JPH04235986A - Pyridopyrimidine derivative, production and use thereof - Google Patents

Abstract

PURPOSE:To provide a novel pyridopyrimidine derivative exhibiting highly selective toxicity against tumor cells and excellent anti-tumor activity as an anti-tumor agent. CONSTITUTION:A compound of formula I (A ring is pyridine ring capable of being hydrogenated and of containing one or more substituents; B is divalent ring-like group capable of containing one or more substituents or 2-5C alkylene; X is amino, hydroxyl; Y is H, amino, etc.; COOR<1>, COOR<2> are carboxyl groups capable of being esterified; n is 2-5) or a salt thereof, e.g. 4-[3-(2,4-diamino-5,6,7,8- tetrahydropyrido[2,3-d]pyrimidin-5-yl)propyl] benzoic acid tert-butyl ester. The compound is produced e.g. by acylating a glutamic acid derivative of formula III with a carboxylic acid of formula III in the presence of a dehydration- condensing agent such as dicyclohexylcarbodiimide. The reaction is preferably carried out at a pH of 5-10 at a temperature of 0-50 deg.C.

Description

Description: [0001] The present invention relates to a novel pyridopyrimidine derivative useful as an antitumor agent, a method for producing the same, and uses thereof. [Prior Art] Folic acid is used as a carrier of C1 units derived from formic acid, formaldehyde, etc. in living organisms, and is used as a coenzyme in various enzymatic reactions such as nucleic acid biosynthesis, amino acid/peptide metabolism, and methane production. plays the role of In particular, in the nucleic acid biosynthesis system, it is essential for the metabolism and transfer reaction of the C1 unit in two pathways, namely, the purine synthesis system and the thymidine synthesis system. Normally, for folic acid to exert its biological activity, it must undergo two steps of reduction and be converted into an active coenzyme form. Amethopterin (methotrexate: MTX) and its surrounding compounds are known as drugs that strongly bind to the enzyme (dihydrofolate reductase) that controls the second step and suppress the reduction of dihydrofolate to tetrahydrofolate. Since these drugs impair DNA synthesis and result in cell death, they were developed as antitumor agents and currently occupy an important position clinically. Furthermore, unlike these drugs, it does not inhibit dihydrofolate reductase, and its main mechanism of action is inhibition of glycinamide ribonucleotide transformylase, which is involved in the early stages of purine biosynthesis. agent (5,10-
Dideaza-5,6,7,8-tetrahydroaminopterin: DDATHF) [Journal of Medici
nal Chemistry) 28, 914 (1
985)] has also been reported. On the other hand, in addition to these folate antagonists whose basic skeleton is a fused ring of a 6-membered ring and a 6-membered ring, there are other folate antagonists that have a pyrrolo[2,3-d]pyrimidine skeleton that is a fused ring of a 5-membered ring and a 6-membered ring. It has been reported that a compound in which the glutamic acid moiety is cross-linked with a group containing a phenylene group also has antitumor activity (Japanese Patent Application No. 01-72235). [0004]Problems to be Solved by the Invention Currently, various studies are being conducted regarding the treatment of cancer, but in particular, treatments based on new mechanisms of action that are more effective and highly selective for cancer cells are being investigated. The development of a drug is eagerly awaited. MTX, an antitumor drug whose mechanism of action is to antagonize folic acid, is currently in clinical use, but it is relatively toxic and not very effective against solid tumors, and has not produced sufficiently satisfactory treatment results. It has not been done. Furthermore, acquisition of resistance by cancer cells to these drugs is also a major problem. [Means for Solving the Problems] In view of the above circumstances, the present inventors have conducted intensive research and found that pyrido[2,3-
d] We have discovered that a novel pyridopyrimidine derivative crosslinked with a carbon chain consisting of 2 to 5 atoms at the 5th position of the pyrimidine skeleton exhibits excellent antitumor activity with high selective toxicity against tumor cells, and have completed the present invention. . That is, the present invention provides (1)
General formula: [Chemical formula 5] (In the formula, ring A is a pyridine ring which may be hydrogenated and may have a substituent, and B is a divalent ring which may have a substituent. is a cyclic group or a lower alkylene group having 2 to 5 carbon atoms, X is an amino group or a hydroxyl group, Y is
represents an amino group, a hydrogen atom or a lower alkyl group, R represents a hydrogen atom or a lower hydrocarbon group, -COOR1 and -
COOR2 is a carboxyl group which may be esterified in the same or different ways, n is an integer of 2 to 5, and R may be different in n repeats) or a pyridopyrimidine derivative represented by The salt, (
2) General formula: A compound represented by the formula 6 (wherein A ring, B, X, Y, R and n have the same meanings as above) or a reactive derivative thereof in the carboxyl group, and : [Chemical formula 7] (wherein -COOR1 and -COOR2 are the same or different and each represents a carboxyl group which may be esterified). Method for producing a compound, (3) General formula: [Formula 8] (wherein A ring, B, X, Y, R and n have the same meanings as above, -COOR3 may be esterified The present invention relates to an antitumor composition containing a pyridopyrimidine derivative represented by (representing a carboxyl group), and (4) the compound according to claim 1 or a salt thereof. In the above formula, when X is a hydroxyl group, compounds (I), (II) and (IV) can exist as an equilibrium mixture with their tautomers. Tautomerizable partial structural formulas are listed below, and the equilibrium relationship between them is shown. embedded image For convenience of presentation, the hydroxyl type is described herein and the corresponding nomenclature is adopted, but in any case, the oxo form, which is a tautomer, is also included. In addition, the compounds (I), (II), and (IV) of the present invention may have multiple asymmetric centers, but the absolute configuration of the asymmetric carbon atom in the side chain derived from glutamic acid in compound (I) is S The absolute configuration of the asymmetric center other than (L) may be any mixture of S, R, or RS. In this case, multiple diastereoisomers exist, but if necessary, they can be easily separated by conventional separation and purification means. All of the above diastereoisomers that can be separated in this way also fall within the scope of the present invention. In the above formula, the lower hydrocarbon group represented by R includes an alkyl group having 1 to 3 carbon atoms (eg, methyl, ethyl, propyl, isopropyl group), an alkenyl group having 2 to 3 carbon atoms (eg, vinyl, 1-methylvinyl, 1-propenyl, allyl, arenyl groups), alkynyl groups having 2 to 3 carbon atoms (e.g., ethynyl, 1-propynyl, propargyl groups), and preferably methyl, ethyl and propargyl groups. be. As the lower alkyl group represented by Y, for example, an alkyl group having 1 to 3 carbon atoms as described for R above can be used. The optionally hydrogenated pyridine ring represented by ring A includes pyridine, dihydropyridine, and tetrahydropyridine, with pyridine and tetrahydropyridine being preferred. The A ring may have one or more substituents at possible substitution positions, and such substituents include, for example, alkyl groups having 1 to 3 carbon atoms (e.g.
methyl, ethyl, propyl, isopropyl groups), alkenyl groups with 2 to 3 carbon atoms (e.g., vinyl, 1-methylvinyl, 1-propenyl, allyl, arenyl groups), 2 to 3 carbon atoms
3 alkynyl group (e.g., ethynyl, 1-propynyl, propargyl group), cyclopropyl group, halogen atom, (
(e.g., fluorine, chlorine, bromine, iodine), alkanoyl groups having 1 to 4 carbon atoms (e.g., formyl, acetyl, propionyl, butyryl, isobutyryl groups), benzoyl groups, substituted benzoyl groups (e.g., p-chlorobenzoyl, p- methoxybenzoyl, 3,4,5-trimethoxybenzoyl group)
, cyano group, carboxy group, carbamoyl group, nitro group, hydroxy group, hydroxymethyl group, hydroxyethyl group, methoxymethyl group, ethoxymethyl group, methoxyethyl group, ethoxyethyl group, alkoxy group having 1 to 3 carbon atoms (e.g. , methoxy, ethoxy, propoxy group), mercapto group, substituted amino group having 1 to 4 carbon atoms (e.g., methylamino, ethylamino, dimethylamino, diethylamino group), alkanoylamino group having 1 to 2 carbon atoms (e.g., formamide , acetamido group), etc. [0009] 2 which may have a substituent represented by B
In a valent cyclic group or a lower alkylene group having 2 to 5 carbon atoms, the divalent cyclic group includes a heteroatom (e.g., N, O
, S) is preferably a divalent saturated or unsaturated 5- to 6-membered cyclic hydrocarbon or heterocyclic group which may contain 1 to 3 of them in the ring, and the bonds come out from non-adjacent positions in the ring. It is preferable to be there. Examples of these cyclic groups include phenylene, cyclopentanylene, cyclohexanylene, pyridinediyl, furandiyl, thiophenediyl, thiazolediyl, and the like. Further, examples of the lower alkylene group having 2 to 5 carbon atoms include ethylene, propylene, butylene, pentanylene, etc., and preferably 1,4-
Phenylene, 2,5-thiophenediyl. [0010] Divalent cyclic group represented by B or carbon number 2
The lower alkylene group of ~5 may have 1 to 2 substituents, and examples of such substituents include alkyl groups having 1 to 3 carbon atoms such as methyl, ethyl, and propyl;
Alkenyl groups with 2 or 3 carbon atoms such as vinyl and allyl, aryl groups such as phenyl and tolyl, fluorine, chlorine,
Examples include halogen atoms such as bromine and iodine, alkoxy groups having 1 to 3 carbon atoms such as methoxy and ethoxy, hydroxyl groups, and amino groups. -COOR1, -COOR2, -COOR
R1, R2, and R3 in the optionally esterified carboxyl group represented by 3 are alkyl groups having 1 to 4 carbon atoms (e.g., methyl, ethyl, propyl, isopropyl, te
rt-butyl), alkenyl groups having 2 or 3 carbon atoms (e.g. vinyl, allyl), aralkyl groups (e.g. benzyl, p
-methoxybenzyl, p-nitrobenzyl, benzhydryl, trityl) and aryl groups (e.g. phenyl, p-
-nitrophenyl, naphthyl), and preferably methyl, ethyl, tert-butyl, and benzyl. Next, a method for producing the compound (I) of the present invention or a salt thereof will be explained. Compound (I) or a salt thereof is
The glutamic acid derivative represented by formula (III) is converted into a glutamic acid derivative represented by formula (II).
) or a reactive derivative thereof at the carboxyl group. As the means for the above acylation, a method known per se is used,
Known reagents and reaction solvents commonly used for peptide synthesis,
It can be carried out by adopting various reaction conditions [Izumiya et al., Fundamentals and Experiments of Peptide Synthesis, Maruzen (1985)]
. For example, a method of acylating compound (III) with compound (II) in the presence of a so-called dehydration condensing agent such as a carbodiimide, a phosphoric acid derivative, or a halogenoaza aromatic quaternary salt can be mentioned. Compound (II) of Compound (III)
The amount used is generally about 1 to 20 molar equivalents, preferably about 1 to 5 molar equivalents. For compound (II), the dehydration condensation agent is
Generally about 1 to 25 molar equivalents, preferably about 1 to 5 molar equivalents. As the carbodiimide, dicyclohexylcarbodiimide is practically preferred, but other examples include diphenylcarbodiimide, di(o- or 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, etc. may be used. As the phosphoric acid derivatives, diphenylphosphoric acid azide, diphenylphosphoric acid chloride, diethyl cyanophosphate, etc. are advantageously used. As halogenoaza aromatic quaternary salts, 2
-Chloro-1-methylpyridinium iodide, 2-fluoro-1-methylpyridinium tosylate, 2-chloro-3-methylbenzothiazolinium trifluoromethanesulfonate, etc. can be used. This acylation reaction is preferably carried out in the presence of an appropriate solvent, such as water, alcohols (e.g. methanol, ethanol), ethers (e.g. dimethyl ether,
diethyl ether, tetrahydrofuran, dioxane,
monoglyme, diglyme), nitriles (e.g. acetonitrile), esters (e.g. ethyl acetate), halogenated hydrocarbons (e.g. dichloromethane, chloroform, carbon tetrachloride), aromatic hydrocarbons (e.g. benzene, toluene) ,
xylene), acetone, nitromethane, pyridine, dimethylsulfoxide, dimethylformamide, hexamethylphosphoramide, sulfolane, or a suitable mixed solvent thereof. [0014] This reaction is usually carried out at a pH of 2 to 14, preferably about 5 to 10, and from about -10°C to the boiling point of the reaction solvent (about 100°C), preferably about 0°C to 50°C. The reaction can be carried out at a reaction temperature of about 0.5 to about 100 hours. The pH of the reaction solution is adjusted appropriately using acids (e.g., hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid), bases (e.g., sodium methylate, sodium ethylate, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide). , sodium carbonate, potassium carbonate, lithium carbonate, calcium carbonate, barium carbonate, sodium bicarbonate, trimethylamine, triethylamine, diisopropylethylamine, triethanolamine, pyridine) or buffers (e.g. phosphate buffer, borate buffer, acetic acid) Adjust as necessary with buffer solution, etc. [0015] The reaction can proceed more advantageously by using a catalyst capable of promoting acylation. Examples of such catalysts include base catalysts and acid catalysts. Such base catalysts include, for example, tertiary amines [aliphatic amines such as triethylamine and diisopropylethylamine; aromatic amines such as pyridine, picoline, lutidine, 4-dimethylaminopyridine, 4-(1-pyrrolidinyl)pyridine, and dimethylaniline; amine], etc. Examples of acid catalysts include Lewis acids (e.g., zinc chloride, aluminum chloride, ferric chloride,
titanium tetrachloride, tin tetrachloride, cobalt chloride, cupric chloride, boron trifluoride etherate, etc.). Among the above catalysts, 4-dimethylaminopyridine or 4
-(1-pyrrolidinyl)pyridine and the like are often preferred. The amount of catalyst to be used is preferably the amount that can promote acylation, and is usually about 0.001% of the amount of catalyst used for compound (II).
~10 molar equivalents, preferably about 0.01-1 molar equivalents. As a means of acylation using reactive derivatives at the carboxyl group of carboxylic acid, for example, acid halides (eg, fluoride, chloride, bromide, iodide), acid anhydrides (eg, iodo anhydride) of carboxylic acid (II), etc. acetic acid, isobutyric anhydride), lower monoalkyl carbonate (monomethyl carbonate, monoethyl carbonate, monopropyl carbonate, monoisopropyl carbonate, monobutyl carbonate, monoisobutyl carbonate, monosec-butyl carbonate, monote)
rt-butyl carbonate), active esters (e.g., cyanomethyl ester, carboethoxymethyl ester, methoxymethyl ester, phenyl ester, o-nitrophenyl ester, p-nitrophenyl ester, p-carbomethoxy phenyl ester, p
-cyanophenyl ester, thiophenyl ester, thiopyridyl ester), acid azide, phosphoric diester (
mixed acid anhydrides, phosphorous diesters (e.g., dimethyl phosphite, diethyl phosphite, dibenzyl phosphite, diphenyl phosphite); Also included are mixed acid anhydrides and the like. In the acylation method using this reactive derivative, the solvent, catalyst, reaction temperature, etc. are the same as in the case of using a dehydration condensation agent such as the above-mentioned carbodiimides. Furthermore, among the compounds (I), -COOR1 and -COOR2 are carboxyl groups (I-
When producing 1), -COO of compound (III)
A compound in which R1 and -COOR2 are esters can be reacted with compound (II) and then subjected to a known decomposition reaction or catalytic reduction reaction to de-esterify the compound. Examples of the decomposition reaction include a hydrolysis reaction under basic conditions (method A) and a hydrolysis reaction under acidic conditions (method A).
Method B-1), decomposition reaction under acidic conditions (Method B-2), and the like. Examples of the base used in Method A include metal alkoxides such as sodium methoxide, sodium ethoxide, sodium butoxide, and potassium butoxide, and metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, and barium hydroxide. , ammonia, triethylamine, pyridine, and other amines. The acids used in the B-1 method include:
Examples include mineral acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, nitric acid, and phosphoric acid, and organic acids such as trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, tosylic acid, camphorsulfonic acid, and trifluoromethanesulfonic acid. , B
Examples of acids (catalysts) used in Method 2 include mineral acids such as hydrogen chloride, hydrogen bromide, perchloric acid, sulfuric acid, nitric acid, and phosphoric acid, trifluoroacetic acid, methanesulfonic acid,
Organic acids such as benzenesulfonic acid, tosylic acid, camphorsulfonic acid, trifluoromethanesulfonic acid, zinc chloride, aluminum chloride, ferric chloride, titanium tetrachloride, tin tetrachloride, antimony pentachloride, cobalt chloride, ferric chloride Examples include Lewis acids such as copper and boron trifluoride etherate. In both cases, the decomposition reaction is carried out in a suitable solvent.
The reaction is carried out at a temperature ranging from 8°C to the boiling point of the solvent, preferably from 0 to 80°C, for 30 minutes to 2 days. In the case of Method A and Method B-1, examples of reaction solvents include water, methanol, ethanol, propanol, butanol, ethylene glycol, methoxyethanol,
Ethoxyethanol, tetrahydrofuran, dioxane, monoglyme, diglyme, pyridine, dimethylsulfoxide, sulfolane or suitable mixtures thereof are used; in the case of process B-2, for example, ethyl acetate, dimethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme , dichloromethane, chloroform, carbon tetrachloride, acetonitrile, benzene, toluene, xylene, nitromethane, pyridine, or an appropriate mixed solvent thereof. The catalytic reduction reaction (method C) is carried out using a suitable solvent at a temperature ranging from about -40°C to the boiling point of the solvent, more preferably from about 0 to 50°C. Solvents used include water, alcohols (e.g. methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, ethylene glycol,
methoxyethanol, ethoxyethanol), acetic acid esters (e.g. methyl acetate, ethyl acetate), ethers (
e.g., dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme), aromatic hydrocarbons (e.g., benzene, toluene, xylene),
Examples include pyridine, dimethylformamide, and appropriate mixed solvents thereof. As the catalyst for catalytic reduction, for example, metals such as palladium, platinum, rhodium, nickel, and ruthenium, and complex compounds thereof are used. At this time, the reaction may proceed advantageously by adding a small amount of acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc. The reaction time is not limited as long as it does not interfere with the reaction, but is usually 20 minutes to 30 hours. Which reaction leads to compound (I-1) depends on the properties of -COOR1 and -COOR2, but usually -COOR1 and -COO
When R2 is a carboxyl group esterified with methyl, ethyl, propyl, butyl, sec-butyl, phenyl or substituted phenyl group, method A or B-1
method, -COOR1 and -COOR2 are isopropyl,
For carboxyl groups esterified with tert-butyl, benzhydryl, trityl groups, method B-2, and for carboxyl groups esterified with benzyl groups, substituted benzyl groups, benzhydryl, trityl groups, etc. method A, method B. Although method C can also be used, method C can be applied more advantageously. In addition, -COOR1 and -CO
When OR2 is different from each other, the above method A, method B-1, method B-
Method 2 and Method C may be combined as appropriate. The oxidation state of ring A (pyridine ring) of compounds (I) and (IV) is completely unsaturated, dihydro,
There are three possibilities for tetrahydro. Furthermore, there are three positional isomers of the dihydro form. As described later, these can be prepared separately at the stage of producing compound (IV), but the A ring can also be produced from the final compound (I) by performing a known oxidation reaction or reduction reaction. can change the oxidation state [M.
M. Hudlicky, Oxidations in Organic Chemistry (Ox)
edations in Organic Chemi
stry), American Chemical S
ocity, Washington, DC (19
90)] and [M. Hudlicky, Reductions in Organic Chemistry
ions in Organic Chemistry
), John Wiley & Sons, New
York (1984)]. The oxidation reaction, that is, the reaction of dehydrogenation to induce the A ring from the tetrahydropyridine state to the dihydro or fully unsaturated state, or the reaction of inducing the dihydro state to the fully unsaturated state, is carried out using an oxidizing agent or , can be carried out in the presence of a dehydrogenating agent. Examples of dehydrogenating agents include metals such as palladium, platinum, rhodium, and ruthenium, those placed on carriers such as activated carbon, asbestos, and alumina, and complex compounds of these metals. Examples include, for example, sulfur, selenium, nitric acid, arsenic acid (As2O5)
, manganese dioxide, potassium ferricyanide, mercuric acetate, mercuric trifluoroacetate, silver oxide, and other oxidizing inorganic compounds, or oxidizing organic compounds such as tert-butylhypochlorite, nitrobenzene, and dichlorodicyanoquinone. A compound is used. The amount of these oxidizing agents or dehydrogenating agents used depends on their properties, but is usually about 0.01 to 20 molar equivalents, more preferably about 0.1 to 5 molar equivalents, relative to the target product. Just use the equivalent amount. This oxidation reaction can be carried out without a solvent or in a gas phase depending on the type of reagent used, but it can also be carried out advantageously in the presence of an appropriate solvent. Examples of the solvent include water, alcohols (e.g. methanol, ethanol), ethers (e.g. dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme), nitriles (e.g. acetonitrile), esters (e.g. , ethyl acetate), halogenated hydrocarbons (
e.g., dichloromethane, chloroform, carbon tetrachloride), aromatic carbons (e.g., benzene, toluene, xylene)
, acetone, nitromethane, pyridine, dimethylsulfoxide, dimethylformamide, hexamethylphosphoramide, sulfolane, carbon disulfide, or a suitable mixed solvent thereof. This reaction is usually
About -10°C to about 400°C, preferably about 30°C to 350°C
The reaction can be carried out at a reaction temperature in the range of °C for about 0.5 to 100 hours. However, when the reaction temperature is higher than the boiling point of the reaction contents, it is preferable to carry out the reaction in a gas phase or in a sealed tube. A reduction reaction, that is, a reaction in which ring A is induced from a completely unsaturated state to a dihydro or tetrahydropyridine state by a hydrogenation reaction, or a reaction in which a dihydro state is induced to a tetrahydropyridine state, is performed using a reducing agent or hydrogenation. It can be carried out in the presence of an agent. This reduction reaction is carried out under so-called catalytic reduction conditions, for example, using metals such as palladium, platinum, rhodium, ruthenium, nickel, cobalt, and chromium, on carriers such as activated carbon, asbestos, and alumina, or using these metals on carriers such as activated carbon, asbestos, and alumina. Examples include methods in which salts, oxides, and complex compounds are allowed to act in a hydrogen atmosphere or in the presence of an organic compound used in a hydrogen transfer reaction such as cyclohexadiene or formic acid. At this time, the reaction may proceed advantageously by adding a small amount of acid (eg, acetic acid, trifluoroacetic acid, hydrochloric acid, sulfuric acid, etc.). Furthermore, the present reduction reaction may be carried out under reducing conditions using metal hydrides (eg, sodium cyanoborohydride). The amount of these reducing agents or hydrogenating agents used depends on their properties, but is usually about 0.01 to 20 molar equivalents, more preferably about 0.1 to 5 molar equivalents, relative to the target product. Just use the equivalent amount. This reduction reaction can be carried out advantageously in the presence of a solvent, depending on the type of reagent used. Examples of the solvent include water, alcohols (e.g., methanol, ethanol), ethers (e.g., dimethyl ether, diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme), esters (e.g., ethyl acetate), aromatic carbonization. Examples include carbon (eg, benzene, toluene, xylene), or a suitable mixed solvent thereof. This reaction is usually
About -80°C to about 200°C, preferably about 0°C to 150°C
The reaction can be carried out at a reaction temperature in the range of about 0.5 to 100 hours. In this case, it is important to select reagents, reaction conditions, etc. that do not reduce other functional groups of compound (I) (for example, carboxylic acid that may be esterified, amide bond, etc.). Below, the raw material compound (I
The manufacturing method of I) will be explained. ##STR10## In the formula, X, Y, R, and R3 have the same meanings as above, and L is a removable group that can be easily derived from a hydroxy group (e.g., a halogen atom, a methanesulfonyloxy group, benzenesulfonyloxy group, p-toluenesulfonyloxy group, trifluoromethanesulfonyloxy group),
W is a functional group that can be converted into an aldehyde by a normal chemical reaction [
For example, carboxylic acid and its derivatives (esters, etc.), hydroxymethyl (-CH2OH) group], Z1 and Z2 are oxygen atoms or sulfur atoms that may be oxidized (S, S
O, SO2), R4, R5, and R7 are lower alkyl groups (e.g., methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, tert-butyl), unsaturated alkyl groups (e.g., vinyl, allyl). ), represents an aralkyl group (e.g. benzyl, p-nitrobenzyl, p-methoxybenzyl, phenethyl, benzhydryl, trityl) or an aryl group (e.g. phenyl, naphthyl), R
4 and R5 may be combined to form a divalent substituent (eg, ethylene, propylene, etc.). R6 represents a cyano group or a carboxylic acid ester residue represented by -COOR8, and the concept of the substituent defined for R7 above is applied to R8. First step: This is a reaction in which a carbon chain having a functional group W that can be converted into an aldehyde is extended from compound (V) by a carbon-carbon bond forming reaction. As such a reaction, a reaction known per se can be used, preferably a Wittig type reaction, an aldol type reaction, etc. [for example,
J. Mathieu & J.W.
eill-Raynal), Formation of
C-C Bonds (Formation of C-C B
onds), Georg Thieme Publish
ers, Stuttgart (1975)]. These reactions can also be combined with a hydrogenation reaction if necessary. The hydrogenation reaction usually proceeds advantageously under catalytic reduction conditions in which a metal catalyst (eg, nickel, palladium, platinum, rhodium, ruthenium) is added in a hydrogen atmosphere. The starting material (V) can be easily obtained by a method known in the literature [JP-A-01-72235, A.R. Hands et al.
．． ), Journal of the Chemical Society (
C) (J. Chem. Soc. (C)), 1967, 1
099)]. Second step This is a reaction in which the functional group W of compound (VI) obtained in the first step is converted into an aldehyde. When W has a higher oxidation degree than an aldehyde, that is, in the case of a carboxylic acid and its derivatives, it is subjected to a reduction reaction, and when W has a lower oxidation degree than an aldehyde, that is, hydroxymethyl (-CH
In the case of a 2OH) group, it is preferable to subject it to an oxidation reaction. As the reduction reaction, a method known per se is used, preferably a reduction reaction using a metal hydride such as diisobutylaluminum hydride. In this case, the reduction of the carboxylic acid (and its derivatives) represented by W is -C
It is desirable to select conditions that give priority to the ester represented by OOR3. Moreover, when W is reduced not only to aldehyde but also to hydroxymethyl by this reduction reaction, the following oxidation reaction conditions can also be applied. As an oxidation reaction, Swern
) oxidation, Moffat type oxidation,
Pyridinium chlorochromate
Oxidation reactions using highly oxidized metal compounds such as m chlorocromate are advantageously applied. 00
27] Third step This is a step in which the compound (VII) obtained in the second step is reacted with an allyl metal compound to lead to the alcohol compound (VIII). The addition reaction of allyl metal can be carried out using known reagents, reaction conditions, etc. [for example, Eiichi Negishi, Organometallics in Organic Synthesis (Organom.
etallics in Organic Synth
esis), John Wiley & Sons, N.
ew York (1980)] is applied, but reactions performed by preparing an allyl metal compound in-system with an allyl halide (e.g., allyl iodide) and a low-valent metal (e.g., tin) (e.g., by Mitsuaki Mukaiyama) et al., Chemistry Letters, (Chem. Lett.), 1981, 152
7) may also be used. Fourth step Homoallylic alcohol obtained in the third step (VI
After oxidatively cleaving the double bond of II) to form an aldehyde, an appropriate protecting group is introduced to form the aldehyde equivalent (IX).
This is the process of manufacturing. For the oxidative cutting method, reactions known per se can be used [for example, A.
A.H. Haines, Methods for the Oxidation of Organic Compounds
of Organic Compounds)
, Academic Press, London (1
985)]. More specifically, aldehydes can be produced by ozone oxidation followed by reduction treatment, or by using catalytic amounts of osmic acid and sodium periodate. Equivalents of protected aldehydes include -CH(
OCH3)2, -CH(OCH2CH3)2, -CH(
SCH3)2, -CH(OCH2C6H5)2, -CH
(OCH2)2, etc., and these alcohols (e.g., methanol, ethanol,
It can be produced from thiols (e.g., methyl mercaptan, mercaptoethanol, propanedithiol), orthoformates, orthothioformates, etc. in the presence of a catalyst. As such a catalyst, those normally used for introducing a protecting group into an aldehyde can be used, but preferably protic acids such as hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, pyridinium p-toluenesulfonate, Examples include Lewis acids such as boron trifluoride etherate, aluminum chloride, and zinc chloride. In this case, the hydroxy group may be esterified, but the hydroxy group can be regenerated from this ester under normal hydrolysis conditions. Fifth Step The hydroxyl group of the alcohol (IX) obtained in the fourth step can be easily converted into the desired leaving group (L) by a commonly used halogenation reaction or acylation reaction. Sixth step: Compound (X) having a leaving group is prepared under basic conditions.
malononitrile or cyanoacetate [NCCH
Compound (XI) can be obtained by a condensation reaction with 2COOR8; R8 has the same meaning as above]. base used,
The solvent, reaction conditions, etc. were in accordance with methods known per se. Seventh step When compound (XI) is treated with guanidine or various amidines (formamidine, acetamidine, etc.), it reacts with the cyano group or ester residue, and then ring closure and cyclization occur, creating a new pyrimidine ring. It is formed. When ring closing is carried out under basic conditions, the reaction can proceed advantageously. Examples of the base used include sodium methoxide, sodium ethoxide, potassium tert.
-There are metal alkoxides such as butoxide. Examples of the reaction solvent include methanol, ethanol, propanol, tert-butyl alcohol, dimethyl sulfoxide, hexamethylphosphoramide, etc., and the reaction temperature is 0 to 150°C, preferably 20 to 100°C.
, and the reaction time is 1 to 24 hours. Eighth Step In the compound (XII) obtained in the seventh step, the protected aldehyde equivalent group [-CH(Z1R4)(Z2
R5)] is removed and cyclized with the amino group on the pyrimidine ring to produce a dihydropyridopyrimidine compound (IV; A ring is dihydro). Removal of the protecting group can be carried out by methods known per se. At this time, if the reaction is carried out under oxidizing conditions (e.g., presence of oxygen-containing air, coexistence with oxidizing compounds such as dichlorodicyanoquinone or sulfur), pyridopyrimidine compounds (IV; Ring A is completely unsaturated). On the other hand, when the reaction is carried out under reducing conditions (e.g., catalytic hydrogenation reaction using a metal catalyst such as palladium, reduction reaction using a metal hydride such as sodium cyanoborohydride), usually 5,6 , 7,8-tetrahydropyridopyrimidine compound (IV; A ring is tetrahydro) is obtained. Regarding the oxidation and reduction conditions,
This can be carried out by methods known per se. In addition, the protecting group [(Z
1R4) (Z2R5)], the carboxylic acid derivative -COOR3 was also deprotected, and the Example compound (I
I) may also occur. Ninth step: Compound (VII) is reacted with an ester of triphenylphosphoranylidene acetic acid (eg, methyl ester),
This is a process for producing an α,β-unsaturated ester compound (XIII), and the reaction conditions may be the solvent, reaction temperature, etc. used in a normal Wittig reaction. Tenth step Malononitrile or cyanoacetate [NCCH2COOR8; R8 has the same meaning as above] under basic conditions to the α,β-unsaturated ester moiety of compound (XIII)
Compound (XIV) can be obtained by Michael addition of . The base, solvent, reaction conditions, etc. used are carried out according to methods known per se. Eleventh step When compound (XIV) is treated with guanidine or various amidines (formamidine, acetamidine, etc.), it reacts with the cyano group or ester residue, and then two cyclization reactions proceed, creating a new pyridine. A [2,3-d]pyrimidine ring is formed. When ring closing is carried out under basic conditions, the reaction can proceed advantageously. Examples of the base used include metal alkoxides such as sodium methoxide, sodium ethoxide, and potassium tert-butoxide. As the reaction solvent, for example,
Examples include methanol, ethanol, propanol, tert-butyl alcohol, dimethyl sulfoxide, hexamethylphosphoramide, etc., and the reaction temperature is 0 to 15
The temperature is 0°C, preferably 20-100°C, and the reaction time is 0.1-48 hours, preferably 0.5-24 hours. Twelfth Step: A tetrahydropyridopyrimidine compound (IV; A ring is tetrahydro) can be produced by converting the oxo moiety of the lactam of compound (XV) into methylene by a reduction reaction. As the reducing agent, a known one can be used, but for example, a borane-tetrahydrofuran complex or the like can be used for efficient reduction. Furthermore, when a known oxidation reaction is applied to this material, a dehydrogenation reaction proceeds,
A pyridopyrimidine compound (IV; ring A is completely unsaturated) is produced. Production of raw material compound (II): Thirteenth step
Ester form (IV) obtained in the eighth and twelfth steps
Method A: Hydrolysis reaction under basic conditions, Method B:
The raw material compound (II) can be obtained by a hydrolysis reaction under acidic conditions, a decomposition reaction under acidic non-aqueous conditions, or method C: catalytic reduction reaction. Which reaction induces compound (II) depends on the nature of R3, but usually when R3 is methyl, ethyl, propyl, butyl or sec-butyl group, method A, R
Method B is advantageously applied when 3 is an isopropyl or tert-butyl group, and method C is advantageously applied when 3 is a benzyl group or a substituted benzyl group. These reactions can also be carried out by methods known per se. The reactions, reagents, reaction conditions, etc. used in the above are known and explained in detail in the following documents. M. Hudlicky, Oxidations
In Organic Chemistry
ns in Organic Chemistry,A
merican Chemical Society,
Washington, DC (1990); M. Hudlicky, Reductions in Organic Chemistry (Red)
uctions in Organic Chemises
try, John Wiley & Sons, Ne
w York (1984); J.F.W.McOmine,
Protective Groups in Organic Chemistry
n Organic Chemistry, Plenu
m Press, London and New Yo
rk (1973); Pine, Hendrickson, and Hammond, Organic Chemistry (4th edition) [I]-[II], Hirokawa Shoten (1982); and M.Fizer et al.
eser and L. Fieser), Reagent for Organic Synthesis No. 1-1
Volume 3 (Reagents for Organic S
Synthesis Vol. 1-13, Wiley-I
terscience, New York, London
n, Sydney and Toronto (196
9-1987)). The compounds (I), (II) and (IV) of the present invention produced by these steps, or the raw material compounds and products in each step, can be purified by conventional separation and purification means such as concentration, solvent extraction, It can be isolated from the reaction mixture by chromatography, recrystallization, etc. Compound obtained by the production method of the present invention (
I), (II) and (IV) may form a salt. Base salts include alkali metals, alkaline earth metals, non-toxic metals, ammonium and substituted ammoniums, such as sodium, potassium, lithium, calcium, magnesium, aluminum, zinc, ammonium, trimethylammonium, triethylammonium, triethanolammonium , pyridinium, substituted pyridinium, and other salts. Examples of acid salts include mineral acid salts with hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, boric acid, etc., silicic acid, tartaric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid. and organic acid salts with camphorsulfonic acid and the like. The compound (I) of the present invention or a salt thereof has an inhibitory effect on one or more enzymes that utilize folic acid and its related compounds as substrates. Therefore, these compounds may be used to treat choriocarcinoma, leukemia, breast adenocarcinoma, epidermal carcinoma of the head and neck, squamous cell carcinoma, small cell lung cancer, and lymphosarcoma, as well as various other tumors that have been treated with MTX to date. It can be used alone or in combination with other antitumor agents. When used as an antitumor agent, compound (I)
or their salts, either by themselves or by using pharmacologically acceptable carriers, excipients, diluents, etc., in the form of powders, granules, tablets, capsules, suppositories, injections, etc. It can be administered orally or parenterally in the form of a drug. The dosage is determined based on the target animal (e.g.
(humans, mixed-breed animals such as dogs, cats, rabbits, monkeys, rats, and mice), diseases, symptoms, type of compound, route of administration, etc.; Approximately 4.0-200mg/day
kg body weight, preferably 10 to 100 mg/kg body weight. Approximately 2.0 to 2 per day for parenteral administration
00mg/kg body weight, preferably 5-100mg/kg
It's weight. Administration methods for injections include intramuscular injection, intraperitoneal injection, subcutaneous injection, and intravenous injection. [0043] The above formulation is carried out according to a method known per se. When manufacturing the above oral preparations, such as tablets, binders (e.g., hydroxypropylcellulose, hydroxypropylmethylcellulose, macrogol, etc.)
, a disintegrant (eg, starch, carboxymethyl cellulose calcium, etc.), a lubricant (eg, magnesium stearate, talc, etc.), etc. can be appropriately blended. In addition, when manufacturing parenteral preparations, such as injections, tonicity agents (e.g., glucose, D-sorbitol, D-mannitol, sodium chloride, etc.), preservatives (e.g., benzyl alcohol, chlorobutanol, Methyl paraoxybenzoate, propyl paraoxybenzoate, etc.), buffers (eg, phosphate buffer, sodium acetate buffer, etc.), etc. can be blended as appropriate. As a specific example of manufacturing a tablet, for example, the amount used per tablet is about 2.0 to 25 mg/kg of the compound (I) of the present invention or a salt thereof, 1 lactose
00-500mg, cornstarch approx. 50-100mg
, about 5 to 20 mg of hydroxypropyl cellulose are mixed in a conventional manner, granulated, mixed with corn starch and magnesium stearate, and then compressed into tablets, each containing about 100 mg of hydroxypropyl cellulose.
~500 mg tablets with a diameter of approximately 3-10 mm. In addition, the usage amount per tablet of this tablet is hydroxypropyl methyl methyl cellulose phthalate (about 10 to 2
0mg) and castor oil (about 0.5-2mg) at a concentration of about 5.
Enteric-coated tablets can also be made by coating with an acetone-ethanol mixture dissolved at ~10%. As a specific example of preparation of an injection, for example, about 4.0 to 100 mg of the sodium salt of the compound (I) of the present invention is added per ampoule (i.
) Pour the ampoule dissolved in about 2 ml of physiological saline, seal it, and heat sterilize it at about 110°C for about 30 minutes, or (ii) add about 10 to 40 mg of mannitol or sorbitol to about 2 ml. It can also be prepared by dissolving it in sterilized distilled water, injecting it into an ampoule, freeze-drying it, and sealing it. When using a lyophilized compound, the ampoule is opened and, for example, physiological saline is injected to prepare a solution in which the compound is dissolved at a concentration of about 2.0 to 25 mg/ml, and then administered subcutaneously, intravenously, or intramuscularly. It can be made into an injection to be administered. [Reference Examples and Examples] The present invention will be specifically explained below with reference examples and examples, but these are merely illustrative and do not limit the present invention in any way. Reference example 1 4-(4-hydroxy-1-butenyl)benzoic acid ter
Production of t-butyl Sodium hydride under argon atmosphere 4
．． 08 g of tetrahydrofuran suspension (400 m
After adding 68.2 g of (3-hydroxypropyl)triphenylphosphonium bromide to (1) and heating under reflux for 4 hours, a solution of 35.1 g of tert-butyl 4-formylbenzoate in tetrahydrofuran (1
00 ml) was added and heated under reflux for 1.5 hours. Ether (500 m
1) was added, and insoluble matter was filtered off using Celite. The solvent was distilled off from the filtrate under reduced pressure, and the resulting residue was subjected to flash column chromatography (silica gel 400
g, developing solvent ethyl acetate-hexane 10:1 → 3:1
) to give 28.1 g of the title compound. IR (Neat): 3410, 2983,
2940, 1713, 1648, 1605,
1568, 870, 848 cm-1.1H-NM
R (CDCl3) δ: 1.48 (1H, brs
), 1.60 (9H, s), 2.30-2.70
(2H, m), 3.65-3.90 (2H, m)
, 5,63-6.70 (2H, m), 7.33
(1H, d, J=8Hz), 7.36 (1H, d,
J=8Hz), 7.91 (1H, d, J=8Hz)
, 7.95 (1H, d, J=7Hz). 0045
] Reference Example 2 Production of tert-butyl 4-(4-hydroxybutyl)benzoate 28.1 g of the compound of Reference Example 1 and 1
A methanol suspension (150 ml) of 3.0 g of 0% palladium-carbon was stirred for 4 hours under a hydrogen atmosphere. The catalyst was filtered off using Celite, and the solvent of the filtrate was distilled off under reduced pressure to obtain 28.3 g of the title compound. IR (Neat): 2980, 1940
, 1720, 1710, 1608, 848 c
m-1.1H-NMR (CDCl3) δ: 1.1
0-1.85 (4H, m), 1.59 (9H, s
), 1.67 (2H, t, J=7Hz), 3.62
(2H, t, J=Hz), 7.20 (2H, d,
J=8Hz), 7.88 (2H, d, J=8Hz)
．． Reference Example 34-(4-oxobutyl)
Production of tert-butyl benzoate Oxalyl chloride 6.
A dichloromethane solution (15 ml) containing 7.50 g of dimethyl sulfoxide was added to a dichloromethane solution (15 ml) containing 7.50 g of dimethyl sulfoxide at -60°C, and the mixture was stirred for 2 minutes. Compound 1 of Reference Example 2 was added to the reaction solution at the same temperature.
0.01 g dichloromethane solution (40 ml)
was added within 5 minutes, and after stirring for 15 minutes, 20.24 g of triethylamine was added dropwise and stirred for 5 minutes. After raising the reaction temperature to 0° C. over 30 minutes, the reaction solution was poured into water (300 ml) and extracted with dichloromethane. The residue obtained by distilling off the solvent under reduced pressure was subjected to flash column chromatography (silica gel 200
g, developing solvent: ethyl acetate-hexane 1:10) to obtain 8.59 g of the title compound.
IR (Neat): 2980, 2940,
1720, 1710, 1608, 848 cm-
1.1H-NMR (CDCl3) δ: 1.60
(9H, s), 1.96 (2H, tt, J=7Hz
,7Hz), 2.43 (2H, dd, J=7Hz,
1Hz), 2.68 (2H, t, J=7Hz),
7.20 (2H, d, J=8Hz), 7.90 (
2H, d, J = 8Hz), 9.78 (1H, t, J
=1Hz). Reference Example 4 Production of methyl 6-[4-(tert-butoxycarbonyl)phenyl]-1-hexenoate 2.42 g of methyl triphenylphosphoranylidene acetate and 1.61 g of the compound of Reference Example 3 toluene Solution (20 ml
) was heated under reflux for 1 hour and then left at 0°C for 1 hour. The generated precipitate was filtered off, the filtrate was concentrated, and the resulting residue was subjected to flash column chromatography (silica gel 75 g, developing solvent: ether-hexane 1:8).
Purification to give 1.54 g of the title compound. IR (Neat): 2975, 2940,
1720, 1710, 1652, 1605,
845 cm-1.1H-NMR (CDCl3) δ
: 1.57 (9H, s), 1.80 (2H, t
t, J=7Hz, 7Hz), 2.22 (2H, dd
t, J=7Hz, 7Hz, 1.5Hz), 2.64
(2H, t, J=7Hz), 3.69 (3H, s)
, 5.84 (1H, dd, J=15.5Hz, 1.
5Hz), 6.93 (1H, dt, J=15.5H
z, 7Hz), 7.17 (2H, d, J=8Hz)
, 7.86 (2H, d, J=8Hz). Reference Example 5 Production of methyl 6-[4-(tert-butoxycarbonyl)phenyl]-3-(dicyanomethyl)hexanoate 1.228 g of the compound of Reference Example 4 and 400 mg of malononitrile in tert-butyl alcohol
Tetrahydrofuran solution (13 ml, 10:3)
A solution of 678 mg of potassium tert-butoxide in tetrahydrofuran (4.03 ml) was added to the mixture, and the mixture was stirred at room temperature for 20 hours. The reaction solution was added to water, extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by flash column chromatography (30 g of silica gel, developing solvent: ethyl acetate-hexane 1:6) to obtain 1.20 g of the title compound. IR (Neat): 2930, 22
50, 1735, 1707, 1605, 843
cm-1.1H-NMR (CDCl3) δ: 1.
40-1.90 (4H, m), 1.58 (9H,
s), 2.30-2.83 (5H, m), 3.63
(3H, s), 4.29-4.37 (1H, m)
, 7.20 (2H, d, J=8Hz), 7.90
(2H, d, J=8Hz). Reference Example 6 4-[3-(2,4-diamino-7-oxo-5,6,
Preparation of tert-butyl 7,8-tetrahydropyrido[2,3-d]pyrimidin-5-yl)propyl]benzoate Potassium tert-butoxide under argon atmosphere 5
Compound 1 of Reference Example 5 was added to a solution of 81 mg of guanidine hydrochloride and 457 mg of guanidine hydrochloride in tert-butyl alcohol-tetrahydrofuran (10 ml, 1:1).
．． 48 g of tert-butyl alcohol solution (
10 ml) was added thereto, and the mixture was heated under reflux for 3 hours. The reaction solution was poured into ice water (100 ml), the white crystals formed were collected by filtration, and the crystals were washed successively with water, methanol, and ether, and then dried under vacuum at 70°C to obtain 1.35 g of the title compound. It was done. IR (KBr)
: 3500, 3355, 3220, 2980
, 2940, 1710, 1663, 1620,
1563,850 cm-1.1H-NMR (M
e2SO-d6) δ: 1.20-1.75 (4H
, m), 1.53 (9H, s), 2.33 (1H
, d, J=15Hz), 2.55-2.70 (1H
, m), 2.60 (2H, t, J=8Hz), 2
．． 83-2.97 (1H, m), 3.33 (1H
,brs), 5.91 (2H,brs), 6.2
1 (2H, brs), 7.28 (2H, d, J=
8Hz), 7.80 (2H, d, J=8Hz). [
Reference Example 7 4-(4-hydroxy-6-heptenyl)benzoic acid te
Production of rt-butyl A suspension of 2.31 g of tin and 4.02 g of the compound of Reference Example 3 in tetrahydrofuran.
A solution of 2.99 g of allyl iodide in tetrahydrofuran (20 ml) was added dropwise to the solution (30 ml), and the mixture was stirred at room temperature for 1 hour. Water (100 ml) to the reaction solution
, ether (100 ml) and 2N K2
The pH was adjusted to 10 by adding CO3 and stirred for 10 minutes. The white precipitate formed was filtered off using Celite, the aqueous layer was extracted with ether, and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The residue obtained by distilling off the solvent under reduced pressure was subjected to flash column chromatography (200 g of silica gel, developing solvent:
Purification with ethyl acetate-hexane (1:6) gave 4.38 g of the title compound. IR (Neat)
: 3425, 2980, 2940, 1712,
1638, 1608, 847 cm-1.1H-
NMR (CDCl3) δ: 1.30-2.00
(5H, m), 1.58 (9H, s), 2.00
−2.30 (2H, m), 2.69 (2H, t, J
=Hz), 3.50-3.80 (1H, m), 4
．． 97-5.10 (1H, m), 5.20 (1H
, s), 5.58-6.05 (1H, m), 7.
20 (2H, d, J=8Hz), 7.90 (2H
, d, J=8Hz). Reference Example 8 4-(4-hydroxy-6,6-dimethoxyhexyl)
Compound 1 of Reference Example 7 for the production of tert-butyl benzoate
．． 00 g water-dioxane mixed solution (12 ml
, 1:3) and added 9 mg of osmium tetroxide to 5
Stir for a minute. While stirring, 1.58 g of sodium periodate was added in several portions over 30 minutes to the solution, which gradually turned dark brown. After further stirring for 10 minutes, water (50 ml) was added to the reaction mixture, and the aqueous layer was extracted with ether. The combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. Methanol (8 ml), methyl orthoformate (5 ml) and 10 mg of boron trifluoride etherate were added to the residue obtained by distilling off the solvent under reduced pressure, and the mixture was stirred at room temperature for 45 minutes. Add 2N potassium carbonate aqueous solution (1
After stirring for an additional hour, methanol was distilled off under reduced pressure and the aqueous layer was extracted with ether. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was subjected to flash column chromatography (silica gel 30
g, developing solvent: ethyl acetate-hexane (1:3) to obtain 890 mg of the title compound. IR
(Neat): 3485, 2945, 1715
, 1609, 848 cm-1.1H-NMR (
CDCl3) δ: 1.30-1.60 (2H, m
), 1.58 (9H, s), 1.71 (1H,
dd, J=6Hz, 6Hz), 2.69 (2H, t
, J=7Hz), 2.73 (1H, brs), 3
．． 33 (3H, s), 3.36 (3H, s),
3.80 (1H, t, J=6Hz), 4.55 (1
H, t, J=6Hz), 7.21 (2H, d, J=
8Hz), 7.90 (2H, d, J=8Hz). Reference Example 9 Production of tert-butyl 4-[6,6-dimethoxy-5-(methylsulfonyloxy)hexyl]benzoate A pyridine solution of 439 mg of the compound of Reference Example 8 (1
ml) at 0°C, methanesulfonic acid chloride 178
mg was added. The temperature was immediately raised to room temperature and stirred for 2.5 hours. After distilling off the solvent under reduced pressure using a vacuum pump, ether (10 ml) and 100 mg of triethylamine were added to the resulting residue and stirred for 5 minutes. The ether layer was washed successively with water, saturated aqueous copper sulfate solution, and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 561 mg of the title compound. IR
(Neat) 2950, 1715, 1610,
903, 847 cm-1.1H-NMR (CD
Cl3) δ: 1.58 (9H, s), 1.66
-1.83 (4H, m), 1.83-2.04 (
2H, m), 2.50-2.80 (2H, m), 2
．． 98 (3H, s), 3.30 (3H, s),
3.32 (3H, s), 4.50 (1H, dd,
J=7Hz, 5Hz), 4.70-5.50 (1H
, m), 7.20 (2H, d, J=8Hz), 7
．． 90 (2H, d, J=8Hz). Reference Example 10 Production of tert-butyl 4-[4-(dicyanomethyl)-6,6-dimethoxyhexyl]benzoate A suspension of 608 mg of sodium hydride in dimethyl sulfoxide (10 ml) was added under an argon atmosphere. After stirring at 70°C for 1 hour, add 1.67 g of malononitrile while cooling on ice.
A dimethyl sulfoxide solution (10 ml) was added dropwise to the mixture and stirred for 10 minutes. Sodium iodide in the reaction solution
543 mg Next, the compound of Reference Example 9 1.51
A dimethyl sulfoxide solution (10 ml) was added thereto, heated at 70°C for 13 hours, and then cooled to room temperature. The reaction solution was poured into ice water, adjusted to pH 6 with a 1N aqueous potassium hydrogen sulfate solution, and extracted with ether. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was subjected to flash column chromatography (silica gel 60
g, developing solvent: ethyl acetate-hexane (1:7) to obtain 785 mg of the title compound. IR (Neat): 2950, 2250, 2
200, 1714, 1608, 848 cm-1
．． 1H-NMR (CDCl3) δ: 1.50-1
．． 90 (7H, m), 1.59 (9H, s),
2.50-2.86 (2H, m), 3.35 (6H
, s), 4.30-4.43 (1H, m), 4.
40 (1H, d, J=4Hz), 7.20 (2H
, d, J=8Hz), 7.91 (2H, d, J=8
Hz). Reference Example 11 4-[4-(2,4,6-triaminopyrimidine-5-
yl)-6,6-dimethoxyhexyl]benzoic acid ter
Preparation of t-butyl Under an argon atmosphere, a 1 M solution of potassium tert-butoxide in tetrahydrofuran (1.32 ml) is added to a suspension of 126 mg of guanidine hydrochloride in tert-butyl alcohol (2 ml).
was added, and after stirring for 10 minutes, the compound of Reference Example 10 was added.
424 mg tert-butyl alcohol solution
(4 ml) was added thereto, and the mixture was heated under reflux for 4 hours. The reaction solution was added to water (20 ml), extracted with ethyl acetate,
The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was subjected to flash column chromatography (dichloromethane-8%
Purification with ammonia-containing ethanol (20:1) gave 391 mg of the title compound. IR (KBr
): 3500, 3400, 3200, 294
0, 1710, 1608, 1570, 844
cm-1.1H-NMR (CDCl3) δ: 1.
45-1.70 (2H, m), 1.57 (9H,
s), 1.70-2.03 (4H, m), 2.55
-2.80 (6H, s), 2.62 (2H, t,
J=7Hz), 3.26 (6H,s), 4.23
(1H, dd, J=6Hz, 5Hz), 4.43
(2H, brs), 4.56 (4H, brs),
7.15 (2H, d, J=8Hz), 7.86 (
2H, d, J=8Hz). Example 1 4-[3-(2,4-diamino-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-5-yl)
Production of tert-butyl propyl]benzoate Suspension of 1.14 g of the compound of Reference Example 6 in tetrahydrofuran
(12 ml) of borane-tetrahydrofuran
M Tetrahydrofuran solution (20.0 ml)
was added and stirred at room temperature for 3.5 hours. Acetic acid in the reaction solution
After adding methanol (12 ml, 1:1) and stirring at room temperature for 18 hours, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to flash column chromatography (30 g of silica gel, developing solvent: concentrated aqueous ammonia). Purification with dichloromethane → dichloromethane-ethanol containing 8% ammonia (20:1) yields the title compound.
1.07 g was obtained. IR (KBr): 3
395, 3340, 3190, 2935, 28
55, 1712, 1663, 1600, 157
7,848 cm-11H-NMR (CDCl3
) δ: 1.25-1.60 (2H, m), 1.
59 (9H, s), 1.60-1.95 (4H,
m), 2.40-2.54 (1H, m), 1.55
-1.82 (2H, m), 3.27 (1H, t,
J=3Hz), 3.27-3.33 (1H, m),
4.29 (2H, brs), 4.39 (2H, b
rs), 4.87 (1H, brs), 7.22
(2H, d, J=8Hz), 7.91 (2H, d,
J=8Hz) Example 2 N-[4-[3-(2,4-diamino-5,6,7,8
-tetrahydropyrido[2,3-d]pyrimidine-5-
Production of diethyl)propyl]benzoyl]-L-glutamate 3 ml of trifluoroacetic acid was added to 574 mg of the compound of Example 1, and the mixture was stirred at room temperature for 1.5 hours. The solvent was distilled off under reduced pressure and dried at 70°C under reduced pressure, and the resulting residue and diethyl L-glutamate hydrochloride
529 mg dimethylformamide solution (5 m
l) Diphenylphosphoryl azide 485 at 0°C
A solution of 669 mg of triethylamine in dimethylformamide (3 ml) was added thereto, and after stirring for 15 minutes, a solution of 669 mg of triethylamine in dimethylformamide (3 ml) was subsequently added dropwise at the same temperature. After stirring at 0°C for 30 minutes and at room temperature for 40 hours, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to flash column chromatography (
Silica gel 30 g, developing solvent: dichloromethane separated with concentrated aqueous ammonia → dichloromethane - ethanol containing 8% ammonia 40:1 → 30:1 → 20:1
) to obtain 634 mg of the title compound. IR (KBr): 3380, 2940,
1735, 1630, 1575, 1440,
1200, 850 cm-11H-NMR (CDC
l3) δ: 1.23 (3H, t, J=7Hz),
1.31 (3H, t, J=7Hz), 1.30-
1.90 (6H, m), 2.03-2.41 (2
H, m), 2.46 (1H, t, J=6Hz),
2.49 (1H, t, J=8Hz), 2.48-2
．． 81 (2H, m), 3.22-3.29 (1H,
m), 3.28-3.34 (1H, m), 4.1
3 (2H, q, J=7Hz), 4.25 (2H,
q, J=7Hz), 4.30 (2H, brs),
4.37 (2H, brs), 4.70-4.82
(1H, m), 4.82 (1H, brs), 7.
06 (1H, d, J=7Hz), 7.25 (2H
, d, J=8Hz), 7.75 (2H, d, J=8
Hz) Example 3 N-[4-[3-(2,4-diamino-5,6,7,8
-tetrahydropyrido[2,3-d]pyrimidine-5-
yl)propyl]benzoyl]-L-glutamic acid A 1N aqueous sodium hydroxide solution (3.62 ml) was added to a tetrahydrofuran-water mixed solution (2:1, 15 ml) of 618 mg of the compound of Example 2, and the mixture was stirred at room temperature. After stirring for 2 hours, the reaction solution was concentrated to 5 ml. Acetic acid (1 ml) and water (5 ml) were added to the reaction solution.
When added, white crystals were formed. After refining the crystal,
It was collected by filtration and thoroughly washed with ice water. The obtained crystals were dried under reduced pressure.
469 mg of the title compound by drying at 0°C
was obtained as white crystals. IR (KBr): 335
0, 2925, 1700, 1650, 1630
, 1555, 843 cm-11H-NMR (M
e2SO-d6) δ: 1.10-2.10 (8H
, m), 2.30 (2H, t, J=7Hz), 2
．． 55-2.75 (3H, m), 3.00-3.37
(2H, m), 4.20-4.37 (1H, m)
, 6.49 (4H,brs), 7.13 (1H
, brs), 7.27 (2H, d, J=8Hz),
7.77 (2H, d, J=8Hz), 8.31
(1H, d, J=7Hz) Example 4 N-[4-[3-(2,4-diaminopyrido[2,3-
d]pyrimidin-5-yl)propyl]benzoyl]-
Diethyl L-glutamate and N-[4-[3-
(2,4-diamino-5,8-dihydropyrido [2,3
-d]pyrimidin-5-yl)propyl]benzoyl]
Production of diethyl-L-glutamate 2 ml of trifluoroacetic acid was added to 200 mg of the compound of Reference Example 11, and the mixture was stirred at room temperature for 18 hours. 1 ml of water was added dropwise to the reaction solution, and the mixture was further stirred for 2 hours.
The solvent was distilled off under reduced pressure, and trifluoroacetic acid was removed azeotropically using toluene. Dry under reduced pressure at 70°C to obtain 4-[3-(2,4-diaminopyrido[2,3
Crude crystals of -d]pyrimidin-5-yl)propyl]benzoic acid were obtained. Under an argon atmosphere, a dimethylformamide solution (1.5 ml) containing 136 mg of diphenylphosphoryl azide was added to this crystal and a dimethylformamide solution (1.5 ml) containing 161 mg of diethyl L-glutamate hydrochloride at 0°C, and the mixture was stirred for 15 minutes. After that, continue to add triethylamine at the same temperature 204
mg of dimethylformamide solution (1.5 ml)
was dripped. After stirring for 30 minutes at 0° C. and 48 hours at room temperature, the reaction was left open to air and stirred for an additional 5 days. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to flash column chromatography (20 g of silica gel, developing solvent: dichloromethane separated with concentrated aqueous ammonia → dichloromethane separated with concentrated aqueous ammonia - ethanol 40:1 → 30 :1→20:1)
First, N-[4-[3-(2,
4-diamino-5,8-dihydropyrido [2,3-d]
pyrimidin-5-yl)propyl]benzoyl]-L-
Diethyl glutamate 40 mg followed by N-[
32 mg of diethyl 4-[3-(2,4-diaminopyrido[2,3-d]pyrimidin-5-yl)propyl]benzoyl]-L-glutamate was obtained. Pyridine IR (KBr): 3350, 2980, 29
30, 1735, 1640, 1610, 157
5 cm-11H-NMR (CDCl3/CD3OD
) δ: 1.23 (3H, t, J=7Hz), 1
．． 32 (3H, t, J=7Hz), 2.00-2.
40 (4H, m), 2.40-2.55 (2H,
m), 2.82 (2H, t, J=7Hz), 2.
94 (2H, t, J=7Hz), 4.12 (2H
, q, J=7Hz), 4.25 (2H, q, J=H
z), 4.78 (1H, dt, J=8Hz, 5Hz
), 6.85 (1H, d, J=5Hz), 7.2
7 (2H, d, J=8Hz), 7.79 (2H,
d, J=8Hz), 8.62 (1H, d, J=5H
z) Dihydropyridine IR (KBr): 3375, 3200, 29
90, 2948, 1735, 1668-1640
, 1610, 1570 cm-11H-NMR (
CDCl3) δ: 1.23 (3H, t, J=7H
z), 1.31 (3H, t, J=7Hz), 1.
35-1.87 (4H, m), 2.00-2.65
(6H, m), 3.27-3.37 (1H, m)
, 4.11 (2H, q, J=7Hz), 4.25
(2H, q, J=Hz), 4.30-4.85 (
1H, m), 6.04 (1H, d, J=5Hz),
6.13 (1H, dd, J=8Hz, 5Hz), 7
．． 07 (1H, dd, J=8Hz, 3Hz), 7.
21 (2H, d, J=8Hz), 7.71 (2H
, d, J=8Hz) Example 5 N-[4-[3-(2,4-diaminopyrido[2,3-
d]pyrimidin-5-yl)propyl]benzoyl]-
Production of L-glutamic acid Diethyl N-[4-[3-(2,4-diaminopyrido[2,3-d]pyrimidin-5-yl)propyl]benzoyl]-L-glutamate 4
5 mg of tetrahydrofuran-water mixed solution (2:
1N aqueous sodium hydroxide solution (0.265 ml) was added to the solution (1.5 ml), stirred at room temperature for 2 hours, and then concentrated to 0.5 ml under reduced pressure. Insoluble matters were removed by filtration using a Millipore filter, acetic acid (0.2 ml) was added to the filtrate, and white crystals formed were collected by filtration and thoroughly washed with ice water. The obtained crystals were heated under reduced pressure for 65 minutes.
23.5 mg of the title compound by drying at °C.
was obtained as white crystals. IR (KBr): 3400, 3215, 29
40, 1712, 1650, 1640, 160
8, 1565 cm-11H-NMR (Me2SO
-d6) δ: 1.84-2.10 (4H, m),
2.34 (2H, t, J=7Hz), 2.73 (
2H, t, J = 7Hz), 3.11 (2H, t, J
=7Hz), 4.30-4.42 (1H, m),
6.61 (2H, brs), 6.90 (1H, d
, J=4.5Hz), 7.17 (2H, brs),
7.30 (2H, d, J=8Hz), 7.80 (
2H, d, J = 8Hz), 8.44 (1H, d, J
=9Hz), 8.47 (1H, d, J=4.5Hz
) Example 6 Preparation of N-[4-[3-(2,4-diamino-5,8-dihydropyrido[2,3-d]pyrimidin-6-yl)propyl]benzoyl]-L-glutamic acid N-[4-
[3-(2,4-diamino-5,8-dihydropyrido[
A mixed solution of 62 mg of diethyl 2,3-d]pyrimidin-6-yl)propyl]benzoyl]-L-glutamate in tetrahydrofuran and water (2:1, 1.5
ml) to 1N aqueous sodium hydroxide solution (0.3
After stirring at room temperature for 2 hours, the mixture was concentrated to 0.5 ml under reduced pressure. Insoluble matter was removed by filtration using a Millipore filter, and acetic acid (0.2
ml) was added and the white crystals formed were collected by filtration and thoroughly washed with ice water. The obtained crystals were dried at 65° C. under reduced pressure to obtain 34.1 mg of the title compound as white crystals. IR (KBr): 3360, 32
40, 2950, 1710, 1660, 164
0, 1568, 1548cm-11H-NMR (
Me2SO-d6) δ: 1.20-1.74 (4
H, m), 1.87-2.12 (2H, m), 2
．． 37 (2H, t, J=7Hz), 2.50-2.
65 (2H, m), 3.27-3.36 (1H,
m), 4.28-4.43 (1H, m), 4.5
7 (1H, dd, J=7Hz, 6Hz), 5.53
(1H,brs), 5.58 (1H,brs),
5.67 (1H, brs), 5.83 (1H,
brs), 5.85 (1H, brs), 7.20
(2H, d, J=8Hz), 7.75 (2H, d
, J=8Hz), 8.46 (1H, d, J=8Hz
) Effects of the Invention According to the present invention, novel pyridopyrimidine derivatives useful as antitumor agents can be obtained.

Claims (4)

[Claims] Claim 1 General formula: [Formula 1] (In the formula, ring A is a pyridine ring which may be hydrogenated and may have a substituent, and B has a substituent. an optional divalent cyclic group or a lower alkylene group having 2 to 5 carbon atoms; X is an amino group or a hydroxyl group;
represents an amino group, a hydrogen atom or a lower alkyl group, R represents a hydrogen atom or a lower hydrocarbon group, -COOR1 and -
COOR2 is a carboxyl group which may be esterified in the same or different ways, n is an integer of 2 to 5, and R may be different in n repeats) or a pyridopyrimidine derivative represented by That salt. Claim 2 General formula: [Formula 2] (In the formula, A ring is a pyridine ring which may be hydrogenated and may have a substituent, and B has a substituent. an optional divalent cyclic group or a lower alkylene group having 2 to 5 carbon atoms; X is an amino group or a hydroxyl group;
represents an amino group, a hydrogen atom or a lower alkyl group, R represents a hydrogen atom or a lower hydrocarbon group, -COOR1 and -
COOR2 is a carboxyl group that may be esterified in the same or different ways, n is an integer of 2 to 5, and R may be different in n repeats) or its carboxyl group and a compound represented by the general formula: [Chemical formula 3] (wherein -COOR1 and -COOR2 are the same or different and each represents a carboxyl group which may be esterified). A method for producing the compound according to claim 1, characterized in that: [Claim 3] General formula: [Formula 4] (In the formula, ring A is a pyridine ring which may be hydrogenated and may have a substituent, and B has a substituent. an optional divalent cyclic group or a lower alkylene group having 2 to 5 carbon atoms; X is an amino group or a hydroxyl group;
represents an amino group, a hydrogen atom or a lower alkyl group, R represents a hydrogen atom or a lower hydrocarbon group, -COOR3 represents an optionally esterified carboxyl group, n represents an integer of 2 to 5, and R represents an integer of 2 to 5. (which may be different in n repeats). 4. An antitumor composition containing the compound according to claim 1 or a salt thereof.