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. In addition, the cause as unknown pain, has been known fibromyalgia.

[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]

　The fibromyalgia, systemic pain as the main symptom, which is a symptom of the neuropsychiatric symptoms and autonomic nervous system diseases and the sub-symptoms. The fibromyalgia of the therapeutic agent, pregabalin, which has been approved in the United States and Japan, duloxetine and milnacipran that have been approved in the United States are mainly used. Non-steroidal anti-inflammatory drugs have not been approved as fibromyalgia therapeutic agents, opioid compounds, antidepressants, it has been used for anti-convulsants and anti-epileptic drugs. However, the therapeutic effects of non-steroidal anti-inflammatory drugs and opioid compounds are generally low (Non-Patent Document 1).

[0005]

　On the other hand, Patent Document 1, certain substituted piperidines are disclosed to have cardiotonic activity. Patent Document 2, imidazole derivatives are disclosed to exhibit FXa inhibiting effect. Patent Document 3, can have efficacy have been suggested to the substitutions piperidines are overweight or obese. Patent Document 4, imidazole derivatives are disclosed to exhibit an analgesic effect.

CITATION

Patent Document

[0006]

Patent Document 1: FR invention No. 2567885 Pat
Patent Document 2: JP 2006-008664 Patent Publication
Patent Document 3: WO 2003/031432 Patent
Patent Document 4: WO 2013/147160

Non-patent literature

[0007]

Non-Patent Document 1: Pain and Therapy, 2013 years, Volume 2, p. 87-104

Summary of the Invention

Problems that the Invention is to Solve

[0008]

　However, the treatment with the therapeutic agent of the conventional neuropathic pain, central side effects (dizziness, nausea or vomiting) is accompanied by a high frequency. To enable long-term administration has been desired to develop a new neuropathic pain therapeutic agent.

[0009]

　Furthermore, pregabalin has been approved for the treatment of fibromyalgia, even duloxetine and milnacipran, therapeutic effect on fibromyalgia is not going clinically satisfactory, even efficacy differences between patients large. Therefore, pharmacological activity is strong, the development of new fibromyalgia therapeutic agents that exert a therapeutic effect has been coveted for a wide range of patients.

[0010]

　It should be noted that the substitution piperidines described in Patent Document 1, have been suggested to the effect that the effectiveness of the migraine, for the imidazole derivatives described in Patent Document 4, it is disclosed that has an analgesic effect there. However, not all the suggestion of relationship between disclosure and analgesic action and chemical structure of the compound itself were revealed analgesic effect in this application. The substituted piperidines according to imidazole derivatives and Patent Document 3 described in Patent Document 2 does not disclose or suggest even likely to have an analgesic effect.

[0011]

　The present invention, pain, and to provide compounds exhibiting an analgesic effect, especially for neuropathic pain and / or fibromyalgia.

Means for Solving the Problems

[0012]

　The present inventors have come to find extensive result of extensive research, pains, especially cyclic amine derivatives having strong analgesic effect on neuropathic pain and / or fibromyalgia in order to solve the above problems.

[0013]

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

wherein the carbon marked with * is an asymmetric carbon, A is of the general formula (IIa), a group represented by (IIb) or (IIc),
[Formula

　2] R 1 is , may be substituted with a halogen atom, a methyl group or an ethyl group, R 2 represents a hydrogen atom or an alkyl group having a carbon number of 2 ~ 5, R 3 are each independently a methyl group or an ethyl radical, n represents 1 or 2. ]

[0014]

　Cyclic amine derivatives of the above, it is preferable that A is a group represented by the general formula (IIa), at that time, R 1 may be substituted with a fluorine atom, a methyl group or an ethyl group more preferably, R 1 is a methyl group, an ethyl group, more preferably a difluoromethyl group or a 2,2,2-trifluoroethyl group. By limitation, it is possible to enhance the analgesic effect.

[0015]

　Further, a cyclic amine derivative of the above, it is preferred that A is a group represented by the general formula (IIb) or (IIc), when its, R 1 is a fluorine atom may be substituted, methyl group, or more preferably an ethyl a group, R 1 is a methyl group, an ethyl group, more preferably a difluoromethyl group or a 2,2,2-trifluoroethyl group. By limitation, it is possible to enhance the analgesic effect.

[0016]

　Further, a cyclic amine derivative described above, A is a group represented by the general formula (IIa), the stereochemistry of the asymmetric carbon is the marked *, is preferably S-configuration, in which, R 1 is a fluorine atom may be substituted, more preferably a methyl group or an ethyl group, R 1 is a methyl group, an ethyl group, to be a difluoromethyl group or a 2,2,2-trifluoroethyl group A further preferred. By limitation, it is possible to further enhance the analgesic effect.

[0017]

　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.

[0018]

　The pharmaceutical is preferably an analgesic, more preferably particularly neuropathic pain therapeutic agent or fibromyalgia treatment.

[0019]

　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. .

[0020]

　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).

[0021]

　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 or fibromyalgia.

[0022]

　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 or fibromyalgia.

[0023]

　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 or fibromyalgia.

[0024]

　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 or fibromyalgia.

Effect of the Invention

[0025]

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

BRIEF DESCRIPTION OF THE DRAWINGS

[0026]

FIG. 1 is a graph showing the effect of the compound of Example 1 against murine spared nerve ligation model (oral administration).
2 is a diagram showing the effect of the compound of Example 2 against mouse sciatic nerve partial ligation model (oral administration).
3 is a graph showing the effect of the compound of Example 3 to the mouse sciatic nerve partial ligation model (oral administration).
4 is a graph showing the effect of the compound of Example 4 to mouse sciatic nerve partial ligation model (oral administration).
5 is a graph showing the effect of the compound of Example 5 against mouse sciatic nerve partial ligation model (oral administration).
6 is a graph showing the effect of the compound of Example 7 against mouse sciatic nerve partial ligation model (oral administration).
7 is a graph showing the effect of the compound of Example 8 on mouse sciatic nerve partial ligation model (oral administration).
8 is a graph showing the effect of the compound of Example 9 on mouse sciatic nerve partial ligation model (oral administration).
9 is a graph showing the effect of the compound of Example 10 for the mouse sciatic nerve partial ligation model (oral administration).
10 is a diagram showing the effect of the compound of Example 11 for the mouse sciatic nerve partial ligation model (oral administration).
11 is a graph showing the effect of the compound of Example 12 for the mouse sciatic nerve partial ligation model (oral administration).
12 is a graph showing the effect of the compound of Example 13 for the mouse sciatic nerve partial ligation model (oral administration).
13 is a graph showing the effect of the compound of Example 11 to rat fibromyalgia model (oral administration).
[14] The effect of the compound of Comparative Example 1 against murine spared nerve ligation model, and, as a comparison, is a graph showing the effect of the compound of Example 11 according to FIG. 10 (oral administration).
[15] The effect of the compounds of Comparative Examples 3-6 to mouse sciatic nerve section ligation model, and, as a comparison, is a graph showing the effect of the compound of Example 11 according to FIG. 10 (oral administration).
[16] The effect of the compound of Comparative Example 1 on rat fibromyalgia models, and, as a comparison, is a graph showing the effect of the compound of Example 11 according to FIG. 13 (oral administration).
17 is a diagram showing changes in the plasma concentration of the compound of Example 11 in Cynomolgus Monkeys (intravenous and oral administration).
18 is a diagram showing the changes in the plasma concentration of the compound of Comparative Example 2 in cynomolgus monkeys (intravenous and oral administration).

DESCRIPTION OF THE INVENTION

[0027]

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

[0028]

　Cyclic amine derivative of the present invention is characterized in that represented by the following general formula (I).
[Chemical Formula 3]

wherein a subjected carbon is an asymmetric carbon *, A of the general formula (IIa), a group represented by (IIb) or (IIc),
Formula

　4] R 1 is , may be substituted with a halogen atom, a methyl group or an ethyl group, R 2 represents a hydrogen atom or an alkyl group having a carbon number of 2 ~ 5, R 3 are each independently a methyl group or an ethyl radical, n represents 1 or 2. ]

[0029]

　Cyclic amine derivative described above, A is preferably a group represented by the general formula (IIa), R 1 is a fluorine atom may be substituted, preferably a methyl group or an ethyl group, R 1 is a methyl group, an ethyl group, more preferably a difluoromethyl group or a 2,2,2-trifluoroethyl group.

[0030]

　Further, a cyclic amine derivative of the above, A is preferably a group represented by the general formula (IIb) or (IIc), R 1 may be substituted with a fluorine atom, a methyl group or an ethyl group it is preferably, R 1 is methyl group, an ethyl group, more preferably a difluoromethyl group or a 2,2,2-trifluoroethyl group.

[0031]

　Further, a cyclic amine derivative of the above, it is preferred that A is preferably a group represented by the general formula (IIa), the stereochemistry of the asymmetric carbon marked with * S configuration, in which, R 1 but fluorine atoms may be substituted is preferably a methyl group or an ethyl group, R 1 is a methyl group, an ethyl group, difluoromethyl group or a 2,2,2-trifluoroethyl group It is more preferable.

[0032]

　In one embodiment of the above cyclic amine derivative of the present invention, A is a group represented by the general formula (IIa), R 1 may be substituted with a fluorine atom, a methyl group or an ethyl group , R 2 represents a hydrogen atom or an alkyl group having a carbon number of 2 ~ 5, R 3 each independently represents a methyl group or an ethyl group. In the present embodiment, it is preferred that the stereochemistry of the asymmetric carbon marked with * is in the S configuration.

[0033]

　In one embodiment of the above cyclic amine derivative of the present invention, A is a group represented by the general formula (IIa), R 1 is a methyl group, an ethyl group, difluoromethyl group or a 2,2,2- It represents a fluoroethyl group, R 2 represents a hydrogen atom or an alkyl group having a carbon number of 2 ~ 5, R 3 each independently represents a methyl group or an ethyl group. In the present embodiment, it is preferred that the stereochemistry of the asymmetric carbon marked with * is in the S configuration.

[0034]

　In one embodiment of the above cyclic amine derivative of the present invention, A is a group represented by the general formula (IIa), R 1 represents a methyl group or a 2,2,2-trifluoroethyl radical, R 2 represents a hydrogen atom or an alkyl group having 2 carbon atoms, R 3 represents a methyl group. In the present embodiment, it is preferred that the stereochemistry of the asymmetric carbon marked with * is in the S configuration.

[0035]

　In one embodiment of the above cyclic amine derivative of the present invention, A is a group represented by the general formula (IIb), R 1 may be substituted with a fluorine atom, a methyl group or an ethyl group , R 2 represents a hydrogen atom or an alkyl group having a carbon number of 2 ~ 5, R 3 each independently represents a methyl group or an ethyl radical, n represents 1 or 2. In the present embodiment, it is preferred that the stereochemistry of the asymmetric carbon marked with * is in the S configuration.

[0036]

　In one embodiment of the above cyclic amine derivative of the present invention, A is a group represented by the general formula (IIb), R 1 is a methyl group, an ethyl group, difluoromethyl group or a 2,2,2- represents a fluoroethyl group, R 2 represents a hydrogen atom or an alkyl group having a carbon number of 2 ~ 5, R 3 each independently represents a methyl group or an ethyl radical, n represents 1 or 2 . In the present embodiment, it is preferred that the stereochemistry of the asymmetric carbon marked with * is in the S configuration.

[0037]

　In one embodiment of the above cyclic amine derivative of the present invention, A is a group represented by the general formula (IIb), R 1 represents a methyl group or a 2,2,2-trifluoroethyl radical, R 2 represents a hydrogen atom or an alkyl group having 2 carbon atoms, R 3 represents a methyl radical, n represents 1 or 2. In the present embodiment, it is preferred that the stereochemistry of the asymmetric carbon marked with * is in the S configuration.

[0038]

　In one embodiment of the above cyclic amine derivative of the present invention, A is a group represented by the general formula (IIc), R 1 may be substituted with a fluorine atom, a methyl group or an ethyl group , R 2 represents a hydrogen atom or an alkyl group having a carbon number of 2 ~ 5, R 3 represents a methyl group or an ethyl group. In the present embodiment, it is preferred that the stereochemistry of the asymmetric carbon marked with * is in the S configuration.

[0039]

　In one embodiment of the above cyclic amine derivative of the present invention, A is a group represented by the general formula (IIc), R 1 is a methyl group, an ethyl group, difluoromethyl group or a 2,2,2- It represents a fluoroethyl group, R 2 represents a hydrogen atom or an alkyl group having a carbon number of 2 ~ 5, R 3 represents a methyl group or an ethyl group. In the present embodiment, it is preferred that the stereochemistry of the asymmetric carbon marked with * is in the S configuration.

[0040]

　In one embodiment of the above cyclic amine derivative of the present invention, A is a group represented by the general formula (IIc), R 1 represents a methyl group or a 2,2,2-trifluoroethyl radical, R 2 represents a hydrogen atom or an alkyl group having 2 carbon atoms, R 3 represents a methyl group. In the present embodiment, it is preferred that the stereochemistry of the asymmetric carbon marked with * is in the S configuration.

[0041]

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

[0042]

　"Optionally substituted with a halogen atom, a methyl group or an ethyl group" and the hydrogen atom, independently, may be substituted by halogen atoms as mentioned above, it means a methyl group or an ethyl group. For example, a methyl group or an ethyl group or a difluoromethyl group, 2-fluoroethyl group, 2-chloroethyl group, 2,2-difluoroethyl group or 2,2,2-trifluoroethyl group.

[0043]

　The "alkylcarbonyl group having 2 to 5 carbon atoms" means a linear, branched or cyclic group, saturated hydrocarbon group is bonded to a carbonyl group having 1 to 4 carbon atoms. For example, an acetyl group, n- propionyl group, n- butyryl group, and isobutyryl group or valeryl group.

[0044]

　The above general formula (I) a cyclic amine derivative (hereinafter, a cyclic amine derivative (I)) represented but specific examples of preferred compounds are shown in Table 1-1 and Table 1-2, the present invention is limited to not shall.

[0045]
[0046]
[0047]

　Note that a cyclic amine derivative (I) is, enantiomers, when containing isomers such as stereoisomers, any isomers and mixtures thereof are also encompassed by the cyclic amine derivative (I). Also, there are cases where isomers by conformation to produce even such isomers and mixtures thereof are included in the cyclic amine derivative (I). Isomer of interest can be obtained by known methods or methods analogous thereto. For example, if there are enantiomers cyclic amine derivative (I) is the enantiomer divided from cyclic amine derivative (I) are also encompassed by the cyclic amine derivative (I).

[0048]

　Enantiomer of interest, known means (e.g., using an optically active synthetic intermediate, or with respect to the racemic mixture of the final product, using known methods or methods analogous thereto (e.g., optical resolution)) it can be obtained by.

[0049]

　The present invention includes prodrugs or pharmacologically acceptable salts of the cyclic amine derivative (I). Prodrugs of a cyclic amine derivative (I), enzymatically or chemically in vivo, is a compound which is converted to the cyclic amine derivative (I). Active principle of the prodrug cyclic amine derivative (I) is a cyclic amine derivative (I), a prodrug itself cyclic amine derivative (I) may have activity.

[0050]

　Examples of the prodrug of a cyclic amine derivative (I), for example, hydroxyl group of the cyclic amine derivative (I) is alkylated, compounds phosphorylated or borated and the like. These compounds according to known methods, can be synthesized from cyclic amine derivative (I).

[0051]

　In addition, the prodrug of the cyclic amine derivative (I), known in the literature ( "Development of Pharmaceuticals", Hirokawa Shoten, 1990, Vol. 7, p.163 ~ 198 and Progress in Medicine, Vol. 5, 1985, p under physiological conditions described in .2157 ~ 2161), or it may be changed to a cyclic amine derivative (I).

[0052]

　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 / or 125 include I.

[0053]

　Examples of the pharmaceutically acceptable salt of the cyclic amine derivative (I), for example, 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.

[0054]

　Cyclic amine derivative (I) can be synthesized according to the production methods described below. Incidentally, the cyclic amine derivatives obtained by the following production method (I) is a known method (e.g., solvent extraction, recrystallization and / or chromatography) can be isolated purified by an object by a known method or a method analogous thereto It can be converted into a salt to be. If the cyclic amine derivative (I) is obtained in the form of salt, by known methods or methods analogous thereto, it can be converted into other salts of the cyclic amine derivative (I) or purpose.

[0055]

　In each reaction of the production methods described below, if the raw material compound has a hydroxyl group, an amino group or carboxyl group, it may be a protective group into these groups have been introduced, deprotecting the protecting group as necessary after the reaction it is possible to obtain the desired compound by.

[0056]

　As the protective group for a hydroxyl group, for example, a trityl group, an aralkyl group having 7 to 10 carbon atoms (e.g., benzyl group) or a substituted silyl group (e.g., trimethylsilyl group, triethylsilyl group or tert- butyldimethylsilyl group) .

[0057]

　As the amino-protecting group, for example, an alkylcarbonyl group having 2 to 6 carbon atoms (e.g., acetyl group), a benzoyl group, an alkyloxycarbonyl group having 2 to 8 carbon atoms (e.g., tert- butoxycarbonyl group or benzyloxycarbonyl carbonyl group), an aralkyl group having 7 to 10 carbon atoms (e.g., benzyl group) or a phthaloyl group.

[0058]

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

[0059]

　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, Inc.) or according to a method analogous thereto it can be carried out.

[0060]

1. Preparation of the compounds
(Ia): 1-1. Process for preparing a compound (Ia-a):
[Formula 5]

[wherein each symbol has the same meaning as defined above. ]

[0061]

(Step 1)
　of the cyclic amine derivative (I), A is a group represented by the general formula (IIa) Compound (Ia-a) is, for example, the presence of a base, with compound (IIIA) and compound (IV) obtained by the aldol-type condensation reaction.

[0062]

　Compounds used in the aldol-type condensation reaction (IIIA) and compound (IV) can be used as it commercially available, for example, can be synthesized according to the production methods described below.

[0063]

　The base used in the aldol-type condensation reaction, for example, lithium diisopropylamide, potassium tert- butoxide, sodium hydride, phenyl lithium or tert- butyl lithium.

[0064]

　The amount of the base used in the aldol-type condensation reaction is preferably 0.5 to 10 moles relative to 1 mole of the compound (IIIA), and more preferably 0.8 to 5 mol.

[0065]

　The amount of compound in the aldol-type condensation reaction (IV) is preferably from 0.5 to 3 moles per 1 mole of the compound (IIIA), and more preferably 0.8 to 1.5 mol.

[0066]

　Aldol-type 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, such as dichloromethane, halogenated hydrocarbons such as chloroform or 1,2-dichloroethane; or tetrahydrofuran or 1,4-dioxane and the like can be mentioned. A mixed solvent thereof may be used.

[0067]

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

[0068]

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

[0069]

1-2. Process for preparing a compound (Ia-b) and (Ia-c):
[Chemical Formula 6]

[wherein, R 2a represents a hydrogen atom, R 2b represents an alkylcarbonyl group having 2 to 5 carbon atoms, other each symbol has the same meaning as defined above. ]

[0070]

(Step 2)
　of the cyclic amine derivative (I), A is a group represented by the general formula (IIa), and, R 2 compound is a hydrogen atom (Ia-b) may, for example, the presence of a base, obtained by aldol-type condensation reaction of the compound (IIIA) and compound (IV).

[0071]

　Compounds used in the aldol-type condensation reaction (IIIA) and compound (IV) can be used as it commercially available, for example, can be synthesized according to the production methods described below.

[0072]

　The base used in the aldol-type condensation reaction, for example, lithium diisopropylamide, potassium tert- butoxide, sodium hydride, phenyl lithium or tert- butyl lithium.

[0073]

　The amount of the base used in the aldol-type condensation reaction is preferably 0.5 to 10 moles relative to 1 mole of the compound (IIIA), and more preferably 0.8 to 5 mol.

[0074]

　The amount of compound in the aldol-type condensation reaction (IV) is preferably from 0.5 to 3 moles per 1 mole of the compound (IIIA), and more preferably 0.8 to 1.5 mol.

[0075]

　Aldol-type condensation reaction is generally carried out in a solvent. The solvent that does not interfere with the reaction is appropriately selected. As such solvent, such as dichloromethane, halogenated hydrocarbons such as chloroform or 1,2-dichloroethane; or ethers such as tetrahydrofuran or 1,4-dioxane Ageraru. A mixed solvent thereof may be used.

[0076]

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

[0077]

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

[0078]

(Step 3)
　of the cyclic amine derivative (I), a group A is represented by the general formula (IIa), and, R 2 compound is a hydrogen atom (Ia-b), the reduction of the compound (VA) obtained by the reaction.

[0079]

　Compound used in the reduction reaction (VA), for example, can be synthesized according to the production methods described below.

[0080]

　The reducing agent used in the reduction reaction, for example, lithium borohydride, sodium borohydride, diisobutylaluminum hydride, lithium aluminum hydride, lithium triethyl hydride, sodium bis (2-methoxyethoxy) include aluminum hydride or borane complexes.

[0081]

　The amount of the reducing agent in the reduction reaction is preferably 0.5 to 10 moles relative to 1 mole of the compound (VA), more preferably 0.8 to 5 mol.

[0082]

　The reduction 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, octane, hexane, hydrocarbons such as benzene or toluene; tetrahydrofuran, 1,4-dioxane, ethers such as ethylene glycol dimethyl or diethyl ether; or methanol, ethanol or 2-propanol and the like alcohols is. A mixed solvent thereof may be used.

[0083]

　The reaction temperature in the reduction reaction is preferably from -78 ° C. ~ 0.99 ° C., more preferably -78 ℃ ~ 100 ℃.

[0084]

　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 24 hours.

[0085]

(Step 4)
　of a cyclic amine derivative (I), A is a group represented by the general formula (IIa), and, R 2 compound is an alkyl group having 2 to 5 carbon atoms (Ia-c) is , for example, the presence of a base, the compound (Ia-b), obtained by an acylation reaction using an acylating agent such as a halide or acid anhydride of carboxylic acid having 2 to 5 carbon atoms.

[0086]

　The acylation reaction, may be used a compound (Ia-b) and salts thereof. As the salt of case, for example, those similar to the salts described above pharmacologically acceptable can be mentioned.

[0087]

　The base used in the acylation reaction, for example, pyridine, triethylamine, diisopropylethylamine or N, N-dimethylaminopyridine and the like.

[0088]

　The amount of the base used in the acylation reaction is preferably 0.5 to 10 moles relative to 1 mole of compound (Ia-b), more preferably 0.8 to 5 mol.

[0089]

　Acylating agent used in acylation reactions, it can be used as it is commercially available.

[0090]

　The amount of the acylating agent in the acylation reaction is preferably 0.5 to 10 moles relative to 1 mole of compound (Ia-b), more preferably 0.8 to 5 mol.

[0091]

　The acylation 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. Aromatic amines such as pyridine when selected as a solvent, it is also possible to carry out the acylation reaction under basic absence.

[0092]

　The reaction temperature in the acylation reaction is preferably -40 ° C. ~ 100 ° C., more preferably -20 ℃ ~ 80 ℃.

[0093]

　The reaction time in the acylation reaction varies depending on the reaction conditions, preferably 5 minutes to 72 hours, more preferably from 30 minutes to 24 hours.

[0094]

1-3. Compound (Ia-a), (Ia -b) and (Ia-c) of the chlorination step:
　Compound (Ia-a), (Ia -b) and pharmaceutically acceptable salts of (Ia-c) is , for example, compound (Ia-a), of (Ia-b) or (Ia-c), obtained by salification with an acid.

[0095]

　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.

[0096]

　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 2-propanol; diethyl ether, ethers such as tetrahydrofuran and 1,4-dioxane or ethylene glycol dimethyl ether; N, N-dimethylformamide or N - amides such as methylpyrrolidone; esters such as ethyl acetate, methyl acetate or acetic n- butyl; sulfoxides such as dimethyl sulfoxide, aliphatic nitriles such as acetonitrile or propionitrile; ketones such as acetone or 2-butanone s; or water. A mixed solvent thereof may be used.

[0097]

2. Preparation of the compound (IIIA):
[Chemical Formula 7]

[wherein, PG represents a protecting group, and other symbols have the same meanings as defined above. ]

[0098]

(Step 5)
　Compound (IIIA) is, PG is obtained by reductive amination reaction of a compound is an acetyl group (VIA) with a compound (VIIA).

[0099]

　Compounds used in the reductive amination reaction (VIA) and compound (VIIA) may be used as a commercial product.

[0100]

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

[0101]

(Step 6)
　Compound (VIIIA) may be obtained by reductive amination reaction of the compound (VIA) with a compound (VIIA).

[0102]

　Compounds used in the reductive amination reaction (VIA) and compound (VIIA) may be used as a commercial product.

[0103]

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

[0104]

(Step 7)
　Compound (IIa-a) is obtained by deprotection of compound (VIIIA).

[0105]

　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, Inc.) or according to a method analogous thereto it can be carried out.

[0106]

(Step 8)
　Compound (IIIA) is obtained by acetylation reaction of compound (IIa-a).

[0107]

　Acetylation reaction, a known method (e.g., Greene, T. W., "Greene's Protective Groups in Organic Synthesis", Wiley-Interscience, Inc.) can be carried out according or a method analogous thereto.

[0108]

3. Preparation of Compound (IV):
[Formula 8]

[wherein, L is a leaving group, and other symbols have the same meanings as defined above. ]

[0109]

(Step 9)
　Compound (X) can be obtained by alkylation reaction to act an alkylating reagent (LI) after deprotonation with a base of compound (IX).

[0110]

　Compound used in the alkylation reaction (IX) can be used as a commercial product.
[0118]

(Step 10)
　Compound (IV) may be obtained by formylation reaction to act formyl group-introducing reagent after deprotonation with a base of the compound (X).

[0119]

　Formylated compound used in the reaction (X), which can be used as it is a commercial product, for example, can be synthesized according to the above manufacturing method.

[0120]

　Examples of the bases used in the formylation reaction, for example, n- butyllithium, and a sec- butyl lithium or tert- butyl lithium.

[0121]

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

[0122]

　The formyl group-introducing reagent used in the formylation reaction, for example, N, N-dimethylformamide. N, N- dimethylformamide can be used as a commercial product.

[0123]

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

[0124]

　Formylation 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, aliphatic hydrocarbons such as heptane or hexane; or tetrahydrofuran, ethers such as diethyl ether or 1,4-dioxane. A mixed solvent thereof may be used.

[0125]

　The reaction temperature in the deprotonation of the formylation reaction is preferably -100 ~ 0 ° C., more preferably -80 ~ -20 ° C.. The reaction temperature in the formylation of formylation reaction is preferably -20 ℃ ~ 150 ℃, 0 ~ 100 ℃ is more preferable.

[0126]

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

[0127]

(Step 11)
　Compound (IV) may be obtained by alkylation reaction to act an alkylating reagent (LI) after deprotonation with a base of the compound (XI).

[0128]

　Compound used in the alkylation reaction (XI) can be used as a commercial product.

[0129]

　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.

[0130]

　The amount of the base used in the alkylation reaction is preferably 0.5 to 3 moles relative to 1 mole of compound (XI), more preferably 0.8 to 2 moles.

[0131]

　Alkylating reagent used in the alkylation reaction (LI) can be used as a commercial product.

[0132]

　The amount of the alkylating reagent (LI) in the alkylation reaction is preferably 0.5 to 3 moles relative to 1 mole of compound (XI), more preferably 0.8 to 2 moles.

[0133]

　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.

[0134]

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

[0135]

　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.

[0136]

4. Preparation of the compound
(VA): 4-1. Process for the preparation of a compound (VA):
[Chemical Formula 9]

[wherein each symbol has the same meaning as defined above. ]

[0137]

(Step 12)
　Compound (VA) is obtained by oxidation of compound (Ia-b).

[0138]

　Compound used in the oxidation reaction (Ia-b) may be synthesized according to the above manufacturing method.

[0139]

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

[0140]

　The amount of the oxidizing agent in the oxidation reaction is preferably 0.5 to 50 mol per 1 mol of compound (Ia-b), more preferably 0.8 to 35 mol.

[0141]

　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.

[0142]

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

[0143]

　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.

[0144]

4-2. Process for the preparation of a compound (VA):
[Formula 10]

wherein, R 4 represents an alkyl group or a number of 7-10 aralkyl group having a carbon number of 1 to 6 carbon atoms, such as methyl, ethyl, n- propyl group, and n- butyl or benzyl group. Other symbols are as defined. ]

[0145]

(Step 13)
　Compound (XII) the presence of a base, (X), a compound of obtained by an esterification reaction using an ester group-introducing reagents.

[0146]

　Compound used in the esterification reaction (X), which can be used as it is a commercial product, for example, can be synthesized according to the above manufacturing method.

[0147]

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

[0162]

　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.

[0163]

(Step 15)
　Compound (VA) is the presence of a base, obtained by condensation reaction of the compound (XII) with the compound (IIIA).

[0164]

　Compound used in the condensation reaction (XII) and the compound (IIIA), which can be used as it is a commercial product, for example, can be synthesized according to the above manufacturing method.

[0165]

　The base used in the condensation reaction, for example, lithium diisopropylamide, potassium tert- butoxide, sodium hydride, phenyl lithium or tert- butyl lithium.

[0166]

　The amount of the base used in the condensation reaction is preferably 0.5 to 10 moles relative to 1 mole of the compound (IIIA), and more preferably 0.8 to 5 mol.

[0167]

　The amount of compound in the condensation reaction (XII) is preferably from 0.5 to 3 moles per 1 mole of the compound (IIIA), and more preferably 0.8 to 1.5 mol.

[0168]

　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, such as dichloromethane, halogenated hydrocarbons such as chloroform or 1,2-dichloroethane; or tetrahydrofuran or 1,4-dioxane and the like can be mentioned. A mixed solvent thereof may be used.

[0169]

　The reaction temperature in the condensation reaction is preferably from -78 ° C. ~ 100 ° C., more preferably -78 ℃ ~ 50 ℃.

[0170]

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

[0171]

4-3. Process for the preparation of a compound (VA):
[Formula 11]

wherein, M represents a hydrogen atom or an alkali metal, the alkali metal, for example, lithium or sodium. Other symbols are as defined. ]

[0172]

(Step 16)
　Compound (XIV) is obtained by hydrolysis of compound (XII).

[0173]

　Compound used in the hydrolysis reaction (XII), which may be used as it is commercially available, for example, can be synthesized according to the above manufacturing method.

[0174]

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

[0175]

　The amount of the base used in the hydrolysis reaction is preferably 0.5 to 3 moles relative to 1 mole of compound (XII), more preferably 0.8 to 2 moles.

[0176]

　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.

[0177]

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

[0178]

　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.

[0179]

(Step 17)
　compound (XVI) a base, the presence carbonyldiimidazole and magnesium salts, obtained by condensation reaction of the compound (XIV) the compound (XV).

[0180]

　The above condensation reaction, a known method (for example, ACS Medicinal Chemistry Letters, 2011 years, Volume 2, P.171-176) can be carried out according to a method analogous to or.

[0181]

(Step 18)
　Compound (VA) is obtained by amidation reaction of the compound (XVI) with the compound (IIa-a).

[0182]

　Compounds used in the amidation reaction (XVI) and Compound (IIa-a), which can be used as it is a commercial product, for example, can be synthesized according to the above manufacturing method.

[0183]

　The amount of the compound in the amidation reaction (IIa-a) is preferably from 0.5 to 3 moles per 1 mole of the compound (XVI), more preferably 0.8 to 1.5 mol.

[0184]

　Amidation 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.

[0185]

　The reaction temperature in the amidation reaction is preferably -20 ° C. ~ 200 ° C., and more preferably 0 ~ 0.99 ° C..

[0186]

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

[0187]

5. Preparation of the compound
(Ib): 5-1. Process for preparing a compound (Ib-a):
[Formula 12]

wherein each symbol has the same meaning as defined above. ]

[0188]

(Step 19)
　Among the cyclic amine derivative (I), A is a group represented by the general formula (IIb) Compound (Ib-a) is, for example, the presence of a base, compound (IIIB) and compound (IV) obtained by the aldol-type condensation reaction.

[0189]

　Compounds used in the aldol-type condensation reaction (IIIB) and compound (IV) can be used as it commercially available, for example, compound (IIIB) can be synthesized according to the production methods described below, the compound (IV) above It can be synthesized according to the method of production.

[0190]

　The base used in the aldol-type condensation reaction, for example, lithium diisopropylamide, potassium tert- butoxide, sodium hydride, phenyl lithium or tert- butyl lithium.

[0191]

　The amount of the base used in the aldol-type condensation reaction is preferably 0.5 to 10 moles relative to 1 mole of compound (IIIB), and more preferably 0.8 to 5 mol.

[0192]

　The amount of compound in the aldol-type condensation reaction (IV) is preferably from 0.5 to 3 moles per 1 mole of compound (IIIB), and more preferably 0.8 to 1.5 mol.

[0193]

　Aldol-type 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, such as dichloromethane, halogenated hydrocarbons such as chloroform or 1,2-dichloroethane; or tetrahydrofuran or 1,4-dioxane and the like can be mentioned. A mixed solvent thereof may be used.

[0194]

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

[0195]

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

[[0234]

　Acetylation reaction, a known method (e.g., Greene, T. W., "Greene's Protective Groups in Organic Synthesis", Wiley-Interscience, Inc.) can be carried out according or a method analogous thereto.

[0235]

7. Preparation of Compound (VB):
[Formula 15]

wherein each symbol has the same meaning as defined above. ]

[0236]

(Step 27)
　Compound (VB) is obtained by oxidation of compound (Ib-b).

[0237]

　Compound used in the oxidation reaction (Ib-b) can be synthesized according to the method of manufacturing the above.

[0238]

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

[0239]

　The amount of the oxidizing agent in the oxidation reaction is preferably 0.5 to 50 mol per 1 mol of compound (Ib-b), more preferably 0.8 to 35 mol.

[0240]

　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.

[0241]

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

[0242]

　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.

[0243]

(Step 28)
　Compound (VB) is the presence of a base, obtained by condensation reaction of the compound (XII) with the compound (IIIB).

[0244]

　Compound used in the condensation reaction (XII) and the compound (IIIB) is may be used as it is commercially available, for example, can be synthesized according to the above manufacturing method.

[0245]

　The base used in the condensation reaction, for example, lithium diisopropylamide, potassium tert- butoxide, sodium hydride, phenyl lithium or tert- butyl lithium.

[0246]

　The amount of the base used in the condensation reaction is preferably 0.5 to 10 moles relative to 1 mole of compound (IIIB), and more preferably 0.8 to 5 mol.

[0247]

　The amount of compound in the condensation reaction (XII) is preferably from 0.5 to 3 moles per 1 mole of compound (IIIB), and more preferably 0.8 to 1.5 mol.

[0248]

　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, such as dichloromethane, halogenated hydrocarbons such as chloroform or 1,2-dichloroethane; or tetrahydrofuran or 1,4-dioxane and the like can be mentioned. A mixed solvent thereof may be used.

[0249]

　The reaction temperature in the condensation reaction is preferably from -78 ° C. ~ 100 ° C., more preferably -78 ℃ ~ 50 ℃.

[0250]

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

[0251]

(Step 29)
　Compound (VB) is obtained by amidation reaction of the compound (XVI) and Compound (IIb-a).

[0252]

　Compounds used in the amidation reaction (XVI) and Compound (IIb-a), which can be used as it is a commercial product, for example, can be synthesized according to the above manufacturing method.

[0253]

　The amount of the compound in the amidation reaction (IIb-a) is preferably from 0.5 to 3 moles per 1 mole of the compound (XVI), more preferably 0.8 to 1.5 mol.

[0254]

　Amidation 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.

[0255]

　The reaction temperature in the amidation reaction is preferably -20 ° C. ~ 200 ° C., and more preferably 0 ~ 0.99 ° C..

[0256]

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

[0257]

[0299]

　Compounds used in the reductive amination reaction (VIC) and compound (XVII) may be used as a commercial product.

[0300]

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

[0301]

(Step 36)
　Compound (IIc-a) is obtained by deprotection of compound (VIIIC).

[0302]

　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, Inc.) or according to a method analogous thereto it can be carried out.

[0303]

(Step 37)
　Compound (IIIC) is obtained by acetylation of the compound (IIc-a).

[0304]

　Acetylation reaction, a known method (e.g., Greene, T. W., "Greene's Protective Groups in Organic Synthesis", Wiley-Interscience, Inc.) can be carried out according or a method analogous thereto.

[0305]

10. Preparation of the compounds (VC):
[Formula 19]

wherein each symbol has the same meaning as defined above. ]

[0306]

(Step 38)
　Compound (VC) is obtained by the oxidation reaction of the compound (Ic-b).

[0307]

　Compound used in the oxidation reaction (Ic-b) can be synthesized according to the method of manufacturing the above.

[0308]

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

[0309]

　The amount of the oxidizing agent in the oxidation reaction is preferably 0.5 to 50 mol per 1 mol of compound (Ic-b), more preferably 0.8 to 35 mol.

[0310]

　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.

[0311]

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

[0312]

　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.

[0313]

(Step 39)
　Compound (VC) is the presence of a base, obtained by condensation reaction of the compound (XII) with the compound (IIIC).

[0314]

　Compound used in the condensation reaction (XII) and the compound (IIIC) can be used in an as commercially available products, for example, it can be synthesized according to the above manufacturing method.

[0315]

　The base used in the condensation reaction, for example, lithium diisopropylamide, potassium tert- butoxide, sodium hydride, phenyl lithium or tert- butyl lithium.

[0316]

　The amount of the base used in the condensation reaction is preferably 0.5 to 10 moles relative to 1 mole of compound (IIIC), and more preferably 0.8 to 5 mol.

[0317]

　The amount of compound in the condensation reaction (XII) is preferably from 0.5 to 3 moles per 1 mole of the compound (IIIC), and more preferably 0.8 to 1.5 mol.

　38] 1- (4- (dimethylamino) piperidin-1-yl) ethanone (0.310 g, 1.82 mmol) in tetrahydrofuran (6.0 mL) in tetrahydrofuran solution of lithium diisopropylamide solution (2.0 M, 2. 19 mL, and 4.37 mmol) was added dropwise at -78 ° C., and stirred for 1 hour at the same temperature. Ethyl reaction at the same temperature 1- (difluoromethyl)-1H-imidazole-2-carboxylate (0.415 g, 2.19 mmol) in tetrahydrofuran (3.0 mL) was added, after stirring for 1 hour, at 0 ℃ and the mixture was stirred for a further 1 hour. The reaction solution, a saturated aqueous ammonium chloride solution was added potassium carbonate aqueous solution sequentially, and 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 flash column chromatography (NH silica gel, hexane / ethyl acetate), 1- (1- (difluoromethyl)-1H-imidazol-2-yl) -3- (4- (dimethylamino) piperidine -1 - yl) propane-1,3-dione (0.311 g, 0.989 mmol, 54%) as a yellow oil.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.38-1.58 (2H, m), 1.80-1.94 (2H, m), 2.05 (6H, s), 2.31-2.42 (IH, m), 2.63-2.72 (1H, m), 3.08-3.18 ( 1H, m), 3.79-3.86 (1H, m), 4.22 (2H, dd, J = 15.6, 24.6 Hz), 4.55-4.62 (1H, m), 7.27 (1H , s), 7.55 (IH, s), 8.08 (IH, t, J = 60.8 Hz).
ESI-MS: m / z = 315 (M + H) + .

[0388]

(Example 1) 1- (4- (ethylmethylamino) piperidin-1-yl) -3-hydroxy-3- (1-methyl -1H- imidazol-2-yl) propan-1-one Synthesis of:
[ of

　39] 1- (4- (ethylmethylamino) piperidin-1-yl) -3- (1-methyl -1H- imidazol-2-yl) propane-1,3-dione (0.160 g, 0.547 mmol in methanol (2.7 mL) solution of), sodium borohydride (0.0220g, 0.582mmol) was added at room temperature, the reaction mixture was stirred for 3 hours at the same temperature. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue of distilled water was added, followed by extraction 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 flash column chromatography (NH silica gel, chloroform / methanol), 1- (4- (ethylmethylamino) piperidin-1-yl) -3-hydroxy-3- (1-methyl -1H- imidazole - 2-yl) propan-1-one (0.0699g, 0.237mmol, 43%) ( hereinafter, to give the compound) example 1 as a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.02-1.10 (3H, m), 1.35-1.58 (2H, m), 1.78 - 1.88 (2H, m), 2.23-2.25 (3H, m), 2.56 -2.67 (4H, m), 2.98-3.09 (2H, m), 3.13-3.23 (1H, m), 3.77 (3H, s), 4.00-4.10 (1H, m), 4.60-4.74 (2H, m) , 5.18-5.25 (IH, m), 6.85-6.87 (IH, m), 6.92-6.94 (IH, m).
ESI-MS: m / z = 295 (M + H) + .

[0389]

(Example 2) 1- (4- (diethylamino) piperidin-1-yl) -3-hydroxy-3- (1-methyl -1H- imidazol-2-yl) propan-1-one Synthesis of:
[Formula 40 ]

　1- (4- (diethylamino) piperidin-1-yl) -3- (1-methyl -1H- imidazol-2-yl) propane-1,3-dione (0.0800g, 0.261mmol) in methanol ( in 1.3 mL) solution, sodium borohydride (0.0109g, 0.287mmol) was added at room temperature, the reaction mixture was stirred for 3 hours at the same temperature. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue of distilled water was added, followed by extraction 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 flash column chromatography (NH silica gel, chloroform / methanol), 1- (4- (diethylamino) piperidin-1-yl) -3-hydroxy-3- (1-methyl -1H- imidazol-2 yl) propan-1-one (0.0561g, 0.182mmol, 70%) ( hereinafter, to give the compound) example 2 as a colorless oil.
1 H-NMR (400 MHz, DMSO-d 6 ) [delta]: 0.94 (6H, t, J = 6.8 Hz), 1.05-1.75 (5H, m), 2.42-3.10 (8H, m), 3.64 (3H, s ), 3.93-4.02 (1H, m) , 4.32-4.43 (1H, m), 5.00-5.08 (1H, m), 5.34-5.42 (1H, m), 6.69-6.71 (1H, m), 7.01-7.03 (IH, m).
ESI-MS: m / z = 309 (M + H) + .

[0390]

(Example 3) 3-hydroxy-3- (1-methyl -1H- imidazol-2-yl) -1- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) propan-1 one synthesis of:
Formula

　41] 1- (1-methyl -1H- imidazol-2-yl) -3- (4- (4-methylpiperazin-1-yl) piperidin-1-yl) propane-1,3 - dione (0.290 g, 0.870 mmol) in methanol (4.4 mL) was added sodium borohydride (0.0360g, 0.957mmol) was added at room temperature, the reaction mixture was stirred for 3 hours at the same temperature. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue of distilled water was added, followed by extraction 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 flash column chromatography (NH silica gel, chloroform / methanol) to 3-hydroxy-3- (1-methyl -1H- imidazol-2-yl) -1- (4- (4-methylpiperazin -1 - yl) piperidin-1-yl) propan-1-one (0.140g, 0.417mmol, 48%) ( hereinafter, to give the compound) of example 3 as a colorless oil.
1 H-NMR (400 MHz, DMSO-d 6 ) [delta]: 1.45-1.66 (4H, m), 1.87-1.95 (2H, m), 2.26-2.30 (3H, s), 2.38-2.70 (8H, m) , 2.98-3.23 (3H, m), 3.77 (3H, s), 4.00-4.10 (1H, m), 4.60-4.70 (2H, m), 5.17-5.25 (1H, m), 6.85-6.88 (1H, m), 6.92-6.95 (IH, m).
ESI-MS: m / z = 336 (M + H) + .

[0391]

(Example 4) 1 - ((R) -3- (3- (dimethylamino) piperidin-1-yl) -3-hydroxy-3- (1-methyl -1H- imidazol-2-yl) propane-1,3 - one synthesis of:
[Formula

　42] (R) -1- (3- (dimethylamino) piperidin-1-yl) -3- (1-methyl -1H- imidazol-2-yl) propane-1,3 dione (0.140 g, 0.503 mmol) in ethanol (2.5 mL) was added sodium borohydride (0.0210g, 0.553mmol) was added at room temperature, the reaction mixture was stirred for 3 hours at the same temperature. the reaction liquid was added a saturated aqueous sodium hydrogen carbonate solution, and concentrated under reduced pressure. the residue in distilled water was added, washed and extracted with chloroform. the organic layer was with 10% aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, . Solution was concentrated under reduced pressure The residue was purified by flash column chromatography (NH silica gel, chloroform / methanol), 1 - ((R) -3- (3- ( dimethylamino) piperidin-1-yl) -3-hydroxy 3- (1-methyl -1H- imidazol-2-yl) propan-1-one (0.120 g, 0.428 mmol, 85%) was obtained (hereinafter, the compound of example 4) as a colorless oil.
1 H-NMR (400 MHz, DMSO-d 6 ) [delta]: 1.33-1.43 (IH, m), 1.57-1.90 (IH, m), 2.14-2.24 (6H, m), 2.45-2.54 (4H, m) , 2.75-3.06 (3H, m), 3.63-4.40 (5H, m), 4.99-5.08 (1H, m), 5.32-5.42 (1H, m), 6.70-6.73 (1H, m), 7.01-7.03 ( IH, m).
ESI-MS: m / z = 281 (M + H) + .

[0392]

(Example 5) 1 - ((R) -3- (dimethylamino) pyrrolidin-1-yl) -3-hydroxy-3- (1-methyl -1H- imidazol-2-yl) propan-1-one synthesis:
[of

　43] (R) -1- (3- (dimethylamino) pyrrolidin-1-yl) -3- (1-methyl -1H- imidazol-2-yl) propane-1,3-dione (0 .220G, in ethanol (4.2 mL) solution of 0.832 mmol), sodium borohydride (0.0350g, 0.916mmol) was added at room temperature, the reaction mixture was stirred for 3 hours at the same temperature. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue of distilled water was added, followed by extraction 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 flash column chromatography (silica gel, chloroform / methanol) to, 1 - ((R) -3- (dimethylamino) pyrrolidin-1-yl) -3-hydroxy-3- (1-methyl -1H- imidazol-2-yl) propan-1-one (0.209g, 0.785mmol, 94%) ( hereinafter, to give the compound) of example 5 as a colorless oil.
1 H-NMR (400 MHz, DMSO-d 6 ) [delta]: 1.50-1.78 (IH, m), 1.93-2.18 (7H, m), 2.60-2.95 (3H, m), 3.05-3.80 (7H, m) , 4.98-5.07 (IH, m), 5.38-5.43 (IH, m), 6.71-6.73 (IH, m), 7.02-7.04 (IH, m).
ESI-MS: m / z = 267 (M + H ) + .

[0393]

(Example 6) 1- (4- (dimethylamino) piperidin-1-yl) -3-hydroxy-3- (1-methyl -1H- imidazol-2-yl) propan-1-one Synthesis of:
Formula

　44] 1- (4- (dimethylamino) piperidin-1-yl) ethanone (0.0500 g, 0.294 mmol) in tetrahydrofuran (0.8 mL) in tetrahydrofuran solution of lithium diisopropylamide solution (2.0 M, 0.162 mL It was added dropwise 0.323 mmol) at -78 ° C., and stirred for 1 hour at the same temperature. To the reaction solution at the same temperature 1-methyl -1H- imidazole-2-carbaldehyde (0.0390g, 0.352mmol) in tetrahydrofuran (0.4 mL) was added, after stirring for 1 hour, further stirring for 1 h at 0 ℃ did. The reaction solution, a saturated aqueous ammonium chloride solution was added potassium carbonate aqueous solution sequentially, and 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 flash column chromatography (silica gel, chloroform / methanol) to 1- (4- (dimethylamino) piperidin-1-yl) -3-hydroxy-3- (1-methyl -1H- imidazol-2 yl) propan-1-one (0.0220g, 0.0785mmol, 27%) as a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.32-1.53 (2H, m), 1.82-1.92 (2H, m), 2.27-2.41 (7H, m), 2.60-2.72 (IH, m), 2.98 -3.23 (3H, m), 3.77 (3H, s), 3.99-4.08 (1H, m), 4.58-4.82 (2H, m), 5.18-5.26 (1H, m), 6.86 (1H, s), 6.93 (IH, s).
ESI-MS: m / z = 281 (M + H) + .

[0394]

(Example 7) Synthesis of 1 (4- (dimethylamino) piperidin-1-yl) -3-hydroxy-3- (1-methyl -1H- imidazol-2-yl) propan-1-one hydrochloride
[ of

　45] 1- (4- (dimethylamino) piperidin-1-yl) -3-hydroxy-3- (1-methyl -1H- imidazol-2-yl) propan-1-one (0.0220g, 0. in water (0.156 mL) solution of 0785mmol), added hydrochloric acid (1.0N, 0.086mL, 0.086mmol) at 0 ° C., the reaction mixture was stirred for 15 hours at room temperature. The reaction mixture was concentrated under reduced pressure, dried at room temperature, 1- (4- (dimethylamino) piperidin-1-yl) -3-hydroxy-3- (1-methyl -1H- imidazol-2-yl) propane - 1-one hydrochloride (0.0220g, 0.0623mmol, 79%) ( hereinafter, the compound of example 7) was obtained as a white solid.
1 H-NMR (400 MHz, D 2 O) [delta]: 1,40-1.70 (2H, m), 1.98-2.10 (2H, m), 2.55-2.68 (IH, m), 2.72-2.77 (7H, m ), 2.95-3.13 (3H, m) , 3.36-3.45 (1H, m), 3.76 (3H, s), 3.97-4.06 (1H, m), 4.38-4.48 (1H, m), 6.40-6.47 (1H , m), 7.24-7.28 (2H, m).
ESI-MS: m / z = 281 (M + H) + .

[0395]

(Example 8) 1- (4- (dimethylamino) piperidin-1-yl) -3- (1-ethyl -1H- imidazol-2-yl) -3-hydroxy-1-one Synthesis of:
Formula

　46] 1- (4- (dimethylamino) piperidin-1-yl) ethanone (0.300 g, 1.76 mmol) in tetrahydrofuran (6.0 mL) in tetrahydrofuran solution of lithium diisopropylamide solution (2.0M, 0.969mL , it was added dropwise 1.94 mmol) at -78 ° C., and stirred for 1 hour at the same temperature. To the reaction solution at the same temperature 1-ethyl--1H- imidazole-2-carbaldehyde (0.262 g, 2.12 mmol) in tetrahydrofuran (2.8 mL) was added, after stirring for 1 hour, further stirring for 1 h at 0 ℃ did. The reaction solution, a saturated aqueous ammonium chloride solution was added potassium carbonate aqueous solution sequentially, and 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 flash column chromatography (NH silica gel, chloroform / methanol), 1- (4- (dimethylamino) piperidin-1-yl) -3- (1-ethyl -1H- imidazol-2-yl) - 3-hydroxy-1-one (0.221g, 0.751mmol, 43%) was obtained (hereinafter, the compound of example 8) as a colorless oil.
1 H-NMR (400 MHz, DMSO-d 6 ) [delta]: 1.04-1.21 (IH, m), 1.32 (4H, t, J = 7.2 Hz), 1.62-1.80 (2H, m), 2.15 (6H, s ), 2.24-2.35 (1H, m) , 2.42-2.59 (1H, m), 2.76-2.88 (1H, m), 2.95-3.13 (2H, m), 3.90-4.08 (3H, m), 4.27-4.35 (IH, m), 5.00-5.10 (IH, m), 5.38-5.42 (IH, m), 6.74 (IH, s), 7.10 (s, IH).
ESI-MS: m / z = 295 (M + H) Tasu .

[0396]

(Example 9) 1- (4- (dimethylamino) piperidin-1-yl) -3-hydroxy-3- (1- (2,2,2-trifluoroethyl) -1H- imidazol-2-yl) propan-1-one synthesis of:
Formula

　47] 1- (4- (dimethylamino) piperidin-1-yl) ethanone (0.267 g, 1.57 mmol) in tetrahydrofuran (6.0 mL) was added lithium diisopropylamide tetrahydrofuran was added dropwise with (2.0M, 0.862mL, 1.72mmol) to -78 ° C., and stirred for 1 hour at the same temperature. The reaction solution at the same temperature 1- (2,2,2-trifluoroethyl) -1H- imidazole-2-carbaldehyde (0.335 g, 1.88 mmol) in tetrahydrofuran (1.9 mL) added, 1 hour after stirring, and stirred for another hour at 0 ° C.. The reaction solution, a saturated aqueous ammonium chloride solution was added potassium carbonate aqueous solution sequentially, and 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 flash column chromatography (NH silica gel, chloroform / methanol), 1- (4- (dimethylamino) piperidin-1-yl) -3-hydroxy-3- (1- (2,2,2 trifluoroethyl)-1H-imidazol-2-yl) propan-1-one (0.192g, 0.551mmol, 35%) ( hereinafter, to give the compound) of example 9 as a colorless oil.
1 H-NMR (400 MHz, DMSO-d 6 ) [delta]: 1.10-1.41 (2H, m), 1.64-1.80 (2H, m), 2.16 (6H, s), 2.25-2.37 (IH, m), 2.47 -2.60 (1H, m), 2.80-3.12 (3H, m), 3.90-4.00 (1H, m), 4.29-4.39 (1H, m), 5.00-5.18 (3H, m), 5.60-5.68 (1H, m), 6.85 (IH, s), 7.17 (s, IH).
ESI-MS: m / z = 349 (M + H) + .

[0397]

(Example 10) 3- (1- (difluoromethyl)-1H-imidazol-2-yl) -1- (4- (dimethylamino) piperidin-1-yl) -3-hydroxy-1-one Synthesis of :
Formula

　48] 1- (1- (difluoromethyl)-1H-imidazol-2-yl) -3- (4- (dimethylamino) piperidin-1-yl) propane-1,3-dione (0.310 g , methanol (10 mL) solution of 0.986Mmol), sodium borohydride (0.0560g, 1.48mmol) was added at room temperature, the reaction mixture was stirred for 3 hours at the same temperature. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The residue of distilled water was added, followed by extraction 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 flash column chromatography (NH silica gel, chloroform / methanol), 3- (1- (difluoromethyl)-1H-imidazol-2-yl) -1- (4- (dimethylamino) piperidin-1 yl) -3-hydroxy-1-one (0.202g, 0.639mmol, 65%) ( hereinafter, the compound) of example 10 was obtained as a yellow oil.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.08-1.40 (2H, m), 1.64-1.80 (2H, m), 2.17 (6H, s), 2.25-2.35 (IH, m), 2.49-2.62 (1H, m), 2.80-3.12 ( 3H, m), 3.88-3.97 (1H, m), 4.28-4.37 (1H, m), 5.18-5.26 (1H, m), 5.83 (1H, d, J = Hz 6.8), 6.95 (IH, s), 7.51 (IH, s), 7.93 (IH, t, J = 60.0 Hz).
ESI-MS: m / z = 317 (M + H) + .

[0398]

(Example 11) (S) -1- (4-(dimethylamino) piperidin-1-yl) -3-hydroxy-3- (1-methyl -1H- imidazol-2-yl) propan-1-one synthesis:
[of

　49] 1- (4- (dimethylamino) piperidin-1-yl) -3-hydroxy-3- (1-methyl -1H- imidazol-2-yl) propan-1-one (3.32 g ) was optically resolved by HPLC purification the eluate was concentrated under reduced pressure. The residue was purified by flash column chromatography (NH silica gel, chloroform / methanol), (S) -1- (4-(dimethylamino) piperidin-1-yl) -3-hydroxy-3- (1-methyl -1H - imidazol-2-yl) propan-1-one (0.467g,> 99% ee) ( hereinafter, to give the compound) of example 11 as a white solid.
HPLC retention time: 8.4Min, Equipment: Shimadzu Corporation LC-10ADvp system, column: CHIRALCEL OZ-H, 4.6 × 250mm ( Ltd. Daicel), solvent: 0.01% ethylenediamine in methanol (v / v), flow rate: 0.5 mL / min, detection method: UV 220 nm, column temperature: 40 ° C..
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.32-1.53 (2H, m), 1.82-1.92 (2H, m), 2.27-2.41 (7H, m), 2.60-2.72 (IH, m), 2.98 -3.23 (3H, m), 3.77 (3H, s), 3.99-4.08 (1H, m), 4.58-4.82 (2H, m), 5.18-5.26 (1H, m), 6.86 (1H, s), 6.93 (IH, s).
ESI-MS: m / z = 281 (M + H) + .

[0399]

(Example 12) 3- (4- (dimethylamino) piperidin-1-yl) -1- (1-methyl -1H- imidazol-2-yl) -3-oxopropyl acetate:
Formula

　50] 1 - (4- (dimethylamino) piperidin-1-yl) -3-hydroxy-3- (1-methyl -1H- imidazol-2-yl) propan-1-one (0.120 g, 0.428 mmol) in dichloromethane to (2.1 mL) solution, pyridine (0.042 mL, 0.51 mmol), was added acetic anhydride (0.042 mL, 0.51 mmol) at 0 ° C., the reaction was stirred for 2 hours at room temperature. Furthermore, addition of acetic anhydride (0.020 mL, 0.24 mmol) at room temperature, the reaction mixture was stirred at the same temperature for 1 hour. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and 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 flash column chromatography (NH silica gel, chloroform / methanol), 3- (4- (dimethylamino) piperidin-1-yl) -1- (1-methyl -1H- imidazol-2-yl) - 3-oxopropyl acetate (0.114 g, 0.353 mmol, 82%) was obtained (hereinafter, the compound of example 12) as a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.08-1.47 (2H, m), 1.68-1.92 (2H, m), 2.04 (3H, dd, J = 2.4 Hz), 2.21-2.38 (7H, m ), 2.47-2.60 (1H, m) , 2.96-3.14 (2H, m), 3.35-3.43 (1H, m), 3.83 (3H, d, J = 4.0 Hz), 3.89-4.00 (1H, m), 4.45-4.53 (IH, m), 6.21-6.29 (IH, m), 6.79 (IH, m), 6.98 (IH, m).
ESI-MS: m / z = 323 (M + H) + .

[0400]

(Example 13) 3- (4- (dimethylamino) piperidin-1-yl) -1- (1-methyl -1H- imidazol-2-yl) -3-oxopropyl pentanoate:
[Formula

　51] 1 - in dichloromethane (4- (dimethylamino) piperidin-1-yl) -3-hydroxy-3- (1-methyl -1H- imidazol-2-yl) propan-1-one (0.200g, 0.713mmol) to (3.5 mL) solution, pyridine (0.069 mL, 0.86 mmol), pentanoyl chloride (0.093 mL, 0.79 mmol) was added at room temperature, the reaction mixture was stirred for 16 hours at the same temperature. Saturated ammonium chloride solution was added to the reaction solution, and 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 flash column chromatography (NH silica gel, chloroform / methanol), 3- (4- (dimethylamino) piperidin-1-yl) -1- (1-methyl -1H- imidazol-2-yl) - 3-oxopropyl pentanoate (0.101 g, 0.277 mmol, 39%) was obtained (hereinafter, the compound of example 13) as a colorless oil.
1 H-NMR (400 MHz, DMSO-d 6 ) [delta]: 0.77-0.85 (3H, m), 0.98-1.33 (4H, m), 1.41-1.50 (2H, m), 1.60-1.79 (2H, m) , 2.11-2.15 (6H, m), 2.20-2.33 (3H, m), 2.89-3.02 (2H, m), 3.22-3.34 (2H, m), 3.65 (3H, s), 3.84-3.92 (1H, m), 4.18-4.26 (IH, m), 6.10-6.15 (IH, m), 6.77-6.82 (IH, m), 7.05-7.10 (IH, m).
ESI-MS: m / z = 365 (M H Tasu) Tasu .

[0401]

　In the following comparative examples, 1- (4- (dimethylamino) piperidin-1-yl) -3- (1-methyl -1H- imidazol-2-yl) propan-1-one hydrochloride (the compound of Comparative Example 1 ), 1- (4- (dimethylamino) piperidin-1-yl) -3- (1-methyl -1H- imidazol-2-yl) propan-1-one sulfate monohydrate (compound of Comparative example 2 ), 1- (4- (dimethylamino) piperidin-1-yl) -3- (1-ethyl -1H- imidazol-2-yl) propan-1-one hydrochloride (the compound of Comparative example 3), 1- (4- (dimethylamino) piperidin-1-yl) -3- (1-propyl -1H- imidazol-2-yl) propan-1-one hydrochloride (the compound of Comparative example 4), 1- (4- ( dimethylamino) piperidin-1-yl) 3- (1-butyl -1H- imidazol-2-yl) (Compound of Comparative Example 5) propan-1-one hydrochloride and 1- (4- (dimethylamino) piperidin-1-yl) -3- (1 - isopropyl -1H- imidazol-2-yl) propan-1-one hydrochloride (compound of Comparative example 6), imidazole derivatives described in WO 2013/147160 (Patent Document 4), suitable comparative compounds It was selected as.

[0402]

　For the compound of Comparative Examples 1-6, similarly as described WO 2013/147160 (Patent Document 4), it was prepared in the following manner.

[0403]

(Reference Example 18) 1-propyl -1H- synthesis of imidazole:
Formula 52]

　imidazole (1.37 g, 20.1 mmol) in tetrahydrofuran (50.0 mL) was added sodium hydride (55%, 0.966 g, 22.1 mmol) was added at room temperature. The reaction was stirred 1 hour at the same temperature, 1-bromopropane (5.48mL, 60.3mmol) was added at room temperature. The reaction mixture was subjected to 16 hours of stirring at the same temperature. The reaction mixture was filtered through celite, washed with tetrahydrofuran, the filtrate and washings were concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, chloroform / methanol) to give 1-propyl-imidazole (2.07 g, 18.8 mmol, 93%) as a colorless oil.
1H-NMR (400 MHz, CDCl3 ) δ: 0.93 (3H, t, J = 7.2 Hz), 1.81 (2H, td, J = 7.2, 14.4 Hz), 3.90 (2H, t, J = 7.2 Hz), 6.91 (1H, s), 7.06 ( 1H, s), 7.46 (1H, s).

[0404]

Synthesis of (Reference Example 19) 1-propyl -1H- imidazole-2-carbaldehyde:
[Chem

　53] 1-propyl -1H- imidazole (1.67 g, 15.2 mmol) in tetrahydrofuran (30.4 mL) solution of It was cooled to -78 ℃. The reaction mixture n- butyllithium (1.62M n- hexane solution, 10.3 mL, 16.7 mmol) was added at -78 ° C.. After stirring for 1 hour at the reaction the same temperature was added N, N- dimethylformamide (1.41 mL, 18.2 mmol) at -78 ° C.. After stirring for 1 hour the reaction solution at the same temperature, and the temperature was raised to room temperature. After addition of saturated aqueous ammonium chloride solution, ethyl acetate was added. 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 flash column chromatography (silica gel, n- hexane / ethyl acetate) to give 1-propyl -1H- imidazole-2-carbaldehyde (0.492 g, 3.56 mmol, 24%) as a colorless oil It was.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 0.91-0.95 (3H, m), 1.79-1.84 (2H, m), 4.34-4.38 (2H, m), 7.15 (IH, s), 7.28 (IH , s), 9.82 (IH, s).
ESI-MS: m / z = 139 (M + H) + .

[0405]

Synthesis of (Reference Example 20) 1-butyl -1H- imidazole-2-carbaldehyde:
[Chem

　54] 1-butyl -1H- imidazole (1.00 g, 8.05 mmol) in tetrahydrofuran (16.1 mL) solution of It was cooled to -78 ℃. The reaction mixture n- butyllithium (1.62M n- hexane solution, 5.5 mL, 8.86 mmol) was added at -78 ° C.. After stirring for 1 hour at the reaction the same temperature was added N, N- dimethylformamide (0.75 mL, 9.66 mmol) at -78 ° C.. After stirring for 1 hour the reaction solution at the same temperature, and the temperature was raised to room temperature. After addition of saturated aqueous ammonium chloride solution, ethyl acetate was added. 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 flash column chromatography (silica gel, n- hexane / ethyl acetate) to give 1-butyl -1H- imidazole-2-carbaldehyde (1.02 g, 6.70 mmol, 83%) as a colorless oil It was.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 0.95 (3H, t, J = 7.2 Hz), 1.33 (2H, td, J = 7.2, 14.8 Hz), 1.75-1.78 (2H, m), 4.34 ( 2H, t, J = 7.2 Hz), 7.15 (IH, s), 7.28 (IH, s), 9.81 (IH, s).
ESI-MS: m / z = 153 (M + H) + .

[0406]

Synthesis of (Reference Example 21) 1-isopropyl -1H- imidazole-2-carbaldehyde:
[Chem

　55] 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 was cooled to room temperature, it was added ethyl acetate and distilled water to the reaction mixture. 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 flash column chromatography (silica gel, n- hexane / ethyl acetate) to give 1-isopropyl -1H- imidazole-2-carbaldehyde (0.355 g, 2.57 mmol, 49%) as a colorless oil It was.
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) + .

[0407]

(Reference Example 22) (E) - Synthesis of methyl 3- (1-methyl -1H- imidazol-2-yl) acrylate:
[Chem

　56] 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 a mixed solvent of hexane / dichloromethane = 19/1, was concentrated cleaning solution. The residue was purified by silica gel column chromatography (hexane / ethyl acetate), (E) - to give methyl 3- (1-methyl -1H- imidazol-2-yl) acrylate as a white solid (11.9 g, 71. 6mmol, 79%).
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) + .

[0408]

(Reference Example 23) (E) - Synthesis of methyl 3- (1-ethyl -1H- imidazol-2-yl) acrylate:
[Chem

　57] l-ethyl -1H- imidazole-2-carbaldehyde (1.17 g, in dichloromethane (28.3 ml) solution of 9.42 mmol), methyl (triphenylphosphoranylidene) acetate (3.15 g, 9.42 mmol) was added at room temperature, after stirring for 16 h, and concentrated under reduced pressure. The residue was washed with a mixed solvent of hexane / dichloromethane = 20/1, was concentrated cleaning solution. The residue was purified by flash column chromatography (silica gel, hexane / ethyl acetate), (E) - to give methyl 3- (1-ethyl -1H- imidazol-2-yl) acrylate as a white solid (0.670 g, 3.72mmol, 39%).
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.45 (3H, t, J = 7.6 Hz), 3.81 (3H, s), 4.10 (2H, dd, J = 7.6, 14.8 Hz), 6.85 (IH, d, J = 15.2 Hz), 7.03 (IH, brs), 7.17 (IH, brs), 7.52 (IH, d, J = 15.2 Hz).
ESI-MS: m / z = 181 (M + H) + .

[0409]

(Reference Example 24) (E) - Synthesis of methyl 3- (1-propyl -1H- imidazol-2-yl) acrylate:
[Chem

　58] 1-propyl -1H- imidazole-2-carbaldehyde (0.492 g, in dichloromethane (10.0 mL) solution of 3.56 mmol), methyl (triphenylphosphoranylidene) acetate (1.31 g, 3.92 mmol) was added at room temperature, after stirring for 16 h, and concentrated under reduced pressure. The residue was washed with a mixed solvent of hexane / dichloromethane = 19/1, was concentrated cleaning solution. The residue was purified by flash column chromatography (silica gel, hexane / ethyl acetate), (E) - to give methyl 3- (1-propyl -1H- imidazol-2-yl) acrylate as a white solid (0.520 g, 2.68mmol, 75%).
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 0.94 (3H, t, J = 7.2 Hz), 1.75-1.85 (2H, m), 3.81 (3H, s), 4.00 (2H, t, J = 7.2 Hz), 6.85 (IH, d, J = 15.6 Hz), 7.00 (IH, brs), 7.16 (IH, brs), 7.50 (IH, d, J = 15.6 Hz).
ESI-MS: m / z = 195 (M Tasu H) Tasu .

[0410]

(Reference Example 25) (E) - Synthesis of methyl 3- (1-butyl -1H- imidazol-2-yl) acrylate:
[Chem

　59] 1-butyl -1H- imidazole-2-carbaldehyde (1.02 g, in dichloromethane (18.0 mL) solution of 6.70 mmol), methyl (triphenylphosphoranylidene) acetate (2.47 g, 7.37 mmol) was added at room temperature, after stirring for 16 h, and concentrated under reduced pressure. The residue was washed with a mixed solvent of hexane / dichloromethane = 19/1, was concentrated cleaning solution. The residue and the residue was purified by flash column chromatography (silica gel, hexane / ethyl acetate), (E) - to give methyl 3- (1-butyl -1H- imidazol-2-yl) acrylate as a white solid (1. 23g, 5.91mmol, 88%).
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 0.95 (3H, t, J = 7.2 Hz), 1.28-1.40 (2H, m), 1.70-1.80 (2H, m), 3.81 (3H, s), 4.03 (2H, t, J = 7.2 Hz), 6.84 (1H, d, J = 15.2 Hz), 7.00 (1H, brs), 7.16 (1H, brs), 7.50 (1H, d, J = 15.2 Hz).
MS-ESI: M / Z = 209 (M Tasu H) Tasu .

[0411]

(Reference Example 26) (E) - Synthesis of methyl 3- (l-isopropyl -1H- imidazol-2-yl) acrylate:
[Chem

　60] l-isopropyl -1H- imidazole-2-carbaldehyde (0.350Mg, in dichloromethane (7.59ML) 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 a mixed solvent of hexane / dichloromethane = 20/1, was concentrated cleaning solution. The residue was purified by flash column chromatography (silica gel, hexane / ethyl acetate), (E) - to give methyl 3- (l-isopropyl -1H- imidazol-2-yl) acrylate as a white solid (0.362 g, 1.86mmol, 74%).
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 .

[0412]

(Reference Example 27) 1- (4- (dimethylamino) piperidin-1-yl) -3- (1-methyl -1H- imidazol-2-yl) propan-1-one Synthesis of:
[Formula

　61] (E ) - room temperature carbon (10% wet, 15 mg) - methyl 3- (1-methyl -1H- imidazol-2-yl) acrylate (0.180 g, in ethanol (4.0 mL) solution of 1.08 mmol), palladium in addition, 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 and concentrated under reduced pressure. The obtained residue chloroform (10.0 mL) was added at room temperature to dissolve. Diisopropylethylamine to the reaction solution (0.568mL, 3.25mmol), HBTU ( 0.616g, 1.63mmol) and 4- (dimethylamino) piperidine (0.125g, 0.975mmol) was added at room temperature, the reaction mixture It 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 flash column chromatography (NH silica gel, chloroform / methanol), 1- (4- (dimethylamino) piperidin-1-yl) -3- (1-methyl -1H- imidazol-2-yl) propane 1-one (0.179g, 0.68mmol, 63%) as a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.29-1.43 (2H, m), 1.80-1.88 (2H, m), 2.27 (6H, s), 2.29-2.38 (IH, m), 2.54-2.63 (1H, m), 2.88-3.04 ( 5H, m), 3.62 (3H, s), 3.98-4.05 (1H, m), 4.57-4.65 (1H, m), 6.79 (1H, d, J = 1.2 Hz ), 6.91 (IH, d, J = 1.2 Hz).
ESI-MS: m / z = 265 (M + H) + .

[0413]

(Reference Example 28) 1- (4- (dimethylamino) piperidin-1-yl) -3- (1-ethyl -1H- imidazol-2-yl) propan-1-one Synthesis of:
[Formula

　62] (E ) - room temperature carbon (10% wet, 65 mg) - methyl 3- (1-ethyl -1H- imidazol-2-yl) acrylate (0.670 g, in methanol (14.8 mL) solution of 3.71 mmol), palladium in addition, 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 (3.70 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 and concentrated under reduced pressure. The obtained residue chloroform (37.0mL) was added at room temperature to dissolve. Diisopropylethylamine to the reaction mixture (1.94 mL, 11.1 mmol), HBTU (2.10 g, 5.54 mmol) and 4- (dimethylamino) piperidine (0.427 g, 3.33 mmol) was added at room temperature, the reaction mixture It 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 flash column chromatography (NH silica gel, chloroform / methanol), 1- (4- (dimethylamino) piperidin-1-yl) -3- (1-ethyl -1H- imidazol-2-yl) propane 1-one (0.365g, 1.31mmol, 35%) as a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.32-1.40 (5H, m), 1.83-1.87 (2H, m), 2.27 (6H, s), 2.31-2.37 (IH, m), 2.56-2.63 (1H, m), 2.93-2.98 ( 5H, m), 3.93-4.04 (3H, m), 4.01-4.04 (1H, m), 6.84 (1H, d, J = 1.6 Hz), 6.94 (1H, d , J = 1.6 Hz).
ESI-MS: m / z = 279 (M + H) + .

[0414]

(Reference Example 29) 1- (4- (dimethylamino) piperidin-1-yl) -3- (1-propyl -1H- imidazol-2-yl) propan-1-one Synthesis of:
[Formula

　63] (E ) - methyl 3- (1-propyl -1H- imidazol-2-yl) acrylate (260 mg, in methanol (5.0 mL) solution of 1.34 mmol), palladium - added carbon (10% wet, 19 mg) at room temperature under a hydrogen atmosphere, after stirring for 4 hours, the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The resulting residue was added methanol (1.50 mL) at room temperature, dissolved, and cooled to 0 ° C.. Aqueous sodium hydroxide to the reaction solution (1.0 N, 1.47 mL, 1.47 mmol) was added at 0 ° C., after stirring for 4 hours at room temperature and concentrated under reduced pressure. The obtained residue chloroform (16.0 mL) was added at room temperature to dissolve. Diisopropylethylamine to the reaction solution (0.863mL, 4.94mmol), HBTU ( 0.937g, 2.47mmol) and 4- (dimethylamino) piperidine (0.190 g, 1.48 mmol) was added at room temperature, the reaction mixture It 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 flash column chromatography (NH silica gel, chloroform / methanol), 1- (4- (dimethylamino) piperidin-1-yl) -3- (1-propyl -1H- imidazol-2-yl) propane 1-one (110mg, 0.376mmol, 28%) as a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 0.93 (3H, t, J = 7.2 Hz), 1.30-1.43 (2H, m), 1.71-1.88 (4H, m), 2.27 (6H, s), 2.28-2.39 (1H, m), 2.55-2.64 (1H, m), 2.90-3.05 (5H, m), 3.86 (2H, t, J = 7.2 Hz), 4.00-4.09 (1H, m), 4.58- 4.66 (IH, m), 6.82 (IH, d, J = 1.6 Hz), 6.93 (IH, d, J = 1.6 Hz).
ESI-MS: m / z = 293 (M + H) + .

[0415]

(Reference Example 30) 1- (4- (dimethylamino) piperidin-1-yl) -3- (1-butyl -1H- imidazol-2-yl) propan-1-one Synthesis of:
[Formula

　64] (E ) - methyl 3- (1-butyl -1H- imidazol-2-yl) acrylate (260 mg, in ethanol (5.0 mL) solution of 1.25 mmol), palladium - added carbon (10% wet, 19 mg) at room temperature under a hydrogen atmosphere, after stirring for 4 hours, the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The resulting residue was added methanol (1.5 mL) at room temperature, dissolved, and cooled to 0 ° C.. Aqueous sodium hydroxide to the reaction solution (1.0 N, 1.47 mL, 1.47 mmol) was added at 0 ° C., after stirring for 4 hours at room temperature and concentrated under reduced pressure. The obtained residue chloroform (15.0 mL) was added at room temperature to dissolve. Diisopropylethylamine to the reaction solution (0.801mL, 4.59mmol), HBTU ( 0.870g, 2.29mmol) and 4- (dimethylamino) piperidine (0.176 g, 1.38 mmol) was added at room temperature, the reaction mixture It 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 flash column chromatography (NH silica gel, chloroform / methanol), 1- (4- (dimethylamino) piperidin-1-yl) -3- (1-butyl -1H- imidazol-2-yl) propane 1-one (120mg, 0.392mmol, 31%) as a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 0.93 (3H, t, J = 7.2 Hz), 1.29-1.43 (4H, m), 1.65 - 1.74 (2H, m), 1.78 - 1.88 (2H, m ), 2.25-2.37 (7H, m) , 2.54-2.64 (1H, m), 2.88-3.04 (5H, m), 3.88 (2H, t, J = 7.2 Hz), 3.98-4.06 (1H, m), 4.56-4.66 (IH, m), 6.81 (IH, brs), 6.92 (IH, brs).
ESI-MS: m / z = 307 (M + H) + .

[0416]

(Reference Example 31) 1- (4- (dimethylamino) piperidin-1-yl) -3- (1-isopropyl -1H- imidazol-2-yl) propan-1-one Synthesis of:
[Formula

　65] (E ) - methyl 3- (l-isopropyl -1H- imidazol-2-yl) acrylate (362 mg, in methanol (7.46ML) solution of 1.86 mmol), palladium - added carbon (10% wet, 36 mg) at room temperature under a hydrogen atmosphere, after stirring for 16 h, the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The resulting residue was added methanol (1.86 mL) at room temperature, dissolved, and cooled to 0 ° C.. Aqueous sodium hydroxide to the reaction solution (1.0 N, 2.05 mL, 2.05 mmol) was added at 0 ° C., after stirring for 16 hours at room temperature and concentrated under reduced pressure. The obtained residue chloroform (18.6 mL) was added at room temperature to dissolve. Diisopropylethylamine to the reaction solution (0.976mL, 5.59mmol), HBTU ( 1.06g, 2.80mmol) and 4- (dimethylamino) piperidine (0.215 g, 1.68 mmol) was added at room temperature, the reaction mixture It 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 flash column chromatography (NH silica gel, chloroform / methanol), 1- (4- (dimethylamino) piperidin-1-yl) -3- (1-isopropyl -1H- imidazol-2-yl) propane 1-one (335mg, 1.15mmol, 62%) as a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.32-1.42 (8H, m), 1.83-1.86 (2H, m), 2.27-2.34 (7H, m), 2.57-2.64 (IH, m), 2.96 -3.02 (5H, m), 4.03-4.06 (IH, m), 4.42-4.49 (IH, m), 4.61-4.64 (IH, m), 6.91 (IH, brs), 6.95 (IH, brs).
ESI -MS: M / Z = 293 (M Tasu H) Tasu .

[0417]

(Comparative Example 1) Synthesis of 1 (4- (dimethylamino) piperidin-1-yl) -3- (1-methyl -1H- imidazol-2-yl) propan-1-one hydrochloride
[formula 66]

　1- (4- (dimethylamino) piperidin-1-yl) -3- (1-methyl -1H- imidazol-2-yl) propan-1-one (1.50 g, 5.67 mmol) in diethyl ether (60 the .0ML) solution was added solution of hydrogen chloride in dioxane (4.0 M, 3.69 mL, 14.8 mmol) 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 (100 mL), after 36 hours drying at room temperature, 1- (4- (dimethylamino) piperidin-1-yl) -3- (1-methyl -1H- imidazol-2-yl) propan-1-one hydrochloride (1.41g, 4.18mmol, 74%) ( hereinafter, to obtain comparative compound of example 1) as a white solid.
1 H-NMR (400 MHz, D 2 O) [delta]: 1.53-1.80 (2H, m), 2.12-2.23 (2H, m), 2.68-2.80 (IH, m), 2.88 (6H, s), 3.01- 3.08 (2H, m), 3.15-3.26 (3H, m), 3.47-3.58 (1H, m), 3.84 (3H, s), 4.08-4.16 (1H, m), 4.50-4.59 (1H, m), . 7.29-7.33 (2H, m)
ESI-MS; 1- (4-(dimethylamino) piperidin-1-yl) -3- (1-methyl -1H- imidazol-2-yl) as propan-1-one : M / Z = 265 (M Tasu H) Tasu .

[0418]

(Comparative Example 2) 1- (4- (dimethylamino) piperidin-1-yl) -3- (1-methyl -1H- imidazol-2-yl) propan-1-one Synthesis sulfate monohydrate:
Formula

　67] 1- (4- (dimethylamino) piperidin-1-yl) -3- (1-methyl -1H- imidazol-2-yl) propan-1-one (6.72 g, 25.4 mmol) of in DMSO (100 mL) solution, concentrated sulfuric acid (2.49 g, 25.4 mmol), water (1.83 g, 102 mmol) and 1- (4- (dimethylamino) piperidin-1-yl) -3- (1-methyl -1H- imidazol-2-yl) propan-1-one sulfate 1 hydrate seed crystals (50 mg, 0.13 mmol) was added at 80 ° C.. 2.5 hours the reaction mixture at the same temperature, 2.5 hours at 50 ° C., and stirred for 15 hours at room temperature. The precipitated white solid was collected by filtration, washed with DMSO (20 mL) and methyl ethyl ketone (40 mL), dried at room temperature, 1- (4- (dimethylamino) piperidin-1-yl) -3- (1-methyl -1H- imidazol-2-yl) propan-1-one sulfate monohydrate (8.42g, 22.1mmol, 87%) ( hereinafter, to give compounds) Comparative example 2 as white crystals.
1 H-NMR (400 MHz, DMSO-d 6 ) [delta]: 1.36 (IH, m), 1.58 (IH, m), 1.95 (2H, br), 2.44-2.57 (IH, m), 2.65 (6H, s ), 2.74-2.88 (4H, m) , 3.00 (1H, t, J = 12.0 Hz), 3.22 (1H, m), 3.61 (3H, s), 4.02 (1H, d, J = 14.0 Hz), 4.47 . (IH, d, J = 12.8 Hz), 6.87 (IH, d, J = 1.2 Hz), 7.11 (IH, d, J = 1.2 Hz)
ESI-MS; 1-(4-(dimethylamino) piperidine - 1-yl) -3- (1-methyl -1H- imidazol-2-yl) propan-1 as an on: m / z = 265 (M + H) + .

[0419]

(Comparative Example 3) Synthesis of 1 (4- (dimethylamino) piperidin-1-yl) -3- (1-ethyl -1H- imidazol-2-yl) propan-1-one hydrochloride
[formula 68]

　1- (4- (dimethylamino) piperidin-1-yl) -3-diethyl ether (1-ethyl--1H- imidazol-2-yl) propan-1-one (0.271 g, 0.973 mmol) (19 the .5ML) solution was added diethyl ether solution of hydrogen chloride (2.0 N, 1.07 mL, 2.14 mmol) 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 (58.5ML), after 36 hours drying at room temperature, 1- (4- (dimethylamino) piperidin-1-yl) -3- (1-ethyl - 1H- imidazol-2-yl) propan-1-one hydrochloride (0.283g, 0.806mmol, 83%) ( hereinafter, to obtain comparative compound of example 3) as a white solid.
1 H-NMR (400 MHz, D 2 O) [delta]: 1.32 (3H, t, J = 7.2 Hz), 1.45 (IH, ddd, J = 4.4, 12.4, 24.4), 1.58 (IH, ddd, J = 4.4 , 12.4, 24.4), 1.99-2.07 ( 2H, m), 2.56-2.63 (1H, m), 2.73 (6H, s), 2.90-2.93 (2H, m), 3.03-3.13 (3H, m), 3.35 -3.41 (1H, m), 3.96-3.99 (1H, m), 4.06 (2H, d, J = 7.2 Hz), 4.38-4.42 (1H, m), 7.18 (1H, d, J = 2.4 Hz), . 7.26 (IH, d, J = 2.4 Hz)
ESI-MS: 1- (4-(dimethylamino) piperidin-1-yl) -3- (1-ethyl -1H- imidazol-2-yl) propane-1,3 - as an on: m / z = 279 (M + H) + .

[0420]

(Comparative Example 4) Synthesis of 1 (4- (dimethylamino) piperidin-1-yl) -3- (1-propyl -1H- imidazol-2-yl) propan-1-one hydrochloride
[formula 69]

　1- (4- (dimethylamino) piperidin-1-yl) -3- (1-propyl -1H- imidazol-2-yl) propan-1-one (0.110 g, 0.376 mmol) in diethyl ether (4 the .00ML) solution was added solution of hydrogen chloride in dioxane (4.0M, 0.245mL, 0.978mmol) 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 (7.00 mL), after 36 hours drying at room temperature, 1- (4- (dimethylamino) piperidin-1-yl) -3- (1-propyl - 1H- imidazol-2-yl) propan-1-one hydrochloride (0.105g, 0.287mmol, 76%) ( hereinafter, to obtain comparative compound of example 4) as a white solid.
1 H-NMR (400 MHz, D 2 O) [delta]: 0.93 (3H, t, J = 7.2 Hz), 1.50-1.80 (2H, m), 1.81-1.92 (2H, m), 2.10-2.23 (2H, m), 2.68-2.78 (1H, m ), 2.86 (6H, s), 3.02-3.08 (2H, m), 3.15-3.28 (3H, m), 3.45-3.57 (1H, m), 4.08-4.16 ( 3H, m), 4.50-4.58 (. IH, m), 7.32 (IH, brs), 7.38 (IH, brs)
ESI-MS; 1-(4-(dimethylamino) piperidin-1-yl) -3- (1-propyl -1H- imidazol-2-yl) propan-1 as an on: m / z = 293 (M + H) + .

[0421]

(Comparative Example 5) Synthesis of 1 (4- (dimethylamino) piperidin-1-yl) -3- (1-butyl -1H- imidazol-2-yl) propan-1-one hydrochloride
[formula 70]

　1- (4- (dimethylamino) piperidin-1-yl) -3- (1-butyl -1H- imidazol-2-yl) propan-1-one (0.120 g, 0.392 mmol) in diethyl ether (4 the .00ML) solution was added solution of hydrogen chloride in dioxane (4.0 M, 0.255 mL, 1.02 mmol) 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 (7.00 mL), after 36 hours drying at room temperature, 1- (4- (dimethylamino) piperidin-1-yl) -3- (1-butyl - 1H- imidazol-2-yl) propan-1-one hydrochloride (0.136g, 0.358mmol, 91%) ( hereinafter, to obtain a comparative compound 5) as a white solid.
1 H-NMR (400 MHz, D 2 O) [delta]: 0.93 (3H, t, J = 6.8 Hz), 1.30-1.40 (2H, m), 1.52-1.86 (4H, m), 2.10-2.22 (2H, m), 2.68-2.78 (1H, m ), 2.86 (6H, s), 3.02-3.08 (2H, m), 3.15-3.27 (3H, m), 3.47-3.57 (1H, m), 4.06-4.18 ( . 3H, m), 4.49-4.57 (IH, m), 7.32 (IH, d, J = 2.0 Hz), 7.38 (IH, d, J = 2.0 Hz)
ESI-MS: 1-(4-(dimethylamino ) piperidin-1-yl) -3- (1-butyl -1H- imidazol-2-yl) propan-1 as an on: m / z = 307 (M + H) + .

[0422]

(Comparative Example 6) Synthesis of 1 (4- (dimethylamino) piperidin-1-yl) -3- (1-isopropyl -1H- imidazol-2-yl) propan-1-one hydrochloride
[formula 71]

　1- (4- (dimethylamino) piperidin-1-yl) -3- (1-isopropyl -1H- imidazol-2-yl) propan-1-one (0.283 g, 0.967 mmol) in diethyl ether (19 the .3ML) solution was added diethyl ether solution of hydrogen chloride (2.0 N, 1.06 mL, 2.13 mmol) 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 (58.5ML), after 36 hours drying at room temperature, 1- (4- (dimethylamino) piperidin-1-yl) -3- (1-isopropyl - 1H- imidazol-2-yl) propan-1-one hydrochloride (0.313g, 0.806mmol, 92%) ( hereinafter, to give the compound) of Comparative example 6 as a white solid.
1 H-NMR (400 MHz, D 2 O) [delta]: 1.36-1.63 (8H, m), 2.00 - 2.08 (2H, m), 2.58-2.74 (IH, m), 2.74 (6H, s), 2.91- 2.94 (2H, m), 3.04-3.16 (3H, m), 3.36-3.44 (1H, m), 3.97-4.01 (1H, m), 4.39-4.42 (1H, m), 4.57-4.65 (1H, m ), 7.21 (IH, d, J = 2.0 Hz), 7.37 (IH, d, J = 2.0 Hz).
ESI-MS: 1-(4-(dimethylamino) piperidin-1-yl) -3- (1 - as isopropyl -1H- imidazol-2-yl) propan-1-one: m / z = 293 (M + H) + .

[0423]

(Example 14) 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.

[0424]

　The cyclic amine derivative (I) or a pharmaceutically acceptable salt, use of the compound of Example 1,2,3,4,5,7,8,9,10,11,12 or 13 for evaluation It had.

[0425]

1. Experimental method:
　Mouse Sciatic Nerve ligation model, Seltzer et al. Method (Malmberg et al., Pain, 1998 year, Vol 76, p.215-222) was prepared according to.

[0426]

　Slc: ICR mice (5 weeks old, male; Japan SLC) or Crl:; in sodium pentobarbital (70 mg / kg, i.p.) CD1 (ICR) mice (Charles River Japan 5 weeks old, male) anesthetized, exposing the sciatic nerve of the right hind thigh, the intensity only half the sciatic nerve with silk (Natsume Seisakusho) 8-0 under a stereomicroscope triple ligated group and spared nerve ligation group, only to expose the sciatic nerve, and the group was not ligated and sham-operated group.

[0427]

　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 or Shinano Seisakusho), the pressure of 0.16g using such filaments (North Coast Medical or Neuroscience), repeated three times at 3 second intervals mechanical tactile stimulus pressing 3 seconds filaments sole of the right hind paw of escape behavior when applying mechanical tactile stimulus the strength scoring (0: no reaction, 1: slight escape behavior in slowly to stimuli, 2: flinching (quick escape to a stimulus that does not involve a shake in quick succession the foot action) and licking (licking behavior) action, 3: quick escape behavior with a flinching or licking), and the sum of the scores of the three times (Hereinafter referred to as the total score) was used as an index of pain.

[0428]

　After sciatic nerve ligation surgery 7 days, the mice of spared nerve ligation group, examples 1,2,3,4,5,7,8,9,10,11,12 or 13 compound of (Examples 1 and 2 the compound of 3,4,5,8,10 and 13, respectively 10 mg / kg, the compound of example 7, 0.01 ~ 1mg / kg, the compound of example 9, 0.01 ~ 10mg / kg , the compound of example 11, 0.001 ~ 0.1 mg / kg, compound of example 12, 0.01 ~ 1mg / kg) or positive control as pregabalin (10 mg / kg; a Bosche Scientific), distilled water dissolved orally administered to. Mice of spared nerve ligation group, the group treated with the compound of Example 1,2,3,4,5,7,8,9,10,11,12 or 13, "spared nerve ligation + Example 1 compound "group," spared nerve ligation + compound of example 2 "group," a compound of spared nerve ligation + example 3 "group," a compound of spared nerve ligation + example 4 "group," sciatic compound "group nerve ligation + example 5," compound of the sciatic nerve partial ligation + example 7 "group," a compound of spared nerve ligation + example 8 "group, the" spared nerve ligation + example 9 compound "group," compound "groups spared nerve ligation + example 10," a compound of spared nerve ligation + example 11 "group," a compound of spared nerve ligation + example 12 "group," spared nerve and compounds "group ligation + example 13, the group treated with pregabalin," sciatic It was through part ligation + pregabalin "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.

[0429]

　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.

[0430]

2. Results:
　The results are shown in Figure 1-12. In the figure, the vertical axis von total score of Frey test (mean ± standard error;. 1 to 12, n = 5 ~ a 6) indicates, it indicates 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 Welch test unpaired two-group or Shirley-Williams test statistical processing was carried out. § indicia or ♯ mark in the drawing, "spared nerve ligation + distilled water" is statistically significant in comparison with the group (§: Welch test (p <0.05), or, ♯: Shirley- Williams test (p <0.025)) show that.

[0431]

　According to the results of the von Frey test, "spared nerve ligation + implemented in the oral administration (Figure of the compound of Example 1,2,3,4,5,7,8,9,10,11,12 or 13 example 1,2,3,4,5,7,8,9,10,11,12 or compound 13 "), as well as the positive control and is pregabalin (" spared nerve ligation + pregabalin "in the figure) a showed a statistically significant analgesic effect.

[0432]

　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.

[0433]

(Comparative Example 7) Effect on mouse sciatic nerve partial ligation model:
　with neuropathic pain can be evaluated mouse sciatic nerve partial ligation model (Seltzer model), analgesic activity of the compounds of Comparative Examples 1, 3, 4, 5 and 6 It was investigated.

[0434]

1. Experimental method:
　Mouse Sciatic Nerve ligation model, Seltzer et al. Method (Malmberg et al., Pain, 1998 year, Vol 76, p.215-222) was prepared according to.

[0435]

　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.

[0436]

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

[0437]

　After sciatic nerve ligation surgery 7 days, the mice of spared nerve ligation group, compound (Compound of Comparative Example 1 is 0.01 ~ 1 mg / kg in Comparative Example 1, 3, 4, 5 or 6, and Comparative Examples 3 to 6 compounds pregabalin as a 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 compound of Comparative Example 1, 3, 4, 5 or 6, respectively, "a compound of spared nerve ligation + Comparative Example 1" group, "spared nerve ligation + comparative example compound 3 "," compounds of the sciatic nerve partial ligation + Comparative example 4 "group," a compound of spared nerve ligation + Comparative example 5 "group, a" compound of spared nerve ligation + Comparative example 6 "group, pregabalin the group was administered, it was a "sciatic nerve partial ligation + pregabalin" 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.

[0438]

　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.

[0439]

2. Result:
　Figure 14 left the results of the compound of Comparative Example 1, FIG. 15 shows the left side the result of the compound of Comparative Example 3, 4, 5 or 6. Further, as a comparison, it shows the effect of the compound of Example 11 according to the right side of FIG. 14 and 15 in FIG. 10 (Example 14).

[0440]

　14 and 15 the left, the ordinate indicates the total score of the von Frey test (mean ± standard error, n = 4 ~ 5), indicating that the numerical pain higher stronger. The horizontal axis shows the time after test compound administration (hr). Efficacy evaluation of Comparative Example 1, 3, 4, 5 or 6 compounds per measurement time "spared nerve ligation + distilled water" group ( "spared nerve ligation + distilled water" in FIG. 14 and 15 in the left side) as a control, a statistical processing was performed by unpaired t-test multigroup (correction by Dunnett). ‡ indicia 14 and 15 in the left, "spared nerve ligation + distilled water" comparison is statistically significant at the group: shows the (‡ p <0.05) that.

[0441]

　According to von Frey testing results, oral administration of the compound of Comparative Example 1, 3, 4, 5 or 6 (in FIG. 14 and 15 "of the sciatic nerve partial ligation + Comparative Example 1, 3, 4, 5 or 6 compound "), similar to the positive control at a pregabalin (" spared nerve ligation + pregabalin "in the figure), showed a statistically significant analgesic effect.

[0442]

　However, the compound of Comparative Example 1 showed statistically significant analgesic effect from the dose of 0.01 mg / kg, most strongly after oral administration 1 hour, after 2 hours and 3 hours attenuation its analgesic effect It tended to. Similarly the compound of Comparative Example 3, 4, 5 or 6, strongest after oral administration 1 hour, after 2 hours and 3 hours its analgesic effect tended to attenuate. On the other hand, the compound of Example 11, a statistically significant analgesic effect from an extremely low dose of 0.001 mg / kg, and its analgesic effect lasted up to 2 hours after oral administration. Furthermore, the analgesic effect of 0.1 mg / kg of the compound of Example 11 lasted up to 3 hours after oral administration. Incidentally, duration of analgesic action, the compound of Example 7 according to FIG. 6, was confirmed for the compound of Example 12 according to the compound, and 11 of Example 9 according to FIG. Therefore, the cyclic amine derivative (I) or a pharmacologically acceptable salt thereof, as compared to imidazole derivatives described in WO 2013/147160 (Patent Document 4), than against neuropathic pain it has been found that shows a sustained analgesic effect.

[0443]

(Example 15) Effect on rat fibromyalgia Model:
　using rat fibromyalgia model that can evaluate fibromyalgia, an analgesic effect of a cyclic amine derivative (I) or a pharmacologically acceptable salt thereof investigated.

[0444]

　The cyclic amine derivative (I) or a pharmacologically acceptable salt thereof, using the compound of Example 11 for evaluation.

[0445]

1. Experimental method:
　fibromyalgia model rats (Sluka et al widely used in general in the foundation of fibromyalgia research, Journal of Pharmacology and Experimental Therapeutics, 2002 year, the first 302 Volume, p.1146-1150; Nagakura et al., Pain, 2009, 146 vol, p.26-33; Sluka et al, Pain, 2009, 146 pp. in order to produce the section on page 3-3), isoflurane acidic saline 100μL adjusted to pH4.0 of continuous inhalation anesthesia under Crl: CD (SD) rats (6-7 weeks old, male; Charles River Japan) twice to the right hind leg gastrocnemius muscle of (the first day of administration of acidic saline solution as 1 day, 1 day eyes by day 6 at a time, respectively) injected intramuscularly, indoor temperature 21-2 5 ° C., in a breeding room adjusted to the room humidity of 40% to 70% were bred while free food & water consumption. Moreover, used in the experiment the rats fibromyalgia reared by similarly injected intramuscularly saline instead of acidic saline is not developed ( "saline + distilled water" group in FIG. 13) did.

[0446]

　Allodynia of each rat 7 days after the first administration day in acidic physiological saline was measured, 50% reaction threshold (right hind the average value of the left hind paw) are fibromyalgia rats became 2g or 6g or less was selected as onset fibromyalgia model rats were used in the following dosage experiments. The measurement of allodynia, known document (Chaplan et al., Journal of Neuroscience Methods, 1994 years, Vol. 53, P.55-63) according to the method described in, were performed using von Frey filaments (North Coast Medical) .

[0447]

　Fibromyalgia model rats thus obtained, 50% reaction threshold (mean of the right hind and left hind limbs) are grouped evenly among the group, 7 days after the initial day of administration of acidic saline to the eye, it was administered the test compound in fibromyalgia model rats.

[0448]

　The compound of Example 11 (0.1 ~ 10 mg / kg) is dissolved in distilled water was orally administered to fibromyalgia model rats ( "compounds of acidic saline + Example 11" in FIG. 13) . Pregabalin as a positive control; and (10mg / kg KEMPROTEC), was orally administered was dissolved in distilled water ( "acidic saline + pregabalin" in FIG. 13). As a control, it was orally administered distilled water fibromyalgia model rats ( "acidic saline + distilled water" in FIG. 13). Further, in rats fibromyalgia is not developed, the distilled water was orally administered (in FIG. 13, "Saline + distilled water"). After oral administration 1 hour and after 3 hours, by measuring the allodynia of each rat was evaluated analgesic effects. At that time, was pre value the value of the 50% reaction threshold in allodynia measurements before oral administration of the first dose day of acidic saline on day 7 of the test compound.

[0449]

2. Results:
　The results are shown in Figure 13. In the figure, the vertical axis is 50% reaction threshold (mean of the right hind and left hind) (g) (mean ± standard error, n = 5 ~ 6) shows the numerical in fibromyalgia model rats higher indicating that the recognized allodynia has been improved.

[0450]

　Figure 13 shows the results of oral administration of the compound of Example 11. In the figure, the horizontal axis shows the prior oral administration of the compound of Example 11 (pre value) and the elapsed time from oral administration (hr). † indicia or ♯ mark in the drawing, "acidic saline + distilled water" group each measurement time ( "acidic saline + distilled water" in the figure) as a control, unpaired t-test or Williams test the results of statistically significant (†: t-test (p <0.05), or, ♯: Williams test (p <0.025)) indicates that.

[0451]

　Group of the compound were administered orally in Example 11 ( "compounds of acidic saline + Example 11" in FIG. 13, the group and the pregabalin positive control was orally administered (in FIG. 13 of "acidic saline + similar to pregabalin "), it was allodynia observed in fibromyalgia model rats was improved by significantly statistically compared with" acidic saline + distilled water "group.

[0452]

　These results cyclic amine derivative (I) or a pharmaceutically acceptable salt thereof pharmacologically was found to be effective against fibromyalgia.

[0453]

(Comparative Example 8) Effect on rat fibromyalgia Model:
　using rat fibromyalgia model that can evaluate fibromyalgia were investigated analgesic activity of the compound of Comparative Example 1.

[0454]

1. Experimental method:
　fibromyalgia model rats (Sluka et al widely used in general in the foundation of fibromyalgia research, Journal of Pharmacology and Experimental Therapeutics, 2002 year, the first 302 Volume, p.1146-50; Nagakura et al., Pain, 2009, 146 vol, p.26-33; Sluka et al, Pain, 2009, 146 pp. in order to produce the section on page 3-3), isoflurane acidic saline 100μL adjusted to pH4.0 under continuous inhalation anesthesia Slc: SD rats (6-7 weeks old, male; Japan SLC) twice to the right hind gastrocnemius (the acidic saline first day of administration as day 1, day 1 and day 6 eyes each once) injected intramuscularly, the room temperature 21 ~ 25 ° C., room humidity 40 In a controlled breeding room to ~ 70%, were bred while free food, water consumption. Moreover, the experimental rats fibromyalgia reared by similarly intramuscular injection of physiological saline in place of the acidic saline is not developed (FIG. 16 "Saline + distilled water" left group) used.

[0455]

　Measure allodynia of each rat 7 days after the first administration day in acidic physiological saline, it was developed 50% response threshold (right hind the average value of the left hind paw) are fibromyalgia rats became 6g below It was selected as fibromyalgia model rats were used in the following administration experiment. The measurement of allodynia, known document (Chaplan et al., Journal of Neuroscience Methods, 1994 years, Vol. 53, P.55-63) according to the method described in, were performed using von Frey filaments.

[0456]

　The resulting fibromyalgia model rats is thus, were grouped as 50% response threshold is equalized between groups on day 7 from the first day of administration of acidic saline, compound of Comparative Example 1 (0 .1 ~ 1 mg / kg) or pregabalin as a positive control (10 mg / kg; a Bosche Scientific Co., Ltd.) was dissolved in each of distilled water was orally administered. As a control, distilled water was orally administered to fibromyalgia model rats (Figure 16 left "acidic saline + distilled water" group). Incidentally, distilled water was orally administered to rats fibromyalgia is not developed ( "saline + distilled water" group). 1 hour after oral administration by measuring the allodynia of each rat at 2 hours and 3 hours was evaluated analgesic effects of the test compounds. At that time, was pre value the value of the 50% reaction threshold in allodynia measurements before oral administration of the first dose day of acidic saline on day 7 of the test compound.

[0457]

2. Results:
　FIG. 16 left the results of the compound of Comparative Example 1. Further, as a comparison, it shows the effect of the compound of Example 11 according to FIG. 16 the right in FIG. 13 (Example 15).

[0458]

　16 left, the vertical axis represents the 50% reaction threshold value (g) (mean ± standard error, n = 4 ~ 6), numeric is improved allodynia observed in higher fibromyalgia model rats It shows that you are. The horizontal axis shows the prior oral administration of the test compound (pre value) or elapsed time from oral administration (hr). ‡ marks in FIG. 16 in the left side, "acidic saline + distilled water" group each measurement time (in Figure 16 the left side "acidic saline + distilled water") as a control, the multigroup unpaired t test (correction by Dunnett) the result of a statistically significant: indicate that (‡ p <0.05).

[0459]

　Group of the compound were administered orally in Comparative Example 1 ( "Compound acidic saline + Comparative Example 1" of FIG. 16 in the left) shows that the group of pregabalin the positive control was orally administered (in Figure 16 the left side "acidic Like the saline + pregabalin "), was allodynia observed in fibromyalgia model rats was improved by significantly statistically compared with" acidic saline + distilled water "group.

[0460]

　However, the compound of Comparative Example 1 showed statistically significant analgesic effect, after oral administration 3 hours tended to its analgesic action is significantly attenuated. On the other hand, the compound of Example 11, statistically showed significant analgesic effect, the analgesic effect lasted up to 3 hours after oral administration. Therefore, the cyclic amine derivative (I) or a pharmacologically acceptable salt thereof, as compared to imidazole derivatives described in WO 2013/147160 (Patent Document 4), than against fibromyalgia it has been found that shows a sustained analgesic effect.

[0461]

(Example 16) Human, monkey, dog and mouse liver microsomes stability test:
　using an in vitro evaluation as known liver microsomes stability test to evaluate the stability against hepatic metabolism of compounds, cyclic amine derivative (I) or human a pharmacologically acceptable salt thereof, monkeys, stability against hepatic metabolism of dogs and mice were evaluated.

[0462]

1. Experimental method:
　carried out as a test compound Example 11, Comparative Example 1 or the compound of Comparative Example 6, human liver microsomes (Xenotech Corp.) as liver microsomes, monkey liver microsomes (Xenotech Corp.), dog liver microsomes (Xenotech Corp.) or mouse liver experiments were carried out using a microsomal (Xenotech Inc.).

[0463]

　Reagents used in the stability test liver microsomes are prepared as follows. D-glucose 6-phosphate disodium salt ( hereinafter, G6P) was dissolved in distilled water to prepare a 100 mmol / L G6P solution. Glucose of 1000units 6-phosphate dehydrogenase from Yeast (hereinafter, G6PDH) was dissolved in distilled water 5 mL, to prepare 200 units / mL G6PDH solution. MgCl 2 was dissolved in distilled water, 100 mmol / L MgCl 2 to prepare an aqueous solution. 200 mmol / L K 2 HPO 4 in aqueous solution 500 mL, 200 mmol / L KH 2 PO 4 was added an aqueous solution (about 130 mL), the pH was adjusted to 7.4, 200 mmol / L KH 2 PO 4 / K　2 HPO 4 Buffer pH7.4 (hereinafter, 200mmol / L PB) was prepared. β-nicotinamide-adenine dinucleotide phosphate, reduced form, tetrasodium salt ( hereinafter, NADPH) was dissolved in distilled water to prepare a 10 mmol / L NADPH solution.

[0464]

　Liver microsomes stability tests were conducted by the following procedure. First, the reagents listed in Table 2 (except for NADPH) were mixed to obtain a reaction mixture. The reaction mixture 96 well Tube plate (BM Equipment; hereinafter, plate) of 4 wells (each, 0 minutes reaction well, 30 minutes reaction well, 20 minutes reaction wells, responsible for 10 min the reaction wells ) to dispensed by 135μL minute, it covered the entire plate a silicon cap, and preincubation immersed in a water bath at 37 ° C. 10 min.

[0465]

　After preincubation, and the lid from the addition of 10 mmol / L NADPH solution 15.0μL the wells for 30 minutes reaction plates, the reaction was initiated by immersing in a water bath at 37 ° C.. The start of the reaction from the 10 mmol / L NADPH solution 15.0μL for 20 minutes the reaction after 10 minutes the wells, after 20 minutes from the start of the reaction by adding respectively 10 mmol / L NADPH solution 15.0μL the wells for 10 min the reaction , it was continued for an additional reaction is immersed in a water bath of 37 ℃.

[0466]

　After 30 minutes from the start of the reaction, the plate was removed from the water bath, was added acetonitrile 120μL to each well, the plate was covered and stirred for 10 seconds with Direct Mixer from the, stop the reaction cooled then 10 minutes the ice It was. After quenching, the addition of 10 mmol / L NADPH solution 15.0μL 0 minutes reaction well.

[0467]

[Table 2]

[0468]

　The compound of Example 11, the reaction solution in each well, 4 ° C., centrifuged for 10 minutes each at 2500 rpm, the supernatant was analyzed LC / MS / MS. LC / MS / MS analysis conditions are as follows.

[0469]

　«Human and mouse liver microsomes for
　analysis» [HPLCsystem] LC-20A / 30A (Shimadzu Corporation)
　Column] Ascentis Express F5,2.7Myuemu
　　　　　　　5 cm × 2.1 mm (SUPELCO, Inc.)
　[Mobile phase] A solution: 0.1 vol % formic acid aqueous
　　　　　　　solution B: 0.1 vol% formic acid acetonitrile
　[flow rate] 0.7 mL / min
　[gradient programs] solution B: 70 → 30 vol%

[0470]

　«Monkey and dog liver microsomes
　analytical» [HPLCsystem] Agiletnt 1200 (Agiletnt Co.)
　Column] CHIRALCEL OZ-3R, 3 [mu] m
　　　　　　4.6 mm × 0.99 mm ID (DAICEL Company)
　[Mobile phase] methanol: 2-propanol: ethylenediamine
　　　　　　　= 500: 500: 0.1
　[flow rate] 0.5 mL / min

[0471]

　For the compound of Comparative Example 1, the reaction solution in each well, 4 ° C., centrifuged for 10 minutes each at 2500 rpm, the supernatant was analyzed LC / MS. LC / MS analysis conditions are as follows.

[0472]

　≪ヒト肝ミクロソーム分析用≫
　［ＨＰＬＣｓｙｓｔｅｍ］　Ｗａｔｅｒｓ　ＨＰＬＣ（Ｗａｔｅｒｓ社）
　［カラム］　ＢＥＨ　Ｃ１８、１．７μｍ
　　　　　　　２．１ｍｍ　ＩＤ×５０ｍｍ（Ｗａｔｅｒｓ社）
　［移動相］　Ａ液：１０ｍＭ　重炭酸アンモニウム水（ｐＨ１０）
　　　　　　　Ｂ液：アセトニトリル
　［流速］　０．３ｍＬ／ｍｉｎ
　［グラジエントプログラム］　Ｂ液：　１→５０ｖｏｌ％

[0473]

　≪サル及びイヌ肝ミクロソーム分析用≫
　［ＨＰＬＣｓｙｓｔｅｍ］　Ｗａｔｅｒｓ　ＨＰＬＣ（Ｗａｔｅｒｓ社）
　［カラム］　ＰＣ　ＨＩＬＩＣ、３μｍ
　　　　　　　２．０ｍｍ　ＩＤ×５０ｍｍ（資生堂）
　［移動相］　Ａ液：０．１ｖｏｌ％ギ酸水
　　　　　　　Ｂ液：アセトニトリル
　［流速］　０．５５ｍＬ／ｍｉｎ
　［グラジエントプログラム］　Ｂ液：　５→６０ｖｏｌ％

[0474]

　≪マウス肝ミクロソーム分析用≫
　［ＨＰＬＣｓｙｓｔｅｍ］　Ｗａｔｅｒｓ　ＨＰＬＣ（Ｗａｔｅｒｓ社）
　［カラム］　ＸＢｒｉｄｇｅ　Ｃ１８、２．５μｍ
　　　　　　　２．１ｍｍ　ＩＤ×５０ｍｍ（Ｗａｔｅｒｓ社）
　［移動相］　Ａ液：１０ｍＭ　重炭酸アンモニウム水（ｐＨ１０）
　　　　　　　Ｂ液：アセトニトリル
　［流速］　０．３ｍＬ／ｍｉｎ
　［グラジエントプログラム］　Ｂ液：　１→２０ｖｏｌ％

[0475]

　For the compound of Comparative Example 6, a reaction solution in each well, 4 ° C., centrifuged for 10 minutes each at 2500 rpm, the supernatant was analyzed LC / MS / MS. LC / MS / MS analysis conditions are as follows.

[0476]

　«For human liver microsomes
　analysis» [HPLCsystem] Agiletnt 1200 (Agiletnt Co.)
　Column] Unison
　　　　　　　UK-Silica 50 mm × 3 mm (Unison Co.)
　[Mobile phase] A solution: 0.05 mM ammonium acetate (pH 4)
　　　　　　　B liquid: Acetonitrile
　[ flow rate] 0.5 mL / min
　[gradient programs] B solution: 50 vol%

[0477]

　«Monkey and dog liver microsomes
　analytical» [HPLCsystem] Agiletnt 1200 (Agiletnt Co.)
　Column] CAPCELL PAK C18 MGIII, 5 [mu] m
　　　　　　　2.0 mm ID × 50 mm (Shiseido)
　[Mobile phase] A solution: Ammonium 10mM formic acid (pH
　　　　　　　3) B liquid: acetonitrile
　[flow rate] 0.4 mL / min
　[gradient programs] B solution: 1 → 90 vol%

[0478]

　The chromatogram of the reaction liquid in each well obtained by the LC / MS analysis or LC / MS / MS analysis, the test compound at each reaction time t (min) in the case where the peak areas of the reaction time of 0 minutes to 100% residual ratio (%) was calculated. The test compound remaining rate was semi-log plotted against the reaction time, was fitted by the least squares method in Equation 1 below, elimination rate constant k (min -1 was calculated). Furthermore, based on Equation 2 below, the resulting k was divided by the microsome protein concentration, hepatic intrinsic clearance CL int was calculated (mL / min / mg).
　　Test compounds remaining rate = A × exp (-kt) ··· Equation
　　1 CL　int = k / microsome protein concentration Equation 2

[0479]

2. Results:
　The value of the resulting hepatic intrinsic clearance in liver microsomes stability test are shown in Table 3. Incidentally, as the value of the hepatic intrinsic clearance is large, indicating that the fast metabolism of the test compound in liver microsomes. "N.E." in the table, indicating that you do not perform the test.

[0480]

[table 3]

[0481]

　As shown in Table 3, the values ​​of hepatic intrinsic clearance in the compound test compounds and hepatic microsomes stability testing of Example 11, the compound of Comparative Example 1 or Comparative Example 6 as compared to the case of the test compound was smaller common to all animal species were present embodiment tests. Thus, the compound of Example 11, human, monkey, and less susceptible to metabolism in dogs and mouse liver, i.e., it was revealed that stably exist in vivo.

[0482]

　From this result, a cyclic amine derivative (I) or a pharmacologically acceptable salt, WO 2013/147160 compared to imidazole derivatives described in (Patent Document 4), a more stable in vivo there it became clear that to.

[0483]

(Example 17) pharmacokinetics (PK) test
　as a test compound, the compound of Example 11 or Comparative Example 2 was investigated in plasma concentration after intravenous or oral administration to monkeys.

[0484]

1. Experimental method:
　chow (Oriental Yeast Co.) to and tap water ad libitum 4-6 age cynomolgus monkey (male) was used after fasted from the evening (16 o'clock) the day before administration. Incidentally, it was resumed feeding after completion blood 4 hours after administration.

[0485]

　The compound of Example 11 or Comparative Example 2, cynomolgus monkeys single intravenous administration (1 mg / kg) or single oral dose (1mg / kg). Intravenous solution of the compound of Example 11 or Comparative Example 2, was dissolved in Japanese Pharmacopoeia physiological saline to prepare a concentration of 10 mg / mL. Furthermore, oral administration solution of the compound of Example 11 or Comparative Example 2 was dissolved in Japanese Pharmacopoeia water for injection to prepare a concentration of 1 mg / mL. Intravenous administration was carried out from the saphenous vein using a syringe with a needle attached. Furthermore, oral administration, by inserting a catheter into the nasal cavity, was performed forcibly into the stomach.

[0486]

　When the intravenous solution of the compound of Example 11 or Comparative Example 2 was administered intravenously, intravenously prior to the administration, each of the time points 5, 15, 30 minutes and 1,2,4,8,24 hours after administration in, and the blood from the forearm cephalic vein of a total of nine times in the absence of anesthesia.

[0487]

　When the oral dosing solution of the compound of Example 11 was orally administered, prior to oral administration, at each time point of 15, 30, 45 minutes and 1,2,4,8,24 hours after administration, the forearm under no anesthesia It was collected from the cephalic vein of a total of nine times. Further, when the oral dosing solution of the compound of Comparative Example 2 were orally administered, prior to oral administration, at each time point of 30 minutes and 1,2,3,4,6,8,24 hours after administration, unanesthetized in was the blood from the forearm cephalic vein of a total of nine times.

[0488]

　4 ° C. collected blood was centrifuged for 15 minutes at 1800 × g, and plasma was obtained. The resulting plasma was stored at about -80 ° C. until preparation of samples for analysis. Incidentally, called a plasma obtained from cynomolgus monkeys dosed with the test compound and blood plasma samples, referred to as a plasma blank plasma obtained from cynomolgus monkeys not administered the test compound.

[0489]

　Plasma samples obtained from cynomolgus administered compound of Example 11, or, in the plasma samples 50μL diluted appropriately with blank plasma, stirred methanol was added to the internal standard solution and 200 [mu] L, 10 minutes at 4 ° C. It cooled. Calibration curve samples, a material obtained by adding standard solutions for calibration curve blank plasma, was prepared similarly treated. Each sample after cooling, 4 ° C., centrifuged for 10 minutes each at 2000 rpm (Hitachi Koki), as analytical sample and the resulting supernatant was analyzed LC / MS / MS. LC / MS / MS analysis conditions are described in Example 16 were the same as monkey and dog liver microsomes stability test of the compound of Example 11 ( «monkey and dog liver microsome analysis»).

[0490]

　Furthermore, plasma samples obtained from cynomolgus administered compound of Comparative Example 2, or, in the plasma samples 50μL diluted appropriately with blank plasma, stirred methanol was added to the internal standard solution and 150 [mu] L, at 4 ° C. and cooled for 10 minutes. Calibration curve samples, a material obtained by adding standard solutions for calibration curve blank plasma, was prepared similarly treated. Each sample after cooling, 4 ° C., centrifuged for 10 minutes each at 2000rpm and (Hitachi Koki), as a sample for analysis which was diluted 10-fold with 0.1 vol% formic acid containing 70 vol% acetonitrile supernatant, LC / MS / and MS analysis. LC / MS / MS analysis conditions are as follows.

[0491]

　[HPLCsystem] Agiletnt 1200 (Agiletnt Co.)
　Column] Ascentis Express F5,2.7Myuemu
　　　　　　　5 cm × 2.1 mm (SUPELCO, Inc.)
　[Mobile phase] A solution: 0.1 vol% formic acid aqueous
　　　　　　　solution B: 0.1 vol% formic acid acetonitrile
　[flow rate] 0.7 mL / min
　[gradient programs] B solution: 70 → 30 vol%

[0492]

　From the results of LC / MS / MS analysis, using Analysis 1.6.2 (Applied Biosystems) to prepare a calibration curve, it was calculated the concentration of test compound analytical sample. Each time when administered intravenously or orally, to calculate the test compound concentration in plasma was performed PK analysis for each individual. PK parameters, analysis does not depend on the model using WinNonlin (Pharsight Corp.) (intravenously: Bolus IV Administration, oral administration: Extravascular Administration; both Weight = 1 / y) was calculated by. Moreover, bioavailability (BA), based on equation 3 below, AUC up to infinite time intravenous administration 0-∞, iv AUC up to infinite time and after oral administration 0-∞, po to each administration It was calculated normalized by dividing by the amount.
　　Bioavailability (BA) = (AUC 0-∞, po / dose) / (AUC 0-∞, iv / dose) Formula 3

[0493]

2. Results:
　The changes in the plasma concentration of the compound of Example 11 in 17, FIG. 18 shows changes in the plasma concentration of the compound of Comparative Example 2. Each plot represents the mean ± standard deviation of the plasma concentration at each time point. Also shows the PK parameters in Table 4. C max (ng / mL) is the highest plasma concentration during oral administration, AUC 0-∞, po (ng · h / mL) is the plasma concentration at the time of oral administration - area under the curve, t 1/2 (h ) is the plasma half-life during oral administration, CL tot (mL / h / kg) systemic clearance when administered intravenously, BA (%) shows the bioavailability.

[0494]

[Table 4]

[0495]

　As shown in FIGS. 17 and 18, plasma concentration average value of cynomolgus monkeys dosed with the compound of Example 11, as compared to the plasma concentration average value of cynomolgus monkeys dosed with the compound of Comparative Example 2, all the time It was higher in.

[0496]

　Further, as shown in Table 4, the maximum plasma concentrations upon oral administration (C max ) is the compound of Example 11 where it is 279ng / mL, the compound of Comparative Example 2 was 146ng / mL. Furthermore, in plasma during oral administration half-life (t 1/2 for) also, the compound of Example 11 where it is 7.55H, a compound of Comparative Example 2 was 6.56H. Systemic clearance representing the rate of disappearance of compound (CL tot ) is the compound of Example 11 where a 195 mL / h / kg, the compound of Comparative Example 2 was 501mL / h / kg. Bioavailability indicates the ratio of oral absorption (BA) is the compound of Example 11 where a 52.6% and 42.6% for the compound of Comparative Example 2.

[0497]

　From this result, a cyclic amine derivative (I) or a pharmacologically acceptable salt thereof, as compared to imidazole derivatives described in WO 2013/147160 (Patent Document 4), have a high oral absorbability and, and, it became clear that a high plasma density.

[0498]

(Example 18) aortic smooth muscle cells cytoplasmic vacuolization induced assessment using:
　using aortic smooth muscle cell line is a cytoplasmic vacuolization induced in vitro evaluation system for evaluating a compound, cyclic amine derivative (I) or to evaluate the cytoplasmic vacuolization induced pharmacologically acceptable salt thereof.

[0499]

1. Experimental method:
　as the test compound was used in Example 3,9,11,12 or the compound of Comparative Example 2-6. Dog aortic smooth muscle cells (Canine Aortic Smooth Muscle Cells, source: Toyobo) or human aortic smooth muscle cells (T / G HA-VSMG, source: ATCC), the test compound 1.0 or 1.2mmol / concentration of L were treated 24 hours or 2 weeks, the cells stained with HE, after staining with LAMP-2 immunostaining or toluidine blue staining, and determine the presence or absence of cytoplasmic vacuolization with an optical microscope.

[0500]

2. Results:
　The results of the evaluation of cytoplasmic vacuolization induced, shown in Tables 5 and 6. Table 5, the results of evaluation using the aortic smooth muscle cells of the canine (test compound concentration: 1.0 mmol / L, the test compound-treated time: 24 hours) indicates, Table 6, use of human aortic smooth muscle cells results of evaluation had (test compound concentration: 1.0 or 1.2 mmol / L, the test compound-treated time: 24 hours or 2 weeks) shows a. "Yes" in the table that the cytoplasmic vacuolization has been confirmed, "no" is that the cytoplasmic vacuolization is not verified, respectively.

[0501]

[table 5]

[0502]

　As shown in Table 5, cytoplasmic vacuolization induced for aortic smooth muscle cells of the canine of the compound of Example 11 is "No", cytoplasmic vacuolization was observed. On the other hand, all the comparative compound was found to have a cytoplasmic vacuolization induced for aortic smooth muscle cells of the canine.

[0503]

[Table 6]

[0504]

　As shown in Table 6, cytoplasmic vacuolization induced for aortic smooth muscle cells of the human of the compound of Example 3,9,11 or 12 are both "no", cytoplasmic vacuolization was observed. Further, for the compound of Example 11, cytoplasmic vacuolization be extended treatment time up to 2 weeks was not confirmed. On the other hand, the compound of Comparative Example 2 was found to have a cytoplasmic vacuolization induced against human aortic smooth muscle cells.

[0505]

　From this result, although cytoplasmic vacuolization induced cyclic amine derivative (I) or a pharmacologically acceptable salt thereof it was not confirmed, imidazole derivatives described in WO 2013/147160 (Patent Document 4) It was revealed to have a cytoplasmic vacuolization induced.

[0506]

(Example 19) Safety in Rats rating:
　using 2-week oral studies in rats, to evaluate the safety of a cyclic amine derivative (I) or a pharmacologically acceptable salt thereof.

[0507]

1. Experimental method
　As a test compound, using the compound of Example 11 or Comparative Example 2. Crl: CD (SD) rats (7 weeks old, female and male; Charles River Japan) to the compound of Example 11 or Comparative Example 2 was administered 2 weeks repeated oral, general state observation, weighed, food consumption measuring, ophthalmological examination (the compound of example 11 only), hematology, blood chemistry, urinalysis, bone marrow examination, autopsy histology, organ weight measurement, histopathological examination and immunotoxicity testing It was carried out. It also conducts Toxicokinetics (TK) measured 1 and 14 days of administration, it was confirmed that each of the test compound is exposed. Dose of the test compound is 0,250,500,1000mg / kg / day, administered volume was 10 mL / kg. The compound of Example 11 as administration solvents phosphate buffered saline, the compound of Comparative Example 2 was used with distilled water.

[0508]

2. Results
　The compounds of Comparative Example 2 was orally administered 2 weeks 250 mg / kg / day rat abnormality was observed in any of the test items. However, the compound of Comparative Example 2 In 500 mg / kg / day or higher, vacuolization is observed in the submandibular gland vessels in the film or the like, non-toxic amount of the compound of Comparative Example 2 was estimated as 250mg / kg / day. On the other hand, in the rats treated with the compound of Example 11, 1000 mg / kg may be administered to / day, no abnormality was observed in any of the test items, non-toxic amount of the compound of Example 11 1000 mg / kg / It was estimated to be more than day.

[0509]

　From this result, a cyclic amine derivative (I) or a pharmacologically acceptable salt thereof, as compared to imidazole derivatives described in WO 2013/147160 (Patent Document 4), the NOAEL high value it became clear it.

[0510]

　From the results of the above embodiments, the characteristics as a medicament (drug efficacy, pharmacokinetics and safety) for the cyclic amine derivative (I) or a pharmacologically acceptable salt thereof of the present invention, WO 2013 / the comparison of the imidazole derivatives described in JP 147160 (Patent Document 4), shown in Table 7. Further, a cyclic amine derivative (I) or a pharmacologically acceptable salt thereof of the present invention, the general formula of the imidazole derivatives described in WO 2013/147160 (Patent Document 4) shown in Table 8.

[0511]

[Table 7]

[0512]

[Table 8]

[0513]

　As shown in Table 7, cyclic amine derivative (I) or a pharmacologically acceptable salt thereof of the present invention, in all the comparison items (efficacy, pharmacokinetics and safety), WO 2013/147160 than imidazole derivatives described in (Patent Document 4), it was revealed to have excellent properties as a medicament.

[0514]

　Imidazole derivatives described in WO 2013/147160 (Patent Document 4) is represented by 8 lower formulas table. Table 8 is a chemical structure shown in the lower part of the formula, "a dimethylamino group, converting X or imidazolyl group each other structures, analgesia significantly reduced" and WO 2013/147160 ( Patent Document 4 discloses in paragraph [0209]). On the other hand, cyclic amine derivative (I) or a salt thereof pharmacologically acceptable of the invention, the chemical structure X shown in 8 in the lower part of the general formula table, corresponds to the compound was converted to other chemical structures . Nevertheless, cyclic amine derivative (I) or a pharmaceutically acceptable salt thereof pharmacologically of the present invention, WO 2013/147160 compared to imidazole derivatives described in (Patent Document 4), excellent not only has an analgesic effect, has also the persistence of the medicinal further, high safety and also has excellent pharmacokinetics (metabolic stability, oral absorption and plasma concentration, etc.), excellent as a medicament it became clear properties is a compound having a.

Industrial Applicability

[0515]

　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 or fibromyalgia, it can be used as medicaments against pain symptoms.

[0516]

　Cyclic amine derivative or a pharmaceutically acceptable salt thereof pharmacologically of the present invention, both high safety, metabolic stability, excellent pharmacokinetics such as oral absorbability and plasma concentration, also combines the persistence of drug efficacy because you are, pain, as especially of neuropathic pain or fibromyalgia treatment, is useful.

The scope of the claims

[Claim 1]

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

wherein the carbon marked with * is an asymmetric carbon, A is of the general formula (IIa), a group represented by (IIb) or (IIc),
[Formula

　2] R 1 is , may be substituted with a halogen atom, a methyl group or an ethyl group, R 2 represents a hydrogen atom or an alkyl group having a carbon number of 2 ~ 5, R 3 are each independently a methyl group or an ethyl radical, n represents 1 or 2. ]

[Claim 2]

　A is a group represented by the general formula (IIa), a cyclic amine derivative or a pharmacologically acceptable salt thereof according to claim 1, wherein.

[Claim 3]

　A is a group represented by the general formula (IIb) or (IIc), a cyclic amine derivative or a pharmacologically acceptable salt thereof according to claim 1, wherein.

[Claim 4]

　A is a group represented by the general formula (IIa), the stereochemistry of the asymmetric carbon marked with * is in the S configuration, a cyclic amine derivative or a pharmacologically acceptable salt thereof according to claim 1, wherein .

[Claim 5]

　R 1 is a fluorine atom may be substituted, a methyl group or an ethyl group, a cyclic amine derivative or a pharmacologically acceptable salt thereof of any one of claims 1-4.

[Claim 6]

　R 1 is a methyl group, an ethyl group, a difluoromethyl group or a 2,2,2-trifluoroethyl group, it is allowed claims 1-4 cyclic amine derivative according to any one claim or a pharmaceutically salt that.

[Claim 7]

　Comprising as an active ingredient a cyclic amine derivative or a pharmacologically acceptable salt thereof of any one of claims 1 to 6, pharmaceutical.

[8.]

　Containing a cyclic amine derivative or a pharmacologically acceptable salt of any one of claims 1 to 6 as an active ingredient, an analgesic.

[Claim 9]

　Containing a cyclic amine derivative or a pharmacologically acceptable salt of any one of claims 1 to 6 as an active ingredient, neuropathic pain therapeutic agent.

[Claim 10]

　Cyclic amine derivative or contains a pharmacologically acceptable salt thereof as an active ingredient, fibromyalgia treatment of any one of claims 1-6.