JPH09241161A - Medicine - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a medicine, comprising a heterocyclic derivative as an active ingredient, having excellent suppressing actions on neuron necrosis and useful as a therapeutic agent for cerebral angiopathy. SOLUTION: This medicine comprises a compound of formula I [R<1> is an aryl or an aromatic heterocyclic ring; R<2> is H, an alkyl, an alkenyl, a cycloalkyl, an alkoxy, etc.; R<3> and R<4> are each H, an alkyl or are bonded to adjacent N to denote a 5- to a 7-membered ring cyclic amino; A is a 2-10C alkylene; W is O, S or (CH)n ; (n) is 0-2; X, Y and Z are each CH, N, etc.] or its salt or a solvate thereof as an active ingredient. 4-(4-Fluorophenyl)-2-methyl-6-(4- piperidinobutoxy)pyrimidine is exemplified as the compound of formula I. The compound of formula I is obtained by reacting a compound of formula II (Q is a halogen) with a compound of formula III in the presence of a base (e.g. NaOH) in a solvent (e.g. DMF) at 0-140 deg.C. The compound is capable of manifesting excellent suppressing actions on neuron necrosis, especially in the acute period of cerebral angiopathy and useful for suppressing the onset of the cerebral angiopathy and a sequela thereto.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a medicine containing a heterocyclic derivative as an active ingredient.

[0002]

2. Description of the Related Art Cerebrovascular disease refers to a condition in which blood vessels that perfuse the brain are damaged due to cerebral infarction, cerebral hemorrhage, head injury, subarachnoid hemorrhage and the like. When cerebrovascular disorder disrupts or reduces blood flow to the brain, resulting in cerebral ischemia, nerve cells are damaged. Even if he / she saves his / her life, the patient will suffer the sequelae of neuronal necrosis due to the neuronal injury. The therapeutic agents for cerebrovascular disorders include those that suppress cerebral infarction and cerebral hemorrhage and those that suppress nerve cell necrosis.
When brain tissue is exposed to ischemia, ischemia is very shortly and then blood flow is completely resumed, and energy metabolism and nerve activity in the brain are once restored, but eventually In recent years, it has been known that it leads to necrosis of nerve cells. Such a nerve cell lesion mainly occurs in the hippocampus, and is characterized in that it develops 3 to 4 days after cerebral ischemia occurs. Therefore, it is called delayed nerve cell necrosis.
Further, even in the region of the brain where the blood flow is not restarted, the blood flow is not completely cut off but there is a part where the blood flow is reduced. It is said that nerve cells in this part also become necrotic when ischemia is prolonged. If you can prevent such neuronal necrosis,
The sequelae of cerebrovascular accidents that occur after ischemia can be prevented. It is known that the brain metabolism improving agent, propentofylline, has an inhibitory effect on delayed neuronal cell death, but it has various side effects and is not sufficiently satisfactory as a pharmaceutical.

A large number of studies have been conducted on inhibitors for excitatory amino acids aiming at therapeutic agents in this field. this is,
It is based on the idea of preventing ischemic nerve cell necrosis by suppressing the hyperexcitation of nerve cells that occurs after cerebral ischemia. Glutamic acid or glutamate is well known as such an excitatory amino acid. As a suppressor for excitatory amino acids, many glutamate antagonists that specifically block the receptor for this amino acid and compounds that inhibit glutamate release are known. The glutamate receptor is N-methyl-D-aspartate (hereinafter
NMDA) receptors and receptors other than NMDA receptors (hereinafter
It is divided into non-NMDA). For example, MK-801 is known as an NMDA antagonist, and YM-90K is known as a non-NMDA antagonist. Examples of glutamate release inhibitors include 2,4-diamino-5- (2,3,5-
Trichlorophenyl) pyrimidine and 2,4-diamino-5- (2-
Chlorophenyl) pyrimidine EP Publication 459830, 6t
h SCI-RSC Medicinal Chemistry Symposium Sept. 8-1
1, 1991 is known.

On the other hand, in International Publication WO 92/04333,
It is described that a phenylpyrimidine derivative has a learning / memory disorder improving effect and is useful for dementia. Although various nervous systems are damaged in dementia, it is known that the acetylcholine nervous system, which plays an important role in learning and memory, is particularly damaged. WO 92/04333
The phenylpyrimidine derivative disclosed in the publication is
By acting on the acetylcholine nervous system and activating the remaining cerebral nerve cells, the learning and memory disorder is improved. Such a learning / memory disorder improving action is a completely different action from the action of inhibiting neuronal necrosis and suppressing the development of sequelae of cerebrovascular accidents. In addition to the above, various pyrimidine derivatives have been reported so far. For example,
48-21949 discloses 4-methyl-2-phenyl-6-2- (4-
It is described that phenylpiperazin-1-yl) ethyloxypyrimidine and the like have an α-sympatholytic effect (sedation, blood pressure lowering and vasodilation). Also, CA 100:
209733u and CA106: 18488r each have, for example, 4-
2- (N, N-Dimethylamino) ethyloxy-6-methyl (or phenyl) -2-phenylpyrimidine and 4-2- (N, N-dimethylamino) ethylthio-6-methyl (or phenyl) -2-phenyl It has been described that pyrimidine amplifies the action of phleomycin. Also, J.
Med. Chem. 31 (6), 1231-40 (1988) describes 2- (2-dimethylamino) ethylthio-4-methyl (or unsubstituted) -6-phenyl (or aromatic heterocyclic group) pyrimidine derivative. Or 2-2
It has been described that-(N, N-dimethylamino) ethoxy-4-thienylpyrimidine derivatives amplify the action of bleomycin.

[0005]

SUMMARY OF THE INVENTION An object of the present invention is to provide a pharmaceutical composition containing a novel heterocyclic compound as an active ingredient and having a neuronal necrosis inhibitory action.

[0006]

The present inventors have synthesized and studied various compounds in order to achieve the above object.
In the process, it was found that the compound represented by the following general formula [I] has a neuronal necrosis inhibitory action which is completely different from the learning and memory impairment improving action, and has low toxicity, and the present invention was completed. It was Since the compound according to the present invention has an excellent nerve cell necrosis inhibitory action particularly in the acute stage of cerebrovascular accident, it is useful for the treatment of cerebrovascular disorder and the suppression of the onset of sequelae of cerebrovascular disorder.

The present invention has the following general formula [I]

Embedded image The present invention relates to a pharmaceutical composition containing as an active ingredient any of the compounds represented by: or a salt thereof or a solvate thereof. In the formula, R ¹ represents an optionally substituted aryl or an aromatic heterocyclic group having 5 to 10 atoms constituting the ring.
The aromatic heterocyclic group is a monocyclic ring or a condensed ring and contains one or more nitrogen, oxygen or sulfur as a ring-constituting atom. Further, such aryl or aromatic heterocyclic groups include hydroxy, halogen, alkyl, haloalkyl, hydroxyalkyl,
From the group consisting of aralkyl, alkenyl, alkoxy, haloalkyloxy, alkylthio, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, alkylsulfonyl, sulfamoyl, alkanoyl, amino, monoalkylamino, dialkylamino, carboxy, alkoxycarbonyl, cyano and nitro. It may be substituted with 1 to 3 same or different selected substituents. R ² is hydrogen, alkyl, alkenyl,
Cycloalkyl, cycloalkylalkyl, hydroxyalkyl, haloalkyl, alkoxy, alkylthio,
Represents amino, monoalkylamino, dialkylamino or optionally substituted phenyl. Such phenyl may be substituted with 1 to 3 same or different substituents selected from the group consisting of halogen, alkyl and alkoxy.

R ³ and R ⁴ are the same or different and each is hydrogen or an optionally substituted alkyl (wherein the alkyl is the same or selected from the group consisting of hydroxy, alkoxy, amino, monoalkylamino and dialkylamino). Which may be substituted by one or two different substituents), or R ³ and R ⁴ together with the adjacent N are NR ³ R ⁴ a 4- to 8-membered cyclic amino group. Represents Such cyclic amino may have nitrogen, oxygen or sulfur as a ring-constituting atom in addition to the nitrogen, and further alkyl, alkoxy, hydroxy, oxo, amino,
It may be substituted by 1 to 3 same or different substituents selected from the group consisting of monoalkylamino, dialkylamino, optionally substituted aryl and pyridyl. Furthermore, N having R ³ and R ⁴ bonded thereto
May form an oxide.

A represents alkylene having 2 to 10 carbon atoms.
Such alkylene is alkoxy at any position,
It may be substituted by a substituent selected from the group consisting of hydroxy and oxo. E represents O or S. W is a single bond, O, S or (CH ₂ ) _n (CH
₂ may be substituted by alkyl. n is 1
Or represents 2. ). X, Y and Z are the same or different and each represents CH, CR (R represents alkyl) or N. However, the case where X, Y and Z are simultaneously carbon such as CH or CR is excluded. G ring is pyridine, pyrimidine, 1,3,
Represents 5-triazine. When one to three of X, Y and Z are N, one of them may form an oxide.

One of the characteristics of the present invention is that it is completely structurally different from the known therapeutic agents for cerebrovascular disorders based on glutamate antagonist-like action and glutamate release inhibitory action,
And a known phenylpyrimidine derivative (WO 92/04333) having a structure similar to that of the compound according to the present invention, and an α-sympathetic nerve of a piperazine derivative described in JP-B-48-21949. The point is to find a cerebral nerve cell necrosis inhibitory effect, which is a completely different effect from the blocking effect. Some of the compounds represented by the general formula [I] are already known. However, the superior neuronal necrosis inhibitory action of these compounds was first discovered by the present inventors.

In the present specification, alkyl is a straight or branched chain having 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, Mention may be made of tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl. Among them, those having 1 to 4 carbon atoms are preferable. The alkenyl has 2 to 6 carbon atoms, for example, vinyl,
Mention may be made of allyl, 3-butenyl, 2-pentenyl, 4-hexenyl. The cycloalkyl is preferably 3 to 10, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-adamantyl and 2-adamantyl. The aryl has 6 to 6 carbon atoms.
Thirteen phenyls, 1-naphthyl, 2-naphthyl and biphenyl can be mentioned. Phenyl is particularly preferable. The aralkyl has 7 to 13 carbon atoms and has a linear or branched alkyl moiety, and examples thereof include benzyl, phenethyl, phenylpropyl, phenylbutyl, diphenylmethyl and naphthylmethyl. Examples of halogen include chlorine, fluorine, bromine, and iodine.

The alkoxy is preferably a linear or branched one having 1 to 6 carbon atoms, and examples thereof include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,
Isobutoxy, sec-butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, n-hexyloxy,
Mention may be made of isohexyloxy. The alkanoyl is preferably a linear or branched one having 1 to 6 carbon atoms, and examples thereof include acetyl, propanoyl, butanoyl, isobutanoyl, pentanoyl, hexanoyl, 2-
Mention may be made of methylpentanoyl. The alkylthio is preferably a linear or branched one having 1 to 6 carbon atoms, for example, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio, Mention may be made of n-pentylthio, isopentylthio, n-hexylthio and isohexylthio. The alkylsulfonyl is preferably a linear or branched one having 1 to 6 carbon atoms, for example, methylsulfonyl, ethylsulfonyl, n-
Propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl, isopentylsulfonyl, n-hexylsulfonyl,
Mention may be made of isohexylsulfonyl. Hydroxyalkyl includes straight or branched chain carbon atoms of 1 to
There may be mentioned 6 compounds, for example, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 4-hydroxybutyl, 3-hydroxybutyl, 5-hydroxypentyl and 6-hydroxyhexyl. Examples of haloalkyl include linear or branched ones having 1 to 6 carbon atoms, for example, trifluoromethyl, fluoromethyl, 2-bromoethyl, 2-chloroethyl.

The monoalkylamino is a linear or branched one having 1 to 6 carbon atoms, for example, methylamino,
Mention may be made of ethylamino, propylamino, butylamino, heptylamino, hexylamino. As the dialkylamino, a linear or branched carbon number 1 to
6, such as dimethylamino, diethylamino,
Mention may be made of dipropylamino, dibutylamino, diheptylamino, dihexylamino. As specific examples of alkoxycarbonyl, linear or branched ones having 2 to 7 carbon atoms are preferable, and examples thereof include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl,
Isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert
-Butoxycarbonyl, n-pentyloxycarbonyl,
Mention may be made of isopentyloxycarbonyl, n-hexyloxycarbonyl and isohexyloxycarbonyl. Specific examples of cycloalkyloxy are preferably those having 3 to 10 carbon atoms, and examples thereof include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy, and 2-adamantyloxy. You can Specific examples of cycloalkylalkyl are preferably those having 4 to 11 carbon atoms, for example, cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl, cyclopentylethyl, cyclopentylpropyl, cyclohexylmethyl, cyclohexyl. Mention may be made of ethyl, cyclohexylpropyl, cycloheptylmethyl, 2-adamantylmethyl.

The 4- to 8-membered cyclic amino is, for example,
Azetidin-1-yl, pyrrolidin-1-yl, piperidino, hexamethyleneimino, tetrahydropyridino, octahydroazocin-1-yl, piperazin-1-yl, homopiperazin-1-yl, morpholino, thiomorpholino be able to. Examples of the substituent of the cyclic amino include alkyl, alkoxy, hydroxy, oxo, amino, monoalkylamino, dialkylamino, optionally substituted aryl or pyridyl. As such a substituent of aryl or pyridyl, R ¹
The substituents listed above can be mentioned. As the aromatic heterocyclic group having 5 to 10 atoms constituting the ring, any one selected oxygen, sulfur or nitrogen atom can be contained in the ring.
It may include one or more and may be a monocyclic ring or a condensed ring. For example, 2-pyridyl, 3-pyridyl, 4-pyridyl,
2-thienyl, 2-furyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 1-isoquinolyl, 4-isoquinolyl, 2-quinazolinyl, 1-methyl-2-indolyl You can

The alkylene represented by A may be linear or branched. As a cerebrovascular disorder therapeutic agent, A is preferably an alkylene having 3 to 6 carbon atoms, and more preferably an alkylene having 4 to 6 carbon atoms. As E, O is preferable. As W, a single bond is preferable. X, Y, and Z are X = Z = N and Y = CH, or Z = N and X = Y.
= CH is preferred. The former is particularly preferable. R ¹ is preferably halogen-substituted phenyl, particularly fluorophenyl. R ² is preferably alkyl or haloalkyl, and more preferably alkyl. Particularly preferred is methyl. As R ³ and R ⁴ , those which form a cyclic amino with —NR ³ R ⁴ together with adjacent N are preferable, and among them, those which contain only one nitrogen atom as a ring-constituting hetero atom are preferable. Particularly, piperidino is preferable.

Particularly preferred compounds are of the formula [I
b)

Embedded image Can be mentioned. A ² is alkylene having 4 to 6 carbon atoms. E ² is O. X ² = Z ² = N and Y ² = CH or X ² = Y ² = CH and Z ² = N. R ²¹ is
Halogen-substituted phenyl. R ²² is alkyl or haloalkyl. R ²³ and R ²⁴ , together with adjacent N, form a 4- to 8-membered cyclic amino with —NR ²³ R ²⁴ , and contain only one nitrogen atom as a ring-constituting hetero atom. Among them, preferable compounds include 4- (4-fluorophenyl) -2-methyl-6- (4-piperidinobutoxy) pyrimidine and 4- (4-fluorophenyl) -2-methyl-6- (1 -Methyl-4-piperidinobutoxy) pyrimidine, 4- (4-fluorophenyl) -2-methyl-6- (5-piperidinopentyloxy)
Pyrimidine, 4- (4-fluorophenyl) -2-methyl-6- (6-
Piperidinohexyloxy) pyrimidine, 2- (4-fluorophenyl) -4-methyl-6- (4-piperidinobutoxy) pyrimidine, 4- (4-fluorophenyl) -2-methyl-6- (3 Mention may be made of -piperidinopropoxy) pyridine and 4- (4-fluorophenyl) -2-methyl-6- (5-piperidinopentyloxy) pyridine, and salts thereof.

Examples of the solvate of compound [I] included in the present invention include hydrate and ethanol solvate. Examples of the salt of the compound [I] included in the present invention include salts of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, hydrobromic acid with mineral acids, or acetic acid, tartaric acid, lactic acid, citric acid. Examples thereof include salts of acids, fumaric acid, maleic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid and camphorsulfonic acid with organic acids.

[0018]

BEST MODE FOR CARRYING OUT THE INVENTION The compound of the present invention represented by the formula [I] can be produced, for example, by the following method. Method A

Embedded image In the formula, R ^{1 to} R ⁴ , A, E, X, Y, Z and W have the same meanings as described above. Q represents halogen. Of these, chlor is preferred. The compound [I] according to the present invention can be produced by reacting the halogen compound [II] with the compound [III] in the presence of a base in a solvent inert to the reaction. As the reaction solvent, N, N-dimethylformamide (DM
Aprotic polar solvent such as F), benzene, toluene,
Aromatic hydrocarbons such as xylene, n-hexane, n-heptane, hydrocarbons such as cyclohexane, tetrahydrofuran, dimethoxyethane, diethyl ether, dioxane, ethers such as diethylene glycol dimethyl ether, or a mixed solvent thereof can be used. . As the base, sodium hydride, sodium amide, potassium tert-butoxide, butyl lithium and the like can be used. The reaction is usually 0 to 140 ° C., preferably
It is carried out at 10 to 110 ° C. The reaction time varies depending on the raw materials, the solvent used and the type of base, but is usually 2 to 24 hours. The amount of the compound [III] and the base used is usually
The amount is preferably 1 to 1.2 mol, based on 1 mol of the compound [II].

Method B

Embedded image In the formula, R ^{1 to} R ⁴ , A, E, X, Y, Z, W and Q are as defined above. Compound [IV] and halogen compound [V] in the presence of a base in a solvent inert to the reaction,
[I] can be produced by reacting at 80 ° C. As the reaction solvent, aprotic polar solvents such as acetonitrile, dimethylsulfoxide, N, N-dimethylformamide (DMF), alcohols such as methanol, ethanol and isopropanol, ethers such as tetrahydrofuran, dimethoxyethane, diethyl ether and dioxane. Glymes such as methyl cellosolve and ethylene glycol dimethyl ether, halogenated hydrocarbons such as methylene chloride and chloroform, aromatic hydrocarbons such as benzene, toluene and xylene, or a mixed solvent thereof can be used. As the base, sodium hydride,
Potassium carbonate, sodium hydroxide, potassium hydroxide, silver carbonate and the like can be used. The reaction time varies depending on the raw materials, the base used, and the type of solvent, but is usually suitable for 2 to 10 hours. Usually, the amount of the halogen compound [V] and the base used is preferably 1 to 1.2 mol per 1 mol of the compound [IV].

Method C

Embedded image In the formula, R ^{1 to} R ⁴ , A, E, X, Y, Z, W and Q are as defined above. Halogen compound [VI] and amine [VI]
[I] can be produced by reacting I] in the presence of a base in a solvent inert to the reaction. As the reaction solvent, acetonitrile, dimethylsulfoxide, N,
Uses aprotic polar solvents such as N-dimethylformamide (DMF) and acetone, ethers such as tetrahydrofuran, dimethoxyethane, diethyl ether and dioxane, aromatic hydrocarbons such as benzene, toluene and xylene, or a mixed solvent thereof. be able to. As the base, an alkali metal salt such as potassium carbonate, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide or potassium hydroxide can be used. It is also possible to use an excess amount of amine [VII] in place of these bases. The reaction is
It is carried out at 10 to 100 ° C. The reaction time varies depending on the raw materials, the base used, and the type of solvent, but is usually suitable for 2 to 20 hours. Usually, the amount of the compound [VII] used is preferably 1 to 3 mol with respect to 1 mol of the compound [VI]. The amount of the base used is usually 1 to 1 mol of the compound [VI].
1.2 mol is preferred.

Method D (when A is an alkylene having 3 to 10 carbon atoms and has hydroxy, oxo or alkoxy at the β-position of NR ³ R ⁴ )

[Chemical 6] In the formula, R ^{1 to} R ⁴ , E, W, X, Y, Z, and Q are as defined above. A ⁰ represents alkylene having 1 to 8 carbon atoms which may be substituted. In the method C, an epoxy compound [VI ^a ] is used instead of the halogen compound [VI] in the same manner to obtain a compound [Id] according to the present invention having hydroxy at the β-position of NR ³ R ^4. it can. This reaction proceeds even without using a base. The amount of amine used varies depending on the type of amine, but usually,
An equimolar amount to an excess amount is used with respect to 1 mol of the compound [VI ^a ]. The compound [Id] is oxidized in a solvent inert to the reaction (eg, DMSO / acetic anhydride) with an oxidizing agent such as chromic acid, manganese dioxide or potassium permanganate according to a known method to obtain NR. A compound having oxo at the β-position of ³ R ⁴ can be produced. Further, the compound [Id] is reacted with an alkyl halide in the presence of a base such as sodium hydride or butyllithium in a solvent inert to the reaction to produce a compound having an alkoxy at the β-position of NR ³ R ^4. can do.

Method E (when W is O or S in the formula [I])

Embedded image In the formula, R ^{1 to} R ⁴ , A, E, X, Y, Z, and Q have the same meanings as described above. Wa represents O or S. Compound [VII
Compound [Ic] in which W is O or S can be produced by reacting I] with compound [III] in the presence of a base in a solvent inert to the reaction. it can. As the reaction solvent, an aprotic polar solvent such as N, N-dimethylformamide (DMF), an ether such as tetrahydrofuran, dimethoxyethane, diethyl ether, dioxane, or a mixed solvent thereof can be used. As the base, sodium hydride, sodium amide, potassium-tert-butoxide, butyllithium and the like can be used. The reaction is carried out at 0 to 80 ° C, preferably 10 to 30 ° C. The reaction time depends on the raw materials, the base used,
Depending on the type of solvent, 2 to 24 hours is usually sufficient. Compound [VIII] and compound [III] are preferably equimolar. The amount of the base used is usually compound [VIII]
It is preferably 1 to 1.2 mol per 1 mol. The compound having an amino group or a hydroxyl group in the compound [I] according to the present invention is prepared by using a raw material protected by a leaving group, if necessary.
After subjecting to any one of the methods ~ E, the protecting group is removed by a usual method. As the amino-protecting group, for example, benzyl, benzyloxycarbonyl, trifluoroacetyl, tert-butoxycarbonyl can be used. As the protective group for the hydroxyl group, methoxymethyl, 2-methoxyethoxymethyl, methylthiomethyl, tetrahydropyranyl, tert-butyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl and the like can be used. For example, the compound according to the present invention having a phenolic hydroxy group can be obtained by using a starting material protected with a benzyl group, reacting it, and then removing the protecting group by catalytic reduction. The catalytic reduction is usually performed in a solvent at 0 to 80 ° C. under normal pressure or increased pressure. As the solvent, alcohols such as methanol and ethanol, water, carboxylic acids such as acetic acid, esters such as ethyl acetate, and ethers such as dioxane and tetrahydrofuran can be used. As the catalyst, palladium-carbon, palladium-black,
Platinum oxide or the like can be used. The reaction time varies depending on the raw materials, the catalyst used, and the type of solvent, but is usually 30 minutes to
48 hours is appropriate.

The starting materials [II] and [IV] will be listed later as reference examples, but they are known methods (WO92 / 04333).
It can be manufactured according to Starting material [VI]
Can be produced according to the following reaction formula.

Embedded image In the formula, R ^{1 to} R ² , A, E, X, Y, Z, W and Q are as defined above. Compound [VI] can be produced by reacting compound [IX] with halogen compound [X] in the presence of a base in a solvent inert to the reaction. As the reaction solvent, aprotic polar solvents such as acetonitrile, dimethyl sulfoxide, N, N-dimethylformamide (DMF), ethers such as tetrahydrofuran, dimethoxyethane, diethyl ether, dioxane, aromatics such as benzene, toluene, xylene, etc. Hydrocarbons or mixed solvents thereof can be used. As the base, silver carbonate, potassium carbonate, sodium carbonate, sodium hydride, sodium hydroxide, potassium hydroxide or the like can be used. The reaction is carried out at 20 to 160 ° C, preferably 70 to
It is carried out at 120 ° C. The reaction time depends on the raw materials, the base used,
Although it depends on the type of solvent, it is usually suitable for 5 to 60 hours. Usually, the amount of the halogen compound [X] used is preferably 1 to 4 mol with respect to 1 mol of the compound [IX]. The amount of the base used is preferably 0.5 to 1.2 mol, based on 1 mol of the compound [IX].

The starting epoxy compound [VI ^a ] is
It can be produced according to the following reaction formula. (First step)

Embedded image (Second step)

Embedded image In the formula, R ^{1 to} R ² , A ⁰ , E, X, Y, Z, W and Q are
It is the same as the above. (Step 1) Compound [XII] can be produced by reacting compound [IV] with halogen compound [XI] in the presence of a base in a solvent inert to the reaction. This reaction can be carried out under the same conditions as in the above-mentioned production method [VI]. Usually, the amount of the halogen compound [XI] used is preferably 1 to 3 mol with respect to 1 mol of the compound [IV]. (Second Step) The epoxy compound [VI ^a ] can be produced by oxidizing the compound [XII] with a suitable oxidizing agent in a solvent inert to the reaction. The reaction solvent, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, tetrahydrofuran,
Ethers such as dimethoxyethane, diethyl ether and dioxane, aromatic hydrocarbons such as benzene, toluene and xylene, or a mixed solvent thereof can be used. As the oxidizer, perbenzoic acid, metachloroperbenzoic acid, peracetic acid, organic peracids such as monoperoxyphthalic acid,
Hydrogen peroxide, tert-butyl hydroperoxide, etc. can be used. The amount of the oxidant used varies depending on the kind of the oxidant, but is usually 1 mol per 1 mol of the compound [XII].
It is preferred to use ~ 2 moles. The reaction is carried out at 0 to 50 ° C, preferably 10 to 30 ° C. The reaction time will differ depending on the raw materials, the oxidizing agent used, and the type of solvent, but is usually suitable for 2 to 24 hours.

The starting material [VIII] can be produced according to the following reaction formula.

Embedded image In the formula, R ¹ , R ² , X, Y, Z, Wa and Q are as defined above. Halogen compound [XIII] and compound [XI
Compound [VIII] can be produced by reacting V] in the presence of a base in a solvent inert to the reaction. This reaction can be carried out under the same conditions as in the production process of the above [I]. The amount of the compound [XIV] used is preferably 2 to 2.5 mol per 1 mol of the halogen compound [XIII].

The compound [I] according to the present invention can form an oxide by treating with a peracid according to a known method. Although some of the compounds according to the present invention have an asymmetric carbon, each of the optical isomers and their racemates are included in the present invention. The optical isomer is an optically active acid (tartaric acid, dibenzoyltartaric acid, mandelic acid, 10-camphorsulfonic acid, etc.) utilizing the basicity of the racemate obtained as described above.
Optically resolved by a known method using, or a previously prepared optically active compound (for example, 1,2-epoxypropane)
Can be used as a raw material. The compound [I] according to the present invention can form the above-mentioned salt by a known method. For example, the compound [I] according to the present invention
The hydrochloride salt of can be obtained by dissolving the compound [I] of the present invention in an alcohol solution of hydrochloric acid. Among the compounds [I] according to the present invention, the compound having carboxy can form a salt by a known method. Examples of the salt include alkali metal salts such as sodium salt and potassium salt, and alkaline earth metal salts such as calcium salt. For example, the alkali metal salt of the compound [I] according to the present invention is preferably obtained by adding 1 equivalent of sodium hydroxide, potassium hydroxide or the like to the compound [I] according to the present invention having carboxy, in an alcohol solvent. Can be obtained. The alkaline earth metal salt of the compound [I] according to the present invention is obtained by dissolving the alkali metal salt produced by the above method in water, methanol, ethanol or a mixed solvent thereof, and adding 1 equivalent of calcium chloride or the like. You can Solvates (including hydrates) of the compound [I] or a salt thereof according to the present invention are also included in the present invention. Depending on the compound, a solvate can be obtained by recrystallizing a solvate from a corresponding solvent or an appropriate mixed solvent containing the corresponding solvent. For example, a hydrate of the compound of the present invention may be obtained by recrystallizing the compound of the present invention from hydrous alcohol. The compound according to the present invention may have polymorphism. The crystal polymorph is also included in the present invention. The target compound [I] produced in this manner can be obtained by a means known per se in the form of a free base or an acid addition salt, for example, concentration, liquid conversion, phase transfer, solvent extraction, crystallization. , Fractional distillation,
It can be isolated and purified by chromatography or the like.

The compound according to the present invention is useful as a therapeutic agent for cerebrovascular disorders and as a drug for suppressing the onset of sequelae due to cerebrovascular disorders. When the compound of the present invention is administered as a medicine, the compound of the present invention is contained as it is or in a pharmaceutically acceptable non-toxic and inert carrier, for example, 0.01 to 99.5%, preferably 0.5 to 90%. It is administered to animals including humans as a pharmaceutical composition. As the carrier, one or more solid, semi-solid, or liquid diluents, fillers, and other prescription auxiliaries are used. Desirably, the pharmaceutical compositions are administered in dosage unit form. The pharmaceutical composition of the present invention can be administered orally, intratissueally (eg, intravenously), locally (eg, transdermally), or rectally. Needless to say, the composition is administered in a dosage form suitable for these administration methods. In particular, intravenous administration or oral administration is preferable. The dose as a cerebrovascular disorder therapeutic agent is preferably adjusted in consideration of the patient's condition such as age and weight, administration route, nature and degree of disease, etc.
In the case of oral administration, the dose of the active ingredient of the present invention for an adult is usually 0.1 mg to 1 g / human per day, preferably 1 to 300 mg / human per day. In the case of intravenous administration, the daily dose range is generally 0.01 mg to 100 mg / human, preferably 0.1 to 30 mg / human. In some cases, lower doses may be sufficient, and conversely, higher doses may be required. 2 to 1 day
It is desirable to administer in 4 divided doses.

For oral administration, solid or liquid dosage units such as powders, powders, tablets, dragees, capsules, granules,
Suspensions, solutions, syrups, drops, sublingual tablets and other dosage forms can be used. The powder is manufactured by making the compound according to the present invention into a fine powder. Powders are prepared by combining the compounds according to the invention in suitable fineness and then mixing with a finely divided pharmaceutical carrier such as starch, edible carbohydrates such as mannitol and the like. If necessary, flavoring agents, preservatives, dispersants, coloring agents, fragrances and the like may be mixed. Capsules are produced by first filling powdered powder, powder or granules as described in the section of tablets as described above into capsule outer skins such as gelatin capsules. To be done. Mixing lubricants and fluidizers such as colloidal silica, talc, magnesium stearate, calcium stearate, and solid polyethylene glycol into powder, and then filling You can also Capsules were ingested by adding disintegrants and solubilizers such as carboxymethylcellulose, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, croscarmellose sodium, sodium carboxymethylstarch sodium, calcium carbonate, sodium carbonate. The effectiveness of the drug at times can be improved. Further, a fine powder of the compound according to the present invention may be suspended and dispersed in vegetable oil, polyethylene glycol, glycerin, and a surfactant, and this may be wrapped with a gelatin sheet to give a soft capsule. Tablets are produced by adding a filler to make a powder mixture, granulating or slugging, and then adding a disintegrating agent or lubricant, and then tableting. The powder mixture is prepared by mixing an appropriately powdered substance with the above-mentioned diluent or base, and optionally a binder (for example, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, gelatin, polyvinylpyrrolidone, polyvinyl alcohol, etc.), A dissolution retarder (eg, paraffin), a resorbent (eg, quaternary salt), and an adsorbent (eg, bentonite, kaolin, dicalcium phosphate, etc.) may also be used in combination. The powder mixture is first prepared from a binder such as syrup, starch paste, gum arabic,
The granules can be obtained by wetting with a cellulose solution or a polymer solution, stirring and mixing, and then drying and pulverizing the granules. Instead of granulating the powder in this way, it is also possible to first apply a tableting machine and then crush the imperfect slag obtained into granules. The granules thus prepared can be prevented from adhering to each other by adding stearic acid, stearic acid salts, talc, mineral oil and the like as a lubricant. The lubricated mixture is then tableted. The uncoated tablets thus produced can be coated with a film or coated with sugar.

The compound according to the present invention may be directly tableted after mixing with a fluid inert carrier without going through the steps of granulation and slag formation as described above. A transparent or translucent protective coating consisting of a shellac sealing coating, a coating of sugar or polymeric material and a polish coating of wax can also be used. Other oral dosage forms such as solution, syrup, elixir and the like can also be in dosage unit form so that a given amount contains a fixed amount of the compound according to the invention. Syrup is produced by dissolving the compound of the present invention in an appropriate flavor aqueous solution, and elixir is produced by using a non-toxic alcoholic carrier. Suspensions are formulated by dispersing the compound in a non-toxic carrier. Solubilizers and emulsifiers (eg, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters), preservatives, flavor enhancers (eg, peppermint oil, saccharin) and the like can also be added if necessary. .. If desired, dosage unit formulations for oral administration can be microencapsulated. The formulations can also provide an extended period of action or sustained release by coating or embedding in polymers, waxes, and the like. Intratissue administration is a liquid dosage unit form for subcutaneous, intramuscular or intravenous injection, for example,
This can be done by using a solution or suspension form. These are non-toxic liquid carriers compatible with the purpose of injection, such as, for example,
It is manufactured by suspending or dissolving in an aqueous or oily medium, and then sterilizing the suspension or solution. Non-toxic salts and salt solutions may be added to make the injection solution isotonic.
Further, stabilizers, preservatives, emulsifiers and the like can be used in combination. For rectal administration, the compound of the present invention is a solid having a low melting point which is soluble or insoluble in water, for example, polyethylene glycol,
Cocoa butter, semi-synthetic oils and fats (for example, Witepsol / registered trademark), higher esters (for example, myristyl palmitate) and suppositories produced by dissolving or suspending in a mixture thereof can be used. it can. Further, the toxicity of the compounds according to the present invention is very low as described later.

[0030]

EXAMPLES Next, the present invention will be described in more detail with reference to Reference Examples and Production Examples for the production of the compounds according to the present invention, formulation examples, and test examples of representative compounds. Reference Example 1 4- (4-Fluorophenyl) -6-hydroxy-2-methylpyri
Midine (First Step) To 1.3 L (liter) of dry tetrahydrofuran (THF), 162 g of 60% sodium hydride (NaH) and 342 g of diethyl carbonate were added. The mixture is heated to reflux under dry TH
A solution prepared by dissolving 200 g of p-fluoroacetophenone in 440 ml of F was added dropwise over about 1 hour, and the mixture was heated under reflux for 6 hours. The reaction solution was cooled, poured into ice water, neutralized with concentrated hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, concentrated, and the residue was distilled under reduced pressure to obtain 291 g of 3- (4-fluorophenyl) -3-oxopropionic acid ethyl ester as a pale yellow oil. Boiling point 145-150 ° C (5mmHg) (2nd step) 3- (4-Fluorophenyl) -3-oxopropionic acid ethyl ester 145g, acetamidine hydrochloride 9
7.8g, ground potassium carbonate 191g and ethanol 1.16L 6
The mixture was stirred at 0 to 70 ° C for 16 hours. The reaction solution was filtered to remove insoluble matter, the filtrate was concentrated, water was added to the residue, and the mixture was neutralized with acetic acid. The precipitated crystals were collected by filtration, washed with water and dried to obtain 88.7 g of the objective compound as white crystals. Melting point 290-292 ℃
(Decomposition) Similarly, the following compound was obtained. 4- (2-chlorophenyl) -6-hydroxy-2-methylpyrimy
Gin 4- (2,4-dichlorophenyl) -6-hydroxy-2-methylpi
Limidine Melting point 271-274 ° C 2,5-Dimethyl-4- (4-fluorophenyl) -6-hydroxypyr
Limidine Melting point 242-243 ° C 4- (4-Fluorophenyl) -6-hydroxy-5-methylpyri
Midine melting point 228-229 ℃

Reference Example 2 4-chloro-6- (4-fluorophenyl) -2-methylpyrimidine 4- (4-fluorophenyl) -6-hydroxy-2-methylpyrimidine 21 g was mixed with 63 ml of phosphorus oxychloride to give 1 Heated to reflux for hours. The reaction solution was cooled, poured into ice water, neutralized with 28% aqueous ammonia, and the precipitated crystals were collected by filtration. The crystals were washed with water and dried to obtain 21 g of the target compound. Melting point 95-98 ° C. Similarly, the following compound was obtained. 4-chloro-6- (2-chlorophenyl) -2-methylpyrimidine Melting point 88-90 ° C 4-chloro-6- (2,4-dichlorophenyl) -2-methylpyrimidi
Emissions mp 104-105 ° C. 4-Chloro-2,5-dimethyl-6- (4-fluorophenyl) pyridinium
Midine melting point 110-113 ° C 4-Chloro-6- (2-fluorophenyl) -5-methylpyrimidine Melting point 88-90 ° C

Reference Example 3 4- (4-chlorobutoxy) -2- (4-fluorophenyl) -6-me
Tylpyridine hydrochloride 2- (4-fluorophenyl) -4-hydroxy-6-methylpyridine 2.5 g, 1-bromo-4-chlorobutane 3.16 g, silver carbonate 1.
7 g and 100 ml of toluene were heated under reflux for 40 hours. The reaction solution is filtered to remove insoluble matter, the filtrate is concentrated, and the residue is purified by silica gel column chromatography to obtain the target compound 1.
45 g was obtained as white crystals. Melting point 59-61 ° C

Reference Example 4 4- (4-Fluorophenyl) -2-hydroxy-6-methylpi
A mixture of 5 g of limidine 4-fluorobenzoylacetone, 1.66 g of urea, 25 ml of ethanol and 3.8 ml of concentrated hydrochloric acid was heated under reflux for 20 hours. The reaction solution was cooled, poured into ice water, made alkaline with an aqueous potassium carbonate solution, and then neutralized with acetic acid. The precipitated crystals were collected by filtration, washed with isopropyl ether and dried to obtain 2.65 g of pale yellow crystals. Melting point 265-268 ℃

Reference Example 5 4,6-bis (4-fluorophenoxy) -2-methylpyrimidi
Dissolve down 4-fluorophenol 448mg in a mixed solvent of THF 13 ml and DMF 2.7 ml, stirring at room temperature, it was added portionwise 60% NaH 160 mg, and stirred at the same temperature for 30 minutes. 326 mg of 4,6-dichloro-2-methylpyrimidine was added, and the mixture was further stirred for 12 hours at room temperature. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 700 mg of the obtained residue was subjected to silica gel column chromatography (Wakogel C-200 (registered trademark), n-
It was purified with hexane: ethyl acetate 9: 1) and recrystallized from n-hexane to obtain 461 mg of white crystals. Melting point 93-97 ° C. The following compound was obtained in the same manner. 4,6-bis (4-fluorophenylthio) -2-methylpyrimi
Gin melting point 134-136 ℃

Reference Example 6 4- (4,5-epoxypentyloxy) -6- (4-fluorophene
Nyl) -2-methylpyrimidine (first step) 4- (4-fluorophenyl) -obtained in Reference Example 1
22 g of a mixture of 2 g of 6-hydroxy-2-methylpyrimidine, 2.8 g of 5-bromo-1-pentene, 1.5 g of silver carbonate and 80 ml of toluene was added.
Heated to reflux for an hour. The reaction solution was filtered to remove insoluble matter, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography, 4- (4-fluorophenyl) -2-
Methyl-6- (4-pentenyl) pyrimidine as white crystals
370 mg was obtained. Melting point 44.5-45.5 ° C (second step) 4- (4-fluorophenyl) -2-methyl-6- (4-
350 mg of pentenyl) pyrimidine were dissolved in 5 ml of methylene chloride. The bath is cooled with ice water and 70% m-
217 mg of chloroperbenzoic acid was added. After the addition, the mixture was stirred at room temperature for 18 hours. N-Hexane and ethyl acetate were added to the residue obtained by concentrating the reaction solution, washed four times with an aqueous sodium hydrogen carbonate solution, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The obtained residue was purified by silica gel column chromatography to obtain 160 mg of the target compound as white crystals. Melting point 63.0-64.0 ° C

Reference Example 7 2-Chloro-4-methyl-6-phenyl-1,3,5-triazine (first step) 2,4,6-trichloro-1,3,5-triazine 50 g
To this, 300 ml of dry tetrahydrofuran was added, and 150 ml of a tetrahydrofuran solution of 2M phenylmagnesium bromide was added dropwise over about 30 minutes while stirring at room temperature. After the dropping, the mixture was stirred at room temperature for 1 hour, and then the reaction solution was concentrated. Ice water was added to the obtained residue, and the mixture was extracted with ether. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated. The obtained crystals were recrystallized from isopropanol to give slightly yellow crystals of 2,4-dichloro-6-phenyl-1,3,5-triazine 21.
1 g was obtained. (Second step) 17 g of 2,4-dichloro-6-phenyl-1,3,5-triazine was dissolved in 85 ml of dry tetrahydrofuran, the bath was cooled with ice water, and 135 ml of a 1M solution of methylmagnesium bromide in tetrahydrofuran was taken for about 30 minutes. Was dropped. After dropping, the mixture was stirred at room temperature for 2 hours, and then the reaction solution was poured into ice water,
It was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography to obtain 3.6 g of the objective compound as white crystals.

Reference Example 8 2-Benzyloxyphenyl-4-hydroxy-6-methylpi
Limidine (Step 1) 200 g of methanol was added to 23 g of 4-benzyloxybenzonitrile to suspend it, and hydrochloric acid gas was blown into the suspension for about 1 hour while cooling the bath with ice water. afterwards,
The mixture was stirred at the same temperature for 2 hours and at room temperature for 1.5 hours. Ether was added to the reaction solution, and the precipitated crystals were filtered to give white crystals.
28 g was obtained. 200 ml of methanol was added to the crystals to suspend them, and ammonia gas was blown into the crystals while cooling the bath with ice water for about 1 hour. Then, the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated, ethyl acetate was added to the obtained residue, and the precipitated crystals were collected by filtration and dried to give 2-benzyloxybenzamidine hydrochloride as white crystals (21.6 g). (Second step) 4-benzyloxybenzamidine hydrochloride
A mixture of 12 g, ethyl acetoacetate 6.3 g, potassium carbonate 13.9 g and ethanol 144 ml was heated under reflux for 24 hours. The reaction solution was filtered, insoluble materials were removed, and the filtrate was concentrated. Water was added to the obtained residue and neutralized with acetic acid. The precipitated crystals were collected by filtration, washed with water and dried to give the target compound as white crystals 12.0.
g was obtained.

Production Example 1 4- (4-Fluorophenyl) -2-methyl-6- (5-piperidinope
Nyloxy) pyrimidine hydrochloride 3.59 g of 60% sodium hydride (NaH) was added to a mixed solvent of 155 ml of dry THF and 33 ml of dry DMF, and 7.06 g of 5-piperidino-1-pentanol was added under stirring at room temperature for 10 minutes. It was stirred. Next, 4-chloro-6- (4-fluorophenyl) -2-methylpyrimidine (10 g) was added, and the mixture was stirred at room temperature for 20 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. Wash the organic layer with water,
After drying over anhydrous magnesium sulfate, it was concentrated and the residue was subjected to silica gel column chromatography (Wakogel C-2
00 / registered trademark, chloroform containing 1% methanol) to give a pale yellow oil. Dissolve this in methanol,
The mixture was adjusted to pH 5 with 1N hydrochloric acid and then concentrated. Ether was added to the residue, and the precipitated crystals were collected by filtration. The crystals were recrystallized from acetonitrile to obtain type I or type II white crystals. Form I crystal Melting point 184-186 ℃ Elemental analysis value (as C ₂₁ H ₂₈ FN ₃ O ・ HCl) Calculated value (%) C: 64.03 H: 7.42 N: 10.67 Measured value (%) C: 63.82 H: 7.39 N: 10.70 Type II crystal Melting point 182-184 ℃ Elemental analysis value (as C ₂₁ H ₂₈ FN ₃ O ・ HCl) Calculated value (%) C: 64.03 H: 7.42 N: 10.67 Measured value (%) C: 63.80 H: 7.38 N 10.74 The compounds of Production Examples 2 to 9 were synthesized in the same manner as in Production Example 1.

Production Example 2 4- (4-fluorophenyl) -2-methyl-6- (4-piperidinob)
Toxyl) pyrimidine hydrochloride Melting point 174-176 ℃ Elemental analysis value (as C ₂₀ H ₂₆ FN ₃ O ・ HCl) Calculated value (%) C: 63.23 H: 7.16 N: 11.06 Measured value (%) C: 62.83 H: 7.23 N: 11.01

Production Example 3 4- (4-fluorophenyl) -2-methyl-6- (6-piperidinohe
Xyloxy) pyrimidine hydrochloride Melting point 190.5-192 ℃ Elemental analysis value (as C ₂₂ H ₃₀ FN ₃ O ・ HCl) Calculated value (%) C: 64.77 H: 7.66 N: 10.30 Measured value (%) C: 64.49 H: 7.66 N: 10.48

Production Example 4 2- (4-Fluorophenyl) -4-methyl-6- (4-piperidinob)
Toxyl) pyrimidine hydrochloride Melting point 168-172 ℃ Elemental analysis value (as C ₂₀ H ₂₆ FN ₃ O ・ HCl) Calculated value (%) C: 63.23 H: 6.90 N: 11.06 Measured value (%) C: 63.10 H: 7.11 N: 10.80

Production Example 5 2- (4-Fluorophenyl) -4-methyl-6- (5-piperidinope
Nyloxy) pyrimidine hydrochloride Melting point 184-185 ℃ Elemental analysis value (as C ₂₁ H ₂₈ FN ₃ O.HCl) Calculated value (%) C: 64.03 H: 7.42 N: 10.67 Measured value (%) C: 63.80 H: 7.52 N: 10.60

Production Example 6 4- (2-chlorophenyl) -2-methyl-6- (4-piperidinobuto
X) Pyrimidine hydrochloride Melting point 147-149 ℃ Elemental analysis value (as C ₂₀ H ₂₆ ClN ₃ O ・ HCl) Calculated value (%) C: 60.01 H: 6.87 N: 10.60 Measured value (%) C: 60.43 H: 7.05 N: 10.80

Production Example 7 4- (2,4-dichlorophenyl) -2-methyl-6- (4-piperidino
Butoxy ) pyrimidine hydrochloride Melting point 144-146 ℃ Elemental analysis value (as C ₂₀ H ₂₅ Cl ₂ N ₃ O.HCl) Calculated value (%) C: 55.76 H: 6.08 N: 9.75 Measured value (%) C: 55.40 H : 6.21 N: 9.74

Production Example 8 4- (4-fluorophenyl) -2-methyl-6-4- (4-phenyl)
Piperidino ) butoxypyrimidine hydrochloride Melting point 169-171 ℃ Elemental analysis value (as C ₂₆ H ₃₀ FN ₃ O ・ HCl) Calculated value (%) C: 68.48 H: 6.85 N: 9.21 Actual value (%) C: 68.20 H: 7.01 N: 9.27

Production Example 9 2- (4-Fluorophenyl) -4-methyl-6-4- (4-phenyl)
Piperidino) butoxypyrimidine hydrochloride Melting point 148-153 ° C Elemental analysis value (as C ₂₆ H ₃₀ FN ₃ O.HCl) Calculated value (%) C: 68.48 H: 6.85 N: 9.21 Measured value (%) C: 68.20 H: 6.89 N: 9.03

Production Example 10 4- (4-Fluorophenyl) -2-methyl-6-4- (4-phenyl)
Piperazino) butoxypyrimidine maleic acid salt After reacting in the same manner as in Production Example 1, an objective compound was obtained using a maleic acid ethanol solution. Melting point 218 ℃ (decomposition) Elemental analysis value (as C ₂₅ H ₂₉ FN ₄ O ・ C ₄ H ₄ O ₄ ) Calculated value (%) C: 64.91 H: 6.20 N: 10.44 Measured value (%) C: 64.93 H: 6.24 N: 10.32 In the same manner as in Production Example 1 or Production Example 10, Production Examples 11 to 1
Compound 3 was synthesized.

Production Example 11 2- (4-Fluorophenyl) -4-methyl-6-4- (4-phenyl)
Piperazino) butoxypyrimidine maleate Melting point 155-156 ℃ Elemental analysis value (as C ₂₅ H ₂₉ FN ₄ O ・ C ₄ H ₄ O ₄ ) Calculated value (%) C: 64.91 H: 6.20 N: 10.44 Measured value (%) ) C: 64.81 H: 6.29 N: 10.48

Production Example 12 2,4-bis (4-fluorophenyl) -6- (4-piperidinobuto
Xy ) pyrimidine hydrochloride Melting point 207-208.5 ° C Elemental analysis value (as C ₂₅ H ₂₇ F ₂ N ₃ O.HCl) Calculated value (%) C: 65.28 H: 6.14
N: 9.14 Measured value (%) C: 65.05 H: 6.26
N: 9.08

Production Example 13 2,4-bis (4-fluorophenyl) -6- (5-piperidinopene
Tyloxy ) pyrimidine hydrochloride Melting point 196-198.5 ℃ Elemental analysis value (as C ₂₆ H ₂₉ F ₂ N ₃ O ・ HCl) Calculated value (%) C: 65.88 H: 6.38 N: 8.87 Measured value (%) C: 65.50 H : 6.44 N: 8.64

Production Example 14 4- (4-hydroxyphenyl) -2-methyl-6-4- (4-phenyl)
Lupiperidino) butoxypyrimidine hydrochloride 4- (4 -phenylpiperidino) -1-butanol and 6- (4-benzyloxyphenyl) -4-chloro-2-methylpyrimidine were used as in Production Example 25 described later. The target compound was obtained. Melting point 182-183 ℃ Elemental analysis value (as C ₂₆ H ₃₁ N ₃ O ₂ · HCl) Calculated value (%) C: 68.78 H: 7.10 N: 9.26 Measured value (%) C: 68.58 H: 6.96 N: 8.99

Production Example 15 2- (4-Fluorophenyl) -4- (4-piperidinobutoxy)-
6-Methylpyridine hydrochloride 1.45 g of 4- (4-chlorobutoxy) -2- (4-fluorophenyl) -6-methylpyridine obtained in Reference Example 3 and 1.26 g of piperidine
And 12 ml of DMF were stirred at 100 ° C. for 1.5 hours.
The reaction solution was cooled, poured into ice water, and extracted with ethyl acetate.
The organic layer was washed with brine several times, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the target compound as an oil 1.
2 g were obtained. This was dissolved in methanol, adjusted to pH 5 by adding 3.5 ml of 1N hydrochloric acid, and concentrated. Ether was added to the residue and the crystals were collected by filtration. The crystals were recrystallized from a mixed solvent of acetonitrile and ether to obtain 1.02 g of the objective compound as white crystals. Melting point 164-166 ℃ Elemental analysis value (as C ₂₁ H ₂₇ FN ₂ O ・ HCl) Calculated value (%) C: 66.57 H: 7.45 N: 7.39 Measured value (%) C: 66.21 H: 7.45 N: 7.09 Production example In the same manner as in 15, compounds of Production Examples 16 to 20 were obtained.

Production Example 16 4- (4-fluorophenyl) -2-methyl-6- (3-piperidinop
(Ropoxy) pyridine hydrochloride Melting point 135 ℃ Elemental analysis value (as C ₂₀ H ₂₅ FN ₂ O ・ HCl) Calculated value (%) C: 65.83 H: 7.18 N: 7.68 Measured value (%) C: 65.40 H: 7.24 N: 7.44

Production Example 17 4- (4-Fluorophenyl) -2-methyl-6- (4-piperidinob)
Toxyl ) pyridine hydrochloride Melting point 148.5-150.5 ℃ Elemental analysis value (as C ₂₁ H ₂₇ FN ₂ O ・ HCl) Calculated value (%) C: 66.57 H: 7.45 N: 7.39 Measured value (%) C: 66.54 H: 7.57 N: 7.41

Production Example 18 4- (4-fluorophenyl) -2-methyl-6- (5-piperidinope
Nyloxy) pyridine hydrochloride Melting point 138-140 ℃ Elemental analysis value (as C ₂₂ H ₂₉ FN ₂ O ・ HCl) Calculated value (%) C: 67.25 H: 7.70 N: 7.13 Measured value (%) C: 67.00 H: 7.68 N: 6.95

Production Example 19 2,4-bis (4-fluorophenyl) -6- (4-piperidinobuto
X ) Pyridine hydrochloride Melting point 219-220.5 ℃ Elemental analysis value (as C ₂₆ H ₂₈ F ₂ N ₂ O ・ HCl) Calculated value (%) C: 68.04 H: 6.37 N: 6.10 Measured value (%) C: 68.40 H : 6.37 N: 6.20

Production Example 20 2,4-bis (4-fluorophenyl) -6- (5-piperidinopene
Yloxy) pyridine salt salt mp 165-166.5 ° C. Elemental analysis _{(C 27 H 30 F 2 N} 2 as O · HCl) Calculated (%) C: 68.56 H: 6.61 N: 5.92 Found (%) C: 68.57 H: 6.74 N: 5.99 In the same manner as in Production Example 1, the following compound was obtained.

Production Example 21 4- (4-Fluorophenyl) -2-methyl-6- (1-methyl-4-pi)
Periminobutoxy) pyrimidine hydrochloride Melting point 146 ℃ Elemental analysis value (as C ₂₁ H ₂₈ FN ₃ O ・ HCl) Calculated value (%) C: 64.03 H: 7.42 N: 10.67 Measured value (%) C: 63.90 H: 7.44 N: 10.42

Production Example 22 4- (4-fluorophenyl) -6-5- (4-hydroxypiperidi
No) Pentyloxy-2-methylpyrimidine hydrochloride 4- (4-fluorophenyl) -6-hydroxy obtained in Reference Example 1
-2-Methylpyrimidine 4g, 1,5-dibromopentane 13.5
g, 2.97 g of silver carbonate and 160 ml of toluene were heated under reflux for 50 hours. The reaction solution was filtered to remove insoluble matter, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography to obtain 2.6 g of a colorless oily substance. To 800 mg of this oily substance, 275 mg of 4-hydroxypiperidine, 468 mg of potassium carbonate and 8 ml of acetonitrile were added, and the mixture was stirred at room temperature for 19 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, concentrated, and the residue was purified by silica gel column chromatography to give an oil (600 mg). This oily substance was dissolved in methanol, adjusted to pH 5 by adding 1.61 ml of 1N HCl, and concentrated. Isopropyl ether was added to the obtained residue, and the precipitated crystals were collected by filtration and recrystallized from acetonitrile / isopropyl ether to give white crystals of the target compound.
559 mg was obtained. Melting point 167.0 to 169.5 ℃ Elemental analysis value (as C ₂₁ H ₂₈ FN ₃ O ₂ · HCl) Calculated value (%) C: 61.53 H: 7.13 N: 10.25 Measured value (%) C: 61.42 H: 7.09 N: 10.47

Production Example 23 4- (4-fluorophenyl) -6- (4-hydroxy-5-piperi
Dinopentyloxy) -2-methylpyrimidine hydrochloride 4- (4,5-epoxypentyloxy) -6- (4 obtained in Reference Example 6
-Fluorophenyl) -2-methylpyrimidine (160 mg), piperidine (140 mg) and acetonitrile (3 ml) at 80 ° C.
For 20 hours. The reaction solution was cooled, poured into ice water, and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography to give an oil 1
Got 58 mg. Dissolve this oil in methanol and add 1N HCl.
The mixture was adjusted to pH 5 with 0.42 ml and concentrated. Isopropyl ether was added to the residue, and the precipitated crystals were collected by filtration and recrystallized from acetonitrile to obtain 121 mg of the target compound as white crystals. Melting point 149.0 to 150.5 ° C Elemental analysis value (as C ₂₁ H ₂₈ FN ₃ O ₂ · HCl) Calculated value (%) C: 61.53 H: 7.13
N: 10.25 actual value (%) C: 61.36 H: 7.06
N: 10.25 It carried out similarly to manufacture example 1, and obtained the compound of manufacture examples 24-26.

Production Example 24 4-5- (N, N-diethylamino) pentyloxy-6- (4- phenyl )
Luorophenyl) -2-methylpyrimidine hydrochloride Melting point 134.5-136.5 ℃ Elemental analysis value (as C ₂₀ H ₂₈ FN ₃ O ・ HCl ・ 1 / 4H ₂ O) Calculated value (%) C: 62.17 H: 7.69 N: 10.87 Actual measurement Value (%) C: 62.15 H: 7.68 N: 10.84

Production Example 25 2-Methyl-4- (5-piperidinopentyloxy) -6- (2-thiee
Nyl ) pyrimidine hydrochloride Melting point 192.5-194.0 ° C Elemental analysis value (as C ₁₉ H ₂₇ N ₃ OS ・ HCl) Calculated value (%) C: 59.75 H: 7.39 N: 11.00 Actual value (%) C: 59.35 H: 7.32 N: 10.98

Production Example 26 2-Methyl-4- (5-piperidinopentyloxy) -6- (pyridi
(4--4 -yl) pyrimidine hydrochloride Melting point 178.5 to 179.5 ° C Elemental analysis value (as C ₂₀ H ₂₈ N ₄ O ・ HCl) Calculated value (%) C: 63.73 H: 7.75 N: 14.86 Measured value (%) C: 63.38 H: 7.70 N: 14.86

Production Example 27 4- (4-fluorophenyl) -6-methyl-2- (5-piperidinope)
Nchiruokishi) as a pyrimidine hydrochloride Reference Example 4 4- (4-fluorophenyl) -2-hydroxy
The target compound was obtained in the same manner as in Production Example 22 using 6-methylpyrimidine. Melting point 173.5 to 175.0 ℃ Elemental analysis value (as C ₂₁ H ₂₈ FN ₃ O ・ HCl) Calculated value (%) C: 64.03 H: 7.42 N: 10.67 Measured value (%) C: 63.85 H: 7.48 N: 10.82 Production example The following compound was obtained as in 27.

Production Example 28 4- (4-fluorophenyl) -6-methyl-2- (5-piperidinope
Nylthio) pyrimidine hydrochloride Melting point 156-158 ℃ Elemental analysis value (as C ₂₁ H ₂₈ FN ₃ S ・ HCl ・ 1 / 4H ₂ O) Calculated value (%) C: 60.85 H: 7.17 N: 10.14 Measured value (%) C: 60.80 H: 7.05 N: 10.02 In the same manner as in Production Example 1, the following compound was obtained.

Production Example 29 4- (4-fluorophenyl) -2-methyl-6- (3-piperidinop
Lopyruthio) pyrimidine hydrochloride Melting point 192-194 ° C Elemental analysis value (as C ₁₉ H ₂₄ FN ₃ S ・ HCl ・ 1 / 4H ₂ O) Calculated value (%) C: 59.05 H: 6.59 N: 10.87 Measured value (%) C: 58.96 H: 6.54 N: 10.79

Production Example 30 4- (4-Fluorophenoxy) -2-methyl-6- (5-piperidino
Pentyloxy ) pyrimidine hydrochloride 60% NaH 51 mg was suspended in a mixed solvent of THF 4.3 ml and DMF 0.9 ml. 5-piperidino-1-pentanol under stirring at room temperature
218 mg was added to this suspension and after stirring for 30 minutes at room temperature,
400 mg of 2,4-bis (4-fluorophenoxy) -6-methylpyrimidine obtained in Reference Example 5 was added, and the mixture was stirred at room temperature for 18 hours.
The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 600 mg of an oily residue. Purification by silica gel column chromatography (Wakogel C-200 (registered trademark), chloroform → chloroform: methanol = 25: 1) gave 200 mg of a pale yellow oil. 190 mg of this oily substance was dissolved in methanol, 0.5 ml of 1N HCl was added to adjust the pH to 5, and the mixture was concentrated under reduced pressure. Ether was added to the residue, and the precipitated crystals were collected by filtration.
The crystals were washed with ether and recrystallized from acetone to give 137 mg of the target compound as white crystals. Melting point 164 to 165 ℃ Elemental analysis value (as C ₂₁ H ₂₈ FN ₃ O ₂ · HCl) Calculated value (%) C: 61.53 H: 7.13 N: 10.25 Measured value (%) C: 61.40 H: 7.08 N: 10.26

Production Example 31 4- (4-Fluorophenylthio) -2-methyl-6- (5-piperidi
Nopentyloxy) pyrimidine hydrochloride 4,6-bis (4-fluorophenylthio) -2-methylpyrimidine obtained in the same manner as in Reference Example 5 was used and in the same manner as in Production Example 30, pale yellow crystals of the target compound were obtained. Got Melting point 127-
131 ℃ (Recrystallized from acetone / ether) Elemental analysis value (as C ₂₁ H ₂₈ FN ₃ OS ・ HCl ・ 1 / 2H ₂ O) Calculated value (%) C: 57.98 H: 6.72 N: 9.66 Measured value (%) C: 58.03 H: 6.86 N: 9.62 In the same manner as in Production Example 1, the compounds of Production Examples 32 to 39 were obtained.

Production Example 32 4- (4-fluorobenzyl) -2-methyl-6- (5-piperidinope
Nyloxy) pyrimidine hydrochloride Melting point 109-115 ° C Elemental analysis value (as C ₂₂ H ₃₀ FN ₃ O ・ HCl ・ H ₂ O) Calculated value (%) C: 62.03 H: 7.81 N: 9.86 Measured value (%) C: 62.30 H: 8.10 N: 9.94

Production Example 33 2-Methyl-4-phenethyl-6- (5-piperidinopentyloxy)
Si) Pyrimidine hydrochloride Melting point 128-130 ℃ Elemental analysis value (as C ₂₃ H ₃₃ N ₃ O ・ HCl ・ 1 / 2H ₂ O) Calculated value (%) C: 66.89 H: 8.54 N: 10.17 Measured value (%) C: 66.83 H: 8.35 N: 10.17

Production Example 34 2,5-Dimethyl-4- (4-fluorophenyl) -6- (4-piperidi
Nobutoxy) pyrimidine hydrochloride Melting point 154-157 ℃ Elemental analysis value (as C ₂₁ H ₂₈ FN ₃ O ・ HCl) Calculated value (%) C: 64.03 H: 7.42 N: 10.67 Measured value (%) C: 63.86 H: 7.30 N: 10.61

Production Example 35 4- (4-fluorophenyl) -5-methyl-6- (4-piperidinob)
Toxyl ) pyrimidine hydrochloride Melting point 146-149 ° C Elemental analysis value (as C ₂₀ H ₂₆ FN ₃ O ・ HCl) Calculated value (%) C: 63.23 H: 7.16 N: 11.06 Measured value (%) C: 63.01 H: 7.10 N: 11.08

Production Example 36 2-Methyl-4-phenyl-6- (4-piperidinobutoxy) -1,3,
5-triazine hydrochloride Melting point 177 to 178 ℃ Elemental analysis value (as C ₁₉ H ₂₆ N ₄ O ・ HCl) Calculated value (%) C: 62.88 H: 7.50 N: 15.44 Measured value (%) C: 62.55 H: 7.68 N: 15.28

Production Example 37 2-Methyl-4-phenyl-6- (3-piperidinopropoxy) -1,
3,5-Triazine hydrochloride Melting point 175 to 178 ℃ Elemental analysis value (as C ₁₈ H ₂₄ N ₄ O ・ HCl) Calculated value (%) C: 61.97 H: 7.22 N: 16.06 Measured value (%) C: 61.87 H : 7.41 N: 16.14

Production Example 38 2- (4-chlorophenyl) -4-methyl-6- (3-piperidinopro
(Poxy) -1,3,5-triazine maleate Melting point 125-128 ℃ Elemental analysis value (as C ₁₈ H ₂₃ ClN ₄ O ・ C ₄ H ₄ O ₄・ 1 / 4H ₂ O) Calculated value (%) C : 56.53 H: 5.93 N: 11.99 Measured value (%) C: 56.22 H: 6.07 N: 12.01

Production Example 39 2-Methyl-4-phenyl-6-3- (4-phenylpiperidino)
Propoxy -1,3,5-triazine hydrochloride Melting point 159-163 ℃ Elemental analysis value (as C ₂₄ H ₂₈ N ₄ O ・ HCl ・ 1 / 2H ₂ O) Calculated value (%) C: 66.58 H: 6.75 N: 12.94 Measured value (%) C: 66.56 H: 7.15 N: 13.30

Production Example 40 2-Methyl-4- (2-naphthyl) -6- (4-piperidinobutoxy)
Pyrimidine hydrochloride Melting point 174 to 175 ℃ Elemental analysis value (as C ₂₄ H ₂₉ N ₃ O ・ HCl) Calculated value (%) C: 69.97 H: 7.34 N: 10.20 Measured value (%) C: 69.80 H: 7.20 N: 10.21 The production examples of the compound represented by the formula [I] are shown below. Those not specifically described in the production method are produced in the same manner as in Production Example 1.

Production Example 41 4- (4-Fluorophenyl) -2-methyl-6- (2-piperidinoe
Toxyl) pyrimidine hydrochloride Melting point 198-199 ℃ Elemental analysis value (as C ₁₈ H ₂₂ FN ₃ O ・ HCl) Calculated value (%) C: 61.45 H: 6.59 N: 11.94 Measured value (%) C: 61.23 H: 6.78 N: 11.74

Production Example 42 4- (4-fluorophenyl) -2-methyl-6- (3-piperidinop
Ropoxy) pyrimidine hydrochloride Melting point 195.5-197 ℃ Elemental analysis value (as C ₁₉ H ₂₄ FN ₃ O.HCl) Calculated value (%) C: 62.37 H: 6.89 N: 11.48 Measured value (%) C: 62.00 H: 7.03 N: 11.13

Production Example 43 2- (4-fluorophenyl) -4-methyl-6- (2-piperidinoe
Toxyl) pyrimidine hydrochloride melting point 216-218 ° C. Elemental analysis value (as C ₁₈ H ₂₂ FN ₃ O.HCl) Calculated value (%) C: 61.45 H: 6.56
N: 11.94 Measured value (%) C: 61.10 H: 6.78 N: 11.63

Production Example 44 2- (4-fluorophenyl) -4-methyl-6- (3-piperidinop
(Ropoxy) pyrimidine hydrochloride Melting point 205-206.5 ℃ Elemental analysis value (as C ₁₉ H ₂₄ FN ₃ O ・ HCl) Calculated value (%) C: 62.37 H: 6.89 N: 11.48 Measured value (%) C: 62.01 H: 6.99 N: 11.47

Production Example 45 2- (4-chlorophenyl) -4-methyl-6- (3-piperidinopro
(Poxy) pyrimidine hydrochloride Melting point 212-214 ℃ Elemental analysis value (as C ₁₉ H ₂₄ ClN ₃ O ・ HCl) Calculated value (%) C: 59.69 H: 6.59 N: 10.99 Measured value (%) C: 59.23 H: 6.53 N: 10.80

Production Example 46 4- (4-Fluorophenyl) -2-methyl-6-2- (4-phenyl)
Piperidino) ethoxypyrimidine hydrochloride Melting point 184-186 ℃ Elemental analysis value (as C ₂₄ H ₂₆ FN ₃ O ・ HCl) Calculated value (%) C: 67.36 H: 6.36 N: 9.82 Measured value (%) C: 67.10 H: 6.73 N: 9.78

Production Example 47 4- (4-fluorophenyl) -2-methyl-6-3- (4-phenyl)
Piperidino ) propoxypyrimidine hydrochloride Melting point 169-171 ℃ Elemental analysis value (as C ₂₅ H ₂₈ FN ₃ O.HCl) Calculated value (%) C: 68.09 H: 6.40 N: 9.53 Measured value (%) C: 67.80 H: 6.60 N: 9.31

Production Example 48 2- (4-Fluorophenyl) -4-methyl-6-2- (4-phenyl)
Piperidino ) ethoxypyrimidine hydrochloride Melting point 211-212 ℃ Elemental analysis value (as C ₂₄ H ₂₆ FN ₃ O ・ HCl) Calculated value (%) C: 67.36 H: 6.36 N: 9.82 Measured value (%) C: 67.01 H: 6.49 N: 9.61

Production Example 49 2- (4-Fluorophenyl) -4-methyl-6-3- (4-phenyl)
Piperidino) propoxypyrimidine hydrochloride Melting point 195-198 ℃ Elemental analysis value (as C ₂₅ H ₂₈ FN ₃ O.HCl) Calculated value (%) C: 67.94 H: 6.61 N: 9.51 Measured value (%) C: 67.82 H: 6.50 N: 9.49

Production Example 50 2- (4-chlorophenyl) -4-methyl-6-2- (4-phenylpi)
Peridino) ethoxy] pyrimidine hydrochloride Melting point 208.5-210 ℃ Elemental analysis value (as C ₂₄ H ₂₆ ClN ₃ O.HCl) Calculated value (%) C: 64.86 H: 6.12 N: 9.46 Measured value (%) C: 64.62 H : 6.10 N: 9.42

Production Example 51 2- (4-Fluorophenyl) -4-3-4- (4-fluorophenyl)
) -1,2,3,6-Tetrahydropyridin-1-yl propoxy
Si-6-methylpyrimidine hydrochloride Melting point 197.5-199.5 ℃ Elemental analysis value (as C ₂₅ H ₂₅ F ₂ N ₃ O ・ HCl) Calculated value (%) C: 65.57 H: 5.72 N: 9.18 Measured value (%) C : 65.30 H: 5.68 N: 9.12

Production Example 52 2- (4-fluorophenyl) -4-methyl-6-3- (4-phenyl)
-1,2,3,6-Tetrahydropyridin-1-yl) propoxy
Pyrimidine hydrochloride Melting point 197-199 ℃ Elemental analysis value (as C ₂₅ H ₂₆ FN ₃ O ・ HCl) Calculated value (%) C: 68.25 H: 6.19 N: 9.55 Measured value (%) C: 68.08 H: 6.24 N: 9.31

Production Example 53 2- (4-Fluorophenyl) -4-3-4- (4-fluorophenyl)
Le) piperidino propoxy-6-methylpyrimidine hydrochloride
Salt melting point 186-187 ℃ Elemental analysis value (as C ₂₅ H ₂₇ F ₂ N ₃ O ・ HCl) Calculated value (%) C: 65.28 H: 6.14 N: 9.14 Measured value (%) C: 64.90 H: 6.23 N: 8.90

Production Example 54 2- (4-fluorophenyl) -4-methyl-6-3--4- (pyridine
-4-yl) Piperidinopropoxy pyrimidine hydrochloride Melting point 186-187 ℃ Elemental analysis value (as C ₂₄ H ₂₇ FN ₄ O ・ HCl) Calculated value (%) C: 65.08 H: 6.37 N: 12.65 Measured value (% ) C: 64.80 H: 6.46 N: 12.35

Production Example 55 4- (4-fluorophenyl) -2-methyl-6-3- (4-phenyl)
Piperazino) propoxypyrimidine maleate Melting point 158-159 ℃ Elemental analysis value (as C ₂₄ H ₂₇ FN ₄ O ・ C ₄ H ₄ O ₄ ) Calculated value (%) C: 64.36 H: 5.98 N: 10.72 Measured value (%) ) C: 64.02 H: 5.93 N: 10.60

Production Example 56 2- (4-Fluorophenyl) -4-methyl-6-3- (4-phenyl)
Piperazino) propoxypyrimidine maleate Melting point 174-175 ℃ Elemental analysis value (as C ₂₄ H ₂₇ FN ₄ O ・ C ₄ H ₄ O ₄ ) Calculated value (%) C: 64.36 H: 5.98 N: 10.72 Measured value (%) ) C: 64.62 H: 6.01 N: 10.79

Production Example 57 2- (4-hydroxyphenyl) -4-methyl-6- (3-piperidino
258 mg of 60% sodium hydride (NaH) was added to a mixed solvent of 13 ml of dry THF containing propoxy) pyrimidine hydrochloride and 1.5 ml of dry DMF. While stirring at room temperature, 461 mg of 3-piperidino-1-propanol was added to this mixture, and the mixture was stirred for 10 minutes. 2- (4) obtained in Production Example 8 was added to this reaction solution.
1 g of -benzyloxyphenyl) -4-chloro-6-methylpyrimidine was added, and the mixture was stirred at room temperature for 48 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, concentrated, and the residue was purified by silica gel column chromatography (Wakogel C-200 / registered trademark, chloroform) to give a pale yellow oil 1.08 g
I got This was dissolved in ethanol, 5% palladium carbon (Pd / C) was added, and catalytic reduction was performed at room temperature and atmospheric pressure. The reaction solution was filtered, and the filtrate was concentrated. The residue was dissolved in methanol, adjusted to pH 5 with 1N hydrochloric acid, and then concentrated. Ether was added to the residue and the crystals were collected by filtration. The crystals were recrystallized from methanol to give 572 mg of the desired compound as white crystals.
Melting point 248-249 ℃ Elemental analysis value (as C ₁₉ H ₂₅ N ₃ O ₂ · HCl) Calculated value (%) C: 62.71 H: 7.20 N: 11.55 Measured value (%) C: 62.36 H: 7.22 N: 11.76 Same Then, the compounds of Production Examples 58 to 63 were obtained.

Production Example 58 4- (4-hydroxyphenyl) -2-methyl-6- (2-piperidino
Ethoxy) pyrimidine hydrochloride Melting point 301 ℃ Elemental analysis value (as C ₁₈ H ₂₃ N ₃ O ₂ · HCl) Calculated value (%) C: 61.80 H: 6.91 N: 12.01 Actual value (%) C: 61.50 H: 6.83 N : 11.87

Production Example 59 4- (4-hydroxyphenyl) -2-methyl-6- (3-piperidino
Propoxy) pyrimidine hydrochloride Melting point 234-235 ℃ Elemental analysis value (as C ₁₉ H ₂₅ N ₃ O ₂ · HCl) Calculated value (%) C: 62.71 H: 7.20 N: 11.55 Measured value (%) C: 62.45 H: 7.24 N: 11.51

Production Example 60 4- (4-hydroxyphenyl) -2-methyl-6-2- (4-phenyl)
Lupiperidino) ethoxypyrimidine hydrochloride Melting point 185 ℃ (decomposition) Elemental analysis value (as C ₂₄ H ₂₇ N ₃ O ₂ · HCl) Calculated value (%) C: 67.67 H: 6.63 N: 9.86 Measured value (%) C: 67.30 H: 6.58 N: 9.72

Production Example 61 2- (4-hydroxyphenyl) -4-methyl-6-3- (4-phenyl)
Lupiperidino) propoxy pyrimidine hydrochloride Melting point 229-230.5 ℃ Elemental analysis value (as C ₂₅ H ₂₉ N ₃ O ₂ · HCl) Calculated value (%) C: 68.25 H: 6.87 N: 9.55 Measured value (%) C: 67.91 H : 7.01 N: 9.64

Production Example 62 4- (4-hydroxyphenyl) -2-methyl-6-3- (4-phenyl)
Lupiperazino) propoxy pyrimidine maleate Melting point 210 ℃ Elemental analysis value (as C ₂₄ H ₂₈ N ₄ O ₂ · C ₄ H ₄ O ₄ ) Calculated value (%) C: 64.60 H: 6.20 N: 10.76 Measured value (%) C: 64.20 H: 6.47 N: 10.36

Production Example 63 2- (4-hydroxyphenyl) -4-methyl-6-3--4-phenyl
Lupiperazino) propoxy pyrimidine hydrochloride Melting point 253-254 ℃ Elemental analysis value (as C ₂₄ H ₂₈ N ₄ O ₂ · HCl) Calculated value (%) C: 65.37 H: 6.63 N: 12.71 Measured value (%) C: 64.98 H : 6.73 N: 12.33

Production Example 64 4- (4-fluorophenyl) -2-methyl-6-2--4- (2-methoxy)
Cyphenyl) piperazino ethoxy pyrimidine hydrochloride Melting point 193.0-194.5 ° C Elemental analysis value (as C ₂₄ H ₂₇ FN ₄ O ₂ · HCl) Calculated value (%) C: 62.81 H: 6.15 N: 12.21 Measured value (%) C : 62.68 H: 6.18 N: 12.34

Production Example 65 4- (4-fluorophenyl) -2-methyl-6-2- (4-phenyl
Piperazino ) ethoxypyrimidine hydrochloride Melting point 201-204 ℃ Elemental analysis value (as C ₂₃ H ₂₅ FN ₄ O ・ HCl) Calculated value (%) C: 64.40 H: 6.11 N: 13.06 Measured value (%) C: 64.21 H: 6.10 N: 13.26

Formulation Example 1 1 ml of injection is prepared according to the following formulation by a conventional method. Formulation Compound of the present invention of Production Example 1 1 mg Sodium chloride 9 mg Water for injection Appropriate amount

Formulation Example 2 According to the following formulation, 1 ml of injection is prepared by a conventional method. Formulation Compound of the present invention in Production Example 1 1 mg Glucose 48 mg Sodium dihydrogen phosphate 1.25 mg Sodium monohydrogen phosphate 0.18 mg Water for injection Appropriate amount

Formulation Example 3 According to the following formulation, 1 ml of injection is prepared by a conventional method. Formulation Compound of the present invention of Preparation Example 1 mg Solbit 48 mg Benzyl alcohol 20 mg Sodium dihydrogen phosphate 2.5 mg Sodium monohydrogen phosphate 0.36 mg Water for injection Appropriate amount

Formulation Example 4 According to the following formulation, 120 mg tablets are prepared by a conventional method. Formulation Compound of the present invention of Production Example 3 3 mg Lactose 58 mg Corn starch 30 mg Crystalline cellulose 20 mg Hydroxypropyl cellulose 7 mg Magnesium stearate 2 mg

Test Example 1 Delayed Neuron Necrosis Using Sandy Rats
l Damage, hereinafter abbreviated as DND) inhibitory action The delayed neuronal necrosis inhibitory action of the compound according to the present invention is
It was confirmed by a test using a sand rat. This test method is the most widely used of the in vivo evaluation methods, and it is reported that drugs showing neuronal necrosis inhibitory activity in these tests can be expected to have clinical effects in humans (modern medicine). 24 129-133 (1992), Neurology 1987, 37 1
281-1287). Experimental method A male sand rat weighing 60-80 g was anesthetized with pentobarbital sodium 35 mg / kg ip and fixed in the dorsal position. After incision of the neck skin, the common carotid arteries on both sides were exposed and a suture was hung.
Both ends of the suture thread were passed through a polyethylene tube, and when suturing an incision, the tube was fixed to the neck skin with the suture thread coming out from the other end of the tube. The next day, under no anesthesia,
The carotid artery was occluded by gently pulling out both ends of the suture and bending and drawing the carotid artery on which the suture was suspended into the tube. Reperfusion was performed after loading with transient cerebral ischemia by bilateral common carotid artery occlusion for 5 minutes. After 7 days, the brain was removed and fixed. Prepare a section centered on the hippocampus and
After performing Nissle staining with 05% cresyl violet, degeneration and necrosis of pyramidal cells in the hippocampal CA-1 region were observed under a microscope. The degree of neuropathy was judged according to the following criteria. Criteria for neuronal necrosis in the hippocampal CA-1 area Score Degeneration and necrosis of pyramidal cells 0-10% Impaired (almost normal) 110-25% Impaired 2 25-50% Impaired 3 50-75% Impaired 475 -100% Injury The test drug was dissolved in physiological saline and administered intraperitoneally with ischemia and reperfusion for 5 minutes. The results are shown in Table 1.

[0108]

[Table 1]

As is clear from the above results, the compound of the present invention markedly suppressed nerve cell necrosis in a transient cerebral ischemia model using sand mice. In addition, the compound according to the present invention suppressed delayed neuronal necrosis even when administered orally. Furthermore, after ischemia, for example, after 1 to 2 hours, a single administration of the compound of Production Example 1 as a test drug exhibited an inhibitory effect on delayed neuronal necrosis. From these results, the compound according to the present invention is useful as a therapeutic agent as well as for preventing the sequelae of cerebrovascular accidents.

Test Example 2 Middle Cerebral Arterial Occlusion Using Rats
ry Occlusion (hereinafter abbreviated as MCAO) model cerebral infarction
Inhibitory effect The inhibitory effect of the compound of the present invention on cerebral infarction was confirmed in a middle cerebral artery occlusion model using rats. This model is a regional cerebral ischemia model similar to human cerebral infarction, and is known to be useful as a model for treatment (Stroke Experiment Handbook 91-97, published by ICP 1990). A drug showing a cerebral infarction inhibitory action in this test can be expected to have clinical effects in humans. Experimental Method Male SD rats aged 7-8 weeks (5 rats per group) were anesthetized with 120-150 mg / kg i.p. of ketamine hydrochloride, and the head was fixed in the lateral decubitus position on the operating table. A linear skin incision was made midway between the external ear canal and the external ocular nucleus, and along the anterior margin of the temporalis muscle to the zygomatic arch. A small hole was made between the foramen ovale and the orbital fissure with an electric dental drill, and the dura was incised. The main trunk of the middle cerebral artery crossing over the transverse olfactory nerve (olfactory chord) was electrocoagulated and cut by a bipolar electrode inside the olfactory chord, and the incision was sutured. Two days after the treatment, the animals were decapitated, the brains were excised, and forehead brain slices were prepared from the rostral side of the olfactory tract at 2 mm intervals. 2,3,5-Triphenyltetrazolium chloride (TTC) in saline solution (2
%) At 37 ° C. for 30 minutes. Next, a photograph of the frontal brain slice was taken, and the infarct area was measured using an image processing device. Forehead section 6 mm caudal to the rostral part of the forebrain, that is, the ratio of the infarct area to the total area of the tissue section at the level of the striatum, and the forehead section 5 prepared at 2 mm intervals from the rostral part of the forebrain The infarct areas of one sheet were totaled, and the ratio of the infarct area to the total area of all the sections was calculated. The compound of Production Example 1 was used as a test drug, and the middle cerebral artery was occluded and then intravenously administered.
As a result, the compound according to the present invention markedly suppressed nerve cell necrosis in a continuous cerebral ischemia model using rats at a dose of 0.125 mg / kg.

Test Example 3 NMDA-induced convulsive suppressive action N-methyl was administered to 6-week-old male ddY mice (4 mice per group).
-D-aspartate (NMDA) 200 mg / kg was intraperitoneally administered,
After that, the presence or absence of convulsions and death that occurred was observed for 30 minutes after administration. The compound of Production Example 1 as a test drug,
The compound of Production Example 2, the compound of Production Example 42, and the compound of Production Example 44 were used and intraperitoneally administered 30 minutes before the administration of NMDA. As a result, seizures In the group administered with the compound of the present invention at 20 mg / kg, the seizure induced by NMDA (100% expression in the control group) was not suppressed. From this fact, it is considered that the compound according to the present invention does not act on the NMDA receptor.

Test Example 4 Acute toxicity test Male SD rats (Slc: SD, Japan SLC, Inc.) were used. The animals that were purchased at the age of 7 weeks and that had undergone the quarantine acclimation period of 1 week were subjected to the experiment as 6 animals per group. The dose volume is
The intraperitoneal administration was 5 ml / kg, and the intravenous administration was 10 ml / kg. Based on the results of preliminary tests, the dose was set so that the mortality rate was 0% and 100%. The administration solution was prepared using physiological saline and filtered with a 0.22 μm sterilizing filter. Production Example 1, Production Example 2, Production Example 3, Production Example 4, Production Example 16, Production Example 18, Production Example 2 as test drug
1. The compound of Production Example 42 was intraperitoneally administered, and the presence or absence of death and general symptoms were observed daily for 7 days from the day of administration. As a result, no significant change was observed in general symptoms. Incidentally, the LD ₅₀ of the compound of Production Example 1 was 65.8 mg / kg for intraperitoneal administration and 22.8 mg / kg for intravenous administration.

[0113]

From the above test results, the compound according to the present invention is administered at the same time as the onset of ischemia or cerebral infarction,
Even when administered several hours after the onset, the compound according to the present invention showed an excellent neuronal necrosis inhibitory action. and,
Low toxicity. Therefore, the compound according to the present invention is useful as a neuropathy inhibitor in the acute stage of cerebrovascular accident. In addition, as a therapeutic agent for cerebral vascular disorders such as cerebral infarction, cerebral hemorrhage, head trauma, subarachnoid hemorrhage, etc. It is useful as a drug for suppressing the onset of psychotic symptoms such as mental disorders and protecting the brain.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Kouichi Ideguchi 14 Shinnoshomonguchi-cho, Kichijoin, Minami-ku, Kyoto-shi, Kyoto Japan Shinyaku Co., Ltd.

Claims (7)

[Claims] 1. A compound represented by the following general formula [I]: A pharmaceutical comprising a compound represented by: or a salt thereof, or a solvate thereof as an active ingredient. In the formula, R ¹ represents an optionally substituted aryl or an aromatic heterocyclic group having 5 to 10 atoms constituting the ring. The aromatic heterocyclic group is a monocyclic ring or a condensed ring and contains one or more nitrogen, oxygen or sulfur as a ring-constituting atom. Further, such aryl or aromatic heterocyclic groups are hydroxy, halogen, alkyl, haloalkyl, hydroxyalkyl, aralkyl, alkenyl, alkoxy, haloalkyloxy, alkylthio, cycloalkyl, cycloalkylalkyl, cycloalkyloxy, alkylsulfonyl, sulfamoyl, 1 to 3 identical or different selected from the group consisting of alkanoyl, amino, monoalkylamino, dialkylamino, carboxy, alkoxycarbonyl, cyano and nitro.
May be substituted with one substituent. R ² is hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, haloalkyl,
Represents alkoxy, alkylthio, amino, monoalkylamino, dialkylamino or optionally substituted phenyl. Such phenyl may be substituted with 1 to 3 same or different substituents selected from the group consisting of halogen, alkyl and alkoxy. R ³ ,
R ⁴ is the same or different and is hydrogen or optionally substituted alkyl (wherein the alkyl may be substituted by a substituent selected from the group consisting of hydroxy, alkoxy, amino, monoalkylamino and dialkylamino). .) Or R ³ and R ⁴ together with the adjacent N represent NR ³ R ⁴ a 4- to 8-membered cyclic amino. Such cyclic amino may have nitrogen, oxygen or sulfur as a ring-constituting atom in addition to the nitrogen, and further alkyl, alkoxy, hydroxy, oxo, amino,
It may be substituted by a substituent selected from the group consisting of monoalkylamino, dialkylamino, optionally substituted aryl and pyridyl. A represents alkylene having 2 to 10 carbon atoms. Such alkylene may be substituted at any position with 1 or 2 identical or different substituents selected from the group consisting of alkoxy, hydroxy and oxo. E represents O or S. W is a single bond, O, S, or (CH ₂ ) _n (wherein
CH ₂ may be substituted with alkyl. n represents 1 or 2. ). X, Y and Z are the same or different and each represents CH, CR (R represents alkyl) or N. However, the case where X, Y and Z are simultaneously carbon is excluded. That is, the G ring represents pyridine, pyrimidine or 1,3,5-triazine. When one to three of X, Y and Z are N, one of them may form an oxide. 2. R ¹ is halogen-substituted phenyl, R ^{1
4 to 8 in which 2} is alkyl or haloalkyl, and -NR ³ R ⁴ contains only one nitrogen atom as a ring-constituting hetero atom.
Membered cyclic amino, A is alkylene having 3 to 6 carbon atoms, E is O or S, W is a single bond, X and Z are N, Y is CH or or Z is N. The drug according to claim 1, wherein X and Y are CH. 3. NR ³ R ⁴ is piperidino, A is alkylene having 4 to 6 carbon atoms, E is O, W is a single bond, X and Z are N and Y is CH or Z. Is N and X and Y are CH. 4. The active ingredient is 4- (4-fluorophenyl) -2-
Methyl-6- (4-piperidinobutoxy) pyrimidine, 4- (4-
Fluorophenyl) -2-methyl-6- (5-piperidinopentyloxy) pyrimidine, 4- (4-fluorophenyl) -2-methyl-6- (6-piperidinohexyloxy) pyrimidine, 4-
(4-Fluorophenyl) -2-methyl-6- (1-methyl-4-piperidinobutoxy) pyrimidine, 2- (4-fluorophenyl) -4-
Methyl-6- (4-piperidinobutoxy) pyrimidine, 4- (4-
Fluorophenyl) -2-methyl-6- (3-piperidinopropoxy) pyridine and 4- (4-fluorophenyl) -2-methyl-6
The therapeutic agent for cerebrovascular disorders according to claim 1, which is a compound selected from the group consisting of-(5-piperidinopentyloxy) pyridine, a salt thereof, or a solvate thereof. 5. A therapeutic agent for cerebrovascular disorders, which comprises the compound according to any one of claims 1 to 4, a salt thereof, or a solvate thereof as an active ingredient. 6. A cerebral nerve cell necrosis inhibitor comprising the compound according to any one of claims 1 to 4, a salt thereof, or a solvate thereof as an active ingredient. 7. An agent for suppressing sequelae of cerebrovascular accident, which comprises the compound according to any one of claims 1 to 4, a salt thereof, or a solvate thereof as an active ingredient.