Pyridopyrimidine derivatives, their production and use

Abstract: The new pyridopyrimidine derivative of the formula (A), wherein n denotes an integer of 0 to 3, Q stands for -(CH₂) m - ( m denotes an integer of 0 to 2), -O-, -S(O) p -( p denotes an integer of 0 to 2 ) or -N-, and R¹ to R⁶ stand for substituents, or its salt is described. Preparation of them and use to endothelin receptor antagonistic agent are exemplified. An endothelin receptor antagonist consisting of said compound is effective as therapeutic composition of acute renal insufficiency, myocardial infarction, hypertension, cerebral infarction, angina pectoris, arteriosclerosis, hepatopathy, pulmonary hypertension, bronchial asthma, organohypofunction occuring during operation or transplantation of organs.

Description: FIELD OF THE INVENTION This invention relates to novel compounds having condensed heterocyclic ring, which have excellent activities as medicines, i.e. endothelin receptor antagonistic activities, and are useful as vasodilators and therapeutic composition of such diseases as hypertension, acute renal insufficiency, myocardial infarction, angina pectoris and cerebral angiospasm, and a method of producing these compounds. DESCRIPTION OF THE PRIOR ART It has been suggested that, among adult diseases increasing in recent years, for example cerebral infarction, angina pectoris, myocardial infarction and renal insufficiency which are caused by ischemia are possibly concerned with endothelin. Endothelin is a peptide consisting of 21 amino acids produced from endothelial cells, and it is obtained as endothelin-1, endothelin-2 and endothelin-3. Hereinafter, in this specification, these endothelin groups are combinedly called "endothelin". It has been reported that endothelin has, among in vivo or synthetic substances which have so far been found, most potent and long-lasting vasoconstrictive action, pressor activity and action of enhancing heart muscle contraction activity. It is considered that the actions of these peptides are performed via endothelin receptor which is considered to exist on smooth muscle membrane of blood vessels etc. As endothelin receptors, have been known endothelin-A receptor and endothelin-B receptor (hereinafter collectively called "endothelin receptor"). Therefore, compounds showing affinity for endothelin receptor while showing endothelin receptor antagonistic activity have prophylactic and therapeutic effects against diseases caused by ischemia, for example, cerebral infarction, angina pectoris, myocardial infarction and renal insufficiency, thus development of these compounds being greatly expected. As endothelin receptor antagonistic substances, compounds derived from natural source have been obtained, as disclosed in several researchers, for example, Ishimaru et al. [JPA H4(1992)-134048], Fujimoto et al. [Federation of European Biochemical Societies Letters, 305 p.41 (1992)], Oh-hata et al. [JPA H3(1991)-047163], Miyata et al. [JPA H4(1992)-046127] and Yano et al. [JPA H3(1991)-094692]. Further, reports were made by Henmi et al. [EP 457195-A2], Ishikawa et al. [EP 460679-A2 and EP 436189-A], Hashimoto et al. [JPA H3(1992)-130299], Masaki et al. [JPA H3(1992)-024099], G. Hamon et al. [EP 487410-A2], W. L. Cody et al [J. Med. Chem., (1992) 35, p. 3303] and Wakimasu et al. [WO9113089-A, EP499266-A1], that peptide compounds were obtained. However, when dosage forms of drugs, stability of compounds, durability of pharmacological actions and stability to metabolism are taken into consideration, synthetic endothelin receptor antagonists prepared by non-peptidizing these peptide compounds are strongly desired. Under the present circumstances, however, very few reports are found on non-peptide synthetic endothelin receptor antagonists, for example, a recent report by K.Bali et al. [EP510526-A1]. On the other hand, a 2,4(1H,3H)-dioxo-pyrido[2,3-d]pyrimidine-3-acetic acid derivative was reported by H.R.Haward et al. [W092/12979], which has relatively similar structure to the compound of present invention. The substituents of these compounds, however, are apparently different from those of the present invention. Furthermore, it is reported that the former compounds are useful in therapy as aldose reductase inhibitors for the control of certain chronic diabetic complications but have no actions as endothelin receptor antagonists. SUMMARY OF THE INVENTION It is an object of the present invention to provide novel and useful compounds each having a condensed heterocyclic ring, especially novel compounds which can be used as non-peptide synthetic endothelin receptor antagonists, wherby the foregoing problems can be overcome. It is another object of the present invention to provide a novel compound having endothelin receptor antagonistic properties which is stable as compound and has long-lasting pharmacological properties and metabolic stability. It is a further object of the present invention to provide a method of producing the compound and an endothelin receptor antagonistic composition. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT The present inventors have conducted diligent research works to attain the above objects, resulting in finding out that these objects can be achieved by novel pyridopyrimidine derivatives having endothelin receptor antagonistic activities, and thus the present invention has been accomplished based on this finding. The present invention provides a pyrido[2,3-d]pyrimidine derivative represented by the formula: wherein R 1 is a benzyl group optionally substituted by 1 or 2 of C 1-6 alkoxy or C 1-6 alkylthio group; R 2 is a hydrogen atom or a C 1-6 alkyl group; R 3 is i) a phenyl group optionally substituted by a C 1-6 alkyl group or a C 1-6 alkoxy group, or ii) a quinolyl group optionally substituted by an oxo group or hydroxy group; R 4 is COOR 6 wherein R 6 is hydrogen or a C 1-6 alkyl group optionally substituted by cyano; and R 5 is a C 1-6 alkyl group; or its salt. Among others, preferable examples of the pyrido[2,3-d]pyrimidine derivative represented by the formula (A) are 2,4(1H,3H)-dioxo-6-ethoxycarbonyl-7-isopropyl-1-(2-methoxybenzyl)-5-(4-tolyl)pyrido[2,3-d]pyrimidine-3-acetic acid or its salt, 2,4(1H,3H)-dioxo-6-ethoxycarbonyl-7-methyl-1-(2-methoxybenzyl)-5-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine-3-acetic acid or its salt, ethyl[2,4(1H,3H)-dioxo-6-carboxy-7-isopropyl-1-(2-methoxybenzyl)-5-[2-(4-quinolonyl)]pyrido[2,3-d]pyrimidine]-3-acetate or its salt, 2,4(1H,3H)-dioxo-6-carboxy-7-isopropyl-1-(2-methoxybenzyl)-5-[2-(4-quinolonyl)]pyrido[2,3-d]pyrimidine-3-acetic acid or its salt, and 2,4(1H,3H)-dioxo-6-carboxy-7-isopropyl-1-(2-methylthiobenzyl)-5-[2-(4-quinolonyl)]pyrido[2,3-d]pyrimidine-3-acetic acid or its salt. The present invention is to provide a process for producing a pyrido[2,3-d]pyrimidine derivative represented by the formula (A) or a salt thereof, which comprises (1) oxidation of a compound or its salt, the compound being represented by the formula (B): wherein each symbol is as defined above; (2) reacting a compound or its salt, the compound being represented by the formula (D): wherein each symbol is as defined above, with a halogenated alkylcarboxylate derivative represented by the formula: X-CH 2 -COOR 2 wherein X is halogen atom, and R 2 is as defined above; (3) in case that R 3 is 2-(4-quinolonyl) group and R 4 is carboxy group, oxidation of a compound or its salt, the compound being represented by the formula (E): wherein each symbol is as defined above; (4) reacting a compound or its salt, the compound being represented by the formula (F): wherein each symbol is as defined above, with a halogenated benzyl derivative represented by the formula: R 1 -X 2 wherein X 2 is halogen atom, and R 1 is as defined above; (5) in case that R 3 is 2-(4-quinolonyl) group, reacting a compound or its salt, the compound being represented by the formula (H): wherein each symbol is as defined above, with a nucleophilic reagent capable of incorporating thereinto a substituent represented by the formula: -OR 6 wherein R 6 is as defined above; or (6) in case that R 2 is a hydrogen, hydrolyzing a compound or its salt, the compound being represented by the formula (A): wherein R 2 is a C 1-6 alkyl group, and the other symbols are as defined above. And, the present invention is to provide an endothelin receptor antagonistic agent containing, as the effective component, a pyrido[2,3-d]pyrimidine derivative represented by the above-mentioned formula (A) or a pharmaceutically acceptable salt thereof. Furthr the present invention is to provide said endothelin receptor antagonistic composition as a therapeutic composition of acute renal insufficiency, myocardial infarction, hypertension, cerebral infarction, angina pectoris, arterial sclerosis, hepatopathy, pulmonary hypertension, bronchial asthma, organohypofunction occuring during operation or transplantation of organs, especially, a therapeutic composition of acute renal insufficiency and/or myocardial infarction. The compound represented by the formula (A) of this invention (hereinafter referred to as compound [A]) will be described in further detail. The phenyl group in the benzyl group for R 1 may have a C 1-6 alkoxy group (e.g. methoxy group, ethoxy group or propoxy group) or a C 1-6 alkylthio group (e.g. methylthio group, ethylthio group or propylthio group), especially preferable ones being a C 1-3 alkoxy group such as methoxy group. Examples of the C 1-6 alkyl group for R 2 include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group, 1-ethylpropyl group, hexyl group, isohexyl group, 1,1-dimethylbutyl group, 2,2-dimethylbutyl group, 3,3-dimethylbutyl group and 2-ethylbutyl group. Among them, C 1-4 alkyl groups as exemplified by methyl group, ethyl group, propyl group, isopropyl group, butyl group and isobutyl group, for example, are preferable. Methyl group is especially preferable. In the formula (A), R 3 means a phenyl group optionally substituted by a C 1-6 alkyl group or a C 1-6 alkoxy group. Such C 1-6 alkyl and C 1-6 alkoxy mean the same ones as described referring to R 1 and R 2 . The C 1-6 alkyl group,for R 5 is the same one as mentioned referring to R 2 . The specific examples of preferable compound of this invention, include 2,4(1H,3H)-dioxo-6-ethoxycarbonyl-7-isopropyl-1-(2-methoxybenzyl)-5-(4-tolyl)pyrido[2,3-d] pyrimidin -3-acetic acid, 2,4(1H,3H)-dioxo-6-ethoxycarbonyl-7-methyl-1-(2-methoxybenzyl)-5-(4-methoxyphenyl)pyrido [2,3-d]pyrimidin -3-acetic acid, ethyl[2,4(1H,3H)-dioxo-6-carboxy-7-isopropyl-1-(2-methoxybenzyl)-5-[2-(4-quinolonyl)] pyrido[2,3-d]pyrimidin ]-3-acetate, 2,4(1H,3H)-dioxo-6-carboxy-7-isopropyl-1-(2-methoxybenzyl)-5-[2-(4-quinolonyl)] pyrido[2,3-d]pyrimidin -3-acetic acid, 2,4(1H,3H)-dioxo-6-carboxy-7-isopropyl-1-(2-methylthiobenzyl)-5-[2-(4-quinolonyl)]pyrido[2,3-d]pyrimidin -3-acetic acid and their salts. As salts of the compound [A] of this invention, pharmaceutically acceptable acid addition salts are mentioned as especially preferable ones. As such salts, use is made of, for example, those with an inorganic acid (e.g. hydrochloric acid, phosphoric acid, hydrobromic acid or sulfuric acid) or those with an organic acid (e.g. acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid or benzenesulfonic acid). And, in the case where the compound [A] of this invention has an acid group such as -COOH, the compound [A] may form a salt with an inorganic base (e.g. an alkali metal or alkaline earth metal such as sodium, potassium, calcium or magnesium; or ammonia) or an organic base (e.g. trialkylamine having a C 1-8 alkyl groups, such as triethylamine). As salts of the starting compounds for producing the compound [A] of this invention, use is made of, for example, salts with an inorganic acid (e.g. hydrochloric acid, phosphoric acid, hydrobromic acid or sulfuric acid) or salts with an organic acid (e.g. (acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid or benzenesulfonic acid). And, in the case where the starting compound has an acid group such as -COOH, it may form a salt with an inorganic base (e.g. an alkali metal or alkaline earth metal such as sodium potassium, calcium or magnesium; or ammonia) or an organic base (e.g. trialkylamine having a C 1-8 alkyl group, such as triethylamine). The compound [A] of this invention and salts thereof can be readily produced by per se known methods, and, as typical ones, the following seven methods are mentioned. [Production Method - 1] A urea derivative (i) represented by the formula R 1 NHCONH 2 wherein R 1 is as defined above, which is synthesized from benzylamine is heated in an appropriate solvent such as ethyl alcohol in the presence of a cyanoacetic acid derivative and a base, at the temperature of 80-120 °C, for 2-240 hours, preferablly 24-100 hours, to give a compound (ii). This compound is stirred, together with a halogenated acetic acid ester derivative or a halogenated propionic acid ester derivative, in the presence of a base in an appropriate solvent such as dimethylacetamide or dimethylformamide at the temperature of 40-70 °C, usually for 4-96 hours, preferablly 12-24 hours, to give a derivative represented by the formula (I'). The derivative (I') thus obtained is, in accordance with the Hantzsch's synthetic method [A. Hantzsch, Ann. Chem. 215, 1 (1882)], subjected to heating with arylaldehyde and beta-keto ester under reflux at the temperature of 80-100 °C, usually for 2-240 hours, preferablly 12-120 hours, in an appropriate solvent such as ethyl alcohol, or subjected beforehand to Knoevenagel condensation reaction [T. Yamamori, Y. Hiramatsu, K. Sakai and I. Adachi, Tetrahedron, 41, 913 (1985)] to synthesize a dehydrated condensed derivative with arylaldehyde and beta keto ester, then the dehydrated condensed derivative and the derivative (I') are heated under reflux at the temperature of 100-130°C, usually for 2-240 hours, preferablly 12-120 hours,in an appropriate solvent such as toluene to give 5,8-dihydropyrido[2,3-d] pyrimidine-2,4-dione derivative (B1). This compound (B1) is subjected to oxidation with an appropriate oxidizing agent such as sodium nitrite in acetic acid to give the compound (A1) of this invention. Further, if necessary, the compound (A1) is subjected to an appropriate conditions, for example, alkali hydrolysis in an appropriate solvent such as methanol, ethanole, tetrahydrofuran or dioxane to give the compound (A2) of this invention. The alkali hydrolysis reaction can be carried out by stirring the reaction mixture in the presence of an appropriate base catalyst(e.g. sodium hydroxide, litium hydroxide, potassium hydroxide and others), at room temperature or at the elevated temperature(e.g. 40-100°C ), usually for 2-48 hours, preferablly 2-24 hours. The reactions in the above-described production method are collectively shown by the following reaction scheme, in which each symbol is of the same meaning as defined above. [Production Method -2 ] A compound (ii) is, in accordance with forementioned Hantzsch's synthetic method [A.Hantzsch, Ann. Chem. 215, 1 (1882)], subjected to heating with a dehydrated condensed derivative of an aldehyde derivative with a beta-keto ester derivative, at a temperature of 40-120°C, usually for 0.5-4 hours, preferably 0.5-1 hour, in an appropriate solvent(e.g. dimethylacetamide, dimethylsulfoxide, dimethylformamide) to give a compound (D1). The dehydrated condensed derivative is previously obtained by heating an aldehyde derivative (e.g. quinoline-2-carboxyaldehyde) with a beta keto ester (e.g. ethyl isobutylylacetate, 2-cyanoethyl isobutylylacetate) under reflux in an appropriate solvent(e.g. benzene, toluene) in the presence of an appropriate catalyst (e.g. pyrrolidine and acetic acid, piperidine and acetic acid) at a temperature of 100-120°C for usually 0.5-1 hour. This compound (D1) is subjected to oxidation with an appropriate oxidizing agent such as sodium nitrite in acetic acid, in an appropriate solvent such as acetic acid, for usually 0.25-24 hours, preferably 1-12 hours, to give the compound (D ). The compound (D ) thus obtained, is allowed to stir with a halogenated acetic acid-ester derivative or a halogenated propinic acid-ester derivative, in the presence of a base (e.g. sodiumu hydride, potassium carbonate), in an appropreate solvent(e.g. dimethylacetamide, dimethylformamide), at room temperature or at an elevated temperature such as 40-120°C, for usually 0.5-12 hours, preferably 0.5-2 hours to give the compound (A1), or propionic acid ester, of this invention. Further, if necessary, the compound (A1) is subjected to alkali hydrolyzing in an appropriate solvent such as methanol, ethanol, tetrahydrofuran or dioxane to give the compound (A2) of this invention. The alkali hydrolysis reaction can be carried out by stirring the reaction mixture in the presence of an appropriate base catalyst(e.g. sodium hydroxide, litium hydroxide, potassium hydroxide and others), at room temperature or at an elevated temperature(e.g. 40-100°C), usually for 2-12 hours. The reactions in the above-described production method are collectively shown by the following reaction scheme, in which each symbol is of the same meaning as defined above. [Production Method - 3] Here is an example of changing the substituent in the compound of this invention. A 5-(2-quinolyl)-6-cyanoethoxycarbonyl derivative (E1) is subjected to stirring in an appropriate solvent(e.g. methanol, ethanol , tetrahydrofuran or dioxane) in the presence of an appropriate weak base (e.g. aqueous solution of sodium carbonate or sodium hydrogen carbonate), at room temperature or at an elevated temperature(e.g. 40-100 °C), usually for 2-12 hours, preferably 0.5-2 hours to give a 6-carboxyl derivative (E ). The compound (E ) is dissolved in an appropriate solvent (e.g. methylene chloride, carbon tetrachloride, 1,2-dichloroethane or toluene) and subjected to heating and reacting with much excess of thionyl chloride(e.g. 10 times of equivalent ) under reflux (e.g. 40-120 °C ) for usually 5-120 minutes, preferably 5-60 minutes. The reaction mixture was then concentrated to dryness while removing the excess of thionyl chloride. The residue is dissolved in an appropriate solvent(e.g. acetonitrile, tetrahydrofuran, dioxane or dimethylacetamide). Being added an appropreate weak base(e.g. aqueous solution of sodium carbonate or sodium hydrogen carbonate), the solution is subjected to stirring at room temperature or at an elevated temperature(e.g. 40-100°C), usually for 2-48 hours, preferably 2-24 hours to give 4-quinolonyl derivative (A3). Further, if necessary, the compound (A3) is subjected to alkali hydrolyzing in an appropriate solvent such as methanol, ethanol, tetrahydrofuran or dioxane to give the compound (A4) of this invention. The alkali hydrolysis reaction can be carried out by stirring the reaction mixture in the presence of an appropriate base catalyst(e.g. sodium hydroxide, litium hydroxide, potassium hydroxide and others), at room temperature or at an elevated temperature(e.g. 40-100°C ), usually for 2-12 hours. The reactions in the above-described production method are collectively shown by the following reaction scheme, in which each symbol is of the same meaning as defined above. [Production Method - 4] A 1-(2,4-dimethoxybenzyl) derivative (F1) is subjected to oxidizing to give 1-hydro derivative (F). The oxidization is carried out as follows. The compound (F1) is dissolved in an appropriate solvent(e.g. an aqueous solution of acetone or acetonitrile), to which an appropriate oxidizing agent such as cerium ammonium nitrate(CAN) is added, and the mixture is allowed to stir at room temperature or at an elevated temperature (e.g. 40-60 °C), usually for 0.5-2 hours, preferably 0.5-1 hour to give the compound (F). Another method of oxidization comprises stirring the compound (F1) in trifluoroacetic acid (TFA) at a temperature of 40-80°C, usually for 1-12 hours, preferably 2-6 hours to give the compound (F). The compound (F) thus obtained is subjected to reacting by stirring with a halogenated lower alkyl derivative(e.g. methyl iodide) or a halogenated aralkyl derivative (e.g. substituted benzyl chloride derivative or substituted benzyl bromide derivative ) in an appropriate solvent(e.g. dimethylacetamide, dimethylformamide, acetone or tetrahydrofuran) in the presence of an appropriate base (e.g. sodium hydride or pottasium carbonate), usually for 0.5-4 hours, preferably 0.5-2 hours to give the compound (A1). Further, if necessary, the compound (A1) is subjected to alkali hydrolyzing in an appropriate solvent such as methanol, ethanol, tetrahydrofuran or dioxane to give the compound (A2) of this invention. The alkali hydrolysis reaction can be carried out by stirring the reaction mixture in the presence of an appropriate base catalyst(e.g. sodium hydroxide, litium hydroxide, potassium hydroxide and others), at room temperature or at an elevated temperature(e.g. 40-100 °C). The reactions in the above-described production method are collectively shown by the following reaction scheme, in which each symbol is of the same meaning as defined above. [Production Method - 5] The compound (A9), whose substituent at 6-position is COOH, is subjected to stirring with a halogenated alkyl, a halogenated cyclic hydrocarbon or halogenated aralkyl derivative(e.g. ethyl bromide, isobutyl bromide or benzyl bromide) in an appropriate solvent(e.g. dimethylacetamide or dimethylformamide) in the presence of an appropriate weak base(e.g. potassium carbonate, triethylamine or sodium hydrogen carbonate), usually for 2-48 hours, preferably 2-24 hours to give a compound (A10) of this invention whose substituent at 6-position is -COOR 6 . Further, if necessary, the compound (A10) is subjected to alkali hydrolyzing in an appropriate solvent such as methanol, ethanol, tetrahydrofuran or dioxane, or acid hydrolyzing in an appropriate solvent such as methylene chloride to give the compound (A11) of this invention. The alkali hydrolysis reaction can be carried out by stirring the reaction mixture in the presence of an appropriate base catalyst(e.g. sodium hydroxide, litium hydroxide, potassium hydroxide and others), at room temperature or at an elevated temperature(e.g. 40-100 °C ), usually for 2-48 hours, preferably 2-24 hours. The acid hydrolysis reaction can be carried out by stirring the reaction mixture with a catalytic amount or excessive amount of an appropriate acid such as trifluoroacetic acid, at room temperature or at an elevated temperature(e.g. 40 -100°C), usually for 2-48 hours, preferably 2-24 hours. The reactions in the above-described production method are collectively shown by the following reaction scheme, in which each symbol is of the same meaning as defined above. [Production Method - 6] Here is an example of the process for producing the compound (A) of this invention wherein the substituent at 5-position is 2-(4-quinolonyl)group. The compound (A12), whose substituent at 1-position is hydrogen atom, is subjected to stirring with excess of thionyl chloride(e.g. 5-20, preferably 5-10 times of equivalent) in an appropriate solvent (e.g. methylene chloride or toluene) at room temperature or at an elevated temperature (e.g. 40-60 °C), usually for 0.5-2 hours, preferably 0.5-1 hour. The reaction mixture is then concentrated to dryness under reduced pressure. The residue is dissolved in an appropriate solvent(e.g. methylene chloride). Filtered off the insoluble material(e.g. by filtration with sellaite), the filtrate is concentrated to dryness, and if necessary washed with an appropriate solvent (e.g. ethyl acetate), to give the compound (H1). The compound (H1) thus obtained is dissolved in an appropriate solvent(e.g. dimethylformamide, dimethylacetamide or acetonitrile), and then is subjected to stirring with usually 1-3, preferably 1-1.5 times of equivalent of an appropriate halogenated alkyl derivative or halogenated aralkyl derivative (e.g. 2-methylthiobenzyl chloride or 2,3-dimethoxybenzyl chroride etc.) in the presence of usually 1-3, preferably 1.5-2 times of equivalent of an appropriate base (e.g. potassium hydrogencabonate, pottasium carbonate or sodium hydride ), at room temperature or at an elevated temperature (e.g. usually 40-100 °C, preferably 40-60 °C) usually for 2-48 hours, preferably 24-48 hours to give the compound (H ). After refining by appropriate method (e.g. silica gel columnchromatography ), if necessary the compound (H2) is dissolved in an appropriate solvent(e.g. acetonitrile or dimethylacetamide), and then is subjected to stirring with excess ( usually 5-30, preferably 5-10 times of equivalent) of a nucleophilic reagent (e.g. 2N aqueous solution of pottasium carbonate, aqueous ammonia or an amine compound ) at room temperature or at an elevated temperature (e.g. usually 40-120°C, preferably 40-80°C) usually for 1-6 hours, preferably 1-2 hours to give the compound (A13). The reactions in the above-described production method are collectively shown by the following reaction scheme, in which R is -OR 6 and each symbol except R is of the same meaning as defined above. The starting compound benzylamine can be produced by a per se known method or an analogous method thereto. The compound [A] thus obtained or a salt thereof can be isolated and purified in conventional manner, e.g. by recrystallization, distillation or chromatography. When the compound [A] is thus obtained as a free compound, it can be converted to a corresponding salt by a per se known method or an analogous method thereto, and, when the compound [A] is obtained as a salt, it can be converted to a free compound or any other salt by a per se conventional method or an analogous method thereto. In the case where the compound [A] or a salt thereof is an optically active compound, it can be isolated into d-isomer and l-isomer by a conventional means for optical resolution. The compound [A] or its salt of this invention has excellent endothelin receptor antagonistic activity; therefore, it can be used as endothelin receptor antagonist for warm-blooded animals(e.g. rat, mouse, guinea pig, chicken, dog, cat, sheep, pig, bovine, monkey, man and others). Moreover, because of its excellent endothelin receptor antagonistic activity, the compound [A] or its salt of this invention can be used as prophylactic and therapeutic composition against cerebral infarction, angina pectoris, myocardial infarction and renal insufficiency. The compound [A] or its salt of this invention is of a safty and low toxycity. When the compound [A] or its salt of this invention is used as endothelin receptor antagonist or as prophylactic and therapeutic agents against acute renal insufficiency, myocardial infarction, hypertension, cerebral infarction, angina pectoris, arteriosclerosis, hepatopathy, pulmonary hypertension, bronchial asthma, organohypofunction occuring during operation or transplantation of organs. They can be administered either orally or non-orally. Usually, they are administered orally in a form of a solid preparation such as tablets, capsules, granules or powder, or non-orally in a form of intravenous, subcutaneous or intramuscular injection, suppositories or sublingual tablets. Dosage amounts will vary with degrees of symptoms; ages of patients, sex, body weight, difference in sensitivity; administration time; interval, quality of medicinal preparations, preparation, kinds; kinds of effective components, among others, and they are not specifically limited. Usually, the dosage for adult per day ranges from about 0.1 to 500 mg, preferably from about 1 to 100 mg, more preferably from 5 to 50 mg, in one to 4 divided doses per day. The compounds of this invention can be administered orally or non-orally, formulated with pharmaceutically acceptable carriers, as a solid preparation including tablets, capsules, granules and powder, or as a liquid preparation such as syrup or injections. The above-mentioned pharmaceutically acceptable carriers include conventional organic or inorganic carriers employed in the field of pharmaceutical preparations; namely, excipients, lubricants, binders and disintegrators in solid preparations; solvents, solubilizers, suspending agents, isotonizers, buffer agents and local anesthetics in liquid preparations. Upon necessity, additives such as preservatives, antioxidants, colorants, sweeteners or the like can also be employed. Preferable excipients are exemplified by lactose, sucrose, D-mannitol, starch, crystalline cellulose and light silicic acid anhydride. Preferable lubricants are exemplified by magnesium stearate, calcium stearate, talc and colloidal silica. Preferable binders are exemplified by crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose and polyvinyl pyrrolidone. Preferable disintegrators are exemplified by starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, closcarmellose sodium and carboxymethyl starch sodium. Preferable solvents are exemplified by distilled water for injection, alcohol, propylene glycol, macrogol, sesame oil and corn oil. Preferable solubilizers are exemplified by polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate and sodium citrate. Preferable examples of suspending agents include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride and glycerin monostearate ; hydrophilic polymers such as polyvinyl alcohol, polyvinyl pyrrolidone, carboxymethyl cellulose sodium, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose and hydroxypropyl cellulose. Preferable isotonizers are exemplified by sodium chloride, glycerin and D-mannitol. Preferable buffer agents are exemplified by buffer solutions such as phosphates, acetates, carbonates and citrates. Preferable local anesthetics are exemplified by benzyl alcohol. Preferable preservatives are exemplified by para-hydroxybenzoic esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid and sorbic acid. Preferable antioxidants are exemplified by sulfite and ascorbic acid. By the addition of a suspending composition, a solubilizer, a stabilizing composition, an isotonizer, a preservative or the like to the compound of this invention, intravenous, subcutaneous and intramuscular injections are prepared by conventional methods. Upon necessity, these injections can be made into lyophilized preparations. Examples The following examples are given for the purpose or illustration and not by any of limitation. The following compounds are within the scope of the present invention: Compound of Example 1, Example 2 Compound No. 1, 2, 5, 6, 10, 20, 21, 26-28 and 30, Compound of Example 3, Example 4 Compound No. 1, 2, 4, 5, 7-14 and 17, Compound of Example 10, Example 11 Compound No. 1, Compound of Example 12, Example 13 Compound No. 1, 2, 5, 6, 10, 11, 20 and 21, Compound of Example 14, Example 15 Compound No. 1, 2, 4 and 9, Compound of Example 16, Example 17 Compound No. 1, 3-6, 9, 10, 13 and 15, Compound of Example 18, Example 19 Compound No. 1, 2, 5, 6, 8 and 10-12, Compound of Example 20, Example 21 Compound No. 1, 3 and 5-10, Compound of Example 22, Compound of Example 23, Example 24 Compound No. 4-11, Compound of Example 25, Example 26 Compound No. 1, 7, 8 and 10, Compound of Example 27, Example 28 Compound No. 1 and 7-10, Compound of Example 29, Example 30 Compound No. 1 and 2, Compound of Example 31, Example 32 Compound No. 1, Compound of Example 35, and Compound of Example 36. All the other Reference Examples and Examples are illustrative for the production of intermediates and for the production of the claimed compounds. [Reference Example 1] Production of 2-methoxybenzyl urea ( chemical formula 1) To an aqueous solution (13 ml) containing 2-methoxybenzylamine (13.7 g, 0.1 mol.) was added dropwise dilute sulfuric acid (prepared from 2.8 ml of conc. sulfuric acid and 6.7 ml of refined water) at room temperature. After completion of the dropwise addition, an aqueous solution (70 ml) containing sodium cyanate (7.65 g, 0.12 mol.) was added to the reaction mixture at room temperature taking 15 minutes. The suspension obtained as reaction mixture was heated at 80°C for one hour. The reaction mixture was cooled, then resulting crystalline precipitates were collected by filtration, followed by recrystallization from ethanol to give 17 g (yield 94%) of colorless prisms. [Reference Example 2] Production of 6-amino-1-(2-methoxybenzyl)pyrimidine-2,4(1H, 3H)-dione ( chemical formula 2) A mixture of the compound (10.8 g, 60 mmol.) obtained in Reference Example 1, ethyl cyanoacetate (7.0 g, 62 mmol.) and sodium methoxide (28% methanol solution, 12.0 g, 62 mmol.) was heated for 72 hours in ethanol (100 ml) under reflux. The reaction mixture was cooled, which was then concentrated to dryness. To the concentrate was added a saturated aqueous solution of ammonium chloride (50 ml). The mixture was stirred, then the pH thereof was adjusted to a range of 6 to 7 with 1N HCl. Resulting precipitates were collected by filtration and recrystallized from a mixture of ethanol and methanol (1:1) to give 10.0 g (yield 68%) of pale yellow prisms, m.p.278 to 279 °C. The elemental analysis values were as shown in Table 1. Elemental Analysis for C 12 H 13 N 3 O 3 C(%) H(%) N(%) Calcd. 58.29 5.30 16.99 Found 58.00 5.36 17.01 [Reference Example 3] The method described as Reference Example 1 and 2 was repeated, while employing various substituted amino compounds in place of 2-methoxybenzylamine. The compounds represented by chemical formula (3) thus obtained were collectively shown in the following Table 2. [Reference Example 4] Production of ethyl [6-amino-2,4(1H,3H)-dioxo-1-(2-methoxybenzyl)]pyrimidine-3-acetate ( chemical formula 4) A mixture of the compound (6.65 g, 27 mmol.) obtained in Reference Example 2, ethyl bromoacetate (15.0 g, 90 mmol.) and potassium carbonate (16.6 g, 120 mmol.) was stirred in dimethylformamide (500 ml) for 72 hours at 60 °C. The reaction mixture was, after cooling, concentrated to dryness, to which were added a saturated aqueous solution of ammonium chloride (30 ml) and ethyl acetate (50 ml), then the mixture was stirred. The organic layer was separated. The aqueous layer was subjected to extraction with ethyl acetate (50 ml). The extract was combined with the organic layer, which was then dried. The solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography to give 3.5 g (yield 39%) of a yellow amorphous product. The NMR spectrum of thus obtained yellow amorphous compound was as follows. 1 H-NMR (200MHz, CDCl 3 ) δ ppm : 1.27(3H,t), 3.93(3H,s), 4.21(2H,q), 4.70(2H,s), 4.91(1H,s), 5.12(2H,s), 5.31(2H,s), 6.91-7.03(2H,m), 7.27-7.40(1H,m), 7.50-7.55(1H,m). [Reference Example 5] Production of ethyl [5,8-dihydro-2,4(1H,3H)-dioxo-6-ethoxycarbonyl-7-isopropyl-1-(2-methoxybenzyl)-5-(4-tolyl)pyrido[2,3-d]pyrimidine]-3-acetate ( chemical formula 5 ) The compound (0.5 g, 1.5 mmol.) obtained in Reference Example 4 was heated for 90 hours under reflux in ethanol (10 ml) together with p-tolualdehyde (0.54 g, 4.5 mmol.) and ethyl isobutyryl acetate (0.71 g, 4.5 mmol.). The reaction mixture was cooled, then the solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography to give 0.2 g (yield 23%) of a yellow amorphous product. The NMR spectrum of thus obtained amorphous compound are as follows. 1 H-NMR(200MHz, CDCl 3 ) δ ppm : 0.80(3H,d), 1.06(3H,d), 1.25(3H,t), 1.26(3H,s), 2.25(3H,s), 3.58(1H,m), 3.96(3H,s), 4.12(2H,q), 4.22(2H,q), 4.62(1H,d), 4.72(1H,d), 5.07(1H,s), 5.22(1H,d), 5.32(1H,d), 6.40(1H,s), 6.90-7.50(8H,m). [Reference Example 6] The method described as Reference Example 5 was repeated, while employing various aldehydes and ethyl isobutyryl acetates or ethyl acetoacetates. Compounds represented by chemical formula (6) thus obtained were collectively shown in the following Table 3. [Reference Example 7] Production of 5,8-dihydro-2,4-(1H,3H)-dioxo-6-ethoxy carbonyl-7-isopropyl-1-(2-methoxybenzyl)-5-(4-tolyl)pyrido[2,3-d]pyrimidine-3-acetic acid ( chemical formula 7 ) The compound (0.2 g, 0.35 mmol.) obtained in Reference Example 5 was dissolved in methanol (20 ml). To the solution was added a 2N aqueous solution of sodium hydroxide (2 ml), and the mixture was stirred for 18 hours at room temperature. The reaction mixture was concentrated under reduced pressure, whose pH was adjusted to pH ranging from 2 to 3 with 1N HCl, followed by subjecting to extraction with ethyl acetate to give 0.13 g (yield 68%) of a yellow oily product. [Reference Example 8] Using compounds referred to in Reference Example 6, the method described in Reference Example 7 was repeated. The compounds represented by the chemical formula (8) thus obtained were collectively listed in the following Table 4. Ref.Ex.8 Cpd.No. 5-substit. 6-substit. 7-substit. Yield (%) m.p. ( °C ) 1 phenyl isopropoxycarbonyl methyl 59 powder 2 4-cyclohexylphenyl ethoxycarbonyl isopropyl 57 -do.- 3 -do.- -do.- methyl 89 -do.- 4 4-cyanophenyl -do.- -do.- 47 -do.- [Reference Example 9] Production of 2,4-(1H,3H)-dioxo-6-(2-cyanoethoxy carbonyl) -7-isopropyl-1-(2-methoxybenzyl)-5-(2-quinolyl)pyrido[2,3-d]pyrimidine ( chemical formula 9 ) The compound (3.9 g, 16 mmol.) obtained in Reference Example 2 was stirred in dimethylsufoxide (23 ml) for 25 mimutes at 125°C together with the compound (6.1g, 19 mmol) obtained by dehydrative condensation of quinoline-2-carboxyaldehyde and 2-cyanoethyl isobutyryl acetate. The reaction mixture was cooled, then poured into Ice water. Resulting brownish crystals were collected by filtration and dissolved in ethyl acetate. Washing the solution with water, pale gray powder 4.3g (yield 49%) was obtained. The compound thus obtained (4.3g, 7.8 mmol) was dissolved in acetic acid (50 ml), to which was added sodium nitrite (5.9g). The mixture was stirred for 15 minutes at room temperature. The reaction mixture was poured into ice water, which was subjected to extraction with ethyl acetate. The organic layer was dried and then the solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography to give 4.1g (yield 47%) of a yellow amorphous product. The elemental analysis values were shown in Table 5. The NMR spectrum and IR spectrum of the compound are as follows. 1 H-NMR(200MHz, CDCl 3 ) δ ppm : 1.14(6H,d), 2.12(2H,t), 3.15(1H,m), 3.89(3H,s), 3.94(2H,t), 5.61(2H,s), 6.80-6.96(3H,m), 7.21(1H,td), 7.53(1H,d), 7.59(1H,td), 7.72(1H,td) 7.88(1H,d), 8.04(1H,d), 8.22(1H,d), 8.77(1H,s). IR(KBr): 3452, 3196, 3068, 2974, 2254, 1736, 1715, 1603, 1572, 1497 cm -1 . Elemental Analysis for C 31 H 27 N 5 O 5 · 1.0H 2 O C(%) H(%) N(%) Calcd. 65.60 5.15 12.34 Found 65.59 5.05 12.11 [Reference Example 10] Using another compounds, the method described in Reference Example 9 was repeated. The compounds represented by the chemical formula (10) thus obtained were collectively listed in the following Table 6. [Reference Example 11] Production of ethyl [2,4-(1H,3H)-dioxo-5-methylthio-6-ethoxycarbonyl-7-isopropyl-1-(2-methoxybenzyl)pyrido[2,3-d]pyrimidine]-3-acetate ( chemical formula 11) To a methanol solution (5 ml) containing ethylisobutylylacetate (0.48 g) was added a methanol solution of sodiumu methoxide (28%, 0.58g) under ice cooling. After stirring for 10 minutes under same condition, to the solution was added dropwise carbon disulfide . After completion of the dropwise addition, dimethyl sulfate (0.75 ml) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 15 minutes. The reaction mixture was poured into water (30 ml), stirred for 5 minutes, which was then subjected to extraction with isopropyl ether to give a yellow oily product( 0.40 g). A mixture of the the oily product, the compound obtained in Reference Example 4 (0.50g, 1.5 mmol ) and potassium carbonate (0.31 g ) was stirred in dimethylformamide (10 ml) for 5 hours at 150°C. The reaction mixture was, after cooling, concentrated to dryness, to which were added a saturated aqueous solution of ammonium chloride (20 ml) and ethyl acetate (20 ml), and then the mixture was stirred. The organic layer was separated. The aqueous layer was subjected to extraction with ethyl acetate (20 ml). The extract was combined with the organic layer, which was then dried. The solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography to give 0.06 g (yield 8%) of a yellow amorphous product. The NMR spectrum and MS spectrum of thus obtained yellow amorphous compound was as follows. 1 H-NMR (200MHz, CDCl 3 ) δ ppm : 1.28(3H,t), 1.35(6H,d), 1.41(3H,t), 2.21(3H,s), 3.86(3H,s), 4.20(2H,q), 4.40(2H,q), 4.40-4.60(1H,m), 4.84(2H,s), 5.59(2H,s), 6.7-7.0(3H,m), 7.15-7.3(1H,m). MS, m/z : 530(MH) + [Reference Example 12] Production of ethyl [1,3,7,13-tetraoxo-1,2,3,4,7,13-hexahydro-6-isopropyl-pyrimido[4",5":6',5']pyrido[3',4':4,3]pyrrolo[1,2-a]quinoline]-3-acetate ( chemical formula 12 ) The compound (1.10 g, 2.38 mmol.) obtained in Example 17 ( Compound No.16 ) was dissolved in dichloromethane (100 ml). To the solution was added thionyl chloride (0.87 ml, 11.89 mmol), and the mixture was stirred for 2 hours at room temperature. 20 ml of toluene was added to the reaction mixture, and then concentrated under reduced pressure. The residue was dissolved in dichloromethane, and then filtered with sellaite. The filtrate was concentrated, and the residue thus obtained was washed with ethyl acetate to give 0.30 g (yield 28%) of a yellow powdery product. The elemental analysis values were shown in Table 7. The NMR spectrum, IR spectrum and MS spectrum of the compound are as follows. 1 H-NMR(500MHz, DMSO-d 6 ) δ ppm 1.32-1.41(9H,m), 4.28(2H,q), 4.37(1H,m), 4.82(2H,s), 7.47(1H,t), 7.78(1H,t), 8.30(1H,d), 8.64(1H,s), 8.78(1H,s), 9.19(1H,d) IR(KBr): 1738, 1682, 1642, 1576, 1477, 1396 cm -1 . FAB-MS, m/z : 461.1(MH) + Elemental Analysis for C 24 H 20 N 4 O 8 :0.3H 2 O:0.2C 4 H 8 O 2 C(%) H(%) N(%) Calcd. 61.62 4.62 11.58 Found 61.41 4.32 11.40 [Reference Example 13] Production of ethyl [1,3,7,13-tetraoxo-1,2,3,4,7,13-hexahydro-6-isopropyl-4-(2-methylthlobenzyl)pyrimido[4",5":6',5'] pyrido[3',4':4,3]pyrrolo[1,2-a]quinoline]-3-acetate ( chemical formula 13 ) A dimethylformamide(5 ml) solution containing the compound (0.20 g, 0.43 mmol.) obtained in Reference Example 12, 2-methylthio benzylchloride(0.74g, 4.30 mmol) and pottasium hydrogencarbonate(0.07g, 0.64 mmol) was stirred for 2 days at room temperature. To the reaction mixture was added saturated aqueous solution of ammonium chloride, which was subjected to distribution to dichloromethane and saturated aqueous solution of sodium chloride. The organic layer was dried with MgSO 4 and then the solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography to give 0.21g (yield 80%) of a yellow powdery product. The elemental analysis values were shown in Table 8. The NMR spectrum, IR spectrum and MS spectrum of the compound are as follows. 1 H-NMR(200MHz, CDCl 3 )δ ppm : 1.14(6H,d), 1.34(3H,t), 2.57(3H,s), 4.23-4.34(3H,m), 4.93(2H,s), 5.76(2H,s), 6.83(1H,d), 7.03(1H,t), 7.22-7.35(2H,m), 7.47(1H,t), 7.77(1H,t), 8.32(1H,d), 8.84(1H,s), 9.18(1H,d). IR(KBr): 1725, 1680, 1640, 1578, 1475 cm -1 . FAB-MS, m/z : 597.1(MH) + Elemental Analysis for C 32 H 28 N 4 O 6 S · 0.8H 2 O C(%) H(%) N(%) Calcd. 62.89 4.88 9.16 Found 63.14 4.67 8.88 [Reference Example 14] Using compounds referred to in Reference Example 12, the method described in Reference Example 13 was repeated. The compounds represented by the chemical formula (14), thus obtained, were collectively listed In the following Table 9. Ref.Ex.14 Cpd.No. 1-substit. ( R 1 ) 7-substit. ( R 5 ) Yield (%) m.p. (°C) 1 2,3-dimethoxybenzyl isopropyl 71 258-259 2 2,3,4-trimethoxybenzyl -do.- 72 209-210 [Example 1 ] Production of ethyl [2,4(1H,3H)-dioxo-6-ethoxycarbonyl-7-methyl-1- (2-methoxybenzyl)-5-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine ]-3-acetate (chemical formula 15) The compound (2.1 g, 6.3 mmol.) obtained in Reference Example 4 was heated for 130 hours under reflux in ethanol (40 ml) together with p-anlsaldehyde (0.81 g, 6.0 mmol.) and ethyl acetoacetate (0.79 g, 6.1 mmol.). The reaction mixture was cooled, then the solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography to give 2.6 g (yield 70%) of a yellow amorphous product. The amorphous compound (2.3 g, 4.1 mmol.) was dissolved in acetic acid (50 ml), to which was added sodium nitrite (2.0 g). The mixture was stirred for one hour at room temperature. The reaction mixture was poured into ice-water, which was subjected to extraction with ethyl acetate (100 ml each, twice). The organic layer was dried, and then the solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography to give 1.8 g (yield 77%) of a yellow oily product. The NMR spectrum of this product was as follows. 1 H-NMR(200MHz, CDCl 3 ) δ ppm: 0.97(3H,t), 1.22(3H,t), 2.51(3H,s), 3.84(3H,s), 3.90(3H,s), 3.98(2H,q), 4.15(2H,q), 4.71(2H,s), 5.65(2H,s), 6.75-7.61(8H,m). [ Example 2 ] Using suitable aldehyde Instead of p-anisaldehyde and ethyl isobutyryl acetate or ethyl acetoacetate, the method described in Example 1 was repeated to give corresponding compounds of chemical formula 16, which were listed in Table 10. Ex.2 Cpd. No. 5-substit. 6-substit. 7-substit. Yield (%) m.p (°C) 1 2-methoxyphenyl ethoxycarbonyl methyl 44 powder 2 2-tolyl -do.- -do.- 76 -do. - 3 2-bromophenyl -do.- -do.- 48 -do.- 4 2-nitrophenyl -do.- -do.- 59 -do. - 5 3-methoxyphenyl -do.- -do.- 67 -do.- 6 3-tolyl -do.- -do.- 43 -do.- 7 3-bromophenyl -do.- -do.- 58 -do.- 8 3-nitrophenyl -do.- -do.- 35 -do.- 9 3-cyanophenyl -do.- -do.- 55 -do.- 10 4-tolyl -do.- -do.- 73 -do.- 11 4-bromophenyl -do.- -do.- 55 -do.- 12 4-nitrophenyl -do.- -do.- 73 -do.- 13 4-biphenyl -do.- -do.- 61 -do.- 14 1-naphthyl -do.- -do.- 43 -do.- 15 2-naphthyl -do.- -do.- 22 -do.- 16 4-pyridyl -do.- -do.- 68 -do.- 17 3-pyridyl -do.- -do.- 69 -do.- 18 2-pyridyl -do.- -do.- 28 -do.- 19 6-methyl-2-pyridyl -do.- -do.- 38 -do.- 20 3-quinolinyl -do.- -do.- 34 -do.- 21 4-quinolinyl -do.- -do.- 58 -do.- 22 2-thienyl -do.- -do.- 50 -do.- 23 3-thienyl -do.- -do.- 44 -do.- 24 3-methyl-2-thienyl -do.- -do.- 44 -do.- 25 5-methyl-2-thienyl -do.- -do.- 63 -do.- 26 3-qunolyl -do.- isopropyl 33 -do.- 27 3,4-dimethoxyphenyl -do.- -do.- 47 -do.- 28 4-methoxyphenyl -do.- isobutyl 12 -do.- 29 -do.- -do.- phenyl 27 -do.- 30 -do.- cyclopentyloxycarbonyl isobutyl 58 -do.- 31 3,4-dimethoxyphenyl ethoxycarbonyl isopropyl 37 -do.- 32 3,3-methylenedioxyphenyl -do.- -do.- 52 -do.- [Example 3 ] Production of t-butyl [2,4(1H,3H)-dioxo-6-(2-cyanoethoxycarbonyl)-7-isopropyl-1-(2-methoxybenzyl)-5-(2-quinolyl)pyrido[2,3-d]pyrimidine]-3-acetate (chemical formula 17) The compound (1.0 g, 1.9 mmol.) obtained in Reference Example 9 was stirred for 40 minutes at room temperature in dimethylformamide (5 ml) together with tert-butyl bromoacetate (0.88 ml, 5.6 mmol) and potassium carbonate(0.76g, 5.6 mmol). The reaction mixture was adjusted to pH ranging from 1 to 2 with 1N HCl, which was subjected to distribution to ethyl acetate and water. The organic layer was dried, then the solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography to give 0.51 g (yield 41%) of a yellow amorphous product. The elemental analysis values of the compound thus obtained were shown in Table 11. The NMR spectrum and IR spectrum of the compound are as follows. Elemental Analysis for C 37 H 37 N 5 O 7 C(%) H(%) N(%) Calcd. 66.96 5.62 10.55 Found 66.77 5.74 10.51 1 H-NMR(200MHz, CDCl 3 ) δ ppm : 1.15(6H,d), 1.40(9H,s), 2.14(2H,t), 3.15(1H,m), 3.90(2H,s), 3.94(2H,t), 4.59(2H,s), 5.69(2H,s), 7.22(1H,td), 7.54(1H,d), 7.60(1H,td) 7.73(1H,td), 7.88(1H,d), 8.04(1H,d), 8.22(1H,d). IR(KBr): 3452, 2976, 2938, 2364, 2258, 1742, 1721, 1678, 1603, 1574 cm -1 . [ Example 4 ] Using the corresponding compound for starting material, the method described in Example 3 was repeated to give compounds of chemical formula 18, which were listed in Table 12. [Example 5] Production of ethyl [2,4(1H,3H)-dioxo-6-(2-cyanoethoxycarbonyl)-7-isopropyl-5-(2-quinolyl)pyrido[2,3-d]pyrimidine]-3-acetate ( Chemical Formula 19 ) The compound (Compound No.10; 10.0 g, 15.0 mmol.) obtained in Example 4 was dissolved in aceton-water(1:1 v/v, 600 ml). To the solution was added cerium(IV)ammonium nitrate(24.7g, 45.0 mmol), and the mixture was stirred for one hour at room temperature. The reaction mixture was concentrated into 1/2 volume, and the residue was subjected to extraction with ethyl acetate. The organic layer was dried (with Na 2 SO 4 ), and the solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography to give 4.59 g (yield 46%) of yellow powdery products. The elemental analysis values were shown in Table 13. The NMR spectrum and IR spectrum of thus obtained compound are as follows. Elemental Analysis for C 27 H 25 N 5 O 6 · 0.5H 2 O C(%) H(%) N(%) Calcd. 61.82 4.99 13.35 Found 61.88 5.23 12.64 1 H-NMR(200MHz, CDCl 3 ) δ ppm 1.21(3H,t), 1.35(6H,d), 2.17(2H,t), 3.25(1H,m), 3.97(2H,t), 4.15(2H,q), 4.61(2H,s), 7.53(1H,d), 7.61(1H,t), 7.74(1H,t), 7.89(1H,d), 8.05(1H,d), 8.23(1H,d), 8.56(1H,s). IR(KBr): 3424, 3264, 2976, 2362, 1734, 1680, 1620, 1578, 1504 cm -1 . [Example 6] Production of ethyl [2,4(1H,3H)-dioxo-6-(2-cyanoethoxycarbonyl)-7-isopropyl-5-(2-quinolyl)pyrido[2,3-d]pyrimidine]-3-acetate ( Chemical Formula 20 ) The solution of the compound (Compound No.10; 9.1 g, 13.7 mmol.) obtained in Example 4 in trifluoroaceticacid (50 ml) was stirred for 4 hours at 60 °C. The reaction mixture was concentrated to remove trifluoroacetic acid, and the residue was subjected to distribution in ethyl acetate-aqueous solution of sodium chloride. The organic layer was dried (with MgSO 4 ), and the solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography to give 6.47 g (yield 92%) of yellow powdery products. [Example 7] Using the compound obtained in Example 4( Compound No.12) , the method described in Example 5 was repeated to give the compound represented by the Chemical Formula 21 ). [Example 8] Production of ethyl [2,4(1H,3H)-dioxo-6-(2-cyanoethoxycarbonyl)- 7-isopropy-1-methyl-5-(2-quinolyl )pyrido[2,3-d]pyrimidine]-3-acetate ( Chemical Formula 22 ) The compound (1.78 g, 3.5 mmol.) obtained in Example 5, methyl iodide(0.98g, 6.9 mmol) and pottasium crbonate(1.42g, 10.4 mmol) were dissolved In dimethylformamide(70 ml). To the solution was added 1N HCl, and was subjected to distribution in ethyl acetate-water. The organic layer was dried (with Na 2 SO 4 ), and the solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography to give 1.42 g (yield 78%) of yellow bubbly products. The elemental analysis values were shown in Table 14. The NMR spectrum and IR spectrum of thus obtained compound are as follows. Elemental Analysis for C 28 H 27 N 5 O 6 · 0. 1 H 2 O C(%) H(%) N(%) Calcd. 63.12 5.10 13.23 Found 63.29 5.15 13.18 1 H-NMR(200MHz, CDCl 3 ) δ ppm : 1.21(3H,t), 1.39(6H,d), 2.14(1H,t), 3.30(1H,m), 3.82(3H,s), 3.96(2H,t), 4.15(2H,q), 4.65(2H,s), 7.50(1H,d), 7.59(1H,t), 7.73(1H,t), 7.88(1H,d), 8.03(1H,d), 8.21(1H,d). IR(KBr): 3452, 2974, 2364, 1742, 1719, 1673, 1620, 1601, 1574, 1506 cm -1 . [Example 9] Using the corresponding compounds as starting material, the method described in Example 8 was repeated to give the compound represented by the Cemical Formula (23), which has various 1-position substituents. Compounds thus obtained were collectively shown in the following Table 15. Ex.9 Cpd.No. 1-substituent ( R 1 ) Yield (%) m.p. ( °C) 1 2-quinolylmethyl 97 powder 2 2-methoxyphenetyl 92 -do.- 3 3-indoleethyl 62 -do.- [Exampl 10] Production of 2,4(1H,3H)-dioxo-6-ethoxycarbonyl-7-isopropy 1-1-(2- methoxbenzyl)-5-(4-tolyl)pyrido[2,3-d]pyrimidine-3-acetic acid ( Chemical Formula 24 ) The compound (0.13 g, 0.24 mmol.) obtained in Reference Example 7 was dissolved in acetic acid (20 ml). To the solution was added sodium nitrite (0.1 g), and the mixture was stirred for one hour at room temperature. The reaction mixture was poured into ice-water, which was subjected to extraction with ethyl acetate (20 ml each, three times). The organic layer was dried, and the solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography. Crude crystals thus obtained were recrystallized from ethyl acetate - isopropyl ether (1:2) to give 0.06 g (yield 54%) of yellow powdery crystals, m.p.190-192 °C (decomp.). The elemental analysis values were shown in Table 16. The NMR spectrum and IR spectrum of thus obtained compound are as follows. Elemental Analysis for C 30 H 31 N 3 O 7 · 2H 2 O C(%) H(%) N(%) Calcd. 61.95 6.07 7.22 Found 61.77 5.80 7.12 1 H-NMR(200MHz, CDCl 3 ) δ ppm : 0.89(3H,t), 1.08(6H,d), 2.25(3H,s), 2.9-3.1(1H,m), 3.41(3H,s), 3.90(2H,q), 4.41(2H,s), 5.53(2H,s), 6.6-7.2(8H,m). IR(KBr): 3456, 1717, 1671, 1562, 1518, 1495, 1466, 1386, 1371, 1305, 1247 cm -1 . [Example 11] Using compounds reffered to in Reference Example 8, the method described in Example 10 was repeated. The compounds thus obtained( Chemical Formula 25) were listed in Table 17. Ex.11 Cpd.No. 5-substit. (QR 3 ) 6-substit. (R 4 ) 7-substit. (R 5 ) Yield (%) m.p. ( °C ) 1 phenyl isopropoxycarbonyl methyl 50 215- 220 2 4-cyclohexylphenyl ethoxycarbonyl isopropyl 55 powder 3 -do.- -do.- methyl 38 -do.- 4 4-cyanophenyl -do.- -do.- 46 155-158 [Example 12] Production of 2,4(1H,3H)-dioxo-6-ethoxycarbonyl-7-methyl-1-(2-methoxybenzyl)-5-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine-3-acetic acid ( Chemical Formula 26 ) The compound (Compound No. 10 :1.5 g, 2.6 mmol.) obtained in Example 2 was dissolved in methanol (30 ml), to which was added a 2N aqueous solution of sodium hydroxide (2.6 ml), and the mixture was stirred for 20 hours at room temperature. The reaction mixture was concentrated under reduced pressure. The concentrate was adjusted to pH ranging from 2 to 3 with 1N HCl, which was subjected to extraction with ethyl acetate. The extract was purified by means of a silica gel columnchromatography to give crude crystals, followed by recrystallization from isopropyl alcohol to give 0.63 g (yield 46%) of yellow powdery crystals, m.p. 190-192 °C. Elemental analysis of the product is shown in Table 18. The NMR spectrum and IR spectrum of the compound were as follows. Elemental Analysis for C 28 H 27 N 3 O 8 · 2.25H 2 O C(%) H(%) N(%) Calcd. 58.58 5.53 7.32 Found 58.73 5.22 7.31 1 H-NMR(200MHz, CDCl 3 ) δ ppm : 0.88(3H,t), 2.39(3H,s), 3.79(3H,s), 3.89(3H,s), 3.92(2H,q), 4.18(2H,s), 5.47(2H,s), 6.78(1H,t), 6.68(1H,d), 6.91(2H,d), 7.01(1H,d), 7.06(2H,d), 7.20(1H,t). IR(KBr): 3450, 1717, 1669; 1609, 1564, 1518, 1483, 1381, 1278, 1247cm -1 . [Example 131 Using compounds reffered to in Example 2 (except Compound No.19), Example 7 and Example 9, the method described in Example 12 was repeated. Compounds thus obtained (Chemical Formula 27 ) are listed in Table 19. Exp.13 Cpd.No. 1-substit. (R 1 ) 5-substit. (QR 3 ) 7-substit. (R 5 ) Yield (%) m.p. (°C ) 1 2-methoxy-benzyl 2-methoxyphenyl methyl 44 powder 2 -do.- 2-tolyl -do.- 45 -do.- 3 -do.- 2-bromophenyl -do.- 65 214-216 4 -do.- 2-nitrophenyl -do.- 44 212-214 5 -do.- 3-methoxyphenyl -do.- 51 192-194 6 -do.- 3-tolyl -do.- 54 powder 7 -do.- 3-bromophenyl -do.- 51 214-216 8 -do.- 3-nitrophenyl -do.- 66 224-226 9 -do.- 3-cyanophenyl -do.- 61 226-228 10 -do.- 4-methoxyphenyl -do.- 46 powder 11 -do.- 4-tolyl -do.- 35 204-206 12 -do.- 4-bromophenyl -do.- 62 208-210 13 -do.- 4-nitrophenyl -do.- 55 powder 14 -do.- 4-biphenyl -do.- 63 -do.- 15 -do.- 1-naphthyl -do.- 36 206-208 16 -do.- 2-naphthyl -do.- 89 powder 17 -do.- 4-pyridyl -do.- 64 -do.- 18 -do.- 3-pyridyl -do.- 53 -do.- 19 -do.- 6-methyl-2-pyridyl -do.- 93 -do.- 20 -do.- 3-quinolyl -do.- 79 -do.- 21 -do.- 4-quinolyl -do.- 66 -do.- 22 -do.- 2-thienyl -do.- 53 202-204 23 -do.- 3-thienyl -do.- 53 powder 24 -do.- 3-methyl-2-thienyl -do.- 48 -do.- 25 -do.- 5-methyl-2-thienyl -do.- 71 -do.- 26 hydrogenatom 2-quinolyl isopropyl 55 135-137 27 2-quinolylmethyl -do.- -do.- 57 > 300 28 2-methoxyphenyl -do.- -do.- 100 163-164 29 3-indolethyl -do.- -do.- 73 210-212 [Example 14] Production of 2,4(1H,3H)-dioxo-6-carboxy -7-isopropyl-1-(2-methoxybenzyl)-5-(2-quinolyl )pyrido[2,3-d]pyrimidine-3-acetic acid ( Chemical Formula 28 ) The compound (Compound No.5 :0.20 g, 0.31 mmol.) obtained in Example 4 was dissolved in the mixture of methanol (1.0 ml) and 1,4-dioxane (2.0 ml) to which was added a 1N aqueous solution of sodium hydroxide (0.63 ml, 1.3 mmol), and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was adjusted to pH ranging from 1 to 2 with 1N HCl, which was subjected to distribution to ethyl acetate and water. The organic layer was washed by a saturated aqueous solution of sodium chloride, and dried, then the solvent was distilled off under reduced pressure. The residue was recrystallized from isopropyl ether to give 0.12 g (yield 71%) of pale yellow powdery crystals, m.p. over 300 °C. Elemental analysis of the product is shown in Table 20. The NMR spectrum and IR spectrum of the compound were as follows. Elemental Analysis for C 30 H 26 N 4 O 7 · 0.75H 2 O C(%) H(%) N(%) Calcd. 63.43 4.88 9.86 Found 63.45 4.66 9.73 1 H-NMR(200MHz, DMSO-d 6 ) δ ppm : 1.05(6H,d), 3.19(1H,m), 3.90(3H,s), 4.47(2H,s), 5.55(2H,s), 6.83(1H,t),6.93(1H,d),7.05(1H,d), 7.24(1H,dd), 7.52(1H,d), 7.65(1H,dd), 7.77(1H,dd), 7.93(1H,d), 8.02(1H,dd), 8.32(1H,d), 12.97(2H,br). IR(KBr): 3430, 2980, 1715, 1671, 1576, 1493, 1464cm -1 . [Example 15] Using compounds reffered to in Example 4, the method described in Example 14 was repeated. Compounds thus obtained (Chemicl Formula 29 ) are listed in Table 21. Ex.15 Cpd.No. 1-substit. ( R 1 ) n 5-substit. ( QR 3 ) Yield (%) m.p. ( °C ) 1 2-methoxybenzylyl 1 4-tolyl 53 245-247 2 -do.- 1 4-methoxyphenyl 71 123-125 3 -do.- 3 -do.- 84 150-152 4 2,4-di-methoxybenzyl 1 2-quinolyl 61 274-282 5 2-methoxyphenethyl 1 -do.- 84 292-293 6 methyl 1 -do.- 75 259-260 7 2-methoxybenzyl 1 2-benzofuranyl 90 248-249 8 -do.- 1 3-methyl-2-benzothienyl 85 144-145 9 -do.- 1 3-quinolyl 61 203-204 [Example 16] Production of t-butyl [2,4(1H,3H)-dioxo-6-carboxy-7-isopropyl-1 -(2-methoxybenzyl)-5-(2-quinolyl )pyrido[2,3-d]pyrimidine] -3-acetate ( Chemical Formula 30 ) The compound ( 2.9 g, 4.3 mmol.) obtained in Example 3 was dissolved in the mixture of methanol (130 ml) and water (17 ml), to which was added a 2N aqueous solution of potassium carbonate (8.6 ml, 8.6 mmol), and the mixture was stirred for 1 hour at room temperature. The reaction mixture was adjusted to pH ranging from 2 to 3 with 1N HCl, which was subjected to distribution to ethyl acetate and water. The organic layer was washed by a saturated aqueous solution of sodium chloride, and dried, then the solvent was distilled off under reduced pressure. The residue was was purified by means of a silica gel columnchromatography to give 2.3 g (yield 87%) of yellow powdery crystals, m.p. over 300 °C. Elemental analysis of the product is shown in Table 22. The NMR spectrum and IR spectrum of the compound were as follows. 1 H-NMR(200MHz, DMSO-d 6 ) δ ppm 1.05(6H,d), 1.34(9H,s), 3.19(1H,m), 3.90(3H,s), 4.45(2H,s), 5.54(2H,s), 6.83-6.92(2H,m), 7.06(1H,d), 7.24(1H,td), 7.53(1H,d), 7.65(1H,t), 7.77(1H,t), 7.94(1H,d), 8.04(1H,d), 8.33(1H,d). IR(KBr): 3454, 2972, 2928, 2366, 1719, 1678, 1605, 1572, 1495cm -1 . Elemental Analysis for C 34 H 34 N 4 O 7 · 0.25H 2 O C(%) H(%) N(%) Calcd. 66.38 5.65 9.11 Found 66.30 5.61 8.92 [Example 17] Using compounds reffered to in Example 4 and others, the method described in Example 16 was repeated. Compounds thus obtained (Chemicl Formula 31 ) are listed in Table 23. [ Example 18 ] Production of t-butyl [2,4(1H,3H)-dioxo-6-carboxy-7-isopropyl-1-(2-methoxbenzyl)-5-[2-(4-quinolonyl)]pyrido[2,3-d]pyrimidine]-3-acetate ( Chemical Formula 32 ) The compound (500 mg, 0.82 mmol.) obtained in Example 16 was dissolved in dichloromethane (20 ml). To the solution was added thionyl chloride (0.60 ml, 8.20 mmol), and the mixture was heated for 30 minutes under reflux. The reaction mixture was cooled and concentrated. The residue was dissolved in dimethylacetamide (40 ml) and stirred with 2N aqueous solution of potassium carbonate for 22 hours at 90°C. After cooling, the reaction mixture was poured into ice-water and was adjusted to pH ranging from 1 to 2 with 1N HCl,which was subjected to extraction with ethyl acetate (150 ml ). The organic layer was washed by a saturated aqueous solution of sodium chloride, and dried, then the solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel columnchromatography to give 190 mg (yield 37%) of pale brown powder. The powder thus obtained were recrystallized from mixed solvent of iso-propanol and isopropyl ether to give 40 mg (yield 8%) of pale brown powdery crystals, m.p. more than 300 °C. The elemental analysis values were shown in Table 24. The NMR spectrum and IR spectrum of thus obtained compound are as follows. 1 H-NMR(200MHz, DMSO-d 6 ) δ ppm : 0.97(3H,d), 1.07(3H,d), 1.33(9H,s), 3.46(1H,m), 3.90(3H,s), 4.48(2H,s), 5.52(2H,q), 5.92(1H,s), 6.80(2H,s), 7.04(1H,d), 7.22(1H,td), 7.28(1H,t), 7.44(1H,d),7.58(1H,td), 8.10(1H,d), 11.81(1H,s). IR(KBr): 3452, 2974, 1717, 1673, 1638, 1601, 1570, 1510, 1473, cm -1 . Elemental Analysis for C 34 H 34 N 4 O 7 · 3.0HCl · 2.0H 2 O C(%) H(%) N(%) Calcd. 52.89 5.35 7.26 Found 52.71 5.16 7.22 [Example 19] Using compounds reffered to in Example 17 and others, the method described in Example 18 was repeated. Compounds thus obtained (Chemicl Formula 33 ) are listed in Table 25. Ex.19 Cpd. No. 1-substit. ( R 1 ) n ( R 2 ) 7-subs tit. ( R 5 ) Yield (%) m.p. ( °C) 1 2-methoxybenzylyl 1 T-butyl methyl 33 > 300 2 -do.- 1 ethyl isopropyl 72 > 300 3 -do.- 3 -do.- -do.- 25 264-266 4 -do.- 1 t-butyl phenyl 51 > 300 5 2,4-dimethoxybenzyl 1 ethyl isopropyl 14 > 300 6 -do.- 1 t-butyl -do.- 20 228-230 7 methyl 1 ethyl -do.- 81 259-261 8 3-methoxybenzyl 1 -do.- methyl 56 280-283 9 2-methoxybenzyl 1 t-butyl 3,4-methylenedioxyphenyl 50 > 300 10 -do.- 1 ethyl normal propyl 41 149-150 11 -do.- 1 -do.- isobutyl 63 283-285 12 -do.- 1 -do.- ethyl 19 > 300 13 2-methoxyphenyl 1 -do.- isopropyl 60 > 300 [Example 20] Production of 2,4(1H,311)-dioxo-6-carboxy -7-isopropyl-1-(2-methoxybenzyl)-5-[2-(4-quinolonyl)pyrido[2,3-d]pyrimidine-3-acetic acid ( Chemical Formula 34 ) The compound (compound No.2: 0.19 g, 0.32 mmol.) obtained in Example 19 was dissolved in the mixture of methanol (2.0 ml) and tetrahydrofuran (2.0 ml), to which was added a 1N aqueous solution of sodium hydroxide (0.64 ml, 1.3 mmol), and the mixture was stirred for 5 hours at room temperature. The reaction mixture was adjusted to pH ranging from 1 to 2 with 1N HCl, which was subjected to extraction with mixed solvent of ethyl acetate and tetrahydrofuran. The organic layer was washed by a saturated aqueous solution of sodium chloride, and dried, then the solvent was distilled off under reduced pressure. The residue was recrystallized from mixed solvent of methanol and isopropyl ether to give 0.08 g (yield 44%) of colorless powdery crystals, m.p. over 300 °C. Elemental analysis of the product is shown in Table 26. The NMR spectrum and IR spectrum of the compound were as follows. 1 H-NMR(200MHz, DMSO-d 6 ) δ ppm : 1.01(3H,d), 1.13(3H,d), 3.18(1H,m), 3.90(3H,s), 4.55(2H, q), 5.53(2H, q), 5.92(1H,s), 6.81-6.94(2H,m), 7.04(1H,d), 7.24(1H,t), 7.35(1H,t), 7.47(1H,d), 7.65(1H,t), 8.12(1H,d), 11.90(1H,s), 13.0(1H,brs). IR(KBr): 3444, 2974, 1719, 1676, 1574, 1493 cm -1 . Elemental Analysis for C 30 H 26 N 4 O 7 · 0.5 H 2 O C(%) H(%) N(%) Calcd. 62.17 4.70 9.67 Found 62.13 4.70 9.41 [Example 21] Using compounds reffered to in Example 19 and others, the method described in Example 20 was repeated. Compounds thus obtained (Chemicl Formula 35 ) are listed in Table 27. [Exampl 22] Production of t-butyl [2,4(1H,3H)-dioxo-6-ethoxycarbonyl-7-isopropyl-1-(2-methoxbenzyl)-5-[2-(4-quinolonyl)]pyrido[2,3-d]pyrimidine]-3-acetate ( Chemical Formula 36 ) The compound (0.35 g, 0.56 mmol.) obtained in Example 18 was stirred with ethyl iodide (0.10 g, 0.91 mmol) in dimethylformamide (5.0 ml) for one hour at room temperature. The reaction mixture was adjusted to pH ranging from 1 to 2 with 1N HCl, and was subjected to distribution in ethyl acetate and water. The organic layer was dried, then the solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel columnchromatography to give 0.18 g (yield 49%) of a pale brown amorphous product. The elemental analysis values of the compound thus obtained were shown in Table 28. The NMR spectrum and IR spectrum of the compound are as follows. Elemental Analysis for C 36 H 38 N 4 O 8 · 0.75 H 2 O C(%) H(%) N(%) Calcd. 64.71 5.96 8.38 Found 64.63 5.71 8.32 1 H-NMR(200MHz, CDCl 3 )δ ppm : 0.98(3H,t), 1.08(3H,d), 1.19(3H,d), 1.42(9H,s), 3.15(1H,m), 3.88(3H,s), 4.09(2H,t), 4.61(2H,q ), 5.64(2H,q ), 6.16(1H,s), 6.79-7.01(3H,m), 7.18-7.37(3H,m), 7.59(1H,td), 8.33(1H,dd). IR(KBr): 3450, 2978, 2936, 1721, 1682, 1638, 1605, 1574, 1510, 1460 cm -1 . [Example 23] Production of 2,4(1H,3H)-dioxo-6-ethoxycarbonyl-7-isopropyl-1 -(2-methoxybenzyl)-5-[2-(4-quinolonyl)] pyrido[2,3-d]pyrimidine-3-acetic acid ( Chemical Formula 37 ) The compound (0.15 g, 0.23 mmol.) obtained in Example 22 was dissolved in dichloromethan and was stirred with trifuluoroacetic acid for 1 hour at room temperature. The reaction mixture was distilled off under reduced pressure. The residue was recrystallized from mixed solvent of isopropyl alkohol and isopropyl ether to give 0.12 g (yield 86%) of pale yellow powdery crystals, m.p. 214-216 °C. Elemental analysis of the product is shown in Table 29. The NMR spectrum and IR spectrum of the compound were as follows. Elemental Analysis for C 32 H 30 N 4 O 8 · 0.5 H 2 O C(%) H(%) N(%) Calcd. 60.46 4.69 8.55 Found 60.14 4.93 8.80 1 H-NMR(200MHz, DMSO-d 6 ) δ ppm : 0.79(3H,t), 0.99(3H,d), 1.13(3H,d), 3.10(1H,m), 3.89(3H,s), 4.00(2H,t), 4.55(2H,q), 5.53(2H,q), 5.92(1H,s), 6.79-6.92(2H,m), 7.05(1H,d), 7.24(1H,t), 7.37(1H,t), 7.49(1H,d), 7.68(1H,t), 8.13(1H,d), 12.18(1H,br). IR(KBr): 3444, 2972, 2936, 1719, 1680, 1603, 1574, 1492, 1462 cm -1 . [Example 24] Using compounds wherein the substituent at 3-position is -CH 2 COO(t-C 4 H 9 ). the method described in Example 23 was repeated. Compounds thus obtained (Chemicl Formula 38 ) are listed in Table 30. [Example 25] Production of ethyl [2,4(1H,3H)-dioxo-6-isobutoxycarbonyl-7-isopropyl-1 -(2-methoxybenzyl)-5-(2-quinolyl)pyrido[2,3-d]pyrimidine]-3-acetate ( Chemical Formula 39 ) The compound (compound No. 1: (0.26 g, 0.44mmol.)obtained in Example 17 was dissolved in dimethylformamide and was stirred with with isobutylbromide(0.14 ml, 1.31 mmol) and potassium carbonate(0.19 g, 1.36 mmol) for 24 hours at room temperature. The reaction mixture was adjusted to pH ranging from 1 to 2 with 1N HCl, and was subjected to distribution in ethyl acetate and water. The organic layer was dried, then the solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel columnchromatography to give 0.21 g (yield 75%) of a colorless amorphous product. Elemental analysis of the product is shown in Table 31. The NMR spectrum and IR spectrum of the compound were as follows. Elemental Analysis for C 36 H 38 N 4 O 7 C(%) H(%) N(%) Calcd. 67.70 6.00 8.77 Found 67.67 6.22 8.59 1 H-NMR(200MHz, CDCl 3 ) δ ppm : 0.66(6H,d), 1.14(6H,d), 1.23(3H,t), 1.55(1H,m), 3.14(1H,m), 3.53(2H,d), 3.91(3H,s), 4.14(2H,q), 4.68(2H,s), 5.69(2H,s), 6.86-7.00(3H,m), 7.21(1H,td), 7.50(1H,d), 7.56(1H,t), 7.71(1H,td), 7.86(1H,d), 8.04(1H,d), 8.19(1H,d). IR(KBr): 3456, 2976, 2968, 1721, 1678, 1574, 1495 cm -1 . [Example 26] Using the compounds obtained in Example 16 and 17, the method described in Example 25 was repeated. The compounds thus obtained( Chemical Formula 40) were listed in Table 32. [Example 27] Production of 2,4(1H,3H)-dioxo-6-isobutoxycarbonyl-7-isopropyl-1 -(2-methoxybenzyl)-5-(2-quinolyl)pyrido[2,3-d]pyrimidine-3-acetic acid ( Chemical Formula 41 ) The compound (0.19 g, 0.30 mmol.) obtained in Example 25 was dissolved in the mixed solvent of methanol (2.0 ml) and tetrahydrofuran (2.0 ml), to which was added a 2N aqueous solution of sodium hydroxide (0.60 ml, 1.2 mmol), and the mixture was stirred for 110 minutes at room temperature. The reaction mixture was adjusted to pH ranging from 1 to 2 with 1N HCl, which was subjected to distribution to ethyl acetate and water. The organic layer was washed by a saturated aqueous solution of sodium chloride, and dried, then the solvent was distilled off under reduced pressure. The residue was recrystallized from mixed solvent of isopropanol and hexane to give 0.11 g (yield 61%) of colorless powdery crystals, m.p. 224-225°C. Elemental analysis of the product is shown in Table 33. The NMR spectrum and IR spectrum of the compound were as follows. 1 H-NMR(200MHz, DMSO-d 6 ) δ ppm : 0.57(6H,d), 1.03(6H,d), 1.38(1H,m), 3.10(1H,m), 3.50(2H,br), 3.90(3H,s), 4.50(2H,s), 5.54(2H,s), 6.83(1H,t), 6.94(1H,d), 7.06(1H,d), 7.24(1H,t), 7.56(1H,d), 7.65(1H,t), 7.78(1H,t), 7.90(1H,d), 8.02(1H,d), 8.34(1H,d). IR(KBr): 3480, 2970, 1717, 1665, 1574, 1466 cm -1 . Elemental Analysis for C 34 H 34 N 4 O 7 · 0.5C 3 H 8 O · 0.5 H 2 O C(%) H(%) N(%) Calcd. 65.17 6,09 8.56 Found 65.04 6.21 8.54 [Example 28] Using the compounds obtained in Example 2 ( Comp.No.27,28 ) and Example 26, the method described in Example 27 was repeated. The compounds thus obtained ( Chemical Formula 42) were listed in Table 34. Ex. 28 Cpd. No. 5-substit. (QR 3 ) 6-substit. (R 4 ) Yield (%) m.p. ( °C ) 1 2-quinolyl isopropoxy-carbonyl 61 224-225 2 -do.- cyclohexyloxy-carbony 75 218-220 3 -do.- cyclohexyl-methoxy-carbonyl 32 116-118 4 -do.- benzyloxy-carbonyl 95 108-110 5 -do.- 2-quinolylmethoxy-carbonyl 16 133-135 6 -do.- carboxymethoxy-carbonyl 93 powder 7 -do.- methoxy-carbonyl 80 > 300 8 -do.- ethoxycarbonyl 86 powder 9 -do.- -do.- 48 155-157 10 3,4-dimethoxy phenyl -do.- 79 135-136 [Example 29] Production of 2,4(1H,3H)-dioxo-6-cyanoethoxycarbonyl-7-isopropyl-1 -(2-methoxybenzyl)-5-(2-quinolyl)pyrido[2,3-d]pyrimidine-3-acetlc acid ( Chemical Formula 43 ) The compound (0.30 g, 0.45 mmol.) obtained in Example 3 was dissolved in dichloromethan(3.0 ml) and was stirred with trifuluoroacetic acid(1 ml) for 4.5 hours at room temperature. The reaction mixture was distilled off under reduced pressure. The residue was purified by means of a silica gel columnchromatography to give 0.31 g of a pale yellow powdery crystals. The crystals were recrystallized from mixed solvent of ethylacetate and hexane to give 0.21 g (yield 78%) of colorless powdery crystals, m.p. 115-116°C. Elemental analysis of the product is shown in Table 35. The NMR spectrum and IR spectrum of the compound were as follows. Elemental Analysis for c 33 H 29 N 5 O 7 :0.5 H 2 O :0.5CF 3 COOH C(%) H(%) N(%) Calcd. 60.62 4.56 10.40 Found 60.86 4.86 9.93 1 H-NMR(200MHz, DMSO-d 6 ) δ ppm : 1.06(6H,d), 2.50(2H,t), 3.78(2H,t), 3.13(1H,m), 3.91(3H,s), 4.50(2H,s), 5.55(2H,s), 6.84(1H,t), 6.95(1H,d), 7.05(1H,d), 7.21(1H,t), 7.59(1H,d), 7.67(1H,t), 7.79(1H,t), 7.97(1H,d), 8.04(1H,d), 8.35(1H,d). IR(KBr): 3438, 2972, 2270, 1719, 1676, 1574, 1495, 1466 cm -1 . [Example 30] Using the compounds obtained in Example 4( Compd.No.1) and Example 26 ( Compd.No.10-12), the method described in Example 29 was repeated. The compounds thus obtained ( Chemical Formula 44) were listed in Table 36. Ex.30 Cpd. No. 5-subs tit. (QR 3 ) 6-substit. (R 4 ) 7-sub stit. (R 5 ) Yield (%) m.p. ( °C) 1 4-tolyl 2-cyanoethoxy carbonyl isopropyl 73 213-215 2 2-quin olyl ethoxycarbonyl methyl 50 112-113 3 -do.- cyclohexyl-methoxy-carbonyl phenyl 90 215-217 4 -do.- benzyloxycarbonyl 3,4-methylendioxyphenyl 97 145-147 [Example 31] Production of ethyl [2,4(1H,3H)-dioxo-6-carboxy-7-isopropyl-1-(2-methylthiobenzyl)-5-[2-(4-quinolonyl)]pyrido[2,3-d]pyrimidine]-3-acetate ( Chemical Formula 45 ) The acetonitrile solution (15 ml) containing the compound (150 mg, 0.25 mmol.) obtained in Reference Example 13, 2N aqueous solution of potassium carbonate( 1.25 ml, 2.50 mmol) and water(1.5 ml) was stirred for 30 minutes at a temperature of 50 °C. To the reaction mixture was added 1N HCl(5 ml), which was subjected to distribution to ethyl acetate and saturated aqueous solution of sodium chloride. The organic layer was dried with MgSO 4 , and then the solvent was distilled off under reduced pressure. The residue was recrystallized from isopropanol to give 83 mg (yield 54%) of colorless powdery product, m.p. 167-170°C. Elemental analysis of the product is shown in Table 37. The NMR spectrum, IR spectrum and MS spectrum of the compound were as follows. 1 H-NMR(500MHz, DMSO-d 6 ) δ ppm : 1.03(6H,d), 1.15(3H,t), 2.59(3H,s), 3.16-3.24(1H,m), 4.11(2H,q), 4.59(1H,d) 4.69(1H,d), 5.53(2H,s), 6.29(1H,s), 6.86(1H,d), 7.09(1H,t) 7.29(1H,t), 7.41(1H,d), 7.50(1H,t), 7.63(1H,d), 7.79(1H,t), 8.21(1H,d), 12.90(1H,bds). IR(KBr): 3428, 1721, 1678, 1574, 1491, 1369 cm -1 . FAB-MS m/z: 615.1(MH + ). Elemental Analysis for C 32 H 30 N 4 O 7 S · 0.5 CHCl 3 C(%) H(%) N(%) Calcd. 57.88 4.56 8.31 Found 57.73 4.51 8.42 [Example 32] Using the compounds obtained In Reference Example 14 the method described In Example 31 was repeated. The compounds thus obtained ( Chemical Formula 46) were listed in Table 38. Ex.32 Cpd. No. 1-substit. (R 4 ) 7-sub stit. (R 5 ) Yield (%) m.p. ( °C) 1 2,3-dimethoxy-benzyl isopropyl 67 245-250 2 2,3,4-trimethoxy-benzyl -do.- 68 158-161 [ Example 33 ] Production of t-butyl [2,4(1H,3H)-dioxo-6-carbamoyl-7-isopropyl-1-(2-methoxbenzyl)-5-[2-(4-quinolonyl)]pyrido[2,3-d]pyrimidine]-3- acetate ( Chemical Formula 47 ) The compound (500 mg, 0.82 mmol.) obtained in Example 16 was dissolved in dichloromethane (20 ml). To the solution was added thionyl chloride (0.60 ml, 8.20 mmol), and the mixture was heated for 30 minutes under reflux. The reaction mixture was cooled and concentrated to dryness. The residue was suspended in a mixed solvent of tetrahydrofuran (5 ml) and dimethylacetamide (20 ml), and then was stirred with 25% aqueous ammonia (10 ml) for 15 minutes at room temperature. The reaction mixture was poured into ice-water and was adjusted to pH ranging from 1 to 2 with 1N HCl, which was then subjected to extraction with ethyl acetate (150 ml ). The organic layer was washed with a saturated aqueous solution of sodium chloride, and dried, then the solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography to give 310 mg (yield 61%) of colorless powder. The powder thus obtained were recrystallized from mixed solvent of iso-propanol and isopropyl ether to give 170 mg (yield 33%) of colorless powdery crystals, m.p. more than 300 °C. The elemental analysis values were shown in Table 39. The NMR spectrum and IR spectrum of thus obtained compound are as follows. 1 H-NMR(200MHz, DMSO-d 6 ) δ ppm : 1.01(3H,d), 1.13(3H,d), 1.37(9H,s), 3.20(1H,m), 3.90(3H,s), 4.53(2H,s), 5.53(2H,s), 6.06(1H,s), 6.83-6.89(2H,m), 7.06(1H,d), 7.23(1H,td), 7.32(1H,t), 7.44(1H,d), 7.63(1H,t), 7.75(1H,br), 7.95(1H,br), 8.11(1H,d), 11.82(1H,br). IR(KBr): 3428, 1721, 1678, 1638, 1605, 1572, 1512, 1475 cm -1 . Elemental Analysis for C 34 H 35 N 5 O 7 · H 2 O C(%) H(%) N(%) Calcd. 63.44 5.79 10.88 Found 63.41 5.80 10.93 [Example 34] Using the compounds obtained in Example 16, the method described in Example 33 was repeated, while employing 70 % aqueous solution of ethylamine in place of 25 % aqueous ammonia. The compound thus obtained ( Chemical Formula 48) was listed in Table 40. Ex.34 Cpd. No. (R 2 ) 5-substit. ( QR 3 ) 6-substit. ( R 4 ) Yield (%) m.p. ( °C) 1 t-butyl 2-(4-quinolonyl) N-ethylcarbamoyl 20 172-173 [ Example 35 1 Production of t-butyl [2,4(1H,3H)-dioxo-6-carboxy-7-isopropyl-1-(2-methoxbenzyl)-5-(quinoline-1-oxide-2-yl)pyrido[2,3-d]pyrimidine]-3-acetate ( Chemical Formula 49 ) The compound (300 mg, 0.49 mmol.) obtained in Example 16 was dissolved in dichloromethane (20 ml). To the solution was added m-chlorobenzoyl hydroperoxide (0.25 g), and the mixture was stirred for 21 hours at room temperature. To the reaction mixture was added Isopropyl ether (80 ml) to give 200 mg (yield 65%) of colorless powdery crystals, m.p. 176-178°C. The elemental analysis values were shown in Table 41. The NMR spectrum and IR spectrum of thus obtained compound are as follows. 1 H-NMR(200MHz, DMSO-d 6 ) δ ppm : 1.07(6H,d), 1.34(9H,s), 3.33(1H,m), 3.90(3H,s), 4.44(2H,s), 5.53(2H,s), 6.79-6.90(2H,m), 7.05(1H,d), 7.24(1H,td), 7.43(1H,d), 7.80-7.97(3H,m), 8.12(1H,d), 8.49(1H,d). IR(KBr): 3445, 2974, 2372, 1719, 1673, 1572, 1460 cm -1 . Elemental Analysis for C 34 H 34 N 4 O 8 · 25 H 2 O C(%) H(%) N(%) Calcd. 62.91 5.67 8.63 Found 62.91 5.42 8.24 [Example 36] Using the compounds obtained in Example 17 (Comp.No.15)the method described in Example 35 was repeated. The compound thus obtained ( Chemical Formula 50) was listed in Table 42. Ex.36 Cpd. No. (R 2 ) 5-substit. ( QR 3 ) Yield (%) m.p. ( °C) 1 ethyl quinoline-1-oxide-3-yl 12 powder [Example 37] Formulation of tablets containing the compound of this invention as effective component (1) Using 100 mg of the compound of compound number 2 in Example 19 of the present invention, 165 mg of lactose, 25 mg of corn starch, 4 mg of polyvinyl alcohol, 5 mg of avicel and 1 mg of magnesium stearate, tablets are prepared by a conventional process. [Example 38] Formulation of tablets containing the compound of this invention as effective component (2) Using 100 mg of the compound of Example 10 of the present invention, 165 mg of lactose, 25 mg of corn starch, 4 mg of polyvinyl alcohol, 5 mg of avicel and 1 mg of magnesium stearate, tablets are prepared by a conventional process. [Example 39] Formulation of tablets containing the compound of this invention as effective component (3) Using 100 mg of the compound of Example 12 of the present invention, 165 mg of lactose, 25 mg of corn starch, 4 mg of polyvinyl alcohol, 5 mg of avicel and 1 mg of magnesium stearate, tablets are prepared by a conventional process. [Example 40] Formulation of tablets containing the compound of this invention as effective component (4) Using 100 mg of the compound of Example 20 of the present invention, 165 mg of lactose, 25 mg of corn starch, 4 mg of polyvinyl alcohol, 5 mg of avicel and 1 mg of magnesium stearate, tablets are prepared by a conventional process. [Example 41] Formulation of tablets containing the compound of this invention as effective component (5) Using 100 mg of the compound of compound number 9 obtained in Example 21 of the present invention, 165 mg of lactose, 25 mg of corn starch, 4 mg of polyvinyl alcohol, 5 mg of avicel and 1 mg of magnesium stearate, tablets are prepared by a conventional process. [Example 42] Formulation of injection containing the compound of this invention as effective component (1) In 15 mg of a 1M aqueous solution of sodium hydroxide is dissolved 5 g of the compound of compound number 2 obtained in Example 19 of the present invention. The solution is adjusted to pH 7.6 with a 0.1 M HCl, to which is added water for injection to make the whole volume 100 ml. This solution is subjected to sterilizing filtration using 0.22 µm membrane filter, which is distributed into sterilized vials in 2 ml each portion, followed by conventional lyophilization to afford lyophilized injections in a form of 100 mg/vial. [Example 43 ] Formulation of injection containing the compound of this invention as effective component (2) In 15 mg of a 1M aqueous solution of sodium hydroxide is dissolved 5 g of the compound of Example 10 of the present invention. The solution is adjusted to pH 7.6 with a 0.1 M HCl, to which is added water for injection to make the whole volume 100 ml. This solution is subjected to sterilizing filtration using 0.22 µm membrane filter, which is distributed into sterilized vials in 2 ml each portion, followed by conventional lyophilization to afford lyophilized injections in a form of 100 mg/vial. [Example 44 ] Formulation of injection containing the compound of this invention as effective component (3) In 15 mg of a 1M aqueous solution of sodium hydroxide is dissolved 5 g of the compound of Example 12 of the present invention. The solution is adjusted to pH 7.6 with a 0.1 M HCl, to which is added water for injection to make the whole volume 100 ml. This solution is subjected to sterilizing filtration using 0.22 µm membrane filter, which is distributed into sterilized vials in 2 ml each portion, followed by conventional lyophilization to afford lyophilized injections in a form of 100 mg/vial. [Example 45 ] Formulation of injection containing the compound of this invention as effective component (4) In 15 mg of a 1M aqueous solution of sodium hydroxide is dissolved 5 g of the compound of Example 20 of the present invention. The solution is adjusted to pH 7.6 with a 0.1 M HCl, to which is added water for injection to make the whole volume 100 ml. This solution is subjected to sterilizing filtration using 0.22 µm membrane filter, which is distributed into sterilized vials in 2 ml each portion, followed by conventional lyophilization to afford lyophilized injections in a form of 100 mg/vial. [Example 46] Formulation of injection containing the compound of this invention as effective component (5) In 15 mg of a 1M aqueous solution of sodium hydroxide is dissolved 5 g of the compound of compound number 9 obtained in Example 21 of the present invention. The solution is adjusted to pH 7.6 with a 0.1 M HCl, to which is added water for injection to make the whole volume 100 ml. This solution is subjected to sterilizing filtration using 0.22 µm membrane filter, which is distributed into sterilized vials in 2 ml each portion, followed by conventional lyophilization to afford lyophilized injections in a form of 100 mg/vial. [Pharmacological Experiment - 1 ] Endothelin Receptor-Assay Endothelin-A receptors was prepared by diluting a fraction of porcine cardiac ventricular muscle membrane with an assay buffer [20 mM Tris-HCl, 2 mM EGTA ( ethyleneglycol bis(2-aminoethylether) tetra acetic acid), 5 mM magnesium acetate, 0.1% BSA (bovine serum albumin), 0.03% NaN 3 , 0.5 mM PMSF(phenyl methyl sulfonyl fluoride), 20µg/ml leupeptin, 4 µg/ml E-64( products of the Peptide Institute ), 1µg/ml pepstatin, (pH 7.2)] to make a solution of the fraction of porcine cardiac ventricular membrane (12 µg/ml). Endothelin-B receptor was prepared by diluting a fraction of bovine cerebral membrane with the same assay buffer as mentioned above to make a solution having a concentration of 180µg/ml. To 100 µl of each portion was added 5 nM[ 125 I] endothelin-1 (2 µl ). A dimethylsulfoxide solution (3 µl) of the sample was added thereto and incubated at 25 °C for 60 minutes. And, to determine the maximum binding amount (B 0 ) and non-specific binding amount (NSB), lots to which a dimethyl sulfoxide solution (3 µl) or a dimethyl sulfoxide solution (3µl) containing endothelin-1 (10 -5 M) was added were also incubated. These lots were supplemented with 0.05% CHAPS(3-[(3-chloroamidopropyl)dimethylammonio]-1-propanesulfonate)-assay buffer (1.5 ml), subjected to filtration through a glass fiber filter GF/F(trade name; product of Wattman Ltd. (England)), and then washed with the same buffer(1.5 ml). Radioactivity on the filter was counted in a gamma-counter to determine the Percent Maximum Binding (PMB) in accordance with the following calculation formula. The concentration causing PMB=50% was determined as IC 50 value. IC 50 values of some of the compounds of this invention, synthesized in the above-mentioned examples, are shown in Table 43. PMB = [(B-NSB) / (B 0 -NSB)] x 100 Compound No. IC 50 value: µM Endothelin-A Receptor (porcine) Endothelin-B Receptor (bovine) Cpd. of Ex.10 11 64 Cpd. of Ex.12 18 130 [Pharmacological Experiment - 2 ] Endothelin Receptor-Assay Endothelin (ET) receptors were prepared by diluting fractions of insect cell (Sf9) membrane having human endothelin-A (ETA) receptors or human endothelin-B (ETB) receptors appeared, with an assay buffer [20 mM Tris-HCI, 2 mM EGTA( ethyleneglycol bis(2-aminoethylether) tetra acetic acid), 5 mM magnesium acetate, 0.1% BSA (bovine serum albumin), 0.03% NaN 3 , 0.5 mM PMSF(phenyl methyl sulfonyl fluoride), 20 µg/ml leupeptin, 4 µg/ml E-64 ( products of the Peptide Institute ), 1µg/ml pepstatin, (pH 7.2)] respectively in a concentration of 1.4 µg/ml in the former case and 0.7µg/ml in the latter case. To 100 µl of each portion was added 5 nM[ 125 I] endothelin-1 (2 µl ). A dimethylsulfoxide solution (3 µl) of the sample was added thereto and incubated at 25 °C for 60 minutes. And, to determine the maximum binding amount (B 0 ) and non-specific binding amount (NSB), lots to which a dimethyl sulfoxide solution (3 µl) or a dimethyl sulfoxide solution (3µl) containing endothelin-1 (10 -5 M) had been added, were also incubated. These lots were supplemented with 0.05% CHAPS(3-[(3-chloroamidopropyl)dimethylammonio]-1-propanesulfonate)-assay buffer (1.5 ml), subjected to filtration through a glass fiber filter GF/F (trade name; product of Wattman Ltd. (England)), and then washed with the same buffer (1.5 ml). Radioactivity on the filter was counted in a gamma-counter to determine the Percent Maximum Binding (PMB) in accordance with the aforesaid calculation formula. The concentration causing PMB=50% was determined as IC 50 value. IC 50 values of some of the compounds of this invention, synthesized in the above-mentioned examples, are shown in Table 44. Compound No. IC 50 value: µM Example No. Compound No. Endothelin-A Receptor (human) Endothelin-B Receptor (human) 10 11 - 12 22 - 14 3.7 67 15 4 0.89 95 16 1.6 69 17 1 0.71 19 18 0.15 69 19 2 0.07 65 19 5 0.98 23 20 0.12 14 21 9 0.056 14 23 0.92 4.3 27 4.5 47 28 8 1.1 76 29 0.57 95 31 0.12 88 According to the result shown in the table 43 and 44, it has been proved that the compound [A] or its salt of this invention have excellent endothelin receptor antagonistic action to both endothelin-A receptor and endothelin-B receptor. The compounds of this invention have an endothelin receptor antagonistic action, which are effective as prophylactic and therapeutic agents against acute renal insufficiency, myocardial infarction, hypertension, cerebral infarction, angina pectoris, arteriosclerosis, hepatopathy, pulmonary hypertension, bronchial asthma, organohypofunction occuring during operation or transplantation of organs.

Claims: A pyrido[2,3-d]pyrimidine derivative represented by the formula: wherein R 1 is a benzyl group optionally substituted by 1 or 2 of C 1-6 alkoxy or C 1-6 alkylthio group; R 2 is a hydrogen atom or a C 1-6 alkyl group; R 3 is i) a phenyl group optionally substituted by a C 1-6 alkyl group or a C 1-6 alkoxy group, or ii) a quinolyl group optionally substituted by an oxo group or hydroxy group; R 4 is COOR 6 wherein R 6 is hydrogen or a C 1-6 alkyl group optionally substituted by cyano; and R 5 is a C 1-6 alkyl group; or its salt. 2,4(1H,3H)-Dioxo-6-ethoxycarbonyl-7-isopropyl-1-(2-methoxybenzyl)-5-(4-tolyl)pyrido[2,3-d]pyrimidine-3-acetic acid or its salt. 2,4(1H,3H)-Dioxo-6-ethoxycarbonyl-7-methyl-1-(2-methoxybenzyl)-5-(4-methoxyphenyl)pyrido[2,3-d]pyrimidine-3-acetic acid or its salt. Ethyl[2,4(1H,3H)-dioxo-6-carboxy-7-isopropyl-1-(2-methoxybenzyl)-5-[2-(4-quinolonyl)]pyrido[2,3-d]pyrimidine]-3-acetate or its salt. 2,4(1H,3H)-Dioxo-6-carboxy-7-isopropyl-1-(2-methoxybenzyl)-5-[2-(4-quinolonyl)]pyrido[2,3-d]pyrimidine-3-acetic acid or its salt. 2,4(1H,3H)-Dioxo-6-carboxy-7-isopropyl-1-(2-methylthiobenzyl)-5-[2-(4-quinolonyl)]pyrido[2,3-d]pyrimidine-3-acetic acid or its salt. A process for producing a pyrido[2,3-d]pyrimidine derivative or its salt, as claimed in Claim 1, which comprises (1) oxidation of a compound or its salt, the compound being represented by the formula (B): wherein each symbol is as defined in Claim 1; (2) reacting a compound or its salt, the compound being represented by the formula (D): wherein each symbol is as defined above, with a halogenated alkylcarboxylate derivative represented by the formula: X-CH 2 -COOR 2 wherein X is halogen atom, and R 2 is as defined above; (3) in case that R 3 is 2-(4-quinolonyl) group and R 4 is carboxy group, oxidation of a compound or its salt, the compound being represented by the formula (E): wherein each symbol is as defined above; (4) reacting a compound or its salt, the compound being represented by the formula (F): wherein each symbol is as defined above, with a halogenated benzyl derivative represented by the formula: R 1 -X 2 wherein X 2 is halogen atom, and R 1 is as defined above; (5) in case that R 3 is 2-(4-quinolonyl) group, reacting a compound or its salt, the compound being represented by the formula (H): wherein each symbol is as defined above, with a nucleophilic reagent capable of incorporating thereinto a substituent represented by the formula: -OR 6 wherein R 6 is as defined above; or (6) in case that R 2 is a hydrogen, hydrolyzing a compound or its salt, the compound being represented by the formula (A): wherein R 2 is a C 1-6 alkyl group, and the other symbols are as defined above. A pharmaceutical composition useful as an endothelin receptor antagonist comprising, as the effective component, at least one compound selected from pyrido[2,3-d]pyrimidine derivative as claimed in Claim 1 or a pharmaceutically acceptable salt thereof. A pharmaceutical as claimed in Claim 8, wherein the endothelin receptor antagonist is used as a therapeutic agent of acute renal insufficiency and/or myocardial infarction. A pharmaceutical as claimed in Claim 8, wherein the endothelin receptor antagonist is used as a therapeutic agent of hypertension, cerebral infarction, angina pectoris, arterial sclerosis, hepatopathy, pulmonary hypertension, bronchial asthma, organohypofunction occurring during operation or transplantation of organs. Use of the pyrido[2,3-d]pyrimidine derivative as claimed in Claim 1 or pharmaceutically acceptable salt thereof, for preparing an endothelin receptor antagonist. Use as claimed in Claim 11, for preparing a therapeutic agent of hypertension, cerebral infarction, angina pectoris, arterial sclerosis, hepatopathy, pulmonary hypertension, bronchial asthma, organohypofunction occurring during operation or transplantation of organs.

Inventors: FURUYA SHUICHI, OHTAKI TETSUYA, FURUYA, SHUICHI, OHTAKI, TETSUYA
Applicants: TAKEDA CHEMICAL INDUSTRIES LTD, TAKEDA CHEMICAL INDUSTRIES, LTD.
Application year: 1993
Main classification: C07D471
IPC codes: A61K31, C07D471, A61P9