CA1117941A - Process for the manufacture of new n-oxacyclic- alkyl-piperidyl-diazacompounds - Google Patents

Abstract

Abstract of the disclosure The invention concerns the manufacture of compound of the formula I

(I), wherein Ph is unsubstituted 1,2-phenylene or 1,2-phenylene substituted by one to three identical or different members selected from lower alkyl, lower alkoxy, lower alkylene-dioxy, halogeno or trifluoromethyl, each of R1 and R2 is hydrogen or lower alkyl, each of R3 and R4 is hydrogen.
lower alkyl or (R3 + R4) is Ph or lower alkylene separating both nitrogens by 2 to 4 carbon atoms. R5 is hydrogen, lower alkyl or HPh, X is oxo, thioxo, imino or lower al-kylimino, Y is epoxy, epithio or sulfinyl, m is an integer from 1 to 7, each of p and q is an integer from 1 to 3, but (p+q) = 4, and acid additional salts thereof. The compounds exhibit stimulant and antidepressive effects.
They are prepared by reduction of corresponding amides.

Description

Case 4-11639/CGC_854/+

Process for the manufacture of new N-oxacyclic-alkylpiperidyl-diazacom ounds P ~

The present in~ention concerns the manufacture of new N-oxacyclic-alkylpiFeridyl-diazacompounds of the general formula I

Ph/ 1 2 / 2 \0/1 m (C~2) Rl q R3..R4 (I~, wherein Ph is unsubstituted 1,2-phenylene or 1,2-phenylene substituted by one to three identical or different members selected from lower alkyl, lower alkoxy, lower alkylene-dioxy, halogeno or trifluoromethyl, each of R1 and R2 is hydrogen or lower alkyl, each of R3 and R4 is hydrogen, lower alkyl or (R3 + R4) is Ph or lower alkylene separating both nitrogens by 2 to 4 carbon atoms, R5 is hydrogen, lower alkyl or ~Ph, X is oxo, thioxo, imino or lower a~
kylimino, Y is epoxy, epithio or sulfinyl, m is an integer .
from 1 to 7, each of p and q is an integer from 1 to 3, but ~p+q) = 4, or of acid addition salts, especially of therapeutically acceptable acid addition salts thereof.

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The 1,2-phenylene group Ph is pre~erably unsubstituted or monosubstituted, and its 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.
metho~y, ethoxy, n- or i-propoxy or -butoxy, lower alkylene-dioxy, e~g. methylenedioxy, l,1- or 1,2-ethylenedioxy, halogeno, e.g. fluoro, chloro or bromo or trifluoromethyl.

Each of Rl to R5 is preferably hydrogen, but also lower alkyl, advantageously methyl, or another of those mentioned above. The symbol R5 may also be phenyl, unsubstituted or substituted as illustrated by H-Ph above. The symbols R3 and R4 taken together may also be Ph or lower alkylene separating both nitrogens by pre~erably 2 or 3 carbon atoms, e.g. 1,2-ethylene, 1, ?- 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 said integers m is preferably l to 4 and CmH2m advantageously represents methylene, l,l- or 1,2-ethylene, l,2- or 1,3-propylene, l,2-, 1,3- or l,4-butylene; and each p and ~ is preferably 2.

All of the basic compounds of the general formula I
can be in the form of acid addition salts, especially thera-peutically acceptable acid addition salts, e.g. derived from the acids listed below.

As used above and hereinafter in connection with organ-ic radicals or compounds respectively, the term "lower"
defines such with up to 7, preferably up to 4, and advan-tageously 1 or 2 carbon atoms.

The compounds of the invention exhibit valuable phar-macological properties, for example, stimulant and anti--.
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depressive effects. This can be demonstrated in animal tests, using advantageously mammals, such as rats or monkeys, as test objects. The compounds of the invention can be applied to the animals enterally, e.g. orally, or parent-erally, e.g. subcutaneously, intraperitoneally or intra-venously, for example in the form of aqueous solutions or starchy suspensions. The dosage may range between about 0.1 to 100 mg/kg/day, preferably between about 1 and 50 mg/kg day, especially between about 5 and 25 mg/kg/day. Said stimulant and antidepressiv~ effects can be observed, for example, in male albino rats, which are allowed unrestrict-ed access to food and water, except during experimental sessions. Behavioral testing takes place in standard, sound-insulated conditioning chambers, which contain a response lever. Electrical shocks are delivered throught the grid 100r. The response lever is connected to solid-state programming equipment, which controls the delivery of the electrical shocks. The number of responses and num-ber of shocks received are both recorded. Said rats are first trained to avoid the onset of electrical shock by pressing the lever. Thereafter, the programming equipment is adjusted so that each lever-press postpons the onset of shock for 30 seconds. If the animal fails to press the lever within this time interval, biref electrical shocks are delivered every 15 seconds until the animal again presses the lever. Prior to each test session the rats are placed in the cham~ers for a fifteen munute warm-up period, during which responding is not recorded. Imme diately thereafter the test compounds are given either within saline, or a 3% colloidal corn starch suspension in 5~i aqueous polyethyleneglycol 400, containing one drop of polyoxyethylene-20-sor~itan monooleate per 10 ml, administ ered either orally or intraperitoneally. Thus, for example, - . ~ :, ~ ' - .
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the 1-[1-[2-(1,4-benzodioxan-2-yl)-ethyl]-4-piperidyl]-2-imidazolidinone, especially the levorotatory fo~m thereof, e.g. the l-(S)-hydrobromide or fumarate, illustrative of the compounds of formula I, when intraperitoneally applied at doses as low as 2.5 mg/kg/day, significantly increases the rat's avoidance responding, which compares favorably with 5 mg/kg/day i.p. of methylphenidate (a classical stimulant).

Said compound of the invention exhibits a unique mecha-nism of action; it is apparently not a biogenic amine up-take blocker, a mianserin-like presynaptic a-noradrenergic blocker, an amphetamine-like stimulant prone to abuse liabi-lity, not an anticholinergic nor antihistaminic, i.e. it is free from said common side-effects of known antidepres-sants.

In another test male s~uirrel monkeys are trained to press a lever in such a Skinner box for avoiding an electric foot shock, applied through the floor grid. Each time a monkey presses the avoidance lever, the shock is postponed for 20 seconds; if it fails to press the lever within said period 0.5 second shocks are delivered at 20 second inter-vals until the monkey again presses the lever. Under control conditions the monkeys press the lever at a moderately steady rate and seldom receive more than 6 shocks during a four hour session. Measured ate the avoidance responses and number of shocks received. Said hydrobormide or fumarate, when orally administered within 0.9~ aqueous sodium chloride, positively changes both the avoidance response rate and number of shocks taken at doses as low as 2.5 mg/kg/day, as compared with a control session (on saline alone)preced-ing the drug session by one day.

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Accordingly, the compounds of the invention are use~ul psychostimulants, for example in the treatment or management of depression or minimal brain dysfunction. Moreover, they are also valuable intermediates in the preparation of other useful products, especially of pharmacologically active compositions.

Particularly useful are compounds of the general for-mula I, wherein Ph is 1,2-phenylene unsubstituted or mono-substituted by lower alkyl, lower alkoxy, lower alkylene-dioxy, halogeno or trifluoromethyl, each of Rl and R2 is hydrogen or lower alkyl, each of R3 and R4 is hydrogen, lower alkyl or (R3 + R4) is Ph or lower alkylene separating both nitrogens by 2 or 3 carbon atoms, R5 is hydrogen, lower alkyl or HPh, X is oxo, thioxo, imino or lower alkyl-imino, Y is epoxy, epithio or sulfinyl, m is an integer from 1 to 4, each of p and q is an integer from 1 to 3, but (p + q) = 4; or a therapeutically acceptable acid addition salt thereof.

Preferred compounds of the invention are those of the general formula I, wherein Ph is 1,2-phenylene unsubsti-tuted or monosubstituted by alkyl or alkoxy, each with up to 4 carbon atoms, halogeno or trifluoromethyl, each of Rl, R2, and R5 is hydrogen or alkyl with up to 4 carbon atoms, each of R3 and R4 is hydrogen or (R3 + R4? represents alkylene with 2 to 4 carbon atoms separating both nitrogens 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 and each of p and q is the ingeger 2, or a therapeutically acceptable acid addition salt thereof.

Outstanding are the compounds of the general formula II

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~.~ ~0~ ./ \_~(CH2) R----~-- i!~ /- (CH2)~ ~ \./ CX---NH (Il), wherein R is hydrogen, alkyl or alkoxy each with up to 4 carbon atoms, halogeno or trifluoromethyl, m is an integer from 1 to 4, n is the integer 2 or 3 and X is oxo, thioxo or imino, or a therapeutically acceptable acid addition salt thereof.

The compound of this invention are prepared according to conventional methods, for example by a) condensing a reactive ester of an oxacyclic alkanol of the general formula III with a l-unsubstituted piperidyl-diazacompound of the general formula IV
y CH-R2 ~ H~< \cH-N-c-N-R5 \0/l m 2m Z (CH2)q R3.. 4 (III) (IV) wherein Z is a reactive esterified hydroxy group.

An esterified hydroxy group Z is, for example, such esterified by a strong inorganic or organic acid, above all a hydrohalic acid, e.g. hydrochloric, hydrobromic or hydr-iodic acid, sulfuric or an aromatic sulfonic acid, e.g.
p-toluene or m-bromobenzene sulfonic acid. Said condensation is preferably carried out in the presence of a basic con-densation agent, such as an alkali or alkaline earth metal hydroxide, carbonate or bicarbonate, e.g. sodium, potassium or calcium hydroxide or carbonate, alkali metal hydrides, : , , ; :

lower alkoxides or alkanoates, e.g. sodium hydride, me-thylate or acetate, as well as organic tertiary nitrogen bases, such as tri-lower alkylamines or pyridines, e.g.
triethylamine or lutidine.

Another process for preparing the compounds of the invention consists in b) reacting a compound of the general formula V with the carbonic acid derivative of the general formula VI
Y
/\
Ph C~-R2 /(CH2)p\

\ ~ I \(CH ) / I ~ Z CX' (VI) (V) wherein Zl is R3 or the grouping R3 .... R4-NH-R5 and Z2CX' is an ammonium or metal cyanate or thiocyanate, a lower alkyl isourea or thiourea, a cyanogen halide or amide, carbon disulfide or oxysulfide, a carbonic acid halide or l,l-carbonyldiimidazole, provided that at least one of Z
and Z2 contains nitrogenO

Said reaction provides either the addition of a carba-moyl group to the compound V, if Zl represents R3, or the insertion of CX into V if Zl is the grouping R3 . . . R~-NH-R5 .
Said cyanate is preferably an alkali metal cyanate, a cyanogen halide advantageously the bromide and the carbonic acid halide preferably phosgene. Said reaction is carried out in the usual manner depending on Z2 In case it is me-tallic, the reaction is performed in a neutral or acidic solvent or diluent, such as a water-miscible polar solvent, for example an aqueous lower alkanol, alkanone or saturated cyclic ether, e.g. ethanol, acetone, tetrahydrofuran or .

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dioxan, or an alkylated formamide or sulfoxide, e.g. di-methylformamide or -sulfoxide. If Z2 is non-metallic, a basic agent may be used as acid binder, such as an alkali or alkaline earth metal hydroxide, carbonate or bicarbonate, e.g. sodium potassium or calcium hydroxide or carbonate;
alkali metal hydrides, lower alkoxides or alkanoates, e.g.
sodium hydride, methylate or acetate, as well as organic tertiary nitrogen bases, such as tri-lower alkylamines or pyridines, e.g. triethyl amine or lutidine.

The compounds of the invention are also obtained by c) reducing a compound of the general formula VII

/ \ ~(C~2) X
\ ~ C - C H -Co--N / CH-N C ;R5 wherein m is an integer from 1 to 7.

The reduction is carried out in the usual manner, pre-ferably with the use of simple or complex light metal hyd-rides, such as diborane or alane, alkali metal boro- or aluminiumhydrides or -alkoxy-hydrides, e.g. lithium alu-miniumhydride and/or sodium trimethoxy-borohydride.

Another process for preparing the compounds of the invention consists in d) hydrogenating a compound of the general formula VIII

~h/ CH-R2 ~(C~2)p \ X
\ C--C H ~-~ ~C2H3 y~N~C~N~RS

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wherein each of x and y is the integer O or 2 and their sum x+y is 2 or 4.

The hydrogenation of said ole~ines VIII is performed in the usual m~nner, preferably with the use of catalyti-cally activated or nascent hydrogen, such as hydrogen in the presence of cobalt, palladium, platinum or rhodium ca-talysts, e.g. cobalt sulfide or tris-(triphenylphosphine~-rhodium chloride (which are not poisoned by sulfur), or hydrogen generated electrolytically.

The compounds of the invention are also obtained by e) ring-closing a reactive ester of a compound of the gene-ral formula IX
y Ph/ \CH R ~ ~ 2 p\ X

R (CH2~ / R3..~4 (IX) wherein Z is a reactive esteri~ied hydroxy group.

A reactive esterified hydroxy group is, for example, such esterified by a strong inorganic or organic acid, above all a hydrohalic acid, e.g. hydrochloric, hydrobromic or hydriodic acid, suluric or an aromatic sulfonic acid, e.g. p-toluene or m-bromobenzene sulfonic acid. Said ring-closure is preferably carried out in the presence of a basic condensation agent, such as an alkali or alkaline earth metal hydroxide, carbonate or bicarbonate, e.g.
sodium, potassium or calcium hydroxide or carbonate, alkali metal hydrides, lower alkoxides or alkanoates, e.g. sodium hydride, methylate or acetate, as well as organic tertiary nitrogen bases, such as tri-lower alkylamines or pyridines, .
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e.g. triethylamine or lutidine.

The compounds of the invention so obtained can be converted into each other according to known methods. Thus, for example compounds with R3 to R5 being hydrogen, can be reacted with reactive esters of lower alkanols, e.g. such esterified by a strong inorganic or organic acid, above all a hydrohalic acid~ e.g. hydrochloric, hydrobromic or hydr-iodic acid, sulfuric or an aromatic sulfonic aicd, e.g.
p-toluene or m-bromobenzene sulfonic acid, in order to ob-tain the corresponding N-substituted compounds. Depending on the molar amount of alkylating agent employed, the successive introduction of each R3, R4 t and R5 is accomp-lished. Compounds in which Y represents a sulfur atom can also be oxidized to the corresponding 4-oxides with the use of mild oxidants, such as periodates, e.g. sodium pe-riodate in said polar solvents and at low temperatures, e.g. between about 0 and room temperature. Care should be taken in order to prevent overoxidation at overly long reaction times.

Finally, the compounds of the invention are either obtained in the free, basic form, or as a salt thereof.
Any resulting base can be converted into a corresponding acid addition salt, preferably with the use of a therapeu-tically useful acid or anion exchange preparation, or re-sulting salts can be converted into the corresponding ree bases, for example, with the use of a stronger ~ase, such -as a metal or ammonium hydroxide, basic salt or cation ex-change, e.g. an alkali metal hydroxide or carbonate. Said acid addition salts are preferably such of therapeutically ;~
acceptable inorganic acids, for example hydrohalic, e.g.
hydrochloric or hydrobromic acid; sulfuric, phosphoric, nitric or perchloric acid; or organic acids such as ali-phatic or aromatic carboxylic or sulfonic acids, e.g.
formic, acetic, propionic, succlnic, glycollic, lactic, malic, tartaric, citric, maleic, fumaric, hydroxvmaleic, pyruvic, phenylacetic, benzoic, 4-aminobenzoic, anthranilic, 4-hyd-roxybenzoic, salicylic, 4-aminosalicylic, pamoic, nicotinic;
methanesuIfonic, ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonic, halogen-benzenesulfonic, toluenesulfonic, naphthalenesulfonic, sulfanilic or cyclohexylsulfamic acid; or ascorbic acid. These or other salts, for example, the picrates, can also be used for purification of the bases obtained; the bases are converted into salts, the salts are separated and the bases are liberated from the salts.

In view of the close relationship between the free compounds and the compounds in the form of their salts, :
whenever a compound is referred to in this context, a cor~
responding salt is also intended, provided such is possible or appropriate under the circumstances.

~he starting materials are known or if new, can be prepared according to known procedures, e.g. those illu- ;
strated in ~he examples hereinO

Compounds of formula III can easily be obtained by reducing the corresponding 1,4-benzodioxan-2-yl-alkanoic acid to the corresponding alcohol with lithium aluminium hydride or sodium 2-methoxyethoxyaluminium hydride, and reactively esterifying it with a strong acid or its deriva-tive mentioned above, e.g. a thionyl, phosphorus or benzene-sulfonyl halide, in an organic solvent, such as benzene, preferably at a raised temperature.

Compounds of formula IV are obtained from correspond-ing l-benzylpiperidones, which are converted into their O-alkyloximes or Schiff's bases of diaminoalkanes or `; :

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-benzenes, which are reduced, either with the use of cata-lytically 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 hydrogen generated electrolytically, or with the use of simple or complex light metal hydrides, such as diborane or alane, alkali metal boro- or aluminiumhydrides or -alk-oxyhydrides, e.g. lithium aluminiumhydride and/or sodium trimethoxyborohydride, to the mono- or diamines. These are further reacted with the carbonic acid derivative Z2CX', e.g. an ammonium or metal cyanate or thiocyanate, a lower alkyl isourea or thiourea, a cyanogen halide or amide, carbon disulfide cr oxysulfide, a carbonic acid halide or l,l-carbonyldiimidazole, provided that at least one of Z
and Z2 contains nitrogen. Finally the benæyl moiety is hydrogenolytically removed in the end, preferably over palladium catalysts.

Compounds of formula V are similarly obtained by react-ing the 3- or 4-piperidone with a reactive ester of the formula III, e.g. such in which the hydroxy group is esteri-fied by a stronginorganic or organic acid, above all a hydrohalic acid, e.g. hydrochloric, hydrobromic or hydriodic acid, sulfuric or an aromatic sulfonic acid, e.g. p-toluene or p-bromobenzene sulfonic acid. The resulting products are converted into their O-alkyloximes or Schiff's bases of di-aminoalkanes or -benzenes, which are reduced either with the use of catalytically activated or nascent hydrogen to the mono- or diamines. The reduction is carried out as des-cribed for the starting materials of the formula IV. Com-pounds of formula V are also obtained from the previous esters of formula III by condensation with corresponding

3- or 4-benzylaminopiperidines and cleaving the ben2yl . . : . .

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group by hydrogenation.

Compo~nds VII are prepared from said 1,4-benzodioxan-2-yl-alkanoic acids by converting them into a halide, mixed anhydride or amide of imidazole, and reacting them with the corresponding piperidines.

The unsaturated compounds of formula VIII are pre-erably enamines prepared from the corresponding aldehydes and said piperidines, and the aldehydes are obtained by reduction of said acid halides according to Rosenmund, or of their nitriles with diisobutylaluminium hydride.

Finally the compounds of formula IX are prepared by the Mannich-reaction of said piperidines with corresponding aldehydes and/or ketones, brominating the resulting pipe ridinoalkanones, condensing the a-bromoketones obtained with mono-acetylcatechol, reducing the ketonic condensation product with sodium borohydride to the corresponding alco-hol and reactively esterifying it as mentioned above.

In case mixt~res of geometrical or optical isomers of the above compounds, e.g. I to IX, are obtained, these can be separated into the single isomers by methods in them-selves known, e.g. by fractional distillation, crystalli-zation and/or chromatography. Racemic products can like-wise be resolved into the optical antipodes, for example, by separation of diastereomeric salts thereof, e.g. by the fractional crystallisation of d- or ~-tartrates~

The above-mentioned reactions are carried out accord-ing to standard methods, in the presence or absence of di-luents, preferably such as are inert to the reagents and are solvents thereof, of catalysts, condensing or said other agents respectively and/or inert atmospheres, at low '` ;

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temperatures, room temperature or elevated temperatures, preferably at the boiling point of the solvents used, at atmospheric or superatmospheric pressure.

The invention further includes any variant of the present process, in which an intermediate product obtainab-le at any stage of the process is used as a starting mate-rial and any remaining steps are carried out, or the pro-cess is discontinued at any stage thereof/ or in which the starting materials are formed under the reaction condi-tions, or in which the reaction components are used in the form of their salts or optically pure antipodes.

Mainly those starting materials should be used in said reactions, that lead to the formation of those compounds indicated above as being especially valuable, e.g. those of formula II.

The pharmacologically active compounds of the inven-tion are useful in the ~anufactureof pharmaceutical com-positions containing an effective amountthereof in conjunc-tion or admixute with excipients suitable for either enter-al or parenteral administration. Preferred are tablets and gelatin capsules comprising the active ingredient together with diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and/or glycine, and lubricants, e.g.
silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also binders, e.g. magnesium aluminium silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone, if desired, disintegrants, e.g. starches, agar, alginic acid or its sodium salt, enzymes of the binders or effervescent mixtures and/or adsorbents, colorants, flavors and sweeteners. Injectable .

compositions are preferably aqueous isotOnic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution pro-moters, salts for regulating the osmotic pressure and/or buffers. They may also contain other therapeutically valuable substances. Said pharmaceutical compositions are prepared according to conventional mixing, granulating or coating methods respectively and contain about 0.1 to 75~, preferably about 1 to 50~ of the active ingredient.

The following examples are intended to illustrate the invention and are not to be construed as being limita-tions thereon. Temperatures are given in degrees Centigrade, and all parts wherever given are parts by weight. If not mentioned otherwise, all evaporations are per~ormed under reduced pressure, preferably between about 15 and 100 mmHg.

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, Example 1 The mixture of 4.9 g of 2-(2-tosyloxyethyl~-1,4-benzo-dioxan, 2.54 g of 1-(4-piperidyl)-2-imidazolidinone, 5 g of anhydrous sodium carbonate and 100 ml of 4-methyl-2-penta-none is stirred and refluxed for 3 days. ~t is filtered, evaporated and the residue recrystallized from isopropanol, to yield the 1-[1-[2-(1,4-benzodioxan-2-yl)-ethyl]-4-piper-idyl]-2-imidazolidinone of the formula O ':
2)2 ~I~J--(CX2~2-M ~ CO~

melting àt 125.

It is suspended in 10 ml of hot isopropanol, the sus-pension neutralized with 5N isopropanolic hydrogen bromide and the precipitate recrystallized from isopropanol, to yield the corresponding hydrobromide melting at 220-221 with decomposition.

The starting materiaI is prepared as follows: The solu-tion of 16 g of bromine in 10 ml of petroleum ether ls slowly added to the solution of 6.7 g of allyl cyanide in 30 ml of the same solvent, while stirring and keeping the `
temperature at about -15. After removal of the solvent the oily 3,4-dibromo-butyronitrile ls obtained in quantitative yield.

227 g thereof are added dropwise in S equal parts to the stirred mixture of 85 g of catechol and 50 g of anhyd-rous potasslum carbonate ln 100 ml of refluxing acetone.

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Another 50 g of potasslum carbonate are added, follow-ed by a slow additlon of another par~ of nitrlle. After 3 more cycles, using 40 g of potasslum carbonate, one part nltrlle each and sufficient acetone to allow stirrlng, the mixture is refluxed for 20 hours. It is filtered, the fll-trate evaporated, the resldue dlstilled and the fraction boiling at 105/O.lS mm ~g collected, to yleld the 1,4-benzodioxan-2-yl-acetonitrile.

The mixture of 111 g thereof, 63.5 ml of sulfuric acid, 160 ml of acetic acid and 160 ml of water is refluxed for 48 hours. It is poured on ice, the resulting solid collected and recrystallized from benzene-petroleum ether, to yield the 1,4-benzodioxan-2-yl-acetic acid melting at 100.

The solution of 5.8 g thereof in 100 ml of benzene is added dropwise to 16.5 ml of a refluxing, 70~ benzene solu-tion of sodium bis (2-methoxyethox~ ~luminium hydride under nitrogen. When addltion ls complete, the mlxture is refluxed for 4 hours, cooled and poured slowly into 20 ml of 25~ sul-furic acid. After filtration and removal of the solvent, the residue is taken up in methylene chloride, the solution washed several times with saturated aqueous sodium bicarbo-nate, dried and evaporated, to yield the oily 2-(2-hydroxy-ethyl)-1,4-benzodioxan.

The mixture of 3.6 g thereof, 5.7 g of p-toluenesul~o-nyl chloride and 20 ml of dry pyridine is stirred and cooled in an ice bath for 2 hours. Ice is then added to the mlx-ture, the resulting solld is flltered off and recrystallized from ethyl acetate-petroleum ether, to yield the 2-(2-tosy-loxyethyl3-1,4-benzodioxan melting at 82-3.

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To the solution of 1.6 g of 4-aminopyridine in 7 ml of dimethylformamide 2 g of 2-chloroethylisocyanate are added while stirring and keeping the temperature below 40. After 2 hours 28 ml of water are added and stirring is continued for 2 hours at room temperature. The preclpitate formed is filtered off, washed with water, dried and recrystallized from aqueous ethanol, to yield the l-(4-pyridyl)-3-(2-chlo-roethyl)-urea melting at 120-122.

To the suspension of 2.66 g thereof in 4 ml of boiling methanol, 2.68 g of 30.8% methanolic sodium methylate are added while stirrlng and the mixture is refluxed for 1 hour.
It is filtered hot, washed wlth hot methanol, the filtrate evaporated and the residue is recrystallized from 90% aqueous ethanol, to yield the l-(4-pyridyl)-2-lmidazolidlnone melting at 204-207.

The solution of 5 g thereof in 45 ml of water is hydro-genated over 0.8 g of 10% ruthenium on carbon at 120 and 120 atm. until the hydrogen absorption ceases. It is filter-ed, the filtrate evaporated, the residue taken up in chloro-form, the solution dried, evaporated and the residue recry-stallized from methylene chloride-petroleum ether, to yield the l-(4-piperidyl)-2-imidazolidinone melting at 155-157.

Example 2 The solution of 4 g of 1-[1-C2-~-1,4-benzodioxan-2-yl) -acetyl]-4-piperidyl]-2-imidazolidinone in 50 ml of tetra-hydrofuran is added to the cooled and stirred suspension of 1 g of llthium alumInium hydride in 100 ml of tetrahydro~
furan at 25. It ls stirred at room temperature overni~ht and decomposed with 10 ml of ethyl acetate, 1 ml of water, 2 ml of 15% aqueous sodium hydroxide and 3 ml of water. The mixture is filtered, the filtrate evaporated and the residue i~
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dissolved in 25 ml of hot isopropanol. The solution is com-bined with that of 1.35 ~ of fumaric acid in 25 ml of hot isopropanol and the precipitate collected after cooling, to yleld the ~ [1-[2-(1,4-benzodioxan-2-yl)~ethyl]-4-piper-idyl]-2-imidazolidinone fumarate melting at 210-213:
~]D=-30.4 (methanol).

In the same manner the dextrorotatory salt is obtained, melting at 210-213; [a]D= +30.8 (methanol).

The starting materlal ls prepared as follows: 19.4 g of 1,4-benzodioxan-2-yl-acetic acld and 12.1 g of d-a-methyl-benzylamlne are dissolved ln 100 ml of hot isopropanol.
After standing overnight, the salt formed ls filtered off and recrystallized five times from isopropanol. Experiments show that this is sufficient to optically resolve said acid. It is liberated wlth diluted hydrochloric acid, the mlxture extrac-ted with dlethyl ether and the extract evaporated, to yield the d-1,4-benzodioxan-2-yl-acetic acld with [a]D= ~49 (eth-anol).

In like manner, using ~-a-methylbenzylamine, the anti-pode acid is obtained, [a]D= -49 (ethanol).

The solution of 3.4 g of said ~-acid in 60 ml of tet-rahydrofuran is stirred with 3.4 g of carbonyldiimidazole for 1 hour. Then 3.05 g of 1-(4-piperidyl)-2-imidazolidi-none, suspended in 20 ml tetrahydrofuran are added and the mixture is stirred overni~ht. It ls evaporated, the residue dissolved in e-hyl acetate, the solution washed with N
hydrochloric acid and 5~ aqueous sodium hydroxlde, dried and evaporated, to yield the 1-~ 2-(~-1,4-benzodioxan-2-yl)-acetyl]-4-piperidyl]-2-imidazolidinone.

,:

: . ~: ~ , , ....................... ~ :

., ., :
, ; . ,. .. :

9~L~

Example 3 The mixture of 3.34 g of 2-12-tosyloxyethyl)-1,4-benzodlo-xan, 1.83 g of 1-(4 plperldyl)-2-hexahydropyrlmldlnone, 4 g of sodlum carbonate and 80 ml of 4-methyl-2-pentanone ls refluxed for 3 days. It is filtered hot, the flltrate eva-porated and the residue taken up ln water. The suspenslon is made basic with ammonium hydroxlde, extracted wlth chlo-roform, the extract dried and evaporated. The residue is dlssolved ln hot ethanol, the solutlon made acidlc wlth

4.5N ethanolic hydrogen chlorlde, cooled and filtered, to yield the 1-[1-[2-(1,4-benzodioxan-2-yl)-ethyl]-4-piper-ldyl]-2-hexahydropyrlmidinone hydrochloride melting at 253-255.

Analogously the 1-[1-[2-(1,4-benzodloxan-2-yl)-ethyl]-4-piperidyl]-2-benzimldazolidinone hydrochloride is obtain-ed, melting at 185-189.

The starting materlal is prepared as follows: To the lce cooled stirred solutlon of 62.5 ml of 1,3-dlaminopro-pane in 100 ml of eithanol, 30 g of 1-benzyl-4-piperidone are added dropwlse. The mlxture ls hydrogenated over 2 g of pre-reduced platinum oxlde at 50~ and 2.7 atm. for 9 -hours. After theoretical hydrogen-uptake the catalyst ls flltered off, the flltrate evaporated, the residue dis-tilled and the fraction bolling at 145-160/0.2 mmHg coll-ected, to yield the 4-(3-aminopropylamino)-1-benzylpiper-ldlne.

To the stlrred, ice-cooled solutlon of 24.1 g thereof ln 100 ml of tetrahydrofuran, 18.3 g of l,l-carbonyldliml-dazole ln 250 ml of tetrahydrofuran are added dropwlse.
After stlrring at room temperature for 18 hours the mlxture ls evaporated, the residue suspended in water, filtered off ! ' , ~ , . ~

~ 79~

and recrystallized from ethanol, to yleld the l~ benzyl-4-piperidyl)-2-hexahydropyrlmldinone melting at 178~180.

The solution of 8 g thereof in 100 ml ethanol-acetic acid (1:1) ls hydrogenated over l.S g 10~ palladlum on charcoal, at 50 and 2.7 atm. for 4 hours. After flltratlon through fllter cell and removal of the solvent, the resldue ls taken up in water, the mlxture made strongly alkaline with 50% aqueous sodium hydroxide, extracted with chloro-form, the extract dried, flltered, evaporated and the resi-due recrystalllzed from ethanol, to yleld the l-(4-piper-ldyl)-2-hexahydropyrimldlnone melting at 206-210.

The 1-(4-piperidyl)-2-benzimidazolldlnone is descrlbed ln U.S.-patent No. 3,929,801.

Example 4 To the stlrred solutlon of 6 g of 1-[2-(1,4-benzodio-xan-2-yl)-ethyl]-4-(2-aminoethylamlno) plperldlne in 10 ml of 50% aqueous ethanol, 1.4 ml of carbon disulfide are added dropwise at 25. The mixture is refluxed for one hour, a drop of concentrated hydrochloric acid is added and refluxing is contlnued for 5 hours. After cooling overnlght the mlxture is il-tered and the resldue washed with ethanol, to yield the l-11-[2-(1,4-benzodioxan-2-yl)-ethyl]-4-piperidyl]-2-imidazolidinthione hydrochloride melting at 292.

The starting material is prepared as follows: The mix-ture of 10 g of 2-(2-tosyloxyethyl)-1,4-benzodioxan, 10 g of 4-piperidone hydrochloride, 20 g of anhydrous sodium carbonate and 160 ml of dimethylformamide is stirred vigor-ously at room temperature for 48 hours. It is filtered, the resldue washed wlth a small amount of dimethylformamide and the filtrate evaporated. The residue is dlssolved in ethyl .. . : . : , :

.. . . . . .
.. : :
. ..
;. ,.: , ~7~

acetate, the solution extracted with hydrochloric acid, the extract made alkaline with 50% aqueous sodlum hydroxlde while cooling and re-extracted wlth methylene chloride. The latter extract ls dried and evaporated,to yield the 2-[2-(4-oxopiperidlno)-ethyl]-1,4-benzodloxan, whlch solldlfies on standing.

To the solutlon of 18 g thereof in 150 ml of ethanol, that of 23 ml of ethylenediamine in 30 ml of ethanol ls added and the whole hydrogenated over 2 g of prereduced platinum oxlde at 50 and 3 atm. untll the requlslte amount of hydrogen has been absorhed. The mlxture ls cooled, fil-tered and the filtrate evaporated, to yield the 1-[2-(1,4-benzodioxan-2-yl)-ethyl]-4-(2-aminoethylamlno)-piperidlne as an oil.

Example 5 According to the methods illustrated by the preceeding examples, advantageously those indlcated in the table below under "Ex.", the following compounds of Formula I are pre-pared from equivalent amounts of the corresponding starting materials:
Rl=R2=H, R3+R4=fCH2)2, X=0 and p=q=2, (2-position of Ph at Y) No. _ ___ ~ m R5 Salt Ex m.p.C
_ _ _ .
1 1,2-phenylene 0 1 H HCl 1 250-1 2 ll 0 3 H ll 2 280-5 3 ll 0 2 phenyl ll 1 263-5 4 4-CH -C H 0 2 H ll 1 245-6

5-CH -C H 0 2 H ll 1 218 0

6 6-CH30-C6H3 0 2 H ll 1 261-1

7 1,2-phenylene S 2 H 2 95-9 ~ 7~

The various startlng materlals can be prepared as follows:

The mixture of 10 g of 2-(2-tosyloxyethyl)-1,4-benzo-dioxan, 2.4 g of sodium cyanlde, 4 ml of water and 20 ml o~
ethanol is refluxed for 48 hours. It is evaporated, the resi-due taken up ln water and extracted with dlethyl ether. The extract is dried, evaporated and 5 g of the crude nitrile stirred and refluxed for 48 hours in a mixture of 2.8 ml of sulfurlc acid, 7.2 ml of water and 7.2 ml of acetic acid.
The mixture is poured into ice water, extracted with diethyl ether, the extract washed with water and re-extracted with aqueous sodlum bicarbonate. The alkaline solution is made acidic with hydrochloric acid and extracted wlth diethyl ether. The extract is drled, evaporated, 2.5 g of the crude acid are dlssolved in 25 ml of tetrahydrofuran and the solu-tlon treated with 3 g of carbonyldiimidazole for 30 minutes while stirring. 2.4 g of 1-(4-plperldyl)-2-imidazolidinone are added and the mixture is stirred overnight. It is evapo-rated, the residue dissolved in ethyl acetate, the solution washed with 5% aqueous sodium hydroxide and ~% hydrochloric acld, dried and evaporated, to yleld the 1-~1-[3-(1,4-benzo-dioxan-2-yl]-propionyl]-4-piperldyl]-2-imidazolidinone.

To the solution of 12.6 g of N-phenylethylenedlamine in 200 ml of methanol, 50 ml of 4.1 N ethanolic hydrogen chlor-ide are added dropwise followed by 18.9 g of 1-benzyl-4-piperidone ln 100 ml of methanol. Then, 9.45 g sodlum cyano borohydrlde are added ln portlons whlle stlrrlng at room temperature. After 72 hours the mlxture ls filtered, the resldue dlssolved ln water and the solutlon made basic with 12.5~i aqueous sodium hydroxlde. It ls extracted wlth methy-lene chlorlde, the extract dried and evaporated to yield the l-benzyl-4-(2-phenylaminoethylamlno)-plperidine.

I

., . ~ ,,. " . . , ~ :

, .. ..
.:.

79~

To the stirred solution of 14 g thereof in 100 ml of dry benzene, 170 ml of 12.5% phosgene ln benzene are added dropwise at room temperature. After stirring overnlght the gelatinous precipitate is filtered through a sintered glass funnel, the solld dissolved ln hot water, the solution made basic with ammonium hydroxide and the preclpitate filtered off, to yield the l-(l-benzyl-4-piperidyl)-3-phenyl-2-imi-dazolidinone melting at 168-170.

- The solutlon of 10 g thereof in 200 ml ethanol-acetlc acld (1:1) ls hydrogenated over 1 g of 10~ palladlum on char-coal for 8 hours at 50 and 2.7 atm. After filtration through filter cell and removal of the solvent, the residue ls made baslc wlth 25% aqueous sodium hydroxlde and the mlxture extracted with diethyl ether. The organic layer is drled and evaporated, to yleld the l-(4-piperidyl)-3-phenyl-2-imldazolidlnone.

The solution of 48.6 g of 2-(7-methyl-1,4-benzodioxan-2-yl)-acetic acid ln the minimum amount of tetrahydrofuran is added dropwise at reflux rate to the stirred suspenslon of 13.4 g of llthlum allminium hydride ln 200 ml of dry tetrahydrofuran. The mixture is refluxed overnlght, cooled, and decomposed by the addltlon of 13.4 ml of water, 13.4 ml 15% aqueous sodium hydroxide and 40 ml of water. It is fll- ;~
tered, evaporated, the resldue distllled ln a molecular stlll, and the fractlon boiling at 155-165/0.1 mmHg coll-ected as colorless oll, to yleld the 2-(2-hydroxyethyl)-7-methyl-1,4-benzodioxan.

~7~

To the refluxing solutlon of 75 g of 2-hydroxythio-phenol in 660 ml of acetone is added 42 g of potasslum carbonate, followed by the dropwise addition of the solutlon of 33.5 g of 3,4-dlbromobutyronitrlle ln 50 rnl of acetone whlle stlrring.
After 30 mlnutes refluxing, a second, third, and fourth addltlon of 42 g potasslum carbonate and 33.5 g of 3,4-dlbromobutyronitrile ls made. The whole mlxture is refluxed for 20 hours, cooled and flltered. The flltrate is evapo-rated and the residue distilled ln a bulb to bulb apparatus at 185 and 0.5 mmHg, to yield the 2-(1,4-benzoxathian-2-yl)-acetonitrile.

The mixture of 57 g thereof, 85 ml water, 85 ml acetic acid and 32.6 ml of sulfuric acld is refluxed for 48 hours, cooled, poured onto ice and extracted with benzene. The organic phase is extracted with aqueous sodium bicarbonate, the aqueous phase acidifled with hydrochloric acld and extracted wlth dlethyl ether. The extract is drled and eva-porated, to yield the correspondlng carboxyllc acid as an oil. Reactlng it with carbonyldiimidazole and then with the 1-(4-plperldyl)-2-lmldazolldinone as descrlbed in Example 2 gives the desired amlde.

... . . . ,. . . . ~ . .

. .: . . ~
- . ~ . , , - ~: , . ~ ;

794~

Example 6 To the stlrred solutlon of 6 g of 1-[~(1,4-benzodloxan-2-yl)-ethyl]-4-(2-amlnoethylamlno)-plperldine ln 15 ml of tetrahydrofuran, that of 1.58 g of cyanogen bromlde ln 15 ml of tetrahydrofuran is added at 5. After 2 hours the mixture is filtered, the resldue dissolved in the mlnimum amount o~
water, the solutlon made strongly baslc wlth sodlum hydro-xide and extracted wlth methylene chloride. The extract is dried, evaporated, the residue taken up in 50 ml of anhyd-rous ethanol and the solution combined wlth 0.1 g of sodlum methoxide. It is refluxed overnight, evaporated, the residue ta~en up ln water and the mixture extracted with methylene chlorlde. The extract ls drled, evaporated, the residue dissolved in the minimum amount of isopropanol, the solu-tion neutralized with ethereal oxalic acld and the solids collected to yleld the 1-[1-[2-(1,4-benzodioxan-2-yl3-ethyl]
-4-plperldyl]-2-imino-lmidazolldine oxalate meltlng at 215-220 wlth decomposition.

Example 7 Preparation of 10,000 tablets each contalning 5 mg of the active lngredient:

Formula:
1-[1-[2-(1,4-benzodioxan-2-yl~-ethyl~~
4-plperidyl]-2-lmidazolidlnone 50 g Lactose 1,157 g Corn starch 75 g Polyethylene glycol 6,000 75 g Talcum powder 75 g Magneslum stearate 18 g Purlfied water q.s.

,; . .. .

~7~

Procedure:

All the powders are passed through a screen wlth open-ings of 0.6 mm. Then the drug substance, lactose, talcum, magnesium stearate and half of the starch are mixed in a suitable mixer. The other half of the starch is suspended in 40 ml of water and the suspension added to the boillng solution of the polyethylene glycol in 150 ml of water. The paste formed is added to the powders which are granulated, if necessary, with an additional amount of water. The granu-late is dried overnlght at 35, broken on a screen with 1.2 mm openings and compressed into tablets using concave punches with 6.4 mm diameter, uppers bisected.

Preparation of 10,000 capsules each containlng 2.5 mg of the active ingredient:

Formula:
2-(1,4-benzodioxan-2-yl)-ethyl]-4-piperidyl]-2-imidazolidlnone 25 g Lactose 1,875 g Talcum powder lO0 g Procedure:

All the powders are passed through a screen with open-ings of 0.6 mm. Then the drug substance ls placed in a suit-able mlxer and mixed first with the talcum, then with the lactose until homogeneous. No. 3 capsules are filled with 200 mg each, using a filling machine.

Analogously tablets and hard gelatin capsules of the other compounds, described in the remaining examples, are prepared.

~:, - ; ,: .. ; : : , , ~ , . . :-:: .

, .

g~

Example ~

To the solution of 2 g o~ [2-(1,4-benzodloxan-2-yl)-ethyl]-4-piperldyl]-2-lmidazolidinone ln the mlnlmum amount of ethanol, the saturated solutlon of 0.78 g of fum-aric acid in boiling ethanol is added. The mixture is cooled to 0 and the preclpitate collected, to yield the corres-ponding fumarate melting at 190.

Exam~le 9 To the solution of 3.47 g of 1-[1-[2-(1,4-benzoxathian-2-yl)-ethyl]-4-piperidyl]-2-imidazolidlnone (Example 5, No.7) in 10 ml of dioxane and 10 ml of methanol, the solution of 2.8 g of sodlum metaperiodate in 20 ml of water is added dropwise while stirring at room temperature. 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 ¢hloride, dried, evaporated and the residue recrystalized from iso-propanol, to yield the 1-[1-[2-(4-oxo-1,4-benzoxathian-2-yl) -ethyl]-4-plperidyl]-2-imidazolidinone; m.p. 145.

Exam~le 10 The 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 tl:l) and 0.1 g of 10~ palladium on charcoal ls hydrogenated at 2.7 atm. and room temperature until one mole equivalent of hydrogen has been absorbed. The catalyst is filtered off, the filtrate evaporated, the resldue dlssolved in 5 ml of water and the solution made basic with aqueous ammonia. The mlxture is extracted with methylene chloride, the extract dried, evaporated and the residue taken up in the minimum amount of isopropanol. The solutlon ls acidlfied ~ , : . . : ~

7~

with ethanollc hydrogen chlorlde and the precipltate collec-ted, to yleld the 1-[1-~3-(1,4-benzodloxan-2-yl)-propyl]-4-piperldyl]-2-lmldazolldlnone hydrochlorlde meltlng at 282-285 wlth decomposltlon; lt ls ldentlcal wlth that obtalned according to Example 5, No.2.

The startlng materlal is prepared as follows:
The mixture of 10 g of 2-(1,4-benzodioxan-2-yl)-oxiran, 2 g of potasslum cyanide, 2 g of ammonium chloride and 25 ml of dimethylformamlde ls stlrred at room temperature for 3 days. The mlxture is dllu-ted with water and extracted wlth methylene chlorlde. The extract ls evaporated and the residue dehydrated by reflux-ing in a mixture of 11 ml of acetic acid, 11 ml of water and 4 ml of sulfuric acld for 24 hours. The mixture ls dlluted wlth lce, extracted wlth diethyl ether and the extract eva-porated to yield the 3-(1,4-benzodioxan-2-yl)-acrylic acid.
The solutlon of 5 g thereof in 25 ml of tetrahydrofuran ls treated with 5.5 g of carbonyldilmidazole and the mixture stirred for 30 minutes. Then the solution of 4.6 g of 1-(4-piperidyl)-2-imidazolidinone ln 25 ml of isopropanol ls added and the mixture allowed to stand overnight. It ls eva porated, the residue taken up in ethyl acetate, the solution washed successlvely with water,diluted aqueous sodlum hydrox-lde and water and evaporated. The residue ls dlssolved in 100 ml of tetrahydrofuran, cooled ln an ice bath and treated dropwise with 20 ml of a 1.2 molar solution of alane trle-thylamine complex while stirring. After 5 hours, the cold mixture is treated dropwise with 10 ml of 25~ aqueous sodlum hydroxide, the organic solvent phase is decanted from the pasty slurry of inorganic salts and evaporated to glve the 1-[1-[3-(1,4-benzodioxan-2-yl)-1-propenyl]-4-piperldyl]-2-lmldazolidlnone.

; `

Example 11 The mixture of 4 g of 2-(2-tosyloxyethyl)-6,7~dichloro-l,~-benzodioxan, 1.69 g of 1-(4-piperidyl)-2-imldazolidi-none, 10 g of anhydrous sodlum carbonate and 100 ml of 4-methyl-2-pentanone is s~irred and refluxed for 2 days. It is filtered, evaporated and the residue recrystallized from acetone, to yield the l-[l-[2-(6,7-dichloro-1,4-benzodioxan-2-yl)-e~hyl]-4-piperidyl]-2-imidazolidinone melting at 165.

It is suspended in 10 ml of hot ethanol, the suspenslon neutralized with 5N ethanolic hydrogen chloride and the pre-cipitate recrystallized from ethanol-diethyl ether, to yield the corresponding hydrochloride melting at 250.

The starting material ls prepared as follows: To the solution of 60 g of catechol in 200 ml of diethyl ether is slowly added 93 g of sulfuryl chloride during 2 hours while stirring and keeping the temperature at about 0. After standing for 2 days at room temperature, the mixture is evaporated and the residue recrystallized twice from benzene, to yield the 4,5-dichlorocatechol melting at 85-90. 2 53.4 g thereof are added dropwise 5 equal parts of 89 g of 3,4-dibromobutyronitrile, in the presence of 33 g of anhyd-rous potassium carbonate and 800 ml of acetone while reflux-ing and stirring. Another 2C g of potassium carbonate are added, followed by the slow addition of another part of nitrile. After 3 more cycles, using 20 g of potassium car-bonate per part of nitrile each, and sufficient acetone to allow stlrring, the mixture is refluxed for 20 hours. It is filtered, the flltrate evaporated, the resldue taken up in methylene chloride, the solution washed with water, dried and evaporated. The residue ls recrystallized from isopro-panol with the aid of charcoal, to yield the 6,7-dichloro-1,4--benzodioxan-2-yl-acetonltrile melting at 110.

. . .;

.. :, ~ , ~

, ~, . , ~ : .: :, .

~.~17~

The mlxture of 59 g thereof, 24 ml of sulfurlc acld, 60 ml of acetic acid and 60 ml of water is refluxed for 48 hours. It is poured on ice, the resultlng solld collected and recrystallized from aqueous ethanol, to yield the 6,7-dlchloro-1,4-benzodioxan-2-yl-acetic acid melting at 145-147.

The solution of 2.63 g thereof in 40 ml of benzene-tet-rahydrofuran (1:1) is added dropwise to 5.5 ml of a reflux-ing, 70% benzene solution of sodium bls (2-methoxyethoxy)-aluminium hydride under nitrogen. When the addition is com-plete, the mixture is refluxed for 2.5 hours, cooled and poured slowly into 6.7 ml of 20~ sulfuric acid. After filt-ration and removal of the solventr the residue is taken up in methylene chloride, the solution washed several times with saturated aqueous sodium bicarbonate, water and satu-rated aqueous sodium chloride, dried and evaporated, to yield the oily 2-(2-hydroxyethyl)-6,7-dichloro-1,4-benzo-dloxan, boiling at 180-190/0.1 mm Hg. ~ ~ ~

The mixture of 15.2 g thereof, 17.5 g of p-toluene-sulfonyl chloride and 40 ml of dry pyridine is stirred and cooled in an ice bath for 2 hours. Ice is then added to the mixture, the resulting solld ls filtered off and recrystal-lized from ethyl acetate, to yield the 2-(2-tosyloxyethyl)-6,7-dichloro-1,4-benzodioxan melting at 135-138.

~ . ,.

' ~ ~7~

EXA~PL~ 12 450 g of d-1-[1-[2-(~-1,4-benzodioxan-2-yl)-acetyl]-4-piperidyl]-2-imidazolidinone axe added portionwise during 100 minutes to the stirred suspension of 100 g of lithium aIuminiumhydridein 6,500 ml of ~etrahydrofuran at 2-6. The mixture is stirred at room temperature for 19 hours, cooled again and 100 ml of water are added during 100 minutes, at

8-12, followed by 100 ml of 15% aqueous sodium hydroxide and 300 ml of water. The mixture is stirred for 30 minutes in the cold and 90 minutes at room temperature. It is fil-tered, the residue washed with 2,000 ml of tetrahydrofuran and the filtrate evaporated to yield the 4-1-[1-[2-(1,4-benzodioxan-2-yl)-ethyl]-4-piperidyl]-2-imidazolidinone melting at 119-122; []25 =~47.3o (c = 1 in methanol).

1,191 g thereof are dissolved in 3,000 ml of 95~ aqueous ethanol at 60, 120 g of charcoal are added and the mixture is stirred for 5 minutes. It is filteredr the residue washed with 200 ml of 95% ethanol and the filtrate combined with the solutiOn of 441 g of fumaric acid in 7,200 ml of 95% ethanol at 60. The resulting suspension is diluted with 1,000 ml of 95% ethanol and stirred at room tempera-ture for 3 hours. It is filtered, the residue washed with 500 ml of 95% ethanol and 800 ml of anhydrous diethyl ether, to yield the ~-1-[1-[2-(1,4-benzodioxan-2-yl)-ethyl]-4-piperidyl]-2-imidazolidinone fumarate melting at 216-217 with decomposition; [a]D5 =~31.6;tc = 13.73 m~/ml, in water);
it is identical with that obtained according to Example 2.

Thestarting material is prepared as follows: To the solution of 1,134 g of bromine in 1,400 ml of ethyl acetate 472 g of allyl cyanide are added dropwise while stirring for 90 minutes at -10-0. The resulting solution of 3,4-dibromo-.

:
. .

~ 7~

butyronitrile is added all at once to the solution pre-pared from 705 g of catechol and 1,987 g of anhydrous potassium carbonate in 5,000 ml of refluxing ethyl acetate, while stirring at 35 under nitrogen. The mixture is re-fluxed for 4 hours and stirred overnight at room tempera-ture. It is filtered, the residue washed with 2,000 ml of ethyl acetate, the filtrate evaporated, the residue di-stilled and the fraction boiling at 138/1.4-131/1.1 mm Hg collected, to yield the 1,4-benzodioxan-2-yl-aceto-nitrile.

The solution of 1,647 g thereof in 2,760 ml of glacial acetic acid is added to the hot mixture of B58 ml of con-centrated sulfuric acid and 2,670 ml of water and the whole is refluxed for 17 hours. It is poured into 8,200 ml of cold water, stirred for 3 hours,filtered and washed with

9,000 ml of water to yield the 1,4-benzodioxan-2-yl-acetic acid melting at 87-90.

To the mixture of 3,374 g thereof and 3,500 ml of anhydrous ethanol the solution of 2,105 g of e~-a-methylbenzylamine in S00 ml anhydrous ethanol is added and the mixture is stirred for 3 hours at room temperature. After standing at 4-5 for 2 days the salt formed is filtered off and washed with 400 ml of ethanol, 400 ml of diethyl ether and 1,200 ml of isopropanol. 2,070 g of the residue are recrystallized from 2,000 ml of ethanol and washed with 500 ml of ethanol and diethyl ether each, to yield the ~-1,4-benzodioxan-2-yl-acetic acide a-methylbenzylammonium salt melting at 132-133.

1,827 g thereof are added to 10,000 ml of lN hydrochloric acid while stirring for 20 minutes, 6,000 ml of diethyl ether are added and stirring is continued for 20 minutes.
The aqueous layer is separated, extracted with 3,000 ml of diethyl ether, the combined ethereal solutions washed with .. . .. . . .. . .. .. ..

~ 7~1 1,000 ml of water, dried and evaporated, to yield -the ~-1,4-benzodioxan-2-yl-acetic acid melting at 83-85;
[a]D = -55,42. (c = 12.325 mg/ml, in methanol).

The mixture of 400 g thereof, 2,000 ml of toluene and 320 ml of thionyl chloride is stirred at 80 for 3 hours and evaporated. The residue is taken up in 500 ml of chloro-form and the solution again evaporated, to yield the ~-1,4-benzodioxan-2-yl-acetyl chloride melting at 60-62.

The solution of 434 g thereof in 1,000 ml of chloroform is added during 2 hours to the mixture of 400 g of 1-(4-pi-perldyl)-2-imidazolidinone, 4,000 ml of chloroform and 2,600 ml of lN aqueous sodium carbonate, while stirring at 20-23. After 2 hours the organic solution is separated, the aqueous phase extreacted with 1,000 ml of chloroform, the combined organic solutions washed with lgO00 ml of water, dried and evaporated. The residue is triturated with 1,000 ml of anhydrous diethyl ether, filtered and the residue washed with another 1~000 ml of diethyl ether, to yield the d-1-[1-[2-(~-1,4-benzodioxan-2-yl)-acetyl]-4-plperidyl]-2-imidazolidinone melting at 161-163;
[a]D = +5 9 (c = 1, in chloroform).

: :, . .. .

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'` ~.: :
, .
.
, ~

~7~

To the stirred solution of 2 g of 1-[2-11,4-benzodi-oxan-2-yl)-ethyl]-4-(2-aminoethylamino)-piperidine in 25 ml isopropanol is added 1.65 ml of 4 N-hydrogenchloride in ethanol followed by 0.45 g of ammonium cyanate. After re-fluxing overnight, the reaction mixture is evaporated and heated in an oil bath at 130C for 4 hours. The residue is dissolved in 100 ml of methylene chloride, washed with wa-ter, dried over anhydrous sodium sulfate and evaporated.
The residue is taken up in 20 ml of hot isopropanol and 0.77 g of fumaric acid is added with stirring to effect solution. On cooling, the fumarate of the desired 1-[1-~2-(1,4-benzodioxan-2-yl)-ethyl]-4-piperidyl]-2-imidazolidinone is obtained, m.p. 190.

A mixture of 10 g of 1-[2-(1,4-benzodioxan-2-yl)-ethyl]-4-(2-aminoethylamino)-piperidine and 8 g of car~onyl diimidazole in 100 ml of tetrahydrofuran is refluxed over night. 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 SO ml of hot isopropanol and 3.8 g fumaric acid added with stirring. On cooling the fumaric acid salt of the desired 1-~1-[2-(1,4-benzodioxan-2-yl)-ethyl]-4-piperidyl]-2-imidazolidinone crystallizes out, m.p. 190.

7~

The mixture of 10 g of 1-[1-~2-(1,4-benzodioxan-2-yl)-ethyl]-4-(1,2,5,6-tetrahydropyridyl)]-2-imidazolidinone, 100 ml of acetic acid, 50 ml of water and one gram of pla-tinum oxide is hydrogenated at 3.4 atm. and 60 until one molar equivalent is a~sorbed. The reac~ion mixture is cooled to room temperature, the catalyst filtered off and the filtrate evaporated. To the residue is added 100 ml of wa-ter, excess o~ 3 N-sodium hydroxide (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 hot isopropanol, treated with 3.8 g fumaric acid with stirring until solu-tion occurs. On cooling, the fumaric aci~ salt of the de-sired 1-[1-[2-(1,4-benzodioxan-2-yl)-ethyl]-4-piperidyl]-2-imidazolidinone crystallizes. It melts at 190.

The starting material is prepared as follows: i The solution of 10 g of 2-(2-tosyloxyethyl)-1,4-benzodi-oxan, 4.9 g of 1-(4-pyridyl)-2-imidazolidinone and 0.3 g potassium iodide is heated at 90 overnight. The reaction mixture is evaporated. The residue is dissolved in 500 ml o~ ethanol and with cooling and stirring treated with 30 g sodium borohydride, added in portions over two hours. The reaction mixture is evaporated to a small volume, diluted with 100 ml of water and extracted with 200 ml of methylene chloride. The methylene chloride solution is washed with water, dried over anhydrous sodium sulfate and evaporated to yield the l-[l-~2-(1,4-benzodioxan~2-yl)-ethyl]-4-~1,2,5,6-tetrahydropyridyl)]-2-imidazolidinon, which is used as starting material.

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I .
. .. ... .

., . . , , .. . ~. .. . . . . . .

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Claims (18)

Claims:

1. Process for the manufacture of new N-oxacyclic-alkyl-piperidyl-diaza compounds of the general formula I

(I) , wherein Ph is unsubstituted 1,2-phenylene or 1,2-phenylene substituted by one to three identical or different members selected from lower alkyl, lower alkoxy, lower alkylene-dioxy, halogeno or trifluoromethyl, each of R1 and R2 is hydrogen or lower alkyl, each of R3 and R4 is hydrogen, lower alkyl or (R3 + R4) is Ph or lower alkylene separa-ting both nitrogens by 2 to 4 carbon atoms, R5 is hydrogen, lower alkyl or HPh, X is oxo, thioxo, imino or lower alkyl-imino, Y is epoxy, epithio or sulfinyl, m is an integer from 1 to 7, each of p and q is an integer from 1 to 3, but (p+q) = 4, or of pharmaceutically acceptable acid addition salts thereof, which consists in a) condensing a reactive ester of an oxacyclic alkanol of the general formula III with a 1-unsubstituted piperidyl diazacompound of the general formula IV

+ (III) (IV), wherein Z is a reactive esterified hydroxy group, or b) reacting a compound of the genreal formula V with the carbonic acid derivative of the general formula VI

(VI) (V) wherein Z1 is R3 or the grouping R3....R4-NH-R5 and Z2CX' is an ammonium or metal cyanate or thiocyanate, a lower alkyl isourea or thiourea, a cyanogen halide or amide, carbon disulfide or oxysulfide, a carbonic acid halide or 1,1-carbonyldiimidazole, provided that at least one of Z1 and Z2 contains nitrogen, or c) reducing a compound of the general formula VII

(VII) wherein m is an integer from 1 to 7, or d) hydrogenating a compound of the general formuIa VIII

(VIII), wherein each of x and y is the integer 0 or 2 and their sum x + y is 2 or 4, or e) ring-closing a reactive ester of a compound of the general formula IX

(IX) wherein Z is a reactive esterified hydroxy group, and if required, converting a resulting compound in which Y
represents a sulfur atom, into the corresponding A-oxide, and if required, converting a resulting free compound into a pharmaceutically acceptable acid addition salt or a resulting acid accition salt into the free compound or into another pharmaceutically acceptable acid addition salt, and/or, if required, resolving a mixture of isomers or racemates obtained into the single isomers or racemates, and/or if required, resolving a racemate obtained into the optical antipodes.

2. Process according to claim 1, a), wherein Z is a hydroxy group esterified by a strong inorganic or organic acid.

3. Process according to either of claims 1, a), wherein the reaction is carried out in the presence of a basic condensation agent.

4. Process according to claim 1, b), wherein the reac-tion is carried out in a neutral or acidic solvent or diluent when Z2 is metallic.

5. Process according to claim 1, b), wherein the reac-tion is carried out in the presence of a basic agent when Z2 is non-metallic.

6. Process according to claim 1, c), wherein the reac-tion is carried out with simple hydrides or complex light metal hydrides.

7. Process according to claim 1, d), wherein the reac-tion is carried out with catalytically activated or nascent hydrogen or hydrogen generated electrolytically.

8. Process according to claim 1, e), wherein a starting material is used in which Z is a hydroxy group esterified by a strong inorganic or organic acid.

9. Process according to claim 1, e), wherein the reaction is carried out in the presence of a basic conden-sation agent.

10. Process according to claim 1, wherein a resulting compound of the formula I, in which Y represents a sulfur atom, is oxidized with the use of a mild oxidant to the corresponding 4-oxide.

11. Process according to claim 1, wherein there is prepared a compound of the general formula I shown in claim 1, in which formula Ph is 1,2-phenylene unsubsti-tuted or monosubstituted by lower alkyl, lower alkoxy, lower alkylenedioxy, halogeno or trifluoromethyl, each of R1 and R2 is hydrogen or lower alkyl, each of R3 and R4 is hydrogen, lower alkyl or (R3 + R4) is Ph or lower alkylene separating both nitrogens by 2 or 3 carbon atoms, R5 is hydrogen, lower alkyl or HPh, X is oxo, thioxo, imino or lower alkylimino, y is epoxy, epithio or sul-finyl, m is an integer from 1 to 4, each of p and q is an integer from 1 to 3, but (p+q) = 4, and a pharmaceuti-cally acceptable acid addition salt thereof.

12. Process according to claim 1, wherein there is prepared a compound of the general formula I shown in claim 1, in which formula Ph is 1,2-phenylene unsubsti-tuted or monosubstituted by alkyl or alkoxy each with up to 4 carbon atoms, halogeno or trifluoromethyl, each of R1, R2 and R5 is hydrogen or alkyl with up to 4 carbon atoms, each of R3 and R4 is hydrogen or (R3 + R4) re-presents alkylene with 2 to 4 carbon atoms separating both nitrogens 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, and each of p and q is the integer 2, and a pharmaceutically acceptable acid addition salt thereof.

13. Process according to claim 1, wherein there is prepared a compound of the general formula II

(II), wherein R is hydrogen, alkyl or alkoxy each with up to 4 carbon atoms, halogeno or trifluoromethyl, m is an integer from 1 to 4, n is the integer 2 or 3 and X is oxo, thioxo or imino, and a pharmaceutically acceptable acid addition salt thereof.

14. Process according to claim 1, wherein 1-[1-[2-(1,4-benzodioxan-2-yl)-ethyl]-4-piperidyl]-2-imidazolidinone, its ? - and d-antipodes, and a pharmaceutically acceptable acid addition salt thereof is prepared.

15. Process for the manufacture of the new 1-[1-[2-(1,4-benzodioxan-2-yl)-ethyl]-4-piperidyl]-2-imidazolidinone, its ? - and d-antipodes and a pharmaceutically acceptable acid addition salt thereof, which consists in a) condensing a reactive ester of the formula IIIa (IIIa) in which Z is a hydroxy group esterified with a strong inorganic acid or organic sulfonic acid, with the compound of the formula IVa (IVa), or b) reacting a compound of the formula Va (Va) with a carbonic acid halide or 1,1-carbonyl-diimidazole, or c) reducing a compound of the formula VIIa (VIIa) with a complex light metal hydride, or d) hydrogenating a compound of the formula VIIIa (VIIIa) with catalytically activated hydrogen, or e) ring closing a compound of the formula IXa (IXa) in which Z is a hydroxy group esterified with a strong inorganic acid or organic sulfonic acid, and, if required, converting a resulting free compound into a pharmaceutically acceptable acid addition salt or a resulting acid addition salt into the free compound or into another acid addition salt, and, if required, resolving a racemate obtained into the optical antipodes.

16. Process for the manufacture of ?-1-[1-[2-(1,4-benzodioxan-2-yl)-ethyl]-4-piperidyl]-2-imidazolidinone and its pharmaceutically acceptable acid addition salts, which consists in reducing 1-[1-[2-(?-1, 4-benzodioxan-2-yl)-acetyl]-4-piperidyl]-2-imidazolidinone with lithium aluminium hydride, an, if a pharmaceutically acceptable acid addition salt is required, converting the free com-pound obtained into such a salt.

17. A compound of the general formula I

(I), wherein Ph is unsubstituted 1,2-phenylene or 1,2-phenylene substituted by one to three identical or different members selected from lower alkyl, lower alkoxy, lower alkylene-dioxy, halogeno or trifluoromethyl, each of R1 and R2 is hydrogen or lower alkyl, each of R3 and R4 is hydrogen, lower alkyl or (R3+R4) is Ph ox lower alkylene separating both nitrogens by 2 to 4 carbon atoms, R5 is hydrogen, lower alkyl or HPh, X is oxo, thioxo, imino or lower alkylimino, Y is epoxy, epithio or sulfinyl, m is an in-teger from 1 to 7, each of p and q is an integer from 1 to 3, but (p+q) = 4, or a pharmaceutically acceptable acid addition salt thereof, whenever prepared or produced by the process of manufacture claimed in claim 1 or by any process which is an obvious chemical equivalent thereof.

18. ?-1-[1-[2-(1,4-Benzodioxan-2-yl)-ethyl]-4-piperidyl]-2-imidazolidinon and a pharmaceutically acceptable acid addition salt thereof, whenever prepared or produced by the process of manufacture claimed in claim 16 or by any process which is an obvious chemical equivalent thereof.