each independently represent a C 1-30 hydrocarbon group which may be substituted, or 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen atoms, and may be substituted 5 or 6 -Heterocyclic, 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:KR19980018486A
    申请号:KR1019970037783
    申请日:1997-08-07
    公开日:1998-06-05
    发明作者:고지 고바야시；히로따다 후꾸니시；마사즈미 와따나베
    申请人:다께다 구니오；다께다 야꾸힝 고오교 가부시끼가이샤；
    IPC主号:
    专利说明:

    Dimethylpropanediol Compound
    The present invention relates to novel dimethylpropanediol compounds having hair regeneration action, in particular hair growth promoting or stimulating effect.
    Typically, hair regenerating tonic compositions containing various vitamins, amino acids, female hormones, and various components such as plant extracts having vasodilating or anti-inflammatory effects are intended to prevent and treat alopecia or prevent or treat hair loss. Has been used for 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 regenerating tonic compositions. Accordingly, it is an object of the present invention to provide novel compounds having a hair regeneration action, among them chemically synthesized compounds having a hair growth promoting or stimulating effect.
    The present inventors synthesized various compounds and investigated their hair promoting effects. As a result, it has now been found that the novel dimethylpropanediol compound having two methyl groups in the 2-position has an excellent hair growth promoting effect and low toxicity.
    That is, the present invention,
    (1) A novel 2,2-dimethylpropanediol compound of formula (1) or a salt thereof having a hair regeneration action, in particular, a hair growth promoting effect:
    [Wherein, R 1 and R 2 contain a C 1-30 hydrocarbon group which may be substituted independently of each other, or 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen atoms, and may be substituted 5 or 6 A membered heterocyclic group, R 3 is hydrogen, an alkyl group which may be substituted, 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) wherein R 1 and R 2 are each independently 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 group, C The compound according to (1), which is a 6-14 aryl group or a C 7-16 aralkyl group; When the groups are substituted, 1 to 5 substituents may be present at a substitutable position or positions, wherein the substituents are halogen atoms; C 3-8 cycloalkyl, hydroxy, mercapto, oxo, thioxo, cyano, carbamoyl, carboxyl, C 1-4 alkoxycarbonyl, sulfonyl, C 1-4 alkoxy, phenoxy, halogenphenoxy C 1-4 alkylthio, phenylthio, C 1-4 alkylsulfinyl, C 1-4 alkylsulfonyl, amino, C 1-6 acylamino, C 1-30 alkylamino, di-C 1-30 Alkylamino, C 1-5 acyl, benzoyl and C 1-10 haloalkyl groups; And oxygen, sulfur and nitrogen atoms can also be selected from the group consisting of 5- or 6-membered heterocyclic groups containing 1 to 4 heteroatoms selected from carbon atoms; It may be optionally substituted with 1 to 4 substituents selected from halogen atom, C 1-4 alkyl group and halogen phenoxy group, R 1 and R 2 are each C 3-8 cycloalkyl group, C 3-10 cycloalkenyl group, In case of a C 6-14 aryl group or a C 7-16 aralkyl group, 1 to 4 C 1-4 alkyl groups may be present at one or several positions in the ring,
    (3) the compound according to (1), wherein R 1 is a C 1-30 hydrocarbon group,
    (4) the compound as described in (1), wherein R 2 is a C 1-30 hydrocarbon group substituted with an amino group which may be substituted;
    (5) The compound according to (1), wherein R 2 is a group of the following 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],
    (6) the compound according to (5), wherein R 4 and R 5 are each independently a C 1-3 alkyl group,
    (7) the compound or salt thereof according to (1), which is 2,2-dimethyl-3-[(3'-dimethylaminopropyl) carbamoyloxy] -1- (octadecylcarbamoyloxy) propane; and
    (8) a process for producing the compound of formula (1) according to (1), wherein b is 1, comprising reacting the compound of formula (4) with the compound of formula (5);
    [Wherein Q 2 is a group or atom capable of activating a carbonyl group, other marks are as defined in (1)]
    HN (R 3 ) -R 2
    Wherein R 2 and R 3 are as defined in (1).
    The compound represented by the formula (1) and salts thereof have a very excellent hair growth promoting effect and, moreover, a hair loss prevention effect and dandruff and scalp itching effect. Thus, the term hair regeneration or hair regeneration action as used herein means at least one of the effects mentioned 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 naphthylmethyl.
    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 (eg, fluorine, chlorine, bromine and iodine) and C 3-8 cycloalkyl, hydroxy, mercapto, oxo, thiooxo, 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 substituents for hydrocarbon groups include amino; 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, tetradecylamino, pentadecyl Amino, hexadecylamino, heptadecylamino, octadecylamino, nonadecylamino, isicosylamino, henicosilamino, docosylamino, tricosylamino, tetracosylamino, pentacosylamino, hexacosylamino, heptacosylamino , Octacosylamino, nonacosylamino and triacontylamino), di-C 1-4 alkylamino (eg, dimethylamino, diethylamino, N-methyl-N-ethylamino and N-methyl-N -Propylamino); Substituted amino such as 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 1-4 heteroatoms which may be substituted and selected from oxygen, sulfur and nitrogen atoms, such as 5-pyrimidyl, 3- or 4-pyridazinyl, quinolyl, imidazoquinolyl and indolyl Containing 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 such 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 on 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 groups. 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 5-containing oxygen, sulfur, and 1 to 4 heteroatoms selected from nitrogen atoms, such as those mentioned above as substituents for the hydrocarbon groups represented by R 2 And 6-membered heterocyclic groups. Preferred examples of the heterocyclic group represented by R 1 and R 2 include 5- or 6-membered aromatic heterocyclic groups such as 2-, 3- or 4-pyridyl and 2-, 3- or 4-piperidyl and aliphatic hetero groups. Ventilation is 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:
    [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]
    Preferred are compounds or salts thereof. 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 have 1 to 3 substituents.
    In the above formula, R 4 and R 5 may be bonded to the connected nitrogen atom to form a nitrogen-containing heterocycle. 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 heterocycle 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) And 3- to 7-membered cyclic aminocarbonyl [eg, (aziridin-1-yl) carbonyl, (azetidin-1-yl) carbonyl, (pyrrolidin-1-yl) carbon 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. Preferred examples of 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 may also be used as an ammonium salt, an alkali metal salt (eg lithium, sodium and potassium salts), or a salt of an organic base (eg amino acids such as arginine and lysine). .
    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) reacts with Compound (II) of Formula 2 with an amine (III) of Formula 3 which may be substituted:
    [Wherein Y is a lower alkylene group which may be substituted and Q 1 is a group that can be easily replaced with nitrogen [halogen (eg chlorine, bromine and iodine), O-tosyl or O-mesyl], Other markers are 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 or atom (hereinafter referred to simply as a group) capable of activating a carbonyl group (such as halogen (eg, chlorine) or phenoxy), and the other markers are as previously defined]
    [Formula 5]
    HN (R 3 ) -R 2
    [Wherein, R 2 is -WZ (wherein W is a single bond or a lower (C 1-10 ) alkylene group, Z is a mono- or di-substituted amino group, or when W is a single bond, 5- or A six-membered nitrogen-containing heterocyclic group is bonded to a carbon atom), and the other markers are as previously defined].
    Mono- or di-substituted amino groups represented by Z include the same as those described as substituents for the hydrocarbon groups 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 a compound of Formula 9 with a compound 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 carried out 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, when water is included in the reaction system, 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 + It may be carried out for about 0.5 to 60 hours at a temperature of 100 ℃.
    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 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 substituents among them include halogen atoms (eg, fluorine, chlorine, bromine and iodine), C 1-6 alkyl-carbonyl (eg, methylcarbonyl, ethylcarbonyl and butylcarbonyl) and nitro The group is contained and the number of substituents is in the range of about 1-3.
    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 substituents among them include halogen atoms (eg, fluorine, chlorine, bromine and iodine), C 1-6 alkylcarbonyl (formyl, methylcarbonyl, ethylcarbonyl and butylcarbonyl) and nitro groups The number of substituents is in the range of about 1-3 pieces.
    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.
    Compound (I) has very low toxicity and therefore can be safely applied to mammals including humans, monkeys, dogs, cats and horses. Compound (I) is useful as an active ingredient for hair regeneration, in particular as a hair regeneration tonic composition, since it exhibits hair regeneration action, in particular hair growth promoting or stimulating effect. The hair regeneration tonic composition may contain not only compound (I) but also pharmaceutically or cosmetically acceptable excipients, carriers and adjuvant or other active ingredients in an amount which does not impair the effects of the present invention. The reinforcing agent includes a reinforcing agent designed to have a hair-generating effect or the like per se. Examples of such additional ingredients include plant extracts such as Swertia herb extract and ginseng extract; Vitamins such as vitamin B6, 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, Capro Hair-generating agents and hair-generating aids such as nium 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 oil, olive oil, squalene, petrolatum, liquid paraffin, higher fatty acid esters (eg isopropyl myristate, isocetyl octanoate), higher fatty acids (eg stearic acid) and higher alcohols (eg Oil components such as cetanol, cetostearyl alcohol); Polyhydric alcohols such as glycerin, propylene glycol, 1,3-butylene glycol, dipropylene glycol and polyethylene glycol; Esters of polyhydric alcohols such as glyceryl monostearate; Alkylsulfate, hydrogenated castor oil ethylene oxide addition product (polyoxyethylene hydrogenated castor oil), cocoacyl N-methyltaurate, polyoxyethylene alkyl ether, fatty acid diethanolamide, ethylene glycol fatty acid ester, stearyltrimethylammonium salt, Surfactants such as alkyltrimethylammonium chloride sorbitan monooleate and amine oxides; High molecular compounds such as carboxymethyl cellulose; Blockers such as hexametaphosphate and edetic acid and salts thereof (eg disodium edate); Spices; Antioxidants; Ultraviolet absorbers; dyes; ethanol; water; Wetting agents; Thickeners; And preservatives.
    In particular, the aforementioned antibacterial agents are preferably used in combination with compound (I).
    The hair regeneration tonic composition containing the compound (I) of the present invention can 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 It can be provided in the form of various products, such as a scalp therapeutic. The hair regeneration tonic composition can be prepared by mixing with various components and then dissolving or kneading the mixture using any apparatus and method conventionally used in the art.
    Compound (I) may be administered in the above dosage form at a concentration of 0.001 to 95 w / w%, preferably 0.01 to 30 w / w%.
    Since compound (I) has very low toxicity to humans as mentioned above, the hair regeneration tonic composition containing the compound (I) of the present invention is applied directly to the skin or hair or directly onto the skin or hair. It can be administered transdermally by nebulization. The dosage of the hair regeneration tonic composition 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 kg body weight. The dosage may be administered once a day or in two to four portions.
    The action and effect of the compound (I) of the present invention can be confirmed by measuring the hair regeneration effect of each compound and, if necessary, using it in practice based on the results obtained above.
    The present invention is explained in more detail with reference to the following reference examples, working examples and formulation examples.
    Reference 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 any insoluble matter. 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 g (35 ml) 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 (30.62 mmol) pyridine 15.31 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)
    It was confirmed that the compounds obtained according to the above Examples 1 and 2 had an excellent hair growth promoting effect compared to the control compound in the hair growth test using the mouse.
    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 2
    Sodium Lauryl Sulfate 0.1% by weight
    Hydrogenated Castor Oil Ethylene Oxide (40 mol) Additive 0.5% by weight
    Succinic acid
    Spices and dyes
    Integer balance
    (Production method)
    Hydrogenated castor oil ethylene oxide (40 moles) adduct and fragrance are dissolved in 95% ethanol, followed by addition of purified water. Then other ingredients are added thereto and dissolved in it under stirring to obtain a clear liquid lotion.
    Therefore, the present invention provides a novel compound (I) useful as a hair regeneration tonic composition by having a hair regeneration action on a mammal (including humans) in need of hair regeneration or hair loss prevention treatment. More specifically, the compound (I) of the present invention is very effective for promoting hair growth, stimulation of hair streak, prevention of hair loss, prevention of scalp itch and prevention of dandruff.
    权利要求:
    Claims (8)
    [1" claim-type="Currently amended] Compound of Formula 1 or a salt thereof:
    [Formula 1]
    Wherein R 1 and R 2 each independently represent a C 1-30 hydrocarbon group which may be substituted, or 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen atoms, and may be substituted 5 or 6 -Heterocyclic,
    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 compound of claim 1, wherein R 1 and R 2 are each independently 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 group, C 6-14 aryl group or C 7-16 aralkyl group; When the groups are substituted, 1 to 5 substituents may be present at a substitutable position or positions, the substituents being a halogen atom; C 3-8 cycloalkyl, hydroxy, mercapto, oxo, thioxo, cyano, carbamoyl, carboxyl, C 1-4 alkoxycarbonyl, sulfonyl, C 1-4 alkoxy, phenoxy, halogeno Phenoxy, C 1-4 alkylthio, phenylthio, C 1-4 alkylsulfinyl, C 1-4 alkylsulfonyl, amino, C 1-6 acylamino, C 1-30 alkylamino, di-C 1- 30 alkylamino, C 1-5 acyl, benzoyl and C 1-10 haloalkyl groups; And 5- or 6-membered heterocyclic groups containing from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen atoms in addition to carbon atoms, from 1 to 4 selected from halogen atoms, C 1-4 alkyl groups and halogenophenoxy groups. Is optionally substituted with 1 substituent, R 1 and R 2 are each C 3-8 cycloalkyl group, C 3-10 cycloalkenyl group, C 6-14 aryl group or C 7-16 aralkyl group, and 1 to 4 C 1 -4 alkyl groups in which the group or groups in the ring may be present.
    [3" claim-type="Currently amended] The compound of claim 1, wherein R 1 is a C 1-30 hydrocarbon group.
    [4" claim-type="Currently amended] The compound of claim 1, wherein R 2 is a C 1-30 hydrocarbon group substituted with an amino group which may be substituted.
    [5" claim-type="Currently amended] A compound according to claim 1, 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].
    [6" claim-type="Currently amended] 6. The compound of claim 5, wherein R 4 and R 5 are each independently C 1-3 alkyl group.
    [7" claim-type="Currently amended] The compound according to claim 1, which is 2,2-dimethyl-3-[(3'-dimethylaminopropyl) carbamoyloxy] -1- (octadecylcarbamoyloxy) propane or a salt thereof.
    [8" claim-type="Currently amended] A process for the production of a compound of formula 1 as claimed in claim 1 wherein b is 1 comprising reacting a compound of formula 4 with a compound of formula 5:
    [Formula 4]
    (Wherein Q 2 is a group or atom capable of activating a carbonyl group and other markers are as defined in claim 1)
    [Formula 5] HN (R 3 ) -R 2
    Wherein R 2 and R 3 are as defined in claim 1.
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    同族专利:
    公开号 | 公开日
    EP0823419A2|1998-02-11|
    TW397809B|2000-07-11|
    CA2212453A1|1998-02-09|
    EP0823419A3|2000-08-16|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1996-08-09|Priority to JP96-210875
    1996-08-09|Priority to JP21087596
    1997-08-07|Application filed by 다께다 구니오, 다께다 야꾸힝 고오교 가부시끼가이샤
    1998-06-05|Publication of KR19980018486A
    优先权:
    申请号 | 申请日 | 专利标题
    JP96-210875|1996-08-09|
    JP21087596|1996-08-09|
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