CS241042B2 - Process for the preparation of 2-benzyl-1,2-dihydro-1-oxophthalazin-4-ylacetic acid derivatives - - Google Patents

Abstract

The invention describes a method for producing novel phthalazin-4-ylacetic acid derivatives which have the ability to inhibit the enzyme aldose reductase in vivo.

Description

The invention describes a method for producing novel phthalazin-4-ylacetic acid derivatives which have the ability to inhibit the enzyme aldose reductase in vivo.

The enzyme aldose reductase is responsible for the catalytic conversion of aldoses, such as glucose and galactose, to the corresponding alditols, such as sorbitol and galactitol, respectively. Alditols do not pass through cell walls well and, once formed, can essentially only be removed by further metabolism. As a result, alditols tend to accumulate in the cells in which they are formed, causing an increase in osmotic pressure, which can then be so great that it can lead to disorders or impairment of the function of the cells themselves. In addition, increased levels of alditol can result in abnormally increased levels of the corresponding metabolites, which can themselves impair or damage cellular functions. However, the enzyme aldose reductase has a relatively low affinity for the substrate, which means that it is only effective in the presence of relatively high concentrations of aldose. Such high concentrations of aldose occur in the clinical conditions of diabetes (excess glucose) and galactosemia (excess galactose). Accordingly, inhibitors of the enzyme aldose reductase are useful in reducing or preventing the development of those peripheral effects of diabetes and galactosemia which may be caused in part by the accumulation of sorbitol or galactitol, respectively. Such peripheral effects are, for example, macular edema, cataracts, retinopathy or impaired nerve conduction.

It is known from our previous work that derivatives of l-benzyl-2-oxoquinol-4-ylalkanoic acids are inhibitors of the enzyme aldose reductase (see British Patent No. 1,502,312). It has now been found that certain derivatives of 2-benzyl-1-oxophthalazin-4-ylacetic acid, defined below, are unexpectedly also inhibitors of the enzyme aldose reductase. This finding is particularly surprising in view of the numerous differences between the 2-oxoquinoline and 1-oxophthalazine ring systems. Related phthalazine derivatives, namely 2-benzyl- and 2-(2-pyrid-2-ylethyl)-1,2-dihydro-1-oxophthalazin-4-ylacetic acid and their methyl and ethyl esters, are known and their effect on blood coagulation has been described (see Sh. Feldeak et al., Chim. Farm. Zh., 1170, 4, 22-26; Chemical Abstracts, 1170, 73, 77 173). However, neither the compounds of the invention described below nor these known phthalazine derivatives are known to act as aldose reductase inhibitors in vivo when administered orally at doses of 100 mg/kg or less.

In agreement with what was stated above.

.241042 describes the invention a process for the production of 2-benzyl-1,2-dihydro-1-oxophthalazin-4-ylacetic acid derivatives, of the general formula I

in which

R ¹ represents a hydroxyl group or an alkoxy group with 1 to 4 carbon atoms, the substituents R ² , R ³ , R ⁴ and R ⁵ on the benzene ring A are selected from the following combinations

a] R ² represents a fluorine atom or a methoxy group,

R ³ represents a hydrogen atom,

R ⁴ represents a chlorine, bromine or iodine atom and R ⁵ represents a hydrogen or halogen atom,

b) R ² , R ³ and R ⁵ represent hydrogen atoms and R ⁴ represents a bromine or iodine atom, cj R ² represents a hydrogen or fluorine atom, R ³ and R ⁵ represent the same or different halogen atoms and

R ¹ represents a hydrogen atom,

d) R ² represents a hydrogen or fluorine atom, R ³ and R ⁴ represent the same or different halogen atoms and R ⁵ represents a hydrogen atom, and

e) R ² represents a hydrogen atom,

R ³ and R ⁵ independently of each other represent fluorine or chlorine atoms and R ⁴ represents a chlorine, bromine or iodine atom, and the substituents R ⁶ , R ⁷ and R ⁶ on the benzene ring B are independently selected from the group consisting of hydrogen atom, halogen atoms, alkyl groups with 1 to 4 carbon atoms and alkoxy groups with 1 to 4 carbon atoms, or R ⁶ and R ⁷ together form a divalent alkylenedioxy radical with 1 to 4 carbon atoms, with at least one of the symbols R ⁶ , R ⁷ and R ⁸ representing a hydrogen atom, and pharmaceutically acceptable salts with bases of those compounds of general formula I, in which R ¹ represents a hydroxyl group, characterized in that the compound of general formula II

in which the individual general symbols have the meanings given above, or its geometry is an isomer, is reacted with hydrazine of the general formula III

in which the individual general symbols have the above-mentioned meaning, and the obtained compound of general formula I, in which R ⁴ represents a hydroxyl group, is optionally converted into its pharmaceutically usable base addition salt by reaction with a base providing a pharmaceutically usable cation.

This reaction is conveniently carried out in an aqueous diluent or solvent, for example, aqueous dioxane, ethanol or dimethylformamide, and in the presence of a base, for example sodium or potassium bicarbonate. The reaction is also conveniently carried out under heating, for example at a temperature of 40 to 110°C.

The compounds of general formula I are derivatives of 1,2-dihydro-1-oxophthalazin-4-ylacetic acid, the ring system of which is numbered throughout this text as in the following formula

It is clear that compounds of general formula I can tautomerize to a structure corresponding to general formula la

.241042 and the invention includes both the tautomer of general formula I (endo-tautomer) and the tautomer of general formula Ia (exo-tautomer), as well as mixtures thereof.

Halogen in the meaning of the symbols R ³ or R ⁵ is, for example, fluorine, chlorine, bromine or iodine, especially chlorine or bromine.

Halogen in the meaning of the symbols R ⁶ , R ⁷ or R ⁸ is, for example, fluorine, chlorine, bromine or iodine, alkyl with 1 to 4 carbon atoms in the meaning of these symbols is, for example, methyl and alkoxy with 1 to 4 carbon atoms in the meaning of these symbols is, for example, methoxy or ethoxy.

An alkoxy group with 1 to 4 carbon atoms as R ¹ is, for example, a methoxy group or an ethoxy group.

A divalent alkylenedioxy group with 1 to 4 carbon atoms, formed together by the symbols R ⁶ and R ⁷ , is, for example, a methylenedioxy group, an ethylenedioxy group or an isopropylidenedioxy group.

Benzene ring A, bearing particularly interesting combinations of symbols R ² , R ³ , R ⁴ and R ⁵ , is, for example, 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-bromophenyl residue.

Particularly interesting combinations of the symbols R ^s , R ⁷ and R ⁸ are, for example, those cases where the benzene ring B is either unsubstituted or bears the following substituents: 6-fluoro,

6-chloro, 6-methyl, 7-fluoro, 7-chloro, 7-methyl,

7-methoxy, 8-fluoro, 8-methyl, 8-ethoxy, 6,7-dichloro or 6,7 methylenedioxy.

Particularly suitable addition salts of compounds of the general formula I, in which R ¹ represents a hydroxyl group, with bases are, for example, salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium salts, or aluminum or ammonium salts, or salts with organic bases providing a pharmaceutically acceptable cation, for example salts with triethylamine.

Specific groups of particularly preferred compounds according to the invention are those of the general formula I, (ij Rt represents a hydroxyl group;

(ii) R ² represents a fluorine atom, R ³ and R ⁵ represent hydrogen atoms and R ⁴ represents a chlorine, bromine or iodine atom;

(iil) R ³ and R ⁴ independently of each other are chlorine, bromine or iodine and R ² and R ⁵ are hydrogen; or (iv) R ⁶ , R ⁷ and R ⁸ are hydrogen;

wherein in each of the above groups (ij to (iv) the remaining symbols Rt, R ² , R·, R ¹ , R ^J , R®, R ⁷ and R ³ have the above meaning or the meaning given in some other of the above groups, and pharmaceutically acceptable salts of these substances, depending on the nature of the symbol Ri

Specific compounds produced by the process of the invention are those described in the examples below, and of these, the following are preferred:

2-{2-fluoro-4-bromobenzyl j -1,2-dihydro-1-oxophthalazin-4-ylacetic acid,

2-(2-fluoro-4-iodobenzyl)-1,2-dihydro-1'oxophthalazine-4-ylacetic acid and

2-(3-chloro-4-bromobenzyl)-1,2-dihydro-1-oxophthalazin-4-ylacetic acid, and its pharmaceutically acceptable addition compounds with bases.

The starting materials used in the process according to the invention can generally be prepared by standard procedures known in the field of heterocyclic chemistry.

Some of the starting materials of general formula II can be conveniently prepared from the appropriately substituted phthalic anhydride of general formula IV.

I by condensation with acetic anhydride, for example in the presence of sodium or potassium acetate and in an excess of boiling acetic anhydride. All of these compounds can, however, be obtained by the Wittig reaction between the corresponding phthalic anhydride of the general formula IV and (methoxycarbonylmethylene)triphenylphosphorane in a suitable solvent, for example in 1,2-dimethoxyethane or tetrahydrofuran, the reaction being expediently accelerated by heating, for example by heating to the boiling temperature of the reaction mixture. It should be borne in mind that in some cases the product of the Wittig reaction may be its geometric isomer corresponding to the general

(IIa)

Alternatively, a mixture of both of these geometric isomers may be formed. Any of these isomers and their mixtures may be used in the process according to the invention. It should also be noted that if R® and one of R and R ⁶ are hydrogen, positional isomers are formed in the Wittig reaction depending on which of the two carbonyl groups of the phthalic anhydride of formula IV enters into the reaction. If R® is other than hydrogen, one of the possible positional isomers predominates, namely the one formed by the reaction of the carbonyl group furthest from R ⁸ .

The pharmaceutically acceptable salts with bases as defined above can be prepared by conventional procedures by reacting the respective compound with the corresponding base to provide a pharmaceutically acceptable cation.

The properties of aldose reductase enzyme inhibitors can be demonstrated by the following standard laboratory test:

. Rats are induced to develop diabetes by streptozotocin and the test compound is then administered to the animals daily for 5 days. The animals are sacrificed, their lenses and sciatic nerves are removed and, after standard processing, the residual sorbitol level in each of these tissues is determined by gas chromatography (after conversion to poly-trimethylsilyl derivatives). Inhibition of aldose reductase in vivo is then determined by comparing the residual sorbitol levels in tissues of a group of diabetic rats to which the test substance has been administered with the residual sorbitol levels in the corresponding tissues of a group of diabetic rats to which the test compound has not been administered and a group of normal rats to which the test compound has not been administered.

Alternatively, a modified test can be used in which rats, in which diabetes has been induced by streptozotocin, are given the test compound daily for 12 days. 2 to 4 hours after the last dose, the animals are sacrificed, their sciatic nerves are removed, and residual sorbitol levels are determined as described above.

The active substances reduce the residual sorbitol levels in both of these tests to a level similar to that in normal rats to which the test substance has not been administered. In general, the compounds of formula I exert a marked inhibition of the aldose reductase enzyme when administered orally at a dose of 100 mg/kg or less. As an illustration, 2-(2-fluoro-4-bromobenzyl)-1,2-dihydro-1-oxophthalazin-4-ylacetic acid, after five days of oral administration at doses of 10 mg/kg, reduces the residual sorbitol level in the sciatic nerve to approximately 60% of the level in control diabetic rats to which the test compound has not been administered. In the above tests, no obvious signs of toxicity or other adverse effects were observed when the compounds of formula I were administered at doses of 100 mg/kg.

The ability to inhibit the aldose reductase enzyme can also be demonstrated in vitro. The procedure is to isolate purified aldose reductase from the lenses of cattle in a known manner and then determine the percentage inhibition of the ability of this enzyme in vitro to reduce aldoses to polyhydric alcohols, in particular to reduce glucose to sorbitol, caused by the test compound, using standard spectrophotometric methods. In this test, those compounds of general formula I in which R ¹ represents a hydroxyl group show significant inhibition of the aldose reductase enzyme at concentrations ranging from 10 ^s to 10~ ⁶ M or lower. As an illustration, it can be stated that 2-(2-fluoro-4-bromobenzyl)-1,2-dihydro-1-oxophthalazin-4-ylacetic acid has a K _f value of 2.0 X X10“ ⁸ M.

When the compound produced by the method according to the invention is used to influence the aldose reductase enzyme in warm-blooded animals, it can be administered primarily orally in a daily dose of 2 to 50 mg/kg, which in humans corresponds to a total daily dose in the range of 20 to 750 milligrams, which can be administered in several divided doses if necessary.

The compounds produced by the method according to the invention can be administered in the form of pharmaceutical compositions.

Particularly suitable pharmaceutical compositions are compositions in a form suitable for oral administration, for example tablets, capsules, suspensions or solutions, which can be prepared by conventional methods and which may optionally contain conventional diluents, carriers or other excipients.

Some of the compounds prepared by the method according to the invention, in addition to their inhibitory effects on aldose reductases, also have anti-inflammatory and/or analgesic properties of the type of non-steroidal anti-inflammatory agents such as indomethacin, naproxen and ketoprofen. These substances may therefore be useful in addition in the treatment of painful inflammatory joint diseases such as rheumatoid arthritis, osteoarthritis and ankylosing spondylitis. In this context, it is envisaged that such substances will be administered preferably orally in a daily dose in the range of 10 to 50 mg/kg. The anti-inflammatory properties of the described compounds can be demonstrated by known standard tests on rats. For example, 2-(2-fluoro-4-bromobenzyl)-1,2-dihydro-1-oxophthalazin-4-ylacetic acid and 2-(3-chloro-4-bromobenzyl)-1,2-dihydro-1-oxophthalazin-4-ylacetic acid exert a significant inhibition of carrageenan edema in the test developed by Winter et al. [Proceedings of the Society of Experimental Biology (New York), 1662, 111, 554] without any obvious signs of toxicity.

The invention is illustrated by the following examples for guidance, but the scope of the invention is not limited in any way. In these examples

(a) all evaporations, unless otherwise stated, are carried out under vacuum on a rotary evaporator;

(b) all operations, unless otherwise stated, are carried out at room temperature, meaning a temperature between 13 and 26 ^° C;

The melting points of acetic acid derivatives are in many cases associated with decomposition;

d) all compounds of general formula I and isolated intermediates are characterized based on microanalysis and NMR and IR spectroscopy;

e) yields, if given for illustration, do not necessarily represent the highest achievable yields.

Example 1

To a mixture of 1.92 g of 3-oxo-A ¹ -phthalacetic acid (also known as phthalideneacetic acid) and 2.0 g of sodium bicarbonate in 50 ml of dioxane and 25 ml of water, 2.5 g of 3-chloro-4-bromobenzylhydrazine were added with stirring. The resulting mixture was refluxed for 3 hours, then cooled to room temperature and poured into 200 ml of water. The aqueous solution was extracted three times with 100 ml of ether each time, after which the aqueous phase was acidified with concentrated hydrochloric acid to pH 2. The solid material that separated was collected, washed thoroughly with water, dried in vacuo and then recrystallized twice from a mixture of toluene, isopropanol and petroleum ether (boiling point 60-80 °C) in a volume ratio of 6:2:3. 0.23 g of 2-(3-chloro-4-bromobenzyl)-1,2-dihydro-1-oxophthalazin-4-ylacetic acid melting at 184-186°C is obtained.

Examples 2 to 4

To 2.29 g of ethyl-4-methyl-3-oxo-α ^,α- phthalate acetate in 200 ml of toluene, a solution of 1.9 g of 3,4-dichlorobenzylhydrazine in 50 ml of toluene is added dropwise, while stirring and boiling under reflux. The mixture is boiled under reflux for a further 3 hours, then cooled and evaporated. The solid residue, after recrystallization from a mixture of isopropanol and petroleum ether (boiling point 60-80 °C) in a volume ratio of 1:2, gives 1.4 g of ethyl-2-(3,4-dichlorobenzyl)-8-methyl-1,2-dihydro-1,2-phthalazin-4-yl acetate (Example 2) with a melting point of 134-137 °C.

In an analogous manner, using ethyl 4-fluoro-3-oxo-A ^la phthalate acetate as the starting material, ethyl 2-(3,4-dichlorobenzyl)-8-fluoro-1,2-dihydro-1-oxophthalazin-4-yl acetate (Example 3) is obtained in a yield of 37%, melting after recrystallization from a mixture of isopropanol and petroleum ether (boiling point 60 to 80 °C) in a volume ratio of 1: 2 at 177 to 178 °C.

By an analogous procedure, a mixture of equal parts of ethyl 6-methyl- and 7-methyl-2-(3,4-dichlorobenzyl)-1,2-dihydro-1-oxophthalazin-4- ^yl acetate (Example 4) melting after recrystallization from isopropanol at 120 to 122 °C is obtained in a yield of 33% from a mixture of equal parts of 5-methyl- and 6-methyl-3-oxo-A la -phthalate acetate.

The necessary starting materials are prepared as follows:

A solution of 7.35 g of 3-fluorophthalic anhydride and 17.5 g of (ethoxycarbonylmethylene)triphenylphosphorane in 200 ml of dry 1,2-dimethoxyethane is heated to reflux under nitrogen for 16 hours with stirring. The solvent is evaporated and the residue is adsorbed onto 20 g of silica gel for chromatography. This silica gel is applied to a column of 300 g of silica gel of the same type and the column is eluted with toluene. The eluate is monitored by thin-layer chromatography [silica gel, solvent system toluene-ethyl acetate (9:1) by volume]. The first fraction containing material visible under UV radiation is combined and evaporated. The solid residue is recrystallized from isopropanol, yielding 2.3 g of ethyl 4-fluoro-3-oxo-A ^{lfI-phthalate} acetate melting at 101 to 103 °C (starting material for working according to the procedure of Example 3).

In an analogous manner, ethyl 4-methyl-3-oxo-A'- ^phthalate acetate is prepared from 3-methylphthalic anhydride in a yield of 56% in the form of a solid melting at 84-88 °C after recrystallization from isopropanol (starting material for the work according to the procedure of Example 2).

By an analogous procedure, a mixture of equal parts of ethyl-5-methyl-6-methyl-3-oxo-A ^; “-phthalate acetate is obtained from 4-methylphthalic anhydride in a yield of 40 percent in the form of a solid melting at 84 to 86 °C after recrystallization from isopropanol (starting material for working according to the procedure of Example 4).

Example 5

To a solution of 9.87 g of 2-(2-fluoro-4-bromobenzyl)-1,2-dihydro-1-oxophthalazin-4-ylacetic acid in 300 ml of methanol, a solution of sodium methoxide (25 ml of a 1.0 M solution in methanol) is added and the resulting mixture is heated to boiling. The methanol is allowed to distill off until the volume of the mixture is approximately 100 ml. 150 ml of isopropanol is added to the residue and then petroleum ether (boiling point 60 to 80 degrees Celsius) is added until turbidity begins to appear. The resulting mixture is allowed to cool to room temperature, the solid material that has separated is filtered off, evaporated twice with 400 ml of toluene each time and the mixture is washed with 300 ml of ether. 6.5 g of sodium 2-(2-fluoro-4-bromobenzyl)-1,2-dihydro-1-oxophthalazin-4-ylacetate is obtained. with a melting point of 244 to 247 °C.

Examples 6 to 15

By a procedure analogous to that in Example 1, using the respective benzyl hydride.341042

The following compounds of general formula I are obtained from the zinc of general formula III and 3-oxo-A'-"-phthaloacetic acid as starting materials, example number substituents on the benzene ring A in which the benzene ring is not substituted and R ¹ represents a hydroxyl group. The yields range between 15 and 45%.

melting point crystallization solvent

4-bromo

3,4-dichloro

2-fluoro-4-bromo

2-fluoro-4-chloro

2-fluoro-4-iodine

4-iodine

3,4-dibromo

2-fluoro-4,5-dibromo

3,5-dichloro-4-bromo

15. 2-methoxy-4-chloro

179—181 ethyl acetate/petroleum ether (60-80) (1:4) 175—176 toluene/isoproanol (2:1) 184—185 *) methanol 193—194 ethanol/water (3 : 1) 189 ethanol/water.(3 : 1} 178—180 isopropanol/petroleum ether (60-80) (1 : 2) 187—189 isopropanol 185—180 isopropanol 219 — 220 Isopropane 1 183-184 isopropane d

Legend:

* This compound may crystallize in polymorphic forms, i.e., in a form melting after crystallization from methanol containing a small amount of water at 184 to 135 degrees Celsius and in a form melting after double crystallization from dry methanol at 180 to 182 ^C C.

Examples 16 to 34

By a procedure analogous to that in Examples 2 to 4, using the respective ethyl-3-ΟΧΟ-Δ ^{1 c} '-phthalane acetate of the general formula II (R ¹ — ethoxy group) _from and benzylhydrazine of the general formula III, the following compounds corresponding to the general formula I, in which R ¹ represents an ethoxy group, are obtained in a yield of 10 to 40%.

example number substituents on benzene ring A substituents on benzene ring B melting point

PČ) crystallization solvent

13 3-chloro-4-bromo — 142—145 isopropanol 17 3,4-dichloro — 130—111 isopropanol 18 2-fluoro-4-bromo — 114 ethanol 19 3,4-dichloro 7-methoxy Γ'3—130 isopropanol 20 2-fluoro-4-chloro — 102 ethanol 21 2-fluoro-4-iodine — - 113 petroleum ether (60—80) 22 3,4-dibromo — 140—142 isopropanol 23 2-fluoro-4,5-dibromine — 129—130 ethyl acetate 24 3,5-dichloro — 100—101 ethyl acetate 25 3,5-dichloro-4-bromo — 146-147 ethanol 26 2-methoxy-4-chloro — 138 isopropanol 27 4-iodine 106 — 107 isopropanol/ /neutral ether (60-80) 28 2-fluoro-4-bromo 8-fluoro 128—130 isopropanol/ /petroleum ether (60-80) 29 2-.fluoro-4;bromine 8-methyl 120—122 isopropanol/ / ether (60—80) (1:3) . 30. 2-fluoro-4-bromo 6,7-Methyleneendloxy 163—165 ethyl acetate 31 3,4-dichloro 7-fluoro 160—162 isopropanol 32 3,4-dichloro 6,7-dichloro 204—205 chloroform/ /ethyl acetate (1:2) 33 3,4-dichloro 6-Chlorine 143—146 ethanol 34 2-fluoro-4-bromo 6-fluoro 121—123 •ethanol

The necessary starting materials can be obtained by a procedure analogous to that in Examples 2 to 4, i.e. by reacting the appropriate phthalic anhydride with (ethoxycarbonylmethylene)triphenylphosphorane. The starting materials thus prepared are generally used in an incompletely purified form.

Example lad35

Using the same procedure as in example 2

Claims (5)

A process for the preparation of 2-benzyl-1,2-dihydro-1-oxophthalazin-4-ylacetic acid derivatives of the general formula I in which: R @ ¹ represents a hydroxyl group or a C1 -C4 alkoxy group, the substituents R @ ² , R @ ³ , R ^{@ 4} and R ^{@ 5} on the benzene ring A are selected from the following combinations a) R ² represents a fluorine atom or methoxy, R ³ represents hydrogen, R ⁴ represents a chlorine, bromine or iodine atom; R ⁵ represents a hydrogen or halogen atom, b) R ² , R ³ and R ⁵ are hydrogen and R ⁴ is bromine or iodine, c) R ² represents a hydrogen or fluorine atom, R ³ and R ⁵ represent the same or different halogen atoms; R ⁴ is hydrogen, d) ^R2 is hydrogen or fluoro, R ³ and R ⁴ represent identical or different halogen atoms and R ⁵ represents a hydrogen atom, and e) R ² is hydrogen, R ³ and R ⁵ independently represent fluorine or chlorine atoms, and R ⁴ is chlorine, bromine or iodine, and the substituents R ⁶ , R ⁷ and R ⁸ on the benzene ring B are independently selected from the group consisting of hydrogen, atoms halides, alkyl groups of 1, using equivalent amounts of methyl 3-oxo-A ^{) and} phthalate acetate and 2-fluoro-4-bromobenzylhydrazine, yielded 20 to 30% solid methyl 2- (2-fluoro-4-bromobenzyl) -1,2-dihydro-1-oxophthalazin-4-yl acetate melting after recrystallization from methanol at 151-153 ° C. or R ( ⁶⁾ and R ( ⁷⁾ together form a divalent alkylenedioxy radical having from 1 to 4 carbon atoms, provided that at least one of R ⁶ , R ⁷ and R ⁸ represent a hydrogen atom, and pharmaceutically acceptable base addition salts of those compounds of formula (I) wherein R ¹ is a hydroxyl group, characterized in that the compound of formula (II): or a geometric isomer thereof, is reacted with a hydrazine of formula (III) in which each is as defined above, and the compound of formula (I) in which R ¹ is a hydroxyl group is optionally converted by treatment with a base providing a pharmaceutically acceptable cation. to a pharmaceutically acceptable base addition salt thereof. 2. The process of claim 1 wherein the reaction is carried out in the presence of a base and an aqueous diluent or solvent. 3. The process of claim 2 wherein the base is an alkali metal bicarbonate and the aqueous diluent or solvent is aqueous dioxane, ethanol or dimethylformamide. 2 4 10 4 4. A process according to any one of claims 1 to 3, wherein the reaction is carried out at a temperature of 40 to 100 ° C. 5. Process according to claims 1-4, characterized by using starting substances of the formulas II and III wherein benzene ring B is unsubstituted, R ¹ is as defined in claim 1; R ² represents a fluorine atom, R ^3, and R ⁵ are hydrogen and R ⁴ is chlorine, bromine or iodine, or R ² and R ⁵ are hydrogen and R ³ and R ^{4 are each} independently chlorine, bromine or iodine. Severography, n. P., Plant 7, Most Price 2,40 Kčs