WO1998009960A1

WO1998009960A1 - 2,4-disubstituted pyrimidine derivatives, process for producing the same, and medicinal compositions containing the same

Info

Publication number: WO1998009960A1
Application number: PCT/JP1997/003079
Authority: WO
Inventors: Teruya Murata; Katsunori Kondo; Kiyoshi Furukawa; Makoto Oka
Original assignee: Dainippon Pharmaceutical Co., Ltd.
Priority date: 1996-09-04
Filing date: 1997-09-03
Publication date: 1998-03-12
Also published as: ZA977427B; ID17076A; AR009523A1; AU4134297A

Abstract

2,4-Disubstituted pyrimidine derivatives represented by general formula (I) or physiologically acceptable acid-addition salts thereof, wherein X represents -O- or -NR4-; R1 represents H, lower alkyl, etc.; R2 represents lower alkyl, lower alkenyl, etc.; R3 represents H, lower alkyl, etc.; R4 represents H or lower alkyl; R5 represents H, lower alkyl, etc. or halogeno, hydroxy(lower)alkyl, lower alkoxy(lower)alkyl, etc.; R6 represents H, lower alkyl, etc. or hydroxy(lower)alkyl, lower alkoxy(lower)alkyl, etc., or R5 and R6 may form together -(CH2)n- (wherein n is 3 to 6); and A represents optionally substituted heteroaryl or optionally substituted phenyl. These compounds are expected to be useful as remedies and preventives for central diseases, for example, diseases associated with anxiety, such as neurosis and psychosomatic disorder, depression and epilepsy; circulatory diseases such as angina pectoris and hypertension; immunologic nervous diseases such as multiple sclerosis; or immunologic inflammatory diseases such as rheumatism.

Description

Specification

2,4-disubstituted pyrimidine derivatives, their preparation and pharmaceutical compositions containing them

Branch art

The present invention relates to a novel 2,4-disubstituted pyrimidine derivative which selectively acts on peripheral benzodiazepine receptors, more specifically, an amide amide moiety in the side chain at the 4-position of the pyrimidine ring, and a 2-position of the pyrimidine ring. The present invention relates to a 2,4-disubstituted pyrimidine derivative having an unsubstituted or substituted heteroaryl group or an unsubstituted or substituted phenyl group, a method for producing the same, and a pharmaceutical composition containing the same.

Background art

The central nervous system of mammals, including humans, has three benzodiazepine (hereinafter sometimes abbreviated as “BZ”) recognition sites, which are called “central ( _ωι , ω ₂ )” and

"Peripheral-type (omega _3)" Benzojiazepin is referred to as receptor (hereinafter, respectively "BZ w ₁ receptor", also referred to as "Betazetaomega ₂ receptor" and "ΒΖ> ₃ receptor"). Among them, peripheral ΒΖ receptors are ubiquitously distributed in peripheral tissues and organs (kidney, liver, heart, etc.), and especially endocrine organs such as adrenal gland and testis, mast cells, lymphocytes, macro cells Recently, there is increasing interest in the physiological role of phages, platelets, etc. because of their high density in cells deeply involved in the inflammatory immune system. On the other hand, in the brain, glial cells are abundant in the mitochondrial membrane, are involved in the uptake of cholesterol into the mitochondrial membrane, are passed through pregnenolone, and are called neurosteroids, such as aropregnanolone and arotetrahydrodeoxycorticosterone ( It is thought to affect the biosynthetic pathway to THDOC). Therefore, when the peripheral 型 receptor is stimulated, Of neurosteroids is promoted by the binding mechanism to a specific recognition site for neurosteroids present in the aminobutyric acid A receptor (hereinafter sometimes abbreviated as “GAB A _A receptor”). It is thought to affect the C 1 ion channel opening process [Romeo, E. et al., J. Pharmacol. Exp. Ther., 262, 971-978 (1992)].

A compound having a non-BZ skeleton and selectively exhibiting an affinity for a peripheral BZ receptor has been reported in JP-A-58-201756 (= EF-A-942771). Since then, considerable numbers have been reported in patent applications and the like. However, no compound has been put to practical use as a pharmaceutical.

Compounds having a non-BZ skeleton and exhibiting selective affinity for peripheral BZ receptors are described in, for example, JP-A-62-5946 and JP-A-2-32058. The compounds described are known.

JP-A-62-5946 [= USP 4788199, EP-A-205375 (patent family)] discloses that amides represented by the following formula bind to peripheral BZ receptors. However, it is described as being useful as an anxiolytic, antispasmodic and antianginal, and a therapeutic agent for immunodeficiency symptoms.

(Wherein, A represents a nitrogen atom or = CH—,

B represents a nitrogen atom or == CH—,

V and W may be the same or different; hydrogen, halogen, Each having 1 to 3 carbon atoms such as alkyl or alkoxy,

Z is attached in the ortho or para position with respect to B and represents phenyl, phenyl, pyridyl, or from halogen, alkyl and alkoxy, respectively having 1 to 4 carbon atoms, alkoxy, trifluoromethyl and nitro. Phenyl substituted by one or two substituents selected,

X- (CH ₂ ) _n — (CHR) _m — CONR iR? Is bonded at the ortho or para position with respect to B, R represents hydrogen or alkyl having 1 to 3 carbons,

And R ₂ may be the same or different and each have

Linear or branched alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, phenyl, each alkyl group having 1 to 3 carbon atoms, and cycloalkyl having 3 to 6 carbon atoms Represents phenylalkyl or cycloalkylalkyl, or alkenyl having 3 to 6 carbon atoms in which the double bond is not located at the 1,2-position with respect to the nitrogen atom; ? ! Pee! ^ And, together with the nitrogen atom to which they are attached, may form a pyrrolidine, piperidine, morpholine or thiomorpholine ring,

X one CHR ₃ -, one NR ₄ -, one SO-, one S0 ₂ -, an oxygen or sulfur,

R 3 represents a hydrogen atom or an alkyl having 1 to 3 carbon atoms,

R ₄ represents an alkyl having 1 to 3 carbon atoms,

m is 0 or 1, and

n is 0, 1 or 2,

As however a condition, X is one SO-, one S0 ₂ - or a NR ₄ - when showing a is equal to 1 at least the sum of m + n, and A and B are each Resona represents nitrogen atom Then, when Z is in the para position with respect to B, X is not a single CHR ₃ --and indicates = 〇11, B indicates nitrogen, Z is in the ortho position with respect to B, and X is an acid. When R represents hydrogen, the sum of m + n is other than 1 and excludes 2-phenyl-14-quinolyl-1-N, N-dimethylcarbamate)

JP-A-2-32058 (= EP-A-346208, US Pat. No. 5,026,1111) discloses that 4-amino-3-carboxyquinolines represented by the following formulas for peripheral BZ receptors in vitro and in vivo. It is described as having affinity and can be used as a prophylaxis and treatment of human cardiovascular disease, or as an anti-allergic agent, and for the prevention or treatment of infectious symptoms, or the treatment of anxiety symptoms.

(Wherein, R丄and R 2 each is hydrogen, alkyl of C i-C _6, or C ₂ - Arukeniru of C _6, or is selected from phenyl or benzyl, or and R _2, it binds them strength ^s Together with the nitrogen atom present, form a C ₄ -C ₈ saturated heterocycle, wherein R ₃ is selected from hydrogen, Ci—C ₆ alkyl, phenyl or C ₇ —C ₉ phenylalkyl,

R 4 is selected from hydrogen or C 1 -C ₄ alkyl;

R ₅ and R ₆ are each hydrogen or halogen, a force selected from C 1 -C ₃ alkyl or alkoxy, nitro or trifluoromethyl, or Forming a methylenedioxy group,

Z is OR _7, wherein R ₇ is selected from hydrogen or C! -C ₆ alkyl; NR ₈ R ₉ , wherein R ₈ and R ₉ are each hydrogen, 1 C ₄ alkyl, phenyl or benzyl; alkyl C〗 one C _4; chosen) benzyl having a hetero atom, or a Ariru of C ₄ one C ₆ without,

R ₁₀ is hydrogen, C—C ₄ alkyl or phenyl (provided that when Z is not benzyl or aryl, R ₃ is not H. The phenyl and benzyl groups are halogen, 1 C ₃ alkoxy, alkyl or thioalkyl, May be substituted by nitro, trifluoromethyl or hydroxy, where alkyl and alkoxy are straight-chain, branched or cyclic),

n is 0, 1, or 2, p is 0 or 1, and one of the symbols A, B, C, and D is N, and the others are CH, or A, B, C, and D each represent CH.)

On the other hand, some acetate amide derivatives having a 2-phenyl-4-pyrimidinylamino moiety are known. For example, U.S. Pat. No. 3,363,036 discloses that a compound represented by 2- (5-cyano-12-phenyl-2-pyrimidinylamino) acetoamide is a 5-amino-2,6-disubstituted compound. As an intermediate for the synthesis of H-pyrro [2,3-d] pyrimidines, US Pat. No. 3,363,045 discloses 2_ (5-cyano 6-methylamino-2-phenyl-2-pyrimidinyl The compound represented by (amino) acetoamide is only described as an intermediate for the synthesis of 4,5-diamino-17H-pyrro [2,3-d] pyrimidines. It has not been.

Also, Pharmazie, 43. 537-538 (1988) states that 2- (5-acetyl-6-methyl- 2-phenyl-1-4-pyrimidinylthio) -1-N- (4-chlorophenyl) acetoamide and 2- (5-acetyl-6_methyl-12-phenyl-2-4-pyrimidinylthio) -1-N- (4-methylphenyl) Several compounds represented by acetoamide have been described as synthetic intermediates for thieno [2,3-d) pyrimidine derivatives. In addition, it is stated that 2— (5-acetyl-1-methyl-2-phenyl-1-phenylpyrimidinylthio) -1-N— (4-chlorophenyl) acetoamide has antibacterial activity against Baci us sufatiis. I have.

Disclosure of the invention

The present inventors have conducted intensive studies to obtain a compound that selectively and strongly acts on the _BZW3 receptor, and as a result, a 2,4-disubstituted pyrimidine derivative represented by the following formula (I) has been developed. The present inventors have found that the present invention meets the purpose and completed the present invention.

The present invention relates to novel 2 acts selective and potent in beta Zeta omega ₃ receptor, 4-di-substituted pin Rimijin derivatives, more particularly having a Heteroariru group or phenylene Le group at the 2-position of the pyrimidine, 4 It is an object of the present invention to provide a 2,4-disubstituted pyrimidine derivative having an acetate amide moiety at the side chain. In particular, an object of the present invention is to provide a useful compound having an anxiolytic effect and a compound useful for treating an immune disease. Another object of the present invention is to provide a method for producing the compound. Still another object of the present invention is to provide a pharmaceutical composition containing the compound. These and other objects and advantages will be apparent to those skilled in the art from the following description.

According to the present invention, a 2,4-disubstituted pyrimidine derivative represented by the following formula (I) and a physiologically acceptable acid addition salt thereof (hereinafter, also referred to as “compound of the present invention”): A method for producing the same and a pharmaceutical composition containing the same are provided.

(Wherein X represents —0— or 1 NR ₄ —, represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, or a cycloalkyl (lower) alkyl group;

R ₂ represents a lower alkyl group, a lower alkenyl group, a cycloalkyl group, an unsubstituted or substituted phenyl group, an unsubstituted or substituted phenyl (lower) alkyl group, or an unsubstituted or substituted heteroaryl group;

R ₃ represents a hydrogen atom, a lower alkyl group or a hydroxy (lower) alkyl group,

R 4 represents a hydrogen atom or a lower alkyl group,

R 5 represents any group included in the following group (a) and group (b): group (a) ——

A hydrogen atom, a lower alkyl group and a lower alkenyl group;

Group (b) ——

Halogen atom, hydroxy (lower) alkyl group, lower alkoxy (lower) alkyl group, unsubstituted or substituted benzyloxy (lower) alkyl group, acyloxy (lower) alkyl group, amino group, mono- or di-lower alkylamino group, acylamino Group, amino (lower) alkyl group, mono- or di-lower alkylamino (lower) alkyl group, nitro group, carbamoyl group, mono- or di-lower alkyl group, rubamoyl group, carboxyl group, protected carboxyl group, carboxy (Lower) alkyl groups, protected power Ruboxy (lower) alkyl group and group represented by the following formula

_{- CON (R 9) - (} CH 2) m -N (R 1 0) (R 1 1)

(Wherein R ₉ , R ₁₎ and R 2 are the same or different and each represent a hydrogen atom or a lower alkyl group, and m represents 1, 2 or 3);

Does R ₆ mean any group included in the following groups (c) and (d):

Group (c) ——

A hydrogen atom, a lower alkyl group and a trifluoromethyl group;

Group (d) ——

Halogen atom, lower alkoxy group, hydroxy (lower) alkyl group, lower alkoxy (lower) alkyl group, unsubstituted or substituted benzyloxy (lower) alkyl group, acyloxy (lower) alkyl group, amino group, mono or di Lower alkylamino, arylamino, aryl (lower) alkylamino, acylamino, amino (lower) alkyl, mono- or di-loweralkylamino (lower) alkyl, nitro, carbamoyl, mono- or mono- Di-lower alkyl groups rubamoyl group, formyl group, lower alkanoyloxy group, aroyloxy group, aryl (lower) alkyloxy group, carboxyl group, protected carboxyl group, carboxy (lower) alkyl group, protected power ruboxyl (lower) ) Alkyl group, lower Groups represented by alkylthio groups and the following formula

-CON (R ₉ )-(CH ₂ ) _m -N (R ₁₀ ) (R ₁₁ )

(Wherein, R ₉ , R j ₀ , R ii and m have the same meaning as described above); or R _c and R _{6 are} linked together to form one (CH ₂ ) _n — (where n is 3, 4, 5 or 6)

A represents an unsubstituted or substituted heteroaryl group or a group represented by the following formula,

(In the formula, R ₇ represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a trifluoromethyl group, a hydroxy group, an amino group, a mono- or di-lower alkylamino group, a cyano group or a nitro group. And R ₈ represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group)

Provided that (i) one of R ₂ and A is an unsubstituted or substituted heteroaryl group,

(ii) when R ₅ is any group included in the group (a), R ₆ means any group included in the groups (c) and (d);

(iii) When R ₅ is any group included in the above group (b), R ₆ means any group included in the above group (c))

The physiologically acceptable acid addition salt of the compound represented by the formula (I) is a physiologically acceptable acid addition salt of the compound of the formula (I) when it has a sufficient basicity to form an acid addition salt. Acid addition salts, for example, inorganic salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, and phosphate, and maleate, fumarate, oxalate, quencher Organic acid salts such as acid salts, tartrate salts, lactates, benzoates, and methanesulfonates. Since the compound represented by the formula (I) and the acid addition salt thereof may exist in the form of hydrate and Z or solvate, these hydrates and solvates are also included in the compound of the present invention. Is performed. The compounds of formula (I) optionally have one or more asymmetric carbon atoms and may give rise to geometric isomerism. Thus, the compounds of formula (I) may optionally exist in more than one stereoisomer. These stereoisomers, mixtures and racemates thereof are included in the compounds of the present invention.

The terms used in this specification are described below.

The lower alkyl group and the lower alkoxy group mean those having 1 to 6 carbon atoms unless otherwise specified, and may be linear or branched. Specific examples of the “lower alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, and hexyl. R ₃ , R ₄ , R ₅ , R ₆ , R ₇ and R ₈ are preferably lower alkyl groups having 1 to 4 carbon atoms. Specific examples of the “lower alkoxy group” include methoxy, ethoxy, propoxy, and butoxy. The term "lower alkenyl group" means a group having 3 to 6 carbon atoms having one double bond other than between 1 and 2, and includes, for example, aryl and 2-butenyl. The “cycloalkyl group” means one having 3 to 8 carbon atoms, and specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The “cycloalkyl (lower) alkyl group” means an alkyl group having 1 to 4 carbon atoms substituted by the above “cycloalkyl group”, and examples thereof include cyclopropylmethyl, cyclopentylmethyl, and cyclohexylmethyl. . “Halogen atom” means fluorine, chlorine, bromine, and iodine.

The "unsubstituted or substituted Fuweniru group", halogen atom, C] - _(3-alkyl,

C j C g Alkoxy, trifluoromethyl, trifluoromethoxy, amino, mono or di (C i C s) alkylamino, cyano, and nitro which may be substituted with one or two selected from dinitro A group, for example phenyl; 2—, 3- or 4-monochlorophenyl; 2-, 3- or 4-bromophenyl; 2-, 3- or 4-fluorophenyl; 2,4-dichlorophenyl; 2,4-dibromophenyl; 2,4-difluoro 2-, 3- or 4-methylphenyl; 2-, 3- or 4-methoxyphenyl; 2-, 3- or 4-trifluoromethylphenyl; 2-, 3- or 4-Trifluoromethoxyphenyl; 2 —, 3- or 4-aminophenyl; 2-, 3- or 4-methylaminophenyl; 2-, 3- or 4-dimethylaminophenyl; 2-, 3- or 4-cyanophenyl; 2 —, 3— or 4 12 trophenyl.

The following formula:

Specific examples of the group represented by are those including those enumerated in the above-mentioned “unsubstituted or substituted phenyl group”. ^ Preferred specific examples include phenyl, 4- or 3-chlorophenyl, and 4- Or 3-bromophenyl, 4- or 3-fluorophenyl, 4-methoxyphenyl. The “unsubstituted or substituted phenyl (lower) alkyl group” means an alkyl group having 1 to 4 carbon atoms which is substituted by the above “unsubstituted or substituted phenyl group”, for example, benzyl; — Or 4-chlorobenzyl; 4-bromobenzyl; 3- or 4-fluorobenzyl; 4-methylbenzyl; 4-methoxybenzyl; phenethyl; 2- (4-chlorophenyl) ethyl.

Specific examples of the "aryl group" include phenyl and naphthyl. An “unsubstituted or substituted heteroaryl group” is defined as C! ~ C ₃ alkyl or trifluorome To a 5- or 6-membered monocyclic heteroaryl group or a 5- or 6-membered bicyclic ring containing at least one nitrogen atom, oxygen atom or sulfur atom which may be substituted with tyl Means a teraryl group, for example 2-, 3- or 4-pyridyl; 5-methyl-2-pyridyl; 5-trifluoromethyl-2-pyridyl; 2- or 3-1000 phenyl; 2- or 3-furyl; 2-, 4- or 5-pyrimidinyl; 2- or 3-birazinyl; 1-pyrazolyl; 2-imidazolyl; 2-thiazolyl; 2-isoxazolyl; 5-methyl-3-isoxazolyl; quinolyl; isoquinolyl.

“Hydroxy (lower) alkyl group” means an alkyl group having 1 to 4 carbon atoms substituted with a hydroxy group, and includes, for example, hydroxymethyl, 2-hydroxyethyl, and 3-hydroxypropyl. “Lower alkoxy (lower) alkyl group” means an alkyl group having 1 to 4 carbon atoms substituted with alkoxy having 1 to 4 carbon atoms, and includes, for example, methoxymethyl, ethoxymethyl, 2-methoxethyl, —Methoxypropyl. “Unsubstituted or substituted benzyloxy (lower) alkyl group” is selected from halogen, C ₃ alkyl and C 1: ₃ alkoxy

A hydroxy (lower) alkyl group substituted by one or two benzyl groups which may be partially substituted with phenyl, for example, benzyloxymethyl; 2-, 3- or 4-chloro 2-benzylbenzyloxymethyl; 4-fluorobenzyloxymethyl; 2,4_ or 3,4-dichlorobenzyloxymethyl; 4-methylbenzyloxymethyl; 2- , 3- or 4-methoxybenzyloxymethyl; 2-benzyloxyshetyl. The "Ashiru group", Arukanoiru group or a halogen carbon atoms. 2 to 4, C 1 through C ₃ alkyl or C 1

-C ₃ alkoxy substituted means may also base Nzoiru groups such Asechi 2-, 3- or 4-chlorobenzoyl; 2-, 3- or 4-bromobenzoyl; 2-, 3- or 4-fluorobenzoyl; 4-methylbenzoyl, 4-methylbenzoyl; Methoxybenzoyl. The term “acyloxy (lower) alkyl group” means a lower alkyl group substituted with an acyloxy derived from the above-mentioned “acyl group”, for example, acetoxymethyl; benzoyloxymethyl; 4-cyclobenzoyloxymethyl. 3-bromobenzoyloxymethyl; 4-fluorobenzoyloxymethyl; 2-methylbenzoyloxymethyl; 4-methoxybenzoyloxymethyl.

"Mono- or di-lower alkylamino group" means an alkyl group having 1 to 4 carbon atoms or two or more substituted amino groups, such as methylamino, ethylamino, propylamino, dimethylamino, getylamino, dipropylamino, And ethyl methylamino. Specific examples of the "arylamino group" include phenylamino and naphthylamino. Specific examples of the “aryl (lower) alkylamino group” mean an amino group substituted with one alkyl group having 1 to 4 carbon atoms, which is substituted with the above “aryl group”, such as benzylamino. Can be The term "acylamino group" means an amino group substituted with the above-mentioned "acyl group", such as acetylamino, propionylamino, benzoylamino, 4-chlorobenzoylamino, 4-fluorobenzoylamino. Lumino. The term "amino (lower) alkyl group" means an alkyl group having 1 to 4 carbon atoms, which is substituted with an amino group, and includes, for example, aminomethyl, 2-aminoethyl, and 3-aminobutyryl. The “mono- or di-lower alkylamino (lower) alkyl group” means an alkyl group having 1 to 4 carbon atoms substituted by the above-mentioned “mono- or di-lower alkylamino group”, such as methylaminomethyl, dimethyla. Minomethyl. "Mono or di-lower alkyl group" refers to a substituted or unsubstituted alkyl group having 1 to 4 carbon atoms. A carbamoyl group, for example, methylcarbamoyl, dimethylcarbamoyl, getylcarbamoyl, dipropylcarbamoyl. Specific examples of the “lower alkenyl group” include acetoxy, propionyloxy, and butyryloxy. Specific examples of the “aroyloxy group” include benzoyloxy. The “aryl (lower) alkyloxy group” means an alkyloxy group having 1 to 4 carbon atoms substituted by the above “aryl group”, and examples thereof include a benzyloxy group.

The term “protected carboxyl group” refers to a protecting group that can be eliminated by hydrolysis or hydrogenolysis, such as a C 1 -C ₄ alkyl group or halogen, C i-(: ₃ alkyl and C ₃ -C ₃ alkoxy. A carboxyl group protected by a benzyl group which may be substituted with one or two, and specific examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, benzyloxycarbonyl, black port base Nji Ruo alkoxycarbonyl, 4-full O b benzyl O key aryloxycarbonyl, 4-methylbenzyl O alkoxycarbonyl, 4-main butoxy benzyl O key sheet force carbonyl include ^s, main butoxycarbonyl, ethoxycarbonyl, benzyl Roxycarbonyl is preferred "Protected carboxy (lower) alkyl" Means an alkyl group having 1 to 4 carbon atoms, which is substituted by the above-mentioned "protected carboxyl group", for example, methoxycarbonylmethyl, ethoxycarbonylmethyl, benzyloxycarbonylmethyl and 2-ethoxycarbonyl. “Lower alkylthio group” means a thio group substituted with the above “lower alkyl group”, and examples include methylthio, ethylthio, and propylthio.

The following formula:

-CON (R _Q )-(CH ₂ ) _m -N (R ₁₀ ) (R ₁₁ ) Specific examples of the group represented by include dimethylaminomethylcarbamoyl and 2-dimethylaminoethylcarbamoyl.

Preferred among the compounds of the present invention are those wherein in formula (I), R is a lower alkyl group and R ₂ is a lower alkyl group, an unsubstituted or substituted phenyl group or an unsubstituted or substituted heteroaryl group. , R ₃ , R ₅ , R ₆ , A and X are the same as described above, and physiologically acceptable acid addition salts thereof.

Among the compounds of the present invention, more preferred are those in the formula (I), wherein R i is a methyl group, an ethyl group, a propyl group, an isopropyl group or a butyl group, and R ₂ is an ethyl group, a propyl group, isopropyl group, butyl group, phenyl group, halogen, C ^ - C ₃ Aruki Le, C i-C ₃ alkoxy, Amino, nitro, phenyl group substituted with Shiano or triflate Ruo Russia methyl, pyridyl group, thienyl group, furyl group, a thiazolyl group or methyl ^-? 3-isoxazolyl a group, R ₃ is a hydrogen atom, an R ₅ is a hydrogen atom or a lower alkyl group, 11 _six-lower alkyl group, a lower alkoxy group, a lower § alkoxy A (lower) alkyl group or a lower alkylamino group, wherein A and X are the same as described above, and a physiologically acceptable acid addition salt thereof.

Among the compounds of the present invention, more preferred are those wherein in formula (I), R is a methyl group, an ethyl group, a propyl group, an isopropyl group or a butyl group, and R ₂ is an ethyl group, a propyl group or an isopropyl group. group, butyl group, phenyl group, halogen, ₍₁ - ○ ₃ Aruki Le one C ₃ alkoxy, Amino, nitro, phenyl group substituted with Shiano or triflate Ruo Russia methyl, pyridyl group, thienyl group, furyl group, thiazolyl Or a methyl-3-isoxazolyl group, R ₃ is a hydrogen atom, and R ₅ is a hydrogen atom. And R ₆ is a methyl group, a methoxy group, a methoxymethyl group or a methylamino group, and A and X are the same as those described above, and the physiologically acceptable compounds thereof. It is an acid addition salt.

More preferable compounds include compounds represented by the following formulas (Ia) and (Ib) and physiologically acceptable acid addition salts thereof.

(Wherein X, represents 10— or 1 NR ₄ , 1, represents a methyl group, ethyl group, propyl group, isopropyl group or butyl group, and R ₂ , represents a methyl group, a propyl group, An isopropyl group, a butyl group, a phenyl group or a halogen- or methoxy-substituted phenyl group, R ₄ ′ represents a hydrogen atom, a methyl group or an ethyl group, and A ′ is unsubstituted or substituted Pyridyl, phenyl or furyl)

(Wherein X, represents 10— or 1 NR ₄ ′ —, represents a methyl group, ethyl group, propyl group, isopropyl group, or butyl group, and R ₂ , represents an ethyl group, a propyl group, With isopropyl, butyl, phenyl or halogen or methoxy R ₄ , represents a hydrogen atom, a methyl group or an ethyl group; R ₅ , represents a hydrogen atom or a methyl group; R ₆ ′ represents a methoxy group, a methoxymethyl group; A or A, means an unsubstituted or substituted pyridyl group, a phenyl group or a furyl group)

In the above formulas (Ia) and (Ib), a compound wherein X 'is 1 NH- or 10- and A' is a pyridyl group or a phenyl group is preferable.

Specific examples of particularly preferred compounds include, for example, the following compounds and physiologically acceptable acid addition salts thereof.

2-[5,6-Dimethyl-1- (4-pyridyl) -1-4-pyrimidinylamino] 1 N-methyl-1 N-phenylacetamide,

N-Ethyl_2- [5,6-Dimethyl_2- (4-pyridyl) -14-pyrimidinylamino] -1-N-phenylacetamide,

N- (4-chlorophenyl) -1-2- [5,6-dimethyl-2- (3-pyridyl) -14-pyrimidinylamino] N-methylacetoamide,

N-Ethyl 2- (5,6-Dimethyl_2- (2-Chenyl) -14-Pyrimidinylamino) 1-N-phenylacetamide,

N-ethyl-1 2— [5,6-dimethyl-2- (4-pyridyl) -14-pyrimidinyloxy] 1-N-phenylacetamide,

N, N-Jetyl 1 2— [5,6-Dimethyl-2- (4-pyridyl) _ 4-pyrimidinylamino] acetamide,

2-[6-Methylamino-1 2- (4-pyridyl) -1-4-pyrimidinylamino] 1 N 1 methyl 1 N-phenylacetamide,

2- [6-Methoxy-1 2- (4-pyridyl) -1 4-pyrimidinylamino] -1 N-meth Chill N-phenylacetamide,

N-methyl-1- (5-methyl-6-methylamino-2- (4-pyridyl) -14-pyrimidinyloxy) -1-N-phenylacetamide,

N-methyl-2- (5-methyl-1-6-methylamino-2- (4-pyridyl) _4-pyrimidinylamino) -1-N-phenylacetamide,

N— (3-chlorophenol) N—methyl 2— [5-Methyl-6-methylamino-12- (3-pyridyl) -14-pyrimidinylamino] acetamide,

N— (3-chlorophenol) 1 2— 6-Methoxy-5-methyl 2- (3-pyridyl) -14-pyrimidinylamino 1-N-methylacetamide,

N— (4-Methoxyphenyl) -1-2— [6-Methoxy-5-methyl-2- (3-pyridyl) _4-pyrimidinylamino] 1-N-methylacetamide,

2-[6-Methoxymethyl-5-methyl-2- (4-pyridyl) -14-pyrimidinylamino] 1-N-methyl-1-N-phenylacetamide,

2- [5,6-dimethyl-1- (3-pyridyl) -14-pyrimidinyloxy] -1-N, N-dipropylacetamide, and

2- [5,6-Dimethyl-1- (2-chenyl) -14-pyrimidinylamino] -1-N, N-diproviracetamide.

Specific examples of the compounds included in the present invention include the compounds shown in the following Tables 1 to 4 and physiologically acceptable acid addition salts thereof in addition to the compounds of the Examples described later. In the present specification, the following abbreviations may be used for simplification of the chemical structural formulas of the compounds, Tables 1 to 4, and Reference Examples and Examples described later.

M e: methyl group

E t: ethyl group

P r: propyl group i-Pr: Isopropyl group

B υ: butyl group

P h: phenyl group

Therefore, even if the Th-4-C1 4 one black port phenyl group, 2-pyridyl - represents a 5-CF ₃ 5-tri Furuoromechiru one 2 _ pyridyl group.

table 1

R, R 丄, 2 A X i-rr i-rr 4- ー Hilling ΝΗ

D 1

Me rh— — 1 4

4 Μ

Me ヒ

Me Ph-2-Br 4—Hill ΝΗ

JVlc rn— — I U2 4 レ ° π ノ Vn 11 / Ι Π

Me Ph - ₂ - H 2 4 over fire. Rishi's ΝΗ

° 1 'no,' il, MU

ΓΠ— — 4 i 4 7 ΙΝΠ ri n n = ri ΓΠ レ

4— Reno) 1 レ, ΐ MΝUΠ

Et Et 2—Hee.シ i-Pr i-Pr 3—Hirishiru ΝΗ iwe ΓΠ— ^ 9 レ u

One i |

7 レ π π

Me Ph-3-F 3 -Piril ΝΗ

Me Ph-4-Br 2 -Piryl ΝΗ

Et Ph- 4- CI 3 -Piryl ΝΗ

Et Ph-4-F 2-Pirils "ΝΗ

Me Ph-2-N0 ₂ 3-Pyryl ΝΗ

Me Ph-2-NH ₂ 3 -Piricil "ΝΗ i -Pr i -Pr 2-Tinyl ΝΗ

Bu Bu 3 -Chenil ΝΗ

Me Ph- 3- Br 2-Chenyl ΝΗ

Me Ph-4-F 3 -Chenyl ΝΗ

Et Ph- 4- CI 2-Chenyl ΝΗ Table 1 continued

R ₂ AX i-Pr i-Pr 2-furyl NH

Bu Bu 3-Ruffle NH

Me Ph-3-Br 2 -Frill NH

Me Ph-4-F 3 -Frill NH

Et Ph-4-Cl 2-furyl NH

Pr Pr 4-Pirish "; L Ne

Et Et 2-Chenille N e

Me Ph 3-Pirishi "le NMe

Me Ph-4-Cl 4-pyryl NMe

Me Ph-4-F 2 -Frill NMe

Me Ph-4-O e 4-pyryl NMe

Pr Pr 4-Piryl NEt

Pr Pr 3 -Pirishi ', Le NEt i-Pr i-Pr 2-Chenyl NEt

Me Ph 4-Pilisir "NEt

Et Et 4-Pirishi "ル〇 i-Pr i-Pr 4-Pirishi ', Le 〇

Bu Bu 4-hi. Rishiru 0

Me Ph-4-0Me 4 -Piril 0

Me Ph-4-Cl 4 -Piryl 〇

Me Ph-2-F 4 ピリ

Et Ph-4-Cl 2-Chenyl 0

Et Ph-4-Cl 2-furyl 0

Et Ph-4-F 2-Chenyl 0 Table 2

D, AX ^κ 1 ^K 2

Pr Pr 3 4-hi. Rishi Pere NH

Pr Pr 4 4-h. Rishi "le NH rr rr-Yale Ale J

Pr Pr 3 2-Frill 0

Pr Pr 4 4 -Pirisile 0

Pr Pr 54-h. Rishi, Le 0

Me Ph 3 4-Pirishi * NH

Me Ph 4 2-CH NH

Me Ph 5 4—Hee. Rishi "le NH

Me Ph- 4-CI 64-Pyryl NH

Me Ph- 4- CI 3 4-pyri / le 〇

Me Ph- 4-CI 4 2-Frill 0

Me Ph-4-F 5 4 1 Pillar 0

Me Ph-4-F64

Table 3

R ₂ R s R ₆ A

Me Ph-CHgCFtCHs H4-H. Rishire

Me Ph Cl H 4-pyryl

Me Ph-C CH ₂ OH H 3-pyryl

Pr Pr-CH ₂ OC Ph H 4-Pirishiru

Pr Pr -CH ₂ OCOC tH ₃ H 2 -Chenyl

Pr Pr -CH ₂ OCOPh H ₂ -Frill

Me Ph -CH ₂ 0Me H 4 -Pirils "

Me Ph-Awake e H 4-Piril

Me Ph -NEt ₂ H 4-

Me Ph -CH ₂ NH ₂ H 4-pyryl

Me Ph -CH ₂ NMe ₂ H 4 -Pyryl

Me Ph -NH ₂ H 4-pyryl

Me Ph -NHCOCH3 H 4 -Piryl

Me Ph -CONHCH ₂ CH ₂ NMe ₂ H 4-pyridyl "

Me Ph -CONH ₂ H 4-H. Rishi ...

Pr Pr -CONHMe H 4-Pyryl

Pr Pr H 2-chill

Me Ph -CONHCH ₂ NMe ₂ H 3 -Pyryl

Me Ph -COOH H 2-furyl

Me Ph -COOCH ₂ Ph H 4—Piricil

Pr Pr -CH ₂ solid H 4

Pr Pr-CH ₂ concealed t H 4

Pr Pr H Me 4-h. Rishire

Pr Pr Pr Me 4-

Pr Pr-CH ₂ OH Me 2-Chenyl

Pr Pr-CH "? CH = CH2 Me 2-Frill

Me Ph Me Et 4-pilir

Me Ph Et Et 4-Pirishiru Table 3 continued

Table 4

R】 R ₂ R _{5 6} AX

Et Ph Me -NHMe 3 -H. Rishile NH

Me Ph Me -NHEt 4 -H. Lil NH

Me Ph Me -N e ₂ 3_ fire. Rishi "le NH

Me Ph-3-CI Me -NHMe 4-Pirishi, Le 0

Et Ph H -NHMe 4-pyryl NH

Me Ph H -NHEt 3-H. Rishi '' Le NH

Me Ph- 3- CI H -NHMe 3 -Pirils "0

Et Ph Me -OMe 3-Pirils' NH

Me Ph Me -OEt 3 -Pirishi Les NH

Me Ph-4-Cl Me -OMe 4

Et Ph H -OMe 3-Pirils "NH

Me Ph-4-Cl H -OMe 3 -Pirisyl 0

Me Ph Me -CH ₂ O e 3 -Piricil "NH

Me Ph Me -CH ₂ 0Me 4 -H. Rishire 0

Me Ph H-CH Mai 4-Piriru NH

Et Ph H -CH ₂ OMe 3-pyryl 0 The compound of the present invention can be produced, for example, by the following method.

Production method (a)

In the formula (I), the compound wherein X is —NR ₄ — is represented by the following formula (II)

Wherein Z represents a leaving atom or a leaving group, and R ₅ and R ₆ i are hydroxy (lower

) Means the same as defined above for R ₅ and R 6 except that the alkyl, amino, amino (lower) alkyl, carboxyl and carboxy (lower) alkyl groups are replaced by protected forms. And A represents the same as described above) and a compound represented by the following formula (III)

HN (R ₄ ) — CH (R ₃ !)-C〇N (R (III)

(Wherein, R ₃₁ represents a hydrogen atom, a lower alkyl group or a protected hydroxy (lower) alkyl group, and R ₂ and R ₄ have the same meanings as described above). It can be produced by reacting and, if necessary, removing the protecting group of the product.

The leaving atom or leaving group represented by Z in the formula (II) means an atom or group capable of leaving in the form of HZ together with the hydrogen atom in the NH portion of the compound of the formula (III) under the reaction conditions. A halogen atom such as chlorine, bromine or iodine, a lower alkylsulfonyloxy group such as methanesulfonyloxy, a trihalogenomethanesulfonyloxy group such as trifluoromethanesulfonyloxy, benzenesulfonyloxy, arylsulfonyloxy groups such as p-toluenesulfonyloxy; It is.

The protected hydroxy groups represented by R ₃ 〗, R ₅ and R ₆ in the above formulas (II) and (III) mean a hydroxy group protected by a protecting group which can be eliminated by hydrogenolysis. Examples thereof include benzyloxy, 4-chlorobenzyloxy, 3-bromobenzyloxy, 4-fluorobenzyloxy, 4-methylbenzyloxy, and 4-methoxybenzyloxy. In formula (II) and the R ₅ 1 or protected by an Amino group or Amino moiety represented by R _6], means protected amino group or amino moiety with a protecting group capable eliminated by hydrogenolysis, For example, benzyloxycarbonylamino, 3- or 4-chlorobenzyloxycarbonylamino, 4-bromobenzyloxycarbonylamino, 4-fluorobenzyloxycarbonylamino, 4-methylbenzyl Oxycarbonylamino and 4-methoxybenzyloxycarbonylamino. In equation (II), R ₅ ! Or the protected hydroxyl group or moiety represented by R ₆ means a carboxyl group or a carboxy moiety protected by a protecting group that can be eliminated by hydrolysis or hydrogenolysis, and specific examples thereof include: Those described in detail in the explanation part of the term are exemplified.

The reaction between the compound represented by the formula (II) and the compound represented by the formula (III) is carried out at normal pressure or under pressure, in the absence of a solvent or in a suitable solvent.

Specific examples of the solvent include aromatic hydrocarbons such as toluene and xylene, ketones such as methyl ethyl ketone and methyl isobutyl ketone, ethers such as dioxane and diglyme, and alcohols such as ethanol, isopropanol and butanol. Examples include coals, acetonitrile, dimethylformamide, and dimethylsulfoxide. This reaction is preferably carried out in the presence of a base. Specific examples of the base include sodium carbonate, alkali carbonates such as potassium carbonate, sodium hydrogen carbonate, and hydrogen carbonate. Potential such as potassium hydrogen carbonate and tertiary amine such as triethylamine, and excess of the compound of the formula (III) can also be used. The reaction temperature varies depending on the type of the starting compound, the reaction conditions and the like, but is usually about 40 to about 200 ° C, preferably about 100 to about 170 ° C.

R ₃ i and / or R ₅ or R ₆ in the product! When having a Ca ⁵ 'protecting group can be deprotected by hydrogenolysis and Roh or hydrolysis pressure.

This hydrogenolysis can be carried out according to a conventional method, for example, by reacting with hydrogen in a suitable solvent in the presence of a catalyst such as palladium on carbon and Raney nickel. Examples of the solvent include alcohols such as ethanol and methanol, water, acetic acid, dioxane, and tetrahydrofuranca. The reaction temperature is usually about 0 ° C. to about 80, and the reaction is carried out under normal pressure or under pressure.

This hydrolysis can be carried out according to a conventional method, for example, by contacting with water in a suitable solvent under acidic or basic conditions. As the solvent, for example, alcohols such as methanol, ethanol, and isopropanol, dioxane, water, or a mixture thereof is used. Specific examples of the acid include mineral acids such as hydrochloric acid and sulfuric acid, and organic acids such as formic acid, acetic acid, propionic acid and oxalic acid. Specific examples of the base include alkali hydroxides such as sodium hydroxide and potassium hydroxide, and alkali carbonates such as sodium carbonate and potassium carbonate. The reaction temperature is usually about 20 to 100.

Starting compound R _{6 1} is a lower alkoxy group (II), the case is a group other than di-lower alkylamino group and a lower alkylthio group, for example, the following formula (IV)

(In the formula, Y denotes an oxygen atom or a sulfur atom, R _{6 2} is a lower alkoxy group, and the same as defined above R ₆ J other than di-lower alkylamino group and a lower alkylthio group, R ₅ and A are Can be produced by halogenating or sulfonylating the compound represented by the same meaning as described above) according to a conventional method.

The halogenation is carried out, for example, by reacting a compound of the formula (IV) with a halogenating agent (for example, phosphorus oxychloride, phosphorus tribromide). Sulfonylation is performed, for example, by using a compound in which Y is an oxygen atom in the formula (IV) and a sulfonylating agent (eg, methanesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonyl chloride, trifluoromethanesulfonate) (Anhydrous anhydride).

The starting material (IV) is commercially available or known per se, for example J. Am.

Chem. Soc., 74, 842 (1952), Chem. Ber., 95, 937 (1962) and J. Org. Chem., 29, 2887 (1964), and the methods described in Reference Examples 1 and 12 below. It can be manufactured by a method according to these.

When the starting compound (II) is R ₆ ! Lower alkoxy group, di-lower alkylamino group or lower alkylthio, for example, the following formula (IV ′)

(Wherein, R _{5 1,} A and Z are the same meaning supra) is reacted in the presence of each alkoxide compound represented by Kaka or reacting a di-lower alkylamine in the presence of a base By reacting in the presence of a thioalkoxide, the corresponding compound of formula (II) can be produced. The compound of the formula (IV ′) has the following formula (IV ″)

(Wherein R ₅ ! And A have the same meanings as described above) can be produced by performing the above-mentioned halogenation or sulfonylation.

The starting material (IV ") can be obtained from commercially available sources or by methods known per se, for example

Heterocycl. Chera., 1 £, 47 (1973) or a method analogous thereto.

The compound of formula (III), which is the other starting compound in the present production method, can be prepared by a method known per se, for example, the method described in JP-A-2-32058 and Reference Examples 63 and 82 described below or It can be manufactured by a method according to these. In the formula (I), the compound in which X is —0— is a compound represented by the following formula (IVa) (IVa)

ヽ A

(Wherein, R _{5 1,} R ₆ and A are the same meaning supra) compound represented by the following formula (V)

Z! -CH (R ₃ i) -CON (R ₁ ) (R ₂ ) (V)

(In the formula, Z i means a halogen atom, and R j, R ₂ and R ₃ mean the same as described above.)

The compound can be produced by reacting with a compound represented by the formula, and if necessary, removing a protecting group from the product.

The reaction between the compound of the formula (IVa) and the compound of the formula (V) can be carried out in the presence of a base, without a solvent or in a suitable solvent under normal pressure or pressure. Examples of the solvent to be used include toluene, xylene, dimethoxetane, 1,2-dichloroethane, acetate, methylethylketone, dioxane, diglyme, ethylethyl acetate, dimethylformamide, and dimethylsulfoxide. Examples of the base include sodium hydride, triethylamine, potassium carbonate, and sodium carbonate. The reaction temperature is usually about 110 ° C to about 150 ° C, preferably about 10 to about 70 ° C.

R ₃ in the product! And no or R ₅ or R ₆ ! When has a protecting group, deprotection can be carried out by hydrogenolysis and / or hydrolysis in the same manner as in the production method (a).

The compound of the formula (V) can be produced by a method known per se, for example, the method described in JP-A-62-64 and Reference Example 84 described below, or a method analogous thereto. The compound of the formula (I) is represented by the following formula (VI)

Wherein A, X, R ₃₁ , R 5 and R ₆ have the same meanings as described above, or a reactive derivative thereof, and a compound represented by the following formula (VII):

HN (R!) (R ₂ ) (VII)

(Wherein, R! And R ₂ have the same meanings as described above), and if necessary, the protecting group of the product is removed to produce the compound.

Examples of the reactive derivative of the compound of the formula (VI) include lower alkyl esters (especially methyl esters), active esters, acid anhydrides, and acid halides (especially acid chlorides). Specific examples of the active ester include p-nitrophenyl ester, 2,4,5-trichloromethyl phenyl ester, and N-hydroxysuccinic acid imidoester. As the acid anhydride, a symmetric acid anhydride or a mixed acid anhydride is used. Specific examples of the mixed acid anhydride include a mixed acid anhydride with an alkyl chlorocarbonate such as ethyl chlorocarbonate and isobutyl chlorocarbonate. , Such as mixed acid anhydrides with aralkyl chlorocarbonate such as benzyl carbonate, mixed acid anhydrides with aryl chlorocarbonate such as funalyl chlorocarbonate, isovaleric acid, and vivalic acid And mixed acid anhydrides with alkanoic acid.

When the compound of the formula (VI) itself is used, N, N′-dicyclohexylcarbodiimide, 1-ethyl-13- (3-dimethylaminopropyl) carbodiimid hydrochloride, N, N'-carbonyldiimidazole, N, Ν'-carbodilsuccinic acid imid, 1-ethoxycarbonyl-1_2-ethoxy-1,2, -dihydroquinoline, diphenyl phosphoryl azide, propanephosphonic anhydride, benzotriazolic anhydride The reaction can be carried out in the presence of a condensing agent such as 1-yloxytris (dimethylamino) phosphonium-hexafluorophosphate.

The reaction of the compound of the formula (VI) or a reactive derivative thereof with the compound of the formula (VII) is carried out in a solvent or without solvent. The solvent used, the force should be applied Yichun selected according the kind of starting compound ^s, such as benzene, toluene, aromatic hydrocarbons such as xylene, Jefferies chill ether, as tetrahydrofuran, E one like Jiokisan Halogenated hydrocarbons such as tertiary salts, dimethylene chloride, and chloroform, alcohols such as ethanol and isopropanol, ethyl acetate, acetone, acetonitrile, dimethylformamide, dimethyl sulfoxide, ethylene glycol, water, etc. These solvents may be used alone or in combination of two or more. This reaction is carried out in the presence of a base, if necessary. Specific examples of the base include alkali hydroxides such as sodium hydroxide and potassium hydroxide, alkali carbonates such as sodium carbonate and potassium carbonate, and hydrogen carbonate. The strength of sodium bicarbonate such as sodium bicarbonate or an organic base such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, excess amount of the compound of formula (VII) Can also be used. The reaction temperature varies depending on the type of the starting compound used, etc .; usually about 130 ° C. to about 200 ° C., preferably about 110 ° C. to about 150 ° C.

R ₃ i and or R ₅ in the product! Or, when R ₆ ] has a protecting group, deprotection by hydrogenolysis and Z or water is carried out in the same manner as in production method (a). It can be performed.

The compound in which X is an oxygen atom in the formula (VI) can be produced, for example, by the above-mentioned production method (b). That is, the compound of the above formula (IVa) and the following formula (VIII)

Z! -CH (R ₃ i) -COOR (VIII) (wherein R represents a lower alkyl group, and Z and R ₃ have the same meanings as described above)

Can be produced by reacting the compound represented by the formula with the method described in the production method (b), and then hydrolyzing the product according to a conventional method.

The compound of the formula (VIII) is commercially available or can be produced by a method known per se.

A compound in which X is represented by —NR ₄ — in the formula (VI) can be produced, for example, by the above-mentioned production method (a). That is, the compound of the formula (II) and the following formula (IX)

HN (R ₄ ) -CH (R ₃ i) -COOR '(IX)

(In the formula, R ′ represents a lower alkyl group, a benzyl group or a benzyl group substituted with one selected from halogen, methyl and methoxy, and R ₃₁ and R ₄ are the same as those described above. means)

Can be produced by reacting the compound represented by the formula with the method described in the production method (a), and then hydrolyzing or hydrogenolyzing the product according to a conventional method.

The compound of the formula (IX) is commercially available or can be produced by a method known per se. In the formula (I), the compound wherein X is —0— and R ₃ is a hydrogen atom is represented by the following formula: (I)

( ^ΙΠ

(Wherein blue R ₅₁ , R ₆ i and A mean the same as described above) and the following formula (X)

HOCH ₂ CON (R!) (R ₂ ) (X)

(Wherein, R and R ₂ have the same meanings as described above), and if necessary, the protecting group of the product is removed to produce the compound. The reaction of the compound of the formula (IΓ;) with the compound of the formula (X) can be carried out in the presence of a base, without a solvent or in a suitable solvent under normal pressure or pressure. Examples of the solvent to be used include toluene, xylene, dimethoxetane, 1,2-dichloroethane, aceton, methylethylketone, dioxane, diglyme, ethylethyl acetate, dimethylformamide, and dimethylsulfoxide. Examples of the base include sodium hydride, triethylamine, potassium carbonate, and sodium carbonate. The reaction temperature is usually about -10 ° C to about 150, preferably about 10 ° C to about 70 ° C.

R ₅ in the product! When has a protecting group, deprotection can be carried out by hydrolysis or hydrolysis in the same manner as in the production method (a). The starting compound (X) is represented by, for example, the following formula (XI)

R OOC-CO-N (R!) (R ₂ ) (XI)

(Where R, R, and R ₂ mean the same as above) Can be produced by reducing the compound represented by the formula according to a conventional method. The reduction of the compound of the formula (XI) is carried out in an alcohol such as methanol or ethanol, an ether such as tetrahydrofuran or a mixture thereof, using a reducing agent such as borohydride. It is performed at about 15 ° C to about 0 ° C.

The starting material (X I) can be produced by a method known per se, a method described in Reference Example 88 (1) below, or a method analogous thereto.

When carrying out the above-mentioned production methods (a) to (d), when there is a group involved in the reaction in the raw material compound, the ability to protect the group in advance, or to easily remove the group after the completion of the reaction It is convenient to react in a form that can be converted. For example, some of the compounds of the formula (I) can also be produced by the following method.

The compound of the formula (I) wherein R ₅ or R ₆ is an amino group can be produced by reducing the compound of the formula (I) wherein R ₅ or R ₆ is a nitro group by a conventional method.

The compound in which R ₅ or R ₆ is an acylamino group in the formula (I) can be obtained by reacting a compound in which R ₅ or R ₆ is an amino group in the formula (I) with a corresponding carboxylic acid or a reactive derivative thereof. Can be manufactured.

In the formula (I), the compound in which R ₅ or R ₆ is a hydroxy (lower) alkyl group is a compound in which R ₅ or R ₆ in the formula (I) is an alkoxycarbonyl group or an alkoxycarbonyl group in which the number of carbon atoms in the alkyl portion is one less. It can be produced by reducing a compound which is a (lower) alkyl group by a conventional method, and this method is specifically shown in Example 78 described later.

Compound R ₇ is a hydroxy group in formula (I), R ₇ turtles preparative In formula (I) It can be produced by treating a compound which is a xy group with hydrogen bromide. The product obtained by each of the above production methods can be isolated and purified by a conventional method such as chromatography, recrystallization, and reprecipitation. The compound of formula (I) having a basicity sufficient to form an acid addition salt can be converted into an acid addition salt by treating with a variety of acids according to a conventional method.

Various stereoisomers of the compound of the formula (I) can be separated and purified according to a conventional method such as chromatography.

The test results of representative compounds of the present invention are shown below, and the characteristics of the pharmacological action of the compounds of the present invention will be described.

Test Example 1: central-type _(ωι, ω ₂₎ and peripheral-type ₃₎ Benzojiazepin receptor binding trial

Preparation of BZ omega i and omega ₂ receptor binding assay and receptor membrane preparation is, Stephens, D.

N. et al. Method [J. Pharmacol. Exp. Ther. , 253, conforming to 334-343 (1990)], beta Zeta omega ₃ receptor binding test and receptor membrane preparation preparation, Schoemaker, H [See J. Pharmacol. Exp. Ther., 225, 61-69 (1983)].

ω ₂ and ω 3 receptor membrane preparation is? It was prepared from the cerebellum, spinal cord or kidney of a male Wistar rat of 8 weeks old by the following procedures.

To the cerebellum or spinal cord, a 20-fold volume of ice-cold buffer (5 OmM trisquarate buffer, H7.1) was added and homogenized, followed by centrifugation at 40,000 g for 15 minutes. The obtained precipitate was washed four times by the same operation, and then stored frozen at 160 ° C for 24 hours. After thawing the frozen precipitate, washing with a buffer and centrifugation, the resulting precipitate is subjected to binding buffer I (1 mM O2 containing 5 mM potassium chloride, 5 mM potassium chloride, 2 mM calcium chloride, ImM magnesium chloride, and 50 mM trisulfate). (1 g tissue wet weight 40 ml) in hydrochloric acid buffer (pH 7.4). _These were used in a binding test as BZ _ωι or ω ₂ receptor membrane preparations. Meanwhile, 2 in the kidney

Add 0 volume of water-cooled binding test buffer II (5 OmM sodium phosphate-potassium phosphate buffer containing 10 OmM sodium chloride, pH 7.4), homogenize, and use quadruplicated gauze. The filtered filtrate was centrifuged at 40,000 g for 20 minutes. Those obtained sediment was suspended in buffer II (1 g tissue wet weight / 1 00 ml) was used in binding experiments as a Betazetaomega ₃ receptor membrane preparation.

The labeled ligand and unlabeled ligands, the beta Zeta _omega and ₂ receptor binding assay [3 Eta] flumazenil (Rol5 1788) [final concentration (ω !: 0.3 ηΜ) (ω 2: Ιη)] and full nitrazepam (final concentration 1 0 / ^ Micromax) to, BZ omega ₃ in receptor binding assay ^[3 H] 4, - click Rorojiazepamu: 7 black opening one 1, 3-dihydrazide mud one 1-methyl-5- (4-black Mouth phenol) —2H-1,4-benzodiazepin-12-one (Ro 5-4864) (final concentration 0.5 nM) and diazepam (final concentration 100 M) were used, respectively. Incubation conditions are BZ ω! And omega ₂ receptor binding for 30 min at 37 ° C for a test was carried out 1 for 50 minutes at 0 in the BZ omega ₃ receptor binding test. The 試験 ω i and ω ₂ receptor binding tests were performed in the presence of bicuculline (13 11 ^ 1111½: final temperature 100 澳).

The receptor binding test was performed according to the following procedure. A test compound of known concentration, tritium-labeled ligand, receptor membrane standard and binding buffer I or II were added to each test tube to make a total volume of 1 ml, and the reaction was started by adding the receptor membrane standard. . After the incubation, the labeled ligand bound to the receptor was suction-filtered on a Wattman GF7B glass fiber filter using a cell harvester (Brandel, USA) to terminate the reaction. Immediately, the _plate was washed three times with 5 ml of ice-cold buffer (5 Om Tris-monohydrochloride buffer (pH 7.7 for _ωι and _ω2 ; buffer Π for _ω2 )). Radioactivity The filter was transferred to a vial, 1 Oml of a liquid scintillation cocktail (ACS-II, manufactured by Amersham, USA) was added, and the mixture was allowed to stand for a certain period of time, followed by measurement with a scintillation counter. The specific binding amount was determined by subtracting the simultaneously measured non-specific binding amount in the presence of the unlabeled ligand from the total binding amount. The concentration at which the test compound inhibited the specific binding amount of the labeled ligand by 50% (IC ₅ o value) was determined by the probit method. Table 5 shows the results. The compounds shown in Table 5 all had an IC _{5 {)} value of binding activity to benzodiazepine _ωι and ω ₂ receptors of 100 OnM or more.

Table 5 ω 3 ω 3

Test compound

I c ₅₀ (nM) test compound

ic ₅₀ (nM)

1 * 1. 3 5 9 1-6

5 0.2 5 6 0 1.4

7 2.3 7 8 2.6

1 7 1.2 82 1.4

26 1.8 9 1 1 1.0

30 7. 8 92 6.5

32 6. 5 94 0.3 8

33 1 5.0 9 5 0.89

39 2 96 0. 0 5

40 0 9 9 2.5

43 6 1 00 7.2

44 1.2 1 0 2 1.1

4 5 72 1 06 0.66

4 7 1 1 1 2 3.1

5 1 1 1 1 6 0.89

54 4 1 26 1 5.0

5 5 0 1 30 1.2

57 3. means 0 1 3 5 0.89 compound of Example 1 (hereinafter, the same) compounds of the present invention shown in Table 5 despite strongly bind to BZ omega ₃ receptors, these IC ₅ of the Β Ζ Ο and Β Ζ ω2 receptors of the compound. It is clear that the compounds of the present invention selectively and strongly bind to the Β 受容 receptor from the value of 100 Οη or more. Test Example 2: Effect test on isodiazide-induced clonic seizures (Pile convulsions) Since isoniazid inhibits the GABA biosynthetic enzyme glutamate decarboxylase, administration of isoniazid induces clonic seizures based on a decrease in the amount of GABA in the brain. Based on the method of Auta, J. et al. [See J. Pharmacol. Exp. Ther., 265, 649-656 (1993)], the test compound was tested for its antagonism against isodiazide-induced clonic seizures. In this study, many drugs having an indirect or direct enhancer of GABA _A receptor function, for example, BZ receptor agonists such as diazebum, alopregnenolone and arotetrahydrodeoxycorticosterone (THDOC), etc. neuro stearyl Roy de or BZ omega ₃ receptor agonists having promoting action of neuro stearyl Roy de generation show positive effects. For the test, six Std-ddY male mice weighing 22 to 24 g were used per group. Thirty minutes after the oral administration of the test compound, isodiazide (20 OmgAg) was subcutaneously administered. Immediately after that, the mouse was placed in a plastic cage, and the onset latency of clonic seizures was observed for 90 minutes. The onset latency in the vehicle control group was about 40 minutes. The antagonism potency of the test compound was expressed as the dose (ED 25 value) that prolonged the expression latency by 25% net compared to the vehicle control group. ED _{2 5} value was calculated by Ritsuchifirudo one Will Cookson method. Table 6 shows the results. Table 6 Anticonvulsant effect Anticonvulsant effect Test compound Test compound

E D 25 (mgAg) E D 25 (mg / kg)

1 * 4.08 95 1 00

5 1 3.8 96 62.4

32 68. 7 98 64. 0

94 84.3 1 00 62.5 *: Means the compound of Example 1 (hereinafter the same)

The compounds of the present invention shown in Table 6 exhibited an anticonvulsant effect at a dose of 10 OmgZkg or less, and particularly the compound of Example 1 exhibited an anticonvulsant effect at a low dose of 10 OmgZkg or less.

Test Example 3: Light / dark box test (Anxiolytic effect)

Crawley, J. and Goodwin, F.K., et al. (Pharmacol. Biochem.

Behav., 13, 167-170 (1980)], and the presence or absence of the anxiolytic effect of the test compound was examined.

This light-dark box test method uses the habit of rodents, such as mice and rats, preferring dark places, and uses the increase in relative residence time in bright places that are uncomfortable as indicators of a positive effect. However, it is an effective and simple method for investigating the anxiolytic effects of drugs on behavioral pharmacology. In this method, many of the cholecystokinin type 11 antagonists and benzodiazepines show positive effects.

In the light and dark box test, a light box made of a transparent acrylic plate (20X17X15cm) illuminated by an incandescent lamp at an illuminance of 1700lux and a dark box (15X17X15cm) made of a black ataryl plate and shielded from light are connected, The measurement was performed using a device (35 X 17 X 15 cm) equipped with a barrier (4.4 X 5.0 cm) that could freely move.

For the test, 10 Std-ddY male mice weighing 25 to 30 g were used per group. Thirty minutes after the oral administration of the test compound, the mouse was placed in the center of the light box, the time spent in the light box during the 5-minute test period was measured, and the light box retention rate for the entire test period was calculated. Based on the bright box retention rate, the relative retention increase rate of the test compound relative to the solvent control group was determined.

The anxiolytic potency of the test compound was expressed as the minimum effective dose (MED) at which the relative retention increase was statistically significant (William-Wilcockson method, 5% risk factor). Table 7 shows the results. Table 7

*: Means the compound of Example 33 (the same applies hereinafter).

Among the compounds shown in Table 7, the compounds of Examples 33, 45, 59, 92 and 99 showed anxiolytic effects at a low dose of 0.01 mgZkg.

Test Example 4: Collagen-induced arthritis inhibition test

The collagen-induced arthritis inhibition test is an experimental rheumatic model reported by Trethan, DE et al. (See J. Exp. Med., 146, 857 (1977)). Its onset mechanism has been shown to be useful not only as an anti-inflammatory drug but also as an evaluation system for immunosuppressants and immunomodulators (see J. Immunol., 140, 78-83 (1988)).

The collagen-induced arthritis inhibition test was carried out according to the method of Kakimoto, K. et al. (See the above-mentioned literature of Kakimoto, K. et al.). That is, the solubilized bovine cartilage-derived type II collagen (Elastin Products, USA) was mixed with Freund's complete adjuvant (DIFC0 Lab., USA) to obtain a uniform emulsion. This emulsion 150 was injected into the base of the tail of a DBA / lj male mouse (6 weeks old; manufactured by Nippon Chills River, Japan) for initial sensitization. 2 One day later, booster immunization was performed by injecting the emulsion 150 / g prepared as above into the base of the tail again. And caused arthritis. The test compound (1 O mg / kg) was orally administered every day immediately after the first sensitization. After 5 days from the booster, the degree of arthritis is visually observed every day, and according to the method of Wood, FD et al. (See Int. Arch. Allergy Appl. Immunol., 35, 456-467 (1969)). As shown in Table 8, a five-point scale was used. The sum of the scores of the four forelimbs and hindlimbs was determined as the arthritis score, and the point at which score 1 was obtained was defined as the date of onset.

Table 8

In the compound-administered group of Example 9, the degree of symptoms as seen from the arthritis score was milder than that in the control group.

As apparent from the above pharmacological test results, the compounds and acid addition salts thereof physiologically allowable of formula (I) are selective and pronounced for beta Zeta omega ₃ receptors in vi tro test It has high affinity and has excellent pharmacological effects in animal tests. It is useful as a therapeutic or prophylactic agent for cardiovascular diseases such as immune neurological diseases, angina pectoris and hypertension, or immune inflammatory diseases such as rheumatism.

The compound of the present invention may be administered orally, parenterally or rectally. Either may be used. The dose varies depending on the type of compound, the administration method, the symptoms and age of the patient, etc. \ Usually 0 1 to 5 OmgZkgZ days, preferably 0.03 to 5 η¾ ^ no days.

The compound of the present invention is usually administered in the form of a preparation prepared by mixing with a preparation carrier. As the carrier for the preparation, a substance which is commonly used in the field of preparation and which does not react with the compound of the present invention is used. Specifically, for example, lactose, inositol, glucose, mannitol, dextran, cyclodextrin, sorbitol, starch, partially-alpha starch, sucrose, magnesium metasilicate aluminate, synthetic aluminum silicate, crystalline cellulose , Carboxymethylcellulose sodium, hydroxypropyl mouth starch, carboxymethylcellulose calcium, ion-exchange resin, methylcellulose, gelatin, gum arabic, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrroli Don, polyvinyl alcohol, alginic acid, sodium alginate, light caffeic anhydride, magnesium stearate, talc, carboxyvinyl Polymer, titanium oxide, sorbitan fatty acid ester, sodium lauryl sulfate, glycerin, fatty acid glycerin ester, refined lanolin, glycerinated gelatin, polysorbate, macrogol, neat spot oil, wax, propylene glycol, water, ethanol, Polyoxydylene hydrogenated castor oil (HC〇), sodium chloride, sodium hydroxide, hydrochloric acid, sodium monohydrogen phosphate, sodium dihydrogen phosphate, cunic acid, glutamate, benzyl alcohol, methyl parahydroxybenzoate, paraoxy Ethyl benzoate and the like.

Dosage forms include tablets, capsules, granules, powders, syrups, suspensions, suppositories, injections and the like. These preparations are prepared according to a conventional method. When used, liquid preparations may be dissolved or suspended in water or other suitable medium. Les ,. Tablets and granules may be coated by a known method. In the case of an injection, the compound of the present invention is prepared by dissolving the compound in water.If necessary, the compound may be dissolved using an isotonic agent or a solubilizing agent. Agents and preservatives may be added.

These preparations may contain the compound of the present invention in an amount of 0.11% or more, preferably 0.1 to 70%. These formulations may also contain other therapeutically active ingredients.

The ultimate bear for giving light

Hereinafter, the present invention will be described more specifically with reference to Reference Examples and Examples, but the present invention is not limited to these Examples. The compounds were identified based on elemental analysis values, mass-spectra, IR spectra, NMR spectra, and the like.

In the following Reference Examples and Examples, the following abbreviations may be used for simplification of the description.

(Recrystallization solvent)

A: Ethanol

A C: Acetonitrile

C F: Black mouth Holm

C M: methylene chloride

E: Jechlje Tenoré

E A: Ethyl acid

H X: n-hexane

I P: Isopropanol

M: methanol

Glue 1 Preparation of 5, 6-dimethyl-2- (4-pyridyl) -14 (3H) -pyrimidinone In a mixture of 45 g of sodium methoxide and 50 ml of absolute ethanol at 0-5 ° C, 4-amidinopyridine hydrochloride 40 g was added. After stirring at room temperature for 15 minutes, 40 g of ethyl 2-methylacetoacetate was slowly added dropwise again at 0 to 5 ° C. After completion of the dropping, the temperature was gradually increased and the mixture was refluxed for 12 hours. The reaction mixture was cooled with ice, concentrated hydrochloric acid was added dropwise until the pH became 4, and the precipitate was collected by filtration, washed with water, then washed with water, then washed with methanol and water, and the desired product was washed with 4 Og. I got

Melting point 26 1 to 26 3 ° C

Reference Example 2-: 1 1

The corresponding starting compounds were used and reacted and treated in the same manner as in Reference Example 1 to obtain the compounds shown in Table 9. The compounds of Reference Examples 5 to 7 and 10 were recrystallized to isolate the intended product, and the compounds of the other Reference Examples were obtained by simply washing with a solvent.

Table 9

*: Wash with methanol and water

Reference example 1 2

Preparation of 5, 6-dimethyl-2- (3-pyridyl) -14 (3H) -pyrimidinone 38.6 g of anhydrous potassium carbonate was dissolved in 400 ml of water, and 40 g of 3-amidinopyridine hydrochloride was added at room temperature. Was. This was stirred at room temperature for 15 minutes, and at the same temperature, 36.2 g of ethyl 2-methylacetate was slowly added dropwise. After completion of the dropwise addition, the mixture was stirred at room temperature for 12 hours, and then the precipitate was collected by filtration, washed with water, then with ethyl ether, and then washed with methanol and water to obtain 28.8 g of the desired product.

Melting point 2 19-220 ° C

See 1 3 ~ 20_ Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as in Reference Example 12 to obtain the compounds shown in Table 10. The compounds of Reference Examples 13 and 16 were recrystallized to isolate the desired product, and the others were obtained by simply washing with a solvent.

Table 10

*: Washed with methanol / water

Reference Example 2 1

Production of 5,6-dimethyl-1- (4-pyridyl) pyrimidine

A mixture of 20 g of 5,6-dimethyl-12- (4-pyridyl) -14 (3H) -pyrimidinone and 27.8 ml of phosphorus oxychloride was stirred at 75 t for 5 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in chloroform, ice water was added, and the mixture was stirred. After neutralization with 1 N sodium hydroxide, the foam layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from isopropanol to obtain 13 g of the desired product. Melting point 1 1 1 1 1 3

Reference Example 2 239 The corresponding starting compound was used and reacted and treated in the same manner as in Reference Example 21 to obtain the compound shown in Table 11.

Reference example R s R e A Melting point (° C) Recrystallization solvent

22 Me Me 2-pill 152-154 A

23 Me Me 3-Hi. Rishiru 77-79 HX-C

24 Me Me 2 -Piracy'nil 112-113 HX-C

2 Me Me? —Frill A

26 Me Me 2-Chenyl 69-71 IP

27 Me Me 3-Chenyl 51-52 A

28 Me Me 2-pyridyl Le - 5- CF ₃ 136-139 A

29 Me Me 4 -Pirisi, Le -2,6- (Cl) ₂ 220-222 IP-AC

30 Me Me Ph 120-122 A

31 Me Me Ph-4-Cl 122-124 IP

32 Me Me Ph-4-CF ₃ 70-71 IP

33 H CF _{3 3} - pyridyl Le 114-117 M

34 H CF ₃ 4 1 pill 163-164 M

35 Me CF ₃ 4-Pirile 87-88 IP

36 - (c¾) ₄ - 4- arsenide. Rishiru 143-145 IP

37 COOEt H 4 1R 194-197 IP

38 Me COOEt 4 IP 124-125 IP

39 CH ₂ TMe 4-Pirishi ', Le 117-118 IP Reference example 40

Production of 4-chloro-5- (2-hydroxyxethyl) -1-6-methyl-2- (4-pyridyl) pyrimidine

Reference Example 39 5 g of 4-chloro-5-ethoxycarbonylmethyl-16-methyl-2- (4-pyridyl) pyrimidine obtained in 9, 5 g of sodium borohydride, 1.9 g of sodium borohydride, 2.0 g of sodium chloride and anhydrous tetrahydrofuran After stirring 50 ml of the mixture at room temperature for 30 minutes, 4 Oml of absolute ethanol was added dropwise while maintaining the reaction temperature at 0 to 5 ° C. After completion of the dropwise addition, the mixture was stirred at room temperature for 12 hours. The reaction mixture was cooled to 0 ° C, 1 N hydrochloric acid was added dropwise until pH 5, and then concentrated under reduced pressure. A saturated saline solution and chloroform were added to the residue, and the chloroform layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with chloroform and purified, and recrystallized from isopropanol to obtain 3.lg of the desired product.

With melting point 2 10 ~ 2 1 2

Participant example 4 1

Production of 4,6-dihydroxy-1-5-methyl-2- (4-pyridyl) pyrimidine

To a mixture of 2 896 sodium methoxide methanol solution (162 g) and methanol (500 ml), 73 g of methyl malonate getyl (73 g) was added dropwise at 0 to 5 ° C. . The reaction mixture was concentrated under reduced pressure, water and water were added to the residue, concentrated hydrochloric acid was added dropwise until pH 4, and the precipitate was collected by filtration, washed with water, then washed with getyl ether, and then methanol-water. After washing, 54 g of the target substance was obtained.

Melting point〉 300

Reference Example 4 2-44

Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as in Reference Example 41. Obtained.

(Reference example 4 2)

4, 6-Dihydroxy-5-Methyl-2- (3-pyridyl) pyrimidine; Melting point> 300 (washed with methanol-water)

(Participant example 4 3)

4, 6-dihydroxy_2_ (4-pyridyl) pyrimidine;

Melting point> 300 ° C (washed with methanol-water)

(Reference example 4 4)

4, 6-dihydroxy-1- (3-pyridyl) pyrimidine;

Melting point> 300 (washed with methanol / water)

Reference example 4 5

Preparation of 4, 6-dichloro-1-5-methyl-1- (4-pyridyl) pyrimidine

A mixture of 2,6-dihydroxy-15-methyl-2- (4-pyridyl) pyrimidine 2 Og and phosphorus oxychloride 36 ml was heated to reflux for 6 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in chloroform, ice water was added, and the mixture was stirred. After neutralization with 1N hydroxy dimethyl sodium, the chloroform layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with chloroform and purified, and recrystallized from isopropanol to obtain 13 g of the desired product.

Participants 4 6 to 4 8

Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as in Reference Example 45 to obtain the following compounds.

(Reference Example 4 6

4, 6-dichloro-5-methyl-1- (3-pyridyl) pyrimidine;

Melting point 1 28-1 291: (recrystallized from isopropanol) (Reference example 4 7)

4, 6-dichloro-1- (4-pyridyl) pyrimidine;

Crude crystal

(Reference Example 4 8)

4, 6-dichro-2- (3-pyridyl) pyrimidine;

Melting point 1 2 to 1 2 3 ° C (recrystallized from isopropanol)

Reference Example 4 9

4 of 1-chloro-5-methyl-1 6-methylamino 2- (4-pyridyl) pyrimidine

To a mixture of 40 g of 4,6-dichloro-5-methyl-2- (4-pyridyl) pyrimidine, 28 g of methylamine hydrochloride and 30 Oml of isopropanol was added 59 g of triethylamine at room temperature. Heated to reflux for 4 hours. After concentrating the reaction mixture under reduced pressure, 5% hydrochloric acid and chloroform were added, the aqueous layer was separated, and made aqueous with sodium hydroxide aqueous solution. The precipitate was collected by filtration, washed with water and then with ethyl acetate, and recrystallized from acetonitrile to obtain 36 g of the desired product.

Melting point 2 2 9 to 2 3 1 ° C

Reference example 50 to 54

Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as in Reference Example 49 to obtain the compounds shown in Table 12.

Reference example R ₅ R ₆ A Melting point (° C) Recrystallization solvent

50 Me NHPh 4-pill 200-201 IP

51 Me NHCH ₂ Ph 3 -Pirils "178-179 AC

52 Me NHMe 3 -Pirils "175-178 AC

53 H NHMe 4-Piryl "206-208 AC

54 H NHMe 3-Pili, Le 153-155 AC m 55

Preparation of 4-Chloro-6-methoxy-5-methyl-1- (4-pyridyl) pyrimidine 4,6-Dichloro-5-methyl-5-methyl (4-pyridyl) pyrimidine 7 g, sodium methoxide A mixture of 1.6 g and 50 ml of methanol was heated to reflux for 4 hours. After concentrating the reaction mixture under reduced pressure, a saturated food solution and chloroform were added to the residue, and the crystalline form layer was separated, dried over anhydrous sodium sulfate, and reduced under reduced pressure to obtain a crystal. Recrystallization from isopropanol gave 5.lg of the desired product. Melting point: 12 1 to 12 22 ° C Reference Examples 56 to 59 Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as in Reference Example 55 to obtain the compounds shown in Table 13.

Reference example R ₅ R ₆ A Melting point (in) Recrystallization solvent

56 Me OMe 3-Pirishil 110-112 M

57 H O e 4-Pyryl 112-114

58 H OMe 3 -Pirissil 87-89 IP

59 H OEt 4 -Piricil 93-94 IP Reference Example 60

6 Preparation of 1-benzyloxy 4- 4-chloro-5-methyl-2- (4-pyridyl) pyrimidine A mixture of 1.5 g of benzyl alcohol and 15 ml of toluene was treated with 0,55 g of sodium hydride at a concentration of 0 to 55%. After adding at 5 ° C and stirring at room temperature for 30 minutes, 3 g of 4,6-dichloro-1-methyl-1- (4-pyridyl) pyrimidine and 3 g of toluene were added dropwise at the same temperature. After the completion of the dropwise addition, the reaction mixture was heated under reflux for 6 hours, water was added, and the mixture was concentrated under reduced pressure. To the residue were added a saturated saline solution and chloroform-form, and the foam-form layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with chloroform and purified, and recrystallized from ethanol to obtain the desired product (3.1 lg). Melting point 1 16 to 1 18 ° C Reference example 6 1

4-—Mouth 6— (2,2,2-Trifluoroethoxy) -1— (3_pyridyl) pyrimidine In place of 4,6-dichloro-1-5- (4-pyridyl) pyrimidine and benzyl alcohol in Reference Example 60, 4,6-dichloro-2- (3-pyridyl) pyrimidine and 2,2 The reaction and treatment were carried out in the same manner as in Reference Example 60 using 2,2-trifluoroethanol, and the product was recrystallized from ethanol to obtain the desired product.

Melting point 88-89 ° C

■ 6 2

Preparation of 4-chloro-6-methylthio-1- (3-pyridyl) pyrimidine

Instead of 4,6-dichloro-5-methyl-2- (4-pyridyl) pyrimidine and sodium methoxide in Reference Example 5, 4,6-dichloro-2- (3-pyridyl) pyrimidine and sodium thiomethoxide were used. The reaction and treatment were carried out in the same manner as in Reference Example 55, and the product was recrystallized from ethanol to obtain the desired product.

Melting point 1 1 2 to 1 1 4 ° C

Reference Example 63

Production of 2-amino-N-methyl-N- (3-pyridyl) acetamide

(1) N-phthaloylglycyl chloride 17.6 g methylene chloride 40 ml solution in a mixture of 3-methylaminoviridine 8.5 g, triethylamine 8. Og and methylene chloride 80 ml was maintained at a reaction temperature of 0 to 5. While dripping. After completion of the dropwise addition, the mixture was stirred at room temperature for 6 hours. Water was added to the reaction mixture, the methylene chloride layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from acetonitrile to obtain 18 g of 2-phthalimidone N-methyl-1-N- (3-pyridyl) acetoamide.

Melting point 197〜 199 ° C

(2) A mixture of 15 g of the above product, 5.lg of hydrazine monohydrate and 100 ml of ethanol was heated to reflux for 1 hour. After the reaction mixture was concentrated under reduced pressure, chloroform was added to the residue and the mixture was filtered. Water was added to the filtrate, and the chloroform layer was separated, and anhydrous sodium sulfate was added. After drying under reduced pressure, the mixture was concentrated under reduced pressure to obtain 8 g of the desired product as an oil.

Reference Examples 64 to 81 The corresponding starting materials were used and reacted and treated in the same manner as in Reference Example 63 to obtain the compounds shown in Table 14 as oils. Table 14

Reference example R i R ₂

6 4 Et 3-pirishil

6 5 Et 3-isoxaso "ryl-5-CH ₃

6 6 Me Me

6 7 Et Et

6 8 Pr Pr

6 9 H Pr

7 0 H CH

7 1 H Ph

7 2 Me Ph

7 3 Me Ph-2-Cl

7 4 Me Ph-3-Cl

7 5 Me Ph-4-Cl

7 6 Me Ph-3-OMe

7 7 Me Ph-4-OMe

7 8 Me Ph-4-0CF ₃

7 9 Et Ph

8 0 Pr Ph-4-O e

8 1 Et CH ₂ Ph Production of N-ethyl-2-N-methylamino-N-phenylacetamide

(1) N- (tert-butoxycarbonyl) -1-N-methylglycine 12 g, N-ethylenaniline 10 g, benzotriazo-1-lu-1-yloxy-tris (dimethylamino) phosphonium.hexafluorophos To a mixture of 20.9 g of phyt (B0P reagent) and 15 Oml of methylene chloride, 7.lg of triethylamine was added dropwise while maintaining the reaction temperature at 0 to 5 ° C. After completion of the dropwise addition, the mixture was stirred at room temperature for 8 hours. Water was added to the reaction mixture, the methylene chloride layer was separated, dried over anhydrous sodium sulfate, and reduced under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with chloroform. Purified, and purified with [N,-(tert-butoxycarbonyl) -1N'-methylamino] -1-N-ethyl-N-phenylacetamide 20 g were obtained as an oil.

(2) Trifluoroacetic acid was added to a mixture of 20 g of the above product and 200 ml of Shiridani methylene.

30 ml was added dropwise at 0-5 ° C. After completion of the dropwise addition, the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, water was added to the residue, and the mixture was made weakly alkaline with a 1N aqueous solution of sodium hydroxide in water while stirring under ice cooling, and chloroform was added thereto. The foam layer was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 12 g of the desired product as an oil.

Reference Example 83

Production of 2-methylamino-N-phenyl N-propylacetamide

N-Propylaniline was used instead of N-ethylaniline in Reference Example 82. The reaction and treatment were carried out in the same manner as in Reference Example 82 to obtain the desired product as an oil.

Reference Example 84

Production of 2-bromo-N, N-dipropylacetamide

To a mixture of 10.1 g of dipropylamine, 10 lg of triethylamine and 80 ml of anhydrous getyl ether, 15.8 g of bromoacetyl chloride in anhydrous getyl ether

A 40 ml solution was added dropwise while maintaining the reaction temperature at 140 ° C. After dropping, gradually increase the temperature The mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by distillation under reduced pressure to obtain 14 g of the desired product.

Boiling point 100-103. C / 1 mraHg

Participants 85-87

Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as in Reference Example 84 to obtain the compounds shown in Table 15 as oils.

Table 15

BrCHn—

Reference Example 88

Production of 2-hydroxy-1-N-methyl-1-N-phenylacetamide

(1) To a mixture of 25 g of N-methylanilinine, 26 g of triethylamine and 250 ml of dimethyl chloride, a solution of 35 g of ethyl oxalyl chloride in 100 ml of methylene chloride was added dropwise with stirring while maintaining the reaction temperature at 120 ° C. did. After completion of the dropwise addition, the mixture was stirred at 0 ° C for 4 hours. Water was added to the reaction mixture, the methylene chloride layer was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and 5 g of 2- (N-methyl-N-phenylamino) -2-oxoacetate was obtained as an oil. Obtained.

(2) A mixture of 5 l of the above product, 19 g of sodium borohydride, 20 g of lithium hydride and 250 ml of anhydrous tetrahydrofuran was stirred at room temperature for 30 minutes, and then 400 ml of anhydrous ethanol was added at a reaction temperature of 0 to 5 ° C. The solution was dropped. After dropping, at room temperature Stirred for 12 hours. The reaction mixture was cooled to 0 ° C., 1 N hydrochloric acid was added dropwise until pH 5, and then concentrated under reduced pressure. To the residue were added saturated saline solution and chloroform-form, and the pore-form layer was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained crystals were recrystallized from n-hexane-ethyl ether. This gave 29 g of the desired product.

Melting point 46-47 ° C

Participants 8 9

Production of 2-hydroxy-1-N- (4-methoxyphenyl) -1-N-methylacetamide Reference Example 88 Using N-methyl-1-p-anisidine instead of N-methylaniline in Example 8, the reaction was carried out in the same manner as in Reference Example 88. The product was recrystallized from _n- hexane-ethyl ether to obtain the desired product.

With melting point 73-74

90

Production of 2- (5,6-dimethyl-1-phenyl-2-pyrimidinyloxy) acetic acid

(1) 5.0 g of 5,6-dimethyl-12-phenyl-14 (3H) -pyrimidinone was added to a mixture of about 60% sodium hydride 1.0 g and dimethylformamide 8 Oml at a reaction temperature of 0 to 5 °. C, the mixture was stirred at 0 ° C for 30 minutes, and then 4.2 g of ethyl bromoacetate was added dropwise at the same temperature. After completion of the dropwise addition, the mixture was stirred at 80 ° C for 3 hours. Ice water and black-mouthed form were added to the reaction mixture, and the black-mouthed form layer was separated, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with a gel form, purified and recrystallized from isopropanol to give 6.2 g of 2- (5,6-dimethyl-12-phenyl 4-pyrimidinyloxy) ethyl acetate. Obtained. Melting point 90 ~ 91 ° C

(2) A mixture of 6.0 g of the above product, 100 ml of 1 N aqueous sodium hydroxide solution and 50 ml of ethanol was stirred at room temperature for 8 hours. Concentrate the reaction mixture under reduced pressure and dissolve in ice water Then, concentrated hydrochloric acid was added until the pH became 1, and the precipitated crystals were collected by filtration, washed with water, and recrystallized from ethanol to obtain 3.5 g of the desired product.

With a melting point of 1 75 to 1 77

Reference Example 9 1

Production of 2- (5,6-dimethyl-l--2-enyl- 4-pyrimidinyloxy) acetic acid Reference Example 90 Instead of 5,6-dimethyl-2-phenyl-4 (3H) -pyrimidinone in (1) The reaction and treatment were carried out in the same manner as in Reference Example 90 using 5,6-dimethyl-12-Chenyl-4 (3H) -pyrimidinone, and the product was recrystallized from ethanol to obtain the desired product.

Melting point 1 98-200 ° C

Reference Example 92

Preparation of 2- (5,6-dimethyl-2-phenyl-4-pyrimidinylamino) acetic acid (1) Mixture of 7.0 g of 4-chloro-5,6-dimethyl-2-phenylpyrimidine and 8.9 g of glycineethyl ester hydrochloride Was stirred at 170 for 2 hours. Water and chloroform were added to the reaction mixture, and the pore-form layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with a gel form, purified and recrystallized from isopropanol to give 8.9 g of 2- (5,6-dimethyl-12-phenyl 4-pyrimidinylamino) ethyl acetate. Obtained. With melting point 107-108

(2) A mixture of 5.2 g of the above product, 50 ml of 2N aqueous sodium hydroxide solution and 50 ml of ethanol was heated under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, dissolved in ice water, concentrated hydrochloric acid was added until the pH reached 1, the precipitated crystals were collected by filtration, washed with water, and recrystallized from ethanol to obtain 2.6 g of the desired product.

Melting point 232 ~ 234 ° C Paste 93

Preparation of 6-methyl-1- (3-pyridyl) -1-4 (3H) -pyrimidinone

Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as in Reference Example 12, and the product was washed with methanol / water to obtain the desired product.

Melting point 2 19-22 1 ° C

Participants 94

4 Production of 6-methyl-1- (3-pyridyl) pyrimidine

Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as in Reference Example 21, and the product was recrystallized from isopropanol-ethyl ether to obtain the desired product.

With melting point 78-79

Participant example 9 5

4 Production of monochloro-5-methyl-6-methylthio-1- (3-pyridyl) hinirimidine

Using the corresponding starting compounds, the reaction was performed in the same manner as in Reference Example 55, and the product was recrystallized from isopropanol to obtain the desired product.

Melting point 1 37 ~ 1 3 9

1

2-[5,6-Dimethyl-1- (4-pyridyl) -1-4-pyrimidinylamino] _ Production of N-methyl-1-N-phenylacetamide

4 -'- Mouth 5,6-dimethyl-2- (4-pyridyl) pyrimidine 4.0g, 2-aminomin N-methyl-1N-phenylacetamide 3.6g and triethylamine 3.7g mixture under stirring At 150 ° C for 3 hours. Water and chloroform were added to the reaction mixture, and the form layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography. The residue was purified and recrystallized from isopropanol to obtain 5.5 g of the desired product.

Melting point 183 ~; I 85 ° C

Example 2 35

Using the corresponding starting compounds, the reaction was carried out in the same manner as in Example 1 to obtain the compounds shown in Table 16.

Table 16

Table 16 continued

Example 26

2 — [6-chloro-1-5-methyl-3- (3-pyridyl) -1-4-pyrimidinylamino] 1-N-methyl-1-N-phenylacetamide

4,6-Dichloro-5-methyl-2- (3-pyridyl) pyrimidine 2 g, 2-amino N-methyl-N-phenylacetamide 1.4 g, triethylamine 0.8 g and isopropanol The 10 ml mixture was heated at reflux for 7 hours. After concentrating the reaction mixture under reduced pressure, water and chloroform were added to separate the pore-form layer, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Silica gel column chromatography of the residue The residue was purified by eluting with chloroform and recrystallized from isopropanol to obtain 2.7 g of the desired product.

With melting point 140-142

¾¾ !! 3 7

2 -— [6-chloro-1-5-methyl-2- (4-pyridyl) -4-pyrimidinylamino] 1 N, N-dipropylacetamide

Instead of 4,6-dichloro-5-methyl-2- (3-pyridyl) pyrimidine and 2-amino-N-methyl-1-N-phenylacetamide in Example 36, 4,6-dichloro-5-methyl-2- The reaction was carried out using (4-pyridyl) pyrimidine and 2-amino-N, N-dipropylacetamide in the same manner as in Example 36, and the product was recrystallized from isopropanol to obtain the desired product. Was.

With a melting point of 16 7 to 16 9

¾MI 3 8

2 -— [6-Methoxy-5-methyl-2- (4-pyridyl) -14-pyrimidinylamino] -1-N, N-dibu

2- [6-chloro-1-5-methyl-4- (4-pyridyl) -14-pyrimidinylamino] -1-N, N-dibu obtained pyracetoamide 1.5 g, 28 obtained in Example 37 A mixture of 0.94 g of a 5% sodium methoxide-methanol solution and 10 ml of methanol was heated to reflux for 12 hours. To the reaction mixture were added water and black form, and the black form layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with chloroform and purified, and recrystallized from isopropanol to obtain 1.4 g of the desired product.

With a melting point of 1 2 4 to 1 2 5

Real example 2 -— [5-Methyl-1-6-methylamino-1 2- (4-pyridyl) -1-4-pyrimidinylamino] 1-N-methyl-N-phenylacetamide

A mixture of 10 g of 4-chloro-5-methyl-6-methylamino-2- (4-pyridyl) pyrimidine, 14 g of 2-amino-1-N-methyl-N-phenylacetamide and 4.7 g of triethylamine is obtained. The mixture was heated under reflux at 170 ° C. for 3 hours with stirring. Water and chloroform were added to the reaction mixture, and the pore-form layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted and purified with chloroform, and recrystallized from acetonitrile to obtain 2.9 g of the desired product. Melting point 228 ~ 230 ° C

荬 examples

The corresponding starting materials were used and reacted and treated in the same manner as in Example 39 to obtain the compounds shown in Table 17.

Table 1 Ί

*: Obtained as a 0.04 port form-containing material.

Discussion 5 2

2- (6-Methoxy-1-5-methyl-2- (4-pyridyl) -1-4-pyrimidinylamino) 1-N-methyl-1-N-phenylacetamide

In place of 4-chloro-5-methyl-16-methylamino-2- (4-pyridyl) pyrimidine in Example 39, 4-chloro-1-5-methyl-6-methoxy-12- (4-pyridyl) pyrimidine was used. The reaction was carried out in the same manner as in Example 39, and the product was recrystallized from isopropanol-acetonitrile to obtain the desired product.

Melting point 1 67-1 69 ° C Example 5 7 1 Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as in Example 39 to obtain the compounds shown in Table 18 Table 18

S t ^ T connection.曰曰Example R ₅ R e R ₂ A melting point C)

solvent

53 Me OMe Me Ph-3-C l 4- -Pyryl 171-172 AC-CF

54 Me OMe Me Ph-4-Cl 4- -Pirils 164-165 IP

55 Me OMe Me Ph-4-0Me 4- —Pirinl 136-138 IP

56 Me OMe Me Ph 3--Hilline 136-137 IP

57 Me OMe Me Ph-3-Cl 3- -Pirin 143-144 AC

58 Me OMe Me Ph-4-Cl 3- -Pirils 157-159 AC

59 Me OMe Me Ph-4-0Me 3- -Pirinl 139-140 IP

60 H OMe Me Ph 4- -Pirils 154-156 IP

61 H OMe Me Ph-3- CI 4- -Pyryl 175-177 IP-AC

62 H OMe Me Ph-3-0 e 4- -pyril 173-176 IP

63 H OMe Me Ph-4-0Me 4--pyriyl 159-161 IP

64 H OMe Me Ph-4-0CF ₃ 4- -Pyryl 172-173 IP

65 H OMe Me Ph 3- -Prilyl 103-105 IP

66 H OMe Me Ph- 3-OMe 3- -pyril 107-108 IP

67 H OMe Me Ph-4-0Me 3- -Pirils 159-161 IP

68 H OMe Me Ph-4-0CF ₃ 3- -H. Reseal 151-152 IP

69 H OEt Me Ph 4- -Pirils 121-122 IP

70 H OEt Me Ph-4-OMe 4--pyridyl 135-137 IP

71 H OEt Me Ph-4- OCF ₃ 4- -Pirils 180-182 IP Par 7 2

2- [6-benzyloxy-5-methyl-1- (4-pyridyl) -1-4-pyrimidinylamino] 1-N-methyl-1-N-phenylacetamide

In place of 4-chloro-5-methyl-6-methylamino 2- (4-pyridyl) pyrimidine in Example 39, 6-benzyloxy 4-chloro-5-methyl-1- (4-pyridyl) pyrimidine was used. The reaction and treatment were carried out in the same manner as in Example 39, and the product was recrystallized from isopropanol to obtain the desired product.

Melting point 1 4 6 to 1 4 7 ° C

Examples 73 to 75

Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as in Example 39 to obtain the following compounds.

(m 1 3)

2- [6- (2,2,2-trifluoroethyl) -1-2- (3-pyridyl) -4-pyrimidinylamino] 1-N-methyl-1-N-phenylacetamide;

Melting point: 160-161 ° C (recrystallized from isopropanol)

(Example 7 4)

2- [6- (2,2,2-trifluoroethyl) -1- (3-pyridyl) -1-pyrimidinylamino] —N— (3-methoxyphenyl) -1-N-methylacetamide; melting point 1 10 to 11 ° C (recrystallized from isopropanol)

(15)

2- [6- (2,2,2-Trifluoroethoxy) -1- (3-pyridyl) -1-pyrimidinylamino] 1-N- (4-methoxyphenyl) -1-N-methylacetamide; melting point 1 34 to 1 36 ° C (recrystallized from isopropanol)

Shin I 7 e> 2- (6-acetoxy 5-methyl-2- (4-pyridyl) -4-pyrimidinylamino) 1-N-methyl-1N-phenylacetamide

(1) 2- [6-benzyloxy-5-methyl-2- (4-pyridyl) -14-pyrimidinylamino] 1-N-methyl-N-phenylacetamide obtained in Example 72 5.7 g, 10 After stirring a mixture of 1.0 g of palladium on carbon and 20 ml of acetic acid at room temperature under a hydrogen atmosphere for 3 hours, the reaction mixture was filtered. After the filtrate was reduced under reduced pressure, a 1 N aqueous solution of sodium hydroxide and chloroform were added to the residue. The aqueous layer was separated, neutralized with concentrated hydrochloric acid, and extracted with chloroform. After washing the form layer with water, and then with a saturated diet, it was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with a gel form, purified and recrystallized from ethanol to give N-methyl-1- (5-methyl-1- (4-pyridyl) -14 (3 H) -Pirimidinone 6-ylamino] 3.9 g of 1-N-phenylacetamide was obtained.

With a melting point of 264-265

(2) To a mixture of 2 g of the above compound and 20 ml of dimethylformamide, add 0.25 g of about 60% sodium hydride (oil) at 0 to 5 and stir at room temperature for 1 hour, and then add 0.64 acetic anhydride at 0 to 5 ° C. g was added and stirred at room temperature for 5 hours. Water and chloroform were added to the reaction mixture, the chloroform layer was separated, washed with water, dried over anhydrous sodium sulfate and reduced under reduced pressure. The residue was subjected to silica gel column chromatography, eluted and purified with chloroform, and recrystallized from isopropanol to obtain 2.0 g of the desired product. Melting point 1 8 1-: I 83

Fine 11

Production of 2- [6-methylthio-1- (3-pyridyl) -14-pyrimidinylamino] -1-N-methyl-1-N-phenylacetamide

In Example 39, 4-chloro-5-methyl-6-methylamino-2- (4-pi Instead of lysyl) pyrimidine, 4-chloro-6-methylthio-12- (3-pyridyl) pyrimidine was used and reacted in the same manner as in Example 39. The product was recrystallized from isopropanol-acetonitrile. The desired product was obtained.

With melting point 18 88-190

Μί 1 8

ェ -Ethyl _ 2 — [Methyl- (5,6-dimethyl-2- (4-pyridyl) -1-pyrimidinyl) amino] Production of 10-phenylacetamide

Instead of 2-amino-1-methyl-phenylphenylacetamide in Example 1, diethyl-2-methylamino-phenylphenylacetamide was used and reacted and treated in the same manner as in Example 1. The product was recrystallized from isopropanol to obtain the desired product. Melting point 1 4 3 to 1 4 5 ° C

Snake 7 9

2- [Methyl- (5,6-dimethyl-1- (2-phenyl) -4-pyrimidinyl) amino] 1-N-phenyl-N-propylacetamide

In place of the 4-methyl-5,6-dimethyl-2- (4-pyridyl) pyrimidine and 2-amino-N-methyl-N-phenylacetamide in Example 1, 4-chloro-5, 6-Dimethyl-1- (2-phenyl) pyrimidine and 2-methylamino-N-phenyl-N-propylacetamide were used, reacted and treated in the same manner as in Example 1, and the product was recycled from isopropanol. Crystallization yielded the desired product.

Melting point 1 1 2 to 1 1 4

8 n

2- [Methyl- (5,6-dimethyl-2- (3-phenyl) -14-pyrimidinyl) amino] 1-N-phenyl-1-N-propylacetamide

In Example 1, 4-chloro-5,6-dimethyl-2- (4-pyridyl) pyrimidi 4-chloro-5,6-dimethyl-12- (3-phenyl) pyrimidine and 2-methylamino-N-phenyl-N instead of 4-amino-N-methyl-N-phenylacetamide The reaction and treatment were carried out in the same manner as in Example 1 using propyl acetoamide, and the product was recrystallized from isopropanol to obtain the desired product.

Melting point 1 1 8 to 1 2 0

8 5

Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as in Example 1 to obtain the following compounds.

(¾M! 1 8 1)

2- [5- (2-Hydroxitytyl) -6-methyl-2- (4-pyridyl) -14-pyrimidinylamino] 10-methyl-Ν-phenylacetamide;

With a melting point of 175-17-177 (recrystallized from isopropanol)

脑 «2)

2-(5,6,7,8-tetrahydro 2- (4-pyridyl) _4-quinazolinylamino) 1-methyl-diphenylacetamide '1/5 pentahydrate;

Melting point 166-168 ° C (recrystallized from isopropanol)

■-

2— [6-Trifluoromethyl-1- (4-pyridyl) -14-pyrimidinylamino] -1-N-methyl-N-phenylacetamide;

Melting point 261-263 (recrystallized from isopropanol-acetonitrile)

2 — [6_Trifluoromethyl-5-methyl-2- (4-pyridyl) -14-pyrimidinylamino] 1-N-methyl-N-phenylacetamide;

Melting point 201 ~ 202 ° C (recrystallized from isopropanol) (m)

2- [6-trifluoromethyl-2- (3-pyridyl) -14-pyrimidinylamino] 1-N-methyl-1N-phenylacetamide;

Melting point 19 1 to 19 2 ° C (recrystallized from isopropanol)

8 8

2- (5-ethoxycarbonyl) 2- (4-pyridyl) -14-pyrimidinylamino] Production of 1N-methyl-1N-phenylacetamide

Example 4 was repeated using 4-chloro-5-ethoxycarbonyl-12- (4-pyridyl) pyrimidine instead of 4-chloro-5,6-dimethyl-2- (4-pyridyl) pyrimidine in Example 1. The reaction and treatment were carried out in the same manner as in 1, and the product was recrystallized from isopropanol to obtain the desired product.

With a melting point of 16 0 to 16 2

8

2- [5-Hydroxymethyl-1- (4-pyridyl) -4-pyrimidinylamino] -N-methyl-N-phenylacetamide

Example 8 2- [5-ethoxycarbonyl-12- (4-pyridyl) -4-pyrimidinylamino] 1-N-methyl-1-N-phenylacetamide 1.2 g obtained in Example 6, sodium borohydride 0 2 g, 0.25 g of lithium chloride and 15 ml of anhydrous tetrahydrofuran, 20 ml of anhydrous ethanol was added dropwise at 0 to 5 "C. The reaction mixture was stirred at room temperature for 5 hours, and then 0 to 5". 1N hydrochloric acid was added to the mixture at pH 5 until the pH reached 5, and the mixture was concentrated under reduced pressure.Brine and brine were added to the residue, and the layer was separated, dried over anhydrous sodium sulfate and dried under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with chloroform and purified, and recrystallized from isopropanol to obtain 0.5 g of the desired product. Melting point 173-174 ° C

8

2- [6-ethoxycarbonyl 5-methyl-2- (4-pyridyl) -14-pyrimidinylamino] 1-N-methyl-1-N-phenylacetamide

4-chloro-6-ethoxycarbonyl-15-methyl-2- (4-pyridyl) pyrimidine was used in place of the 4-chloro-1,5-dimethyl-2- (4-pyridyl) pyrimidine in Example 1. The reaction product was treated in the same manner as in Example 1, and the product was recrystallized from n-hexane-methylene chloride to obtain the desired product.

Melting point 152-153 ° C

Example 9

2- (6-Carboxy-5-methyl-1- (4-pyridyl) -1-pyrimidinylamino) Production of 1N-methyl-1N-phenylacetamide

Example 8 2- [6-ethoxycarbonyl-5-methyl-2- (4-pyridyl) -14-pyrimidinylamino] _N_methyl-1-N-phenylacetamide obtained in 8 4.0 g, 1N water A mixture of 50 ml of an aqueous sodium oxide solution and 4 Oml of ethanol was stirred at room temperature for 2 hours. The reaction mixture was漉縮in vacuo, dissolved in ice water, added until concentrated hydrochloric acid _P H4, was collected by filtration and washed with water and the precipitated crystals, the desired product 3.0g was recrystallized from black port Holm over acetonitrilate Le Was obtained as a 1/4 hydrate.

Melting point 18 1-1 84 ° C

Example 90

Preparation of 2- [5-methyl-16- (N, N-dimethylcarbamoyl) -1- (4-pyridyl) -4-pyrimidinylamino] 1-N-methyl-N-phenylacetamide Obtained in Example 89 2— [6-Carboxy-5-methyl-2- (4-pyridyl) —4-pyrimidinylamino] 1 N-methyl-1-N-phenylacetamide 1.0 g, di- To a mixture of 0.3 g of methylamine, 1.3 g of benzotriazole-1-yloxytris (dimethylamino) -phosphonium / hexafluorophosphate (B0P reagent) and 2 Oml of dimethylformamide, While maintaining the temperature at 0 to 5 ° C, 0.6 g of triethylamine was added dropwise. After completion of the dropwise addition, the mixture was stirred at room temperature for 12 hours. After concentrating the reaction mixture under reduced pressure, water and black form were added, the black form layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with chloroform and purified, and recrystallized from isopropanol to obtain 0.75 g of the desired product.

Melting point 1 78-1 80 ° C

Fine 9 1

2- (6-Hydroxymethyl-1-5-methyl-2- (4-pyridyl) -1-4-pyrimidinylamino) Production of 1N-methyl-1N-phenylacetamide

Using 2- [6-ethoxycarbonyl-2-5- (4-pyridyl) -14-pyrimidinylamino] 1N-methyl-1N-phenylacetamide obtained in Example 88, Example 87 The product was recrystallized from isopropanol to obtain the desired product as a 1/4 hydrate.

Melting point 154 ~: 1 56 "C

Example 92

2- (6-Methoxymethyl-5-methyl-2- (4-pyridyl) -1-4-pyrimidinylamino) 1-N-methyl-N-phenylacetamide

Example 9 2- [6-hydroxymethyl-15-methyl-1- (4-pyridyl) -14-pyrimidinylamino] 1-N-methyl-1-N-phenylacetamide obtained in 1 1.0 g and To a mixture of dimethylformamide (5 ml) was added 0.12 g of about 60% sodium hydride (oil) at 0 to 5 and stirred at room temperature for 1 hour. 3 g was added, and the mixture was stirred at room temperature for 1 hour and at 60 ° C for 1 hour. To the reaction mixture were added water and black form, the black form layer was separated, washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with chloroform, purified, and recrystallized from isopropanol to obtain 0.3 g of the desired product.

Melting point 13 1 to 1 32 ° C

Example 93

2 -— [6-Formyl-5-methyl-2- (4-pyridyl) -1-4-pyrimidinylamino] 1-N-methyl-N-phenylacetamide

Example 9 2- [6-hydroxymethyl-15-methyl-2- (4-pyridyl) -14-pyrimidinylamino] 1-N-methyl-N-phenylacetamide obtained in Example 1.

A mixture of 2 g, 8.4 g of manganese dioxide and 30 ml of black-mouthed form was stirred at room temperature for 24 hours. The reaction mixture was filtered, and the filtrate was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with chloroform.

7 g were obtained.

Melting point 2 19-22 1 ° C

¾ΜΙ 94

2- (5,6-Dimethyl-2- (4-pyridyl) -1 4-pyrimidinyloxy) 1-N-methyl-N-phenylacetamide

5,60-Dimethyl-2- (4-pyridyl) -14 (3H) -pyrimidinone 2.5 g and 60 ml of dimethylformamide in a mixture at 0-5 ° C approx. 60% sodium hydride (oil-based) 0 After adding 5 g and stirring at room temperature for 1 hour, 2.8 g of 2-promote N-methyl-N-phenylacetamide was added at 0 to 5 and stirred at room temperature for 1 hour and at 60 ° C. for 1 hour. Water and chloroform were added to the reaction mixture, and the foam layer was separated, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with ethyl acetate and purified, and recrystallized from isopropanol to obtain 2.8 g of the desired product.

Melting point 1 86-1 88 ° C

Example 9 5 to 10 9

Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as in Example 94 to obtain the compounds shown in Table 19.

Table 19

Example 1 1 0 1 1 4

Using the corresponding starting compounds, the reaction and treatment were conducted in the same manner as in Example 94 to obtain the compounds shown in Table 20. Table 20

¾M1 1 I 5

2- [6-Hydroxymethyl-1-5-methyl-2- (4-pyridyl) -14-pyrimidinyloxy] -1-N-methyl-N-phenylacetamide

Using 2- [6-ethoxycarbonyl-5-methyl-2- (4-pyridyl) -14-pyrimidinyloxy] -1-N-methyl-N-phenylacetamide obtained in Example 14 The reaction was performed in the same manner as in Example 87, and the product was recrystallized from isopropanol to obtain the desired product.

Melting point 194-: 195 ° C

Example 1 1 6

2- (5-Methyl-6-methylamino-1- (4-pyridyl) -14-pyrimidinyloxy) 1-N-methyl-N-phenylacetamide

A mixture of 5.6 g of 2-hydroxy N-methyl-N-phenylacetamide and 20 ml of dimethylformamide at 0 to 5 at about 60% 1.4 g of sodium hydride (oily). After stirring at room temperature for 1 hour, 4.0 g of 4-chloro-5-methyl-6-methylamino-2- (4-pyridyl) pyrimidine and 0 ml of dimethylformamide were added at 0 to 5 ° C. The mixture was stirred at 140 ° C for 3 hours for 1 hour. Water and chloroform were added to the reaction mixture, and the pore form layer was separated, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted and purified with chloroform for purification, and recrystallized from chromatography formic acetonitrile to obtain 2.8 g of the desired product as 0.3 aqueous solution.

Melting point 2 55 ~ 2 56 ° C

Example 1 1 7: L 2 5

Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as in Example 116 to obtain the compounds shown in Table 21.

Table 2 1

Example 1 26 to 1 32

(Example 26)

N-methyl-2- (5,6-dimethyl-12-phenyl-14-pyrimidinylamino) -1-N- (3-pyridyl) acetamide '1Z pentahydrate;

Melting point 1 1 2 to 1 1 4 (recrystallized from getyl ether)

1 2 7)

N-methyl-2- [5,6-dimethyl-1- (4-chlorophenyl) -14-pyrimidinylamino] -1-N- (3-pyridyl) acetamide; Melting point: 168 to 170 ° C (recrystallized from isopropanol)

(V. 1 28)

N-methyl-2- [5,6-dimethyl-2- (4-trifluoromethylphenyl) -14-pyrimidinylamino] -1-N- (3-pyridyl) acetamide '1/5 hydrate; melting point 19 5 to 1 97 ° C (recrystallized from acetonitrile)

(Example 1 2 9)

N-ethyl-1 2- (5,6-dimethyl-2-phenyl-2-pyrimidinylamino) -1-N- (3-pyridyl) acetamide;

Melting point 139-141 ° C (recrystallized from isopropanol)

(Example 1 30)

N-ethyl-1- (5,6-dimethyl-12-phenyl-14-pyrimidinylamino) -1-N- (5-methyl-13-isoxazolyl) acetamide;

Melting point 1 3 1 to 1 34 ° C (recrystallized from acetonitrile)

(m L3JJ

N-methyl-1- [5,6-dimethyl-2- (4-pyridyl) 4-pyrimidinylamino] 1-N_ (3-pyridyl) acetamide;

Melting point: 160-162 ° C (recrystallized from isopropanol)

(Example 1 32)

N-ethyl-2— [5,6-dimethyl-1- (3-Chenyl) -14-pyrimidinylamino] -N- (3-pyridyl) acetamide 1Z tetrahydrate;

Melting point 132-135 ° C (recrystallized from isopropanol)

Example 1 3 3

Production of N-ethyl-2- (5,6-dimethyl-12-phenyl-14-pyrimidinylamino-N- (2-thiazolyl) acetamide 1-g of 2- (5,6-dimethyl-1-phenyl-4-pyrimidinylamino) acetic acid, 0.7 g of 2-ethylaminothiazole, benzotriazo-1-yl 11-yloxy-tris (dimethylamino) phosphonium A mixture of 1.9 g of xafluorophosphate (BOP reagent) and 2 Oral of dimethylformamide is stirred at room temperature for 8 hours with 0.43 lb of triethylamine at 0-5 ° C while maintaining the reaction temperature at 0-5 ° C. did. The port mixture and water were added to the reaction mixture, and the port form layer was separated, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with chloroform, purified, and recrystallized from acetonitrile to obtain 0.86 g of the desired product.

200-202 ° C

Μί 1 34

Ν—Methyl-1- (5,6-dimethyl-12-phenyl 4-pyrimidinyloxy) — Preparation of Ν— (3-pyridyl) acetamide

2- (5,6-dimethyl-1-phenyl-4-pyrimidinyloxy) acetic acid 1.8 g, 3-methylaminoviridine lg, benzotriazo-1-lu 1-yloxystris (dimethylamino) phosphonium hexafluo 0.8 g of triethylamine was added to a mixture of 3.5 g of lophosphate (BOP reagent) and 3 Oml of dimethylformamide while maintaining the reaction temperature at 0 to 5 ° C, followed by stirring at room temperature for 8 hours. The form and water were added to the reaction mixture, and the form layer was separated, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted and purified with chloroform, and recrystallized from methanol to obtain 2.lg of the desired 1Z tetrahydrate.

Melting point 162-164 ° C Example 13 to 13

Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as in Example 134 to obtain the compounds shown in Table 22.

Table 2 2

Example 1 4 0

2- [5,6-Dimethyl_2- (2-Chenyl) -14-Pyrimidinyloxy] 1-N-Methyl-1-N- (2-thiazolyl) acetamide

Example 13 Instead of 2- (5,6-dimethyl-12-phenyl-4-pyrimidinyloxy) acetic acid and 3-methylaminoviridine in 34, 2- [5,6-dimethyl-1- ( [2-Chenyl) -14-pyrimidinyloxy] The reaction and treatment were carried out using acetic acid and 2-methylaminothiazole in the same manner as in Example 134. The product was recrystallized from acetonitrile to obtain the desired product. Was.

Melting point 18 1 ~: in 1 8 3

Example 1 4 1 Production of N- (4-methoxyphenyl) -1-N-methyl-1-2- [6-methylamino-2- (3-pyridyl) -14-pyrimidinylamino] acetoamide

Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as in Example 116. The product was recrystallized from isopropanol to obtain the desired product.

Melting point 16 0 to 16 3 C

Example 1 4 2

Production of N-methyl-N-phenyl 2- [2- (3-pyridyl) -14-pyrimidinylamino] acetamide

Example 7 2- [6-Methylthio-12- (3-pyridyl) -14-pyrimidinylamino] 1-N-methyl-N-phenylacetamide obtained in 7 2.0 g, Raney nickel 2 A mixture of 5 g and 30 ml of ethanol was heated to reflux for 4 hours. The reaction mixture was subjected to ceritic filtration, and the filtrate was concentrated under reduced pressure. Then, water and chloroform were added, and the pore form layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with ethyl acetate and purified, and recrystallized from isopropanol to obtain 1.3 g of the desired product.

With a melting point of 1 2 7 to 1 2 9

Example 1 4 3

2- [6-Methyl-2- (3-pyridyl) -1 4-pyrimidinylamino] 1-N-methyl N-phenylacetamide

Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as in Example 1, and the product was recrystallized from isopropanol to obtain the desired product.

Melting point 1 26 to 1 28 ° C

Example 1 4 4

2-C5-methyl-6-methylthio-1- (3-pyridyl) -14-pyrimidinyl Production of 1N-methyl-1N-phenylacetamide Using the corresponding starting compounds, the reaction and treatment were carried out in the same manner as in Example 39, and the product was recrystallized from isopropanol to give the desired product. Obtained as 0.3 hydrate. Melting point 15 2 to 15 4 ° C

mm 1 5

Preparation of 2- [5-methyl-1- (3-pyridyl) -1-pyrimidinylamino] -1-N-methyl N-phenylacetamide 2- [5-methyl obtained in Example 144 1-Methylthio-12- (3-pyridyl) -14-pyrimidinylamino] Using 1N-methyl-N-phenylacetamide, the reaction was carried out in the same manner as in Example 142, and the product was treated with isopropanol. The residue was recrystallized from dimethyl ether to give the desired product as pentahydrate. Melting point 1 1 1 to 1 1 3 ° C Manufacturing example 1: Production of tablets

• 2— [5,6-dimethyl-1- (4-pyridyl) -1-

4Pyrimidinylamino] N-methyl-N

Fenilacetamide 1 g

-Lactose 84 g

-30 g corn starch • 25 g microcrystalline cellulose

-Hydroxypropyl cellulose 3 g

-0.7 g of light caffeic anhydride

'Magnesium stearate 1.3 g The above ingredients are mixed and granulated in a conventional manner, and tableted at 14.5 mg per tablet to make 100 tablets. Production example 2: Tablet production

N, N-Jetyl-2-[5,6-Dimethyl-2

(4-pyridyl) 4-pyrimidinylamino) acetamide 25 g

-Lactose 70 g

-20 g of corn starch-25 g of crystalline cellulose-3 g of hydroxypropyl cellulose-0.7 g of light caffeic anhydride-1.3 g of magnesium stearate The above ingredients are mixed and granulated in the usual way. Tablets are produced at a dose of 14.5 mg per tablet to produce 100 tablets. Formulation Example 3: Production of capsules • 2— [6-Methoxymethyl-1-5-methyl-1 2—

(4-pyridyl) -1-pyrimidinylamino]

N-methyl-N-phenylacetamide 2 g

Lactose 1 65 g

• 25 g corn starch

-Hydroxypropyl cellulose 3.5 g

• 1.8 g of light caffeic anhydride

'' 2.7 g of magnesium stearate The above ingredients were mixed and granulated according to the usual method, and 20 mg of granules were filled in a capsule, and 10 mg

Make 0 0 capsules. Formulation Example 4: Production of powder

'2-[5-Methyl-1 6-methylamino-2-

(4-pyridyl) _ 4-piridimidinylamino] N-methyl-N-phenylacetamide 10 g-lactose 960 g

-Hydroxypropylcellulose 25 g

-Light Keiic anhydride 5 g Mix the above ingredients by a conventional method to make a powder.

Formulation Example 5: Production of injection

■ 2-[5,6-dimethyl-1- 2 _ (4

Pyridyl) -1 4-pyrimidinylamino]

N-methyl-N-phenylacetamide 10 g 'Ethanol 200 g

-HCO- 60 2 g

• Cuenoic acid 10 g

• 50 g sorbitol

-Sodium hydroxide

-Water for injection

2000 ml total volume

2- [5,6-Dimethyl-2- (4-pyridyl) -14-pyrimidinylamino] 1 N-methyl-N-phenylacetamide is dissolved in a mixture of ethanol and HCO-60, and the appropriate amount After adding citrate and sorbitol, adjust the pH value to 4.5 with sodium hydroxide, and add water for injection to prepare the whole volume. This solution is filtered through a membrane filter (0.22 m), and the filtrate is filled into a 2 ml ampoule, which is then sterilized at 121 ° C for 20 minutes.

Availability of business

As described above, the compound of the present invention represented by the formula (I) and a physiologically acceptable compound thereof Acid addition salts are the selective and remarkable affinity for the peripheral-type BZ omega ₃ receptors with indicate to, the anxiolytic effects in animal tests, than exhibit superior pharmacological action of antiepileptic action and the like Useful for the treatment and prevention of anxiety-related diseases (neurosis, psychosomatic disorders, other anxiety disorders), central illness such as depression and epilepsy, circulatory diseases such as angina pectoris and hypertension . Further, the compound of the present invention represented by the formula (I) and a physiologically acceptable acid addition salt thereof can be used as a therapeutic drug for an immune neurological disease such as multiple sclerosis or an immunoinflammatory disease such as rheumatism. And expected as a prophylactic.

Claims

The scope of the claims

1. A 2,4-disubstituted pyrimidine derivative represented by the following formula (I) or a physiologically acceptable acid addition salt thereof.

(Wherein, X represents 10— or —NR ₄ —, represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, or a cycloalkyl (lower) alkyl group;

R 2 represents a lower alkyl group, a lower alkenyl group, a cycloalkyl group, an unsubstituted or substituted phenyl group, an unsubstituted or substituted phenyl (lower) alkyl group, or an unsubstituted or substituted heteroaryl group. ,

R ₃ represents a hydrogen atom, a lower alkyl group or a hydroxy (lower) alkyl group; R ₄ represents a hydrogen atom or a lower alkyl group;

R ₅ represents any group included in the following groups (a) and (b): group (a) ——

A hydrogen atom, a lower alkyl group and a lower alkenyl group;

Group (b) ——

Halogen atom, hydroxy (lower) alkyl group, lower alkoxy (lower) alkyl group, unsubstituted or substituted benzyloxy (lower) alkyl group, acyloxy (lower) alkyl group, amino group, mono- or di-lower alkylamino group, Acylamino group, amino (lower) alkyl group, mono- or di-lower alkylamino (lower) alkyl group, Toro, carbamoyl, mono- or di-lower alkyl carbamoyl, carboxyl, protected carboxyl, carboxy (lower) alkyl, protected ruboxy (lower) alkyl and represented by the formula Base

-CON (R ₉ )-(CH ₂ ) _m -N (R! ₀ ) (R !!) wherein R ₉ , R! 0 and R are the same or different and are each a hydrogen atom or a lower alkyl group. Means m, 1, 2 or 3);

Does R ₆ mean any of the groups included in the following group (c) and group (d):

Group (c) ——

A hydrogen atom, a lower alkyl group and a trifluoromethyl group;

Group (d) ——

Halogen atom, lower alkoxy group, hydroxy (lower) alkyl group, lower alkoxy (lower) alkyl group, unsubstituted or substituted benzyloxy (lower) alkyl group, acyloxy (lower) alkyl group, amino group, mono- or di- Lower alkylamino, arylamino, aryl (lower) alkylamino, acylamino, amino (lower) alkyl, mono- or di-loweralkylamino (lower) alkyl, nitro, carbamoyl, mono- or mono- Di-lower alkyl group rubamoyl group, formyl group, lower alkanoyloxy group, aryloxy group, aryl (lower) alkyloxy group, carboxyl group, protected carboxyl group, carboxy (lower) alkyl group, protected carboxy (lower) Alkyl group, lower Groups represented by alkylthio groups and the following formula

-CON (R ₉ )-(CH ₂ ) _m -N (R! ₀ ) (R! I) (wherein R ₉ , R! ₀ , R! And m mean the same as above); Alternatively, R ₅ and R ₆ may be linked to form one (CH ₂ ) _n — (where n means 3, 4.5 or 6),

(Wherein, R ₇ is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, preparative Rifuruoromechiru group, hydroxy group, amino group, mono- or di-lower alkylamino amino group, Shiano group or a nitro group, R ₈ Represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group),

(ii) when R ₅ is any group contained in the above group (a), R ₆ means any group contained in the above groups (c) and (d),

(iii) R ₅ ^force? R ₆ when it is any of the groups contained in the groups (b) refers to any group contained in the group (c))

2. The compound according to claim 1, wherein R 1 is a lower alkyl group, and R ₂ is a lower alkyl group, an unsubstituted or substituted phenyl group, or an unsubstituted or substituted heteroaryl group.

3. is methyl, ethyl, propyl, isopropyl or butyl, and R ₂ is ethyl, propyl, isopropyl, butyl, phenyl, nitrogen, C—C alkyl, C ₃ Alkoxy, amino, nitro, cyano Or phenyl, pyridyl, thienyl, furyl, thiazolyl or methyl-3-isoxazolyl substituted with trifluoromethyl, R ₃ is a hydrogen atom, R ₅ hydrogen atom or lower alkyl 2. The compound according to claim 1, wherein R <" is a lower alkyl group, a lower alkoxy group, a lower alkoxy (lower) alkyl group, or a lower alkylamino group.

4. The compound according to claim 3, wherein R ₅ is a hydrogen atom, a methyl group or an ethyl group, and R ₆ is a methyl group, a methoxy group, a methoxymethyl group or a methylamino group.

5. A 2,4-disubstituted pyrimidine derivative represented by the following formula (Ia) or a physiologically acceptable acid addition salt thereof.

(Wherein, X ′ represents 10— or 1 NR ₄ , 1, represents a methyl group, an ethyl group, a propyl group, an isopropyl group or a butyl group, and R ₂ , represents an ethyl group, a propyl group, An isopropyl group, a butyl group, a phenyl group or a phenyl group substituted with halogen or methoxy, R ₄ ′ represents a hydrogen atom, a methyl group or an ethyl group, A ′ represents an unsubstituted or substituted pyridyl group, Chenyl group or furyl group)

6. A 2,4-disubstituted pyrimidine derivative represented by the following formula (Ib) or a physiologically acceptable acid addition salt thereof.

(Wherein X, represents 10— or 1 NR ₄ , 1; R! ′ Represents methyl, ethyl, propyl, isopropyl, or butyl; R ₂ ′ represents ethyl, propyl; R ₄ , represents a hydrogen atom, a methyl group or an ethyl group, and R ₅ ′ represents a hydrogen atom, a methyl group or an ethyl group, a phenyl group substituted with a halogen or a methoxy group. A represents an atom or a methyl group, R ₆ 'represents a methoxy group, a methoxymethyl group or a methylamino group, and A, represents an unsubstituted or substituted pyridyl group, a phenyl group, or a furyl group.

7. The compound according to claim 5, wherein X ′ is 10 − or 1 NH—, and A, is a pyridyl group or a phenyl group.

8. The compound according to claim 6, wherein X ′ is 10— or 1 NH—, and A ′ is a pyridyl group or a phenyl group.

9. 2— [5,6-Dimethyl-1- (4-pyridyl) -14-pyrimidinylamino] 1-N-methyl-1-N-phenylacetamide,

N-ethyl 2- (5,6-dimethyl- 1 2 _ (4-pyridyl) -1 4-pyrimidinylamino) 1-N-phenylacetamide,

N- (4-chlorophenyl) -1-2- [5,6-dimethyl-2- (3-pyridyl) -14-pyrimidinylamino] 1-N-methylacetamide,

N-ethyl 2- (5,6-dimethyl-1- (2-phenyl) -1-pyrimidinylamino) 1-N-phenylacetamide, N-ethyl-2— [5,6-dimethyl-2- (4-pyridyl) -14-pyrimidinyloxy] 1-N-phenylacetamide,

N, N-Jetyl-2- (5,6-dimethyl-2- (4-pyridyl) -14-pyrimidinylamino) acetamide,

2— [6-Methylamino-2- (4-pyridyl) -1-4-pyrimidinylamino] 1-N-methyl-N-phenylacetamide,

2-[6-Methoxy-1 2- (4-pyridyl) -1 4-pyrimidinylamino] 1-N-methyl-N-phenylacetamide,

N-Methyl-1-2- (5-methyl-6-methylamino) 2- (4-pyridyl) -14-pyrimidinyloxy] -1-N-phenylacetamide,

N-methyl-2- [5-methyl-1-6-methylamino-1- (4-pyridyl) -14-pyrimidinylamino] phenylacetamide,

N- (3-chlorophenol) -1-N-methyl-1-2- [5-methyl-16-methylamino-12- (3-pyridyl) -14-pyrimidinylamino] acetamide,

N— (3-chlorophenol) 1 2— [6-Methoxy-5-methyl-2- (3-pyridyl) -14-pyrimidinylamino] 1-N-methylacetamide,

N- (4-Methoxyethoxy) 1-2- [6-Methoxy-5-methyl-12- (3-pyridyl) -14-pyrimidinylamino] 1-N-methylacetamide,

2- [6-Methoxymethyl-5-methyl-1- (4-pyridyl) -14-pyrimidinylamino] N-methyl-N-phenylacetamide,

2— [5,6-Dimethyl-1- (3-pyridyl) -14-pyrimidinyloxy] -1-N, N-dipropylacetamide, and

2-5,6-Dimethyl-2- (2-Chenyl) -1-pyrimidinylamino] -N, N-Dipropylacetamide Any compound selected from:

10. By the method shown in the following (a), (b), (c) or (d), the following formula (I)

(Wherein, X represents —〇 or 1 NR ₄ —, represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, or a cycloalkyl (lower) alkyl group;

R ₂ represents a lower alkyl group, a lower alkenyl group, a cycloalkyl group, an unsubstituted or substituted phenyl group, an unsubstituted or substituted phenyl (lower) alkyl group, or an unsubstituted or substituted heteroaryl group. ,

R 4 represents a hydrogen atom or a lower alkyl group,

A hydrogen atom, a lower alkyl group and a lower alkenyl group;

Group (b) ——

Halogen atom, hydroxy (lower) alkyl group, lower alkoxy (lower) alkyl group, unsubstituted or substituted benzyloxy (lower) alkyl group, acyloxy (lower) alkyl group, amino group, mono- or di-lower alkylamino group, Acylamino, amino (lower) alkyl, mono- or di-lower alkylamino (lower) alkyl, nitro, carbamoyl, mono- or di-lower alkyl rubamoyl, carboxyl, protected carboxyl , Carboxy (lower) alkyl group, protected power Ruboxy (lower) alkyl group and group represented by the following formula

-CON (R ₉ )-(CH ₂ ) _m -N (R ₁₀ ) (R)

(Wherein R ₉ , R ₀ and R i are the same or different and each represents a hydrogen atom or a lower alkyl group, and m represents 1, 2 or 3);

Does R ₆ mean any group included in the following groups (c) and (d):

Group (c) ——

A hydrogen atom, a lower alkyl group and a trifluoromethyl group;

Group (d) ——

Halogen atom, lower alkoxy group, hydroxy (lower) alkyl group, lower alkoxy (lower) alkyl group, unsubstituted or substituted benzyloxy (lower) alkyl group, acyloxy (lower) alkyl group, amino group, mono or mono Di-lower alkylamino group, arylamino group, aryl (lower) alkylamino group, acylamino group, amino (lower) alkyl group, mono- or di-lower alkylamino (lower) alkyl group, nitro group, carbamoyl group Mono- or di-lower alkyl groups rubamoyl, formyl, lower alkanoyloxy, aroyloxy, aryl (lower) alkyloxy, carboxyl, protected carboxyl, carboxy (lower) alkyl, protected Carboxy (lower) alkyl group, low Groups represented by Arukiruchio groups and the following formula

-CON (R ₉ )-(CH ₂ ) _m -N (RJ ₀ ) (R 1 i)

(Wherein, R ₉ , R! ₀ , R ii and m mean the same as described above); or R _c and R ₆ together form one (CH ₂ ) _π — (where η is 3 , Four, 5 or 6)

(Wherein, R ₇ represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a trifluoromethyl group, a hydroxy group, an amino group, a mono- or di-lower alkylamino group, a cyano group or a nitro group, ₈ represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group),

(ii) When R ₅ is any group included in the above group (a), R ₆ means any group included in the above groups (c) and (d),

(iii) when R 5 is any group included in the above group (b), R ₆ means any group included in the above group (c))

A method for producing a 2,4-disubstituted pyrimidine derivative represented by the formula and, if necessary, producing a physiologically acceptable acid addition salt thereof.

(a) In the case of a compound in which X is -NR 1 in the formula (I), the following formula (II)

(Wherein, Z represents a leaving atom or leaving group, and R ₅ ! And R ₆ ! Are hydroxy (lower) ) R ₅ and R ₅ supra except that the alkyl, amino, amino (lower) alkyl, carboxyl and carboxy (lower) alkyl groups are replaced by protected forms.

A means the same as defined in ₆ , and A means the same as described above) and a compound represented by the following formula (III)

HN (R ₄ ) -CH (R ₃ i) -CON (R ₁ ) (R ₂ ) (III)

(Wherein, R ₃ i represents a hydrogen atom, a lower alkyl group or a protected hydroxy (lower) alkyl group, and R, R _2, and R ₄ have the same meanings as described above.) And, if necessary, removing the protecting group of the product,

(b) In the compound of the formula (I) wherein X is —0—, the compound represented by the following formula (IVa)

(Wherein, R ₅ ], R ₆ i and A have the same meanings as described above) and a compound represented by the following formula (V)

Z! -CH (R ₃ i) -CON (R ^ (Rs) (V)

(In the formula, Z represents a halogen atom, and R _} , R 2 and R ₃ have the same meanings as described above.)

Reacting with the compound represented by the formula, and if necessary, removing the protecting group of the product.

(c) The following formula (VI)

(Wherein, A, X, R ₃ , R ₅ ! And R ₆ ! Mean the same as described above) or a reactive derivative thereof, and the following formula (VI I)

HN (R _{Interview) (R 2) (VI I} )

(Wherein R and R ₂ have the same meanings as described above), and if necessary, the protecting group of the product is removed; or

(d) In the compound of the formula (I) wherein X is -〇 and R ₃ is a hydrogen atom, the following formula (I Γ)

Wherein, in the formula, R ₅₁ , R ₆ j and A mean the same as described above, and a compound represented by the following formula (X):

(Wherein R〗 and R ₂ have the same meanings as described above), and the protecting group of the product is removed as necessary.

1 1. A pharmaceutical composition comprising a normal pharmaceutical carrier and a 2,4-disubstituted pyrimidine derivative or a physiologically acceptable acid addition salt thereof according to claim 1 as an active ingredient.

12. A pharmaceutical composition comprising a normal pharmaceutical carrier and a 2,4-disubstituted pyrimidine derivative or a physiologically acceptable acid addition salt thereof according to claim 5 or 6 as an active ingredient.

13. A therapeutic agent for anxiety-related diseases, comprising the 2,4-disubstituted pyrimidine derivative according to claim 1 or a physiologically acceptable acid addition salt thereof as an active ingredient.

14. A method for treating an anxiety-related disease, comprising administering an effective amount of the 2,4-disubstituted pyrimidine derivative or the physiologically acceptable acid addition salt thereof according to claim 1 to a patient having the anxiety-related disease.

15. Use of the 2,4-disubstituted pyrimidine derivative or the physiologically acceptable acid addition salt thereof according to claim 1 for the treatment of a patient with an anxiety-related disease.

16. An anxiolytic drug comprising, as an active ingredient, the 2,4-disubstituted pyrimidine derivative or the physiologically acceptable acid addition salt thereof according to claim 1.

17. A therapeutic drug for an immune inflammatory disease, comprising the 2,4-disubstituted pyrimidine derivative or the physiologically acceptable acid addition salt thereof according to claim 1 as an active ingredient.

18. A method for treating an immune inflammatory disease, which comprises administering an effective amount of the 2,4-disubstituted pyrimidine derivative or the physiologically acceptable acid addition salt thereof according to claim 1 to a patient having the immune inflammatory disease.

19. Use of the 2,4-disubstituted pyrimidine derivative or the physiologically acceptable acid addition salt thereof according to claim 1 for the treatment of a patient with an immune inflammatory disease.