CS241009B2 - Method of 2-acyl-oxo-hexahydro-4h-pyrazino-(2,1-a-)isoquinoline derivatives preparation - Google Patents

Description

The invention relates to a preparation process. 2-Acyl-4-oxo-hexahydro-4H-pyrazino [2,1-a] isoquinoline derivatives of formula I

wherein R is a straight or branched alkyl group having up to 15 carbon atoms, a methyl group one to three times substituted by chlorine, methoxy, phenyl, chlorophenoxy, acetoxyphenyl, or thienylmercapto, ethenyl or ethynyl substituted by phenyl, cycloalkyl of 3- to 12 atom carbon, ketocyclohexyl, acetoxycyclohexyl or carboxycyclohexyl, cycloalkenyl of 3 to 12 carbon atoms, phenoxy, ethoxycarbonyl, adamantyl, phenyl substituted by one or more C1-C4 alkyl, hydroxy, fluoro, chloro, chloro, chloro, dimethylamino, nitro,

NH — CHO,

NH — COCH3,

NH-CO-CH2-OCH3, trifluoromethyl, cyano and / or methoxycarbonyl, naphthyl or unsubstituted saturated or unsaturated mono- or bicyclic heterocyclic radical having 1 to 2 nitrogen atoms, oxygen atom and / or sulfur atom or substituted with oxygen, methyl, chloro, bromo, amino, CHO, and / or NO 2 and optionally condensed with one benzene ring, and their optical antipodes and physiologically acceptable salts.

In the following, the term "HPI" will be used for "4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino [2,1- aisoquinoline".

Accordingly, the compounds of formula I may be designated as "2-acyl-HPI".

SUMMARY OF THE INVENTION It was an object of the present invention to provide novel medicaments for human and veterinary medicine.

The compounds of formula I have been found to have excellent anti-241009 parasitic and pharmacological properties with good tolerability. They are, inter alia, effective anthelmintics and develop a particularly broad spectrum of action against Cestodes and Trematodes worms. In addition, they have psychotropic effects and properties affecting blood pressure. The compounds of the formula I can therefore be used as medicaments in human and / or veterinary medicine, in particular to achieve anthelminthic effects, and also as intermediates for the preparation of other medicaments.

Likewise the racemic compounds of the formula I are also active optical antipodes, in particular those which correspond, in terms of optical configuration, to the levorotatory compounds.

The preparation of similar compounds is claimed in the Austrian OE-PS 261615, OE-PS 263-781 and OE-PS 263 782. These, however, show no anthelmintic effect.

Particularly preferred are compounds of formula I wherein the radical R has the following meanings: cyclohexyl, η-, m- and p-fluorophenyl, p-chlorophenyl, m- and p-aminophenyl, m- and p-formylaminophenyl, p-nitrophenyl, and 3-. pyridyl, methyl, ethyl, cyclopropyl, cyclobutyl, cyclo-. .

pentyl, cycloheptyl, m-chlorophenyl, m- and p-hydroxyphenyl, m- and p-methylaminophenyl, m- and p-dimethylaminophenyl, m- and p-dimethylaminophenyl, m- and p-acetylaminophenyl, m- and p-dimethylaminophenyl; and p-methoxyacetylamino-phenyl, 2-thienyl, 3-thienyl, thienyl-2-mercaptomethyl, 2-furyl, 2- or 3-pyridyl, 1-oxido-3-pyridino.

The present invention provides a process for the preparation of compounds of formula I, characterized in that the compound of formula II-

./---Τ '..

co-r; τΤ T '(II) where Ø has the meaning given in formula I and in which the dotted line means that a double bond may be present at the 6, 7 position, reacted with a reducing agent, preferably catalytically hydrogenated, and optionally recovered raceinicl the compound of formula I is resolved into optical antipodes and / or the base of formula I obtained is converted into a physiologically acceptable acid addition salt or the base of formula I is liberated from the acid addition salt.

Preferably R is alkyl of up to 8 carbon atoms which may be substituted with alkoxy of up to 4 carbon atoms; cycloalkyl of up to 7 carbon atoms which may be substituted by fluorine, chlorine, amino, hydroxy or alkoxy of up to 4 carbon atoms; phenyl substituted by fluorine, chlorine, nitro, amino, alkylamino or dialkylamino of up to 4 carbon atoms in the alkyl radical, benzylamino-, hydroxybenzylamino-, alkanoylamino or 18-carbon atoms, benzylideneamino, hydroxybenzylideneamino, hydroxy-, alkoxy up to 4 carbon atoms or an alkoxyacetylamino group up to 4 carbon atoms in the alkoxy radical; a thienyl, thienylmercaptomethyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl or pyridyl group; or a piperidinyl group, which may be substituted with alkyl of up to 4 carbon atoms or formyl.

If they are present in the radical R, the carboxy- or sulfo- residues can also be in the form of alkali metal, caustic earth metal or ammonium salts, preferably in the form of sodium or potassium salts.

The preparation of the compounds of the formula I and also the conversion of the obtained compounds of the formula I into other compounds of the formula I are carried out by conventional methods known in the literature (e.g. Houben-Weyl, Methoden der Organischen Chemie, Georg-Thieme-Verlag, Stuttgart J). and suitable reaction conditions for each reaction.

All the starting materials for the preparation of the compounds of the formula I can optionally also be formed in situ, so that they are not isolated from the reaction mixture, but are immediately reacted further to the compounds of the formula I.

The reduction is preferably carried out by catalytic hydrogenation. Suitable catalysts for this reaction are the customary catalysts known in the literature, preferably a noble metal, but also copper-chromium oxide and nickel and cobalt catalysts. For example, noble metals can be used on a support (e.g. palladium on carbon), as oxide catalysts (e.g. platinum oxide) or as finely divided metal catalysts (e.g. Mohr platinum). Nickel and cobalt catalysts are preferably used as Raney metals, nickel also on silica gel or only as supports. The hydrogenation can be carried out at a pressure in the range of 0.1 to 20.0 MPa and a temperature in the range of 0 to 200 ° C, preferably in the presence of a solvent, preferably an alcohol such as methanol, ethanol, isopropanol or tert-butanol, ethyl acetate, ether. , such as dioxane or tetrahydrofuran, water and / or alkaline lye. Alternatively, the hydrogenation can also be carried out in a homogeneous phase. Suitable catalysts are, for example, heavy metal complex compounds, for example soluble rhodium complexes, such as hydrido-carbonyl-tris (triphenyl-phosphin) rhodium.

The reduction of the compounds can also be controlled to form the antipod itself of the compound of formula I or to a large extent, for example, asy241009 by metric hydrogenation. Suitable catalysts are, for example, Raney nickel, which is treated with asymmetrically modified reagents, for example an aqueous solution of an optically active hydroxy or amino acid such as tartaric, citric, alanine, isoleucine, lysine, phenylalanine, valine or leucine.

Furthermore, heavy metal catalysts which can be applied to natural or artificial polymers, for example palladium or platinum on silk or on specially formulated silica or polyamino acid supports, as described in the literature, can be used for asymmetric hydrogenation. In the homogeneous phase, asymmetric hydrogenation is carried out, for example, on optically active soluble rhodium complexes. The asymmetric hydrogenation is carried out under the conditions mentioned above, preferably at 0.1 to 0.3 MPa and a temperature in the range of 20 to 50 ° C. .

For example, the starting compounds of formula (II) may be prepared by the corresponding compound of formula (I) saturated at the 11b position (1j 'dehydrogenated with sulfur, selenium, chloranil or other dehydrogenating agents known in the literature). 11b (1) occurs as an optically active antipode and is less potent than another possible antipode, in which case the less potent antipode can be converted by dehydrogenation to a compound of formula II followed by hydrogenation to a (more effective) saturated racemate of formula I or asymmetric hydrogenation to a more potent antipod of formula AND.

The starting compounds of the formula II can furthermore be obtained by acylation of the corresponding compounds which, however, contain a hydrogen atom in place of the —CO — R group.

In the compound of formula (I) obtained, it is possible to optionally convert the radical R according to the methods described in the literature to another radical R. For example, the substituents already present can be converted to other substituents.

It is also possible to reduce a reducible substituent such as a nitro group, preferably by catalytic hydrogenation or also chemically. The catalytic hydrogenation can be carried out according to known literature conditions. Metals (e.g. iron, zinc) with acids (e.g. HCl, CH 3 COOH) or stannous chloride are also suitable for reduction.

Another keto group in the acyl residue of a compound of formula I can be converted by hydrogenation or by chemical means to a hydroxyl group. Suitable methods for hydrogenation are known from the literature. Further, the keto group can be reduced by the hydrogen at birth, for example by reaction with a zinc / acid or zinc / alkaline lye mixture; acetic acid is, for example, suitable as an acid. Sodium or other alkali metal in a low alcohol (such as ethanol, isopropanol, isoamyl alcohol) may also be used. The keto group can also be reduced by metal hydrides. Preferred are complex metal hydrides which do not interfere with the amide group of the ring system, such as sodium borohydride, lithium borohydride, potassium tri (sec. Butylityl-borohydride, potassium methoxyborohydride, preferably in the presence of an inert solvent such as ether such as diethyl ether, tetrahydrofuran, dioxane). Sodium borohydride can also be used in an aqueous or aqueous-alcoholic solution, the reaction being carried out in the range of -80 to +100 ° C, in particular in the range of -20 ° C and the boiling point of the solvent used.

Further, the keto group can be converted into a methylene group by reaction with hydrazine and subsequent decomposition of the formed hydrazone according to the Wolff-Kishner method. Further, double bonds to single bonds and triple bonds to double or single bonds may be hydrogenated under the above conditions. Hydrogen (palladium) can also reduce the N-oxide group in the residue R according to known methods to the corresponding tertiary amine.

The obtained compound of formula I which contains a tertiary nitrogen atom in the acyl radical can be converted by reaction with inorganic or organic peroxides such as hydrogen peroxide (preferably a 30% aqueous solution or mixtures of hydrogen peroxide with formic acid), peracetic acid, perbenzoic acid, with 3-chloroperbenzoic acid or tert-butyl hydroperoxide, to the corresponding N-oxide. Suitable solvents for organic peroxides are, for example, methylene chloride, chloroform or an alcohol such as methanol or isopropanol. The reaction is carried out at a temperature in the range from 0 to 50 ^DEG C., preferably at room temperature. The reaction time is between 1 and 48 hours.

The compounds of the formula I obtained which have a thioether group in the radical R, for example alkylmercapto compounds, can be converted, for example, with nitric acid, aqueous hydrogen peroxide solution or 3-chloroperbenzoic acid, into sulfoxides or sulfones.

The alcohol groups in the residue R can be converted to carbonyl groups, for example by oxidation with manganese dioxide or chromic acid.

Compounds of formula I which contain one or more free hydroxyl, amino or monoalkylamino groups as substituents may be alkylated to the corresponding alkoxy, monoalkylamino, dialkylamino or trialkylammonium compounds or acylated to the corresponding acyl compounds.

For O-alkylation, the starting materials are preferably first converted by addition of a base such as sodium hydroxide, potassium hydroxide or potassium carbonate to the corresponding salts. Suitable alkylating agents are, for example, alkyl halides such as methyl 241009 chloride, methyl bromide or methyl iodide, ethyl chloride. ethyl bromide or ethyl iodide, corresponding esters of dialkylsulphuric acid or alkylsulphonic acid, for example dimethyl sulphate, diethyl sulphate or methyl ester of p-toluenesuifonic acid, or a pazo compound, such as diazomethane. The amino compounds can also be allcylated reductively with formaldehyde or acetaldehyde in the presence of hydrogen on the catalyst or in the presence of formic acid. As the solvent, for example, water, aqueous sodium hydroxide solution; alcohols such as methanol, ethanol or n-butanol; hydrocarbons such as benzene or xylene; ethers such as tetrahydrofuran or dioxane; amides such as dimethylformamide. The alkylations are preferably carried out at a temperature in the range of -10 ° C to + 150 ° C, especially in the range of room temperature and the boiling point of the solvent used.

The corresponding acylation is preferably carried out with carboxylic acid or carboxylic acid derivatives, e.g. under known conditions. The acylation can also be carried out with ketenes, preferably in an inert solvent such as ether, dichloromethane, chloroform, benzene or toluene, optionally with the addition of acid catalysts such as sulfuric acid or p-toluenesulfonic acid.

Further, it is possible to convert an alkanoyloxy group (e.g. a formyloxy-, acetoxy-J or alkoxycarbonyl group (e.g., methoxycarbonyl or ethoxycarbonyl)) in the obtained compounds of formula I by treating with a solvolyzing agent to a hydroxy- or carboxy group. or bases such as sodium or potassium carbonate, calcium, barium, sodium or potassium hydroxide, e.g. in aqueous methanol, mild reaction conditions are preferred to avoid disturbing the acid amide groups. -40 ^C to +90 C and in the range of 2-5 hours.

The benzylidene and hydroxybenzylidene amino compounds of formula I can be converted by hydrogenation to the corresponding secondary amines. For hydrogenation, for example, hydrogen in the presence of platinum or Raney nickel at room temperature and normal pressure is used.

The benzylamine compounds can be cleaved, e.g., with hydrogen in the presence of a noble metal catalyst, e.g., palladium, into the corresponding primary amines.

Bisulfite adducts of formula I wherein R is 1,3-disulfo-3-phenylpropylamino are also obtained by direct reaction of the bisulfite and cinnamic aldehyde addition product with a compound of formula I wherein R is aminophenyl.

Furthermore, keto groups in the R residue of the compounds of formula I can be converted to amino groups. For example, ketones can be reacted with hydroxylamine or hydrazine, and the oximes or hydrazones formed, for example, are hydrogenated on Raney nickel at 0.1-5.0 MPa. According to another embodiment, ketones can be hydrogenated in the presence of ammonia or primary or secondary amines. The primary, secondary or tertiary amines of formula I are then obtained. The reaction is preferably carried out at a pressure of from 1 to 20 bar and a temperature of from -40 to 150 ° C, e.g. in methanol, ethanol, isopropanol, tetrahydrofuran, dioxane or liquid ammonia.

It is also possible to cleave the alkoxy groups present in the obtained compounds of formula I to form hydroxy groups. The reaction conditions must be chosen in which the acid amide groups are retained. Conveniently, a Lewis acid such as boron tribromide is employed in an inert solvent such as dichloromethane, chloroform or carbon tetrachloride at a temperature in the range of -40 to +50 ° C.

Compounds of formula I which contain one or more amino groups can be converted in the conventional manner by diazotization to the corresponding diazonium compounds in which the diazonium group can be replaced by, for example, fluorine, chlorine, bromine, iodine, OH, Ο-alkyl or S-alkyl. The diazotization of the respective amine compounds can, for example, be carried out in an aqueous solution of sulfuric, hydrochloric or hydrobromic acid or tetrafluoroboric acid by addition of an inorganic nitrite, preferably NaNO2 or KNO2, at a temperature in the range of -20 to +10 ° C. It is also possible to work with an organic nitrite, such as n-butylate, n-amylate or isoamide, at a temperature in the range of -20 to +5 ° C in an inert organic solvent such as diethyl ether, tetrahydrofuran or dioxane.

To introduce a fluorine atom, it is diazotized, e.g., in anhydrous hydrofluoric acid, and then the diazonium salts are heated or allowed to react with HBF1 to sparingly soluble diazonium tetrafluoroborates. These can be isolated and thermally converted, for example by heating in an inert solvent, to the desired fluoro compounds. However, diazonium tetrafluoroborates (especially heterocyclic compounds) can also be irradiated in an aqueous suspension with a mercury lamp without isolation and the desired fluorocompounds are then obtained. The diazonium group may be exchanged for chlorine or bromine, preferably in a hot aqueous solution in the presence of CU2Cl2 or CusBri. The iodine exchange of the diazonium iodide group is already achieved by gentle heating, and CU 2 J 2, CusBr? or CU2Cl2. The replacement of the diazonium group with a CN group is carried out, for example, in the presence of Cu 2 (CN) 2 and alkali metal cyanides (such as NaCN, KCN) at 0 to +50 ^° C. The diazonium salt group can also be replaced by alkoxy, .

The diazonium compounds can also be pulsed with salicylic acid to the corresponding azobai'viva.

The basic compounds of the formula I can optionally be converted into physiologically acceptable acid addition salts. Suitable are inorganic or organic, e.g. aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic or sulfonic acids, e.g. mineral acids such as hydrochloric, hydrobromic or hydroiodic acids. sulfuric acid, nitric acid, phosphoric acid such as orthophosphoric acid, suifaminic acid; organic acids such as formic, acetic, propionic, butyric, pivalic, diethylacetic, oxalic, malonic, succinic, pimelic, fumaric, maleic, citric, gluconic, lactic, tartaric, malic, benzoic, salicylic, phenylpropionic, ascorbic, ascotonic, isotonic, isonic, , ethanedisulfonic acid, 2-hydroxyethanesulfonic acid (isethionic), p-toluenesulfonic acid, naphthalenone mono- or naphthalenedisulfonic acid {e.g. naphthalene-1- or -2-sulfonic acid or naphthalene-1,5- or 2,6-disulfonic acid).

Compounds of formula I having a free carboxyl or sulfo group can be converted by treatment with a base into a physiologically acceptable metal or ammonium salt. Suitable salts are, in particular, sodium, potassium, magnesium, calcium and ammonium salts, further substituted ammonium salts such as dimethylammonium and diethylammonium, cyclohexylammonium, dicyclohexylammonium salts, N-alkyl- or N-aryl-substituted piperazinium salts { methylpiperazinium, ethylpiperazinium salts) and N, N-dibenzyl-ethylenediammonium salts.

Conversely, the basic compounds of formula I may be liberated from acid addition salts by treatment with bases such as sodium or potassium hydroxide, sodium or potassium carbonate, the acidic compounds of formula I may be liberated from metal and ammonium salts by treatment with acids, especially mineral acids such as dilute hydrochloric or sulfuric acid. .

Compounds of formula I having primary, secondary or tertiary amino groups can be converted into physiologically acceptable quaternary ammonium salts by treatment with an alkylating agent such as methyl iodide, dimethyl sulfate or ethyl halide.

The optically active compounds of the formula I are preferably obtained in that starting materials which are already optically active are used. However, it is also possible to cleave the obtained racemates of the formula I into optical antipodes. The method of chemical cleavage is preferred. E.g. The racemate of the formula I can be reacted with an optically active excipient and the resulting diastereomeric mixtures can be resolved in a suitable manner. For example, a racemate of formula I that contains an acidic group (e.g. a carboxyl group) may be reacted with an optically active base - or conversely, a racemate of formula I that contains a basic group (eg an amino group) may react with an optically active acid. Suitable optically active bases are, for example, amines such as quinine, cinchonidine, brucine, cinchonine, hydroxyhydrindamine, morphine, 1-phenylethylamine, 1-naphthylethylamine, quinidine, sfrychnine, basic amino acids (such as lysine or arginine) or amino acid esters. Conversely, the (+) and (-) - tartaric, dibenzoyltartaric, diacetyltartaric, camphoric, (3-camphorsulfonic, mandelic, malic, 2-phenylbutyric, dinitrodiphenic, lactic or quinic acid forms of the tartaric acid are suitable as optically active acids. The isolated diastereomeric compounds can then be hydrolytically decomposed to the desired optically active compounds.

The compounds of formula I preferably act against tapeworms and flukes. They may be used against the following tapeworms (organized by host), as appropriate:

1. Ruminants: Moniezia, Stilesia, Avitellina, Thysanosoma, Thysaniazia, Finnen-Taenia sp., Coenurus cerebralis, Echinococcen-Fininnen; ,

2. Solipeds: Anoplocephala;

3. Rodents: Hymenolepis (especially n. Nana and H. diminuta);

4. Poultry, Davainea, Raillietina, Hymenolepis;

5. Canine and felines: Taenia (especially T. hydatigena, T. pisiformis, T. taeniaeformis, T. ovis, T. sherialis, T. worms, T. multiceps), Dipylidium (especially D. Caninum), Eehinococcus (especially E. granulosus and E. multilocularis);

6. Human: Taenia (especially T. solium, T. saginata, T. serialis), Hymenolepis (especially H. nana and H. diminuta), Drepanidotaenia, Dipylidium, Diplopylidium, Coenurus (especially C. cerebralis), Diphylloborthrium (especially D latum), Echinocuccus-Finnen (especially E. granulosus and E.multilocularis).

In particular, fluke important in human and veterinary medicine, such as the family Schistosomidae, in particular the genus Schistosoma (Sch. Mansoni, Sch. Haematobium, Sch. Japonicum), are suitable for combating. Alternatively, the genera Fasciola, Dicrocoelium, Clonorchis, Opisthorchis, Paragonimus, Paramphistomum, Echinostoma and others can also be influenced.

The compounds of formula I may be used to control tapeworms or fluke and / or their larvae inter alia in the following hosts and / or inter-hosts: human, monkey, most important domestic and wild animals, eg, canines such as dog, fox; cats, such as cat; solipeds such as horse, donkey, mules; cervids such as deer, deer, fallow deer; chamois; rodents; ruminants such as cattle, sheep, goats;

birds such as chickens, ducks; hog; fish.

The habitat of the controllable parasites or their larvae is especially the gastrointestinal tract, e.g., the stomach, intestines, salivary glands or biliary tract. However, other organs (eg, liver, kidney, lung, heart, spleen, lymph nodes, brain, spinal cord or testes), abdominal cavity, ligament, muscle, peritoneum, pleura or diaphragm, lungs or veins are also contemplated; thus, the compounds of the formula I act well against Schistosoma sp. in the blood circulation system, against Hymenoiepis microstoma in the bile tract and against T. hydaigena-Finnen in the liver.

. The compounds of formula I may be used as such or combined with pharmaceutically acceptable, inert carriers. The carriers may consist, for example, of capsules, solid diluents or fillers, sterile aqueous media, and / or various non-organic organic solvents.

The preparations may be administered in the form of tablets and dragees (which may optionally contain the active ingredient in a depot form), effervescent tablets, capsules, granules, aqueous suspensions, injectable solutions, emulsions and suspensions, elixirs, syrups or pastes. by adding the active ingredient to a solvent and / or carrier, optionally with an emulsifying and / or dispersing agent, using, for example, water, non-toxic organic solvents (eg paraffins or alcohols such as glycerin or polyethylene glycol), vegetable oils ( eg sesame oil}, solid carriers such as natural or synthetic stone meal (eg talc or aerosil), sugar, emulsifiers (eg ionic or non-ionic), dispersants (eg methylcellulose and polyvinylpyrrolidone) and / or glidants (eg Tablets may also contain additives such as saline didlo, sodium citrate, calcium carbonate and middle calcium phosphate, together with additives such as starch, gelatin, etc. Optionally, flavor enhancers and colorants may be added to the aqueous suspensions and / or elixirs. The compounds of formula I may optionally also be administered without or almost free of excipients, e.g. in capsules.

The active compounds of the formula I are preferably administered orally, parenterally, in particular subcutaneously or intramuscularly, but dermal administration is also possible.

To combat adult tapeworms, it is preferable to administer the active compounds one or more times in a daily amount of 0.01 to 250, preferably 0.5 to 100 mg / kg orally or subcutaneously. Larger amounts of active substance may be needed to control the corresponding roundworm larvae (Finnen) or to control Schistosom.

When administering larger amounts of active ingredient, smaller individual doses may also be divided per day. For example, 5 single doses of 200 mg may be administered instead of 1000 mg. In veterinary medicine, it is also possible to administer the active compound with the feed, and it is expedient to prepare a premix (praemix). Here too, all the usual additives can be added.

Where appropriate, the amount indicated must be varied, depending on the body weight or the mode of administration, but also on the basis of the species to be controlled and its individual behavior towards the medicaments or formulations or the time interval in which the product is administered. In some cases, it may be sufficient to use less than the lowest limit, while in other cases the upper limit must be exceeded.

Depending on the method of application, the ratio between the compound of formula (I) and the carrier and / or excipient used can vary widely. When the compound of formula I is administered, for example, as a tablet or dragee, 0.01 to 2500 mg of active ingredient may be combined with 1 to 10,000 mg of excipient. Conversely, when the compound of formula I is used in the praemix for medicinal feedingstuffs, 0.1 to 400 g of the compound of formula I may be added per kg of carrier or excipient. For injection, a solution containing 1 liter of liquid may contain 0.5 up to 100 g of a compound of formula I; similarly, 0.5 to 250 g of the compound of formula 1 can be dissolved or suspended in 1 liter of juice.

The compounds of the formula I can also be present in the formulations in admixture with other active substances. To achieve a broader spectrum of activity, it is optionally beneficial to add an active substance that acts on roundworms, for example Thiabcidazole [2- (4-thiazolyl) benzimidazole] or piperazine (or piperazine derivatives such as N-methylpiperazine). It is also possible to combine 2 or more compounds of formula I.

In the following examples, (]] =. [Α] _D ^w in chloroform;

IR = KBr. Example 1 g of a nickel-aluminum alloy (1: 1) is added in portions with stirring to 200 ml of 20% sodium hydroxide solution over 5 minutes and held at 80 ° C for 45 minutes. Allow to settle, decant, wash with water and add 1 000 ml of a 1% (-) - tartaric acid solution which has been adjusted to pH 5 with 1N sodium hydroxide solution. Shake to 90 ° C for 90 minutes, shake decanted with water and methanol. The (? -Tartaric-Raney nickel) acid catalyst thus obtained was added to a solution of 322 mg of 2- (4-fluorobenzoyl) -4-oxo-2,3,6,7-tetrahydro-4H-pyrazino [2,1-ajisoquinoline [obtainable] by dehydrogenation of (±) - or (+) -2- (4-fluorobenzoyl) -HPI sulfur] in 40 ml of methanol and hydrogenated at nor241009 at ambient pressure and room temperature. (4-fluorobenzoyl) -HPI in 23% optical purity, mp 190-193 ° C, [α] D = -7.5 °, 70%.

Analogously obtained from 2-cyclohexylcarbonyl-4-oxo-2,3,6,7-tetrahydro-4H-pyrazino [2,1-a] isoquinoline (mp 140-141 ° C) (-) - 2-cyclohexylcarbonyl-HPI in 20% optical purity; mp 122-127 ° C, [α] D = - 29.3 °; 76%.

Example 2

a) Analogously to Example 1, 322 mg of 2- (4-fluorobenzoyl) -4-oxo-2,3,6,7-tetrahydro-4H-pyrazino [2,1-a] isoquinoline are hydrogenated in 40 ml of methanol in the presence of 300 ml. mg Raney nickel. Racemic 2- (4-fluorobenzoyl) -HPI, mp 181-182 ° C; 70%.

Analogously prepare:

2-acetyl-HPI, mp 139 ° C,

2-isobutyryl-HPI, mp 120 ° C,

2- (2-methylbutyryl) -HPI, mp 95-96 ° C,

2-trimethylacetyl-HPI, mp 150 ° C,

2- (2-ethyl-n-butyryl) -HPI, mp 121 ° C,

2- (3,3-dimethyl-n-butyryl) -HPI, m.p. 113 ^C C

2-heptanoyl-HPI, mp 90-91 ° C,

2- (2,2-dimethylvaleryl) -HPI, mp 129 ^e C,

2- (2-n-butylhexanoyl) -HPI, mp 96 ° C,

2-hexadecanoyl-HPI, mp 101-102 ° C,

2-dichloroacetyl-HPI, mp 151-152 ° C,

2-trichloroacetyl-HPI, mp 184-185 ° C,

2-tris- (chloromethyl) -acetyl-HPI, mp 133-135 ° C,

2- [2-methoxyacetyl) -HPI, mp 135 ^° C,

2- (2-phenylacetyl) -HPI, mp 123-124 ° C,

2- (2-acetoxy-2-phenylacetyl) -HPI, m.p. 101-102 ° C,

2- (4-chlorophenoxyacetyl) -HPI, mp 159-160 ° C,

2- (thienyl-2-mercaptoacetyl) -HPI, mp 89-90 ° C,

2-cinnamoyl-HPI, mp 152 ° C,

2-phenylpropioloyl-HPI, mp 155 ° C,

2-phenoxycarbonyl HPI, mp 136-137 ° C,

2-ethoxalyl-HPI, mp 126 ^° C,

2-cyclopropylcarbonyl-HPI, mp 148 ° C,

2-cyclobutyl-carbonyl-HPI, mp 154-155 ° C,

2-cyclopentyl-carbonyl-HPI, mp 127 ° C,

2-cyclohexylcarbonyl-HPI, mp 136-138 ° C,

2- (1-cyclohexenyl-carbonyl) -HPI, mp 123-124 ° C,

2- (3-cyclohexenyl-carbonyl) -HPI, mp 126 ° C,

2- (4-ketocyclohexylcarbonyl) -HPI, mp 154 ° C, cis-2- (3-acetoxycyclohexylcarbonyl) -HPI, mp 130-132 ° C,

2-cycloheptylcarbonyl-HPI, mp 91 ° C,

2-cyclooctylcarbonyl-HPI, mp 109 ° C,

2-cycloundecylcarbonyl-HPI, mp 150-151 ° C,

2- (adamantyl-carbonyl) -HPI, mp 159-160 ° C,

2- [3-methylbenzoyl) -HPI, mp 124 ° C,

2- (4-methylbenzoyl) -HPI, mp 183-184 ° C,

2- (4-tert-butylbenzoyl) -HPI, mp 1988 ° C,

2- (2-fluorobenzoyl) -HPI, mp 129 ° C,

2- (3-fluorobenzoyl) -HPI, mp 164-166 ° C,

2- (3-chlorobenzoyl) -HPI, mp 181-182 ° C,

2- (4-chlorobenzoyl) -HPI, mp 214-215 ° C,

2- (3,5-dichlorobenzoyl) -HPI, mp 165-166 ° C,

2- (2,3,4,5,6-pentafluorobenzoyl) -HPI, mp 156 ° C,

2- (3-hydroxybenzoyl) -HPI, mp 153 ° C,

2- (4-hydroxybenzoyl) -HPI, mp 243-245 ° C,

2- [3,5-dihydroxybenzoyl} -HPI, mp 250-254 ° C (decomposition),

2- (4-methoxybenzoyl) -HPI, mp 204-205 ° C,

2- (4-dimethylamino-benzoyl J-HPI, mp 225-226 ° C),

2- (3-formamidobenzoyl) -HPI, mp 176 ° C,

2- (4-formamidobenzoyl) -HPI, mp 207-208 CC,

2- (4-acetamidobenzoyl) -HPI, mp 247-248 ° C,

2- (4-methylmercaptobenzoyl) -HPI, mp 195 ° C,

2- (2-nitrobenzoyl) -HPI, mp 188-189 ° C,

2 ^: (3-nitrobenzoyl) -HPI, mp 172 ^° C,

2- (4-nitrobenzoyl) -HPI, mp 212-213 ° C,

2- (3,4-dinitrobenzoyl) -HPI, mp 219 ° C,

2- (3,5-dinitrobenzoyl) -HPI, mp 251-252 ^° C,

2- (3-trifluoromethylbenzoyl) -HPI, mp 148-149 ° C,

2- (4-cyanobenzoyl) -HPI, mp 214-215 ° C,

2- (4-methoxycarbonylbenzoyl) -HPI, mp 178 ° C,

2- (2-chloro-4-nitro-benzoyl) -HPI. mp 176-177 ° C,

2- (4-chloro-3-nitro-benzoyl) -HPI, mp 192-194 ^° C,

2- (2-hydroxy-5-chloro-benzoyl) -HPI, mp 180 ° C,

2-naphthyl-1-carbonyl-HPI, mp 135 ° C,

2-naphthyl-2-carbonyl-HPI, mp 178 ° C,

2- (pyryl-2-carbonyl) -HPI, mp 174 ° C,

2- (thienyl-2-carbonyl) -HPI, mp 132-133 ° C,

2- (thienyl-3-carbonyl) -HPI, mp 142-143 ° C,

2- (5-nitro-thienyl-2-carbonyl) -HPI, mp 172-173 ° C,

2- (5-methyl-thienyl-2-carbonyl) -HPI, mp 134-136 ° C,

2- (furyl-2-carbonyl) -HPI, mp 120 ° C,

2- (5-bromo-furyl-2-carbonyl) -HPI, mp 209 ° C,

2- (5-nitro-furyl-2-carbonyl) -HPI, mp 182 ° C,

2- (indolyl-5-carbonyl) -HPI, mp 235 ° C,

2- (5-methyl-pyrazolyl-3-carbonyl) -HPI, mp 201 ° C,

2- (thiazolyl-4-carbonyl) -HPI, mp 154 ° C,

2- (2,4-dimethyl-thiazolyl-5-carbonyl) -HPI, mp 162-163 ° C,

2- (5-methyl-isoxazolyl-3-carbonyl) -HPI, mp 173-174 ° C,

2-picolinoyl-HPI, hydrobromide, mp 163 ° C,

2-nicotinoyl-HPI, mp 172 ° C,

2- (6-chloronicotinoyl) -HPI, mp 158 ° C,

2-isonicotinoyl-HPI, mp 140-141 ° C,

2- (2,6-Dichloro-isonicotinoyl) -HPI, m.p. 207-208 ° C, (cilinolyl-2-carbonyl) -HPI, m.p. 198-200 ° C,

2- (isoquinolyl-1-carbonyl) -HPI, mp 157 ° C,

2- (pyrazinyl-2-carbonyl) -HPI, mp 1.153-154 ° C,

2- (4-methyl-piperazinyl-1-carbonyl) -HPI hydrochloride, m.p. 290 ° C,

2- (1-methyl-1,2,5,6-tetrahydropyridyl-3-carbonyl) -HPI hydrochloride, mp 211 ° C,

2- (1-formylpiperidyl-4-carbonyl) -HPI, mp 160 ° C,

2- (tetrahydropyranyl-4-carbonyl) -HPI;

Mp 172 ° C,

2- (chromone-2-carbonyl) -HPI, mp 155-156 ° C,

2- (tetrahydrothiopyranyl-4-carbonyl) -HPI, mp 168 ° C,

2- (2,1,3-benzothiadiazolyl-5-carbonyl) -HPI, mp 144 ° C, (+) -2-acetyl-HPI, mp 175-176 ° C, (-) -2 acetyl-HPI, mp 177-178 ° C, (+) -2-cyclohexylcarbonyl-HPI,

mp 103-110 ° C; [.alpha.] = + 145.2 °, (-) -2-cyclohexylcarbonyl-HPI, mp 107-108 ° C; [Α] D = -166.9 °, (+) -2- (4-methylbenzoyl) -HPI, mp 180-1818 ° C; [α] D = + 29.2 °, (-) - 2 (4-methylbenzoyl) -HPI, mp 181-182 ^° C; [Α] D = -28.5 °, (+) -2- (4-tert-butylbenzoyl) -HPI, mp 181-182 ° C; (?) = + 21.5 °, (-) -2- (4-tert-butylbenzoyl) -HPI, mp 168-169 ° C; [α] = -20.5 ', (+) -2- ( 2-fluorobenzoyl) -HPI, mp 155-156 ° C; [?] = + 49.1 °, (-) -2- (2-fluorobenzoyl) -HPI, mp 159-161 ^° C; [a] = - 49.9 ^c , (+) -2- (3-fluorobenzoyl) -HPI, mp 156-158 ° C (sintering 148 ° C);

[Α] = + 40.2 =, (-) - 2- (3-Fluorobenzoyl) -HPI, mp; 156 [deg.] C .; [α] D = -41.6 °, (+) -2- (4-fluorobenzoyl) -HPI, mp 200-201 ^° C; [α] = + 33.5 °, (-) - 2- (4-fluorobenzoyl) -HPI, mp 202-203 ° C; [a] = -32.6 ° (+) -2- (4-chlorobenzoyl 1) -HPI, mp 231-232 ^C. C; [α] = +20.4 °, (-) - 2- (4-chlorobenzoyl) -HPI, mp 233-234 ° C; [α] D = - 20.7 °, (+) -2- (4-methoxybenzoyl) -HPI, mp 215 ^° C; [α] D = + 19.8 °, (-) - 2- (4-methoxybenzoyl) -HPI, mp 216 ° C; [Α] D = -18.7 °, (+) -2- (4-formamidobenzoyl) -HPI, mp 193 ° C; [α] = +8.6 ', (-) - 2- (4-Formamidobenzoyl) -HPI, mp 193 ° C; [α] D = -8.4 °,.

(+) - 2- (3-nitro-benzoyl) -HPI, mp 139 ° C; (a] == ^c +2.9, [from (-) - bázej, (-) - 2- (3-nitrobenzoyl) -HPI, m.p. 139 ^J C [ «] = -2.9 °, [ z (2)-throw, (+) -2- (4-nitrobenzoyl) -HPI, mp 223-224 ° C; [α] = +18.5 ', (-) - 2 (4-nitrobenzoyl) -HPI, mp 223-224 ° C (α) = -21.4 °, (+) -2-nicotinoyl-HPI, mp 148 ^° C;

[Α] D = + 25.5 °, (-) - 2-nicotinoyl-HPI, mp 156 ° C;

[α] D = -28.4 °.

b) A solution of 67.7 g of 2- (4-nitrobenzoyl) -HPI in 1500 ml of methanol was hydrogenated to 12 g of 5% palladium on carbon at 20 ° C under normal pressure. The catalyst was filtered off, the filtrate was evaporated. The residue gave 2- (4-aminobenzoyl) -HPI, mp 212-213 ° C (ethanol), 80%, hydrochloride mp 165 and 166 ^° C (decomposition), sulphate mp 234-235 ° C, isehionate mp 233-234 Deň: 32 ° C.

By analogy, hydrogenation of the corresponding nitro compounds is obtained:

cis-2- (4-aminocyclohexyl-carbonyl) -HPI, amorphous; IR: 3500, 3300 and 1645 cm ^-1 , trans-2- (4-aminocyclohexylcarbonyl) -HPI, mp 284 ° C,

2- (2-aminobenzoyl) -HPI, hydrobromide, mp 279-280 ° C,

2- (3-aminobenzoyl) -HPI, mp 161-162 ° C, (+) -2- (3-aminobenzoyl) -HPI, mp 164-165 ° C; (?) = + 35.9 °, [z { - j nitroantipodůj (-) -2- (3-aminobenzoyl) -HPI, m.p. 164-165 ° C, [ «] = -36.5 ^c '[z (j + nitroantipodůj, (±) -2 - (4-aminobenzoyl) -HPI, mp 231-232 ° C (α) = + 23.1 ° hydrobromide: mp from 193 ° (decomposition) isethionane: mp 200-210 ° C;

[Α] D = + 16.0 °, (-) -2- (4-aminobenzoyl) -HPI, mp 231-232 ^° C; [α] = - 23.0 ^c ; hydrobromide; mp 205 ° C (dec.); isethionane: mp 200-210 ° C;

[Α] D = - 16.3 °, 2- (3,4-diaminobenzoyl) -HPI, mp 143 ° C,

2- (3,4-diaminobenzoyl) -HPI, mp 235-236'C,

2- (2-chloro-4-aminobenzoyl) -HPI, mp 145 ° C; hydrochloride, 181-182 ^° C,

2- (3-amino-4-chloro-benzoyl) -HPI; hydrobromide, mp 208-210 ° C,

2- (4-Amino-tetrahydro-thiopyranyl-4-carbonyl) HPI, mp 157-158 ° C.

c) To 9.6 g of 2- (4-aminobenzayl) -HPI and 3.1 g of triethylamine in 300 ml of chloroform was added 2.4 g of acetyl chloride in 100 ml of chloroform and left to stand for 2 hours at 20 ° C. 2.4 g of acetyl chloride and 3.1 g of triethylamine are then added and the mixture is boiled for 3 hours. The reaction mixture is washed with dilute hydrochloric acid and water. After evaporation of the solvent, 2- (4-acetamidobenzoyl) -HPI, mp 247 248 [deg.] C. [from acetone]; 80%.

d) A mixture of 8 g of 2- (4-methoxycarbonylbenzo241009)

yl) -HPI and 500 ml of 10% sodium hydroxide solution were stirred at 20 ° C for 12 hours. The insoluble matter is filtered off, the filtrate is acidified with hydrochloric acid and extracted with chloroform. The residue is purified by chromatography on silica gel (eluent: chloroform / methanol). 2- (4-carboxybenzoyl) -HPI, mp 251 ° C; 70%.

Similarly, it is obtained by alkaline saponification:

trans-2- (2-carboxycyclohexyl-carbonyl) -HPI, m.p. 208 to 210 ^C C, cis-2- (2-carboxycyclohexyl-carbonyl) -HPI,

mp 194-196 ° C.

(e) To a solution of 32 g of 2- (4-hydroxybenzoyl) -HPI in 150 ml of methanol / water (10: 1) was added an excess of ethereal diazomethane solution until a faint yellow color persisted. washed with dilute sodium hydroxide solution and water, dried over sodium sulfate, evaporated to give 2- (4-methoxybenzoyl) -HPI, mp 204-205 ° C; 60%.

f) To 5.4 g of 2- (4-methoxybenzoyl) -HPI in 100 ml of methylene chloride, 7.5 g of boron tribromide was added dropwise at -5 to -10 ^° C. Stir 1 hour at 20 ° C and pour onto ice. The organic phase is separated and the aqueous phase is shaken several times with methylene chloride. The combined organic phases were dried over sodium sulfate and then evaporated. The residue gave 2- (4-hydroxybenzoyl) -HPI, mp 243-245 ° C (from ethanol); 60%.

g) A mixture of 4.8 g of 2- (4-aminobenzoyl) -HPI and 1.5 g of a 33% solution of formaldehyde in 200 ml of methanol was hydrogenated to 0.5 g of 5% palladium on carbon. Then it is filtered, the solvent is evaporated and the residue is purified by chromatography on silica gel (eluent: chloroform). 2- (4-methylaminobenzoyl) -HPI, m.p. 220 ° C. 30%.

h) Analogously to Example "g", 4.8 g of 2- (4-aminobenzoyl) -HPI and 4 g of a 33% solution of 2- (4-dimethylaminobenzoyl) -HPI formaldehyde, m.p. 225-226 ° C; 50%.

(i) To 3.2 g of 2- (4-aminobenzoyl) -HPI in 100 ml of dioxane was added 2.5 g of dimethyl sulphate over 2 hours in the absence of moisture and stirred at 100 ° C for 15 hours. It is then cooled, 1.4 g of potassium hydroxide in 5 ml of water are added and extracted with chloroform. Evaporation gave 2- (4-dimethylaminobenzoyl) -HPI, mp 225-226 ° C; 60%.

j) 10.4 g of 2- (4-trifluoroacetamidobenzoyl) -HPI [obtainable with 2- (4-aminobenzoyl) -HPI with trifluoroacetanhydride / triethylamine] is heated with 34.2 g of methyl iodide in 300 ml of acetone to near boiling point, 13.4 g of powdered potassium hydroxide is added and boiled for 5 min. Evaporate, add water and stir at 20 ° C for 2 hours. It is then extracted with chloroform, washed with water and evaporated. 2- (4-methyl-3-aminobenzoyl) -HPI, m.p.

220 DEG C., 50%.

If methyl iodide is not removed prior to hydrolysis, 2- (4-dimethylaminobenzoyl) -HPI is obtained, mp 225-226 ° C; 62%.

k) To 6.5 g of 2- (4-oxocyclohexylcarbonyl) -HPI in 100 ml of ethanol was added portionwise at 0 ^° C 1.15 g of sodium borohydride. Stir for 12 hours at 20 ° C, poured onto ice to give 2- (4-hydroxycyclohexylcarbonyl) -HPI as a mixture of isomers. Amorf. 60%.

l) To a solution of 3.25 g 2 ^; (4-Oxocyclohexylcarbonyl) -HPI in 35 mL of absolute tetrahydrofuran was added under nitrogen at -70 °. Celsius 24 ml of a 0.5 molar solution of potassium tris (sec-butyl) -bromohydride in tetrahydrofuran. After 3 hours, 35 mL of water was added, allowed to warm to 20 ° C and treated with chloroform. Purification by chromatography on silica gel with chloroform gave cis-2- (4-hydroxycyclohexylcarbonyl) -HPI, m.p.

mp 162-163 ° C; 60%.

m) 6.5 g of 2- (4-oxocyclohexylcarbonyl) -HPI in 100 ml of methanol are hydrogenated in the presence of 2 g of Raney nickel at 50 ° C and 10.0 MPa until saturation. The catalyst was filtered off, the solvent was distilled off to give 2- (4-hydroxycyclohexylcarbonyl) -HPI as a mixture of isomers. Amorf. 70%.

n) 3.16 g of 2- (4-oxocyclohexylcarbonyl) -NPI was hydrogenated in 100 ml of methanol, which was saturated at 10 ° C with ammonia, in the presence of 1 g of Raney nickel at 70 ° C and 10 MPa for 10 hours. The catalyst was filtered off, the solvent was evaporated and the residue was dissolved in ethanol. After addition of HBr in ethanol and then ether, trans-2- (4-aminocyclohexylcarbonyl) -HPI-hydrobromide, m.p. 284 DEG C., crystallizes; 60%.

o) 3.1 g of 2- (4-oximinocyclohexylcarbonyl) -HPI, [t. 194 C; obtainable from 2- (4-oxocyclohexylcarbonyl) -HPI and hydroxylamine] is hydrogenated in 100 ml of ethanol at room temperature and 0.5 MPa in the presence of 4 g of Raney nickel until saturation. carbonyl) -IPI (mixture of isomers) Amorph 80%.

p) A solution of 5.5 g of 2-isonicotinoyl-HPI and 6.3 g of 3-chloroperbenzoic acid (50%) in methylene chloride is allowed to stand overnight at 20 ⁼ C. Ammonia is then introduced until saturation, filtered off with suction and washed with methylene chloride. . Evaporation of the filtrate gave 2-isonicotinoyl-HPI-1'-N-oxide, mp 250 ° C (from ethanol). 70%.

Analogously obtained from 2-nicotinoyl-HPI-2-nicotinoyl-HPI-1‘-N-oxide, mp 178 ° C; 83%.

q) 3.2 g of 2- (4-dimethylaminobenzoyl) -HPI and 5 g of methyl iodide are heated in 600 ml of acetonitrile at 75 ° C overnight, the solvent is evaporated and the mixture is purified on silica gel (eluent, chloroform-methanol). ) to give methojodid 2- (4 dimethylaminobenzoyl) -HPI, m.p. 215-216 ^r C (from ethanol); 60%.

r) Analogously to d), 8 g of 2- (4-acetoxybenzoyl) -HPI are saponified in the presence of 10% sodium hydroxide solution. 2- (4-hydroxybenzoyl) -HPI, mp 243-245 ° C; 70%.

Similarly, it is obtained by saponification of the corresponding acetates:

2- (3,4-cis-dihydroxycyclohexyl-carbonyl) -HPI, hydrate, mp 100-102 ° C.

s) 6.4 g of 2- (4-aminobenzoyl) -HPI, 2.7 g of salicylaldehyde and 100 mg of p-toluenesulfonic acid chloride were boiled in 150 ml of toluene for 12 hours to remove the water formed. Evaporate and triturate with ether. 2- (4-O-hydroxybenzylideneamino-benzoyl) -HPI, m.p. 196-197 ° C (from benzene / petroleum ether); 80%.

Analogously obtained with benzaldehyde:

2- (4-Benzylideneamino-benzoyl) -HPI (amorphous). .

t) 3 g of 2- (4-benzylideneamino-benzoyl) -HPI was hydrogenated for 3 hours in 50 ml of methanol to 1 g of platinum at 20 ° C and normal pressure. Filtration of the catalyst and evaporation gave 2- (4-benzylaminobenzoyl) -HPI, mp 204-205 ° C; 60%.

Analogously from 2- (4-o-hydroxybenzylideneamino-benzoyl) -HPI by hydrogenation: 2- (4- (2-hydroxybenzyl) -aminobenzoyl) -HPI,

mp 201-202 ° C.

u) A diazonium solution prepared from 3.21 g of 2- (4-aminobenzoyl) -HPI, 5 ml of 6N hydrochloric acid, is added to a solution of 1.38 g of salicylic acid in 15 ml of 2N sodium hydroxide solution at 5-10 ^° C. 7 g of sodium nitrite and 4 ml of water, taking care to keep the solution alkaline. After half an hour, the product obtained is precipitated with hydrochloric acid, filtered off, washed with water and a little ethanol and dried. 2- [4- (3-carboxy-4-hydroxy-phenylazo) -benzoyl] -HPI was obtained as an orange-yellow powder; mp 241-244 ° C; 80%.

(v) 300 ml of a 3.7 N sodium bisulfite solution are heated for half an hour with 49 g of cinnamic aldehyde at 90 ° C, 111.7 g of 2- (4-aminobenzoyl) -HPI in 1 liter of dioxane are added and the mixture is heated for 12 hours to 90 ° C. After cooling, it is extracted with chloroform; the aqueous phase is concentrated and the product is precipitated by addition of ethanol. There was obtained 2- (4- (1,3-disulfo-3-phenylpropylamino) -benzoyl] -HPI disodium salt, m.p. 221-222 ° C (dec.), 30 percent.

(w) 4.8 g of 2- (3-cyclohexenyl-1-carbonyl) -HPI and 4 g of osmium tetroxide are stirred overnight at 20 ° C in 60 ml of pyridine, then a solution of 7 g of sodium bisulfite in 130 ml of water is added; 85 ml of pyridine, stirred for 30 minutes and extracted with methylene chloride. After drying and evaporation, 2- (3,4-cis-dihydroxycyclohexyl-1-carbonyl) -HPI hydrate is obtained, m.p. 100-102 ° C, 30%.

x) 3.1 g of 2- (3-cyclohexenyl-1-carbonyl) -HPI is hydrogenated at 20 ° C and normal pressure to 300 mg of platinum oxide in 100 ml of methanol until the reaction is complete. Filtered, evaporated to give 2-cyclohexylcarbonyl-HPI, mp 136-138 ° C, 80%.

(y) A solution of 3.3 g of 2- (tetrahydrothiopyran-4-carbonyl) -HPI and 1.05 ml of a 30% aqueous solution of hydrogen peroxide in 20 ml of acetic acid is left overnight at 20 ^DEG C., evaporated, treated with chloroform and water to give 2- (tetrahydrothiopyran-4-carbonyl) -HPI-S-oxide as a mixture of isomers, mp 175-180 ° C, 60%.

(z) 3.3 g of 2- (tetrahydrothiopyran-4-carbonyl) -HPI and 2.5 ml of a 30% aqueous solution of hydrogen peroxide in 25 ml of acetic acid are heated at 60 ° C for 2 hours, evaporated, treated with chloroform and water; 2- (tetrahydrothiopyran-4-carbonyl) -HPI-S, S-dioxide, mp 253-255 ° C (from ethanol), 70% is obtained.

za) To a solution of 4.9 g of 2- (4-oxocyclohexylcarbonyl) -HPI in 50 ml of absolute tetrahydrofuran was added slowly under nitrogen at -70 ° C 35 ml. 0.5 molar solution of potassium sec-butylborohydride in tetrahydrofuran. After 3 hours, 50 mL of water was added, allowed to warm to room temperature, acidified with HCl and extracted with chloroform. The chloroform extract is purified by chromatography (silica gel / chloroform). Pure cis-2- (4-hydroxycyclohexylcarbonyl] -HPI, mp 162-163 ^° C (from isopropanol / dimethyl ether), 47%, is obtained.

The active compounds of the formula I can be formulated according to methods known in the literature into pharmaceutical preparations, as shown in the following examples:

Example A

Tablets for the control of tapeworms (adult worms)

(a) Tablets containing 500 mg of 2-cyclohexyl-carbonyl-HPI as active substance are prepared by processing a powder mixture containing 5 kg of 2-cyclohexyl-carbonyl-HPI, 3 kg of lactose, 1.8 kg of corn starch and 0.2 kg of stearate magnesium.

b) The same mixture may be used to prepare tablets containing 50, 250 and 1000 mg of 2-cyclohexylcarbonyl-HPI.

Tablets containing 250 and 500 mg of 2-cyclohexylcarbonyl-HPI as active ingredient are preferably used in human medicine;

!

all of the listed tablets can also be used for veterinary purposes.

Example B

The tablets to be coated preferably are Cestodes-Finnen or Schistosom

(a) effervescent tablets

each tablet contains: 2-cyclohexylcarbonyl-HPI citric acid sodium carbonate saccharin sucrose do 1000 mg 800 mg 900 mg 5 mg 4000 mg chewable tablets Each tablet contains: 2-Cyclohexyl-carbonyl-HPI 2000 mg cellulose 80 mg sodium carboxymethylcellulose 40 mg

color and aroma at will, sucrose up to 4000 mg

Example G

Dragees to combat tapeworms in human medicine

The dragee core contains: 2-cyclohexyl-carbonyl-HPI 250 mg lactose 150 mg corn starch 90 mg magnesium stearate 10 mg

The dragee coating consists of: talc, sucrose, titanium dioxide, calcium carbonate, polyvinylpyrrolidone, methylcellulose, glycerine, magnesium oxide, lacquer.

This composition can also be used for dragees which contain 500 mg of 2-cyclohexylcarbonyl-HPI as active ingredient.

Example D

Juice to control tapeworms (human medicine)

The juice is prepared by suspending:

2-Cyclohexyl-carbonyl-HPI 3.5 kg Distilled water 2 1 buffer 0.1 1 glycerine 3 kg sorbit 3 kg sucrose 53 kg

a mixture of 60% methyl p-hydroxybenzoate and 40% propyl p-hydroxybenzoate 0.1 kg ethanol 12 1

Add color and flavor to the mixture and make up to 100 L with distilled water.

Example E

Capsules to combat Cestodes and Schistosom in human and veterinary medicine

The size of the container is filled with a mixture containing:

2-cyclohexylcarbonyl-HPI 5000 mg talc 250 mg magnesium stearate 150 mg

Capsules containing 1000 mg a are prepared

000 mg of 2-cyclohexylcarbonyl-HPI.

Example F

Solution for injection for human and veterinary use

For subcutaneous administration in an oily or aqueous suspension, a 15 mg ampoule is filled with a solution of 500 mg of 2-cyclohexylcarbonyl-HPI in 5 ml of water and 4 ml of propylene glycol with the addition of a solubiliser. Ampu-. when hot sterilized or a preservative is added.

An ampoule is prepared containing 100 mg of 2-cyclohexyl-carbonyl-HPI (for small animals) and 1000 mg of 2-cyclohexyl-carbonyl-HPI (for large animals).

Example G

Peiletky

A powder mixture is prepared from equal parts by weight of 2-cyclohexylcarbonyl _: HPI and lactose, which is worked up in a conventional manner together with sodium carboxymethylcellulose into a uniform granulate with an average grain diameter of 1.5 mm.

Example H

Veterinary premix which is suitable for mixing with feed as carrier for medicinal feed and 25% premix (preferably for larger animals:

kg of 2-cyclohexylcarbonyl-HPI is mixed with 75 kg of fine bran (wheat flour) and / or lactose.

(b) 5% premix (preferably for small animals):

kg of 2-cyclohexylcarbonyl-HPI was processed analogously to Example a).

(c) Example of the use of the masterbatch prepared according to (a) to control Moniezia species in bovine intestines.

To obtain a suitable medicinal feed, 1 kg of the masterbatch prepared according to a) is mixed with 9 kg of conventional nuclear feed. 400 grams of this medicinal feed containing 10,000 mg of 2-cyclohexylcarbonyl-HPI is administered to adult bovine animals to control the moniezia species.

Analogously to Examples A to H, other active compounds of the formula I or their physiologically acceptable salts can also be used instead of 2-cyclohexyl-carbonyl-HPI and processed into pharmaceutical preparations.

Claims (1)

SUBJECT Process for the preparation of 2-acyl-4-oxo-hexahydro-4H-pyrazino [2,1-a] isoquinoline derivatives of the general formula I Π) wherein the radical R represents a straight or branched group having up to 15 carbon atoms, a methyl group one to three times substituted by chlorine, methoxy, phenyl, chlorophenoxy, acetoxyphenyl or thienylmercapto, ethenyl or ethinyl substituted by phenyl, cycloalkyl of 3 to 12 carbon, ketocyclohexyl, acetoxycyclohexyl or carboxycyclohexyl, ethoxycarbonyl, adamantyl, phenyl mono- or poly-substituted with up to 4 carbon atoms, fluorine, chlorine, hydroxy, methoxy, dimethylamino, nitro, NH — CHO, NH — COCH3, NH-CO-CH2-OCH3, trifluoromethyl, cyano and / or BETWEEN a methoxycarbonyl, naphthyl or unsubstituted saturated or unsaturated mono- or bicyclic heterocyclic radical having 5 or 6 ring members containing 1 to 2 nitrogen atoms, oxygen atom and / or sulfur atom or substituted by oxygen, methyl, chlorine, bromine, amino, CHO a group and / or a NO 2 group and optionally condensed with a single benzene ring, and their optical antipodes and physiologically acceptable salts, wherein R is as defined in formula I and wherein the dashed line means that at position 6,7 can be preferably, it is catalytically hydrogenated, and optionally the racemic compound of the formula I obtained is resolved into optical antipodes and / or the base of the formula I obtained is converted into a physiologically acceptable acid addition salt or a base of the general formula I of Formula I is liberated from the acid addition salt.