Entitled cyclic amine derivatives and pharmaceutical use

Technical field

[0001]

　The present invention relates to cyclic amine derivatives and their pharmaceutical use.

Background technique

[0002]

　The pain is that experience with unpleasant sensations or unpleasant emotion that occurs when there is a time or potential tissue damage is caused. Pain, by the cause, mainly, are classified as nociceptive pain, neuropathic pain or psychogenic pain.

[0003]

　The neuropathic pain is pathological pain caused by dysfunction of the peripheral or central nervous system itself, despite nociceptors receives no noxious stimuli, by direct damage or compression or the like of nerve tissue It refers to the resulting pain. The therapeutic agent for neuropathic pain, anticonvulsants, antidepressants, antianxiety agents or anti-epileptic drugs (gabapentin or pregabalin or the like) is used.

[0004]

　On the other hand, compounds having similar derivative with a compound of the present invention as a partial structure (Patent Document 1) is disclosed, it can have efficacy have been suggested for them are overweight or obese. Patent Document 2, some of the compounds of the nitrogen-containing heterocyclic derivatives are disclosed to exhibit specific antagonism against NR1 / NR2B receptor which is one of the NMDA receptor. Further, Patent Document 3, an imidazole derivatives are disclosed to exhibit an analgesic effect.

CITATION

Patent Document

[0005]

Patent Document 1: Patent No. 4563675 Patent
Patent Document 2: WO 2006/137465
Patent Document 3: WO 2013/147160

Summary of the Invention

Problems that the Invention is to Solve

[0006]

　However, the treatment with the therapeutic agent of the conventional neuropathic pain, central side effects (dizziness, nausea or vomiting, etc.) with a high frequency, because the long-term administration is difficult, the novel neuropathic pain therapeutic agent development is desired.

[0007]

　It should be noted that the substitution piperidines described in Patent Document 1, analgesic effects including effects on neuropathic pain is unclear. Analgesics, have not been reported, especially as lead compounds neuropathic pain therapeutic agent, a hitherto For utility of substituted piperidines described in Patent Document 1. As for the nitrogen-containing heterocyclic derivative described in Patent Document 2, suggesting the effect that have utility as analgesics have been made. The imidazole derivatives described in Patent Document 3, it is disclosed that has an analgesic effect. However, for the compounds of the invention not described at all.

[0008]

　Accordingly, the present invention aims at providing pain, compounds which exhibit particularly strong analgesic effect on neuropathic pain.

Means for Solving the Problems

[0009]

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

[0010]

　That is, the present invention provides a cyclic amine derivative or a pharmacologically acceptable salt thereof represented by the following general formula (I).
[Formula 1]

[wherein, n stands for 1 or 3, R 1 is substituted with unsubstituted or substituted with a halogen atom, or an alkyl group having 1 to 4 carbon atoms represents an alkyl group having 1 to 6 carbon atoms, R 2 represents a hydrogen atom or a halogen atom. ]

[0011]

　The above cyclic amine derivative or a pharmacologically acceptable salt thereof, R 2 is preferably is a hydrogen atom or a chlorine atom. R 2 By limiting the hydrogen atom or a chlorine atom, it is possible to enhance the analgesic effect.

[0012]

　Furthermore, the above cyclic amine derivative or a pharmaceutically acceptable salt thereof pharmacologically is, R 1 is preferably an alkyl group having 1 to 6 carbon atoms which is unsubstituted. R 1 by limiting the alkyl group having 1 to 6 carbon atoms which are not substituted with, it is possible to further enhance the analgesic effect.

[0013]

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

[0014]

　Aforementioned medicament is preferably an analgesic, more preferably neuropathic pain therapeutic agent.

[0015]

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

[0016]

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

[0017]

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

[0018]

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

[0019]

　The present invention, in the manufacture of a medicament for the treatment of pain, there is provided the use of salts cyclic amine derivative or a pharmacologically acceptable represented by the above general formula (I). Pain is preferably neuropathic pain.

[0020]

　This invention also provides a method of treating pain, administration of a cyclic amine derivative or a pharmacologically acceptable salt thereof represented by the therapeutically effective amount of the above general formula to a patient in need of treatment (I) the method comprising the. Pain is preferably neuropathic pain.

Effect of the Invention

[0021]

　Cyclic amine derivative or a pharmacologically acceptable salt thereof of the present invention exhibit a strong analgesic effect pain, particularly neuropathic pain.

BRIEF DESCRIPTION OF THE DRAWINGS

[0022]

FIG. 1 is a graph showing the effect of the compound of Example 13 for the mouse sciatic nerve partial ligation model (oral administration).
2 is a diagram showing the effect of the compound of Example 14 for the mouse sciatic nerve partial ligation model (oral administration).
3 is a graph showing the effect of the compound of Example 15 for the mouse sciatic nerve partial ligation model (oral administration).
4 is a graph showing the effect of the compound of Example 16 for the mouse sciatic nerve partial ligation model (oral administration).
5 is a graph showing the effect of the compound of Example 17 for the mouse sciatic nerve partial ligation model (oral administration).
6 is a graph showing the effect of the compound of Example 18 for the mouse sciatic nerve partial ligation model (oral administration).
7 is a graph showing the effect of the compound of Example 19 for the mouse sciatic nerve partial ligation model (oral administration).
8 is a graph showing the effect of the compound of Example 20 for the mouse sciatic nerve partial ligation model (oral administration).
9 is a graph showing the effect of the compound of Example 21 for the mouse sciatic nerve partial ligation model (oral administration).
10 is a diagram showing the effect of the compound of Example 22 for the mouse sciatic nerve partial ligation model (oral administration).
11 is a graph showing the effect of the compound of Example 23 for the mouse sciatic nerve partial ligation model (oral administration).
12 is a graph showing the effect of the compound of Example 24 for the mouse sciatic nerve partial ligation model (oral administration).

DESCRIPTION OF THE INVENTION

[0023]

　The following terms used herein, unless otherwise specified, as defined below.

[0024]

　Cyclic amine derivative of the present invention is characterized in that represented by the following general formula (I).
[Formula 2]

[In the formula, n represents 1 or 3, R 1 is substituted with unsubstituted or substituted with a halogen atom, or an alkyl group having 1 to 4 carbon atoms represents an alkyl group having 1 to 6 carbon atoms, R 2 represents a hydrogen atom or a halogen atom. ]

[0025]

　In one embodiment of the above cyclic amine derivative of the present invention, n represents 1, R 1 is unsubstituted or fluorine-substituted with atoms or substituted by an alkyl group having 1 to 4 carbon atoms represents an alkyl group having 1 to 6 carbon atoms which is, R 2 represents a hydrogen atom or a halogen atom.

[0026]

　In one embodiment of the above cyclic amine derivative of the present invention, n represents 1, R 1 is unsubstituted or fluorine-substituted with atoms or substituted by an alkyl group having 1 to 4 carbon atoms represents an alkyl group having 1 to 6 carbon atoms which is, R 2 represents a hydrogen atom or a chlorine atom.

[0027]

　In one embodiment of the above cyclic amine derivative of the present invention, n represents 1, R 1 is unsubstituted or fluorine atom is substituted with, or substituted with an alkyl group having 1 carbon atoms It represents an alkyl group having 1 to 6 carbon atoms are, R 2 represents a hydrogen atom or a chlorine atom.

[0028]

　In one embodiment of the above cyclic amine derivative of the present invention, n represents 1, R 1 is unsubstituted or fluorine atom is substituted with, or substituted with an alkyl group having 1 carbon atoms It represents an alkyl group having 1 to 3 carbon atoms are, R 2 represents a hydrogen atom or a chlorine atom.

[0029]

　In one embodiment of the above cyclic amine derivative of the present invention, n represents 1, R 1 represents an alkyl group having 1 to 6 carbon atoms which is not substituted, R 2 represents a hydrogen atom or a chlorine atom .

[0030]

　In one embodiment of the above cyclic amine derivative of the present invention, n represents 1, R 1 represents an alkyl group having 1 to 3 carbon atoms which is not substituted, R 2 represents a hydrogen atom or a chlorine atom .

[0031]

　In one embodiment of the above cyclic amine derivative of the present invention, n represents 3, R 1 is unsubstituted or fluorine-substituted with atoms or substituted by an alkyl group having 1 to 4 carbon atoms represents an alkyl group having 1 to 6 carbon atoms which is, R 2 represents a hydrogen atom or a halogen atom.

[0032]

　In one embodiment of the above cyclic amine derivative of the present invention, n represents 3, R 1 is unsubstituted or fluorine-substituted with atoms or substituted by an alkyl group having 1 to 4 carbon atoms represents an alkyl group having 1 to 6 carbon atoms which is, R 2 represents a hydrogen atom or a chlorine atom.

[0033]

　In one embodiment of the above cyclic amine derivative of the present invention, n represents 3, R 1 is unsubstituted or fluorine atom is substituted with, or substituted with an alkyl group having 1 carbon atoms It represents an alkyl group having 1 to 6 carbon atoms are, R 2 represents a hydrogen atom or a chlorine atom.

[0034]

　In one embodiment of the above cyclic amine derivative of the present invention, n represents 3, R 1 is unsubstituted or fluorine atom is substituted with, or substituted with an alkyl group having 1 carbon atoms It represents an alkyl group having 1 to 3 carbon atoms are, R 2 represents a hydrogen atom or a chlorine atom.

[0035]

　In one embodiment of the above cyclic amine derivative of the present invention, n represents 3, R 1 represents an alkyl group having 1 to 6 carbon atoms which is not substituted, R 2 represents a hydrogen atom or a chlorine atom .

[0036]

　In one embodiment of the above cyclic amine derivative of the present invention, n represents 3, R 1 represents an alkyl group having 1 to 3 carbon atoms which is not substituted, R 2 represents a hydrogen atom or a chlorine atom .

[0037]

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

[0038]

　The "alkyl group having 1 to 4 carbon atoms" means a straight chain, branched chain or cyclic groups saturated hydrocarbon groups linked to an oxygen atom of 1 to 4 carbon atoms, such as methoxy group, ethoxy group, n- propyl group, an isopropyl group, a cyclopropyl group, n- butoxy group, and a sec- butoxy group or tert- butoxy.

[0039]

　"Not substituted, or a halogen atom is substituted with, or an alkyl group having 1 to 6 carbon atoms which is substituted by an alkyl group having 1 to 4 carbon atoms" and is unsubstituted, or the above-mentioned are substituted with halogen atoms, or is substituted by the above alkyl group having 1 to 4 carbon atoms means a straight, branched or cyclic saturated hydrocarbon group having 1 to 6 carbon atoms, For example, a methyl group, an ethyl group, n- propyl group, an isopropyl group, cyclopropyl group, cyclopropylmethyl group, n- butyl group, sec- butyl group, tert- butyl group, n- pentyl group, isopentyl group, n- hexyl group, isohexyl group, or a cyclohexyl group or a 2-chloroethyl group, 2,2-difluoroethyl group, 2,2,2-trifluoroethyl group, a 2-methoxyethyl group, 2 Ethoxyethyl group or 2-isopropyloxyethyl group.

[0040]

　Specific examples of preferred compounds of the above cyclic amine derivative are shown in Table 1-1 and Table 1-2, the present invention is not limited thereto.

[0041]

[Table 1-1]

[0042]

[Table 1-2]

[0043]

　Incidentally, when there is an asymmetric carbon in the cyclic amine derivatives of the above, all enantiomers and mixtures thereof are included in the cyclic amine derivatives of the above. Also, if the stereoisomers are present in cyclic amine derivatives of the above, all stereoisomers and mixtures thereof are included in the cyclic amine derivatives of the above.

[0044]

　Cyclic amine derivatives of the above may also be labeled with a radioisotope, the radioisotope that is labeled, for example, 3 H, 14 C and / or 125 include I.

[0045]

　Further, a cyclic amine derivative described above may be a deuterium converter.

[0046]

　Salts pharmacologically acceptable the above cyclic amine derivative, e.g., hydrochloride, sulfate, inorganic salts such as phosphate or hydrobromide; or, oxalate, malonate, citrate, fumarate, lactate, malate, succinate, tartrate, acetate, trifluoroacetate, maleate, gluconate, benzoate, salicylate, xinafoate, pamoic , ascorbate, adipate, methanesulfonate, and organic acid salts such as p- toluenesulfonate or cinnamate. In addition these salts, hydrates may form solvates or polymorphs.

[0047]

　Cyclic amine derivatives of the above may be synthesized according to the production method described below. Note that cyclic amine derivatives obtained by the following manufacturing method, known means (e.g., solvent extraction, recrystallization and / or chromatography) can be isolated purified by, salts of interest by a method analogous to known methods or It can be converted to. If the cyclic amine derivative is obtained in the form of salt, by a method analogous to known methods or can be converted into other salts of the cyclic amine derivative or purpose.

[0048]

1. Method for producing a cyclic amine derivative:
[Chemical Formula 3]

[wherein, M represents a hydrogen atom or an alkali metal, the alkali metal, for example, lithium or sodium. Other symbols are as defined. ]
　Cyclic amine derivative represented by the general formula (I) (hereinafter, referred to as a cyclic amine derivative (I);. Abbreviated Similarly for derivative represented by other formulas), for example, the presence or absence of a base obtained by condensation reaction of 3-dimethylamino-cyclic amine derivative (II) with a carboxylic acid derivative (III) using a condensing agent.

[0049]

　The condensation reaction can be used 3-dimethylamino cyclic amine derivative (II) and salts thereof. As the salt of case, for example, those similar to the salts described above pharmacologically acceptable can be mentioned.

[0050]

　Used in the condensation reaction 3-dimethylamino-cyclic amine derivative (II) and carboxylic acid derivative (III), which can be used as it is a commercial product, for example, can be synthesized according to the production methods described below.

[0051]

　The base used in the condensation reaction, for example, aromatic amines such as pyridine or lutidine; or triethylamine, triisopropylamine, tributylamine, cyclohexyldimethylamine, 4-dimethylaminopyridine, N, N- dimethylaniline, N- methyl piperidine, N- methylpyrrolidine, tertiary amines such as N- methylmorpholine or diisopropylethylamine (DIEA) and the like.

[0052]

　The amount of the base used in the condensation reaction is preferably 0.5 to 10 moles relative to 1 mole of 3-dimethylamino cyclic amine derivative (II), and more preferably 0.8 to 5.0 mol.

[0053]

　The condensing agent used in the condensation reaction, for example, O- (benzotriazol-1-yl) -N, N, N ', N'- tetramethyluronium hexafluorophosphate (HBTU), dicyclohexylcarbodiimide (DCC), N- (3- dimethylaminopropyl) -N'- ethylcarbodiimide (EDC) or a hydrochloride salt, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroxy-quinoline (EEDQ), carbonyldiimidazole (CDI), diethyl phosphoryl cyanide, benzotriazol-pyrrolidinophosphonium hexafluorophosphate (PyBOP), diphenylphosphoryl azide (DPPA), 4- (4,6- dimethoxy-1,3,5-triazin-2-yl) -4-methyl morpholinium chloride Li (DMTMM), isobutyl chloroformate, diethyl-acetyl chloride or trimethylacetyl chloride. These condensing agents may be used alone or, N- hydroxysuccinimide (HONSu), hydroxybenzotriazole (HOBT), 3- hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOOBT ) or in combination with 4-dimethylaminopyridine (DMAP) additives such as are used.

[0054]

　The amount of condensing agent in the condensation reaction is preferably 0.5 to 10 moles relative to 1 mole of 3-dimethylamino cyclic amine derivative (II), and more preferably 0.8 to 5.0 mol.

[0055]

　The amount of carboxylic acid derivative (III) in the condensation reaction is preferably 0.5 to 3 moles relative to 1 mole of 3-dimethylamino cyclic amine derivative (II), and more preferably 0.8 to 1.5 mol .

[0056]

　The condensation reaction is generally carried out in a solvent. The solvent that does not interfere with the reaction is appropriately selected. As such a solvent, for example, aromatic amines such as pyridine; dichloromethane, chloroform or 1,2-halogenated hydrocarbons such as dichloroethane; ethers such as tetrahydrofuran or 1,4-dioxane; N, N- amides such as dimethylformamide or N- methylpyrrolidone; alcohols such as methanol, such as ethanol or 2-propanol, aliphatic nitrites such as or acetonitrile or propionitrile and the like. A mixed solvent thereof may be used. Aromatic amines such as pyridine when selected as a solvent, it is also possible to carry out the condensation reaction under basic absence.

[0057]

　The reaction temperature in the condensation reaction is preferably from -20 ℃ ~ 150 ℃, 0 ~ 100 ℃ is more preferable.

[0058]

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

[0059]

2. Chlorination step of the cyclic amine derivative (I):
　pharmaceutically acceptable salts of the cyclic amine derivative (I) is obtained by, for example, chloride reaction by mixing the an acid cyclic amine derivative (I).

[0060]

　The acid used for the salification include, for example, hydrochloric, sulfuric, inorganic acids such as phosphoric acid or hydrobromic acid; or oxalic acid, malonic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid , trifluoroacetic acid, maleic acid, gluconic acid, benzoic acid, salicylic acid, xinafoate, pamoic acid, ascorbic acid, adipic acid, methanesulfonic acid, and organic acids such as p- toluenesulfonic acid or cinnamic acid.

[0061]

　The reaction chloride is generally carried out in a solvent. The solvent that does not interfere with the reaction is appropriately selected. As such solvent, such as methanol, aliphatic alcohols such as ethanol or isopropanol; diethyl ether, ethers such as tetrahydrofuran and 1,4-dioxane or ethylene glycol dimethyl ether; N, N- dimethylformamide or N- methyl amides such as pyrrolidones; sulfoxides such as dimethyl sulfoxide; aliphatic nitriles such as acetonitrile or propionitrile; ketones such as acetone or 2-butanone; esters such as ethyl acetate, such as acetic acid methyl or acetate n- butyl ; or water. A mixed solvent thereof may be used.

[0062]

3.3- manufacturing method of dimethylamino cyclic amine derivative (II):
[Chemical Formula 4]

[wherein, PG represents a protecting group, n represents the same meaning as defined above. ]
(Step 1)
　3-dimethylamino cyclic amine derivative (V) is obtained by reductive amination of the keto cyclic amine derivative (IV) and dimethylamine.

[0063]

　Keto cyclic amine derivative used in the reductive amination reaction (IV) can be used as a commercial product.

[0064]

　Reductive amination reaction, a known method (for example, Journal of Organic Chemistry, 2003 years, Vol. 68, P.770-779) can be carried out according to the method pursuant to or.

[0065]

(Step 2)
　3-dimethylamino cyclic amine derivative (V) is obtained by 3-reductive alkylation reaction of the amino cyclic amine derivative (VI) with formaldehyde.

[0066]

　Used in reductive alkylation of 3-amino cyclic amine derivative (VI) can be used as a commercial product.

[0067]

　Reductive alkylation reaction, a known method (for example, Journal of Organic Chemistry, 2003 years, Vol. 68, P.770-779) can be carried out according to the method pursuant to or.

[0068]

(Step
　3) 3-dimethylamino cyclic amine derivative (II) is obtained by deprotection of the 3-dimethylamino cyclic amine derivative (V).

[0069]

　Deprotection of the protecting group varies depending on the kind of protecting group, a known method (e.g., Greene, T. W., "Greene's Protective Groups in Organic Synthesis", Wiley-Interscience Co.) performed in accordance with or methods analogous thereto be able to.

[0070]

4. Method for producing a carboxylic acid derivative (III):
[Chemical Formula 5]

wherein, L is a leaving group, for example, a chlorine atom, a bromine atom or an iodine atom. R 3 represents an alkyl group having 1 to 6 carbon atoms, for example, a methyl group, an ethyl group, and n- propyl or n- butyl. Other symbols are as defined. ]
(Step
　4) 2-formyl imidazole derivatives (VIII) are obtained by alkylation reaction to act an alkylating reagent (LI) after deprotonation with a base of 2-formyl imidazole derivative (VII).

[0071]

　Used in the alkylation reaction of 2-formyl imidazole derivative (VII) can be used as a commercial product.

[0072]

　Examples of the bases used in alkylation reactions, for example, sodium carbonate, metal carbonates such as potassium carbonate or cesium carbonate; alkali metal hydroxides such as or sodium hydroxide or potassium hydroxide.

[0073]

　The amount of the base used in the alkylation reaction is preferably 0.5 to 3.0 mol per 1 mol of 2-formyl imidazole derivative (VII), and more preferably 0.8 to 2.0 mol.

[0074]

　The amount of the alkylating reagent (LI) in the alkylation reaction is preferably 0.5 to 3.0 mol per 1 mol of 2-formyl imidazole derivative (VII), more 0.8 to 2.0 mol preferable.

[0075]

　The alkylation reaction is generally carried out in a solvent. The solvent that does not interfere with the reaction is appropriately selected. As such solvent, for example, ethers such as tetrahydrofuran or 1,4-dioxane; N, amides such as N- dimethylformamide or N- methylpyrrolidone, aliphatic nitrites such as or acetonitrile or propionitrile and the like. A mixed solvent thereof may be used.

[0076]

　The reaction temperature in the alkylation reaction is preferably -20 ℃ ~ 150 ℃, 0 ~ 100 ℃ is more preferable.

[0077]

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

[0078]

(Step
　5) 2-formyl imidazole derivative (VIII) is obtained by oxidation of the alcohol derivative (IX).

[0079]

　Alcohol derivatives used in the oxidation reaction (IX), which can be used as it is a commercially available product can also be synthesized by a known method.

[0080]

　The oxidizing agent used in the oxidation reaction, for example, sulfur trioxide - pyridine, activated dimethyl sulfoxide or death Martin reagent.

[0081]

　The amount of the oxidizing agent in the oxidation reaction is preferably 0.5 to 3.0 mol relative to 1 mol of the alcohol derivative (IX), and more preferably 0.8 to 2.0 mol.

[0082]

　Oxidation reaction is generally carried out in a solvent. The solvent that does not interfere with the reaction is appropriately selected. As such a solvent, for example, aromatic amines such as pyridine; dichloromethane, halogenated hydrocarbons such as chloroform or 1,2-dichloroethane; ethers such as tetrahydrofuran or 1,4-dioxane; or acetonitrile or pro aliphatic nitriles such as Pionitoriru like. A mixed solvent thereof may be used.

[0083]

　The reaction temperature in the oxidation reaction is preferably from -78 ° C. ~ 100 ° C., more preferably -78 ℃ ~ 40 ℃.

[0084]

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

[0085]

(Step 6)
　acrylic acid ester derivative (X) is obtained by olefination reaction of 2-formyl imidazole derivatives (VIII).

[0086]

　The reagent used in the olefin reaction, for example, Wittig reagents such as methyl 2- (triphenylphosphoranylidene) acetate; and the Horner-Emmons reagent such as or ethyl diethylphosphonoacetate. Wittig reagent or Horner-Emmons reagent can be used as a commercial product.

[0087]

　The amount of Wittig reagent or Horner-Emmons reagent in olefination reaction is preferably 0.5 to 3.0 mol per 1 mol of 2-formyl imidazole derivatives (VIII), 0.8 to 2.0 mol more preferable.

[0088]

　Olefination reaction is generally carried out in a solvent. The solvent that does not interfere with the reaction is appropriately selected. As such a solvent, such as toluene, aromatic hydrocarbons such as chlorobenzene or xylene; ethers such as tetrahydrofuran or 1,4-dioxane; N, N- dimethylformamide or N- methylpyrrolidinone amides such as pyrrolidone; or aliphatic nitriles such as acetonitrile or propionitrile and the like. A mixed solvent thereof may be used.

[0089]

　The reaction temperature in the olefination reaction is preferably -20 ℃ ~ 150 ℃, 0 ~ 100 ℃ is more preferable.

[0090]

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

[0091]

(Step 7)
　ester derivative (XI) is, with respect to acrylic acid ester derivative (X), obtained by a reduction reaction using a transition metal catalyst under a hydrogen atmosphere.

[0092]

　The transition metal catalyst used in the reduction reaction, for example, palladium - and carbon.

[0093]

　The amount of transition metal catalyst in the reduction reaction is preferably from 0.1 to 100 wt% for the acrylic acid ester derivative (X), more preferably 1-50 wt%.

[0094]

　The reduction reaction is generally carried out in a solvent. The solvent that does not interfere with the reaction is appropriately selected. As such a solvent, for example, aliphatic hydrocarbons such as heptane or hexane; or methanol, aliphatic alcohols such as ethanol or propanol. A mixed solvent thereof may be used.

[0095]

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

[0096]

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

[0097]

(Step 8)
　a carboxylic acid derivative (III) is obtained by hydrolysis of the ester derivative (XI).

[0098]

　The base used in the hydrolysis reaction, for example, lithium hydroxide, potassium hydroxide or sodium hydroxide.

[0099]

　The amount of the base used in the hydrolysis reaction is preferably 0.5 to 3.0 mol relative to 1 mol of the ester derivative (XI), more preferably 0.8 to 2.0 mol.

[0100]

　The hydrolysis reaction is generally carried out in a solvent. The solvent that does not interfere with the reaction is appropriately selected. As such a solvent, such as methanol, aliphatic alcohols such as ethanol or propanol; or water and the like. A mixed solvent thereof may be used.

[0101]

　The reaction temperature in the hydrolysis reaction is preferably -20 ℃ ~ 150 ℃, 0 ~ 100 ℃ is more preferable.

[0102]

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

[0103]

　Analgesic effect of cyclic amine derivative (I) or a pharmacologically acceptable salt thereof, in particular therapeutic effect of neuropathic pain can be evaluated using a suitable animal model. Suitable animal models of neuropathic pain, for example, a mouse or rat sciatic nerve partial ligation model (Malmberg et al., Pain, 1998 year, Vol 76, p.215-222) or mouse or rat spinal nerve ligation model (Kim et al., Pain, 1992 years, Vol. 50, P.355-363), and the like.

[0104]

　Cyclic amine derivative (I) or a pharmaceutically acceptable salt thereof pharmacologically has excellent analgesic action, since it is particularly have a therapeutic effect for neuropathic pain may be used as a pharmaceutical, preferably as analgesics used, particularly preferably used as a neuropathic pain therapeutic agent.

[0105]

　Also, acceptable salts cyclic amine derivative (I) or a pharmaceutically, since central side effects are reduced, analgesics possible long-term administration is particularly applicable as a neuropathic pain therapeutic agent.

[0106]

　Neuropathic pain here, for example, cancer pain, shingles pain, postherpetic neuralgia, AIDS-related neuralgia, diabetic neuropathy pain, or trigeminal neuralgia.

[0107]

　Cyclic amine derivative (I) or a salt acceptable in the pharmacological are also useful for the treatment of acute and chronic pain. Acute pain is usually short-term, for example, postoperative pain, and a post-extraction pain or trigeminal neuralgia. Chronic pain is usually defined as 3-6 months persistent pain, and including somatogenic pain and psychogenic pain, e.g., chronic rheumatoid arthritis, osteoarthritis or postherpetic neuralgia .

[0108]

　A medicament containing a cyclic amine derivative (I) or a salt thereof pharmacologically acceptable active ingredient, a mammal (e.g., mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey or human) , especially when administered to humans, excellent analgesic action against particular neuropathic pain exert a therapeutic effect.

[0109]

　When using a cyclic amine derivative (I) or a pharmacologically acceptable salt thereof as a medicament, combined with a carrier to a cyclic amine derivative (I) or a pharmacologically acceptable salt thereof, it is acceptable as it is or a pharmaceutical to, may be administered orally or parenterally.

[0110]

　A medicament comprising as an active ingredient a cyclic amine derivative (I) or a pharmacologically acceptable salt thereof as dosage forms for oral administration include, for example, tablets (including dragees and film-coated tablets), pills, granules, powders, (including soft capsules and micro capsules) capsules, syrups, emulsions or suspensions. As the dosage form for parenteral administration of a medicament comprising as an active ingredient a cyclic amine derivative (I) or a pharmacologically acceptable salt thereof, for example, injections, infusions, drip infusions, suppositories include liniments or patches. Furthermore, a suitable base (e.g., polymer of butyric acid, polymer of glycolic acid, butyric acid - copolymers of glycolic acid, a mixture of the polymers of glycolic acid acid or polyglycerol fatty acid ester) and combination, it is also effective to sustained release formulations.

[0111]

　Preparation of the dosage form of the preparation can be carried out according to a known production method generally used in the pharmaceutical field. In this case, if necessary, commonly used excipients in the pharmaceutical field, binders, lubricants, disintegrating agents, sweetening agents, surfactants, prepared by incorporating a suspending agent or emulsifier such as be able to.

[0112]

　Preparation of a tablet, for example, excipients, binders, can be carried out by incorporating a disintegrating agent or lubricant. Preparation of pills and granules, for example, can be carried out by incorporating an excipient, a binder or disintegrant. Further, the preparation of powders and capsules, for example, can be carried out by incorporating an excipient. Preparation of syrups are, for example, can be carried out by incorporating the sweeteners. Preparation of emulsions or suspensions, for example, can be carried out by containing a surfactant, suspending agent or emulsifying agent.

[0113]

　Examples of the excipient include lactose, glucose, starch, sucrose, microcrystalline cellulose, powdered glycyrrhiza, mannitol, sodium hydrogen carbonate, and calcium phosphate or calcium sulfate.

[0114]

　As the binder, for example, starch paste solution, gum arabic solution, gelatin solution, tragacanth solution, carboxymethylcellulose solution, sodium alginate solution, or glycerol.

[0115]

　Examples of the disintegrant include starch, or calcium carbonate.

[0116]

　Examples of the lubricant include magnesium stearate, stearic acid, calcium or purification talc stearate.

[0117]

　Sweetening agents, for example, glucose, fructose, invert sugar, sorbitol, xylitol, glycerine, or simple syrup.

[0118]

　As the surfactant, for example, sodium lauryl sulfate, polysorbate 80, and a sorbitan mono fatty acid ester or stearic acid polyoxyl 40.

[0119]

　Suspending agents, such as gum arabic, sodium alginate, sodium carboxymethyl cellulose, methyl cellulose or bentonite.

[0120]

　Emulsifiers, such as gum arabic, tragacanth and gelatin or polysorbate 80.

[0121]

　Furthermore, a medicament comprising as an active ingredient a cyclic amine derivative (I) or a pharmacologically acceptable salt thereof, in preparing the above dosage forms may contain coloring agents generally used in the pharmaceutical field, storage agents, fragrances, flavoring agents, may be added stabilizers or thickeners, and the like.

[0122]

　The daily dose of a pharmaceutical containing a cyclic amine derivative (I) or a pharmacologically acceptable salt thereof as an active ingredient varies depending on the patient's condition or body weight, type of compound or the route of administration and the like. For example, in the case of oral administration to an adult (body weight about 60kg) is in the range of 1 ~ 1000 mg of a cyclic amine derivative (I) or a pharmacologically acceptable salt thereof as an active ingredient amount, divided 1-3 times it is preferably administered Te. Adults When parenteral administration to (weighing about 60 kg), if injection, cyclic amine derivative (I) or 0.01 ~ 100 mg per kg 1kg a pharmacologically acceptable salt thereof as an active ingredient amount it is preferably administered intravenously in a range of.

[0123]

　Cyclic amine derivative (I) or a pharmacologically acceptable salt thereof, complement or enhance the therapeutic or prophylactic effect, or to reduce the dosage, may also be appropriate amount, or combination with other agents. Other agents in this case, for example, amitriptyline, milnacipran or antidepressants such as duloxetine; anxiolytics such as alprazolam; anticonvulsants such as carbamazepine; local anesthetics such as lidocaine; sympathetic such adrenaline agonist; NMDA receptor antagonists, such as ketamine; GABA transaminase inhibitors of sodium valproate, and the like; calcium channel blockers such as pregabalin; serotonin receptor antagonist such as risperidone; GABA receptor function stimulants, such as diazepam; or anti-inflammatory drugs diclofenac and the like.
Example

[0124]

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

[0125]

　In the following description, the solvent name indicated in the NMR data show the solvents for measurement. Further, 400 MHz NMR spectra were measured using JNM-AL400 type nuclear magnetic resonance apparatus (Nippon Denshi). Chemical shift, based on tetramethylsilane, [delta] (Unit: ppm) expressed by each signal s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), sept (septet), m (multiplet), br (broad), dd (double doublet), dt (double triplet), ddd (double double doublet) , dq (double quartet), td (triplet doublet), expressed in tt (triplet triplet). ESI-MS spectra were measured using Agilent Technologies 1200 Series, G6130A (manufactured AgilentTechnology). The solvent using all commercially available. Flash chromatography was used YFLC W-prep2XY (Yamazen Co., Ltd.).

[0126]

　Materials and intermediates of cyclic amine derivative (I) was synthesized according to the methods described in the following Reference Examples. As for those not described in the synthesis method in compounds used in the synthesis of Reference Example compounds were used commercially available compounds.

[0127]

(Reference Example 1) N, the synthesis of N- dimethyl azetidine-3-amine hydrochloride:
[formula

　6] tert-butyl 3- oxoazetidine-1-carboxylate (0.500 g, 2.92 mmol) in dichloromethane (12. the 0 mL) solution, a tetrahydrofuran solution (2.0 M of dimethylamine, 0.185 mL, 3.65 mmol), acetic acid (0.017 mL, 0.292 mmol) and sodium triacetoxyborohydride (0.232 g, 1.10 mmol) and It was added at 0 ℃. The reaction was stirred at the same temperature for 30 minutes, sodium triacetoxyborohydride (0.232 g, 1.10 mmol) was added at 0 ° C.. The reaction solution was stirred for 30 minutes at the same temperature, sodium triacetoxyborohydride (0.464 g, 2.19 mmol) was added at 0 ° C., was 16 hours of stirring at room temperature. The reaction was cooled to 0 ° C.. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, chloroform / methanol). The resulting residue in 1,4-dioxane (4.0 mL) was added at room temperature to dissolve. 1,4-dioxane solution of hydrogen chloride to the reaction solution (4.0 N, 4.04 ml, 16.2 mmol) was added at room temperature, the reaction mixture was stirred for 3 hours at the same temperature. The precipitated white solid was collected by filtration, washed with hexane to give after drying at room temperature, N, the crude product of N- dimethyl azetidine-3-amine hydrochloride as a white solid.

[0128]

(Reference Example 2) (S) -N, N- synthesis of dimethyl-3-amine hydrochloride:
[formula

　7] (S)-tert-butyl-3-amino-1-carboxylate (0.500 g, 2 in dichloromethane (12.0 mL) solution of .50mmol), aqueous formaldehyde (35%, 0.884mL, 11.2mmol) , acetic acid (0.029 mL, 0.50 mmol) and sodium triacetoxyborohydride (0.278 g, 1 .31mmol) was added at 0 ℃. The reaction was stirred at the same temperature for 30 minutes, sodium triacetoxyborohydride (0.278 g, 1.31 mmol) was added at 0 ° C.. The reaction solution was stirred for 30 minutes at the same temperature, sodium triacetoxyborohydride (0.556 g, 2.62 mmol) was added at 0 ° C., was 60 hours of stirring at room temperature. The reaction was cooled to 0 ° C.. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, chloroform / methanol). The resulting residue diethyl ether (15.0 mL) was added at room temperature to dissolve. Diethyl ether solution of hydrogen chloride to the reaction solution (2.0N, 7.49mL, 15.0mmol) was added at 0 ° C., the reaction mixture was stirred for 3 hours at room temperature. The precipitated white solid was collected by filtration, washed with diethyl ether and dried at room temperature to give (S) -N, crude N- dimethyl-3-amine hydrochloride.

[0129]

(Reference Example 3) (R) -N, N- synthesis of dimethyl-3-amine:
[Chem

　8] (R)-tert-butyl-3-amino-1-carboxylate (3.00 g, 15.0 mmol in dichloromethane (30.0 mL) solution of), aqueous formaldehyde solution (37%, 2.55 g, 31.5 mmol), acetic acid (0.086 mL, 1.50 mmol) and sodium triacetoxyborohydride (4.00 g, 18.9 mmol ) was added at 0 ℃. The reaction solution was stirred for 30 minutes at the same temperature, sodium triacetoxyborohydride (3.94 g, 18.6 mmol) was added at 0 ° C., was 28 hours of stirring at room temperature. The reaction was cooled to 0 ° C.. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, chloroform / methanol). The resulting residue was added dichloromethane (60.0 mL) at room temperature to dissolve. Trifluoroacetic acid to the reaction solution (11.5 mL, 150 mmol) was added at 0 ° C., the reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was concentrated under reduced pressure, the residue sodium 1N hydroxide solution obtained was added, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure to obtain (R) -N, crude N- dimethyl-3-amine.

[0130]

Synthesis of Reference Example 4 1-isopropyl -1H- imidazole-2-carbaldehyde:
[Chem

　9] 1H-imidazole-2-carbaldehyde (0.500 g, 5.20 mmol) in N, N- dimethylformamide (5 the .2ML) was added potassium carbonate (0.863 g, 6.24 mmol) and 2-iodopropane (0.614mL, 6.24mmol) was added at room temperature, was stirred for 4 hours at 60 ° C.. The reaction mixture was cooled to room temperature, ethyl acetate and distilled water was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with 10% aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, n- hexane / ethyl acetate) to afford 1-isopropyl -1H- imidazole-2-carbaldehyde (0.355 g, 2.57 mmol, 49%) as a colorless oil .
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.48 (3H, d, J = 6.4 Hz), 1.48 (3H, d, J = 6.4 Hz), 5.48 (IH, quint, J = 6.4 Hz), 7.30 (IH, s), 7.33 (IH, s), 9.83 (IH, s).
ESI-MS: m / z = 139 (M + H) + .

[0131]

Synthesis of Reference Example 5 1- (2-methoxyethyl)-1H-imidazole-2-carbaldehyde:
[Chem

　10] N of 1H- imidazole-2-carbaldehyde (0.500 g, 5.20 mmol), N - dimethylformamide (5.2 mL) was added potassium carbonate (1.44 g, 10.4 mmol) and 1-bromo-2-methoxy ethane (0.545mL, 5.72mmol) was added at room temperature, 5 at 60 ° C. followed by stirring time. The reaction mixture was cooled to room temperature, ethyl acetate and distilled water was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with 10% aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, n- hexane / ethyl acetate) to give 1- (2-methoxyethyl)-1H-imidazole-2-carbaldehyde (0.113g, 0.733mmol, 14%) as a white It was obtained as a solid.
1 H-NMR (400 MHz, DMSO) [delta]: 3.21 (3H, s), 3.61 (2H, d, J = 5.2 Hz), 4.53 (2H, d, J = 5.2 Hz), 7.27 (IH, s), 7.62 (IH, s), 9.69 (IH, s).
ESI-MS: m / z = 155 (M + H) + .

[0132]

Synthesis of Reference Example 6 1- (2,2,2-trifluoroethyl) -1H- imidazole-2-carbaldehyde:
[Chem

　11] (1- (2,2,2-trifluoroethyl) -1H - imidazol-2-yl) methanol (0.360 g, dichloromethane (20.0 mL) solution of 2.00 mmol), Dess-Martin reagent (1.02 g, 2.40 mmol) was added at 0 ° C., 1 hour at room temperature It stirred. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, n- hexane / ethyl acetate) to give 1- (2,2,2-trifluoroethyl) -1H- imidazole-2-carbaldehyde (0.313 g, 1.76 mmol, 88%) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 5.16 (2H, q, J = 8.0 Hz), 7.25 (IH, brs), 7.38 (IH, brs), 9.83-9.85 (IH, m).
ESI- MS: M / Z = 179 (M Tasu H) Tasu .

[0133]

Synthesis of (Reference Example 7) 5-Chloro-1-methyl -1H- imidazole-2-carbaldehyde:
[Formula

　12] (5-chloro-1-methyl -1H- imidazol-2-yl) methanol (0.300 g in dichloromethane (20.0 mL) solution of 2.05 mmol), Dess Martin reagent (1.04 g, 2.46 mmol) was added at 0 ° C., and stirred for 4 hours at room temperature. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, n- hexane / ethyl acetate) to give 5-chloro-1-methyl -1H- imidazole-2-carbaldehyde (0.289 g, 2.00 mmol, 98%) as a white solid It was obtained as a.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 3.97 (3H, s), 7.24 (IH, s), 9.70 (IH, s).
ESI-MS: m / z = 145 (M + H) + .

[0134]

(Reference Example 8) (E) - Synthesis of methyl 3- (1-methyl -1H- imidazol-2-yl) acrylate:
[Formula

　13] 1-methyl -1H- imidazole-2-carbaldehyde (10.0 g, in dichloromethane (240 mL) solution of 90.8 mmol), methyl (triphenylphosphoranylidene) acetate (33.4 g, 99.9 mmol) was added at room temperature, after stirring for 16 h, and concentrated under reduced pressure. The residue was washed with n- hexane / dichloromethane = 19/1 mixed solvent, and concentrated washing solution. The residue was purified by column chromatography (silica gel, n- hexane / ethyl acetate), (E) - methyl 3- (1-methyl -1H- imidazol-2-yl) acrylate (11.9 g, 71.6 mmol, 79 %) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 3.76 (3H, s), 3.81 (3H, s), 6.82 (IH, d, J = 15.6 Hz), 6.98 (IH, brs), 7.16 (IH, brs), 7.53 (IH, d, J = 15.6 Hz).
ESI-MS: m / z = 167 (M + H) + .

[0135]

(Reference Example 9) (E) - Synthesis of methyl 3- (l-isopropyl -1H- imidazol-2-yl) acrylate:
[Formula

　14] 1-isopropyl -1H- imidazole-2-carbaldehyde (0.350 g, in dichloromethane (7.6 mL) solution of 2.53 mmol), methyl (triphenylphosphoranylidene) acetate (0.932 g, 2.79 mmol) was added at room temperature, after stirring for 16 h, and concentrated under reduced pressure. The residue was washed with n- hexane / dichloromethane = 20/1 mixed solvent, and concentrated washing solution. The residue was purified by column chromatography (silica gel, n- hexane / ethyl acetate), (E) - methyl 3- (l-isopropyl -1H- imidazol-2-yl) acrylate (0.362 g, 1.86 mmol, 74 %) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.50 (3H, d, J = 6.4 Hz), 1.50 (3H, d, J = 6.4 Hz), 3.81 (3H, s), 4.62 (IH, quint, J = 6.4 Hz), 6.87 (IH, d, J = 15.6 Hz), 7.10 (IH, brs), 7.18 (IH, brs), 7.56 (IH, d, J = 15.6 Hz).
ESI-MS: m / = 195 Z (M Tasu H) Tasu .

[0136]

(Reference Example 10) (E) - Synthesis of methyl 3- (1- (2,2,2-trifluoroethyl) -1H- imidazol-2-yl) acrylate:
[Formula

　15] 1- (2,2, 2-trifluoroethyl)-1H-imidazole-2-carbaldehyde (0.313 g, dichloromethane (5.0 mL) solution of 1.76 mmol), methyl (triphenylphosphoranylidene) acetate (0.640 g, 1. 92 mmol) was added at room temperature, after stirring for 16 h, and concentrated under reduced pressure. The residue was washed with n- hexane / dichloromethane = 20/1 mixed solvent, and concentrated washing solution. The residue was purified by column chromatography (silica gel, n- hexane / ethyl acetate), (E) - methyl 3- (1- (2,2,2-trifluoroethyl) -1H- imidazol-2-yl) acrylate (0.320g, 1.37mmol, 78%) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 3.82 (3H, s), 4.56-4.64 (2H, m), 6.93 (IH, d, J = 15.2 Hz), 7.10 (IH, brs), 7.24 ( IH, brs), 7.44 (IH, d, J = 15.2 Hz).
ESI-MS: m / z = 235 (M + H) + .

[0137]

(Reference Example 11) (E) - ethyl 3- (1- (2-methoxyethyl)-1H-imidazol-2-yl) Synthesis of acrylate:
[Chemical Formula 16]

　Sodium hydride (0.455 g, 10.4 mmol, in tetrahydrofuran (49.6mL) suspension of 55%) under ice-cooling, ethyl diethylphosphonoacetate (1.99 mL, 9.92 mmol) was added. After stirring for 60 minutes at the same temperature, 1- (2-methoxyethyl)-1H-imidazole-2-carbaldehyde (1.53 g, 9.92 mmol) in tetrahydrofuran (10 mL) was added a solution of stirring at room temperature for 3 hours did. Saturated ammonium chloride solution was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with 10% aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, n- hexane / ethyl acetate), (E) - ethyl 3- (1- (2-methoxyethyl)-1H-imidazol-2-yl) acrylate (1.80 g, 8.03 mmol, was obtained 81%) as a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.32 (3H, t, J = 7.2 Hz), 3.32 (3H, s), 3.63 (2H, t, J = 5.2 Hz), 4.20 (2H, t, J = 5.2 Hz), 4.26 ( 2H, q, J = 7.2 Hz), 6.84 (1H, d, J = 15.4 Hz), 7.08 (1H, brs), 7.16 (1H, brs), 7.52 (1H, d, = 15.4 Hz J).
ESI-MS: m / z = 225 (M + H) + .

[0138]

(Reference Example 12) (E) - Synthesis of methyl 3- (5-chloro-1-methyl -1H- imidazol-2-yl) acrylate:
[Formula

　17] 5-chloro-1-methyl -1H- imidazol-2 - carbaldehyde (0.289 g, 2.00 mmol) in dichloromethane (6.0 mL) solution of methyl (triphenylphosphoranylidene) acetate (0.738 g, 2.21 mmol) was added at room temperature, after stirring for 16 hours , and concentrated under reduced pressure. The residue was washed with n- hexane / dichloromethane = 20/1 mixed solvent, and concentrated washing solution. The residue was purified by column chromatography (silica gel, n- hexane / ethyl acetate), (E) - methyl 3- (5-chloro-1-methyl -1H- imidazol-2-yl) acrylate (0.312 g, 1 .56Mmol, to obtain a 78%) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 3.67-3.69 (3H, m), 3.80-3.82 (3H, m), 6.78-6.85 (IH, m), 7.08-7.10 (IH, m), 7.44 -7.50 (IH, m).
ESI-MS: m / z = 201 (M + H) + .

[0139]

Synthesis of (Reference Example 13) 3- (1-methyl -1H- imidazol-2-yl) propanoic acid:
[Chem

　18] (E) - methyl 3- (1-methyl -1H- imidazol-2-yl) acrylate (0.180 g, 1.08 mmol) in ethanol (4.0 mL) solution of palladium - carbon (10% wet, 15mg) was added at room temperature under a hydrogen atmosphere and stirred for 4 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was added methanol (1.0 mL) at room temperature, dissolved, and cooled to 0 ° C.. Aqueous sodium hydroxide to the reaction solution (1.0 N, 1.19 mL, 1.19 mmol) was added at 0 ° C., after stirring for 2 hours at room temperature, concentrated under reduced pressure, 3- (1-methyl -1H- imidazol-2 - yl) to give a crude product of propanoic acid.

[0140]

Synthesis of (Reference Example 14) 3- (l-isopropyl -1H- imidazol-2-yl) propanoic acid:
[Formula

　19] (E) - methyl 3- (l-isopropyl -1H- imidazol-2-yl) acrylate (0.670 g, 3.71 mmol) in methanol (14.8 mL) solution of palladium - carbon (10% wet, 65mg) was added at room temperature under a hydrogen atmosphere and stirred for 16 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was added methanol (3.7 mL) at room temperature, dissolved, and cooled to 0 ° C.. Aqueous sodium hydroxide to the reaction solution (1.0 N, 4.07 mL, 4.07 mmol) was added at 0 ° C., after stirring for 16 hours at room temperature, concentrated under reduced pressure, 3- (l-isopropyl -1H- imidazol-2 - yl) to give a crude product of propanoic acid.

[0141]

Synthesis of (Reference Example 15) 3- (1- (2,2,2-trifluoroethyl) -1H- imidazol-2-yl) propanoic acid:
[Formula

20] (E) - methyl 3- (1- ( 2,2,2-trifluoroethyl)-1H-imidazol-2-yl) acrylate (0.160 g, in ethanol (7.0 mL) solution of 0.683 mmol), palladium - carbon (10% wet, 36mg) at room temperature under a hydrogen atmosphere and stirred for 16 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was added methanol (2.0 mL) at room temperature, dissolved, and cooled to 0 ° C.. Aqueous sodium hydroxide to the reaction solution (1.0N, 2.05mL, 2.05mmol) was added at 0 ° C., and stirred for 4 hours at room temperature. To the reaction mixture, after neutralized by adding 1.0N aqueous hydrogen chloride, and concentrated under reduced pressure, 3- crude (1- (2,2,2-trifluoroethyl) -1H- imidazol-2-yl) propanoic acid the product was obtained.

[0142]

Synthesis of (Reference Example 16) 3- (1- (2-methoxyethyl)-1H-imidazol-2-yl) propanoic acid:
[of

　21] (E) - ethyl 3- (1- (2-methoxyethyl) -1H- imidazol-2-yl) acrylate (1.80 g, in methanol (32.0 mL) solution of 8.03 mmol), palladium - carbon (10% wet, 0.180 g) was added at room temperature under a hydrogen atmosphere, and the mixture was stirred for 15 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was added methanol (8.0 mL) at room temperature, dissolved, and cooled to 0 ° C.. Aqueous sodium hydroxide to the reaction solution (1.0N, 8.43mL, 8.43mmol) was added at the same temperature, and stirred heated 3 hours at room temperature. To the reaction mixture, after neutralized by adding 1.0N aqueous hydrogen chloride solution, and concentrated under reduced pressure. After filtration the residue ethanol was added to precipitate, the filtrate was concentrated under reduced pressure to obtain 3- (1- (2-methoxyethyl)-1H-imidazol-2-yl) crude propanoic acid.

[0143]

(Reference Example 17) Methyl 3- (5-chloro-1-methyl -1H- imidazol-2-yl) propanoate Synthesis of:
[Formula

　22] (E) - methyl 3- (5-chloro-1-methyl -1H - imidazol-2-yl) acrylate (0.240 g, in ethanol (12.0 mL) solution of 1.20 mmol), platinum oxide (IV value, 0.027 g, 0.120 mmol) was added at room temperature under a hydrogen atmosphere, and the mixture was stirred for 6 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, n- hexane / ethyl acetate) to give methyl 3- (5-chloro-1-methyl -1H- imidazol-2-yl) propanoate (0.104 g, 0.513 mmol, 43 %) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 2.84-2.96 (4H, m), 3.53 (3H, s), 3.70 (3H, s), 6.84 (IH, s).
ESI-MS: m / z 203 = (M Tasu H) Tasu .

[0144]

Synthesis of (Reference Example 18) 3- (5-chloro-1-methyl -1H- imidazol-2-yl) propanoic acid:
[Chem 23]

　Methyl 3- (5-chloro-1-methyl -1H- imidazol-2 - yl) propanoate (0.100 g, in methanol (1.0 mL) solution of 0.493 mmol), aqueous sodium hydroxide (1.0N, 0.543mL, 0.543mmol) was added at 0 ° C., 4 hours at room temperature It stirred. To the reaction mixture, after neutralized by adding 1.0N aqueous hydrogen chloride and concentrated in vacuo to give the crude product of 3- (5-chloro-1-methyl -1H- imidazol-2-yl) propanoic acid.

[0145]

(Example 1) 1- (3- (dimethylamino) azetidin-1-yl) -3- (1-methyl -1H- imidazol-2-yl) propan-1-one Synthesis of:
Formula

　24] 3- (1-methyl -1H- imidazol-2-yl) propanoic acid (0.0600g, 0.389mmol) in chloroform (3.0 mL) was added diisopropylethylamine (0.204 mL, 1.17 mmol), HBTU (0. 177 g, 0.467 mmol) and 3- (dimethylamino) azetidine hydrochloride (0.0674g, 0.389mmol) was added at room temperature, the reaction mixture was stirred at the same temperature for 16 hours. Saturated aqueous sodium hydrogen carbonate solution to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with 10% aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, chloroform / methanol), 1- (3- (dimethylamino) azetidin-1-yl) -3- (1-methyl -1H- imidazol-2-yl) propane - 1-one (0.0710g, 0.300mmol, 77%) was obtained (hereinafter, the compound of example 1) as a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 2.16 (6H, s), 2.62-2.68 (2H, m), 2.92-2.98 (2H, m), 3.02-3.09 (IH, m), 3.60 (3H , m), 3.78-3.85 (1H, m), 3.93-4.02 (2H, m), 4.11-4.17 (1H, m), 6.78 (1H, d, J = 1.2Hz), 6.91 (1H, d, J 1.2 Hz =).
ESI-MS: m / z = 237 (M + H) + .

[0146]

(Example 2) (S) -1- (3- (dimethylamino) piperidin-1-yl) -3- (1-methyl -1H- imidazol-2-yl) propan-1-one Synthesis of:
Formula

　25] 3- (1-methyl -1H- imidazol-2-yl) propanoic acid (0.0600g, 0.389mmol) in chloroform (3.0 mL) was added diisopropylethylamine (0.204 mL, 1.17 mmol), HBTU (0.177 g, 0.467 mmol) and (S)-3-(dimethylamino) piperidine hydrochloride (0.0780g, 0.389mmol) was added at room temperature, the reaction mixture was stirred for 16 hours at the same temperature. Saturated aqueous sodium hydrogen carbonate solution to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with 10% aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, chloroform / methanol), (S) -1- (3- (dimethylamino) piperidin-1-yl) -3- (1-methyl -1H- imidazol-2 yl) propan-1-one (0.0860g, 0.325mmol, 84%) ( hereinafter, to give the compound) example 2 as a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.34-1.44 (2H, m), 1.92-2.24 (3H, m), 2.30 (6H, s), 2.40-2.57 (IH, m), 2.78-2.98 (5H, m), 3.60 (3H, s), 3.79-4.05 (IH, m), 4.44-4.67 (IH, m), 6.75-6.78 (IH, m), 6.88-6.90 (IH, m).
ESI -MS: M / Z = 265 (M Tasu H) Tasu .

[0147]

(Example 3) (R) -1- (3- (dimethylamino) piperidin-1-yl) -3- (1-methyl -1H- imidazol-2-yl) propan-1-one Synthesis of:
Formula

　26] 3- (1-methyl -1H- imidazol-2-yl) propanoic acid (0.0980g, 0.638mmol) in methanol (4.3 mL) solution of, (R)-3-(dimethylamino) piperidine ( 0.0540g, 0.425mmol) and DMTMM (0.176 g, 0.638 mmol) was added at room temperature, the reaction mixture was stirred for 3 hours at the same temperature. Saturated potassium carbonate solution was added to the reaction solution, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, ethyl acetate / methanol), (R) -1- (3- (dimethylamino) piperidin-1-yl) -3- (1-methyl -1H- imidazol-2 - yl) propan-1-one (0.0594g, 0.225mmol, 53%) ( hereinafter, to give the compound) of example 3 as a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.34-1.44 (2H, m), 1.92-2.24 (3H, m), 2.30 (6H, s), 2.40-2.57 (IH, m), 2.78-2.98 (5H, m), 3.60 (3H, s), 3.79-4.05 (IH, m), 4.44-4.67 (IH, m), 6.75-6.78 (IH, m), 6.88-6.90 (IH, m).
ESI -MS: M / Z = 265 (M Tasu H) Tasu .

[0148]

(Example 4) 1- (3- (dimethylamino) azetidin-1-yl) -3- (1-isopropyl -1H- imidazol-2-yl) propan-1-one Synthesis of:
[formula

　27] 3- (l-isopropyl -1H- imidazol-2-yl) propanoic acid (0.0700g, 0.384mmol) in chloroform (3.0 mL) was added diisopropylethylamine (0.201mL, 1.15mmol), HBTU ( 0. 175 g, 0.461 mmol) and 3- (dimethylamino) azetidine hydrochloride (0.0665g, 0.384mmol) was added at room temperature, the reaction mixture was stirred at the same temperature for 16 hours. Saturated aqueous sodium hydrogen carbonate solution to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with 10% aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, chloroform / methanol), 1- (3- (dimethylamino) azetidin-1-yl) -3- (1-isopropyl -1H- imidazol-2-yl) propane - 1-one (0.0820g, 0.310mmol, 81%) was obtained (hereinafter, the compound of example 4) as a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.38-1.42 (6H, m), 2.16 (6H, s), 2.67-2.72 (2H, m), 2.93-3.09 (3H, m), 3.79-3.85 (1H, m), 3.95-4.02 ( 2H, m), 4.12-4.18 (1H, m), 4.39-4.47 (1H, m), 6.89-6.91 (1H, m), 6.94-6.95 (1H, m) .
ESI-MS: m / z = 265 (M + H) + .

[0149]

(Example 5) (S) -1- (3- (dimethylamino) piperidin-1-yl) -3- (1-isopropyl -1H- imidazol-2-yl) propan-1-one Synthesis of:
Formula

　28] 3- (l-isopropyl -1H- imidazol-2-yl) propanoic acid (0.0200 g, 0.110 mmol) in chloroform (3.0 mL) was added diisopropylethylamine (0.058 mL, 0.33 mmol), HBTU (0.0499g, 0.132mmol) and (S)-3-(dimethylamino) piperidine hydrochloride (0.0221g, 0.110mmol) was added at room temperature, the reaction mixture was stirred for 16 hours at the same temperature. Saturated aqueous sodium hydrogen carbonate solution to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with 10% aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, chloroform / methanol), (S) -1- (3- (dimethylamino) piperidin-1-yl) -3- (1-isopropyl -1H- imidazol-2 yl) propan-1-one (0.0268g, 0.0916mmol, 84%) ( hereinafter, to give the compound) of example 5 as a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.39-1.44 (6H, m), 1.68-1.83 (3H, m), 1.98-2.60 (9H, m), 2.80-3.05 (5H, m), 3.84 -4.09 (IH, m), 4.40-4.71 (2H, m), 6.89-6.96 (2H, m).
ESI-MS: m / z = 293 (M + H) + .

[0150]

(Example 6) (R) -1- (3- (dimethylamino) piperidin-1-yl) -3- (1-isopropyl -1H- imidazol-2-yl) propan-1-one Synthesis of:
Formula

　29] 3- (l-isopropyl -1H- imidazol-2-yl) propanoic acid (0.0600g, 0.329mmol) in chloroform (3.0 mL) was added diisopropylethylamine (0.173mL, 0.988mmol), HBTU (0.150 g, 0.395 mmol) and (R)-3-(dimethylamino) piperidine (0.0422g, 0.329mmol) was added at room temperature, the reaction mixture was stirred at the same temperature for 16 hours. Saturated aqueous sodium hydrogen carbonate solution to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with 10% aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, chloroform / methanol), (R) -1- (3- (dimethylamino) piperidin-1-yl) -3- (1-isopropyl -1H- imidazol-2 yl) propan-1-one (0.0820g, 0.280mmol, 85%) ( hereinafter, to give the compound) of example 6 as a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.39-1.44 (6H, m), 1.68-1.83 (3H, m), 1.98-2.60 (9H, m), 2.80-3.05 (5H, m), 3.84 -4.09 (IH, m), 4.40-4.71 (2H, m), 6.89-6.96 (2H, m).
ESI-MS: m / z = 293 (M + H) + .

[0151]

(Example 7) 1- (3- (dimethylamino) azetidin-1-yl) -3- (1- (2,2,2-trifluoroethyl) -1H- imidazol-2-yl) propan-1 on synthesis of:
[formula

　30] 3- (1- (2,2,2-trifluoroethyl) -1H- imidazol-2-yl) propanoic acid (0.120 g, 0.540 mmol) in chloroform (6.0 mL a) a solution, diisopropylethylamine (0.284mL, 1.62mmol), HBTU ( 0.246g, 0.649mmol) and 3- (dimethylamino) azetidine hydrochloride (0.0934g, 0.540mmol) was added at room temperature, the reaction was stirred 16 hours at the same temperature. Saturated aqueous sodium hydrogen carbonate solution to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with 10% aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, chloroform / methanol), 1- (3- (dimethylamino) azetidin-1-yl) -3- (1- (2,2,2-trifluoroethyl) - 1H- imidazol-2-yl) propan-1-one (0.150g, 0.493mmol, 91%) ( hereinafter, to give the compound) of example 7 as a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 2.16 (6H, s), 2.62-2.69 (2H, m), 2.93-3.10 (3H, m), 3.75-3.82 (IH, m), 3.92-3.98 (2H, m), 4.09-4.16 (IH, m), 4.56-4.68 (2H, m), 6.87-6.89 (IH, m), 6.98-7.00 (IH, m).
ESI-MS: m / z = 305 (M Tasu H) Tasu .

[0152]

(Example 8) (R) -1- (3- (dimethylamino) piperidin-1-yl) -3- (1- (2,2,2-trifluoroethyl) -1H- imidazol-2-yl) propan-1-one synthesis of:
Formula

　31] 3- (1- (2,2,2-trifluoroethyl) -1H- imidazol-2-yl) propanoic acid (0.0600g, 0.270mmol) in chloroform (3.0 mL) was added diisopropylethylamine (0.142mL, 0.810mmol), HBTU ( 0.123g, 0.324mmol) and (R)-3-(dimethylamino) piperidine (0.0346g, 0.270mmol ) at room temperature, the reaction mixture was stirred at the same temperature for 16 hours. Saturated aqueous sodium hydrogen carbonate solution to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with 10% aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, chloroform / methanol), (R) -1- (3- (dimethylamino) piperidin-1-yl) -3- (1- (2,2,2 trifluoroethyl)-1H-imidazol-2-yl) propan-1-one (0.0790g, 0.238mmol, 88%) ( hereinafter, to give the compound) of example 8 as a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.32-1.45 (2H, m), 1.65-1.85 (IH, m), 2.02-2.21 (2H, m), 2.29-2.31 (6H, m), 2.40 -2.56 (1H, m), 2.78-3.00 (5H, m), 3.74-4.01 (1H, m), 4.38-4.75 (3H, m), 6.85-6.88 (1H, m), 6.96-6.98 (1H, m).
ESI-MS: m / z = 333 (M + H) + .

[0153]

(Example 9) (R) -1- (3- (dimethylamino) piperidin-1-yl) -3- (1- (2-methoxyethyl)-1H-imidazol-2-yl) propan-1-one synthesis:
[formula

　32] 3- (1- (2-methoxyethyl)-1H-imidazol-2-yl) propanoic acid (0.126 g, 0.635) in chloroform (6.4 mL) was added diisopropylethylamine (0.222mL, 1.27mmol), HBTU ( 0.361g, 0.953mmol) and (R)-3-(dimethylamino) piperidine (0.0810g, 0.635mmol) was added at room temperature, the reaction was the same and the mixture was stirred for 15 hours at a temperature. Saturated potassium carbonate solution was added to the reaction solution, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, chloroform / methanol), (R) -1- (3- (dimethylamino) piperidin-1-yl) -3- (1- (2-methoxyethyl) -1H - imidazol-2-yl) propan-1-one (0.165g, 0.536mmol, 84%) ( hereinafter, to give the compound) of example 9 as a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.37-1.45 (2H, m), 1.75-1.81 (IH, m), 2.00-2.20 (2H, m), 2.31-2.33 (6H, m), 2.43 -2.57 (1H, m), 2.81-3.02 (5H, m), 3.32 (3H, s), 3.59-3.62 (2H, m), 3.84-4.11 (3H, m), 4.49-4.69 (1H, m) , 6.89-6.93 (2H, m).
ESI-MS: m / z = 309 (M + H) + .

[0154]

(Example 10) 3- (5-chloro-1-methyl -1H- imidazol-2-yl) -1- (3- (dimethylamino) azetidin-1-yl) propan-1-one Synthesis of:
Formula

　33] 3- (5-chloro-1-methyl -1H- imidazol-2-yl) propanoic acid (0.0524g, 0.278mmol) in chloroform (2.8 mL) was added diisopropylethylamine (0.146 mL, 0 .834mmol), HBTU (0.158g, 0.417mmol ) and 3- (dimethylamino) azetidine hydrochloride (0.0457g, 0.264mmol) was added at room temperature, the reaction mixture was stirred for 16 hours at the same temperature. Saturated potassium carbonate solution was added to the reaction solution, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, ethyl acetate / methanol), 3- (5-chloro-1-methyl -1H- imidazol-2-yl) -1- (3- (dimethylamino) azetidine -1 - yl) propan-1-one (0.0656g, 0.242mmol, 87%) ( hereinafter, to give the compound) of example 10 as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 2.17 (6H, s), 2.56-2.69 (2H, m), 2.87-3.00 (2H, m), 3.03-3.09 (3H, m), 3.53 (3H , s), 3.81 (IH, dd, J = 9.9, 5.2 Hz), 3.95-4.01 (2H, m), 4.13-4.17 (IH, m), 6.83 (IH, s).
ESI-MS: m / z 271 = (M Tasu H) Tasu .

[0155]

(Example 11) (S)-3-(5-chloro-1-methyl -1H- imidazol-2-yl) -1- (3- (dimethylamino) piperidin-1-yl) propan-1-one synthesis:
[of

　34] 3- (5-chloro-1-methyl -1H- imidazol-2-yl) propanoic acid (0.0840g, 0.445mmol) in chloroform (5.0 mL) was added diisopropylethylamine (0 .233mL, 1.34mmol), HBTU (0.253g , 0.668mmol) and (S)-3-(dimethylamino) piperidine hydrochloride (0.0900g, 0.445mmol) was added at room temperature, the reaction was the same It was stirred for 16 hours at a temperature. Saturated aqueous sodium hydrogen carbonate solution to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with 10% aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, chloroform / methanol), (S)-3-(5-chloro-1-methyl -1H- imidazol-2-yl) -1- (3- (dimethylamino) piperidin-1-yl) propan-1-one (0.0800g, 0.268mmol, 60%) ( hereinafter, to give the compound) of example 11 as a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.30-1.48 (2H, m), 1.68-1.84 (IH, m), 1.92-2.22 (2H, m), 2.28-2.31 (6H, m), 2.40 -2.58 (1H, m), 2.77-3.00 (5H, m), 3.51-3.54 (3H, m), 3.75-4.02 (1H, m), 4.42-4.64 (1H, m), 6.80 (1H, s) .
ESI-MS: m / z = 299 (M + H) + .

[0156]

(Example 12) (R)-3-(5-chloro-1-methyl -1H- imidazol-2-yl) -1- (3- (dimethylamino) piperidin-1-yl) propan-1-one synthesis:
[formula

　35] 3- (5-chloro-1-methyl -1H- imidazol-2-yl) propanoic acid (0.0466g, 0.247mmol) in chloroform (2.5 mL) was added diisopropylethylamine (0 .0863mL, 0.494mmol), HBTU (0.141g , 0.371mmol) and (R)-3-(dimethylamino) piperidine (0.0301g, 0.235mmol) was added at room temperature, the reaction solution at the same temperature 16 hours and the mixture was stirred. Saturated potassium carbonate solution was added to the reaction solution, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (NH silica gel, ethyl acetate / methanol), (R)-3-(5-chloro-1-methyl -1H- imidazol-2-yl) -1- (3- (dimethylamino ) piperidin-1-yl) propan-1-one (0.0585g, 0.196mmol, 79%) ( hereinafter, to give the compound) of example 12 as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.30-1.48 (2H, m), 1.68-1.84 (IH, m), 1.92-2.22 (2H, m), 2.28-2.31 (6H, m), 2.40 -2.58 (1H, m), 2.77-3.00 (5H, m), 3.51-3.54 (3H, m), 3.75-4.02 (1H, m), 4.42-4.64 (1H, m), 6.80 (1H, s) .
ESI-MS: m / z = 299 (M + H) + .

[0157]

(Example 13) 1- (3- (dimethylamino) azetidin-1-yl) -3- (1-methyl -1H- imidazol-2-yl) - Synthesis of propane-1-one hydrochloride
[formula 36 ]

　1- (3- (dimethylamino) azetidin-1-yl) -3- (1-methyl -1H- imidazol-2-yl) - propan-1-diethyl ether-on (0.0710g, 0.300mmol) to (3.0 mL) solution was added diethyl ether solution of hydrogen chloride (2.0N, 0.391mL, 0.781mmol) at 0 ° C.. After stirring for 1 hour the reaction solution was stirred at the same temperature for 30 minutes at room temperature. The precipitated white solid was collected by filtration, washed with diethyl ether and dried at room temperature, 1- (3- (dimethylamino) azetidin-1-yl) -3- (1-methyl -1H- imidazol-2-yl ) - propan-1-one hydrochloride (0.0831g, 0.269mmol, 90%) ( hereinafter, to give the compound) of example 13 as a white solid.
1 H-NMR (400 MHz, D 2 O) [delta]: 2.74-2.80 (2H, m), 2.89 (6H, s), 3.21-3.28 (2H, m), 3.82 (3H, s), 4.12-4.28 ( 2H, m), 4.32-4.50 (. 2H, m), 4.57-4.66 (IH, m), 7.28 - 7.36 (2H, m)
ESI-MS: 1-(3- (dimethylamino) azetidin-1-yl ) -3- (1-methyl -1H- imidazol-2-yl) - propan-1 as an on: m / z = 237 (M + H) + .

[0158]

(Example 14) (S) -1- (3- (dimethylamino) piperidin-1-yl) -3- (1-methyl -1H- imidazol-2-yl) Synthesis of propane-1-one hydrochloride:
Formula

　37] (S) -1- (3- (dimethylamino) piperidin-1-yl) -3- (1-methyl -1H- imidazol-2-yl) propan-1-one (0.0860g, 0 in diethyl ether (3.0 mL) solution of .325mmol), it was added diethyl ether solution of hydrogen chloride (2.0N, 0.423mL, 0.846mmol) at 0 ° C.. After stirring for 1 hour the reaction solution was stirred at the same temperature for 30 minutes at room temperature. The precipitated white solid was collected by filtration, washed with diethyl ether and dried at room temperature, (S) -1- (3- (dimethylamino) piperidin-1-yl) -3- (1-methyl -1H- imidazole 2-yl) propan-1-one hydrochloride (0.0576g, 0.171mmol, 53%) ( hereinafter, to give the compound) of example 14 as a white solid.
1 H-NMR (400 MHz, D 2 O) [delta]: 1.60-1.73 (IH, m), 1.85 - 1.98 (2H, m), 2.15-2.30 (IH, m), 2.92-3.09 (8H, m), 3.20-3.44 (5H, m), 3.70-3.80 (IH, m), 3.83 (3H, s), 4.15-4.35 (IH, m), 7.27 - 7.33 (2H, m).
ESI-MS: (S) -1- (3- (dimethylamino) piperidin-1-yl) -3- (1-methyl -1H- imidazol-2-yl) propan-1 as an on: m / z = 265 (M + H) + .

[0159]

(Example 15) (R) -1- (3- (dimethylamino) piperidin-1-yl) -3- (1-methyl -1H- imidazol-2-yl) Synthesis of propane-1-one hydrochloride:
Formula

　38] (R) -1- (3- (dimethylamino) piperidin-1-yl) -3- (1-methyl -1H- imidazol-2-yl) propan-1-one (0.0594 g, 0 in diethyl ether (2.3 mL) solution of .225mmol), it was added diethyl ether solution of hydrogen chloride (2.0N, 0.281mL, 0.562mmol) at 0 ° C.. After 1 hour stirring the reaction mixture at the same temperature, and stirred at room temperature for 1 hour. The precipitated white solid was collected by filtration, washed with diethyl ether and dried at room temperature, (R) -1- (3- (dimethylamino) piperidin-1-yl) -3- (1-methyl -1H- imidazole 2-yl) propan-1-one hydrochloride (0.0492g, 0.146mmol, 65%) ( hereinafter, to give the compound) of example 15 as a white solid.
1 H-NMR (400 MHz, D 2 O) [delta]: 1.60-1.73 (IH, m), 1.85 - 1.98 (2H, m), 2.15-2.30 (IH, m), 2.92-3.09 (8H, m), 3.20-3.44 (5H, m), 3.70-3.80 (IH, m), 3.83 (3H, s), 4.15-4.35 (IH, m), 7.27 - 7.33 (2H, m).
ESI-MS: (R) -1- (3- (dimethylamino) piperidin-1-yl) -3- (1-methyl -1H- imidazol-2-yl) propan-1 as an on: m / z = 265 (M + H) + .

[0160]

(Example 16) 1- (3- (dimethylamino) azetidin-1-yl) -3- (1-isopropyl -1H- imidazol-2-yl) Synthesis of propane-1-one hydrochloride
[formula 39]

　1- (3- (dimethylamino) azetidin-1-yl) -3- (1-isopropyl -1H- imidazol-2-yl) propan-1-one (0.0820g, 0.310mmol) in diethyl ether (3 the .0ML) solution was added diethyl ether solution of hydrogen chloride (2.0N, 0.393mL, 0.787mmol) at 0 ° C.. After stirring for 1 hour the reaction solution was stirred at the same temperature for 30 minutes at room temperature. The precipitated white solid was collected by filtration, washed with diethyl ether and dried at room temperature, 1- (3- (dimethylamino) azetidin-1-yl) -3- (1-isopropyl -1H- imidazol-2-yl ) propan-1-one hydrochloride (0.0942g, 0.279mmol, 90%) ( hereinafter, to give the compound) of example 16 as a white solid.
1 H-NMR (400 MHz, D 2 O) [delta]: 1.47-1.51 (6H, m), 2.74-2.80 (2H, m), 2.88 (6H, s), 3.24-3.30 (2H, m), 4.13- 4.24 (2H, m), 4.33-4.48 (2H, m), 4.58-4.74 (2H, m), 7.36-7.38 (IH, m), 7.49-7.51 (IH, m).
ESI-MS: 1-( 3- (dimethylamino) azetidin-1-yl) -3- (1-isopropyl -1H- imidazol-2-yl) propan-1 as an on: m / z = 265 (M + H) + .

[0161]

(Example 17) (S) -1- Synthesis of (3- (dimethylamino) piperidin-1-yl) -3- (1-isopropyl -1H- imidazol-2-yl) propan-1-one hydrochloride:
Formula

　40] (S) -1- (3- (dimethylamino) piperidin-1-yl) -3- (1-isopropyl -1H- imidazol-2-yl) propan-1-one (0.0900g, 0 in diethyl ether (3.0 mL) solution of .308mmol), it was added diethyl ether solution of hydrogen chloride (2.0N, 0.401mL, 0.801mmol) at 0 ° C.. After stirring for 1 hour the reaction solution was stirred at the same temperature for 30 minutes at room temperature. The precipitated white solid was collected by filtration, washed with diethyl ether and dried at room temperature, (S) -1- (3- (dimethylamino) piperidin-1-yl) -3- (l-isopropyl -1H- imidazole 2-yl) propan-1-one hydrochloride (0.0840g, 0.230mmol, 75%) ( hereinafter, to give the compound) of example 17 as a white solid.
1 H-NMR (400 MHz, D 2 O) [delta]: 1.48-1.70 (8H, m), 1.86-1.98 (2H, m), 2.12-2.28 (IH, m), 2.89-3.12 (8H, m), 3.24-3.45 (5H, m), 3.71-3.82 (IH, m), 4.14-4.36 (IH, m), 7.35 (IH, brs), 7.50 (IH, brs).
ESI-MS: (S) -1 - (3- (dimethylamino) piperidin-1-yl) -3- (1-isopropyl -1H- imidazol-2-yl) propan-1 as an on: m / z = 293 (M + H) + .

[0162]

(Example 18) (R) -1- Synthesis of (3- (dimethylamino) piperidin-1-yl) -3- (1-isopropyl -1H- imidazol-2-yl) propan-1-one hydrochloride:
Formula

　41] (R) -1- (3- (dimethylamino) piperidin-1-yl) -3- (1-isopropyl -1H- imidazol-2-yl) propan-1-one (0.0820g, 0 in diethyl ether (3.0 mL) solution of .280mmol), it was added diethyl ether solution of hydrogen chloride (2.0N, 0.365mL, 0.730mmol) at 0 ° C.. After stirring for 1 hour the reaction solution was stirred at the same temperature for 30 minutes at room temperature. The precipitated white solid was collected by filtration, washed with diethyl ether and dried at room temperature, (R) -1- (3- (dimethylamino) piperidin-1-yl) -3- (l-isopropyl -1H- imidazole 2-yl) propan-1-one hydrochloride (0.0625g, 0.171mmol, 61%) ( hereinafter, to give the compound) of example 18 as a white solid.
1 H-NMR (400 MHz, D 2 O) [delta]: 1.48-1.70 (8H, m), 1.86-1.98 (2H, m), 2.12-2.28 (IH, m), 2.89-3.12 (8H, m), 3.24-3.45 (5H, m), 3.71-3.82 (IH, m), 4.14-4.36 (IH, m), 7.35 (IH, brs), 7.50 (IH, brs).
ESI-MS: (R) -1 - (3- (dimethylamino) piperidin-1-yl) -3- (1-isopropyl -1H- imidazol-2-yl) propan-1 as an on: m / z = 293 (M + H) + .

[0163]

(Example 19) 1- (3- (dimethylamino) azetidin-1-yl) -3- (1- (2,2,2-trifluoroethyl) -1H- imidazol-2-yl) propan-1 synthesis of one hydrochloride:
[formula

　42] 1- (3- (dimethylamino) azetidin-1-yl) -3- (1- (2,2,2-trifluoroethyl) -1H- imidazol-2-yl ) propan-1-one (0.150 g, diethyl ether (6.0 mL) solution of 0.493 mmol), was added diethyl ether solution of hydrogen chloride (2.0N, 0.650mL, 1.30mmol) at 0 ℃ It was. After stirring for 1 hour the reaction solution was stirred at the same temperature for 30 minutes at room temperature. The precipitated white solid was collected by filtration, washed with diethyl ether and dried at room temperature, 1- (3- (dimethylamino) azetidin-1-yl) -3- (1- (2,2,2-trifluoro ethyl)-1H-imidazol-2-yl) propan-1-one hydrochloride (0.137g, 0.363mmol, 74%) ( hereinafter, to give the compound) of example 19 as a white solid.
1 H-NMR (400 MHz, D 2 O) [delta]: 2.77-2.84 (2H, m), 2.89 (6H, s), 3.27-3.33 (2H, m), 4.13-4.26 (2H, m), 4.32- 4.47 (2H, m), 4.57-4.64 (IH, m), 5.08-5.16 (2H, m), 7.42 - 7.46 (IH, m), 7.51-7.55 (IH, m).
ESI-MS: 1-( 3- (dimethylamino) azetidin-1-yl) -3- (1- (2,2,2-trifluoroethyl) -1H- imidazol-2-yl) propan-1 as an on: m / z = 305 (M Tasu H) Tasu .

[0164]

(Example 20) (R) -1- (3- (dimethylamino) piperidin-1-yl) -3- (1- (2,2,2-trifluoroethyl) -1H- imidazol-2-yl) synthesis of propane-1-one hydrochloride
[formula

　43] (R) -1- (3- (dimethylamino) piperidin-1-yl) -3- (1- (2,2,2-trifluoroethyl) -1H- imidazol-2-yl) propan-1-one (0.0790g, in diethyl ether (3.0 mL) solution of 0.238 mmol), diethyl ether solution of hydrogen chloride (2.0N, 0.309mL, 0 .618mmol) was added at 0 ℃. After stirring for 1 hour the reaction solution was stirred at the same temperature for 30 minutes at room temperature. The precipitated white solid was collected by filtration, washed with diethyl ether and dried at room temperature, (R) -1- (3- (dimethylamino) piperidin-1-yl) -3- (1- (2,2, 2-trifluoroethyl)-1H-imidazol-2-yl) propan-1-one hydrochloride (0.0349g, 0.0861mmol, 36%) ( hereinafter, to give the compound) of example 20 as a white solid.
1 H-NMR (400 MHz, D 2 O) [delta]: 1.42-1.70 (IH, m), 1.83-1.94 (2H, m), 2.12-2.27 (IH, m), 2.87-2.94 (6H, m), 3.04-3.14 (2H, m), 3.23-3.42 (5H, m), 3.70-3.78 (1H, m), 4.12-4.32 (1H, m), 5.10-5.18 (2H, m), 7.43-7.45 (1H , m), 7.52-7.54 (IH, m).
ESI-MS: (R) -1- (3- (dimethylamino) piperidin-1-yl) -3- (1- (2,2,2 as fluoroethyl)-1H-imidazol-2-yl) propan-1-one: m / z = 333 (M + H) + .

[0165]

(Example 21) (R) -1- (3- (dimethylamino) piperidin-1-yl) -3- (1- (2-methoxyethyl)-1H-imidazol-2-yl) propan-1-one synthesis of the hydrochloride salt:
[Chemical formula

　44] (R) -1- (3- (dimethylamino) piperidin-1-yl) -3- (1- (2-methoxyethyl)-1H-imidazol-2-yl) propane 1-one (0.165 g, 0.536 mmol) in diethyl ether (10.7 mL) solution of was added diethyl ether solution of hydrogen chloride (2.0N, 0.670mL, 1.34mmol) at 0 ° C.. After 1 hour stirring the reaction mixture at the same temperature and stirred at room temperature for 3 hours. The precipitated white solid was collected by filtration, washed with diethyl ether and dried at room temperature, (R) -1- (3- (dimethylamino) piperidin-1-yl) -3- (1- (2-methoxyethyl )-1H-imidazol-2-yl) propan-1-one hydrochloride (0.177g, 0.463mmol, 86%) ( hereinafter, to give the compound) of example 21 as a white solid.
1 H-NMR (400 MHz, D 2 O) [delta]: 1.44-1.68 (IH, m), 1.74-1.93 (2H, m), 2.16-2.24 (IH, m), 2.89-2.93 (6H, m), 3.00-3.08 (2H, m), 3.23-3.41 (8H, m), 3.70-3.76 (1H, m), 3.82-3.85 (2H, m), 4.14-4.30 (1H, m), 4.36-4.38 (2H , m), 7.33-7.34 (IH, m), 7.40-7.42 (IH, m).
ESI-MS: (R) -1- (3- (dimethylamino) piperidin-1-yl) -3- (1 - (2-methoxyethyl)-1H-imidazol-2-yl) propan-1 as an on: m / z = 309 (M + H) + .

[0166]

(Example 22) 3- (5-chloro-1-methyl -1H- imidazol-2-yl) -1- (3- (dimethylamino) azetidin-1-yl) Synthesis of propane-1-one hydrochloride:
Formula

　45] 3- (5-chloro-1-methyl -1H- imidazol-2-yl) -1- (3- (dimethylamino) azetidin-1-yl) propan-1-one (0.0655g, 0 in diethyl ether (4.8 mL) solution of .242mmol), it was added diethyl ether solution of hydrogen chloride (2.0N, 0.302mL, 0.605mmol) at 0 ° C.. After 1 hour stirring the reaction mixture at the same temperature, and stirred at room temperature for 1 hour. The precipitated white solid was collected by filtration, washed with diethyl ether and dried at room temperature, 3- (5-chloro-1-methyl -1H- imidazol-2-yl) -1- (3- (dimethylamino) azetidine 1-yl) propan-1-one hydrochloride (0.064g, 0.186mmol, 77%) ( hereinafter, to give the compound) of example 22 as a white solid.
1 H-NMR (400 MHz, D 2 O) [delta]: 2.78 (2H, t, J = 7.1 Hz), 2.92 (6H, s), 3.26 (2H, t, J = 7.1 Hz), 3.77 (3H, s ), 4.17-4.28 (2H, m), 4.37-4.41 (IH, m), 4.45-4.48 (IH, m), 4.61-4.66 (IH, m), 7.44 (IH, s).
ESI-MS: 3 - (5-chloro-1-methyl -1H- imidazol-2-yl) -1- as (3- (dimethylamino) azetidin-1-yl) propan-1-one: m / z = 271 (M + H ) + .

[0167]

(Example 23) (S)-3-(5-chloro-1-methyl -1H- imidazol-2-yl) -1- (3- (dimethylamino) piperidin-1-yl) propan-1-one hydrochloride synthesis of salts:
[formula

　46] (S)-3-(5-chloro-1-methyl -1H- imidazol-2-yl) -1- (3- (dimethylamino) piperidin-1-yl) propan -1 - one (0.0800g, 0.268mmol) in diethyl ether (1.0 mL) solution of was added diethyl ether solution of hydrogen chloride (2.0N, 0.348mL, 0.696mmol) at 0 ° C.. After stirring for 1 hour the reaction solution was stirred at the same temperature for 30 minutes at room temperature. Deposited were collected by filtration white solid, washed with diethyl ether (3.0 mL), after 36 hours drying at room temperature, (S) -3- (5- chloro-1-methyl -1H- imidazol-2-yl) -1- (3- (dimethylamino) piperidin-1-yl) propan-1-one hydrochloride (0.0512g, 0.138mmol, 51%) was obtained (hereinafter, the compound of example 23) as a white solid .
　1 H-NMR (400 MHz, D 2 O) [delta]: 1.60-1.71 (IH, m), 1.78-1.96 (2H, m), 2.14-2.28 (IH, m), 2.89-2.96 (6H, m), 3.01-3.10 (2H, m), 3.23-3.44 (5H, m), 3.70-3.80 (4H, m), 4.20-4.33 (IH, m), 7.43 (IH, s).
ESI-MS: (S) 3- (5-chloro-1-methyl -1H- imidazol-2-yl) -1- (3- (dimethylamino) piperidin-1-yl) propan-1 as an on: m / z = 299 (M H Tasu) Tasu .

[0168]

(Example 24) (R)-3-(5-chloro-1-methyl -1H- imidazol-2-yl) -1- (3- (dimethylamino) piperidin-1-yl) propan-1-one hydrochloride synthesis of salts:
[formula

　47] (R)-3-(5-chloro-1-methyl -1H- imidazol-2-yl) -1- (3- (dimethylamino) piperidin-1-yl) propan -1 - one (0.0585g, 0.196mmol) in diethyl ether (3.9 mL) solution of was added diethyl ether solution of hydrogen chloride (2.0 N, 0.245 ml, 0.489 mmol) at 0 ° C.. After 1 hour stirring the reaction mixture at the same temperature, and stirred at room temperature for 1 hour. The precipitated white solid was collected by filtration, washed with diethyl ether and dried at room temperature, (R)-3-(5-chloro-1-methyl -1H- imidazol-2-yl) -1- (3- ( dimethylamino) piperidin-1-yl) propan-1-one hydrochloride (0.0644g, 0.173mmol, 88%) ( hereinafter, to give the compound) of example 24 as a white solid.
　1 H-NMR (400 MHz, D 2 O) [delta]: 1.60-1.71 (IH, m), 1.78-1.96 (2H, m), 2.14-2.28 (IH, m), 2.89-2.96 (6H, m), 3.01-3.10 (2H, m), 3.23-3.44 (5H, m), 3.70-3.80 (4H, m), 4.20-4.33 (IH, m), 7.43 (IH, s).
ESI-MS: (R) 3- (5-chloro-1-methyl -1H- imidazol-2-yl) -1- (3- (dimethylamino) piperidin-1-yl) propan-1 as an on: m / z = 299 (M H Tasu) Tasu .

[0169]

(Example 25) Mouse Sciatic Nerve ligation model for effects:
　a mouse sciatic nerve section ligation model of neuropathic pain can be evaluated (Seltzer model), cyclic amine derivative (I) or a pharmacologically acceptable salt thereof We examined the analgesic action.

[0170]

1. Experimental Methods
　Mice spared nerve ligation model, Seltzer et al. Method (Malmberg et al., Pain, 1998 year, Vol 76, p.215-222) was prepared according to.

[0171]

　Slc: ICR mice (5 weeks old, male; Japan SLC) were anesthetized with sodium pentobarbital (70 mg / kg, i.p.) to expose the sciatic nerve of the right hind thigh, under a stereomicroscope 8 the group receiving the triple ligated to the intensity only half the sciatic nerve using -0 silk (Natsume Seisakusho) and spared nerve ligation group, only to expose the sciatic nerve, and the group was not ligated and sham-operated group.

[0172]

　Evaluation of neuropathic pain (hereinafter, von Frey test), after mice were acclimated a minimum of 1 hour in the measuring acrylic cages placed on the network (Natsume Seisakusho), pressure of 0.16g takes filaments ( with North Coast Medical), repeated three times at 3 second intervals mechanical tactile stimulus pressing 3 seconds filaments sole of the right hind paw scoring the intensity of the escape behavior when applying a mechanical tactile stimulus ( 0: no reaction, 1: slight escape behavior in slowly to stimuli, 2: flinching quick escape behavior to a stimulus that does not involve the (shake in quick succession the foot action) and licking (licking behavior), 3: flinching or quick escape behavior) and with the licking, the total value of the scores of the three times (hereinafter, the total score) as an indicator of pain.

[0173]

　After sciatic nerve ligation surgery 7 days, the mice of spared nerve ligation group, the compounds of Examples 13-24 (compounds of Examples 13-15 and 22-24, 0.3 ~ 10 mg / kg, Examples 16 to the compounds of 21, pregabalin as 10 mg / kg) or positive control, respectively (10 mg / kg; a Bosche Scientific), were orally administered by dissolving in distilled water. Mice of spared nerve ligation group, the group treated with the compounds of Examples 13-24, respectively, "a compound of spared nerve ligation + Example 13" group, "a compound of spared nerve ligation + Example 14" group , "compound of spared nerve ligation + example 15" group, "a compound of spared nerve ligation + example 16" group, "a compound of spared nerve ligation + example 17" group, "spared nerve ligation + implementation example compound 18 "group," compound "groups spared nerve ligation + example 19," a compound of spared nerve ligation + example 20 "group," a compound of spared nerve ligation + example 21 "group," compound "groups spared nerve ligation + example 22," compound "groups spared nerve ligation + example 23, a" compound of spared nerve ligation + example 24 "group, a group treated with pregabalin," sciatic nerve partial ligation + Puregaba It was down "group. Further, the group of distilled water was orally administered to mice of spared nerve ligation group, and "spared nerve ligation + distilled water" group, a group distilled water was orally administered to mice of the sham surgery group, "Sham + It was distilled water "group.

[0174]

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

[0175]

2. Results
　The results shown in Figure 1-12. In the figure, the vertical axis von total score of Frey test (mean ± standard error;. 1 to 12, n = 4 to 6) shows the shows that numerical pain higher stronger. The horizontal axis shows the time after test compound administration (hr). Efficacy evaluation "spared nerve ligation + distilled water" group each measurement time ( "spared nerve ligation + distilled water" in the figure) as a control, the multigroup unpaired t-test (correction by Dunnett) ( the statistical processing was performed by FIGS. 1-3 and 10-12) or unpaired two groups of t-test (FIGS. 4-9). * Mark in the figure indicates that "spared nerve ligation + distilled water" is statistically significant in comparison with the group (p <0.05).

[0176]

　According to the results of the von Frey test, ( "the compounds of the sciatic nerve partial ligation + Examples 13-24" in the figure) oral administration of the compounds of Examples 13-24 are positive controls pregabalin (in the figure " Like the spared nerve ligation + pregabalin ") showed a statistically significant analgesic effect.

[0177]

　From this result, a cyclic amine derivative (I) or a pharmacologically acceptable salt thereof, may exhibit a strong analgesic effect on neuropathic pain was revealed.

Industrial Applicability

[0178]

　Cyclic amine derivative or a pharmacologically acceptable salt thereof of the present invention, pain, because it can exert an analgesic effect, especially for neuropathic pain, it can be used as medicaments against pain symptoms.

The scope of the claims

[Claim 1]

　Cyclic amine derivative or a pharmacologically acceptable salt thereof represented by the general formula (I).
[Formula 1]

[wherein, n stands for 1 or 3, R 1 is substituted with unsubstituted or substituted with a halogen atom, or an alkyl group having 1 to 4 carbon atoms represents an alkyl group having 1 to 6 carbon atoms, R 2 represents a hydrogen atom or a halogen atom. ]

[Claim 2]

　R 2 is a hydrogen atom or a chlorine atom, a cyclic amine derivative or a pharmacologically acceptable salt thereof according to claim 1, wherein.

[Claim 3]

　R 1 is an alkyl group having 1 to 6 carbon atoms which is unsubstituted, cyclic amine derivative or a pharmacologically acceptable salt thereof according to claim 2, wherein.

[Claim 4]

　Comprising as an active ingredient a cyclic amine derivative or a pharmacologically acceptable salt thereof of any one of claims 1 to 3, a pharmaceutical.

[Claim 5]

　Containing a cyclic amine derivative or a pharmacologically acceptable salt of any one of claims 1 to 3 as an active ingredient, an analgesic.

[Claim 6]

　Containing a cyclic amine derivative or a pharmacologically acceptable salt of any one of claims 1 to 3 as an active ingredient, neuropathic pain therapeutic agent.