DE4114542A1 - 3,4-CYCLOAMIDRAZONE, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL AGENT CONTAINING THEM - Google Patents

Abstract

The invention relates to partly novel 3,4-cycloamidrazones, a process for producing them and their use in pharmaceutical preparations. The 3,4-cycloamidrazones are lactam-aryl hydrazones and cycloimide-aryl hydrazones. They are produced by the reaction of activated lactam and cycloimide derivatives with aryl hydrazines or aryl hydrazine hydrochlorides. The 3,4-cycloamidrazones 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

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

The object of the invention is the development of 3,4-cycloamidrazone 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 a phenyl radical or one by alkyl groups, Alkoxy groups, halogen atoms, trifluoromethyl groups, nitro groups or carbalkoxy groups, single or multiple, identical or different substituted phenyl radical, A is a tetragonal or trigonal carbon atom, e.g. B. the carbon atom of a carboxyl group, or a SO₂ group and the underlying cycle a heteromono- represents or bicyclus and optionally their physiological tolerated acid addition salts, has been a very strong Inhibition of lipoxygenase and, based on this, a new application as anti-inflammatory, anti-rheumatic, anti-anaphylactic Medicines found.

Arachidonic acid and other polyunsaturated fatty acids (PUFA) are metabolized by the enzymes cyclooxygenase (COX) and lipoxygenase (LOX) primarily peroxygenated and then to numerous, biologically active metabolites further broken down; the Metabolite pattern is in the case of LOX-mediated metabolism particularly diverse because these enzymes depend on their origin have a different substrate specificity (attack in 5-, 12- or 15-position = 5-LOX, 12-LOX, 15-LOX). The LOX-dependent PUFA metabolites (leukotrienes) are mediators anaphylactic and allergic processes and work pro-inflammatory. By substances that affect the activity of the LOX should inhibit biosynthesis and, consequently, its effects of the mediators to be suppressed. Enzyme inhibitors this type is known. 5-LOX inhibitors are e.g. B. 3-Amino-1- (3-trifluoromethylphenyl) -2-pyrazoline (BW 755 C) (e.g. prostagl., Leukotr. Med. 10/1983/187), Nordihydroguajaretsäure (e.g. J. Immune. 125/1980/163), 5.8.11.14-eicosatetrainic 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-eicosa tetraenoic acid (J. Med. Chem. 26/1983/72), various thioara chidonic acids (J. Amer. Chem. Soc. 107/1985/713, Tetrahedron Lett. 26/1985/3919) and many other connections, e.g. T. also 12- and 15-LOX inhibitors (e.g. Biochem. Pharmacol. 28/1979/1959, FEBS Letters 110/1980/213, Biochim. Biophys. Acta 487/1977, 517, Prostagland. 14/1977/261) and even COX inhibitors. As selective 12 and / or 15 LOX inhibitors are u. a. Acetone phenyl hydrazone (e.g. Adv. Prost. Tromb. Res. 6/1980/111, Agents Actions 12/1982 / 360), Baicalein (Biochem. Biophys. Res. Commun. 105/1982/1090), Luteolin (Prostagl. 20/1980/627) and 1,5-dihydroxynaphthalene (Biochem. Pharmacol. 30/1981/1677). It is also known that acylic amidrazones such as N (1) -phenyl-benzamidrazone (CBS-1114) LOX inhibitors are (Drugs Fut. 9/1984/102).

The vast majority of known LOX inhibitors are liable for their elaborate Accessibility (e.g. polyacetylenic acids), their insufficient effectiveness (e.g. flavones, flavonols) and / or their great toxicity (e.g. acetone phenyl hydrazone) as an application limiting or even -preventing blemish.

The invention has for its object by a modification to develop the amidrazone structure LOX inhibitors, which in suitable pharmaceutical preparations for the treatment of diseases can be used, the cause of which is an increased Leukotriene biosynthesis is. Surprisingly, it was found that the incorporation of the atoms with 3 and 4 numbered acyclic Amidrazone II leads to compounds I in ring systems, which have a very high effectiveness.

Such compounds, which are usually lactam or cycloimide arylhydrazones are combined in this invention referred to as 3,4-cycloamidrazone.  

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

Tetrahydropyrrol-2-one-2-arylhydrazone (III)
Hexahydro-pyridin-2-one-2-arylhydrazone (IV)
Hexahydro-1H-azepin-2-one-2-arylhydrazone (V)
Perhydro-azocin-2-one-2-arylhydrazone (VI)
2,3,4,5-tetrahydro-1H-1-benzazepin-2-one-2-arylhydrazone (VII)
2,3,4,5-tetrahydro-1H-2-benzazepin-1-one-1-arylhydrazone (VIII)
5,6,7,8-tetrahydro-4H-thieno / 3,2-c / azepin-4-one-arylhydrazone, (IX)
Perhydro-1-benzazepin-2-one-2-arylhydrazone (X)
Pyrrolidine-2,5-dione-2-arylhydrazone (XI)
Isoindoline-1,3-dione-1-arylhydrazone (XII)
3-arylhydrazone-1,2-benzisothiazolin-1,1-dioxide (XII)

R and Ar here have those for the general formula I. given meaning, R 'denotes a hydrogen atom or a Substituents from the group Hal, OCH₃, OC₈H₁₇ (n), Obenzyl.

It has been found that the compounds of the general formula I can be prepared in such a way that 1,3-cyclohexanediones general formula II

wherein R¹ and R² have the above meaning, with one in the usual Way prepared aryldiazonium salt III, wherein R³ and R⁴ the have the above meaning, implemented at 5-20 ° C, the primary result Arylazo compound IV by a nucleophile HX, wherein X has the meaning given above, cleaves to give the hydrazonoyl chloride V and this with amines of the type HA, where A explained one above Represents the rest, optionally in the presence of a Auxiliary base, converted to amidrazone I.

The coupling reaction II → V can be in aqueous or not aqueous solvents containing sodium acetate will. When using lower alcohols as a solvent the corresponding reaction occurs directly in the coupling reaction Esterhydrazononylchloride V, where X is OR⁵. The preparation of the acid amide hydrazonoylchloride V, in which under X the remainder -NR⁵R⁶ is to be understood in one hydroxyl-free solvents, such as. B. acetonitrile or Dioxane, in such a way that a equimolar amount of an amine of the HNR⁵R⁶ type is added. The Hydrazonoylchloride V isolated in the usual way to the amidrazone I by placing it in a suitable Solvent, preferably ethanol, dimethylformamide or ethanol, with twice the molar amount of an amine HA, in the case of aromatic amines, each with equimolar amounts of Amine and triethylamine.

The reactions that follow the azo coupling become at temperatures between 20 ° and 80 ° C, preferably at 20-25 ° C carried out. The response times are 1-15 hours. The compounds according to the invention are excellent inhibitors the soybean lipoxygenase. The following table shows the effectiveness.  

table

Inhibition of soybean lipoxygenase

The IC₅₀ was determined by evaluating the initial rate of the enzyme reaction under the following assay conditions: 22.5 μm soybean lipoxygenase (40 U / mg), 227 μmol potassium linolate, Tris.HCl 0.1 mol / l, pH 8.5 ; Ca ⁺⁺ 0.01 mol / l. Inhibitor dissolved in DMF, final DMF concentration <1% by volume. Incubation at 37 ° C for 3 min.

The inhibitory effect of chemical compounds in this test system clearly correlates with the inhibitory effect on lipoxygenases different origins and different substrate specificity, also on the physiologically and pythophysiologically important 5-lipoxy recover.

In the pharmaceutical preparations according to the present invention are in addition to the amidrazone to be used according to the invention also inert, non-toxic, pharmaceutically suitable carriers and contain auxiliary substances. These are pharmaceutically acceptable Understand substances that after mixing with the active ingredient in a suitable form for administration Deliver shape.

As a rule, the pharmaceuticals according to the invention contain Preparations 0.5 to 95% of those to be used according to the invention Amidrazone derivatives.

In humans, the daily dose is based on body weight 0.1 to 50 mg / kg.

The dosage unit (tablet, capsule, etc.) contains in the Rule 1 to 200 mg of the amidrazone derivatives to be used according to the invention.

The following exemplary embodiments explain the connection, without restricting them.  

Embodiments 1st example 5-Oxo-6-phenylhydrazono-6-piperidino-hexanoic acid methyl ester

To a solution of 300 ml of methanol, 14.7 g (0.1 mol) of 2-chloro cyclohexane-1,2'-dione and 25 g of anhydrous sodium acetate one at 10 ° C a phenyldiazonium chloride solution within drop in with stirring for about 30 min. The phenyldiazonium chloride solution is obtained in the usual way from 9.3 g (0.1 mol) of aniline, 6.9 g, (0.1 mol) sodium nitrite, dissolved in 40 ml water and 50 ml 18% hydrochloric acid. The one that forms after a short time Suspension is stirred for a further 30 min after the end of the dropping and then left to stand at 5-10 ° C for 1 hour. The precipitation is separated and washed several times with water. After this Drying gives 22.6-24.0 g (80-85%) of 6-chloro-5-oxo-6-phenyl methyl hydrazone-hexanoate (mp 112-114 ° C).

14.1 g (0.05 mol) of this substance are dissolved in 150 ml of dioxane. After the addition of 8.5 g (0.1 mol) of piperidine, the Stand for 15 hours at room temperature. After that is filtered, the filtrate is concentrated in vacuo and the resulting 150 ml of water are added to the residue. After 3 hours the waxy product is filtered off, several times with water washed and dried.

The 5-oxo-6-phenylhydrazono-6-piperidino-hexanoic acid methyl ester is obtained in the form of a yellow crystalline powder.
Yield: 23.2-24.8 g (70-75%, based on 6-chloro-5-oxo-6-phenylhydrazono-hexanoic acid methyl ester)
Mp 48-50 ° C (methanol).

In an analogous procedure, when using appropriate aryldiazonium salts and aliphatic amines, the following compounds are obtained which, for. T. were isolated as hydrochlorides:
Active cutaneous anaphylaxis was also significantly inhibited both after local injection and after systemic (ip) 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

The anti-inflammatory activity was tested on the arachidone acid-induced mouse ear edema (see Example 12). The in vivo results after local application of the substances resulted significant inhibitory effects that work well with lipoxygenase correlate inhibition.  

Influence on arachidonic acid-induced mouse ear edema

Testing for antagonism against an inflammatory mediator in In vivo, rat paw was seen on PAF edema (see Example 13). According to the table, the substances showed on the PAF paws edema surprisingly strong, e.g. T. highly significant inhibitory effects.

Influence on rat PAF paw edema after late application

The in vitro and in vivo results given show that it are very effective in the 3,4-cycloamidrazone according to the invention Lipoxygenase inhibitors are anti-inflammatory, anti Show asthmatic, antiallergic and antithrombotic effects. Derived from this for compounds of general Structure I as active ingredients for oral, perlingual, rectal, parenteral or percutaneously as well as medicinal products that can be used as an aerosol Indications in human and veterinary medicine are: all forms of inflammation, allergic diseases, Asthma, bronchitis and psoriasis. Because of their particularly affordable biological properties are:

1-methyl-2-pyrrolidone-2-phenylhydrazone
1-methyl-2,3,4,5,6,7-hexahydro-1H-azepin-2-one-2-phenylhydrazone
Isoindoline-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-phenylhydrazone-2,3-dihydro-1,2-benzisothiazole-1,1-dioxide
3 (3-chlorophenylhydrazono) -2,3-dihydro-1,2-benzisothiazole-1,1-dioxide
3 (3-trifluoromethylphenylhydrazono) -2,3-dihydro-1,2-benzisothiazole-1, -1-dioxide
1,3,4,5-tetrahydro-2H-1-benzazepin-2-one-2 (3-chlorophenylhydrazone)
Perhydro-2H-1-benzazepin-2-one-2-phenylhydrazone
7- (n-octyloxy) -1,3,4,5-tetrahydro-2H-1-benzazepin-2-one-2-phenylhydra-zone.

The present invention includes pharmaceutical preparations which in addition to pharmaceutical auxiliaries and raw materials or contain several active substances according to the invention. As preferred pharmaceutical preparations are tablets, coated tablets, capsules, Granules, syrups, suppositories, solutions, suspensions, emulsions, Called ointments, gels, powders, sprays and aerosols.

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

Embodiments Example 1 1-methyl-pyrolidin-2-one-2-phenylhydrazone hydrochloride

10 g (0.058 mol) of 2,2-diethoxy-1-methyl-pyrrolidine and 5.8 g (0.054 mol) of phenylhydrazine are 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-pyrrolidin-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-methyl-piperidine and 5.15 g (0.048 mol) of phenylhydrazine are 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-pyrrolidine-2,5-dione-2-phenylhydrazone

14.1 g (0.01 mol) of N-propylsuccinimide (J. Chem. Soc./1931/52) and 19 g (0.1 mol) of triethyloxonium tetrafluoroborate (Liebigs Ann. Chem. 190/1878/67) are combined in one Separating funnel mixed and left overnight with exclusion of moisture at room temperature. 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, dirty yellow, oily 5,5-diethoxy-1-n-propyl pyrrolidin-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 for 24 hours at room temperature, then the solvent is removed in vacuo, the residue is treated with 10% hydrochloric acid and extracted with ether. The extract is discarded. The aqueous phase is obtained by alkalizing, ether extraction, drying the extract and introducing dry HCl. 5.9 g (48%) colorless crystals,
M. 142-44 ° C
Analytical values for C₁₃H₁₇N₃O · HCl (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-phenyl hydrazone hydrochloride

To a solution of 0.045 mol 1,3,4,5-tetrahydro-2H-1-benzazepine 2-thione in 120 ml dry DMF and 60 ml dry toluene 0.1 mol of sodium hydride was added in portions with stirring. To ceased hydrogen evolution becomes a solution of 0.045 mol Methyl iodide slowly added dropwise in 60 ml of dry toluene and the mixture was stirred for 8 hours at room temperature. After encore the layers are separated from water, the organic phase after most of the toluene has been stripped off in vacuo distilled. The 2-methylthio-4,5-dihydro-3H-1-benzazepine is formed in a yield of 80%, Kp₁₁ 148-150 ° C.

0.015 mol of this thiolactimether are refluxed with 0.015 mol of phenyl hydrazine 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.
Educ. 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-tetra hydro-1H-2-benzazepin-2-thione via the stage of 1-methylthio-4,5-dihydro-3H-2-benzazepine (yield 15%, Kp₁₂ 146-150 ° C).
Educ. 23%, mp 205 ° C (dec.)

Example 6 5,6,7,8-tetrahydro-4H-thieno / 3.2-c / azepin-4-one-4- phenylhydrazone hydrochloride

0.05 mol of 5,6,7,8-tetrahydro-4H-thieno / 3.2-c / azepin-4-one are refluxed with 0.02 mol of P₄S₁₀ 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 concentration of 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, Kp₁₁ 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) of 1,3,4,5-tetrahydro-2H-1-benzazepin-2-one are dissolved in 200 ml of ethanol, 15 g of Raney nickel are added and the mixture is 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.
C₁₀H₁₇NO (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 methylated (yield 38%, based on the lactam, Kp₁₁ 134-140 ° C) and analogously to that in Example 4 specified method implemented for the end product.
Educ. 31%; F. 150 ° C (dec.)

Example 8 Determination of the inhibition of soybean lipoxygenase in vitro

The lipoxygenase activity was determined by means of an amperometric measurement procedure with registration of the in the enzymatic lipoperoxidation of suitable substrate fatty acids consumed oxygen. The pO₂ partial pressure was in a closed measuring cell by means of a Chlark sensor (SMZ 300, Metra Radebeul), pO₂ measurement (M 80 F, Metra Radebeul) and a recorder (endim, Messapparatewerk Schlotheim) continuously registered.

For each batch, 50 nmol / l lipoxygenase from soybeans (SERVA, 40 U / mg) with the substances to be tested were 3 min at 37 ° C in Tris / HCl 0.1 mol / 1, pH 8.5, in the presence of 10 ^-2 mol / l Ca ²⁺ incubated in the measuring cell. If the inhibitors could not be solubilized in the above-mentioned buffer solution, the solution was in DMF (freshly distilled); the final DMF 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 / l 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 using arithmetic and / or graphic evaluation of the function l / initial speed = f (inhibitor concentration). For comparison, described inhibitors such as BW 755 c, propyl gallate, coffee acid and stearic acid were tested, all of which are considerably weaker inhibitors than the structures described by us. In no case was Ca ²⁺ involved in the expression of inhibitory effects by the investigated substances.

Example 9 Inhibition of LTB₄ formation of human polymorphonuclear Leukocytes (PMN)

Human PMN was prepared using a method from BØYUM (Bøym, A., Scand. J. Chlin. Lab. Invest., 21, Suppl. 97, 77-89 [1968]), modified according to SCHEWE and LUDWIG (Schewe, T and P. Ludwig, personal communication): Heparinized venous blood was mixed with 0.2 VT of a 6% dextran solution (Infukoll®). 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 wash in PBS, 5 × 10 ^-6 cells / ml were resuspended in HBS and incubated with test compounds or solvent 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 / l 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 by LUDERER (Luderer, JR, DL Riley and LM Demers, J. Chromatogr. Biomed. Appl. 273, 402-409 [1983]) and STEINHILBER (Steinhilber, D., K. Schmidt, K. Eger and HJ Roht, Pharmaceutical Res. 3, 271-277 [1986]): 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 C₁₉ cartridges (TESSEK, Prague), which were conditioned with 2 ml of methanol, 2 ml of water and 2 ml of 25% by volume of methanol. The elution of the eicosanoids was carried out 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. The detection of LTB₄ and its isomers was carried out 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

Example 10 Active anaphylactic paw edema of the rat

Male rats (80-100 g body weight) were examined by i. m. Injection of 0.2 ml of a 0.5% human serum albumin (HSA) solution containing 2 · 10¹⁰ contained killed germs from Bordetella pertussis in the right Thigh sensitized. The addition of Bordetella per Tussis germs are said to activate macrophages and increased sensitivity in some mouse and rat strains lead to histamine and serotonin (Eichelber, D., W. Schnitzler, immune. Infect. 1989, 11: 109; G. Konstantinov et al., Amer. Immunol. Hung. 26, 345 1986). After 12-17 days, the anaphylactic reaction by subplantar injection of 0.1 ml a 1% HSA solution in the left hind paw. The local application of test substances was carried out together with the 1% HSA solution to provoke the anaphylactic reaction. To p. o. Connections were given 24 hours before the start of the experiment fasted rats that only received water ad libitum, by means of a pharyngeal tube 1 hour before the provocation of the edema (dissolved or suspended) probed. The control animals received at the same time 0.5 ml of vehicle p. o. The course of the anaphylactic Paw edema was plethysmometric according to LENCE (Arch. Int. Pharmacology 136, 237 (1962)) 0.5, 1, 2, 3, 4 and Determined 5 hours after injection.

The inhibitor was tested in isotonic NaCl solution dissolved or suspended and 0.1 ml of Preparation see p. injected. The control animals received 0.1 ml isotonic NaCl solution.  

Example 11 Active cutaneous anaphylaxis in the rat

Male rats were sensitized as described under 1. After 11-16 days, the rats were given 0.4 ml / 100 g body mass (KM) IV injected with a 2% Evans Blue solution. By i. p. injection of 1.3 g / kg urethane and 50 mg / kg KM pentobarbital, respectively Rats anesthetized. After the back hair was sheared off, we loosened it the anaphylactic reaction by intracutaneous (i. c.) injection 0.1 ml of a 1% HSA solution at 6 points in the back skin out. For the local application of substances, these became common injected with the provocation solution. For i. p. Testing of active substances the application took place 30 min after i. c. Injection of 0.1 ml 0.1% HSA in 3 places on one back half and 30 min after adding the substances, the injection of 0.1 ml 0.1% HSA 3 other places on the other back half. Thus, intra individual controls possible. Testing a p. o. to appli Ornamental substance required probing of the rats for 1 hour before provoking the anaphylactic reaction.

30 min after the provocation, the animals were sacrificed with chloroform, the dorsal skin separated and the wheals in 5 ml each N, N-dimethylformamide extracted for 24 hours at T = 40 ° C. To The extraction solutions were filtered photometrically Spekol (spectrophotometer 5, VEB Carl Zeiss Jena) at λ = 607 nm measured.

Example 12 Arachidonic acid-induced mouse ear edema

On the ear of the mouse, after topical application of AA an edema, the course of which is controlled by measuring the ear thickness could be. AA and the test substances were each in a mixture of acetone / pyridine / water = 97: 2: 1 (v / v / v) (R.P. Carlson, Agents Actions 21, 379 (1987)). Before the start of the experiment was the thickness of the left ear of each mouse using a special dial indicator for pharmacological purposes measured at a light, constant pressure. After that 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) with ventilation applied to the inner ear surface, 10, 15, 20, 30, 40, 50 and 60 minutes after application of the AA solution, the current one  Ear thickness measured. The difference in ear thickness at the start of the experiment and at the later times of measurement the ear thickness increased.

Example 13 PAF paw edema of the rat

The PAF paw edema was caused by s. p. 0.5 µg / 0.1 ml injection PAF in the left hind paw of male rats (110-130 g body weight) induced. The changes in paw volume became plethysmometric according to LENCE (see above) 0.5, 1, 1.5, 2, 3, 4 and 5 hours determined after the injection of the phospholipid. The local gift of Active substances took place together with the provocation solution.

Claims (23)

1. 3,4-cycloamide zone of 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 mono- or polysubstituted, identically or differently, by alkyl groups, alkoxy groups, trifluoromethyl groups, nitro groups, carbalkoxy groups or halogen atoms, A is a tetragonal or trigonal carbon atom and the underlying cycle is one Heteromono- or -bicyclus represents as well as their physiologically acceptable acid addition salts. 2. Compounds according to claim 1, wherein R represents a preferably low molecular weight alkyl radical, Ar has the meaning given, A is the C atom of a CH₂ group and the underlying cycle is a pyrrolidine, piperidine or hexahydro-1H-azepine ring. 3. Compounds according to claim 2, wherein R represents a methyl group 4. 1-methyl-2-phenylhydrazone-pyrrolidine
1-methyl-2-phenylhydrazone piperidine
1-methyl-2-phenylhydrazono-2,3,4,5,6,7-hexahydro-1H-azepine 5. Compounds according to claim 1, wherein Ar has the meaning given, R is a preferably low molecular weight alkyl group, A is the C atom of a carbonyl group and the cycle is a pyrrolidine ring. 6. Compounds according to claim 5, wherein R represents a propyl group. 7. 1-n-propyl-2,5-dioxopyrrolidine phenylhydrazone
1-n-propyl-2,5-dioxopyrrolidine (4-chlorophenylhydrazone) 8. Compounds according to claim 1, wherein R is a hydrogen atom, Ar has the meaning given, A is the C atom of a CH₂ group and the underlying heterocycle is a 2,3,4,5-tetrahydro-1H-1-benzazepine is. 9. Compounds according to claim 1, wherein R is a hydrogen atom, Ar has the meaning given, A is the C atom of a CH₂ group and the underlying cycle is a perhydro-1-benzazepine. 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-tetra hydro-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 CH₂ group and the underlying cycle is a 5,6,7,8-tetrahydro thieno / 3,2-C ) is azepine. 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-NH₂, where Ar has the meaning as in the general formula I of claim 1, are reacted. 13. A process for the preparation of compounds of claim 5, characterized in that succinimide acetals of the general structure 2, wherein R is a preferably low molecular weight alkyl radical, with arylhydrazines Ar-NH-NH₂, wherein Ar has the meaning as in the general formula I of claim 1, are reacted. 14. A process for the preparation of compounds according to claim 8, characterized in that thiolactim ether of the general structure 3, wherein R 'is a substituent from the group hydrogen, halogen, alkoxy, aralkoxy, with arylhydrazine hydrochlorides ArNHNH₂ · HCl, wherein 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-NH₂ · HCl, wherein Ar has the meaning as in the general formula I of Claim 1 has to be implemented. 16. A method for producing compounds according to claim 11, characterized in that 4-methylthio-7,8-dihydro-6H- reacts thieno / 3,2-c / azepine with arylhydrazines, in which Ar is the Meaning as in the general formula I of claim 1 owns. 17. Process for the preparation of perhydro-1-benzazepin-2-one-2- phenylhydrazone according to claim 9, characterized in that 1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in a solvent hydrogenated with Raney nickel under pressure, with P₄S₁₀ and then converted into the thiolactim ether with methyl iodide and finally reacted with arylhydrazine hydrochloride. 18. Pharmaceutical preparation, characterized in that it contains at least one 3,4-cycloamidrazone of the general structure I according to claim 1 or according to claims 2-11, wherein R, Ar and A compatible acid addition salts as active ingredient. 19. Use of compounds according to claims 1-11 and of pharmaceutical preparations according to point 18 as universal Lipoxygenase inhibitors. 20. agents for the treatment of broncho-contradictory conditions, especially all forms of asthma, asthmoid bronchitis and obstructive pulmonary emphysema due to the content of one or more active substances Claims 1-11. 21. Means to treat all forms of psoriasis, labeled by a content of one or more active ingredients according to claims 1-11. 22. Agents for the treatment of inflammatory phenomena of all kinds, ins special rheumatic and arthritic diseases through the content of one or more active ingredients according to claims 1-11. 23. agents for the treatment of all forms of allergic diseases, especially the skin and mucous membranes by the content of one or more active ingredients according to claims 1-11