JP2000302757A - N-substituted piperidine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound having such a structure that an ether linkage-contg. higher alkyl group is bound to a piperidine residue, and useful as an ingredient of hair growers. SOLUTION: This new compound is a compound of formula I [R1 and R2 are each a (substituted) 1-30C hydrocarbon group or five- or six-membered (substituted) heterocyclic group containing 1-4 sulfur or nitrogen atom (s); R3 is H, a (substituted) alkyl or the like; (a) and (m) are each 0 or 1; X is a single bond or NH; and a group of the formula: (CH2)m-O-(CONR3)a-R2 is bound to the 2- or 3-position], e.g. 2- [3-(N,N-dimethylamino) propylcarbamoyloxy]methyl}-1-(octadecylcarbamoyl)piperidine. The compound of formula I is obtained, for example, by condensation reaction between a compound of formula II and an isocyanate: OCN-R1 to form a compound of formula III which, in turn, is reacted with a compound of formula IV [R4 is H, a (substituted) alkyl or the like].

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an N-substituted piperidine derivative, and more specifically to an N- and 2- or 3-disubstituted piperidine derivative and a hair restorer containing the derivative as an active ingredient.

[0002]

2. Description of the Related Art For example, compounds having a higher alkyl group containing an ether bond or a urethane bond and a compound containing an amine or ammonium moiety as a substituent of a disubstituted derivative of 1,3-propanediol have antiallergic and antiinflammatory effects. Japanese Patent Publication No. 10-109
No. 968. Japanese Patent Application Laid-Open No. 10-114630 describes a similar compound having a hair-growth action.

The present inventors have found that compounds having quite a different substituent from those of the above-mentioned compounds, but having a completely different category in that the basic atomic group to which these substituents are bonded are piperidine residues, are excellent. It has been found that it has a hair nourishing action.
The present invention is based on such findings.

[0004]

Therefore, according to the present invention, the compound represented by the general formula (I)

[0005]

Embedded image [Wherein, R ¹ and R ² are each independently a substituted or unsubstituted C _1-30 hydrocarbon group or a heterocyclic group containing 1 to 4 hetero atoms selected from oxygen, sulfur and nitrogen atoms, or 5 or R ³ represents a hydrogen atom, an optionally substituted alkyl group, an acyl group, an alkoxycarbonyl group, a phenoxycarbonyl group or an optionally substituted carbamoyl group; Or 1 and m
Represents 0 or 1, X represents a single bond or —NH—, and a group of the formula — (CH ₂ ) _m —O— (CONR ³ ) _a —R ² represents 2 or 3
Or a salt thereof.

Further, as another aspect of the present invention, there is provided a hair restorer containing a compound represented by the general formula (I) or a salt thereof as an active ingredient.

[0007] In the definition of formula (I), the hydrocarbon group C _1-30 in R ^1, R ^2, an alkyl group of C _1-30, cycloalkyl group of C _3-8, C _2- Examples thereof include a ₁₀ alkenyl group, a C _2-10 alkynyl group, a C _3-10 cycloalkenyl group, a C _6-14 aryl group and a C _7-16 aralkyl group.

The C _1-30 alkyl group includes, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl,
Heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, icosyl, henicosyl, docosyl, tricosyl, tetracosyl, pentacosyl, hexacosyl, heptacosyl, octacosyl, nonacosyl, direct triacyl, etc. Chain alkyl; for example, 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-methyldocosyl, 2-pentyloctadecyl, 22-methyltricosyl, 12-hexyloctadecyl, 6-methyltetracosyl, Examples include branched alkyl groups such as 24-methylheptacosyl, 2-decylhexadecyl, 2-nonyloctadecyl, 2-dodecyloctadecyl, 3-methyltetracosyl, and 3-methyltricosyl.

[0009] Of these, the hydrocarbon group of C _1-30 in the preferred R ^1, R ^2, a straight-chain or branched alkyl group of C _{6- 22,} more preferably C _10-22 linear or branched alkyl Groups.

The C _3-8 cycloalkyl group includes, for example, cyclopropyl, cyclopentyl, cyclohexyl and the like.

Examples of the C _2-10 alkenyl group include vinyl, allyl, 2-methylallyl, 2-butenyl, 3-
Butenyl, 3-octenyl, 2-nonenyl, 4-decenyl and the like.

Examples of the C _2-10 alkynyl group include ethynyl, 2-propynyl, 3-hexynyl and the like.

Examples of the C _3-10 cycloalkenyl group include cyclopropenyl, cyclopentenyl, cyclohexenyl and the like.

As the C _6-14 aryl group, for example, phenyl, naphthyl and the like can be mentioned.

Examples of the C _7-16 aralkyl group include benzyl and phenylethyl.

The C _1-30 hydrocarbon group in R ¹ and R ² may have a plurality of, for example, 1 to 5 substituents at any substitutable position in the carbon chain. Specific examples of the substituent include C _3-8 cycloalkyl,
Hydroxyl group, mercapto, oxo, thioxo, cyano, carbamoyl, carboxyl, C _1-4 alkoxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, etc.), sulfo, halogen (fluorine, chlorine, bromine, iodine), C _1-4 alkoxy ( For example, methoxy, ethoxy,
Propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc., phenoxy, halogenophenoxy (eg, o-, m- or p-chlorophenoxy, o-, m- or p-bromophenoxy, etc.), C _1-4 lower alkylthio (eg, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, tert-butylthio, etc.), phenylthio, C _1-4 alkylsulfinyl (eg, methylsulfinyl, ethylsulfinyl, etc.), C _{1 -4} alkylsulfonyl (eg, methylsulfonyl, ethylsulfonyl, etc.), C _1-10 haloalkyl (eg, difluoromethyl, trifluoromethyl, trifluoroethyl, trichloroethyl, etc.), formyl, C _1-5 alkanoyl (eg, Acetyl, etc. , Benzoyl, and the like. Further, as a substituent of the hydrocarbon group, amino, optionally substituted amino, that is, C _1-6 acylamino (eg, acetylamino, propionylamino, etc.), 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, pentadecylamino, hexadecylamino, heptadecylamino, octadecylamino, nonadecylamino, icosylamino, henicosylamino, docosylamino, tricosyl amino,
Tetracosylamino, pentacosylamino, hexacosylamino, heptacosylamino, octacosylamino,
Nonacosylamino, triacontylamino, etc.), di-C
_1-4 alkylamino (for example, dimethylamino, diethylamino, N-methyl-N-ethylamino, N-methyl-
N-propylamino and the like).

Another specific example of the substituent of the C _1-30 hydrocarbon group is a 5- or 6-membered optionally substituted heterocyclic group containing 1 to 4 hetero atoms selected from oxygen, sulfur and nitrogen atoms. Ring groups such as pyrrolidyl, piperidyl, morpholino, 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,
H or 2H-tetrazolyl, 2-, 3- or 4-pyridyl, 2-, 4- or 5-pyrimidyl, 3- or 4-pyridazinyl, quinolyl, imidaquinolyl, indolyl and the like. These heterocyclic groups are usually C _1-2
With a hydrocarbon group. These heterocyclic groups may have 1 to 4 substituents, and specific examples of such substituents include halogens such as fluorine, chlorine, and bromine, such as methyl and ethyl. _C1-4 alkyl such as, propyl, isopropyl and the like, for example o
-, M-, or p-chlorophenoxy, o-, m-,
Or halogenophenoxy such as p-bromophenoxy.

C_1-30The above is a specific example of a hydrocarbon group of
C_3-8A cycloalkyl, C_3-10Of cycloalkenyl,
C_6-14Aryl or C_7-16Preferred aralkyl groups
Substituents include, for example, methyl, ethyl, propyl,
C such as isopropyl and butyl _1-4List of alkyl groups
And can have from one to four of these
You.

When the substituent of the C _1-30 hydrocarbon group in the definition of R ¹ and R ² is a C _3-8 cycloalkyl group, the hydrocarbon group is a C _6-14 straight chain. It is preferably an alkyl group.

As the heterocyclic group in the definition of R ¹ and R ² , specifically, 2-, 3- or 4-pyridyl or 2
Examples thereof include 5- or 6-membered aromatic or alicyclic heterocycles such as-, 3- or 4-piperidyl.
These heterocyclic groups may be substituted with halogen, C _1-4 alkyl, or oxo.

Among the groups defined above for R ¹ and R ² , particularly preferred compounds are those wherein R ¹ is a C _1-30 hydrocarbon group, more preferably a C _1-30 alkyl group,
R ² is substituted with an optionally substituted amino group.
Examples thereof include a compound having 1 to ₃₀ hydrocarbon groups or a salt thereof. In particular, R ² is a general formula

[0022]

Embedded image [Wherein R ⁴ and R ⁵ are each independently a hydrogen atom, an optionally substituted C _1-5 alkyl group, and n is an integer of 1 to 10] or a salt thereof. . R ⁴ and R ⁵ are the same or different and are preferably C _1-3 alkyl. Examples of the substituent of the C _1-5 alkyl group include a hydroxyl group and a phenyl group.

Further, in the above equation, R^Four, R^FiveAre they
A nitrogen-containing heterocyclic ring taken together with the bonding nitrogen atom, for example,
It may form a 5- or 6-membered heterocyclic ring. Specifically
Is R ^FourAnd R^FiveBinds to tetramethylene, pentamethylene
It may form a chain. Also R^Four, R^FiveAre they combined
Other heteroatoms (e.g., oxygen, nitrogen)
Form a 5- or 6-membered heterocyclic ring through
May be formed.

In the general formula (I), the alkyl group in the optionally substituted alkyl group represented by R ³ includes:
Examples thereof include C _1-5 alkyl groups such as methyl, ethyl, propyl, butyl, pentyl and the like. Such C _1-5
Alkyl groups such as carboxyl, lower (C _1-5 )
It may be substituted by alkoxycarbonyl (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl) and the like.

Examples of the acyl group in the definition of R ³ include formyl, C _2-5 lower alkanoyl (eg, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl) and benzoyl.

Examples of the alkoxycarbonyl group in the definition of R ³ include C _1-5 lower alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and pentyloxycarbonyl. Examples of the optionally substituted carbamoyl group in the definition of R ³ include carbamoyl, lower (C _1-5 ) alkylcarbamoyl (eg, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, butylcarbamoyl), di-lower (C _{1- 5} ) alkylcarbamoyl (eg, dimethylcarbamoyl, methylethylcarbamoyl, diethylcarbamoyl, methylpropylcarbamoyl), 3- to 7-membered cyclic aminocarbonyl (eg, (aziridin-1-yl) carbonyl, (azetidin-1-yl) carbonyl, (Pyrrolidin-1-yl) carbonyl, piperidinocarbonyl, (piperazin-1-yl) carbonyl, morpholinocarbonyl, thiomorpholinocarbonyl) and the like.

R ³ together with R ² together with the nitrogen atom to which they are attached, together with oxygen and sulfur atoms, and C 2
_1-3 atoms which form a 5- or 6-membered optionally substituted nitrogen-containing heterocyclic group which may contain up to 3 heteroatoms selected from an alkyl group or a nitrogen atom which may be bonded to a hydrogen atom Could be a troupe. Specific examples of the 5- or 6-membered nitrogen-containing heterocyclic group which may be substituted are exemplified as the substituents of the C _1-30 hydrocarbon group in the definition of R ¹ and R ² . Examples of the heterocyclic group include nitrogen-containing heterocyclic groups and those described below.

Preferably, the nitrogen-containing heterocyclic group formed by R ² and R ³ together with the nitrogen atom to which they are bonded has the general formula

[0029]

Embedded image [Wherein Y represents an oxygen or sulfur atom, or a C _1-3 alkyl group or a nitrogen atom to which a hydrogen atom is bonded].

When R ³ independently represents one substituent, R ³ is preferably a hydrogen atom or a C _1-5 lower alkanoyl, more preferably a hydrogen atom.

X represents a single bond or -NH-, and -NH
When-, R ¹ is preferably bonded to the nitrogen atom via the carbon atom in the group.

In the compound of the general formula (I), when a is 0,
R ² is bonded via an ether bond. When a is 1, R ² is bonded via —OCONR ³ —.

The group of the formula-(CH ₂ ) _m -O- (CONR ³ ) _a -R ² is bonded to the 2- or 3-position of the piperidine ring, especially when m is 1 Is preferred.

When the compound of the formula (I) has a basic group such as an amino group or an imino group in the molecule, the compound of the formula (I) can be an acid addition salt. Such salts include pharmacologically or cosmetically or dermatologically acceptable inorganic acid salts, such as hydrogen halide salts (eg, hydrochloride, hydrobromide, etc.), sulfates, nitrates,
Phosphates and the like, or organic acid salts such as acetate, propionate, hydroxyacetate, 2-hydroxypropionate, 2-oxopropionate, ethanedioate, propanedioate, butanedioate Methanesulfonate, ethanesulfonate, benzenesulfonate, 4-methylbenzenesulfonate, 2-hydroxybenzoate, citrate, oxalate and the like. When the compound of the general formula (1) has an acidic group such as a carboxyl group or a sulfo group in the molecule, the compound may be mixed with an ammonium salt, an alkali metal salt (for example, a lithium salt, a sodium salt, or a potassium salt) or an organic base. They can also be used as salts, for example, salts with amino acids such as arginine salts and lysine salts.

The compound represented by the general formula (I) or a compound thereof
The salts may be anhydrous or hydrated. Also one
The compound represented by the general formula (I) or a salt thereof is an isotope
(E.g., ^ThreeH,¹⁴C,³⁵S,¹²⁵I etc.)
Is also good.

The compound represented by the general formula (I) or a salt thereof can be produced by a method known per se according to any of the following reaction schemes or a modified manner thereof.

X in the general formula (I) is -NH-,
There is 1, R ³ is H, and R ² is - (CH _{2) n} -
Production of a compound represented by the following formula (I-1) which is NR ⁴ R ⁵

[0038]

Embedded image Each symbol in the formula has the same meaning as defined above unless otherwise specified (the same applies hereinafter). The compound represented by the formula (I-1) can be produced, for example, according to the following reaction schemes AA to AG.

In the following reaction scheme, the case where R ^{3 in the} general formula (I) is a hydrogen atom is exemplified. However, when R ³ has a corresponding reactant having a group other than a hydrogen atom, any one of By carrying out the reaction according to an appropriate reaction scheme, the compound of the present invention in which R ³ of the general formula (I) has a group other than a hydrogen atom can be produced (the same applies hereinafter).

[0040]

Embedded image According to Reaction Scheme AA, in the first step, a condensation reaction between compound (II) and isocyanate (IV), or
Compound (III) is obtained by the reaction with amine (V).

In the addition reaction, for example, boron trifluoride ethyl etherate, hydrochloric acid,
Acids such as aluminum chloride, dialkyltin dichloride, dialkyltin acetate, or triethylamine, N, N
Bases such as diisopropylethylamine, pyridine, N-methylmorpholine, N-methylpiperidine, sodium acetate and the like are used. As the solvent, for example, dichloromethane, halogenated hydrocarbons such as chloroform, benzene,
Aromatic hydrocarbons such as toluene and xylene, ethers such as tetrahydrofuran and 1,4-dioxane, and amides such as N, N-dimethylformamide and N, N-dimethylacetamide are used. This addition reaction may be carried out in a temperature range from 0 ° C. to the reflux temperature of the solvent, although the reaction temperature and the reaction time may be changed according to the starting compound and the reagent used. Specifically, for example, in a solvent such as dichloromethane using triethylamine as a reaction accelerator,
The compound (III) can be obtained by reacting the compound (II) with the isocyanate (IV) in the range of 0 ° C. to room temperature.

The compound (II) is reacted with the compound (V) by protecting either the imino group or the hydroxyl group in the compound (II), and then phenyl chlorocarbonate, phosgene, diphosgene, triphosgene, di-2-pyridyl. The compound (II) is converted into its corresponding carbonate derivative using a ketone or the like, and then reacted with the amine (V). Examples of the protecting group for protecting either the imino group or the hydroxyl group in the compound (II) include those known as protecting groups for these groups, and groups that themselves constitute the compound (I) of the present invention, for example,- it can be a CO-X-R ^1. In this reaction, as a reaction accelerator, for example, pyridine, triethylamine, N, N-diisopropylethylamine,
Bases such as pyridine and sodium carbonate can be used. Examples of the reaction solvent include halogenated hydrocarbons such as dichloromethane and chloroform, aromatic hydrocarbons such as benzene, toluene, and xylene, and ethers such as tetrahydrofuran and 1,4-dioxane. The reaction temperature and reaction time are based on the starting compound used,
Although it may be changed according to the reagent, it is usually carried out in the range of -15 ° C to the reflux temperature of the solvent. Specifically, for example,
Using pyridine, N, N-diisopropylethylamine or the like as an additive, the amine (V) is reacted with phenyl chlorocarbonate, triphosgene or the like in a solvent such as chloroform or dichloromethane at a temperature ranging from -15 ° C to room temperature. The obtained corresponding carbonate derivative is subjected to no solvent or a solvent such as chloroform or dichloromethane at room temperature to 100 ° C.
Compound (III) can be obtained by reacting with compound (II) in the range of

In the second step, compound (III) and compound (V
The reaction with I) is carried out according to the first-stage addition reaction of isocyanate, while compound (III) and compound (VII)
Can be carried out according to the reaction between compound (II) and compound (V). Thus, the desired compound (I-
1) is obtained.

[0044]

Embedded image According to Reaction Scheme AB, the target compound is prepared from the compound protected the nitrogen atom of the piperidine ring with a protecting group L ¹ (VIII). The protecting group L ^1, can also be used in any protecting groups as long as it does not adversely affect the reaction used, for example, tert-butyloxycarbonyl group, benzyloxycarbonyl group, a 9-fluorenylmethyloxycarbonyl Urethane-type protecting groups such as carbonyl groups, 2
A sulfonyl-type protecting group such as-(trimethylsilyl) ethanesulfonyl group, a sulfenyl-type protecting group such as 2,2,2-trifluoro-1,1-diphenylethanesulfenyl group, a benzyl group, a trityl group, and 9-phenylfuran; Represents an alkyl-type protecting group such as an oleenyl group. The definition of L ^{1 has} the same meaning in the following.

In the first step of Reaction Scheme AB,
By a method according to the first step of the above reaction scheme AA,
Compound (IX) is obtained by reacting compound (VIII) with isocyanate (VI) or amine (VII).

In the second step of the reaction scheme AB, the compound (IX) is first subjected to a deprotection reaction and then reacted with an isocyanate or an amine to give the desired compound (I-
1) is obtained. The deprotection reaction of the former per se can be used various known methods depending on the type of amino protecting group L ^1. Specifically, for example, when L ¹ is a benzyloxycarbonyl group, palladium-carbon is used as a catalyst in a solvent such as ethanol or ethyl acetate under a hydrogen gas atmosphere at room temperature to the reflux temperature of the solvent. The purpose can be achieved by performing the reaction. The latter reaction is
The reaction can be carried out by a method according to the first step of the reaction formula AA.

[0047]

Embedded image According to Reaction Scheme AC, compound (X) and amine (X
The target compound (I-1) can be obtained by reacting I) usually in the presence of a base. L ² in the compound (X) means an atom or a group that easily substitutes for nitrogen, and examples thereof include a halogen atom, a tosyloxy group, and a mesyloxy group. Definition of L ² are the same also in the following. As the base for this reaction, for example, inorganic bases such as potassium carbonate, potassium hydroxide, sodium hydroxide, and sodium hydride, and organic bases such as triethylamine and pyridine are used. As the solvent, toluene, ether, tetrahydrofuran, chloroform, dichloromethane, acetone, N, N-dimethylformamide and the like are used. Specifically, for example, the reaction can be performed using potassium carbonate as a base in a solvent such as acetone or N, N-dimethylformamide at room temperature to the reflux temperature of the solvent.

The compound (I-1a) of the present invention wherein R ⁴ and R ⁵ are both hydrogen atoms can be synthesized according to the following reaction scheme AD.

Reaction Scheme AD:

[0050]

Embedded image According to Reaction Scheme AD, the amino-protected compound (XII)
Is subjected to a deprotection reaction to obtain the target compound.
L ³ and L ⁴ in compound (XII) each represent an amino-protecting group, which may be any protecting group as long as the purpose of the reaction is not adversely affected, and either one of them may be a tert-butyloxycarbonyl group or a benzyloxycarbonyl group. Urethane-type protecting groups such as, 9-fluorenylmethyloxycarbonyl group,
Sulfonyl-type protecting groups such as 2- (trimethylsilyl) ethanesulfonyl group and the like, sulfenyl-type protecting groups such as 2,2,2-trifluoro-1,1-diphenylethanesulfenyl group, benzyl group, trityl group and 9-phenyl An amino-protecting group such as an alkyl-type protecting group such as a fluorenyl group,
The other can be a hydrogen atom, or L ³ and L ⁴ can be a phthalimide-type amino protecting group formed together. The definitions of L ³ and L ^{4 have} the same meaning in the following.

In this deprotection reaction, various methods known per se can be used depending on the types of the amino protecting groups L ³ and L ⁴ . Specifically, for example, when L ³ is a benzyloxycarbonyl group and L ⁴ is a hydrogen atom, ethanol,
The reaction can be carried out in a solvent such as ethyl acetate using palladium-carbon as a catalyst in a hydrogen gas atmosphere at room temperature to the reflux temperature of the solvent. In the case of a phthalimide-type amino protecting group formed by combining L ³ and L ⁴ , hydrazine is used as a deprotecting agent, and the reaction is carried out in ethanol at a temperature ranging from room temperature to the reflux temperature of the solvent. It can be carried out.

[0052]

Embedded image According to the reaction scheme AE, the compound (I-1a) is reacted with the halide (XIII) in the presence of a base, or the carbonyl compound corresponding to R ⁴ is reacted with the compound (I-1a)
The compound (I-1b) of the present invention is obtained by subjecting the compound to a reductive alkylation reaction. X in the compound (XIII) represents a halogen atom. The definition of X in the following reaction schemes is also synonymous.

In the reaction with the halide (XIII),
As the base, for example, potassium carbonate, potassium hydroxide,
Inorganic bases such as sodium hydroxide and sodium hydride, and organic bases such as triethylamine and pyridine are used.
Specifically, for example, using potassium carbonate as a base,
The reaction can be carried out in a solvent such as acetone or N, N-dimethylformamide at room temperature to the reflux temperature of the solvent.

In the reductive alkylation reaction, the carbonyl compound corresponding to R ⁴ may be condensed with the compound (I-1a), and the resulting imine or iminium ion may be reduced with a reducing agent. As the reducing agent, for example, sodium cyanoborohydride or the like may be used, or the reaction may be performed under catalytic reduction conditions using palladium or the like as a catalyst. Specifically, for example, palladium-catalyst under catalytic reduction conditions
The reaction can be carried out using carbon in a solvent such as ethanol at room temperature to the reflux temperature of the solvent.

[0055]

Embedded image According to the reaction scheme AF, by reacting the compound (I-1b) and the halide (XIV) in the presence of a base,
The compound (I-1) of the present invention can be obtained. This reaction can be carried out by a method according to the above Reaction Scheme AE.

[0056]

Embedded image According to the reaction scheme AG, the compound of the present invention (I-1a)
Is reacted with about 2 equivalents of a halide (XIII) in the presence of a base to give a compound of the present invention (I-1c) in which R ⁴ and R ⁵ are the same. This reaction can be carried out by a method according to the above-mentioned reaction scheme AE.

Further, in the same manner as in Reaction Scheme AG, the compound (I-1a) is reacted with a corresponding dihalogenated hydrocarbon compound which may be interrupted by a nitrogen, oxygen or sulfur atom to obtain a compound of the general formula In (I-1), the compound of the present invention in which R ⁴ and R ⁵ together with the nitrogen atom to which they are bonded form a 5- or 6-membered optionally substituted heterocyclic group is obtained.

The method for producing the main starting compounds used in each of the above reaction schemes AA to AG will be described.

The isocyanate (IV) or (VI) in the reaction scheme AA can be obtained commercially, or can be produced according to the following reaction scheme AH or reaction scheme AI, respectively.

[0060]

Embedded image According to reaction scheme AH, phosgene is added to amine (V),
Isocyanate (IV) is obtained by reacting diphosgene, triphosgene or the like in the presence or absence of a base, or by reacting carboxylic acid (XV) with diphenylphosphoryl azide or the like in the presence of a base.

As the base in this reaction, for example, organic bases such as triethylamine, N, N-diisopropylethylamine, pyridine and the like are preferably used. Examples of the solvent include halogenated hydrocarbons such as dichloromethane and chloroform, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as tetrahydrofuran and 1,4-dioxane, N, N-dimethylformamide, N, N -Amides such as dimethylacetamide and the like are used. The reaction temperature and reaction time are based on the starting compound used,
Although the reaction may be changed depending on the reagent, the reaction is usually carried out at a temperature in the range of -15 ° C to the reflux temperature of the solvent. Specifically, for example, using triethylamine as a base, performing a reaction between carboxylic acid (XV) and diphenylphosphoryl azide in a solvent such as N, N-dimethylformamide in a range of room temperature to the reflux temperature of the solvent. Can be.

According to the reaction scheme AI, the amine (VI
When R ⁴ or R ⁵ in the carboxylic acid (XV) has a tertiary amine structure together with the nitrogen atom to which it is bonded, the amine (VII) or the carboxylic acid (XVI)
To give isocyanate (VI) by a method according to reaction scheme AH.

The starting compound (XI
I) can be produced by the following reaction scheme AJ.

[0064]

Embedded image In the first step of Reaction Scheme AJ, compound (III) is obtained by addition reaction of compound (II) with isocyanate (IV) or reaction with amine (V). Then, the compound (III) is converted to an isocyanate (XVII) or an amine (X
The desired compound (XII) is obtained by reacting with VIII). All of these reactions are described in Reaction Scheme A above.
A can be performed by a method according to the first step of A.

In addition, the starting compound (XII) can be prepared by reacting the compound (VII)
It can also be produced according to the following reaction scheme AK using I) as a raw material.

[0066]

Embedded image According to the reaction scheme AK, an addition reaction between the compound (VIII) and the isocyanate (XVII) or an amine (XVIII)
The compound (XIX) is obtained by the reaction with Then
After subjecting compound (XIX) to a deprotection reaction, compound (X) is obtained by reacting with isocyanate (IV) or amine (V). All of these reactions can be performed by a method according to the above-mentioned reaction scheme AB.

The starting material isocyanate (XVII) in Reaction Schemes AJ and AK can be obtained commercially or, as shown in Reaction Scheme AL below, from amine (XVIII) or carboxylic acid (XX).
It is produced by a method according to Reaction Scheme AH.

[0068]

Embedded image The starting compound (XII) in Reaction Scheme AD can be produced according to the following Reaction Scheme AM.

[0069]

Embedded image In the first step of reaction scheme AM, compound (III) is obtained by addition reaction of compound (II) with isocyanate (IV) or reaction with amine (V). Then, the compound (III) is reacted with an isocyanate (XXI) or an amine (XXII) to give the desired compound (XII)
Is obtained. All of these reactions can be performed by a method according to the first step of the above-mentioned reaction scheme AA.

The starting compound (XII) can be prepared by reacting the compound (VII)
It can also be produced according to the following reaction scheme AN using I) as a starting material.

[0071]

Embedded image According to Reaction Scheme AN, a compound (XXIII) is obtained by an addition reaction of the compound (VIII) with an isocyanate (XXI) or a reaction with an amine (XXII). Then
After subjecting compound (XXIII) to a deprotection reaction, compound (XII) is obtained by reacting with compound (XXIII) with isocyanate (IV) or amine (V). All of these reactions can be performed by a method according to the above-mentioned reaction scheme AB.

Isocyanate (XXI) which is a starting compound in reaction schemes AM and AN can be produced from amine (XXII) or carboxylic acid (XXIV) by a method according to reaction scheme AH according to the following reaction scheme AO.

[0073]

Embedded image It should be noted that those skilled in the art will appreciate that the compounds of the present invention in which R ² is a group other than-(CH ₂ ) _n NR ⁴ R 5 also refer to each of the above reaction schemes and use the raw materials used in them as separate raw materials. It can be easily manufactured by replacing it. For example, the object can be achieved by using another raw material in which the —NR ⁴ R ⁵ part of the compounds (VI) and (VII) in the reaction scheme AA is replaced with another group.

In the general formula (I), X is -NH-, a is 1, R ³ is H, and R ¹ is-(CH
₂ ) For the compound having a group corresponding to _n- NR ⁴ R ⁵ , for example, in the first step of the reaction scheme AA, the hydroxyl group of the compound (II) is appropriately protected, and then the isocyanate (IV) )), Or using compound (VII) instead of compound (V).

X in the general formula (I) is -NH-, and a is
0 and R ² is — (CH ₂ ) _n NR ⁴ R ⁵
Production of the compound represented by 2)

[0076]

Embedded image Such compounds are described, for example, in the following reaction scheme BA:
It can be manufactured according to BB or BC.

[0077]

Embedded image According to the reaction scheme BA, the compound (I-2) of the present invention can be obtained by alkylating the hydroxyl group of the compound (III) obtained in the above reaction scheme AA. This reaction is achieved by a substitution reaction between compound (III) and halide (XXV) or sulfonic acid ester (XXVI), or when n is 3 or more, an addition reaction with alkene (XXVII).

In the substitution reaction, the compound (III) is converted into the corresponding alkoside using sodium metal, sodium hydride or the like and then reacted with the halide (XXV), or the compound (III) is reacted with the halide (XXV). ) Can be directly reacted in the presence of a base. As the base,
Sodium amide, potassium carbonate, sodium hydroxide,
Barium oxide, silver oxide, or the like can be used. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as tetrahydrofuran and 1,4-dioxane; amides such as N, N-dimethylformamide, N, N-dimethylacetamide and hexamethylphosphoramide. , Acetonitrile, dimethyl sulfoxide and the like can be used. The reaction temperature and reaction time may be changed according to the starting compounds and reagents used, but the reaction is usually carried out in the range of 0 ° C. to the reflux temperature of the solvent. Specifically, for example, compound (III), halide (XXV) and potassium carbonate can be reacted in acetone at room temperature to reflux temperature.

The substitution reaction with the sulfonic acid ester (XXVI) is carried out by using benzene, tetrahydrofuran, 1,4
-Dioxane, N, N-dimethylformamide, dimethylsulfoxide, dichloromethane, water and the like. The reaction temperature and reaction time may be changed according to the starting compounds and reagents used, but the reaction is usually carried out in the range of 0 ° C. to the reflux temperature of the solvent. The sulfonic acid ester (XXVI) can be easily synthesized from the corresponding alcohol compound and p-toluenesulfonyl chloride in the presence of a base such as pyridine. Specifically, for example, a solution of the corresponding alcohol compound and a solution of p-toluenesulfonyl chloride in 1,4-dioxane is added to an aqueous sodium hydroxide solution at 0 ° C. to room temperature, and then the compound (III) is added. Can be achieved. The sulfonic acid ester (XX
In VI), Ar represents a 4-methylphenyl group, a naphthyl group, or the like, which is synonymous in the definition of Ar below.

Further, in the present invention, the compound (I-2) of the present invention can also be obtained by carrying out a substitution reaction in the same manner as above except that the sulfonic acid ester (XXVI) is replaced with another ester compound. For example, a phosphoric acid ester, a trichloroacetimidic acid ester, or the like corresponding to the sulfonic acid ester (XXVI) can be used.

The addition reaction with the alkene (XXVII) is carried out in the presence of an acid catalyst. As the catalyst, hydrochloric acid, sulfuric acid, boron trifluoride, trifluoromethanesulfonic acid, tetrafluoroboric acid and the like are used. An organic metal compound such as sodium methoxide can be used instead of the acid catalyst. This reaction is carried out in the presence or absence of a solvent, and benzene, tetrahydrofuran, diethyl ether, 1,4-dioxane, N, N-dimethylformamide, dichloromethane or the like is used as the solvent. The reaction temperature and reaction time may be changed depending on the starting compounds and reagents used, but the reaction is usually carried out in the range of -100 ° C to 200 ° C. Specifically, for example, compound (III)
-Alkene (XXVII) in dichloromethane solution
The reaction can be carried out by adding trifluoromethanesulfonic acid at a temperature in the range of 0 ° C to 0 ° C.

[0082]

Embedded image According to Reaction Scheme BB, in the first step, compound (XXXI) is obtained by alkylating the hydroxyl group of Compound (III) obtained in Reaction Scheme AA. This reaction is a substitution reaction of a compound (III) with a halide (XXVIII) or a sulfonate (XXIX) as in the above Reaction Scheme BA, or addition of an alkene (XXX) when n is 3 or more. Achieved by reaction.

In the second step of Reaction Scheme BB,
The compound (I-2) of the present invention can be obtained by reacting the compound (XXXI) with the amine (XI) in the presence of a base. This reaction can be carried out by a method according to Reaction Scheme AC.

[0084]

Embedded image According to the reaction scheme BC, in the first step, the compound (XXXV) is obtained by alkylating the hydroxyl group of the compound (III). In this reaction, similarly to the above Reaction Scheme BA, substitution reaction between compound (III) and halide (XXXII) or sulfonic acid ester (XXXIII), or addition reaction with alkene (XXXIV) when n is 3 or more Is performed.

In the second step of the reaction scheme BC, the compound (XXXV) is subjected to a deprotection reaction by a method according to the above reaction scheme AD, whereby the compound of the present invention wherein both R ⁴ and R ⁵ are hydrogen atoms (I-2a) can be obtained. Further, the compound of the present invention (I-2a) was prepared by a method according to the above Reaction Schemes AE to AG.
2) can be led.

Compound (I-2) is compound (VIII)
Is used as a starting material, an ether compound corresponding to the compound (IX) in the above reaction scheme AB is first synthesized by a method according to the above reaction scheme BA, and then, after the deprotection reaction,
It can also be produced by performing a reaction with an isocyanate (IV) or an amine (V). Similarly, an ether compound corresponding to the compound (XIX) in the reaction scheme AK or the compound (XXII) in the reaction scheme AN
First, an ether compound corresponding to I) is synthesized, followed by a deprotection reaction, and then an isocyanate (IV) or an amine (V).
The target compound of the present invention (I-2) can also be synthesized by a method via the reaction with These methods can be basically used similarly when the reaction scheme described below is followed.

The compound (XXV), (XXVI) or (XXVII) used in producing the compound (I-2)
By using a compound in which the (CH ₂ ) _n R ⁴ R ⁵ moiety is replaced with a structure corresponding to another R ² , the compound (I) of the present invention other than the compound (I-2) can be produced in the same manner. (Less than,
Similar).

Further, a compound in which X in the general formula (I) is -NH-, a is 0, and R ¹ is-(CH ₂ ) _n -NR ⁴ R 5 is also used in each of the above reaction schemes. It can be easily manufactured by changing the order of each step.

X in the general formula (I) is a single bond, and a is
1 and R ² is — (CH ₂ ) _n —NR ⁴ R ⁵ in the following formula (I-3)
Production of the represented compound

[0090]

Embedded image Such compounds can be prepared, for example, by the following reaction schemes CA, C
It can be manufactured according to B or CC.

[0091]

Embedded image According to the reaction scheme CA, in the first step, the amide compound (XXXIX) is obtained by acylating the amino group of the compound (II). The reaction is carried out with compound (II)
And carboxylic acid compounds (XV), acid halides (XXXV
I), acid anhydride (XXXVII) or mixed acid anhydride (XXXVI)
II) and the like.

In the method using a condensing agent in the reaction with the carboxylic acid compound (XV), for example, N, N'-dicyclohexylcarbodiimide (DCC), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride ( Carbodiimides such as WSCI) and carbonyldiimidazoles such as 1,1'-carbonyldiimidazole;
Chloride such as titanium tetrachloride and silicon tetrachloride is used as a condensing agent. As the solvent, for example, dichloromethane,
Halogenated hydrocarbons such as chloroform, aromatics such as benzene, toluene, xylene and pyridine; ethers such as tetrahydrofuran and 1,4-dioxane;
Amides such as N-dimethylformamide and N, N-dimethylacetamide are used. This reaction can be carried out by adding 1-hydroxybenzotriazole (HOBt) or N-hydroxysuccinimide (HOSu) as necessary. The reaction temperature and reaction time may be changed according to the starting compound used, but the reaction is usually carried out at a temperature within the range of -78 ° C to the reflux temperature of the solvent.

The carboxylic acid compound (XV) is converted into its corresponding azide using, for example, diphenylphosphoryl azide as an activator, and then the compound (I
The target compound can also be produced by reaction with I) (azide method). As the additive, for example, organic bases such as triethylamine, pyridine, and N-methylmorpholine are used. Examples of the solvent include halogenated hydrocarbons such as dichloromethane and chloroform; aromatics such as benzene, toluene, xylene and pyridine; ethers such as tetrahydrofuran and 1,4-dioxane; N, N-dimethylformamide; Amides such as N-dimethylacetamide and sulfoxides such as dimethylsulfoxide are used. The reaction temperature and reaction time may be changed according to the starting compound used, but the reaction is usually carried out in the range of 0 ° C. to the reflux temperature of the solvent.

When the acid halide (XXXVI) or the acid anhydride (XXXVII) is used, for example, an organic base such as triethylamine, pyridine or N-methylmorpholine;
The target compound can be produced by reacting with compound (II) in the presence of an inorganic base such as sodium hydroxide or a salt such as sodium acetate or potassium carbonate. As the solvent, for example, dichloromethane, halogenated hydrocarbons such as chloroform, benzene, toluene,
Aromatics such as xylene and pyridine; ethers such as diethyl ether, tetrahydrofuran and 1,4-dioxane; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; sulfoxides such as dimethyl sulfoxide; water Alternatively, a mixed solvent thereof is used. The reaction temperature and reaction time may be changed according to the starting compound used, but the reaction is usually carried out in the range of 0 ° C. to the reflux temperature of the solvent.

In the case of the mixed acid anhydride method, a carboxylic acid compound (XV) is used as an activator using, for example, ethyl chloroformate, isobutyl chloroformate, pivaloyl chloride, diphenylphosphinic chloride, phosphorus oxychloride and the like. ) Is converted to its corresponding mixed anhydride (XXXVIII) and then reacted with compound (II). As the reaction accelerator, for example, organic bases such as triethylamine, pyridine, and N-methylmorpholine are used. Examples of the solvent include halogenated hydrocarbons such as dichloromethane and chloroform, aromatics such as benzene, toluene, xylene and pyridine, ethers such as tetrahydrofuran and 1,4-dioxane, N, N-dimethylformamide, N, N Amides such as dimethylacetamide,
Sulfoxides such as dimethyl sulfoxide are used. The reaction temperature and reaction time may be changed according to the starting compound used, but the reaction is usually carried out at a temperature in the range of -15 ° C to the reflux temperature of the solvent. The mixed acid anhydride (XXXVII
L ^{6 in} I) represents a group corresponding to the above-mentioned activator, and examples thereof include an ethyloxycarbonyl group, an isobutyloxycarbonyl group, and a pivaloyl group. The definition of L ⁶ below is also synonymous.

Specifically, when a dehydrating condensing agent is used, for example, HOBt, WSC is added to a solution of compound (II) and carboxylic acid compound (XV) in N, N-dimethylformamide.
I can be added and the reaction can be carried out in the range of 0 ° C. to room temperature.

In the second step of Reaction Scheme CA,
Compound (XXXIX) was converted to isocyanate (VI) or amine (VI) in the same manner as in the second step of Reaction Scheme AA.
Compound (I-3) of the present invention can be obtained by subjecting it to reaction with I).

[0098]

Embedded image In the first step of Reaction Scheme CB, the compound (XXXIX) obtained in the above Reaction Scheme CA is converted to an isocyanate (XV
The compound (XL) can be obtained by carrying out a reaction with II) or an amine (XVII). In the second stage,
Compound (I-3) of the present invention can be obtained by reacting compound (XL) with amine (XI) in the same manner as in the above Reaction Scheme AC.

[0099]

Embedded image In the first step of the reaction scheme CC, the above reaction formula C
The compound (XXXIX) obtained in A
The amino-protected compound (XLI) can be obtained by performing a reaction with an isocyanate (XXI) or an amine (XXII) in the same manner as in the second step of M. In the second step, the amino-protected compound (XLI) is subjected to a deprotection reaction in the same manner as in the above Reaction Scheme AD, whereby
The compound (I-3a) of the present invention in which both R ⁴ and R ⁵ are hydrogen atoms can be obtained. Further, the present compound (I-3a) can be led to the present compound (I-3) by a method according to the above reaction schemes AE to AG.

X in the general formula (I) is a single bond, and a is
0 and R ² is-(CH ₂ ) n -NR ⁴ R ⁵ in the following formula (I-4)
Production of the represented compound

[0101]

Embedded image Such compounds are described, for example, in Reaction Scheme DA below,
It can be manufactured according to DB or DC.

[0102]

Embedded image

[0103]

Embedded image

[0104]

Embedded image Each of the reactions in Reaction Schemes DA to DC uses the compound (LXXXII) obtained in the above Reaction Scheme CA as a starting material instead of the starting material (III) in the above Reaction Schemes BA to BC, and describes the Reaction Schemes BA to BC. Is achieved by using each of the methods.

According to the reaction scheme DA, the compound (XXXI
The compound (I-4) of the present invention can be obtained by alkylating X).

In the reaction formula DB, the compound (XXXIX)
Is alkylated to give an intermediate (XLII), which is then subjected to a substitution reaction with an amine (XI) to give the compound of the present invention (I-4).

In the reaction formula DC, the compound (XXXIX)
By alkylating the amino-protected compound (XLII)
I). Then, the amino-protected compound (X
By subjecting LIII) to a deprotection reaction, the compound of the present invention (I-4a) in which R ⁴ and R ⁵ are both hydrogen atoms can be obtained. Further, the present compound (I-4a) is prepared by reacting the above-mentioned reaction scheme A
The compound of the present invention (I-4) can be obtained by a method according to E to AG.

When the compound represented by the general formula (I) has a basic group such as an amino group or an imino group in the molecule,
Formation of an acid addition salt of the compound with an inorganic acid or an organic acid,
The reaction can be carried out by a known salt-forming reaction in which both are mixed and contacted in an appropriate solvent.

Usually, as the solvent, water or any one of water-miscible organic solvents such as butanol, ethanol, isopropanol, acetone, tetrahydrofuran, 1,4-dioxane and acetonitrile, or a mixture thereof is used. it can. When the compound represented by the general formula (I) has a carboxyl group or a sulfo group in the molecule, the formation of a base addition salt between the compound and an inorganic base or an organic base is carried out by a salt-forming reaction of the acid addition salt. Can be carried out by bringing them into contact with each other in a solvent such as the one used for the above. These salt formation reactions are carried out at a temperature at which the compound of the formula (I) and the acid or base are dissolved in the solvent, and which does not adversely affect the pharmacological activity of the compound of the formula (I).

Thus, the compounds of the general formula (I) or salts thereof provided by the present invention, especially pharmaceutically or cosmetically or dermatologically acceptable salts, are so-called male pattern baldness and androgenic alopecia. It can be safely administered to mammals (eg, humans) in preventing or treating pathological alopecia such as alopecia areata, pityriasis alopecia, and seborrheic alopecia in addition to hair and hair loss. it can. The amount of the disubstituted benzene derivative or a salt thereof of the present invention should be appropriately determined depending on sex, age, degree of symptoms such as hair loss and light hair, etc., and is usually 0.01 to 20 m.
g / cm ² is applied to the scalp once or several times a day per adult.

Use of the N-substituted piperidine derivatives or their salts of the present invention in pharmaceuticals, quasi-drugs or cosmetic preparations for the purpose of promoting hair growth such as promoting hair growth, promoting hair growth and preventing hair loss. The dosage form in that case can be arbitrarily selected as long as the dosage form can exert the effects of the present invention, and examples thereof include tonics, lotions, emulsions, creams, ointments, gels, sprays, and mousses. .
These preparations can be prepared by a method known per se. At that time, in these preparations, in addition to the N-substituted piperidine derivative of the present invention or a salt thereof,
In the fields of pharmaceuticals, quasi-drugs, and cosmetics, various components that can be blended into hair restorers can be blended. Although not limited, in addition to various medicinal ingredients, alcohols, oils,
Examples include a surfactant, a fragrance, a chelating agent, a humectant, water, and a stabilizer.

More specifically, for example, peppermint,
Extracts such as Altea, seaweed, Cordyceps, buttonpicks, hops, yokuinin, Altea, coriander, carrot, kujin, assembly, etc. hyaluronic acid,
Moisturizers such as propylene glycol, maltitol, atelocollagen, sodium lactate, thickeners such as quince, carboxyvinyl polymer, xanthan gum, nicotinamide, benzyl nicotinate, vitamin E acetate, carpronium chloride, assembly extract, and acetylcholine derivatives Vasodilators, such as serine, methionine,
Amino acids such as arginine, vitamin B ₆ and vitamin E
And derivatives thereof, vitamins such as biotin, pantothenic acid and its derivatives glycyrrhetinic acid and its derivatives, nicotinic acid esters such as benzyl nicotinate,
Skin function enhancers such as cepharanthin, female hormones such as estradiol, for example, antibacterial agents such as hinokitiol, hexachlorophene, benzalkonium chloride, cetylpyridinium chloride, undecylenic acid, trichlorocarbanilide and bithionol, and cooling agents such as menthol The present invention includes drugs such as salicylic acid, zinc and its derivatives, lactic acid and its alkyl esters, organic acids such as citric acid, polyhydric alcohols such as glycerin, fragrances, antioxidants, ultraviolet absorbers, pigments, ethanol, water and the like. Can be appropriately compounded within a range that does not impair the effect of the above.

[0113]

EXAMPLES The present invention will be described more specifically with reference to specific examples, but the present invention is not intended to be limited to these.

Example 1 2-{[3- (N, N-dimethylamino) propylcarbamoyloxy] methyl} -1- (octadecylcarbamoyl) piperidine (Compound 1)

[0115]

Embedded image 1) 2- (Hydroxymethyl) -1- (octadecylcarbamoyl) piperidine 2- (hydroxymethyl) piperidine (1.20 g) in methylene chloride (12 ml)
To this was added triethylamine (1.16 g) and octadecyl isocyanate (3.08 g), and the mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with chloroform, washed sequentially with saturated sodium hydrogen carbonate and water, dried over sodium sulfate and concentrated. The residue was subjected to silica gel column chromatography (silica gel 100 g, chloroform: methanol =
30: 1) to give the title compound (4.1) as colorless crystals.
7 g) were obtained.

¹ H-NMR (CDCl ₃ ) d: 0.88 (3H, t, J = 7.3 H
z), 1.26 (30H, m), 1.40-1.70 (8H, m), 2.91 (1H,
m), 3.18 (2H, m), 3.28 (1H, m), 3.57 (1H, m), 3.80
(1H, m), 3.90 (1H, ddd, J = 10.7, 10.7, 5.4 Hz), 4.
19 (1H, m), 4.83 (1H, brt). 2) 2-{[3- (N, N-dimethylamino) propylcarbamoyloxy] methyl} -1- (octadecylcarbamoyl) piperidine 2- (hydroxymethyl)-
1- (octadecylcarbamoyl) piperidine (2.6
To a solution of 1 g) in methylene chloride (26 ml) was added pyridine (0.75 g) and phenyl chlorocarbonate (1.10 g) under ice-cooling and an argon gas atmosphere, followed by stirring at room temperature for 1.5 hours. The reaction solution was diluted with chloroform, washed sequentially with saturated sodium hydrogen carbonate and water, dried over sodium sulfate and concentrated. N, N-dimethyl-1,3-propanediamine (0.72 g) was added to the residue, and under an argon gas atmosphere,
Stirred at 70 ° C. for 6 hours. The reaction solution was subjected to silica gel column chromatography (silica gel 100 g, chloroform: methanol = 20: 1) to give the title compound (3.39 g) as colorless crystals.

¹ H-NMR (CDCl ₃ ) d: 0.88 (3H, t, J = 6.8 H
z), 1.25 (30H, m), 1.40-1.76 (10H, m), 2.21 (6H,
s), 2.34 (2H, t, J = 6.4 Hz), 2.73 (1H, m), 3.15-
3.30 (4H, m), 3.98 (1H, m), 4.10 (2H, m), 4.24 (1H,
m), 5.22 (1H, brt), 5.83 (1H, brt).

Example 2 2- [3- (N, N-dimethylamino) propylcarbamoyloxy] -1- (octadecylcarbamoyl) piperidine (Compound 2)

[0119]

Embedded image 1) 2-Hydroxy-1- (octadecylcarbamoyl) piperidine The title compound is obtained in the same manner as 1) in Example 1 using 2-hydroxypiperidine and octadecyl isocyanate. 2) 2- [3- (N, N-dimethylamino) propylcarbamoyloxy] -1- (octadecylcarbamoyl) piperidine Performed in the same manner as 2) of Example 1. 2-hydroxy-
React with 1- (octadecylcarbamoyl) piperidine, pyridine and phenyl chlorocarbonate. Next, the obtained residue is reacted with N, N-dimethyl-1,3-propanediamine to obtain the title compound as colorless crystals.

Example 3 3- [3- (N, N-dimethylamino) propylcarbamoyloxy] -1- (octadecylcarbamoyl) piperidine (Compound 3)

[0121]

Embedded image 1) 3-Hydroxy-1- (octadecylcarbamoyl) piperidine Example 1 was prepared using 3-hydroxypiperidine (1.00 g) and octadecyl isocyanate (3.80 g).
In the same manner as in 1), the title compound (3.22) as colorless crystals
g) was obtained.

¹ H-NMR (CDCl ₃ ) d: 0.88 (3H, t, J = 7.1 H
z), 1.25 (30H, m), 1.42-1.62 (4H, m), 1.75-1.9
0 (2H, m), 2.77 (1H, d, J = 4.6 Hz), 3.16-3.22 (4
H, m), 3.36 (1H, m), 3.57 (1H, dd, J = 13.2, 3.2 H
z), 3.77 (1H, m), 4.58 (1H, brt). 2) 3- [3- (N, N-dimethylamino) propylcarbamoyloxy] -1- (octadecylcarbamoyl) piperidine Performed in the same manner as in 2) of Example 1. 3-hydroxy-
1- (octadecylcarbamoyl) piperidine (2.2
9g), pyridine (0.69 g) and phenyl chlorocarbonate (0.99 g). Next, the obtained residue was reacted with N, N-dimethyl-1,3-propanediamine (0.65 g) to give the title compound (2.78 g) as colorless crystals.

¹ H-NMR (CDCl ₃ ) d: 0.88 (3H, t, J = 7.1 H
z), 1.26 (30H, m), 1.45-1.95 (8H, m), 2.22 (6H,
s), 2.34 (2H, t, J = 6.7 Hz), 3.15-3.59 (8H, m),
4.60 (1H, m), 4.72 (1H, brt), 5.80 (1H, brt).

Example 4 2 (R)-{[3- (N, N-dimethylamino) propylcarbamoyloxy] methyl} -1- (octadecylcarbamoyl) piperidine (Compound 4)

[0125]

Embedded image In the same manner as in 1) of Example 1, 2 (R)-(hydroxymethyl) piperidine and octadecyl isocyanate
(R)-(Hydroxymethyl) -1- (octadecylcarbamoyl) piperidine is synthesized. Next, 2 of Example 1)
2 (R)-(hydroxymethyl) -1-
(Octadecylcarbamoyl) piperidine, pyridine,
After reacting phenyl chlorocarbonate, the obtained residue is reacted with N, N-dimethyl-1,3-propanediamine to obtain the title compound.

Example 5 2 (S)-{[3- (N, N-dimethylamino) propylcarbamoyloxy] methyl} -1- (octadecylcarbamoyl) piperidine (Compound 5)

[0127]

Embedded image In the same manner as in 1) of Example 1, 2 (S)-(hydroxymethyl) piperidine and octadecyl isocyanate
(S)-(Hydroxymethyl) -1- (octadecylcarbamoyl) piperidine is synthesized. Next, 2 of Example 1)
2 (S)-(hydroxymethyl) -1-
(Octadecylcarbamoyl) piperidine, pyridine,
After reacting phenyl chlorocarbonate, the obtained residue is reacted with N, N-dimethyl-1,3-propanediamine to obtain the title compound.

Example 6 2-[(N, N-dimethylamino) propylcarbamoyloxy) methyl] -1- (octadecylcarbamoyl)
Piperidine hydrochloride (compound 6)

[0129]

Embedded image 2-[(N, N-dimethylamino) propylcarbamoyloxy) methyl] -1- (octadecylcarbamoyl) piperidine (0.201 g) in ethyl acetate (4
4N hydrochloric acid / ethyl acetate solution (0.1 ml) was added to the mixture, and the mixture was stirred at room temperature for 30 minutes. After concentration of the reaction solution, the residue was recrystallized from ethyl acetate to give the title compound (0.1) as a white solid.
47 g) were obtained.

¹ H-NMR (CDCl ₃ ) d: 0.88 (3H, t, J = 6.8 H
z), 1.20-1.50 (30H, m), 1.40 -1.80 (8H, m), 2.07
(2H, m), 2.73-2.89 (1H, m), 2.81 (6H, s), 3.02
-3.30 (4H, m), 3.35 (2H, m), 3.97 (2H, m), 4.22
(1H, m), 4.35 (1H, dd, J = 11.2, 7.8 Hz), 4.97 (1H,
brt), 5.94 (1H, brt).

Example 7 3-{[3- (N, N-dimethylamino) propylcarbamoyloxy] methyl} -1- (octadecylcarbamoyl) piperidine hydrochloride (Compound 7)

[0132]

Embedded image In the same manner as in 1) of Example 1, 3- (hydroxymethyl) piperidine and octadecyl isocyanate were used.
(Hydroxymethyl) -1- (octadecylcarbamoyl) piperidine is synthesized. Next, 3- (hydroxymethyl) -1- (octadecylcarbamoyl) piperidine, pyridine and phenyl chlorocarbonate were reacted in the same manner as in 2) of Example 1, and the obtained residue was reacted with N, N-dimethyl- By reacting 1,3-propanediamine, 3-{[3- (N, N-dimethylamino) propylcarbamoyloxy] methyl} -1- (octadecylcarbamoyl) piperidine is obtained. After dissolving the present compound in ethyl acetate, 1N hydrochloric acid / ethyl acetate is added under ice cooling, and the precipitated crystals are collected by filtration to obtain the title compound.

Example 8 2- [3- (N, N-dimethylamino) propylcarbamoyloxy] -1- (octadecylcarbamoyl) piperidine hydrochloride (Compound 8)

[0134]

Embedded image After dissolving 2- [3- (N, N-dimethylamino) propylcarbamoyloxy] -1- (octadecylcarbamoyl) piperidine obtained in Example 2 in ethyl acetate, 1N hydrochloric acid / ethyl acetate is added under ice cooling. The precipitated compound is collected by filtration to give the title compound.

Example 9 2-{[3- (N, N-dimethylamino) propylcarbamoyloxy] methyl} -1- (octylcarbamoyl) piperidine (Compound 9)

[0136]

Embedded image In the same manner as in 1) of Example 1, 2- (hydroxymethyl) -1- (octylcarbamoyl) piperidine is synthesized from 2- (hydroxymethyl) piperidine and octyl isocyanate. Next, in the same manner as in 2) of Example 1,
After reacting 2- (hydroxymethyl) -1- (octylcarbamoyl) piperidine, pyridine and phenyl chlorocarbonate, the resulting residue is reacted with N, N-dimethyl-1,3-propanediamine to give the title. Obtain the compound.

Example 10 2-{[3- (N, N-dimethylamino) propylcarbamoyloxy] methyl} -1- (dodecylcarbamoyl) piperidine (Compound 10)

[0138]

Embedded image In the same manner as in 1) of Example 1, 2- (hydroxymethyl)
1- (Dodecylcarbamoyl) -2- (hydroxymethyl) piperidine was obtained from piperidine and dodecyl isocyanate. Next, in the same manner as in 2) of Example 1, the reaction was carried out using 1- (dodecylcarbamoyl) -2- (hydroxymethyl) piperidine, pyridine and phenyl chlorocarbonate. Dimethyl-1,3-
The title compound is obtained by reacting propanediamine.

Example 11 1- (Cyclohexylcarbamoyl) -2-{[3-
[(N, N-dimethylamino) propylcarbamoyloxy] methyl} piperidine (Compound 11)

[0140]

Embedded image In the same manner as in 1) of Example 1, 1- (hydroxymethyl) piperidine and cyclohexyl isocyanate
-(Cyclohexylcarbamoyl) -2- (hydroxymethyl) piperidine was obtained. Next, in the same manner as in 2) of Example 1, 1- (cyclohexylcarbamoyl) -2-
After reacting with (hydroxymethyl) piperidine, pyridine and phenyl chlorocarbonate, the obtained residue is reacted with N, N-dimethyl-1,3-propanediamine to obtain the title compound.

Example 12 1- (4-butylphenylcarbamoyl) -2- [3-
(N, N-dimethylamino) propylcarbamoyloxy] piperidine (compound 12)

[0142]

Embedded image In the same manner as in 1) of Example 1, 2-hydroxypiperidine and 4-butylphenyl isocyanate were used to give 1- (4-
(Butylphenylcarbamoyl) -2-hydroxypiperidine was obtained. Next, in the same manner as in 2) of Example 1, 1-
After reacting with (4-butylphenylcarbamoyl) -2-hydroxypiperidine, pyridine and phenyl chlorocarbonate, the obtained residue and N, N-dimethyl-1,
The title compound is obtained by reacting 3-propanediamine.

Example 13 2-{[3- (N, N-dimethylamino) propylcarbamoyloxy] methyl} -1- (phenethylcarbamoyl) piperidine (Compound 13)

[0144]

Embedded image In the same manner as 1) of Example 1, 2-hydroxymethyl-1- (phenethylcarbamoyl) piperidine was obtained from 2- (hydroxymethyl) piperidine and phenethyl isocyanate. Next, in the same manner as in 2) of Example 1, 2-
After reacting with hydroxymethyl-1- (phenethylcarbamoyl) piperidine, pyridine and phenyl chlorocarbonate, the obtained residue and N, N-dimethyl-1,3
-Reacting propanediamine to give the title compound.

Example 14 2-{[2- (1-pyrrolidinyl) ethylcarbamoyloxy] -1- (octadecylcarbamoyl) piperidine (Compound 14)

[0146]

Embedded image 2-hydroxy-1- (octadecylcarbamoyl) obtained in 1) of Example 1 in the same manner as 2) of Example 1)
The title compound is obtained by reacting piperidine with phenyl chlorocarbonate in the presence of pyridine, and reacting the resulting residue with N- (2-aminoethyl) pyrrolidine.

Example 15 1- (Octadecylcarbamoyl) -2-{[2- (1
-Pyrrolidinyl) ethylcarbamoyloxy] methyl}
Piperidine (compound 15)

[0148]

Embedded image The 2-hydroxymethyl-1- (octadecylcarbamoyl) piperidine obtained in 1) of Example 2 was reacted with phenyl chlorocarbonate in the presence of pyridine in the same manner as 2) of Example 1 to obtain a residue. Reaction with N- (2-aminoethyl) pyrrolidine gives the title compound.

Example 16 1- (Octadecylcarbamoyl) -2-[(3-piperidinopropylcarbamoyloxy) methyl] piperidine (Compound 16)

[0150]

Embedded image The 2-hydroxymethyl-1- (octadecylcarbamoyl) piperidine obtained in 1) of Example 1 was reacted with phenyl chlorocarbonate in the presence of pyridine in the same manner as 2) of Example 1 to obtain a residue. Reaction with 3-piperidinopropylamine gives the title compound.

Example 17 2-{[2- (4-methylpiperidino) ethylcarbamoyloxy] methyl} -1- (octadecylcarbamoyl) piperidine (Compound 17)

[0152]

Embedded image The 2-hydroxymethyl-1- (octadecylcarbamoyl) piperidine obtained in 1) of Example 1 was reacted with phenyl chlorocarbonate in the presence of pyridine in the same manner as 2) of Example 1 to obtain a residue. By reacting with 1- (2-aminoethyl) -4-methylpiperidine,
Obtain the title compound.

Example 18 1- (Octadecylcarbamoyl) -2-[(2-piperazinylethylcarbamoyloxy) methyl] piperidine dihydrochloride (Compound 18)

[0154]

Embedded image The 2-hydroxymethyl-1- (octadecylcarbamoyl) piperidine obtained in 1) of Example 1 was reacted with phenyl chlorocarbonate in the presence of pyridine in the same manner as 2) of Example 1 to obtain a residue. By reacting with 1- (2-aminoethyl) -4-benzyloxycarbonylpiperazine, 2-{[2- (4-benzyloxycarbonylpiperazinyl) ethylcarbamoyloxy]
Methyl I-1- (octadecylcarbamoyl) piperidine is obtained. This compound is subjected to a catalytic reduction reaction in the presence of 10% Pd-C to give 1- (octadecylcarbamoyl) -2-[(2-piperazinylethylcarbamoyloxy) methyl] piperidine. Next, the title compound is obtained by subjecting this compound to hydrochlorination in the same manner as in Reference Example 3.

Example 19 2- [3- (4-Methylpiperazinyl) propylcarbamoyloxy] -1- (octadecylcarbamoyl) piperidine (Compound 19)

[0156]

Embedded image The 2-hydroxymethyl-1- (octadecylcarbamoyl) piperidine obtained in 1) of Example 2 was reacted with phenyl chlorocarbonate in the presence of pyridine in the same manner as 2) of Example 1 to obtain a residue. Reaction with 1- (3-aminopropyl) -4-methylpiperazine gives the title compound.

Example 20 2-[(2-morpholinoethylcarbamoyloxy) methyl] -1- (octadecylcarbamoyl) piperidine (Compound 20)

[0158]

Embedded image The 2-hydroxymethyl-1- (octadecylcarbamoyl) piperidine obtained in 1) of Example 1 was reacted with phenyl chlorocarbonate in the presence of pyridine in the same manner as 2) of Example 1 to obtain a residue. Reaction with N- (2-aminoethyl) morpholine gives the title compound.

Example 21 2- (3-morpholinopropylcarbamoyloxy)-
1- (octadecylcarbamoyl) piperidine (compound 21)

[0160]

Embedded image The 2-hydroxymethyl-1- (octadecylcarbamoyl) piperidine obtained in 1) of Example 2 was reacted with phenyl chlorocarbonate in the presence of pyridine in the same manner as 2) of Example 1 to obtain a residue. Reaction with N- (3-aminopropyl) morpholine gives the title compound.

Example 22 1- (Octadecylcarbamoyl) -2-[(5-pyrrolidinopentylcarbamoyloxy) methyl] piperidine (Compound 22)

[0162]

Embedded image The 2- (hydroxymethyl) -1- (octadecylcarbamoyl) piperidine obtained in 1) of Example 1 was reacted with phenyl chlorocarbonate in the presence of pyridine in the same manner as 2) of Example 1 to obtain the compound. The residue is reacted with 5-pyrrolidinoamylamine to give the title compound.

Example 23 2- [3- (1-Imidazolinyl) propylcarbamoyloxy] -1- (octadecylcarbamoyl) piperidine (Compound 23)

[0164]

Embedded image 2-hydroxy-1- (octadecylcarbamoyl) obtained in 1) of Example 2 in the same manner as 2) of Example 1)
Piperidine is reacted with phenyl chlorocarbonate in the presence of pyridine, and the resulting residue is treated with 1- (3-aminopropyl)
Reaction with imidazole gives the title compound.

Example 24 1- (octadecylcarbamoyl) -2-{[3- (2
-Oxopyrrolidino) propylcarbamoyloxy] methyl} piperidine (Compound 24)

[0166]

Embedded image The 2-hydroxymethyl-1- (octadecylcarbamoyl) piperidine obtained in 1) of Example 1 was reacted with phenyl chlorocarbonate in the presence of pyridine in the same manner as 2) of Example 1 to obtain a residue. Reaction with 1- (3-aminopropyl) -2-pyrrolidinone gives the title compound.

Example 25 2- [2- (N, N-diisobutylamino) ethylcarbamoyloxy] -1- (octadecylcarbamoyl)
Piperidine (compound 25)

[0168]

Embedded image 2-hydroxy-1- (octadecylcarbamoyl) obtained in 1) of Example 2 in the same manner as 2) of Example 1)
The title compound is obtained by reacting piperidine with phenyl chlorocarbonate in the presence of pyridine and reacting the resulting residue with 2-diisobutylaminoethylamine.

Example 26 2-{[4- (N, N-diethylamino) butylcarbamoyloxy] methyl} -1- (octadecylcarbamoyl) piperidine (Compound 26)

[0170]

Embedded image The 2-hydroxymethyl-1- (octadecylcarbamoyl) piperidine obtained in 1) of Example 1 was reacted with phenyl chlorocarbonate in the presence of pyridine in the same manner as 2) of Example 1 to obtain a residue. Reaction with 4-diethylaminobutylamine gives the title compound.

Example 27 2- [3- (N-methyl-N-benzylamino) propylcarbamoyloxy] methyl-1- (octadecylcarbamoyl) piperidine (Compound 27)

[0172]

Embedded image The 2-hydroxymethyl-1- (octadecylcarbamoyl) piperidine obtained in 1) of Example 1 was reacted with phenyl chlorocarbonate in the presence of pyridine in the same manner as 2) of Example 1 to obtain a residue. Reaction with N-benzyl-N-methyl-1,3-propanediamine gives the title compound.

Example 28 2- [4- (N, N-dimethylamino) butoxymethyl] -1- (octadecylcarbamoyl) piperidine (Compound 28)

[0174]

Embedded image 2- (hydroxymethyl)-obtained in 1) of Example 1
By reacting 1- (octadecylcarbamoyl) piperidine with 1-bromo-4-chlorobutane in acetone in the presence of potassium carbonate at reflux temperature, 2- (4
-Chlorobutoxymethyl) -1- (octadecylcarbamoyl) piperidine is obtained. The title compound is obtained by reacting this compound with dimethylamine in acetone in the presence of potassium carbonate at reflux temperature.

Example 29 2- [4- (N, N-dimethylamino) butoxy] -1
-(Octadecylcarbamoyl) piperidine (compound 2
9)

[0176]

Embedded image The 2-hydroxy-1- (octadecylcarbamoyl) piperidine obtained in 1) of Example 2 was reacted with 1-bromo-4-chlorobutane at reflux temperature in acetone in the presence of potassium carbonate to give 2- ( 4-Chlorobutoxy) -1- (octadecylcarbamoyl) piperidine is obtained. This compound and dimethylamine in acetone,
Reaction at reflux temperature in the presence of potassium carbonate gives the title compound.

Example 30 2-[(3-morpholinopropylcarbamoyloxy)
Methyl] -1-octadecanoylpiperidine (compound 3
0)

[0178]

Embedded image 1) 2- (Hydroxymethyl) -1-octadecanoylpiperidine To a solution of 2- (hydroxymethyl) piperidine (1.52 g) in methylene chloride (16 ml) was added triethylamine (2.05 ml) and stearoyl chloride (16 ml) under ice-cooling. 4.13 g) and stirred for 2 hours. The reaction solution was diluted with chloroform, washed successively with 1N hydrochloric acid, saturated sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate and concentrated. The residue was subjected to silica gel column chromatography (silica gel 100 g, chloroform: methanol = 6).
0: 1) to give the title compound (3.69) as a colorless solid.
g) was obtained.

¹ H-NMR (CDCl ₃ ) δ: 0.88 (3H, t, J = 6.8
Hz), 1.2-1.4 (28H, m), 1.4-1.8 (9H, m), 2.35
(t-like), 2.55, 3.17 (t-like), 3.66, 3.81 (q-lik
e), 3.94 (t-like), 4.08, 4.59 (d-like) & 4.78 (tot
al 7H). 2) 2-[(3-morpholinopropylcarbamoyloxy) methyl] -1-octadecanoylpiperidine 2- (hydroxymethyl) -1-octadecanoylpiperidine (2.300 g) in methylene chloride (23 m
l) In ice-cooled, argon gas atmosphere, pyridine (0.1
74 ml) and phenyl chlorocarbonate (0.84 ml)
Was added and stirred at room temperature for 3 hours. The reaction solution was diluted with chloroform, washed successively with 1N hydrochloric acid, saturated sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate and concentrated.
The residue was treated with N- (3-aminopropyl) -morpholine (0.1%).
98 ml) at 70 ° C. under an argon gas atmosphere.
Stirred for hours. The reaction solution was subjected to silica gel column chromatography (silica gel 100 g, ethyl acetate: methanol = 50: 1 to 10: 1) to give the title compound (3.040 g) as a colorless paste.

¹ H-NMR (CDCl ₃ ) δ: 0.88 (3H, t, J = 6.8
Hz), 1.2-1,5 (28H, m), 1.5-1.8 (10H, m), 2.43
(6H, m), 3.70 (4H, t, J = 4.4 Hz), 2.29 (t-like), 2.
62 (t-like), 3.1-3.3, 3.67, 4.09, 4.21, 4.32 (t-like
like), 4.58 (d-like), 5.01, 5.60 & 5.74 (total 10
H).

Example 31 2-[(3-morpholinopropylcarbamoyloxy)
Methyl] -1-octadecanoylpiperidine hydrochloride (Compound 31)

[0182]

Embedded image 2-[(3-morpholinopropylcarbamoyloxy)
Methyl] -1-octadecanoylpiperidine (2.90
To a 0 g) ethyl acetate solution (30 ml) was added a 4N hydrochloric acid / ethyl acetate solution (1.58 ml), and the mixture was stirred at room temperature for 30 minutes. After concentration of the reaction solution, the residue was recrystallized from ethyl acetate to give the title compound (2.784 g) as a white solid.

¹ H-NMR (CDCl ₃ ) δ: 0.88 (3H, t, J = 6.8
Hz), 1.2-1.5 (28H, m), 1.5-1.8 (8H, m), 2.04,
2.18, 2.33, 2.43, 2.68 (t-like), 2.8-3.6, 3.70
(d-like), 3.8-4.4, 4.49 (d-like), 4.67 (t-like),
5.01, 5.56 & 5.83 (total 22H), 12.59 (1H, brs).

Example 32 2-{[3- (N, N-dimethylamino) propylcarbamoyloxy] methyl} -1-octadecanoylpiperidine (Compound 32)

[0185]

Embedded image To a solution of octadecanoic acid in N, N-dimethylformamide was added 2- (hydroxymethyl) piperidine, H
OBt and WSCI were added and reacted at room temperature to obtain 2
-(Hydroxymethyl) -1-octadecanoylpiperidine is synthesized. Next, in the same manner as in 2) of Example 1,
After reacting 2- (hydroxymethyl) -1-octadecanoylpiperidine and phenyl chlorocarbonate in the presence of pyridine, by reacting the obtained residue with N, N-dimethyl-1,3-propanediamine, Obtain the title compound.

Example 33 2- [3- (N, N-dimethylamino) propylcarbamoyloxy] -1-octadecanoylpiperidine (Compound 33)

[0187]

Embedded image To a solution of octadecanoic acid in N, N-dimethylformamide was added 2-hydroxypiperidine, HOBt, W
By adding SCI and reacting at room temperature, 2-hydroxy-1-octadecanoylpiperidine is synthesized. Next, 2) in the presence of pyridine,
-Hydroxy-1-octadecanoylpiperidine is reacted with phenyl chlorocarbonate.
By reacting -dimethyl-1,3-propanediamine, the title compound is obtained.

Example 34 2- [4- (N, N-dimethylamino) butoxymethyl]
-1-octadecanoylpiperidine (compound 34)

[0189]

Embedded image 2- (hydroxymethyl) -1- obtained in Example 30
Octadecanoyl piperidine is reacted with sodium hydride in tetrahydrofuran at 0 ° C.
-Chloro-4-tosyloxybutane is added to react with 2- (4-chlorobutoxymethyl) -1-.
Octadecanoyl piperidine is obtained. The title compound is obtained by reacting this compound with dimethylamine in acetone in the presence of potassium carbonate at reflux temperature.

Example 35 2- [4- (N, N-dimethylamino) butoxy] -1
-Octadecanoylpiperidine (compound 35)

[0191]

Embedded image 2- (4-chlorobutoxy) was obtained by reacting 2-hydroxy-1-octadecanoylpiperidine obtained in Example 33 with 1-bromo-4-chlorobutane in acetone in the presence of potassium carbonate at reflux temperature. ) -1-
Octadecanoyl piperidine is obtained. The title compound is obtained by reacting this compound with dimethylamine in acetone in the presence of potassium carbonate at reflux temperature.

Hair growth test 1) Test method The hair growth test was carried out using the C3H / HeNCrj mouse in the telogen phase of the hair cycle, according to the method of Ogawa et al. (Normal and Abnormal Epidermal Differentiation, Norm
al and Abnormal Epidermal Differentiation, M. Seij
i and IABernstein, pp. 159-170, 1982,
The University of Tokyo Press).

That is, a group of 10 mice was prepared, and the back of each mouse was shaved 3 × 4 cm with a clipper and a shaper. Ethanol (control) and an ethanol solution of each test compound at the indicated concentrations were added to the mice once a day. .1 ml was applied. The hair growth effect of each test compound was determined by measuring the area of the hair growth part on the back of the mouse, and evaluating the area ratio of the hair growth part to the area of the shaved part as the hair regeneration area ratio. 2) Results Table 1 shows the hair regeneration area ratio by each test compound. Table 1 Hair regrowth area ratio Compound No. Compound concentration (w / v%) Days after application start Hair regrowth area ratio (%) Control 0 30 0 1 0.2 24 87 1 0.2 30 97 3 0.2 24 67 3 0.2 30 81 6 0.223 80 31 0.2 24 100 or less, showing non-limiting examples of the formulation of a hair restorer according to the present invention Formulation Example 1 Hair restoration tonic Compound 1 0.5% by weight Pyridoxine dioctanoate 0.1 Pantothenyl ethyl ether 0.2 Hinokitiol 0.05 Poly Oxyethylene (12) polyoxypropylene (6) decyltetradecyl 1.0 1-menthol 0.1 bactericide qs 1,3-butylene glycol 3.0 ethanol 70.0 purified water residue <Preparation method> Ethanol at room temperature The dissolved components are added to ethanol with stirring to dissolve, the water-soluble components are dissolved in purified water, and the aqueous solution is added to the ethanol solution to make it homogeneous.
Filtered. Formulation Example 2 Hair growth promoting liquid compound 3 0.2% by weight carpronium chloride 1.0 pantothenyl ethyl ether 0.5 diphenhydramine hydrochloride 0.1 hinokitiol 0.1 dl-α-tocopherol acetate 0.1 salicylic acid 0.2 1 -Menthol 0.2 Glycyrrhizic acid 0.1 dl-Sodium pyrrolidonecarboxylate solution 1.0 Ethanol 70.0 Purified water Residue <Preparation method> Add ethanol-soluble components to ethanol at room temperature while stirring to dissolve, The components are dissolved in purified water, and the aqueous solution is added to the ethanol solution to make it homogeneous.
Filtered. Formulation Example 3 Hair restoration tonic Compound 6 0.5% by weight Pyridoxine dioctanoate 0.1 Pantothenyl ethyl ether 0.2 Hinokitiol 0.05 Polyoxyethylene (12) polyoxypropylene (6) Decyltetradecyl 1.0 1-Menthol 0.1 Disinfectant Appropriate amount 1,3-butylene glycol 3.0 Ethanol 70.0 Purified water Residue <Preparation method> At room temperature, ethanol-soluble components are added to ethanol while stirring, and dissolved. After dissolving and adding an aqueous solution to the ethanol solution to make it homogeneous,
Filtered. Formulation Example 4 Hair growth promoting compound Compound 31 0.2% by weight Carpronium chloride 1.0 Pantothenyl ethyl ether 0.5 Diphenhydramine hydrochloride 0.1 Hinokitiol 0.1 dl-α-tocopherol acetate 0.1 Salicylic acid 0.2 1 -Menthol 0.2 Glycyrrhizic acid 0.1 dl-Sodium pyrrolidonecarboxylate solution 1.0 Ethanol 70.0 Purified water Residue <Preparation method> Add ethanol-soluble components to ethanol at room temperature while stirring to dissolve, The components are dissolved in purified water, and the aqueous solution is added to the ethanol solution to make it homogeneous.
Filtered. Formulation Example 5 O / W emulsion (phase A) Polyoxyethylene (60 mol) addition-hardened castor oil 2.0% by weight glycerin 10.0 dipropylene glycol 10.0 1,3-butylene glycol 4.0 Compound of the present invention (Compound 1) 0.1 Polyethylene glycol 1500 5.0 (Phase B) Isocetyl octanoate 10.0 Squalane 5.0 Vaseline 2.0 Propylparaben 2.0 (Phase C) Carboxyvinyl polymer 1% aqueous solution 30.0 Hexamethaline Acid soda 0.03 Ion-exchanged water 8.35 (Phase D) Ion-exchanged water 4.5 (E-phase) Potassium hydroxide 0.12 Ion-exchanged water Residue The gel was dissolved, mixed and treated with a homomixer to prepare a gel.
Phase D was gradually added to the gel and dispersed with a homomixer. Next, the previously dissolved phase C was added to this gel dispersion, and the previously dissolved phase E was further added and emulsified with a homomixer to obtain an O / W emulsion. Formulation Example 6 Cream (Phase A) N, N-dimethyl-2-tetradecylamine oxide 2.5% by weight Liquid paraffin 5.0 Cetostearyl alcohol 5.5 Glyceryl monostearate 3.0 Polyoxyethylene (20 mol) 2-octyldodecyl ether 3.0 propylparaben 0.3 perfume 0.1 (phase B) Compound of the present invention (compound 6) 1.0 glycerin 8.0 dipropylene glycol 20.0 polyethylene glycol 4000 5.0 hexametaphosphoric acid Soda 0.005 ion-exchanged water residue <Preparation method> The phases A and B were each dissolved by heating, mixed, and emulsified with a homomixer to obtain a cream. Formulation Example 7 Aerosol spray (stock solution formulation) 95% ethanol 50.0% by weight glycyrrhizic acid 0.1 Compound of the present invention (Compound 3) 0.5 Assembly extract 0.1 Sodium lauryl sulfate 0.1 Hardened castor oil ethylene oxide (40 mol) ) Adduct 0.5 Lactic acid proper amount Sodium lactate proper amount Fragrance proper amount Deionized water residue (filling prescription) stock solution 50.0 liquefied petroleum gas 50.0 The undiluted solution was filled in a can, and after mounting a valve, gas was charged to obtain an aerosol spray. Formulation Example 8 Shampoo (1) Sodium cocoyl methyl taurine 2.0% by weight (2) Polyoxyethylene (8 mol) oleyl alcohol ether 2.0 (3) Lauric acid diethanolamide 4.0 (4) Ethylene glycol fatty acid ester 1 0.0 (5) Glycerin 0.2 (6) Menthol 0.1 (7) Compound of the present invention (Compound 31) 0.1 (8) Disodium edetate 0.1 (9) Perfume appropriate amount (10) Purified water residue <Preparation method> (10) was heated to 70 ° C, and (1)
The components (9) to (9) were sequentially added, mixed by stirring and dissolved, and then cooled to obtain a shampoo. Formulation Example 9 Rinse (1) Stearyl trimethylammonium chloride 1.5% by weight (2) Dimethylpolysiloxane (20cs) 3.0 (3) Polyoxyethylene (10 mol) oleyl alcohol ether 1.0 (4) Glycerin 5. 0 (5) Compound of the present invention (Compound 1) 0.5 (6) Appropriate amount of 4-tert-butyl-4'-methoxydibenzoylmethane (7) Appropriate amount of ultraviolet absorber (8) Purified water residue <Preparation method> (8 ) Was added to (1), (3) and (4), and the mixture was heated to 70 ° C. to obtain an aqueous phase. The other components were heated and melted and heated to 70 ° C. to obtain an oil phase. The aqueous phase was added, the mixture was stirred and mixed by an emulsifier, and then cooled to obtain a rinse. Formulation Example 10 Scalp treatment (stock solution formulation) (1) Liquid paraffin 27.0% by weight (2) Stearic acid 5.0 (3) Cetanol 5.0 (4) Sorbitan monooleate 2.0 (5) Polyoxyethylene Sorbitan monooleate 3.0 (6) Compound of the present invention (compound 3) 0.1 (7) 1,3-butylene glycol 5.0 (8) Preservative appropriate amount (9) Purified water residue (filling formula) stock solution 50.0 Liquefied petroleum gas 50.0 <Preparation method> Components (5) and (6) were replaced with components (1) to (4)
And heated to 80 ° C to dissolve uniformly, then 30 ° C
And cooled. The components (7) to (9) were heated to 30 ° C.
And mixed with stirring to prepare a stock solution. This stock solution was filled in a can with a propellant to obtain a scalp treatment.

[0194]

According to the present invention, new N- and 2-
Alternatively, 3-disubstituted piperidine derivatives are provided, and these derivatives have an excellent hair growth promoting effect and a hair growth effect, and are useful for treating and improving hair loss of human hair and preventing hair loss.

 ──────────────────────────────────────────────────の Continued on the front page (72) Inventor Hirotada Fukunishi 1050 Nippa-cho, Kohoku-ku, Yokohama, Kanagawa Prefecture Inside Shiseido Daiichi Research Center (72) Inventor Yoshiharu Tsuji 1050 shares in Nippa-cho, Kohoku-ku, Yokohama, Kanagawa Company Shiseido Daiichi Research Center (72) Inventor Masazumi Watanabe 54F term (reference) 4C054 AA02 BB01 CC04 DD04 DD12 EE01 FF01 4C063 AA01 CC10 CC25 DD03 DD10 EE01 4C083 AA112 AB032 AB282 AC012 AC022 AC072 AC102 AC122 AC172 AC182 AC212 AC242 AC302 AC352 AC422 AC432 AC472 AC482 AC532 AC552 AC562 AC612 AC642 AC692 AC782 AC792 AC841 AC842 AD042 AD092 AD152 AD532 AD552 AD632 AD662 CC05 CC37 CC38 CC39 DD08 DD23 DD33

Claims (6)

[Claims] 1. A compound of the general formula [Wherein, R ¹ and R ² are each independently a substituted or unsubstituted C _1-30 hydrocarbon group or a heterocyclic group containing 1 to 4 hetero atoms selected from oxygen, sulfur and nitrogen atoms, or 5 or R ³ represents a hydrogen atom, an optionally substituted alkyl group, an acyl group, an alkoxycarbonyl group, a phenoxycarbonyl group or an optionally substituted carbamoyl group, which represents a 6-membered optionally substituted heterocyclic group; And a
Represents 0 or 1, m represents 0 or 1, X represents a single bond or —NH—, and has the formula — (CH ₂ ) _m —O— (CONR ³ )
the group of _a -R ² is bonded to the 2- or 3-position] or a salt thereof. 2. The compound according to claim 1, wherein R ¹ is a C _1-30 hydrocarbon group. 3. The compound according to claim 1, wherein R ² is a C _1-30 hydrocarbon group substituted with an _optionally substituted amino group. 4. R ² is a compound of the general formula [In the formula, R ⁴ and R ⁵ each independently represent a hydrogen atom, an optionally substituted C _1-5 alkyl group, or a nitrogen atom to which they are bonded to form an oxygen and sulfur atom, _1-3 atomic group forming a 5- or 6-membered optionally substituted heterocyclic group which may contain up to three heteroatoms selected from an alkyl group or a nitrogen atom to which a hydrogen atom may be bonded And n represents an integer of 1 to 10.]. 5. R ¹ is a C _1-30 hydrocarbon and R ² is of the general formula [In the formula, R ⁴ and R ⁵ each independently represent a hydrogen atom, an optionally substituted C _1-5 alkyl group, or a nitrogen atom to which they are bonded to form an oxygen and sulfur atom, _1-3 atomic group forming a 5- or 6-membered optionally substituted heterocyclic group which may contain up to three heteroatoms selected from an alkyl group or a nitrogen atom to which a hydrogen atom may be bonded And n represents an integer of 1 to 10.]. 6. A hair restorer comprising the compound according to claim 1 as an active ingredient.