CS241042B2 - Method of 2-benzyl-1,2-dihydro-1-oxophtalazine-4-ylacetic acid derivatives production - Google Patents

Abstract

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

Description

The invention provides a process for the preparation of novel phthalazin-4-ylacetic acid derivatives having the ability to inhibit the enzyme aldose reductase in vivo.

The aldose reductase enzyme is responsible for the catalytic conversion of aldoses, for example glucose and galactose, to the corresponding alditols, such as sorbitol, respectively. galactitol. Alditols poorly pass through the cell walls and, if formed, can be removed essentially only by further metabolism. As a result, alditols tend to accumulate in the cells in which they originate, causing an increase in osmotic pressure, which can then be so great that it can lead to disturbances or impaired function of the cells themselves. In addition, elevated alditol levels may result in abnormal elevation of the corresponding metabolites, which may themselves impair or impair cellular function. However, the aldose reductase enzyme has a relatively low affinity for the substrate, meaning that it is only effective in the presence of relatively high concentrations of aldose. Such high aldose concentrations occur in the clinical conditions of diabetes (excess glucose) and galactosemia (excess galactose). Accordingly, aldose reductase enzyme inhibitors are useful for reducing or preventing the onset of those peripheral effects of sugar and galactosemia, which may be due in part to the accumulation of sorbitol, respectively. galactitol. Such peripheral effects are, for example, macular edema, cataract, retinopathy or impaired conduction of nerve impulses.

It is known from our earlier work that 1-benzyl-2-oxoquinol-4-ylalkanoic acid derivatives are inhibitors of the enzyme aldose reductase (see British Patent No. 1,502,312). It has now been found that certain 2-benzyl-1-oxophthalazin-4-ylacetic acid derivatives as 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 has been described for blood clotting (see Sh. Feldeak et al., Chim. Farm. Ž., 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 accordance with the above.

No. 241042 describes 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 an alkoxy group having 1 to 4 carbon atoms, R ^2, R ^3, R ⁴ and R ⁵ no benzene ring A are selected from the following combinations

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

R ³ represents hydrogen,

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 are hydrogen atoms and J ⁴ is bromine or iodine, R ² is hydrogen or fluorine, R ³ and R ⁵ are the same or different halogen atoms, and

R ^! means a hydrogen atom,

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 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, atoms halogens, (C1-C4) alkyl and (C1-C4) alkoxy, or R ( ⁶⁾ and R ( ⁷⁾ together form a divalent alkylenedioxy radical of from 1 to 4 carbon atoms, provided that at least one of R ⁶ , R ⁷ and R ⁸ represents a hydrogen atom, and pharmaceutically acceptable base salts of those compounds of formula I wherein R ¹ is a hydroxyl group, characterized in that the compound of formula II

in which the individual general symbols are as defined above, or their geometry isomer, reacted with the hydrazine of formula III

wherein the individual symbols are as defined above, and the compound of formula I, wherein R ⁴ is a hydroxyl group, is optionally converted by treatment with a base providing a pharmaceutically acceptable cation to its pharmaceutically acceptable base addition salt.

This reaction is preferably 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 to a temperature of 40 to 110 ° C.

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

It will be appreciated that the compounds of formula (I) may be tautomerized to a structure corresponding to formula (Ia)

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

Halogen represented by R ³ or R ⁵ is, for example, fluorine, chlorine, bromine or iodine, especially chlorine or bromine.

Halogen for R ⁶ , R ⁷ or R ⁸ is, for example, fluorine, chlorine, bromine or iodine, C 1 -C 4 alkyl such as methyl and C 1 -C 4 alkoxy is, for example, a methoxy or ethoxy group.

Alkoxy having 1 to 4 carbon atoms represented by R ¹ is, for example methoxy or eíhoxyskupina.

The divalent C 1 -C 4 alkylenedioxy group, taken together with R ⁶ and R ⁷ , is, for example, methylenedioxy, ethylenedioxy or isopropylidenedioxy.

The benzene ring A bearing particularly interesting combinations of 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-go, 3,5-dlchloro, 3-chloro-4-bromo, 3,4-dichloro, 3,4-dibromo or a 3,5-dichloro-4-bromophenyl radical.

Especially interesting combination of symbols R ^s, R ⁷ and R ⁸ include those cases in which benzene ring B is either unsubstituted or carries 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 acid addition salts of compounds of formula I wherein R ¹ is a hydroxy group, with bases include salts with alkali metals or alkaline earth metals such as sodium, potassium, calcium or magnesium or aluminum or ammonium salts. or salts with organic bases providing a pharmaceutically acceptable cation, such as salts with triethynolamine.

Particular groups of particularly preferred compounds of the invention are those compounds of formula (I) (ij Rt is hydroxyl;

(ii) R ² is fluorine, R ³ and R ⁵ are hydrogen and R ⁴ is chlorine, bromine or iodine;

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

wherein in each of the above groups (ij to (iv)), the remaining of R ¹ , R ² , R 6, R ¹ , R ^J , R ⁷ , R ^7, and R ^{3 have the} meanings given above or as defined in any other of the above and the pharmaceutically acceptable salts thereof, depending on the nature of the R 1 symbol

Specific compounds produced by the process of the invention are those described in the Examples below, of which the following are preferred:

2- {2-Fluoro-4-bromobenzyl] -1,2-dihydro-1-oxophthalazin-4-ylacetic acid,

2- (2-fluoro-4-iodobenzyl) -1,2-dihydro-isoxophthalazin-4-ylacetic acid; and

2- (3-chloro-4-bromobenzyl) -1,2-dihydro-1-oxophthalazin * 4-ylacetic acid, and their pharmaceutically acceptable base addition salts.

The starting materials used in the process of the invention may generally be prepared by standard procedures known in the art of heterocyclic compound chemistry.

Some of the starting materials of formula II may conveniently be prepared from an appropriately substituted phthalic anhydride of formula IV

Condensation with acetic anhydride, for example in the presence of sodium or potassium acetate and in excess of boiling acetic anhydride. However, all of these compounds can be obtained by a Wittig reaction between the appropriate phthalic anhydride of formula IV and (methoxycarbonylmethylene triphenylphosphorane in a suitable solvent, for example 1,2-dimethoxyethane or tetrahydrofuran), expediently accelerating the reaction by heating, e.g. to bear in mind that, in some cases, the product of the Wittig reaction may, instead of the compound of formula II, be its geometric isomer corresponding to the general

(II a)

Alternatively, a mixture of both geometric isomers may be formed. Any of these isomers and mixtures thereof may be used in the process of the invention. It should also be noted that when R @ ⁶ and one of R @ ⁶ and R @ ^{6 are} hydrogen, the Wittig reaction produces positional isomers in the base; depending on which of the two carbonyl. of the phthalic anhydride groups of the formula IV. enters the reaction. When R @ 2 has a meaning other than hydrogen, one of the possible positional isomers is that of the carbonyl group furthest from R @ ⁸ .

The above-defined pharmaceutically acceptable base salts can be prepared by conventional reaction procedures. appropriate compounds with a corresponding base providing a pharmaceutically acceptable cation.

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

. In rats, streptozotocin is induced by diabetes and the animals are then treated for 5 days. administer the test compound daily. The animals are sacrificed, their eye lenses and sciatic nerves are removed, and after standard processing, residual sorbitol levels are detected in each of these tissues by gas chromatography (after conversion to poly-trimethylsilyl derivatives). In vivo inhibition of aldose reductase is then determined by comparing the residual levels of sorbitol in the tissues of the diabetic rat group receiving the test substance with the residual levels of sorbitol in the corresponding tissues of the non-administered diabetic rat group and the normal rat groups. the test compound was not administered.

Alternatively, modified may also be used. a test in which rats induced with diabetes by streptozotocin were given daily the test compound for a period of /2 hours. days. Two to four hours after the last dose, the animals are sacrificed, their sphincic nerves are removed, and residual sorbitol levels are determined as described above.

Substances that are effective reduce residual sorbitol levels in both of these tests. to a condition similar to that in normal rats not receiving the test substance. The compound (s) does not cause the compounds of formula (I). significant inhibition of the aldose reductase enzyme when administered orally at a dose of 100 mg, kg or less. By way of illustration, 2- (2-fluoro-4-bromobenzyl) -1,2-dihydro-1-oxophthalazin-4-ylacetic acid reduces the residual sorbitol level after 5 days of oral administration at doses of 10 mg / kg. in the sciatic nerve to about 60% of the control diabetic rats to which the test compound was not administered In the above tests, no marked signs of toxicity or other adverse effects were observed with the compounds of Formula I 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 bovine eye lenses in a known manner and, using standard spectrophotometric methods, to determine in percent the inhibition of the enzyme's ability to reduce aldoses to polyhydric alcohols in particular, particularly to reduce glucose to sorbitol caused by the test compound. . In this test those compounds of formula I wherein R ¹ represents a hydroxyl group, significant inhibition of the enzyme aldose reductase at a concentration in the range from 10 ^s to 10 ^-6 M or lower in concentration. To illustrate specifically, 2- (2-fluoro-4-bromobenzyl) -l, 2-d.ihydro-L-oxoftalazm-4-ylacetic acid has a K value of 2.0 X _F X 10 ^"8 M.

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

The compounds of the present invention may be administered in the form of pharmaceutical compositions.

Particularly suitable pharmaceutical compositions are those 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 auxiliaries.

Some of the compounds produced by the process of the invention, in addition to the aldose reductase inhibitory effects, also have anti-inflammatory and / or analgesic properties of the type as non-steroidal anti-inflammatory agents such as indomethacin, naproxen and ketoprofen. Thus, these agents may additionally be useful in the treatment of painful inflammatory joint diseases such as rheumatoid arthritis, osteoarthritis and ankyllotic spondylitis. In this context, it is contemplated that such agents will be administered primarily orally at a daily dose in the range of 10 to 50 mg / kg. The anti-inflammatory properties of the disclosed compounds can be demonstrated by known standard tests in 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-oxophthalazine 4-Ylacetic acid, in a test developed by Winter et al. (Proceedings of the Society of Experimental Biology (New York), 1662, 111, 554), exerts a marked inhibition of carrageenin edema without any apparent evidence of toxicity.

The following examples illustrate the invention, but are not intended to limit the scope of the invention in any way. In these examples

(a) all evaporations, unless otherwise indicated, shall be carried out in a vacuum evaporator;

(b) all operations, unless otherwise indicated, are carried out at room temperature, meaning a temperature in the range of 13 to 26 ^° C;

cj the melting points of acetic acid derivatives are in many cases linked to decomposition;

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

(e) yields, when given by way of illustration, do not necessarily represent the highest achievable yields.

Example 1

To a mixture of 1.92 g of 3-oxo-A ^1- phthalaneacetic 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 are added. -4-bromobenzylhydrazine. 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 with ether (3.times.100 ml) and the aqueous phase acidified to pH 2 with concentrated hydrochloric acid. The precipitated solid was collected, washed thoroughly with water, dried in vacuo and then recrystallized twice from toluene / isopropanol / petroleum ether ( boiling point 60 to 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 is obtained, melting at 184-186 ° C.

Examples 2 to 4

To 2.29 g of ethyl 4-methyl-3-oxo-N ^, α-phthalate acetate in 200 ml of toluene was added dropwise a solution of 1.9 g of 3,4-dichlorobenzylhydrazine in 50 ml of sealant while stirring and refluxing. The mixture was refluxed for 3 hours, then cooled and evaporated. The solid residue was recrystallized from isopropanol / petroleum ether (b.p. 60-80 ° C) 1: 2 v / v to give 1.4 g of ethyl 2- (3,4-dichlorobenzyl) -8-methyl-1,2- m.p. 134-137 ° C; dihydro-1-phthalazin-4-yiacetate (Example 2);

In an analogous manner starting from ^{ethyl-4-fluoro-3-oxo-la} ftalanacetátu as starting material to give 37% yield of ethyl 2- (3,4-dichlcrbenzyl) -8-f Iuor-l, 2-dihydro-l -oxophthalazin-4-yl acetate (Example 3) melting after recrystallization from isopropanol / petroleum ether (b.p. 60-80 ° C) 1: 2 v / v at 177-178 ° C.

By analogous procedure from a mixture of 5-methyl- and ^{6-methyl-3-oxo-la} -ftalanacetátu obtained in 33% yield 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 120-122 ° C.

The required 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 was refluxed under nitrogen for 16 hours under stirring. This silica gel was applied to a column of 300 g of the same type of silica gel and eluted with toluene, and the eluate was monitored by thin layer chromatography [silica gel, toluene-ethyl acetate solvent system (9: 1} by volume). The solid residue was recrystallized from isopropanol to give 2.3 g of ethyl 4-fluoro-3-oxo- ^.alpha. - ^phthalate acetate melting at 101 DEG-103 DEG C. (starting material for work-up procedure). according to Example 3).

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

By analogy, a mixture of equal parts of ethyl 5-methyl-6-methyl-3-oxo-A is obtained from 4-methylphthalic anhydride in 40% yield ^; M-phthalate acetate as a solid melting after recrystallization from isopropanol at 84-86 ° C (starting material according to Example 4).

Example 1 a d 5

To a solution of 9.87 g of 2- (2-fluoro-4-bromobenzyl) -1,2-dihydro-10-oxophthalazin-4-ylacetic acid in 300 ml of methanol was added a solution of sodium methoxide (25 ml of 1.0 M solution in methanol) and the resulting mixture was Methanol is distilled off until the volume of the mixture is about 100 ml, 150 ml of isopropanol is added to the residue, and then petroleum ether (b.p. 60-80 degrees Celsius) is added until the turbidity begins. The mixture is allowed to cool to room temperature, the precipitated solid is filtered off, evaporated twice with 400 ml of toluene each and washed with 300 ml of ether to give 6.5 g of sodium 2- (2-fluoro-4-bromobenzyl) -1, 244 DEG-247 DEG C. 2-Dihydro-1-oxophthalazin-4-yl acetate.

Examples 6 to 15

In an analogous manner to that of Example 1, the corresponding benzylhydra 344424 was used

The following compounds of the general formula I, the example number of the substituents on the benzene ring A in which the benzene ring is obtained, obtain the zine of the formula III and 3-oxo-N '-' - phthalaneacetic acid. It is not substituted and R ¹ is a hydroxyl group. The yields are between 15 and 45%.

melting point crystallization solvent

4-bromo

3,4-dichloro

2-fluoro-4-bromo

2-fluoro-4-chloro

2-fluoro-4-iodo

4-iodo

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 / isopronanol (1: 1) 184—185 *) methanol 193—194 ethane ol / 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:

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

Examples 16 to 34

Analogously as in Examples 2-4 but starting from the appropriate ethyl ^3-ΟΧΟ-1 Δ ^c '-fíalanacetátu of formula II (R ¹ - ethoxy) and benzyl _of formula III obtained in a yield of 10 to 40% of a compound corresponding to of formula I wherein R ¹ is ethoxy.

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

P) 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 Dec 3,4-dichloro 7-methoxy Γ'3—130 isopropanol 20 May 2-fluoro-4-chloro - 102 ethanol 21  2-fluoro-4-iodo - - 113 petroleum ether (60—80) 22nd 3,4-dibromo - 140—142 isopropanol 23 2-fluoro-4,5-dibromo - 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 Mar: 4-iodo 106-107 isopropanol / / netrolether (60—80) 28 2-fluoro-4-bromo 8-fluoro 128—130 isopropanol / / petroleum ether (60—80) 29 2-fluoro-4; bromo 8-methyl 120—122 isopropanol / netrol ether (60-80) (1: 3). 30. 2-fluoro-4-bromo 6,7-methylenedloxy 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: 1) 33 3,4-dichloro 6-chloro 143—146 ethanol 34 2-fluoro-4-bromo 6-fluoro 121—123 • ethanol

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

Example35

Analogous to 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