DE3544409A1 - 2-Arylsulphonamido-benzo- and acetophenones and their oximes, processes for their preparation and their use in medicaments - Google Patents

Abstract

The invention relates to novel 2-arylsulphonamido-benzo- and acetophenones and their oximes, processes for their preparation and their use in pharmaceutical compositions. The compounds of the formula I according to the invention <IMAGE> are biologically well-tolerable inhibitors of the lipoxygenase and cyclooxygenase reaction and are distinguished by pharmacologically useful properties, in particular by antiasthmatic, antiallergic, anti-inflammatory, antihypertensive, spasmolytic, antirheumatic and antithrombotic properties and are suitable in human and veterinary medicine for use in the therapy of bronchial asthma, allergic disorders, inflammatory and rheumatic disorders of various types, of disorders accompanied by spasms of the smooth musculature, of high blood pressure in the general and lesser circulation and also of thrombosis.

Description

Title of the invention

2-Arylsulfonamido-benzo- and -acetophenones and their oximes, processes for their production and their use in pharmaceuticals, field of application of the invention The invention relates to new 2-ArylsulSonamido-benzo- and -acetophenones and the oximes obtainable from them, process for their preparation and their application in pharmaceutical preparations. The compounds as such and containing them pharmaceutical agents show valuable pharmacological, especially antiasthmatic, antiallergic, antiinflammatory, antihypertensive, spasmolytic, antirheumatic and antithrombotic properties and are used in human and veterinary medicine for use in the therapy of bronchial asthma and other allergic Diseases, from inflammatory and rheumatic diseases of various kinds as well as thrombosis and cardiovascular diseases.

Characteristics of the known technical solutions 2-Amino-benzophenone and l- (2-aminopheriyl) -ethanone- (l) as starting ketones for the inventive Compounds have long been known and their syntheses have been described (e.g.

H.J. Scheifele Jr. and D * P. De Tar in Org. Syntheses 32, 8 (1952) or Coll. Vol. IV, 34 (1963); J. Mouzin, H. Cousse, J.M. Autin, French Pat. FR 2476070 (1980); G.T. Morgan et al.

J.E. Moss, J. Soc. Chem. Ind. 42, T 461 (1923); W.S. Emerson et. al., J. Am. Raw. Soc. 69, 706 (1947)). In recent years, the number of such im aromatic ring of differently substituted amino-ketones as a result of their increasing Significance as precursors for pharmaceuticals increased sharply.

Those on the amino group are less varied in terms of their residues carboxamide compounds prepared by acylation with carboxylic acids or carboxylic acid derivatives (e.g.

Beilstein XIV, Syst. No. 1873, Switzerland. Pat. 581606 (1967).

Only recently were some sulfonamido-ketones and their oximes described as selective extractants for the extraction of metals from aqueous solutions can be used (US Pat. 4160807 (1978)). Via an application of the new ketones and oxime compounds according to the invention as pharmaceuticals in the Buman- and veterinary medicine no information was found.

Among the previously known anti-inflammatory drugs of a non-steroid nature ("non-steroidal antiphlogistic drugs") no satisfactory means are known their mode of action on the simultaneous inhibition of the lipoxygenase and cyclooxygenase pathways based on the arachidonic acid cascade. However, such a principle of action is for the anti-inflammatory Properties of a drug are crucial. Corresponding connections are either not systemically effective (e.g. nordihydroguajaretic acid, 5,8,11,14-icosatetrainic acid and their analogues) or as a result of excessive toxicity in pharmaceutical preparations cannot be used (e.g. benoxaprofen, BW 755C and related pyrazoline derivatives). the New oximes according to the invention differ fundamentally in their chemical structure all previously known inhibitors of the arachidonic acid cascade. You do not assign the undesirable side effects of the steroids (e.g.

Prednisolone, dexamethazone) and show in toxicological animal experiments an extraordinarily high tolerance.

All non-steroidal drugs that have been used in therapy so far Anti-inflammatory drugs are exclusively cyclooxygenase inhibitors (indomethacin, Sulfindac, acetylsalicylic acid, etc.), which also have some undesirable side effects, how E.g. the ulcerogenic (magnetic ulcer promoting) show, whereas for lipoxygenase inhibiting compounds the opposite, ie. gastroprotective properties are known.

OBJECT OF THE INVENTION The aim of the invention is to provide pharmaceuticals Preparations with pharmacologically valuable, especially antiasthmatic, antiallergic, anti-inflammatory, anti-rheumatic, antihypertensive, spasmolytic, antithrombotic and cardioprotective properties.

Statement of the essence of the invention The object of the invention is development of new 2-arylsulfonamido-benzo- and -acetophenones and their oximes with antiasthmatic and other pharmacologically valuable properties on the simultaneous Inhibition of lipoxygenase and cyclooxygenase are based as well as processes for their Manufacturing.

It has been found that 2-arylsulfonamido-benzo- and -acetophenones and their oximes of the general formula I. in which: R is Me or Ph or p-substituted phenyl; R¹ is C1-18 alkyl, C1-18 alkoxy; Amino or acylamino; Hydrogen R2 is hydrogen, halogen, NO2 or NHR3, where R3 is hydrogen, an acyl or arylsulfonyl radical; X 0 or NOR4, where R4 stands for hydrogen, C112-A1kyl, aralkyl, COR5 or CONHR5 and R5 is aliphatic or aromatic radicals, have pharmacologically valuable, in particular antiasthmatic, antiallergic, anti-inflammatory and antithrombotic properties and are effective components of pharmaceuticals Preparations can be used.

It has also been found that a process for the production of Sulfonamido-ketones and their oxime compounds of general formula 1 thereby is characterized in that one which is easily accessible according to known regulations substituted methyl or phenyl (2-aminophenyl) ketones with suitable sulfonyl halo geniden implements. According to a preferred, very simple procedure, the Methyl or phenyl (2-aminophenyl) ketone and a suitable substituted benzenesulfonyl chloride together in an organic base or a solution of an organic base in one inert organic solvent in a sealed flask for 12 - Left to stand at room temperature for 24 hours. After a few minutes, one usually sets weak exothermic reaction. In general, cooling is not necessary.

The reaction mixture can optionally also be used for 15-30 minutes heated to 60 - 80 ° C. After the specified time is a clear or a reaction mixture containing precipitated pyridinium salt formed, which is appropriate is poured onto ice. The solid sulfonamido-ketone formed can then be removed by suction recovered and purified by recrystallization.

The substituted benzenesulfonyl chlorides used as starting material can in a known manner from the corresponding alkyl or alkoxybenzenes with chlorosulfonic acid getting produced. The sulfonamido-oximes are obtained by having a corresponding Sulfonamido-ketone, a hydroxylamine salt, preferably hydroxylamine hydrochloride and a basic substance * in particular potassium or sodium hydroxide, potassium or Sodium acetate, sodium formate, piperidine, pyridine, morpholine, N-methylpiperazine, Diethanolamine, among other things, in an organic solvent, z. : B. in lower aliphatic alcohols or glycols, acetonitrile, dioxane, but preferably in ethanol or a mixture of these with water, under reflux cooling 0> 5 - 4 Hours heated, working in the temperature range of 50 - 15,000.

By evaporation of the solvent, if appropriate in vacuo and by adding water or by adding water directly to the reaction mixture the oxime can be obtained. The oximes of the sulfonamido-benzophenones always fall as mixtures of the anti and syn isomers.

Using this procedure, many new ones have been found in the literature so far not described and with regard to elemental analysis, melting point as well as by IR- and NMR spectra characterized ketones and oximes are obtained, one of which Selection is listed in Tables 1 a and 1 b. These in the tables and examples The connections contained therein illustrate the existing possibilities and limitations this not about one.

Table 1a: Substituted 2-benzenesulfonamidophenyl ketones (formula I; X = 0) ¹H-NMR data (in CDCl3, HMDS) Name R R¹ R² mp ° C Yield R R aromatic SO2NH% d. Th. Protons CH3 (CH2) n CHnO od.

CHnAr 2- (p-Ethylbenzenesulfon- Me Et H 125-28 80 2.45s 1.10t - 2.56 qu 6.7-7.8 m 11.37 (s) amido) acetophenone 2- (p-methoxybenzenesul- Me MeO H 135 90 2.45s - - 3.70s 6.6-7.8 m 11.35 (s) fonamido) acetophenone 2- (p-pentoxybenzenesulfone- Ph C5H11O H 94-95 80 - 0.83t 1.0-3.70t 6.5-7.8 m 9.89 (s) amido) benzophenone 2- (p-dodecyloxybenzene- Ph C12H24O H 64-65 70 - 0.78t 1.18 3.70t 6.57.8 m 9.85 (s) sulfonamido) benzophenone 2- (p-Acetaminobenzene- Ph CH3CONH H 173-75 50 - CH3CO: 2.00s 6.9-7.75m 9.96 (s) sulfonamido) benzophenone 2- (p-Toluenesulfonamido) - Ph Me 5-Cl 120-22 83 - - - 2.10s 6.7-7.75m 9.59 (s) 5-chloro-benzophenone Tabel 1b: Substituted 2-benzenesulfonamidophenyl-ketoximes (formula I, X = NOH) 1 H-NMR data (in CDCl3 / DMSO, HMDS) Name R R¹ R² Mp ° C Yield R R¹ aromatic- SO2NH = NOH% of theory. Th. Protons (CH2) nCH2Ood.

CH3 CH2Ar 2- (p-toluenesulfonamido) - Me Me H 138-42 55 1.95s 2.24s - - 6.9-7.6m 11.16s 12.21s acetophenone oxime 2- (p-ethylbenzenesulfone- Me Et H 120-21 58 1.93s 1.10t - 2.55 qu 6.6-7.6m 11.09s 11.17s amido) acetophenone oxime 2- (p-methoxybenzenesulfone- Me MeO H 136-38 90 1.97s 3.68s - - 6.6-7.7 m 11.12m 11.32s amido) acetophenone oxime 2- (p-Toluenesulfonamido) - Ph Me H 156-80 90 2.10 + 2.28sa) - - 6.55-7.8m 11.08m 11.08s 11.28s benzophenone oxime 2- (p-pentoxybenzenesulfone- Ph C5H11O 95-103 40 0.84 + 0.85t 1.1- 3.66+ 6.35-7.75m 10.86+ 11.60s amido) benzophenone oxime 1.9m 3.82t 2- (p-decyloxybenzensulfone-Ph C10H21O H 104-05 65 0.84t 1.0- 3.68+ 6.4-7.9m 10.74s c) amido) benzopenone oxime 1.8m 3.85t 2- (p-Dodecyloxybenzensul- Ph C12H25O H 85-86 0.80t 1.0-3.69+ 6.35-7.8m 11.0+ 11.57s fonamido) benzophenone oxime 1.8m 3.86t 11.23s 2- (p-acetaminobenzene sulfone- Ph CH3CONH H 129-30 55 CH3CO: 2.05s 6.5-7.7m 9.70+ 11.32s amido) benzophenone oxime 11.03s 2- (p-Toluenesulfonamido) -5- Ph Me 5-Cl 170-82 80 2.07 + 2.23sb) - - 6.3-7.7m 10.85s c) chlorobenzophenone oxime 2- (p-methoxybenzenesulfone- Ph Me O 5- NO2224-26 42 3.67s - - 6.5-8.3m c) c) amido) -5-nitro-benzophenone oxime a) anti / syn mixture 82: 18% b) anti / syn mixture 70: 30% c) not recoverable Surprisingly it was found that the compounds of the general formula I according to the invention in animal experiments in vitro and in vivo pronounced anti-asthmatic, antiallergic or anti-anaphylactic, spasmolytic, antihypertensive effects demonstrate. The test for the pharmacological properties mentioned was carried out, for. T. by measuring methods known in principle from the literature, which are modified in Form were used, namely on the isolated trachea of the guinea pig, on the isolated lung strip from guinea pigs, including on the arachidonic acid-induced one and the potassium ionophore-induced contraction of the isolated pulmonary strip (see. Example 15) and the isolated pulmonary artery (see. Example 16), on the specifically allergically induced bronchoconstriction in ovalbumin-sensitized persons anesthetized and artificially ventilated guinea pigs ("guinea pig asthma" or "anaphylaxis of the guinea pig") as well as in the isolated human bronchus (see.

Example 17, 18). [N.W. Drazen et al., J. Clin. Invest. 63: 1 (1979); M.W. Schneider and J.M. Drezen, Amer. Rev. Resp. Dis.

121: 835 (1980); S.S. Yen and W. Kreutner, Agents Actions 10, 274 (1980); S.S. Yen, Prostaglandins 22: 183 (1981); Adcock, J.J .; Garland, L, G .; Brit. J. Pharmacol. 69: 167 (1980); W.

Diamantis, J.L. Melton; D. Sofia et al., Europ. J. Pharmacol.

56: 407 (1979); F. Andersson, Brit. J. Pharmacol, 77: 301 (1982); M.H. Saad and J.F. Burka, Eur. J. Pharmacol. 100, 13 (1984)].

The compounds of general formula I according to the invention lead to a complete inhibition of the ovalbumin-induced asthma reaction in ovalbumin-sensitized persons Guinea pig.

This effect in allergic asthma is comparable to ketotifen, a modern anti-asthmatic, but its molecular mechanism of action is different differs from that of the compounds according to the invention (see below). The invention However, compounds surpass ketotifen by a much broader range of indications; i.e. in effectiveness even in non-allergic forms of bronchial asthma. Furthermore, the inhibition of the arachidonic acid-induced contraction on the isolated Rabbit pulmonary artery (Example 16) the antihypertensive and spasmolytic effect.

The whole animal method is an adequate animal model for forms of bronchial asthma with involvement of IgE- and IgG-mediated allergic reactions Reactions. Andersson, Brit. J. Pharmacol. 77, 301 (198217. Therefore, closed that the compounds of the general formula I according to the invention are also pronounced Must have anti-inflammatory properties. This conclusion could on a suitable animal experimental model of inflammation in vivo, the carrageenin-induced Edema of the rat paw, according to the method of Winter et al.

[C.A. inter, E.A. Risley and G.W. Nut, Proc. Soc. Exp.

Biol. Med. 111, 544 (1962)] (see Example 19). 2- (p-Toluenesulfonamido) -benzophenone-oxime exercised in this inflammation model at a dosage of 50 mg / kg body mass i.p. strong, highly significant inhibitory effects from none of the conventional anti-phiogistic Pharmaceuticals, e.g.

Indomethacin, exceeded in parallel batches of the same test series became.

As a molecular point of attack for the pharmacological effects the compounds of the invention was the inhibition of both lipoxygenase as also identified by cyclooxygenase. Bs is known that the enzyme lipoxygenase formed metabolites of arachidonic acid in the formation of inflammatory and allergic processes are involved [cf. G.A. Higgs, C.M.R. Bac and S. Moncada, Leukotrienes and other lipoxygenase products, Raven Pross, Nevr York 1982,.

331, E.J. Goetzl, Immunology, 40, 709 (1980); Ford-Hutchinson et al. J. Pharm. Pharmacol, 32, 517 (1980); B. Samuelsson, Trends in Pharmacol. Sci, May 1980, 227; Borgeat et al., J.

Med. Chem. 24, 121 (1981)]. Likewise, the key role of products is the cyclooxygenase reaction, especially the prostaglandins, in inflammatory processes today sufficiently secured [p. Moncada and J.R. Vane, Pharmacol. Rev. 30, 293 (1979)].

The inhibition of lipoxygenase was convincingly based on a suitable one animal lipoxygenase detected after Procedure of Rapoport and co-workers [S.M. Rapoport et al., Eur. J. Biochem. 96, 545 ((1979j7 from Rabbit reticulocytes were isolated. The compounds of the invention worked in a final concentration of 1 mM predominantly heamulations of 90% or more (cf. Example 20). The strong inhibitions were for some of the compounds according to the invention also detectable at a final concentration of 0.1. By varying the substance concentration could see the titration curves of the inhibition and from them the half-inhibition concentrations (150 values) can be determined * It was e.g. for 2- (p-toluenesulfonamido) -benzophenone-oxime 75 pL Since these, like many of the other compounds according to the invention, are due their limited water solubility at this concentration in the in vitro test system failed - visible from a clear clouding of the measurement base, it is to be assumed, that the true I50 values are far lower. The suitability of lipoxygenase Rabbit reticulocytes as a model for the molecular-pharmacological site of action of the Compounds according to the invention were proven by others from the literature known lipoxygenase inhibitors such as 3-amino-1- (3-trifluoromethylphenyl) pyrazoline, 5,8,11,14-eicosatetrainic acid, 5,8,11-eicosatriinic acid, nordihydroguajaretic acid, Propyl gallate, 4-nitrocatechol and 3-tert-butyl-4-hydroxy-anisole also have this enzyme highly effective inhibit. However, the previously known lipoxygenase inhibitors do not achieve this the anti-asthmatic effectiveness of the compounds according to the invention. Likewise was the other important enzyme in the arachidonic acid cascade, cyclooxygenase, which consists of Semen vesicles of rams according to the method of F.J.G. van der Ouderaa and M. Butytenhek, Methods in Enzymology 86, 60 (1982), with an I50 value inhibited by 100 µM. In this regard, the compounds of the invention are many previously known anti-inflammatory drugs superior to only the cyclooxygenase inhibit (e.g. 13.

Acetylsalicylic acid, indomethacin, etc.), from which these are known Compounds produce undesirable pharmacological side effects (e.g. ulcerogenic, gastrotoxic and proasthmatic effects of acetylsalicylic acid).

As for the new drugs the inhibition of lipoxygenase than molecular The point of attack identified was its influence on platelet aggregation examined. This is achieved through the cyclooxygenase pathway of the arachidonic acid cascade resulting thromboxane A2 triggered [see e.g. J.M.

Bailey, Trends Biochem. Sci. 4, 68 (197917.

An unwanted platelet aggregation occurs with thrombotic and cardiovascular disease. Therefore the Be-Bund is of extraordinary importance, that the compounds according to the invention increase platelet aggregation depending on the test conditions either inhibit completely or make it reversible (see Example 22). In the experiments platelet aggregation was achieved either by arachidonic acid or by platelet activating factor (PAF-Acether) triggered.

The experiments mentioned provide evidence of suitable biological models the antiasthmatic, antiallergic, antihypertensive, spasmolytic, antithrombotic and anti-inflammatory effects.

Of particular importance to the potential value of the invention new compounds than new drugs is the extraordinarily high biological Tolerance in animal experiments. Even at the highest dose used (6 g per kg body mass p.o.) showed no acute toxicity for 2- (p-toluenesulfonamido) -benzophenone-oxime in the rat can be detected (see. Example 23).

As indication areas in human and veterinary medicine, for example The following are mentioned: 1. All forms of bronchial asthma including infection-related Bronchial asthma (intrinsic asthma), exogenous allergic bronchial asthma (extrinsic asthma) of types 1, II and IV according to Coombs and Gell R.R.A. Coombs and P.C.H.

Gell: The classification of allergy reactions responsible for clinical hypersensitivity and disease. In: Clinical aspects of immunology, ed. By P.G.H. Gell and R.R.A. Coombs, P. 575, Blackwell Scientific Publications, Oxford, 1968, des analgesic-induced bronchial asthma (aspirin-induced asthma) exercise-induced asthma, cold asthma, bronchial asthma caused by irritation and bronchial asthma caused by psychogenic factors.

2. Asthmoid bronchitis and obstructive pulmonary emphysema as well as all bronchoconstrictive conditions that accompany other diseases or Side effects of medical measures, e.g. complications from anesthesia or bronchospastic Reactions after the application of beta-adrenergic blocking substances occur.

3. Allergic diseases in the broader sense, in particular: - atopic Dermatitis - allergic 1thinitis (seasonal rhinitis, but perenial shinitis also vasomotor rhinitis) - urticaria - angioedema contact dermatitis (contact eczema) - allergic diseases of the gastrointestinal tract - allergic conjuctivitis.

4. All forms of thrombosis, both for the treatment of existing thrombosis (Thrombophlebitis) and for thrombosis prophylaxis in - chronic ischemic Heart disease - follow-up treatment for myocardial infarction - chronic recurrent thrombosis - chronic thrombophlebitis.

5. Use as a nonsteroidal anti-inflammatory drug, with the compounds of the formula I are indicated especially in those inflammatory processes in which the conventional anti-inflammatory drugs (e.g. acetylsalicylic acid, salicylate, etc.) have a point of attack outside of lipoxygenase, insufficient therapeutic Effects show, especially at purulontic inflammation and at rheumatic and arthritic diseases.

6. All forms of arterial high pressure, especially pulmonary hypertension High pressure (in the pulmonary circulation).

7. Spastic conditions of smooth muscles of various origins, especially in various sections of the digestive and urogenital tracts as well as the blood vessel muscles.

Due to other pharmocological effects known from the literature of lipoxygenase inhibitors can be used for the compounds of the invention Formula I also antiatherosclerotic, cardiovascular protective, gastroprotective as well as derive antimetastatic effects.

The compounds of general formula 1 are suitable as active ingredients for oral, perlingual, rectal, parenteral, intravenous or percutaneous as well as aerosols or Nebulizer drugs applicable to the treatment of various Forms of bronchial asthma as well as thrombosis, rheumatic, arthritic and other inflammatory diseases.

Among the compounds according to the invention, the 2- (p-toluenesulfonaniido) -benzophenone oxime particularly favorable pharmacological properties.

The present invention includes pharmaceutical preparations, which in addition to non-toxic, inert pharmaceutically suitable carrier substances or contain more than one active ingredient according to the invention, or one or more Active ingredients according to the invention exist. Under non-toxic, inert pharmaceutical Suitable carriers are solid, semi-solid or liquid diluents, To understand fillers and formulation auxiliaries of all kinds.

Preferred pharmaceutical preparations are tablets, coated tablets, Capsules,: pills, granules, syrups, suppositories, Solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders, sprays, and aerosols Spray preparations for inhalation application (topical application after Principle of disodium chromoglycate). Tablets, dragees, capsules, pills and granules can contain the active ingredient (s) in addition to the usual carriers; as a) Fillers and extenders, e.g. starches, milk sugar, cane sugar, glucose, mannitol and Silicic acid, b) binders, e.g. carboxymethyl cellulose, alginates, gelatine, polyvinylpyrrolidone, c) humectants, æ.Be glycerine, d) disintegrants, e.g. agar-agar, calcium carbonate and Sodium bicarbonate, e) dissolution retarders, e.g., paraffin, and f) absorption accelerators 1 e.g.

quaternary ammonium compounds 1 g) wetting agent, e.g. cetyl alcohol, glycerine monostearate, h) adsorbents, e.g. kaolin and bentonite and i) lubricants, e.g. 13. Talc, Calcium and magnesium stearate, sodium auryl sulfate and solid polyethylene glycols or Mixtures of the substances listed under a) to i).

The tablets, coated tablets, capsules, pills and granules can be used with the customary coatings optionally containing opalizing agents and also be composed in such a way that they only or prefer the active ingredient (s) in a certain part of the intestinal tract, possibly with a delay, where as embedding materials z.3. Polymer substances and waxes can be used.

The active ingredient (s) can optionally be combined with one or more the above-mentioned carrier substances are also in microencapsulated form suppositories In addition to the active ingredient (s), the usual water-soluble or water-soluble ones can be used Contain carrier substances, e.g. polyethylene glycols, fats, e.g. cocoa fat and higher Esters (e.g. C14 alcohol with C16 fatty acid / or mixtures of these substances).

Ointments, pastes, creams and gels can be used in addition to the active ingredient (s) contain the usual carriers, e.g. animal and herbal Fats, axis, paraffins (e.g. oil fractions), starch, tragacanth, cellulose derivatives, Polyethylene glycols, silicones, bentonites, talc, silica and zinc oxide or Mixtures of these substances.

Sprays, powders, and atomizers can be used alongside the Active ingredients contain the usual carriers, e.g.

Milk sugar, talc, silica, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances.

Sprays can also use the usual propellants, e.g. chlorofluorocarbons, contain.

Solutions and emulsions can, in addition to the active ingredient or ingredients, the common carriers such as non-toxic organic solvents, solubilizers and emulsifiers, e.g. water, dimethyl sulfoxide, ethyl alcohol, isopropyl alcohol, Methyl glycol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, especially cottonseed oil, peanut oil, Cashew nut oil, corn oil, olive oil, castor oil and sesame oil, glycerine, glycerine formal, Tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan or Contain mixtures of these substances.

The solutions and emulsions can also be used for parenteral administration are in sterile and blood isotonic form.

In addition to the active ingredient (s), suspensions can contain the usual carriers such as liquid diluents, e.g. water, dimethyl sulfoxide, ethyl alcohol, propylene glycol, Suspending agents, e.g. ethoxylated Is os tearyl alcohols, polyoxyethylene sorbitol and Sorbitan ester, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar or contain tragacanth or mixtures of these substances.

Dispersants (e.g .: 3.

Lignin, sulphite waste liquors, methyl cellulose, starch and polyvinylpyrrolides) be used.

The formulation forms mentioned can also contain colorants and preservatives as well as odor and taste improving Additives, e.g. peppermint oil and eucalyptus oil and sweet.

agents, e.g. saccharin.

The therapeutically active compounds are intended in those listed above pharmaceutical preparations preferably in a concentration of about 0.1 to 99.5, preferably from about 0.5 to 90% by weight of the total mixture.

in amounts sufficient to cover the stated dosage range to reach.

The pharmaceutical preparations listed above can except the active ingredients according to the invention also contain further pharmaceutical active ingredients, e.g. antihistamines and mast cell degranulation inhibitors.

The manufacture of the pharmaceutical preparations listed above takes place in the usual way according to known methods, e.g. by mixing the active ingredients with the carriers.

The present invention also includes the use of the invention Active ingredients and pharmaceutical preparations that contain one or more active ingredients contained in human and veterinary medicine for prevention, amelioration and / or Treatment of the diseases listed above.

The active ingredients or the pharmaceutical preparations can be used locally, orally, parenterally, intraperitoneally and / or rectally, preferably orally, in particular can be applied as aerosol or atomized preparations.

In general, it has proven advantageous to use the Active ingredients according to the invention in total amounts of about 0.05 to about 100, preferably 0> 1 to 50 mg / kg body mass per 24 hours, if necessary in the form of several single doses to be administered to achieve the desired results.

However, it may be necessary to deviate from the stated dosages, depending on the type and the Body weight of the object to be treated, the type and severity of the disease, the type of preparation and the application of the drug and the period or interval within to which the administration takes place. In some cases it can be sufficient get by with less than the above amount of active ingredient, while in others Cases the amount of active ingredient listed above must be exceeded.

The following examples are intended to explain the invention in more detail however, do not limit their scope in any way.

Working Examples Example 1 2- (p-Toluenesulfonamido) -benzophenone-oxime 14 g (0.04 mol) of 2- (p-toluenesulfonamido) benzophenone are mixed with 6 g ~ 0.08 mol) of hydroxylamine hydrochloride and 16 g of potassium acetate (anhydrous) in 100 ml of ethanol refluxed for 3 hours. The colorless oxime is then precipitated from the filtered solution with water. To recrystallization from ethanol / water, melting point 156-180 ° (syn / anti mixture).

Example 2 2- (p-Toluenesulfonamido) acetophenone oxime 29 g (0.1 mol) 2- (p-Toluenesulfonamide) acetophenone are added with 17.5 g (0.25 mol) of hydroxylamine hydrochloride and 50 g of potassium acetate (anhydrous) in 300 ml of ethanol heated under reflux for 3 hours. The filtered solution is then mixed with water and the precipitated oxime is precipitated Recrystallized from water / ethanol, melting point 138-142 °.

Example 3 2- (p-Ethylbenzenesulfonamido) acetophenone 6.75 g (0.05 mol) 2-Amino-acetophenone in 50 rta dried pyridine are taken at room temperature Shake with 12.2 g (0.06 ol) p-ethylbenzenesulfonyl chloride was added. After 5 - 10 minutes warming occurs and after a while the pyridinium salt falls the end. The mixture is left in a closed flask for 24 hours and then poured onto ice.

The deposited ketone is filtered off with suction and from an ethanol-water mixture recrystallized, melting point 125 ° -128 °.

Example 4 2- (p-Ethylbenzenesulfonamido) acetophenone oxime 6.1 g (0.02 Mol) 2- (p-Ethylbenzensulfonamido) -acetophenon are in 100 ml of ethanol with 10 ml dried pyridine and 3.1 g (0.044 mol) of hydroxylamine hydrochloride for 3 hours Heated to reflux. The solvent is then evaporated off in vacuo and the Water is added to the residue. An oil separates out, which after a short time crystallized. Recrystallized from an ethanol-water mixture, the melting point was 120-121 ° C.

Example 5 2- (p-Pentoxybenzenesulfonamido) -benzophenone 5 g (0.025 mol) 2-aminobenzophenone with 7.8 g (0.03 mol) of p-pentoxybenzenesulfonyl chloride in Put 25 ml of dried pyridine in a closed flask at room temperature for approx. Left for 24 hours. Then it is poured onto ice and it separates in the process often a greasy substance first, which solidifies after standing for a while and can be suctioned off. Recrystallized from ethanol or n-heptane shows the ketone a m.p. 94-950C. It was characterized by elemental analysis, IR and NMR spectrum.

Example 6 2- (p-Pentoxybenzenesulfonamido) -benzophenone oxime 4.2 g (0.01 Mol) 2- (p-Pentoxybenzenesulfonamido) -benzophenon are in 60 ml of ethanol with 1.5 g (0.022 lAol) hydroxylamine hydrochloride and 3 g potassium acetate for 3 hours under reflux cooked, then it is filtered hot and washed with hot ethanol. After concentrating the filtrate, the residue crystallizes. By recrystallization from a toluene-n-iieptane mixture, the oxime melts at 95-10,300 Elemental analysis, IR and NMR spectra characterized.

Example 7 2- (p-Dodecyl oxybenzens u19 onamido) -benzophenone 5 g (0.025 mol) of 2-aminobenzophenone are mixed with 10.8 g (0.03 ìlol) of dodecyloxybenzenesulfonyl chloride in 30 ml of dried pyridine at room temperature in a sealed flask ditched. After 24 hours, the reaction mixture is poured onto ice. the initially greasy substance crystallizes after repeated renewal of the aqueous one Phase and is then first made from n-heptane, then from an ethanol-water mixture recrystallized, m.p. 64-6500.

Example 8 2- (p-Dodecyloxybenzenesulfonamido) -benzophenone-oxime 2,6 g (0.005 mol) of 2- (p-dodecyloxybenzensulfonamido) benzophenone are dissolved in 30 ml of ethanol with 1 g (0.014 sol) of hydroxylamine hydrochloride and 1.5 g of potassium acetate for 3 hours Boiled reflux, filtered hot and the solvent evaporated in vacuo.

The residue is recrystallized from n-neptane, melting point 85.degree.-86.degree.

Example 9 2- (p-Methoxybenzenesulfonamido) acetophenone 6.75 g (0.05 Mol) 2-aminoacetophenone are dried in 50 nil pyridine at room temperature mixed with 122 g (0.06 mol) of p-methoxybenzenesulfonyl chloride, after a few Minutes a slight warming of the reaction mixture occurs and after a few minutes Time pyridinium salt separates. do 24 hours of standing in a locked one Flask, the mixture is poured onto ice and the separated ketone from an ethanol-water mixture recrystallized, mp 135 ° C.

Example 10 2- (p-Methoxybenzenesulfonamido) acetophenone oxime 6.1 g (0.02 mol) 2- (p-Methoxybenzenesulfonamido) -acetophenon are in 100 ml of ethanol with 3.1 g (0.044 mol) of hydroxylamine hydrochloride and 10 ml of dried pyridine for 3 hours heated to reflux. The solvents are then evaporated in vacuo and the Water is added to the residue. The separated oxime is first obtained as an oil, that becomes solid after a short time and can be vacuumed. From an ethanol-water wipe recrystallized, it melts at 136-138 ° C.

Example 11 2- (p-Acetaminobenzenesulfonamido) -benzophenone 2 g (0.01 Mol) 2-minobenzophenone, 2.5 g (0.11 mol) p-acetaminobenzene sulfonyl chloride and 10 ml of dried pyridine are in a sealed flask for 24 hours Left to stand at room temperature. Then it is poured onto ice, whereby a greasy Substance separates, which soon solidifies by renewing the aqueous phase several times will. Recrystallized from ethanol, Afp. 173-175 ° C.

Example 12 2- (p-Acetaminobenzenesulfonamido) -benzophenone-oxime 1,2 g (0.003 mol) of 2- (p-acetaminobenzensulfonamido) benzophenone are dissolved in 20 ml of ethanol with 0.45 g (0.0065 mol) of hydroxylamine hydrochloride and 0.7 g of potassium acetate under reflux Boiled for 3 hours, then evaporated to dryness in a vacuum, mixed with warm water and aspirated the remaining oxime. Recrystallized from an ethanol-water mixture becomes an Fp.

obtained from 129 - 130 ° C.

Example 13 2- (p-Toluenesulfonamido) -5-chloro-benzophenone 6.1 1 g (0.025 mol) of 2-amino-5-chlorobenzophenone are mixed with 4.8 g (0.025 mol) of p-toluenesulfonyl chloride in 30 ml of dried left flask to stand. Afterward the reaction mixture is poured onto ice and the separated ketone from ethanol recrystallized, m.p. 120-122 ° C.

Example 14 2- (p-Toluenesulfonamido) -5-chloro-benzophenone-oxime 3.85 g (0.01 mol) of 2- (p-toluenesulfonamido) -5-chlorobenzophenone are dissolved in 40 ml of ethanol with 1.5 g (0.022 mol) of hydroxylamine hydrochloride and 4.9 g of potassium acetate for 4 hours refluxed. The solvent is then largely in vacuo evaporated and the residue mixed with warm water.

The remaining oxime is recrystallized from ethanol, melting point 170 - 18200 (syn / anti mixture).

Example 15 Effect of 2- (p-toluenesulfonamido) acetophenone oxime.

2- (p-Methoxybenzenesulfonamido) acetophenone oxime. 2- (p-methoxybenzene ulf onamido) benzophenone oxime and of 2- (p-toluene sulfonamido) benzophenone oxime on the contraction of the isolated guinea pig lung strip triggered by exogenous arachidonic acid The test of the compound for antiasthmatic activity was carried out on the isolated Lung strips from guinea pigs according to literature (M.H. Saad and J.F. Burka, Europ. Per Pharmacol. 100, 13 (1984)) known measurement methods in modified form. The measurements were carried out isotonic in the thermostated organ bath using a Contraction measuring device with lever transducer measuring coil, measuring amplifier (inductive Measurement with the help of a high-frequency oscillating circuit).

The gassing took place with air. The suspension solution was as follows Composition: 39.46 g NaOL, 2.2 g KCl, 6.07 g Tris, 1.0 g CaCl2, 9.9 g glucose, 1.0 ml saturated MgCl2 solution, 43 ml 1 M HCl per 5 l, pH 7.4.

The contraction was here by increasing concentrations of Arachidonic acid (concentrated solution in ethanol, stored in N2 atmosphere) triggered and measured cumulatively.

50 μM of the above-mentioned compounds according to the invention led to a strong Reduction and partial abolition of the nontraction response to arachidonic acid im Range from 0.1 - 100 µM ("Metactoide Inhibition" according to "General Theory of Drug-Receptor-Interactions") by F.G. van den Brink in Kinetics of Drug Action ed. by J.M. van Rossum, jumper Berlin, Heidelberg, New York, 1977, chap. 4, pp. 169-254). The results are in Figs. 1a - 1d shown from the comparison of the effects of the invention Compounds with known active ingredients (Tab. 2) shows that they are modern themselves Developments such as B. the lipoxygenase-inhibiting anti-inflammatory drug benoxaprofen clearly surpass.

% MA X. CONTROL (%) LOG. CONC MS [M] Fig. 1 a Inhibition of arachidonic acid-induced contraction by 2- (p-toluenesulfonamido) -benzophenone-oxime on the isolated lung strip preparation of the guinea pig. Ordinate: mean values and standard deviation of the 5-fold measured normalized contraction responses in pair organs in a parallel experiment after incubation with 5 × 10 -5 M (solid line) and without (dashed line) test substance.

At the same time it was incubated with indometazine 5 × 10-6 M and prothazine 5 x 10-6 M. Standardization of the individual values: contraction in mm, expressed in percent the maximum contraction response of the preparation to the standard agonist acetylcoline. Abscissa: 10g M bath concentration for arachidonic acid. The normalized measurement data were adapted to the model function specified in the text by means of a computer program.

Computer adapted model parameters and goodness of fit: (--------): S.A.Q. = 0.11 ED50 = 3.6 x 10-4 M, nH = 0.666 (- - - -): S.A.Q. = 2.7 ED 50 = 9.2 x 10-4 M, nH = 0.383.

Isotonic contraction, modified Krebs-Henseleit solution, 3700, nH 7.4, 20 ml organ bath, model "Hoechst", cumulative dose addition of the varying agonist in the fluid ratio 1 s 100 g% MA X. CONT ROL (x) LOG CON C. M @ [H] Fig. 1 b: Inhibition of arachidonic acid-induced contraction by 2- (p-toluenesulfonamido) acetophenone oxime on the isolated lung strip preparation of the guinea pig. Identical conditions as in Fig. 1 a. Computer adapted model parameters and goodness of fit: (): SQA r 1.0 ED50 = 4.5 x 10-5 M, nH = 1.724 (- - - -): SAQ = 6.0 ED50 = 3.1 x 10-5 M, nH = 3.896.

% MA X. CONTROL (x) LOG CON C. MS [M] Fig. 1 c: Inhibition of the arachidonic acid-induced contraction by 2- (p-methoxybenzenesulfonamido) -benzophenone oxime on the isolated lung strip preparation of the guinea pig.

Identical conditions as in Fig. 1 a. Computer adapted model parameters and goodness of fit: (------): S.A.Q. = 4.9 ED50 = 4.5 x 10-4 M, nH = 0.44 (- - - -): S.A.Q. = 11.0 ED50 = 2.6 x 10-5 M, nH = 1.722.

% MA X. CONTROL (x) LOG CONC. MS [M] Fig. Qd: Inhibition of arachidonic acid-induced contraction by 2- (p-methoxybenzenesulfonamido) acetophenone oxime on the isolated lung strip preparation of the guinea pig.

Identical conditions as in Fig. 1 a. Computer adapted model parameters and goodness of fit: (------): S.A.Q.

8.0 ED50 = 2.4 x 10-5 M, nH = 2.808 (- - - -): S.A.Q.

27.0 ED50 = 1.6 x 10-5 M, nH = 0.599.

Table 2: Overview of the effect of 2-arylsulfonamidobenzo and -acetophenone oximes on the arachidonic acid-induced contraction¹ of the isolated Guinea pig lung strips in comparison with known active substances Test substance Bath concentration inhibition (%) (μM) of the control disodium cromoglycate 50 0 (DSCG; Intal, known) Ketotifen (known) 1 20 Benoxaprofen (known) 50 30 t-butylhydroxyanisole (Known to BHA) 100 45 BW 755C (known) 50 50 2- (p-Methoxybenzesulfonamide) -acetophenone-oxime 50 60 2- (p-Toluenesulfonaido) -acetophenon-oxime 50 65 Nordihydroguajaretic acid (NDGA, known) 50 80 2- (p-Toluenesulfonwnido) -benzophenone-oxime 50 80 2- (p-Methoxybenzenesulfonamido) -benzophenone-oxime 50 80 1 all attempts in the presence of 5. 10-6 i indometazine and 5. 10-6 M prothazine.

Example 16 Effect of 2- (p-toluenesulfonamido) -benzophenone-oxime, 2- (p-Toluenesulfonamido) -acetophenone-oxime, 2- (p-Methoxybenzenesulfonamido) -acetophenone-oxime and from 2- (p-methoxybenzenesulfonamido) -benzophenone oxime to exogenous arachidonic acid induced contraction of the isolated pulmonary artery from the rabbit The experimental The arrangement of this test system corresponds to example 15.

Isolated strips of the pulmonary artery of rabbits were used as test objects The contraction was initiated in the presence of 10 ».I indometazine (blockage of the cyclooxygenase pathway arachidonic acid utilization) by increasing concentrations of arachidonic acid triggered and measured cumulatively.

50 µM each of the test substances led to a reduction in the response to contraction on arachidonic acid in the range of 0.1 - 100 µM by 80 to 85% ("Metactoide inhibition" based on "General Theory of Drug-Receptor-Interactions" by F.G. van den Brink in Kinetics of Drug Action ed. by I.M. van Rossum, Springer Berlin, Heidelberg, New York, 1977, Cape. 4,.

169-254).

Example 17 Effect of 2- (p-toluenesulfonamido) -benzophenone-oxime on the allergen-induced bronchial construction in sensitized guinea pigs in vivo ("allergic guinea pig asthma") The investigation was carried out on male. Guinea pigs, 21-28 days after sensitization with 100 mg Al (OH) 3 and 100 mg ovalbumin in 0.5 ml of isotonic saline solution i.p. per kg of body mass.

[Method modified from P. Anderson, Britt.J. Pharmacol.

77, 301 (1982)].

The investigations were carried out in several series, each with different Application forms or doses of the 7th substance to be examined on sensitized male guinea pigs weighing between 350-600 g, made from different Breeds originated.

The animals were injected intraperitoneally (i.p.) with 20% Urethane solution anesthetized (1.3 g / kg KM).

A flexible venous catheter (jugular vein dextra) and a tracheostomy tube (2.8 mm) placed. The animals prepared in this way were fixed in the supine position in a tank respirator. After relaxation with Pavulo (2 mg / kg KH) i.v. artificial ventilation was carried out in the tank ventilator with a rhythmic Negative pressure (f = 16 min-1, I: E = 1: 1, p = 2 kpa). Au the outwardly directed rpracheal cannula A Fleisch nozzle was attached (0 r 2.8 mm, 1 = 40 mm), over which with a Pneumotachograph (Hertel, Lengenfeld) the respiratory parameters were measured (flow velocity V and tidal volume VT).

The primary data were recorded with a 12-channel UV recorder (Meßgerätewerk Zwönitz) recorded.

The evaluation could be reduced to the Volwn signal, since the Tidal volume is a representative one with our standardized ventilation technology Quantity to characterize Changes in breathing mechanics represents. The mean tidal volume after 3 minutes of ventilation was used as the baseline (VTA). To control the vitality of the animals, a non-standardized ECG lead created, tracked via monitor and together with the breathing parameters The bronchoconstrictions were registered uniformly with one IV injection triggered with egg white (0.4 mg / kg BM) or lyophilized ovalbumin (4 mg / kg BM). Before the first bronchospasm was triggered, the animals received (randomly selected) the pretreatment with 2- (p-toluenesulfonamido) -benzophenone oxime. The pre-treatment the animals were given 2 injections i.p. Slurried by finely ground test substance in agar-agar, in doses of 20 mg / kg body mass 90 and 60 minutes before the start of the experiment.

The substance resulted in a complete in 90% of the animals examined Inhibition of the ovalbumin-induced asthma response.

All control animals, however, strayed after a single application of 4 mg ovalbumin IV after a protracted severe asthmoid reaction in respiratory arrest due to complete bronchial obstruction.

Comparable anti-asthmatic, anti-allergic or anti-anapylactic Effects on the whole animal model are also from modern anti-asthmatics such as ketotifen and disodium cromoglycate not known [C. Armor and D.M. Temple, Agents Actions 12: 285 (1982)].

Example 18 Effect of 2- (p-toluenesulfonamido) -acetophenone-oxime, 2- (p-Methoxybenzensulfonanido) -acetophenone-oxime, 2- (p-Methoxybenzensulfonamido) -benzophenone-oxime, 2- (p-Toluenesulfonamido) -benzophenone-oxime on the basal tone of the isolated human Bronchus.

The experimental arrangement of this test system corresponds to example 15th

Isolated human bronchial rings were used as test objects.

When the test substances were added in a cumulative dose, bath concentrations occurred from 1 - 10 µN to measurable dilatory effects in an extent of 10 - 30 % of the maximum isoprenaline effect.

Example 19 Inhibition of rat paw carrageenin edema. Carrageenin edema is used in the international literature as a model system for inflammation-causing uses (prophlogistic) processes and offers the possibility of in vivo testing of substances on anti-inflammatory (anti-inflammatory) activity. The testing was carried out according to the international methodology [C.A. Winter, E.A. Risley and G.W. Nut, Proc. Soc. Exp. Biol. Med. 111, 544 (1962)].

2- (p-Toluenesulfonamido) -benzophenone-oxime was administered i.p. to 10 rats.

at a dose of 50 mg / kg body mass with simultaneous administration of 0.1 ml of 0.1% carrageenin solution is applied per animal. The extent of the paw edema was measured every hour after application and compared with the control group.

The following results were obtained: Table 3: Inhibition of carrageenin edema by 2- (p-toluenesulfonamido) -benzophenone-oxime time (h) inhibition (%) 0.5 40+ 1 56 ++ 2 55 ++ 3 55 ++ 4 45 ++ 5 46 ++ + significant with P <0.05 ++ significant with P <0.01 example 20 Inhibition of the activity of lipoxyenase from rabbit reticulocytes. Lipoxygenase from rabbit reticucocytes was prepared according to the procedure described in the literature obtained in electrophoretically and immunologically pure form .M. Rapoport et al., Eur. J. Biochem. 96: 545 (1979)]. The lipoxygenase activity was determined at 2500 via the amperometric measurement of O2 consumption using a Clark electrode in the following system: 0.1 l potassium phosphate pH 7.4 with 0.2% sodium cholate and 0.53 nftI linonic acid. The enzyme concentration in the measurement mixture was 25 nM. The ones to be examined Substances were dissolved in methyl glycol (freshly distilled in vacuo) and 10 min at the measuring temperature with the enzyme in the absence of sodium cholate and linoleic acid preincubated.

The dilutions of the compounds were chosen so that the final concentrations of methyl glycol in the preincubation mixture did not exceed 2%; under these conditions there were no significant inhibitions in the control batches. The enzyme reaction was started by adding sodium cholate and linoleic acid. By varying the The drug concentration became the titration curve of the inhibition and from this the required one Concentrations determined for 50% inhibition. In contrast to the invention Compounds proved to be the modern anti-asthmatic drugs ketotifen and i) sodium cromoglycate on the iieticulocyte lipoxygenase itself in a final concentration of 1mM than ineffective.

Table 4: Inhibition of lipoxygenase from rabbit reticulocytes Compound Half-inhibition concentration (µM) 2- (p-toluenesulfonamido) -benzophenone-oxime 75 2- (p-toluenesulfonamido) -acetophenone-oxime 200 2- (p-methoxybenzenesulfonamido) -bnzophenonoxime 70 2- (p-toluenesulfonamido) p-Methoxybenzenesulfonamido) acetophenone oxime 160 (%) Activity Fig. 2: Titration curve of the inhibition of the isolated lipoxygenase from rabbit reticulocytes by 2- (toluenesulfonamido) -benzophenone oxime Example 21 Inhibition of the isolated cyclooxygenase from sheep seminal vesicles by 2- (p-toluenesulfonamido) -benzophenone oxime Cystic glands of approximately 9 months old ram isolated according to the method described in the literature [JFG van der Ouderaa and M. Buytenhek, Methods in Enzymology 86, 60 (982)] and used for the tests after storage in liquid nitrogen in a suitable dilution.

The batches contained: 1.9 ml 0.1 µ Tris-HCl, pH 8.0, 100 µl 100 µ m Tryptophan, 100 µl 2.5 mM arachidonic acid, 115 µg (1.66 nmol) cyclooxygenase, and 20 µl of the test substances dissolved in isopropanol. The start of the reaction took place through Addition of 20 μl of 100 μM Htimin. The O2 consumption was measured oxygraphically using a Clark electrode with polypropylene film at 29 ° C. The activity of the control approach with solvent it was 14.1 pl.iol 02 / mg min Inhibitory effect on the control activity. The initial speed was evaluated in each case the reaction.

The suitability of the enzyme preparation and the approach for the measurements was adequately inhibited by various cyclooxygenase inhibitors known from the literature, such as acetylsalicylic acid, indomethacin, phenylbutazone and others

proven. Fig. 2 shows the titration curve for the inhibition of cyclooxygenase by 2- (p-toluenesulfonamido) -benzophenone-oxime. The half-inhibition concentration was 100% µM activity (%) Fig. 3: Titration curve of the inhibition of the isolated cyclooxygenase from sheep semen vesicles by 2- (p-toluenesulfonamido) -benzophenone-oxime Example 22 Inhibition of arachidonic acid- or PAF-induced platelet aggregation The compounds were tested for antithrombotic and thrombolytic activity on the authentic cell system dc iischen in vitro. Platelet-rich plasma from the blood of healthy donors was obtained by centrifugation at 1000 × g. The platelet aggregation was measured by means of an aggregometer on the basis of the diffuse light scattering or the light absorption of the resulting cell aggregates.

The platelet-rich plasma was at 37 ° C for 3 min with the active ingredients preincubated; afterwards platelet aggregation was stopped by adding either 0.8 mM arachidonic acid or 1 µM platelet activating factor (PAF-Acether) triggered. The batches were stirred at a speed of 800 revolutions / min. Depending on the concentration of active ingredient used, there was either a strong delay or a complete inhibition of platelet aggregation.

The aggregation caused by PAF-acetate was investigated Compounds in a concentration of 4.0 µM dissolve the initially formed Cell aggregates.

Identical effects were observed when in washed platelet suspensions aggregation was triggered with 16 µM arachidonic acid. From this behavior goes show that the examined lipoxygenase inhibitors the platelet aggregation in their block irreversible phase and are therefore thrombolytically active.

For example, 2- (p-toluenesulfonamido) -benzophenone-oxime caused a Concentration of 44 µM delay aggregation by cy. 2 min, during 60 µM caused complete inhibition. Similar results have been found with others compounds according to the invention as well as with known lipoxygenase inhibitors, e.g. 4-nitrocatechol.

Example 23 Evaluation of the acute toxicity of 2- (p-toluenesulfonamido) -benzophenone-oxime The acute toxicity of the compound according to the invention was determined after a single oral Administration to 15 female (172 + 13 g) and 15 male (171 t 11 g) rats of the Wistar tribe (VEB Laboratory Animal Production Schönwalde). The bracket the test animals took place under conventional conditions with an artificial light regime (12 h: 12 h) at a room temperature of 22 t 20C in groups of a maximum of 10 animals in plastic bowls (56.5 x 37.5 cm2) with a grid attachment and wood shavings litter. The Animals were fed standard pellets with the formulation R 13 (VEB experimental animal production Schönwalde) and tap water available ad libitum before application of the test substance there was an approx. 16-hour nutritional leave. The test substance was in the form of a 40 C / o suspension in 0.5% aqueous solution of Tylose 4000 P (VEB LAW) once administered orally with a rigid Solilund probe. Before making the suspension was the test substance ground in a porcelain mortar, the average particle size was then 10.2 µM. All test animals received a dose of 6000 mg / kg body mass; they were observed over 14 days. The experimental animals of both sexes showed no noticeable symptoms during the entire observation period. jiortality did not occur. The level of the dose administered suggests that the Close substance after a single application.

Example 24 2- (p-Methoxybenzenesulfomamido) -5-nitro-benzophenone-oxime 8.2 g (0.02 mol) of 2- (p-methoxybenzenesulfonamido) -5-nitrobenzophenone are with 2.8 g (0.04 mole) hydroxyamine hydrochloride and 7.9 g (0.08 mole) anhydrous potassium acetate heated under reflux in 80 ml of ethanol for 3 hours. The ethanol is then used on a rotary evaporator drawn off and the residue stirred with 100 ml of water. The undissolved, crystalline The crude product of the oxime is filtered off with suction and washed with water.

After repeated crystallization from glacial acetic acid or ethanol / water 3.6 g of the oxime (43% of theory) with a melting point of 224-26 ° C. are obtained. The identity was proven by elemental analysis, IR and 1 H-NMR spectra.

Example 25 2- (p-Decyloxybenzenesulfonamido) -benzophenone-oxime 2.4 g (0.005 mol) 2- (p-Decyloxybenzensulfonamido) -benzophenon are dissolved in 50 ml of ethanol with 1.0 g (0.014 mol) of hydroxylamine hydrochloride and 3.0 g (0.03 mol) of anhydrous Potassium acetate refluxed for 3 hours. Then add 100 ml of water and let stand overnight. 1.6 g (60% of theory) of an oxime crude product are obtained with a melting point of 90-95 ° C. This oxime was recrystallized from a mixture of toluene and n-hexane. The melting point of the analytically pure substance is 104 - iOSoCq elemental analysis, IR and H-NMR spectra show the structure indicated.

Claims (13)

Claims: 1. Pharmaceutical composition, characterized by a content of 2-arylsulfonamido-benzo- or -acetophenones and / or their oximes of the general formula (I), in which: R1 is methyl or phenyl or p-substituted phenyl, R1 is C1-18-alkyl, C1-18-alkoxy, amino- or acylamino, hydrogen, R2 is hydrogen, halogen, KO2 or NHR3, where R3 is hydrogen, an acyl or arylsulfonyl radical XO or NOR4, where R4 is hydrogen, C1-12-alkyl, aralkyl, COR5 or CONHR5 and R5 is aliphatic or aromatic, the best active ingredients. 2. 2- (p-Toluenesulfonamido) -benzophenone-oxime 2- (p-Toluenesulfonamido) -acetophenono-oxime 2- (p-Ethylbenzenesulfonamido) -acetophenone 2- (p-Ethylbenzenesulfonamido) -acetophenone oxime 2- (p-Pentoxybenzensulfonamido) -benzophenon 2- (p-Pentoxybenzensulfonatnido) -benzophenone-oxime 2- (p-Do de cyl oxybenzens ulf ona: iiido) -benzophenone 2- (p-dodecyloxybenzensulfonamido) -benzophenone-oxime 2- (p-Methoxybenzenesulfonamido) -acetophenone 2- (p-Methoxybenzenesulfonamido) -acetophenono-oxime 2- (p-Acetaminobenzenesulfonamido) -benzophenone 2- (p-Acetaminobenzenesulfonamido) -benzophenone-oxime 2- (p-Toluenesulfonamido) -5-chlorobenzophenone 2- (p-Toluenesulfonamido) -5-chlorobenzophenone oxime 2- (p-Methoxybenzenesulfonamido) -5-nitro-benzophenone-oxime 2- (p-decyloxybenzenesulfonamido) -benzophenone-oxime 3. Use of pharmaceutical compositions according to claim 1 or compounds according to claim 2 as universal lipoxygenase and cyclooxygenase inhibitors. 4. Means for the treatment of all forms of bronchial asthma, the astmoid Bronchitis and obstructive pulmonary emphysema as well as all other bronchoconstrictor Conditions, characterized by the content of one or more active substances according to claim 1 or 2. 5. Means for the treatment of all allergic diseases, in particular atopic dermatitis, allergic rhinitis, urticaria, angioedema, ontact dermatitis, allergic conjunctivitis and allergic diseases of the gastrointestinal tract, characterized by the cured one or more active ingredients according to claim 1 or 2. 6. Agents for the treatment of inflammatory diseases, in particular those where the conventional anti-inflammatory drugs are not their point of attack the lipoxygenase is to show inadequate therapeutic effects, especially at purulent inflammation as well as rheumatic and arthritic diseases, characterized by the content of one or more active ingredients according to claim 1 or 2. 7. agents for the treatment of all forms of thrombosis, in particular thrombophlebitis, and thrombosis prophylaxis in chronic ischemic heart disease, Follow-up treatment for hyocardial infections, chronic recurrent thrombosis and chronic ones Thrombophlebitis, characterized by the content of one or more active substances according to claim 1 or 2. 8. Agents for use as anti-artherosclerotic, cardiovascular protective, gastroprotective or antimetastatic drugs, characterized by the content one or more active ingredients according to claim 1 or 2. 9. means for the treatment of all forms of arterial hypertension, especially the arterial high pressure in the pulmonary circulation by the salary of a or more active ingredients according to claim 1 or 2. 10. Agents for use as antispasmodics for treating spasticity Conditions of the glutinous muscles of various origins, especially in various ways Sections of the digestive and urogenital tracts as well as the blood vessel muscles, characterized by the content of one or more active ingredients according to claim 1 or 2. 11. Medicaments containing at least one compound of the formula I according to claim 1 in combination with at least one of the traditional antiallergic, antias tfrnatic, aitiphl ogis tables, antihypertensive, antispasmolytic, anti-arteriosclerotic, cardiovascular protective, antimetastatic and antithrombotic Active ingredients. 12. Process for the preparation of compounds of the general formula I according to claim 1, characterized in that a 2-amino-benzophenone is obtained in a simple manner or a 1- (2-aminophenyl) ethanone- (1), a substituted benzenesulfonyl halide and a liquid organic base or the solution of an organic base in one indifferent solvent together and in a sealed flask Room temperature can react with each other to the oulfonamido-ketone and this in known ., otherwise in the presence of a basic substance, vo-Yugs wise potassium acetate or pyridine, with Hydroxylamiiiiiiiydrochlorid in an organic solvent, advantageously in Ethanol or a lower alkyl glycol at temperatures between 50 and 150 ° C for Oxime converts. 13. Process for the production of pharmaceuticals, characterized in that that pharmaceutical compositions according to claim 1 * or compounds according to claim 2, if necessary together with auxiliary and carrier materials in a suitable application form be convicted.