JP3033087B2 - Hair restorer - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a hair restorer and a carnitine derivative having a hair restorer.

[0002]

2. Description of the Related Art ATP, which is produced by metabolizing glucose through a glycolysis system and a TCA cycle, is usually used as energy required for hair growth. However, in androgenetic alopecia, phosphofructokinase (PFKase), one of the enzymes that catalyze the glycolysis, is inhibited by male hormones, and the supply of energy is suppressed.

[0003] Conventionally, hair tonics containing a pentadecanoic acid monoglyceride or carnitine [(3-carboxy-2-hydroxypropyltrimethylammonium hydroxide, inner salt)] as a pelargonate or heptadecanoate as an active ingredient are known. Kosho 63-4
No. 1363, Tokuhei 6-45533). Also, a hair restorer containing a linear aliphatic monohydric alcohol having an odd carbon chain length of 5 to 25 carbon atoms as an active ingredient is known (Japanese Patent Publication No. 63-41364). Further, Japanese Unexamined Patent Application Publication No.
No. 5 describes that γ-trialkylammonium-β-hydroxybutyrate chloride (carnitine hydrochloride) has a hair-growth action.

On the other hand, JP-A-5-339218 discloses undecanoyl-L-carnitine undecyl ester chloride [(R)-(2-undecanoyloxy-3-undecyloxycarbonylpropyl) trimethylammonium chloride] and the like. A carnitine derivative is disclosed. Although there is a description that these compounds have an antibacterial action, there is no description about a hair-growth action. Japanese Patent Application Laid-Open No. 5-339219 discloses that the same compound as disclosed in Japanese Patent Application Laid-Open No. 5-339218 has an antifungal effect, but there is no description regarding hair growth effect. Further, Japanese Patent Application Laid-Open No. 55-167262 describes that propionylcarnitine isopropyl ester and isobutyrylcarnitine isobutyl ester are useful as a therapeutic agent for low myocardial contraction and the like, but there is no description on hair-growth action.

[0005]

SUMMARY OF THE INVENTION The present invention provides an excellent hair restorer containing a carnitine derivative as an active ingredient.

[0006]

According to the present invention, there is provided a compound represented by the general formula [I]:

[0007]

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[Wherein, R ^{1 to} R ³ are an alkyl group having 1 to 6 carbon atoms, R ⁴ is a substituted or unsubstituted aliphatic acyl group having 3 to 31 carbon atoms, and R ⁵ is a substituted or unsubstituted carbon atom. An alkyl group having 3 to 31 or a substituted or unsubstituted alkenyl group having 3 to 31 carbon atoms, X ⁻ represents a pharmacologically acceptable acid anion. And a hair restorer comprising a carnitine derivative of formula (I) as an active ingredient.

The carnitine derivative [I] according to the present invention comprises
It has an excellent hair restoring action as compared with conventional hair restoring agents and is useful as a hair restoring agent.

As specific examples of the carnitine derivative [I] which is the active ingredient of the present invention, R ^{1 to} R ³ are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, 3-pentyl, An alkyl group having 1 to 6 carbon atoms such as a methylbutyl group, a hexyl group or an isohexyl group, wherein the aliphatic acyl group having 3 to 31 carbon atoms in R ⁴ is a propionyl group, a butyryl group, an isobutyryl group, a crotonoyl group, a methacryloyl group, or a valeryl group; Group, isovaleryl group, pivaloyl group, hexanoyl group, 4-methylvaleryl group, sorbinoyl group, heptanoyl group, octanoyl group, 2-propylvaleryl group, nonanoyl group, decanoyl group, undecanoyl group, 10-undecenoyl group,
Dodecanoyl group, tridecanoyl group, tetradecanoyl group, pentadecanoyl group, hexadecanoyl group, heptadecanoyl group, octadecanoyl group, oleoyl group, eridoyl group, linoleoyl group, linolenoyl group, nonadecanoyl group, 2,6,10 , 14-Tetramethylpentadecanoyl, icosanoyl, 3,7,11,15
-Tetramethylhexadecanoyl group, arachidoyl group,
Hen'ikosanoiru group, docosanoyl group, Torikosanoiru group, Tetorakosanoiru group, a Pentakosanoiru group, Hekisakosanoiru group, Heputakosanoiru group, Okutakosanoiru group, Nonakosanoiru group, triacontanyl alkanoyl group or hen triacontanyl alkanoyl group, R carbons at the ⁵ 3
To 31 are propyl, isopropyl, butyl, isobutyl, 1-methylpropyl, 1,1
-Dimethylethyl group, pentyl group, 1-methylbutyl group, 2-methylbutyl group, 3-methylbutyl group, 1,1
-Dimethylpropyl group, 1,2-dimethylpropyl group,
2,2-dimethylpropyl group, 1-ethylpropyl group,
2-ethylpropyl group, hexyl group, isohexyl group,
1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl Group, 2,2-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethyl-1-methylpropyl group, 1-
Ethyl-2-methylpropyl group, 2-ethyl-1-methylpropyl group, 2-ethyl-2-methylpropyl group, 1
-Methyl-2-ethylpropyl group, 1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group,
Heptyl, octyl, 2-propylpentyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, henycosyl , docosyl group, tricosyl group, tetracosyl group, pentacosyl group, hexacosyl group, heptacosyl group, octacosyl group, nonacosyl group, a triacontyl group or hentriacontyl group, an alkenyl group of 3-31 carbon atoms in R ⁵ is 2-
Propenyl group, 1-methylethynyl group, 10-undecenyl group, 14-pentadecenyl group, 3,7,11,15
-Tetramethyl-2-hexadecenyl group, 20-henicosenyl group, 30-hentriacontenyl group and the like,
An aliphatic acyl group having 3 to 31 carbon atoms for R ⁴ or R ⁵
A C3-C31 alkyl group or C3
A substituent of an alkenyl group of from 31 to a hydroxyl group, or a methoxycarbonyl group, an ethoxycarbonyl group, a propyloxycarbonyl group, an isopropyloxycarbonyl group, a butyloxycarbonyl group, an isobutyloxycarbonyl group, a pentyloxycarbonyl group, or a 3-methylbutyl Examples of the compound include an alkoxycarbonyl group having 2 to 7 carbon atoms, such as an oxycarbonyl group, a hexyloxycarbonyl group, an isohexyloxycarbonyl group, a heptyloxycarbonyl group, and 5-methylhexyloxycarbonyl.

Examples of preferred compounds [I] include R ^{1 to} R ³
Is a compound having 1 to 4 carbon atoms, R ⁴ is an aliphatic acyl group having 3 to 18 carbon atoms, and R ⁵ is an alkyl group or an alkenyl group having 3 to 21 carbon atoms, more specifically,
For example, when R ⁴ is a propionyl group, an isobutyryl group, a valeryl group, a hexanoyl group, a 4-methylvaleryl group, a heptanoyl group, an octanoyl group, a 2-propylvaleryl group, a nonanoyl group, an undecanoyl group, a 10-undecenoyl group, a dodecanoyl group, a tridecanoyl group Group, tetradecanoyl group, pentadecanoyl group, hexadecanoyl group, heptadecanoyl group, linoleoyl group or 3-ethoxycarbonylpropionyl group, R ⁵ is propyl, isobutyl, pentyl, 1-ethylpropyl, 1-
Methylbutyl group, 2-methylbutyl group, isohexyl group, heptyl group, 2-propylpentyl group, nonyl group,
Decyl group, undecyl group, dodecyl group, tridecyl group,
Tetradecyl group, pentadecyl group, henicosyl group, 1
A compound which is a 0-undecenyl group, a 3-ethoxycarbonylpropionyl group or a 12-hydroxydodecyl group. Among them, R ⁴ is a propionyl group, an isobutyryl group, a valeryl group, a hexanoyl group, a 4-methylvaleryl group, a heptanoyl group, a 2-propylvaleryl group, a nonanoyl group, an undecanoyl group, a 10-undecenoyl group, a tridecanoyl group, and a tetradecanoyl group. Decanoyl group, pentadecanoyl group, hexadecanoyl group, heptadecanoyl group or linoleoyl group, R ⁵ is propyl, pentyl, 2-methylbutyl, isohexyl, heptyl, nonyl, decyl, undecyl, dodecyl Group,
Compounds which are a tridecyl, tetradecyl, pentadecyl, henicosyl or 10-undecenyl group are preferred.

Further preferred examples of the compound [I] include R ¹
To R ³ is an alkyl group having 1 to 4 carbon atoms, R ⁴ is 3 carbon
An aliphatic acyl group of 15 and a compound wherein R ⁵ is an alkyl group having 3 to 15 carbon atoms;
⁴ is propionyl group, isobutyryl group, valeryl group, 4
- methylvaleryl group, hexanoyl group, heptanoyl group, undecanoyl group, 10-undecenoyl group, tridecanoyl group or pentadecanoyl group, R ⁵ is propyl group, pentyl group, 2-methylbutyl group, heptyl group, nonyl group, undecyl group, dodecyl A compound which is a group, tridecyl group, tetradecyl group or pentadecyl group.

Another preferred compound is the sum (a +) of the number of carbon atoms (= a) of the aliphatic acyl group in R ⁴ and the number of carbon atoms (= b) of the alkyl group or alkenyl group in R ⁵ .
Those wherein b) is 6 to 34, especially 14 to 26 can be mentioned. Specific examples of the combination of a and b include, for example, (1) a + b = 6, (a, b) =
(3,3), (2) a + b = 8,
(A, b) = (5, 3), (3) a + b = 12
Are (a, b) = (5,7), (4) a
+ B = 14, (a, b) = (3,11) or (11,3), (5) a + b = 15
(A, b) = (4,11), (6) a + b = 1
6 is (a, b) = (3,13), (5,1
1), (7,9), (11,5) or (13,3), (7) a + b = 17, (a, b) =
(4,13), (5,12) or (6,11), (8) a + b = 18, (a, b) = (3,1
5), (4,14), (5,13), (6,12),
(7,11), (9,9), (11,7), (13,
(5) or (15,3), (9) a + b = 19, (a, b) = (4,15), (6,13),
(8,11), (11,8), (13,6), (15,
4) or (16,3), (10) a + b = 20, (a, b) = (5,15), (7,13),
(9, 11), (11, 9) or (13, 7), (11) a + b = 21, (a, b) = (8, 1)
3), (16,5) or (18,3), (12)
For a + b = 22, (a, b) = (7,15),
(11,11) or (13,9), (13) a +
b = 23, (a, b) = (8,15), (14) a + b = 25, (a, b) = (13,
12), (14, 11) or (16, 9),
(15) When a + b = 26, (a, b) = (13,1
3) or (15, 11), (16) a + b = 27
Are (a, b) = (16,11), (1
7) For a + b = 28, (a, b) = (15,1
3), (17,11) or (16,12),
(18) When a + b = 30, (a, b) = (15,1
5), (19) a + b = 34, (a,
b) = (13, 21) can be given respectively.

Examples of other preferred compounds [I] include R ^1-
R ³ is an alkyl group having 1 to 6 carbon atoms, and R ⁴ is an alkyl group having ⁴ to 3 carbon atoms.
A compound in which 1 aliphatic acyl group and R ⁵ are an alkyl group having 11 to 31 carbon atoms.

Further, examples of other preferred compounds [I] include those wherein the aliphatic acyl group for R ⁴ or the alkyl group for R ⁵ is a branched aliphatic acyl group or alkyl group having 4 to 15 carbon atoms. And among them, a compound in which a methyl group is branched to form a branched chain is preferable. Further, the position at which the methyl group is branched is preferably an even-numbered position of the main carbon chain, and particularly preferably the even-numbered position is a position adjacent to the terminal carbon atom of the main carbon chain.

In the carnitine derivative [I] which is the active ingredient of the present invention, the aliphatic acyl group represented by R ⁴ has an even carbon chain length, an odd carbon chain length, or a linear type. And those of a branched chain type, or a saturated type and an unsaturated type. Examples of the alkyl group or alkenyl group for R ⁵ include those having an even-numbered carbon chain length, those having an odd-numbered carbon chain length, and those of a straight-chain type and a branched-chain type.

Examples of the most preferred compound [I] are (1) R
^{1 to} R ³ are a methyl group, R ⁴ is a pentadecanoyl group, R ⁵
Is an undecyl group; (2) R ^{1 to} R ³ are methyl groups, and R ⁴ is 4
A methylvaleryl group, R ⁵ is an undecyl group; (3) R ¹ to
R ³ is a methyl group, R ⁴ is valeryl group, R ⁵ is tridecyl group; (4) R ¹ ~R ³ is a methyl group, R ⁴ is a propionyl group, R ⁵ is undecyl group; (5) R ¹ ~R ³ Is a methyl group,
R ⁴ is a tridecanoyl group, R ⁵ is a pentyl group; (6) R ¹
To R ³ is a methyl group, R ⁴ is heptanoyl group, R ⁵ is nonyl group; (7) R ¹ ~R ³ is a methyl group, R ⁴ is heptanoyl group, R ⁵ is tridecyl group; (8) R ¹ ~R ³ is a methyl group,
R ⁴ is an undecanoyl group, R ⁵ is a pentyl group; (9) R ¹
To R ³ is a methyl group, R ⁴ is valeryl group, R ⁵ is undecyl group; (10) R ¹ ~R ³ is a methyl group, R ⁴ is undecanoyl group, R ⁵ is heptyl group; (11) R ¹ ~R ³ is a methyl group,
R ⁴ is a tridecanoyl group, R ⁵ is a heptyl group; (12) R ¹
To R ³ is a methyl group, R ⁴ is an isobutyryl group, R ⁵ is tridecyl group; (13) R ¹ ~R ³ is a methyl group, R ⁴ is a propionyl group, R ⁵ is tridecyl group; (14) R ¹ ~R ³ is a methyl group, R ⁴ is a 4-methylvaleryl group, R ⁵ is a dodecyl group;
(15) R ^{1 to} R ³ are a methyl group, R ⁴ is a 4-methylvaleryl group, R ⁵ is a tridecyl group; (16) R ^{1 to} R ³ are a methyl group,
R ⁴ is an isobutyryl group, R ⁵ is tetradecyl group; (17) R
¹ to R ³ is a methyl group, R ⁴ is valeryl group, R ⁵ is pentadecyl group; (18) R ^{1 ~R 3} is a methyl group, R ⁴ is a propionyl group, R ⁵ is pentadecyl group; (19) R ¹ ~ R ³ is a methyl group, R ⁴ is a hexanoyl group, and R ⁵ is an undecyl group; among these, compounds other than (2) and (7) are novel compounds.

The carnitine derivative [I] according to the present invention comprises
Carnitine (3-carboxy-2-hydroxypropyltrimethylammonium hydroxide, inner salt) 2
Asymmetric carbon atom and R ¹ , R ² , R ³ , R ⁴ or R ⁵
And optically isomers based on the asymmetric carbon atom present in the above and any mixtures thereof. Among them, those in which the asymmetric carbon atom at the 2-position of carnitine has the R configuration are particularly preferable in terms of medicinal effect.

In the present invention, the alkyl group having 1 to 6 carbon atoms (R ^{1 to} R ³ ) has 1 to 4 carbon atoms, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group,
A butyl group, an isobutyl group and the like are more preferred, and a methyl group is most preferred. As the alkoxycarbonyl group having 2 to 7 carbon atoms which is a substituent of the aliphatic acyl group for R ⁴ or the alkyl group or alkenyl group for R ⁵ , those having 2 to 5 carbon atoms are more preferable, and an ethoxycarbonyl group is particularly preferable. . Examples of the pharmacologically acceptable acid anion (X ⁻ ) include, for example, chloride,
Acetate, citrate, nicotinate, nitrate,
Sulfonate and salicylate can be mentioned. Of these, chloride, nicotinate, nitrate and sulfonate are preferable, and chloride, nicotinate and nitrate are particularly preferable.

The hair restorer of the present invention can be used in various forms such as a hair tonic, a hair tonic, a hair lotion, a hair cream, a shampoo, and a rinse according to a conventional method. In addition to the carnitine derivative which is the active ingredient of the present invention, those usually used for the production thereof may be added to these hair restorers. For example, distilled water as a base,
Alcohols, polyhydric alcohols, surfactants, oils and fats are blended, and as active ingredients vitamins, hormones, vasodilators, amino acids, anti-inflammatory agents, skin function enhancers, keratolytic agents, etc. What is blended with a known hair restorer can be blended at the same time.

The compounding amount of the active ingredient of the present invention is not particularly limited, and may be appropriately added according to the amount and type of other compounding agents such as a base. A suitable amount is about weight%.

The carnitine derivative [I] of the present invention is, for example, a compound represented by the general formula [II]

[0023]

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(Wherein the symbols have the same meanings as described above) by converting the compound represented by the general formula [III]

[0025]

Embedded image

(Wherein R ⁵ has the same meaning as described above;
Represents a halogen atom. )).

The carnitine derivative of the present invention [I]
Is, for example, the general formula [II]

[0028]

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(Wherein the symbols have the same meanings as described above) or a reactive derivative of the carboxyl group thereof represented by the general formula [IV]

[0030]

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(Wherein the symbols have the same meanings as described above).

The condensation reaction of the compound [II] with the compound [III] and the reactive derivative of the compound [II] with the compound [I
V] in a suitable solvent (eg, dimethylformamide, tetrahydrofuran, methylene chloride, ethyl acetate, acetonitrile, etc.) in a deoxidizing agent (eg, an alkali metal hydroxide, an alkali metal carbonate, an alkali metal hydrogencarbonate, N 2 , N-dialkylaniline, pyridine, N-alkylmorpholine, tri-lower alkylamine, etc.) in the presence or absence. Reaction is 0 ° C
It proceeds favorably at a temperature of ６０60 ° C.

In the condensation reaction of the compound [II] and the compound [IV], a condensing agent (eg, N, N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholino) is used in the same solvent as used in the above condensation reaction. Carbodiimide, N-ethyl-N ′-(3-dimethylaminopropyl) carbodiimide or the like). The reaction suitably proceeds at a temperature of -30C to 30C.

The reactive derivative of the compound [II] includes
Corresponding acid halides, mixed acid anhydrides, active esters and the like can be used.

[0035] Thus carnitine derivatives of the present invention obtained [I], optionally, for example, pharmacologically alkali metal salts of acceptable acids (e.g., sodium salt, potassium salt, etc.) is reacted with, X ^- a It can be converted to the anion of another pharmacologically acceptable acid.

The starting compound [II] has the general formula [V]

[0037]

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The carnitine derivative represented by the general formula [VI]

[0039]

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(Wherein the symbols have the same meanings as described above), and can be produced by a conventional method, for example, in the same manner as in the above condensation reaction.

[0041]

[Action]

Experimental Example 1 (Hair-growing action of shaved mice) (Method) The back of 10 male C3H / HeN mice (6 weeks old), 10 rats per group, was shaved 3 days before the start of application of the sample with an electric clipper and then a safety razor. 0.1% of a 2% (W / V) or 0.5% (W / V) ethanol solution or ethanol (control group) of the specimen is applied to the shaved site once a day for 5 days a week for 30 days from 7 weeks of age. did. The evaluation of the hair growth effect was performed by scoring the degree of hair growth into the following six levels.

Hair growth is not observed: 0 Hard hair grows in less than 25% of shaved area: 1 Hard hair grows in 25% or more and less than 50% of shaved area: 2 Hard hair grows in shaved area Hair growth in 50% or more and less than 75% of hair: 3 Hair growth in 75% or more and less than 100% of shaved site: 4 Hair growth in 100% of shaved site: 5 (Results) It is as described in Tables 1 and 2 below. Table 1 shows the results obtained using a 2% (W / V) ethanol solution of the sample, and Table 2 shows the result obtained with 0.5% of the sample.
(W / V) The result obtained using the ethanol solution is shown.

[0043]

[Table 1]

[0044]

[Table 2]

[0045]

[Table 3]

[0046]

[Table 4]

[0047]

【Example】

Example 1 (R)-(3-carboxy-2-tridecanoyloxypropyl) trimethylammonium chloride (1.5
g; 3.81 mmol) of dimethylformamide 30 m
To the suspension was added triethylamine (0.53 ml; 3.81).
mmol), 1-bromotridecane (5.0 g;
0 mmol) in order, and then, under argon atmosphere, 50-6
Stir at 0 ° C. for 23 hours. The reaction solvent was distilled off under reduced pressure, and 20 ml of diethyl ether was added to the residue. After stirring at room temperature, the insoluble matter was collected by filtration, washed with diethyl ether, dried, and crude (R)-(2-tridecanoyloxy- 2.5 g of (3-tridecyloxycarbonylpropyl) trimethylammonium bromide are obtained as a colorless solid. 2.5g of this product
50 ml of water was added to the mixture, and the mixture was stirred at room temperature for 1 hour, and then extracted with tetrahydrofuran-ethyl acetate (1: 1). 100 ml of saturated saline and 30 ml of water were added to the extracted organic layer,
After stirring at room temperature for 18 hours, the organic layer is separated. The organic layer was washed with saturated saline and water, the solvent was distilled off under reduced pressure, azeotroped with ethyl acetate, and dried at room temperature under reduced pressure to obtain 1.75 g of a crude target product.
Get. This product was recrystallized from ethyl acetate to give (R)-(2-
Tridecanoyloxy-3-tridecyloxycarbonylpropyl) trimethylammonium chloride 1.58
g are obtained as colorless crystals.

M. p. 146-147 ° C IR (Nujol) cm ^-1 : 735, 1725 NMR (CDCl ₃ ) δ: 0.88 (6H, t, J =
6.8 Hz), 1.26 (38H, brs), 1.55
-1.65 (4H, m), 2.31-2.36 (2H,
m), 2.80 (1H, dd, J = 17, 5.9H)
z), 2.85 (1H, dd, J = 17, 6.8H
z), 3.52 (9H, s), 4.01-4.13 (3
H, m), 4.32 (1H, brd), 5.64-5.
71 (1H, m).

Example 2 (R)-(3-Carboxy-2-pentadecanoyloxypropyl) trimethylammonium chloride was treated in the same manner as in Example 1 to give (R)-(2-pentadecanoyloxy-3). -Tridecyloxycarbonylpropyl) trimethylammonium chloride is obtained.

M. p. : 153-154 ° C IR (Nujol) cm ^-1 : 1760,1740,17
30 NMR (CDCl ₃ ) δ: 0.88 (6H, t, J =
6.8 Hz), 1.26 (42H, brs), 1.55
-1.65 (4H, m), 2.30-2.36 (2H,
m), 2.80 (1H, dd, J = 17, 6.0H
z), 2.85 (1H, dd, J = 17, 6.8H
z), 3.53 (9H, s), 4.03-4.12 (3
H, m), 4.34 (brd), 5.64-5.71.
(1H, m).

Example 3 (R)-(3-carboxy-2-pentadecanoyloxypropyl) trimethylammonium chloride (2 g;
Oxalyl chloride (1.41 g; 11.1 mmol) is added dropwise to a suspension of 4.74 mmol) in 10 ml of methylene chloride under ice-cooling, and the mixture is stirred at room temperature for 2.5 hours. After evaporating the reaction solvent under reduced pressure, azeotropic distillation with toluene (15 ml × 2) is performed to obtain a crude acid chloride as a colorless solid. Add 10 ml of methylene chloride to the whole amount of this product, and cool with ice under an argon atmosphere.
1-undecanol (1.49 ml; 7.2 mmol)
Is dropped. After stirring the reaction solution for 2.5 hours on ice and 30 minutes at room temperature, the solvent is distilled off. Diethyl ether 6 in the residue
0 ml was added, and the mixture was stirred at room temperature for 15 minutes. The insoluble matter was collected by filtration, washed with diethyl ether, and dried to obtain 2.62 g of a crude target product as a colorless solid. 50 ml of water was added to 2.62 g of the crude product, and the mixture was stirred at room temperature for 1 hour, extracted with tetrahydrofuran-ethyl acetate (1: 1), the extract was distilled off under reduced pressure, azeotroped with ethyl acetate, and the residual solid was acetonitrile. Further recrystallization gives 2.0 g of (R)-(2-pentadecanoyloxy-3-undecyloxycarbonylpropyl) trimethylammonium chloride as colorless crystals.

M. p. : 152-153 ° C IR (Nujol) cm ^-1 : 1760, 1740, 17
30 NMR (CDCl ₃ ) δ: 0.88 (6H, t, J =
6.7Hz), 1.26 (38H, brs), 1.54
-1.66 (4H, m), 2.30-2.36 (2H,
m), 2.80 (1H, dd, J = 17, 5.9H)
z), 2.85 (1H, dd, J = 17, 6.7H
z), 3.53 (9H, s), 4.03-4.11 (3
H, m), 4.34 (brd), 5.64-5.71.
(1H, m).

Examples 4 to 5 By treating the corresponding starting compounds in the same manner as in Example 3, the compounds shown in Table 3 below are obtained.

[0054]

[Table 5]

Example 6 (R)-(2-Pentadecanoyloxy-3-tridecyloxycarbonylpropyl) trimethylammonium chloride obtained in Example 2 (1.5 g; 2.48 mmol)
l) and sodium nicotinate (3.0 g; 20.7 m)
mol) of tetrahydrofuran-ethyl acetate (1: 1)
15 ml of water is added to 30 ml of the suspension, and the mixture is stirred at room temperature for 46.5 hours. The organic layer is separated, washed with 10 ml of water, the solvent is distilled off under reduced pressure, and azeotroped with ethyl acetate. The residual oil was dissolved in 20 ml of diethyl ether, a trace amount of insolubles was removed by filtration, diethyl ether was distilled off under reduced pressure, and the residue was dried at room temperature under reduced pressure to obtain (R)-(2-pentadecanoyloxy-3).
1.62 g of (tridecyloxycarbonylpropyl) trimethylammonium nicotinate are obtained as a colorless solid.

M. p. : 62-68 ° C IR (Nujol) cm ^-1 : 1740,1610 NMR (CDCl ₃ ) δ: 0.88 (6H, t, J =
6.7 Hz), 1.26 (42H, brs), 1.56
-1.63 (4H, m), 2.25-2.31 (2H,
m), 2.77 (1H, dd, J = 17, 5.7H
z), 2.82 (1H, dd, J = 17, 6.9H
z), 3.49 (9H, s), 3.97-4.18 (3
H, m), 4.35 (1H, brd), 5.63-5.
71 (1H, m), 7.25 (1H, dd, J = 7.
7, 4.8 Hz), 8.30 (1H, dt, J = 7.
7, 1.8 Hz), 8.56 (1H, m), 9.23
(1H, brs).

Examples 7 to 11 By treating the corresponding starting compounds in the same manner as in Examples 1 or 3, the compounds shown in Tables 4 and 5 below are obtained.

[0058]

[Table 6]

[0059]

[Table 7]

Example 12 The (R)-(2-tridecanoyloxy) obtained in Example 1 was obtained.
(R)-(2-Tridecanoyloxy-3-tridecyloxycarbonylpropyl) trimethylammonium nicotinate was treated with 3-tridecyloxycarbonylpropyl) trimethylammonium chloride in the same manner as in Example 6 to give an oily substance. Get as.

IR (Neat) cm ^-1 : 2920, 28
40,1740 NMR (CDCl ₃ ) δ: 0.88 (6H, t, J =
7.0Hz), 1.26 (38H, s), 1.55-
1.65 (4H, m), 2.28 (2H, t, J = 7.
3Hz), 2.76 (1H, dd, J = 5.5, 17H)
z), 2.85 (1H, dd, J = 7.3, 17H
z), 3.46 (9H, s), 4.00-4.20 (3
H, m), 4.34 (1H, d, J = 14 Hz), 5.
65-5.68 (1H, m), 7.20-7.25 (1
H, m), 8.31 (1H, dt, J = 7.8, 1.9)
Hz), 8.56 (1H, dd, J = 1.1, 4.6H)
z), 9.22 (1H, s).

Examples 13 to 14 By treating the corresponding starting compounds in the same manner as in Examples 1 or 3, the compounds shown in Table 6 below are obtained.

[0063]

[Table 8]

Example 15 (R)-(3-Carboxy-2-propionyloxypropyl) trimethylammonium chloride and 1-bromoundecane were treated in the same manner as in Example 1 (however, when saturated saline was replaced with saturated sodium nitrate). Instead of an aqueous solution, the reaction time is 20 minutes) to obtain (R)-(3-undecyloxycarbonyl-2-propionyloxypropyl) trimethylammonium nitrate.

M. p. : 68-70 ° C IR (Nujol) cm ^-1 : 1740 NMR (CDCl ₃ ) δ: 0.88 (3H, t, J =
6.9 Hz), 1.14 (3H, t, J = 7.5H)
z), 1.25 (16H, brs), 1.55-1.6
5 (2H, m), 2.39 (2H, q, J = 7.5H
z), 2.75 (1H, dd, J = 17, 5.9H
z), 2.82 (1H, dd, J = 17, 6.7H
z), 3.35 (9H, s), 4.00-4.10 (4
H, m), 5.60-5.70 (1H, m).

Example 16 (R)-(3-Carboxy-2-propionyloxypropyl) trimethylammonium chloride and 1-bromotridecane were treated in the same manner as in Example 1 except that a saturated saline solution was (Instead of aqueous sodium)) to give (R)-(2-propionyloxy-3-tridecyloxycarbonylpropyl) trimethylammonium nitrate.

M. p. : 79-80 ° C IR (Nujol) cm ^-1 : 1740 NMR (CDCl ₃ ) δ: 0.88 (3H, t, J =
7.0 Hz), 1.14 (3H, t, J = 7.3H)
z), 1.26 (20H, brs), 1.55-1.6
5 (2H, m), 2.39 (2H, q, J = 7.3H
z), 2.75 (1H, dd, J = 17, 5.9H
z), 2.82 (1H, dd, J = 17, 6.6H
z), 3.35 (9H, s), 4.00 (2H, d, J
= 5.1 Hz), 4.00-4.10 (2H, m),
5.60-5.70 (1H, m).

Example 17 (R)-(3-Carboxy-2-propionyloxypropyl) trimethylammonium chloride and 1-pentadecanol were treated in the same manner as in Example 3 (provided that the extract was treated with an aqueous sodium nitrate solution). Process)
(R)-(2-propionyloxy-3-pentadecyloxycarbonylpropyl) trimethylammonium nitrate is obtained.

M. p. : 83.5-84.5 ° C IR (Nujol) cm ^-1 : 1740 NMR (CDCl ₃ ) δ: 0.88 (3H, t, J =
7.0 Hz), 1.14 (3H, t, J = 7.6H)
z), 1.26 (24H, brs), 1.55-1.6
5 (2H, m), 2.39 (2H, q, J = 7.7H
z), 2.75 (1H, dd, J = 17, 5.9H
z), 2.82 (1H, dd, J = 17, 6.6H
z), 3.35 (9H, s), 4.00-4.10 (4
H, m), 5.60-5.70 (1H, m).

Examples 18 to 26 By treating the corresponding starting compounds in the same manner as in Examples 1, 3 or 15, the compounds shown in Tables 7 to 10 below are obtained.

[0071]

[Table 9]

[0072]

[Table 10]

[0073]

[Table 11]

[0074]

[Table 12]

Example 27 By treating (R)-(3-carboxy-2-pentanoyloxypropyl) trimethylammonium chloride and 1-bromotridecane in the same manner as in Example 1 (however, a saturated saline solution was saturated). (R) (R)-(3-tridecyloxycarbonyl-2)
-Pentanoyloxypropyl) trimethylammonium 1/2 sulfonate is obtained.

M. p. :> 57 ° C IR (Nujol) cm ^-1 : 1740 NMR (CDCl ₃ ) δ: 0.88 (3H, t, J =
6.9 Hz), 0.90 (3H, t, J = 7.3H)
z), 1.26-1.38 (22H, m), 1.50-
1.61 (4H, m), 2.29 (2H, t, J = 7.
6Hz), 2.83 (1H, dd, J = 17, 7.2H)
z), 3.08 (1H, dd, J = 17, 4.5H
z), 3.44 (9H, s), 3.76 (1H, dd,
J = 14,9.6 Hz), 3.95-4.03 (2H,
m), 4.51 (1H, brd), 5.69-5.77.
(1H, m).

Examples 28 to 92 The corresponding starting compounds were prepared in Examples 1, 3, 6, 15, 17 or 2.
By treating in the same manner as in 7, compounds shown in the following Tables 11 to 42 are obtained.

[0078]

[Table 13]

[0079]

[Table 14]

[0080]

[Table 15]

[0081]

[Table 16]

[0082]

[Table 17]

[0083]

[Table 18]

[0084]

[Table 19]

[0085]

[Table 20]

[0086]

[Table 21]

[0087]

[Table 22]

[0088]

[Table 23]

[0089]

[Table 24]

[0090]

[Table 25]

[0091]

[Table 26]

[0092]

[Table 27]

[0093]

[Table 28]

[0094]

[Table 29]

[0095]

[Table 30]

[0096]

[Table 31]

[0097]

[Table 32]

[0098]

[Table 33]

[0099]

[Table 34]

[0100]

[Table 35]

[0101]

[Table 36]

[0102]

[Table 37]

[0103]

[Table 38]

[0104]

[Table 39]

[0105]

[Table 40]

[0106]

[Table 41]

[0107]

[Table 42]

[0108]

[Table 43]

[0109]

[Table 44]

Reference Example 1 n-pentadecanoic acid (25 g; 103 mmol) and thionyl chloride (3.15 g; 26.5 mmol) were added to 75-8.
After stirring at 0 ° C. for 3 hours, the temperature was raised to 60 ° C., and L-carnitine (4.27 g; 26.5 mmol) in trichloroacetic acid 2 was added.
Add 5 g solution and stir at 80 ° C. for 3 hours under argon atmosphere. The reaction solution was poured into 100 ml of stirred diethyl ether, and the precipitate was collected by filtration, washed with diethyl ether, and dried to obtain 11.8 g of a crude product as a colorless solid. The crude product (11.8 g) was recrystallized from isopropanol to give (R)-(3-carboxy-2) as colorless needles.
9.38 g of -pentadecanoyloxypropyl) trimethylammonium chloride are obtained.

M. p. : 167-169 ° C IR (Nujol) cm ^-1 : 3020-2480, 17
_{40,1710 NMR (DMSO-d 6)} δ: 0.85 (3H, t, J
= 6.7 Hz), 1.24 (22H, brs), 1.4
7-1.57 (2H, m), 2.23-2.40 (2
H, m), 2.62-2.76 (2H, m), 3.12.
(9H, s), 3.68 (1H, brd), 3.81
(1H, dd, J = 14, 8.1 Hz), 5.42-
5.49 (1H, m).

Reference Examples 2 to 14 The corresponding starting compounds were treated in the same manner as in Reference Example 1 to give
~ 46 The compounds shown in Table are obtained.

[0113]

[Table 45]

[0114]

[Table 46]

[0115]

[Table 47]

[0116]

[Table 48]

Reference Example 15 L-carnitine (2.0 g; 12.4 mmol) was dissolved in 3 ml of trifluoroacetic acid by heating (60 ° C.), 8 ml (37.2 mmol) of 10-undecenoyl chloride was added, and the mixture was sealed. Stir vigorously by hand for 5 minutes until homogeneous at the same temperature. After the mixture becomes homogeneous, the mixture is further stirred at the same temperature for 10 minutes. After evaporating the solvent of the reaction solution, the residue is dissolved in 100 ml of petroleum ether, poured into 100 ml of ice water, and stirred at room temperature for 30 minutes. Then, 100 ml of ethanol-100 ml of ether are added to these mixed liquids and extracted. The aqueous layer is further extracted twice with 60 ml of ethanol and 60 ml of ether. 120 ml of n-butanol was added to the separated aqueous layer.
, And water is appropriately added and extracted to form two layers. n
-Butanol layer is further 40 ml of water, 40 parts of phosphate buffer
ml (67 mmol; pH 7.2) and 40 ml of water. The n-butanol layer was separated, the solvent was distilled off, and the residue was azeotropically distilled with toluene and ethyl acetate. The oily residue was recrystallized from ethyl acetate to give (R)-[3-carboxy-2- (1
0-undecenoyloxypropyl)] 1.81 g of trimethylammonium chloride as colorless crystals.

M. p. 154-156 ° C IR (Nujol) cm ^-1 : 1740 NMR (DMSO-d ₆ ) δ: 1.20-1.40 (1
0H, m), 1.45-1.60 (2H, m), 1.9
5-2.05 (2H, m), 2.25-2.35 (2
H, m), 2.65 (2H, d, J = 6.1 Hz),
3.11 (9H, s), 3.66 (1H, d, J = 13
Hz), 3.81 (1H, dd, J = 14, 8.3H)
z), 4.90-5.05 (2H, m), 5.40-
5.50 (1H, m), 5.70-5.90 (1H,
m).

Reference Example 16 L-carnitine and linoleoyl chloride were used in Reference Example 1.
By treating in the same manner as in step 5, (R)-(3-carboxy-2-linoleoyloxypropyl) trimethylammonium chloride is obtained.

IR (Neat) cm ^-1 : 1740 NMR (DMSO-d ₆ ) δ: 0.86 (3H, t, J
= 6.7 Hz), 1.20-1.40 (14H, m),
1.45-1.60 (2H, m), 1.95-2.05
(4H, m), 2.25-2.35 (2H, m), 2.
68 (2H, d, J = 5.9 Hz), 2.74 (2H,
t, J = 5.5 Hz), 3.10 (9H, s), 3.6
2 (1H, d, J = 13 Hz), 3.81 (1H, d
d, J = 15, 8.3 Hz), 5.25-5.40 (4
H, m), 5.40-5.50 (1H, m).

Reference Example 17 L-carnitine and dodecanoyl chloride were used in Reference Example 1.
To give (R)-(3-carboxy-2-dodecanoyloxypropyl) trimethylammonium chloride.

M. p. 174-176 ° C IR (Nujol) cm ^-1 : 735,1705 NMR (DMSO-d ₆ ) δ: 0.86 (3H, t, J
= 6.8 Hz), 1.24 (16H, brs), 1.4
8-1.57 (2H, m), 2.24-2.40 (2
H, m), 2.63-2.77 (2H, m), 3.12.
(9H, s), 3.69 (1H, brd), 3.82
(1H, dd, J = 14, 8.2 Hz), 5.43−
5.49 (1H, m).

MS (ESI) m / z: 366 [(MNa
-HCl) ⁺ ], 344 [(MH-HCl) ⁺ ].

Reference Example 18 L-carnitine and octanoyl chloride were used in Reference Example 1.
(R)-(3-carboxy-2-octanoyloxypropyl) trimethylammonium chloride is obtained.

M. p. 176-177 ° C IR (Nujol) cm ^-1 : 735,1705 NMR (DMSO-d ₆ ) δ: 0.86 (3H, t, J
= 6.7 Hz), 1.25 (8H, brs), 1.48
−1.58 (2H, m), 2.24-2.40 (2H,
m), 2.63-2.77 (2H, m), 3.13 (9
H, s), 3.70 (1H, brd), 3.82 (1
H, dd, J = 14, 8.1 Hz), 5.42-5.4.
9 (1H, m), 12.8 (1H, br).

MS (ESI) m / z: 288 [(MH-
HCl) ⁺ ].

Reference Example 19 Ethyl succinyl chloride (17.6 g; 107 mmol)
l) and water (1.28 g; 71.0 mmol) in 60-7.
After stirring at 0 ° C. for 1.5 hours, a solution of L-carnitine (3.83 g; 23.8 mmol) dissolved in 12 g of trifluoroacetic acid (40 ° C.) is added to the mixture. After stirring such a mixture at 60-70 ° C. for 21.5 hours,
Cool to room temperature. The mixture is charged with 200 parts of diethyl ether.
of the resulting oil and diethyl ether 200
Wash twice with ml. The residual oil is solidified by adding 150 ml of tetrahydrofuran. The obtained solid is pulverized, collected by filtration, washed with tetrahydrofuran, and further dried to give (R)-[3-carboxy-2- (3-ethoxycarbonylpropionyloxy) propyl] trimethylammonium chloride 6.5.
g are obtained as a colorless solid.

M. p. : 97-99 ° C IR (Nujol) cm ^-1 : 3400 (br), 173
0 NMR (DMSO-d ₆ ) δ: 1.18 (3H, t, J
= 7.1 Hz), 2.54-2.64 (4H, m),
2.68-2.71 (2H, m), 3.13 (9H,
s), 3.69 (1H, brd), 3.85 (1H, d
d, J = 14, 8.6 Hz), 4.06 (2H, q, J
= 7.1 Hz), 5.44-5.51 (1H, m), 1
2.8 (1H, br).

MS (ESI) m / z: 290 [(MH-
HCl) ⁺ ].

[0130]

The carnitine derivative according to the present invention [I]
Has an excellent hair-growth effect. Further, the carnitine derivative according to the present invention has low toxicity and high safety. For example, a 2% ethanol solution of (R)-(2-tridecanoyloxy-3-tridecyloxycarbonylpropyl) trimethylammonium chloride, which is an active ingredient of the present invention, is added to 3%
No skin abnormality was observed even after application for 0 days. Therefore, the carnitine derivative [I] according to the present invention is useful as a hair restorer, and is a human or an animal (for example, sheep or goat) that supplies a hair product (for example, a product made of wool or cashmere).
Can be effectively used for promoting hair growth or hair growth.
In addition, the carnitine derivative [I] according to the present invention is useful for preventing orrogenetic alopecia, senile alopecia, telogen effluvium, gray hair, etc.
It can be used effectively for treatment.

Continuation of the front page (56) References JP-A-1-199905 (JP, A) JP-A-7-76561 (JP, A) EP 559625 (EP, A2) EP 552137 (EP, A) A2) European Patent Application Publication 552138 (EP, A2) (58) Fields investigated (Int. Cl. ⁷ , DB name) A61K 7/06 CA (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] 1. A compound of the general formula [I][Wherein, R¹~ R^ThreeIsMethylGroup, R^FourIsTridecanoyl
Group, R^FiveIsHeptylGroup, X^-Is a pharmacologically acceptable acid
Represents a nonion. The effective synthesis of carnitine derivatives
Hair restorer 2. A hair restorer comprising (R)-(3-heptyloxycarbonyl-2-tridecanoyloxypropyl) trimethylammonium nitrate as an active ingredient.