AT366673B - METHOD FOR PRODUCING NEW PHTHALAZINE-4YLESSIGS [UREN AND ITS SALTS - Google Patents

Description

  

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   The invention relates to a process for the preparation of new phthalazin-4-ylacetic acids which have the property of inhibiting the enzyme aldose reductase in vivo.



   The enzyme aldose reductase is responsible for the catalytic conversion of aldoses, e.g. B. glucose and galactose, in the corresponding alditols, e.g. B. sorbitol or galactitol. Alditols penetrate cell membranes poorly and, once formed, tend to be removed only by another metabolic process. Alditols therefore tend to accumulate in cells where they are formed, which increases the internal osmotic pressure, which in turn may be sufficient to completely or partially hinder the function of the cells themselves. Elevated alditol levels can also lead to an abnormal accumulation of their metabolites, which in turn can impair cell function.

   However, the enzyme aldose reductase has a relatively low substrate affinity, i. H. it is only effective in the presence of relatively high aldose concentrations. Such high concentrations of aldose are present in clinical conditions of diabetes (excess glucose) and galactosemia (excess galactose). Agents that inhibit the enzyme aldose reductase are therefore valuable in reducing or preventing the development of those peripheral effects of diabetes or galactosemia that may occur in part due to the accumulation of sorbitol or galactitol. Such peripheral effects are e.g. B. macular edema, cataracts, retinopathy or impaired nerve conduction.
 EMI1.1
 and their methyl and ethyl esters are known and their effect on the blood coagulation system has been described (Sh. Feldeak u.

   Collaborator, Khim. Farm. Zh., 1970.4, 22-26; Chemical Abstracts, 1970, 73, 77173), but in contrast to the compounds which can be prepared according to the invention described below, none of these known phthalazine derivatives is an inhibitor of aldose reductase in vivo at oral doses of 100 mg / kg and below.



   The invention relates to a process for the preparation of a new 2-benzyl-1, 2-dihydro-1-oxo- - phthalazin-4-ylacetic acid of the general formula
 EMI1.2
 in which the substituents R2, R ', R' and RS on the benzene ring A are selected from one of the following combinations: a) R2 represents fluorine or the methoxy group, R3 represents hydrogen, R '* represents chlorine, bromine or
Iodine and R for hydrogen or halogen; b) R2, R3 and R 5 represent hydrogen and R is bromine or iodine;

   c) R2 is hydrogen or fluorine, R and R represent identical or different halogen radicals and R 'is hydrogen; d) R2 is hydrogen or fluorine, R'andRR are identical or different halogen radicals and R 5 is hydrogen; and e) R2 is hydrogen, R3 and RS are independently fluorine or chlorine and R is chlorine, bromine or iodine;

   and in which furthermore RS, R 7 and RB on the benzene ring B independently of one another represent hydrogen, halogen, C 1-4-alkyl or C 1-4-alkoxy groups or RS and R7 together form a C, ¯4-alkylene-dioxydi group , wherein at least one of the substituents R, R 'and R is hydrogen;

   X

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 represents oxygen or sulfur; or a pharmaceutically acceptable base addition salt thereof, which method is characterized in that an ester of the general formula
 EMI2.1
 in which R * is a C-alkoxy group or a group of the general formula
 EMI2.2
 is in which X, the benzene rings A and B and the substituents thereon have the meanings given above, reacting to produce a pharmaceutically acceptable base addition salt, the acetic acid of the general formula (I) with a pharmaceutically acceptable cation-providing base.



   The hydrolysis can be carried out in the presence of an acid or a base, e.g. B. hydrochloric acid or alkali metal hydroxide or carbonate, e.g. As sodium or potassium hydroxide or carbonate, are carried out.
 EMI2.3
 advantageously by heating, e.g. B. accelerated to 35 to 110 C.



   The compounds of the general formula (I) are derivatives of l, Z-dihydro-l-oxo (or thioxo) phthalazin-4-ylacetic acid, which is numbered here as follows:
 EMI2.4
 X stands for oxygen or sulfur.



   The compounds of the general formula (I) can also be used as tautomers of the general formula
 EMI2.5
 

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 are present, and the invention comprises the preparation of tautomers of the general formula (I) (endo-tautomeres) or of the general formula (Ia) (exo-tautomeres) and mixtures thereof.



   A halogen R 3 or R 5 can e.g. B. fluorine, chlorine, bromine or iodine and in particular chlorine or bromine.



   If R R or R are halogen, it may e.g. B. fluorine, chlorine, bromine or iodine; a suitable C 1-4 alkyl group is e.g. B. a methyl group and a suitable C 1-4 alkoxy group is z. B. a methoxy or ethoxy group.
 EMI3.1
 if the benzene ring B is unsubstituted or a 6-fluoro, 6-chloro, 6-methyl, 7-fluorine, 7-chloro, 7-methyl, 7-methoxy, 8-fluoro, 8- Methyl or 8-ethoxy or a 6, 7-dichloro or 6, 7-methylenedioxydirest carries.



   A specific base addition salt of a compound of general formula (I) is e.g. B. an alkali metal or alkaline earth metal salt, e.g. B. a sodium, potassium, calcium or magnesium salt, an aluminum or ammonium salt or a salt of a pharmaceutically acceptable cation-providing organic base, e.g. B. a salt of triethanolamine.



   Special groups of compounds which are particularly preferred include those compounds of the general formula (I) in which (I) R is fluorine, R 'and R are hydrogen and R4 is chlorine, bromine or iodine; (II) R 3 and R 4 independently of one another are chlorine, bromine or iodine and R2 and R are hydrogen; (III) R6 and R7 and R8 are hydrogen; or (IV) X represents oxygen; and in each of groups (I) to (IV) the other symbols R2, R \ R \ RI, RI, R7, RI and X have one of the meanings given above or one of the meanings given in another group; and their pharmaceutically acceptable base addition salts.



   Specific compounds that can be produced according to the invention are described in the examples, and the following are preferred:
 EMI3.2
 azin-4-ylacetic acid and its pharmaceutically acceptable base addition salts.



   The required starting materials of the general formula (II) can be prepared by methods known in organic chemistry for the preparation of chemically analogous compounds
 EMI3.3
 unless otherwise stated, the benzene rings A and B have one of the meanings above.



   (a) Preparation of a compound of the general formula (II), in which X means oxygen, by reacting a compound of the general formula
 EMI3.4
 with a halide of the general formula

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 EMI4.1
 where Hal is chlorine, bromine or iodine in the presence of a suitable base.



  The method is preferably carried out in a solvent or diluent, e.g. B. ethanol, dimethylformamide, dimethyl sulfoxide or water and expediently accelerated by heating to about 40 to 100 C.
 EMI4.2
 is used as a solvent.



  (b) Preparation of a compound of the general formula (II), in which X represents oxygen, by reacting a compound of the general formula
 EMI4.3
 or a geometric isomer thereof with a hydrazine of the general formula
 EMI4.4
 
 EMI4.5
 orR1 represents a C1 -4 alkoxy group by catalytic decomposition of a diazoketone of the general formula
 EMI4.6
 

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 EMI5.1
 or ethanol, tetrahydrofuran or dioxane and expediently carried out using an excess of the compound of the general formula Q. H, optionally together with tetrahydrofuran or dioxane.



  The process is advantageously carried out by heating, e.g. B. accelerated to a temperature in the range of 40 to 110 C.
 EMI5.2
 in which the benzene ring B has a halogen substituent, e.g. B. fluorine, with an alkali metal C-alkoxide, e.g. B. sodium methoxide or ethoxide.



   The reaction is preferably carried out in a solvent or diluent, e.g. B. in an excess of the corresponding C, 4-alkanol, for example methanol or ethanol, and can be carried out by heating to z. B. 40 to 1100C or expediently accelerated to the boiling point of the reaction mixture.



   (e) A compound of the general formula (II) in which X represents sulfur can be obtained by converting the corresponding oxo compound of the general formula (II), in which
X is oxygen, according to known processes and under usual conditions, in the sulfur compound, e.g. B. by reaction with phosphorus pentasulfide in boiling xylene or
Pyridine.



   These two known methods are explained in the examples.



   The starting materials of the general formulas (IV), (VII) and (VIII) can be prepared by standard methods known in heterocyclic chemistry, as described, for. B. by N.R. Patel in "The Chemistry of Heterocyclic Compounds", vol. 27, Interscience, New York. A typical procedure for this is e.g.

   B. the preparation of the diazoketone of the general formula (IX) required for process (d), which is shown in Scheme 1; The following reagents were used: (i) n-Bu.Li, Ät2 O or (MeOCH2) 2, -10 to 0 C (ii) diethyl oxalate, 0 to 5 C (iii) H + / HO / dioxane, 90 to 100 C ( iv) K2CO3 / KMnO4 / H2O, 100 C (v) H2NNH2.H2O, 90 to 100 C (vi) as procedure (a) (vii) SO. (Hal). "(Hal = Cl or Br) or (COCl) (viii) excess CHN / ÄtO;
 EMI5.3
 for example, by reacting their sodium salt with methyl iodide in dimethylformamide before performing the alkylation with the benzyl halide (step vi).

   This modification is described in Examples 7 and 8 and requires conventional hydrolysis to the corresponding acid after the alkylation and before carrying out step (vii).

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 EMI6.1
 
 EMI6.2
 

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 To avoid oxalate derivatives. When carrying out process (d), it is also expedient to prepare the diazoketone (VIII) in situ from the acid halide (X).



   The starting materials of the general formula (IV) for process (a) can be obtained analogously to process (b) d. that is, by reacting a compound of the general formula (VI) with hydrazine hydrate and then converting the phthalazin-4-ylacetic acid product as the free acid or acid chloride into the corresponding ester in a conventional manner.



   Some of the starting materials of the general formula (VI) can advantageously be obtained from the correspondingly substituted phthalic anhydride of the general formula
 EMI7.1
 by condensation with acetic anhydride, e.g. B. in the presence of sodium or potassium acetate and in an excess of boiling acetic anhydride. However, you can also all by a Wittig reaction between the corresponding phthalic anhydride of the general formula (XIII) and (carbäthoxymethylene) triphenylphosphorane in a suitable solvent, e.g. B. 1, 2-dimethoxyethane or tetrahydrofuran can be obtained, the reaction can be expediently accelerated by heating, for example to the boiling point of the reaction mixture.

   In some cases, the product of the Wittig reaction can be the geometric isomer of the general formula
 EMI7.2
 instead of that shown in formula (VI). However, a mixture of both geometrical isomers can also be formed. Any isomer or a mixture thereof can be used in process (b). It should also be noted that the Wittig reaction, if R and R 7 and R are hydrogen, gives positional isomers, depending on which of the two carbonyl groups of the phthalic anhydride (XIII) reacts. If Re is different from hydrogen, a positional isomer predominates, u. between that formed by reaction of the furthest carbonyl group from RB.



   The above-mentioned pharmaceutically acceptable base addition salts can be prepared in the usual way by reaction with the corresponding base, which supplies a pharmaceutically acceptable cation.



   The property of inhibiting the enzyme aldose reductase can be demonstrated in the following standard laboratory experiment: rats are diabetic by administration of streptozotocin and the test compound is then administered to them for 5 days a day. The animals are then sacrificed and the eye lenses and sciatic nerves are removed. Using a standard work-up procedure, the residual sorbitol levels in each tissue are determined by gas liquid chromatography after conversion to the polytrimethylsilyl derivatives. Inhibition of aldose reductase in vivo is then determined by comparing residual sorbitol levels in tissues of the treated diabetic group of rats with that of an untreated group of diabetic rats and an untreated group of normal rats.

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   However, a modified test can also be used, in which the test compound is administered to rats diabetic by means of streptozotocin for two days a day. 2 to 4 hours after the last administration, the animals are sacrificed, the sciatic nerves are removed and examined for residual sorbitol levels as described above.



   Compounds active in either test reduce residual sorbitol levels to levels similar to those of normal, untreated rats. In general, however, they do
 EMI8.1
 Sciatic nerve residual sorbitol level of about 60% of that obtained in untreated, diabetic control animals. No apparent toxic or other undesirable effects were found for compounds of general formula (I) at 100 mg / kg in the above tests.



   The property of inhibiting the enzyme aldose reductase can also be demonstrated in vitro. Purified aldose reductase is isolated from bovine lentils in a known manner. The percentage of inhibition by a test compound of the ability of this enzyme to reduce aldoses in vitro to polyhydric alcohols and in particular glucose to sorbitol is then determined using known spectrophotometric methods. In this test, those compounds of the general formula (I) in which R 'is a hydroxyl group show a clear inhibition
 EMI8.2
 To exercise the enzyme aldose reductase in warm-blooded animals, it can first be administered orally in a daily dose of 2 to 50 mg / kg, which corresponds to a total daily dose in humans of 20 to 750 mg, if necessary in partial doses.



   The compounds obtainable according to the invention can be administered in the form of pharmaceutical compositions.



   Pharmaceutical compositions which are in a form suitable for oral administration are particularly preferred, e.g. B. tablets, capsules, suspensions or solutions, which can be obtained in a conventional manner and, if desired, can contain customary diluents, carriers or other binders.



   In addition to the aldose reductase-inhibiting properties, several compounds which can be prepared according to the invention also have anti-inflammatory / analgesic properties of the type used in non-steroidal anti-inflammatory agents, e.g. B. indomethacin, naproxen and ketoprofen.



  These compounds may also be useful in the treatment of painful inflammatory joint diseases such as rheumatoid arthritis, osteoarthritis and stiffening spondylitis. In this connection, it is intended to be administered orally first in a daily dose in the range from 10 to 50 mg / kg. The anti-inflammatory properties can be demonstrated in known standard laboratory tests on rats. For example, both
 EMI8.3
 caused edema in the winter and Employee developed test [Proceedings of the Society of Experimental Biology (New York), 1962, 111, 554] with no evidence of apparent toxicity.



   The invention is illustrated by the following examples, to which it is not limited, in which (a) unless otherwise stated, all evaporation is carried out by rotary evaporation in vacuo; (b) all operations, unless otherwise stated, are carried out at room temperature (in the range from 18 to 26 C), (c) petroleum ether (Kp.

   60 to 800C are designated as "petroleum (60 to 80)" and other petroleum ether fractions accordingly, (d) melting points of the acetic acids are often associated with decomposition, (e) all compounds of the general formula (I) and isolated intermediates based

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 are characterized by microanalysis and KMR and IR spectroscopy, (f) yields, where indicated, are only for illustration and do not necessarily represent the maximum achievable; and (g) Examples 4 to 6.9, 10.13 to 15.34 to 50 and 52 explain the process according to the invention itself, while the remaining examples serve to explain the preparation of starting materials required here.



   Example 1: A mixture of 11.5 g of 1,2-dihydro-1-oxo-phthalazin-4-ylacetate and 2.7 g of sodium hydride (50% by weight dispersion in mineral oil) in 125 ml of dimethylformamide is added for 1 hour Nitrogen stirred at 600C. The solution obtained is cooled to room temperature, then 15.0 g of 4-bromo-3-chlorobenzyl bromide are added, and the mixture is stirred at 60 ° C. for 2 hours.



  The mixture is cooled to 25 ° C. and the reaction mixture is poured into 500 ml of water. The aqueous mixture obtained is extracted with 400 ml of ethyl acetate. The extracts are washed with water, dried (MgSO 4) and evaporated. A solid is obtained which is recrystallized from propan-2-ol. 7.3 g of ethyl 2- (3-chloro-4-bromobenzyl) -1, 2-dihydro-1-oxo-phthalazin-4-ylacetate, mp 142 to 145 C., are obtained.



   Examples 2 to 3: Using a procedure similar to that described in Example 1, the following compounds of the general formula are obtained
 EMI9.1
 in which the ring B is unsubstituted, from ethyl 1, 2-dihydro-2-oxo-phthalazin-4-ylacetate and the corresponding bromide of the general formula
 EMI9.2
 
 EMI9.3
 
 <tb>
 <tb> substituents <SEP> yield <SEP> Fp. <SEP> recrystallization example <SEP> on <SEP> benzene ring <SEP> A <SEP> (%) <SEP> (OC) <SEP> solvent
 <tb> 2 <SEP> x) <SEP> 3, <SEP> 4-dichloro <SEP> 40 <SEP> 139 <SEP> - <SEP> 141 <SEP> i-PrOH <SEP>
 <tb> 3 <SEP> 2-fluoro-4-bromo <SEP> 60 <SEP> 114 <SEP> ÄtOH
 <tb>
   Note: 3, 4-dichlorobenzyl chloride is used as the starting material.



   Example 4: A solution of 7.0 g of ethyl 2- (3-chloro-4-bromobenzyl) -1, 2-dihydro-1-oxo-phthalazin- - 4-ylacetate in 70 ml of ethanol, which was 7.0 g Contains potassium hydroxide, is heated under reflux for 30 min. The solution is then poured into 250 ml of water and the aqueous solution is extracted with ether (2 x 150 ml). The aqueous phase is concentrated with. Acidified hydrochloric acid to a pH of 2. The solid which precipitates out is separated off, washed with water, dried in vacuo and then recrystallized from a 6: 2: 3 (parts by volume) mixture of toluene, propanol and petroleum (60 to 80); 3.9 g of 2- (3-chloro-4-bromobenzyl) -1, 2-dihydro-1-oxo-phthalazin-4-ylacetic acid, mp. 186 C., are obtained.



   Examples 5 to 6: Following similar procedures as in Example 4, the following compounds of the general formula

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 EMI10.1
 in which the ring B is unsubstituted, obtained by hydrolysis of the corresponding ethyl ester of the general formula (I):
 EMI10.2
 
 <tb>
 <tb> substituents <SEP> yield <SEP> Fp. <SEP> recrystallization <SEP>
 <tb> example <SEP> on <SEP> benzene ring <SEP> A <SEP> (%) <SEP> (OC) <SEP> solvent
 <tb> 5 <SEP> 3, <SEP> 4-dichloro <SEP> 60 <SEP> 175 <SEP> - <SEP> 176 <SEP> toluene / i-PrOH <SEP> (2nd <SEP>: <SEP> 1) <SEP>
 <tb> 6 <SEP> 2-fluoro-4-bromo <SEP> 64 <SEP> x) <SEP> 184 <SEP> - <SEP> 185 <SEP> methanol <SEP>
 <tb>
 x) Note:

   This compound can be in polymorphic forms, i.e. i. a shape with a
Mp from 185 to 185 C (from methanol which contains some water) and one
Mold with a mp. 180 to 182 C (from two crystallizations from dry
Methanol), crystallize.



   Example 7: A stirred mixture of 1.9 g of 2- (3,4-dichlorobenzyl) -7-methoxy-1,2-dihydro-1--oxo-phthalazin-4-ylcarboxylic acid in 10 ml of thionyl chloride, the 0.1 Contains ml of dimethylformamide, is heated under reflux for 3 h. The solution obtained is then evaporated. The residue is dissolved in dry toluene and the solution is evaporated. This process is carried out three times and 2- (3, 4-dichlorobenzyl) -7-methoxy-1,2-dihydro-1-oxo-ph thalazin-4-yl-carboxylic acid chloride is obtained in essentially quantitative yield as a solid with a satisfactory IR -Spectrum.



   A solution of the above acid chloride in 50 ml of dry tetrahydrofuran is added dropwise to a stirred, cooled to 0 ° C. solution of diazomethane in dry ether (200 ml) [
 EMI10.3
 and allowed to warm to room temperature for 2 hours. The mixture is then filtered. The residue obtained is washed with dry tetrahydrofuran (20 ml) and the combined
 EMI10.4
 terization is used.



   A solution of 0.2 g of silver benzoate in 1 ml of triethylamine is slowly added dropwise to a solution of the above 4- (a-diazo) acetyl derivative in 50 ml of absolute ethanol and 30 ml of tetrahydrofuran, which is heated under reflux. (After each addition there is an effervescence which is allowed to subside before further solution is added.)
 EMI10.5
 (100 g) purified using an increasing concentration of ethyl acetate in toluene as the eluent. The corresponding fractions are thus obtained, assessed by thin layer chromatography (TLC) on silicon dioxide plates using ethyl acetate / toluene (1: 3 vol.
 EMI10.6
 azin-4-ylacetate, mp 129-1300C.



   The required starting material is obtained as follows:

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 (a) A mixture of 10.0 g, 7-methoxy-1, 2-dihydro-1-oxo-phthalazin-4-ylcarboxylic acid 15.0 g sodium hydrogen carbonate and 15.0 ml methyl iodide in 200 ml dry dimethylformamide is added for 16 hours Room temperature stirred. The mixture is then poured into 600 ml of water. The solid which precipitates is separated off, washed first with water and then with cold methanol, and recrystallized from methanol; 8.6 g of methyl 7-methoxy-1,2-dihydro-1-oxo-phthalazine-4-ylcarboxylate, mp. 222 to 225 C., are obtained.



   (b) A solution of the methyl ester (8.29 g) obtained in (a) above in 200 ml of dry dimethylformamide is treated with 1.75 g of sodium hydride (50% by weight dispersion in mineral oil). The mixture is stirred at 600C for 1 h, cooled to room temperature, and 7.0 g of 3,4-dichlorobenzyl chloride are added. The resulting mixture is stirred at room temperature for 2 hours and then poured into 600 ml of water. The solid formed is separated off, washed with water,
 EMI11.1
 



   (c) A solution of 9.0 g of the methyl ester obtained in (b) above in 100 ml of ethanol and 100 ml of water containing 10.0 g of potassium hydroxide is heated under reflux for 4 h. The solution obtained is then diluted with 200 ml of water and concentrated with. Acidified hydrochloric acid to a pH of 2. The solid which precipitates is separated off, washed with water, dried in vacuo and recrystallized from a 1: 1 (v / v) mixture of propan-2-ol and dimethylformamide. This gives 6.1 g of 2- (3,4-dichlorobenzyl) -7-methoxy-1,2-dihydro-1-oxo-phthalazin-4-ylcarbon-
 EMI11.2
 



  Soc. 1946.68 1314)
Example 8: According to a similar procedure as in Example 7, but starting from 2- (3,4-dichlorobenzyl) -7-chloro-1,2-dihydro-1-oxo-phthalazin-4-ylcarboxylic acid (A) , Is obtained in 8% yield ethyl 2- (3, 4-dichlorobenzyl) -7-chloro-1, 2-dihydro-1-oxo-phthalazin-4-ylacetate as a solid with a satisfactory KMR spectrum.



   The carboxylic acid derivative (A) used as the starting material is, according to a similar process (a) to (c), as described in Example 8 for the starting material, but
 EMI11.3
 lat, mp 178 to 180 C [recrystallized from 1: 3 (v / v) propan-2-ol / petrol (60 to 80)]; from stage (c): 2- (3, 4-dichlorobenzyl) -7-chloro-1, 2-dihydro-1-oxo-phthalazin-4-ylcarboxylic acid, mp. 260 to 262 C (recrystallized from 1: 1, vol . / Vol., Methanol / dimethylformamide).



   [Note: The carboxylic acid (B) is obtained as a solid, mp 241 to 243 C, according to the Vaughan et al. Employee (J. Amer. Chem. Soc., 1946, 68, 1314) similar processes, but obtained from 4-chloro-2-methylacetophenone.]
Examples 9 to 10: Using a procedure similar to that described in Example 4, but starting from the corresponding ethyl ester, the following acids are obtained: (Example 9): 2- (3, 4-dichlorobenzyl) -7-methoxy-1 , 2-dihydro-1-oxo-phthalazin-4-ylacetic acid,
 EMI11.4
 43%.



   Examples 11 and 12: Following a procedure similar to that described in Example 1, the following esters are obtained using the appropriate benzyl bromide or chloride:
 EMI11.5
 (Example 12): ethyl 2- (2-fluoro-4-iodobenzyl) -1, 2-dihydro-1-oxo-phthalazin-4-ylacetate, mp 1130C recrystallized from petroleum (60 to 80); Yield 50%].

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   Examples 13 to 15: A procedure similar to that described in Example 4 is used, but starting from the corresponding ethyl ester, and the following acids are obtained: (Example 13): 2- (2-fluoro-4-chlorobenzyl) -1, 2-dihydro-1-oxo-phthalazin-4-ylacetic acid, mp 193 to 1940C (recrystallized from 3: 1, v / v, ethanol / water); Yield 63%; (Example 14): 2- (2-fluoro-4-iodobenzyl) -1, 2-dihydro-1-oxo-phthalazin-4-ylacetic acid, mp 1890C (recrystallized from 3: 1 v / v ethanol / water ); Yield 55%; (Example 15): (Hydrolysis is carried out with aqueous methanolic sodium hydroxide solution for 10 min under reflux cooling.)
 EMI12.1
 (recrystallized from propanol-2-ol); Yield 25%.



   Example 16: A mixture of 1.8 g of ethyl 2- (3-chloro-4-bromobenzyl) -1, 2-dihydro-1-oxo-phthalazin-4-ylacetate and 2.5 g of phosphorus pentasulfide in 100 ml of xylene is Stirred for 1 h and heated under reflux. The reaction solution is then cooled to room temperature, 25 ml of ethyl acetate are added, and the mixture is filtered through chromatographic silica (20 g); the filtrate is evaporated and the solid residue obtained is recrystallized from ethanol.



  1.1 g of 2- (3-chloro-4-bromobenzyl) -1, 2-dihydro-l-thioxo-phthalazin-4-ylacetate are obtained, mp 124 to 126 C.



   Examples 17 to 22: Following a procedure similar to that described in Example 1, but using the corresponding benzyl bromide of the general formula (XV), the following compounds of the general formula (XIV) are obtained, in which the ring B is unsubstituted.
 EMI12.2
 
 <tb>
 <tb>



  Substituents <SEP> yield <SEP> recrystallization example <SEP> on <SEP> benzene ring <SEP> A <SEP> (%) <SEP> Fp. <SEP> (OC) <SEP> solvent
 <tb> 17 <SEP> 3, <SEP> 4-dibromo <SEP> 44 <SEP> 140 <SEP> - <SEP> 142 <SEP> i-PrOH
 <tb> 18 <SEP> 2-fluoro-4, <SEP> 5- <SEP>
 <tb> -dibrom <SEP> 21 <SEP> 129 <SEP> - <SEP> 130 <SEP> ÄtOAc
 <tb> 19 <SEP> 3, <SEP> 5-dichloro <SEP> 36 <SEP> 100 <SEP> - <SEP> 101 <SEP> ÄtOAc
 <tb> 20 <SEP> 3. <SEP> 5-dichloro- <SEP>
 <tb> - <SEP> 4-bromine <SEP> 19 <SEP> 146 <SEP> - <SEP> 147 <SEP> ÄtOH <SEP>
 <tb> 21 <SEP> 2-methoxy-4-chlorine <SEP> 22 <SEP> 138 <SEP> i-PrOH
 <tb> 22 <SEP> 4-iodine <SEP> 43 <SEP> 106 <SEP> - <SEP> 107 <SEP> i-PrOH / petrol <SEP> (60 <SEP> - <SEP> 80)
 <tb> 1 <SEP>: <SEP> 3
 <tb>
 
Examples 23 to 25

   2.29 g of ethyl 4-methyl-3-oxo-la-phthalana acetate are stirred in 200 ml of toluene during the dropwise addition of a solution of 1.9 g of 3,4-dichlorobenzylhydrazine in 50 ml of toluene and heated under reflux. The mixture is refluxed for a further 3 h, cooled and evaporated.

   The solid residue is recrystallized from 1: 2 (v / v) isopropanol and petroleum (60 to 80), and 1.4 g of ethyl 2- (3, 4-dichlorobenzyl) -6-methyl-1 are obtained. 2-dihydro-1-oxo-phthalazin-4-ylacetate (Example 23), mp. 134 to 137 C. In a similar manner, but starting from ethyl 4-fluoro-3-oxo-la-phthalane acetate, ethyl is obtained -2- (3, 4-dichlorobenzyl) -8-fluoro-1, 2-dihydro-1-oxo-phthalazin-4-ylacetate (Example 24), mp. 177 to 1780C [recrystallized from 1: 2 (vol. / Vol.) Isopropanol / petrol (60 to 80)], in 37% yield.
 EMI12.3
 installed from isopropanol) in 33% yield.



   The required starting materials are obtained as follows:
A solution of 7.35 g of 3-fluorophthalic anhydride and 17.5 g of carbethoxymethylene) triphenylphosphorane in 200 ml of dry 1,2-dimethoxyethane is stirred for 16 hours in a nitrogen atmosphere and heated under reflux. The solvent is then evaporated and the residue

  <Desc / Clms Page number 13>

 adsorbed on 20 g of chromatographic silica gel. This silica gel is then applied to the top of a column of the same silica gel (300 g) and the column is eluted with toluene. The eluate is examined by TLC (SiO 2 gel: eluent 9: 1 v / v toluene / ethyl acetate), and the first fractions containing UV-visible material are combined and evaporated.

   The solid residue is recrystallized from isopropanol, and ethyl 4-fluoro-3-oxo-Ala-phthalan acetate (2.3 g), mp. 101 to 103 C, which is required for Example 24, is obtained.



   In a similar way, ethyl 4-methyl-3-oxo-Ala-phthalanacetat (required for Example 23) as a solid, 84 to 86 C, in 56% yield after recrystallization from isopropanol, starting from 3-methylphthalic anhydride.
 EMI13.1
 in 40% yield as a solid, mp. 84 to 86 C (recrystallized from isopropanol).



   Examples 26 to 28: Using a procedure similar to that described in Example 1, the following compounds are obtained from the appropriately substituted 1,2-dihydro-1-oxo-phthalazin-4-ylacetate and 2-fluoro-4-bromobenzylhydrazine: (Example 26): Ethyl-2- (2-fluoro-4-bromobenzyl) -8-fluoro-1,2-dihydro-1-oxo-phthalazin-4-y-acetate, mp. 128 to 1300C [recrystallized from 1: 3 vol . / Vol. Isopropanol / petrol (60 to 80)] in 36% yield; (Example 27): Ethyl 2- (2-fluoro-4-bromobenzyl) -8-methyl-1,2-dihydro-1-oxo-phthalazin-4-ylacetate, mp 120 to 1220C [recrystallized from 1: 3 Vol. / Vol.

   Isopropanol / petrol (60 to 80)] in 43% yield; and (Example 28): ethyl 2- (2-fluoro-4-bromobenzyl) -6, 7-methylenedioxy-1, 2-dihydro-1-oxo-phthalazin- - 4-ylacetate, mp 163 to 1650C (recrystallized from ethyl acetate) in 56% yield.



   The required starting materials are obtained as follows: (a) ethyl-8-fluoro-1,2-dihydro-1-oxo-phthalazin-4-ylacetate (for example 27)
A solution of 3.5 g of ethyl 4-methyl-3-oxo-a-phthalanacetate in 100 ml of ethanol is stirred during the dropwise addition of hydrazine hydrate (15 ml of a 1m solution in ethanol) and heated under reflux. When the addition is complete, the mixture is stirred for a further 3 h and heated under reflux and then allowed to cool to room temperature. The solid which precipitates is collected and washed well with petroleum (60 to 80) and recrystallized from isopropanol / petrol (60 to 80). 1.0 g of ethyl 8-methyl-1,2-dihydro-1-oxo-phthalazin-4- ylacetate is obtained, mp 197 to 199OC.



   (b) ethyl-8-fluoro-1,2-dihydro-1-oxo-phthalazin-4-ylacetate (for example 26)
This ester is obtained as a solid, mp. 207 to 2100C (recrystallized from ethyl acetate) in 51% yield from ethyl 4-fluoro-3-oxo-A la-phthalanacetate and hydrazine hydrate according to the procedure described in (a) above.



   (c) ethyl 6,7-methylenedioxy-1,2-dihydro-1-oxo-phthalazin-4-ylacetate (for example 28)
This ester is obtained as a solid, mp. 226 to 228 C, in 70% yield from ethyl 5, 6-
 EMI13.2
 (A) for its part is obtained as a solid, mp 189 to 191 C (recrystallized from ethanol), in 64% yield from 4,5-methylenedioxyphthalic anhydride by a process which is analogous to that for the corresponding intermediates in Examples 23 to 25 . (This method is based on that of Knight and Porter, Tetrahedron Letters, 1977, 4543 to 4547).



   Examples 29 to 32: The following esters of the general formula (XIV) are obtained from the corresponding starting materials by an analogous procedure to that described in Example 7:

  <Desc / Clms Page number 14>

 
 EMI14.1
 
 <tb>
 <tb> From on-substituents <SEP> substituents <SEP> booty <SEP> recrystallization game <SEP> on <SEP> ring <SEP> B <SEP> on <SEP> ring <SEP> A <SEP> (%) <SEP> Fp. <SEP> (C) <SEP> solvent
 <tb> 29 <SEP> 7-fluorine <SEP> 3, <SEP> 4-dichloro <SEP> 26 <SEP> 160 <SEP> - <SEP> 162 <SEP> i-PrOH
 <tb> 30 <SEP> 6, <SEP> 7-dichlor <SEP> 3, <SEP> 4-dichloro <SEP> 70 <SEP> x) <SEP> 204-205 <SEP> CHCI./ÄtOAc <SEP> (l <SEP>:

    <SEP> 2)
 <tb> 31 <SEP> 6-chlorine <SEP> 3, <SEP> 4-dichloro <SEP> 10 <SEP> 143 <SEP> - <SEP> 146 <SEP> ÄtOH <SEP>
 <tb> 32 <SEP> 6-fluorine <SEP> 2-fluoro-4-bromo <SEP> 60 <SEP> x) <SEP> 121 <SEP> - <SEP> 123 <SEP> ÄtOH <SEP>
 <tb>
 
Note: Diazomethane is produced from bis (N-methyl-N-nitroso) terephthalamide using the improved method of Moore and Reed (Organic Syntheses, Collected
Vol. 5, pp. 351 to 355).



   The phthalazin-4-ylcarboxylic acids used as the starting material can be obtained as follows:
 EMI14.2
 (3, 4-dichlorobenzyl) -7-fluoro-1, 2-dihydro-1-oxo-phthalazin-4-ylcarboxylic acid 243 C, in 52% yield according to a method described by Vaughan et al. Coworker, J. Amer. Chem. Soc. 1946, 68, 1314, similar process) is converted into its sodium salt and reacted with iodomethane by the process described in part (a) of Example 7; the corresponding methyl ester is obtained as a solid, mp. 234 to 237 C [recrystallized from 3: 1 vol./VO!. Methanol / dimethylformamide (DMF)], in 68% yield.

   This ester is then alkylated with 3,4-dichlorobenzyl chloride by the process according to part (b) of Example 7, and methyl-2- (3,4-dichlorobenzyl) -7- - fluoro-1,2-dihydro-l is obtained -oxo-phthalazin-4-ylcarboxylate, mp. 147 to 149 C [recrystallized from l: l v / v. Toluene / petrol (60 to 80)] in 68% yield.

   This ester is then made using a mixture of aqueous potassium carbonate and dioxane after that in Example 34
 EMI14.3
 
This acid is obtained analogously to that described under (a) above; the relevant intermediates, melting points, solvents and yields are as follows:
6, 7-dichloro-1,2-dihydro-1-oxo-phthalazin-4-ylcarboxylic acid: mp 294 to 296 C (recrystallized from DMF), yield 42%; Corresponding methyl ester: mp 234 to 236 C (recrystallized from DMF), yield 51%;
 EMI14.4
 (600 ml), which is kept at -5 to 0 C and under an atmosphere of dry argon.

   After the addition has ended, the mixture is stirred at this temperature for a further 30 min and the solution is then slowly added to a stirred solution of 326 ml of dry diethyl oxalate in 500 ml of ether which is kept at 0 ° C. During this addition, air and water are excluded using an atmosphere of dry argon. After the addition has ended, the reaction mixture is stirred further and allowed to warm to room temperature over 1 h. The ethereal mixture is then washed with water (2 x 150 ml), dried over MgSO 4 and evaporated under reduced pressure (1.33 kPa) until all excess diethyl oxalate has been removed. The backlog will

  <Desc / Clms Page number 15>

 dissolved in 500 ml of dioxane and the solution is added 5N hydrochloric acid (500 ml).

   The mixture is heated under reflux for 18 h, evaporated to half the volume and the remaining solution is filtered. The filtrate is adjusted to a pH of 8 by adding hydrazine hydrate, and the solution is heated to 90 C for 30 min and then concentrated. Acidified hydrochloric acid to a pH of 4. The mixture is cooled and the solid which precipitates is filtered off, washed with water (2 × 500 ml) and dried in vacuo over phosphorus pentoxide. 21.0 g of 6-chloro-1,2-dihydro-1-oxo-phthalazin-4-ylcarboxylic acid are obtained.



   This acid is suspended in 250 ml of DMF and the mixture is treated with 21.0 g of sodium hydrogen carbonate and 40 ml of iodomethane. The combined mixture is stirred overnight and then diluted with 250 ml of water. The precipitated solid is collected, washed with water (2 x 200 ml) and extracted from 2: 1 VOl./Vol. Isopropanol / DMF recrystallized. 17.0 g of methyl 6-chloro-1,2-dihydro-1-oxo-phthalazin-4-ylcarboxylate are obtained, mp 248 to 250 C.



   This ester is then reacted with 3,4-dichlorobenzyl chloride in an analogous manner as described above under (a) and (b). This gives methyl 2- (3, 4-dichlorobenzyl) -6-chloro-1, 2-dihydro-1- - oxo-phthalazin-4-ylcarboxylate, mp. 168 to 170 C (recrystallized from toluene), in 45% yield. This ester is then hydrolyzed as described under (a) above, and 2- (3, 4-dichlorobenzyl) -6-chloro-1,2-dihydro-l-oxo-phthalazin-4-ylcarboxylic acid, mp. 222 to 223 C (recrystallized from ethanol), in 60% yield.



   (d) 2- (2-Fluoro-4-bromobenzyl) -6-fluoro-1,2-dihydro-1-oxo-phthalazin-4-ylcarboxylic acid
This acid is obtained in a manner analogous to that described under (c) above, and the relevant intermediates, melting points, solvents and yields are as follows:
 EMI15.1
 installed from ethanol) in 22% yield by introducing sulfur (thiation) into ethyl -2- (2-fluoro-4-bromobenzyl) -1,2-dihydro-1-oxo-phthalazin-4-ylacetate.



   Examples 34 to 37: 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-oxo-phthalazin-4-ylacetate is heated under reflux for 24 h and then evaporated. The residue is dissolved in 100 ml of water and the solution is washed with ether (2 x 100 ml). The aqueous phase is by adding conc. Acidified hydrochloric acid to a pH of 2. The solid formed is filtered off, washed with water and recrystallized from a 7: 1: 5 (v / v / v) mixture of toluene / isopropanol / petroleum (60 to 80). 0.5 g of 2- (2-fluoro-4-bromobenzyl) -8-fluorine-1,2-dihydro-
 EMI15.2
 



   The following acetic acid derivatives are obtained by an analogous process, starting from the corresponding ethyl esters:
 EMI 15.3
 until 2020C [recrystallized from 1: 2 vol. / vol. Ethyl acetate / petrol (60 to 80)], yield 90%; (Example 36): 2- (3, 4-dichlorobenzyl) -6, 7-dichloro-1, 2-dihydro-1-oxo-phthalazin-4-ylacetic acid, mp. 204 to 205 C (recrystallized from 5: 1 vol . / Vol.

   Methanol / DMF), yield 76%; (Example 37): 2- (3,4-dichlorobenzyl) -6-chloro-1,2-dihydro-1-oxo-phthalazin-4-ylacetic acid, mp. 208
 EMI 15.4
 Acetic acid derivatives of the general formula (XV) obtained by hydrolysis of the corresponding ethyl ester with potassium hydroxide:

  <Desc / Clms Page number 16>

 
 EMI16.1
 x) 1: 2 mixture of 6-methyl and 7-methyl derivatives. xx) according to KMR exo-tautomeres
In a similar manner, 2- (2-fluoro-4-bromobenzyl) -1, 2-dihydro-1-thioxo-phthalazin-4-yl-acetic acid (Example 50) is obtained as a solid, mp. 194 to 196 C (recrystallized from Methanol), in 30% yield by hydrolysis of the corresponding ethyl ester with aqueous methanolic sodium hydroxide solution.



   Example 51: 1.8 g of ethyl 2- (3,4-dichlorobenzyl) -8-fluoro-1,2-dihydro-l-oxo-phthalazin-4-ylacetate are converted into a solution of 1.5 g of sodium in 150 ml dry ethanol added. The solution obtained is heated under reflux for 3 h and then evaporated. 100 ml of water are added to the residue and the solid obtained is filtered off and dried. This gives ethyl 2- (3, 4-dichlorobenzyl) -8-ethoxy-l, 2-dihydro-l-oxo-phthalazin-4-yla acetate (0.5 g).



   Example 52: A sodium methoxide solution (25 ml of a 1, Om solution in methanol) is a solution of 9, 87 g of 2- (2-fluoro-4-bromobenzyl) -1, 2-dihydro-l-oxo-phthalazin-4- Add ylacetic acid in 300 ml of methanol and the mixture is heated to its boiling point. Methanol is then allowed to evaporate until the volume of the mixture reaches approximately 100 ml. Then 150 ml of isopropanol and then petroleum (60 to 80) are added until the mixture just becomes opaque. The mixture is then allowed to cool to room temperature. The solid formed is filtered off, evaporated with toluene (2 × 400 ml) and washed with 300 ml of ether; 6.5 g of sodium 2- (2-fluoro-4-bromobenzyl) -1, 2-dihydro-1-oxo-phthalazin-4-ylacetate are obtained, mp 244 to 247 C.

 

Claims (1)

PATENT CLAIMS: 1. Process for the preparation of a new 2-benzyl-1, 2-dihydro-1-oxo-phthalazin-4-ylacetic acid of the general formula  EMI17.1  in which the substituents R2, R3, R4 and R5 on the benzene ring A are selected from one of the following combinations:  EMI17.2  or iodine and Rs for hydrogen or halogen; b) R ', R3 and RS are hydrogen and R' * is bromine or iodine; c) R2 is hydrogen or fluorine, R3 and R5 represent the same or different halogen radicals and R4 is hydrogen;  d) R2 is hydrogen or fluorine, R3 and R's are the same or different halogen radicals and R is hydrogen; and e) R2 is hydrogen, R3 and R5 are independently fluorine or chlorine and R is chlorine, bromine or iodine; and in which R6 and R7 and R8 on the benzene ring B independently of one another are hydrogen,  EMI17.3  form a dioxy group, at least one of the substituents R, R7 and R8 being hydrogen;  X represents oxygen or sulfur; or a pharmaceutically acceptable base addition salt thereof, characterized in that an ester of the general formula  EMI17.4  in which R * is a CC alkoxy group or a group of the general formula  EMI17.5  is in which X, the benzene rings A and B and the substituents thereon have the meanings given above, reacting to produce a pharmaceutically acceptable base addition salt, the acetic acid of the general formula (I) with a pharmaceutically acceptable cation-providing base.    EMI17.6    <Desc / Clms Page number 18>  and X, the benzene rings A and B and the substituents thereon have the above meanings, hydrolyzed, the acetic acid of the general formula (I) being reacted with a base supplying a pharmaceutically acceptable cation to produce a pharmaceutically acceptable base addition salt.  3. The method according to claim 1 or 2, characterized in that the hydrolysis is carried out in the presence of an aqueous mineral acid and at a temperature in the range from 18 to 1100C.  4. The method according to claim 1 or 2, characterized in that the hydrolysis is carried out in the presence of an alkali metal hydroxide or carbonate and at a temperature between 18 and 110 C.  5. The method according to any one of claims 1 to 4, characterized in that starting Ma  EMI18.1