JPH075599B2 - Pyrrolopyrimidine derivative, production method and use thereof - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel pyrrolopyrimidine derivative useful as an antitumor agent, its production method and use.

BACKGROUND ART Folic acid plays a role of a coenzyme for various enzymatic reactions such as nucleic acid biosynthesis system, amino acid / peptide metabolism system and methanogenesis system as a carrier of C1 unit derived from formic acid and formaldehyde in vivo. There is. Particularly, in the nucleic acid biosynthesis system, it is essential for the formylation reaction in two pathways, that is, the purine synthesis system and the thymidine synthesis system.
Normally, 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. Amethopterin (methotrexate: MTX) and its peripheral compounds are known as drugs that strongly bind to the enzyme (dihydrofolate reductase) that controls the second step and suppress the reduction of dihydrofolate to tetrahydrofolate. Since these drugs are drugs that impair DNA synthesis and result in cell death, they have been developed as antitumor agents and currently occupy a clinically important position. On the other hand, unlike these drugs, a novel tetrahydroaminopterin system that does not show dihydrofolate reductase inhibition and is mainly involved in the inhibition of glycinamide ribonucleotide transformylase involved in the early stage of purine biosynthesis Antitumor agent (5,
10-Dideaza-5,6,7,8-tetrahydroaminopterin: DD
ATHF) has also been reported. [Journal of Medicinal Chemist
ry) 28, 914 (1985) ] SUMMARY OF THE INVENTION Currently, various studies have been made for the treatment of cancer,
What is particularly expected is the development of a more effective drug having a high selective toxicity to cancer cells based on a new mechanism of action. MTX, an antitumor agent whose mechanism of action is folate antagonism, is currently widely used clinically, but it has relatively satisfactory therapeutic results such as relatively strong toxicity and little effect on solid cancer. Not obtained.

Means for Solving the Problems In view of the above circumstances, the present inventors have conducted intensive studies, and as a result, the novel pyrrolopyrimidine derivative has high selective toxicity to tumor cells and shows an excellent antitumor effect. The inventors have found out and completed the present invention.

That is, the present invention provides (1) general formula (I) [Wherein, the ring is a pyrrole or pyrroline ring, X is an amino group or a hydroxy group, Y is a hydrogen atom, an amino group or a hydroxy group, R is a hydrogen atom, a fluorine atom, an alkyl group, an alkenyl group or an alkynyl group, and -COOR. ¹ and −COOR ²
Are the same or different and optionally esterified carboxy groups, n is an integer of 2 to 4, and R is
May be different in each of the n repetitions. ]
A compound represented by: or a salt thereof, (2) general formula (II) [Wherein the ring is a pyrrole or pyrroline ring, X is an amino group or a hydroxy group, Y is a hydrogen atom, an amino group or a hydroxy group, R is a hydrogen atom, a fluorine atom, an alkyl group, an alkenyl group or an alkynyl group, and n is Each represents an integer of 2 to 4, and R may be different from each other in n repeating units. ] The compound represented by these, the reactive derivative in the carboxyl group or those salts, and general formula (III) [In the formula, -COOR ¹ and -COOR ² are the same or different and each represents an optionally esterified carboxy group. ] The manufacturing method of compound (I) or its salt characterized by reacting with the compound or its salt represented by these, (3) General formula (IV) [Wherein, the ring is a pyrrole or pyrroline ring, X is an amino group or a hydroxy group, Y is a hydrogen atom, an amino group or a hydroxy group, R is a hydrogen atom, a fluorine atom, an alkyl group, an alkenyl group or an alkynyl group, and -COOR. ³ represents an optionally esterified carboxy group, n represents an integer of 2 to 4, and R may be different in n repeating units. ] The compound or its salt represented by these,
And (4) an antitumor agent containing the compound (I) or a salt thereof.

In the above formula, when X or Y is a hydroxy group, compounds (I), (II) and (IV) can exist as equilibrium mixtures with their tautomers. The partial structural formulas capable of tautomerism are listed below, and the equilibrium relationship between them is shown.

For convenience of display, the hydroxy form is described throughout this specification and the corresponding nomenclature is adopted, but in each case, the tautomeric oxo form is also included.

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

In the above formula, the alkyl group represented by R has 1 carbon atom.
To 3 alkyl groups (eg, methyl, ethyl, propyl, iso-propyl groups).

Examples of the alkenyl group represented by R include an alkenyl group having 2 to 3 carbon atoms (eg, vinyl, 1-methylvinyl, 1-propenyl, allyl, allenyl groups).

Examples of the alkynyl group represented by R include an alkynyl group having 2 to 3 carbon atoms (eg, ethynyl, 1-propynyl, propazyl group).

The optionally esterified carboxy group represented by —COOR ¹ , —COOR ² and —COOR ³ has an alkyl group having 1 to 5 carbon atoms and a substituent (eg, nitro, methoxy group, etc.). Optionally a benzyl group or a substituent (eg,
Examples thereof include a carboxy group esterified with a phenyl group which may have a nitro group, a methoxy group and the like. Examples of the alkyl group include methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, sec-
Pentyl, neo-pentyl, tert-pentyl, etc., benzyl which may have the substituent, benzyl,
Nitrobenzyl, methoxybenzyl and the like, and examples of the phenyl which may have the substituent include phenyl, nitrophenyl and methoxyphenyl.

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

The compound (I) can be obtained by acylating the glutamic acid derivative represented by the formula (III) with a carboxylic acid represented by the formula (II) or a reactive derivative at the carboxy group thereof. Examples of the acylation means include a method in which compound (III) is acylated with compound (II) in the presence of carbodiimides, diphenylphosphoryl azide or diethyl phosphorocyanidate. The amount of compound (III) used relative to compound (II) is generally about 1-2.
It is 0 molar equivalent, preferably about 1 to 5 molar equivalents. The carbodiimide, diphenylphosphoryl azide or diethylphosphorusanidate is generally about 1 to 25 molar equivalents, preferably about 1 to 5 with respect to the compound (II).
Molar equivalents may be used. As the carbodiimides, dicyclohexylcarbodiimide is practically preferable, and other carbodiimides such as diphenylcarbodiimide, di-o-tolylcarbodiimide, di-p-tolylcarbodiimide, 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) carbodiimide You may use. 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, etc.), ethers (eg, dimethyl ether, diethyl ether, tetrahydrofuran). , Dioxane, monoglyme, diglyme etc.), nitriles (eg acetonitrile etc.), esters (eg ethyl acetate etc.), halogenated hydrocarbons (eg dichloromethane, chloroform, carbon tetrachloride etc.), aromatic hydrocarbons ( (Eg, benzene, toluene, xylene, etc.), acetone, nitromethane, pyridine, dimethylsulfoxide, dimethylformamide, hexamethylphosphoramide, sulfolane, or an appropriate mixed solvent thereof is used. This reaction is usually carried out at a pH of about 2 to 14, preferably about 6 to 9, at a temperature of about -10 ° C to the boiling point of the reaction solvent (up to about 100 ° C), preferably about 0 to 50 ° C. At a reaction temperature of about 1 to 100
It can be carried out by reacting for a time. The pH of the reaction solution may be appropriately adjusted with an acid (eg, hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, etc.) or a base (eg,
Sodium methylate, sodium ethylate and other sodium alcoholates, sodium hydroxide, potassium hydroxide, lithium hydroxide, and barium hydroxide and other alkali metal or alkaline earth metal hydroxides, sodium carbonate, potassium carbonate, barium carbonate , Alkali metal or alkaline earth metal carbonates or bicarbonates such as calcium carbonate and sodium bicarbonate, trimethylamine,
If necessary, adjust with amines such as triethylamine, triethanolamine and pyridine) or buffers (eg, phosphate buffer, borate buffer, acetate buffer, etc.). In addition, the reaction can be proceeded more advantageously by using a catalyst capable of promoting acylation. Examples of such a catalyst include a base catalyst and an acid catalyst. Examples of such a base catalyst include tertiary amines (for example, aliphatic tertiary amines such as triethylamine; pyridine, α-, β- or γ-picoline, 2,6-lutidine, 4-dimethylaminopyridine, 4- (1 -Pyrrolidinyl) pyridine, aromatic tertiary amines such as dimethylaniline, diethylaniline) and the like, and examples of the acid catalyst include Lewis acids [eg, anhydrous zinc chloride, anhydrous aluminum chloride (Al Cl ₃ ), anhydrous tertiary chloride. Diiron, titanium tetrachloride (TiCl ₄ ), tin tetrachloride (SnCl ₄ ), antimony pentachloride, cobalt chloride, cupric chloride, boron trifluoride etherate, etc.] and the like. Of the above catalysts, 4-dimethylaminopyridine or 4- (1-pyrrolidinyl) pyridine is often preferred. The amount of the catalyst used is such that the amount of the catalyst that can accelerate the acylation is good, and is usually about 0.01 to 10 molar equivalents, preferably about 0.1 to 1 molar equivalents to the compound (II). Examples of the reactive derivative at the carboxy group of carboxylic acid (II) include, for example, acid halides (eg, fluoride, chloride, bromide, iodide) of carboxylic acid (II), acid anhydrides (eg, iodoacetic anhydride,
Anhydrous isobutyric acid), monoalkyl carbonate (eg, monomethyl carbonate, monoethyl carbonate, monopropyl carbonate, mono iso-propyl carbonate, monobutyl carbonate, mono iso-butyl carbonate, mono sec-butyl carbonate, Mixed acid anhydride with mono tert-butyl carbonate, active ester (eg, cyanomethyl ester, carboethoxymethyl ester, methoxymethyl ester, phenyl ester,
o-nitrophenyl ester, p-nitrophenyl ester, p-carbomethoxyphenyl ester, p-cyanophenyl ester, thiophenyl ester), acid atide, phosphoric acid diester (eg, dimethyl phosphate, diethyl phosphate, dibenzyl phosphate, diphenyl) Examples thereof include mixed acid anhydrides with phosphate) and phosphoric acid diesters (eg, dimethyl phosphite, diethyl phosphite, dibenzyl phosphite, diphenyl phosphite). In the acylation means using this reactive derivative, the solvent, the catalyst, the reaction temperature and the like are the same as those in the acylation performed in the presence of the carbodiimides.

Among the compound (I), if -COOR ¹ and -COOR ² to produce a compound which is a carboxy group ^(I-1), -COOR 1 and -COOR ² of the compound (III) is esterified After reacting a compound which is a carboxy group with the compound (II), it is preferable to subject it to a decomposition reaction or a catalytic reduction reaction known per se for deesterification. As the decomposition reaction, for example, a hydrolysis reaction (A
Method), a hydrolysis reaction under acidic conditions (method B-1),
The decomposition reaction (B-2 method) and the like under acidic non-aqueous conditions can be mentioned. Examples of the base used in Method A include sodium methoxide, sodium ethoxide,
Metal alkoxides such as sodium butoxide and potassium butoxide, metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide and barium hydroxide, and amines such as ammonia, triethylamine and pyridine are mentioned. As the acid used,
Examples thereof include mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, and organic acids such as trifluoroacetic acid, trichloroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and camphorsulfonic acid. And B
Examples of the catalyst used in the -2 method include mineral acids such as hydrogen chloride, hydrogen bromide, perchloric acid, sulfuric acid, nitric acid, phosphoric acid, trifluoroacetic acid, trichloroacetic acid, methanesulfonic acid, benzenesulfonic acid, p - toluenesulfonic acid, an organic acid such as camphorsulfonic acid, anhydrous zinc chloride, anhydrous aluminum chloride (Al Cl _3), anhydrous ferric chloride, titanium tetrachloride (TiCl _4), tin tetrachloride (SnCl _4), pentachloride Lewis acids such as antimony, cobalt chloride, cupric chloride and boron trifluoride etherate can be mentioned. In any case, the decomposition reaction is carried out by reacting in a suitable solvent at 0 ° C to the boiling point of the solvent, preferably 10 to 80 ° C, for 30 minutes to 2 days. As the reaction solvent, in the case of Method A and Method B-1, for example, water, methanol, ethanol, propanol, butanol, ethylene glycol, methoxyethanol, ethoxyetal, tetrahydrofuran, dioxane, monoglyme, diglyme, pyridine, dimethylformamide, dimethyl. Sulfoxide,
Sulfolane or suitable mixtures thereof are used, B
In the case of method -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 one thereof. Mixed solvents are used. The catalytic reduction reaction (C
Method) is carried out at a temperature in the range of about -40 ° C to the boiling point of the reaction solvent, more preferably about 0 to 50 ° C, using an appropriate solvent. Solvents used include water, alcohols (eg, methanol, ethanol, propanol, is
o-propanol, butyl alcohol, sec-butyl alcohol, tert-butyl alcohol, ethylene glycol,
Methoxyethanol, ethoxyethanol), acetic acid esters (eg, methyl acetate, ethyl acetate), ethers (eg, dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme), aromatic hydrocarbons (eg, benzene, toluene, Xylene),
Pyridine, dimethylformamide, and an appropriate mixed solvent thereof are included. As the catalyst for catalytic reduction, for example, palladium, platinum, rhodium, Raney nickel, etc. are used. At this time, the addition of a small amount of acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid or the like may allow the reaction to proceed advantageously.

Compound (I-1) or induced to the varies depending on the nature of -COOR ¹ and -COOR ² by any reaction, usually, -COOR ¹ and -COOR ² are methyl, ethyl, propyl, butyl, sec- butyl , Phenyl or carboxy esterified by a substituted phenyl group, A
Method or B-1 method, when -COOR ¹ and -COOR ² are carboxy groups esterified by iso-propyl or tert-butyl group, B-2 method, or by benzyl group or substituted benzyl group When it is a carboxy group, method B-1 or method C is advantageously applied. In addition,
When -COOR ¹ and -COOR ² are different, the above method A, B-1
Method, B-2 method and C method may be appropriately combined.

Next, the method for producing the starting compound (II) will be described.

Of the compound (II), the compound whose ring is a pyrrole ring is
For example, it can be produced by the following reaction steps.

In the above steps, X, Y and R ³ have the same meanings as described above,
R ^a , R ^b and R ^c are the same or different and each is hydrogen, fluorine or an alkyl group (similar to the alkyl group represented by R above).
R ⁴ is a cyano group or an esterified carboxy group represented by the formula —COOR ⁵ , A is a hydrogen atom or a halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), and B is a halogen atom. Atom (eg, chlorine atom, bromine atom,
An iodine atom) or a removable group that can be easily derived from a hydroxy group (eg, methanesulfonyloxy group, benzenesulfonyloxy group, p-toluenesulfonyloxy group, trifluoromethanesulfonyloxy group), m
Indicates 0, 1 or 2, respectively. R ⁵ in the esterified carboxy group represented by the formula —COOR ⁵ is an alkyl group having 1 to 4 carbon atoms (eg, methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, te
rt-butyl etc.), phenyl or substituted phenyl (p-nitrophenyl, p-methoxyphenyl etc.), benzyl or substituted benzyl (eg p-nitrobenzyl, p-methoxybenzyl etc.).

The compound (V) may be dehydrogenated at a possible position between two adjacent carbon atoms or may form an unsaturated bond.

Hereinafter, the reaction step will be described in detail.

Step 1 Compound (V) and (VI) are subjected to a condensation reaction, and the resulting product is then subjected to a reduction reaction to give compound (VII)
Can be manufactured.

As the condensation reaction, a known reaction (eg, aldol type reaction,
Reformatsky type reaction, Wittig reaction) is applied, and as the reduction reaction, usually, catalytic reduction in which a catalyst (eg, nickel, palladium, platinum, rhodium) is added under a hydrogen atmosphere is advantageously applied.

When an aldol type reaction is used as the condensation reaction,
Examples of the base catalyst used include sodium hydroxide,
Metal hydroxides such as potassium hydroxide, lithium hydroxide, barium hydroxide, sodium methoxide, sodium ethoxide, metal alkoxides such as potassium tert-butoxide, sodium amide, metal amides such as lithium diisopropylamide, sodium hydride, Metal hydrides such as potassium hydride, organometallic compounds such as phenyllithium and butyllithium, triethylamine, pyridine, α-, β- or γ-picoline, 2,6-lutidine, 4-dimethylaminopyridine, 4- (1 -Pyrrolidinyl) pyridine, dimethylaniline, diethylaniline, and other amines, and examples of the acid catalyst include:
Mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and boric acid, and organic acids such as oxalic acid, tartaric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and camphorsulfonic acid. To be Also,
Known method [Ei-ichi Negishi, Organometallics in Organic Synthesis]
rganic Synthesis) vol.1, John Wiley & Sons, New Yor
k, Chichester, Brisbane, Toronto (1980)],
Leading from a ketone body to a silyl enol ether body, Lewis acid [eg, anhydrous zinc chloride, anhydrous aluminum chloride (AlC
l ₃ ), anhydrous ferric chloride, titanium tetrachloride (TiCl ₄ ), tin tetrachloride (SnCl ₄ ), antimony pentachloride, cobalt chloride, cupric chloride, boron trifluoride etherate, etc.],
It is subjected to a condensation reaction with an aldehyde or its equivalent or an α, β-unsaturated carbonyl compound, or a ketone is converted to an amine (eg, triethylamine, pyridine, α-,
β- or γ-picoline, 2,6-lutidine, 4-dimethylaminopyridine, 4- (1-pyrrolidinyl) pyridine, dimethylaniline, diethylaniline),
After conversion to an enolate treated with a metal triflate (eg, dialkylboron triflate, tin (II) triflate), the aldehyde or its equivalent or α,
It can also be carried out by subjecting it to a condensation reaction with a β-unsaturated carbonyl compound. The condensation reaction is carried out in a suitable solvent at -100
℃ to the boiling point of the solvent, preferably -78 to 100 ℃
It is carried out by reacting for 1 minute to 3 days in the range. As the reaction solvent, for example, water, liquid ammonia,
Alcohols (eg, methanol, ethanol, propanol, iso-propanol, butyl alcohol, sec-butyl alcohol, tert-butyl alcohol, ethylene glycol, methoxyethanol, ethoxyethanol),
Ethers (eg, dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme), halogenated hydrocarbons (eg, dichloromethane,
Chloroform, carbon tetrachloride), aliphatic hydrocarbons (eg, pentane, hexane, heptane), aromatic hydrocarbons (eg,
Benzene, toluene, xylene), dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, sulfolane or an appropriate mixed solvent thereof is used. When the Wittig reaction is used as the condensation reaction, the reagent used is, for example, sodium hydroxide,
Metal hydroxides such as potassium hydroxide, lithium hydroxide, barium hydroxide, sodium methoxide, sodium ethoxide, metal alkoxides such as potassium tert-butoxide, sodium amide, metal amides such as lithium diisopropylamide, sodium hydride, Metal hydrides such as potassium hydride, organometallic compounds such as phenyllithium and butyllithium, triethylamine, pyridine, α-, β- or γ-picoline, 2,6-lutidine, 4-dimethylaminopyridine, 4- (1 Amines such as -pyrrolidinyl) pyridine, dimethylaniline and diethylaniline. The reaction is carried out in a suitable solvent,
It is carried out by reacting at −78 ° C. to the boiling point of the solvent, preferably in the range of 0 to 150 ° C. for 1 minute to 10 days. Examples of the reaction solvent include liquid ammonia, alcohols (eg, methanol, ethanol, propanol, iso-
Propanol, butyl alcohol, sec-butyl alcohol, tert-butyl alcohol, ethylene glycol, methoxyethanol, ethoxyethanol), ethers (eg, dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme), aliphatic hydrocarbons (eg. , Pentane, hexane, heptane),
Aromatic hydrocarbons (eg, benzene, toluene, xylene), dimethylformamide, dimethylsulfoxide,
Hexamethylphosphoramide, sulfolane or an appropriate mixed solvent thereof is used.

Furthermore, it is also possible to carry out condensation using a Reformatsky type reaction. The reaction conditions of the Reformatsky type reaction include, for example, zinc, magnesium, aluminum and tin as reagents to be used. The reaction itself is carried out in an appropriate solvent from −20 ° C. to the boiling point of the solvent, preferably 0. ~ 150
It is carried out by reacting for 30 minutes to 3 days in the range of ° C. Examples of the reaction solvent include ethers (eg, dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme), aliphatic hydrocarbons (eg, pentane, hexane, heptane), aromatic hydrocarbons (eg, benzene, toluene). , Xylene) or an appropriate mixed solvent thereof.

The reaction conditions for catalytic reduction include --COOR ^{1 of} compound (III).
The conditions used in the deesterification reaction of -COOR ² (method C) can be applied as they are.

The starting materials (V) and (VI) can be easily obtained by a method known in the literature. [B.Neiseset al., Angebuante Chemie International Edition (Angew.Chem.Int.Ed.Engl.), 17, 522 (1978)] Step 2 compound active methylene moiety (carboxylic acid ester (VII) This is a step of introducing a removable functional group B at the α-position), which can be easily carried out by a known method using a known reagent.

Third step The compound (VIII) obtained in the second step is malononitrile or cyanoacetic acid ester [NC-
CH ₂ COOR ⁵ ; R ⁵ has the same meaning as defined above] to obtain the compound (IX). As for the base, solvent, reaction conditions and the like used, a method known per se can be adopted.

Step 4 When compound (IX) is treated with guanidine, it reacts with a cyano group or an ester residue, followed by ring closure / cyclization to form a new pyrrolopyrimidine ring. When the ring-closing is carried out under basic conditions, the reaction can be advantageously progressed. Examples of the base used include metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide. Examples of the reaction solvent include methanol, ethanol, propanol, tert-butyl alcohol, dimethyl sulfoxide, and hexamethylphosphoramide, and the reaction temperature is 0 to 150 ° C, preferably 20 to 100 ° C, and the reaction time is 1 to 48 hours.

Fifth step Compound obtained in the fourth step (IV-1: Y = NH ₂ or OH)
Is the ester residue [-COOR ³ ] of the compound (I-1)
The compound can be converted to a compound (II-1: Y = NH ₂ or OH) by subjecting it to the deesterification reaction used in the production of

Sixth Step The compound (II-2: Y = H) can be produced by subjecting the compound (II-1: Y = OH) obtained in the fifth step to a reduction reaction. The conditions for the reduction reaction are known per se, but a reduction reaction with a metal hydride (eg, borane, alane, or a lower (C _1-5 ) alkyl-substituted product or ate complex thereof) can be advantageously applied.

The order of applying the fifth step and the sixth step may be reversed. That is, in the seventh step, the compound (IV-1: Y = OH) was treated with the same reduction reaction as in the sixth step to form the compound (IV-2: Y = H), and then in the eighth step, the fifth step was performed. When subjected to a deesterification reaction in the same manner as in the process, the compound (II
−2: Y = H) is obtained. Whether to carry out the deesterification reaction or the reduction reaction first can be appropriately selected according to the nature of the substituent of the compound (IV-1: Y = OH).

In the sixth and eighth steps, a mixture containing compounds (II-2) and (II-2 ′), compounds (IV-2) and (IV-
Each compound may be separated from the mixture containing 2 ') by a known method, or the compounds (II-2) and (II-
2 '), compounds (IV-2) and (IV-2') can also be preferentially synthesized by selectively reducing each.

Further, in the compound (II), a compound represented by the formula (II-3: X = OH) [In the formula, R, Y and n have the same meanings as described above. ] The compound represented by the following can also be obtained by the production method described below.

In the above steps, R, R ³ , Y and n have the same meanings as described above, and Z has the formula RCH ₂ CO— [wherein R has the same meanings as described above. ],formula [In the formula, L represents phenyl, butyl or cyclohexyl, and R and n have the same meanings as described above. ] Or an expression [In the formula, M represents ethyl or phenyl, R and n
Has the same meaning as above. ] Is shown.

Note that Y is preferably hydrogen.

Hereinafter, the reaction step will be described.

Step 9 Compound (X) [T.Kondo et al., Chemistry Letters, 419 (1983)] and para-substituted benzoic acid ester derivative (XI) are subjected to a condensation reaction (aldol reaction, Wittig reaction). Then, the compound (XII) is obtained by subjecting it to catalytic reduction in a hydrogen atmosphere. For the condensation reaction, the reaction conditions, reaction solvent, reaction temperature, reagents and the like used in the first step can be applied as they are. Catalytic reduction under a hydrogen atmosphere is performed by -COOR ¹ and -COOR ² of compound (III).
The conditions used in the deesterification reaction (method C) can be applied as they are.

Step 10 By treating compound (XII) under acidic conditions, 3
The isopropyloxymethyl group at the position can be deprotected and converted to compound (XIII). The reaction conditions, reaction solvent, reaction temperature, etc. are the deesterification reaction of -COOR ¹ and -COOR ² of compound (III) (method B-1 and method B-2).
The conditions used in can be applied mutatis mutandis.

Eleventh Step The compound (XIII) obtained in the tenth step can be easily converted into the compound (IV-3: Y = H) by subjecting it to a dehydrogenation reaction by a known method.

Twelfth step The compound (IV-3: Y = H) obtained in the eleventh step can be converted to the compound (II-3) by subjecting it to a deesterification reaction. The reaction conditions, reaction solvent and reaction temperature used are -COOR ¹ and -COOR ² of the compound (III).
Deesterification reaction (method A, method B-1, method B-2 and C)
The conditions detailed in the Act) can be applied as they are. In addition, any of the 10th to 12th steps may be performed first, and the corresponding products are obtained, but in the end, it may be converted to the target compound (II-3). I can. Which process is to be performed first depends on the compound (XI
It can be appropriately selected depending on the properties of the substituents of I), (XIII) and (IV-3). The compound (II
If necessary, -3) can be converted into compound (II-2) by a substituent conversion reaction on the pyrimidine ring known in the literature. [Separate Volume Protein Nucleic Acid Enzyme, Chemical Synthesis of Nucleic Acid, Kyoritsu Shuppan (1968)] Further, compounds other than the compound (II-3) in which X is a hydroxyl group are also subjected to the above substituent conversion reaction to obtain the corresponding compound (X is It can also be converted to an amino group).

The reactions, reagents and reaction conditions used in the above-mentioned 1st to 12th steps or in the production of the starting compounds (V) and (XIII) are known in the following documents and explained in detail. Has been done.

[JFWMcOmine, Protective Groups in Organic Chemistry
Organic Chemistry), Plenum Press, London and New
York (1973)], [Pine Hendrickson Hammond, Organic Chemistry (4th Edition) [I]-[II], Hirokawa Shoten (19
82)] and [M.Fieser and L.Fieser, Regent for Organic Synthesis, Volumes 1-13 (Re
agents for Organic Synthesis vol.1-10), Wiley-In
terscience, New York, London, Sydney and Toronto
(1969-1988)] Further, the intermediate of the compound of the present invention produced by these steps and the compound (I) of the present invention can be isolated by a usual separation and purification means such as concentration, solvent extraction, chromatography and recrystallization. It can be isolated from the reaction mixture.

The compounds (I), (II) and (III) of the present invention may form salts, and examples of such salts include salts with pharmaceutically acceptable bases or acids and quaternary salts. Base salts include alkali metals, alkaline earth metals, non-toxic metals, ammonium and substituted ammonium such as sodium, potassium, lithium, calcium, magnesium, aluminum, zinc, ammonium, trimethylammonium, triethylammonium, triethanolammonium. , Pyridinium, substituted pyridinium and the like. Examples of the acid salt include mineral acid salts 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-toluenesulfonic acid, Organic acid salts with camphorsulfonic acid and the like can be mentioned. Examples of the quaternary salt include salts with methyl bromide, methyl iodide, methanesulfonic acid methyl ester, benzenesulfonic acid methyl ester, p-toluenesulfonic acid methyl ester and the like.

Further, the compounds (I), (II) and (IV) may form an inner salt.

Specific examples of the compound (I) of the present invention include, for example, N- [4- [3- (2,4-diamino-7H-pyrrolo [2,3-
d] pyrimidin-5-yl) propyl] benzoyl]-
L-Glutamate diethyl, N- [4- [3- (2,4-diamino-7H-pyrrolo [2,3-
d] pyrimidin-5-yl) propyl] benzoyl]-
L-glutamic acid, N- [4- [3- (2,4-diamino-6-hydroxy-7
H-pyrrolo [2,3-d] pyrimidin-5-yl) propyl] benzoyl] -L-glutamate diethyl, N- [4- [3- (2,4-diamino-6-hydroxy-7)
H-pyrrolo [2,3-d] pyrimidin-5-yl) propyl] benzoyl] -L-glutamic acid, N- [4- [3- (2-amino-4-hydroxy-7H-
Pyrrolo [2,3-d] pyrimidin-5-yl) propyl]
Benzoyl] -diethyl L-glutamate, N- [4- [3- (2-amino-4-hydroxy-7H-
Pyrrolo [2,3-d] pyrimidin-5-yl) propyl]
Benzoyl] -L-glutamic acid, N- [4- [3- (2-amino-4-hydroxy-6,7
-Dihydro-5H-pyrrolo [2,3-d] pyrimidine-5-
Iyl) propyl] benzoyl] -diethyl L-glutamate, N- [4- [2- (2-amino-4-hydroxy-6,7
-Dihydro-5H-pyrrolo [2,3-d] pyrimidine-5-
Iyl) ethyl] benzoyl] -diethyl L-glutamate, N- [4- [3- (2,4-diamino-6,7-dihydro-5H
-Pyrrolo [2,3-d] pyrimidin-5-yl) propyl] benzoyl] -diethyl L-glutamate, N- [4- [3- (2-amino-4-hydroxy-6,7)
-Dihydro-5H-pyrrolo [2,3-d] pyrimidine-5-
Yl) propyl] benzoyl] -L-glutamic acid, N- [4- [2- (2-amino-4-hydroxy-6,7
-Dihydro-5H-pyrrolo [2,3-d] pyrimidine-5-
Iyl) ethyl] benzoyl] -L-glutamic acid, N- [4- [3- (2,4-diamino-6,7-dihydro-5H
-Pyrrolo [2,3-d] pyrimidin-5-yl) propyl] benzoyl] -L-glutamic acid, N- [4- [3- (2,4-diamino-6,7-dihydro-5H
-Pyrrolo [2,3-d] pyrimidin-5-yl) -1-methylpropyl] benzoyl] -diethyl L-glutamate, N- [4- [3- (2,4-diamino-6,7-dihydro- 5H
-Pyrrolo [2,3-d] pyrimidin-5-yl) -1-methylpropyl] benzoyl] -L-glutamic acid, N- [4- [3- (2,4-diamino-7H-pyrrolo [2,3 −
d] pyrimidin-5-yl) -1-methylpropyl] benzoyl] -L-glutamic acid, N- [4- [3- (2,4-diamino-7H-pyrrolo [2,3-]
d] pyrimidin-5-yl) -1-methylpropyl] benzoyl] -L-glutamic acid, N- [4- [3- (2,4-diamino-7H-pyrrolo [2,3-]
d] pyrimidin-5-yl) -2-methylpropyl] benzoyl] -L-glutamic acid, N- [4- [3- (2,4-diamino-7H-pyrrolo [2,3-]
d] pyrimidin-5-yl) -1-ethylpropyl] benzoyl] -L-glutamic acid, N- [4- [3- (2,4-diamino-7H-pyrrolo [2,3-]
d] pyrimidin-5-yl) -2-ethylpropyl] benzoyl] -L-glutamic acid, N- [4- [3- (2,4-diamino-7H-pyrrolo [2,3-]
d] pyrimidin-5-yl) -1-vinylpropyl] benzoyl] -L-glutamic acid, N- [4- [3- (2,4-diamino-7H-pyrrolo [2,3-]
d] pyrimidin-5-yl) -2-vinylpropyl] benzoyl] -L-glutamic acid, N- [4- [3- (2,4-diamino-7H-pyrrolo [2,3-]
d] pyrimidin-5-yl) -1-allylpropyl] benzoyl] -L-glutamic acid, N- [4- [3- (2,4-diamino-7H-pyrrolo [2,3-]
d] pyrimidin-5-yl) -2-allylpropyl] benzoyl] -L-glutamic acid, N- [4- [3- (2,4-diamino-7H-pyrrolo [2,3-]
d] pyrimidin-5-yl) -1- (propen-1-yl) propyl] benzoyl] -L-glutamic acid, N- [4- [3- (2,4-diamino-7H-pyrrolo [2,3-]
d] pyrimidin-5-yl) -2- (propen-1-yl) propene] benzoyl] -L-glutamic acid, N- [4- [3- (2,4-diamino-7H-pyrrolo [2,3-]
d] pyrimidin-5-yl) -1-thienylpropyl]
Benzoyl] -L-glutamic acid, N- [4- [3- (2,4-diamino-7H-pyrrolo [2,3-
d] pyrimidin-5-yl) -2-ethynylpropyl]
Benzoyl] -L-glutamic acid, N- [4- [3- (2,4-diamino-7H-pyrrolo [2,3-
d] pyrimidin-5-yl) -1-propadylpropyl] benzoyl] -L-glutamic acid, N- [4- [3- (2,4-diamino-7H-pyrrolo [2,3-]
d] pyrimidin-5-yl) -2-propadylpropyl] benzoyl] -L-glutamic acid, N- [4- [3- (2,4-diamino-7H-pyrrolo [2,3-]
d] pyrimidin-5-yl) -1- (propyn-1-yl) propyl] benzoyl] -L-glutamic acid, N- [4- [3- (2,4-diamino-7H-pyrrolo [2,3-]
d] pyrimidin-5-yl) -2- (propyn-1-yl) propyl] benzoyl] -L-glutamic acid, N- [4- [3- (2,4-diamino-6,7-dihydro-5H
-Pyrrolo [2,3-d] pyrimidin-5-yl) -2-methylpropyl] benzoyl] -L-glutamic acid, N- [4- [3- (2,4-diamino-6,7-dihydro-5H
-Pyrrolo [2,3-d] pyrimidin-5-yl) -1-ethylpropyl] benzoyl] -L-glutamic acid, N- [4- [3- (2,4-diamino-6,7-dihydro-5H
-Pyrrolo [2,3-d] pyrimidin-5-yl) -2-ethylpropyl] benzoyl] -L-glutamic acid, N- [4- [3- (2,4-diamino-6,7-dihydro-5H
-Pyrrolo [2,3-d] pyrimidin-5-yl) -1-vinylpropyl] benzoyl] -L-glutamic acid, N- [4- [3- (2,4-diamino-6,7-dihydro-5H
-Pyrrolo [2,3-d] pyrimidin-5-yl) -2-vinylpropyl] benzoyl] -L-glutamic acid, N- [4- [3- (2,4-diamino-6,7-dihydro-5H
-Pyrrolo [2,3-d] pyrimidin-5-yl) -1-allylpropyl] benzoyl] -L-glutamic acid, N- [4- [3- (2,4-diamino-6,7-dihydro-5H
-Pyrrolo [2,3-d] pyrimidin-5-yl) -2-allylpropyl] benzoyl] -L-glutamic acid, N- [4- [3- (2,4-diamino-6,7-dihydro-5H
-Pyrrolo [2,3-d] pyrimidin-5-yl) -1-
(Propen-1-yl) propyl] benzoyl] -L-
Glutamic acid, N- [4- [3- (2,4-diamino-6,7-dihydro-5H
-Pyrrolo [2,3-d] pyrimidin-5-yl) -2-
(Propen-1-yl) propyl] benzoyl] -L-
Glutamic acid, N- [4- [3- (2,4-diamino-6,7-dihydro-5H
-Pyrrolo [2,3-d] pyrimidin-5-yl) -1-ethynylpropyl] benzoyl] -L-glutamic acid, N- [4- [3- (2,4-diamino-6,7-dihydro-5H
-Pyrrolo [2,3-d] pyrimidin-5-yl) -2-enitylpropyl] benzoyl] -L-glutamic acid, N- [4- [3- (2,4-diamino-6,7-dihydro- 5H
-Pyrrolo [2,3-d] pyrimidin-5-yl) -1-propadylpropyl] benzoyl] -L-glutamic acid, N- [4- [3- (2,4-diamino-6,7-dihydro- 5H
-Pyrrolo [2,3-d] pyrimidin-5-yl) -2-propadylpropyl] benzoyl] -L-glutamic acid, N- [4- [3- (2,4-diamino-6,7-dihydro- 5H
-Pyrrolo [2,3-d] pyrimidin-5-yl) -1-
(Propin-1-yl) propyl] benzoyl] -L-
Glutamic acid, N- [4- [3- (2,4-diamino-6,7-dihydro-5H
-Pyrrolo [2,3-d] pyrimidin-5-yl) -2-
(Propin-1-yl) propyl] benzoyl] -L-
Examples thereof include glutamic acid.

Action The compound (I) in the present invention is used in the mouse tumor cell line system (P388, L1210, L5178Y, B16 melanoma, MethA, Lewis).
Lung Carcinoma, S180 sarcoma, Erhlich Carcinoma, C
olon38), and human tumor cell line (HL60, KB, Lu65)
It has an excellent anti-tumor effect against tumors and is a tumor that warm-blooded animals raise [eg, melanoma, sarcoma (sarcom).
a), mastocytoma, carcinoma (carcinom)
a), neoplasia, etc.], as well as prolonging the survival of tumor-bearing warm-blooded animals.

The experimental results showing the pharmacological effect of the compound (I) in the present invention are described below.

The cell growth inhibitory effect (IC ₅₀ ) on the KB cells of the compounds obtained in Examples described later was measured by the following method.

Human nasopharyngeal carcinoma KB cells (1 × 10 ⁴ cells / m ² ) prepared by a conventional method
0.1 ml of each well was inoculated into a 96-well microcawell plate, and static culture was carried out at 37 ° C. and 5% CO ₂ for 24 hours.
A 10% MEM (Nissui Pharmaceutical Co., Ltd.) solution of the example compound was added thereto, and again static culture was carried out under the conditions of 37 ° C. and 5% CO ₂ for 72 hours. Then, the culture solution was removed with a micropipette, 0.1 ml of 10% MEM solution (1.0 mg / ml) of MTT (Dojindo) was newly added, and the mixture was incubated at 37 ° C for 4 hours and further 10% SDS (Wako Pure Chemical Industries).
0.1 ml of the solution was added and the culture was continued at 37 ° C. for 24 hours. 590nm
Absorbance was measured at the wavelength of
The concentration of the drug required to reduce the IC _{50 of the} compound
Value. The results obtained are shown in Table 1.

Next, the growth inhibitory effect (IC ₅₀ ) of the compound obtained in Example 14 described later on HL-60 and HEL was measured by the following method.

(1) Human leukemia cells HL-60 (2 × 10 ⁵ cells / ml) were suspended in a GIT medium (Wako Pure Chemical Industries, Ltd.) containing the compound of the present invention, and 0.2 ml of each well was inoculated into a 96-well microwell plate. 37
After static culture for 68 hours at 5 ° C and 5% CO ₂ , 1 μCi [ ³
[H] thymidine (5 Ci / mmol) was added, and the culture was continued for another 4 hours. To measure uptake of thymidine into cells,
The acid-insoluble fraction was collected on a glass filter, and its radioactivity was measured with a liquid scintillation counter. The concentration of the drug required to reduce the radioactivity incorporated into cells to 50% of that of the untreated control group was determined as the IC ₅₀ value of the compound. (2) Human fetal normal lung fibroblast HEL (1
X 10 ⁴ cells / ml) is suspended in MEM medium (Nippon Flow Laboratories), and each well is 0.1m in a 96-well microwell plate.
I inoculated each l. After standing still at 37 ° C. and 5% CO ₂ for 24 hours, MEM medium containing the compound of the present invention was added, followed by 72
Incubated for hours. The medium was exchanged with a medium containing 1 μg / ml of MTT (Dojindo), 10% SDS (Wako Pure Chemical Industries) was added, and after culturing overnight, the absorbance at 590 nm was measured by Multiscan (Titer Tech). IC compared to untreated control group
₅₀ values were determined. The results obtained are shown in Table 2.

As is clear from the above experimental results, Compound (I) exhibits an excellent cell growth inhibitory effect on human nasopharyngeal carcinoma KB cells and human leukemia cells HL-60, and on human fetal normal lung fibroblasts HEL. Shows almost no cytotoxicity. Also,
The compound (I) of the present invention or a salt thereof has low toxicity and has a remarkable antitumor effect. Therefore, the preparation containing the compound (I) or a salt thereof is used as an antitumor agent for treating tumors of warm-blooded animals, particularly mammals (eg, mice, rats, cats, dogs, rabbits, etc.). Can be done.

When used as an antitumor agent, the compound (I) or a salt thereof may be used by itself or a pharmacologically acceptable carrier, excipient, diluent or the like by a commonly used method, for example, powder, Granules, tablets, capsules, suppositories,
It may be administered orally or parenterally in the form of an injection. The dose varies depending on the target animal, disease, symptom, type of compound, administration route, etc.
It is 2.0 to 100 mg / kg body weight, and about 1.0 to 50 mg / kg per day for parenteral administration. Examples of the administration method as an injection include intramuscular injection, intraperitoneal injection, subcutaneous injection, intravenous injection and the like.

The above formulation is carried out according to a method known per se. 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 manufacturing a parenteral preparation, for example, an injection,
Isotonic agents (eg, glucose, D-sorbitol, D-mannitol, sodium chloride, etc.), preservatives (eg, benzyl alcohol, chlorobutanol, methyl paraoxybenzoate, propyl paraoxybenzoate, etc.), buffers (eg, A phosphate buffer solution, a sodium acetate buffer solution, etc.) can be appropriately blended.

Specific examples of the production of tablets include, for example, about 1.0 to 25 mg of the compound of the present invention and 100 to 500 mg of lactose as the amount used per tablet.
About 50 to 100 mg of corn starch and about 5 to 20 mg of hydroxypropyl cellulose were mixed by a conventional method, granulated, mixed with corn starch and magnesium stearate,
Tablets are made into tablets each having about 100 to 500 mg and a diameter of about 3 to 10 mm. In addition, the amount of this tablet used per tablet is hydroxypropylmethylcellulose phthalate (about 10-
20 mg) and castor oil (0.5 to 2 mg) were dissolved at a concentration of about 5 to 10% using an acetone-ethanol mixed solution,
By coating, an enteric coated tablet can be prepared.

As a specific example of the preparation of the injection, for example, the amount of sodium salt of the compound of the present invention is about 2.
A solution obtained by dissolving 0 to 50 mg in about 2 ml of physiological saline was injected into an ampoule and then sealed and heat sterilized at about 110 ° C. for about 30 minutes, or about 2.0 to 50 mg of the sodium salt was added to about 1
It can also be adjusted by dissolving 0 to 40 mg of mannitol or sorbitol in about 2 ml of sterilized distilled water, injecting it into an ampoule, freeze-drying this and sealing it. When using the freeze-dried compound, the ampoule is opened and the concentration of the compound is adjusted to about 1.0 in physiological saline, for example.
It can be prepared as a solution that is dissolved at a concentration of up to 25 mg / ml, and can be an injection for subcutaneous, intravenous or intramuscular administration.

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

Reference Example 1 Production of methyl 5- [4- (tert-butoxycarbonyl) phenyl] pentanoate: Dry tert-butyl alcohol (820 m
Potassium (25 g) was added to (l) and the mixture was heated under reflux for 3 hours to completely dissolve it. After cooling to 20 ° C and adding ether (300 ml), a solution of methyl crotonate (63.93 g) and tert-butyl 4-formylbenzoate (71.0 g) in tert-butyl alcohol-ether (2: 1,300 ml) was added. Add slowly while keeping the temperature at 10 ℃. After stirring at the same temperature for 2 hours, 1N potassium hydrogensulfate aqueous solution (750 ml) was added while cooling to adjust the pH to 4. After extraction with ether, washing with water and then with saturated saline, the solvent was distilled off under reduced pressure. The obtained residue was dissolved in ethyl acetate (100 ml), 5 × Pd—C (15 g: manufactured by Engelhardt) was added, and the mixture was vigorously stirred at room temperature for 3 hours under a hydrogen pressure of 4 kg / cm ² . The catalyst was filtered off, the solvent was evaporated under reduced pressure, dry methanol (200 ml), 4- (N, N-dimethylamino) pyridine (30 mg) and dichloromethane (250 ml) were added to the residue, and then 1,3-dicyclohexene was added. Cicarbodiimide (132g)
Dichloromethane solution (250 ml) was slowly added dropwise at 0 ° C. After stirring at room temperature for 18 hours, the mixture was cooled to 0 ° C., and acetic acid (30
ml) was added and the mixture was stirred at 0 ° C. for 30 minutes and at room temperature for 30 minutes. The precipitate formed was filtered off, the filtrate was concentrated to dryness under reduced pressure, ethyl acetate (100 ml) was added to the residue and the mixture was left standing at 0 ° C. for 2 hours, and the precipitate formed again was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (carrier; silica gel, 100 g, developing solvent; ether: hexane = 1: 15 → 1: 5) to obtain the desired product (59.7 g).

Boiling point (Bp) 145-155 ° C / 0.2-0.3mmHg. IR (Neat): 2980, 2950, 1740, 1712, 1605cm ^{-1 1} H-NMR (CDCl ₃ ) δ: 1.40-1.75 (4H, m), 1.55 (9H, s),
2.15-2.45 (2H, m), 2.50-2.75 (2H, m), 3.62 (3H, s),
7.16 (2H, d, J = 8Hz), 7.85 (H, d, J = 8Hz). Reference Example 2 Production of methyl 5- [4- (tert-butoxycarbonyl) phenyl] -2-iodopentanoate: Dibutylamine (24.5 mmol) was added to a tetrahydrofuran solution (100 ml) of diisopropylamine (2.48 g) under an argon atmosphere at 0 ° C. ) Was added to the hexane solution (15.3 ml) and stirred for 10 minutes, and a solution of the compound (6.53 g) obtained in Reference Example 1 (6.53 g) in tetrahydrofuran (50 ml) was added dropwise at -78 ° C over 30 minutes. After stirring for 30 minutes, iodine (5.66g)
Tetrahydrofuran solution (30 ml) was added and the mixture was further stirred for 20 minutes. The temperature was raised to 0 ° C. over 30 minutes, 30 ml of 1N potassium hydrogen sulfate aqueous solution was added dropwise to adjust the pH to 4, and the mixture was extracted with ether. The organic layer was washed with a 1N aqueous solution of potassium carbonate and then with saturated saline, and then dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by column chromatography (ether-hexane, 1: 9) to obtain the desired product (4.736 g).

IR (Neat): 2990,2905,1744,1718,1612cm ^-1 . ¹ H-NMR (CDCl ₃ ) δ: 1.45-1.80 (2H, m), 1.58 (9H, s),
1.80-2.16 (2H, m), 2.69 (2H, t, J = 7Hz), 3.72 (2H, s),
4.30 (1H, t, J = 7Hz), 7.20 (2H, d, J = 8Hz), 7.90 (2H, d, J
= 8Hz). Reference Example 3 5- [4- (tert-butoxycarbonyl) phenyl] -2-
(Production of methyl dicyanomethylpentanoate: A solution of malononitrile (3.37 g) in dimethyl sulfoxide (8 ml) was added to a suspension of sodium hydride (1.356 g) in dimethyl sulfoxide (8 ml) under water cooling, and the mixture was stirred for 15 minutes. A solution of the compound (4.736 g) obtained in Reference Example 2 in dimethyl sulfoxide (12 ml) was added dropwise to the mixture and stirred at room temperature for 1 hour, then 45 ml of 1N potassium hydrogensulfate aqueous solution was added at 0 ° C., and the mixture was extracted with ether. Was washed with water, dried over anhydrous magnesium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was purified by column chromatography (carrier; silica gel, 200 g, developing solvent; ethyl acetate: hexane = 1: 5). The desired product (3.33 g) was obtained.

IR (Neat): 2970,2930,2252,1740,1713,1608cm ^-1 . ¹ H-NMR (CDCl ₃ ) δ: 1.60-2.05 (4H, m), 1.48 (9H, s),
2.70 (2H, brt, J = 7Hz), 2.90-3.15 (1H, m), 3.82 (3H,
s), 4.04 (1H, d, J = 7Hz), 7.20 (2H, d, J = 8Hz), 7.92 (2
H, d, J = 8Hz). Reference Example 4 4- [3- (2-amino-7-benzyl-3-isopropyloxymethyl-4 (3H) -oxopyrrolo [2,3-d] pyrimidin-5-yl) -1-oxo-2-propenyl ] Methyl Benzoate Preparation: 2-Amino-7-benzyl-3-isopropyloxymethyl-
4 (3H) -Oxopyrrolo [2,3-d] pyrimidine-5-carbaldehyde (1.7g) was suspended in a methanol-tetrahydrofuran mixture (10: 1, 33ml), and sodium methylate in methanol (6.25mM) was added to the suspension. Equivalent, 3.75 ml) was added and dissolved. Then, 4-methoxycarbonylacetophenone (2.23 g) was added, and the mixture was stirred at room temperature for 15 hours. 1 The precipitate was collected by filtration, washed with a small amount of methanol and ether,
When dried, the desired product (2.02 g) was obtained as yellow needle crystals.

IR (KBr): 3480,3350,1710,1680,1620,1550,1375,1280,
1210,1110,1060,775.cm ^-1 . ¹ H-NMR (CDCl ₃ ) δ: 1.23 (6H, d, J = 6Hz), 3.93 (3H,
s), 3.80-4.07 (1H, m), 5.15 (2H, s), 5.63 (2H, s), 6.
92 (1H, s), 7.10-7.40 (5H, m), 7.73 (1H, d, J = 15Hz),
8.13 (4H, s), 8.60 (1H, d, J = 15Hz). Reference Example 5 4- [3- (2-amino-3-isopropyloxymethyl-4
Production of methyl (3H) -oxo-5,6-dihydropyrrolo [2,3-d] pyrimidin-5-yl) propyl] benzoate: The compound (2.01g) obtained in Reference Example 4 was mixed with methanol-tetrahydrofuran. It was dissolved in (3: 4, 350 ml), 1N hydrochloric acid (8 ml) and 10% Pd-C (4 g, manufactured by Engelhard Co.) were added, and then catalytic reduction was carried out for 48 hours in a hydrogen atmosphere. After removing the contact by filtration and neutralizing the filtrate, the solvent was distilled off under reduced pressure, and the residue was separated and purified by silica gel column chromatography (carrier: 100 g, developing solvent: chloroform containing 2 to 4% ethanol) to obtain the desired product ( 0.68 g) was obtained as a colorless powder.

IR (KBr): 3210,2980,1725,1625,1580,1510,1435,1275,
1175,1100,1060cm ^-1 . ¹ H-NMR (CDCl ₃ ) δ: 1.17 (3H, d, J = 6Hz), 1.19 (3H, d, J
= 6Hz), 1.50-2.13, (4H, m), 2.70 (2H, t, J = 7.5Hz), 3.0
7-3.77 (3H, m), 3.80-4.06 (1H, m), 3.87 (3H, s), 5.03
And 5.57 (2H, ABq), 7.21 (2H, d, J = 7.5Hz), 7.91 (2
H, d, J = 7.5Hz). Reference Example 6 4- [2- (2-amino-7-benzyl-3-isopropyloxymethyl-4 (3H) -oxopyrrolo [2,3-
Preparation of methyl [d] pyrimidin-5-yl) ethenyl] benzoate: 2-amino-7-benzyl-3-isopropyloxymethyl-4 (3H) -oxopyrrolo [2,3-d] pyrimidin-5-carbaldehyde ( 2.04 g) in dry methanol (84 ml) was added with p-methoxycarbonylbenzyltriphenylphosphonium bromide (3.24 g) and stirred.
Then, a methanol solution of sodium methylate (corresponding to 6.6 mM as sodium) was added, and the mixture was stirred at room temperature for 1.5 hours to precipitate yellow needle crystals. This is collected by filtration, washed with methanol and ether, and dried to give the desired product (cis isomer, 1.49
g) was obtained. Silica gel column for mother liquor (carrier: 100g)
Purification by chromatography (developing solvent: ethyl acetate-hexane, 1: 4 → 1: 3) further gave the desired product, a cis-trans mixture (0.9 g), as a yellow powder.

Cis form; IR (KBr): 3340,3220,2980,1715,1690,1625,160
0,1530,1430,1280,1175,1105,1060,995cm ^{-1 1} H-NMR (CDCl ₃ ) δ: 1.20 (6H, d, J = 6Hz), 3.87 (3H,
S), 3.80-4.07 (1H, m), 5.14 (2H, s), 5.32 (2H, s),
5.60 (2H, s), 6.77 (1H, s), 7.10-7.35 (5H, m), 7.43
(2H, s), 7.50 (2H, d, J = 9Hz), 7.95 (2H, d, J = 9Hz). Reference Example 7 4- [2- (2-amino-3-isopropyloxymethyl-4 (3H) -oxo-5,6-dihydropyrrolo [2,3-
Production of d] pyrimidin-5-yl) ethyl] methyl benzoate: The compound (1.6 g) obtained in Reference Example 6 was subjected to the same reaction as in Reference Example 5 to obtain the desired product (0.62 g). ¹ H-NMR (CDCl ₃ ) δ: 1.17 (3H, d, J = 6Hz), 1.20 (3H, d,
J = 6Hz), 1.47−2.0 (1H, m), 2.10−2.43 (1H, m), 2.65
(2H, t, J = 9Hz), 2.97-3.60 (3H, m), 3.73-4.07 (1H,
m), 3.90 (3H, s), 4.47 (2H, s), 5.30 (1H, d, J = 12H
z), 5.60 (1H, d, J = 12Hz), 7.13-7.50 (7H, m), 7.92
(1H, d, J = 9Hz). Reference Example 8 4- [2- (2-amino-4-hydroxy-6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-5-yl)
Production of ethyl] methyl benzoate: The compound (1.25 g) obtained in Reference Example 7 was dissolved in dry tetrahydrofuran (50 ml), and a dichloromethane solution of 0.21N hydrobromic acid (150 ml) was added, followed by room temperature for 20 hours. It was stirred at. Then, 3 times the volume of n-hexane was added and the deposited precipitate was collected by filtration to obtain the desired hydrobromic acid (0.51 g)
Was obtained as a colorless powder.

IR (KBr): 3400,3300,2920,1740,1710,1680,1640,1600,
1570,1435,1310,1280,1110,1020 cm ^{-1 1} H-NMR (DMSO-d ₆ / D ₂ O) δ: 1.53-2.27 (2H, m), 2.70
(2H, t, J = 9Hz), 3.0-3.26 (2H, m), 3.47-3.63 (1H,
m), 3.83 (3H, s), 7.35 (2H, d, J = 9Hz), 7.85 (2H, d, J
= 9 Hz). Reference Example 9 Structure of ethyl 5- [4- (tert-butoxycarbonyl) phenyl] hexanoate: tert-butyl 4-acetylbenzoate (19.90 g) in benzene-ether-tetrahydrofuran solution (3: 3: 2; 200 m
Zinc (11.81 g) was suspended in l), ethyl 4-bromocrotonate (17.44 g) was slowly added with heating and stirring, and then iodine (about 20 mg) was added. Reaction mixture at 60-70 ° C
After heating under reflux in the oil bath for 1 hour, ethyl 4-bromocrotonate (3.00 g) was added, and the mixture was heated under reflux for 15 minutes. After cooling to room temperature, the reaction solution was poured into water (500 ml) and adjusted to pH 4.9 with acetic acid. Extract with ether and extract 5 layers
The extract was washed with% ammonia water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (carrier: silica gel, 300 g, developing solvent; ethyl acetate: hexane = 1: 5) to give 5- [4- (tert-
Butoxycarbonyl) phenyl] -5-hydroxy-2
-Ethyl hexenoate (22.3 g) was obtained.

IR (Nert): 3480, 2975, 1720, 1700, 1650, 1605 cm ^-1 1H-NMR (CDCl ₃ ) δ: 1.20 (3H, t, J = 7Hz), 1.53 (12H,
s), 2.64 (2H, d, J = 7Hz), 2.67 (1H, brs), 3.63 (3H,
s), 4.08 (2H, q, J = 7Hz), 5.80 (1H, d, J = 8Hz), 7.90 (2
H, d, J = 8Hz). The whole amount of the ethyl hexenoate derivative (22.3 g) was dissolved in a mixed solution (200 ml) of ethanol-acetic acid (20: 1), 5% palladium-carbon (5.0 g) was added, and the mixture was mixed with hydrogen in an atmosphere of 11
Stir vigorously for 5 hours. Palladium with Celite-
Carbon was separated, the solvent was distilled off under reduced pressure, and the residue was subjected to reduced pressure distillation to obtain the desired product (15.66 g) as a colorless oil. Boiling point (Bp) 162-165 ° C / 0.3 mgHg IR (Nert): 2980,2940,1735,1710,1607,848 cm ^-1 . ¹ H-NMR (CDCl ₃ ) δ: 1.20 (3H, t, J = 7Hz), 1.23 (3H, d, J
= 6Hz), 1.30-1.80 (4H, m), 1.58 (9H, s), 2.24 (2H, br
t, J = 6Hz), 2.77 (1H, dq, J = 6Hz, 6Hz), 4.08 (2H, q, J = 7H
z), 7.20 (2H, d, J = 8Hz), 7.90 (2H, d, J = 8Hz). Reference Example 10 5- [4- (tert-butoxycarbonyl) phenyl]-
Production of ethyl 2-iodohexanoate: When the compound of Reference Example 9 (6.41 g) was subjected to the reaction of Reference Example 2, the target product (3.90 g) was obtained.

IR (Nert): 2980, 2940, 1738, 1715, 1610, 850cm ^-1 1H-NMR (CDCl ₃ ) δ: 1.23 (3H, t, J = 7Hz), 1.23 (2H, d, J
= 7Hz), 1.40-1.95 (4H, m), 1.60 (9H, s), 2.75 (1H, dq,
J = 6Hz, 6Hz), 4.15 (2H, q, J = 7Hz), 4.18 (1H, t, J = 7Hz),
7.20 (2H, d, J = 8Hz), 7.90 (2H, d, J = 8Hz). Reference Example 11 5- [4- (tert-butoxycarbonyl) phenyl]-
Production of ethyl 2- (dicyanomethyl) hexanoate: When the compound of Reference Example 10 (3.90 g) was subjected to the reaction of Reference Example 3, the target product (3.19 g) was obtained.

IR (Nert): 2980, 2930, 2250, 1735, 1710, 1605, 847 cm ^{-1 1} H-NMR (CDCl ₃ ) δ: 1.26 (1.5H, t, J = 7Hz), 1.26 (3H,
d, J = 7Hz), 1.27 (1.5H, t, J = 7Hz), 1.35-1.80 (4H, m),
1.58 (9H, s), 2.50-3.08 (2H, m), 4.00 (1H, dd, J = 8Hz, 4
Hz), 4.22 (1H, q, J = 7Hz), 4.23 (1H, q, J = 7Hz), 7.18 (2
H, d, J = 8Hz), 7.92 (2H, d, J = 8Hz). Example 1 4- [3- (2,4-diamino-6-hydroxy-7H-pyrrolo [2,3
Preparation of tert-butyl [-d] pyrimidin-5-yl) propyl] benzoate: Reference example in a tert-butyl alcohol solution (10 ml) of potassium tert-butoxide (2.35 g) and guanidine hydrochloride (1.07 g) under argon atmosphere. Compound obtained in 3 (3.33g)
Tert-Butyl alcohol solution (30 ml) was added and the mixture was heated under reflux for 20 hours. Add potassium tert-butoxide (434
mg) and guanidine hydrochloric acid (370 mg) were added, and the mixture was heated under reflux for 8 hours, then the reaction solution was cooled, and the pH was adjusted to 9 by adding 1N potassium hydrogen sulfate aqueous solution (about 10 ml) at 0 ° C. After extraction with a tetrahydrofuran-chloroform mixed solvent, the solvent was distilled off under reduced pressure and the resulting residue was subjected to column chromatography (carrier; silica gel, 100 g, developing solvent;
Purification with dichloromethane: ethanol = 15: 1 → concentrated aqueous ammonia and partitioning with dichloromethane: ethanol = 15: 1) gave the desired product (1.90 g).

IR (KBr): 3430,3360,1710,1627,1583,1432cm ^-1 . ¹ H-NMR (CDCl ₃ / We ₂ SO-d ₆ ) δ: 1.15-1.73 (2H, m), 1.
55 (9H, s), 1.73-2.10 (2H, m), 2.61 (2H, t, J = 7Hz), 3.
35 (1H, t, J = 6Hz), 5.40 (2H, brs), 5.51 (2H, brs), 6.3
0 (1H, brs), 7.12 (2H, d, J = 8Hz), 7.29 (2H, d, J = 8H
z). Example 2 Preparation of tert-butyl 4- [3- (2,4-diamino-7H-pyrrolo [2,3-d] pyrimidin-5-yl) propylbenzoate: The compound of Example 1 (575 mg) in tetrahydrofuran Borane-tetrahydrofuran complex (7.5 ml) was added to the solution (6 ml) at 0 ° C.
tetrahydrofuran solution (7.5 ml) was added to 4.5
After stirring for an hour, acetic acid-methanol (1: 1,6m
l) was added and the mixture was stirred at room temperature for 15 hours. The residue obtained by distilling off the solvent under reduced pressure is subjected to column chromatography (carrier;
Purification with silica gel, 30 g, developing solvent; dichloromethane: ethanol = 100: 6 → 100: 7 → 100: 8 → 10: 1 → 8: 1) gave the desired product (263 mg).

IR (KBr): 3335,3180,2975,2935,1710,1607,1287,1163,
1110 cm ^-1 . ¹ H-NMR (Me ₂ SO-d ₆ ) δ: 1.54 (9H, s), 1.77-1.90 (2H,
m), 2.68 (2H, t, J = 8Hz), 2.72 (2H, t, J = 8Hz), 5.54 (2
H, brs), 6.11 (2H, brs), 6.45 (1H, s), 7.33 (2H, d, J = 8
Hz), 7.82 (2H, d, J = 8Hz), 10.51 (1H, s). Example 3 Preparation of N- [4- [3- (2,4-diamino-7H-pyrrolo [2,3-d] pyrimidin-5-yl) propyl] benzoyl] -L-glutamate diethyl: Example 2 Compound (381mg) to trifluoroacetic acid (3ml)
Was added, and the mixture was stirred at room temperature for 3 hours. The trifluoroacetic acid was distilled off under reduced pressure, and the residue obtained by drying under reduced pressure at 70 ° C and a solution of diethyl L-glutamic acid diethyl hydrochloride (748 mg) in dimethylformamide (4 ml) were added at 0 ° C to diphenylphosphoryl azide (8
58 mg) in dimethylformamide solution (4 ml) was added, and subsequently, a solution of triethylamine (631 mg) in dimethylformamide (4 ml) was added dropwise at the same temperature. After stirring at 0 ° C. for 30 minutes and at room temperature for 63 hours, the precipitate was filtered off. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to column chromatography (carrier; lysica gel, 20 g, developing solvent; concentrated ammonia water and separated dichloromethane → concentrated ammonia water and separated dichloromethane: ethanol = 40: 1). → The target product (260 mg) was obtained by purification with 30: 1).

IR (KBr): 3380,3160,1735,1632,1575,1540,1500,1200c
m ^-1 . ¹ H-NMR (Me ₂ CO-d ₆ ) δ: 1.17 (3H, t, J = 7Hz), 1.20 (3
H, t, J = 7Hz), 1.80-2.20 (4H, m), 2.44 (2H, t, J = 7Hz),
2.68 (2H, t, J = 7Hz), 2.72 (2H, t, J = 7Hz), 4.05 (2H, q, J
= 7Hz), 4.11 (2H, q, J = 7Hz), 4.35-4.50 (1H, m), 5.34
(2H, s), 5.91 (2H, s), 6.42 (1H, s), 7.31 (2H, d, J = 8H
z), 7.80 (2H, d, J = 8Hz), 8.66 (1H, d, J = 8Hz), 10.51 (1
H, s). Example 4 Preparation of N- [4- [3- (2,4-diamino-7H-pyrrolo [2,3-d] pyrimidin-5-yl) propyl] benzoyl] -L-glutamic acid: compound of Example 3 (250 mg) was dissolved in a tetrahydrofuran-water mixed solvent (1: 1; 7 ml), 1N aqueous sodium hydroxide solution (2.52 ml) was added, and the mixture was stirred at room temperature for 1.5 hr.
The solvent was concentrated to 3 ml under reduced pressure, and the resulting insoluble material was filtered off with a Millipore filter. The acetic acid (0.
(5 ml) was added and the generated crystals were collected by filtration and washed well with ice water. The obtained crystal was dried under reduced pressure at 70 ° C. to obtain the desired product (201 mg) as a white crystal.

IR (KBr): 3340,3200,2940,1660-1630,1540,1500,1397c
m ^-1 . ¹ H-NMR (Me ₂ SO-d ₆ ) δ: 1.75-2.20 (4H, m), 2.35 (2H,
t, J = 7Hz), 2.68 (2H, t, J = 7Hz), 2.71 (2H, t, J = 7Hz), 4.
30-4.47 (1H, m), 5.53 (2H, brs), 6.15 (2H, s), 6.46
(1H, s), 7.31 (2H, d, J = 8Hz), 7.81 (2H, d, J = 8Hz), 8.4
8 (1H, d, J = 8Hz), 10.51 (1H, s). Example 5 Preparation of N- [4- [3- (2,4-diamino-6-hydroxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl) propyl] benzoyl] -L-glutamate diethyl: The target compound (164 mg) was obtained by subjecting the compound (200 mg) obtained in Example 1 to the same reaction as in Example 3.

1R (KBr): 3355,3230,2995,2990,1740,1638,1595,1590c
m ^-1 . ¹ H-NMR (CDCl ₃ / Me ₂ SO-d ₆ ) δ: 1.20 (3H, t, J = 7Hz),
1.25 (3H, t, J = 7Hz), 1.25-2.70 (11H, m), 3.25-3.45 (1
H, m), 4.05 (2H, q, J = 7Hz), 4.15 (2H, q, J = 7Hz), 4.38-
4.68 (1H, m), 5.63 (2H, brs), 5.66 (2H, brs), 7.16 (2
H, d, J = 8Hz), 7.76 (2H, d, J = 8Hz), 8.39 (1H, d, J = 8Hz),
10.50 (1H, s). Example 6 Preparation of N- [4- [3- (2,4-diamino-6-hydroxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl) propyl] benzoyl] -L-glutamic acid: Example The target compound (60 mg) was obtained by subjecting the compound (112 mg) obtained in Example 5 to the reaction of Example 4.

IR (KBr): 3350,3210,2950,1730,1660,1630cm ^-1 . ¹ H-NMR (Me ₂ SO-d ₆ ) δ: 1.20-1.56 (2H, m), 1.65-2.20
(4H, m), 2.35 (2H, t, J = 7Hz), 2.50-2.65 (2H, m), 3.25
-3.35 (1H, m), 4.32-4.46 (1H, m), 5.90 (2H, brs), 6.0
0 (2H, brs), 7,22 (2H, d, J = 8Hz), 7.78 (2H, d, J = 8Hz),
8.52 (1H, d, J = 8Hz), 10.45 (1H, s). Example 7 N- [4- [3- (2-amino-4-hydroxy-6,7-dihydro-
5H-pyrrolo [2,3-d] pyrimidin-5-yl) propyl]
Production of methyl benzoate: The compound (0.66 g) obtained in Reference Example 5 was dissolved in dry tetrahydrofuran (31.5 ml), and a dichloromethane solution of 0.21N hydrobromic acid (78.3 ml) was added, followed by room temperature for 20 hours. It was stirred at. Then, 3 times the volume of n-hexane was added and the deposited precipitate was collected by filtration. The target dihydrobromide (0.59
g) was obtained as a colorless powder.

IR (KBr): 3290,3030,2950,1720,1690,1680,1620,1480,
1350,1275,1100,1035,760cm ^-1 . ¹ H-NMR (DMDO-d ₆ ) δ: 1.40-1.83 (4H, broad), 2.65 (2
H, t, J = 5Hz), 3.07-3.37 (2H, m), 3.50-3.77 (1H, m), 3.
82 (3H, s), 7.33 (2H, d, J = 7.5Hz), 7,86 (2H, d, J = 7.5H
z). Example 8 N- [4- [3- (2-Amino-4-hydroxy-6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-5-yl) propyl] benzoyl] -L- Production of diethyl glutamate: The compound (1.47 g) obtained in Reference Example 7 was suspended in tetrahydrofuran (60 ml), 0.1N sodium hydroxide solution (120 ml) was added, and the mixture was stirred at room temperature for 21 hours. Then 0.1
The mixture was neutralized with normal hydrochloric acid (60 ml) and concentrated to dryness under reduced pressure. The residue was suspended in dry dimethylformamide (112.5 ml),
Under ice-cooling, diethyl L-glutamic acid hydrochloride (2.88 g), diphenyl acid azide (1.295 ml) and triethylamide (2.52 ml) were added, and the mixture was returned to room temperature and left stirring for 63 hours.

The generated precipitate was filtered off, and the filtrate was concentrated to dryness under reduced pressure.
The residue is subjected to silica gel column chromatography (carrier: 100
g, developing solvent: ethanol containing 6.9% ammonia-chloroform, 1: 20 → 1: 10)
g) was obtained as a colorless powder.

IR (KBr): 3330,2930,1740,1670,1640,1570,1540,1440,
1375,1300,1200,1095,1020cm ^-1 . ¹ H-NMR (CDCl ₃ -CD ₃ OD) δ: 1.20 (3H, t, J = 7.5Hz), 1.2
7 (3H, t, J = 7.5Hz), 1.47-1.83 (4H, m), 2.0-2.36 (2H,
m), 2.37-2.50 (2H, m), 2.67 (2H, t, J = 7.5Hz), 3.10-3.
37 (2H, m), 3.53-3.80 (1H, m), 3.96-4.33 (4H, q, × 2, J
= 7.5Hz), 4.60-4.87 (1H, m), 7.25 (2H, d, J = 9Hz), 7.75
(2H, d, J = 9Hz). Example 9 N- [4- [3- (2-amino-4-hydroxy-7H-pyrrolo [2,3
-D] pyrimidin-5-yl) propyl] benzoyl]-
Production of diethyl L-glutamate: The compound (150 mg) obtained in Reference Example 8 was treated with ethanol (22,
5 ml), 10% Pd-C (450 mg: manufactured by Engelhardt) and 2 drops of acetic acid were added, and the mixture was vigorously stirred at room temperature for 62.5 hours. The catalyst was filtered off, the filtrate was concentrated to dryness, and the residue was subjected to column chromatography (carrier: silica gel, 10 g, developing solvent:
Target product (3% chloroform containing 5% ethanol)
3 mg) was obtained.

IR (KBr): 3340,2940,1740,1680,1670,1630,1540,1440,
1380,1340,1210,1100,1020,860cm ^-1 . ¹ H-NMR (CDCl ₃ / CD ₃ OD) δ: 1.20 (3H, t, J = 6Hz), 1.28
(3H, t, J = 6Hz), 1.87-2.36 (4H, m), 2.40-2.57 (2H,
m), 2.60-2.87 (4H, m), 3.96-4.37 (4H, q, × 2, J = 6Hz),
4.56-4.90 (1H, m), 6.37 (1H, s), 7.23 (2H, d, J = 7.5H
z), 7.71 (2H, d, J = 7.5Hz). Example 10 N- [4- [3- (2-amino-4-hydroxy-7H-pyrrolo [2,3
-D] pyrimidin-5-yl) propyl] benzoyl]-
Production of L-glutamic acid: The compound (27 mg) obtained in Example 9 was dissolved in a tetrahydrofuran-water mixed solution (1: 1; 2.16 ml), and 1N aqueous sodium hydroxide solution (0.189 ml) was added, The mixture was stirred at room temperature for 2.5 hours. Most of the tetrahydrofuran was distilled off, acetic acid (0.189 ml) was added under ice cooling, and the mixture was stirred. The deposited precipitate was collected by filtration and dried to obtain the desired product (19 mg).

IR (KBr): 3400,3300,2950,1700,1650,1540,1510,1400,
1340,1240,1080,1020cm ^-1 . ¹ H-NMR (Me ₂ SO-b ₆ ) δ: 1.80-2.17 (4H, m), 2.23-2.40
(2H, m), 2.53-2.83 (4H, m), 4.27-4.56 (1H, m), 6.33
(1H, s), 7.27 (2H, d, J = 7.5Hz), 7.78 (2H, d, J = 7.5H
z). Example 11 Preparation of tert-butyl 4- [3- (2,4-diamino-6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-5-yl) propyl] benzoate: Example 1 In a tetrahydrofuran solution (10 ml) of the compound (430 mg) of Example 1 was added borane-hitrahydrofuran complex salt (16.8 mmo
A tetrahydrofuran solution (10 ml) was added to (l) and the mixture was heated under reflux for 4 hours. After cooling, the reaction solution was added to ice water, adjusted to pH 2 with 1N hydrochloric acid for 3 minutes, further stirred with 2N aqueous potassium carbonate solution to pH 10.5 for 5 minutes, and then extracted with a tetrahydrofuran-chloroform mixed solvent. The residue obtained by distilling off the solvent under reduced pressure was subjected to column chromatography (carrier: silica gel, 20 g, dichloromethane-ethanol, 30: 1 → 15: 1 → concentrated ammonia water and dichloromethane-ethanol, 20: 1). When purified, the target product (114m
g) was obtained.

IR (KBr): 3375,3325,3190,2970,2930,1712,1603cm ^-1 . ¹ H-NMR (CDCl ₃ / Me ₂ SO-d ₆ ) δ: 1.45-2.15 (4H, m), 1.
57 (9H, s), 2.65 (2H, t, J = 7Hz), 3.00-3.28 (2H, m),
3.44-3.70 (1H, m), 4.85 (2H, brs), 4.90 (2H, brs),
5.30 (1H, brs), 7.19 (2H, d, J = 8Hz), 7.80 (2H, d, J = 8H
z). Example 12 N- [4- [2- (2-amino-4-hydroxy-6,7
-Dihydro-5H-pyrrolo [2,3-d] pyrimidine-5-
Production of diethyl) ethyl] benzoyl] -L-glutamate: The compound (0.315 g) obtained in Reference Example 8 was subjected to the same reaction as in Example 8 to obtain the desired product (0.247 g).

IR (KBr): 3310,2990,1740,1730,1690,1640,1620,1570,
1530,1440,1375,1330,1300,1240,1200,1090,1010,850cm
^{-1 1} H-NMR (CDCl ₃ / CD ₃ OD) δ: 1.22 (3H, t, J = 7.5Hz), 1.
30 (3H, t, J = 7.5Hz), 1.53-2.87 (8H, m), 3.13-3.90
(3H, m), 4.0−4.43 (4H, q × 2.J = 7.5Hz), 4.57−4.90
(1H, m), 7.25 (2H, d, J = 9Hz), 7.72 (2H, d, J = 9Hz). Example 13 N- [4- [3- (2,4-diamino-6,7-dihydro-5H
-Preparation of pyrrolo [2,3-d] pyrimidin-5-yl) propyl] benzoyl] -L-glutamate diethyl: The compound of Example 11 (94 mg) was dissolved in 1 ml of trifluoroacetic acid and stirred at room temperature for 3 hours. . The solvent was distilled off under reduced pressure at 70 ° C.
The residue obtained by drying under reduced pressure at 0.degree. C. and a solution of diethyl L-glutamate (304 mg) in dimethylformamide (2 ml)
A solution of diphenylphosphoryl azide (350 mg) in dimethylformamide (1.5 ml) was added at 0 ° C., and then a solution of triethylamine (180 mg) in dimethylformamide (1.5 ml) was added dropwise at the same temperature. 30 minutes at 0 ℃, 78 at room temperature
After stirring for an hour, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography (carrier: silica gel, 20 g,
Dichloromethane separated with concentrated ammonium water → Dichloromethane separated with concentrated ammonia water → Ethanol, 40: 1 →
The desired product (88 mg) was obtained by purification with 30: 1).

IR (KBr): 3350,2990,2945,1740,1610,1540,1508,1438c
^{m -1 1 H-NMR (CDCl} 3) δ: 1.23 (H, q, J = 7Hz), 1.43-1.80
(3H, m), 1.85-2.77 (7H, m), 2.95-3.30 (2H, m), 3.5
8 (1H, t, J = 11Hz), 4.07 (2H, q, J = 7Hz), 4.20 (2H, q, J
= 7Hz), 4.25 (1H, brs), 4.63-4.83 (1H, m), 4.68 (1
H, brs), 7.00−7.23 (1H, m), 7.13 (2H, d, J = 8Hz), 7.6
7 (2H, d, J = 8Hz). Example 14 N- [4- [3- (2-amino-4-hydroxy-6,7
-Dihydro-5H-pyrrolo [2,3-d] pyrimidine-5-
Preparation of (yl) propyl] benzoyl] -L-glutamic acid: The compound (1.05 g) obtained in Example 8 was dissolved in tetrahydrofuran-water (2: 1, 63 ml) and 1N sodium hydroxide solution (7.35 ml) was added. After adding, the mixture was stirred at room temperature for 2.5 hours.
Tetrahydrofuran was distilled off, a small amount of insoluble matter was filtered off, acetic acid (7.35 ml) was added to the filtrate, and the deposited precipitate was collected by filtration. After washing with water and drying, the desired product (0.85 g) was obtained as a colorless powder.

IR (KBr): 3340,2930,1690,1630,1540,1440,1300,1080,
850 cm ^{-1 1} H-NMR (DMSO-d ₆ ) δ: 1.20-1.80 (4H, m), 1.87-2.1
7 (2H, m), 2.23-2.40 (2H, m), 2.50-2.77 (2H, m), 2.
83-3.20 (2H, m), 3.30-3.63 (1H, m), 4.23-4.53 (1
H, m), 7.26 (2H, d, J = 9Hz), 7.77 (2H, d, J = 9Hz). Example 15 N- [4- [2- (2-amino-4-hydroxy-6,7
-Dihydro-5H-pyrrolo [2,3-d] pyrimidine-5-
Production of (yl) ethyl] benzoyl] -L-glutamic acid: The target compound (0.153 g) was obtained by subjecting the compound (0.195 g) obtained in Example 12 to the same reaction as in Example 14.

IR (KBr): 3250, 2900, 1650, 1580, 1440, 1300, 1090 cm ^{-1 1} H-NMR (DMSO-d ₆ ) δ: 1.43-1.76 (1H, m), 1.98 (2H,
t, J = 7.5Hz), 1.80-2.10 (1H, m), 2.13-2.40 (2H, m)
m), 2.67 (2H, t, J = 9Hz), 2.90−3.23 (2H, m), 3.33−
3.60 (1H, m), 4.10-4.43 (1H, m), 7.28 (2H, d, J = 9H
z), 7.75 (2H, d, J = 9Hz). Example 16 N- [4- [3- (2,4-diamino-6,7-dihydro-5H
Preparation of -pyrrolo [2,3-d] pyrimidin-5-yl) propyl] benzoyl] -L-glutamic acid: When the compound of Example 13 (41 mg) was subjected to the same reaction as in Example 14, the desired product (32 mg) was obtained. was gotten.

IR (KBr): 3700-2350, 3215, 1690-1620, 1540 cm ^-1 . ¹ H-NMR (Me ₂ SO-d ₆ ) δ: 1.02-1.85 (4H, m), 1.85-2.
83 (6H, m), 2.90-3.30 (2H, m), 3.55 (1H, t, J = 11H
z), 4.15-4.45 (1H, m), 6.38 (2H, brs), 6.77 (2H, br
s), 6.90 (1H, brs), 7.22 (2H, d, J = 8Hz), 7.74 (2H, d,
J = 8Hz), 8.22 (1H, d, J = 7Hz). Example 17 Preparation of tert-butyl 4- [3- (2,4-diamino-6-hydroxy-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -1-methylpropyl] benzoate: Reference The target product (2.61 g) was obtained by subjecting the compound of Example 11 (3.18 g) to the reaction of Example 1.

IR (KBr): 3360,3235,2975,2700,1715,1625,1584,1438,
1290,1163,1118,848cm ^-1 . ¹ H-NMR (Me ₂ SO-d ₆ ) δ: 1.14 (3H, d, J = 7Hz), 1.20-1.5
0 (2H, m), 1.54 (9H, s), 1.55-1.80 (1H, m), 1.80-2.05
(1H, m), 2.60-2.78 (1H, m), 3.20-3.30 (1H, m), 5.86
(2H, brs), 5.96 (2H, brs), 7.25 (2H, d, J = 8Hz), 7.81
(2H, d, J = 8Hz), 10.42 (1H, s). Example 18 tert-Butyl 4- (3- (2,4-diamino-6,7-dihydro-5H-pyrrolo [2,3-d] pyrimidin-5-yl) -1-methylpropyl] benzoate (A ) And 4- [3-
(2,4-diamino-7H-pyrrolo [2,3-d] pyrimidine-
Preparation of tert-butyl 5-yl) -1-methylpropyl] benzoate (B): Borane-tetrahydrofuran complex (40.3 mmol) was added to a suspension of the compound of Example 17 (2.00 g) in tetrahydrofuran (25 ml) at 0 ° C. Was added to a tetrahydrofuran solution (40.3 ml), the mixture was stirred for 10 minutes, then returned to room temperature and further stirred for 5 hours. Acetic acid-methanol (1: 1, 40 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 18 hours. The residue obtained by distilling off the solvent under reduced pressure is column chromatography (carrier; silica gel, 10
0g, developing solvent: dichloromethane: ethanol = 20: 1 → 2
Purification with 5: 2 followed by dichloromethane: ammonia (6%) in ethanol = 20: 1) gives the desired product (A) (579m
g) and (B) (1.214 g) were obtained.

(A) IR (KBr): 3350,3200,2980,2940m, 1714,1650,160
8,1290,1163,1115,848cm ^{-1 1} H-NMR (CDCl ₃ ) δ: 1.31 (3H, d, J = 7Hz), 1.60 (9H,
s), 1.94 (2H, dt, J = 8Hz), 2.40-2.60 (2H, m), 2.85 (1
H, tq, J = 7Hz), 4.50-5.50 (4H, br), 6.46 (1H, s), 7.27
(2H, d, J = 8Hz), 7.96 (2H, d, J = 8Hz), 9.20 (1H, brs). (B) IR (KBr): 3340,3195,2980,2935,1715,1607,143
0,1295,1163,1115,847cm ^{-1 1} H-NMR (Me ₂ SO-d ₆ ) δ: 1.18 (2.25H, d, J = 7Hz), 1.19
(0.75H, d, J = 7Hz), 1.23-1.42 (2H, m), 1.45-1.65 (2H,
m), 1.54 (9H, s), 2.64-2.70 (1H, m), 2.90-3.08 (2H,
m), 3.30-3.50 (1H, m), 5.43 (4H, s), 5.95 (0.25H,
s), 6.00 (0.75H, s), 7.32 (2H, d, J = 8Hz), 7.82 (2H, d,
J = 8Hz). Example 19 N- [4- [3- (2,4-diamino-6,7-dihydro-5H
Preparation of -pyrrolo [2,3-d] pyrimidin-5-yl) -1-methylpropyl] benzoyl] -diethyl L-glutamate: Compound (A) of Example 18 (581 mg) is subjected to the reaction of Example 3. The desired product (640 mg) was obtained.

IR (KBr): 3375,3200,2975,2930,1738,1608,1430,1200,
1008,853cm ^-1 . ¹ H-NMR (Me ₂ SO-d ₆ ) δ: 1.17 (3H, t, J = 7Hz), 1.18 (3
H, d, J = 7Hz), 1.19 (3H, t, J = 7Hz), 1.26-1.44 (2H, m),
1.44-1.63 (2H, m), 1.90-2.20 (2H, m), 2.44 (2H, t, J
= 7Hz), 2.63-2.80 (1H, m), 2.90-3.08 (2H, m), 3.30-3.
50 (1H, m), 4.05 (2H, q, J = 7Hz), 4.11 (2H, q, J = 7Hz),
4.37-4.50 (1H, m), 5.36 (2H, s), 5.37 (2H, s), 5.87
(0.25H, s), 5.91 (0.75H, s), 7.30 (2H, d, J = 8Hz), 7.8
0 (2H, d, J = 8Hz), 8.66 (1H, d, J = 8Hz). Example 20 N- [4- [3- (2,4-diamino-6,7-dihydro-5H
Preparation of -pyrrolo [2,3-d] pyrimidin-5-yl) -1-methylpropyl] benzoyl] -L-glutamic acid: The compound of Example 19 (600 mg) was subjected to the reaction of Example 4 to give the desired product ( 508 mg) was obtained.

IR (KBr): 3350,3200,1690,1680-1610,1635,1530,1400,
1300,850 cm ^-1 . ¹ H-NMR (Me ₂ SO-d ₆ ) δ: 1.20 (3H, t, J = 7Hz), 1.25-1.6
5 (4H, m), 1.87-2.20 (2H, m), 2.30 (2H, t, J = 7Hz), 2.6
0-2.80 (1H, m), 3.00-3.20 (2H, m), 3.42-3.60 (1H, m
m), 4.22-4.40 (1H, m), 6.20-5.08 (5H, m), 7.28 (2H,
d, J = 8Hz), 7.78 (2H, d, J = 8Hz), 8.28-8.36 (1H, m). Example 21 N- [4- [3- (2,4-diamino-7H-pyrrolo [2,3-
Preparation of d] pyrimidin-5-yl) -1-methylpropyl] benzoyl] -L-glutamate diethyl: When the compound (B) (540 mg) of Example 18 was subjected to the reaction of Example 3, the desired product (556 mg) was obtained. Was obtained.

IR (KBr): 3340,3180,2935,1735,1640,1610,1580,1200,
1095,1018,850 cm ^-1 . ¹ H-NMR (CDCl ₃ ) δ: 1.23 (3H, t, J = 7Hz), 1.30 (3H, d, J
= 7Hz), 1.31 (3H, t, J = 7Hz), 1.80-2.05 (4H, m), 2.15
2.57 (4H, m), 2.83 (1H, tq, J = 7Hz, 7Hz), 4.12 (2H, q, J =
7Hz), 4.25 (2H, q, J = 7Hz), 4.68 (2H, brs), 4.75-4s),
7.26 (2H, d, J = 8Hz), 7.37 (1H, dd, J = 7Hz), 7.77 (2H, d,
J = 8Hz), 8.81 (1H, brs). Example 22 N- [4- [3- (2,4-diamino-7H-pyrrolo [2,3-
Production of d] pyrimidin-5-yl) -1-methylpropyl] benzoyl] -L-glutamic acid: The compound of Example 21 (533 mg) was subjected to the reaction of Example 4 to obtain the desired product (436 mg).

IR (KBr): 3350,3205,1650,1640,1540,1400,850cm ^-1 . ¹ H-NMR (Me ₂ SO-d ₆ ) δ: 1.25 (3H, d, J = 7Hz), 1.73-2.2
0 (4H, m), 2.35 (3H, t, J = 8Hz), 2.40-2.68 (2H, m), 2.8
5 (1H, tq, J = 7Hz, 7Hz), 4.32-4.45 (1H, m), 5.54 (2H, br
s), 6.06 (2H, brs), 6.38 (1H, s), 7.33 (2H, d, J = 8H
z), 7.83 (2H, d, J = 8Hz), 8.49 (1H, d, J = 8Hz), 10.45 (1
H, s). Example 23 Compound obtained in Example 14 (50 mg per tablet), lactose (250 mg per tablet), corn starch (51 m per tablet)
g) and hydroxypropylcellulose L (9 mg per tablet) are mixed by a conventional method, and the granules are mixed with corn starch (8 mg per tablet) and magnesium stearate (2 mg per tablet), and then mixed according to a conventional method. Lock
Tablets (370 mg per tablet) were obtained.

Example 24 10 g of the sodium salt of the compound obtained in Example 14 is dissolved in physiological saline 1, filtered through a microfilter, dispensed in 2.2 ml portions into ampoules and sealed. It was sterilized at 110 ° C. for 30 minutes to give an ampoule for subcutaneous, intravenous or intramuscular injection of the compound.

Example 25 5 g of the hydrochloride of the compound obtained in Example 14 and 10 mannitol
Dissolve g and 1 in distilled water 1, sterilize and filter, then 2 ml in an ampoule.
Dispense each. 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, for example, 2 ml of physiological saline to prepare an injection for administration.

EFFECTS OF THE INVENTION The compound (I) of the present invention or a salt thereof has an excellent antitumor action, and thus can be used as an antitumor agent for mammals.

Claims (4)

[Claims] 1. A general formula [Wherein, the ring is a pyrrole or pyrroline ring, X is an amino group or a hydroxy group, Y is a hydrogen atom, an amino group or a hydroxy group, R is a hydrogen atom, a fluorine atom, an alkyl group, an alkenyl group or an alkynyl group, and -COOR. ¹ and −COOR ²
Are the same or different and optionally esterified carboxy groups, n is an integer of 2 to 4, and R is
May be different in each of the n repetitions. ]
Or a salt thereof. 2. General formula [Wherein the ring is a pyrrole or pyrroline ring, X is an amino group or a hydroxy group, Y is a hydrogen atom, an amino group or a hydroxy group, R is a hydrogen atom, a fluorine atom, an alkyl group, an alkenyl group or an alkynyl group, and n is Each represents an integer of 2 to 4, and R may be different from each other in n repeating units. ] The compound represented by these, the reactive derivative in the carboxyl group or those salts, and general formula [In the formula, -COOR ¹ and -COOR ² are the same or different and each represents an optionally esterified carboxy group. ] The compound or its salt represented by these is made to react, The manufacturing method of the compound or its salt of Claim (1) characterized by the above-mentioned. 3. General formula [Wherein, the ring is a pyrrole or pyrroline ring, X is an amino group or a hydroxy group, Y is a hydrogen atom, an amino group or a hydroxy group, R is a hydrogen atom, a fluorine atom, an alkyl group, an alkenyl group or an alkynyl group, and -COOR. ³ represents an optionally esterified carboxy group, n represents an integer of 2 to 4, and R may be different in n repeating units. ] The compound or its salt represented by these. 4. An antitumor agent comprising the compound according to claim (1) or a salt thereof.