JPH08333349A - New pyrimidine derivative useful as psychotropic agent and its production - Google Patents

Abstract

PURPOSE: To obtain a new pyrimidine derivative having strong affinity for a neutral nerve-based receptor such as dopamine, serotonin, etc., useful as a therapeutic agent for schizophrenia, Parkinson's disease, etc., namely a psychotropic agent. CONSTITUTION: This pyrimidine derivative is shown by formula I [X is sulfur atom or oxygen atom; A is a halogen, a lower alkyl, a cycloalkyl, an aryl, etc., when X is S atom and A is a lower alkyl, a cycloalkyl, an aryl, etc., when X is oxygen atom; B<1> is H, a lower alkyl, a cycloalkyl, an aryl, amino, etc.; B<2> is amino or a substituted amino; R<1> is a group of formula II (Y<1> to Y<5> are each H, a halogen, a lower alkyl, a cycloalkyl, an aryl, a heterocyclic group, etc.), etc.] or its pharmacologically permissible salt such as 2,4,6-trichloro-5-(4- chlorophenylthio)pyrimidine. The compound of formula I, for example, is obtained by reacting a compound of formula III (A<2> is a halogen) with an amine of the formula H-B<2> .

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel pyrimidine derivative, a process for producing the same, and a psychotropic drug containing them as an active ingredient. Furthermore, the present invention relates to an intermediate for producing the derivative and a method for producing the intermediate.

[0002]

2. Description of the Related Art Conventionally, phenothiazine drugs (chlorpromazine, etc.), butyrophenone drugs (haloperidol, etc.) as therapeutic agents for schizophrenia, manic depression, Parkinson's disease, psychotic symptoms due to substance abuse, and psychotic symptoms associated with senile dementia. , Benzamide-based drugs (such as sutupiride) have been used as useful drugs while considering the balance with side effects. Further, JP-B-54-16510, JP-B-58-049548, and French Patent No. 7206981 describe that a pyrimidine derivative having a methylthio group is a compound useful as a drug having a psychotropic action. Has been done.

[0003]

The object of the present invention is to strongly interact with receptors of the central nervous system such as dopamine and serotonin, to have a higher absorbability and stability in the body, to have weak extrapyramidal disorders, and It is intended to provide a psychotropic drug with reduced side effects such as lowering of consciousness due to receptor blockade and orthostatic hypotension. Further, the present invention aims to provide an intermediate useful for producing the compound.

[0004]

Means for Solving the Problems As a result of intensive studies, the present inventors have found a novel pyrimidine derivative which strongly interacts with receptors of the central nervous system such as dopamine and serotonin. That is, the gist of the present invention is as follows: (1) Formula [I]

[Chemical 6] [In the formula, X represents a sulfur atom or an oxygen atom. A
¹ represents a halogen atom, a lower alkyl group, a cycloalkyl group, an aryl group, a substituted lower alkyl group or a substituted cycloalkyl group when X is a sulfur atom, and a lower alkyl group or a cycloalkyl group when X is an oxygen atom. , An aryl group, a substituted lower alkyl group or a substituted cycloalkyl group. B ¹ represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, an aryl group, a substituted aryl group, an amino group or a substituted amino group. B ² represents an amino group or a substituted amino group. R ¹ is the formula (1) to (6)

[Chemical 7] (Y ¹ , Y ² , Y ³ , Y ⁴ , Y ⁵ , Y ⁶ and Y ⁷ are the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group, a cycloalkyl group, a lower alkenyl group, a lower alkynyl group. , An aryl group, a heterocyclic group, a substituted lower alkyl group, a substituted cycloalkyl group, a substituted lower alkenyl group, a substituted lower alkynyl group, a substituted aryl group or a substituted heterocyclic group.). ] The pyrimidine derivative represented by these, or its pharmacologically acceptable salt,

Formula (2) [II]

Embedded image [In the formula, A ¹ , B ¹ , X, and R ¹ have the same meanings as described above. Z ¹ represents a hydrogen atom, a lower alkyl group or a substituted lower alkyl group. ] The pyrimidine derivative represented by these, or its pharmacologically acceptable salt,

(3) Formula [III]

[Chemical 9] [In the formula, A ¹ , B ¹ , X, and R ¹ have the same meanings as described above. A ² represents a halogen atom. Compound of the formula H-B ² [formula represented by], B ² represents an amino group or a substituted amino group. ] The method of manufacturing the said pyrimidine derivative [I] or its pharmacologically acceptable salt characterized by reacting the amine represented by these,

Formula (4) [IV]

[Chemical 10] [In the formula, A ² , Y ¹ , Y ² , Y ³ , Y ⁴ , and Y ⁵ have the same meanings as described above. ] Concerning the compound represented. The lower alkyl group includes, for example, a straight chain or branched chain alkyl group having 1 to 6 carbon atoms, specifically, methyl,
Ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 1-ethylpropyl, hexyl, 1-methylpentyl, 1-ethylbutyl, 2-methylpentyl and the like can be mentioned. Examples of the cycloalkyl group include cycloalkyl groups having 5 to 7 carbon atoms, and specific examples thereof include cyclopentyl, cyclohexyl and cycloheptyl.

The lower alkenyl is, for example, 2 carbon atoms.
To alkenyl groups having 1 to 3 straight-chain or branched double bonds of 3 to 6, specifically vinyl, 1
-Propenyl, 2-propenyl, 1-methylvinyl, 1
-Butenyl, 2-butenyl, 1-pentenyl, 1-hexenyl and the like can be mentioned. Examples of the lower alkynyl include an alkynyl group having 1 to 3 linear or branched triple bonds having 2 to 6 carbon atoms, and specifically, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 1-pentynyl. , 1-hexynyl and the like. The aryl group includes, for example, 6 to 14 carbon atoms.
And aryl groups such as phenyl, 1-naphthyl, 2-naphthyl, 1-anthranyl, 2-anthranyl and the like.

The heterocyclic group is, for example, a 5- to 7-membered 1-ring system, 9 to 1 containing 1 to 4 heteroatoms arbitrarily selected from the group of oxygen atom, nitrogen atom and sulfur atom.
Examples thereof include 0-membered bicyclic or 12 to 14-membered tricyclic, saturated or unsaturated heterocyclic groups. The nitrogen atom and sulfur atom may be optionally oxidized. The point of attachment of the heterocyclic group is on any nitrogen atom or carbon atom. Specifically, a 6-membered 1-ring saturated heterocyclic group containing 1 or 2 heteroatoms arbitrarily selected from the group of oxygen atom, nitrogen atom, and sulfur atom such as piperidyl, piperazinyl, morpholinyl, pyridyl, pyridazinyl, 1 such as pyrazinyl
6-membered 1-ring aromatic heterocyclic group containing 2 to 2 nitrogen atoms, 1 to 2 heteroatoms arbitrarily selected from the group of oxygen atom, nitrogen atom, sulfur atom such as oxolanyl and pyrrolidinyl 5 Membered monocyclic saturated heterocyclic group, imidazolyl, furyl, 2-oxo-1,3-dioxolenyl, pyrrolyl, 5-oxo-2-tetrahydrofuranyl, etc., selected from the group consisting of oxygen atom, nitrogen atom and sulfur atom. 1
To 5-membered 1-ring aromatic heterocyclic group containing 3 to 3 heteroatoms, quinolyl, isoquinolyl, indolyl, oxygen atom such as 1,3-dihydro-3-oxo-1-isobenzofuranyl, nitrogen atom, sulfur 9 to 10-membered bicyclic aromatic heterocyclic group containing 1 to 3 heteroatoms arbitrarily selected from the group of atoms, oxygen atom such as anthraquinolyl, nitrogen atom, and sulfur atom A 12 to 14 membered tricyclic aromatic heterocyclic group containing 1 to 3 heteroatoms and the like can be mentioned.

The substituted lower alkyl group includes a cycloalkyl group, a substituted cycloalkyl group, an aryl group, a substituted aryl group, a heterocyclic group, a substituted heterocyclic group, a halogen atom and -O.
P ¹ (in the formula, P ¹ represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, an aryl group or a protective group for a hydroxyl group), —OCOP ² (in the formula, P ² is a hydrogen atom, a lower alkyl group, a cycloalkyl group). alkyl group, an aryl group or a heterocyclic ^{group), -. NP 3 P 4} ( wherein, P ³ represents a hydrogen atom or a lower alkyl group, P ⁴ is a hydrogen atom, a lower alkyl group, a cycloalkyl group, an aryl Group, a heterocyclic group or an amino group-protecting group), -C (= NP ⁵ ) NH
P ⁶ (wherein P ⁵ and P ⁶ are the same or different and represent a hydrogen atom, a lower alkyl group, a cycloalkyl group or a guanidino group protecting group), —NHC (═N
P ⁵ ) NHP ⁶ (in the formula, P ⁵ and P ⁶ are as defined above), nitro group, cyano group, —COOP ⁷ (in the formula,
P ⁷ is a hydrogen atom, a lower alkyl group, a cycloalkyl group,
It represents a protective group for an aryl group, a heterocyclic group or a carboxyl group. ), - CONP ⁸ P ⁹ (wherein, P ⁸ represents a hydrogen atom or a lower alkyl group, P ⁹ represents a protecting group of a hydrogen atom, a lower alkyl group or an amide group), -. SP
¹⁰ (in the formula, P ¹⁰ represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, an aryl group, a heterocyclic group or a thiol protecting group), —COP ¹¹ (in the formula, P ¹¹ is a hydrogen atom, a lower alkyl group). Group, a cycloalkyl group, an aryl group or a heterocyclic group), -NHCOP ¹² (in the formula, P ¹² represents a hydrogen atom, a lower alkyl group, a cycloalkyl group or an aryl group), -S (O). sP ¹³ (wherein P ¹³ represents a lower alkyl group, a cycloalkyl group or an aryl group,
s represents 1 or 2. ), —SO ₂ NP ¹⁴ P ¹⁵ (in the formula, P ¹⁴ and P ¹⁵ are the same or different and each represents a hydrogen atom, a lower alkyl group, a cycloalkyl group or an aryl group) and —OCOOP ¹⁶ (in the formula, P ¹⁶ represents a lower alkyl group, a cycloalkyl group, an aryl group or a heterocyclic group) 1 to 5 arbitrarily selected from the group
Lower alkyl groups substituted with 4 substituents.

As such a substituted lower alkyl group,
Specifically, benzyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 6-phenylhexyl, 4-chlorobenzyl, indolylmethyl, 2- (3-indolyl) ethyl, bromomethyl. , Pivaloyloxymethyl, 1-ethoxycarbonyloxyethyl, 5-methyl-2-oxo-1,3-
Dioxolen-4-ylmethyl, 2-chloroethyl, 2
-Dimethylaminoethyl, diethylaminoethyl, 3-
Dimethylamino-2- (dimethylaminomethyl) propyl, 2- (1-morpholinyl) ethyl, 1-acetoxyethyl, 1-methoxycarbonyloxyethyl, acetoxymethyl, 1-acetoxy-1-phenylmethyl, methoxycarbonylmethyl, 1 -Pivaloyloxyethyl, 2-hydroxyethyl, 3-hydroxypropyl and the like.

The substituted lower alkenyl group includes a cycloalkyl group, an aryl group, a heterocyclic group, a halogen atom and -O.
P ¹⁷ (in the formula, P ¹⁷ represents a hydrogen atom, a lower alkyl group or a hydroxyl-protecting group), —OCOP ¹⁸ (in the formula, P ¹⁸ represents a hydrogen atom or a lower alkyl group), a nitro group,
A cyano group, -COOP ¹⁹ (in the formula, P ¹⁹ represents a hydrogen atom or a protective group for a carboxyl group), -CONP ⁸ P ⁹
(In the formula, P ⁸ and P ⁹ are as defined above.), -C
OP ²⁰ (in the formula, P ²⁰ represents a hydrogen atom or a lower alkyl group) and -OCOOP ²¹ (in the formula, P ²¹ represents a hydrogen atom or a lower alkyl group), 1 to. Examples thereof include a lower alkenyl group substituted with 5 substituents. Specific examples include 3-phenyl-2-propenyl, 5-methoxy-2-pentenyl, 2-carboxyl vinyl and the like.

The substituted lower alkynyl group includes a cycloalkyl group, an aryl group, a heterocyclic group, a halogen atom and --O.
P ¹⁷ (In the formula, P ¹⁷ has the same meaning as above.), —OCOP
¹⁸ (in the formula, P ¹⁸ has the same meaning as described above), nitro group, cyano group, —COOP ¹⁹ (in the formula, P ¹⁹ has the same meaning as described above), —CONP ⁸ P ⁹ (in the formula, P ⁸ and P ⁹ are as defined above, -COP ²⁰ (wherein P ²⁰ is as defined above) and -OCOOP ²¹ (wherein P ²¹ is as defined above). 1 to 5 arbitrarily selected from
Examples include lower alkynyl groups substituted with one substituent, and specific examples include 3-phenyl-2-propynyl.

The substituted cycloalkyl group includes a lower alkyl group, an aryl group, a heterocyclic group, a halogen atom and -OP.
¹⁷ (in the formula, P ¹⁷ has the same meaning as described above), —OCOP ¹⁸
(In the formula, P ¹⁸ has the same meaning as above.), -NP ²² P
²³ (in the formula, P ²² represents a hydrogen atom or a lower alkyl group, P ²³ represents a hydrogen atom, a lower alkyl group or a protective group of an amino group), -C (= NP ²⁴ ) NHP ²⁵ (in the formula,
P ²⁴ and P ²⁵ are the same or different and each represents a hydrogen atom or a guanidino group-protecting group. ), -NHC
(= NP ²⁴ ) NHP ²⁵ (wherein P ²⁴ and P ²⁵ are as defined above), nitro group, cyano group, —COOP
¹⁹ (in the formula, P ¹⁹ has the same meaning as above), —CONP ⁸
P ⁹ (wherein P ⁸ and P ⁹ have the same meanings as described above),
-SP ²⁶ (in the formula, P ²⁶ represents a hydrogen atom, a lower alkyl group or a thiol protecting group), -COP ²⁰ (in the formula, P
²⁰ has the same meaning as above. ), -NHCOP ²⁷ (in the formula, P
²⁷ represents a hydrogen atom or a lower alkyl group. ), -S
(O) sP ²⁸ (wherein P ²⁸ represents a lower alkyl group, s
Is as defined above. ), -SO ₂ NP ²⁹ P ³⁰ (wherein
P ²⁹ and P ³⁰ are the same or different and each represents a hydrogen atom or a lower alkyl group. ) And -OCOOP
²¹ (in the formula, P ²¹ has the same meaning as defined above), and a cycloalkyl group substituted with 1 to 3 substituents arbitrarily selected from the group. Specific examples include 4-chlorocyclohexyl, 4-cyanocyclohexyl, 2-dimethylaminocyclohexyl, 4-methoxycyclohexyl and the like.

As the substituted heterocyclic group, a lower alkyl group,
A cycloalkyl group, an aryl group, a heterocyclic group, a halogen atom, -OP ¹⁷ (in the formula, P ¹⁷ has the same meaning as above),-
OCOP ¹⁸ (in the formula, P ¹⁸ has the same meaning as above), -N
P ²² P ²³ (wherein P ²² and P ²³ have the same meanings as described above), -C (= NP ²⁴ ) NHP ²⁵ (in the formula, P ²⁴ and P ²⁵ have the same meanings as described above),- NHC (= NP ²⁴ ) N
HP ²⁵ (in the formula, P ²⁴ and P ²⁵ have the same meanings as described above), nitro group, cyano group, —COOP ⁷ (in the formula, P
⁷ has the same meaning as above. ), -CONP ⁸ P ⁹ (in the formula,
P ⁸ and P ⁹ are as defined above. ), -SP ²⁶ (in the formula, P ²⁶ has the same meaning as above), -COP ²⁰ (in the formula,
P ²⁰ has the same meaning as above. ), -NHCOP ²⁷ (wherein
P ²⁷ has the same meaning as above. ), -S (O) sP ²⁸ (in the formula, s and P ²⁸ have the same meanings as described above), -SO ₂ N.
1 to 3 optionally selected from the group of P ²⁹ P ³⁰ (wherein P ²⁹ and P ³⁰ have the same meanings as described above) and —OCOOP ²¹ (wherein P ²¹ has the same meanings as described above). And a heterocyclic group substituted with one substituent, specifically, 1-
Acetyl-4-piperidinyl, 1-benzyl-4-imidazolyl, 1-methyl-3-indolyl, 5-methyl-
2-oxo-1,3-dioxolen-4-yl and the like can be mentioned.

The substituted aryl group includes the following (a):
Examples thereof include an aryl group substituted with 1 to 5 substituents arbitrarily selected from the group consisting of (b) and (c). (A) lower alkyl group, lower alkenyl group, lower alkynyl group, cycloalkyl group, aryl group, heterocyclic group, substituted alkenyl, substituted alkynyl, substituted cycloalkyl,
Substituted heterocyclic group, halogen atom, -OP ¹ (wherein P ¹ has the same meaning as described above), -OCOP ² (wherein P ² has the same meaning as described above), -NP ³ P ⁴ ( In the formula, P ³ and P ⁴ have the same meanings as above.), —C (= NP ⁵ ) NHP
⁶ (in the formula, P ⁵ and P ⁶ have the same meanings as described above),
NHC (= NP ⁵ ) NHP ⁶ (wherein P ⁵ and P ⁶ are as defined above), nitro group, cyano group, —COO
P ⁷ (In the formula, P ⁷ has the same meaning as above.), —CONP
⁸ P ⁹ (in the formula, P ⁸ and P ⁹ have the same meanings as described above), -SP ¹⁰ (in the formula, P ¹⁰ has the same meaning as described above), -COP ¹¹ (wherein P ¹¹ represents the above). , -NHCOP ¹² (wherein P ¹² is as defined above), -S (O) sP ¹³ (in the formula, s and P ¹³ are as defined above),- SO ₂ NP ¹⁴ P ¹⁵ (wherein P ¹⁴ and P ¹⁵ have the same meanings as described above) and —OCOOP ¹⁶
(In the formula, P ¹⁶ has the same meaning as above.),
(B) a lower alkyl group substituted with -OP ¹ (wherein P ¹ has the same meaning as described above) or -NP ³ P ⁴ (wherein, P ³ and P ⁴ have the same meaning as described above). , (C) optionally selected from fluorine atom, chlorine atom or bromine atom 1
To lower alkyl groups substituted with 5 to 5 atoms. Here, when two substituents are adjacent to each other, they are bonded to each other to form 4 to 7 such as methylenedioxy group.
You may form a member ring.

Specific examples of the substituted aryl group include 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 4-iodophenyl, 2,4-dichlorophenyl, 4-hydroxyphenyl, 3,4-dihydroxyphenyl, 4-methylphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 3,4-methylenedioxyphenyl, 4
-Aminophenyl, 4-guanidinophenyl, 4-aminomethylphenyl, 4-cyanophenyl, 4-carboxyphenyl, 4-acetylphenyl, 4-chloro-1
-Naphthyl, 4-amidinophenyl, 4-nitrophenyl, 4-ethoxycarbonylphenyl, 4-acetoxyphenyl, 4-benzyloxyphenyl, 2-fluoro-4-hydroxyphenyl, 5-indanyl, 4- (2
-Carboxyl vinyl) phenyl, 4- (2-butyl)
Phenyl, 3,5-dichloro-2-hydroxylphenyl, 2,3,4-trichlorophenyl, 2,4,5-trichlorophenyl, 2,4,6-tri- (2-propyl) phenyl, 2,5- Dimethylphenyl, 2-nitrophenyl, 3-nitrophenyl, 2,4-dinitrophenyl, 4-chloro-3-nitrophenyl, 2,5-dimethoxyphenyl, 2,5-dimethylphenyl, 2-methoxycarbonylphenyl, 3 -Carboxylphenyl,
2-methoxy-5-carboxylphenyl, 4-t-butylphenyl, 4-ethylphenyl, 2-methylphenyl, 3-methylphenyl, 2,4,6-trimethylphenyl, 5-dimethylamino-1-naphthyl, 4 -Acetaminophenyl, 2,3,4,5,6-pentafluorophenyl, 2,3,4,5,6-pentamethylphenyl, 4-dimethylamino-3-nitrophenyl, 2,
3,5,6-tetramethylphenyl, 2,5-dichlorophenyl, 4-trifluoromethylphenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 3,5-ditrifluoromethylphenyl and the like can be mentioned.

The halogen atom is, for example, a fluorine atom,
Examples thereof include chlorine atom, bromine atom and iodine atom. The amino group or the substituted amino group is represented by the formula: -NQ ¹ Q ² (wherein Q ¹ and Q ² are the same or different, and each is a hydrogen atom, a lower alkyl group, a cycloalkyl group, a substituted lower alkyl group or a substituted cycloalkyl). A group, or Q ¹ and Q ² are bound to each other and, together with the nitrogen atom to which they are bound, a saturated or unsaturated cyclic amino of 5-8 membered ring containing 1-3 nitrogen atoms in the ring. When a plurality of nitrogen atoms are contained, they may be substituted with a lower alkyl group.) And an amino group or a substituted amino group. Specifically, methylamino group, dimethylamino group, ethylmethylamino group, cyclohexylmethylamino group, dicyclohexylamino group, 4-methylcyclohexylethylamino group, piperidyl group, pyridyl group, N-methylpiperazyl group, pyridazyl group Etc.

Formula H-B ² [B ² represents an amino group or a substituted amino group. ] The amine represented by the formula is HNQ ¹ Q
² (wherein Q ¹ and Q ² are as defined above). Specific examples include methylamine, dimethylamine, ethylmethylamine, cyclohexylmethylamine, dicyclohexylamine, 4-methylcyclohexylethylamine, piperidine, pyridine, N-methylpiperazine, pyridazine and the like. Hydroxyl protecting group, amino protecting group, guanidino protecting group, carboxyl protecting group,
The protecting group for the amide group and the protecting group for the thiol group may be any one commonly used as a protecting group in the reaction, for example, Izumiya et al., “Basics and Experiments of Peptide Synthesis” (Maruzen,
(1985) or the amino acid side chain protecting group described in "Protective Groups in Organic Synthesis" (Jones Willey & Sons, 1991) such as Green et al. Examples of the hydroxyl-protecting group include ether-type protecting groups and acyl-type protecting groups. Examples of the ether type protecting group include benzyl, 2-nitrobenzyl, 2,6-dichlorobenzyl, t-butyl and the like, and examples of the acyl type protecting group include a lower alkanoyl group. Examples of the lower alkanoyl group include linear or branched alkanoyl groups having 5 or less carbon atoms, and specific examples include acetyl, propanoyl, butanoyl and the like.

Examples of the amino-group-protecting group include urethane-type protecting groups and acyl-type protecting groups. Examples of the urethane-type protecting groups include benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2 -Methanesulfonylethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl,
Examples thereof include t-butyloxycarbonyl, fluorenyloxycarbonyl and the like, and examples of the acyl type protecting group include formyl, acetyl, benzoyl, trifluoroacetyl and the like. Examples of the guanidino group-protecting group include urethane-type protecting groups such as benzyloxycarbonyl and t-butyloxycarbonyl, 4-toluenesulfonyl, 4-methoxybenzenesulfonyl, and nitro groups. As the protecting group for the carboxyl group,
Ester type protecting groups are mentioned, for example, lower alkyl,
2,2,2-trichloroethyl, benzyl, 4-methoxybenzyl, diphenylethyl and the like can be mentioned. Examples of the protecting group for the amide group include 2,4-dimethoxybenzyl and the like. Examples of the thiol-protecting group include sulfide-type protecting groups such as benzyl, 4-methylbenzyl, 4-methoxybenzyl, 4-nitrobenzyl,
Examples include acetamidomethyl. The compounds having these protecting groups can also be used as intermediates,
It can be used as it is as a substance showing pharmacological activity.

Specific preferred examples of A ¹ include halogen such as chloro group and bromine group, and lower alkyl group such as methyl group and ethyl group. Specific preferred examples of A ² include a chlorine atom and a bromine atom.
Preferable examples of Y ¹ , Y ² , Y ³ , Y ⁴ , Y ⁵ , Y ⁶ and Y ⁷ include hydrogen atom, lower alkyl group such as methyl group, ethyl group and propyl group, cyclohexyl and benzyl. , Acetoxymethyl, 1-acetoxyethyl, 1-acetoxy-1-phenylmethyl, pivaloyloxymethyl, 1-pivaloyloxyethyl, etc.
COP ³¹ (wherein P ³¹ represents a lower alkyl group, a cycloalkyl group, an aryl group, or a heterocyclic group), a lower alkyl group substituted with 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl, etc. -OC
Lower alkyl group substituted with OOP ³² (wherein P ³² represents a lower alkyl group, a cycloalkyl group, an aryl group, or a heterocyclic group), 5-methyl-2-oxo-1,
Lower alkyl group substituted with a substituted heterocyclic group such as 3-dioxolen-4-ylmethyl, 2- (1-molyfornyl) ethyl, 5-oxo-2-tetrahydrofuranyl,
Heterocyclic groups such as 1,3-dihydro-3-oxo-1-isobenzofuranyl group, substituted aryl groups such as 5-indanyl group, 3-dimethylamino-2- (dimethylaminomethyl) propyl, 2-dimethylaminoethyl, 2- Examples include diethylaminoethyl, methoxycarbonylmethyl, 2-dimethylaminocyclohexyl and the like.

Preferable examples of Z ¹ include a hydrogen atom, a lower alkyl group such as a methyl group, an ethyl group and a propyl group. Specific preferred examples of B ¹ include a hydrogen atom, a methylamino group, a dimethylamino group, an N-methylpiperazinone group and the like. Specific preferred examples of B ² include a methylamino group, a dimethylamino group, and an N-methylpiperazinone group. When the compound represented by the formula [I] has an asymmetric carbon atom, any isomer or a mixture thereof may be used, and when two or more asymmetric carbon atoms are present, the diastereomer may be an enantiomer. It may exist as stereomers or as mixtures thereof, eg as racemates. Unless otherwise specified, the compound of the present invention represented by the formula [I] can be produced from easily available raw materials and reagents by using known synthetic reactions, for example, the method described below or a modified method thereof. be able to.

[Chemical 11] [In the formula, A ¹ , A ² , B ¹ , B ² , X, and R ¹ are the same as defined above]

Compound [III] and 1 to 3 equivalents of B ² -H
In an inert solvent such as benzene, toluene, xylene, dichloromethane, chloroform, carbon tetrachloride, etc. in the presence of a base such as pyridine, triethylamine, diisopropylethylamine, etc. The compound [I] is obtained by reacting at an appropriate temperature of room temperature to 80 ° C. for 30 minutes to 2 hours. The compound [III], which is the starting material of the above reaction, is a novel compound when X is S. Next, the method for producing the compound (III) will be described with reference to (A) to (C). (A) A production method in which X is S and B ¹ is a lower alkyl group, a cycloalkyl group, an aryl group, a substituted aryl group, an amino group or a substituted amino group.

[Chemical 12] [Wherein A ¹ , A ² and R ¹ have the same meanings as defined above, A ¹¹ represents a lower alkyl group, a cycloalkyl group, an aryl group, a substituted lower alkyl group or a substituted cycloalkyl group, and B ¹¹ represents a lower alkyl group. Group, a cycloalkyl group, an aryl group, a substituted aryl group, an amino group or a substituted amino group, Y ⁶
Represents a lower alkyl group, a cycloalkyl group, an aryl group, a substituted lower alkyl group, or a substituted cycloalkyl group. ] The thiol derivative [VII] is dissolved in water or dimethylformamide, and sodium hydroxide, potassium hydroxide,
A base such as sodium carbon, potassium carbonate or sodium hydrogen carbonate, or an aqueous solution of such a base at an appropriate concentration is added, and then an iodine compound Y ⁶ I [Y ⁶ has the same meaning as above] is added, and the mixture is added at 0 to 40 ° C. The reaction is completed by stirring at a suitable temperature for 2 hours to 24 hours. Post-treatment by a conventional method gives the sulfide derivative [VIII]. The compound [VIII] is suspended in water, an oxidizing agent such as hydrogen peroxide or sodium periodate is added, and the mixture is stirred at an appropriate temperature of 0 ° C. to room temperature for 1 to 2 days to complete the reaction. Post-treatment by a conventional method gives sulfoxide [IX]. The obtained [IX] and barbituric acid are dissolved in acetic acid, acetic anhydride is added as a dehydrating agent, and the mixture is reacted at an appropriate temperature of 60 to 120 ° C. to give a compound-stable iowilide [V
I] can be obtained.

Iouwilide [V
Examples of [I] include 4-chlorophenylmethylsulfonium barbityride, 3-chlorophenylmethylsulfonium barbityride, methylphenylsulfonium barbitilide and the like. The compound [IV ′] is a novel compound and can be obtained by halogenating the compound [VI] with a halogenating agent. As the halogenating agent, thionyl halide such as thionyl chloride and thionyl bromide, phosphorus halide such as phosphorus oxychloride and phosphorus oxybromide, and hydrogen halide such as hydrogen chloride and hydrogen bromide can be used. As the solvent, a solvent such as benzene, toluene, xylene, dichloromethane, chloroform, carbon tetrachloride, dimethylformamide, diethyl ether may be used.
Under these solvents, as it is, or in the presence of a tertiary amine such as pyridine, quinoline, dimethylaniline, triethylamine, diisopropylamine, etc., if necessary, an excessive amount of a halogenating agent is used to react with Compound [VI],
Compound [IV ′] is obtained by reacting at an appropriate temperature of 90 ° C. for 1 to 24 hours. Compound [IV '] and B
^The compound [V] in which B ¹¹ is an amino group or a substituted amino group can be obtained by regiospecifically aminating by reaction with an amine represented by ^11- H.

That is, the compound [IV '] is dissolved in a mixture of water and a hydrophilic solvent such as acetone or methyl ethyl ketone in an appropriate ratio, and 1 to 1.5 equivalents of amine are added to the mixture at -10 ° C to The reaction is completed by stirring at a suitable temperature of 0 ° C. for 30 minutes to 3 hours. At that time, the compound [V] is obtained by post-treatment according to a conventional method. Further, the compound [IV ′] can be subjected to an ordinary regioselective Grignard reaction to obtain a compound [V] in which B ¹¹ is a lower alkyl group, a cycloalkyl group, an aryl group, or a substituted aryl group. That is, the compound [I
[V]] can be obtained by dissolving V '] in an ether-based inert solvent such as tetrahydrofuran or diethyl ether, forming a Grignard reagent with metallic magnesium, and then performing a Grignard reaction with a ketone, an aldehyde or an epoxide. ． Alternatively, the compound [I
V ′] is reacted with a metal halide such as NaH or KH and an alkyl halide, an aryl halide or the like to give a compound [V] in which B ¹¹ is a lower alkyl group, a cycloalkyl group, an aryl group or a substituted aryl group. Can be obtained. Further, the compound [V] is dissolved in an ether-based inert solvent such as tetrahydrofuran or diethyl ether to prepare a Grignard reagent with metallic magnesium, and then a Grignard reaction with a ketone, an aldehyde or an epoxide is performed, whereby A ¹¹ is a lower alkyl group. , A cycloalkyl group, an aryl group, a substituted lower alkyl group, a substituted cycloalkyl group, [V ′] can be obtained.

(B) X is O and B ¹ is a lower alkyl group, a cycloalkyl group, an aryl group, a substituted aryl group,
Production method for amino group or substituted amino group

[Chemical 13] [In the formula, A ¹¹ , A ² , B ¹¹ , B ² and R ¹ have the same meanings as described above, and W ¹ represents a halogen atom. W ² represents a lower alkyl group, a cycloalkyl group, a substituted lower alkyl group or a substituted cycloalkyl group. ] Compound [X] is mixed with benzene, toluene, xylene, dichloromethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran, 1 to 1.2 equivalents of sodium hydride, and 1 to 1.2 in an inert solvent such as dioxane.
Add an equivalent amount of the phenol derivative [XI], room temperature to 90 ° C
After reacting for 5 minutes to 2 hours at an appropriate temperature, the compound [XII] can be obtained by a conventional method. next,
Compound [XII] is an alcohol such as methanol or ethanol, or 2 to 4 equivalents of a guanidine derivative [in an inert solvent such as benzene, toluene, xylene, dichloromethane, chloroform, carbon tetrachloride, diethyl ether, tetrahydrofuran or dioxane. XIII] is added, and the mixture is reacted at an appropriate temperature of room temperature to 60 ° C. for 1 to 2 hours and treated by a conventional method to give compound [XIV]. Then, the compound [XIV] is halogenated with a halogenating agent in the same manner as in the above (A) to give the compound [XIV].
V] is obtained, and the compound [XV] is converted to B as in the above (A).
Compound [XVI] can be obtained by reacting with an amine represented by ^2- H. (C) Method for producing compound [III] when B ¹ is a hydrogen atom

Embedded image [In the formula, A ¹¹ , A ² , B ² , R ¹ and X have the same meanings as described above. The compound [XVIII] is the same as the compound [XVII] in the presence of NaOH in an inert solvent such as benzene, toluene, xylene, dichloromethane, chloroform and carbon tetrachloride.
R ¹ -SH or R at an appropriate temperature of 0 ° C to 100 ° C
It can be obtained by reacting with a compound represented by ^1- OH. Then, in the same manner as in the above (A), the compound [X
Compound [XIX] is obtained by halogenating VIII] with a halogenating agent, and compound [XIX] is reacted with an amine represented by B ² —H in the same manner as in (A) above to give compound [XIX]. ] Can be obtained, and the compound [XX] can be obtained by further performing a Grignard reaction in the same manner as in the above (A).

The compound [II] is the compound [III]
And one nitrogen atom is substituted with Z ¹ [Z ¹ has the same meaning as above] to easily obtain it. This reaction can be carried out in the same manner as in the case of the reaction between compound [III] and an amine described above. Examples of the pharmacologically acceptable salt include pharmacologically acceptable acid addition salts. Examples of acid addition salts include inorganic acid addition salts such as hydrochlorides, sulfates, and phosphates, or acetates, methanesulfonates, trifluoroacetates, citrates, fumarates, maleates, succinic acids. Organic acid addition salts such as salts, tartrates and salicylates are mentioned. Such salts can be easily produced by known means. For example, in the case of acetate salt, it is produced by dissolving the compound of the formula [I] in water and adding the required amount of acetic acid.

The compound represented by the formula [I] can be purified by a conventional purification method such as recrystallization, thin layer chromatography and high performance liquid chromatography. Specific examples of the compound and intermediate thus obtained are as follows.

[Table 1]

[Table 2]

[Table 3]

[Table 4]

[Table 5]

[Table 6]

[Table 7]

[Table 8]

[Table 9]

[Table 10]

[Table 11]

[Table 12]

[Table 13]

[Table 14]

[Table 15]

[Table 16]

[Table 17]

[Table 18]

[Table 19]

[Table 20]

[Table 21]

[Table 22]

[Table 23]

[Table 24]

[Table 25]

[Table 26]

[Table 27]

[Table 28]

[Table 29]

[Table 30]

[Table 31]

[Table 32]

[Table 33]

[Table 34]

[Table 35]

[Table 36]

[Table 37]

[Table 38]

[Table 39]

[Table 40]

[Table 41]

[Table 42]

[Table 43]

[Table 44]

[Table 45]

[Table 46]

[Table 47]

[Table 48]

[Table 49]

[Table 50]

[Table 51]

[Table 52]

[Table 53]

[Table 54]

[Table 55]

[Table 56]

[Table 57]

[Table 58]

[Table 59]

[Table 60]

[Table 61]

[Table 62]

[Table 63]

[Table 64]

[Table 65]

[Table 66]

[Table 67]

[Table 68]

[Table 69]

[Table 70]

[Table 71]

[Table 72]

[Table 73]

[Table 74]

[Table 75]

[Table 76]

[Table 77] 2,4,6-Trichloro-5- (4-chlorophenylthio) pyrimidine, 2,4,6-trichloro-5- (3-chlorophenylthio) pyrimidine, 2,4,6-trichloro-5-phenylthiopyrimidine, 4,6-dichloro-5- (4-chlorophenylthio) -2-methylaminopyrimidine, 4,6-dichloro-5- (3-chlorophenylthio) -2-methylaminopyrimidine, 4,6-dichloro-2-methylamino-5-phenylthiopyrimidine, 4,6-dichloro-2- Dimethylamino-5-phenylthiopyrimidine, 4-chloro-5- (4-chlorophenylthio) -2-methylamino-6- (4-methylpiperazino) pyrimidine, 4-chloro-5- (3-chlorophenylthio) -2-methylamino-6- ( 4-methylpiperazino) pyri Gin, 4-chloro-2-methylamino-6- (4-methylpiperazino) -5-phenylthiopyrimidine, 4-chloro-2-dimethylamino-6- (4-methylpiperazino) -5-phenylthiopyrimidine, 4-chloro-6 -Methyl-2-methylamino-5-phenyloxypyrimidine, 4-methyl-2-methylamino-6- (4-methylpiperazino) -5-phenyloxypyrimidine.

The animals to which the compound of the present invention is administered are not particularly limited, and not only humans but also mice, rats, dogs, cats, cows, horses, goats, sheep, rabbits,
Various mammals such as pigs are targeted. Administration to these humans and animals can be carried out by the usual administration routes such as oral, intramuscular, intravenous, subcutaneous, intraperitoneal and intranasal routes. The dose and the number of doses vary depending on the species of animal, route of administration, degree of symptoms, sex difference, body weight, etc. and are not particularly limited, but in humans, usually 1 mg to 300 mg per day for adults is once or more times a day. Is administered in. Dosage forms include powders, fine granules, tablets,
Capsules, suppositories, injections, nasal preparations, etc. are mentioned. When formulating, use a conventional drug carrier and manufacture by a conventional method. That is, when preparing an oral preparation, after adding a binder, a disintegrating agent, a lubricant, a coloring agent, etc., if necessary,
Tablets, granules, powders, capsules, etc. are prepared by a conventional method. When preparing an injection, if necessary, a pH adjuster,
Add buffers, stabilizers, solubilizers, etc. to make injections by a conventional method.

[0030]

INDUSTRIAL APPLICABILITY The novel pyrimidine derivative represented by the above general formula [I] according to the present invention has a strong affinity for central nervous system receptors such as dopamine and serotonin, and is useful as a psychotropic drug. For example, it is useful as a therapeutic drug for schizophrenia, manic depression, Parkinson's disease, psychiatric symptoms due to substance abuse, and psychiatric symptoms associated with senile dementia. The compound [I] of the present invention is characterized by a weak action on the α ₁ receptor and a strong affinity for the dopamine and serotonin receptors. Further, conventional psychotropic drugs such as chlorpromazine had side effects such as lowering of consciousness level and orthostatic hypotension due to α ₁ receptor blocking action, but the compound of the present invention has affinity for α ₁ receptor. Is weak and has a strong affinity for, for example, dopamine D ₃ and serotonin 5-HT ₂ receptors.

Further, the compound represented by the formula [III] is important as an intermediate in the production of the compound represented by the formula [I], and the compound represented by the formula [I] is obtained by way of this compound. The final target compound of the present invention can be easily produced.

The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples. Example 1 2,4,6-Trichloro-5- (4-chlorophenylthio) pyrimidine

[Chemical 15] 1) 4-Chlorophenylmethylsulfonium barbityride 4-chlorothiophenol (7.23 g) was dissolved in dimethylformamide (100 ml), and the reaction solution was heated to 5 ° C. After adding NaH (2.88 g) and stirring for 30 minutes, the reaction solution was gradually warmed to room temperature. Methyl iodide (8.52
A solution of g) in dimethylformamide (100 ml) was added dropwise, and the mixture was stirred overnight. After the excess NaH was decomposed with water, it was extracted with ethyl acetate, the organic layer was washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a pale yellow oily substance (7.90 g). This was dissolved in water without purification, and sodium periodate (10.7
g) was added. After stirring for 24 hours, the precipitate was filtered off and the filtrate was extracted with methylene chloride. Methylene chloride was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give a colorless oil (4.15 g).

Without purification, acetic acid (20 m
It was dissolved in 1), barbituric acid (2.56 g) and acetic anhydride (3.68 g) were added, and the mixture was heated to 90 ° C. After stirring for 7 hours, 10 ml of water was added and the reaction solution was cooled to room temperature. Since colorless crystals were precipitated, they were collected by filtration and washed with acetone to obtain the desired product (7.10 g). ¹ H-NMR (500 MHz (CDCl ₃ ), TM
S): δ3.46 (3H, s), 7.66 (2H, d,
J = 9.0 Hz), 7.76 (2H, d, J = 9.0H)
z), 10.31 (2H, s). MS (EI, direct): 284 (M ⁺ ).

2) 2,4,6-trichloro-5- (4
-Chlorophenylthio) pyrimidine 4-chlorophenylmethylsulfonium barbityride (2.0 g) obtained above was dissolved in 20 ml of phosphorus oxychloride, and 1 ml of dimethylaniline was added.
The mixture was heated and stirred for an hour. Excess phosphorus oxychloride was hydrolyzed with water and ice, and the precipitated colorless crystals were washed with water to obtain the desired product (2.28 g). ¹ H-NMR (500 MHz (CDCl ₃ ), TM
S): δ7.23 (2H, dt, J = 2.0 and
8.5 Hz), 7.30 (2H, dt, J = 2.0an
d 8.0 Hz). ¹³ C-NMR (125 MHz (CDCl ₃ ), TM
S): δ127.94, 129.84, 130.46.
131.56, 134.53, 158.85, 167.
42.

Example 2 2,4,6-Trichloro-5- (3-chlorophenylthio) pyrimidine

Embedded image 1) 3-Chlorophenylmethylsulfonium barbityride In the same manner as in Example 1 except that 3-chlorothiophenol was used instead of 4-chlorothiophenol in Example 1, 3-chlorothiophenol (7.23 g) was used. )
To obtain the desired crystal (7.08 g). ¹ H-NMR (500 MHz (CDCl ₃ ), TM
S): δ 3.48 (3H, s), 7.60-7.66
(1H, m), 7.66-7.67 (3H, m), 1
0.32 (1H, s). MS (EI, direct): 284 (M ⁺ ).

2) 2,4,6-trichloro-5- (3
-Chlorophenylthio) pyrimidine The same procedure as in Example 1 was repeated except that the 3-chlorophenylmethylsulfonium barbityride obtained above was used in place of the 4-chlorophenylmethylsulfonium barbityride obtained in Example 1. Crystals of the target compound (2.26 g) were obtained from -chlorophenylmethylsulfonium barbityride (2.0 g). ¹ H-NMR (500 MHz (CDCl ₃ ), TM
S): δ 7.13 (1H, dt, J = 1.5, 7.0H
z), 7.24-7.28 (3H, m). ¹³ C-NMR (125 MHz (CDCl ₃ ), TM
S): δ127.36, 127.79, 128.34,
129.43, 130.61, 133.91, 135.
39, 159.09, 167.62.

Example 3 2,4,6-Trichloro-5-phenylthiopyrimidine

[Chemical 17] 1) Methylphenylsulfonium barbityride The target crystal (7.50 g) was obtained from methylphenyl sulfoxide (4.90 g) and barbituric acid (3.84 g) in the same manner as in Example 1. ¹ H-NMR (CDCl ₃ ) δ (ppm) 3.46
(3H, s), 7.57-7.59 (3H, m), 7.
73-7.75 (2H, m), 10.27 (2H, m)
m). 2) 2,4,6-Trichloro-5-phenylthiopyrimidine Example 1 except that the 4-chlorophenylmethylsulfonium barbityride obtained in Example 1 was replaced by the methylphenylsulfonium barbityride obtained above.
Similarly to the above, crystals of the target compound (5.70 g) were obtained from methylphenylsulfonium barbityride (7.50 g). ¹ H-NMR (500 MHz (CDCl ₃ ), TM
S): δ7.26-7.33 (5H, m). ¹³ C-NMR (125 MHz (CDCl ₃ ), TM
S): δ128.01, 129.56, 130.08,
132.05, 128.31, 153.48, 167.
42.

Example 4 4,6-dichloro-5- (4-chlorophenylthio) -2-methylaminopyrimidine

Embedded image 2,4,6-trichloro-5- (4-chlorophenylthio) pyrimidine (1.
14 g) was dissolved in methyl ethyl ketone (6 ml) to give 3
ml water and methylamine (40% aqueous solution, 270 m
g) was added and the reaction temperature was adjusted to 5 ° C or lower. After stirring for 30 minutes, the temperature was gradually raised to room temperature and 5% of 30% NaOH aqueous solution was added.
ml was dropped. After stirring vigorously at room temperature for 2 hours, the precipitated crystal (495 mg), which was the target substance, was collected by filtration. ¹ H-NMR (500 MHz (CDCl ₃ ), TM
S): δ3.05 (3H, d, J = 4.5Hz), 7.
05 (2H, d, J = 7.0Hz), 7.27 (2H,
d, J = 8.0 Hz). ¹³ C-NMR (125 MHz (CDCl ₃ ), TM
S): δ 28.91, 105.37, 128.25, 1
28.94, 129.28, 129.72, 131.0
0, 133.08, 160.70, 164.62.

Example 5 4,6-dichloro-5- (3-chlorophenylthio) -2-methylaminopyrimidine

[Chemical 19] 2,4,6-trichloro-5- (4-chlorophenylthio) pyrimidine was replaced by 2,4,6-trichloro-5- (3-chlorophenylthio) pyrimidine obtained in the same manner as in Example 2 except that 2,4,6-trichloro-5- (4-chlorophenylthio) pyrimidine was used. In the same manner as in Example 4, crystals of the target substance (480 mg) were obtained from 2,4,6-trichloro-5- (3-chlorophenylthio) pyrimidine (1.14 g). ¹ H-NMR (500 MHz (CDCl ₃ ), TM
S): δ3.07 (3H, d, J = 5.0Hz), 7.
05-7.06 (1H, m), 7.11-7.12 (1
H, m), 7.15-7.17 (1H, m), 7.19.
-7.22 (1H, m). ¹³ C-NMR (125 MHz (CDCl ₃ ), TM
S): δ 28.70, 111.01, 125.27, 1
26.54, 126.80, 130.15, 135.0
4,137.56, 160.85, 167.00.

Example 6 4,6-dichloro-2-methylamino-5-phenylthiopyrimidine

Embedded image Same as Example 4 except that 2,4,6-trichloro-5-phenylthiopyrimidine obtained by the same method as in Example 3 was used in place of 2,4,6-trichloro-5- (4-chlorophenylthio) pyrimidine. Then 2, 4, 6
Crystals of -trichloro-5-phenylthiopyrimidine were obtained. ¹ H-NMR (500 MHz (CDCl ₃ ), TM
S): δ3.05 (3H, d, J = 5.0Hz), 5.
91 (1H, s), 7.17-7.29 (5H, m). ¹³ C-NMR (125 MHz (CDCl ₃ ), TM
S): δ 28.63, 112.07, 126.40, 1
27.50, 129.15, 135.42, 160.7
0,167.23.

Example 7 4,6-Dichloro-2-dimethylamino-5-phenylthiopyrimidine

[Chemical 21] Example 4 from 2,4,6-trichloro-5-phenylthiopyrimidine (1.00 g) obtained in the same manner as in Example 3 and dimethylamine (40% aqueous solution, 387 mg).
The target crystals (730 mg) were obtained in the same manner as. ¹ H-NMR (500 MHz (CDCl ₃ ), TM
S): δ 3.21 (6H, s), 7.5-7.20 (2
H, m), 7.22-7.30 (3H, m). ¹³ C-NMR (125 MHz (CDCl ₃ ), TM
S): δ 37.35, 112.61, 135.44, 1
38.75, 143.46, 144.90, 167.2
8, 169.08.

Example 8 4-chloro-5- (4-chlorophenylthio) -2-methylamino-6- (4-methylpiperazino) pyrimidine

[Chemical formula 22] 4,6-dichloro-5 obtained in the same manner as in Example 4
Crystals of-(4-chlorophenylthio) -2-methylaminopyrimidine (495 mg) were dissolved in 20 ml of ethanol, and N-methylpiperazine (464 mg) was added,
The mixture was heated under reflux for 3 hours. The reaction solution was cooled to −30 to −40 ° C., and the precipitated crystals were recrystallized from ethanol to obtain the target colorless crystals (460 mg). ¹ H-NMR (500 MHz (CDCl ₃ ), TM
S): δ2.27 (3H, s), 2.39 (4H, br)
t, J = 4.5 Hz), 2.98 (3H, d, J =
5.0 Hz), 3.57 (4H, br s), 5.47
(1H, br s), 6.98 (2H, d, J = 8.5
Hz), 7.22 (2H, d, J = 8.5 Hz). ¹³ C-NMR (125 MHz (CDCl ₃ ), TM
S): δ 28.36, 45.92, 47.93, 54.
90, 126.66, 129.10, 131.07, 1
36.17, 126.66, 160.54, 167.2
3,169.42. MS (EI, direct): 38
3 (M ⁺ ).

Example 9 4-Chloro-5- (3-chlorophenylthio) -2-methylamino-6- (4-methylpiperazino) pyrimidine

[Chemical formula 23] 4,6-dichloro-5 obtained in the same manner as in Example 5
A crystal of the desired product (450 mg) was obtained in the same manner as in Example 8 from the crystal of-(3-chlorophenylthio) -2-methylaminopyrimidine (480 mg). ¹ H-NMR (500 MHz (CDCl ₃ ), TM
S): δ2.26 (3H, s), 2.38 (4H, br)
t, J = 4.5 Hz), 2.99 (3H, d, J =
5.0 Hz), 3.75 (4H, br s), 5.40
(1H, br s), 6.93 (1H, ddd, J =
1.5, 2.0, 8.0 Hz), 7.02 (1H, t,
J = 2.0 Hz, 7.09 (1H, ddd, J = 1.
5, 2.0, 8.0 Hz), 7.17 (1H, t, J =
8.0 Hz). ¹³ C-NMR (125 MHz (CDCl ₃ ), TM
S): δ 28.04, 45.96, 47.95, 54.
91, 123.38, 125.01, 125.41, 1
30.00, 134.96, 161.00, 167.1
8, 167.00. MS (EI, direct): 38
3 (M ⁺ ).

EXAMPLE 10 4-Chloro-2-methylamino-6- (4-methylpiperazino) -5-phenylthiopyrimidine

[Chemical formula 24] 4,6-dichloro-2 obtained by the same method as in Example 6
A crystal of the target compound (460 mg) was obtained from the crystal of -methylamino-5-phenylthiopyrimidine (490 mg) in the same manner as in Example 8. ¹ H-NMR (500 MHz (CDCl ₃ ), TM
S): δ 2.25 (3H, s), 2.37 (4H, t,
J = 4.5Hz), 2.98 (3H, d, J = 5.0H
z), 3.77 (4H, br s), 5.40 (1H,
brs), 7.05-7.26 (5H, m). ¹³ C-NMR (125 MHz (CDCl ₃ ), TM
S): δ 28.36, 45.92, 47.88, 54.
90, 125.22, 125.38, 128.97, 1
37.49, 160.51, 167.26, 168.8
7. MS (EI, direct): 349 (M ⁺ ).

Example 11 4-Chloro-2-dimethylamino-6- (4-methylpiperazino) -5-phenylthiopyrimidine

[Chemical 25] 4,6-dichloro-2 obtained by the same method as in Example 7
In the same manner as in Example 8, crystals of the target compound (710 mg) were obtained from the crystals of -dimethylamino-5-phenylthiopyrimidine (720 mg). ¹ H-NMR (500 MHz (CDCl ₃ ), TM
S): δ 2.24 (3H, s), 2.36 (4H, br)
t, J = 5.0 Hz), 3.16 (6H, s), 3.
70 (4H, br t, J = 3.0Hz), 7.04
(2H, d, J = 8.5 Hz), 7.10 (1H, t,
J = 7.5 Hz), 7.21-7.26 (2H, m). ¹³ C-NMR (125 MHz (CDCl ₃ ), TM
S): δ36.97, 45.93, 47.95, 54.
85, 125.08, 125.36, 128.88, 1
37.70, 159.62, 167.10, 168.7
0. MS (EI, direct): 363 (M ⁺ ).

Example 12 4-chloro-6-methyl-2-methylamino-5-phenyloxypyrimidine

[Chemical formula 26] NaH (2.43 g) was suspended in benzene (60 ml), phenol (5.71 g) was added, and the mixture was heated under reflux for 5 minutes. After allowing the reaction solution to cool to room temperature, a solution of ethyl chloroacetoacetate (10 g) in benzene (10 ml)
Was dripped. The reaction solution was gently refluxed for 4 hours. The reaction solution was cooled, poured into ice water, and washed with water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure.
Purification by a conventional method gave a colorless oil (6.26 g).
NaH (1.08 g) was dissolved in ethanol (10 ml), N-methylguanidine hydrochloride (2.58 g) was added, and the mixture was stirred at room temperature for 10 minutes. The colorless oil (3.
An ethanol solution (5 ml) of 0 g) was added dropwise, and the mixture was heated under reflux for 1 hour. Concentrate ethanol under reduced pressure, add ice water,
It was neutralized with acetic acid. The precipitate was collected by filtration to give colorless crystals (2.5
2 g) was obtained. The obtained crystals (1.5 g) were dissolved in phosphorus oxychloride (6 ml) and heated under reflux for 4 hours. The reaction solution was allowed to cool to room temperature, poured into ice water, made basic with ammonia water, and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purify by a conventional method and obtain the desired product (300
mg). ¹ H-NMR (270 MHz, CDCl ₃ ) δ: 2.2
3 (3H, s), 3.00 (3H, d, J = 4.9H
z), 5.22 (1H, m), 6.79-7.32 (5
H, m).

Example 13 4-Methyl-2-methylamino-6- (4-methylpiperazino) -5-phenyloxypyrimidine

[Chemical 27] To an ethanol solution (1 ml) of 4-chloro-6-methyl-2-methylamino-5-phenyloxypyrimidine (11.2 mg) obtained in the same manner as in Example 12, was added N 2.
-Methylpiperazine (13.5 mg) was added, and the mixture was heated under reflux for 8 hr. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with chloroform. Purification by a conventional method to obtain the desired product (14 mg) as a colorless oil. ¹ H-NMR (270 MHz, CDCl ₃ ) δ: 2.0
7 (3H, s), 2.17 (3H, s), 2.22 (4
H, m), 2.93 (3H, d, J = 4.9 Hz),
3.67 (4H, m), 4.80 (1H, m), 6.7
6-7.27 (5H, m). Reference Example 1 Production of dihydropyrimidine-4,6-dione To 36 g of sodium hydride, 500 ml of dry ethanol was added dropwise. The sodium ethoxide formed was dissolved, and then 40.25 g of formamidine hydrochloride was added. After stirring at room temperature for 2 hours, the mixture was left standing overnight. After filtering the resulting solid matter, 80 g of ethyl malonate was added dropwise to the filtrate. After stirring at room temperature for 8 hours, the reaction solution was concentrated under reduced pressure. This solution was poured into ice water, and the precipitated crystals were collected by filtration. The crystals were washed with cold water and then dried. The crude crystals were recrystallized from water to obtain 25 g of dihydropyridi-4,6-dione as yellow crystals. NMR (DMSO-d6) δ (ppm); 5.21 (1H, s), 8.00 (1
H, s), 11.77 (2H, br) Reference Example 2 Preparation of 5-bromo-pyrimidine-4,6-diol 15 g of dihydropyridine-4,6-dione was dissolved in 25 ml of glacial acetic acid and heated to 70 ° C. Here, 23.3 g of bromine is mixed with 50
The solution dissolved in ml was slowly added dropwise. The reaction was cooled to room temperature and left overnight. After standing, the precipitated crystals were collected by filtration. The crude crystals were recrystallized from water to obtain 14.5 g of 5-bromo-pyrimidine-4,6-diol as orange crystals. NMR (DMSO-d6) δ (ppm); 8.18 (1H, s), 12.60
(2H, br) Example 14 Preparation of 4,6-dichloro-5-phenylsulfanylpyrimidine 207 mg of sodium hydride (60% oil dispursion) was suspended in 5 ml of dimethylformamide. To this was added 628 mg of thiophenol. Stirred at room temperature for 1 hour. (Solution 1)
On the other hand, 1.0 g of 5-bromo-pyrimidine-4,6-diol was dissolved in 5 ml of dimethylformamide (solution 2) and (solution 1).
Was added dropwise to (solution 2). After stirring at room temperature for 3 hours, the reaction solution was poured into ice water. The precipitated crystals were collected by filtration and dried. Next, the crystals were dissolved in 3 ml of phosphorus oxychloride and heated under reflux. The reaction solution was cooled to room temperature and then poured into ice water. Aqueous ammonia was added to make the mixture basic, and the mixture was extracted with methylene chloride. After the organic layer was washed with water, anhydrous magnesium sulfate was added and dried. The desiccant was removed and the solvent was evaporated under reduced pressure to give crude crystals. This was recrystallized from methanol / water to obtain 490 mg of 4,6-dichloro-5-phenylsulfanylpyrimidine as light brown crystals. NMR (CDCl ₃ ) δ (ppm); 6.89-7.02 (3H, m), 7.15
-7.20 (2H, m), 8.42 (1H, s) Example 15 Preparation of 4-chloro-6- (4-methylpiperazinyl) -5-phenylsulfanylpyrimidine 4,6-dichloro-5-phenylsulfanylpyrimidine 200
mg and N-methylpiperazine 85.7 mg were dissolved in dry ethanol and heated under reflux for 5 hours. The reaction solution was extracted with toluene and acidified with 1N hydrochloric acid. Aqueous ammonia and toluene were added to the aqueous layer, the toluene layer was separated, washed with saturated brine, and dried over anhydrous magnesium sulfate. The desiccant was removed, and the solvent was evaporated under reduced pressure to give a colorless oily substance. This was purified with a preparative TLC plate (developing solvent, chloroform: methanol = 9: 1), and 4-chloro-6
80 mg of-(4-methylpiperazinyl) -5-phenylsulfanylpyrimidine was obtained. NMR (CDCl ₃ ) δ (ppm); 2.22 (3H, s), 2.25-2.34
(4H, m), 3.71-3.80 (4H, m), 6.99-7.04 (1H, m),
7.13-7.50 (4H, m), 8.36 (1H.s) Example 16 Preparation of 4,6-dichloro-5- (4-chlorophenylsulfanyl) -pyrimidine Sodium hydride (60% oil dispursion) 249 mg was added to dimethylformamide 5 ml. Suspended in. To this was added 628 mg of 4-chlorothiophenol. The mixture was stirred at room temperature for 1 hour (Solution 1). On the other hand, 1.0 g of 5-bromo-pyrimidine-4,6-diol
Is dissolved in 5 ml of dimethylformamide (solution 2),
(Solution 1) was added dropwise to (Solution 2). After heating under reflux for 8 hours, the reaction solution was cooled to room temperature and poured into ice water. The precipitated crystals were collected by filtration, washed with water and dried. Next, the crystals were dissolved in 3 ml of phosphorus oxychloride and heated under reflux for 2 hours. The reaction solution was cooled to room temperature and then poured into ice water. Aqueous ammonia was added to make it basic, and the mixture was extracted with toluene.
After the organic layer was washed with water, anhydrous magnesium sulfate was added and dried. The desiccant was removed and the solvent was evaporated under reduced pressure to give 660 mg of 4,6-dichloro-5- (4-chlorophenyl) sulfanylpyrimidine as yellow crystals. NMR (CDCl ₃ ) δ (ppm); 7.21-7.40 (4H, m), 8.72
(1H, s) Example 17 Preparation of 4-chloro-6- (4-methylpiperazinyl) -5- (4-chlorophenylsulfanyl) pyrimidine 4,6-dichloro-5-phenylsulfanylpyrimidine 200 m
g and N-methylpiperazine 85.7 mg were dissolved in dry ethanol, and the mixture was heated under reflux for 5 hours. The reaction solution was extracted with toluene and acidified with 1N hydrochloric acid. Aqueous ammonia and toluene were added to the aqueous layer, the toluene layer was separated, washed with saturated brine, and dried over anhydrous magnesium sulfate. The desiccant was removed, and the solvent was evaporated under reduced pressure to give a colorless oily substance. This was purified with a preparative TLC plate (developing solvent, chloroform: methanol = 9: 1), and 4-chloro-6-
80 mg of (4-methylpiperazinyl) -5- (4-chlorosulfanyl) pyrimidine was obtained. NMR (CDCl ₃ ) δ (ppm); 2.25 (3H, s), 2.33-2.37
(4H, m), 3.75-3.79 (4H, m), 6.93-7.00 (2H, m),
7.20-7.27 (2H, m), 8.37 (1H, s) Example 18 Preparation of 4,6-dichloro-5- (2-chlorophenylsulfanyl) -pyrimidine Sodium hydride (60% oil dispursion) 249 mg was added to dimethylformamide 5 ml. Suspended in. To this was added 628 mg of 2-chlorothiophenol. The mixture was stirred at room temperature for 1 hour (Solution 1). On the other hand, 1.0 g of 5-bromo-pyrimidine-4,6-diol
Is dissolved in 5 ml of dimethylformamide (solution 2),
(Solution 1) was added dropwise to (Solution 2). After heating under reflux for 8 hours, the reaction solution was cooled to room temperature and poured into ice water. The precipitated crystals were collected by filtration, dried and washed with water. Next, the crystals were dissolved in 3 ml of phosphorus oxychloride and heated under reflux for 2 hours. The reaction solution was cooled to room temperature and then poured into ice water. Aqueous ammonia was added to make it basic, and the mixture was extracted with toluene.
After the organic layer was washed with water, anhydrous magnesium sulfate was added and dried. The desiccant was removed and the solvent was evaporated under reduced pressure to give 453 mg of 4,6-dichloro-5- (2-chlorophenyl) sulfanylpyrimidine as yellow crystals. NMR (CDCl ₃ ) δ (ppm); 6.91-7.56 (4H, m), 8.75
(1H, s) Example 19 Preparation of 4-chloro-6- (4-methylpiperazinyl) -5- (2-chlorophenylsulfanyl) pyrimidine 4,6-dichloro-5-phenylsulfanylpyrimidine 200 m
g and 75.6 mg of N-methylpiperazine were dissolved in dry ethanol and heated under reflux for 6 hours. The reaction solution was extracted with toluene and acidified with 1N hydrochloric acid. Aqueous ammonia and toluene were added to the aqueous layer, the toluene layer was separated, washed with saturated brine, and dried over anhydrous magnesium sulfate. The desiccant was removed, and the solvent was evaporated under reduced pressure to give a colorless oily substance. This was purified with a preparative TLC plate (developing solvent, chloroform: methanol = 9: 1), and 4-chloro-6-
(4-methylpiperazinyl) -5- (2-chlorosulfanyl)
50 mg of pyrimidine was obtained. NMR (CDCl ₃ ) δ (ppm); 2.22 (3H, s), 2.29-2.33
(4H, m), 3.75-3.80 (4H, m), 6.64-7.10 (1H, m),
7.09-7.16 (2H, m), 7.34-7.41 (1H, m), 8.39 (1H, m
s)

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display area C07D 401/12 239 C07D 401/12 239

Claims (5)

[Claims] 1. The formula [I]: [In the formula, X represents a sulfur atom or an oxygen atom. A
¹ represents a halogen atom, a lower alkyl group, a cycloalkyl group, an aryl group, a substituted lower alkyl group or a substituted cycloalkyl group when X is a sulfur atom, and a lower alkyl group or a cycloalkyl group when X is an oxygen atom. , An aryl group, a substituted lower alkyl group or a substituted cycloalkyl group. B ¹ represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, an aryl group, a substituted aryl group, an amino group or a substituted amino group. B ² represents an amino group or a substituted amino group. R ¹ is represented by formulas (1) to (6) (Y ¹ , Y ² , Y ³ , Y ⁴ , Y ⁵ , Y ⁶ and Y ⁷ are the same or different and each represents a hydrogen atom, a halogen atom, a lower alkyl group, a cycloalkyl group, a lower alkenyl group, a lower alkynyl group. , An aryl group, a heterocyclic group, a substituted lower alkyl group, a substituted cycloalkyl group, a substituted lower alkenyl group, a substituted lower alkynyl group, a substituted aryl group or a substituted heterocyclic group.). ] The pyrimidine derivative represented by these, or its pharmacologically acceptable salt. 2. The formula [II]: [Wherein A ¹ , B ¹ , X, and R ¹ have the same meanings as in claim 1. Z ¹ represents a hydrogen atom, a lower alkyl group or a substituted lower alkyl group. ] The pyrimidine derivative of Claim 1 represented by these, or its pharmacologically acceptable salt. 3. The compound according to claim 2, wherein A ¹ is a halogen atom and X is a sulfur atom, or a pharmaceutically acceptable salt thereof. 4. A compound of the formula [III]: [Wherein A ¹ , B ¹ , X, and R ¹ have the same meanings as in claim 1. A ² represents a halogen atom. Compound of the formula H-B ² [formula represented by], B ² represents an amino group or a substituted amino group. ] The pyrimidine derivative [I] of Claim 1 which makes the amine represented by these react.
Alternatively, a method for producing a pharmacologically acceptable salt thereof. 5. A compound of the formula [IV]: [In the formula, A ² represents a halogen atom. Y ¹ , Y ² ,
Y ³ , Y ⁴ and Y ⁵ are the same or different,
Hydrogen atom, halogen atom, lower alkyl group, cycloalkyl group, lower alkenyl group, lower alkynyl group, aryl group, heterocyclic group, substituted lower alkyl group, substituted cycloalkyl group, substituted lower alkenyl group, substituted lower alkynyl group, substituted Represents an aryl group or a substituted heterocyclic group. ] The compound represented by.