CS198191B2 - Method of producting new 2-piperidinoalkyl-1,4-benzodioxanes - Google Patents

Description

DESCRIPTION OF THE INVENTION CZECHOSLOVAK SOCIALISTS

REPUBLIC (19) 198191 (11) (B2j

THE PATENT

INVENTORY OFFICE DISCOVERY (51) Int. Cl.3

(β Ó9 δ gadAnSj307 / 78} (22) PmhlúflGno 22 06 76 (21) (PV 411-78} (32) (31) (33) Priority from 23 06 75 (589118) United States (40) Posted 31 08 79 (45) Released 15 03 83

(72J

The author of the HUEBNER CHARLES FERDINAND dr., CHATHAM (Sr.) (73)

Proprietor of CIBA-GEIGY AG, BASILE (Switzerland) (54) Method of production of new 2-piperidinoalkyl-1,4-benzodioxanes

The present invention relates to a process for the preparation of novel 2-piperidinoalkyl-1-benzofuranes or -1,4-benzooxioxanes of the general formula I

Ph> —X in which

Ph is a 1,2-phenyl radical optionally substituted with one to three identical or different substituents selected from the group consisting of lower alkyl groups, lower alkoxy groups, halogen atoms, atrifluomethyl, X is oxygen or sulfur, 2 is 1 to 3, wherein the sum of p + q is 4, each of R 1 and R 2 is hydrogen, R 3 is hydrogen, hydroxy, lower alkoxy or lower alkanoyloxy, and R 6 is lower alkyl, HPh-lower alkyl or HPh, thienyl, pyridyl or benzothienyl, and their acid addition salts, especially therapeutically useful acid addition salts. In the foregoing, " lower " is meant to denote radicals and compounds containing at most 7, preferably 4 and especially 1 or 2 carbon atoms, and " higher " refers to radicals containing 8 to 20 carbon atoms, preferably 10 to 16 carbon atoms. carbon atoms. The 1,2-phenyl radical of Ph is preferably monosubstituted, wherein the substituents are exemplified by the following: lower alkyl groups, for example 198191 or bromine, or trichlorometnyl shupine. Of the aforementioned integers, m is preferably 1 when the general formula I is 1,4-benzodioxanes or 1,4-benzoxathians, or 1,4-benzoxathians, or 0 in the case of that the formula I is 1-benzofurans. The alkylene group CnH2n 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 preferably, the symbol p a represents a free, etherified or esterified hydroxyl group, such as a lower alkoxy group, for example, one of the lower alkoxy groups listed above, lower or higher alkynyloxy groups, e.g. , propionyloxy, pivaloyloxy, ocanoyloxy, decanoyloxy, un-decanoyloxy, lauroyloxy, myoroyloxy, palmitoyloxy or stearoyloxy, but also hydrogen.

The lower alkyl group R 4 is preferably a 3 to 7 carbon secondary or tertiary alkyl group, such as isopropyl, iso- or t-butyl, -pentyl or -hexyl. preferably HPh-CnH2n-, for example benzyl or 1- or 2-phenylethyl. Particularly preferred R 4 groups are the phenyl groups of the formula HPh already mentioned above.

Since the compounds of general formula (I) contain at least one nitrogen atom, they may be in the form of acid addition salts, in particular therapeutically acceptable acid addition salts, for example those derived from the acids mentioned below.

The compounds of the present invention exhibit valuable pharmacological effects, for example, analgesic and mainly neuroleptic, and their beneficial properties vary widely (dose-dependently) from the extrapyramidal side effects. This sharp separation of the mode of action has not yet been observed by other neuroleptic agents such as haloperidol. These properties can be demonstrated by animal experiments, particularly mammals, such as mice, rats, dogs and especially monkeys. The compounds of the invention may be administered orally, for example, orally or parenterally, for example, subcutaneously, intraperitoneally or intravenously, for example in the form of gelatin capsules, suspensions containing starch, aqueous solutions or suspensions. In oral administration at the previously indicated doses, in particular at a dose of 0.5 and 5 mg / kg / day, in monkeys, inhibition of refex such that the animals actuate the device to get rid of unpleasant stimuli. This test is performed as follows:

Electric shocks are given to the feet of the monkeys at certain times. Animals will avoid these electrical pulses by pressing a button. The monkey is trained to crush the button before it reaches an electrical discharge. 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 electric shocks (0.5 seconds) every 20 seconds until the next button press. Under control conditions, monkeys press the button at a relatively constant rate, so that rarely more than 5 or 6 shocks occur over a four hour trial period. New compounds tested for neuroleptic effects suppress this learned conditioned behavior of experimental animals. The blocking of this property is manifested by the suppression, the ability to get an electric shock, so that the experimental animals receive significantly higher numbers. Furthermore, the novel compounds, for example the esters of the above dioxane derivatives, induce propionic acid in the above-mentioned orally administered dose, in particular at about 5 and 10 mg / kg / day, in mice with analgesic effects. These effects can be demonstrated by a test in which the test animals draw the tail from the site of the painful stimulus and, on the other hand, the test for painful convulsions induced by the administration of phenylquinone. In the first mentioned test, the tail of the male rat is measured. the heat stream is measured and the irradiation time is measured. The end of this time interval is the moment when the animal retracts its tail from the irradiated area. Heat irritation is never applied for more than 10 seconds. A time value (control value) is determined for each animal prior to administration of the test compound. The mean of control values is calculated to determine the presence of analgesic effects and three deviations of the standard are added to it. The time values obtained in animals after administration of the test compound, lying above the above-mentioned mean value, indicate an analgesic effect. In the test for pain cramps, 2.5 mg / kg of phenylquinone were administered to male mice at 20 minutes after oral administration of the compounds of the invention, after which the number of mice clenching after 5 to 15 minutes after injection was determined. In the case of the analgesic effect of the test compound, the animals do not change their behavior.

Preferably, the enzyme is preferably in mammals. The compounds of the invention can also be used as intermediates for the preparation of other valuable, especially pharmacologically active substances. Compounds of formula I are preferred in which

Ph represents a 1,2-phenyl radical or a pin, a methoxy group, an ethoxy group or a C2 -C12 alkanoyloxy group and 'R' represents an isopropyl group, an isobutyl or tert-butyl group, a benzyl group, an Rx-phenyl group, a 2- or 2-carbon atom; or

3-thienyl; neb ^

HIM

those comprising alkyl and alkoxy groups each having at most 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 the symbols p a is 2, each of R 1 and R 2 is hydrogen, R 3 is hydrogen, hydroxy, alkoxy having up to 4 carbon atoms, or alkanoyloxy of at most 16 carbon atoms, and R 4 is a secondary or tertiary alkyl group with 3 to 7 carbon atoms, HPh-CH2, HPh, 2- or 3-thienyl, 2-, 3- or 4-pyridyl, and therapeutically acceptable acid addition salts of these compounds.

Particularly preferred are compounds of general formula II

illl ííffl

addition of acid addition compounds.

Especially preferred are you. a compound of formula II wherein R is hydrogen, methyl, methoxy, fluorine, atomic, or trifluoromethyl, each at position 7 or 8, x is 1 or 2, y is R 2 is hydroxy, methoxy or alkanoyloxy of 3 to 10 carbon atoms and R 'is m- or p-R 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 reducing the compound of formula (III) / (c) C; R <in which &amp;

A — N / ty you. As 7-VI (III) in which R represents a hydrogen atom, an alkyl or alkoxy group having at most 4 carbon atoms, a halogen atom or a trifluoromethyl group, x is a number of 1 or 2, y is an integer of 2 to 4, R 'represents a hydrogen atom, a hydroxy atom, an alkoxy group having not more than 4 carbon atoms, or an alkanoyloxy group having no more than 16 carbon atoms, and R' represents a C 3 -C 7 secondary or tertiary alkyl group, R x -phenyl , Rx-benzyl, 2- or 3-thienyl or 2-, 3- or 4-pyridyl, and therapeutically acceptable acid addition salts thereof.

Particularly preferred are compounds of formula II wherein R is hydrogen, methyl, ethoxy, methoxy or ethoxy, fluorine, chlorine or trifluoromethyl, x is 1 or 2, y is a number of 2 or 3, R 'is a substituent of A is a group of the formula C11H12n-2-CO, CnH2n-2 or Y' -C 'H2n-i, where Y' represents an active esterified hydroxyl group,

R 5 represents a hydrogen atom or

R 1 and R 5 together form another bond between the carbon atoms,

R 1 has the same meaning as R 4, or, when R 3 represents a hydrogen atom, HPH-alkanoyl of at most 7 carbon atoms in the alkanoyl moiety and the remaining general symbols of the above may be mentioned, or a compound of general formula of Formula IV

Pb. 7-a-n-IR-e-Ru

(IVJ in which A ’means a group of formula Cn-iH2n-2-CO, Z * 1 T T · · 198191

O reactive esterified hyroxyl group and s have a value of 0 or 2,

R 5 represents a hydrogen atom, or R 1 and R 5 together form an additional bond between the carbon atoms

Rd and the remaining general symbols have the meanings indicated.

Preferably, Y 'is a hydroxyl group esterified with an inorganic or organic acid, especially a hydrohalic acid such as hydrochloric acid, hydrobromic acid or hydroiodic acid, sulfuric acid, or an aromatic sulfonic acid such as p-toluenesulfonic acid or p-bromobenzenesulfonic acid. The reduction is carried out in a conventional manner, always taking into account the presence of a keto group and / or an aminocarbonyl group. The latter group is preferably reduced by simple or complex hydrides of light metals such as diborane or borohydridyalkali metals, alkali metal aluminum hydrides or alkali metal alkoxyborohydrides, for example lithium aluminum hydride and / or sodium trimethoxyborohydride. The reduction of ketones or olefins is preferably carried out by catalytically activated hydrogen or hydrogen in the presence of hydrogen, hydrogen in the presence of palladium catalysts, or by electrolytically produced hydrogen, or preferably cyanoborohydride. Reductive elimination of the Y &apos; moiety is accomplished by the above-mentioned hydride reducing agents; with the exception of lithium aluminum hydride, for the above-mentioned esters.

The compounds of the invention can be converted into each other by methods known per se. Thus, for example, the compounds obtained in which R 3 is a hydroxy group can be esterified, i.e. their alkali metal salts, for example lithium, with reactive derivatives of alkanoic acids, 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 the free form or in the form of acid addition salts, which also fall 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, metal hydroxides or ammonium hydroxide, by the action of basic salts or ion exchangers such as alkali metal hydroxides or carbonates. Conversely, the free base obtained can be converted into salts with organic or inorganic acids. In particular, acids which provide therapeutically acceptable salts are used to prepare acid addition salts. Such acids are, for example, inorganic acids such as strong mineral acids, such as calogenic acids, such as hydrochloric, hydrobromic or hydroiodic, sulfuric acid, phosphoric acid, nitric acid or acid chloroacids, organic acids, e.g. aromatic carboxylic or sulphonic acids such as formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, maleic, hydroxymaleic or pyruvic, phenylacetic, benzoic, p-aminobenzoic, anthranilic, p-hydroxybenzoic, S-butyl or, p-aminosalicylic acid, acetic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethane sulfonic acid and ethylene sulfonic acid, halobenzene sulfonic acid, toluenesulfonic acid and naphthalenesulfonic acids, sulfanilic acid, cyclohexane sulfamic or ascorbic acid.

These or other salts of the novel compounds, such as picrates, can also be used to purify the free compounds obtained. This is by converting the free compounds into salts, separating them and releasing the corresponding free compounds from them. -niny.

Due to the close relationship between the new compounds in the free form and the acid addition salts, the corresponding acid addition salts, where appropriate, are meant, where appropriate, for the free compounds. The starting materials of the formulas III and IV are new but can be prepared by methods known per se, such as those described below in the Examples.

The compounds of the formulas III and IV can be prepared from the corresponding .beta.-benzofuran or 1,4-benzodioxan-2-ylalkanoic acids by converting the acid into a halide, a mixed anhydride or an amide with i-midazole, and with the appropriate piperidines. Preferably, the unsaturated starting materials are those prepared from the corresponding aldehydes and the abovementioned piperidines. The aldehydes used can be obtained from the abovementioned acid halides by reduction with Rosenmund, or by reduction of the nitriles of the respective acids with diisobutylaluminum hydride. corresponding to the starting materials of the formulas III and IV, wherein A and A 'respectively represent Y'-CnH2n-is by condensation of 1-benzofuran or 1,4-benzodioxan-2-yl-alkylene oxides with the aforementioned piperidines, or by reaction with α-bromoketone and reduction with sodium borohydride. These alcohols are known. These substances can be converted in a manner known per se, either by reaction with acids of formula HY 'under anhydrous conditions, for example in the presence of sulfuric acid, or by reaction with the halides with the anhydrides of the abovementioned acids, e.g. The starting materials and the resulting products of the general formulas I to IV, which are mixtures of isomers, can be separated by known methods, for example fractional distillation, crystallization and / or chromatography, into individual isomers. Racemic products can be resolved into optical isomers. antipodes, for example by separation of their diastereoisomeric salts, for example by fractional crystallization of d- or 1-tartrate or α-methylbenzylammonium salt.

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

The invention also includes modifications of the process of the invention wherein the starting material used is an intermediate obtained at any stage of the process which is then carried out for the remaining reactions or at which the constituent material forms under the reaction conditions or at which the starting material is used in the form of a salt or an optically pure antipode. The process according to the invention preferably employs those starting materials which lead to the preparation of the above-mentioned particular compounds, in particular the compounds of the general formula II.

For example, pharmacologically acceptable compounds of the invention may be used 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, and glidants such as silica, talc, acid stearic or herisols, such as magnesium or calcium stearate, and / or polyethylene glycols. The tables also contain binders, for example magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone and, if desired, tablet disintegrating agents such as starches, agar alginic acid or salts thereof, such as sodium alginate, enzymes or binders and / or non-effervescent mixtures, or adsorbents, coloring agents, flavoring agents and sweetening agents. The injectable preparations are preferably isotonic aqueous solutions or suspensions, and the suppositories are in the first instance a fatty emulsion or suspension. The pharmaceutical preparations may be sterilized and / or may contain adjuvants such as preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating osmotic pressure and / or buffers. The present pharmaceutical preparations which, if desired, may also contain other pharmacological agents, are prepared by methods known per se, for example by conventional mixing, granulating or draining techniques and contain from about 0.1 to about 75% , in particular from about 1 to about 50% of the active ingredient.

The invention is illustrated by the following non-limiting Examples. In these examples, temperatures are given in degrees Celsius. Unless otherwise stated, evaporation of the solvents in these examples is carried out under reduced pressure. EXAMPLE 1 A solution of 5.5 g of 1- [2- (1-1,4-benzodioxan-2-yl] acetyl-4-hydroxy-4-phenyl) was added to a suspension of 1.2 g of lithium aluminum hydride in 20 ml of tetrahydrofuran while stirring and cooling. The reaction mixture was stirred overnight at room temperature and quenched by the addition of several drops of ethyl acetate, 1.2 mL of water, 1.2 mL of 15% aqueous sodium hydroxide and 3.6 mL of water. the mixture is filtered, the filtrate is evaporated and the residue is recrystallized from isopropanol to give 1- 2- [2- (4-hydroxy-4-phenylpiperidino) ethyl] -1,4-benzodioxane, m.p. 141 DEG-143 DEG C. [.alpha.] D = -44.8 DEG (methanol) The hydrochloride of the compound melts at 225 DEG-227 DEG C. [.alpha.] D = -36.5 DEG (methanol).

An analogous d-base is also obtained, m.p. 141-143 °; [Α] D = + 44.8 ° (methanol), whose hydrochloride melts at 225-227 °; []] □ - + 36.5 ° (methanol). The starting material was prepared as follows: 19.4 g of 4-benzodioxan-2-yl acetic acid and 12.1 g of d, .alpha.-methylbenzylamine was dissolved in 100 ml of hot isopropanol, the solution was allowed to stand overnight, the salt formed was filtered off. and five times recrystallized from isopropanol. Experiments show that this crystallization is sufficient to separate the optical isomers of the acid. The acid was liberated with dilute hydrochloric acid, extracted with diethyl ether and the extract evaporated. There was thus obtained d-1,4-benzodioxan-2-yl-acetic acid [d] = + 49 ° (ethanol).

In an analogous manner, the antipode of the corresponding acid was obtained with 1- [alpha] -methylbenzylamine [[alpha]] D = -49 [deg.] (Ethanol).

A solution of 3 g of 1, 1,4-benzodioxan-2-yl-acetic acid in 20 ml of tetrahydrofuran is stirred with 3 g of carbonyl diimidazole for 1 hour. Addition of a suspension of 4-hydroxy-4-phenylpiperidine in 20 ml of tetrahydrofuran was stirred overnight, then evaporated and the residue was dissolved in ethyl acetate. The solution was washed with dilute aqueous hydrochloric acid 198191 with aqueous sodium hydroxide solution, dried and evaporated. 1,4-Benzodioxan-2-yl) acetyl] -4-hydroxy-4-phenylpiperidine is obtained. Example 2 To a mixture of 2 g of lithium aluminum hydride and 50 ml of tetrahydrofuran was added a solution of 5 g of 1- (3- (1,4-benzodioxan-2-yl) propionyl] -4-hydroxy-4-phenylpiperidine at room temperature. The reaction mixture was quenched by the addition of a few drops of ethyl acetate, 2 mL of water, 4 mL of 15% aqueous sodium hydroxide solution and 4 mL of water, filtered, the filtrate was evaporated, and the residue was recrystallized from ethyl acetate. 2- [3- (4-Hydroxy-4-phenylpiperidino) propyl] -1,4-benzodioxane melting at 95-98 [deg.] C. is obtained and the hydrochloride of this product is prepared by ethanolic hydrogen chloride. and recrystallizing from isopropanol melts at 155 to 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 was refluxed for 48 hours. The reaction mixture was evaporated, the residue was taken up in water and extracted with diethyl ether. The extract was dried and evaporated. To a mixture of 2.8 g of sulfuric acid, 7.2 ml of water and 7.2 ml of acetic acid was added 5 g of the above prepared crude nitrile, and the resulting mixture was refluxed under stirring for 48 hours. it is poured into ice water and extracted with diethyl ether. The extract was washed with water and extracted with aqueous sodium bicarbonate solution. The alkaline solution was acidified with hydrochloric acid and extracted with diethyl ether. The extract obtained is dried and evaporated. 2.5 g of crude acid are dissolved in 25 ml of tetrahydrofuran and 3 g of carbonyldiimidazole are added to the solution with stirring over 30 minutes. To the resulting mixture was added 4-hydroxy-4-phenylpiperidine (2.5 g), the reaction mixture was stirred overnight, then evaporated, the residue dissolved in ethyl acetate, washed with dilute aqueous sodium hydroxide solution and hydrochloric acid, dried and evaporated. 1- (3- (1,4-Benzodioxan-2-yl) propionyl) -4-hydroxy-4-phenylpiperidine is obtained Example 3 To a solution of 20 g of 2- (2- (4-hydroxy-4 -phenyl-piperidino) -1-tosyloxyethyl] -1,4-benzodioxane in 500 ml of tetrahydrofuran is added 7 g of lithium aluminum hydride, the mixture is refluxed for 6 hours and 2 ml are added with stirring. of ethyl acetate, 7 ml of water, 7 ml of 15% aqueous

IX sodium hydroxide flow and 22 ml water. The organic residue is filtered off, the filtrate is evaporated, ethanolic hydrogen chloride is added to the residue and the product is recrystallized from a mixture of ethanol and diethyl ether. 2- (2- (4-Hydroxy-4-phenylpiperidino) ethyl] -1,4-benzodioxane hydrochloride, melting at 203 ° C, is obtained. The corresponding free base melts at 142 ° C. : Sodium borohydride (12 g) was added to a solution of 42 g of 2- (2-bromoacetyl) -1,4-benzodioxane in 360 ml of methanol under stirring and cooling to 0 DEG C. After 5 hours, the mixture was cooled to 0 DEG. Sodium hydroxide (13.2 g) in methanol (150 ml) was added, the mixture was cooled to -15 ° C overnight, then poured onto ice and extracted with diethyl ether, washed with saturated aqueous sodium chloride solution and evaporated to dryness. 1,4-benzodioxan-2-yl-ethylene oxide.

A mixture of the latter compound (7.1 g) and 4-hydroxy-4-phenylpiperidine (3.54 g) in isopropanol (75 ml) was refluxed for 5 hours and evaporated. The residue was dissolved in ethyl acetate and the solution extracted with aqueous methanesulfonic acid. The substituted piperidine is separated between the aqueous and organic layers. After evaporation of the organic layer, a resinous residue is obtained which slowly crystallizes. Recrystallization from isopropanol gave 2- [2- (4-hydroxy-4-phenylpiperidino) -1-hydroxyethyl] -1,4-benzodioxane methanesulfonate, m.p. The aqueous extract was basified with ammonium hydroxide and extracted with semethylene chloride. The organic phase is dried, evaporated and the residue is recrystallized from a mixture of isopropanol and petroleum ether. The corresponding free base is obtained, melting at 95 °. To a solution of 20 g of the latter compound in 80 ml of pyridine was added portionwise 11.8 g of toluenesulfonyl chloride with stirring and cooling in ice. The reaction mixture was allowed to stand in ice for 3 hours, then poured into 200 g of ice-water and the aqueous phase was decanted from the crude material. The residue is washed several times with water, filtered and dried; There was thus obtained 2- [2- (4-hydroxy-4-phenylpiperidino) -1-tosyloxyethyl] -1,4-benzodioxane. Example 4 To 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 was added 8 ml of 4.5 N ethanolic hydrogen chloride. These conditions gave 2- [2- (4-hydroxy-4-phenylpiperidino) vinyl] -1,4-benzodioxane in situ.

After 1 hour, a solution of 2.4 g sodium cyanoborohydride in 30 ml methanol was added dropwise to the reaction mixture with stirring at room temperature. After 1 hour, the resulting solution was basified with aqueous sodium hydroxide 198191, concentrated, diluted to a small volume and diluted with water. The mixture was extracted with ethyl acetate, the extract was dried and evaporated. Ethanolic hydrogen chloride was added to the residue and the precipitate was recrystallized from ethanol / diethyl ether. There was thus obtained 2- [2- (4-hydroxy-4-phenylpiperidino) ethyl] -1,4-benzodioxane hydrochloride, melting at 203 °. The starting material was prepared as follows: To a solution of 20 g of 1,4-benzodioxan-2-yl-acetonitrile in 200 ml of benzene was added dropwise 71 ml of 1.6 N diisobutylaluminum hydride in benzene under stirring at 10 ° C. After 6 hours, the reaction mixture was treated with 50 mL of methanol and then with 200 mL of water, and the organic layer was separated and evaporated to dryness. 1,4-Benzodioxan-2-yl-acetaldehyde is obtained. EXAMPLE 5 To a solution of 5 g of 2- (2- (4-phenyl-1,2,5,6-tetrahydropyrid-1-yl) ethyl) 1,4-benzodioxanhydrochloride in 100 ml. 10 ml of 10% palladium carbon catalyst are added to the acetic acid / water mixture (9: 1 ml) and the mixture is hydrogenated at a pressure of 0.3 MPa until the equivalent amount of hydrogen is consumed. The reaction mixture is filtered, the filtrate is evaporated and the residue is taken up. The mixture is basified with ammonium hydroxide, extracted with methylene chloride, dried and evaporated, taken up in isopropanol and acidified with ethanolic hydrogen chloride to give 2- (2- (4-phenylpiperidino) ethyl). A solution of 16 g of bromine in 10 ml of petroleum ether is slowly added to a solution of 6.7 g of allyl cyanide in 30 ml of petroleum ether under stirring at about 15 DEG C. with stirring. The solvent is evaporated, yielding an olefinic nitrile of 3,4-dibromoam in quantitative yield Chem. Soc., 67, 400 (1945)].

The latter nitrile was separated into five-fold portions (45.4 g). The first portion is slowly added to a stirred mixture of 85 gpyrocatechin and 50 g anhydrous potassium carbonate in 100 ml acetone, boiling under reflux. Then, 50 g of potassium carbonate and a second portion of nitrile were added to the mixture while stirring. 3 more portions of the nitrile are then added, with the addition of 40 g of potassium carbonate and the required amount of acetone to the reaction mixture in advance to facilitate mixing. The resulting mixture was refluxed for 20 hours, filtered and the filtrate evaporated. The residue is subjected to distillation, with a fraction boiling at 105 720 Pa. 1,4-Benzodioxan-2-yl acetohitrile is obtained (see Belgian Pat. No. 643,853, August 14, 1964). 14

A mixture of 111 g of the latter compound, 63.5 ml of sulfuric acid, 160 ml of acetic acid and 160 ml of water was refluxed for 48 hours. The resulting mixture was poured onto ice, and the precipitated solid was separated and recrystallized from benzene / petroleum ether. There was obtained 1,4-benzodioxan-2-yl-acetic acid melting at 100 ° (see Belgian Patent No. 613,211 of July 30, 1962). A solution of 5.8 g of the above-mentioned compound in 100 ml of benzene was added dropwise to a 16.5 ml of 70% benzene solution of na-trium bis (2-methoxy ethoxy) aluminum hydride under reflux in a reflux condenser. 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 saturated, aqueous sodium bicarbonate solution and evaporated to dryness. 2- (2-Hydroxyethyl) -1,4-benzodioxane oleate is obtained.

A mixture of the latter compound (3.6 g), p-toluenesulfonyl chloride (5.7 g) and dry pyridine (20 ml) was stirred under ice-cooling for 2 hours. The reaction mixture is then added to the reaction mixture, and the precipitated solid is separated off and recrystallized from ethyl acetate / ether. 2- (2-tosyloxyethyl) -1,4-benzodioxane is obtained, melting at 82-83 °.

Reaction with 4-phenyl-1,2,5,6-tetrahydropyridine and conversion of the free base to hydrochloride gave the starting material melting at 200 to 201 °. Example 6 To a solution of 5 g of 2- [2- (4-benzoylpiperidino) ethyl] -1,4-benzodioxane hydrobromide in 100 ml of 90% aqueous acetic acid, 1 g of 10% palladium on carbon catalyst is added and the mixture is hydrogenated. at a pressure of 0.3 MPa and at 50 ° C until consumption of 2 molar equivalents of hydrogen. The reaction mixture is filtered, the filtrate is evaporated and the residue is taken up in water. The mixture was basified with hydroxy ammonium and extracted with methylene chloride. The extract was dried and evaporated, the residue was neutralized with ethanolic hydrogen chloride and the solid was separated. 2- (2- (4-Benzylpiperidino) ethyl] -1,4-benzodioxane hydrochloride is obtained, in which the IC spectrum is 2447 and 748 cm -1, starting material is prepared as described in Example 5 and has a melting point. 193-195 °.

Analogously, by hydrogenation of 2- (2- (4-fluorobenzoylmethylpiperidino) ethyl] -1,4-benzodioxane hydrochloride, m.p. 165-166 ° C, 2- [2- (4-p-fluorophenylethylpiperidino]] is obtained. ethyl] -1,4-benzodioxane hydrochloride, in which the IR spectrum of the bands is at 2485 and 695 cm @ -1.

1S 18 198191 Example 7

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

Composition:

Component

Amount 2- [2- (4-hydroxy-4-phenylpiperidino) ethyl] -1,4-benzodioxane hydrochloride 50 g milk sugar 1157 g corn starch 75 g polyethylene glycol 6000 75 g talc powder 75 g stearate Magnesium 18 g purified water as needed Preparation: All powder ingredients are screened through a 0.6 mm sieve, then the active ingredient is mixed with a lactic sugar, talc, magnesium stearate and starch in a suitable mixer. The other half of the starch is suspended in 40 ml of water and the suspension is placed in a boiling solution of polyethylene glycol in 150 ml of water. The paste formed is added to the powder mixture and granulated, optionally with additional water. The granulate is dried overnight at 35 °, then passed through a sieve of 1.2 mm mesh size and compressed to break the tablets with a diameter of 6.4 mm. The following describes the composition and preparation of 10,000 capsules, each containing 2.5 mg of active ingredient.

Composition:

Component Quantity 1- 2- [2- (4-Hydroxy-4-phenylpiperidino) ethyl] -1,4-benzodioxane hydrochloride (δ = -36.5 °) 25 g milk sugar 1875 g talc powder 100 g Preparation: All powdered ingredients are screened through a 0.6 mm sieve and the active ingredient is homogenized first with talc and then with milk sugar in a suitable mixer. The obtained mixture is filled with gelatin capsules No. 3 in the filling apparatus so as to each contain 200 mg of the mixture.

Similarly, tablets and hard gelatin capsules containing other compounds described in the Examples were prepared. Example 8 To a mixture of 1.44 g of lithium aluminum hydride in 150 ml of anhydrous tetrahydrofuran was added a solution of 14 g of l- 2- (1,4-benzene). -oxathian-2-yl] acetyl] -4-hydroxy-4-phenylpiperidine in 140 ml of tetrahydrofuran The reaction mixture was stirred overnight at room temperature, then 1.4 ml of water, 2.9 was added. sodium bicarbonate (19 ml) and water (2.9 ml), the resulting mixture is filtered and the filtrate is evaporated, the residue is taken up in hot isopropanol (10 ml) and cyclohexane sulfamic acid (4.5 g) is added to the solution. 176 DEG C. 2- (4-Hydroxy-4-phenylpiperidino) ethyl] -1,4-benzoxathian cyclamate, m.p. 176 DEG C. The starting material was prepared as follows: To a solution of 21 g of 2-hydroxythiophenol in 290 ml of acetone under heating and the reflux condenser dropped 12.5 g 3, 4-dibromobutyronitrile, while 15.8 g of potassium bicarbonate are added in small portions. After 30 minutes, the addition of the above-mentioned amounts of dibromo derivative and potassium carbonate was repeated. After a further 30 minutes, the addition was repeated a third time. The reaction mixture was then refluxed for 20 hours and filtered after cooling. The salts obtained as a residue were washed with acetone and, after filtration, the filtrate was evaporated. The residue was subjected to distillation, whereby a fraction boiling at 185 ° C / 67Pa was removed. There was thus obtained 2- (1,4-benzoxathian-2-yl) acetonitrile.

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 was refluxed for 48 hours. After cooling, the reaction mixture is extracted three times with 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. 9.2 g of carbonyl imidazole are added to a solution of 10 g of the latter compound in 45 ml of anhydrous tetrahydrofuran and 10.1 g after 30 minutes. The reaction mixture was evaporated, the residue was taken up in ethyl acetate, the solution was washed with water, acidified with hydrochloric acid and evaporated to dryness to give 1- [2-methylpiperidine-4-phenylpiperidine]. - (1,4-benzo, xathian-2-yl) acetyl] -4-hydroxy-4-phenylpiperidine.

Analogously, 2- [2- (4-phenylpiperidino) ethyl] -1,4-benzoxa-thian-cyclamate was also prepared and melted at 146-148 ° C to a mixture of 0.7 g of lithium aluminum hydride and 100 ml of tetrahydrofuran with stirring, a solution of 4.9 g of 1- [2- (1,4-benzodioxan-2-yl) acetyl] -4-ethoxy-4-phenylpiperidine in 50 ml of tetrahydrofuran is added with stirring. 198191 17 18

The reaction mixture was stirred overnight, then quenched by the addition of a few drops of ethyl acetate, 0.7 mL of water, 1.4 mL of 15% aqueous sodium hydroxide solution and 2.1 mL of water. The resulting mixture was filtered, the filtrate evaporated and 5 g of residue dissolved in a minimal amount of ethanol. 1.7 g of maleic acid in ethanol are added to the obtained solution, the mixture is cooled, filtered and the residue is recrystallized from ethanol. There was thus obtained 2- [2- (4-ethoxy-4-phenylpiperidino) ethyl] -1,4-benzodioxane maleate, melting at 160-162 ° C. The starting material was prepared as follows: To a solution of 3.2 g of 4-benzodioxan-2'-yl-acetic acid in 30 ml of tetrahydrofuran was first added 3.1 g of Ι, Γ-carbonyldiimidazole and the like. 3.5 g of 4-ethixix-4-phenylpiperidine in 30 ml of tetrahydrofuran for 30 minutes. The mixture was stirred at room temperature for 18 hours, then evaporated and the residue was taken up in ethyl acetate. The solution was washed with water, 1 N hydrochloric acid and saturated aqueous sodium chloride solution, dried and evaporated. This gives 1- (2- (1,4-benzodioxan-2-yl) acetyl] -4-ethoxy-4-phenylpiperidine.

A mixture of 5 g of 2- (2- (4-hydroxy-4-phenylpiperidino) ethyl] benzourane, 100 ml of acetic acid and 1 g of 10% platinum on carbon as catalyst at room temperature and under pressure, The reaction mixture is filtered, the filtrate is evaporated, the residue is taken up, the mixture is basified with 2N aqueous sodium hydroxide solution and extracted with methylene chloride, the extract is dried, evaporated and the residue is taken up. The solution is neutralized with ethanolic hydrochloric acid and the precipitate formed is recrystallized from ethanol / diethyl ether to give 2- (2- (4-hydroxy-4-phenylpiperidinoethyl (- 2,3-dihydrobenzofuran)). Hydrocyl chloride, melting at 185 to 187 ° C. The starting material is prepared as follows:

A mixture of 16 g of 2-acetylbenzofuran, 4.8 g of sulfur and 13.2 ml of morpholine was refluxed for 8 hours, then 160 µl of 10% ethanolic sodium hydroxide was added thereto, and the reaction mixture was refluxed for 6 hours. and then concentrated to low volume, acidified with hydrochloric acid and extracted with diethyl ether. The extract was evaporated and the residue was subjected to distillation while boiling at 145 ° / 13Pa. 2-Benzofuranylacetic acid is obtained. A solution of 10.5 g of the above compound in 50 ml of THF was added to a mixture of lithium alumina hydride (3.4 g) and tetrahydrofuran (50 ml) with stirring. The resulting mixture was refluxed for 12 hours, then cooled with ice and quenched by the addition of 3.4 ml of 15% aqueous sodium hydroxide solution and 10.2 ml of water. The inorganic salts are filtered off, washed with diethyl ether, dried and evaporated. 2- (2-Hydroxyethyl) benzofuran is obtained. 5.7 g of p-toluenesulfonyl chloride are added to a solution of 3.25 g of the latter compound in 10 ml of pyridine while stirring at 5 ° C. After 2 hours the mixture was poured onto ice, the solid material was separated and recrystallized from ethyl acetate / petroleum ether. 2- (2-tosyloxyethyl) benzolurane is obtained.

A mixture of the latter compound (4.55 g), 4-hydroxy-4-phenylpiperidine (2.64 g) and sodium bicarbonate (10%) was refluxed under stirring in 100 ml of 4-methyl-2-pentanone for 2 days. The reaction mixture is filtered, the filtrate is evaporated, the residue is dissolved in hot isopropanol, the solution is clarified with charcoal and filtered. After cooling, 2- (2- (4-hydroxy-4-phenylpiperidino) ethylbenzofuran, m.p. 195-197 GC, crystallized.

The following compounds of formula (II) are also prepared from the equivalent amounts of the corresponding starting materials by the procedures described in the previous examples. In the compounds listed in the following table, y - 2. RX number R 'R "Salt Melting point (° C) 1 H 1 4 -CH3-C6H4 OH HC1 190 2 H1 4-CH3O-C6H4 OH HC1 155 3 H1 4-F-C6H4 OH HBr 235 4 7-Cl 6 H 5 OH HBr 135-138 5 H 1 benzyl OH HCl 214 6 H 1 4 -C1-CsH4 OH CH3SO3H 184—185 7 8-CH3 1 C6H5 OH HC1 202–203 8 7-CH1 1 CeHs OH HG1 225 9 8-OCH3 1 CeHs OH HCl 199–200 10 6.7-Cl 2 CsH5 OH - , 225—227 11 6,7,8-Cl 3 C 6 H 5 OH HCl ICX) 12 H 1 C [CH 3) 3 OH CH 3 SO 3 H 182—185 13 H 1 2-pyridyl OH HCl 260—262 14 H 1 3 “pyridyl OH HCl 245-250 15 H 1 3-CF 3 -4-C 1 -C 6 H 3 OH 219-220 16 H 1 -benzothien-2-yl OH 175-178 17, H 1 C 6 H 5 OCH 3 HCl 247 ** 3580.1280 and 1033 cm -1 1.

Claims (7)

The compounds listed in the preceding table are: 1 to 3) 2- [2- (4-hydroxy-4- (p-tolyl, p-methoxyphenyl or p-fluorophenyl) piperidino) ethyl -1,4-benzodioxane; 4) 7-chloro-2- [2- (4-hydroxy-4-phenylpiperidinoethyl] -1,4-benzodioxane; 5-6} 2- {2- (4-hydroxy-4- / benzyl or p) -7-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-trifluoro-phenyl or 1-benzothien-2-yl / piperidino] ethyl] -1,4-benzodoxane; 17} 2- [2- (4- methoxy-4-phenylpiperidino) ethyl] -1,4-benzodioxane The following compounds were prepared in an analogous manner: 2- [2- (4-Hydroxy-4-thienyl-2-piperidino) ethyl] -1 4-benzodioxane melting upon crystallization from isopropanol at 117-118 ° C 2- [2- (4-Hydroxy-4- (2-benzothiyl) piperidino] ethyl] -1,4-benzodioxane, m.p. ethanol and acetone at 175-178 ° C, 2- [2- (4-hydroxy-4- (2-pyridyl) piperidino] ethyl] -1,4-benzodioxane dihydrochloride melting from ethane of ol and diethyl ether at 260-262 °. An analogously prepared 3-pyridyl isomer melts at 245-250 ° with decomposition; 2- [2- [4-propionyloxy-4-phenylpiperidino] ethyl] -1,4-benzodioxane hydrochloride, which upon recrystallization from an isopropanol / ethyl ether mixture decomposes at 170 ° C with decomposition; 2- [2- (4-n-decanoyl-4-phenylpiperidino) ethyl] -1,4-benzodioxane as a pale oil which is purified by chromatography on a silica gel column in chloroform-ethyl acetate (4: 1) solvent system. Rcr = 4.5; 2- [2- (4-propionyloxy-4-pyridyl-2-piperidino-ethyl] -1,4-benzodioxane hydrochloride, melting, recrystallization from isopropanol with decomposition at 125-130 °; 2- [2- (4-pivaloyloxy-4) -phenylpiperidino] ethyl] -1,4-benzodioxane hydrochloride, melting at 195 to 200 ° C. A process for the preparation of new 2-piperidinoalkyl-1,4-benzodioxanes of general formula (I) carbon or an alkanoyloxy group containing up to 20 carbon atoms and R4 represents an alkyl group of not more than 7 carbon atoms, an HPh-alkyl group wherein the alkyl group contains not more than 7 carbon atoms, an HPh group, a thienyl, a pyridyl or a benzothienyl group; with acids, wherein the compound of formula (III) is substituted in which Ph is a 1,2-phenylene radical optionally substituted by one to three identical different substituents selected from the group consisting of alkyl groups having not more than 7 carbon atoms, alkoxy groups having no more than 7 atoms carbon, halogen 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 1, 3, wherein the sum of p + q is 4, each of R 1 and R 2 is hydrogen, R 3 is hydrogen, hydroxy, a pin, an alkoxy group having not more than 7 atoms / v; / c-Rtt (wherein J is a group of formula C 11 H 12 N 2 -Z-CO, C 11 H 11n-2 or Y 1-C 11 H 2 -i, where Y 1 represents an active esterified hydroxyl group, R 8 represents a hydrogen atom or R 1 and R 8 together form another carbon-carbon bonding, R'4 has the same meaning as R4 or, when R3 represents a hydrogen atom, R14 can also be a HPH-alkanoyl radical with 19819121 of not more than 7 carbon atoms in the alkanoyl moieties; or a compound of general formula IV (CH is Ph 's with C-R 1 (IV) in which A' is a group of formula C n 1 H 2n 2 -CO, C n H 2 n-s or Υ'-O-2η-2-kde, where Y 'is-is' the reactive esterified hydroxyl group having a value of 0 or 2, R 5 represents a hydrogen atom or R 1 and R 5 together form a further bond between the carbon atoms and R 1 and the remaining general symbols have the meanings indicated, whereupon the free compound obtained, if any, is converted into an additive or an acid or acid addition salt thereof to the free compound or to another salt, and / or the recovered isomer or racemate mixture is optionally separated into individual isomers or racemates, and / or the obtained racemates are optionally resolved into optical antipodes. 2. A process according to claim 1 wherein the reaction is carried out by simple hydrides or complex hydrides of light metals, catalytically activated hydrogen, hydrogenated hydrogen, or electrolytically produced hydrogen. . 3. Process according to claim 1 or 2, characterized in that the starting materials used are the compounds of the general formulas (I) and (IV) above, wherein Ph is 1,2-phenylene or substituted by one or two substituents. the substituents independently selected from alkyl and alkoxy groups having at most 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 are 2, R 1 and R 2 are each hydrogen, R 3 is hydrogen, hydroxy-22, alkoxy having no more than 4 carbon atoms, or alkanoyloxy having no more than 16 carbon atoms, and R 4 is secondary or tertiary alkyl of 3 Ch 7-C HP,, HP--CHz, HP,, 2- or 3-thienyl, 2-, 3- or 4-pyridyl; as Rd or, when R 3 represents a hydrogen atom, R 4 may also represent the residue HPh-CO, and the remaining general symbols are as defined in point 1. 4. The process of clause 1 or 2, for the preparation of compounds of formula II wherein R represents a hydrogen atom, an alkyl or alkoxy group having at most 4 carbon atoms, a halogen atom or a trifluoromethyl group, x is a number of 1 or 2, y is an integer of 2 to 4, R 'represents a hydrogen atom, a hydroxy atom -pine, an alkoxy group having not more than 4 carbon atoms or an alkanoyloxy group having no more than 16 carbon atoms, and R 'is a C3-C7 secondary or tertiary alkyl group, an Rx-phenyl group, an Rx-benzyl group, a 2- or 3-thienyl group, or 2-, 3- or 4-pyridyl, and their acid addition salts, characterized in that the compound of formula (III) is reduced; wherein A represents a group of formula (CH 2) y -i-CO, CyH 2 -y-2 or Y'-CyH 2 y-1, wherein only direct groups come into consideration in 198191 23 24, where Y 'is as defined in point 1, R 1a has the meaning as R 'or, when R' is hydrogen, R * and Rx-phenyl-CO may also be represented and the remaining general symbols are as defined above or IVa wherein A 'is a group of formula (CH2) y1-CO, CyH2y-s or Y'-CyH2y_i, wherein only straight groups are introduced, wherein Y' and the abovementioned meanings are 0 or 2, and R 'and the remaining general symbols have Meaning. 5. The process according to claim 1 or 2, wherein R is hydrogen, methyl, ethyl, methoxy or ethoxy, fluorine, chlorine or trifluoromethyl, x is 1 or 2 is a number of 2 or 3, R 'is hydrogen, hydroxy, methoxy, ethoxy or C2-C12 alkanoyloxy, and R' is isopropyl, iso-butyl or tert-butyl, benzyl, Rx-phenyl, 2-or 3-thienyl, 2-, 3- or 4-pyridyl, and acid addition salts thereof, wherein the compound of formula IIIa or IVa is reduced in which A, R'a, Y ', A' and s are as defined in point 4 and the remaining generic symbols are as defined above, provided that when R 'is in the general formula IIIa, the hydrogen atom may represent also benzo -yl group. 6. A process according to claim 1 or 2, for the preparation of compounds of formula II, wherein R is hydrogen, methyl, methoxy, fluorine, atomic, or trifluoromethyl, each at the 7 or 8 position, x is 1 or 2, y is 2 or 3, R 'is hydroxy, methoxy or alkanoyioxyscapto having from 3 to 10 carbon atoms and R' is m- or p-Rx-phenyl, and with acid addition salts, characterized in that the compound of formula IIIa or IVa is reduced, wherein A, Y ', A' and s are as defined in point 4, R'a has the same meaning as R 'and the other general symbols have from above meaning. Severografla, n. P 7, Most