JPH0578362A - Condensed heterocyclic compound, its production and use, and intermediate therefor - Google Patents

Abstract

PURPOSE:To provide a new compound giving highly selective toxicity on cancerous cells, having excellent therapeutic effect on cancer, thus useful as an antineoplastic agent. CONSTITUTION:The objective compound of formula I (A-ring is a five-membered ring; B is divalent cyclic or chain group; Q<1> and Q<2> are such than one of them is N, the other being N or CH; Y is H, halogen or group gridged by C, N, O or S; X is amino, hydroxyl or mercapto; Z is C or divalent straight chaing group; COOR<1> and COOR<2> are each carboxyl), e.g. 4-[2-(2-amino-7-benzyl-6- bromo-4-hydroxy-7H-pyrrolo[2,3-d]pyrimidine-5-yl)ethyl]benzoic acid methyl ester. This compound can be obtained by acylation of a compound of formula III with a compound of formula II in a solvent (e.g. dichloromethane) pref. in the presence of a catalyst (e.g. 4-dimethylaminopyridine) at 0-50 deg.C.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel fused heterocyclic compound useful as an antitumor agent and a method for producing the same.

[0002]

BACKGROUND OF THE INVENTION Folic acid and its related compounds are carriers of C1 units derived from formic acid, formaldehyde and the like in the living body, and are complementary to various enzymatic reactions such as nucleic acid biosynthesis system, amino acid / peptide metabolism system and methanogenesis system. It plays the role of an enzyme. Particularly in the nucleic acid biosynthesis system, 2
It is essential for the metabolism / transfer reaction of the C1 unit in one of the two pathways, the purine synthesis system and the thymidine synthesis system. Normal,
In order for folic acid to exert its biological activity, it must be reduced in two steps and converted to the active coenzyme form. Amesopterin (methoxrexate: MTX) and its peripheral compounds are known as drugs that strongly bind to the enzyme (dihydrofolate reductase) that controls the second step and suppress the reduction of dihydrofolate to tetrahydrofolate. Since these drugs impair DNA synthesis and result in cell death, they have been developed as antitumor agents and occupy a clinically important position. Furthermore, a mechanism of action different from dihydrofolate reductase inhibition is a folate antagonist, that is, tetrahydroaminopterin whose main mechanism of action is inhibition of glycinamide ribonucleotide transformylase involved in the early stage of purine biosynthesis. Antitumor agent (5,10-dideaza-5,6,7,8-tetrahydroaminopterin: DDATHF) [Journal of Medici]
na1 Chemistry) 28 , 914 (198).
5)] Alternatively, a quinazoline antitumor agent (2-desamino-) having a main mechanism of action is inhibition of thymidylate synthetase involved in conversion of 2-deoxyuridylic acid to thymidylate.
2-Methyl-10-propargyl-5,8-dideazafolate: DMPDDF) [British Journal of Cancer]
al of Cancer) 58 , 241 (198).
8)] etc. have been reported. On the other hand, these 6-membered ring and 6
In addition to folic acid antagonists whose basic skeleton is a condensed ring with a member ring,
Pyrrolo [2,3-d], which is a condensed ring of a 6-membered ring and a 5-membered ring
It has been reported that compounds having a pyrimidine skeleton have antitumor activity. However, this pyrrolo [2,3-d] pyrimidine compound has a —NH— group (having an active proton on a nitrogen atom) derived from a pyrrole ring at its 7-position and a side chain bonded at the β-position of the pyrrole ring. It is described as an essential condition. [Japanese Patent Application 01-
72235]

[0003]

DISCLOSURE OF INVENTION Problems to be Solved by the Invention At present, what is particularly desired in the field of cancer treatment is the creation of a drug based on a new mechanism of action, which exhibits high selective toxicity to cancer cells and has an excellent therapeutic effect. Is. MTX, whose main mechanism of action is inhibition of dihydrofolate reductase, is currently widely used clinically, but it is relatively toxic and has little effect on solid cancer. Not listed.

[0004]

Means for Solving the Problems The present inventors have conducted intensive studies in view of the above circumstances, and as a result, a novel fused heterocyclic compound inhibits one or more biosynthetic pathways involved in folic acid and its related compounds. The inventors have found that they have high selective toxicity to various tumor cells and have an excellent antitumor effect, and completed the present invention.

That is, the present invention provides (1) the general formula

[Chemical 5] [Wherein the ring A is a 5-membered ring, and in the case of a pyrrole or pyrroline ring, (i) has no active proton on the nitrogen atom or (ii) is bonded to Z at the α-position, B is a substituent has optionally may be divalent cyclic or chain group, one Q ¹ and Q ² are the N other is N or CH, Y is a hydrogen atom, a halogen atom or a carbon, nitrogen, oxygen or sulfur atom, , X is an amino group, a hydroxyl group or a mercapto group, and Z is a carbon atom which may have a substituent, or a carbon atom which may have a substituent and a substituent. A straight-chain 2 having 2 to 5 atoms, which is composed of one hetero atom which may be
As the valent group, -COOR ¹ and -COOR ² are the same or different and each represents a carboxyl group which may be esterified. ] The compound or its salt represented by these,

(2) General formula

[Chemical 6] [Wherein the ring A is a 5-membered ring, and in the case of a pyrrole or pyrroline ring, (i) has no active proton on the nitrogen atom or (ii) is bonded to Z at the α-position, B is a substituent has optionally may be divalent cyclic or chain group, one Q ¹ and Q ² are the N other is N or CH, Y is a hydrogen atom, a halogen atom or a carbon, nitrogen, oxygen or sulfur atom, , X is an amino group, a hydroxyl group or a mercapto group, and Z is a carbon atom which may have a substituent, or a carbon atom which may have a substituent and a substituent. A straight-chain 2 having 2 to 5 atoms, which is composed of one hetero atom which may be
A valence group is shown respectively. ] The compound represented by or a reactive derivative at the carboxyl group thereof, and a general formula

[Chemical 7] [In formula, -COOR < ¹ > and 1-COOR < ² > shows the same or different carboxyl group which may be esterified. ] The compound or its salt of the preceding clause characterized by reacting with the compound represented by these,

(3) An antitumor composition containing the compound according to (1) or a salt thereof, and

(4) General formula

[Chemical 8] [Wherein the ring A is a 5-membered ring, and in the case of a pyrrole or pyrroline ring, (i) has no active proton on the nitrogen atom or (ii) is bonded to Z at the α-position, B is a substituent has optionally may be divalent cyclic or chain group, one Q ¹ and Q ² are the N other is N or CH, Y is a hydrogen atom, a halogen atom or a carbon, nitrogen, oxygen or sulfur atom, , X is an amino group, a hydroxyl group or a mercapto group, and Z is a carbon atom which may have a substituent, or a carbon atom which may have a substituent and a substituent. A straight-chain 2 having 2 to 5 atoms, which is composed of one hetero atom which may be
A valent group and -COOR3 each represent an optionally esterified carboxyl group. ] It is related with the compound or its salt represented. In the above formula, Q ¹ is N
Where X is an amino group, a hydroxyl group or a mercapto group, compounds (I), (II) and (IV) can exist as equilibrium mixtures with their tautomers.
The partial structural formulas capable of tautomerism are listed below, and the equilibrium relationship between them is shown.

[Chemical 9] For convenience of display, amino type, hydroxyl type, and mercapto type are described throughout this specification, and nomenclatures corresponding to them are adopted, but in each case, imino type and oxo type which are tautomers, respectively. And thioxo type are also included.

Further, the compound (I) of the present invention may have a plurality of asymmetric centers, but other asymmetry except that the absolute configuration of the asymmetric carbon atom of the side chain derived from glutamic acid is S (L). The absolute configuration of the center may be any mixture of S, R or RS. In this case, a plurality of diastereoisomers exist, but if necessary, they can be easily separated by a usual separation and purification means. All of the above diastereoisomers which can be separated in this way are within the scope of the invention.

In the above formula, ring A is a 5-membered ring, and examples thereof include a 5-membered ring composed of carbon atoms or carbon atoms and one hetero atom (nitrogen atom, oxygen atom or sulfur atom). These rings may have a substituent, but when they represent a pyrrole or pyrroline ring, (i) they have no active proton on the nitrogen atom, or (ii) they are bonded to Z by α. Examples of the ring include cyclopentadiene,
Cyclopentene, furan, dihydrofuran, thiephene, dihydrothiophene, thiephen-1-oxide,
Dihydrothiophen-1-oxide, thiophen-1,
1-dioxide, dihydrothiophene-1,1-dioxide, N-substituted pyrrole, N-substituted pyrroline and the like. These rings may have 1 to 2 substituents at possible positions, and examples of such substituents include, for example, an alkyl group having 1 to 3 carbon atoms (eg, methyl, ethyl, propyl, iso). -Propyl group), an alkenyl group having 2 to 3 carbon atoms (eg vinyl, 1-methylvinyl, 1-propenyl, aryl, allenyl group), an alkynyl group having 2 to 3 carbon atoms (eg ethynyl, 1-propynyl, Propargyl group), 3-6 cycloalkyl group (eg, cyclopropyl group), halogen atom (eg, fluorine, chlorine, bromine, iodine), alkanoyl group having 1 to 4 carbon atoms (eg, formyl, acetyl, propionyl, butyryl) , Isobutyryl group), benzoyl group, substituted benzoyl group (eg, D-chlorobenzoyl, p-methoxybenzoyl, 3,4,5-trimethoxybenzene) Benzoyl group), a cyano group, a carboxyl group, a carbamoyl group, a nitro group,
Hydroxyl group, hydroxymethyl group, hydroxy-C
_1-4 alkyl group (eg, hydroxyethyl group), C
_1-4 alkoxy-C _1-4 alkyl group (eg, methoxymethyl group, ethoxymethyl group, methoxyethyl group, ethoxyethyl group), alkoxy group having 1 to 3 carbon atoms (eg, methoxy, ethoxy, propoxy group), Mercapto group, alkylthio group having 1 to 3 carbon atoms (eg, methylthio, ethylthio, propylthio group), amino group, substituted amino group having 1 to 4 carbon atoms (eg, methylamino, ethylamino, dimethylamino, diethylamino group), Examples thereof include an alkanoylamino group having 1 to 2 carbon atoms (eg, formamide, acetamide group) and the like. The N-substituted portion in the N-substituted pyrrole and the N-substituted pyrroline ring (when the ring A represents a pyrrole or a pyrroline ring and does not have an active proton on the nitrogen atom) has 1 carbon atom as described above.
To C3 alkyl group, C2 to C3 alkenyl group, C2 to C3 alkynyl group, cyclopropyl group, C1 to C4 alkanoyl group, benzoyl group, substituted benzoyl group, hydroxyethyl group, methoxyethyl Group, ethoxyethyl group, phenyl group, substituted phenyl group (eg, p-chlorophenyl, p-methoxyphenyl, 3,4,5-trimethoxyphenyl group), benzyl group or substituted benzyl group (eg, p-chloro) Benzyl, p-methoxybenzyl, diphenylmethyl group). The ring A may be bonded to -Z- at any possible position, but when the ring A represents a pyrrole or pyrroline ring and has an active proton on the nitrogen atom, it is bonded to Z at the α-position. To do. Further, when the A ring is an N-substituted pyrrole or N-substituted pyrroline ring, it may be bonded at the N-substituted portion.

2 which may have a substituent represented by B
As the divalent cyclic group in the valent cyclic group, a 5- to 6-membered cyclic hydrocarbon having 1 to 3 hetero atoms (eg, N, O, S) in the ring but having 2 bonds, or Heterocyclic groups are preferred, and the two bonds preferably come out of non-adjacent positions in the ring. Examples of the divalent 5-membered cyclic hydrocarbon or heterocyclic group represented by B include 1,3- or 3,5-cyclopentadiene-1,3-ylene, cyclopentene- (1,3-, 1,4 -Or 3,5-)
Irene, cyclopentane-1,3-ylene, thiophene- (2,4-, 2,5- or 3,4-) ylene, furan- (2,4-, 2,5- or 3,4-) ylene , Pyrrole- (1,3-, 2,4-, 2,5- or 3,4-) ylene, thiazole- (2,4- or 2,5-) ylene, imidazole- (1,4-, 2 , 4
-Or 2,5-) ylene, thiadiazole-2,5
-Irene or partially reduced or fully reduced compounds thereof, and the like. Examples of the divalent 6-membered cyclic hydrocarbon or heterocyclic group represented by B include phenyl- (1,
3- or 1,4-) ylene, cyclohexane- (1,
3- or 1,4-) ylene, cyclohexene- (1,
3-, 1,4-, 1,5-, 3,5-or 3,6
-) Ylene, 1,3-cyclohexadiene- (1,3
-, 1,4-, 1,5-, 2,4-, 2,5- or 2,6-) ylene, 1,4-cyclohexadiene-
(1,3-, 1,4- or 1,5-) ylene, pyridine- (2,4-, 2,5-, 2,6- or 3,5
-) Irene, pyran- (2,4-, 2,5-, 2,6
-, 3,5-, 3,6- or 4,6-) ylene, pyratin- (2,5- or 2,6-) ylene, pyrimidine- (2,4- or 2,5-) ylene, pyridatin −
Examples thereof include 3,5-ylene and partially reduced or completely reduced compounds thereof. In particular, 2 indicated by B
As the valent cyclic group, phenyl-1,4-ylene and thiophene-2,5-ylene are preferable. The divalent chain group which may have a substituent represented by B is preferably a divalent chain hydrocarbon group having 2 to 4 carbon atoms,
For example, C of ethylene, ethenylene, ethynylene, trimethylene, propenylene, propynylene, propadienylene, tetramethylene, butenylene, butynylene.
_2-4 alkylene, _C2-4 alkenylene, _C2-4 alkynylene, butanedienylene, etc. are mentioned. The divalent cyclic group or chain group represented by B may have 1 or 2 substituents at substitutable positions. Examples of the substituent include an alkyl group having 1 to 3 carbon atoms (eg, methyl, ethyl, propyl, iso-propyl group), an alkenyl group having 2 or 3 carbon atoms (eg, vinyl,
1-methylvinyl, 1-propenyl, aryl, allenyl group), alkynyl group having 2 or 3 carbon atoms (eg, ethynyl, 1-propynyl, propargyl group), cyclopropyl, halogen (eg, chlorine, bromine, fluorine, iodine) ), Hydroxyl, methoxy, dimethylamino, trifluoromethyl, oxo, formyl, methoxymethyl, 2-ethoxyethyl and the like.

The group represented by Y via a carbon, nitrogen, oxygen or sulfur atom is a cyano group, a carboxyl group,
Carbamoyl group, amino group, nitro group, hydroxyl group, mercapto group or lower hydrocarbon group such as alkyl group having 1 to 3 carbon atoms (eg, methyl, ethyl, propyl, iso-propyl group), 2 or 3 carbon atoms An alkenyl group (eg, vinyl, 1-methylvinyl, 1-propenyl, aryl, allenyl group), an alkynyl group having 2 or 3 carbon atoms (eg, ethynyl, 1-propynyl, propargyl group), a cyclopropyl group and the like may be used. C
_It may be a _6-10 aryl group, for example, a phenyl group or a naphthyl group, and is a 5- or 6-membered heterocyclic group, for example, pyrrolyl, imidazolyl, pyrazolyl, cenyl, furyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, pyridyl, pyranyl, pyrazinyl, pyrimidinyl. ，
It may be pyridatinyl or a partially reduced or completely reduced group thereof, dioxolanyl, piperidino, morpholino, N-methylpiperazinyl, N-ethylpiperazinyl, dioxanyl and the like. Y is a lower hydrocarbon group,
When it is an aryl group or a 5- or 6-membered heterocyclic group,
It may have 1 or 2 substituents, and examples of such a substituent include an alkyl group having 1 to 3 carbon atoms (eg, methyl, ethyl, propyl, iso-propyl group), 2 carbon atoms or 3 alkenyl groups (eg vinyl,
1-methylvinyl, 1-propenyl, aryl, allenyl group), alkynyl group having 2 or 3 carbon atoms (eg, ethynyl, 1-propynyl, propargyl group) or cyclopropyl group, as well as fluorine, hydroxyl, oxo,
Methoxy, dimethylamino, diethylamino, trifluoromethyl, formyl, hydroxymethyl, 2-hydroxyethyl, methoxymethyl, 2-ethoxyethyl and the like can be mentioned. Examples of the halogen atom represented by Y include fluorine, chlorine, bromine and iodine. The group represented by Y via a carbon, nitrogen, oxygen or sulfur atom may be an alkoxy group, an alkylthio group, an alkanoylamino group and an alkanoyloxy group,
As the alkyl moiety of these groups, the groups exemplified when Y is a lower hydrocarbon group can be mentioned as they are. Y
The group via the carbon, nitrogen, oxygen or sulfur atom represented by may be an aryloxy group, an arylthio group, an aroylamino group and an aroyloxy group. Examples of the aryl moiety of these groups include a phenyl group and a naphthyl group. Be done. Further, the group represented by Y via a carbon, nitrogen, oxygen or sulfur atom may be a heterocyclic oxy group, a heterocyclic thio group, a heterocyclic carbonylamino group or a heterocyclic carbonyloxy group, and these heterocyclic moieties include The groups exemplified when Y is a 5- to 6-membered heterocyclic group can be mentioned as they are. The group mediated by a carbon, nitrogen, oxygen or sulfur atom represented by Y may be a substituted amino group such as a mono-substituted or di-substituted amino group, and the substituent moiety may be a lower hydrocarbon group represented by Y or aryl. The groups and 5- to 6-membered heterocyclic groups can be mentioned as they are.

-COOR ¹ , -COOR ² and -CO
The optionally esterified carboxyl group represented by OR ³ is a lower alkyl group having 1 to 5 carbon atoms,
Examples thereof include a benzyl group which may have a substituent or a carboxyl group which may be esterified with a phenyl group which may have a substituent. Examples of the lower alkyl group include methyl, ethyl, propyl, i
so-propyl, n-butyl, iso-butyl, sec
-Butyl, tert-butyl, n-pentyl, iso-
Pentyl, sec-pentyl, neo-pentyl, te
Examples of benzyl which rt-pentyl and the like may have have a substituent include benzyl, nitrobenzyl and methoxybenzyl, and examples of the phenyl which may have a substituent include phenyl, methoxyphenyl and the like. Is mentioned.

A carbon atom represented by Z, which may have a substituent, or a carbon atom which may have a substituent and one hetero atom (a nitrogen atom, which may have a substituent). , An oxygen atom or a sulfur atom), and a linear divalent group having 2 to 5 atoms, examples of the group consisting of carbon atoms include C such as ethylene, trimethylene, tetramethylene and pentamethylene. _2-5 alkylene groups such as vinylene, propenylene, 1- or 2-butenylene, butadienylene,
1- or 2-pentenylene, 1,3- or 1,4-
A C _2-5 alkenylene group such as pentadienylene, for example, a C _2-5 alkynylene group such as ethynylene, 1- or 2-propynylene, 1- or 2-butynylene, 1-, 2- or 3-pentynylene is used, and a carbon atom is used. And a single hetero atom (nitrogen atom, oxygen atom or sulfur atom) is represented by formula -Z ¹ -Z ² -Z
^3- [wherein Z ¹ and Z ³ are the same or different and each is a divalent lower hydrocarbon group having 1 to 4 carbon atoms which may have a bond or a substituent (provided that Z ¹ and Z ^{3 are} The total number of carbon atoms of 1 to 4), Z ² is —O—, and is of the formula —S.
(O) _n − (where n is 0

[Chemical 11] Represents a lower hydrocarbon group which may have. ] The group represented by is used. The divalent lower hydrocarbon group which may have a substituent represented by Z ¹ and Z ³ is, for example, a C _1-4 alkylene group such as methylene, ethylene, trimethylene and tetramethylene, for example, vinylene and propenylene. , 1- or 2-butenylene, butadienylene and other C _2-4 alkenylene groups, for example ethynylene, 1- or 2-propynylene, 1- or 2-butynylene and other C _2-4 alkynylene groups are used, and R ⁴
The lower hydrocarbon group which may have a substituent represented by is an alkyl group having 1 to 3 carbon atoms (eg, methyl,
Ethyl, propyl, iso-propyl group), alkenyl group having 2 or 3 carbon atoms (eg vinyl, 1-methylvinyl, 1-propenyl, aryl, allenyl group), alkynyl group having 2 or 3 carbon atoms (eg ethynyl) , 1-propynyl, propargyl group) and cyclopropyl group. The carbon atom and hetero atom constituting the divalent group represented by Z, the lower hydrocarbon group of Z ¹ , Z ² Z ³ and R ⁴ may have 1 or 2 substituents,
Examples of such a substituent include an alkyl group having 1 to 3 carbon atoms (eg, methyl, ethyl, propyl, iso-
Propyl group), an alkenyl group having 2 or 3 carbon atoms (eg,
Vinyl, 1-methylvinyl, 1-propenyl, aryl, allenyl group), alkynyl group having 2 or 3 carbon atoms (eg, ethynyl, 1-propynyl, propargyl group) or cyclopropyl group, as well as fluorine, hydroxy, oxo , Methoxy, dimethylamino, diethylamino, trifluoromethyl, formyl, hydroxymethyl, 2-hydroxyethyl, methoxymethyl, 2-ethoxyethyl and the like.

Next, a method for producing the compound (I) of the present invention or a salt thereof will be described.

The compound (I) or a salt thereof has the formula (II)
It is obtained by acylating the glutamic acid derivative represented by I) with the carboxylic acid represented by the formula (II) or a reactive derivative at the carboxyl group thereof. Examples of the acylation means include a method of acylating compound (III) with compound (II) or its reactive derivative in the presence of carbodiimides, diphenylphosphoric acid azide or diethyl cyanophosphate. The amount of compound (III) used is generally about 1-20 molar equivalents, preferably about 1-5 molar equivalents, relative to compound (II) or its reactive derivative. The carbodiimides and the like may be used generally in about 1-25 molar equivalents, preferably about 1-5 molar equivalents, relative to compound (II).

As the carbodiimides, dicyclohexylcarbodiimide is practically preferable, and other carbodiimides such as diphenylcarbodiimide, di-o-tolylcarbodiimide, di-p-tolylcarbodiimide, di-tert-butylcarbodiimide, 1-cyclohexyl-carbodiimide. 3- (2-morpholinoethyl) carbodiimide, 1-cyclohexyl-3- (4-diethylaminocyclohexyl) carbodiimide, 1-ethyl-3-
(2-Diethylaminopropyl) carbodiimide and 1-ethyl-3- (3-diethylaminopropyl) carbodiimide may be used. This acylation reaction is preferably carried out in the presence of an appropriate solvent, and examples of the solvent include water, alcohols (eg, methanol,
Ethanol), ethers (eg, dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme), nitriles (eg, acetonitrile), esters (eg, ethyl acetate), halogenated hydrocarbons (eg, dichloromethane, chloroform) , Carbon tetrachloride), aromatic hydrocarbons (eg, benzene, toluene, xylene), acetone, nitromethane, pyridine, dimethylsulfoxide, dimethylformamide, hexamethylphosphoramide, sulfolane or a suitable mixed solvent thereof. To be done. This reaction is usually carried out at a pH of about 2 to 14, preferably at a pH of about 6 to 9, at about -1.
0 ° C to the boiling point of the reaction solvent (up to about 100 ° C),
Preferably at a reaction temperature in the range of about 0 to 50 ° C., about 1
The reaction can be carried out for 100 to 100 hours. PH of reaction solution
Are, for example, acids (eg, hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid), bases (eg, sodium methylate, sodium ethylate, sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide, sodium carbonate, If necessary, use potassium carbonate, barium carbonate, calcium carbonate, sodium hydrogen carbonate, trimethylamine, triethylamine, triethanolamine, pyridine) or a buffer solution (eg, phosphate buffer solution, borate buffer solution, acetate buffer solution), etc. adjust. The reaction can be more favorably promoted by using a catalyst capable of promoting acylation. Examples of such a catalyst include a base catalyst and an acid catalyst. Examples of such a base catalyst include tertiary amines (eg, aliphatic tertiary amines such as triethylamine; pyridine, α-, β- or τ-picoline, 2,6-lutidine, 4-dimethylaminopyridine, 4- (1 -Pyrrolidinyl) pyridine, aromatic tertiary amines such as dimethylaniline, diethylaniline) and the like, and examples of the acid catalyst include Lewis acids [eg, anhydrous zinc chloride, anhydrous aluminum chloride (AlCl ₃ ), anhydrous secondary chloride]. Iron, titanium tetrachloride (TiCl ₄ ), tin tetrachloride (SnCl ₄ ), antimony pentachloride, cobalt chloride, cupric chloride, boron trifluoride etherate and the like]. Among the above catalysts, 4-dimethylaminopyridine or 4- (1-
Pyrrolidinyl) pyridine and the like are often preferred. The amount of the catalyst used is such that the amount of the catalyst that can accelerate acylation is good, and is usually about 0.01-10 molar equivalents, preferably about 0.1-1 molar equivalents, relative to compound (II). Examples of the reactive derivative at the carboxyl group of carboxylic acid (II) include acid halides (eg, fluoride, chloride, bromide, iodide) of carboxylic acid (II), acid anhydrides (eg, iodoacetic anhydride, isobutyric anhydride). ), Lower monoalkyl carbonate (eg, monomethyl carbonate, monoethyl carbonate, monopropyl carbonate, mono iso-propyl carbonate, monobutyl carbonate, mono iso-butyl carbonate, mono sec-butyl carbonate, mono tert) −
Butyl carbonate) mixed acid anhydride, active ester (eg, cyanomethyl ester, ethoxycarbonylmethyl ester, methoxymethyl ester, phenyl ester, o-nitrophenyl ester, p-nitrophenyl ester, p-carbomethoxyphenyl ester, p-
Cyanophenyl ester, phenyl thioester), acid amide, phosphoric acid diester (eg, dimethyl phosphate, diethyl phosphate, dibenzyl phosphate,
Examples thereof include mixed acid anhydrides with diphenyl phosphate) and phosphite diesters (eg, dimethyl phosphite, diethyl phosphite, dibenzyl phosphite, diphenyl phosphite) and the like. In the acylation means using this reactive derivative, the solvent, catalyst, reaction temperature and the like are the same as in the case of the acylation performed in the presence of the carbodiimides and the like.

Of the compounds (I) or salts thereof,
When producing compound (I-1) or a salt thereof in which -COOR ¹ and -COOR ² are carboxy groups, a compound (III) in which -COOR ¹ and -COOR ² are esterified carboxy groups is used. Compound (I
After reacting with I) or a reactive derivative at the carboxy group, it is preferable to subject it to a decomposition reaction or a catalytic reduction reaction known per se for deesterification. Examples of the decomposition reaction include a hydrolysis reaction under a basic condition (method A) and a hydrolysis reaction under an acidic condition (B-1).
Method), a decomposition reaction under acidic non-aqueous conditions (method B-2), and the like. Examples of the base used in Method A include metal alkoxides such as sodium methoxide, sodium ethoxide, sodium butoxide and potassium butoxide, metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide and barium hydroxide. Amines such as ammonia, triethylamine and pyridine. Examples of the acid used in the B-1 method include mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, trifluoroacetic acid and trichloroacetic acid. Acetic acid,
Organic acids such as methane sulfonic acid, benzene sulfonic acid, p-toluene sulfonic acid, camphor sulfonic acid, etc. can be mentioned, and examples of the acid (catalyst) used in the B-2 method include hydrogen chloride, hydrogen bromide, perchlorine. Acid, sulfuric acid,
Mineral acids such as nitric acid and phosphoric acid, trifluoroacetic acid, trichloroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-
Organic acids such as toluene sulfonic acid, camphor sulfonic acid, anhydrous zinc chloride, anhydrous aluminum chloride (AlC
l ₃ ), anhydrous ferric chloride, titanium tetrachloride (TiC)
l ₄ ), tin tetrachloride (SnCl ₄ ), antimony pentachloride,
Lewis acids such as cobalt chloride, cupric chloride and boron trifluoride etherate can be mentioned. In any case, the decomposition reaction is carried out by reacting in a suitable solvent at 0 ° C to the boiling point of the solvent, preferably 10-80 ° C for 30 minutes to 2 days. As the reaction solvent, Method A and B-
In the case of the 1st method, for example, water, methanol, ethanol,
Propanol, butanol, ethylene glycol, methoxyethanol, ethoxyethanol, tetrahydrofuran, dioxane, monoglyme, diglyme, pyridine,
Dimethylformamide, dimethylsulfoxide, sulfolane or an appropriate mixture thereof is used, and in the case of Method B-2, for example, ethyl acetate, dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme, dichloromethane, chloroform, tetrachloride. Carbon, acetonitrile, benzene, toluene, xylene, nitromethane, pyridine or an appropriate mixed solvent thereof is used. The catalytic reduction reaction (method C)
The reaction is carried out using a suitable solvent at a reaction temperature in the range of about -40 ° C to the boiling point of the reaction solvent, more preferably about 0-50 ° C. Examples of the solvent used include water, alcohols (eg, methanol, ethanol, propanol, iso-propanol, butyl alcohol, sec.
-Butyl alcohol, tert-butyl alcohol, ethylene glycol, methoxyethanol, ethoxyethanol), acetic acid esters (eg, methyl acetate, ethyl acetate), ethers (eg, dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme) , Aromatic hydrocarbons (eg, benzene, toluene, xylene), pyridine, dimethylformamide, and an appropriate mixed solvent thereof. As the catalyst for the catalytic reduction, for example, palladium, platinum, rhodium, Raney nickel, etc. are used. At this time, the reaction may be advantageously progressed by adding a slight amount of acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid or the like. The reaction time is
It is not limited as long as it does not interfere with the reaction, but usually 20 minutes to 3
It's 0 hours. Compound (I-1)
Also differ by the nature of -COOR ¹ and -COOR ² are either directed to, usually, -COOR ¹ and -CO
OR ² is methyl, ethyl, propyl, butyl, sec-
When it is a carboxy group esterified by butyl, phenyl or a substituted phenyl group, method A or method B-1;
When -COOR ¹ and -COOR ² are carboxyl groups esterified with an iso-propyl or tert-butyl group, the B-2 method is used. When -COOR ¹ and -COOR ² are carboxyl groups esterified with a benzyl group or a substituted benzyl group, B-method is used. The -1 method or the C method is advantageously applied. When -COOR ¹ and -COOR ² are different from each other, the A method, B-1 method, B-2 method and C method may be appropriately combined.

Next, the method for producing the starting compound (II) will be described. Compound (II) can be produced, for example, by the reaction steps shown below.

[Chemical formula 12]

In the above formula, A ring, B, --COOR ³ ,
Q ¹ , Q ² , X, Y and Z have the same meaning as described above.
D and E are groups which can bond to each other to form Z.

In the above reaction step, a covalent bond is formed between D and E, so that a carbon atom represented by Z, which may have a substituent, or a carbon atom, which may have a substituent, may be present. A linear divalent group having 2 to 5 atoms, which is composed of a carbon atom and one hetero atom which may have a substituent, can be produced. As a synthetic method for forming a covalent bond between the compound (V) and the compound (VI), when Z is a group composed of only carbon atoms which may have a substituent,

[Chemical 13]

[Chemical 14]

[Chemical 15] When D = E 'and E = D', a so-called carbon-carbon bond forming reaction is carried out between the compounds (V) and (VI), and then the obtained product is subjected to a reducing reaction if necessary. Thus, the compound (IV) can be produced.

In the above formula, a, b, m, n (= a + b) and m + n represent integers in the range of 0 to 3, G represents phenyl, butyl or cyclohexyl, and M represents ethyl or phenyl. R ⁵ , R ⁶ and R ⁷ are the same or different and each is a bond, a hydrogen atom or a substituent (Z ¹ , Z ³
And substituents on the lower hydrocarbon group described in detail for R ⁴ ), which may be different from each other in m and n repetitions.

When Z is a group composed of Z = -Z ¹ -Z ² -Z ^3- ,

[Chemical 16]

[Chemical 17] When E = D ¹ , a so-called alkylation type reaction is used,

[Chemical 18]

[Chemical 19] = D ² , a so-called amine exchange type reaction (gramine decomposition type reaction) is advantageously used,

[Chemical 20]

[Chemical 21] When E = D ^3, a method of forming a Schiff base and reducing it if necessary, or directly subjecting it to a reductive alkylation reaction is used.

In the above formula, m, n, m + n, R ⁴ , R ⁵ ,
R ⁶ , R ⁷ and Z ² have the same meanings as described above, L is a leaving group, and R ⁸ and R ⁹ are the same or different and are a hydrocarbon group which may have a hydrogen atom or a substituent. Indicates. The leaving group represented by L is a halogen atom (eg,
Releasable groups (eg, methanesulfonyloxy group, benzenesulfonyloxy group, p) that can be easily derived from a chlorine atom, bromine atom, iodine atom) or hydroxyl group.
-Toluenesulfonyloxy group, trifluoromethanesulfonyl group). Hydrocarbon group represented by R ⁸ and R ⁹ may have a substituent, and R ⁸ and R
⁹ and ⁹ may form a cyclic amino group with the adjacent nitrogen atom. The hydrocarbon group represented by R ⁸ and R ⁹ is an alkyl group having 1 to 18 carbon atoms (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tetradecyl, hexadecyl, octadecyl, 1,2-dimethylpropyl, 1-ethylpropyl, 1,2, 2-trimethylpropyl, 1-propylbutyl, 2-ethylhexyl group), an alkenyl group having 1 to 12 carbon atoms (eg vinyl, allyl, 1-methylvinyl, 2-methylvinyl, 1)
-Octenyl, 1-desenyl group), carbon number 3 to 12
Cycloalkyl group (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, andamantyl group), a cycloalkenyl group having 3 to 8 carbon atoms (eg, cyclopentenyl,
Cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclopentadienyl, cyclohexadienyl, cycloheptadienyl, cyclooctadienyl group), aralkyl groups having 7 to 13 carbon atoms (eg, benzyl, α-methylbenzyl, phenethyl, diphenylmethyl) Group), and an aryl group having 6 to 10 carbon atoms (eg, phenyl,
α-naphthyl, β-naphthyl group). The cyclic amino group formed by R ⁸ and R ⁹ together with the adjacent nitrogen atom is preferably a 4- to 10-membered ring, for example, azetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, imidazolyl, pyrazolyl, imidazolinyl, piperidino, morpholino, dihydropyridyl. , Tethydropyridyl, N-methylpiperazinyl, N-ethylpiperazinyl, azacycloheptyl, azacyclooctyl, isoindolyl, indolyl, indolinyl, 2-isoindolinyl, azacyclononyl and azacyclodecyl groups.

The hydrocarbon groups represented by these R ⁸ and R ⁹ cyclic amino group or R ⁸ and R ⁹ are formed together with the adjacent nitrogen atom, it may also be one to have two substituents Good. Examples of the substituent include an alkyl group having 1 to 4 carbon atoms (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t
ert-butyl group), an alkoxy group having about 1 to 4 carbon atoms (eg, methoxy, ethoxy, propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec).
-Butoxy, tert-butoxy group), alkanoyl group having 1 to 4 carbon atoms (eg formyl, acetyl, propionyl, n-butyryl, iso-butyryl group), alkanoyloxy group having 1 to 4 carbon atoms (eg, Formyloxy, acetyloxy, propionyloxy, n
-Butyryloxy, iso-butyryloxy group), carboxy group, alkoxycarbonyl group having about 2 to 4 carbon atoms (eg, methoxycarbonyl, ethoxycarbonyl,
n-propoxycarbonyl, iso-propoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl group), halogen atom (eg, fluorine, chlorine, bromine, iodine), hydroxyl group, nitro group, cyano group, trifluoro Methyl group, amino group, mono-substituted amino group (eg, methylamino, ethylamino, propylamino, isopropylamino, butylamino group),
Disubstituted amino group (eg, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino group), alkanoylamide group (eg, formamide, acetamide, trifluoroacetamide, propionylamide, butyrylamide, isobutyrylamide group) ，
Carbamoyl group, N-substituted carbamoyl group (eg, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N
-Butylcarbamoyl group), N, N-disubstituted carbamoyl group (eg, N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, N, N-dipropylcarbamoyl, N, N-dibutylcarbamoyl, 1-acetylidini Rucarbonyl, 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, N-
Methylpiperazinylcarbonyl, morpholinocarbonyl group), carbamoylamino group, N-substituted carbamoylamino group (eg, N-methylcarbamoylamino, N-ethylcarbamoylamino, N-propylcarbamoylamino, N-isopropylcarbamoylamino, N-isopropylcarbamoylamino, N- Butylcarbamoylamino group), N, N-disubstituted carbamoylamino group (eg, N, N-dimethylcarbamoylamino group,
N, N-diethylcarbamoylamino, N, N-dipropylcarbamoylamino, N, N-dibutylcarbamoylamino, 1-acetylidinylcarbonylamino, 1-azetidinylcarbonylamino, 1-pyrrolidinylcarbonylamino, 1 -Piperidinylcarbonylamino, N-
Methylpiperazinylcarbonylamino, morpholinocarbonylamino group), mercapto group, sulfo group, sulfino group, phosphono group, sulfamoyl group, N-substituted sulfamoyl group (eg, N-methylsulfamoyl, N-ethylsulfamoyl, N-propylsulfamoyl, N-
Isopropylsulfamoyl, N-butylsulfamoyl group), N, N-disubstituted sulfamoyl group (eg, N, N
-Dimethylsulfamoyl, N, N-diethylsulfamoyl, N, N-dipropylsulfamoyl, N, N-
Dibutylsulfamoyl, 1-pyrrolidinylsulfonyl, 1-piperidinylsulfonyl, N-methyl-1-piperazinylsulfonyl, morpholinosulfonyl group), an alkylthio group having 1 to 4 carbon atoms (eg, methylthio, ethylthio) , Propylthio, isopropylthio, n
-Butylthio, sec-butylthio, tert-butylthio group), an alkylsulfinyl group having 1 to 4 carbon atoms (eg, methylsulfinyl, ethylsulfinyl,
Propylsulfinyl, butylsulfinyl group), an alkylsulfonyl group having 1 to 4 carbon atoms (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl,
Butylsulfonyl group) and the like.

The first step will be described in detail below.
Condensation reaction by carbon-carbon bond formation is a known reaction (eg,
Aldol reaction, Reformatsky reaction, Wittig reaction) are used, and as the reduction reaction, the above-mentioned catalytic reduction reaction (method C) is usually advantageously used. When the aldol reaction is used as the condensation reaction, examples of the base catalyst to be used include metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide and barium hydroxide, sodium methoxide, sodium ethoxide, potassium. t
Metal alkoxides such as ert-butoxide, metal amides such as sodium amide and lithium diisopropylamide, metal hydrides such as sodium hydride and potassium hydride, organometallic compounds such as phenyllithium and butyllithium, triethylamine, pyridine, α-, β-
Or τ-picoline, 2,6-lutidine, 4-dimethylaminopyridine, 4- (1-pyrrolidinyl) pyridine,
Examples thereof include amines such as dimethylaniline and diethylaniline. Examples of acid catalysts include mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and boric acid, oxalic acid, tartaric acid,
Organic acids such as acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and camphorsulfonic acid can be mentioned. In addition, known methods [Ei-Ichi Negishi, Organome
tallics in Organic Synthes
sisvol. 1, John Wiley & Son
s, New York, Chichester, Bri
Svane, Tronto (1980)], a ketone body is converted into a silyl enol ether body, and a Lewis acid [eg, anhydrous zinc chloride, anhydrous aluminum chloride (AlCl
₃ ), anhydrous ferric chloride, titanium tetrachloride (TiCl ₄ ),
Tin tetrachloride (SnCl ₄ ), antimony pentachloride, cobalt chloride, cupric chloride, boron trifluoride etherate, etc.] in the presence of an aldehyde or its equivalent, or a ketone Amines (eg, triethylamine, pyridine, α-, β- or τ-picoline, 2,6
-Lutidine, 4-dimethylaminopyridine, 4- (1-
(Pyrrolidinyl) pyridine, dimethylaniline, diethylaniline) in the presence of a metal triflate (eg, dialkylboron triflate, tin (II) triflate, etc.)
It can also be carried out by subjecting the compound to a enolate, and then subjecting it to a condensation reaction with an aldehyde or its equivalent.
The condensation reaction is carried out in an appropriate solvent at -100 ° C to the boiling point of the solvent, preferably -78-100 ° C, for 1 minute-
It is carried out by reacting for 3 days. As the reaction catalyst,
For example, water, liquid ammonia, alcohols (eg, methanol, ethanol, propanol, iso-propanol, butyl alcohol, sec-butyl alcohol,
tert-butyl alcohol, ethylene glycol, methoxyethanol, ethoxyethanol), ethers (eg, dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme), halogenated hydrocarbons (eg, dichloromethane, chloroform, carbon tetrachloride) , Aliphatic hydrocarbons (eg pentane,
Hexane, heptane), aromatic hydrocarbons (eg, benzene, toluene, xylene), dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, sulfolane or an appropriate mixed solvent thereof is used.
When the Wittig reaction is used as the condensation reaction, examples of reagents to be used include metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide and barium hydroxide, sodium methoxide, sodium ethoxide, potassium tert. -Metal alkoxides such as butoxide, metal amides such as sodium amide and lithium diisopropylamide, metal hydrides such as sodium hydride and potassium hydride, organometallic compounds such as phenyllithium and butyllithium, triethylamine, pyridine, α-, β And amines such as τ-picoline, 2,6-lutidine, 4-dimethylaminopyridine, 4- (1-pyrrolidinyl) pyridine, dimethylaniline and diethylaniline. The reaction is carried out in a suitable solvent,
-20 ° C to the boiling point of the solvent, preferably 0-150 ° C
It is carried out by reacting for 1 minute to 10 days in the range. Examples of the reaction solvent include liquid ammonia, alcohols (eg, methanol, ethanol, propanol, iso-propanol, butyl alcohol, sec.
-Butyl alcohol, tert-butyl alcohol, ethylene glycol, methoxyethanol, ethoxyethanol), ethers (eg, dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme), aliphatic hydrocarbons (eg, pentane,
Hexane, heptane), aromatic hydrocarbons (eg, benzene, toluene, xylene), dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, sulfolane or an appropriate mixed solvent thereof is used.

Further, the condensation can also be carried out by using the Reformatsky reaction. The reaction conditions of the Reformatsky reaction include, for example, zinc, magnesium, aluminum and tin as reagents to be used, and the reaction itself is
It is carried out by reacting for 30 minutes to 3 days in a suitable solvent at a boiling point of -20 ° C to the boiling point of the solvent, preferably 0-150 ° C. Examples of the reaction solvent include ethers (eg, dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme),
Aliphatic hydrocarbons (eg, pentane, hexane, heptane), aromatic hydrocarbons (eg, benzene, toluene, xylene) or a suitable mixed solvent thereof is used.

In the alkylation type reaction or amine exchange type reaction, the compound (V) and the compound (VI) are used by themselves or in a suitable reaction solvent from about -10 ° C to the boiling point of the reaction solvent, preferably about 10-. The reaction is carried out at a temperature in the range of 80 ° C. for about 10 minutes to 48 hours. The ratio of compound (VI) to be used is about 1-50 mol, more preferably about 1-10 mol, per 1 mol of compound (V). Examples of the reaction solvent include water, alcohols (eg, methanol, ethanol, propanol, iso
-Propanol, butyl alcohol, sec-butyl alcohol, tert-butyl alcohol, ethylene glycol, methoxyethanol, ethoxyethanol),
Ethers (eg, diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme), halogenated hydrocarbons (eg, dichloromethane, chloroform, carbon tetrachloride), nitriles (eg, acetonitrile), aliphatic hydrocarbons (eg, Pentane, hexane, heptane, octane), cycloaliphatic hydrocarbons (eg, cyclopentane,
Cyclohexane), aromatic hydrocarbons (eg, benzene,
Toluene, xylene), nitromethane, pyridine, dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, sulfolane or an appropriate mixed solvent thereof is used. If necessary, it may be better to carry out the reaction in the presence of a base. Examples of the base used include the base used in the Wittig reaction. Furthermore, when a phase transfer catalyst (eg, cetyltrimethylammonium chloride, etc.) is used in an amount of 0.01 to 0.2 equivalents, preferably 0.02 to 0.05 equivalents, relative to compound (V) or compound (VI). The reaction can also proceed advantageously. In the case of the amine exchange reaction, the compound (V) is further relaxed by using a quaternary salt such as methyl bromide, methyl iodide, methyl methanesulfonate, methyl benzenesulfonate and methyl p-toluenesulfonate. The reaction may be allowed to proceed under various conditions. In the reaction for forming the Schiff base, the compound (V) and the compound (VI) are in a molar ratio (V) / (VI) =
About 10 to 0.1, using itself or a suitable reaction solvent, from −10 ° C. to the boiling point of the reaction solvent, preferably 0-
The reaction is performed at a temperature in the range of 50 ° C. for about 10 minutes to 48 hours. In this reaction,
A compound in which the aldehyde or ketone moiety of compound (V) and compound (VI) is protected in the form of acetal or ketal may be used. The reaction solvent is preferably a non-aqueous solvent such as alcohols (eg, methanol, ethanol, propanol, iso-propanol, butyl alcohol, sec-butyl alcohol,
tert-butyl alcohol, ethylene glycol, methoxyethanol, ethoxyethanol), ethers (eg, dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme), esters (eg, methyl acetate, ethyl acetate), halogenated hydrocarbons (Eg, dichloromethane, chloroform, carbon tetrachloride), nitrites (eg, acetonitrile), aliphatic hydrocarbons (eg, pentane, hexane, heptane, octane), cycloaliphatic hydrocarbons (eg, cyclopentane,
Cyclohexane), aromatic hydrocarbons (eg, benzene,
Toluene, xylene), acetone, nitromethane, pyridine, dimethylformamide, dimethylsulfoxide,
Hexamethylphosphoramide, sulfolane or an appropriate mixed solvent thereof is used. As a dehydrating agent, for example, molecular sieves, calcium chloride, magnesium sulfate, sodium sulfate, calcium sulfate, etc. may be added, or the pH of the reaction solution may be adjusted to an acid (eg, hydrochloric acid, hydrobromic acid, hydrogen iodide) as appropriate. Acid, sulfuric acid, nitric acid, phosphoric acid), base (eg sodium hydroxide, potassium hydroxide,
Metal hydroxides such as lithium hydroxide and barium hydroxide,
Sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate, potassium carbonate, barium carbonate, calcium carbonate, sodium hydrogencarbonate, trimethylamine, triethylamine, triethanolamine, pyridine) or a buffer (eg, phosphate buffer, The reaction rate and yield can be improved by adjusting with a borate buffer solution or an acetate buffer solution. The reduction reaction of the Schiff base and the reductive alkylation reaction are carried out by hydride reduction or catalytic reduction using a suitable solvent at a reaction temperature of about -40 ° C to the boiling point of the solvent, more preferably about 0 to 50 ° C. Be seen. As the solvent used, acetic acid esters (eg, methyl acetate, ethyl acetate) and the like are used in addition to the reaction solvent used in the above-mentioned alkylation type reaction or amine exchange type reaction. For the catalytic reduction reaction, the above-mentioned method C is applied as it is. Examples of the hydride reducing reagent include lithium aluminum hydride, sodium borohydride, lithium borohydride, lithium cyanoborohydride, and the like. About twice the mole, usually 2-20
Double moles are used. Further, ring A has furan, thiophene, thiophene-1-oxide, thiophene-1,1-
In dioxide or N- substituted pyrrole ring -Z ² - is -
In the case of NH-, the -NH- group is condensed and closed with the ring A to form a tricyclic compound (eg, pyrrolo [3 ', 2': 4,5] pyrrolo [2,3-d] pyrimidine, etc.). There is something to do. In this case, the desired bicyclic compound can be easily converted by treating with an acid or a base.

Second Step The compound (IV) obtained in the first step is obtained by subjecting the ester residue [—COOR ³ ] of the compound (IV) to the deesterification reaction used in the production of the compound (I-1). It can be converted to (II). In addition, the compound (I
If necessary, I) or (IV) can be subjected to a catalytic reduction reaction based on the C method to partially reduce the A ring.

A ring A of the starting compound (II) contains a hetero atom (nitrogen atom, oxygen atom, sulfur atom) and Q ¹ = Q
^The compound (II _N ) in which ² = N can be produced, for example, by the reaction steps shown below.

[Chemical formula 22]

[Chemical formula 23]

During the above process, ring A, B, R ³ , X and Z
Has the same meaning as above, J ¹ and J ² are the same or different and are oxygen or sulfur, R ¹⁰ and R ¹¹ are the same or different and are hydrocarbon groups, and L ′ is a halogen atom (eg, chlorine, bromine). , Iodine) and T is a cyano group or the formula —COOR ¹² , —CSOR ¹² or —CSSR.
¹² groups [In formula, R < ¹² > represents a hydrocarbon group. ], Y ′ is a hydrogen atom defined or exemplified by Y, a lower hydrocarbon group, an aryl group, a 5- to 6-membered heterocyclic group,
Hydroxyl group, alkoxy group, aryloxy group, 5
A 6-membered heterocyclic oxy group, a mercapto group, an alkylthio group, an arylthio group, a 5- or 6-membered heterocyclic thio group, a substituted amino group, an alkanoylamino group, an aroylamino group or a 5- or 6-membered heterocyclic carbonylamino group , R ′ and R ″ are the same or different and each is a hydrogen atom or a substituent on the A ring and is described in detail as an alkyl group having 1 to 3 carbon atoms, an alkenyl group having 2 to 3 carbon atoms,
An alkynyl group or a cyclopropyl group having 2 to 3 carbon atoms is shown. The hydrocarbon group represented by R ¹⁰ , R ¹¹ and R ¹² is a lower alkyl group having 1 to 5 carbon atoms (eg, methyl, ethyl, propyl, iso-propyl,
n-butyl, iso-butyl, sec-butyl, ter
t-butyl, n-pentyl, iso-pentyl, sec
-Pentyl, neo-pentyl, tert-pentyl), a benzyl group or a phenyl group.
These lower alkyl group, benzyl group or phenyl group may have 1 to 3 substituents. Examples of such a substituent include a halogen atom (eg, fluorine, chlorine, bromine,
(Iodine), nitro group, cyano group, alkoxy group having 1 to 4 carbon atoms (eg, methoxy, ethoxy, propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy group), carbon Number 1 to 4 alkyl groups (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-
Butyl, tert-butyl group), alkanoyl group having about 1 to 4 carbon atoms (eg, formyl, acetyl, propionyl, n-butyryl, iso-butyryl group), trifluoromethyl group and the like.

The above reaction step will be described in detail below. Step 3 Double bond (R ¹⁰ -J ¹ -CH = C) of compound (VII)
H-)

[Chemical formula 24]

[Chemical 25] Or about 0.8-1.5 molar equivalents. This reaction is carried out in the presence of a suitable solvent at a reaction temperature of about -10 ° C to about the boiling point of the reaction solvent (up to about 100 ° C), preferably about 0 to 50 ° C, for about 30 minutes to 48 hours. It can be carried out. Examples of the solvent used in the reaction include alcohols (eg, methanol, ethanol), ethers (eg, dimethyl ether, diethyl ether,
Tetrahydrofuran, dioxane, monoglyme, diglyme), nitriles (eg acetonitrile), esters (eg ethyl acetate), halogenated hydrocarbons (eg dichloromethane, chloroform, carbon tetrachloride), aromatic hydrocarbons (eg , Benzene, toluene, xylene) or an appropriate mixed solvent thereof. During the reaction, it is possible to proceed more advantageously by adding light or an organic peroxide. Examples of the organic peroxide include t-butyl hypochloride, peracetic acid, perbenzoic acid,
Examples include p-chloroperbenzoic acid and the like. The compound (VIII) thus obtained is relatively highly reactive and may be isolated at this stage, but it is also possible to proceed directly to the next step without isolation.

Fourth Step The compound (VIII) obtained in the third step is R ¹¹ -J
An alcohol or thiol represented by ^2- H,
In the presence of a suitable solvent, about -10 ° C to the boiling point of the reaction solvent (up to about 100 ° C), preferably about 0 to 50.
Compound (IX) can be obtained by reacting at a reaction temperature in the range of ° C for about 10 minutes to 24 hours. Examples of the solvent used in the reaction include ethers (eg, dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme), nitriles (eg, acetonitrile), esters (eg, ethyl acetate), halogenated carbonization. Hydrogen (eg, dichloromethane, chloroform, carbon tetrachloride), aromatic hydrocarbons (eg, benzene, toluene, xylene), or an appropriate mixed solvent thereof is used. Further, the alcohol or thiol itself represented by R ¹¹ -J ² -H may be used in excess as a solvent.

Fifth step

[Chemical formula 26] Indicates. ] When reacted with a compound represented by the following formula or a salt thereof, it reacts with a cyano group, an ester group or a thioester group, and then undergoes cyclization to form a pyrimidine ring to form a compound (X). As the acid salt of compound (XI),
For example, mineral acid salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, boric acid, oxalic acid, tartaric acid, lactic acid, citric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, Ethanesulfonic acid, benzenesulfonic acid,
Examples thereof include organic acid salts with p-toluenesulfonic acid, camphorsulfonic acid, etc., and compounds (XI-1: Y ′ =
Examples of the base salt of hydroxyl group or mercapto group include salts with sodium, potassium, lithium, calcium, magnesium, aluminum, zinc, ammonium, trimethylammonium, triethylammonium, triethanolammonium, pyridinium, and substituted pyridinium. Can be mentioned. When the ring is closed,
When carried out under basic conditions, the reaction can proceed advantageously. Examples of the base used include metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide. Examples of the reaction solvent include methanol, ethanol, propanol, tert-butyl alcohol, dimethyl sulfoxide, hexamethylphosphoramide, etc., and the reaction temperature is 0 to 150 ° C., preferably 20 to 100 ° C., and the reaction time is It is 1-48 hours. Examples of the reaction solvent include methanol, ethanol, propanol,
tert-butyl alcohol, dimethyl sulfoxide,
Hexamethylphosphoramide or an appropriate mixed solvent thereof is used.

Sixth step

[Chemical 27]

[Chemical 28] And the dehydration reaction is induced, the compound (IV _N ) can be converted. The reversion reaction to a carbonyl group is carried out, for example, by using the compound (X) per se or a suitable reaction solvent, from about -10 ° C to the boiling point of the reaction solvent (about 1
(Up to 00 ° C), preferably at a reaction temperature in the range of about 0 to 50 ° C for about 10 minutes to 100 hours. As the decomposition reaction, for example,
Hydrolysis reaction under acidic conditions (B-1 method), decomposition reaction under acidic non-aqueous conditions (B-2 method), catalytic reduction reaction (C method), decomposition reaction using metal salt (D method) or oxidizing agent And the decomposition reaction (method E). B-
The 1st method, the B-2 method and the C method have the formulas -COOR ¹ and
The method detailed in the decomposition reaction of COOR ² can be applied as it is. Examples of the metal salt used in Method D include cupric chloride, silver nitrate, silver oxide, mercuric chloride, tellurium salts (eg, tellurium nitrate, tellurium trifluoroacetate), and the oxidation used in Method E. As the agent, oxygen-light, hydrogen peroxide, perbenzoic acid, m-chloroperbenzoic acid, perchlorate (eg, lithium perchlorate,
Silver perchlorate, mercuric perchlorate, tetrabutylammonium perchlorate), nitrosylsulfuric acid, alkyl nitrite (eg, isoamyl nitrite), iodine, bromine, chlorine, N-
Bromosuccinimide, sulfuryl chloride, chloramine T
Etc.

[Chemical 29] It can be appropriately selected depending on the chemical properties of J ¹ -R ¹⁰ and -J ² -R ¹¹ . As the reaction solvent, in the case of Method D and Method E, for example, water, alcohols (eg, methanol, ethanol, propanol, iso-propanol, butyl alcohol, sec-butyl alcohol, tert-butyl alcohol, ethylene glycol, Methoxyethanol, ethoxyethanol), ethers (eg, dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme), aromatic hydrocarbons (eg, benzene, toluene, xylene), halogenated hydrocarbons (eg, dichloromethane) , Chloroform, carbon tetrachloride), acetone, acetonitrile or an appropriate mixed solvent thereof. The intramolecular ring closure reaction and dehydration reaction in the step of producing the compound (IV _N ) are usually carried out by a carbonyl group.

[Chemical 30] Reacts spontaneously to form the A ring. At this time, the presence of the acid catalyst also allows the reaction to proceed rapidly and in a high yield. Examples of such acid catalysts include mineral acids, organic acids, Lewis acids and the like, which are described in detail in Method B-1 and Method B-2. Also,

[Chemical 31] Then, after converting the hydroxy moiety into a leaving group L, the group X in the molecule is subjected to an alkylation reaction to form A
It is also possible to produce a compound (IV _N ′) in which the ring is partially reduced. A method known per se is used for the reduction reaction of the carbonyl group, the conversion reaction of the hydroxyl group into a leaving group, and the intramolecular alkylation reaction. In addition, compound (II _N ) or (IV _N ) was subjected to catalytic reduction reaction based on Method C to give A
Compound (II _N ') or (IV
It can also be converted to _N '). Compound (IV _N ),
When the ring A in (IV _N ′) is a pyrrole or a pyrroline ring, the compounds (X), (IV _N ) or (I
V _N ') stage subjected to a per se known alkylation or acylation reaction in the present compound a is N- substituted pyrrole or N- substituted pyrroline ring can be converted to a compound having. Furthermore, known compounds [Japanese Patent Application No.
-72235] as a starting material, the compound of the present invention in which the A ring is an N-substituted pyrrole or an N-substituted pyrroline ring can also be produced by carrying out the above-mentioned alkylation reaction or acylation reaction. A of raw material compound (II)
The compound (IIc) in which the ring is composed of only carbon atoms and Q ¹ = Q ² = N can be produced, for example, by the reaction steps shown below.

[Chemical 32]

In the above process, ring A, B, R ³ , R ¹² ,
R ′, R ″, X, Y ′ and Z have the same meanings as defined above,
R ', R "and -Z-B-COOR ³ is assumed to be combined with three consecutive positions on the cyclopentane ring.

Step 7 When compound (XII) synthesized by a conventional method is heat-treated with dicyandiamide, a cyclization reaction occurs to form a condensed pyrimidine ring to obtain compound (IV _c1 ). In this case, the reaction temperature is 100 to 300 ° C., more preferably 1
It is 50-250 ° C., and the reaction time is suitably 1-24 hours. Further, if necessary, an unsaturated bond can be introduced into the A ring by dehydrogenating with a known reagent by a method known per se.

Step 8 Of the α-positions on both sides of the carbonyl group in compound (XII), hydrogen at the α-position which is not substituted by R ', R "or -Z-B-COOR ³ is abstracted by a conventional method, and a carbanion is obtained. Is formed and an ester residue is introduced into the activated position to give compound (XIII).

Step 9 When compound (XIII) is treated with general formula (XI), it reacts with a carbonyl group and an ester residue to cause ring closure and cyclization, and a fused pyrimidine ring is newly formed to give compound (I
V _C2 ) is obtained. The reaction conditions are the same as those used in the fifth step. Further, if necessary, an unsaturated bond can be introduced into the A ring by dehydrogenating with a known reagent by a method known per se.

The ester bodies (IV _C1 ) and (IV _C2 ) obtained in the seventh step and the ninth step are subjected to a deesterification reaction in the same manner as in the second step, and the corresponding carboxylic acids (II _C1 ) and (IV _C1 ) are obtained, respectively. II _C2 ). When B is a cycloalkenylene group or a phenylene group having a substituent, these groups may be subjected to a catalytic reduction reaction in an appropriate step among the first to ninth steps to be converted into a corresponding cycloalkylene group. . As the catalytic reduction reaction, the above-mentioned method C is advantageously applied as it is.

Y'is a hydroxyl group, an alkoxy group, an aryloxy group, a 5- or 6-membered heterocyclic oxy group, a mercapto group, an alkylthio group, an arylthio group, a 5- or 6-membered heterocyclic thio group, a substituted amino group, an alkanoyl group. In the case of an amino group, an aroylamino group or a 5- or 6-membered heterocyclic carbonylamino group, the second step, the sixth step, the seventh step
Subject to a conversion reaction known per se in an appropriate step of the step or the ninth step, and a 5- or 6-membered heterocyclic group exemplified by Y, a halogen atom, a cyano group, a carboxyl group, a carbamoyl group, a nitro group, a hydroxyl group Group, alkoxy group, aryloxy group, 5- or 6-membered heterocyclic oxy group, mercapto group, alkylthio group, arylthio group,
5 to 6 membered heterocyclic thio group, substituted amino group, alkanoylamino group, aroylamino group, 5 to 6 membered heterocyclic carbonylamino group, alkanoyloxy group, aroyloxy group or 5 to 6 membered heterocyclic carbonyloxy group You may convert.

When the ring A and the ring B contain a sulfur atom, and when -Z ² -is -S- (sulfur atom), the compound (I) of the present invention is directly subjected to an oxidation reaction or at any possible step. Oxidation reaction at any of the steps, ring A, B
And -Z 2 ^- of the sulfur atom can be converted to compounds that are S (O) n [n = 1 to 2]. The oxidation reaction is usually 0.3 to 3.0 equivalents relative to the compound to be oxidized,
Preferably in the presence of 0.5 to 2.5 equivalents of oxidizing agent, in a suitable solvent, -10 to + 100 ° C, preferably 0 to +50.
10 minutes to 48 hours at 30C, preferably 30 minutes to 24
It can be produced by reacting for a time. As the oxidizing agent used in the reaction, peracids (eg, hydrogen peroxide, peracetic acid, perbenzoic acetic acid, m-chloroperbenzoic acetic acid)
Is preferred. As the reaction solvent, water, acetic acid, ketones (eg, acetone, ethyl methyl ketone), ethers (eg, dimethyl ether, diethyl ether, dioxane, monoglyme, diglyme), halogenated hydrocarbons (eg, dichloromethane, chloroform, Carbon tetrachloride),
Aliphatic hydrocarbons (eg, pentane, hexane, heptane, octane), cycloaliphatic hydrocarbons (eg, cyclopentane, cyclohexane), aromatic hydrocarbons (eg, benzene, toluene, xylene) or their suitable Mixed solvent of is used. Further, in the compounds (I), (II) and (IV), the amino group, hydroxyl group or mercapto group represented by X may be converted into each other by a substituent conversion reaction on a pyrimidine ring known in the literature, if necessary. It is also possible [Separate volume protein nucleic acid enzyme, chemical synthesis of nucleic acid, Kyoritsu Shuppan (1968)].

Furthermore, regarding the reactions, reagents, reaction conditions and the application of protective groups to each functional group used as necessary, etc., which are carried out or used in the first to ninth steps, or in the step of producing the starting material compound, , Which are known and explained in detail in the following documents. [J.
F. W. McOmine, Protective Groups in Organic Chemistry (Protect
Ive Groupin Organic Chem
Istry), Plenum Press London
and New York (1973)], (Pine Hendrickson Hammond, Organic Chemistry (4th edition).
[I]-[II], Hirokawa Shoten (1982)] and [M. Fieser and L.F. Fieser, Regent for Organic Synthesis No. 1-1
Volume 3 (Reagents for Organic S
synthesis vol. 1-13), Wiley-
Interscience, New York, Lon
don, Sydney and Toronto (196
9-1988)] Each of the intermediates of the compound of the present invention produced by the above method and the compound (I) of the present invention or a salt thereof can be subjected to an ordinary separation means such as concentration, solvent extraction, chromatography and recrystallization. It can be isolated from the reaction mixture.

The compounds (I), (II) and (IV) obtained by the production method of the present invention may form a salt. Base salts include alkali metals, alkaline earth metals, non-toxic metals, ammonium and substituted ammonium such as sodium, potassium, lithium, calcium, magnesium, aluminum, zinc, ammonium, trimethylammonium, triethylammonium, triethanolammonium. , Pyridinium, substituted pyridinium and the like. As the acid salt,
For example, with mineral acid salts with hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, boric acid, oxalic acid, tartaric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, etc. The organic acid salts of

[0045]

The compound (I) of the present invention or a salt thereof has an inhibitory effect on one or more kinds of enzymes using folic acid and its related compounds as substrates. Therefore, these compounds are intended to treat various tumors such as choriocarcinoma, leukemia, breast adenocarcinoma, head and neck epidermoid carcinoma, squamous cell carcinoma, small cell lung cancer and lymphosarcoma which have been treated with MTX until now. Can be used alone or in combination with other antitumor agents.

When used as an antitumor agent, the compound (I)
Alternatively, a salt thereof is used by itself or by using a pharmacologically acceptable carrier, excipient, diluent and the like by a commonly used method, for example, powder, granules, tablets, capsules, suppositories, injections. It may be administered orally or parenterally in the form of a drug or the like. The dose depends on the target animal (human, dog,
Warm-blooded animals such as cats, rabbits, monkeys, rats, and mice), diseases, symptoms, types of compounds, administration routes, etc. 2.0-200 mg / kg body weight, preferably 4.0-80 mg / kg body weight, and about 1.0-100 mg / k per day for parenteral administration.
g body weight, preferably 2.0-40 mg / kg body weight. Examples of the administration method as an injection include intramuscular injection, intraperitoneal injection, subcutaneous injection, intravenous injection and the like. The above formulation is carried out according to a method known per se. In producing the above oral preparations, for example, tablets, a binder (eg,
Hydroxypropylcellulose, hydroxypropylmethylcellulose, macrogol, etc.), disintegrating agents (eg, starch, carboxymethylcellulose calcium, etc.), lubricants (eg, magnesium stearate, talc, etc.) and the like can be appropriately added. In the case of producing parenteral preparations, for example, injections, isotonic agents (eg, glucose, D-sorbitol, D-mannitol, sodium chloride, etc.), preservatives (eg, benzyl alcohol, chlorobutanol, Methyl paraoxybenzoate, propyl paraoxybenzoate, etc.), buffer (eg,
A phosphate buffer solution, a sodium acetate buffer solution, etc.) can be appropriately blended. Specific examples of the production of tablets include, for example, the compound (I) of the present invention or a salt thereof in an amount of about 1.0-50 mg, lactose 100-
500 mg, cornstarch about 50-100 mg, and hydroxypropylcellulose about 5-20 mg were mixed by a conventional method, granulated, mixed with cornstarch and magnesium stearate, and then tabletted to give about 100-50 tablets.
The tablet is 0 mg and the diameter is about 3-10 mm. In addition, the amount of this tablet used per tablet is hydroxypropylmethylmethylcellulose phthalate (about 10-20 m
g) and castor oil (about 0.5-2.0 mg) in a concentration of about 5
An enteric coated tablet can also be obtained by coating with an acetone-ethanol mixed solution dissolved to -10%. As a specific example of the preparation of the injection, for example, the amount of sodium salt of the compound of the present invention is about 2.0-50 mg (i) about 2 per ampoule.
After injecting the solution dissolved in ml of physiological saline into an ampoule and sealing it, heat sterilize it at about 110 ° C. for about 30 minutes, or (ii) sterilize about 10-40 mg of mannitol or sorbitol to about 2 ml. It can also be adjusted by dissolving it in distilled water, pouring it into an ampoule, freeze-drying this, and sealing. When the lyophilized compound is used, the ampoule is opened and physiological saline is injected into the ampoule so that the concentration of the compound is about 1.
It can be prepared as a solution that is dissolved so as to be 0 to 50 mg / ml, and can be an injection for subcutaneous, intravenous or intramuscular administration.

[0047]

Reference Examples and Examples The present invention will be specifically described below with reference to Reference Examples and Examples.

Reference Example 1 4- [2- (2-amino-7-benzyl-3-isopro
Pyroxymethyl-4 (3H) -oxopyrrolo [2,3
-D] pyrimidin-5-yl) ethyl] methyl benzoate
Preparation of 4- [2- (2-amino-7-benzyl-3-
Isopropyloxymethyl-4 (3H) -oxopyrrolo
[2,3-d] pyrimidin-5-yl) ethenyl benzoin
Methyl acid (4.36 g) was added to methanol-tetrahydrofuran.
Dissolve in orchid mixture (1: 1,400 ml) and contain 50% water
10% Pd-C (4.36 g, manufactured by Engelhard)
After the addition, catalytic reduction was performed for 30 minutes in a hydrogen atmosphere. Touch
The solvent is removed by filtration, and the filtrate is concentrated under reduced pressure to give the title compound.
(4.03g) was obtained. IR (Neat): 3320, 2980, 1720, 1
680, 1620, 1540, 1280, 1110, 1
060 cm^{-1  1}H-NMR (CDCl_Three) Δ: 1.20 (6H,
d), 3.03 (4H, s), 3.87 (3H, s),
3.73-3.97 (1H, m), 5.05 (2H,
s), 5.60 (2H, s), 6.10 (1H, s),
7.00-7.40 (7H, m), 7.88 (2H,
d)

Reference Example 2 4- [2- (2-amino-7-benzyl-6-promo-]
Preparation of methyl 3-isopropyloxymethyl-4 (3H) -oxopyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoate:

The compound of Reference Example 1 (4.00 g) was dissolved in dry dichloromethane (188 ml), and N-prosuccinimide (1.68 g) was added to this solution under ice-cooling stirring, and the mixture was kept at the same temperature for 30 minutes. I left it. The solvent was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography [carrier; 100 g, developing solvent; hexane: ethyl acetate = 7:
3] was separated and purified to give the title compound (4.74 g). ¹ H-NMR (CDCl ₃ ) δ: 1.20 (6H,
d), 3.03 (4H, s), 3.87 (3H, s),
3.70-4.00 (1H, m), 5.18 (2H,
s), 5.57 (2H, s), 7.00-7.33 (7)
H, m), 7.88 (2H, d)

Reference Example 3 4-Amino-5-formyl-7-methylpyrrolo [2,3]
Preparation of -d] pyrimidine 4-amino-5-cyano-7-methylpyrrolo [2,3-
d] Formic acid solution of pyrimidine (600 mg) (25 ml)
After adding Raney nickel (5.0g) to
It was stirred for 1.5 hours. The reaction solution was filtered while hot and washed with formic acid until the wash solution became colorless. The filtrate is concentrated under reduced pressure,
The obtained residue was dissolved in hot water and then adjusted to pH 7.0 with a 1N aqueous sodium hydroxide solution. This was extracted with chloroform, the extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a colorless powder (370
mg). ¹ H-NMR (DMSO-d ₆ ) δ: 3.78 (3H,
s), 7.57 (2H, m), 8.21 (1H, s),
8.27 (1H, s), 9.67 (1H, s) IR (KBr): 3350,3100,1650,15
95 cm ^-1

Reference Example 4 4- [2- (4-amino-7-methylpyrrolo [2,3-
d] Pyrimidin-5-yl) ethenyl] methyl benzoate Preparation p-Carbomethoxybenzyltriphenylphosphonium bromide (500 mg) in dry N, N-dimethylformamide (10 ml) under argon flow, 4.9.
Mole-sodium methylate in methanol (0.2
ml) was added and the mixture was stirred at room temperature for 15 minutes. To this solution was added a solution of the compound of Reference Example 3 (180 mg) in dry N, N-dimethylformamide (10 ml), and the mixture was further stirred at room temperature for 3 days. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography [carrier: 60
g, developing solvent: chloroform / methanol = 19/1]
The title compound (200 mg) was obtained after purification by. ¹ H-NMR (CDCl ₃ ) δ: 3.83 (3H,
s), 3.93 (3H, s), 5.46 (2H, m),
6.70-6.94 (1H, m), 7.16 (1H,
s), 7.29-7.39 (1H, m), 7.53 (2
H, d, J = 8.4 Hz), 7.87 (2H, d, J =
8.4 Hz), 8.35 (1H, s)

Example 1 4- [2- (2-amino-7-benzyl-6-promo-
Preparation of methyl 4-hydroxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoate

0.2% of the compound of Reference Example 2 (4.51 g)
It was dissolved in a dichloromethane solution of 1N hydrogen bromide (407 ml), and left stirring at room temperature for 17 hours. Hexane (800 ml × 2) was added to the reaction solution, and the supernatant was removed. The residue is subjected to silica gel column chromatography [carrier; 50
0 g, developing solvent; hexane: ethyl acetate = 3: 2 → ethanol: chloroform = 8: 92] to separate and purify to obtain the title compound (2.93 g). ¹ H-NMR (DMSO-d ₆ ) δ: 2.93 (4H,
bs), 3.87 (3H, s), 5.13 (2H,
s), 6.87-7.07 (2H, m) 7.13-7.
33 (5H, m), 7.82 (2H, d)

Example 2 4- [2- (2-amino-7-benzyl-6-bromo,
Preparation of 4-hydroxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoic acid:

The compound of Example 1 (306 mg) was added to 0.2
Normal sodium hydroxide solution (15.9 ml) and tetra
Dissolve in a mixture with hydrofuran (8 ml) and stir at room temperature
It was left stirring for 18 hours. Most of the tetrahydrofuran
After evaporation, 0.2N hydrochloric acid (15.9 ml) was added with stirring under ice cooling.
Was added to neutralize. The precipitate formed was collected by filtration and washed with water and methanol.
It was washed with ether, then with ether and dried to give the title compound (2
68 mg) was obtained. IR (Nujol): 3470, 3130, 1710,
1680, 1650, 1605, 1460, 1380,
1260, 1170 cm^{-1  1}1 H-NMR (DMSO-d₆) Δ: 2.92 (4
H, s), 5.13 (2H, s), 6.27 (2H,
s), 6.87-7.07 (2H, m), 7.13-
7.37 (5H, m), 7.82 (2H, d)

Example 3 N- [4- [2- (2-amino-7-benzyl-6-promo-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoyl ] -Production of diethyl L-glutamate:

The compound of Example 2 (234 mg) and diethyl glutamate hydrochloride (240 mg) were dissolved in dry dimethylformamide (15 ml), and after cooling to 0 ° C. diphenylphosphoryl azide (162 μl) and triethylamine (280 μl) were added. The mixture was added at the same temperature for 2 hours, returned to room temperature, and left stirring for 5 hours. The precipitate is filtered off,
The filtrate was concentrated to dryness, and the residue was separated and purified by silica gel column chromatography [carrier; 75 g, developing solvent; hexane: ethyl acetate = 3: 7 → ethyl acetate] to give the title compound (229 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.20 (3H,
t), 1.27 (3H, t), 2.00-2.63 (4
H, m), 3.00 (4H, s), 3.97-4.33.
(4H, q × 2), 4.63-4.93 (1H, m),
5.17 (2H, s), 7.00-7.43 (7H,
m), 7.70 (2H, d)

Example 4 N- [4- [2- (2-amino-7-benzyl-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidine-5]
-Yl) Ethyl] benzoyl] -diethyl L-glutamate: Compound of Example 3 (234 mg) mixed with ethanol-tetrahydrofuran (2: 1, 15 ml)
Dissolved in 1N hydrochloric acid (0.66 ml) and 50% water containing 10% Pd-C (862 mg, manufactured by Engelhard)
Was added, and catalytic reduction was performed for 5 hours in a hydrogen atmosphere at 4 atm. The catalyst was filtered off, the filtrate was neutralized with 1N aqueous sodium hydroxide solution, and concentrated under reduced pressure to dryness. The residue is subjected to silica gel column chromatography [carrier; 45 g, developing solvent; ethanol: chloroform = 4: 96 → 15: 8].
5] was separated and purified to give the title compound (135 mg). ¹ H-NMR (CDCl ₃ ) δ: 1.20 (3H,
t), 1.29 (3H, t), 1.87-2.60 (4
H, m), 3.00 (4H, s), 3.97-4.35.
(4H, q × 2), 4.63-4.93 (1H, m),
5.07 (2H, s), 5.24 (2H, s), 6.1
4 (1H, s), 7.05 (2H, d), 7.10-
7.37 (5H, m), 7.68-7.70 (2H,
d)

Example 5 N- [4- [2- (2-amino-7-benzyl-6-bromo-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoyl]- Production of L-glutamic acid:

The compound of Example 3 (160 mg) was dissolved in a water-tetrahydrofuran mixture (1: 2, 6 ml),
1N sodium hydroxide aqueous solution (0.736
ml) was added and the mixture was stirred at room temperature for 1 hour. The solvent was concentrated to 2 ml under reduced pressure, the resulting insoluble matter was filtered off with a Millipore filter, the filtrate was cooled to 0 ° C., and acetic acid (0.2 ml) was added. The produced precipitate was collected by filtration, washed with ice water, and dried under reduced pressure to give the title compound (128 mg). ¹ H-NMR (DMSO-d ₆ ) δ: 1.82-2.4
5 (4H, m), 2.91 (4H, s), 4.15-
4.46 (1H, m), 5.12 (2H, s), 7.0
5-7.42 (7H, m), 7.73 (2H, d)

Example 6 N- [4- [2- (2-amino-7-benzyl-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidine-5]
Preparation of -yl) ethyl] benzoyl] -L-glutamic acid: In the same manner as in Example 5, the compound of Example 4 (160
The title compound (115 mg) was obtained from (mg).

¹ H-NMR (DMSO-d ₆ ) δ: 1.
79-2.50 (4H, m), 2.93 (4H, s),
4.18-4.50 (1H, m), 5.03 (2H,
s), 6.11 (1H, s), 7.06 (2H, d),
7.12-7.39 (5H, m), 7.69 (2H,
d)

Example 7 N- [4- [2- (2-amino-4-hydroxy-7-
Methyl-7H-pyrrolo [2,3-d] pyrimidine-5-
Preparation of diethyl) ethyl] benzoyl] -L-glutamate 4- [2- (2-amino-7-methyl-3-isopropyloxymethyl) in the same manner as in Reference Example 1, Reference Example 2 and Example 1. -4 (3H) -oxopyrrolo [2,2
4- [2- (2-amino-6-bromo-4-hydroxy-7-methyl-7H-pyrrolo [2,3] obtained from methyl 3-d] pyrimidin-5-yl) ethenyl] benzoate
Methyl -d] pyrimidin-5-yl) ethyl] benzoate (4.06 g) was sequentially subjected to the same method as in Example 2, Example 3, Example 4 and Example 6 to give the title compound (3. 03 g) was obtained. ¹ H-NMR (CDCl ₃ / CD ₃ OD) δ: 1.22
(3H, t, J = 7.2 Hz), 1.30 (3H, t,
J = 7.2 Hz), 2.07-2.39 (2H, m),
2.44-2.57 (2H, m), 3.03 (4H,
s), 3.57 (3H, s), 4.11 (2H, q, J
= 7.2 Hz), 4.24 (2H, q, J = 7.2H)
z), 4.73-4.86 (1H, m), 5.31 (2)
H, s), 6.21 (1H, s), 7.25 (2H,
d, J = 8.2 Hz), 7.32 (1H, d, J = 7.
4Hz), 7.70 (2H, d, J = 8.2Hz)

Example 8 N- [4- [2- (2-amino-4-hydroxy-7-
Methyl-7H-pyrrolo [2,3-d] pyrimidine-5-
Preparation of (yl) ethyl] benzoyl] -L-glutamic acid When the same hydrolysis reaction as in Example 5 was applied to the compound of Example 7 (0.995 g), the title compound (0.768 g) was obtained.
was gotten. 3.04 (4H, m), 3.55 (3H, s), 4.3
1-4.43 (1H, m), 6.12 (2H, s),
6.39 (1H, s), 7.27 (2H, d, J = 8.
2Hz), 7.75 (2H, d, J = 8.2Hz),
8.41 (1H, d, J = 7.4Hz), 10.25
(1H, s)

Example 9 N- [4- [2- (2-amino-4-hydroxy-7-
Methyl-6,7-dihydro-5H-pyrrolo [2,3-
d] pyrimidin-5-yl) ethyl] benzoyl] -L
-Production of diethyl glutamate The compound of Example 7 (1.99 g) was dissolved in trifluoroacetic acid (40 ml), and 50% water content 10% Pd-C.
After adding (1.0 g), the mixture was vigorously stirred under a hydrogen atmosphere for 48 hours. The catalyst was filtered off, the filtrate was neutralized and then concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography [carrier; 140 g, single solvent; chloroform: methanol =
1: 39 → 1: 9] and the title compound (0.92
g) was obtained. 48-1.69 (1H, m), 1.93-2.18 (3
H, m), 2.46 (2H, t, J = 7.4Hz),
2.66 (2H, t, J = 7.2Hz), 3.02-
3.17 (2H, m), 3.43-3.56 (1H,
m), 3.58 (3H, s), 4.05 (2H, q, J
= 7.2 Hz), 4.11 (2H, q, J = 7.2H)
z), 4.38-4.50 (1H, m), 6.15 (2
H, s), 7.30 (2H, d, J = 8.2Hz),
7.78 (2H, d, J = 8.2Hz), 8.64 (1
H, d, J = 7.4 Hz), 9.54 (1H, s)

Example 10 N- [4- [2- (2-amino-4-hydroxy-7-
Methyl-6,7-dihydro-5H-pyrrolo [2,3-
d] pyrimidin-5-yl) ethyl] benzoyl] -L
-Production of glutamic acid The same hydrolysis reaction as in Example 5 was applied to the compound of Example 9 (0.85 g) to give the title compound (0.64 g). t, J = 7.8 Hz), 2.68 (2H, t, J = 7.
2 Hz), 3.02-3.19 (2H, m), 3.41
-3.55 (1H, m), 3.56 (3H, s), 4.
37-4.49 (1H, m), 6.17 (2H, s),
7.30 (2H, d, J = 8.4Hz), 7.79 (2
H, d, J = 8.4 Hz), 8.50 (1H, d, J =
7.8Hz)

Example 11 4- [3- (2-Amino-4-hydroxy-7-methyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl)
Production of propyl] benzoic acid 4- [3- (2-amino-3-isopropyloxymethyl-7-methyl-4 (3H) -oxopyrrolo [2,3-]
Methyl [d] pyrimidin-5-yl) -1-oxo-2-propenyl] benzoate (6.37 g) was dissolved in a methanol-tetrahydrofuran mixed solution (1: 1,300 ml), and 50% water-containing 10% Pd-C ( After adding 6.4 g (manufactured by Engelhard), the mixture was vigorously stirred for 36 hours under a hydrogen atmosphere. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give crude 4- [3- (2-amino-3-isopropyloxy-7).
Methyl -methyl-4 (3H) -oxopyrrolo [2,3-d] pyrimidin-5-yl) propyl] benzoate was obtained. The entire amount of this product was subjected to the same deisopropylation reaction as in Example 1 and then hydrolyzed in the same manner as in Example 2 to obtain the title compound (1.98 g). s), 6.03 (2H, s), 6.41 (1H, s),
7.26 (2H, d, J = 8Hz), 7.77 (2H,
d, J = 8Hz)

Example 12 N- [4- [3- (2-amino-4-hydroxy-7-
Methyl-7H-pyrrolo [2,3-d] pyrimidine-5-
Preparation of diethyl) propyl] benzoyl] -diethyl L-glutamate In the same manner as in Example 3, the compound of Example 11 (1.63) was used.
The title compound (1.74 g) was obtained from g). , 1.87-2.35 (4H, m), 2.37-2.5.
7 (2H, m), 2.61-2.93 (4H, m),
3.58 (3H, s), 4.10 (2H, q, J = 7.
2Hz), 4.22 (2H, q, J = 7.2Hz),
4.60-4.87 (1H, m), 6.29 (1H,
s), 7.24 (2H, d, J = 8.2Hz), 7.5
3 (1H, d, J = 7.6Hz), 7.72 (2H,
d, J = 8.2 Hz)

Example 13 N- [4- [3- (2-amino-4-hydroxy-7-
Methyl-7H-pyrrolo [2,3-d] pyrimidine-5-
Preparation of (yl) propyl] benzoyl] -L-glutamic acid The same hydrolysis reaction as in Example 5 was applied to the compound of Example 12 (1.54 g) to give the title compound (1.13 g). 1 (4H, m), 3.58 (3H, s), 4.26-
4.57 (1H, m), 6.01 (2H, s), 6.4
2 (1H, s), 7.62 (2H, d, J = 8Hz),
7.78 (2H, d, J = 8Hz), 8.47 (1H,
d, J = 7.4 Hz)

Example 14 4- [3- (2-Amino-4-hydroxy-7-methyl-6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-5-yl) propyl] benzoic acid Manufacturing 4- [3
-(2-amino-3-isopropyloxymethyl-7-
Methyl-4 (3H) -oxopyrrolo [2,3-d] pyrimidin-5-yl) -1-oxo-2-propenyl] benzoate (5.09 g) was mixed with methanol-tetrahydrofuran mixture (1: 1,240 ml). Dissolved in 1N-hydrochloric acid (24 ml) and 50% water containing 10% Pd-C (2.
6 g (manufactured by Engelhardt) was added, and the mixture was vigorously stirred under a hydrogen atmosphere for 48 hours. After the catalyst was filtered off and neutralized,
The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [carrier; 300 g, developing solvent; chloroform-methanol = 1:39 → 1:19] to give 4-
Methyl [3- (2-amino-3-isopropyloxy-7-methyl-6,7-dihydro-4 (3H) -oxopyrrolo [2,3-d] pyrimidin-5-yl) propyl] benzoate was obtained. It was The whole amount of this product was subjected to the same deisopropyloxymethyl reaction as in Example 1 and then hydrolyzed in the same manner as in Example 2, to give the title compound (1.02).
g) was obtained. 6 (2H, m), 3.32-3.65 (1H, m),
3.58 (3H, s), 6.13 (2H, s), 7.2
7 (2H, d, J = 8Hz), 7.79 (2H, d, J
= 8 Hz)

Example 15 N- [4- [3- (2-amino-4-hydroxy-7-
Methyl-6,7-dihydro-5H-pyrrolo [2,3-
d] pyrimidin-5-yl) propyl] benzoyl]-
Production of L-Diethyl Glutamate In the same manner as in Example 3, the compound of Example 14 (0.98
The title compound (1.017 g) was obtained from 5 g). , 1.49-1.88 (4H, m), 2.01-2.3.
4 (2H, m), 2.35-2.55 (2H, m),
2.66 (2H, brt), 3.11-3.38 (2
H, m), 3.56 (3H, s), 3.52-3.78.
(1H, m), 4.08 (2H, q, J = 7.2H
z), 4.21 (2H, q, J = 7.2Hz), 4.5
7-4.89 (1H, m), 5.70 (2H, s),
7.26 (2H, d, J = 8Hz), 7.59 (1H,
d, J = 7.5 Hz), 7.75 (2H, d, J = 8H)
z)

Example 16 N- [4- [3- (2-amino-4-hydroxy-7-
Methyl-6,7-dihydro-5H-pyrrolo [2,3-
d] pyrimidin-5-yl) propyl] benzoyl]-
Production of L-glutamic acid When the same hydrolysis reaction as in Example 5 was applied to the compound of Example 15 (0.924 g), the title compound (0.716) was obtained.
g) was obtained. 3 (2H, m), 2.47-2.77 (2H, m),
2.87-3.26 (2H, m), 3.31-3.64.
(1H, m), 3.57 (3H, s), 4.26-4.
52 (1H, m), 6.14 (2H, s), 7.26
(2H, d, J = 8 Hz), 7.78 (2H, d, J =
8Hz), 8.46 (1H, d, J = 7.4Hz)

Example 17 4- [2- (4-amino-7-methylpyrrolo [2,3-
Production of d] pyrimidin-5-yl) ethyl] methyl benzoate A solution of the compound of Reference Example 4 (90 mg) in methanol (25
10% palladium-carbon (45 mg) was added to (ml) and the mixture was stirred at room temperature for 2.5 hours under a hydrogen atmosphere. The catalyst was removed by filtration using Celite, and the filtrate was evaporated under reduced pressure to give the title compound (88 mg). ¹ H-NMR (CDCl ₃ ) δ: 3.07 (4H, b
s), 3.73 (3H, s), 3.92 (3H, s),
5.07 (2H, m), 6.62 (1H, s), 7.2
4 (2H, d, J = 8.0 Hz), 7.97 (2H,
d, J = 8.0 Hz), 8.29 (1H, s)

Example 1 Preparation of 8 N- [4- [2- (4-amino-7-methylpyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoyl] -L-glutamate diethyl under argon atmosphere. The compound of Example 17 (80 mg) was dissolved in a mixed solution (24 ml) of methanol-water-tetrahydrofuran (5: 5: 2), and 1N aqueous sodium hydroxide solution (0.76 ml) was added thereto, and then 40 Stir at 4 ° C. for 4 hours. 1N Hydrochloric acid (0.76 ml) was added to this solution, the solvent was evaporated under reduced pressure, and the residue was dried under reduced pressure at 80 ° C. to give crude 4- [2- (4-amino-7-methylpyrrolo [2,3- d] Pyrimidin-5-yl) ethyl] benzoic acid was obtained. The whole amount of this product and L-glutamic acid diethyl hydrochloride (92 mg) were dissolved in dry N, N-dimethylformamide (4 ml), and a solution of diethyl cyanophosphate (50 mg) in dry N, N-dimethylformamide (2 ml) was added at 0 ° C. Was added and stirred for 15 minutes. Then, a dry N, N-dimethylformamide solution (2 ml) of triethylamine (78 mg) was added dropwise at the same temperature, and the mixture was stirred at 0 ° C. for 3 days.
The mixture was stirred for 0 minutes and at room temperature for 14 hours. The insoluble material was filtered off, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [carrier: 15 g developing solvent: chloroform / 10% ammonia-containing ethanol = 19/1] to give the title compound (77 mg )was gotten. ¹ H-NMR (CDCl ₃ ) δ: 1.23 (3 H, t,
J = 7.0 Hz), 1.31 (3H, t, J = 7.0H
z), 2.08-2.53 (4H, m), 3.07 (4
H, bs), 3.73 (3H, s), 4.12 (2H,
q, J = 7.0 Hz), 4.25 (2H, q, J = 7.
0 Hz), 4.78-4.80 (1H, m), 5.10
(2H, m), 6.61 (1H, s), 7.07 (1
H, d, J = 7.6 Hz), 7.25 (2H, d, J =
8.0 Hz), 7.76 (2H, d, J = 8.0H
z), 8.29 (1H, s)

Example 19 Preparation of N- [4- [2- (4-amino-7-methylpyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoyl] -L-glutamic acid The compound of Example 18 (69 mg) was dissolved in a mixed solution (10 ml) of tetrahydrofuran-water (3: 2) and 1
After adding a specified aqueous sodium hydroxide solution (0.45 ml), the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and when the content reached about 5 ml, the mixture was filtered with a Millipore filter, and the filtrate was neutralized with 1N hydrochloric acid (0.45 ml). The resulting precipitate was collected by filtration, washed successively with ice water, methanol and ether, and dried at 60 ° C. under reduced pressure to give the title compound (22 mg). 0 (2H, m), 3.06-3.16 (2H, m),
3.61 (3H, s), 4.37-4.45 (1H,
m), 6.51 (2H, m), 6.87 (1H, s),
7.36 (2H, d, J = 7.8Hz), 7.81 (2
H, d, J = 7.8 Hz), 8.04 (1H, s),
8.48-8.52 (1H, m)

Example 20 Preparation of N- [4- [3- (4-hydroxy-7-methylpyrrolo [2,3-d] pyrimidin-5-yl) propyl] benzoyl] -L-glutamic acid Similar to Example 11. To methyl 4- [3- (4-hydroxy-7-methylpyrrolo [2,3-d] pyrimidin-5-yl) -1-oxo-2-propenyl] benzoate to give crude 4- [3- (4 -Hydroxy-7-methylpyrrolo [2,3-d] pyrimidin-5-yl) propyl] benzoic acid was obtained. This was subjected to the same reactions as in Example 3 and Example 5 to obtain the title compound. -2.77 (4H, m), 3.58 (3H, s), 4.
35-4.44 (1H, m), 6.81 (1H, s),
7.32 (2H, d, J = 8Hz), 7.83 (2H,
d, J = 8 Hz), 8.43 (1H, s)

Example 21 The following compounds are obtained by a method similar to the production method of Example 1-Example 20. (1) N- [4- [2- (4-hydroxy-7-methylpyrrolo [2,3-d] pyrimidin-5-yl) ethyl]
Benzoyl] -L-glutamic acid (2) N- [4- [3- (4-amino-7-methylpyrrolo [2,3-d] pyrimidin-5-yl) propyl] benzoyl] -L-glutamic acid

Example 22 By applying the same reduction reaction as in Example 9 to the compounds of Examples 19 to 21, the following compounds are obtained. (1) N- [4- [2- (4-amino-7-methyl-
6,7-Dihydro-5H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoyl] -L-glutamic acid (2) N- [4- [3- (4-hydroxy-7-methyl- 6,7-Dihydro-5H-pyrrolo [2,3-d] pyrimidin-5-yl) propyl] benzoyl] -L-glutamic acid (3) N- [4- [2- (4-hydroxy-7-methyl- 6,7-Dihydro-5H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoyl] -L-glutamic acid (4) N- [4- [3- (4-amino-7-methyl-
6,7-Dihydro-5H-pyrrolo [2,3-d] pyrimidin-5-yl) propyl] benzoyl] -L-glutamic acid (5) N- [4- [3- (4-hydroxy-2-methyl- 7-methyl-6,7-dihydro-5H-pyrrolo [2,2
3-d] pyrimidin-5-yl) propyl] benzoyl] -L-glutamic acid (6) N- [4- [2- (4-hydroxy-2-methyl-7-methyl-6,7-dihydro-5H- Pyrrolo [2
3-d] pyrimidin-5-yl) ethyl] benzoyl]
-L-glutamic acid

Example 23 Preparation of N- [4- [2- (2,4-diamino-7H-pyrrolo [2,3-d] pyrimidin-6-yl) ethyl] benzoyl] -L-glutamic acid 4- [ 4- [2- (2,4-Diamino-7H-] obtained from methyl 3,3-dimethoxy-5- (2,4,6-triamino-pyrimidin-5-yl) pentyl] benzoate
Pyrrolo [2,3-d] pyrimidin-6-yl) ethyl]
Methyl benzoate (3.12 g) was subjected to the same reaction as in Example 2, Example 3 and Example 5 to give the title compound (1.9
3 g) was obtained. 8 (4H, brs), 4.32-4.45 (1H,
m), 6.06 (1H, s), 7.33 (2H, d, J
= 8 Hz), 7.79 (2H, d, J = 8 Hz)

Example 24 N- [4- [2- (2,4-diamino-6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-6-yl) ethyl] benzoyl] -L- Production of Glutamic Acid The title compound (0.57 g) was obtained from the compound (1.49 g) of Example 23 by performing the same reduction reaction by replacing Pd—C with platinum oxide as the reduction catalyst in Example 22. .. 3 (3H, m), 2.60-2.76 (2H, m),
2.78-2.95 (1H, m), 3.70-3.88
(1H, m), 4.27-4.42 (1H, m), 6.
15 (2H, brs), 6.29 (2H, brs),
7.08 (1H, brs), 7.33 (2H, d, J =
8 Hz), 7.81 (2H, d, J = 8 Hz), 8.3
5 (1H, d, J = 7.6Hz)

Example 25 Preparation of N- [4- [3- (2,4-diamino-7H-pyrrolo [2,3-d] pyrimidin-6-yl) propyl] benzoyl] -L-glutamic acid Example 23 Similarly to, the title compound (1.89 g) was obtained from methyl 4- [3- (2,4-diamino-7H-pyrrolo [2,3-d] pyrimidin-6-yl) propyl] benzoate (3.26 g). )was gotten. 7 (2H, t, J = 7Hz), 2.70 (2H, t, J
= 7 Hz), 4.30-4.45 (1H, m), 6.1
6 (1H, s), 7.32 (2H, d, J = 8Hz),
7.81 (2H, d, J = 8Hz)

Example 26 N- [4- [3- (2,4-diamino-6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-6-yl) propyl] benzoyl] -L- Production of Glutamic Acid In the same manner as in Example 24, the compound of Example 25 (1.7
The title compound (0.726 g) was obtained from 6 g). -2.32 (2H, m), 2.28 (1H, dd, J =
15.6 Hz), 2.57-2.70 (2H, m),
2.80 (1H, dd, J = 15.9Hz) 3.70-
3.86 (1H, m), 4.24-4.40 (1H,
m), 6.17 (2H, brs), 6.34 (2H, b
rs), 7.04 (1H, brs), 7.29 (2H,
d, J = 8 Hz), 7.78 (2H, d, J = 8H
z), 8.33 (1H, d, J: 7Hz)

Example 27 The following compounds are obtained by a method similar to the production method of Example 1-Example 26. (1) N- [4- [2- (4-hydroxy-7H-pyrrolo [2,3-d] pyrimidin-6-yl) ethyl] benzoyl] -L-glutamic acid (2) N- [4- [3 -(4-Hydroxy-7H-pyrrolo [2,3-d] pyrimidin-6-yl) propyl] benzoyl] -L-glutamic acid (3) N- [4- [2- (4-hydroxy-6,7- Dihydro-5H-pyrrolo [2,3-d] pyrimidine-6-
(4) N- [4- [3- (4-hydroxy-6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidine-6-
(5) N- [4- [2- (2-amino-4-hydroxy-6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidine-6-) (6) N- [4- [3- (2-Amino-4-hydroxy-6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidine-6-))-ethyl] benzoyl] -L-glutamic acid (7) N- [4- [2- (2-amino-4-hydroxy-7-methyl-6,7-dihydro-5H-pyrrolo [2,2) propyl] benzoyl] -L-glutamic acid
3-d] pyrimidin-6-yl) ethyl] benzoyl]
-L-glutamic acid (8) N- [4- [3- (2-amino-4-hydroxy-7-methyl-6,7-dihydro-5H-pyrrolo [2,
3-d] pyrimidin-6-yl) propyl] benzoyl] -L-glutamic acid (9) N- [5- [3- (2-amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidine-6- Ill)
Propyl] -5-thenoyl] -L-glutamic acid

Example 28 N- [4- [N- (2-amino-4-hydroxy-7H
-Pyrrolo [2,3-d] pyrimidin-6-ylmethyl)
Preparation of -N-methylamino] benzoyl] -L-glutamic acid 6- (N, N-dimethylamino) methyl-4-hydroxy-2-octanoylamino-7H-pyrrolo [2,3-
d] Pyrimidine (2.34 g) was dissolved in an ethanol-tetrahydrofuran mixed solution (1: 1,460 ml), dimethylsulfate (0.7 ml) was added, and the mixture was stirred at room temperature for 28 hours. N- (4-methylaminobenzoyl) in the reaction mixture
Diethyl L-glutamate (5.72 g) and 28% sodium methylate in methanol (1.35 g) were added, and the mixture was stirred at room temperature for 66 hours. Silica gel 20 in this solution
g was added and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [500 g of carrier, developing solvent; chloroform: ethanol = 1: 49] to give N-.
[4- [N- (2-Octanoylamino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidin-6-ylmethyl) -N-methylamino] benzoyl] -L-glutamate diethyl was obtained. . The whole amount of this is Example 5
Applying a hydrolysis reaction similar to that of the title compound (0.9
8 g) was obtained. (3H, s), 4.09-4.36 (1H, m), 4.
48 (2H, s), 5.95 (1H, s), 6.78
(2H, d, J = 8Hz), 7.65 (2H, d, J =
8Hz)

Example 29 N- [5- [N- (2-amino-4-hydroxy-7H
-Pyrrolo [2,3-d] pyrimidin-6-ylmethyl)
Preparation of -N-methylamino] -2-thenoyl-L-glutamic acid In the same manner as in Example 28, 6- (N, N-dimethylamino) methyl-4-hydroxy-2-octanoylamino-7H-pyrrolo [ 2,3-d] pyrimidine (1.67
g) and N- (5-methylamino-2-thenoyl) -L-
The title compound (0.54 g) was obtained from diethyl glutamate (4.28 g). (3H, s), 4.13-4.35 (1H, m), 4.
51 (2H, s), 5.97 (1H, s), 6.02
(1H, d, J = 4Hz), 7.54 (1H, d, J =
4Hz)

Example 30 N- [4- [N- (2-amino-4-hydroxy-7H
-Pyrrolo [2,3-d] pyrimidin-5-ylmethyl)
Preparation of -N-methylamino] benzoyl-L-glutamic acid N- [2-amino-4-hydroxy-7-methylpyrrolo [2,3-d] pyrimidine- was prepared in the same manner as in Example 28.
5-yl] -N, N, N-trimethylammonium methyl sulfate (1.74 g) and diethyl N- [4- (N-methylamino) benzoyl] -L-glutamate (0.84 g) were used to give the title compound ( 2.90 g) was obtained. (3H, s), 3.61 (3H, s), 4.10-4.
18 (1H, m), 4.63 (2H, s), 6.77
(1H, s), 7.29 (2H, d, J = 8Hz),
7.80 (2H, d, J = 8Hz)

Example 31 By the method according to Example 28, the following compound is obtained. (1) N- [5- [N- (2-amino-4-hydroxy-7-methylpyrrolo [2,3-d] pyrimidin-5-ylmethyl) -N-methylamino] -2-thenoyl] -L
-Glutamic acid (2) N- [4- [N- (2-amino-4-hydroxy-7-methylpyrrolo [2,3-d] pyrimidin-5-ylmethyl) -N-propargylamino] benzoyl]-
L-glutamic acid (3) N- [4- [N- (2-amino-4-hydroxy-7-methylpyrrolo [2,3-d] pyrimidin-6-ylmethyl) -N-propargylamino] benzoyl]-
L-glutamic acid

Example 32 N- [4- [2- (2,4-diaminothieno [2,3-
d] pyrimidin-5-yl) ethyl] benzoyl] -L
-Production of glutamic acid 4- [2- (2,4-diamino-thieno [2,3-d]
Pyrimidin-5-yl) ethyl] methyl benzoate (0.
26 g) was subjected to the same reaction as in Example 2, Example 3 and Example 5 to give the title compound (0.21 g). ． 96-3.08 (2H, brt), 3.12-3.2.
4 (2H, bdt), 4.34-4.47 (1H,
m), 6.54 (1H, s), 7.33 (2H, d, J
= 8.4 Hz), 7.79 (2H, d, J = 8.4)

Example 33 The following compounds were obtained by a method similar to the production method of Example 1-Example 32. (1) N- [4- [3- (2,4-diamino-thieno [2,3-d] pyrimidin-5-yl) propyl] benzoyl] -L-glutamic acid (2) N- [4- [3 -(2-Amino-4-hydroxythieno [2,3-d] pyrimidin-6-yl) propyl] benzoyl] -L-glutamic acid (3) N- [4- [3- (2-amino-4-hydroxy) Furo [2,3-d] pyrimidin-6-yl) propyl]
Benzoyl] -L-glutamic acid (4) N- [4- [3- (2-amino-4-hydroxy-6,7-dihydro-5H-cyclopentapyrimidine-
5-yl) propyl] benzoyl] -L-glutamic acid (5) N- [4- [3- (2-amino-4-hydroxy-6,7-dihydro-5H-cyclopentapyrimidine-
6-yl) propyl] benzoyl] -L-glutamic acid

Example 34 N- [4- [3- (4-hydroxy-2-methyl-7-
Preparation of methylpyrrolo [2,3-d] pyrimidin-5-yl) propyl] benzoyl] -L-glutamic acid 4- [3- (4-Hydroxy-2-methyl-7-methylpyrrolo [2,3-d] pyrimidine- Methyl 5-yl) propyl] benzoate (0.509 g) was subjected to the same reaction as in Example 2, Example 3 and Example 5 to obtain the title compound (0.293 g). ¹ H-NMR (Me ₂ SO-d ₆ + D ₂ O) δ;
79-2.20 (4H, m), 2.34 (3H, s),
2.36 (2H, t, J = 7Hz), 2.73 (2H,
t, J = 8 Hz), 2.81 (2H, t, J = 8H
z), 3.62 (3H, s) 4.35-4.46 (1
H, m), 6.78 (1H, s), 7.31 (2H,
d, J = 8 Hz), 7.81 (2H, d, J = 8 Hz)

Example 35 N- [4- [2- (4-hydroxy-2-methyl-7-
Preparation of methylpyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoyl] -L-glutamic acid 4- [3
Methyl-(4-hydroxy-2-methyl-7-methylpyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoate (0.749 g) was used as in Example 2, Example 3 and Example 5. The title compound (0.48
6 g) was obtained. ^{_{1 H-NMR (Me 2 SO}} -d 6 + D 2 O) δ; 1.9
0-2.16 (2H, m), 2.31 (3H, s),
2.33 (2H, t, J = 7Hz), 2.75-3.0
3 (4H, m), 3.58 (3H, s), 4.32-
4.47 (1H, m), 6.76 (1H, s) 7.30
(2H, d, J = 8Hz), 7.81 (2H, d, J =
8Hz)

Example 36 N- [4- [2- (2-amino-4-hydroxy-7H
-Preparation of pyrrolo [2,3-d] pyrimidin-6-yl) ethyl] benzoyl] -L-glutamic acid 4- [2- (2-amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidine Methyl-6-yl) ethyl] benzoate (0.812 g) was subjected to the same reaction as in Example 2, Example 3 and Example 5 to give the title compound (0.5
89 g) was obtained. ^{_{1 H-NMR (Me 2 SO}} -d 6 + D 2 O) δ; 1.7
9-1.98 (2H, m), 2.34 (2H, t, J =
7 Hz), 2.76-3.02 (4H, m), 4.32
-4.45 (1H, m), 6.01 (1H, s), 7.
25 (2H, d, J = 8Hz), 7.74 (2H, d,
J = 8Hz)

Example 37 N- [4- [2- (2-amino-4-hydroxy-7H
-Preparation of pyrrolo [2,3-d] pyrimidin-6-yl) propyl] benzoyl] -L-glutamic acid 4- [2- (2-amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidine Methyl-6-yl) propyl] benzoate (0.523 g) was subjected to the same reaction as in Example 2, Example 3 and Example 5 to give the title compound (0.
318 g) was obtained. ¹ H-NMR (Me ₂ SO-d ₆ + D ₂ O) δ; 1.8
1-2.16 (4H, m) 2.30 (2H, t, J =
7.4 Hz), 2.52-2.85 (4H, m), 4.
38-4.53 (1H, m), 6.04 (1H, s),
7.27 (2H, d, J = 8Hz), 7.77 (2H,
d, J = 8Hz)

Example 38 N- [4- [2- (2-amino-4-hydroxy-7-
Preparation of methylpyrrolo [2,3-d] pyrimidin-6-yl) ethyl] benzoyl] -L-glutamic acid 4- [2- (2-amino-4-hydroxy-7-methylpyrrolo [2,3-d] pyrimidine- 6-yl) ethyl]
Methyl benzoate (0.425 g) was used in Example 2 and Example 3.
Then, the mixture was subjected to a reaction similar to that in Example 5 to obtain the title compound (0.310 g). ¹ H-NMR (Me ₂ SO-d ₆ + D ₂ O) δ;
77-1.99 (2H, m), 2.33 (2H, t, J
= 7 Hz), 2.72-3.03 (4H, m), 3.6
0 (3H, s), 4.33-4.47 (1H, m),
6.00 (1H, s), 7.26 (2H, d, J = 8H
z), 7.75 (2H, d, J = 8Hz)

Example 39 N- [4- [2- (2-amino-4-hydroxy-7-
Methylpyrrolo [2,3-d] pyrimidin-6-yl) propyl] benzoyl] -L-glutamic acid Preparation 4- [2- (2-Amino-4-hydroxy-7-methylpyrrolo [2,3-d] pyrimidine- Methyl 6-yl) propyl] benzoate (0.341 g) was subjected to the same reaction as in Example 2, Example 3 and Example 5 to obtain the title compound (0.232 g). ¹ H-NMR (Me ₂ SO-d ₆ + D ₂ O) δ; 1.8
0-2.14 (4H, m), 2.31 (2H, t, J =
7.4 Hz), 2.51-2.84 (4H, m), 3.
58 (3H, s), 4.36-4.50 (1H, m),
5.99 (1H, s), 7.27 (2H, d, J, = 8
Hz), 7.78 (2H, d, J = 8Hz)

Example 40 N- [4- [2- (2-amino-4-hydroxy-7H
-Preparation of pyrrolo [2,3-d] pyrimidin-6-yl) ethyl] -2-thenoyl] -L-glutamic acid 4- [2- (2-amino-4-hydroxy-7H, pyrrolo [2,3-] When d] pyrimidin-6-yl) ethyl] thiophene-2-carboxylate methyl (0.621 g) was subjected to the same reaction as in Example 2, Example 3 and Example 5,
The title compound (0.346g) was obtained. ^{_{1 H-NMR (Me 2 SO}} -d 6 + D 2 O) δ; 1.7
9.2.01 (2H, m), 2.35 (2H, t, J =
7.4 Hz), 2.74-3.01 (4 H, m), 4.
37-4.51 (1H, m), 5.98 (1H, s),
6.81 (1H, d, J = 3.6Hz) 7.62 (1
H, d, J = 3.6Hz)

Example 41 Preparation of N- [4- [2- (2-amino-4-hydroxythieno [2,3-d] pyrimidin-5-yl) ethyl] benzoyl] -L-glutamic acid 4- [2 -(2-amino-4-hydroxythieno [2,
Methyl 3-d] pyrimidin-5-yl) ethyl] benzoate (0.824 g) was subjected to the same reaction as in Example 2, Example 3 and Example 5 to give the title compound (0.433 g).
was gotten. ¹ H-NMR (Me ₂ SO-d ₆ ) δ; 1.85-2.
18 (2H, m), 2.36 (2H, t, J = 7H
z), 2.88-3.13 (4H, m), 4.34-
4.47 (1H, m), 6.55 (1H, s), 7.3
2 (2H, d, J = 8Hz), 7.81 (2H, d, J
= 8 Hz)

Example 42 Preparation of N- [4- [2- (2-amino-4-hydroxythieno [2,3-d] pyrimidin-5-yl) propyl] benzoyl] -L-glutamic acid 4- [2 -(2-amino-4-hydroxythieno [2,
Methyl 3-d] pyrimidin-5-yl) propyl] benzoate (0.721 g) was subjected to the same reaction as in Example 2, Example 3 and Example 5 to give the title compound (0.356).
g) was obtained. ^{_{1 H-NMR (Me 2 SO}} -d 6 + D 2 O) δ; 1.7
5-2.12 (4H, m), 2.35 (2H, t, J =
7Hz), 2.52-2.93 (4H, m), 4.35
-4.49 (1H, m), 6.53 (1H, s), 7.
36 (2H, d, J = 8Hz), 7.88 (2H, d,
J = 8Hz)

Example 43 Preparation of N- [4- [2- (2-amino-4-hydroxythieno [2,3-d] pyrimidin-6-yl) ethyl] benzoyl] -L-glutamic acid 4- [2 -(2-amino-4-hydroxythieno [2,
Methyl 3-d] pyrimidin-6-yl) ethyl] benzoate (0.396 g) was subjected to the same reaction as in Example 2, Example 3 and Example 5 to give the title compound (0.218 g).
was gotten. ¹ H-NMR (Me ₂ SO-d ₆ + D ₂ O) δ; 1.8
1-2.05 (2H, m), 2.32 (2H, t, J =
7 Hz), 2.90-3.13 (1H, m), 4.33
-4.48 (1H, m), 6.24 (1H, s), 7.
38 (2H, d, J = 8Hz), 7.89 (2H, d,
J = 8Hz)

Example 44 Preparation of N- [4- [2- (2-amino-4-hydroxyfuro [2,3-d] pyrimidin-6-yl) ethyl] benzoyl] -L-glutamic acid 4- [2 -(2-amino-4-hydroxyfuro [2,3
Methyl -d] pyrimidin-6-yl) ethyl] benzoate (0.654 g) was used in Example 2, Example 3 and Example 5.
Subjected to a reaction similar to the above, the title compound (0.428 g) was obtained. ¹ H-NMR (Me ₂ SO-d ₆ + D ₂ O) δ; 1.8
4-2.08 (2H, m) 2.34 (2H, t, J = 7)
Hz), 2.94-3.15 (4H, m), 4.36-
4.49 (1H, m), 6.19 (1H, s), 7.3
3 (2H, d, J = 8Hz), 7.90 (2H, d, J
= 8 Hz)

Example 45 N- [4- [N- (2-amino-4-hydroxy-7-
Preparation of methylpyrrolo [2,3-d] pyrimidin-6-ylmethyl) -N-methylamino] benzoyl] -L-glutamic acid N- [2-amino-4-hydroxy-7-methylpyrrolo was prepared in the same manner as in Example 28. [2,3-d] pyrimidine-
6-yl] -N, N, N-trimethylammonium methylsulfate (0.521 g) and N- [4- (N-
Methylamino) benzoyl] -diethyl L-glutamate (0.576 g) and the title compound (0.152
g) was obtained. ^{_{1 H-NMR (Me 2 SO}} -d 6 + D 2 O) δ; 1.7
4-2.12 (2H, m), 2.26 (2H, t, J =
7Hz), 3.02 (3H, s), 3.57 (3H,
s), 4.12, 4.38 (1H, m), 4.46 (2
H, s), 5.98 (1H, s), 6.77 (2H,
d, J = 8 Hz), 7.66 (2H, d, J = 8 Hz)

Example 46 N- [4- [2- (2-amino-4-hydroxy-6,6
Preparation of 7-dihydro-5H-cyclopentapyrimidin-5-yl) ethyl] benzoyl] -L-glutamic acid 4- [2- (2-amino-4-hydroxy-6,7-dihydro-5H-cyclopentapyrimidine- Methyl 5-yl) ethyl] benzoate (0.470 g) was subjected to the same reaction as in Example 2, Example 3 and Example 5 to obtain the title compound (0.289 g). ¹ H-NMR (Me ₂ SO-d ₆ + D ₂ O) δ; 1.3
8-2.13 (8H, m), 2.20-2.55 (4
H, m), 2.58-2.79 (3H, m), 4.23.
-4.39 (1H, m), 7.31 (2H, d, J = 8)
Hz), 7.81 (2H, d, J = 8Hz)

Example 47 N- [4- [2- (2-amino-4-hydroxy-6,6
Preparation of 7-dihydro-5H-cyclopentapyrimidin-6-yl) ethyl] benzoyl] -L-glutamic acid 4- [2- (2-amino-4-hydroxy-6,7-dihydro-5H-cyclopentapyrimidine- Methyl 6-yl) ethyl] benzoate (0.392 g) was subjected to the same reaction as in Example 2, Example 3 and Example 5 to obtain the title compound (0.241 g). ¹ H-NMR (Me ₂ SO-d ₆ + D ₂ O) δ; 1.5
4-2.08 (5H, m), 2.10-2.43 (4
H, m), 2.47-2.71 (4H, m), 4.19.
-4.40 (1H, m), 7.30 (2H, d, J = 8)
Hz), 7.79 (2H, d, J = 8Hz)

[0105]

INDUSTRIAL APPLICABILITY According to the present invention, there is provided a novel compound having an inhibitory action on an enzyme utilizing folic acid and its related compound as a substrate, and therefore usable as an antitumor agent.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Office reference number FI technical display location C07D 471/04 104 Z 8415-4C 491/048 7019-4C 495/04 105 105 Z 7329-4C A 7329 -4C

Claims (5)

[Claims] 1. A general formula: [Wherein the ring A is a 5-membered ring, and in the case of a pyrrole or pyrroline ring, (i) has no active proton on the nitrogen atom or (ii) is bonded to Z at the α-position, B is a substituent has optionally may be divalent cyclic or chain group, one Q ¹ and Q ² are the N other is N or CH, Y is a hydrogen atom, a halogen atom or a carbon, nitrogen, oxygen or sulfur atom, , X is an amino group, a hydroxyl group or a mercapto group, and Z is a carbon atom which may have a substituent, or a carbon atom which may have a substituent and a substituent. A straight-chain 2 having 2 to 5 atoms, which is composed of one hetero atom which may be
As the valent group, -COOR ¹ and -COOR ² are the same or different and each represents a carboxyl group which may be esterified. ] The compound or its salt represented by these. 2. A general formula: [Wherein the ring A is a 5-membered ring, and in the case of a pyrrole or pyrroline ring, (i) has no active proton on the nitrogen atom or (ii) is bonded to Z at the α-position, B is a substituent has optionally may be divalent cyclic or chain group, one Q ¹ and Q ² are the N other is N or CH, Y is a hydrogen atom, a halogen atom or a carbon, nitrogen, oxygen or sulfur atom, , X is an amino group, a hydroxyl group or a mercapto group, and Z is a carbon atom which may have a substituent, or a carbon atom which may have a substituent and a substituent. A straight-chain 2 having 2 to 5 atoms, which is composed of one hetero atom which may be
A valence group is shown respectively. ] Or a reactive derivative at the carboxyl group thereof, represented by the general formula: [In formula, -COOR < ¹ > and -COOR < ² > shows the same or different carboxyl group which may be esterified. ] The compound represented by these is reacted, The manufacturing method of the compound or its salt of Claim (1) characterized by the above-mentioned. 3. An antitumor composition containing the compound according to claim (1) or a salt thereof. 4. A general formula: [Wherein the ring A is a 5-membered ring, and in the case of a pyrrole or pyrroline ring, (i) has no active proton on the nitrogen atom or (ii) is bonded to Z at the α-position, B is a substituent has optionally may be divalent cyclic or chain group, one Q ¹ and Q ² are the N other is N or CH, Y is a hydrogen atom, a halogen atom or a carbon, nitrogen, oxygen or sulfur atom, , X is an amino group, a hydroxyl group or a mercapto group, and Z is a carbon atom which may have a substituent, or a carbon atom which may have a substituent and a substituent. A straight-chain 2 having 2 to 5 atoms, which is composed of one hetero atom which may be
A valent group and —COOR ³ each represent an optionally esterified carboxyl group. ] The compound or its salt represented by these. 5. The compound or salt thereof according to claim 1, wherein ring A is an N-substituted pyrrole or an N-substituted pyrroline ring.