DE2132175A1 - New heterocyclic compounds and processes for their preparation - Google Patents

Description

CIBA-CiKICiY AG BA ^ EL (SWITZERLAND)

Case 4-7101 / 1 + 2 / =

Germany

New heterocyclic compounds and processes for their preparation.

The invention relates to new heterocyclic compounds of the formula

(D,

where J ?, and ίίρ are independent; from each other hydrogen atoms., Alkyl or alkoxy radicals, Hcilogonatomcj, Trifluorir.ethylgruppen

109883 / 196Ί

8AO ORIGINAL

or nitro groups or together alkylenedioxy radicals, R and Rk each represent a monovalent or together a divalent one, the sulfur atoms separated by at most 4 carbon atoms, optionally substituted hydrocarbon or acyl radical and together can also stand for a direct bond, R ₁ - and R, - independently of one another represent hydrogen atoms or lower alkyl radicals or together represent a radical of the formula - (CHp) - in which η stands for a small integer, preferably 1 or 2, and processes for their preparation.

Alkyl radicals R 1 and R p are in particular lower Alkyl radicals. The term "lower" in connection with alkyl radicals and groups and compounds derived from these radicals, such as alkylidene, alkylene, alkenyl, alkoxy or alkanoyl radicals, alkanols, alkanecarboxylic acids, etc. - is here and in the following used to identify those residues that contain no more than 6 and preferably 1-4 carbon contain atoms. Lower alkyl radicals are e.g. methyl, ethyl, propyl or isopropyl radicals or straight or branched ones, Butyl, pentyl or hexyl radicals bound in any position.

Alkoxy radicals R, and R _? .sind especially lower alkoxy groups, such as methoxy, ethoxy, propoxy, isopropoxy or butoxy groups. Halogen atoms R ₁ and R ₂ are, for example, fluorine, bromine or especially chlorine atoms. Are alkylenedioxy radicals

109883/1961

preferably lower alkylenedioxy radicals, e.g. methylenedioxy, Ethylenedioxy or 1,2-propylenedioxy radicals.

Hydrocarbon radicals R and R. can be aliphatic radicals Be of character or aromatic residues. Residues of aliphatic character are those residues, whose free valence comes from a carbon atom that is not part of an aromatic system.

Hydrocarbon radicals of aliphatic character are, for example, aliphatic, cycloaliphatic, cyclo- ■ aliphatic-aliphatic and araliphatic hydrocarbon radicals.

Monovalent aliphatic hydrocarbon radicals are, for example, lower alkyl radicals, such as those mentioned above, or lower alkenyl radicals, such as allyl or methallyl radicals.

Monovalent cycloaliphatic hydrocarbon radicals and cycloaliphatic parts of cycloaliphatic aliphatic Hydrocarbon radicals are polycyclic ^ e.g. bi- or tricyclic hydrocarbon radicals, such as 1-adamantyl radicals, or monocyclic radicals, for example optionally lower-alkylated monocyclic radicals with 3-7 j in particular 5-7 ring members, such as cyelopropyl, cyclopentyl, cyclohexyl and cycloheptyl radicals.

Aliphatic parts of monovalent cycloaliphatic

aliphatic and araliphatic hydrocarbon radicals

109883/1981

are in particular lower alkyl radicals, such as those mentioned above. Examples of monovalent cycloaliphatic-aliphatic marriage Hydrocarbon residues are cyclopentyl-methyl-, 2-cyelohexyl-ethyl- and cycloheptyl-methyl residues.

Monovalent araliphatic hydrocarbon radicals are in particular phenyl lower alkyl radicals, such as phenylethyl and benzyl residues.

Monovalent aromatic hydrocarbon radicals are in particular phenyl and α- and .8-naphthyl radicals.

If R and R ₂ together form a divalent hydrocarbon radical, this radical preferably has an aliphatic character and is, for example, a cycloaliphatic, but above all an aliphatic or araiiphatic hydrocarbon radical. First and foremost, alkylene and alkylidene radicals should be mentioned, in particular lower alkylene and alkylidene radicals such as methylene, ethylene, ethylenene, 1,2-propylene, 1,5-propylene, 2,2-propylidene, 2 , 2-butylidene, 2,5-butylene and 1,4-butylene radicals. Also to be mentioned are aryl, especially phenyl-substituted, especially lower alkylene and alkylidene radicals derived, for example, from the alkylene and alkylidene radicals mentioned, such as benzylidene, 2-phenylethylidene, 1-phenylethylidene, phenylethylene and l- Phenyl-propylene (1,3) radicals. Divalent cycloaliphatic hydrocarbon radicals are preferably derived from the cycloalkyl radicals mentioned,

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ßAD ORIGINAL

especially from residues with 5-7 ring members. In these The free valences are mainly derived from adjacent carbon atoms or from the same carbon atom the end. For example, Cyeloheptyliden-, Cyelohexyliden-,

Cyclopentylidene, 1,2-cyclohexylene and 1,2-cyclopentylene radicals called.

Any substituents of the hydrocarbon radicals IU and R _{2 that may be present} . are, for example, halogen atoms such as those indicated. Hydroxy groups, which can also be etherified or esterified, for example with lower alkyl groups, such as those mentioned, or with lower alkanoyl groups, for example acetyl groups, or benzoyl groups, and also free or functionally modified carboxyl groups.

Functionally modified carboxyl groups are, for example, cyano groups or, in particular, esterified ones or arnidated carboxyl groups. Esterified carboxyl groups are primarily those groups in which the alcohol component is of the monovalent aliphatic, cycloaliphatic or araliphatic hydrocarbon radicals mentioned derives. The ester-forming alcohols are preferably lower alkanols, cycloalkanols or phenylalkanols, which can also have other substituents, e.g. methanol, ethanol, propanols, butanols, hexanols, cyclopentanols, Cyclohexanols or phenyl lower alkanols, such as

1098837196t

Benzyl alcohols or phenylethanols, those in the phenyl ring also substituted by radicals of the type of radicals R and R. could be.

In the amidated carboxyl groups (carbamyl groups), the amide nitrogen atom can be unsubstituted, mono- or disubstituted, for example by aliphatic hydrocarbon radicals such as alkyl, alkenyl or alkylene radicals, which can also be interrupted by heteroatoms such as oxygen, nitrogen or sulfur atoms . Particularly suitable amide substituents are: lower alkyl, alkenyl and alkylene radicals, such as the _{f mentioned} or corresponding radicals interrupted by the heteroatoms mentioned, such as lower alkoxyalkyl, alkylmerc'aptoalkyl or mono- or dialkylaminoalkyl radicals, or oxa -, aza or thiaalkylene radicals, such as optionally C-lower alkylated "jj-oxa-, 3-aza- or 5-thiapentylene- (l, 5), 5-methyl-, 3-ethyl-3-aza-hexylene- (l, 6), 3-azahexylene- (l, 6) or ^ -Methyl- ^ - azaheptylene- (2,6), or phenylalkyl radicals which are unsubstituted or, above all, substituted in the phenyl radical as indicated for the phenyl lower alkano-Ie The term C-lower alkylated here, as in the following, means that the radical in question is substituted on C atoms by lower alkyl radicals, such as those mentioned, and in particular by C 1 -C 6 -alkyl radicals.

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The amino group of the amides is. accordingly in particular a free, mono- or di-lower alkylated amino group, or an optionally C-lower alkylated, especially C 1 -alkylated pyrrolidinor, piperidino, morpholino, thiomorpholino, piperazino, N ¹ -lower alkylpiperazino or N ¹ - ( Hydroxy lower alkyl) piperazino group.

Substituents of aromatic rings in the radicals PU and R ₂ are above all lower alkyl and alkoxy groups, in particular the halogen atoms mentioned, especially fluorine, chlorine or bromine atoms, and trifluoromethyl groups.

Acyl radicals R and R ₂ are acyl radicals derived from carboxylic acids. The carboxylic acids can be derived from radicals of aliphatic character or from aromatic radicals, with any rings present being able to be carbocyclic or heterocyclic. For example, aliphatic, preferably saturated, carboxylic acids, especially lower alkanecarboxylic acids, such as acetic acid, propionic acid and butyric acid, are suitable. Also mentioned are, for example: unsaturated lower fatty acids, such as acrylic, methacrylic and crotonic acid, cycloaliphatic carboxylic acids which contain, for example, the monovalent cycloaliphatic radicals mentioned, such as cyclopentane, cyclohexane, cycloheptane arboxylic acid or cyclohexylacetic acid, araliphatic carboxylic acids, in particular phenyl lower alkane carboxylic acids

10 9 8 8 3/1961

■ - 8 -

such as phenylacetic acid or cc-phenylpropionic acid, aromatic, e.g. carbocyclic carboxylic acids, such as benzoic acid or α- or β-naphthalenecarboxylic acid, or aromatic heterocyclic acids Carboxylic acids, especially monocyclic carboxylic acids of this type, which are e.g. a nitrogen, oxygen or contain sulfur atom, such as pyridine-2-carboxylic acid, pyridine-4-carboxylic acid, thiophene-5-carboxylic acid, - thiophene-2-carboxylic acid, Furan-J-carboxylic acid or purane-2-carboxylic acid, but above all pyridine-3-carboxylic acid.

The acyl radicals PL · and Rj can also be derived from the Derive carbonic acid or a derivative thereof and represent, for example, esterified or amidated carboxyl groups, in particular for the esterified and amidated mentioned above as substituents of the hydrocarbon radicals R- and R ^ Carboxyl groups.

If R ^ and R. together form a bisacyl radical, then Particularly suitable for this purpose are bisacyl radicals derived from dicarboxylic acids of aliphatic character. Acids of this type are in particular aliphatic dicarboxylic acids, such as alkanedicarboxylic acids, e.g. succinic acid, malonic acid or oxalic acid. Also, for example, are cyeloalkane dicarboxylic acids to mention, especially 1,2-diacids, which are derived from the above-mentioned cycloalkyl radicals, such as Cyclopentane-1,2-dicarboxylic acid and cyelohexane-1,2-dicarboxylic acid.

109883/1961

The acyl radicals R and R ₂ can also carry substituents, in particular the radicals mentioned _{as substituents on the hydrocarbon radicals R and R 2.} For example, the aromatic, carbocyclic or heterocyclic rings, for example phenyl, naphthyl, pyridyl, thienyl or puryl, can be replaced by lower alkyl radicals, for example those mentioned above, in particular methyl, ethyl, propyl or butyl, lower alkoxy radicals, e.g. those mentioned above, especially methoxy or ethoxy, halogen atoms, especially chlorine or bromine atoms, or trifluoromethyl groups. be substituted one, two, three or more times.

The acyl radicals of aliphatic character can, for example by halogen atoms, such as fluorine, bromine or especially chlorine atoms, or hydroxyl groups or by amino groups be substituted. Amino groups are unsubstituted, monosubstituted or, in particular, disubstituted amino groups. Substituents of the amino groups are mainly aliphatic hydrocarbon radicals, e.g. those above as substituents on the carbamyl groups mentioned radicals, which are also substituted, e.g. substituted by hydroxyl groups, and / or by heteroatoms, such as Oxygen, sulfur or nitrogen atoms can be interrupted *. The amino groups are accordingly, for example, alkylamino, such as Methylamino, ethylamino or propylamino, mono- or dialkylamino-alkylamino, Dialkylamino, such as dimethylamino or

109883/1961

- · ίο -

Diethylamino-, or optionally C-lower alkylated, in particular C ^ -alkylated pyrrolidino, piperidino, morpholine, l-J?

Thiomorpholine, piperazino, N'-lower alkyl piperazino or N ¹ - (hydroxy lower alkyl) piperazino groups.

The carbonyl groups of the acyl radicals R-, and R ^ can also be functionally modified and for example. Irninocarbonyl, hydrazinocarbonyl, hydroxyiminoearbonyl groups or represent acetalized carbonyl groups. R ^ and R ^ radicals with such modified carbonyl groups are e.g. also amidino or hydroxyamidino groups.

Lower alkyl radicals R ₁ - and R ^ are, for example, ^ methyl or

Ethyl residues.

The new compounds have valuable pharmacological properties Properties, especially an effect against viruses, as can be shown, for example, in animal experiments. For example, they show on the intraperitoneally infected mouse with herpes simplex virus (oral type or genitalis type) in doses of I25-5OO mg / kg p.o. a pronounced antiviral effect. the 'Antiviral effect also occurs when the treatment occurs 48 hours after infection. The new connections act against the herpes simplex virus even when applied locally, as e.g. in the cornea test on rabbits when applied a 0.2 liter solution of the compounds in glycol shows

109883/1961

The compounds can therefore be used as agents against viral diseases Find use, in particular against diseases caused by the viruses mentioned.

However, the new compounds are also valuable intermediates for the preparation of other useful ones Substances, especially of pharmacologically active compounds.

Compounds of the formula are particularly valuable because of their good anti-viral action

(II),

wherein R ₁ and R _{2 have} the meanings given, R-, 'and Rh' independently of one another mean a monovalent araliphatic, cycloaliphatic ^ cycloaliphatic-aliphatic or, above all, aliphatic hydrocarbon radical or an acyl radical which is different from an araliphatic, cyeloaliphatic or in the first place Line aliphatic, or aromatic carboxylic acid or from the carbonic acid

109883/1961

re or one of its derivatives and can also be functionally modified, or R 'and R ^ together represent a direct bond or an araliphatic, cycloaliphatic or, above all, aliphatic divalent hydrocarbon radical which separates the two sulfur atoms by one or two carbon atoms, the mentioned radicals R 'and R ^ also by halogen atoms, especially fluorine or chlorine atoms, hydroxyl groups, lower alkoxy groups, carboxyl groups, lower alkoxycarbonyl groups, possibly lower alkylated carbamyl groups, amino groups, especially alkylamino, dialkylamino, such as dimethylamine or diethylamino, or optionally C-lower alkylated, in particular C 1 -alkylated pyrrolidino, piperidino, morpholino, thiomorpholine, piperazino, N'-lower alkylpiperazino or N ¹ - (hydroxy-lower alkyl) piperazino groups, and R 'and Rg lower alkyl radicals or, in particular, represent hydrogen atoms.

formula

Particularly noteworthy are connections of the

CH-S-R "

(III),

CH-S-R "

wherein R ₁ 'and R ₃ ¹ independently of one another are methyl, methoxy

10 9 8 8 3/1961 ^

or trifluoromethyl groups, fluorine, chlorine or hydrogen atoms or together represent methylenedioxy or ethylenedioxy groups, PU "and R ₁₁ " independently of one another are carbamyl or amidino radicals, lower alkyl radicals, for example one of the lower alkyl radicals mentioned above, preferably methyl, ethyl, n -Propyl, isopropyl, η-butyl or tert. Butyl, Phenylnlederalkylreste, for example phenethyl or benzyl residues, phenyl lower alkanoyl residues, e.g. Phenylacetylreste, or especially at most by hydroxyl, fluorine or especially chlorine substituted lower alkanoyl radicals, such as butyryl, propionyl or especially acetyl radicals, the phenyl radicals also by methyl, Methoxy or trifluororrriethyl groups, fluorine or

Substituted chlorine atoms and the oxo oxygen atoms of the phenyl lower alkanoyl and lower alkanoyl groups through an imino group can be replaced, or R "and Rj! together for a direct bond, a lower alkylidene radical / e.g. the 2,2-propylidene or 2,2-butylidene radical, or for a lower alkylene radical stand, which separates the sulfur atoms by 2 carbon atoms, like the ethylene, 1,2-propylene or 2,3-butylene radical and R " and R ^ for »lower alkyl radicals or especially hydrogen atoms stand.

Compounds of the formula are particularly valuable

(IV),

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where R ₁ "and R ₃ " independently of one another mean chlorine atoms, methoxy groups or hydrogen atoms or together the ethylenedioxy _{radical and R 7} and Rg independently of one another unsubstituted amidino groups, lower alkyl radicals, for example methyl, ethyl, isopropyl, n-propyl or η-butyl or especially through Hydroxy, fluorine or especially chlorine-substituted lower alkanoyl radicals, e.g. acetyl, pro

k mean pionyl or butyryl, or together for a lower one Alkylidene radical, e.g. 2,2-propylidene or 2,2-butylidene, or stand for a lower alkylene radical which separates the sulfur atoms with 2 carbon atoms, such as ethylene, 1,2-propylene or 2,5-butylene.

Particularly noteworthy are compounds of the formula IV in which R "and R" are independently chlorine atoms, Methoxy groups or hydrogen atoms or together denote the ethylenedioxy radical and R and Rq are independently of one another unsubstituted amidino groups, the acyl radicals, monocyclic, homo- or preferably heterocyclic, aromatic carboxylic acids, such as benzoyl, 4-pyridoyl and very particularly 5-pyridoyl radicals, mean, which by lower alkyl radicals, e.g. methyl, ethyl, n-propyl, isopropyl, η-butyl or tert. Butyl, lower alkoxy radicals such as propoxy, ethoxy, before but especially methoxy, halogen atoms such as fluorine, bromine or, in particular, chlorine, or trifluoromethyl groups twice or Above all, can be monosubstituted, but preferably

10 9883/1961 sad original

are unsubstituted, and especially the 2,3-bis- (nicotinoylrnercaptomethyl) -ehinoxalin the formula

3-σο-

that infected e.g. intrapei'itoneally with herpes simplex virus Mice given an oral dose of 125 mg / kg and in the cornea test shows a clear antiviral effect on rabbits when a 0.2% solution in glycol is applied.

The new compounds can be obtained by methods known per se.

The procedure is preferably such that in a compound of the formula

(V)

wherein X is a convertible into the radicals -S-R ^, and -S-Rh

Rest means and

have the meanings given,

the radicals X converted into the radicals -S-R, and -S-R ^.

X is in particular one against the radicals -S-R

and -S-Ru exchangeable radical, e.g., one reactive

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^8A0 origi _Nal

esterified hydroxy group. Reactively esterified hydroxyl groups are, for example, organic sulfonyloxy groups, such as alkanesulfonyloxy groups or arylsulfonyloxy groups, such as toluene or benzenesulfonyloxy groups, but above all halogen atoms, in particular chlorine or bromine atoms. The exchange of X for -SR ₇ and -SR ^ is preferably carried out by reaction with compounds of the formula R., SH and R ₂₁ SH or HS (RSR ^) SH, or with their tautomers or salts., Eg alkali metal, such as Sodium or potassium salts. The reaction is carried out in a customary manner, for example in the presence of acid-binding, in particular basic, inorganic or organic agents, for example alkali metal hydroxides or carbonates, such as sodium or potassium hydroxide or carbonate, or tertiary amines, for example pyridine or trimethylamine, in a solvent , for example water, methanol or ethanol, and possibly with heating.

However, X can also represent the mercapto group, for example stand. The conversion into the radicals -SR- and -SRh takes place then in particular by reaction with compounds of the formula R-Y and R ^ Y, in which Y is one through the mercapto groups means interchangeable remainder.

Stand R-, and R ^. for any substituted Acyl radicals, an exchangeable radical Y is e.g. an esterified hydroxyl group, such as a reactive

10 9 8 8 3/1961 _gAD

esterified hydroxyl group, for example one of the above, such as a chlorine atom, or a hydroxyl group esterified with a carboxylic acid, so that the compounds R., Y and R ^ Y represent carboxylic acid anhydrides. In this case, it is expedient to use pure anhydrides, that is to say compounds of the formula R, -OR, and Rk-OR ₂ , 'or R + R _2,.

If R and R ₂ stand for any substituted hydrocarbon radicals, then is an exchangeable radical

Y in particular a reactive esterified hydroxyl group, especially one of the specified. The reaction of these compounds with the compounds of the formula V, wherein X denotes the mercapto group, can be carried out in a customary manner, for example in the presence of basic agents, in particular those mentioned above, and in a solvent, e.g. one of the specified, possibly with cooling.

If R- and Rk together mean one substituted hydrocarbon radical, which separates the sulfur atoms by a carbon atom, the two radicals can

Y together also stand for an oxo group, which are also reactive can be modified. The reaction can be carried out, for example, under the conditions customary for acetal formation preferably in the presence of an acid such as an inorganic acid such as sulfuric acid or hydrogen chloride or a Lewis acid, such as zinc chloride, conveniently in the presence of a solvent,

109883/1961

e.g. an excess of the reacting ketone or aldehyde, and possibly with cooling.

FU and R ^ together mean a direct bond and X mercapto groups, the conversion of compounds of formula V into the end products according to the invention by oxidation. The oxidation takes place appropriately under mild conditions and with the usual oxidizing agents for disulfide formation, such as atmospheric oxygen, iodine, oxidizing agents Salts, such as copper (II) salts, hydrogen peroxide or Salts, such as copper (II) salts, hydrogen peroxide or Hypohalites, e.g. sodium hypochlorite.

Another process for the preparation of the new compounds, in which R, and R ^ are hydrocarbon radicals, consists in making compounds of the formula

(VI)

with compounds of the formula

H S-R 0 C

(VII) IU

0 C

10988 3/1961

or with functional derivatives thereof, where the radicals Ri-Rg have the meanings given. Functional derivatives are, for example, oximes, preferably monoximes, hydrates, ketals, acylals or bisulfite addition compounds of the diketo compound. The compounds of the formula VII can also be in tautomeric form, for example as enol ethers or enol esters _; in particular with lower alkanols and alkanecarboxylic acids, for example those mentioned above.

The. Implementation of the compounds of the formulas VI ■ and VII can be carried out in the usual way, preferably in an inert solvent such as ethanol or glacial acetic acid, expediently with heating.

In the compounds obtained, substituents can be introduced, modified or split off within the scope of the end products.

For example, free or functionally modified carboxyl groups present in the compounds obtained, such as cyano groups or esterified or aminated carboxyl groups of the type mentioned in one another according to standard methods convert.

In compounds obtained which contain free hydroxyl groups, these can be etherified. The etherification takes place in the usual way, e.g. by reaction with a reactive ester of an alkanol, preferably in the presence of a strong base, or optionally

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SAD original

with diazomethane.

Modified acyl radicals R, and R ^ can be in free Acyl groups, i.e. residues with a carbonyl function are converted, e.g. by hydrolysis, preferably in the presence of acids or bases such as those indicated. .

The reactions mentioned can be carried out in the customary manner in the presence or absence of diluents or condensation agents and / or catalytic agents at reduced, ordinary or elevated temperature, optionally in a closed vessel and / or under an inert gas atmosphere be performed. The conversion of end products into end products can also take place in any sequence.

Depending on the process conditions and starting materials the end products are in free form or in the form of their salts, which is also included in the invention. Received Free compounds with acidic groups, such as carboxylic acids, can - in the usual way, e.g. by reacting with appropriate basic agents, in the salts with bases, especially in therapeutically usable salts with bases, e.g. salts with organic amines, or metal salts. The main metal salts are Alkali metal salts or alkaline earth metal salts, such as sodium, potassium, magnesium or calcium salts, or aluminum salt: u ;,

10 98 83/1961 _ßA0

into consideration. The free compounds can be extracted from the salts in the usual way, e.g. by reacting with acidic Funds, release. Salts obtained with acids can be used in a manner known per se, e.g. with alkalis or ion exchangers be converted into the free compounds. The latter can be converted into organic ones or inorganic acids, especially those which are suitable for the formation of therapeutically useful salts win acid addition salts. Examples of such acids are: hydrohalic acids, sulfuric acids, phosphoric acids, Nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, such as formic, acetic, propionic, amber, Glycol, milk, apple, V / a, lemon, ascorbic, Maleic, hydroxyrnalic or pyruvic acid; Phenylacetic, ' Benzoic, p-aminobenzoic, anthranil, p-hydroxybenzoic, salicylic or p-aminosalicylic acid, emboxylic acid, Methanesulphonic, ethanesulphonic, hydroxyethanesulphonic, ethylene sulphonic acid; Halobenzenesulfone, toluenesulfone, naphthalenesulf onic acid or sulfanilic acid; Methionine, tryptophan, " Lysine or arginine.

These or other salts can also be used to purify the new compounds, e.g. by adding the free compounds converted into their salts, these isolated and converted back into the free compounds. In-

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follow the close relationships, between the new connections in free form and in the form of their salts are meaningful above and below under the free compounds and expediently, optionally also the corresponding salts to understand.

The new connections can, depending on the V / ahl the starting materials and working methods and depending on the number of the asymmetric carbon atoms, as optical antipodes, racemates or as isomer mixtures (Raeematgemisehe).

Isomer mixtures obtained (Raeematgemisehe) can due to the physico-chemical differences between the components in a known manner in the two stereoisomers Pure (diastereomeric) racemates are separated, for example by chromatography and / or fractionated Crystallization.

Racemates obtained can be by known methods, 'for example by recrystallization from a optically active solvent, with the aid of microorganisms, or by reacting with one with the racemic compound Optically active acid or base forming salts and separation of the salts obtained in this way, e.g. Because of their different solubilities, in the diastereomers, from which the antipodes are more suitable by action Means released can decompose. Particularly good

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Common optically active acids are e.g. the D- and L-porms of tartaric acid, di ~ o-toluyltartaric acid, malic acid, Mandelic acid, camphorsulfonic acid or quinic acid. Preferred optically active bases are e.g. brucine, strychnine, morphine, Methylamine or cc-phenylethylamine or their quaternary Ammonium bases. It is advantageous to isolate the more effective or less toxic of the two antipodes.

But it is also possible to produce pure isomers, racemates or optical antipodes by using appropriate Starting materials in the form of their pure isomers, racemates or optical antipodes starts out.

The invention also relates to those embodiments of the method, after which one of a at any stage of the process as an intermediate product and the missing process steps carries out, or in which a starting material is formed under the reaction conditions, or at where a reaction component is optionally present in the form of its salts.

In particular, the compounds of the formula V in which X is the mercapto group can be used in the form of them Use salts, especially of the alkali salts, e.g. sodium salts.

You can also form the diamino compounds of the formula VI under the reaction conditions by ent-

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Talking compounds with other nitrogen functions, e.g. nitroamino compounds or benzfuroxanes or benzfurazans, in the usual way, e.g. catalytically, such as with hydrogen in the presence of a palladium catalyst, reduced.

Furthermore, one can start from compounds of the formula V in which one of the radicals X has already been replaced by the radical -SR ^, or -S-Rk, and the other radical X, as indicated, is converted into the radical -SR ₂ or -SR .

For carrying out the reactions according to the invention, it is expedient to use those starting materials which the groups of end products especially mentioned at the beginning and especially those specifically described or emphasized Lead end materials.

The starting materials are known or can, if so they are new, produced by methods known per se

* will.

The new compounds can be used, for example, in the form of pharmaceutical preparations which they can be used in free form or, if appropriate, in the form of their salts, especially the alkali metal salts, or the therapeutically usable acid addition salts in a mixture with a pharmaceutical, for example suitable for enteral, parenteral or topical application. organic or inorganic, solid or "liquid carrier material. B ¹ Ur the formation

1098 83/196 1

of the same, such substances come into question, those with the new Compounds do not react, such as water, gelatine, Lactose, starch, stearyl alcohol, magnesium stearate, talc, vegetable oils, benzyl alcohol, gum, propylene glycols, Petroleum jelly or other known excipients. The pharmaceutical Preparations can e.g. as tablets, coated tablets, capsules, suppositories, creams, ointments or in liquid form In the form of solutions (e.g. as an elixir or syrup), suspensions or emulsions'. If applicable, they are sterilized and / or contain auxiliary substances such as preservatives, Stabilizing, wetting or emulsifying agents,. Solubilizers or salts to change the osmotic Pressure or buffer. You can also receive other therapeutically valuable substances. Pharmaceutical preparations v / earth obtained by customary methods.

The invention is illustrated in the following examples. described in more detail. The temperatures are in degrees Celsius specified.

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6j3 g of 2,3-bis (bromomethyl) -quinoxaline and 504 g Thiourea are suspended in 150 ml of ethanol. These Suspension is refluxed for 5 hours, whereby a homogeneous solution is created. After cooling, crystals precipitate, which are suction filtered and recrystallized from water will. This gives 2,5-bis- (isothiuroniummethyl) -quinoxaline-dibromide the formula

. 2HBr

CH SCMH Il
NH

from P. 214-215 ° (decomp.)

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- 27 Example 2

h, ^l [ g of 2,5-bis (mercaptomethyl) ~ quinoxaline are dissolved in 80 ml of acetone in the cold. 0.1 g of zinc chloride are added to this solution and added to the reaction mixture over a period of 1.5 hours. Introduced hydrogen chloride. Afterward
is evaporated to dryness in a water jet vacuum. Of the
Saturated soda solution is added to the residue and the mixture is extracted with methylene chloride. The methylene chloride extract
is dried and evaporated. The residue forms a crystalline mass which is dissolved in methylene chloride and chromatographed on an aluminum oxide column. With
Chloroform, crystals are eluted which, on recrystallization from methylene chloride-methanol, ^{give 1,5-dihydro-5,3-dimethyl-5H-2, 1-} l-dithiepino [5,6-b] quinoxaline of the formula

CH.

from F. 192-194 deliver.

The 2,3-bis (mercaptomethyl) quinoxaline used as a starting material in this example can be as follows will be obtained:

5 g 2,3-bis- (isothiuroniummethyl) -quinoxaline ~ di-

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8AD ORIGINAL

bromide are in 50 rnl 2-n. Sodium hydroxide solution UNTL * ^{"! / Ü} JO minutes at 80 C. The reaction mixture is heated .. _cooled} treated with activated charcoal and filtered. The Piltrat is neutralized with 2N hydrochloric acid." Here, the 2 _J 5-Bi ^s falls - ^(merca Pt ° methyl) ~ quinoxaline of the formula

j that after recrystallization from ethanol the P.

92-93 °.

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Example 5

3.0 g of 2,3-bis (mercaptomethyl) quinoxaline will be dissolved in hot methemol. In the solution heated to 60 C. air is blown through for JO minutes. Fall after cooling Crystals of 1, ^ - dihydro- ^ j ^ -dithiaphenazine of the formula

from, which after recrystallization from methylene chloride ether have the P. 164-165 °.

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3.6 g of 2,3-bis (mercaptomethyl) -quinoxaline in 70 ml 2-n. Sodium hydroxide solution and 5 ml Acetic anhydride added. The reaction mixture is shaken vigorously in an ice bath for 15 minutes. The 2,3-bis- (acetylmercaptomethyl) -quinoxaline falls the formula

crystalline. Recrystallization twice from methanol-water delivers a preparation from F. 101-102.

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- 51 Example 5

6.5 g of 2,5-bis- (bromomethyl) -quinoxaline, 4.5 g (5.55 ml) of n-butyl mercaptan and 20 g of sodium hydroxide are dissolved in a mixture of > 0 ml of water and 50 ml of methanol. The reaction mixture is stirred for 5 hours at room temperature and then refluxed for a further 15 minutes. After cooling, the 2,5-bis- (n-butylmercaptomethyl) -quinoxaline of the formula falls

from, which after recrystallization from methanol the P.

55-54 °.

109883/1961

6j5 S 2 _i 3-bis (bromomethyl) quinoxaline 2.4 g (2j2 ml) ethanedithiol and 2.0 g sodium hydroxide are dissolved in a mixture of 50 ml water and 50 ml methanol. . The reaction mixture is stirred for 50 minutes at room temperature and then refluxed for a further hour. The hot solution is filtered and the filtrate is cooled. This drops the 1 _i 5 _J 4,6-tetrahydro-2,5-dithiocino [6j7-t)] quinoxaline of the formula

from, which has the F, 200-202 ° after recrystallization from methanol.

109883/1961

7.48 2,3-bis (bromomethyl) ~ 7,8-dihydro-p-dioxino- [2., 3-g-jehinoxaline and 5.1 g of thiourea are in 200 ml Dissolved ethanol. The solution is refluxed for 5 hours. Then it is almost up to in a water jet vacuum concentrated to dryness. The residue crystallizes on cooling. The 2,3-bis- (isothiuroniummethyl) -7.8-dihydro-p-dioxino [2,3-g] quinoxaline dibromide obtained the formula

NH

- . 2HBr

CH SGNH I! NH

after recrystallization from water has the decomposition

point 188-189 °.

The 2,3-bis-

(Bromomethyl) -7,8-dihydro-p-dioxino [2,5-g] quinoxaline can can be produced as follows:

28 g of 6,7-diminO-1,4-benzodioxane

are dissolved in 1 liter of methanol and treated with 52 g of dibromodiacetyl at room temperature. A crystalline precipitate separates out after a few minutes. The reaction mixture is left to stand for a further hour, with occasional shaking. The 2,3-bis (bromomethyl) -7 _i 8-dihydro-p-

109883/1961

_ 54 -

dioxino

the formula

O λ Ν

is sucked off. After recrystallization from methylene chloride-methanol, it has the P. 209-210 ⁰ C.

109883/1961

Example 8

7 * 7 g of 2 _i 3-bis- (mercaptomethyl) -quinoxaline are in 80 ml of 2-n. Dissolved sodium hydroxide solution and added dropwise JO ml of ethyl chloroformate while cooling with ice. The reaction mixture is left to stand at room temperature overnight. The deposited precipitate is filtered off and washed with ethanol. Recrystallization of the residue from methylene chloride-hexane gives 2,3-bis (S-carbäthoxymercapto-methyl) -quinoxaline of the formula

jj ^ CH ₂ SCOC ₂ H ₅

CH ₀ SCOC ₀ H ^ 2 "2 5

from Έ. 85-86 °.

109883/1961

Example 9

7 * 5 g 2 _i 3-bis (mercaptomethyl) -ehinoxalin In 80 ml of 2-n. Sodium hydroxide solution dissolved. 30 ml of propionic anhydride are added while cooling with ice. The reaction mixture is then shaken in an ice bath for 20 minutes. The 2nd, 3-BiS- (S-propionylmercapto-methyl) -quinoxaline of the formula falls

Il · ■

CH SOOH CH

CH SCCH CH ^Δ Il ^ά ■> 0

crystalline. Recrystallization from methylene chloride-hexane gives a product with a melting point of 88 ° -89 °.

109883/1961

Example 10

27 g of 2,5-bis- (mercaptomethyl) -quinoxaline are in Dissolved 200 ml of methylene chloride. 5 ^ g nicotinic anhydride are added to this solution at room temperature. The reaction mixture is then stirred at room temperature for one hour, the precipitated crystals are filtered off and dissolved in methanol digested. The residue gives the 2,5-bis- (S-nicotinoylmercaptomethyl) -quinoxaline the formula

from P. I75-I76 ⁰ . Recrystallize from methylene chloride-etha-

nol increases the melting point to 179-180.

109883/1961

- 58 -

Example 11

17 * 5 g of 2 _J j5-bis (bromomethyl) -6-chloro-quinoxaline are suspended together with 7.5 g of thiourea in 1 ^ 0 ml of ethanol. The reaction mixture is then refluxed for 5 hours. After cooling, the 2,3-bis (isothiuroniummethyl) -6-chloro-quinoxaline dibromide of the formula falls

NH

2 HBr

crystalline. The product has the P. 197-202 (decomp.) ·

The 2,3-bis (bromomethyl) -6-chloroquinoxaline used as starting material can be obtained in a manner analogous to that described in Example 7 (F. 146-148).

109883/1961

Example 12

10 g of 2j5-bis (isothiouroniummethyl) -6-chloro-quinoxa-Hn-dibromide are in 80 ml of 2-n. Suspended sodium hydroxide solution and then heated to 80 C for 30 minutes. The mixture is filtered hot and the Piltrat cooled and treated with 20 ml of acetic anhydride while cooling with ice .. The reaction mixture is 30 minutes in. Shaken ice bath. The 2 _J 3-bis (acetylmercaptomethyl) -6-chloroquinoxaline of the formula falls

Il
CH SCCH

CH SCCH ^ά Il ^ 0

crystalline. Recrystallization twice from methylene chloride-hexane gives a product from F. 9 ^ -95 ·

109883/1961

- 4ο -

Example 15

10, 0 g of 2,3-bis (mercapt.oraethyl) -quinoxaline four solved the "in 100 ml of chloroform. At room temperature, a solution of 15 g chloroacetic anhydride in 4θ ml of chloroform is added dropwise to this solution. After the addition is still 2 The reaction mixture is then extracted with cold 2N sodium carbonate solution, the organic phase is dried with sodium sulfate and evaporated. The residue crystallizes and melts crude at 105-107. -quinoxaline of the formula

Il
CH SCCH Cl

from P. 122-123 °.

109883/1961

Example l4

10.0 g of 2,3-bis (mercaptomethyl) -quinoxaline are in 80 ml of 2-n. Sodium hydroxide solution dissolved. This solution is under Ice cooling, 15 g of chloroacetic anhydride were added. The reaction mixture is then shaken at 0 ° C. for 1 hour. The unusual Crude crystals melt at 174-176 with decomposition. Recrystallization from methanol-chloroform gives the 2,3-bis-CS-glycolylmercaptomethylJ-quinoxaline the formula

from P. 181-182 ° (decomp.).

CH SCCH OH Il 0

109883/1961

Example 15

20.0 g of 2 _J 5-bis (raercaptomethyl) quinoxaline dissolved in 80 ml of pyridine. To this end, a solution of 25.0 g of isonicotinic acid chloride in 80 ml of pyridine is added dropwise while cooling with ice. The reaction mixture is stirred for a further hour at room temperature and then poured onto ice. A crystalline precipitate separates out, which is filtered off with suction, dissolved in ethanol and treated with activated charcoal. The 2, J-bis- (S-isonicotinoyl-mercaptomethyl) -quinoxaline of the formula falls from the filtrate

GH SO

CH SO

from F, 142-144 °.

Recrystallization from methylene chloride-ethanol increases the F, to I50-I5I ⁰ .

109883/1961

Example 16

In a manner analogous to that described in the preceding examples, the following compounds, for example, can also be obtained will:

2,5-bis- [S- (2-pyridoyl) -mercaptomethylJ-quinoxalln, 2,5-bis- [S- (2-furoyl) mercaptomethyl] -quinoxaline 2,> - bis- [S- (2-thenoyl) -mercaptomethyl] -quinoxaline, 2,5-bis- [S- (2-pyrazinyl-carbonyl) -mercaptomethyl] -quinoxaline, ^, ^ - Bis-CS-benzoyl-mercaptomethyl) -quinoxaline.

109883/1961

Example 17

per tablet mg 500.0 mg 70.0 mg 30.0 mg 6.0 mg 19.0

Tablets containing 5-00 mg of 2,3-bis- (nicotinoylmercaptomethyl) -quinoxaline can be produced in the following composition:

2,3-bis (nicotinoyl mercaptomethyl) quinoxaline

Wheat starch

Colloidal silica with hydrolyzed starch magnesium stearate
Talk

625.0 mg production

Half of the wheat starch is gelatinized on the water bath with 4 times the amount of water. The active ingredient is with kneaded with this paste until a plastic mass is formed. Then the colloidal silica is hydrolyzed with Starch incorporated in portions. The plastic mass is forced through a sieve with a mesh size of 4-5 mm and dried at 45 ° C. The dried granules are through A sieve with a mesh size of 0.8-1.4 mm was beaten and the remaining disintegrants, lubricants and lubricants were added. After again Homogenization is done using tablets in the usual way Pressed 11.5 mm in diameter and weighing 625 mg.

109883/1961 «ad oriq, _wal

Claims (1)

- 45 claims 1. Process for the preparation of heterocyclic compounds of the formula I. S-IL (D S-R, where R, and R_ independently of one another hydrogen atoms, alkyl or alkoxy radicals, halogen atoms, tri fluorine thyl groups or nitro groups or together alkylenedioxy groups, R ^, and Rk each a monovalent or together a divalent one, the sulfur atoms by at most H carbon atoms separating, possibly substituted carbon / denote asnerstoff- or acyl radical and together can also stand for a direct bond, R, - and R ^ independently of one another for hydrogen atoms or 5 ο lower alkyl radicals or together form a radical of the formula - (CfI ,.) - mean, in which η stands for a small integer stands, characterized in that in a compound of the formula 109883/1961 (ν) wherein X is one into the radicals -S-FU and -S-Rj. transferable Rest means and R -Rg have the meanings given., the radicals X into the radicals -S-R ^ and -S-Rj. convicted or Compounds of the formula with compounds of the formula H S-R, 0 G H S-R, (VII) 109883/1961 or with functional derivatives thereof, where the radicals R ₁ -Rg have the meanings given and, if desired, in compounds obtained within the scope of End substances introduces, modifies or splits off substituents ^ and / or optionally obtained isomer mixtures (racemate niches) into the pure isomers (racemates) splits, and / or separates pure racemates obtained into the optical antipodes, and / or obtained converting free compounds into their salts or obtained salts into the free compounds. 2. The method according to claim 1, characterized in that -X is a reactive esterified hydroxyl group means. J). Process according to Claim 2, characterized in that X is a halogen atom. k. Process according to Claim J, characterized in that X is a chlorine or bromine atom. 5.. Method according to one of the claims. 1- ¹ I, characterized in that a compound of the formula V is reacted with compounds of the formula R, SH and R ^ SH or HS (Ry-R or tautonation thereof. 1 09883/1 961 6. The method according to any one of claims 1-5 * characterized in that the reaction is carried out in the presence of basic agents. 7. Process according to Claim I _3, characterized in that compounds of the formula V in which X stands for the mercapto group are reacted with compounds of the formula FUY and PUY or Y (R ^ h-FU) Y in which Y is an exchangeable radical. 8. The method according to claim ¹ J> characterized in that compounds of the formula V, in which X stands for the mercapto group, are reacted with compounds of the formula R-, Υ and Rj | Y or Y (R -, + R ^) Y, where Y is an esterified hydroxyl group and R and Rj are any substituted acyl radicals. 9. The method according to claim 8, characterized in that Y is a reactive esterified hydroxyl group or denotes a hydroxyl group esterified with a carboxylic acid. 10. The method according to claim 9, characterized in that with compounds of the formula R -, - O-R-, and R. -O-R2, or Rν + Rh converts. 109883/1961 11. The method according to claim 7, characterized in that compounds of the formula V, in which X stands for the mercapto group, are reacted with compounds of the formula FUY and RnY or Y (R _V + R ^) Y, in which Y is a reactive esterified hydroxyl group and R ^ and R ^ are at most substituted hydrocarbon radicals. 12. The method according to claim ¹ J, characterized in that for the preparation of compounds of the formula I in which R ^ and Ru together represent an optionally substituted hydrocarbon radical which separates the sulfur atoms by a carbon atom, compounds of the formula V in which X is the Mercapto group is reacted with compounds of the formula Y (R- ^ lR ₁ ,) Y, in which the two radicals Y together represent an oxo group, which can also be reactively modified. Process according to Claim 12, characterized in that the reaction is carried out in the presence of an acid. 1 ^} \. Process according to Claim 1, characterized in that compounds of the formula V in which X stands for the mercapto group are oxidized to prepare compounds of the formula I in which R _{v and IU together represent a direct bond.} . 109883/1961 15. The method according to claim l4, characterized in that that one is oxidized with atmospheric oxygen. 16. The method according to claim 1, characterized in, that the compounds of the formula VII are used as monoximes. 17. The method according to any one of claims 1-10, 12, 15 and l6, characterized in that modified acyl groups R _v and R || converts to free acyl groups. 18. The method according to any one of claims 1-17 * characterized in that one of a compound obtainable as intermediates at any stage of the process goes out and carries out the missing process steps, or the process is terminated at any stage or forms a starting material under the reaction conditions, or a reaction component optionally in In the form of their pure isomers (racemates) or optical antipodes and / or in the form of their salts. 19. · - The method according to claim 18, characterized in that a compound of the formula V, wherein X is the Mercapto group means used in the form of an alkali salt. 109883/1961 20. The method according to claim 18, characterized in that a diamino compound of the formula V under the reaction conditions by forming a corresponding compound with other nitrogen functions reduced. 21. The method according to any one of claims 1-10, 12, 15, and 18-20, characterized in that compounds are prepared in which R and R. are functionally modified acyl radicals. 22. The method according to any one of claims 1-20, characterized in that compounds of the formula CH-S-R (II) CH-S-R where R and Rp are those given in claim 1 Have meanings, R-, 'and R ^,' independently of one another a monovalent araliphatic, cycloaliphatic, cycloaliphatic-aliphatic or aliphatic hydrocarbon radical or mean an acyl radical which differs from an araliphatic, cycloaliphatic, aronia- 109883/1961 table or aliphatic carboxylic acid, or from the carbonic acid " re or one of its derivatives and can also be functionally modified, or R ^ and R ^ together form a direct bond or an araliphatic, cycloaliphatic or all- = phatic divalent hydrocarbon radical mean the the two sulfur atoms by one or two carbon atoms separates, the radicals R 'and R ^ mentioned also by halogen atoms, Hydroxy groups, lower alkoxy groups, carboxyl groups, lower alkoxycarbonyl groups or at most lower alkylated ones Carbamyl groups or amino groups can be substituted, and Rl and Rj- mean lower alkyl radicals or hydrogen atoms. 5 ο 25. The method according to any one of claims 1-20, characterized in that that you can get compounds of the formula (in) CH-S-R " where R ₁ 'and R ₃ ^{1 are} independently methyl, methoxy or trifluoromethyl groups, fluorine, chlorine or hydrogen atoms or together are methylenedioxy or acetylenedioxy groups, R-, "and R ^" independently ofe. carbamyl or amide amino radicals, lower alkyl, phenyl lower alkyl, phony lower alkanoyl 109883/1961 or especially lower alkanoyl radicals, where the "Phenyj radicals can also be substituted by methyl, methoxy or trifluoromethyl groups, fluorine or chlorine atoms and the oxo oxygen atoms of the phenyl lower alkanoyl and lower alkanoyl radicals can be replaced by an irinino group, or R-, "and R ^," together represent a direct bond, a lower alkylidene radical, or a lower alkylene radical which separates the sulfur atoms by 2 carbon atoms, and R _1. " and R ^ "represent lower alkyl radicals or hydrogen atoms. 2h. Process according to one of Claims 1-13 and »16-20, characterized in that compounds of the formula (IV) in which R "and R" independently of one another mean chlorine atoms, methoxy groups or hydrogen atoms or together denote ethylendoxyront and R "and Rn independently of-jinander, lower-nikyl or leather alkanoyl, to odor the arminidino group or together for ο im .. · ι j uif / ioren Alky] id (? rir-oijt, uäar for a lower Al.ky] oriro ;; t stand for the. '! ciiwoi'o! ; toi '/ Ti torn- tronut. 109883/1961 25. The method according to any one of claims 1-10 and 17-19., Characterized in that compounds of the formula (IV) • produces ₃ where R! ' and R ″ independently of one another denote chlorine atoms, methoxy groups or hydrogen atoms or together the ethylenedioxy radical and R ″ and Rq independently of one another denote the acyl radicals of monocyclic, aromatic carboxylic acids which are mono- or disubstituted or unsubstituted by lower alkyl or alkoxy radicals, halogen atoms or trifluoromethyl groups . 26. The method according to any one of claims 1-10 and 16-20, characterized in that the 2,) - bis- (never otinoy linercaptomethyl) -quinoxaline the formula CH ₂ -S-CO- manufactures. Λ 09883/1961 27. The method according to any one of the claims 1-21, 23 and 9Λ, characterized in that the new compounds are produced in free form. 28. The method according to any one of claims 22, 25 and 26, characterized in that the new compounds are prepared in free form. 29. The method according to any one of claims 1-21, 25 and 2k, characterized in that the new compounds are prepared in the form of their salts. 30. The method according to any one of claims 22, 25 and 26, characterized in that the new compounds are prepared in the form of their salts. 31. The according to one of the methods of claims 1 to available connections. Compounds of the formula 109883/1961 (D, «40 where R, and Rp independently of one another hydrogen atoms, alkyl or alkoxy radicals, halogen atoms, trifluorinethyl groups or nitro groups or together represent alkylenedioxy groups, R- and Rj Mean acyl radical and together can also stand for a direct bond, R and R / r independently of one another mean a hydrocarbon radical or hydrogen atoms and R ″ and R ₀ stand for 7 ο Hydrogen atoms or together a radical of the formula - (CHp) - mean, in which η stands for a small whole Number stands. 33 · Compounds of the type specified in claim 32, wherein R-, and R ₂ . mean modified acyl radicals. Compounds of the formula CH-S - R CH-S-R ' (II), wherein R ₁ and R _{2 have} the meanings given in claim 1 109883/1961 BAD QHi ^ ihP R-, ¹ and R ^ ¹ independently of one another mean a monovalent araliphatic, cycloaliphatic ^ cycloaliphatic-aliphatic or aliphatic hydrocarbon radical or an acyl radical which is derived from an araliphatic, cycloaliphatic, aliphatic or aromatic carboxylic acid or from carbonic acid or one of its carboxylic acids or derived from carbonic acid or one of its derivatives and can also be functionally modified, or R-, ¹ and R ^, 'together represent a direct bond or an araliphatic, cycloaliphatic or aliphatic divalent hydrocarbon radical which connects the two sulfur atoms with one or two carbon a tome separates, wherein said radicals R ₇ 'and R ^, ^{1 can} also be substituted by halogen atoms, hydroxyl groups, lower alkoxy groups, carboxyl groups, lower alkoxycarbonyl groups, possibly lower alkylated carbamyl groups or amino groups, and R _t - and R ^ lower alkyl radicals or hydrogen atoms mean. 55. Compounds of Formula (II), 109883/1961 wherein R and FU have the meanings given in claim 1, R 'and Rl independently mean a monovalent araliphatic, cycloaliphatic, cycloaliphatic aliphatic or aliphatic hydrocarbon radical or an acyl radical which is derived from an araliphatic, cycloaliphatic or aliphatic carboxylic acid or from carbonic acid or one of its derivatives and can also be functionally modified, or R 'and R ^ together represent a direct bond or an araliphatic, cycloaliphatic or aliphatic divalent hydrocarbon radical which separates the two.Schulfelatome by one or two carbon atoms, the radicals R mentioned 'and R ^ can also be substituted by halogen atoms, hydroxyl groups, lower alkoxy groups, carboxyl groups, lower alkoxycarbonyl groups or possibly lower alkylated carbamyl groups, and R' and Rj- mean lower alkyl radicals or hydrogen atoms. 36. Compounds of Formula (HI) , R ₁ 'CH-SR ₄ " where R 'and R' independently of one another are methyl, methoxy 10 9 8 8 3/1961 or "trifluoromethyl groups, fluorine, chlorine or hydrogen atoms mean or together for methylenedioxy or Ethylenedioxy groups, R-, "and Rj" are independent of one another Carbamyl or amidino radicals, lower alkyl, phenyl-lower alkanoyl or in particular lower alkanoyl radicals, the phenyl radicals also being replaced by methyl, methoxy or trifluoromethyl groups, fluorine or chlorine atoms and the oxo oxygen atoms of the phenyl _{lower alkanoyl and lower alkanoyl radicals can be replaced by an imino group, or R v} "and R ^ together represent a direct bond, a lower alkylidene radical, or a lower alkylene radical, which separates the sulfur atoms by 2 carbon atoms, and R _r "and R ^" stand for lower alkyl radicals or hydrogen atoms ". 57 · Compounds of the formula (IV), where R-, "and Rp" independently of one another are chlorine atoms, Methoxy groups or hydrogen atoms or together denote the ethylenedioxy radical and R.sup.1 and R.sup.4 independently of one another Lower alkyl or lower alkanoyl radicals or the 109883/1961 - 6ο - Amldino group mean or together for a lower one Alkylidenrestj or for a lower alkylene radical stand, which separates the sulfur atoms by 2 carbon atoms. "58. Compounds of Formula (IV) wherein R "and R" independently of one another are chlorine atoms, methoxy groups or hydrogen atoms or together represent the ethylenedioxy radical and R and IL, independently of one another, represent the acyl radicals monocyclischer ^ aromatic carboxylic acids mean, the by lower alkyl or alkoxy radicals, halogen atoms or JrI-fluoromethyl groups. substituted one or two times or unsubstituted are. 59. 2,> - bis (acetylmercaptomethyl) quinoxaline. 40. 2,3-bis [(2-isothioureido) methyl] quinoxaline. 41. 1,5-Dihydr'o-5,5-ci5 rr.et.iiyl -> !! -), ·! -Dit hj eplno [?, I ^; -b] quinoxaline. 8Ä0 ORIGINAL 1 09883/1961 42. 1,4-dihydro-2,3-dithiaphenaziii. 45-2,3-bis (n-butylmercaptomethyl) chlnoxaline. 44. 1,3 * 4 _J 6-tetrahydro-2,5-dithiocino [6 _J 7-bJ-quinoxaline. 45. 2,3-Bis - [(2-isothioureido) methyl J-7,8-dihydro-pdioxino [2.5-g] quinoxaline. 46. 2, 5-bis (nicotinoylmercaptomethylj-quinoxaline. 47. 2,3-bis (propionyl mercaptomethyl) hirioxaline. 48. 2,3-bis (acetylmercaptomethyl) -6-chloro-quinoxaline. 49 · Ps 3-bis- [(2-isothioureido) methyl] -ö -chloroquinoxaline. 50. 2,3-bis (ethoxycarbonylmercaptomethyl) -ohinoxalln. 51. 2,5-bis (2-pyridoyl-mercaptomethyl) -quinoxaline. 52. 2,5-BJ s- (2-furoyl-mercaptomethyl) -quinoxaline. \ j'j. 2, 5-B i:; - (? '- thoru> yl-mi-rca {)'; methyl) -quinoxaline. ύΛ, - 109883/1961 2132775 5 ^ - · 2,5-BIs- (S ¹ -pyrazinylearbonyl-mereaptomethyl) -quinoxaline. 55-2,5-bis (benzoyl-mercaptomethyl) -quinoxaline. 56. 2,, 5-bis (isonieotinoyl-mercaptomethyl) -chiriox.alin. 57-2,5-bis (S-chloroacetyl-mercaptomethyl) -quinoxaline. 58.. 2j5-bis (S-glycolyl-icercaptomethyl) -quinoxaline. 59 · The compounds described in claims 52-56 in the form of their pure isomers (racemates). 60. The compounds described in claims 5 ² ~ 56 and 59 with at least one asymmetric center in the form j of their optical antipodes. 61. The compounds mentioned in one of claims 52-60 in free form. 62. The compounds mentioned in one of claims 52-60 in the form of their salts. 65. The compounds mentioned in one of claims 52-60 in the form of their therapeutically usable acid addition 109883/1961 bad o _RIGI na _L 64. The new compounds described in the examples, 65. Pharmaceutical preparations containing compounds of the type shown in one of claims 52-61 and 65, together with a pharmaceutical carrier material. "SAD ORIGINAL 1 09883/1961