NO762158L - - Google Patents

Description

Process for the production of new 2-piperidinoalkyl-1,4-benzodioxanes.

The invention relates to the production of new 2-piperidinoalkyl-(1-benzofurans or 1,4-benzodioxanes)

with the general formula I

in which Ph means a 1,2-phenylene residue, which is optionally substituted with one to three, the same or different substituents selected from lower alkyl, hydroxy, mercapto, lower alkoxy,

lower alkylenedioxy, benzyloxy, lower alkylthio, halogen, trifluoromethyl, nitro or amineb, X means oxygen or sulphur, m means the integers 0 or 1 and n means the integers from 1 to H, each of the symbols p and q means an integer numbers from 1 to 3, where (p+q) is the number 4, each of the symbols R-^ and means

hydrogen, lower alkyl or HPh, means hydrogen, hydroxy, lower alkoxy, lower or higher alkanoyloxy, R^ means lower alkyl, HPh-lower alkyl, HPh or naphthyl, which is optionally substituted as Ph, furyl, thienyl, pyridyl, benzofuryl, benzothienyl, quinolyl or isoquinolyl, which heterocyclic residues are optionally substituted as Ph as well as S-oxides or acid addition salts, especially therapeutically applicable acid addition salts of these compounds.

A 1,2-phenylene residue Ph is preferably monosubstituted, the substituents being illustrated by the following groups: Lower alkyl, e.g. methyl, ethyl, n- or i-propyl or -butyl hydroxy, mercapto; lower alkoxy, e.g. methoxy, ethoxy, n- or i-propoxy or -butoxy, lower alkylenedioxy, e.g. methylenedioxy, 1,1- or 1,2-ethylenedioxy, benzyloxy, lower alkylthio, e.g. methylthio or ethylthio, halogen, e.g. fluoride,

chlorine or bromine, trifluoromethyl, nitro or amino.

Of the whole numbers mentioned, m is preferably 1, when formula I means 1,^-benzodioxanes or 1,^-benzoxathianes or zero when the formula means 1-benzofurans. The alkylene group <C>n<H>2n preferably means methylene, 1,1- or 1,2-ethylene, 1,2- or 1,3-propylene, 1,2-, 1,3- or 1,4-butylene and each of the symbols p and q preferably means the number 2.

Each of the symbols R 1 and R 2 preferably means hydrogen, but also lower alkyl, especially methyl, or another above-mentioned lower alkyl residue. One of these symbols, especially R2 can also mean optionally substituted phenyl, the substituents being those of an H-Ph residue.

The symbol R 1 preferably means free, etherified or esterified hydroxy, such as lower alkoxy, e.g. an above-mentioned lower alkoxy residue, lower or higher lower alkanoyloxy, e.g. acetoxy, propionyloxy...or pivalyloxy; octa-noyloxy, decanoyloxy, undecanoyloxy, lauryloxy, myristoyloxy, palmitoyloxy or stearoyloxy; but also hydrogen.

A lower alkyl group. R 1 is preferably a secondary or tertiary alkyl group with 3 to 7 carbon atoms, such as 1-propyl, i- or tert-butyl, -pentyl, or -hexyl. An aralkyl group R 1 is preferably a HPh-CnH 2n group, e.g. benzyl, 1- or 2-phenylethyl. Particularly preferred groups R1 are phenyl groups HPh, which have already been mentioned above, but also 1- or 2-naphthyl groups, which may be substituted as indicated for HPh. Heterocyclic R 1 groups are preferably unsubstituted 2- or 3-furyl or -thienyl; 2-, 3- or 4-pyridyl; 2- or 3-(1-benzofuryl or 1-benzothienyl);

2-, 3- or 4-quinolyl or 1-, 3- or 4-isoquinolyl, these groups may be substituted with one to three lower alkyl, preferably methyl, groups.

Since at least one nitrogen atom is present in the compounds of the general formula I, they can be present in the form of acid addition salts, especially therapeutically applicable acid addition salts, e.g. such as are derived from those below

said acids. The S-oxides according to the invention are such compounds of formula I, in which X means the group of formula SO.

By the term "lower" is meant in the above and following mentioned organic residues or compounds such with a maximum of 7, preferably 4, especially 1 or 2 carbon atoms. The term "higher" denotes residues with 8 to 20, preferably 10 to 16, carbon atoms.

The compounds according to the invention show valuable pharmacological, e.g. analgesic and mainly neuroleptic effects, the most favorable properties being far from the extrapyramidal side effects (depending on the dose). This sharp separation of action type has not yet been observed with other neuroleptic agents, e.g. haloperidol. These properties can be demonstrated in animal experiments, preferably on mammals, e.g. mice, rats, dogs and especially monkeys as test subjects. The compounds according to the invention can be administered to the animals enterally, e.g. orally or parenterally, e.g. subcutaneously, intraperitoneally or intravenously, for example, in the form of gelatin capsules, starchy suspensions, aqueous solutions or suspensions. Oral doses of approximately 0.1 to 10 mg/kg/day, preferably approximately 0.5 to 5 mg/kg/day, especially 1 to 2.5 mg/kg/day, are thereby used. The aforementioned compounds, e.g. 2-/_ 2-(4-Hydroxy-4-phenylpiperidino)-ethyl_l/-l, 4-benzodioxane, or its hydrochloride, causes

in the above-mentioned and oral doses, especially between approx. 0.5 and

5 mg/kg/day, a reduction of the weight arm operating reflex in squirrel monkeys.• This test is carried out as follows: Monkeys are exposed at certain time intervals to an electric shock that is given through the foot. The animals can avoid this electrical impulse when they press a button. The monkeys are trained to press a button before the onset of the electrical discharge. Each button press advances the electric shock by 20 seconds. If the monkeys neglect to press the button within 20 seconds, they will receive a short (0.5 second) electric shock every 20 seconds, until the next button press. Under the control conditions, the monkey presses the lever at a relatively steady rate, so that they rarely receive more than 5 or 6 shocks in the course of. a four-hour trial period. The new compounds that are being tested for their neuroleptic effects suppress the trained conditioned avoidance behavior of experimental animals. The blocking of this property manifests itself in a decrease in the ability to avoid electric shock, as the test animals undergo a significantly higher number of shocks.

Furthermore, they produce new compounds, e.g.

the propionic acid ester of the above-mentioned dioxane compound,

at an above-mentioned oral dose, especially between about 5 and 10 mg/kg/day, analgesic effect in mice. These effects

can be detected according to the tail abduction or phenylquinone curvature test. In the first test, a heat beam is directed at the tail of male rats and the duration of the radiation is measured. The end point of this time interval is the moment in which the animal pulls its tail away from the radiation area. The heat irritation is never used for longer than 10 seconds. The time value (control value) is determined before medication for each animal. For determining the presence of analgesic effects, the average value of the control values is calculated and three standard deviation values are selected for this. The time values obtained after medication of the animals which lie above the above-mentioned increased average value show the presence of an analgesic effect.

In the curvature tests, male mice are injected intraperitoneally with 2.5 mg/kg of phenylquinone for 20 minutes after the oral administration of the compounds according to the invention. One determines the number of mice which, after 5-15 minutes after the injection, curl up in pain, as the unchanged experimental animals show

presence of analgesic effect. *

The compounds according to the invention can consequently be used as analgesics and preferably as neuroleptic agents, e.g. in the treatment of aggressive conditions, agitation, • anxiety and pain in animals, preferably mammals. The compounds according to the invention can also be used as intermediates in the production of other valuable, particularly pharmacologically active compounds.

Preferred compounds are those of the general formula I, in which Ph means a 1,2-phenylene residue, which is optionally substituted with one or two substituents, selected from lower alkyl, hydroxy, mercapto, lower alkoxy, lower alkylenedioxy, benzyloxy, lower alkylthio, halogen, trifluoromethyl , nitro or amino, X means oxygen or sulphur, m means the integers 0 or 1, n means the integers from 1 to ^, each of the symbols p and q means an integer from 1 to 3, where (p+ q) is the number 4, each of the symbols R-^ and R2 means hydrogen or lower alkyl, R-^ means hydrogen, hydroxy, lower alkoxy, lower or higher alkanoyloxy, R^ means lower alkyl, HPh-CnH2n, HPh or optionally with one or two lower alkyl radicals substituted furyl, thienyl or pyridyl as well as therapeutically usable acid addition salts of these compounds.

Further compounds of the general formula I are preferred, in which Ph means a 1,2-phenylene residue,

which is optionally substituted with one or two substituents, selected from alkyl, alkoxy or alkylthio with a maximum of 4 carbon atoms each, halogen or trifluoromethyl, X means oxygen, m means the whole number 0 or 1, n means the whole numbers 2 to 4, each of the symbols p and q mean the number 2, each of the symbols R]_ °g ^2betvr hydrogen or alkyl with a maximum of 4 carbon atoms, FU means hydrogen, hydroxy, alkoxy with a maximum of 4 or alkanoyloxy with a maximum of 16 carbon atoms, R^means sec. or tart. alkyl with 3 to 7 carbon atoms, HPh-CH2, HPh, 2- or 3-furyl or -thienyl, 2-, 3- or 4-pyridyl as well as therapeutically usable acid addition salts of these compounds.

Of particular note are compounds of the general formula II

in which R means hydrogen, alkyl, alkoxy or alkylthio each having a maximum of 4 carbon atoms, halogen or trifluoromethyl,

x means the numbers "1 or 2, y means the whole numbers from 2 to 4, R" means hydrogen, hydroxy, alkoxy with a maximum of H or alkanoyloxy with a maximum of 16 carbon atoms, R' means sec. or tart. alkyl with 3 to 7 carbon atoms, R^-benzyl, Rx-phenyl, 2- or 3-furyl or -thienyl, 2-, 3- or 4-pyridyl as well as therapeutically usable acid addition salts of these compounds.

Particularly preferred are compounds of the general formula II, wherein R means hydrogen, methyl, ethyl, methoxy, ethoxy, methylthio, ethylthio, fluorine, chlorine or trifluoromethyl, x means the numbers 1 or 2, y means the numbers 2 or 3, R" means hydrogen, hydroxy, methoxy, ethoxy or alkanoyloxy with 2 to 12 carbon atoms, R' means i-propyl, i-or tert-butyl, benzyl, Rx-phenyl, 2- or 3-furyl or -thienyl, 2 -, 3- or 4-pyridyl as well as therapeutically applicable acid addition salts of these compounds.

Of particular note are compounds with the general formula II, in which R means hydrogen, methyl, methoxy, fluorine, chlorine or trifluoromethyl, each time in the 7- or 8-position, x means the numbers 1 or 2, y means the numbers 2 or 3, R" means hydroxy, methoxy or alkanoyloxy with 3 to 10 carbon atoms, R' m- or p-Rx-phenyl as well as therapeutically usable acid addition salts of these compounds.

The compounds according to the invention are produced according to methods known per se, e.g. by that

a) compounds of the general formulas III and IV

is condensed, as one of the symbols Y and Z2 means amino or

imino and the other means a reactive esterified hydroxy group.

A reactive esterified hydroxy group is e.g. a hydroxy group esterified with a strong inorganic or organic acid, above all a hydrohalic acid, e.g. hydrochloric acid, hydrobromic acid or hydroiodic acid, sulfuric acid or an aromatic sulphonic acid, e.g. p-toluenesulfonic acid or p-bromobenzenesulfonic acid. The condensation is preferably carried out in the presence of basic condensation agents, e.g. alkali metal or alkaline earth metal hydroxides, carbonates or hydrogen carbonates, such as . sodium, potassium or calcium hydroxide or carbonate, alkali metal hydrides, lower alkyl alkoxides or lower alkyl alkanoates, such as sodium hydride, sodium methylate or sodium acetate, or of organic tertiary nitrogen bases, such as trilower alkyl amines or pyridines, e.g. triethylamine or lutidine.

A further method for producing the new compounds consists in that

b) a compound of the general formula V

is reduced, with A meaning a group of formula cn<H2>n-2~COj<C>n<H>2n-s orY'"CnH2n-l'where Y' means a reactive esterified hydroxy group, R^means hydrogen' or R-^ and R^ together form a further C,C bond, R^ means R^ or HPh-lower alkanoyl, each of the symbols r and s means the whole numbers 0 or 2, with (r+s) being the numbers 2 or 4.

The group Y' is preferably a hydroxy group, esterified with a strong inorganic or organic acid, above all a hydrohalic acid, e.g. hydrochloric acid, hydrobromic acid or hydroiodic acid, sulfuric acid or an aromatic sulphonic acid, e.g. p-toluenesulfonic acid or p-bromobenzenesulfonic acid. The reduction is carried out in a manner known per se, depending on the presence of a keto and/or amide carbonyl group. The latter is preferably carried out with simple or complex light metal hydrides such as diborane or alkali metal borohydrides, alkali metal aluminum hydrides or alkali metal alkoxy borohydrides, e.g. lithium aluminum hydride and/or sodium trimethoxyborohydride. The reduction of ketones or olefins is preferably carried out with catalytically activated or nascent hydrogen, such as hydrogen in the presence of palladium or platinum catalysts, or with electrolytically produced hydrogen or preferably with cyanoborohydride. Finally, the reductive elimination of Y' is carried out by treating said ester with the above-mentioned hydride reducing agents, preferably with lithium aluminum hydride.

A further method for producing the new compounds consists in that

c) compounds of formula VI

is condensed with R^ metal compounds.

The reagents mentioned are preferably lithium or halomagnesium (Grignard) compounds. The reaction is carried out in a manner known per se, preferably in the presence of polar solvents such as open-chain or cyclic ethers, e.g. diethyl ether, tetrahydrofuran or dioxane.

A further method for producing the new compounds consists in

d) a cyclization of a compound of formula VII.

wherein Y means a reactive esterified hydroxy group.

A reactive esterified hydroxy group is e.g. a hydroxy group esterified with a strong inorganic or organic acid, above all a hydrohalic acid, e.g. hydrochloric acid, hydrobromic acid or hydroiodic acid, sulfuric acid or an aromatic sulphonic acid, e.g. p-toluenesulfonic acid or p-bromobenzenesulfonic acid. The ring closure is preferably carried out in the presence of basic condensation agents, e.g. alkali metal or alkaline earth metal hydroxides, carbonates or hydrogen carbonates, such as sodium, potassium or calcium hydroxide or carbonate, alkali metal hydrides, lower alkoxides or lower alkanoates, such as sodium hydride, sodium methylate or sodium acetate or of organic tertiary nitrogen bases, such as trilower alkyl- amines or pyridines, e.g. triethylamine or lutidine.

The compounds produced according to the invention can on i and for. in a known way are transferred into each other. Thus, e.g. compounds formed, in which R-^ means hydroxy, are etherified or esterified or their alkali metal, e.g. lithium salts are reacted with reactive esters of lower alkanols or with reactive alkanoic acid derivatives,

e.g. their halides or anhydrides. Formed esters can be hydrolysed according to methods known per se, preferably with aqueous alkalis. Furthermore, phenols formed can be etherified with diazoalkanes. Benzyl ethers formed can also be cleaved hydrogenolytically, e.g. in the presence of palladium-

or platinum catalysts. These methods can also be used for the dehalogenation of a Ph residue or for the reduction of a nitro group of this residue to the amino group. The nitration of a Ph group can also be carried out in a manner known per se, e.g. during heating. of a compound formed with a mixture of fuming nitric and sulfuric acids or acetic anhydride or its nitrate in trifluoroacetic acid. An iodine atom in the Ph residue can be replaced by trifluoromethyl, e.g. by reacting an iodide with trifluoromethyl iodide in the presence of copper powder. Formed compounds can be oxidized to sulfoxides with common mild oxidizing agents, e.g. alkali metal periodicates,

as sodium periodate.

Depending on the process conditions, the final substances are obtained in free form or in the form of their acid addition salts, which is also covered by the invention. Formed salts can in a manner known per se, e.g. with a stronger base, such as metal or ammonium hydroxide, a basic salt or ion exchangers, such as alkali metal hydroxide or carbonate, are transferred in the free compound. On the other hand, the free bases formed with organic or inorganic acids can form salts. For the preparation of the acid addition salts, acids are used in particular which give therapeutically usable salts. Such acids are e.g. inorganic acids such as strong mineral acids, e.g. hydrohalic acids, such as hydrochloric, hydrobromic or hydroiodic acid, sulfuric acid, phosphoric acid, nitric acid or perchloric acid, organic acids, e.g. aliphatic or aromatic carboxylic acids or ■ sulphonic acids,

such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, maleic acid, hydroxy-maleic acid or pyruvic acid, phenylacetic acid, benzoic acid, p-aminobenzoic acid, anthranilic acid, p-hydroxybenzoic acid, salicylic acid

or p-amino-salicylic acid, pamoic acid, nicotinic acid., methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, halobenzenesulfonic acid, toluenesulfonic acid, naphthalene sulfonic acids, sulfanilic acid or cyclohexanesulfamic acid or ascorbic acid.

These or other salts of the new compounds, such as e.g. the picrates, can also serve to purify the free compounds formed, as one transfers the free compounds to the salts and separates them and releases the free compound from the salts again.

Due to the narrow relationship between the new compound in free form and in the form of its acid addition salt, in the foregoing and the following, free compound is to be understood as appropriate, possibly also the corresponding acid addition salts.

The starting materials with the formulas III to VIII are

new, they can, however, be produced according to known methods, as e.g. are discussed in the examples.

The compounds of formula III can be easily prepared by reduction of a corresponding 1-benzofuran- or 1,4-benzodioxan-2-yl-alkanoic acid with lithium aluminum hydride

or sodium 2-methoxy-ethoxy-aluminium hydride to the corresponding alcohol and its esterification with the above-mentioned strong acids or their derivatives. The formed reactive esters can, by reaction with ammonia in an organic solvent, e.g. ethanol or benzene, preferably under elevated pressure or elevated temperature are transferred in the corresponding amines.

Compounds of formula V can be obtained from the previously mentioned acids by converting them into a halide, mixed anhydride or amide of imidazole, and reacting these compounds with corresponding piperidines. The unsaturated starting materials are preferably enamines, which are prepared from the corresponding aldehydes and the previously mentioned piperidines.

The aldehydes used can be obtained by reduction of the above-mentioned acid halides according to Rosenmund, or acid nitriles with diisobutylaluminum hydride. ' Finally, they can to the starting substances of formula V correspond to alcohols, in which starting substances A means the group of formula Y'"cnH2n-l f1,61713^1!63 by condensation of a 1-benzofuran- or 1,4-benzodioxane-2- yl-alkylene-oxide with the already mentioned piperidines or by reaction of the -corresponding α-bromoketone and reduction with sodium borohydride. These alcohols are discussed in US Patent No. ■ 3•914,238. They can be converted into their reactive esters in a manner known per se, either by reaction with the acids HY' under anhydrous conditions, e.g. in the presence of sulfuric acid, or with halides or anhydrides of the above-mentioned acids, e.g. tosyl chloride.

The starting substances with formula VI can be prepared analogously to method a), i.e. by reacting corresponding piperidones with the reactive esters mentioned in this method.

Finally, the starting substances with formula VII can be obtained by Mannich reaction of the above-mentioned piperidines with corresponding aldehydes and/or ketones by bromination of the formed piperidinoalkanones, condensation of the formed α-bromoketones with monoacetyl-pyrocatechin, reduction of the ketonic condensation product with sodium borohydride to the corresponding alcohol and its esterification as indicated in the procedure

a),

Starting materials and end products with formula I

to VII, which are mixtures of isomers, can be resolved into the individual isomers according to methods known per se, e.g. by fractional distillation, crystallization and/or chromatography. Racemic products can be divided into the optical antipodes, e.g. by separation of their diastereoisomeric salts, e.g. by fractional crystallization of d- or 6-tartrates or, a-methylbenzylammonium salts.

The above-mentioned reactions are carried out according to methods known per se in the presence or absence of diluents. agents, preferably in such, which are inert towards the reagents and dissolve them, catalysts, condensation and neutralization agents and/or in an inert atmosphere, under cooling, at room temperature or at elevated temperatures, preferably at the solvent used - boiling point at. normal or elevated pressure.

The invention also relates to modifications of the present method according to which an intermediate product obtainable at one or other step of the method is used as starting material and the remaining method steps are carried out or the method is interrupted at one or another step or according to which a starting material is formed under the reaction conditions, or in which a starting material is used in the form of an S-oxide, a salt or an optically pure antipode.

In the method according to the invention, such starting materials are preferably used which belong to the compounds mentioned at the outset as particularly valuable, especially those with formula II.

The pharmacologically usable compounds produced according to the invention can e.g. are used for the production of pharmaceutical preparations that contain one effective amount of the active substance together or in a mixture with carriers, which are suitable for enteral or parenteral administration. Tablets or gelatin capsules are preferably used, which contain the active substance together with the diluent, e.g. lactose, dextrose, cane sugar, mannitol, sorbitol, cellulose and/or glycine and lubricants, e.g. diatomaceous earth, talc, stearic acid or salts thereof, such as magnesium or calcium stearate and/or polyethylene glycol. Tablets also contain the binder, e.g. magnesium aluminum silicate, starch pastes, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose and/or polyvinyl pyrrolidone, and if desired, the explosive, e.g. starch,

agar, alginic acid or a salt thereof, such as sodium alginate, enzymes of the binder and/or fizzy mixtures, or adsorbents, colourings, flavorings and sweeteners. Injectable preparations are preferably isotonic aqueous solutions or suspensions and suppositories primarily fat emulsions or suspensions. The pharmacological preparations may be sterilized and/or contain excipients, e.g. preservatives, stabilisers, wetting and/or emulsifiers, solubility mediators, salts for regulation of. the osmotic pressure and/or buffers. The present pharmaceutical preparations which, if desired, can contain additional, pharmacologically valuable substances are prepared in a manner known per se, e.g. using usual mixing, granulating or coating methods and contains from approx. 0.1% to approx. 75%, especially from approx. 1% to approx. 50% of the active substance.

The invention must be ■explained in more detail with help

of some examples. When nothing else is specified, the evaporation of the solvent is carried out under reduced pressure. Example 1.

A mixture of 6.68 g of 2-(2-tosyloxyethyl)-1,4-benzodioxane, 3.54 g of 4-hydroxy-4-phenylpiperidine, 10 g of anhydrous sodium carbonate and 100 ml of 4-methyl-2-pentanone is boiled for 48 hours during reflux. The mixture is filtered, evaporated and the residue recrystallized from isopropanol. This gives 2-[_2-(4-hydroxy-4-phenylpiperidino)-ethyl]-1,4-benzodioxane, which melts at 142°C.

The product is suspended in 20 ml of ethanol, the suspension is neutralized with ethanolic hydrogen chloride and the precipitate formed is recrystallized from ethanol-diethyl ether. You get the corresponding hydrochloride which melts at 203°C.

In an analogous manner, 2-(4-hydroxy-4-phenylpiperidinomethyl)-1,4-benzodioxane is also produced, which after recrystallization from methanol melts at 215-217°C.

The starting material is prepared as follows: A solution of 16 g of bromine in 10 ml of petroleum ether is added slowly to a solution of 6.7 g of allyl cyanide in 30 ml of petroleum ether with stirring and at a temperature of approximately -15°C. The solvent is evaporated and the oily 3,4-dibromobutyric acid nitrile is obtained in quantitative yield (J.A.C.S. 67, 400 (1945)).

The latter nitrile compound is divided into

five equal parts (45.4 g). The first portion is slowly added to a stirred mixture of 85 g of pyrocatechin and 50 g of anhydrous potassium carbonate in 100 ml of acetone under reflux. The stirred mixture is then slowly mixed with 50 g of potassium carbonate and with the second portion of the nitrile compound. It is then used. the further three parts of the nitrile, each time adding .40 g of potassium carbonate and an amount of acetone to the reaction mixture in advance to facilitate stirring. The reaction mixture is then boiled for 20 hours under reflux, cooled, filtered and the filtrate evaporated. The residue is distilled and the fraction boiling at 105°C/0.15 mm Hg is collected. 1,4-benzodioxan-2-yl-acetonitrile is obtained (Belgian patent no. 643,853).

The reaction mixture is filtered, the filtrate is evaporated, the residue is distilled and the fraction boiling at 105°C/ 0.5 mm Hg is collected. 1,4-benzodioxan-2-yl-acetonitrile is obtained

French Patent No. 643,853)-'

A mixture of 111 g of the latter compound, 6.3.5 ml of sulfuric acid, 160 ml of acetic acid and 160 ml of water is boiled for 48 hours under reflux. The mixture is poured onto ice, the solid material formed is separated and recrystallized from benzene-petroleum ether. 1,4-benzodioxan-2-yl-acetic acid is obtained, which melts at 100°C (Belgian patent no. 613-211).

A solution of 5.8 g of the latter compound in 100 ml of benzene is added dropwise under reflux in a nitrogen atmosphere to 16.5 ml of a 70% benzene solution of sodium bis(2-methoxyethoxy)-aluminum hydride. The mixture is then boiled for 4 hours under reflux, cooled and slowly poured into 20 ml of 25% sulfuric acid. The reaction mixture is filtered, the solvent is evaporated, the residue is taken up in methylene chloride. The solution is washed several times with saturated aqueous sodium bicarbonate solution, dried and evaporated. The oily 2-(2-hydroxyethyl')-1,4-benzodioxane is obtained.

A mixture of 3.6 g of the latter compound, 5.7 g of p-toluenesulfonic acid chloride and 20 ml of dry pyridine is stirred while cooling in an ice bath for 2 hours. The reaction mixture is then mixed with ice, the solid material formed is separated and recrystallized from the acetic ester-kerosene.ef'. 2-(2-tosyloxyethyl)-1,4-benzodioxane is obtained, which melts at 82-83°C.

According to the above-mentioned method, the starting materials for the compounds of formula II, which are discussed in example 8, are also prepared, starting from equivalent amounts of corresponding compounds. The melting points of these starting materials are indicated in the last column of the table in example 8. Example 2.

A solution of 5.5 g of 1-[2-([alpha]-1,4-benzodioxan-2-yl)-acetyl-17-4-hydroxy-4-phenylpiperidine in 50 ml of tetrahydrofuran is heated under cooling to a suspension of '1 .2 g of lithium aluminum hydride in 20 ml of tetrahydrofuran with stirring. The reaction mixture is stirred overnight at room temperature and partitioned with a few drops of acetic acid, 1.2 ml of water, 1.2 ml of a 15% aqueous sodium hydroxide solution and 3.6 ml of water. The mixture is not filtered, the filtrate is evaporated and the residue is recrystallized from isopropanol. One obtains £-2-1^ 2-(4-hydroxy-4-phenyl-piperidino)-ethyl7-1,4-benzodioxane, which melts at 141-143°C. /~o7D= -44.8° (methanol). Its hydrochloride melts at 225-

227°C. a7D<=><->36.5° (methanol).

' The d-base is also obtained in the same way. Melting point l4l-l43°C. /~ci7D = +44.8° (methanol). Its hydrochloride melts at 225-227°C.'/f"a7D= +36.5°C (methanol).

The starting material is prepared as follows: 19.4 g of 1,4-benzodioxan-2-yl-acetic acid and 12.1 g of d-a-methyl-benzylamine are dissolved in 100 ml of hot isopropanol. The solution is allowed to stand overnight, the salt formed is filtered off and recrystallized five times from isopropanol. The experiments show that this is sufficient for optical separation of

the aforementioned acids. The acids are released with dilute hydrochloric acid, the mixture is extracted with diethyl ether and the extracts are evaporated. One obtains d-1,4-benzodioxan-2-y 1-acetic acid. J_ a/D= + 49° (ethanol.).

In an analogous manner using -£-α-methylbenzylamine, the corresponding antipodic acid is obtained. I_ a/^ =

-49° (ethanol).

A solution of 3 g of -£-1,4-benzodioxan-2-yl-acetic acid in 20 ml of tetrahydrofuran is stirred for one hour with 3 g of carbonyldiimidazole. A suspension of 4-hydroxy-4-phenylpiperidine in 20 ml of tetrahydrofuran is added and the mixture is stirred overnight. It is then evaporated and the residue is dissolved in vinegar. The solution is washed with dilute aqueous hydrochloric acid and aqueous sodium hydroxide solution, dried and evaporated. One obtains 1-[2-(t-1,4-benzodioxan-2-yl)-acetyl-1/-1-hydroxy-2-phenylpiperidine.

Example 3»

A solution of 5 g of 1-/_~3-(1,4-benzodioxan-2-yl)-propiony]/-4-hydroxy-yl-phenylpiperidine in 50 ml of tetrahydrofuran is added to the stirred mixture of 2 g of lithium aluminum hydride and 50 ml of tetrahydrofuran at room temperature and continue stirring. 12 hours. The reaction mixture is then split with a few drops of acetic acid, 2 ml of water, 4 ml of a 15% aqueous sodium hydroxide solution and 4 ml of water. The mixture is filtered, the filtrate is evaporated and the residue is recrystallized from isopropanol. One obtains 2-/_ 3-(4-hydroxy-4-phenylpiperidino)-propyl7-1,4-benzodioxane, which melts at 95~98<<>?C. Its hydrochloride is prepared as indicated above and recrystallized from isopropanol. Melting point 155-157°C.

The starting material is prepared as follows: A mixture of 10 g of 2-(2-tosyloxyethyl)-1,4-benzodioxane, 2.4 g of sodium cyanide, 4 ml of water and 20 ml of ethanol is boiled for 48 hours under reflux. The reaction mixture is evaporated, the residue is taken up in water and extracted with diethyl ether. The extract is dried and evaporated. A mixture of 2.8 g of sulfuric acid, 7.2 ml of water and 7.2 ml of acetic acid is mixed with 5 g of the crude nitrile formed, stirred and refluxed for 48 hours. The mixture is poured into ice water, extracted with diethyl ether, the extract is washed with water and re-extracted with aqueous sodium hydrogen carbonate solution. The alkaline solution is acidified with hydrochloric acid and extracted with diethyl ether. The extract is dried and evaporated. Dissolve 2.5 g of the crude acid in 25 ml of tetrahydrofuran and mix the stirred solution with 3 g of carbonyldiimidazole over the course of 30 minutes. Man to-

add 2.5 g of ,4-hydroxy-4-phenylpiperidine and stir the mix-

none overnight. The reaction mixture is evaporated, the residue is dissolved in ethyl acetate, the solution is washed with dilute aqueous sodium hydroxide solution and hydrochloric acid, dried and evaporated. 1-(1,4-benzodioxan-2-yl)-propionyl-17-4-hydroxy-4-phenylpiperidine is obtained.

Example 4.

A solution of 1.9 g of thiofSn in 25 ml of tetrahydrofuran is mixed in a nitrogen atmosphere with stirring at -75°C, dropwise in 16 ml of 1.6 N butyllithium in hexane. After 15 minutes, a solution of 4 g of 2-[2-(4-oxopiperidino)-ethyl-17-1,4-benzodioxane in 25 ml of tetrahydrofuran is added dropwise while stirring and the mixture is allowed to warm to room temperature. It is mixed with 10 ml of saturated, aqueous ammonium chloride. The organic layer is separated, evaporated and the residue recrystallized from isopropanol. 2-(4-Hydroxy-4-thienyl-2-piperidino)-ethyl 7-1,4-benzodioxane is obtained, which melts at 117-118°C.

The starting material is prepared as follows: A mixture of 10 g of 2-(2-tosyloxyethyl)-1,4-benzodioxane, 10 g of 4-piperidone hydrochloride, 20 g of anhydrous sodium carbonate and 160 ml of dimethylformamide is stirred vigorously at room temperature for 48 hours. The reaction mixture is filtered, the residue is washed with a small amount of dimethylformamide and the filtrate is evaporated. The residue is dissolved in acetic acid, the solution is extracted with hydrochloric acid, the extract is made basic under cooling with a 50% aqueous sodium hydroxide solution and re-extracted with methylene chloride. The 'last extract is dried and. is evaporated. 2-[2-(4-oxo-piperidino)-ethyl]-1,4-benzodioxane is obtained, which becomes solid on standing.

Example 5■

A mixture of 4.6 g of 2-(2-t.oxyloxyethyl)-2,3~ dihydrobenzofuran, 2.64 g of 4-hydroxy-4-phenylpiperidine, 10 g of anhydrous sodium carbonate and 100 ml of 4-methyl-2-pentanone is boiled 48 hours during reflux. The reaction mixture is filtered, evaporated and the residue is recrystallized from isopropanol-petroleum ether. 2-[2-(4-hydroxy-4-phenylpiperidino)-ethyl]-2,3-dihydrobenzofuran is obtained, which melts at 107°C.

The product is suspended in ethanol, neutralized with ethanolic hydrogen chloride and the precipitate recrystallized from ethanol-diethyl ether. The corresponding hydrochloride is obtained, melting point 185-187°C.

The starting substance is prepared as follows: A solution of 14.2 g of 2-(2,3-dihydrobenzofuran-2-yl)-acetic acid (Gazz.. Chim. Ital. 93, 52 (1963j_7) in 100 ml of tetrahydrofuran is added dropwise to a stirred suspension of 4.55 g of lithium aluminum hydride

in 200 ml of tetrahydrofuran. The mixture is refluxed for 18 hours, then cooled in an ice bath and decomposed by adding 4.5 ml of water, 4.5 ml of a 15% aqueous sodium hydroxide solution and 14.6 ml of water. The mixture is filtered, evaporated and

the residue is taken up in vinegar. The solution is washed with aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried and evaporated. The residue is distilled in a bubble tube at 140°C/0.1 mm Hg. 2-(2-hydroxyethyl)-2,3-dihydrobenzofuran is obtained.

A mixture of 10 g of the latter compound, 17.4 g of p-toluenesulfonic acid chloride and 30 ml of pyridine is cooled with stirring for 2 hours in an ice bath. The mixture is then mixed with ice, the solid material formed is filtered off and recrystallized from ethyl acetate-petroleum ether. 2-(2-tosyloxyethyl)-2,3-dihydrobenzofuran is obtained, which melts at 51-54°C.

Example 6.

A mixture of 2 g of 2-[2-(4-hydroxy-4-phenyl-1-piperidino)-ethyl]-1,4-benzodioxane hydrochloride, 4 ml of propionic anhydride and 4 ml of pyridine is boiled with stirring for 10 minutes during reflux. The reaction mixture. diluted with diethyl ether, the semi-solid material is filtered off, washed with diethyl ether and recrystallized from isopropanol-diethyl ether. 2-(4-propionyloxy-4-phenylpiperidino)-ethyl 7-1,4-benzo dioxane hydrochloride is obtained, which melts during decomposition at 170°C.

Example 7-

A solution of 3 g of 2-[2-(4-hydroxy-4-phenyl-piperidino)-ethyl]-1,4-benzodioxane in 50 ml of tetrahydrofuran is mixed with stirring with 8 ml of 1.6 N butyllithium in hexane. After 3 hours, a solution of 2.4 g of n-decanoyl chloride in 10 ml of tetrahydrofuran is added, the mixture is refluxed for 48 hours and treated with 10 ml of saturated aqueous ammonium chloride solution. The organic phase is separated, evaporated and the residue is chromatographed on silica gel plates. Elute with chloroform-acetic ester (4:1). The material is collected at Rcm= 4.5. Analytically pure 2-[2-(4-n-decanoyl-oxy-4-phenylpiperidino)-ethyl]-1,4-benzodioxane is obtained as a pale yellow oil.

For the preparation of injections with a long-lasting effect, the product can be dissolved in sesame oil.

Example 8.

According to the methods mentioned in the preceding examples, the following compounds of formula II are also prepared, starting from equivalent amounts of corresponding starting substances.

In the table, y = 2, the relevant example is indicated in column Ex and the last column indicates the melting point of the corresponding tosylate starting material:

The compounds mentioned in the table are the following: 1-3) 2-/_ 2-(4-hydroxy-4-/_ p-tolyl, p-methoxyphenyl or p-fluorophenylV-piperidino)-ethyl_1/-1, 4-benzodioxane; 4) 7-chloro-2-(2-(4-hydroxy-4-phenylpiperidino)-ethyl IV-1,4-benzodioxane;

5-6) 2-/_ 2-(4-hydroxy-4-_/ benzyl or p-chlorophenyl/-

(piperidino)-ethyl N -l,r -benzodioxane;

7-11) 8-methyl-, 7-methyl-, 8-methoxy-, 6,7-dichloro-

or 6,7,8-trichloro-2-[2-(4-hydroxy-4-phenyl-1-piperidino)-ethyl-17-1,4-benzodioxane;

12-16) 2-[2-(4-hydroxy-4-7-t-butyl) 2-pyridyl, 3-pyridyl,

p-chloro-m-trifluorophenyl or 1-benzothien-2-yl(piperidino)-ethyl-17-1,4-benzodioxane; 17) 2-[2-(4-phenylpiperidino)-ethyl-17-14-benzodioxane and 18) 2-[2-(4-methoxy-4-phenylpiperidino)-ethyl7-1,4-benzodioxane.

The production of various new starting materials is illustrated as follows:

A suspension of 13.4 g of lithium aluminum hydride

in 200 ml of dry tetrahydrofuran is mixed dropwise with stirring and boiling at reflux with a solution of 48.6 g of 2-(7-methyl-1,4-benzodioxan-2-yl)-acetic acid in a minimal amount of tetrahydrofuran. The mixture is refluxed overnight, cooled and decomposed by adding 13.4 ml of water, 13.4 ml of a 15# aqueous sodium hydroxide solution and 40 ml of water. The reaction mixture is filtered, the filtrate is evaporated, the residue is distilled in a molecular distillation apparatus and the fraction boiling at 155-165°C70.1 mm Hg is collected as a colorless oil. 2-(2-Hydroxyethyl)-7-methyl-1,4-benzodioxane is obtained.

A Grignard reagent prepared from 3.6 g of magnesium and 18.9 g of benzyl bromide in 50 ml of diethyl ether is mixed with a solution of 18.4 g of 1-benzyl1-4-piperidone in 100 ml of diethyl ether and the mixture is refluxed for 1 hour . The mixture is split with 30 ml of saturated aqueous ammonium chloride solution, the ethereal solution is separated, dried and evaporated. You get a thick oil. 26 g of this oil are hydrated over 3 g of 10$-ig palladium-on-charcoal catalyst in a mixture of 120 ml of ethanol and 120 ml of acetic acid, at 3 atmospheres and 50°C, until uptake of a molar equivalent. hydrogen. The mixture is filtered, the filtrate is evaporated, the residue is treated with ammonium hydroxide and extracted with methylene chloride.

The extract is dried and evaporated. 4-benzyl-4-hydroxy-piperidine is obtained, which is sufficiently pure for the further reaction.

In an analogous manner, 4-hydroxy-4-(4-methoxyphenyl)-piperidine is prepared, which after recrystallization from isopropanol-petroleum ether melts at 121-123°C.

A solution of 11.64 g of 2-(1,4-benzodioxan-2-yl)-acetic acid in 60 ml of tetrahydrofuran is mixed with stirring with 12 g of 1,1-carbonyldiimidazole. After carbon dioxide evolution has ceased, the reaction mixture is mixed with 10.6 g of 4-hydroxy-4-phenylpiperidine and stirred overnight at room temperature. The mixture is evaporated, the residue is taken up in ethyl acetate, the solution is washed with water, normal hydrochloric acid and water, dried and evaporated. 1-/_ 2-(1,4-benzodioxan-2-yl)-acetyl_/-4-hydroxy-4-phenylpiperidine is obtained.

Example £)•

A solution of 20 g of 2-1_ 2-(4-hydroxy-4-phenyl-piperidino)-1-tosyloxyethyl./-1,4-benzodioxane in 500 ml of tetrahydrofuran is mixed with 7 g of lithium aluminum hydride and the mixture is refluxed, with stirring in 6 hours. The mixture is then treated with stirring with 2 ml of acetic acid, 7 ml of water, 7 ml of a 15% aqueous sodium hydroxide solution and 22 ml of water. The inorganic residue is filtered off, the filtrate evaporated residue is treated with ethanolic hydrogen chloride and recrystallized from ethanol-diethyl ether. Moon obtains 2-1_ 2-(4-hydroxy-4-phenylpiperidino)-ethyl 1,7-1,4-benzodioxane hydrochloride, which melts at 203°C.

The starting material is prepared as follows: A solution of 42 g of 2-(2-bromoacetyl)-1,4-benzodioxane in 360 ml of methanol is mixed with 12 g of sodium borohydride while stirring and cooling at a temperature below 10°C. After 5 hours, the mixture is cooled to 0°C, mixed with 13.2 g of sodium hydroxide in 150 ml of methanol and kept overnight at -15°C. The mixture is then poured onto ice and extracted with diethyl ether, the extract is washed with saturated aqueous sodium chloride solution, dried and evaporated. 1,4-benzodioxan-2-y1-ethylene oxide is obtained.

A mixture of 7.1 g of the latter compound and 3.54 g of 4-hydroxy-4-phenylpiperidine in 75 ml of isopropanol is boiled for 5 hours under reflux and evaporated. The residue is dissolved in ethyl acetate and the solution is extracted with aqueous methanesulfonic acid. The substituted piperidine is distributed between the aqueous and the organic layers. After evaporation of the organic layer, a gummy residue is obtained, which slowly crystallizes. After recrystallization from isopropanol, 2-[_2-(4-hydroxy-4-phenylpiperidino)-1-hydroxyethyl-1/-1,4-benzodioxane-methanesulfonate is obtained, which melts at 208-210°C.

The aqueous extract is made basic with ammonium hydroxide and extracted with methylene chloride, the organic phase is dried and evaporated. The residue is recrystallized from isopropanol-petroleum ether. The corresponding free base is obtained, which melts at 95°C.

A solution of 20 g of the latter compound

in 80 ml of pyridine, mixed with stirring and cooling in an ice bath, with 11.8 g of toluenesulfonyl chloride. The reaction mixture is allowed to stand for 3 hours in an ice bath, poured into 200 g of ice water and decanted

teres the aqueous phase from raw solid material. The residue is washed several times with water, filtered and dried. 2-(4-Hydroxy-4-phenyl-piperidino)-1-tosyloxyethyl-1-4-benzodioxane is obtained.

Example 10.

A solution of 10 g of 1,4-benzodioxan-2-yl-acetaldehyde and 12.7 g of 4-hydroxy-4-phenylpiperidine in 300 ml of methanol is mixed with 8 ml of 4.5 N ethanolic hydrogen chloride. Under these conditions, 2-_12-(4-hydroxy-4-phenyl-piperidino)-viriyl7-1,4-benzodioxane is obtained in situ. After one hour, the reaction mixture is mixed dropwise with stirring at room temperature with a solution of 2.4 g of sodium cyanoborohydride in 30 ml of methanol. After one hour, the solution is made strongly basic with aqueous sodium hydroxide solution, concentrated to a small volume and diluted with water. The mixture is extracted with vinegar, the extract is dried and evaporated. The residue is treated with ethanolic hydrogen chloride and the resulting precipitate is recrystallized from ethanol-diethyl ether. 2-[2-(4-hydroxy-4-phenylpiperidino)-ethyl-7-1,4-benzodioxane hydrochloride is obtained, which melts at ■203°C.

The starting material is prepared as follows: A solution of 20 g of 1,4-benzodioxan-2-yl-acetotritrile in 200 ml of benzene is mixed dropwise with stirring at 10 o C with 71 ml of a 1.6 N solution of diisobutylaluminum hydride in benzene. After 6 hours, the reaction mixture is first mixed with 50 ml of methanol and then with 200 ml of water. The organic layer is separated, dried and evaporated. 1,4-benzodioxan-2-yl-acetaldehyde is obtained.

Example 11.

A solution of 7 g of sodium methylate in 200 ml of methanol is mixed with 20 g of l-/_ 4-(2-acetoxyphenoxy)-3-tosyl-oxybutyl_l/-4-hydroxy-4-phenylpiperidine, the mixture is refluxed for 6 hours and evaporated to a small volume. The reaction mixture is diluted with water, extracted with methylene chloride, the extract is dried and evaporated. The residue is treated with ethanolic hydrogen chloride and the residue is recrystallized several times from ethanol-diethyl ether. This gives 2-[2-(4-hydroxy-4-phenylpiperidino)'-ethyl-7-1,4-benzodioxane hydrochloride, which melts at 203°C.

The starting material is prepared as follows: A solution of 20 g of 4-hydroxy-4-phenylpiperidine hydrochloride, 10 ml of acetone, 5.6 g of paraformaldehyde and 100 ml of nitromethane is boiled for 12 hours under reflux. The reaction mixture is diluted with 500 ml of cyclohexane and the precipitate is separated. 4-(4-hydroxy-4-phenylpiperidino)-2-butanone hydrochloride is obtained.

A suspension of 20 g of the latter compound

in 100 ml of acetic acid is mixed with vigorous stirring with 3.7 ml of bromine in 25 ml of acetic acid dropwise, keeping the temperature at 25°C. After an hour, the bromine color disappears completely. Half of the acetic acid is then distilled off. The concentrate is diluted with diethyl ether and the precipitate formed is separated. 1-Bromo-4-(4-hydroxy-4-phenyl-piperidino)-2-butanone hydrochloride is obtained.

An ice-cooled suspension of 10 g of 56#-ig sodium hydride in mineral oil and 100 ml of dimethylformamide is mixed with stirring slowly in sequence, with 16 g of o-acetylpyro-catechin and 20 g of 1-bromo-4-(4-hydroxy-4- phenylpiperidino)-2- - butanone hydrochloride. The reaction mixture is stirred for 12 hours at 5°C and then mixed with 2 g of sodium borohydride. The temperature of the mixture is allowed to rise to room temperature, after 1 hour it is poured onto ice and extracted with methylene chloride. The extract is dried and evaporated. 1-(2-acetoxyphenoxy)-4-(4-hydroxy-4-phenylpiperidino)-2-butanol is obtained as an oil. Dissolve 20 g of this in 70 ml of pyridine, cool the solution in an ice bath and mix it with stirring in portions with 10 g of p-toluenesulphonic acid chloride. After 3 hours, the mixture is diluted with 500 ml of ice water, the solid material formed is separated, washed several times with water and dried over phosphorus pentoxide. !-/_ 4 - (2-acetoxyphenoxy)-3-tosyloxybutyl 17-4-hydroxy-4-phenyl 1-piperidine is obtained.

Example 12.

A solution of 5 g of 2-[2-(4-phenyl-1,2,5,6-tetrahydropyridyl-1)-ethyl]-1,4-benzodioxane hydrochloride in 100 ml of acetic acid-water (9:1) is mixed with 0.5 g of 10% palladium-p-charcoal catalyst and the mixture is hydrogenated at 3 atmospheres until uptake of the equivalent amount of hydrogen. The mixture is filtered, the filtrate is evaporated and the residue is taken up in water. The mixture is made basic with ammonium hydroxide, extracted with methylene chloride, the extract is dried and evaporated. The residue is taken up in isopropanol and the solution acidified with ethanolic hydrogen chloride. 2-7 2-(4-phenylpiperidino)-ethyl/-1,4-benzodioxane hydrochloride is obtained, which melts at 224-225°C. The product is identical to compound No. 17 from Example 8.

The starting material is produced according to that method

which is indicated in example 1. Melting point 200-201°C.

Example 13.

A solution of 5 g of 2-1_ 2-(4-benzoylpiperidino)-ethyl_l/-l,4-benzodioxane hydrobromide in 100 ml of 90% aqueous acetic acid is mixed with 1 g of 10# palladium-on-charcoal catalyst and the mixture is hydrogenated at 3 atmospheres and 50°C to absorb two molar equivalents of hydrogen. The reaction mixture is then filtered, the filtrate is evaporated and the residue is taken up in water. The mixture is made basic with ammonium hydroxide and extracted with methylene chloride. The extract is dried, evaporated, the residue is neutralized with ethanolic hydrogen chloride and the solid material is separated. 2-f~ 2-(4-benzyl piperidino)-ethyl_7-1,4-benzodioxane hydrochloride is obtained, which in the I.R. spectrum shows bands at 2447 and 748 cm"<1>.

The starting material is prepared analogously to the method mentioned in the example. Melting point 193-195°C.

In an analogous way, by hydrogenating 2-1_ 2-(4-p-fluorobenzoylmethylpiperidino)-ethyl/-1,4-benzodioxane hydrochloride (melting point 165-166°C) you get 2-<T>2-( 4-p-Fluorophenylethyl-piperidino)-ethyl_l/-l,4-benzodioxane hydrochloride, which in the I.R.--1 '■ spectrum shows bands at 2485 and 695 cm .. Example 14.

Production of 10,000 tablets with a content

on every 5 mg of the active substance:

Ingredients:

Method: All powdered ingredients are sieved with a sieve of 0.6 mm mesh size. The active substance is then mixed with milk sugar, talc, magnesium stearate and half of the starch in a suitable mixer. The other half of the starch is suspended in 40 ml of water and the suspension is brought to a boiling solution of ■ polyethylene glycol in 150 ml of water. The resulting paste is ground into powders and granulated, possibly with the addition of a further amount of water. The granulate is dried overnight at 35°C, passed through a sieve of 1.2 mm mesh and pressed into tablets of 6.4 mm diameter, which have a breaking drill.

Production of 10,000 capsules each containing 2.5 mg of the active substance:

Components:

Procedure: All powdered components are sieved with a sieve of 0.6 mm mesh size. The active substance is then homogenized, first with talc and then with milk sugar in a suitable mixer. Gelatin capsules No. 3 are filled each time with 200 mg of the resulting mixture in a filling machine.

In an analogous way, tablets and hard gelatin capsules are prepared with other compounds mentioned in the examples. Example 15.

A mixture of 2.2 g of 2-(4-hydroxy-4-pyridyl-2-piperidino)-ethyl]L/-l, 4-benzpdioxane hydrochloride, 4 ml of pyridine and 4 ml of propionic anhydride is boiled with stirring 20 minutes during reflux. The reaction mixture is diluted with diethyl ether and the precipitate formed is recrystallized from isopropanol. 2-[2-(4-propionyloxy-4-pyridy 1-2-piperidino)-ethyl]-1,4-benzodioxane hydrochloride is obtained, which melts at 125-130°C during decomposition.

Example 16.

A solution of 4 g of 2-[2-(4-hydroxy-4-phenyl-piperidino)-ethyl7-1,4-benzodioxane in 50 ml of anhydrous tetrahydrofuran is mixed with stirring at 0°C with 1.6 N n-butyllithium in hexane. The mixture is allowed to warm to room temperature, split while stirring with 1.5 ml of pivaloyl chloride in 10 ml of tetrahydrofuran and boiled for 24 hours under reflux. After cooling, the reaction mixture is mixed with 10 ml of saturated aqueous ammonium chloride solution and then with 200 nil of diethyl ether. The organic layer is separated, washed with water, dried, evaporated and the residue dissolved in isopropanol. The solution is acidified with 6 N ethanolic hydrogen chloride and the precipitate is separated. 2-1_ 2-(4-pivaloyloxy-4-phenylpiperidino)-ethyl/-1,4-benzodioxane hydrochloride is obtained which melts during cleavage at 195-200°C.

Example 17.

A mixture of 1.44 g of lithium aluminum hydride i

150 ml of anhydrous tetrahydrofuran are mixed with stirring with a solution of 14 g of 1-_/2-(1,4-benzoxathian-2-yl)-acetyl_1/-4-hydroxy-4-phenyl-piperidine in 140 ml of tetrahydrofuran. The reaction mixture is stirred overnight at room temperature, mixed with 1.4 ml of water, 2.9 ml of 15% aqueous sodium hydroxide solution and 2.9 ml of water, filtered and the filtrate evaporated. The residue is taken up in 10 ml of hot isopropanol, the solution is treated with 4.5 g of cyclohexanesulfamic acid. After cooling, 2-1_ 2-(4-hydroxy-4-phenylpiperidino)-ethyl 7-1,4-benzoxathiane-cyclamate crystallizes out. Melting point 17.6°C.

The starting material is prepared as follows: A solution of 21 g of 2-hydroxythiophenol in 290 ml of acetone is mixed dropwise with stirring and boiling under reflux, with 12.5 g of 3,4-dibromobutyronitrile and also with small portions of 15 .8 g anhydrous potassium carbonate. After 30 minutes, the parallel addition of the mentioned quantities of the dibromine compound and of the potassium carbonate is repeated. After a further 30 minutes, the aforementioned addition is repeated for a third time. The reaction mixture is then refluxed for 20 hours, cooled and filtered. The salts formed as a residue are washed with acetone and the filtrate is evaporated. The residue is distilled and the fraction boiling at 185°C/0.5 mm Hg is collected. 2-(1,4-Benzoxathian-2-yl)-acetonitrile is obtained.

A mixture of 50 g of the latter compound,

74 ml of water, 74 ml of acetic acid and 28.6 g of sulfuric acid are boiled for 48 hours

during reflux. After cooling, the reaction mixture is extracted. three times with each time 150 ml of benzene. The extract is washed with aqueous sodium bicarbonate solution and the aqueous phase is acidified with hydrochloric acid. The mixture is extracted with diethyl ether. The extract is dried and evaporated. 2-(1,4-Benzoxathian-2-yl)-acetic acid is obtained.

A solution of 10 g of the latter compound

in 45 ml of anhydrous tetrahydrofuran is mixed with stirring with 9.2 g of carbonyldiimidazole and then. 30 minutes with 10.1 g of 4-hydroxy-4-

f phenylpiperidine and stirring is continued for 24 hours. The reaction mixture is evaporated, the residue is taken up in ethyl acetate and the mixture is washed with water, acidified with hydrochloric acid, dried and evaporated. 2-(1,4-Benzoxathian-2-yl)-acetyl/-4-hydroxy-4-phenylpiperidine is obtained.

2-[2-(4-phenyl-piperidino)-ethyl]-1,4-benzoxathane cyclamate is also prepared in an analogous manner. Melting point 146-148°C.

Example 18.

A solution of 3.55 g of 2-/_ 2-(4-hydroxy-4-phenylpiperidino)-ethyl_/-1,4-benzoxathane in 10 ml of dioxane and 10 ml of methanol is added dropwise to a stirred solution of 2.67 g

sodium metaperiodate in 20 ml of water. The reaction mixture is stirred

2 hours at room temperature, evaporate and absorb the residue

i'methylene chloride. The solution is dried, evaporated and 2.3 g of the residue is dissolved in a minimal amount of ethanol. The solution is mixed with a solution of 1.45 g of cyclohexane-sulfamic acid in ethanol and the precipitate formed is separated. The corresponding S-oxide cyclamate is obtained, which melts at 158-160°C.

Example 19.

A solution of 4.9 g of 2-(1,4-benzodioxan-2-yl)-acetyl-1/-4-ethoxy-4-phenylpiperidine in 50 ml of tetrahydrofuran is added to the stirred mixture of 0.7 g of lithium aluminum hydride

in and 100 ml of tetrahydrofuran at room temperature. The reaction mixture is stirred overnight and then mixed with a few drops of acetic acid, 0.7 ml of water, 1.4 ml of a 15% aqueous

sodium hydroxide solution and 2.1 ml of water. The mixture is filtered, the filtrate is evaporated and 5 g of the residue is dissolved in a minimal amount of ethanol. The solution is combined with the solution of 1.7 g of maleic acid in ethanol. The mixture is cooled, filtered and the residue recrystallized from ethanol. 2-1-2-(4-ethoxy-4-phenylpiperidino)-ethyl-1/-1,4-benzodioxane maleate is obtained, which melts at 160-162°C.

The starting material is prepared as follows: A solution of 3.3 g of 1,4-benzodioxan-2-yl-acetic acid in 30 ml of tetrahydrofuran is mixed with stirring first with 3.1 g of 1,1'-carbonyldiimidazole and after 30 minutes with 3, 5 g of 4-ethoxy-4-phenyl-piperidine in 30 ml of tetrahydrofuran. The mixture is stirred for 18 hours at room temperature, evaporated and the residue taken up in vinegar. The solution is washed with water, normal hydrochloric acid and with saturated aqueous sodium chloride solution, dried and evaporated. 2-(1,4-benzodioxan-2-yl)-acetyl-1H-4-ethoxy-4-phenylpiperidine is obtained.

Example 20.

A mixture of 5 g of 2-_/-2-(^1-hydroxy-^-phenyl-piperidino)-ethyl-7-benzofuran, 100 ml of acetic acid and 1 g of 10$-ig platinum-on-charcoal catalyst is hydrated at room temperature and 3 atmospheres to absorb the theoretical amount of hydrogen. The reaction mixture is filtered, the filtrate is evaporated, the residue is taken up in water, the mixture is made basic with 2 N aqueous sodium hydroxide solution and extracted with methylene chloride. The extract is dried, evaporated and the residue taken up in ethanol. The solution is neutralized with ethanolic hydrogen chloride and the precipitate formed is recrystallized from ethanol-diethyl ether. 2-1_ 2-(4-hydroxy-4-phenylpiperidino)-ethyl/-2,3-dihydrobenzofuran hydrochloride is obtained, which melts at 185-187°C. The product is identical to the product from example 5.

The starting material is prepared as follows: "A mixture of 16 g of 2-acetyl-benzofuran, 4.8 g of sulfur and 13.2 ml of morpholine is refluxed for 8 hours. The reaction mixture is then mixed with 160 ml of 10% ethanolic sodium hydroxide and further boiled for 6 hours under reflux. The mixture is concentrated to a small volume, acidified with hydrochloric acid, : extracted with diethyl ether and the extract evaporated. The residue is distilled and the fraction boiling at 145°C70.1 mm Hg is collected. Benzofuran-2-yl-acetic acid is obtained.

A solution of 10.5 g of the latter compound in 50 ml of tetrahydrofuran is added to the stirred and refluxing mixture of 3.4 g of lithium aluminum hydride in 50 ml of tetrahydrofuran. The mixture is refluxed for 12 hours, cooled in ice and split with 3.4 ml of a 15% aqueous sodium hydroxide solution and 10.2 ml of water. The inorganic salts are filtered off, washed with diethyl ether, the filtrate is dried and evaporated. 2-(2-Hydroxyethyl)-benzofuran is obtained.

A solution of 3.25 g of the latter compound in 10 ml of pyridine is mixed with stirring at 5°C with 5.7 g of p-toluenesulfonic acid chloride. After 2 hours, the mixture is poured onto ice, the solid material is separated and recrystallized from ethyl acetate. 2-(2-tosyloxyethyl)-benzofuran is obtained.

A mixture of 4.55 g of the latter compound, 2.64 g of 4-hydroxy-4-phenylpiperidine and 10 g of sodium carbonate in 100 ml of 4-methyl-2-pentanone is stirred and refluxed for 2 days. The reaction mixture is then filtered, the filtrate is evaporated, the residue is dissolved in hot isopropanol, treated with activated carbon and filtered. After cooling, 2-[2-(4-hydroxy-4-phenylpiperidino)-ethyl]-benzofuran crystallizes out.

Melting point 195-197°C

Patent claims:

1.. Process for the production of new 2-piperidinoalkyl-(1-benzofurans or 1,4-benzodioxanes) of the general formula I

wherein Ph means a 1,2-phenylene residue, which is optionally substituted with 1 to 3, the same or different substituents, selected from lower alkyl, hydroxy, mercapto, lower alkoxy, lower alkylenedioxy, benzyloxy, lower alkylthio, halogen, trifluoromethyl, nitro or amino, X means oxygen or sulphur, m means the whole numbers 0 or 1 and n means the whole numbers from 1 to 4, each of the symbols p and q means a whole number from 1 i to 3, (p+q) being the number 4, each of the symbols R-^ and R2 means hydrogen, lower alkyl or HPh, R-^ means hydrogen,

hydroxy, lower alkoxy, lower or higher alkanoyloxy,

Rj| means lower alkyl, HPh-lower alkyl, HPh or naphthyl,

which is optionally substituted as Ph, furyl, thienyl, pyridyl, benzofuryl, benzothienyl, quinolyl or isoquinolyl, which heterocyclic residues are optionally substituted as Ph, as well as S-oxides and acid addition salts of these compounds, characterized in that

a) compounds of the general formula III and IV

in which one of the symbols Y and Z2 means amino or imino and the other means a reactive esterified hydroxy group or

b) a compound of the general formula V

is reduced,

in which A means a group with formula CnH2n_2-CO*

cn<H>2n-s or Y'~CnH2n-]'where Y' means a reactive esterified hydroxy group, Rc means hydrogen or R-^and R^together form a further C,C bond, R^ means R^or HPh -low-alkanoyl, each of the symbols r and s means the whole in the number 0 or 2, (r+s) being the number 2 or 4, or

c) connection with VI

is condensed with R^ metal compounds, or d) a compound of formula VII in which Y means a reactive esterified hydroxy group, is ring-closed, and if desired, a compound formed is converted into another compound according to the invention and/or, if desired, a formed compound is oxidized compound to the S-oxide and/or if desired, a formed free compound is transferred in an acid addition salt or a formed acid addition salt in the free compound or, in another acid addition salt, and/or if desired, a formed mixture of isomers is separated or racemates into the individual isomers or racemates and/or if desired, the racemates formed are resolved into the optical antipodes. 2. Process according to claim la), characterized in that starting substances are used, in which Y or Z means a hydroxy group esterified with a strong inorganic or organic acid. | 3. Method according to one of claims la) and 2, characterized in that the reaction is carried out in the presence of basic condensation agents. 4. Method according to claim lb), characterized in that the reaction is carried out with simple hydrides or complex light metal hydrides, catalytically activated, nascent or electrolytically produced hydrogen. 5- Method according to claim 1c), characterized in that the reaction is carried out with an Rjj-lithium or an Rj-halogenmagnesium compound. 6. Method according to claim ld), characterized in that starting substances are used,

wherein Y means a hydroxy group esterified with a strong inorganic or organic acid.

7- Method according to one of claims ld) and 6, characterized in that the reaction is carried out

in the presence of basic condensing agents.

8. Method according to one of claims 1 to 7, characterized in that a formed compound with

formula I, in which R^ denotes hydroxy or their alkali metal salts are reacted with reactive esters of lower alkanols or with reactive alkanoic acid derivatives and thereby produce a corresponding etherified or esterified compound. 9. Method according to one of claims 1 to 8, characterized in that one formed ester is hydrolysed. 10. Method according to one of claims 1 to 9, characterized in that a compound formed which has a phenolic hydroxy group is etherified with diazole lower alkanes. 11. • Process according to one of claims 1 to 9, characterized in that the compound formed, which has a b.enzyloxy-1,2-phenylene group, is hydrogenolysed. 12. Method according to one of claims 1 to 10, characterized in that "the compound formed which has a halogen-1,2-phenylene group is dehalogenated. 13- Method according to one of claims 1 to 10, characterized in that in a compound formed, which has a nitro-1,2-phenylene group, the nitro group is reduced to the amino group. 14. Method according to one of claims 1 to 10, characterized in that in a formed compound the 1,2-phenylene group is nitrated Ph. 15. Method according to one of claims 1 to 10 ,characterized by the fact that in a formed compound, which in a 1,2-phenylene residue Ph has an iodine atom, this is replaced by a trifluoromethyl group. 16. Method according to one of claims 1 to 15, characterized by the fact that a formed compound of formula I is oxidized with mild oxidizing agents to sulfoxide.

17* Process according to one of the claims 1 to 16, characterized in that an intermediate product formed in a desired process step is used as starting material and the remaining process steps are carried out or the process is interrupted at one or the other step, or a starting substance f is formed under the reaction conditions or used in the form of an S-oxide, a salt or an optically pure antipode.

l8. Method according to one of claims 1 to 15 and 17,

characterized in that compounds are prepared with the formula I shown in claim 1, in which Ph means a 1,2-phenylene residue, which is optionally substituted with one or two substituents, selected from lower alkyl, hydroxy, mercapto,

lower alkoxy, lower alkylenedioxy, benzyloxy, lower alkylthio, halogen, trifluoromethyl, nitro or amino, X means oxygen or sulphur, m means the whole numbers 0 or 1, -n means the whole numbers from 1 to 4, each of the symbols p and q means a whole number from 1 to 3, where (p+q) is the number 4, each of the symbols R-^ and R2 means hydrogen or lower alkyl, R-^ means hydrogen, hydroxy, lower alkoxy, lower or higher alkanoyloxy, R^ means lower alkyl, HPn ~CnH2n, HPh or optionally with one or two lower alkyl residues substituted furyl, thienyl or pyridyl,

as well as their acid addition salts.

19«. Method according to one of claims 1 to 10, 12, 15 and 17, characterized in that it is produced

compounds with the general formula I specified in claim 1,

in which Ph means a 1,2-phenylene residue, which is optionally substituted with one or two substituents, selected from among alkyl, ' alkoxy, or alkylthio with a maximum of 4 carbon atoms each, halogen or trifluoromethyl, X means oxygen, m means all of them. ^.number 0 or 1, n means the whole numbers from 2 to 4, each of the symbols

in p and q the number means 2, each of the symbols R-^ and R2 means hydrogen or alkyl with a maximum of 4 carbon atoms,' R^ means !

■hydrogen, alkoxy with a maximum of 4 or alkanoyloxy with a maximum of 16 carbon atoms, R^means secondary or tertiary alkyl with 3 to 7 carbon atoms, HPh-CH"2, HPh,. 2- or 3-furyl or -thienyl, 2-, 3_ or 4-pyridyl and their acid addition salts 20. Process according to one of claims 1 to 10, 12, 15 and 17, characterized in that compounds of the general formula II are prepared

in which R means hydrogen, alkyl, alkoxy or alkylthio with a maximum of 4 carbon atoms each, halogen or trifluoromethyl, x means the numbers' 1 or 2, y means the whole numbers from 2 to 4, R" means hydrogen,•hydroxy, alkoxy with a maximum 4 or

alkanoyloxy with a maximum of 16 carbon atoms. R' means secondary or tertiary alkyl with 3 to 7 carbon atoms, Rx~benzyl, R -A.-phenyl, 2- or 3-furyl or -thienyl, 2-, 3- or 4-pyridyl and their acid addition salts. 21. Method according to one of claims 1 to 10, 12, 15 and 17, characterized in that compounds are prepared with the general formula II shown in claim 20, in which R means hydrogen, methyl, ethyl, methoxy, ethoxy, methylthio, ethylthio , fluorine, chlorine or trifluoromethyl, x means the numbers 1 or 2, y means the numbers 2 or 3, R" means hydrogen, hydroxy, methoxy, ethoxy or alkanoyloxy with 2 to 12 carbon atoms, R' means i-propyl, i- or, tert-butyl, benzyl, Rx-phenyl, 2- or 3-furyl or -thienyl, 2-, 3- or 4-pyridyl and their acid addition salts. 22.. Method according to one of claims 1 to 10, 12, 15 and 17, characterized in that compounds are prepared with the general formula II specified in claim 20, in which R means hydrogen, methyl, methoxy, fluorine, chlorine or trifluoromethyl, each in the 7- or 8-position, x means the numbers 1 or 2, y means the numbers 2 or 3, R" means hydroxy, methoxy or alkanoyloxy with 3 to 10 carbon atoms, R' means m-or p-Rx~phenyl and their acid addition salts r. 23-, Method according to one of claims 1 to 7, 9, 12 and 17, characterized in that it is produced. 2-</_>2-(4-H<y>drox<y->4-phenylpyr<p>eridino)-ethyl<l>7-1,4-benzodioxane and its acid addition salts.