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WO1998009960A1 - Derives de pyrimidine 2,4-bisubstitues, procede pour leur production et compositions medicales les contenant - Google Patents

Derives de pyrimidine 2,4-bisubstitues, procede pour leur production et compositions medicales les contenant Download PDF

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Publication number
WO1998009960A1
WO1998009960A1 PCT/JP1997/003079 JP9703079W WO9809960A1 WO 1998009960 A1 WO1998009960 A1 WO 1998009960A1 JP 9703079 W JP9703079 W JP 9703079W WO 9809960 A1 WO9809960 A1 WO 9809960A1
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group
methyl
alkyl
alkyl group
pyridyl
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PCT/JP1997/003079
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English (en)
Japanese (ja)
Inventor
Teruya Murata
Katsunori Kondo
Kiyoshi Furukawa
Makoto Oka
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Dainippon Pharmaceutical Co., Ltd.
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Priority to AU41342/97A priority Critical patent/AU4134297A/en
Publication of WO1998009960A1 publication Critical patent/WO1998009960A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom

Definitions

  • 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.
  • central ( ⁇ , ⁇ 2 ) The central nervous system of mammals, including humans, has three benzodiazepine (hereinafter sometimes abbreviated as “BZ”) recognition sites, which are called “central ( ⁇ , ⁇ 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 " ⁇ > 3 receptor”).
  • BZ w 1 receptor also referred to as "Betazetaomega 2 receptor”
  • ⁇ > 3 receptor endocrine organs such as adrenal gland and testis, mast cells, lymphocytes, macro cells
  • peripheral ⁇ 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.
  • neurosteroids such as aropregnanolone and arotetrahydrodeoxycorticosterone ( It is thought to affect the biosynthetic pathway to THDOC). Therefore, when the peripheral ⁇ 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)].
  • 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,
  • R represents hydrogen or alkyl having 1 to 3 carbons
  • 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,
  • 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
  • n 0 or 1
  • n 0, 1 or 2
  • 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
  • B indicates nitrogen
  • Z is in the ortho position with respect to B
  • X is an acid.
  • R represents hydrogen
  • the sum of m + n is other than 1 and excludes 2-phenyl-14-quinolyl-1-N, N-dimethylcarbamate
  • R ⁇ 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 0, 1, or 2
  • p is 0 or 1
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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) ———
  • 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
  • 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);
  • 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
  • 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
  • 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.
  • R 8 represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group
  • R 6 means any group included in the groups (c) and (d);
  • 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.
  • 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 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.
  • 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.
  • cycloalkyl group means one having 3 to 8 carbon atoms, and specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • 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 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.
  • aryl group examples 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
  • -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.
  • 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.
  • 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.
  • lower alkenyl group examples include acetoxy, propionyloxy, and butyryloxy.
  • aroyloxy group examples include benzoyloxy.
  • 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.
  • 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 alkylthi
  • 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.
  • R i is a methyl group, an ethyl group, a propyl group, an isopropyl group or a butyl group
  • 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 -?
  • 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.
  • R is a methyl group, an ethyl group, a propyl group, an isopropyl group or a butyl group
  • R 2 is an ethyl group, a propyl group or an isopropyl group.
  • R 3 is a hydrogen atom
  • R 5 is a hydrogen atom
  • R 6 is a methyl group, a methoxy group, a methoxymethyl group or a methylamino group
  • 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.
  • X represents 10— or 1 NR 4 , 1, represents a methyl group, ethyl group, propyl group, isopropyl group or butyl group
  • R 2 represents a methyl group, a propyl group
  • R 4 ′ represents a hydrogen atom, a methyl group or an ethyl group, and A ′ is unsubstituted or substituted Pyridyl, phenyl or furyl
  • 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
  • particularly preferred compounds include, for example, the following compounds and physiologically acceptable acid addition salts thereof.
  • 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.
  • 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.
  • 2-pyridyl - represents a 5-CF 3 5-tri Furuoromechiru one 2 _ pyridyl group.
  • Pr Pr-CH 2 concealed t H 4
  • the compound of the present invention can be produced, for example, by the following method.
  • Z represents a leaving atom or a leaving group
  • R 5 and R 6 i are hydroxy
  • 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.
  • 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.
  • 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.
  • 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.
  • aromatic hydrocarbons such as toluene and xylene
  • ketones such as methyl ethyl ketone and methyl isobutyl ketone
  • ethers such as dioxane and diglyme
  • alcohols such as ethanol, isopropanol and butanol.
  • This reaction is preferably carried out in the presence of a base.
  • the base include sodium carbonate, alkali carbonates such as potassium carbonate, sodium hydrogen carbonate, and hydrogen carbonate.
  • 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.
  • a catalyst such as palladium on carbon and Raney nickel.
  • 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.
  • a suitable solvent for example, alcohols such as methanol, ethanol, and isopropanol, dioxane, water, or a mixture thereof is used.
  • 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)
  • 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).
  • 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).
  • a sulfonylating agent eg, methanesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfony
  • the starting material (IV) is commercially available or known per se, for example J. Am.
  • the starting material (IV ) can be obtained from commercially available sources or by methods known per se, for example
  • 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.
  • the compound in which X is —0— is a compound represented by the following formula (IVa) (IVa)
  • Z i means a halogen atom
  • 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.
  • a base examples include toluene, xylene, dimethoxetane, 1,2-dichloroethane, acetate, methylethylketone, dioxane, diglyme, ethylethyl acetate, dimethylformamide, and dimethylsulfoxide.
  • 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)
  • 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.
  • 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.
  • This reaction is carried out in the presence of a base, if necessary.
  • a 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)
  • 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)
  • 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
  • the compound of the formula (IX) is commercially available or can be produced by a method known per se.
  • the compound wherein X is —0— and R 3 is a hydrogen atom is represented by the following formula: (I)
  • the reaction of the compound of the formula (I ⁇ ;) 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.
  • a base without a solvent or in a suitable solvent under normal pressure or pressure.
  • the solvent to be used include toluene, xylene, dimethoxetane, 1,2-dichloroethane, aceton, methylethylketone, dioxane, diglyme, ethylethyl acetate, dimethylformamide, and dimethylsulfoxide.
  • 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, R, and R 2 mean the same as above
  • 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.
  • 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.
  • 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.
  • 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 ( ⁇ , ⁇ 2) and peripheral-type 3) Benzojiazepin receptor binding trial
  • ⁇ 2 and ⁇ 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.
  • 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 ⁇ and ⁇ 2 ; buffer ⁇ for ⁇ 2 )).
  • 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% 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 ⁇ and ⁇ 2 receptors of 100 OnM or more.
  • 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.
  • 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
  • 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)
  • 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.
  • rodents such as mice and rats
  • it is an effective and simple method for investigating the anxiolytic effects of drugs on behavioral pharmacology.
  • many of the cholecystokinin type 11 antagonists and benzodiazepines show positive effects.
  • 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.
  • mice 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
  • 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.
  • 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.
  • 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 ⁇ 3 ⁇ 4 ⁇ no days.
  • the compound of the present invention is usually administered in the form of a preparation prepared by mixing with a preparation carrier.
  • a preparation 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,
  • 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.
  • 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.
  • compositions 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.
  • Glue 1 Preparation of 5, 6-dimethyl-2- (4-pyridyl) -14 (3H) -pyrimidinone
  • 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.
  • 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.
  • phyt B0P reagent
  • 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.
  • Trifluoroacetic acid was added to a mixture of 20 g of the above product and 200 ml of Shiridani methylene.
  • 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.
  • 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.
  • Example 39 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.
  • 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.
  • Example 2 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
  • Example 2 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.
  • 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.
  • 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.
  • 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".
  • Example 1 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.
  • 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 ⁇ 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.
  • Example 87 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.
  • 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.
  • Example 9 2- [6-hydroxymethyl-15-methyl-2- (4-pyridyl) -14-pyrimidinylamino] 1-N-methyl-N-phenylacetamide obtained in Example 1.
  • Example 14 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.
  • 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
  • BOP reagent xafluorophosphate
  • 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.
  • 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.
  • 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.
  • Example 1 Production of N- (4-methoxyphenyl) -1-N-methyl-1-2- [6-methylamino-2- (3-pyridyl) -14-pyrimidinylamino] acetoamide
  • Example 116 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.
  • 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.
  • 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 .
  • 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.

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Abstract

L'invention concerne des dérivés de pyrimidine 2,4-bisubstitués, représentés par la formule générale (I), dans laquelle X représente O ou NR4; R1 représente H, alkyle inférieur, etc.; R2 représente alkyle inférieur, alkényle inférieur, etc.; R3 représente H, alkyle inférieur, etc.; R4 représente H ou alkyle inférieur; R5 représente H, alkyle inférieur, etc., ou halogéno, hydroxy-alkyle (inférieur), alcoxy (inférieur)-alkyle (inférieur), etc.; R6 représente H, alkyle inférieur, etc., ou hydroxy-alkyle (inférieur), alcoxy (inférieur)-alkyle (inférieur), etc.; ou R5 et R6 peuvent former ensemble (CH2)n (où n est 3 à 6); et A représente hétéro-aryle éventuellement substitué ou phényle éventuellement substitué; ainsi que leurs sels d'addition acide physiologiquement acceptables. Ces composés peuvent être utiles comme agents thérapeutiques et préventifs dans les maladies du système nerveux central telles que celles associées à l'angoisse, névroses et troubles psychosomatiques par exemple, la dépression et l'épilepsie; les troubles circulatoires tels que l'angine de poitrine et l'hypertension; les troubles neurologiques d'origine immunologique tels que la sclérose en plaques; et les troubles inflammatoires d'origine immunologique tels que les rhumatismes.
PCT/JP1997/003079 1996-09-04 1997-09-03 Derives de pyrimidine 2,4-bisubstitues, procede pour leur production et compositions medicales les contenant WO1998009960A1 (fr)

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WO1999059980A1 (fr) * 1998-05-18 1999-11-25 Dainippon Pharmaceutical Co., Ltd. Derives de [2-alkyle-5-halogeno-6-(4-trifluoromethylphenyle)-4-pyrimidinylamino]acetamide, procede relatif a l'elaboration des derives en question, composition medicinale renfermant les derives consideres, et intermediaires pour ces derives
WO2000042025A1 (fr) * 1999-01-14 2000-07-20 Meiji Seika Kaisha, Ltd. Inhibiteurs de poly(adp-ribose) polymerase consistant en des derives de pyrimidine
US6432947B1 (en) 1997-02-19 2002-08-13 Berlex Laboratories, Inc. N-heterocyclic derivatives as NOS inhibitors
US6525051B2 (en) 2000-03-27 2003-02-25 Schering Aktiengesellschaft N-heterocyclic derivatives as NOS inhibitors
WO2003049739A1 (fr) * 2001-12-07 2003-06-19 Vertex Pharmaceuticals, Inc. Composes a base de pyrimidine utiles en tant qu'inhibiteurs des gsk-3
US6620817B1 (en) 1999-11-17 2003-09-16 Dainippon Pharmaceutical Co., Ltd. [5-chloro-6-phenyl-2-(4-trifluoromethylphenyl)-4-pyrimidinylamino]acetamide derivatives, process for producing the same, medicinal compositions containing the same and intermediate of these compounds
US6982259B2 (en) 2002-04-30 2006-01-03 Schering Aktiengesellschaft N-heterocyclic derivatives as NOS inhibitors
JP2007527413A (ja) * 2003-10-24 2007-09-27 エグゼリクシス， インコーポレイテッド ｐ７０Ｓ６キナーゼモジュレーターおよび使用方法
JP2010514713A (ja) * 2006-12-27 2010-05-06 サノフィ−アベンティス ヘテロアリール置換カルボキサミド及びｎｏシンターゼの発現を刺激するためのその使用
JP2010522210A (ja) * 2007-03-22 2010-07-01 バーテックス ファーマシューティカルズ インコーポレイテッド Ｊａｋ阻害薬として有用なｎ−複素環式化合物
EP2303015A2 (fr) * 2008-05-13 2011-04-06 Syngenta Limited Composes chimiques
US8586751B2 (en) 2009-06-12 2013-11-19 Bristol-Myers Squibb Company Nicotinamide compounds useful as kinase modulators
US10881656B2 (en) 2008-12-10 2021-01-05 The General Hospital Corporation HIF inhibitors and use thereof
CN113454076A (zh) * 2018-11-30 2021-09-28 细胞结构公司 用于激活造血干细胞和祖细胞的芳香族化合物
WO2021235420A1 (fr) * 2020-05-19 2021-11-25 ユニマテック株式会社 Composé de fluoropyrimidine et composé de fluoropyrimidinone

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US6887865B2 (en) 1997-02-19 2005-05-03 Berlex Laboratories, Inc. N-heterocyclic derivatives as NOS inhibitors
US6864263B2 (en) 1997-02-19 2005-03-08 Berlex Laboratories, Inc. N-heterocyclic derivatives as NOS inhibitors
US6432947B1 (en) 1997-02-19 2002-08-13 Berlex Laboratories, Inc. N-heterocyclic derivatives as NOS inhibitors
US6864368B2 (en) 1997-02-19 2005-03-08 Berlax Laboratories, Inc. N-heterocyclic derivatives as NOS inhibitors
US6849739B2 (en) 1997-02-19 2005-02-01 Berlex Laboratories, Inc. N-heterocyclic derivatives as NOS inhibitors
US6846829B2 (en) 1997-02-19 2005-01-25 Berlex Laboratories, Inc. N-heterocyclic derivatives as NOS inhibitors
US6670473B2 (en) 1997-02-19 2003-12-30 Berlex Laboratories, Inc. N-heterocyclic derivatives as NOS inhibitors
US6747031B2 (en) 1997-02-19 2004-06-08 Berlex Laboratories, Inc. N-heterocyclic derivatives as NOS inhibitors
US6841673B2 (en) 1997-02-19 2005-01-11 Berlex Laboratories, Inc. N-heterocyclic derivatives as nos inhibitors
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