CS241008B2 - Method of 2-acyl-4-oxo-hexahydro-4h-pyrazino-(2,1-a-)isoquinoline derivatives preparation - Google Patents

Description

The invention relates to a process for the preparation of 2-acyl-4-oxo-hexahydro-4H-pyrazino [2,1-a] isoquinoline derivatives of the general formula I

wherein R is straight or branched alkyl of up to 15 carbon atoms, methyl substituted one to three times with chlorine, methoxy, phenyl, chlorophenoxy, acetoxyphenyl or thienylmercapto, ethenyl or ethynyl substituted with phenyl, cycloalkyl of 3 to 12 carbon atoms, kethoxycyclohexyl, acetoxycyclohexyl or carboxycyclohexyl, C 3 -C 12 cycloalkenyl, phenoxy, ethoxycarbonyl, adamantyl, phenyl mono- or poly-substituted with up to 4 carbon atoms, fluoro, chloro, hydroxy, hydroxy dimethylamino, nitro,

NH-CHO NH-COCH3 NH-CO-CH3-OCH3 with 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 a sulfur atom or substituted with oxygen, methyl, chlorine, bromine, amino, CHO and / or NO 2 and optionally condensed with one benzene ring, and their optical antipodes and physiologically acceptable salts.

In the following will be used for "4-oxo-l, 2,3,6,7, llb-hexahydro-4H-pyrazino [2,1-a] ^{isoquinoline:} 'designation" HPI ". Accordingly, the compounds of formula I may be designated as "2-acyl-HPI".

A new drug for human and veterinary medicine has been found around the invention.

The compounds of formula I have been found to have excellent antiparasitic and pharmacological properties with good tolerability. Among others, anthelmintics are effective and divide241008

241003 eats a particularly broad spectrum of action against Cestodes and Trematodes worms. They also 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 for anthelmintic effects, and also as intermediates for the preparation of other medicaments.

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

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

Particularly preferred are compounds of formula I wherein the radical R is as follows: cyclohexyl, o-, m- and p-fluorophenyl, p-chlorophenyl, m- and p-aminophenyl, m- and p-formylaminophenyl, p-nitrophenyl and 3- pyridyl, methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cycloheptyl, m-chlorophenyl, m- and p-n-hydroxyphenyl, m- and p-methylaminophenyl, m- and p-dimethylaminophenyl, m- and p-acetylaminophenyl, m- and p-methoxyacetylaminophenyl, 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:. wherein the compound of formula (II) is n-co-ch ₂ -x (II) wherein R is as defined in formula (I); and X represents fluoro, chloro, bromo, iodo of methylsulfonyloxy or arylsulfonylOx of 6 to 10 carbon atoms, preferably p-toluenesulfonyloxy, cyclizes in the presence of a cyclizing agent, preferably a strong base such as butyllithium, potassium tert-butylate, phenyllithium, hydride an alcoholate such as sodium or potassium methylate, sodium or potassium efhylate, sodium or potassium propylate, sodium or potassium isopropylate, sodium or potassium n-butylate or sodium or potassium tert-butylate or an amide such as lithium, sodium or potassium diisopropylamide; and, optionally, the racemic compound of formula I obtained 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-, up to 18 carbon atoms, benzylideneamino, hydroxybenzylideneamino, hydroxy- , alkoxy of up to 4 carbon atoms or alkoxyacetylamino of up to 4 carbon atoms in the alkoxy radical; a thienyl, thienyl mercaptomethyl, furyl, thiazolyl, isothiazolyl, oxazalyl, 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, carboxy- or sulfo-radicals can also be in the form of alkali metal, caustic earth metal or ammonium salts, preferably in the form of sodium or potassium salts.

when the radical X is an arylsulfonyloxy group, it is preferably phenylsulfonyloxy and p-tolylsulfonyloxy, furthermore, for example, naphthyl-1-sulfohyloxy or naphthyl-2-sulfonyloxy.

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). and suitable reaction conditions for each reaction.

If desired, all the starting materials for the preparation of the compounds of the formula I can 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.

Suitable cyclizing agents are strong bases such as preferably butyllithium or potassium tert-butylate, furthermore phenyllithium, sodium hydride, alcoholates such as methylate, ethylate, proylate, isopropylate, n-butylate, sodium or potassium tert-butylate, amides such as lithium diisopropylamide or the corresponding sodium or potassium amide. As a rule, the reaction is carried out in an inert solvent such as benzene, hexane, tert-butanol, tetrahydrofuran, hexamethylphosphoric triamide, dioxane, ether, dimethylformamide, dimethylsulfoxide, acetonitrile, optionally under nitrogen. The reaction temperature is between -20 ° C and the boiling point of the solvent used. The reaction takes from 15 minutes to 30 hours, preferably from 10 to 14 hours.

The cyclization can also be carried out with the optically active compound of formula II as starting material and then the optically active compounds of formula I are obtained.

The starting compounds of the formula II can be obtained according to known methods described in the literature, for example from the corresponding 1-cyano-1,2-dihydro- or 1-cyano-1,2,3,4 tetrahydro-isoquinolines which are substituted in the 2-position by the radical R = CO- (as defined for Formula I). These are hydrogenated on Raney nickel at higher temperature and pressure as the residue R-CO is transferred to the corresponding N- (1,2,3,4-tetrahydroisoquinolyl-1-methyl) acylamides, which are then converted with a compound of formula X- CH 2 -CO-X, for example with chloroacetyl chloride, to compounds of formula II.

In the compound of the 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 already present substituents 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 may also be reduced metal hydrides, complex metal hydrides which do not interfere with the amide group of the ring system such as sodium borohydride, lithium borohydride, potassium - (sec-butyl) -borohydride, potassium trimethoxyborohydride, preferably in the presence of an inert solvent such as an ether such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane or dlglyme Sodium borohydride can also be used in aqueous or aqueous-alcoholic solutions. 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 30% aqueous solution or mixtures of hydrogen peroxide with formic acid), peracetic acid, perbenzoic acid For example, methylene chloride, chloroform or an alcohol such as methanol or isopropanol is suitable as a solvent for organic peroxides, and is operated at a temperature in the range of 0 to 50 ^° 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 sulpho: Tdv or sulphones.

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

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

For O-alkylation, the starting materials are preferably first converted by addition of a base, for example sodium hydroxide, potassium hydroxide or potassium carbonate, to the corresponding salts. Suitable alkylating agents are, for example, alkyl halides such as methyl chloride, methyl bromide or methyl iodide, ethyl chloride, ethyl bromide or ethyl iodide, the corresponding esters of dialkylsulfuric acid or alkylsulfonic acid, for example dimethylsulfate, diethylsulfate or methyl p-toluenesulfonic acid, or diazo compounds such as diazomethane. The amino compounds may also be alkylated reductively. 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 p-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, in particular between room temperature and the boiling point of the solvent used.

The corresponding acylation is preferably carried out with carboxylic acid or carboxylic acid derivatives, for example 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 methoxyyloxy, acetoxy) or an alkoxycarbonyl (e.g., methoxycarbonyl or ethoxycarbonyl) in the compounds of formula I obtained by treating the hydroxy or carboxy group with solvolyzing agents. Acids (e.g. hydrochloric or acetic acid) or preferably bases such as sodium or potassium carbonate, calcium, barium, sodium or potassium hydroxide, for example in aqueous methanol, are used for this reaction. Mild reaction conditions are preferred to avoid disturbing the amide groups. acid. in general, temperatures between -40 to +90 C, and ¹ in the range of 2-50 hours.

The benzylidene and hydroxybenzylidene amino compounds of formula (I) may be converted by the hyd-. by rogenation 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, for example, with hydrogen in the presence of a noble metal catalyst, for example 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 editor 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 are, for example, hydrogenated on Raney nickel at 0.1 to 5 bar. In another embodiment, ketones can be hydrogenated in the presence of ammonia or primary or secondary amines. The primary, secondary or tertiary amines of the 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, for example in methanol, ethanol, isopropanol, tetrahydrofuran, dioxane or liquid ammonia.

It is also possible to cleave the alkoxy groups present in the compounds of formula (I) obtained to form hydroxy groups. The reaction conditions must be chosen in which the acid amide groups are retained. The steel is treated with a Lewis acid such as boron tribromide 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 into the corresponding diazonium compounds in which the diazonium group can be replaced, for example, by fluorine, chlorine, bromine, iodine, OH, O-alkyl. or S-alkyl. The diazotization of the corresponding amine compounds is. for example, it may be carried out in an aqueous solution of sulfuric, hydrochloric or hydrobromic acid or tetrafluoroboric acid by the addition of an inorganic nitrite, preferably NaNO 2 or KNO 3, at a temperature in the range of -20 to + 10 ° C. It can also operate with an organic nitrite such as n-butyldusitanein, n-amyldusitanem or isoamyl nitrite at a temperature between -20 and +5 ^c C. in an inert organic solvent such as diethyl ether, tetrahydrofuran or dioxane.

To introduce a fluorine atom, for example, it is palzotized in anhydrous hydrofluoric acid and then the diazonium salts are heated or allowed to react with HBF 3 to form 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) may also be irradiated in an aqueous suspension with a mercury lamp without isolation to obtain the desired fluorocompounds. The diazonium group may be exchanged for chlorine or bromine, preferably in a hot aqueous solution in the presence of CU2Cl2 or CuzSrz. The iodine exchange of the diazonium iodide group is already achieved by gentle heating, and CU2J2, Cu2Br2 or Cu.Ch. The substitution of the diazonium group with a CN group is carried out, for example, in the presence of CU (((CNjidů alkali metal cyanides (such as NaCN, KCN) at 0 to +50 ° C ⁾ . The diazonium salt group can also be replaced by an alkoxy group.

The diazonium compounds can also be coupled with salicylic acid to the corresponding. azo dyes.

The basic compounds of the formula I can optionally be converted into physiologically acceptable acid addition salts. Suitable are inorganic or organic, for example aliphatic, alicyclic, araliphatic, aromatic or heterocyclic monohydric or vorous carboxylic or sulphonic acids, for example mineral acids such as hydrochloric, hydrobromic or hydroiodic acids, sulfuric, nitric, phosphoric acids, orthophosphoric acid sulfamine; organic acids such as formic, acetic, propionic, butyric, pivalic, diethylacetic, oxalic, malonic, succinic, pimelic, fumaric, maleic, citric, glultonic, lactic, tartaric, malic, benzoic, salicylic, phenylpropionic, methoxysic, , ethanedisulfonic, 2-hydroxyethanesulfonic (isothionic, p-toluenesulfonic, naphthalene-mono- or naphthalenedisulfonic acid (for example, 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, for example, dimethylammonium and diethylammonium, cyclohexylammonium, dicyclohexylammonium salts, N-alkyl- or N-aryl-substituted piperazine salts (such as methylpiperazinium salts). , 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, methyl iodide, dimethyl sulfate or ethyl halides.

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. For example, the racemate of formula I can be reacted with an optically active excipient, and the diastereomeric mixtures obtained can be resolved appropriately. For example, a racemate of formula I which contains an acidic group (for example a carboxyl group) may be reacted with an optically active base. Or conversely, a racemate of formula I which contains a basic group (for example an amino group) may be reacted with an optically active acid. optically active bases are suitable, for example, amines such as quinine, cinchonidine, brucine, cinchonine, hydroxyhydrindamine, morphine, 1-phenylethylamine, 1-naphthylhylamine, quinidine, strychnine, basic amino acids (such as lysine or arginine) or amino acid esters. active (+) - and (-) - tartaric, dibenzoyltartaric, diacetyltartaric, camphoric, β-camphorsulfonic, mandelic, malic, 2-phenylbutyric, dinitrodiphenic, lactic or quinic acid forms The diastereomeric mixtures can then be separated by selective crystallization or by hand The isolated diastereomeric compounds may then be hydrolytically decomposed to form a diastereomeric compound 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,

Thysaniezia, Finnen-Taenia sp., Coenurus cerebralis, Echinococcen-Finnen;

2. Solipeds:

Anoplocephala;

*

3. Rodents:

Hymenolepis (especially H. nana and H. diminuta);

4. Poultry:

Davainea, Raillietina, Hymenolepis;

5. Canines and felines:

Taenia (especially T. hydatigena, T. pisiformis, T. taeniaeformis, T. ovis, T. serialis, T. worms, T. multices), Dipylidium (especially D. Caninum), Echinococcus (especially E. granulosus and E. multilocularis );

8. Man:

Taenia (especially T. solium, T. saginata, T. serialis), Hymenolepis (especially H. nan ^ and H. diminuta), Drepanidotaenia, Dipylidium, Diplopylidium, Coenurus (especially C. cerabralis), Diphyllobothrium (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 combat tapeworms or fluke and / or their larvae, inter alia, in the following hosts and / or between hosts: humans, monkeys, most important domestic and wild animals, for example, 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 gastrotestinal tract, for example the stomach, intestines, salivary glands or biliary tract. However, other organs are also contemplated (e.g., liver, kidney, lung, heart, spleen, lymph node, brain, spinal cord or testes), abdominal cavity, ligaments, muscle, peritoneum, pleura or diaphragm, lungs or veins; thus, the compounds of the formula I act against Schistosoma sp. in the blood circulation system, against Hymenolepis microstoma in the bile tract and against 7th hydatigena-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-toxic organic solvents.

The formulations can be administered in the form of tablets and dragees (which optionally contain the active ingredient in a depot form), effervescent tablets, capsules, granules, aqueous suspensions, injectable solutions, emulsions and suspensions, elixirs, syrups or pastes. The preparations are prepared in a known manner, for example by adding the active ingredient to a solvent and / or carrier, optionally using an emulsifying and / or dispersing agent. For example, water, non-toxic organic solvents (e.g. paraffins or alcohols such as glycerin or polyethylene glycol), vegetable oils (e.g. sesame oil), solid carriers such as natural or synthetic stone meal (e.g. talc or aerosil, sugar, emulsifiers (for example ionogenic or non-ionic), dispersants (for example me, thylcellulose and polyvinylpyrrolidone) and / or glidants (for example magnesium stearate) The tablets may also contain additives such as sweetener, sodium citrate, calcium carbonate and calcium phosphate together If desired, 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 without excipients, for example 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 Scbistosom.

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 the mixture in advance (praemixj). Here too, all conventional additives can be added.

Where appropriate, the amount indicated must be varied, depending on the body weight or 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 may be me12

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, if the compound of formula I is used in the praemix for medicinal feed, then 0.1 to 400 g of the compound of formula I may be used per kg of carrier or excipient.

The compounds of formula I may be. in preparations also in admixture with other active substances. To achieve a broader spectrum of activity, it is optionally beneficial to add an active agent that acts on roundworms, for example Thiabendazole [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] 1 = [α] ²⁰ in chloroform;

IR = KBr. He did

(a) To 8,5 g of N- (2-chloroacetyl-1,2,3,4-tetrahydroisoquinolinyl-1-methyl) -4-fluorobenzamide [obtainable by hydrogenation of 1-cyano-2- (4-fluorobenzoyl) -1, Of 2-dihydroisoquinoline on Raney nickel at 100 ° C and 2.50 MPa and reaction of the obtained N- (1,2,3,4-tetrahydroisoquinolinyl-1-methyl) -4-fluorobenzamide with chloroacetyl chloride in chloroform in the presence of triethylamine] in 300 ml of absolute tetrahydrofuran was added dropwise at 20 ^° C under nitrogen with 12 ml of a 20% solution of butyllithium in hexane, stirred for 2 hours at 20 ° C and boiled for an additional 12 hours, after addition of water the solvent was removed and the residue was dissolved in chloroform. shake with water, dried and evaporated to give 2- (4-fluorobenzoyl) -4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino [2,1-a] isoquinoline, mp 181-182 ° C (from methanol), 60%.

Analogously prepare:

2-acetyl-HPI, m.p. 139 ° C

2-isobutyryl-HP1, mp 120 ° C,

2- (2-methylbutyryl) -HPI, m.p. 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, mp 113 ° C.

2-Heptanoyl-HPI

mp 90-91 ° C,

2- (2,2-Dimethyl-valeryl) -HPI, mp 129 ° C,

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

2-hexadecanoyl-HPI, mp 101-102 ° C,

2410Q3 dichloroacetyl-HPI, mp 151-152 ^° C,

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

2-tris- (chloromethyl) acetyl-HPI, m.p. 133-135 ° C;

2- (2-Methoxyacetyl) -1-IPI, mp 135 ° C.

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

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

2- (4- chlorophenol: yacetyl) -HPI, mp 159-160 C ^5,

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

2-cinnamoyl-HPI, mp 152 ^° C,

2-phenylpropioloyl-HPI, mp 155 Έ,

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

2-ethoxy allyl-HPI, mp 126 ° C,

2-cyclopropyl-carbonyl-HPI, mp 148 ° C,

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

2-cyclopentyl-carbonyl-HPI, m.p. mp 127 ° C,

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

2- (1-cyclohexenylcarbonyl) -HPI, mp 123-124 ^° C,

2- (3-cyclohexenyl carbonyl) -HPI, m.p. 126 ^C 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- (adamantylcarbonyl) -HPI, mp 159-160 ° C,

2- (3-metbylbenzoyl) -HPI, m.p. 124 ^C C

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

2- (4-tert-butylbenzoyl) -HPI, mp 198 ° 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-hydroxy-benzoyl) -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-dimethylaminobenzoyl) -HPI, mp 225-226 ^e C,

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

2- (4-formamidobenzoyl) -HPI, mp 207-208 ° C, (4-scamidamidobenzoyl) HPI, mp 247-243 ° C,

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

2- (2-nitrobenzoyl) -HPI

mp 188-189 ° C,

2- (3-nitrobenzovl) -HPI, mp 172 ° C,

2- (4-nitro-benzyl) -HPI, mp 212-213 ^° C,

2- (3,4-dinitrobenzoyl) -HPI, mp 219 ^DEG C .;

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

2- (3-trifluoromethylbenzoyl) -HPI, m.p. 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, (4-chloro-3-nitro-benzoyl) -HPI, mp 192-194 ° C, (2-hydroxy-5) -chlorobenzyl) -HPI, mp 180 ° C,

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

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

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

2- (thienyl-2-carbonyl) -HP, m.p. 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 134-133 ^° C;

(furyl-2-carbonyl) -HPI, mp 120 ° C,

2- (5-bromo-furyl-2-carbonyl) -HPI, m.p. 209 ^C C

2- (5-nitro-furyl-2-carbonyl) -HPI, m.p. 182 ° C,

2- (5-indolyl-carbonyl) -HPI, m.p. 235 DEG C. (5-methyl-pyrazolyl-3-carbonyl) -HPI, m.p. 201 ^C C

2- (thiazoles 1-4-carbonyl) -HPI, mp 154 ^° C,

2- (2,4-dimethyl-thiazoyly-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, mp 207-208 ° C,

2- (quinolyl-2-carbonyl) -HPI, m.p. 198-200 ° C,

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

2- (pyrazinyl-2-carbonyl) -HPI, mp 153-154 ° C,

2- (4-methyl-piperazinyl-1-carbonyl) -HPI hydrochloride, mp 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-chloro-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, (+ j-2 cyclohexylcarbonyl-HPI, mp 108-110 ° C, [α] = + 145.2 °, (-) -2-cyclohexylcarbonyl-HPI, mp 107-110 ° C 108 ° C, [α] = -146.9 °, (+) -2- (4-methylbenzoyl) -HPI, mp 180-181 ° C, [α] = + 29.2 °, (-) - 2 - (4-methylbenzoyl) -HPI, mp 181-182 ° C, [α] -28.5 °, (+) -2- (4-tert-butylbenzoyl) -HPI, mp 181-182 ° C, [α] ] = + 21.5 DEG (-) - 2- (4-butylbenzoyl) -HP I, mp 168-169 ^C. C, [a] = -20.5 ° (+) - 2- (2 -f-fluorobenzoyl) -HPI, m.p. 155-156 ° C, _[a] = + 49.1 DEG (-) -2- (2-fluorb'enzoyl) -HPI, mp 159-161 ° C, _{[a] =} 49.9 ³ , (+) -2- (3-fluorobenzoyl) -HPI, mp 156-158 ° C (sintering 148 ° C), [α] = + 40.2 °, (-) - 2- (3-fluorobenzoyl J-HPI, m.p. 156 ° C, _[a] = -41.6 ° (+) - 2- (4-fluorobenzoyl) -HPI, mp 200-201 ° C [= +33 etc. 5 °, [-] - 2- (4-fluorobenzoyl) -HPI,

t. í. 202 DEG -203 DEG, [.alpha.] D @ 20 = 32.6 DEG, (+) -2 (4-chlorobenzoyl) -HPI, mp 231 ^DEG- 232 ^DEG C., [.alpha.] D = + 20.4 DEG.

(-) - 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] = -18.7 °, (+) -2- (4-formamidobenzoyl) HPI, mp 193 ° C, [α] = + 8.6 °, (-) -2- (4-formamidobenzoyl) -HPI, mp 1.93 ° C, [α] = -8.4, (+) -2- ( 3-nitrobenzoyl) -HPI,

mp 139 = C, [α] = + 2.9 ° [from (-) - base], (-) - 2- (3-nitrobenzoyl) -HPI, mp 139 ° C, [α] = -2, 9 ° [from (+) - base], (+) -2 (1-nitrobenzoyl) -HPI, mp 223-224 ° C, (-d - + 18.5 °, (-) - 2- (4-nitrobenzoyl) -HPI

mp 223-224 ° C, [α] = -21.4 °, (+) -2-nicotinoyl-HPI, mp 148 ° G.

[Α] D = + 25.5 °, (-) -2-nicotinoyl-HPI, mp 156 ° C, [α] = -23.4 °.

h) 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. 2- (4-aminobenzoyl) -HPI, mp: 212-213 ° C (from ethanol), 80%, is obtained from the residue. Hydrochloride, mp 165-166 ° C (dec.), Sulfate mp 234-235 ° C, isethionate mp 233-234 ° C.

Similarly, it is obtained by hydrogenation of the corresponding nitro compounds:

cis-2- (4-aminocyclohexyl-carbonyl) -HPI, amorphous, IR: 3500, 3300 and 1645 ^cm-1, trans-2- (4-aminocyclohexyl-carbonyl) -HPI, m. p 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, (α = + 35.9 ° [from (- j-nitroantipodes)), (-) - 2- (3-aminobenzoyl) -HPI,

mp 164-165 ^° C;

fa | = - 36.5 ° [from (+) - nitroantipore, (+) -2- (4-aminobenzoyl) -HPI, mp 231-232 ° C, [ _K] - + 23 °, hydrobromide: mp from 193 ° ( (dec) - + 16.0 °, (-) - 2- (4-aminobenzoyl) -HPI, mp 231-232 ° C, [α] = - 23.01 hydrobromide: mp 205 ° C (dec.), Isethionane: mp 200-210 ° C, [α] D = -16.3 °,

2- (3,4-diaminobenzoyl) -HPI, mp 143 -C,

2- (3,5-diaminobenzoyl) -HPI, mp 235-236 ° C,

2- (2-chloro-4-aminobenzoyl) -H-1,

tt 145 -'C hydrochloride 131.až 182 ^C C

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

2- (4-Amino-tetrahydrothiopyranyl-4-carbonyl) HPI, m.p. 157-158 ° C.

c) To 9.6 g of 2- (4-aminobenzoyl) -HPI and 3.1 grams 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. Then 2.4 g of acetyl chloride and 3.1 g of triethylamine are added and the mixture is boiled for 3 hours. The reaction mixture was washed with dilute hydrochloric acid and water. Evaporation of the solvent gave 2- (4-acetamidobenzoyl) -HPI, mp 247-248 ° C (from acetone), 80%.

d) A mixture of 8 g of 2- [4-methoxycarbonylbenzoyl] -HPI and 500 ml of 10% sodium hydroxide solution was stirred at 20 ^° C for 12 hours. Insoluble materials were filtered off, the filtrate 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% was obtained.

Similarly, it is obtained by alkaline saponification:

trans-2- (2-carboxycyclohexylcarbonyl) -HPI, m.p. 208-210 ° C, cis-2- (2-carboxycyclohexylcarbonyl) -HPI,

mp 194-196 ⁵ 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 an ethereal diazomethane solution until a faint yellow color persisted. Evaporate, dissolve the residue in ether, wash with dilute sodium hydroxide solution and water, dry over sodium sulfate, concentrate to give 2- (4-methoxybenzoyl) -HPI, mp 204-205 ° C, 60 ° C.

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, mp 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 DEG-226 DEG C., were obtained, 50%.

i) To 3.2 g of 2- (4-aminobenzoyl) -HPI in 100 ml of dioxane was added 2.5 g of dimethyl sulfate over 2 hours in the absence of moisture, and then 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, m.p. 225 to 226 C for ^7, 60%.

(i) 10.4 g of 2- (4-trifluoroacetamidobenzoyl) -HPI (obtainable with 2- (4 aminobenzoyl) -HPI with trifluoroacetanhydride / triethylamine) are heated with 34,2 g of methyl iodide in 300 ml of acetone to near boiling point, 13 4 g of powdered potassium hydroxide and boiled for 5 min. Evaporate, add water and stir for 2 hours at 20 ^° C. Then extract with chloroform, wash with water and evaporate to give 2- (4-methylaminobenzoyl) -HPI, mp 220 ^C , 50%.

If methyl iodide is not removed prior to hydrolysis, 2- (4-dimethylaminobenzoyl) -HP1 is obtained, m.p. 225 DEG-226 DEG C., 62%.

(k) To 6,5 g of 2- (4-oxocyclohexylcarbonyl} -Ι-ΪΡΙ in 10 ml of ethanol, 1,15 g of sodium borohydride are added in portions at 0 ° C and stirred for 12 hours at 20 ^° C, Poured onto ice to give 2- (4-hydroxycyclohexylcarbonyl) -HPI as a mixture of isomers.

l) To a solution of 3.25 g of 2- (4-oxocyclohexylcarbonyl) HPI in 35 ml of absolute tetrahydrofuran is added under nitrogen at -70 ° C 24 ml of a 0.5 molar solution of tris (sec-butyl) -borohydride in tetrahydrofuran at 3 hours. 35 ml of water are added, the mixture is allowed to warm to 20 [deg.] C. and treated with chloroform. After chromatography on silica gel with chloroform, cis-2- (4-hydroxycyclohexylcarbonyl) -HPI is obtained.

mp 162-163 ° C, 60%.

m) 6.5 g of 2- (4-oxocyclohexylcarbonyl) -HPI in 100 ml of methanol is hydrogenated in the presence of 2 g of Raney nickel at 50 ° C

20 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, amorphous 70%.

n) 3.16 g of 2- (4-oxocyclohexylcarbonyl) -HPI is hydrogenated in 100 ml of methanol, which has been saturated at 10 ° C with ammonia, in the presence of 1 g of Raney nickel at 70 ° C and 10.0 MPa for 10 hours . The catalyst was filtered off, the solvent was evaporated and the residue was dissolved in ethanol. After addition of I-IBr in ethanol and then ether, trans-2- (4-aminocyclohexylcarbonyl) -HPI-hydrobromide, mp 234 ° C, 60 crystallizes.

o) 3.1 g of 2- (4-oximino-cyclohexyl-carbonyl) -HPI, mp 194 ^° C, obtainable from 2- (4-oxocyclohexyl-carbonyl) -HPI and hydroxylamine are hydrogenated in 100 ml of ethanol at room temperature and 0.5 MPa for presence of 4 g of Raney nickel until saturation to give 2- (4-aminocyclohexylcarbonyl) -HPI (mixture of isomers) amorphous 80%.

p) A solution of 5.5 g of 2-isonicotinoyl-HPI and 6.3 g of 3-chloroperbenzoic acid (50%) in methylene chloride was allowed to stand overnight at 20 ^° C, then ammonia was 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, 2-nicotinoyl-HPI-1‘-N-oxide was obtained from 2-nicotinoyl-HPI, mp 178 ° C, 83%.

q) 3.2 g of 2- (4-dimethylaminobenzoyl) -HPI and 5 g of methyl iodide were heated in 600 ml of acetonitrile overnight at 75 ^° C, the solvent was evaporated, the resulting mixture was purified on silica gel (eluent: chloroform / methanol) to give 2- (4-dimethylamino-benzoyl) -HPI methoiodide, mp 215-216 ° 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. There was obtained 2- (4-hydroxybenzoyl) -HPI, m.p. 243-245 ° C, 70%.

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

2- (3,4-cis-dihydroxycyclohexylcarbonyl) -HPI, hydrate, m.p. 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, evaporated and triturated with ether. 2- (4-o-hydroxybenzylideneamino-benzoyl) -HPI, mp 196-197 ^° C (from benzene / petroleum ether), 80%.

Analogously obtained with benzaldehyde:

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

ie 3 g of 2- (4-benzylideneamino-benzoyl) -HPI is 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 obtained from 2- (4-o-hydroxybenzylideneaminobenzoyl) -HPI 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 6 N hydrochloric acid is allowed to flow at 5-10 ° C to a solution of 1.38 g of salicylic acid in 15 ml of 2 N sodium hydroxide solution. 0.7 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, m.p. 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-aininobenzoyl) -HPI in 1 liter of dioxane are added and the mixture is heated for 12 hours 90 [deg.] C. After cooling, it is extracted with chloroform, the aqueous phase is concentrated and the product is precipitated by the addition of ethanol.

2- [4- (1,3-Disulfo-3-phenylpropylamino) -benzovl] -HPI, m.p. 221 ^DEG- 222 ^DEG C. (dec.), 30%.

w) 4.8 g of 2- (3-cyclohexenyl-1-carbonylb-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 110 ml of water and After drying and evaporation, 2- (3,4 cis-dihydroxycyclohexyl-1-carbonyl) -HPI, hydrate, mp 100-102 ° C, 30% is obtained.

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

y) Koztok 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 are left overnight at 20 ° 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 to give 2- (tetrahydrothiopyran-4-carbonyl) -HPI-S, S-dioxide, mp 253-255 ^° C (from ethanol),

%.

za) To a solution of 4.9 g of 2- (4-oocyclohexylcarbonyl) -HPI in 50 ml of absolute tetrahydrofuran is added slowly under nitrogen at -70 ° C 35 ml of a 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, m.p. 162-164 ° C (isopropanol / diethyl ether), 47%.

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 feverish.

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 tablets may be used for veterinary purposes.

Example B

Tablets for combating preferably Cestodes-Finnen or Schistosom maize starch magnesium stearate mg 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 60% methyl ester p-hydroxybenzoic acid and 40% propyl ester p-hydroxybenzoic acid 0.1 kg ethanol,. 12 1

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

Example E

Capsules to combat Cestodes. and Schistosom in human and veterinary medicine

(a) effervescent tablets each tablet comprising: 2-cyclohexyl ^; carbonyl-HPI 1000 mg. citric acid 800 mg sodium carbonate 900 mg saccharin 5 mg sucrose to 4000 mg

(b) chewable tablets, each tablet containing:

2-cyclohexylcarbonyl-HPI 2000 mg cellulose 80 mg sodium carboxymethyl- cellulose 40 mg dyes and aroma as you wish sucrose up to 4000 mg Example C Dragees to combat tapeworms in humane medicine The dragee core contains: 2-Cyclohexyl-carbonyl-HPI 250 mg lactose 150 gm

Capsules of appropriate size shall be filled with a mixture containing:

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

Capsules containing 1000 mg and 10,000 mg of 2-cyclohexylcarbonyl-HPI are prepared.

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 6 ml of water and 4 ml of propylene glycol with the addition of a solubiliser. The vials are 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

Pelletky

A powder mixture is prepared from equal parts by weight of 2-cyclohexylcarbonyl-HPI and lactose and is uniformly processed together with sodium carboxymethylcellulose in the usual manner. granulate with a mean 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 is:

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

Claims (5)

SUBJECT Preparation method 2-acyl-4-oxo-hexahydro-4H-pyrazino (2,1-a) isoquinoline derivatives of the general formula I wherein the radical R represents a straight or branched alkyl group having up to 15 carbon atoms, a methyl group substituted one to three times with chlorine, methoxy, phenyl, chlorophenoxy, acetoxyphenyl or thienylmercapto, ethenyl or ethynyl substituted by phenyl, C 2 -C 12 cyclopropyl, ketocyclohexyl, acetoxycyclohexyl or carboxycyclohexyl, cycloalkenyl C 3 -C 12 carbon atoms, phenoxy, ethoxycarbonyl, adamantyl, phenyl mono- or poly-substituted by alkyl 4 carbon atoms, fluorine, chlorine, hydroxy, methoxy, dimethylamino, nitro, NH — CHO— NH-COCH NH-CO-CH2-OCH3 with trifluoromethyl, cyano and / or methoxycarbonyl, naphthyl or unsubstituted saturated or unsaturated mono- or bicyclic heterocyclic 24 b 5% masterbatch (preferably for small animals): 5 kg of 2-cyclohexylcarbonyl-HPI were treated 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 g of this medicinal feed containing 10,000 mg of 2-cyclohexylcarbonyl-HPI is administered to adult bovine animals to control the said species of Moniezia. 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-cyclohexylcarbonyl-HPI and processed pharmaceutical preparations. invention ký radical having 5 or 6 ring members containing 1 to 2 nitrogen, oxygen and / or sulfur or substituted by oxygen, methyl, cholrem _fc bromo, amino, CHO-group and / or a knife-group .. and optionally fused with a compound of formula (II) wherein R is as defined in formula (I) and X is fluorine, chlorine, bromine, iodine, methylsulfonyloxy or arylsulfonyloxy having a radical of formula (II) C 1 to 10 carbon atoms, preferably p-toluenesulfonyloxy, are cyclized in the presence of a cyclizing agent, preferably a strong base such as butyllithium, tert-butylate. potassium, phenyllithium, sodium hydride, alcoholate such as sodium or potassium methylate, sodium or potassium ethylate, sodium or potassium propylate, sodium or potassium isopropylate, sodium or potassium n-butylate or sodium or potassium tert-butylate or amide such as lithium diisopropylamide, sodium or potassium, under HX cleavage conditions, and optionally the racemic compound of formula I obtained 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.