JPH06501926A - heterocyclic compound - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] This invention relates to novel heterocyclic compounds.

More specifically, this invention provides novel heterocyclic compounds with pharmacological activity and Pharmaceutically acceptable salts thereof, processes for their production, and pharmaceutical compositions containing the same and its use.

Therefore, one objective of this invention is to have antithrombotic, vasodilatory and anti-inflammatory effects. Provided are novel and useful heterocyclic compounds and pharmaceutically acceptable salts thereof having It is to be.

Another object of the present invention is to provide a method for producing this heterocyclic compound and its salts. That's true.

Yet another object of this invention is to provide the above-mentioned heterocyclic compounds or pharmaceutically acceptable It is an object of the present invention to provide a pharmaceutical composition containing a salt thereof.

Yet another object of the invention is to provide the above-mentioned heterocyclic compounds or pharmaceutically acceptable compounds. Its salts can be used to treat thrombosis, hyperemia, coronary or cerebrovascular diseases and inflammation, especially To provide an invention for use as a pharmaceutical for the prevention and treatment of thrombosis in humans and animals. That's true.

The heterocyclic compound targeted by this invention is novel and is represented by the following general formula (I). Ru.

In the formula, R1 and R2 each represent a lower alkoxy group, and R3 represents pyridyl or tetrahydro. selected from the group consisting of lopyridyl, piperidyl, piperazinyl and morpholinyl groups. Heterocyclic group which may have one or more suitable substituents; substituted amino group ; Carboxy (lower) alkenyl group; Carboxy (lower) alkyl group; Hydroxy (lower) alkyl group: an amino (lower) alkyl group which may have one or more suitable substituents; The group of the following formula (In the formula, R4 is hydrogen, ethoxy, mono(or di)lower alkylamino, di(lower (class) alkylamino-(lower) alkylamino, with one or more suitable substituents a heterocyclic amino group that may have one or more suitable substituents, or a heterocyclic group that may have one or more suitable substituents. show) or a group of the following formula, (In the formula, RS is lower alkyl or alkyl which may have one or more suitable substituents ( (lower) alkyl group, Xl represents an acid residue) Y is CH or N, Z represents CH or N.

However, R3 is a pyridyl group; a piperidyl group that may have a hydroxy group; a lower alkali Piperazinyl group having a kill group or a hydroxy (lower) alkyl group; morpholinyl group; Nyl group: lower alkenylamino group; hydroxy (lower) alkylamino group; ben A phenylamino group which may have a lower alkoxy group or a halogen on the zene ring; Halophenyl (lower) alkylamino group; nitro group, amino group or or halogen-containing phenylsulfonylamino group; or lower alkyl group and hydrogen Substituted with two substituents selected from the group consisting of droxy (lower) alkyl groups an amino group, and further When Y is N, Z represents CH.

The object compound (I) of the present invention is produced by the following method.

Futa Yuyue the salt or its salt or its salt or its salt or its salt Disappeared Yudan 1 or its salt 瑁 五 ゆ た ぎょう or its salt or its salt or its salt or its salt Selection 1 upper 1 or its salt or its salt Kenkuunidanko or its salt R tayu upper yu L or its salt or its salt or its salt or its salt or its salt or its salt "Seitai" upper mutual engineering or its salt or its salt or its salt Seiyo Nijin Rikai and (XV) (XVI) (XVII) or its salt or its salt or its salt “Civil Law” Upper Yu L or its salt or its salt In the formula, R', R'', R3, R', Y, Z and x' are each defined above. street, (lower) alkylamino (lower) alkylamino group, having one or more suitable substituents or a heterocyclic amino group which may have one or more suitable substituents. both are heterocyclic groups containing one nitrogen atom, R3 is protected amino (lower) alkyl group, R are amine (lower) alkyl groups, R3 is an acylamino (lower) alkyl group, and J is a carboxy group or a protected carbon group. ruboxy group, R6 and R7 are each lower alkyl group, R8 and R9 are each hydrogen , lower alkyl group, cyclo(lower) alkyl group, al(lower) alkyl group, appropriate means a heterocyclic group which may have one or more substituents, or Even if R' and R9 are connected to each other together with the nitrogen atom and have one or more suitable substituents, form a good heterocyclic group, X2 is a leaving group, RIQ is hydrogen or lower alkyl group, R11 represents a lower alkyl group or a 1-amino-1-iminomethyl group, or R10 and R11 are connected together with the nitrogen atom and have one or more suitable substituents; R12 and R+x each form a lower alkyl group, and R3 is a carbonyl group. A carboxy (lower) alkenyl group, R) represents a carboxy (lower) alkyl group, In production method (6), = means a single bond or a double bond, and R3 is pyridyl or tetrahydryl. From the group consisting of dropyridyl, piperidyl, piperazinyl and morpholinyl groups Heterocyclic group which may have one or more selected and appropriate substituents: substituted amino Group: Carboxy (lower) alkenyl group: Carboxy (lower) alkyl group; Hydro Xy (lower) alkyl group; amino (lower) which may have one or more suitable substituents alkyl group; or Group of the following formula: (In the formula, R4 is hydrogen, ethoxy, mono(or di)lower alkylamino, di(lower (class) alkylamino-(lower) alkylamino, with one or more suitable substituents a heterocyclic amino group that may have one or more suitable substituents, or a heterocyclic group that may have one or more suitable substituents. show) Or represents a group of the following formula.

(In the formula, R5 is a lower alkyl group or an alkyl group which may have one or more suitable substituents. (lower) alkyl group, Xl represents an acid residue) Yl is CH or N, Zl represents CH or N.

Starting compound (III) or a salt thereof is produced by the following method.

Kata A mutual L (XTX) (XX) or its salt or its salt (III) or its salt In the formula, R3 is the same as above.

Suitable pharmaceutically acceptable salts of the target compound (I) are common non-toxic salts, including alkali metal salts (e.g. sodium salts, potassium salts, etc.) and alkaline earth metal salts (e.g. sodium salts, potassium salts, etc.) metal salts such as calcium salts, magnesium salts, ammonium salts, Organic base salts (e.g. trimethylamine salt, triethylamine salt, pyridine salt, Picoline salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine organic acid salts (e.g. acetate, maleate, tartrate, methanesulfate), phonate, benzenesulfonate, formate, toluenesulfonate, trifluoride inorganic acid salts (e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.) , salts with amino acids (e.g. arginine, aspartic acid, glutamic acid, etc.) Including.

In the foregoing and subsequent descriptions of this specification, various definitions that fall within the scope of this invention will be described. The definition and preferred examples are explained below.

The term "lower" shall mean groups containing 1 to 6 carbon atoms, unless otherwise specified; Preferably, it means a group having 1 to 4 carbon atoms.

Suitable "lower alkoxy groups" include methoxy, ethoxy, propoxy, and isopropoxy. butoxy, isobutoxy, tertiary butoxy, pentyloxy, t-pentyl Contains oxy, hexyloxy, etc.

"Pyridyl, tetrahydropyridyl, piperidyl, piperazinyl and morpholinyl" a compound selected from the group consisting of nyl groups and optionally having one or more suitable substituents; Suitable “substituents” in the term “substituents” include lower alkyl, halogen [e.g. Al (lower) which may have a suitable substituent such as (fluorine, chlorine, bromine, iodine) Includes alkyl.

In the words "carboxy(lower) alkenyl" and "lower alkenylamino" Suitable "lower alkenyls" include vinyl, propenyl, butenyl, and isobutenyl. Straight chain having 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms, such as Or contains branched chains.

Suitable "substituted amino groups" include cyanoamino; imidazolinylamino; guar Di(lower) alkylguanidino: Lower alkylguanidino; Cyclo(lower) class) alkylguanidino; al(lower) alkylguanidino; al(lower) al Heterocyclic guanidino which may be substituted with suitable substituents such as kyl; lower alkyl guanidino; with suitable substituents such as kyl, ar(lower) alkyl, lower alkoxy, etc. (1-hetero ff1- 1-iminomethyl)amino; di(lower) alkylamino group, etc.

"Carboxy (lower) alkyl", "Hydroxy (lower) alkyl", "Amino (lower)alkyl", [di(lower)alkylamino-(lower)alkylamino" , [acylamino(lower)alkyl], "protected amine(lower)alkyl" , “di(lower)alkylamino”, “di(lower)alkylguanidino”, “lower "alkylguanidino", "al(lower)alkyl", "hydroxy(lower)alkyl" ``kylamino'', ``mono(or di)lower alkylamino'', ``herophenyl (lower In the words "alkylamino" and "al(lower)alkylguanidino" Suitable "lower alkyl" and "lower alkyl moieties" include methyl, ethyl, and propyl. , isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl , t-pentyl, hexyl, etc., preferably 1 to 4 carbon atoms, such as t-pentyl, hexyl, etc. Straight or branched chains with children are included.

In the term "protected amine (lower) alkyl", the appropriate "protected amino" The "moiety" includes an acylamino group and the like.

Suitable "protected carboxy" includes esterified carboxy groups, etc. It will be done.

A suitable example of the ester moiety of the esterified carboxy group is lower alkyl Esters (e.g. methyl ester, ethyl ester, propyl ester, isoester) Propyl ester, butyl ester, isobutyl ester, tertiary butyl ester l-, pentyl ester, hexyl ester, l-cyclopropylethyl ester etc.) are shown. These may have one or more suitable substituents (e.g. lower alkanoyloxy (lower) alkyl esters [e.g. acetoxymethylene] ester, propionyloxymethyl ester, butyryloxymethyl ester Valeryloxymethyl ester, pivaloyloxymethyl ester, hexa Noyloxymethyl ester, 1 (or 2)-acetoxyethyl ester, 1 (or 2 or 3)-acetoxypropyl ester, ■ (or 2 or 3)-acetoxypropyl ester, is 3 or 4)-acetoxybutyl ester, 1 (or 2)-propionyl Oxyethyl ester, 1 (or 2 or 3)-propionyloxypropyl ester, l (or 2)-butyryloxyethyl ester, l (or 2)-isobutyryloxyethyl ester, 1 (or 2)-pivaloyloxy Ethyl ester, 1 (or 2)-hexanoyloxyethyl ester, i sobutyryloxymethyl ester, 2-ethylbutyryloxymethyl ester, 3,3-dimethylbutyryloxymethyl ester, 1 (or 2)-pentano yloxyethyl ester, etc.], lower alkanesulfonyl (lower) alkyl ester, etc. ester (such as 2-methylethyl ester), mono (or di- or tri-ester), )-halo(lower)alkyl ester (for example, λ2-iodoethyl ester, 2 ．． 2.2-trichloroethyl ester, etc.), lower alkoxycarbonyloxy (lower) alkyl esters (e.g. methoxycarbonyloxymethyl ester) , ethoxycarbonyloxymethyl ester, 2-methoxycarbonyloxyester Tyl ester, 1-ethoxycarbonyloxyethyl ester, 1-isopropyl ester (oxycarbonyloxyethyl ester, etc.), phthalidylidene (lower) alkyl Ester, or (5-lower alkyl-2-di-1,3-di)゛kinru-4 -yl) (lower) alkyl ester [for example (5-methyl-2-yl) 1. 3-dioxol-4-yl) methyl ester, (5-ethyl-2-oxo-1, 3-dioxol-4-yl) methyl ester, (5-propyl-2-oxo-1 , 3-dioxol-4-yl) ethyl ester, etc.]; lower alkenyl ester (e.g. vinyl ester, allyl ester, etc.); lower alkynyl ester (e.g. ethynyl ester, propynyl ester, etc.); one or more suitable substituents Mono (or di or tri) phenyl (lower) alkyl ester which may be present on Al (lower) alkyl ester which may have one or more suitable substituents such as ter (e.g. benzyl ester, 4-methoxybenzyl ester, 4-nitro Benzyl ester, phenethyl ester, trityl ester, benzhydryl ester Stell, bis(methoxyphenyl)methyl ester, 3,4-dimethoxybenzi ester, 4-hydroxy-3,5-di-tert-butylbenzyl ester, etc. ); Aryl esters which may have one or more suitable substituents (e.g. phenyl esters); ester, 4-chlorophenyl ester, tolyl ester, tertiary butyl phenylene ester nyl ester, xylyl ester, mesityl ester, cumenyl ester, etc.) : Examples include phthalidyl ester.

Appropriate terms in the words "acylamino" and "acylamino (lower) alkyl" "Acyl" refers to carbamoyl, aliphatic acyl group, acyl group containing aromatic ring (hereinafter referred to as aromatic ring) aromatic acyl) or an acyl group containing a heterocyclic ring (hereinafter referred to as heterocyclic acyl) included.

Suitable examples of the above acyl group include the following. That is, Carbamoyl; aliphatic acyl such as lower or higher alkanoyl (e.g. lumyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pen Tanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl Tanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, trideca Noyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadeca (noyl, octadecanoyl, nonadecanoyl, icosanoyl, etc.); is a higher alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl) tertiary butoxycarbonyl, tertiary pentyloxycarbonyl, heptyloxycarbonyl, (e.g. xycarbonyl), lower alkylcarbamoyl (e.g. methylcarbamoy) , ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butyl carbamoyl): lower or higher alkanesulfonyl (e.g. meth (sulfonyl, ethanesulfonyl, etc.); lower or higher alkoxysulfonyl (e.g. methoxysulfonyl, ethoxysulfonyl, etc.); aromatic acyl For example, aroyl (e.g. benzoyl, toluoyl, naphthoyl, etc.); (lower)alkamyl [e.g. phenyl(lower)alkanoyl (e.g. phenyl) Nylacetyl, phenylpropanoyl, phenylbutanoyl, phenylisobutylene lyl, phenylpentanoyl, phenylhexanoyl, etc.), naphthyl (lower) Alkamyls (e.g. naphthylacetyl, naphthylpropanoyl, naphthylbutylene) [e.g., phenyl (lower)], acyl (lower) alkenoyl [such as phenyl (lower) Alkenoyl (e.g. phenylpropenoyl, phenylbutenoyl, phenyl methacryloyl, phenylbentenoyl, phenylhexenoyl, etc.), naphthi (lower)alkenoyl (e.g. naphthylpropenoyl, naphthylbutenoyl) , naphthylpentenoyl, etc.], acyl lower) alkoxycarbonyl [etc. For example, phenyl(lower)alkoxycarbonyl (e.g. benzyloxycarbonyl) Aryloxycarbonyl (such as phenoxycarbonyl); (alkanoyl, naphthyloxycarbonyl, etc.), aryloxy(lower)alkanoyl ( For example, phenoxyacetyl, phenoxypropionyl), arylcarba moyl (such as phenylcarbamoyl), arylthiocarbamoyl (such as phenylcarbamoyl), (e.g. phenylthiocarbamoyl) narylglyoxyloyl (e.g. phenylglyoxyloyl, naphthylglyoxyloyl, etc.): Allensulfony (e.g. benzenesulfonyl, p-toluenesulfonyl, etc.) It will be done.

Examples of heterocyclic acyl include heterocyclic carbonyl; heterocyclic (lower) alkanoyl; (e.g., thenyl acetyl, thenylpropanoyl, thenylbutanoyl, chenylpentanoyl, chenylhexanoyl, thiazolyl acetyl, thiazia zolylacetyl, tetrazolylacetyl, etc.); heterocyclic (lower) alkenoyl ( For example, heterocycle propenoyl, heterocycle butenoyl, heterocycle bentenoyl, heterocycle Heterocyclic glyoxyloyl (such as hexenoyl): Heterocyclic glyoxyloyl (such as thiazolylglyoxy) royl, chenylglyoxyloyl, etc.). And the above "heterocyclic carbonyl", "heterocyclic (lower) alkanoyl", "heterocyclic (lower) alkane" Suitable heterocyclic moieties in the terms "noyl" and "heterocycloglyoxyloyl" are: More specifically, we need to reduce the number of heteroatoms such as oxygen, sulfur, nitrogen, etc. means a saturated or unsaturated monocyclic or polycyclic heterocyclic group containing one. And especially Among the preferred heterocyclic groups, unsaturated 3- to 8-membered rings containing 1 to 4 nitrogen atoms (more Examples of the heterocyclic group (preferably a 5- or 6-membered ring) include pyrrolyl, pyrolini imidazolyl, pyrazolyl, pyridyl and their N-oxides, dihydro Pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, tetrahydropyridazinyl (e.g. 2.3.4.5-tetrahydropyridazinyl), triazolyl ( For example, 4H-1,2,4-1-riazolyl, IH-1,2,3-triazolyl , 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g. 11(-te trazolyl, 2H-trazolyl, etc.).

Other particularly preferred heterocyclic groups include saturated heterocyclic groups containing 1 to 4 nitrogen atoms. 3- to 8-membered (more preferably 5- or 6-membered) heterocyclic groups, such as pyrrolidinium Examples include imidazolidinyl, piperidino, piperazinyl, and the like. moreover, Particularly preferred heterocyclic groups include unsaturated fused heterocyclic groups containing 1 to 4 nitrogen atoms. , for example indolyl, isoindolyl, indolinyl, intridinyl, ben Diimidazolyl, quinolyl, isoquinolyl, imidazolyl, benzotriazolyl unsaturated 3- to 8-membered ring containing 1-2 oxygen atoms and 1-3 nitrogen atoms (such as (preferably a 5- or 6-membered ring), such as oxasilyl, isoxa Silyl, oxadiazolyl (e.g. l, 2.4-oxadiazolyl, 1.3. 4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.); 1 to 2 A saturated 3- to 8-membered ring containing an oxygen atom and 1 to 3 nitrogen atoms (more preferably a 5- or 8-membered ring) is a 6-membered 3' heterocyclic group, such as morpholinyl, cytononyl, etc.; 1 to 2 acids An unsaturated fused heterocyclic group containing an elementary atom and 1 to 3 nitrogen atoms, e.g. 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as sasilyl, benzoxadiazolyl, etc. an unsaturated 3- to 8-membered ring (more preferably 5- or 6-membered ring) heterocyclic group containing atoms, Examples λ include thiazolyl, isothiazolyl, thiadiazolyl (e.g. l, 2.3-thi Diazolyl, 1.2.4-thiadiazolyl, 1.3.4-thiadiazolyl, 1 ．． 2゜5-thiadiazolyl, etc.), dihydrothiazinyl, etc.; 1-2 hard sulfur a saturated 3- to 8-membered ring (more preferably 5 or 6 unsaturated heterocyclic groups containing 1 to 2 sulfur atoms, such as thiazolidinyl a 3- to 8-membered ring (more preferably a 5- or 6-membered ring) heterocyclic group, such as chenyl , dihydrodithionyl, dihydrodithionyl, etc.; 1 to 2 sulfur atoms and 1 to 3 unsaturated fused heterocyclic groups containing nitrogen atoms, such as benzothiazolyl, benzothiazolyl, Asiazolyl, etc.; unsaturated 3- to 8-membered ring containing one oxygen atom (more preferably 5- or 6-membered ring) heterocyclic group, such as furyl group; 1 oxygen atom and 1 to 2 an unsaturated 3- to 8-membered ring (more preferably a 5- or 6-membered ring) containing a sulfur atom cyclic groups, such as dihydroxathinyl groups; unsaturated containing 1 to 2 sulfur atoms; fused heterocyclic groups, such as benzothenyl, penzodithiinyl groups, etc.; one oxygen unsaturated fused heterocyclic groups containing atoms and 1 to 2 sulfur atoms, such as benzoxathi Examples include inyl. The above acyl moieties are halogens (e.g. fluorine, chlorine, odor hydroxy, nitro, oxo, lower alkyl (e.g. methyl, ethyl) ru, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, 1 to 10 of the same or different suitable substituents, such as hexyl, etc. You may.

"Heterocyclic group which may have one or more suitable substituents", r (1-hetero!-1-i "minomethyl)amino", "heterocyclic guanidino" and [with one or more suitable substituents] An appropriate "heterocyclic group" in the term "heterocyclic amino which may have" also includes the above-mentioned Something like this is shown.

Appropriate “substituents” in the term “heterocyclic group which may have one or more suitable substituents” ” refers to lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl) tyl, isobutyl, sec-butyl, tertiary-butyl, pentyl, hexyl, etc.), Includes al(lower) alkyl, hydroxy(lower) alkyl, etc.

"Even if R8 and R9 are connected together with the nitrogen atom and have one or more suitable substituents, ", rR" and RI+ are linked together with the nitrogen atom to form a suitable heterocyclic group. "forming a heterocyclic group which may have one or more substituents" and "forming a heterocyclic group which may have one or more substituents" In the definition of "heterocyclic group containing at least one nitrogen atom" Examples of "cyclic groups" include pyrrolidinyl, imidazolidinyl, piperidino, piperazine, etc. a saturated 3- to 8-membered ring containing 1 to 4 nitrogen atoms (more preferably Heterocyclic group consisting of a 5- or 6-membered ring; for example, morpholinyl, cytononyl, etc. a saturated 3- to 8-membered ring containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (more preferably and a heterocyclic group consisting of a 5- or 6-membered ring.

Appropriate "substituted amino" in the term "heterocyclic amino which may have one or more suitable substituents" Examples of "groups" include alkyl (lower) alkyl and the like.

"Even if R8 and R9 are connected together with the nitrogen atom and have one or more suitable substituents, "Formation of a good heterocyclic group" and "R10 and R port are connected together with the nitrogen atom to form a suitable heterocyclic group." Appropriate substitutions in the definition of “forming a heterocyclic group which may have one or more suitable substituents” Atoms having lower alkyl, alkyl (lower) alkyl, or lower alkoxy as a substituent Includes reels, etc.

"A heterocyclic ring containing one nitrogen atom (both containing one nitrogen atom) which may have one or more suitable substituents" Lower alkyl, al(lower) alkyl, and hydroxy (lower) alkyl.

The appropriate "cyclo (lower) alkylguanidino" in the term "cyclo (lower) alkylguanidino" cyclopropyl, cycloalkyl, and cyclo(lower) alkyl moieties. Butyl, cyclopentyl, cyclohexyl, cyclohebutyl, cyclooctyl Any 3 to 8 membered ring (preferably one having 5 to 7 carbon atoms) cycloa Includes Lukiru.

In the term "amine (lower) alkyl which may have one or more suitable substituents" Suitable "substituents" include lower alkyl, acyl as in the above examples, and the like.

Suitable "acid residues" include halogens as described above.

Suitable "leaving groups" include acid residues such as those mentioned above.

The words “al(lower)alkyl” and “al(lower)alkylguanidino” Suitable “aryl” and “aryl moieties” include phenyl, naphthyl, etc. is included.

Appropriate terms in the term "al(lower)alkyl which may have one or more suitable substituents" Suitable "substituents" include halogens as mentioned above.

Appropriate “halogen J” and “herophenyl (lower) alkylamino” The "halogen moiety" includes the halogens mentioned above.

Preferred specific examples of target compound (I) are as follows.

R1 is a lower alkoxy group, R2 is a lower alkoxy group, R3 is pyridyl, tetrahydropyridyl, piperidyl, piperazinyl and mole selected from the group consisting of folinyl groups, and 1 to 3 (more preferably 1 or 2) ) is a heterocyclic group which may have an appropriate substituent, [more preferably pyridyl, consisting of tetrahydropyridyl, piperidyl, piperazinyl and morpholinyl groups. selected from the group consisting of lower alkyl and 1 or 2 halogens. having one or two substituents selected from the group consisting of alkyl (lower) alkyl; heterocyclic groups, most preferably pyridyl, tetrahydropyridyl, piperidyl , piperazinyl and morpholinyl, and one lower alkyl , the group consisting of phenyl(lower)alkyl and halophenyl(lower)alkyl? [heterocyclic group which may have one or two substituents selected from]; cyanoamino; imidazolinylamino; guanidinodi(lower)alkylguanidino; lower alkyl Kyrguanidino; Cyclo(lower) alkylguanidino; Al(lower) alkylg Anidino [more preferably phenyl (lower) alkylguanidino]; 1 to 3 pieces (more preferably one) suitable substituent! Heterocyclic guanidino [ More preferably heterocyclic guanidino which may have al(lower)alkyl, most preferably Preferably phenyl (lower) alkylpiperidyl guanidino]; 1 to 3 (more (preferably 1) suitable substituents (1-heterocyclic 1-iminomethyl ) amino [more preferably lower alkyl, al(lower) alkyl and lower alkyl] May have a substituent selected from the group consisting of aryl which may have lukoxy (1-heterocycle-1-iminomethyl)amino, most preferably (morpholinyl(iminomethyl)amino, (mino)methyl)amino, phenyl(lower)alkyl (piperidyl) (imino)methyl)amino, or lower alkyl, phenyl(lower)alkyl or and lower alkoxyphenyl (p- and lower-alkoxyphenyl). perazinyl(imino)methyl)amino] di(lower)alkylamino; hydro xy(lower)alkyl: carboxy(lower)alkyl; carboxy(lower)alkyl Kenyl: 1 to 3 selected from the group consisting of lower alkyl and acyl (more preferably amino(lower)alkyl which may have one or two substituents [more preferably Preferably, lower argyl, lower alkanoyl, lower alkylcarbamoyl, lower alkyl, etc. Rukoxycarbonyl and heterocyclic carbonyl which may have 1 to 3 suitable substituents Amino (lower ) Alkyl: most preferably lower alkyl, lower alkanoyl, lower alkyl Rubamoyl, lower alkoxycarbonyl and tetrahydrogen which may have an oxo group. having one or two substituents selected from the group consisting of dropyridazinylcarbonyl; amino (lower) alkyl]; (wherein, R4 is hydrogen, ethoxy, mono (or di)lower alkylamino, di(lower)alkylamino-(lower)alkylamino Ruamino, or lower alkyl, lower alkoxy, halogen and al (lower) 1 to 3 (more preferably 1 or 2) groups selected from the group consisting of alkyl; Heterocyclic amino which may have a substituent [more preferably lower alkyl, lower alkoxy] one selected from the group consisting of halogen, phenyl (lower) alkyl, or 5 saturated heterocyclic amino which may have 2 substituents contains 1 to 3 nitrogen atoms or a 6-membered heteromonocyclic amino, most preferably phenyl(lower)alkylpipe [lysyl amino], or lower alkyl, lower alkoxy, halogen, al (lower ) 1 to 3 selected from the group consisting of alkyl and hydroxy (lower) alkyl Heterocyclic group which may have (more preferably 1 or 2) substituents [more preferably or lower alkyl, lower alkoxy, halogen, phenyl (lower) alkyl and one or two substituents selected from the group consisting of saturated 5 or 6 containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, which may have Member heteromonocyclic group, or lower alkyl, lower alkoxy, halogen, phenyl ( one or more selected from the group consisting of (lower) alkyl and hydroxy (lower) alkyl; or a saturated 5- or 6-membered nitrogen atom containing 1 to 3 nitrogen atoms which may have 2 substituents a heteromonocyclic group, most preferably morpholinyl, or lower alkyl, hydroxy piperazini optionally having cy(lower)alkyl or phenyl(lower)alkyl ]; or represents a group of the following formula, (In the formula, R5 is lower alkyl, or halogen, lower alkyl, and lower alkyl. 1 to 3 (more preferably 1 or 2) substituents selected from the group consisting of xy Al(lower) alkyl which may have [more preferably halogen, lower alkyl] and one or two substituents selected from the group consisting of lower alkoxy a good phenyl(lower) alkyl, most preferably a phenyl(lower) alkyl which may contain a halogen; nyl (lower) alkyl], and Xl is an acid residue, preferably a halogen]), Y is CH or N, 2 indicates CH or N, However, R3 is a pyridyl group; a piperidyl group that may have a hydroxy group, a lower alkali group; Piperazinyl with a kill group or a hydroxy (lower) alkyl group: morpholini Le: Lower alkenylamino: Hydroxy (lower) alkylamino; on benzene ring Phenylamino which may have a lower alkoxy group or halogen; halophenyl (lower) alkylamino: nitro group, amine group or halogen on the benzene ring phenylsulfonylamino; or lower alkyl and hydroxy (lower) An amino group substituted with two substituents selected from the group consisting of alkyl, When Y 755 N, Z indicates CH.

The purpose of this invention and the method for preparing the starting compounds are detailed below.

Compound (Ia) or a salt thereof is a combination of compound (II) and compound (III) or its salt. It can be produced by reacting the salts of

This reaction involves water, alcohol (e.g. methanol, ethanol, isopropyl alcohol) (coal, etc.), tetrahydrofuran, dioxane, chloroform, methylene chloride Common substances such as chloride, dimethylacetamide, N,N-dimethylformamide or any other organic solvent that does not adversely affect the reaction. child Among these solvents, hydrophilic solvents may be used in combination with water.

This reaction is preferably performed with an inorganic acid (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, etc.) or an organic acid. Acids (e.g. formic acid, acetic acid, trifluoroacetic acid, propionic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.).

This reaction also reacts with alkali metal hydroxides, alkali metal bicarbonates, and alkali metal carbons. acid salts, alkali metal acetates, tri(lower)alkylamines, pyridines (e.g. pyridine, lutidine, picoline, dimethylaminopyridine, etc.), N- (low class) alkylmorpholine, N, N-di(lower) alkylbenzylamine, N, carried out in the presence of a free or organic base such as N-di(lower)alkylaniline, etc. be exposed. When the base, acid and/or starting compounds are liquids, they can be used as solvents. You can also use it.

The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling to heating.

Suitable salts of compounds (1) and (Ia) include those exemplified for compound (1). It will be done.

Seta Yuyue Compound (Ib) or a salt thereof is compound (■) or its carboxy group Reacting a reactive derivative or a salt thereof with compound (V) or a salt thereof It can be manufactured by

Suitable reactive derivatives of the above at the carboxy group include acid halides, acid anhydrides, , activated amides and esters. Acid chlorides and acids as suitable examples Acid halides such as bromides, various acids [e.g. substituted phosphoric acids such as dialkyl phosphoric acids] , sulfuric acid, aliphatic carboxylic acids, aromatic carboxylic acids, etc.], mixed acid anhydrides, symmetrical acids Anhydrides, activated amides with various imidazoles, and lower alkyl esters For example, methyl ester, ethyl ester, etc.], cyan methyl ester, methoxy dimethyl ester, P-nitrophenyl ester, 2,4-dinitrophenyl ester ster, pentachlorophenyl ester, phenylazophenyl ester, cal Boxymethylthioester, N-hydroxysuccinimide ester, etc. Examples include esters such as.

The reaction is usually carried out using methylene chloride, chloroform, alcohol [e.g. methanol, ], benzene, toluene, pyridine, diethyl ether, dioxa , tetrahydrofuran, acetone, acetonitrile, ethyl acetate, N,N-di Common solvents such as methylformamide or other solvents that do not adversely affect the reaction It is also carried out in an organic solvent. If compound (V) is a liquid, it can be used as a solvent. It is also used.

The reaction temperature is not particularly limited, and the reaction can be carried out in cooling, at room temperature, or under heating. Ru.

This reaction can typically be carried out in the presence or absence of a reaction promoter such as a base. can.

Suitable bases include tertiary amines [e.g. triethylamine, pyridine, N , N-dimethylaniline], alkali metal hydroxides [e.g. aluminum, potassium hydroxide, etc., alkali metal carbonates [e.g. sodium carbonate, potassium carbonate, etc.], alkali metal bicarbonates [sodium hydrogen carbonate, etc.], organic This includes acid salts [such as sodium acetate]. If the base is liquid, salt The group can be used as a solvent.

Suitable salts of compounds (IV), (V) and (Ib) are those exemplified for compound (I). You can use it.

Settora Yudanri Compound (Id) or its salt has a lower R3 value than compound (Ic) or its salt. It can be produced by performing a reaction to remove the amino protecting group. this reaction Suitable methods include conventional methods such as hydrolysis, reduction, etc.

(i) Hydrolysis: Hydrolysis is preferably carried out in the presence of a base or an acid, including a Lewis acid.

Alkali metals [e.g. sodium, potassium, etc.] as suitable bases; hydroxides or carbonates or bicarbonates, trialkylamines [e.g. thylamine, triethylamine, etc.], picoline, 1,5-diazabicyclo[4 ,3,0]-]non-5-enel, 4-diazabicyclo[2,2,2]octa Inorganic compounds such as 1,8-diazabicyclo[5,4,0]undec-7-ene, etc. Includes bases and organic bases.

Suitable acids include peracic acid [such as formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid] and inorganic acids [e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, chloride Contains hydrogen, hydrogen bromide, etc. Trihaloacetic acid [e.g. trichloroacetic acid, Elimination reactions using Lewis acids, such as fluoroacetic acid, are preferably cationic. It is carried out in the presence of a carbon scavenger [eg anisole, phenol, etc.].

This reaction usually involves water, alcohol [e.g. methanol, ethanol, etc.], chloride, etc. tyrene, tetrahydrofuran, mixtures thereof, or those that do not adversely affect the reaction. It is carried out in a solvent such as another solvent.

Liquid bases or acids can also be used as solvents. The reaction temperature is not particularly limited. The reaction is usually carried out under cooling to heating.

(ii) Reduction: Reduction reactions are carried out in conventional manner and include chemical reduction and catalytic reduction.

Suitable reducing agents used in chemical reduction are metals (e.g. tin, zinc, iron, etc.) or Metal compounds (e.g. chromium chloride, chromium acetate, etc.) and organic or inorganic acids (e.g. For example, formic acid, acetic acid, propionic acid, trifluoroacetic acid, P-toluenesulfonic acid, Examples include combinations of hydrochloric acid, hydrobromic acid, etc.).

Suitable catalysts used for catalytic reduction include platinum catalysts (e.g. platinum plates, platinum sponges). di, platinum black, platinum colloid, platinum oxide, platinum wire, etc.), palladium catalyst (e.g. Palladium sponge, palladium black, palladium oxide, palladium carbon, colloy palladium, palladium/barium carbonate, palladium/barium carbonate, etc.), Nickel catalysts (e.g. reduced nickel, nickel oxide, Raney nickel, etc.), Baltic catalysts (e.g. reduced cobalt, Raney cobalt, etc.), iron catalysts (e.g. reduced iron, Raney iron, etc.), copper catalysts (e.g. reduced copper, Raney copper, Ullmann copper, etc.), etc. Common examples include: Reduction reactions usually involve water, methanol, or ethanol. , propatool, N,N-dimethylformamide, tetrahydrofuran, or These mixtures are carried out in common solvents that do not adversely affect the reaction. addition Therefore, if the above acids used in chemical reduction are liquids, they can also be used as solvents. Wear.

The reaction temperature for this reduction is not particularly limited, and the reaction is usually carried out under cooling to heating.

Suitable salts of compounds (Ic) and (Id) are those exemplified for compound (I). I can.

4th grade” Compound (Ie) or a salt thereof is compound (Id) or its amino group It can be produced by subjecting reactive derivatives or their salts to an acylation reaction. can.

A suitable acylating agent used in this acylation reaction is a compound of the following formula: R14-OH(XXII) (In the formula, R14 is acyl) or reactive derivatives thereof or salts thereof.

Compound (Id) as a suitable reactive derivative at the amino group of compound (Id) Schiff is produced by the reaction of carbonyl compounds such as aldehyde and L-ketone. Imino type of base or its tautomeric enamine type; Compound (Id) and N, O- Bis(trimethylsilyl)acetamide, N-trimethylsilylacetamide, etc. Silyl derivatives produced by the reaction of various silyl compounds; Compound (Id) and Examples include derivatives produced by the reaction of phosphorus chloride or phosgene.

Suitable salts of compounds (Id) and (Ie) are the same as those exemplified for compound (I). can be used.

Suitable reactive derivatives of compound (XXII) include acid halides, acid anhydrides, activated a Examples include mido, active ester, incyanate, and the like. A suitable example is acid chloride. Lido, acid azide: substituted phosphoric acids (e.g. dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid) dibenzyl phosphoric acid, dibenzyl phosphoric acid, halophosphoric acid, etc.), dialkyl phosphorous acid, sulfite, thiosulfuric acid acids, alkanesulfonic acids (e.g. methanesulfonic acid, ethanesulfonic acid, etc.) , sulfuric acid, alkyl carboxylic acids, aliphatic carboxylic acids (e.g. pivalic acid, valeric acid) , isovaleric acid, 2-ethylbutyric acid or trichloroacetic acid) or aromatic carboxylic acids. mixed acid anhydrides with acids such as benzoic acid (e.g. benzoic acid); symmetrical acid anhydrides; dazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole activated amide with torazol; or activated ester (e.g. cyan methyl ester); ter, methoxymethyl ester, dimethyliminomethyl [(CH3) 2N=C H-]ester, vinyl ester, propargyl ester, P-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, Pentachlorophenyl ester, mesyl phenyl ester, phenylazophenyl ester, phenylthioester, P-nitrophenylthioester, P-k Resyl thioester, carboxymethyl thioester, pyranyl ester, pyryl thioester ester, piperidyl ester, 8-quinolyl thioester, etc.), or N-hydroxy compounds (e.g. N,N-dimethylhydroxylamine, 1-hydroxy Droxy-2-(IH)-pyridone, N-hydroxysuccinimide, N-hydro Roxybenzotriazole, N-hydroxyphthalimide, l-hydroxy-6 -chloro-IH-benzotriazole, etc.); substituted or unsubstituted esters; Ryl isocyanate; substituted or unsubstituted aryl isothiocyanate, etc. can be lost. These reactive derivatives depend on the type of compound (XXII) used. can be selected arbitrarily.

Reactions typically involve water, acetone, dioxane, acetonitrile, chloroform, and chloride. Methylene, dichloroethane, tetrahydrofuran, ethyl acetate, N,N-dimethylene Common solvents such as formamide, pyridine or others that do not adversely affect the reaction in any organic solvent. These common solvents are used mixed with water. It's okay.

When compound (XXII) is used in the reaction in the form of free acid or its salt In this case, the reaction is preferably carried out in the presence of a conventional condensing agent. With such a condensing agent N,N-dicyclohexylcarbodiimide; N-cyclohexyl-N-mol Folinoethylcarbodiimide; N-cyclohexyl-N'-(4-diethylamide nocyclohexyl)carbodiimide, N,N'-diethylcarbodiimide, N, N'-diisopropylcarbodiimide; N-ethyl-N'-(3-dimethylamino) nopropyl)carbodiimide, N,N-carbonylbis-(2-methylimidazo pentamethyleneketene-N-cyclohexylimine, diphenylketene -N-cyclohexylimine: ethoxyacetylene; 1-alkoxy-1-ri4 polyethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; Phosphorus oxychloride (phosphoryl chloride); phosphorus trichloride; thionyl chloride: Oxalyl chloride: Triphenylphosphine: 2-ethyl-7-hydroxybenz Isoxazinium salt; 2-ethyl-5-(m-sulfenyl)inoxasily hydroxide inner salt; 1-(P-chlorobenzenesulfonyloxy)-6-k Rolo-IH-benzotriazole, N,N-dimethylformamide and thionichloride The so-called Pilsumi produced by reaction with phosphorus, phosgene, phosphorus oxychloride, etc. Examples include a reagent.

The reaction also includes alkali metal bicarbonates, tri(lower)alkylamines, pyridine, N -(lower)alkylmorpholine, N,N-di(lower)alkylbenzylamine, etc. It may be carried out in the presence of any inorganic or organic base. The reaction temperature is not particularly limited. The reaction is carried out under cooling to heating.

luxury five unie Compound (If) or a salt thereof is a combination of compound (XVIII) or a salt thereof and a compound It can be produced by reacting (Vl).

This reaction involves water, alcohol (e.g. methanol, ethanol, isopropyl alcohol) (coal, etc.), tetrahydrofuran, dioxane, chloroform, methylene chloride , dimethylacetamide, N,N-dimethylformamide or It can also be carried out in any other organic solvent that does not adversely affect the reaction. of these solvents Among them, the hydrophilic solvent may be used in combination with water.

The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling to heating.

Suitable salts of compounds (XVIII and (If) are those exemplified for compound (I) is used.

1st category Compound (Ih) or its salt cannot reduce compound (Ig) or its salt. It can be manufactured by

Reduction is carried out by conventional methods and includes chemical reduction and catalytic reduction.

Suitable reducing agents used in chemical reduction include hydrides (e.g. hydrogen iodide, sulfide). Hydrogen, lithium aluminum hydride, sodium borohydride, etc.) or metals ( (e.g. tin, zinc, iron) or metal-containing compounds (e.g. chromium chloride, acetate, etc.) rom) and organic or inorganic acids (e.g. formic acid, acetic acid, propionic acid, triflic acid, fluoroacetic acid, P-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.) Can be mentioned.

Suitable catalysts used for catalytic reduction include platinum catalysts (e.g. platinum plates, platinum spots). metal, platinum black, platinum colloid, platinum oxide, platinum wire, etc.), palladium catalyst (and For example, palladium sponge, palladium black, palladium oxide, palladium carbon, and Lloyd's palladium, palladium/barium sulfate, palladium/barium carbonate, etc. ), nickel catalysts (e.g. reduced nickel, nickel oxide, Raney nickel, etc.) ), cobalt catalysts (e.g. reduced cobalt, Raney cobalt, etc.), iron catalysts (e.g. (e.g. reduced copper, Raney iron, etc.), copper catalysts (e.g. reduced copper, Raney copper, Ullmann copper, etc.) ), etc. Reduction reactions usually involve water, alcohol (e.g. methanol, ethanol, etc.), N,N-dimethylformamide, tetra Run in hydrofuran, mixtures of these or other solvents that do not adversely affect the reaction. be exposed.

Additionally, if the acids mentioned above used in chemical reduction are liquids, they can also be used as solvents. Can be used.

The reaction temperature for this reduction is not particularly limited, and the reaction is usually carried out under cooling to heating.

Suitable salts of compounds (Ig) and (Ih) are those exemplified for compound (I). I can.

Destruction 9 Compound (Ij) or a salt thereof is obtained by preparing compound (Ii) or a salt thereof by manufacturing method (6). It can be produced by reduction according to the method described.

Suitable salts of compounds (Ii) and (Ij) are those exemplified for compound (I). I can.

[Ta] l1 Compound (Ik) or a salt thereof is a combination of compound (XXI) or a salt thereof and compound (■ ) can be produced by reacting.

This reaction involves water, alcohol (e.g. methanol, ethanol, isopropyl alcohol) (coal, etc.), tetrahydrofuran, dioxane, chloroform, methylene chloride , dimethylacetamide, xylene, 2-methoxyethanol, N,N-dimethyl A general purpose solvent such as formamide or any other organic solvent that does not adversely affect the reaction. It is also carried out in a solvent.

The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling to heating.

As suitable salts of compounds (Ik) and (XXI), those exemplified for compound (I) can be used. be exposed.

ΣA tanri Compound (Ij2) or its salt is compound (■) or its salt and compound (IX) Alternatively, it can be produced by reacting a salt thereof.

This reaction is usually carried out in a common solvent as exemplified in production method (8).

The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling to heating.

This reaction typically involves alkali metal hydroxides, alkali metal bicarbonates, and alkali metal carbons. Acid salts, alkali metal acetates, tri(lower)alkylamines, alkali metal methoxides side, pyridines (e.g. pyridine, lutidine, picoline, dimethylaminopyridine) lysine, etc.), N-(lower)alkylmorpholine, N,N-di(lower)alkylmorpholine, Inorganic or is carried out in the presence of an organic base. When the base and/or starting compound is liquid, These can also be used as solvents.

A suitable salt of compound (■) can be an acid addition salt as exemplified for compound (I). Wear.

As suitable salts of compounds (IX) and (Iff), those exemplified for compound (I) can be used. I can.

Luxury once Compound (In) or its salt can reduce compound (Im) or its salt. It can be manufactured by

Reduction is carried out by conventional methods and includes chemical reduction and catalytic reduction.

Suitable reducing agents used in chemical reduction include hydrides (e.g. hydrogen iodide, sulfide). Hydrogen, lithium aluminum hydride, sodium borohydride, etc.) or metals ( compounds containing metals (e.g. tin, zinc, iron, etc.) or metal-containing compounds (e.g. chromium chloride, acetic acid). chromium) and organic or inorganic acids (such as formic acid, acetic acid, propionic acid, and (Lifluoroacetic acid, P-)-luenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.) There are many problems.

Suitable catalysts used for catalytic reduction include platinum catalysts (e.g. platinum plates, platinum spots). metal, platinum, platinum colloid, platinum oxide, platinum wire, etc.), palladium catalyst (and For example, palladium sponge, palladium black, palladium oxide, palladium carbon, and Lloyd's palladium, palladium/barium sulfate, palladium/barium carbonate, etc. ), nickel catalysts (e.g. reduced nickel, nickel oxide, Raney nickel, etc.) ), cobalt catalysts (reduced cobalt, Raney cobalt, etc.), iron catalysts (reduced cobalt, Raney cobalt, etc.), (e.g. reduced iron, Raney iron, etc.), copper catalysts (e.g. reduced copper, Raney copper, Ullmann Examples include common materials such as copper (copper, etc.). Reduction reactions are usually carried out using methanol, ethanol, Tanol, propatool, N,N-dimethylformamide, tetrahydrofuran , or mixtures thereof, in common solvents that do not adversely affect the reaction. Ru. In addition, if the above acids used in chemical reduction are liquids, they can also be used as solvents. It can be used as

The reaction temperature for this reduction is not particularly limited, and the reaction is usually carried out under cooling to heating.

As a suitable salt of compound (Im), those exemplified for compound (I) can be used. Wear.

Selection number 11 Compound (In) or its salt is subjected to an oxidation reaction of compound (In) or its salt. It can be manufactured by

The oxidation reaction is carried out in the usual manner, and hydroxymethyl groups can be oxidized to formyl groups. Suitable oxidizing agents include periodates (e.g. sodium periodate), peracids ( For example, perbenzoic acid, metachloroperbenzoic acid), magnesium dioxide, etc. Can be mentioned.

This reaction is usually caused by common solvents such as those exemplified in production method (8) or which have an adverse effect on the reaction. It can also be carried out in any other solvent that does not degrade. Among these solvents, water is the hydrophilic solvent. It may be used in combination with

The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling to heating.

Suitable salts of compounds (In) and (Io) can be prepared by acid addition as exemplified for compound (I). You can use salt.

"Okibi" Part 11 Compound (Ip) or its salt is compound (Ip) or its salt and compound (X) Alternatively, it can be produced by reacting a salt thereof.

This reaction is usually carried out in a common solvent as exemplified in production method (8) or in a solvent that has an adverse effect on the reaction. It is also carried out in any other organic solvent that does not affect the reaction.

The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling to heating.

This reaction typically involves alkali metal hydroxides, alkali metal bicarbonates, and alkali metal carbons. Acid salts, alkali metal acetates, tri(lower)alkylamines, piperidine, pipera gin, pyridines (e.g. pyridine, lutidine, picoline, dimethylaminopyridine) lysine, etc.), N-(lower)alkylmorpholine, N,N-di(lower)alkylmorpholine, Inorganic or is carried out in the presence of an organic base. When the base and/or starting compound is a liquid , these can also be used as solvents.

A suitable salt of compound (X) can be a base salt as exemplified for compound (I). Ru.

As suitable salts of compound (Ip), those exemplified for compound (I) can be used. .

"L" once Compound (Ir) or a salt thereof is a compound (Iq) or a salt thereof and a compound (X I) or a salt thereof.

This reaction is usually carried out in a common solvent as exemplified in production method (8) or in a solvent that has an adverse effect on the reaction. It is also carried out in any other organic solvent that does not affect the reaction.

The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling to heating. Compound (XI ) can also be used as a solvent if it is a liquid.

As suitable salts of compounds (Ir) and (XI), those exemplified for compound (I) can be used. I can do it.

Luxury Yu±A Engineering Compound (Is) or a salt thereof is a compound (Iq) or a salt thereof and a compound (X It can be produced by reacting [l) or a salt thereof.

This reaction is usually carried out in a common solvent as exemplified in production method (8) or in a solvent that has an adverse effect on the reaction. It is also carried out in any other organic solvent that does not affect the reaction.

The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling to heating. Compound (XI If l) is a liquid, it can be used as a solvent.

Suitable salts of compounds (Iq), (Is), and (x[l) are exemplified by compound (I). Various acid addition salts can be used.

Selected uniform presentation Compound (It) or a salt thereof is a combination of compound (X[[l) or a salt thereof and compound (X IV) or a salt thereof.

This reaction is usually carried out in a common solvent as exemplified in production method (8) or in a solvent that has an adverse effect on the reaction. It is also carried out in any other organic solvent that does not affect the reaction.

The reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.

Compound (X[[l), (XIV), (It) (7) A suitable salt is compound (I) You can use something like the one shown.

11th grade building Compound (Iu) or its salt is compound (XV) or its salt and compound (XV Produced by reacting I) and compound (XVII) or a salt thereof be able to.

This reaction is typically performed with alcohols (e.g. methanol, ethanol, ethylene glycol). (recall), chloroform, ether, tetrahydrofuran, benzene, etc. in a common solvent or any other organic solvent that does not adversely affect the reaction. be exposed.

The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling to heating.

The reaction is usually carried out in the presence of an acid.

Suitable acids include organic acids (such as formic acid, acetic acid, propionic acid, etc.) and inorganic acids. (For example, hydrochloric acid, hydrobromic acid, sulfuric acid, etc.). When the acid is a liquid, this It can also be used as a solvent.

Compound (XV), (XVII), (Iu) (7) A suitable salt is compound (I) Acid addition salts such as those exemplified can be used.

R Kyoji Jin17) Compound (Iw) or its salt is prepared by preparing the compound according to the method explained in production method (10). It can be produced by reducing (Iv) or a salt thereof.

As suitable salts of compounds (Iw) and (Iv), those exemplified for compound (I) can be used. I can do it.

civil law agreement Compound (III) or its salt is compound (XIX) or its salt and compound (X X) or a salt thereof.

This reaction can be carried out in the presence or absence of conventional solvents.

The reaction temperature is not particularly limited, and the reaction is usually carried out with cooling or at room temperature.

As a suitable salt of compound (XX), acid addition salts exemplified for compound (I) can be used. Ru.

As suitable salts of compounds (XIX) and (III), use those exemplified for compound (I). be able to.

The novel heterocyclic compound (I) of the present invention and its pharmaceutically acceptable salts have strong antithrombotic properties. cyclooxygenase, thrombin, phosphogesterase, etc. and/or inhibit platelet aggregation; further inhibit vasodilation. tonic effect; anti-inflammatory effect; has especially antithrombotic effect and is therefore an antithrombotic agent, vasodilator and It is useful as an antiinflammatory and anti-inflammatory agent, especially as an antithrombotic agent.

Therefore, the novel heterocyclic compound CI) and its pharmaceutically acceptable salts can be used to treat cerebral thrombosis, Blood slow thrombosis, coronary artery thrombosis, transitional thrombosis, venodilatory thrombosis, jumping blood Embolism, mural thrombosis, placental thrombosis, platelet thrombosis, post-traumatic arterial thrombosis, congestion peripheral vascular disorders such as sexual thrombosis, compression thrombosis, chronic arterial occlusion, transient ischemic attacks, After myocardial infarction, cerebral infarction, percutaneous coronary angioplasty or percutaneous intracoronary thrombolysis Hypertension such as reocclusion, arteriosclerosis, cerebrovasospasm, disseminated vasocoagulopathy, and pulmonary hypertension. , psoriasis, arthritis, nephritis, inflammatory bowel disease, septic shock, memory impairment, senile dementia. It can be used for the prevention and treatment of stupor, endotoxic shock, etc.

Additionally, these compounds are useful in preventing thrombosis during extracorporeal circulation such as dialysis. .

Additionally, these compounds also have antipyretic, analgesic, antiviral, antifungal, and antiinflammatory properties. It is expected to have allergic properties and 5-lipoxygenase inhibitory properties.

This heterocyclic compound (I) and its pharmaceutically acceptable salts have an adverse effect on patients. Has almost no side effects.

To demonstrate the usefulness of the heterocyclic compound (I) of the present invention and its pharmaceutically acceptable salts , pharmaceutical test data of representative compounds of heterocyclic compound (I) are explained below.

“Example 1-(1) J,” “Example 2-(1) J,” “Example 7” in the following tests. - (3) J, [Example ty-(2) J, [Example 2l-(1) J, “Actual Example 24-(1) The description J is Example 1-(11, 2-(11, 7-), respectively. (3), 17-(2), 21-(]), 24-(1) do.

Itsukigai hemostasis ball I potato 1. Test method Male Hartley guinea pigs weighing approximately 300 g were used after fasting for 24 hours. trial 6 hours after oral administration of test compound or test compound vehicle, 0.1 volume of only 3.8 Collect blood into test tubes containing % sodium citrate and collect platelet-rich plasma (PRP). Created.

To 250μm PRP, 5LLl of arachidonic acid was added as an aggregation inducer (most 50 μM final). The degree of aggregation was measured using an aggregometer (NKK Hema Tracer 1). Established. The results below are based on the dose of the test compound and its inhibitory effect on platelet aggregation. shows the relationship between the percentage (%) of

2. Test results T1 Rat Oishige Ni・Suruya'Rika 1. Test method Spiral strips of rat thoracic aorta were incubated at 37 °C under a load of 0.5 g at 95% The tube was suspended in a Magnus bath containing Tyrode's solution aerated with % carbon dioxide. Potassium chloride Contraction was induced by addition of an aqueous solution of lium (final concentration was 30 mM) . After the tension reaches a plateau, the chemical solution (dissolved in dimethyl sulfoxide) is added Finally, 10-'M papaverine was added to obtain maximal relaxation values. Testing The action of the compound is determined by the ED50 value (dose required to relax isolated rat aorta by 50%). given amount).

2. Test results Malondialdehyde (MDA) used in the blood: How to make it 1, Test method Washed rabbit PRP (990 μm) was added to a drug solution (dimethyl sulfoxide). (10 μm) for 5 min at 37°C. next , 2.5mM arachidonic acid solution (20μl) was added to the reaction mixture. after 3 minutes , thiobarbyrate reagent (1000 μM) was added, and the reaction mixture was boiled. Heated in water for 10 minutes. After centrifugation at 1500g for 10 minutes, the absorbance of the supernatant was measured at 532 nm. This test evaluates the effect of the test compound on cyclooxygenase. This was done to see the inhibitory effect on

2. Test results For therapeutic administration, the object compound (I) of the invention and a pharmaceutically acceptable The salts are organic or inorganic solid or liquid excipients suitable for oral, parenteral or topical use. For use in the form of conventional pharmaceutical preparations mixed with conventional pharmaceutically acceptable carriers such as excipients. used. Pharmaceutical preparations can be in solid form such as granules, capsules, tablets, sugar-coated tablets, or herbal medicines. is prepared in liquid form such as a solution, suspension, or emulsion for injection, oral administration, eye drops, etc. Ru. If necessary, stabilizers, wetting or emulsifying agents, buffering agents and other commonly used agents may be added to the above formulations. It may also contain auxiliary substances such as adducts.

This active ingredient is usually administered in doses ranging from 0.001 mg/kg to 500 mg/kg. g/kg, preferably O, 01 mg/kg to 10 mg/kg per day. It is administered 1 to 4 times per day. However, the above dosages may vary depending on the patient's age, weight and symptoms. may be increased or decreased as appropriate according to the administration method.

The preparations and examples below are merely for the purpose of illustrating the invention in more detail. It is given.

11 yu Anilyl (25g) and sodium hydroxide (21,62g) in methanol (1, 5°C) solution, 2,3-dimethylaminepropanoic acid hydrobromide (36.52g) added. The mixture was heated under reflux for 1 hour, and then the cooled mixture was filtered. filtrate The solution was concentrated under reduced pressure to 200 ml, and insoluble matter was collected by filtration. to this insoluble matter , water (100 ml) and ethyl acetate (50 ml) were added to 3N hydroxide. Adjust the pH to 1O.5 with an aqueous sodium solution, and add 4N hydrochloric acid to the resulting mixture. The pH was set to 4.0. The precipitate was collected and washed with water to give 2,3-bis(4-methoxyphene). pyrazine-5-carboxylic acid was obtained.

mp: 233°C (dec,) Engineering R (Nujol): 1690.1600.1510 cm-1HMR (D M50-d6.6): 2.80 +6H,s), 6.97.7.46 ( 8H.

Yu stands up in tears 2.3-bis(4-methoxyphenyl)pyrazine-5-carboxylic acid (0.5g) , 3-methyl-1-P-tolyltriazi: / (0,44g) +7) Tetrahy The mixture in Dorofuran (15ml) was stirred at 40°C for 1 hour. reaction mixture was poured into a mixture of ethyl acetate and water, and the pH was adjusted to about 2 with 6N hydrochloric acid. separated The organic layer was washed with brine and dried over magnesium sulfate. After filtration, remove the solvent under reduced pressure The precipitate obtained was washed with diisopropyl ether to obtain 5-methoxycarbonyl -2,3-bis(4-methoxyphenyl)pyrazine (0.36 g) was obtained.

Engineering R (Nujol): 1720.1600.1505 cm-1NrI! R tcDc13.6): 3-82 (3H, s) - 3,83+3H, s).

4.04 +3H, sl, 6.85 +4H, d, J=9Hz), 7.47 ( 2H,d.

Example 1 (1) 2-acetylamino-1-thioxoethylamine (0°50g) and ethylamine Add hydrazine 1 hydrate (Q, 18 ml) to the mixture of alcohol at -70°C. The mixture was stirred for 30 minutes at the same temperature. 2-acetylamino-1-hydrazo P-anilyl (1,02 g) was added to the reaction mixture containing noethylamine at -20 °C. In addition, a solution of hydrochloric acid in ethanol (3 drops) was added thereto.

The reaction mixture was also stirred and refluxed for 20 minutes. After cooling to room temperature, pour the mixture into water and vinegar. Extracted with ethyl acid. Wash the organic layer with saturated aqueous sodium bicarbonate, water and brine. The solution was washed, dried over magnesium sulfate, and treated with activated charcoal. After filtration, the solvent is distilled under reduced pressure. , the residue was subjected to column chromatography on silica gel (50 g) and chromatographed with chloroform. The mixture was mixed with methanol. Combine the fractions containing the target compound and evaporate under reduced pressure to remove the residue. was treated with diisopropyl ether to give 3-(acetylaminomethyl)-5, 6-bis(4-methoxyphenyl)-1,2,4-triazine (0.20g) I got it.

6.8-7.1 [5H, m), 7.55 (2H, d, J=9Hz).

The following compounds were obtained in the same manner as in Example 1-(1).

(2) 3-ethoxycarbonyl-5,6-bis(4-methoxyphenyl) NMR (CDCl2.δ): 1.50 [3H, t, J=7Hz), 3.84 (3)! , s).

3.86 (3H, s), 4.6 +2H, q, J=7Hz), 6.88 +2H,d.

J=9Hz), 6.96 +2H,d, J=9Hz), 7.62 (2) ! , d.

(3) 3- (2-tertiary butyloxycarbonylaminoethyl) -5,6 -bis(4-methoxyphenyl)-1,2,4-triazine mp: 102 -105°C Engineering R (Nujol): 3320. 16B0.　1610. 1490.　 1250 cm-1HMR (DMSO-d6.6): 1.33 +9H,s ), 3.18 +2H, SE, J=6Hz).

3.48 (2H, q, J=6Hz), 3.78 (3H, s), 3.8 0 (3H, s).

6.95 [2H, 6, J=9Hz), 6.99 (2H, d, J=9Hz ).

7.43 +2H, d, 7=9Hz), 7.52 (2H, d, J=9 Hz) MASS fm/z): 436 (M) (4) 3-(1-Third class Butyloxycarbonylamino-1-methylethyl)-5,6-bis(4-methyl Toxyphenyl)-1,2,4-triazine 3.79 (3) 1. s), 3.80 (3H, s), 6.97 (2H, d, J=9Hz).

7.01 +2) i, d, J=9Hz), 7.46 (2H, (1, J= 9Hz).

7.51 (2H, d, J=9H2) MASS (m/z): 450 ( M) (513-(N, N-dimethylaminomethyl)-5,6-bis(4-methyl Toxyphenyl)-1,2,4-triazine MASS (m/z): 35 Q (M) (6) 5.6-bis(4-methoxyphenyl)-3-((4-methyl biperazin-1-yl)-carbonyl)-1,2,4-triazine hydrochloride mp : 252-254’C IRfNujol): 3400.　2400. 1645.　1600.　 1575 cm-1 Example 2 (1) 3-ethoxycarbonyl-5,6-bis(4-methoxyphenyl)-1, 2,4-triazine (1,00g) and N-methylbiperazine (1,82ml) The mixture was heated at 80-90°C for 4 hours and 40 minutes. After cooling to room temperature, the mixture It was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine and soaked in magnesium sulfate. and treated with activated charcoal. After filtration, the solvent was distilled off under reduced pressure and the residue was dissolved in diethyl The mixture was dissolved in ether, and an ethanol solution of hydrochloric acid was added thereto. Filter the formed precipitate. 5.6-bis(4 -methoxyphenyl)-3-((4-methylbiperazin-1-yl)carbonyl 'r　-1,2°4-triazine hydrochloride (0.76 g) was obtained.

mp: 252-254°C IR (Nujol): 3400.　2400. 1645.　1600.　 1575 am-17,03+2H,d, J=9Hz), 7.53 (4H , d, J=9Hz) MASS [m/z): 418 [M f419) of free compound-1] The following compounds are the same as in Example 2-(1). obtained in various ways.

(2) 3-((4-(2-hydroxyethyl)piperazin-1-yl)cal (bonyl)-5,6-bis(4-methoxyphenyl)-1,2,4-triazid ion hydrochloride mp: 141-147°C Engineering R (Nujol): 1650.1610 am-1 (3) 3- (mol holinocarbonyl) -5,6-bis(4-methoxyphenyl) -1,2,4 -triazine MASS fm/z): 406 (M) (4) 3- (N, N-jime thylaminocarbonyl) -5,6-bis(4-methoxyphenyl) -1,2 ,4-triazine mp: 50-60@C Engineering R (Nujol): 1650.1600 cm-1 (5) 3- [(2 -(N,N-dimethylamino)ethyl)carbamoyl]-5,6-bis(4- methoxyphenyl)-1,2,4-triazine (3H,s), 6.98 ( 2H, d, J=8Hz), 7.02 (2H, d.

(6) 3-[(4-benzylpiperazin-1-yl)carbonyl]-5, 6-bis(4-methoxyphenyl)-1,2,4-triazine mp: 12 6-129°C Engineering R (Nujol): 1630, 1600.1480 cm-1NMR (C DC13,6) = 2.4-2.7 (4H7m), 3.57 (2H1s).

3.1-4.0 (4H, m+, 3.83 +3H,s), 3.85 (3 H, sL6.84 (2H, d, J=8.9)1z), 6.92 (2H, d, J=8.9Hz).

7.2-7.45 [5H, ml, 7.56 (2H, d, J=8.9Hz l, 7.66 [2H, d, J=8.9Hz) (7) 3-[(1-benzylpiperidin-4-yl)carbamoyl)-5゜ 6-bis(4-methoxyphenyl)-1,2,4-triazine 3.54 (2 H, s), 3.84 (3H, s), 3.86 (3H, s).

4.03-4.18 (IH, m), 6.86 (2H, d, J=8.9H z), 6.93 (2H, d, J=8.9Hz), 7.18-7.5 (5H, m), 7.59 +2H, d.

J=8.9Hz), 7.69 (2H, d, J=8.9Hz), 8.01 [LH, d.

J=8.2Hz1 MASS [m/z): 509 (M) Example 3 3-(acetylaminomethyl)-5,6-bis(4-methoxyphenyl)-1 , 2,4-triazine (0.79 g) and concentrated hydrochloric acid (5 ml) were stirred for 2 hours. Refluxed. After cooling to room temperature, the mixture was poured into water. Then add sodium bicarbonate to this The pH was adjusted to 10 by adding an aqueous solution of , and the mixture was extracted with ethyl acetate. The organic layer was washed with water and Washed with brine, dried over magnesium sulfate and treated with activated charcoal. Reduce solvent after filtration The residue was dissolved in ethanol and an ethanol solution of hydrochloric acid was added to it. . This mixture was treated with diethyl ether and 3-(aminomethyl)-5,6 -bis(4-methoxyphenyl)-1,2,4-triazine hydrochloride (0,18 A powder of g) was obtained.

4.52 (2H, br s), 6.98 + 2H, d, J = 9Hzl.

7.03 (2H, 6, J=9Hz), 7.49 (2H, d, J=9Hz ).

7.63 (2H, d, J=9Hz), 9.00 +3H, br s) MA SS [m/z): 322 (M of free compound) real Example 4 3-(aminomethyl)-5,6-bis(4-methoxyphenyl)-1,2゜ 4-triazine hydrochloride (1,00 g), chloroform and sodium bicarbonate The aqueous mixture was stirred at room temperature for 30 minutes and the separated organic layer was treated with magnesium sulfate. It was dried and treated with activated carbon. After filtration, the solvent was distilled off under reduced pressure, and the residue was diluted with N,N-di Dissolve in methylformamide (10 ml) and add 6-carboxy-3 to this mixture. -Saikiso 2.3.4,5-tetrahydropyridazine (0.40g), 1 -Ethyl-3-(3-dimethylaminobrobyl)carbodiimide hydrochloride (0,5 3 g) and triethylamine (0.39 ml). 100% of this mixture Stirred at °C for 15 hours. After cooling to room temperature, the mixture was poured into water and extracted with ethyl acetate. did. The separated organic layer was dissolved in water, dilute hydrochloric acid, saturated aqueous sodium bicarbonate, water and salt. Washed with water, dried over magnesium sulfate and treated with activated carbon. After filtration, distill the solvent The residue was subjected to column chromatography on silica gel (25 g) and chromatographed with chloroform. It was eluted with a mixture of water and methanol. Combine the fractions containing the target compound and evaporate in vacuo to remove the residue. The distillate was treated with ethanol and diethyl ether to give 5,6-bis(4-methoxyphenyl) phenyl)-3-((3-oxo-2,3,4,5-tetrahydropyridazine- 6-yl)carbonylaminomethyl)-1,2,4-triazine (0.07g ) was obtained.

mp: 183-187@C NMRfDMso-d6. δ): 2.47 +2H,t, J=8.2Hz ), 2.78 (2H.

t, , 7=8.2Hz), 3.78 (3H, s), 3.80 (3H, s).

4.78 (2) 1. d, J=5.8Hz), 6.95 (2J d, J=8.3Hz).

7.00 +2H, d, J=8.3Hz), 7.45 +2H, d, J= 8.3Hz).

7.49 (2H, a, J=8.3Hz), 8.75 flH, se, 7=5. 8Hz) MASS (m/zl: 446 (M) Example 5 (1) 5.6-bis(4-methoxyphenyl)-3-[2-(tertiary butyl) [oxycarbonylamino)ethyl]-1,2,4-triazine (1,00g) and methylene chloride (10 ml) was stirred at 2'C. In this reaction mixture Add 4N-hydrochloric acid/1,4-dioxane (10I111) and stir at room temperature for 1 hour. After that, the solvent was distilled off under reduced pressure. Diisopropyl ether (50 ml) was added to the residue. The mixture was stirred at 2°C for 3 hours. The formed precipitate was collected by filtration and diisopropyl ether 3-(2-aminoethyl)-5,6-bis(4-methoxyphenyl) )-1,2,4-triazine hydrochloride (0.73 g) was obtained.

mp: 98@C (decomp,) 7.01 (3H, d, J=9Hz) , 7.46 (3H, d, J=9Hz).

7.53 (3H, a, J=9Hz), 8.01 (2H, br s) MA SS: m/z 136 (M of free compound) or less The compound was obtained in the same manner as in Example 5-(1).

(2) 3-(1-amino-1-methylethyl)-5,6-bis(4-meth xyphenyl)-1,2,4-triazine hydrochloride mp: 245-247° C IRfNujol): 3600-3300.1600.1490.1300 cm-1HMR [DMSO-d, s, 6): 1-79 (6H1s), 3-80 (3H1S).

3.81 (3H, s), 6.99 (2H, d, J=9Hz).

7.03 (2H, d, J=9Hz), 7.50 (2H, d, J=9H z).

Example 6 (1) Add 3-(1-amino-1- ethyl)-5,6-bis(4-methoxyphenyl)-1,2,4-tri Azine hydrochloride (1,30g), 3-oxo-6-carboxy-2,3,4,5 -tetrahydropyridazine (0,48 g) and 1-hydroxybenzotriazo 1-(3-dimethylaminopropyl) )-3-Ethylcarbodiimide (0.62 ml) was added under stirring at room temperature and the mixture The mixture was stirred for 1 hour under the same conditions. The reaction mixture was poured into water and extracted with ethyl acetate.

The extract was washed with saturated aqueous sodium bicarbonate solution, water and brine, and treated with magnesium sulfate. dried in a vacuum. After filtration, the solvent was distilled off. The formed precipitate was collected by filtration and diluted with diethyl ether. 5,6-bis(4-methoxyphenyl)-3-[1-((3-o) xo-2,3,4,5-tetrahydropyridazin-6-yl)carbonylamino )-1-methylethyl]-1,2,4-1-riazine (1,33 g) was obtained.

mp: 221-22211C N'II! R (DMSo-d6.6): 1.83 (6H7s), 2.42 (2H, SE, 7=8Hz).

2.72 (2H, t, J=8Hzl, 3.79 +3H,s), 3.8 0 (3H, sl.

6.97 (2H, d, J=9Hz), 7.02 (2H, d, J=9H z).

7.48 (2H, d, J: 9Hz), 7.53 +2H, d, J=9H z).

8j2 (LH, s), 11.20 flH, 5) KASS (m/zl): 474 (M) The following compounds were obtained in the same manner as in Example 6-(1).

(2) 5.6-bis(4-methoxyphenyl)-3-[2-((3-oxo- 2゜3,4,5-tetrahydropyridazin-6-yl)carbonylamino)ethyl ]-1,2,4-triazine NKR (DMSO-d6.6): 2.36 (2H, t, J=8Hz).

2.70 (2H, t, J=8Hz), 3.30-3.36 (2H, ml .

17B (3H, sl, 3.80 (3H, sl, 6.91 (2H, d, J=9Hz).

7.00 (2H, d, J=9Hzl, 7.45 (2H, d, J=9H z).

7.50 (2H, a, , 7=9Hz), 8.33 (LH, t, J=6 Hz).

Example 7 (1) 3-(aminomethyl)-5,6-bis(4-methoxyphenyl)- 1゜2,4-1-Ryazine hydrochloride (0.80 gl, chloroform and bicarbonate The mixture of sodium aqueous solution was stirred at room temperature for 30 minutes, and the separated organic layer was soaked in a sulfuric acid magnet. dried with sodium and treated with activated carbon. After filtration, the solvent was distilled off under reduced pressure. Tet on the residue Add a mixture of lahydrofuran (20 ml) and methanol (7 ml), and Isopropylisocyanate (0.26 ml) was added to the mixture. reaction mixture The mixture was stirred at room temperature for 3 hours and 50 minutes. The mixture was dried under reduced pressure and the residue was dissolved in diisopropyl ether. ether and diethyl ether to give 3-(N-isopropylureidomethyl )-5,6-bis(4-methoxyphenyl)-1,2,4-triazine(0 , 75g) was obtained.

4.64 (2H, d, J=5.8Hz), 6.14 (IH, a, 7 =7.71(z).

6.45 +LH, t, J=5.8Hzl, 6.95 (2H, d, J= 8.8Hz).

7.00 +21. d, J=8-8Hz), 7.45 +2H, d, J =8.8Hz).

7.52 +2H, d, J=84Hz) rilAss (m/z): 40 7 (M) The following compounds were obtained in the same manner as in Example 7-(1).

(2) 3-(N'-ethylureidomethyl)-5,6-bis(4-methoxy Cyphenyl)-1,2,4-)-riazine mp = 69-74”C Engineering R (Nujol): 3300.1640.1600.1560 cm-' 4.64 +2H, d, J=5.9Hz), 6.23 +LH, ce, J=5.5 H2)/6-56 (LH, t, J = 5.5Hz), 6.95 (2H, d, J =9Hz).

7.00 (2H, d, J=9Hz), 7.45 +2)! , d, J=9Hz) .

7.52 +2H, d, J=9Hz) MASs (m/z): 393 [M) (3) 3- [2-(N-iso propylureido)ethyl]-5,6-bis(4-methoxyphenyl)-1, 2,4-triazine mp: 157-160'C IR (Nujoll: 3400-3200.1640.1620.1570 ．． 1180 cm-INMR (DMSO-ds, 6): 0.9B (6H1 d, J=6.5Hz), 3-20 (2H-t, J=7Hz), 3.51 -3.72 (3H, ml, 3.79 (3H, s).

3.80 (3H, s), 5.73 (LH, d, J=7.5Hz).

5.85 (IH, t, J=6Hz), 6.96 +2H, d, J=9H z).

6.99 +2H, d, J=9Hz), 7.45 [2H, d, J=9H z).

7.52 +2H, d, J=9H2) MAsS (m/z): 421 ( M) Example 8 (1) Add 5.6-bin to a mixture (20 ml) of chloroform and methanol (9:l). Su(4-methoxyphenyl)-3-(pyridin-4-yl)-1,2,4-1 - A solution of riazine (0.50 g) and methyl iodide (0.75 ml) was added to the room. It was left at room temperature for one day. 4-[5,6-bis(4-methoxyphenyl)-triazid The reaction mixture containing 1-methylpyridinium iodide was evaporated under reduced pressure. It was dried and the residue was dissolved in a mixture of methanol (30 ml) and water (10 ml).

Add a small amount of sodium borohydride (0.10 g) to this solution while stirring at 5-10°C. Added one by one. The reaction mixture was stirred at the same temperature for 2.5 hours. Dissolve water (100ml) The resulting precipitate was collected by filtration. Dissolve the precipitate in chloroform and brine and dried over magnesium sulfate. The separated organic layer was dried under reduced pressure and the residue was Washing with diethyl ether gave 5,6-bis(4-methoxyphenyl)-3-( 1-methyl-1,2,3,6-tetrahydrobiridin-4-yl)-1,2, 4-triazine (0.32 g) was obtained.

mp: 163-165°C Engineering R (Nujol): 1600.1300.1250 am-1HMR (D MSO-ds, δ): 2.33 (3H, s), 2.64 (2H, ml .

2.76 +2H, ml, 3.17 +2H, m), 3.78 (3H, s ).

3.80 (3H, s), 6.95 (2H, d, J-9Hz).

7.00 (2H, d, J=9Hz), 7.33 (IH, ml.

The following compounds were obtained in the same manner as in Example 8-(1).

(2) 5.6-bis(4-methoxyphenyl)-3-[1-(4-fluorobe -1,2,3,6-tetrahydrobiridin-4-yl) -1,2, 4-triazine 6.91-7.00 (4H, ml, 7.12-7.20 (2H, ml.

Example 9 (1) In xylene (400ml) 3-ethoxycarbonyl-5,6-bis(4-methoxyphenyl)-1,2, Add 4-triazine (10g) and 2.5-norbornadiene (5.55g) The mixture was refluxed under stirring for 24 hours. The reaction mixture was dried under reduced pressure to produce The precipitate was diluted with diethyl ether to give 6-ethoxycarponyl-2,3-bis( 4-methoxyphenyl)pyridine (6.47 g) was obtained.

mp: 10B-1-09°C IR [Nujol): 1700.　1600. 1505 am-1H'M R (CDC13, δ): 1.45 [3H, t, J=7Hz), 3.7 9 (3H, S).

3.81 +3H, sl, 4.4812H, q, J=7Hz), 6.78 (2H, d.

J=8Hz), 6.84 (2H, d, J=8Hz), 7.12 (2) 1. d.

J=8Hzl, 7.37 (2H, d, J=8Hzl, 7.78+LH ,d.

J=8Hz), 8.05 (LH, d, J=8HzlKASS (m/zl : 363 (M) The following compounds were obtained in the same manner as in Example 9-(1). Ta.

(2) 6-acetylaminomethyl-2,3-bis(4-methoxyphenyl)6. 7-7.0 (5H, ml, 7.07 (2H, d, J=8Hz).

7.2-7.4 (3H, m), 1.64 +LH, d, J=8)1z)M ASS +m/Z): 362 (M) (3) 6- (pyridine-4-y -2,3-bis(4-methoxyphenyl)pyridine mp: 175-178°C Engineering R1Nujol): 1610.　1600. 1510. 1250c m-1NTG (DMSO-ds, 6): 3.77 +6H,s), 6 ．． 90 (2H, d, J=8Hzl.

6.94 +2H, d, J=8Hz), ? , 19 (2H, d, J=8H z).

7.37 (2H, d, , C3Hz), 7.93 [IH, br s).

(4) 2,3-bis(4-methoxyphenyl)-6-(N, N-dimethyl aminomethyl)pyridine mp: 103-108'C (dec,) Engineering R (Nujol): 1610 ．． 1510.1250 cm-'J=8Hz), 7.32 [2H, d, J =8Hz), 7.63 (LH, d.

J=8Hz), 7.85 (2H, d, J=8Hz) Example 10 (1) 6-ethoxycarbonyl-2,3-bis(4-methoxyphenyl)pyridi (1,03 g) and N-methylpiperazine (1,87 ml) was added to 26.5 g of The mixture was refluxed with stirring for an hour. After cooling to room temperature, the reaction mixture was poured into water and ethyl acetate. is. The separated organic layer was washed with water, saturated aqueous sodium bicarbonate, water and brine. , dried over magnesium sulfate and treated with activated carbon.

After filtration, the solvent was distilled off under reduced pressure, and the residue was dissolved in diethyl ether. A solution of hydrogen chloride in ethanol was added. The formed precipitate was collected by filtration and mixed with ethanol and diethyl alcohol. Washing with methyl ether gave 2,3-bis(4-methoxyphenyl)-6-[(4 -methylbiperazin-1-yl)carbonyl]pyridine dihydrochloride (0.25g) I got it.

mp: 213-2166C Engineering α (DMSO-ds, 6)' 2-11 (3H, s), 2.8-4-8 (aH, m).

3.75 (3H, sL 3.76 + 3H, s), 6.85 (2H, d , J=9Hz).

6.91 (2H, d, J=9Hzl, 7.15 +2H, d, J=9H zl.

7.26 (2H, d, J=9Hz), 7.68 (IH, d, J=9H z).

7.92 flH, d, J=9Hz1MASS (m/z): 415 [ M f417) of free compound-2] The following compounds are Example 1O-(obtained in a similar manner to 11).

(2) 2.3-bis(4-methoxyphenyl)-6-[(2-(N, N- Dimethylamine)ethyl)carbamoylcopyridine dihydrochloride mp: 6B-7 1@C Engineering R (Nujol): 1600.1510.1300.1250 cm-1 MASS (m/z): 405 (M” of free compound d) (3) 2.3-bis(4-methoxyphenyl)-6-[(4-benzylpipe Radin-1-yl) carbamoylcopyridine mp: 126-132@c Engineering RfNujol): 1610.1500 am-1 Example 11 (1) Lithium aluminum hydride (0.24 g) and tetrahydrofuran (2 6-ethoxycarponyl-2.3-bis(4-methoxyphene) ) Pyridine (2.1 gl of tetrahydrofuran (2.1 ml) was cooled with water. The mixture was added with stirring and the mixture was stirred at the same temperature for 1 hour. Ethyl acetate to the reaction mixture (20 ml) and water (20 ml) were added very carefully. The organic layer was washed with brine. , dried over magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure to remove 6-hydroxymethane. Chil-2,3-bis(4-methoxyphenyl)pyridine (2.04 g) was obtained.

NMIR (CDC13,6) = 3.79 (3H, s), 3.81 (3H, s).

4.82 (2H, s), 6.79 +2H, d, J=9Hz).

6.84 (2H, d, J=9Hz), 7.0-7.4 (5H, ml.

7.67 (1)! , d, J=8Hz) Mass + m/z): 321 fM) (2) 6-hydroxymethyl-2, chloroform (20ml) 3-bis(4-methoxyphenyl)pyridine (2g) and activated manganese dioxide (6 g) was added and the resulting mixture was stirred at room temperature for 5.5 hours. After filtration, remove the solvent Distillation under reduced pressure was performed, and the resulting precipitate was washed with diisopropyl ether to obtain 2,3-bis (4-methoxyphenyl)-6-pyridinecarbaldehyde (1,61g) was obtained. Ta.

MMR (CDCl2.6): 3.81. (3H, S), 3.82 (3 H, S).

6.81 (2H, a, J=9Hz), 6.84 (2H, d, J=9H z).

7.12 (2H, d, J=9Hz), 7.37 (2H, d, J=9H z).

Example 12 The following compounds were prepared in the same manner as in Example 11. It was obtained by reacting s(4-methoxyphenyl)pyridine.

2.3-bis(4-methoxyphenyl)-6-virazinecarpaldehyde R1N ujol): 1700.1600.1505 cm-1 Example 13 (1) 2.3-bis(4-methoxyphenyl)-6-pyridinecarbaldehyde (0.6g), malonic acid (0.98g), piperidine (0.1ml) and A mixture of pyridine (6 ml) was refluxed under stirring for 1 hour and 20 minutes. cooled to room temperature Afterwards, the mixture was poured into water and ethyl acetate, and the pH was adjusted to 1 with 4N aqueous sodium hydroxide solution. Adjusted to O15. The separated aqueous layer was washed with ethyl acetate, and the aqueous layer was adjusted to pH with 6N hydrochloric acid. was adjusted to about 4 and extracted with ethyl acetate. Wash the organic layer with brine and dilute with magnesium sulfate. dried in a vacuum. After filtration, the solvent was distilled off under reduced pressure to obtain 3-[2,3-bis(4-meth) xyphenyl)pyridin-6-yl]-(E)-propenoic acid (0,35 g) was obtained. Ta.

7.67 T: LH, d, J=16H2), 7.69 (LH, d, J= 8Hzl.

7.8 (LH, d, J=8Hz+ MASS (m/zl: 361 (M) Compounds of 1 or less are Example 13-(1 ) was obtained in a similar manner.

(2) 3-[2,3-bis(4-methoxyphenyl)pyrazin-5-ylco -(E)-propenoic acid mp: 23B-240"C XRTNujol): 1680.1630.1600.1500 cm-1 6,85-6,93 (4H, m), 7.07 flH, d, J = 15.6H z).

7.35-7.54 (4H, m), 7.75 (IH, d, J=15.6 Hz).

Example 14 (1) Add 3-[2,3-bis(4-methoxyphenyl) to methanol (8 ml). ) pyridin-6-yl]-(E)-propenoic acid (0,8 g) and 10% palladium - Addition of carbon (0.16 g) to the mixture for 5 hours at room temperature under a low pressure hydrogen atmosphere Stirred. Filter the insoluble matter, wash with a mixture of chloroform and methanol, and remove the solvent. It was distilled off under reduced pressure. The residue was dissolved in a mixture of ethyl acetate and water, and the resulting solution was dissolved in 6N hydrochloric acid. The pH was adjusted to approximately 4. The organic layer was washed with brine and dried over magnesium sulfate. . The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography. Elution was performed with a mixture of form and methanol (10:1). The eluate was dried under reduced pressure and The formed precipitate was washed with diethyl ether to give 3-[2,3-bis(4-methoxy) Cyphenyl)pyridin-6-yl]propanoic acid (495l!1g) was obtained.

mp: 146-147@c Engineering R (Nuol): 1710.　1600. 1510 cm-1NIi ! R (CDCl2.6): 2.8-2.95 +2H, m), 3.15- 3.29 (2H, ml.

3.8 (3H, s), 3.81 D) I, s), 6.75-7.33 (91, m).

7.76 +IH, d, J = 8H21MASS fm/z): 363 T M) The following compounds were obtained in the same manner as in Example 14-(1).

(2) 3-[2,3-bis(4-methoxyphenyl)pyrazin-5-yl] propanoic acid mp: 120-128'C Example 15 (1) 6-acetylaminomethyl-2,3-bis(4-methoxyphenyl)pyri A mixture of gin (1.64 g) and concentrated hydrochloric acid (3.3 ml) was refluxed with stirring for 1.5 hours. I set it. Pour the reaction mixture into a mixture of ethyl acetate and ice water and add 4N sodium hydroxide solution. The pH was adjusted to 10 with the solution. The separated organic layer was washed with brine and treated with magnesium sulfate. dried in a vacuum. After filtration, the filtrate was dried under reduced pressure, and the residue was dissolved in ethanol. A solution of hydrogen chloride in ethanol was added to the solution. Add diethyl ether to this mixture 6-aminomethyl-2,3-bis(4-methoxyphenyl)pyridine 2 Hydrochloride (1.13 g) was obtained.

mp: 150’Cfdec,) The following compounds were obtained in the same manner as in Example 15-(1).

(2) 2-aminomethyl-4,5-bis(4-methoxyphenyl)pyrimidine salt acid salt Engineering RTNujol): 1605.15B5.1570.1510 am-1 Example 16 (1) 6-aminomethyl-2,3-bis(4-methoxyphenyl)pyridine disalt Acid acid (0,2g), 6-carboxy-3=oxo-2,3,4,5-tetrahydride Ropyridazine (72mg), N-hydroxybenzotriazole (69mg) , l-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride ( 97 mg) and triethylamine (0.15 g) in tetrahydrofurane. The mixture was stirred at room temperature for 15 hours in a tube (4 ml). Pour the reaction mixture into water to remove the formed precipitate. Wash the precipitate with water and tetrahydrofuran to obtain 2,3-bis(4-methoxyphene). Nyl)-6-[(3-oxo-2,3゜4.5-tetrahydropyridazine-6- yl) carbonylaminomethylcopyridine f126 mg) was obtained.

mp: 234-235'C Engineering R (Nujol): 3380.1670.1655.1620.1500 cm-17,64TIE, d, J=8Hz), 8.1 TIH, br s).

8.63 +LH, 5) KASS (m/z): 444 [M] The following compounds are Example 16-(1 ) was obtained in a similar manner.

(2) 2,3-bis(4-methoxyphenyl)-6-[2-[(3-oxo- 2゜3,4,5-tetrahydropyridazin-6-yl)carbonylamino]ethyl ] Pyridine mp: 148-151°C i f Nujol): 1685.　1650.　1600. 1510.　 1240 am-1HMR (DMSO-d6.61: 2.38 (2H, Se, J=8Hz), 2.73 (2H, t.

J=8Hz), 3.0O12H, ce, J=6Hz), 3.58 (2H, q.

, C6Hz), 3.13 (3H, s), 3+74 (3H, s), 6.8 2 (2H, d.

J=8H2), 6.87 (2H, d, J=8Hzl, 7.08 (2H ,d.

J = -8Hz), 7.24 (2H, d, J = 8Hzl, 7.48 (2 H,d.

J=8Hz), 7.65 (2) 1. d, J=8Hz), 8.26+ LH,t.

Example 17 (1) 6-aminomethyl-2,3-bis(4-methoxyphenyl)pyridine disalt A mixture of the acid salt (0.3 g), methylene chloride and aqueous sodium bicarbonate solution was heated to room temperature. The mixture was stirred for 30 minutes, and the separated organic layer was dried over magnesium sulfate. After filtration, filtrate was dried under reduced pressure. Add tetrahydrofuran (6 ml) and methanol (2 ml) to the residue. ml) was added, followed by isopropyl isocyanate (0.1 ml). . The reaction mixture was stirred at room temperature for 14 hours. The mixture was dried under reduced pressure and the residue was dissolved in diisopropylene. 6-(3-isopropylureidomethyl)-2 by treatment with propyl ether , 3-bis(4-methoxyphenyl)pyridine (0.24 g) was obtained.

mp: 120’C (dec,) XRfNujol): 3300.1610.1565.1500 am-1 The following compounds were obtained in the same manner as in Example 17-(L).

(214,5-bis(4-methoxyphenyl)-2-(3-isopropylurei) domethyl)pyrimidine Example 18 (1) 1,2-bis(4-methoxyphenyl)-3-dimethylamino-2-pro Pen-1-one (3,1 g), dicyandiamide (1,68 g) and 28% Sodium methylate/methanol soluble g! A mixture of i (4 ml) was diluted with ethanol ( 50 ml) under stirring for 5 hours. The reaction mixture was dried under reduced pressure and the residue was dissolved in vinegar. Dissolved in a mixture of ethyl acid and water. This solution was adjusted to pH 7.0 with 10% hydrochloric acid. . The separated organic layer was washed with brine and dried over magnesium sulfate. Evaporate the solvent under reduced pressure The residue was subjected to silica gel column chromatography and chromatographed with chloroform and methanol. It was eluted with a mixture of 97:3 and 97:3. The eluate was dried under reduced pressure and the residue was mixed with ethyl acetate. Recrystallized from a mixture of diisopropyl ether to give 4,5-bis(4-methoxyph). phenyl)-2-cyanoaminopyrimidine (2.0 g) was obtained.

mp: 208@C (dec,) The following compounds were obtained in the same manner as in Example 1g-(1).

(2) 2-acetylaminomethyl-4,5-bis(4-methoxyphenyl)-bis Limidine J=9H2), 6.90! 2H, d, J=9Hz), 7.15 (2H ,d.

J=9Hzl, 7j8 (2H, d, J=9Hz), 8.45 (1)! , ml, 8.60flH, 5) (3) 4.5-bis(4-methoxyphenyl)-2-(1-methyl-1,2 ,3゜6-tetrahydrobiridin-4-yl)pyrimidine mp: 131-1 32.5°C Engineering RfNujol): 1650.1605.15B0.1560.1500 am-1 Example 19 (1) 1,2-bis(4-methoxyphenyl)-3-dimethylamino-2-pro Pen-1-one (3,1 g), 4-amidino-morpholine hydrobromide (4,2 g) and 28% sodium methylate/methanol (4 ml). The mixture was refluxed in ethanol (30 ml) with stirring for 7 hours. Dry the reaction mixture under vacuum. The residue was dissolved in a mixture of ethyl acetate and 10% hydrochloric acid. 20% charcoal for the separated water layer The pH was adjusted to 8.0 with an aqueous potassium acid solution and extracted with ethyl acetate. extract solution in brine and dried over magnesium sulfate. After filtration, the filtrate was dried under reduced pressure and the residue was dissolved in acetic acid. Recrystallized from a mixture of ethyl and diisopropyl ether, 4.5-bis(4-methane) Toxyphenyl)-2-morpholinopyrimidine (0.47 g) was obtained.

mp: 147-150'c Engineering RfNujol): 1605.　1585. 1570. 1525a m-1HMR (DlilSO-ds, 6): 3.73 [6H, s), 3.73 (8H, sL6.80 + 2H, d, J=8Hz), 6.85 +2H, d, J=9Hz).

7.05 (2H, d, J=9Hz), 7.32 (2H, d, J=9H z).

8.26 (IH,s) Elemental Analysis Calcd, for C22H23 N303:C70,f)1. )! 6.14. N 1113 Found: Compounds with C70,25, H6,26, N 11.25 or less are Example 19-( Obtained in the same manner as 1).

(2) 4.5-bis(4-methoxyphenyl)-2-(pyridin-4-yl) pyrimidine 7.50 (2H, d, J=9Hz), 8.30 (2H, dd, J=2 ．． 5Hzl.

(3) 4,5-bis(4-methoxyphenyl)-2-(2,6-dimethyl mol sl, 4.40-4.72 (2H, ml, 8.78 (2H, d, J= 9Hz).

6.82 (2H, d, J: 9Hz), 7-03 (2)! , d, J= 9Hz).

7.32 (2B, d, J=9Hz), 8j2 (LH, s) MASS fm/zl: 405 (M) Elemental Analysis C a1cd, for C24H27N303:C71,09,H6,71,N 10.36 Found: C70, 82, H6, 69, N 10.30 Example 20 4.5-bis in a mixture of chloroform and methanol (2:4) (30 mm1) (4-methoxyphenyl)-2-(pyridin-4-yl)pyrimidine (2,6 g) and 3-fluorobenzyl iodide (2.36g) were added to obtain the The solution was left at room temperature for 2 days. The reaction mixture was dried under reduced pressure to give 4-[4,5-bi (4-methoxyphenyl)pyrimidin-2-yl]-1-(3-fluoroben The residue containing pyrimidinium iodide was dissolved in methanol (40 ml) and Dissolved in a mixture of loloform (10 ml) and water (10 ml). This solution Add sodium borohydride (0.54 g) little by little while stirring at 5-10°C. I got it. The reaction mixture was stirred at the same temperature for 1 hour. The reaction mixture was dried under reduced pressure to remove the remaining The material was dissolved in chloroform, washed with brine and dried over magnesium sulfate. After filtration, The filtrate was dried under reduced pressure, and the residue was subjected to silica gel column chromatography. Elution was performed with a mixture of form and acetone (19:1). Concentrate the eluate under reduced pressure to remove the crystalline residue. The distillate was collected by filtration and dried under vacuum to give 4.5-bis(4-methoxyphenyl)-2-[ 1-(3-fluorobenzyl)-1,2゜3.6-tetrahydropyridine-4 -yl]pyrimidine (1.33 g) was obtained.

NMRLDMSO-ds, 6): 2.55-2-”71 (4H, m), 3 -03-3-27 +2H.

m), 3.60 (2H, s), 3.71 +3H, s), 3.77 ( 3H,s).

6.77 (21, d, J=9Fiz), 6.85 (21i, d, J =9Hz).

7.1 () (2H, d, J=9Hz), 7.31 (2H, d, J=9 Hz).

6.70-7.40 +5H, m), 8.53 (LM, s) Example 21 (1) Add 4.5- to a mixture of chloroform and methanol (9:1) (30ml) Bis(4-methoxyphenyl)-2-(pyridin-4-yl)pyrimidine(3 , 7g) and methyl iodide (4Iol) and the resulting solution was left at room temperature for 2 days. I placed it. The reaction mixture was dried under reduced pressure and the residue was dissolved in methanol (50 ml) and water ( 10 ml) of the mixed solution. Boron hydride was added to this solution while stirring at 5-10°C. Sodium (0.76 g) was added in portions. The reaction mixture was stirred at the same temperature for 1 hour. Stirred. Water (16 ml) was added to the reaction mixture, and the precipitate was collected by filtration. The precipitate is treated with chloroform. The solution was washed with brine and dried over magnesium sulfate. After filtration, dry the filtrate under reduced pressure. and the residue was recrystallized from aqueous methanol to give 4,5-bis(4-methoxyph). phenyl)-2-(1-methyl-1,2,3,6-tetrahydrobiridine-4- pyrimidine (1.7 g) was obtained.

mp: 131-132.5@c IR (Nujol): 1650.1605.1580.1560.1500 am-1HMRLDMSO-ds, 6): 2.30 (3)! , s), 2.40-2.80 (41 (, m).

], 00-120 (2H, m), 3.75 (3H, s), 3.77 ( 31i, s).

6.83 (2L d, J=9Hz), 6.89 +2H, d, J=91 (z).

7.13 (2H, a, J=7Hz), 7.18 (LH, s), 7.3 7 (2H.

d, J=9H2), 8.58tlE, 5) (2) Example 21-(1) 4.5-bis(4-methoxyphenyl)-2-(1-ethyl- 1,2,3,6-tetrahydrobiridin-4-yl)pyrimidine was obtained. child This was dissolved in a hydrochloric acid/ethanol solution, and the solution was dried under reduced pressure. Remove the residue Recrystallized from a mixture of alcohol and ether to give 4,5-bis(4-methoxyphenyl) ) -2-(1-ethyl-1,2,3,6-tetrahydrobiridin-4-yl) Pyrimidine hydrochloride was obtained.

mp: 183-1866C (dec,) RfNujol): 1660 ．． 1610. :L590.1565.1510 am-1HMR (DMSO- d6.6): 1.35 +3H,t, J=7Hz).

3.05-4.13 (6H, m), 3.04 +2H, ml.

3.52-4.18 (21(, ml, 6.90 (21(, a, J=9H z).

6.96 (2H, d, J=9Hz), 7.18 (LH, s).

7.20 (2H, d, J=9Hz), 7.42 +2H, d, J=9H z).

8.72 flH,S) The following compounds were obtained in the same manner as in Example 2l-(1).

(3) 2.3-bis(4-methoxyphenyl)-6-[1-(4-fluorobe )-1,2,3,6-tetrahydrobiridin-4-ylcopyridine mp : 115-117'C (4) 4.5-bis(4-methoxyphenyl)-2-[1-(4-fluoro benzyl)-1,2,3,6-tetrahydropyridin-4-yl]pyrimidine mp: 118-1200c IR [Nujol): 1645.　1600. 1570. 1500a m-1HMRiDMso-d6.6): 2.67 (4H, br s), 3.17 (2H, brs).

3.61 - [2H, s), 3.75 + 3H, s), 3.77 (3H, s), 6.87 (2H, d, J=9Hz), 6.94 (2H, d, J =9Hz), 7.11-7.20 (3H, ml, 7.13 (2H, d, J=9Hz), 7.33 (2H, d.

J=9Hzl, 7.20-7.42 (2H, ml, 8.64 (IJ(, 5) (5) 4.5-bis(4-methoxyphenyl)-2-[1-(2-phenylphenyl) ethyl)-1,2,3,6-tetrahydropyridin-4-yl]pyrimidine m), 3.76 (6H, s), 6.87 +2H, d, J=9Hz), 6.94 +2H.

d, J=9Hz), 7.16-7.33 (6H, ml, 7.46 (2 H,d.

J=9Hz), 8.65 (LH, slMASS (m/z): 477 ( M) (6) 4.5-bis(4-methoxyphenyl)-2-[1-'(2 -fluorobenzyl) -1,2,3,6-tetrahydrobiridin-4-yl] Pyrimidine mp: 96-99°C Engineering R (Nujol): 1650.1600.1570.1550 cm-1 HMR (DMSO-d6.61: 2.69 (4H, brs), 3.2 3 (2L brs).

3.68 +2H,s), 3.75 (3H,s), 3.77 (3H,s ), 6.86 (2H, d, J=9Hz), 6.93 +2H, d, J= 9Hz), 7.18 +2H.

d, J=9Hz), 7.13-7.47 +5H, ml, 7.39 +2 H,d.

J=9Hz), 8.67 flH, S) MASS [m/z): 481 (M) (7) 4.5-bis(4-methoxyphenyl)-2-[1-benzyl -1,2゜3.6-tetrahydrobiridin-4-yl]pyrimidine mp: 1 2B-130°C Engineering R (Nujol): 1645.1600.1570.1545 am-1 f2H, d, J=9Hz), 6.93 (2H, d, J=9Hz), 7 ．． 17+2H.

d, J=9)iz), 7.16-7.42 (5H, m), 7.25 ( LH, s), 7.39f2H, d, J=9Hz), 8.64 (IH, s ) MASS [m/z): 463 fM) Example 22 (1) Add 4.5-bis(4-methoxyphenyl)-(1-methoxyphenyl) to acetic acid (40ml). tyl-1,2,3,6-tetrahydrobiridin-4-yl)pyrimidine(2,1 0 g), a mixture of 10% palladium/carbon and ammonium formate (1,71 g) The mixture was stirred for 2 hours at 100-110'c. After reaction, filter the mixture and dry the filtrate under reduced pressure. Hardened. The residue was dissolved in a mixture of ethyl acetate, tetrahydrofuran and water, This solution was adjusted to pH 8.0 with a 20% aqueous potassium carbonate solution. separated organic layer was washed with brine and dried over magnesium sulfate. After filtration, the filtrate was dried under reduced pressure to remove the residue. The distillate was subjected to silica gel column chromatography and mixed with chloroform and methanol (8 : It was eluted with a mixture of 2). The eluate was dried under reduced pressure and the oily residue was dissolved in hydrochloric acid/ethanol. This solution was dried under reduced pressure, and the residue was dissolved in a mixture of ethanol and ether. Recrystallized from 4.5-bis(4-methoxyphenyl)-2-(1-methyl Piperidin-4-yl)pyrimidine dihydrochloride (0.34 g) was obtained.

NMR+DMSO-d6. δ): 2.02-2.20 (4H, ml, 2 ．． 72 (3H, s).

2.96-3.64 (6H, m), 3.77 +58. s), 6.90 +2H,d.

J=9) (z), 6.96 (2H, d, J=98z), 7.21 (2 H,d.

J=9Hzl, ’, 42 (2H, d, J=9Hz), 8.72 (I H, s) The following compounds were obtained in the same manner as in Example 22-(1).

4.5-bis(4-methoxyphenyl)-2-[1-(3-fluoropencyl) ) Piperidin-4-yl]pyrimidine hydrochloride mp: 207-211'C(d ec,) Engineering R (Nujol): 1595.1510 am-1HMRiDM so-9, 6): 2.16-2.22 +4H, ml, 3.00-3. 54+5H.

ml, 3.77 (2H, s), 4.39 (2H, d, C3Hz).

6.85 (2H, d, J=9Hz), 6.96 (2H, d, J=9H z).

7.20 (2H, 6, J=9Hz), 7.41 +2H, d, J=9Hz ).

7.27-7.75 +4H, m), 8.70 flH, sl Example 23 (1) 4.5-bis(4-methoxyphenyl)-2 in ethanol (10ml) - Add cyanoaminopyrimidine (1,0 g) and morpholine (1,3 g) The solution was refluxed for 1 hour with stirring. The reaction mixture was dried under reduced pressure and the residue was evaporated with acetic acid. It was dissolved in a mixture of chill and 10% hydrochloric acid. The separated aqueous layer was added to a 20% potassium carbonate aqueous solution. The pH was adjusted to 8.0 and extracted with a mixture of ethyl acetate and tetrahydrofuran. Yes The organic layer was washed with brine and dried over magnesium sulfate. After filtration, dry liquid a under reduced pressure to remove the residue. The distillate was recrystallized from a mixture of ethyl acetate and ether to give 4,5-bis(4-methoxy). Cyphenyl) -2-[(4-morpholinecarboximidoyl)aminocopyly Midin (0.72 g) was obtained.

mp: 176-178°C Engineering R (Nujol): 3270.　3150.　1610. 1590c m-1HMRfDMSO-d6,6): 3-33 (4H,s), 3-60 (4Ht S).

3.75 +6H, s), 6.83 [2H, d, J=9H2).

6.85 (2H, d, J=9Hz), , 7.08 +2H, d, J=7 Hz).

C65, 85, H6, 01, N: L6.70 Found: C65, 60, Compounds with H6,07,N 16.67 or less were prepared in the same manner as in Example 23-(1). Obtained.

(2) 4.5-bis(4-methoxyphenyl)-2-[(4-methyl-1-pi perazinecarboximidoyl) aminocopyrimidine mp: 138-140 ’C [dec,] Engineering R (Nujol): 32B0.3130.1610.1 590.1-510 am-'NMR (DMSO-d6.6): 2.19 (3H, sl, 2.00-2.43 (4H, m).

3.40-3.70 (4)! , ml, 3.73 (6H, s), 6.8 4 (2H, d.

J = 9Hz), 6.86 (2H, d, J = 9Hzl, 7.06 (2H ,d.

J=9Hz), 7.27 (2H, d, J=9Hz), 8.33 (LH ,sl.

8.10-8.66 +2H, m) KASS (mlz): 432 (M 1(3)4.5-bis(4-methoxy) Cyphenyl)-2-[(4-benzyl-1-piperazinecarboximidoyl ) Aminocopyrimidine ml, 3.74 (6H, s), 6.78-7.05 (4H, m).

7.13 (2H, d, J=9Hz), 7.23-7.38 (8H, mL8 ．． 35 (IH, s), 8.35-8.43 +2H, mlMASS (ml zl: 50B (M) (4) 4.5-bis(4-methoxyphenyl) - 2-[3-(1-benzylpiperidin-4-yl)guanidinocopyrimidine mp : 157-159'C (dec,) Engineering R (Nujol): 3150.　 3300. 1640 (schl, 1605. 1580 am-INMRf DMso-d6.6): 1.17-1.52 (2H, ml, 1.Ell -2,28,(4H.

mL 2.67-2.73 (2H, m), 3.44 +2H, sl, 3. 75 (6H.

s), 3.64-3.89 +LH, ml, 6.82 +2H, d, J= 9Hzl.

6.91 [2H, d, J=9Hz), 7.11 (2H, d, J=9H z).

(514,5-bis(4-methoxyphenyl)-2-[(4-benzyl-1- piperidinecarboximidoyl) aminocobyrimidine mp: 160'C ( dec, 1 Engineering R (Nujol): 3300.　3150.　1600. 1580.　 1520 cm-1HMRfDMso-d6.61: 1.02-1.15 (2H, ml, 1.57-1.78 (3H.

m), 2.70-2.82 (2H, m), 3.22-186 (2H, ml, 3.75 (6H, s), 4.33-4.40 (2H, ml, 6.83-6 ．． 90 (4H, ml.

7.07 (2H, d, J: 9Hz), 7.10-7.31 +8H, m) , 8.33 (IH, sl, 8.37 +2H, br s) MASS (mlzl : 507 (M) (614,5-bis(4-methoxyphenyl)-2- [(4-(2-methoxyphenyl)-1-piperazinecarboximidoyl)a minocyrimidin mp: 199-200°C Engineering R (Nujol): 3320.31B0.1605.1570.1.51 5 Cm-1 yen (DMSo-d6', 5): 3.00 (4H, brs) , 3.75 +9H,s).

3.82 (4H, br　s), 6.84-7.07 +8H, ml, 7.1 5 (2H, d.

J=9Hz), 7.31 +2H,d, J=9Hz), 8.38 (IH ,s), 8.49(21(,br　s) Example 24 (11 methyl cellosolve (511+1) to 4,5-bis(4-methoxyphenyl) )-2-cyanoaminobilimicin (1,0g) and piperidine (1,1g) The resulting solution was stirred at 120-125°C for 3 hours. reaction mixture in water The mixture was poured and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. . After filtration, the filtrate was dried under reduced pressure and the residue was mixed with ethyl acetate and diisopropyl ether. Recrystallize from the liquid to give 4゜5-bis(4-methoxyphenyl)-2-[(1-pipe Lysinecarboximidoyl)aminocopyrimidine (0.65g) was obtained.

mp: 185-187'c Engineering R (Nujoll: 3330.3170.1610.1590.1565 ．． 1525 am-INMRtDMSo-a6.61: 1-30-1-10 f6a, m), 3-40-3-10 (4)i.

m), 3.73 (6H, s), 6.81- +2H, d, 7=9Hz ), 6.83 +2H.

d, J=9Hzl, 7.05 (2H, d, J=9Hz), 7.27 (2H, d.

Compounds below J=9H2l, 8.30 (IH, s), 8j2 (2H, m) The product was obtained in the same manner as in Example 24-(11).

(2) 4.5-bis(4-methoxyphenyl)-2-(3-cyclohexylg anidino)pyrimidine mp: 203-205°C XR (Nujoll: 3310. 3205. 1595. 1510 a m-1! (DMSO-(16, δl): 0.86-2.03 (11H, m l, 3.75 (6H, s).

6.85 [2H, d, J=9Hz), 6.88 (2H, cl, J=9 Hz).

7.10 [2H, d, J=9Hz), 7.30 (2H, d, J=9H z).

8.47 (IH, sl MASS (mlzl: 431 (M) (3) 4.5-bis(4-meth) xyphenyl)-2-[(2-imidacillin-2-yl)aminocobyrimidine mp: 190-192°C J=9Hz), 8.15 (IH, 5) (4) 4.5-bis(4-methoxyf phenyl)-2-(3-isopropylgua(LH, ml, 3.75 [6H, s ), 6.60-7.50 (8H, ml, 8.46(5) 4.5-bis( 4-methoxyphenyl)-2-(3-benzylguanidino)pyrimidine mp: 204-206@C Engineering R (Nujol): 3460.1630.1610.1560 am-1 HMRIDMsO-d6.6): 3.80 +6H,s), 4.62 ( 2H,s).

6.92 +2H, d, J=9Hz), 6.97 (2H, d, J=9H z).

7.20 (2H, d, J=9Hz), 7.38 +2H,, d, J=9 Hz).

1.43 (5H=sl, 8-43 (Sho, S) Example 25 4.5-bis(4-methoxyphenyl)-2=sia in ethanol (20rnl) Noaminopyrimidine (0.67g) and dimethylamine hydrochloride (0.4g) The solution was refluxed with stirring for 10 hours. Evaporate the reaction mixture in vacuo to remove the residue. The distillate was dissolved in a mixture of ethyl acetate and 10% hydrochloric acid. The separated aqueous layer was heated with 20% carbonate. The pH was adjusted to 8.0 with aqueous sodium chloride solution and extracted with ethyl acetate. Wash the extract with salt water and dried over magnesium sulfate. After filtration, the filtrate was dried under reduced pressure and the oily residue was dissolved in hydrochloric acid/ Dissolved in ethanol solution. This solution was dried under reduced pressure and the residue was dissolved in ethanol and ether. 4,5-bis(4-methoxyphenyl)-2-(3, 3-dimethylguanidino)pyrimidine hydrochloride (0.28 g) was obtained.

mp: 23B-239@C XRfNujol): 3130.1640.1605.1580 am-1 ? 'iMR (DMSO-d6.6): 120, (6H, sl, 3.78 +6H,s).

6.88 (2H, d, J=7Hz), 6.95 (2H, d, J=9H z).

7.17 +2H,6,, r=9Hz), 7.39 (2H,d, J=91 'lz).

8.62 +IL s), 9.22 (24m) MASS (m/z): 377 [M) Elemental, balysis Calcd, for C21H23 N502: C60,94, H5,84, N 1-6.92. C18,57Fou nd: C60, 9Q, I (5, 64, N 16.7B, C1B, 64 Example 26 2,3-bis(4-methoxy) in N,N-dimethylformamide (20ml) Phenyl) pyrazine-5-carboxylic acid (1,01g), 1-hydroxyben Zotriazole (446 mg) and l-ethyl-3-(3-dimethylaminopropylene) ropyru) carbodiimide hydrochloride (573 mg) was added to the mixture for 1 hour at room temperature. It was stirred with To this was added N-methylpiperazine (500 mg) and the mixture was stirred for 2 hours. Stir for a while. After removing the solvent, chloroform (30 ml) and water (20 ml) were added to the residue. ) and the mixture was adjusted to pH 9 with saturated aqueous potassium carbonate solution. isolated organic The layers were washed with water (20I111), dried over magnesium sulfate, and concentrated. residual Dissolve the product in ethyl acetate (20 ml) and add diethyl ether solution saturated with hydrogen chloride. to precipitate crystals, collect the precipitate, wash with ethyl acetate, and add 2,3-bis(4-methane) (toxyphenyl)-5-[(4-methylbiperazin-1-yl)carbonyl]pyl Radin hydrochloride was obtained.

mp:90-93°C Engineering R (Nujol): 1630.　1600. 1505cm-'NMR (D20.δl: 3.23 [3H, s), 3.70 (6H, s).

3.1-4.3 f8H, ml, 6.6-7.1 (4H, ml, 7.2- 7.7 (4H.

rr+), 9.03 tll(,s/)+1LASS (m/z): 41 8 (M of free compound) Example 27 (2,3-bis(4-meth) in 11N,N-dimethylformamide (20ml) xyphenyl) pyrazine-5-carboxylic acid (1,03g), 1-hydroxy Benzotriazole (446 mg) and 1-ethyl-3-(3-dimethylamidine) (nopropyl) carbodiimide hydrochloride (573 mg) was added for 1 hour. Stir at room temperature. Add 30% methylamine/methanol solution (5 ml) to this and mix. The mixture was stirred for 3 hours. After removing the solvent, chloroform (30 ml) and water were added to the residue. (20 ml) was added and the mixture was adjusted to pH 9 with a saturated aqueous solution of potassium carbonate.

The separated organic layer was dried over magnesium sulfate and concentrated. Remove residue from silica gel It was subjected to ram chromatography and eluted with a 15% methanol/chloroform solution.

Fractions containing the target compound were collected and concentrated. The residue was saturated with diethyl chloride. 2.3-bis(4-methoxyphenyl) )-5-(methylcarbamoyl)pyrazine hydrochloride was obtained.

mp: 125-127'C IRfNujoll: 1680.　1600. 1520. 1510a Compounds of m-1 or less were obtained in the same manner as in Example 27-(1).

(2) 2.3-bis(4-methoxyphenyl)-5-[(1-benzylpiperidi (4-yl)carbamoyl] pyrazine mp = 157-159°C Engineering R (Nujol): 3400.1655.1600.1500 am-1 HMR (CDCl2.6): 1.5-2.33 (6H, ml, 2.77 -3.0 (2H, ml.

3.53 [2H, s), 3.82 (3H, s), 3.85 (3H, s ).

3.95-4.2 (LH, m), 6.8-7.02 (4H, ml, 7. 15-7.53 Example 28 N,N-dimethylformamide (5 ml) contains 5-di-4-2,3-bis(4 -methoxyphenyl) pyrazine (653 mg), and guanidine carbonate (90 0 mg) was heated at 140°C for 15 hours. After removing the solvent under reduced pressure, the remaining Add water (15 ml) and 5% methanol/chloroform (30 ml) to the distillate iFli added. The separated organic layer was washed with saturated brine and dried over magnesium sulfate. . The solvent was distilled off and the residue was subjected to column chromatography on silica gel (50 g). Elution was performed with a 15% methanol/chloroform solution. Collect fractions containing the target compound and concentrated. The residue was treated with diethyl ether to give 5-(N,N-dimethyl Amino)-2,3-bis(4-methoxyphenyl)pyrazine was obtained.

NMR+DMSO-(16, δ): 3.10 (6H, s), 3.68 [6H,s).

6.80 (2H, d, J=lOHz), 6.82 f2H, d, J=l (OHz).

7.20 (2H, d, J=lOHz), 7.30 (2H, d, J=1 0Hz).

8.07 [1) (,s) MSS (m/z): 335 (M) Example 29 5-chloro-2,3-bis(4-methoxyphenyl)pyrazine (980mg) , guanidine (1,8 g) and N, N-dimethylformamide (1,0 ml) was heated at 150°C for 8 hours. After distilling off the solvent under reduced pressure, the residue was subjected to column chromatography on silica gel (50 g) and chromatographed with 15% methanol. It was eluted with roform solution. Collect the fraction containing the target compound and! I shrunk. residue was dissolved in ethyl acetate (20 ml) and crystallized with an ethanol solution saturated with hydrogen chloride. was precipitated. The precipitate was collected and washed with ethyl acetate to give 5-guanidino-2,3- Bis(4-methoxyphenyl)pyrazine hydrochloride was obtained.

mp: 246-2696C (dec,) Engineering R (Nujol): 3250 ．．　1680.　1620.　1600. 1510 cm-'NMR (DMS O-d6.6): 3. '74 (6)! , s), 6.7-7.0 (4H , m).

Example 30 Morpholine (3ml) and 5-chloro-2,3-bis(4-methoxyphenyl) A mixture of pyrazine (980 mg, ) was stirred at 100"C for 3 hours. The solvent was removed under reduced pressure. After distillation under Methoxyphenyl)-5-(morpholin-4-yl)pyrazine was obtained.

mp: 138-139°C1 Engineering R (Nujol): 1603. 1573. 1545. Is○5 a m-1! Punishment fcDc13.6): 3.5-4.0 (8H, m), 3.7 6 (6H, sl.

6.89 (4H, a, J=lOHz), 7.2-7.5 (4H, m).

8.03 (LM, s) MASS (m/z): 377 [M] Example 31 Piperazine (5g) and 5-chloro-2,3-bis(4-methoxyphenyl)pyra A mixture of gin (980 mg) was refluxed in ethanol (10 ml) for 3 hours.

After evaporating the solvent, ethyl acetate (20 ml) and water (30 ml) were added to the residue. The separated organic layer was washed with saturated brine and dried over magnesium sulfate. After removing solvent , the residue was treated with ether to precipitate crystals, and 2,3-bis(4-methoxyphenyl) phenyl)-5-(piperazin-1-yl)-pyrazine was obtained.

mp: 128-129@C 3,73(6H,s), 6.82+4H,6, ]=91(z).

Example 32 5-chloro-2,3-bis(4-methoxyphenyl)pyrazine (980mg) and A mixture of N-methylbiperazine (3 ml) was stirred at 60°C for 3 hours, then heated to 100°C. The mixture was stirred for 2 hours. After distilling off the solvent under reduced pressure, the residue was dissolved in diethyl ether (30 ml). ) and treated with an ether solution saturated with hydrogen chloride to precipitate crystals.

The precipitate was collected and washed with ether to give 2,3-bis(4-methoxyphenyl)- 5-(4-methylbiperazin-1-yl)-pyrazine dihydrochloride was obtained.

MASS (m/z): 390 (M of free compound ) Example 33 2,3-bis(4-methoxyphenyl)-5-methylpyrazine in acetic acid (3ml) (1,07g), dimethylamine hydrochloride (346mg) and paraformal Dehyde (126 mg) was added and the mixture was stirred at room temperature for 10 days. solvent After distillation, the residue was mixed with water (10 ml) and 5% methanol/chloroform solution (20 ml). l) was added and the mixture was adjusted to pH 9 with saturated aqueous potassium carbonate solution. Separated The organic layer was dried with magnesium sulfate.

The solvent was distilled off and the residue was subjected to column chromatography on silica gel (50 g). A 0% methanol/chloroform solution was dispensed. Collect the fraction containing the target compound. Concentrated. The residue was dissolved in ethyl acetate (30 ml) and diluted with an ethereal solution of hydrogen chloride. treatment to precipitate crystals, 5-[2-(N, N-dimethylamino)ethyl] -2,3-bis(4-methoxyphenyl)pyrazine hydrochloride was obtained.

mp: 203-207”C (dec,) Engineering R (Nujol): 3350 ．． 2600.1600.1520 cm-1N! I! R (D20.6): 2 ．． 8-3.2 (2H, ml, 3.0 (6H, s).

3.6-4.0 (2H, ml, 3.85 (6H, sl, 6.8-7.6 (8H, m).

8.83 (IH, sl MASS (ITI/Z): 363 (M) Example 34.

3-(2-tert-butoxycarbonylaminoethyl) in xylene (200 ml) -5,6-bis(4-methoxyphenyl)-1,2,4-1-riazine(5 ,00g) and 2,5-norbornadiene (12,0ml). The mixture was stirred and refluxed for 3 days. The reaction mixture was dried under reduced pressure. Add 4N chloride water to the residue A solution of neat 1,4-dioxane was added and the mixture was stirred at 0°C for 2 hours. reaction mixture The mixture was dried under reduced pressure, and the precipitate formed was washed with diethyl ether and dried to give 6- (2-aminoethyl)-2,3-bis(4-methoxyphenyl)pyridine hydrochloride Salt (5.35g) was obtained.

international search report 1MernjliM+Ill++ll+m~, 7p "M! 1) Ql/+110 17 International Search Report PCT/JP 91101042 S^　34780 Continuation of front page (51) Int, C1,5 identification symbol Internal office reference number CO7D 253106 7433-4C4011042398829-4C 2418829-4C 2538829-4C 401/14213 8829-4C (81) Designated countries EP (AT, BE, CH, DE.

DK, ES, FR, GB, GR, IT, LU, NL, SE), JP, US I

Claims (13)

[Claims] 1. formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R1 and R2 each represent a lower alkoxy group, and R3 represents pyridyl or tetrahydro. selected from the group consisting of lopyridyl, piperidyl, piperazinyl and morpholinyl groups. Heterocyclic group which may have one or more suitable substituents; substituted amino group ; Carboxy (lower) alkenyl group: Carboxy (lower) alkyl group; hydroxy (lower) alkyl group; an amino (lower) alkyl group which may have one or more suitable substituents; The group of the following formula ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R4 is hydrogen, ethoxy, mono(or di)lower alkylamino, di(lower (class) alkylamino-(lower) alkylamino, with one or more suitable substituents a heterocyclic amino group that may have one or more suitable substituents, or a heterocyclic group that may have one or more suitable substituents. show) or a group of the following formula, ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R5 is lower alkyl or alkyl which may have one or more suitable substituents ( (lower) alkyl group, (X1 represents an acid residue) Y is CH or N, Z represents CH or N. However, R3 is a pyridyl group; a piperidyl group which may have a hydroxy group; a lower alkali group; Piperazinyl group having a kill group or a hydroxy (lower) alkyl group; morpholinyl group; Nyl group; Lower alkenylamino group; Hydroxy (lower) alkylamino group; Ben A phenylamino group which may have a lower alkoxy group or a halogen on the zene ring; Halophenyl (lower) alkylamino group; nitro group, amino group or or phenylsulfonylamino group having halogen; or lower alkyl group and hydrogen Substituted with two substituents selected from the group consisting of droxy (lower) alkyl groups an amino group, and further When Y indicates N, Z indicates CH. and pharmaceutically acceptable salts thereof. 2. R3 is pyridyl, tetrahydropyridyl, piperidyl, piperazinyl and selected from the group consisting of morpholinyl groups, and having 1 to 3 suitable substituents Good heterocyclic group; cyanoamino; imidazolinylamino; guanidino; di(lower) Alkylguanidino; lower alkylguanidino; cyclo(lower) alkylguanidino Dino; Al(lower)alkylguanidino; substituted with 1 to 3 suitable substituents may have 1 to 3 suitable substituents (1-heterocyclic guanidino) -1-iminomethyl)amino; di(lower)alkylamino; hydroxy(lower) Alkyl: carboxy(lower) alkyl; carboxy(lower) alkenyl; lower May have 1 to 3 substituents selected from the group consisting of alkyl and acyl amino (lower) alkyl; Group of the following formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R4 is hydrogen: ethoxy; mono (or di) lower alkylamino; di (lower (lower) alkylamino; lower alkyl, lower alkoxy , 1 to 3 substitutions selected from the group consisting of halogen and al(lower) alkyl Heterocyclic amino which may have a group; or lower alkyl, lower alkoxy, halogen selected from the group consisting of (represents a heterocyclic group which may have 1 to 3 substituents); Or a group of the following formula, ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R5 is lower alkyl, halogen, lower alkyl, lower alkoxy Al (lower) alkyl which may have 1 to 3 substituents selected from the group consisting of , and (X1 represents an acid residue) The compound according to claim 1, which is 3. R3 is pyridyl, tetrahydropyridyl, piperidyl, piperazinyl and morpholinyl group, and lower alkyl and one or two 1 selected from the group consisting of alkyl (lower) alkyl which may have a halogen Heterocyclic group which may have two substituents; cyanoamino; imidazolinylamino; Guanidino; di(lower)alkylguanidino; lower alkylguanidino; cyclo (lower) alkylguanidino; phenyl (lower) alkylguanidino; Heterocyclic guanidino which may have an alkyl group; lower alkyl, al(lower) alkyl; alkyl and aryl optionally having lower alkoxy. (1-heterocyclic-1-iminomethyl)amino which may have a substituent; di(lower)al Kylamino; hydroxy (lower) alkyl; carboxy (lower) alkyl; Boxy (lower) alkenyl; lower alkyl, lower alkanol, lower alkylcar Bamoyl, lower alkoxycarbonyl and with 1 to 3 suitable substituents Even if it has one or two substituents selected from the group consisting of good heterocyclic carbonyl Good amino (lower) alkyl; Group of the following formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R4 is hydrogen; ethoxy; mono(or di)lower alkylamino; di(lower (lower) alkylamino; lower alkyl, lower alkoxy , 1 or 2 selected from the group consisting of halogen and phenyl (lower) alkyl A saturated 5-carbon heterocyclic group in which the heteromonocyclic group moiety which may have 1 to 3 substituents contains 1 to 3 nitrogen atoms. or 6-membered heteromonocyclic amino; lower alkyl, lower alkoxy, halogen, phenylene selected from the group consisting of nyl (lower) alkyl and hydroxy (lower) alkyl 1 to 2 oxygen atoms which may have 1 or 2 substituents and 1 to 3 nitrogen atoms a saturated 5- or 6-membered heteromonocyclic group containing children; or lower alkyl, lower alkoxy cy, halogen, phenyl (lower) alkyl and hydroxy (lower) alkyl? 1 to 3 nitrogen atoms optionally having 1 or 2 substituents selected from the group consisting of ) or a group of the following formula, ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R5 is lower alkyl, or halogen, lower alkyl, and lower alkyl. phenyl which may have one or two substituents selected from the group consisting of class) alkyl, and (X1 represents halogen) The compound according to claim 2, which is a compound as shown in claim 2. 4. R3 is pyridyl, tetrahydropyridyl, piperidyl, piperazinyl and selected from the group consisting of morpholinyl, lower alkyl, phenyl (lower) alkyl, 1 or 2 selected from the group consisting of pyl and halophenyl (lower) alkyl Heterocyclic group which may have a substituent; cyanoamino; imidazolinylamino; guar di(lower) alkylguanidino; lower alkylguanidino; cyclo(lower) phenyl (lower) alkylguanidino; phenyl (lower) alkylguanidino; class) alkylpiperidylguanidino; {morpholinyl(imino)methyl}amino {piperidyl(imino)methyl}a which may have phenyl(lower)alkyl; Mino; lower alkyl, phenyl (lower) alkyl and lower alkoxyphenyl It may have a substituent selected from the group consisting of {piperazinyl(imino)methyl }Amino; Di(lower)alkylamino; Hydroxy(lower)alkyl; Carboxy Cy(lower)alkyl; Carboxy(lower)alkenyl; Lower alkyl, lower alkyl Kanoyl, lower alkylcarbamoyl, lower alkoxycarbonyl and oxo selected from the group consisting of tetrahydropyridazinylcarbonyl which may have a group Amino (lower) alkyl which may have 1 or 2 substituents; Group of the following formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R4 is hydrogen, ethoxy, mono(or di)lower alkylamino, di(lower (class) alkylamino (lower) alkylamino, phenyl (lower) alkylpiperi dylamino, morpholinyl, or lower alkyl, hydroxy (lower) alkyl or piperazinyl which may have phenyl (lower) alkyl) Or a group of the following formula, ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R5 is lower alkyl or phenyl (lower) which may have a halogen. alkyl, X1 represents halogen) 4. The compound according to claim 3, which is 5. R3 represents a group of the following formula, ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R4 represents a lower alkylpiperazinyl group) Y is N, and Z is N 5. The compound according to claim 4, which is 6. The compound is 5,6-bis(4-methoxyphenyl)-3-{(4-methylpipe Radin-1-yl) carbonyl}-1,2,4-triazine hydrochloride. Compounds according to scope 5. 7. R3 represents a lower alkyltetrahydropyridyl group, Y is CH, and Z is N, 5. The compound according to claim 4, which is 8. The compound is 4,5-bis(4-methoxyphenyl)-2-(1-methyl-1, Claim 7: 2,3,6-tetrahydropyridin-4-yl)pyrimidine Compounds described. 9. formula ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R1 and R2 each represent a lower alkoxy group, and R3 represents pyridyl or tetrahydro. selected from the group consisting of lopyridyl, piperidyl, piperazinyl and morpholinyl groups. Heterocyclic group which may have one or more suitable substituents; substituted amino group ; Carboxy (lower) alkenyl group; Carboxy (lower) alkyl group; hydroxy (lower) alkyl group; an amino (lower) alkyl group which may have one or more suitable substituents; The group of the following formula ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R4 is hydrogen, ethoxy, mono(or di)lower alkylamino, di(lower (class) alkylamino-(lower) alkylamino, with one or more suitable substituents a heterocyclic amino group that may have one or more suitable substituents, or a heterocyclic group that may have one or more suitable substituents. show) or a group of the following formula, ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R5 is lower alkyl or alkyl which may have one or more suitable substituents ( (lower) alkyl group, (X1 represents an acid residue) Y is CH or N, Z represents CH or N. However, R3 is a pyridyl group; a piperidyl group which may have a hydroxy group; a lower alkali group; Piperazinyl group having a kill group or a hydroxy (lower) alkyl group; morpholinyl group; Nyl; lower alkenylamino; hydroxy (lower) alkylamino; benzene ring Phenylamino which may have a lower alkoxy group or halogen on it; halofe Nyl (lower) alkylamino; nitro group, amino group, or halo group on the benzene ring phenylsulfonylamino with gen, or lower alkyl and hydroxy (lower Indicates an amino group substituted with two substituents selected from the group consisting of (class) alkyl. , when Y indicates N, Z indicates CH. In producing the compound or its salt represented by formula (1): ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ A compound represented by the formula, where R1 and R2 are each the same as above, formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R3 is the same as above, By reacting with a compound represented by the formula or a salt thereof, the formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R1, R2, and R3 are each the same as above, or a compound represented by Obtain the salt or (2) formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R1, R2, Y and Z are each the same as above, or is a reactive derivative at its carboxy group, or a salt thereof; formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ In the formula, ▲ includes mathematical formulas, chemical formulas, tables, etc. ▼ is mono (or di) lower alkyl amine -, di(lower)alkylamino(lower)alkylamino, with appropriate substituents at least one nitrogen atom which may have an optional heterocyclic amino or a suitable substituent; Reacting with a compound represented by or a salt thereof representing a heterocyclic group containing a compound of the formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R1R2Y, Z, and ▲ there are mathematical formulas, chemical formulas, tables, etc. ▼ are respectively shown above. Same as above, Or obtain a compound or a salt thereof represented by formula (3): ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R1, R2, Y and Z are each the same as above, and R is a protected amino Representing a (lower) alkyl group, remove the amino protecting group from the compound represented by or its salt. By subjecting it to a dissociation reaction, Formula: ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ In the formula, R1, R2, Y and Z are each Same as above, R■ represents an amino (lower) alkyl group, or obtains its salt, or formula (4): ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ A compound represented by the formula, where R1, R2, R■, Y and Z are each the same as above , or reactive derivatives or salts thereof at the amino group in the acylation reaction. By attaching the formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R1, R2, Y and Z are respectively the same as above, and R■ is acylamino (low or a salt thereof, or (5) formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R1 and R2 are each the same as above, Y1 is CH or N, Z1 represents CH or N, A compound represented by or a salt thereof, formula: X1-R5 In the formula, R5 and X1 are each the same as above, and by reacting a compound represented by formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R1, R2, R5, Y1, Z1 and X1 are each the same as above, Or obtain a compound or a salt thereof represented by formula (6): ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R1, R2, R5, Y, Z and X1 are each the same as above, By subjecting the compound represented by the formula or its salt to a reduction reaction, the formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R1, R2, R5, Y and Z are the same as above, and ■ is a single bond or means a double bond, or obtain a compound or a salt thereof, or (7) formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ A compound represented by the formula, where R1, R2, R5, Y and Z are each the same as above or by subjecting its salt to a reduction reaction, the formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ A compound represented by the formula, where R1, R2, R5, Y and Z are each the same as above or its salt, or formula (8): ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R1 and R2 are the same as above, and R■ is pyridyl or tetrahydropyridine. selected from the group consisting of ole, piperidyl, piperazinyl and morpholinyl groups, and A heterocyclic group which may have one or more suitable substituents; a substituted amino group; Carboxy (lower) alkenyl group; Carboxy (lower) alkyl group; hydroxy (lower) alkyl group; an amino (lower) alkyl group which may have one or more suitable substituents; or The group of the following formula ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R4 is hydrogen, ethoxy, mono(or di)lower alkylamino, di(lower (class) alkylamino (lower) alkylamino, or having one or more suitable substituents a heterocyclic amino group which may have one or more suitable substituents, or a heterocyclic ring which may have one or more suitable substituents (indicates the group) or a group of the following formula, ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R5 is lower alkyl or alkyl (lower alkyl) which may have one or more suitable substituents. class) alkyl group, X1 represents an acid residue) A compound represented by or a salt thereof, ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ React the compound shown by formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R1, R2, and R■ are each the same as above, or a compound represented by To obtain its salt, or formula (9): ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R1 and R2 are each the same as above, and R6 and R7 are each lower atom. a compound represented by or a salt thereof, and formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R3 is the same as above, A compound represented by the formula or a salt thereof is reacted to form the formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R1, R2 and R3 are each the same as above, or a compound represented by or obtain the salt of (10): ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R1, R2, Y, and Z are each the same as above, and R is carboxy or represents a protected carboxy group, and the compound represented by or its salt is subjected to a reduction reaction. By attaching the formula: In the formula, R1, R2, Y and Z are each the same as above, or To obtain its salt, or (11) formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R1, R2, Y, and Z are each the same as above, or a compound represented by By subjecting the salt to an oxidation reaction, the formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R1, R2, Y and Z are each the same as above, or Obtain its salt or formula (12): ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R1, R2, Y and Z are each the same as above, or The salt and formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ A compound represented by the formula or a salt thereof is reacted to form the formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R1, R2, Y and Z are each the same as above, or Obtain its salt or formula (13): ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R1, R2, Y and Z are each the same as above, or The salt and formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R8 and R9 are hydrogen, lower alkyl, and cyclo(lower) alkyl, respectively. , al(lower) alkyl, or a heterocyclic group optionally having one or more suitable substituents or R8 and R9 are connected together with the nitrogen atom to form one or more suitable A compound represented by or a salt thereof forming a heterocyclic group which may have a substituent is reacted with Accordingly, the formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R1, R2, R8, R9, Y and Z are each the same as above, or a compound represented by the formula (14): ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R1, R2, Y and Z are each the same as above, or The salt and formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ A compound represented by the formula or a salt thereof is reacted to form the formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R1, R2, Y and Z are each the same as above, or Obtain its salt or formula (15): ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R1, R2, Y and Z are each the same as above, X2 represents a leaving group, A compound represented by or a salt thereof, formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R10 is hydrogen or lower alkyl, R11 is lower alkyl or 1-amino -1-iminoethyl, or R10 and R11 are connected to a nitrogen atom and have one or more suitable substituents; A compound of the formula or a salt thereof is reacted to form a heterocyclic group which may be : ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R1, R2, R10, R11, Y and Z are each the same as above, or a compound represented by the formula (16): ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R1, R2, Y and Z are each the same as above, or The salt and Formula: HCHO A compound represented by and formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R12 and R13 each represent lower alkyl, or or its salt to form the formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R1, R2, R12, R13, Y and Z are each the same as above, or a compound represented by the formula (17): ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R1, R2, Y, and Z are the same as above, and R is carboxy (low (class) representing an alkenyl group, or subjecting the compound represented by or its salt to a reduction reaction. By the formula: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ In the formula, R1, R2, Y and Z are the same as above, and R is carboxy (lower ) exhibiting an alkyl group, and obtaining a compound represented by or a salt thereof. Manufacturing method. 10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient A pharmaceutical composition in admixture with a pharmaceutically acceptable carrier. 11. The compound according to claim 1 or a pharmaceutically acceptable salt thereof is used as an antithrombotic agent. , usage as a vasodilator or anti-inflammatory agent. 12. The compound according to claim 1 or a pharmaceutically acceptable salt thereof can be administered to humans or thrombosis, hypertension, cardiovascular or cerebrovascular disease, or is a method of preventing or treating inflammation. 13. The compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable salt thereof. A method for producing a pharmaceutical composition comprising admixing an acceptable carrier.