JPH04128287A - Pyrrolo(2,3-d)pyrimidine derivative, its production, its use and intermediate therefor - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [ring A is (hydrogenated) pyrrole ring; X is NH2, OH or SH; Y is H or OH; COOR<1> and COOR<2> are (esterified) carboxy; ring B is (substituted) cycloalkylene, (substituted) cycloalkenylene or substituted phenylene; Z is (substituted) bivalent group composed of serially connected 2-4 C atoms] or its salt. EXAMPLE:N-[3-chloro-4-[3-(2,4-diamino-7H-pyrrolo [2,3-d]pyrimidin-5-yl)- propyl]benzoyl]-L-glutamic acid. USE:An antitumor agent having highly selective toxic effect on various tumor cells and antitumor effect on methotrexate-resistant strain. PREPARATION:The objective compound of formula I can be produced by reacting a compound of formula II or its reactive derivative at carboxyl group with a compound of formula III.

Description

[Detailed description of the invention] [0001]

[Industrial application field]

The present invention provides novel pyrrolo[2,3-d
] Concerning pyrimidine derivatives and methods for producing them. [0002]

[Conventional technology]

Folic acid and its related compounds play the role of coenzymes in various enzymatic reactions such as nucleic acid biosynthesis, amino acid/peptide metabolism, and methane production as carriers of 01 units derived from formic acid and formaldehyde in living organisms. ing. In particular, in the nucleic acid biosynthesis system, it is essential for the 01 unit metabolism/transfer reaction in two pathways, namely, the purine synthesis system and the thymidine synthesis system. Normally, in order for folic acid to exert its biological activity, it must be converted into an active coenzyme form through two steps of reduction. Amethopterin (mentrexate: MTX) and its surrounding compounds are known as drugs that strongly bind to the enzyme (dihydrofolate reductase) that controls the second step and inhibit the reduction of dihydrofolate to tetrahydrofolate. These drugs are DN
Because it impairs A synthesis and results in cell death, it has been developed as an antitumor agent and holds a clinically important position. Furthermore, we have added a folate antagonist with a different mechanism of action than dihydrofolate reductase inhibition, namely tetrahydroaminopterin, whose main mechanism of action is inhibition of glycinamide ribonucleotide transformylase, which is involved in the early stages of the purine biosynthesis system. system antitumor agent (5,10-dibuaza-5,6
, 7゜8-tetrahydroaminopterin: DDATHF
) [Journal of Medicinal Chemistry (
Journal of Medicinal C
hemistry) 28, 914 (1985)] or] Quinazoline antitumor agent (2-desamino-2-methyl- 10-propargyl-58-dideazaforay)
:DMPDDF) [) British Journal of Cancer
of Cancer) 58241 (1988)]
etc. have been reported. [0003] On the other hand, in addition to these folate antagonists whose basic skeleton is a fused ring of a 6-membered ring and a 6-membered ring, there is a pyrrolo[2,3-d,l-pyrimidine skeleton that is a fused ring of a 6-membered ring and a 5-membered ring]. It has been reported that a compound in which a glutamic acid moiety is cross-linked with a group containing a phenylene group also has antitumor activity. however,
The crosslinking moiety of the above pyrrolo(2,3-d,l pyrimidine derivative) is limited to a group containing an unsubstituted phenylene group. [Patent Application No. 01-72235] [0004]

[Problem to be solved by the invention]

Currently, there are particular expectations regarding cancer therapeutics.
The goal is to create a drug that has a new mechanism of action, exhibits highly selective toxicity against cancer cells, and has excellent therapeutic effects. MTX, an antitumor drug whose main mechanism of action is antagonism against folic acid, is currently widely used clinically, but it is relatively toxic and not very effective against solid tumors, making it an unsatisfactory treatment. No effect has been obtained. Additionally, acquired resistance to this type of drug has become a major problem. [0005]

[Means to solve the problem]

In view of the above circumstances, the present inventors have conducted extensive research and have discovered that the pyrrolo[2,3-d)pyrimidine skeleton and the glutamic acid moiety are combined with a cycloalkylene group that may have a substituent, and a cycloalkylene group that may have a substituent. A crosslinked compound containing a cycloalkenylene group or a phenylene group with a substituent has high selective toxicity against various tumor cells and MTX.
The present invention was completed by discovering an antitumor effect against resistant strains. [0006] That is, the present invention provides: (1) General formula (I)

embedded image X [wherein A ring is a pyrrole ring which may be hydrogenated,
X is an amino group, a hydroxyl group or a mercapto group,
Y is a hydrogen atom or a hydroxyl group, -COOR1 and -C00R2 are the same or different carboxyl groups that may be esterified, and B ring is a cycloalkylene group that may have a substituent, or a cycloalkylene group that may have a substituent. represents a cycloalkenylene group which may have a substituent or a phenylene group which may have a substituent, and Z is a divalent group consisting of 2 to 4 carbon atoms arranged in series and may have a substituent. ]
A compound represented by or a salt thereof, (2) general formula (II)

embedded image [wherein A ring, X, Y, B ring and Z have the same meanings as above. ] or its reactive derivative at the carboxyl group and general formula (III) [wherein -CO
OR1 and -COOR2 have the same meanings as above. ] The preceding item (
1) A method for producing the compound described above, (3) an antitumor agent containing the compound (I) described in the preceding section (1) or a salt thereof, (4
) General formula (IV)

embedded image [In the formula, A ring, X, Y, B ring and Z have the same meanings as above, and -C○OR3 represents a carboxyl group which may be esterified. ] or a salt thereof. [0007] In the above formula, when X is a hydroxyl group or a mercapto group and when Y is a hydroxyl group, compound (I), (
II) and (IV) can exist as equilibrium mixtures with their tautomers. Tautomerizable partial structural formulas are listed below, and the equilibrium relationship between them is shown.

[Chemical formula 7] (χ= OI-[or Sl・t, X-=O or S)
[0008] For convenience of presentation, hydroxyl groups and mercapto forms are described throughout this specification and corresponding nomenclature is adopted; however, in any case, the tautomers, oxo and thioxo forms, are shall also be included. [0009] In addition, the compound (I) of the present invention may have multiple asymmetric centers, but other than the absolute configuration of the asymmetric carbon atom in the side chain derived from glutamic acid being S (L), other asymmetric centers may exist. The absolute configuration at the center may be S, R1, or a mixture of R and S. In this case, multiple diastereoisomers exist, but if necessary, they can be easily separated by conventional separation and purification means. All of the above diastereoisomers that can be separated in this way fall within the scope of the present invention. [0010] In the above formula, the optionally hydrogenated pyrrole ring represented by ring A includes, for example, a pyrrole ring and a pyrroline ring, and preferably a pyrrole ring is used. [0011] In the above formula, Z represents a divalent group consisting of 2 to 4 carbon atoms in series (strictly speaking, 2 to 4 carbon atoms and 0 to 8 hydrogen atoms in series); Examples of such divalent groups include C2-4 alkylenes such as ethylene, trimethylene and tetramethylene, such as vinylene, propenylene, 1- or 2-butenylene, C alkenylenes such as butadienylene, such as ethynylene, 1- or 2-
C alkynylene such as butenylene, 1- or 2-butenylene, etc. are used. Particularly preferred Z is C alkylene, more preferably trimethylene. The divalent group represented by Z may have one or two substituents, and in the case of two substituents, they may be the same or different. Examples of such substituents include alkyl groups having 1 to 3 carbon atoms (e.g., methyl, ethyl, propyl, 1so-propyl groups), alkenyl groups having 2 or 3 carbon atoms (e.g., vinyl, 1-methylvinyl), , 1-propenyl, aryl, allenyl group), carbon number 2
or 3 alkynyl groups (ethynyl, 1-propynyl,
In addition to propargyl group) or cyclopropyl group,
Fluorine, hydroxyl, oxo, methoxydimethylamino, diethylamino, trifluoromethyl, formyl,
Examples include hydroxymethyl, 2-hydroxyethyl, methoxymethyl, 2-ethoxyethyl and the like. Particularly preferred substituents include methyl, ethyl, propylaryl, propargyl, formyl, hydroxymethyl, and methoxymethyl. [0012] Examples of the carboxyl group that may be present include a lower alkyl group having 1 to 5 carbon atoms, a benzyl group that may have a substituent (eg, C alkoxy such as nitromethoxy, ethoxy, etc.), or a substituent. (eg, 01-4 alkoxy such as nitromethoxy, ethoxy, etc.) and a carboxyl group esterified with a phenyl group or the like. Examples of the lower alkyl group include methyl. ethyl, propyl, 1so-propyl, n-butyl, 1
so-butyl, 5ec-butyl, tert-butyl, n
-pentyl, 1so-pentyl, 5ec-pentyl, n
eo-pentyl, tert-pentyl, etc., benzyl which may have the substituent include benzyl, nitrobenzyl, methoxybenzyl, etc., and phenyl which may have the substituent, phenyl , nitrophenyl. Examples include methoxyphenyl. A particularly preferable example of the esterified carboxyl group is one having 1 carbon number.
A carboxyl group esterified with 5 to 5 lower alkyl groups or benzyl groups is used. -COOR
As a preferable example of 1,-COOR2-COOR3,
A carboxyl group or a carboxyl group esterified with a lower alkyl group having 1 to 5 carbon atoms is used. [0013] The cycloalkylene group represented by ring B is preferably a 5- or 6-membered ring group, such as cyclopentane-1,3-
ylene, cyclohexane-(1,3- or 1,4-
) ylene, preferably cyclohexane-1,4
-ylene is used. The cycloalkenylene group represented by ring B is preferably a 5- or 6-membered ring group, such as cyclopentene-(1,3-, 1,4- or 3.
5-)ylene, cyclohexene-(1,3-,1,4-
, 1,5-, 3,5- or 36-)ylene, cyclopentadiene-(1,3-, 1,4- or 2,5-)
)ylene, 1,3-cyclohexadiene-(1,3-,
1,4-, 1,5-, 24-, 2,5- or 2.6
-)ylene, 1,4-cyclohexadiene-(1,3-
, 1,4- or 1,5-)ylene, preferably cyclopentadiene-2,5-ylene and 1,
3-cyclohexadiene-1,4-ylene and the like are used. [0014] JP-A-4-128287 (jQ) The cycloalkylene group and cycloalkenylene group represented by ring B may have 1 or 2 substituents at substitutable positions, and in the case of 2 substituents, they are the same. or may be different. In the case of a phenylene group having a substituent represented by ring B, the number of substituents is preferably 1 or 2, and in the case of 2, they may be the same or different. Examples of substituents on the cycloalkylene group, cycloalkenylene group and phenylene group represented by ring B include alkyl groups having 1 to 3 carbon atoms (e.g., methyl, ethyl, propyl, 1so-propyl groups), 2 or 3 carbon atoms; 3 alkenyl groups (e.g. vinyl, 1-methylvinyl, 1-propenyl, aryl, allenyl groups), alkynyl groups having 2 or 3 carbon atoms (ethynyl, 1-propynyl, propargyl groups), cyclopropyl, halogen (e.g. chlorine, bromine, fluorine, iodine), methoxy, dimethylamino, trifluoromethyl, oxo, formyl, methoxymethyl, 2-
Examples include ethoxyethyl, and methyl, halogen, methoxy, trifluoromethyl and the like are preferably used. Particularly preferred examples of ring B include halogen-substituted phenylene, cyclohexane, and the like. [0015] Among the compounds represented by the general formula (I), preferred are those represented by the formula

[Formula 8] (r) [In the formula, -COORlo and -C○OR2' are the same or different carboxyl groups which may be esterified with lower alkyl or benzyl, and ring B is a cycloalkylene group or a halogen group. In the substituted phenylene group, Z' represents an alkylene group having 2 to 4 carbon atoms. ] is used. [0016] 11 Kaihei 4-12828? (11) The lower alkylene group of the carboxyl group represented by -COOR'' and -COOR2-, which may be esterified with the same or different lower alkyl, includes, for example, methyl, ethyl, propyl, isopropyl,
n-butyl, iso-butyl, 5ec-butyl, tert
-C alkyl such as -butyl, n-pentyl, inpentyl, 5ec-pentyl, etc., preferably methyl,
C alkyl such as ethyl is used. The cycloalkylene group represented by ring B or the halogen-substituted phenylene group is preferably a 5- or 6-membered ring group, such as cyclopentan-1,3-ylene, cyclohexane-(1,3- Or 1.4-)
ylene etc., preferably cyclohexane-1,4
-ylene is used. In addition, halogens in phenylene groups substituted with halogens include fluorine, chlorine, bromine,
Examples include iodine, and chlorine is preferably used. Z
The alkylene group having 2 to 4 carbon atoms represented by
Examples include methylene, dimethylene, trimethylene, tetramethylene, etc., and trimethylene is preferably used. [0017] Further, as specific examples of preferable compounds among the compounds represented by the general formula (I), there may be mentioned the compounds shown in Table 1 below.

[Table 1] X

[Table 2]

[0018] Next, a method for producing the compound (I) of the present invention or a salt thereof will be explained. Compound (I) or a salt thereof can be obtained by acylating a glutamic acid derivative represented by formula (III) with a carboxylic acid represented by formula (II) or a reactive derivative at its carboxy group. Examples of the above-mentioned acylation method include a method of acylating compound (III) with compound (II) or a reactive derivative thereof in the presence of a carbodiimide, diphenylphosphate azide, or diethyl cyanophosphate. The amount of compound (III) to be used is generally about 1 to 20 molar equivalents, preferably about 1 to 5 molar equivalents of 1N H4-128287 (15), relative to compound (II) or its reactive derivative. The carbodiimide is generally used in an amount of about 1-25 molar equivalents, preferably about 1-5 molar equivalents, relative to compound (II).
Molar equivalents may be used. [0019] As the carbodiimide, dicyclohexylcarbodiimide is practically preferred, and other carbodiimides such as diphenylcarbodiimide, di-tolylcarbodiimide, di-p-)lylcarbodiimide, 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-diethylaminopropylcarpodiimide, etc. may be used. This acylation reaction is preferably carried out in the presence of an appropriate solvent, such as,
Water, alcohols (e.g. methanol, ethanol) ethers (e.g. dimethyl ether, diethyl ether, tetrahydrofuran dioxane, monoglyme, diglyme)
, nitriles (e.g., acetonitrile) esters (e.g.,
ethyl acetate), halogenated hydrocarbons (e.g. dichloromethane, chloroform, carbon tetrachloride), aromatic hydrocarbons (e.g. benzene, toluene, xylene), acetone, nitromethane, pyridine, dimethylsulfoxide, dimethylformamide, hexamethylphosphor Amide, sulfolane or an appropriate mixed solvent thereof may be used. This reaction is usually carried out at a pH of about 2 to 14, preferably at a pH of about 6.
from about -10°C to about the boiling point of the reaction solvent (up to about 100°C), preferably from about 0 to 50°C.
The reaction can be carried out at a reaction temperature in the range of about 1 to 100 hours, preferably 4 to 50 hours. The pH of the reaction solution can be adjusted as appropriate, such as acids (e.g., hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid), bases (e.g., sodium methylate, sodium ethylate, sodium hydroxide, potassium hydroxide,
barium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, barium carbonate, calcium carbonate, sodium bicarbonate, trimethylamine, triethylamine, triethanolamine, pyridine) or buffers (e.g.
Adjust as necessary with phosphate buffer, borate buffer, acetate buffer, etc. Note that the reaction can proceed more advantageously by using a catalyst that can promote acylation. Examples of such catalysts include base catalysts and acid catalysts. Such base catalysts include, for example, tertiary amines (e.g. aliphatic tertiary amines such as triethylamine; pyridine, α-1β- or γ-picoline, 2,
6-lutidine, 4-dimethylaminopyridine ring, 4-(
(1-pyrrolidinyl) pyridine, dimethylaniline, diethylaniline (aromatic tertiary amines such as Iron, titanium tetrachloride (TiC1), tin tetrachloride (S n
Among the above catalysts, 4-dimethylaminopyridine or 4-(1-pyrrolidinyl)pyridine is preferred. There are many. The amount of catalyst to be used is preferably the amount that can promote acylation, and is usually about 0% for chemical compound (II).
．． 01-10 molar equivalents, preferably about 0.1-10 molar equivalents. Examples of reactive derivatives at the carboxy group of carboxylic acid (II) include carboxylic acid (II)
) acid halides (e.g. fluoride, chloride, bromide, iodide), acid anhydrides (e.g. iodoacetic anhydride, isobutyric anhydride), lower monoalkyl carbonate esters (
Examples, monomethyl carbonate, monoethyl carbonate, monopropyl carbonate mono 1SO-propyl carbonate, monobutyl carbonate, monoiso
-butyl carbonate, mono-5ec-butyl carbonate, mono-tert-butyl carbonate) mixed acid anhydrides, active esters (e.g., cyanomethyl ester, ethoxycarbonylmethyl ester, methoxymethyl ester, phenyl ester 0-nitrophenyl ester) ,p-
nitrophenyl ester, p-carbomethoxyphenyl ester, p-cyanophenyl ester, phenylthioester) acid azide, mixed acid anhydride with phosphoric acid diester (e.g. dimethyl phosphate, diethyl phosphate, dibenzyl phosphate, diphenyl phosphate);
Also included are mixed acid anhydrides with phosphorous acid diesters (eg, dimethyl phosphite, diethyl phosphite, dibenzyl phosphite, diphenyl phosphite). In the acylation procedure using this reactive derivative, the pH
1. The solvent, catalyst, reaction temperature, etc. are the same as in the case of the acylation carried out in the presence of carbodiimides. [0020] In addition, among compound (I) or a salt thereof, -COOR1
and -C00R2 is a carboxyl group (I
-1) or a salt thereof, when producing compound (II
Compound (II) is a compound in which -COOR1 and -COOR2 are esterified carboxyl groups in I).
After reacting with a reactive derivative at the carboxyl group thereof, it is preferable to deesterify it by subjecting it to a known decomposition reaction or catalytic reduction reaction. Examples of the decomposition reaction include a hydrolysis reaction under basic conditions (hereinafter referred to as 11A method), a hydrolysis reaction under acidic conditions (hereinafter referred to as "B-1 method"), and acidic non-aqueous conditions. Examples include the decomposition reaction described below (hereinafter referred to as "B-2 method"). 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; Examples include amines such as ammonia, triethylamine, and pyridine, and examples of acids used in method B-1 include mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, trifluoroacetic acid, trichloroacetic acid, Examples include organic acids such as methanesulfonic acid, benzenesulfonic acid, p)luenesulfonic acid, and camphorsulfonic acid;
Examples of catalysts used in Method 2 include hydrogen chloride, hydrogen bromide, perchloric acid, mineral acids such as sulfuric acid, nitric acid, and phosphoric acid, trifluoroacetic acid, trichloroacetic acid, methanesulfonic acid, benzenesulfonic acid, p -) Organic acids such as luenesulfonic acid and camphorsulfonic acid, anhydrous zinc chloride, anhydrous aluminum chloride (AlCl2), anhydrous ferric chloride, titanium tetrachloride (TiC1), tin tetrachloride (S n C
l 4 ), antimono pentachloride, cobalt chloride, cupric chloride, boron trifluoride etherate, and other Lewis acids. The decomposition reaction is carried out in any case in a suitable solvent at a temperature ranging from 0°C to the boiling point of the solvent, preferably 10-80°C, for 30 minutes to 2 days, preferably 1 hour to 2 days.
This is done by reacting for 4 hours. In the case of Method A and Method B-1, examples of reaction solvents include water, methanol, ethanol, propatool, butanol, ethylene glycol, methoxyethanol, ethoxyethanol, tetrahydrofuran, dioxane, monoglyme, diglyme, pyridine, dimethylform, etc. Kaihei 4-12828
7 (1 day) Amides, dimethyl sulfoxide, sulfolane or suitable mixtures thereof are used, in the case of method B-2, for example ethyl acetate, dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, monoglyme,
diglyme, dichloromethane, chloroform, carbon tetrachloride, acetonitrile, benzene, toluene. Xylene, nitromethane, pyridine or an appropriate mixed solvent thereof is used. The catalytic reduction reaction (hereinafter referred to as “'C
As a method (referred to as ゛゛), using an appropriate solvent, approximately -4
0°C to the boiling point of the reaction solvent, more preferably about 0-5
It is carried out at a range temperature in the range of 0°C. Solvents used include water, alcohols (e.g. methanol, ethanol, propatool, 1so-propatool, butyl alcohol, 5ec-butyl alcohol, tert
-butyl alcohol, ethylene glycol, methoxyethanol, ethoxyethanol), acetic acid esters (e.g. methyl acetate, ethyl acetate), ethers (e.g. dimethyl ether, diethyl ether, tetrahydrofuran,
dioxane, monoglyme, diglyme), aromatic hydrocarbons (eg, benzene, toluene, xylene), pyridine, dimethylformamide, and appropriate mixed solvents thereof. As the catalyst for catalytic reduction, for example, palladium platinum, rhodium, Raney nickel, etc. are used. At this time, the reaction may proceed advantageously by adding a small amount of acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc. Which reaction leads to compound (I-1) depends on the properties of -COOR1 and -COOR2, but usually -COOR1 and -co. When R2 is a carboxyl group esterified with methyl, ethyl, propyl, butyl, 5ec-butyl, phenyl or a substituted phenyl group, method A or method B-1;
When -COOR' and -COOR2 are carboxyl groups esterified with 1so-propyl or tert-butyl groups, method B-2 is used, and when they are carboxyl groups esterified with benzyl groups or substituted benzyl groups, B- Method 1 or method C are advantageously applied. In addition, when -COOR1 and -COOR2 are different, the above methods A, B-1, B-2 and C may be combined as appropriate. [0021] Next, a method for producing raw material compound (II) will be explained. Compound (II) can be produced, for example, by the following reaction steps.

[Chemical formula 9]

[Chemical formula 101] or ■ (1'/-1) or (IV -2) [0022] In the above step, X, Y, R3, B ring and Z have the same meanings as above, and R4 is of the formula -COOR6 R5 is a cyano group or an esterified carboxyl group represented by the formula -C
In the esterified carboxyl group represented by OOR6, L is a halogen atom (e.g., chlorine atom, bromine atom, iodine atom) or a removable group that can be easily derived from a hydroxyl group (e.g., methanesulfonyloxy group, Benzenesulfony 7N Kaihei 4-128287 (21) Represents a luoxy group, p-)luenesulfonyloxy group, trifluoromethanesulfonyl group). R6 in the esterified carboxyl group represented by the formula -〇〇OR6
as lower alkyl having 1 to 4 carbon atoms (e.g. methyl, ethyl, propyl, 1so-propyl, butyl, 5
ec-butyl, tert-butyl, etc.) or benzyl or substituted benzyl (e.g. p-nitrobenzyl, p
-methoxybenzyl, etc.). [0023] The above reaction step will be explained in detail below. The first step raw material compound (V) is prepared under basic conditions as malononitrile or cyanoacetic ester [NC-CH2COOR;
R has the same meaning as above] to convert it into compound (VI). For the chlorine to be used, the solvent 1 reaction conditions, etc., methods known per se can be adopted. [0024] Second step When the compound (VI) is treated with guanidine, it reacts with a cyano group or an ester group, and then ring closure and cyclization occur to form a new pyrrolo(2,3-d)pyrimidine ring. . When ring closing is carried out under basic conditions, the reaction can proceed advantageously. Examples of the base used include sodium methoxide, sodium ethoxide,
Examples include metal alkoxides such as potassium tert-butoxide. Examples of the reaction medium include methanol, ethanol, propafur, tert-butyl alcohol, dimethyl sulfoxide, hexamethylphosphoramide, etc., the reaction temperature is 0-150°C, preferably 20-100°C, and the reaction time is 1-48 hours, preferably 2-24 hours. [0025] Third step V-2: , the compound (any 1:
) to a reduction reaction, the compound (II-1, and ll-1": X=NH2, Y=H1 or ll
-2' and I I-2": X=OH, Y=H
) can be manufactured. The conditions for the reduction reaction are known per se, but a reduction reaction using a metal hydride (eg, borane, alane, or an ate complex thereof), etc. may be applied. [0027] Furthermore, the third step and the fourth step may be performed in reverse order. That is, in the fifth step, the compound (
IV-1 or IV-2) was treated with the same reduction reaction as in the fourth step to produce compounds (IV-1 and IV-1'':
X=NH2, Y=H, IV-2' and IV
-2°':
The compound (I
It can be appropriately selected depending on the properties of the substituent (V-1 or IV-2). [0028] Furthermore, among the compounds (II) and (IV), compounds in which Y is hydrogen can also be produced by the reaction steps shown below. embedded image 1z represents a - [0029] group. The hydrocarbon residues represented by R7 and R8 include lower alkyl groups having 1 to 5 carbon atoms (e.g., methyl, ethyl, propyl, 1so-propyl, n-butyl, 1so-butyl, 5ec-butyl, tert -butyl, n-pentyl, 1SO-pentyl, 5eC-pentyl, neo-pentyl, tert-pentyl) benzyl group, or phenyl group. These lower alkyl groups, benzyl groups, or phenyl groups may have 1 to 3 substituents, and when there are 2 or more substituents, they may be the same or different. Such substituents include halogen atoms (e.g., fluorine, chlorine, bromine, iodine), nitro groups, cyano groups, alkoxy groups having about 1 to 4 carbon atoms (e.g., methoxy, ethoxy, propoxy, 1so-propoxy, n-butoxy, 1so-butoxy, 5ec-butoxy,
tert-butoxy group) alkyl group having 1 to 4 carbon atoms (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 5eC-butyl, tert-butyl group), alkanoyl group having 1 to 4 carbon atoms (e.g., formyl, acetyl, propionyl, n-butyryl, 1so
-butyryl group), trifluoromethyl group, etc. R9 in the formula -COOR9-C8OR9 or -C8SR9 group includes the hydrocarbon residues detailed for R7 and R8. [0030] The above reaction step will be explained in detail below. This is a step of producing compound (VIII) by adding the seventh step. The amount is equivalent to compound (VII). This reaction is carried out in the presence of an appropriate solvent from about -10°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, for about 30 minutes to 48 hours, preferably 1 to 24 hours.The solvent used in the reaction includes: For example, alcohols (e.g. methanol, ethanol), ethers (e.g. dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme), nitriles (e.g. acetonitrile), esters (e.g. ethyl acetate), halogenated Hydrocarbons (e.g., dichloromethane, chloroform, carbon tetrachloride), aromatic hydrocarbons (e.g., benzene, toluene, xylene), or appropriate mixed solvents thereof are used. The process can be made even more advantageous by adding an oxide. Examples of the organic peroxide include t-butyl hypochloride,
Examples include peracetic acid, perbenzoic acid, and p-chloroperbenzoic acid. 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 step without isolation. [0031] The compound (VIII) obtained in the seventh step of the eighth step is R8J2
In the presence of alcohols or thiols represented by H and an appropriate solvent, from about -10°C to the boiling point of the reaction solvent (up to about 100°C), preferably from about O to 50°C.
Compound (IX) is reacted at a reaction temperature in the range of about 10 minutes to 24 hours, preferably 20 minutes to 12 hours.
You can do something like that. Examples of solvents used in the reaction include ethers (e.g. dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme), nitriles (e.g. acetonitrile), esters (e.g. ethyl acetate),
Halogenated hydrocarbons (eg, dichloromethane, chloroform, carbon tetrachloride), aromatic hydrocarbons (eg, benzene, toluene, xylene), or appropriate mixed solvents thereof are used. Alternatively, the alcohol represented by R8J2H or the thiol itself may be used in excess as a solvent. [0032] 9th Step 11 Kaihei 4-128287 (26) When compound (IX) is treated with guanidine in an appropriate solvent, it reacts with a cyano group, ester residue or thioester residue, causing cyclization and forming a pyrimidine ring. is formed to produce compound (X). The reaction temperature of this reaction is 0-1
50°C, preferably 20-100°C, and the reaction time is 1
-48 hours, preferably about 2 to 24 hours. Furthermore, the reaction can be advantageously carried out under basic conditions. Examples of the base used include sodium methoxide, sodium ethoxide, potassium tert.
-Metal alkoxides such as butoxide. As the reaction solvent, for example, methanol, ethanol, propatool, tert-butyl alcohol, dimethyl sulfoxide, hexamethylphosphoramide, or an appropriate mixed solvent thereof is used. [0033] Step 10 This is a reaction in which the group of compound (X) is restored to a carboxyl group (>C=O), spontaneously causing an intramolecular ring-closing reaction, and converting into compound (IV). The restoration reaction to a carbonyl group can be carried out, for example, by using compound (X) itself or a suitable reaction solvent at a temperature from about -10°C to about the boiling point of the reaction solvent (about 100°C).
C), preferably in the range of about 0 to 50 DEG C., by subjecting the decomposition reaction to about 10 minutes to 10,000 hours, preferably 20 minutes to 48 hours. The decomposition reactions include, for example, hydrolysis reaction under acidic conditions (Method B-1), decomposition reaction under acidic non-aqueous conditions (Method B-2), catalytic reduction reaction (Method C), and decomposition using metal salts. Examples include a reaction (hereinafter referred to as "Method D") or a decomposition reaction using an oxidizing agent (hereinafter referred to as "Method E").Method B-1, Method B-2 and Method C are based on the formula -COO
The method detailed in the decomposition reaction of R1 and -COOR2 can be applied as is. Examples of the metal salts used in Method D include cupric chloride, silver nitrate, silver oxide, mercuric chloride, tellurium salts (e.g., tellurium nitrate, tellurium trifluoroacetate), and the oxidation salts used in Method E. Agents include oxygen-light, hydrogen peroxide, perbenzoic acid, m-chlorobenzoic acid, perchlorates (e.g., lithium perchlorate, silver perchlorate, mercuric perchlorate, perchloric acid). (tetrabutylammonium), nitrosyl sulfate, alkyl nitrite (eg, isoamyl nitrite), halogen (eg, iodine, bromine, chlorine), N-bromosuccinimide, sulfuryl chloride, chloramine T, and the like. Which method is applied to restore the carboxyl group (>C=O) can be appropriately selected depending on the chemical properties of -J1-R7 and -J2R8. In the case of methods D and E, examples of reaction solvents include water, alcohols (e.g., methanol, ethanol, propatool, 1so-propatool, butyl alcohol, 5ec-butyl alcohol, tert-butyl alcohol, ethylene). Glycol, methoxyethanol, ethoxyethanol), ethers (e.g. dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme), aromatic hydrocarbons (e.g. benzene, toluene, xylene), halogenated hydrocarbons (e.g. dichloromethane, (chloroform, carbon tetrachloride), acetone, acetonitrile, or an appropriate mixed solvent thereof. Compound (IV
), the intramolecular ring-closing reaction in the process of producing pyrrolo(2,3-d ] A pyrimidine ring is formed. At this time, if an acid catalyst is present, the ring-closing reaction can proceed quickly and in high yield. Such an acid catalyst is described in detail in Method B-1 and Method B-2. Examples include mineral acids, organic acids, Lewis acids, etc. [0034] Compounds in which the A ring obtained in the 11th step and the 10th step is a pyrrole ring (
IV) can be easily converted into a compound (IV'') in which ring A is a pyrroline ring by subjecting it to a catalytic reduction reaction, if necessary.If ring B is a cycloalkylene group or a phenylene group having a substituent In this case, these groups can be converted into the corresponding cycloalkylene group or cycloalkenylene group by subjecting them to a catalytic reduction reaction in this step or any appropriate step among the first to tenth steps.Furthermore, if ring B is In the case of an unsubstituted cycloalkenylene group or an unsubstituted cyclohexenylene group, these groups can also be obtained by subjecting an unsubstituted phenylene group to a catalytic reduction reaction.The above-mentioned method C is advantageous as it is as the catalytic reduction reaction. [0035] In addition, if necessary, compound (IV) or compound (IV'') is subjected to a deesterification reaction in the same manner as in the third step to form compound (II) or compound (I). [0036] From the 1st step to the 10th step, or from the raw material compound (II
Regarding the reactions carried out or used in the manufacturing process of I), (V) and (VI), the reaction conditions of Reagent 1, and the application of protecting groups to each functional group used as necessary, etc., please refer to the following documents: It is known and has been deciphered in detail. [”J, F, W, Matsukuomin (J, F
, W. McOmine), Protective Groups in Organic Chemistry (Prote
Active Groups in Organi
c ChemiStry), Plenum Press
London and New York (Plenum Pr
ess London and New Yo
rK) (1973)), [Pine Hendrickson Hammond, Organic Chemistry (4th Edition) [■]-[■■], Houyo Shoten (1982)) and [M, Fieserand
L. Fieser, Regent for Organic Synthesis Volumes 1-13.
for Organic 5ynthes i
s Vo 1. 1-13), Wiley-Interscience, Wiley-Intersc.
1ence, New York, London, 5
ydney snd toronto) (1969
-1988)) [0037] Furthermore, in compounds (I), (II) and (IV), the amino group, hydroxyl group or mercapto group represented by They can also be converted into each other by conversion reactions. [Separate volume Protein Nucleic Acid Enzyme, Chemical Alloy of Nucleic Acid, Kyoritsu Shuppan (1968)] [0038] The compound of the present invention (I
), (II) and (TV), or the raw material compounds and products in each step can be isolated from the reaction mixture by conventional separation and purification means, such as concentration, solvent extraction, chromatography, recrystallization, etc. . [0039] Compound (I) obtained by the production method of the present invention, (
II) and (IV) may form salts. Base salts include alkali metals, alkaline earth metals, non-toxic metals, ammonium and substituted ammonium salts, e.g.
Examples include salts of sodium, potassium, lithium, calcium, magnesium, aluminum, zinc, ammonium trimethylammonium, triethylammonium, triethanolammonium, pyridinium, substituted pyridinium, and the like. Examples of acid salts include mineral acid salts with hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, boric acid, oxalic acid,
Tartaric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid,
Benzene sulfone WLp) Organic acid salts with luenesulfonic acid, camphorsulfonic acid, etc. can be mentioned. [0040] The compound (I) of the present invention or a salt thereof has an inhibitory effect on one or more enzymes that utilize folic acid and its related compounds as substrates. Therefore, these compounds can be used alone or for the purpose of treating not only hair cancer, leukemia, breast adenocarcinoma, epidermal carcinoma of the head and neck, squamous cell carcinoma, small cell lung cancer, and lymphosarcoma, but also various other tumors that have been treated with MTX to date. It can be used in combination with other antitumor agents. [0041] When used as an antitumor agent, compound (I) or a salt thereof can be prepared by itself or by a commonly used method using a pharmacologically acceptable carrier, excipient, diluent, etc., for example. , powder, 9 tablets of granules, capsules, suppositories,
It may be administered orally or parenterally in the form of a parking agent or the like. The dosage varies depending on the target animal, disease, symptom, type of compound, administration route, etc., but for example, in the case of oral administration, the compound of the present invention may be administered to mice, rats, rabbits,
Approximately 2.0 per day for warm-blooded animals such as dogs, cats, and humans.
-100 mg/kg body weight, preferably 40-80
mg/kg body weight. For parenteral administration, about 1.0-50 mg/kg body weight per day, preferably 20-40 m
g/kg body weight. Administration methods for injections include intramuscular injection, intraperitoneal injection, subcutaneous injection, and intravenous injection. [0042] The above formulation is performed according to a method known per se. When manufacturing the above oral preparations, for example, tablets, a binder (
For example, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, macrogol), disintegrants (e.g., starch, carboxymethyl cellulose calcium, etc.), lubricants (e.g., magnesium stearate, talc, etc.) may be added as appropriate. I can do it. [0043] In addition, when manufacturing parenteral preparations, for example, injections,
Isotonic agents (e.g., glucose, D-sorbitol, D-mannitol, sodium chloride, etc.), preservatives (e.g., benzyl alcohol, chlorobutanol, methyl p-oxybenzoate, propyl p-oxybenzoate, etc.), buffers (e.g., phosphorus (acid acid buffer, sodium acetate buffer, etc.) can be blended as appropriate. [0044] As a specific example of manufacturing a tablet, for example, the amount used per tablet is 1.0-25 mg of the compound of the present invention, 100 mg of lactose.
-500mg, cornstarch approx. 50-100mg,
Approximately 5-20 mg of hydroxypropyl cellulose is mixed in a conventional manner, granulated, mixed with cornstarch and magnesium stearate, and then compressed into tablets, each having a yield of approximately 100 mg.
Tablets are 500 mg and 3-10 mm in diameter. Also,
The amount used per tablet is hydroxypropyl methylcellulose phthalate (approximately 10-10-2O
Enteric-coated ring-locked tablets can also be made by coating with an acetone-ethanol mixture containing 5 to 10% of castor oil (approximately 0.5 to 2 mg) dissolved at a concentration of 5 to 10%. . [0045] As a specific example of the preparation of an injection, for example, the amount used per ampoule is about 20% of the sodium salt of the compound of the present invention.
．． 0-50 mg (i) dissolved in about 2 ml of physiological saline, injected into an ampoule, sealed, and mixed with about 11
Heat sterilize at 0°C for about 30 minutes, or (ii) dissolve about 10-40 mg of mannitol or sorbitol in about 2 ml of sterile distilled water and pour into an ampoule and lyophilize. Adjustments can also be made by sealing the container. To determine the amount of lyophilized compound to be used, open the ampoule, prepare a solution of the compound in physiological saline, for example, to a concentration of about 1.0-25 mg/ml, and administer subcutaneously, intravenously, or intramuscularly. It can be made into an injection. [0046]

[Reference examples and working examples]

The present invention will be specifically described below with reference to Reference Examples and Examples. However, these are merely examples and do not limit the invention in any way. The NMR spectra in the following examples were generated using tetramethylsilane as an internal standard.
The total δ value was measured in ppm. Symbols in the examples have the following meanings. S: Singlet d: Doublet t Nitriplet ABq: AB type triplet dd: Double doublet dt: Double triplet td:) Ripple doublet ddd: Double double doublet tdd:
) Ripple double doublet m: multiplet br, : wide brs: wide singlet J: coupling constant Sh: shoulder [0047] Reference example 1 of t-butyl 3-chloro-4-(5-methoxy-4-pentenyl)benzoate Production: To a toluene solution (12 ml) of (methoxymethyl)triphenylphosphonium chloride (3,77 g) was added a 1,0 mol solution of potassium tert-butoxide in tetrahydrofuran (11,0 ml) at 0°C.
) was added and stirred for 10 minutes, then 3-chloro-4-(
t-Butyl 4-oxobutyl)benzoate (2,84g)
A toluene solution (10 ml) of was added dropwise to the mixture, and the mixture was stirred at 0°C for 20 minutes. Ether (40 ml) was added to the reaction solution to separate the organic layer, which was washed successively with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, hexane was added to the resulting residue, and the resulting triphenylphosphine oxide was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (80 g of silica gel, ether, hexane = 1:20) to give the title compound (1
, 92g) was obtained. [0048] IR (Neat): 2980, 2940, 2860, 1
710,1665,1605.860,845 cm-1 [0049] IH-NMR (CDCl3) δ: 1.53-1.7
4 (2H, m), 1.60 (9H, s), 1.9
6 (0,6H, dt, J=7Hz, 7Hz), 2.1
1 (0, 4H, tdd, J=7Hz, 7Hz, 7H
z), 2.65 (2H, t, J=8Hz), 3.
50 (1,8H,S), 3.58 (1,2H,s)
, 4.35 (0,4H, td, J=7Hz, 6Hz)
, 4.74 (0.6H, dt, J=13Hz, 7Hz
), 5.90 (0,4H, dt, J=6Hz, IHz
), 6.30 (0,6H,d, J=13Hz), 7.3
5 (LH, d, J=8Hz), 7.90 (LH, d
, J=8Hz) 7.95 (IH,s) [0050
] Reference Example 2 Production of t-butyl 3-chloro-4-(5,5-dicyano-4-(dimethoxymethyl)pentyl)benzoate: Under an argon atmosphere, bromomalononitrile (1,27 g) and The compound (1,91 g) was dissolved in dichloromethane (66 ml) and added to Molecular Sheep (3A, 1
．． After adding 0 g), ultraviolet rays were irradiated for 2 hours using an analytical ultraviolet lamp with the filter removed. Methanol (4 ml) was added to the reaction solution, and after stirring for 10 minutes, it was poured into ice water containing a 2N aqueous potassium carbonate solution (5 ml), extracted with dichloromethane, and the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by color chromatography (75 g of silica gel, ethyl acetate-hexane = 1:10) to give the title compound (2.08 g).
) was obtained as a colorless oil. [0051] IR (Neat): 2970, 2930, 2245, 1
710,1605,860.845 cm' 1H-NMR (CDCl3) δ: 1.59 (9H
, s), 1.60-1.91 (4H, m), 2.1
9-2.31 (LH, m), 2.71 (2H, t
, J=7Hz), 3.40 (3H,s), 3.45
(3H, s), 4.10 (LH, d. J=4Hz), 4.30 (IH, d. J=5Hz),
7.36 (LH, d, J=8Hz), 7.90 (L
H, d, J = 8 Hz), 7.96 (IH, s) [00
52] Reference Example 3 Production of t-butyl 3-chloro-4-(4-(2,4,6-triaminopyrimidin-5-yl)-5,5-dimethoxypentyl)benzoate: Under argon atmosphere, hydrochloric acid A solution of 1.0M potassium tert-butoxide in tetrahydrofuran (6°70ml) was added to a suspension of guanidine (640mg) in tert-butyl alcohol (30ml), and after stirring for 10 minutes, the compound of Reference Example 2 (2.20g
) was added thereto, and the mixture was heated under reflux for 2 hours. The reaction solution was mixed with water (200 ml) containing a 1.0 N potassium hydrogen sulfate aqueous solution (1 ml).
and dichloromethane, and the organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by color chromatography (50 g of silica gel, dichloromethane-methanol = 30:1 → 15:1) to yield the title compound (2.27 g) as a white amorphous powder. Obtained. [0053] IR (KBr): 34,80,3375,3150,
2980, 2940, 1715.1605, 1570,
1435,850,805cm-1 (9H,s), 1
．． 73-2.06 (LH, m), 2.60 (2H
, 't, J=7Hz), 2.79 (LH, ddd,
J=11Hz, 3Hz, IHz), 3.45(3H,s
), 3.50 (3H,s), 4.33 (L
H, J=3Hz), 4.45 (4H, brs)
, 5.17 (2H,brs) , 7.34 (I
H, d, J=8Hz), 7.88 (LH, d, J=
8Hz), 7.94 (IH,s) [0054] Example I N-[3-chloro-4-(3-(2,4-diamino-7
Preparation of diethyl H-pyrrolo[2,3-d]pyrimidin-5-yl)-propyl]benzoyl)-L-glutamate: The compound of Example 3 (200 mg) was dissolved in trifluoroacetic acid (1 ml) and water (20 mg). Dissolved and stirred at room temperature for 2 hours. Trifluoroacetic acid was distilled off under reduced pressure, and the resulting residue and diethyl glutamate hydrochloride (172 mg) were suspended in dimethylformamide (2 ml), and diethyl cyanophosphate (8
2mg) in dimethylformamide (2ml) was added and stirred for 15 minutes. Next, a dimethylformamide solution (2 ml) of triethylamine (218 mg) was added at the same temperature.
was added dropwise, and after stirring at 0°C for 30 minutes and at room temperature for 2 hours, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography (15 g of silica gel, dichloromethane separated from concentrated aqueous ammonia → dichloromethane - 10%). Purification with ammonia-containing ethanol (40:1→30:1) gave the title compound (175 mg) as a colorless amorphous powder. [0055] IR (KBr): 3320, 3160, 1735, 16
30,1575,1540,1500,1200cm
' IH-NMR (CDCl3) δ: 1.17 (3H
, t, J=7Hz), 1.21 (3H, t, J
=7Hz), 1.82-2.20 (4H, m), 2.
42 (2H, t, J=7Hz), 2.66 (2H,
t, J=7Hz, ), 2.72 (2Ht, J=7Hz
), 4.07 (2H, q, J=7Hz), 4.12
(2H, qJ=7Hz), 4.34-4.51 (LH
, m), 5.33 (2H,s), 595 (2H,s
), 6.40 (LH,s), 7.38 (LH,d,
J=8Hz1:! F Kaihei 4-128287 (35))
, 7.82 (LH, d, J=8Hz), 7.88 (
LH, s), 8.62 (LH, d, J=8Hz), 1
0.49 (LH,s)[0056] Example 2 N-[3-chloro-4-(3-(2,4-diamino-7
Production of H-pyrrolo(2,3-d)pyrimidin-5-yl)-propyl]benzoyl]-L-glutamic acid: The compound of Example 1 (80 mg) was added to a tetrahydrofuran-water temperature solution (2:1.3 ml), A 1.0N aqueous sodium hydroxide solution (0,497ml) was added, and the mixture was stirred at room temperature for 1 hour. The solvent was concentrated to 1.0 ml under reduced pressure, the resulting insoluble matter was filtered off using a Millipore filter, the filtrate was cooled to 0°C, and acetic acid (0.1 ml) was added. The generated crystals were collected by filtration, thoroughly washed with ice water, and dried at 70°C under reduced pressure to obtain the title compound (64 mg) as white crystals. IR (KBr): 3340, 3200, 2940, 16
60,1632,1540.1500.1397cm
' IHNMR (Me So d6) δ: 1.76-2.
21 (4H, m), 234 (2H, t, J°=
7Hz), 2.68 (2H, t, J=7Hz), 2.
72 (2H, t, J=7Hz), 4.29-4.4
8 (IH, m), 5.50 (2H, brs), 6
．． 13 (2H, s), 6.45 (LH, s),
7°41 (IHd, J=8Hz), 7.84 (IH
, d, J=8Hz), 7.90 (LH,s), 8.5
0 (LH, d, J=8Hz), 10.53 (LH
,s) [0057] Example 3 N-[4-('3-(2,4-diamino-7H-pyrrolo[2,3-d)pyrimidin-5-yl)-propylcyclohexylcarbonyl]-L- Production of diethyl glutamate: The compound of Example 1 (531 mg) was mixed with acetic acid (2
After adding platinum dioxide (100 mg) to 4 kg/cm 2 (1) under hydrogen atmosphere,
The mixture was stirred vigorously at 40° C. for 15 hours. The catalyst was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography [developing solvent: chloroform:ethanol = 19:1] to give the title compound (180 mg).
was gotten. IR (KBr): 3330, 3165, 1730, 16
30,1570.1540cm' 1H-NMR (MeSO-ds) δ: 1.15
(3H, t, J=7Hz) 1.19 (3H, t,
J=7Hz), 1.26-2.15 (16H, m),
2゜26-2.39 (2H, m), 2.54-2.6
7 (2H, m), 4.03 (2H, q, J=7H
z), 4.10 (2H, q, J=7Hz),
4. 14-4.27 (IH, m), 5.35
(2H,s), 5.90(2H,s), 6.38(
LH, d, J=1.8Hz), 7.96-8.09
(LH, m), 10.34 (IH, d, J=1
．． 8Hz) [0058] Example 4 N-[4-(3-(2,4-diamino-7H-pyrrolo(
Production of 2,3-d,lpyrimidin-5-yl)-propylcyclohexylcarbonyl]-L-glutamic acid:
The compound of Example 3 (151 mg) was subjected to the same reaction as in Example 2 to obtain the title compound (112 mg). IR (KBr): 3340, 3250, 2930, 16
55,1630.1540cm' IHNMR (Me SOds) δ: 1.30-2.1
2 (16H, m)2.27 (2H,t, J=7Hz
), 2.52-2.67 (2H, m), 4.10-4
．． 23 (IH, m), 5.54 (2H, s), 6.
14 (2H, s), 641 (LH, s), 7.80
-7.93 (LH,m), 10.47 (LH,s[
0059]

【Effect of the invention】

According to the present invention, a novel pyrrolo(2,3-d)pyrimidine derivative that can be used as an antitumor agent is provided.

Claims (4)

[Claims] [Claim 1] (1) General formula [Chemical formula 1] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, ring A is a pyrrole ring which may be hydrogenated,
X is an amino group, a hydroxyl group or a mercapto group,
Y is a hydrogen atom or a hydroxyl group, -COOR^1
and -COOR^2 is a carboxyl group that may be the same or different and esterified, ring B is a cycloalkylene group that may have a substituent, a cycloalkenylene group that may have a substituent, or It represents a phenylene group having a substituent, and Z is a divalent group consisting of 2 to 4 carbon atoms arranged in series and may have a substituent. ] or its salt. [Claim 2] (2) General formula [Chemical formula 2] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, ring A is a pyrrole ring which may be hydrogenated,
X is an amino group, a hydroxyl group or a mercapto group,
Y represents a hydrogen atom or a hydroxyl group, B ring represents a cycloalkylene group that may have a substituent, a cycloalkenylene group that may have a substituent, or a phenylene group that has a substituent, and Z represents a series is a divalent group consisting of 2 to 4 carbon atoms, which may have a substituent. ] or its reactive derivatives at the carboxyl group and the general formula ▲ Numerical formulas, chemical formulas, tables, etc. This indicates a good carboxyl group. ] The method for producing the compound according to claim 1, which comprises reacting with a compound represented by: 3. An antitumor agent comprising the compound according to claim 1 or a salt thereof. [Claim 4] General formula [Chemical formula 3] ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, ring A is a pyrrole ring which may be hydrogenated,
X is an amino group, a hydroxyl group or a mercapto group,
Y is a hydrogen atom or a hydroxyl group, -COOR^3
represents a carboxyl group that may be esterified, ring B represents a cycloalkylene group that may have a substituent, a cycloalkenylene group that may have a substituent, or a phenylene group that has a substituent, Z is a divalent group consisting of 2 to 4 carbon atoms arranged in series and may have a substituent. ] or its salt.