Process for making N-((4-phenyl) methylphenyl) piperazines

Abstract: 1. A process for producing a compound having the formula (XII'): wherein Q' represents an optionally substituted phenyl group and X represents a hydrogen atom, a halogen atom, an alkoxy group, or an optionally substituted alkyl group, that process comprises reacting a benzophenon derivative having the formula (XIII): wherein Q' and X are the same as defined above, and L represents a group which can be easily exchanged with an amino group, with a piperazine derivative having the formula (XIV): wherein W represents a hydrogen atom, a benzyl group, a p-methoxybenzyl group, a benzyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group, a p-nitrobenzyloxycarbonyl group, a tert-butoxycarbonyl group, an ethoxycarbonyl group or an acetyl group to give a compound having the formula (XV): wherein Q', W and X are the same as defined above, and the subsequent reduction and deprotection of the compound having the formula (XV).

Description: This invention relates to processes for making compounds which may be used as intermediates in making arylpiperazinopropanol derivatives, their pharmaceutically acceptable salts, hydrates, hydrate salts and solvates effective for the alleviation and treatment of symptoms due to ischemic diseases, for example, cerebral infarction, cerebral edema, intracerebral hemorrhage, transient ischemic attack, subarachnoid hemorrhage, head trauma, after effects of brain surgery, after effects of cerebral arteriosclerosis, and other cerebrovascular disorders, or variant angina, unstable angina, myocardial infarction, cardiovascular system disorders accompanying surgery for revascularization by PTCA (percutaneous transluminal coronary angioplasty)/PTCR (percutaneous transluminal coronary revascularization)/CABG (coronary artery bypass grafting) etc., malignant arrhythmia and myocardial ischemia-reperfusion injury, and further disorders of transplanted organs at the time of organ transplants and temporary blockage of the blood flow in organs at the time of surgery, symptoms due to neurodegenerative diseases, for example, Alzheimer's, Parkinson's and Huntington's diseases, ALS (amyotrophic lateral sclerosis), and other neurodegenerative disorders or symptoms derived from seizures, epilepsy, migraine headaches, diabetes, arteriosclerosis, and inflammatory diseases. BACKGROUND ART In cellular disorders caused by advanced ischemia, the depletion of ATP, the fall in the pH in the cells, and the destruction of the mechanism for maintenance of the energy-dependent ion homeostasis inside and outside the cell cause the accumulation of a large amount of intracellular divalent Ca ions (Ca 2+ ). It is believed that the Ca 2+ overload causes functional disorders in the mitochondria and randomly activates various enzyme reactions and invites further Ca 2+ overload [F. B. Meyer: Brain Res. Rev., 14, 227 (1989); E. Boddeke et al.: Trends Pharmacol. Sci., 10, 397 (1989)]. On the other hand, while a small amount of active oxygen and free radicals such as superoxide anion radical (O 2 - ·), hydrogen peoxide (H 2 O 2 hydroxy radical (OH·) and peroxynitrite (ONOO - ) produced along with the production of energy in the body and the metabolic process are effectively scavenged by enzymes such as SOD (superoxide dismutase) and catalase and natural antioxidants such as α-tocopherol ingested into the body, it is known that the excessive production of active oxygen/free radicals in ischemic diseases, neurodegenerative diseases, diabetes, arteriosclerosis, inflammatory diseases, or other diseases, imparts irreparable damage to the cell membrane through extensive lipid peroxidation or various radical reactions. Furthermore, arachidonic acid produced by the decomposition of the phospholipids in the cell membrane at that time is converted, through a peroxidation process (arachidonic acid cascade), to thromboxane A 2 , which has a vascular constrictive and blood platelet aggregating actions, resulting in a cause of formation of thrombus, and therefore aggravates the cellular disorder. The two processes of the above Ca 2+ overload and excess production of active oxygen/free radicals, in cellular disorders caused by ischemia, act as mutually aggravating factors and are repeated in a vicious cycle which finally leads to cell death [J. M. McCall et al.: Ann. Rep. Med. Chem., 27, 31 (1992); C.-M. Andersson et al.: Advances in Drug Research, 28, 65 (1996)]. Therefore, pharmaceuticals which not only suppress cytotoxic Ca 2+ overload but also scavenge active oxygen/free radicals or suppress lipid peroxidation are considered to be those for the alleviation or treatment of various ischemic diseases, for example, cerebral infarction, cerebral edema, intracerebral hemorrhage, transient ischemic attack, subarachnoid hemorrhage, head trauma, after effects of brain surgery, after effects of cerebral arteriosclerosis, and other cerebrovascular disorders, or variant angina, unstable angina, myocardial infarction, cardiovascular system disorders accompanying surgery for revascularization by PTCA/PTCR/CABG etc., malignant arrhythmia and myocardial ischemia-reperfusion injury, and further disorders of transplanted organs at the time of organ transplants and temporary blockage of the blood flow in organs at the time of surgery, various neurodegenerative diseases, for example, Alzheimer's, Parkinson's and Huntington's diseases and ALS, and seizures, epilepsy, migraine headaches, and diabetes, arteriosclerosis, inflammatory diseases, etc. Arypiperidine and arylpiperazine derivatives having an action of suppressing Ca 2+ overload, are known for example, there is known the compound described in International Patent Publication Nos. WO 96/22977 and WO 96/26924. No compound, however, is mentioned which has an action of suppressing lipid peroxidation as well as Ca 2+ overload. DISCLOSURE OF INVENTION Consequently, an objective underlying the present invention is to provide a compound having an action of suppressing cytotoxic Ca 2+ overload and lipid peroxidation and effective for the alleviation and treatment of symptoms due to ischemic diseases, neurodegenerative diseases and symptoms derived from seizures, epilepsy, migraine headaches, diabetes, arteriosclerosis, inflammatory diseases, and other diseases which is high in safety and suitable for use for preparations such as injections. The present inventors synthesized and screened a series of compounds by evaluating the action of suppressing cytotoxic Ca 2+ overload and lipid peroxidation considered to cause ischemic cellular disorders and, as a result, found that arylpiperidinopropanol and arylpiperazinopropanol derivatives having the formula (I): wherein R 1 to R 4 independently represent a hydrogen atom, a halogen atom, a hydroxy group, an alkoxy group, an optionally substituted alkyl group, an optionally substituted aryl group, or an optionally substituted aralkyl group, R 5 represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aryl group, or an optionally substituted aralkyl group, E 1 represents an oxygen atom, a sulfur atom, or a group -NR 6 , where R 6 represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aryl group, or an optionally substituted aralkyl group, E 2 represents an oxygen atom, a sulfur atom, or a group -NR 7 , where R 7 represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aryl group, or an optionally substituted aralkyl group, A represents CH, C(OH), or a nitrogen atom, X represents a hydrogen atom, a halogen atom, an alkoxy group, or an optionally substituted alkyl group, and Q represents an optionally substituted phenyl group, an optionally substituted phenoxy group, an optionally substituted phenylmethyl group, or an optionally substituted cycloalkyloxy group, where when E 1 represents an oxygen atom or a sulfur atom, E 2 does not represent an oxygen atom or a sulfur atom, have not only an action in blocking non-L type Ca 2+ channels and Na + channels reported to be involved in the manifestation of Ca 2+ overload [P. J. Pauwels et al. : Life Science, 48, 1881 (1991)], but also a powerful action in suppressing lipid peroxidation. Further, we confirmed that these compounds were effective in various pharmacological tests, with high safety, and were suitable for pharmaceutical preparations. The present invention provides a process as set out in claim 1, and further explained below, for producing a compound having the formula XII which is useful as an intermediate in preparing some compounds of formula (I) in which A is a nitrogen atom. CARRYING OUT THE INVENTION While the flunarizine being used as an agent for improvement of the brain circulation [J. P. Pauwels et al.: Life Science, 48, 1881 (1991); G. E. Billman: Eur. J. Pharmacol., 212, 231 (1992)] has the major defect in use of the side effect of manifestation of symptoms of Parkinson's disease due to the dopamine D 2 receptors blocking action, the compound having the general formula (I) was found to have an extremely low affinity with respect to the cause of the side effects of flunarizine, the dopamine D 2 receptors. In the present invention, as ischemic diseases, cerebral ischemic diseases, for example, cerebral infarction, intracerebral hemorrhage, transient ischemic attack, subarachnoid hemorrhage, head trauma, after effects of brain surgery, after effects of cerebral arteriosclerosis, and other cerebrovascular disorders, ischemic cardiac diseases, for example, variant angina, unstable angina, myocardial infarction, cardiovascular system disorders accompanying surgery for revascularization by PTCA/PTCR/CABG etc., malignant arrhythmia and other myocardial ischemia-reperfusion injury, and also disorders of transplanted organs at the time of organ transplants, and temporary blockage of the blood flow in organs at the time of surgery may be mentioned, and as neurodegenerative diseases, for example, Alzheimer's, Parkinson's and Huntington's diseases, ALS may be mentioned. The compounds having the formula (I) of the present invention include compounds having the formulas (Ia), (Ib), and (Ic): In the formula (Ia) [wherein,] R1 to R5, E1, E2, X, and Q are the same as defined above. It can be seen that A in formula (I) is C OH) in formula (Ia). In the formula (Ib) R 1 to R 5 , E 1 , E 2 , X, and Q are the same as defined above. It can be seen that A in formula (I) is C-H in formula (Ib). In the formula (Ic) R 1 to R 5 , E 1 , E 2 , X, and Q are the same as defined above. It can be seen that A in formula (I) is a nitrogen atom in formula (Ic). As the halogen atom indicated by R 1 to R 4 , a fluorine atom, a chlorine atom, or a bromine atom may be mentioned, as the alkoxy group, a C 1 to C 5 linear or branched alkoxy group such as a methoxy group or an ethoxy group may be mentioned, and as the optionally substituted alkyl group, a C 1 to C 5 linear or branched alkyl group optionally substituted with a halogen atom such as a methyl group, an ethyl group, a propyl group, or a trifluoromethyl group may be mentioned. As the aryl group of the optionally substituted aryl group, indicated by R 1 to R 4 , a C 4 to C 14 aryl group which may contain one or more hetero atoms such as a nitrogen atom or an oxygen atom may be mentioned, preferably a phenyl group, a naphthyl group, a pyridyl group, a quinolyl group, an isoquinolyl group, an indolyl group, etc. may be mentioned, and as preferable substituents of the optionally substituted aryl group, a halogen atom such as a fluorine atom, a chlorine atom, or a bromine atom, a hydroxy group, a C 1 to C 5 linear or branched alkoxy group such as a methoxy group, or an ethoxy group, and a C 1 to C 5 linear or branched alkyl group optionally substituted with a halogen atom such as a methyl group, an ethyl group, or a trifluoromethyl group may be mentioned. As the aralkyl group of the optionally substituted aralkyl group indicated by R 1 to R 4 , a C 5 to C 12 aralkyl group which may contain on its ring one or more hetero atoms such as a nitrogen atom or an oxygen atom may be mentioned, preferably a benzyl group, a phenylethyl group, a pyridylmethyl group, a pyridylethyl group, etc. may be mentioned, and as examples of the preferable substituent of the optionally substituted aralkyl group, a halogen atom such as a fluorine atom, a chlorine atom, or a bromine atom, a hydroxy group, a C 1 to C 5 linear or branched alkoxy group such as a methoxy group, or an ethoxy group, a C 1 to C 5 linear or branched alkyl group optionally substituted with a halogen atom such as a methyl group, an ethyl group, or a trifluoromethyl group, etc. may be mentioned. As the optionally substituted alkyl group indicated by R 5 , a C 1 to C 5 linear or branched alkyl group optionally substituted with a halogen atom such as a methyl group, an ethyl group, a propyl group, or a trifluoromethyl group may be mentioned. As the aryl group of the optionally substituted aryl group, indicated by R 5 , a C 4 to C 14 aryl group which may contain one or more hetero atoms such as a nitrogen atom or an oxygen atom may be mentioned, preferably a phenyl group, a naphthyl group, a pyridyl group, a quinolyl group, an isoquinolyl group, an indolyl group, etc. may be mentioned, and as preferable substituents of the optionally substituted aryl group, a halogen atom such as a fluorine atom, a chlorine atom, or a bromine atom, a hydroxy group, a C 1 to C 5 linear or branched alkoxy group such as a methoxy group, or an ethoxy group, and a C 1 to C 5 linear or branched alkyl group optionally substituted with a halogen atom such as a methyl group, an ethyl group, or a trifluoromethyl group may be mentioned. As the aralkyl group of the optionally substituted aralkyl group indicated by R 5 , a C 5 to C 12 aralkyl group which may contain on its ring one or more hetero atoms such as a nitrogen atom or an oxygen atom may be mentioned, preferably a benzyl group, a phenylethyl group, a pyridylmethyl group, a pyridylethyl group, etc. may be mentioned, and as examples of the preferable substituent of the optionally substituted aralkyl group, a halogen atom such as a fluorine atom, a chlorine atom, or a bromine atom, a hydroxy group, a C 1 to C 5 linear or branched alkoxy group such as a methoxy group, or an ethoxy group, and a C 1 to C 5 linear or branched alkyl group optionally substituted with a halogen atom such as a methyl group, an ethyl group, or a trifluoromethyl group may be mentioned. In the group -NR 6 of E 1 and the group -NR 7 of E 2 , as the optionally substituted alkyl group indicated by R 6 or R 7 , a C 1 to C 5 linear or branched alkyl group optionally substituted with a halogen atom such as a methyl group, an ethyl group, a propyl group, or a trifluoromethyl group may be mentioned. As the aryl group of the optionally substituted aryl group indicated by R 6 or R 7 , a C 4 to C 14 aryl group which may contain one or more hetero atoms such as a nitrogen atom or an oxygen atom may be mentioned, preferably a phenyl group, a naphthyl group, a pyridyl group, a quinolyl group, an isoquinolyl group, an indolyl group, etc. may be mentioned, and as preferable substituents of the optionally substituted aryl group, a halogen atom such as a fluorine atom, a chlorine atom, or a bromine atom, a hydroxy group, a C 1 to C 5 linear or branched alkoxy group such as a methoxy group, or an ethoxy group, and a C 1 to C 5 linear or branched alkyl group optionally substituted with a halogen atom such as a methyl group, an ethyl group, or a trifluoromethyl group may be mentioned. As the aralkyl group of the optionally substituted aralkyl group indicated by R 6 or R 7 , a C 5 to C 12 aralkyl group which may contain on its ring one or more hetero atoms such as a nitrogen atom or an oxygen atom may be mentioned, preferably a benzyl group, a phenylethyl group, a pyridylmethyl group, a pyridylethyl group, etc. may be mentioned, and as examples of the preferable substituent of the optionally substituted aralkyl group, a halogen atom such as a fluorine atom, a chlorine atom, or a bromine atom, a hydroxy group, a C 1 to C 5 linear or branched alkoxy group such as a methoxy group, an ethoxy group, a C 1 to C 5 linear or branched alkyl group optionally substituted with a halogen atom such as a methyl group, an ethyl group, or a trifluoromethyl group may be mentioned. As the halogen atom indicated by X, a fluorine atom, a chlorine atom, or a bromine atom may be mentioned, as the alkoxy group, a C 1 to C 5 linear or branched alkoxy group such as a methoxy group or an ethoxy group may be mentioned, and as the optionally substituted alkyl group, a C 1 to C 5 linear or branched alkyl group optionally substituted with a halogen atom such as a methyl group, an ethyl group, a propyl group, or a trifluoromethyl group may be mentioned. As the cycloalkyloxy group indicated by Q, a C 4 to C 8 cycloalkyloxy group such as a cyclobutyloxy group, a cyclopentyloxy group, a cyclohexyloxy group, or a cycloheptyloxy group may be mentioned. As preferable substituents of the optionally substituted phenyl group, the optionally substituted phenoxy group, the optionally substituted phenylmethyl group or the optionally substituted cycloalkyloxy group indicated by Q, a halogen atom such as a fluorine atom, a chlorine atom, or a bromine atom, a hydroxy group, a C 1 to C 5 linear or branched alkoxy group such as a methoxy group, or an ethoxy group, and a C 1 to C 5 linear or branched alkyl group optionally substituted with a halogen atom such as a methyl group, an ethyl group, or a trifluoromethyl group may be mentioned. As the halogen atom of the C 1 to C 5 linear or branched alkyl group optionally substituted with a halogen atom, a fluorine atom, a chlorine atom, or a bromine atom may be mentioned. Among the compounds represented by the formula (Ic), particularly preferable examples are listed below. wherein, R 1 to R 7 and X are the same as defined above. The compounds having the formula (I) of the present invention include isomers thereof. The present invention includes all of the individual isomers and mixtures thereof. That is, in the formula (I), there are structural isomers resulting from the difference in orientation of the substituent on the benzene ring and there are a pair of optical isomers for the asymmetric carbon atom to which the hydroxy group of the propanol moiety is bonded. The compounds of the present invention include all isomers resulting from combinations of these and mixtures of the same. The compounds having.the formula (I) can be synthesized in, for example, the following manner. These methods will be explained below. The compound (Ia) wherein, in the formula (I), A is C(OH) can be obtained in the following way. That is, it is possible to obtain the compound (III) from the known starting material (II) (Step 1) and convert it to the compound (IV) (Step 2). Reaction of the compound (V) and the compound (VIa) or (VIb) gives the compound (VIIa), (VIIb) or (VIIc) (Step 3), which is then allowed to react with the compound (IV) to afford the compound (Ia) (Step 4). The compound (Ib) wherein, in the formula (I), A is CH can be obtained by converting the compound (III) into the compound (X) (Step 5) followed by the reaction with the compound (VIIa) or (VIIb) (Step 6). The formula (Ic) denotes compounds of the formula (I) in which A is a nitrogen atom. When Q denotes an optionally substituted phenylmethyl group, such compounds can be obtained by converting the compound (XIII) into the compound (XII') (Step 8) followed by the reaction with the compound (VIIa) or (VIIb) (Step 9) Step 1 It is possible to synthesize the compound (III) from the known starting substance (II) by the following method. wherein, X and Q are the same as defined above, D represents a benzyl group, a p-methoxybenzyl group, a benzyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group, a tert-butoxycarbonyl group, an ethoxycarbonyl group, or an acetyl group. That is, an aryl bromide derivative (II) is converted by conventional method to the corresponding aryl Grignard reagent or aryl lithium reagent, then reacted in tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, toluene, or another solvent not participating in the reaction, at -100°C to 50°C, preferably -78°C to room temperature, with 1 to 1.5 equivalents of the known starting material N-benzyl-4-piperidone, N-(p-methoxybenzyl)-4-piperidone, N-benzyloxycarbonyl-4-piperidone, N-(p-methoxybenzyloxycarbonyl)-4-piperidone, N-(p-nitrobenzyloxycarbonyl)-4-piperidone, N-tert-butoxycarbonyl-4-piperidone, N-ethoxycarbonyl-4-piperidone, or N-acetyl-4-piperidone for 1 to 6 hours, whereby a compound having the formula (III) is obtained. The starting substance (II) used in the present reaction is a known compound or alternatively can be synthesized by known methods [L. Martin et al.: J. Med. Chem., 22, 1347 (1979); J.-P. Genet et al.: Tetrahedron Lett., 37, 3857 (1996); G. Faye Crr et al.: J. Med. Chem., 40, 1179 (1997)]. For example, 4-bromodiphenyl ether, 4-bromophenyl ether, 4-bromo-4'-fluorodiphenyl ether, 4-bromo-3'-fluorodiphenyl ether, 4-bromo-2'-fluorodiphenyl ether, 4-bromodiphenyl methane, 4-bromo-4'-fluorodiphenyl methane, 4-bromo-4'-chlorodiphenyl methane, 4-bromo-4'-methoxydiphenyl methane, 4-bromo-4'-trifluoromethyldiphenyl methane, 4-bromobiphenyl, 4-bromo-2-fluorobiphenyl, 4-bromo-4'-fluorobiphenyl, 4-bromo-4'-methoxybiphenyl, 4-bromo-4'-methylbiphenyl, 4-bromo-4'-trifluoromethylbiphenyl, 4,4'-dibromobiphenyl, 4-bromophenylcyclopentyl ether, 4-bromophenylcyclohexyl ether, etc. can be used. As the conditions for preparing the Grignard reagent and the organolithium reagent, it is possible to use the various methods described in the "Compendium for Organic Synthesis" (Wiley-Interscience: A Division of John Wiley & Sons) etc. The compound obtained in the above reaction can be used as is for the next step or, if necessary, can be used after purification by a conventional method such as recrystallization or column chromatography. Step 2 It is possible to synthesize the compound (IV) from the compound (III) obtained in Step 1. wherein, X and Q are the same as defined above, D' represents a benzyl group, a p-methoxybenzyl group, a benzyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group, or a p-nitrobenzyloxycarbonyl group. The compound (III) obtained in Step 1 can be converted to the compound having the formula (IV) by hydrogenation in ethyl acetate, methanol, ethanol, isopropyl alcohol, or another solvent not participating in the reaction, in the presence of a catalytic amount of palladium carbon, palladium hydroxide, platinum, etc. at a pressure to 6 atmospheres. Further, in the reaction, if necessary, acetic acid, hydrochloric acid, or other acid may be added. Step 3 The compound (V) can be reacted with the compound (VIa) or (VIb) to synthesize the compound (VIIa), (VIIb) or (VIIC). wherein, R 1 to R 4 , E 1 and E 2 are the same as defined above, R 8 represents an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted aralkyl group, a benzyl group, a p-methoxybenzyl group, a benzyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group, a p-nitrobenzyloxycarbonyl group, a tert-butoxycarbonyl group, an ethoxycarbonyl group, an acetyl group, or a formyl group, and L represents a group which can be easily exchanged with an amino group. That is, the compound (V) is stirred in benzene, toluene, tetrahydrofuran, dioxane, dimethylformamide, dimethylsulfoxide, acetonitrile, acetone, methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, ethylene glycol or another solvent not participating in the reaction and, if necessary, in the presence of an organic base such as triethylamine, diisopropylethylamine, or pyridine or an inorganic base such as sodium, sodium hydride, potassium, potassium hydride, sodium methoxide, sodium ethoxide, potassium ethoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, cesium fluoride, sodium hydrogencarbonate, or potassium hydrogencarbonate at -20°C to 150°C, preferably 0°C to 100°C, with 1.0 to 1.5 equivalents of the compound (VIa) or (VIb), whereby the compound (VIIa), (VIIB) or (VIIc) is obtained. Further, in this reaction, if necessary, a plurality of organic bases and inorganic bases may be combined for use or sodium iodide or tetrabutylammonium iodide etc. may be added. L is a leaving group easily exchangeable with an amino group. A halogen atom such as a chlorine atom, a bromine atom, or an iodine atom, an alkylsulfonyloxy group such as a methanesulfonyloxy group, an arylsulfonyloxy group such as a p-toluenesulfonyloxy group or a 3-nitrobenzenesulfonyloxy group, etc. may be exemplified. As the compounds (V), (VIa) and (VIb) used in this reaction, commercially available or known compounds or alternatively those which can be synthesized by known methods can be used. As the compound (V), 4-(tert-butoxycarbonylamino)-phenol, 4-(benzyloxycarbonylamino)-phenol, 4-(p-methoxybenzyloxycarbonylamino)-phenol, 4-(p-nitrobenzyloxycarbonylamino)-phenol, 4-(tert-butoxycarbonylamino)-2,3,5-trimethylphenol, 4-(benzyloxycarbonylamino)-2,3,5-trimethylphenol, 4-(p-methoxybenzyloxycarbonylamino)-2,3,5-trimethylphenol, 4-(p-nitrobenzyloxycarbonylamino)-2,3,5-trimethylphenol, 4-(tert-butoxycarbonylamino)-2-chloro-3,5,6-trimethylphenol, 4-(benzyloxycarbonylamino)-2-chloro-3,5,6-trimethylphenol, 4-(p-methoxybenzyloxycarbonylamino)-2-chloro-3,5,6-trimethylphenol, 4-(p-nitrobenzyloxycarbonylamino)-2-chloro-3,5,6-trimethylphenol, 4-(tert-butoxycarbonylamino)-2,3,6-trimethylphenol, 4-(benzyloxycarbonylamino)-2,3,6-trimethylphenol, 4-(p-methoxybenzyloxycarbonylamino)-2,3,6-trimethylphenol, 4-(p-nitrobenzyloxycarbonylamino)-2,3,6-trimethylphenol, 4-(tert-butoxycarbonylamino)-2,3-dimethylphenol, 4-(benzyloxycarbonylamino)-2,3-dimethylphenol, 4-(p-methoxybenzyloxycarbonylamino)-2,3-dimethylphenol, 4-(p-nitrobenzyloxycarbonylamino)-2,3-dimethylphenol, 4-(tert-butoxycarbonylamino)-2,5-dimethylphenol, 4-(benzyloxycarbonylamino)-2,5-dimethylphenol, 4-(p-methoxybenzyloxycarbonylamino)-2,5-dimethylphenol, 4-(p-nitrobenzyloxycarbonylamino)-2,5-dimethylphenol, 2-(tert-butoxycarbonylamino)-4,6-dimethylphenol, 2-(benzyloxycarbonylamino)-4,6-dimethylphenol, 2-(p-methoxybenzyloxycarbonylamino)-4,6-dimethylphenol, 2-(p-nitrobenzyloxycarbonylamino)-4,6-dimethylphenol, 5-(tert-butoxycarbonylamino)-2-methoxyphenol, 5-(benzyloxycarbonylamino)-2-methoxyphenol, 5-(p-methoxybenzyloxycarbonylamino)-2-methoxyphenol, 5-(p-nitrobenzyloxycarbonylamino)-2-methoxyphenol, 5-(tert-butoxycarbonylamino)-4-chloro-2-methoxyphenol, 5-(benzyloxycarbonylamino)-4-chloro-2-methoxyphenol, 5-(p-methoxybenzyloxycarbonylamino)-4-chloro-2-methoxyphenol, 5-(p-nitrobenzyloxycarbonylamino)-4-chloro-2-methoxyphenol, 4-(tert-butoxycarbonylamino)-2,6-dichlorophenol, 4-(benzyloxycarbonylamino)-2,6-dichlorophenol, 4-(p-methoxybenzyloxycarbonylamino)-2,6-dichlorophenol, 4-(p-nitrobenzyloxycarbonylamino)-2,6-dichlorophenol, 4-(tert-butoxycarbonylamino)-2,3,4,6-tetramethylaniline, 4-(b-enzyloxycarbonylamino)-2,3,4,6-tetramethylaniline, 4-(p-methoxybenzyloxycarbonylamino)-2,3,4,6-tetramethylaniline, 4-(p-nitrobenzyloxycarbonylamino)-2,3,4,6-tetramethylaniline, 4-methoxy-2-methylaniline, etc. may be exemplified. As the compound (VIa), epibromohydrin, epichlorohydrin, (R)-epichlorohydrin, (S)-epichlorohydrin, glycidyltosylate, (R)-glycidyltosylate, (S)-glycidyltosylate, (R)-glycidyl 3-nitrobenzenesulfonate, (S)-glycidyl 3-nitrobenzenesulfonate, (R)-glycidyl 4-nitrobenzoate, (S)-glycidyl 4-nitrobenzoate, glycidyl trimethylammonium chloride, etc. may be exemplified. As the compound (VIb), 3-bromo-1,2-propanediol, 3-chloro-1,2-propanediol, (R)-3-chloro-1,2-propanediol, (S)-3-chloro-1,2-propanediol, etc. may be exemplified. Step 4 The compound (IV) obtained in Step 2 and the compound (VIIa), (VIIb) or (VIIc) obtained in Step 3 can be reacted to synthesize the compound (Ia) where in the formula (I), A is C(OH). wherein R 1 to R 5 , R 8 , E 1 , E 2 , X, Q, and L are the same as defined above. The compound (VIIa) or (VIIb) obtained at Step 3 is reacted in benzene, toluene, tetrahydrofuran, diethyl ether, ethylene glycol dimethylether, dioxane, dimethylformamide, dimethylsulfoxide, acetonitrile, methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, ethylene glycol, or another solvent not participating in the reaction at room temperature to 200°C, preferably 50°C to 150°C, with 0.9 to 1.5 equivalents of the compound (IV) obtained in Step 2 for 1 to 24 hours, whereby the compound (VIII) can be obtained. Further, the compound (VIIc) obtained in Step 3 is converted to the compound (VIIa) or (VIIb) by known methods [e.g., K.B. Sharpless et al.: Tetrahedron, 48, 10515 (1992); S. Takano et al.: Synthesis, 503 (1985); A.K. Ghosh et al.: J. Chem. Soc., Chem. Commun., 273 (1992); M.K. Ellis et al.: Organic Synthesis, Collective Volume 7, 356 (1990); S. Takano et al.: Heterocycles, 16, 381 (1981); A.K.M. Anisuzzaman et al.: J. Chem. Soc., C, 1021 (1967)], followed by carrying out the same reactions with the compound (IV) to give the compound (VIII). Further, in this reaction, if necessary, an organic base such as triethylamine, diisopropylethylamine, or pyridine, an inorganic base such as sodium carbonate, potassium carbonate, cesium carbonate, cesium fluoride, sodium hydrogencarbonate, or potassium hydrogencarbonate, or a metal salt such as sodium iodide, tetrabutylammonium iodide, lithium carbonate, lithium chloride, zinc bromide, or magnesium bromide may be added alone or in combination. Further, by hydrogenation of the compound (VIII) where R 8 is a benzyl group, a p-methoxybenzyl group, a benzyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group, or a p-nitrobenzyloxycarbonyl group or by an acid treatment with hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, etc. of the compound (VIII) where R 8 is a tert-butoxycarbonyl group, a p-methoxybenzyloxycarbonyl group, an ethoxycarbonyl group, an acetyl group, or a formyl group, it is possible to synthesize the compound (Ia) wherein, in the formula (I), A is C(OH). The compounds obtained by the above reactions can be used as they are for the next step or, if necessary, can be used after purification by a conventional method such as recrystallization or column chromatography. Further, the reactions in Step 3 and Step 4 can be carried out successively in one-pot without isolating the compounds obtained by the each reaction. Step 5 The compound (X) can be synthesized from the compound (III) obtained in Step 1. wherein, X, Q, and D are the same as defined above, D'' represents a hydrogen atom, a benzyl group, a p-methoxybenzyl group, a benzyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group, or a p-nitrobenzyloxycarbonyl group. The compound (III) obtained in Step 1 is treated under non-solvent conditions or in a solvent not participating in the reaction, for example, tetrahydrofuran, diethyl ether, ethylene glycoldimethyl ether, benzene, toluene, methylene chloride, chloroform, carbon tetrachloride, water, methanol, or ethanol at -20°C to 150°C, preferably 0°C to 80°C, with 1 to 20 equivalents of an organic acid such as acetic acid, trifluoroacetic acid, methanesulfonic acid, or trifluoromethanesulfonic acid or an inorganic acid such as hydrochloric acid, sulfuric acid, or nitric acid for 1 to 12 hours or the compound (III) is treated in a solvent not participating in the reaction, for example, benzene, toluene, methylene chloride, chloroform, or carbon tetrachloride, if necessary, in the presence of triethylamine, pyridine, or diisopropylethylamine, or other bases at -20°C to 150°C, preferably 0°C to 100°C, with 1 to 5 equivalents of thionyl chloride, methanesulfonyl chloride, trifluoromethanesulfonyl chloride, trifluoromethanesulfonate anhydride, p-toluenesulfonyl chloride, phosphorus oxychloride, or other acid chloride derivatives for 1 to 6 hours, and the subsequent acid treatment similar to the above is repeated, whereby the compound (IX) is obtained. Next, the compound (IX) is processed by a similar method as in Step 2, to give the compound having the formula (X). The compounds obtained by the above reactions can be used as they are for the next step, but if necessary can also be used after purification by a conventional method such as recrystallization or column chromatography. Step 6 Starting with the compound (VIIa), (VIIb) or (VIIc) obtained in Step 3 and the compound (X) obtained in Step 5, it is possible to synthesize the compound (Ib) wherein, in the formula (I), A is CH, by a similar method as in Step 4. wherein, R 1 to R 5 , E 1 , E 2 X, and Q are the same as defined above. Step 8 In the compound (XII) X and Q are the same as defined above. The compound (XII') among the compound represented by the formula (XII), wherein Q is an optionally substituted phenylmethyl group can be synthesized from the compound (XIII) and compound (XIV). wherein L and X are the same as defined above, Q' represents an optionally substituted phenyl group, and W represents a hydrogen atom, a benzyl group, a p-methoxybenzyl group, a benzyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group, a p-nitrobenzyloxycarbonyl group, a tert-butoxycarbonyl group, an ethoxycarbonyl group or an acetyl group. That is, a benzophenone derivative (XIII) is reacted with 1 to 20 equivalents of piperazine derivative (XIV) at 50 - 300°C for 1 hour to 20 days under non-solvent conditions, or in a solvent not participating in the reaction, such as methanol, ethanol, n-butanol, tert-butyl alcohol, acetonitrile, nitromethane, dioxane, tetrahydrofuran, dimethylacetamide, dimethylsulfoxide, N-methyl-2-pyrrolidone, to give the compound (XV). In this reaction, if necessary, an organic base such as triethylamine, diisopropylethylamine, pyridine, or an inorganic base such as sodium, sodium hydride, potassium hydride, sodium ethoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, cesium fluoride, sodium hydrogenbicarbonate, potassium hydrogenbicarbonate, or any combination thereof may be added. Then, the compound (XV) is treated in the same way as in Step 2, or is treated with 1 to 20 equivalents of sodium, triethylsilane or borane in a solvent not participating in the reaction, such as ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, methylene chloride, chloroform, benzene, toluene, acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, liquid ammonia, methanol, ethanol, 2-propanol, to give the compound (XII'). If necessary, in this reaction, a catalytic amount of acid such as hydrochloric acid, sulfuric acid, hydrobromic acid, nitric acid, boran trifluoride may be added. Furthermore, the compound which W represents an ethoxycarbonyl group or an acetyl group in the general formula (XV) can be converted into the compound (XII') by the above mentioned procedure followed by stirring at 50 - 200°C for 1 hour to 3 days in an aqueous acidic solution such as acetic acid, acetic acid/hydrochloric acid, hydrobromic acid, sulfuric acid. As the compound (XIII) usable in the present reaction, for example, 2,4-difluorobenzophenone, 2,4'-difluorobenzophenone, 3,4-difluorobenzophenone, 4,4'-difluorobenzophenone, 4-bromo-4'-fluorobenzophenone, 4-chloro-4'-fluorobenzophenone, 4-fluoro-4'-methoxybenzophenone, 4'-bromo-4'-methoxybenzophenone, 4-fluoro-4'-methylbenzophenone, 4-bromo-4'-methylbenzophenone may be mentioned. As the compound (XIV), for example, piperazine, 1-benzylpiperazine, 1-(p-methoxybenzyl)piperazine, 1-benzyloxycarbonylpiperazine, 1-(p-methoxybenzyloxycarbonyl)piperazine, 1-(p-nitrobenzyloxycarbonyl)piperazine, 1-(tert-butoxycarbonyl)piperazine, 1-ethoxycarbonylpiperazine, acetylpiperazine may be mentioned. The compound obtained in the above each reaction ca n be used as is for the next step or, if necessary, can be used after purification by a conventional method such as recrystallization or column chromatography. Step 9 Starting with the compound (VIIa), (VIIb) or (VIIc) obtained in Step 3 and the compound (XII') obtained in Step 8, it is possible to synthesize the compound (Ic) where, in the general formula (I), A is a nitrogen atom, by a similar method as in Step 4. [R 1 to R 5 , E 1 , E 2 , X are the same as defined above, and Q' is optionally substituted phenylmethyl group.] Individual isomers included in the compounds of general formula (I) of the present invention can be separated by a conventional method, for example, recrystallization, column chromatography, thin layer chromatography, high performance liquid chromatography, or a similar method using optically active reagents. The compound having the general formula (I) of the present invention can be dissolved in a suitable organic solvent, for example, methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, ether, tetrahydrofuran, methylene chloride, chloroform, benzene, toluene, and treated with an inorganic acid or an organic acid to afford the corresponding salt. As the inorganic acid used here, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, periodic acid, etc. and as the organic acid, formic acid, acetic acid, butyric acid, oxalic acid, malonic acid, propionic acid, valeric acid, succinic acid, fumaric acid, maleic acid, tartaric acid, citric acid, malic acid, benzoic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, etc. may be mentioned. It should be noted that the salts comprising 1 to 3 molecules of the acid can be selectively prepared by adjusting the amount of the above-mentioned inorganic acid or organic acid used between 1 to 3 equivalents depending upon the number of the basic nitrogen atom present in the compound (I). The crude crystal of the resultant salt can be purified by recrystallization thereof from a solvent such as water, methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, ether, diisopropyl ether, tetrahydrofuran, methylene chloride, chloroform, dichloroethane, hexane, cyclohexane, petroleum ether, acetonitrile, acetic acid, ethyl acetate or any mixture thereof. In this purification step, a small amount of an inorganic or organic acid corresponding to the salt may be added. The compound having the formula (I) of the present invention is low in toxicity and can be used alone by itself, or if desired, can be converted into a pharmaceutical preparation with other normal pharmaceutically allowable known and generally used carriers designed for the alleviation and treatment of symptoms due to ischemic diseases and neurodegenerative diseases, symptoms derived from seizures, epilepsy, and migraine headaches and symptoms arising from diabetes, arteriosclerosis, and inflammatory diseases. For example, the effective ingredient can be administered orally or nonorally by itself or a capsule, tablet, injection, or a suitable preparation together with usually used excipients. For example, capsules can be prepared by mixing the original powder with an excipient such as lactose, starch or its derivative, or a cellulose derivative and filling the resultant mixture into gelatin capsules. Further, tablets can be prepared by kneading in, in addition to the above excipient, sodium carboxymethylcellulose, alginic acid, arabic gum or other binders and water, if necessary, granulating the same, then further adding talc, stearic acid, or other lubricants and preparing the final form using a normal compression tabletizer. At the time of non-oral administration by injection, the effective ingredient is dissolved with a solubilizer in sterilized distilled water or sterilized saline and sealed into an ampule to make the injection preparation. If necessary, it is also possible to add a stabilizer, buffer, etc. The dosage of the pharmaceutical composition of the present invention differs depending on various factors, for example, the symptoms, the gravity of symptoms, the age, the complications of the patient to be treated, etc. and further depending on the route of administration, the form of the preparation, the frequency of administration, etc. In the case of oral administration, as the effective ingredient, normally 0.1 to 1000 mg/day/person, preferably 1 to 500 mg /day/person, while in the case of non-oral administration, 1/100 to 1/2 the amount of the case of oral administration can be administered. The amounts of dosages may be suitably adjusted according to the age, symptoms, etc. of the patient. EXAMPLES The present invention will now be explained in further detail with reference to the Reference Examples and Examples, but the scope of the present invention is by no means limited to these Examples. Example 1: Synthesis of 1-[4-(-4-fluorophenyl)methylphenyl]piperazine To a 10 ml acetonitrile solution of 426 mg of 4,4'-difluorobenzophenone and 841 mg of piperazine, 395 mg of triethylamine was added and stirred at 100°C for 12 hours. After cooling to room temperature, saturated aqueous sodium hydrogenbicarbonate solution was added, followed by extracting with chloroform. The extract was dried, filtered and concentrated under reduced pressure. The residue obtained was dissolved in 5 ml of trifluoroacetic acid and treated with 520 mg of triethylsilane and 60 mg of concentrated sulfuric acid, and stirred at room temperature for 1 hour. The reaction mixture was adjusted to pH=9 to 11 with 10% aqueous sodium hydroxide solution, followed by extracting with ethyl acetate. The extract was dried, filtered and concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (chloroform:methanol:water (2% acetic acid)=65:35:5) to give the above-referenced compound, 1-[4-(4-fluorophenyl)methylphenyl]piperazine in an amount of 305 mg (yield 58%). Reference Example 2: Synthesis of 4-(4-phenoxyphenyl)piperidine Step A To an 100 ml tetrahydrofuran solution of 3.5 g of N-tert-butoxycarbonyl-4-piperidone, a 35 ml of 4-phenoxyphenyl magnesium bromide prepared from 4-bromodiphenyl ether (0.6 mol/l tetrahydrofuran solution) was dropwise added under ice cooling and the resultant mixture was stirred for 1 hour. To the reaction mixture was added a 30 ml of saturated aqueous ammonium chloride solution. The product was extracted with ether. The extract was washed with saturated saline, dried, filtered, then concentrated under reduced pressure to give a residue, which was then purified by silica gel column chromatography (hexane:ethyl acetate =3:1) to give N-tert-butoxycarbonyl-4-(4-phenoxyphenyl)-4-piperidinol in an amount of 2.92 g (yield 45%). Step B To a 3 ml of methylene chloride solution of 772 mg of N-tert-butoxycarbonyl-4-(4-phenoxyphenyl)-4-piperidinol synthesized in Step A, a 3 ml of trifluoroacetic acid was dropwise added under ice cooling. The resultant mixture was stirred at room temperature for 2 hours, then adjusted by 10% aqueous sodium hydroxide solution to pH=9 to 10 and extracted with ether. The extract was dried, filtered, then concentrated under reduced pressure to give a residue, which was then recrystallized from ether/methylene chloride to give 4-(4-phenoxyphenyl)-1,2,3,6-tetrahydropyridine in an amount of 250 mg (yield 47%). Step C To an 100 ml methanol solution of 3.51 g of the 4-(4-phenoxyphenyl)-1,2,3,6-tetrahydropyridine synthesized in Step B was added a 200 mg of palladium carbon and 1 ml of acetic acid. The resultant mixture was hydrogenated under atmospheric pressure at room temperature. After completion of the reaction, the insolubles were filtered off and the filtrate was concentrated under reduced pressure. The residue obtained was dissolved in methylene chloride, adjusted by 10% aqueous sodium hydroxide solution to pH=9 to 10, then shaken. The organic layer was dried, filtered, then concentrated under reduced pressure to give a residue, which was then purified by silica gel column chromatography (methylene chloride:methanol =20:1) to give the above-referenced compound, 4-(4-phenoxyphenyl)piperidine in an amount of 2.32 g (yield 66%). Reference Example 3: Synthesis of (2S)-1-[4-(tert-butoxycarbonylamino)phenoxy]-2,3-epoxypropane (9) To an 8 ml dimethylformamide suspension of 60 mg of sodium hydride was added, under ice cooling, 300 mg of 4-(tert-butoxycarbonylamino)phenol. The resultant mixture was stirred at room temperature for 1 hour. Under ice cooling, 372 mg of (S)-glycidyl 3-nitrobenzenesulfonate was gradually added, then the resultant mixture was stirred at room temperature for 2 hours. The reaction was quenched with a 5 ml of saturated aqueous ammonium chloride solution, then the product was extracted with ether. The extract was washed with saturated saline, dried, filtered, then concentrated under reduced pressure to give a residue, which was then purified by silica gel column chromatography (hexane:ethyl acetate =3:1) to give the above-referenced compound (9) in an amount of 315 mg (yield 83%). Reference Example 4: Synthesis of (2S)-1-[(4-tert-butoxycarbonylamino-2,3,5-trimethyl)phenoxy]-2,3-epoxypropane (10) The same procedure was followed as in Reference Example 3 using (4-tert-butoxycarbonylamino-2,3,5-trimethyl)phenol to produce the above. Reference Example 5: Synthesis of (2S)-1-[(4-tert-butoxycarbonylamino-2,5-dimethyl)phenoxy]-2,3-epoxypropane (11) The same procedure was followed as in Reference Example 3 using (4-tert-butoxycarbonylamino-2,5-dimethyl)phenol to produce the above. Reference Example 6: Synthesis of (2S)-1-[(4-tert-butoxycarbonylamino-2,3-dimethyl)phenoxy]-2,3-epoxypropane (12) The same procedure was followed as in Reference Example 3 using (4-tert-butoxycarbonylamino-2,3-dimethyl)phenol to produce the above. Reference Example 7: Synthesis of (2S)-1-[(4-tert-butoxycarbonylamino-2,3,6-trimethyl)phenoxy]-2,3-epoxypropane (13) The same procedure was followed as in Reference Example 3 using (4-tert-butoxycarbonylamino-2,3,6-trimethyl)phenol to produce the above. Reference Example 8: Synthesis of (2S)-1-[(5-tert-butoxycarbonylamino-2-methoxy)phenoxy]-2,3-epoxypropane (14) The same procedure was followed as in Reference Example 3 using (5-tert-butoxycarbonylamino-2-methoxy)phenol to produce the above. Reference Example 9: Synthesis of (2S)-1-[(2-tert-butoxycarbonylamino-4,6-dimethyl)phenoxy]-2,3-epoxypropane (15) The same procedure was followed as in Reference Example 3 using (2-tert-butoxycarbonylamino-4,6-dimethyl)phenol to produce the above. Reference Example 10: Synthesis of (2S)-1-[(5-tert-butoxycarbonylamino-4-chloro-2-methoxy)phenoxy]-2, 3-epoxypropane (16) The same procedure was followed as in Reference Example 3 using (5-tert-butoxycarbonylamino-4-chloro-2-methoxy)phenol to produce the above. Reference Example 11: Synthesis of (2S)-1-[(4-tert-butoxycarbonylamino-2,6-dichloro)phenoxy]-2,3-epoxypropane (17) The same procedure was followed as in Reference Example 3 using (4-tert-butoxycarbonylamino-2,6-chloro)phenol to produce the above. Reference Example 12: Synthesis of (2S)-1-[(4-tert-butoxycarbonylamino-2-chloro-3,5,6-trimethyl)phenoxy]-2,3-epoxypropane 18) The same procedure was followed as in Reference Example 3 using (4-tert-butoxycarbonylamino-2-chloro-3,5,6-trimethyl)phenol to produce the above. Reference Example 13: Synthesis of (2R)-1-[(4-tert-butoxycarbonylamino-2,3,5-trimethyl)phenoxy]-2,3-epoxypropane (19) The same procedure was followed as in Reference Example 3 using (4-tert-butoxycarbonylamino-2,3,5-trimethyl)phenol and (R)-glycidyl 3-nitrobenzenesulfonate to produce the above. Reference Example 14: Synthesis of (2R)-1-[(5-tert-butoxycarbonylamino-2-methoxy)phenoxy]-2,3-epoxypropane (20) The same procedure was followed as in Reference Example 3 using (5-tert-butoxycarbonylamino-2-methoxy)phenol and (R)-glycidyl 3-nitrobenzenesulfonate to produce the above. Reference Example 15: Synthesis of 1-chloro-3-[(4-methoxy-2-methyl)phenyl]amino-2-propanol (21) A mixture of 300 mg of 4-methoxy-2-methylaniline and 213 mg of epichlorohydrin in 5 ml of isopropyl alcohol was stirred at 80°C overnight. The reaction was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (methylene chloride:hexane:ethyl acetate =10:2:1) to give the above-referenced compound (21) in an amount of 315 mg (yield 63%). Reference Example 16: Synthesis of (2R)-1-chloro-3-[(4-methoxy-2-methyl)phenyl]amino-2-propanol (22) The same procedure was followed as in Example Reference 15 using (R)-epichlorohydrin to produce the above. Reference Example 17: Synthesis of (2S)-1-chloro-3-[(4-methoxy-2-methyl)phenyl]amino-2-propanol (23) The same procedure was followed as in Reference Example 15 using (S)-epichlorohydrin to produce the above. Reference Example 18: Synthesis of 1-chloro-3-[(4-tert-butoxycarbonylamino-2,3,5,6-tetramethyl)phenyl]amino-2-propanol (24) The same procedure was followed as in Reference Example 15 using (4-tert-butoxycarbonylamino-2,3,5,6-tetramethyl)aniline and epichlorohydrin to produce the above. Reference Example 19: Synthesis of (2S)-1-(4-aminophenoxy)-3-[4-(4-phenoxyphenyl)piperidin-1-yl]-2-propanol (25) A mixture of 300 mg of the compound (9) synthesized in Example 3 and 287 mg of 4-(4-phenoxyphenyl)piperidine synthesized in Reference Example 2 in 8 ml of isopropyl alcohol was stirred at 100°C for 2 hours. The reaction was concentrated under reduced pressure to give a residue. Under ice cooling, 5 ml of ethanol saturated with hydrochloric acid and 2 ml of trifluoroacetic acid were added. The resultant mixture was stirred at room temperature for 1 hour, then the solvent was removed under reduced pressure to give crude crystals, which were recrystallized to give the hydrochloric acid salts of the above-referenced compound (25) in an amount of 156 mg (yield 82%). Reference Example 20: Synthesis of (2S)-1-[(4-amino-2,3,5-trimethyl)phenoxy]-3-[4-(4-(4-fluorophenyl)methylphenyl)piperazin-1-yl]-2-propanol (28) The compound (10) synthesized in Reference Example 4 and 1-[4-(4-fluorophenyl)methylphenyl]piperazine synthesized in Example 1 were used to produce the above in the same way as in Reference Example 19. Reference Examples 21: Synthesis of (2S)-1-[(4-amino-2,5-dimethyl)phenoxy]-3-[4-(4-(4-fluorophenyl)methylphenyl)piperazin-1-yl]-2-propanol (34) The compound (11) synthesized in Reference Example 5 and 1-[4-(4-fluorophenyl)methylphenyl]piperazine synthesized in Example 1 were used to produce the above in the same way as in Reference Example 19. Reference Example 22: Synthesis of (2S)-1-[(4-amino-2,3-dimethyl)phenoxy]-3-[4-(4-(4-fluorophenyl)methylphenyl)piperazin-1-yl]-2-propanol (37) The compound (12) synthesized in Reference Example 6 and 1-[4-(4-fluorophenyl)methylphenyl]piperazine synthesized in Example 1 were used to produce the above in the same way as in Reference Example 19. Reference Example 23: Synthesis of (2S)-1-[(4-amino-2,3,6-trimethyl)phenoxy]-3-[4-(4-(4-fluorophenyl)methylphenyl)piperazin-1-yl]-2-propanol (40) The compound (13) synthesized in Reference Example 7 and the 1-[4-(4-fluorophenyl)methylphenyl]piperazine synthesized in Example 1 were used to produce the above in the same way as in Reference Example 19. Reference Example 24: Synthesis of (2S)-1-[(5-amino-2-methoxy)phenoxy]-3-[4-(4-(4-fluorophenyl)methylphenyl)piperazin-1-yl]-2-propanol (44) The compound (14) synthesized in Reference Example 8 and 1-[4-(4-fluorophenyl)methylphenyl]piperazine synthesized in Example 1 were used to produce the above in the same way as in Reference Example 19. Reference Example 25: Synthesis of (2S)-1-[(2-amino-4,6-dimethyl)phenoxy]-3-[4-(4-(4-fluorophenyl)methylphenyl)piperazin-1-yl]-2-propanol (48) The compound (15) synthesized in Reference Example 9 and 1-[4-(4-fluorophenyl)methylphenyl)piperazine synthesized in Examples 1 were used to produce the above in the same way as in Reference Example 19. Reference Example 26: Synthesis of (2S)-1-[(5-amino-4-chloro-2-methoxy)phenoxy]-3-[4-(4-(4-fluorophenyl)methylphenyl)piperazin-1-yl]-2-propanol (50) The compound (16) synthesized in Example Reference 10 and 1-[4-(4-fluorophenyl)methylphenyl)piperazine synthesized in Example 1 were used to produce the above in the same way as in Reference Example 19. Reference Example 27: Synthesis of (2S)-1-[(4-amino-2,6-dichloro)phenoxy]-3-[4-(4-(4-fluorophenyl)methylphenyl)piperazin-1-yl]-2-propanol (52) The compound (17) synthesized in Reference Example 11and 1-[4-(4-fluorophenyl)methylphenyl]piperazine synthesized in Example 1 were used to produce the above in the same way as in Example 19. Reference Example 28: Synthesis of 1-[4-(4-phenoxyphenyl]piperidin-1-yl]-3-[(4-methoxy-2-methyl)phenylamino]-2-propanol (53) A mixture of 91 g of the compound (21) synthesized in Reference Example 15, 100 mg of the 4-(4-phenoxyphenyl)piperidine synthesized in Reference Example 2 and 109 mg of potassium carbonate in 4 ml of isopropyl alcohol was stirred at 80°C for 3 hours. The insolubles were filtered off, then the filtrate was concentrated under reduced pressure to give a residue. This was then purified by silica gel column chromatography (methylene chloride:methanol=30:1) to give the above-referenced compound (53) in an amount of 146 mg (yield 84%). Reference Example 29: Synthesis of 1-[4-(4-(4-fluorophenyl)methylphenyl)piperazin-1-yl]-3-[(4-methoxy-2-methyl)phenylamino]-2-propanol (55). The same procedure was followed as in Reference Example 28 using 1-[4-(4-fluorophenyl)methylphenyl]piperazine synthesized in Example 1 to produce the above. Reference Example 30: Synthesis of (2R)-1-[(4-amino-2,3,5-trimethyl)phenoxy]-3-[4-(4-(4-fluorophenyl)methylphenyl)piperazin-1-yl]-2-propanol (60) The compound (19) synthesized in Reference Example 13 and 1-[4-(4-fluorophenyl)methylphenyl]piperazine synthesized in Example 1 were used to produce the above in the same way as in Reference Example 19. Reference Example 31 : Synthesis of (2S)-1-[(4-amino-2,3,5-trimethyl)phenoxy]-3-[4-(4-(4-fluorophenyl)methylphenylphenyl)piperazin-1-yl]-2-propanol dimethanesulfonate (62 ) A 10 ml isopropyl alcohol solution of 480 mg of the compound (10) synthesized in Reference Example 4 and 432 mg of 1-[4-(4-fluorophenyl)methylphenyl]piperazine was stirred at 100°C for 2 hours. To the reaction mixture, 0.65 ml of concentrated hydrochloric acid was added and, after heating at reflux for 1 hour, the mixture was adjusted to pH = 8 to 10 with 10% aqueous sodium hydroxide solution and the corresponding free base was extracted therefrom with ethyl acetate. The solvent was removed under reduced pressure to give the residue, which was then treated with 306 mg (i.e., 2 equivalents) of methanesulfonic acid in a conventional manner. The resultant crude crystal was purified by recrystallization to give the above-referenced compound (62) in an amount of 940 mg (yield 88%). Reference Example 32: Synthesis of (2S)-1-[(4-amino-2,3,5-trimethyl)phenoxy]-3-[4-(4-(4-fluorophenyl)methylphenyl)piperazin-1-yl]-2-propanol dihydrochloride (64) The same procedure was followed as in Reference Example 31 to give the corresponding free base, followed by treating with 2 equivalents of hydrochloric acid to produce the above referenced compound. Reference Example 33: Synthesis of (2S)-1-[(4-Amino-2,3,5-trimethyl)phenoxy]-3-[4-(4-(4-fluorophenyl)methylphenyl)piperazin-1-yl]-2-propanol 1/2sulfonate (65) The above compound was synthesized by treating the corresponding free base with 1/2 equivalent of sulfuric acid in the same way as in Reference Example 31. Reference Example 34: Synthesis of (2S)-1-[(4-Amino-2,3,5-trimethyl)phenoxy]-3-[4-(4-(4-fluorophenyl)methylphenyl)piperazin-1-yl]-2-propanol sulfonate (66) The above compound was synthesized by treating the corresponding free base with an equivalent of sulfuric acid in the same way as in Reference Example 31. The physical data of the compounds obtained in the Examples are shown in Table 1. Inhibitory Effect of Veratrizine-induced Sodium Channel Activity The membrane potential of the synaptozomes prepared from the brain membrane of Wistar rats (male, 10 to 12 weeks old) was measured by the method of Aiuchi et al. [T. Aiuchi et al: Biochimi. Biophys. Acta. 771 , 228 (1984)] using a membrane sensitive fluorescent dye Rhodamine 6G to evaluate the effects of suppression of the compound on the veratrizine-inducing depolarization response. The results are shown in Table II. Compound no. Anti-veratrizine effect (inhibiting rate %) (compound 0.1 µM) 25 21 28 27.9 34 17.2 37 24.3 40 33.9 44 12.2 48 17.5 53 23.8 55 21.3 T-Type Calcium Channel Inhibitory Effect The hippocampal CA1 pyramidal cells were isolated from Wistar rats (female, 1 week old) in according to the method reported by Takahashi et al. [K. Takahashi et al.; J. Pharmacol. Exp. Ther., 256 , 169 (1991)] and the T-type calcium current was measured under conditions of a fixed membrane potential using the whole-cell configuration of the patch clamp technique. The effects of the compounds were evaluated from the rate of suppression of the peak current after 1 minute of application using the concentration clamp method. The results are shown in Table III. Compound no. T-type Ca 2+ channel inhibitory effect IC 50 (µM) 28 3.0 53 2.2 Lipid Peroxidation Suppressing Effect The whole brains of Wistar rats (10 weeks old, male) were excised and homogenized in the 10 times volumes of 50 mM phosphate-buffered solution (pH=7.4) (hereinafter referred to as PBS). The centrifuged supernatent was further diluted fourfold and the result was used as the brain membrane preparation. The membrane preparation was incubated in the presence of vehicle (0.5% DMSO) or compound at 37°C for 30 minutes and an automatic oxidation reaction promoted. The reaction was stopped by 35% perchloric acid, then the total of the main decomposition products of the peroxidized lipids present in the centrifuged supernatent, that is, malonaldehyde and 4-hydroxyalkenals, was measured using a BIOXYTECH®/LPO-586™ peroxidized lipid colorimetric assay kit (OXIS International, Inc.) and used as an indicator of the lipid peroxidation. The IC 50 value was found from the curve of the concentration for suppressing production of these aldehydes in the presence of the compound. The results are shown in Table IV. Compound no. Lipid peroxidation suppressing effect IC 50 (µM) 28 0.22 34 0.80 37 0.86 53 0.27 Flunarizine 42 Dopamine D 2 Receptor Blocking Action 57 µl of the membrane fraction prepared from the striatum of Wistar male rats (6 weeks old) was incubated together with the compound and 1.0 nM [ 3 H] raclopride in a buffer at 25°C for 1 hour. A GF/C glass filter (0.1% polyethylene imine treatment) was used for B/F separation. A beta plate was used for measurement of the radioactivity to evaluate the effect of the compound. The results are shown in Table V. Compound no. Dopamine D 2 receptor blocking action IC 50 (nM) 28 12000 40 12000 53 11000 Flunarizine 228 Audiogenic Seizure Suppressing Effect The audiogenic seizure suppressing effect of the compounds was evaluated by the method of Sarro et al. [G. B. De Sarro et al., Br. J. Pharmacol., 93, 247 (1988)]. That is, the compound dissolved in 10% 2-hydroxypropyl-β-cyclodextrin was administered intraperitoneally to DBA/2N type mice (male, 3 weeks old). After 20 minutes, a supersonic washer was used to apply audio stimulus of at least 90 dB for 1 minute. The wild running (WR), clonic seizures (clonus), tonic seizures (tonus), and the respiratory arrest (RA) were observed. The seizure suppressing effect was evaluated from the rate of suppression of the average value of the seizure score found as 0 = no response, 1 = WR, 2 = clonus, 3 = tonus, and 4 = RA. The results are shown in Table VI. Compound no. Antiseizure effect (suppression rate %) (compound 10 mg/kg, i.p.) 25 58 28 76 34 74 37 76 40 80 44 80 48 70 53 46 55 70 Acute Toxicity Test A pharmaceutical preparation was administered intravenously to ddY mice (male, 6 weeks old). The 50% lethal dosage LD 50 of the acute toxicity was calculated by an ordinary method from the death rate up to 24 hours after administration. The results are shown in Table VII. Compound no. LD 50 (mg/kg, i.v.) 28 47.3 40 49.1 INDUSTRIAL APPLICABILITY As explained above, the arylpiperidinopropanol and arylpiperazinopropanol derivatives represented by the formula (I) have effects suppressing cytotoxic Ca 2+ overload and lipid peroxidation, are high in safety, and are useful as pharmaceuticals for the alleviation or treatment of ischemic diseases.

Claims: A process for producing a compound having the formula (XII'): wherein Q' represents an optionally substituted phenyl group and X represents a hydrogen atom, a halogen atom, an alkoxy group, or an optionally substituted alkyl group, the process comprising reacting a benzophenone derivative having the formula (XIII): wherein Q' and X are the same as defined above, and L represents a group which can be easily exchanged with an amino group, with a piperazine derivative having the formula (XIV): wherein W represents a hydrogen atom, a benzyl group, a p-methoxybenzyl group, a benzyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group, a p-nitrobenzyloxycarbonyl group, a tert-butoxycarbonyl group, an ethoxycarbonyl group or an acetyl group to give a compound having the formula (XV): wherein Q', W and X are the same as defined above, and the subsequent reduction and deprotection of the compound having the formula (XV).

Inventors: ANNOURA HIROKAZU, NAKANISHI KYOKO, TAMURA SHIGEKI, ANNOURA, HIROKAZU, NAKANISHI, KYOKO, TAMURA, SHIGEKI
Applicants: DAIICHI SUNTORY PHARMA CO LTD, DAIICHI SUNTORY PHARMA CO., LTD.
Application year: 1998
Main classification: C07D295
IPC codes: C07C217, A61K31, A61P25, C07D295, C07C271, A61P9, C07D211, A61P3