WO1998014430A1 - Pyrimidine derivatives - Google Patents

Abstract

Novel pyrimidine derivatives represented by general formula (I) wherein W represents optionally substituted aryl, etc.; X represents halogeno, etc.; Y represents sulfur, etc.; and A, G and Z have the meaning as defined in the following case (1) or (2): (1) A represents optionally substituted amino, etc.; G represents nitrogen; and Z represents a group represented by general formula (II) (wherein A2 represents hydrogen or optionally substituted alkyl; W1 represents optionally substituted aryl, etc.; and m and n are the same or different and each represents 0, 1 or 2); or (2) A and G form together with the carbon atom to which they are bonded an optionally substituted benzene ring; and Z represents a group represented by the following general formula: -N(Q1)Q2 (wherein Q?1 and Q2¿ are the same or different and each represents hydrogen, optionally substituted lower alkyl, etc.), which are psychotropic drugs having a potent affinity for the D4 receptor but no affinity for the αl receptor and being useful as remedies for, e.g., mental symptoms of schizophrenia, periodic psychosis, Parkinson's disease or drug abuse or those accompanying senile dementia or Alzheimer's disease.

Description

 T JP97 / 03476

 1

 Specification

 Pyrimidine derivatives Technical field

 The present invention relates to novel pyrimidine derivatives and psychotropic drugs containing them as active ingredients. Background art

 Psychotropic drugs such as phenothiazines (chlorpromazine, etc.), petit mouth phenones (haloperidol, etc.), benzamides (sulpiride), etc. are used for schizophrenia, manic depression, Parkinson's disease, and psychiatric symptoms due to substance abuse. It has been used as a useful therapeutic agent for psychiatric symptoms associated with senile dementia or Alheimer's disease, but is known to have side effects such as extrapyramidal disorders. In addition, psychotropic drugs such as chlorpromazine, haloperidol, and tiapride also have side effects such as a decrease in the level of consciousness and orthostatic hypotension in addition to the α1 receptor-blocking action.

 In schizophrenic patients, the dopamine D4 receptor is greatly increased compared to the dopamine D2 and D3 receptors, and the D4 receptor is a good research target for future antischizophrenic drugs Are known (TiPS, 15, 264 (1994)). Clozapine is a psychotropic drug with preferential affinity for the D4 receptor, has no side effects such as extrapyramidal disorders, and is resistant to treatment for typical psychotropic drugs. It is also effective for severe schizophrenia, etc., but is known to have a serious side effect of granulocytopenia.

Japanese Patent Application Laid-Open No. Hei 6-504054 describes that an aminomethylphenylimidazole derivative is a useful compound having a psychotropic effect as a specific ligand of a new type of dopamine receptor subtype, and WO95 / 18118 describes a bicyclic compound. It is described that a sex aromatic amine derivative is a useful medicine for central nervous system and cardiovascular diseases. WO 96/31488 describes pyrimidine derivatives which are effective as psychotropic drugs. Disclosure of the invention

 It is an object of the present invention to find a psychotropic drug having a strong affinity for the D4 receptor without undesirable side effects such as extrapyramidal disorders and granulocytopenia. As a result of intensive studies, the present inventors have found a novel pyrimidine derivative having a strong affinity for the D4 receptor and completed the present invention.

 That is, the present invention is as follows.

[1] Equation 1:

 [In the formula, W represents an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group or an optionally substituted heterocyclic group.

 X represents a halogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group or an optionally substituted aryl group.

 Y represents an oxygen atom or a sulfur atom.

 A, G and Z have the following meanings in the group (1) or (2).

(1) A represents an optionally substituted amino group or an optionally substituted lower alkyl group. G represents a nitrogen atom.

 Z is the formula:

N (A ² ) — (.Η ₂ ) ίίτ <^^ Ν— (CH ₂ ) _n —W ¹

(A ² represents a hydrogen atom or a lower alkyl group which may be substituted. W ¹ may represent a lower alkyl group which may be substituted, a cycloalkyl group which may be substituted, a aryl group which may be substituted or substituted. And m and n are the same or different and each represents 0, 1 or 2.)). (2) A and G are bonded to each other together with the carbon atom to which they are bonded by the formula:

(RR ² , R ³ and R ⁴ each independently represent a hydrogen atom, a halogen atom, a lower alkyl group which may be substituted, a lower alkenyl group which may be substituted, a lower alkynyl group which may be substituted, Represents a cycloalkyl group which may be substituted, a aryl group which may be substituted or a heterocyclic group which may be substituted.) Represents a ring represented by:

Z is the formula: — N (Q ^l ) Q ²

(Q ¹ and Q ² are the same or different and each represents a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group or an optionally substituted heterocyclic group, or Q ¹ and Q ² Q ² represents a 5- or 7-membered nitrogen-containing heterocyclic group which may be substituted together with the nitrogen atom bonded to each other. ]

Or a pharmacologically acceptable salt thereof.

[2] Equation 2

Wherein, X, Y, W, A 2, W 1, m and n are defined as above. A ¹ represents an optionally substituted amino group or an optionally substituted lower alkyl group. ]

Or a pharmacologically acceptable salt thereof according to [1]. [3] The compound according to [2], wherein X is a halogen atom and Y is a sulfur atom, or a pharmacologically acceptable salt thereof.

[4] W is a halogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, 1 to 5 groups independently selected from the group consisting of an aryl group and an optionally substituted heterocyclic group are phenyl groups which may be substituted [2] or [ 3] The compound of the above or a pharmacologically acceptable salt thereof. [5] W is a halogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, A phenyl group optionally substituted at the 4-position, wherein the group independently selected from the group consisting of an aryl group and an optionally substituted heterocyclic group is [2] or [3]. A compound or a pharmacologically acceptable salt thereof.

[6] The compound according to any one of [2] to [5], wherein W ¹ is an optionally substituted phenyl group, or a pharmacologically acceptable salt thereof.

[7] The compound according to any one of [2] to [6], wherein m is 0, or a pharmacologically acceptable salt thereof.

[8] The compound according to any one of [2] or [7], wherein n is 1. or a pharmacologically acceptable salt thereof. [9] Equation 3

[Wherein, X, Y, RR ² , RR ⁴ , QQ ² and W are as defined above. ] The compound according to [1] or a pharmacologically acceptable salt thereof.

[10] The compound according to [9], wherein Y is a sulfur atom, or a pharmacologically acceptable compound thereof.

[11] W is an optionally substituted lower alkyl group, an optionally substituted phenyl group, an optionally substituted pyridyl group, an optionally substituted pyrimidyl group or an optionally substituted naphthyl group [ [9] The compound according to [10] or a pharmacologically acceptable salt thereof.

[12] The compound according to any one of [9] to [11], wherein X is a halogen atom, or a pharmacologically acceptable salt thereof.

[13] A medicament comprising, as an active ingredient, the compound according to any one of [1] to [12] or a pharmacologically acceptable salt thereof. [14] A psychotropic drug comprising, as an active ingredient, the compound according to any one of [1] to [12] or a pharmacologically acceptable salt thereof. The lower alkyl group includes, for example, a linear or branched alkyl group having 1 to 6 carbon atoms. PT / JP97 / 03476

And alkyl groups such as methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 1-ethylbutyl, hexyl, Examples include 1-methylpentyl, 1-ethylbutyl, 2-methylpentyl and the like.

 Examples of the cycloalkyl group include a cycloalkyl group having 5 to 7 carbon atoms, and specific examples include cyclopentyl, cyclohexyl, and cycloheptyl.

 As the lower alkenyl, for example, an alkenyl group having 1 to 3 linear or branched double bonds having 2 to 6 carbon atoms can be mentioned, and specific examples thereof include vinyl, 1-propyl, and 2-propyl. Nyl, 1-methylvinyl, 1-butenyl, 2-butenyl, 1-pentenyl, 1-hexenyl and the like.

 Examples of the lower alkynyl include an alkynyl group having 1 to 3 straight-chain or branched triple bonds having 2 to 6 carbon atoms, and specific examples thereof include ethynyl, 1-propynyl, 2-propynyl, and 1-butynyl. , 1-pentynyl, 1-hexynyl and the like.

 Examples of the aryl group include an aryl group having 6 to 14 carbon atoms, and specific examples include phenyl, 1-naphthyl, 2-naphthyl, 1-anthranyl, 2-anthranyl, and the like.

Examples of the heterocyclic group include a 5- to 7-membered monocyclic, 9 to 10-membered cyclic, including 1 to 4 heteroatoms arbitrarily selected from the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom. Or a 12- to 14-membered tricyclic, saturated or unsaturated heterocyclic group. The nitrogen atom and the sulfur atom may be oxidized as the case may be. The point of attachment of the heterocyclic group is on any nitrogen or carbon atom. Specifically, a 6-membered monocyclic saturated heterocyclic group containing one or two heteroatoms arbitrarily selected from the group consisting of oxygen, nitrogen, and sulfur atoms such as piperidyl, piperazinyl, and morpholinyl, pyridyl, and pyridazinyl 6-membered monocyclic unsaturated heterocyclic group containing 1 or 2 heteroatoms arbitrarily selected from the group consisting of oxygen atom, nitrogen atom, sulfur atom such as 5-membered monocyclic saturated heterocyclic group containing 1 or 2 heteroatoms arbitrarily selected from the group consisting of oxygen, nitrogen, and sulfur atoms, such as phenol and pyrrolidinyl, imidazolyl, furyl, 2-oxo-1 5-membered monocyclic unsaturated heterocyclic group containing 1 to 3 heteroatoms arbitrarily selected from the group consisting of oxygen, nitrogen and sulfur atoms such as, 3-dioxorenyl and pyrrolyl, quinolyl, isoquinolyl , A 9- to 10-membered bicyclic unsaturated heterocyclic group containing 1 to 3 heteroatoms arbitrarily selected from the group consisting of oxygen atom, nitrogen atom, sulfur atom such as indolyl, and oxygen atom such as anthraquinolyl And a 12- to 14-membered tricyclic unsaturated heterocyclic group containing 1 to 3 hetero atoms arbitrarily selected from the group consisting of a nitrogen atom and a sulfur atom.

Examples of the 5- to 7-membered nitrogen-containing heterocyclic group include at least one nitrogen atom, and one or two hetero atoms arbitrarily selected from the group consisting of an oxygen atom, a nitrogen atom, and a sulfur atom. A 5- to 7-membered monocyclic saturated or unsaturated heterocyclic group which may further be included, and a 5- to 7-membered monocyclic saturated heterocyclic group is preferable. Specific examples include a 6-membered monocyclic saturated heterocyclic group such as piperidyl, piperazinyl and morpholinyl, and a 5-membered monocyclic saturated heterocyclic group such as pyrrolidinyl. Examples of the substituted lower alkyl group include a cycloalkyl group which may be substituted, a aryl group which may be substituted, a heterocyclic group which may be substituted, a halogen atom, an oxo group, --OP ¹ (P ¹ is a hydrogen atom, Represents a lower alkyl, cycloalkyl, aryl or hydroxyl modifying group), —OCOP ² (P ² represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, an aryl group or a heterocyclic group) ), — — (Ρ 3) Ρ ⁴ (Ρ ³ represents a hydrogen atom or a lower alkyl group, and P ⁴ is a modification of a hydrogen atom, a lower alkyl group, a cycloalkyl group, an aryl group, a heterocyclic group or an amino group. C (= NP ⁵ ) NHP ⁶ (where P ⁵ and P ⁶ are the same or different and each represents a hydrogen atom, a lower alkyl group, a cycloalkyl group or a guanidino group modifying group). ^{NHC (= NP 5) NHP 6} (P 5 Contact Fine P ⁶ are as defined above.), A nitro group, Shiano group, One COOP ⁷ (P ⁷ represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, Represents a modifying group for an aryl group, a heterocyclic group or a carboxyl group. ), One CON (P ⁸ ) P ⁹ (P ⁸ represents a hydrogen atom or a lower alkyl group, and P ⁹ represents a hydrogen atom, a lower alkyl group or an amide group modifying group.), One SP ^1Q (P ^1Q represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, an aryl group, a heterocyclic group or a modifying group of a thiol group.), —COP ¹¹ (P ¹¹ is a hydrogen atom, a lower alkyl group, a cycloalkyl group, ), — NHCOP ¹² (P ¹² represents a hydrogen atom, a lower alkyl group, a cycloalkyl group or an aryl group.), — S (O) _s P ¹³ (P ¹³ represents a lower alkyl group, a cycloalkyl group or a Ariru group, s is 1 or represents _{2;.), - S0 2} N (P 14) P 15 (P 14 and P ¹⁵ are the same or different from each other, a hydrogen atom, Represents a lower alkyl group, a cycloalkyl group or an aryl group.) And — OCOOP ¹⁶ (where P ¹⁶ represents a lower alkyl group, a cycloalkyl group, an aryl group or a heterocyclic group), and a lower alkyl group substituted with 1 to 5 substituents arbitrarily selected from the group of .

 Examples of such substituted lower alkyl groups include benzyl, 2-phenyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 6-phenylhexyl, 1-indolylmethyl , 2- (3-Indolyl) ethyl, bromomethyl, Bivaloyloxymethyl, 1-Ethoxycarbonyloxethyl, 5-Methyl_2-Oxo-1,3-Dioxolen-1-ylmethyl, 2-Chloroethyl , 2-dimethylaminoethyl, getylaminoethyl, 3-dimethylamino 2- (dimethylaminomethyl) propyl, 2- (1-morpholinyl) ethyl, 1-acetoxetil, 1-methoxycarbonyloxetyl, acetoxmethyl , 1-acetoxy-1-phenylmethyl, methoxycarbonylmethyl, 1-pivaloyloxityl, etc. And the like.

The substituted lower alkenyl group, a cycloalkyl group, Ariru group, a heterocyclic group, a halogen atom, - OP ¹⁷ (P ¹⁷ is a hydrogen atom, a lower alkyl group or hydroxyl group of the modifying ^{group.), - OCOP 18 (P} 18 Represents a hydrogen atom or a lower alkyl group.), Nitro group, cyano group, COOP ¹⁹ (P ¹⁹ is a hydrogen atom or a carboxyl group) Represents a decoration group. ), CON (P ⁸ ) P ⁹ (P ⁸ and P ⁹ are as defined above), CO P ²⁰ (P ^2Q represents a hydrogen atom or a lower alkyl group.) And —OCOO P ²¹ (P ²¹ represents a lower alkyl group, for example, a lower alkenyl group substituted with 1 to 5 substituents arbitrarily selected from the group Specific examples include 3-phenyl-12-propenyl, 5-methoxy-2-pentenyl, 2-carboxyvinyl and the like.

Examples of the substituted lower alkynyl group include a cycloalkyl group, an aryl group, a heterocyclic group, a halogen atom, one OP ¹⁷ (P ¹⁷ has the same meaning as described above.), — OCOP ¹⁸ (P ¹⁸ has the same meaning as described above.) ), Nitro group, cyano group, —COO P ¹⁹ (P ¹⁹ is as defined above), —CON (P ⁸ ) P ⁹ (P ⁸ and P ⁹ are as defined above), one COP ²⁰ (P ²⁰ has the same meaning as described above.) And —OCOOP ²¹ (P ²¹ has the same meaning as described above.) And a lower alkynyl group substituted with 1 to 5 substituents arbitrarily selected from the group And specifically, 3-phenyl-2-propynyl and the like.

The substituted cycloalkyl group, a lower alkyl group, Ariru group, a heterocyclic group, c androgenic atom, One 〇_P ^17, (P ¹⁷ is as defined ^{above.) - OCO P 18 (P} 18 before Symbol synonymous ), — N (P ²² ) P ²³ (P ²² represents a hydrogen atom or a lower alkyl group, and P ²³ represents a hydrogen atom, a lower alkyl group or a modifying group of an amino group.), One C (= NP ²⁴⁾ NHP ²⁵ (wherein, P ²⁴ and P ²⁵ are the same or to different dates, represents a modifying group of a hydrogen atom or Guanijino group), -. NHC (= NP 24) N HP 25 (P 24 and P ²⁵ is as defined above.), a nitro group, Shiano group, one CO OP ¹⁹ (P ¹⁹ is as defined above.), one ^{CON (P 8) P 9 (} P 8 and P ⁹ are a front Stories ), One SP ²⁶ (P ²⁶ represents a hydrogen atom, a lower alkyl group or a thiol modifying group.), —CO P ²⁰ (P ²⁰ has the same meaning as described above.) ), —NHCO P ²⁷ (P ²⁷ represents a hydrogen atom or a lower alkyl group.), — S (0) _s P ²⁸ (P ²⁸ represents a lower alkyl group, and s has the same meaning as described above.) SO 2 N (P ²⁹ ) P ^3Q (P ²⁹ and P ^3Q are the same or different and are each a hydrogen atom or a lower alkyl group. PT / JP97 / 03476

Represents 10. ) And —OCOOP ²¹ (P ²¹ has the same meaning as described above.), And a cycloalkyl group substituted with 1 to 3 substituents arbitrarily selected from the group of). Specific examples include 4-chlorochlorohexyl, 4-cyanocyclohexyl, 2-dimethylaminocyclohexyl, 4-methoxycyclohexyl and the like.

Examples of the substituted heterocyclic group include a lower alkyl group, a cycloalkyl group, an aryl group, a complex ring group, a halogen atom, an oxo group, —OP ¹⁷ (where P ¹⁷ is as defined above), and one OCOP ¹⁸ (P ¹⁸ has the same meaning as described above;;), —N (P ²² ) P ²³ (P ²² and P ²³ have the same meanings as above.), —C (= NP ²⁴ ) NHP ²⁵ (P ²⁴ and P ²⁵ is as defined above.), One NHC (= NP ²⁴ ), NHP ²⁵ (P ²⁴ and P ²⁵ are as defined above), a nitro group, a cyano group, and one COOP ⁷ (P ⁷ is as defined above) ), -CONP ⁸ P ⁹ (P ⁸ and P ⁹ are as defined above), one SP ²⁶ (P ²⁶ is as defined above), and one COP ²⁰ (P ²⁰ is as defined above). are synonymous.) one NHCOP ²⁷ (P ²⁷ is as defined above.), one ^{_{S (0) s P 28 (}} s and P ²⁸ are as defined above. :) one SO ₂ NP ²⁹ P ³⁰ (P ²⁹ and P ³⁰ are as defined above.) And —O A heterocyclic group substituted with 1 to 3 substituents arbitrarily selected from the group of COOP ²¹ (P ²¹ has the same meaning as described above.) Specifically, 1-acetyl-4- Piperidinyl, 1-benzyl-4-imidazolyl, 1-methyl-3-indolinyl, 5_methyl-12_oxo-1,1,3-dioxolen-14-yl, 5-oxo-12-tetrahydrofuranyl, 1, 3-dihydro-3-oxo-11-isobenzofuranyl and the like. Examples of the substituent in the substituted 5- to 7-membered nitrogen-containing heterocyclic group include the same substituents as those in the substituted heterocyclic group. Examples of the substituted aryl group include an aryl group substituted with 1 to 5 substituents arbitrarily selected from the group consisting of the following (a), (b) and (c).

(a) a lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, an optionally substituted cycloalkyl group, an aryl group, an optionally substituted heterocyclic group, a halogen atom, One OP ¹ (P) is as defined above; one OC OP ² (P ² is as defined above); one N (P ³ ) P ⁴ (P ³ and P ⁴ are as defined above) It is synonymous. ), — C (= NP ⁵ ) NHP ⁶ (P ⁵ and P ⁶ have the same meanings as above;;), one NHC (= NP ⁵ ) NHP ⁶ (P ⁵ and P ⁶ have the same meanings as above.) ), A nitro group, a cyano group, —COOP ⁷ (P ⁷ is as defined above), —CON (P ⁸ ) P ⁹ (P ⁸ and P ⁹ are as defined above), one SP ^{1 ( 3} (P ¹⁰ is as defined above.) one COP ¹¹ (P ¹¹ is as defined above.) one NHCOP ¹² (P ¹² is as defined _{above.), _S (0) S} P 13 (s and P ¹³ are as defined above.), - S 02 N ( P 14) P 15 (. P 14 and P ¹⁵ are the same as defined above) and single OC OOP ¹⁶ (P ¹⁶ is as defined above A group consisting of

(b) a lower alkyl group substituted with one OP ¹ (P ¹ has the same meaning as described above) or one N (P ³ ) P ⁴ (where P ³ and P ⁴ have the same meanings as above).

 (c) A lower alkyl group substituted with 1 to 5 atoms arbitrarily selected from a fluorine atom, a chlorine atom and a bromine atom.

 Here, when two substituents are adjacent to each other, they may be bonded to each other and form a 4- to 7-membered ring such as a methylenedioxy group.

 Examples of the substituted phenyl group include a phenyl group substituted with 1 to 5 substituents arbitrarily selected from the group consisting of the above (a), (b) and (c).

Specific examples of the substituted aryl group include 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 4-hydrophenyl, and 2,4-dichlorophenyl. , 4-hydroxyphenyl, 3,4-dihydroxyphenyl, 4-methylphenyl, 4-methoxyphenyl, 3,4 dimethoxyphenyl, 3,4-methylenedioxyphenyl, 4-aminophenyl, 4-guanidine Nophenyl, 4-aminomethylphenyl, 4-Cyanophenyl, 4-Carboxyphenyl, 4-Acetylphenyl, 4-Chloro-1-naphthyl, 4-Amidinophenyl, 4-Trophenyl, 4-Ethoxycarbonylphenyl, 4-Acetoki Cyphenyl, 4-benzyloxyphenyl, 2-fluoro-4-hydroxyphenyl, 5-indanyl, 4- (2 Carboxyvinyl) phenyl, 4- (2-butyl) phenyl, 3, 5-dichloro 2-hydroxy phenyl, 2,3,4-trichloromouth phenyl, 2,4,5-tricyclomouth phenyl, 2,4,6_tri (2-propyl) monophenyl, 2,5-dimethylphenyl, 2-nitrophenyl, 3-nitrophenyl Nitrophenyl, 2,4-dinitrophenyl, 4-chloro-3-nitrophenyl, 2,5-dimethyphenyl, 2,5-dimethylphenyl, 2-methoxycarbonylphenyl, 3-carboxylphenyl, 2-methoxy-5 Monocarboxylphenyl, 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-ditrifluoro Methylphenyl and the like.

 Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like.

Examples of the amino group which may be substituted include those represented by the following formula: N (Q ³ ) Q ⁴ (wherein Q ³ and Q ⁴ are the same or different and each are a hydrogen atom, a lower alkyl group which may be substituted, A cycloalkyl group or an optionally substituted heterocyclic group, or Q ³ and Q ⁴ are bonded to each other together with the nitrogen atom to which they are bonded, and And a 5- or 7-membered nitrogen-containing heterocyclic group, which may be substituted. Specifically, methylamino group, N, N-dimethylamino group, N-ethyl-N-methylamino group, N-cyclohexyl-N-methylamino group, N, N-dicyclohexylamino group, N— (4 —Methylcyclohexyl) — N-ethylamino group, piperidyl group, pyridyl group, N-methylbiperazyl group, pyridazyl group, piperazyl group, pyrrolidyl group, morphonyl group, imidazolidinyl group, pyridazolidinyl group and the like. Examples of the modifying group for the hydroxyl group, the modifying group for the amino group, the modifying group for the guanidino group, the modifying group for the carboxyl group, the modifying group for the amide group, and the modifying group for the thiol group include protecting groups that are usually used in the reaction. For example, Izumiya et al., Amino acids described in “Basic and Experimental Peptide Synthesis” (Maruzen, 1985) or “Protective Groups in Organic Synthesis” by Green et al. (Jillon Willett & Sons, 1991) Side chain protecting groups and the like can be used.

 Examples of the hydroxyl-modified group include an ether-type modified group and an acyl-type modified group. Examples of the ether-type modifying group include benzyl, 2-nitrobenzyl, 2,6-dichlorobenzyl, t-butyl, and the like, and examples of the acyl-type modifying group include a lower alkanol group. Examples of the lower alkanoyl group include a straight-chain or branched-chain alkanoyl group having 5 or less carbon atoms, and specific examples include acetyl, propanoyl, and butanoyl.

 Examples of the modifying group for the amino group include a urethane-type modifying group and an acyl-type modifying group. Examples of the urethane-type modifying group include benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, and 4-methoxybenzyloxycarbonyl. , 2-methanesulfonylethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, t-butyloxycarbonyl, fluorenyloxycarbonyl and the like. Examples of the acyl-type modifying group include formyl and acetyl Benzoyl, trifluoroacetyl, methanesulfonyl and the like.

 Examples of the modifying group for the guanidino group include urethane-type modifying groups such as benzyloxycarbonyl and t-butyloxycarbonyl, 4-toluenesulfonyl, 4-methoxybenzenesulfonyl, and nitro group.

 Examples of the carboxyl group-modifying group include ester-type modifying groups, such as lower alkyl, 2,2,2-trichloroethyl, benzyl, 4-methoxybenzyl, diphenylethyl and the like.

Examples of the modifying group for the amide group include 2,4-dimethoxybenzyl. Examples of the thiol group-modifying group include a sulfide-type modifying group. Examples thereof include jyl, 4-methylbenzyl, 4-methoxybenzyl, 4-nitrobenzyl, and acetamidomethyl.

X is preferably a halogen atom, more preferably a chlorine atom, a bromine atom, or an iodine atom, and particularly preferably a chlorine atom or a bromine atom.

 When Y is an oxygen atom, X is preferably an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group or an optionally substituted aryl group.

W is preferably an optionally substituted lower alkyl group, an optionally substituted phenyl group, an optionally substituted pyridyl group, an optionally substituted pyrimidyl group or an optionally substituted naphthyl group. More preferably, a lower alkyl group such as a methyl group, an ethyl group, and a propyl group, cyclohexyl, benzyl, acetoxmethyl, 1-acetoxityl, 1-acetox-1-phenylmethyl, pivaloyloxymethyl, and 1-bivaloyl Kishechiru etc. - OCOP ² (. P ² are as defined above) substituted lower alkyl group, 1 - main butoxycarbonyl O key Chez chill, 1 one ethoxycarbonyl O key share one OCOOP ¹ chill like ⁶ (where P ¹⁶ is as defined above), a lower alkyl group substituted with, 5-methyl-2-oxo_1,3-dioxolen-4- Lower alkyl group substituted by a substituted complex such as ylmethyl, 2- (1-morpholinyl) ethyl, 5-oxo-12-tetrahydrofuranyl, 1,3-dihydro-3-oxo-1-isobenzofuranyl Heterocyclic group such as group, substituted aryl group such as 5-indanyl group, ₃ -dimethylamino-2- (dimethylaminomethyl) propyl, 2-dimethylaminoethyl, 2-getylaminoethyl, methoxycarbonylmethyl, 2-dimethyl Examples include aminocyclohexyl and a phenyl group which may be substituted. In Formula 2, A ¹ preferably includes an amino group which may be substituted, and specific examples thereof include a methylamino group, a dimethylamino group, and an N-methylbiperazinone group. A ² is preferably a hydrogen atom and a lower alkyl group such as a methyl group, an ethyl group, and a propyl group. In addition, W ¹ is preferably an optionally substituted aryl group or an optionally substituted heterocyclic group, and particularly preferably an optionally substituted phenyl group. Preferably, Q ¹ and Q ² in Formula 3 each include a secondary or tertiary amino group.For example, preferred examples of N (Q ¹ ) Q ² include an optionally substituted pyrazinyl group , Formula:

(A ² , W m and n have the same meanings as described above.). When the compound of the present invention represented by the formula 1 has an asymmetric carbon, any of the isomers or a mixture thereof may be used, and when two or more asymmetric carbons are present, the compound may be used as an enantiomer. It may exist as a diastereomer or as a mixture thereof, for example, as a racemate. Examples of pharmacologically acceptable salts include pharmacologically acceptable addition salts with inorganic acids and organic acids, and addition salts with inorganic bases and organic bases. Examples of the addition salt with an inorganic acid include hydrochloride, hydrobromide, hydroiodide, sulfate and the like. Examples of addition salts with organic acids include acetate, oxalate, citrate, malate, tartrate, maleate, fumarate, methanesulfonate, 4-toluenesulfonate, etc. Is mentioned. Examples of the addition salt with an inorganic base include a sodium salt, a potassium salt, a calcium salt and the like. Examples of the addition salt with an organic base include amine salts such as arginine salt, lysine salt, and triethylamine salt. The compound represented by the formula 1 and the pharmacologically acceptable salts thereof also include solvates such as hydrates thereof. The compound represented by the formula 2 can be produced, for example, by the following production method.

Manufacturing method 1

[Wherein, AAW, W ¹ m and n are as defined above. X ¹ represents a halogen atom. R ⁵ represents a lower alkyl group. ]

 This production method 1 can be carried out in the same manner as the method described in J. Med. Chem., 25, 1459 (1982). Specifically, it can be carried out as follows.

 Compound (6) can be obtained by reacting malonic ester (4) with amidine or guanidine (5) in the presence of a base in a reaction inert solvent at room temperature to 80 ° C. it can. As the base used in this reaction, for example, a metal base such as sodium ethoxide can be used. As a solvent inert to the reaction, for example, an organic solvent such as ethanol can be used.

By reacting compound (6) with a brominating agent such as bromine at room temperature or the like, compound (7) is converted to Obtainable. As a reaction solvent, for example, glacial acetic acid or the like can be used. The compound (9) can be obtained by reacting the compound (7) with the compound (8) in a solvent inert to the reaction at room temperature to 150 ° C in the presence of a base. A metal base such as sodium hydride can be used as the base used in this reaction, and N, N-dimethylformamide (DMF) or the like can be used as a solvent inert to the reaction.

 The compound (10) can be obtained by reacting the compound (9) with a halogenating agent at 0 to 120 ° C. Examples of the halogenating agent include thionyl chloride 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. . Examples of the solvent used in the reaction include solvents that do not affect the reaction, and for example, solvents such as benzene, toluene, xylene, dichloromethane, chloroform, carbon tetrachloride, DMF, and methyl ether can be used. The reaction can also be carried out without a solvent. If necessary, the reaction can be carried out in the presence of an amine such as pyridine, quinoline, dimethylaniline, triethylamine or diisopropylamine. Further, a halogen exchange reaction can be performed.

 The compound of the present invention represented by (12) can be obtained by reacting the compound (10) with the amine (11) in the presence of a base, for example, at 0 to 85 ° C. As a base in this reaction, for example, an inorganic base such as potassium carbonate can be used, and as a solvent, for example, dimethoxetane, a mixed solvent of dimethoxetane and water, ethanol and the like can be used.

Alternatively, the compound (9) can be obtained by halogenating the malonic ester (4), reacting the compound (8), and then reacting it with amidine or guanidine (5). Manufacturing method 2

[Wherein, A ² , X ¹ , W, W ¹ , m and n are as defined above. A ³ represents an amino group which may be substituted, and R ⁶ represents a lower alkyl group. ]

 This Production Method 2 can be carried out in the same manner as the method described in J. Med. Chem., \ 8, 553 (1975). Specifically, it can be carried out as follows.

 Compound (14) can be obtained by oxidizing compound (13) at 0 ° C. to room temperature. Examples of the oxidizing agent used in the reaction include hydrogen peroxide, sodium periodate and the like.

 The compound (16) can be obtained by reacting the compound (14) with the barbituric acid (15) at 60 to 120 ° C. Examples of the solvent used in the reaction include acetic acid and the like, and it is also preferable to add acetic anhydride as a dehydrating agent.

Compound (17) is obtained by reacting compound (16) with a halogenating agent be able to. This reaction can be carried out under the same conditions as for the production of compound (10) in Production method 1.

 The compound (19) can be obtained by reacting the compound (17) and the amine (18) regiospecifically by limiting the molar ratio or suppressing the reaction temperature. Subsequently, in the same manner as in the production of compound (12) from compound (10) in production method 1, compound (20) can be obtained from compound (19). Manufacturing method 3

Wherein W, W ¹ , AA ² , X ¹ , R ⁵ , Y, m and n are as defined above. X ² represents an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group or an optionally substituted aryl group. X ³ represents a chlorine atom, a bromine atom, methanesulfonyloxy or 4-toluenesulfonyloxy. ]

Compound (21) is inactivated with benzene, xylene, dichloromethane, chloroform, carbon tetrachloride, methyl ether, tetrahydrofuran (THF), dioxane, etc. Compound (22) is obtained by adding 1-2 equivalents of sodium hydride and 1-1.2 equivalents of compound (8) in a neutral solvent and reacting at room temperature to 90 ° C for 5 minutes to 2 hours. Can be obtained.

 Next, compound (22) is dissolved in an alcohol such as methanol or ethanol, or in an inert solvent such as benzene, toluene, xylene, dichloromethane, chloroform, carbon tetrachloride, diethyl ether, THF, dioxane, or the like. Compound (23) can be obtained by adding an equivalent amount of amidine or guanidine (5) and reacting at room temperature to 60 ° C for 1 to 2 hours. Subsequently, compound (25) can be obtained from compound (23) in the same manner as in the production of compound (12) from compound (9) in production method 1. Manufacturing method 4

 The compound of the present invention represented by the formula 3 can be carried out in the same manner as in the method described in W096 / 31488 and J. Med. Chem., 25, 1459 (1982). Specifically, for example, it can be implemented as follows.

[Wherein, R ¹ R ² , R ³ , R ⁴ , X ¹ , QQ ² , Y and W are as defined above. ] JP9703 76

21 The compound (27) can be obtained by reacting the aniline derivative (26) with a malonic ester in the presence of a base in a solvent inert to the reaction at room temperature to 80 ° C, and then closing the ring by heating. . As the base used in this reaction, for example, a metal base such as sodium ethoxide can be used. As a solvent inert to the reaction, for example, an organic solvent such as ethanol can be used. The reaction temperature at the time of ring closure includes, for example, a range of 50 to 120 ° C. Subsequently, compound (29) can be obtained from compound (27) in the same manner as in the production of compound (12) from compound (6) in production method 1. Further, in the compound (12), the compound (20) and the compound (29), the halogen atom represented by X ¹ is converted to a substituted, lower alkyl or optionally substituted cycloalkyl group. be able to. For example, these compounds are reacted with a metal magnet in a ether solvent such as THF or getyl ether to obtain a Grignard reagent, which is then reacted with a ketone, aldehyde, epoxide, or the like corresponding to the target compound. It can be carried out by combining a reduction reaction, an oxidation reaction and the like according to the conditions.

In compound (12), compound (20) and compound (29), the halogen atom represented by X ¹ can be converted to an aryl group which may be substituted. For example, halogenated aryl compounds corresponding to the target compound and these compounds can be prepared in the presence of t-butyllithium and trisacetylacetylacetonate iron (J. Org. Chem., 48, 4728 (1983)), or In the presence of nickel tetrakistriphenylphosphine (J. Med. Chem., 26, 1653 (1983); J. Am. Chem. So, 103, 6460 (1981)), THF, DMF or dimethoxyethane It can be carried out by reacting in an inert solvent. The compound of the present invention represented by the formula 1 can be purified by a usual purification method, for example, recrystallization, thin-layer chromatography, high-performance liquid chromatography and the like. The pharmacologically acceptable salt of the compound of the present invention can be produced by a usual method. TJP97 / 03476

 22 Preferred examples of the compound of the present invention represented by the formula 1 include those shown below.

( 1

(1

LO

本発明の医薬の投与は、 通常の投与経路、 例えば経口、 筋肉内、 静脈内、 皮下、 腹腔内、 鼻腔内投与により行うことができる。 投与量及び投与回数は動物種、 投 与経路、 症状の程度、 性差、 体重等によって異なり、 特に制限されないが、 ヒト においては、 通常成人 1 日あたり 1 m g〜 1， 0 0 0 m g、 好ましくは 2 m g〜 2 0 O m gを 1 日 1回もしくはそれ以上の回数に分けて投与される。 投与剤型と しては、 例えば散剤、 細粒剤、 錠剤、 カプセル剤、 坐剤、 注射剤、 経鼻剤等が挙 げられる。 製剤化の際は、 通常の製剤担体を用い、 常法により製造する。 すなわ ち、 経口用製剤を調製する場合は、 必要に応じて、 結合剤、 崩壊剤、 潤沢剤、 着 色剤等を加えた後、 常法により、 錠剤、 顆粒剤、 散剤、 カプセル剤等とする。 注 射剤を調製する場合は、 必要により P H調製剤、 緩衝剤、 安定化剤、 可溶化剤等 を添加し、 常法により注射剤とする。

Administration of the medicament of the present invention can be carried out by a usual administration route, for example, oral, intramuscular, intravenous, subcutaneous, intraperitoneal, or intranasal administration. The dose and frequency of administration vary depending on the animal species, administration route, symptom severity, sex difference, body weight, etc., and are not particularly limited. In humans, it is usually 1 mg to 100 mg per adult day, preferably 2 mg to 20 mg is administered once or more times a day. Examples of the dosage form include powders, fine granules, tablets, capsules, suppositories, injections, nasal preparations and the like. At the time of formulation, it is manufactured by a usual method using an ordinary formulation carrier. That is, when preparing an oral preparation, a binder, a disintegrant, a lubricant, a coloring agent, etc. are added as necessary, and then tablets, granules, powders, capsules, etc. are prepared in a conventional manner. And When preparing an injection, add a PH adjuster, a buffer, a stabilizer, a solubilizing agent, etc. as necessary, and use it as an injection in the usual manner.

 The medicament of the present invention can be applied not only to humans but also to various mammals such as mice, rats, dogs, cats, cats, pomas, goats, sheep, peas, pigs, etc. . Example

 Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

Example 1

6— (1 —Benzyl-4-piperidinyl) amino 4- 4-methyl-2- (methyl-5- (4-chlorophenyl)) Preparation of pyrimidine

 (1) Production of 5-bromo-4,6-dihydroxy-2-methylpyrimidine

 Under a nitrogen atmosphere, 11.8 g of acetamidine hydrochloride was added to an ethanol solution of 20.8 g of sodium ethoxide (prepared from 7.3 g of sodium hydride and 120 ml of dehydrated ethanol), and the mixture was stirred at room temperature for 1 hour. To this, a dehydrated ethanol solution (120 ml) of 20 g of getyl malonate was added dropwise, and the mixture was refluxed for 10 hours. The mixture was cooled to room temperature, added to ice water, and further added with acetic acid to make it acidic to precipitate crystals. The crystals were collected by filtration, washed with water, and dried to obtain 19.5 g of 4,6-dihydroxy-2-methylpyrimidine as white crystals.

 Of these, 10 g was dissolved in 50 ml of acetic acid, and at 0 ° C., a solution of 16 g of bromine in acetic acid (35 ml) was added dropwise. The reaction temperature was returned to room temperature, and left as it was for 12 hours. The precipitated crystals were collected by filtration and washed with cold acetic acid to obtain 9.0 g of 5-bromo-4,6-dihydroxy-12-methylbirimidine as white crystals.

_{1 H-NMR (DMSO- d 6} , 270ΜΗζ) δ (ppm): 2.66 (3H, s)

(2) Production of 5- (4-chlorophenethylthio) 1-4,6-dichloro-1-methylpyrimidine

Under a nitrogen atmosphere, 283 mg of sodium hydride (60% in mineral oil) was suspended in 5 ml of dehydrated DMF, and a DMF solution (10 ml) of 1.41 g of 4-chlorothiophenol was dropped therein and stirred at room temperature for 1 hour. 5-promo 4,6-dihydroxy-2-methylpyrimi 3 76

 27

2.0 g was added little by little and the mixture was refluxed for 9 hours. The reaction solution was cooled to room temperature, added to ice water, and made acidic by adding dilute hydrochloric acid. The precipitated crystals are collected by filtration, washed with cold water and getyl ether, and dried under reduced pressure to give 5 g of 4- (4-chlorophenol) —4,6-dihydroxy-2-methylpyrimidine 2.7 g Was obtained as pale brown crystals. 5 g of phosphorus oxychloride was added to 1.5 g of the mixture, and the mixture was heated under reflux for 1 hour. The reaction solution was cooled, added to ice water, made basic with aqueous ammonia, and then extracted with chloroform. The organic layer is washed with a small amount of water, dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is purified by silica gel column chromatography (developing solvent: black form) to give 5- (4- 314 mg of 4,6-dichloro-2-methylpyrimidine were obtained as a colorless oil.

_{1 H-NMR (CDC1 3,} 270MHz) 8 (pm): 2.70 (3H, s), 7.16-7.41 (4H, m)

(3) Preparation of 6- (1-benzyl-1-4-pyridinyl) amino-4-chloro-2-methyl-5- (4-chlorophenylthio) pyrimidine

 5- (4-chlorophenethylthio) 1,4,6-dichloro-12-methylpyrimidine 500 mg, 4-amino-1-benzylpiperidine 470 mg, potassium carbonate 113 mg are dissolved in 10 ml of methylethyl ketone to which lOmg of water is added. And heated to reflux for 4 hours. Water was added to the reaction solution and extracted with toluene. The organic layer was acidified by adding dilute hydrochloric acid, and the aqueous layer was separated. Toluene and aqueous ammonia were added to the aqueous layer to make it basic, and the organic layer was separated. The organic layer was washed with a small amount of saturated saline, and dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (solvent: chloroform: methanol = 36: 1) to give 6- (1-benzyl 4-piperidinyl) amino-4-chloro 310 mg of 2-methyl-5- (4-chlorophenylthio) pyrimidine was obtained as a colorless oil.

_{1 H-NMR (CDC1 3,} 270ΜΗζ) δ (ppm): 1.37 - 1.52 (2H, m), 1.82 one 1.96 (2H, m), 2.12 - 2.23 (2H, m), 2.49 (3H, s), 2.63 -2.74 (2H, m), 3.44 (2H, s), 4.00-4.04 (1H, m), 5.92 (1H, d, J = 7.9Hz), 7.01-7.06 (2H, m), 7.19- 7.33 (7H, m) Example 2

 6- (1 Benzyl 4-piperidinyl) Methylamino 4- 4-chloro-2- 2-methylamino-5-phenylthiopyrimidine

 (1) Preparation of 4-aminomethyl-1-benzylpiperidine

571 mg of 4-aminomethyl-piperidine and 633 mg of benzyl chloride were dissolved in 5 ml of ethyl alcohol. 690 mg of potassium carbonate and lOmg of potassium iodide were added thereto, and the mixture was refluxed for 6 hours. The reaction solution was cooled to room temperature, water was added, and extracted with toluene. The organic layer was washed with dilute hydrochloric acid and a small amount of saturated saline, and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and preparative TLC (solvent: Purification with chloroform: methanol = 4: 1) yielded 760 mg of 4-aminomethyl-1-benzylpiperidine as a colorless oil.

_{^{1 H-NMR (CDC1 3,}} 270MHz) δ (ppm): 1.15 - 1.40 (5H, m), 1.61 - 1.73 (2H, m), 1.89 - 1.98 (2H, m), 2.49 - 2.57 (2H, m) , 2.83-2.84 (2H, m), 3.48 (2H, s), 7.21-7.31 (5H, m)

(2) Production of 5-bromo-2-methylamino-4,6-dihydroxypyrimidine In a nitrogen atmosphere, sodium ethoxide in ethanol solution (sodium hydride

27.5 g of N-methyldanidine hydrochloride was added to the mixture (prepared from 12 g and 300 ml of dehydrated ethanol), followed by stirring at room temperature for 1 hour. Next, a dehydrated ethanol solution (300 ml) of 43.5 g of getyl malonate was added dropwise, and the mixture was refluxed for 5 hours. After cooling to room temperature, the reaction solution was added to ice water, acetic acid was added, and the mixture was made acidic to precipitate crystals. The crystals were collected by filtration, washed with water, and dried to obtain crude crystals. By recrystallizing this from water, 19.5 g of 2-methylamino-1,4,6-dihydroxypyrimidine was obtained as white crystals. Of these, 10 g was dissolved in 40 ml of glacial acetic acid, and a solution of 14.6 g of bromine dissolved in 40 ml of glacial acetic acid was added dropwise at 70 ° C. The reaction temperature was returned to room temperature, and left as it was for 12 hours. The precipitated crystals were collected by filtration and washed with cold acetic acid to obtain crude crystals. This was recrystallized from water to give 6.1 g of 5-promo-2-methylamino-4,6-dihydroxypyrimidine as light orange crystals.

_{1 H-NMR (DMS0- d 6} , 270ΜΗζ) δ (ppm): 2.78 (3H, d, J = 4.9 Hz), 6,73 (1H, br), 11.0 - 11.2 (2H, br)

(3) Manufacture of 4,6-dichloro mouth-2-methylamino-5-phenylthiopyrimidine Under a nitrogen atmosphere, 259 mg of sodium hydride (60% in mineral oil) is suspended in 5 ml of dehydrated DMF, and 991 mg of thiophenol is added here. Was added to a DMF solution (10 ml), and the mixture was stirred at room temperature for 1 hour. Then, 2 g of 5-promo 2-methylamino-4,6-dihydroxypyrimidine was added little by little, and the reaction solution was heated to reflux for 3 hours. Then, the reaction solution Was cooled to room temperature, added to ice water, and acidified by adding diluted hydrochloric acid. The precipitated crystals were collected by filtration, washed with cold water and diethyl ether, and dried under reduced pressure to obtain 2.3 g of 4,6-dihydroxy-12-methylamino-15-phenylthiopyrimidine as white crystals. . To 2.0 g of the mixture, 3.3 ml of phosphorus oxychloride was added, and the mixture was heated under reflux for 1 hour. The reaction solution was cooled, added to ice water, made basic with ammonia water, and then extracted with chloroform. After the organic layer was washed with a small amount of water, it was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: chloroform) to obtain 980 mg of 4,6-dichloro-2-methylamino-5-phenylthiopyrimidine as a colorless oil. Was.

_{^{1 H-NMR (CDC1 3,}} 270MHz) δ (ppm): 3.05 (3H, d, J = 4.9 Hz), 5.63 (1H, br), 7.15 one 7.30 (5H, m)

(4) Production of 6- (1-benzyl-4-piperidinyl) methylamino-4-chloro-2-methylamino-5-phenylthiopyrimidine

 150 mg of 4,6-dichloro-1-methylamino-5-phenylthiopyrimidine, 218 mg of 1-benzyl-4-aminomethyl-piperidine, llOmg of potassium carbonate are added to 5 ml of methyl ethyl ketone to which 20 mg of water is added, and heated for 10 hours. Reflux. Water was added to the reaction solution, extracted with toluene, diluted hydrochloric acid was added to the organic layer, and the aqueous layer was separated. The aqueous layer was made basic by adding toluene and aqueous ammonia, and the organic layer was separated. The organic layer was washed with a small amount of saturated saline, and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and the residue is purified by preparative TLC (solvent: chloroform: methanol = 9: 1) to give 6- (1-benzyl-4-piberidinyl) methylamino-1-chloro-2- 100 mg of methylamino-5-phenylthiopyrimidine was obtained as pale red crystals.

¹ H-NMR (CDCU, 270 MHz) δ (ppm): 1.15-1.28 (2H, m), 1.40-1.56 (2H, m), 1.80-1.90 (2H, m), 2.79-2.83 (2H, m), 2.96-2.98 (3H, d), 3.22 3.36 (2H, m), 3.45 (2H, s), 5.00-5.14 (1H, m), 6.06 (1H, br), 7.08 7.16 (2H, m), 7.20-1.30 (6H, m)

Preparation of 6- (N- (1-benzyl 4-piberidinyl) -N-methylamino) 1-4-chloro-1- 2-methylamino-5-phenylthiopyrimidine

 (1) Production of 4,6-dichloro_2-methylamino-5-phenylthiopyrimidine 4.90 g of methylphenylsulfoxide was dissolved in 20 ml of acetic acid, and 3.84 g of barbituric acid and 3.68 g of acetic anhydride were added. The mixture was heated and stirred for 7 hours. lOinl of water was added and the reaction was cooled to room temperature. The precipitated crystals were collected by filtration and washed with acetone to give 7.5 g of methylphenylsulfonium barbitilide as colorless crystals.

_{1 H-NMR (CDC1 3,} 500MHz) δ (ppm): 3.46 (3H, s), 7.57 - 7.59 (3H, m), 7.73 - 7.75 (2H, m), 10.27 (2H, m)

 7.5 g of the methylphenylsulfonium barbitilide obtained above was dissolved in 20 ml of phosphorus oxychloride, 1 ml of N, N-dimethylaniline was added, and the mixture was heated under reflux for 24 hours. Ice water was added, and the precipitated crystals were collected by filtration and washed with water to give 2.70 g of 2,4,6-trichloro-5-phenylthiopyrimidine as colorless crystals.

_{1 H-NMR (CDC1 3,} 500MHz) 8 (ppm): 7.26 -7.33 (5H, m) P 703476

 32

1.14 g of 2,4,6-trichloro-5-phenylthiopyrimidine was dissolved in 6 ml of methylethyl ketone, and 3 ml of water and 270 mg of methylamine (40% aqueous solution) were added at 0 to 5 ° C. After stirring for 30 minutes, the temperature was gradually raised to room temperature, and 5 ml of a 30% aqueous sodium hydroxide solution was added dropwise. After vigorous stirring at room temperature for 2 hours, 495 mg of 4,6-dichloro-2-methylamino-5-phenylthiopyrimidine was obtained.

_{^{1 H-NMR (CDC1 3,}} 500MHz) δ (ppm): 3.05 (3H, d, J = 5.0Hz), 5.91 (1H, s), 7.17 - 7.29 (5H, m)

(2) Preparation of 6- (N- (1-benzyl-4-piberidinyl) 1-N-methylamino) 1-4-chloro-1-2-methylamino-1-5-phenylthiopyrimidine

 4,6-Dichloro mouth_2-Methylamino-5-phenylthiopyrimidine 44 mg, 1-benzyl-4-methylaminopiperidine 47 mg, lium carbonate 1 lmg were added to 5 ml of methylethyl ketone to which a small amount of water was added. The mixture was refluxed for 9 hours. Water was added to the reaction solution, extracted with toluene, diluted hydrochloric acid was added to the organic layer, and the aqueous layer was separated. The aqueous layer was made basic by adding toluene and aqueous ammonia, and the organic layer was separated. The organic layer was washed with a small amount of saturated saline and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and the residue is purified by preparative TLC (solvent: black form: methanol = 4: 1) to give 6- (N- (1-benzyl-4-piberidinyl) _N-methylamino) 40 mg of 1-4-methyl-2-methylamino-5-phenylthiopyrimidine were obtained as pale red crystals.

_{^{1 H-NMR (CDC1 3,}} 270MHz) δ (ppm): 1.61 - 1.82 (6H, m), 2.81 one 2.86 (2H, m), 2.94 (3H, s), 2.95 (3H, d, J = 7.6 Hz ), 3.37 (2H, s), 4.23 (1H, m), 5.37 (1H, br), 7.01-7.34 (ΙΟΗ'm)

Preparation of 6- (1-Benzyl-1-piperidinyl) amino-1 4-methyl-2-methylamino-5-methylthiopyrimidine P 7 76

 33

 4,6-Dichloro-1-methylamino-5-methylthiopyrimidine (J. Med. Chem., 18, 553 (1975)) 100 mg, 4-amino-1-benzylpiperidine 127 mg, potassium carbonate 62 mg, water 10 mg Was added to 5 ml of methyl ethyl ketone, and the mixture was heated under reflux for 7 hours. Water was added to the reaction solution, extracted with toluene, diluted hydrochloric acid was added to the organic layer, and the aqueous layer was separated. The aqueous layer was made basic by adding toluene and aqueous ammonia, and the organic layer was separated. The organic layer was washed with a small amount of saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by preparative TLC (solvent: chloroform-form: methanol = 9: 1) to give 6- (1-benzyl-1-piperidinyl) amino-4-chloro- 130 mg of 2-methylamino-5-methylthiopyrimidine were obtained as pale red crystals.

_{^{1 H-NMR (CDC1 3,}} 270MHz) 8 (ppm): 1.45 - 1.59 (2H, m), 1.86 - 1.99 (2H, m), 2.10 (3H, s), 2.13 - 2.18 (2H, m), 2.70 ― 2.81 (2H, m), 2.86 (3H, d, J = 4.6 Hz), 3.47 (2H, s), 3.85 (1H, m), 4.93 (1H, br), 6.11 (1H.d, J = 7.3 Hz), 7.18-7.27 (5H, m) Example 5

 2-(1 Benzylpiperidine-1 4) 1-4-Chloro-1- 3-phenylthioquinoline

-CH ₂ -Ph

乾燥 DMFlOmlに、 2， 4ージクロロー 3—フエ二ルチオキノリン 200mg、 1 一 ベンジルー 4—アミノビペリジン 440mg、 炭酸カリウム 320mg、 およびヨウ化力 リウム 10mgを加え、 4時間加熱還流させた。 反応液を室温にもどし、 トルエンで 抽出した。 つぎに 1規定の塩酸水を加え、 水層を酸性として分液した。 この水層 に 2 8 %アンモニア水を加えて塩基性として、 トルエンで抽出した。 少量の飽和 食塩水で、 有機層を洗浄し、 無水硫酸マグネシウムで乾燥させた。 乾燥剤をろ別 し、 溶媒を減圧下留去させて、 粗生成物を得た。 これを分取用薄層クロマトダラ フィ一に付し （展開溶媒： クロ口ホルム： メタノール = 3 0 : 1 ) の目的物（Rf=0. 5) 180mgを淡黄色の結晶として得た。

200 mg of 2,4-dichloro-3-phenylthioquinoline, 440 mg of 1-benzyl-4-aminobiperidine, 320 mg of potassium carbonate, and 10 mg of potassium iodide were added to the dried DMFlOml, and the mixture was heated under reflux for 4 hours. The reaction solution was returned to room temperature and extracted with toluene. Next, 1N hydrochloric acid aqueous solution was added, and the aqueous layer was acidified and separated. The aqueous layer was made basic by adding 28% aqueous ammonia, and extracted with toluene. The organic layer was washed with a small amount of saturated saline and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was distilled off under reduced pressure to obtain a crude product. This was subjected to preparative thin-layer chromatography, and 180 mg of the desired product (Rf = 0.5) as a developing solvent (chloroform: methanol = 30: 1) was obtained as pale yellow crystals.

] _{H- NMR (CDC1 3, 500MHz)} δ (ppm): 7,97 (1H, d, J = 8.0 Hz), 7.92 (1H, d, J = 8.0 Hz), 7.68 (1H, dd, J = 8.0 and 8.0 Hz), 7.44 (1H, dd, J = 8.0 and 8.0 Hz), 7.22-7.30 (3H, m), 6.90-7.16 (2H, m), 6.02 (1H, d, J = 8.5 Hz), 3 90-4.00 (1H, m), 3.45 (2H, s), 2.66-2.76 (m, 2H), 2.04-2.14 (m, 2H), 1.86-1.96 (m, 2H), 1.52-1.62 (m, 2H)

_{^{13 C-NMR (CDC1 3,}} 125MHz): 157.3, 155.8, 148.6, 138.0, 135.1, 131.1, 129.3, 129.2, 129.0, 128.2, 127.2, 127.1, 126.3, 126.1, 125.2, 124.3, 120. 0, 67.0, 62.8 , 51.6, 33.6 Example 6

Production of 4-alk- mouth-2- (4-methyl-1-piperazinyl) 3-phenylthioquinoline

The title compound was obtained in the same manner as in Example 5 using the corresponding starting materials. C ¹ H_NMR (CDCI3, 270 MHz) 8 (ppm): 8.08 (1H, dd, J = 8 and 1 Hz), 7.84 (1 H, dd, J = 8 and 1 Hz), 7.65 (1H, ddd, J = 8 , 8 and 1 Hz), 7.41 (1H, ddd, J = 8, 8 and 1 Hz), 7.1-7.3 (3H, m), 7.0-7.1 (2H, m), 3.4-3.5 (4H, br), 2.4-2.5 (4H, m), 2.27 (3H, s)

_{^{13 C-NMR (CDC1 3,}} 125MHz): 161.2, 150.0, 146.9, 135.9, 130.9, 128.9, 127.9, 127.1, 125.9, 125.0, 124.9, 123.9, 120.0, 54.8, 49.7, 46.1 Example 7

 2— (4— (Naphthalene 1—2—1—piperazinyl)

Production of 3-phenylthioquinoline

 The title compound was obtained in the same manner as in Example 5 using the corresponding starting materials.

One _{NMR (CDC1 3, 500MHz) δ} (ppm): 8.19 (1H, d, J = 8.5 Hz), 7.98 (1H, d, J = 8.5 Hz), 7.80 - 7.84 (3H, m), 7.75 - 7.76 ( 1H, m), 7.72 (1H, ddd, J = 8.5, 7.0 and 1.5 Hz), 7.51-7.56 (2H, m), 7.43-7.49 (2H, m), 7.21 (1H, ddd, J = 8.0, 8.0 and 1.5 Hz), 7.11 (1H, dd, J = 7.5 and 7.5 Hz), 7.01 (1H, dd, J = 7.5 and 1.5 Hz), 3.75 (2H, s), 3.45-1 3.55 (4H, br ), 2.65-2.70 (4H, br)

¹³ C—NMR (CDCI3, 125 MHz): 163.0, 157.2, 148.3, 137.7, 135.5, 133.3, 132.8, 131.1, 129.1, 128.0, 127.8, 127.7, 127.4, 126.6, 126.3, 126.0, 125.7, 125.5, 124.8, 119.2, 63.5, 53.9, 52.0 Example 8

 Production of 4-chloro-2- (4-phenethyl-1-piperazinyl) _3-phenylthioquinoline

 The title compound was obtained in the same manner as in Example 5 using the corresponding starting materials.

_{'H-NMR (CDC1 3,} 270ΜΗΖ) δ (ppm): 8.11 (1H, d, J = 8.3 Hz), 7.93 (1H, d, J = 8.3 Hz), 7.67 (1H, ddd, J = 8.5, 7.0 and 1.0 Hz), 7.49 (1H. dd. J = 7.3 an d 7.3 Hz), 7.1-7.3 (8H, m), 6.94 (2H, d, J = 7.3 Hz), 3.35-3.55 (4H, br), 2.75-2.81 (2H, m), 2.61-2.67 (6H, m)

¹³ C-NMR (CDClg, 125 MHz): 163.0, 157.2, 148.3, 137.7, 135.5, 133.3, 132.8, 131.1, 129.1, 128.0, 127.8, 127.7, 127.4, 126.6, 126.3, 126.0, 125.7, 125.5, 124.8, 119.2, 63.5, 53.9, 52.0 Example 9

2- (1-Benzyl-1-4-) 1-4-Chloro-1- 3-Propylthioquinoline

 The title compound was obtained in the same manner as in Example 5 using the corresponding starting materials.

] H-NMR (CDCI3, 270MHz) δ (ppm): 7.88 (1H, d, J = 8 Hz), 7.80 (1H, d, J = 8 Hz), 7.56 (1H, dd, J = 8 Hz, 8Hz) ), 7.34 (1H, dd, J = 8 Hz, 8Hz), 7.1-7.3 (5H, m), 6.17 (1H, d, J = 9.6 Hz), 3.75-3.95 (1H, m), 3.45 (2H, s), 3.30 (1H, qq, J = 6.6 Hz), 2.70-2.85 ( 2H, m), 1.90-1.15 (4H, m), 1.55-1.70 (2H, m), 1.19 (6H, d, J = 6.9 Hz)

_{^{13 C - NMR (CDC1 3,}} 125MHz): 157.5, 155.7, 148.1, 138.0, 130.5, 129.2, 129.1, 128.2, 127.1, 124.9, 124.2, 119.4, 111.1, 82.9, 55.5, 51.9, 33,9, 33.8, 23.2 Example 10

 4-Mono — 2- (4- (2-cyclohexyl) ethyl) 1-piperazinyl) 1-3-phenylthioquinoline

 The title compound was obtained in the same manner as in Example 5 using the corresponding starting materials.

! H-NMR (CDCI3, 270MHz) 5 (ppm): 8.17 (1H, dd, J = 8 and 1 Hz), 7.97 (1H, dd, J = 7 and 1 Hz), 7.70 (1H, ddd, J = 8, 7 and 1 Hz), 7.52 (1H, ddd, J = 8, 7 adn 1 Hz), 7.0-7.25 (3H, m), 6.9-7.0 (2H, m), 3.46 (4H, br), 2.56 (4H, br), 2.19 (2H, d, J = 7.1 Hz), 1.6-1.8 (6H, m), 1.2-1.25 (1H, m), 1.1-1.2 (4H, m), 0.8-1.0 ( 2H, m) Reference example 1

3-bromo-2,4-dihydroxyquinoline

2,4-Dihydroxyquinoline 16. Dissolve lg in 25 ml of glacial acetic acid and heat to 70 ° C with stirring. To this solution, 75 ml of glacial acetic acid in which 16 g of bromine was dissolved was slowly dropped. After completion of the dropwise addition, the reaction solution was returned to room temperature and stirred for 4 hours. Next, The reaction was poured into ice water. The mixture was left for a while, and the precipitated solid was collected by filtration. The crude product was recrystallized from ethanol to obtain 16.Og as a light brown crystal (yield 67%).

_{^ -NMR (CD 3 0D, 270MHz} ) δ (ppm): 6.97 - 7.13 (2H, m), 7.29 - 7.36 (1 H, m), 7.71 one 7.78 (1H, m) Reference Example 2

 2,4-dihydroxy-3-phenylthioquinoline

 Under a nitrogen atmosphere, 770 mg of sodium hydride was suspended in 100 ml of dry DMF. Here, 3.21 g of thiophenol was dripped slowly. After the reaction solution was stirred at room temperature for 1 hour, 3-promo 2,4-dihydroxyquinoline 7.Og was added. After the reaction solution was stirred at room temperature for 3 hours, it was poured into a small amount of ice water. Next, acetic acid was added for neutralization. The precipitated solid was collected by filtration and washed with getyl ether. After drying the solid, it was recrystallized from ethanol to give 2.94 g of the desired product as pale brown crystals.

_{! H-NMR (DMSO- d 6} , 270MHz) 8 (ppm): 11.6 (1H, br), 11.2 (1H, br), 7.9 1 (1H, d, J = 7.3 Hz), 7.60 (1H, ddd, J = 7.7, 7.7 and 0.8 Hz), 7.35 (1H, d, J = 7.3 Hz), 7.18-7.28 (3H, m), 7.06-7.14 (2H, m) Reference example 3

 2,4-dihydroxy-1-isopropylthioquinoline

 The title compound was obtained in the same manner as in Reference Example 2 using the corresponding starting materials.

^ -NMR (CD3OD, 300MHz) 5 (ppm): 7.95 (1H, dd, J = 8.1 and 0.9Hz), 7.55 (1H, ddd, J = 7.1, 7.1 and 1.3 Hz), 7.31 (1H, d, J = 8.1 Hz), 7.23 (1H, ddd, J = 8.1, 7.1 and 0.9 Hz), 3.37 (1H, qq, J = 6.8 and 6.8 Hz), 1.23 (6H, d, J = 6.8 Hz) Reference example 4

 2. 4-Dichloro-3-phenylthioquinoline

 1.4 ml of phosphorus oxychloride was added to 2,4-dihydroxy-13-phenylthioquinoline l.Og, and the mixture was heated under reflux for 1 hour. After cooling to room temperature, the reaction solution was gently poured into ice water. Next, 28% aqueous ammonia was gently added to make it basic. This was extracted using black-mouthed form. The separated organic layer was washed with water, and then dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was distilled off under reduced pressure to obtain a crude product. This was subjected to silica gel column chromatography (developing solvent: black-mouthed form) to obtain 880 mg of the target compound as pale-light-colored crystals.

] _{H- NMR (CDC1 3, 270MHz)} δ (ppra): 7.22 - 7.32 (5H, m), 7.69 - 7.74 (1H, m), 7.82 one 7.88 (1H, m), 8.26 one 8.30 (1H, m)

_{^{1 3 C- NMR (CDC1 3,}} 125MHz): 154.5, 150.8, 150.0, 134.6, 132.0, 129.2, 129.9, 128.5, 128.4, 126.8, 126.7, 126.0, 125.4 Reference Example 5

 2,4-dichloro-3-isopropylthioquinoline

 The title compound was obtained in the same manner as in Reference Example 4 using the corresponding starting materials.

 H—NMR (CDCI3, 270 MHz) δ (ppm): 1.31 (2H, d, J = 6.9 Hz), 3.67 (1H, qq, J = 6.9 and 6.9 Hz), 7.66 (1H, ddd, J = 6.9, 6.9 and 1.3 Hz), 7.78 (1H, ddd, J = 6.9, 6.9 and 1.3 Hz), 8.01 (1H, ddd, J = 6.9, 1.3 and 0.6 Hz), 8.23 (1H, ddd, J = 6.9, 1.3 and 0.6 Hz) Example 1 1

Human dopamine D4 receptor and dopamine D2 receptor binding activity.

 1) Experimental method for human dopamine D4 receptor activity

The activity of the compound was determined using a D4 receptor membrane preparation prepared from CH0-K1 cells transfected with human D4 receptor cDNA according to the method described in Nature, 350, 610-614 (1991). The inhibitory rate of the radioligand [ ³ H] -spiperone to the binding reaction to the D 4 receptor membrane standard by a predetermined concentration of the test compound was determined.

 2) Experimental method for human dopamine D2 receptor activity

 The inhibition rate was determined in the same manner as described above using the human D2 receptor cDNA.

 3) Result

 Table 1 shows the binding activity of the compounds as Ki values. table 1

 Compound 04 binding activity (:) D 2 binding activity (Ki: nM) Compound 1.9 209 of Example 3

 Compound of Example 56.7 2 2 4

 Compound of Example 7 1 1.5 7 8 6 Industrial Applicability

 The novel pyrimidine derivative of the present invention is a psychotropic drug having a strong affinity for the D4 receptor and no affinity for the α1 receptor, for example, schizophrenia, manic depression, Parkinson's disease, substance abuse It is useful as a remedy for psychiatric symptoms caused by senile dementia or psychiatric symptoms associated with Alzheimer's disease.

Claims

Scope of Claim Formula: wherein W is an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group or an optionally substituted heterocyclic ring Represents a group. X represents a halogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group or an optionally substituted aryl group. Y represents an oxygen atom or a sulfur atom. A, G and Z have the following meanings in the group (1) or (2). (1) A represents an optionally substituted amino group or an optionally substituted lower alkyl group. G represents a nitrogen atom.  Z is the formula: — N

(A ² represents a hydrogen atom or an optionally substituted lower alkyl group. W ¹ represents an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group or an optionally substituted lower alkyl group. M and n are the same or different and each represents 0, 1 or 2.)). (2) A and G are bonded to each other together with the carbon atom to which they are bonded by the formula:

(RR ² , R ³ and R ⁴ each independently represent a hydrogen atom, a halogen atom, a lower alkyl group which may be substituted, a lower alkenyl group which may be substituted, a lower alkynyl group which may be substituted, Represents a cycloalkyl group which may be substituted, a aryl group which may be substituted or a heterocyclic group which may be substituted.) Represents a ring represented by: Z is the formula: I N (Q ^l ) Q ² (Q ¹ and Q ² are the same or different and each represents a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group or an optionally substituted heterocyclic group, or Q ¹ and Q ² Q ² represents a 5- or 7-membered nitrogen-containing heterocyclic group which may be substituted together with the nitrogen atom bonded to each other. ] Or a pharmacologically acceptable salt thereof. 2. Equation 2:

[Wherein, X, Y, W, A ² , W m and n have the same meanings as in claim 1]. A ¹ represents an optionally substituted amino group or an optionally substituted lower alkyl group. ] 2. The compound according to claim 1, which is represented by: or a pharmacologically acceptable salt thereof. 3. The compound according to claim 2, wherein X is a halogen atom and Y is a sulfur atom, or a pharmaceutically acceptable salt thereof. 4. W is a halogen atom, an optionally substituted lower alkyl group, an optionally substituted 独立 independently from the group consisting of cycloalkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted aryl and optionally substituted heterocyclic 4. The compound or a pharmaceutically acceptable salt thereof according to claim 2, wherein 1 to 5 arbitrarily selected groups are optionally substituted phenyl groups. 5. W is a halogen atom, an optionally substituted lower alkyl group, an optionally substituted cycloalkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, an optionally substituted The compound according to claim 2 or 3, wherein a group arbitrarily selected from the group consisting of a good aryl group and an optionally substituted heterocyclic group is a phenyl group optionally substituted at the 4-position. Pharmacologically acceptable salt. 6. The compound or its pharmaceutically acceptable salt of any one of W ¹ is claims 2 to 5 is a phenyl group which may be substituted. 7. The compound according to any one of claims 2 to 6, wherein m is 0, or a pharmacologically acceptable salt thereof. 8. The compound according to any one of claims 2 to 7, wherein n is 1, or a pharmacologically acceptable salt thereof. 9. Equation 3:

[Wherein, X, Y, RR ² , R ³ , R ⁴ , Q ^1, Q ² and W have the same meanings as in claim 1]. ] 2. The compound according to claim 1, which is represented by: or a pharmacologically acceptable salt thereof. 10. The compound according to claim 9, wherein Y is a sulfur atom, or a pharmacologically acceptable thereof; fa. 1 1. W is an optionally substituted lower alkyl group, an optionally substituted phenyl group, an optionally substituted pyridyl group, an optionally substituted pyrimidyl group or an optionally substituted naphthyl group. 9. The compound according to 9 or 10 or a pharmacologically acceptable salt thereof. 12. The compound according to any one of claims 9 to 11, wherein X is a halogen atom, or a pharmacologically acceptable salt thereof. 1 3. A medicament comprising the compound according to any one of claims 1 to 12 or a pharmacologically acceptable salt thereof as an active ingredient. 14. A psychotropic drug containing the compound according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient.