JPH06239841A - 6.7-dihydro-5h-cyclopenta(d)pyrimidine derivative - Google Patents

Abstract

PURPOSE:To obtain a new compound, having inhibitory action on a dihydrofolate reductase and useful as an antitumor agent CONSTITUTION:This compound is expressed by formula I [R<1> is OH or amino; R<2> is indolindiyl, indoldiyl, indandiyl or indendiyl; (n) is 0-4], e.g. ethyl 1-[2-(2,4- diamino-6,7-dihydro-5Hcyclpenta[d]pyrimidin-5-yl)ethyl]indole-5-carbox ylate. The compound expressed by formula I is obtained by condensing a compound expressed by formula II or a reactive derivative at the carboxyl group thereof with a compound expressed by formula III (R<3> and R<4> are carboxyl-protecting group), providing a carboxylic acid ester derivative expressed by formula IV and then hydrolyzing the resultant ester derivative in the presence of an acid or an alkali or removing the protecting groups of the carboxyl groups according to the hydrogenolysis including catalytic reduction.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to 6,7 of glutamate binding.
TECHNICAL FIELD The present invention relates to a dihydro-5H-cyclopenta [d] pyrimidine derivative, a process for producing the same, and use thereof.

[0002]

BACKGROUND OF THE INVENTION Methotrexate (hereinafter abbreviated as MTX) is one of the antifolate drugs and is the only antitumor agent clinically used in this system. This M
TX has a strong inhibitory activity on dihydrofolate reductase (DHFR), and is used mainly in choriocarcinoma, osteosarcoma, and lymphocytic leukemia. Since DHFR is present in tumor cells and normal cells and affects both of them, MT
X has a strong side effect on the digestive tract, bone marrow, kidney, liver and the like.
In addition, the use of MTX causes tumor cells to easily acquire drug resistance, which has drawbacks such as reduced drug efficacy. These are MTX
Has become a limiting factor in clinical use of. Heretofore, the synthesis of a large number of antifolates has been reported by studies in this field, particularly by analog synthesis and pharmacological studies. These are for example Progress in Medi by Andre Rosowsky
cinal Chemistry, 26, 1-252 (1989), Elsevier Scien
Comprehensive and detailed on cePublishers. The first structural feature of these antifolates is in the heterocyclic part, and most of the known antifolates have a bicyclic heterocyclic structure in which two 6-membered rings of pteridine are fused. It is in. Relatively recently, various deazapteridine compounds such as 5-deazapteridine, 8-deazapteridine, 10-deazapteridine, 5,8-dideazapteridine, 5,10-dideazapteridine, or their Many dihydro or tetrahydro compounds have been synthesized,
It has been reported to have biological activity.

On the other hand, a folate antagonist having a bicyclic heterocyclic structure formed by the condensation of a 5-membered ring and a 6-membered ring has not been known so far. By LTWeinstock
Journal Medicinal Chemistry, 13, 995 (1970) describes a compound in which the pteridine ring is converted to a purine ring. D
It is reported that no HFR inhibition or antitumor effect was observed. Meanwhile, Miwa et al.'S Journal Medicinal Chemistry,
34, 555-560 (1991) describes that a benzoylglutamic acid derivative having a pyrrolo [2,3-d] pyrimidine ring has a folate antagonistic activity and exhibits a higher inhibitory activity than MTX on the growth of human tumor cells. ing.

[0004]

As described above, many studies have been made in the past, but none have been practically used as pharmaceuticals since MTX.
Therefore, it is still strongly desired to find a drug in this field which has a selective toxicity to tumor tissue and a high therapeutic effect, and to provide it to the clinical field. Considering the above situation,
An object of the present invention is to provide a novel 6,7-dihydro-5H-cyclopenta [d] pyrimidine derivative having excellent antitumor activity. Moreover, it aims at providing the manufacturing method of this compound, and the pharmaceutical composition which uses this compound as an active ingredient.

[0005]

[Means for Solving the Problems] As a result of intensive research to solve the above problems, the present inventors have found that the glutamic acid bond 6,7-
The inventors have found that the dihydro-5H-cyclopenta [d] pyrimidine derivative can be a novel and useful antitumor agent and completed the present invention. That is, the present invention has the general formula (1)

[0006]

[Chemical 6]

[In the formula, R ¹ represents a hydroxyl group or an amino group. R ² represents an optionally substituted indolinediyl group, an indolediyl group, an indandiyl group or an indenediyl group. n shows the integer of 0-4. ] The present invention provides a 6,7-dihydro-5H-cyclopenta [d] pyrimidine derivative represented by the following formula or a pharmaceutically acceptable salt thereof. Further, the present invention is represented by the general formula (2)

[0008]

[Chemical 7]

[In the formula, R ¹ represents a hydroxyl group or an amino group. R ² represents an optionally substituted indolinediyl group, an indolediyl group, an indandiyl group or an indenediyl group. n shows the integer of 0-4. ] The compound represented by the above or its reactive derivative at the carboxyl group, and a compound represented by the general formula (3)

[0010]

[Chemical 8]

[Wherein R ³ and R ⁴ represent the same or different carboxyl-protecting groups] and are condensed to give a compound of the general formula (4)

[0012]

[Chemical 9]

[Wherein, R ¹ , R ² , R ³ , R ⁴ and n have the same meanings as described above. ] To obtain a carboxylic acid ester body,
Then, the ester is hydrolyzed in the presence of an acid or an alkali, or a free carboxylic acid derivative is obtained by hydrogenolysis including catalytic reduction, which is represented by the general formula (1). The present invention provides a method for producing a 7,7-dihydro-5H-penta [d] pyrimidine derivative or a pharmaceutically acceptable salt thereof. Further, the present invention is
General formula (5)

[0014]

[Chemical 10]

[In the formula, R ¹ represents a hydroxyl group or an amino group. R ² represents an optionally substituted indolinediyl group, an indolediyl group, an indandiyl group or an indenediyl group. n shows the integer of 0-4. −COOR
⁵ represents a carboxyl group which may be esterified with a protecting group. ] The compound or its salt represented by these are provided. Furthermore, the present invention provides an antitumor agent comprising a 6,7-dihydro-5H-cyclopenta [d] pyrimidine derivative represented by the above general formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient. To do.

In the above formula, when R ¹ is a hydroxyl group, the compounds (1), (2), (4) and (5) are keto-enol compatible isomers in equilibrium. In this specification, for convenience of display, enol type (hydroxyl type) is described,
Although the name is given thereto, in any case, the compound of the present invention includes not only the enol type but also the keto type (oxo type, that is, amide type). Further, in the compound (1) of the present invention, in addition to the asymmetric center of the L-glutamic acid moiety, an asymmetric carbon exists at the 5-position of the heterocyclic moiety and / or on the condensed ring R ² , but the asymmetric carbon of the glutamic acid moiety is present. Other than the absolute configuration of the atoms being S (L type), the other absolute configuration of the asymmetric center may be any of a mixture of S, R or SR. In this case, (1) is obtained as a diastereoisomer or a mixture of diastereoisomers, and these components can be easily separated and purified by a conventional method such as fractional crystallization or chromatography if necessary. . Any separated diastereoisomers are within the scope of the invention. The compound (1) of the present invention is generally obtained as a powder, crystalline solid or crystal.

In the above general formula (1), R ² represents an optionally substituted indolinediyl group, an indolediyl group, an indandiyl group or an indenediyl group, and the bond may occur anywhere, for example, , 1,3 −, 1,4
−, 1,5 −, 1,6 −, 2,4 −, 2,5 −, 2,6 −, 2,7
-, 3,5-, 3,6-, 3,7- and the like can be mentioned, and particularly representative ones are represented by the following structural formulas. Further, examples of the substituent on the ring include an alkyl group such as methyl, ethyl and propyl, an alkenyl group and the like.

[0018]

[Chemical 11]

(In the formula, R represents a substituent.) Further, the protecting group for the carboxy group represented by R ³ , R ⁴ and R ⁵ has an alkyl group having 1 to 5 carbon atoms and a substituent. Examples thereof include an optionally substituted benzyl group, an optionally substituted phenyl group, and a trisubstituted silyl group. Examples of the alkyl group here include a methyl group, an ethyl group,
A propyl group, an isopropyl group, a butyl group, an isobutyl group, a tertiary butyl group, a pentyl group, and the like, and a benzyl group which may have a substituent is a benzyl group, a nitrobenzyl group, a methoxybenzyl group, or the like, which is further substituted. Examples of the phenyl group which may have a group include a phenyl group, a methoxyphenyl group and a nitrophenyl group, and examples of the trisubstituted silyl group include a tert-butyldimethylsilyl group and a tert-butyldiphenylsilyl group.

Next, a method for producing the compound (1) of the present invention will be described. Compound (1) has the formula shown in the following reaction formula.
The glutamic acid derivative represented by the formula (3), its inorganic salt or fatty acid salt is condensed with the carboxylic acid represented by the formula (2) or a reactive derivative thereof to obtain an intermediate represented by the formula (4). The compound can be obtained by removing the carboxy-protecting group by a method such as hydrolysis or hydrogenolysis.

[0021]

[Chemical 12]

[Wherein R ¹ , R ² , R ³ , R ⁴ and n are as defined above. As the above-mentioned condensation method, a conventional synthetic technique for peptide formation can be applied. For example, in the compound (2), a carboxylic acid activating reagent such as chlorocarbonic acid ester, organic acid anhydride, diphenylphosphoryl atide, diethylphosphorocyanidate, carbonyldiimidazole, chlorophosphoric acid ester or carbodiimide is present in the presence of a base. The intermediate compound (4) can be obtained by allowing the compound (3) to react under the presence or absence of the compound and then reacting the compound (3).
The amount of the activating reagent used with respect to the compound (2) is 1 to 25 molar equivalents, preferably 1 to 5 molar equivalents. Methyl chlorocarbonate or ethyl chlorocarbonate is used as the chlorocarbonic acid ester used as an activating reagent, fluoroacetic anhydride is used as the organic acid anhydride, chloroacetic anhydride is applied, and diphenylchlorophosphate is used as the chlorophosphoric acid ester. Diethyl chlorophosphate etc. can be used. Further, diphenylphosphoroazidate or a homologue thereof is preferable, and as the carbodiimides, dicyclohexylcarbodiimide is preferable for practical purposes, and in addition, diphenylcarbodiimide, 1,3-diparatolylcarbodiimide or 1-cyclohexyl-
It can be appropriately selected from carbodiimides such as 3 (2-morpholinoethyl) carbodiimide.

This reaction is preferably carried out in the presence of a solvent, and the solvent used is, for example, water, alcohols (methanol, ethanol, propanol etc.), ethers (diethyl ether, tetrahydrofuran, dioxane etc.), nitrile. Selected from aromatic hydrocarbons (benzene, toluene, etc.), halogenated hydrocarbons (dichloromethane, chloroform, carbon tetrachloride, etc.), acetone, pyridine, dimethylformamide, dimethylsulfoxide, etc. Appropriate mixtures may also be used. This reaction is carried out in the presence or absence of a base, and the base used is sodium methylate, sodium ethylate, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate,
It is appropriately selected from inorganic bases such as sodium bicarbonate, and tertiary organic bases such as triethylamine, trimethylamine, pyridine, p-dimethylaminopyridine, and triethanolamine.

Next, the ester intermediate obtained in the condensation step
Compound (1) can be obtained by converting (4) into a free carboxylic acid by subjecting it to hydrolysis or hydrogenolysis. The hydrolysis reaction is carried out in an aqueous solution or optionally in a water-affinitive organic solvent such as methanol, ethanol, tetrahydrofuran, dioxane, dimethylformamide, dimethylsulfoxide or the like, or an aqueous solution or trifluoroacetic acid of an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid or phosphoric acid. Organic acids such as acetic acid, trichloroacetic acid, p-toluenesulfonic acid, benzenesulfonic acid and methanesulfonic acid are used, or aqueous caustic alkalis such as sodium hydroxide or potassium hydroxide, alkali carbonates such as sodium carbonate or potassium carbonate It is carried out using an aqueous solution of alkoxides or an alcohol solution of metal alkoxides such as sodium methoxide or sodium ethoxide. The reaction temperature is under ice cooling to the boiling point of the solvent used, preferably in the range of 10 to 70 ° C., and the reaction is carried out for 0.5 hours to about 2 days.
When an alkali or organic base is used, the product is formed with the glutamic acid moiety as an acid or intermediate salt. The hydrogenolysis reaction is a suitable means when R ³ and R ⁴ are optionally substituted benzyl groups or optionally substituted phenyl groups, and is carried out as follows. That is, catalytic reduction is carried out in a suitable solvent at a temperature in the range of −20 ° C. to the boiling point of the solvent used, preferably 0 to 50 ° C. in the presence of a reducing catalyst under the action of hydrogen under normal pressure or pressure. Examples of the solvent used include water, methanol, ethanol, propanol, ethyl acetate, diethyl ether, tetrahydrofuran, dioxane, benzene, toluene, dimethylformamide, pyridine, etc., and the reducing catalyst includes palladium, platinum, rhodium, etc. alone or as a carrier. For example, a catalyst or Raney nickel supported on is used.

Next, a method for producing the starting compound (2) will be described. Among the compounds (2), the compound in which R ¹ is an amino group can be produced, for example, by the following reaction steps.

[0026]

[Chemical 13]

In the above steps, R ¹ represents an amino group, R ² and R ⁵
And n are as defined above. Y represents a halogen atom such as chlorine atom, bromine atom and iodine atom, and R ⁶ represents a general enol protecting group such as methyl group, ethyl group, benzyl group and tetrahydropyranyl group. Below, the said reaction process is demonstrated. 2-cyanocyclopentene-
1-one (7) is obtained by reacting cyclopentenone with an aromatic thiol such as tri-lower alkylaluminum and thiophenol or a bulky aliphatic thiol such as isopropylthiol, followed by reaction with tosyl cyanide, followed by silica gel or BF. It can be synthesized smoothly and in good yield by allowing a Lewis acid such as ₃ -ether to act. In this case, 2-cyanocyclopenten-1-one
(7) is produced via the intermediate 3-alkylthio or aromatic thio-2-cyanocyclopentane.

The compound (8) can be synthesized by reacting a cyclic carboxylic acid ester (6) having an ω-halogenoalkyl bond with 2-cyanocyclopenten-1-one (7). In this case, it is carried out in the presence of a tin hydride such as trialkyltin hydride or triphenyltin hydride, or a radical initiator such as trialkylgermanium and azobisisobutyronitrile. 3-
Substituted alkyl-2-cyanocyclopentan-1-one
Conversion of (8) to lower alkyl enol ether (9) is performed by reacting diazomethane or its analog, 2,2-dimethoxypropane and paratoluenesulfonic acid, or a general protective group-introducing reagent for hydroxyl groups such as orthoformate ester. To be achieved.

The 1-alkoxy-2-cyano-3-substituted alkyl-1-cyclopentene compound (9) is a target 2,4-diamino compound when guanidine or a salt thereof is allowed to act under atmospheric pressure or in a sealed tube while heating. -6,7 - give dihydro -5H- cyclopenta [d] pyrimidine compound _{^{(5, R 1 = NH 2}} ). Guanidine is in excess (2) with respect to enol ether (9).
It is preferable to use a protic solvent such as methanol, ethanol, methoxyethanol, propanol, 2-methyl-2-propanol and the like at a temperature of 50 to 200. C., preferably 100 to 185.degree. C., and reaction time is 8 to 70 hours. However, the carboxylic acid (2) may be directly obtained under the reaction conditions of high temperature and long time. Generally, a carboxylic acid (2) having a 6,7-dihydro-5H-cyclopenta [d] pyrimidine ring is prepared by converting the corresponding carboxylic acid ester (5) from compound (4) to compound (1) according to the production method of compound (1). Alternatively, it can be obtained by hydrolysis or hydrogenolysis including catalytic reduction in the presence of an alkali.

Next, among the compounds (5), compounds in which R ¹ is a hydroxyl group can be produced by the following reaction steps.

[0031]

[Chemical 14]

In the above steps, R ¹ represents a hydroxyl group, R ² , R ⁵ ,
R ⁶ , n and Y have the same meanings as defined above, and R ⁷ has 1 to 4 carbon atoms.
Is a lower aralkyl group of 2-carbalkoxy-
2-Cyclopenten-1-one (10) is synthesized by a known method. That is, MA Guaciaro et al. Tetrahedrons, 4
2-Cyclopentene-1- according to the method of 7 , 4661 (1978).
Or synthesized from HJ Reich et al., J. Am. Chem. Soc.,
It can be used for the purpose of the present invention by synthesizing from 2-carbethoxycyclopentanone according to the method of 97, 5434 (1975). The keto compound (11) is a 2-carbalkoxy-2-cyclopenten-1-one (10) obtained by adding a cyclic carboxylic acid ester (6) having an ω-halogenoalkyl group bond to tin hydride and azobisisobutyronitrile. It can be synthesized by reacting with.

The keto form, that is, the conversion of the cyclopentanone ring-containing carboxylic acid ester (11) to the enol ether (12) is carried out by diazomethane or its analog (trimethylsilyldiazomethane, etc.), 2,2-dimethoxypropane and paratoluenesulfonic acid. Alternatively, the reaction proceeds smoothly by reacting a general protective group-introducing reagent for hydroxyl groups such as orthoformate. 2-amino-4 by reacting cyclopentanone ring-containing carboxylic acid ester (11) or 1-alkoxy-3-substituted alkyl-2-carboalkoxy-1-cyclopentene compound (12) with guanidine or a salt thereof in a solvent. Converted to the ester of an alkanecarboxylic acid containing a hydroxypyrimidine ring (5, R ¹ = OH). The type of solvent, the reaction temperature, and the time are almost the same as those when R ¹ is an amino group.

The synthesis of the intermediate compound ω-halogenoalkyl group-bonded cyclic carboxylic acid ester (6) is carried out by the following method. In cyclic carboxylic acid ester (6), R ² is 1,5-indandiyl group, n = 2
The compound (compound (6a)) can be synthesized by the following first synthetic method.

[0035]

[Chemical 15]

In the above steps, R ⁵ and Y are as defined above,
R ⁸ represents a protecting group for a carboxyl group. Organic solvent (aprotic solvent, for example, dimethylformamide, ether, tetrahydrofuran, a hydrocarbon solvent such as hexane,
Or a mixture thereof) in a base (potassium t-butoxy / tetrahydrofuran, sodium hydride, lithium hydride, phenyllithium, 1,5-diazabicyclo [4.3.
[0] A 6 / 5-ring carboxylic acid ester having a ketone group (13) in a mixed solution obtained by adding a trialkylphosphonoacetate (trimethyl or triethylphosphonoacetate) in the presence of non-5-ene (DBN)) Slowly add
When reacted at room temperature or under heating, α, β-unsaturated carboxylic acid ester (14) is produced. Carboxylic acid ester (13)
Can be obtained by the method described in Aono et al., Chem. Pharm. Bull., 26, 2475-82 (1978). Further, a Wittig reagent is prepared from triphenylphosphine and a halogenoacetic acid ester in place of trialkylphosphonoacetate, and a Wittig reaction according to a conventional method is performed to obtain an α, β-unsaturated carboxylic acid ester (14). Α with 6.5 rings
The β-unsaturated carboxylic acid ester (14) is converted to the corresponding saturated carboxylic acid ester (15) by catalytic reduction under atmospheric pressure or under pressure, and then decarboxylated according to a conventional method to give a carboxylic acid having a 6.5 ring. The acid (16) is obtained.
Then, the carboxyl group is reduced to convert it to the corresponding alcohol (17a). As the reducing agent, for example, borane or borane analog (for example, borane-dimethyl sulfide, borane-tetrahydrofuran, 9-borabicyclo [3.3.1] nonane, etc.) can be used, and as the solvent, tetrahydrofuran, ether, etc. can be used. Next, alcohol (17a) is subjected to sulfonic acid esterification represented by mesylation or tosylation in the presence of a base, and then halogenated by reacting with an alkali metal halide in an aprotic solvent under heating to produce ω- Cyclic carboxylic acid ester having a halogenoalkyl group (6a) (in the compound (6), R ² is 1,5-indandiyl group, n = 2, R ⁵
And Y have the same meaning as above).

Among cyclic carboxylic acid esters (6), compounds (6b) to (6c) in which R ² is 1,5-indandiyl group and n = 3 to 4 were synthesized by the second synthetic method shown below. it can.

[0038]

[Chemical 16]

In the above steps, R ⁵ has the same meaning as described above, R ⁹ represents a protecting group, and n '= n-1. That is, the carbonyl group of the compound (13) is converted into an exomethylene group by the Wittig reaction to obtain the compound (18). The Wittig reagent uses a triphenyl (substituted oxyalkyl) phosphonium halide obtained from a protected ω-hydroxyalkyl halide. Examples of the protecting group include tetrahydropyranyl, benzyl, substituted silyl (for example, t-butyldimethylsilyl) and the like. The corresponding 6.5-ring saturated carboxylic acid ester (19) can be obtained by subjecting the exomethylene compound (18) to catalytic reduction under atmospheric pressure or pressure. Compounds (17b) and (17c) can then be obtained by subjecting the protecting group R ⁹ to deprotection. Compound
(17b) and (17c) are respectively ω − by carrying out a halogenation reaction in the same manner as in the case of the above compound (17a).
A halogenoalkyl compound (6b) [in the compound (6), R ²
Is 1,5-indandiyl group, n = 3, R ⁵ and Y are as defined above, and compound (6c) [in compound (6), R ² is 1,5-
Indandiyl group, n = 4, R ⁵ and Y have the same meanings as described above.

Carboxylic acid ester having a bicyclic cyclic group
Compound (6b) in which R ² is 1,5-indandiyl group and n = 3 among (6) can also be synthesized by the third method shown below.

[0041]

[Chemical 17]

In the above steps, R ⁵ has the same meaning as above. That is, the carbonyl group of the compound (13) is converted to an exomethylene group by the Wittig reaction using [2- (1,3-dioxolan-2-yl) ethyl] triphenylphosphonium bromide to obtain an exomethylene compound (20). . The compound (20) is catalytically reduced and then treated with an acid to give an aldehyde (21), which is then converted to an alcohol (17b) with NaBH ₄ .
Compound (17b) is a ω-halogenoalkyl compound (6b) [in compound (6), R ² is a 1,5-indandiyl group, n = 3, R ⁵ and Y have the same meaning as above]. Two
In the carboxylic acid ester (6) having a cyclic group,
Compounds in which R ² is 1,5-indendiyl group, n = 2 to 3
(6d) and (6e) can be synthesized by the following method.

[0043]

[Chemical 18]

In the above steps, R ⁵ and Y have the same meanings as described above, and n "
= N-2 is shown. That is, by reacting the compound (13) with vinylmagnesium bromide or allylmagnesium bromide in an ether solvent such as tetrahydrofuran or diethyl ether, a tertiary alcohol compound (2
2a) or (22b) is obtained. Obtained tertiary alcohol
After hydrolyzing (22a) or (22b) with 9-BBN,
The primary alcohol derivative (23a) or (23b) is obtained by oxidizing with NaOH and hydrogen peroxide. Further, the obtained alcohol compound (23a) or (23b) is treated with an acid such as sulfuric acid or tosylic acid to eliminate the tertiary hydroxyl group to obtain an indene derivative (24a) or (24b). Indene derivative (24a) or (24b) is halogenated in the same manner as in the case of compound (17a) → (6a) ω-halogenoalkyl compound (6d) (compound (6)
Wherein R ² is a 1,5-indendiyl group, n = 2, R ⁵
Y is as defined above, compound (6e) (in compound (6),
R ² is a 1,5-indendiyl group, n = 3, and R ⁵ and Y have the same meanings as described above.

Compound (6f) having an alkyl side chain bonded to the 2-position of indane (in compound (6), R ² is 2,5-indandiyl group, n = 1 to 4, R ⁵ and Y have the same meanings as described above) Is 2-
(Ω-hydroxyalkyl) indan-5-carboxylic acid ester (25) can be used as a starting material and obtained according to the above-mentioned method. 2- (ω-hydroxyalkyl) indan-5-carboxylic acid ester (25) is disclosed in JP-A-61-27.
It can be synthesized by the method described in Japanese Patent No. 969.

[0046]

[Chemical 19]

In the general formula (6), the compound (6g) YR ² —COOR ⁵ (6g) in the case of n = 0 (wherein R ² , R ⁵ and Y have the same meanings as described above). Is a compound (8) in which R ² and the cyclopentane ring are directly bonded.
(n = 0) is obtained. Examples of the compound (6g) include 2-halogenoindan-5-carboxylic acid ester and N-protected 2-halogenoindoline-5-carboxylic acid ester. The former is 2-hydroxymethylindan
2 from 5-carboxylic acid ester via 2-carboxy body
− Can be converted to a halogeno form (J. Meek et al., Organic Synthe
sis, V126 (1973)). The latter is indoline-2-on-5
Carboxylic acid ester (Nozaka Chem. Pharm. Bull., 36,
2259 (1988)) can be used as a starting material.

On the other hand, in the carboxylic acid ester (6) having a bicyclic cyclic group, R ² is a 1,5-indolediyl group or a 1,5-indolinediyl group, and n = 2 (6
h) and (6i) are synthesized by the following first synthesis method.

[0049]

[Chemical 20]

In the above steps, R ⁵ and Y have the same meanings as described above, and X
Represents a halogen atom. Indole carboxylic acid ester
(26) in an aprotic solvent such as dimethylformamide,
When α-halogenoacetic acid ester is allowed to act in the presence of a base, an acetic acid ester group is introduced into N to give compound (27). As the base used in this reaction, sodium hydride, potassium hydride and the like are preferable, and the reaction is preferably performed at room temperature or below room temperature. The corresponding carboxylic acid (28) can be obtained by saponification of the compound (27) by 1N-NaOH in an alcohol solvent such as methanol. The reaction is near room temperature. When the compound (28) is subjected to borane reduction in an ether solvent, the corresponding alcohol compound (29) is obtained. BH ₃ -THF, BH ₃ -SMe _{2 and the} like are used as the borane reagent, and it is preferable to use 2 to 6 times the molar amount thereof. The temperature is preferably room temperature or lower. Then, the alcohol compound (29) in a suitable solvent such as acetic acid, Na
It can be converted into N-hydroxyethylindolinecarboxylic acid ester (29 ′) by reducing it by acting BH ₄ or NaBH ₃ CN. The corresponding carboxylic acid ester (29 ′) can be obtained by performing the same reaction on the indolinecarboxylic acid ester (26 ′).

The N- (hydroxyethyl) carboxylic acid ester form (29), (29 ') is obtained by reacting i) in the presence of an organic base with metal sulfonyl chloride or toluene sulfonyl chloride at room temperature or below, and then acetone 2-butanone. The corresponding N- (halogenoethyl) carboxylic acid ester (6h), (6i) can be obtained by reacting an alkali halide such as sodium halide or lithium halide in a solvent such as at room temperature or under heating. . Also, halogenation is ii)
A method in which tetrahalogenocarbon (2 to 4 times by mole) such as triphenylphosphine carbon tetrachloride is allowed to act at room temperature to under heating, and tetrahydrogenocarbon is also used as a solvent or CH ₂ Cl ₂ , DMF, or benzene is used, iii) It can also be achieved smoothly by a method of reacting triphenylphosphine dibromide or triphenylphosphine diiodide [a small excess with respect to compound (29)] in a neutral solvent such as DMF, DMSO, or THF.

By the above method, the hydroxyethyl derivative (2
9), (29 ') to the corresponding halogenoethyl compound (6h) [Compound
In (6), R ² is a 1,5-indolediyl group, R ⁵ and Y
Is as defined above, when n = 2], halogenoethyl compound (6i)
[In the compound (6), R ² is a 1,5-indolinediyl group, R ⁵ and Y have the same meanings as described above, and n = 2].

In the cyclic carboxylic acid ester (6) having a halogenoalkyl group, R ² is a 1,5-indolediyl group or a 1,5-indolinediyl group, and n
The compounds (6j) to (6m) in which = 3 or 4 can be synthesized by the following second synthetic method.

[0054]

[Chemical 21]

In the above steps, R ⁵ , R ⁹ , X, Y and n'have the same meanings as described above. The ω-position was protected by reacting the indolecarboxylic acid ester (26) and the indolinecarboxylic acid ester (26 ') with a protected ω-hydroxyalkyl halide (30) in the presence of an alkali metal metal hydride. -Hydroxyalkyl compounds (31), (31 ') are obtained. In this case, examples of the protecting group include tetrahydropyranyl, benzyl, substituted silyl (for example, 1-butyldimethylsilyl) and the like. Compound (26) or (26 ')
A compound which is an N- (ω-hydroxyalkyl) -substituted product of
(32) and (32 ′) can be obtained by deprotecting the protecting group R ⁹ of the compounds (31) and (31 ′). ω-Substituted alkylindolecarboxylic acid ester compounds (31) and (32) are generally prepared by reduction reaction with NaBH ₄ or NaBH ₃ CN in a suitable solvent to give the corresponding ω-substituted alkylindolinecarboxylic acid ester (3
Can be converted to 1 '), (32'). From ω-hydroxyalkyl compounds (32) or (32 ') to ω-halogenoalkyl compounds
Conversion to (33) or (33 ') can be accomplished according to the above halogenation method (29 → 6h).

According to the above reaction route, the corresponding halogenoalkyl compound (33) from the bicyclic cyclic carboxylic acid ester (26), (26 ') [in the compound (6), R ² is 1,5-indolediyl group, R ⁵ and Y have the same meaning as above, and when n = 3; (6j),
In the case of n = 4; (6l)], a halogenoalkyl derivative (33 ′) [in the compound (6), R ² is a 1,5-indolinediyl group, R ⁵
And Y 2 have the same meanings as described above, when n = 3; (6k), when n = 4; (6m)] can be synthesized.

The compound (6) synthesized as described above is the compound (8) or compound (11) which is an important intermediate of the present invention.
Used in the synthesis of.

In the carboxylic acid ester (5), when R ² is an indolinediyl group (R ¹ , R ⁵ and n are as defined above),
It can be converted to the indole ring by dehydrogenation of the indoline ring. Dehydrogenation was carried out by subjecting compound (5) to a) light irradiation in the presence of a ketone such as acetophenone, b) dehydrogenation in the presence of an oxidizing agent such as manganese dioxide, c) Pd / C or RuCl ₂ (PPh ₃ ) _{3 and the} like in the presence of a metal catalyst (Tsuji et al., J. Chem. Soc., Chem. Commun.,
1986, 1575) and the like. On the other hand, when R ² is an indolediyl group, a carboxylic acid ester
(5) (R ¹ , R ⁵ , and n have the same meanings as described above) is NaBH ₄ in a suitable solvent.
Or the corresponding indoline carboxylic acid ester (5) by a reduction reaction using NaBH ₃ CN (where R ² is an indolinediyl group,
R ¹ , R ⁵ _{, and} n can be converted into the same meaning as above.

In the carboxylic acid ester (5), R ² is 1,
A compound having a 5-indolediyl group and n = 2 to 4 can also be synthesized by the following method.

[0060]

[Chemical formula 22]

In the above steps, R ¹ , R ⁵ , R ⁶ , R ⁹ and X have the same meanings as described above. That is, the compound (34) was prepared by converting the ω-hydroxyhalide (30) protected with R ⁹ into 2-cyanocyclopenten-1-one (7) by the same method as the synthesis method of the compound (8).
It can be synthesized by reacting with. Conversion to lower alkyl enol ether (35) is carried out in the same manner as in the synthesis method of compound (9). Next, the enol ether (35) is hydrolyzed with an aqueous sodium hydroxide solution in ethanol to obtain a primary alcohol body (36). The alcohol compound (36) is halogenated in the same manner as in the synthesis method of the compound (6) to obtain a halide (37). Then treated with halide (37) and potassium hydride 5
Compound (38) can be synthesized by reacting with -alkoxycarbonyl-indole. Further, the compound (38)
Reacts with guanidine or a salt thereof in the same manner as in the synthesis of compound (9) to compound (5) to give the desired 6,7-dihydro-5H-cyclopenta [d] pyrimidine compound (5 ′). .

The compounds of the present invention form pharmaceutically acceptable salts with organic or inorganic acids. Examples of acids suitable for salt formation are hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, malonic acid, salicylic acid, malic acid, fumaric acid, maleic acid, succinic acid, ascorbic acid, methanesulfonic acid and the like. The organic acid salt or the inorganic acid salt is prepared by adding an equal amount of acid to the free base type by a conventional method. The free base can be regenerated by treating salts of organic and inorganic acids with a base. Aqueous solutions of sodium hydroxide, potassium carbonate, ammonia, sodium bicarbonate are suitable for this purpose. The compounds of this invention also form pharmaceutically acceptable carboxylates by reacting a suitable base with one or more free carboxyl groups. Suitable bases are alkali metal hydroxides or carbonates, such as sodium hydroxide, potassium hydroxide and the corresponding carbonates, and ammonia,
Include nitrogen bases such as alkylamines such as triethylamine.

Specific examples of the compound (1) of the present invention include: N- {1- [2- (2,4-diamino-6,7-dihydro-
5H-cyclopenta [d] pyrimidin-5-yl) ethyl] indole-5-carbonyl} -L-glutamic acid N- {1- [3- (2,4-diamino-6,7-dihydro-
5H-cyclopenta [d] pyrimidin-5-yl) propyl] indole-5-carbonyl} -L-glutamic acid N- {1- [2- (2,4-diamino-6,7-dihydro-
5H-cyclopenta [d] pyrimidin-5-yl) ethyl] indoline-5-carbonyl} -L-glutamic acid N- {1- [3- (2,4-diamino-6,7-dihydro-
5H-cyclopenta [d] pyrimidin-5-yl) propyl] indoline-5-carbonyl} -L-glutamic acid N- {1- [2- (2-amino-4-hydroxy-6,6
7-dihydro-5H-cyclopenta [d] pyrimidine-5
-Yl) ethyl] indole-5-carbonyl} -L-
Glutamic acid N- {1- [2- (2-amino-4-hydroxy-6,
7-dihydro-5H-cyclopenta [d] pyrimidine-5
-Yl) ethyl] indoline-5-carbonyl} -L-
Glutamic acid N- {1- [3- (2-amino-4-hydroxy-6,
7-dihydro-5H-cyclopenta [d] pyrimidine-5
-Yl) propyl] indole-5-carbonyl} -L
-Glutamic acidN- {1- [3- (2-amino-4-hydroxy-6,
7-dihydro-5H-cyclopenta [d] pyrimidine-5
-Yl) propyl] indoline-5-carbonyl} -L
-Glutamic acid N- {1- [2- (2,4-diamino-6,7-dihydro-
5H-cyclopenta [d] pyrimidin-5-yl) ethyl] indan-5-carbonyl} -L-glutamic acid N- {1- [3- (2,4-diamino-6,7-dihydro-
5H-cyclopenta [d] pyrimidin-5-yl) propyl] indan-5-carbonyl} -L-glutamic acid N- {1- [2- (2,4-diamino-6,7-dihydro-
5H-cyclopenta [d] pyrimidin-5-yl) ethyl] indene-5-carbonyl} -L-glutamic acid
N- {1- [3- (2,4-diamino-6,7-dihydro-5H
-Cyclopenta [d] pyrimidin-5-yl) propyl] indene-5-carbonyl} -L-glutamic acid N- {1- [3- (2-amino-4-hydroxy-6,6
7-dihydro-5H-cyclopenta [d] pyrimidine-5
-Yl) propyl] indan-5-carbonyl} -L-
Glutamic acid N- {1- [2- (2-amino-4-hydroxy-6,
7-dihydro-5H-cyclopenta [d] pyrimidine-5
-Yl) ethyl] indan-5-carbonyl} -L-glutamic acid N- {1- [2- (2-amino-4-hydroxy-6,
7-dihydro-5H-cyclopenta [d] pyrimidine-5
-Yl) ethyl] indene-5-carbonyl} -L-glutamic acid N- {1- [3- (2-amino-4-hydroxy-6,
7-dihydro-5H-cyclopenta [d] pyrimidine-5
-Yl) propyl] indene-5-carbonyl} -L-
Glutamic acid N- [2- (2,4-diamino-6,7-dihydro-5H-
Cyclopenta [d] pyrimidin-5-yl) indan-
5-Carbonyl] -L-glutamic acid N- [2- (2,4-diamino-6,7-dihydro-5H-
Cyclopenta [d] pyrimidin-5-yl) indene-
5-Carbonyl] -L-glutamic acid N- {2-[(2,4-diamino-6,7-dihydro-5H-
Cyclopenta [d] pyrimidin-5-yl) methyl] indan-5-carbonyl} -L-glutamic acid N- {2-[(2,4-diamino-6,7-disidro-5H-
Cyclopenta [d] pyrimidin-5-yl) methyl] indene-5-carbonyl} -L-glutamic acid N- {2- [2- (2,4-diamino-6,7-dihydro-
5H-cyclopenta [d] pyrimidin-5-yl) ethyl] indan-5-carbonyl} -L-glutamic acid N- [2- (2,4-diamino-6,7-dihydro-5H-cyclopenta [d] pyrimidine -5-yl) -1-propylindoline-5-carbonyl] -L-glutamic acidN- [2- (2,4-diamino-6,7-dihydro-5H-cyclopenta [d] pyrimidin-5-yl) Indoline-
5-carbonyl] -L-glutamic acid N- [2- (2,4-diamino-6,7-dihydro-5H-cyclopenta [d] pyrimidin-5-yl) indole-
5-Carbonyl] -L-glutamic acidN- [2- (2,4-diamino-6,7-dihydro-5H-cyclopenta [d] pyrimidin-5-yl) -1-propylindole-5-carbonyl]- L-glutamic acid N- {2- [2- (2,4-diamino-6,7-dihydro-
5H-cyclopenta [d] pyrimidin-5-yl) ethyl] -1-methylindoline-5-carbonyl} -L-
Glutamic acid N- {2- [2- (2,4-diamino-6,7-dihydro-
5H-cyclopenta [d] pyrimidin-5-yl) ethyl] -1-methylindole-5-carbonyl} -L-
Examples thereof include glutamic acid.

[0064]

The following pharmacological experimental examples are shown to describe the effects of the compounds of the present invention. Experimental Example 1 Dihydrofolate reductase (DHFR) inhibitory activity is basically measured by the method of DK Misra et al. (Nature, 18
Based on 9, 39-42 (1961). DHFR was prepared from mouse leukemia cell P388 cells. Preparation method is JMWhi-te
Rey et al. (Arch. Biochem. Biophys., 150, 15-22 (1
According to 972)). The method is potassium phosphate buffer (pH 7.
5, 75 mM), mercaptoethanol (7.5 mM), NADPH (0.
(25 mM) to which the purified DHFR solution was added to bring the total volume to 0.75 ml. 0.015 ml of each serial dilution of the compound of the present invention is added to this, and pre-heating at 37 ° C. for 5 minutes is performed. Next, 0.015 ml of a 25 µM solution of dihydrofolic acid is added, and the reaction is carried out at 37 ° C for 5 minutes. The decrease in absorbance at 339 nm per minute was measured to determine the amount of tetrahydrofolic acid produced, and 50% of each compound was compared with the control solution (no compound was added).
The% DHFR inhibitory concentration (IC ₅₀ ) is calculated. The results are shown in Table 1.

[0065]

[Table 1]

Experimental Example 2 Tumor cell growth inhibitory activity As tumor cells, mouse leukemia cell P388 cells, mouse colon cancer cells Colon26 cells, and human nasopharyngeal cancer cell KB cells were used. RP
Using a pipette, place each of the above cancer cell liquids prepared in MI-1640 medium (10% fetal bovine serum) into a 96-well microplate. These are placed in a carbon dioxide gas incubator containing 5% CO _{2 and} incubated at 37 ° C. for 1 day. The compound of the present invention is DMSO
After thawing, add the culture solution to prepare serial dilutions. After adding a certain amount of these solutions to each well containing cultured cells,
Incubate at ℃ for 3 days. Live cells measured by MTT method, 50%
Determine the cell growth inhibitory concentration (IC ₅₀ ). The measurement method is MCAlle
y et al. (Cancer Research, 48, 589 −601 (198
According to 8)). The results are shown in Table 2.

[0067]

[Table 2]

According to the above experimental examples, the compound of the present invention has a dihydrofolate reductase (DHFR) inhibitory action, and exhibits clear growth inhibition on mouse leukemia cell P388, mouse colon cancer cell Colon26, human epidermoid cancer cell KB and the like. Furthermore, it provides a therapeutic effect such as a life-prolonging effect or a tumor tissue growth-suppressing effect to mice subcutaneously transplanted with leukemia cells or a certain type of solid tumor cells, and the compound of the present invention is useful in the treatment or maintenance therapy of human tumors. Can be expected to be. Conventional MTX
With regard to tumors such as choriocarcinoma, leukemia, female breast adenocarcinoma, head and neck epidermal cancer, squamous cell or small cell lung cancer and various lymphosarcoma that have been treated with Can be used in combination.

The compound of the present invention is administered as it is or in the form of a pharmacologically acceptable carboxylic acid salt or acid addition salt by oral or parenteral administration. The dose is not particularly limited and varies depending on the degree of illness; patient weight, age, sex, difference in sensitivity; administration method (route), administration interval (schedule); type of active ingredient; type and properties of pharmaceutical preparation. However, the usual daily dosage is 60 kg (1.
1 to 300 mg / ma for subjects weighing 62 m ² / man)
n, preferably 10 mg to 150 mg / man, is administered once a day continuously or intermittently 1 to 3 times a week.

Suitable forms for oral therapeutic administration of the compounds of the invention include tablets, buccal forms, capsules, suspensions, syrups and troches. Conveniently the percentage of active compound in each formulation to excipients is conveniently about 0.5-50% by weight of the dosage unit. The amount of such active compounds is such that a suitable dosage will be obtained. For tablets, capsules, troches, etc., binders such as tragacanth gum, gum arabic, starch, gelatin; dicalcium phosphate,
Various starches, excipients such as alginic acid and stearic acid, disintegrating agents, and lubricants may be added. Tablets, capsules and the like may be coated with methyl cellulose, shellac, sugar or the like as a coating agent. Suitable forms for parenteral therapeutic administration of the compound of the present invention include injections, dispersions, emulsions and the like. Solutions of the active compound are prepared in water mixed with a surfactant such as hydroxypropyl cellulose. Injectable solutions are sterile aqueous solutions or dispersions, and for the preparation of injection solutions at the time of use-
Includes sterile powder. The carrier may be a solvent including water, ethanol, glycerol, polyols mixtures and vegetable oils. Dispersions are prepared in water and oil containing glycerol, liquid polyethylene glycols and mixtures thereof. For preparation of injection solution before use-Sterile powder is preferably prepared by subjecting the sterile-filtered solution to vacuum concentration drying or freeze drying to obtain the desired active ingredient.

[0071]

EXAMPLES The present invention will be described in more detail with reference to production examples and examples, but the present invention is not limited to the following production examples and examples.

Production Example 1 Indole-5-carboxylic acid ethyl ester Indole-5-carboxylic acid (25 g, 0.155 mol), sodium hydrogen carbonate (52.1 g, 0.621 mol) and iodoethane (9
6.8 g, Ca50 ml, 0.621 mol) was dissolved in 250 ml of anhydrous DMF, and the mixture was stirred for 12 hours in a 60 ° C. oil bath under a nitrogen atmosphere. About 200 ml of DMF was distilled off under reduced pressure to give a solid.
To this, 500 ml of diethyl ether and 250 ml of water were added and stirred to dissolve. The aqueous layer is further diethyl ether (250 ml x 2)
It was extracted with. The organic layers were combined, washed with brine (200 ml × 3), dried over magnesium sulfate, and the solvent was distilled off to obtain the desired product as an almost white solid (29 g, 0.153 mol).

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.42 (3H,
t, J = 7.2Hz), 4.40 (2H, q, J = 7.2Hz), 6.64-6.68 (1H, m),
7.28 (1H, t, J = 2.8Hz), 7.41 (1H, d, J = 8.4Hz), 7.92 (1H, d
d, J = 8.4Hz, 1.6Hz), 8.43 (1H, d, J = 1.6Hz), 8.40-8.60 (1
H, br) Production Example 2 1-Ethoxycarbonylmethylindole-5-carbo
Acid ethyl ester sodium hydride min. 60% mineral oil disp. (6.4g,
Ca.0.161mol) under nitrogen atmosphere anhydrous hexane (20ml × 3)
After washing with water, it was suspended in 100 ml of anhydrous DMF and stirred in a NaCl-ice bath. Indole-5-carboxylic acid ethyl ester (29 g, 0.153 mol) in anhydrous DM
The F 200 ml solution was added dropwise over 45 minutes. After stirring for 45 minutes in an ice bath, bromoacetic acid ethyl ester (26.9 g, Ca.
A solution of 8 ml, 0.161 mol) in 100 ml of anhydrous DMF was added dropwise over 45 minutes, and the mixture was stirred at room temperature for 30 minutes. After distilling off the solvent under reduced pressure,
Ethyl acetate (500 ml) and water (150 ml) were added to the residue and the mixture was transferred to a separating funnel and extracted. The aqueous layer was further extracted with ethyl acetate (100 ml x 2). The organic layers were combined, washed with brine (150 ml × 3), dried over magnesium sulfate and the solvent was distilled off to obtain the desired product (purity 95% or more, 37.4 g, 0.136 mol).

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.25 (3H,
t, J = 7.2Hz), 1.41 (3H, t, J = 7.2Hz), 4.22 (2H, q, J = 7.2H
z), 4.39 (2H, q, J = 7.2Hz), 4.86 (2H, S), 6.66 (1H, dd, J =
3.2,0.8Hz), 7.15 (1H, d, J = 3.2Hz), 7.25 (1H, d, J = 8.8Hz),
7.94 (1H, dd, J = 8.8,1.6Hz), 8.40 (1H, dd, J = 1.6,0.8Hz) Production Example 3 (5 -Ethoxycarbonylindol -1-yl) acetic acid 1-Ethoxycarbonylmethylindole-5 -Carboxylic acid ethyl ester (purity 95% or more, 37.4g, 0.136mo
l) was dissolved in 250 ml of ethanol and stirred in an ice bath. 150 ml of 1N sodium hydroxide solution was added dropwise thereto over about 30 minutes, and the mixture was further stirred at room temperature for 2 hours. Ethanol was distilled off at 40 ° C or lower, and 350 ml of water was added to the remaining aqueous solution. Transfer it to a separatory funnel and wash with ethyl acetate (100 ml x
The indole-5-carboxylic acid ethyl ester extracted in 3) and mixed in the raw material was removed. Transfer the aqueous layer to a Meyer, add 500 ml of ethyl acetate and stir vigorously to 1N hydrochloric acid.
150 ml was added (the resulting white turbidity and white precipitation were dissolved in ethyl acetate). The aqueous layer was further extracted with ethyl acetate (100 ml x 3),
The organic layers were combined, washed with brine (150 ml × 3), dried over magnesium sulfate, and then the solvent was distilled off to obtain the desired product as an almost white solid (33 g, 0.133 mol).

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.41 (3H,
t, J = 7.2Hz), 4.39 (2H, q, J = 7.2Hz), 4.92 (2H, S), 6.67 (1
H, d, J = 3.2Hz), 7.14 (1H, d, J = 3.2Hz), 7.25 (1H, d, J = 8.8H
z), 7.95 (1H, dd, J = 8.8,1.6Hz), 8.41 (1H, d, J = 1.6Hz) Production Example 4 1- (2-hydroxyethyl) indole-5-carbo
Acidic acid ethyl ester (5-ethoxycarbonylindol-1-yl) acetic acid (33 g, 0.133 mol) was dissolved in 200 ml of anhydrous THF, and the mixture was stirred under an atmosphere of nitrogen in an ice bath. Borane-THF complex 1.0M
A solution of 400 mL of THF was added dropwise over about 40 minutes, the ice bath was removed, and the mixture was stirred at room temperature for 30 minutes. After confirming the disappearance of the raw materials by TLC, the mixture was ice-cooled again and 100 ml of methanol was added dropwise over about 20 minutes to decompose excess borane. After distilling off the solvent, the residue was dissolved in 500 ml of diethyl ether and brine (100 ml x
After washing in 3) and drying with magnesium sulfate, the solvent was distilled off. The crude product obtained was passed through a silica gel column (eluent
It was purified with n-hexane: ethyl acetate = 2: 1 to 1: 1). Concentrate the desired fraction to yield a white-yellow solid (3
0 g, 0.129 mol) was obtained.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.42 (3H,
t, J = 7.2Hz), 1.50-1.70 (1H, br), 3.95-4.05 (2H, m), 4.3
2 (2H, t, J = 5.2Hz), 4.39 (2H, q, J = 7.2Hz), 6.62 (1H, dd, J =
3.2,0.8Hz), 7.23 (1H, d, 3.2Hz), 7.38 (1H, d, J = 8.8Hz), 7.9
2 (1H, dd, J = 8.8,1.6Hz), 8.41 (1H, dd, J = 1.6,0.8Hz) Production Example 5 1- (2-iodoethyl) indole-5-carboxylic acid
Ethyl ester 1- (2-hydroxyethyl) indole-5-carboxylic acid Ethyl ester (30 g, 0.129 mol) and triethylamine (19.4 g, 0.192 mol) were dissolved in 400 ml of methylene chloride and stirred under ice cooling. A solution of methanesulfonyl chloride (19 g, 0.166 mol) dissolved in 100 ml of methylene chloride was added dropwise over about 30 minutes, and the mixture was further stirred for 1 hour. 1 /
The reaction was stopped by adding 300 ml of 2M sodium hydrogen sulfite. The aqueous layer was further extracted with methylene chloride. The organic layers were combined, washed with brine, dried over magnesium sulfate, and then the solvent was distilled off to obtain a mesyl derivative. The obtained mesyl derivative and sodium iodide (28 g, 0.192 mol) were added to 500 ml of acetone.
And was stirred with heating at 40-60 ° C for about 6 hours. The reaction solution was cooled and the white precipitate formed was filtered off. The residue obtained by concentrating the filtrate was purified with a silica gel column to obtain the desired product (14.7 g, 0.857 mmo
l) got

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.42 (3H,
t, J = 7.2Hz), 3.46 (2H, t, J = 7.6Hz), 4.40 (2H, q, J = 7.2H
z), 4.54 (2H, t, J = 7.6Hz), 6.63 (1H, dd, J = 3.2,0.8Hz),
7.19 (1H, d, J = 3.2Hz), 7.34 (1H, d, J = 8.8Hz), 7.95 (1H, d
d, J = 8.8,1.6Hz), 8.41 (1H, dd, J = 1.6,0.8Hz) Production Example 6 1- [2- (2-cyano-3-methoxy-2-cyclope
Inten-1-yl) ethyl] indole-5-carvone
Acid ethyl ester 1- (2-iodoethyl) indole-5-carboxylic acid ethyl ester (14.7 g, 0.857 mmol) in benzene (350 ml)
And was refluxed. 2-cyano-2-cyclopenten-1-one (9.2g, 85.7mmol) in 100ml benzene, tributyltin hydride (18.8g, 17.3ml) and AI
A solution of BN (0.35 g, 2.1 mmol) in 100 ml of benzene was added dropwise over about 1 hour. After refluxing for further 15 minutes, the solvent was distilled off and the residue was dissolved in 500 ml of diethyl ether. This was washed with an aqueous solution of sodium fluoride and the white precipitate formed was filtered off. The organic layer was washed with brine and dried over magnesium sulfate, and the solvent was evaporated. The obtained residue was purified by a silica gel column to give 1- [2- (2-cyano-1-cyclopentenon-3-yl) ethyl] indole-5-carboxylic acid ethyl ester. This was dissolved in 50 ml of a 1: 1 mixture of methanol: acetonitrile, Ca.10% trimethylsilyldiazomethane-hexane solution was added in the presence of N, N-diisopropylethylamine, and the mixture was stirred at room temperature for about 2 hours. The reaction was stopped by adding acetic acid, and the solvent was distilled off.
The residue was dissolved in 200 ml of diethyl ether and washed with brine,
After drying over magnesium sulfate, the solvent was distilled off. The obtained residue was purified by a silica gel column, and 1- [2- (2-
Cyano-3-methoxy-2-cyclopenten-1-yl) ethyl] indole-5-carboxylic acid ethyl ester (0.43 g, 1.27 mmol) was obtained.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.42 (3H,
t, J = 7.2Hz), 1.54-1.70 (1H, m), 1.86-1.98 (1H, m), 1.99
-2.10 (1H, m), 2.23-2.54 (1H, m), 2.42-2.49 (2H, m), 2.80
-2.92 (1H, m), 4.04 (3H, s), 4.27 (2H, t, J = 7.2Hz), 4.40 (2
H, q, J = 7.2Hz), 6.61 (1H, dd, J = 3.2,0.8Hz), 7.19 (1H, d, J =
3.2Hz), 7.36 (1H, d, J = 8.4Hz), 7.93 (1H, dd, J = 8.4,1.6H
z), 8.40 (1H, d, J = 1.6Hz) IR v = 2202,1713,1627 cm ^-1 Preparation Example 7 1- (2-hydroxyethyl) indoline-5-carbo
Acid ethyl ester 1- (2-hydroxyethyl) indole-5-carboxylic acid ethyl ester (22.2 g, 95 mmol) was added to glacial acetic acid 500 ml
Sodium cyanoborohydride (36 g, 0.573 mol) was added with stirring at room temperature, and the mixture was stirred for 3 hours. After distilling off acetic acid, the residue was dissolved in ethyl acetate, washed with aqueous ammonia and brine, and dried over magnesium sulfate. After distilling off the solvent,
Target product (21.8g, 92.7mmol) after purification by silica gel column
Got

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.36 (3H,
t, J = 7.2Hz), 1.80-1.90 (1H, br), 3.04 (2H, t, J = 8.4Hz),
3.34 (2H, t, J = 5.4Hz), 3.57 (2H, t, J = 8.4Hz), 3.80-3.87
(2H, br), 4.31 (2H, q, J = 7.2Hz), 6.45 (1H, d, J = 8.4Hz), 7.
72 (1H, d, J = 1.2Hz), 7.82 (1H, dd, J = 8.4,1.2Hz) Production Example 8 1- (2-iodoethyl) indoline-5-carboxylic acid
Ethyl ester Using the alcohol compound (21.8 g, 92.7 mmol) obtained in Production Example 7 as a starting material, the target compound (31 g, 89.
9 mmol) was obtained.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.36
(3H, t, J = 7.2Hz), 3.06 (2H,
t, J = 8.4 Hz), 3.27 (2H, t, J =
7.2 Hz), 3.54 to 3.62 (4H, m),
4.31 (2H, q, J = 7.2Hz), 6.38
(1H, d, J = 8.4 Hz), 7.72 (1H,
d, J = 1.2 Hz), 7.82 (1H, dd, J =
8.4, 1.2 Hz) Production Example 9 1- [2- (2-cyano-3-methoxy-2-cyclope
Inten-1-yl) ethyl] indoline-5-carvone
Acid ethyl ester Using the iodo compound (24.2 g, 70 mmol) obtained in Production Example 8 as a starting material, the target compound (6.8 g, 20 mmol) was prepared in the same manner as in Production Example 6.
Got

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.36 (3H,
t, J = 7.2Hz), 1.54-1.68 (2H, m), 2.02-2.23 (2H, m), 2.48
-2.54 (2H, m), 2.92-3.04 (1H, m), 3.02 (2H, t, J = 8.8Hz),
3.17-3.33 (2H, m), 3.44-3.60 (2H, m), 4.05 (3H, s), 4.30
(2H, q, J = 7.2Hz), 6.36 (1H, d, J = 8.4Hz), 7.70 (1H, d, J = 1.
2Hz), 7.81 (1H, dd, J = 8.4,1.2Hz) Production Example 10 2- (2-Cyano-3-methoxy-2-cyclopentene
-1-yl) -1-propylindoline-5-carvone
Acid ethyl ester 1- (3-iodopropyl) indoline-5-carboxylic acid ethyl ester (22.5 g, 71.0 mmol) was dissolved in anhydrous benzene and heated under reflux to give 2-cyano-cyclopentene-
A solution of 1-one (18.0 g, 177 mmol) in anhydrous benzene and a catalytic amount of azoisobutyronitrile (AIBN) and a solution of tributyltin hydride (29 ml, 108 mmol) in anhydrous benzene were simultaneously added dropwise over about 1 hour. After completion of the reaction, the solvent was distilled off and the residue was purified by silica gel column chromatography to give 2- (2-cyano-1cyclopentenone-3).
-Yl) -1-propylindoline-5-carboxylic acid
Obtained the ethyl ester. This product and N, N-diisopropylethylamine (1 ml) were dissolved in a mixed solution of methanol-acetonitrile (1:10), 10% by weight of trimethylsilyldiazomethane was added thereto, and the mixture was stirred at room temperature for 4 hours. After distilling off the reaction solvent, the residue was purified by silica gel column chromatography to obtain the desired product (3.5
g).

¹ H-NMR (CDCl ₃ ) δ (ppm): 0.90 (3H,
t, J = 7.3Hz), 1.34 (3H, t, J = 7.1Hz), 1.50-1.75 (4H, m), 1.
79-1.89 (1H, m), 2.46-2.52 (1H, m), 2.69 (1H, dd, J = 7.2,1
6.6Hz), 3.04-3.26 (2H, m), 3.42-3.48 (1H, m), 4.03 (3H,
s), 4.20-4.26 (1H, m), 4.29 (2H, q, J = 7.1Hz), 6.29 (1H, d,
J = 8.4Hz), 7.64 (1H, s), 7.78 (1H, dd, J = 1.5,8.2Hz) Production Example 11 3- (2-Cyano-3-methoxy-2-cyclopentene)
-1-yl) propylbenzoate Bromopropylbenzoate (17 g) and cyanocyclopentenone (15 g) were radical-coupled to form a cyanoketone body. Further, it was treated with TMS diazomethane to obtain 2.9 g of the desired enol ether compound.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.44-2.18
(6H, m, 5-H ₂ , -C H ₂ C H ₂ CH ₂ OBz), 2.46-2.52 (2H, m, 4-H ₂ ), 2.8
9-2.98 (1H, m, 1-H), 4.05 (3H, s, -OMe), 4.32-4.37 (2H, m, -C
H ₂ CH ₂ C H ₂ OBz), 7.42-7.47 (2H, m, ArH), 7.54-7.58 (1H, m, A
rH), 8.03-8.06 (2H, m, ArH) Production Example 12 2-Cyano-1- (3-hydroxypropan-1-y)
) -3-Methoxy-2-cyclopentene The benzoate compound (2.9 g) obtained in Production Example 11 was dissolved in ethanol (80 ml), 1N NaOH aqueous solution (20 ml) was added, and the mixture was stirred at room temperature for 3 hr. After completion of the reaction, extraction was performed with ethyl acetate, and the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography. Solvent (ethyl acetate-n
-Hexane: 1-1) was eluted to obtain 1.52 g (yield 84%) of the intended primary alcohol.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.36-2.16
(6H, m, 5-H ₂ , -C H ₂ C H ₂ CH ₂ OH), 2.45-2.51 (2H, m, 4-H ₂ ), 2.86
-2.94 (1H, m, 1-H), 3.65-3.71 (2H, m, -CH ₂ CH ₂ C H ₂ OH), 4.05
(3H, s, -OMe) Production Example 13 2-Cyano-1- (3-bromopropan-1-yl)-
3-methoxy-2-cyclopentene The primary alcohol (1.52 g) obtained in Production Example 12 was
It was converted to a halide using LiBr and 1.8 g (yield) of the target compound was obtained.
89%) obtained.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.45-2.15
(6H, m, 5-H ₂ , -C H ₂ C H ₂ CH ₂ Br), 2.46-2.51 (2H, m, 4-H ₂ ), 2.85
-2.93 (1H, m, 1-H), 3.36-3.47 (2H, m, -CH ₂ CH ₂ C H ₂ Br), 4.05
(3H, s, -OMe) Production Example 14 1- [3- (2-cyano-3-methoxy-2-cyclope
Nten-1-yl) propyl] indole-5-carbo
Acidic acid ethyl ester KH (0.23 g, 35 wt% mineral oil dispersion) in THF (10 ml)
A solution of indole-5-carboxylic acid ethyl ester (0.76 g) in THF (2 ml) was added dropwise to the suspension while stirring with ice cooling. After stirring under ice-cooling to dissolve KH, the bromide derivative (0.5 g) obtained in Production Example 13 was stirred under ice-cooling under stirring with THF (2 m
l) The solution was added dropwise and stirred at room temperature for 1 hour. After completion of the reaction, saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The solvent was evaporated, and the obtained residue was subjected to silica gel column chromatography. Solvent (ethyl acetate-
By eluting with n-hexane: 1-8), 0.43 g (yield 61%) of the target N-alkylindole was obtained.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.28-2.10
(9H, m, 5-H ₂ , -C H ₂ C H ₂ CH ₂ N, -CO ₂ CH ₂ C H ₃ ), 2.40-2.45 (2H, m,
4-H ₂ ), 4.02 (3H, s, -OMe), 4.37 (2H, q, -CH ₂ CH ₂ C H ₂ N), 4.39
(2H, q, -CO ₂ C H ₂ CH ₃ ), 6.59 (1H, d, J = 3.6Hz, indole 3-
H), 7.16 (1H, d, J = 3.6Hz, Indole 2-H), 7.34 (1H, d, J =
8.4Hz, indole 7-H), 7.92 (1H, dd, J = 1.6,8.4Hz, indole 8-H), 8.39 (1H, d, J = 1.6Hz, indole 4-H) Example 1 1- [ 2- (2,4-diamino-6,7-dihydro-5H-
Cyclopenta [d] pyrimidin-5-yl) ethyl] y
Ndol-5-carboxylic acid ethyl ester

[0087]

[Chemical formula 23]

1- [2- (2-cyano-3-methoxy-2-cyclopenten-1-yl) ethyl] indole-5-carboxylic acid ethyl ester obtained in Preparation Example 6
(0.43g, 1.27mmol) and guanidine carbonate (1.14g, 6.34
mmol) to 25 ml of ethanol and autoclave 160
The mixture was heated and stirred at ℃ for about 14 hours. The precipitate was filtered off and washed with ethanol. The filtrate and washings were combined and concentrated, and the obtained residue was purified by a silica gel column, and 1- [2- (2,4-diamino-6,7-dihydro-5H-cyclopenta [d] pyrimidin-5-yl was used. ) Ethyl] indole-5-carboxylic acid ethyl ester (0.37 g, 1.0 mmol) was obtained.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.42 (3H,
t, J = 7.2Hz), 1.79-1.93 (2H, m), 2.16-2.28 (2H, m), 2.67
(1H, ddd, J = 17.6,5.6,3.6Hz), 2.78-2.91 (2H, m), 4.13-
4.35 (2H, m), 4.32 (2H, br-s), 4.40 (2H, q, J = 7.2Hz), 4.72
(2H, br-s), 6.62 (1H, dd, J = 2.8,0.4Hz), 7.16 (1H, d, J = 2.
8Hz), 7.34 (1H, d, J = 8.8Hz), 7.93 (1H, dd, J = 8.8,1.6Hz),
8.41 (1H, dd, J = 1.6,0.4Hz) Example 2 1- [2- (2,4diamino-6,7-dihydro-5H-si)
Clopenta [d] pyrimidin-5-yl) ethyl] yne
Dole-5-carboxylic acid

[0090]

[Chemical formula 24]

The ester form obtained in Example 1 (0.33 g,
0.9 mmol) was dissolved in 30 ml of a mixture of ethanol: THF = 1: 1, 5 ml of 1N sodium hydroxide was added, and the mixture was heated with stirring under a nitrogen atmosphere for about 4 hours. After completion of the reaction, 1N hydrochloric acid was added for neutralization, and the organic solvent was evaporated under reduced pressure. The resulting white precipitate was collected by filtration, washed with a small amount of distilled water, and dried with a desiccator in the presence of P ₂ O ₅ to obtain the desired product (0.28g, 0.83mmol).

¹ H-NMR (DMSO-d ₆ ) δ (ppm): 1.58-1.
74 (2H, m), 1.88-2.10 (2H, m), 2.32-2.44 (1H, m), 2.56-
2.70 (1H, m), 2.99-3.09 (1H, m), 4.20 (2H, t, J = 8.0Hz), 5.
60-5.80 (2H, br), 6.11 (2H, br-s), 6.54 (1H, d, J = 3.2Hz),
7.46 (1H, d, J = 3.2Hz), 7.56 (1H, d, J = 8.8Hz), 7.72 (1H, d
d, J = 8.8,1.6Hz), 8.18 (1H, d, J = 1.6Hz) Example 3 N- [1- [2- (2,4-diamino-6,7-dihydro-
5H-cyclopenta [d] pyrimidin-5-yl) eth
]] Indole-5-carbonyl] -L-glutamic acid

[0093]

[Chemical 25]

The carboxylic acid obtained in Example 2 (0.27 g,
0.8 mmol) was dissolved in 40 ml of anhydrous DMF and stirred under ice cooling.
Diethyl L-glutamate hydrochloride (0.96g, 4mmo
l) was added, and DPPA (1.1 g, 4 mmol) and then triethylamine (0.81 g, 8 mmol) were added dropwise. After stirring for another 30 minutes in an ice bath, the mixture was stirred at room temperature for about 3 hours. The precipitate was filtered off and the filtrate was concentrated. The obtained residue was purified with a silica gel column. The obtained diethyl ester compound was dissolved in 20 ml of ethanol, 5 ml of 1N sodium hydroxide was added thereto, and the mixture was stirred at room temperature for 3 hours. After neutralizing with the addition of 1N hydrochloric acid, ethanol was distilled off, and the residue was filtered through a silica gel column (developing solution chloroform: methanol: acetic acid = 10: 1: 1 to 1: 1).
Purified 5: 1: 1). Dilute alkali solution-reprecipitate by adding dilute hydrochloric acid to obtain white powder (0.14 g, 0.34 g)
mmol) was obtained.

¹ H-NMR (DMSO-d ₆ ) δ (ppm): 1.60-1.
75 (2H, m), 1.90-2.12 (4H, m), 2.36 (2H, t, J = 7.6Hz), 2.3
0-2.47 (1H, m), 2.52-2.70 (1H, m), 3.02-3.12 (1H, m), 4.
23 (2H, t, J = 7.6Hz), 4.35-4.44 (1H, m), 5.80-5.98 (2H, b
r), 6.24-6.40 (2H, br), 6.54 (1H, d, J = 3.2Hz), 7.47 (1H,
d, J = 3.2Hz), 7.53-7.60 (1H, m), 7.65-7.71 (1H, m), 8.15
(1H, d, J = 1.6Hz), 8.38 (1H, d, J = 7.2Hz) Example 4 1- [2- (2,4-diamino-6,7-dihydro-5H-
Cyclopenta [d] pyrimidin-5-yl) ethyl] y
Andrin-5-carboxylic acid ethyl ester

[0096]

[Chemical formula 26]

Using the cyclopentene derivative (6.8 g, 20 mmol) obtained in Preparation Example 9 as a starting material, the corresponding target product (5.3 g, 14.4 mmol) was obtained in the same manner as in Example 1.

¹ H-NMR (CDCl ₃ ) δ (ppm): 1.36 (3H,
t, J = 7.2Hz), 1.75-1.93 (3H, m), 2.20-2.33 (1H, m), 2.64
(1H, ddd, J = 17.2,9.6,2.4Hz), 2.84-2.95 (1H, m), 2.95-
3.08 (1H, m), 3.03 (2H, t, J = 8.4Hz), 3.12-3.22 (1H, m),
3.25-3.39 (2H, m), 3.58-3.66 (1H, m), 4.32 (2H, q, J = 7.2H
z), 4.71 (2H, br-s), 4.80 (2H, q, J = 7.2Hz), 6.45 (1H, d, J
= 8.0Hz), 7.74 (1H, d, J = 1.2Hz), 7.82 (1H, dd, J = 8.0,1.2H
z) Example 5 1- [2- (2,4 diamino-6,7-dihydro-5H-shi
Clopenta [d] pyrimidin-5-yl) ethyl] yne
Drin-5-carboxylic acid

[0099]

[Chemical 27]

The ester form obtained in Example 4 (4.3 g, 1
1.7 mmol) was used as the starting material and the corresponding target product (3.3 g, 9.7 mmol) was obtained in the same manner as in Example 2.

¹ H-NMR (DMSO-d ₆ ) δ (ppm): 1.37-1.
50 (1H, m), 1.70-1.86 (2H, m), 1.94-2.06 (1H, m), 2.39 (1
H, ddd, J = 16.8,9.6,2.8Hz), 2.58-2.70 (1H, m), 2.89 (2H,
t, J = 8.4Hz), 2.94-3.02 (1H, m), 3.06-3.23 (2H, m), 3.36
-3.50 (2H, m), 5.62 (1H, br-s), 5.64 (1H, br-s), 6.06 (2H,
br-s), 6.43 (1H, d, J = 8.4Hz), 7.49 (1H, d, J = 1.2Hz), 7.60
(1H, dd, J = 8.4,1.2Hz) Example 6 N- [1- [2- (2,4-diamino-6,7-dihydro-
5H-cyclopenta [d] pyrimidin-5-yl) eth
] Indoline-5-carbonyl] -L-glutamic acid

[0102]

[Chemical 28]

The carboxylic acid obtained in Example 5 (1.6 g, 4.
The target compound (0.86 g, 1.7 mmol) was obtained in the same manner as in Example 3 using 7 mmol) as the starting material.

¹ H-NMR (DMSO-d ₆ ) δ (ppm): 1.38-1.
52 (1H, m), 1.73-2.10 (5H, m), 2.30 (2H, t, J = 7.2Hz), 2.3
7-2.48 (1H, m), 2.61-2.74 (1H, m), 2.90 (2H, t, J = 7.6Hz),
2.95-3.05 (1H, m), 3.05-3.24 (2H, m), 3.35-3.50 (2H,
m), 4.26-4.35 (1H, m), 5.80-6.00 (2H, br), 6.20-6.40
(2H, br), 6.45 (1H, dd, J = 8.4,2.0Hz), 7.53 (1H, s), 7.57
(1H, d, J = 8.4Hz), 8.06 (1H, d, J = 6.8Hz) Example 7 2- (2,4-diamino-6,7-dihydro-5H-cyclope
[D] pyrimidin-5-yl) -1-propylin
Drin-5-carboxylic acid ethyl ester

[0105]

[Chemical 29]

2- (2-Cyano-obtained in Preparation Example 10
3-methoxy-2-cyclopenten-1-yl) -1-
Propyl indoline-5-carboxylic acid ethyl ester
(3.1 g, 8.7 mmol) and guanidine carbonate (4.7 g, 26 mmol) were mixed with ethanol and placed in a pressure resistant container under a nitrogen atmosphere,
The mixture was heated with stirring at 165 ° C. for 21 hours. The reaction solution was allowed to cool, the precipitate was filtered off, the filtrate was concentrated, and the residue was separated and purified by silica gel column chromatography to obtain the desired product (yield 640 mg).

¹ H-NMR (DMSO-d ₆ ) δ (ppm): 0.85 (3H
× 0.5, t, J = 7.3Hz), 0.92 (3H × 0.5, t, J = 7.3Hz), 1.25 (3H,
t, J = 7.1Hz), 1.49-1.58 (1H, m), 1.61-1.72 (2H, m), 1.79-
1.90 (1H, m), 2.34 (1H, dd, J = 7.5,16.8Hz), 2.40-2.61 (2
H, m), 2.67 (1H, dd, J = 10.4,16.8Hz), 3.11-3.19 (1H, m),
3.37-3.45 (1H, m), 3.57-3.62 (1H, m), 4.18 (2H, q, J = 7.1H
z), 4.39 (1H, ddd, J = 4.1,7.8,10.1Hz), 5.75 (2H, br-s),
6.18 (1H, br-s), 6.37 (1H, d, J = 8.4Hz), 6.58 (1H, br-s),
7.43 (1H, d, J = 1.1Hz), 7.62 (1H, dd, J = 1.6,8.2Hz) Example 8 2- (2,4-diamino-6,7-dihydro-5H-cyclope
[D] pyrimidin-5-yl) -1-propylin
Drin-5-carboxylic acid

[0108]

[Chemical 30]

2- (2,4-diamino-obtained in Example 7
6,7-Dihydro-5H-cyclopenta [d] pyrimidin-5-yl) -1-propylindoline-5-carboxylic acid ethyl ester was dissolved in ethanol, 1N aqueous sodium hydroxide solution (4 ml) was added and heated for 5 hours. Refluxed. The reaction solution was concentrated to remove ethanol and then neutralized by adding 1N hydrochloric acid to obtain the desired product as a precipitate (yield: 540 m
g).

¹ H-NMR (DMSO-d ₆ ) δ (ppm): 0.90 (3
H, t, J = 7.3Hz), 1.45-1.67 (2H, m), 1.73-1.80 (1H, m), 1.8
7-1.98 (1H, m), 2.34 (1H, dd, J = 8.1,16.8Hz), 2.54-2.61
(1H, m), 2.63-2.74 (2H, m), 3.06-3.14 (1H, m), 3.31-3.42
(1H, m), 3.60-3.64 (1H, m), 4.32-4.38 (1H, m), 6.35 (1H,
d, J = 8.4Hz), 6.63 (2H, br-s), 7.10 (2H, br-s), 7.40 (1H,
s), 7.59 (1H, dd, J = 1.5,8.2Hz) Example 9 N- [2- (2,4-diamino-6,7-dihydro-5H-si)
Clopenta [d] pyrimidin-5-yl) -1-propyi
Ruindoline-5-carbonyl] -L-glutamic acid

[0111]

[Chemical 31]

2- (2,4-diamino-obtained in Example 8
6,7-Dihydro-5H-cyclopenta [d] pyrimidin-5-yl) -1-propylindoline-5-carboxylic acid (510 mg) was dissolved in N, N-dimethylformamide and, under ice cooling, glutamic acid diethyl ester hydrochloride. Salt (1.0
g, 4.2mmol) and azide diphenyl phosphate (0.8ml, 3.7m
mol) and triethylamine (1.4 ml, 10 mmol) were added.
After stirring as it was at room temperature overnight, the solvent was distilled off and the residue was purified by silica gel column chromatography. This was dissolved in ethanol and a 1N aqueous sodium hydroxide solution (4
ml) was added and the mixture was stirred overnight. The reaction solution was neutralized with 1N hydrochloric acid and then purified by silica gel column chromatography to obtain the desired product (yield 150 mg).

¹ H-NMR (DMSO-d ₆ ) δ (ppm): 0.9 (3H,
t, J = 7Hz), 1.4-2.0 (8H, m), 2.1-2.7 (4H, m), 3.1-3.6 (3
H, m), 3.9-4.4 (2H, m), 5.7 (2H, br-s), 6.1 (2H, br-s), 6.
3 (1H, d, J = 8Hz), 7.3 (1H, s), 7.5 (1H, d, J = 8Hz), 7.6 (1H, b
rs) Example 10 1- [3- (2,4-diamino-6,7-dihydro-5H-
Cyclopenta [d] pyrimidin-5-yl) propyl]
Indole-5-carboxylic acid ethyl ester

[0114]

[Chemical 32]

1- [3- (2-cyano-3-methoxy-2-cyclopenten-1-yl) obtained in Preparation Example 14
Propyl] indole-5-carboxylic acid ethyl ester (1.0 g) and guanidine carbonate (2.6 g) were added to ethanol (50 ml), and the mixture was heated and stirred in an autoclave at 150 ° C for about 24 hours. The precipitate was filtered off and washed with ethanol. The filtrate and washings were combined and concentrated, and the obtained residue was purified by a silica gel column, and 1- [3- (2,4-diamino-6,7-
Dihydro-5H-cyclopenta [d] pyrimidine-5-
Il) propyl] indole-5-carboxylic acid ethyl ester (0.77 g) was obtained.

¹ H-NMR (CD ₃ OD) δ (ppm): 1.25-2.26
(9H, m, 6-H ₂ , -C H ₂ C H ₂ CH ₂ N, -CO ₂ CH ₂ C H ₃ ), 2.62-2.86 (2H, m,
7-H ₂ ), 3.01-3.09 (1H, m, 5-H), 4.23 (2H, dt, J = 1.6,6.8Hz,-
CH ₂ CH ₂ C H ₂ N), 4.35 (2H, q, -CO ₂ C H ₂ CH ₃ ), 6.56-6.58 (1H, m,
Indole 3-H), 7.32 (1H, d, J = 3.2Hz, Indole 2-H), 7.
45 (1H, d, J = 8.4Hz, Indole 7-H), 7.83 (1H, dd, J = 1.6,
8.4 Hz, indole 6-H), 8.29-8.30 (1H, m, indole 4-H) Example 11 1- [3- (2,4 diamino-6,7-dihydro-5H-si)
Clopenta [d] pyrimidin-5-yl) propyl] y
Ndol-5-carboxylic acid

[0117]

[Chemical 33]

The ester obtained in Example 10 was dissolved in 20 ml of a mixture of ethanol: THF = 1: 1, 4 ml of 1N sodium hydroxide was added, and the mixture was heated and stirred under a nitrogen atmosphere for about 4 hours. After completion of the reaction, 1N hydrochloric acid was added for neutralization, and the organic solvent was evaporated under reduced pressure. The white precipitate thus formed was collected by filtration, washed with a small amount of distilled water, and dried in a desiccator in the presence of P ₂ O _{5 to} obtain the desired product (0.54
g) was obtained.

¹ H-NMR (CD ₃ OD) δ (ppm): 1.26-2.28
(6H, m, 6-H ₂ , -C H ₂ C H ₂ CH ₂ N), 2.64-2.89 (2H, m, 7-H ₂ ), 3.05-
3.11 (1H, m, 5-H), 4.24 (2H, dt, J = 2.4,6.4Hz, -CH ₂ CH ₂ C H
₂ N), 6.57 (1H, d, J = 3.2, indole 3-H), 7.31 (1H, d, J = 3.2
Hz, indole 2-H), 7.45 (1H, d, J = 8.4Hz, indole 7-
H), 7.84 (1H, dd, J = 1.6,8.4Hz, indole 6-H), 8.3 (1H, d,
J = 1.6 Hz, indole 4-H) Example 12 N- [1- [3- (2,4-diamino-6,7-dihydro-
5H-cyclopenta [d] pyrimidin-5-yl) pro
Pill] indole-5-carbonyl] -L-glutamine
acid

[0120]

[Chemical 34]

The carboxylic acid obtained in Example 11 was treated with anhydrous D
It was dissolved in 40 ml of MF and stirred under ice cooling. L-Glutamic acid diethyl hydrochloride was added thereto, and DPPA and then triethylamine were added dropwise. After stirring for another 30 minutes in an ice bath, the mixture was stirred at room temperature for about 3 hours. The precipitate was filtered off and the filtrate was concentrated. The obtained residue was purified with a silica gel column. The obtained diethyl ester compound was dissolved in 20 ml of ethanol, and 5 ml of 1N sodium hydroxide was added thereto, and the mixture was stirred at room temperature for 3
Stir for hours. After neutralizing by adding 1N hydrochloric acid, ethanol was distilled off and the residue was purified by a silica gel column. The target substance (0.13 g) was obtained as a white powder by reprecipitation operation by dissolving diluted alkali and adding diluted hydrochloric acid.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Kyosuke Kito 8-10-10 Tokodai, Tsukuba City, Ibaraki Prefecture

Claims (4)

[Claims] 1. A general formula (1): [In the formula, R ¹ represents a hydroxyl group or an amino group. R ² represents an optionally substituted indolinediyl group, an indolediyl group, an indandiyl group or an indenediyl group. n shows the integer of 0-4. ] A 6,7-dihydro-5H-cyclopenta [d] pyrimidine derivative represented by the following or a pharmacologically acceptable salt thereof. 2. A general formula (2): [In the formula, R ¹ represents a hydroxyl group or an amino group. R ² represents an optionally substituted indolinediyl group, an indolediyl group, an indandiyl group or an indenediyl group. n shows the integer of 0-4. ] Or a reactive derivative of the compound at the carboxyl group thereof, represented by the general formula (3): [Wherein R ³ and R ⁴ represent the same or different carboxyl-protecting groups] and are condensed with each other,
General formula (4) [In the formula, R ¹ , R ² , R ³ , R ⁴ and n are as defined above. ] To obtain a carboxylic acid ester body, then,
The free carboxylic acid derivative is obtained by hydrolyzing the ester in the presence of an acid or an alkali, or by hydrogenolysis including catalytic reduction.
A process for producing a 6,7-dihydro-5H-penta [d] pyrimidine derivative represented by the general formula (1) or a pharmaceutically acceptable salt thereof. 3. A general formula (5): [In the formula, R ¹ represents a hydroxyl group or an amino group. R ² represents an optionally substituted indolinediyl group, an indolediyl group, an indandiyl group or an indenediyl group. n shows the integer of 0-4. —COOR ⁵ represents a carboxyl group which may be esterified with a protecting group. ] The compound or its salt represented by these. 4. The 6,7-dihydro-5H- according to claim 1.
An antitumor agent comprising a cyclopenta [d] pyrimidine derivative or a pharmacologically acceptable salt thereof as an active ingredient.