DIPHENYL-METHANE DERIVATIVE, PHARMACEUTICAL COMPOSITION AND USE

Abstract: A new diphenyl-methane derivative is useful to inhibit agglomeration of blood and is defined by the formula, including a diphenylethylene derivative and a benzophenone oxime ether derivative. in which R1 and R2 each are hydrogen, hydroxyl or a lower alkoxy, U is =CXY or =N-O-W, X is hydrogen, cyano or -COR6, R6 being hydroxyl or an amino, Y is -R10-COOR3, R3 being hydrogen or a lower alkoxy, R10 being an alkylene having 1 to 3 carbon atoms, straight or branched, -CO-NR4R5, R4 and R5 each being hydrogen, a lower alkyl or a lower arylalkyl, -CH2-NHSO2-C6H5 or -C(R8)=NR7, R7 being a lower alkoxy or an aryl, R8 is -VR9, V being oxygen, sulfur or nitrogen, R9 being an alkyl or an aryl, W is -CH2-CO-CH2-C00R13, R13 being hydrogen or a lower alkyl, -CH2-C(=NOR14)-CH2-COOR15, R15 being hydrogen or a lower alkyl, R14 being a lower alkyl, -CH(CN)-(CH2)q-COOR16, R16 being hydrogen or a lower alkyl, q being an integer of 1 to 3, or -(CH2)p-Z, Z being -SH, -SCN or a monovalent group derived from a five- or six-membered ring which may be substituted by a ring having one or more sulfur atoms in the ring, p being 1 or 2. A pharmaceutical composition containing compounds of formula (XX) or their pharmaceutically acceptable salts as active ingredients, and the use of compounds of for­ mula (XX) or their pharmaceutically acceptable salts in the preparation of a medicament for treatment of diseases caused by blood stream disorders are also disclosed.

Description: The invention relates to a diphenylethylene derivative, a process for preparing the same and the pharmaceutical use thereof. The most serious diseases for mankind at present include acute vascular diseases such as myocardial infarction, cerebral apoplexy, cerebral thrombosis, cerebral infarction, pulmonary embolus, deep phlebothrombosis and peripheral arteriothrombosis. Recently antiplatelet agents have attracted public attention and been clinically employed for treating these diseases. However their application has been only lately realized. Thus it is expected to develop better drugs in future. EP-A-0 124 791 discloses aralkanamido compounds being useful as pharmaceutical agents for ameliorating atherosclerosis. The problem to be solved by the present invention is to provide products showing high activity in the inhibition of agglutination of platelets and low toxicity. The invention provides a diphenylethylene derivative with the formula (I): wherein R¹ and R² are independently from each other hydrogen, hydroxyl or a lower alkoxy group, X is cyano, Y is -R¹⁰-COOR³, wherein R³ is hydrogen or a lower alkyl group, and R¹⁰ is an alkylene group having 1-3 carbon atoms, straight or branched, or a pharmaceutically acceptable salt thereof. In the above definition, a lower alkyl group as mentioned with regard to R³ includes straight-chain or branched alkyl groups carrying one to six carbon atoms, e.g. methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl, 1-methylpropyl, tert-butyl, n-pentyl, 1-ethylpropyl, isoamyl and n-hexyl groups. An alkoxy group as mentioned with regard to R¹ and R² includes any lower alkoxy group derived from the lower alkyl groups as cited above. Among these groups, methyl and ethyl groups are the most desirable lower alkyl groups while a methoxy group is the most desirable lower alkoxy group. A pharmaceutically acceptable salt of the aimed compound wherein R³ is a hydrogen atom includes metal salts such as Na, K, Ca and Mg salts. In a preferred embodiment the substituents R¹ and R² represent lower alkoxy groups, especially methoxy groups. Specifically preferred compounds are 4-cyano-5,5-bis(4-methoxyphenyl)-4-pentenoic acid, methyl 5-cyano-6,6-bis(4-methoxyphenyl)-5-hexenoate and ethyl 4-cyano-5,5-bis(4-methoxyphenyl)-4-pentenoate. In addition, the invention provides a process for preparing the above defined diphenylethylene derivative. This process comprises reacting a diphenylethylene derivative of the formula (I): wherein R¹ and R² are independently from each other hydrogen, hydroxyl or a lower alkoxy group, X is cyano and Y is -R¹⁰-COOR³, wherein R³ is hydrogen or a lower alkyl group, and R¹⁰ is an alkylene group having 1-3 carbon atoms and may have a branched alkyl group, or a pharmaceutically acceptable salt thereof which comprises reacting a ketone of the general formula (VI): wherein R¹ and R² are as defined above, with a halide of the general formula (VII): wherein Hal represents a halogen atom, and R³ and R¹⁰ are as defined above, in the presence of zinc in a Reformatsky reaction to give a hydroxy compound of the formula (VIII): wherein R¹, R², R³ and R¹⁰ are as defined above, followed by dehydration of the hydroxy compound (VIII) thus obtained in a conventional manner, and if necessary conversion of the product to a pharmaceutically acceptable salt. Examples of a solvent available for the Reformatsky reaction are tetrahydrofuran, benzene and ether. Further a solvent mixture comprising, for example, trimethyl borate or triethyl borate with tetrahydrofuan may be employed. This reaction may be usually carried out at a temperature of approximately -70 to 150°C. Examples of the solvent available for the dehydration are benzene, toluene, tetrahydrofuran, ether and dioxane, while examples of the catalyst therefor are p-toluenesulfonic acid, thionyl chloride, phosphorus pentaoxide, iodine and hydrochloric acid. This reaction may be carried out at a temperature of approximately -70 to 150°C. Moreover the invention provides a pharmaceutical composition which comprises a pharmacologically effective amount of the diphenylethylene derivative as defined above or a pharmacologically acceptable salt thereof and a pharmacologically acceptable carrier. In this connection, the invention provides the use of the diphenylethylene derivative as defined above or a pharmacologically acceptable salt thereof in preparing a medicament for treating a disease caused by the blood stream disorder. In order to further illustrate the present invention, typical examples of the compound of the present invention will be given. Each compound will be shown in free form. ethyl 4-cyano-5,5-bis(4-methoxyphenyl)-4-pentenoate, 4-cyano-5,5-bis(4-methoxyphenyl)-4-pentenoic acid, methyl 5-cyano-6,6-bis(4-methoxyphenyl)-5-hexenoate, ethyl 3-cyano-4,4-bis(4-methoxyphenyl)-3-butenoate, ethyl 4-cyano-5,5-bis(4-ethoxyphenyl)-4-pentenoate, methyl 4-cyano-5,5-bis(4-ethoxyphenyl)-4-pentenoate, 4-cyano-5,5-bis(4-ethoxyphenyl)-4-pentenoic acid, 5-cyano-6,6-bis(4-ethoxyphenyl)-5-hexenoic acid, and 3-cyano-4,4-bis(4-ethoxyphenyl)-3-butenoic acid, ethyl 3-cyano-4,4-bis(4-ethoxy- or 4-hydroxy-phenyl)-3-betenoate ethyl 3-cyano-4-(4-methoxyphenyl)-4-(4-ethoxyphenyl)-3-betenoate 3-cyano-4,4-bis(4-methoxyphenyl)-3-butenoic acid 3-cyano-4,4-bis(4-hydroxyphenyl)-3-butenoic acid 3-cyano-4-(4-methoxyphenyl)-4-(4-ethoxyphenyl)-3-butenoic acid ethyl 4-cyano-5,5-bis(4-methoxyphenyl)-4-pentenoate ethyl 4-cyano-5,5-bis(4-hydroxyphenyl)-4-pentenoate ethyl 4-cyano-5-(4-methoxyphenyl)-5- (4-ethoxyphenyl)-4-pentenoate ethyl 4-cyano-5-(4-hydroxyphenyl)-(Z)- or -(E)-5-(4-methoxyphenyl)-4-pentenoate ethyl 4-cyano-5-(4-hydroxyphenyl)-(Z)- or -(E)-5-(4-ethoxyphenyl)-4-pentenoate 4-cyano-5-(4-methoxyphenyl)-5-(4-ethoxyphenyl)-4-pentenoic acid ethyl 4-cyano-2-methyl-5,5-bis(4-methoxy-, 4-ethoxy- or 4-hydroxy-phenyl)-4-pentenoate ethyl 4-cyano-2-methyl-5-(4-methoxyphenyl)-5-(4-ethoxyphenyl)-4-pentenoate 4-cyano-2-methyl-5,5-bis(4-ethoxy- or 4-hydroxy-phenyl)-4-pentenoic acid 4-cyano-2-methyl-5-(4-methoxyphenyl)-5-(4-ethoxyphenyl)-4-pentenoic acid methyl 5-cyano-6,6-bis(4-ethoxy- or 4-hydroxy-phenyl)-5-hexenoate methyl 5-cyano-6-(4-methoxyphenyl)-6-(4-ethoxyphenyl)-5-hexenoate 5-cyano-6,6-bis(4-methoxy- or 4-hydroxy-phenyl)-5-hexenoic acid 5-cyano-6-(4-methoxyphenyl)-6-(4-ethoxyphenyl)-5-hexenoic acid The diphenylethylene derivative of the invention exhibits an excellent effect from the pharmacological point of view. It effectively inhibits the agglutination of platelets and eventually is useful for a remedy of an antiplatelet and antithrombotic agent. In particular, it is useful for treating and/or preventing cerebrovascular diseases such as transient ischemic attack (TIA), cerebral infarction (thrombus and embolus) and cerebral arteriosclerosis; postoperative thrombus, embolus and blood stream disorders accompanying vascular operation and extracorporeal circulation; chronic arterial obstructions such as Buerger's disease, obstructive arteriosclerosis, peripheral arteriosclerosis, SLE and Raynaud's disease; and ischemic cardial diseases such as stenocardia and myocardial infarction. It is further useful for preventing recurrence of these diseases and for improving prognosis thereof. The effect of the invention product will be supported by the below given pharmacological tests, first about the diphenylethylene derivative. Test Example 1. Effect of inhibiting aggulutination of platelets (in vitro) The blood was collected from a human cubital vein in such a manner as to contain a 3.8% solution of sodium citrate in an amount 1.10 time by volume as much as the blood. Then platelet-rich plasma (PRP) was prepared therefrom according to the method reported by Packham et al. (cf. Packham, M.A., et al, J. Exp. Med., 126 , 171 - 189 (1967)). To 0.2 ml of the obtained PRP, 25 µl portions of solutions of each compound of the present invention (A to C) at various concentrations were added and incubated at 37°C for three minutes. Then the agglutination of platelets was induced with arachidonic acid, collagen, ADP and PAF. The agglutination of platelets was evaluated according to the method reported by Mustard et al. (cf. Mustard, J.F., et al., J. Lab. Clin. Med., 64 , 548 - 559 (1964) with the use of an aggregometer available from Schenko or Niko Bioscience Co. In other words, this test is carried out to examine the effect on platelet aggregation (in vitro). Table 1 shows the result. Test Cpd. Effect of inhibiting collagen agglutination I C₅₀(µM) Effect of inhibiting arachidonic acid agglutination I C₅₀(µM) Effect of inhibiting ADP agglutination I C₅₀(µM) Effect of inhibiting PAF agglutination I C₅₀(µM) Cpd. A (Ex. 1) 0.2 0.07 0.2 1.8 Cpd. B (Ex. 2) 1.7 0.8 1.9 2.8 Cpd. C (Ex. 3) 0.15 0.06 0.2 1.3 Note: The compounds A to C as shown above corresponds to the aimed compounds obtained in Examples 1 to 3, respectively. 2. Effect of inhibiting agglutination of platelets (ex vivo) The compounds A to C, which were typical examples of the compound of the present invention, were orally administered to guinea pigs. After two hours, the blood of each animal was collected from the abdominal aorta thereof under etherization. Then the effect of each compound on the agglutination of platelets induced by collagen (3 µl/ml) and arachidonic acid (50 µM) was examined. Table 2 shows the 50% effective doses determined from the solvent administration ratios. In other words, this test is conducted to examine the effect on platelet aggregation (ex vivo). Test Cpd. Effect of inhibiting collagen agglutination ED₅₀(mg/kg) Effect of inhibiting arachidonic acid agglutination ED₅₀(mg/kg) Cpd. A (Ex. 1) 0.05 0.03 Cpd. B (Ex. 2) 0.05 0.03 Cpd. C (Ex. 3 1 0.3 Ticlopidine ≦200 150 3. Acute toxicity The acute toxicities of the compounds A to C, which were typical examples of the compound of the present invention, wore examined by administering these compounds to male Wistar rats of 300 to 400 g in body weight. As a result, the LD₅₀ of each compound was higher than 500 mg per kg. When the compound of the present invention is used as an antiplatelet and antithrombotic agent, it may be orally or parenterally, for example, intramuscularly, subcutaneously or intravenously administered. The dose thereof may vary depending on, for example, the disease, the condition and the age of each patient. Unless particularly limited, it may be administered in a dose of 0.1 to 300 mg, preferably 0.1 to 60 mg, particularly preferably 0.3 to 30 mg, further particularly preferably 0.6 to 10 mg to an adult per day. The compound of the present invention may be formulated into, for example, tablets, granules, powders, capsules, injections or suppositories in conventional manners known in the art. When it is to be formulated into solid preparations for oral administration, excipients and, if required, other additives such as binders, disintegrants, lubricants, colorants and corrigents are added to the base and the obtained mixture is then formulated into, for example, tablets, coated tablets, granules, powders or capsules in conventional manners. Examples of the excipients are lactose, corn starch, white sugar, glucose, sorbitol and crystalline cellulose. Examples of the binders are polyvinyl alcohol, polyvinyl ether, ethylcellulose, methylcellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropylcellulose, hydroxypropylstarch and polyvinylpyrrolidone. Examples of the disintegrants are starch, agar, powdery gelatin, crystalline cellulose, calcium carbonate, calcium hydrogencarbonate, calcium citrate, dextrin and pectin. Examples of the lubricants are magnesium stearate, talc, polyethylene glycol, silica and hardened vegetable oils. Examples of the colorants are those approved as additives for drugs. Examples of the corrigents are cocoa powder, methol, aromatic acids, peppermint oil, Borneo camphor and cinnamon powder. These tablets and granules may be, as a matter of course, coated with, for example, sugar or gelatin if required. When an injection is to be prepared, various additives such as pH adjustors, buffers, stabilizers and preservatives are added to the base and the obtained mixture is formulated into an injection for subcutaneous, intramuscular or intravenous administration. To further illustrate the present invention, and not by way of limitation, the following Examples will be given. Example 1: Ethyl 4-cyano-5,5-bis(4-methoxyphenyl)-4-pentenoate 2.42 g (0.01 M) of 4,4'-dimethoxybenzophenone, 1 g of zinc and 2.1 g of trimethyl borate were suspended in 15 ml of tetrahydrofuran. To the obtained suspension, 2.2 g of ethyl 4-bromo-4-cyanobutyrate and a catalytic amount of iodine were added and the mixture was allowed to react at room temperature for five hours. After the completion of the reaction, 10 ml of a saturated aqueous solution of ammonium chloride was added thereto and the mixture was stirred for one hour. After filtering the zinc off, the filtrate was extracted with ethyl acetate. The obtained crude product was purified by silica gel chromatography to give 1.5 g or crystals. The crystals were dissolved in 10 ml of benzene and 1 ml of thionyl chloride was added to the obtained solution. After stirring at room temperature for one hour, the reaction mixture was concentrated in vacuo and dispersed into ice/water. Then it was extracted with benzene, washed with water and concentrated. Thus 1.3 g of the title compound was obtained in the form of a colorless oily product. NMR (CDCl₃)δ : 6.7 - 7.3(8H), 4.1(2H), 3.8(6H), 2.7(4H) and 1.3(3H). Example 2: 4-Cyano-5,5-bis(4-methoxyphenyl)-4-pentenoic acid 3.6 g of ethyl 4-cyano-5,5-bis(4-methoxyphenyl)-4-pentenoate was dissolved in 10 ml of dioxane and 3 ml of a 5N aqueous solution of NaOH was added thereto. The obtained mixture was stirred at 60°C for five hours. After the completion of the reaction, the reaction mixture was acidified and extracted with ethyl acetate. Thus 3.2 g of the title compound having the following physicochemical properties was obtained. This product could be further purified by recrystallizing from ethyl acetate/hexane. m.p.: 124 - 125°C. NMR (CDCl₃)δ : 9.5(1H), 6.8-7.4(8H), 3.8(6H), 2.7(4H) Example 3: Methyl 5-cyano-6,6-bis(4-methoxyphenyl)-5-hexenoate The procedure of Example 1 was followed except that the ethyl 4-bromo-4-cyanobutyrate was replaced by 2.2 g of methyl 5-bromo-5-cyanopentanoate. Thus the title compound having the following physicochemical properties was obtained. NMR (CDCl₃)δ : 6.7 - 7.3(8H), 3.8(6H), 3.6(3H) and 1.8 - 2.6(6H). Example 4 4-cyano-5,5-bis(4-ethoxyphenyl)-4-pentenoic acid Example 3 was followed except for using 4,4'-diethoxybenzophenone and tetrahydrofurane as a solvent. The product mixture was dehydrated with thionyl chloride and hydrolyzed in the same way as shown in Example 2. Example 5 4-cyano-5-(4-hydroxyphenyl)-(Z)-5-(4-methoxyphenyl)-4-pentenoic acid and the (E) compound thereof Example 1 was followed except for using 4-methoxy-4'-methoxymethoxybenzophenone. The product mixture was treated with hydrochloric acid and hydrolyzed in the same way as shown in Example 2. The elution of the product mixture with a mixture of methanol and chloroform at a ratio of 5:95 in the chromatography using silicagel provided the (Z) compound. The elution with the mixture at a ratio of 10:90 provided the (E) compound. Example 6 4-cyano-5-(4-hydroxyphenyl)-(Z)-5-(4-ethoxyphenyl)-4-pentenoic acid and the (E) compound thereof Example 5 was followed except for using 4-ethoxy-4'-methoxymethoxybenzophenone. Example 7 4-cyano-5,5-bis(4-hydroxyphenyl)-4-pentenoic acid Example 8 4-cyano-2-methyl-5,5-bis(4-methoxyphenyl)-4-pentenoic acid Example 5 was followed except for using 4,4'-dimethoxymethoxybenzophenone and 4,4'-dimethoxybenzophenone. The hydrolysis product was the above intended compound. Example 9 5-cyano-6,6-bis(4-methoxyphenyl)-5-hexenic acid 260 mg of the ester obtained in Example 3 was treated in the same way as shown in Example 2 to obtain 250 mg of the above intended compound. The data of the NMR analysis about the compounds obtained in Examples 4 to 9 is listed below. The analysis was conducted with CDCl₃, δ examples analysis 4 9.5(1H), 6.6-7.2(8H), 4.0(4H), 2.6(4H), 1.4(6H) 5 8.0-9.5(2H), 7.1-7.5(2H), 6.7-7.0(6H), 3.8(3H), 2.7(4H) 6 7.5-9.5(2H), 7.0-7.3(2H), 6.6-6.9(6H), 4.0(2H), 2.6(4H), 1.4(3H) 7 8.5-10.0(3H), 6.7-7.4(8H), 2.6(4H) 8 9.0(1H), 7.1-7.3(2H), 6.6-7.0(6H), 3.8(6H), 2.3-3.1(3H), 1.2(3H) 9 8.0-9.0(1H), 7.1-7.3(2H), 6.7-7.0(6H), 3.8(6H), 2.2-2.5(4H), 1.8-2.2(2H)

Claims: Claims for the following Contracting States : BE, CH, DE, FR, GB, IT, LI, LU, NL, SE A diphenylethylene derivative with the formula (I): wherein R¹ and R² are independently from each other hydrogen, hydroxyl or a lower alkoxy group, X is cyano, Y is -R¹⁰-COOR³, wherein R³ is hydrogen or a lower alkyl group, and R¹⁰ is an alkylene group having 1-3 carbon atoms, straight or branched, or a pharmaceutically acceptable salt thereof. A diphenylethylene derivative as claimed in claim 1, wherein both of R¹ and R² are lower alkoxy groups or a pharmaceutically acceptable salt thereof. A diphenylethylene derivative as claimed in claim 2, wherein both of R¹ and R² are methoxy groups or a pharmaceutically acceptable salt thereof. A diphenylethylene derivative as claimed in claim 1, which is 4-cyano-5,5-bis(4-methoxyphenyl)-4-pentenoic acid or a pharmaceutically acceptable salt thereof. A diphenylethylene derivative as claimed in claim 1, which is methyl 5-cyano-6,6-bis(4-methoxyphenyl)-5-hexenoate or a pharmaceutically acceptable salt thereof. A diphenylethylene derivative as claimed in claim 1, which is ethyl 4-cyano-5,5-bis(4-methoxyphenyl)-4-pentenoate or a pharmaceutically acceptable salt thereof. A process for preparing a diphenylethylene derivative of the formula (I): wherein R¹ and R² are independently from each other hydrogen, hydroxyl or a lower alkoxy group, X is cyano, Y is -R¹⁰-COOR³, wherein R³ is hydrogen or a lower alkyl group, and R¹⁰ is an alkylene group having 1-3 carbon atoms, straight or branched, or a pharmaceutically acceptable salt thereof which comprises reacting a ketone of the general formula (VI): wherein R¹ and R² are as defined above, with a halide of the general formula (VII): wherein Hal represents a halogen atom, and R³ and R¹⁰ are as defined above, in the presence of zinc in a Reformatsky reaction to give a hydroxy compound of the formula (VIII): wherein R¹, R², R³ and R¹⁰ are as defined above, followed by dehydration of the hydroxy compound (VIII) thus obtained in a conventional manner, and if necessary conversion of the product to a pharmaceutically acceptable salt. A pharmaceutical composition which comprises a pharmacologically effective amount of the diphenylethylene derivative as defined in any of claims 1 to 6 or a pharmacologically acceptable salt thereof and a pharmacologically acceptable carrier. Use of the compounds of any of claims 1-6 in the preparation of a medicament for the treatment of diseases caused by blood stream disorders. Claims for the following Contracting States : AT, ES, GR A process for preparing a diphenylethylene derivative of the formula (I): wherein R¹ and R² are independently from each other hydrogen, hydroxyl or a lower alkoxy group, X is cyano and Y is -R¹⁰-COOR³, wherein R³ is hydrogen or a lower alkyl group, and R¹⁰ is an alkylene group having 1-3 carbon atoms, straight or branched, or a pharmaceutically acceptable salt thereof which comprises reacting a ketone of the general formula (VI): wherein R¹ and R² are as defined above, with a halide of the general formula (VII): wherein Hal represents a halogen atom, and R³ and R¹⁰ are as defined above, in the presence of zinc in a Reformatsky reaction to give a hydroxy compound of the formula (VIII): wherein R¹, R², R³ and R¹⁰ are as defined above, followed by dehydration of the hydroxy compound (VIII) thus obtained in a conventional manner, and if necessary conversion of the product to a pharmaceutically acceptable salt. A process as claimed in claim 1, wherein both of R¹ and R² are lower alkoxy groups. A process as claimed in claim 2, wherein both of R¹ and R² are methoxy groups. A process as claimed in claim 1, wherein the compound of the formula (I) is 4-cyano-5,5-bis(4-methoxyphenyl)-4-pentenoic acid or a pharmaceutically acceptable salt thereof. A process as claimed in claim 1, wherein the compound of the formula (I) is methyl 5-cyano-6,6-bis(4-methoxyphenyl)-5-hexenoate or a pharmaceutically acceptable salt thereof. A process as claimed in claim 1, wherein the compound of the formula (I) is ethyl 4-cyano-5,5-bis(4-methoxyphenyl)-4-pentenoate or a pharmaceutically acceptable salt thereof. A process for preparing a pharmaceutical composition comprising the steps of mixing a pharmacologically effective amount of the diphenylethylene derivative as defined in any of claims 1-6 or a pharmacologically acceptable salt thereof with a pharmacologically acceptable carrier. Use of the diphenylethylene derivatives of any of claims 1-6 in the preparation of a medicament for the treatment of diseases caused by blood stream disorders.

Inventors: ABE, SHINYA, AKASAKA, KOZO, FUJIMORI, TOHRU, HARADA, KOUKICHI, HAYASHI, KENJI, IKUTA, HIRONORI, MIYAMOTO, MITSUAKI, NAKAMOTO, KOUJI, OKANO, KAZUO, SUZUKI, TAKESHI, YAMAGISHI, YOUJI, YAMATSU, ISAO, YOSHIMURA, HIROYUKI
Applicants: EISAI CO., LTD.
Application year: 1987
Main classification: C07C251
IPC codes: C07D207, C07C255, C07C327, C07C311, C07D249, A61K31, C07C233, C07C251, C07C59, C07D213, C07D339, C07D521, C07D257