FI66373C - FRAMEWORK FOR THE PHARMACOLOGICAL PROPERTIES OF N-XACYKLYL-ALKYL-PIPERIDINER - Google Patents

Description

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Patent · och register Sty relsen Amilun nthfd och «UkrlftM pabMcarad 3 '(32) (33) (31) Pnfdstty front · -Begird prior ** 20.03.78 USA (US) 888089 (71) Ciba-Geigy AG, CH-4002 Basel, Switzerland-Switzerland (CH) (72) Charles Ferdinand Huebner, Chatham, New Jersey, USA (74) Oy Jalo Ant-Wuorinen Ab (54) Method for the preparation of pharmacologically active N-oxacyclyl-alkyl-piperidines - For the preparation of pharmacologically active N-oxacyclyl-1-1-piperidine

DE 2 400 094 describes 1- {1- (2- (1,4-benzodioxan-2-yl) -2-hydroxyethyl) -4-piperidyl) -2-benzimidazolinones which have a clear antihypertensive effect. It has now surprisingly been found that N-oxacyclyl-alkyl piperidines, namely 1,4-benzodioxan-2-yl-lower alkyl-3-piperidyl compounds and the corresponding benzoxate derivatives which, instead of the hydroxyethyl group, contain an unsubstituted lower alkyl residue of the formula is

X

II

-N-C-N-R 5

t I

R3 .......... R4 where the individual symbols have the same meaning as in formula I below, have stimulant and antidepressant effects.

The invention relates to a process for the preparation of novel N-oxacyclyl-alkyl-piperidyl-diazo compounds of the general formula 2 66373 / \ h2 <ch2) v

Ph / ^ 'il \ C-C H „-N CH-N-C-N-R, (1), X /, n> 2n. / I 1 5 ° h V <CH2> q wherein Ph represents unsubstituted 1,2-phenylene or 1,2-phenylene having one to three identical or different substituents from the group consisting of lower alkyl, lower alkoxy, halogen or trifluoromethyl, ( R3 + R4) means 1,2-phenylene or lower alkylene having 2 or 3 carbon atoms which separates both nitrogen atoms by two or three carbon atoms, R1. represents hydrogen, or is HPh, X represents oxo, thioxo or imino, Y represents epoxy, epithio or sulfinyl, m represents an integer from one to three, p and q represent an integer from one to three, where (p + q) is 4, and acid addition salts of these compounds , especially therapeutically useful acid addition salts.

The 1,2-phenylene residue Ph is preferably unsubstituted or monosubstituted, and up to three substituents are illustrated by the following groups: lower alkyl, e.g. methyl, ethyl, n- or i-propyl or -butyl; lower alkoxy, e.g. methoxy, ethoxy, n- or i-propoxy or butoxy, lower alkylenedioxy, e.g. methylenedioxy, 1,1- or 1,2-ethylenedioxy, halogen, e.g. fluorine, chlorine or bromine or trifluoromethyl. The symbols R 1 and R 2 may also together denote a pH residue or lower alkyl which separates both nitrogen atoms, in particular by two or three carbon atoms, e.g. 1,2-ethylene, 1,2- or 1,3-propylene, 1.2 -, 1,3- or 2,3-butylene. The symbol X is primarily oxo but also thioxo or imino and Y means primarily epoxy but also epithio or sulfinyl. Of said integers, m is predominantly 2 and CmH2m denotes primarily methylene, 1,1- or 1,2-ethylene, 1,2- or 1,3-propylene, and each of the symbols p and q denotes predominantly 2.

All the basic compounds of the general formula I can be present in the form of their acid addition salts, in particular the therapeutically useful acid addition salts, which are derived from the acids mentioned below.

The word "lower" in said organic residues or compounds defines compounds having up to 7, mainly 4, in particular 1-2 carbon atoms.

The compounds of the invention have valuable pharmacological, e.g. stimulating and antidepressant effects. This can be demonstrated in animal experiments using mammals such as rats or monkeys as experimental animals. The compounds of the invention may be administered to Voe-3 66373 animals enterally, e.g. orally, or parenterally, e.g. subcutaneously, intraperitoneally or intravenously, e.g. in the form of aqueous solutions or starch-containing suspensions. The doses used may be between 0.1 and 100 mg / kg / day, in particular between 1 and 50 mg / kg / day, in particular between 5 and 25 mg / kg / day. Said stimulatory and antidepressant effects can be observed, for example, in male albino rats. The animals had free access to food and water except during the experiment. Examination of the reactions of the animals was performed in controlled sound-insulated conditioning chambers with a switch lever. In the experiment, rats are exposed to electric shocks through the bottom grid of the chamber. The lever is connected to a programmed device that adjusts the delivery of electric shocks. The number of lever applications and the number of shocks delivered are recorded. Rats are further trained prior to this to avoid these electrical impulses by lever pressing. The device is then set so that each lever operation delays the onset of shock by about 30 seconds. If the animal forgets to press the lever during this period, a short electric shock is given every 15 seconds until the animal presses the lever again. Prior to each test period, rats are kept in a test chamber for 15 minutes to warm them. During this time, the number of lever drives is not registered. Immediately after this period, the test compounds are administered either as saline or as a 3% suspension of corn starch in 5% aqueous polyethylene glycol-400 containing one drop of polyethylene-20-sorbitan monooleate in 10 ml, either orally or intraperitoneally. Thus e.g. 1- (1- (2- (1,4-benzodioxan-2-yl) ethyl) -4-piperidyl) -2-imidazolidinone, especially its levorotatory form, e.g. 1- (S) hydrobromide or fumarate, which are typical of the compounds of formula I, significantly improve the shock avoidance response in rats. The active substance is administered in doses up to 2.5 mg / kg / day. The observed improvement in shock avoidance response is proportional to the effect achieved with a dose of 5 mg / kg / day of methylphenidate (a classic recreational agent) administered intraperitoneally. This compound of the invention has a simple mechanism of action. It is apparently not an inhibitor of biogenic amines, a presynaptic α-noradrenergic blocker such as mianserin, or an amphetamine-like addictive recreational agent. In addition, it has no peristaltic inhibitory or antihistaminic effect, i. the compound is free of these conventional side effects associated with known antidepressants.

The antidepressant and stimulatory effect of the products according to the invention is demonstrated in a shock-avoidance reaction test in the rat.

The methodology for this experiment is described in the specification. The active ingredients are administered intraperitoneally (i.p.) or orally (p.o.). The increase in the activity of experimental animals under the influence of a given active ingredient is expressed as a percentage compared to their activity without the active ingredient.

The following process products were used in the experiment: 1) 1- (1- (2- (1,4-benzodiosan-2-yl) ethyl) -4-piperidyl) -4-imidazolidinone, 2) 1- (1- (2 - (1,4-benzoxathian-2-yl) -ethyl) -4-piperidyl) -2-imidazolidinone, 3) d-1- (1- (2- (1,4-benzodioxan-2-yl)) (ethyl) -4-piperidyl) -2-imidazolidinone fumarate, 4) N- (1- (2- (1,4-benzodioxan-2-yl) ethyl) -4-piperidyl) -2-imidazolidinone fumarate.

Results: mg / kg

Compound Dosage Dose% Increase in Activity 1) i.p. 2.5 + 38 1) i.p. 5.0 +70 2) p.o. 3.0 +61 2) p.o. 10 +111 3) p.o. 20 + 15 4) p.o. 10 +59

The table shows that the compounds of the invention have a clear potentiating effect. Thus, it has good stimulant and antidepressant effects.

In the second experiment, silk monkeys have been trained to avoid electric shock delivered to their feet through the bottom grid by pressing a lever in the test cage. Each press transfers the electric shock by 20 seconds. If the monkey does not press the button within 20 seconds, it will suffer short (0.5 second lasting) electric shocks every 20 seconds until it presses the button next time. Under inspection conditions, monkeys press the lever at a relatively constant rate so that they rarely receive more than 5,667,373 six shocks during a 4-hour trial period. Determine the number of avoidance reactions and the number of shocks received. When administered orally in 0.9% aqueous saline, said hydrobromide or fumarate produces positive changes both in the extent of avoidance reactions and in the number of shocks obtained. The active substance is administered in small doses up to 2.5 mg / kg / day. The day before the examination of the active substances, the study was carried out using only saline to obtain control values.

Accordingly, the compounds of the invention are valuable psychostimulants, e.g. in the treatment or treatment of depression or minor brain dysfunction. In addition, the new compounds can be used as intermediates for the preparation of other valuable compounds, in particular pharmacologically active compounds.

Particular emphasis should be placed on the compounds of the general formula II • 0 · Χ · / Χ · \ X; —N— (CH0) R —v A A- <ch?> —Ϊ́ / '' \ / 2m CX — NH (II), wherein R represents hydrogen, alkyl or alkoxy, up to 4 carbon atoms, halogen or trifluoromethyl, m is an integer from 1 to 3, n represents an integer from 2 or 3, and X is oxo, thioxo or imino, and therapeutically useful acid addition salts of these compounds.

The compounds of this invention are prepared by methods known per se, e.g. by a) condensing a reactive oxocyclic alkanol ester of general formula III with a 1-unsubstituted piperidyl diaza compound of general formula IV:

Ah2 / (CVpN ii

Ph I + HN ^ \ CH-N-C-N-R

V .C-C H, -Z \ r „n / I 1

Vi m2m <CV / K, .. *.

(III) (IV), wherein Z represents a reactive esterified hydroxy group.

The reactive esterified hydroxy group Z is, for example, with a strong 6 66373 inorganic or organic acid, in particular hydrohalic acid, e.g. hydrochloric acid, hydrobromic acid or iodohydric acid, sulfuric acid or aromatic sulfonic acid, e.g. The condensation is preferably carried out with basic condensation compounds, 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, sodium hydroxide, , or in the presence of nitrogen-based organic tertiary amines such as tri-lower alkylamines or pyridines, e.g. triethylamine or lutidine.

Another way to prepare new compounds is to b) react a compound of general formula V with a carbonic acid derivative of general formula VI:

Ph CH, (CH,) \ I / 2 p \

\ C ~ C H_ -N CH-NH

V1 ”\ ch,) / 1 * Z2CX '(VI) · H 2'q ll (V) wherein Z1 is R1 or a group R3. . . . R 1 -NH-R 2 and Z 2 CX 'are ammonium cyanate or thiocyanate, metal cyanate or thiocyanate, lower alkyl iso-urea or iso-thiourea, halocyano or cyanamide, carbon disulphide or carbonyl sulphide, carbonic acid halide or 1,1-carbonyl.-diimidazole, wherein at least one of Zj and contains nitrogen.

In this reaction, either a carbamoyl group is attached to a compound of formula V (when R 1 is) or a group CX is attached to a compound of formula V (when Z 1 represents a group of formula R 1 ... · R 2 -NH-R 2). Said cyanate is preferably an alkali metal cyanate, a halogen cyanide especially bromocyanide and a carbonic acid halide is preferably phosgene. The method is carried out in a manner known per se, always according to the purpose of Z2. If Z2 is metallic, the reaction is carried out in a neutral or acidic solvent or diluent, e.g. a water-miscible polar solvent such as an aqueous lower alkanol, alkanone or saturated cyclic ether, e.g. ethanol, acetone, tetrahydrofuran or or in alkylated formamide or sulfoxide, e.g. dimethylformamide or dimethyl sulfoxide. If the group Z2 does not contain a metal, a basic substance can be used to bind the resulting acid. Such substances include an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate, e.g. sodium, potassium or calcium hydroxide or carbonate, early metal hydride, lower alkoxide or alkanoate, such as sodium hydride, methylate or acetates, but also organic nitrogen bases such as tri-Alem-alkylalkamine or pyridine, e.g. triethylamine or lutidine.

Another method for preparing the novel compounds is to c) reduce the compound of general formula VII

Ph CH «. (CH0) v y \, 2/2 p \ ί

\ yC - C —CO — N CH-N-C-N-R

X 2 ^ 2 2 ~ 2 \ / I 5 H (VII) (CH 2) q R 3 "R 4

The reaction is carried out in a manner known per se, preferably with simple or complex light metal hydrides, such as diborane or alanine, alkali metal borohydrides, alkali metal aluminum hydrides or alkali metal alkoxyborohydrides, e.g. lithium aluminum hydride and / or sodium trimethoxyborohydride.

Another process for the preparation of new compounds comprises d) a compound of general formula VIII / \? 2/2 * \ i \ / 2Η3 - / “* 5 66373 wherein each symbol x and y represents the number 0 or 2 and their sum x + y is 2 or 4, hydrogenation.

The hydrogenation of olefins of the general formula VIII is carried out in a manner known per se, preferably with a catalytically activated or emerging hydrogen, such as hydrogen, in combination with a cobalt, palladium, platinum or rhodium catalyst, e.g. cobalt sulphide or tris- (triphenylphosphine) rhodium chloride (non-rhodium chloride) , or with electrolytically produced hydrogen.

Another method for preparing the novel compounds comprises e) a compound of general formula IX

Y

n / CH, (CH). „, 2 / 2p \ Ϊ \ C — C H, - M CH-N-C-N-R.

oh / i m2 “\ / 1.5 H (CH2) q / R3" R4 (IX) · where Z represents a reactive esterified hydroxy group, ring-coupling.

The reactive esterified hydroxy group is, for example, with a strong inorganic or organic acid, in particular a hydrohalic acid, e.g. hydrochloric acid, hydrobromic acid or hydroiodic acid, sulfuric acid or an aromatic sulfonic acid, e.g. The condensation is preferably carried out with alkaline metal hydrides, alkali metal hydrides, lower alkoxides or lower alkoxides of basic condensation compounds, e.g. alkali metal or alkaline earth metal hydroxides, carbonates or bicarbonates, such as sodium, potassium or calcium hydroxide or carbonate. such as sodium hydride, sodium methylate or sodium acetate, or in the presence of organic tertiary nitrogen bases such as tri-Alem palkylamines or pyridines, e.g. triethylamine or lutidine.

The compounds obtained according to the invention can be interchanged in a manner known per se. Thus, for example, the compounds obtained in which R3 to R5 are hydrogen can be reacted with the reactive esters of lower alkanols. These reactive esters are derived from strong inorganic or organic acids, in particular hydrohalic acid, e.g. hydrochloric, hydrobromic or hydroiodic acid, sulfuric acid or aromatic sulfonic acid, e.g. p-toluenesulfonic acid or m-bromobenzenesulfonic acid. The corresponding N-substituted compounds are obtained. Depending on the molar amounts of alkylating agents used, continuous coupling of R 1, R 2 and R 2 to the compounds is carried out, compounds in which Y represents a sulfur atom can be oxidized to their 4-oxides by means of mild oxidizing agents. For example, a periodate such as sodium periodate is used in said polar solvents and worked at low temperatures, e.g. between about 0 ° C and room temperature. Care must be taken to prevent over-oxidation by too long a reaction chamber.

Finally, the compounds of the invention may be obtained in the form of free bases or as salts. The free base obtained can be converted into the corresponding acid addition salt, preferably with acids which give therapeutically useful acid addition salts or with the aid of anion exchangers. The resulting salts can be converted into the corresponding free bases, e.g. by means of a stronger base such as a metal hydroxide or ammonium hydroxide, a basic salt or a cation exchanger, e.g. an alkali metal hydroxide or carbonate. Therapeutically useful acid addition salt-producing acids include, for example, inorganic acids such as hydrohalic acid, e.g. hydrochloric or hydrobromic acid, or sulfuric, phosphoric, nitric or perchloric acid; or organic acids such as aliphatic or aromatic carboxylic or sulfonic acids, e.g. formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid-rye acid, tartaric acid, citric acid, maleic acid, maleic acid, fu , 4-aminobenzoic acid, anthranilic acid, 4-hydroxybenzoic, salicylic, 4-aminosalicylic acid, EMBO acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, hydroksisulfonihappo, ethylene, halogeenibentseenisul-sulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, sulphanilic acid, or cyclohexylsulfamic acid; or ascorbic acid. These or other salts, e.g. picrates, can also be used in the purification of free bases. The bases are converted into their salts, the salts are separated and the bases are liberated from the salts.

10 66373

Thus, due to the close relationship between the free form and the salt form of the new compounds, the free compounds and salts in the above and the following may also be understood to mean the corresponding salts or free compounds.

The starting materials are known or, if they are new, can be prepared by methods known per se, e.g. as explained in the examples.

Compounds of formula III can be readily prepared by reducing the corresponding 1,4-benzodioxan-2-ylalkanoic acid to the corresponding alcohol and converting the hydroxy group to a reactive esterified hydroxy group. The reduction is carried out with lithium aluminum hydride or sodium 2-methoxyethoxyaluminum hydride and the esterification is carried out with the abovementioned strong acid or its derivatives, e.g. thionyl, phosphorus or benzosulphonyl halide, in an organic solvent, e.g. benzene, preferably at a temperature.

The compounds of formula IV are prepared starting from the corresponding 1-benzylpiperidones and converting them into O-alkyloximes or Schiff bases of their diaminoalkanes or benzenes. These are reduced to mono- or diamines with catalytically activated or nascent hydrogen. For the reduction, for example, hydrogen is used in the presence of a cobalt, palladium, platinum or rhodium catalyst, e.g. cobalt sulphide or tris- (triphenylphosphine) rhodium chloride (which is not poisoned with sulfur), or electrolytically prepared hydrogen, or simple or complex light metal hydrides. diborane or alanine, alkali metal borohydrides, aluminum hydrides or alkoxyhydrides, e.g. lithium aluminum hydride and / or sodium trimethoxyborohydride. The amines obtained are further converted into a carbonic acid derivative Z2CX ', e.g. ammonium cyanate or metal cyanate or thiocyanate, lower alkyl isourea or isoisothiourea, halogen cyano or cyanamide, sulfuric carbon or carbonyl sulphide, carbonic acid halide or 1,1-carbonic halide or provided that at least one of the residues Z1 and Z2 contains nitrogen. Finally, the benzyl group is hydrolytically cleaved, preferably with a palladium catalyst.

11 66373

The compounds of formula V are prepared in an analogous manner. First, 3- or 4-piperidone reacts with the reactive ester of formula III. In the reactive ester, the hydroxy group is esterified with, for example, a strong inorganic or organic acid, especially a hydrohalic acid, e.g. hydrochloric acid, hydrobromic acid or hydroiodic acid, sulfuric acid or an aromatic sulfonic acid such as p-toluenesulfonic acid or m-bromobenzene. The resulting compounds are converted to the O-alkyloximes or Schiff bases of their diaminoalkanes or benzenes. These are reduced to mono- or diamines by catalytically activated or in the hydrogen state. The reduction is carried out in the same manner as described for the preparation of the starting material of formula IV. Compounds of formula V may also be obtained by condensing the above ester of formula III with the corresponding 3- or 4-benzylaminopiperidines and cleaving the benzyl group.

Compounds of formula VII may be prepared from said 1,4-benzidioxan-2-yl-alkanoic acids. These acids are first converted to their imidazole halides, mixed anhydrides or amides and then reacted with the corresponding piperidines.

The unsaturated compounds of the formula VIII are preferably enamine, which are prepared from the corresponding aldehydes and the piperidines already mentioned. Aldehydes can be obtained by reduction of the above acid chlorides according to Rosenmund or by reduction of the corresponding nitriles with diisobutylaluminum hydride.

Finally, the compounds of formula IX can be prepared by the Mannich reaction of said piperidines with the corresponding aldehydes and / or ketones, by bromination of the resulting piperidinoalkanones, by condensation of α-bromoketone with monoacetylpyrocatechol, by reduction of the ketone obtained by condensation with sodium borohydride its hydroxy group to react as mentioned above.

The starting materials and final products of the formulas I to IX, which are mixtures of isomers, can be separated into the individual isomers in a manner known per se, e.g. by fractional distillation, crystallization and / or chromatography. Racemic products can be separated into optical antipodes, e.g., by resolution of their diastereomeric salts, e.g., by fractional crystallization of d- or ε-tartrate.

> '* · * "·‘ 12 66373

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

The invention also relates to modifications of this process according to which the intermediate obtained at some stage of the process is used as starting material and the remaining process steps are completed, or the process is stopped at some stage, or according to which the element is formed under reaction conditions, or using a starting material in salt or optically pure antipode.

In the process according to the invention, the starting materials used are those which lead to the compounds initially described as being particularly valuable, in particular those of the formula II.

The pharmacologically useful compounds of this invention can be used to prepare pharmaceutical agents containing an effective amount of the active substance, alone or in admixture with carriers, suitable for enteral or parenteral administration. Preferably tablets or gelatine capsules are used which contain the active ingredient together with a diluent, e.g. lactose, dextrose, cane sugar, mannitol, sorbitol, cellulose and / or glycine and lubricants, e.g. milk, talc, stearic acid or a salt thereof, such as magnesium. or calcium stearate, and / or polyethylene glycol. The tablets also contain binders, e.g. magnesium aluminosilicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone and, if desired, effervescents and disintegrants, e.g. starch, agar, alginic acid or , or absorbents, colorants, flavors and sweeteners. Injectables are preferably isotonic aqueous solutions or suspensions, and suppositories are primarily fat emulsions or suspensions. The pharmacologically active compounds may be sterilized and / or may contain adjuvants, e.g. preservatives, stabilizers, wetting agents and / or emulsifiers, solubility mediators, salts for regulating the osmotic pressure and / or a buffer. These pharmaceutical substances, which may, if desired, contain other pharmacologically valuable substances, are prepared in a manner known per se, e.g. using a conventional mixing, granulating or granulating method, and contain from about 0.1 to 75%, preferably from about 1% to 50%, of active ingredient.

The following examples are intended to illustrate the invention. Temperatures are expressed in degrees Celsius, and parts are by weight. Unless otherwise specified, the evaporation of the solvents is carried out under reduced pressure, e.g. between about 15 and 100 mrnHg.

Example 1: 4.9 g of 2- (2-tosyloxyethyl) -1,4-dioxane, 2.54 g of 1- (4-piperidyl) -2-imidazolidinone, 5 g of anhydrous sodium carbonate and 100 ml of 4-methyl-2- the mixture containing the pentanone is boiled under stirring at reflux for 3 days. The reaction solution is filtered, evaporated and the residue is recrystallized from isopropanol. There is obtained 1- (1- (2- (1,4-benzodioxan-2-yl) -ethyl) -4-piperidyl) -2-imidazolidinone of the formula • δ * {Yxi i / NrN- (cV2

% / \ / “^ CH2 ^ 2 ~ ^ \ / * I I

* ° ’CO-NH, and which melts at 125 °.

The product is suspended in 10 ml of hot isopropanol, the suspension is neutralized with 5N hydrobromic acid in isopropanol and the precipitate is recrystallized from isopropanol. The corresponding hydrobromide is obtained, which melts at 220-221 ° with decomposition.

The starting material is prepared as follows: To a solution of 6.7 g of allyl cyanide in 30 ml of petroleum ether is added, with stirring at -15 °, a solution of 16 g of bromine in 10 ml of petroleum ether. After evaporation of the solvent, oily 14 66373 3,4-dibromo-butyronitrile is obtained in quantitative yields.

In five similar portions, a total of 227 g of the latter compound is added dropwise to a stirred mixture of 85 g of pyrocatechol and 50 g of anhydrous potassium carbonate in 100 ml of acetone under reflux. After the first addition, a further 50 g of potassium carbonate are added and then a second portion of the nitrile is slowly fed into it. This is repeated three times, however, each using 40 g of potassium carbonate and one part of nitrile. The reaction mixture is then diluted with acetone to facilitate stirring. The mixture is then allowed to reflux for 20 hours and filtered. The filtrate is evaporated, the residue is distilled and the fraction boiling at 105 ° and 0.15 mmHg is collected. 1,4-Benzodioxan-2-yl-acetonitrile is obtained.

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 is refluxed for 48 hours. The reaction mixture is poured onto ice, the solid obtained is separated and recrystallized from benzene-petroleum ether. 1,4-Benzodioxan-2-yl-acetic acid is obtained, melting at 100 °.

16.5 ml of a 70% benzene solution of sodium bis (2-methoxy-ethoxy) -aluminum hydride are allowed to reflux under nitrogen and a solution of 5.8 g of 1,4-benzodioxan-2-yl is added dropwise. -acetic acid in 100 ml of benzene. After complete dosing, the mixture is refluxed for 4 hours, cooled and slowly poured into 20 ml of 25% sulfuric acid. The mixture is filtered and the solvent is evaporated. The residue is taken up in methylene chloride, the solution is washed with saturated aqueous sodium bicarbonate solution, dried and evaporated. An oily 2- (2-hydroxyethyl) -1,4-benzodioxane is obtained.

A solution of 3.6 g of the latter compound, 5.7 g of p-toluenesulfonyl chloride and 20 ml of dry pyridine is cooled for 2 hours in an ice bath with stirring. Ice is then added to the mixture, the solid obtained is filtered and recrystallized from ethyl acetate-petroleum ether. 2- (2-Tosyloxyethyl) -1,4-benzodioxane is obtained, melting at 82-83 °.

To a solution of 1.6 g of 4-aminopyridine in 7 ml of dimethylformamide is added, with stirring at 40 °, 2 g of 2-chloroethyl isocyanate. After 2 hours, 28 ml of water are added to the mixture and stirring is continued for 2 hours. The resulting precipitate is filtered, washed with water, dried and recrystallized from aqueous ethanol. 1- (4-pyridyl) -3- (2-chloroethyl) urea is obtained, melting at 120-122 °.

To a suspension of 2.66 g of the latter compound in 4 ml of boiling methanol is added, with stirring, 2.68 g of a 30.8% solution of sodium methylate in methanol, and the mixture is stirred at reflux for 1 hour. It is filtered hot, washed with hot methanol, the filtrate is evaporated and the residue is recrystallized from 90% aqueous ethanol. 1- (4-pyridyl) -2-imidazolidinone is obtained, melting at 204-207 °.

A solution of 5 g of the latter compound in 45 ml of water is hydrogenated with 0.8 g of 10% ruthenium-carbon catalyst at 120 ° and 120 atmospheres until hydrogen uptake ceases. The reaction mixture is filtered, the filtrate is evaporated, the residue is dissolved in chloroform, the solution is dried and evaporated. The residue is recrystallized from methylene chloride-petroleum ether. 1- (4-Piperidyl) -2-imidazolidinone is obtained, melting at 155-157 °. Example 2:

A solution of 4 g of 1- (1- (2- (E-1,4-benzodioxan-2-yl) -acetyl) -4-piperidyl) -2-imidazolidinone in 50 ml of tetrahydrofuran is added. At 25 ° to a suspension of 1 g of lithium aluminum hydride in 100 ml of tetrahydrofuran, with stirring and cooling. The reaction mixture is stirred at room temperature overnight and 10 ml of ethyl acetate, 1 ml of water, 2 ml of 15% aqueous sodium hydroxide solution and 3 ml of water are added. The mixture is filtered, the filtrate is evaporated and the residue is dissolved in 25 ml of hot isopropanol. To the solution is added 1.35 g of fumaric acid in 25 ml of hot isopropanol and, after cooling, the precipitate is separated. E 1 - (1- (2- (1,4-benzodioxan-2-yl) ethyl) piperidyl) -2-imidazolidinone fumarate is obtained, melting at 210-213 ° (ot) D = -30 ° (methanol).

In the same way, a dextrorotatory salt is obtained, melting at 210-213 ° (a) D = + 30.8 ° (methanol).

The starting materials are prepared as follows: 66.43 g of 1,4-benzodioxan-2-ylacetic acid and 12.1 g of d-α-methylbenzylamine are dissolved in 100 ml of hot isopropanol. The solution is allowed to stand overnight, the salt obtained is filtered off and recrystallized from iso-propanol five times. Experiments show that this is sufficient for the optical separation of said acid. The acid is liberated with dilute hydrochloric acid, the mixture is extracted with diethyl ether and the extract is evaporated. D-1,4-Benzodioxan-2-yl-acetic acid is obtained (a) D = + 49 ° (ethanol).

In an analogous manner, a second acid anipod is obtained using N, N-methylbenzylamine. (a) D = -49 ° (ethanol).

A solution of 3.4 g of said E-acid in 60 ml of tetrahydrofuran is stirred for one hour with 3.4 g of carbonyldiimidazole. A suspension of 3.05 g of 1- (4-piperidyl) -2-imidazolidinone in 20 ml of tetrahydrofuran is then added and the mixture is stirred overnight. It is evaporated, the residue is dissolved in ethyl acetate, the solution is washed with normal hydrochloric acid and 5% aqueous sodium hydroxide solution, dried and evaporated. 1- (1- (2- (E-1,4-benzodioxan) -2-yl) acetyl) -4-piperidyl) -2-imidazolidinone is obtained.

Example 3:

A mixture of 3.34 g of 2- (2-tosyloxyethyl) -1,4-benzodioxane, 1.83 g of 1- (4-piperidyl) -2-hexahydropyrimidinone, 4 g of sodium carbonate and 80 ml of 4-methyl 2-Pentanone is refluxed for 3 days. The hot reaction solution is filtered, the filtrate is evaporated and the residue is dissolved in water. The suspension is basified with ammonium hydroxide, extracted with chloroform, the extract is dried and evaporated. The residue is dissolved in hot ethanol, the solution is acidified with 4,5N hydrochloric acid in ethanol, cooled and filtered. 1- (1- (2- (1,4-benzodioxan-2-yl) ethyl) -4-piperidyl) -2-hexahydropyrimidinone hydrochloride is obtained, melting at 253-255 °.

In an analogous manner, 1- (1- (2- (1,4-benzodioxan-2-yl) ethyl) -4-piperidyl) -2-benzimidazolidinone hydrochloride is also obtained. It melts at 185-189 °.

The starting material is prepared as follows: To a solution of 62.5 ml of 1,3-diaminopropane in 100 ml of ethanol is added, with stirring and ice-cooling, 30 g of 1-benzyl-4-piperidone dropwise. The mixture is hydrogenated with 2 g of pre-reduced platinum oxide at 50 ° and 2.7 atmospheres for 9 hours. After the theoretical amount of hydrogen has bound, the catalyst is filtered off, the filtrate is evaporated and the residue is distilled. The fraction boiling at 145-160 ° and 0.2 mmHg is collected. 4- (3-Amino-propylamino) -1-benzyl-piperidine is obtained.

To a solution of 24.1 g of the latter compound in 100 ml of tetrahydrofuran is added dropwise, with stirring and ice-cooling, 18.3 g of 1,1-carbonyldiimidazole in 250 ml of tetrahydrofuran. The reaction mixture is stirred at room temperature for 18 hours, evaporated, the residue is suspended in water, filtered and recrystallized from ethanol.

1- (1-benzyl-4-piperidyl) -2-hexahydropyrimidinone, melting at 178-180 °.

A solution of 8 g of the latter compound in 100 ml of ethanol-acetic acid (1: 1) is hydrogenated with 1.5 g of 10% palladium-on-carbon catalyst for 4 hours at 50 ° and 2.7 atmospheres. The reaction mixture is filtered through a filter element, the solvent is evaporated off and the residue is taken up in water. The mixture is made strongly alkaline with 50% aqueous sodium hydroxide, extracted with chloroform, the extract dried, filtered and evaporated. The residue is recrystallized from ethanol. 1- (4-Piperidyl) -2-hexahydropyrimidinone is obtained, melting at 206-210 °.

1- (4-piperidyl) -2-benzimidazolidinone is disclosed in U.S. Patent 3,192,9,801.

Example 4:

To a solution of 6 g of 1- (2- (1,4-benzodioxan-2-yl) ethyl) -4- (2-aminoethylamino) piperidine in 10 ml of 50% aqueous ethanol is added 25 °: 1.4 ml of carbon disulphide. The mixture is refluxed for one hour, one drop of concentrated hydrochloric acid is added and the mixture is refluxed for a further 5 hours. The reaction mixture is allowed to cool overnight, filtered and the residue is washed with ethanol. 1- (1- (2- (1,4-benzodioxan-2-yl) ethyl) -4-piperidyl) -2-imidazolidinedione hydrochloride is obtained, melting at 292 °.

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 ethyl acetate, the solution is extracted with hydrochloric acid, the extract is made alkaline with 50% aqueous sodium hydroxide solution and extracted with methylene chloride. The latter extract is dried and evaporated. 2- (2- (4-oxopiperidino) ethyl) -1,4-benzodioxane is obtained, which hardens on standing.

To a solution of 18 g of the latter compound in 150 ml of ethanol is added a solution of 23 ml of ethylenediamine in 30 ml of ethanol and hydrogenated with 2 g of prehydrated platinum oxide at 50 ° and 3 atmospheres to bind the required amount of hydrogen. The mixture is cooled, filtered and the filtrate is evaporated. 1- (2- (1,4-Benzodioxan-2-yl) -ethyl) -4- (2-amino-ethylamino) -piperidine is obtained in the form of an oil.

Example 5:

In accordance with the methods described in the previous examples, in particular in the examples indicated in the "Example" column of the table, the following compounds of formula I are also prepared from equivalent amounts of the corresponding starting materials. The compounds in the table have R 1 = R 2 = H, (R 1 - + R 2) = (CH 2) 2 '3a P = (3 = 2 *

Ph is Y).

Koi Ph Y m Salt Eg F ° c 1 1,2-phenylene 0 1 H HCl 1 250-1 2 "0 3 H" 2 280-5 3 "0 2 phenyl" 1 263-5 4 4-CH -C ,B. 0 2 H "1 245-6

J 0 J

5 5-CH - C H 0 2 H "1 218-0 J o ό 6 6-CH30-C6H3 0 2 H" 1 261-1 7 if2-phenylene S 2 H - 2 95-9

The various starting materials are 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 refluxed for 48 hours. The reaction mixture is evaporated, the residue is taken up in water and extracted with ether. The extract is dried, evaporated and 5 g of crude nitrile are boiled under stirring and refluxing for 48 hours in a mixture of 2.8 ml of sulfuric acid, 7.2 ml of water and 7.2 ml of acetic acid. The reaction 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. Dissolve 2.5 g of crude acid in 25 ml of tetrahydrofuran and treat the solution with 3 g of carbonyldiimidazole with stirring for 30 minutes. 2.4 g of 1- (4-piperidyl) -2-imidazolidinone are added to the solution and stirred overnight. It is evaporated, the residue is dissolved in ethyl acetate, the solution is washed with 5% aqueous sodium hydroxide solution and 5% hydrochloric acid, dried and evaporated. 1- (1- (3- (1,4-benzodioxan-2-yl) propionyl) -4-piperidyl) -2-imidazolidinone is obtained.

To a solution of 12.6 g of N-phenylethylenediamine in 200 ml of methanol is added first 50 ml of 4,1-normal hydrochloric acid and then 18.9 g of 1-benzyl-4-piperidone in 100 ml of methanol. 9.45 g of sodium cyanoborohydride are then added portionwise with stirring at room temperature. After 72 hours, the mixture is filtered, the residue is dissolved in water and the solution is basified with 12.5% aqueous sodium hydroxide solution. The mixture is extracted with methylene chloride, the extract is dried and evaporated. 1-Benzyl-4- (2-phenylamino-ethylamino) -piperidine is obtained.

To a solution of 14 g of the latter compound in 100 ml of dried benzene is added dropwise, with stirring at room temperature, 170 ml of 12.5% phosgene in benzene. The reaction mixture is stirred overnight, the gelatinous precipitate is filtered on a Sint glass funnel and the substance is dissolved in hot water. The solution is basified with ammonium hydroxide and the precipitate is filtered off. 1- (1-Benzyl-4-piperidyl) -3-phenyl-2-imidazolidinone is obtained, melting at 168-170 °.

A solution of 10 g of the latter compound in 200 ml of ethanol-acetic acid (1: 1) is hydrogenated with 1 g of 10% palladium-carbon catalyst for 8 hours at 50 ° at 2.7 atmospheres. The reaction mixture is filtered through a filter element and the solvent is evaporated. The residue is basified with 25% aqueous sodium hydroxide solution and the mixture is extracted with diethyl ether. The organic layer is dried and evaporated. 1- (4-piperic acid) is obtained.

66373 20-Dyl) -3-phenyl-2-imidazolidinone.

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 stirred suspension which is refluxed with 13.4 g of lithium aluminum hydride 200 ml of dried tetrahydrofuran. The mixture is refluxed overnight, cooled and decomposed by adding 13.4 ml of water, 13.4 ml of 15% aqueous sodium hydroxide solution and 40 ml of water. The mixture is filtered, evaporated, the residue is distilled in a molecular distillation apparatus and the fraction boiling at 155-165 ° and 0.1 mm / g is collected as a colorless oil. 2- (2-hydroxyethyl) -7-methyl-1,4-benzodioxane is obtained.

To a stirred solution of 75 g of 2-hydroxytithiophenol in 660 ml of acetone is added first to a stirred solution of 33.5 g of 3,4-dibromobutyric acid nitrile in 50 ml of acetone. The mixture is refluxed for 30 minutes and then a second, third and fourth portion of 42 g of potassium carbonate and 33.5 g of 3,4-dibromobutyronitrile are added. The reaction mixture is refluxed for 20 hours, cooled and filtered. The filtrate is evaporated and the residue is distilled in a ball tube apparatus at I85 ° and 0.5 mmHgm. 2- (1,4-Benzoxathian-2-yl) -acetonitrile is obtained.

A mixture of 57 g of the latter compound, 85 ml of water, 85 ml of acetic acid and 32.6 ml of sulfuric acid is refluxed for 48 hours, cooled, poured onto ice and extracted with benzene. The organic phase is extracted with aqueous sodium hydrogen carbonate solution, the aqueous phase is acidified with hydrochloric acid and extracted with diethyl ether. The extract is dried and evaporated. The corresponding carboxylic acid is obtained as an oil. This compound is reacted first with carbonyldiimidazole and then with 1- (4-piperidyl) -2-imidazolidinone according to Example 2 to give the desired amide.

Example 6: To a stirred solution of 6 g of 1- (2- (1,4-benzodioxan-2-yl) ethyl) -4- (2-aminoethylamino) piperidine in 15 ml of tetrahydrofuran at 5 ° , 1.58 g of bromocyanide in 15 ml of tetrahydrofuran are added. After two hours, the mixture is filtered and the residue is dissolved in a minimal amount of water. The solution is made strongly basic with sodium hydroxide and extracted with methylene chloride. The extract is dried, evaporated and the residue is dissolved in 50 ml of anhydrous ethanol. 0.1 g of sodium methoxide is added to the solution. The mixture is refluxed overnight and evaporated. The residue is mixed with water and the mixture is extracted with methylene chloride. The extract is dried, evaporated and the residue is dissolved in a minimum amount of isopropanol. The solution is neutralized with oxalic acid in diethyl ether and the resulting precipitate is separated. 1- (1- (2- (1,4-benzodioxan-2-yl) ethyl) -4-piperidyl) -2-iminoimidazolidine oxalate is obtained, melting with decomposition at 215-220 °.

Example 7:

To a solution of 2 g of 1- (1- (2- (1,4-benzodioxan-2-yl) ethyl) -4-piperidyl) -2-imidazolidinone in a minimum amount of ethanol is added a solution of 0.78 g of fumaric acid in boiling ethanol. The mixture is cooled to 0 ° and the precipitate is separated. The corresponding fumarate is obtained, melting at 190 °. Example 8:

To a solution of 3.47 g of 1- (1- (2- (1,4-benzoxathian-2-yl) ethyl) -4-piperidyl) -2-imidazolidinone (Example 5, No. 7) in 10 ml: in dioxane and 10 ml of methanol, a solution of 2.8 g of sodium metaperiodate in 20 ml of water is added dropwise with stirring at room temperature. After 2 hours, the mixture is evaporated, the residue is taken up in water and the mixture is extracted with methylene chloride. The extract is washed with saturated aqueous sodium chloride solution, dried, evaporated and the residue is recrystallized from isopropanol. 1- (1- (2- (4-oxo-1,4-benzoxathian-2-yl) ethyl) -4-piperidyl) -2-imidazolidinone is obtained, melting at 145 °.

Example 9:

A mixture of 0.5 g of 1- (1- (3- (1,4-benzodioxan-2-yl) -1-propenyl) -4-piperidyl) -2-imidazolidinone, 25 ml of ethanol-acetic acid (1: 1) and 0.1 g of 10% palladium-on-carbon catalyst are hydrogenated at room temperature and 2.7 atmospheres to bind a molar equivalent of hydrogen. The catalyst is filtered off, the filtrate is evaporated, the residue is dissolved in 5 ml of water and the solution is basified with aqueous ammonia. The mixture is extracted with methylene chloride, the extract is dried, evaporated and the residue is dissolved in a minimum amount of isopropanol. The solution is acidified with hydrochloric acid in ethanol and the precipitate is separated. 1- (1- (3- (1,4-benzodioxan-2-yl) propyl) -4-piperidyl) -2-imidazolidinone hydrochloride is obtained, melting at 282-285 ° with decomposition.

The product is identical to Example 5 No. 2.

The starting material is prepared as follows: A mixture of 10 g of 2- (1,4-benzodioxan-2-yl) oxirane, 2 g of potassium cyanide, 2 g of ammonium chloride and 25 ml of dimethylformamide is stirred for 3 days at room temperature. The mixture is diluted with water and extracted with methylene chloride. The extract is evaporated and the residue is dehydrated in a mixture of 11 ml of acetic acid, 11 ml of water and 4 ml of sulfuric acid, refluxing for 24 hours. The mixture is diluted with ice, extracted with diethyl ether and the extract is evaporated. 3- (1,4-Benzodioxan-2-yl) -acrylic acid is obtained. A solution of 5 g of this compound in 25 ml of tetrahydrofuran is treated with 5.5 g of carbonyldiimidazole and the mixture is stirred for 30 minutes. A solution of 4.6 g of 1- (4-piperidyl) -2-imidazolidinone in 25 ml of isopropanol is then added and the mixture is allowed to stand overnight. The reaction mixture is evaporated, the residue is dissolved in ethyl acetate, the solution is washed successively with water, dilute aqueous sodium hydroxide solution and water and evaporated. The residue is dissolved in 100 ml of tetrahydrofuran, cooled in an ice bath and treated dropwise with stirring in 20 ml of 1,2-molar alane-triethylamine complex. After 5 hours, 10 ml of 25% aqueous sodium hydroxide solution are added dropwise to the cold mixture. The organic solvent is separated by decantation from the paste-like slurry of inorganic salts and evaporated. 1- (X-3- (1,4-benzodioxan-2-yl) -1-propenyl) -4-piperidyl) -2-imidazolidinone is obtained.

Example 10:

A mixture of 4 g of 2- (2-tosyloxyethyl) -6,7-dichloro-1,4-benzodioxane, 1.69 g of 1- (4-piperidyl) -2-imidazolidinone, 10 g of anhydrous sodium carbonate and 100 ml of 4 -methyl-2-pentanone is boiled with stirring for 2 days at reflux. The reaction solution is filtered, the filtrate is evaporated and the residue is recrystallized from acetone. 1- (1- (2- (6,7-dichloro-1,4-benzodioxan-2-yl) ethyl) -4-piperidyl) -2-imidazolidinone is obtained, melting at 165 °.

The product is suspended in 10 ml of hot ethanol, the suspension is neutralized with 5N hydrochloric acid in ethanol and the precipitate is recrystallized from ethanol-diethyl ether. The corresponding hydrochloride is obtained, melting at 250 °.

The starting material is prepared as follows: To a solution of 60 g of pyrocatechol in 200 ml of diethyl ether is added 93 g of sulfuryl chloride slowly (over two hours) with stirring, keeping the temperature at about 0 °. The reaction mixture is allowed to stand for 2 days at room temperature, evaporated and the residue is recrystallized twice from benzene. 4,5-Dichloro-pyrocatechol is obtained, melting at 85-90 °. To a mixture of 53.4 g of the latter compound, 33 g of anhydrous potassium carbonate and 800 ml of acetone are added dropwise, with stirring and refluxing, in five equal portions, a total of 89 g of 3,4-dibromobutyronitrile. After the first portion, an additional 20 g of potassium carbonate is added to the reaction mixture, followed slowly by a second portion of the nitrile. This is repeated three more times, using 20 g of potassium carbonate for each part of the nitrile and diluting the mixture with acetone to facilitate stirring. The reaction mixture is refluxed for 20 hours, filtered, the filtrate is evaporated, the residue is dissolved in methylene chloride, the solution is washed with water, dried and evaporated. Using activated carbon, the residue is recrystallized from isopropanol. 6,7-Dichloro-1,4-benzodioxan-2-yl-acetonitrile is obtained, melting at 110 °.

A mixture of 59 g of the latter compound, 24 ml of sulfuric acid, 60 ml of acetic acid and 60 ml of water is refluxed for 48 hours. The reaction mixture is poured onto ice. The resulting solid is separated and recrystallized from aqueous ethanol. 6,7-Dichloro-1,4-benzodioxan-2-yl-acetic acid is obtained, melting at 145-147 °.

A solution of 2.63 g of the latter compound in 40 ml of benzene-tetrahydrofuran (1: 1) is added dropwise under nitrogen to 5.5 ml of 70% sodium bis (2-methoxyethoxy) aluminum hydride. solution which is boiled at reflux. At the end of the addition, the mixture is refluxed for 2.5 hours, cooled and slowly added to 6.7 ml of 20% 24 66373 sulfuric acid. The mixture is filtered and the solvent is evaporated. The residue is dissolved in methylene chloride, the solution is washed several times with saturated aqueous sodium hydrogencarbonate solution, water and saturated aqueous sodium chloride solution, dried and evaporated. Oily 2- (2-hydroxyethyl) -6,7-dichloro-1,4-benzodioxane is obtained, boiling at 180-190 ° and 0.1 mmHg.

A mixture of 15.2 g of the latter compound, 17.5 g of p-toluenesulfonyl chloride and 40 ml of dried pyridine is cooled and stirred for 2 hours in an ice bath. Ice is then added to the reaction mixture, the precipitate obtained is filtered off and recrystallized from ethyl acetate. 2- (2-tosyloxyethyl) -6,7-dichloro-1,4-benzodioxane is obtained, melting at 135-138 °.

Example 11:

To a suspension of 100 g of lithium aluminum hydride in 6500 ml of tetrahydrofuran is added 450 g of d-1- (1- (2- (2,1-1,4-benzodioxan-2-yl)) portionwise over 100 minutes with stirring at 2-6 °. ) -acetyl) -4-piperidyl) -2-imidazolidinone. The reaction mixture is stirred for 19 hours at room temperature, cooled and then first 100 ml of water are added over 100 minutes at 8-12 °, then 100 ml of 15% aqueous sodium hydroxide solution and 300 ml of water. The mixture is stirred for 30 minutes under cooling and 90 minutes at room temperature. The reaction mixture is filtered, the residue is washed with 2000 ml of tetrahydrofuran and the filtrate is evaporated. 2-1- [1- (2- (1,4-benzodioxan-2-yl) ethyl) -4-piperidyl) -2-imidazolidinone is obtained, melting at 119-122 °. (α) 20 D = -47.3 ° (c = 1, in methanol).

1191 g of the compound obtained are dissolved in 3000 ml of 9S% aqueous ethanol at 60 °, 120 g of activated carbon are added to the solution and the mixture is stirred for 5 minutes. It is filtered, the residue is washed with 200 ml of 95% ethanol and the filtrate is combined with a solution of 441 g of fumaric acid in 7200 ml of 95% ethanol at 60 °. The resulting suspension is diluted with 1000 ml of 95% ethanol and stirred for 3 hours at room temperature. The mixture is filtered, the residue is washed with 500 ml of 95% ethanol and 800 ml of anhydrous diethyl ether. 2,1-1- (1- (2- (1,4-benzodioxan-2-yl) ethyl) -4-piperidyl) -2-imidazolidinonium fumarate is obtained, melting at 216-217 ° with decomposition. (α) D = -31.6 °.

66373 (c = 13.73 rag / ml, in water). The product is identical to the product of Example 2.

The starting material is prepared as follows: To a solution of 1134 g of bromine in 1400 ml of ethyl acetate is added, in 90 minutes, 472 g of allyl cyanide with stirring and dropwise addition at -10-0 °. The resulting solution of 3,4-dibromo-butyronitrile is added in one portion, under stirring under a nitrogen atmosphere at 35 °, to a solution of 705 g of pyrocatechol and 1987 g of anhydrous potassium carbonate in 5000 ml of ethyl acetate, which is refluxed. The mixture is refluxed for 4 hours and stirred at room temperature overnight. It is filtered, the residue is washed with 2000 ml of ethyl acetate and the filtrate is evaporated. The residue is distilled and the fraction boiling at 138 ° / 1.4 mmHg to 131 ° / 1.1 mmHg is collected. 1,4-Benzodioxan-2-yl-acetonitrile is obtained.

A solution of 1647 g of the latter compound in 2760 ml of glacial acetic acid is added to a hot mixture of 858 ml of concentrated sulfuric acid and 2670 ml of water and all are refluxed for 17 hours. The mixture is poured into 8200 ml of cold water, stirred for 3 hours, filtered and washed with 9000 ml of water. 1,4-Benzodioxan-2-yl-acetic acid is obtained, melting at 87-90 °.

To a solution of 3374 g of the latter compound and 3500 ml of anhydrous ethanol is added a solution of 2105 g of α-α-methylbenzylamine in 500 ml of anhydrous ethanol, and the mixture is stirred at room temperature for 3 hours. The mixture is allowed to stand for two days at 4-5 °, the salt obtained is filtered off and washed with 400 ml of ethanol, 400 ml of diethyl ether and 1200 ml of isopropanol. 2070 g of precipitate are recrystallized from 2000 ml of ethanol and the crystals are washed with 500 ml of both ethanol and diethyl ether. 8-1,4-Benzodioxan-2-yl-acetic acid-2.-α-methyl-benzylammonium salt is obtained, melting at 132-133 °.

Dissolve 1827 g of the latter compound in 10,000 ml of normal hydrochloric acid with stirring for 20 minutes, add 6000 ml of diethyl ether and stir for a further 20 minutes. The aqueous layer is separated, extracted with 3000 ml of diethyl ether, the combined ether solutions are washed with 1000 ml of water, dried and evaporated. E-1,4-benzodioxan-2-yl-26 66373 acetic acid is obtained, melting at 83-85 ° (α) = 5 = -55.42 °. (c = 12.325 mg / ml, in methanol).

A mixture of 400 g of the latter compound, 2000 ml of toluene and 320 ml of thionyl chloride is stirred for 3 hours at 80 ° and evaporated. The residue is dissolved in 500 ml of chloroform and the solution is evaporated again. E-1,4-benzodioxan-2-ylacetyl chloride is obtained, melting at 60-62 °.

A solution of 434 g of the latter compound in 1000 ml of chloroform is fed over a period of two hours into a mixture of 400 g of 1- (4-piperidyl) -2-imidazolidinone, 4000 ml of chloroform and 2600 ml of normal aqueous sodium carbonate solution, stirring. -23 ° C. After two hours, the organic solution is separated and the aqueous phase is extracted with 1000 ml of chloroform. The combined organic solutions are washed with 1000 ml of water, dried and evaporated. The residue is triturated with 1000 ml of anhydrous diethyl ether, filtered and the residue is washed with a further 1000 ml of diethyl ether.

There is obtained d-1- (1- (2- (E-1,4-benzodioxan-2-yl) acetyl) -4-piperidyl) -2-imidazolidinone, melting at 161-163 °. = + 5.9 ° (c = 1, in chloroform).

Example 12:

To a solution of 2 g of 1- (2- (1,4-benzodioxan-2-yl) ethyl) -4- (2-aminoethylamino) piperidine in 25 ml of isopropanol is added, with stirring, 1.65 ml of 4- normal hydrochloric acid in ethanol and then 0.45 g of ammonium cyanate. The reaction mixture is refluxed overnight, then evaporated and heated in an oil bath at 130 ° for 4 hours. The residue is dissolved in 100 ml of methylene chloride, washed with water, dried over anhydrous sodium sulfate and evaporated. The residue is dissolved in 20 ml of hot isopropanol and 0.77 g of fumaric acid is added with stirring. Cooling gives 1- (1- (2- (1,4-benzodioxan-2-yl) ethyl) -4-piperidyl) -2-imidazolidinone fumarate, melting at 190 °.

Example 13:

A mixture of 10 g of 1- (2- (1,4-benzodioxan-2-yl) ethyl) -4- (2-aminoethylamino) piperidine and 8 g of carbonyldiimidazole in 100 ml of tetrahydrofuran , boil overnight to reflux. The reaction mixture is evaporated, the residue is dissolved in 150 ml of methylene chloride and extracted with 50 ml of water.

27 66373

The methylene chloride is dried over anhydrous sodium sulfate and evaporated. The residue is dissolved in 50 ml of hot isopropanol and 3.8 g of fumaric acid are added with stirring. On cooling, 1- (1- (2- (1,4-benzodioxan-2-yl) ethyl) -4-piperidyl) -2-imidazolidinone fumarate is obtained, melting at 190 °. Example 14:

Dissolve 10 g of 1- (1- (2- (1,4-benzodioxan-2-yl) ethyl) -4- (1,2,5,6-tetrahydropyridyl)) -2-imidazolidinone in 100 ml of acetic acid and To 50 ml of water, 1 g of platinum oxide is added and the mixture is hydrogenated at 60 ° and 3.4 atmospheres so that one molar equivalent of hydrogen is bound. The reaction mixture is cooled to room temperature, the catalyst is filtered off and the filtrate is evaporated. To the residue are added 100 ml of water, an excess of 3N sodium hydroxide solution (to pH 10) and 100 ml of methylene chloride. The methylene chloride extract is washed with water, dried over anhydrous sodium sulfate and evaporated. The residue is dissolved in 50 ml of hot isopropanol and treated with 3.8 g of fumaric acid with stirring. On cooling, the fumaric acid salt of the desired 1- (1- (2- (1,4-benzodioxan-2-yl) ethyl) -4-piperidyl) -2-imidazolidinone is obtained, melting at 190 °.

The starting material is prepared as follows: A solution of 10 g of 2- (2-tosyloxyethyl) -1,4-benzodioxane, 4.9 g of 1- (4-pyridyl) -2-imidazolidinone and 0.3 g of potassium iodide is heated overnight 90 ° C. The reaction mixture is then evaporated. The residue is dissolved in 500 ml of ethanol and treated portionwise with stirring and cooling over two hours with 30 g of sodium borohydride. The reaction mixture is evaporated to a small volume, diluted with 100 ml of water and extracted with 200 ml of methylene chloride. The extract is washed with water, dried over anhydrous sodium sulfate and evaporated. There is obtained 1- (1- (2- (1,4-benzodioxan-2-yl) ethyl) -4- (1,2,5,6-tetrahydropyridyl)) -2-imidazolidinone, which is used as starting material .

Claims (2)

1. Menetelmä pharmacologisesti vaikuttavien N-oxacyclyyli-alkyly-li-piperidyyli-diatsayhdisteiden valmistamiseksi, joiden yleinen kaava on A / CH? (CH_) Ph I ✓ 2 N li r \ jfc-C H „-N CH-NCNR, (I), V. m 2m \ / 1 15 H (CH2 ^ q R3 '* RA jossa Ph tarkoittaa substituoimatonta 1,2 -phenyleeniä tai 1,2-pheny-leeniä, jossa on yhdestä kolmeen together with tai erilaista substituentia ryhmästä, joka koostuu alempialkyylistä, alempialkoksista, halogenista tai trifluorimethylylä, (R 2 + R 2) on 1,2 hiiliatomia sisältävä alempialkyleeni, joka erottaa molemmat typpiatomit kahdella tai kolmella hiiliatomilla, R q tarkoittaa kokonaislukua 1-3, jolloin (p + q) on 4, yes naiden yhdisteiden happoadditiosuoloja, tunnettu siitä, etä a) yleisen kaavan III mukaisen oxazyclisen alkanolin reactio-lookin odds Y / X (CH) X / ch2 / 1 p \ ph | + HN ^ \ cH-NCN-R5 \ .CC H. -Z \, ru x / II OI 2 q R_ .. R ^ H (III) (IV), jossa Z tarkoittaa reactiokykyistä esteröityä hydroksiryhmää tai b) yleisen kaavan V mukainen yhdiste saatetaan reagoimaan yleisen kaavan VI mukaisen hiilihappojohdannaisen kanssa 29 6 6 3 7 3 / \ Λ CH? . (CH,) \ · / 2p \ V · '"\ (ch2, /' h + V * · (ΪΙ> · (V) jossa Z ^ on tai tarkoittaa ryhmittymää .... R ^ -NH-R ^ yes, Z2CX 'tarkoittaa ammonium syanaattia tai -tiosyanaattia, alempialkyyli-isocarbamidia tai -isothiocarbamidia, halogeenisyaania tai syaani-amidia, rikkihiiltä tai karbonyylisulfidia, hiilihappohalogenia tai 1,1 ) pelkistetään yhdiste, young yleinen kaava VII on Ph CH (CHj) · X \ i q 3 4 tai d) hydrate yhdiste, jonka yleinen kaavan VIII on / Y \> 2 / ™ Λχ X \ 1 \ f * 5 ° ^ H «V, -! ( »1«). jossa jokainen symboleista x yes y tarkoittaa lukua 0 tai 2 yes niiden sum x + y on 2 tai 4, yes haluttaessa hapetetaan kaavan mukainen yhdiste joksikin toiseksi keksinnön mukaiseksi yhdisteeksi, ja / tai muutetaan haluttaessa SAA 30 66373 tu vapaa yhdiste happoadditiosuolaksi tai happoadditiosuola vapaaksi yhdisteeksi tai toiseksi happoadditiosuolaksi, ja / tai haluttaessa erotetaan isomeerien tai rasemaattien saatu seos yksinäisiksi isomeereiksi tai rasemaateiksi, ja / tai haluttaessa lohkaistaan saadut rasemaatit optisiksi antipodeiksi. 2. Patent tivaatimuksen 1 mucaine menetelmä, tunnettu siitä, et valmistetaan 1- (1- (2- (1,4 (bentsodioxan-2-ylyl) ethyl) -4-piperidyyl) -2-imidatesolidinonia, then d-ja f- antipodia yes late happoadditiosuoloja. Patentkray: A process for the preparation of pharmacologically active N-oxacyclyl-alkyl-piperidyl-diaza compounds of the general formula I A / CH, (CH,> v Ph I 2 / 2 P \ in CH-NC-II-R-(I), a group consisting of lower alkyl, lower alkoxy, halogen or trifluoromethyl, (R 2 + R 3) is 1,2-phenylene or lower alkyl of 2 or 3 carbon atoms separating the two nitrogen atoms with 2 or 3 carbon atoms, R5 is hydrogen or HPh , X is oxo, thioxo or imino, Y is epoxy, epithio or sulfinyl, m is an integer from 1 to 3, each symbol p and q represents an integer from 1 to 3, where (p + q) is The number 4, and the acid addition salts of these compounds, characterized in that a) a reactable ester of oxacyclic alkanol of the general formula III is condensed with a 1-unsubstituted piperidyl-diaza compound of the general formula IV 66373 31 / Χ (CH) X / CH / 2 ρ Ph I + HNf \ ch-NCN-R5 \ .CC Η, -Ζ \ ΓΗ χ / »1 Vi" 2m "V / r, .. r4 H (III) (IV), where Z refers to a reactively esterified hydroxy group, or b) a compound of the general formula V is reacted with the carbonic acid derivative of the general formula VI / \ Ph CH2, (CH_) \ '/ 2p \ Vi X (CH,) / 1 * z2a (T1) · H 2 q Zj (V) where Z 2 is R 3 or refers to the grouping ..... R 2 -NH-R 2 and Z 2 CX ' , 1-Carbonyldiimidazole, on the condition that at least one of the groups Z 2 and Z 2 contains nitrogen, or c) a compound of the general formula VII / λ-C-CO-H Ja-HCN-R '| Is reduced, or d) a compound of the general formula VIII