JPH0543529A - Alkaneamide ammonium compound - Google Patents

Abstract

(57) [Summary] [Objective] To provide a compound having a new type of hair growth action. [Structure] [Wherein R ¹ represents an alkyl group or a cycloalkyl group, R ² represents an alkylene group, R ³ represents a hydrogen atom or an alkyl group, R ⁴ represents an alkylene group, R ^4
5 and R ⁶ are the same or different and each represents an alkyl group,
⁷ is an alkyl group, an alkenyl group or a “phenyl group-substituted alkyl group”, A is an oxygen atom or (Wherein n represents an integer of 0 to 2 in Chemical Formula 17,) X represents an atom or an atomic group which becomes an anion. ] The alkanamido ammonium compound represented by these.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an alkaneamido ammonium compound having a hair growth effect.

[0002]

BACKGROUND OF THE INVENTION Conventionally, the compounds of the present invention are similar in structure to
A compound having a similar action is not known.

[0003]

The object of the present invention is to provide a compound having a new type of hair growth action.

[0004]

The present invention comprises:

[0005]

[Chemical 3]

[In the chemical formula 3, R ¹ represents an alkyl group having 1 to 22 carbon atoms or a cycloalkyl group having 3 to 8 carbon atoms, R ² represents an alkylene group having 1 to 15 carbon atoms, and R ^{2 3} represents a hydrogen atom or a lower alkyl group, R ⁴
Represents an alkylene group having 2 to 10 carbon atoms, R ⁵ and R ⁶ are the same or different and represent a lower alkyl group, and R ⁷
Is an alkyl group having 1 to 22 carbon atoms, 2-1 carbon atoms
0 represents an alkenyl group or a “lower alkyl group substituted with a phenyl group”, A is an oxygen atom or

[Chemical 4] (Wherein n represents an integer of 0 to 2 in Chemical Formula 4), X represents an atom or an atomic group which becomes an anion. ]
It is an alkaneamido ammonium compound represented by.

In the present invention, the alkyl group having 1 to 22 carbon atoms means methyl group, ethyl group, n-propyl group,
Isopropyl group, n-butyl group, isobutyl group, sec
-Butyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, tert-pentyl group, n-hexyl group, isohexyl group, n-heptyl group, n-octyl group, n-nonyl group, n- Decyl group, n
-Undecyl group, n-dodecyl group, n-tridecyl group,
n-tetradecyl group, n-pentadecyl group, n-hexadecyl group, n-heptadecyl group, n-octadecyl group,
A linear or branched chain such as an n-nonadecyl group, an n-icosyl group, an n-henicosyl group, and an n-docosyl group.

The cycloalkyl group having 3 to 8 carbon atoms includes cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group and the like. The alkylene group having 1 to 15 carbon atoms means methylene group, ethylene group, trimethylene group, tetramethylene group, pentamethylene group, hexamethylene group, octamethylene group, nonamethylene group, decamethylene group, undecamethylene group, dodecamethylene. Group, tridecamethylene group, pentadecamethylene group, propylene group, 1-methyl-trimethylene group, 2,2-dimethyl-
A straight-chain or branched-chain group such as trimethylene group, 1-methyl-hexamethylene group, ethylidene group, propylidene group and butylidene group. The alkylene group having 2 to 10 carbon atoms means an alkylene group having 2 to 10 carbon atoms among the alkylene groups having 1 to 15 carbon atoms.

The lower alkyl group means a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group,
1 to 1 carbon atoms such as isobutyl group and n-pentyl group
5 refers to a linear or branched alkyl group. The alkenyl group having 2 to 10 carbon atoms includes vinyl group, allyl group, 1-butynyl group, prenyl group, geranyl group and the like. The lower alkyl group substituted with a phenyl group is a linear or branched alkyl group having 1 to 5 carbon atoms which is substituted with a phenyl group such as a benzyl group, a phenylethyl group and a phenylpropyl group. ..

The atom or atomic group to be an anion includes fluorine atom, chlorine atom, bromine atom, iodine atom, sulfate group, nitrate group, nitrite group, methyl sulfate group, ethyl sulfate group, dimethyl phosphate group, methane. A sulfonic acid group, a benzenesulfonic acid group, a p-toluenesulfonic acid group, or the like can be used.

The compound of the present invention can be produced, for example, according to the following method (hereinafter, R ¹ , R ² and R
The symbols of ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , A and n have the same meanings as described above unless otherwise specified. ). That is, first,

[Chemical 5] And a compound represented by

[Chemical 6] By reacting an amine represented by with a usual amide bond formation reaction,

[Chemical 7] A compound represented by can be obtained.

Here, as the amide bond forming reaction, usual conditions for the amide bond forming reaction can be applied.
For example, (a) heat dehydration method, (b) acid halide method, (c) mixed acid anhydride method, (d) active ester method,
(E) The carbodiimide method or the like can be used,
It is preferable to use the method (a) or (b). The method (a) is carried out without solvent or in the presence of a solvent until 1 mol of water is distilled off. When the method is carried out without solvent, the reaction temperature is usually about 130 to 200 ° C., preferably 150 to
It is carried out at 170 ° C., and when carried out in the presence of a solvent, it is carried out at the boiling point of the solvent. A solvent that does not adversely affect the reaction and that is azeotropic with water can be used, and examples thereof include xylene. The method (b) is a method of reacting the compound of formula 6 with an acid halide obtained by reacting the compound of formula 5 with a halogenating agent. That is, a halogenating agent (e.g., thionyl chloride, phosphorus pentachloride, phosphorus oxychloride, oxalyl chloride, thionyl bromide, phosphorus tribromide, etc.) in an equimolar amount to a large excess amount with the compound of Chemical formula 5 is used with or without a solvent. 0.5-10 at room temperature to the boiling point of the solvent in an active solvent (eg, benzene, toluene, tetrahydrofuran, methylene chloride, chloroform, etc.)
The acid halide of the compound of Chemical formula 5 is obtained by stirring for a period of time, and this compound and the compound of Chemical formula 6 are used with or without a solvent (for example, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran, dioxane). Etc., ethers such as benzene, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as methyl acetate and ethyl acetate, and aprotic polar solvents such as N, N-dimethylformamide and dimethyl sulfoxide) 30 to 100 ° C (preferably 0
˜50 ° C.). Here, a catalyst is not necessarily required in the first half reaction, but the reaction can be promoted by adding pyridine, triethylamine, N, N-dimethylformamide and the like in catalytic amounts to equimolar amounts.

Then, with the compound of

[Chemical 8] (Wherein Y represents a halogen atom), a mineral acid ester (in this case, the ester moiety is a group of R ⁷ ), or an organic acid ester (in this case, the ester moiety is R ^7). The compound of the present invention can be obtained by a quaternization reaction in which a group of 4) is reacted with or without a solvent. Here, a chlorine atom, a bromine atom or an iodine atom can be used as the halogen atom. As the mineral acid ester and the organic acid ester, dimethyl sulfate, diethyl sulfate, trimethyl phosphate, methyl methanesulfonate, methyl benzenesulfonate, methyl p-toluenesulfonate, pentyl p-toluenesulfonate and the like can be used. it can. As the solvent, water, acetone, alcohols (eg, methanol, ethanol, etc.), diethyl ether, benzene, acetonitrile, etc. can be used. The reaction temperature is from 0 ° C to the boiling point of the solvent.

In the compound of the chemical formula 3, A is a group of the chemical formula 4, and n is 1 or 2, and the compound of the chemical formula 7 obtained by the above-mentioned method (A is the group of the chemical formula 4, Further, it can also be produced by reacting (in which n is 0) in a solvent with a 1- to 3-fold molar amount of an oxidizing agent, and then reacting it in the same manner as the above method. Here, hydrogen peroxide, organic peracid (eg, peracetic acid, trifluoroperacetic acid, perbenzoic acid, perphthalic acid, m-chloroperbenzoic acid, etc.) can be used as the oxidizing agent. As the solvent, water, methylene chloride, chloroform, dichloroethane, benzene, toluene, ethyl acetate, acetic acid or the like can be used. The reaction temperature is -30 to 150 ° C.

Further, in the compound of Chemical formula 3, a compound in which X is a fluorine atom, a chlorine atom, a bromine atom, a sulfuric acid group, a nitric acid group or a nitrite group can also be produced by the following method. That is, one of the compounds of the present invention produced by the above method,

[Chemical 9] By reacting a compound represented by with a silver salt (silver fluoride, silver chloride, silver bromide, silver sulfate, silver nitrate or silver nitrite) that exchanges ions with iodine ions, in a solvent at room temperature to the boiling point of the solvent. In the compound of Chemical formula 3, a compound in which X is a fluorine atom, a chlorine atom, a bromine atom, a sulfate group, a nitrate group, or a nitrite group can be obtained. Here, as the solvent, water, alcohols (for example, methanol, ethanol, etc.), a mixed solvent thereof, or the like can be used.

By the way, the compound of Chemical formula 5, which is a starting material, can be produced from a known compound by the following method. (1) In the compound of Chemical formula 5, A is a group of Chemical formula 4, and n is 0

[Chemical 10] A thiol compound represented by

[Chemical 11] (Wherein Z ¹ represents a halogen atom in Chemical formula 11), in the presence of a base, at 0 ° C. to the boiling point of the solvent at 0 ° C.
By stirring for 5 to 10 hours, a compound of Chemical formula 5 in which A is a group of Chemical formula 4 and n is 0 can be obtained. Here, a chlorine atom, a bromine atom or an iodine atom can be used as the halogen atom. As the base, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, triethylamine, etc. can be used. As the solvent, water, alcohols (eg, methanol, ethanol, etc.), acetone, N, N-dimethylformamide, acetonitrile, dioxane, tetrahydrofuran and the like can be used. Furthermore, a reaction accelerator such as potassium iodide may be added.

(2) In the compound of Chemical formula 5, A is the group of Chemical formula 4 and n is 1 or 2, and A is the group of Chemical formula 4 obtained by the method of the above (1), Furthermore, by reacting a compound of Chemical formula 5 in which n is 0 with a 1 to 3 molar amount of an oxidizing agent in a solvent, a compound of Chemical formula 5 in which A is a group of Chemical formula 4 and n is 1 or 2 Can be obtained. Here, hydrogen peroxide, organic peracid (eg, peracetic acid, trifluoroperacetic acid, perbenzoic acid, perphthalic acid, m-chloroperbenzoic acid, etc.) can be used as the oxidizing agent. As the solvent, water, methylene chloride, chloroform, dichloroethane, benzene, toluene, ethyl acetate, acetic acid or the like can be used. The reaction temperature is -30 to 150 ° C.

(3) In the compound of Chemical formula 5, A is an oxygen atom

[Chemical formula 12] Alcohol represented by

[Chemical 13] (In Chemical formula 13, Z ² represents a halogen atom), in the presence of a base, in a solvent, at 0 ° C. to the boiling point of the solvent, 1 to
By stirring for 48 hours, a compound of Chemical formula 5 in which A is an oxygen atom can be obtained. Here, a chlorine atom, a bromine atom or an iodine atom can be used as the halogen atom. Also, as the base, sodium hydroxide,
Potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, sodium amide, triethylamine,
Barium oxide, silver oxide or the like can be used. As the solvent, water, acetone, ether, tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide, 1,2-dimethoxyethane, acetonitrile, dioxane or the like can be used. Furthermore, a reaction accelerator such as potassium iodide may be added.

Further, with the compound of

[Chemical 14] (In the formula 14, Z ³ and Z ⁴ are the same or different and each represents a halogen atom.) The compound represented by In sulfoxide, 1,2-dimethoxyethane, etc.), the mixture is stirred at 0 ° C. to the boiling point of the solvent for 1 to 48 hours to give a halogenated ether, which is then reacted with magnesium in a solvent (ether, tetrahydrofuran, etc.) to produce a Grignard reagent. Then, by reacting with carbon dioxide, it is possible to obtain a compound of Chemical formula 5 in which A is an oxygen atom. Here, a chlorine atom, a bromine atom or an iodine atom can be used as the halogen atom. As the base, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, sodium amide, triethylamine, barium oxide, silver oxide or the like can be used.

Further, with the compound of

[Chemical 15] (Wherein Z ⁵ represents a halogen atom in Chemical formula 15) is converted into a base (for example, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydride, sodium amide, triethylamine, barium oxide, oxidation). In the presence of a solvent such as water, acetone,
Ether, tetrahydrofuran, N, N-dimethylformamide, dimethylsulfoxide, 1,2-dimethoxyethane, etc.) at 0 ° C. to the boiling point of the solvent for 1 to 48 hours to give an ether nitrile compound, which is then hydrolyzed Thus, a compound of Chemical formula 5 in which A is an oxygen atom can also be obtained. Here, a chlorine atom, a bromine atom or an iodine atom can be used as the halogen atom. The hydrolysis is performed by stirring in a solvent at room temperature to the boiling point of the solvent for 1 to 12 hours in the presence of an acid or a base. Here, hydrochloric acid, sulfuric acid, acetic acid, formic acid or the like can be used as the acid, and sodium hydroxide as the base.
Potassium hydroxide, barium hydroxide or the like can be used. As the solvent, water or hydrous alcohols (eg, methanol aqueous solution, ethanol aqueous solution) can be used.

Regarding the dose and method of administration of the compound of formula 3, one or two or more compounds of formula 3 are used, for example, an external preparation such as lotion, emulsion, cream, gel, aerosol, etc. using a common base. And apply this to the scalp several times a day. In addition, other medicinal substances can be added to this preparation.

Examples of the usual bases and other medicinal substances mentioned above include solvents (ethyl alcohol, isopropyl alcohol, 1,3-butylene glycol, 1,4-
Butylene glycol, propylene glycol, dipropylene glycol, glycerin, diglycerin, polyethylene glycol, purified water, etc., mucopolysaccharide (hyaluronic acid, chondroitin-4-sulfate, chondroitin-6)
-Sulfuric acid, dermatan sulfate, keratan sulfate, heparan sulfate, polysulfate of chondroitin sulfate, etc.), preservatives (paraben, benzoic acid, etc.), vitamins [vitamin A, vitamin B ₁ , vitamin B ₂ , vitamin B ₆ , vitamin B ₆ , Vitamin C, vitamin D, vitamin E and derivatives thereof (for example, vitamin E acetate ester)], oil (liquid paraffin, white petrolatum, solid paraffin,
Ceresin, microcrystalline wax, cholesterol, squalane, olive oil, rosehip oil, mink oil, jojoba oil, hydrogenated castor oil, hydrogenated coconut oil, isopropyl myristate, ethyl caprate, ethyl caprylate, palmitoleic acid, ethyl palmitoleate, linole. Ethyl acid, ethyl linolenate, oleic acid, stearic acid, linoleic acid, linolenic acid, palmitic acid, behenic acid, lauric acid, stearyl alcohol, cetyl alcohol, lauryl alcohol, oleyl alcohol,
Cetyl isooctanoate, etc.), bactericides [sulfur, chlorhexidine gluconate, chlorhexidine hydrochloride, cetyl pyridine chloride, decalinium chloride, isopropylmethylphenol, quaternary ammonium salts (such as benzalkonium chloride), hinokitiol], nonionic Surfactants (polyoxyethylene fatty acid ester, polyoxyethylene sorbitan fatty acid ester, sorbitan fatty acid ester, glycerin fatty acid ester, polyoxyethylene glycerin fatty acid ester, polyglycerin fatty acid ester, propylene glycol fatty acid ester,
Polyglycerin alkyl phenyl ether, polyoxyethylene hydrogenated castor oil, copolymer of polyoxyethylene and polypropyrin glycol, etc., anionic surfactant (N-acyl amino acid salt, N-acyl sarcosine salt, alkyl phosphate ester) Salt, acylmethyl taurine salt, etc.), cationic surfactant (alkyl trimethyl ammonium, alkyl-N, N-dialkylaminoacetic acid ester etc.), amphoteric surfactant (imidazoline, amine oxide etc.), polymer surfactant (Casein etc.), Silicone derivative (Silicone oil, Polyol modified silicone, Silicone resin etc.), Thickener (Methylcellulose, Polyvinylpyrrolidone, Carboxymethylcellulose, Carboxyethylcellulose, Hydroxypropyl cellulose) , Carboxyvinyl polymers, etc.), clay minerals (montmorillonite, saponite, hectorite, etc.), pH adjusters (diisopropanolamine, citric acid, etc.), antioxidants (dibutylhydroxytoluene, sodium bisulfite, catechin, glucnodeltalactone) Etc.), whitening agents (arbutin, kojic acid, etc.), cooling agents (1-menthol, camphor, etc.),
Anti-inflammatory agents (glycyrrhetinic acid, dipotassium glycyrrhizinate, berberine chloride, shikonin, guaiazulene, allantoin, δ-aminocaproic acid, etc.), peripheral vasodilators (methyl nicotinate, benzyl nicotinate, cheliamarin, minoxidil, diazoxide, capsicum extract) , Capsaicin, carpronium chloride, etc.),
Corticosteroids (hydrocortisone acetate, betamethasone valerate, etc.), antihistamines (diphenhydramine hydrochloride, isothipendyl hydrochloride, etc.), local anesthetics (dibucaine hydrochloride, lidocaine hydrochloride, etc.), keratolytic agents (urea, salicylic acid, etc.), keratinization regulators [Vitamin A acid and its derivatives (eg, 13-cis-retinoic acid, etretinate, etc.)], estrogen (17β-estradiol, ethinylestradiol, estrone, etc.), progesterone (progesterone, 17α-hydroxyprogesterone acetate, etc.), antiandrogen Agents (cyproterone acetate, 4-androstene-3
-On-17β-carboxylic acid, etc.), fragrance, sequestering agent, ultraviolet absorber, moisturizer (hechima extract, carrot extract, diisopropyl acetate,
Pyrrolidone carboxylic acid, polyglutamic acid, polyoxyalkylene alkyl glucoside ether, collagen,
Lecithin, ceramide, 2-aminoethanesulfonic acid, etc., herbal medicine extract (Kamuyu extract, Ginseng extract,
Langicic extract, saffron extract, etc.) and the like.

[0023]

The compound of the present invention has an excellent hair-growth action and is useful as a hair-growth agent.

[0024]

EXAMPLES The present invention will be described in more detail with reference to production examples, examples and test examples. Example 1 Production Example 1 A mixture of 101.2 g of dodecyl mercaptan 11- (dodecylthio) undecanoate, 132.6 g of 11-bromoundecanoic acid and 300 ml of ethanol was stirred at 60 ° C. and 120 ml of an aqueous solution of 40.0 g of sodium hydroxide was added. It was dropped and refluxed for 3 hours. 3N after cooling
The mixture was acidified with hydrochloric acid, extracted with chloroform, washed with water and saturated brine in that order, and dried over anhydrous sodium sulfate. After distilling off the solvent, the product was recrystallized from chloroform to obtain 174.5 g of the title compound. m. p. 69-71 ° C

The following compounds were obtained in the same manner as in Production Example 1. 11- (isopentylthio) undecanoic acid m. p. 47-49 ° C. 11- (Cyclohexylthio) undecanoic acid m. p. 46-48 ° C. 11- (decylthio) undecanoic acid m. p. 63-65 ° C. 3- (tetradecylthio) propionic acid m.p. p. 66-68 ° C. 5- (tetradecylthio) valeric acid m.p. p. 59-61 ° C. 5- (Hexadecylthio) valeric acid m.p. p. 65-67 ° C. (octadecylthio) acetic acid m.p. p. 73-75 ° C. 3- (octadecylthio) propionic acid m.p. p. 78-80 ° C 2- (octadecylthio) propionic acid m.p. p. 65-67 ° C 2- (octadecylthio) butyric acid m.p. p. 55-57 ° C 5- (octadecylthio) valeric acid m.p. p. 72-74 ° C

Production Example 2 3- (tetradecylsulfonyl ) propionic acid 5.2 g of 3- (tetradecylthio) propionic acid obtained in the same manner as in Production Example 1 was dissolved in 70 ml of methylene chloride,
Under room temperature stirring, 8.9 g of m-chloroperbenzoic acid dissolved in 70 ml of methylene chloride was added dropwise, and the mixture was stirred at room temperature for 66 hours. The precipitated crystals were collected by filtration, purified by column chromatography using silica gel, and recrystallized from ethyl acetate to obtain 2.5 g of the title compound. m. p. 136-138 ° C The following compound was obtained in the same manner as in Production Example 2. 3- (octadecylsulfonyl) propionic acid m. p. 135-137 ° C

Preparation Example 3 5- ( Tridecyloxy ) valeric acid (1) 28.0 g, 1,4-dibromobutane 60.5 g and tetra-n-butylammonium hydrogensulfate 0.4 g were added to 40%. 56 ml of an aqueous sodium hydroxide solution was added, and the mixture was stirred overnight at room temperature. After extraction with ether and drying over anhydrous magnesium sulfate, the solvent was distilled off and the residue was distilled under reduced pressure to obtain 11.7 g of 1- (4-bromobutoxy) tridecane. b. p. 148-149 ° C / 0.80 mmHg (2) Magnesium 2.4 g, tetrahydrofuran 2
0 ml and a small amount of iodine were added, and the mixture was refluxed under an argon stream until the color of iodine disappeared. A solution of 26.8 g of the compound obtained in (1) in 30 ml of tetrahydrofuran was added dropwise to this reaction solution, and the mixture was refluxed for 30 minutes. −
The mixture was cooled to 5 ° C., 150 g of dry ice was added so that the reaction liquid did not rise above 0 ° C., and the mixture was further stirred at room temperature for 1 hour. After hydrolyzing by adding 100 ml of 25% sulfuric acid, the mixture was extracted with ether, made alkaline with a 20% aqueous sodium hydroxide solution, and the aqueous phase was separated, acidified again, extracted with chloroform, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 11.8 g of the title compound. m. p. 43-44 ° C

Production Example 4 5- ( Tetradecyloxy ) valeric acid (1) 1-tetradecanol (15.0 g) was dissolved in a solution of 70 ml of tetrahydrofuran, and under ice-cooling 12.2 ml of 5-bromopentanenitrile and 96% hydroxylation. 4.9 g of potassium powder was added. After stirring at room temperature for 24 hours, ethyl acetate was added, the reaction solution was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent; ether: n-hexane = 1: 4) to give 5-
7.4 g of (tetradecyloxy) pentanenitrile was obtained. m. p. 30 to 31 ° C. The following compound was obtained in the same manner as in Production Example 4 (1). 5- (hexadecyloxy) pentanenitrile m. p. 40-41 ° C 5- (octadecyloxy) pentanenitrile m. p. 46-47 ° C

(2) 8.6 g of the compound obtained in (1) was dissolved in 50 ml of ethanol, 50 ml of 25% aqueous potassium hydroxide solution was added, and the mixture was refluxed for 8 hours. After cooling, concentrated hydrochloric acid was added to acidify, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (8.6 g). m. p. 56-57 ° C The following compound was obtained in the same manner as in Production Example 4 (2). 5- (hexadecyloxy) valeric acid m. p. 64-65 ° C 5- (octadecyloxy) valeric acid m.p. p. 68-69 ° C

Production Example 5 N- [3- (dimethylamino) propyl] -11- (d
Decylthio) undecanoamide 11- (dodecylthio) undecanoic acid 1 obtained in Preparation Example 1
50.0 g and 47.6 g of N, N-dimethyl-1,3-diaminopropane were refluxed in 200 ml of xylene for 5 hours while removing generated water. After cooling, the product was collected by filtration and recrystallized from methyl ethyl ketone to obtain 153.3 g of the title compound. m. p. 68-70 ° C

Using the compounds produced in Production Examples 1 to 4,
The following compounds were obtained in the same manner as in Production Example 5. N- [3- (dimethylamino) propyl] -11- (isopentylthio) undecanamide m. p. 47-49 ° C. N- [3- (Dimethylamino) propyl] -11- (cyclohexylthio) undecane amide m.p. p. 61-63 ° C. N- [3- (dimethylamino) propyl] -11- (decylthio) undecanamide m.p. p. 62-64 ° C. N- [2- (dimethylamino) ethyl] -11- (dodecylthio) undecanamide m.p. p. 71-73 ° C N- [2- (diethylamino) ethyl] -11- (dodecylthio) undecanamide m.p. p. 63-65 ° C. N- [3- (diethylamino) propyl] -11- (dodecylthio) undecanamide m.p. p. 59-61 ° C. N- [2,2-dimethyl-3- (dimethylamino) propyl] -11- (dodecylthio) undecanamide m.p. p. 59-61 ° C N- [3- (dimethylamino) propyl] -3- (tetradecylthio) propanamide m.p. p. 46-48 ° C N- [3- (dimethylamino) propyl] -3- (tetradecylsulfonyl) propanamide m.p. p. 89-91 ° C. N- [3- (dimethylamino) propyl] -5- (tetradecylthio) pentanamide m.p. p. 58-60 ° C

N- [3- (dimethylamino) propyl]
-5- (hexadecylthio) pentanamide m. p. 68-70 ° C. N- [3- (dimethylamino) propyl] -2- (octadecylthio) acetamide m.p. p. 53-55 ° C. N- [3- (dimethylamino) propyl] -3- (octadecylthio) propanamide m.p. p. 58-60 ° C N- [3- (Dimethylamino) propyl] -3- (octadecylsulfonyl) propanamide m.p. p. 98-100 ° C. N- [2- (dimethylamino) ethyl] -5- (octadecylthio) pentanamide m.p. p. 72-74 ° C. N- [3- (dimethylamino) propyl] -5- (octadecylthio) pentanamide m.p. p. 68-70 ° C. N- [3- (dimethylamino) propyl] -5- (tetradecyloxy) pentanamide m.p. p. 53-54 ° C. N- [2- (dimethylamino) ethyl] -5- (tridecyloxy) pentanamide m.p. p. 52-53 ° C. N- [3- (dimethylamino) propyl] -5- (tridecyloxy) pentanamide m.p. p. 46-47 ° C. N- [2- (dimethylamino) ethyl] -5- (tetradecyloxy) pentanamide m.p. p. 58-59 ° C N- [3- (Dimethylamino) propyl] -5- (hexadecyloxy) pentanamide m.p. p. 58-59 ° C N- [3- (Dimethylamino) propyl] -5- (octadecyloxy) pentanamide m.p. p. 66-67 ° C

Production Example 6 N- [3- (dimethylamino) propyl] -3- (meth)
Luthio) propanamide 3- (methylthio) propionic acid 4.3 g was added to toluene 4
Dissolve in 0 ml, add 8.5 g of thionyl chloride, and add 80 ° C.
It was stirred for 3 hours. Toluene and excess thionyl chloride were distilled off under reduced pressure to obtain crude chloride. This was dissolved in 10 ml of chloroform, and N, N-dimethyl-
1,3-diaminopropane 3.7 g chloroform 20
The solution was added dropwise to the ml solution and further stirred at room temperature for 16 hours. This reaction solution was washed with saturated aqueous sodium hydrogen carbonate, water, and saturated saline in this order,
It was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 6.0 g of the title compound as an oily liquid. ¹ H-NMR (CDCl ₃ ) δ (ppm); 1.75
(2H, quint., J = 6.3Hz), 2.14
(3H, s), 2.35 (6H, s), 2.43-2.
61 (4H, m), 2.80 (2H, t, J = 6.9H
z), 3.37 (2H, quart., J = 6.0H)
z), 7.22 (1H, br.s)

Production Example 7 N- [3- (dimethylamino) propyl] -11- (d
Decyl sulfinyl) obtained in undecanamide Preparation 5 N-[3- (dimethylamino) propyl] -11-(dodecylthio) undecanamide 1.0
g of m-chloroperbenzoic acid dissolved in 15 ml of chloroform under ice-cooling stirring.
5 g was added dropwise, and the mixture was further stirred under ice cooling for 4 hours. The reaction solution was washed with saturated aqueous sodium hydrogen carbonate, water and saturated brine in this order, and dried over anhydrous sodium sulfate. After distilling off the solvent, the product was recrystallized from chloroform-ether to obtain 0.91 g of the title compound. m. p. 110-112 ° C

Example 1 N- {3- [11- (dodecylthio) undecanaami
De] propyl} -N, N, N-trimethylammonium
= N- [3- (dimethylamino) propyl] -11- (dodecylthio) undecanamide 12 obtained in Iodide Production Example 5
Dissolve 0.0 g in 1 L of ethanol, and add methyl iodide 5
2.4 g was added and the mixture was stirred at room temperature for 3 days. The product
The title compound 1 was obtained by taking and recrystallizing with ethanol.
41.5 g was obtained. m. p. 103-105 ° C ¹ H-NMR (CDCl ₃ ) δ (ppm) =; 0.8
8 (3H, t, J = 6.5Hz), 1.19 to 1.71
(36H, m), 2.06 to 2.24 (2H, m),
2.32 (2H, t, J = 7.5Hz), 2.50 (4
H, t, J = 7.4 Hz), 3.32 to 3.49 (11
H, m), 3.80 to 3.93 (2H, m), 7.30
~ 7.41 (1H, m)

The following compounds were obtained in the same manner as in Example 1. N- {3- [3- (methylthio) propanamide] propyl} -N, N, N-trimethylammonium = iodide m.p. p. 118-120 ° C. N- {2- [N′-methyl-3- (methylthio) propanamide] ethyl} -N, N, N-trimethylammonium = iodide m.p. p. 132-134 ° C. N- {3- [11- (isopentylthio) undecanamido] propyl} -N, N, N-trimethylammonium = iodide m.p. p. 98-100 ° C. N- {3- [11- (cyclohexylthio) undecanamido] propyl} -N, N, N-trimethylammonium = iodide m.p. p. 101-103 ° C. N- {3- [11- (decylthio) undecanamide]
Propyl} -N, N, N-trimethylammonium = iodide m.p. p. 99-101 ° C. N- {2- [11- (dodecylthio) undecanamido] ethyl} -N, N, N-trimethylammonium =
Iodide m. p. 115-117 ° C. N- {2- [11- (dodecylthio) undecanamido] ethyl} -N, N-diethyl-N-methylammonium = iodide m.p. p. 75-77 ° C. N- {3- [11- (dodecylsulfinyl) undecanamido] propyl} -N, N, N-trimethylammonium = iodide m.p. p. 123-125 ° C. N- {3- [11- (dodecylthio) undecanamido] propyl} -N, N-diethyl-N-methylammonium = iodide m.p. p. 88-90 ° C. N- {2,2-dimethyl-3- [11- (dodecylthio) undecanamido] propyl} -N, N, N-trimethylammonium = iodide m.p. p. 127-129 ° C. N- {3- [3- (tetradecylthio) propanamide] propyl} -N, N, N-trimethylammonium = iodide m.p. p. 116-118 ° C. N- {3- [3- (tetradecylsulfonyl) propanamide] propyl} -N, N, N-trimethylammonium = iodide m.p. p. 76-78 ° C. N- {3- [5- (tetradecylthio) pentanamido] propyl} -N, N, N-trimethylammonium = iodide m.p. p. 91-93 ° C. N- {3- [5- (hexadecylthio) pentanamido] propyl} -N, N, N-trimethylammonium = iodide m.p. p. 95-97 ° C. N- {3- [3- (octadecylthio) propanamide] propyl} -N, N, N-trimethylammonium = iodide m.p. p. 116-118 ° C. N- {3- [3- (octadecylsulfonyl) propanamide] propyl} -N, N, N-trimethylammonium = iodide m.p. p. 96-98 ° C. N- {3- [2- (octadecylthio) propanamide] propyl} -N, N, N-trimethylammonium = iodide m.p. p. 131-133 ° C. N- {2- [5- (octadecylthio) pentanamido] ethyl} -N, N, N-trimethylammonium =
Iodide m. p. 88-90 ° C. N- {3- [5- (octadecylthio) pentanamido] propyl} -N, N, N-trimethylammonium = iodide m.p. p. 96-98 ° C

Example 2 N- {3- [5- (tetradecyloxy) pentanami
De] propyl} -N, N, N-trimethylammonium
= 2.5 g of N- [3- (dimethylamino) propyl] -5- (tetradecyloxy) pentanamide obtained in the same manner as in Iodide Production Example 5 was dissolved in 10 ml of ethanol, and 0.6 ml of methyl iodide was added. The mixture was stirred at room temperature for 24 hours. The solvent was distilled off under reduced pressure, and the product was recrystallized from ethanol-ether to obtain 2.9 g of the title compound. m. p. 94-96 ° C ¹ H-NMR (CDCl ₃ ) δ (ppm); 0.88
(3H, t, J = 6.5Hz), 1.26 (22H,
s), 1.46 to 1.78 (6H, m), 2.03 to
2.22 (2H, m), 2.34 (2H, t, J = 7.
0 Hz), 3.32 to 3.48 (15H, m), 3.7
8 to 3.91 (2H, m), 7.17 to 7.27 (1
H, m)

The following compounds were obtained in the same manner as in Example 2. N- {2- [5- (tridecyloxy) pentanamido] ethyl} -N, N, N-trimethylammonium =
Iodide m. p. 91-92 ° C. N- {3- [5- (tridecyloxy) pentanamido] propyl} -N, N, N-trimethylammonium = iodide m.p. p. 96-98 ° C. N- {2- [5- (tetradecyloxy) pentanamido] ethyl} -N, N, N-trimethylammonium =
Iodide m. p. 93-94 ° C. N- {3- [5- (hexadecyloxy) pentanamide] bropyr} -N, N, N-trimethylammonium = iodide m.p. p. 98-100 ° C. N- {3- [5- (octadecyloxy) pentanamido] propyl}, N, N, N-trimethylammonium = iodide m.p. p. 101-103 ° C

Example 3 N- {3- [11- (dodecylthio) undecanaami ]
De] propyl} -N, N, N-trimethylammonium
= N- [3- (dimethylamino) propyl] -11- (dodecylthio) undecanamide 1.5 obtained in Production Example 5 of bromide
g was dissolved in 100 ml of ethanol, and methyl bromide 0.8
g was added and the mixture was stirred at room temperature for 4 days. The solvent was distilled off and the residue was recrystallized from ethanol to obtain 1.2 g of the title compound. m. p. ^{92~94 ℃ 1 H-NMR (CDCl} 3) δ (ppm); 0.88
(3H, t, J = 6.5Hz), 1.20 to 1.74
(36H, m), 2.11 to 2.29 (2H, m),
2.40 to 2.56 (6H, m), 3.31 to 3.53
(11H, m), 3.89 to 4.04 (2H, m),
8.62 (1H, br.s)

Example 4 N-benzyl-N- {3- [11- (decylthio) un]
Decanamide] propyl} -N, N-dimethylammoni
Um = chloride N- [3- (dimethylamino) propyl] -11- (decylthio) undecanoamide (1.5 g) obtained in the same manner as in Production Example 5 and benzyl chloride (0.5 g) were dissolved in ethanol (20 ml) and refluxed for 11 hours. did. After distilling off the solvent,
The product was recrystallized from ethanol to obtain 1.8 g of the title compound. m. p. 75-77 ° C. ¹ H-NMR (CDCl ₃ ) δ (ppm); 0.88
(3H, t, J = 6.5 Hz), 1.16 to 1.70
(32H, m), 2.13 to 2.32 (2H, m),
2.37 (2H, t, J = 7.8Hz), 2.49 (4
H, t, J = 7.3 Hz), 3.19 (6H, s),
3.35-3.47 (2H, m), 3.85-3.98
(2H, m), 4.79 (2H, s), 7.41-7.
63 (5H, m), 8.60 (1H, br.s) Propyl bromide or allyl bromide was used instead of benzyl chloride to carry out the reaction in the same manner as in Example 4 to obtain the following compound. N- {3- [11- (decylthio) undecanamide]
Propyl} -N, N-dimethyl-N-propylammonium bromide m. p. 70-72 ° C. N-allyl-N- {3- [11- (dodecylthio) undecanamido] propyl} -N, N-dimethylammonium bromide m.p. p. 80-82 ° C

Example 5 N- {3- [11- (dodecylthio) undecanaami ]
De] propyl} -N, N, N-trimethylammonium
= M -Sulfate N- [3- (dimethylamino) propyl] -11- (dodecylthio) undecanamide 2.0 obtained in Production Example 5
g and 0.6 g of dimethyl sulfate were dissolved in 30 ml of methanol and refluxed for 2 hours. After evaporating the solvent, the product was recrystallized from methanol to obtain 2.4 g of the title compound. m. p. 90-92 ° C ¹ H-NMR (CDCl ₃ ) δ (ppm) =; 0.8
8 (3H, t, J = 6.5Hz), 1.20 to 1.69
(36H, m), 2.02 to 2.19 (2H, m),
2.34 (2H, t, J = 7.7Hz), 2.50 (4
H, t, J = 7.3 Hz), 3.24 (9H, s),
3.33 to 3.47 (2H, m), 3.58 to 3.71
(2H, m), 3.72 (3H, s), 8.07 (1
H, br. s) The following compounds were obtained by reacting in the same manner as in Example 5 except that trimethyl phosphate was used instead of dimethyl sulfate. N- {3- [11- (dodecylthio) undecanamido] propyl} -N, N, N-trimethylammonium dimethyl phosphate m. p. 65-67 ° C

Example 6 N- {3- [11- (dodecylthio) undecanaami ]
De] propyl} -N, N, N-trimethylammonium
= P-toluenesulfonate N- [3- (dimethylamino) propyl] -11- (dodecylthio) undecanamide 1.5 obtained in Production Example 5
g and 0.7 g of methyl p-toluenesulfonate were dissolved in 25 ml of ethanol and refluxed for 2 hours. After distilling off the solvent,
The product was recrystallized from ethanol-ether to obtain 1.6 g of the title compound. m. p. 90-92 ° C ¹ H-NMR (CDCl ₃ ) δ (ppm); 0.88
(3H, t, J = 6.5Hz), 1.11 to 1.66
(36H, m), 1.98-2.26 (4H, m),
2.36 (3H, s), 2.50 (4H, t, J = 7.
3 Hz), 3.23 (9 H, s), 3.29 to 3.43
(2H, m), 3.67 to 3.81 (2H, m), 7.
18 (2H, d, J = 7.9 Hz), 7.72 (2H,
d, J = 8.1 Hz), 8.30 (1H, br.s)

The following compounds were obtained by reacting with various sulfonates and sulfates in the same manner as in Example 6. N- {3- [11- (dodecylthio) undecanamido] propyl} -N, N, N-trimethylammonium = methyl sulfonate m.p. p. 88-90 ° C. N- {3- [11- (dodecylthio) undecanamido] propyl} -N, N, N-trimethylammonium = benzenesulfonate m.p. p. 86-88 ° C. N- {3- [11- (dodecylthio) undecanamido] propyl} -N, N, N-trimethylammonium = ethylsulfate m.p. p. 98-100 ° C. N- {3- [11- (dodecylthio) undecanamido] propyl} -N-ethyl-N, N-dimethylammonium = ethylsulfate m.p. p. 52-54 ° C

Example 7 N- {3- [11- (dodecylthio) undecanaami ]
De] propyl} -N, N, N-trimethylammonium
= Nitrate N- {3- [11- (dodecylthio) undecanamido] propyl} -N, N, N-trimethylammonium obtained in Example 1 = 1.5 g of iodide in 150 parts of ethanol.
0.1 ml of silver nitrate dissolved in 15 ml of water.
4 g was added, and the mixture was stirred at room temperature for 15 hours. The precipitated silver iodide was removed, the solvent was distilled off, and the product was recrystallized from ethanol to obtain 0.5 g of the title compound. m. p. 93-95 ° C ¹ H-NMR (CDCl ₃ ) δ (ppm); 0.8
8 (3H, t, J = 6.5 Hz), 1.19 to 1.69
(36H, m), 2.00 to 2.17 (2H, m),
2.27 (2H, t, J = 7.5Hz), 2.50 (4
H, t, J = 7.4 Hz), 3.27 (9H, s),
3.30-3.43 (2H, m), 3.64-3.78
(2H, m), 7.78 (1H, br.s)

The following compounds were obtained by reacting with various silver salts in the same manner as in Example 7. N- {3- [11- (dodecylthio) undecanamido] propyl} -N, N, N-trimethylammonium fluoride m.p. p. 63-65 ° C. N- {3- [11- (dodecylthio) undecanamido] propyl} -N, N, N-trimethylammonium chloride m.p. p. 93-95 ° C. N- {3- [11- (dodecylthio) undecanamido] propyl} -N, N, N-trimethylammonium nitrite m.p. p. 94-96 ° C

(Test Example) Hair Growth Effect Test The hair growth effect test of the alkanamide ammonium compound is as follows.
Five C3H mice (male, 7 weeks old) were used as a group, their back hairs were hair-removed, and 0.2 ml of the sample shown in Table 1 was applied to the site once a day for 10 days. The degree of hair growth was evaluated visually with the following 6 grades. No hair growth is observed 0 points Slight vellus hair is growing 1 point Slight bristles are growing 2 points Bristles are growing on 25% of the hair removal site 3 points Hair bristles are 50 parts of the hair removal site % 5% bristles grow on 75% of the hair removal site 5 points Bristles grow on 100% of the hair removal site 6 points The result after 42 days from the start of sample application is the average of the evaluation points. Table 2 by value
Shown in.

[0047]

[Table 1]

[0048]

[Table 2]

 ─────────────────────────────────────────────────── ─── Continued Front Page (72) Inventor Taro Matsumoto 3-24-1 Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. (72) Inventor Katsuo Hatayama 3-24-1 Takada, Toshima-ku, Tokyo Taisho Within Pharmaceuticals Co., Ltd.

Claims (1)

[Claims] Claims: [In Chemical Formula ¹ , R ¹ represents an alkyl group having 1 to 22 carbon atoms or a cycloalkyl group having 3 to 8 carbon atoms, R ² represents an alkylene group having 1 to 15 carbon atoms, and R ³ represents hydrogen. Represents an atom or a lower alkyl group, and R ⁴ has 2 carbon atoms
-10 is an alkylene group, R ⁵ and R ⁶ are the same or different and each is a lower alkyl group, and R ⁷ is a carbon atom of 1
To 22 alkyl group, alkenyl group having 2 to 10 carbon atoms or “lower alkyl group substituted with phenyl group”, A is an oxygen atom or (Wherein n represents an integer of 0 to 2 in Chemical Formula 2), X represents an atom or an atomic group which becomes an anion. ]
Alkaneamido ammonium compound represented by.