WO1998003172A1 - Arylpiperidinol and arylpiperidine derivatives and drugs containing the same - Google Patents

Abstract

Arylpiperidinol or arylpiperidine derivatives represented by general formula (I) and drugs containing the same, in particular, those for improving or treating symptoms on the basis of ischemic diseases, convulsion, epilepsy and symptoms originating in hemicrania and calcium ion superloading inhibitors. In said formula (I) R represents H, optionally substituted phenyl, optionally substituted phenoxy or optionally substituted benzoyl; A represents a bond, cycloalkylene or alkenylene optionally substituted by lower alkyl; B represents alkylene optionally substituted by OH or alcoxy or -NHCO(CH2)n- (wherein n is an integer of 1 to 5); E represents a bond, O or methylene; X represents OH or H, provided that X is not H when E is O or methylene; and Y and Z independently represent each H, halogeno, alkoxy or optionally halogenated alkyl.

Description

 SPECIFICATIONS Derivatives of arylubiperidinol and arylpyperidin derivatives and pharmaceutical technology containing them

 The present invention relates to ischemic diseases such as cerebral infarction, cerebral hemorrhage, transient cerebral ischemia, subarachnoid hemorrhage, cerebral vascular disorders such as head trauma, sequelae of cerebral surgery, sequelae of cerebral atherosclerosis, or atypical angina , Unstable angina, myocardial infarction, PTCA (percutaneous transluminal coronary angioplasty) / PTCR (percutaneous transluminal coronary rev ascularization) perforated coronary thrombolysis cardiovascular damage due to revascularization due to artery bypass grafting (coronary artery bypass surgery), etc., myocardial ischemia-reperfusion damage such as severe arrhythmia, transplanted organ damage at the time of organ transplantation, organ damage at the time of surgery The present invention relates to an agent for ameliorating or treating symptoms caused by temporary blockage of blood flow or symptoms resulting from convulsions, epilepsy, migraine, and the like, and a Ca overload inhibitor. The present invention also provides a novel aryl piperage which has a Ca overload inhibitory effect and is useful for ameliorating or treating symptoms based on the ischemic disease and symptoms derived from spasticity, epilepsy, migraine and the like. The present invention relates to a nor or aryl piperidin derivative and a pharmaceutically acceptable salt thereof, and a synthetic intermediate for producing the compound. Background art

In severe ischemia-induced cell damage, ATP depletion, decreased intracellular pH, and disruption of energy-dependent intracellular and extracellular ion homeostasis result in large intracellular Ca accumulation. appear. Ca ² overload (Ca ^2f overload) causes a vicious cycle of causing dysfunction of mitochondria, randomly activating various enzyme reactions, and further overloading of Ca ^2. It is thought to cause irreversible damage to cell membranes and cause cell death [FB Meyer: Brain Res. Rev., 14, 227 (1989); Β. Boddeke et al .: Trends Pharmacol. Sci., 10, 397 (1989). ].

Drugs that suppress cytotoxic Ca ² overload can be used for various ischemic diseases, such as cerebral infarction, cerebral hemorrhage, transient cerebral ischemia, subarachnoid hemorrhage, head trauma, sequelae of brain surgery, cerebral atherosclerosis Cerebral vascular disorders such as sequelae, or angina angina, unstable angina, myocardial infarction, cardiovascular disorders due to revascularization due to PTCAZPTCRZCABG, etc., myocardial ischemia-reperfusion disorders such as severe arrhythmias, and organs It is considered to be an effective improvement and therapeutic agent, such as organ damage at the time of transplantation and temporary blockage of blood flow at the time of surgery. Disclosure of the invention

Against this background, the present invention has an inhibitory effect on cytotoxic Ca ² ′ overload, and is a highly safe ischemic disease-based symptom and symptom derived from convulsions, epilepsy, and migraine. It aims to provide improvements and treatments.

The present invention also provides a novel arylpyridinol or arylpyridin derivative, a pharmaceutically acceptable salt thereof, and a synthetic intermediate thereof, which are useful as the medicament. The purpose is to do so. According to the invention, the general formula (I): R-

[In the formula, R represents a hydrogen atom, a phenyl group which may be substituted, a phenyl group which may be substituted or a benzoyl group which may be substituted, and A represents a bond Represents an alkylene group which may be substituted with a cycloalkylene group or a lower alkyl group, and B represents an alkylene group or a group which may be substituted with a hydroxyl group or an alkoxy group.

-NHC0 (CH,) _n- (where n is an integer of 1 to 5), E represents a bond, an oxygen atom or a methylene group, X represents a hydroxyl group or a hydrogen atom (provided that When E represents an oxygen atom or a methylene group, X does not represent a hydrogen atom), and Y and Z may be the same or different and are a hydrogen atom, a halogen atom, an alkoxy group or a halogen atom. Represents an alkyl group which may be substituted]

Or a pharmaceutically acceptable salt thereof as an active ingredient, which is used for improving or treating symptom based on ischemic disease and symptom derived from convulsions, epilepsy and migraine. BEST MODE FOR CARRYING OUT THE INVENTION

The present inventors have, Ca ^{2 1} over the expression of the load has been reported to be involved Non- L-type Ca ^{2 +} channels and Na ⁺ channels [PJ Pauwel s et: Life Science, 48, 1881 ( 1991 ) disk cleanings a result of the inhibitory effect of as an indicator compound of the compound represented by the general formula (I), Itaomikuron'ita- L-type Ca ² 'T-type Ca ² which is a type of switch catcher tunnel Has a strong inhibitory effect on the 'channel and Na' channels, The inventors have found that the present invention is also effective in a model, and have completed the present invention.

 In the present invention, the ischemic disease is a cerebral ischemic disease, for example, cerebral infarction, cerebral hemorrhage, transient cerebral ischemia, subarachnoid hemorrhage, head trauma, cerebral atherosclerosis, sequelae of cerebral atherosclerosis Functional and organic disorders in the brain, such as ischemic disorders, such as dysmorphic angina, unstable angina, myocardial infarction, cardiovascular disorders associated with revascularization by PTCA / PTCR CABG, etc., and severe arrhythmias Myocardial ischemia-reperfusion injury, transplant organ damage at the time of organ transplantation, and temporary blockage of organ blood flow during surgery.

 The compound represented by the general formula (I) of the present invention includes the compounds represented by the general formulas (la) and (lb).

 General formula (la):

(Wherein, R, A, B, E, Y and Z are as defined above), and may be a substituted or unsubstituted phenyl group represented by R. Preferred substituents of the group or the benzoyl group which may be substituted include a halogen atom such as a fluorine atom, a chlorine atom and a bromine atom, and a carbon number such as a hydroxyl group, a methoxy group and an ethoxyquin group. C1-C5 optionally branched alkyl having 1-5 carbon atoms which may be substituted with a halogen atom such as an optionally branched alkoxy group, methyl group, ethyl group, trifluoromethyl group, etc. Groups. Examples of the halogen atom of the optionally branched alkyl group having 1 to 5 carbon atoms which may be substituted with a halogen atom include a fluorine atom, a chlorine atom, And a bromine atom.

 In the formula (la), the cycloalkylene group represented by A includes 1,1-cyclopropylene group, 1,2-cyclopropylene group, 1,1-cyclobutylene group, 1,1 A cycloalkylene group having 3 to 6 carbon atoms, such as a cyclopentylene group or a 1,1-cyclohexylene group, particularly preferably a 1,1-cyclopropylene group, Preferred examples of the alkenylene group of the alkenylene group include 2-cyclopentene propylene group, which may be substituted with a lower alkyl group, such as vinylene group and butadiene group. Or an alkylene group having 2 to 4 carbon atoms, particularly preferably a butadiene group. Examples of the alkyl group of the alkenylene group which may be substituted with a lower alkyl group include a methyl group and Ethyl group, propyl group, a And a isopropyl group.

In the formula (la), preferred examples of the alkylene group of the alkylene group which may be substituted with a hydroxyl group or an alkoxy group represented by B include a methylene group, a dimethylene group, a trimethylene group, An optionally branched alkylene group having 1 to 6 carbon atoms, such as a tetramethylene group, a methylmethylene group or a cyclopropylmethylene group, particularly preferably a methylene group or a dimethylene group Examples include a styrene group, a trimethylene group, a tetramethylene group, and a cyclopropylmethylene group. Preferred examples of the alkoxy group of the alkylene group which may be substituted with an alkoxy group include a C 1 to C 5 optionally branched alkoxy group such as a methoxy group and an ethoxy group. . Moreover, group - NHC0 (CH ₂₎ "- is an integer n of 1 to 5, is rather to preferred are 1 and 3.

In the formula (la), preferred examples of the halogen atom represented by Y or Z include a fluorine atom, a chlorine atom, and a bromine atom. Preferred examples of the alkoxy group include: Examples thereof include an optionally branched alkoxy group having 1 to 5 carbon atoms such as a methoxy group and an ethoxyquin group. Preferable examples of the alkyl group which may be substituted with an atom include an alkyl group which may be branched and has 5 to 5 carbon atoms, such as a methyl group, an ethyl group, and a trifluoromethyl group. Examples of the halogen atom of the alkyl group which may be substituted with a halogen atom include a fluorine atom, a chlorine atom, and a bromine atom.

General formula (lb):

 (lb)

(Wherein, R, A, B, Y and Z are as defined above), and may be a substituted or unsubstituted phenyl group or a substituted or unsubstituted phenoxy group represented by R. Preferred substituents of the optionally substituted benzoyl group include halogen atoms such as a fluorine atom, a chlorine atom and a bromine atom, and a number of carbon atoms 1 such as a hydroxyl group, a methoxy group and an ethoxyquin group. 5 to 5 carbon atoms which may be substituted by a halogen atom such as an alkoxy group, a methyl group, an ethyl group, and a trifluoromethyl group which may be branched. And an alkyl group. Examples of the halogen atom of the optionally branched alkyl group having 1 to 5 carbon atoms which may be substituted with a halogen atom include a fluorine atom, a chlorine atom and a bromine atom.

In the formula Ub), the cycloalkylene group represented by A includes 1,1-cyclopropylene group, 1,2-cyclopropylene group, 1,1—cyclobutylene group, 1, A cycloalkylene group having 3 to 6 carbon atoms, such as a 1-cyclopentylene group or a 1,1-cyclohexylene group, particularly preferably a 1,1-cyclopropylene group; 2 — cyclic propylene group, which may be substituted with a lower alkyl group Preferable examples of the alkenylene group of the alkarylene group include alkenylene groups having 2 to 4 carbon atoms, such as vinylene group and butadiene group, and particularly preferably butadiene group. Examples of the alkyl group of the alkenylene group which may be substituted with a lower alkyl group include a methyl group, an ethyl group, a propyl group, and an isopropyl group.

In the formula (lb), preferred examples of the alkylene group of the alkylene group which may be substituted with a hydroxyl group or an alkoxy group represented by B include a methylene group, a dimethylene group, a trimethylene group, and a tert-methyl group. An optionally branched alkylene group having 1 to 6 carbon atoms, such as a tramethylene group, a methylethylene group and a cyclopropylmethylene group, particularly preferably a methylene group or a dimethylene group. Examples include a lene group, a trimethylene group, a tetramethylene group, and a cyclopropylmethylene group. Preferred examples of the alkoxy group of the alkylene group which may be substituted with an alkoxy group include a C 1 to C 5 optionally branched alkoxy group such as a methoxy group and an ethoxy group. . Moreover, group - NHC0 (CH _2). The integer n from 1 to 5 of-is preferably 1 and 3.

 Preferable examples of the halogen atom represented by Y or Z include a fluorine atom, a chlorine atom and a bromine atom, and preferable examples of the alkoxy group include a methoxy group and an ethoxy group. Examples of the alkyl group which may be substituted with a halogen atom include a methyl group, an ethyl group, and a trifluoro group. Examples thereof include an optionally branched alkyl group having 1 to 5 carbon atoms such as a tyl group. Examples of the halogen atom of the alkyl group which may be substituted with a halogen atom include a fluorine atom, a chlorine atom and a bromine atom.

Among the compounds represented by the general formula (I), particularly preferred examples are as follows.

l £ SZ0 / I6df / XDJ ηιεο / 86 OAV

(In the above formula, ΑΓ represents an optionally substituted phenyl group;

Y and Z are as defined above. ) Further, according to the present invention, the general formula (I ′)

[In the formula, R ′ represents a phenyl group which may be substituted, a phenyl group which may be substituted or a benzoyl group which may be substituted, and A represents a bond, a cycloalkylene group or optionally substituted with a lower alkyl group represents an optionally alkenylene group, B is a hydroxyl group also rather is optionally substituted alkylene group or a group with an alkoxy group _{- NHC0 (CH 2) "-} ( where, n is Is an integer of 1 to 5, E represents a bond, an oxygen atom or a methylene group, X represents a hydroxyl group or a hydrogen atom (provided that E represents an oxygen atom or a methylene group). X represents no hydrogen atom, Y and Z represent the same or different and may be a hydrogen atom, a halogen atom, an alkoxy group or an alkyl group optionally substituted by a halogen atom (provided that X represents a hydrogen atom, and R represents When it represents a phenyl group which may be substituted or a phenyl group which may be substituted, B does not represent an alkylene group, X represents a hydroxyl group, and R may be substituted When B represents a phenolic group, B does not represent an unsubstituted alkylene group; X represents a hydroxyl group; R represents an optionally substituted phenyl group; and A represents a bond. B is an unsubstituted aralkyl Coptidis group or a group - NHC0 (CH _{2) n} - not show, X represents a hydroxyl group, R represents匱換which may be full We two Le group, a is consequent b If an alkylene group, B is a group - NHC0 (CH ₂₎ "- shows no)]

And a pharmaceutically acceptable salt thereof. Preferred substituents of the optionally substituted phenyl group, the optionally substituted phenoxy group and the optionally substituted benzoyl group represented by R ′ include a fluorine atom and a chlorine atom. Atom, bromine atom or other halogen atom, hydroxyl group, methoxy group, ethoxy group, etc., which may have 1 to 5 carbon atoms, which may be branched, alkoxy group, methyl group, ethyl group, trifluoromethyl group, etc. And an optionally branched alkyl group having 1 to 5 carbon atoms which may be substituted by a halogen atom. Examples of the halogen atom of the optionally branched alkyl group having 1 to 5 carbon atoms which may be substituted with a halogen atom include a fluorine atom, a chlorine atom and a bromine atom.

Preferred examples of the alkenylene group optionally substituted by a cycloalkylene group and a lower alkyl group represented by A, and preferred examples of the alkylene group optionally substituted by a hydroxyl group or an alkoxy group represented by B and groups - NHC0 (CH ₂₎ "- correct preferred of the integer n are a halogen atom represented by Y or Z, preferred correct example of alkoxy group, an alkyl group which may be substituted by a halogen atom, each of the general They are the same as A, B, η, Y and Z in equation (I).

 Preferable examples of the compound represented by the general formula (1 ′) include: In the general formula (I ′), R ′, A, B, and X are

1) R and R are a phenyl group which may be substituted, A is an alkenyl group which may be substituted with a lower alkyl group, B is an alkylene group which may be substituted with a hydroxyl group or an alkoxy group; Group-NHCOCCH ₂ ) „-(where n is an integer of 1 to 5), X is a hydroxyl group;

 2) R 'is a phenyl group which may be substituted, A is a bond or a cycloalkylene group, B is an alkylene group substituted with a hydroxyl group, X is a hydroxyl group;

3) R 'is an optionally substituted phenyl group, A is a bond or A cycloalkylene group, B is a group —NHC0 (CH ₂ ) „— (where n is an integer of 1 to 5), X is a hydroxyl group or a hydrogen atom;

 4) R 'is an optionally substituted phenyl group, A is a bond, a cycloalkylene group or an alkenylene group which may be substituted with a lower alkyl group, and B is a hydroxyl group. An alkylene group, X is a hydroxyl group;

5) R 'is a benzoyl group which may be substituted, A is a bond, an alkylene group which may be substituted with a cycloalkylene group or a lower alkyl group, and B is a hydroxyl group or an alkoxy group. is an alkylene group or a group optionally _{- NHC0 (CH 2) "-} ( where, n is an integer of 1 ~ 5), X is a hydroxyl group or a hydrogen atom;

Wherein E is a bond, an oxygen atom or a methylene group, and Y and Z may be the same or different and are a hydrogen atom, a halogen atom, an alkoxy group or Examples of the compound include an alkyl group which may be substituted with a halogen atom.

 The compound represented by the general formula (1 ') of the present invention includes the compounds represented by the general formulas U'a) and (1'b).

 General formula (l'a):

(Wherein R ′ A, B, E, Y and Z are as defined above). —General formula (b):

 (I'b)

 (In the formula, R ′ A, B, Y and Z are as defined above.) The compounds represented by the general formulas (I) and (1 ′) of the present invention include those in which isomers exist. The present invention includes all these individual isomers and mixtures thereof in the present invention. For example, in the general formulas (I) and (I '), when A represents an alkenylene group which may be substituted with a lower alkyl group, the two geometric isomers of the (E) form and the (Z) form When present, when B represents an alkylene group substituted with a hydroxyl group or an alkoxy group, there are two types of optical isomers, and the compound of the present invention includes individual isomers in all combinations thereof and mixtures thereof. . According to the present invention, there is also provided a compound of the general formula (II):

(In the formula, E ′ represents an oxygen atom or a methylene group, and Y and Z may be the same or different, and may be a hydrogen atom, a halogen atom, an alkoxy group, or an alkyl group optionally substituted with a halogen atom. The compound represented by this is provided.

The compounds represented by the general formulas (I) and (I ') according to the present invention can be synthesized, for example, as follows. Hereinafter, those methods will be sequentially described. In the general formulas (I) and (I ′), the compounds (la) and (l′ a) in which X represents a hydroxyl group can be obtained as follows. That is, the compound (IV) is obtained from the known starting material (III) (Step 1), converted into the compound (11a) (Step 2), and then reacted with the compound (V) or (V '). Compounds Ua) and (a) are obtained (Step 3). In the compounds (la) and (l'a), when B represents an alkylene group substituted with a hydroxyl group, the compound (11a) is obtained from the compound (VI) or (Vi '). Four ) . In the general formula (I), the compound (lb) and U ′ b) in which E represents a bond and X represents a hydrogen atom are obtained from the compound (IV ′) as a compound (lib) (Step 5), It is obtained by reacting with (V) or (V ') (Step 6). In the compounds (lb) and (1'b), those in which B represents an alkylene group substituted with a hydroxyl group are obtained from the compound (lib) and the compound (VI) or (VI '). 7)

 Process 1:

 Compound (iV) can be synthesized from known starting material (Π1) by the following method.

(In the formula, E, Y and Z are as defined above, and D represents a benzyl group, a p-methoxybenzyl group, a tert-butoxycarbonyl group, an ethoxycarbonyl group or an acetyl group.)

That is, the bromide aryl derivative (ΗΠ is converted to the corresponding aryl After conversion to a Grignard reagent or aryl lithium reagent, in a solvent that does not participate in the reaction, such as tetrahydrofuran, getyl ether, ethylene glycol dimethyl ether, toluene, etc., —100 to 50 ° C, preferably 1 to 1.5 equivalents of known starting materials N-benzyl-14-piperidone, N- (p-methoxybenzyl) 14-piperidone, N-t By reacting ert-butoxycarbonyl-1-piperidone, N-ethoxycarbonyl-2-piperidone, N-acetyl-4-piperidone for 1 to 6 hours, the compound represented by the general formula (IV) The compound represented is obtained.

The starting material (III) used in this reaction is a known compound or a known method [Martin et al .: J. Med. Chem., 22, 1347 (1979); J. -P. Gnet 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-14'-fluorodiphenyl ether, 4-bromo-3'-fluorodiphenyl ether, 4-bromo-2'-fluorodiphenyl ether, 3-bromo — 4′-Fluoro diphenyl ether, 3—Bromo-3′—Fnorolelo diphenyl ether, 3—Bromo—2′—Funolol diphenyl ether, 2—Bromo 4′-Fluoro diphenyl ether, 2—Bromo 1 3'-Fenorolodifeninolete ether, 2—Bromo-2'-Fluorodiphenyl ether, 2—Bumodiphenylmethane, 3—Bromodiphenylmethane, 4-Bromodiphenylmethane, 2—Bromo-4'-1 Fluorodiene ethanol, 3—Bromo-4'-Funoleo Lodiphenyl imethane, 4—bromo-4′-fluorodiphenylmethane, 2—bromo-4′—chlorodiphenylmethane, 3—bromo-4′-chlorodiphenylmethane, 4- Bromo 4'-chlorodiphenylmethane, 2-bromo-4'-methoxy Cis diphenyl methane, 3—bromo 4′-methoxy diphenyl methane, 4—bromo-4′—methoxy diphenyl methane, 2—bromo-4′-trif noreolo Methinoresif enolemethane, 3 — Bromo 4'-trifluoronormelo diphenyl methane, 4 — Bromo 4'-trifluorometyl diphenyl methane, 3 — Bromo41-fluorodiphenylmethane, 3—Bromo-4,4'-diphnorelodiphenylmethorane, 3—Bromo-4—Funoleo 1-4-4—Chlorodiphenyl Ninolemethane, 3-bromo-1-41-fluoro-4'-methoxydiphenylmethane, 3-Bromo-4'-fluoro-4'-trifnorolelo-methino-resin Tan, 3 — Bromo 4 Sigma-phenylene methane, 3 — bromine 4-methodine 4 '— fluoro phenylmethane, 3 — bromone 4-methodone 4'-chloro Diphenylephthalene, 3 — bromide 4, 4 '— dimethoxydiphenylmethane, 3 — bromide 4 — methanol 1 4' Ninoremetane, 5 — Bromo 2 — Methoxy diphenyl methane, 5 — Bromo 2 — Methoxy 4 ′ — Phenoleodifeninoletan, 5 — Bromone 2-methoxy 4'-chlorophenylmethane, 5-bromo 2,4 '-dimethoxy diphenyl methane, 5-bromo 2-methoxy One 4 '— Trifluoromethyltildipheninolemethan, 4 — Bromobif inil, 4-bromo-2 — Fluoro-biphenyl, 4-bromo-14'-Fluoro-biphenyl, 4-bromo--4'-methoxy-biphenyl, 4-Promo 4'-methyl-biphenyl, 4 —Bromo-4′-trifluoromethinolevifenyl, 4,4′—Jib mouth mobifil and the like can be used. Conditions for preparing the Grignard reagent and the organolithium reagent include “Compendium for Organic Synthesis” (Wi-Fi). ley-Interscience: A Division of John Wiley & Sons) The compound obtained in the above reaction can be used as it is in the next step, but if necessary, it can be used after purification by a commonly used purification method, for example, recrystallization or column chromatography. Good

 Process 1:

 Compound (Ila) can be synthesized from compound (IV) obtained in Step 1.

(In the formula, E, Y and Z are as defined above, and D 'represents a benzyl group or a P-methoxybenzyl group.)

 Compound (IV) obtained in Step 1 was treated with a catalytic amount of palladium carbon or palladium hydroxide in a solvent not involved in the reaction such as ethyl acetate, methanol, ethanol, or isopropyl alcohol. Hydrogenation at normal pressure to 6 atm in the presence of platinum or the like can convert the compound represented by the general formula (Ila). In this reaction, an acid such as acetic acid or hydrochloric acid may be added as necessary.

 Step 3:

By reacting the compound (Ila) obtained in the step 2 with the compound (V) or (V ′), the compounds (la) and (la) in which X is a hydroxyl group in the general formulas (I) and (1 ′) I 'a) can be synthesized.

(In the formula, R, R'A, B, E.Y and Z are as defined above, and W represents a group which can be easily exchanged with an amino group.)

That is, the compound (Ila) obtained in Step 2 was converted from benzene, toluene, tetrahydrofuran, dioxane, dimethylhonolemamide, dimethylsulfoxide, acetonitril, and acetonone. Organic solvents such as triethylamine, diisopropylethylamine, pyridin, etc., or sodium carbonate, calcium carbonate, cesium carbonate, cesium fluoride 1.0 to 1.5 equivalents of the compound (V) at room temperature to 150, preferably at room temperature to 100 ° C, in the presence of an inorganic base such as sodium hydrogen carbonate, potassium hydrogen carbonate, etc. Alternatively, by heating and stirring with (V ′), compounds represented by general formulas (la) and (a) are obtained. Further, in this reaction, if necessary, sodium iodide or tetrabutylammonium iodide may be added. W easily interacts with the amino group A halogen atom such as a chlorine atom or a bromine atom; an alkylsulfonyloxy group such as a methanesulfonyloxy group; or an arylsulfonyloxy group such as a toluenesulfonyloxy group. And a thio group.

As the compound (V) or (V ') used in this reaction, commercially available or known compounds or compounds that can be synthesized by known methods can be used. For example, methyl iodide, iodide compound Chill, bromide chill, propyl bromide, cinnamyl bromide, 3—promo 2—methyl—1 phenyl-1 1-propene, bromide 4—fluorosinnamyl, bromide (2 , 3,4—trimethoxy) cinnamyl, 1—bromo-13—phenylprone, (1-bromoethyl) benzene, (2-bromoethyl) benzene, 4-bromoethoxy cinnamyl 2- (4-fluorophenyl) oxethyl, bromide 2- (phenyloxy) tyl, bromide 4- (4-fluorophenyl) oxybutyl, bromide 4-uniloxybutyl, bromide 2 — phenyl Quinpropyl, trans-bros— (2-phenyl) cyclopropylmethyl, bromide-1-phenyl-1-cyclopropylmethyl, bromide-11-phenylpropyl-1—cyclopropanemethyl, 1-fluoro bromide 1-cyclopentanemethyl, phenacyl bromide, 2-bromo-4'-methoxyacetphenone, 2-bromo-4'-fluoroacetopheno 2-bromo-4'-chloroacetophenone, 2-bromopropionone, 2-promo 2'4'-dimension phenone, 2-promo 2 ' 5, 1-Dimethoxyacetophenone, 2—Bromo 4′-Methylacetophenone, 4—Chlorobutyrophenone, 4—Chloro 4′-Fluorobutyrophenone, 2 —Bro Momme Chillou 2 —Fujirou 1,3—Dioxolane, 2—Bromomethyl 2— (4-Fluorophenyl) 1-1,3—Dioxolane, 2—Bromomethyl-2— (4—Chlorophenyl) 1-1,3— Geoxo La 2-, bromomethyl-2— (4-methoxyethoxy) 1-1,3—dioxolan, 2— (1—bromoethyl) 12-2—vinyl-1,3-dioxolan, 2-bromobromo _ 2 — (4-Methylfenyl) 1-1, 3 — Dioxolane, 2 — Bromomethyl 1 2 — (2, 4 _ Dimethoxytoluene) 1-1, 3 — Dioxolane, 2 — Promoter Chill 2 — (2, 5 — dimethyloxy) 1 1, 3 — dioxolane, chloride

2,3,4-trimethoxybenzyl, benzyl bromide, bromide 4—fluorobenzyl, bromide 2—fluorobenzyl, bromide 3—fluorobenzyl, bromide 41 (trifluoromethyl) Benzyl, bromide 2 — (trifluoromethyl) Benzyl, bromide 3 — (trifluoromethyl) benzyl, 2 — bromo-1 — indanone, 2 — bromomethylbenzofuran, (2 — Promo 1 — Hydroxyminoethyl) Benzene, chloride

3—Methoxybenzyl, chloride 4—Methoxybenzyl, cinnamyl chloride, (2—promo 1—methoxethyl) benzene, bromide 1— (4-chlorophenyl) cyclobutane methyl, odor Formula 1 — (4-chlorophenyl) cyclopentanemethyl, odorant 111 (4 — methoxyphenyl) cyclopentanemethyl, (2 — bromo-1,1-diethylquinethyl) ) Benzene,! \ ^: — (2, 6 — dimethyl phenyl) 1 2 — Promorecetamide, 2 — Bromo 1 N— (trans — 2 — phenylcyclopropyl) acetamide, N — (1 — Diphenyl) cyclopropyl-2- (bromoacetamide), N- (2,6-dimethylthiophenyl) -1-bromobutyramide, N- (2,4,6-trimethyltylphenyl) 4- Bromo butyl amide, N—Fe2L 2 —Bromoacetamide, N— (2,

6-diisopropyrenyl) 1-2-promocetamide, N-(1-phenyl) cyclopropyl-2-promocetamide, etc. can be used.

In the general formula (l'a), R 'may be a phenyl group which may be substituted. , A represents a bond, and B represents an alkylene group substituted with a hydroxyl group. R ′ obtained in this step may be a substituted benzoyl group, A represents a bond, and B represents an alkylene group. It can also be synthesized by reducing the compound (a) representing a group by a conventional method.

 Process 4:

 From the compound (11a) obtained in the step 2, from the compounds () and (I ′ a), compounds (la ′) and (I ′) in which A is a bond and B is an alkylene group substituted by a hydroxyl group a ') can be synthesized.

 (la ')

Or

 (I'a ')

(Wherein, R, R ′ E, Y and Z are as defined above, and P represents an integer of 0 or 1.)

That is, the compound (IIa) obtained in the step 2 was converted from benzene, toluene, tetrahydrofuran, dimethyl ether, ethylene glycol methyl dimethyl ether, dioxane, dimethylformamide, Jime Tilsnorejo Room temperature to 200 ° C in solvents not involved in the reaction, such as kind, acetate nitrol, methanol, ethanol, isopropanol, tert-butyl alcohol, and ethylene glycol The reaction can also be carried out by reacting C, preferably 50 to 150 with 0.9 to 1.5 equivalents of the compound (VI) or (VI ') for 1 to 24 hours.

 As the compound (VI) or (VI ') used in this reaction, a commercially available or known compound or a compound which can be synthesized by a known method can be used. For example, 2- (2-epoxyethylbenzene) (R) — (+) — 1, 2 — Epoxyethylbenzene, (S) — (—) 1 1, 2 — eboxixyl benzene, (1 R, 2 R) 1 (+) 1 1 — F Peroxypropylenoxide, (IS, 2S) — (—) — 1 — Phenylpropylenoxide, 1,2_epoxy-1 3 — Phenoxypropane, (R) 1 (1) 1 2 — (Benziloxymethyl) oxysilane, (S) — (+) — 2 — (Benziloxymethyl) oxylan, 2,3 —epoxypropylbenzene, glycidyl 2 — Methylphenyl Ether, 4-tert-butylphenyl 2,3-epoxypropylate 1,4-epoxypropyl ether, 2,3-epoxypropyl 4-methoxyethoxy ether, (R) — (1-1) 1-1,2—epoxy-3 —Phenoxypropane, (S) — (+) — 1,2—Epoxy-3—Phenoxypropane, etc. can be used.

In this reaction, if necessary, an organic base such as triethylamine, diisopropylethylamine, pyridin or the like, or sodium carbonate, potassium carbonate, cesium carbonate, phenyl carbonate, etc. Inorganic bases such as cesium iodide, sodium hydrogencarbonate, and potassium hydrogencarbonate, or sodium iodide, tetrabutylammonium iodide, lithium carbonate, lithium chloride, bromide Metal salts such as zinc and magnesium bromide You may add in combination.

 Step 5:

 Compound (1 lb) can be synthesized from compound (IV ′), in which E represents a bond, among compounds represented by compound (IV) obtained in step 1.

(In the formula, Y, Z, D and D ′ are as defined above.) The compound (IV ′) obtained in the step 1 is treated under a solvent-free condition or under tetrahydrohydran, Does not participate in the reaction of ether, ethylene glycol dimethyl ether ether, benzene, toluene, methylene chloride, chloroform, carbon tetrachloride, water, methanol, ethanol, etc. Organic solvents such as acetic acid, trifluoroacetic acid, methansulfonic acid, trifluoromethansulfonate, etc. in a solvent at a temperature of 20 to 150, preferably 1 to 20 equivalents at 0 to 80 ° C. Treatment with an acid or an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, etc. for 1 to 12 hours, or the reaction of compound (IV ') with benzene, toluene, methylene chloride, macroform, carbon tetrachloride, etc. In solvents not involved, triethylamine, pyridine In the presence of a base such as din, diisopropylpyramine, etc., at 20 to 150 ° C, preferably 1 to 5 equivalents of thionyl chloride, methansulfonyl chloride, triflurochloride at 0 to 100 ° C. Acid chloride derivatives such as rometansulfonyl, trifluoromethan sulphonic anhydride, P-toluenesulfonyl chloride, and oxine chloride After reacting for ~ 6 hours, compound (VII) is obtained by performing the same acid treatment as described above. Next, the compound (VII) is treated in the same manner as in Step 2 to obtain a compound represented by the general formula (lib).

 The compound obtained in each of the above reactions can be used as it is in the next step, but if necessary, it can be purified by a commonly used purification method, for example, recrystallization / column chromatography. You may use it from.

 Step 6:

 According to the compound (lib) obtained in the step 5 and the compound (V) or (V ′), in the same manner as in the step 3, in the general formulas (I) and (1 ′), X is a hydrogen atom Compounds (lb) and (b) can be synthesized.

 (I'b)

(Wherein, R, R′A, B, Y and Z are as defined above.) Step 7:

From the compound (1 lb) obtained in Step 5, in the same manner as in Step 4, in the compounds (lb) and (I'b), A is a bond and B is an alkylene group substituted with a hydroxyl group. Compounds (lb ') and (I'b') can be synthesized.

 (lb ')

 'b')

 (In the formula, R, R′Y, Z and p are as defined above.) The individual isomers contained in the compounds represented by the general formulas (I) and (1 ′) of the present invention are usually For example, the separation can be performed by a recrystallization method, column chromatography, thin-layer chromatography, high-performance liquid chromatography, or a similar method using an optically active reagent. It is possible.

 The compounds represented by the general formulas (I) and (I ') according to the present invention may be any suitable organic solvent, for example, ether, tetrahydrofuran, methylene chloride, formaldehyde, benzene, toluene. The corresponding salt can be obtained by dissolving the compound in, for example, and treating with an inorganic acid or an organic acid. Hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, periodic acid, etc. are used as inorganic acids, and formic acid, acetic acid, butyric acid, oxalic acid, malonic acid, propionic acid are used as organic acids. Examples include acids, butyric acid, valeric acid, succinic acid, fumaric acid, maleic acid, tartaric acid, citric acid, lingic acid, benzoic acid, p-toluenesulfonate, methansulfonate, and the like.

The compounds according to the invention have low toxicity. For example, the drug is intravenously administered to ddY strain mice (male, 6 weeks old) by a conventional method, and the 50% lethal dose LD50 of acute toxicity for the compound of Compound No. Π is calculated from the mortality up to 24 hours after administration The weight was 32 mgZ kg. The compounds represented by the general formulas (I) and (I ') according to the present invention have low toxicity and may be used alone. However, if desired, other conventional pharmaceutically acceptable and commonly used compounds may be used. Together with such a carrier, it can be prepared into a preparation for the purpose of ameliorating and treating symptoms caused by ischemic disease. For example, the active ingredient can be administered orally or parenterally, alone or together with a conventional excipient, in an appropriate dosage form such as capsules, tablets, injections and the like. For example, capsules are prepared by mixing the powdered drug substance with excipients such as lactose, starch or derivatives thereof, and cellulosic derivatives and filling the mixture in gelatin capsules. The tablets are kneaded with a binder such as carboxymethylcellulose sodium, alginic acid, arabic gum and water in addition to the above-mentioned excipients and kneaded to form granules, if necessary. A lubricant such as stearic acid is added and prepared using a normal compression tableting machine. For parenteral administration by injection, the active ingredient is dissolved in sterile distilled water or sterile physiological saline together with a solubilizing agent, and the solution is then enclosed in an ampoule to prepare an injectable preparation. If necessary, a stabilizer, a buffer substance and the like may be contained.

 The dose of the therapeutic agent for ameliorating ischemic disease of the present invention varies depending on various factors, for example, the condition, severity, age, presence or absence of complications, etc. of the patient to be treated. Depending on the form, the number of doses, etc., in the case of oral administration, the active ingredient is usually 0.1 to 1000 mg / day Z, preferably 1 to 500 mg / day / person, parenteral administration In this case, the dose of 1Z100 to 1Z2 in the case of oral administration may be administered. These dosages can be adjusted appropriately according to the patient's age, symptoms, and the like. Example

Hereinafter, the present invention will be described more specifically with reference to Reference Examples and Examples, but the scope of the present invention is not limited to these Examples. Yes, obviously.

 Example 1: Synthesis of N-benzyl-4_ (3-fluor-4-phenyl) _n-4-l-piberidine (1) (Note: Compound No. 1 in Table 1 (the same applies hereinafter))

 Prepared from 3-promo 2-bifluorophenyl in a solution of 3 g of N-benzyl-1-piperidone in 15 ml of tetrahydrofuran under ice-cooling (3—Funolero-4-phenyl) 32 ml of phenylmagnesium bromide (0.6 mol / 1 tetrahydrofuran solution) was added dropwise and stirred for 1 hour. 30 ml of a saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted with ether. The extract was washed with a saturated saline solution, dried, filtered, and concentrated under reduced pressure to obtain a residue. Silica gel chromatography chromatograph (clo mouth form: methanol = 20: 1) ) To give 3.56 g (yield 62%) of the title compound (1).

 Example 2 Synthesis of N-benzyl-1- (4-phenyl-2-phenyl-4-piveridinole (2)

 Manufactured in the same manner as in Example 1 from 4-bromobiphenyl. Example 3 Synthesis of N-Penzihino 4- (4-phenyloxy) phenyl J_-piberidine (3)

 4 Produced in the same manner as in Example 1 from 1-promodiphenyl ether.

 Example 4: Synthesis of N-benzyl-41- [4- (4-fluorophenyl) methylphenyl, 1-4-piberdinol (4)

3.6 ml of n-butyllithium (1.6 mol / 1 hexane solution) was added dropwise to a 12 ml ether solution of 1.4 g of 4-bromo-4′-fluorodiphenylmethane at 178 ° C. — After heating to 20 ° C and stirring for 1 hour, a 5 ml ether solution of N-benzyl 4-piperidone ig was added dropwise. After stirring at 0 ° C for 3 hours, add 10 ml of a saturated aqueous ammonium chloride solution, and add Extracted with The extract was washed with a saturated saline solution, dried, filtered, concentrated under reduced pressure to obtain a residue, and silica gel chromatography chromatograph (clo-form: methanol) was used. By purifying in 1), 1.03 g of the title compound (4) was obtained (yield: 52%).

 Example 5: Synthesis of N-benzyl-1- [4- (fluoro) phenyl] vinyl-4-piveridinole (5)

 Prepared in the same manner as in Example 1 from 4-bromo-4′-fluorodiene ether.

 Example 1—: Synthesis of N-tert-butoxycarbonyl—4— (3—fluoro24—phenyl) phenyl 4piveridinole (6)

 The compound was produced in the same manner as in Example 1 from 4-tert-butoxycarbone 4-piperidone and 4-bromo-12-fluorobiphenyl. Reference Example 2: Synthesis of N—t ert—butoxycarbone 4 — (4-phenylphenylani 4-piveridge (7)

 Production was carried out in the same manner as in Example 1 from N_tert-butyncanolevonyl-4-piperidone and 4-bromobiphenyl.

 Reference Example 3: Synthesis of 4- (3-—Fluoro-4-phenyl) phenyl 1,2,3,62 2-tetrahydropyridine— (8)

 Under ice-cooling, 30 ml of trifluoroacetic acid was added dropwise to 1.76 g of the compound (6) synthesized in Reference Example 1 in 10 ml of methylene chloride. After stirring overnight at room temperature, the pH was adjusted to 9 to 10 with a 10% aqueous sodium hydroxide solution, and the mixture was extracted with ether. The extract is dried, filtered, and concentrated under reduced pressure to obtain a residue. The residue is purified by silica gel chromatography chromatography (clo form: methanol: 10: 1) to give the title compound. 855 mg (yield 71%) of (8) was obtained.

Reference Example 4: Synthesis of 4- (3-fluoro-4-phenyl) phenylenobiperidine (9) To a 100 ml methanol solution of 855 mg of the compound (8) synthesized in Reference Example 3, 130 mg of palladium carbon and 0.5 ml of acetic acid were added, and hydrogenated at normal pressure and room temperature. After the reaction was completed, insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride: methanol = 10: 1) to give 782 mg (yield 91%) of the title compound (9). .

 Reference Example 5: Synthesis of 4- (4-phenyl) phenyl—1 _ ^ _ 2,3,6—tetrahydropyridine (10)

 It was produced in the same manner as in Reference Example 3 from the compound (7) synthesized in Reference Example 2.

 Reference Example 6: Conjugation of 4- (4-phenyl) phenylpyridine (11)

 It was produced in the same manner as in Reference Example 4 from the compound (10) synthesized in Reference Example 5.

 Example 6: Synthesis of 4— (3—Fluoro-4—Phenyl) Phenyl—4—Piperidinol (12)

 To a solution of 1.39 g of the compound (1) synthesized in Example 1 in 50 ml of methanol, 280 mg of palladium hydroxide was added and hydrogenated at room temperature and 5 atm. After the reaction was completed, insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride: methanol = 10: 1) to give 710 mg of the title compound (12) (yield 68). %) Obtained.

 Example 7: Synthesis of 4- (4-phenyl) phenyl-1-4-piveridinole (13)

 It was produced in the same manner as in Example 6 from the compound (2) synthesized in Example 2.

Example 8: 4- (4-phenoxy) phenyl 4-piperidine Synthesis of Le (14)

 It was produced in the same manner as in Example 6 from the compound (3) synthesized in Example 3.

 Example 9: Synthesis of 4- [4- (4-fluorophenyl) methylphenyl] -4-pyveridinole (15)

 From the compound (4) synthesized in Example 4, jfe was produced in the same manner as in Example 6.

 Example 10: —Synthesis of 4— [4— (4-fluoro) poxy) phenyl 4-piveridinole 6)

 The compound was produced in the same manner as in Example 6 from the compound (5) synthesized in Example 5.

 Example 11: (E) -4- (3-Fluoro-4-phenyl) phenyl _ 1 _ (3—phenyl 2-propenyl) 1-4—piveridinole Synthesis of (17)

 To a solution of 300 mg of the compound (12) synthesized in Example 6 in 8 ml of acetonitrile, 220 mg of cinnamyl bromide and 0.4 ml of triethylamine were added and heated under reflux for 2 hours. 10 ml of ice water was added to the reaction solution, and extracted with ethyl acetate. The extract is dried, filtered and concentrated under reduced pressure to obtain a residue, which is then adjusted with silica gel ram chromatograph (methylene chloride: methanol = 25: 1). This gave 302 mg (72% yield) of the title compound (17).

 Example 12: (E) -4-(3-Fluoro mouth-4-X x 2-Nole) Phenol — 1 — (3 — Phenol 2 — Propenyl) Pyridine (18 Constellation

 The compound was produced in the same manner as in Example 11 using the compound (9) synthesized in Reference Example 4.

Example 1: Synthesis of 4- (3-fluoro-4-phenyl) phenyl-1- (2-phenyl-1-2-cysoethyl) piperidine (19) It was produced in the same manner as in Example 11 from the compound (9) synthesized in Reference Example 4 and funinasyl bromide.

 Example 14: Synthesis of 4- (3-7-lo-P-4-phenyl) phenyl-1-1 (2-phenyl-1-2-oxoethyl) -14-piperidinole 丄 20 ^

 It was produced in the same manner as in Example 11 from the compound (12) synthesized in Example 6 and phenacyl bromide.

 Example 15: 4- (3-fluoro-4-phenyl) phenyl

 [2- (4—Methoxythienyl) 121-oxol] —Synthesis of 4-pidinol (21)

 It was produced in the same manner as in Example 11 from the compound (12) synthesized in Example 6 and 2-promo 4′-methoxyacetic acid pentanone.

 Example 16: Synthesis of (E) -4-1 (4-phenyl) phenyl-1-1 (3-phenyl-2-propenyl) piperidine (22)

 The compound was produced in the same manner as in Example 11 from the compound (11) synthesized in Reference Example 6.

 Example Π: 4 _ (4-vinyl) vinyl) 1-1 (2-1-2-oxoethyl) pyridin (23-inch constellation)

 It was produced in the same manner as in Example 11 from the compound (11) synthesized in Reference Example 6 and phenacyl bromide.

 Example 18: 4 — (3 — 2_fluoro 4 — phenyl) phenyl-1 1 (2 — hydroxy 3 — phenyl oxy) propyl 1 4 — piveriginol (24) Synthesis of

A solution of 300 mg of the compound (12) synthesized in Example 6 and 160 mg of phenylidyl sidyl ether in 8 ml of isopropyl alcohol was stirred at 100 ° C. for 2 hours. The reaction mixture is concentrated under reduced pressure to obtain a residue, which is purified by silica gel chromatography (cross-hole form: methanol = 40: 1). This gave 420 mg (96% yield) of the title compound (24).

 Example 19: Synthesis of 4 — (3 — Fluoro — 4 — Phenyl) Phenyl 1 _ (trans — 2 — Phenyl 1-cyclopropylpyrmethyl) — Piperidine (25)

 It was produced in the same manner as in Example 11 from the compound (9) synthesized in Reference Example 4 and trans-2--2-phenyl-1-cyclopropylmethyl bromide. Example 20 Synthesis of 4- (3-fluoro-4-phenyl) phenyl—1 _— (1—phenyl-11-cyclopropyl) methyl-1—piperidinole (26)

 It was produced in the same manner as in Example 11 from the compound (12) synthesized in Example 6 and 1-phenylene 1-bromo-1-propane methyl bromide.

 Example 21: Synthesis of-(4-phenyl) phenyl-1- (trans-2-phenyl-1-cyclopropylmethyl) piperidine (27) Compound (11) synthesized in Reference Example 6 And bromide trans-2-phenyl-1-cyclopropylmethyl, prepared in the same manner as in Example 11. Example 22: Synthesis of 4- (4-phenyl) vinyl _— _1-(1 —vinyl 11-cyclopropene) methylbiperidine (28)

 It was produced in the same manner as in Example 11 from the compound (11) synthesized in Reference Example 6 and 1-fluoro-1-cyclopropane methyl bromide.

 Example 23: Synthesis of 4— (4-phenyl) _phenyl—1- (2-hydroxy-3- (phenyloxy) propylpyridine (29)

 It was produced in the same manner as in Example 18 from the compound (11) synthesized in Reference Example 6.

 Example 24: Synthesis of N- (26-dimethylphenyl) 141- (3-fluoro-4-phenyl) phenyl-1-piperidineacetamide (30)

The compound (9) synthesized in Reference Example 4 and N— (2,6—dimethyl) It was produced in the same manner as in Example 11 from 12-bromoacetamide [I. Mezo et al .: J. Label, Compounds, 8, 359 (1972)].

 Example 25: Synthesis of N- (trans-2-1-phenyl-1-prop-α-4-1- (3-fluoro-4-phenyl) phenyl-1-piperidinacetamide (31)

 Compound (9) synthesized in Reference Example 4 and 2-promoΝ (trans-2-phenylcyclopropyl) acetamide [N. Bodor et al .: J. Pharm. Sci., 80, 255 (1991)] Thus, it was produced in the same manner as in Example 11. Example ^: Synthesis of 4- (1-phenyl) phenyl-1- (trans-phenyl-1- (cyclopropylmethyl))-14-piberidinole (32)

 The compound (12) synthesized in Example 6 and trans-2--2-phenyl-1-cyclopropylmethyl were produced in the same manner as in Example 11. Example 27: Synthesis of (E) —4— (j-phenyl) phenyl-1- (3-phenyl-2-propenyl) -14—piveridinole (33) A compound was prepared from the compound (13) synthesized in Example 7 in the same manner as in Example 11.

 Performed! L ^: (E) — 4 — (4-enoxy) Fe 1-(3 — phenyl ^ — 2 — propionyl) 1-4-pyridine Synthesis of (34) The compound (14) synthesized in Example 8 was produced in the same manner as in Example 1).

 Example 29: Synthesis of 4- (4-phenyloxy) phenyl-3- (1- (2-fluoro-2-oxoxotyl)-4-pyberininole (35)

 The compound was produced in the same manner as in Example 11 from the compound (14) synthesized in Example 8 and phenacyl bromide.

Conducted [10: 4 -_ (4-phenoxy) phenyl (1-2-hydroxy 3-phenoxy) propyl-4-piveriginole (36) Combination Prepared from compound (14) synthesized in Example 8 in the same manner as in Example 18. Example 31: (_E) —4— [4— (4-fluorophenyl) methylphenyl, 1-1— (3 — Synthesis of (vinyl-2-propenyl) -14-piperidinol (37)

 The compound was produced in the same manner as in Example 11 from the compound (15) synthesized in Example 9.

 Example 32: Synthesis of 4— “4— (4—fluorophenyl) methylphenyl—11- (2—phenyl-2-oxoxoethyl) -14-piveriginol (38)

 It was produced in the same manner as in Example 11 from the compound (15) synthesized in Example 9 and phenacyl bromide.

 Example 33: 4— [4— (4-fluorophenyl) methyl phenyl]-1- (2—hydroquinone 3—phenoxy) propyl-14-pyridine 39) Synthesis

 The compound was produced in the same manner as in Example 18 from the compound (15) synthesized in Example 9.

Example 34 _: Synthesis of 1-(2-phenyl-1 2-quinoethyl) 1-4-(4-phenyl) phenyl 4-piberinol (40)

 It was produced in the same manner as in Example 11 from the compound (13) synthesized in Example 7 and phenacyl bromide.

 Example 35: Synthesis of 1-hydroxyl-3-phenoquine) propyl 4-((4-phenyl) phenyl-4-piberdinol (41) Compound synthesized in Example 7 ( According to 13), the production was carried out in the same manner as in Example 18.

Example 36: (S) —4— (3—fluoro-4-phenyl) phenyl Synthesis of 1- (2—hydroxy-3-phenoxy) propyl-4- (pyridine) phenol (42)

 Compound (12) synthesized in Example 6 and (S) — (+) — 12—epoxy—3—produced in the same manner as in Example 18 from funoxypropane / o

 Example 37: (R) —4— (3—fluoro-4—phenyl) phenyl 1— (2—hydroxy-3—phenoxy) propyl- (4-pyridine) 43) Synthesis

 The compound (12) synthesized in Example 6 and (R)-(1) -1,2-epoxy-3--3-furanoxypropane were produced in the same manner as in Example 18.

 Example 38: Synthesis of 1— (2—Hydroxy—2—Phenyl) Trityl—4—1 (4—Phenyl) phenyl 4—Piveri dinonoré (44) Performed under ice cooling To a solution of 124 mg of the compound (40) synthesized in Example 34 in 5 ml of methanol was added 18 mg of sodium borohydride, and the mixture was stirred for 1 hour. 8 ml of ice water was added to the reaction solution, and extracted with ethyl acetate. The extract is dried, filtered and concentrated under reduced pressure to obtain a residue, which is purified by silica gel column chromatography (clo-form: methanol = 20: 1). The title compound (44) was obtained as llimg (yield 90%).

 Example 3: (S) -4-(4-phenoxy) phenyl 1-(2-hydroxy 3-phenoxy) propyl-4-piveri Synthesis of

 It was produced in the same manner as in Example 18 from the compound (14) synthesized in Example 8 and (S) — (+) — 1,2—epoxy-3- 3-hydroxypropane.

Example 40: (R) 1-4 (4-phenoxy) phenyl-1-(2-hydroxy 3-phenoquine) propyl-4-piberidine (: 46) Synthesis

 The compound (14) synthesized in Example 8 and (R)-(I) -I-1.2-epoxy-13-phenyloxypropane were produced in the same manner as in Example 18.

 Example 41: (S _)-4- [4- (4-fluorophenyl) methylphenyl] —1— (2—hydroxy-13—phenyl) -propyl-4-4-piveridino Synthesis of the tool (47)

 It was produced in the same manner as in Example 18 from the compound (15) synthesized in Example 9 and (S)-(+)-di-2-epoxy-3-propoxypropane.

 Example 42: (R) —4- [4- (4-Fluorophenyl) methinolephenyl] —11- (2—hydroxy-3—phenoxy) propyl-4-piberage Synthesis of Knoll (48)

 The compound (15) synthesized in Example 9 and (R)-(1) -l, 2-epoxy-13-phenyloxypropane were prepared in the same manner as in Example 18 from o.

 Example 43: 4— (っ ^^; n, 1 ェ 1—1 一 1 1 (1 フ 2—1—1 シ cyclopropane) methyl —4 — (piberidine) (49) Constellation

 The compound was produced in the same manner as in Example 11 from the compound (14) synthesized in Example 8 and propane methyl bromide-1-propene.

 Example—Example 44: (4—Phenocyn) _7—Trans 1- (trans-2-phenyl-1-pyrropropyl) 1—4—Piveridinol (50) Synthesis

The compound (14) synthesized in Example 8 and trans-2-2-phenyl-1-cyclopropylmethyl were prepared in the same manner as in Example 11. Example 45: 4— [4— (4—fluorophenyl) methylphenyl 1-1-(1 -Phenyl- 1 -cycloprononone) methyl-Synthesis of 4-Pyridinol (51)

 It was produced in the same manner as in Example 11 from the compound (15) synthesized in Example 9 and propanyl methyl bromide-1-propene.

 Example 46: 4— [4- (4-fluorophenyl) methyl) 1- 1— (t rans—2—phenyl 1-cyclopropylmethyl) 14-pidinol (52 Synthesis of

 It was produced in the same manner as in Example 11 from compound (15) synthesized in Example 9 and trans-2-phenyl-1-cyclopropylmethyl bromide. Example 47: 1- (trans-2—Phenyl-1-cyclopropyl) 1-4—Hydroquinone 4- (4—Phenoquine) Fluorine 1—Piveridinacetamide (53) Synthesis of

 From the compound (14) synthesized in Example 8 and 2—promo N— (trans-2 monophenylcyclopropyl) acetamide [N. Bodor et al .: J. Pharm. Sci., 80, 255 (1991)] It was manufactured in the same manner as in Example 11. Example 48: N- (trans-2-Phenyl—1-cyclopropyl pill) -4— [4— (4-Phenylophenyl) methyl phenyl] 1-4—Hydro 1—Piperi Synthesis of diacetamide (54)

 The compound was produced in the same manner as in Example 11 from the compound (15) synthesized in Example 9 and 2-bromo-N- (trans-2-phenylcyclopropyl) acetamide.

 Example 49: Synthesis of-(2,6-dimethylphenyl) -14-hydroxy-14- (4-phenoquin) phenyl-1-1-pyridinacetamide (55)

Compound (14) synthesized in Example 8 and N— (2,6—dimethylethylinole) -12-bromoacetamide [I. Mezo et al .: J. Label. Compounds, j, 859 (1972)] Thus, it was produced in the same manner as in Example 11. Example 50: Synthesis of N— (2,6—dimerphenyl) 24— “4— (4-fluorophenyl) methylphenyl-14-hydroxy-11-piperidineacetamide (56)

 It was produced in the same manner as in Example 11 from compound (15) synthesized in Example 9 and N- (2,6-dimethyldimethyl) -2-promocetamide.

 Implementation 51: —Synthesis of (4-vinyl) cyclopropyl 4—hydroxy 4- (4-phenyl) phenyl 1-piperidine acetate (57)

 It was produced in the same manner as in Example 11 from the compound (14) synthesized in Example 8 and N- (1-phenyl) cyclopropyl-2-promocetamide.

Example 52: N— (1-Phenyl) cyclopropyl 4-hydroxyl 4- [4- (4—Fusoleo mouth) —Metinolef ethanol——1 The sum of the resinat ( ⁵⁸ ) ^

 Compound (15) synthesized in Example 9 and N- (1-phenyl) cyclopropyl-1 2-promorecetamide synthesized according to the method of Kirino et al. [Publication Patent Publication, Sho 56-26854 (1981)] And manufactured in the same manner as in Example 11.

 Example 53: Synthesis of (E) 1-4-1 [4- (4-fluoro) phenyl] phenyl-1- (3-phenyl-2-propenyl) -14-piperidinole (59)

 The compound was produced in the same manner as in Example 11 from the compound (16) synthesized in Example 10.

Example 54: Synthesis of 4- (4-fluorene) phenoxy 2_phenyl 2- 1- (2—phenyl 2-oxoxotyl) 1-4—piberdinol (60) It was produced in the same manner as in Example 11 from the compound (16) synthesized in Example 10 and funacyl bromide.

 Example 55: (S) — 4 — [4 — (4 Fluoro) hydroxy]

X-Niru 1 (2-Hydroxy-1-3-Henoxy) Propyl_4 Synthesis of Piveridinol (61)

 It was produced in the same manner as in Example 18 from the compound (16) synthesized in Example 10 and (S) — (+) _ 1,2-epoxy-13-phenylquinpropane.

Table 1 shows the physical property data of the compounds obtained in Reference Examples and Examples.

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J £ SZ0 / l6df / lDd Table I (continued)

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I € SrO /, 6df / X3d ^ ICO / 86 O Veratridine-induced inhibition of sodium channel activation ―

According to the method of Aiuchi et al. [T. Aiuchi et al .: Biochimi. Biophys. Acta, —7 71. 228 (1984)] The membrane potential of the tosome was measured using a membrane-sensitive fluorescent dye, Mouth-Dammin 6G, to evaluate the inhibitory effect of the compound on veratridine-induced depolarization response. The results are shown in Table II.

 Table I I Pile veritridine action (inhibition rate%) Compound No. ^ "(compound 01 / M)

 1 7 2 6. 8

 1 8 1 3. 1

 1 9 1 2. 9

 2 0 2 0 2

 2 1 1 8 .6

 2 3 1 1 .3

 2 4 2 3 .8

 2 5 5 7

 2 6 3 0

 2 7 4 1

 2 8 2 4

 2 9 4 0

 3 1 1 4

 3 2 2 7. 3

3 3 1 2 .8

3 4 2 9. 9

3 5 2 7. 7 (Continued) Anti-heterin action (Inhibition rate 率> J Compound number (Compound 0.1 M)

 3 6 2 8.6

 3 7 3 9. 7

 3 8 1 8

 3 9 1 8.7

 4 0 2 3

 4 1 2 3.7

 4 2 2 1

 4 3 2 1. 2

 4 5 1 9.8

 4 6 1 9.8

 4 7 3 9.5

 4 8 2 2. 7

 4 9 1 8.9

 5 0 3 3.4

 5 3 3 2.3

 5 4 2 0.4

 5 5 2 8.3

 5 7 4 0.1

5 8 1 1 .3 T-type calcium channel inhibitory action

 According to the method of Takahashi et al. [K. Takahasi et al .: J. Pharmacol. Exp. Ther., 256, 169 (1991)], hippocampal CA1 pyramidal cells were obtained from Wistar rats (male and female, 1 week old). Were isolated acutely, and the T-type calcium current was recorded using a modified whole-cell patch clamp method with the membrane potential fixed. The effects of the compounds were evaluated from the suppression rate of the peak current one minute after application using the concentration clamp method. The results are shown in Table 111.Table π

Audiogenic spasm inhibitory action

 Sarro et al. [G. B. De Sarro et al .: Br. J. Pharmacol., 93,

247 (1988)], to evaluate the inhibitory effect of the compounds on audiogenic convulsions. That is, DBAZ 2 — mice (male, 3 weeks old) were intraperitoneally administered with a compound dissolved in 10% 2 -hydroxy pill pill -cyclodextrin, and 20 minutes later, an ultrasonic cleaner was used. We observed wild running (WR), clonic spasms (clonus), tonic convulsions (tonus), and respiratory arrest (RA) that occurred when a sound stimulus of 90 dB or more was given for 1 minute. The anticonvulsant effect was calculated as 0 = no response, 1 = WR, 2 = clonus, 3 = tonus, 4 = RA The evaluation was based on the suppression rate of the average value of the scavenging score. The results are shown in Table 1 V

Table IV Anticonvulsant activity (inhibition rate%) Compound number (Compound 10 mg / kg, i.p.)

 1 7 8 8

 1 8 6 2

 1 9 5 2

 2 0 9 1 .3

2 1 9 1 .3

2 2 7 2

 2 3 8 4

 2 4 7 4

 2 5 5 4

 2 7 5 2

 2 8 5 6

 2 9 6 8

 3 4 8 0

 3 5 9 8

 3 6 6 8

3 7 8 8

Table I V (continued)

Industrial applicability

As described above, the arylpyridinol or pyrididine derivative of the general formula (I) according to the present invention has an effect of suppressing cytotoxic Ca ² —overload and has high safety. It is useful as a remedy for ischemic diseases.

Claims

1. General formula (I):

Blue

[In the formula, R represents a hydrogen atom, a substituted or unsubstituted phenyl group, a substituted or unsubstituted benzyl group or a substituted or unsubstituted benzoyl group; A bond, an alkenylene group which may be substituted with a cycloalkylene group or a lower alkyl group, and B represents an alkylene group or a group which may be substituted with a hydroxyl group or an alkoxy group

-NHC0 (CH _{2) n} - (where, n is an integer of 1-5) indicates, E is illustrated a bond, an oxygen atom or a main switch les emission group, X represents a hydroxyl group or a hydrogen atom (provided that When E represents an oxygen atom or a methylene group, X does not represent a hydrogen atom), and Y and Z may be the same or different and are a hydrogen atom, a halogen atom, an alkoxy group or a halogen atom. Represents an alkyl group which may be substituted]

An agent for ameliorating or treating symptoms based on ischemic diseases and symptoms derived from spasticity, epilepsy and migraine, which comprises a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

2. In the general formula (I), R represents an optionally substituted phenyl group, A represents an alkenylene group optionally substituted by a lower alkyl group, and X represents a hydroxyl group. Ischemic disease containing the compound according to claim 1 as an active ingredient and a pharmaceutically acceptable salt thereof. Or symptom derived from epilepsy and migraine.

 3. In the general formula (I), R represents an optionally substituted benzoyl group, A represents a bond, and X represents a hydroxyl group. An agent for ameliorating or treating symptoms from epilepsy and migraine.

 4. In the above general formula (I), R represents an optionally substituted phenyl group, A represents a bond, B represents a dimethylene group substituted with a hydroxyl group, and X represents 2. An agent for ameliorating or treating a symptom based on ischemic disease according to claim 1 showing a hydroxyl group and a symptom derived from spasticity, epilepsy and migraine.

 5. In the general formula (I), R represents a phenyl group which may be substituted, A represents a bond, and B represents a trimethylene group substituted with a hydroxyl group. 2. The method according to claim 1, wherein X represents a hydroxyl group, or a remedy or a remedy for symptoms based on ischemic disease and symptoms derived from convulsions, epilepsy and migraine.

 6. General formula (I)

[Wherein, R represents a hydrogen atom, a phenyl group which may be substituted, a phenyl group which may be substituted or a benzoyl group which may be substituted, and A represents a bond, a cycloalkyl group; Represents an alkenylene group which may be substituted with a hydroxyl group or a lower alkyl group, and B represents a hydroxyl group Or an alkylene group or group optionally substituted with an alkoxy group.

-NHC0 (CH ₂ ) „-(where n is an integer of 1 to 5), E represents a bond, an oxygen atom or a methylene group, X represents a hydroxyl group or a hydrogen atom (provided that When E represents an oxygen atom or a methylene group, X does not represent a hydrogen atom), and Y and Z may be the same or different and are a hydrogen atom, a halogen atom, an alkoxy group or a halogen atom. Represents an alkyl group which may be substituted]

And a pharmaceutically acceptable salt thereof as an active ingredient.

7. In the general formula (I), R represents an optionally substituted phenyl group, A represents an alkenylene group optionally substituted by a lower alkyl group, and X represents a hydroxyl group. 7. The Ca ² overload inhibitor according to claim 6, wherein

8. The Ca ² -overload inhibitor according to claim 6, wherein in the general formula (I), R represents a benzoyl group which may be substituted, A represents a bond, and X represents a hydroxyl group.

9. In the general formula (I), R represents an optionally substituted phenyl group, A represents a bond, B represents a dimethylene group substituted with a hydroxyl group, and X represents a hydroxyl group. 7. The Ca ² excess overload inhibitor according to claim 6, which shows:

 10. In the general formula (I), R represents a phenyl group which may be substituted, A represents a bond, and B represents a trimethylene group substituted with a hydroxyl group. 7. The Ca overload inhibitor according to claim 6, wherein X represents a hydroxyl group.

11. —General formula (I '): '-A

[In the formula, R 'represents a substituted or unsubstituted phenyl group, a substituted or unsubstituted benzoyl group or an optionally substituted benzoyl group, and A represents a bond, a cycloalkylene An alkylene group or a group -NHCOCCH ₂ ) „(where n is an alkylene group or a group optionally substituted with a hydroxyl group or an alkoxy group) E is an integer of 1 to 5, E is a bond, an oxygen atom or a methylene group, X is a hydroxyl group or a hydrogen atom (however, E is an oxygen atom or a methylene group) In this case, X does not represent a hydrogen atom), and Y and Z represent the same or different and may represent a hydrogen atom, a halogen atom, an alkoxy group or an alkyl group optionally substituted with a halogen atom (where X is Indicates a hydrogen atom and R is When it represents a phenyl group which may be optionally substituted or a phenyl group which may be substituted, B does not represent an alkylene group, X represents a hydroxyl group, and R represents an optionally substituted phenyl group. When an enoxy group is represented, B does not represent an unsubstituted alkylene group, X represents a hydroxyl group, R represents a substituted or unsubstituted alkyl group, and A represents a bond. And B do not represent an unsubstituted alkylene group or the group -NHC0 (CH ₂ ) _n- , X represents a hydroxyl group, and the scale represents a phenyl group which may be replaced, and A represents a cycle. when showing the mouth alkylene group, B is a group - NHC0 (CH ₂₎ "- shows no) compound and its pharmaceutically acceptable salts of represented by.

12. In the above general formula (I ′), R ′, A.B, and X are 1) a phenyl group which may be substituted with R ′, and A is a lower alkyl group. Substituted optionally may be alkenylene group group, B is a hydroxyl group also rather is § Rukokin an optionally substituted alkylene group or group with a group - NHC0 CH ₂₎ "- (where, n is an integer of 1 to 5 X is a hydroxyl group;

 2) R 'is a phenyl group which may be substituted, A is a bond or a cycloalkylene group, B is an alkylene group substituted with a hydroxyl group, X is a hydroxyl group;

3) R 'is optionally substituted off Weniru group, A is a bond or consequent Roaruki les emission group, B is a group _{- NHC0 (CH 2) "-} ( where, n is the integer of 1 to 5 ), X is a hydroxyl group or a hydrogen atom;

 4) R 'is a substituted phenyl group, A is a bond, a cycloalkylene group which may be substituted with a cycloalkylene group or a lower alkyl group, and B is a hydroxyl group. An alkylene group, wherein X is a hydroxyl group;

5) R 'is a benzoyl group which may be substituted, A is a bond, a alkenylene group which may be substituted with a cycloalkylene group or a lower alkyl group, and B is a hydroxyl group or an alkoxy group. optionally substituted alkylene les emissions or a group with a group _{- NHC0 (CH 2) "-} ( where, n is the integer of 1 ~ 5), X is a hydroxyl group or a hydrogen atom;

Wherein E is a bond, an oxygen atom or a methylene group, and Y and Z may be the same or different and are a hydrogen atom, a halogen atom, an alkoxy group or a halogen atom 12. The compound according to claim 11, which represents an alkyl group optionally substituted with: and a pharmaceutically acceptable salt thereof.

13. In the general formula (1 ′), R ′ represents an optionally substituted phenyl group, A represents an alkylene group optionally substituted with a lower alkyl group, and X 13. The compound according to claim 11 or 12, which represents a hydroxyl group, and a pharmaceutically acceptable salt thereof.

14. The compound according to claim 11 or 12, wherein in the general formula (ベ ン ゾ ′), R ′ represents an optionally substituted benzoyl group, A represents a bond, and X represents a hydroxyl group. Pharmaceutically acceptable salts.

 15. In the general formula (1 ′), R ′ represents an optionally substituted phenyl group, A represents a bond, and B represents a dimethylene group substituted with a hydroxyl group. 13. The compound according to claim 11, wherein X represents a hydroxyl group, and a pharmaceutically acceptable salt thereof.

 16. In the general formula (1 ′), R ′ represents a phenylene group which may be substituted, A represents a bond, and B represents a trimethylene group substituted with a hydroxyl group. 13. The compound according to claim 11, wherein X represents a hydroxyl group, and a pharmaceutically acceptable salt thereof.

17. In the general formula (1 ′), R ′ represents a phenyl group which may be substituted, A represents a bond or a cycloalkylene group, and B represents a group —NHC0 (CH ₂ ) _n - (where, n is an integer of 1-5) salt indicates, that X is acceptable of compound and its pharmaceutically claim 11 or claim 12 represents a hydroxyl group or a hydrogen atom.

 18. The compound according to claim 11 or 12 and a pharmaceutically acceptable compound thereof, wherein in the general formula (1 ′), R ′ represents an optionally substituted benzoyl group, and A and E represent a bond. Salt.

 19. A medicament comprising the compound according to claim 11 represented by the general formula (1 ′) and a pharmaceutically acceptable salt thereof as an active ingredient.

 20. General formula (II):

(In the formula, E ′ represents an oxygen atom or a methylene group, and Y and Z are the same or different, and represent a hydrogen atom, a halogen atom, an alkoxy group, or an alkyl group optionally substituted with a halogen atom. Shown)).