DD142341A5 - METHOD FOR PRODUCING N-OXACYCLYL-ALKYL-PIPERIDYL-DIAZAVER BINDINGS - Google Patents

Description

The invention relates to a process for the preparation of novel 1-oxacycloyl-alkyl-piperidyl-diazabene compounds having valuable pharmacological properties,

The compounds according to the invention are used as active ingredients in pharmaceutical preparations for the treatment and cure of depression

Characteristic of most African th tech solutions

As a classical stimulant, methylphenidate is known. U.S. Patent 3,629,267. Benzofuran derivatives with neuroleptic effects described «

Z _n JeJ. _the invention ' .

The aim of the invention is the preparation of compounds which are suitable for the treatment and cure of depression «

-Χ- Berlin, d. 28.7.1979 AP C 07 D / 211 661 55 174 11

The invention is based gave up to develop _s a manufacturing process can be made to the compounds which are useful in the treatment and cure of depression "

According to the invention, new Ν-oxacyclyl-alkyl-piperidyl diazo compounds of the general formula I

, (CH ₀ )

produced, in which. Ph is unsubstituted 1,2-phenylene or 1 _S 2 "phenylene which is substituted by one to three identical or different substituents from the group consisting of ITiederalkyl, Hiederalkoxy, ITiederalkylendioxy, halogen or trifluoromethyl, means ^ ach of the symbols R ₁ and R ₂ each of R and R is hydrogen or! Tiederalkyl, ^ hydrogen or liiederalkyl means or (R ^ + R) for Ph or IT is _{iederalkylen?} which separates the two nitrogen atoms by 2 to 4 carbon atoms, R _{1 is} hydrogen, Hiederalkyl or HPh, X is oxo, thioxo, imino or Uiederalkyliinino, Y is epoxy, epithio or sulfinyl, m is an integer from 1 to 7 each of the symbols ρ and q is an integer from 1 to 3, where (p + q) is the number 4, as well as acid addition salts, in particular therapeutically usable acid addition salts of these compounds.

A 1,2-phenylene radical Ph is preferably unsubstituted or inono-substituted, and its at most 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.

Each of the symbols R_ to R ₁ . is preferably hydrogen, but also lower alkyl, in particular methyl, or another lower alkyl radical mentioned above. The symbol R can also be phenyl which may be unsubstituted or substituted, the substituents being those of an H-Ph radical. The symbols R "and R, together may also represent the radical Ph or represent lower alkylene which separates the two nitrogen atoms, in particular by 2 or 3 carbon atoms, for example for 1,2-ethylene, 1,2- or 1,3-propylene .

1,2-, 1,3- or 2,3-butylene. The symbol X is preferably oxo, but also thioxo, imino or lower alkylimino and Y is preferably epoxy, but also epithio or sulfinyl. Of the above integers m is preferably 1 to 4 and C H "is preferably methylene,

m 2m

1,1- or 1,2-ethylene, 1,2- or 1,3-propylene, 1,2-, 1,3- or 1,4-butylene, and each of the symbols ρ and q is preferably 2.

All basic compounds of general formula I may be in the form of their acid addition salts, in particular therapeutically acceptable acid addition salts, which are e.g. derived from below acids are present.

The term "lower" defines in the organic radicals or compounds mentioned above or below those having at most 7, preferably 4, in particular 1 or 2, carbon atoms.

The compounds of the invention show valuable pharmacological, e.g. stimulating and antidepressant effects., These can be used in animal experiments, preferably on mammals, such as rats or monkeys, as test

objects are detected. The compounds of the invention may be enterally administered to them e.g. oral, or parenteral, e.g. subcutaneously, intraperitoneally or intravenously, e.g. in the form of aqueous solutions or starch-containing suspensions. The dose used may range between about 0.1 and 100 mg / kg / day, preferably about 1 and 50 mg / kg / day, more preferably about 5 and 25 mg / kg / day. The said stimulatory and antidepressant effects may e.g. observed on male albino rats. The animals have free access to food and water, except for the duration of the experiment. The study of animal behavior is carried out in standardized, sound-insulated conditioning machines containing a shifter. According to the test, the rats are exposed to electrical shock through the bottom grid of the chamber. The lever is connected to a programmed device which controls the delivery of electrical shocks. The number of actuation of the lever and the number of shocks suffered are recorded. The rats are previously trained to avoid this electrical pulse by pressing the button. Then the apparatus is adjusted so that each lever action shifts the shock entrance by 30 seconds. If the animal forgets to press the lever within this time interval, short electrical shocks will be delivered every 15 seconds until the animal operates the lever again. Before each test period, rats are kept in the test chambers for 15 minutes to warm. During this time, the number of lever operations is not registered. Immediately after this period, the test compounds are pre-administered either in saline or in 3% corn starch suspension in 5% aqueous polyethylene glycol-400 containing one drop of polyethylene 20 sorbitan monooleate, either orally or intraperitoneally. Thus, significantly increases e.g. the 1- [1- [2- (1,4-benzodioxan-2-yl) ethyl] -4-piperidyl] -2-imidazolidinone, especially its levorotatory form, e.g. the! - (S) -hydrobromide or fumarate, - typical representatives of compounds of the formula I, the rat shock-avoidance reaction. The drug is administered intraperitoneally at doses as low as 2.5 mg / kg / day. The estimated increase in the shock response may be beneficial to those receiving a dose of 5 mg / kg / day of methylphenidate (a classic stimulant) with intraperitoneal administration.

cause, compare. This compound according to the invention shows a unique mechanism of action. It appears not to be a biogenic amine uptake inhibitor, a presynaptic c-noradrenergic blocker such as mianserin, and no amphetamine-like addictive stimulant. It also has neither an anticholinergic nor an antihistaminic effect, i. the compound is free from these common side effects associated with known antidepressants.

In another test, squirrel monkeys are trained to push the lever in such a Skinner cage to avoid the electrical shock being applied to the feet by the floor grid. Each press of the button shifts the electrical shock by 20 seconds. If the monkey fails to press the button within 20 seconds, it will experience short (0.5 second) electrical shocks every 20 seconds until its next button press. Under control conditions, the monkeys push the lever at a relatively steady rate, so they rarely receive more than 6 shocks during a four-hour trial period. The number of avoidance reactions and the number of shocks received are determined. When administered orally in 0.9% aqueous saline solution, said hydrobromide or fumarate produces positive changes both in the extent of avoidance reactions and in the number of shocks suffered. The drug is administered in low doses down to 2.5 mg / kg / day. The assay for recovery of control values is performed using saline alone one day before the assay of the drugs.

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

- β - 4.

Preferred compounds are those of general formula I wherein Ph is 1,2-phenylene monosubstituted or monosubstituted by lower alkyl, lower alkoxy, lower alkylenedioxy, halo or trifluoromethyl, each of the symbols R and R is hydrogen or lower alkyl, each of the symbols R and R is hydrogen or lower alkyl or (R "+ R.) the radical is Ph or lower alkylene which separates the two nitrogen atoms by: 2 or 3 carbon atoms, the symbol R is hydrogen, lower alkyl or HPh, X is oxo, thioxo, imino or lower alkylimino Y is epoxy, epithio or sulfinyl, m is an integer from 1 to 4, each of the symbols ρ and q is an integer from 1 to 3, where (p + q) is 4, and therapeutically useful Acid addition salts of these compounds.

Preference is further given to compounds of the general formula I in which Ph is unsubstituted or by alkyl or alkoxy, in each case monosubstituted with at most carbon atoms, halogen or trifluoromethyl, 1,2-phenylene, each of the symbols R, R "and R is hydrogen or alkyl with at most '4 carbon atoms, each of the symbols R ₃ and

R, is hydrogen or (R "+" R,) for alkylene having 2 to 4 carbon-4 j 4

atoms which separates the two nitrogen atoms by 2 or 3 carbon atoms, X is oxo, thioxo or imino, Y is epoxy or epithio, m is an integer from 1 to 4, each of the symbols ρ and q 2 is and therapeutically acceptable acid addition salts of these compounds.

Particularly noteworthy are compounds of general formula II

VV ^{2 m} V CX-NH (II),

wherein R is hydrogen, alkyl or alkoxy, each having at most 4 carbon atoms, halogen or trifluoromethyl, m is an integer from 1 to 4, η is the integer 2 or 3, and X is oxo, thioxo or imino, and therapeutically acceptable acid addition salts of these compounds.

21 1 6

The compounds of the present invention are prepared by methods known per se, e.g. made by that one

a) a reactive ester of an oxacyclic alkanol of the general formula III is condensed with a 1-unsubstituted piperidyl diaza compound of the general formula IV:

Vr ₂ / <* iK ;

^Ph I + HJS ^ XCH-NCNR ₅ \, CC H -Z \, _Λ / I! VI ^{m 2m} ^ r / R

VI ^{m 2m} "r / RR

(III) (IV),

wherein Z represents a reactive esterified hydroxy group.

A reactive esterified hydroxy group Z is e.g. one with a strong inorganic or organic acid, especially a hydrohalic acid, e.g. Hydrochloric acid, hydrobromic acid or hydriodic acid, sulfuric acid or an aromatic sulphonic acid, e.g. p-Toluolsulfousäure or m-bromobenzenesulfonic acid esterified hydroxy group. The condensation is preferably carried out in the presence of basic condensing agents, e.g. Alkali metal or alkaline earth metal hydroxides, carbonates or bicarbonates, such as sodium, potassium or calcium hydroxide or carbonate, alkali metal hydrides, lower alkoxides or lower alkanoates, such as sodium hydride, sodium methoxide or sodium acetate, or of organic tertiary nitrogen bases, such as tri-lower alkylamines or Pyridines, eg Triethylamine or lutidine.

Another method for preparing the new compounds is that

b) reacting a compound of general formula V with the carbonic acid derivative of general formula VI:

(VI)

(V)

wherein Z is R or the group R is R-NH-R

and Z represents "CX" for ammonium cyanate or thiocyanate, a metal cyanate or thiocyanate, a lower alkyl isourea or isothiourea, a cyanogen halide or cyanamide, carbon disulfide or carbonyl sulfide, a carbonyl halide or 1,1-carbonyldiimidazole, with U.S. Pat Provided that at least one of Z and Z contains nitrogen.

In this reaction, either a carbamoyl group is added to the compound V (when Z is R) or the group CX is incorporated into the compound V (when Z is the grouping of the formula R .. .R, -NH-R _1. ) , The said cyanate is preferably an alkali metal cyanate, a cyanogen halide especially the cyanogen bromide and a carbonic acid halide preferably the phosgene. The process is carried out in a manner known per se, depending on the meaning of Z ". If Z is metallic, the reaction is carried out in a neutral or acidic solvent or diluent, for example in a water-miscible polar solvent, such as in an aqueous medium alkanol, alkanol or in a saturated cyclic ether, for example ethanol, acetone, tetrahydrofuran or dioxane , or in an alkylated formamide or sulfoxide, for example dimethylformamide or dimethylsulfoxide performed. If the group Z "contains no metal, a basic agent can be used for the binding of the acid formed. Such agents are an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate, eg, sodium, potassium or calcium hydroxide or carbonate, alkali metal hydrides, lower alkoxides or alkanoates, such as sodium hydride, methylate or acetate, but also organic tertiary nitrogen bases, such as tri-lower alkylamines or pyridines, for example triethylamine or lutidine.

Another method for preparing the new compounds is that

c) a compound of general formula VIl

Ph CH-R ₀ , (CHj _v

ι ² / ^2p \ ί

^R l (VII) ^(C Vq ^R 3- ' ^R 4 reduced.

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

Another method for preparing the new compounds is that

d) a compound of general formula VIII

C ₀ H. -NCNR ₁ . 2 3 5

^(VIII) '

wherein each of the symbols χ and y is 0 or 2 and their sum χ + y is 2 or 4, hydrogenated.

The hydrogenation of olefins of general formula VIII is carried out in a manner known per se, preferably with catalytically activated or nascent hydrogen, such as hydrogen in the presence of cobalt, palladium, platinum or rhodium catalysts, e.g. Cobalt sulfide or tris (triphenylphosphine) rhodium chloride (which are not poisoned by sulfur), or with electrolytically generated hydrogen.

-ΊΟ-

2t 1 661

Another method for preparing the new compounds is that

e) a compound of general formula IX

Y,

Ph 'CH-R ₀ XCRj

\ Ι ^2/2

^{2/2 p} \ ί

C- CH - N CH-NCNR ₁ . OH / 1 ^{m 2m} / II ⁵ R ₁ ^N (CH ₂ ) ^XR 3 '.- ^R 4

wherein Z represents a reactive esterified hydroxy group, ringschliesst.

A reactive esterified hydroxy group is e.g. one with a strong inorganic or organic acid, especially a hydrohalic acid, e.g. Hydrochloric acid, hydrobromic acid or hydriodic acid, sulfuric acid or an aromatic sulfonic acid, e.g. p-Toluenesulfonic acid or m-bromobenzenesulfonic esterified hydroxy group. The condensation is preferably carried out in the presence of basic condensing agents, e.g. Alkali metal or alkaline earth metal hydroxides, carbonates or bicarbonates. such as sodium, potassium or calcium hydroxide or carbonate, alkali metal hydrides, lower alkoxides or lower alkanoates such as sodium hydride, sodium methylate or sodium acetate, or organic tertiary nitrogen bases such as tri-lower alkylamines or pyridines, e.g. Triethylamine or lutidine.

The compounds obtained according to the invention can be converted into one another in a manner known per se. Thus, e.g. Compounds obtained in which R to R is hydrogen are reacted with reactive esters of lower alkanols. These reactive esters are derived from strong inorganic or organic acids, primarily from a hydrohalic acid, e.g. Hydrochloric, hydrobromic or hydroiodic acid, sulfuric acid or an aromatic sulphonic acid, e.g. p ~ toluenesulfonic acid or m-bromobenzenesulfonic acid derived. This gives the corresponding N-substituted compounds. Depending on the amount of mol used

Alkylating agent, the successive introduction of R_, R and R is performed. Compounds in which Y represents a sulfur atom can be oxidized to their 4-oxides with mild oxidants. For example, one uses Periodates such as sodium periodate in said polar solvents and operating at low temperatures, e.g. between about 0 ° C and room temperature. Care must be taken to prevent overoxidation due to excessive reaction time.

Finally, the compounds of the invention can be obtained in the form of free bases or as salts. A free base obtained may be converted into the corresponding acid addition salt, preferably with acids which yield therapeutically acceptable acid addition salts or with anion exchangers. Salts obtained can be converted to the corresponding free bases, e.g. by treatment with a stronger base, such as with a metal hydroxide or ammonium hydroxide, basic salt or a cation exchanger, e.g. with an alkali metal hydroxide or carbonate. Acids which give therapeutically useful acid addition salts are e.g. 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 sulphonic acids, e.g. Ant, vinegar, propion, amber, glycol, milk ,. Apple, wine, citric, maleic, fumaric, hydroxymalein, pyruvic, phenylacetic, benzoic, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic, salicylic, 4-aminobenzylalic, pamoic, nicotinic , Methanesulfonic, ethanesulfonic, hydroxyäthansulfon, Aetlr / lensulffon, halobenzenesulfonic, toluenesulfonic, naphthalenesulfonic, sulfanilic or cyclohexylsulfamic acid; or the ascorbic acid. These or other salts, e.g. the picrates, can also be used in the purification of free bases. The bases are converted into their salts, the salts are separated off and the bases are released from the salts.

- • la-

As a result of the close relationship between the new compounds in free form and in the form of their salts, the corresponding salts or free compounds are to be understood as meaningful and appropriate in the preceding and following under free compounds and salts.

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

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

In the preparation of compounds of formula IV starting from corresponding 1-benzyl-piperidones and converts them into their 0-Alkyloxime or Schiff bases of Diaminoalkaneii or -benzenes. These are reduced with catalytically activated or nascent hydrogen to the mono- or diamines. For reduction one uses e.g. Hydrogen in the presence of cobalt, palladium, platinum or rhodium catalysts, e.g. Cobalt sulfide or tris (triphenylphosphine) rhodium chloride (which are not poisoned by sulfur), or electrolytically generated hydrogen, or simple or complex light metal hydrides, e.g. Diborane or Alan, alkali metal borohydrides, aluminum hydrides or alkoxy hydrides, e.g. Lithium aluminum hydride and / or sodium trimethoxyborohydride. The resulting amines are further treated with the carbonic acid derivative Z "CX ', e.g. with ammonium cyanate or a metal cyanate or thiocyanate, lower alkyl isourea or isothiourea, Ilalogencyan or cyanamide, carbon disulfide or carbonyl sulfide, carbonic acid halide or

21 ί 6

1,1-carbonyldiimidazole, with the proviso that at least one of Z and Z contains nitrogen, reacted. Finally, the benzyl group is preferably removed by hydrogenolysis over a palladium catalyst.

Compounds of formula V are prepared in an analogous manner. First, the 3- or 4-piperidone is reacted with a reactive ester of formula III. In the reactive ester, the hydroxy group is e.g. by a strong inorganic or organic acid, primarily a hydrohalic acid, e.g. Hydrogen chloride, hydrobromic or hydriodic acid, sulfuric acid or an aromatic sulfonic acid, such as p-toluenesulfonic acid or m-bromobenzenesulfonic esterified. The resulting compounds are converted to their O-alkyloximes or Schiff's bases of diaminoalkanes or -benzenes. These are reduced with catalytically activated or nascent hydrogen to the mono- or diamines. The reduction is carried out the same way as described in the preparation of starting materials of the formula IV. Compounds of formula V can also be obtained by condensation of the aforementioned esters of formula III with corresponding 3- or 4-benzylamino-piperidines and removal of the benzyl group.

Compounds of the formula VII can be prepared starting from the abovementioned 1,4-benzodioxan-2-yl-alkanoic acids. These acids are first converted to their halides, mixed anhydrides or amides of imidazo I and then reacted with corresponding piperidines.

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

Finally, the compounds of formula IX can be prepared by Mannich reaction of said piperidines with corresponding aldehydes and /

_.- louder ketones, bromination of the obtained piperidino-alkanones, condensation of the a-bromoketones with monoacetyl catechol, reduction of the ketone obtained by condensation with sodium borohydride to the corresponding alcohol and conversion of its hydroxy group into a reactive, as described above.

Starting materials and end products of the formulas I to IX, which are isomeric mixtures, can be prepared by methods known per se, e.g. by fractional distillation, crystallization and / or chromatography, are separated into the individual isomers. Racemic products may be incorporated into the optical antipodes, e.g. upon separation of their diastereomeric salts, e.g. by fractional crystallization of the d or - tartrates.

The abovementioned reactions are carried out by methods known per se, in the presence or absence of diluents, preferably in those which are inert towards and dissolve the reagents, catalysts, condensing or neutralizing agents and / or in an inert atmosphere, with cooling Room temperature or at elevated temperatures, preferably at the boiling point of the solvent used, carried out at normal or elevated pressure.

The invention also relates to modifications of the present process, according to which an intermediate product obtainable at any stage of the process is used as starting material and the remaining process steps are carried out, or the process is stopped at any stage, or after which a starting material is formed under the reaction conditions, or in which Starting material is used in the form of a salt or an optically pure antipodes.

In the process of the present invention, preference is given to using those starting materials which lead to the compounds described above as being particularly valuable, in particular those of the formula II.

Berlin, ά.28 * 7 · 1979 AP C 07 D / 211 661 55 174 11

The pharmacologically useful compounds of the present invention may be used for the preparation of pharmaceutical preparations containing an effective amount of the active ingredient together or in admixture with excipients suitable for enteral or parenteral administration. Preferably, tablets or gelatin capsules comprising the active ingredient are used with diluents, eg lactose, dextrose. Cane sugar, mannitol, .Sorbitol ,. Cellulose and / or glycine, and lubricants, z * B. Silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol; Tablets also contain excipients, for example, magnesium aluminum silicate, starch paste, gelatin, tragacanth, methyl cellulose, sodium carboroxymethyl cellulose and / or polyvinylpyrrolidone, and, if desired, disintegrants, eg starches, agar, alginic acid or a salt thereof _. such as sodium alginate, enzymes of the binders and / or effervescent omi loop, or adsorbent. Injectable preparations are preferably isotonic aqueous solutions or suspensions, and spoppers primarily fat emulsions or suspensions. The pharmacological preparations may be sterilized and / or adjuvants, eg. Preservatives, stabilizers, wetting agents and / or emulsifiers, solubilizers, salts for regulating the osmotic pressure and / or buffers. The present pharmaceutical preparations which, if so, may contain further pharmacologically valuable substances are desired, such "B _s, granulating or coating prepared in a conventional manner using conventional Mj_sch ~, and contain from about 0.1% to about 75 In particular from about Λ% to about 50% of the active substance

The following examples serve to illustrate the invention * Temperatures are given in degrees centigrade, and the rivets over ropes refer to parts by weight "Unless otherwise defined, solvent evaporation is carried out under reduced pressure.

- 16 ~ Berlin, d _e 28 "7" 1979 AP C 07 D / 211 661 55 174 11

lower pressure, ζ _β 3 _β between about 15 and 100 mmHg, passes _e

The invention will be explained in more detail hereinafter in some embodiments ₀

Example 1 A mixture of 4.9 g of 2- (2-tosyloxyethyl) -1,4-benzodioxane, 2.54 g of 1- (4-piperidyl) -2-imidazolidinone, 5 g of anhydrous sodium carbonate and 100 ml of 4-methyl -2-pentanone is refluxed with stirring for 3 days. The reaction mixture is filtered, evaporated and the residue recrystallized from isopropanol. This gives the 1- [l- [2- (1,4-benzodioxan-2-yl) ethyl] -4-piperidyl] -2-imidazolidinone of the formula

I Il I Il W- ¹ O ^y O

I "II / m, \ Jr I ₁ 1 * *

CO-IiH, which melts at 125 ° »

The product is suspended in 10 ml of hot isopropanol, the suspension is neutralized with 5-nonnal 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: A solution of 6.7 g of allyl cyanide in 30 ml of petroleum ether is slowly added with stirring at -15 °, with a solution of 16 g Srom in 10 ml of petroleum ether. After evaporation of the solvent, the oily 3,4-dibromo-butyronitrile is obtained in quantitative yield.

In five equal parts are added dropwise a total of 227 g of the latter compound to a stirred mixture of 85 g of catechol and 50 g of anhydrous potassium carbonate in 100 ml of acetone under reflux. After adding the first part, add another 50 g of potassium carbonate and slowly add the second part of the nitrile. This is repeated three times, but using 40 g of potassium carbonate and one part of nitrile used. The reaction mixture is diluted with acetone to facilitate stirring. Then the mixture is refluxed for 20 hours and filtered. The filtrate is evaporated, the residue is distilled and collected at 1O5 ° / O, 15 mm Hg fraction. The l, 4-benzodioxan-2 is obtained.

yl-acetonitrile.

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 resulting solid material separated and recrystallized from benzene-petroleum ether. This gives the l, 4-benzodioxan-2-yl-acetic acid, which melts at 100 °.

16.5 ml of a 70% solution of sodium bis (2-methoxyethoxy) aluminum hydride are refluxed in benzene in a nitrogen atmosphere and treated dropwise with a solution of 5.8 g, Benzodioxan-2-yl-acetic acid in 100 ml benzene. After the addition has ended, the mixture is refluxed for 4 hours, cooled and poured slowly into 20 ml of 25% sulfuric acid. The mixture is filtered and the solvent evaporated. The residue is taken up in methylene chloride, the solution washed with a saturated aqueous sodium bicarbonate solution, dried and evaporated. The oily 2- (2-hydroxyethyl) -1,4-benzodioxan is obtained.

A mixture 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 with stirring in an ice bath. The mixture is then treated with ice, the resulting solid material is filtered off and recrystallized from ethyl acetate-petroleum ether. The 2- (2-tosyloxyethyl) -1,4-benzodioxane is obtained, which melts at 82-83 °.

A solution of 1.6 g of 4-aminopyridine in 7 ml of dimethylformamide is added with stirring under 40 °, with 2 g of 2-chloroethyl isocyanate. The mixture is added after 2 hours with 28 ml of water and stirring at room temperature continued for 2 hours. The resulting precipitate is filtered off, washed with water, dried and recrystallized from aqueous ethanol. This gives the l ~ (4-pyridyl) -3- (2-chloroethyl) urea , which melts at 120-122 °.

-Ί3-

2t 1 6 6

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 for 1 hour under reflux. It is filtered hot, washed with hot methanol, the filtrate evaporated and the residue recrystallized from 90% aqueous Ae ethanol. This gives the 1- (4-pyridyl) -2-imidazolidinone, which melts at 204-207 °.

A solution of 5 g of the latter compound in 45 ml of water is hydrogenated over 0.8 g of 10% ruthenium-on-carbon catalyst at 120 ° and 120 atmospheres until hydrogen uptake ceases. The reaction mixture is filtered, the filtrate evaporated, the residue taken up in chloroform, the solution dried and evaporated. The residue is recrystallized from methylene chloride-petroleum ether. This gives the 1- (4-piperidyl) -2-imidazolidinone, which melts at 155-157 °.

Example 2 A solution of 4 g of 1- [1- [2- ('"Cl, 4-benzodioxan-2-yl) -acetyl] -4-piperidyl] -2-imidazolidinone in 50 ml of tetrahydrofuran is added at 25 ° The mixture is stirred at room temperature overnight and decomposed with 10 ml of ethyl acetate, 1 ml of water, 2 ml of a 15% aqueous sodium hydroxide solution and 3 ml of water , the filtrate is evaporated and the residue is dissolved in 25 ml of hot isopropanol, the solution is combined with 1.35 g of fumaric acid in 25 ml of hot isopropanol and, after cooling, the resulting precipitate is separated off to give t- 1 - [- - (l, 4-3enzodioxan-2-yl) ethyl] -4-piperidyl] -2-imidazolidinone fumarate, which melts at 210-213 °, [^] _n = "30 (methanol).

In the same way, the dextrorotatory salt is obtained, which melts at 210-213 °. [<*] = + 30.8 ° (methanol).

The starting material is prepared as follows: Dissolve 19.4 g

l, 4-benzodioxan-2-yl-acetic acid and 12.1 g of _d-ethyl-methylbenzylamine in 100 ml of hot isopropanol. The solution is allowed to stand overnight, the salt obtained is filtered off and recrystallized from isopropanol five times. The 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. The d-l, 4-benzodioxan-2-yl-acetic acid is obtained. = + 49 ° (ethanol).

Analogously, using the -V- ^ Q-methylbenzylamine,

the other acidic antipodes are obtained, [cö] «= -49 ° (ethanol).

A solution of 3.4 g of said ("acid in 60 ml of tetrahydrofuran is stirred for one hour with 3.4 g of carbonyldiimidazole, followed by suspension of 3.05 g of 1- (4-piperidyl) -2-imidazolidinone The mixture is stirred overnight in 20 ml of tetrahydrofuran and the mixture is stirred overnight, the residue is dissolved in ethyl acetate, the solution is washed with normal hydrochloric acid and 5% aqueous sodium hydroxide solution, dried and concentrated by evaporation - ( 'll, 4-benzodioxan-2-yl) acetyl] -4-piperidyl] -2 ~ imidazolidinone.

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 mixture is filtered off, the filtrate is evaporated and the residue taken up in water. The suspension is basified with ammonium hydroxide, extracted with chloroform, the extract dried and evaporated. The residue is dissolved in hot ethanol, the solution acidified with 4.5 N hydrochloric acid in ethanol, cooled and filtered. This gives the 1- [l- [2- (1,4-benzodioxan-2-yl) ethyl] -4-piperidyl] -2-hexahydropyrimidinone hydrochloride, which melts at 253-255 °.

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

211 66t

The starting material is prepared as follows: A solution of 62.5 ml of 1,3-diaminopropane in 100 ml of ethanol is added dropwise with stirring and cooling with ice, with 30 g of 1-benzyl-4-piperidone. The mixture is hydrogenated over 2 g of prereduced platinum oxide at 50 ° and 2.7 atmospheres for 9 hours. After the theoretical amount of hydrogen has been absorbed, the catalyst is filtered off, the filtrate is evaporated and the residue is distilled. The fraction boiling at 145-160V0.2 mm Hg is collected. 4- (3-Amino-propylamino) -1-benzyl-piperidine is obtained.

A solution of 24.1 g of the latter compound in 100 ml of tetrahydrofuran is added dropwise with stirring and cooling with ice, with 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 suspended in water, filtered and recrystallized from ethanol. This gives the 1- (1-benzyl-4-piperidyl) -2-bexahydropyrimidinone, which melts at 178-180 °.

A solution of 8 g of the latter compound in 100 ml of ethanol-acetic acid (1: 1) is hydrogenated over 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 evaporated and the residue taken up in water. The mixture is made strongly alkaline with 50% aqueous sodium hydroxide solution, extracted with chloroform, the extract dried, filtered and evaporated. The residue is recrystallized from ethanol. This gives the 1- (4-piperidyl) -2-hexahydropyrimidium ion, which melts at 206-210 °.

The 1- (4-piperidyl) -2-benzimidazolidinone is described in U.S. Patent 3,929,801.

Example 4 A solution of 6 g of 1- [2- (1,4-benzodioxan-2-yl) ethyl] -4- (2-amino-ethylamino) -piperidine in 10 ml of 50% aqueous ethanol is added at 25 ° with 1.4 ml of carbon disulfide dropwise.

-33-

21 1 6

puts. The mixture is boiled under reflux for one hour, treated with a drop of concentrated hydrochloric acid and further boiled under reflux for 5 hours. The reaction mixture is allowed to cool overnight, filtered and the residue is washed with ethanol. This gives the 1- [l- [2- (1,4-benzodioxan-2-yl) ethyl] -4-piperidyl] -2-imidazolidinethione hydrochloride, which melts at 292 °.

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

A solution of 18 g of the latter compound in 150 ml of ethanol is treated with a solution of 23 ml of ethylenediamine in 30 ml of ethanol and hydrogenated over 2 g of prehydrated platinum oxide at 50 ° and 3 atmospheres until the required amount of hydrogen. The mixture was cooled, filtered and the filtrate evaporated. The 1- [2- (1,4-benzodioxan-2-yl) ethyl] -4- (2-amino-ethylamino) -piperidine is obtained as an OeI.

Example 5 According to the methods described in the preceding examples, preferably those of the examples given in the table by "Ex", the following compounds of formula I are also prepared starting from equivalent amounts of appropriate starting materials. In the compounds of the table R = R = H, (R + R) = ₂ , X = O and p = q = 2. (The position 2 in the remainder Ph is at Y).

"23 ·

Berlin, el. 28.7.1979 AP C 07 D / 211 661 55 174 11

ITr. Ph Y m H Sals r- Ex ₀ P ⁰ C 1 1,2-phenylene 0 1 II HCl 1 250-1 2 H 0 3 phenyl H 2 280-5 3 ! I 0 CVI H H 1 263-5 4 4-CH ₃ -C ₆ H ₃ 0 2 - H tt 1 245-6 5 5-CH ₃ -C ₆ H ₃ 0 2 H ti 1 218-0 β 6-CH ₀ -C H ₀ 0 2 H H 1 26i _r 1 7 1,2-phenylene S 2 - 2 95-9

The different starting materials are prepared as follows:

A mixture of 10 g of 2 ~ (2-tosyloxyethyl) -1,4-benzodioxil, 2.4 g of sodium cyanide, 4 ml of water and 20 ml of ethanol is refluxed for 48 hours. The reaction mixture was evaporated, the residue taken up in water and extracted with ether. The extract was dried, evaporated and 5 g of the crude 1 hour in a mixture of 2.8 ml of sulfuric acid, 7.2 ml of water and 7 , 2 ml of acetic acid, with stirring, refluxed for ₀ the reaction mixture is poured into ice water, extracted with diethyl ether, the extract with V / ater washed with aqueous latriumhydrogencarbonatlösung reextracted "the alkaline solution is extracted with hydrochloric acid-acidified and extracted with diethyl ether." The extract is dried and evaporated, 2.5 g of the crude acid is dissolved in 25 ml of tetrahydrofuran, and the solution is treated with 3 g of carbonyldiimidazole for 30 minutes with stirring, and the mixture is treated with 2.4 g of 1 ~ (4-piperidyl). '-2-imidasolidinon versetat and stirred overnight, it is evaporated, the residue dissolved in ethyl acetate _f,' the solution with 5% aqueous Natriumhydroxydlösun washed with 5 g of hydrochloric acid, dried and evaporated. This gives the 1-pi-3- (1,4-benzodioxan-2-yl) -propionyl-1-piperidyl-2-imidazolidinone.

-2H-

A solution of 12.6 g of N-phenyl-ethylenediamine in 200 ml of methanol is added dropwise first with 50 ml of 4,1-normal hydrochloric acid and then with 18.9 g of 1-benzyl-4-piperidone in 100 ml of methanol. Then 9.45 g of sodium cyanoborohydride are added in portions, with stirring at room temperature. After 72 hours, filter the mixture, dissolve the residue in water, and basify the solution with 12.5% aqueous sodium hydroxide. The mixture is extracted with methylene chloride, the extract is dried and evaporated. This gives l-benzyl-4- (2-phenylamino-ethylamino) -piperidine.

A solution of 14 g of the latter compound in 100 ml of dry benzene is added dropwise with stirring at room temperature with 170 ml of 12.5% strength phosgene in benzene. The reaction mixture is stirred overnight, the gelatinous precipitate is filtered with a sintered glass funnel and the material is dissolved in hot water. The solution is basified with ammonium hydroxide and the precipitate filtered off. The 1- (1-benzyl-4-piperidyl) -3-phenyl

-2-imidazolidinone, which melts at 168-170 °.

A solution of 10 g of the latter compound in 200 ml of ethanol-acetic acid (1: 1) is hydrogenated over 1 g of 10% palladium on carbon catalyst for 8 hours at 50 ° and 2.7 atmospheres. The reaction mixture is filtered through a filter element and the solvent 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. This gives the 1- (4-piperidyl) -3-phenyl-2-imidazolidinone.

21 1 6 61

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 refluxing, stirred suspension of 13.4 g of lithium aluminum hydride in 200 ml. ml of dry 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 ° C./1 mmols is collected as a colorless oil. 2- (2-hydroxyethyl) -7-methyl-1,4-benzodioxan is obtained.

A stirred, refluxing solution of 75 g of 2-Hyd.roxy- -thiophenol in 660 ml of acetone is first treated with 42 g of potassium carbonate then dropwise with a solution of 33.5 g of 3,4-Dibrombuttersäurenitril in 50 ml of acetone. The mixture is refluxed for 30 minutes and then a second, third and fourth addition of 42 g of potassium carbonate and 33.5 g of 3,4-dibromobutyronitrile are carried out. The reaction mixture is refluxed for 20 hours, cooled and filtered. The filtrate is evaporated and the residue is distilled in a Kugelrohparparat at 185 ° 0.5 mmHg. The 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 bicarbonate 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 OeI. This compound is reacted first with carbonyldiimidazoi and then with 1- (4-piperidyl) -β-imidazolidinone according to Example 2 to give the desired amide.

-a * - 2116

Example 6 . A solution of 6 g of 1- [2- (1,4-benzodioxan-2-yl) ethyl] -4- (2-amino-ethylamino) -piperidine in 15 ml of tetrahydrofuran, which has been stirred at 5 °, is mixed with 1.58 g Cyanogen bromide in 15 ml of tetrahydrofuran. After 2 hours, the mixture is filtered and the residue dissolved in a minimum 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 taken up in 50 ml of anhydrous ethanol. The solution is mixed with 0.1 g of sodium methoxide. The mixture is refluxed overnight and evaporated. The residue is taken up in water and the mixture extracted with methylene chloride. The extract is dried, evaporated and the residue dissolved in a minimum amount of isopropanol. The solution is neutralized with oxalic acid in diethyl ether and the resulting precipitate separated. This gives the 1- [l- [2- (l, 4-benzodioxan-2-yl) ethyl] -4-piperidyl] -2-imino-imidazolidin oxalate, which melts at 215-220 ° with decomposition.

Example 7 Preparation of 10000 tablets containing 5 mg each of the active substance:

ingredients

l- [l- [2- (l, 4-benzodioxan-2-yl) ethyl] -4-piperidyl] -2-

imidazolidinone 50 g

Lactose 1157 g

Cornstarch 75 g

Polyethylene glycol 6000 75 g

Talcum powder 75 g

Magnesium stearate 18 g

purified water q. s.

Procedure : All powdery ingredients are sieved with a sieve of 0.6 mm mesh size. Then the active ingredient is mixed with lactose, talc, magnesium stearate and half of the starch in a suitable mixer. The other half of the starch is suspended in 40 ml of water and the suspension is added to the boiling solution of polyethylenglycol in 150 ml of water. The resulting paste is added to the powders and optionally granulated with the addition of another amount of water. The granules are dried overnight at 35 °, forced through a sieve of 1.2 mm mesh size and pressed into tablets of 6.4 mm diameter having a score line.

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

Ingredients :

l- [l- [2- (l, 4-benzodioxan-2-yl) ethyl] ~ 4-piperidyl] -

imidazolidinone '25 g

Lactose 1875 g

Talcum powder 100 g

Procedure : All powdery ingredients are sieved with a sieve of 0.6 mm mesh size. Then the active ingredient is first homogenized with talc and subsequently with lactose in a suitable mixer. Gelatine capsules No. 3 are filled with 200 mg of the resulting mixture in a filling machine.

In an analogous manner, tablets and hard gelatin capsules are also prepared using products of the other examples.

Example 8 A solution of 2 g of 1- [1- [2- (1,4-benzodioxan-2-yl) -thyl] -4-piperidyl] -2-imidazolidinone in a minimum amount of ethanol is added with a solution of 0, 78 g of fumaric acid in boiling ethanol. The mixture is cooled to 0 ° and the precipitate separated. The corresponding fumarate is obtained, which melts at 190 °.

Example 9 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

Dioxane and 10 ml of methanol is added dropwise with stirring at room temperature with a solution of 2.8 g of sodium metaperjodat in 20 ml of water. After 2 hours, the mixture is evaporated, the residue taken up in water and the mixture extracted with methylene chloride. The extract is washed with saturated aqueous sodium chloride solution, dried, concentrated by evaporation and the residue is recrystallised from isopropanol. The l- [1- [2- (4-oxo-1,4-benzoxathian-2-yl) ethyl] -4 is obtained -piperidyl] -2-imidazolidinone ,. which melts at 145 °.

Example 10 A mixture of 0.5 g of 1- [1- [3- (1,4-benzodioxan-2-yl) -l-propenyl] -4-piperidyl] -2-imidazolidinone, 25 ml of ethanol-acetic acid (1 : 1) and 0.1 g of 10% Pal ladiunr-on-carbon catalyst is hydrogenated at room temperature and 2.7 atmospheres until one molar equivalent of hydrogen. The catalyst is filtered off, the filtrate evaporated, the residue dissolved in 5 ml of water and the solution made basic with aqueous ammonia. The mixture is extracted with methylene chloride, the extract dried, evaporated and the residue taken up in a minimum amount of isopropanol. The solution is acidified with hydrogen chloride in ethanol and the precipitate separated. This gives the 1- [l- [3- (l, 4-benzodioxan-2-yl) propyl] -4-piperidyl] -2-imidazolidinone hydrochloride, which melts at 282-285 ° with decomposition. The product is identical to that of 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 at room temperature for 3 days. 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, by refluxing for 24 hours. The mixture is diluted with ice, extracted with diethyl ether and the extract evaporated. The 3- (l, 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. Then one will

.23-

Solution of 4.6 g of 1- (4-piperidyl) -2-imidazolidinone in 25 ml of isopropanol and the mixture allowed to stand overnight. The reaction mixture is evaporated, the residue taken up in acetic acid ethyl ester, the solution 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 20 ml of an i, 2-molar solution of alaa-triethylamine complex with stirring. After 5 hours, the cold mixture is treated dropwise with 10 ml of 25% aqueous sodium hydroxide solution. The organic solvent phase is separated by decantation from the pasty sludge of the inorganic salts and evaporated. This gives the 1- [l- [3- (1,4-benzodioxan-2-yl) -l-propenyl] -4-piperidyl] -2-imidazolidinone.

Example 11 A mixture of 4 g of 2- (2-tosyloxyethyl) -6,7-dichloro-1,4-banzodioxane, 1.69 g of i- (4-piperidyl) -2-imidazolidine, 10 g of anhydrous sodium carbonate and 100 ml of 4-methyl-2-pentanone is refluxed with stirring for 2 days. The reaction mixture is filtered, the filtrate is evaporated and the residue is recrystallized from acetone. The l- [1- [2- (6,7-dichloro-1,4-benzodioxan-2-yl) ethyl] -4 ~ is obtained piperidyl] -2-imidazolidinone, which melts 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, which melts at 250 °.

The starting material is prepared as follows: A solution of 60 g of catechol in 200 ml of diethyl ether is added slowly with stirring (in 2 hours) with 93 g of sulfuryl chloride, wherein the. Keeps the temperature at about 0 °, the reaction mixture is allowed to stand for 2 days at room temperature, evaporated and the residue is recrystallized from benzene twice. The 4,5-dichlorobenzaphatechin _{5 is obtained,} which melts at 85 ° -90 °. To a mixture of 53.4 g of the last

- so-

called compound, 33 g of anhydrous potassium carbonate and 800 ml of acetone are added dropwise with stirring and boiling under reflux, in five equal parts, a total of 89 g of 3,4-dibromo-butyronitrile. Then another 20 g of potassium carbonate and then slowly the second part of the nitrile to the reaction mixture. This is repeated three more times, using one part of nitrile per 20 g of potassium carbonate and diluting the mixture with acetone to facilitate stirring. The reaction mixture is refluxed for 20 hours, filtered, the filtrate is evaporated, the residue taken up in methylene chloride, the solution washed with water, dried and evaporated. Using activated carbon, the residue is recrystallized from isopropanol. This gives the 6,7-dichloro-l, 4-benzodioxan-2-yl-acetonitrile, which melts 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 on ice. The resulting solid material is separated and recrystallized from aqueous ethanol. This gives the 6,7-dichloro-l, 4-benzodioxan-2-yl-acetic acid, which melts at 145-147 °.

A solution of 2.63 g of the latter compound in 40 ml of benzene-tetrahydrofuran (1: 1) is added dropwise to 5.5 ml of a refluxing 70% solution of sodium bis (2-methoxy-ethoxy) in a nitrogen atmosphere. ~ aluminum hydride. After the addition has ended, the mixture is refluxed for 2.5 hours, cooled and poured slowly into 6.7 ml of 20% sulfuric acid. The mixture is filtered and the solvent evaporated. The residue is taken up in methylene chloride, the solution washed several times with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried and evaporated. This gives the oily 2- (2-hydroxyethyl) -6,7-dichloro-l, 4-benzodioxane, which at 180 ~ 19O ° / O, 1 mm Hg boils.

A mixture of 15.2 g of the latter compound, 17.5 g of p-toluenesulfonyl chloride and 40 ml of dry pyridine is 2 hours in

cooled and stirred in an ice bath. The reaction mixture is then treated with ice, the precipitate obtained is filtered off and recrystallized from ethyl acetate. This gives 2- (2-tosyloxyethyl) -6,7-dichloro-1,4-benzodioxane, which melts at 135-138 °.

Example 12 A suspension of 100 g of lithium aluminum hydride in 6500 ml of tetrahydrofuran is added with stirring at 2-6 °, in portions, within 100 minutes, with 450 g of dl- [l- [2 - (-) -l, 4-benzodioxan-2 -yl) -acetyl] -4-piperidyl] -2-imidazolidinone. The reaction mixture is stirred for 19 hours at room temperature, cooled again and treated first with 100 ml of water in 100 minutes at 8-12 °, then with 100 ml of 15% aqueous sodium hydroxide solution and 300 ml of water. The mixture is stirred for 30 minutes with cooling and 90 minutes at room temperature. The reaction mixture is filtered off, the residue is washed with 2000 ml of tetrahydrofuran and the filtrate is evaporated. This gives the ε-1- [1- [2- (1,4-benzodioxan-2-yl) ethyl] -4-piperidyl] -2-imidazolidinone, which melts at 119-122 °. [L = - 47.3 ° (c = 1, in methanol.)

Dissolve 1 191 g of the compound obtained in 3000 ml of 95% aqueous ethanol at 60 °, the solution is mixed with 120 g of activated charcoal and the mixture is stirred for 5 minutes. It is filtered, the residue washed with 200 ml of 95% ethanol and the filtrate 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 at room temperature for 3 hours. The mixture is filtered, the residue washed with 500 ml of 95% ethanol and 800 ml of anhydrous diethyl ether. This gives the -Cl- [1- [2- (1,4-benzodioxan-2-yl) ethyl] -4-piperidyl] -2-imidazolidinone fumarate, which melts at 216-217 ° with decomposition , [ci.] ^ = - 31.6 °. (c = 13.73 mg / ml, in water). The product is identical to that of Example 2.

The starting material is prepared as follows: A solution of 1134 g of bromine in 1400 ml of ethyl acetate is added within 90 minutes, with stirring. -10-0 °, with 472 g of allyl cyanide added dropwise. The resulting solution of 3,4-dibromo-butyronitrile is at once, under

Stir in a nitrogen atmosphere at 35 °, to a solution prepared from 705 g of catechol and 1987 g of anhydrous potassium carbonate in 5000 ml of refluxing ethyl acetate. The mixture is refluxed for 4 hours and stirred overnight at room temperature. It is filtered, the residue washed with ethyl acetate (2000 ml) and the filtrate is evaporated. The residue is distilled and collected at 138 ° / 1.4-131 ° / 1.1 mm boiling fraction. This gives the l, 4-benzodioxan-2-yl-acetonitrile.

A solution of 1647 g of the latter compound in 2760 ml of glacial acetic acid is added to the hot mixture of 858 ml of concentrated sulfuric acid and 2670 ml of water and boiled under reflux 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. This gives the l, 4-benzodioxan-2-yl-acetic acid, which melts at 87-90 °.

A mixture of 3 374 g of the latter compound and 3500 ml of anhydrous ethanol is added to a solution of 2105 g of (-ct-methylbenzylamine in 500 ml of anhydrous ethanol and the mixture is stirred at room temperature for 3 hours After standing for 2 days, the salt obtained is filtered off with suction and washed with 400 ml of ethanol, 400 ml of diethyl ether and 1200 ml of isopropanol, 2070 g of the precipitate are crystallized in 2000 ml of ethanol and the crystals are washed with 500 ml of ethanol and diethyl ether This gives the {-1,4-benzodioxan-2-yl-acetic acid-vat- ^c- t-methyl-benzylammonium salt _, which melts 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 stirred for 20 minutes. The aqueous layer is separated, extracted with 3000 ml of diethyl ether, the combined ethereal solutions are washed with 1000 ml of water, dried and evaporated. This gives the <-l, 4-benzodioxan-2-yl-acetic acid, which melts at 83-85 °. [cC] ^ ⁵ "- 55.42 °. (c = 12.325 mg / ml, in methanol).

21 1 661

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 taken up in 500 ml of chloroform and the solution is evaporated again. This gives the \ -l, 4-benzodioxan-2-ylacetylchlorid, which melts at 60-62 °.

A solution of 434 g of the latter compound in 1000 ml of chloroform is added over 2 hours to 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 at 20 ° C. 23 ° given. After 2 hours, the organic solution is separated and the aqueous phase 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 washed with a further 1000 ml of diethyl ether.

This gives the d-1- [1- [2 - (- ^ - l, 4-benzodioxan-2-yl) acetyl] -4-

piperidyl] -2-imidazo1idinone, which melts at 161-163 °.

95 [<*] "= + 5.9 ° (c = 1, in chloroform).

Example 13 A solution of 2 g of 1- [2- (1,4-benzodioxan-2-yl) ethyl] -4- (2-aminoethylamino) -piperidine in 25 ml of isopropanol is first stirred with 1.65 ml of 4 -Ncrmaler hydrochloric acid in ethanol and then mixed with 0.45 g of ammonium cyanate. The reaction mixture is refluxed overnight, then evaporated and heated at 130 ° C in an OeI bath 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 treated with stirring with 0.77 g of fumaric acid. Upon cooling, the fumarate of 1- [1- [2- (1,4-benzodioxan-2-yl) ethyl] -4-piperidyl] -2-imidazolidinone, which melts at 190 ° C., is obtained.

Example 14 A mixture of 10 g of 1- (2- (1,4-benzodioxan-2-yl) ethyl] -4- (2-amino-ethylamino) -piperidine and 8 g of carbonyldiimidazole in 100 ml of tetrahydrofuran is transferred Cooked under reflux overnight. The reaction mixture is evaporated, the residue taken up in 150 ml of methylene chloride and extracted three times with 50 ml of water. The methylene chloride is dried over anhydrous sodium sulfate and evaporated. The residue is dissolved in 50 ml of hot isopropanol and admixed with 3.8 g of fumaric acid with stirring. Upon cooling, one obtains the l- [l- [2- (l, 4-benzodioxan-2-yl) ethyl] -4 ~ piperidyl] -2-imidazolidinone fumarate, melting at 190 ⁰ C.

Example 15 Dissolve 10 g of 1- [1- [2- (1,4-benzodioxan-2-yl) ethyl] -4- (l, 2,5,6-tetrahydropyridyl)] - 2-imidazolidinone in 100 ml Acetic acid and 50 ml of water, 1 g of platinum oxide is added and hydrogenated the mixture at 60 ⁰ C and 3.4 atmospheres until the intake of one molar equivalent of hydrogen. The reaction mixture is cooled to room temperature, the catalyst is filtered off and the filtrate is evaporated. The residue is mixed with 100 ml of water, with excess 3-normal sodium hydroxide solution (up 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 taken up in 50 ml of hot isopropanol and treated while stirring with 3.8 g of fumaric acid. On cooling, the fumaric acid salt of the desired 1- [1- [2- (1,4-benzodioxan-2-yl) ethyl] -4-piperidyl] -2-imidazolidinone, which melts at 19O ⁰ C, is obtained.

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 added overnight heated at 90 ⁰ C. The reaction mixture is then evaporated. The residue is dissolved in 500 ml of ethanol and treated with stirring and cooling within 2 hours with 30 g of sodium borohydride in portions. 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. This gives the 1- [l- [2- (1,4-benzodioxan-2-yl) ethyl] -4- (l, 2,5,6-tetrahydropyridyl)] - 2-imidazolidinone, which is used as starting material ,

Claims (1)

Erfindun £ sanspruch 1, Process for the preparation of novel IT-oxacyclyl-alkyl piperidyl diazaverbindungen of the general formula I. X (CHp) ^ ι CL JXy eli ^ wherein Ph represents unsubstituted 1,2-phenylene or 1,2-phenylene substituted by one to three identical or different substituents of the group consisting of lower alkyl, lower-valentoxy, lower alkylenedioxy, halogen or trifluoromethyl, each of the symbols R.. and R , -, is hydrogen or lower alkyl, each of the symbols R ^ and R is hydrogen or Hie alkyl or (Ro4-R ^) is Ph or lower alkyl which separates the two nitrogen atoms by 2 to 4 carbon atoms, Rr hydrogen haloalkyl or ffPh means X for 0xo _? TM0X0} is imino or lower alkylimino, Y is epoxy, epithio or sulfinyl, m is an integer from 1 to 7, each of the symbols ρ and q is an integer from 1 to 3, where (piq) is the number 4 , and acid addition salts of these compounds, characterized in that a) condensing a reactive ester of a Ⓒ acyclic alkanol of the general formula III with a 1-unsubstituted piperidyl diazaverbindung of the general formula IV 11 , 1T-CHR ₅ R ₃ .0R ₄ (III) (IV), -35- -3? "- Berlin, d., 28.7.1979 AP C 07 D / 211 661 55 174 11 wherein Z represents a reactive esterified Hydroixygruppe or b) reacting a compound of the general formula V with the carbonic acid derivative of the general formula VI CH-HH I (V) wherein Z ^ is R ^ or the group R ^ # ··. R, -UH-R ₁ - and ZpCX 'for ammonium cyanate or thiocyanate, a metal cyanate or thiocyanate, a liiederalkyl-isourea or -isothiourea, a cyanogen halide or cyanide, carbon disulfide or carbonyl sulfide, a carbonyl halide or 1,1-carbonyldiimidasol, with the proviso that at least one of the groups Z and Zp contains nitrogen or c) a compound of general formula VII (VII) reduced or d) a compound of general formula VIII -ZB- Berlin _e 28.7 "1979 AP C 07 D / 211 661 55 174 11 wherein each of the symbols χ and y is the number 0 or 2 and their sum χ + y is 2 or 4, hydrogenated or e) a compound of general formula IX ^k 0H Zn ^mm \ S 1 ^C -f ~ ^R 5 (IX), R ₁ wherein Z represents a reactive esterified hydroxy group, and when desired converts a compound of formula I obtained into another compound of the invention, and / or, if desired, a resulting free compound in an acid addition scale into the free compound or converted another acid addition salt, and / or, if desired, a resulting mixture of isomers or racemates in the individual isomers or Eacemate separates, and / or, if desired, received racemates split into the optical antipodes 2o method according to item 1a), characterized in that one uses starting materials, wherein Z is a hydroxy group esterified with a strong inorganic or organic acid « -33-. Berlin, d.28.7.1979 AP C 07 D / 211 661 55 174 11 3 · Method according to one of the points 1a) and 2, characterized in that ma-n carries out the reaction in the presence of basic condensation agents. 4 "Process according to item 1b), characterized in that the reaction, when Zp is metallic, is carried out in a neutral or acidic solvent or diluent", 5 * process according to item Ib), characterized in that, if the group Zp contains no metal, the reaction is carried out in the presence of a basic agent « 6 »Method according to item 1c), characterized in that the reaction is carried out with simple hydrides or complex light metal hydrides» 7e method according to item 1d), characterized in that the reaction is carried out with catalytically activated, nascent or electrolytically generated hydrogen « 8c process according to item Ie), characterized in that starting materials are used in which Z is a hydroxy group esterified with a strong inorganic or organic acid » 9 »method according to one of the items 1e) and 8, characterized in that one carries out the reaction in the presence of basic condensing agents. 10, Process according to one of Pankte 1 to 9, characterized in that reacting a compound of formula 1, wherein R- to R _{5 is} hydrogen, with reactive esters of liederalkanolen and thereby an N-substituted compound corresponding to the formula I. manufactures. - HOE · Berlin, d _{e e} 7.28 1979 AP C 07 D / 211 661 55 174 11 11, process according to any one of items 1 to 10, characterized in that an obtained compound of the formula 1 in which Y is a sulfur atom is oxidized with mild oxidizing agents to give its 4-oxides * 12e Process according to one of the items 1 to 11, characterized in that an intermediate product obtainable at any process stage is used as the starting material and performs the remaining process steps, or terminates the process at any stage, or forms a starting material under the reaction conditions or used in the form of a salt or an optically pure antipode ο Method according to one of the items 1 to 12, characterized in that compounds of the general formula I shown in point 1, in which Ph is unsubstituted or by lower alkyl, lower alkoxy, lower alkylenedioxy, halogen or trifluoromethyl monosubstituted 1,2-plienylene, each of the symbols R- and Rp is hydrogen or lower alkyl, each of the symbols R. and R. is hydrogen or lower alkyl or (R ~ -iR,) the radical is Ph or lower alkylene which separates the two nitrogen atoms by 2 or 3 carbon atoms, the symbol R ₁ - represents hydrogen, lower alkyl or HPh, X is oxo, thioxo, imino or lower alkylimino. where Y is epoxy, epithio or sulfinyl, m is an integer from 1 to 4, each of the symbols ρ and q is an integer from 1 to 3, where (p + q) - the number is 4, and their acid addition salts produces ^ 14 * Process according to one of the items 1 to 10 and 12, characterized in that compounds of the formula X ₅ given in point 1, wherein Berlin, d _# 28.7.1979 AP C 07 D / 211 661 55 174 11 Ph is unsubstituted or substituted by alkyl or alkoxy, each having at most 4 carbon atoms, halogen or Trifluprmethyl monosubstituted 1,2-phenylene, each of the symbols R-, R ₂ .and R ^ is hydrogen or alkyl having at most 4 carbon atoms, each of the symbols R and R 1 represent hydrogen or (R 1 + R 3) represents alkylene having 2 to 4 carbon atoms which separates the two nitrogen atoms by 2 or 3 carbon atoms, X represents oxo, thioxc or imino, Y represents epoxy or epithio, m is an integer from 1 to 4, each of the symbols ρ and q is 2, and produces their acid addition salts * 15 »Process according to one of the points 1 to 9 and 12, characterized in that compounds of the general formula II ^{l (kUn} 2 ^; m- ^l * ^ v CX- KH (II), vjorin R is hydrogen, alkyl or alkoxy, each having at most 4 carbon atoms, halogen or trifluoromethyl, m is an integer from 1 to 4, η is the integer 2 or 3, and X is oxo, thioxo or imino, and their Makes acid addition salts, 16. A method according to any one of items 1 to 3 and 12, characterized in that 1- ^ 1-f2- (1,4-benzodioxan-2-yl) -äthyÜJ ~ 4 "piperidyl-2-imidazolidinone, its d- and & antipodes and their acid addition salts