JPH06172358A - Condensed pyrimidine derivative, it production and use - Google Patents

Abstract

PURPOSE:To obtain a new compound useful as a thymidylate synthase inhibitor and an antitumor agent. CONSTITUTION:A compound of formula I [ring A is (substituted) pyrroline ring; B is (substituted) bifunctional 5-to 6-membered homocyclic or heterocyclic ring; Y is H, halogen or group through C, N or S; R<1> and R<2> are H or (substituted) lower pydrocarbon; COOR<3> and COOR<4> are (esterified) carboxy; (n) is 1-6] such as N-[5-(2-amino-4-hydroxy-7H-pyrrolo[2,3-alpha]pyrimidin-5-yl) methyl-2-thenoyl]-L-glutamic acid. The compound of formula I is obtained by reacting a compound of formula II with a compound of formula III.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a thymidylate synthase inhibitor, a novel condensed pyrimidine derivative which is an active ingredient thereof, a process for producing the same and an intermediate thereof.

[0002]

BACKGROUND ART 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. Especially 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 pyrimidine synthesis system. Usually, in order for folic acid to exert its biological activity, it must undergo reduction in two steps and be converted into an active coenzyme form.
The enzyme that controls the second step (dihydrofolate reductase:
Amethopterin (methotrexate: MTX) and its peripheral compounds are known as drugs that strongly bind to DHFR) and suppress the reduction of dihydrofolate to tetrahydrofolate. These drugs impair DNA synthesis,
As a result, it causes cell death, so that it occupies a clinically important position as a therapeutic drug mainly for leukemia. Furthermore, with the remarkable progress in the field of biochemistry, especially in the field of folic acid in cancer research, it is a novel DHFR inhibitor 10
-Deaza aminopterin antitumor agent (10-ethyl-10-deaza aminopterin: 10-EDAM) [NCI Monograph] 5 , 127 (198)
7)] or an aminopteroyl ornithine derivative (N
(α)-(4-Amino-4-deoxypteroyl) -N (δ) -hemiphthaloyl-L-ornithine: PT523) [USP 4,767,76
1], and a competitive inhibitor that targets an enzyme different from DHFR, that is, the main mechanism of action is glycinamide ribonucleotide transformylase inhibition 5-
Deazatetrahydroaminopterin antitumor agent (5,10-
Dideaza-5,6,7,8-tetrahydroaminopterin: DD
ATHF) [Journal of Medicinal Chemistry 28 , 914
(1985)] or a quinazoline antitumor agent whose main mechanism of action is thymidylate synthase inhibition (2-desamino-2-methyl-10-propargyl-5,8-dideazafolate:
DMPDDF) [British Journal of
Cancer (British Journal of Cancer) 58 , 241 (1
988)] and the like are also reported. However, all these compounds do not fall under the category of a heterocyclic compound group having a condensed ring of 6-membered ring and 6-membered ring (6-6 condensed ring) as a basic skeleton. On the other hand, not a condensed ring of a 6-membered ring and a 6-membered ring, but a condensed ring formed of a 6-membered ring and a 5-membered ring (6-5 condensed ring),
That is, the pyrrolo [2,3-d] pyrimidine ring is
It has been reported that the anti-tumor activity of antifolates is also present [USP4, 997,838, EP-A-400,562, EP-A
-402,903, EP-A-418,924, EP-A-431,953, EP-A-434,42
6, EP-A-438,261, USP4,996,206, USP4,895,946, EP-A-4
92,316 and Japanese Patent Application No. 03-202,042].

[0003]

DISCLOSURE OF INVENTION Problems to be Solved by the Invention At present, what is particularly desired in the field of cancer therapy 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 the inhibition of dihydrofolate reductase, is currently widely used clinically, but it has relatively satisfactory toxicity and is not very effective against solid cancer. Not listed. Furthermore, the acquisition resistance to MTX is becoming a big problem. As a resistance mechanism of MTX, DHF
These include increased R levels, decreased cell membrane drug transport capacity, and decreased levels of folate polyglutamate synthase (FPGS). By overcoming at least one of these resistance factors, it is expected to develop a drug showing an excellent therapeutic effect also on MTX resistant cancer.

[0004]

[Means for Solving the Problems] The inventors of the present invention have conducted intensive studies in view of the above circumstances, and as a result, USP 4,997,838, EP-A
-400,562, EP-A-418,924, EP-A-431,953, EP-A-434,42
6, EP-A-438,261, EP-A-492,316, USP 4,996,206 and Japanese Patent Application No. 03-202,042, a fused pyrimidine derivative having a different chemical structure, thymidyl folic acid and its related compounds involved It has an unexpectedly excellent inhibitory action as an acid synthase and exerts high selective toxicity to various tumor cells (especially human lung cancer cells) and MTX.
The present invention has been completed by discovering that resistance is also overcome and an excellent therapeutic effect is exhibited. That is, the present invention provides (1) the general formula:

[Chemical 7] [Wherein, ring A is a pyrrole or pyrroline ring which may have a substituent, B is a divalent 5- or 6-membered homocyclic or heterocyclic group which may have a substituent, Y Is a hydrogen atom,
A halogen atom or a group via a carbon, nitrogen or sulfur atom, R ¹ and R ² are the same or different and are a hydrogen atom or a lower hydrocarbon group which may have a substituent, -C
OOR ³ and —COOR ₄ are the same or different and are optionally esterified carboxy groups, and n is 1 to 6
And R ³ may be different from each other in n repeating units. ] The compound or its salt represented by these,

(2) General formula,

[Chemical 8] [In the formula, the A ′ ring represents an N-substituted pyrrole or pyrroline ring, and other symbols have the same meanings as described above. ] The compound or its salt represented by these, (3) N- [4- (2-amino-4-hydroxy-7H
-Pyrrolo [2,3-d] pyrimidin-5-yl) methylbenzoyl] -L-glutamic acid, or a salt or ester thereof, (4) general formula,

[Chemical 9] [The symbols in the formulas have the same meanings as described above. ] Or a reactive derivative at the carboxy group thereof represented by the general formula

[Chemical 10] [The symbols in the formulas have the same meanings as described above. ] The compound represented by these are reacted, The manufacturing method of the compound of (1) description, (5) General formula,

[Chemical 11] [The symbols in the formulas have the same meanings as described above. ] Or a salt or ester thereof, and (6) a thymidylate synthase inhibitor containing compound [I] or a salt thereof.

In the above formula, the compounds [I], [I '] and [II] 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 12] For convenience of presentation, throughout this specification, the hydroxy form is described and the corresponding nomenclature is adopted,
It also includes an oxo form that is a tautomer. Also,
The compounds [I], [I '], [II] and [III] may have an asymmetric center, but the partial structural formulas in [I], [I']

[Chemical 13] Other than the absolute configuration of S (L), the other absolute configuration of the asymmetric center may be any of S, R, or RS. In this case, diastereoisomers exist, but if necessary, they can be easily separated by ordinary separation and purification means. All the above diastereoisomers which can be separated in this way are within the scope of the invention.

In the above formula, the pyrrole ring or the pyrroline ring which may have a substituent represented by ring A has 1 or 2 substituents at substitutable positions on the nitrogen atom or carbon atom. Examples of such a substituent include, for example, an alkyl group having 1 to 4 carbon atoms (eg, methyl, ethyl, propyl, iso-propyl group), an alkenyl group having 2 to 4 carbon atoms (eg, vinyl, 1 -Methyl vinyl, 1-propenyl, aryl, allenyl group), carbon number 2 to 4
An alkynyl group (eg, ethynyl, 1-propynyl, 2-
Propynyl group), C _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, p-chlorobenzoyl, p-methoxybenzoyl, halogenobenzoyl such as 3,4,5-trimethoxybenzoyl group or mono-, di- or tri-C _1-4
Alkoxybenzoyl), cyano group, carboxy group, carbamoyl group, nitro group, hydroxy group, hydroxy-
C _1-4 alkyl group (eg, hydroxymethyl group, hydroxyethyl group), C _1-4 alkoxy-C _1-4 alkyl group (methoxymethyl group, ethoxymethyl group, methoxyethyl group, ethoxyethyl group), carbon number An alkoxy group having 1 to 4 (eg, methoxy, ethoxy, propoxy group), a mercapto group, an alkylthio group having 1 to 4 carbon atoms (eg, methylthio, ethylthio, propylthio group), an amino group,
Mono - or di -C _1-4 alkylamino group (e.g., methylamino, ethylamino, dimethylamino, diethylamino group), to 4 alkanoylamino group 1 carbon atoms (eg, formamide, acetamide group), a phenyl group, a substituted Phenyl group (eg, halogenophenyl such as p-chlorophenyl, p-methoxyphenyl, 3,4,5-trimethoxyphenyl or mono-, di- or tri-C _1-4
Alkoxyphenyl), benzyl group or substituted benzyl group (eg, halogenobenzyl such as p-chlorobenzyl, mono-, di- or tri-C _1-4 alkoxybenzyl such as p-methoxybenzyl, diphenylmethyl group)
And the like, and more preferably, the above-mentioned alkyl group having 1 to 4 carbon atoms, alkenyl group having 2 to 4 carbon atoms, alkynyl group having 2 to 4 carbon atoms, alkanoyl group having 1 to 4 carbon atoms, and benzoyl group. A substituted benzoyl group, a hydroxy-C _1-4 alkyl group, a C _1-4 alkoxy-C _1-4 alkyl group, a benzyl group or a substituted benzyl group.

A and

[Chemical 14] The bond with is either at the nitrogen atom of the pyrrole or pyrroline ring or at a bondable position on the carbon atom.

[Chemical 15] May have a bond at the β (beta) position of the pyrrole ring or the pyrroline ring.

B represents a divalent 5- or 6-membered homocyclic or heterocyclic group which may have a substituent, and two bonds are out of non-adjacent positions in the ring. Is preferred. B
As the homocyclic group represented by, for example, a divalent 5- or 6-membered cyclic hydrocarbon group is used, and as such a hydrocarbon group, a 5- or 6-membered cyclic aliphatic hydrocarbon group (eg, cycloalkyl group) is used. Pentylene, cyclohexylene) or phenylene is used. The heterocyclic group represented by B includes 1 to 3 hetero atoms (eg, N,
A divalent 5- or 6-membered heterocyclic group containing O, S) is used. Examples of the 5-membered ring group represented by B include:
1,3- or 3,5-cyclopentadiene-1,3-
Irene, cyclopentene- (1,3-, 1,4- or 3,5-) ylene, 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-ylene or their partially reduced type (one part of the multiple bond is reduced) or fully reduced type compound (multiplexed) Those in which all the bonds are reduced) are used, and examples of the 6-membered ring group 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-) ylene, pyran- (2,4-, 2,5-,
2,6-, 3,5-, 3,6- or 4,6-) ylene, pilatin- (2,5- or 2,6-) ylene, pyrimidine- (2,4- or 2,5-) Irene, pyridatin-3,5-ylene, or their partially reduced or fully reduced compounds are used. Particularly preferable examples of B include phenyl-1,4-ylene, thiophene-2,5-ylene, thiazole-2,5-ylene, pyridine-2,5-ylene and the like. The divalent 5- or 6-membered homo or heterocyclic group represented by B may have 1 or 2 substituents at substitutable positions. Examples of the substituent include an alkyl group having 1 to 4 carbon atoms (eg, methyl, ethyl, propyl, iso-propyl group), an alkenyl group having 2 or 4 carbon atoms (eg, vinyl, 1-methylvinyl, 1 -Propenyl, aryl, allenyl groups), alkynyl groups having 2 or 4 carbon atoms (ethynyl,
1-propynyl, 2-propynyl group), C _3-6 cycloalkyl group (eg, cyclopropyl group), halogen atom
(Eg chlorine, bromine, fluorine, iodine), hydroxy group,
C _1-4 alkoxy group (eg, methoxy group), di-C _1-4 alkylamino group (eg, dimethylamino group), halogeno-
C _1-4 alkyl group (eg, trifluoromethyl group), oxo group, C _1-4 acyl group (eg, formyl group), C _1-4 alkoxy-C _1-4 alkyl group (eg, methoxymethyl, 2 -Ethoxyethyl group) and the like are used.

As the halogen atom represented by Y, fluorine, chlorine, bromine or iodine is used. The group represented by Y through a carbon, nitrogen, oxygen or sulfur atom is a cyano group, a carboxy group, a carbamoyl group, an amino group, a nitro group, a hydroxy group, a mercapto group or a lower hydrocarbon group, for example, having 1 to 4 carbon atoms. Alkyl groups (eg, methyl, ethyl, propyl, iso-propyl groups),
Alkenyl group having 2 or 4 carbon atoms (eg, vinyl, 1-methylvinyl, 1-propenyl, aryl, allenyl group), alkynyl group having 2 or 4 carbon atoms (eg, ethynyl, 1-propynyl, 2-propynyl group) And C _3-6 cycloalkyl group (eg, cyclopropyl group), etc.
_{It may be} a _6-10 aryl group (eg, phenyl group, naphthyl group), and is a 5- or 6-membered heterocyclic group containing 1 to 4 hetero atoms such as N, S, O (eg, pyrrolyl, imidazolyl, Pyrazolyl, tenyl, furyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, pyridyl, pyranyl, pyrazinyl, pyrimidinyl, pyridatinyl or their partially reduced or fully reduced groups, dioxolanyl, piperidino, morpholino, N-methylpiperazinyl, N -Ethylpiperazinyl, dioxanyl) and the like. 1 to 2 when Y is a lower hydrocarbon group, an aryl group or a 5- or 6-membered heterocyclic group
May have one or more substituents, and examples of such a substituent include an alkyl group having 1 to 4 carbon atoms (eg, methyl, ethyl, propyl, iso-propyl group), an alkenyl having 2 or 4 carbon atoms. Groups (eg vinyl, 1-methyl vinyl,
1-propenyl, aryl, allenyl group), alkynyl group having 2 or 4 carbon atoms (eg, ethynyl, 1-propynyl, 2
-Propynyl group) or C _3-8 cycloalkyl group (eg,
In addition to cyclopropyl group, etc., halogen atom (eg, fluorine), hydroxy group, oxo group, C _1-4 alkoxy group (eg, methoxy group), di-C _1-4 alkylamino group (eg, dimethylamino) , Diethylamino group), halogeno-C _1-4 alkyl group (eg, trifluoromethyl group), C
_1-4 acyl group (eg, formyl group), hydroxy-C _1-4 alkyl group (eg, hydroxymethyl, 2-hydroxyethyl group), C _1-4 alkoxy-C _1-4 alkyl group (eg, methoxymethyl) , 2-ethoxyethyl group) and the like are used. The group via a carbon, nitrogen, oxygen or sulfur atom represented by Y may be an alkoxy group, an alkylthio group, an alkylcarbonylamino group or an alkylcarbonyloxy group, and the alkyl moiety of these groups is represented by Y The groups described in detail in the above lower hydrocarbon group and the like are used as they are.

The group represented by Y via a carbon, nitrogen, oxygen or sulfur atom may be an aryloxy group, an arylthio group, an aroylamino group and an aroyloxy group, and the aryl moiety of these groups is represented by the above Y. The C _6-10 aryl group and the like shown are used, for example, a phenyl group, a naphthyl group and the like are frequently used. Furthermore Y
The group having a carbon, nitrogen, oxygen, or sulfur atom represented by may be a heterocyclic oxy group, a heterocyclic thio group, a heterocyclic carbonylamino group, or a heterocyclic carbonyloxy group. The groups represented by the above 5- or 6-membered heterocyclic groups represented by Y and Y are used as they are. The group via 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 the above lower hydrocarbon group represented by Y, An aryl group,
Alternatively, a 5- or 6-membered heterocyclic group is used as it is.
The lower hydrocarbon group represented by R ¹ and R ^2, which may have a substituent, has a carbon number of 1 or less.
To 4 alkyl groups (eg, methyl, ethyl, propyl, iso-propyl groups), alkenyl groups having 2 or 4 carbon atoms (eg, vinyl, 1-methylvinyl, 1-propenyl, aryl, allenyl groups), carbon numbers 2 or 4 alkynyl groups (eg, ethynyl, 1-propynyl, 2-propynyl groups),
A C _3-6 cycloalkyl group (eg, cyclopropyl group) or the like is used. The lower hydrocarbon group for R ¹ and R ² may have 1 or 2 substituents, and examples of such a substituent include an alkyl group having 1 to 4 carbon atoms (eg, methyl, ethyl, Propyl, iso-propyl group), alkenyl group having 2 or 4 carbon atoms (eg vinyl, 1-methylvinyl,
1-propenyl, aryl, allenyl group), alkynyl group having 2 or 4 carbon atoms (eg, ethynyl, 1-propynyl, 2
-Propynyl group) or C _3-8 cycloalkyl group (eg,
In addition to cyclopropyl group, etc., halogen atom (eg, fluorine), hydroxy group, oxo group, C _1-4 alkoxy group (eg, methoxy group), di-C _1-4 alkylamino group (eg, dimethylamino, Diethylamino group), halogeno-C _1-4 alkyl group (eg, trifluoromethyl group), C
_1-4 acyl group (eg, formyl group), hydroxy-C _1-4 alkyl group (eg, hydroxymethyl, 2-hydroxyethyl group), C _1-4 alkoxy-C _1-4 alkyl group (eg, methoxymethyl) , 2-ethoxyethyl group) amino group, nitro group and the like are used. Examples of the optionally esterified carboxy group represented by —COOR ³ and —COOR ⁴ include a lower alkyl group having 1 to 5 carbon atoms, an optionally substituted benzyl group or an optionally substituted group. A carboxy group esterified with a phenyl group which may be present is used. Examples of the lower alkyl group include methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, sec-pentyl, neo-pentyl, te
Examples of benzyl optionally substituted by rt-pentyl and the like include benzyl such as benzyl, nitrobenzyl, methoxybenzyl and the like, or a benzyl group substituted with 1 to 3 C _1-4 alkoxy, and the like. Examples of the phenyl which may have a substituent include phenyl such as phenyl, nitrophenyl, methoxyphenyl and the like, or a phenyl group substituted by 1 to 3 C _1-4 alkoxy.

Preferred examples of the compound [I] include the following compounds. 1) N- [4- (2-amino-4-hydroxy-7H-
Pyrrolo [2,3-d] pyrimidin-5-yl) methyl-
2-Fluorobenzoyl] -L-glutamic acid 2) N- [4- (2-amino-4-hydroxy-7H
-Pyrrolo [2,3-d] pyrimidin-5-yl) methyl-2-chlorobenzoyl] -L-glutamic acid 3) N- [4- (2-amino-4-hydroxy-7H
-Pyrrolo [2,3-d] pyrimidin-5-yl) methyl-
3-Fluorobenzoyl] -L-glutamic acid 4) N- [4- (2-amino-4-hydroxy-7H
-Pyrrolo [2,3-d] pyrimidin-5-yl) methyl-3-chlorobenzoyl] -L-glutamic acid 5) N- [5- (2-amino-4-hydroxy-7H
-Pyrrolo [2,3-d] pyrimidin-5-yl) methyl-2-thenoyl] -L-glutamic acid 6) N-[[5- (2-amino-4-hydroxy-7
H-pyrrolo [2,3-d] pyrimidin-5-yl) methylthiazolo-2-yl] carbonyl] -L-glutamic acid 7) N- [4- (4-hydroxy-2-methyl-7H)
-Pyrrolo [2,3-d] pyrimidin-5-yl) methylbenzoyl] -L-glutamic acid 8) N- [4- (4-hydroxy-2-methyl-7H)
-Pyrrolo [2,3-d] pyrimidin-5-yl) methyl-2-fluorobenzoyl] -L-glutamic acid 9) N- [4- (4-hydroxy-2-methyl-7H)
-Pyrrolo [2,3-d] pyrimidin-5-yl) methyl-2-chlorobenzoyl] -L-glutamic acid 10) N- [4- (4-hydroxy-2-methyl-7H)
-Pyrrolo [2,3-d] pyrimidin-5-yl) methyl-
3-Fluorobenzoyl] -L-glutamic acid

11) N- [4- (4-hydroxy-2-
Methyl-7H-pyrrolo [2,3-d] pyrimidine-5-
Iyl) methyl-3-chlorobenzoyl] -L-glutamic acid 12) N- [5- (4-hydroxy-2-methyl-7H
-Pyrrolo [2,3-d] pyrimidin-5-yl) methyl-2-thenoyl] -L-glutamic acid 13) N-[[5- (4-hydroxy-2-methyl-7
H-pyrrolo [2,3-d] pyrimidin-5-yl) methylthiazolo-2-yl] carbonyl] -L-glutamic acid 14) N- [4- (2-amino-4-hydroxy-7H
-Pyrrolo [2,3-d] pyrimidin-5-yl) methyl-2-fluorobenzoyl] -L-diglutamic acid 15) N- [4- (2-amino-4-hydroxy-7H
-Pyrrolo [2,3-d] pyrimidin-5-yl) methyl-
2-chlorobenzoyl] -L-diglutamic acid 16) N- [4- (2-amino-4-hydroxy-7H
-Pyrrolo [2,3-d] pyrimidin-5-yl) methyl-3-fluorobenzoyl] -L-diglutamic acid 17) N- [4- (2-amino-4-hydroxy-7H
-Pyrrolo [2,3-d] pyrimidin-5-yl) methyl-
3-chlorobenzoyl] -L-diglutamic acid 18) N- [5- (2-amino-4-hydroxy-7H
-Pyrrolo [2,3-d] pyrimidin-5-yl) methyl-2-thenoyl] -L-diglutamic acid 19) N-[[5- (2-amino-4-hydroxy-
7H-pyrrolo [2,3-d] pyrimidin-5-yl) methylthiazolo-2-yl] carbonyl] -L-diglutamic acid 20) N- [4- (4-hydroxy-2-methyl-7H)
-Pyrrolo [2,3-d] pyrimidin-5-yl) methylbenzoyl] -L-diglutamic acid

21) N- [4- (4-hydroxy-2-
Methyl-7H-pyrrolo [2,3-d] pyrimidine-5-
Methyl-2-fluorobenzoyl] -L-diglutamic acid 22) N- [4- (4-hydroxy-2-methyl-7H
-Pyrrolo [2,3-d] pyrimidin-5-yl) methyl-
2-chlorobenzoyl] -L-diglutamic acid 23) N- [4- (4-hydroxy-2-methyl-7H
-Pyrrolo [2,3-d] pyrimidin-5-yl) methyl-3-fluorobenzoyl] -L-diglutamic acid 24) N- [4- (4-hydroxy-2-methyl-7H)
-Pyrrolo [2,3-d] pyrimidin-5-yl) methyl-
3-chlorobenzoyl] -L-diglutamic acid 25) N- [5- (4-hydroxy-2-methyl-7H
-Pyrrolo [2,3-d] pyrimidin-5-yl) methyl-2-thenoyl] -L-diglutamic acid 26) N-[[5- (4-hydroxy-2-methyl-7
H-pyrrolo [2,3-d] pyrimidin-5-yl) methylthiazolo-2-yl] carbonyl] -L-diglutamic acid 27) N- [4- (2-amino-4-hydroxy-7H
-Pyrrolo [2,3-d] pyrimidin-5-yl) methyl-2-fluorobenzoyl] -L-triglutamic acid 28) N- [4- (2-amino-4-hydroxy-7H
-Pyrrolo [2,3-d] pyrimidin-5-yl) methyl-2-chlorobenzoyl] -L-triglutamic acid 29) N- [4- (2-amino-4-hydroxy-7H
-Pyrrolo [2,3-d] pyrimidin-5-yl) methyl-3-fluorobenzoyl] -L-triglutamic acid 30) N- [4- (2-amino-4-hydroxy-7)
H-pyrrolo [2,3-d] pyrimidin-5-yl) methyl-3-chlorobenzoyl] -L-triglutamic acid

31) N- [5- (2-amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidine-5-
Methyl-2-thenoyl] -L-triglutamic acid 32) N-[[5- (2-amino-4-hydroxy-7
H-pyrrolo [2,3-d] pyrimidin-5-yl) methylthiazolo-2-yl] carbonyl] -L-triglutamic acid 33) N- [4- (4-hydroxy-2-methyl-7H)
-Pyrrolo [2,3-d] pyrimidin-5-yl) methylbenzoyl] -L-triglutamic acid 34) N- [4- (4-hydroxy-2-methyl-7H
-Pyrrolo [2,3-d] pyrimidin-5-yl) methyl-2-fluorobenzoyl] -L-triglutamic acid 35) N- [4- (4-hydroxy-2-methyl-7H)
-Pyrrolo [2,3-d] pyrimidin-5-yl) methyl-2-chlorobenzoyl] -L-triglutamic acid 36) N- [4- (4-hydroxy-2-methyl-7H)
-Pyrrolo [2,3-d] pyrimidin-5-yl) methyl-3-fluorobenzoyl] -L-triglutamic acid 37) N- [4- (4-hydroxy-2-methyl-7H)
-Pyrrolo [2,3-d] pyrimidin-5-yl) methyl-3-chlorobenzoyl] -L-triglutamic acid 38) N- [5- (4-hydroxy-2-methyl-7H)
-Pyrrolo [2,3-d] pyrimidin-5-yl) methyl-2-thenoyl] -L-triglutamic acid 39) N-[[5- (4-hydroxy-2-methyl-7
H-pyrrolo [2,3-d] pyrimidin-5-yl) methylthiazolo-2-yl] carbonyl] -L-triglutamic acid 40) N- [4- (2-amino-4-hydroxy-7-
Methylpyrrolo [2,3-d] pyrimidin-5-yl) methylbenzoyl] -L-glutamate diethyl

41) N- [4- (2-amino-4-hydroxy-7-methylpyrrolo [2,3-d] pyrimidine-
5-yl) methylbenzoyl] -L-glutamic acid 42) N- [4- (2-amino-4-hydroxy-7H
-Pyrrolo [2,3-d] pyrimidin-5-yl) methylbenzoyl] -diethyl L-glutamate 43) N- [4- (2-amino-4-hydroxy-7H
-Pyrrolo [2,3-d] pyrimidin-5-yl) methylbenzoyl] -L-glutamic acid 44) N- [4- (2-amino-4-hydroxy-7-
Methylpyrrolo [2,3-d] pyrimidin-5-yl) methylbenzoyl] -triethyl 45-diglutamate 45) N- [4- (2-amino-4-hydroxy-7-
Methylpyrrolo [2,3-d] pyrimidin-5-yl) methylbenzoyl] -L-diglutamic acid 46) N- [4- (2-amino-4-hydroxy-7H
-Pyrrolo [2,3-d] pyrimidin-5-yl) methylbenzoyl] -L-diglutamate triethyl 47) N- [4- (2-amino-4-hydroxy-7H
-Pyrrolo [2,3-d] pyrimidin-5-yl) methylbenzoyl] -L-diglutamic acid 48) N- [4- (2-amino-4-hydroxy-7-
Methylpyrrolo [2,3-d] pyrimidin-5-yl) methylbenzoyl] -tetraethyl tetraethyl 49-N- [4- (2-amino-4-hydroxy-7-
Methylpyrrolo [2,3-d] pyrimidin-5-yl) methylbenzoyl] -L-triglutamic acid 50) N- [4- (2-amino-4-hydroxy-7H
-Pyrrolo [2,3-d] pyrimidin-5-yl) methylbenzoyl] -L-triglutamate tetraethyl

51) N- [4- (2-amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidine-5-
) Methylbenzoyl] -L-triglutamic acid 52) N- [4- (2-amino-4-hydroxy-7)
H-pyrrolo [2,3-d] pyrimidin-5-yl) methylpicolinyl] -L-glutamic acid 53) N- [4- [1- (2-amino-4-hydroxy-7H-pyrrolo [2,3 -D] pyrimidin-5-yl)
Ethyl] benzoyl] -L-glutamic acid 54) N- [4- [1- (2-amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl)
Propyl] benzoyl] -L-glutamic acid 55) N- [4- [1- (2-amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl)
2-Propenyl] benzoyl] -L-glutamic acid 56) N- [4- [1- (2-amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl)
-3-Butenyl] benzoyl] -L-glutamic acid 57)
N- [4- [1- (2-amino-4-hydroxy-7
H-pyrrolo [2,3-d] pyrimidin-5-yl)-
3-butynyl] benzoyl] -L-glutamic acid 58) N- [4- [1- (2-amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl)
2-Nitroethyl] benzoyl] -L-glutamic acid 59) N- [4- [1- (2-amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl)
2-Aminoethyl] benzoyl] -L-glutamic acid 60) N- [4- [1- (2-amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl)
-2-Hydroxyethyl] benzoyl] -L-glutamic acid

61) N- [4- [1- (2-amino-4
-Hydroxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -3-aminopropyl] benzoyl] -L
-Glutamic acid 62) N- [4- [1- (2-amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl)
-3-Hydroxypropyl] benzoyl-L-glutamic acid 63) N- [4- (2-amino-4-hydroxy-7)
H-pyrrolo [2,3-d] pyrimidin-5-yl) formylmethylbenzoyl] -L-glutamic acid 64) N- [4- [1- (2-amino-4-hydroxy-7H-pyrrolo [2,3 -D] pyrimidin-5-yl)
2-Formylethyl] benzoyl] -L-glutamic acid 65) N- [4- [1- (2-amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl)
-3-Oxobutanyl] benzoyl] -L-glutamic acid 66) N- [4- [1- (2-amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl)
-2-carbamoylethyl] benzoyl] -L-glutamic acid 67) N- [4- [1- (2-amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl)
2-N-methylaminoethyl] benzoyl] -L-glutamic acid 68) N- [4- [1- (2-amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl)
-2-N, N-dimethylaminoethyl] benzoyl]-
L-glutamic acid 69) N- [4- [1,1-dimethyl (2-amino-4
-Hydroxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl) methyl] benzoyl] -L-glutamic acid 70) N- [4- [1,1-diethyl (2-amino-4)
-Hydroxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl) methyl] benzoyl] -L-glutamic acid

71) N- [5- [1- (2-amino-4
-Hydroxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] -2-thenoyl] -L-glutamic acid 72) N- [5- [1- (2-amino-4-hydroxy-7H -Pyrrolo [2,3-d] pyrimidin-5-yl)
Propyl] -2-thenoyl] -L-glutamic acid 73) N- [5- [1- (2-amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl)
2-Propenyl] -2-thenoyl] -L-glutamic acid 74) N- [5- [1- (2-amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl)
-3-Butenyl] -2-thenoyl] -L-glutamic acid 75) N- [5- [1- (2-amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl)
-3-Butynyl] -2-thenoyl] -L-glutamic acid 76) N- [5- [1- (2-amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl)
2-Nitroethyl] -2-thenoyl] -L-glutamic acid 77) N- [5- [1- (2-amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl)
2-Aminoethyl] -2-thenoyl] -L-glutamic acid 78) N- [5- [1- (2-amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl)
2-Hydroxyethyl] -2-thenoyl] -L-glutamic acid 79) N- [5- [1- (2-amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl)
-3-Aminopropyl] -2-thenoyl] -L-glutamic acid 80) N- [5- [1- (2-amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl)
-3-Hydroxypropyl] -2-thenoyl] -L-glutamic acid

81) N- [5- (2-amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidine-5-
82) N- [5- [1- (2-amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl))) formylmethyl-2-thenoyl] -L-glutamic acid
2-Formylethyl] -2-thenoyl] -L-glutamic acid 83) N- [5- [1- (2-amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -4-Oxobutanyl] -2-thenoyl] -L-glutamic acid 84) N- [5- [1- (2-amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl)
-2-carbamoylethyl] -2-thenoyl] -L-glutamic acid 85) N- [5- [1- (2-amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl)
-2-N-methylaminoethyl] -2-thenoyl] -L
-Glutamic acid 86) N- [5- [1- (2-amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl)
-2-N, N-dimethylaminoethyl] -2-thenoyl] -L-glutamic acid 87) N- [5- [1,1-dimethyl (2-amino-4)
-Hydroxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl) methyl] -2-thenoyl] -L-glutamic acid 88) N- [5- [1,1-diethyl (2-amino-4
-Hydroxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl) methyl] -2-thenoyl] -L-glutamic acid 89) N- [4- [4-hydroxy-2-methyl-7H]
-Pyrrolo [2,3-d] pyrimidin-5-yl) methylpicolinyl] -L-glutamic acid 90) N- [4- [1- (2-hydroxy-2-methyl-7H-pyrrolo [2,3- d] pyrimidin-5-yl)
Ethyl] benzoyl] -L-glutamic acid

91) N- [4- [1- (4-Hydroxy-2-methyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) propyl] benzoyl] -L-glutamic acid 92) N- [4- [1- (4-hydroxy-2-methyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl)
2-Propenyl] benzoyl] -L-glutamic acid 93) N- [4- [1- (4-hydroxy-2-methyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl)
-3-Butenyl] benzoyl] -L-glutamic acid 94) N- [4- [1- (4-hydroxy-2-methyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl)
-3-butynyl] benzoyl] -L-glutamic acid 95) N- [4- [1- (4-hydroxy-2-methyl-7H-pyrrolo [2,3-d] pyrimidine-5-)-2)
-Nitroethyl] benzoyl] -L-glutamic acid 96) N- [4- [1- (4-hydroxy-2-methyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl)
2-Aminoethyl] benzoyl] -L-glutamic acid 97) N- [4- [1- (4-hydroxy-2-methyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl)
2-Hydroxyethyl] benzoyl] -L-glutamic acid 98) N- [4- [1- (4-hydroxy-2-methyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl)
-3-Aminopropyl] benzoyl] -L-glutamic acid 99) N- [4- [1- (4-hydroxy-2-methyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl)
-3-Hydroxypropyl] benzoyl] -L-glutamic acid 100) N- [4- (4-hydroxy-2-methyl-7H
-Pyrrolo [2,3-d] pyrimidin-5-yl) formylmethylbenzoyl] -L-glutamic acid

101) N- [4- [1- (4-hydroxy-2-methyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-formylethyl] benzoyl] -L
-Glutamic acid 102) N- [4- [1- (4-hydroxy-2-methyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl)
-3-Oxobutanyl] benzoyl] -L-glutamic acid 103) N- [4- [1- (4-hydroxy-2-methyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl)
2-carbamoylethyl] benzoyl] -L-glutamic acid 104) N- [4- [1- (4-hydroxy-2-methyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl)
2-N-methylaminoethyl] benzoyl] -L-glutamic acid 105) N- [4- [1- (4-hydroxy-2-methyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl)
-2-N, N-dimethylaminoethyl] benzoyl]-
L-glutamic acid 106) N- [4- [1,1-dimethyl (4-hydroxy-2-methyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) methyl] benzoyl] -L-glutamic acid 107 ) N- [4- [1,1-diethyl (4-hydroxy-2-methyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) methyl] benzoyl] -L-glutamic acid 108) N- [ 5- [1- (4-hydroxy-2-methyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl)
Ethyl] -2-thenoyl] -L-glutamic acid 109) N- [5- [1- (4-hydroxy-2-methyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl)
Propyl] -2-thenoyl] -L-glutamic acid 110) N- [5- [1- (4-hydroxy-2-methyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl)
-2-Propenyl] -2-thenoyl] -L-glutamic acid

111) N- [5- [1- (4-hydroxy-2-methyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -3-butenyl] -2-thenoyl] -L −
Glutamic acid 112) N- [5- [1- (4-hydroxy-2-methyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl)
-3-Butynyl] -2-thenoyl] -L-glutamic acid 113) N- [5- [1- (4-hydroxy-2-methyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl)
2-Nitroethyl] -2-thenoyl] -L-glutamic acid 114) N- [5- [1- (4-hydroxy-2-methyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl)
2-Aminoethyl] -2-thenoyl] -L-glutamic acid 115) N- [5- [1- (4-hydroxy-2-methyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl)
2-Hydroxyethyl] -2-thenoyl] -L-glutamic acid 116) N- [5- [1- (4-hydroxy-2-methyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl)
-3-Aminopropyl] -2-thenoyl] -L-glutamic acid 117) N- [5- [1- (4-hydroxy-2-methyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl)
-3-Hydroxypropyl] -2-thenoyl] -L-glutamic acid 118) N- [5- (4-hydroxy-2-methyl-7H
-Pyrrolo [2,3-d] pyrimidin-5-yl) formylmethyl-2-thenoyl] -L-glutamic acid 119) N- [5- [1- (4-hydroxy-2-methyl-7H-pyrrolo [2 , 3-d] pyrimidin-5-yl)
2-Formylethyl] -2-thenoyl] -L-glutamic acid 120) N- [5- [1- (4-hydroxy-2-methyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl)
-3-Oxobutanyl] -2-thenoyl] -L-glutamic acid

121) N- [5- [1- (4-hydroxy-2-methyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-carbamoylethyl] -2-thenoyl]- L-glutamic acid 122) N- [5- [1- (4-hydroxy-2-methyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl)
-2-N-methylaminoethyl] -2-thenoyl] -L
-Glutamic acid 123) N- [5- [1- (4-hydroxy-2-methyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl)
2-N, N-Dimethylaminoethyl] -2-thenoyl] -L-glutamic acid 124) N- [5- [1,1-dimethyl (4-hydroxy-2-methyl-7H-pyrrolo [2,3- d] pyrimidin-5-yl) methyl] -2-thenoyl] -L-glutamic acid 125) N- [5- [1,1-diethyl (4-hydroxy-2-methyl-7H-pyrrolo [2,3-d] ] Pyrimidin-5-yl) methyl] -2-thenoyl] -L-glutamic acid Diglutamic acid corresponding to 52) to 125), triglutamic acid

Next, a method for producing the compound [I] of the present invention or a salt thereof will be described. Of the compounds [I] or salts thereof, for example, compounds [I ′] in which ring A has an N-substituent or salts thereof are novel compounds and are represented by the ring A ′ in formula [I ′]. Examples of the substituent at the N-position of the pyrrole or the pyrroline ring in the N-substituted pyrrole or the pyrroline ring include, for example, a carbon number of 1 to 1 described in the A ring above.
C3 alkyl group, C2-3 alkenyl group, C2-3 alkynyl group, C3-6 cycloalkyl group (eg, cyclopropyl), C1-4 alkanoyl group, benzoyl group , Substituted benzoyl group, hydroxy-
In addition to a C _1-3 alkyl group, a C _1-3 alkoxy-C _1-3 alkyl group, etc., a phenyl group, a substituted phenyl group, preferably a halogen atom, an alkoxy group having 1 to 4 carbon atoms and 1 to 3
Individually substituted phenyl groups (eg, p-chlorophenyl, p
-Methoxyphenyl, 3,4,5-trimethoxyphenyl group), a benzyl group or a substituted benzyl group, preferably a halogen atom, an alkoxy group having 1 to 4 carbon atoms, and a benzyl group substituted with 1 to 3 phenyl groups ( Examples thereof include p-chlorobenzyl, p-methoxybenzyl, diphenylmethyl group) and the like. Of these, an alkyl group having 1 to 3 carbon atoms is preferable, and methyl is particularly preferable. A'ring and

[Chemical 16] The bond with may be bonded at any possible position,
N-substituted portion of the pyrrole or pyrroline ring (ie N position)
so

[Chemical 17] May be combined with.

The compound [I] or its salt has the formula [III]
It can be obtained by acylating an amino acid derivative represented by the formula (II) with a carboxylic acid represented by the formula [II] or a reactive derivative at the carboxyl group. As the means of acylation, for example, a method of acylating compound [III] with compound [II] or its reactive derivative is used.
This reaction is advantageously carried out in the presence of carbodiimides, diphenylphosphoric acid azide, diethyl cyanophosphoric acid and the like. The amount of the compound [III] used is generally about 1-20 mol, preferably about 1-5 mol, relative to 1 mol of the compound [II] or its reactive derivative. Carbodiimides, diphenylphosphoric acid azide, diethyl cyanophosphoric acid, etc.
Generally, about 1-25 mol, preferably about 1-5 mol may be used. As the carbodiimides, dicyclohexylcarbodiimide is practically preferable, and other carbodiimides such as diphenylcarbodiimide and di-o
-Tolyl carbodiimide, di-p-tolyl carbodiimide,
Di-tert-butylcarbodiimide, 1-cyclohexyl-3-
(2-morpholinoethyl) carbodiimide, 1-cyclohexyl-3- (4-diethylaminocyclohexyl) carbodiimide, 1-ethyl-3- (2-diethylaminopropyl) carbodiimide and 1-ethyl-3- (3-diethylaminopropyl)
You may use carbodiimide etc. 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). -Ter, 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, N, N-dimethylformamide, hexamethylphosphoramide, sulfolane, or an appropriate mixed solvent thereof is used. This reaction is usually p
H is carried out in the range of about 2 to 14, preferably about pH 6 to 9. Usually about -10 ° C to the boiling point of the reaction solvent
It is carried out at reaction temperatures (up to about 100 ° C.), preferably in the range of about 0 to 50 ° C. The reaction can be carried out for about 1 to 100 hours. The pH of the reaction solution is appropriately set, for example, with an acid (eg, hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid), a base (eg, sodium methylate, sodium ethylate, sodium hydroxide, potassium hydroxide, barium hydroxide). , Lithium hydroxide, sodium carbonate, potassium carbonate, barium carbonate, calcium carbonate, sodium hydrogen carbonate, trimethylamine, triethylamine, triethanolamine, pyridine) or buffer (eg, phosphate buffer, borate buffer, acetate buffer) Liquid) etc. as necessary. The reaction is
It can be proceeded further advantageously by using a catalyst capable of promoting acylation.

As such a catalyst, for example, a base catalyst or an acid catalyst is used. Examples of such a base catalyst include tertiary amines (eg, aliphatic tertiary amines such as triethylamine; pyridine, α-, β- or γ-picoline,
2,6-lutidine, 4-dimethylaminopyridine, 4-
(1-Pyrrolidinyl) pyridine, dimethylaniline, aromatic tertiary amines such as diethylaniline) and the like are used, and examples of the acid catalyst include Lewis acids (eg, anhydrous zinc chloride, anhydrous aluminum chloride (AlCl ₃ ), anhydrous chloride). Ferric acid, titanium tetrachloride (TiCl ₄ ), tin tetrachloride (SnCl ₄ ), antimony pentachloride, cobalt chloride, cupric chloride, boron trifluoride etherate, etc.] are used. Of the above catalysts, 4-dimethylaminopyridine or 4- (1-pyrrolidinyl) pyridine is often preferred. The amount of the catalyst used is preferably a catalyst amount capable of promoting the acylation, and is usually about 0.01-1 with respect to 1 mol of the compound [II] or a salt thereof.
It is 0 mol, preferably about 0.1-1 mol. Examples of the reactive derivative at the carboxy group of carboxylic acid [II] include, for example, acid halides of carboxylic acid [II] (eg, fluoride, chloride, bromide, iodide), acid anhydrides (eg, iodoacetic anhydride, anhydrous Isobutyric acid), lower monoalkyl carbonate (eg, monomethyl carbonate, monoethyl carbonate, monopropyl carbonate, mono iso-propyl carbonate, monobutyl carbonate, mono iso-butyl carbonate,
Mixed acid anhydride with mono-sec-butyl carbonate, mono-tert-butyl carbonate, active ester (eg, cyanomethyl ester, ethoxycarbonylmethyl ester, methoxymethyl ester, phenyl ester, o-
Nitrophenyl ester, p-nitrophenyl ester, p-carbomethoxyphenyl ester, p-cyanophenyl ester, phenylthioester, succinimide ester), acid atide, phosphoric acid diester (eg, dimethyl phosphate, diethyl) Mixed acid anhydride with phosphate, dibenzyl phosphate, diphenyl phosphate), phosphorous acid diester (eg, dimethyl phosphite, diethyl phosphite, dibenzyl phosphite,
A mixed acid anhydride with diphenylphosphite) is also used. In the acylation means using this reactive derivative, the solvent, the catalyst, the reaction temperature, the reaction time and the like are the same as those in the acylation performed in the presence of the carbodiimides and the like.

Of the compounds [I] or salts thereof,
A hydroxy group as a substituent of B, Y, R ¹ or R ² ,
When a compound containing an amino group, a mercapto group, a carboxy group or the like or a salt thereof is produced, or a compound in which —COOR ³ and —COOR ⁴ are a carboxy group or a salt thereof is produced, hydroxy is used.
A group, an amino group, a mercapto group or a carboxy group with a protecting group known per se, and then a compound [II] or its reactive derivative at the carboxy group and a compound [III]
The desired compound [I] or a salt thereof can also be produced by reacting with and then subjecting it to a deprotection reaction known per se. The starting compound [II] or a salt or ester thereof can be prepared by a method known in the literature [for example, JA Secrist III and
PS Liu, Journal of Organic Chemistry, Vol. 43, p.
3937-3941 (1978); B. Roth, R. Laube, MY Tidwe
ll, and BS Rauckman, Journal of Organic Chemistr
y), vol. 45, p. 3651-3657 (1980); USP 4,997,838; EP
-A-438,261; USP4,996,206; USP5,028,608 etc.]. Compound [I
[I] may form a salt. As a salt with a base,
For example, alkali metal, alkaline earth metal, non-toxic metal,
Ammonium or substituted ammonium is used, and specifically, for example, sodium, potassium, lithium,
Calcium, magnesium, aluminum, zinc, ammonium, trimethylammonium, triethylammonium, triethanolammonium, pyridinium,
Examples thereof include salts with substituted pyridinium and the like. Examples of salts with acids include salts with mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and boric acid, oxalic acid, tartaric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-
A salt with an organic acid such as toluene sulfonic acid or camphor sulfonic acid is used. As the ester of the compound [II], for example, the ester as described for -COOR ³ and -COOR ⁴ and the like can be used. The starting compound [III] can be produced by a method known per se or a method analogous thereto, and for example, a method known in the literature [for example, Jay P. Greenstein et al.
reenstein and M. Winitz), Chemistry of the
The Amino Acids Vol. 1-3 (Chemistry of the
Amino Acids vol. 1-3), John Wiley & Sons, Inc., N
ew York, London (1961)] etc.
I can.

The compound [I] produced by the above method can be isolated from the reaction mixture by a conventional separation means such as concentration, solvent extraction, chromatography and recrystallization. Compound [I] obtained by the above production method
May form a salt. As the salt with a base, for example, an alkali metal, alkaline earth metal, non-toxic metal, ammonium or substituted ammonium is used, and specifically, for example, sodium, potassium, lithium, calcium, magnesium, aluminum, zinc, ammonium. , Trimethylammonium, triethylammonium, triethanolammonium, pyridinium, substituted pyridinium and the like. Examples of salts with acids include salts with mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and boric acid, oxalic acid, tartaric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluene. A salt with an organic acid such as sulfonic acid or camphorsulfonic acid is used.

[0030]

The compound [I] or a salt thereof has an excellent inhibitory action on thymidylate synthase utilizing thymidylate and its related compounds as substrates. Therefore, these compounds treat various tumors resistant to MTX as well as choriocarcinoma, leukemia, breast adenocarcinoma, epidermoid carcinoma of the head and neck, squamous cell carcinoma, small cell lung cancer and lymphosarcoma which have been treated with MTX to date. For the purpose, it can be used alone or in combination with other antitumor agents. For example, compound [I] or a salt thereof is used in the mouse tumor cell line system (P388, L1
210, L5178Y, B16 melanoma, MethA, Lewis Lung Carci
noma, S180 sarcoma, Erhlich Carcinoma, Colon26 and 38), and human tumor cell line (A549, HL6)
(0, KB, etc.) and a tumor (eg, leukemia) possessed by a warm-blooded animal.
Melanoma, sarcoma, mastoc
ytoma), carcinoma (neoplasia, etc.)], and tumor-bearing tumors of warm-blooded animals, especially mammals (eg, humans, mice, rats, cats, dogs, rabbits, etc.) It can be used as a safe antitumor agent for therapeutic purposes. When used as an antitumor agent,
Compound [I] or a salt thereof may be used by itself or a pharmaceutically acceptable carrier by a commonly used method,
Using excipients, diluents, etc., for example powders, granules,
It may be administered orally or parenterally in the form of tablets, capsules, suppositories, injections and the like. The dose varies depending on the target animal, disease, symptom, type of compound, administration route, etc., but, for example, in the case of oral administration, it is about 1.0-500 mg, preferably 10 mg / day, as the compound of the present invention to the warm-blooded animal. 0.0-200 is mg / kg body weight, and about 1.0-200 mg, preferably 5.0-100 mg / kg per day for parenteral administration. As a method of administration as an injection, intramuscular injection, intraperitoneal injection, subcutaneous injection, intravenous injection and the like are used.

The above-mentioned formulation is carried out according to a method known per se. When producing the above oral preparations, for example, tablets, binders (eg, hydroxypropylcellulose, hydroxypropylmethylcellulose, macrogol, etc.), disintegrants (eg, starch, carboxymethylcellulose calcium, etc.), lubricants (eg. , Magnesium stearate, talc, etc.) can be appropriately mixed. In addition, when a parenteral preparation such as an injection is produced, a tonicity agent (eg, glucose, D-sorbitol, D-
Mannitol, sodium chloride, etc.), preservatives (eg, benzyl alcohol, chlorobutanol, methyl paraoxybenzoate, propyl paraoxybenzoate, etc.), buffers (eg, phosphate buffer, sodium acetate buffer, etc.)
And the like can be appropriately mixed. Specific examples of the production of tablets include, for example, the amount of compound [I] or a salt thereof of about 1.0-50 mg, and lactose of 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 compressed into a tablet, 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
It is also possible to form an enteric coated tablet by coating with an acetone-ethanol mixed solution dissolved to -10%. As a specific example of the preparation of the injection, for example, as a usage amount per ampoule, about 2.0-50 mg of sodium salt of the compound (I) of the present invention is dissolved in (1) about 2 ml of physiological saline. After injecting into an ampoule, the ampoule is sealed and heat-sterilized at about 110 ° C. for about 30 minutes, or (2) about 10-40 mg of mannitol or sorbitol is dissolved in about 2 ml of sterilized distilled water, and then the ampoule is dissolved. It can also be adjusted by injecting it into, and freeze-drying this and sealing. When using the freeze-dried injection, the ampoule is opened at the time of use, and physiological saline is used to adjust the concentration of the compound to about 1.0-5.
The solution can be dissolved by injecting so as to be 0 mg / ml, and can be administered subcutaneously, intravenously or intramuscularly.

[0032]

EXPERIMENTAL EXAMPLE The pharmacological action of the compound (I) or a salt thereof in the present invention will be shown based on experiments. The representative target compound thymidylate synthase (T
S) Inhibitory effect and in vitro cell growth inhibitory effect on Meth A fibrosarcoma cells were measured by the following methods. Experimental Example 1 Measurement of TS inhibitory action The crude TS purified fraction was subcultured in vitro to Me.
It was purified from th A fibrosarcoma cells (Meth A). Cell culture is Eagle's minimum essential m containing 10% fetal calf serum
edium [MEM; Nissui Pharmaceutical] was used. The cells in the logarithmic growth phase were collected, washed twice with phosphate buffered saline,
2M sucrose, 0.01M Tris-HCl buffer (pH
After suspending in 7.5), the cells are sonicated to 100,00
0xg centrifugation supernatant was obtained. The protein concentration was determined by protein dye reagent (Bio-Rad) using bovine γ-globulin as a standard protein, and the protein concentration was adjusted to 100 mg / ml. The enzymatic reaction was performed by D. Roberts [Biochemistry 5 , 3546 (196).
6)] was partially modified and carried out as follows. The reaction composition is 0.058% formaldehyde, 6.78 mM
Sodium fluoride, 0.2 mM 2-mercaptoethanol, 6.24 mg / ml bovine serum albumin, 80 μM2
′ -Deoxy-5′-1 phosphate (dUMP), 80 μM tetrahydrofolic acid, 2 mg / ml TS crudely purified fraction, 0.17
A 3M Tris-hydrochloric acid buffer solution (pH 7.5) was used, and various concentrations of the example compounds were added. [ ³ H] dUMP of 540 kBq was added per 50 μl of the final reaction solution, and the mixture was reacted in a 96-well plate at 37 ° C. for 1 hour. 2 after the reaction
6.65% trichloroacetic acid, 3.33 mg / ml dUMP
To stop the reaction, add 220 μl of 11.4 mg / ml activated carbon, centrifuge the whole amount and measure the radioactivity in 100 μl of the supernatant by liquid scintillation method to inhibit TS activity by 50%. The required concentration (IC ₅₀ value) was obtained. The results are shown in [Table 1].

Experimental Example 2 Measurement of cell growth inhibitory effect on Meth A fibrosarcoma (Meth A) cells Meth A cells (2 × 10 ⁴ cells / ml) prepared by a conventional method
2.0 ml of each well was inoculated into a 12-well well plate and statically cultured under the conditions of 37 ° C. and 5% CO ₂ . The example compound dissolved in an appropriate concentration was serially diluted 2 to 10 times with a MEM (Nissui Pharmaceutical) solution, added to the medium, and again added with 37
The culture was allowed to stand for 72 hours under the condition of ℃ and 5% CO ₂ . Then, the total number of cells at each concentration was calculated using a Coulter counter (Coulter
(Electronics, FL), the average value of 3 wells is 1 ml
It was expressed by the number of cells per unit. For each compound, the concentration of the drug required to reduce the number of cells in the untreated control group to 50% was taken as the IC ₅₀ value for that compound. The results are shown in [Table 2].

Table 1 TS Inhibitory Action Compound IC ₅₀ (μM) Example 2 0.86 Example 6 0.083 Example 8 0.49 Example 10 0.039 Example 14 0.037 Example 16 0.59

Table 2 Meth A Cell Growth Inhibitory Action Compound IC ₅₀ (μM) Example 4 0.076 Example 6 0.063 Example 8 0.11 Example 10 0.066 Example 12 0.039 Example 140 0.091 Example 16 0.093 Example 18 0.81 In the above [Table 1] and [Table 2], the compound (I) or a salt thereof has excellent TS inhibitory action and Meth A cell proliferation inhibitory action. Reveal that.

[0034]

EXAMPLES The present invention will be specifically described below with reference to examples. Example 1 Preparation of N- [4- (2-amino-4-hydroxy-7-methylpyrrolo [2,3-d] pyrimidin-5-yl) methylbenzoyl] -L-glutamate diethyl 4- (2-amino- T-Butyl 4-hydroxy-7-methylpyrrolo [2,3-d] pyrimidin-5-yl) methylbenzoate (2.35 g) in dichloromethane (50 m
l) Trifluoroacetic acid (10 ml) was added to the solution, and the mixture was stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure, and the obtained residue and diethyl glutamate hydrochloride (1.90 g) were dried with N, N-dimethylformamide (DMF; 200 m).
It was dissolved in 1). The reaction solution was cooled to 0 ° C., a solution of diethyl cyanophosphate (1.30 g) in dry DMF (25 ml) was added, and the mixture was stirred for 15 minutes. Then, a dry DMF (25 ml) solution of triethylamine (5.72 g) was added, and the mixture was stirred at 0 ° C. for 1 hr and further at room temperature for 18 hr. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography [carrier; 250 g, developing solvent: chloroform-10% ammonia-containing ethanol =
9.5: 0.5] and the title compound (2.15
g) was obtained. ¹ H-NMR (Me ₂ SO-d ₆ ) δ: 1.17 (3H,
t, J = 7 Hz), 1.19 (3H, t, J = 7H)
z), 1.92-2.17 (2H, m), 2.43 (2
H, t, J = 8 Hz), 3.43 (3H, s), 3.9
9 (2H, s), 4.05 (2H, q, J = 7Hz),
4.11 (2H, q, J = 7Hz), 4.37-4.4
9 (1H, m), 6.17 (2H, s), 6.34 (1
H, s), 7.38 (2H, d, J = 8 Hz), 7.7
7 (2H, d, J = 8Hz), 8.60 (1H, d, J
= 8 Hz), 10.18 (1 H, s) IR (KBr): 3340, 3150, 2990, 29
40,1740,1690 cm ^-1

Example 2 Preparation of N- [4- (2-amino-4-hydroxy-7-methylpyrrolo [2,3-d] pyrimidin-5-yl) methylbenzoyl] -L-glutamic acid The compound of Example 1 (2.12 g) was dissolved in a mixed solution of water (90 ml) / tetrahydrofuran (60 ml), and 1N aqueous sodium hydroxide solution (13.1 ml) was added.
Stir at room temperature for 4 hours. Tetrahydrofuran was distilled off under reduced pressure, and a small amount of impurities was filtered through a Milopore filter,
When 1N hydrochloric acid (13.1 ml) was added to the filtrate, white powder was deposited. This was collected by filtration and dried to give the title compound (1.51g). ¹ H-NMR (Me ₂ SO-d ₆ ) δ: 1.80-2.20
(2H, m), 2.34 (2H, t, J = 7Hz),
3.42 (3H, s), 3.98 (2H, s), 4.2
9-4.46 (1H, m), 6.16 (2H, s),
6.32 (2H, s), 7.37 (2H, d, J = 8H
z), 7.76 (2H, d, J = 8Hz), 8.47
(1H, d, J = 8Hz), 10.18 (1H, s) IR (KBr): 3400, 3300, 3150, 29
30,1700,1680,1525,1500 cm
^-1

Example 3 Preparation of N- [4- (2-amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl) methylbenzoyl] -L-glutamate diethyl Example 1 and Similarly, the title compound (1.70 g) was obtained from t-butyl 4- [2-amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl] methylbenzoate (1.39 g). was gotten. ¹ H-NMR (Me ₂ SO-d ₆ ) δ: 1.16 (3H,
t, J = 7 Hz), 1.18 (3H, t, J = 7 Hz),
1.91-2.20 (2H, m), 2.42 (2H,
t, J = 7 Hz), 3.99 (2H, s), 4.04
(2H, q, J = 7 Hz), 4.10 (2H, q, J =
7 Hz), 4.37-4.47 (1H, m), 5.99
(2H, s), 6.32 (1H, s), 7.37 (2
H, d, J = 8Hz), 7.74 (2H, d, J = 8H)
z), 8.58 (1H, d, J = 7Hz), 10.11
(1H, s), 10.71 (1H, s) IR (KBr): 3430,3280,3150,29
80, 1735, 1710, 1675, 1650, 16
20, 1580, 1540, 1430, 1375, 13
00, 1250, 1190, 1090, 1020 cm ^-1

Example 4 Preparation of N- [4- (2-amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl) methylbenzoyl] -L-glutamic acid Similar to Example 2. To give the compound of Example 3 (1.60
The title compound (1.39 g) was obtained from g). ¹ H-NMR (Me ₂ SO-d ₆ ) δ: 1.85-2.20
(2H, m), 2.34 (2H, t, J = 7Hz),
3.98 (2H, s), 4.34-4.47 (1H,
m), 5.99 (2H, s), 6.32 (1H, s),
7.37 (2H, d, J = 8Hz), 7.75 (2H,
d, J = 8Hz), 8.46 (1H, d, J = 8H)
z), 10.13 (1H, s), 10.71 (1H,
s) IR (KBr): 3320, 2930, 1700, 16
50, 1535, 1500, 1430, 1400, 13
40, 1220, 1180, 1070 cm ^-1

Example 5 N- [5- (2-amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl) methyl-2-
Preparation of diethyl thenoyl] -L-glutamate In the same manner as in Example 1, 5- (2-amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl) methyl-2-thiophenecarvone was prepared. T-Butyl acid (8
The title compound (1.095 g) was obtained from 00 mg). ¹ H-NMR (Me ₂ SO-d ₆ ) δ: 1.16 (3H,
t, J = 7 Hz), 1.20 (3H, t, J = 7H
z), 1.89-2.22 (2H, m), 2.40 (2
H, t, J = 7 Hz), 4.04 (2H, q, J = 7H)
z), 4.10 (2H, q, J = 7Hz), 4.13
(2H, s), 4.24-4.41 (1H, m), 6.
10 (2H, s), 6.45 (1H, s), 6.91
(1H, d, J = 4Hz), 7.65 (1H, d, J =
4 Hz), 8.58 (1H, d, J = 8 Hz), 10.
22 (1H, s), 10.82 (1H, s) IR (KBr): 3320, 2980, 1735, 17
00 cm ^-1

Example 6 N- [5- (2-amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl) methyl-2-
Preparation of thenoyl] -L-glutamic acid The compound of Example 5 (1.09) was prepared in the same manner as in Example 2.
The title compound (416 mg) was obtained from g). ¹ H-NMR (Me ₂ SO-d ₆ ) δ: 1.81-2.19
(2H, m), 2.22-2.47 (2H, m), 4.
14 (2H, s), 4.24-4.41 (1H, m),
6.05 (2H, s), 6.45 (1H, s), 6.9
1 (1H, d, J = 3Hz), 7.65 (1H, d, J
= 3 Hz), 8.45 (1H, d, J = 7 Hz), 1
0.18 (1H, s), 10.81 (1H, s) IR (KBr): 3350, 3240, 2930, 17
00-1640, 1540 cm ^-1

Example 7 N- [4- (2-amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl) methyl-3-
Preparation of diethyl fluorobenzoyl] -L-glutamate Methyl 4- (2-amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl) methyl-3-fluorobenzoate (803 mg) in water. (10 ml)
-Tetrahydrofuran (15 ml) -Methanol (2 m
l) and dissolved in 1N NaOH aqueous solution (8.89 ml)
Was added. After stirring at room temperature for 2.5 hours, tetrahydrofuran and methanol were distilled off under reduced pressure, and 1N hydrochloric acid was added to 8.8.
When 9 ml was added, white powder was precipitated. This was collected by filtration and dried, and this product and diethyl glutamate hydrochloride (630
mg) was dissolved in dry DMF (50 ml). After the reaction solution was cooled to 0 ° C, diethyl cyanophosphate (428 mg)
Was added to the dry DMF (5 ml) solution and stirred for 15 minutes. Then dry D of triethylamine (886 mg)
An MF (5 ml) solution was added, and the mixture was stirred at 0 ° C. for 1 hr and further at room temperature for 18 hr. The solvent was distilled off under reduced pressure,
The obtained residue was purified by silica gel column chromatography [carrier; 70 g, developing solvent: chloroform-10% ammonia-containing ethanol = 9.5: 0.5] to give the title compound (1.02 g). ¹ H-NMR (Me ₂ SO-d ₆ ) δ: 1.17 (3H,
t, J = 7 Hz), 1.19 (3H, t, J = 7H)
z), 1.92-2.21 (2H, m), 2.46 (2
H, t, J = 5 Hz, 4.01 (2H, q, J = 7H)
z), 4.05 (2H, q, J = 7Hz), 4.07
(2H, s), 4.34-4.49 (1H, m), 6.
03 (2H, s), 6.28 (1H, s,), 7.40
(1H, t, J = 8Hz), 7.57-7.66 (2
H, m), 8.72 (1H, d, J = 8 Hz), 10.
16 (1H, s), 10.78 (1H, s) IR (KBr): 3320, 2980, 1740, 16
70,1640 cm ^-1

Example 8 N- [4- (2-amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl) methyl-3-
Production of Fluorobenzoyl] -L-glutamic acid In the same manner as in Example 2, the compound of Example 7 (1.02
The title compound (759 mg) was obtained from g). ¹ H-NMR (Me ₂ SO-d ₆ ) δ: 1.82-2.19
(2H, m), 2.35 (2H, t, J = 7Hz),
4.02 (2H, s), 4.33-4.47 (1H,
m), 6.05 (2H, s), 6.27 (1H, s),
7.40 (1H, t, J = 8Hz), 7.59-7.6
7 (2H, m), 8.59 (1H, d, J = 7Hz),
10.18 (1H, s), 10.78 (1H, s) IR (KBr): 3350,2930,1710-15
40 cm ^-1

Example 9 N- [4- [1- (2-amino-4-hydroxy-7H
Preparation of diethyl-pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoyl] -L-glutamate 4- [1- (2-amino-4-hydroxy-7H-pyrrolo] was prepared in the same manner as in Example 1. [2,3-d] pyrimidine-5
The title compound (974 mg) was obtained from t-butyl (-yl) ethyl] benzoate (800 mg). ¹ H-NMR (Me ₂ SO-d ₆ ) δ: 1.16 (3H,
t, J = 7.2 Hz), 1.18 (3H, t, J = 7.
2Hz), 1.55 (3H, d, J = 7.4Hz),
1.94-2.18 (2H, m), 2.42 (2H,
t, J = 7.4 Hz), 4.05 (2H, q, J = 7.
2Hz), 4.10 (2H, q, J = 7.2Hz),
4.30-4.49 (2H, m), 5.98 (2H,
s), 6.34 (1H, d, J = 1.6Hz), 7.3
9 (2H, d, J = 8.4 Hz), 7.75 (2H,
d, J = 8.4 Hz), 8.58 (1H, d, J = 7.
6Hz), 10.05 (1H, s), 10.71 (1
H, d, J = 1.6 Hz) IR (KBr): 3350, 2970, 2920, 17
35, 1680-1580, 1530, 1500 cm
^-1

Example 10 N- [4- [1- (2-amino-4-hydroxy-7H
Preparation of -pyrrolo [2,3-d] pyrimidin-5-yl) ethyl] benzoyl] -L-glutamic acid In the same manner as in Example 2, the compound of Example 9 (920m
The title compound (674 mg) was obtained from g). ¹ H-NMR (Me ₂ SO-d ₆ ) δ: 1.55 (3H,
d, J = 7.2 Hz), 1.88-2.18 (2H,
m), 2.34 (2H, t, J = 7.4Hz), 4.3
1-4.47 (2H, m), 5.98 (2H, s),
6.32 (1H, s), 7.38 (2H, d, J = 8.
2Hz), 7.75 (2H, d, J = 8.2Hz),
8.45 (1H, d, J = 8.0Hz), 10.04
(1H, s), 10.70 (1H, s) IR (KBr): 3350, 3200, 2960, 17
00,1660 cm ^-1

Example 11 N- [4- [1- (2-amino-4-hydroxy-7H
Preparation of -pyrrolo [2,3-d] pyrimidin-5-yl) propyl] benzoyl] -diethyl L-glutamate 4- [1- (2-amino-4-] was prepared in the same manner as in Example 1.
Hydroxy-7H-pyrrolo [2,3-d] pyrimidine-
5-yl) propyl] t-butyl benzoate (500 m
The title compound (528 mg) was obtained from g). ¹ H-NMR (Me ₂ SO-d ₆ ) δ: 0.81 (3H,
t, J = 7.0 Hz), 1.16 (3H, t, J = 7.
0Hz), 1.18 (3H, t, J = 7.0Hz),
1.84-2.23 (4H, m), 2.42 (2H,
t, J = 7.4 Hz), 4.04 (2H, q, J = 7.
0Hz), 4.10 (2H, q, J = 7.0Hz),
4.11-4.19 (1H, m), 4.35-4.49
(1H, m), 5.98 (2H, s), 6.40 (1
H, d, J = 1.4 Hz), 7.41 (2H, d, J =
8.4 Hz), 7.74 (2H, d, J = 8.4H
z), 8.58 (1H, d, J = 7.8Hz), 10.
06 (1H, s), 10.72 (1H, d, J = 1.4
Hz) IR (KBr): 3425, 3300, 3240, 31
50, 2960, 2925, 2870, 1730, 16
80, 1650, 1625, 1600 cm ^-1

Example 12 N- [4- [1- (2-amino-4-hydroxy-7H
Preparation of -pyrrolo [2,3-d] pyrimidin-5-yl) propyl] benzoyl] -L-glutamic acid In the same manner as in Example 2, the compound of Example 11 (513m
The title compound (292 mg) was obtained from g). ¹ H-NMR (Me ₂ SO-d ₆ ) δ: 0.80 (3H,
t, J = 7.4 Hz), 1.81-2.21 (4H,
m), 2.34 (2H, t, J = 7.4Hz), 4.1
4 (1H, t, J = 7.4Hz), 4.31-4.45
(1H, m), 5.97 (2H, s), 6.39 (1
H, s), 7.40 (2H, d, J = 8.2Hz),
7.74 (2H, d, J = 8.2Hz), 8.45 (1
H, d, J = 7.8 Hz), 10.05 (1 H, s),
10.71 (1H, s) IR (KBr): 3350, 2960, 2920, 28
70, 1700-1600, 1530cm ^-1

Example 13 N- [4- [1- (2-amino-4-hydroxy-7H
-Pyrrolo [2,3-d] pyrimidin-5-yl) -2-
Preparation of diethyl propenyl] benzoyl] -L-glutamate In the same manner as in Example 1, 4- [1- (2-amino-4-) was used.
Hydroxy-7H-pyrrolo [2,3-d] pyrimidine-
5-yl) -2-propenyl] t-butyl benzoate (1
The title compound (171 mg) was obtained from 65 mg). ¹ H-NMR (Me ₂ SO-d ₆ ) δ: 1.16 (3H,
t, J = 7.0 Hz), 1.18 (3H, t, J = 7.
0 Hz), 1.92-2.16 (2H, m), 2.42
(2H, t, J = 7.4 Hz), 4.04 (2H, q,
J = 7.0 Hz), 4.09 (2H, q, J = 7.0H
z), 4.33-4.48 (1H, m), 4.99 (1
H, d, J = 16.4 Hz), 5.04 (1H, d, J
= 10.0 Hz), 5.01-5.07 (1H, m),
6.00 (2H, s), 6.43 (1H, d, J = 1.
6Hz), 6.44 (1H, ddd, J = 8.2Hz,
10.0 Hz, 16.4 Hz), 7.31 (2H, d,
J = 8.4 Hz), 7.74 (2H, d, J = 8.4H)
z), 8.58 (1H, d, J = 7.6 Hz), 10.
07 (1H, s), 10.81 (1H, d, J = 1.6
Hz) IR (KBr): 3350, 3215, 2980, 17
40, 1680-1600, 1540, 1500cm ^-1

Example 14 N- [4- [1- (2-amino-4-hydroxy-7H
-Pyrrolo [2,3-d] pyrimidin-5-yl) -2-
Production of propenyl] benzoyl] -L-glutamic acid In the same manner as in Example 2, the compound of Example 13 (146m
The title compound (82 mg) was obtained from g). ¹ H-NMR (Me ₂ SO-d ₆ ) δ: 1.87-2.18
(2H, m), 2.34 (2H, t, J = 7.2H
z), 4.32-4.45 (1H, m), 4.93-
5.12 (3H, m), 6.00 (2H, s), 6.3
4-6.53 (1H, m), 6.44 (1H, s),
7.31 (2H, d, J = 8.0Hz), 7.75 (2
H, d, J = 8.0 Hz), 8.46 (1H, d, J =
7.8Hz), 10.07 (1H, s), 10.81
(1H, s) IR (KBr): 3350,2940,1700-16
00,1540 cm ^-1

Example 15 N- [4- [1- (2-amino-4-hydroxy-7H
-Pyrrolo [2,3-d] pyrimidin-5-yl) -2-
Production of diethyl nitroethyl] benzoyl] -L-glutamate In the same manner as in Example 1, 4- [1- (2-amino-4-) was used.
Hydroxy-7H-pyrrolo [2,3-d] pyrimidine-
The title compound (151 mg) was obtained from t-butyl 5-yl) -2-nitroethyl] benzoate (131 mg). ¹ H-NMR (Me ₂ SO-d ₆ ) δ: 1.18 (3H,
t, J = 7 Hz), 1.19 (3H, t, 7 Hz),
1.86-2.13 (2H, m), 2.42 (2H, m
t, J = 7 Hz), 4.04 (2H, q, J = 7H)
z), 4.10 (2H, q, J = 7Hz), 4.36-
4.48 (1H, m), 5.04 (1H, t, J = 8H
z), 5.30-5.57 (2H, m), 6.14 (2
H, s), 6.52 (1H, d, J = 2 Hz), 7.5
5 (2H, d, J = 8Hz), 7.77 (2H, d, J
= 8 Hz), 8.65 (1H, d, J = 7 Hz), 1
0.34 (1H, s), 10.93 (1H, d, J = 2
Hz) IR (KBr): 3300, 2980, 1735, 16
80-1640, 1550 cm ^-1

Example 16 N- [4- [1- (2-amino-4-hydroxy-7H
-Pyrrolo [2,3-d] pyrimidin-5-yl) -2-
Production of nitroethyl] benzoyl] -L-glutamic acid In the same manner as in Example 2, the compound of Example 15 (141m
The title compound (43 mg) was obtained from g). ¹ H-NMR (Me ₂ SO-d ₆ ) δ: 1.83-2.19
(2H, m), 2.34-2.47 (2H, m), 4.
29-4.41 (1H, m), 5.03 (1H, t, J
= 8 Hz), 5.28-5.54 (2H, m), 6.1
0 (2H, s), 6.52 (1H, s), 7.54 (2
H, d, J = 8Hz), 7.77 (2H, d, J = 8H)
z), 8.51 (1H, d, J = 8Hz), 10.29
(1H, s), 10.92 (1H, s) IR (KBr): 3350, 3230, 2940, 17
00-1600, 1550cm ^-1

Example 17 N- [4- [1- (2-amino-4-hydroxy-7H
-Pyrrolo [2,3-d] pyrimidin-5-yl) -2-
Production of Aminoethyl] benzoyl] -diethyl L-glutamate The compound of Example 15 (260 mg) in ethanol (30
10% Pd / C (200 mg) was added to the solution, and the mixture was stirred under a hydrogen atmosphere at room temperature for 14 hours. The catalyst was removed by filtration using Celite, and the solvent of the filtrate was evaporated under reduced pressure to give the title compound (80 mg).

Example 18 N- [4- [1- (2-amino-4-hydroxy-7H
-Pyrrolo [2,3-d] pyrimidin-5-yl) -2-
Production of Aminoethyl] benzoyl] -L-glutamic acid The compound of Example 17 (75m
The title compound (41 mg) was obtained from g). ¹ H-NMR (Me ₂ SO-d ₆ + D ₂ O) δ: 1.83-
2.03 (2H, m), 2.04-2.12 (2H,
m), 3.38-3.72 (2H, m), 4.19-
4.23 (1H, m), 4.61 (1H, m), 6.5
9 (1H, s), 7.43 (2H, d, J = 8Hz),
7.73 (2H, d, J = 8Hz)

Example 19 N- [4- [1,1-dimethyl (2-amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidine-5-
Preparation of diethyl) methyl] benzoyl] -diethyl L-glutamate In the same manner as in Example 7, 4- [1,1-dimethyl (2-
Amino-4-hydroxy-7H-pyrrolo [2,3-d]
Pyrimidin-5-yl) methyl] methyl benzoate (2.
The title compound (3.77 g) was obtained from 8 g). ¹ H-NMR (Me ₂ SO-d ₆ ) δ: 1.16 (3H,
t, J = 7.0 Hz), 1.18 (3H, t, J = 7.
0 Hz), 1.69 (6 H, s), 1.87-2.20
(2H, m), 2.42 (2H, t, J = 7.4H
z), 4.04 (2H, q, J = 7.0 Hz), 4.1
0 (2H, q, J = 7.0Hz), 4.85-4.98
(1H, m), 5.99 (2H, s), 6.31 (1
H, d, J = 2.0 Hz, 7.33 (2H, d, J =
8.4 Hz), 7.69 (2H, d, J = 8.4H
z), 8.58 (1H, d, J = 7.6 Hz), 9.8
5 (1H, s), 10.72 (1H, d, J = 2.0H
z) IR (KBr): 3350, 2980, 2930, 17
30, 1670, 1630, 1610, 1580, 15
30 cm ^-1

Example 20 N- [4- [1,1-dimethyl (2-amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidine-5-
Preparation of (yl) methyl] benzoyl] -L-glutamic acid In the same manner as in Example 2, the compound of Example 19 (1.70) was prepared.
The title compound (1.32 g) was obtained from g). ¹ H-NMR (Me ₂ SO-d ₆ ) δ: 1.69 (6H,
s), 1.86-2.17 (2H, m), 2.35 (2)
H, t, J = 7.2 Hz), 4.32-4.46 (1
H, m), 5.99 (2H, s), 6.30 (1H,
d, J = 2.0 Hz, 7.32 (2H, d, J = 8.
4Hz), 7.70 (2H, d, J = 8.4Hz),
8.46 (1H, d, J = 7.6Hz), 9.86 (1
H, s), 10.72 (1H, d, J = 2.0 Hz) IR (KBr): 3350, 2970, 1690, 16
45,1610 cm ^-1

Example 21 N- [4- [1- (2-amino-4-hydroxy-7H
- pyrrolo [2,3-d] pyrimidin-5-yl) propyl] benzoyl] -O ¹ - in the same manner as in Preparation Example 1 of methyl-gamma-L-glutamyl] -γ- benzyl -L- glutamic acid methyl, 4- [1- (2-amino-4-
Hydroxy-7H-pyrrolo [2,3-d] pyrimidine-5
-Yl) propyl] t-butyl benzoate (316 mg)
Gave the title compound (535 mg). However, in place of diethyl glutamate hydrochloride [O ¹ -methyl-γ
-L-glutamyl] -γ-benzyl-L-glutamic acid methyl trifluoroacetate salt (496 mg) was used. ¹ H-NMR (Me ₂ SO-d ₆ ) δ: 0.80 (3H,
t, J = 7.0 Hz), 1.76-2.23 (6H,
m), 2.27 (2H, t, J = 8.0 Hz), 2.4
3 (2H, t, J = 8.0Hz), 3.59 (3H,
s), 3.63 (3H, s), 4.10-4.49 (3
H, m), 5.08 (2H, s), 5.99 (2H,
s), 6.41 (1H, s), 7.35 (5H, s),
7.40 (2H, d, J = 8.4Hz), 7.75 (2
H, d, J = 8.4 Hz), 8.28 (1H, d, J =
8.0 Hz), 8.63 (1H, d, J = 8.0H
z), 10.07 (1H, s), 10.74 (1H,
s) IR (KBr): 3300, 2950, 1740, 16
80-1620, 1530 cm ^-1

Example 22 N- [4- [1- (2-amino-4-hydroxy-7H
Production of -pyrrolo [2,3-d] pyrimidin-5-yl) propyl] benzoyl] -γ-L-glutamyl] -L-glutamic acid In the same manner as in Example 2, the compound of Example 21 (512m
The title compound (292 mg) was obtained from g). However,
3.34 ml of 1N aqueous sodium hydroxide solution was used. ¹ H-NMR (Me ₂ SO-d ₆ ) δ: 0.81 (3H,
t, J = 7.0 Hz), 1.63-2.38 (10H,
m), 4.09-4.49 (3H, m), 5.99 (2
H, s), 6.40 (1H, s), 7.41 (2H,
d, J = 8.0 Hz), 7.77 (2H, d, J = 8.
0 Hz), 8.12 (1H, d, J = 7.6 Hz),
8.54 (1H, d, J = 7.6Hz), 10.08
(1H, s), 10.73 (1H, s) IR (KBr): 3350, 2960, 2930, 17
00, 1640, 1540 cm ^-1

Formulation Example 1 The compound obtained in Example 4 (50 mg per tablet), lactose (250 mg per tablet), corn starch (51 mg per tablet) and hydroxypropylcellulose L (9 mg per tablet) were used in a conventional manner. The mixture was mixed with the above to granulate, and the granules were mixed with corn starch (8 mg per tablet) and magnesium stearate (2 mg per tablet), and the mixture was tableted according to a conventional method to give tablets (370 mg per tablet). It was

Formulation Example 2 10 g of the sodium salt of the compound obtained in Example 4 is dissolved in 1 liter of physiological saline, filtered through a microfilter, dispensed in 2.2 ml aliquots and sealed. This one
Sterilization at 10 ° C. for 30 minutes gave ampoules for subcutaneous, intravenous or intramuscular injection of the compound.

Formulation Example 3 5 g of the hydrochloride of the compound obtained in Example 4 and 10 g of mannitol are dissolved in 1 liter of distilled water, sterile filtered and dispensed into ampoules in 2 ml portions. When this was placed in a freeze dryer, dried and sealed, an ampoule for dissolution at the time of use was obtained. At the time of use, the ampoule is opened and dissolved in 2 ml of physiological saline to prepare an injection for administration.

[0059]

EFFECT OF THE INVENTION A novel thymidylate synthase inhibitor having high selective toxicity to various tumor cells (especially human lung cancer cells) and also showing excellent therapeutic effect on methotrexate-resistant tumor cells is provided. To do.

Claims (30)

[Claims] 1. A general formula: [Wherein, ring A is a pyrrole or pyrroline ring which may have a substituent, B is a divalent 5- or 6-membered homocyclic or heterocyclic group which may have a substituent, Y Is a hydrogen atom,
A halogen atom or a group via a carbon, nitrogen or sulfur atom, R ¹ and R ² are the same or different and are a hydrogen atom or a lower hydrocarbon group which may have a substituent, -C
OOR ³ and —COOR ⁴ are the same or different and are optionally esterified carboxy groups, and n is 1 to 6
And R ³ may be different from each other in n repeating units. ] The compound or its salt represented by these. 2. A general formula: [In the formula, A'ring is an N-substituted pyrrole or pyrroline ring, B is a divalent 5- or 6-membered homo- or heterocyclic group which may have a substituent, Y is a hydrogen atom, halogen An atom or a group through a carbon, nitrogen or sulfur atom is represented by R ¹
And R ² are the same or different and each is a lower hydrocarbon group which may have a hydrogen atom or a substituent, and -COOR ³ and -COOR ⁴ are the same or different and may each be a carboxy group which may be esterified; Represents an integer of 1 to 6, and R ³ may be different in n repeating units. ] The compound of Claim 1 which is a compound or its salt represented by these. 3. A general formula: [In the formula, R represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, an alkynyl group having 2 to 4 carbon atoms, a C _3-6 cycloalkyl group, or 1 carbon atom.
To 4 alkanoyl groups, benzoyl groups, halogenobenzoyl groups, mono-, di- or tri-C _1-4 alkoxybenzoyl groups, hydroxy-C _1-4 alkyl groups, C _1-4
Alkoxy-C _1-4 alkyl group, phenyl group, halogenophenyl group, mono-, di- or tri-C _1-4 alkoxyphenyl group, benzyl group, halogenobenzyl group, mono-, di- or tri-C _{1- 4} Alkoxybenzyl group or diphenylmethyl group, and other symbols have the same meanings as in claim 1. ] The compound of Claim 1 which is a compound or its salt represented by these. 4. B is an alkyl group having 1 to 4 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, an alkynyl group having 2 to 4 carbon atoms, a C _3-6 cycloalkyl group, a halogen atom, a hydroxy group, C _{1 -4} alkoxy group, di-C _1-4 alkylamino group, halogeno-C _1-4 alkyl group, oxo group, C _1-4
It is a divalent 5- or 6-membered cyclic hydrocarbon group or heterocyclic group which may have 1 or 2 substituents selected from an acyl group and a C _1-4 alkoxy-C _1-4 alkyl group. The compound according to claim 1, 2 or 3. 5. Y is (1) hydrogen atom (2) halogen atom (3) cyano group, carboxy group, carbamoyl group, amino group, nitro group, hydroxy group or mercapto group, (4)
An alkyl group having 1 to 4 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, an alkynyl group having 2 to 4 carbon atoms, C _3-6
Cycloalkyl group, halogen atom, hydroxy group, oxo group, C _1-4 alkoxy group, di-C _1-4 alkylamino group, halogeno-C _1-4 alkyl group, C _1-4 acyl group, hydroxy-C _{1 -4} alkyl groups and C _1-4 alkoxy-C
_An alkyl group having 1 to 4 carbon atoms, optionally having 1 or 2 substituents selected from _1-4 alkyl groups, an alkenyl group having 2 to 4 carbon atoms, an alkynyl group having 2 to 4 carbon atoms, or A C _3-6 cycloalkyl group, (5) an alkyl group having 1 to 4 carbon atoms, an alkenyl group having 2 to 4 carbon atoms,
Alkynyl group having 2 to 4 carbon atoms, C _3-6 cycloalkyl group, halogen atom, hydroxy group, oxo group, C _1-4
Alkoxy group, di-C _1-4 alkylamino group, halogeno-C _1-4 alkyl group, C _1-4 acyl group, hydroxy-C
_A C _6-10 aryl group optionally having 1 or 2 substituents selected from a _1-4 alkyl group and a C _1-4 alkoxy-C _1-4 alkyl group, (6) a carbon number of 1 to 4 alkyl groups, C 2-4 alkenyl groups, C 2-4 alkynyl groups, C _3-6 cycloalkyl groups, halogen atoms, hydroxy groups, oxo groups, C _1-4 alkoxy groups,
Selected from a di-C _1-4 alkylamino group, a halogeno-C _1-4 alkyl group, a C _1-4 acyl group, a hydroxy-C _1-4 alkyl group and a C _1-4 alkoxy-C _1-4 alkyl group A heterocyclic group optionally having 1 or 2 substituents, (7) an alkyl moiety having 1 to 4 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, an alkynyl group having 2 to 4 carbon atoms Group, C _3-6 cycloalkyl group, halogen atom, hydroxy group, oxo group, C _1-4 alkoxy group, di-C _1-4 alkylamino group, halogeno-C _1-4 alkyl group, C _1-4 acyl C _1-4 alkoxy group optionally having 1 or 2 substituents selected from a group, a hydroxy-C _1-4 alkyl group and a C _1-4 alkoxy-C _1-4 alkyl group, C _{1 -4} alkylthio group, C _1-4 alkylcarbonylamino group or C _1-4
Alkylcarbonyloxy group, (8) aryl moiety having 1 to 4 carbon atoms, alkenyl group having 2 to 4 carbon atoms, alkynyl group having 2 to 4 carbon atoms, C _3-6 cycloalkyl group, halogen atom, hydroxy Group, oxo group, C _1-4 alkoxy group, di-C _1-4 alkylamino group,
It has 1 or 2 substituents selected from halogeno-C _1-4 alkyl group, C _1-4 acyl group, hydroxy-C _1-4 alkyl group and C _1-4 alkoxy-C _1-4 alkyl group. and optionally C _6-10 aryloxy group optionally, C _6-10 arylthio group, C _6-10 aroylamino group or a C _6-10 aroyloxy group, (9) heterocyclic moiety is an alkyl group having 1 to 4 carbon atoms, An alkenyl group having 2 to 4 carbon atoms, an alkynyl group having 2 to 4 carbon atoms, a C _3-6 cycloalkyl group, a halogen atom, a hydroxy group, an oxo group, a C _1-4 alkoxy group,
Selected from a di-C _1-4 alkylamino group, a halogeno-C _1-4 alkyl group, a C _1-4 acyl group, a hydroxy-C _1-4 alkyl group and a C _1-4 alkoxy-C _1-4 alkyl group A heterocyclic oxy group which may have 1 or 2 substituents, a heterocyclic thio group, a heterocyclic carbonylamino group or a heterocyclic carbonyl group, or (10) above (4), (5) and ( 6. An amino group substituted with 1 or 2 selected from 6),
The compound according to 2 or 3. 6. The compound according to claim 1, wherein Y is an amino group.
The described compound. 7. R ¹ and R ² are the same or different and each is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, an alkynyl group having 2 to 4 carbon atoms, or C _3-8. Cycloalkyl group, halogen atom, hydroxy group, oxo group, C _1-4 alkoxy group, di-C _1-4 alkylamino group, halogeno-C _1-4 alkyl group, C _1-4 acyl group, hydroxy-C _{1 -4} alkyl group, C _1-4 alkoxy-
A C _1-4 alkyl group, an alkyl group having 1 to 4 carbon atoms which may have 1 or 2 substituents selected from an amino group and a nitro group, an alkenyl group having 2 to 4 carbon atoms,
The compound according to claim 1, 2 or 3, which is an alkynyl group having 2 to 4 carbon atoms or a C _3-6 cycloalkyl group. 8. R ¹ and R ⁴ are the same or different and are selected from (1) hydrogen atom, (2) alkyl group having 1 to 5 carbon atoms, (3) nitro group and C _1-4 alkoxy group. To a benzyl group optionally having 3 substituents or a phenyl group optionally having 1 to 3 substituents selected from (4) nitro group and C _1-4 alkoxy group. A compound according to claim 1, 2 or 3. 9. The compound according to claim 1, 2 or 3, wherein n is 1. 10. Y is an amino group, R is a hydrogen atom or C
_1-4 Alkyl group, R ¹ and R ² are the same or different and each is a hydrogen atom, or an alkyl group having 1 to 4 carbon atoms, which may be substituted with an amino group or a nitro group, an alkenyl group having 2 to 4 carbon atoms or a carbon number. An alkynyl group of 2 to 4, a phenyl-1,4-ylene or thiophene-2,5-ylene group in which B may be substituted with a halogen atom, R ³ and R ⁴ are a hydrogen atom or a 1 to 5 carbon atom The compound according to claim 3, wherein n is 1 or 2 in the alkyl group. 11. Y is an amino group, R is a hydrogen atom, R ¹ and R ² are the same or different and are a hydrogen atom, alkyl having 1 to 4 carbons, alkenyl having 2 to 4 carbons or having 2 to 4 carbons. An alkynyl group, a phenyl-1,4-ylene or thiophene-2,5-ylene group in which B may be substituted with a halogen atom, R ³ and R ⁴ are hydrogen atoms, and n is 1 or 2. The described compound. 12. Y is an amino group, R is a hydrogen atom or C
_1-4 alkyl group, R ¹ and R ² are the same or different and each is a hydrogen atom, or an alkyl group having 1 to 4 carbon atoms or an alkenyl group having 2 to 4 carbon atoms, which may be substituted with an amino group or a nitro group, B Is a phenyl-1,4-ylene or thiophene-2,5-ylene group optionally substituted with a halogen atom, R ³ and R ⁴ are hydrogen atoms, and n is 1
The compound according to claim 3, which is 13. The compound according to claim 1, 2 or 3, wherein B is a phenyl-1,4-ylene group. 14. The compound according to claim 1, 2 or 3, wherein B is a thiophene-2,5-ylene group. 15. The compound according to claim 1, 2 or 3, wherein R ¹ and R ² are hydrogen atoms. 16. The compound according to claim 1, 2 or 3, wherein R ³ and R ⁴ are hydrogen atoms. 17. The compound according to claim 3, wherein R is a hydrogen atom. 18. N- [5- (2-amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl) methyl-2-thenoyl] -L-glutamic acid or a salt thereof. The compound according to claim 3. 19. N- [4- [1- (2-amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidine-5.
The compound according to claim 3, which is -yl) ethyl] benzoyl] -L-glutamic acid or a salt thereof. 20. N- [4- [1- (2-amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidine-5.
The compound according to claim 3, which is -yl) propyl] benzoyl] -L-glutamic acid or a salt thereof. 21. N- [4- [1- (2-amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidine-5.
The compound according to claim 3, which is -yl) -2-propenyl] benzoyl] -L-glutamic acid or a salt thereof. 22. N- [4- (2-amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl) methyl-2-fluorobenzoyl] -L-glutamic acid or a salt thereof. A compound according to claim 3. 23. N- [4- [1- (2-amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidine-5)
-Yl) -3-butenyl] benzoyl] -L-glutamic acid or a salt thereof. 24. N- [4- [1- (2-amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidine-5.
The compound according to claim 3, which is -yl) -3-butynyl] benzoyl] -L-glutamic acid or a salt thereof. 25. N- [4- [1,1-dimethyl (2-amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl) methyl] benzoyl] -L-glutamic acid or The compound according to claim 3, which is a salt thereof. 26. N- [4- [1,1-diethyl (2-amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl) methyl] benzoyl] -L-glutamic acid or The compound according to claim 3, which is a salt thereof. 27. N- [4- (2-Amino-4-hydroxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl) methylbenzoyl] -L-glutamic acid, or a salt or ester thereof. 28. A general formula: [Wherein, ring A is a pyrrole or pyrroline ring which may have a substituent, B is a divalent 5- or 6-membered homocyclic or heterocyclic group which may have a substituent, Y Is a hydrogen atom,
A halogen atom or a group through a carbon, nitrogen or sulfur atom is R ¹ and R ^{2 which are the} same or different and each is a lower hydrocarbon group which may have a hydrogen atom or a substituent. ]
A compound represented by or a reactive derivative at the carboxy group, and a compound represented by the general formula: [In the formula, -COOR ³ and -COOR ⁴ are the same or different and each represents an optionally esterified carboxy group;
Represents an integer of 1 to 6, and R ³ may be different in n repeating units. ] The compound represented by these is reacted, The manufacturing method of the compound of Claim 1 characterized by the above-mentioned. 29. A general formula: [Wherein, ring A is a pyrrole or pyrroline ring which may have a substituent, B is a divalent 5- or 6-membered homocyclic or heterocyclic group which may have a substituent, Y Is a hydrogen atom,
A halogen atom or a group via a carbon, nitrogen or sulfur atom, and R ¹ and R ² are the same or different and represent a hydrogen atom or a lower hydrocarbon group which may have a substituent. ] The compound represented by these, its salt, or ester. 30. A thymidylate synthase inhibitor, which comprises the compound [I] according to claim 1 or a salt thereof.