CH636604A5 - Process for preparing novel N-(2-aminocycloheptyl)-N-alkanoyl thioanilides - Google Patents

Abstract

Novel compounds of the formula <IMAGE> in which the substituents are defined in Claim 1, are prepared. These compounds are obtained by heating an appropriate alkanoyl compound with a thiolating agent in a solvent under reflux and, where appropriate, converting resulting compounds into the corresponding salts. The novel compounds may be used as antidepressants.

Description

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PATENT CLAIM Process for the preparation of new compounds of the formula

R

; = s in which the wavy line (■ -) in the 1-position of the cycloheptyl ring indicates an ic or trans configuration of the substituents in 1- and 2-positions of the cycloheptyl ring and in which:

p = 0 or 1;

R is a CrC3 alkyl radical, a C3 to Ce cycloalkyl, vinyl, ethoxy or methoxymethyl radical;

Rj alone is a Cr to C3 alkyl group;

R2 alone is a Cr to C3 alkyl radical or, in the case where Rj is a Cr to Cs alkyl radical, a radical of the formulas:

-ch2ch2n (ch,) 2,

-CH2CH2CH2N (CH3) 2,

-CH2CcH5,

-CH2CH2CeH5 or C3 to Cg alkenyl;

R; and R2 together with the nitrogen atom to which they are attached, an N-pyrrolidinyl or N-piperidinyl ring;

Y and Z, which may be the same or different, are a hydrogen atom, a halogen atom with an atomic number from 9 to 35, a trifluoromethyl radical, a Cr to C2-alkyl radical, an azidor radical or a Cr to C2-alkyloxy radical, or Z in the case that Y represents a trifluoromethyl radical or azidor radical, a hydrogen atom, and it is true that in the event that Y represents a Cr to C2-alkyloxy radical and Z represents a hydrogen atom, the Cj- to Cz-alkyloxy radical is in the 3-position, and im If Y and Z both represent halogen atoms or Cr to C2-alkyloxy radicals, these radicals are in 3- and 4- or 3- and 5-positions, as well as their acid addition salts, characterized in that compounds of the formula

R

: = o

N

heated under reflux with a thiolating agent in a solvent and any compounds obtained are converted into the corresponding salts.

The invention relates to a process for the preparation of new N- (2-aminocycloheptyl) -N-alkanoylthioanilides which have a pharmaceutical activity on the central nervous system. The compounds mentioned can be present as cis- and trans-N- (2-aminocycloheptyl) -N-alxanoylanilide compounds or as corresponding pharmacologically acceptable salts. It has been shown that the compounds in question have strong antidepressant properties which act on the central nervous system and which, after conversion into suitable pharmaceutically leonsumable preparation forms and administration in suitable doses, enable them to be used as antidpressants.

By W.G. Stoll and co-workers are reported in “Helvetica Chemica Acta”, volume 34, pages 1937 to 1943 (1951) about N- [2- (dimethylamino) cyclohexyl] aniline and processes for its preparation from N (2-hydroxycyclohexyl) aniIin. The authors also report that such compounds are pharmacologically active as antihistamines. However, there is no reference in the cited literature reference to the compounds according to the invention or their use as antidepressants.

J.W. Lewis and co-workers report in “The Reactions of Aromatic Nitroso-compounds with En-amines. Part I. The Reaction of Nitrosobenzene with 1-Morpholine-l-cyclohexene »article titled in« J. Chem. Soc. (London) (1972) », Perkins Transactions I, Part III, pages 2521 to 2524, inter alia on N- (2-morpholin-l-yl-cyclohexyl) phenylhydroxylamine and its hydrochloride. However, there is no reference in the cited reference to the alkanoylanilides according to the invention or their antidepressant properties.

Furthermore, J.W. Lewis and co-workers in an article entitled “Chemistry and Biological Activity of N-Substituted Hydroxylamines” in “J. Pharmaceutical Sciences », December 1974, Volume 63, No. 12, pages 1951 to 1953, about some N-arylhydroxylamines, such as N- [2- (N-pyrrolidinyl) cyclohexyl] -N-phenylhydroxylamine; however, these compounds have no central nervous system properties. For example, for the alcohols, e.g. [2- (N-Piperidinyl) cyclohexyl] - (4-methoxy-phenyl) methanol, a diuretic activity reported. It is also said that when the alcohol is acetylated, depressive activity occurs on the central nervous system. Furthermore, the reaction of propionyl chloride with N- [2- (N-piperidinyl) -l, l-dimethylethyl] -N-phe-nylhydroxylamine to form the N-chloro compound and subsequent conversion thereof into a mixture of chlorinated aniline derivatives is reported. However, the cited literature reference lacks any reference to the compounds according to the invention, to their preparation or to their antidepressant properties.

US Pat. No. 3,510,492 discloses some 2-anilino- and 2-anilinomethyl-cycloalkylamines which are suitable as antidiabetics (when administered in low doses to lower the blood sugar). The structural formula IV given in column 2 of US Pat. No. 3,510,492 does quite generally include some of the compounds of the formula I according to the invention, but the compounds in question represent chemical intermediates on the way to their 2-amino-cycloalkylamines. In the US patent mentioned there is no indication of the practical utility of compounds of structural formula IV as end products.

The object of the invention was to create new and promising antidepressants, namely N- (2-aminocyclo-heptyl) alkanoylthioanilides, the preferred types of which in particular should have a better therapeutic ratio or a better therapeutic index than imipramines and further with regard to s

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longer periods between the individual administrations should have a longer-lasting effectiveness. These compounds or their pharmacologically acceptable salts (optionally together with a pharmaceutical carrier) can be used in the form of a pharmaceutical dosage unit or unit dose in the treatment or control of depressive conditions in mammals and humans.

The compounds which can be prepared according to the invention have the following formula

R

: = s

N

in which the wavy line (-) in the 1-position of the cycloheptyl ring indicates an ic or trans configuration of the substituents in the 1 and 2 positions of the cycloheptyl ring and in which:

p = 0 or 1;

R is a C ^ Cj ethyl radical, a C3 to C6 cycloalkyl, vinyl, ethoxy or methoxymethyl radical;

R-! alone a Ct to C3 alkyl radical;

R2 alone is a Ct to C3 alkyl radical or in the event that R! represents a Cr to C3 alkyl radical, a radical of the formulas:

-CH2CH, N (CH,) 2,

-CH2CH2CH2N (CHj) 2,

-ch2c6h5,

-CH2CH2C6H5 or C3 to C6 alkenyl;

Rj and R2 together with the nitrogen atom to which they are attached represent an N-pyrrolidinyl or N-piperidinyl ring;

Y and Z, which may be the same or different, are a hydrogen atom, a halogen atom with an atomic number of 9 to 35, a trifluoromethyl radical, a Cr to C2 alkyl radical, an azidor radical or a Ci to C2 alkyloxy radical, or Z in the case that Y represents a trifluoromethyl radical or azidorest, a hydrogen atom, and it is true that in the case that Y represents a Cr to C2-alkyloxy radical and Z represents a hydrogen atom, the Cr to C2-alkoxy radical is in the 3-position, and in the case that Y and Z both represent halogen atoms or Cj to C2 alkyloxy radicals, these radicals are in 3- and 4- or 3- and 5-positions.

The process according to the invention for their preparation is characterized in that compounds of the formula

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R

> 0

N,

heated under reflux with a thiolating agent in a solvent and any compounds obtained are converted into the corresponding salts.

The compounds mentioned and their pharmacologically acceptable salts have powerful central nervous system antidepressant properties, optionally together with a pharmaceutical carrier, namely in the treatment or control of depressive conditions in mammals or humans. The compounds mentioned are preferably suitable in the form of suitable pharmaceutical dosage units or unit doses for administration to humans in doses of 4 to 400 mg per day as part of the therapy for the treatment of depressive conditions. In the case of conventional laboratory test animals which were used to determine these properties, the compounds in question suggest a rapid response or a rapid reappearance of the antidepressant properties (of the respective medicament). The preferred compounds also have a lower toxicity in standard laboratory tests than the usual standard antidepressant imipramine, and a longer duration of activity of the test compound in the test animal. These properties enable the new compounds to be administered as antidepressants in a smaller amount and / or after a longer period between the individual administrations, for example once a day, in order to achieve a desired given antidepressant effect.

If the compounds obtained according to the invention or their acid addition salts e.g. in crystalline form as solvates, i.e. with a very specific amount of solvent, for example water, ethanol and the like, in physical connection, the solvent can be removed per se without an effective change in the chemical unit, so that solvates of this type should therefore also come under the invention.

In formula I, the expression “Ct to Cs-alkyl radical” stands for a methyl, ethyl, n-propyl or isopropyl radical. The expression “C3 to C6 cycloalkyl radical” stands for a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl radical. The expression “C3- to C6- (allyl) alkenyl radical” includes radicals which have non-adjacent double bonds, for example allyl, 2-butenyl and 2-methyl-2-butenyl, 2-pentenyl and 3-methyl-2-pentenyl as well as the different 2-witch-nyl remains. «Halogen atoms with atomic numbers from 9 to 35»

are fluorine, chlorine and bromine atoms.

The preferred compounds obtainable according to the invention are in trans configuration.

New compounds preferred in pharmaceuticals or pharmaceutical preparations are those of the formulas given, in which:

R is a Cr to C3 alkyl radical, preferably an ethyl radical;

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Rj and R2 each have a Cr to C3 alkyl radical and at least one of the radicals Y and Z is a halogen atom with an atomic number of 9 to 35, preferably in the 3- or 4-position, a C 1 -C 2 -alkoxy or trifluoromethyl radical in the 3-position or a methyl radical in the 3- or 4-position in combination with one of the halogen atoms mentioned in the adjacent 3- or 4-position.

In the same way, their pharmacologically acceptable salts are preferred.

Another preferred subgroup of new compounds includes those of the formula given, in which:

R is a Cr to C3 alkyl radical, preferably an ethyl radical;

Rj and R2 together with the nitrogen atom to which they are attached, an N-pyrrolidinyl or N-piperidinyl ring and at least one of the radicals Y and Z represent a halogen atom with an atomic number from 9 to 35 in the 3- or 4-position.

These connections are also in particular in the trans configuration.

Another preferred subgroup of the new compounds includes those of the formula given, in which:

R is a C3 to C6 cycloalkyl radical;

Ri and R2 are a Cr to C3 alkyl radical and at least one of the radicals Y and Z is a halogen atom with an atomic number from 9 to 35 in the 3- or 4-position, a trifluoromethyl radical in the 3-position or a methyl radical in the 3- or 4-position in Combination with one of the halogen atoms in the adjacent 3- or 4-position, and their pharmacologically acceptable salts.

Examples of acid addition salts, including pharmacologically acceptable salts, of compounds of the formula I are the salts of hydrogen chloride, methanesulfone, pamoe, hydrogen bromide, sulfur, vinegar, cyclo-hexanesulfame, p-toluenesulfone and amber -, ß-naphthalene-sulfonic, maleic, fumaric, citric, lactic and oxalic acid.

For use of the new compounds in antidepressant drugs, the compounds in question can be in suitable pharmaceutical preparation forms, for example oral administration forms, such as tablets, powders, capsules and solutions or suspensions, in suitable solvents or suspending media, or parenteral administration forms, e.g. dry powders in sterile, tightly closed containers which are mixed with a sterile solvent immediately before administration, sterile solutions or suspensions in water or other suitable solvents or suspending media, optionally together with a pharmaceutical carrier, excipient or diluent, for convenient administration to patients be transferred or packaged in an amount effective to relieve depressive conditions. As a rule, the dose of compound of the formula I or its pharmacologically acceptable salt is about 4 to 400, preferably 50 to 200 mg. The particular dose depends on the strength of the particular compound of formula I, the condition to be treated, the weight of the patient or other factors relevant to the decision.

The new N-thioacylaminoanilide compounds of the formula I are obtained, as described above, by heating the corresponding N-acyl (C = 0) aminoanilides with a thiolating agent, such as phosphorus pentasulfide or diethyldithiophosphate [P (S) SH (OC2H5) 2 ], in a solvent such as pyridine to reflux temperature. You work for a sufficient time to replace the acyl oxygen atom with sulfur and then you can

Recovery and purification of the M-thioaxylaminoanilide compound can be carried out in a conventional manner.

A preferred connection that can be produced according to the invention is:

3,4-dichloro-N- [2- (dimethylamino) cycloheptyl] thiopropionanilide.

If appropriate, the compounds of the formula I obtained according to the invention can be separated or dissolved in their d- and 1-optical isomers in a customary known manner. In such a case, the optical resolution or separation can take place according to at least two process variants. The separating or dissolving agents in both process variants are known, e.g. optically active camphor sulfonic acid, bis-p-toluene tartaric acid, tartaric acid and di-acetyltartaric acid. These compounds are commercially available and are usually used for the separation or dissolution of amines (bases) (cf. “Organic Syntheses”, volume V, page 932 (1973), dissolution or separation of R - (+) and S - (-) - a-Phenylethylamine with (+) - tartaric acid).

In the first process variant for dissolving or separating the compounds mentioned, for example, one of the aminoamide compounds is converted into its optically active diastereomeric salts by reaction with an optically active acid of the type mentioned in the conventional isomer separation of the type described. These diastereomeric salts can be separated from one another in a conventional manner, for example by fractional crystallization. Diastereomeric salts have different crystallization properties which are used in this separation. When each diastereomeric salt is neutralized with an aqueous base, the corresponding optically active free aminoamide is obtained. Each optically active free aminoamide can then be converted into the desired acid addition salt separately and in the manner described above.

In the second process variant, which is preferred for some of the new compounds, the compounds of the formula I are converted into their corresponding d- and 1-isomers by first the asymmetric, trans or 1,2-cycloaliphatic substituted diamine by treatment with a separating or dissolving agent, crystallization, separation and recovery of the corresponding trans-d-diamine, trans-1-diamine or the cis-d-diamine or eis-1-diamine into their corresponding d- and 1-isomers are converted and then the respectively separated diamine starting material is allowed to react with the desired carboxylic acid anhydride or halide to form the corresponding cis or trans-d- or -1-compound of the formula I. The latter can then be converted into any pharmaceutically acceptable acid addition salt in the manner already described.

If the acid addition salt used to extract the new compound of formula I from its reaction mixture is not pharmacologically acceptable as such, the free aminoamide base of formula I can be prepared therefrom and then converted into a pharmacologically acceptable salt in the usual known manner.

When using the new compounds of the formula I as antidepressants, the compound of the formula I to be used in each case from the active ingredient can be administered in the form of a unit dose or dosage unit with a suitable pharmaceutical diluent or carrier for a pharmaceutical preparation or a medicament for oral, parenteral or rectal administration . Such unit doses or dosing units are examples

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White tablets, powder sachets, capsules, dragees, capsules, solutions, suspensions, sterile injectable forms of administration, suppositories, bougies and the like. Suitable diluents or carriers are, for example, carbohydrates (lactose), proteins, lipids, calcium phosphate, corn starch, stearic acid, methyl cellulose and the like. These substances can be used as carriers or for the production of coatings on suitable administration forms. Water and oils, for example coconut, sesame, safflower, cottonseed or peanut oil, are suitable for preparing solutions or suspensions of the active ingredient. If necessary, sweeteners, colors and flavors can be added. The regulations for the dosage units or unit doses vary from compound of formula I to compound of formula I, they depend in particular on the physical properties of the compound of formula I or its pharmacologically acceptable salt, weight and age of the respective patient and the effect to be achieved from. The pharmaceutical unit dose or dosage unit for these compounds is based on the general description given above, with about 4 to about 400 mg of compound of the formula I or their pharmacologically acceptable salt generally being contained per unit dose or dosage unit. The dosage regimen with regard to the amount of compound of the formula I should be sufficient to enable the respective patient to be relieved or relieved of the depression or depression states when a non-toxic amount is administered.

The following preparations and examples illustrate the production and further processing of the starting amines and the preparation of the new compounds. Unless otherwise stated, all temperature data are given in ° C.

Preparation 1

Preparation of trans-3,4-dichloro-N- [2- (dimethylamino) cycloheptyljpropionanilide and its maleate salt:

A. Preparation of trans-2-dimethylaminocycloheptanol and its fumarate salt:

A mixture of 89.0 g (0.80 mol) of cycloheptenoxide and 275 ml (2.4 mol) of a 40% aqueous dimethylamine solution is shaken for 24 hours at a temperature of about 125 ° C. in a shake bomb, whereby receives a brown solution. The reaction solution is then saturated with about 50 g of potassium carbonate, two layers being formed. After adding 1 ml of a 40% aqueous potassium hydroxide solution, the mixture obtained is extracted 3 times with ether. The ether extracts obtained are combined, dried with anhydrous magnesium sulfate and then concentrated by evaporating the ether. Distillation of the evaporation residue gives 114.6 g of trans-2-dimethylaminocyclo-heptanol with a bp of 98 ° to 100 ° C. in a yield of 91% with a 10 mm Hg column. The nuclear magnetic resonance spectrum, IR spectrum and mass spectrum confirm the structure ascribed to the reaction product.

A crystalline fumarate salt is now produced from the cycloheptanol obtained. After recrystallization from ethanol / ether, this has an mp of 136 ° to 137 ° C.

The elemental analysis of the amino alcohol C9H19NO gives the following values:

calculated: C 68.74 H 12.18 N 8.91 found: C 68.48 H 12.39 N 8.53

B. Preparation of trans-N- [2- (dimethylamino) cycloheptyl] -3,4-dichloroaniline and its oxalic acid salt: A mixture of 15.7 g (0.10 mol) of 2-dimethylamino-cycloheptan-l-ol and 4.8 g (0.10 mol) of sodium hydride (50% dispersion) in 50 ml of tetrahydrofuran is heated on a steam bath for 1 hour and then cooled in ice. Now 11.5 g (0.10 mol) of methanesulfonyl chloride in 25 ml of tetrahydrofuran are added within 30 minutes. Then 32.4 g (0.20 mol) of 3,4-dichloroaniline are added in one portion to -10. After the tetrahydrofuran solvent has been distilled off, the reaction mixture is heated on a steam bath overnight. 200 ml of a 20% aqueous sodium hydroxide solution are then added and the mixture is heated for 1 hour. After extracting the reaction mixture 13 with 10% aqueous hydrochloric acid, the aqueous acid layer is washed with ether, made basic with 40% aqueous sodium hydroxide solution and then extracted with 250 ml ether. The ether layer is washed with a saturated aqueous sodium chloride solution, dried with magnesium sulfate and freed from the ether by evaporation. The oily evaporation residue obtained in this way is distilled, 17.3 g of trans-N- [2- (dimethylamino) cycloheptyl] -3,4-dichloroaniline having a bp of 170 ° to 180 ° C. at 0.3 in 57% yield mm Hg column received. 25 The oxalic acid salt of the amine is prepared from 5.2 g (0.057 mol) of oxalic acid and the diamine obtained in a solvent mixture of 25 ml of methanol and 200 ml of ether. When recrystallizing from the same solvent mixture, 15.5 g of pure 30 oxalic acid salt of the diamine mentioned, mp 153 ° to 154 ° C., are obtained in 69% yield. The structure ascribed to the compound is confirmed by the nuclear magnetic resonance spectrum, IR, UV and mass spectrum.

The elemental analysis of the compound C15H22N2C12. C2-35 H204 gives the following values:

calculated: C 52.15 H 6.18 N 7.16 Cl 18.12 found: C 52.25 H 6.34 N 6.98 Cl 18.23

40 C. Preparation of trans-3,4-dichloro-N- [2- (dimethylamino) cycloheptyljpropionanilide and its maleate salt:

An ice-cooled solution of 3.01 g (0.01 mol) of trans-N- [2- (dimethylamino) cycloheptyl] -3,4-dichloroaniline and 2.02 g (0.02 mol) of triethylamine in 100 ml of ether 45 1.85 g (0.02 mol) of propionyl chloride are added within 30 minutes. After the reaction mixture was stirred at room temperature overnight, 100 ml of a saturated aqueous sodium bicarbonate solution was added. The organic layer is washed with water and then with a saturated sodium chloride solution,

then dried over anhydrous magnesium sulfate and finally concentrated to a yellow oily residue consisting of the desired propionanilide. The oily evaporation residue obtained is dissolved in a mixture 55 of 10 ml of methanol and 75 ml of ether, whereupon 1.16 g (0.01 mol) of maleic acid are added. Here, a crystalline precipitate is formed. When recrystallized from the same solvent mixture in an 82% yield, 3.90 g of trans-3,4-dichloro-N- [2- (dimethylamino) -60 cycloheptyl] propionanilide, maleate salt with an mp of 165 ° to 166 ° C. The structure ascribed to the compound is confirmed by the nuclear magnetic resonance, IR, UV and mass spectrum.

The elementary analysis of the compound Ci8H26N2C120. C4-

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H404 gives the following values:

calculated: C 55.81 H 6.39 N 5.92 Cl 14.98 found: C 56.05 H 6.46 N 6.07 Cl 15.16

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Preparation 2

Preparation of trans-3-trifluoromethyl-N- [2- (l-pyrrolidinyl) cycloheptyl] propionanilide:

Corresponding to preparation 1, but with replacement of the dimethylamine in part A by a stoichiometrically equivalent amount of pyrrolidine (for the production of trans-2- (N-pyrrolidinyl) cycloheptanol) and replacement of 3,4-dichloraniiine in part B by one a stoichiometrically equivalent amount of 3-trifluoromethylanilide gives trans-N- [2- (N-pyrrolidinyl) cyclo-heptyl] -3-trifluoromethylaniline. This can then be according to Example 1, Part C, in its propionanilide and, if desired, in its acid addition salt, e.g. transfer the hydrochloride or maleate salt.

example 1

Preparation of trans-4-bromo-N- [2- (dimethylamino) cycloheptyl] thiopropionanilide

Equimolar amounts of trans - 4-bromo-N- [2- (dimethylamino) cycloheptyl] propionanide and phosphorus pentasulfide prepared analogously to the compound obtained according to preparation 1 are dissolved in pyridine, whereupon the mixture is heated to the reflux temperature. After the pyridine has been distilled off, trans-4-bromo-N- [2- (dimethylamino) cycloheptyl] thiopropionanilide is isolated by working up in the weakly basic and neutral range. The maleic acid addition salt of the thiopropionanilide obtained is obtained in accordance with preparation 1, part C. Other acid addition salts are obtained in a corresponding manner.

Example 2

Preparation of 3,4-dichloro-N- [2- (dimethylamino) cyclo-heptyl] thiopropionanilide:

According to Example 1, but with the replacement of 4-bromo-N- [2- (dimethylamino) cycloheptyl] propionanilide by a stoichiometrically equivalent amount of 3,4-dichloro-N- [2- (dimethylamino) cycloheptyl] propionanilide is obtained 3,4-dichloro - N- [2- (dimethylamino) cycIoheptyI] thiopropionanilide.

For oral administration, either solid or liquid dosage units or unit doses of the respective alkanoylanilide can be prepared. For the manufacture of solid forms of administration, e.g. of tablets, the compounds of formula I are mixed or blended with customary components, such as talc, magnesium stearate, dicalcium phosphate, magnesium aluminum silicate, calcium sulfate, starch, lactose, acacia, methyl cellulose and substances which function functionally similarly as pharmaceutical diluents or carriers. Wafer capsules are obtained in a similar way to tablets, the only difference being the different form and the addition of cane sugar or other sweeteners and flavors. In its simplest embodiment, capsules similar to tablets are obtained by mixing the compounds with inert pharmaceutical diluents and filling the mixture obtained in each case into hard gelatin capsules of a suitable size. Soft gelatin capsules are obtained by mechanically encapsulating a slurry of the compound in an acceptable vegetable oil, light liquid petroleum jelly, or other inert oil.

Flowable unit doses or dosage units for oral administration, such as syrups, elixirs and suspensions, can also be prepared. The water-soluble forms can be dissolved in aqueous carriers together with sugar, aromatic flavors and preservatives to form a syrup. An elixir is obtained using an aqueous alcoholic (e.g. aqueous-ethanolic) carrier, and suitable sweeteners such as sugar and the sodium salt of benzoic acid sulfimide, along with aromatic flavors or ingredients.

Suspensions are obtained with aqueous carriers with the addition of suspending agents such as acacia, tragacanth, methyl cellulose and the like.

Flowable unit doses or dosage units suitable for parenteral administration are obtained from the compounds in question and a sterile carrier, preferably water; depending on the carrier and the concentration required, the compound in question can either be suspended or dissolved in the carrier. When preparing solutions, the compounds in question are dissolved in water suitable for injection purposes and then, prior to filling into suitable vials or ampoules and sealing them, are sterilized by filtration. Aids, e.g. Local anesthetics, preservatives and buffers, with dissolved. To improve stability, the respective mass can be frozen under vacuum after filling into the vial and removing the water. The dry lyophilized powder is then sealed in the vial, which vial is packed with a vial filled with water for injections to reprocess the liquid before use. Parenteral suspensions are obtained in practically the same manner, except that the compound is suspended therein instead of being dissolved in the carrier. In this case, too, no filtration sterilization can take place. Rather, the compound in question is sterilized by exposure to ethylene oxide before being suspended in the sterile carrier. A wetting agent or surface-active agent is expediently incorporated into the respective composition in order to better and more evenly distribute the compound.

Rectal suppositories here and below mean solid bodies for insertion into the rectum, which melt or become soft at body temperature and release at least one pharmacologically or therapeutically active component.

Pharmaceutically acceptable substances for the production of rectal suppositories are the basis or carrier and means for increasing the melting point.

Examples of bases or carriers are cocoa butter (theobroma oil), glycerin / gelatin, carbowax, (polyoxyethylene glycol) and suitable mixtures of mono-, diurni triglycerides of fatty acids. Combinations of the different basics can also be used. Means for increasing the melting point of suppositories are, for example, spermaceti and wax. Rectal suppositories can be. either by pressing or by other shaping processes. The usual weight of rectal suppositories is approximately 2.0 g.

Tablets and capsules for rectal administration are obtained using the same pharmaceutically acceptable substances and according to the same methods as are used or carried out in the preparation of tablets and capsules for oral administration.

Rectal suppositories, tablets or capsules are packaged either individually in the form of unit doses or dosage units or in multiples thereof, for example in amounts of 2, 6 or 12.

The term “dosing unit” or “unit dose” means physically delimitable units which are suitable as dosing units or unit doses for humans and animals, each of which contains a given amount of active material,

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which is aimed at achieving the desired therapeutic effect, contains diluents, carriers or extenders. The regulations for such dosing units or unit doses are determined and are directly dependent on (a) the characteristics of the active material and the desired success and (b) the inherent limitations of the art of packaging an active material by administration to humans and animals.

Examples of suitable dosage units or unit doses are tablets, capsules, pills, suppositories, powder sachets, wafers, wafer capsules, teaspoonfuls, tablespoonfuls, dropperfuls, ampoules, vials, divided multiples of any of the administration forms mentioned and other forms of administration.

The dosage of the compound in question for treatment will depend on the route of administration and the age, weight and condition of the patient. A dosage specification of about 4 to about 400 mg, preferably from 50 to 200 mg, per day, given as a single dose or in multiple doses, corresponds to the range of effectiveness of the medicaments or pharmaceutical preparations according to the invention intended to relieve depression. The dose to be administered is calculated on the basis of about 0.08 to about 6 mg / kg of body weight

Patient. The respective compound is brought into the form of a dosage unit with a suitable pharmaceutical carrier for convenient and effective administration. Dosage units or unit doses of medicaments according to the invention preferably contain 5, 10, 25, 30, 50, 100 or 200 mg of the respective compound for systemic treatment. Sterile preparations of the active material for parenteral treatment expediently contain 0.1 to 25% by weight of the compound in question. The dosage of at least one compound of the formula I and at least one other active ingredient-containing medicament according to the invention is determined according to the actual metering instructions for each such ingredient.

15 In addition to the administration of compounds of the formula I alone or as medicaments containing main constituents, the compounds of the formula I can also be used in the medicinal products in question with other active substances, e.g. Analgesics such as acetylsalicylic acid, acetaminophen, 20 PAC compound (phenacetin / acetylsalicylic acid / caffeine), anti-inflammatory or anti-inflammatory agents such as ibuprofen and the like, anti-anxiety agents such as perphenazines, amitriptylene hydrochloride, combined chlorodiazepoxides, alpoxzoin lamole, whoever -25 den.

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