NO832664L - 4H-1,4-BENZOTHIAZINE, THE PROCEDURE FOR THEIR PREPARATION AND THEIR USE AS A MEDICINE - Google Patents

Abstract

1. 4H-1,4-Benzothiazines of the formula see diagramm : EP0100527,P16,F4 in which R**1 denotes hydrogen, aryl with 6 to 20 carbon atoms, which can optionally be mono- to trisubstituted by halogen, trifluoromethyl or nitro, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl or 5-pyrimidyl, which can optionally be mono- or polysubstituted by alkyl, alkoxy, hydroxyl or halogen, cyano or the group see diagramm : EP0100527,P16,F6 in which R**6 represents alkyl (C1 to C8 ), aryl (C6 to C20 ), amino, pyrrolidino, piperidino, morpholino, cycloalkoxy or the radical -O-CH2 -R**8 in which R**8 denotes straight-chain or branched alkyl with 1 to 7 carbon atoms, which is optionally mono- to trisubstituted by halogen, C6 to C20 -aryl, hydroxyl, alkoxy, alkylthio or cyano, R**2 denotes alkyl (C1 to C8 ), which is optionally mono- to trisubstituted by halogen, pyrrolidino, piperidiono, aryl (C1 to C20 ) or by the group in which R**7 represents aryl (C6 to C20 ), hydroxyl, amino, dialkylamino, pyrrolidino, piperidino or morpholino, R**3 denotes hydrogen or one of the groups mentioned under R**2 , and R**4 and R**5 are identical or different and denote hydrogen, halogen, hydroxyl, alkoxy, nitro or cyano, or one of the groups mentioned under R**2 , for therapeutic use.

Description

The invention relates to 4H-1,4-benzothiazines, several methods for their preparation, their use as medicine, in particular their use as lipoxygenase inhibitors, agents containing these, and their preparation.

It is known that the metabolites of arachidonic acid leukotrienes and slow reacting substance oganaphylaxis (SRS-A) formed with the help of the enzyme lipoxygenase are involved in the formation of inflammatory and allergic processes, etc. E.J. Goetzl, Immunology 40 709 (1980) and Medical Clinics of North America 65, 809 (1981).

Known lipoxygenase inhibitors such as nordihydroguaretic acid, 3-amino-1-(3-trifluoromethylphenyl)-pyrazoline, phenidone and 5, 8,11,14-^eicosatetraenoic acid are either simultaneously effective as cyclooxygenase inhibitors or are only effective at very high concentrations. The inhibition of the enzyme cyclooxygenase of the arachidonic acid metabolism leads to a global inhibition of prostaglandin synthesis and to a stimulation of the lipoxygenase pathway, which causes a gastrotoxicity, resp. pro-inflammatory and asthmatic effects. In addition, already known lipoxygenase inhibitors such as 3-amino-1-(m-trifluoromethylphenyl)-pyrazoline-2 have toxic side effects when administered systemically (e.g. orally). There is therefore a need for orally active compounds that do not have these unwanted side effects.

Surprisingly, the 4H-1,4-benzothiazines according to the invention inhibit lipoxygenase already at such concentrations where cyclooxygenase is little affected.

The compounds according to the invention surprisingly also stimulate the synthesis of prostacyclin in arterial vessels in vitro, possibly as a result of their lipoxygenase-inhibiting properties

cabinet. With regard to this effect, the compounds according to the invention are more effective than the known lipoxygenase inhibitor 3-amino-1-(m-trifluoromethylphenyl)-pyrazoline-2. (Proe. of British Pharmacological Soc. 920 P (1981). The compounds according to the invention also stimulate prostacyclin synthesis in rabbit aortic strips.

The compounds according to the invention also have an anti-phlogistic effect in the carrageenan-induced edema model, when they are administered systemically, especially orally and locally, especially cutaneously.

They also have an antimetastatic effect.

The lipoxygenase-inhibiting 4H-1,4-benzothiazines according to the invention can thus be used as medicine in the treatment of inflammatory and allergic processes. They can spe-

find use as antiphlogistics, antirheumatics, antiatheroscl erotics, antithrombotics, antiarthrotics, antiasthmatics, antiallergics, antimetastatics and gastroprotectives.

The subject of the invention is therefore compounds with the formula I defined below, as well as the methods listed below for preparing the compound according to formula I, as well as the compounds with the general formula I for use in combating diseases, especially as lipoxygenase inhibitors, antiphlogistics and/or antimetastatics, as well as medicinal product containing at least one compound of the general formula I, as well as the use of a compound of the general formula I to combat diseases, in particular as lipoxygenase inhibitors, antiphlogistics and/or antimetastatic agents, as well as the method for producing medicinal products containing at least one compound of the formula I, in that a compound of the general formula I is transferred, possibly using usual auxiliary and carrier substances, into a suitable application form.

The 4H-1,4-benzothiazines according to the invention correspond to the general formula I,

in which

R means hydrogen, aryl (optionally substituted) hetaryl (optionally substituted), alkyl (optionally substituted), alkoxy, cyano,

-CO-R<6>,

R 2 means hydrogen, alkyl (optionally substituted), aryl, (optionally substituted) -CO-R<6>,

R 3 means hydrogen, alkyl, (optionally substituted),

> R 4 and R 5 mean hydrogen, alkyl (optionally substituted), halogen, hydroxy, alkoxy, nitro, acyloxy, cyano, alkylsulfonyl, arylsulfonyl, and R<4> and R<5> can be the same or different,

R<6> means hydrogen, alkyl (optionally substituted), aryl,

(optionally substituted), cycloalkyl, amino (optionally substituted), hydroxy, optionally substituted alkoxy, cycloalkoxy for combating diseases.

The compounds of formula I are preferably used as lipoxygenase inhibitors, antiphlogistics and/or antimetastatics.

The 1,4-benzothiazines according to the invention preferably correspond to the general formula Ia,

in which

R means hydrogen, aryl (optionally substituted), hetaryl (optionally substituted) or

R 2 means alkyl (optionally substituted),

R 3 means H, alkyl (optionally substituted),

4 5

R , R means H, alkyl (optionally substituted),

halogen, hydroxy, alkoxy, NO,,, acyloxy, cyano, alkylsulfonyl, arylsulfonyl and wherein R<4> and R^ may be the same or different,

R<6> stands for amino (optionally substituted), cycloalkoxy, substituted

8 R

methoxy with the formula -0-CH2~R , where R must not mean unsubstituted methyl, and

R° o means optionally substituted alkyl, or optionally substituted aryl,

with the proviso that when R 3 does not mean hydrogen, R fi also means alkyl, aryl, methoxy and ethoxy.

In the general formula I, optionally substituted alkyl, R<1>, R<2>, R<3>, R<4>, R<5> and R<6> means straight or branched alkyl with preferably 1 to 8, particularly preferred 1 to 4 carbon atoms. For example, optionally substituted methyl, ethyl, n- and i-propyl, n-, and i- and t-butyl should be mentioned with particular preference.

The alkyl radicals R 1 to R fl can be substituted 1 to 3 times, preferably once with the following substituents,

Halogen, especially fluorine and/or chlorine, dialkylamino, pyrroli-

dino, piperidino, optionally substituted aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, -CO-R 7 , where R 7 means alkyl, optionally substituted aryl, hydroxy, alkoxy, amino, alkylamino, dialkylamino, pyrrolidino, piperidino and morpholino.

12 6 7 8

As optionally substituted aryl R, R, R, R, R

and the substituent alkyl residue R to R and R is aryl with preferably 6 to 20 carbon atoms in the aryl part. Examples include phenyl or naphthyl. The alkyl radicals can be substituted 1 to 3 times, preferably once in the 0-, m- or p-position with the following substituents: Halogen, alkyl, alkoxy, trifluoromethyl, nitro.

As optionally substituted hetaryl, R particularly preferably means 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl.

These residues may be substituted one or more times by alkyl, alkoxy, hydroxy or halogen, especially fluorine and/or chlorine,

Optionally substituted alkoxy R<6> is straight or branched alkoxy with preferably 1 to 8, particularly preferably 1 to 4 carbon atoms. Alkoxy radicals can be substituted 1 to 3 times, preferably once with the following substituents: Halogen, especially fluorine and/or chlorine, aryl (optionally substituted .hydroxy), alkoxy, alkylthio, cyano.

Optionally substituted alkyl R is straight or branched alkyl with preferably 1 to 7 carbon atoms. The alkyl radical R can preferably be substituted 1 to 3 times

once with the following substituents: Halogen, especially fluorine and/or chlorine, aryl (optionally substituted) hydroxy, alkoxy, alkylthio, cyano.

As optionally substituted amino-R c are monoalkyl-amino, dialkylamino, pyrrolidino, piperidino, morforlino.

The compounds according to the invention with the general formula I can be prepared according to method variant 1, whereby 2-aminothiophenols of formula II are reacted with compounds of formula III in dimethylsulfoxide (cf. J. Chemical Soc.

Perkin Trans I, 1976, 1146-49).

In the general formulas II and III, the residues have the following meaning: R"'" means hydrogen, aryl (optionally substituted), hetaryl (optionally substituted), alkyl (optionally substituted), alkoxy, cyano,

-CO-R6,

R 2 means hydrogen, alkyl (optionally substituted), aryl (optionally substituted), -CO-R<6>,

R 3 means hydrogen, alkyl (optionally substituted),

R 4 , R 5 means hydrogen, alkyl (optionally substituted), halogen, hydroxy, alkoxy, nitro, acyloxy, cyano, alkylsulfonyl, aryl-4 5

sulfonyl, wherein R and R can be the same or different.

The compounds of formulas II and III are either known from the literature or can be prepared analogously to compounds known from the literature. The reaction temperature can be between 50° and 200°C, preferably between 100° and 150°C. In some cases, it is appropriate to work under oxygen exclusion.

The substances according to the invention can be prepared according to method variant 2, whereby 2-aminothiophenols of formula II are reacted with compounds of formula IV (cf. Ann. Chem. 744, 20-32 (1971)).

X means halogen, preferably Cl, Br,

Y means oxygen, alkyl-N, aryl-N.

The reaction can preferably also be carried out

in the presence of an acid scavenger such as triethylamino, I^CO^, Na2CO3, NaOH, NH^.

Solvents include: alcohol

hollows (e.g. methanol, ethanol) ethers, (e.g. diethyl ether, THF, dioxane, dimethoxyethane, diethylene glycol dimethyl ether), hydrocarbons (e.g. benzene, toluene), chlorinated hydrocarbons, (e.g. methylene chloride, chloroform , chlorobenzene), DMSO, DMF, pyridine and water. In some cases, it is appropriate to work under oxygen exclusion.

The reaction temperature can be between 0°C and 200°C, preferably between 35 and 110°C.

The compounds according to the invention can be prepared according to method variant 3, whereby disulfides of formula V are brought into reaction with carbonyl compounds of formula III (cf. Phosphorus and Sulfur 3, 309-314 (1977).

The reaction is catalysed by means of acids (e.g. p-toluenesulfonic acid).

Suitable solvents include: Benzene, toluene, pyridine, DMSO and DMF.

The reaction temperature can be between 20 and 180°C, preferably between 35 and 110°C.

It is appropriate to work under oxygen exclusion.

The reaction is mostly carried out with equimolar amounts of the starting material, while an excess (up to HO%) of carbonyl compound is also used.

The compound according to the invention with formula I can be prepared according to method variant 4, whereby disulfides of formula V are reacted with alkynes of formula VI (cf.

J. Heterocyclic Chem. 17, 377 (1980).

The reaction is preferably carried out with equimolar amounts of the starting material while an excess (up to 110%) of alkyne, (VI) is used. Solvents include: Alcohols (e.g. methanol, ethanol), ethers, hydrocarbons (e.g. benzene, toluene), chlorinated hydrocarbons, DMSO, DMF and pyridine. The reaction temperature is between 20 and 180°C, preferably between 35 and 120°C.

It is appropriate to work under oxygen exclusion.

The compound according to the invention with formula I, where R 3 means alkyl (optionally substituted) can also be prepared from the corresponding compounds, in which R 3 means hydrogen, according to the usual alkylation methods, e.g. by reaction with CH^J, C^Hi-Br or io-bromoacetof enone.

The detection of the lipoxygenase-inhibiting properties of the compounds according to the invention proceeded analogously to the method of Bailey et al., J. of Biol.Chem. 255, 5996 (1980), and according to Blackwell and Flower, Prostaglandin 16, 417, (1978). In this test method, the metabolism of radioactively labeled arachidonic acid is applied to adult human thrombocytes. In this in vitro test, the radioactively labeled metabolites are extracted from the reaction mixture and separated by thin-layer chromatography. The aut.oradiogram is assessed on a thin-layer scanner. Under these test conditions, the marked metabolites are separated from the unconverted arachidonic acid, and can then be assessed quantitatively. The distribution of the radioactivity of the cyclooxygenase product thromboxane B2 (TXB2) and 12-hydroxy-5,8,10-hepadectrienoic acid (HHT) resp. the lipoxygenase product 12-hydroxy-5,8,11,14-eicosatetraenoic acid (HETE) under the influence of the inhibitors is a measure of the inhibition of the enzymes.

The lipoxygenase inhibition of the compound according to the invention can be measured by the inhibition of HETE synthesis. It appears that the synthesis of TXB2 and of HHT remains unaffected while arachidonic acid turnover decreases. As can be seen from the following tables, the compounds according to the invention cause a clear inhibition of platelet lipoxygenases (HETE synthesis) (cf. table 1).

Analogous to the above, the lipoxygenase-inhibiting properties of the compound according to the invention can also be demonstrated for leukocytes.

The polymorph-removed leukocytes in humans and rabbits metabolize arachidonic acid to 5-hydroxy-5,8,11,14-eicosatetraenoic acid (5-HETE) and leukotriene B4(5S, 12R-dihydroxy-6 cis, 8, 10, trans-14 cis- eicosatetraenoic acid). The inhibition of the release of 5-HETE and leukotriene B^ from leukocytes is a measure of the lipoxygenase-inhibiting effect of the compound according to the invention (cf. Table 1).

The test with human leukocytes was carried out according to Borgeat and Samuelsson (J. Biol, Chem. 254, 2643, 1979 and Proe. Nati. Acad. Sei. USA, 76, 2148, 1979) with rabbit leukocytes according to Walker and Parish (inter. Archs. Allergy Appl. Immun. 66, 83, 1981).

The detection of prostacyclin-stimulating effect took place by the determination of the release of prostacyclin after 1 hour of incubation of rabbit aortic strips with the compound according to the invention (analogously according to Moncada et al. Lancet 1977 I, 18), and subsequent radioimmunological determination of the stable prostacyclin metabolite 6-keto-PGF 1 (B,M, Peskar et al. FEBS

Letters 121, 25 1980).

The compounds according to the invention are also effective

in vivo. This effect is demonstrated by measuring the inhibition of leukocyte migration according to methods known per se (cf.

Higgs et al, Biochemical Pharmacol, 28, 1959, (1979) and Eur. J. Pharmacol, 66, 81 (1981)).

The new active substances can be transferred in a known manner

in the usual formulations such as tablets, capsules, dragees, pills, granules, aerosols, syrups, emulsions, suspensions, solutions using inert, non-toxic pharmaceutical excipients, or solvents. Hereby, the therapeutically active compound must each time be present in a concentration from approx. 0.5 to 90% by weight of the overall mixture, i.e. in amounts sufficient to achieve a desired dosage margin.

The formulations are produced, for example, by brewing

of active substances with solvents and/or carriers, possibly using emulsifiers and/or dispersants, by e.g. use of water as a diluent, organic solvents may optionally be used as auxiliary solvents.

As excipients, for example, the following must be stated:

Water, non-toxic organic solvents, such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. peanut/sesame oil), alcohols (e.g. ethyl alcohol, glycerol), glycols, (e.g. propylene glycol, polyethylene glycol), N-alkyl-pyrrolidone, solid carriers, such as e.g. natural stone flour

(e.g. kaolins, clay soil, talc, chalk), synthetic stone

flour, (e.g. highly dispersed silicic acid, silicates), sugars, (e.g. beet, milk and grape sugars), emulsifiers such as non-ionic anionic emulsifiers, (e.g. polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol esters, alkylsulfonates and arylsulfonates), dispersants, (e.g. lignin, sulphite liquor, methylcellulose, starch and polyvinylpyrrolidone) and lubricants

(e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulfate).

The application takes place in the usual way, preferably orally or parenterally, especially cutaneously. In the case of oral use, tablets can of course, in addition to the mentioned carriers, also contain additives such as sodium citrate, calcium carbonate

nat, and dicalcium phosphate, together with suitable additives, such as starch, preferably potato starch, gelatins and the like. Furthermore, lubricants such as magnesium stearate, sodium lauryl sulfate and talc can also be used for tableting. In the case of aqueous suspensions and/or elixirs, which are intended for oral use, the active substances, in addition to the above-mentioned excipients, can be mixed with various flavor enhancers, or colored, resp. coloring substances.

For parenteral use, solutions of the active substances can be used using suitable liquid carriers.

Generally, it has been found advantageous for intra-venous application to administer amounts from approx. 0.01 to 10 mg/kg, preferably approx. 0.05 to 5 mg body weight/day to achieve effective results, and with oral application the dosage is approx. 0.05 to 100 mg/kg, preferably 0.1 to 10 mg/kg body weight/day.

Nevertheless, it may be necessary to deviate from the mentioned amounts, namely depending on body weight, resp. the type of method of application, but also because of the type of their individual relationship to drugs resp. the type of its formulation and the time resp. the interval to which administration takes place. Thus, in some cases it may be sufficient to come out with less than the above-mentioned minimum quantity, while in other cases the above-mentioned limit must be exceeded. In the case of application of larger amounts, it may be advisable to distribute these in several individual applications throughout the day. The above statements apply to application in both human and veterinary medicine in the same way.

The invention shall be explained in more detail with the help of some examples (see also table 1)

Example 1

3-methyl-4H-1,4-benzothiazone-2-carboxylic acid-(2-cyanoethyl)-ester

10 g (0.08 mol) of 2-aminothiophenol and 12.4 g (0.08 mol) of acetoacetic acid (2-cyanoethyl) ester were dissolved in 40 ml of dimethylsulfoxide. The mixture was heated for 2 hours to boiling, and after cooling, mixed with 250 ml of water. A precipitate formed which was filtered off with suction, recrystallized from isopropanol.

Sm.p. 152 - 154°C, Yield: 8.2 g (39% of theory).

In the same way, the following pre-

prepare :

Cont.

Example 27 3-Benzyl-4H-1,4-benzothiazine-2-carboxylic acid ethyl ester

To a boiling solution of 24.8 g (0.1 mol) of 2,2'-dithiodianiline and 100 mg of p-toluenesulfonic acid in 300 ml of toluene, a solution of 20.6 g (0.1 mol) was added dropwise under nitrogen 4-phenylacetoacetic acid ethyl ester in 100 ml of toluene. The mixture was dried for 5 hours under a water separator. After cooling, it was washed with soda solution, the organic phase separated, dried with Na 2 SO 4 and evaporated.

The residue was separated chromatographically (silica gel 0.063-0.2). 4.8 g of m.p. were formed. 140-143°C.

In the same way (as example 27) the following preparations can be prepared

Example 30 4-ethoxy-4H-1,4-benzothiazine-2-carboxylic acid ethyl ester

A solution of 5.05 g of 5,5<1->diethoxy-2,2'-dithio-dianiline and 2.94 g of propiolic acid ethyl ester in 7.5 ml of dimethyl sulfoxide heated for 1% hour under nitrogen at 130°C. After cooling, the mixture was mixed with ice water. A precipitate formed which was suctioned off and dissolved in vinegar. This solution was washed twice with water, dried with Na 2 SO 4 and evaporated. The residue was recrystallized from methanol.

Sm.p. 172°C, yield 2.3 g.

In the same way as in example 30, the following preparations can be prepared:

3.15 g (0.01 mol)

3.0 g (0.03 mol) N-methylpiperazine

50 ml of DMSO.

The substances are brought together and kept for 1^ hours at 15°C.

DMSO was distilled off in an oil pump, the residue was extracted with NaOH, the organic phase was separated and evaporated, the residue was recrystallized from acetone.

Yield 1.4 g

Sm.p. 156-159°C.

Example 34

8.8 g (0.023 mol)

250 ml as methanol

88 0 mg Pd/coal.

H2 was introduced for a total of 16 hours at room pressure, catalyst was sucked off, ML evaporated, the residue recrystallized from acetone/ether.

Yield 4.5 g, sp.p. 180-186°C.

Example 35

2.0 g (0.063 mol)

20 ml of dioxane

20 ml of 6% NaOH.

The substances are brought together and heated for 4 hours at 50°C. Dioxane is removed on a rotary evaporator, diluted with H20, filtered. The filtrate is acidified with HC1, left for 24 hours and suctioned off.

Yield 1.5 g

Sm.p. 176-180°C.

Example 36

2.0 g (.0053 mol)

20 ml of dioxane

20 ml of 6% NaOH.

The substances are brought together and kept for 3 hours at 50°C. The dioxane is removed on a rotary evaporator, the residue is taken up in a little H2O, filtered. The filtrate is acidified with HC1, after a 24-hour standstill, the crystals are suctioned off.

Yield 1.8 g, m.p. ) 2 5 0°C.

Example 37

1.0g (0.00357mol) MG = 266/3

20 ml dioxane/H 2 O

0.143 g of NaOH.

The substances are brought together and heated for 3 hours at reflux temperature. Dioxane/H20 is distilled off using an oil pump. The residue is taken up in a little H2O, filtered, acidified with HCl, and allowed to stand for 24 hours, after which the crystals are suctioned off. Yield 0.4 g, melting point 193-195°C.

Example 38

3.15 g (0.01 mol)

50 ml abs. dioxane

1.57 Pd/coal,

hydrogenated in 100 ml at room temperature. After 3 hours at room temperature, the catalyst is suctioned off, and the mother liquor is evaporated, the residue is slurried in petroleum ether and suctioned off.

Yield: 2.81 g 98.6% of the theoretical with m.p. 147-150°C.

Cyclization of open-chain derivatives with potassium tert.-butylate General regulation:

One has 0.01 mol of α-(subst.) phenylsulfinyl-6-ethylaminoacrylic acid esters in 50 ml abs. DMSO and add at room temperature 0.01 mol freshly sublimed potassium tert-butylate in portions. After 8 hours at 100°C, the DMSO is removed in vacuo, the residue is taken up in water/dichloromethane and the organic phase is separated. After evaporation, the residue is crystallized with ether.

Claims (1)

Patent claims 1. 4H-1,4-benzothiazines of the general formula Yes in which R means hydrogen, aryl (optionally substituted), heteroaryl (optionally substituted) or R 2 means alkyl, (optionally substituted), R 3 means H, alkyl (optionally substituted), 4 5 R , R means H, alkyl (optionally substituted), halogen, hydroxy, alkoxy, NO_, acyloxy, cyano, alkylsulfonyl, arylsulfonyl, 4 5 where R and R can be the same or different, R <6> means amino, (optionally substituted), cycloalkoxy, substituted methoxy of formula while R does not mean unsubstituted methyl, and R P means optionally substituted alkyl or optionally substituted aryl, provided, however, that when RJ does not mean hydrogen, means R <6> also alkyl, aryl, methoxy and ethoxy.2. 4H-1,4-benzothiazines ■■ : of the general formula I in which R means hydrogen, aryl (optionally substituted), hetaryl (optionally substituted), alkyl (optionally substituted), alkoxy, cyano, -CO-R <6>, R 2 means hydrogen, alkyl (optionally substituted), aryl (optionally substituted) -CO-R, R3 means hydrogen, alkyl (optionally substituted), R <4> , R <5> means hydrogen, alkyl (optionally substituted), halogen, hydroxy, alkoxy, nitro, acyloxy, cyano, alkylsulfonyl, arylsulfonyl, and where R4 and R <5> were the same or different, R means hydrogen, alkyl (optionally substituted), aryl (optionally substituted), cycloalkyl, amino (optionally substituted), hydroxy, alkoxy, (optionally substituted), cycloalkyl, for use in combating diseases. 3. Compound with the general formula I according to claim 2 for use in combating diseases, preferably as lipoxygenase inhibitors, antiphlogistics and/or antimetastatics. 4. Medicine containing at least one compound with the general formula I, according to claim 2. 5. Use of a compound with the general formula I according to claim 2 for combating diseases, preferably as lipoxygenase inhibitors, antiphlogistics and/or antimetastatics. 6. Process for the production of a medicinal product containing at least one compound of the general formula I according to claim 2, characterized in that the compound of the general formula I, possibly using usual excipients and carriers, is transferred in a suitable application form. 7. Process for preparing a compound of the general formula I according to claim 2, characterized in that 2-amino-thiophenols of formula II reacted with compound of formula III in dimethylsulfoxide at temperatures between 50° and 200°C, the specified residues having the meaning specified in claim 2. 8. Process for preparing compounds of the general formula I according to claim 2, characterized in that 2-aminothiophenols of formula II is reacted with a compound of formula IV at temperatures between 0 and 200°C, the residues having the meaning stated in claim 1, and X meaning halogen and Y oxygen, alkyl-N or aryl-N. 9. Process for the preparation of a compound of the general formula I according to claim 2, characterized in that disulfides of formula V is reacted with a carbonyl compound of formula III optionally in the presence of acids at temperatures between 20 and 18 0°C, the residues having the meaning specified in claim 2. 10. Process for the preparation of a compound of the general formula I, according to claim 2, characterized in that disulfides of formula V is reacted with alkynes of formula VI at temperatures between 2 0° and 18 0°C, the listed residues having the meaning stated in claim 2.