DE2456863A1 - NEW DICARBONIC ACID IMIDES - Google Patents

Description

CIBA-GEIGY AG, BASET, (SWITZERLAND)

Case 4-9155 / + Germany

DR. ERLEND ϋΙΝΝέ PATENT ADVERTISER 28 BREMEN

UHLANDSTRASSE 25

New dicarboximides

The invention relates to new 3,6-dithiacyclohexene-1,2-dicarboxylic acid-N-arylimides the general formula

• X.

R-,

^ xAc /

Il

(D

509825/1068

wherein the radicals X independently of one another are thio, sulfinyl or Sulfonyl mean, R .. halogen, trifluoromethyl, lower alkyl, Lower alkoxy, lower alkanoyl, lower alkylsulphonyl, optionally functionally modified carboxyl, hydroxy or nitro means, R "means halogen, lower alkyl or trifluoromethyl and R "represents halogen or hydrogen, as well as processes for their manufacture.

Above and below, lower radicals are to be understood as meaning those radicals which are not more than 7, in particular contain no more than 4 carbon atoms (hereinafter referred to as carbon atoms).

Halogen R ^, R2 and _R3 is for example, halogen having an atomic number 35, in particular of Atomnumrner V, to 35, such as bromine or especially chlorine.

Lower alkyl R ₁ and R contains, for example, 1 to 7, in particular 1 to 4, carbon atoms and can be straight-chain or branched and bonded in any position, such as straight-chain or branched heptyl, hexyl or pentyl bonded in any position, or in particular n- , iso-, sec- or tert-butyl, η- or iso-propyl, ethyl or especially methyl.

Lower alkoxy R. contains e.g. 1 to 7, especially up to 4 carbon atoms and can be straight-chain or branched and bonded in any position, such as straight-chain or branched, Heptyloxy, hexyloxy, pentyloxy, butoxy or especially isopropoxy, propoxy, ethoxy bound in any position or especially methoxy.

S0982S / 1066

Lower alkanoyl R contains e.g. 1 to 7, especially 1 to 4 carbon atoms, such as valeroyl, isovaleroyl, pivaloyl. or in particular butyryl, isobutyryl, propionyl, formyl

or especially acetyl. .

Lower alkyl sulfonyl contains in the lower alkyl part e.g.

one of those defined above, in particular that of them by name called lower alkyls, and is e.g. methyl or, above all, ethyl sulfonyl. '

Functionally modified carboxyl R- is, for example, esterified or amidated carboxyl or cyano.

Esterified carboxyl is, for example, with a lower Alkanol, especially with one of those mentioned above Lower alkyl radicals R, derived lower alkanol, esterified Carboxyl, like. one of the isomeric heptyloxy, hexyloxy, Pentyloxy or butyloxycarbonyl groups or especially isopropoxy, propoxy or especially ethoxy or methoxycarbonyl. . - *

Amidated carboxyl is, for example, optionally mono- or di-lower alkylated carbamoyl, with lower alkyl radicals especially those mentioned above come into consideration and. e.g. N-mono- or Ν, Ν-dibutylinocarbonyl, N-mono- or N, N-dipropyl- or -isopropylaminocarbonyl or especially N-mono- or N, N-diethyl- or -methylaminocarbonyl.

S0982 & / - 1066

In the new compounds of the formula I, at least one of the radicals X is preferably thio and the other is optionally Sulfinyl or especially sulfonyl.

The 3,6-dithiacyelohexene-1,2-dicarboxylic acid-N-arylimides according to the invention have valuable pharmacological properties, especially a serum lipid-lowering effect. So effect in the normally fed male rat with repeated administration of 10-100 mg / kg p.o. a significant decrease in Serum cholestrin concentration and from 30-100 mg / kg p.o. eire significant reduction in serum triglyceride concentration. The registration requirements Compounds can therefore be used as pharmaceuticals, especially as hypolipidemic agents.

In particular, the invention relates to:

Compounds of the formula I in which R, the radicals X are independent of one another Thio, sulfinyl or sulfonyl mean, R, halogen up to atomic number 35, lower alkoxycarbonyl, lower alkoxy, lower alkyl, lower alkyl sulfonyl, carboxyl, trifluoromethyl, hydroxy or nitro or lower alkanoyl, e.g. one with 1 to 4 carbon atoms, R2 denotes halogen up to atomic number 35, lower alkyl or trifluoromethyl and R ~ is hydrogen or chlorine.

In particular, the invention relates to:

Compounds of the formula I in which the radicals X, independently of one another, denote thio, sulfinyl or sulfonyl. R ₁ halogen with atom number 19-35, such as chlorine or bromine, optionally with a lower alkanol with 1 to 4 carbon atoms esterified carboxyl, such as carboxyl or methoxy or ethoxycarbonyl, lower alkyl or

609826/106 *

Lower alkoxy each with 1 to 4 carbon atoms, such as methyl or methoxy, or lower alkyl sulfonyl with 1 to 4 carbon atoms, such as Ae thy I denotes sulfonyl, trifluoromethyl or nitro, R ₉ denotes chlorine, methyl or trifluoromethyl and R ₃ denotes hydrogen or means chlorine.

The invention primarily relates to:

Compounds of the formula I in which the radicals X are independent of one another Thio, sulfinyl or sulfonyl, R, chlorine, bromine, Trif Itiormethyl, nitro, methyl, methoxy, carboxyl, methoxy or Aethoxycarbonyl, methyl or AethyIsulfonyl means, R "chlorine, Is methyl or trifluoromethyl and R "is hydrogen or, if Ro is chlorine or methyl, also mean chlorine can. '

First and foremost, the invention relates to compounds of the formula I in which the radicals X independently of one another are thio, sulfinyl or sulfonyl, R, halogen with atom number 19 to 35j such as chlorine or bromine, lower alkyl with up to 4 carbon atoms such as methyl, or Nitro in the 2-, 3- or 4-position, lower alkoxy with up to 4 carbon atoms, such as methoxy, lower alkylsulfonyl with up to 4 carbon atoms, such as ethy1sulfonyl, or lower alkoxycarbonyl with up to 5 carbon atoms, such as methoxycarbonyl, or Carboxyl in the 2-position or tri fluorine Lhyl, lower alkoxy carbonyl with up to 5 carbon atoms, such as methoxy or ethoxycarbonyl, or lower alkanoyl with up to 4 carbon atoms, such as propionyl, or bromine in the 2-position or trifluoromethyl in 3 Position denotes, R ₂ denotes chlorine, trifluoromethyl or methyl in the 4-, 5- or 6-position and Rj denotes hydrogen or, provided that

IL, 2-position lower alkyl and R _{2 is} 5-position chlorine or R 4-position halogen and R _{2 is} 6-position chlorine, also for 3-position chlorine or, if R, 2-position lower alkoxy and R _{2 is} 5-position methyl or R ^ 2-position carboxyl and R ₉ 6-position chlorine, can also stand for 4-position chlorine.

In particular, the invention relates to compounds of formula I in which the radicals X independently of one another are thio, sulfonyl or, in the second line, sulfinyl, R .. 2-, 3- or 4-position halogen with atom number 19 to 35, such as chlorine or bromine, 2 -Carboxyl or 3-position lower alkoxycarbonyl with up to 5 carbon atoms, such as ethoxycarbonyl, lower alkanoyl with up to 5 carbon atoms, such as propionyl, or trifluoromethyl and R _{9 is} 6-position chlorine or R, 2- or 4-position Lower alkyl with up to 4 carbon atoms, such as methyl, 2-position carboxyl, 3-position halogen with atomic number 19 to 35, such as chlorine, or 4-position trifluoromethyl and R _{9 is} 5-position chlorine or R _{1 is} 2- or 3-position nitro, 2-position lower alkoxycarbonyl with up to 5 carbon atoms, such as methoxycarbonyl, or trifluoromethyl or 3-position halogen with atom number 19 to 35, such as chlorine, or trifluoromethyl and R ₂ 4-position chlorine or R, 2-position Lower alkoxy, such as methoxy, and R ₉ denotes methyl in the 5-position and R-Λ denotes hydrogen or, if R, 2-position carboxyl or 3-position halogen and R _{2 is} 6-position chlorine or R .. 2-position nisderalkoxy and R _{9 is} 5-position methyl, also for 4-position chlorine or , provided that R ^ 2-position lower alkyl and R _{2 is} 5-position chlorine, can also stand for 3-position chlorine.

509825/1068

Specifically, the invention also relates to compounds of the formula I in which the radicals X independently of one another are thio or sulfonyl or, in the second line, sulfinyl, R _{1 is} 4-position halogen with atomic number 19 to 35, such as chlorine, or nitro and R is 6-position trifluoromethyl or R, 3-position tri fluorine thy i, 2-position liiederalkylsulfonyl "with up to 4 carbon atoms, such as ethylsulfonyl, or 2- or 4-position halogen with atom number 19 to 35, such as chlorine, and R ₉ 5-position trifluoromethyl or R, -2-position nitro or 3-position halogen with atomic number 19 to 35, such as chlorine, and R ₉ denotes 4-position trifluoromethyl and R ~ denotes hydrogen.

The invention relates very specifically to compounds of the formula I in which R, 3-position trifluoromethyl and R ₉ 5-position trifluoromethyl or R ₁ 3-position trifluoromethyl and R ₉ 4-position chlorine or R ^ 3-position chlorine and R "4- Trifluoromethyl in position and R "denotes hydrogen, the radicals X are thio or, in particular, if Ri is 3-position trifluoromethyl and R _{9 is} 4-position chlorine, also for sulfinyl or above

all sulfonyl "can stand."

In particular, the invention relates to: The compounds of the formula I mentioned in the examples.

The new ⁵ BG-Dithiacyclohexen-l ^ -dicarboxylic acid-

N-ary! Imide "can" be produced by methods known per se will. "" - '■ "■ ■ - ■ ■ ·

For example, kah ^: can proceed in such a way that a 3,6-dithiacyclohexene-2-carboxy "carboxylic acid anilide is used

general formula II

^R l

^x S _n ^ CONH - ^ ^> . (II)

wherein X, R ₁ and R .. have the meanings given, or a suitable functional carboxy derivative thereof is cyclized.

Suitable functional derivatives of carboxylic acids, the Formula II are e.g. anhydrides, such as anhydrides with hydrohalic acids, e.g. acid chlorides or bromides, with carboxylic acids, such as lower alkanoic acids, e.g. mixed anhydrides with acetic acid or pivalic acid, or with half-esters of carbonic acid, e.g. mixed anhydrides with phenyl or 2,2,2-trichloro- or 2,2,2-tribromoethyl carbonate, or especially esters, such as lower alkyl esters, of the same.

The cyclization can be carried out in a manner known per se, for example by gentle heating, for example to 50-150 ⁰ C, preferably to the reflux temperature of the reaction mixture, advantageously in an inert solvent such as a lower aliphatic carboxylic acid, for example in acetic acid, an anhydride of a lower aliphatic Carboxylic acid, for example in acetic anhydride, or a preferably aromatic or araliphatic hydrocarbon, for example in benzene, toluene or a xylene, or, starting from carboxylic acids and esters of the formula II, also in a lower alkanol, for example in methanol, ethanol, a propanol or a butanol , if necessary with removal of

lating water of reaction and / or in the presence of catalytic! Agents based on anhydrides of the formula II, for example basic condensing agents, e.g. pyridine, and ex- * ned of carboxylic acids of the formula II of dehydrating agents.

But you can also proceed in such a way that you get a maleic acid-N-arylamide of formula III

Y ₂ -CH ₂ -CH ₂ - S

(HD,

wherein one of the radicals Y, and Y ₀ , especially Y, »is a reactive esterified hydroxyl group and the other, especially Y ₀ , is a free mercapto group or, in particular, is in metal salt form and R _{1, R 0 and R 0 have} the meanings given , cyclized intramolecularly.

A reactive esterified hydroxyl group is, for example, one with an inorganic acid such as Hydrohalic acid, e.g. with hydrogen chloride, bromine or hydrogen iodide acid, or in the second line with an organic sulfonic · acid, e.g. with benzene, p-toluene, p-bromobenzene, methane, " Ethane or ethene sulfonic acid, esterified hydroxyl group. '

A mercapto group present in metal salt form is, for example, a group of the formula - SM, in which M is an alkali metal atom, e.g. lithium, sodium or potassium.

509826/1066

The intramolecular cyclization can in the usual, in particular take place in the manner known from the literature for analogous reactions, for example in an inert solvent, such as an alkanol, e.g. in ethanol, butanol or amyl alcohol, a dialkyl sulfoxide, e.g. in dimethyl sulfoxide, a N.N-dialkyl alkanoic acid amide, e.g. in N, N-dimethylformamide, or in hexamethylphosphoric triamide. It is advantageous to work with the exclusion of oxygen, e.g. under an argon or nitrogen atmosphere, using the dilution principle, e.g. in dilute solution, and if necessary with increased, e.g. Boiling, tempera door.

For example, in a preferred embodiment there is under argon by means of a dilution attachment very slowly a solution of the mercaptan to be cyclized in absolute Add amyl alcohol to a boiling suspension of potassium carbonate in anhydrous amyl alcohol.

In obtained S.ö-Dithiacyclohexen-1.Z-dicarbon-

Acid-N-arylimides can be used in the context of the definition of the end products Introduce, convert or split off substituents.

_{For example, halogen R 1} and / or R _{2 can be} exchanged for trifluoromethyl in the usual manner in the compounds obtained, for example by reaction with trifluoroiodomethane in the presence of a metal such as copper powder, advantageously in an inert solvent such as pyridine, dimethylformamide or Acetonitrile works. Man

5098-26 / 1068

2456363

■ · JLJL ■ · ■

but can also be converted into trifluoromethyl groups, for example by reaction with sulfur tetrafluoride, and / or methyl groups R ^ and / or R ~, for example by reaction with antimony trifluoride, in the usual way in the compounds obtained, optionally containing oxo groups functionally modified, for example esterified, carboxyl groups. Can furthermore be iodine, bromine or Chlor.R-, R ₉ and / or R "by means of, for example, potassium (hydrogen) fluoride, for example in dimethylformamide or Di.methylsulfoxid, if necessary in the presence of a catalyst such as antimony tri- or -pentafluorid , replace with fluorine.

Furthermore, one can free in compounds obtained

and functionally modified carboxyl groups R 1 into one another convert. .

Functionally modified carboxyl groups, such as esterified or amidated carboxyl groups or cyano groups, can in the usual way, e.g. by hydrolysis, preferably in the presence of strong bases or strong acids, such as of Alkali metal hydroxides or carbonates, e.g. of potassium or sodium hydroxide or carbonate, or of mineral acids, e.g. from hydrochloric or hydrobromic acid, sulfuric acid or phosphoric acid, are converted into free carboxyl groups. If desired, one can hydrolyze carbamoyl groups Add oxidizing agents such as nitrous acid.

Free or esterified carboxyl groups can also be converted into amidated carboxyl groups in the usual way, e.g. by reacting with ammonia or nitrogen

6 & 9S26 / 1Q66

atom containing at least one hydrogen atom and optionally dehydration of the intermediate Ammonium salt, e.g. with phosphorus pentoxide.

Unsubstituted carbamoyl groups can be converted into cyano groups in the usual way, e.g. by dehydration, preferably by reaction with chloroform and a base, such as sodium or potassium hydroxide, in the presence a quaternary ammonium salt such as benzyltrimethylammonium chloride or with phosphorus pentoxide.

Free carboxyl groups can be esterified in the usual way, for example by reaction with a corresponding one Alcohol, advantageously in the presence of a catalyst, such as boron trifluoride etherate or an acid, such as a mineral acid, e.g. sulfuric acid or hydrochloric acid, or in the presence of a water-binding agent such as Dicyclohexylcarbodiimide, or by reaction with a corresponding diazo compound, e.g. a diazoalkane. The esterification can also be esterified by reacting a salt of the acid, e.g. the sodium salt, with a reactive one Alcohol, e.g., a halide such as a chloride.

Free carboxyl groups can, for example, also be converted into acid halide or anhydride groups in the usual way e.g. by reacting with halides of phosphorus or sulfur, such as thionyl chloride, phosphorus pentachloride or phosphorus tribromide, or with acid halides, such as Chloroformic acid esters. The acid anhydride or halide

$ 09826/1006

2456883

groups can then in the usual way, by reacting with. corresponding alcohols, if desired in the presence of acid-binding agents, such as organic or inorganic -Bases, or with ammonia or amines in esterified or amidated Carboxyl groups are transferred.

Obtained 3, o-dithiacyclohexene-l ^ -dicarboxylic acid-N-arylimide, where X stands for thio, one can add to the S-oxides' Oxidize (sulfoxides) or S-dioxides (sulfones).

The oxidation to the sulfoxides or sulfones can be carried out in be carried out in a manner known per se, e.g. by implementation, with an S-oxidizing agent such as hydrogen peroxide, peracids, in particular peracetic acid, perbenzoic acids or phthalic monoperacids, which can also be substituted, e.g. by halogen atoms, chromic acid, potassium permanganate, hypohalites, Halogenates, perhalates, e.g. periodates, or nitric acid, nitrous gases and the like, or electrolytically. In these implementations is obtained at lower temperatures, especially with good cooling, or when using only one molar equivalent of the "oxidizing agent, E.g. of sodium perjodate or peracetic acid, the sulfoxides, while with heating and / or use of at least 2 molar equivalents of the oxidizing agent, e.g. of m-chloroperbenzoic acid, the sulfones are obtained.

S-oxides obtained can be classified as S-dioxides oxidize. This oxidation can be carried out in a manner known per se take place, e.g. v / ie in the above-described oxidation leading to the dioxides.

EftQAOE / 1Dßß

S-oxides obtained can lead to the corresponding S-unsubstituted ones Compounds of the formula I are reduced, for example, with a reducing agent such as nascent. Hydrogen, e.g. zinc and mineral acid, such as hydrochloric acid, or e.g. with sulfites or hydriodic acid.

The reactions mentioned can optionally be carried out simultaneously or in succession and in any order be performed.

The reactions mentioned are carried out in the usual manner in the presence or absence of dilution, condensation and / or catalytic agents, at reduced, ordinary or elevated temperature, optionally in the closed Vessel carried out.

Depending on the process conditions and starting materials, salt-forming end products may be obtained in free form or in the form of their salts, which can be converted into one another or into other salts in the usual way. So get acidic end products, e.g. those - in which a hydroxyl or carboxyl group is present, in free form or in the form of their salts with bases. Obtained free acidic compounds can in the usual way, e.g. by reacting with appropriate basic agents, into the salts with bases, especially in therapeutically usable salts with bases, e.g. salts with organic amines, or metal salts are converted. as Metal salts are mainly alkali metal salts or alkaline earth metal salts, such as sodium, potassium, magnesium or CaI

609826/1068

- ciuasalze into consideration .. From the salts can be in usual Way, e.g. by reacting with acidic agents, the free compounds release.

These and other salts, e.g. picrates, can also be used to purify the new compounds e.g. the free compounds are converted into their salts. As a result of the close relationships between the new connections in Free form and in form, their salts are in the preceding and following · under the free compounds meaningful and expediently, if appropriate, also to understand the corresponding salts. Salts of compounds of formula I are therefore also an object of the invention.

The invention also relates to those embodiments of the process, according to which one obtainable as an intermediate product at any stage of the process Connections runs out and 'the missing procedural steps carries out or the process is stopped at any stage or forms a starting material under the reaction conditions or a reaction component, optionally in the form of a salt, racemate, isomer or optical antipode begins.

So you can preferably use a Sjo-dithiacyclohexene-l ^ -dicarboxylic acid ester, e.g. di-lower alkyl ester, or anhydride, e.g. chloride, bromide or anhydride of the formula IV

B09826 / 1066

(IV),

where X has the meaning given, and this with an aniline of the general formula V

wherein R,, R ^ and R "have the meanings given, or condense with a salt thereof. This forms an intermediate a 3,6-dithiacyclohexene-2-carboxy-carboxylic acid anilide of the formula II, which can be used as a crude reaction mixture and, according to the invention, with elimination of water cyclized.

The reaction described above is carried out in the usual VJeise, for example by the reactants, advantageously in an inert solvent such as an alkanol, for example in methanol, ethanol, a propanol or a butanol, a lower aliphatic carboxylic acid, for example in acetic acid, or in a, preferably aromatic or araliphatic hydrocarbon, eg benzene, toluene or xylene, to say the least, for example to 20-100 ⁰ C, if necessary with removal by distillation of the reaction water, heated.

50 9 826 / 10β'β

SUBSCRIBED

But you can also use a maleic acid-N-arylimide of the formula VI

(VI),

with a compound of the formula VII

Y ₂ - CH ₂ CH ₂ - Y ₂

react, in which "R ₁ , R 2, R-, Y- and Y _{2 have} the meanings given above for the intramolecular cyclization of compounds of the formula III. A maleic acid-N-arylimide of the formula III, which according to the invention The reaction can be carried out in a manner analogous to that given above for the cyclizations of compounds of the formula III.

The new connections can, depending on the choice the starting materials and working methods in the form of one or more of the possible isomers, e.g. as positional isomers or mixtures thereof and / or, depending on the number of asymmetric carbon atoms, as optical antipodes, racemates or as mixtures of racemates.

Isomer mixtures obtained, such as mixtures of positional isomers and / or mixtures of racemates can be based on the

B09 82B / 106S

SUFFICIENT

Physico-chemical differences between the constituents are separated into the pure isomers or racemates in a known manner for example by chromatography and / or fractional crystallization.

Obtained racemates can be according to known Me-r break down methods into the optical antipodes, for example by recrystallization from an optically active solvent, with the help of microorganisms. or by reacting a free carboxylic acid with one with the racemic compound Salt-forming optically active base and separation of the salts thus obtained, for example on the basis of their different solubilities, into the diastereomers; from these the antipodes can then be more appropriately acted upon Funds are released. Optically active bases that are particularly common are e.g. (-) - brucine, (+) - quinidine, (-) - quinine, (+) - Cinchonine, (+) - Dehydroabietylamine, (+) - and (-) - Ephedrine. "(+) - and (-) - l-phenylethylamine or their N-mono- or dialkylated Derivatives. It is advantageous to isolate the more effective of the two antipodes.

. The starting materials are known or, if they are new, can be prepared by methods known per se will.

The 3,6-dithiacyclohexene-2-carboxy-carboxylic acid anilides mentioned as starting materials of the formula II and functional carboxylic acid derivatives thereof can be obtained, for example

50982 5/1066

the j by adding an optionally S-mono- or S, S-dioxydated Sjö-Dithiacyclohexen-l ^ -dicarboxylic acid anhydride with an aniline of the formula V in the usual, in particular in the one for this implementation already indicated, condensed manner and.the resulting carboxylic acid of the formula II, if desired, in the customary manner functionally modified, e.g. esterified. .

The anilines mentioned as starting materials of the general Formula V-- can be produced in turn, for example by the usual reduction of the corresponding nitro compounds, e.g. with iron and a mineral acid such as hydrochloric acid, ' or with sulfided sodium borohydride, or by introducing one or more of the substituents R,, R ~ and / or Ro into corresponding anilines or acetanilides and optionally, e.g. hydrolytic, cleavage of the N-acetyl group. Included For example, chlorine and bromine atoms can be introduced Reaction with the corresponding halogen, advantageously in the presence of a metal halide, such as iron (III) chloride, or Chlorine e.g. also by means of N- * chlorosuccinimide, lower alkyl, lower alkyl sulfonyl and lower alkanoyl groups by reaction with corresponding lower alkyl, lower alkyl sulfonic acid or Lower alkanoyl halides or acid anhydrides in the presence of catalysts, such as metal halides, e.g. of aluminum chloride, or bromide, and a nitro group R. by nitration, e.g. by means of nitric acid / sulfuric acid. For the preparation of anilines of the formula V, however, the above for the optional mutual conversions of the registration

B0 9 82 B / 10 6S

measured compounds listed reactions used by, for example, in suitable anilines or the corresponding nitro compounds in the usual, e.g. in the there specified, exchanges existing chlorine or bromine for fluorine, methyl groups or carboxyl groups in trifluoromethyl groups transferred, chlorine or bromine with potassium (hydrogen) fluoride, e.g. in dimethyl sulfoxide or dimethylformamide, if necessary converted into fluorine in the presence of antimony halides or halogen, e.g. by means of triethyltin hydride, replaced by hydrogen and optionally reduced the nitro group.

The maleic acid N-arylimides mentioned as starting materials of the formula VI can be prepared starting from the corresponding maleic anhydrides in a manner analogous to that for 3, 6-Dithiacycloliexen-l, 2-dicarboxylic acid-N-arylimide starting from 3, o-Dithiacyclohexen-l ^ -dicarboxylic acid anhydride given above.

The pharmacologically acceptable compounds of

The present invention can be used, for example, for the manufacture of pharmaceutical Preparations are used which contain an effective amount of the active ingredient together or in admixture with Inorganic or organic, solid or liquid, pharmaceutically acceptable carriers that are suitable for enteral, parenteral. or topical administration. Preferably, tablets or gelatine capsules are used which contain the active ingredient together with diluents, e.g.

509826/10 * 6

Lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, lubricants, e.g. silica, talc, Stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol; Tablets also contain binding agents, e.g. magnesium aluminum silicate, Starches, such as corn, wheat, rice or arrowroot starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose and / or polyvinylpyrrolidone, and, if desired, disintegrants, e.g., starches, agar, alginic acid or a salt of it, such as sodium alginate, enzymes of the binders and / or Erausemischungen, or adsorbents, colorants, flavorings and sweets. Injectable preparations are preferably isotonic aqueous solutions or suspensions, Suppositories or ointments, primarily fat emulsions or suspensions. Pharmacological drugs can be sterilized and / or auxiliary materials, e.g. preservatives, stabilizers, wetting and / or emulsifying agents, solubilizers, Salts for. Regulation of the osmotic pressure and / or buffer included. The present pharmaceutical Preparations which, if desired, can be further pharmacologically valuable substances can be processed in a manner known per se, e.g. by means of conventional mixing, Granulating or coating processes, produced and containing from about 0.1% to about 75%, in particular from about 1% to about 50% of the active ingredient. .

The following examples serve to illustrate the invention. Temperatures are given in degrees Celsius.

e λ ö ö ^ K J 1 Ü fi ß>

example 1

18.8 g of 3, o-pithacyclohexene-l ^ -dicarboxylic acid anhydride were together with 19.6 g of 5-amino-2-chloro ~ benzotrifluoride in 200 ml of ethanol and 10 ml of acetic acid heated to reflux for 2 hours. After cooling the reaction mixture to 0 ° crystallized the 3, ö-dithiacyclohexene-1,2-dicarboxylic acid-N- (4-chloro-3-trifluoromethyl) -phenyl-imide in the form of yellow crystals with a melting point of 163-165 °.

Example 2

18.8 g of S.o-dithiacyclohexene-1-4 -dicarboxylic acid anhydride and 19.6 g of 3TAmino-4-chloro-benzo-trifluoride were suspended in 200 ml of acetic acid and refluxed for 6 hours. To Cooling to room temperature, the orange-colored solution was poured into ice water and the precipitate formed was filtered off.

The moist crude product was recrystallized from ethanol / dioxane. Pure S.ö-Dithiacyclohexen-l ^ - is obtained in this way. dicarboxylic acid-N- (2-chloro-5-trifluoromethyl) -phenyl-imide in the form of bright yellow crystals with a melting point of 203-204 °.

Example 3

In a manner analogous to that described in Example 1 starting from S.o-dithiacyclohexene-l ^ -dicarboxylic anhydride and

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4-chloro-2-trifluoromethyl-aniline the S.ö-Dithiacyclohexen-l ^ - dicarboxylic acid N- (4-chloro-2-trifluoromethyl) phenylimide of m.p. 209-210 ° produced.

Example 4

34 g of 3, o-dithiacyclohexene-1,2-dicarboxylic anhydride and 32 g of 3-chloro-4-trifluoromethyl aniline were dissolved in a mixture of 80 ml of acetic acid and 80 ml of ethanol and heated to 80 ° for 4 hours. After cooling, the 3,6-dithiacyclohexene-l ₎ 2-dicarboxylic acid N- (3-chloro-4-trifluoromethyl) phenylimide with a melting point of 184 ° -186 ° crystallized out.

Example 5

In a manner analogous to that described in Example 1, starting from S ^ -dithiacyclohexene-l ^ -dicarboxylic acid anhydride and 3,5-bis-trifluoromethyl-aniline, 3,6-dithiacyclohexene-1,2-dicarboxylic acid-N- (3,5-bis-trifluoromethyl) -phenyl-imide of m.p. 124-125 °.

Example 6

In a manner analogous to that described in Example 1, starting from 3,6-dithiacyclohexene-1,2-dicarboxylic acid anhydride and 3,5-dichloro-aniline the 3, o-dithiacyclohexene-l ^ -dicarboxylic acid-M- (3,5-dichloro) -phenyl-imide of m.p. 196-198 °.

509828/1088.

Example 7

18.8 g of 3, o-dithiacyclohexene-1,2-dicarboxylic acid anhydride were together with 16.2 g of 2,6-dichloroaniline in 50 ml of ethanol and refluxed 0.5 ml of acetic acid for 50 hours. After cooling to room temperature, 30 ml of ethanol were distilled off. The reaction solution was cooled to 0 ° and the precipitate was filtered off. The crude product was recrystallized from acetone / acetic acid The 3,6-dithiacyclohexene-1,2-dicarboxylic acid N- (2,6-dichlorophenyl) imide was thus obtained in the form of yellow crystals with a melting point of 208-209 °. "

Example 8

18.8 g of 3, o-dithiacyclohexene-l ^ -dicarboxylic acid anhydride were together with 17.2 g of 4-chloroanthranilic acid in 120 ml of acetic acid suspended and refluxed for 24 hours. After cooling to room temperature, the yellow precipitate was filtered off with suction and washed with 50 ml of ethanol. The raw product was recrystallized from ethanol. The 3,6-dithiacarboxylic acid N- (2-carboxy-5-chloro) -phenyl-imide was obtained in this way of m.p. 226-228 °.

Example 9

In a manner analogous to that described in Example 2, starting from 3,6-dithiacyclohexene-1,2-dicarboxylic acid anhydride

50982S / 1D68

and 2-ethylsulfonyl-5-trifluoromethyl-aniline the 3,6-dithiacyclo hexene-1,2-dicarboxylic acid N- (2-ethylsulfonyl-5-trifluoromethyl) phenylimide of m.p. 245 °.

. Example 10

In a manner analogous to that described in Example 1 starting from S ^ G-dithiacyclohexene-l ^ -dicarboxylic anhydride and 2-chloro <-5-propionyl-aniline, 3,6-dithiacyclohexene-1,2-dicarboxylic acid-N- (2-chloro-5-propionyl) -phenylimide of m.p. 182 °.

Example 11

In a manner analogous to that described in Example 2, starting from 3, o-dithiacyclohexene-l ^ -dicarboxylic anhydride and 2-carbomethoxy-5-chloro-aniline-the 3,6-dithiacyclohexene-1,2-dicarboxylic acid-N- (2-carbomethoxy-5-chloro) -phenyl-imide produced from m.p. 230 °.

Example 12

In a manner analogous to that described in Example 1 starting from 3,6-dithiacyclohexene-1,2-dicarboxylic acid anhydride and 2-nitro-4-trifluoromethyl-aniline, S.o-dithiacyclohexene-1 ^ -dicarboxylic acid-N- (2-nitro-4-tri fluorine thyl) -phenylimid vom M.p. 179 ° produced.

(ü λ ö ώ 6 C J 1 £ 1 ft S

Example 13

In a manner analogous to that described in Example 1, starting from 3,6-dithiacyclohexene-1,2-dicarboxylic anhydride and 3-nitro-2-toluidine 3,6-dithiacyclohexene-1,2-dicarboxylic acid-N -. (2-methyl-5-nitro) -phenylimide of m.p. 210-212 °.

Example 14

In a manner analogous to that described in Example 1. starting from 3,6-dithiacydohexene-1,2-dicarboxylic anhydride and 2,4-dichloro-6-methyl-aniline 3,6-dithiacyclohexene-1,2-dicarboxylic acid-N- (2,4-dichloro-6-methyl) -phenylimide produced of m.p. 174 °.

Example 15

73 g of S ^ -dithiacyclohexene-l ^ -dicarboxylic acid-N- (4-chloro-3-tri £ luoromethyl) -phenyl-imide were dissolved in 1000 ml of methylene chloride and the solution was cooled to 0 °. Then were 162 g of m-chloroperbenzoic acid, dissolved within 4 hours, in 1700 ml of methylene chloride, added dropwise. The reaction temperature thereby became kept at 0 ° by external cooling. The reaction solution was then initially for 24 hours at 0 °

SUBMITTED I

and then stirred for a further 48 hours at room temperature. Then the solution was suction filtered and the piltrate successively washed with 1000 ml of water and three times with 1000 ml of a '2 η-thiosulfate solution. The last step was long repeated until the starch iodine sample was negative. Then 500 ml of 1N sodium hydroxide solution and 1000 ml of water were used again washed and the solution dried over sodium sulfate. The supernatant liquid was evaporated in vacuo, the residue was recrystallized from 300 ml of methylene chloride and the crystals sucked off. The crude product was recrystallized twice from ethyl acetate and twice from tetrahydrofuran until the crystals were pure by thin-layer chromatography.

The S ^ -Dioxo-Sjö-dithiacyclohexenl ^r , 2-dicarboxylic acid-N- (4-chloro-3-trifluoromethyl) -phenylimide, ie the monosulfone of So-dithiacyclohexene-l ^ -dicarboxylic acid-N- (4-chloro) was obtained -3-trifluoromethyl) phenylimides, of m.p. 227-228 °.

Example 16

7.7 g of 3,6-dithiacyclohexene-1,2-dicarboxylic acid N- (4-chloro-3-trifluoromethyl) phenylimide were dissolved in 300 ml of glacial acetic acid and the solution was cooled to 10 °. To the cooled solution a solution of 40.7 g of 30% strength hydrogen peroxide in 100 ml of acetic acid was then added dropwise over the course of 32 hours. The reaction solution was stirred for a further 2 hours at room temperature and then poured into water. the

500825 / Ί08-6

jvi Submitted I.

aqueous phase was extracted with chloroform, the organic Phase washed with water 2N sodium thiosulphate solution and again with water, dried over sodium sulphate, suction filtered and the Evaporated filtrate. The crude product obtained was chromatographed on 500 g of silica gel. The first with a liter of one Mixture of 19 parts of chloroform and 1 part of methanol gave eluted fractions after evaporation and crystallization Ethanol / water the pure bis-sulfoxide of 3,6-dithiacyclohexene-1,2-dicarboxylic acid-N- (4-chloro-3-trifluoromethyl) -phenyl-imide, i.e. 3,6-dioxo-3,6-dithiacyclohexene-1,2-dicarboxylic acid N- (4-chloro-3-trifluoromethyl) phenylimide, of m.p. 203-204 °.

Example 17

In a manner analogous to that described in one of the examples Ί, '2 and starting from Sjo-dithiacyclohexene-l ^ - dicarboxylic anhydride and 3,4-dichloroaniline, 3,6-dithiacyclo hexene-1,2-dicarboic acid-N- (3,4-dichloro) -phenyl-imide of melting point 205-205.5 °.

Example 18

In an analogous manner to one of Examples 1, 2 and

As described, starting from ~ 5, 6-dithiacyclohexene-1,2-dicarboxylic anhydride and 2,4,5-trichloroaniline, the 3,6-dithiaeyclohexenedicarboxylic acid N- (2,4,5-trichloro) -phenyl-imide of m.p. 195-196 °.

509825/1066

Example I ₉

In a manner analogous to that described in one of Examples I ₃ 2 and 4, starting from 3j6-dithiacyclohexene-1,2-dicarboxylic anhydride and 4-bromo-3-chloro-aniline, 3,6-dithiacyclohexene-1 _J 2-dicarboxylic acid was obtained. N- (4-bromo-3-chloro) -phenyl-imide of m.p. 233-234.

Example 20

In a manner analogous to that described in one of Examples 1, '2 and 4, starting from 3 * 6-dithiacyclo- · hexene-1,2-dicarboxylic anhydride and 3-chloro-p-toluidine das 3,6-Dithlacyclohexene-1,2-dicarboxylic acid Nr- (3-chloro-4-methyl) -phenyl-imide from m.p. 155-156.

Example 21

In a manner analogous to that described in one of Examples 1, 2 and 4, starting from 3j6-dithiacyclohexene-1,2-dicarboxylic acid anhydride and 4-chloro-m-nitroaniline, 3,6-dithiacyclohexene-1 _J 2-dicarboxylic acid-N- (4-chloro-3-nitro) -phenyl-imide with a melting point of 185.

Example 22

Tablets with a content of 0.05 g of the active substance are made as follows:

-3C-

REJECTED]

"" "" ■ 1

Ingredients (for 1000 tablets):

S.o-dithiacyclohexene-l ^ -dicarboxylic acid-

N- (4-chloro-3-trifluoromethyl) phenylimide. 50.0 g

Milk sugar 67.7 g

Corn starch 30.0 g

Stearic acid. 1.0 g

Magnesium stearate 'At, 0 g

Silica gel 0.3 g

purified water q.s.

All in powder form! Substances are sifted individually through a sieve of 0.5 mm mesh size and mixed thoroughly. A paste for granulating the active ingredient is prepared from one third of the starch and a suitable amount of water, one third of the lactose and another third of the starch, optionally with the addition of a further amount of water. The granules are dried for 16 hours at 35, driven through a sieve with 2.2 mm mesh size and mixed with the remainder of the starch, with stearic acid, magnesium stearate and silica gel and made into tablets of 0.15 g (7 mm 0) , which have a score have, pressed.

The recommended daily dose for about
Warm-blooded animals weighing 75 kg is 200-2000 mg in 1 to 3
Single doses.

Claims (1)

Claims 1 »Process for the production of new S.ö-Dithiacyelohexe: 1,2-dicarboxylic acid-N-arylimides of the general formula (D ' wherein the radicals "X are independently thio, sulfinyl or sulfonyl, R ^ means halogen, trifluoromethyl, lower alkyl, lower alkoxy, lower alkanoyl, lower alkylsulphonyl, optionally functionally modified carboxyl, hydroxy or nitro, B. ^ means halogen, lower alkyl or trifluoromethyl; and Ro Means halogen or hydrogen, and their salts, characterized in that a 3,6-dithiacyclohexene-2-carboxy-carboxylic acid anilide of the general formula II ^L \> CONH , X / ScOOH (II), 5 0 "9 826/1066 ORIGINAL INSPECTED in which R ₁ , R 2, Ro and X have the meanings given, or a suitable functional carboxy derivative thereof or a maleic acid-N-aryldide of the formula III -CH ₂ - S (III). wdrin one of the radicals Y, and Y ₂ , especially Y-. »A reactive esterified hydroxyl group and the other, especially Y ^, a free or in particular present in metal salt form mercapto group and R ,, R" and R "have the meanings given, cyclized intramolecularly, and if desired, in compounds obtained in the context of Definition of the end products introduces, converts or splits off substituents and / or separates the obtained isomer mixtures into the pure isomers and / or splits the obtained racemates into the pure antipodes and / or converts the obtained salts into the free compounds or the obtained free compounds into their salts. 2. Process for the preparation of new 3,6-dithiacyclohexene-1,2-dicarboxylic acid-N-arylimides of the general formula I. 509825/1068 24568S3 (D where X is thio, R, halogen, trifluoromethyl, lower alkyl, Lower alkanoyl, lower alkylsulphonyl, optionally functionally modified carboxyl, hydroxy or nitro denotes, Rp is halogen, Is lower alkyl or trifluoromethyl and R ~ is halogen or Means hydrogen, and its salts, characterized in that a 3,6-dithiacyclohexene-2-carboxy-carboxylic acid anilide, of the general formula II. NyCONH- ^ ^ (II) .X / NCOOH wherein R,, R2, R-, "and X have the meanings given, or a suitable functional carboxy derivative thereof is cyclized and, if desired, introduces, converts or substitutes in compounds obtained within the scope of the definition of the end products split off and / or obtained isomer mixtures into the pure 'Isomers separates and / or obtained racemates into the pure Antipodes split and / or obtained salts in the free Compounds or free compounds obtained converted into their salts. 3. The method according to claim 1, characterized in that one of an acid of the formula II or an anhydride or Ester of the same goes out. 4. The method according to claim 2 _5, characterized in that one starts from an acid of the formula II or an ester thereof. 5. The method according to claim I _5, characterized in that one starts from a compound of the formula III in which Y is a chlorine, bromine or iodine atom and Y «denotes the mercapto group optionally present in alkali metal salt form. 6. The method according to any one of claims 1, 3 and 5, characterized characterized in that one starts from a compound obtainable as an intermediate product at any stage of the process and carries out the missing process steps or terminates the process at any stage or a starting material under the reaction conditions or forms a reaction component, optionally in the form of a salt, racemate, isomer or optical antipodes. cn Q ft 05/1068 7. The method according to any one of claims 2 and 4, characterized characterized in that one starts from a compound obtainable as an intermediate product at any stage of the process and carries out the missing process steps or terminates the process at any stage or a starting material or forms a reaction component under the reaction conditions optionally in the form of a salt, racemate, isomers or optical antipodes. 8, method according to any one of claims 1, 3 and 6, characterized characterized in that one has an acid of the formula II in the form of a by reacting a 3, o-dithiacyclohexene-ljZ-dicarboxylic acid anhydride of formula IV ■ (IV), wherein X has the meaning given, and an aniline of Formula V R wherein R ^, R ^ ^{un <} i Ro have the meanings given, or a salt of the same obtainable crude reaction mixture is used. , .. ' 509825/1066 9. The method according to any one of claims 2, 4 and 7, characterized in that an acid of the formula II in the form of a by reacting a S ^ -dithiacyclohexene-l ^ -dicarboxylic acid anhydride of formula IV (IV), wherein X has the meaning given, and an aniline of the formula V _R ' ² (V), in which R 1, R ₂ and R "have the meanings given, or a salt of the same available crude reaction mixture is used. ^r ■ 10. _ The method according to any one of claims 1, 5 and 6, characterized characterized in that a compound of the formula III is obtained in the form of a by reaction of a maleic acid-N-arylimide of the formula R, (VI), 509825/1066 , and a compound of the formula Y ₂ -CH ₂ -CH ₂ -Y ₂ , (VII), in which R., R ₂ , Ro, Yi and Y _{2 have} the meanings given, uses the crude reaction mixture obtainable. 11. The method according to any one of claims 1, 3, 5, 6, 8 and 10, characterized in that compounds of the formula I in which the radicals X are independent of one another. Thio, sulfinyl or sulfonyl, R, halogen up to atomic number 35, lower alkyl, lower alkoxy, lower alkoxycarbonyl, lower alkylsulfonyl, lower alkanoyl, carboxyl, trifluoromethyl, hydroxy or nitro, R ^ is halogen up to atomic number 35, lower alkyl or trifluoromethyl and R _{3 is} hydrogen or Chlorine means producing. 12. The method according to any one of claims 2, 4, 7 and 9, characterized in that compounds of the formula I in which X is thio, R, door halogen up to atomic number 35, lower alkoxycarbonyl, lower alkyl, lower alkylsulfonyl, carboxyl, trifluoromethyl, nitro or Means lower alkanoyl with 1 to 4 carbon atoms, R _{2 stands} for halogen up to atom number 35 or trifluoromethyl and R ~ signifies hydrogen or chlorine. 13. The method according to one of claims 1, 3, 5, 6, 8 and 10, characterized in that compounds of the formula I ₁ in which the radicals X are independently thio, sulfinyl or sulfonyl, R, halogen with atom number 19 -35, optionally with a lower alkanol with 1 to 4 carbon atoms esterified carboxyl, lower alkyl or lower alkoxy with 1 to 4 each 509825/1066 C atoms, Tri fluorine thy 1 or Nitro means, R means chlorine, methyl or trifluoromethyl and R ~ denotes hydrogen or chlorine, manufactures. 14. The method according to any one of claims 2, 4, 7 and 9, characterized in that compounds of the formula I in which X is thio, R _{1 is} halogen with atom number 19-35, optionally carboxyl esterified with a lower alkanol with 1 to 4 carbon atoms, lower alkyl with 1 to 4 carbon atoms, or lower alkylsulfonyl with 1 to 4 carbon atoms, 'means trifluoromethyl or nitro, R _{2 means} chlorine or trifluoromethyl and R ~ means hydrogen or chlorine. 15. The method according to any one of claims 1, 3, 5, 6, 8 and 10, characterized in that compounds of the formula I in which the radicals X are independently thio, sulfinyl or sulfonyl, R, chlorine, bromine, trifluoromethyl, nitro, methyl, methoxy, carboxyl, methoxy or ethoxycarbonyl, methyl or ethy1sulfonyl R ₂ denotes chlorine, methyl or trifluoromethyl and R ″ denotes hydrogen or, if R ₂ denotes chlorine or methyl, can also denote chlorine. 16. The method according to any one of claims 2, 4, 7 and 9, characterized in that; compounds of the formula I in which X is thio, R, chlorine, bromine, trifluoromethyl, nitro, methyl, carboxyl, methoxy- or ethoxycarbonyl, methyl or ethylsulfonyl, R _{2 is} chlorine or trifluoromethyl 509825/1066 and R "represents hydrogen or, if R _{2 represents} chlorine, can also represent chlorine, produces. 17. The method according to any one of claims 1, 3, 5, 6, 8 and 10, characterized in that compounds of the formula I in which the radicals X are independently thio, sulfinyl or sulfonyl, R, halogen with atomic number 19-35 , Lower alkyl with up to 4 carbon atoms or nitro in 2-, 3- or 4-position, lower alkoxy with up to 4 carbon atoms, lower alkylsulfonyl with up to 4 carbon atoms, lower alkoxycarbonyl with up to 5 carbon atoms in 2 Position or trifluoromethyl in the 3-position, R _{2 is} chlorine, Tr i fluorine thy 1 or methyl in A-, 5- or 6-position and Ro is hydrogen or, if R, 2-position _{lower alkyl and R 2} 5- Permanent chlorine or R, 4-position halogen and R «means 6-position chlorine, also for 3-position chlorine or, if R, 2-position lower alkoxy and Ra 5-position chlorine or methyl or R-2-position carboxyl and R _fi 6-position chlorine means, can also stand for 4-position chlorine, produces. 18. The method according to any one of claims 2, 4, 1 and 9, characterized in that compounds of the formula I in which X is thio, R _{1 is} chlorine, nitro or methyl in the 2-, 3- or 4-position, carboxyl, Methoxycarbonyl or ethylsulfonyl in the 2-position, trifluoromethyl or ethoxycarbonyl in the 3-position or bromine in the 4-position, R ₂ denotes chlorine or trifluoromethyl in the 4-, 5- or 6-position or methyl in the 4-position 509825/1066 and R is hydrogen or, if R2 is 5-position chlorine and R _{1 is} 2-position methyl or R _{2 is} 6-position chlorine and R, is 4-position chlorine, also for 3-position chlorine or, if R- is 2-position carboxyl and R _? 6-position chlorine means, can stand for 4-position chlorine, produces. 19. The method according to any one of claims 1, 3, 5, 6, 8 and 10, characterized in that compounds of the formula I ₁ wherein X is thio, R _{1 is} chlorine, nitro or methyl in 2-, 3- or 4- Position, methoxy, methoxycarbonyl or ethylsulfonyl in the 2-position, trifluoromethyl or ethoxycarbonyl in the 3-position or bromine in the 4-position, R _{9 is} chlorine or trifluoromethyl in the 4-, 5- or 6-position or methyl in the 4- or 5-position and R "is hydrogen or, if R" is 5-position chlorine and R _{1 is} 2-position methyl or R _{2 is} 6-position and R _{1 is} 4-position chlorine, also for 3-position chlorine or, if R, 2- Methoxy and R "means 5-position methyl, can stand for 4-position chlorine. 20. The method according to any one of claims 1, 3, 6, 8 and 10, characterized in that compounds of the formula I in which the radicals X are independently thio, sulfinyl or sulfonyl, R 2-, 3- or 4- Permanent halogen with atom number 19-35 or 3-position lower alkoxycarbonyl with up to 5 carbon atoms, lower alkanoyl with up to 5 carbon atoms or trifluoromethyl and R _{2 is} 6-position chlorine or R _{1 is} 2- or 4-position lower alkyl with up to to 4 carbon atoms, 2-position carboxyl, 3-position halogen with atomic number 509825/1066 Ϊ9-35 or 4-position tri fluorine thy 1 and R _{2 means} 5-position chlorine or R, 2- or 3-position nitro, 2-position lower alkoxycarbonyl with up to 5 carbon atoms or trifluoromethyl or 3-position halogen with atom number 19-35 or trifluoromethyl · and R ^ is 4-position chlorine or R is 2-position lower alkoxy and R is 5-position methyl and R_ is hydrogen or, if R _{1 is} 2-position methoxy and R _{2 is} 5-position methyl, also for 4-position chlorine or if R _{1 is} 2-position methyl and R _{2 is} 5-position chlorine, it can also stand for 3-position chlorine. 21. The method according to any one of claims 2, 4, 7 and 9, characterized in that compounds of the formula I in which X is thio, R _{2 is} 6-position chlorine and R, 4-position bromine or nitro, 2- or 3-position - Chlorine, 2-position carboxyl or 3-position ethoxycarbonyl or trifluoromethyl or R ₂ 5-position chlorine and R, 2-position methyl, 4-position methyl or trifluoromethyl, 3-position chlorine or 2-position carboxyl or R 4- Standing chlorine and R _{1 is} 2-position methoxycarbonyl, trifluoromethyl or nitro or 3-position chlorine, trifluoromethyl or nitro "and R _{3 is} hydrogen or, if R _{2 is} 6-position chlorine and R _{1 is} 3-position chlorine or 2-position Carboxyl means 4-position or, if R _{2 is} 5-position chlorine and R _{1 is} 2-position methyl, is 3-position chlorine. 509825/1066 22. The method according to any one of claims 1, u, 5, 6, 8 and 10, characterized in that compounds of the formula I in which the radicals X are independently thio, sulfinyl or sulfonyl, R “6-position chlorine and R, 4-position bromine or nitro, 2- or 3-position chlorine or 3-position ethoxycarbonyl, methyl or trifluoromethyl or R ₂ 5-position chlorine and R ^ 2-position methyl, 4-position methyl or trifluoromethyl, 3- Standing chlorine or 2-position carboxyl oder_R ₂ 4-position chlorine and R, 2-position methoxycarbonyl, trifluoromethyl or nitro or 3-position chlorine. Trifluoromethyl or nitro or R _{1 is} 2-position methoxy and R _{2 is} 5-position methyl and R "is hydrogen or, if R" is 6-position chlorine and R., 3-position chlorine or methyl or R _{2 is} 5-position methyl and R. is methoxy in 2 positions, for 4 position or, if R «is 5 position chlorine and R is 2 position methyl, is 3 position chlorine. 23. · The method according to any one of claims I ₁ 3, 5, 6, 8 and 10, characterized in that compounds of the formula I in which the radicals X are independently thio, sulfinyl or sulfonyl, R ^ 4 halogen with Atom number 19-35 or nitro and R ₂ 6-position trifluoromethyl or R- 3-position trifluoromethyl, 2-position lower alkylsulfonyl with up to 4 carbon atoms or 2- or 4-position halogen with atom number 19-35 and R ₂ 5- Trifluoromethyl or R-2 position 509825/1066 Nitro or 3-position halogen means atom number 19-35 and 4-position trifluoromethyl and R _{3 represents} hydrogen. 24. The method according to any one of claims 2, 4, 7 and 9, characterized in that compounds of the formula I in which X is thio, R _{1 is} 4-position chlorine and R «is 2-position trifluoromethyl or R _{1 is} 6-position chlorine and R "is 3-position trifluoromethyl and R" is hydrogen. 25. The method according to any one of claims 1, 3, 5, 6, 8 and ΙΟ, characterized in that compounds of the formula I in which the radicals X are independently thio, sulfinyl or. Sulfonyl ^ R., 4-position chlorine and R _{2 is} 2-position trifluoromethyl or R _{1 is} δ-position chlorine and R _{2 is} 3-position trifluoromethyl or ethoxycarbonyl and R,. Is hydrogen or R-6 is methoxy, R «is 3-position methyl and R-4 is chlorine. 26. The method according to any one of claims 1, 3, 5, 6, 8 and 10, characterized in that compounds of the formula I in which at least one of the radicals X is thio and the other can also be sulfinyl or sulfonyl, R, 3 - Trifluoromethyl in position and R _{2 in} 5 position in trifluoromethyl or R _{1 in} 3 position in trifluoromethyl and R _{2 in} 4 position in chlorine or R _{1 in} 3 position in chlorine or R _{2 in} 4 position in trifluoromethyl and R ~ in hydrogen. 509825/1066 27.: The method according to any one of claims 2, 4, 7 and 9, characterized in that compounds of the formula I in which X is thio, R _{1 is} 3-position trifluoromethyl and R _{2 is} 4-position chlorine or 5-stända.ges Trifluoromethyl or R is 3-position chlorine and R _{2 is} 4-position trifluoromethyl and R ^ is hydrogen. • 28. The method according to any one of claims 1, 3, 5, 6, 8 and 10, characterized in that compounds of the formula I in which radicals X are independently thio, sulfinyl or sulfonyl, R, 3-position tri fluorine thy 1 and R _{2 is} 4-position chlorine or R, 3-position chlorine and R _{2 is} 4-position trifluoromethyl and R_ is hydrogen. 29. The method according to any one of claims 1, 3, 5, 6, 8 and 10, characterized in that the 3,6-dithiacyclohexenl, 2-dicarboxylic acid N- (4-chloro-3-trifluoromethyl) phenylimide manufactures. 30. The method according to any one of claims 1, 3, 5, 6, 8 and 10, characterized in that the 3,6-dithiacyclohexene-1,2-dicarboxylic acid-N- (3,5-bis-trifluoromethyl) -phenylimide manufactures. 509825/1066 3l. Method according to one of claims 1, 3, 5, 6, 8 and 10, characterized in that the 3,6-dithiacyclohexenl ^ -dicarboxylic acid-N-O-chloro- ^ trifluoromethyl) phenylimide manufactures. 32 .. The method according to any one of claims 1, 3, 5, 6, 8 and 10, characterized in that the 3,3-dioxo-3,6-dithi'acyclohexen-l ^ -dicarboxylic acid-N- (4-chloro-3-trifluorinethyl) -phenylimide manufactures. 33. The method according to any one of claims 1, 3, 5, 6, 8 and 10, characterized in that the 3,6-dioxodithiacyclohexene-1,2-dicarboxylic acid N- (4-chloro-3-trifluoromethyl) phenylimide manufactures. 34. The method according to any one of claims 2, 4, 7 and 9,
characterized in that the So-dithiacyclohexene-l ^ - dicarboxylic acid-N- (4-chloro-3-trifluoromethyl) -N-phenylimide is prepared. 35. The method according to any one of claims 2, 4, 7 and 9,
characterized in that the S.ö-dithiacyclohexene-l.idicarboxylic acid-N- (3,5-bis-trifluoromethyl) -phenylimide is produced. 36. The method according to any one of claims 2, -4, 7 and 9,
characterized in that the so-dithiacyclohexene-l ^ - dicarboxylic acid-N- (3-chloro-4-trifluoromethy]) - i) henylimide is prepared. fin9825 / 1Q66 37. The method according to any one of claims 1, 3, 5, 6, 8, 10, 11, 13, 15, 17, 19, 20, 22, 23, 25, 26 and 28-33, characterized in that that one produces the new compounds in the form of the pure isomers. 38. The method according to any one of claims 2, 4, 7, 9, 12, 14, 16, 18, 21, 24, 27 and 34-36 ,. characterized in that the new compounds are prepared in the form of the pure isomers. 39. The method according to any one of claims 1, 3, 5, 6, 8, 10, 11, 13, 15; 17, 19, 20, 23, 25, 26 and 28-33, characterized in that the new compounds are in the form of the pure optical antipodes. 40. The method according to any one of claims 2, 4, 7, 9, 12, 14, 16, 18, 21, 24, 27 and 34-36, characterized in that one establishes the new connections in the form of the pure optical antipodes. . 41. The method according to any one of claims 1, 3, 5, 6, 8, 10, 11, 13, 15, 17, 19, 20, 22, 23, 25, 26, 28-33, 37 and 39, dadurcl characterized in that the new compounds are made in free form. 42. The method according to any one of claims 2, 4, 7, 9, 12, 14, 16, 18, 21, 24, 27, 24-36, 38 and 40, characterized in that the new compounds are produced in free form. • B09825 / 1066 43. The method according to any one of claims 1, 3, 5, 6, 8, 10, 11, 13, 15, 17, 19, 20, 22, 23, 25, 26, 28-33, 37 and 39, thereby characterized in that the new compounds are prepared in the form of their salts. . 44. The method according to any one of claims 2, 4, 7, 9, 12, 14, 16, 18 ,. 21, 24, 27, 34-36, 38 and 40, characterized in that the new compounds are prepared in the form of their salts. (is j So-Dithiacyclohexen-l ^ -dicarboxylic acid-il-arylj'mide of the general formula - (D in which the radicals X independently of one another are thio, sulfinyl or sulfonyl, R ^ is halogen, tri fluorine thy 1, 'lower alkyl, nrederalkoxy, lower alkanoyl, lower alkylsulfonyl, optionally functionally modified carboxyl, hydroxy or nitro, R _{2 is} halogen, lower alkyl or trifluoroethyl and R _{3 is} halogen or hydrogen, and their salts. 3,6-dithiacyclohexene-1,2-dicarboxylic acid-N-arylimide the general formula ¹ 509825/106 6 Il _{wherein X denotes fhio, R 1} denotes halogen, trifluoromethyl, lower alkyl, lower alkanoyl, lower alkylsulfonyl, optionally functionally modified carboxyl, hydroxy or nitro, R _£ denotes halogen, lower alkyl or trifluoromethyl and R ₃ denotes halogen or hydrogen, and their salts. 47. Compounds of the formula I in which the radicals X independently of one another are thio, sulfinyl or sulfonyl, R ^ denotes halogen up to atomic number 35, lower alkyl, lower alkoxy, lower alkoxycarbonyl, lower alkylsulfonyl, lower alkanoyl , carboxyl, trifluoromethyl, hydroxy or nitro, R ₂ represents halogen up to atomic number 35, lower alkyl or trifluoromethyl and R _{3 represents} hydrogen or chlorine. 48. Compounds of the formula I in which X denotes thio, R denotes halogen up to atomic number 35, lower alkoxycarbonyl, lower alkyl, lower alkylsulfonyl, carboxyl, trifluoromethyl, nitro or _{lower alkanoyl with 1 to 4 carbon atoms, R 2} denotes halogen up to atomic number 35 or Trifluoromethyl and R ~ is hydrogen or chlorine. 509825/1066 - 49 -. 2456363 In which the radicals X is 49. Compounds of formula I are independently ₁ thio, SuIfinyl or sulfonyl, R is halogen with an atomic number of 19-35, such as chlorine or bromine, optionally with a lower alkanol having 1 to 4 carbon atoms esterified carboxyl lower alkyl having _s 1 to 4 carbon atoms, lower alkylsulfonyl with 1 to 4 carbon atoms, trifluoromethyl or nitro means, R _? Is chlorine or trifluoromethyl and R is hydrogen or chlorine. "50. Compounds of the formula I in which X is thio, R _{1 is} halogen with atom number 19-35, such as chlorine or bromine, optionally carboxyl esterified with a lower alkanol with 1 to 4 carbon atoms, lower alkyl with 1 to 4 carbon atoms , Lower alkylsulfonyl with 1 to 4 carbon atoms, trifluoromethyl or nitro, R "denotes chlorine or trifluoromethyl and R ^ denotes hydrogen or chlorine. 51.. Compounds of the formula I in which the radicals X, independently of one another, denote thio, sulfinyl or sulfonyl, R ₁ denotes chlorine, bromine, trifluoromethyl, nitro, methyl, methoxy, carboxy, methoxy or ethoxycarbonyl, methyl or ethyisulfonyl, R ₂ denotes chlorine, methyl or trifluoromethyl denotes and R ₃ denotes hydrogen or, if R ₂ denotes chlorine or methyl, can also denote chlorine. 52. Compounds of the formula I in which X is thio, R- ^ is chlorine, bromine, trifluoromethyl, nitro, methyl, carboxyl, methoxy- or ethoxycarbonyl, methyl or ethylsulforiyl, R ₂ ■ $ 09825/1066 NAOHGEREtOH-r] Chlorine or Tri fluorine thy means 1 and R ^ is hydrogen or, if R _{2 is} chlorine, it can also mean chlorine. 53 .. Compounds of the formula I in which the radicals X independently of one another are thio, sulfinyl or sulfonyl, R, halogen with atom number 19-35, lower alkyl with up to 4 carbon atoms or nitro in 2-, 3- or 4- Position, lower alkoxy with up to 4 carbon atoms, lower alkylsulfonyl with up to 4 carbon atoms, lower alkoxycarbonyl with up to 5 carbon atoms in the 2-position or trifluoromethyl in the 3-position, R _{2 means} chlorine, trifluoromethyl or methyl in 4- , 5- or 6-position and R ~ is hydrogen or, if R, is 2-position lower alkyl and R _{2 is} 5-position chlorine or R _{1 is} 4-position halogen and R _{2 is} 6-position chlorine, also for 3-position Chlorine or, if R _{1 is} 2-position lower alkoxy and R is 5-position chlorine or methyl or R, 2-position carboxyl and Ry is 6-position chlorine, can stand for 4-position chlorine. 54. Compounds of the formula I in which X is thio, R-. Chlorine, nitro or methyl in the 2-, 3- or 4-position, methoxy, methoxycarbonyl or ethylsulfonyl in the 2-position, trifluoromethyl or ethoxycarbonyl in the 3-position or bromine in the 4-position, R _{2 is} chlorine or trifluoromethyl in the 4-, 5- or 6-position or methyl in 4- or 5-position and R "denotes hydrogen or if R ₂ denotes 5-position chlorine and R, 2-position methyl or R ₂ denotes 6-position and R. 4-position chlorine , also for 3-position chlorine or, if R, 2-position methoxy and R _{2 is} 5-position methyl, can stand for 4-position chlorine. 509825/1066 naghqereichtI 55 .. Compounds of the formula I in which the radicals X are independently thio, sulfinyl or sulfonyl, R. 2-, 3- or 4-position halogen with atom number 19-35 or 3-position lower alkoxycarbonyl with up to 5 carbon atoms , Lower alkanoyl with up to 5 carbon atoms or trifluoromethyl and R2 denotes 6-position chlorine or R denotes 2- or 4-position lower alkyl with up to 4 carbon atoms. 2-position carboxyl, 3-position halogen with atom number 19-35 or 4-position trifluoromethyl and R "means 5-position chlorine or R- 2- or 3-position nitro, 2-position lower alkoxycarboxylic with up to 5 carbon atoms or Trifluoromethyl or 3-position halogen with atomic number 19-35 or trifluoromethyl and R _{2 is} 4-position chlorine or R, 2- _{position lower alkoxy and R 2 is} 5-position methyl and R "is hydrogen or, if R. is 2-position methoxy and R ₂ denotes 5-position methyl, can also stand for 4-position chlorine or, if R, 2-position methyl and R ₂ denotes 5-position chlorine, can also stand for 3-position chlorine. 56. Compounds of the formula I in which X is thio, R ₉ ^! 6-position chlorine and R ₁ 4-position bromine or nitro, 2- or 3-position chlorine, 2-position carboxyl or 3-position etho- ■ I xycarbonyl or trifluoromethyl or R _? 5-hour aethocycarbo nyl or trifluoromethyl or R ₂ 5-position chlorine and R ₁ 2-position methyl, 4-position methyl or trifluoromethyl, 3-position chlorine or 2-position carboxyl or R ₂ 4-position chlorine i 509825/1066 "« "■ ■ 2456883 or R ^ is 2-position methoxycarbonyl, trifluomethyl or nitro or 3-position chlorine, trifluoromethyl or nitro and R «is hydrogen or, if R ~ is 6-position chlorine and R, 3-position chlorine or 2-position carboxyl, for 4-position o4, if R «denotes 5-position chlorine and R ₁ denotes 2-position methyl, represents 3-position chlorine. 57. Compounds of the formula I in which the 'radicals X are independently thio, sulfinyl or sulfonyl, R «is 6-position chlorine and R, 4-position bromine or nitro, 2- or 3-position chlorine or 3-position ethoxycarbonyl, Methyl or Tri fluorine thy I or R ₂ 5-position chlorine and R- 2-position methyl, 4-position methyl or trifluoromethyl, 3-position chlorine or 2-position carboxyl or R „4-position chlorine and R, 2-position Methoxycarbonyl, trifluoromethyl or nitro or 3-position chlorine, trifluoromethyl or nitro or R. 2-position methoxy and R ^ 5-position methyl and ¹ R ₃ stands for hydrogen or, if R. 6-position chlorine and R, 3- Standing chlorine or methyl or R "means 5-position methyl and R, 2-position methoxy, for 4-" position or, if R _{9 is} 5-position chlorine and R _{1 is} 2-position methyl, stands for 3-position chlorine. 58. Compounds of the formula I in which the radicals X independently of one another are thio, sulfinyl or sulfonyl, R, 4-position Halogen with atom number 19-35 or nitro and R “6-position trifluoromethyl or R, 3-position trifluoromethyl, 2-position lower alkylsulfonyl with up to 4 carbon atoms or 2- or 4-position 509825/1066 . - 53 - Halogen with atom number 19-35 and R ₂ denotes 5-position trifluoromethyl or R, 2-position nitro or 3-position halogen with atom number 19-35 and R ₂ denotes 4-position trifluoromethyl and R ₃ denotes. Hydrogen stands. 59. Compounds of the formula I in which X is thio, R- ^ is 4-position chlorine and R _{2 is} 2-position trifluoromethyl or R ^ is 6-position chlorine and R _{2 is} 3-position trifluoromethyl and Ro is hydrogen. 60. Compounds of the formula I in which at least one of the radicals X is thio and the other can also be sulfinyl or sulfonyl, R, 4-position chlorine and R "2-position trifluoromethyl or R ₁ 6-position chlorine and R" 3- Trifluoromethyl or ethoxycarbonyl in the position and R "is hydrogen or R" is 6-position methoxy, R "is 3-position methyl and R _{3 is} 4-position chlorine. 61. Compounds of the formula I in which X is thio, R, 3-position trifluoromethyl and R _{2 is} 4-position chlorine or S-position trifluoromethyl, or R, 3-position chlorine and R _{2 is} 4-position trifluoromethyl and R ₃ Means hydrogen. 62. Compounds of the formula I in which the radicals X independently of one another are thio, sulfinyl or sulfonyl, R, 3-position trifluoromethyl and R 4-position chlorine or 5-position trifluoromethyl or R, 3-position chlorine and R ₂ 4- Permanent trifluoromethyl means and R ₃ means hydrogen. 63. 3,6-Dithiacyclohexene-1,2-dicarboxylic acid N- (4-chloro-3-trifluoromethyl) phenylimide. 64. S.o-Dithiacyclohexene-1-4 -dicarboxylic acid-N-O.S-bis-trifluoromethyl) -phenylimide. 65. 3,6-Dithiacyclohexene-1,2-dicarboxylic acid N- (3-chloro-4-trifluoromethyl) phenylimide. "" * ^, ö-Dioxo-j ^ ö-dithiacyclGhexene-l ^ -. dicarboxylic acid- (4-chloro-5-trifluoromethyl) -phenylimide. 67. 3,3-Dioxo-3,6-dithiacyclohexene-1,2-dicarboxylic acid-N-. (4-chloro-3-trifluoromethyl) phenylimide. 68. The in one of claims 45, 47, 49, 52, 53, 55, 57, 58, 60, 62, 66 and 67 claimed compounds in the form of the pure isomers. 69. The in one of claims 46, 48, 50, 51, 54, 56, 59, 61 and 63-65 claimed compounds in the form of the pure isomers. 70. The in one of claims 45, 47, 49, 51, 52, 53, 55, 57, 58, 60, 62 and 66-68 claimed compounds in free form. Λ Λ Α 71 The compounds claimed in any one of claims 46, 48, 50, 52, 54, 56, 69, 61, 63-65 and 69 in the form of their salts. 72. Pharmaceutical preparations containing one of the claims 45, 47, 49, 51, 52, 53, 55, 57, 58, 60, 62, 66-68 and 70 claimed compounds together with a pharmaceutical carrier material. 73. Pharmaceutical preparations contain one of the claims 46, 48, 50, 52, 54, 56, 59, 61, 63-65, 69 and 71 claimed compounds together with a pharmaceutical carrier material. 50982 5/1066 ' ORIGINAL INSPECTED