CH670389A5 - - Google Patents

Description

DESCRIPTION

The invention relates to new 2-arylsulfonamido-benzophenones and acetophenones and to the oximes obtainable from them, processes for their preparation and their use in pharmaceutical preparations. The compounds as such and pharmaceutical compositions containing them show valuable pharmacological, in particular antiasthmatic, antiallergic, antiphlogistic, antihypertensive, spasmolytic, antirheumatic and antithrombotic properties and are in human and veterinary medicine for use in the therapy of bronchial asthma and other allergic Diseases, inflammatory and rheumatic diseases of various types as well as thrombosis and cardiovascular diseases.

2-Amino-benzophenones and l- (2-aminophenyl) -ethano-ne- (l) as starting ketones for the compounds according to the invention have long been known and their syntheses have been described (for example HJ Scheifele Jr. and DF De Tar in Org. Syntheses 32, 8 (1952) or Coll. Vol. IV, 34 (1963); J. Mou-zin, H. Cousse, JM Autin, French Pat. Fr 2 476 070 (1980); GT Morgan and JE Moss, J. Soc. Chem. Ind. 42, T 461, (1923); WS Emerson et. Al., J. Am. Chem. Soc. 69,706 (1947)). In recent years, the number of such amino ketones substituted differently in the aromatic ring has increased significantly due to their increasing importance as precursors for pharmaceuticals. The carboxylic acid amide compounds produced on the amino group by acylation with carboxylic acids or carboxylic acid derivatives (eg Beilstein XIV, Syst. No. 1873, Switzerland. Pat. 581 606 (1967) are less varied in terms of their residues. Only recently have been some Sulfonamido-ketones and their oximes are described which are used as selective extractants for the extraction of metals from aqueous solutions (US Pat. No. 4,160,807 (1978). About an application of the ketones and oxime compounds described below as pharmaceuticals in human - and veterinary medicine were found no information.

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670 389

Among the previously known anti-inflammatory drugs with a non-steroidal nature ("non-steroidal anti-inflammatory-stic drugs"), no satisfactory agents are known whose mode of action is based on the simultaneous inhibition of the lipoxygenase and cyclooxygenase pathways of the arachidonic acid cascade. However, such an active principle is of crucial importance for the anti-inflammatory properties of a drug. Corresponding compounds are either not systemically active (e.g. nordihydro-guajaretic acid, 5,8,11,14-icosatetraenoic acid and their analogues) or cannot be used in pharmaceutical preparations due to their high toxicity (e.g. benoxaprofen, BW 7550 and related pyrazoline derivatives). The chemical structure of the oximes described below differs fundamentally from all previously known inhibitors of the arachidonic acid cascade. They do not have the undesirable side effects of the steroids (e.g. prednisolone, dexamethazone) and are extremely well tolerated in toxicological animal experiments. All non-steroidal anti-inflammatory drugs that have been used in therapy so far are exclusively cyclooxygenase inhibitors (indomethacin, sulfindac, acetylsalicylic acid, etc.), which also have some undesirable side effects, e.g. B. show the ulcerogenic (gastric ulcer promoting), whereas for lipoxygenase inhibiting compounds the opposite, i.e. gastroprotective properties are known.

The aim of the invention is to provide pharmaceutical preparations with pharmacologically valuable, in particular antiasthmatic, antiallergic, antiphlogistic, antirheumatic, antihypertensive, spasmolytic, antithrombotic and cardioprotective properties.

The object of the invention is the development of new 2-arylsulfonamido-benzo and acetophenones and their oximes with antiasthmatic and other pharmacologically valuable properties which are based on the simultaneous inhibition of lipoxygenase and cyclooxygenase, and of processes for their preparation.

It was found that 2-arylsulfonamido-benzo- and -acetophenones and their oximes of the general formula I

X

in which mean:

R Me or Ph or p-substituted phenyl; R1 Ci-i8 alkyl, Ci i8 alkoxy; Amino or acylamino; hydrogen

R2 is hydrogen, halogen, NOj or NHR3, where R3 is hydrogen, an acyl or arylsulfonyl radical;

X O or NOR4, where R4 is hydrogen, Ci_i2-alkyl, aralkyl, COR5 or CONHR5 and R5 are aliphatic or aromatic radicals,

possess pharmacologically valuable, in particular anti-asthmatic, anti-allergic, anti-inflammatory and antithrombotic properties and can be used as effective components of pharmaceutical preparations.

It has also been found that a process for the preparation of new sulfonamido-ketone oximes according to claim 11 is characterized in that the substituted methyl or

Reacts phenyl (2-aminophenyl) ketones with suitable sulfonyl halides. According to a preferred very simple procedure, the methyl or phenyl (2-aminophenyl) ketone and a suitable substituted benzenesulfonyl chloride are combined in an organic base or the solution of an organic base in an inert organic solvent in a sealed flask for Allow to stand for 12-24 hours at room temperature. After a few minutes, a mostly weak exothermic reaction begins. In general, cooling is not necessary. The reaction mixture can optionally be additionally heated to 60-80 C for 15-30 minutes. After the specified time, a clear reaction mixture or a reaction mixture containing pyridium salt has formed, which is expediently poured onto ice. The solid sulphonamido-ketone formed can then be collected by suction and purified by recrystallization. The substituted benzenesulfonyl chlorides used as starting material can be prepared in a known manner from the corresponding alkyl or. Alkoxybenzenes are prepared with chlorosulfonic acid. The sulfonamido oximes are obtained by using 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, pipidine, pyridine, morpholine , N-methylpiperazine, diethanolamine and others in an organic solvent, e.g. in lower aliphatic alcohols or glycols, acetonitrile, dioxane, but preferably in ethanol or in their mixtures with water, heated under reflux for 0.5 to 4 hours, working in the temperature range from 50 to 150 ° C. The oxime can be obtained by evaporating the solvent, if appropriate in vacuo and by adding water or by adding water directly to the reaction mixture. The oximes of the sulfone-amido-benzophenones are always obtained as mixtures of the anti and the syn isomers.

Many new ketones and oximes, not previously described in the literature and characterized in terms of elemental analysis, melting point and IR and NMR spectra, of which a selection is listed in Tables la and lb, could be obtained by this process. These connections contained in the tables and examples illustrate the available possibilities.

Surprisingly, it was found that the compounds of general formula I show pronounced antiasthmatic, antiallergic or antianaphylactic, spasmolytic, antihypertensive effects in animal experiments in vitro and in vivo. The testing for the pharmacological properties mentioned was partly carried out. According to measurement methods known in principle from the literature, which were used in modified form, namely on the isolated trachea of guinea pigs, on the isolated lung strip from guinea pigs, including the arachidonic acid-induced and calcium-ionophore-induced contraction of the isolated lung strip (cf. Example 15) and the isolated pulmonary artery (see Example 16), on the specifically allergy-induced bronchoconstriction on ovalbumin-sensitized anesthetized and artificially ventilated guinea pigs ("guinea pig asthma" or "anaphylaxis of the guinea pig") and on the isolated human Bronchus (see Example 17, 18). [M.W. Drazen et al., J. Clin. Invest. 63: 1 (1979); M.W. Schneider and J.M. Drazen, 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.

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

The compounds of the general formula I lead to a complete inhibition of the ovalbumin-induced asthma reaction in ovalbumin-sensitized guinea pigs. This effect in allergic asthma is comparable to ketotifen, a modern anti-asthmatic, the molecular mechanism of which is, however, different from that of the compounds (see below). However, the compounds outperform ketotifen through a much broader range of indications; i.e. effectiveness even in non-allergic forms of bronchial asthma. Furthermore, the inhibition of the arachidonic acid-induced contraction on the isolated artery pulmonalis of rabbits (Example 16) demonstrates the antihypertensive and spasmolytic effect.

The whole animal method is an adequate animal model for forms of bronchial asthma with 20 involvement of IgE and IgG mediated allergic reactions [P. Andersson, Brit. J. Pharmacol. 77: 301 (1982). It could therefore be concluded that the compounds of the general formula I must also have pronounced anti-inflammatory properties. This conclusion 25 could be based on a suitable animal experimental inflammation model in vivo, the carrageenin-induced edema of the rat paw, according to the Winter and Mitarb method. [C.A. Winter, E.A. Risley and G.W. Nut, proc. Soc. Exp. Biol. Med. III, 544 (1962)] (cf. 30 Example 19). In this inflammation model, 2- (p-toluenesulfonamido) -benzophenone-oxime practiced i.p. at a dosage of 50 mg / kg body mass. strong, highly significant inhibitory effects that none of the conventional anti-inflammatory drugs, such as Indomethacin, in parallel-35 batches of the same series of experiments, was surpassed.

The inhibition of both lipoxygenase and cyclooxygenase was identified as the molecular target for the pharmacological effects of the compounds. It is known that the metabolites of arachidonic acid formed by the enzyme Lipoxyge-40 nose are involved in the development of inflammatory and allergic processes [cf. G. A. Higgs, C.M.R. Bac and S. Moncada, Leukotrienes and other Lipoxygenase produets, Raven Press, New York, 1982, p. 331, E. J. Goetzl, Immunology, 45 40, 709 (1980); Ford-Hutchinson et al. J. Pharm. Pharmacol. 32, 517 (1980); B. Samuelsson, Trends in Pharmacol. Sei, May 1980, 227; Borgeat et al., J. Med. Chem. 24, 121 (1981)]. Likewise, the key role of products of the cyclooxygenase reaction, in particular the prostaglandins, in inflammation processes is adequately assured today [p. Moncada and J.R. Vane, Pharmacol. Rev. 30, 293 (1979)]. The inhibition of lipoxygenase was convincingly demonstrated on a suitable animal lipoxygenase, which was carried out by the method of Rapoport and co-workers. [S.M. Rapoport 55 et al., Eur. J. Biochem. 96, 545 (1979)] was isolated from rabbit reticulum locytes. In a final concentration of 1 mM, the compounds predominantly caused inhibitions of 90% or more (cf. Example 20). The strong inhibitions were detectable for some of the compounds even at a final 60 concentration of 0.1 mM. By varying the substance concentration, the inhibition titration curves and the half inhibition concentrations (150 values) could be determined. It was e.g. for 2- (p-toluenesulfonamido) benzophenone oxime 75 | iM. Since these, like many of the other compounds, failed due to their limited water solubility at this concentration in the in vitro test system - visible from a clear turbidity of the measurement approach, it can be assumed that the real ones

Table 1 b: Substituted 2-benzenesulfonamidophenyl ketoxime (formula I, X = NOH)

Name R R1 R2 Fp ° C Yield

% d. Th.

2- (p-T oluenesulfonamido) -aceto-

phenonoxime

Me

Me h

138-42

55

2- (p-ethylbenzenesulfone-

amido) acetophenone oxime

Me

Et h

120-21

58

2- (p-methoxybenzenesulfone-

amido) acetophenone oxime

Me

MeO

H

136-38

90

2- (p-t oluenesulfonamido) benzo

phenonoxime

Ph

Me h

156-80

90

2- (p-pentoxybenzenesulfone-

amido) benzophenone oxime

Ph c5h "o h

95-103

40

2- (p-decyloxybenzenesulfone-

amido) benzophenone oxime

Ph

C10H21O

H

104-05

65

2- (p-dodecyloxybenzenesulfone-

amido) benzopenone oxime

Ph

C12H250

H

85-86

55

2- (p-acetaminobenzenesulfone-

amido) benzophenone oxime

Ph

CH3CONH

H

129-30

55

2- (p-toluenesulfonamido) -5-chloro

benzophenone oxime

Ph

Me

5-C1

170-82

80

2- (p-methoxybenzenesulfonamido) -

5-nitro-benzophenone oxime

Ph

Me

5-NO2

224-26

42

a) anti / syn mixture 82: 18%

b) anti / syn mixture 70: 30% c 'not found

'H NMR data (in CDCb / DMSO, HMDS) R R1 aromatics-SO2NH = NOH

protons

CH3 (CH2) n CH2O or

CH2Ar

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l5o values are much lower. The suitability of lipoxygenase from rabbit reticulocytes as a model for the molecular-pharmacological site of action of the compounds has been proven by the fact that other lipoxygenase inhibitors known from the literature, such as e.g. 3-amino-1- (3-trifluoromethyl-phenyl) -pyrazoline, 5,8,11,14-eikosatetraenoic acid, 5,8,11-egg-kosatrienoic acid, nordihydroguajaretic acid, propyl gallate, 4-nitrocatechol and 3-tert.-butyl -4-hydroxy-anisole is also a highly effective inhibitor of this enzyme. However, the lipoxygenase inhibitors known to date do not achieve the antiasthmatic activity of the compounds. Likewise, the other important enzyme in the arachidonic acid cascade, cyclooxygenase, which was produced from ram's seminal vesicles using the method of F. J.G. van der Ouderaa and M. Buyten-hek, Methods in Enzymology 86, 60 (1982), was inhibited with an iso value of 100 nM. In this regard, the compounds are superior to many previously known anti-inflammatory drugs that only inhibit cyclooxygenase (e.g. acetylsalicylic acid, indomethacin, etc.), resulting in undesirable pharmacological side effects with these known compounds (e.g. ulcerogenic, gastrotoxic and proasthmatic effects of acetylsalicylic acid).

Since the inhibition of lipoxygenase was identified as a molecular target for the new drugs, their influence on platelet aggregation was investigated. This is triggered by the thromboxane A2 formed via the cyclooxygenase pathway of the arachidonic acid cascade [see e.g. J.M. Bailey, Trends Biochem. Be. 4, 68 (1979)].

Undesired platelet aggregation occurs in thrombotic and cardiovascular diseases. It is therefore extremely important to find that the compounds either completely inhibit platelet aggregation or make them reversible, depending on the test conditions (cf. Example 22). In the experiments, platelet aggregation was triggered either by arachidonic acid or by the platelet activation factor (PAF-Acether).

The experiments mentioned demonstrate the antiasthmatic, antiallergic, antihypertensive, spasmolytic, antithrombotic and antiinflammatory effects on suitable biological models.

The exceptionally high biological compatibility in animal experiments is of particular importance for the potential value of the compounds as new drugs. Even at the highest dose used (6 g per kg body mass p.o.), no acute toxicity to 2- (p-toluenesulfonamido) benzophenone oxime could be detected in the rat (see Example 23).

Areas of indication in human and veterinary medicine include:

1. All forms of bronchial asthma including infection-related bronchial asthma (intrinsic asthma), exogenous allergic bronchial asthma (extrinsic asthma) of type I, II and IV according to Coombs and Gell R. R. A. Coombs and P.C.H. Right; 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, of the analgesic-induced bronchial asthma (aspirin-induced asthma), the exercise-induced asthma (exercise-induced asthma), the cold asthma, the irritant-related bronchial asthma and the psycho- gene-induced bronchial asthma.

2. Asthmoid bronchitis and obstructive pulmonary emphysema as well as all bronchoconstrictive conditions that are associated with other diseases or side effects of medical measures, e.g. Anesthesia complications or bronchospastic reactions occur after application of beta-adrenergic blockers.

3. Allergic diseases in a broader sense, in particular:

- Atopic dermatitis

- allergic rhinitis (seasonal rhinitis, perenial rhinitis but also vasomotor rhinitis)

Urticaria

- angioedema

- contact dermatitis (contact eczema)

- allergic diseases of the gastrointestinal tract

Allergic conjunctivitis.

4. All forms of thrombosis, both for the treatment of existing thrombosis (thrombophlebitis) and for thrombosis prophylaxis

- chronic ischemic heart disease

- Follow-up treatment for myocardial infarction

- chronic recurrent thrombosis

- chronic thrombophlebitis.

5. Use as non-steroidal anti-inflammatory drugs, the compounds of the formula I being indicated above all in those inflammatory processes in which the conventional anti-inflammatory drugs (for example acetylsalicylic acid, salicylate, etc.) which have a point of attack outside of lipoxygenase show inadequate therapeutic effects, in particular for purulent inflammation and rheumatic and arthritic diseases.

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

7. Spastic states of the smooth muscles of various origins, in particular in different sections of the digestive and urogenital tract as well as the blood vessels muscles.

On the basis of other pharmacological effects of lipoxygenase inhibitors known from the literature, anti-atherosclerotic, cardiovascular protective, gastroprotective and an-time-static effects can also be derived for the compounds of the formula I.

The compounds of general formula I are suitable as active ingredients for oral, perlingual, rectal, parenteral, intravenous or percutaneous, as well as medicinal products which can be used as aerosols or nebulizing preparations for the treatment of various forms of bronchial asthma and thrombosis, rheumatic, arthritic and other inflammatory diseases.

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

The present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients, contain one or more active ingredients or which consist of one or more active ingredients. Non-toxic, inert pharmaceutically suitable carriers are to be understood as solid, semi-solid or liquid diluents, fillers and formulation auxiliaries of all kinds.

Preferred pharmaceutical preparations are tablets, dragees, capsules, pills, granules, syrups, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders, sprays, aerosols and atomizing preparations for inhalation (topical Use according to the principle of disodium chromoglycate). Tablets, coated tablets, 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 silica, b) binders, e.g. Carboxymethylcellulose, Algina-

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te, gelatin, polyvinylpyrrolidone, c) humectants, e.g. B. glycerin, d) disintegrants, e.g. Agar-agar, calcium carbonate and sodium bicarbonate, e) solution retarders, e.g. Paraffin and f) absorption accelerators, e.g. B. quaternary ammonium compounds, g) wetting agents, e.g. Cetyl alcohol, glycerol monostearate, h) adsorbents, e.g. Kaolin and bento-nit and i) lubricants, e.g. Talc, calcium and magnesium stearate, sodium lauryl sulfate and solid polyethylene glycols or mixtures of the substances listed under a) to i).

The tablets, dragees, capsules, pills and granules can be provided with the customary coatings which optionally contain opalizing agents and can also be composed in such a way that they release the active ingredient (s) only or preferably in a certain part of the intestinal tract, optionally with a delay, Polymer substances and waxes can be used.

The active ingredient (s) can optionally also be in microencapsulated form with one or more of the excipients just specified.

In addition to the active ingredient (s), suppositories can contain the usual water-soluble or water-insoluble excipients, e.g. Polyethylene glycols, fats, e.g. Cocoa fat and higher esters (e.g. Ci4 alcohol with Qö fatty acid / or mixtures of these substances).

In addition to the active ingredient (s), ointments, pastes, creams and gels can contain the usual carriers, e.g. animal and vegetable fats, waxes, paraffins (e.g. petroleum fractions), starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, talc, silica and zinc oxide or mixtures of these substances.

Sprays, powders and atomizing preparations can contain the usual excipients in addition to the active ingredient or ingredients, e.g. Milk sugar, talc, silica, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances. Sprays can also contain the usual propellants, e.g. Chlorofluorocarbons.

In addition to the active ingredient (s), solutions and emulsions can contain the usual carriers such as non-toxic organic solvents, solubilizers and emulators, e.g. .B. 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, ri-oil and sesame oil, glycerin, glycerin formal, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances.

For parenteral administration, the solutions and emulsions can also be 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 isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar or tragacanth or mixtures of these substances.

Dispersants (e.g. lignin, sulfite liquor, methyl cellulose, starch and polyvinyl pyrrolides) can also be used for the formulation.

The formulation forms mentioned can also contain colorants, preservatives and additives which improve the smell and taste, e.g. Peppermint oil and eucalyptus oil and sweeteners, e.g. Saccharin.

The therapeutically active compounds in the pharmaceutical preparations listed above should preferably be present in a concentration of about 0.1 to 99.5, preferably about 0.5 to 90% by mass of the total Mi670 389

existing, i.e. in amounts sufficient to achieve the dosage range indicated.

In addition to the active ingredients, the pharmaceutical preparations listed above may also contain other pharmaceutical active ingredients, e.g. Antihistamines and mast cell degranulation inhibitors.

The pharmaceutical preparations listed above are prepared in a conventional manner by known methods, e.g. by mixing the active ingredients with the carriers.

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

In general, it has proven to be advantageous to administer the active ingredient (s) in a total amount of about 0.05 to about 100, preferably 0.1 to 50 mg / kg body mass per 24 hours, optionally in the form of several individual doses, in order to achieve the desired results .

However, it may be necessary to deviate from the doses mentioned, depending on the type and body weight of the object to be treated, the type and severity of the disease, the type of preparation and administration of the drug, and the period or interval within which the administration takes place. In some cases it may be sufficient to make do with less than the above-mentioned amount of active ingredient, while in other cases the above-mentioned amount of active ingredient has to be exceeded.

The following examples explain the invention in more detail.

Embodiments

example 1

2- (p-toluenesulfonamido) benzophenone oxime 14 g (0.04 mol) 2- (p-toluenesulfonamido) benzophenone are mixed with 6 g (~ 0.08 mol) hydroxylamine hydrochloride and 16 g potassium acetate (anhydrous) in 100 ml Ethanol refluxed for 3 hours. The colorless oxime is then precipitated from the filtered solution with water. After recrystallization from ethanol / water, mp 158-180 ° (syn / anti mixture).

Example 2

2- (p-toluenesulfonamido) acetophenone oxime 29 g (0.1 mol) 2- (toluenesulfonamido) acetophenone are mixed with 17.5 g (0.25 mol) hydroxylamine hydrochloride and 50 g potassium acetate (anhydrous) in 300 ml ethanol Heated under reflux for 3 hours. The filtered solution is then mixed with water and the precipitated oxime recrystallized from water / ethanol, mp. 138-142 °.

Example 3

2- (p-ethylbenzenesulfonamido) acetophenone 6.75 g (0.05 mol) of 2-amino-acetophenone in 50 ml of dried pyridine are shaken at room temperature with 12.2 g (0.06 mol) of p-ethylbenzenesulfonylchloride transferred. Warming occurs after 5-20 minutes and after some time pyridinium salt precipitates. The mixture is left in a closed flask for 24 hours and then poured onto ice. The separated ketone is suctioned off and recrystallized from an ethanol-water mixture, mp. 125-128 °.

Example 4

2- (p-ethylbenzenesulfonamido) acetophenone oxime 6.1 g (0.02 mol) 2- (p-ethylbenzenesulfonamido acetophe-

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670 389

are heated in 100 ml of ethanol with 10 ml of dried pyridine and 3.1 g (0.044 mol) of hydroxylamine hydrochloride under reflux for 3 hours. The solvent is then evaporated off in vacuo and water is added to the residue. An oil separates, which crystallizes after a short time. Recrystallized from an ethanol-water mixture, the mp was 120-121 °.

Example 5

2- (p-pentoxybenzenesulfonamido) -benzophenone 5 g (0.025 mol) of 2-aminobenzophenone are left in a sealed flask for approx. 24 hours with 7.8 g (0.03 mol) of p-pentoxybenzenesulfonyl chloride in 25 ml of dried pyridine at room temperature . Then it is poured onto ice and a greasy substance often separates out first, which solidifies after standing and can be suctioned off. Recrystallized from ethanol or n-heptane, the ketone has an mp of 94-95 ° C. It was characterized by elemental analysis, IR and NMR spectra.

Example 6

2- (p-pentoxybenzenesulfonamido) benzophenone oxime 4.2 g (0.01 mol) 2- (pentoxybenzenesulfonamido) benzophenone are dissolved in 60 ml ethanol with 1.5 g (0.022 mol) hydroxylamine hydrochloride and 3 g potassium acetate 3 Cooked under reflux for hours, then filtered hot and washed with hot ethanol. After concentrating the filtrate, the residue crystallizes. By recrystallization from a toluene-n-heptene mixture, the oxime melts at 95-103 ° C. It was characterized by elemental analysis, IR and NMR spectra.

Example 7

2- (p-dodecyloxybenzenesulfonamido) benzophenone 5 g (0.025 mol) of 2-aminobenzophenone are left in a sealed flask with 10.8 g (0.03 mol) of dodecyloxybenzenesulfonyl chloride in 30 ml of dried pyridine at room temperature. After 24 hours the reaction mixture is poured onto ice. The initially greasy substance crystallizes after repeated renewal of the aqueous phase and is then recrystallized first from n-heptane, then from an ethanol-water mixture, mp. 64-65 ° C.

Example 8

2- (p-Dodecyloxybenzenesulfonamido) -benzophenone-oxime 2.6 g (0.005 mol) of 2- (p-dodecyloxybenzenesulfonamido) -benzophenone are boiled under reflux for 3 hours in 30 ml of ethanol lg (0.014 mol) of hydroxylamine hydrochloride and 1.5 g of potassium acetate , filtered hot and the solvent evaporated in vacuo. The residue is recrystallized from n-heptane, mp. 85-86 ° C.

Example 9

2- (p-methoxybenzenesulfonamido) acetophenone 6.75 g (0.05 mol) of 2-aminoacetophenone are added to 50.2 ml of dried pyridine at room temperature with 12.2 g (0.06 mol) of p-methoxybenzenesulfonyl chloride, after a few minutes the reaction mixture heats up slightly and the pyridinium salt separates out after some time. After standing in a sealed flask for 24 hours, the mixture is poured onto ice and the separated ketone is recrystallized from an ethanol-water mixture, mp 135 C.

Example 10

2- (p-methoxybenzenesulfonamido) acetophenone oxime

6.1 g (0.02 mol) of 2- (p-methoxybenzenesulfonamido) acetophenone are heated under reflux for 3 hours in 100 ml of ethanol with 3.1 g (0.044 mol) of hydroxylamine hydrochloride and 10 ml of dried pyridine. The solvents are then evaporated in vacuo and water is added to the residue. The separated oxime is first obtained as an oil, which solidifies after a short time and can be suctioned off. Recrystallized from an ethanol-water mixture, it melts at 136 - 138 ° C.

Example 11

2- (p-acetaminobenzenesulfonamido) benzophenone

2 g (0.01 mol) of 2-aminobenzophenone, 2.5 g (0.011 mol) of p-acetaminobenzenesulfonyl chloride and 10 ml of dried pyridine are left in a sealed flask at room temperature for 24 hours. It is then poured onto ice, a greasy substance separating out, which soon becomes solid by renewing the aqueous phase several times. Recrystallized from ethanol, mp 173-175 ° C.

Example 12

l- (p-Acetaminobenzenesulfonamido) benzophenone oxime

1.2 g (0.003 mol) of 2- (p-acetaminobenzenesulfonamido) benzophenone are refluxed in 20 ml of ethanol with 0.45 g (0.0065 mol) of hydroxylamine hydrochloride and 0.7 g of potassium acetate for 3 hours, then evaporated to dryness in vacuo , mixed with warm water and suctioned off the remaining oxime. An mp of. Is recrystallized from an ethanol-water mixture

129-130 5C obtained.

Example 13

2- (p-toluenesulfonamido) -5-chloro-benzophenone

6.1 g (0.025 mol) of 2-amino-5-chloro-benzophenone are left in a sealed flask with 4.8 g (0.025 mol) of p-toluenesulfonyl chloride in 30 ml of dried pyridine at room temperature for 20 hours. The reaction mixture is then poured onto ice and the separated ketone is recrystallized from ethanol.

Mp 120-122 ° C.

Example 14

2- (p-toluenesulfonamido) -5-chloro-benzophenone oxime

3.85 g (0.01 mol) of 2- (p-toluenesulfonamido) -5-chloro-benzophenone are refluxed 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. The solvent is then largely evaporated in vacuo and warm water is added to the residue. The remaining oxime is recrystallized from ethanol,

Mp 170-182 cc (sy n / anti mixture).

Example 15

Effect of 2- (p-toluenesulfonamido) acetophenone oxime, 2- (p-methoxybenzenesulfonamido) acetophenone oxime, 2- (p-methoxybenzenesulfonamido) benzophenone oxime and 2- (p-toluenesulfonamido) benzophenone oxime the contraction of the isolated guinea pig lung strip triggered by exogenous arachidonic acid

The compound was tested for antiasthmatic activity on the isolated lung strips of guinea pigs using modified measurement methods known from the literature (M.H. Saad and J.F. Bur-ka, Europ. J. Pharmacol. 100, 13 (1984)). The measurements were carried out isotonic in the thermostated organ bath using a contraction measuring device with a lever transducer,

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Measuring coil, measuring amplifier (inductive measurement using a high-frequency resonant circuit). Fumigation took place with air. The suspension solution had the following composition: 39.46 g NaCl, 2.2 g KCl, 6.07 g Tris, 1.0 g CaCk, 9.9 g glucose, 1.0 ml saturated MgCl2 solution, 43 ml 1N HCl per 51, pH 7.4.

The contraction was triggered by increasing concentrations of arachidonic acids (concentrated solution in ethanol, stored in a ^ atmosphere) and measured cumulatively.

50 | iM the above Compounds led to a strong reduction and partial abolition of the contraction response to arachidonic acid in the range of 0.1-100 nM (“metactoid inhibition” according to “General Theory of Drug Receptor Interactions” by FG van den Brink in Kinetics of Drug Action ed. by JM van Rossum, Springer Berlin, Heidelberg, New York, 1977, chap. 4, pp. 168-254). The results are shown in fig. A comparison of the effects of the compounds with known active substances (Tab. 2) shows that they themselves are modern developments such as significantly outperform the lipoxygenase-inhibiting anti-rheumatic benoxaprofen.

Fig la:

Inhibition of the 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 standardized contraction responses on paired organs in a parallel experiment after incubation with 5 x 10 "5 M (solid) and without (dashed) test substance.

At the same time, incubation was carried out with indometazine 5 x 10 ~ 6 M and prothazine 5 x ~ 6 M. Standardization of the individual values: contraction in mm, expressed as a percentage of the maximum contraction response of the preparation to the standard ardagonist (acetylcholine). (% max. standard). Abscissa:

10 g M bath concentration for arachidonic acid (Log. Konz. AS [M]). The standardized measurement data were adapted to the model function specified in the text using a computer program. Computer-adjusted model parameters and quality

5 of adjustment: (): S.A.Q. = 0.11 ED50 =

3.6 x 10 ~ 4 M, nH = 0.666 (): S.A.Q. = 2.7 ED50 =

9.2 x 10-4 M, nH = 0.383. Isotonic contraction, modified Krebs-Hanseleit solution, 37 ° C, nH 7.4, 20 ml organ bath, model «Hoechst», cumulative dose addition of the variable agonist in a liquid ratio of 1: 100 g

Fig. Lb:

Inhibition of the arachidonic acid-induced contraction by 2- (p-toluenesulfonamido) acetophenone oxime on the i5 isolated lung strip preparation of the guinea pig. Identical conditions as in Fig. La. Computer-adapted model parameters and quality of adaptation:

(): S.A.Q. = 1.0 ED50 = 4.5 x 10 ~ 5 M, nH = 1.724

(): S.A.Q. = 6.0 ED50 = 3.1 x 10 -5 M, nH = 3.896.

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Inhibition of the arachidonic acid-induced contraction by 2- (p-methoxybenzenesulfonamido) benzophenone oxime on the isolated lung strip preparation of the sea-25 pig. Identical conditions as in Fig. La. Computer-adapted model parameters and quality of adaptation:

(): 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.

30 Fig. Ld:

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. La. Com-35 computer-adjusted model parameters and quality of adaptation:

(): 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 strip in comparison with known ones

Active ingredients

Test substance bath concentration (| iM) inhibition (%) of

control

Disodium cromoglycate (DSCG; Intal, known)

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2- (p-methoxybenzenesulfonamido) acetophenone oxime

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2- (p-toluenesulfonamido) acetophenone oxime

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Nordihydroguajaretic acid (NDGA, known)

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2- (p-toluenesulfonamido) benzophenone oxime

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2- (p-methoxybenzenesulfonamido) benzophenone oxime

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1 all experiments in the presence of 5-10 6 M 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 on the contraction of the isolated pulmonary artery from rabbit triggered by exogenous arachidonic acid

The experimental arrangement of this test system corresponds to Example 15.

Isolated strips of the rabbit pulmonary artery were used as the test object.

65 The contraction was triggered in the presence of 10 nM indometazine (blocking the cyclooxygenase pathway of arachidonic acid utilization) by increasing concentrations of arachidonic acid and measured cumulatively.

670 389

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50 (xM each of the test substances led to a reduction in the contraction response to arachidonic acid in the range from 0.1-100 nM by 80 to 85% (“metactoid inhibition” according to “General Theory of Drug Receptor Interactions” by FG van den Brink in Kinetics of Drug Action ed. By IM van Rossum, Springer Berlin, Heidelberg, New York, 1977, Chap. 4, pp. 169-254).

Example 17

Effect of 2- (p-toluenesulfonamido) benzophenone oxime on allergen-induced bronchoconstriction on sensitized guinea pigs in vivo ("allergic guinea pig asthma")

The examination was carried out on the male guinea pig, 21-28 days after sensitization with 100 mg Al (OH) a and 100 (ig ovalbumin in 0.5 ml isotonic saline solution ip per kg body mass. [Method modified according to P. An-dersson, Brit J. Pharmacol. 77: 301 (1982)].

The investigations were carried out in several series, each with different application forms or doses of the substance to be examined, on sensitized male guinea pigs with a weight between 350-360 g, which came from different breeds.

The animals were anesthetized by intraperitoneal (i.p.) injection with 20% urethane solution (1.3 g / kg KM). A flexible venous catheter (vena jugularis dextra) and a tracheal cannula (0 2.8 mm) were then placed on the animals. The animals prepared in this way were fixed in a supine position in a tank respirator. After relaxation with PavulonR (2 mg / kg KM) i.v. the artificial respiration in the tank respirator was carried out with a rhythmic negative pressure (f = 16 min-1.1: E = 1: 1, p = 2 kPa). A Fleisch's nozzle was attached to the tracheostomy tube (0 = 2.8 mm, 0 = 40 mm), via which the respiratory parameters were measured with a pneumotachograph (Hertel, Lengenfeld) (flow velocity V and tidal volume VT) .

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

The evaluation could be reduced to the volume signal, since the tidal volume with our standardized ventilation technique represents a representative quantity for the characterization of changes in the respiratory mechanics. The mean tidal volume after 3 minutes of ventilation was taken as the baseline (Vta). To check the vitality of the animals, a non-standard ECG lead was created, followed on a monitor and recorded together with the breathing parameters.

The bronchoconstrictions were consistently triggered by IV injection with egg white (0.4 mg / kg KM) or lyophilized ovalbumin (4 mg / kg KM). Before the first bronchospasm was triggered, the animals received (after random selection) the pretreatment with 2- (p-toluenesulfonamido) benzophenone oxime. The animals were pretreated with 2 injections i.p. of finely ground test substance slurried in agar agar, in doses of 20 mg / kg body mass 90 and 60 minutes before the start of the test.

The substance completely inhibited ovalbumin-induced asthma in 90% of the animals examined. In contrast, all control animals died after a single application of 4 mg ovalbumin i, v. after the most severe asthmoid reaction during respiratory arrest due to complete bronchial obstruction.

Comparable antiasthmatic, antiallergic or antianaphylactic effects on the whole animal model are also not known from modern antiasthmatics such as ketotifen and disodium umcromoglycate [C. Armor u. DM. Temple, Agents Actions 12: 285 (1982)].

Example 18

Effect of 2- (p-toluenesulfonamido) acetophenone oxime,

2- (p-methoxybenzenesulfonamido) acetophenone oxime, 2- (p-methoxybenzenesulfonamido) 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 15.

Isolated human bronchial rings served as the test object. When the test substances were added cumulatively, there were measurable dictatorial effects to a degree of 10 - 30% of the maximum isoprenaline effect at bath concentrations of 1 - 10 nM.

Example 19

Inhibition of carrageenin edema of the rat paw Carrageenin edema is used in the international literature as a model system for inflammatory (pro-phlogistic) processes and offers the possibility of in vivo testing of substances for anti-inflammatory (anti-inflammatory) activity. The testing was carried out according to the internationally customary methodology [C. A. Winter, E.A. Risley and G.W. Nuss, Proc-Soc. Exp. Biol. Med. 111, 544 (1962)]. 2- (p-toluenesulfonamido) benzophenone oxime was i.p. 10 rats. administered in a dose of 50 mg / kg body mass with simultaneous administration of 0.1 ml 0.1% carrageenin solution per animal. The extent of the paw edema was measured every hour after application and compared with the control group. The results were as follows:

Table 3:

Inhibition of carrageenin edema by 2- (p-toluenesulfone-amido) -benzophenone-oxime

Time (h) inhibition (%)

0.5 40+

1 56 ++

2 55+ +

3 55+ +

4 45+ +

5 46 ++

+ significant with P <0.0 5 + + significant with P <0.01

Example 20

Inhibition of the Activity of Lypoxygenase from Rabbit Reticulocytes The lipoxygenase from rabbit reticulocytes was obtained in an electrophoretically and immunologically pure form according to the method described in the literature [S.M. Rapoport et al., Eur. J. Biochem. 96, 545 (1979)]. The lipoxygenase activity was determined at 25 ° C. by means of the amperometric measurement of the 02 consumption using a Clark electrode in the following system: 0.1 M potassium phosphate pH 7.4 with 0.2% sodium cholate and 0.53 mM linoleic acid. The enzyme concentration in the measurement mixture was 25 nM. The substances to be tested were dissolved in methylglycol (freshly distilled in vacuo) and preincubated for 10 min at the measuring temperature with the enzyme in the absence of sodium cholate and linoleic acid. The dilutions

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of the compounds were chosen so that the final concentrations of methyl glycol in the pre-incubation batch 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. The titration curve of the inhibition and the concentrations required for 50% inhibition were determined by varying the active substance concentration. In contrast to the compounds, the modern antiasthmatics ketotifen and disodium cromoglycate proved ineffective on reticulocyte lipoxygenase even in a final concentration of 1 mM.

Table 4:

Inhibition of rabbit reticulocyte lipoxygenase

Connection semi-locking

concentration (| iM)

2- (p-toluenesulfonamido) benzophenone oxime 75

2- (p-toluenesulfonamido) acetophenone oxime 200

2- (p-methoxybenzenesulfonamido) benzophenone oxime 70

2- (p-methoxybenzenesulfonamido) acetophenone oxime 160

Fig. 2:

Titration curve of the inhibition of the isolated lipoxygenase from rabbit reticulocytes by 2- (toluenesulfona-mido) -benzophenone-oxime

Example 21 Inhibition of the isolated cyclooxygenase from sheep's seminal vesicles by 2- (p-toluenesulfonamido) benzophenone oxime

The cyclooxygenase was isolated from vesicles of approximately 9 months old goats by the method described in the literature [J.F.G. van der Ouderea and M. Buytenhek, Methods in Enzymology 86, 60 (1982)] and after storage in liquid nitrogen in a suitable dilution for the tests.

The measurement batches contained: 1.9 ml 0.1 M Tris-HCl, pH 8.0, 100 μl 100 mM tryptophan, 100 μl 1 2.5 mM arachidonic acid, 115 μg (1.66 nmol) cyclooxygenase, and 20 jal of the test substances dissolved in isopropanol. The reaction started by adding 20 jxl 100 | xM hemin. The on-consumption was measured oxygraphically using a Clark electrode with polypropylene film at 29 ° C. The activity of the control mixture with solvent was 14.1 (iMol O2 / mg min. The solvent itself had no inhibitory effect on the control activity. The initial rate of the reaction was evaluated in each case.

The suitability of the enzyme preparation and the measurement approach for the tests was determined by adequate inhibitions by various cyclooxygenase inhibitors known from the literature, such as e.g. Acetylsalicylic acid, indomethacin, phenylbutazone and the like. a. proven. Fig. 2 shows the titration curve for the inhibition of cyclooxygenase by 2- (p-toluenesulfonamido) benzophenone oxime. The half inhibition concentration was 100 (iM.

Fig. 3:

Titration curve of the inhibition of the isolated cyclooxygenase from sheep seminal 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 human cell system in vitro. Platelet-rich plasma from the blood of healthy donors was obtained by centrifugation at 1000 x g. The platelet aggregation was measured using an aggregometer based on the diffuse light scattering or the light absorption of the resulting cell aggregates. The platelet-rich plasma was preincubated with the active ingredients at 37 ° C. for 3 min; the platelet aggregation was then triggered by adding either 0.8 mM arachidonic acid or 1 (iM platelet activation factor (PAF-Acether). The approaches were carried out at a rate of 88 revolutions / min, depending on the active substance concentration used either a strong delay or a complete inhibition of platelet aggregation occurred.

In the aggregation triggered by PAF-Acether, all investigated compounds in a concentration of 40 (iM caused a dissolution of the cell aggregates initially formed. Identical effects were observed when the aggregation with 16 | iM arachidonic acid was triggered in washed platelet suspensions. This behavior shows that the investigated lipoxygenase inhibitors block platelet aggregation in its irreversible phase and are therefore thrombolytically active.

For example, 2- (p-toluenesulfonamido) -benzophe-non-oxime at a concentration of 44 | iM delayed the aggregation by about 2 min, while 60 | iM caused complete inhibition. Similar results were also obtained with other compounds as well as with known lipoxygenase inhibitors, e.g. 4-nitrocatechol.

Example 23 Determination of the acute toxicity of 2- (p-toluenesulfonamido) benzophenone oxime

The acute toxicity of the compound was carried out after a single oral administration to 15 female (172 ± 13 g) and 15 male (171 ± 11 g) rats of the Wistar strain (VEB test animal production Schönwalde). The animals were kept under conventional conditions with an artificial light regime (12 h: 12 h) at a room temperature of 22 + 2 "C in groups of up to 10 animals in plastic trays (56.5 x 37.5 cm2) with a lattice attachment and shavings. Standard pellets of the recipe R 13 (VEB test animal production Schönwalde) and tap water ad libitum were available to the animals as feed. Before application of the test substance, there was an approximately 16-hour nutritional grace period. The test substance was in the form of a 40% suspension in 0.5% aqueous solution of Tylose 4000 P (VEB LAW) once orally with a rigid pharyngeal tube Before the preparation of the suspension, the test substance was ground in a porcelain mortar, the average particle size was then 10.2 μm, and all test animals received a dose of 6000 mg / kg Body mass, observed over a period of 14 days, the test animals of both sexes showed no abnormalities during the entire observation period symptoms. Mortality did not occur. The amount of the dose administered indicates that the substance is well tolerated after a single application.

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Example 24

2- (p-methoxybenzenesulfonamido) -5-nitro-benzophenone-oxime 8.2 g (0.02 mol) of 2- (p-methoxybenzenesulfonamido) -5-nitro-benzophenone are mixed with 2.8 g (0.04 mol) Hydroxylamine hydrochloride and 7.9 g (0.08 mol) of anhydrous potassium acetate in 80 ml of ethanol were heated under reflux for 3 hours. The ethanol is then removed on a rotary evaporator and the residue is stirred with 100 ml of water. The undissolved, crystalline crude product of the oxime is filtered off and washed with water. After multiple 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 determined by elemental analysis, IR and 'H NMR spectra proven.

Example 25

2- (p-decyloxybenzenesulfonamido) benzophenone oxime

2.4 g (0.005 mol) of 2- (p-decyloxybenzenesulfonamido) benzophenone are refluxed 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 for 3 hours . 100 ml of water are then added and the mixture is left to stand overnight. 1.6 g (60% of theory) of a crude oxime product of mp 90 ° -95 ° C. are suctioned off. This oxime was recrystallized from a mixture of toluene / n-hexane. The melting point of the pure analytical substance is 104-105: C.

Elemental analysis, IR and H NMR spectra confirm the given structure.

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2 sheets of drawings

Claims (2)

670 389 PATENT CLAIMS 1. Pharmaceutical composition, characterized by a content of 2-arylsulfonamido-benzo- or ace-to-phenones and / or their oximes of the general formulas SH X - in which mean: R is methyl or phenyl or p-substituted phenyl R1 Ci_is alkyl, Çi ig alkoxy, amido or acylamino, hydrogen R2 is hydrogen, halogen, N02 or NHR3, where R3 is hydrogen, an acyl or arylsulfonyl radical, X O or NOR4, where R4 is hydrogen, Ci_i2-alkyl, aralkyl, COR5 or CONHR5 and R5 are aliphatic or aromatic radicals as the active ingredient. 2. Composition according to claim 1 for the treatment of all forms of bronchial asthma, asthmoid bronchitis and obstructive pulmonary emphysema and all other bron-cho-constrictive conditions. 3. Means according to claim 1 for the treatment of all allergic diseases, in particular atopic dermatitis, allergic rhinitis, urticaria, angioedema, contact dermatitis, allergic conjunctivitis and allergic diseases of the gastrointestinal tract. 4. Means according to claim 1 for the treatment of inflammatory diseases, in particular those in which the anti-inflammatory drugs, the point of attack of which is not lipoxygenase, show insufficient therapeutic effects, in particular in the case of purulent inflammations and in rheumatic and arthritic diseases. 5. Means according to claim 1 for the treatment of all forms of thrombosis, in particular thrombophlebitis, and for thromboprophylaxis in chronic ischemic heart disease, aftertreatment for myocardial infarction, chronic recurrent thrombosis and chronic thrombophlebitis. 6. Composition according to claim 1 in the form of an antiatheroskle-rotic, cardiovascular protective, gastroprotective or antimetastatic medicament. 7. Means according to claim 1 for the treatment of all forms of arterial high pressure, in particular also the arterial high pressure in the pulmonary circuit. 8. Composition according to claim 1 as spasmolytics for the treatment of spastic conditions of the smooth muscles of various origins, in particular in different sections of the digestive and urogenital tract and the blood vessel muscles. 9. Medicament according to claim 1, comprising at least one compound of the formula I in combination with at least one additional antiallergic, antiasthmatic, antiphlogistic, antihypertensive, spasmolytic, antiarteriosclerotic, cardiovascular protective, antimetastatic and antithrombotic active substance. 10. A process for the preparation of medicaments according to claim 1, characterized in that compounds of the formula I according to claim 1 are converted into a suitable administration form. 11.2- (p-toluenesulfonamido) benzophenone oxime 2- (p-toluenesulfonamido) acetophenone oxime 2- (p-ethylbenzenesulfonamido) acetophenone 2- (p-ethylbenzenesulfonamido) -acetophenone-oxime 2- (p-pentoxybenzenesulfonamido) -benzophenone 2- (p-pentoxybenzenesulfonamido) -benzophenone-oxime 2- (p-dodecyloxybenzenesulfonamido) -benzophenon 2- (p-dodbenzophenone) oxime 2- (p-methoxybenzenesulfonamido) -acetophenone 2- (p-methoxybenzenesulfonamido) -acetophenone-oxime 2- (p-acetaminobenzenesulfonamido) -benzophenone 2- (p-acetaminobenzenesulfonamido) -benzophenone-oxime 2- (p-toluenesulfonam) chloro-benzophenone 2- (p-toluenesulfonamido) -5-chloro-benzophenone oxime 2- (p-methoxybenzenesulfonamido) -5-nitro-benzophenone oxime 2- (p-decyloxybenzenesulfonamido) benzophenone oxime. 12. A process for the preparation of the compounds of the formula I according to claim 11, wherein X is the NOH group, characterized in that a 2-amino-benzophenone or a 1- (2-aminophenyl) -ethanone (1) Substituted benzenesulfonyl halide and a liquid organic base or the solution of an organic base in an inert solvent together and in a sealed flask at room temperature to react with each other to form sulfonamido-ketone and this in the presence of a basic substance with hydroxylamine hydrochloride in an organic solvent at temperatures converted between 50 and 150 ° C to the oxime.