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, the United States and duloxetine and milnacipran that have been approved in the pregabalin and the United States that have been approved in Japan are mainly used. Non-steroidal anti-inflammatory drugs have not been approved as fibromyalgia therapeutic agents, opioid compounds, antidepressants, it has also been used anticonvulsant and antiepileptic 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 disclosed to substituted 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, etc.) with a high frequency, long-term administration is difficult. Therefore, it has been desired to develop novel 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, the development of new fibromyalgia therapeutic agents that exhibit a sufficient therapeutic effect has been desired.

[0010]

　Furthermore, for the substitution piperidines described in Patent Document 1, and efficacy it is suggested to migraine, for the imidazole derivatives described in Patent Document 4, it is disclosed that has an analgesic effect. However, there is no disclosure about the cyclic amine derivative revealed an analgesic effect in the present application, not even suggestion of relationship between analgesia and chemical structure. Furthermore, for the substitution piperidines according to imidazole derivatives and Patent Document 3 described in Patent Document 2, there is no any described or suggested about analgesia.

[0011]

　Accordingly, the present invention aims at providing pain, compounds which exhibit particularly strong analgesic effect on 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).
[Formula 1]

[In the formula, A represents a group of formula (IIa) or (IIb),
[Formula 2]

* the stereochemistry of the asymmetric carbon attached is of the S configuration, R 1 is represents an alkyl group having 3 to 8 carbon atoms, when if it represents a group a is represented by formula (IIa), n represents represents 2, represents a group a is represented by the formula (IIb), n is It represents 1. ]

[0014]

　A of the above cyclic amine derivative is preferably a group represented by the formula (IIa). Cyclic amine derivative described above, (S) -3- (2- (3- (3- (dimethylamino) pyrrolidin-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) propanoic acid n - butyl, (S) -3- (2-(3- (3- (dimethylamino) pyrrolidin-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) propanoic acid n- hexyl, ( S) -3- (2- (3- (3- (dimethylamino) pyrrolidin-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) n- heptyl and propanoate (S) -3 - is (2- (3- (3- (dimethylamino) pyrrolidin-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) compound selected from the group consisting of propanoic acid n- octyl it is preferred more There. By limitation, it is possible to enhance the analgesic effect.

[0015]

　Further, A in the above cyclic amine derivative is preferably a group represented by the formula (IIb). The above cyclic amine derivative is 2- (2- (3- (4-morpholino-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) acetic acid n- propyl, 2- (2- (3- (4-morpholino-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) acetic acid n- butyl, 2- (2- (3- (4-morpholino-1-yl ) -3-oxopropyl)-1H-imidazol-1-yl) acetic acid n- pentyl, 2- (2- (3- (4-morpholino-1-yl) -3-oxopropyl)-1H-imidazole - 1-yl) acetic acid n- hexyl, 2- (2- (3- (4-morpholino-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) acetic acid n- heptyl and 2- ( 2 3- (4-morpholino-1-yl) -3 and more preferably oxopropyl)-1H-imidazol-1-yl) a compound selected from the group consisting of acetic acid n- octyl. By limitation, it is possible to enhance the analgesic effect.

[0016]

　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.

[0017]

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

[0018]

　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. .

[0019]

　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).

[0020]

　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.

[0021]

　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.

[0022]

　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.

[0023]

　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

[0024]

　Cyclic amine derivative or a pharmacologically acceptable salt thereof of the present invention, pain, in particular to show a strong analgesic effect on neuropathic pain and fibromyalgia, analgesics, especially neuropathic pain therapeutics and / or it can be used as a fibromyalgia treatment.

BRIEF DESCRIPTION OF THE DRAWINGS

[0025]

FIG. 1 is a graph showing the effect of the compound of Example 4 to mouse sciatic nerve partial ligation model (oral administration).
2 is a diagram showing the effect of the compound of Example 6 to the mouse sciatic nerve partial ligation model (oral administration).
3 is a graph showing the effect of the compound of Example 8 on mouse sciatic nerve partial ligation model (oral administration).
4 is a graph showing the effect of the compound of Example 10 for the mouse sciatic nerve partial ligation model (oral administration).
5 is a graph showing the effect of the compound of Example 12 for the mouse sciatic nerve partial ligation model (oral administration).
6 is a graph showing the effect of the compound of Example 14 for the mouse sciatic nerve partial ligation model (oral administration).
7 is a graph showing the effect of the compound of Example 16 for the mouse sciatic nerve partial ligation model (oral administration).
8 is a graph showing the effect of the compound of Example 18 for the mouse sciatic nerve partial ligation model (oral administration).
9 is a graph showing the effect of the compound of Example 20 for the mouse sciatic nerve partial ligation model (oral administration).
10 is a diagram showing the effect of the compound of Example 6 to rat fibromyalgia model (oral administration).
11 is a graph showing the effect of the compound of Example 18 to rat fibromyalgia model (oral administration).

DESCRIPTION OF THE INVENTION

[0026]

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

[0027]

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

[In the formula, A represents a group of formula (IIa) or (IIb),
[Chemical Formula 4]

　* the stereochemistry of the asymmetric carbon attached is of the S configuration, R 1 is represents an alkyl group having 3 to 8 carbon atoms, when if it represents a group a is represented by formula (IIa), n represents represents 2, represents a group a is represented by the formula (IIb), n is It represents 1. ]

[0028]

　A of the above cyclic amine derivative is preferably a group represented by the formula (IIa). Cyclic amine derivative described above, (S) -3- (2- (3- (3- (dimethylamino) pyrrolidin-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) propanoic acid n - butyl, (S) -3- (2-(3- (3- (dimethylamino) pyrrolidin-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) propanoic acid n- hexyl, ( S) -3- (2- (3- (3- (dimethylamino) pyrrolidin-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) n- heptyl and propanoate (S) -3 - is (2- (3- (3- (dimethylamino) pyrrolidin-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) compound selected from the group consisting of propanoic acid n- octyl it is preferred more There.

[0029]

　Further, A in the above cyclic amine derivative is preferably a group represented by the formula (IIb). The above cyclic amine derivative is 2- (2- (3- (4-morpholino-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) acetic acid n- propyl, 2- (2- (3- (4-morpholino-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) acetic acid n- butyl, 2- (2- (3- (4-morpholino-1-yl ) -3-oxopropyl)-1H-imidazol-1-yl) acetic acid n- pentyl, 2- (2- (3- (4-morpholino-1-yl) -3-oxopropyl)-1H-imidazole - 1-yl) acetic acid n- hexyl, 2- (2- (3- (4-morpholino-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) acetic acid n- heptyl and 2- ( 2 3- (4-morpholino-1-yl) -3 and more preferably oxopropyl)-1H-imidazol-1-yl) a compound selected from the group consisting of acetic acid n- octyl.

[0030]

　The "alkyl group having 3-8 carbon atoms" means a straight chain, branched chain or cyclic saturated hydrocarbon group having 3 to 8 carbon atoms, for example, n- propyl group, an isopropyl group, a cyclopropyl group , n- butyl group, sec- butyl group, an isobutyl group, tert- butyl group, cyclobutyl group, cyclopropylmethyl group, n- pentyl group, a cyclopentyl group, n- hexyl group, a cyclohexyl group, n- heptyl, cycloheptyl group, and n- octyl or cyclooctyl group.

[0031]

　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.

[0032]

[Table 1-1]

[0033]

[Table 1-2]

[0034]

　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).

[0035]

　Enantiomer of interest, known means (e.g., using an optically active synthetic intermediate, or a known method or a method analogous thereto with respect to the racemic mixture of the final product (e.g., using an optical resolution)) by it is possible to obtain.

[0036]

　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.

[0037]

　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.

[0038]

　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.

[0039]

　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.

[0040]

　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) .

[0041]

　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.

[0042]

　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).

[0043]

　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.

[0044]

1-1. Method for producing a cyclic amine derivative (I):
[Chemical Formula 5]

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

[0045]

(Step 1)
　a cyclic amine derivative (I) is, for example, the presence or absence of a base can be obtained by a condensation reaction compound (III) with the compound (IV) using a condensing agent.

[0046]

　Compound used in the condensation reaction (III) and Compound (IV), which can be used as it is a commercial product, for example, can be synthesized according to the production methods described below.

[0047]

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

[0048]

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

[0049]

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

[0050]

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

[0051]

　The amount of compound in the condensation reaction (IV) is preferably 0.5 to 5 mol per 1 mol of compound (III), more preferably 0.8 to 2 moles.

[0052]

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

[0053]

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

[0054]

　The reaction time in the condensation reaction varies depending on the reaction conditions, preferably 5 minutes to 72 hours, more preferably from 30 minutes to 60 hours.

[0055]

1-2. Chlorination step of the cyclic amine derivative (I):
　pharmaceutically acceptable salts of the cyclic amine derivative (I) is obtained by, for example, chloride reaction by mixing the an acid cyclic amine derivative (I).

[0056]

　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.

[0057]

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

[0058]

2. Process for the preparation of compounds (III):
[Chemical Formula 6]

[wherein, R 2 represents an alkyl group having 1 to 6 carbon atoms, for example, include a methyl group, an ethyl group, n- propyl or n- butyl It is. Other symbols are as defined. ]

[0059]

(Step 2)
　Compound (VII) is the presence or absence of a base can be obtained by a condensation reaction compound (V) with the compound (VI) using a condensing agent.

[0060]

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

[0061]

　Compound used in the condensation reaction (V) and compound (VI), which can be used as it is a commercial product, for example, can be synthesized according to the production methods described below.

[0062]

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

[0063]

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

[0064]

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

[0065]

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

[0066]

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

[0067]

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

[0068]

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

[0069]

　The reaction time in the condensation reaction varies depending on the reaction conditions, preferably 5 minutes to 72 hours, more preferably from 30 minutes to 60 hours.

[0070]

(Step 3)
　Compound (III) is the presence of a base, obtained by hydrolysis reaction of the compound (VII).

[0071]

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

[0072]

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

[0073]

　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.

[0074]

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

[0075]

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

[0076]

3. Process for the preparation of compounds (VI):
[Chemical Formula 7]

wherein, L is a leaving group, for example, a chlorine atom, a bromine atom or an iodine atom. R 3 represents an aralkyl group having 7 to 10 carbon atoms, for example, benzyl group. Other symbols are as defined. ]

[0077]

(Step 4)
　Compound (IX) is the presence or absence of a base, obtained by reacting an olefin by using the olefin reagent and the compound (VIII).

[0078]

　Compounds used in the olefination reaction (VIII) can be a commercially available compound.

[0079]

　Examples of the bases used in the olefination reaction, for example, sodium hydride.

[0080]

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

[0081]

　The olefination reagent used in olefination reaction, for example, Horner-Emmons reagent such as dimethyl phosphonoacetate benzyl acetate; or benzyl 2- (triphenylphosphoranylidene) Wittig reagent such as acetate and the like. Horner-Emmons reagent or Wittig reagent can be used as a commercial product.

[0082]

　The amount of the olefin reagent in the olefination reaction is preferably 0.5 to 3 moles relative to 1 mole of compound (VIII), and more preferably 0.8 to 2 moles.

[0083]

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

[0084]

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

[0085]

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

[0086]

(Step 5)
　Compound (X) can be obtained by alkylation reaction to act an alkylating reagent (LI) after deprotonation with a base of compound (IX).

[0087]

　Examples of the bases used in alkylation reactions, for example, sodium carbonate, metal carbonates such as potassium carbonate or cesium carbonate; alkali metal hydrides such as potassium hydride, sodium or hydride; or n- butyl lithium, sec- butyl lithium or tert- butyl-butyl lithium such as lithium hydroxide.

[0088]

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

[0089]

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

[0090]

　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.

[0091]

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

[0092]

　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.

[0093]

(Step 6)
　Compound (XI) can be obtained by alkylation reaction to act an alkylating reagent (LI) after deprotonation with a base of the compound (VIII).

[0094]

　Examples of the bases used in alkylation reactions, for example, sodium carbonate, metal carbonates such as potassium carbonate or cesium carbonate; alkali metal hydrides such as potassium hydride, sodium or hydride; or n- butyl lithium, sec- butyl lithium or tert- butyl-butyl lithium such as lithium hydroxide.

[0095]

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

[0096]

　Alkylating reagent used in the alkylation reaction (LI) can be a commercially available compound.

[0097]

　The amount of the alkylating reagent (LI) in the alkylation reaction is preferably 0.5 to 10 moles relative to 1 mole of compound (VIII), and more preferably 0.8 to 5 mol.

[0098]

　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, 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.

[0099]

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

[0100]

　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.

[0101]

(Step 7)
　Compound (X) is the presence or absence of a base, obtained by reacting an olefin by using the olefin reagent with the compound (XI).

[0102]

　Examples of the bases used in the olefination reaction, for example, sodium hydride.

[0103]

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

[0104]

　The olefination reagent used in olefination reaction, for example, Horner-Emmons reagent such as dimethyl phosphonoacetate benzyl acetate; or benzyl 2- (triphenylphosphoranylidene) Wittig reagent such as acetate and the like. Horner-Emmons reagent or Wittig reagent can be used as a commercial product.

[0105]

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

[0106]

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

[0107]

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

[0108]

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

[0109]

(Step 8)
　Compound (VI) is the compound (X), obtained by a reduction reaction using a transition metal catalyst under a hydrogen atmosphere.

[0110]

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

[0111]

　The amount of transition metal catalyst in the reduction reaction is preferably from 0.1 to 100% by weight relative to compound (X), more preferably 1-50 wt%.

[0112]

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

[0113]

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

[0114]

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

[0115]

4. Process for the preparation of compounds (Va):
[Formula 8]

[wherein, PG represents a protecting group. Other symbols are as defined. ]

[0116]

(Step 9)
　Compound (XIV) is obtained by reductive amination reaction of the compound (XII) compound (XIII).

[0117]

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

[0118]

　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.

[0119]

(Step 10)
　Among of compound (V), the compound represents a group A is represented by the general formula (IIb) (Va) is obtained by deprotection of compound (XIV).

[0120]

　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.

[0121]

　Therapeutic effect of a cyclic amine derivative (I) or a pharmacologically analgesia acceptable salts, in particular neuropathic pain and fibromyalgia can be evaluated using a suitable animal model. Suitable animal models of neuropathic pain, for example, a mouse or rat sciatic nerve partial ligation model (Malmberg et al., Pain, 1998 year, Vol 76, p.215-222) or mouse or rat spinal nerve ligation model (Kim et al., Pain, 1992 years, Vol. 50, P.355-363), and the like. Suitable animal models of fibromyalgia, for example, fibromyalgia model of rat (Sluka et al., 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 vol, section on page 3-3) can be mentioned.

[0122]

　Cyclic amine derivative (I) or a pharmaceutically acceptable salt thereof pharmacologically, since it has a therapeutic effect of good analgesic effect, especially neuropathic pain and / or fibromyalgia, be used as medicaments It can be, preferably used as analgesics, in particular preferably used as a neuropathic pain therapeutic and / or fibromyalgia treatment.

[0123]

　Further, a cyclic amine derivative (I) or a pharmacologically acceptable salt thereof, because it is expected that the central side effects are reduced, long-term administration in the treatment of neuropathic pain and / or fibromyalgia it is possible.

[0124]

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

[0125]

　The term "fibromyalgia" refers to a condition that has been diagnosed with fibromyalgia by the specialist. Diagnosis of specialists, generally carried out in reference to the classification criteria of the American College of Rheumatology.

[0126]

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

[0127]

　A medicament containing a cyclic amine derivative (I) or a salt thereof pharmacologically acceptable active ingredient, a mammal (e.g., mouse, rat, hamster, rabbit, cat, dog, cow, sheep, monkey or human) , especially when administered to humans, with respect to superior analgesia, particularly neuropathic pain and / or fibromyalgia exert a therapeutic effect.

[0128]

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

[0129]

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

[0130]

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

[0131]

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

[0132]

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

[0133]

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

[0134]

　Examples of the disintegrant include starch, or calcium carbonate.

[0135]

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

[0136]

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

[0137]

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

[0138]

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

[0139]

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

[0140]

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

[0141]

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

[0142]

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

[0143]

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

[0144]

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

[0145]

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

[0146]

(Reference Example 1) 3- (1H-imidazol-2-yl) acrylic acid (E) - Synthesis of benzyl:
[Formula 9]

　Sodium hydride (55%, 1.12g, 25.6mmol) in tetrahydrofuran (40. the 0 mL) suspension, dimethylphosphono benzyl acetate (5.12 ml, 24.4 mmol) was added at 0 ° C., the reaction mixture was stirred at the same temperature for 1 hour. To the reaction solution 1H- imidazole-2-carbaldehyde (2.46 g, 25.6 mmol) was added at 0 ° C., the reaction was stirred for 60 hours at room temperature. Saturated ammonium chloride solution was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with 10% aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, chloroform / methanol) to, 3- (1H-imidazol-2-yl) acrylic acid (E) - benzyl (0.380 g, 1.66 mmol, 7%) as a white solid It was obtained as a.
　1 H-NMR (400 MHz, CDCl 3 ) [delta]: 5.25 (2H, s), 6.62 (IH, d, J = 15.6 Hz), 7.14-7.23 (2H, m), 7.28-7.43 (5H, m), 7.57 (IH, d, J = 16.0 Hz).
ESI-MS: m / z = 229 (M + H) + .

[0147]

(Reference Example 2) 3- (1- (3-ethoxy-3-oxopropyl)-1H-imidazol-2-yl) acrylic acid (E) - Synthesis of benzyl:
[Formula

　10] 3- (1H-imidazol - 2-yl) acrylic acid (E) - benzyl (0.500 g, N of 2.19 mmol), N- dimethylformamide (7.3 mL) was added potassium carbonate (0.606 g, 4.38 mmol), ethyl 3- bromopropanoate (0.419 mL, 3.29 mmol), potassium iodide (0.364 g, 2.19 mmol) was added at room temperature, the reaction was stirred heated 4 hours 90 ° C.. Distilled water was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with 10% aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n- hexane / ethyl acetate) to give 3- (1- (3-ethoxy-3-oxopropyl)-1H-imidazol-2-yl) acrylic acid (E) - benzyl (0.520g, 1.59mmol, 72%) as a yellow oil.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.23 (3H, t, J = 7.2 Hz), 2.76 (2H, t, J = 7.2 Hz), 4.13 (2H, q, J = 7.2 Hz), 4.35 (2H, t, J = 7.2 Hz), 5.26 (2H, s), 6.91 (1H, d, J = 15.6 Hz), 7.06 (1H, brs), 7.15 (1H, brs), 7.30-7.42 (5H, m), 7.55 (IH, d, J = 15.6 Hz).
ESI-MS: m / z = 329 (M + H) + .

[0148]

Synthesis of Reference Example 3 The crude 3- (1- (3-ethoxy-3-oxopropyl)-1H-imidazol-2-yl) propanoic acid:
[Chem

　11] 3- (1- (3-ethoxy -3 - oxopropyl)-1H-imidazol-2-yl) acrylic acid (E) - benzyl (0.520 g, in ethanol (9.0 mL) solution of 1.59 mmol), palladium - carbon (10% wet, 0.169g added 0.159 mmol) at room temperature under a hydrogen atmosphere, the reaction mixture was stirred at the same temperature for 16 hours. The reaction mixture was filtered through Celite, the filtrate was concentrated under reduced pressure to obtain 3- (1- (3-ethoxy-3-oxopropyl)-1H-imidazol-2-yl) crude propanoic acid.

[0149]

(Reference Example 4) (S) -3- (1-2-(3- (3- (dimethylamino) pyrrolidin-yl) -3-oxopropyl)-1H-imidazol-1-yl) Synthesis of propanoate :
[Formula 12]

　crude 3- (1- (3-ethoxy-3-oxopropyl)-1H-imidazol-2-yl) propanoic acid (0.0800g, 0.333mmol) in dichloromethane (1.6 mL) solution of , diisopropylethylamine (0.0870mL, 0.499mmol), HBTU ( 0.152g, 0.400mmol), was added at room temperature (S)-3-(dimethylamino) pyrrolidine (0.0420mL, 0.333mmol), the reaction liquid was stirred for 5 hours at the same temperature. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (NH silica gel, chloroform / methanol), (S) -3- (2- (3- (3- ( dimethylamino) pyrrolidin-1-yl) -3-oxopropyl) - 1H- imidazol-1-yl) propanoate (0.103 g, 0.306 mmol, 92%) was obtained as a red-brown oil.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.23-1.27 (3H, m), 1.67-1.91 (IH, m), 2.06-2.26 (7H, m), 2.58-3.36 (9H, m), 3.43 -3.83 (2H, m), 4.12-4.28 (4H, m), 6.85-6.93 (2H, m).
ESI-MS: m / z = 337 (M + H) + .

[0150]

(Reference Example 5) (S) -3- Synthesis of (2- (3- (3- (dimethylamino) pyrrolidin-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) propanoic acid:
Formula

　13] (S) -3- (2-(3- (3- (dimethylamino) pyrrolidin-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) propanoate (0. 290 g, in ethanol (1.0 mL) solution of 0.862 mmol), aqueous sodium hydroxide (1.0N, 0.948mL, 0.948mmol) was added at room temperature, the reaction mixture was stirred for 2 hours at the same temperature. After cooling to 0 ° C., then neutralized with hydrochloric acid (1.0 N) was added to the reaction solution, and concentrated under reduced pressure. Azeotroped with toluene, was added ethanol. The precipitate was filtered through Celite, the filtrate was concentrated under reduced pressure, (S) -3- (2- ( 3- (3- ( dimethylamino) pyrrolidin-1-yl) -3-oxopropyl)-1H-imidazole -1 - yl) propanoic acid (0.220g, 0.713mmol, 83%) as a white solid.
1 H-NMR (400 MHz, CD 3 OD) [delta]: 1.95-2.50 (3H, m), 2.74-3.10 (11H, m), 3.54-4.46 (7H, m), 7.27 - 7.32 (IH, m), 7.42 - 7.46 (IH, m).
ESI-MS: 309 (M + H) + .

[0151]

Synthesis of Reference Example 6 4- (piperidin-4-yl) morpholine:
[Chemical

　14] 1-tert-butoxycarbonyl-4-piperidinone (1.51 g, 7.58 mmol) in dichloromethane (25.0 mL) solution of , morpholine (0.792 g, 9.09 mmol), sodium triacetoxyborohydride (1.93 g, 9.09 mmol), acetic acid (0.0460g, 0.758mmol) was added at 0 ° C., and stirred for 16 hours at room temperature. The reaction was cooled to 0 ° C.. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in hydrochloric acid (1.0 N), and extracted with ethyl acetate. It was basified by addition of 48% sodium hydroxide aqueous solution to the aqueous layer was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (25.0 mL), and stirred for 12 hours at 40 ° C. After adding concentrated hydrochloric acid (5.0 mL). It was dissolved in distilled water After the reaction mixture was concentrated to dryness. It was basified by addition of 48% sodium hydroxide solution and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 4- (piperidin-4-yl) morpholine (1.52g, 5.63mmol, 74%) as a yellow solid.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.34 (2H, dd, J = 12.0, 4.0 Hz), 1.40 (2H, dd, J = 12.0, 4.0 Hz), 1.85 (2H, d, J = 12.4 Hz), 2.28 (1H, tt , J = 11.2, 4.0 Hz), 3.53-3.63 (6H, m), 3.15 (2H, d, J = 12.4 Hz), 3.73 (4H, t, J = 4.4 Hz).
MS-ESI: M / Z = 171 (M Tasu H) Tasu

[0152]

(Reference Example 7) 2- (2-formyl -1H- imidazol-1-yl) Synthesis of ethyl acetate:
Formula

　15] 1H-imidazole-2-carbaldehyde (0.500 g, 5.20 mmol) N of, N - dimethylformamide (10.0 mL) was added potassium carbonate (1.44 g, 10.4 mmol), ethyl chloroacetate (0.585mL, 5.46mmol), at room temperature potassium iodide (0.864 g, 5.20 mmol) in addition, the reaction was stirred heated 4 hours 90 ° C.. Distilled water was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with 10% aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, chloroform / methanol), 2- (2-formyl -1H- imidazol-1-yl) acetate (0.269 g, 1.48 mmol, 28%) as a yellow oil It was obtained as a.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.29 (3H, t, J = 7.2 Hz), 4.25 (2H, q, J = 7.2 Hz), 5.14 (2H, s), 7.15 (IH, brs) , 7.33 (IH, s), 9.79-9.91 (IH, m).
ESI-MS: m / z = 183 (M + H) + .

[0153]

(Reference Example 8) 3- (1- (2-ethoxy-2-oxoethyl)-1H-imidazol-2-yl) acrylic acid (E) - Synthesis of benzyl:
[Chemical Formula 16]

　Sodium hydride (55%, 0 .958G, in tetrahydrofuran (30.0 mL) suspension of 22.0 mmol), dimethyl phosphonoacetate benzyl acetate (4.61 mL, 22.0 mmol) was added at 0 ° C., the reaction mixture was stirred at the same temperature for 1 hour. To the reaction solution 2- (2-formyl -1H- imidazol-1-yl) acetate (4.00 g, 22.0 mmol) was added at 0 ° C., the reaction was stirred at room temperature for 3 hours. Saturated ammonium chloride solution was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with 10% aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, n- hexane / ethyl acetate) to give 3- (1- (2-ethoxy-2-oxoethyl)-1H-imidazol-2-yl) acrylic acid (E) - benzyl (4.31g, 13.7mmol, 62%) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.28 (3H, t, J = 7.2 Hz), 4.24 (2H, q, J = 7.2 Hz), 4.77 (2H, s), 5.25 (2H, s) , 6.92 (IH, d, J = 15.6 Hz), 7.02 (IH, brs), 7.21 (IH, brs), 7.28-7.45 (6H, m).
ESI-MS: m / z = 315 (M + H) + .

[0154]

(Reference Example 9) The crude 3- (1- (2-ethoxy-2-oxoethyl)-1H-imidazol-2-yl) Synthesis of propanoic acid:
[Formula

　17] 3- (1- (2-ethoxy-2 oxoethyl)-1H-imidazol-2-yl) acrylic acid (E) - benzyl (4.31 g, in ethanol (80.0 mL) solution of 13.7 mmol), palladium - carbon (10% wet, 1.46g, 1 the .37Mmol) was added at room temperature under a hydrogen atmosphere, the reaction mixture was stirred for 24 hours at the same temperature. The reaction mixture was heated to 40 ° C., and stirred for 1 hour. The reaction mixture was filtered through Celite, the filtrate was concentrated under reduced pressure to obtain 3- (1- (2-ethoxy-2-oxoethyl)-1H-imidazol-2-yl) crude propanoic acid.

[0155]

(Reference Example 10) 2- (2- (3- (4-morpholino-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) Synthesis of ethyl acetate:
[Formula 18]

　crude 3- (1- (2-ethoxy-2-oxoethyl)-1H-imidazol-2-yl) propanoic acid (0.200 g, 0.884 mmol) in dichloromethane (10.0 mL) was added diisopropylethylamine (0.171 g, 1 .33mmol), HBTU (0.402g, 1.06mmol ), added 4- (piperidin-4-yl) morpholine (0.151 g, 0.884 mmol) at room temperature, the reaction mixture was stirred for 12 hours at the same temperature. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography (NH silica gel, n- hexane / ethyl acetate and chloroform / methanol) to give 2- (2- (3- (4-morpholino-1-yl) -3-oxopropyl) - 1H- imidazol-1-yl) acetate (0.265 g, 0.700 mmol, 79%) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 1.29 (3H, t, J = 7.2 Hz), 1.30-1.45 (2H, m), 1.81-1.92 (2H, m), 2.39 (IH, tt, J = 10.8, 3.6 Hz), 2.53 (4H, t, J = 4.8 Hz), 2.59 (1H, td, J = 13.2, 2.8 Hz), 2.91 (4H, s), 3.01 (1H, td, J = 13.2, 2.8 Hz), 3.71 (4H, t, J = 4.8 Hz), 3.97-4.04 (1H, m), 4.23 (2H, q, J = 7.2 Hz), 4.54-4.62 (1H, m), 4.75 (2H, s), 6.82 (IH, d, J = 1.6 Hz), 6.96 (IH, d, J = 1.6 Hz).
ESI-MS: m / z = 379 (M + H) + .

[0156]

(Reference Example 11) 2- (2- (3- (4-morpholino-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) -acetic acid:
[Formula

　19] 2- (2 - (3- (4-morpholino-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) acetate (0.500 g, in ethanol (1.4 mL) solution of 1.32 mmol), aqueous sodium hydroxide (1.0 N, 1.45 mL, 1.45 mmol) was added at room temperature, the reaction mixture was stirred for 2 hours at the same temperature. After cooling to 0 ° C., then neutralized with hydrochloric acid (1.0 N) was added to the reaction solution, and concentrated under reduced pressure. Azeotroped with toluene, was added ethanol. The precipitate was filtered through Celite, the filtrate was concentrated under reduced pressure, 2- (2- (3- (4-morpholino-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) acetic acid (0. 380 g, 1.08 mmol, was obtained 82%) as a white solid.
1 H-NMR (400 MHz, CD 3 OD) [delta]: 1.44-1.76 (2H, m), 2.07-2.18 (2H, m), 2.57-2.70 (IH, m), 2.82-3.00 (2H, m), 3.05-3.35 (8H, m), 3.84-4.07 (5H, m), 4.59-4.68 (IH, m), 4.76-4.90 (2H, m), 7.35 - 7.43 (2H, m).
ESI-MS: 351 (M Tasu H) Tasu .

[0157]

(Example 1) (S) -3- (2- (3- (3- ( dimethylamino) pyrrolidin-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) propanoic acid n- butyl synthesis:
[Formula

　20] (S) -3- (2-(3- (3- (dimethylamino) pyrrolidin-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) propanoic acid ( 0.100 g, chloroform (3.0 mL) solution of 0.324 mmol), diisopropylethylamine (0.113mL, 0.649mmol), HBTU ( 0.184g, 0.486mmol), butan-1-ol (0.0590ML added 0.649 mmol) at room temperature, the reaction mixture was stirred at the same temperature for 16 hours. 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), (S) -3- (2- (3- (3- ( dimethylamino) pyrrolidin-1-yl) -3-oxopropyl) - 1H- imidazol-1-yl) propanoic acid n- butyl (0.115g, 0.316mmol, 97%) ( hereinafter, to give the compound) example 1 as a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 0.92 (3H, t, J = 7.2 Hz), 1.28-1.40 (2H, m), 1.54-1.85 (IH, m), 2.05-2.28 (8H, m ), 2.56-3.53 (10H, m) , 3.63-3.85 (2H, m), 4.08 (2H, t, J = 7.2 Hz), 4.22-4.27 (2H, m), 6.85-6.95 (2H, m).
MS-ESI: M / Z = 365 (M Tasu H) Tasu .

[0158]

(Example 2) (S) -3- (2- (3- (3- ( dimethylamino) pyrrolidin-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) propanoic acid n- butyl synthesis of the hydrochloride salt:
[Chemical formula

　21] (S) -3- (2-(3- (3- (dimethylamino) pyrrolidin-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) propane acid n- butyl (0.115 g, 0.316 mmol) in diethyl ether (2.0 mL) solution of diethyl ether solution of hydrogen chloride (2.0N, 0.347mL, 0.694mmol) was added at 0 ° C., the reaction liquid was stirred for 30 minutes at the same temperature. Deposited were collected by filtration white solid, washed with diethyl ether (8.0 mL), after 36 hours drying at room temperature, (S) -3- (2- ( 3- (3- ( dimethylamino) pyrrolidin-1-yl ) -3-oxopropyl)-1H-imidazol-1-yl) propanoic acid n- butyl hydrochloride (0.124g, 0.283mmol, 90%) ( hereinafter, to give the compound) example 2 as a white solid .
1 H-NMR (400 MHz, D 2 O) [delta]: 0.86 (3H, t, J = 7.6 Hz), 1.22-1.36 (2H, m), 1.53-1.62 (2H, m), 2.07-2.35 (IH, m), 2.45-2.63 (1H, m ), 2.99-3.07 (10H, m), 3.25-4.14 (9H, m), 4.45-4.52 (2H, m), 7.34-7.37 (1H, m), 7.41- 7.44 (IH, m).
ESI-MS: (S) -3- (2-(3- (3- (dimethylamino) pyrrolidin-1-yl) -3-oxopropyl)-1H-imidazol-1-yl ) propanoic acid n- butyl: m / z = 365 (M + H) + .

[0159]

(Example 3) (S) -3- (2- (3- (3- ( dimethylamino) pyrrolidin-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) propanoic acid n- hexyl synthesis:
[Formula

　22] (S) -3- (2-(3- (3- (dimethylamino) pyrrolidin-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) propanoic acid ( 0.100 g, chloroform (3.0 mL) solution of 0.324 mmol), diisopropylethylamine (0.113mL, 0.649mmol), HBTU ( 0.184g, 0.486mmol), hexan-1-ol (0.0810ML added 0.649 mmol) at room temperature, the reaction mixture was stirred at the same temperature for 16 hours. 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), (S) -3- (2- (3- (3- ( dimethylamino) pyrrolidin-1-yl) -3-oxopropyl) - 1H- imidazol-1-yl) propanoic acid n- hexyl (0.0700g, 0.178mmol, 55%) ( hereinafter, to give the compound) of example 3 as a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 0.82-0.92 (3H, m), 1.22-1.38 (8H, m), 1.65-1.92 (IH, m), 2.05-2.27 (7H, m), 2.55 -3.52 (9H, m), 3.62-3.85 (2H, m), 4.07 (2H, t, J = 7.2 Hz), 4.22-4.28 (2H, m), 6.83-6.86 (1H, m), 6.89-6.92 (IH, m).
ESI-MS: m / z = 393 (M + H) + .

[0160]

(Example 4) (S) -3- (2- (3- (3- ( dimethylamino) pyrrolidin-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) propanoic acid n- hexyl synthesis of the hydrochloride salt:
[Chemical formula

　23] (S) -3- (2-(3- (3- (dimethylamino) pyrrolidin-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) propane acid n- hexyl (0.0700g, 0.178mmol) in diethyl ether (2.0 mL) solution of diethyl ether solution of hydrogen chloride (2.0 N, 0.196 mL, 0.392 mmol) was added at 0 ° C., the reaction liquid was stirred for 30 minutes at the same temperature. Deposited were collected by filtration white solid, washed with diethyl ether (8.0 mL), after 36 hours drying at room temperature, (S) -3- (2- ( 3- (3- ( dimethylamino) pyrrolidin-1-yl ) -3-oxopropyl)-1H-imidazol-1-yl) propanoic acid n- hexyl hydrochloride (0.0649g, 0.139mmol, 78%) ( hereinafter, to give the compound) of example 4 as a white solid .
1 H-NMR (400 MHz, D 2 O) [delta]: 0.80-0.88 (3H, m), 1.20-1.40 (6H, m), 1.53-1.63 (2H, m), 2.05-2.32 (IH, m), 2.42-2.61 (1H, m), 2.89-3.04 (10H, m), 3.20-3.27 (2H, m), 3.38-4.15 (7H, m), 4.44 (2H, t, J = 6.4 Hz), 7.23- 7.38 (2H, m).
ESI-MS: (S) -3- (2-(3- (3- (dimethylamino) pyrrolidin-1-yl) -3-oxopropyl)-1H-imidazol-1-yl ) propanoic acid n- hexyl: m / z = 393 (M + H) + .

[0161]

(Example 5) (S) -3- (2- (3- (3- ( dimethylamino) pyrrolidin-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) propanoic acid n- heptyl synthesis:
[Formula

　24] (S) -3- (2-(3- (3- (dimethylamino) pyrrolidin-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) propanoic acid ( 0.100 g, chloroform (3.0 mL) solution of 0.324 mmol), diisopropylethylamine (0.113mL, 0.649mmol), HBTU ( 0.184g, 0.486mmol), heptan-1-ol (0.0920ML added 0.649 mmol) at room temperature, the reaction mixture was stirred at the same temperature for 16 hours. 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), (S) -3- (2- (3- (3- ( dimethylamino) pyrrolidin-1-yl) -3-oxopropyl) - 1H- imidazol-1-yl) propanoic acid n- heptyl (0.0950g, 0.234mmol, 72%) ( hereinafter, to give the compound) of example 5 as a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 0.85-0.92 (3H, m), 1.22-1.34 (8H, m), 1.58-1.90 (4H, m), 2.04-2.27 (7H, m), 2.56 -3.52 (8H, m), 3.63-3.85 (2H, m), 4.07 (2H, t, J = 6.8 Hz), 4.22-4.28 (2H, m), 6.84-6.86 (1H, m), 6.90-6.92 (IH, m).
ESI-MS: m / z = 407 (M + H) + .

[0162]

(Example 6) (S) -3- (2- (3- (3- ( dimethylamino) pyrrolidin-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) propanoic acid n- heptyl synthesis of the hydrochloride salt:
[Chemical formula

　25] (S) -3- (2-(3- (3- (dimethylamino) pyrrolidin-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) propane acid n- heptyl (0.0950g, 0.234mmol) in diethyl ether (2.0 mL) solution of diethyl ether solution of hydrogen chloride (2.0N, 0.257mL, 0.514mmol) was added at 0 ° C., the reaction liquid was stirred for 30 minutes at the same temperature. Deposited were collected by filtration white solid, washed with diethyl ether (8.0 mL), after 36 hours drying at room temperature, (S) -3- (2- ( 3- (3- ( dimethylamino) pyrrolidin-1-yl ) -3-oxopropyl)-1H-imidazol-1-yl) propanoic acid n- heptyl hydrochloride (0.0740g, 0.154mmol, 66%) ( hereinafter, to give the compound) of example 6 as a white solid .
1 H-NMR (400 MHz, D 2 O) [delta]: 0.82-0.90 (3H, m), 1.18-1.30 (8H, m), 1.54-1.65 (2H, m), 2.05-2.35 (IH, m), 2.45-2.64 (1H, m), 2.92-2.98 (8H, m), 3.01-3.08 (2H, m), 3.26-3.34 (2H, m), 3.39-4.16 (7H, m), 4.45-4.52 (2H , m), 7.30-7.45 (2H, m).
ESI-MS: (S) -3- (2-(3- (3- (dimethylamino) pyrrolidin-1-yl) -3-oxopropyl) -1H - imidazole-1-yl) propanoic acid n- heptyl: m / z = 407 (M + H) + .

[0163]

(Example 7) (S) -3- (2- (3- (3- ( dimethylamino) pyrrolidin-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) propanoic acid n- octyl synthesis:
[Chemical Formula

　26] (S) -3- (2-(3- (3- (dimethylamino) pyrrolidin-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) propanoic acid ( 0.100 g, chloroform (3.0 mL) solution of 0.324 mmol), diisopropylethylamine (0.113mL, 0.649mmol), HBTU ( 0.184g, 0.486mmol), octan-1-ol (0.103 mL added 0.649 mmol) at room temperature, the reaction mixture was stirred at the same temperature for 16 hours. 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), (S) -3- (2- (3- (3- ( dimethylamino) pyrrolidin-1-yl) -3-oxopropyl) - 1H- imidazol-1-yl) propanoic acid n- octyl (0.0850g, 0.202mmol, 62%) ( hereinafter, to give the compound) of example 7 as a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 0.84-0.92 (3H, m), 1.20-1.36 (10H, m), 1.55-1.90 (2H, m), 2.02-2.18 (2H, m), 2.26 (6H, s), 2.57-3.85 (11H, m), 4.07 (2H, t, J = 6.8 Hz), 4.20-4.27 (2H, m), 6.82-6.92 (2H, m).
ESI-MS: m / Z = 421 (M Tasu H) Tasu .

[0164]

(Example 8) (S) -3- (2- (3- (3- ( dimethylamino) pyrrolidin-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) propanoic acid n- octyl synthesis of the hydrochloride salt:
[Chemical formula

　27] (S) -3- (2-(3- (3- (dimethylamino) pyrrolidin-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) propane acid n- octyl (0.0850g, 0.202mmol) in diethyl ether (2.0 mL) solution of diethyl ether solution of hydrogen chloride (2.0 N, 0.222 mL, 0.444 mmol) was added at 0 ° C., the reaction liquid was stirred for 30 minutes at the same temperature. Deposited were collected by filtration white solid, washed with diethyl ether (8.0 mL), after 36 hours drying at room temperature, (S) -3- (2- ( 3- (3- ( dimethylamino) pyrrolidin-1-yl ) -3-oxopropyl)-1H-imidazol-1-yl) propanoic acid n- octyl hydrochloride (0.0733g, 0.149mmol, 74%) ( hereinafter, to give the compound) of example 8 as a white solid .
1 H-NMR (400 MHz, D 2 O) [delta]: 0.84 (3H, t, J = 6.8 Hz), 1.18-1.35 (10H, m), 1.52-1.62 (2H, m), 2.04-2.30 (IH, m), 2.40-2.60 (1H, m ), 2.84-2.94 (8H, m), 2.97-3.04 (2H, m), 3.17-3.27 (2H, m), 3.36-4.14 (7H, m), 4.39- 4.46 (2H, m), 7.20-7.38 (2H, m).
ESI-MS: (S) -3- (2-(3- (3- (dimethylamino) pyrrolidin-1-yl) -3-oxopropyl )-1H-imidazol-1-yl) propanoic acid n- octyl: m / z = 421 (M + H) + .

[0165]

(Example 9) 2- (2- (3- (4-morpholino-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) -acetic acid n- propyl:
[Formula

　28] 2 - (2- (3- (4-morpholino-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) chloroform acetic acid (0.200 g, 0.571 mmol) (3.0 mL) solution to, diisopropylethylamine (0.199mL, 1.14mmol), HBTU ( 0.325g, 0.856mmol), propan-1-ol (0.0860mL, 1.14mmol) was added at room temperature, the reaction solution at the same temperature 16 hours and the mixture was stirred. 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), 2- (2- (3- (4-morpholino-1-yl) -3-oxopropyl)-1H-imidazol-1-yl ) acetic acid n- propyl (0.201g, 0.512mmol, 90%) ( hereinafter, to give the compound) of example 9 as a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 0.90-0.98 (3H, m), 1.29-1.48 (2H, m), 1.54-1.72 (4H, m), 2.34-2.65 (6H, m), 2.88 -3.05 (5H, m), 3.68-3.76 (4H, m), 3.95-4.05 (1H, m), 4.10-4.14 (2H, m), 4.54-4.64 (1H, m), 4.76 (2H, s) , 6.81-6.83 (IH, m), 6.96-6.98 (IH, m).
ESI-MS: m / z = 393 (M + H) + .

[0166]

(Example 10) Synthesis of 2 (2- (3- (4-morpholino-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) acetic acid n- propyl hydrochloride:
[Formula 29 ]

　diethyl ether 2- (2- (3- (4-morpholino-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) acetic acid n- propyl (0.201 g, 0.512 mmol) to (2.0 mL) solution of diethyl ether solution of hydrogen chloride (2.0N, 0.560mL, 1.12mmol) was added at 0 ° C., the reaction was stirred at the same temperature for 30 minutes. Deposited were collected by filtration white solid, washed with diethyl ether (8.0 mL), after 36 hours drying at room temperature, 2- (2- (3- (4-morpholino-1-yl) -3-oxopropyl) -1H- imidazol-1-yl) acetic acid n- propyl hydrochloride (0.160g, 0.344mmol, 67%) ( hereinafter, to give the compound) of example 10 as a white solid.
1 H-NMR (400 MHz, D 2 O) [delta]: 0.85-0.95 (3H, m), 1.48-1.73 (4H, m), 2.17-2.27 (2H, m), 2.65-2.75 (IH, m), 2.96-3.04 (2H, m), 3.10-4.12 (13H, m), 4.18-4.24 (2H, m), 4.47-4.57 (1H, m), 5.17 (2H, s), 7.35-7.37 (2H, m .)
ESI-MS: 2- as (2- (3- (4-morpholino-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) acetic acid n- propyl: m / z = 393 (M Tasu H) Tasu .

[0167]

(Example 11) 2- (2- (3- (4-morpholino-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) -acetic acid n- butyl:
[Formula

　30] 2 - (2- (3- (4-morpholino-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) chloroform acetic acid (0.100 g, 0.285 mmol) (3.0 mL) solution to, diisopropylethylamine (0.100mL, 0.571mmol), HBTU ( 0.162g, 0.428mmol), butan-1-ol (0.0520mL, 0.571mmol) was added at room temperature, the reaction solution at the same temperature 16 hours and the mixture was stirred. 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), 2- (2- (3- (4-morpholino-1-yl) -3-oxopropyl)-1H-imidazol-1-yl ) acetate n- butyl (0.0980g, 0.241mmol, 85%) ( hereinafter, to give the compound) of example 11 as a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 0.93 (3H, t, J = 7.6 Hz), 1.23-1.66 (6H, m), 1.80-1.90 (2H, m), 2.34-2.44 (IH, m ), 2.50-2.64 (5H, m) , 2.89-3.05 (5H, m), 3.68-3.74 (4H, m), 3.96-4.04 (1H, m), 4.08-4.19 (2H, m), 4.53-4.61 (IH, m), 4.75 (2H, s), 6.80-6.82 (IH, m), 6.91-6.93 (IH, m).
ESI-MS: m / z = 407 (M + H) + .

[0168]

(Example 12) Synthesis of 2 (2- (3- (4-morpholino-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) acetic acid n- butyl hydrochloride
[formula 31 ]

　diethyl ether 2- (2- (3- (4-morpholino-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) acetic acid n- butyl (0.0980g, 0.241mmol) to (2.0 mL) solution of diethyl ether solution of hydrogen chloride (2.0 N, 0.265 mL, 0.530 mmol) was added at 0 ° C., the reaction was stirred at the same temperature for 30 minutes. Deposited were collected by filtration white solid, washed with diethyl ether (8.0 mL), after 36 hours drying at room temperature, 2- (2- (3- (4-morpholino-1-yl) -3-oxopropyl) -1H- imidazol-1-yl) acetic acid n- butyl hydrochloride (0.0790g, 0.165mmol, 68%) ( hereinafter, to give the compound) of example 12 as a white solid.
1 H-NMR (400 MHz, D 2 O) [delta]: 0.85-0.93 (3H, m), 1.28-1.40 (2H, m), 1.50-1.76 (4H, m), 2.19-2.29 (2H, m), 2.67-2.77 (1H, m), 2.98-3.04 (2H, m), 3.12-3.60 (8H, m), 3.75-4.20 (5H, m), 4.23-4.30 (2H, m), 4.48-4.58 (1H , m), 5.19 (2H, m), 7.38 - 7.43 (2H, m).
ESI-MS: 2-(2-(3- (4-morpholino-1-yl) -3-oxopropyl) -1H - imidazol-1-yl) as the acetic acid n- butyl: m / z = 407 (M + H) + .

[0169]

(Example 13) 2- (2- (3- (4-morpholino-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) -acetic acid n- pentyl:
[Formula

　32] 2 - (2- (3- (4-morpholino-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) chloroform acetic acid (0.200 g, 0.571 mmol) (3.0 mL) solution to, diisopropylethylamine (0.199mL, 1.14mmol), HBTU ( 0.325g, 0.856mmol), pentan-1-ol (0.124 mL, 1.14 mmol) was added at room temperature, the reaction solution at the same temperature 16 hours and the mixture was stirred. 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), 2- (2- (3- (4-morpholino-1-yl) -3-oxopropyl)-1H-imidazol-1-yl ) acetic acid n- pentyl (0.199g, 0.473mmol, 83%) ( hereinafter, to give the compound) of example 13 as a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 0.85-0.94 (3H, m), 1.22-1.45 (6H, m), 1.55-1.68 (2H, m), 1.80-1.90 (2H, m), 2.34 -2.44 (1H, m), 2.48-2.65 (5H, m), 2.88-3.05 (5H, m), 3.67-3.74 (4H, m), 3.95-4.05 (1H, m), 4.13-4.18 (2H, m), 4.52-4.62 (IH, m), 4.75 (2H, s), 6.80-6.83 (IH, m), 6.95-6.98 (IH, m).
ESI-MS: m / z = 421 (M + H ) + .

[0170]

(Example 14) Synthesis of 2 (2- (3- (4-morpholino-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) acetic acid n- pentyl hydrochloride
[formula 33 ]

　diethyl ether 2- (2- (3- (4-morpholino-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) acetic acid n- pentyl (0.199 g, 0.473 mmol) to (2.0 mL) solution of diethyl ether solution of hydrogen chloride (2.0N, 0.521mL, 1.04mmol) was added at 0 ° C., the reaction was stirred at the same temperature for 30 minutes. Deposited were collected by filtration white solid, washed with diethyl ether (8.0 mL), after 36 hours drying at room temperature, 2- (2- (3- (4-morpholino-1-yl) -3-oxopropyl) -1H- imidazol-1-yl) acetic acid n- pentyl hydrochloride (0.181g, 0.367mmol, 78%) ( hereinafter, to give the compound) of example 14 as a white solid.
1 H-NMR (400 MHz, D 2 O) [delta]: 0.83-0.88 (3H, m), 1.25-1.33 (4H, m), 1.45-1.72 (4H, m), 2.15-2.25 (2H, m), 2.65-2.75 (1H, m), 2.95-3.02 (2H, m), 3.12-4.13 (13H, m), 4.20-4.26 (2H, m), 4.48-4.56 (1H, m), 5.15 (2H, s ), 7.30 - 7.35 (. 2H, m)
ESI-MS: 2-(2-(3- (4-morpholino-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) acetic acid n - as pentyl: m / z = 421 (M + H) + .

[0171]

(Example 15) 2- (2- (3- (4-morpholino-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) -acetic acid n- hexyl:
[Formula

　34] 2 - (2- (3- (4-morpholino-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) chloroform acetic acid (0.100 g, 0.285 mmol) (3.0 mL) solution to, diisopropylethylamine (0.100mL, 0.571mmol), HBTU ( 0.162g, 0.428mmol), hexan-1-ol (0.0370mL, 0.405mmol) was added at room temperature, the reaction solution at the same temperature 16 hours and the mixture was stirred. 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), 2- (2- (3- (4-morpholino-1-yl) -3-oxopropyl)-1H-imidazol-1-yl ) acetic acid n- hexyl (0.0950g, 0.219mmol, 77%) ( hereinafter, to give the compound) of example 15 as a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 0.85-0.93 (3H, m), 1.24-1.45 (8H, m), 1.58-1.64 (2H, m), 1.80-1.91 (2H, m), 2.38 -2.44 (1H, m), 2.50-2.64 (5H, m), 2.89-3.05 (5H, m), 3.68-3.74 (4H, m), 3.95-4.04 (1H, m), 4.12-4.18 (2H, m), 4.53-4.60 (IH, m), 4.75 (2H, s), 6.80-6.82 (IH, m), 6.95-6.97 (IH, m).
ESI-MS: m / z = 435 (M + H ) + .

[0172]

(Example 16) Synthesis of 2 (2- (3- (4-morpholino-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) acetic acid n- hexyl hydrochloride
[formula 35 ]

　diethyl ether 2- (2- (3- (4-morpholino-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) acetic acid n- hexyl (0.0950g, 0.219mmol) to (2.0 mL) solution of diethyl ether solution of hydrogen chloride (2.0 N, 0.240 mL, 0.480 mmol) was added at 0 ° C., the reaction was stirred at the same temperature for 30 minutes. Deposited were collected by filtration white solid, washed with diethyl ether (8.0 mL), after 36 hours drying at room temperature, 2- (2- (3- (4-morpholino-1-yl) -3-oxopropyl) -1H- imidazol-1-yl) acetic acid n- hexyl hydrochloride (0.0809g, 0.159mmol, 73%) ( hereinafter, to give the compound) of example 16 as a white solid.
1 H-NMR (400 MHz, D 2 O) [delta]: 0.84 (3H, t, J = 6.4 Hz), 1.23-1.35 (6H, m), 1.50-1.75 (4H, m), 2.18-2.30 (2H, m), 2.67-2.76 (1H, m ), 2.98-3.05 (2H, m), 3.13-3.63 (8H, m), 3.74-4.28 (7H, m), 4.48-4.57 (1H, m), 5.17- 5.22 (2H, m), 7.37-7.42 (2H, m).
ESI-MS: 2-(2-(3- (4-morpholino-1-yl) -3-oxopropyl)-1H-imidazole -1 - yl) as the acetic acid n- hexyl: m / z = 435 (M + H) + .

[0173]

(Example 17) 2- (2- (3- (4-morpholino-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) -acetic acid n- heptyl:
[Formula

　36] 2 - (2- (3- (4-morpholino-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) chloroform acetic acid (0.100 g, 0.285 mmol) (3.0 mL) solution to, diisopropylethylamine (0.100mL, 0.571mmol), HBTU ( 0.162g, 0.428mmol), heptan-1-ol (0.0810mL, 0.571mmol) was added at room temperature, the reaction solution at the same temperature 16 hours and the mixture was stirred. 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), 2- (2- (3- (4-morpholino-1-yl) -3-oxopropyl)-1H-imidazol-1-yl ) acetic acid n- heptyl (0.110g, 0.245mmol, 86%) ( hereinafter, to give the compound) of example 17 as a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 0.86-0.92 (3H, m), 1.20-1.46 (10H, m), 1.55 - 1.65 (2H, m), 1.80-1.91 (2H, m), 2.34 -2.44 (1H, m), 2.48-2.64 (5H, m), 2.89-2.92 (4H, m), 2.96-3.04 (1H, m), 3.68-3.73 (4H, m), 3.96-4.04 (1H, m), 4.15 (2H, t, J = 6.8 Hz), 4.53-4.61 (IH, m), 4.75 (2H, s), 6.80-6.82 (IH, m), 6.95-6.97 (IH, m).
ESI -MS: M / Z = 449 (M Tasu H) Tasu .

[0174]

(Example 18) Synthesis of 2 (2- (3- (4-morpholino-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) acetic acid n- heptyl hydrochloride
[formula 37 ]

　diethyl ether 2- (2- (3- (4-morpholino-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) acetic acid n- heptyl (0.110 g, 0.245 mmol) to (2.0 mL) solution of diethyl ether solution of hydrogen chloride (2.0N, 0.270mL, 0.540mmol) was added at 0 ° C., the reaction was stirred at the same temperature for 30 minutes. Deposited were collected by filtration white solid, washed with diethyl ether (8.0 mL), after 36 hours drying at room temperature, 2- (2- (3- (4-morpholino-1-yl) -3-oxopropyl) -1H- imidazol-1-yl) acetic acid n- heptyl hydrochloride (0.0819g, 0.157mmol, 64%) ( hereinafter, to give the compound) of example 18 as a white solid.
1 H-NMR (400 MHz, D 2 O) [delta]: 0.82-0.88 (3H, m), 1.20-1.34 (8H, m), 1.46-1.70 (4H, m), 2.15-2.26 (2H, m), 2.65-2.75 (1H, m), 2.94-3.02 (2H, m), 3.10-4.12 (13H, m), 4.24 (2H, t, J = 6.4 Hz), 4.47-4.66 (1H, m), 5.12 ( 2H, s), 7.26-7.34 (. 2H, m)
ESI-MS: 2-(2-(3- (4-morpholino-1-yl) -3-oxopropyl)-1H-imidazol-1-yl as) acetate n- heptyl: m / z = 449 (M + H) + .

[0175]

(Example 19) 2- (2- (3- (4-morpholino-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) -acetic acid n- octyl:
Formula

　38] 2 - (2- (3- (4-morpholino-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) chloroform acetic acid (0.100 g, 0.285 mmol) (3.0 mL) solution to, diisopropylethylamine (0.100mL, 0.571mmol), HBTU ( 0.162g, 0.428mmol), octan-1-ol (0.0900mL, 0.571mmol) was added at room temperature, the reaction solution at the same temperature 16 hours and the mixture was stirred. 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), 2- (2- (3- (4-morpholino-1-yl) -3-oxopropyl)-1H-imidazol-1-yl ) acetic acid n- octyl (0.0980g, 0.212mmol, 74%) ( hereinafter, to give the compound) of example 19 as a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) [delta]: 0.84-0.92 (3H, m), 1.20-1.45 (12H, m), 1.55 - 1.65 (2H, m), 1.80-1.92 (2H, m), 2.32 -2.44 (1H, m), 2.49-2.64 (5H, m), 2.87-3.05 (5H, m), 3.66-3.74 (4H, m), 3.94-4.05 (1H, m), 4.15 (2H, t, = 6.8 Hz J), 4.53-4.63 (IH, m), 4.75 (2H, s), 6.80-6.84 (IH, m), 6.94-6.98 (IH, m).
ESI-MS: m / z = 463 ( Tasu H M) Tasu .

[0176]

(Example 20) Synthesis of 2 (2- (3- (4-morpholino-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) acetic acid n- octyl hydrochloride
[formula 39 ]

　diethyl ether 2- (2- (3- (4-morpholino-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) acetic acid n- octyl (0.0980g, 0.212mmol) to (2.0 mL) solution of diethyl ether solution of hydrogen chloride (2.0N, 0.233mL, 0.466mmol) was added at 0 ° C., the reaction was stirred at the same temperature for 30 minutes. Deposited were collected by filtration white solid, washed with diethyl ether (8.0 mL), after 36 hours drying at room temperature, 2- (2- (3- (4-morpholino-1-yl) -3-oxopropyl) -1H- imidazol-1-yl) acetic acid n- octyl hydrochloride (0.755g, 0.141mmol, 66%) ( hereinafter, to give the compound) of example 20 as a white solid.
1 H-NMR (400 MHz, D 2 O) [delta]: 0.85 (3H, t, J = 6.8 Hz), 1.20-1.35 (10H, m), 1.52-1.77 (4H, m), 2.18-2.30 (2H, m), 2.67-2.76 (1H, m ), 2.97-3.05 (2H, m), 3.13-3.59 (8H, m), 3.74-4.28 (7H, m), 4.48-4.67 (1H, m), 5.20 ( 2H, s), 7.38 - 7.42 (. 2H, m)
ESI-MS: 2-(2-(3- (4-morpholino-1-yl) -3-oxopropyl)-1H-imidazol-1-yl as) acetate n- octyl: m / z = 463 (M + H) + .

[0177]

(Example 21) 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.

[0178]

　The cyclic amine derivative (I) or a pharmacologically acceptable salt thereof, using the compound of Example 4,6,8,10,12,14,16,18 or 20 for evaluation.

[0179]

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.

[0180]

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

[0181]

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

[0182]

　After sciatic nerve ligation surgery 7 days, the mice of spared nerve ligation group, the compound (compounds of Examples 4, 6 and 8 of Example 4,6,8,10,12,14,16,18 or 20, compound of each 1 ~ 10 mg / kg, examples 16 and 18, respectively 0.1 ~ 10 mg / kg, the compounds of examples 10, 12 and 14, respectively 0.01 ~ 10 mg / kg, the compound of example 20 It is, 0.1 ~ 1mg / kg) or positive control as pregabalin (10 mg / kg; a KEMPROTEC), was orally administered by dissolving in distilled water. Mice of spared nerve ligation group, the group treated with the compound of Example 4,6,8,10,12,14,16,18 or 20, "a compound of spared nerve ligation + Example 4" group, "compound of spared nerve ligation + example 6" group, "a compound of spared nerve ligation + example 8" group, "a compound of spared nerve ligation + example 10" group, "spared nerve ligation + example compound 12 "group," a compound of spared nerve ligation + example 14 "group," a compound of spared nerve ligation + example 16 "group," a compound of spared nerve ligation + example 18 "group," sciatic and compounds "group nerve ligation + example 20, the group treated with pregabalin, was" spared nerve 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.

[0183]

　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.

[0184]

2. Results:
　The results are shown in Figure 1-9. In the figure, the vertical axis von Frey total score of the test (mean ± standard error;. Figure 1-9, n = 5 ~ a 6) indicates, 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), ♯: Shirley-Williams test (p <0.025)) indicates that.

[0185]

　According to the results of the von Frey test, carried out oral administration of the compound of Example 4,6,8,10,12,14,16,18 or 20 ( "spared nerve ligation + examples in FIG. 4, 6 and 8 the compound of 10,12,14,16,18 or 20 "), in a manner similar to the positive control at a pregabalin (" spared nerve ligation + pregabalin "in the figure), shows a statistically significant analgesic effect It was.

[0186]

　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.

[0187]

(Example 22) 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.

[0188]

　The cyclic amine derivative (I) or a pharmacologically acceptable salt thereof, using the compound of Example 6 or 18 for evaluation.

[0189]

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, experimental rats fibromyalgia reared by similarly injected intramuscularly saline instead of acidic saline is not developed ( "saline + distilled water" group in FIG. 10 or 11) I was used to.

[0190]

　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) .

[0191]

　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.

[0192]

　Compound of Example 6 or 18 (compound of Example 6, 10 ~ 100 mg / kg, the compound of Example 18, 1 ~ 100mg / kg) is orally dissolved in distilled water fibromyalgia model rats was administered ( "compounds of acidic saline + example 6" in FIG. 10, in FIG. 11, "compounds of acidic saline + example 18"). Pregabalin as a positive control; and (10mg / kg KEMPROTEC), was orally administered was dissolved in distilled water ( "acidic saline + pregabalin" in FIG. 10 or in 11). As a control, it was orally administered distilled water fibromyalgia model rats ( "acidic saline + distilled water" in FIG. 10 or in 11). Further, in rats fibromyalgia is not developed, the distilled water was orally administered (in FIG. 10 or in 11 "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.

[0193]

2. Results:
　The results are shown in FIG. 10 or 11. In the figure, the vertical axis is 50% reaction threshold (mean of the right hind and left hind) (g) (mean ± standard error, n = 4 ~ 6) shows the numerical in fibromyalgia model rats higher indicating that the recognized allodynia has been improved.

[0194]

　10 or 11 shows the results of oral administration of each compound of Example 6 or 18. In the figure, the horizontal axis shows the prior oral administration of the compound of Example 6 or 18 (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, Welch test , as a result of Williams test or Shirley-Williams test, statistically significant (§: t-test or Welch-test (p <0.05), ♯: Williams test or Shirley-Williams test (p <0. 025)) show that.

[0195]

　Group of the compound were administered orally in Example 6 or 18 (in FIG. "Compounds of acidic saline + Example 6 or 18"), the group with pregabalin positive control was orally administered (in Figure "acidic physiological Like the saline + pregabalin "), was allodynia observed in fibromyalgia model rats was improved by significantly statistically compared with" acidic saline + distilled water "group.

[0196]

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

Industrial Applicability

[0197]

　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.

The scope of the claims

[Claim 1]

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

[In the formula, A represents a group of formula (IIa) or (IIb),
[Formula 2]

　* the stereochemistry of the asymmetric carbon attached is of the S
　configuration, R 1 is represents an alkyl group having 3 to 8 carbon atoms,
　if it represents a group a is represented by formula (IIa), n represents 2,
　if it represents a group a is represented by the formula (IIb) is n It represents one. ]

[Claim 2]

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

[Claim 3]

　Cyclic amine derivative represented by the general formula (I), (S) -3- (2- (3- (3- (dimethylamino) pyrrolidin-1-yl) -3-oxopropyl)-1H-imidazole -1 - yl) propanoic acid n- butyl, (S) -3- (2- (3- (3- (dimethylamino) pyrrolidin-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) propane acid n- hexyl, (S) -3- (2- (3- (3- (dimethylamino) pyrrolidin-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) propanoic acid n- heptyl and from (S) -3- (2- (3- (3- (dimethylamino) pyrrolidin-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) group consisting of propanoic acid n- octyl compounds der selected , A cyclic amine derivative or a pharmacologically acceptable salt thereof according to claim 2, wherein.

[Claim 4]

　A is a group of formula (IIb), a cyclic amine derivative or a pharmacologically acceptable salt thereof according to claim 1, wherein.

[Claim 5]

　Cyclic amine derivative represented by the general formula (I), 2- (2- (3- (4-morpholino-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) acetic acid n- propyl , 2- (2- (3- (4-morpholino-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) acetic acid n- butyl, 2- (2- (3- (4- morpholino-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) acetic acid n- pentyl, 2- (2- (3- (4-morpholino-1-yl) -3-oxopropyl )-1H-imidazol-1-yl) acetic acid n- hexyl, 2- (2- (3- (4-morpholino-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) acetic acid n - hept And 2- (2- (3- (4-morpholino-1-yl) -3-oxopropyl)-1H-imidazol-1-yl) compound selected from the group consisting of acetic acid n- octyl, wherein cyclic amine derivative or a pharmacologically acceptable salt thereof to claim 4.

[Claim 6]

　Comprising as an active ingredient a cyclic amine derivative or a pharmacologically acceptable salt of any one of claims 1-5, pharmaceutical.

[Claim 7]

　Containing a cyclic amine derivative or a pharmacologically acceptable salt of any one of claims 1 to 5 as an active ingredient, an analgesic.

[8.]

　Containing a cyclic amine derivative or a pharmacologically acceptable salt of any one of claims 1 to 5 as an active ingredient, neuropathic pain therapeutic agent.

[Claim 9]

　Containing a cyclic amine derivative or a pharmacologically acceptable salt of any one of claims 1 to 5 as an active ingredient, fibromyalgia treatment.