CS198190B2 - Method of producing new 2-piperidinoalkyl-1,4-benzodioxanes - Google Patents

Description

The present invention relates to a process for the preparation of novel 2-piperidinoalkyl-1-benzofurans or -1,4-benzodioxanes of the general formula I / Cl 2.

u ^u C _n Hfcn.

/ (0¾¼ ^R ¥ (IJ in which

Ph is a 1,2-phenylene radical optionally substituted by one to three identical or different substituents selected from the group consisting of lower alkyl groups, lower alkoxy groups, halogen atoms, and trifluoromethyl groups,

X is oxygen or sulfur, m is an integer of 0 or 1, n is an integer of 1 to 4, each of p and q is an integer of 1 to 3, where the sum of pjq is 4, each of R 1 and R2 represents a hydrogen atom,

R 5 represents a hydrogen atom, a hydroxyl group, a lower alkoxy group or a lower or higher alkanoyloxy group, and

R 8 represents a lower alkyl group, an HPh-lower alkyl group or an HPh, a thienyl, pyridyl benzothienyl group, and their acid addition salts, especially therapeutically useful acid addition salts.

As used hereinbefore and hereinafter, the term " lower " denotes residues and compounds containing at most 7, preferably 4 and especially 1 or 2 carbon atoms and the term " higher " denotes residues containing 8 to 20 carbon atoms, preferably 10 to 16 carbon atoms.

The 1,2-phenylene radical Ph is preferably monosubstituted, the substituents being illustrated by the following list: lower alkyl groups, for example methyl, ethyl, or isopropyl or butyl, lower alkoxy groups, for example methoxy, ethoxy, n- or isopropoxy or -butoxy, halogen atoms such as fluorine, chlorine or bromine, or trifluoromethyl.

Of the above integers, m preferably has a value of 1 when formula I is 1,4-benzodioxanes or 1,4-benzoxathianes, or a value of 0 when formula I is 1-benzofurans.

The alkylene group in the meaning of the group C _n H _2n is preferably methylene, 1,1- or 1,2-ethylene, 1,2- or

1,3-propylene, 1,2-, 1,3- or 1,4-butylene and each of p and q is preferably 2.

R5 is preferably a free, etherified or esterified hydroxyl group such as a lower alkoxy group, for example one of the aforementioned lower alkoxy group, a lower or higher alkanoyloxy group, for example acetoxy, propionyloxy, pivaloyloxy, octanoyloxy, octanoyloxy, decanoyloxy, laanoyloxy, but also a hydrogen atom.

The lower alkyl group R a is preferably a secondary or tertiary alkyl group having 3 to 7 carbon atoms, such as isopropyl, iso- or tert-butyl, -pentyl or -hexyl. R 6 is preferably an HPh-C _n H _2n - group, for example benzyl or 1- or 2-phenylethyl. Particularly preferred groups in the meaning of Rd are the phenyl groups of the formula HPh mentioned above.

Since the compounds of the formula I contain at least one nitrogen atom, they can be present in the form of acid addition salts, in particular of therapeutically useful acid addition salts, for example those derived from the acids mentioned below.

The compounds according to the invention exhibit valuable pharmacological effects, for example analgesic and, in particular, neuroleptic effects, the beneficial properties of which differ widely (in a dose-dependent manner) from extrapyramidal side effects. This sharp separation of the mode of action has not been observed with other neuroleptic agents, such as haloperidol. These properties can be demonstrated by experiments on animals, especially mammals, such as mice, rats, dogs, and especially monkeys. The compounds of the invention may be administered to animals enterally, for example, orally, or parenterally, for example, subcutaneously, intraperitoneally or intravenously, for example in the form of gelatin capsules, starch-containing suspensions, aqueous solutions or suspensions. For oral administration, dosages of about 0.1 to 10 mg / kg / day / day, preferably about 0.5 to 5 mg / kg / day, and in particular 1 to 2.5 mg / kg / day, are used. The compounds described, for example 2- [2- (4-hydroxy-4-phenylpiperidino) ethyl] -1,4-benzodioxane or its hydrochloride, cause oral administration at the above-mentioned doses, in particular between about 0.5 and 5 mg. / kg / day, in the case of monkeys, a deepening of the reflex manifested by the fact that the animals activate the device in order to get rid of unpleasant stimuli. This test is performed as follows:

Monkeys are given electrical shocks at certain intervals. Animals can avoid these electrical impulses by pressing a button. The monkeys are trained to press the button before the electric shock occurs. Each press of the button shifts the electric shock by 20 seconds. If the monkey fails to press the button within 20 seconds, it receives short electrical shocks (0.5 seconds) every 20 seconds until the next button is pressed. Under control conditions, monkeys press the button at a relatively constant speed, so they rarely ever get more than 5 or 6 shocks during the four-hour experiment. The novel compounds tested for neuroleptic effects suppress this learned conditional behavior of experimental animals. Blocking this property results in a suppression of the ability to avoid electric shock, so that the test animals receive a significantly higher number of shocks.

Furthermore, the novel compounds, for example the esters of the above-mentioned dioxane derivatives with propionic acid, induce analgesic effects in mice at the above-mentioned orally administered dose, in particular at a dose of between about 5 and 10 mg / kg / day. These effects can be demonstrated by a test in which animals draw their tail away from the site of a painful stimulus and a test for painful convulsions induced by phenylquinone. In the first test, a heat current is measured on the tail of a male rat and the irradiation time is measured. The end of this time interval is when the animal withdraws its tail from the irradiated area. Heat irritation is never applied for more than 10 seconds. A time value (control value) was determined for each animal prior to administration of the test compound. To determine the presence of analgesic effects, the mean of the control values is calculated and three deviations from the standard are added. Time values obtained in animals after administration of the test compound above the above-mentioned elevated mean value indicate an analgesic effect.

In the pain spasm test, male mice were injected intraperitoneally with 2.5 mg / kg of phenylquinone 20 minutes after oral administration of the compounds of the invention, and the number of mice writhing in pain 5-15 minutes after injection was determined. In the case of the analgesic effect of the test compound, the animals do not change their behavior.

In accordance with the above, the compounds of the invention may be used as analgesic and preferably neuroleptic agents, for example, in the treatment of aggression, arousal, anxiety and pain conditions in animals, preferably mammals. Compounds

S according to the invention can also be used as intermediates for the preparation of other valuable, in particular pharmacologically active substances.

Preferred are compounds of formula I wherein:

Ph is a 1,2-phenylene radical optionally substituted by one or two substituents independently selected from the group consisting of alkyl and alkoxy groups containing up to 4 carbon atoms, halogen atoms and trifluoromethyl,

X is oxygen, m is an integer of 0 or 1, n is an integer of 2 to 4, each of p and q being 2, each of R 1 and R 2 being a hydrogen atom,

R3 is hydrogen, hydroxy, alkoxy of up to 4 carbon atoms or alkanoyloxy of up to 16 carbon atoms, and

R 1 represents secondary or tertiary C 3 -C 7 alkyl, HPh-CH 2, HPh, 2- or 3-thienyl, 2-, 3- or 4-pyridyl, and therapeutically useful acid addition salts of these compounds .

Particularly preferred compounds of formula II

in which

R represents a hydrogen atom, an alkyl or alkoxy group containing not more than 4 carbon atoms, a halogen atom or a trifluoromethyl group, x being a number of 1 or 2, y being an integer of 2 to 4,

R 'is hydrogen, hydroxy, alkoxy of up to 4 carbon atoms or alkanoyloxy of up to 16 carbon atoms, and

R 1 represents a C 3 -C 7 secondary or tertiary alkyl group, R ₁ -phenyl, R ₁ -benzyl, 2- or 3-thienyl or 2-, 3- or 4-pyridyl, and therapeutically useful addition groups salts of these compounds with acids.

Particularly preferred are compounds of formula II wherein:

R represents a hydrogen atom, a methyl, ethyl, methoxy or ethoxy group, a fluorine atom, a chlorine atom or a trifluoromethyl group,

X is a 1 or 2 number, y is a 2 or 3 number,

R 'is hydrogen, hydroxy, methoxy, ethoxy or C 2 -C 12 alkanoyloxy and' R 'is isopropyl, isobutyl or tert-butyl, benzyl, R ₁ -phenyl, 2- or 3-thienyl , 2-, 3- or 4-pyridyl, and therapeutically useful acid addition salts of these compounds.

Particularly preferred are those compounds of formula II wherein:

R is hydrogen, methyl, methoxy, fluoro, chloro or trifluoromethyl in the 7 or 8 position, x is 1 or 2, y is 2 or 3,

R 3 is hydroxy, methoxy or C 3 -C 10 alkanoyloxy; and

R 'is m- or pR _x -phenyl, and therapeutically useful acid addition salts of these compounds.

The compounds of the invention are prepared in a manner known per se by condensing compounds of formulas III and IV / ^IX V5.

Ph (IIO

S \ / ’» c

^(IV) in which either Y represents a reactive esterified hydroxyl group and the two symbols Z together form an NH group, or Z

Y is amino and each Z is a reactive esterified hydroxyl group, and the other general symbols are as defined above.

A reactive esterified hydroxy group is, for example, a hydroxy group esterified with a strong inorganic or organic acid, especially a hydrohalic acid, for example hydrochloric, hydrobromic or hydroiodic acid, sulfuric acid or an aromatic sulfonic acid, for example p-toluenesulfonic or p-bromobenzenesulfonic acid. The condensation is preferably carried out in the presence of basic condensation agents, for example alkali or alkaline earth metal hydroxides, carbonates or bicarbonates, such as sodium hydroxide or carbonate, calcium potassium, hydrides, lower alkoxides or lower alkali metal alkanoates such as sodium hydride , sodium methoxide or sodium acetate, or organic tertiary nitrogen bases such as lower trialkylamines or pyridines, for example triethylamine or lutidine.

The compounds obtained by the process according to the invention can be converted into each other in a manner known per se. Thus, for example, the compounds obtained in which R @ 3 is hydroxy can be esterified, i. their alkali metal salts, for example lithium salts, with reactive alkanoic acid derivatives, for example their halides or anhydrides. The esters obtained can be hydrolyzed in a manner known per se, preferably with aqueous alkaline agents.

Depending on the reaction conditions, the resulting compounds are obtained in free form or in the form of acid addition salts, which are also within the scope of the invention. The salts obtained can be converted into the free compounds in a manner known per se, for example by treatment with strong bases such as metal hydroxides or ammonium hydroxide, with basic salts or ion exchangers, such as alkali metal hydroxides or carbonates. Conversely, the free bases obtained can be converted into salts with organic or inorganic acids. In particular, acids which produce therapeutically useful salts are used to prepare acid addition salts. Such acids are, for example, inorganic acids such as strong mineral acids such as hydrohalic acids such as hydrochloric, hydrobromic or hydroiodic acids, sulfuric acid, phosphoric acid, nitric acid or perchloric acid; organic acids such as aliphatic or aromatic carboxylic or sulfonic acids such as formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, maleic, hydroxymaleinic or pyruvic acid, phenylacetic, benzoic, p-amnobenzoic, anthranilic, p-hydroxybenzoic, salicylic or p-aminosalicylic, pamic, , methanesulfonic, ethanesulfonic, hydroxyethanesulfonic and ethylenesulfonic acids, halobenzenesulfonic acids, toluenesulfonic and naphthalenesulfonic acids, sulfanilic acid, cyclohexanesulfamic or ascorbic acid.

These or other salts of the novel compounds, such as for example, may also serve to purify the free compounds obtained. In this process, the free compounds are converted into salts, separated and the corresponding free compounds released again.

Due to the close relationship between the novel compounds in free form and in the form of acid addition salts, in the foregoing and the following text, where appropriate and intended, the corresponding free acid addition salts are meant, where appropriate, under the free compounds.

The starting materials of formula (III) are new, but can be prepared by methods known per se, such as those described in the Examples below.

Compounds of formula III can be readily prepared by reducing the corresponding 1-benzofuran- or 1,4-benzodioxan-2-ylalkanoic acid with lithium aluminum hydride or sodium 2-methoxyethoxyaluminium hydride to the corresponding alcohol and esterifying it with the aforementioned strong acids or derivatives thereof. The reactive esters obtained can be converted to the corresponding amines by treatment with ammonia in an organic solvent, for example ethanol or benzene, preferably at elevated pressure or elevated temperature.

The starting materials and the resulting products of formulas I to IV, which are mixtures of isomers, can be separated into the individual isomers by known methods, for example, by fractional distillation, crystallization and / or chromatography. Racemic products can be resolved into optical antipodes, for example, by separation of their diastereoisomeric salts, such as by fractional crystallization of d- or 1-tartrates or α-methylbenzylammonium salts.

The above reactions are carried out by methods known per se, in the presence or absence of diluents, preferably those diluents which are inert to and reactive with the reactants, catalysts, condensation and neutralizing agents and / or inert atmosphere, under cooling, at temperature at room temperature or at elevated temperature, preferably at the boiling point of the solvent used, at normal or elevated pressure.

The invention also encompasses modifications of the process according to the invention in which the intermediate material obtained at any stage of the process is used as the starting material, which is then subjected to the remaining reactions, or in which the starting material is formed under the reaction conditions, or in the form of a salt or optically pure antipodes.

In the process according to the invention, it is preferable to use those starting materials which lead to the preparation of the above-mentioned particularly valuable compounds, in particular the compounds of the general formula II.

The pharmacologically acceptable compounds of the invention may be used, for example, to prepare pharmaceutical preparations containing an effective amount of the active ingredient together or in admixture with carriers suitable for enteral or parenteral administration. Preferably, tablets or gelatin capsules are used which contain the active ingredient together with diluents, for example lactose, dextrose, cane sugar, mannitol, sorbitol, cellulose and / or glycine,

The tablets also contain binders, for example magnesium aluminum silicate, starch paste, gelatin, tragacanth, and / or polyethylene glycols. , methylcellulose and / or polyvinylpyrrolidone and, if desired, tablet disintegrants such as starches, agar, alginic acid or salts thereof such as sodium alginate, enzymes or binders and / or effervescent mixtures, or adsorbents, colorants, The injectable preparations are preferably isotonic aqueous solutions or suspensions, and the suppositories are primarily fat emulsions or suspensions.The pharmacological preparations may be sterilized and / or may contain adjuvants such as preservatives, stabilizers, wetting agents and / or or emulsifiers, solubilizers, salts for regulating osmotic pressure and / or buffers The pharmaceutical preparations, which, if desired, may contain other pharmacologically valuable substances, are prepared by methods known per se, for example by conventional mixing, granulating or auctioning processes, and contain from about 0.1 to about 75%, in particular from about 1 to about 50% of active ingredient.

The invention is illustrated by the following non-limiting examples. In these examples, temperatures are given in degrees Celsius. Unless otherwise stated, the solvents of these examples are evaporated 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. under reflux. The reaction mixture was filtered, the filtrate was evaporated and the residue was recrystallized from isopropanol. 2- (2- (4-Hydroxy-4-phenylpiperldino) ethyl) -1,4-benzodioxane, m.p.

The product is suspended in 20 ml of ethanol, the suspension is neutralized with ethanolic hydrogen chloride, and the precipitate formed is recrystallized from a mixture of ethanol and diethyl ether. The corresponding hydrochloride melting at 203 ° is obtained

2- (4-Hydroxy-4-phenylpiperidinomethyl) -1,4-benzodioxane is also prepared in an analogous manner, which melts at 215-217 ° after recrystallization from methanol.

The starting material is prepared as follows:

To a solution of 6.7 g of allyl cyanide in 30 ml of petroleum ether, a solution of 16 g of bromine in 10 ml of petroleum ether is slowly added while stirring at about -15 °. The solvent was evaporated to yield S8 in quantitative yield.

m honor Joc JL úoo (

The latter nitrile was divided into five equal portions (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. 50 g of potassium carbonate and then a second portion of nitrile are added slowly with stirring. Three additional portions of nitrile are added, 40 g of potassium carbonate and acetone are added to the reaction mixture in advance to facilitate stirring. The resulting mixture was refluxed for 20 hours, then filtered and the filtrate was evaporated. The residue is distilled, collecting the fraction boiling at 10.5 mm Hg. 1,4-Benzodioxan-2-yl-acetonitrile is obtained (see Belgian Patent Specification 643 853 of 14 August 1964).

A mixture of 111 g of the latter,

63.5 ml of sulfuric acid, 160 ml of acetic acid and 160 ml of water were refluxed for 48 hours. The resulting mixture was poured onto ice, the precipitated solid material was collected and recrystallized from a mixture of benzene and petroleum ether. 1,4-Benzodioxan-2-yl-acetic acid melting at 100 ° is obtained (see Belgian Patent No. 613,211 of July 30, 1962).

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

A mixture of 3.6 g of the latter,

5.7 g of p-toluenesulfonyl chloride. and 20 ml of dry pyridine were stirred for 2 hours under ice-cooling. Ice is added to the reaction mixture, the precipitated solid is collected and recrystallized from a mixture of ethyl acetate and petroleum ether. 2- (2-tosyloxyethyl) -1,4-benzodioxane is obtained, melting at 82-83 °.

The starting materials for the preparation of the compounds of formula (II) as described in Example 3 are also prepared from the above-described equivalent amounts of the respective compounds.

Example 2

A mixture of 4.6 g of 2- (2-tosyloxyethyl) -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 under heating for 48 hours. The reaction mixture was filtered, evaporated, and the residue was recrystallized from isopropanol / petroleum ether to give 2- [2- (4-hydroxy-4-phenylpiperidino) ethyl] -2,3-dihydrobenzofuran, melting at 107 °. .

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

The starting material is prepared as follows:

To a suspension of 4.55 g of lithium aluminum hydride in 200 ml of tetrahydrofuran was added dropwise a solution of 14.2 g of (2- (2,3-dihydrobenzofuran-2-yl) acetic acid (Gazz. Chim. Ital. 93, 52 (1983)) with stirring. The reaction mixture was cooled in ice and quenched by the addition of 4.5 ml of water, 4.5 ml of 15% aqueous sodium hydroxide solution and 14.6 ml of water. The solution was washed with aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried and evaporated, and the residue was distilled in a flask at 140 ° (13 Pa) to give 2- (2-hydroxyethyl) -2,3-dihydrohenzofuran.

A mixture of 10 g of the latter,

17.4 g of p-toluenesulfonyl chloride and 30 ml of pyridine are cooled in ice for 2 hours with stirring. Ice is then added to the resulting mixture, the precipitated solid is filtered off and recrystallized from a mixture of ethyl acetate and petroleum ether. 2- (2-tosyloxyethyl) -2,3-dihydrobenzofuran melting at 51-54 ° C is obtained. Example 3

The following compounds of formula (II) are also prepared from the equivalent amounts of the corresponding starting materials by the procedures described in the preceding examples. In the compounds listed in the following table, y = 2.

number R x R ‘ R " Salt Melting point (° C) 1 H 1 4-CH3-CeH1 OH HCl 190 2 H 1 4-CH 3 O-CeHi OH HCl 155 3 H 1 4-F — CeHi OH HBr 235 4 7-C1 1 CeHs OH HBr 135-138 5 H 1 benzyl OH HCl 214 6 H, 1 4-C 1 -C 6 H 4 OH CH3SO3H 184—185 7 8-CH3 1 CeHs OH HCl 202—203 8 7-CHs 1 CeHs OH HCl 225 9 8-OCHs 1 C0H5 OH HCl 199—200 10 6,7-Cl 2 CeHs OH - 225—227 11 6,7,8-Cl 3 CeHs OH HCl IČ *) 12 H 1 C (CH 3) 3 OH CH3SO3H 182—185 13 H 1 2-pyridyl OH HCl 260-262 14 H 1 3-Pyridyl OH HCl 245-250 15 Dec H 1 3-CF3-4-Cl-C6H3 OH HCl 219—220 16 H 1 1-Benzothien-2-yl OH - 175—178 17 H 1 CeHs H HCl 224—225 18 H 1 CeHs OCHs HCl 247

*) 3580, 1280 and 1033 cm ' ¹

The compounds listed in the table above are:

1-3)

2- [2- (4-hydroxy-4- (p-tolyl, p-methoxyphenyl or p-fluorophenyl) piperidino) ethyl] -1,4-benzodioxane,

4)

7-chloro-2- (4-hydroxy-4-phenylpiperidino) ethyl] -1,4-benzodioxane,

5—6)

2- (2- (4-hydroxy-4- / benzyl or p-chlorophenyl / piperidino) ethyl) -1,4-benzodioxane,

7—11)

8-methyl-, 7-methyl-, 8-methoxy-, 6,7-dichloro- or 6,7,8-trichloro-2- [2- (4-hydroxy-4-phenylpiperidino] ethyl] -1, 4-benzodioxane,

12—16)

2- [2- (4-hydroxy-4- tert -butyl, 2-pyridyl),

3-pyridyl, p-chloro-m-trifluorophenyl or

1-Benzothien-2-yl / piperidino) ethyl] -1,4-benzodioxane

17)

2- [2- (4-phenylpiperidino] ethyl) -1,4-benzodioxane a

18)

2- [2- (4-methoxy-4-phenylpiperidino) ethyl] -1,4-benzodloxane.

The following procedures illustrate the preparation of the various new starting materials:

A solution of 48.6 g of 2- (7-methyl-1,4-benzodioxan-2-yl) acetic acid in a minimal amount of tetrahydrofuran is added dropwise to a suspension of 13.4 g of lithium aluminum hydride in 200 ml of dry tetrahydrofuran. The mixture is refluxed overnight, then cooled and quenched by the addition of 13.4 ml of water,

13.4 ml of 15 '% aqueous solution of sodium hydroxide and 40 _t mL water. The reaction mixture is filtered, the filtrate is evaporated and the residue is distilled in a molecular distillation apparatus, collecting a fraction boiling at 155-165 ° C / 13 Pa. 2- (2-hydroxyethyl) -7-methyl-1,4-benzodioxane is obtained as a colorless oil.

To a Grignard reagent prepared from 3.6 g magnesium and 18.9 g benzyl bromide in 50 ml diethyl ether, a solution of 18.4 g 1-benzyl-4-piperidone in 100 ml diethyl ether was added and the mixture was refluxed for 1 hour. The reaction was quenched by the addition of 30 ml of saturated aqueous ammonium chloride solution, the ethereal solution was separated and evaporated, dried. A thick oil is obtained as a residue. 26 g of this oil are hydrogenated in a mixture of 120 ml of ethanol and 120 ml of acetic acid at 50 psi at a temperature of 50 DEG C. in the presence of 3 g of 10% palladium on carbon catalyst at a temperature of 50 DEG C. until one mol. The resulting mixture was filtered, the filtrate was evaporated, the residue was stirred with ammonium hydroxide and extracted with methylene chloride. The extract was dried and evaporated to yield

4-Benzyl-4-hydroxypiperidine, which is sufficiently pure for the next reaction.

Analogously, 4-hydroxy-4- (4-methoxyphenyl) piperidine is obtained, melting after recrystallization from a mixture of isopropanol and petroleum ether at 121-123 ° C.

The following compounds are also prepared in an analogous manner:

1- 2- (2- (4-Hydroxy-4-phenylpiperidino) ethyl) -1,4-benzodioxane melting after recrystallization from isopropanol at 141-143 ° C, [α] D - 44.8 ° ( m.p. 225 DEG-227 DEG; [.alpha.] D = -36.5 DEG (methanol); d-2- [2- (4-hydroxy-4-phenylpiperidino) ethyl] -1; 4-benzodioxane, m.p. 141-143 °, [ce] _D - + 44.8 ° (MeOH). the hydrochloride of this compound has a melting point of 225-227 ° and [a] _D - + 36.5 ° (methanol)

2- (3- (4-hydroxy-4-phenylpiperidino) propyl) -1,4-benzodioxane, m.p. 95 DEG-98 DEG (crystallized from isopropanol), melting at 155 DEG-157 DEG after recrystallization from isopropanol. ,

2- (2- (4-hydroxy-4-thienyl-2-piperidino) ethyl) -1,4-benzodioxane melting after crystallization from isopropanol at 117-118 °;

2- (2- (4-benzylpiperidino) ethyl) -1,4-benzodioxane hydrochloride, with IC bands at 2447 and 748 cm ^-1 ,

2- (2- (4-p-fluorophenylethylpiperidino) ethyl) -1,4-benzodioxane hydrochloride in which the IC spectra show bands at 2485 and 695 cm ^-1 ,

2- (2- (4-hydroxy-4-phenylpiperidino) ethyl) -1,4-benzoxathiancyclamate, m.p.

2- (2- (4-phenylpiperidino) ethyl) -1,4-benzoxathiancyclamate, m.p. 146 DEG-148 DEG C.,

2- (2- (4-ethoxy-4-phenylpiperidino) ethyl) -1,4-benzodioxane maleate, m.p. 160-162 °;

2- [2- (4-hydroxy-4- (2-benzothienyl) piperidino) ethyl] -1,4-benzodioxane melting after crystallization from ethanol / acetone at 175-178 °,

2- (2- (4-Hydroxy-4- (2-pyridyl) piperidino) ethyl) -1,4-benzodioxane dihydrochloride melting after crystallization from a mixture of ethanol and diethyl ether at 260 DEG to 262 DEG C. Analogously prepared 3-pyridyl -isomer melts at 245 to 250 ° with decomposition,

2- (2- (4-propionyloxy-4-phenylpiperidino) ethyl) -1,4-benzodioxane hydrochloride melting after recrystallization from a mixture of isopropanol and diethyl ether with decomposition at 170 °,

2- (2- (4-n-decanoyloxy-4-phenylpiperidino) ethyl) -1,4-benzodioxane as a pale yellow oil which is purified by thin layer chromatography on silica gel in chloroform-ethyl acetate (4: 1) solvent system ,

Rcm 4,5,

2- (2- (4-propionyloxy-4-pyridyl-2-piperidino) ethyl) -1,4-benzodioxane hydrochloride melting after recrystallization from isopropanol with decomposition at 125 to 130 °,

2- (2- (4-pivaloyloxy-4-phenylpiperidino) ethyl) -1,4-benzodioxane hydrochloride, m.p. 195 DEG-200 DEG.

This example describes the composition and preparation of 10,000 tablets, each containing 5 mg of active ingredient.

Ingredients:

Component Quantity

2- [2- (4-hydroxy-4-f ⁵ enylpiperi dino) ethyl] -1,4-benzodioxane hydrochloride 50 g Lactose 1157 g Corn starch 75 g Polyethylene glycol 6000 75 g talc powder 75 g Magnesium stearate 18 g Purified water as needed

Preparation:

All the powdered ingredients are sieved through a 0.6 mm sieve, then the active ingredient is 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 added to a boiling solution of polyethylene glycol in 150 ml of water. The resulting paste is added to the powder mixture and granulated, optionally with additional water. The granulate is dried overnight at 35 °, then sieved through a 1.2 mm sieve and compressed into 6.4 mm diameter tablets with a breaking line.

The following describes the composition and preparation of 10,000 capsules, each containing 2.5 mg of the active ingredient.

Ingredients:

1-2- [2- (4-hydroxy-4-phenylpiperidinoethyl) -1,4-benzodioxane hydrochloride (α = -36.5 °) 25 g milk sugar 1875 g talc powder 100 g

Preparation:

All the powdered ingredients are sieved through a 0.6 mm sieve, and the active ingredient is then homogenized first with talc and then with milk sugar in a suitable mixer. The mixture obtained is filled into gelatin capsules No. 3 in a filling device, each containing 200 mg of the mixture.

Tablets and hard gelatin capsules containing other compounds in the examples are also prepared in an analogous manner.

Claims (7)

SUBJECT OF THE INVENTION 1. A process for preparing the novel 2-piperidinoalkyl-l, 4-benzodioxan of the formula I / CH ⁰ C 'H N / C ^x (CH _{Z) 9} alkyl contains up to 7 carbon atoms, HPH, thienyl, pyridyl or benzothienyl, and acid addition salts thereof, characterized in that the compounds of formulas III and IV are condensed In which Ph is a 1,2-phenylene radical, optionally substituted with one to three identical or different substituents selected from the group consisting of alkyl groups of up to 7 carbon atoms, alkoxy groups of up to 7 carbon atoms, halogen atoms, and trifluoromethyl, X is oxygen or sulfur, m is an integer of 0 or 1, n is an integer of 1 to 4, each of p and q is an integer of 1 to 3, where the sum of p -j + q is 4, each R1 and R2 are hydrogen, R3 represents a hydrogen atom, a hydroxyl group, an alkoxy group having at most 7 carbon atoms or an alkanoyloxy group containing up to 20 carbon atoms, and R represents an alkyl group having not more than 7 C atoms, HPh-alkyl, wherein the Al ^ (C ^ / ^<IV> in which either Y is a reactive hydroxyl group and esterlfikovanou two sym \ boluses Z together form a group NH, or Y is an amino group and each of Z is a reactive esterified hydroxyl group, and the other general symbols are as defined above, whereupon the optionally obtained free compound is converted to an acid addition salt or the obtained acid addition salt to the free compound or to another salt, and and / or the resulting mixture of isomers or racemates is optionally resolved into individual isomers or racemates, and / or the resulting racemates are optionally resolved into optical antipodes. 2. A process according to claim 1, wherein the starting materials of formulas III and IV are those in which Y or Z is a hydroxyl group esterified with a strong inorganic or organic acid. 3-thienyl, 2-, 3- or 4-pyridyl and Y and Z are as defined in 1. 3. The process according to claim 1, wherein the reaction is carried out in the presence of basic condensing agents. Process according to any one of Claims 1 to 3, characterized in that the starting materials used are compounds of the abovementioned formula III and IV in which: Ph is a 1,2-phenylene radical optionally substituted by one or two substituents independently selected from the group consisting of alkyl and alkoxy groups containing up to 4 carbon atoms, halogen atoms and trifluoromethyl, X is oxygen, m is an integer of 0 or 1, n is an integer of 2 to 4, each of p and q being an integer of 2, each of R 1 and R 2 being a hydrogen atom, R 3 represents a hydrogen atom, a hydroxy group, an alkoxy group having a maximum of 4 carbon atoms or an alkanoyloxy group having a maximum of 16 carbon atoms, and R 4 represents a C 3 -C 7 secondary or tertiary alkyl group, HPh-CH 2, HPh, 2- or 3-thienyl, 2-, 3- or 4-pyridyl, and Y and Z are as in point 1. Process according to one of Claims 1 to 3, characterized in that compounds of formulas IIIa and IVa (III +) are used as starting materials. In which R represents a hydrogen atom, an alkyl or alkoxy group containing not more than 4 carbon atoms, a halogen atom or a trifluoromethyl group, x being a number of 1 or 2, y being an integer of 2 to 4, R 'is hydrogen, hydroxy, alkoxy of up to 4 carbon atoms or alkanoyloxy of up to 16 carbon atoms, and R 1 represents a C 3 -C 7 secondary or tertiary alkyl group, R ₁ -phenyl, R ₁ -benzyl, 2- or 3-thienyl or 2-, 3- or 4-pyridyl and Y and Z are as defined above as in point 1. 6. A process according to any one of claims 1 to 3, wherein the starting materials are compounds of the above formulas IIIa and IVa, of which: R represents a hydrogen atom, a methyl, ethyl, methoxy or ethoxy group, a fluorine atom, a chlorine atom or a trifluoromethyl group, x being a number of 1 or 2, y being a number of 2 or 3, R 'is hydrogen, hydroxy, methoxy, ethoxy or C 2 -C 12 alkanoyloxy; and R 'is isopropyl, isobutyl or tert-butyl, benzyl, R _x -phenyl, 2- or 7. A process according to any one of claims 1 to 3, wherein the starting materials are compounds of the above formulas IIIa and IVa in which: R is hydrogen, methyl, methoxy, fluoro, chloro or trifluoromethyl in the 7 or 8 position, x is 1 or 2, y is 2 or 3, R 3 is hydroxy, methoxy or C 3 -C 10 alkanoyloxy; and R 'is m- or pR _x -phenyl, and Y and Z are as in 1. ssverograíia, n. p., plant 7, Most