IL33530A - Benzylidene amino-oxyalkyl carboxylic acids and carboxylic acid derivatives,their preparation and pharmaceutical compositions containing them - Google Patents

Description

33530/2 m '^'Dpiinp ' e-OpiR-ia'as-in-' 'Taa nisoin n K o' 'Dan ninpn *n»tt m fiuon , *nn ini Benzylidene amino-oxyalkyl carboxylic acida and derivatives thereof, their preparation and pharmaceutical compositions containing them N.V. PHILIPS' GLO ILA PiiiiFABRI BH C. 31636 ~ 2 - 33530/2 The Invention relates to novel benzylidene amino oxyalkyl carboxylic acids and carboxylic acid derivative So It is known that rheumatic affections belong under the serious diseases. Medicaments for combating these affections are known, but they usually have undesirable side effects. For example, the vary potent (N°p» chloro<= phenyl- 5-methoxy indolyl-3) aoetic acid has a high toxioity so that in the final analysis the therapeutic index is The invention relates to novel benzyl^ idene amino oxyalkyl oarboxylic acids and carboxylio aoid derivatives of the general formula ι which were found to have a strong anti=inflammatory acti= vity and a strong analgetio effect. These compounds further have a slight toxicity, whilst some have an interesting activity against Rhino virus.

In formula I the symbols have the following meanings s a halogen atom," R2 s a halogen atom or hydrogen; - 3 - 33530/2 is hydrogen or CH^; R^. is a possibly branched alkylene group containing up to 3 carbon atoms; Rg is OH, alkoxy containing up to 8 carbon atoms, ΝΗ^» monoalkylamino , in which the alkyl group contains up to 3 carbon atoms, benzyloxy or the radical OR^, where R^ represents a metal atom, an ammonium^hydroxyethyl dimethyl ammonium br hydroxyethyl diethyl ammonium group, with the proviso that when ^ is hydrogen, then Rg is an alkoxy group.

Especially compounds of the general formula where R^ is bromine or chlbrine and Rg* is NHg, OH„ an alkoxy containing up to three carbon atoms or the radical OR^, where R^ has the same meaning as in formula I, have a very strong activity. This applies specifically to ( =methyl° -chlorobenzylideneamino) oxyj| aoetic acid and its salts and to (<Λ -methyl~ -chlorobenzylidene° amino)oxy)j| acetic acid methyl ester and particularly to oxyJ acetamide o , On the ground of their properties the compounds according to the invention can be used for combating rheumatoid arthritis, Bechterew's disease, arthritis psoriatica, collagen disease, serious osteoarthrosis , acute gout, periarthritis humeroscapularis „ acute sterile non°infeoted bursitis, thrombophlebitis and aout® poly~ PHN. 37 10 arthritis rheumatica, and the like.

The amounts in which and the frequency at which the compounds are to be administered for combating these affections depend on their seriousness. However, as a rule, the doctor in charge will have no difficulty to find the correct treatment. Generally, patients will be given from 50 to 1000 mg daily, if required divided in several portions „ Usually, from 100 to 500 mg daily will suffice The anti-inflammatory activity of the compounds was determined in the carageenin test carried out according to a modification of the method of Winter, Risley and Nuss, Proc. Soc. Exp. Biol. 1 1 1 - 5^ - ( 1 62 In this test, the reduction of th^ swelling produced by the carrageenin serves as a measure of the anti-inflammatory effect.

The test was performed with male rats of weight about 220 g. The animals are made to fast for the 16 hours preceding the test. The substances to be tested are suspended in a 1 $ tragacanth solution and aministered orally. Immediately after the administration of the substance, a water loading of up to 5 ml per animal is performed. 1 hour thereafter, 0 .05 ml of 1 . 5$ carrageenin solution is intraplantarly injected and the thickness of the foot (dorsal plantar distance) is determined by means of a special micrometer. 3 hours after the administration of the carageenin the thickness of the oedema is determined. The swelling of the foot is expressed in a percentage relative to the zero hour value. The inhibition percentage is calculated according to the relation; percentage of blanko group percentage of test group percentage of blank group - 100 From the results of a series of dosages an value was computed. This is the dosage which gives a reduction of 50$ relative to the blank group.

The analgetic activity of the compounds was determined by a modification of the method of Randall and Sellito (Arch. Int. Pharmacodyn. 109 ^09 (1957)).

The reduction of the pain response due to increasing pressure on a yeast—inflamed rat foot is used as a criterion for the analgetic activity.

The test is performed with male rats, weight from 100 to 150 g. One hour before the administration of the test preparation the animals are given, .an intraplantar injection of 0.1 ml of 20$ yeast suspension. The compounds to be tested are suspended in a 1$ tragacanth solution and administered orally. One hour, two hours and four hours after the administration of the test substance the pain threshold value is measured with increasing pressure on the inflamed foot.

As a comparison, the pain reaction of a group of animals not treated, with a pharmacon was determined.

The results are expressed as a percentage of the mean blank value.

From the results of a series of dosages an ED^^ value, i.e. the dosage which produces a 100$ increase of the pain threshold, was calculated.

As compounds having an interesting activity against Rhino virus we may mentions [ (a methyl«-4-chlorobenzylidene amino)oxy] acetamlde, [ ( -methyl-314-dichloro¾enzylidene amino}oxy] acetamlde, $~n.butyl~[(eH_aethyl-4-ehlorobenzylidene aminojoxy] acetamide, 4#-[(e-metbyl-4-chlorobenzylidene amino)oxy] butyric acid.

The compounds according to iiis invention can be prepared by known methods* Accordingly, the invention relates also to a method of producing novel benzylidene amino oxyalkyl earboxylic acids and oarboxylic acid derivatives which is characterized in that compounds of the general formula Rg is a halogen atom or hydrogen? is hydrogen or CH^i is a possibly branched alkyiene group containing up to 3 carbon atoms; Eg is OH, alkoxy containing up to 8 carbo atoms, a benzyloxy group,!^, monoalkylamino in which the alkyl group contains up to 3 carbon Atoms, or the ndical OR^, where represents a metal ^tom, an ammonium group, a hydroxyethyldimethyl ammoniumgrou or a hydroxye hyldiethyl-ammonium groupj with the proviso that when is hydroge ,then Rg is an alkosy grou ; are prepared by methods which are kmum or preparing compounds of this type and by similar methods* The compounds according to the invention may, for example, be obtained by reacting a compound of the formula with a compound of the formula in which formulas to have the same meanings as in the formula I, M is a metal atom, for example la or I, Sal i© a haloge stom, for example chlorine or bromine, and R is OH monoalkylamino g o p in which the alkyl group contains up to 3 carbon stoma, an alkosy group containing up to 8 carbon atoms or a bonzyloxy group* She reaction is preferably carried out in a polar solvent, such as dimethyl orma ide, dimethylsulfoxide, alcohols and the like at temperatures between room temperature and the boiling point of the reaction mixture and in the presence of an 33530/2 PH . 3710 be converted into the salts of the formula I (Rg * OR^).

The compounds according to the invention may alternatively be prepared by reacting a compound of the general ormula: with a compound of the general formula: in which formulae the symbols have the same meanings as in the formula I. This reaction also preferably is carried out in a polar inert solvent, for example one of the aforementioned solvents. The reaction temperature as a rule lies between room temperature and the boiling point of the ϊ solvent. j The acids of the formula VI ' 1 and their salts, in which formula R- to have the same meanings as in the formula I and ^* is a propylene or a possibly branched ethylene group, can be prepared by reacting a compound of the formula II in which R^, and R^ have the same meaning as in formula. I and M is a metal atom, tilth a compound o the formula in which R£ has the seme meaning as in formula ¥1 above.

The reaction is preferably performed in an inert solvent, such as, for example, ®«-methyl-2«-pyrrolidon, benzene or the like, at temperatures between room temperature and the boiling r>oint of the solvent * The compounds of the .formula trtiere R^ to ^ and Rg have the same meanings as in the formula I and Rjl Is a propylene or possibly branched ethylene group, can be obtained by reacting a compound of the formula i which ^, ^ and ^ have the same meaning as in formula I and K is a metal atom, with a compound <£ the formula - 53550/2 PHN. 3710 group* The reaction is preferably carried out in an inert solvent, for example in an alcohol, for example ethanol. Th:e:. reaction temperature as a rule lies between 0°C and the boiling point of the reaction mixture.

The compounds of the formula j and their salts have the same meanings as in the formula I - may also be obtained by saponifying a nitrile of the formula where R1 to have the same meanings as in the formula I> with a base. The reaction is preferably carried out in an inert solvent, such as an alcohol, at a temperature not higher than the boiling point of the reaction mixture.

Esters of the formula may also be obtained by reactin a nitrile of the formula: PH „ 3710 with an alcohol ROH in the presence of an acid, and decomposing the reaction product with water. In the¾e same meanings as in the formula 1 represent^ an alkyl group cuntaining up to 8 carbon atoms or a benzyl group. The reaction is preferably carried out in an inert solvent, for example an ether, such as diisopropyl ether. The reaction temperature lies between 0°C and k0°Co Acids of the formula I can be converted into the corresponding esters of the formula I by means of alcohols, as the case may be by way of the acid chlorides 0 Esters of the formula I can be converted into amides as -J-Qcdaeaeid^e-e- of the formula I by means of ammonia or a /alkylamina. mono*--8¥- άί-3^.^γ1--θ^-ΐ¾^τ^^^Ύ¾^^^^·¾:¾·β-^--¾ηο opoo tivo-lyy The acids of the formula I can be obtained from amides and esters of the formula I by saponification.

The compounds according to the invention can be converted into pharmaceutical preparations, such as, for example, tablets, pills, powders, injection liquids, salves, suppositories dragees and the like, by known methods .Hence the invention also relates to the production of pharmaceutical preparations and to the preparations themselves.

Suitable carrier materials are the substances commonl used for this ur ose in harmac .

The Invention will now he described more fully with reference to e following examplea* 1) i(g. ethyl-¾>4-dichloro¾engylidene amino)oxv1 acetle acj.d 4·733 of 3,4-dlchloroacetophenone and 2.74 g of hemihydrochloride of amino-oxyacetie acid tere dissolved in 50 ml of 80 ethanol. The solution was mixed with 6.15 S of sodium acetate and then refluxed for one hour. The reaction mixture was subsequently concentrated by evaporation in a vacuum.

After an excess of H sodium hydroxide had been dded, the residue was wice extracted with ether, after which the remaining aqueous solution was acidified with 2 hydrochloric acid and again extracted twice T?ith ether. ¾e latter ethereal solution was shed twice with water, then dried over anhydrous sodium sulfate and subsequently concentrated by evaporation. The residue was re-crystallised from a mixture of benzene and petroleum ether* The title compound obtained melted at 128°C - 129°C PH . 3710 2 r |^( (k -methyl- -chlorobenzylidene amino )oxy~j acetic acid. · 7 S °f ' -chloroacetophenone oxime was added to a solution of 2 , 13 g of sodium in 80 ml of absolute ethanolo The solvent was distilled off as far as possible from the solution in a vacuum. The residue was mixed with 33 g of ^ -chloroacetic acid ethyl ester and then re-fluxed for half an hour. Subsequently, the excess of (A -chloroacetic ester was removed at 80°C in a vacuum. ethyl ester of ( -methyl -4-chlorobenzylidene amino)oxyj acetic acid.

This ester was saponified by boiling it with 55 ml of 2N sodium hydroxide for 1 hour. The reaction mixture was cooled and then extracted 5 times with ether. The extracted alkaline solution was acidified with 100 ml of 2N hydrochloric acid and then extracted twice with ether. The latter ethereal extracts were washed 4 times with water, ~ after which the ether was distilled off. The solid residue was crystallized once from a mixture of benzene and petro-leum ether and then purified by washing a solution of the residue in a caustic soda solution with ether and re-acidifying it. After another crystallisation from a mixture of benzene and petroleum ether the pure substance was obtained. Melting point 1 15 ° 5°C to 1 16 , 5°C, To a solution of 1 .85 g of sodium in 150 ml of absolute ethanol 6.8 g of 4-chloroacetophenone oxime and 8 .6 g of -bromopropionic acid were added in this order with PHN. 3710 stirring. After the mixture had been stirred for 1 hour the ethanol was removed in a vacuum. The residue was mixed with water and the mixture was washed twice with ether.

The aqueous solution then was acidified and extracted twice with ether. The ethereal extracts were washed 6 times with water, dried over anhydrous sodiumsulfate and concentrated by evaporation. After crystallisatio of the residue from petroleum ether, the superscribed substance was obtained. After it had been washed once with water and crystallized from a mixture of benzene and petroleum ether the melting point was 88°C-89°C. i>) ( -methyl- -chlorobenzylidene amino ) oxy "~ acetamide .

A solution of 2.9 g of sodium in 75 ml of absolute ethanol was mixed with 21 . 4 g of h ' -chloroacetophenone oxime and then concentrated by evaporation in a vacuum to a constant weight. The residue was mixed with 75 ml of dimethyl formamide and 1 1 . 8 g of ø( -chloroacetamide .

The temperature was maintained below o°C by cooling.

The mixture was stirred overnight at room temperature, after which the solvent was removed in a vacuum. The residue was dissolved in ether and water. The ethereal solution was washed twice with sodium hydroxide and thrice with water. The solution was mixed with a small amount of chloroform, treated once with activated carbon and a filter aid (hyflo) , whereupon after some concentration by evaporation and after the addition of petroleum ether the superscribed substance crystallized out. It was recrystallized from a mixture of chloroform, ether and petroleum ether. Melting point 103°C- 10 °C. ( A solution of 17.0 g of the ( J -methyl- -chloro-benzylidene acetic acid obtained by a method as described in one of the preceding examples in 60 ml of methanol, to which 1 ml of concentrated sulfuric acid had been added, was refluxed for 8 hours. The larger part of the methanol was then distilled off in a vacuum and the residue was washed with ether.

This ethereal solution was washed once with water and times with portions of 20 ml of 2N sodium hydroxide each. The solution was dried over anhydrous sodium sulfate and the solvent was distilled off. After distillation in a vacuum the residue yielded the superscribed substance.

Boiling point 130°C-132°G at a pressure of 0.1 mm. ) ( -methyl- -chlorobenzylidene amino ) oxy ~J -N-methyl acetamide.

A mixture of 5 - 0 g of the ( ( -methyl- -chlorobenzyl-idene amino) o yj acetic acid methyl ester obtained by the method described in example 3 and ho ml of 35$ aqueous methylamine solution was stirred for 2 hours. The precipitated solid substance was then dissolved by thrice extracting the mixture with an ether chloroform mixture.

The extract was washed thrice with water, dried over anhydrous sodium sulfate and then concentrated by evaporation. Crystallisation of the residue from a benzene petroleum ether mixture yielded the above substance.

Melting point 115°C-116°C. 33530/2 - 16 rj) ( <-meth.yl-3. -dichlorobenzylidene amino)oxyJ acetamide » A solution of 5.0 g of 3 ' , ¾'-dichloroacetophenone in 50 ml of 90$ ethanol was mixed with .2.4 g of amino-oxyacetamide and subsequently boiled. The solvent was removed in a vacuum ^and the residue was extracted with chloroform. The chloroform solution was washed thrice with water, dried over anhydrous sodium sulfate and subsequently concentrated by evaporation in a vacuum. After the addition of ether and petroleum ether the superscribed substance crystallized out from the concentrate. Melting point 1 1 1°C- 1 1 1 , 5°C.

Of the (<Λ-methyl-^-chlorobenzylidene amino )ox acetonitrile (melting point 57°C-58.5°C) which was ob*-tained by reacting the sodium salt of '-chloroaceto-phenone oxime , with chloroacetohitrile in dimethylfor-mamide, an amount of 1 1 .3 g was dissolved in diisopropyl ether in which 1 ·° g of hydrogen chloride and 1 .73 g of methanol had also been dissolved.' The solution was diluted with 25 ml of diisopropyl ether and subsequently stirred over night. Then the precipitate was drawn off, Δ■ ΡΗΝ. 3 710 washed with absolute ether and dried in a vacuum. The resulting hydrochloride of methyl -methyl-4-chloro- benzylidene amino) oxy acetimidate melted at 95°C with decomposition. After this substance had been dissolved in water, the superscribed ester separated out from the solution. It was extracted with ether and distilled in a vacuum. Boiling point at a pressure of 0. 1 mm : 130°C- 132°C. Γ*( After the oxime had dissolved, the solvent was removed in a vacuum and the residue was suspended in 150 ml of benzene To this suspension a solution of . 32 g of -propiolactone < in 20 ml of benzene was added with stirring and cooling to 5°C in a nitrogen atmosphere. The reaction mixture was then stirred for 1 .5 hour at 5°C and subsequently for 2 PHN. 3710 distilled off in a vacuum at 30°C and the residue was mixed with 750 ml of water. The non-dissolved substance was removed by filtration, after which the solution was acidified with acetic acid and extracted thrice with 150 ml of ether.

The ethereal extract was washed thrice with 25 ml of water and then extracted with 2N sodium hydroxide. The alkaline extract was washed twice with ether, then acidified with 2N hydrochloric acid and then extracted thrice with 150 ml of ether. The latter ethereal extracts were washed thrice with a small amount of water and then dried over sodium sulfate. After the ether had been distilled off, a solid substance of the superscribed structure was left, which after crystallisation from petroleum ether melted in a range from 80°C to 83°C. onic acid.

In 10 minutes 75 g of acrylic acid ethyl ester was added drop by drop with stirring to a solution of 4l, g of ' -chloroacetophenone oxime in 75 ml of sodium ethylate solution (made from 0. 50 g of sodium and ethanol). After the addition, the mixture was cooled to room temperature and then stirred for 16 hours. Subsequently, 3 · 0 ml of acetic acid was added and the resulting mixture was concentrated by evaporation at 70°C and a pressure of 0.0 1 mm until no longer anything distilled over. The residue was mixed with 300 ml of petroleum ether and the resulting solution was filtered. The filtrate was washed thrice with dilute sodium hydroxide, then dried over anhydrous sodium ΡΗΝ. 3710 temperature of 50°C and a pressure of 1 2 mm. The residue consisted of the ethyl ester of the 3 (< -ethyl- -chloro-benzylidene amino )oxy~j propionic acid (boiling point 130°C- 132°C at a pressure of 0. 7 mm). By allowing a 5$ solution of this ester in 0. 5 N alcoholic potassium hydroxide to stand for 2k hours at room temperature the potassium salt of the above-mentioned acid was obtained. By extracting an aqueous solution of this salt after acidification with an equivalent amount of 2N hydrochloric acid with ether, drying the ethereal extract and concentrating it by evaporation, the above-mentioned acid was obtained. Melting point range from 80°C to 85°Ce propionamide . 1 5. 6 g of the ethyl ester of 3 £ ( < -methyl- -chloro-benzylidene amino )oxy | propionic acid obtained by the method described in Ex Jample 1 #} was dissolved in 100 ml of methanol saturated with ammonia at 25°C. This solution was heated at 70°C in an autoclave for 7 hours. It was then concentrated by evaporation in a vacuum at 40°C and the semisolid residue was dissolved by means of 200 ml of diethyl ether, 100 ml of benzene, 200 ml of chloroform and 200 ml of methylene chloride. The resulting solution was extracted thrice with dilute sodium hydroxide, then dried over anhydrous sodium sulfate and finally concentrated by evaporation in a vacuum. The residue obtained was recrystallized from a mixture of 50 ml of benzene, 0 ml of chloroform and 25 ml of petroleum ether. Melting point 1 -+9°C- 1 0°C. propionic acidB A solution of 2. 4 g of sodium hydroxide in 55 ml of 85$ ethanol was mixed with 6 , 78 g of 4 ' -chloroaceto-phenone oxime and 2088 g of acrylic acid. The mixture was then refluxed for 2. 5 hours, subsequently diluted with ml of water, and concentrated by evaporation in a vacuum after 2 hours. The residue was dissolved in 50 ml of ether and 50 ml of water, and the layers were separated,, The water layer was extracted with 50 ml of ether and then acidified with 40 ml of 2N hydrochloric acid. The acid solution was extracted with 100 ml of ether and the ethereal solution was dried over sodium sulfate . Then the solvent was distilled off and its last traces were removed together with higher boiling substances at a pressure of 0.01 mm and a temperature of 50°C. The residue was crystallized from petroleum ether. Melting point 80°C-83°C. butyric acid.

A solution of 1 1 « S °f 4 * -chloroacetophenone oxime in 28 ml of N-methyl-2-pyrrolidon was mixed with 1 . 72 g of comminuted sodium and stirred at 60°C until all the sodium had dissolved. The reaction mixture was then cooled to room temperature and subsequently mixed with 6.0 g of j-butyrolactone . The reaction mixture was then heated to boiling and refluxed for 4 hours. After part of the solvent had been distilled off in vacuum, the residue was poured into 1 liter of water. This aqueous solution was filtered and then acidified with acetic acid. As a result, a 33550/2 It was drawn off, washed with water and r ecrystalllsed from 30?S acetic acid. Melting point 106.5°C - 108.5°C.

The following substances w ere prepared by methods similar to those described in the above examples.

TABLE I ■ R, 4 R, Phys.Const. C correspond- ing example P CI Br CI H* OH, CH2 bp 0.05 mm 173 CI CH2 OCHgCgHg bp 0.05 mm 175-195 5 CI 0H2 NH(n-C4H9) 65.5 - 66 , 6 • t 1^) A tablet containing 0.2 g of ( < -methyl-¾-chloro-benzylidene amino)oxy~j acetic acid. 200 g of -methyl- -chlorobenzylidene amino)oxy acetic acid was mixed with 190 g o sec. calcium phosphate, 90 g of microcrystalline cellulose and 120 g of a mixture consisting of 200 parts of maize starch, 32 parts of talcum and 4 parts of magnesium stearate, until a homogeneous mixture had been obtained. From this mixture tablets having a diameter of 13 nun and a weight of 600 mg each were struck. - 100 mg of ((3^ -methyl- -chlorobenzylidene amino)oxy^j acetamide together with 1.5 g of suppository medium was shaped to form a suppository.

In.jection liquid. 100 g of -methyl-4-chlorobenzylidene amino )o yJ acetic acid was dissolved in an equimolar amount of 1 N sodium hydroxide, and the solution was mixed with 15 g of benzyl alcohol. This solution was diluted with distilled water to a volume of 1000 ml. The dilute solution was filtered through a bacterial filter, after which ampoules of 1 or 2 ml are aseptically filled with it.

Claims (1)

1. 23 Compounds of the general formula a possibly branched alkylene group containing up to 3 carbon is an alkoxy group containing up to 8 carbon a a in which the group contains up to 3 carbon atoms or the radical where is a metal an a hydrox ethyldiiaethyl or a h ammonium with the proviso that is 4 then is an alkoxy Compounds of the general formula where is chlorine or bromine and is an alkoxy group containing up to three carbon or the radical where has the same meaning as in formula 24 acetic aoid and its lorobenzylidene acetio aoid methyl aoetamide 6V acetic onic aoid and its 8 propionio aoid and its butyrio acid and its acetic acid its acetic acid acid ite acetic acid acetic acid butyl process of preparing compounds of I in Claim wherein a compound of the general formula in which and have same meaning as in Claim 1 and is a metal is reacted with a compound of the general formula Hal 26 a where has t e same meaning as in Claim Hal alogen atom and is a grou in which the group contains up to 3 carbon a group or an group containing 1 to 8 carbon and the acids thus obtained if converted into salts by means of process of preparing of formula I in Claim wherein a compound of the formula is reacted with a compound of the formula e and have the same meaning as in Claim A process of preparing compounds of formula I in Claim wherein acids of the formula and their in which ormula have the same meaning as in Claim 1 and is a propylene group or a possibly branched ethylene are prepared by reacting a compound of the formula II in which have the meanings as in the ormula I and is a metal a compound of the formula where has the same meaning as in formula VI A process of preparing compounds of formula I in Claim where compounds of the formula and is a propylene group or a possibly branched ethylene are prepared by reacting a compound of the in which meanin as in Claim with a compound of the formula in which is an h group or a or 28 A process of preparing compounds of formula X in Claim wherein acids of the formula in which as in Claim 1 and their are prepared by saponifying a compound of the formula in which and have the same as in Claim with a A process of preparing compounds of formula I in Claim wherein compounds of the formula in have the same meaning as in Claim and R is an alkyl group containing up to 8 carbon atoms or a benzyl prepared by reacting a compound of in which each have the same meaning as in Claim with an alcohol ROE in presence of an acid and by decomposing the reaction product with 29 A method according to any of Claims 19 to the are converted into their ponding esters tilth alcohols of the formula where is containing up to 8 carbon atoms or a benzyl A method according to any of Claims 209 22 and wherein the esters e converted into corresponding amides with or where the group contains up to 3 carbon method according to any of 22 and wherein the resulting amides and estera are converted into the corresponding acids and the salts thereof by Pharmaceutical preparations containing a compound according to any one 1 to 18 the active For the insufficientOCRQuality