PL118444B1 - Process for preparing novel derivatives of phtalazinyl-4-acetic acidh-uksusnojj kisloty - Google Patents

Description

The subject of the invention is a method of producing new derivatives of phthalazin-4-ylacetic acid, which are inhibitors of enzymatic aldose reductase in vivo. Enzymatic aldose reductase causes catalytic conversions of aldoses into the corresponding alditols (i.e. polyhydric alcohols), e.g. glucose is converted into sorbitol and galactose into dulcite. Alditols poorly penetrate cell membranes and if they are produced, their removal is possible only through further metabolism. Alditols therefore tend to accumulate in the cells in which they are formed, causing an increase in osmotic pressure to such an extent that it can destroy these cells or weaken their functions. In addition, elevated alditol levels can cause abnormal levels of metabolites, which in turn can impair or destroy cellular functions. Aldose reductase has a relatively low affinity for its substrate, meaning that it is effective in the presence of relatively high concentrations of aldose. Such high concentrations of aldose occur in the clinical setting of diabetes (glucose overload) and galactosemia (galactose overload). Aldose reductase inhibitors are therefore useful because they reduce or prevent the peripheral effects of diabetes or galactosemia, which may be partly due to accumulated sorbitol or dulcit. Such peripheral effects may include, for example, macular edema, cataracts, retinopathy, or impaired nerve conduction. 10 15 20 25 30 Derivatives of 1-benzyl-2-ketoquinol-4-yl alkanoic acid are known to be inhibitors of the enzyme aldose reductase (British Patent Specification No. 1,502,312). It has now been surprisingly found that certain derivatives of 2-benzyl-1-ketophthalazin-4-ylacetic acid are also inhibitors of aldose reductase. This statement is surprising, especially because there are fundamental differences between these compounds in the structure of 2-ketoquinoline and 1-ketophthalazine rings. The corresponding phthalazine derivatives, i.e. 2-benzyl- and 2-(2-pyrid-2-yIoethyl)-1,2-dihydro-l-ketophthalazine acids lasyn-4ylacetic acid and their methyl and ethyl esters are known and their effect on blood clotting has been found (Sh. Feldeak et. al., Khim. Farm. Zh., 1970, 4, 22^26; Chemical Abstracts, 1970, 73, 77173); but, unlike the compounds of the invention, none of these known phthalazine derivatives are aldose reductase inhibitors in vivo at a dose of 100 mg/kg or less. The phthalazin-4-ylacetic acid derivatives of the invention are comprised by the general formula I, wherein the substituents R2, R3, R4 and RJ on the benzene ring A may have the following combinations of meanings: a) R2 represents a fluorine atom or a methoxy group, R3 represents a hydrogen atom, R4 represents a chlorine, bromine or iodine atom, and R5 represents a hydrogen or halogen atom, b) R2, R3 and R5 represent hydrogen atoms, and R4 represents a bromine or iodine atom, c) R2 represents a hydrogen or fluorine atom, R3 and R5 represent 444118 444 halogen atoms, which may be the same or different, and R4 represents a hydrogen atom, d) R2 represents a hydrogen or fluorine atom, R3 and R4 represent halogen atoms, which may be the same or different, and R5 represents a hydrogen atom, and e) R2 represents a hydrogen atom, R3 and k5 independently represent a fluorine or chlorine atom, and R4 represents a chlorine, bromine or iodine atom, the substituents R6, R7 and R8 in the benzene ring B independently of each other represent a hydrogen or halogen atom or a G-4-alkyl or G-4-alkoxy radical, or R6 and R7 together form a G-4-alkylene dioxy radical, provided that at least one of the symbols R6, R7 and R8 represents a hydrogen atom and X represents an oxygen or sulfur atom; Formula 1 also includes pharmaceutically acceptable base addition salts of these compounds. The compounds of formula 1 are derivatives of 1,2-dihydro-1-keto(or thioketo)-phthalazin-4-ylacetic acid. The principle of numbering the individual positions in the phthalazine ring is explained by formula 2. The compounds of formula 1 exhibit the phenomenon of tautomerism, i.e. they can also exist in the form of formula Ia. The invention includes within its scope the preparation of both tautomers of formula 1 (erTdo-tautomers), tautomers of formula Ia (exotautomers) and mixtures thereof. When R 3 or R 5 is a halogen atom, it is preferred, for example, fluorine, chlorine, bromine or iodine; in this case, chlorine and bromine are particularly preferred. ¦ ' When R6, R7 or R8 denotes a halogen atom, it is preferably e.g. fluorine, chlorine, bromine or iodine, and when it denotes an alkyl radical, it is e.g. methyl, * when it denotes an alkoxy radical, it is e.g. methoxy or ethoxy. Examples of the G-4-alkylene dioxy radical which R6 and R7 can together form are methylene dioxy, ethylene dioxy or isopropylidene dioxy. Examples of combinations of the meanings R2, R3, R4 and R5 are especially the following radicals of the benzene ring A: 2-fluoro-4-bromo-, 2-fluoro-4-chloro-, 2-fluoro-4-iodo-, 2-fluoro-4,5-dibromo-, 2-methoxy-4-chloro-, 4-bromo- -4-iodo-, 3,5-dichloro-, 3-chloro-4-bromo-, 3, 4-dichloro-, 3, 4-dibromo- or 3, 5-dichloro-4-bromo-phenyl. Examples of preferred benzene ring radicals B with optional substituents R6, R7 and R8 are in particular: phenyl unsubstituted or substituted with 6-fluoro-, 6-chloro-, 6-methyl, 7-fluoro, 7-chloro-, 7-methyl-, 7-methoxy, 8-fluoro, 8-methyl, or 8-ethoxy or 6,7-dichloro or 6,7-methylenedioxy. Preferred base salts of the compounds of formula 1 are, for example, alkali metal and alkaline earth metal salts, such as sodium, potassium, calcium or magnesium salts, aluminum and ammonium salts, as well as salts with organic bases which give a pharmaceutically acceptable cation, for example triethanolamine. Particularly preferred are the compounds of formula 1, in which: a) R2 is fluoro, R3 and R5 are H," and R4 is chloro, bromo or iodo, -^ b) R3 and R4 independently of each other are chloro, bromo or iodo, and R2 and Rs are H or c) R«, R7 and R8 are H d) X is an oxygen atom and in each of these groups (a) — (d) the remaining substituents R2 — R8 and X may have any meaning. These groups also include salts of the above compounds with bases. 20 Some of the specific compounds of formula 1 prepared according to the invention are described in the examples given below, and among them, 2-(2-fluoro-4-bromobenzyl)-5-1,2-dihydro-1-ketophthalazin-4-ylacetic acid, 2-(2-flu- oro-4-iodobenzyl)-1,2-dihydro-1-ketophthalazin-4-ylacetic acid and 2-(3-chloro-4-bromobenzyl)-1,2-dihydro-1-ketophthalazin-4-ylacetic acid and their pharmaceutically acceptable salts with bases. According to the invention, a process for the preparation of compounds of formula 1 as defined above consists in hydrolyzing an ester of formula 3, wherein R 1 is a G-4-alkoxy radical or a radical of formula 4, wherein in these formulae R 2 - R 8 and X have the meanings given above and if the product is required in the form of a pharmaceutically acceptable salt with a base, the obtained compound of formula 1 is reacted with a base giving a pharmaceutically acceptable cation. The hydrolysis can be carried out in the presence of an acid or a base, e.g. in the presence of a mineral acid, such as hydrochloric acid, or in the presence of an alkali metal hydroxide or carbonate, e.g. in the presence of sodium or potassium hydroxide or carbonate. When a starting material containing a labile substituent in ring B, e.g. 8-fluoro, is used, then an alkali metal carbonate is preferred. The hydrolysis is carried out in the presence of water. A solvent or diluent, e.g. acetic acid, methanol, ethanol or dioxane, may also be present. The hydrolysis may be carried out at room temperature, e.g. 18-25°C, but it is conveniently accelerated by heating, e.g. 35-110°C. The required new starting materials of formula 3 can be prepared by conventional methods well known in organic chemistry. Thus, in order to prepare a compound of the formula III in which a) X is oxygen, a compound of the formula V is reacted with a halide of the formula VI in which Hal is chlorine, bromine or iodine, in the presence of a suitable base. The reaction is advantageously carried out in a diluent, for example ethanol, diethylformamide, dimethylsulfoxide or water, and is conveniently accelerated by heating the reactants, for example K at a temperature of 40° to 110° C. A particularly preferred base is an alkali metal hydride, carbonate, hydroxide or G-4-alkanoate, for example sodium or potassium hydride, carbonate, hydroxide, methanolate or ethoxide. If a hydride is used, a non-aqueous solvent, e.g. dimethylformamide, is required, and if an alcoholate is used, methanol or ethanol is preferably used as the solvent. Starting compounds of formula 3, in which: b) X is an oxygen atom, is obtained by reacting a compound of formula 7 or a geometric isomer thereof with a hydrazine of formula 8. The reaction is preferably carried out in an aqueous diluent or solvent, e.g. in aqueous dioxane, ethanol or dimethylformamide, in the presence of a base, e.g. sodium or potassium bicarbonate. Heating can also be used, e.g. at 40-110°C. The starting compounds of formula 3, in which: c) X is an oxygen atom and R1 is a C-4-alkoxy radical, are obtained by decomposing a diazo ketone of formula 9 in the presence of a compound of formula QH, in which Q is a C1-4-alkoxy radical, e.g. methoxy or ethoxy. A catalyst, e.g. colloidal silver or silver benzoate, is required and is preferably used in the presence of a base, e.g. triethylamine, pyridine or ε-collidine. The reactions are advantageously carried out in the presence of a diluent or solvent, for example water, a C-4-alkanol such as methanol or ethanol, tetrahydrofuran or dioxane, and an excess of the compound is preferred. The reactions are advantageously accelerated by heating, for example in the range 40°-110°C. The starting compounds of formula III, in which: d) the benzene ring B contains a C-4-alkoxy substituent, are obtained by reacting a compound of formula I, in which ring B contains a halogen substituent, for example fluorine, with an alkali metal C-4-alkanoate, for example sodium methanolate or ethoxide. The reaction is preferably carried out in a solvent or diluent, for example in an excess of the appropriate γ-alkanol, for example methanol or ethanol, and is preferably accelerated by heating, for example at 40° to 110° C. or at the boiling point of the reaction mixture. The compounds of formula III, wherein: (e) X is sulfur, are prepared by exchanging oxygen for sulfur in the appropriate compound of formula III, wherein X is oxygen, using conventional procedures and conditions, for example by reaction with phosphorus pentassulfide in boiling xylene or pyridine. The above-mentioned methods (a) to (e), which are well known in the art, are illustrated by the examples given below. The starting compounds of formulae 6, 8 and 9 can generally be prepared by: by the usual methods known from the chemistry of heterocyclic compounds. For example, N. R. Patel reviewed these methods in "The Chemistry of Heterocyclic Compounds", vol. 27, Interscience, New York. An example is the preparation of the diazo ketone of formula 9, required as a starting compound in method (d), shown in the attached scheme. The following reagents and conditions are used in the individual stages I-VIII: I) n-Bu, Li, Et2O or (MeOCH2),2 temp. -10-0 °C, II) diethyl oxalate, 0-5 °C, III) H+(H2O)dioxane, 90-100 °C, IV) K2CO3 (KMnO+)H2O, 100 °C, V) H2NNH2. H2O, 90—100°C, VI) as in method (a), VII) SO.( Hal)2, (Hal = Cl or Br) or (COCl)2, VIII) excess CH2N2/Et2O. In the formulas in the scheme, for greater clarity, the substituents R2 — R8 are not indicated. In many cases, before carrying out the alkylation with the benzyl halide (Step V), it is advantageous to first convert the acid of formula I to its methyl ester, for example by reacting the sodium salt of this acid with methyl iodide in dimethylformamide. This modification is described in Examples 7 and 8 and requires a conventional hydrolysis procedure to obtain the acid which will be reacted in Step VII. Depending on the nature of the substituents which may be introduced on the benzene ring B, the most suitable starting materials may be 2-acyltoluene of formula XI or 2-phenyloxazoline of formula XI. It may also be advisable to omit the isolation and purification of some of the intermediates shown in the scheme, for example the lithium and oxalate derivatives prepared in Steps (I) and (II). Similarly, in method (d) it is convenient to prepare the diazo ketone 6 of formula 9 in situ from the corresponding acid halide of formula 12. The starting compounds of formula 7 required in method (a) can be obtained in an analogous manner to method (b), i.e. by reacting the compound of formula 7 with hydrazine hydrate and then reacting the resulting phthalazin-4-yl acetic acid, either as such or as the acid chloride, with esterification in a conventional manner. Some of the starting compounds of formula 7 can be conveniently obtained from the corresponding substituted phthalic anhydride of formula 14 by condensing it with acetic anhydride, for example in the presence of sodium or potassium acetate in an excess of boiling acetic anhydride. However, all of these compounds can be prepared by the Wittig reaction using the corresponding phthalic anhydride of formula 14 (14) and (carboethoxymethylene)triphenylphosphate in a suitable solvent, e.g. 1,2-dimethoxyethane or tetrahydrofuran. The reaction is conveniently accelerated by heating, e.g. by keeping the reaction mixture at boiling. In some cases the product of the Wittig reaction may turn out to be the geometric isomer of formula 7a rather than of formula 7. It is also possible for a mixture of both of these isomers to be formed. Either of these isomers or a mixture thereof may be used in method (b). It should also be noted that when in the starting material of formula 14 both R8 and one of R7 and R6 are hydrogen atoms, the Wittig reaction gives rise to substitution isomers depending on which of the two carbonyl groups of phthalic anhydride (14) is reacted. When R8 is not hydrogen, then the Wittig reaction predominates. one substitution isomer, i.e. the reaction mainly occurs with the carbonyl group located furthest from the R8 substituent. Pharmaceutically acceptable salts of the compounds of formula I are obtained by conventional methods by reacting with a suitable base which furnishes a pharmaceutically acceptable cation. Inhibition of aldose reductase can be demonstrated in the following typical laboratory test: Rats in which diabetes had been induced by streptozotocin were administered the compound under test for five consecutive days. The animals were then sacrificed and the ocular lenses and sciatic nerves were removed. The residual level of sorbitol in each of these tissues was determined by previously converting it to the poly(trimethylsilyl) derivative using gas-liquid chromatography. Inhibition of The in vivo aldose reductase activity is calculated by comparing the tissue sorbitol levels in a group of diabetic rats treated with the test compound with those in a group of diabetic rats not treated with the test compound and with those in a group of normal rats not treated with the test compound. This test can be performed somewhat differently. Namely, rats made diabetic by streptozotocin are treated with the test compound for two days and 2-4 hours after the last dose, they are sacrificed, the sciatic nerves are removed and the residual sorbitol level is determined as described above. In both of these tests, the active compounds reduce the residual sorbitol level to the level corresponding to that in normal rats not treated with the test compound. In general, however, the compounds of formula I cause marked inhibition of the reductase at an oral dose of 100 mg/kg or less. Thus, for example, 2-(2-(2-fluoro-4-bromobenzyl)-1,2-dihydro-1-ketophthalazin-4-yl-acetic acid reduced by about 60% the residual sorbitol level in the sciatic nerve of diabetic rats, which were administered this compound at a dose of 10 mg/kg for 15 20 25 30 35 40 45 50 55 60118 4 7 5 days. In the above studies, no overt toxic or other undesirable symptoms were observed at a dose of 100 mg/kg of the compounds of formula 1. Inhibition of aldose reductase can also be demonstrated in vitro: purified aldose reductase is isolated from goiter lenses in a known manner and the percentage inhibition of the ability of this enzyme in vitro to reduce aldoses to polyhydric alcohols, in particular the reduction of glucose to sorbitol, caused by the compound under test is determined spectrophotometrically. In this test, the compounds of formula I show clear inhibition of the reductase at concentrations in the range of 10-8 - 10-6 M or lower. For example, for 2-(2-fluoro-4-bromobenzyl)-1,2-dihydro-1-ketophthalazin-4-ylacetic acid, the Ki is 2.0-10-8 M. 15 In order to induce an effect on the enzymatic reductase aldose in warm-blooded animals, the compound of formula 1 is administered to them in a daily oral dose of 2-50 mg/kg, which in humans corresponds to a total daily dose of 20-750 mg per patient, and this dose can, if necessary, be divided into smaller amounts administered several times a day. ^ The compounds of formula 1 can be administered in the form of a pharmaceutical composition. Particularly recommended are pharmaceutical compositions suitable for oral administration, e.g. tablets, capsules, suspensions or solutions, prepared in a conventional manner, optionally with the addition of suitable excipients. A number of compounds of formula 1, apart from their aldose reductase-inhibiting properties, exhibit anti-inflammatory/analgesic properties similar to non-steroidal anti-inflammatory agents such as indomethacin, naproxen and hetoprofen. Thanks to this, the compounds of formula I can be used in the treatment of painful inflammation of the joints, and therefore in diseases such as rheumatoid arthritis, arthritis, pathological osteoarthritis and ankylosing spondylitis. For these purposes, the compound of formula I is administered orally in a daily dose in the range of 10-50 mg/kg. The anti-inflammatory properties are confirmed in a typical test on rats. For example, 2-(2-fluoro-4-bromobenzyl)-1,2-dihydro-1-ketophthalazin-4-ylacetic acid and 2-(3-chloro-4-bromobenzyl)-1,2-dihydro-1-ketophthalazin-4-ylacetic acid very significantly inhibit the swelling induced by carrageenan in the test developed* by Winter 45 et al., Proceedings of the Society of Experimental Biology (New York), 1962, 111, 554, without any visible toxic symptoms. The invention is illustrated by the examples given below, in which, unless otherwise stated: 50 a) evaporation was carried out in a vacuum, b) the operations were carried out at room temperature, i.e. in the range of 18-26°C, c) petroleum ether with a boiling point of 60-80°C or other fractions thereof were used, 55 d) phthalazinylacetic acid derivatives often decomposed during the determination of the melting point, e) all compounds of formula 1 and intermediate compounds were identified on the basis of microanalysis and NMR and IR spectroscopy, and 60 f) the yields are illustrative, i.e. (g) Examples IV-VI, IX, X, XUI-XV, XXXIV-L and LII illustrate the process of the invention, the remainder illustrate the preparation of the starting materials. Example I A mixture of 11.5 g of ethyl 1,2-dihydro-1-ketophthalazin-4-ylacetate and 2.7 g of a 50% suspension of sodium hydride in mineral oil in 125 ml of dimethylformamide was stirred at 60° C. under a nitrogen atmosphere for one hour. The resulting solution was cooled to room temperature, 15.0 g of 4-bromo-3-chlorobenzyl bromide was added and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was cooled to 25° C. and poured into 500 ml of water. The mixture the aqueous mixture was extracted with 400 ml of ethyl acetate and the extracts were washed with water, dried over MgSO4 and evaporated. The solid residue was crystallized from 2-propanol to obtain 7.3 g of ethyl 2-(3-chloro-4-bromobenzyl)1,2-dihydro-1-ketophthalazin-4-ylacetate, m.p. 142-145 °C. Examples II-III. Proceeding similarly to Example I, the following compounds of formula 15 were obtained from 11,2-dihydro-2-ketophtalazin-4-yl-ethyl acetate and the corresponding bromide of formula 16, in which ring B is unsubstituted. Table I Example III IV Substituents in the benzene ring A 3,4-dichloro*) 2-fluoro-4- -bromo Yield (%) 40 60 Melting point (°C) 139—141 114 Solvent for crystallization isopropanol r ethanol *) 3,4-dichlorobenzyl chloride was used as the starting compound. Example IV. A solution of 7.0 g of ethyl 2-(3-chloro-4-bromo- -benzyl)-1,2-dihydro-1-oxophthalazin-4-ylacetate in 70 ml of ethanol containing 7.0 g of potassium hydroxide was heated under reflux for 30 minutes. Then the solution was poured into 250 ml of water and the aqueous solution was extracted with 2x150 ml of ether. The aqueous phase was acidified concentrated hydrochloric acid to pH 2. A precipitate was formed which, after filtration, washing with water and drying in vacuo, was crystallized from a 6:2:3 (v/v) mixture of toluene, 2-propanol and petrol, boiling at 60-80°C. 3.9 g of 2-(3-chloro-4-bromobenzyl)-1,2-dihydro-1-oxophthalazin-4-ylacetic acid were obtained, melting at 186°C. Examples V-VI Following the same procedure as in Example IV, the compounds of formula 17 given below, in which ring B is unsubstituted, were obtained by hydrolysis of the appropriate ethyl ester of formula I. Table II Example V VI Substituents on the benzene ring A of 3,4-di- chloro 2-fluoro-4- -bromo Yield (%) 60 64 Melting point (°C) 175-176 184-185*) Solvents for crystallization [ Toluene/isopropanol 1 (2:1) 1 methanol *) This compound can crystallize in polymorphic forms, i.e. in a form with a melting point of 184-185°C (from methanol containing some water) and in a form with a melting point of 180-182°C (after recrystallization twice from dry methanol).118 444 9 Example 8 A mixture of .1.9 g of 2-(3,4-di-chlorobenzyl)-7-methoxy-1,2-dihydro-1-ketohthalazin-yl-acid 4-Carboxylic acid chloride and 10 ml of thionyl chloride containing 0.1 ml of dimethylformamide were heated under stirring under reflux for 3 hours. After evaporation of the obtained solution, the residue was dissolved in dry toluene and the solution was evaporated. This operation was repeated 3 times and an essentially quantitative yield of 2-(3,4-dichlorobenzyl)-7-methoxy-1,2-dihydro-1-ketophthalazyl-4-carboxylic acid chloride was obtained in the form of a solid, the infrared spectroscopy of which gave a satisfactory result. A solution of the obtained acid chloride in 50 ml of dry tetrahydrofuran was added dropwise, with stirring, to 200 ml of a solution of diazomethane in dry ether cooled to 0°C, obtained from 10 g of bis- (N-methyl-N-nitroso)terephthalamide was added in the manner described by J. A. Moore in Organic Syntheses 1961, 41, 16. After completion of the dropwise addition, the mixture was stirred for a further 2 hours until it reached room temperature. The mixture was then filtered and the precipitate washed with 20 ml of dry tetrahydrofuran. Evaporation of the combined filtrate and washings gave 2-(3,4-dichlorobenzyl)-4-(a-diazo)acetyl-7-methoxy-1,2-dihydro-1-ketohthalazine as a solid, which was used without purification or testing. To a solution of the 4-(a-diazo)acetyl derivative obtained above in 50 ml of absolute ethanol and 30 ml of tetrahydrofuran was added dropwise slowly, while heating under reflux, a solution of 0.2 g of silver benzoate in 1 ml of triethylamine. After each dropwise addition, the mixture erupted and the next portion was added only after the eruption had ceased. After the addition was complete, the reaction mixture was heated under reflux, while stirring, for another 30 minutes and filtered hot. After evaporating the filtrate, the residue was dissolved in 200 ml of ethyl acetate and the resulting solution was washed with 3x100 ml of water, dried over MgSO4 and evaporated. The residue was purified by chromatography on 100 g of silica, using mixtures of ethyl acetate and toluene with increasing content of ethyl acetate as eluent. The appropriate fractions were subjected to thin layer chromatography (TLC) on silica plates using ethyl acetate:toluene (1:3,v/v) as eluent to give ethyl 2-(3,4-dichlorobenzyl)-7-methoxy-1,2-dihydro-1-oxophthalazin-4-ylacetate (0.9 g), m.p. 129-130°C. The starting material was prepared as follows: a) A mixture of 7-methoxy-1,2-dihydro-1-oxophthalazin-4-ylcarboxylic acid (10.0 g), sodium hydrogen carbonate and methyl iodide (15.0 g) in dry dimethylformamide (200 ml) was stirred for 16 hours at room temperature. and poured into 600 ml of water. The precipitate was filtered off, washed first with water and then with cold methanol and crystallized from methanol. 8.6 g of methyl 7-methoxy-1,2-dihydro-1-ketophthalazin-4-ylcarboxylate was obtained, melting at 222-225°C. (b) A solution of 8.29 g of the methyl ester obtained in step (a) above in 200 ml of dry dimethylformamide was treated with 1.75 g of a 50% (w/w) suspension of sodium hydride in mineral oil. The mixture was stirred for 1 hour at 60°C and after cooling to room temperature, 7.0 g of 3,4-dichlorobenzyl chloride were added. The mixture was stirred at room temperature for 2 hours and poured into 600 ml of water. The precipitate was filtered off, washed with water, dried in vacuo and crystallized from a 1:3 (v/v) mixture of 2-propanol and petrol (bp 60-80°C). This gave 9.0 g of methyl 2-(3,4-dichlorobenzyl)-7-methoxy-1,2-dihydrp-1-ketohthalazin-4-ylcarboxylate, melting at 144-146°C. (c) A solution of 9.0 g of the methyl ester obtained in step (b) in 100 ml of ethanol and 100 ml of water containing 10.0 g of potassium hydroxide was heated under reflux for 4 hours. The solution was then diluted with 200 ml of water and acidified concentrated hydrochloric acid to pH 2. The precipitate was separated, washed with water, dried in vacuo and crystallized from a 1:1 mixture (v/v) of 2-propanol and dimethylformamide. 6.1 g of 2-(3, 4-dichlorobenzyl)-7-methoxy-1,2-dihydro-1-ke-15-ketophthalazinylcarboxylic acid-4 were obtained, m.p. 238—240 °CW Note: 7-methoxy-1,2-dinydró-1-ketophthalazinyl-carboxylic acid-4 as a solid with a melting point. 229-230°C, obtained as reported by Vanghan et al. in J.Amer. Chem. Soc. 1946, 68, 1314. 20 " Example VIII. Proceeding as described in Example VII and starting from 2-(3,4-dichlorobenzyl)-7-chloro-1,2-dihydro-1-ketophthalazinylcarboxylic acid - 4 (A), 2-(3,4-dichlorobenzyl)-7-chloro-1 was obtained in a yield of 8%, Ethyl 2-dihydro-1-ketophthalazin-4-ylacetate 25 in solid form, the NMR spectrum of which gave a satisfactory result. The starting carboxylic acid derivative (A) was prepared using similar steps (a) - (c) described in Example VII for the starting compound, but starting from 7-chloro-1 acid, 2-dihydro-1-ketophthalazinylcarboxylic acid-4 (B). The necessary intermediates had the following melting points: from step (a): methyl 7-chloro-1,2-dihydro-1-ketophtalazin-4-yl-carboxylate, m.p. 255-257°C (crystallized from a mixture of 2:t (by volume) methanol and dimethylformamide), from step (b): methyl 2-(3,4-dichlorobenzyl)-7-chloro-1,2-dihydro-1-ketophthalazin-4-ylcarboxylate, mp. 178-180°C (crystallized from a 1:3 mixture (by volume) of propanol-2 and gasoline with a boiling point of 60-80 °C). from step (c): 2-(3,4-dichlorobenzyl)-7-chloro-1,2-dihydro-1-ketophthalazinylcarboxylic acid-4, m.p. 260-262°C (crystallized from a 1:1 mixture (v/v) of methanol and dimethylformamide). Note: carboxylic acid (B), solid, mp. 241-243°C, obtained in a manner similar to that described by Vanghan et al. in J. Amer. Chem. Soc. 1946, 68, 1314, but starting from 4-chloro-2-methylacetophenone. 53 Examples IX-X. Proceeding as described in Example IV and starting from the appropriate ethyl ester, the following acids were obtained: Example IX: 2-(3,4-dichlorobenzyl)-7-methoxy-1,2-dihydro-1-ketophthalazin-4-ylacetic acid, mp. 55 198-200°C (crystallized from propanol-2), yields . strength 50%, Example with melting point £n 203-205 °C (crystallized from a 1:1 mixture (by volume) of propanol-2 and gasoline with a boiling point of 60-80 °C), yield; 43%. Examples XI-XII. Similarly as described in Example I, the following esters were obtained from the appropriate benzyl bromide or chloride: 118 444 11 12 Example 102 °C - (crystallized from gasoline with a boiling point of 60-80 °C and then from ethanol), with a yield of 45%. Example XII: Ethyl 2-(2-fluoro-4-iodobenzyl)-1,2-dihydro-1-ketophthalazin-4-ylacetate, m.p. 113°C (crystallized from gasoline with a boiling point of 60-80°C), with a yield of 50%. Examples XIII-XV. Similarly as described in Example IV, the following acids were obtained from the appropriate ethyl ester: Example XIII: 2-(2-fluoro-4-chlorobenzyl)-1,2-dihydro-1-ketophthalazin-4-yl ethyl acid, mp. 193--194°C (crystallized from a 3:1 (volume) mixture of ethanol and water), with a yield of 63%. Example 189 °C (crystallized from a 3:1 mixture (v/v) of ethanol and water), yield 55%, Example 197--199°C (crystallized from propanol-2), yield 25%. *) Hydrolysis was carried out in an aqueous methanolic solution of sodium hydroxide, the mixture being heated under reflux for 10 minutes. Example XVIV A mixture of 1.8 g of ethyl 2-(3-chloro-4-bromobenzyl)-1,2-dihydro-1-ketophthalazin-4-ylacetate and 2.5 g of phosphorus pentasulfide in 100 ml of xylene was heated for an hour under reflux with stirring. The solution was then cooled to room temperature, 25 ml of ethyl acetate were added and the mixture was filtered through 20 g of chromatographic silica. After evaporation of the filtrate, the solid residue was crystallized from ethanol to obtain 1.1 g of ethyl 2)-(3-chloro-4-bromobenzyl)l,2-dihydro-l-thioketophthalazin-4-yIacetate with a melting point of 124--126°C. Examples XVII-XXII. Similarly as described in Example I, the following compounds of formula 15 were obtained from the corresponding benzyl bromide of formula 16, in which ring B is unsubstituted: Table III Example XVII XVIII XIX xx XXI XXII Substituents in the benzene ring A 3,4-dibromo 2-fluoro-4,5--di-bromo 3,5-dichloro 3,5-dichloro-4-bromo 2-methoxy-4-chloro 4-iodo Yield (%) 44 21 36 19 22 43 Temp. M.p. (°C) 140-142 129-130 100-101 146-147 138 106-107 Solvent(s) for crystallization isopropanol 1 ethyl acetate ethyl acetate ethanol isopropanol isopropanol/petrol (60-80) 1:3 | 10 15 Examples XXIII-XXV A solution of 1.9 g of 3,4-dichlorobenzylhydrazine in 50 ml of toluene was added dropwise to a stirred and refluxed mixture of 2.29 g of ethyl 4-(3-methyl-3-oxophthalanoate)acetate and 200 ml of toluene. The mixture was heated under reflux for a further 3 hours, then cooled and evaporated. The solid residue was crystallised from a 1:2 (v/v) mixture of isopropanol and petrol, bp 60-8°C, to give 1.4 g of ethyl 2-(3,4-dichlorobenzyl)-8-methyl-1,2-dihydro-1-oxophthalazin-4-ylacetate, m.p. 134°-137°C (Example 23). In a similar manner, starting from ethyl 4-fluoro-3-keto-2lla-phthaloacetate, ethyl 2-(3,4-dichlorobenzyl)-8-fluoro-1,2-dihydro-1-ketophthaloacetate was obtained with a yield of 37%, mp. 177-178°C (crystallized from a 1:2 mixture (by volume) of isopropanol and gasoline with a boiling point of 60-80°C) (Example XXIV). Similarly, starting from a 1:1 mixture of 5-methyl- and 6-methyl-3-keto-zUa-phthalateacetate, a 1:1 mixture of 6-methyl- and 7-methyl-2 (3,4-di-chlorobenzyl)-1,2-dihydro-1-ketophthalazin-4-ylacetate of ethyl acetate was obtained with a yield of 33%. melting point 120-122°C (crystallized from isopropanol) (Example XXV). - The required starting materials were obtained as follows: A solution of 7.35 g of 3-fluorophthalic anhydride and 17.5 g of (carbothoxymethylene)triphenylphosphate in 200 ml of dry 1,2-dimethoxyethane was stirred and heated under reflux in a nitrogen atmosphere for 16 hours. The solvent was then evaporated and the residue adsorbed onto 20 g of chromatographic silica. This silica was placed on top of a column containing 300 g of the same silica and the column was eluted with toluene. A section from the column was subjected to thin-layer chromatography on SiC2 using a mixture of: 9:1 (v/v) toluene and ethyl acetate. The first fractions, containing the product visible under UV light, were combined and evaporated. The solid residue was crystallized from isopropanol to give 2.3 g of ethyl 4-fluoro-3-keto-1-a-phthalanoacetate, m.p. 101-103°C, starting material in Example XXIV. - In a similar manner, starting from 3-methylphthalic anhydride, solid ethyl 4-methyl-3-oxo-/for-phthalanoacetate, the starting material in Example XXIII, was obtained in a yield of 5(5%). The product obtained had a melting point of 84-86°C after crystallization from isopropanol. Similarly, starting from 4-methylphthalic anhydride, a 1:1 mixture of ethyl 5-methyl- and 6-methyl-3-oxo-/for-phthalanoacetate was obtained in a yield of 40%. The product obtained had a melting point of 84-86°C after crystallization from isopropanol. Examples XXVI-XXVIII. Proceeding similarly as described in Example 1, the following compounds were obtained from appropriately substituted 1,2-dihydro-1-ketophthalazin-4-ylacetate and 2-fluoro-4-bromobenzylhydrazine: 2-(2-fluoro-4-bromobenzyl)-8-fluoro-1,2-drhydro-1-ke- ethyl tophtalazin-4-ylacetate, mp. 128-130 °C (crystallized from a 1:3 mixture (volume) of isopropanol^ and gasoline with a boiling point of 60-80°C), with a yield of 36%. (example XXVI), ethyl 2-(2-fluoro-4-bromobenzyl)-8-methyl-1,2-dihydro-1-ketophthalazin-4-ylacetate, m.p. 120-122 °C (crystallized from a 1:3 mixture (by volume) of isopropanol and gasoline with a boiling point of 60-80°C), with a yield of 43% (Example XXVII) and 2-(2-fluoro-4-bromobenzyl)-6, 7-methylenedioxy-1, 2- -ethyl dihydro-l-ketophtalazin-4-ylacetate, mp. 163-165°C (crystallized from ethyl acetate), 56% yield (Example XXVIII). 10 15 20 118 444 13 The required starting compounds were prepared as follows: 1) Ethyl 8-methyl-1,2-dihydro-1-ketophtalazin-4-ylacetate (for example XXVII). To a stirred and refluxed solution of 3.5 g of ethyl 4-hydroxy-3-tetrahydrophthalate in 100 ml of ethanol was added dropwise 15 ml of a 1 molar solution of hydrazine hydrate in ethanol. After addition was complete, the mixture was stirred and refluxed for a further 3 hours and then set aside to reach room temperature. The precipitate was collected, washed carefully with gasoline (bp. 60-80°C) and crystallized from a mixture of isopropanol and gasoline (bp. 60-80°C). There was obtained 1.0 g of ethyl 8-methyl-1,2-dihydro-1-ketophthalazin-4-ylacetate, m.p. 197-199 °C. 2) Ethyl 8-fluoro-1,2-dihydro-ketophthaylazin-4-ylacetate (for example XXVI). Using the method described in point (1) and starting from ethyl 4-fluoro-3-keto-1-phthalanoacetate and hydrazine ihydrate, the desired ester was obtained in a yield of 51% in the form of a solid with a melting point of 207--210°C (crystallized from ethyl acetate). 3) ethyl 6,7-methylenedioxy-1,2-dihydro-1-ketophthalazin-4-ylacetate (for example XXVII). This ester, prepared from ethyl 5,6-methylenedioxy-3-keto-Ila-phthalanoacetate (A) and hydrazine hydrate, was obtained with a yield of 70% in the form of a solid with a melting point of 226-228 °C. Phthalanoacetate (A) was prepared from 4,5-methylene-dioxyphthalic anhydride in a manner analogous to the corresponding intermediates in Examples XXIII-XXV, obtaining a solid with a yield of 64%, melting point. 189-191 °C (crystallized from ethanol). This method was carried out according to Knight and Porter. Tetrahedron Letters, 1977, 4543— —4547. Examples XXIX-XXXII. Similarly as described in Example 7, the following esters of formula XV were obtained from the appropriate starting materials: The starting 4-phthalazinylcarboxylic acids may be prepared as follows: (1) 2-(3,3-dichlorobenzyl)-7-fluoro-1,2-dihydro-1-oxophthalazinyl)-4-carboxylic acid, obtained in a yield of 52% as a solid, m.p. 241°-243°C, in a manner similar to that described by Vaughan et al., J. Amer. Chem. Soc. 1946, 68, 1314, was converted into the sodium salt and reacted with iodomethane in the manner described in stage (a) of Example 7. The corresponding methyl ester was obtained in a solid form in 68% yield, m.p. 234-237°C (crystallized from a 3:1 (v/v) mixture of methanol and dimethylformamide (DMF). This ester was then alkylated with 3,4-dichlorobenzyl chloride in the manner described in Stage (b) of Example 7, to give methyl 2-(3,4-dichlorobenzyl)-7-fluoro-1,2-dihydro-1-ketophthalates-4-ylcarboxylate in 68% yield, m.p. 147-149°C (crystallized from a 1:1 (v/v) mixture of toluene and petrol, b.p. 60-80°C). The obtained ester was hydrolyzed with a mixture of an aqueous solution of potassium carbonate and dioxam in the manner described in Example XXXIV below, obtaining 2-(3, 4-dichlorobenzyl)-7-fluoro-1, 2-dihydro-1- acid with a yield of 87%. -ketophthalazinylcarboxylic acid-4 in solid form with a melting point 222-224 °C (crystallized from isopropanol). 2) 2(3,4-dichlorobenzyl)-6,7-dichloro-1,2-dihydro-1-ketophthalazinylcarboxylic acid-4. This acid was prepared in a manner analogous to that in stage (1) above, and the intermediates, melting points, solvents and yields used in the process were as follows: 6,7-Dichloro-1,2-dihydro-1-ketophthalazin-4-ylcarboxylic acid: mp 294-296°C (crystallized from DMF), yield 42%. The corresponding methyl ester: mp 234-236°C (crystallized from DMF), yield 51%; methyl 2-(3,4-dichlorobenzyl)-6,7-dichloro-1,2-dihydro-1-ketophthalazin-4-ylcarboxylate: mp 155-156°C (crystallized from DMF), yield 85%. 2-(3,4-dichlorobenzyl)-6,7-dichloro-1,2-dihy4ro-1-ketophthalazinylcarboxylic acid-4: m.p. 240-242 °C (crystallized from ethanol), yield 62%. 3) 2-(3,4-dichlorobenzyl)-6-chloro-1,2-dihydro-1-ketophthalazinylcarboxylic acid-4. Into a solution kept at -5 to 0°C, 50.0 g of 2-(4-chlorophenyl)4,4-dimethyl-2-oxazoline, prepared as described by Meyers et al., J. Org. Chem. 1974, 39, 2787, in 600 ml of sodium-dried ether was slowly added, with stirring in an atmosphere of dry argon, 165 ml of a 1.6 molar solution of butyllithium in hexane. After the entire amount of butyllithium solution had been added, the solution was stirred at this temperature for another 30 minutes, after which it was slowly added, with stirring, to a solution of 326 ml of dry diethyl oxalate in 500 ml of ether kept at 0°C. The addition of the solution was carried out in an atmosphere of dry argon, which excluded the presence of air and water, and after completion of this operation the reaction mixture was stirred further and then set aside for an hour to warm to room temperature. The ether mixture was then washed with 2 x 150 ml of water, dried over MgSO 4 and evaporated in a vacuum at 10 mm Hg until all excess diethyl oxalate had been removed. The residue was dissolved in 500 ml of dioxane and the resulting solution was added to 500 ml of 5 N hydrochloric acid. The mixture was heated under reflux for 18 hours, then evaporated to half its volume and filtered. The pH of the filtrate was adjusted to 8 with hydrazine hydrate, the solution was heated at 90°C for 30 minutes and filtered. Table IV 1 Example XXIX XXX XXXI XXXII Substituents on Ring B 7-fluoro 6,7-dichloro 6-chloro 6-fluoro Substituents on Ring B 3,4-dichloro 3,4-dichloro 3,4-dichloro 2-fluoro-4-bromo Yield (%) 26 70*) 10 60*) M.p. 1. (°C 160-162 204-205 143_146 121-123 Solvent(s) for crystallization | isopropanol trichloromethane/ethyl acetate (1:2) ethanol ethanol *) Diazomethane was prepared from bis-N-methyl-N-nitrosoterephthalamide, according to the improved method of Moore and Reed (Qr„ganic Syntheses, Collected Vol. 5, pp. 351-355).118 444 15 16 acidified with concentrated hydrochloric acid until pH 4. After cooling the mixture, a precipitate formed, which was filtered off and washed with 2 x 500 ml of water and dried in vacuo over phosphorus pentoxide 21.0 g of sodium bicarbonate i 40 ml of iodomethane. The whole was stirred overnight and then diluted with 250 ml of water. The precipitate was collected, washed with 2 x 200 ml of water and crystallized from a 2:1 (v/v) mixture of isopropanol and DMF. There was obtained 17.0 g of methyl 6-chloro-1,2-dihydro-1-ketophthalazin-4-ylcarboxylate, melting at 248-250°C. The resulting ester was reacted with 3,4-dichlorobenzyl chloride in a manner analogous to that described in stages (1) and (2) above, to give 2-(3,4-dichlorobenzyl)-6-chloro-1,2-dihydro-1-ketophthalazin-4-ylcarboxylate in a yield of 45%. methyl lasyn-4-ylcarboxylate, m.p. 168-170°C ?{ crystallized from toluene). This ester was then hydrolyzed as described above in step (1), obtaining 2-(3,4-dichlorobenzyl)-6-chloro-1,2-dihydro-1-ketophthalazinylcarboxylic acid-4 with a yield of 60% (crystallized from ethanol). - 4) 2-(2-fluoro-4-bromobenzyl)-6-fluoro-1,2-dihydro-1-ketophthalazinylcarboxylic acid-4. This acid was prepared in a manner analogous to that in stage (3) above, and the intermediates, melting points, solvents and yields used in the process were as follows: methyl 6-fluoro-1,2-dihydro-1-ketophthalazin-4-ylcarboxylate: m.p. 221-223°C (crystallized from a 2:1 (v/v) mixture of methanol and DMF), yield 15%; methyl 2-(2-fluoro-4-bromobenzyl)-6-fluoro-1,2-dihydro-1-ketophthalazin-4-ylcarboxylate: m.p. 131-134°C — crystallized from methanol, yield 51%; 2-(2-fmoro-4-bromobenzyl)-6-fluoro-1,2-dihydro-1-ketophthalazinylcarboxylic acid-4: mp. 210--211 °C (crystallized from isopropanol), yield 70%. Example XXXIII. As in Example 16, by treatment with phosphorus pentasulfide on 2-(2-fluoro-4- Table V Example 1 XXXVIII XXXIX XL XLI XLII XLIII XLIV XLV XLVI XLVII XLVIII 6,7-methylenepdiooxy 6-fluoro 8-ethoxy2) [ Substituents in the A ring 3 4-iodo 3,4-dibromo 2-fluoro-4,5-dibromo 3,5-dichloro-4-bromo 2-methoxy-4-chloro 3,4-dichloro 3,4-dichloro 3,4-dichloro 2-fluoro-4-bromo 3,4-dichloro 2-fluoro-4-bromo 2-fluoro-4-bromo 3,4-dichloro 1 Yield (%) 4 64 6.1 71 60 55 68 43 37 44 72 72' 65 Melting point (°C) 5 178—180 187—189 184—186 219^220 183—184 143_145 182—184 195—197 203—205 209—210 187—188 204—206 . Solvents for crystallization _ ^ ' isopropanol/petrol (60-80°C) 1:2 isopropanol isopropanol isopropanol isopropanol ethyl acetate/toluene 1:2 isopropanol isopropanol/petrol (60-80°C) 1:2 isopropanol/petrol (60-80 °C) 1:2 isopropanol isopropanol isopropanol 0 1:2 mixture of 6-methyl and 7-methyl derivatives 2) the exo-tautomer was detected by NMR. Ethyl 2-(2-fluoro-4-bromobenzyl)-1,2-dihydro-l-ketophthalazin-4-ylacetate was prepared with a yield of 22%, m.p. 97-99 °C (crystallized from ethanol). 5 Examples XXXIV-XXXVII. A mixture of 1.5 g of potassium carbonate, 16 ml of water, 50 ml of dioxane and 1.0 g of ethyl 2-(2-fluoro-4-bromobenzyl)-8-fluoro-1,2-dihydro-1-ketophthalazin-4-ylacetate was heated under reflux for 24 hours and then evaporated. The residue was dissolved in 100 ml of water and the solution was washed with 2 x 100 ml of ether. The aqueous phase was acidified with concentrated hydrochloric acid to pH 2. A precipitate was formed, which was filtered off, washed with water and crystallized from a 7:1:5 (v/v) mixture of toluene, isopropanol and petrol, b.p. 60-80°C, to give 0.5 g of 2-(2-fluoro-4-bromobenzyl)-8-fluoro-1,2-dihydro-1-ketophthalazin-4-ylacetic acid, m.p. 173-175°C (Example XXXIV). Proceeding similarly and starting from the appropriate ethyl esters, the following acetic acid derivatives were obtained: 2-(3, 4-dichlorobenzyl)-7-fluoro-1,2-dihydro-1-ketophthalazin-4-ylacetic acid, mp. 201-202 °C crystallized from a 1:2 mixture (by volume) of ethyl acetate and gasoline with a boiling point. 60-80 °C, yield 90% (example XXXV); 25 2-(3, 4-dichlorobenzyl)-6, 7-dichloro-1,2-*4-hydro-1-ketophthalazin-4-ylacetic acid, mp* 204--205 °C (crystallized from a 5:1 mixture (v/v) of methanol and DMF), yield 76% (Example XXXVI); 2-(3, 4-dichlorobenzyl)-6-chloro-1,2-dihydro-30-1-ketophthalazin-4-ylacetic acid, mp. 208-209 °C (crystallized from isopropanol), yield 55% (Example XXXVII)). EXAMPLES XXXVIII-L. Proceeding as in Example IV, the corresponding ethyl esters were hydrolyzed with potassium hydroxide to give the following acetic acid derivatives of the formula (XVII): Similarly, by hydrolyzing the corresponding ethyl ester with an aqueous methanolic solution of sodium hydroxide, solid 2-(2-fluoro-4-?-bromobenzyl)-1,2-dihydro-1-thioketophthalazin-4-yl acetic acid was obtained in a 30% yield, melting at 194°-196°C (crystallized from methanol) (Example LT). 1.8 g of 2-(3,4-dichlorobenzyl)-8-5-fluorb-1,2-dihydro-l-ketophthalazin-4-ylacetate was added to a solution of 1.5 g of sodium in 150 ml of dry ethanol and the obtained solution was heated under reflux for 3 hours and then evaporated. To the residue 100 ml of water were added and the precipitate was filtered off. After drying the precipitate, 0.5 g of ethyl 2-(3,4-dichlorobenzyl)-10-8-ethoxy-1,2-dihydro-1-ketophtalazin-4-ylacetate was obtained. Example 11: 9.87 g of 2-(2-) acid. -fluoro-4-bromobenzyl)-1,2-dihydro-1-ketophthalazin-4-yl-acetic acid in 300 ml of methanol was added 25 ml of a 1.0 molar solution of sodium methoxide in methanol and the mixture was heated to boiling. While evaporating the methanol, the mixture was concentrated to a volume of about 100 ml, then 150 ml of isopropanol and enough gasoline (bp. 60-80°C) were added to it until the mixture became distinctly turbid. The mixture was then left to stand at room temperature. A precipitate precipitated, which was filtered off, extracted with 2 x 400 ml of toluene and washed with 300 ml of ether. 6.5 g were obtained Sodium 2-(2-fluoro-4-bromobenzyl)-1,2-dihydro-1-keto-phthalazin-4-ylacetate, m.p. 244-247°C. Patent claims 1. A method for the preparation of new derivatives of phthalazin-4-yl-acetic acid of the general formula 1, wherein R2 is a fluorine atom, R3 is a hydrogen atom, R4 is a chlorine, bromine or iodine atom, and R5 is a hydrogen or halogen atom, or R2, R3 and R5 are hydrogen atoms, and R4 is a bromine or iodine atom, or R2 is a hydrogen or fluorine atom, R3 and R5 are the same or different halogen atoms, and R4 is a hydrogen atom, or R2 is a hydrogen or fluorine atom, R3 and R4 are the same or different halogen atoms, and R5 is a hydrogen atom, or R2 is a hydrogen or fluorine atom, R3 and R4 are the same or different halogen atoms, and R5 is a a hydrogen atom, or R2 is a hydrogen atom, R3 and R5 independently are a fluorine or chlorine atom, and R4 is a chlorine, bromine or iodine atom, R6, R7 and R8 independently are a hydrogen or halogen atom, a G-4-alkyl or G-4-alkoxy radical, or R6 and R7 together form a G-4-alkylene dioxy radical, provided that at least one of the symbols R6, R7 and R8 is a hydrogen atom and X" is an oxygen or sulfur atom, optionally in the form of pharmaceutically acceptable base addition salts, characterized in that an ester of formula 3 in which R1 is a G-4-alkoxy radical and R2, R3, R4, R5, R6, R7, R8 and X have the meanings given above is hydrolyzed, wherein, if the product is required in the form of a pharmaceutically acceptable base addition salt, a pharmaceutically acceptable base addition salt, the compound of formula 1 is reacted with a base to give a pharmaceutically acceptable cation. 2. The method of claim 1, wherein the hydrolysis is carried out in the presence of an aqueous mineral acid. 3. The method of claim 1, wherein the hydrolysis is carried out in the presence of an alkali metal hydroxide or carbonate. 4. The method of claim 1, wherein the hydrolysis is carried out at a temperature in the range of 18 to 110°C. 5. A method for the preparation of new derivatives of phthalazin-4-yl-acetic acid of the general formula 1, wherein R2 is a methoxy radical, R3 is a hydrogen atom, R4 is a chlorine, bromine or iodine atom, R6 is a hydrogen or halogen atom, R6, R7 and R8 independently are a hydrogen or halogen atom, a G-4-alkyl radical or a C1-4-alkoxy radical, or R6 and R7 together form a G-4-alkylene dioxy diradical, provided that. at least one of the symbols R6, R7 and R8 is hydrogen and X is oxygen or sulfur, optionally in the form of pharmaceutically acceptable base addition salts, characterized in that an ester of formula 3 in which R1 is a G-4-alkoxy radical and R2, R3, R4, R5, R6, R7, R8 and X are as defined above is hydrolyzed, wherein, if a pharmaceutically acceptable base addition salt product is required, the compound of formula 1 is reacted with a base giving a pharmaceutically acceptable cation. 6. The process of claim 5, characterized in that the hydrolysis is carried out in the presence of an aqueous mineral acid. 7. The process of claim 5, characterized in that the hydrolysis is carried out in the presence of an alkali metal hydroxide or carbonate. 8. The process of claim 1, wherein the hydrolysis is carried out in the presence of an alkali metal hydroxide or carbonate. The method of claim 5, wherein the hydrolysis is carried out at a temperature in the range of 18 to 110°C. 9. A method for the preparation of new derivatives of phthalazin-4-yl acetic acid of the general formula 1, wherein R2 is a fluorine atom, R3 is a hydrogen atom, R4 is a chlorine, bromine or iodine atom, and R5 is a hydrogen or halogen atom, or R2, R3 and R5 are hydrogen atoms, and R4 is a bromine or iodine atom, or R2 is a hydrogen or fluorine atom, R3 and R5 are the same or different halogen atoms, and R4 is a hydrogen atom, or R2 is a hydrogen or fluorine atom, R3 and R4 are the same or different halogen atoms, and R5 is a hydrogen atom, or R2 is a hydrogen atom, R3 and R5 independently are fluorine or chlorine atoms, and R4 is a nitrogen or iodine atom, R6, R7 and R8 independently are hydrogen or halogen atoms, the radical G-4-alkyl or G-4-alkoxy, or R6 and R7 together form a G-4-alkylenedioxy radical, provided that at least one of the symbols R6, R7 and R8 is hydrogen and X is oxygen or sulfur, optionally in the form of pharmaceutically acceptable base addition salts, characterized in that an ester of formula 3, wherein R1 is a radical of formula 4, the remaining symbols R2, R3, R4, R5, R6, R7, R8 and X in these formulae have the meanings given above, is hydrolyzed, wherein, if a pharmaceutically acceptable base addition salt product is required, the compound of formula 1 is reacted with a base to give a pharmaceutically acceptable cation.' 10. A process according to claim 10. 11. The method of claim 9, wherein the hydrolysis is carried out in the presence of an aqueous mineral acid. 12. The method of claim 9, wherein the hydrolysis is carried out in the presence of an alkali metal hydroxide or carbonate. The process of claim 9, characterized in that the hydrolysis is carried out at a temperature in the range of 18 to 110°C. 118 444 R^ R7- & R8 CHoCO.R1 I I 0 WFORMULA 1 c:42cc2h WZtfR 2 "W^ CH.CO.R 1 ^T NH i R8 0 CH2 FORMULA 1a CH2CO.R1 C02Et Rs Hal. CH2^( \-R4 AA o R^ R3 WZtfR 6 CO.R1 WZCiR 10 SCHEMATIC 118 444 rIco R5 H2N.NH-CH2 R2 r3 WZCiR 8 C0CH.N2 R' R2&3 VII CO.Hal B II Lv //a\\ N—Y—('A FORMULA 12 VIII CO.CH.N2 N N—Y -© WZCiR 9 SCHEMAi cont.R8 About WZCiR 14 WZdR 15 CH2C02H 4k Br—CH2—^A^ WZCiR 16 PL PL PL PL

Claims (1)

1.