DE4126543A1 - Drug compsn. contg. 3(5)-(hydroxyaryl)-pyrazole derivs. - for inhibition of lipoxygenase and cyclo:oxygenase in treatment of asthma, allergy, inflammation, skin disorders, myocardial infarction etc. - Google Patents

Abstract

A drug compsn. contg. 3(5)-(hydroxyaryl)-pyrazole derivs. (I) is claimed. Ar = opt. susbtd. 2-hydroxyphenyl; R = H, alkyl or opt. substd. phenyl or naphthyl; and R1 = H, alkyl or cycloalkyl; or R+R1 = 3-5C alkylene. Certain cpds. (I) are known from DE856297, DE931284, DE932909, GB707669, J. Chem.Soc. 1952, 1303 and J.Indian Chem.Soc. 65,852(1988), whereas others are new. Pref. opt. substits. on 2-hydroxyphenyl include alkyl, alkoxy, haloalkyl, CF3, F, Cl, Br, CN, NO2, OH, 3-6C alkylene or a fused benzene ring, and opt. substits. on phenyl or naphthyl include alkyl, alkoxy, CF3, F, Cl, Br, CN, NO2 and OH. USE/ADVANTAGE - Cpds. (I) are dual inhibitors of lipoxygenase and cyclooxygenase used for the treatment and prophylaxis of bronchial asthma, allergies, inflammations, shock states, skin disorders, esp. psoriasis and polymorphic photodermatoses, cerebral ischaemia and myocardial infarction, and for the prevention of rejection in organ transplants. Cpds. (I) readily obtainable and have high activity combined with low toxicity. In partic., they inhibit 5-lipoxygenase in the micromolar range. Cpds. (I) are administered by the oral, parenteral, intraperitoneal or rectal route or topically in conventional pharmaceutical dosage forms. Daily dosage is 0.1-50 mg/kg.

Description

Field of application of the invention

The invention relates to the use of 3 (5) - (hydroxyaryl) - pyrazoles as active pharmaceutical ingredients for the production of Medicines for human and veterinary medicine. The Compounds according to the invention act by inhibiting the Lipoxygenases and the cyclooxygenase and can be used for the therapy of all forms of bronchial asthma, inflammatory processes, of allergic diseases in the broadest sense and of others Diseases are used.

Characteristic of the known technical solutions

It is known that the enzyme family of lipoxygenases formed oxygenation products of arachidonic acid and others Polyene fatty acids are significant in the symptom complex of a variety of inflammatory and allergic processes as well as other disorders are involved (see Samuelsson, B. et al .: Science 237, 1171-6 (1987); Parker, C.W .: Ann. Rev. Immunol. 5, 65-84 (1987); Drazen, J.M., Austen, K.F .: Am. Rev. Respir. to. 136, 985-98 (1987); Hagmann, W., Keppler, D .: The Liver, Biology and Pathobiology, 2nd Ed. (I.M. Arias et al., Eds.), Raven Press,  New York, 1988, pp. 793-806; Malle, E. u. a .: Int. J. Biochem. 19th 1013-22 (1987); Feuerstein, G., Hallenbeck, S.M .: FASEB J. 1, 186-92 (1987)). It follows from this that by inhibiting the Lipoxygenase reaction beneficial therapeutic effects in the drug treatment of the corresponding diseases can be achieved.

Known lipoxygenase inhibitors, such as nordihydroguajaretic acid, 3-amino-1- (3-trifluoromethylphenyl) pyrazoline, phenidone and 5,8,11,14-eikosatetraic acid, either do not show sufficient therapeutic effects in vivo or are too toxic. Even newer developments in lipoxygenase inhibitors have not yet achieved a breakthrough for the same reasons. On the other hand, it is clear from the current state of research in the field of arachidonic acid metabolism that lipoxygenase inhibitors offer greater chances for drug development than the highly specific receptor antagonists for lipoxygenase products, since the latter always only switch off a single group of inflammation mediators, whereas one lipoxygenase inhibitor simultaneously biosynthesizes several of these Mediators (leukotriene B ₄ , peptidoleukotrienes, lipoxins, various hydroxyyeosatetraenoic acids, octadecanoids, etc.) are suppressed. Also of particular interest are those lipoxygenase inhibitors which simultaneously inhibit the cyclooxygenase pathway of the arachidonic acid metabolism. These so-called dual inhibitors, as "non-steroidal anti-inflammatory drugs of the second generation", are superior to those of the first generation (selective cyclooxygenase inhibitors, such as acetylsalicylic acid, indomethacin and others) in that simultaneous stimulation of the lipoxygenase pathway and the resulting pro-inflammatory and asthmatic effect (cf. Higgs, cf. Higgs : Prostaglandins, Leukotrienes and Medicine 13, 89-92 (1984); Szczeklik, A .: Eur. Respir. J. 3, 588-93, (1990)) cannot occur.

In recent times, some of these dual inhibitors are different Classes belonging to organic chemistry have become known. From Pyrazole derivatives have been pharmacological for a long time Properties known and several times in a summarized form (e.g. Batulin, Ju.M., Grandberg, I.I., Kost,  A.N .: Izv. Timirjazevskoj Sel′skochozjajstvennoÿ Akad. 1967 (4) 174-88; Orth, R.E .: J. Pharm. Sci. 57, 537-56 (1968)). These Reviews show a wide range of pharmacological Effect of pyrazole derivatives, the representatives with carcinostati anti-viral and anti-inflammatory properties as well with effect on the central nervous system. In the German Patents DE 8 56 297, DE 9 31 284 and DE 9 32 909 are also Pyrazole derivatives for pharmaceutical purposes with bactericidal and fungicidal properties described. Pyrazole derivatives with lipoxygenase and / or cyclooxygenase inhibiting properties have only recently become known. B. the 1- Phenylpyrazolidone (Blackwell, G.J .; Flower, R.J .: Prostaglandins 16, 417-25 (1978)), various amino-1- / 3- (trifluoromethyl) phenyl / -2-pyrazollne (Higgs, G.A. et al .: Biochem. Pharmac. 28, 1959-61 (1979), Copp, F.C. u. a .: Biochem. Pharmac. 33, 339-40 (1984)), but also 3- (1,5-diaryl-3-pyrazolyl) -N-hydroxy propionic acid amides (EP 02 93 220, EP 02 93 221) and some pyrazole carboxylic acid hydrazides (Tihany, E. et al .: Eur. J. Med. Chem.-Chim. Ther. 19, 433-9 (1984)).

Object of the invention

The object of the invention is to develop new pharmacologically highly effective, little toxic and easy to manufacture dual inhibitors from the group to provide the pyrazole.

Surprisingly, it was found that the 3 (5) - (hydroxyaryl) pyrazoles of the general formula I,

in the Ar a 2-hydroxyphenyl radical which is substituted by one or more identical or different substituents, such as, for. B. alkyl, alkoxy, haloalkyl, CF ₃ , F, Cl, Br, CN, NO ₂ , OH, a 3- to 6-membered alkylene bridge between two adjacent carbon atoms or with a fused-on benzene ring,
R is hydrogen, alkyl, phenyl, naphthyl, phenyl and naphthyl radicals optionally being substituted by one or more identical or different substituents, such as, for. B. alkyl, alkoxy, F, Cl, Br, CF ₃ , CN, NO ₂ , OH, may be substituted,
R ^{1 is} hydrogen, alkyl, cycloalkyl and
R and R ¹ together can represent a 3- to 5-membered alkylene bridge,
mean, simultaneously inhibit both lipoxygenases and cyclooxygenase, the inhibition of 5-lipoxygenase already occurring at lower concentrations (µM range).

It will be apparent to those skilled in the art that the inventive Compounds may exist in a tautomeric equilibrium, as shown in general formulas Ia and Ib. Under

however, normal conditions are the two individual individuals not to isolate. The invention excludes both tautomers Forms. To simplify this invention description of the compounds of the invention in the form of Formula Ia written.

Some of the compounds of the general formula I according to the invention with the meanings given for Ar, R and R ¹ are known (Baker, W., Harborne, JB, Ollis, WD: J. Chem. Soc. 1952, 1303; DE 8 56 297; DE 9 31 284; DE 9 32 909; GB 7 07 669; Ingle, VN: J. Indian Chem. Soc. 65, 852 (1988)), but a large part of it is new. They can be made by various known methods. The easiest way to do this is to use the general standard method for the preparation of pyrazoles, as described in each relevant textbook, by reacting corresponding β-dicarbonyl compounds or their functional derivatives, such as, for. B. enol ethers, acetals, enamines, etc., with hydrazine hydrate or its aqueous or alcoholic solutions or hydrazinium salts, such as. B. hydrazinium chloride, sulfate or acetate, obtained in aqueous, alcoholic or aqueous-alcoholic solution at room temperature or with heating (see Behr, S., Fusco, R., Jarboe, CA: The Chemistry of Heterocyclic Compounds Vol. 22 , Pyrazoles, Pyrazolines, Pyrazolidines, Indazoles and Condensed Rings; Edited by A. Weissberger, Interscience Publishers, New York-London-Sidney 1967 and literature cited there). 1- (Hydroxyaryl) -3-aryl-propane-1,3-diones or 1- (hydroxyaryl) -alkane-1,3-diones with 20 to 80% strength aqueous hydrazine solution in ethanol at boiling temperature are preferred in accordance with reaction equation A, where Ar, R and R ^{1 have} the meaning given, implemented.

The 1- (hydroxy aryl) -1,3-dicarbonyl compounds of the general formula II either known or can be according to standard methods of organic-preparative chemistry, e.g. B. by Claisen condensation of hydroxyaryl alkyl ketones with aliphatic or aromatic Carboxylic acid esters, by rearrangement of 2-acyloxyacetophenones or O-acyl acetonaphthols according to Baker-Venkataraman or by Acylation of ketones or corresponding enamines with Produce acyl halides, wherein in at least one of the Reaction partner the hydroxyaryl group must be specified.

Furthermore, the compounds of the general formula I according to the invention can be obtained by reacting hydrazine hydrate or hydrazinium salts with chalcondibromides (Sharma, TC; Saksena, V .; Reddy NJ: Acta chim. Acad. Sci. Hung. 93, 415 (1977)) with 3- Bromine flavanones (Reddy, NJ; Sharma, TC: jndian J. Chem. 248, 715 (1985)) or with flavones (Baker, W .; Harborne, JB; Ollis, WD: J. Chem. Soc. London 1952, 1294; Kallay, F .; Janzso, G .; Koczor, I .: Tetrahedron Letters 1968, 3853; Reddy, NJ; Sharma, TC: Indian J. Chem. 248, 715 (1985)). The reaction of chalcones with an o-hydroxy group in a phenyl ring with hydrazine leads to 2-hydroxyphenyl-pyrazolines, from which oxidation, e.g. B. with MnO ₂ (Sharma, TC; Saksena, V .; Reddy, HJ: Acta chim. Acad. Sci. 64, 408 (1987)), or by catalytic dehydrogenation (DE 24 41 504; DE 26 02 965) also the compounds of the invention can be obtained. The starting materials required for these synthetic methods are either known or can be prepared by known methods. Scheme B outlines the individual reaction routes for the preparation of the compounds according to the invention. The production of these connections is explained in more detail using selected exemplary embodiments. Typical representatives of the compounds according to the invention are listed in Table I.

Scheme B:

Representation of different ways of producing the compounds of general formula I according to the invention using the example of Ar = 2-hydroxyphenyl

Table 1

Selection of typical representatives of the compounds of general formula I according to the invention

The lipoxygenase inhibition of the compounds of the invention general formula I was in two independent Test systems of non-plant lipoxygenases detected:

• - on the isolated 15-lipoxygenase from rabbits reticulocytes, the suitability of which is known as a test system for potential medicinal products (cf. Schewe, T. et al .: Prostaglandins, Leukotrienes and Medicine 23 , 155-60 (1986); Slapke, J. et al .: Biomed Biochim. Acta 45, 1267-75 (1986),
• - on the cellular 5-lipoxygenase system from human polymorphonuclear leukocytes.

The cyclooxygenase inhibition was on the particulate Prostaglandin H synthase from ram's goat vesicles shown. Determination of the activities of 15-lipoxygenase and the prostaglandin H synthase were each performed oxygraphically at 25 ° C at pH 7.4 or 8.0 with linoleic acid or arachidonic acid as a substrate, as described elsewhere (cf. Schewe, T. u. a .: Prostaglandins and related substances - A practical approach (C. Benedetto et al., eds.) IRL Press Oxford 1987, pp. 229-42) The respective enzyme was in the measuring buffer with the Test substance five minutes each until the reaction starts Pre-incubated substrate. The test substances were Methoxyethanol dissolved added, the solvent concentration did not exceed 1% by volume.

The procedure for testing for inhibition of 5-lipoxygenase way is described in Example 5.

Table 2 shows the results of the inhibition test 15-lipoxygenase, 5-lipoxygenase and cyclooxygenase some selected compounds according to the invention.  

Table 2

Half-inhibitory concentrations of selected compounds according to the invention in the three test systems

Inhibition of the 5-lipoxygenase pathway of arachidonic acid change continued in more complex biological systems proven, e.g. B. arachidonic acid-induced contraction of lung strips of the guinea pig and in whole animal ver are looking at guinea pigs sensitive to ovalbumin.

The latter findings and the values given in Table 2 show that the compounds according to the invention are effective 5-lipoxygenase inhibitors in vitro and in vivo. Based on today's knowledge of the role of the 5-lipoxygenase pathway, valuable pharmacological properties are derived from it. They can be used as medicines in the treatment of a number of inflammatory processes and other diseases, for example B. as antiallergics, antiasthmatics, anti-rheumatics, antiatherosclerotics, antimetastics, gastroprotectives, as a means of prophylaxis and therapy of all forms of shock (endotoxin shock, etc.), for post-treatment of myocardial infarction, for the treatment of ischemic states of the brain, such as. B. stroke and migraines, and organ transplants to prevent graft rejection. They are particularly therapeutically effective in those inflammatory diseases that are associated with leukocyte infiltration, which is mediated by the lipoxygenase product leukotriene B ₄ , in particular in inflammatory skin diseases including psoriasis, in liver cirrhosis and in glomerulonephritis.

The compounds of general formula I according to the invention can in a known manner to pharmaceutical preparations in addition to suitable, non-toxic, pharmaceutically inert solid or liquid carriers, fillers, Formulation aids and, if necessary, others Additives such as B. for coloring or improving the Smell or taste, one or more of the Contain compounds of the invention are processed. Preferred pharmaceutical preparations are tablets, Dragees, capsules, pills, ointments, gels, creams, lotions, powders, Sprays, aerosols and nebulizers for inhalation Application. The active ingredient (s) can also, if appropriate together with carriers, fillers and / or auxiliaries Microcapsules are processed. They can also together with other suitable active pharmaceutical ingredients processed the pharmaceutical preparations specified above will.

The therapeutically active compounds can be found in the above mentioned preparations in 0.1 to 99.5 percent by mass, preferably from 0.5 to 90 percent by mass.  

The active substances or the preparations made from them can be local, oral, parenteral, intraperitoneal and / or rectal be applied. The dosages are generally in a range between 0.1 and 50 mg / kg body mass within of 24 hours, but can in special cases go up or deviate below. The application can be given as a single dose or in multiple submissions.

Examples

The following examples explain the invention in more detail without but restrict them.

Example 1: Preparation of 3 (5) - (2-hydroxy-5-methylphenyl) - 5 (3) ethyl pyrazole

6.65 g (0.032 mol) of 1- (2-hydroxy-5-methylphenyl) -1,3-pentadione (obtained from Baker, W .: J. Chem. Soc. London 1933, 1381-9) are dissolved in 150 ml of ethanol and 11 g of 50% aqueous Hydrazine solution added. The reaction mixture is one hour heated to boiling and after cooling in 400 ml of cold water stirred in. The precipitated solid is suctioned off with Washed water and from aqueous alcohol with the addition of something Activated carbon recrystallized. 5.0 g (= 76.7% of theory) are obtained. white crystals, mp 144-5 ° C.

Example 2: Preparation of 3 (5) - (5-chloro-2-hydroxyphenyl) -5 (3) - phenylpyrazole (current No. 17 in Tab. 1)

7.0 g (0.025 mol) of 1- (5-chloro-2-hydroxyphenyl) -3-phenyl-propane 1,3-dione are dissolved in 100 ml of ethanol and with 10 ml of one 50% aqueous hydrazine solution added. The reaction mixture is now heated to boiling for 1 to 2 hours, the initially intense yellow solution becomes almost colorless. After the reaction has ended (Control by TLC) about 50 ml are stirred into water and excess hydrazine with dilute hydrochloric acid neutra lized. The light gray precipitate is suctioned off with Washed water, dried and recrystallized from methanol.  

4.8 g (= 69.6% of theory) of white crystals, mp 177-9 ° C. are obtained. In the thin layer chromatogram (Merck finished film silica gel GF ₂₅₄ , eluent toluene / ethyl acetate 9: 1), only one spot is detected in UV light and by spraying with 5% FeCl ₃ solution.

Instead of 50% aqueous hydrazine solution, the appropriate amount of hydrazine hydrochloride are used, advantageously an acid acceptor, such as. B. a Alkali carbonate or acetate is added.

The 1- (5-chloro-2-hydroxyphenyl) -3-phenyl-propane-1,3-dione was obtained as follows:
34.1 g (0.2 mol) of 2-hydroxy-5-chloroacetophenone (prepared from p-chlorophenylacetate by Fries' shift in the presence of anhydrous AlCl ₃ ) are dissolved in 40 ml of dry pyridine and slowly stirred and cooled 28, 2 g (0.2 mol) of benzoyl chloride were added dropwise. After the addition has ended, the mixture is heated to 90 ° C. for one hour. The cooled reaction mixture is then poured into dilute hydrochloric acid. The resulting 2-benzoyloxy-5-chloroacetophenone separates from the weakly acidic aqueous phase and is taken up in 200 ml of toluene. The toluene phase is separated off, washed neutral, dried azeotropically by means of a water separator and then heated to boiling with 60 g of anhydrous potassium carbonate for 6 to 10 hours with stirring. After cooling, the resulting yellow crystal slurry is filtered off, washed with toluene and hexane and dried. Then the crystal slurry is added in portions with vigorous stirring in 20% acetic acid, excess potassium carbonate dissolving and the desired 1- (5-chloro-2-hydroxyphenyl) -3-phenyl-propane-1,3-dione remaining. The solid is filtered off, washed well with water and dried. 24.2 g (= 44% of theory) of golden-yellow crystals are obtained, which were reacted as described above without further purification.

Example 3: Preparation of 3- (2-hydroxyphenyl) -4,5,6,7- tetrahydroindazole (serial number 12 in Tab. 1)

13 g (0.062 mol) of 2-salicyloyl-cyclohexanol are dissolved in 50 ml of ethanol, heated to 50 ° C. and 16 g of a 50% aqueous hydrazine solution are added dropwise. After the addition has ended, the mixture is heated to boiling for a further two hours, a clear brownish solution being formed. Now part of the solvent is distilled off, the residue is stirred into 200 ml of water and neutralized with dilute hydrochloric acid. The brownish solid which has precipitated is filtered off with suction, washed with water, dried and recrystallized from toluene with the addition of a little activated carbon. 4.2 g (= 32.8% of theory) of a white powder, melting point 140-3 ° C., are obtained. In the thin layer chromatogram (Merck finished film silica gel GF ₂₅₄ , eluent toluene / ethyl acetate 9: 1), only one spot is detected in UV light and by spraying with 5% FeCl ₃ solution.

The 2-salicyloyl-cyclohexanone used as the starting product was obtained as follows:
16.7 g (0.1 mol) of morpholinocyclohexene, 12.1 g (0.12 mol) of triethylamine dried over sodium and 150 ml of benzene are heated together to 35 ° C. and then added dropwise with 23.8 g (0.12 mol ) Acetylsalicylic acid chloride added. After the addition has ended, the reaction mixture is stirred at 35 ° C. for a further two hours and then left to stand at room temperature overnight. The precipitated triethylamine hydrochloride is filtered off and the filtrate is heated to boiling for one hour with 50 ml of 20% hydrochloric acid. After cooling, the phases are separated, the aqueous phase is brought to pH 5 and extracted with benzene. The benzene phases are combined, washed neutral and dried. After distilling off the benzene, 15.8 g (= 72.2% of theory) of a brown, syrupy residue remain, which was reacted as described above without further purification.

Example 4: Preparation of 3 (5) - (1-hydroxy-2-naphthyl) -5 (3) - phenylpyrazole (serial number 30 in Tab. 1)

7.25 g (0.025 mol) of 1- (1-hydroxy-2-naphthyl) -3-phenylpropane-1,3- dione are suspended in 100 ml of ethanol, with 8 g of a 50%  added aqueous hydrazine solution and boiling with stirring heated. The initially orange-yellow reaction mixture changes color initially dark green and gradually takes on a light yellow color at. When the reaction is complete after about two hours (Control by TLC), the reaction mixture is poured into 400 ml cold water, neutralized with dilute hydrochloric acid and sucks the precipitated crystals. After washing with water dried and washed again with hot toluene. You get 5.1 g (= 71.2% of theory) of a white, crystalline product, F. 219-21 ° C. Recrystallization from a lot of toluene led to none Increase in melting point.

The 1- (1-hydroxy-2-naphthyl-propane-1,3-dione was obtained as follows:
13.1 g (0.07 mol) of 1-hydroxy-2-acetonaphthone (obtained from Witt, ON, Braun, O .: Ber. 47, 3216 (1914)) are dissolved in 100 ml of dry acetone and 9.7 g (0.07 mol) of anhydrous potassium carbonate were added. 9.8 g of benzoyl chloride are then added dropwise with stirring and the mixture is then heated to boiling for 10 hours. After cooling, the resulting potassium chloride and excess potassium carbonate are suction filtered and washed well with acetone. The filtrate and washing acetone are combined and then the solvent is distilled off. 16.3 g of crude 1- (benzoyloxy) -2-acetonaphthone remain, which is rearranged to Baker-Venkataraman without further purification. To do this, it is dissolved in 60 ml of dimethyl sulfoxide and 6.7 g of powdered potassium hydroxide are added with stirring at room temperature. After standing for two hours at room temperature, the red-brown solution is stirred into 400 ml of cold water and the mixture is neutralized with acetic acid. The precipitated yellow crystals are now filtered off and then washed with water until neutral and finally with warm methanol. This gives 13.2 g (65% of theory) of an almost clean product, melting point 138-43 ° C., which was reacted as described above without further purification.

Example 5: Determination of the inhibition of the 5-lipoxygenase pathway of the Arachidonic acid metabolism

Isolated polymorphonuclear leukocytes (neutrophil granulocytes) of humans were used as test objects to demonstrate the inhibition of the lipoxygenase pathway of arachidonic acid metabolism. The cells were obtained by conventional methods from the blood of voluntary donors who did not take any medication and did not undergo any detectable diseases at the time of the examinations and were labeled with 5 μM ¹⁴ C at 37 ° C. in the presence of the calcium ionophore A 23187 Arachidonic acid in the absence (control batches) or in the presence of one of the compounds according to the invention (test batches) for 5 minutes. The reaction was then stopped by adding 1 M citric acid. The lipids were extracted with ethyl acetate and then separated by thin layer chromatography on silica gel plates in the eluent system chloroform-methanol-glacial-water 90: 7: 1: 0.7. After the lipids had been made visible by iodine vapor, the radioactivity distribution was recorded using a DC radio scanner. Arachonic acid as well as the lipoxygenase products 5-HETE, 15-HETE and leukotriene B _{4 were} included as authentic standards. While reproducible amounts of the products of the 5-lipoxygenase pathway 5-HETE and leukotriene B _{4 were} detectable in the control batches, clear inhibitions of the formation of these products occurred in the test batches depending on the type and concentration of the compound according to the invention, as derived from the size of the peak areas could be. The half-inhibitory concentrations (IC ₅₀ ) were determined graphically from the inhibitory values of the individual compounds at different concentrations. From thin-layer chromatographic studies it further emerged that the inhibition of the formation of lipoxygenase products by the leukocytes takes place very specifically, since the incorporation of the labeled arachidonic acid into phospholipids and triacylglycerols was not inhibited under the same conditions, but was even stimulated. The test results of some selected compounds according to the invention are listed in Table 2.

Claims (3)

1. Medicament, characterized by a content of 3 (5) - (hydroxyaryl) pyrazoles of the general formula I. wherein
Ar is a 2-hydroxyphenyl radical, optionally with one or more identical or different substituents, such as. B. alkyl, alkoxy, haloalkyl, CF ₃ , F, Cl, Br, CN, NO ₂ , OH, a 3- to 6-membered alkylene bridge between two adjacent carbon atoms or with a fused-on benzo ring,
R is hydrogen, alkyl, phenyl, naphthyl, phenyl and naphthyl radicals optionally being substituted by one or more identical or different substituents, such as, for. B. alkyl, alkoxy, F, Cl, Br, CF ₃ , CN, NO ₂ , OH, may be substituted,
R ^{1 is} hydrogen, alkyl, cycloalkyl and
R and R ¹ together can represent a 3- to 5-membered alkylene bridge. 2. Use of 3 (5) - (hydroxyaryl) pyrazoles according to claim 1 as a lipoxygenase and cyclooxygenase inhibitor for the treatment and / or prophylaxis of all forms of Bronchial asthma, from inflammatory and allergic Diseases of various organs (e.g. lungs, liver, Kidney, heart, eye), of shock states, of Skin diseases - especially psoriasis and polymorphic Light dermatosis, in ischemic states of the brain, for the aftercare of the heart attack as well as for the Organ transplant to prevent the graft rejection.   3. Pharmaceutical preparations, characterized in that they one or more compounds of the general formula I included according to claim 1.