WO1992019572A2 - I-aza-2-phenylhydrorazino-heterocycles, process for producing them and pharmaceuticals containing them - Google Patents

Abstract

The invention relates to partly novel I-aza-2-phenylhydrazino-heterocycles of formula I, a process for producing them and their use in pharmaceutical preparations. They are produced by the reaction of activated lactam and cycloimide derivatives with aryl hydrazines or aryl hydrazine hydrochlorides. The compounds of the invention are highly effective lipoxygenase inhibitors and may be used in medicaments to treat all kinds of inflammations, allergic conditions, asthma, bronchitis and psoriasis.

Description

 3, 4-Cycloamidrazone, process for their preparation and pharmaceutical compositions containing them

The invention relates in part to new 3, 4-cycloamidrazone, processes for their preparation and their use in pharmaceutical preparations.

The object of the invention is the development of 3,4-cycloamidra zones with valuable pharmacological properties. For the compounds of general structure I according to the invention,

in which R is hydrogen or a preferably low molecular weight alkyl radical, Ar is a phenyl radical or a phenyl radical which is monosubstituted or polysubstituted by the same or different means, substituted by alkyl groups, alkoxy groups, halogen atoms, trifluoromethyl groups, nitro groups or carbalkoxy groups, A is a tetragonal or trigonal carbon atom , e.g. B. represents the carbon atom of a carbonyl group, or a S02 group and the underlying cycle is a heteromono or bicyclic and, where appropriate, their physiologically compatible acid addition salts, a very strong inhibition of the lipoxygenase and starting from there was found new application as anti-inflammatory, anti-rheumatic, anti-anaphylactic drugs. Arachidonic acid and other polyunsaturated fatty acids (PUFA) are primarily peroxygenated in the metabolism by the enzymes cyclooxygenase (COX) and lipoxygenase (LOX) and then further broken down into numerous, biologically active metabolites; the metabolic pattern in the case of the LOX-mediated metabolism is particularly varied because these enzymes have a different substrate specificity depending on the origin (attack in the 5-, 12- or 15-position = 5-LOX, 12-LOX , 15-LOX). The LOX-dependent PUFA metabolites (leukotrienes) are mediators of anaphylactic and allergic processes and have a pro-inflammatory effect. The biosynthesis and consequently the effects of the mediators should be suppressed by substances which inhibit the activity of the LOX. Enzyme inhibitors of this type are known. 5-LOX inhibitors are e.g. B. 3-amino-1- (3-trifluoromethylphenyl) -2-pyrazole in (BW 755 C) (e.g. Prosagl., Leukotr. Med. 10/1983/187), nordihydroguajaretic acid (e.g. J. Immun . 125/1980/163), 5.8.11.14-eicosatetraenoic acid (e.g. prostagl. 16/1978/529), 5,6-dihydroarachidonic acid (J. Amer. Chem. Soc. 104/1982/1752), trans-5,6 -Methano- (E, E, Z, Z) -7,9,11, 14-eicosatetraenoic acid (J. Med. Chem. 26/1983/72), various thioarachidonic acids (J. Amer. Chem. Soc. 107 / 1985/173, Tetrahedron Lett. 26/1985/3919) and many other compounds, e.g. T. also 12- and 15-LOX inhibitors (e.g. Bioche. Pharmacol. 28/1979/1959, FEBS Letters 110/1980/213, Biochi. Biophys. Acta 487/1977, 517, Prostagland. 14 / 1977/261) and even COX inhibitors. Selective 12- and / or 15-LOX inhibitors include acetone phenyl hydrazone (e.g. Adv. Prost. Tromb. Res. 6/1980/111, Agents Actions 12/1982/360), Baicalein (Biochem. Biophys. Res 105/1982/1090), luteolin (Prostagl. 20/1980/627) and 1,5-dihydroxynaphthalene in (Biochem. Pharmacol. 30/1981/1677). It is also known that acylic amidrazoπe such as N (1) -phenyl-benzamidrazone (CBS-1114) are LOX inhibitors (Drugs Fut. 9/1984/102).

The vast majority of known LOX inhibitors are associated with their complex accessibility (e.g. polyacetylenic acids), their inadequate effectiveness (e.g. flavones, flavonols) and / or their great toxicity (e.g. acetonephenylhydrazone) as an application-limiting or even - preventing defect.

It is the object of the invention to develop LOX inhibitors by modifying the amidrazone structure, which can be used in suitable pharmaceutical preparations for the therapy of diseases, the cause of which is increased leukotriene biosynthesis. Surprisingly, it was found that the incorporation of the 3 and 4 numbered atoms of acyclic amidrazones II into ring systems leads to compounds I which have a very high activity.

II

Compounds of this type, which are generally lactam or cycloimidaryl hydrazones, are referred to collectively as 3,4-cycloamidrazones in this invention.

Specific examples of the 3,4-cycloamide zone according to the invention are

the tetrahydropyrrol-2-one-2-arylhydrazones III, the hexahydro-pyridin-2-one-2-arylhydrazones IV, the hexahydro-1H-azepin-2-one-2-arylhydrazones V, the perhydro-azocin-2-one -2-arylhydrazone VI, the 2,3,4,5-tetrahydro-1H-1-benzazepin-2-one-2-arylhydrazone VII, the 2,3,4,5-tetrahydro-1H-2-benzazepine -1-one-1-arylhydrazone VIII, the 5, 6,7,8-tetrahydro-4H-thieno / 3, 2-c / azepin-4-one-arylhydrazone IX, the perhydro-1-benzazepine -2-one-2-arylhydrazone X, the pyrrole idin-2,5-dione-2-arylhydrazone XI, the isoindole in-1, 3-dion-1-arylhydrazone XII and ie 3-arylhydrazono-1, 2-benzi sothiazole in-1, 1-dioxide XII. R and Ar have the meaning given for the general formula I, R 'denotes a hydrogen atom or a substituent from the group Hai, OCH3, OCßHiy n) 0-benzyl.

To produce the 3,4-cycloamidrazone according to the invention, various, for. T. known methods are used. They start from the key structures XIV-XVI, which are each reacted with arylhydrazines,

Are there

XIV X = halogen, cyclic imide chlorides such as 7-chloro-3,4,5, 6-tetrahydro-2H-azepine.

XIV X = OAlk: lactim ethers such as 5-methoxy-3,4-dihydro-2H-pyrrole, 6-methoxy-2,3,4,5-tetrahydro-pyridine, 7-methoxy-3,4,

5,6-tetrahydro-2H-azepine, 8-methoxy-2,3, 4, 5, 6, 7-hexa-hydroazocin and 2-methoxy-4,5-dihydro-3H-1-benzazepine

X = SAlk: thiolactim ether such as 2-methylthio-4,5-dihydro-

3h-1-benzazepine, 1-methylthio-4,5-dihydro-3H-2-benzazepin, 2-methylthio-octahydro-3H-1-benzazepine, 4-methylthio-7,8-dihydro-6H- thieno / 3,2-c / azepine

XV Z = S: thiolactams such as 1-thioxo-isoindole in-3-one and thiosaccharin

XV Z = NH: cycloidines such as isoindole in-1, 3-dione-imine XVI X = Y = OET: lactam and cycloimidacetals such as 2,2-diethoxy-1-methyl-pyrrolidine, 2,2-diethoxy-1 -methyl-hexa-hydroazepine and 5,5-diethoxy-1-propyl-pyrrole idin-2-one.

The key structures XIV-XVI are produced by largely conventional methods, the lactimether XIV, X = OAlk (Adv. Heterocycl. Chem. 12/1970/185, Msp. Chimicii 38/1969/166) z. B. by methylation of the lactams XV, Z = 0, with dimethyl sulfate (for example Chimica 27/1973/65), similar to the Thiolac¬ timether XIV, X = SMe (for example Liebigs Ann. Chem. 607 / 1957/67, 623/1959/166) from thiolactams XV, Z = S, which are accessible even from the lactams with P4S10 (e.g. Helv. Chim. Acta 18/1935/659). The lactamimines and especially the cycloimidineimines, Z = NH, are formed during nitrile cyclizations, e.g. B. isoindolin-1, 3-dione-1-imine from o-cyano-benzamide (Ber. Dtsch. Chem. Ges. 40/1907/2709). The lactam and cycloimidacetals 5 XVI, X = Y = OEt, are obtained from the N-substituted lactams and cycloimides by the action of triethyloxonium tetrafluoroborate and subsequently of sodium ethylate (Z. Chem. 9/1969/201, Usp. Chimii 46/1977/685).

Compounds of general structure I are in simple 10 substituent patterns z. T. known. For example, published patent applications DE 2235113 and DE 2235 177 and patent CS 191 584 claim hexahydro-1H-azepin-2-one-2-arylhydrazone V (R = H) as fungicides. DE 1957 783 describes compounds of structure V, VI and VII with R = H in the form of their 15 tautomers as antihypertensive substances. In the published patent application DE 3035822, structures V with R = H are recorded as acaricides. Similar compounds V (R = H, Ar = phenyl, nitrophenyl, chlorophenyl) are described in patent CS 197975 as fungitoxic. 20 compounds of structure XI (R = CH3, Ar = phenyl and 4-nitrophenyl) are described in Zh.Org. Klin. 1969, 5 / (7), 1318-9. Isoindoline-1, 3-dione-1-arylhydrazone XII are, for. T. known (J. Heterocycl. Chem. 1984, 2Λ_, 961-4). Substances of structure XIII are mentioned in J. Med. Chem. 25 1967, 10 (5), 844-9 and DE 3408539 as hypotensives or pesticides.

The z. T. outstanding inhibitory activities on lipoxygenases, which are documented in Table 1 using the example of soybean lipoxygenase I, a 15-lipoxygenase, remained undetected in each case. For comparison, the IC5 _Q value of the known LOX inhibitor 3-amino-1 (3-trifluoromethylphenyl) -2-pyrazoline is listed at the end of the table. Tab. 1: Effect of 3,4-cycloamidrazone on soybean lipoxygenase in vitro

Tab. 1 - Fortsetzung

Tab. 1 - continued

Tab. 1 Fortsetzung

Tab. 1 continued

XI a (n) C ₃ H _? ^C 6 ^H 5 9.7 x 10 ^" XI b (n) C ₃ H ₇ 4-Cl-C ₆ H ₄ 8.0 x 10 -9

XII a - - C ₆ H ₅ 9.1 x 10 ^"8

XII b - - 2-Cl-C ₆ H ₅ 1.6 x 10 ^"6

XII c - - 3-Cl-C ₆ H ₅ 3.5 x 10 ^"7

XII d - - 4-Cl-CgH ₅ 2.5 x 10 ^"7

XII e - - 4-Br-C ₆ H ₅ 1.5 x 10 ~ ⁷

XIII a - - C ₆ H ₅ 2.8 x 10 ^"9

XIII b 3-Cl-C ₆ H ₄ 8.5 x 10 ^"9

XIII c - - 3-CF ₃ -C ₆ H ₄ 1.5 x 10 ^"8

XIII d - - 2,4,6-Cl ₃ -C ₆ H ₄ 9.0 x 10 ~

3-amino

1 (3-trifluoromethylphenyl) -2-pyrazole in 4.6 x 10 ^"

1)% inhibition at 5 x 10 ^"8 mol / 1

2) ^* % inhibition at 2.5 x 10 ^"8 mol / 1

3)% inhibition at 5 ^* x 10 ^"4 mol / 1

4) BW 755 C The results of the in vitro test for inhibition of 15-lipoxygenase / T. Köhler, J. Landgraf u. P. Nuhn, Pharmazie 43 (1988) 178 / (see Example 8) were also reflected in the inhibition of 5-lipoxygenase from blood cells (see Example 9), which was determined by HPLC determination of the lipoxygenase products / Steinhiller , D., K. Schmidt, K. Eger and HJ Roth; Pharmacist. Res. 3: 271-277 (1986) /. Other lipoxygenase inhibitors known from the literature (BW 755 C, propylgal lat, caffeic acid, 0 stearic acid) were also effective on this model. In contrast to lipoxygenase, the other key enzyme of the arachidonic acid cascade, cyclooxygenase, was not significantly inhibited. Because of this selective attack on the lipoxygenase and the z. In some cases with very low toxicity, it was concluded that the compounds should have a number of valuable pharmacological properties. The antiallergic-antianaphylactic effects were determined using the models of active anaphylactic paw edema or active cutaneous anaphylaxis in the rat (cf. Examples 10 and 11).

Substance dose inhibitions after {%)

0.5 h 1 h 2 h 3 h 4 h 5 h

V e sp 0.1 mg 28 ^l 35 ⁽ 32 ⁽ 28 ^l 26 '26 ¹

V b s.p. 0.1 mg 17 16 15 25 '18 16

V b sp 1 mg 38 '38 43 28 ^l 20 ^C 17

V f po 100 mg / kg ^£ 30 11 30 ^α 45 ^£ 49 37

V a 01, sp 0.5 mg 44 ° 51 32 '32 43 29 ^t

(a: p <0.05, b: p <0.01, c: p <0.001) According to the table, selected compounds (Ve, Vb, Vf, Va) have a significant inhibitory effect on active anaphylactic edema after both local and systemic application. The doses required for the specified effects indicate a medium potency of the compounds.

Active cutaneous anaphylaxis was also significantly inhibited both after local injection and after systemic (i.p.) application of the substances. Here too there is a medium potency. The results on both models correspond to each other.

Influence on active cutaneous anaphylaxis in the rat (b: p <0.01; c: p <0.001)

Substance dose inhibition (%)

33 ^l 48 *

42 ^l 60 '36 «16 ¹ 65 ⁽

9

The antiinflammatory effect was tested on arachidonic acid-induced ear edema of the mouse (cf. Example 12). The in vivo results after local application of the substances showed significant inhibitory effects which correlate well with the inhibition of lipoxygenase. Influence on arachidonic acid-induced mouse ear edema (a: p <0.05; b: p <£ 0.01; c: p <0.001)

in vivo erfolgte am PAF-Ödem der Rattenpfote (vgl. Beispiel

In vivo, rat paw was seen on PAF edema (see example

13).

According to the table, the substances on the PAF paw edema showed surprisingly strong, e.g. T. highly significant inhibitory effects.

Influence on rat PAF paw edema after s.p. Application (a: p <0.05, b: p <0.01, c: p <0.001)

Substance dose inhibitions

(mg / paw) 0.5 h 1 h 1.5 h 2 h 3 h 4 h 5 h

V e

V b

Die angeführten in-vitro- und in-vivo-Ergebni sse belegen, daß es sich bei den erfindungsgemäßen 3 ,4-Cycloamidrazonen um sehr wirksame Lipoxygenase-Inhibitoren handelt, die anti- phlogi sti sehe, anti asthmati sehe, antiallergische und anti- thromboti sehe Effekte zeigen. Davon abgeleitet können für Verbindungen der allgemeinen Struktur I als Wirkstoffe für oral, perlingual, rektal, parenteral oder perkutan sowie als Aerosol anwendbare Arzneimittel folgende Indikationsgebiete in der Human- und Veterinärmedizin genannt werden: alle Formen von Entzündungen, allergischen Erkrankungen, Asthma,V a

The in-vitro and in-vivo results cited prove that the 3,4-cycloamidrazone according to the invention are very effective lipoxygenase inhibitors which see anti-phlogi, anti-asthmatic, anti-allergic and anti-thrombotic see effects show. Derived from this, the following indication areas in human and veterinary medicine can be named for compounds of general structure I as active ingredients for oral, perlingual, rectal, parenteral or percutaneous and as aerosol medicinal products: all forms of inflammation, allergic diseases, asthma,

Bronchitis and psoriasis. Due to their particularly favorable biological properties, the following should be mentioned:

1-methyl-2-pyrrolidone-2-phenylhydrazone

1-ethyl-2, 3,4,5, 6,7-hexahydro-1H-azepin-2-one-2-phenylhydrazone isoindolin-1, 3-dione-1-phenylhydrazone

1-n-propyl-pyrrolidine-2,5-dione-2-phenylhydrazone 1-n-propyl-pyrrolidine-2,5-dione-2 (4-chlorophenylhydrazone) 2,3,4,5,6,7-hexahydro -1H-azepin-2-one-2-phenylhydrazone 2,3,4,5,6,7-hexahydro-1H-azepin-2-one-2 (4-chlorophenylhydrazone) 3-phenylhydrazono-2,3-dihydro- 1,2-benzisothiazole-1,1-dioxide 3 (3-chlorophenylhydrazono) -2,3-dihydro-1,2-benzisothiazole-1,1-dioxide

3 (3-trifluoroethylphenylhydrazono) -2,3-dihydro-1,2-benzisothiazole-1,1-dioxide 1,3,4,5,5-tetrahydro-2H-1-benzazepin-2-one-2 (3rd -chlorophenylhydra¬ zone)

Perhydro-2H-1-benzazepin-2-one-2-phenylhydrazone 7- (n-octyloxy) - 1.3.4.5-tetrahydro-2H-1 -benzazepin-2-one-2-phenylhydrazone.

The present invention includes pharmaceutical preparations which, in addition to pharmaceutical auxiliaries and basic substances, contain one or more active substances according to the invention. Preferred pharmaceutical preparations are tablets, dragees, capsules, granules, syrups, suppositories, solutions, suspensions, emulsions, ointments, gels, powders, sprays and Called aerosols.

The active ingredients can also be present in microencapsulated form in one of these pharmaceutical preparations. In addition to the active substances according to the invention, the listed pharmaceutical preparations can also contain further active substances. In general, it has proven to be advantageous to use the active substance or substances according to the invention in total amounts of from about 0.05 to about 100, preferably 0.1 to 50 mg / kg of body mass per 24 hours, if necessary, to be administered in several separate doses.

embodiments

Example 1 1-methyl-pyrrole idin-2-one-2-phenylhydrazone-

Hydrochloride 10 g (0.058 mol) of 2,2-diethoxy-1-ethyl-pyrrole idin and 5.8 g (0.054 mol) of phenylhydrazine are each dissolved in 25 ml of anhydrous ether. Both solutions are combined and then left to stand at room temperature for 15 hours. The hydrochloride of 1-methyl-pyrrole idin-2-one-2-phenylhydrazone is then precipitated by passing in a dried HCl stream.

Mp 120-130 ° C (methanol / ether) yield 88% of theory Th.

Example 2 1-Methyl-piperidin-2-one-2-phenylhydrazone hydrochloride

10 g (0.053 mol) of 2,2-diethoxy-1-methylpiperidine and 5.15 g (0.048 mol) of phenylhydrazine are each dissolved in 25 ml of anhydrous ether. Both solutions are combined and then left to stand at room temperature for 15 hours. The mixture is then diluted with 250 ml of anhydrous ether and the hydrochloride of 1-methyl-2-piperidone-phenylhydrazone is precipitated by introducing dry HCl. Mp 100-104 ° C (methanol / ether) yield 83% of theory Th.

Example 3 1-n-propyl-pyrrole idin-2,5-dione-2-phenylhydrazone

14.1 g (0.1 mol) of N-propyl succinimide (J. Chem. Soc./1931/52) and 19 g (0.1 mol) of triethyloxonium tetrafluoroborate (Liebigs Ann. Chem. 190/1978/67) are described in a separating funnel mixes and allowed to stand at room temperature overnight without moisture. It separates out as the lighter phase ether. The lower phase is stirred with a clear solution of 3.3 g of sodium in 50 ml of abs. Dripped in ethanol. The mixture is stirred for 1 hour, then the separated salt is quickly filtered off and washed with a little chloroform. When the combined filtrates are concentrated in vacuo, a dirty yellow, oily 5,5-diethoxy-1-n-propylpyrrole idin-2-one remains which is further processed raw. 10 g are abs in 20 ml. Chloroform dissolved; To do this, the solution of 4.95 g of phenylhydrazine in likewise 20 ml of anhydrous chloroform is added dropwise with stirring and external cooling with water. The reaction mixture is left at room temperature for 24 hours, then the solvent is removed in vacuo, the residue is treated with 10% hydrochloric acid and extracted with ether. The extract is discarded. 5.9 g (48%) of colorless crystals, melting point 142-44 ° C., are obtained from the aqueous phase by alkalizing, ether extraction, drying the extract and introducing dry HC1, analysis values for C ₁₃ H ₁₇ N ₃ 0.HC1 (267.8); C 58.45% (calc.

58.31%), H 6.77% (6.78%), N 15.54% (15.69%), Cl 12.75% (13.24%).

Example 4: 1, 3, 4,5-tetrahydro-2H-1-benzazepin-2-one-2-phenylhydrazone hydrochloride To a solution of 0.045 mol 1, 3, 4,5-tetrahydro-2H-1-benza- zepin-2-thione in 120 ml dry DMF and 60 ml dry toluene, 0.1 mol sodium hydride are added in portions with stirring. When the evolution of hydrogen has ended, a solution of 0.045 mol of methyl iodide in 60 ml of dry toluene is slowly added dropwise and the mixture is stirred at room temperature for 8 hours. After adding water, the layers are separated, the organic phase is after stripping off most of the toluene, distilled in vacuo. The 2-methylthio-4,5-dihydro-3H-1-benzazepine is produced in a yield of 80%, bp ^ 148-150 ° C.

0.015 mol of this thiolactimether are refluxed with 0.015 mol of phenylhydrazine hydrochloride in 50 ml of ethanol for 1 hour. After concentration of the solution, the substance crystallizes out. The purification is carried out by recrystallization from ethanol yield. 87%, F. 230 ° C (dec.)

Example 5: 2, 3, 4,5-tetrahydro-1H-2-benzazepin-1-one-phenyl-hydrazone-hydrochloride Representation analogous to the above compound from 2,3,4,5-tetrahydro-1H-2-benzazepine -2-thione via the step of 1-methylthio-4,5-dihydro-3H-2-benzazepine (yield 15%, bp ₁₂ 146-150 ° C). Educ. 23%, mp 205 ° C (dec.)

Example 6: 5,6,7,8-tetrahydro-4H-thieno / 3.2-c / aze-pin-4-one-4-phenylhydrazone hydrochloride 0.05 mol 5, 6, 7, 8-tetrahydro-4H- thieno / 3.2.-c / azepin-4-one are refluxed with 0.02 mol P _Λ S ₁₀ and 5 g of annealed sea sand in 200 ml of toluene for 2.5 hours. The mixture is filtered hot, the residue washed with chloroform and the washing solution combined with the filtrate. After concentrating the organic phase, a light yellow, wax-like mass remained which was subjected to the methylation without further purification. Further processing was carried out in accordance with the methods given for Example 4. The product was obtained via the step of 4-methylthio-7,8-dihydro-6H-thieno / 3.2-c / azepine (yield 20%, based on the lactam used, bp ^ 150-156 ° C). Educ. 24%, mp 190 ° C (dec.) Example 7: Perhydro-2H-1-benzazepin-2-one-2-phenylhydrazone hydrochloride 25 g (0.155 mol) 1, 3,4,5-tetrahydro-2H-1-benzazepin-2-one dissolved in 200 ml of ethanol, mixed with 15 g of Raney nickel and subjected to high pressure hydrogenation (initial pressure 12 MPa, temperature 160 ° C., 8 hours hydrogenation time). After the hydrogenation has ended, the filtered solution is concentrated and the deca-hydro-2H-benz (b) azepin-2-one is recrystallized. C _1Q H _t7 N0 (167.25) F. 168-71 ° C (ethanol) Yield: 19.2 g = 74%

The thionation to the perhydro-1-benzazepin-2-thione was carried out analogously to the method given in Example 6, without further purification was ethylated (yield 38%, based on the lactam, bp., 134-140 ° C.) and analogously to implemented in Example 4 to the end product. Educ. 31%; F. 150 ° C (dec.)

Example 8: Determination of the inhibition of the soybean

Lipoxygenase in vitro The lipoxygenase activity was determined by means of an amperometric measurement method with registration of the oxygen used in the substrate fatty acids suitable for the enzymatic lipoperoxidation. The pO partial pressure was continuously recorded in a closed measuring cell using a Clark sensor (SMZ 300, Metra Radebeul), p0 ₂ measuring amplifier (M 80 F, Metra Radebeul) and a recorder (endim, Messapparatewerk Schlotheim). For each batch, 50 nmol / 1 lipoxygenase from soybeans (SERVA, 40 U / mg) were mixed with the substances to be tested for 3 min at 37 ° C in Tris / HCl 0.1 mol / l, pH 8.5, in the presence of 10 ^"2 mol / 1 Ca ⁺ in the measuring cell If the inhibitors could not be solubilized in the above-mentioned buffer solution, the solution was dissolved in DMF (freshly distilled); concentration in the measuring cell was a maximum of 1% and had no influence on the enzymatic activity. The enzymatic reaction was started by adding 227 µmol / 1 potassium linoleate (MERCK, 99% or SIGMA, 90-95%). The inhibitory parameters were determined via the initial speeds in the presence and absence of inhibitors of different concentrations on the basis of computational and / or graphic evaluation of the function 1 / initial speed = f (inhibitor concentration). For comparison, described inhibitors such as BW 755 c, propyl gallate, caffeic acid and stearic acid were tested, all of which are considerably weaker inhibitors than the structures we have described. In no case was Ca 2+ involved in the expression of inhibitory effects by the substances examined.

Example 9: Inhibition of LTB ₄ Formation of Human Polymorphonuclear Leukocytes (PMN)

Human PMN was prepared according to a BYOM I M method, modified according to SCHEWE and LUDWIG 121: Heparinized venous blood was mixed with 0.2 VT of a 6% p

Dextran solution (Infukoll) mixed. After 15-20 min, the supernatant, which was rich in leukocytes, was underlaid with a Ficoll-Paque gradient (density 1,077 g / cm ³ , PHARMACIA), centrifuged at 400 g for 30 min, and resuspended in PBS, pH 7.4. Erythrocytes remaining after washing were lysed. After a further washing in PBS, 5 x 10 ^" cells / ml were resuspended in HBS and incubated with test compounds or solvents for 5 min. In most cases, methanol was used as the solvent, the maximum final concentration was 5 µmol / l. After stimulation of the Cells with 5 µmol / 1 A 23187 and a further 5 min incubation, the reaction was stopped by adding 1 ml of cold methanol and 5 ml of glacial acetic acid. The extraction and analysis of the LOX products was carried out according to modified methods from LUDERER 13 / and STEINHILBER / 4 /: After centrifugation, the supernatant was reduced to a final methanol concentration of 25% by volume with water. The eicosanoid extraction was carried out using PRESEP C, _g cartridges (TESSEK, Prague), which were conditioned with 2 ml of methanol, 2 ml of water and 2 ml of -25 vol. Methanol. The eicosanoids were eluted with 2 ml of methanol. After the eluent had been driven off and dissolved in 100 ml of methanol, 40 μl of this sample were placed on an RP-18 column (250 × 4 mm, particle size 10 μm) and eluted with methanol / water / glacial acetic acid (B1 / 19 / 0.1 VT). A HEWLETT-PACKARD 1084 B Liquid Chromatograph was used. LTB ₄ and its isomers were detected at 254 nm, 5-HETE was detected at 235 nm. The identification was carried out on the basis of co-injected standards. To determine the percentage inhibition, the proportion of eicosanoids formed was used as a function of the inhibitor concentration applied. PBS: phosphate buffered saline HBS: HANK's buffered saline

I M By, A., Scand. J. Clin. Lab. Invest., 21, Suppl. 97,

77-89 (1968) Hl Schewe, T. and P. Ludwig, personal communication 131 Luderer, J.R., D.L. Riley and L.M. Demers, J. Chromatorgr. Biomed. Appl. 273, 402-409 (1983)

IM Steinhilber, D., K. Schmidt, E. Eger and H.J. Roth,

Pharmacist. Res. 3, 271-277 (1986)

Example 10: Active anaphylactic paw edema of the rat. Male rats (80-100 g body weight) were injected with 0.2 ml of a 0.5% human serum albumin (HSA) solution containing 2 ^* 10 killed germs from Bordetella pertussis. in the right thigh is sensitive. The addition of Bordeella pertussis germs is said to bring about the activation of macrophages and, in some strains of mice and rats, to increase sensitivity to histamine and serotonin (Eichelberg, D., W. Schnitzler, Immun. Infect. JJ_, 109 (1989); G. Kostantinov et al., Amer. Immunol. Hung. 26_, 345 (1986)). After 12-17 days, the anaphylactic reaction was triggered by subplantar injection of 0.1 ml of a 1% HSA solution into the left hind paw. The local application of test substances was carried out together with the 1% HSA solution to provoke the anaphylactic reaction. For po administration of compounds, the active substance (dissolved or suspended) was probed by rats placed sober 24 hours before the start of the experiment and only receiving water ad libitum, by means of a pharyngeal tube 1 hour before the provocation of edema. The control animals received 0.5 ml of the vehicle po at the same time. The course of the anaphylactic paw edema was plethysmometric according to LENCE (Arch. Int. Pharmacology J_36, 237 (1962), 0.5, 1, 2, 3, 4 and 5 The inhibitor was dissolved or suspended in isotonic NaCl solution and 0.1 ml of the preparation was injected sp. To control the tissue tolerance, the control animals received 0.1 ml of isotonic NaCl solution.

Example 11: Active cutaneous anaphylaxis of the rat

Male rats were sensitized as described under 1. After 11-16 days, the rats were injected iv with 0.4 ml / 100 g body mass (KM) of a 2% Evans blue solution. The rats were anesthetized by ip injection of 1.3 g / kg urethane or 50 mg / kg KM pentobarbital. After the Ab¬ Rückenh ^scissors' aare we solved the anaphylactic Reak¬ tion by intracutaneous (ie) injection of 0.1 ml of 1% HSA solution at 6 spots of the dorsal skin. For lo- kalen application of substances were injected together with the provocation solution. For ip testing of active substances, the application was carried out 30 minutes after the injection of 0.1 ml 0.1% HSA at 3 sites on one half of the back and 30 minutes after the substance had been injected, the injection of 0.1 ml 0.1% HSA in 3 other places on the other half of the back. Intra-individual controls were therefore possible. Testing a substance to be administered po required the rats to be probed 1 hour before the provocation of the anaphylactic reaction.

30 min after the provocation, the animals were sacrificed with chloroform, the dorsal skin was separated off and the wheals were extracted in 5 ml of N, N-dimethylformamide at T = 40 ° C. for 24 hours. After filtering the extraction solutions, they were measured photometrically on a Spekol (spectrophotometer 5, VEB Carl Zeiss Jena) at = 607 nm.

EXAMPLE 12 Arachidonic Acid-Induced Ear Edema of the Mouse After topical application of AA, an edema developed in the ear of the mouse, the course of which could be controlled by measuring the ear thickness. AA and the test substances were each dissolved in a mixture of acetone / pyridine / water = 97: 2: 1 (v / v / v) (RP Carlson, Agents Actions 21, 379 (1987). Before the start of the experiment, the thickness of the left ear of each mouse was determined 10 μl of the test solution of the solvent mixture (control group) and 30 min later 10 μl of the AA solution (0.3 mg AA / ear) were ventilated onto the surface using a special dial gauge for pharmacological purposes at a constant pressure applied to the inner ear surface, the current ear thickness was measured 10, 15, 20, 30, 40, 50 and 60 min after the application of the AA solution The difference in ear thickness at the start of the experiment and at the later measurement times resulted in the increase in ear thickness. Example 13: PAF paw edema of the rat

The PAF paw edema was caused by s.p. Injection of 0.5 µg / 0.1 ml PAF into the left hind paw of male rats (110-130 g body weight) induced. The changes in paw volume were plethysmometrically according to LENCE (see above) 0.5, 1, 1.5, 2, 3, 4 and. Determined 5 hours after the injection of the phosphol ipid. Active substances were administered locally together with the provocation solution.

Claims

Claim 1. 3,4-Cycloamidrazone of the general structure I

in which R is hydrogen or a preferably low molecular weight alkyl radical, Ar is a phenyl radical or a phenyl radical which is monosubstituted or polysubstituted, identically or differently, by alkyl groups, alkoxy groups, trifluoromethyl groups, nitro groups, halogen atoms, A is a tetragonal or trigonal carbon atom and underlying cycle represents a heteromono- or -bicyclus as well as their physiologically tolerated acid addition salts. Compounds according to claim 1, wherein R preferably one

represents a low molecular weight alkyl radical, Ar has the meaning mentioned, A is the C atom of a CH ₂ group and the underlying cycle is a pyrrolidine, piperidine or hexahydro-1H-azepine ring. Compounds according to claim 2, wherein R represents a methyl group

1-methyl-2-phenylhydrazonopyrrole idin 1-methyl-2-phenylhydrazonopiperidine 1-methyl-2-phenylhydrazono-2,3,4,5,6,7-hexahydro-1H-azepine Compounds according to Claim 1, in which Ar has the meaning mentioned, R is a preferably low molecular weight alkyl group, A is the C atom of a carbonyl group and Cyclus is a pyrrole.

Compounds according to Claim 5, in which R represents a propyl group. 0

1-n-propyl-2,5-dioxopyrrole idine phenyl hydrazone 1-n-propy1-2,5-dioxopyrrolidine (4-chlorophenylhydrazone) Compounds according to claim 1, wherein R is a hydrogen atom, Ar has the meaning given, A is the C atom of a CH group and the underlying heterocycle is a 2,3,4,5-tetrahydro-1H-1-benzazepine is.

Compounds according to claim 1, wherein R is a hydrogen atom, Ar has the meaning given, A is the C atom of a CH ₂ group and the underlying cycle is a perhydro-1-benzazepine. W7

10. Compounds according to claim 1, wherein R is a hydrogen atom, Ar has the meaning given, A is the C atom of a benzene ring and the underlying cycle is a 2,3,4,5-tetrahydro-1H-2-benzazepine.

11. Compounds according to claim 1, wherein R is a hydrogen atom, Ar has the meaning given, A is the C atom of a CH ^ group and the underlying cycle is a 5,6,7,8-tetrahydro-thieno / 3,2 -C / azepine is.

12. A process for the preparation of compounds according to claim 2, characterized in that lactam acetals of the general structure 1, wherein R is a preferably low molecular weight alkyl radical,

and n is the number 0.1 or 2, with arylhydrazines Ar-NH-NH _? , in which Ar has the meaning as in the general formula I of claim 1, are implemented. 13. A process for the preparation of compounds of claim 5, characterized in that succinimide acetals of the general structure 2,

where R is a preferably low molecular weight alkyl radical, with arylhydrazines Ar-NH-NH _? , wherein Ar has the meaning as in the general formula I of claim 1, are implemented. 14. A process for the preparation of compounds according to claim 8, characterized in that thiol actimethers of the general structure 3_,

wherein R 'is a substituent from the group hydrogen, halogen, alkoxy, aralkoxy, with arylhydrazine hydrochlorides ArNHNH' HCl, where Ar has the meaning as in the general formula I of claim 1, are reacted. 15. A process for the preparation of compounds according to claim 10, characterized in that 1-methylthio-4,5-dihydro-3H-2-benzazepine with arylhydrazine hydrochlorides Ar-NH-NH "HC1, wherein Ar has the meaning as in the general formula I. of claim 1 has to be implemented. 16. A process for the preparation of compounds according to claim 11, characterized in that 4-methylthio-7, 8-di-hydro-6H-thieno / 3, 2-c / azepine is reacted with arylhydrazines in which Ar has the meaning as in that has general formula I of claim 1. 17. A process for the preparation of perhydro-1-benzazepin 2-one-2-phenylhydrazones according to claim 9, characterized in that 1, 3,4,5-tetrahydro-2H-1-benzazepin-2-one in a solvent was hydrogenated with Raney nickel under pressure, converted into the thiol acetate with P _Λ S. _Q and then with methyl iodide and finally reacted with arylhydrazine hydrochloride. 5 18. Pharmaceutical preparations, characterized by a content of at least one 3,4-cycloamidrazone of the general structure I

according to claim 1 or claims 2-11, wherein R, Ar and A have the above meaning, or his or her 10 physiologically tolerable acid addition salts as active ingredient. 19. Use of compounds according to claims 1-11 and of pharmaceutical preparations according to item 18 as universal lipoxygenase inhibitors. 15 20. Agents for the treatment of broncho-contradictory conditions, in particular all forms of asthma, asthmoid bronchitis and obstructive pulmonary emphysema, characterized by a content of one or more active ingredients according to claims 1-11. 20 21. Agents for the treatment of all forms of psoriasis, characterized by a content of one or more active substances according to claims 1-11. 22. Agents for the treatment of inflammatory phenomena of all kinds, in particular rheumatic and arthritic diseases, characterized by a content of one or more active substances according to claims 1-11. 23. Agents for the treatment of all forms of allergic diseases, in particular the skin and mucous membranes, characterized by the content of one or more active substances according to claims 1-11.