WO2021172488A1

WO2021172488A1 - Cyclic amine derivative and pharmaceutical use thereof

Info

Publication number: WO2021172488A1
Application number: PCT/JP2021/007254
Authority: WO
Inventors: 泉本直樹; 盛田康弘; 伊関克彦; 宇田川秀二; 岩野俊介; 三好智也; 新井唯正
Original assignee: 東レ株式会社
Priority date: 2020-02-28
Filing date: 2021-02-26
Publication date: 2021-09-02
Also published as: JPWO2021172488A1

Abstract

A purpose of the present invention is to provide a compound that exhibits an analgesic effect against pain, especially neuropathic pain. The present invention provides a cyclic amine derivative represented by the chemical formula below or a pharmacologically acceptable salt thereof.

Description

Cyclic amine derivatives and their pharmaceutical uses

The present invention relates to a cyclic amine derivative and its pharmaceutical use.

Pain is an experience with unpleasant sensations and emotions that occurs when or may cause tissue damage. Pain is mainly classified into nociceptive pain, neuropathic pain or psychogenic pain according to its cause.

Neuropathic pain is pathological pain caused by dysfunction of the peripheral or central nervous system itself, and is caused by direct damage or compression of nerve tissue even though nociceptors are not stimulated. It refers to the pain that occurs. Anticonvulsants, antidepressants, anxiolytics or antiepileptic drugs (gabapentin, pregabalin, etc.) are used as therapeutic agents for neuropathic pain.

Patent Document 1 suggests that substituted piperidines may have a medicinal effect on overweight or obesity, and Patent Document 2 or Patent Document 3 discloses that an imidazole derivative exhibits an analgesic effect. There is.

International Publication No. 2003/031432 International Publication No. 2013/147160 International Publication No. 2016/136944

However, treatment of neuropathic pain with conventional therapeutic agents such as anticonvulsants, antidepressants, anxiolytics or antiepileptic drugs is frequently accompanied by central side effects such as dizziness, nausea or vomiting. Therefore, the development of a new therapeutic agent for neuropathic pain is desired.

It has been suggested that the substituted piperidins described in Patent Document 1 are effective for migraine, and the imidazole derivative described in Patent Document 2 or Patent Document 3 has an analgesic effect. Is disclosed. However, there is no disclosure of the compound itself whose analgesic effect has been clarified in the present application, or any suggestion regarding the relationship between the analgesic effect and the chemical structure.

Therefore, an object of the present invention is to provide a compound having an analgesic effect on pain, particularly neuropathic pain.

As a result of intensive studies to solve the above problems, the present inventors have found a cyclic amine derivative having a strong analgesic effect on pain, especially neuropathic pain.

That is, the present invention provides a cyclic amine derivative represented by the following general formula (I) or a pharmacologically acceptable salt thereof.

[In the formula, A represents a group represented by the general formula (IIa), (IIb) or (IIc).

R ¹ independently represents a methyl group or an ethyl group, R ² represents a hydrogen atom or a hydroxyl group, and R ³ represents a methyl group or an ethyl group which may be substituted with a halogen atom. ]

In the above cyclic amine derivative, A is preferably a group represented by the general formula (IIa) or (IIb), in which case R ¹ is a methyl group or an ethyl group and R ² is a hydroxyl group. , R ³ is more preferably a methyl group or an ethyl group, which may be substituted with a fluorine atom, R ¹ is a methyl group or an ethyl group, R ² is a hydroxyl group, and R ³ is a hydroxyl group. , Methyl group, ethyl group, difluoromethyl group or 2,2,2-trifluoroethyl group is more preferable.

By limiting to these, the analgesic effect can be enhanced.

The present invention also provides a medicament containing the cyclic amine derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient.

The above-mentioned medicine is preferably an analgesic, and more preferably a neuropathic pain therapeutic agent.

The present invention also provides a pharmaceutical composition containing a cyclic amine derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable carrier.

The present invention also provides a cyclic amine derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof for use as a pharmaceutical.

The present invention also provides a cyclic amine derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof for use in the treatment of pain. The pain is preferably neuropathic pain.

The present invention also provides the use of the cyclic amine derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof for treating pain. The pain is preferably neuropathic pain.

The present invention also provides the use of the cyclic amine derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof in the manufacture of a pharmaceutical for treating pain. The pain is preferably neuropathic pain.

The present invention is also a method for treating pain, in which a therapeutically effective amount of a cyclic amine derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof is administered to a patient in need of treatment. Provide methods that include doing. The pain is preferably neuropathic pain.

The cyclic amine derivative of the present invention or a pharmacologically acceptable salt thereof exhibits an analgesic effect on pain, especially neuropathic pain.

It is a figure which showed the effect of the compound of Example 2 on a mouse sciatic nerve partial ligation model (oral administration). It is a figure which showed the effect of the compound of Example 4 on a mouse sciatic nerve partial ligation model (oral administration). It is a figure which showed the effect of the compound of Example 6 on a mouse sciatic nerve partial ligation model (oral administration). It is a figure which showed the effect of the compound of Comparative Example 1 on a mouse sciatic nerve partial ligation model (oral administration). It is a figure which showed the effect of the compound of Comparative Example 2 on a mouse sciatic nerve partial ligation model (oral administration).

Unless otherwise specified, the following terms used in this specification are as defined below.

The cyclic amine derivative of the present invention is characterized by being represented by the following general formula (I).

In the above cyclic amine derivative, A is a group represented by the general formula (IIa) or (IIb), R ¹ is a methyl group or an ethyl group, R ² is a hydroxyl group, and R ³ is a hydroxyl group. It is preferably a methyl group or an ethyl group which may be substituted with a fluorine atom, A is a group represented by the general formula (IIa) or (IIb), and R ¹ is a methyl group or an ethyl group. Yes, R ² is a hydroxyl group, and R ³ is more preferably a methyl group, an ethyl group, a difluoromethyl group or a 2,2,2-trifluoroethyl group.

"Halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

"Methyl or ethyl group optionally substituted with halogen atom" means a methyl group or ethyl group in which hydrogen atoms may be independently substituted with the above halogen atoms, for example. , Methyl group or ethyl group or difluoromethyl group, 2-fluoroethyl group, 2-chloroethyl group, 2,2-difluoroethyl group or 2,2,2-trifluoroethyl group.

Specific examples of preferable compounds of the cyclic amine derivative (hereinafter, cyclic amine derivative (I)) represented by the above general formula (I) are shown in Table 1-1, Table 1-2 and Table 1-3, but the present invention. Is not limited to these.

The compounds listed in Table 1-1, Table 1-2 and Table 1-3 are their isomers and their pharmacologically acceptable salts, their hydrates or solvates and their isomers. Also includes mixtures.

When the cyclic amine derivative (I) contains isomers such as a mirror image isomer and a stereoisomer, one of the isomers and a mixture thereof are also included in the cyclic amine derivative (I). In addition, conformational isomers may be produced, and such isomers and mixtures thereof are also included in the cyclic amine derivative (I). With these isomers, the desired isomer can be obtained by a known method or a method similar thereto. For example, when the cyclic amine derivative (I) has an enantiomer, the enantiomer divided from the cyclic amine derivative (I) is also included in the cyclic amine derivative (I).

Examples of the enantiomer of the cyclic amine derivative (I) include compounds in which ^{R 2 is a hydroxyl group among the cyclic amine derivatives (I).} The stereochemistry of the asymmetric carbon (carbon atom to which the hydroxyl group is bonded) of the compound is that the compound having the R configuration, the compound having the S configuration, and a mixture thereof (for example, racemic mixture) are also the cyclic amine derivative (I). Included.

The enantiomer is the enantiomer of interest by using known means, such as an optically active synthetic intermediate, or by optically resolving the final racemic mixture by a known method or a method similar thereto, for example. You can get a body.

The present invention also includes a prodrug of the cyclic amine derivative (I) or a pharmacologically acceptable salt thereof. The prodrug of the cyclic amine derivative (I) is a compound that is enzymatically or chemically converted into the cyclic amine derivative (I) in vivo. The active body of the prodrug of the cyclic amine derivative (I) is the cyclic amine derivative (I), but the prodrug itself of the cyclic amine derivative (I) may have activity.

Examples of the prodrug of the cyclic amine derivative (I) include compounds in which the hydroxyl group of the cyclic amine derivative (I) is alkylated, phosphorylated or borated. These compounds can be synthesized from the cyclic amine derivative (I) according to known methods.

In addition, the prodrug of the cyclic amine derivative (I) is described in known literature (“Drug Development”, Hirokawa Shoten, 1990, Vol. 7, p.163-198 and Progress in Medicine, Vol. 5, 1985, p. It may be changed to the cyclic amine derivative (I) under the physiological conditions described in .2157 to 2161).

Cyclic amine derivative (I) may be labeled with isotope, the isotope labeled, for ^{^{^{^{example, 2 H, 3 H, 13}}}} C, 14 C, 15 N, 15 O, 18 O and / Alternatively, ¹²⁵ I can be mentioned.

Examples of the pharmacologically acceptable salt of the cyclic amine derivative (I) include inorganic acid salts such as hydrochloride, sulfate, phosphate or hydrobromide, or oxalate, malonate and citrate. Acid salt, fumarate, lactate, malate, succinate, tartrate, acetate, trifluoroacetate, maleate, gluconate, benzoate, salicylate, xinafoate, pamoic acid Examples thereof include organic acid salts such as salts, ascorbates, adipates, methanesulfonates, p-toluenesulfonates and silicates. In addition, these salts may form hydrates, solvates or polymorphs.

The cyclic amine derivative (I) can be synthesized, for example, according to the production method described below. The cyclic amine derivative (I) obtained by the following production method can be isolated and purified by known means, for example, solvent extraction, recrystallization and / or chromatography, and is intended by a known method or a method similar thereto. When the cyclic amine derivative (I) is obtained in the form of a salt, it can be converted to the cyclic amine derivative (I) or another salt of interest by a known method or a method similar thereto.

In each reaction of the production method described below, when the raw material compound has a hydroxyl group, an amino group or a carboxyl group, a protecting group may be introduced into these groups, and the protecting group may be deprotected as necessary after the reaction. By doing so, the target compound can be obtained.

Examples of the hydroxyl-protecting group include a trityl group, an aralkyl group having 7 to 10 carbon atoms (for example, a benzyl group) or a substituted silyl group (for example, a trimethylsilyl group, a triethylsilyl group or a tert-butyldimethylsilyl group). ..

Examples of the amino group protecting group include an alkylcarbonyl group having 2 to 6 carbon atoms (for example, an acetyl group), a benzoyl group, and an alkyloxycarbonyl group having 2 to 8 carbon atoms (for example, tert-butoxycarbonyl group or benzyloxy). Carbonyl group), aralkyl group having 7 to 10 carbon atoms (for example, benzyl group) or phthaloyl group.

Examples of the carboxyl group protecting group include an alkyl group having 1 to 6 carbon atoms (for example, a methyl group, an ethyl group or a tert-butyl group) or an aralkyl group having 7 to 10 carbon atoms (for example, a benzyl group).

Deprotection of the protecting group depends on the type of protecting group, but according to a known method (for example, Greene, TW, "Greene's Protective Groups in Organic Synthesis", Wiley-Interscience) or a method similar thereto. It can be carried out.

1. 1. Production of compound (Ia):
1-1. Method for producing compound (Ia):

[In the formula, M represents a hydrogen atom or an alkali metal, and examples of the alkali metal include lithium and sodium. Each other symbol is synonymous with the above definition. ]

(Step 1)
Among the cyclic amine derivatives (I) ^{, the compound (Ia) in which R 2} is a hydrogen atom is, for example, a condensation of compound (III) and compound (IV) with or without a base using a condensing agent. Obtained by reaction.

As the compound (III) used in the condensation reaction, a commercially available product can be used as it is.

As the compound (IV) used in the condensation reaction, a commercially available product may be used as it is, or may be synthesized, for example, according to a production method described later.

Examples of the base used in the condensation reaction include aromatic amines such as pyridine and rutidin, or triethylamine, triisopropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, and N-methylpiperidin. , N-Methylpyrrolidin, N-methylmorpholine or diisopropylethylamine (DIEA) and other tertiary amines.

The amount of the base used in the condensation reaction is preferably 0.5 to 10 mol, more preferably 0.8 to 5.0 mol, relative to 1 mol of compound (III).

Examples of the condensing agent used in the condensation reaction include O- (benzotriazole-1-yl) -N, N, N', N'-tetramethyluronium hexafluorophosphate (HBTU), cyclohexylcarbodiimide (DCC), and the like. N- (3-Dimethylaminopropyl) -N'-ethylcarbodiimide (EDC) or its hydrochloride, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroxyquinoline (EEDQ), carbonyldiimidazole (CDI), diethyl Phosphoryl cyanide, benzotriazole-1-yloxytrispyrrolidinophosphonium hexafluorophosphate (PyBOP), diphenylphosphoryl azide (DPPA), isobutyl chlorophosphate, diethylacetyl chloride or trimethylacetyl chloride. These condensing agents can be used alone or with N-hydroxysuccinimide (HONSu), hydroxybenzotriazole (HOBT), 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOOBT). ), 4- (4,6-dimethoxy-3,5-triazine-2-yl) -4-methylmorpholinium chloride or 4-dimethylaminopyridine (DMAP) and other additives are used in combination.

The amount of the condensing agent used in the condensation reaction is preferably 0.5 to 10 mol, more preferably 0.8 to 5.0 mol, based on 1 mol of the compound (III).

The amount of compound (IV) used in the condensation reaction is preferably 0.5 to 3 mol, more preferably 0.8 to 1.5 mol, based on 1 mol of compound (III).

The condensation reaction is generally carried out in a solvent, and a solvent that does not inhibit the reaction is appropriately selected. Examples of such a solvent include aromatic amines such as pyridine, halogenated hydrocarbons such as dichloromethane, chloroform or 1,2-dichloroethane, ethers such as tetrahydrofuran or 1,4-dioxane, and N, N-. Examples thereof include amides such as dimethylformamide and N-methylpyrrolidone, and aliphatic nitriles such as acetonitrile and propionitrile, and a mixed solvent thereof may be used. When aromatic amines such as pyridine are selected as the solvent, the condensation reaction can also be carried out in the absence of a base.

The reaction temperature in the condensation reaction is preferably −20 to 150 ° C., more preferably 0 to 100 ° C.

The reaction time in the condensation reaction varies depending on the reaction conditions, but is preferably 5 minutes to 72 hours, more preferably 30 minutes to 48 hours.

1-2. Chloride step of compound (Ia):
A pharmacologically acceptable salt of compound (Ia) is obtained, for example, by a chlorination reaction of compound (Ia) with an acid.

Examples of the acid used for the chloride reaction include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic acid, or oxalic acid, malonic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid and acetic acid. Examples thereof include organic acids such as trifluoroacetic acid, maleic acid, gluconic acid, benzoic acid, salicylic acid, xinafoic acid, pamoic acid, ascorbic acid, adipic acid, methanesulfonic acid, p-toluenesulfonic acid and silicic acid.

The chlorination reaction is generally carried out in a solvent, and a solvent that does not inhibit the reaction is appropriately selected. Examples of such a solvent include aliphatic alcohols such as methanol, ethanol or 2-propanol, ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane or ethylene glycol dimethyl ether, N, N-dimethylformamide or N. -Amids such as methylpyrrolidone, sulfoxides such as dimethyl sulfoxide, aliphatic nitriles such as acetonitrile or propionitrile, ketones such as acetone or 2-butanone, esters such as ethyl acetate, methyl acetate or n-butyl acetate. Classes or water may be mentioned, and a mixed solvent thereof may be used.

2. Production of compound (IV):
2-1. Method for Producing Compound (IV) Using Wittig Reagent:

(Step 2)
Compound (VI) is obtained by reacting compound (V) with a Wittig reagent.

As the compound (V) used for the reaction with the Wittig reagent, a commercially available product may be used as it is, or for example, it can be synthesized according to the production method described later.

Examples of the Wittig reagent include methyl (triphenylphosphoraniliden) acetate. Commercially available compounds can be used as the Wittig reagent.

The amount of the Wittig reagent used in the reaction between the compound (V) and the Wittig reagent is preferably 0.5 to 3.0 mol, more preferably 0.8 to 2.0 mol, based on 1 mol of the compound (V). ..

The reaction with the Wittig reagent is generally carried out in a solvent, and a solvent that does not inhibit the reaction is appropriately selected. Examples of such a solvent include aromatic hydrocarbons such as toluene, chlorobenzene and xylene, ethers such as tetrahydrofuran and 1,4-dioxane, amides such as N, N-dimethylformamide and N-methylpyrrolidone, or amides such as N-methylpyrrolidone. Examples thereof include aliphatic nitriles such as acetonitrile and propionitrile, and a mixed solvent thereof may be used.

The reaction temperature in the reaction with the Wittig reagent is preferably −20 to 150 ° C., more preferably 0 to 100 ° C.

The reaction time in the reaction with the Wittig reagent varies depending on the reaction conditions, but is preferably 5 minutes to 72 hours, more preferably 30 minutes to 48 hours.

(Step 3)
Compound (VII) is obtained by a reduction reaction with compound (VI) using a transition metal catalyst in a hydrogen atmosphere.

Examples of the transition metal catalyst used in the reduction reaction include palladium-carbon.

The amount of the transition metal catalyst used in the reduction reaction is preferably 0.1 to 100% by weight, more preferably 1 to 50% by weight, based on the compound (VI).

The reduction reaction is generally carried out in a solvent, and a solvent that does not inhibit the reaction is appropriately selected. Examples of such a solvent include aliphatic hydrocarbons such as heptane and hexane, and aliphatic alcohols such as methanol, ethanol and propanol, and a mixed solvent thereof may be used.

The reaction temperature in the reduction reaction is preferably 0 to 80 ° C, more preferably 10 to 40 ° C.

The reaction time in the reduction reaction varies depending on the reaction conditions, but is preferably 5 minutes to 72 hours, more preferably 30 minutes to 48 hours.

(Step 4)
Compound (IV) is obtained by a hydrolysis reaction of compound (VII).

Examples of the base used in the hydrolysis reaction include lithium hydroxide, potassium hydroxide and sodium hydroxide.

The amount of the base used in the hydrolysis reaction is preferably 0.5 to 3.0 mol, more preferably 0.8 to 2.0 mol, based on 1 mol of the compound (VII).

The hydrolysis reaction is generally carried out in a solvent, and a solvent that does not inhibit the reaction is appropriately selected. Examples of such a solvent include aliphatic alcohols such as methanol, ethanol and propanol, and water, and a mixed solvent thereof may be used.

The reaction temperature in the hydrolysis reaction is preferably −20 to 150 ° C., more preferably 0 to 100 ° C.

The reaction time of the hydrolysis reaction varies depending on the reaction conditions, but is preferably 5 minutes to 72 hours, more preferably 30 minutes to 48 hours.

2-2. Method for Producing Compound (IV) Using Horner-Emmons Reagent:

(Step 5)
Compound (VIII) is obtained by reacting compound (V) with the Horner-Emmons reagent.

As the compound (V) used for the reaction with the Horner-Emmons reagent, a commercially available product may be used as it is, or for example, it can be synthesized according to the production method described later.

Examples of the Horner-Emmons reagent include benzyl dimethylphosphonoacetate. Commercially available compounds can be used as the Horner-Emmons reagent.

The amount of the Horner-Emmons reagent used in the reaction of the compound (V) with the Horner-Emmons reagent is preferably 0.5 to 3.0 mol, preferably 0.8 to 2.0 mol, relative to 1 mol of the compound (V). Mol is more preferred.

The reaction with the Horner-Emmons reagent is generally carried out in a solvent, and a solvent that does not inhibit the reaction is appropriately selected. Examples of such a solvent include aromatic hydrocarbons such as toluene, chlorobenzene and xylene, ethers such as tetrahydrofuran and 1,4-dioxane, amides such as N, N-dimethylformamide and N-methylpyrrolidone, or amides such as N-methylpyrrolidone. Examples thereof include aliphatic nitriles such as acetonitrile and propionitrile, and a mixed solvent thereof may be used.

The reaction temperature in the reaction with the Horner-Emmons reagent is preferably −20 to 150 ° C., more preferably 0 to 100 ° C.

The reaction time in the reaction with the Horner-Emmons reagent varies depending on the reaction conditions, but is preferably 5 minutes to 72 hours, more preferably 30 minutes to 48 hours.

(Step 6)
Compound (IV) is obtained by a reduction reaction of compound (VIII) with a transition metal catalyst under a hydrogen atmosphere.

The amount of the transition metal catalyst used in the reduction reaction is preferably 0.1 to 100% by weight, more preferably 1 to 50% by weight, based on the compound (VIII).

3. 3. Production of compound (Ib):
3-1. Method for producing compound (Ib):

[In the formula, each symbol is synonymous with the above definition. ]

(Step 7)
Among the cyclic amine derivatives (I) ^{, the compound (Ib) in which R 2} is a hydroxyl group is obtained, for example, by an aldol-type condensation reaction between the compound (IX) and the compound (V) in the presence of a base.

As the compound (IX) used for the aldol-type condensation reaction, a commercially available product can be used as it is.

As the compound (V) used for the aldol-type condensation reaction, a commercially available product may be used as it is, or may be synthesized, for example, according to a production method described later.

Examples of the base used for the aldol-type condensation reaction include lithium diisopropylamide, potassium tert-butoxide, sodium hydride, phenyllithium, and tert-butyllithium.

The amount of the base used in the aldol-type condensation reaction is preferably 0.5 to 10 mol, more preferably 0.8 to 5 mol, based on 1 mol of the compound (IX).

The amount of compound (V) used in the aldol-type condensation reaction is preferably 0.5 to 3 mol, more preferably 0.8 to 1.5 mol, based on 1 mol of compound (IX).

The aldol-type condensation reaction is generally carried out in a solvent, and a solvent that does not inhibit the reaction is appropriately selected. Examples of such a solvent include halogenated hydrocarbons such as dichloromethane, chloroform or 1,2-dichloroethane, and ethers such as tetrahydrofuran or 1,4-dioxane, and a mixed solvent thereof may be used. ..

The reaction temperature in the aldol-type condensation reaction is preferably −78 to 100 ° C., more preferably −78 to 50 ° C.

The reaction time in the aldol-type condensation reaction varies depending on the reaction conditions, but is preferably 5 minutes to 48 hours, more preferably 30 minutes to 24 hours.

3-2. Chloride step of compound (Ib):
A pharmacologically acceptable salt of compound (Ib) is obtained, for example, by a chlorination reaction of compound (Ib) with an acid.

4. Method for producing compound (Va):

[In the formula, R ³ is synonymous with the above definition. ]

(Step 8)
Of the compound (V), the compound (Va) in which A is the group represented by the general formula (IIa) is obtained by a formylation reaction in which a formyl group-introducing reagent is allowed to act after deprotonation of the compound (X) with a base. ..

As the compound (X) used for the formylation reaction, a commercially available product can be used as it is.

Examples of the base used in the formylation reaction include n-butyllithium, sec-butyllithium and tert-butyllithium.

The amount of the base used in the formylation reaction is preferably 0.5 to 3 mol, more preferably 0.8 to 2 mol, based on 1 mol of the compound (X).

Examples of the formyl group-introducing reagent used in the formylation reaction include N, N-dimethylformamide. As N, N-dimethylformamide, a commercially available product can be used as it is.

The amount of the formyl group-introducing reagent used in the formylation reaction is preferably 0.5 to 3 mol, more preferably 0.8 to 2 mol, based on 1 mol of the compound (X).

The formylation reaction is generally carried out in a solvent, and a solvent that does not inhibit the reaction is appropriately selected. Examples of such a solvent include aliphatic hydrocarbons such as heptane and hexane, and ethers such as tetrahydrofuran, diethyl ether and 1,4-dioxane, and a mixed solvent thereof may be used.

The reaction temperature for deprotonation of the formylation reaction is preferably -100 to 0 ° C, more preferably -80 to -20 ° C. The reaction temperature in the formylation reaction is preferably −20 to 150 ° C., more preferably 0 to 100 ° C.

The reaction time of the formylation reaction varies depending on the reaction conditions, but is preferably 5 minutes to 72 hours, more preferably 30 minutes to 48 hours.

5. Production of compound (Ic):
5-1. Method for producing compound (Ic):

[In the formula, each symbol is synonymous with the above definition. ]

(Step 9)
Compound (XII) is obtained by a condensation reaction between compound (IX) and compound (XI) in the presence of a base.

As the compound (IX) and the compound (XI) used in the condensation reaction, commercially available products can be used as they are.

Examples of the base used in the condensation reaction include lithium diisopropylamide, potassium tert-butoxide, sodium hydride, phenyllithium and tert-butyllithium.

The amount of the base used in the condensation reaction is preferably 0.5 to 10 mol, more preferably 0.8 to 5 mol, based on 1 mol of the compound (IX).

The amount of the compound (XI) used in the condensation reaction is preferably 0.5 to 3 mol, more preferably 0.8 to 1.5 mol, based on 1 mol of the compound (IX).

The condensation reaction is generally carried out in a solvent, and a solvent that does not inhibit the reaction is appropriately selected. Examples of such a solvent include halogenated hydrocarbons such as dichloromethane, chloroform or 1,2-dichloroethane, and ethers such as tetrahydrofuran or 1,4-dioxane, and a mixed solvent thereof may be used. ..

The reaction temperature in the condensation reaction is preferably −78 to 100 ° C, more preferably −78 to 50 ° C.

The reaction time in the condensation reaction varies depending on the reaction conditions, but is preferably 5 minutes to 48 hours, more preferably 30 minutes to 24 hours.

(Step 10)
Among the cyclic amine derivatives (I), the compound (Ic) in which A is the group represented by the general formula (IIa) and R ² is a hydroxyl group can be obtained, for example, by a reduction reaction of the compound (XII).

Examples of the reducing agent used in the reduction reaction include lithium borohydride, sodium borohydride, diisobutylaluminum hydride, lithium aluminum hydride, lithium triethyl hydride, sodium bis (2-methoxyethoxy) aluminum hydride or borane complex.

The amount of the reducing agent used in the reduction reaction is preferably 0.5 to 10 mol, more preferably 0.8 to 5 mol, based on 1 mol of the compound (XII).

The reduction reaction is generally carried out in a solvent, and a solvent that does not inhibit the reaction is appropriately selected. Examples of such a solvent include hydrocarbons such as octane, hexane, benzene and toluene, ethers such as tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether and diethyl ether, and methanol, ethanol and 2-propanol. Alcohols may be mentioned, and a mixed solvent thereof may be used.

The reaction temperature in the reduction reaction is preferably −78 to 150 ° C., more preferably −78 to 100 ° C.

5-2. Chloride step of compound (Ic):
A pharmacologically acceptable salt of compound (Ic) is obtained, for example, by a chlorination reaction of compound (Ic) with an acid.

The analgesic effect of the cyclic amine derivative (I) or its pharmacologically acceptable salt, particularly the therapeutic effect of neuropathic pain, can be evaluated using an appropriate animal model. Suitable animal models of neuropathic pain include, for example, a mouse or rat sciatic nerve partial ligation model (Malmberg et al., Pain, 1998, Vol. 76, p. 215-222) or a mouse or rat spinal nerve ligation. Models (Kim et al., Pain, 1992, Vol. 50, p. 355-363) can be mentioned.

The cyclic amine derivative (I) or a pharmacologically acceptable salt thereof has an excellent analgesic effect, particularly a therapeutic effect on neuropathic pain, and thus can be used as a medicine and is preferable as an analgesic. It is used, and is particularly preferably used as a therapeutic agent for neuropathic pain.

Examples of the neuropathic pain referred to here include cancer pain, herpes zoster pain, postherpetic neuralgia, AIDS-related neuralgia, diabetic neuropathy pain, and trigeminal neuralgia.

Cyclic amine derivative (I) or a pharmacologically acceptable salt thereof is also useful in the treatment of acute and chronic pain. Acute pain is usually short-term, but includes, for example, postoperative pain, post-extraction pain or trigeminal neuralgia. Chronic pain is usually defined as pain that lasts for 3 to 6 months and includes somatic and psychogenic pain, including, for example, rheumatoid arthritis, osteoarthritis or postherpetic neuralgia. ..

Pharmaceuticals containing the cyclic amine derivative (I) or a pharmacologically acceptable salt thereof as an active ingredient are mammals (eg, mice, rats, hamsters, rabbits, cats, dogs, cows, sheep, monkeys or humans). , Especially when administered to humans, exerts an excellent analgesic effect, particularly a therapeutic effect on neuropathic pain.

When the cyclic amine derivative (I) or a pharmacologically acceptable salt thereof is used as a medicine, the cyclic amine derivative (I) or the pharmacologically acceptable salt thereof is used as it is or as a pharmaceutically acceptable carrier (drug). It can also be administered orally or parenterally in combination with a physically acceptable carrier).

Dosage forms for oral administration of a drug containing the cyclic amine derivative (I) or a pharmacologically acceptable salt thereof as an active ingredient include, for example, tablets (including sugar-coated tablets and film-coated tablets), pills, and pills. Examples include granules, powders, capsules (including soft capsules and microcapsules), syrups, emulsions or suspensions. The dosage form for parenteral administration of a drug containing the cyclic amine derivative (I) or a pharmacologically acceptable salt thereof as an active ingredient includes, for example, injections, infusions, infusions, and suppositories. , Coating agent or patch. In addition, with a suitable base (eg, butyric acid polymer, glycolic acid polymer, butyric acid-glycolic acid copolymer, mixture of butyric acid polymer and glycolic acid polymer, or polyglycerol fatty acid ester). It is also effective to combine them into a sustained-release preparation.

The preparation of the above-mentioned dosage form can be carried out according to a known production method generally used in the field of preparation. In this case, if necessary, it is produced by containing excipients, binders, lubricants, disintegrants, sweeteners, surfactants, suspending agents, emulsifiers and the like generally used in the pharmaceutical field. be able to. Pharmacologically acceptable carriers include, for example, these agents.

The preparation of tablets can be carried out, for example, by incorporating an excipient, a binder, a disintegrant or a lubricant, and the preparation of pills and granules can be carried out, for example, by adding an excipient, a binder or a disintegrant. It can be contained. Also, for the preparation of powders and capsules, for example, excipients, for the preparation of syrups, for example, sweeteners, for the preparation of emulsions or suspensions, for example, surfactants, suspending agents or emulsifiers. Can be contained.

Examples of excipients include lactose, glucose, starch, sucrose, microcrystalline cellulose, citrus powder, mannitol, sodium hydrogen carbonate, calcium phosphate or calcium sulfate.

Examples of the binder include starch paste solution, Arabic rubber solution, gelatin solution, tragant solution, carboxymethyl cellulose solution, sodium alginate solution, and glycerin.

Examples of the disintegrant include starch or calcium carbonate.

Examples of the lubricant include magnesium stearate, stearic acid, calcium stearate, and purified talc.

Examples of the sweetener include glucose, fructose, invert sugar, sorbitol, xylitol, glycerin or simple syrup.

Examples of the surfactant include sodium lauryl sulfate, polysorbate 80, sorbitan monofatty acid ester, and polyoxyl 40 stearate.

Examples of the suspending agent include gum arabic, sodium alginate, sodium carboxymethyl cellulose, methyl cellulose or bentonite.

Examples of the emulsifier include gum arabic, tragant, gelatin or polysorbate 80.

Furthermore, when a pharmaceutical containing the cyclic amine derivative (I) or a pharmacologically acceptable salt thereof is prepared as an active ingredient in the above dosage form, a colorant generally used in the pharmaceutical field and storage Agents, fragrances, flavoring agents, stabilizers, thickeners and the like can be added.

The daily dose of a drug containing the cyclic amine derivative (I) or a pharmacologically acceptable salt thereof as an active ingredient varies depending on the patient's condition or body weight, the type of compound, the route of administration, etc., for example. When orally administered to an adult (body weight: about 60 kg), the cyclic amine derivative (I) or a pharmacologically acceptable salt thereof is used as an active ingredient in the range of 1 to 1000 mg, divided into 1 to 3 times. It is preferable to administer it, and when it is administered parenterally to an adult (body weight about 60 kg), if it is an injection, the cyclic amine derivative (I) or a pharmacologically acceptable salt thereof is used as the active ingredient amount and the body weight is 1 kg. It is preferably administered by intravenous injection in the range of 0.01 to 100 mg per dose.

The cyclic amine derivative (I) or a pharmacologically acceptable salt thereof may be combined or used in combination with another drug in an appropriate amount in order to supplement or enhance the therapeutic or prophylactic effect, or to reduce the dose. Other agents in this case include, for example, antidepressants such as amitriptyline, milnasiplan or duroxetine, anxiolytics such as alprazolam, anticonvulsants such as carbamazepine, local anesthetics such as lidocain, and sympathetic nerves such as adrenaline. An agonist, an NMDA receptor antagonist such as ketamine, a GABA transaminase inhibitor such as sodium valproate, a calcium channel blocker such as pregabalin, a serotonin receptor antagonist such as lisperidone, a GABA receptor function promoter such as diazepam, or diclofenac. And other anti-inflammatory agents.

Hereinafter, the present invention will be described in detail with reference to Examples, Comparative Examples and Reference Examples, but the present invention is not limited thereto.

In the following description, the solvent name shown in the NMR data indicates the solvent used for the measurement. The 400 MHz NMR spectrum was measured using a JNM-AL400 type nuclear magnetic resonance apparatus (manufactured by JEOL Ltd.). The chemical shift is expressed in δ (unit: ppm) with reference to tetramethylsilane, and the signals are s (single line), d (double line), t (triple line), q (quadruple line), and quint, respectively. (Five-fold line), sept (seven-fold line), m (multiple line), br (wide), dd (double double line), dt (double triple line), ddd (double double double line) , Dq (double quadruple line), tt (triple double line), tt (triple triple line). The ESI-MS spectrum was measured using Agilent Technologies 1200 Series, G6130A (manufactured by Agilent Technologies). All commercially available solvents were used. YFLC W-prep2XY (manufactured by Yamazen Co., Ltd.) was used for flash column chromatography.

The raw material and intermediate of the cyclic amine derivative (I) were synthesized by the method described in the following reference example. Commercially available compounds were used for the compounds used in the synthesis of the reference example compounds for which the synthesis method was not described.

(Reference Example 1) Synthesis of 1-methyl-1H-1,2,4-triazole-5-carbaldehyde:

1. A solution of 1-methyl-1H-1,2,4-triazole (1.00 g, 12.0 mmol) in tetrahydrofuran (26.5 mL) and a solution of n-butyllithium in hexane (1.6 M, 8.17 mL, 13. 2 mmol) was added dropwise at −78 ° C., and the mixture was stirred at the same temperature for 1 hour. N, N-dimethylformamide (1.11 mL, 14.4 mmol) was added to the reaction solution at the same temperature, the temperature was raised to room temperature, and the mixture was stirred for 15 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a 10% aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (NH silica gel, hexane / ethyl acetate) and 1-methyl-1H-1,2,4-triazole-5-carbaldehyde (0.634 g, 5.71 mmol, 47%) was added. Obtained as a colorless oil.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 4.23 (3H, s), 8.03 (1H, s), 10.02 (1H, s).

(Reference Example 2) Synthesis of crude 3- (1-methyl-1H-pyrazole-4-yl) propanoic acid:

Palladium-carbon (10% wet, 24 mg) in a solution of (E) -3- (1-methyl-1H-pyrazole-4-yl) acrylic acid (0.310 g, 2.04 mmol) in methanol (10.0 mL). Was added, and the mixture was stirred at room temperature under a hydrogen atmosphere. After 3 hours, the reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. Methanol (6.0 mL) was added to the residue at room temperature, and then an aqueous sodium hydroxide solution (1.0 N, 6.12 mL, 6.12 mmol) was added at room temperature. After stirring the reaction solution at the same temperature for 3 hours, a 1.0 N aqueous hydrogen chloride solution was added to adjust the pH to 5. The reaction mixture was concentrated under reduced pressure to obtain a crude product of 3- (1-methyl-1H-pyrazole-4-yl) propanoic acid.

(Reference Example 3) Synthesis of crude methyl (E) -3- (1-methyl-1H-pyrazole-5-yl) acrylate:

Methyl (triphenylphosphoraniliden) acetate (2.28 g, 6.81 mmol) in a solution of 1-methyl-1H-pyrazole-5-carbaldehyde (0.500 g, 4.54 mmol) in dichloromethane (12.0 mL). It was added at 0 ° C. After 10 minutes, the reaction solution was heated to room temperature, stirred at the same temperature for 16 hours, and then concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, hexane / ethyl acetate) to obtain a crude product of methyl (E) -3- (1-methyl-1H-pyrazole-5-yl) acrylate.

(Reference Example 4) Synthesis of crude 3- (1-methyl-1H-pyrazole-5-yl) propanoic acid:

Palladium-carbon (10% wet, 23 mg) in a solution of crude methyl (E) -3- (1-methyl-1H-pyrazol-5-yl) acrylate (0.330 g, 1.99 mmol) in methanol (10.0 mL). ) Was added, and the mixture was stirred at room temperature under a hydrogen atmosphere. After 3 hours, the reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. Methanol (6.0 mL) was added to the residue at room temperature, and then an aqueous sodium hydroxide solution (1.0 N, 5.50 mL, 5.50 mmol) was added at room temperature. After stirring the reaction solution at the same temperature for 3 hours, a 1.0 N aqueous hydrogen chloride solution was added to adjust the pH to 5. The reaction mixture was concentrated under reduced pressure to obtain a crude product of 3- (1-methyl-1H-pyrazole-5-yl) propanoic acid.

Example 1 Synthesis of 1- (4- (dimethylamino) piperidine-1-yl) -3- (1-methyl-1H-1,2,4-triazole-5-yl) propan-1-one:

Sodium hydride (55%, 0.118 g, 24.0 mmol) in tetrahydrofuran (3.5 mL) with benzyl dimethylphosphonoacetate (0.662 g, 2.57 mmol) in tetrahydrofuran (3.5 mL) and 1-. A solution of methyl-1H-1,2,4-triazole-5-carbaldehyde (0.300 g, 2.70 mmol) in tetrahydrofuran (6.5 mL) was added at 0 ° C. and stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with a 10% aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (NH silica gel, hexane / ethyl acetate). Methanol (2.1 mL) and palladium-carbon (10% wet, 10 mg) were added to the obtained crude product at room temperature, and the reaction solution was stirred at the same temperature under a hydrogen atmosphere. After 16 hours, the reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. 4- (4,6-dimethoxy-1,3,5-triazine-2-yl) -4-methylmorpholinium chloride (148 mg, 0) in a 2-propanol solution (4.1 mL) of the obtained crude product. .534 mmol) and 4- (dimethylamino) piperidine (53.0 mg, 0.411 mmol) were added at room temperature. After stirring the reaction solution at the same temperature for 12 hours, an aqueous sodium hydroxide solution (1.0 M, 0.82 mL) was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with a 10% aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (NH silica gel, ethyl acetate / chloroform) and 1- (4- (dimethylamino) piperidine-1-yl) -3- (1-methyl-1H-1,2,4-). Triazole-5-yl) propan-1-one (66.7 mg, 0.251 mmol, 9.3%) (hereinafter, the compound of Example 1) was obtained as a colorless oil.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 1.30-1.45 (2H, m), 1.81-1.90 (2H, m), 2.27-2.39 (7H, m), 2.56-2.64 (1H, m), 2.88 -2.93 (2H, m), 2.98-3.07 (3H, m), 3.89 (3H, s), 3.92-3.99 (1H, m), 4.53-4.61 (1H, m), 7.76 (1H, s).
ESI-MS: m / z = 266 (M + H) ⁺ .

(Example 2) 1- (4- (dimethylamino) piperidine-1-yl) -3- (1-methyl-1H-1,2,4-triazole-5-yl) propan-1-one dihydrochloride Synthesis:

1- (4- (Dimethylamino) piperidine-1-yl) -3- (1-methyl-1H-1,2,4-triazole-5-yl) propan-1-one (66.7 mg, 0.251 m mmol) ) In Diethyl ether (5.0 mL), a solution of hydrogen chloride in diethyl ether (2.0 M, 0.314 mL, 0.628 mmol) was added at 0 ° C. The reaction mixture was stirred at room temperature for 1 hour, the precipitated white solid was collected by filtration, washed with diethyl ether (5.0 mL), dried at room temperature, and then 1- (4- (dimethylamino) piperidine-1-yl). ) -3- (1-Methyl-1H-1,2,4-triazole-5-yl) propan-1-one dihydrochloride (57.4 mg, 0.170 mmol, 68%) (hereinafter referred to as Example 2) Compound) was obtained as a white solid.
^{1 1} H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.52-1.63 (1H, m), 1.65-1.77 (1H, m), 2.10-2.22 (2H, m), 2.68-2.78 (1H, m) , 2.87 (6H, s), 3.04-3.10 (2H, m), 3.14-3.28 (3H, m), 3.45-3.58 (1H, m), 3.99 (3H, s), 4.08-4.16 (1H, m) , 4.48-4.56 (1H, m), 8.35 (1H, s).
ESI-MS: 1- (4- (dimethylamino) piperidine-1-yl) -3- (1-methyl-1H-1,2,4-triazole-5-yl) propan-1-one: m / z = 266 (M + H) ⁺ .

(Example 3) Synthesis of 1- (4- (dimethylamino) piperidine-1-yl) -3- (1-methyl-1H-pyrazole-4-yl) -propane-1-one:

Diisopropylethylamine (1.07 mL, 6.11 mmol), HBTU in a solution of crude 3- (1-methyl-1H-pyrazol-4-yl) propanoic acid (0.314 g, 2.04 mmol) in chloroform (20.0 mL). (1.16 g, 3.06 mmol), 4- (dimethylamino) piperidine (0.235 g, 1.83 mmol) was added at room temperature. After stirring the reaction solution at the same temperature for 16 hours, distilled water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with a 10% aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (NH silica gel, chloroform / methanol) and 1- (4- (dimethylamino) piperidine-1-yl) -3- (1-methyl-1H-pyrazole-4-yl)-. Propane-1-one (0.272 g, 1.03 mmol, 56%) (hereinafter, the compound of Example 3) was obtained as a colorless oil.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 1.29-1.42 (2H, m), 1.80-1.88 (2H, m), 2.27 (6H, s), 2.28-2.38 (1H, m), 2.54-2.62 (1H, m), 2.88-3.04 (5H, m), 3.80 (3H, s), 3.98-4.04 (1H, m), 4.56-4.64 (1H, m), 7.46-7.56 (2H, m).
ESI-MS: m / z = 265 (M + H) ⁺ .

(Example 4) Synthesis of 1- (4- (dimethylamino) piperidine-1-yl) -3- (1-methyl-1H-pyrazole-4-yl) -propane-1-one dihydrochloride:

1- (4- (Dimethylamino) piperidine-1-yl) -3- (1-methyl-1H-pyrazole-4-yl) -propane-1-one (270 mg, 1.02 mmol) diethyl ether (10. A dioxane solution of hydrogen chloride (4.0 M, 0.332 mL, 1.33 mmol) was added to the 0 mL) solution at 0 ° C. After stirring the reaction solution at the same temperature for 30 minutes, the precipitated white solid was collected by filtration, washed with diethyl ether (10.0 mL), dried at room temperature, and then 1- (4- (dimethylamino) piperidine-1-). Il) -3- (1-methyl-1H-pyrazole-4-yl) -propan-1-one dihydrochloride (195 mg, 0.577 mmol, 57%) (hereinafter referred to as the compound of Example 4) as a white solid. Obtained.
^{1 1} H-NMR (400 MHz, D ₂ O) δ: 1.46-1.62 (2H, m), 2.08-2.22 (2H, m), 2.64-2.92 (11H, m), 3.10-3.22 (1H, m), 3.44-3.56 (1H, m), 3.98 (3H, s), 4.08-4.18 (1H, m), 4.54-4.62 (1H, m), 7.78-7.86 (2H, m).
ESI-MS: 1- (4- (dimethylamino) piperidine-1-yl) -3- (1-methyl-1H-pyrazole-4-yl) -propane-1-one: m / z = 265 (M) + H) ⁺ .

(Example 5) Synthesis of (1- (4- (dimethylamino) piperidine-1-yl) -3- (1-methyl-1H-pyrazole-5-yl) -propane-1-one:

Diisopropylethylamine (0.962 mL, 5.51 mmol), HBTU in a solution of crude 3- (1-methyl-1H-pyrazole-5-yl) propanoic acid (0.283 g, 1.84 mmol) in chloroform (18.0 mL). (1.04 g, 2.75 mmol), 4- (dimethylamino) piperidine (0.212 g, 1.65 mmol) was added at room temperature. After stirring the reaction solution at the same temperature for 16 hours, distilled water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with a 10% aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, chloroform / methanol, then NH silica gel, chloroform / methanol) and 1- (4- (dimethylamino) piperidine-1-yl) -3- (1-methyl-1H-). Pyrazole-5-yl) -propan-1-one (0.385 g, 1.46 mmol, 88%) (hereinafter, the compound of Example 5) was obtained as a colorless oil.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 1.28-1.44 (2H, m), 1.80-1.90 (2H, m), 2.28 (6H, s), 2.30-2.38 (1H, m), 2.52-2.70 (3H, m), 2.90-3.04 (3H, m), 3.76-3.90 (4H, m), 4.56-4.66 (1H, m), 5.98-6.04 (1H, m), 7.34-7.40 (1H, m) ..
ESI-MS: m / z = 265 (M + H) ⁺ .

(Example 6) Synthesis of 1- (4- (dimethylamino) piperidine-1-yl) -3- (1-methyl-1H-pyrazole-5-yl) -propane-1-one dihydrochloride:

1- (4- (Dimethylamino) piperidine-1-yl) -3- (1-methyl-1H-pyrazole-5-yl) -propane-1-one (385 mg, 1.46 mmol) diethyl ether (10. A dioxane solution of hydrogen chloride (4.0 M, 0.479 mL, 1.92 mmol) was added to the 0 mL) solution at 0 ° C. After stirring the reaction solution at the same temperature for 30 minutes, the precipitated white solid was collected by filtration, washed with diethyl ether (10.0 mL), dried at room temperature, and then 1- (4- (dimethylamino) piperidine-1-). Il) -3- (1-methyl-1H-pyrazole-5-yl) -propan-1-one dihydrochloride (197 mg, 0.583 mmol, 40%) (hereinafter referred to as the compound of Example 6) as a white solid. Obtained.
^{1 1} H-NMR (400 MHz, D ₂ O) δ: 1.46-1.60 (2H, m), 2.06-2.20 (2H, m), 2.60-2.94 (11H, m), 3.10-3.22 (1H, m), 3.40-3.54 (1H, m), 4.04-4.20 (4H, m), 4.54-4.64 (1H, m), 6.14-6.20 (1H, m), 7.50-7.56 (1H, m).
ESI-MS: 1- (4- (dimethylamino) piperidine-1-yl) -3- (1-methyl-1H-pyrazole-5-yl) -propane-1-one: m / z = 265 (M) + H) ⁺ .

(Example 7) 1- (4- (dimethylamino) piperidine-1-yl) -3-hydroxy-3- (1-methyl-1H-1,2,4-triazole-5-yl) propan-1- On synthesis:

A solution of 1- (4-dimethylaminopiperidine-1-yl) etanone (0.124 g, 0.728 mmol) in tetrahydrofuran (2.0 mL) and a solution of lithium diisopropylamide in tetrahydrofuran (2.0 M, 0.874 mL, 1.75 mmol). ) Was added dropwise at −78 ° C., and the mixture was stirred at the same temperature for 1 hour. A solution of ethyl 1-methyl-1H-1,2,4-triazole-5-carboxylate (0.113 g, 0.728 mmol) in tetrahydrofuran (1.0 mL) was added to the reaction solution at the same temperature, and the mixture was stirred for 1 hour. The mixture was further stirred at 0 ° C. for 1 hour. A saturated aqueous ammonium chloride solution and an aqueous potassium carbonate solution were added to the reaction solution in this order, and the mixture was extracted with chloroform. The organic layer was washed with a 10% aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (NH silica gel, hexane / ethyl acetate). Sodium borohydride (0.0321 g, 0.848 mmol) was added to a solution of the obtained crude product in methanol (5.7 mL) at 0 ° C., and the reaction solution was stirred at room temperature for 1 hour. An aqueous potassium carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with a 10% aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (NH silica gel, chloroform / methanol) and 1- (4- (dimethylamino) piperidine-1-yl) -3-hydroxy-3- (1-methyl-1H-1,2). , 4-Triazole-5-yl) propan-1-one (0.121 g, 0.430 mmol, 59%) (hereinafter, the compound of Example 7) was obtained as a colorless oil.
^{1 1} H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.02-1.40 (2H, m), 1.62-1.80 (2H, m), 2.10-2.33 (7H, m), 2.45-2.60 (1H, m) , 2.83-3.07 (3H, m), 3.84-3.96 (4H, m), 4.24-4.33 (1H, m), 5.10-5.20 (1H, m), 5.70-5.78 (1H, m), 7.72-7.78 ( 1H, m).
ESI-MS: m / z = 282 (M + H) ⁺ .

(Example 8) Synthesis of 1- (4- (dimethylamino) piperidine-1-yl) -3-hydroxy-3- (1-methyl-1H-pyrazole-5-yl) propan-1-one:

A solution of 1- (4-dimethylaminopiperidine-1-yl) etanone (0.300 g, 1.76 mmol) in tetrahydrofuran (6.0 mL) and a solution of lithium diisopropylamide in tetrahydrofuran (2.0 M, 0.969 mL, 1.94 mmol). ) Was added dropwise at −78 ° C., and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture, add 1-methyl-1H-pyrazole-5-carbaldehyde (0.233 g, 2.12 mmol) in tetrahydrofuran (2.8 mL) at the same temperature, stir for 1 hour, and then stir at 0 ° C. for another 1 hour. bottom. A saturated aqueous ammonium chloride solution and an aqueous potassium carbonate solution were added to the reaction solution in this order, and the mixture was extracted with chloroform. The organic layer was washed with a 10% aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (NH silica gel, chloroform / methanol) and 1- (4- (dimethylamino) piperidine-1-yl) -3-hydroxy-3- (1-methyl-1H-pyrazol-5). -Il) Propan-1-one (0.230 g, 0.820 mmol, 47%) (hereinafter, the compound of Example 8) was obtained as a colorless oil.
^{1 1} H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.06-1.38 (2H, m), 1.66-1.79 (2H, m), 2.11-2.35 (7H, m), 2.47-2.60 (1H, m) , 2.66-2.77 (1H, m), 2.83-3.04 (2H, m), 3.81 (3H, s), 3.90-3.99 (1H, m), 4.30-4.38 (1H, m), 5.07 (1H, br) , 5.44 (1H, s), 6.16-6.20 (1H, m), 7.27 (1H, s).
ESI-MS: m / z = 281 (M + H) ⁺ .

The compound of Comparative Example 1 and the compound of Comparative Example 2 were prepared by the following methods.

(Reference Example 5) Synthesis of crude 3- (1-methyl-1H-pyrazole-3-yl) propanoic acid:

Palladium-carbon (10% wet, 24 mg) in a solution of (E) -3- (1-methyl-1H-pyrazole-3-yl) acrylic acid (0.310 g, 2.04 mmol) in methanol (10.0 mL). Was added, and the mixture was stirred at room temperature under a hydrogen atmosphere. After 3 hours, the reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. Methanol (6.0 mL) was added to the residue at room temperature, and then an aqueous sodium hydroxide solution (1.0 N, 5.65 mL, 5.65 mmol) was added at room temperature. After stirring the reaction solution at the same temperature for 3 hours, a 1.0 N aqueous hydrogen chloride solution was added to adjust the pH to 5. The reaction mixture was concentrated under reduced pressure to obtain a crude product of 3- (1-methyl-1H-pyrazole-3-yl) propanoic acid.

(Reference Example 6) Synthesis of 1- (4- (dimethylamino) piperidine-1-yl) -3- (1-methyl-1H-pyrazole-3-yl) propan-1-one:

Diisopropylethylamine (0.986 mL, 5.64 mmol), HBTU in a solution of crude 3- (1-methyl-1H-pyrazol-3-yl) propanoic acid (0.290 g, 1.88 mmol) in chloroform (19.0 mL). (1.07 g, 2.82 mmol), 4- (dimethylamino) piperidine (0.217 g, 1.69 mmol) was added at room temperature. After stirring the reaction solution at the same temperature for 16 hours, distilled water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with a 10% aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, chloroform / methanol, then NH silica gel, chloroform / methanol) and 1- (4- (dimethylamino) piperidine-1-yl) -3- (1-methyl-1H-). Pyrazole-3-yl) propan-1-one (0.284 g, 1.07 mmol, 63%) was obtained as a colorless oil.
^{1 1} H-NMR (400 MHz, CDCl ₃ ) δ: 1.28-1.42 (2H, m), 1.80-1.90 (2H, m), 2.26-2.42 (7H, m), 2.52-2.60 (1H, m), 2.64 -2.80 (2H, m), 2.92-3.02 (3H, m), 3.84 (3H, s), 3.90-4.02 (1H, m), 4.58-4.66 (1H, m), 6.02-6.06 (1H, m) , 7.20-7.22 (1H, m).
ESI-MS: m / z = 265 (M + H) ⁺ .

(Comparative Example 1) Synthesis of 1- (4- (dimethylamino) piperidine-1-yl) -3- (1-methyl-1H-pyrazole-3-yl) -propane-1-one dihydrochloride:

1- (4- (Dimethylamino) Piperidine-1-yl) -3- (1-Methyl-1H-Pyrazole-3-yl) Propane-1-one (280 mg, 1.06 mmol) diethyl ether (6.0 mL) ) A dioxane solution of hydrogen chloride (4.0 M, 0.344 mL, 1.38 mmol) was added at 0 ° C. After stirring the reaction solution at the same temperature for 30 minutes, the precipitated white solid was collected by filtration, washed with diethyl ether (10.0 mL), dried at room temperature, and then 1- (4- (dimethylamino) piperidine-1-). Il) -3- (1-methyl-1H-pyrazole-3-yl) -propane-1-one dihydrochloride (97.3 mg, 0.288 mmol, 27%) (hereinafter, the compound of Comparative Example 1) is white. Obtained as a solid.
^{1 1} H-NMR (400 MHz, D ₂ O) δ: 1.44-1.66 (2H, m), 2.08-2.24 (2H, m), 2.66-2.92 (11H, m), 3.10-3.22 (1H, m), 3.44-3.56 (1H, m), 3.96 (3H, s), 4.06-4.18 (1H, m), 4.52-4.62 (1H, m), 6.16-6.22 (1H, m), 7.36-7.40 (1H, m) ).
ESI-MS: 1- (4- (dimethylamino) piperidine-1-yl) -3- (1-methyl-1H-pyrazole-3-yl) -propane-1-one: m / z = 265 (M) + H) ⁺ .

(Comparative Example 2) Synthesis of 1- (4- (dimethylamino) piperidine-1-yl) -3-hydroxy-3- (1-methyl-1H-pyrazole-3-yl) propan-1-one:

A solution of 1- (4-dimethylaminopiperidine-1-yl) etanone (0.300 g, 1.76 mmol) in tetrahydrofuran (6.0 mL) and a solution of lithium diisopropylamide in tetrahydrofuran (2.0 M, 0.969 mL, 1.94 mmol). ) Was added dropwise at −78 ° C., and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture, add 1-methyl-1H-pyrazole-3-carbaldehyde (0.233 g, 2.12 mmol) in tetrahydrofuran (2.8 mL) at the same temperature, stir for 1 hour, and then stir at 0 ° C. for another 1 hour. bottom. A saturated aqueous ammonium chloride solution and an aqueous potassium carbonate solution were added to the reaction solution in this order, and the mixture was extracted with chloroform. The organic layer was washed with a 10% aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (NH silica gel, chloroform / methanol) and 1- (4- (dimethylamino) piperidine-1-yl) -3-hydroxy-3- (1-methyl-1H-pyrazol-3). -Il) Propan-1-one (0.296 g, 1.06 mmol, 60%) (hereinafter, the compound of Comparative Example 2) was obtained as a colorless oil.
^{1 1} H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.06-1.38 (2H, m), 1.66-1.77 (2H, m), 2.10-2.33 (7H, m), 2.47-2.82 (3H, m) , 2.81-3.00 (1H, m), 3.76 (3H, s), 3.88-3.97 (1H, m), 4.33-4.40 (1H, m), 4.88-4.96 (1H, m), 5.10-5.17 (1H, m), 6.15-6.18 (1H, m), 7.55 (1H, s).
ESI-MS: m / z = 281 (M + H) ⁺ .

(Example 9) Effect on mouse sciatic nerve partial ligation model:
Using a mouse sciatic nerve partial ligation model (Selzer model) capable of evaluating neuropathic pain, the analgesic effect of the cyclic amine derivative (I) or its pharmacologically acceptable salt was examined.

As the cyclic amine derivative (I) or a pharmacologically acceptable salt thereof, the compound of Example 2, the compound of Example 4 or the compound of Example 6 was used for evaluation.

1. 1. experimental method:
A mouse sciatic nerve partial ligation model was prepared according to the method of Seltzer et al. (Malmberg et al., Pain, 1998, Vol. 76, p. 215-222).

Slc: ICR mice (5 weeks old, male; Nippon SLC) were anesthetized with pentovalbital sodium (70 mg / kg, intraperitoneally administered) to expose the sciatic nerve of the right hind limb thigh and 8 under a stereomicroscope. The group in which the sciatic nerve was triple-ligated with a force of -0 silk thread (Natsume Seisakusho) was defined as the sciatic nerve partial ligation group, and the group in which the sciatic nerve was only exposed but not ligated was defined as the sciatic nerve sham surgery group.

The evaluation of neuropathy pain (hereinafter referred to as von Frey test) is performed by acclimatizing a mouse in a measurement acrylic cage (Natsume Seisakusho) installed on a net for at least 2 hours, and then applying a pressure of 0.16 g to a filament (Filament). Using North Coast Medical, mechanical tactile stimulus that presses the filament against the sole of the right hind limb for 3 seconds is repeated 3 times at 3 second intervals, and the intensity of escape behavior when mechanical tactile stimulus is applied is scored (0). : No response, 1: Slow and slight escape behavior to the stimulus, 2: Quick escape behavior to the stimulus without flinching (quick and continuous shaking of the foot) or licking (foot licking behavior) 3: flinching or A quick escape action accompanied by licking) was performed, and the total value of the scores of the three times (hereinafter referred to as the total score) was used as an index of pain.

Seven days after sciatic nerve ligation surgery, mice in the sciatic nerve partial ligation group were given compound of Example 2, compound of Example 4 or compound of Example 6 (10 mg / kg, respectively) or pregabalin as a positive control (10 mg / kg; Bosche Scientific) was dissolved in distilled water and orally administered. Mice in the sciatic nerve partial ligation group were administered with the compound of Example 2, the compound of Example 4, or the compound of Example 6, respectively, in the "sciatic nerve partial ligation + compound of Example 2" group and "sciatic nerve". The group to which "partial ligation + compound of Example 4" and "partial sciatic nerve ligation + compound of Example 6" were used, and the group to which pregabalin was administered was defined as the "partial sciatic nerve ligation + pregavalin" group. In addition, the group in which distilled water was orally administered to the mice in the sciatic nerve partial ligation group was defined as the "sciatic nerve partial ligation + distilled water" group, and the group in which distilled water was orally administered to the mice in the sciatic nerve partial ligation group was defined as "sham surgery +". It was designated as the "distilled water" group.

The von Frey test was conducted before oral administration (pre value) of the test compound, 1 hour, 2 hours, and 3 hours after oral administration.

2. result:
The results are shown in FIGS. 1 to 3. In the figure, the vertical axis shows the total score of the von Frey test (mean ± standard error; FIGS. 1 to 3 show n = 4 to 5, respectively), and the higher the value, the stronger the pain. The horizontal axis shows the time (hr) after administration of the test compound. The drug efficacy evaluation is based on the "sciatic nerve partial ligation + distilled water" group ("sciatic nerve partial ligation + distilled water" in the figure) for each measurement time as a control, and the unpaired two groups of t-test or Welch's test (Fig. 1). Statistical processing was performed by 3) or two unpaired t-tests (Fig. 2). The * mark in the figure indicates that it is statistically significant (p <0.05) in comparison with the "partial sciatic nerve ligation + distilled water" group.

According to the results of the von Frey test, oral administration of the compound of Example 2, the compound of Example 4, or the compound of Example 6 (“sciatic nerve partial ligation + compound of Example 2” in the figure, “sciatic nerve portion” The ligation + compound of Example 4 or “partial sciatic nerve ligation + compound of Example 6”) is statistically similar to the positive control pregabalin (“partial sciatic nerve ligation + pregabalin” in the figure). It showed a significant analgesic effect.

(Comparative Example 3) Effect on mouse sciatic nerve partial ligation model:
Using a mouse sciatic nerve partial ligation model (Selzer model) capable of evaluating neuropathic pain, the analgesic effect of the compound of Comparative Example 1 or the compound of Comparative Example 2 was examined.

Slc: ICR mice (5 weeks old, male; Japan SLC) or Crl: CD1 (ICR) mice (5 weeks old, male; Japan Charles River) with pentovalbital sodium (70 mg / kg, intraperitoneal administration) The group in which the sciatic nerve in the right hind limb thigh was exposed and the sciatic nerve was triple-ligated with 8-0 silk thread (Natsume Seisakusho) under a stereoscopic microscope was defined as the sciatic nerve partial ligation group. The group in which the sciatic nerve was only exposed but not ligated was defined as the sham operation group.

In the von Frey test, after acclimatizing the mouse for at least 2 hours in a measurement acrylic cage (Natsume Seisakusho) installed on the net, a filament (North Coast Medical or neuroscience) to which a pressure of 0.16 g is applied is used, and the right side is used. The mechanical tactile stimulus that presses the filament against the sole of the hind limb for 3 seconds is repeated 3 times at 3 second intervals, and the intensity of escape behavior when the mechanical tactile stimulus is applied is scored (0: no reaction, 1: stimulus). Slow and slight escape behavior, 2: quick escape behavior for stimuli without flinching (quick and continuous shaking of the foot) or licking (quick escape behavior with flinching or licking) However, the total value of the three scores (hereinafter referred to as the total score) was used as an index of pain.

Seven days after sciatic nerve ligation surgery, mice in the sciatic nerve partial ligation group were given the compound of Comparative Example 1 or the compound of Comparative Example 2 (10 mg / kg, respectively) or pregabalin (10 mg / kg; Bosche Scientific or KEMPROTEC) as a positive control. , Dissolved in distilled water and orally administered. Mice in the sciatic nerve partial ligation group were administered with the compound of Comparative Example 1 or the compound of Comparative Example 2, respectively, in the "sciatic nerve partial ligation + compound of Comparative Example 1" group and "sciatic nerve partial ligation + comparative example", respectively. The group to which pregabalin was administered was designated as the "compound of 2" group, and the group to which pregabalin was administered was designated as the "partial sciatic nerve ligation + pregavalin" group. In addition, the group in which distilled water was orally administered to the mice in the sciatic nerve partial ligation group was defined as the "sciatic nerve partial ligation + distilled water" group, and the group in which distilled water was orally administered to the mice in the sciatic nerve partial ligation group was defined as "sham surgery +". It was designated as the "distilled water" group.

2. result:
The results are shown in FIG. 4 or FIG. In the figure, the vertical axis shows the total score of the von Frey test (mean ± standard error; in FIG. 4 or 5, respectively, n = 5 to 6), and the higher the value, the stronger the pain. The horizontal axis shows the time (hr) after administration of the test compound. The drug efficacy evaluation is based on the "sciatic nerve partial ligation + distilled water" group ("sciatic nerve partial ligation + distilled water" in the figure) for each measurement time as a control, and the t-test or Welch test of two unpaired groups (Fig. 4). ) Or two unpaired Welch tests (FIG. 5). The * mark in the figure indicates that it is statistically significant (p <0.05) in comparison with the "partial sciatic nerve ligation + distilled water" group.

According to the results of the von Frey test, oral administration of the compound of Comparative Example 1 or the compound of Comparative Example 2 (“Sciatic nerve partial ligation + Compound of Comparative Example 1” in the figure, “Sciatic nerve partial ligation + Comparative Example 2” None of the compounds ") showed a statistically significant analgesic effect.

From this result, it was clarified that the cyclic amine derivative (I) or a pharmacologically acceptable salt thereof exhibits a strong analgesic effect on neuropathic pain.

The cyclic amine derivative of the present invention or a pharmacologically acceptable salt thereof can exert an analgesic effect on pain, particularly neuropathic pain, and thus can be used as a medicine for pain symptoms.

Claims

A cyclic amine derivative represented by the general formula (I) or a pharmacologically acceptable salt thereof.

[In the formula, A represents a group represented by the general formula (IIa), (IIb) or (IIc).

R 1 independently represents a methyl group or an ethyl group, R 2 represents a hydrogen atom or a hydroxyl group, and R 3 represents a methyl group or an ethyl group which may be substituted with a halogen atom. ]
A is the cyclic amine derivative according to claim 1, which is a group represented by the general formula (IIa) or (IIb), or a pharmacologically acceptable salt thereof.
R 2 is a hydroxyl group, a cyclic amine derivative or a pharmacologically acceptable salt thereof according to claim 1 or 2, wherein.
R 3 is a cyclic amine derivative according to any one of claims 1 to 3, which is a methyl group or an ethyl group which may be substituted with a fluorine atom, or a pharmacologically acceptable salt thereof.
R 3 is a methyl group, an ethyl group, a difluoromethyl group or a 2,2,2-trifluoroethyl group, is allowed claims 1-4 cyclic amine derivative according to any one claim or a pharmaceutically Salt.
A pharmaceutical agent containing the cyclic amine derivative according to any one of claims 1 to 5 or a pharmacologically acceptable salt thereof as an active ingredient.
An analgesic containing the cyclic amine derivative according to any one of claims 1 to 5 or a pharmacologically acceptable salt thereof as an active ingredient.
A neuropathic pain therapeutic agent containing the cyclic amine derivative according to any one of claims 1 to 5 or a pharmacologically acceptable salt thereof as an active ingredient.