TW200950782A - Therapeutic agent for cerebral infarction - Google Patents

Abstract

The invention provides a novel therapeutic agent for cerebral infarction using piperazine compounds as active component. Related compounds of the invention can be used to make a novel therapeutic agent for cerebral infarction with effect of inhibiting volume of damaged brain or improving neurological symptom by inhibiting generation of majority inflammatory cells intein and chemokine such as TNF-α,IL-1β,IL-6 and MCP-1 et cetera.

Description

200950782 IX. Description of the Invention [Technical Field of the Invention] The present invention relates to a novel therapeutic agent for cerebral infarction. [Prior Art] Conditions of cerebral ischemia can be classified into a hyperacute phase (from the onset to 3 hours) and an acute phase (from onset to 2 weeks). Neuronal cell death of cerebral ischemic sputum is known to be associated with excitatory amino acid toxicity and free radicals. Regarding the excitomic acid toxicity, in the hyperacute phase, the glutamate caused by the energy disorder is free, or the cellular disorder caused by the calcium influx to the receptor is generated, and an inflammatory reaction is caused in the acute phase ( Non-patent document 1). Regarding free radicals, their increase or hypoxia state is transmitted through the transcription factor Kappa B ( Nuclear factor /c'B, hereinafter referred to as NF-zcB) and Hypoxia-inducible transcription factor-1 (hereinafter). Expression of an inflammatory gene (proinflammatroy gene) by the generation of a transcription factor such as HIF-1 and signal transducer and activator of transcription 3 (hereinafter referred to as STAT3) (Non-Patent Document 2) ). Through these mechanisms, 'Tumor necrosis factor-α (hereinafter referred to as TNF-α), interleukin-1β' (hereinafter referred to as IL-Ιβ), and interleukin-6 (Interleukin-6) are produced. Inflammatory interleukin (Cyt〇kine), hereinafter referred to as IL-6, is believed to cause brain edema or inflammatory cell infiltration due to these interferons, which contribute to nerve damage. -4- 200950782 Now, in the case of drugs that exhibit brain protection during ischemia, only EDAROVONE, which captures free radicals (hydroxyl radicals), can be used for cerebral infarction (atherosclerotic cerebral infarction, small Treatment of hole infarction, cardiogenic cerebral embolism. On the other hand, ion channel (Ca2+, Na+) inhibitory drugs or glutamate receptor inhibitors, although inhibiting cerebral infarction in animal experiments, did not show efficacy in clinical tests. Therefore, a brain protective drug is expected to have a new action sequence such as inhibition of nerve inflammation, and to protect brain cells and to inhibit the expansion of the ischemic nest. Regarding the inhibition of inflammatory interleukins that are reported to have a neurotoxic effect in cerebral ischemic conditions, it has been reported that, for example, in animal experiments, local cerebral deficiencies are induced in rats by administration of TNF-α. In the case where the blood disorder is deteriorated, cerebral ischemic disturbance is weakened by intraventricular administration of the TNF-α antibody (Non-Patent Document 3). Furthermore, it has been reported that TNF-α-converting enzyme inhibitor DPH-0675 17 inhibits TNF-α expression in the cerebral infarction side in a rat model of cerebral infarction, and reduces neurological symptoms or cerebral infarction volume (Non-Patent Document 4 ❹) . In addition, it has been reported that injection of recombinant IL-Ιβ into the rat brain causes an increase in cerebral infarction (Non-Patent Document 5), and further, it is disclosed that administration of IL-Ιβ receptor anti-drug (recombinant IL-lra) The mitigating effect of cerebral ischemic disorder occurs (Non-Patent Document 6). In addition, it has been reported that in the clinical trial (Phasell), administration of recombinant IL-1 r a produces a mitigating effect of cerebral ischemic disorder (Non-Patent Document 7). However, no low molecular compound having an effect on the IL-Ιβ molecule itself has been reported so far, and the above-mentioned DPH-0675 17 does not inhibit the IL-Ιβ expression on the cerebral infarction side. As described above, various inflammatory mediators and cerebral infarction have been reported so far, but the effects are not sufficient. On the other hand, the present inventors have found that a piperazine compound having the characteristics as described in Patent Documents 1 and 2 can be used as a compound which inhibits TNF-α. Patent Document 1 describes diseases in which the compound is caused by abnormalities in various TNF-α, TNF-a mediation, or diseases which can be treated by interleukin 10 (IL-1 0) (transplantation, osteoporosis, It is effective for myocardial infarction, chronic heart failure, blood stasis heart failure, ischemia-reperfusion injury, and the like, and Patent Document 2 describes that the compound is effective for non-viral hepatitis. Further, in Non-Patent Documents 8 and 9, it is reported that the compound inhibits the production of inflammatory mediators of TNF-α and IL-12, and promotes the production of IL-10 against inflammatory mediators. And the joint rheumatism model is effective. However, whether or not the compound is effective against cerebral infarction, whether or not it further has a therapeutic effect on cerebral infarction, is not described or suggested. [Patent Document 1] WO 99/19301 (Patent Document 2) WO20 05/1 0301 No. 3 [Non-Patent Document 1] Dirnagl, U. et al., Trends. Neurosci., 22, 3 9 1 -397 (1 999) [Non-Patent Document 2] 0 Bu 113 § 1, 11.61 & 1., 1 > 611 (13· Neurosci., 26, 248-254 (2003) [Non-Patent Document 3] Barone, FC Et al., Stroke, 28, 1 223-1 244 (1 997) [Non-Patent Document 4] Wang, X., et al., Molecular 200950782 pharmacology, 65, 8 90-896 (2004) [Non-Patent Document 5 ] Yamazaki, Y. et al., Stroke, 26, 676-681 (1995) [Non-Patent Document 6] Betz, A. L. et al., J. Cereb. Blood Flow Metab., 15, 547-5 5 1 (1955) [Non-Patent Document 7] Emsley, HCA et al., J. Neurol. Neurosurg. Psych., 76, 1366-1372 (2005) ❹ [Non-Patent Document 8] Fukuda, T. et al_, J . pharmacy

Pharmacol., 57, 1-6 (2005) [Non-Patent Document 9] 33 (1〇1116,]^.61&1., ugly 111······ Pharmacol., 497, 3 5 1 -3 5 9 (2004) [Problems to be Solved by the Invention] The present inventors have found that by using a monkey's middle cerebral artery to permanently block a sputum type, magnetic resonance imaging (Magnetic resonance imaging) is used in the same manner as clinical practice. Hereinafter, the MRI is used to measure the brain damage volume, and the detailed neurological symptoms (high-order function) can be determined, and a certain piperazine compound can be provided as a therapeutic agent for novel cerebral infarction, and the present invention can be completed. Further, it has been found that the present compound not only inhibits, for example, TNF-α inflammatory interleukin or IL-12, interferon γ (interferon γ, hereinafter referred to as IFN-γ) 'Μ inhibits IL-1 β, IL-6 and monocyte chemotactic protein- 1, hereinafter referred to as MPC-1) and other interleukins and chemokines. It was further confirmed that this compound inhibits the TNF-α, IL-Ιβ, IL-6 and MPC- present in the brain 200950782. 1 or more complex interleukins and chemotactic factors. [Methods for solving the problem] The present invention is as follows. [1] A therapeutic agent for cerebral infarction, which is a piperazine compound represented by the formula <1> (hereinafter, described as a compound of the present invention <1>) Or its pharmaceutically acceptable salt as an active ingredient, [Chemical 1]

R1 and R2 are the same or different and each represents an amine or a nitro group which is mono- or disubstituted by a group selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, amine, lower alkyl and lower alkyl. , hydroxy or cyano; R 3 , R 4 , R 5 are the same or different and each represents a group selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, nitro, amine, lower alkyl and lower alkyl. Mono- or di-substituted amine, hydroxy or cyano; R6, R7 are the same or different, each represents a lower alkyl, aralkyl, fluorene substituted by hydrogen, lower alkyl, 1 to 3 halogens a lower sulfhydryl group substituted by 1 to 3 halogens; R8 and R9 are the same or different and each represents hydrogen or a lower alkyl group; -8- 200950782

Ra~R are the same or different, each represents a hydrogen, a lower alkyl group, an aralkyl group or a lower-stage courtyard group; or any two of Ra~Rd are bonded to each other to form a group of a C 1 or 2 alkylene group; Y is a group represented by the following formula, [Chem. 2]

(in the formula,

Rl (>, Rn are the same or different, each represents hydrogen or lower alkyl; R12, R13 are the same or different 'each represents hydrogen or lower alkyl, or Ri2, Rl3 are taken together to form an alkylene group. R14, R15 are the same or different, each represents hydrogen or lower alkyl; m represents an integer of 0 to 2, η represents an integer of 0 to 2, and 〇Sm + n ^ 2); Phenyl, pyrimidinyl, thiazolyl, pyridyl, pyrazolyl or imidazolyl; ring B represents phenyl, pyridyl or thienyl). [2] The therapeutic agent for cerebral infarction according to [i], wherein the active ingredient is a compound represented by the formula <1> wherein the ring B represents a phenyl group, or a pharmaceutically acceptable salt thereof. [3] The therapeutic agent for cerebral infarction described in $2, wherein the active ingredient is in the general formula <1>

R1, R2 represents hydrogen; -9- 200950782 R, R, R5 are the same or different, each represents hydrogen, halogen or lower alkoxy t R6, R7 are the same or different, each represents hydrogen or a hydrazine group; R8, R9 are the same Or different, each represents hydrogen or lower alkyl; R1 Q, R11 represents hydrogen; R 1 4, R 15 represents hydrogen;

Ra ' Rb, Re, Rd means hydrogen, or any two of them are bonded to each other, and represent a carbon number of 1 to form an alkyl group, and the other group represents hydrogen; ring A represents a phenyl group, a pyrimidinyl group, a thiazolyl group or a pyridine group. A compound of the Tpc group or a pharmaceutically acceptable salt thereof. [4] The therapeutic agent for cerebral infarction according to the above [2], wherein the active ingredient is at least one selected from the group consisting of or a pharmaceutically acceptable salt thereof, N-{4-[(4-phenylphene) Pyrazin-1-yl)methyl]phenylmethyl}acetamide, N-(4-{[4-(4-fluorophenyl)piperazine-1-yl]methylindole phenylmethyl) Q Acetamine, N-(4-{ 〔4-(2-fluorophenyl)piperazin-1-yl)methyl}phenylmethyl)acetamide, N-(4- { 〔4- (2 ,4-difluorophenyl)piperazine_ι_yl]methylhydrazine phenylmethyl)acetamide, N-(2-{4-[(4-phenylpiperazin-1-yl)methyl Phenyl}ethyl)acetamide, N-[2-(4-{[4-(4-fluorophenyl)piperazine-indolyl]methyl}phenyl)ethyl]acetamidamine, -10- 200950782 N-( 1- { 4- [(4-Phenylpiperazine-buyl)methyl]phenyl}ethyl)ethylamine, ]^-[1-(4-{[4- (4-oxophenyl)indol-1-yl]methyl}phenyl)ethyl]acetamidamine, N-[l-(4-{[4-(2,4-difluorophenyl)per Xiao-1-yl]methyl}phenyl)ethyl]acetamidamine, N-[l-(4-{[4-(4-fluorophenyl)piperazin-1-yl]methyl}phenyl )-Q 卜 methyl ethyl Indoleamine, N-(l-{4-[(4-phenylindole-1-yl)methyl]phenyl}cyclopropyl)acetamidamine, N-[l-(4-{[4- (4-fluorophenyl)piperazin-1-yl]methyl}phenyl)cyclopropyl]acetamidamine, Ν-{4-[1-(4-phenylpiperazin-1-yl)ethyl Phenylmethyl}acetamidoxime-(4-{1-[4-(4-fluorophenyl)piperazin-1-yl]ethyl}phenylmethylhydrazine) acetamidine, N-( 4-{l-[4-(2,4-difluorophenyl)piperazin-1-yl]ethyl}phenylmethyl)acetamide, 1^-(4-{1-[4-( 4-gashyl) mai-1-yl]-1-methylethyl}phenylmethyl)acetamidine, Ν-(4-{1-[4-(4-fluorophenyl)piperazine -1-yl]-1-methylethyl}phenylmethyl)acetamide, N-[ 1 - ( 4 - { 1 -[ 4 -(pyrimidin-2-yl)piperazine-1-yl] Ethyl}phenyl)cyclopropyl]acetamidamine, and -11 - 200950782 N_ [ 1_ ( 4- { 〔 (is,4S) -5-(pyrimidin-2-yl)-2,5-diaza Bicyclo[2.2.1]heptyl-2-yl]methylindole phenyl)cyclopropyl]acetamidamine [5] The therapeutic agent for cerebral infarction according to [1], wherein the active ingredient is in the general formula <1> a compound represented by a pyridyl group, or a pharmaceutically acceptable compound thereof Salt. [6] The therapeutic agent for cerebral infarction according to [5], wherein the active ingredient is in the formula <1>, R1, R2 represent hydrogen; r3, r4, R5 are the same or different, each represents hydrogen, halogen Or lower alkoxy groups R6, R7 are the same or different, each represents hydrogen or a fluorenyl group; R8, R9 are the same or different, each represents hydrogen or lower alkyl; R1 (), R11 represents hydrogen; R1 4 ' R15 represents hydrogen ;

Ra' Kb' Rd represents hydrogen or any two groups bonded to each other to form a C 1 alkyl group; the other group represents hydrogen; ring A represents phenyl 'pyrimidinyl, thiazolyl or pyridyl; ring B represents A pyridyl compound or a pharmaceutically acceptable salt thereof. [7] The therapeutic agent for cerebral infarction according to the above [5], wherein the active ingredient is at least one selected from the group consisting of the following compounds or a pharmaceutically acceptable salt thereof. N-( 1 - { 5-[ { 4-(pyrimidin-2-yl)piperazine-1-yl}methyl]pyridine-2-yl}cyclopropyl)acetamide, and 1'}-[1 -(5-{[(18,48)-5-(pyrimidin-2-yl)-2,5-diazabis-12- 200950782 ring [2·2·1]heptan-2-yl]methyl Indole pyridin-2-yl) ring

[8] The therapeutic agent for cerebral infarction according to [1], wherein R12 and R13 in the formula <1> are combined to form a stretch or a pharmaceutically acceptable salt thereof [9] as described above. 8] The cerebral infarction therapeutic agent described in which it is selected from at least one of the following compounds or the pharmaceutical 10 N-(l-{4-[(4-phenylpiperazine-bu)methyl]benzene Acetamine, N-[1-(4-{[4-(4-fluorophenyl)piperazin-1-yl]cyclopropyl]acetamidamine, N-[ 1- ( 4- { 1-[ 4-(唆症-2-yl)pyridazin-1-yl)cyclopropyl]acetamidamine, N-[l-(4-{[(lS-4S)-5-(pyrimidin-2-yl)) Ring [2.2.1]hept-2-yl]methyl}phenyl)cyclopropyl]indole N-( 1- { 5-[ { 4-(pyrimidin-2-yl)piperazine- l-yl} 2 -yl}cyclopropyl)acetamide, and N-[1-(5-{[(1S,4S)-5-(pyrimidin-2-yl).cyclo[2.2.1]hept-2-yl] Methyl}pyridin-2-yl)cycloindole [10] The cerebral infarction therapeutic composition as described in the above [2] or [8] is N-[1-(4-{1-[4-( chew D- 2-yl)piperidin-1-yl)cyclopropyl]acetamide or a pharmaceutically acceptable salt thereof. Divided into the base of the alkyl group, the active ingredient is 叮 allowed salt, based on cyclopropyl)methyl}phenyl)]ethyl}phenyl-2,5-diazabisacetamide, a methyl]pyridine--2,5-diazabispropyl]acetamidine therapeutic agent, wherein there is an ethyl}phenyl-13- 200950782 [1 1] as described in the above [2] or [8] A therapeutic agent for cerebral infarction, wherein the active ingredient is Ν-[1-(4-{1·[4-(pyrimidin-2-yl)piperazin-1-yl]ethyl}phenyl)cyclopropyl]acetamide Hydrochloride. [12] The therapeutic agent for cerebral infarction according to [1], wherein the cerebral infarction is atherosclerotic cerebral infarction, small hole infarction or cardiogenic cerebral embolism. [13] a piperazine compound or a pharmaceutically acceptable salt thereof, which is a formula

< 2 >

Wherein R1 and R2 are the same or different and each represents an amine which is mono- or disubstituted by a group selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, amine, lower alkyl and lower alkyl. a group, a nitro group, a hydroxy group or a cyano group, and R3, R4, and R5 are the same or different, each represented by a group selected from the group consisting of hydrogen, halogen, lower-grade, lower alkoxy, nitro, amine, lower alkyl, and lower. The thiol group is a mono- or di-substituted amine group, a hydroxyl group or a cyano group, and R6 and R7 are the same or different, each represents a lower alkyl group substituted by hydrogen, a lower alkyl group, and 1 to 3 halogens. Alkyl, fluorenyl or a lower awake group substituted by 1 to 3 halogens, R8 'R9 are the same or different, each represents hydrogen or lower alkyl, -14- 200950782

Ra~Rd are the same or different, each of which represents hydrogen, a lower alkyl group, an aralkyl group or a combination of two lower-ordered bases or Ra~Rd to form a alkyl group having a carbon number of 1 to 2, Y Is a base represented by the following formula, [Chemical 4]

❹ (wherein, or R1(), R11 are the same or different, each represents hydrogen or lower alkyl, Rl2, R13 are the same or different, each represents hydrogen or lower alkyl, and Rl3 is taken together to form a stretch. The base of R, R is the same or different, each represents hydrogen or lower alkyl, ❹ m represents an integer of 〇~2, „ represents an integer of 0~2, and m + n ^ 2 ), ring A Is a phenyl, pyrimidinyl, thiazolyl, pyridyl, pyrazolyl or imidazolyl group, and ring B1 represents a pyridyl or thienyl group. [I4] A piperazine compound or a pharmaceutically acceptable salt thereof, Expressed by the general formula < 3 >, -15- 200950782 [Chemical 5]

R1 and R2 are the same or different and each represents an amine group which is mono- or disubstituted by a group selected from the group consisting of hydrogen, halogen, lower alkyl group, lower alkoxy group, amine group, lower alkyl group and lower alkyl group. R3, R4, R5 are the same or different, each represented by a group selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, nitro, amine, lower alkyl and lower sulfhydryl The mono- or di-substituted amine group, hydroxyl group or cyano group, R6, R7 are the same or different, each represents a lower alkyl group, an aralkyl group substituted by hydrogen, a lower alkyl group, a halogen of 1 to 3, Sulfhydryl or a lower fluorenyl group substituted by 1 to 3 halogens, ❹ R8 'R9 are the same or different and each represents hydrogen or lower alkyl,

At least one of Rla to Rld's Rla to Rld is a group which represents any two of lower alkyl, aralkyl or hydroxy lower alkyl' or Rla to Rld bonded to each other to form an alkylene group having 1 to 2 carbon atoms. Other substituents are the same or different, each represents hydrogen, lower alkyl, aralkyl or hydroxy lower alkyl, and Y represents a group represented by the following formula, -16-200950782 [Chem. 6]

(wherein R 1Q and R11 are the same or different, each represents hydrogen or a lower alkyl group, and U R12 and R13 are the same or different, each represents hydrogen or a lower alkyl group, or Rs and R13 are taken together to form a stretch. The alkyl group, R14, R15 are the same or different 'each represents hydrogen or lower alkyl, m is an integer of 0 to 2 'n represents an integer of 〇~2, and 〇gm + n ^ 2 ), Ring A is a non-phenyl group, a mouth π group, a thiazolyl group, a pyridyl group, a pyridyl group or an imidazolyl group. [15] The piperazine compound of [13] or a pharmaceutically acceptable sulfonium salt thereof is represented by the formula <4>, [Chem. 7]

<4> (wherein R and R2 are the same or different from each other' each represents a group consisting of a group selected from the group consisting of hydrogen, halogen, lower alkyl 'lower alkoxy, amine, lower alkyl and lower alkyl; -17- 200950782 Disubstituted amine, nitro, hydroxy or cyano, R3, R4, R5 are the same or different, each represented by a group selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, nitro, The amine group, the lower alkyl group and the lower alkyl group are mono- or disubstituted amine groups, hydroxyl groups or cyano groups, and R6 group represents a mercapto group or a lower mercapto group substituted by 1 to 3 halogens.

Ra to Ra are the same or different and each represents hydrogen, a lower alkyl group, an aralkyl group or a hydroxy lower alkyl group, or any two of Ra to Rd are bonded to each other to form a group having a carbon number of 1 to 2. [16] The piperazine compound of [14] or a pharmaceutically acceptable salt thereof, which is represented by the formula <5>, [Chem. 8]

<5>

Wherein R1 and R2 are the same or different and each represents an amine which is mono- or disubstituted by a group selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, amine, lower alkyl and lower alkyl. R3, R4, R5 are the same or different, each represented by a group selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, nitro, amine, lower alkyl and lower The base of the thiol group is mono- or disubstituted with an amine group, a hydroxyl group or a cyano group, and R6 represents a fluorenyl group or a lower sulfhydryl group substituted with 1 to 3 halogens, and 1113~1 1 1 is a 'Rla~Rld at least 1 One means that the lower alkyl group, the aralkyl group-18-200950782 or the hydroxy lower alkyl group, or any two of Rla~Rld are bonded to each other to form a group of a C 1 to 2 alkyl group, and the other substituents are the same or Different, each represents hydrogen, lower alkyl, aralkyl or hydroxy lower alkyl). [17] The piperazine compound of any one of [14] or [16] or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of N-(l-{4-[(3,5-) Dimethyl-4-pyrimidin-2-ylpiperazin-1-yl)methyl]phenyl}cyclopropyl)acetamide, N-[l-(4-{ 〔(3S) -3 -methyl 4-pyran-2-ylindole-1-yl]methyl}phenyl)cyclopropyl]acetamidamine, 1&lt;[-[1-(4-{[(18,48)-5-) (pyrimidin-2-yl)-2,5-diazabicyclo[2.2-1]hept-2-yl]methyl}phenyl)cyclopropyl]acetamidamine, N-( 1- { 4-[ { 2,5-Dimethyl-4-(pyrimidin-2-yl)}piperazin-1-yl)methyl]phenyl}cyclopropyl)acetamidamine, [(2R)-2-methyl 4-(pyrimidin-2-yl))piperazine-1-yl]methyl}phenyl)cyclopropyl]acetamidamine and Q 1 (Bu {4-[{(2,6-dimethyl-) 4-(pyrimidin-2-yl))piperazin-1-yl}methyl]phenyl}cyclopropyl)acetamide or a pipe according to any one of [13] or [15] a compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of N _ ( 1 _ { 5 -[ { 4 -(pyrimidin-2-yl)piperazin-1 -yl)methyl]pyridine-2-yl} ring Propyl)acetamide and N-[l-(5-{ 〔 lS,4S)-5-(Butidine-2-yl)-2,5-azabicyclo[2.2.1]hept-2-yl]methyl}pyridin-2-yl)cyclopropyl]B Awakening amine-19-200950782 [Effect of the invention] The compound of the formula <1> is useful as a therapeutic drug for cerebral infarction. These compounds' inhibit inflammatory mediators or chemokines such as TNF-α, IL-Ιβ, IL-6, MCP-1, which are produced in the brain. Further, in the monkey model of permanent occlusion of the middle cerebral artery, these compounds reduce the volume of brain damage and improve high-grade neurological function. [Embodiment] Hereinafter, the present invention will be described in further detail. The therapeutic agent of the present invention contains the compound represented by the above formula &lt;1&gt; as an active ingredient. The meaning of each symbol in the above formula &lt;1&gt; is as follows. R1,! The halogen in ^2 means fluorine, chlorine, bromine or iodine. The lower alkyl group in R1 and R2 means an alkyl group having 1 to 4 carbon atoms, and is represented by a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a third butyl group or the like. R1,! The lower alkoxy group in the term "alkoxy group having 1 to 4 carbon atoms" means a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a butyloxy group or the like. In the case of R1 and R2 which are selected from the group consisting of a lower alkyl group and a lower alkyl group, the lower alkyl group as a substituent means an alkyl group having 1 to 4 carbon atoms. Base, ethyl, propyl, isopropyl, butyl, isobutyl, butyl, and the like. The lower fluorenyl group as a substituent means a lower alkyl fluorenyl group, a lower alkoxycarbonyl group or a lower alkyl fluorenyl group substituted by a phenyl group having a carbon number of 1 -20 to 200950782 to 4, for example, a fluorenyl group or a Indenyl, propyl fluorenyl, butyl fluorenyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, butyloxycarbonyl, benzoyl Anthracenyl, phenylethenyl, phenylpropanyl. The amine group which is mono- or disubstituted by the substituents represents a methylamino group, a dimethylamino group, an ethylamino group, a diethylamino group, a propylamino group, a butylamino group, an acetamide. Base, diethylamine hydrazino, propyl decylamino group, dipropyl decylamino group, butyl decylamino group, N-methyl-N-ethyl decylamino group, N-ethyl-N-ethyl oxime amino group, N-methyl-N-propionylamino, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butyloxycarbonylamino, benzhydrylamino, Phenylethylamino group and the like. The halogen in R3, R4 and R5 represents fluorine, chlorine and bromine. The lower alkyl group in R3, R4 and R5 means an alkyl group having 1 to 4 carbon atoms and represents a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a ternary butyl group or the like. The lower alkoxy group of 〇R3, R4 and R5 means an alkoxy group having 1 to 4 carbon atoms, and represents a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, and a third group. Butoxy and the like. R3, R4' R5 is a mono- or di-substituted amino group selected from the group consisting of a lower alkyl group and a lower mercapto group, and the lower alkyl group as a substituent means an alkyl group having 1 to 4 carbon atoms, which means Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, butyl, and the like. The lower fluorenyl group as a substituent means a lower alkyl fluorenyl group having a carbon number of 1 to 4, a lower alkoxycarbonyl group or a lower alkyl fluorenyl group substituted with a phenyl group, and represents, for example, a fluorenyl group, an ethyl fluorenyl group, a propylene group. , butyl thiol-21 - 200950782 'methoxycarbonyl' ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl 'butoxycarbonyl, isobutoxycarbonyl, butyloxycarbonyl, benzamidine Base, phenylethylhydrazine, phenylpropyl fluorenyl. The amine group which is mono- or disubstituted by the substituents means methylamino group, dimethylamino group, ethylamino group, diethylamino group, propylamino group, butylamino group, acetamide. , dimethylamino, propyl decylamino, dipropyl decylamino, butyl decyl amide, N-methyl-N-ethyl hydrazino, N-ethyl-N-ethyl amide, N -methyl-N-propionylamino, © methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butyloxycarbonylamino, benzhydrylamino, Phenylethylamino group and the like. The lower alkyl group in R6 and R7 means an alkyl group having 1 to 4 carbon atoms and represents a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a ternary butyl group or the like. One to three halogen-substituted lower alkyl groups in R6 and R7 are those in which a lower alkyl group having 1 to 4 carbon atoms is substituted by halogen (fluorine, chlorine, bromine, etc.), and represents a fluoromethyl group or a trifluoro group. Methyl, chloromethyl, bromomethyl, 2-fluoroethyl < 2,2,2-trifluoroethyl, 2-chloroethyl, 2-bromoethyl, 3-fluoropropyl, 3-chloro Propyl, 4-fluorobutyl, 4-chlorobutyl, and the like. The aralkyl group in R6 or R7 represents a benzyl group, a 2-phenylethyl group, a 3-phenylpropyl group or the like. The fluorenyl group in R6 and R7 means a lower alkyl alkoxide group having 1 to 5 carbon atoms, a lower alkoxycarbonyl group having 1 to 4 carbon atoms, and a lower alkyl group having 1 to 4 carbon atoms substituted by a phenyl group or a pyridyl group. Alkyl fluorenyl or a lower alkyl sulfonyl group having 1 to 4 carbon atoms, which represents a fluorenyl group, an ethyl fluorenyl group, a propyl fluorenyl group, a butyl fluorenyl group, a pentamidine group, an isovaleryl group, a trimethyl acetyl group, a Oxycarbonyl, ethoxycarbonyl, propoxycarbonyl-22- 200950782, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, butyloxycarbonyl, benzamidine, nicotine Sulfhydryl, isonicotinicinyl, pyridinium, phenylethenyl, phenylpropionyl, methylsulfonyl and the like. One or three halogen-substituted lower fluorenyl groups in R6 and R7 are those in which a lower fluorenyl group having 1 to 4 carbon atoms is substituted by halogen (fluorine, chlorine, bromine, etc.), and represents a fluoroethane group or a trifluoro group. Ethylene, chloroethyl, bromoethyl, 3-chloropropenyl, 3-bromopropyl, 4-chlorobutenyl, 4-bromobutenyl, and the like. The lower alkyl group in 〇r8 and r9 means an alkyl group having 1 to 4 carbon atoms, and represents a methyl group, an ethyl group, a propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a 2nd butyl group, and a first 3 butyl and the like.

The lower alkyl group in Ra, Rb, Re, and Rd means an alkyl group having 1 to 4 carbon atoms, and represents a methyl group, an ethyl group, a propyl group, an isopropyl group, a n-butyl group, an isobutyl group, and a second group. Base, 3rd butyl, etc.

The aralkyl group in Ra, Rb, Re, and Rd represents a benzyl group, a 2-phenylethyl group, a 3-phenylpropyl group or the like. The lower alkyl group of the hydroxy lower alkyl group in Ra, Rb, Re, and Rd means an alkyl group having 1 to 4 carbon atoms, and represents a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, and a different alkyl group. Butyl, t-butyl, ternary butyl and the like.

Ra, Rb, R. Any two of Rd, which are bonded to each other to form a alkyl group having 1 or 2 carbon atoms, represent a methylene group, an ethylidene group and the like. The lower alkyl group in R1() and R11 means an alkyl group having 1 to 4 carbon atoms, and represents a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group or the like. The lower alkyl group in R12 and R13 means an alkyl group having 1 to 4 carbon atoms, and represents a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group or the like. -23- 200950782 R12 and R13 are taken together to form an alkyl group, which means a methylene group, an ethyl group, a trimethylene group, a tetramethylene group or a pentamethylene group. The lower alkyl group in R14 and R15 means an alkyl group having a carbon number of 丨 to 4, and represents a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group or the like. A pyrimidinyl, thiazolyl, pyridyl, pyrazolyl, imidazolyl group of ring A, which is a 2-non-spotty group, a 4-s-steep group, a 5-n-steep group, a 2-thiazino group, a 4-thiazolyl group , 5-thiazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pioxazolyl, 2-imidazolyl, and the like. The pyridyl group and the thienyl group of the ring B represent a 2-pyridyl-3-pyridyl group, a 4-deuterium D-group, a 2-thienyl group, a 3-thienyl group and the like.

The lower alkyl group in Rla, Rlb, Rie, and Rld means a group having 1 to 4 carbon atoms, which means methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, and second. Base, third butyl, and the like.

The aralkyl group in Rla, Rlb, Rle, and Rld means a benzyl group, a 2-phenylethyl group, a 3-phenylpropyl group or the like. The lower alkyl group of the hydroxy lower alkyl group in Rla, Rlb, Rle, and Rld means an alkyl group having 1 to 4 carbon atoms, and represents a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, and a different alkyl group. Butyl group, second butyl group, third butyl group and the like.

Any two of Rh, Rlb, Rle, and Rid are bonded to each other to form a group having a C 1 to 2 alkyl group, which means a methylene group or an exoethyl group. In particular, in the general formula &lt;1&gt;, R1 and R2 represent hydrogen, and R3, R4 and R5 are the same or different, each represents hydrogen, halogen or lower alkoxy, and R6 and R7 are the same or different. Each represents hydrogen or a fluorenyl group, and R9 is the same or different from each, 'each represents hydrogen or lower alkyl, Rio, RM represents hydrogen, -24-200950782 R14, and R15 represents hydrogen, Ra, Rb, R°, Rd Represents hydrogen' or any two groups bonded to each other to form a C1 alkyl group, the other group represents hydrogen, and ring A represents phenyl, pyrimidinyl, thiazolyl or pyridyl' ring B represents phenyl or A pyridyl compound or a pharmaceutically acceptable salt thereof is preferred. Particularly preferred is a compound or a pharmaceutically acceptable salt thereof. Among the above compounds, Ra, Rb, Re, and Rd represent hydrogen, and ring B represents a phenyl group. The pharmaceutically acceptable salt of the compound &lt;1&gt; of the present invention may, for example, be an inorganic acid salt such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid or phosphoric acid, or acetic acid, maleic acid or fumar. Acidic acid, benzoic acid, citric acid, succinic acid, tartaric acid, malic acid, mandelic acid, methanesulfonic acid, benzene acid, P-toluenesulfonic acid, 10-camphorsulfonic acid and the like. Further, the compound of the present invention &lt;1&gt; may also be a fourth-order ammonium salt. The compound of the present invention &lt;1&gt; or a pharmaceutically acceptable salt thereof may also be a hydrate (1 hydrate, 1/2 hydrate, 1/4 hydrate, 1/5 hydrate, 2 hydrate, 3/). 2 hydrate, 3/4 hydrate hydrazine, etc.), solvate. Further, the compound &lt;1&gt; of the present invention has at least two kinds of optical isomers in the case of having an asymmetric atom. Such optical isomers and their racemates are also included in the present invention. The specific compound to be used may, for example, be a compound described in the above [4], [7], [9], [10], [11] or [17] or a pharmaceutical thereof. Salt that can be tolerated. In particular, 'N-[1 -(4 -([4-(pyrimidin-2-yl)piperazin-1-yl)methyl}phenyl)cyclopropyl]acetamide) or its pharmaceutically acceptable Salt, N-[1-(4-{[(ls,4S)-5-(pyrimidin-2-yl)-2,5-di-25- 200950782 azabicyclo[2.2.1]hept-2- Methyl}phenyl)cyclopropyl]acetamide or a pharmaceutically acceptable salt thereof, and N-(1- { 5-[ { 4-(pyrano-2-yl)piperazine-l -yl}methyl]pyridine·2_ylindole propyl)acetamide or a pharmaceutically acceptable salt thereof, wherein N_[4-{[4-(pyridin-2-) Base). piperidin-1-yl]methyl}phenyl)cyclopropyl]acetamidamine hydrochloride, N-[ 1- (4- { 〔 ( 1S,4S) -5- (pyrimidine) -2-yl)-2,5-diazabicyclo[2-2.1]hept-2-yl]methyl}phenyl)cyclo propyl propyl acetamide. hydrochloride, and N-(l- {5-[ {4-(pyrimidin-2-yl)piperazine-1-yl}methyl]pyridine-2 _yl}cyclopropyl)acetamidamine hydrochloride is suitable. Further, a part of the above compound can be produced according to the method described in International Publication WO 99/1 93 0 1 (hereinafter referred to as Patent Document 1), and the compound exemplified as the above-mentioned suitable compound has been Specific synthesis examples can be referred to. Further, 'may be synthesized by the following methods', but is not limited by the above. In the compound of the present invention, the compound of the compound &lt;1&gt;, wherein the ring B is a phenyl group and all of Ra to Rd are hydrogen, can be produced according to the method described in Patent Document 1. In the compound of the present invention, the ring B is a phenyl group, and one or more of Ra to Rd are compounds other than hydrogen, and the compound III can be replaced with the compound &lt;5-1&gt; by the method A described in Patent Document 1, for example. The method (Aa method) or the method of the K method described in Patent Document 1 (Ka method) is carried out. -26- 200950782 (A-a method)

[In the formula, the compound &lt; 4 &gt; is similar to the compound (π) described in Patent Document 1, and Lv is a cleavage group widely used in the field of organic synthetic chemistry, and represents, for example, spectrin (fluorine, chlorine, bromine, iodine). , methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxy. P1 and P2 include the above-defined R6 and R7, and other protecting groups of an amine group widely used in the field of organic synthetic chemistry, and represent, for example, a benzyloxycarbonyl group, a third butoxycarbonyl group, further P&gt; P2 may be combined with an adjacent nitrogen atom to form a quinone imine group such as quinone. Other notations are synonymous with the foregoing. But at R3 'r4' R5, Rla, Rlb, R1. When Rld has a functional group, it may be protected as necessary. The condensation reaction of the compound &lt;4&gt; with the compound &lt;5-1&gt; can be carried out in the same manner as the method A described in Patent Document 1. Further, the compound <5-1> can be used commercially, or can be synthesized from a commercially available piperazine derivative &lt;6-1&gt; by, for example, (A_a_1 method) shown below. (Α-a-l method) -27- 200950782 〔化1 〇〕

R1a R1b 3 λ~Ι\ P3—N NH R3

Xid &lt;6-1 &gt; 鹸, solvent or solvent free

&lt;5-1 &gt; [In the formula, P3 represents a protecting group widely used for an amine group in the field of organic synthetic chemistry, such as a third butoxycarbonyl group, a benzyloxycarbonyl group, and an LV1 aromatic nucleophilic substitution reaction. A widely used de-bonding group, meaning halogen (fluoro 'chloro, bromo, iodine), methanesulfonyloxy, p-toluenesulfoxy, trifluoromethanesulfonyloxy, phenylsulfonylphenyl, benzenesulfonate Alkoxy, phenylsulfonyl, azide, aryloxy, alkoxy, alkylthio, amine, other symbols, as defined above. The condensation reaction of the compound &lt;6-1&gt; with the compound &lt;7&gt; can be carried out by the same method as in the (K method) described in Patent Document 1, or in the DD method described in Patent Document 1. (XLII) is carried out in the same manner as the method of directly obtaining the compound (III). The deprotection reaction system can be carried out by, for example, a general amine group described in the literature such as Protective groups in organic synthesis (John Willey &amp; Sons, INC.) (hereinafter, referred to as Non-Patent Document 1). The protective reaction proceeds. Further, the compound &lt;6-1&gt; can be used as a commercially available one, or can be carried out by a suitable protecting group by using a method described in the literature such as Non-Patent Document 1 by using an amine group of a commercially available piperazine derivative. Protected and synthesized. (K-a method) -28- 200950782 〔化11〕

[Formula] P4 represents a protecting group widely used for a hydrogen atom or an amine group in the field of organic synthetic chemistry, such as a third butoxycarbonyl group, a benzyloxycarbonyl group, and other symbols are as described above. The condensation reaction of the compound &lt;4&gt; with the compound &lt;6-2&gt; is the same as the (κ method) described in Patent Document 1, or in the (DD method) described in Patent Document 1, In the same manner as the method of directly obtaining the compound (xlII), the compound (xlII) is subjected to 'deprotection by the method described in Non-Patent Document 等' in the case where p4 is a protecting group. ; 8 &gt;. The compound &lt;8 &gt; was reacted with the compound &lt;8&gt; under the same conditions as the K method described in Patent Document 1, whereby Compound &lt;3&gt; was obtained. The compound &lt;6-2&gt; can be obtained by a commercially available person, or by an amine group of a commercially available piperazine derivative, using a method described in, for example, Non-Patent Document 1 and the like, with an appropriate protecting group. Protected and synthesized. 2) The compound of the present invention, wherein the cyclic oxime in the compound &lt;1 &gt; is a pyridyl group or a thienyl group, can be synthesized, for example, by the same method as the oxime method described in Patent Document 1 (A-b method). -29- 200950782 (A-b method) [Chem. 1 2]

Φ'

[In the formula, the cyclic oxime 1 is a pyridyl group or a thienyl group, and the other symbols are as described above. The condensation reaction of the compound &lt;9&gt; with the compound &lt;5-2&gt; can be carried out in the same manner as in the method described in Patent Document 1. Further, the compound &lt;5-2&gt; can be synthesized from a commercially available carbazine derivative by a commercially available method or a method similar to (A-a-1), for example, in the same manner as in &lt;5-1&gt;. 3) Among the compounds of the present invention, the ring β in the compound &lt;ι&gt; is pyridyl or thienyl, m = n = 0, and R12 and R13 are taken together to form an ethyl group of R6 and R7. One compound is hydrogen, the other is an ethyl hydrazine group, and R8 and R9 are hydrogen compounds &lt;1&gt;, and the compound &lt;16&gt; can be synthesized by, for example, the following method, and by, for example, the patent document The method described in the A method described in 1 is synthesized. (Α-b-l method) -30- 200950782

[In the formula, W represents a carboxylic acid derivative which can be easily converted into each other by a basic and general-purpose method in the field of organic synthetic chemistry, such as a carboxylic acid or a carboxylic acid ester, and the P5 system is broadly described in the field of organic synthetic chemistry. The protecting group used for the hydroxy group, for example, represents a third butyl dimethyl fluorenyl group and the like, and other symbols are as described above. The carboxylic acid derivative &lt;1 〇&gt; is reduced by the same method as the L method described in Patent Document 1, and the compound &lt;1 1 &gt; is produced, and then, for example, the method described in Non-Patent Document 10 or the like is used. A suitable protecting group protects the hydroxyl group to form a compound &lt;12&gt;, as described in J. Org. Chem. 2002, 67, 3965-3968, and Organic Letters 2003, 5 (5), 753-755, etc. The cyano group is converted into a 1-aminocyclopropyl-1-yl group to give a compound &lt;13&gt;, and the method described in, for example, Non-Patent Document 1 ,, or the B 1 method described in Patent Document 1 - 31 - 200950782 In the same manner, the amino group is acetylated to obtain a compound &lt;1 4 &gt; 'and then the compound of the hydroxy group is deprotected to form a compound &lt;15&gt; by the method described in Non-Patent Document 10 or the like. The compound &lt;16&gt; can be obtained by converting a hydroxyl group to a leaving group Lv by a method well known in the art of organic synthetic chemistry. In the method of converting a hydroxyl group to a leaving group Lv, for example, in the case where the leaving group is a sulfonate such as a methanesulfonyloxy group, in a nonaqueous solvent such as methylene chloride or tetrahydrofuran, and in the case of triethyl A method in which an alkyl group or a chlorinated aromatic group or the like acts on the alcohol &lt;14&gt; in the presence of a base such as an amine. The reaction of the compound &lt;16&gt; with the compound &lt;5-2&gt; can be carried out in the same manner as the method A described in Patent Document 1. Further, in the 'compound &lt;9&gt;, m = n = 0 in Y, R12 and R13 are taken together to form a group of an ethyl group, one of R6 and R7 is hydrogen, and the other is an ethyl group. R8 and R9 are compounds other than hydrogen, and can also be produced by combining a method similar to the above and a known method. Further, the carboxylic acid derivative &lt;1〇&gt; can be used commercially, or can be synthesized from a commercially available carboxylic acid derivative of an allyl halide by the following formula A-b-1-l. (A-b-1-l method) [Chemical 1 4]

[In the formula, Hal represents a halogen such as chlorobromide or iodine, and other symbols are as described above in -32-200950782]. The compound &lt;18&gt; is cyanated to give the compound &lt;19&gt;. The cyanide agent used in the cyanidation reaction may, for example, be sodium cyanide, potassium cyanide, copper cyanide, zinc cyanide or trimethylsulfonium p-toluenesulfonyl cyanide. In order to promote the reaction, a metal salt such as palladium acetate or a combination of a ligand such as triphenylphosphine or a metal complex such as tetrakis(triphenylphosphine)palladium or a base such as N-methylpyrrolidine may be used. Or these can be used in combination. The solvent used for the cyanation reaction may, for example, be a lower alcohol such as methanol or ethanol, acetonitrile, dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone or the like or a mixture thereof. The reaction temperature is usually 〇~150 °C, and the temperature above or below may be selected as necessary. The reaction time is usually in the range of 30 minutes to 2 days, and the time above or below may be selected as necessary. In the present invention, a therapeutic agent for brain infarction using the above compound as an active ingredient can be provided. In the case of cerebral infarction, atherosclerotic cerebral infarction, small hole infarction, and cardiogenic cerebral embolism can be cited. Further, in the present invention, an inflammatory interleukin (TNF-α, IL-Ιβ, IL-6, MCP-1, IL-8, IFN-γ) associated with the cerebrospinal cord can be provided as the active ingredient of the above compound. Etc.) related disease treatment drugs. For diseases related to the inflammatory mediators associated with the cerebrospinal fluid, for example, diseases including other diseases such as encephalitis and encephalomyelitis or autoimmune diseases caused by central nervous system inflammation and other diseases can be cited. When the above compound is used as a therapeutic agent for cerebral infarction or the like, it can be prepared into a general pharmaceutical preparation. For example, a mixture of the above compound and an acceptable carrier (excipient, binding agent, disintegrating agent, flavoring agent, odor-33-200950782 agent, emulsifier, diluent, dissolution aid, etc.) can be obtained. Medicinal composition or lozenge, nine-dose, powder, granule, capsule, containing, syrup, liquid, emulsion, suspension, injection (liquid, suspension, etc.), sitting, inhalant Formulations such as skin absorbents, eye drops, nose drops, eye ointments, etc., are suitable for oral or non-oral administration. In the case of a solid preparation, the additive may be, for example, sucrose, lactose, cellulose sugar, D-mannitol, maltitol, dextrin, starch, eg, amaranth, alginate, chitin, several Butan, pectin, dolan, gum arabic, gelatin, collagen 'casein, albumin, calcium phosphate, sorbitol, glycine, carboxymethyl cellulose, polyvinylpyrrolidone, Hydroxypropyl cellulose, hydroxypropyl methylcellulose, glycerin, polyethylene glycol, sodium hydrogencarbonate, magnesium stearate, talc, and the like. Further, the tablet may be formed into a tablet to which a usual lotion is applied, for example, as a sugar-coated tablet, an enteric coated ingot, a film-coated ingot or a two-layer ingot, or a multi-layer ingot. For the preparation of semi-solid preparations, animal and vegetable oils (olive @oil, corn oil, castor oil, etc.), mineral oils (Vaseline, white petrolatum, solid paraffin, etc.), waxes (jojoba oil, cards) can be used. Napa wax, honey wax, etc.), partially synthesized or fully synthesized glycerol fatty acid esters (lauric acid, myristic acid, palmitic acid, etc.). Examples of such commercial products include WITEPSOL (manufactured by Dynamit Nobel Co., Ltd.) and PHARMASOL (manufactured by Nippon Oil & Fats Co., Ltd.). In the case of a liquid preparation, the additive may, for example, be sodium chloride, glucose, sorbitol, glycerin, olive oil, propylene glycol, ethyl alcohol or the like. In particular, in the case of injection, a sterile aqueous solution can be used, for example, physiological saline-34-200950782, isotonic liquid, or an oily liquid such as sesame oil or soybean oil. Further, a suitable suspending agent such as sodium carboxymethylcellulose ionic surfactant, a dissolution aid such as benzyl benzoate, an alcohol or the like is used as necessary. Further, in the case of an eye drop or a nasal spray, an aqueous or aqueous solution is used, and in particular, a sterile aqueous solution for injection is exemplified. At this point or in the nasal liquid solution, it is also possible to add a buffer such as a buffer (for the purpose of reducing the concentration of borate buffer, acetate buffer, carbonate buffer), isotonic agent, and dissolution aid. Agents, preservatives, thickeners, chelating pH adjusters (pH is usually adjusted to about 6 to 8.5 is preferred), aromatic additives. The content of the active ingredient in the preparations is from 1 to 1% by weight of the preparation, suitably from 1 to 50% by weight. The dosage can be changed according to the patient's symptoms, age, etc., and in the case of usual oral administration, it is 0.1 to 30 〇〇 mg in a day, and it can be administered or divided into several doses. [Examples] Hereinafter, the examples will be described in further detail, and the present invention is not limited by the following description. 1·Compound Synthesis Example Example 1. N-(1-{4-[(3,5-Dimethyl.4.pyridin-2-ylpiperidyl)methyl]phenyl}cyclopropyl)B Indoleamine can also be used as a non-benzylic liquid eye, such as light thorn, etc., the amount of the agent is more than -35- 200950782 [Chemical 1 5]

(1) Synthesis of 3,5-dimethylpiperazinecarboxylic acid tert-butyl ester [Chem. 1 6]

571 g of 2,6-dimethylpiperazine was dissolved in dioxane i5 〇ml, and 3.64 g of dibutyl butyl dicarbonate was added, and the mixture was stirred overnight at room temperature. After the solvent was distilled off, 50 ml of water was added to the residue, and the mixture was extracted with methylene chloride (1 ml, 50 ml each). The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. • H-NMR (CDC13) δ : 1_〇6 ( 3H,d,J = 6.3Hz), 1.46 ( 9H,s), 2.23~2.3l (2H,m), 2.27~2.84(2H,m), ❹ 3.80 ~ 4.15 ( 2H, m ). MS: 2 14 (M + +l). (2) Synthesis of 3,5-dimethyl-4-pyrimidin-2-ylpiperazine-i-carboxylic acid tert-butyl ester [Chem. 1 7]

I.676 g of 3,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester was mixed with 2-chloro-36-200950782 pyrimidine 716 mg, melted at an oil bath temperature of 120 ° C, and stirred for 5 hours and 30 minutes. After adding water and stirring, the mixture was extracted with 30 ml of ethyl acetate and washed with saturated brine. After the extract is dried over anhydrous sodium sulfate, the solvent is distilled off, and the obtained residue is purified by column chromatography (Hanashan hi-flashtm COLUMN size L, eluting solvent: hexane/ethyl acetate). The labeled compound 3 3 3 mg was obtained. 'H-NMR (CDC13) δ : 1.25 (6Η, d, J = 6.9Hz), 1.51 ( 9H, s), 2.97 ~ 3.08 ( 2H, m), 3.95~4.16 ( 2H, m), 4·65 〜 4.82 ( 2H,m) , 6.51 ( 1H, t, J = 4.5Hz), 8.34 ( 2H, d, J = 4.8Hz ). MS: 237 (M + + 1 in the form of the third butyl being cleaved). (3) Synthesis of 2-(2,6-dimethylpiperazin-1-yl)pyrimidine hydrochloride [Chem. 1 8]

2,94 mg of 3,5-dimethyl-4-pyrimidin-2-ylpiperazine-carboxylic acid tert-butyl ester was dissolved in 2 ml of ethanol, and 4 hydrochloric acid (ethyl acetate solution) 2 m 1 was added thereto. Stir at room temperature for 4 hours. The solvent was distilled off. The obtained residue was added to ethyl acetate (3 ml), and ethyl acetate insoluble solid was filtered, and dried to give a labeled compound of 281 g. *H-NMR ( DMSO-de ) δ : 1.32 ( 6Η, d, J = 7.2Hz), 3.12~3_43(4H,m), 4.80~4.98(2H,m),6.74(lH,t, J = 5.1 Hz ) , 8.45 ( 2H, d, J = 5. 1 Hz ) , 9.26 ( 1H, brs ), -37- 200950782 10.02 ( 1H, brs ). MS: 1 93 (M + + 1). (4) Synthesis of N-( 1- { 4-[( 3,5-dimethyl-4-pyrimidin-2-ylpiperazin-1-yl)methyl]phenyl}cyclopropyl)acetamide 〔化1 9〕

2 Dissolve 22.3 mg of N-[l-(4-chloromethylphenyl)cyclopropyl]acetamide with 265 mg of 2-(2,6-dimethylpiperazin-1-yl)pyrimidine hydrochloride In Ν, Ν-dimethylformamide 10 mL, potassium 415 mg was added, and stirred at 80 ° C for 8 hours. After adding 20 mL of water and stirring, it was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by column chromatography (Hysan HI-FLASHTM COLUMN size 2L, eluting solvent: hexane / ethyl acetate) to give 245 mg of the title compound. iH-NMR (CDC13) δ : 1.20 〜1.43 ( 10H,m), 2.01 ( 3H, s ) , 2.17 ～2.26 (2H,m ), 2.74 ( 2H, d, J=1 1 . 1 Hz ), 3.48&amp ;3.51(2H,s&amp;s), 4.63~4.69(2H,m),6.10(1H, s),6.43~6.47( 1H,m), 7.10~7.39( 4H,m), 8.32 ( 1H, d, J = 4.8 Hz) 〇MS : 3 80 ( M + + 1 ). Example 2: N-[1-(4-{[(3S)-3-methyl-4-pyrimidin-2-ylpiperazin-1-yl]methyl}phenyl)cyclopropyl]acetamide -38- 200950782 〔化20〕

AcHN (3S)-1-tert-butoxycarbonyl-3-methylpiperazine was used, and the same reaction as in Examples 1 (2) and (3) was carried out in order to obtain (3S)-3A. The group 4-pyrimidin-2-ylpiperazine hydrochloride was then subjected to the same reaction as in Example 1 (4) to give the title compound 2 16 mg. ® 'H-NMR ( CDC13 ) δ : 1.27 ~1 .3 8 ( 7Η,d and m, J = 6.3Hz ), 2.01 (3H, s ) , 2.07 ~2.21( 2H,m ), 2.71 ( 2H, d , J = 1 1 . 1 Hz ) , 2.89 ( 1 H, d, J = 10.8 Hz ) , 3.16 ～ 3.26 (1H, m ) , 3.39 ( 1 H, d, J = 13.2 Hz ) , 3.54 ( 1H, d , J=13.2Hz) , 4.44 ( 1H, d, J = 12.9Hz ) , 4.8 1 ( 1H, brs ), 6.69 ( 1H, s ) , 6.43~6.47 (lH, m), 7.09~7.34 (4H, m ), 8.30 ( 1 H, d, J = 4.8 Hz). MS: 3 66 (M + +1).实施 Example 3: N-[ 1-(4-{ 〔( IS, 4S ) -5-(pyrimidin-2-yl)-2,5-diazabicyclo[2.2.1]hept-2-yl] Methyl phenyl phenyl) cyclopropyl] acetamidine [Chemical 2 1]

AcHN was carried out by the same reaction as in Example 1 (2) and (3) using (IS, 4S)-2,5-diazabicyclo[2.2.1]heptane to obtain (-39-200950782 IS). , 4S)-2-pyrimidin-2-yl-2,5-diazabicyclo[2.2.1]heptane hydrochloride, and then obtained by the same reaction as in Example 1 (4) Compound 2 0 1 mg. ^-NMR ( DMSO-de ) δ : 1.09 ( 4 Η, d, J = 2.7 Hz), 1.75 ( 1 H, d, J = 9.6 Hz ) , 1.88 ( 3H, s ) , 1.90 ( 1H, d, J = 9.6Hz ) , 2.44 ( 1H, d, J = 9.6Hz ) , 2.83 ( 1H, dd , J = 2.1 Hz , 9.6Hz ) , 3.56 ( 1H, d, J = 1 8.6Hz ) , 3.63 ( 2H, s φ ) , 4.71 ( 1H, s ), 6.58 ( 1H, t, J = 5. 1Hz ) , 7.04 ( 2H, d, J = 8,4Hz ) , 7.19 ( 2H, d, J = 8.4Hz) , 8.3 1 ( 2H, d, J = 4.8Hz ), 8.51 ( 1H, s). MS : 3 64 ( M + +1 ). Example 4: N-(l-{4-[{2,5-Dimethyl-4-(pyrimidin-2-yl)}piperazin-1-yl)methyl]phenyl}cyclopropyl) Amidoxime

❹

AcHN was reacted in the same manner as in Examples 1 (1), (2), and (3) using 2,5-trans-dimethylpiperazine to obtain 2-(2,5-dimethylpiperidyl). The pyridyl-1 -ylpyrimidine hydrochloride was then reacted in the same manner as in Example 1 (4) to give 64 mg of the title compound. H-NMR ( DMSO-de ) δ : 0.91 ( 3Η, d, J = 6.6Hz ), 1.12 ( 4H, d, J = 5.4Hz) , 1.18 ( 3H, d, J = 6.6Hz ) , 1.84 ( 3Hs ) ), 2.29 ( 1H, d, J = 11.4 Hz), 2.69 ( 1H, dd, J = 4.5 Hz, -40 - 200950782 12.0 Hz), 3.02 ( 1 H, m ) , 3.44 ( 1 H, d, J = 13.5 Hz) , 3.59 (1 H, d, J = 13.4 Hz), 4.3 3 ( 1 H. d, J = 1 3 . 5 H z ), 4 · 7 5 ( 1 H, t, J = 5.1 Hz) , 6.57 ( 1 H, t, J = 4.5 Hz ) , 7.07 ( 2H, d, J = 8. 1 Hz ) , 7.26 ( 2H, d, J = 8. 1 Hz ) , 8.32 ( 2H, d, J = 5 . 1 Hz ), 8.52 ( 1 H, s ). MS : 3 80 ( M + + 1 )

Example 5: N-[l-(4-{[(2R)-2-methyl-4-(pyrimidin-2-yl))piperazin-1-yl]methyl}phenyl)cyclopropyl Acetamine (23)

(1) (311)-4-{4-[1-(Ethylamino)cyclopropyl]benzyl}-3-

Synthesis of tert-butyl methylpiperazine-1-carboxylate [Chem. 24]

In (4) of Example 1, (3R)-1-tert-butoxycarbonyl-3-methylpiperazine l.〇〇g was used instead of 2-(2,6-dimethylpiperazin-1- The pyrimidine hydrochloride was subjected to the same reaction and treatment to obtain the labeled compound 1 · 119 g. *H-NMR ( DMSO-dg ) δ : 1.03 ( 3Η, d, J = 6.3Hz ), 1.10 ( 4H, m ) , 1.38 ( 9H, s ) , 1.83 ( 3H, s ) , 2.00 ( 1H, n) , 2.36 ( 1H, m) , 2.54 ( 1H, m) , 2.89 ( 1H, m) , 3.02 -41 - 200950782 (1H, m ) , 3.15 ( 1Η, d, J=13.2Hz) , 3.42 to 3.55 (2H , m ), 3.83 ( 1H, d, J=13, 2Hz ) , 7.05 ( 2H, d, J = 8. 1Hz ), 7.17( 2H, d, J = 8. 1 Hz ) , 8.52 ( 1H, s ) . MS: 3 8 8 (M + + 1). (2) Synthesis of N-[l-4-{[(2R)-methylpiperazin-1-yl]methyl}phenyl]cyclopropyl]acetamide hydrochloride © 〔 25

1.97 g of (3R)-4-4{4-[1-(ethylamino)cyclopropyl]benzyl}-3-methylpiperazine-1-carboxylic acid tert-butyl ester was dissolved in ethanol 2 2 ml, 2 ml of 4 hydrochloric acid (ethyl acetate solution) as specified, and stirred at room temperature for 4 hours. The solvent was distilled off to give the labeled compound 1.11 g. 'H-NMR ( DMSO-d6) δ : 1.17 ( 4 Η, m) , 1.57 ( 3H, d, 5.7 Hz ) , 1.87 ( 3H, s), 3.00 to 3.60 (7H, m) , 4.16 ( 1 H, d , J = 12.9Hz), 4.64 ( 1H, d, J = 12.9Hz ) , 7.16 ( 2H, d, J = 7.8Hz ) , 7.52 ( 2H, d, J = 7.8Hz ), 8.64 ( 1H, s ), 9.84 (2H, brs ) , 12.33 ( 1H, brs ). MS: 2 8 8 (M + + 1 ). (3) N-( 1-(4-{[((2R)-2-methyl-4-(pyrimidin-2-yl))piperazin-1-yl]methyl}phenyl)cyclopropyl] Synthesis of acetaminophen-42- 200950782 [Chem. 26]

Vm_〇〇〇nh - TJ u △ (hydrochloride) N-[l-4-{[(2R)-methylpiperazine-buyl]methyl}phenyl]cyclopropyl]acetamide The hydrochloride salt 532 mg and 170 mg of 2-chloropyrimidine and 0.75 ml of diisopropylethylamine were heated at an oil bath temperature of 100 ° C for 2 hours and 10 minutes. 20 ml of water was added, and the mixture was extracted with toluene (20 ml twice) and ethyl acetate (30 ml once), and the organic layer was washed successively with water and saturated brine. After drying over anhydrous sodium sulfate, the solvent was evaporated, and the obtained residue was purified by column chromatography (yield: HI-FLASHTM COLUMN size L, eluting solvent: hexane/ethyl acetate) to give the title compound 196 mg. W-NMR ( DMSO-cU) δ : 1.05 〜 1.12 ( 7H, m), 1.84 (1H, s) , 2.06 ( 1H, m) , 2.43 ( 1H, m) , 2.62 ( 1H, m) , 3.05 ( 1H , dd, J = 8.7Hz, 12.9Hz), 3.13 ( 1H, d, J = 13.2Hz ), 3.20 ( 1H, m ), 3.92 ( 1H, d, J = 13.2Hz ), 4.14 ( 1H, m) , 4.19 ( 1H, m) , 6.59 ( 1H, t, J = 4.8Hz), 7.07 ( 2H,d, J = 8.4Hz ) , 7.21 ( 2H, d, J = 8.4Hz ), 8.32 ( 2H, d, J = 4.8Hz) , 8.52 ( 1H, s ). MS: 3 66 (M + +l). Example 6: Heart (1-{4-[{(2,6-dimethyl-4-(pyrimidin-2-yl))piperazine-l-yl}methyl]phenyl}cyclopropyl)B Guanamine [27] -43- 200950782

AcHN

4-{4-[1] was synthesized in the same manner as in Example 5 (1) using the 3,5-methylpiperidin-1-decanoic acid tert-butyl ester 1.76 g' synthesized in Example 1 (1). -(ethylammonium)cyclopropyl]]}}, 3,5·dimethyl oxazide 1-3 1-butyl carbonate 333 mg 'then, by sequential operation with Example 5(2), ( 3) The same reaction gave the labeled compound 23 mg. 'H-NMR ( DMS〇-d6) δ=1.〇1 (6H,d, J = 6.0Hz), 1.09 (4H,d, J = 4.5Hz), 1.83 ( 3H, s) , 2.74 ( 2H, Dd, J = 10.5 Hz, 12.6 Hz), 3.28 ( 2H, d, J = 12.9 Hz), 3.72 ( 2H, s ), 4.4 1 ( 2H, d, J = 1 1.4 Hz ), 6.59 ( 1H, t, J = 4.5Hz), 7.04 ( 2H, d, J = 7.8Hz ) , 7.25 ( 2H, d, J = 7.8Hz ) , 8.33 ( 2H, d, J = 4.5Hz ) , 8.50 ( 1H, s ). MS : 3 80 ( M + + 1 ).

Example 7: N-(l-{5-[ {4-(pyrimidin-2-yl)pyrazine-1-yl}methyl]pyridin-2-yl}cyclopropyl)acetamide

(1) Synthesis of 6-cyanonicotinic acid methyl ester -44 - 200950782 [Chem. 29]

COOH ooch3 50 mg of 6-cyanonic acid was dissolved in 25 ml of dichloromethane, and 776 mg of water-soluble carbodiimide, 0.164 ml of methanol, and 49 mg of 4-dimethylaminopyridinium were added, and the mixture was stirred for 2 hours and 10 minutes. The reaction solution was washed successively with saturated sodium bicarbonate and saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was distilled off, and the obtained residue was subjected to column chromatography (Mountain HI-FLASHtm COLUMN size 2L, washed). The solvent extraction = hexane / ethyl acetate) was purified to give the labeled compound. The same reaction was carried out again using 547 mg of 6-cyanonicotinic acid to obtain a total of 951 mg of the labeled compound. ^-NMR (CDC13) δ : 4.01 ( 3Η, s) , 7.81 ( 1H, dd, J = 1.2Hz, 8.1Hz) , 8.45 ( 1H, dd, J = 2.4Hz, 8.1Hz) , 9.30 (1 H, t, J = 1, 2Hz). MS : 1 63 ( M + + l ). ❹ (2) Synthesis of 5-(hydroxymethyl)pyridine-2-carbonitrile [30] fH3— 701 mg of 6-cyanonicotinic acid methyl ester was dissolved in a mixed solvent of 1 ml of methanol and 7 ml of tetrahydrofuran in an ice-cold state. 197 mg of sodium borohydride was added thereto, and the mixture was directly allowed to rise to room temperature, and stirred overnight. 20 ml of water was added, and the mixture was extracted with ethyl acetate (50 ml, 30 ml each time), and washed with saturated brine -45-200950782, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by column chromatography (yield HI-FLASHTM COLUMN size 2L, eluting solvent = hexane / ethyl acetate) to afford 264 mg of the title compound. 'H-NMR (CDC13) δ : 2.09 ( 1Η, m) , 4.86 ( 2H, d, J = 5.1Hz ) , 7.71 ( 1H, d, J = 8.1Hz ) , 7.89 ( 1H, dd, J=1 , 8Hz, 8. 1Hz), 8.70 ( 1H, s ). MS: 13 5 (M + +1 ). e (3) Synthesis of 5-(t-butyldimethylsilyloxymethyl)-pyridine-2-carbonitrile 31]

The amine was 8 nU, and 347 mg of tributyldimethylchloromethane and 326 mg of imidazole were added, and the mixture was stirred at room temperature for 1 hour. After adding 20 ml of water and stirring, the mixture was extracted with ethyl acetate (50 ml, 20 ml each time), washed with brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by column chromatography (Hysan HI-FLASHTM COLUMN size 2L, eluting solvent: hexane/ethyl acetate) to give the title compound 40 5 mg. ^-NMR (CDCI3) δ : 0.13 ( 6Η, s) , 0.95 ( 9H, s), 4.83 ( 2H, s ) , 7.68 ( 1H, d, J = 7.8Hz) , 7.8 1 ( 1H, dd, J= 1. 5Hz, 7.8Hz), 8.66 ( 1 H, d, J = 1.5 Hz). MS: 249 (M + +1). -46 - 200950782 (4) Synthesis of 1-[3-(t-butyldimethylsilyloxymethyl)pyridine-2-yl]cyclopropylamine [Chemical 3 2]

Dissolving 5-(t-butyldimethylsilyloxymethyl)-pyridine-2-carbonitrile in 10 ml of tetrahydrofuran, adding 62 ml of tetraisopropoxide, and further dropping the tetrahydrofuran of ethylmagnesium bromide. The solution (1 mo 1/1 ) 4.83 ml was stirred for 1 hour and 30 minutes. To the reaction mixture, 6 ml of a predetermined aqueous sodium hydroxide solution was added, and 20 ml of tetrahydrofuran was further added thereto and stirred, followed by filtration. The filtrate was washed with saturated brine, dried over anhydrous sodium sulfate and then evaporated. The obtained residue was purified by column chromatography (Hysan HI-FLASHTM COLUMN size 2L, eluting solvent: hexane / ethyl acetate) to obtain 192 mg of the labeled compound. *H-NMR (CDC13) δ : 0.10 ( 6Η, s) , 0.93 ( 9H, s), 1.13 ( 2H, m) , 1.26 ( 2H, m) , 4.72 ( 2H, s) , 7.31 ( 2H, d, J = 8. 1 Hz ) , 7.58 ( 2H, d, J = 2.1 Hz, 8.1 Hz), 8.44 ( 1H, s ) ° MS : 2 80 ( M + + 1 ). (5) Synthesis of 1-[3-(t-butyldimethylammonyloxymethyl)pyridin-2-yl]cyclopropylacetamide -47- 200950782 33

190 mg of 1-[5-(t-butyldimethylsilyloxymethyl)pyridin-2-yl]cyclopropylamine was dissolved in 2 ml of pyridine '0.13 ml of anhydrous acetic acid and 4-dimethylaminopyridine 1 7 mg was stirred at room temperature for 4 hours. After adding 2 ml of methanol and stirring for about 10 minutes, the solvent was distilled off, and the residue was purified by column chromatography (yield: HI-FLASHTM COLUMN size L, eluting solvent: hexane/ethyl acetate) to obtain 158 mg of the title compound. H-NMR (CDC13) δ: 0,09 and 0.11 (6H, s), 0.92 and 0.94 (9Η, s), 1_24 to 1.32 (2Η, m), 1.60 to 1.76 (2Η, m), 1.99, 2.07 ( 3H, s), 4.73 and 4.76 (2H, s), 6.12 and 6.24 (1H, s), 7.29 and 7.44 (2H, d, J = 8 · 1 Hz), 7 · 5 6 and 7.61 ( 2H, dd, J = 1.8 Hz, 8 · 1 Ηζ ), 8.40 and 8.44 (1Η, d, ❹ J = 1 · 5Hz). MS : 32 1 ( M + +1 ). (6) Synthesis of N-{ 1-[ 5-(hydroxymethyl)pyridin-2-yl]cyclopropyl}acetamide [Chem. 34]

156 mg of [5-(t-butyldimethylsilyloxymethyl)pyridine-2-48-200950782]cyclopropylacetamide was dissolved in 2 ml of tetrahydrofuran, and tetrahydrofuran of tetrabutylammonium fluoride was added. The solution (lmol/1) 1.46 ml was stirred at room temperature for 25 minutes. The solvent was distilled off. The obtained residue was purified by column chromatography (H.sub.2 HI-FLASHTM COLUMN size L' eluting solvent: ethyl acetate/methanol) to give the title compound 109 mg. !H-NMR ( DMSO-d6) δ : 1.07 ( 2Η, m) , 1.40 ( 2H, m ), 1.90 ( 3H, s ) , 4.46 ( 2H, d, J = 5.7Hz ) , 5.22 ( 1H, t, ❹ J = 5.7Hz ) , 7.28 ( 2H, d, J = 8.1Hz ) , 7.60 ( 2H, dd, J = 2.1Hz, 8.1Hz) , 8.33 ( 1H, d, J=1.8Hz) , 8.62 ( 1H, s) MS : 207 ( M + + 1 ). (7) Synthesis of N-(l-{5-[ {4-(pyrimidin-2-yl)piperazine-l-yl}methyl]pyridin-2-yl}cyclopropyl)acetamide

100 mg of N-{1-[ 5-(hydroxymethyl)pyridin-2-yl]cyclopropyl}acetamide was dissolved in 10 ml of tetrahydrofuran, and methyl sulfonium chloride 0.045 ml, triethylamine hydrazine. Stir for 2 hours and 50 minutes. After adding 1 ml of water and stirring, the mixture was extracted with ethyl acetate (20 ml twice), washed with saturated aqueous sodium hydrogen carbonate and brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was dissolved in 2 ml of dimethylformamide, and 134 mg of potassium carbonate and 120 mg of 1-(2-pyrimidinyl)piperazine were added thereto at an oil bath temperature of -49 to 200950782 8 ° C. Heat for 1 hour. After adding 1 ml of water and stirring, the mixture was extracted with ethyl acetate (30 ml once, 20 ml twice), washed with brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the obtained residue was purified by column chromatography (yield: HI-FLASHTM COLUMN size L, eluting solvent: ethyl acetate/methanol) to obtain 63.9 mg of the labeled compound. • H-NMR ( DMSO-d6 ) δ : 1.08 ( 2Η, dd, J = 4.1Hz, 7.2Hz), 1.42 ( 2H, dd, J = 4.1Hz, 7.2Hz ) , 1.90 ( 3H, s), ❿ 2.40 ( 4H, t, J = 4.7Hz), 3.48 ( 2H, s ) , 3.70 ( 4H, t, H = 4.7Hz ), 6.61 ( 1H, t, J = 4.6Hz ) , 7.29 ( 1H, d, J = 8.0 Hz), 7.63 (1H, dd, J = 2.1 Hz, 8.2 Hz), 8.34 (3H, m), 8.63 (1H, s). MS ; 3 5 3 ( M + +1 ). Example 8: N ·[ 1 - ( 5 - { 〔( 1 S,4 S ) - 5 -(pyrimidin-2-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl Methyl}pyridin-2-yl)cyclopropyl propyl acetamide (chemical 3 6)

Dissolve N- { 1-[ 5-(hydroxymethyl)pyridin-2-yl]cyclopropyl}acetamidamine 3.138 in tetrahydrofuran 15 〇 111 b. Add methanesulfonium chloride 1.7 6111 b triethylamine 4.25 ml 'stirring 1 hour. After adding 150 ml of water and stirring, it was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue obtained was added to diisopropyl ether to give 3.76 g of white solid. 1.50 g of this white solid from -50 to 200950782 and 2.02 g of (1S,4S)-2-pyrimidin-2-yl-2,5-diazabicyclo[2.2.1]heptane hydrochloride were dissolved in dimethyl 25 ml of formamide, 679 mg of potassium iodide and 3.84 g of potassium carbonate were added, and heated at an oil bath temperature of 80 ° C for 1.5 hours. The reaction solution was returned to room temperature 'ethyl acetate' and the precipitated solid was filtered off, concentrated under reduced pressure, and the obtained residue was purified by column chromatography (c. Methanol) refining 'to obtain labeled compound 1. 〇 5 g. 0 'H-NMR ( DMSO-d6) δ : 0.95-1.14 ( m, 2H) , 1.32- 1.55 ( m, 2H ) , 1.70- 1.82 ( m, 1H) , 1_89 ( 3H, s), 1 · 8 9 -1 · 9 4 ( m,1 H ),2.4 6 ( 1 H,d,J = 9.4 H z ) , 2 · 8 4 ( 1 H, J = 9.5, 0.9, 0.8H, ddd), 3.48 ( 2H , s), 3.28-3.35 ( m, 1H ), 3.55 ( 1H, brs), 3.60 ( 1H, dd, J = 10.3, 0.9H), 3.66 (Brs, 2H), 4.72 ( 1H, s), 6.59 ( 1H,t,J = 4.8Hz), 7.25 (1H, d, J = 8.2Hz), 7.61 ( 1H, dd, J = 7.9Hz, 2.1Hz), 8.34 ( 3H,m), 8.19-8.45 ( m, 3H), 8.61 (1H, s). ❹ MS : 3 65 ( M + +1 ). 2. Effect on Cerebral Infarction Model The test compound A' used in the following was produced according to the method described in Example 71 of Patent Document 1. Test compound A: N - ( 1 - ( 4 - (4- 4 - (pyrimidin-2-yl)piperidin-1 -yl)methyl)phenyl)cyclopropyl)acetamidamine hydrochloride hydrochloride pharmacology Experimental Example 1: Intracerebral artery occlusion-recanction model in the brain -51 - 200950782 The effects of TNF-α, IL-Ιβ, IL-6 and MCP-1 on embolization (coated nylon) In the middle cerebral artery occlusion of male Wistar rats (Japanese medical department), test compound A (10 mg/kg) dissolved in physiological saline was administered intravenously 30 minutes after the occlusion, and the midbrain was administered for 60 minutes. The artery is recanalized. Further, only the rats used for the TNF-α assay were administered orally for the administration of the test compound A. The brain was removed 12 hours after the obstruction (see Koizumi, J. et al., Jpn J. Stroke, ❹ 8, 1 -8, 1 98 6 ). After brain tissue homogenization, centrifugation was performed and the supernatant was taken, and interleukin and chemokine were measured by ELISA. TNF-α, IL-Ιβ and IL-6 in the brain were determined using the Immunoassay Kit (BIOSOURCE) according to the manufacturer's protocol. MCP-1 was assayed using the MCP-1 Instant ELISA (Beneer MedSystems) according to the manufacturer's protocol. As a result, the concentration of TNF-α, IL-Ιβ and IL-6 and MCP-1 of chemokine increased in the brain due to transient cerebral ischemia (Figs. 1 to 4). Test compound A inhibited the concentration of increased TNF-α, IL-Ιβ, IL-6 and MCP-1, respectively. Pharmacological Experiment 2: Effect on Brain Injury Volume and Neurological Symptoms in a Model of Permanent Cerebral Artery Artery in Monkeys In the model of permanent middle cerebral artery occlusion in monkeys, MRI (FLAIR method) was used to measure brains after 1 and 7 days of obstruction. Damage volume. Test compound A (5 mg/kg) dissolved in 0.5% tragacanth was administered twice a day, and repeated into -52-200950782 for 14 days. Neurological symptoms are the assessment of neurological function by scoring consciousness, perception systems, motor systems, and muscle control systems. The permanent occlusion of the middle cerebral artery is performed according to the method of Furuichi et al. (Furuichi, Y et al., J- Cereb. Blood Flow Metab., 23, 1 1 83 -1 1 94, 20 03 ). Specifically, it is as follows. The cynomolgus monkeys who had been hungered for more than 12 hours in advance were introduced into the anesthesia by intramuscular administration of ketamine hydrochloride (10 mg/kg), and intravenously administered with sodium pentobarbital (25 mg/kS). After anesthesia, it is fixed to the operating table. A dental drill is used to make a small hole of about 5 mm in the vicinity of the foramen ovale and the eye hole, and the dura mater and the arachnoid membrane are cut open, and the cerebral artery in the vicinity of the branch portion of the inner carotid artery is exposed. A cerebral infarction is made by obstructing the cerebral arteries in the vicinity of the branching site of the internal carotid artery by electrical coagulation. Test compound A was administered orally for 1 day within 1 hour and 6 hours after the middle cerebral artery occlusion, and within 30 minutes after eating from the next day (twice a day). 0 In 7 cases of each group, 3 cases in the vehicle group and 2 cases in the test compound group A died. In the results other than the death case, the test compound A showed a day and 7 days after the middle cerebral artery occlusion. The expansion inhibition of cerebral infarction nest (Fig. 5). In addition, test compound A showed an improvement in neurological symptoms (Fig. 6). Pharmacological Experiment Example 3: Effect on the production of interleukin in the brain of mice LPS (lip〇p〇lysaccharide, E. coli 0111: obtained from B4, Sigma, 500/zg/kg) was administered intraperitoneally. To female BALB/c mice (-53- 200950782 Japan CHARLES·RIVER). After 90 minutes of LPS administration, blood was taken under anesthesia and centrifuged to prepare plasma. The TNF-α line was assayed using the Immunoassay Kit (R &amp; D Systems), and the IL-10, MCP-1 and IL-6 lines were assayed using the Immunoassay Kit (BIOSOURCE). The compound synthesized in Test Compound A, Example 3 (test compound B) and the compound synthesized in Example 7 (test compound C) were dissolved in physiological saline, each administered at 10 mg/kg in LPS for 30 minutes. 〇 Oral administration. The results are shown in Tables 1, 2 and 3. For the effect of each intracellular interleukin of each test compound, as shown in the table, the concentration of each interleukin in the blood of the group administered with the test compound was relative to the blood of the group not administered the test compound. The ratio of the interleukin concentrations was calculated. Each of the test compounds A, B, and C in the above LPS model of mice inhibited the production of TNF-α, IL-6, and MCP-1, and increased IL-10.

[Table 1] Test compound TNF-a production (%) IL-10 production (〇/〇) A 43.5 397.1 B 53.9 350.1 C 50.6 401.4 [Table 2], test compound IL~6 production (%) MCP-1 production ( %) A 74.4 61.7 B 78.7 63.9 -54- 200950782 [Table 3] Test compound IL-6 production (%) MCP-1 production (%) A 78.4 72.2 C 81 72.1 Pharmacological test example 4 · · Rat middle cerebral artery The cerebral infarction volume of the obstruction-recanction model was used to occlude the middle cerebral artery of Wistar rats (Japanese medical sputum) by embolization (coated nylon), and intravenous saline was administered intravenously 30 minutes after the obstruction ( Vehicle, n = 7), test compound A (10 mg/kg, n = 6) dissolved in physiological saline, test compound B (10 mg/kg, n = 7) dissolved in physiological saline or dissolved in physiological saline Test compound C (10 mg/kg. n = 7) was recanciated 90 minutes after blocking. The brain was taken out after 24 hours. A 2 mm brain slice was prepared and stained with PBS (pH 7.4, 37 ° C) containing 1% 2,3,5-triphenyl tetrazolium chloride (TCC-Wako). The area of cerebral infarction was measured by image analysis, and the volume of cerebral infarction was counted. As a result, Compound A, Compound B, and Compound C inhibited the cerebral infarct volume to 42.5%, 17.8%, and 43.2%, respectively (Fig. 7). Pharmacological Experiment 5: Evaluation of Bioavailability of Rats Test compound A, test compound B, and test compound C were administered in an oral dose of 5%. HPMC (hydroxypropylmethyl) The aqueous solution of cellulose is dissolved, and it is dissolved in physiological saline in the case of intravenous administration, and is administered orally or intravenously to male SD (IGS) rats at 3 mg/kg in each of -55-200950782 (Japanese CHARLES) 'RIVER). The unconverted body concentration in the plasma of each rat was measured, and the bioavailability (F (%)) was calculated (F (%) - CA UC 〇 - ° 〇, p 〇 / AUC 〇. 〇〇, iv7inean ) ^ (D〇S6iv-/D〇Sfip.〇) X 1 00 ). The test compound was administered orally (P.o.) or administered to the tail vein (i.v.) using an oral probe. In the case of oral administration, blood is drawn at 15 and 30 minutes, 1, 2, 4, 6, 8 and 24 hours after administration, and in the case of intravenous administration, 5 and 30 minutes after administration. Blood was drawn at 1, 2, 4, 6, 8 and 2 4 hours. The results are shown in Table 4 (test compound A), 5 (test compound B) and 6 (test compound C). Further, the Cmax of i.v. in Tables 4, 5, and 6 is the plasma concentration 値 after 5 minutes of administration. The Cmax of test compound A, test compound B and test compound C were 1459.7 ng/mL, 470.8 ng/mL and 2003.0 ng/mL, respectively, and the bioavailability was 1 〇 4 · 3 %, 7 5.5, respectively. % and 8 0 · 7 % [Table 4] Compound A: Mean+SD, n=3_____

Dose Cmax AUC〇.24h AUC〇^〇p1) (ng/mL) fng'h/mL) (ng'h/niL) (%) 3 mg/kg 1459.7 4032.9 4008.2 104.3 Po_±262.7 ±501.8 ±491.5 ± 12.8 3 mg/kg 2291.9 3850 3841.3 _ iv_±103.82) 士78.4 ±77.4 _

1) F(%)=(AUC(^0&gt;p.〇/AUCo^oLv mea^xCDoseLyy/DosepoJxlOO 2) C^rnm -56- 200950782 [Table 5] Compound B: Mean+SD, n=4_

Dose Cmax AUCo-ja^t AUCq^ F” _(ng/mL) (ng.h/mL) (ng.h/mL) (%) 3 mg/kg 470.8 1082.8 1105.7 75.5 po_士154.4士171.1士170.8 ±11.6 3 mg/kg 1604.6 1449.8 1464.6 _

Lv._±58.32) ^123.3 ±122.3_—

1) F(%)=(AUC〇^〇&lt;P〇./AUCo^v^aJxCDoseiv/Dosepo^xlOO 2) Csmin [Table 6] Compound C: Mean+SD, n=4

Dose ^max AUC〇〇AUC〇^ F1) fne/mL') fng*h/mL) (ηκΊι/πϋΙ,') (%) 3 mg/kg 2003 8192.2 8434.3 80.7 po ±338.3 ±3114.3 ±2981.5 ±28.5 3 Mg/kg 4514.7 10173.6 10446:3 iv ±358.62) 3012.9 士 2852.3

1) F(%)=(AUC〇.0〇iP.0.//AUC〇.GOji.v.&gt;meail)xCDoseLv/Dosep.0.)xlOO 2) Csmin Pharmacological Experiment 6: Rat Brain Evaluation of internal metastasis Test compound A 3 0 mg / kg dissolved in 〇.5% HPMC aqueous solution, test compound B and test compound C 3 mg / kg were administered orally to SD (IGS) rats by oral administration. Japan CHARLES· RIVER). After the test compound was administered, blood was drawn 1 hour and 4 hours later, and the brain (brain, cerebellum) was taken out. The plasma concentration and brain concentration of each test compound were measured, and the ratio (Kp値) was calculated, and the intracerebral metastasis was evaluated. As a result, it was confirmed that the test compound A, the test compound hydrazine, and the test compound C were transferred to the brain. Further, Kp値 at 1 hour and 4 hours after administration of each test compound, test compound A was 0.5 and 0.5, respectively, test compound B was 0.2 and 0.3, respectively, and test compound C was 0.2 and 0.2 for -57-200950782, respectively. [Industrial Applicability] According to the present invention, a novel cerebral infarction therapeutic drug can be provided by suppressing the production of a plurality of inflammatory interleukins in the brain. In particular, in the present invention, as shown in the pharmacological experiment example 2, the monkey middle cerebral artery permanent occlusion model is used, and the brain damage volume is measured non-invasively by MRI, and the neurological symptoms (high-order function) of the detailed © are measured over time, The compound exhibits a phenomenon which is effective as a therapeutic drug for cerebral infarction. Generally, clinically, cerebral infarction is assessed by MRI, and various indicators are used to measure and score the disease. However, the above-mentioned anti-interleukin antibody or inhibitory drug, for the effect on the volume of cerebral infarction in animal experiments, is measured by phenyltetrazolium chloride (hereinafter TTC) staining, and only simple neurological symptoms are observed (Bederson method, Paralysis) 'The clinically correct condition improvement was not tested. On the other hand, in the present invention, it is revealed that a therapeutic agent for cerebral infarction which is clinically effective is predicted. The cerebral infarction therapeutic agent of the present invention can also provide encephalitis and encephalomyelitis (encephalomyelitis and other diseases caused by neuroinflammation of infectious diseases or autoimmune diseases) as an inflammatory disease of the cerebrospinal cord. Therapeutic drugs. The present invention has been described in detail with reference to the particular embodiments of the invention, and various modifications and changes may be made without departing from the spirit and scope of the invention. The present application is based on Japanese Patent Application No. 2007-137504 (filed on May 24, 2007), which is incorporated herein in its entirety. -58- 200950782 [Simplified Schematic] FIG. 1 is a graph showing the concentration of TNF-α in the brain in a rat middle cerebral artery infarction-recanction model. "Sham" indicates that the group of sham operations that are blocked by embolization is not performed, "Vehicle" indicates that the blockage is performed and only physiological saline is administered, and "test compound A" indicates that the test compound A is administered. . © Figure 2 is a graph showing the concentration of IL-Ιβ in the brain in a rat middle cerebral artery infarction-recanction model. The meaning of each column is the same as that of Fig. 1. Figure 3 is a graph showing the concentration of IL-6 in the brain in a rat middle cerebral artery infarction-recanction model. The meaning of each column is the same as that of Fig. 1. Figure 4 is a graph showing the concentration of MPC-1 in the brain in a rat middle cerebral artery infarction-recanction model. The meaning of each column is the same as that of Fig. 1. ® 5 represents a map of the brain damage volume in the monkey model of permanent occlusion of the middle cerebral artery. The black strip indicates the Vehicle group (only 0.5% of the group of tragacanth was administered). The diagonal line indicates the group to which the test compound A was administered. ® 6 is a graph showing the scores of neurological symptoms in the monkey model of permanent occlusion of the middle cerebral artery. The dotted line graph represents the Vehicle group (only 0.5% of the jaundice @β group is administered), and the solid line graph indicates the group to which the test compound A is administered. Fig. 7 is a graph showing the cerebral infarction volume in a rat middle cerebral artery infarction-recanction model. The white bars indicate the group of vehicles (groups of only physiological saline). The black bars indicate the group to which each test compound was administered. -59-

Claims (1)

200950782 X. Patent application scope 1. A therapeutic agent for cerebral infarction characterized in that a piperazine compound represented by the formula &lt;1&gt; or a pharmaceutically acceptable salt thereof is used as an active ingredient, [Chemical Formula 1] Wherein R1 and R2 are the same or different and each represents an amine which is mono- or disubstituted by a group selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, amine, lower alkyl and lower alkyl. a group of 'nitro, hydroxy or cyano; R3, R4, R5 are the same or different, each represented by a group selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, nitro, amine, lower alkyl and lower The thiol group is mono- or disubstituted amine, hydroxy or cyano; R6, R7 are the same or different, each represents a lower alkyl, aryl substituted by hydrogen, lower alkyl, 1~3 halogen An alkyl group, a fluorenyl group or a lower fluorenyl group substituted by 1 to 3 halogens; R8 and R9 are the same or different, each represents a hydrogen or a lower-order courtyard group; and Ra~Rd are the same or different, each representing hydrogen, A lower alkyl group, an aralkyl group or a hydroxy lower alkyl group or any two of Ra to Rd are bonded to each other to form a group of a C 1 or 2 alkyl group, and Y represents a group represented by the following formula, -60- 200950782 〔化2〕 (wherein R1G, R11 are the same or different, each represents hydrogen or lower alkyl; R12, R13 are the same or different, each represents hydrogen or lower alkyl or Rl2, R13 are taken together to form an alkylene group. R14, R15 are the same or different, each represents hydrogen or lower alkyl; m represents an integer of 〇~2, η represents an integer of 0~2, and 0§m + ^ 2 ), ring A represents Phenyl, pyrimidinyl, thiazolyl, pyridyl, pyrazolyl or oxazolyl; ring B represents phenyl, pyridyl, thienyl). 2. The therapeutic agent for cerebral infarction according to claim 1, wherein the effective ingredient is a compound of the formula wherein ring B represents a phenyl group, or a pharmaceutically acceptable salt thereof. 3. The therapeutic agent for cerebral infarction according to claim 2, wherein the active ingredient is in the formula, R1, R2 represent hydrogen; R'R'R5 is the same or different, each represents hydrogen, halogen or lower alkoxy t R , R are the same or different, each represents hydrogen or a fluorenyl group; R, R are the same or different, each represents a hydrogen or a lower alkyl; -61 - 200950782 R1 (), R1 1 represents hydrogen; R14, R15 represents hydrogen Ra, Rb, Re, Rd represent hydrogen or any two groups bonded to each other to form a C 1 alkyl group; the other group represents hydrogen; ring A represents a phenyl group, a pyrimidinyl group, a thiazolyl group or a pyridyl group; B represents a compound of a phenyl group or a pharmaceutically acceptable salt thereof. 0. The therapeutic agent for cerebral infarction according to claim 2, wherein the active ingredient is at least one selected from the group consisting of: or a pharmaceutically acceptable salt, N-{4-[(4-benzene) Piperazin-1-yl)methyl]phenylmethyl}acetamide, N-(4-{[4-(4-fluorophenyl)piperazin-1-yl]methyl}phenylmethyl Ethylamine, N-(4-{[4-(2-fluorophenyl)piperazin-1-yl)methyl}phenylmethyl)acetamide, ❹N- (4- { 〔 4- (2,4-difluorophenyl)piperazin-1-yl]methyl}phenylmethyl)acetamide, N-(2-{4-(4-phenylpiperazin-1-yl) Methyl]phenyl}ethyl)acetamide, N-[2-(4-{[4-(4-fluorophenyl)piperazin-1-yl]methyl}phenyl)ethyl]acetamidine Amine, N-(l-{4-[(4-phenylpiperazin-1-yl)methyl]phenyl}ethyl)acetamide, N-[l-(4-{[4-(4 -fluorophenyl)piperazin-1-yl]methyl}phenyl) -62- 200950782 ethyl]acetamide, N-[l-(4-{[4-(2,4-difluorophenyl) Piperazine-1-yl]methyl}phenyl)ethyl]acetamidamine, N-[l-(4-{[4-(4-fluorophenyl)piperazin-1-yl]methyl} benzene )--Methylethyl]acetamide, N-(l-{4-[(4-phenylpiperazin-1-yl)methyl]phenyl}cyclopropyl)acetamide, 0 N-[l -(4-{[4-(4-fluorophenyl)piperazin-1-yl]methyl}phenyl)cyclopropyl]acetamidamine, Ν-{4-[1-(4-phenylperidine) Pyridazin-1-yl)ethyl]phenylmethyl}acetamidamine, Ν-(4-{1-[4-(4-cyclopropenyl)-decyl-1-yl]ethyl}phenylmethyl Ethylamine, "(4-{1-[4-(2,4-difluorophenyl)piperazin-1-yl]ethyl}phenylmethyl)acetamide, Q N-(4- { l-[ 4-(4-Fluorophenyl)piperazin-1-yl]-1-methylethyl}phenylmethyl)acetamidine, Ν-(4·{ 1-[4-(4 -fluorophenyl)piperazin-1-yl]-1-methylethyl}phenylmethyl)acetamidine, Ν-[ 1- (4- { 1-[ 4-(pyrimidin-2-yl)) Piperazine-1-yl]ethyl}phenyl)cyclopropyl]acetamidamine, and N-[l-(4-{[(lS,4S)-5-(pyrimidin-2-yl)-2, 5-diazabicyclo[2.2.1]hept-2-yl]methyl}phenyl)cyclopropyl]acetamide. 5. The therapeutic agent for cerebral infarction according to claim 1, wherein -63 - 200950782 The effect component is in the general formula &lt;1&gt;, the ring B table A pyridine-based compound, or a pharmaceutically acceptable salt thereof, wherein the active ingredient is in the formula &lt;1&gt;, R1 and R2 represent hydrogen; R3, R4, R5 are the same or different and each represents hydrogen, halogen or lower alkoxy <r6, r7 is the same or different 'each represents hydrogen or a fluorenyl group; R8, R9 are the same or different' each represents hydrogen or lower alkyl; R10, R11 represents nitrogen; R14, R15 represents nitrogen; Ra'Rb'R&lt;: 'Rd represents hydrogen or any two groups bonded to each other to form a carbon number 1; other groups represent hydrogen; Phenyl, pyrimidinyl, thiazolyl or pyridyl; ring B represents a compound of the ruthenium group or a pharmaceutically acceptable salt thereof. 7. The cerebral infarction therapeutic agent according to claim 5, wherein the active ingredient is at least one selected from the group consisting of the following compounds, or a pharmaceutically acceptable salt thereof, N-(I* { 5-(丨4_) (喃)-2-yl)piperazine-l-yl}methyl]pyridine-2-yl}cyclopropyl)acetamide, and N-[l_(5-{ 〔 (iS,4S)-5_( Pyrimidin-2-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]methyl}oxime ratio 11-but-2-yl)cyclopropyl]acetamidamine-64 - 200950782 8 The cerebral infarction therapeutic agent according to claim 1, wherein the active ingredient is in the formula <1>, and R12 and R13 represent a compound which is combined to form an alkyl group or a pharmaceutically acceptable substance thereof. The above-mentioned therapeutic agent for cerebral infarction according to claim 8 wherein the active ingredient is at least one selected from the group consisting of or a pharmaceutically acceptable salt thereof, N-(l-{4-[ ( 4-phenylpiperazin-1-yl)methyl]phenyl}cyclopropyl) indoleamine, ί I-C 4-{[4-(4-fluorophenyl)piperazin-1-yl] Methyl}phenyl)cyclopropyl]acetamidamine, Ν-[1-(4-{1-[4-(pyrimidin-2-yl)piperazine-1- Ethyl}ethyl)phenyl)cyclopropyl]acetamidamine,]^-[1-(4-{[(18,43)-5-(pyrimidin-2-yl)-2,5-diaza Bicyclo[2.2.1]hept-2-yl]methyl}phenyl)cyclopropyl]acetamidamine, Ν-( 1- { 5-[ { 4-(pyrimidin-2-yl)piperazine- l- Methyl]pyridine- 〇2-yl}cyclopropyl)acetamide, and N-[l-(5-{[(18,48)-5-(pyrimidin-2-yl)-2,5 -diazabicyclo[2.2.1]heptan-2-yl]methylpyridinium-2-yl)cyclopropyl]acetamidamine ·10. The therapeutic agent for cerebral infarction according to claim 2 or 8 The active ingredient is Ν·[ 1-(4-{ 1-[4-(pyrimidin-2-yl)piperazine-buyl]ethyl}phenyl)cyclopropyl]acetamide or its pharmaceutically acceptable Salt 〇1 1 . For the treatment of cerebral infarction according to the second or eighth patent application, the active ingredient in -65-200950782 is N-[1-(4-{l-[4-(pyrimidin-2-yl)) Piperazine-l-yl]ethyl}phenyl)cyclopropyl]acetamide hydrochloride. 12. The therapeutic agent for cerebral infarction according to claim 1 of the patent scope, wherein the cerebral infarction is a atherosclerotic cerebral infarction, a small hole infarction or a cardiomyogenic cerebral embolism. 13. A piperazine compound or a pharmaceutically acceptable substance thereof a salt characterized by the general formula &lt;2&gt;, ❹ [Chemical 3] Wherein R1 and R2 are the same or different and each represents an amine which is mono- or disubstituted by a group selected from the group consisting of hydrogen, halogen, lower alkane «lower alkoxy, amine, lower alkyl and lower alkyl. a group, a nitro group, a hydroxyl group or a cyano group; K3, R4, and R5 are the same or different and each represents a group selected from the group consisting of hydrogen, halogen, lower fluorenyl, lower alkoxy, nitro, amine, lower alkyl and The lower fluorenyl group is mono- or disubstituted amine, hydroxy or cyano; K6, R7 are the same or different, each represents a lower alkyl substituted by hydrogen, lower alkyl, 丨~3 halogen, An aralkyl group, a fluorenyl group or a lower fluorenyl group substituted by 1 to 3 halogens; R ' R9 are the same or different and each represents hydrogen or a lower alkyl group; Ra to Rd are the same or different and each represents hydrogen, Lower alkyl, aralkyl or -66 - 200950782 Any two of the lower sulfhydryl groups or Ra~Rd are bonded to each other to form a alkyl group having a carbon number of 1 to 2; Y is represented by the following formula Base, [4] R, Rl 1 are the same or different 'each represents hydrogen or lower alkyl; R12, R13 are the same or different, each represents hydrogen or lower alkyl or ri2, R13 are taken together to form an alkyl group; Rl4 R15 is the same or different and each represents hydrogen or lower alkyl; m represents an integer of 〇~2' η represents an integer of 〇~2, and OS m + n ^ 2), and ring A represents phenyl, Pyrimidinyl, soxazolyl, pyridyl, pyrazolyl or imidazolyl; ring B1 represents pyridyl, thienyl). A piperazine compound or a pharmaceutically acceptable salt thereof, which is characterized by the formula &lt;3&gt;, -67-200950782 [Chemical 5] (wherein R1 and R2 are the same or different and each represents a mono- or di-substituted group of a mercapto group selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, amine, lower alkyl and lower alkyl. Amine, nitro, hydroxy or cyano; R3, R4, R5 are the same or different, each represented by a group selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, nitro, amine, lower alkyl and The lower fluorenyl group is mono- or disubstituted amine, hydroxy or cyano; R6, R7 are the same or different, each represents a lower alkyl group substituted by hydrogen, lower alkyl '1~3 halogens, Aralkyl, fluorenyl or lower fluorenyl substituted by 1 to 3 halogens; R8, R9 are the same or different, each represents hydrogen or lower alkyl: ® Rla~Rld, at least one of Rla~Rld Any two of the lower alkyl, aralkyl or hydroxy lower alkyl 'Rla~Rld are bonded to each other to form a alkyl group having 1 to 2 carbon atoms; the other substituents are the same or different and each represents hydrogen. a lower alkyl group, an aralkyl group or a hydroxy lower alkyl group; Y system represents a group represented by the following formula; -68- 200950782 (wherein R1Q and R11 are the same or different and each represents hydrogen or lower alkyl; R12 and R13 are the same or different, each represents hydrogen or lower alkyl or RU and R13 are taken together to form Alkyl group; R 14 and R 15 are the same or different, each represents hydrogen or lower alkyl; m represents an integer of 〇~2, η represents an integer of 0 to 2, and 〇gm + 1] ^ 2 Ring A represents phenyl, pyrimidinyl, thiazolyl, pyridyl, pyrazolyl or imidazolyl). The piperazine compound of claim 13 or a pharmaceutically acceptable salt thereof, which is represented by the formula &lt;4&gt;, [Chem. 7] Q &lt;4&gt; (wherein R1 and R2 are the same or different and each represents a radical of a radical selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, amine, lower alkyl and lower alkyl) Or a disubstituted amine group, a nitro group, a hydroxyl group or a cyano group; R3, R4, R5 are the same or different, each represented by a group selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, nitro, amine, a lower alkyl group and a lower alkyl group are mono- or disubstituted amine groups, hydroxyl groups or cyano groups; R6 means a fluorenyl group or a lower sulfhydryl group substituted by 1 to 3 halogens; -69- 200950782 Ra~R is the same Or different 'each' means hydrogen, lower alkyl, aralkyl or any two of the lower alkyl or Ra~Rd bonded to each other to form a C 2 alkyl group). 16. The piperazine compound of claim 14 or a pharmaceutically acceptable salt thereof, which is represented by the formula &lt;5&gt;, [Chem. 8] &lt;5&gt; (wherein 'Ri'R2 are the same or different, each represents a group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, amine, lower alkyl and lower alkyl; Disubstituted amine, nitro, hydroxy or cyano; R3, R4, R5 are the same or different, each represented by a group selected from the group consisting of hydrogen, halogen, lower φ alkyl, lower alkoxy, nitro, amine a lower alkyl group and a lower fluorenyl group having a mono- or disubstituted amino group, a hydroxyl group or a cyano group; R6 means a fluorenyl group or a lower fluorenyl group substituted by 1 to 3 halogens; Rla~Rld ' is Rla~Rid At least one of the lower alkyl groups, the aryl group or the hydroxy lower alkyl group, and any two of Rla to Rld are bonded to each other to form a group having a C 1 to 2 alkyl group; the other substituents are the same or different Each represents hydrogen, lower alkyl, aralkyl or hydroxy lower alkyl). 1 7 · A piperazine compound or a pharmaceutically acceptable salt thereof according to claim 14 or 16 of the patent application, which is selected from the group consisting of ^(3,5-dimethyl-4-pyrimidine- 2-piperazine-1-yl)methyl-70- 200950782]phenyl}cyclopropyl)acetamidamine, N-[1-(4-{[[3S]-3-methyl-4-pyrimidine) -2-ylpiperazin-1-yl]methyl}phenyl)cyclopropyl]acetamidamine, N-[l-(4-{[(lS,4S)-5-(pyrimidin-2-yl)) -2,5-diazabicyclo[2.2.1]hept-2-yl]methyl}phenyl)cyclopropyl]acetamidamine, N-( 1- { 4-[ { 2,5-dimethyl 4--4-(pyrimidin-2-yl)}piperazin-1-yl)methyl]phenyl}cyclopropyl)acetamide, _ N-[l-(4-{ 〔 (2R) -2 -methyl-4-(pyrimidin-2-yl))piperazine-1-yl]methyl}phenyl)cyclopropyl]acetamidamine, and ^(1-{4-[{(2,6-) Dimethyl-4-(pyrimidin-2-yl))piperazine-:1-yl}methyl]phenyl}cyclopropyl)acetamide, or as in the scope of claim 13 or 15 a azine compound or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of N -( 1 - { 5 -[ { 4 -(pyrimidin-2-yl)piperazine-1-yl}methyl]pyridine-2-yl} Cyclopropyl Ethylamine, and hydrazine&gt;^-[1-(5-{[(18,43)-5-(pyrimidin-2-yl)-2,5-diazabicyclo[2.2.1]heptane- 2-yl]methyl}pyridin-2-yl)cyclopropyl]acetamidamine-71