NO792233L - PROCEDURE FOR THE PREPARATION OF PHENYL PIPERIDE INGREDIENTS - Google Patents

Description

The invention relates to a process for the production of new phenylpiperidine derivatives, especially substituted, optionally monounsaturated 1-benayl-phenyl-piperidine-eid f onael

in which Kj botyr an in 1-position and optionally substituted ben-

zyl substituted, optionally monounsaturated piperldyl residue. Ph is an optionally substituted phenyl residue and B2 means an optionally substituted lower alkyl residue with the proviso that Ph optionally means

tyr substituted 1,2- or 1,3-phenylene»when E2 contains i

alpha position a hydroxy-, hydroxymethyl-, lower alkaoyjl-,

2-oxo lower alkanoyl or 2-hydroxy lower alkanoyl group

and added the further caveat that Kj is different from 4-(l-benzyl)

^piperidyl and 4-(1-ben2yl)-, 4- [1-(monoalkylbenzyl)] - and 4- [1-(monohalo-benzyl)]-1, 2»5, 6-tetrahydro-pyridyl when Ph.D

denotes optionally substituted 1,4-phenylene and E2be*yr lower alkyl

or lower alkane-free or lower 1-hydroalkyl down to at least 2 C atoms and their salts*

The 1 l-position with optionally substituted benzyl substituted" optionally unsaturated piperldyl residue is, for example, a corresponding piperidyl or in another line t, 2, 5, 6-tetrahydro-pyridyl residue. As substitutes for these koauaor, for example i

consideration of lower alkyl, lower alkoxy, lower alkylthio, hydroxy, halogen and/or trifluonaethyl, whereby one or more

of the said substituents, especially halogen atoms, may be present.

The optionally substituted phenylene residue is an example

one optionally with lower alkyl, lower alkoxy, hydroxy and/or

halogen substituted 1,4-or in another line 1,3-phenyl ester,

whereby in the substituted f phenylene residue one can be present, preferably in o-position to the E^bond, or in a different line than oa aubstituont.

An optionally substituted lower alkyl group is, for example, an oxo- or hydroxy-substituted lower alkyl residue, preferably unsubstituted or with hydroxy or, in another line, simply oxo-substituted lower alkyl, i.e. lower alkyl, hydroxy lower alkyl, preferably alpha-hydroxy lower alkyl or oxo lower alkyl , preferably lower alkanoyl.

Before and after "lower" residues and organic compounds should preferably be understood to mean those which contain up to and including 7, preferably up to and including 4, C atoms.

Lower alkyl is, for example, methyl, ethyl, propyl, isopropyl, n-, iso-, sec.- or tert.-butyl, further n-pentyl, n-hexyl or n-heptyl.

Lower alkoxy or, for example, methoxy, ethoxy, propyloxy, isopropyloxy or n-butyloxy.

Lower alkylthio is, for example, methylthio, ethylthio, propylthio, isopropylthio or n-butylthio.

Hydroxy lower alkyl is, for example, 2-hydroxyethyl, 2- or 3-byhydroxypropyl, 4-hydroxybutyl or preferably alpha-hydroxy lower alkyl, such as hydroxymethyl, 1-hydroxyethyl, 1-hydroxypropyl or 1-hydroxybutyl, further 1-hydroxypentyl,

-hexyl or -heptyl.

Oxo lower alkyl is, for example, 2-oxoethyl, 2- or 3-oxopropyl, 4-oxobutyl, preferably lower alkanoyl, formyl, acetyl, propionyl, butyryl, isobutyryl or, furthermore, caproyl or onantyl.

Halogen is, for example, halogen to atomic number 35, which

chlorine or 1 other line bromine or Fluorine.

Salts of compounds of formula I are, for example, their acid addition salts, preferably pharmaceutical usable acid addition salts, with pharmacologically harmless mineral, sulfonic or carboxylic acids such as hydrohalogenidej$ e.g. hydrochlorides or bromides, hydrogen sulphates, sulphonates, e.g. benzyl,

p-toluene or methane sulfonates, sulfaminates, e.g. cyclohexylsulfaminates, or carbonic acid salts, e.g. acetates,

fumarates, maleinates or tartrates.

The invention relates in the first line to a compound of formula 1, in which Rj means an in l-position with an optionally lower alkyl, lower alkoxy, hydroxy, halogen and/or chlorine substituent, benzyl residue substituted, optionally monounsaturated optionally osrd lower® alkyl, lower alkoxy, hydroxy and/or halogen substituted phenylene residue and &2means an optionally 1 i-position or 1 higher as 2-position with oxo or in l-position with hydroxy substituted lower alkyl residue, as medicine pharmaceutical preparations containing these and the aforementioned compounds even with the proviso that Ej is different from in the 1-position with unsubstituted benzyl optionally substituted in the 3,4-position monounsaturated 4-piperidyl when Ph denotes optionally substituted 1,4-phenylone and 3R2 is lower alkyl or lower alkanoyl with 1 at least 2 C atoms*

The invention preferably relates to a compound of formula X, in which Hf means a in the phenyl part optionally with lower alkyl with even. 4 C atoms, such as methyl, lower alkoxy with up to and including 4 C atoms, such as methoxy, hydroxy, halogen with atomic number up to and including 35, such as chloro-, hydroxy and/or trifluoromethyl substituted 3- or 4-(l- benzyl)-piperidyl- respectively 3- or 4-(l-benzyl-1, 2, 5, 6-tetrahydro)-pyridyl residue, Ph denotes optionally, especially in the o-position to ftj, with lower alkyl with up to and including 4 C -atoms such as methyl, lower alkoxy with up to and including 4 C atoms such as methoxy, hydroxy or halogen with atomic number up to and including 35t

as chlorine, substituted 1,4-or alternatively 1,3-phenylene, and R2, optionally in higher than 2-position with hydroxy or in 1-position or 1 higher than 2-position with oxo substituted lower alkyl with to and with 4 C atoms, such as methyl, ethyl, 3-hydroxypropyl, 4-hydroxypropyl, formyl or acetyl, as medicine, pharmaceutical preparations containing these and the aforementioned compounds themselves, <,; with the proviso that K1 is different from unsubstituted 4- (i->benayl)-piperidyl and 4-(1-benzyl-1, 2, 5, 6-tetrahydro-pyridyl or Ph©r different from optionally substituted 1,4-phenylene when R2 is lower alkyl or lower alkanoyl with in minimum 2 C atoms*

The invention preferably relates to a compound of formula I, in which S| in the phenyl part means lower alkoxy with up to and including 4 C atoms, such as methoxy, and/or halogen with atomic number up to and including 35# such as chlorine, mono- or disubstituted 3- or preferably 4-(1-benayl)-piperidyl, Ph means 1,4-phenylene and S2 is optionally in the l-position or in the higher than the 2-position with oxo or in the higher than the 2-position with hydroxy monosubstituted lower alkyl with to and with 4 C atoms, e.g. ethyl, 3-hydroxypropyl or acetyl" and their pharmaceutically usable acid addition salts.

The invention relates in the first line to a compound of formula I, wherein &|means in the phenyl part with lower alkoxy with up to and including 4 C-atoms, such as methoxy, mono-substituted or sod halogen up to and including Atomic number 35» as chlorine, di-substituted 4-(l- benisyl)-piperidyl, Ph prepares 1,4-phenylone and Rz represents lower alkyl with up to 4 C atoms, such as ethyl, and their pharmaceutically useful acid addition salts.

Namely, the invention relates to the compounds of formula X 1 specified in the examples in free form or in the form of pharmaceutically usable acid addition salts.

See new compounds can be produced by methods known per se, such as, for example, taking a compound of formula

in which &Å means a 5-acetylation in the phenyl part optionally substituted bonsylamino substituted, Containing in the 1-position an exchangeable residue X or in the 1,2-position an optional additional double bond, optionally single unsaturated a-peatyl residue, or a salt thereof, ^«ri *g joins RA to the corresponding residue R± and if necessary separates an erhalt-stereoisomer mixture into the components, transfers erhalt-compound into another compound of the formula I and/or converts an erhalt-compound into a salt or an erhalt-salt 1 a free compound or in another salt.

Replaceable residues are, for example, optionally esterified or preferred hydroxy groups or optionally substituted mereapto- or amino groups.

iEsterified hydroxy groups are, for example, esterified hydroxy groups capable of reacting, preferably with mineral acids or hydroxy groups esterified with organic sulfonic acids, such as halogen, e.g. chlorine, bromine or iodine, fluorosulfonyloxy or aromatic or allphatic sulfonyloxy, e.g.* methane-,

ethane-, ethenesulfonyloxy, benzene-, p-toluene- or p-broobenzenesulfonyloxy* As esterified hydroxy groups, esterified hydroxy groups such as lower alkanoyloxy or optionally, e.g.* against halogen eg/or nitro, substituted beaaoyloxy are also taken into consideration against organic acids *

Preferred hydroxy groups are, for example, with aliphatic alcohols versus optionally substituted phenols, preferred hydroxy groups such as lower alkoxy or optionally added halogen and/or nitro-substituted phenoxy groups.

Substituted mercapto groups are, for example, aliphatylthio groups or optionally substituted phenylthio groups, such as lower alkylthio or optionally halogen and/or nitro substituted phenylthio or benzylthio. As further substituted merca<p>to<g>rup<p>s come into consideration corresponding sulfonium esters .. such as di-lower alkylsulfonxum or optionally with halogen and/or nitro-substituted dif eaylsulfoaiura.

Substituted amino groups are, for example, aliphatic and/or with optionally substituted phenyl or benzyl substituted amino groups, such as mono- or di-lower alkylatuino or optionally with lower alkyl, lower alkoxy, hydroxy, halogen and/or trifluoromethyl substituted amino-, benzylamino- or diphenyl- amino groups. As further substituted amino groups, corresponding quaternary ammonium groups, such as tri-

lower ammonium or di»lower alkylamino oxide groups*

Salts of compounds of formula II are, for example, their acid addition salts, preferably mineral addition salts such as hydrohalides, for example, hydrochlorides, hydrobromides, hydrogen sulfates and the like.

The cyclization of the RÅ residue is carried out in the usual way, for example thermally, e.g. when heated to approx. 50 to 250°C., if necessary in the presence of a condensing agent and/or water-binding agent 1 an inert solvent and/or under inert gas such as nitrogen.

Condensing agents starting from compounds of formula II in which X means an optionally esterified hydroxy or an optionally esterified mercapto- or amino group, especially basic condensation agents come into consideration such as, for example, hydrogen alcoholates or amides of alkali metals, e.g. * sodium hydride, alkali metal lower alkanolates such as sodium eubethanolate or sodium ethanolate, or alkali metal amides such as sodium amide or lithium diiopropylamide, further quaternary ammonium compounds such as benzyl triethylammonium hydroxide, or also tertiary organic nitrogen bases, e.g.* pyridln or triethylamine* For cyclization of connecting acid with the formula II, in which X possibly means etherified hydroxy», for example, acid condensation agents such as mineral acids are used, e.g. sulfuric acid or phosforayre, or sour© loaeutbyttore, and for the cyclization of compounds in which H A exhibits a 1,2-double bond csan exo»-pelvis lve.wls acids such as boron trifluoride or zinc chloride are used.

lignode solvents or, for example, during the reaction betisgol zone inert, organic, preferably polar solvents such as lower alkanols, e.g. ethanol, low© alkane* acid amides, e.g. K,N-dimethylforatamide or M-iaethylpyrrolidone, lower dialkylsulfoxides such as diethylsulfoxide, by using quaternary ammonium bases as condensate JonsEaiddel further water-containing two-phase systems, such as ethylene chloride-vaim, benzene-water or omyl alcohol-water.

Vas binding agents are, for example, anhydrido or , ., anhydrides such as dicyclohexylcarbodiimide or phosphorus pentoxide.

Starting substances with the formula II are advantageously prepared under reaction conditions in situ, for example when asm. converts on connection with the formula

in which Rj^ means an optionally single unsaturated α-peatyl rust which exhibits in the 1- and 5-positions a residue X and in the 1,2- and 1,5-positions each an additional double bond, or a salt thereof, optionally substituted in the phenyl part benaylamine or a salt thereof. The new compounds can further be prepared by substituting a compound with the formula

in which R|jmeans a 1-unsubstituted, optionally monounsaturated piperidyl residue or a salt thereof, with an agent which, upon reaction, has any substituted benayl residue in the <_ Ol position, and if desired separates an erhalt-stereoisomer mixture into the components, passes erbalt-combination acid in another connection with formula I

and/or converts an orhalt free compound into a salt or oa-forms an orhalt salt into a free compound or into another salt.

Kidlot for the introduction of optionally substituted benayl residues or, for example, reactive esters, sotafineral acid esters, e.g. halogen, preferably chloro, bromo or iodohydrogonic acid esters, or organic sulfonic acid esters, e.g. s j ico tau-, ethane-, otea-, won^cn-, p-ioIuQl«> ei lor pobrotuben&ensul-i'onic acid esters corresponding to benzylalfcholor or under reducing conditions corresponding to bon^-aldelbidoor.

Xnnxøringoa of the eveatually substituted benzyirost finnex'stood by reaction ued do above specified fco noodles on usual food, oie necessary in ot inert solvent part, in the presence of ot condesaussion middcl and/oilor at pre-eye or reduced 'temperature, i', okay water approx. 0° tii approx. 15Ci°C.

When OESotaing against reaktionsyktigo ben^yl-ostor©Ejan works in solution suiidies which above reaktionodeltagorno is inorto, od necessary a nerve*' of oi basic.©ad ensas joaouiduoi, at elevated or down&att theatera tur, i* «ex. at approx. 0° to 150°(i., and/or uador xsiort j^ass aoa ni pheromone.. Lia si ske kon=» densation agents areOiisoispoivio do organic bases a out alkuli-motall- oller joititilka.iiiaetailhyurokayder oller -carbonates, 2'. oka. uatriuEjhydro^syd, kaiiuMiydroxide, cal s-iutiihydr oxide, carbon iuucarbonat or^aisiutakapbonnt, or tertiere organic nitrogen bases, soa yyriuxu or triotylaaiJLia. ugaod©. solsiiagsuxdie are©køeispQAviiu ketones soe) lavore di-alkylcoto&å©r, x ".e.g. acetone, alcohols, souj lower"alkaaols, e.g.e.so aeSanoi, otanoi or a&ylalkoaol, eveatuoit h&logoaorte hydrocarbons aom benzene, tolnaol or Lte ty lenk lor id, oller JJ,N=disubstitu» orte lower 'alkanoi a&iides such as dxactylloroauid oller iS-methyl-pyrrolidoa..

Vod oiiisetaiiigea down bon^aldehydor by reducing be©°tingelsor aavexidor saan so&s reducing agent for aminoalkyleriag common© uldier as loitiueetalluydride, . i'.eg. aatriusaborhydrid or©r iortrlaasvis aati-iuu-cyaaborhydx*idfka&aly tisis. activated hydrogen or hydrogen in iiarver of on hydrogenation catalyst, such as palladium-, piatia- or aikokaitaiysutor, i<*>.eg» platinum, evetuolt on carboa,, platino&syd, palliadiucu pk carboa or iianey-iiikcol, further ctauric acid or its salts. The turnover in ncsrvtcr of the indicated • redukjoasEiiidels is carried out in the usual way, advantageously x an inert solution ciideleuauor aeutral bo tingels or else osu necessariat "weakly acidic conditions, in the case of non-analytical hydrogen reactions ota nevedven" djig cod elevated pressure, f.ok. to approx. 10 bars. As iaorte up-løoaiagSEidlor nuveacos. i'ortriaasvis alcohols socs lavare alka-aoior, 'e.g. uetauol oi Jer etaaol, evontuolt in mixture with vasa.

In the application of lettøotaili&ythridor arbidos* without advantage at neutral and voa iiatriucicyasiføorhydride uaxder weak acid© be ting© le or, f.tuis. vod ea.. yH 3 to 6,<q>é<q>s aiaa utforox-catalytic© hydrorijagcx- advantageous in saærvas: av©ri jaineralic acid, i<*>«ex. hydrochloric acid respectively ousottor realtsjøiiecoEa<p>oxysiteno with formula III in fora of corresponding acid addition salts, i'.ex.3QS1iihydrochloride..

Starting atom for taud foraelen 111 can be prepared' on i and for sog known© .uetodor» compound sod foreaolar lii, in which Kg means in alpha-stiliag with oxo substituted lower alkyl, orliai(S©s f.ekø. idet iaaa oasettor sn forbindoiso aad forete fief

in which botyr o<q>nitrogonatoiu-protected, f.oke. acylex-t, e.g. lower alkanoyl root, possibly simply unoated plperidyl root, in the presence of a leuis-eyre, e.g. alwaiaiuia trichloride, caed a ro-action capable lower alkaic acid derivative, f.eko. ors laver©alkairi-cartoonic acid aahydride oilor -chloride, and a vs pa in tor b©skytols©sg:rup-ttexi pd usual aåto, e.g. by acid-catalyzed hydrolysis. Vorbindolsor tsod the formula 111, in which i%g means for-tuyl, can advantageously be obtained ©ttor vauxilgo f orunaieringsuaotodor, e.g. by turnover of on connection eiod forcieien

Gied SJ,M«disubstituorte forsnataldor such as N-ej© tyl»forman in lid oller diC30tylforaatQid, 1 mæmar of phosphorus oxychloride©Iler tcod dimotyl-foxrøataid-ootosulphate.. Forbindoisoped for<a>élea 121, in which H2 u©d hydrocoy substituted lavoro alkyl, can e.g. orhold starting from corresponding forbiixdolso mod formula III, in which Hg is mod oxo substituted lavoro alkyl, iuod reduction, e.g. tacd aa« triUEibox^hydride in ©sx lavoro alLonol. Forbindoiso mod x^orstene III, hvox-i kt», .©r toratinai-hydroxy-substituted lavore alkyl, kais analog is prepared by reduction of estoro, sota lavoro alkyl ester,

•corresponding .oiaoga-carbokoy lavore alkylfo&yipiporidine-forblndel-sor can for example be rodusores suod litiuiaalusairiiuathydride in diotylctor©Iler tstrahydrofuran. i?orbia.dols©taod phonaolen III, in which I4g or laver©'alkyl, can for example be obtained from compounds containing røofc kg ocd hydrousy substituted lower aiLyl9raod

reduction of &2*** lower'alkyl, preferably under the influence of hydrogen in the presence of a hydrogenation catalyst, • e.g. palladium on carbon, preferably in organic acid sod .oddiksyro.

The new compounds can then be further prepared in the same way as the original compound

in which Hq botyr.cn taed hydrogou-exchangeable substituted residue and/or possibly dobbeIt bond containing residue , or ot salt thereof, reduces the rust kctii k-j and oia desirably separates an erhalt's storeoisomorbiandin<g>in the column ten©, overforor esa erhalt-forfoindols© in another compound iaed forjueloa X e<g/ or converts an ©erhalt free compound into a salt or ot erhalt-salt into a free compound or into another salt»

I2ed hydrogen exchangeable groups or for example reductive eaed hydrogen exchangeable groups such as ovoatual functional osidaai-JiGtio oxfohydroxy- or aercaptogruppor or organic oul-fonyl groups. Functionally converted oxo groups or, for example, oxo- or thione groups, scnicarbazone groups or ©vomtual i^ position with organic sulfonyi such as bondene-, p-toluaol-, p-tarom-benzol or uotur.sulf ouyi, substituted© hydrazone group*

Functionally converted hydroxy groups are, for example, preferred or esterified hydroxy groups, as well as functionally converted or capto groups or particularly preferred parent capto groups in consideration. Preferred hydroxy groups are, for example, lower alkoxy groups such as aethoxy or ethoxy. For-©stored hydroxy groups© are for example iaod a taineral acid or organic carbonic or sulphonic acid esteredo hydroxy groups. Organic carboxylic acids are e.g. optionally substituted bejisol acids, alkane, preferably lower alkane carboxylic acids, e.g. benzo or acetic acid. Organic sulfonic acids are e.g. b©ns©n°, p-toluene-, p-broiabenzene-, taétano-, ethane- or othenesulfonic acid. Ctineral acids are preferably halogen hydrogeic acids» e.g. chloro-, bromo-eilor iodohydrogenayre. Preferred tercapto groups are, for example, lower alkyloxy or lower alkonylated tercapto groups such as ethylthio, octylthio or ethylenethio.

Optionally functionally added oxo groups are also especially in the alpha position to the nitrogen atom, optionally esterified hydroxy groups and preferred aercaptogrnaps are especially bound to the bonylic C atom. Preferred hydroxy groups are located especially on the C atom of a C-J-J double bond. Any additional double bonds can be oriented both ecso- and endo-cyclically.

There reductive conversion of &q in Ll^outfort in the usual way «ed oasotization with a suitable reducing agent.

Sea reduction aiddel kosmaor especially in consideration! Nasating, for example exposed to the influence of a compound feed labile hydrogen on the number, e.g. a protonic acid©sota a halogenhydrogen acid or lower alkasicarbonic acid, on iron or possibly aiaalgorted zinc, magnesium or aluminum or taed water on, preferably ataalgered aluniniura, magnesium or sodium, e.g. hatriuiaaiualgae, or for example produced by hydrogenation catalyst soa a nickel-©Iler©del-laetal catalyst, e.g. vod Ikmoy-oller possibly on chemical or on©n bsrebonded foro, e.g. as oxide, present platinum, sop platinum on carbon or, poa platyhokeyd or by homogeneous odeliaétal catalystsor sota triphenylphosphine-platinum-chloride or triphenyiiosphine-rhodiuiachloride, catalytically activated hydrogen, further © low-valued transition raetal compounds sos tin-II-©Iler chromium-II- salts, e.g. tin-II chloride, or hydrides such as calcium hydride or borohydride-tetrahydrofurancox complex or dilettiotal hydrides such as lithiuaaiulfiniurahydride, ovone-tuolt in a mixture with aluciniua chloride, natriuc3-bis-(2-E5otoxy-ethokey)-aluciniucaihydrid or natriuta-tris-( 2-diethylamino-ethoxy)-alucylaminohydride, atriutinoborohydride or sodium cyanoborohydride.

The turnover can be carried out on a basis which for the turnover in question has been found to be acceptable in the literature.

Optionally enlarged or substituted, hydroxy groups, ketonic oxy groups and/or groups Rq sota contain at least one double bond, bound to a benayl carbonator, can by ordinary reactions, e.g. as stated above, is reduced with catalytically active hydrogen, for example hydrogen in grains of palladium on carbon, oa necessary in an inert solution such as a lower alkanol, a lower alkanol or an aliphatic ether, e.g.* in ethanol, acetic acid©© Hear dioxane, and/or vod elevated tea temperature.

Horses Rc containing ketonic oxygroups»sulfonyl groups and/or preferred thieraptogroups can be reduced by ordinary reaction»eg, sota above froeastilt, nas-cerendo hydrogen»for example after fresagangsiaat of Clecaconsst, preferably with zinc and hydrochloric acid.

Hester Uq which contains a halogen bound to the C atom in a C-N double bond with a preferred hydroxy group and the soot contains at least one, additional double bond and/or lactaoic, respectively ataidic oxo groups, can for example be reduced by normal reaction with a suitable dilettol hydride as a of the aforementioned, is necessary in an inert solution part and/or at elevated temperature, e.g. boiling point temperature, starting from halogen compounds exeiapolwise with sodium borohydride in water, alcohols such as ethanol, or ethylene glycomoyaeryether, or amines sota pyr in din, triothiamine, with natriuta-bis-(2-iaethoxyotoxy)- aluminum miniurahydride in aromatic or aralphatic hydrocarbons sota beiisol or toluene, or taed natriuGJ-tris-(ditaotylatainoethoxy)-alutniniuiahydride, or starting from lactotaer or auidcr for example with low-malutainiurnhydride 1 an aliphatic oter, e.g. in diethyl ether, tetrahydrofuran or dioxane, if necessary at boiling temperature.

Substituted hydraano groups, e.g. (p-toluenesulfo^nyl)-hydrazone, sont contained in res tor Kg can sop indicated be replaced by taed hydrogen by ordinary reaction taed©t dilettaetal hydride, e.g. taed sodium cyanoborohydride in hexamethylphosphoric acid triamide, oat necessary at elevated temperature. Semicarbazone or unsubstituted hydrazone groups that are contained in residues Rq can, for example, be reduced by ordinary addition against a strong base, for example by the method from Uolf-Kishnor. taed ot alkali alcoholate, e.g. down sodium ethanolate, if necessary under elevated pressure and/or at elevated temperature or after modifications from Huang-Minlon taed an alkali metal hydroxide, e.g. potassium hydroxide, i ct inert, high-boiling part of solution, e.g. in di- or triethylene glycol or diethylene glycol taonoBiethyl ether.

In a preferred embodiment of the present method, the reaction starts, for example, from a compound of the formula IV, in which the residue Hq means a residue lij, at least one carbonyl group bound to the nitrogen atom, for example on in the 1-position etod optionally substituted benaoyl substituted plperldyl or 2 - piperidone residue or else in 1-ethyl alcohol with optionally substituted bonsyl substituted 2-piperidone residue, and reduces the oxo group(o) without addition with an ognot dilettaethyl hydride, e.g. moti- li-titaaaluiainiuobydrid in an otter, e.g. in diethyl ether or totra-hydrofuraa, oa necessary at a suitable temperature, e.g. at boiling point toiispora turn.

In a particularly preferred embodiment, one starts from a compound of the formula IV, in which &c botyr an optionally substituted Kf-bønaylpyridinium ester s in the phenyl part of the beasayyl ester and reduces at least two of the double bonds in the gyridinium ester to single carbon bonds. If hydrogen is used as a reducing agent in the form of a platinum-©Iler riiodiocatalyst, e.g. piatin on carbon, platinum oxide, or triphenyphosphin-fihodicia-chloride kotaploxote, or litiuiaaluuiniuahydride in an ether, eoe diethylether©Iler tetrahydrofuran, laan preferably obtains compounds taed forael 1, where H-j contains an aetated piperidyl residue.

In contrast, aan is obtained by using weakly acting di°lottiaetal hydrides, e.g. sodium borohydride in on lavoro alkanol such as ethanol, preferably connecting Is or seed formula I, in which R|contains a 1, 2, 5»6-tetrahydropyridyirosfc.

Likewise, the carboxyl group ooeq can optionally be present in salt form, e.g. Natriuosalt, copper salt or assaoniuosalt, or replaced by hydrogen. The carboxyl group is preferably bound to the C atom to which the rust -PhKg is bound in the ruston Hc. The exchange of this with hydrogen is preferably carried out vod dém' carboxylation, oxoapolwise by increasing to approx. 100 to 250° CWota necessary in a high-boiling endo solution toiddol, f.ok3« in ethylene glycol, ditaetyforiaaoiu, ethylene glycol EJonoeotylots or diphenyl ether.

The starting materials aed forael IV are known or can be prepared by methods known in and of themselves.

Compounds with formolon IV, in which &c butyr one to don taed a lower alkylphenyl rust -PMi2 connected C-a totn taed hydroxy-substituted, optionally in the phenyl part substituted 1~benzylpiperidyl rust, can e.g. is prepared by the addition of the corresponding N-bacylpiperidone but by the action of a lower alkylhalobenzene with hydrogen, or relatively lower alkylphenylEaagne» alcoholichalogonide, for example against foriseleai i^-Ph-i-SgDr, preferably in an ether such as diethyl ether or tetrahydrofuran. Analogously, the starting st or foot can also be prepared 1 which Bg contains oxo-or hydroxy, as aaa starts from oxo-or lower hydroxy-alkylhalobenzone, in which the oxo or hydroxy group is protected, e.g. okso is acotalisort, and spins off the management group after the completion of the transactions.

Compounds against the foraol IV, in which Uq means on taod esterified or preferably hydroxy substituted, possibly .1 the phenyl part substituted by 1-benzylpiperidyl residue, can be obtained from corresponding, e.g. sosa above Retainable hydroxy compounds, in that taaa esterifies ©llér foredbnarirj hydroxy group in ordinary tadto, e.g. with the halogonoring part ses thionyl chloride or phosphorus tribroide, and transfers in halogen or in a lower alkanoyloxy^ tBöd ot lower alkane carbonic acid anhydride sota acotyl chloride, or vod otasotniag to ot lower alkoxy with a lower alkanolate such as nati-iutaetaaolate.

Compounds described IV, in which the residue H contains a preferred morcapto group, can be obtained exemplarily by adding a corresponding one, e.g. sora stated above is-holdable, halogen f compound so taed a lower alkalinity tall alkyl thioate on a regular basis.

Compounds according to preface IV, in which the residue tic contains an aulfonyl group, are for example available by ordinary oxidation of corresponding thioethers, preferably using an organic poric acid such as SB-chloro-perbeasonic acid. The aed sulfonyl substituted compound taed formula IV taed the residue -Ph-Rg bound to the C atom can further be obtained by condensing taan on ordinary tflat*benzylsulfone taed dolsfkruktur K2-Ph-CH2-SO2- csed corresponding to 1,3-dihalo-, sota 1,5-dibromo-N-benzyl-pontane respectively

- pretty.

In an analogous way, a compound of the formula IV can also be considered, in which the residue Uq contains a carboxy group bound to the C-atom to which the residue -PhRg is also bound, as one condenses in the usual way the phenolic dioxyroster containing the structure I^-Ph- Ciu^-COG- taod corresponds to 1,5-dihalo-I>J-b©n2!yi-pentane and -pentoa respectively.

Compounds of the formula I¥, in which Eg butyrone is optionally substituted in the phenyl part with a 1-benzyl-2-piperledone residue, can for example be prepared by using the usual taå©cycliser to correspond to 5-ben2<y>lataino-(1Lj-<f>enyl) -valoric acid or a reactive such as an ester or an anhydride thereof. On analogue Etåtø aan can also prepare compounds against forethelone IV in which means an optionally substituted 1-benayl»2,6-dioxopiperidyl rust. Ber-wood starts from a corresponding kg-phenylglutaric acid © or a reactive derivative, e.g. a diester or anhydride, and reacts in the usual way towards a corresponding bonzylamine.

Compounds of the formula IV, in which R contains a functional converted oxo, can for example be obtained as moa in corresponding oxo compounds functionally converts the oxo group(s) in the usual way, e.g. by reaction with seaicarbazide or optionally transfers substituted hydra2in in aoaicarbasono, respectively hydrosono. Analogously, iaan can transfer oxo compounds with the formula IV by alphacylation, e.g. cod lower trialkyl oxonium salts, in corresponding ouol- or laetitaetor. Usubatiated hydrazonophorbindolsor against the foraol IV can thereby be advantageously prepared in situ, by carrying out the reaction with hydrazine at an elevated temperature, e.g. at approx. 100 to 250°C, if necessary in a highly concentrated solvent sota di- or triethyleneglycol©lier diethyleneglycolianomoethylether, and in the presence of a base, e.g. a metal alkoliolate sota natriustaethanolate, or an alkali metal hydroxide, e.g. ca ilurahydroxide.

Compounds of the formula IV, in which the residue Rq contains an optionally substituted benzoyl group in the l position, can for example be prepared by substituting a compound of the formula l& £ - Ph-&2(IVa)»in which Rq\ is unsubstituted in l -position, preferably a compound of the formula Hg-Ph-R2(il)" in which Ig means an unsubstituted in the l-position, optionally monounsaturated piperidyl residue, taed©t bemsoylation part, e.g. benzoyl chloride, if necessary in the presence of a basic condensation ion salt, e.g. sodium hydroxide or an organic nitrogen base, e.g. pyridine or triethylamine. In an analogous way, oxo compounds according to IV can be obtained, in which Rq means an optionally substituted N-benzylpyridine residue, with æaa quaternizing a corresponding Mg-phenylpyridine with a reactive derivative, e.g. the bromide of a corresponding benzyl alcohol.

The new compounds in which Kj means ©n in the l-position with an optionally substituted benzyl substituted alcohol unsaturated piperidyl residue, can further be frotostilled as the taan in a corresponding compound with the formula

in which the Sjjbetyr©n in the l-position with optionally substituted beaayl and by an alpha, bota-elimination available residue substituted piperidyl rust, or ot salt thereof, eliminates this to the same with a beta-standing hydrogen atom, and if desired separates an erhalt Stereo mixture in the components, transfers the obtained compound into another compound of the formula I and/or oa-forms an obtained free compound in a salt or an orhalt salt in the free compound or in another salt"

Costs sos together with a hydrogen atom standing in the beta position can be split off are, for example, any pre-redo hydroxy groups, possibly preferred or pre-redoated Eaoreapt© groups, sulfonyl groups, sulfinyl groups, sulfonyl groups and ammonium groups. For example, ester redo hydroxy or morcapto is against a mineral acid soa on halogenhydrogen acid©, e.g.* against bromine or hydrogen chloride, esters^ hydroxy or with an organic acid such as a lower alkane carboxylic acid, e.g. acetic acid or aed xantogenoyre, esterified hydroxy or morcapto. Preferred morcapto is sometimes lower alkylthio, ooia aethylthio ©Iler ethylthio, ©Iler©vontuolt substituted phenylItlo, e.g. fe<° nyl- p-aøtylf®nyl« or p-broiafenyItio. Sulfinyl and sulfonyl groups or, in particular, of the above-mentioned preferred organic groups, derived sulfinyl or sulfonyl groups, e.g. methane, ethane, benzene, p-tbluol-aulfteyl © dialkylsulfoniiata groups so<q>diaethylsulfoniuta. Ammonium groups are usually lower di°alkyl- or trialkylss<p>raoniuu groups, soa diethylaEataonium or triotylaEjaoniucs or lower dialkylacsinoxide groupings, such as diotylaialinoxide groups.

The elimination is carried out in the usual way and, if necessary, 1 ilsrvcr of catalytic and/or avøpaltningøproduct«bind©ade nidior, at an elevated temperature, e.g. at cae 50 to 200°C by e.g.Deatllative especially azotrope-distillative .removal of r©°= action products, and/or under inert-gas soa nitrogen, for=> stepwise in a laort oploeningømiddjfeU Catalytic©Eiidier©r eliko sora eased©limineriiragon of ekoeapolvio water, avov©lhy>= drogoa, orgaaioke oyrer, ammonia and o©kundar© amines 0 pro pr©= tonic acids, f»oka. mineral acids, preferably chlorohydrogonic acid, sulfuric acid ©Hor alkali metal hy<y>dro<g>ensulfator, phosphoric acid, p-toluenesulfonic acid or ion exchangers, or weak ©nauclophilic bases, e.g., collium hydroxide, so lettor the elimination!of mineral acids. Cleavage product-binding agents or, for example, water-binding agents such as dicyclohexylcarbodiimide, or sulphur, hydrogen or mercapta-leaving agents such as tungiaetal salt, e.g. copper, zinc or silver salts, further©aaiaoai&kk- respectively amine binding agents such as mineral acids.

The starting substances with the formula V were known or can

produced in a manner known per se.

Compounds with the formula V, in which il^ contains hydroxy or inercapto to the C»ato% connected to the rust -PhlR^ can be obtained, for example, by reacting a corresponding i-beasyl-piperidone or 1-bonsyl-plporidine-thione with an optional to an oxo-ellor hydroxy group intertaedior boskyttot ll^ > phenylmagnesium halide, e.g. with the formula R2-S<>>h-MgBr.

£)e new compounds can be vidcro prepared by using a compound with the formula

in which R-tø means a 1 a residue R^ transferable group,©Iler et.salt thereof, transferor HE in fl2and if desired separates the obtained stereoisomer mixture into the components, transfers the obtained compound into another compound with the formula X and/or converts© a free compound obtained in a salt or a salt obtained in a free compound or in another salt.

In residues li2 transferable groups are, for example, different from Sg and reductively and/or solvolytically in R2 transferable groups, for example unsaturated and/or functionally converted oxo and/or functionally converted hydroxy substituted lower aliphatic residues.

Functionally converted oxo groups or, for example, thioxo, above-twin substituted iraino groups or acetalized or thioacetylserto oxo groups, further hydrated © oxo groups and esters of the same

As substitutes for imiaio kocmer okeocspelvio in consideration of optionally substituted feayl, lower alkyl or further©hydroxy©Hor mod lavore 2-sulfoaylaikyl,. ooa lavoro 2<=besiaen° sulfonylalkyl ©Here 2-(p-toluenesulfonyl)-alkyl, and substituted aiaino. Acotalized ©oxo groups are, for example, aed ot laver© alcohol, such as methanol or ethanol, ©Iler ot laver©alkandiol,3 or ethylene or propylene glycol, acotalized© oxo groups. Analogously, vod thioacetalized oxo groups are understood, for example, against lower alkanethiol, sosa methyl or ethylmorcaipitan, ©Here a lower alkandlthiol, such as 1,2-dimercaptoetaa or 1,3«,tliai©r<» captopropane, thioacetalizedto oxo groups» Ester©with hydrati » sorto oxo groups or, for example, such©with a caiaør&løyr© soaa©n halogenohydrogen acid, e.g. chlorhydrogoacido.

Functionally converted hydroxy groups are predominantly esterified hydroxy groups. Substituted hydroxy is, for example, lower alkoxy such as methoxy or ethoxy or optionally substituted phenoxy. Esterified hydroxy er'exem-. pelvl8mod©n minoraløyro, as a halohydrogen acid©, fores terot hydroxy, e.g. chlorine or bromine, mod on organic sulphonic acid, as a lower alkane or an optionally substituted benzene sulphonic acid © esterified hydroxy, e.g. Methane-, methane-, p-toluene-, p-bromobenzene- or acetylenesulfonyloxy, ©Iler with a carboxylic acid, such as a lower alkaayro©Ir optionally substituted benzoic acid, or optionally partially esterified or or<*>amidated carboxylic acid esterified hydroxy, soa lower alkaoyloxy, e.g. acetoxy, benzoyloxy, lower alkoxy', e.g. methoxycarbonyloxy or corbamyloxy.

As groups ur-, chamber especially 1 consideration.

Lower alkenyl, such as vinyl, allyl or metally, lower alkyl, such as ethynyl or 1-propynyl, optionally esterified Here aahyd-ridisort carboxy-, carboxy lower alkyl and carboxy lower alkeayl groups, which correspondingly lower© alytoxycarbonyl, ©yl halocarboyl containing residues, esterified or preferably lower hydroxyalkyl(en)yl residues, such as lavor©alkanoyloxy-or possibly benzoyloxycarbonylIresters, lavaro alpha-or omega-haloalkyl residues, omega-sulfonyloxy-, e.g. omega-(p-toluenesulfonyloxy)-lower alkyl residues, or lower alkyl ethers of lower alkyl onols, further thioxfpalkyl residues or geminal© lower dialkoxy or alkylenedioxy alkyl groups.

The reductive © transfer in ESj. is carried out in and of itself known©methods,©for example by catalytic hydrogenation or reaction with a light metal or dilettmetal hydridor0 In this way, one can reduce©lower alkenyl, lower alkynyl for example by the influence of catalytically activated hydrogen, such as hydrogen in .V. presence of a hydride catalyst, preferably a nickel, platinum or rhodium catalyst, e.g. Ran oy-nick© 1, pla tisa or platinum oxide on carbon or ot platlnchlorldol- or rhodium-um chloride-triphenylphosphine complex, to lower alkyl. Thereby, one usually works with preferably 1 ot inert solvent, such as a lower alkanol, e.g. methanol or a lower alkanecarboxylic acid, e.g. acetic acid, if necessary at elevated pressure, e.g. up to approx. 25 bar, preferably in a closed vessel. Analogously, one can also reduce halocarbonyi or halocarbonyl lower© alk(en)yl to lower hydroxyalkyl1.

Lower hydra a onalfcy1 K£can further be reduced in the usual way©vod base treatment, e.g. to the method of tfolff-Kishner, med©t alka lim© tal lalkoholat, e.g. with natriutoaiota nolate, if necessary under elevated pressure at approx. 100 to 250°C, or according to Huang-Minlon with an alkali metal hydroxide, e.g. with potassium hydroxide, in an inert, high-boiling solvent, e.g. di- oi-io./..Oiiglycol, to lower alkyl Ii2.

Furthermore, oan can, for example, reduce any foredrotio

.oller analyariclyserto carboxy- or carboxyl-lower alkyl group by reaction with light metal or dilite metal hydride to oxo- or lower hydroxyalkyl. For the reduction to lower oxoalkyl, lower alkyl lithium aluminum hydrides are preferably used, such as diisobutyl or triisobutyl lithium aluminum hydride, whereby for the reduction to lower hydroxyalkyl, lithium aluminum hydride is preferably used in an ether, such as diethyl ether or tetrahydrofuran. In the aforementioned reaction, one preferably works under inert gas, e.g. under nitrogen or argon, if necessary during cooling or heating, e.g. at approx. - 20 to ♦ S0°C. In an analogous way, one can also prime© halogen or sulfonyloxy containing halogen-respectively lower sulfonylalkyl groups reduce© to lower© alkyl against a carboxylic acid or the partially enlarged redo

amidated carboxylic acid esterifiedV, lower hydroxyalkyl groups \to lower hydroxyalkyl. Analogously, as indicated, substituted lower hydrazone alkyl can also be reduced to lower alkyl, for example with sodium borohydride and xoxaphosphoric acid triamide.

Similarly, reduction is to be understood as the reductive ©lower alkylation of possibly esterified© ©Here anhydridloort©carboxy- or carboxy lowero alkyl group por K-^aed lower©al-kyisaetal compounds to oxo-or hydroxy lower alkyl groups Kg. Lower alkyl metal compounds are, for example, the same, such as a total radical with a group aed foraol -W<1>, -H<I3:>-Hal ©Iler 1^/ 2, in which 14^" is a metal atom from group I, r-3 Xi- means ot cio» tall atom from group II in the periodic table and Hal means halogen, sota chlorine, brota or iodine. Preferred taetal radicals of the mentioned species are such aed formula -Li, -23gHal>= and -Gci/2.

Possibly functionally converted carbokai groups are available, for example, in salt form, such as beef samp©! 1 form of alkali metal salt, e.g. such as sodium salt, ©Iler sop anhydridisorto carbokaygruppor, preferably aakydridioort mod on halogen hydrogenear© such as fluorine, chlorine, bromo- or iodo0as foreator-ed carboca<y>gru<p>por, as lavoro alkoxycarbonyyi, or©vontuolt substituted benzoyloxycarboyl or disubstituted carbamyl groups, such as lower N,N-dialkylcarbamyl or 1-imidazoline carbonyl. The reaction with possibly functionally converted carboxylic acids towards the formula VX with the above-mentioned lower alkyl metal compound© is carried out in the usual mdto. preferably in an inorganic solvent such as an ether, e.g. in diethyl ether ©Hor totrahydro-furan, a hydrocarbon, e.g. bonson,©iler mixtures of disa©, if required during cooling or during light waiting, e.g. at approx. -fcJO to approx. 100°C, e.g. above boiling temperature, and/or under mineral gas, e.g. under nitrogen. Depending on the starting material used and the reaction conditions, ketones are obtained (Kg not oxo lower alkyl) or higher alcohols (Hg hydroxy lower alkyl) against form I. o<? application - of reactive lower alkyl shagn©siuEshalog©nid©r©Iler lower lithium alkyls, and vod normal or elevated temperature, e.g. water approx. 0°C to approx. 100°C, mainly © compounds with the formula I, in which Sg & r lower hydroxyalkyl, and vod reduced temperature, e.g. at -80 to 0°C, ©Iler by use of less reactive lower alkyl metal compounds, e.g. lower alkyl cadmium compounds, under normal temperature conditions preferably compounds of the formula 1, in which &«-> is okoo lower alkyl. Obtain an analogous way of oxophorbindoloo against the formula I, in which Rg is lower alkyl, ©rholdoe idot oa» converts em for«= biadols© aed the formula VI, in which R~ is halogen- or auIfonyl-oxy lower© alkyl, with one of the mentioned © lower alkyl motal compounds, especially a lower litim alkyl.

By solvolysis, one can, for example, transfer at least a functionally converted oxo»©g/or hydroxy group containing a residue Kg into an oxo-or ©a hydroxy group containing residue Eg. For example, compounds of the formula VI, in which lig contains thioxo, possibly substituted ioino, geminal or preferred hydroxy groups bound to a double bond, can be hydrolyzed to compounds of the formula I, in which kg means oxo lower alkyl, or a compound of the formula VI, in which the ester contains hydroxy, to compounds similar to formelon I, in which £2e^r lower hydroxyalkyl. The hydrolysis is carried out in the usual way, for example in the presence of a basic or acidic hydrolysis agent, if necessary in the presence of a solvent and/or at an elevated temperature, e.g. at approx. 20 to 150°C.

Basic© condensing agents©r exoiapelvls alkali metal-, ammonium-©Iler chloralkali metal hydroxides ©Hor corresponding carbonates, e.g. sodium, potassium or calcium hydroxide, ammonia ©Hor potassium or sodium carbonate• Acid hydrolysis© agents or for example protonic acids such as mineral acids, e.g. sulfuric or sulfuric acid, sulphonic acids, e.g. p-toluenesulfonic acid, or carboxylic acids, such as acetic acid©. Inert solvents are, for example, with water-miscible solvents that reduce alkanol, e.g. methanol or ethanol, ketones, e.g. acotone, amides, e.g. dimethylformaiide or N-methylpyrrolidone, or sulfoxide, e.g. dimotyl sulfoxide. In the case of hydrolysis of lower thioxoalkyl, further work is carried out if necessary in the presence of a tuaga©tallfor» bond, e.g. copper oxide, or ot oxidationoiddol, e.g. hydrogen peroxide or organic peracids.

Iled©n carboxylic acid forostorot laver©, hydroxyalkyl residue il-f, can be vidoro by reaction with a lower©alcohol, such as a lower©alkanol, preferably methanol, in the presence of a minoral acid, e.g. hydrochloric acid, or ot alka linieta 1 lalk oho lat, such as sodium» methanolate, is transferred aminolytically or by reaction with ammonia» ack or ot organic amine, to a lower hydroxyalkyl.

The starting materials with the formula IV can be prepared by methods known per se.

Thus, for example, a compound of the formula VI can be prepared, which contains a functionally converted oxo- and/or hydroxy group, as mani©a is connected to the formula Kg-Ph-E^ (XII), in which ©a means 1-unsubstituted, ero -tual single unsaturated piperidyl residue, transfers the group H2 by transfer of oxo with phosphorous potassium sulphide or aluminum triaulfide 1 thioxo, transfers by reaction with ammonia or organic amine, hydroxylamine or optionally substituted hydrazine in an optionally substituted imino group, transfers towards an orthoester in acetal type respectively with ot lavare alkathiol in thioacetalized oxo containing £1^ and/or hydroxy by esterification in the esterified hydroxy containing and then, for example vod reaction with an optionally substituted bonsyl bromide Transfers the residue R^, in a desired residue £ij«

A compound with the formula VI, in which the acetal type contains, respectively, a thioacetalized or an oxo group present in enoletor form, can for example be further prepared by acetalizing the corresponding halogen-phenyloxo lower alkane, e.g. with the formula halogen-SPh-Rg (Via) by reaction with an orthoester, respectively thioacatalyzer by reaction with a mercaptaa or dimercaptaa or in the usual way©onolfor-otors, transfers the product, e.g. against halogen-Ph-E-g (VIb), against magnesium in the Grignard compound, e.g. with formolea halogen-Mg-Ph-Rj; (VIc), reacts this with optionally substituted 1-beasal-halo-piperidine and works up basic. From dls-s© can be obtained by reaction against hydrogen sulphide corresponding compounds with the formula VI, in which Bjg contains thioxo.

Compounds of the formula VI, in which R-^means carboxy or lower carboxyalkyl, can also be prepared by transferring a halobeiionic acid or haloafo-yllavore alkanoic acid into the acid chloride and reacting with amioiso-butanol or 2,2-dimethylaziridia to the corresponding 2 - (ha-logoafeayl)- respectively 2- (halogenaphenyl lower alk<y>l)-**,4-respectively ->r5-dimethyl-oxazolyl-(2) or transfers the corresponding nitrile under acid catalysis with the help of 4- amino-2-mothyl-pentan-2-ol or 2-methyl-pentan-2,4-diol in corresponding 2-(halo-phenyl)- or 2-(halo-phenyl-lower©alkyl)-4,ht6-trimethyl -5,é-dihydro-oxazinyl, transfers the reaction product with magnesium in the corresponding Grlgaard reaction, reacts the product with a corresponding l-benzoylpiperdylhalogenide honholdsvic l-benzylpiperidoa, cleaves off water in the latter case from the reaction product, then removes the current protecting groups with acid treatment- bg oet necessary fores tor©rholtend© øyrer©iler converter an aahydride, f., ox. with,thioayl chloride, in acid chloride•

Compound with the formula VI, in which Etg means a substituted optionally esterified here anhydride carboxy, containing in the 2" position to said hydroxy or in the 2,3 position an unsaturated residue, can be further prepared by alkanoylating the above-mentioned monounsaturated 1-acetyl -phenylpiperidene in the piperidyl part with a lower alkanoyl halide in the presence of aluminum trichloride in the phenyl part, builds up rostone H£in the so-called lower alkanoyl-(1-acylpiporidyl)-phenol in the usual way, e.g. by reaction with ea lavoro alkakai-boasyro-osters in the presence of an alkallmctali alcoholate, with oa alpha-halogen lower alkaasyro-ester and slack or with a lowcx^e alkakacarboasyreaaahydride in amrvmr of ot corresponding olkalimottal carboxylate, or else with the help of©a phosphorylidoneacetic acid osters , such as trifeaylphosphorylide acetic acid ethyl ester, cleaves the 1-acylreate hydrolytically 1-bea-sylates the reaction product in the usual way, e.g. by reaction with optionally substituted beacyl bromide in the form of triethylamia, if desired hydrolyzes functionally converted carboxy and/or halogenates carboxy, e.g. with thioacyl chloride.

Analogously, 1-acyl-plporidyl-bea-zaldehydes and 1-acylpiperidyl-lavoro alkanalor can be obtained, for example, by formyl ringing. by means of dimethylformamide and phosphorus oxychloride, corresponding l-acylpiperidyl-benzenes and unusual chain extension with methoxymethylene-trifoyl-phosphoraa, compounds of the formula VI can be obtained, in which Ig contains ©a oxo- or phosphorous carboxy group and ©a in addition, a beta-standing hydroxy group or a conjugated double bond, by reaction with lower alkanals or lower alkalic acid esters in acrvar of a strong base or lower alkali metal alkanolate. Analogously, one can in iiärvo:r of a metal, e.g. slack, converted to alpha-halogen lower alka acid esters whereby the corresponding 2-hydroxy lower alka acid esters are obtained.

Compounds of formula VI, in which the lower alkyl or lower alkyal ketyr can be further removed from the corresponding halogeafoayl—lower alkene or lower alkyl in an azotall forbiadels, e.g. wet turnover m©dmagnesium i'corresponding to kaiogeneagaooiuiEf orbindalso, condensation©-»

rer the doane in the usual way with an optionally substituted 1-bemsyl-halopiperidine, respectively l-bacylpiperidoa and in the latter case•cleaves off water.

Compounds of the formula VI, in which Mr, contains halogea can be optionally prepared by liquid halogen or halohydrogea addition to the corresponding compound of the formula VI, which inaoholdor an unsaturated rust u^o

£>© for the preparation of the starting compound®lson© mod for-moion VI anvoadfc® low©alkylaetalforbiadolsor is preferably prepared la^qltu» by omatting a corresponding halogen-, e.g. chlorine, iodo°or preferably lower bromoalcone, for°

trihnovis in on ether, e.g. in diethylether©Hor t©trahydrofasran,Eod lifciuoj oilor fortriaaoviø ma<g>aesiura. Andro lower alkyl©~tallforbiadolsor kaa oriAoldeø ira don sa erholto halo<g>oa«=, for» trinasvis brociaagiaos inside bond© Is is, at obsq timing aed©t corresponding aotallhalogoald, f.eka. with cadmium chloride, copper chloride, or copper chloride.

D©new forbiadolsor kari vidoro is prepared idot raaa on oia mixture of compounds taed don goneroll©the formula* ■

whereion of rostoaao il®q 11^ botyr on roat ii, and d©a ana©n022rest rig, and iij_ botyr©n abovetuolt reactive foreo-terote hy~drokoygrupp©©Hor osi to aabokarboaaatoot ©trokkond© toiadoloo, lets influence © ot egaot surt jjidMol and gjønnouforor oa cnskolig ©a©lier floro of aovato access operations. Rootoa & i©r for trinnovis'©a forøotorot hydroxy9 sp©=> øiolt halogen mod atomic matrasor 17 and raises Op son chlorine. As bun<= dot rost 2s.jj_ to lavoro alkanoyl i.^kocmor vider© eyror with the formula U^-OH forosterot hydroxykcy in botraktaingo jiSgaodo acid midlor or for example caiaoralayres such as fluorhydrogeacidiro©iler Gvoatuolt in aahydride form foroliggoado oxygenearor of phosphorus ollar sulvol, f .Axe. phosphoric acid, -diphos-forsyr®, polyphoøphosphoric acid oilor fooforpoafcaoxyd oilor avov©!-»©yro, preferably Letsløøyror, ooib halogeaids of olemoatea© from hovodgruippoa £' T£9 I' V and V and øidegrupoia©II and in dot periodic aystea of olououtøno soa boron, aIrøniaiunD gallium^ . txmi9 antimony and ja>ra0 f.okø. vod oidoa of jo^a trichloride, zinc-

chloride, stannous chloride and aatimopentachloride, preferably boron trichloride and fluoride and aluminum trichloride and bromide, vidor©complex©metallic acids, such as totrafluoroboronic or •hexachloroathiomonic acid.

Gmsotaingea is carried out in the usual way, for example in an inert solvent such as carbon disulfide, nitrobene, tetrachloromethane, diethyl ether, tetrahydrofuran ©Hor with an excess of starting material against the formula Vill, at normal, moderately elevated ©Iler lowered temperature, f .Axe. at approx. -30 to approx. iOO^C, preferably under exclusion of moisture and/or under protective gas, e.g. under nitrogen.

In a preferred embodiment of the present method, a mixture of compounds with formulas VIX and VIII is allowed, for example, in which UQ is a residue 11^. and & 0 - Xj_ botyr on lavoro aikanoyIhalogenide, e.g. -chloride, ©Hor lavero alkanoic anhydride, affect aluminum trichlorld, whereby maia for^ trinasvis arboids in boiling sulfur carbon.

The new compounds can further be prepared by condensing compounds against formulas

in which one of the residues kQ and U Q means a residue 21 ^ and the caaen©a rost Ug and oa of the residues X* > and Xo means a metal radical and doa other halogen or ea to ea lowore alkylr©st buad©t oxo or to ea laver ©aikanoyIrost l^ bound in any form available-geado forodrot©Hor the esterified hydroxy, and if desired separates ea obtained storeo-mixlandiag in the components, transfers the die ør° contained compound in another connection with formoloa I and/or omdaaaor oa obtained free compound in a salt ©Iler ot erhalt-salt in a free forbiade ©Here to©t other salt. Metal radicals are, for example, groups with the formula -M1,-M1<1>©Hor -M<I3>"/2, where ot means a metal atom from group I, U^~means a metal atom from group II in the periodic system of the elements and Hal means halogen, such as chlorine, bromine or iodine. Use metal radicals of any type such as against the formula

-Li, MgKal- and -Cd/2.

Preferred hydroxy is, for example, lower alcohol. Preferred hydroxy is e.g. with ea acid with foraøloa U0 => UH forosterot hydrokay. In salt form, hydroxy©s present, for example, in an alkali metal form, e.g. sosa siatrlusisalt* present hydroxy, halogen,©r preferably fluorine, chlorine,

brom©ll©r iodine.

The reaction with compounds of the formulae XX and X is carried out in the usual way, preferably in a diluted solvent, such as an ether, e.g. in diethyl ether or tetrahydrofuran, or hydrocarbon, e.g. benzene or mixtures thereof, cheese. necessary during cooling ©Hor light heating, e.g.» vod approx. -30 more

about. 100°C, e.g. boiling temperature, and/or under inert gas,

e.g. under nitrogen. Particular embodiments of this process are, in particular, the reaction of cadmium compounds (IX) with acid chlorides (X) in benzene diethyl ether to give compounds of the formula 1, wherein U is 1-oxo lower alkyl, reaction of halomagnesium forbiaidoles (lii) with lower alkanones ( x) to compounds against formoloh2, in which E^ is 1-hydroxy lavore alkyl, and the reaction of lithium or halogenoataagaøeluEJcombindolsor-sor (X) with compindolsor with the formula IX, in which RQor on rost SUj, and ' Vii^ or halogen.

Starting materials of formulas IX and X are known or

can, if new, be produced using and for so well known©methods,

Be sota starting material f are applicable oligo-anti-organic compounds, e.g. with the formula IX, in which R denotes a lower alkyl radical R2 and X^ the metal radical, is preferably produced in situ by reacting a corresponding halogen, e.g. chlorine, iodine or especially bromine compounds, preferably ethers, e.g. in dlethyl ether or tetrahydrofuran, against lithium or especially magnesium. Other counter-organic© compounds can be obtained from d©thus orholt halogen; i-preferably bromine-magazine compounds by reaction with a corresponding non-metalhalogen, e.g. cadmium chloride, copper chloride©Hear siac chloride. Halogen compounds which are thereby to be aveaded can, for example, be prepared by halogenating or 1-acylpiperidyl-benzoa or lis-bonaone in a suitable solvent, e.g. with bromine or chlorine in nor-vor avjera or with M-chlorosucciamide, Z^ ^^^^^^^~ ZJ liserendo ot erhalt l-aeylpiporidyl-halog©ab©nsoa and then 1-boasyiøror, e.g. with tllsvaread©boaayl bromide. Beventually substituted l-boaylhalogøapiporldiaforbiadois©r cas» aaalogt froo» is set by l-boazyleriag of corresponding l-taoubstitu©n feayl-' piporidia respectively feayl-tetrahydropyridia.

Obtainable compounds with the formula I according to the invention can be converted into other compounds with the formula I in a manner known per se.

Then, for example, in compounds with formula I, you can reduce your residue Rg containing oxo to the corresponding residue B.^ containing hydroxy. Thereby, a dilate metal hydride, such as an alkali metal boron hydride or alkali metal aluminum hydride, is used as a reducing agent, e.g. sodium borohydride, sodium cyanohydride or JijBiumaluminium hydride, preferably in an inert solvent, if necessary under cooling

or, heating, e.g. at approx. 0° to 120°C, and/or below: inert gas such as nitrogen. Particularly preferred is reduction with sodium borohydride in an inert, polar solvent such as a lower alkanol, e.g. in methanol, ethanol or butanol, or in dimethylformamide, respectively in, optionally aqueous, mixtures of these or with lithium aluminum hydride in an ether such as diethyl ether, dioxane or tetrahydrofuran. The reduction of the oxb group to hydroxy can further be carried out by reaction with et

ketone such as acetone, in the presence of an aluminum alkoxide, e.g. with aluminum isopropylate, especially according to the method of Meerwein-Pbnndorf-Verley. IIT I

However, oxo can also be reductively alkylated, for example by reaction with a lower alkyl alkali metal or alkyl alkaline earth metal compound, such as a lower alkyl lithium, e.g. methyl or ethyllithium, or a lower alkylmagnesium halide, e.g.

methyl magnesium bromide or ethyl magnesium bromide, preferably in an ether such as diethyl ether.

Furthermore, in a residue R£ which contains oxo or hydroxy, oxo or hydroxy can be replaced by a hydrogen. Oxo can, for example, be replaced by a hydrogen by ..reduction, for example by transfer with an optionally with 2-sulfonylethyl, such as 2-benzene-, 2-(p-toluene)-, 2-methane- or 2-mesitylenesulfonyl-ethyl, substituted hydrazine in optionally substituted hydrazone. ' As a reducing agent for 2-sulfonylethylhydrazone groups use

preferably a light metal hydride such as sodium cyanoborohydride in an inert, polar solvent, e.g. in hexamethylenephosphoric acid triamide. The reductive yield of unsubstituted. hydrazone to hydrogen is preferably carried out by base '> reduced disproportionation, for example by reaction with an alkali

tie talla Ikoholat sou iiatriurauetario la fc, if necessary under too-high pressure, e.g. up to 10 bar, or when affected by

an alkali metal hydroxide, e.g. potassium hydroxide, in an inert high-boiling solvent, e.g. in di»oller triethylene glycol or diethylene glycol monomothyl ether, if necessary under heating, e.g. at approx. 100 to 250°C. Ketonic oxogroups can also be substituted for hydrogen against nascent hydrogen^^, which e.g. produced by the action of a protonic acid such as hydrochloric or acetic acid, and base metals such as zinc, iron or aluminum or by the action of water on fortrisine amalgamated aluminium, or by the action of sodium on alcohols such as methanol, vlan can also use low-value metal compounds sor as tin-XI- ©Hor krota-II-saitor, e.g. stannous chloride. Hydroxy can be replaced by hydrogen, for example by the effect of catalytically activated hydrogen, such as hydrogen in the grains of a hydrogenation catalyst, e.g. iiano-nikkoi or a platinum compound such as platinum oxide or platinum on carbon or barium oxide, preferably in an acidic solvent such as a lower alkanoic acid, e.g. in acetic acid.

In connection with formula I, oxidative hydroxy or oxo can be introduced into the rust ii2 and/or hydroxy can be transferred into oxo. The introduction of hydroxy, especially in the wJ position, is carried out, for example, by air oxidation or the introduction of halogen is carried out in particular by reaction with N-bromouccinimide, and subsequent hydrolysis. The oxidative introduction of oxo is likewise preferably carried out in the 'l-position, for example by reaction with selenium dioxide. In the residue Si,, hydroxy can further be oxidized to oxy, for example by reaction with a ketone such as acetone, in the presence of an aluminum alcoholate, such as aluminum isopropylate, preferably according to the method of Opponauer.

Furthermore, lower alkyl residues can also be removed in the usual way, preferably by reaction with a metal or phosphorus compound of lower dlalkyl or phenylethyl ether, e.g. methoxymethylmagnesium bromide or with methoxyphosphorane,

and subsequent hydrolysis of the erholte©nol ether.

Furthermore, in connection with formula 1, in which K± butyr©ne with optionally substituted benzyl 1-substituted, singly unsaturated piperidyl residue, its double leafing can be reduced, for example by reaction with catalytically activated hydrogen, i", oies. with h<y>dro <g>ena in the amrvmr of a nickel-coal, platinum» or rho» dium catalyst, for example» Liaaey-nickel», platia oxide or com» ploxet of platin- or rhodium chloride and tri©aylf os f in, oller with the help of a dilotte metal hydride, for example with sodium borohydride or with lithium aluminum hydride.

E2o new forbiudelsor can © choice of starting material for or

and methods of preparation exist in the form of ot of the possible © ioo^isomers, ©Iler as a mixture of these, eke»©ttor aatallöt of asymmetric© carbon atoms as pure© optical© isomers, as aati» poder or as isomeric mixtures as a racociator, diferstereoisoioor» mixtures ©Hor racenat mixtures. . Erhalt© isomers such as diastereoisomer mixtures and racemate mixtures can be obtained due to physics, high-chemistry and ©n«=. creation of the constituent© in a known way is due in rono isoeroor, dlastorooisomeror or raceaator, exosapoivio by chromatography and/or fractional crystallization. • Retaining the raeemateur allows you to • further otter, kynto progress" methods. separate into optical antipoders, for example by recrystallization from an optically active solvent, with the help of saccro-organisms, or water. reaction of the final product with aod racetal bases forming optical actives and separation of them in this way orhalto salts, e.g. due to difference» Hg solubility, in diastereomers, from which the antipod©' vod action of a suitable agent is released. Preferably, one isolates the most effective of the antipodes©•

Lir-containing free compounds of the formula I can in and of themselves be transferred into salts, except for wet treatment with a corresponding acid, usually in the form of a solvent or diluent.

Acid-containing salts can be converted into free compounds, e.g. by treatment mod & n base soa an alkali metal hydroxide.

The compounds, including their salts, can be obtained in the form of their hydrates, or in the form of solvent, by crystallisation.

Due to d©xisbto kinship relationship taellom ay©for» blndolsør in free form and in the form of door©® salts shall be appropriate-above and below understood as a©d free© forbiadolsor ©Hor their salts also ovoatuolle salts, heahold free connection. © Ice is.

The invention also relates to methods of carrying out a process where a compound is obtained from a soa mollomprodiak, which is obtained at any step of the method and where a missing step is carried out where the masi starts from the starting material in the first part of a salt and/e II or raceeat, respectively use antipodes or especially form such© under reaction conditions©Icer.

In the method according to the present invention, the starting material is preferably used as a precursor to the valuable compounds described above. My© starting materials and methods for their production are likewise an object of the present invention.

In this connection, the compound of the formula VII, in which R0 is substituted with the residue K^., i.e. the compound with the formula IZj-Ph-H (la), in which °£^ ^ar doaa above significance. These show the same pharmacological properties in comparable potency as the compound of formula 1 according to the invention. The invention therefore also relates to compounds of the formula Ia and their applicable salts, methods for the preparation of dores, as well as their use and pharmaceutical preparations containing these.

The invention therefore particularly relates to such compounds!» shows with the formula Ia, in which il^ and Ph has the indicated meaning for preferred compound groups, namely -rv;- 1-(o-chloro-bonayl)-3-phenyl-piperidine and its pharmaceutically usable salts as its hydrochloride.

A compound with the formula I can be prepared in a unique way, for example by the above-mentioned method for a compound with the formula I, starting from hydrogenism containing compounds of the formula II, IIa, III, IV, V, VII and VIII, respectively IX and X, whereby UQ means hydrogen and RQrespectively H0means a residue K^.<0>

Compounds of formula I and their pharmaceutically acceptable salts have valuable pharmacological properties. For example, diss© has pronounced antithrombotic effects. Can this, for example, be documented on Nicor due to inhibition of thrombocytopenia after induction of ABS? 1 dose of approx. 100 to 300 mg/kg p.o. likewise on account of Arthias røakajonon, so Brit. J. Pharmacology 57, p.%4l (197&)»in doses of approx. 30 to 300 sne/ hg p• o*on teminers 'due to their hcmiaels©of the Arachidoasyro induced luageemboii in a dose of approx. 100 to 300 tags/kg p.o. ollers in vitro on the gixum of their prostaglondiasynthe-se inhibition of Arachidonic acid by enzymes extracted the ox's ocsd bladder in the kona en tras ions area of approx. 0.1 to 1 sig/liter. Por-Compound with the formula I is further anti-inflammatory, which e.g. can be detected © on rats due to Kaolia-Pfotenoedems and Adjuvaas-Arthritis in a dose of approx. 10 to 100 mg/kg p.o. These new compounds are also antioeptively active, which can be demonstrated in f©nyl-p-benzochiaoa-writing syndromes in mice in a dose of approx. 1 to 10 mg/kg p.o. and acetic acid-xsjritiagsya-droms on rats in doses of approx. 1 to 10 mg/kg p.o. Bo or, ©ade-liguuricosurically active, no© which can be detected due to a<y>feaolrod clearance on rats in doses of approx. 30 to 100 mg/kg p»o.

Compounds of the formula I are therefore excellently suitable for the treatment of thrombotic diseases, also inflammatory diseases, especially with inflammatory components and can be used as an active ingredient in nati thrombotic and/or inflammatory diseases drugs respectively as anti-aoceptive and/or uricds-urica. The present invention therefore also relates to pharmaceutical preparations which contain ea of the compound of the formula X respectively 111, according to the invention and a pharmaceutically usable salt thereof. Pharmaceutical preparations according to the invention relate to those intended for topical or local as well as etheral, as oral or rectal, as well as parenteral administration and for inhalation of warm-blooded animals and which contain pharmacologically active substances or together with a pharmaceutically usable bar© material. The dosage of the active substance depends on the type of warm-blooded animal, age and individual condition as well as the method of administration.

The aye pharmaceutical preparations contain e.g. from approx. 10$ to approx. 95W preferably approx. 2©£ to approx. 90$ active substance. Pharmaceutical preparations according to the invention or e.g. such in dosage forms, such as drugs, tablets, capsules or suppositories, further ampoules.

The pharmaceutical preparations according to the invention are prepared in a manner known in the art, e.g. by convective oil mixture ©»»grasaaler, dragler, solution-©Iler lyophilization process

Pharmaceutical preparations for oral use can then be obtained by combining the active substance with the solid berry material, or an oral mixture, respectively granules, which can be processed if necessary or required. Addition of suitable excipients to tablets or dragé containers. 2Sgn©d© boring substances are especially whole substances such as sugar, e.g. lactose, saccharoso, maanite or sorbitol, collulosoproparator and/ollor calcium phosphates, e.g. tricalcium phosphate or calcium bydrogen phosphate, further binder such as starch paste, e.g. of corn, wheat, rice or potato starch isosclists, golatia, tragaate, motyl cellulose and/or polyvinylpyrrolidone, and/or, if desired, sproagalder such as the above stated starches, yid©r©caroxymethyl starch, cross-linked polyvinylpyrrolidone, agar»alginic acid© ll©r©t salt thereof, as aatrium alginoå. Auxiliaries are primarily float regulation and lubrication agents, e.g. silicic acid, talc, stearic acid© or salts thereof such as magnesium or calcium stearate, and/or polyethylene glycol• Dragé containers are supplied with a coated, possibly gastric juice-resistant coating, whereby, among other things, concentrated sugar dissolving agents must be used, which contain possibly gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, varnish solvents 1 suitable organic solvents©lier solvent sheets oilor, for the production of stomach juice t -ros ice tant© coatings, solutions of©good©collose preparations such as acotyl cellulose ^phthalate or hydroxypropylethyl cellulose phthalate. Tablotteao or drag<S-over©rtrekkea© kaa be added dyes or pigments, e.g. for indolation or for the administration of different doses of aati-stoff©ae.

Pharmaceutical preparations that can be used are also gelatin capsules such as soft, closed gelatin capsules and plasticizers such as glyceryl sorbitol. The suppositories may contain the active substance in the form of a granule, e.g. in mixtures against solids such as lactose, leavening agents such as starch and/or lubricants such as talcum©Iler magnesium©tearate, and optionally stabilizers. In soft capsules, the active substance is preferably dissolved or suspended in a liquid such as fatty oils, paraffin oil or liquid solutions or polyethyl oil glycols,

whereby also stabilizers lean were© added. As rectal-painless" pharmaceutical© preparations come e.g. suppositories in consideration, which consist of a combination of active substance f one with a suppository base mass. Som3suppositoriogruna mass is suitable, e.g. natural or synthetic triglyceridea paraffin hydrocarbons, polyethylene<y>len<g>l<y>cols or higher alkanols. Furthermore, gelatia-re&talkapelor can also be used as iano-. holds a combination of active substances against, among other things, the base mass; as base material can e.g. liquid triglycerides, polyethylene glycols or paraffin hydrocarbons are used.

■ For parenteral administration, the first-line solution is an aqueous solution of an active substance in normally insoluble form, e.g. wax-soluble salt, further suspensions of active substances such as corresponding oily iaexjoas suspensions, whereby lyophilic solvents or carriers such as fatty oils must be used, e.g. sesame oil or synthetic fatty acid esters, e.g. ethyl oleate and triglycerides, or aqueous aqueous suspensions containing viscosity-increasing substances, e.g. sodium carboxymethylcellulose©, sorbitol and/or dextran and

possibly also stabilizers.

Pharmaceutical preparations for topical and local application or e.g. for the treatment of skin lotions and creams containing a liquid or semi-solid oil-in-vana- or vaan-l-oil emulsion and salves which preferably contain a preservative

The invention also relates to the use of the new binders of the formula I and their salts as medicine, especially as antithrombotics, preferably in the form of pharmaceutical preparations.

The following examples illustrate the above-described invention; however, they shall in no way limit dea's scope. Temperatures are indicated in degrees Celsius.

Example 1

8 g of 4-(p-ethyleaphenyl)-piperidia, 7.3 g of 3,4-dichlorobeazyl chloride and 16 g of anhydrous potassium carbonate are suspended with stirring in 300 ml of ethanol and heated for 5 hours with stirring at reflux. allow to cool somewhat, filter off undissolved and evaporate the filtrate at reduced pressure to dryness. The residue is added to 200 ml and extracted twice with 250 ml of diethyl ether. The ether extracts are combined, washed with 100 ml of 2a-sodium salt and then with 100 ml of saturated sodium chloride solution, dried over sodium sulfate and iandampot, whereby the reiodioate forms crude 1-(3,4-dichlorobea:yl)-4-(p-ethylphenyl) )-pip©ridine. This is dissolved in 100 ml©tanol and the solution is acidified with ©ethanolic hydrochloric acid (2m) to pK » 1. Bett© felt l-(3,4-dicIorb©nsyl)-4-(p« .©tylph©jiyl)-piperidine hydrochloride is sawn off, washed with diothylotor and dried.Bet smoltor at 253-257°.

The output material can e.g. prepare©© as follows» A solution of 12.0 g of alpha-g>-(-4-piperJ.dyl)-feayl]-©tanol in 120 ml of ls-acetic acid is added 1.2 g of palladium (5^«*ig on carbon) and hydrated at 40-50° until absorption of 1 equivalent of hydrogen vod normal pressure. ^ Then filter off the maxi catalyst and evaporate the filtrate in vacuum to dryness. The crude 4-(4-otylf©nyl)-piperidine remaining in the solution can be further purified by treatment with activated carbon and subsequent transfer into the hydrochloride. The melting point of the hydrochloride is 198-202° (from ethanol-ether).

Example 2

In an analogous way as described in example 1, v©d is obtained

reaction of 4-(p-otylphoyl)-piperidine

with 2,4-dichlorobeazyl chloride 1-(2,4-dichlorobeazyl)-4-(p-ethylfoayl)-piperidia hydrochloride against melting point 230°,

with o-chlorobeazyl chloride l-(o-chloroboazyl)-4-(p-ethylphenyl)=> piperidine hydrochloride with melting point 195-196°»

with p-chlorobenzylchlorold 1-(p-chlorobeaayl)-4-(p-©tylph©ayl)-piperidia hydrochloride with melting point 263-265°,

with m-chlorobenzyl chloride 1-(sa-chlorobenzyl)-4-(p-ethylfoyl)-piperidia hydrochloride m.p. -phenyl)-piperidine hydrochloride with melting point 157-158°.

Example 3

ca g of 4-(p»actyIf©nyl)-piperidine is analogously©, as described in ©exompol 1 reacted with o-corbo&syl chloride to 1-^-chlorobeasylJ-^-Cp-acetylfeaylJ-piperidine towards melting point 96- 97°.

iiksoragel k

By reacting 5 g of 4-[p-(1-hydroxybutyl)-phenyl)-piperidine with o-chlorobenzyl chloride using the wood stove method in example 1, 1-(o-chlorobenzyl)-4-[p-(l -hydroxyethyl )-phenyl] piperidine hydrochloride pod sneltopuakt 178-179°.

•acsecigel 5

Tablets containing 100 mg of active substance f, 1-(3,4-dichlorobeneyl)-4-(p-otylphonyl)-piperidine hydrochloride can, for example, be freely added in the following composition

Fratastillin^

The active ingredient is mixed with the milk sugar, a dollop of wheat starch and colloidal silicon dioxide, but the mixture is passed through a sieve, the other part of the wheat starch is pasted onto the water bath with 5~ga^g of water and the powder mixture is kneaded together with the paste until a weak plastic øasfso is formed* The mass is driven through a sieve with approx. 3 E*m mesh size, the dried and dot dry granules are driven through the sieve again. Borett becomes residual wheat starch, talc and magaesium stoarat tllblondot.- Bon©rholto blaadiag

becomes prossøt mod tablets of 250 ag aed bruddrill©(s).

To a reflux heated suspension of 1.2 g of -lithium-, iHaaluminusi hydride in 50 al of 'absolute totraay&rofuran is long» to which is added a solution of 19»7 g of Iv°(3#4-dlc}Ctok3yboa2oyl)-k-(Z* -©tylph©nyl)-piperidine 1 50 ni absolute tctranydrofuran and heated a further 24 hours at reflux. After the reaction mixture has cooled, about 10 ol of vinegar and a little water are added, filtered and the totrabydrofuran is extracted. The acid is dissolved in 2a-hydrochloric acid and washed with a small amount of tor. The aqueous phase is made alkaline with 2a-sodium chloride and oke" traaört with tor. Large washing of otorfasea. warm water, drying over aga©sium sulfate and iandamping orhold©r one r#tt in-(3»4<=>diQethoxyb©acyl)-4-(p-©tylfonyl)-pipe©ridine» as an aqueous solution at addition of an equivalent amount of fuaroic acid©, dissolved in ethanol, crystallisorto as furarate mod emeltopuakt 151-153°.

The starting material can, for example, be prepared analogously to that described in example 1 by reacting 4-(p-otylpheyl)=piperidine with 3'4-dimethoxybeazoyl chloride, which melts at 110-112°.

In an analogous way, one can prepare by reacting 4-(p-ethylphenyl)-piperidine with 3'4-dichlorobenzoyl chloride over 1-(3,4-dichlorobenzoyl)-4-(p-ethylphenyl)-piperidine and melting point 77-79° 1-(3,4-dichlorobonayl)-k-(p-ethylphenyl)-piperidine against melting point 255-257°.

In an analogous way ©as described in example 1 ©raøldor

one by reacting 4-(o-ethylfoyl)-piperidine against 3,4»dichlorobenzyl chloride 1-(3t 4-dichlorobenzyl)-4-(o-ethylfoyl)-piperidiahydrochloride with a melting point of 250°.

The starting material can be prepared in the following manner. To a suspension of 10 g of magnoslum poa in lit©tetra-bydrofuraa, add dropwise while stirring and with constant addition of water or dissolve 75 g of l-ethyl-2-bromobeas©a in 50 ml of tetrahydrofuran so slowly that the reaction temperature of 60° is not exceeded. A solution of 57 g of £3-benzyl-4-piperidone in 150 al of tetrahydrofuran is added over the course of 45 minutes. After the addition is complete, it is allowed to stir© yttorligor©<m hour© at 60°. The reaction mixture cooled to 0° is added to 1000 ml of ice-cold, saturated ammonium chloride solution and extracted twice with 2x 1000 ml of ether. Then organic extracts are dried over sodium sulfate and evaporated in vacuo. Distillation of the dia-evaporation residue 1 high vacuum gives in don at 175-130° (0.05 mm) boiling fraction 52 g of 4-hydroxy-4-(2-othyl-phenyl)-H-beneylpiperidine as a colorless oil.

To a solution of the above-mentioned product in 120 ml of acetic acid, add 40 ml of concentrated hydrochloric acid and 30 ml of water and heat for 3 hours under reflux* Then evaporate the above in a vacuum, adjust with caustic soda alkaline to pH 14 and extract with 2 times with 1000 ml of acetic ester. The late organic phase is washed with water, dried over sodium sulphate and evaporated in vacuo. He thus obtains crude oily 1-benzyl-4-(o-ethylphenyl)-1,2,3,6-tetrahydro-pyridine, which is directly further processed. (hydrochloride: Melting point 205°).

To a solution of 43.5 g of 1-benzyl-4-(o-ethylphenyl)-1,2,5,6-totetrahydro-pyridine in 450 ml of 1-acetic acid, add 48.1 ml of 3,4 α-ethaolic hydrochloric acid and 22.5 g palladium (5>j-ig on carbon) and hydrogenated at 40-45° until absorption of 2 equivalents of hydrogen. The catalyst is then filtered off, the filtrate is evaporated

vacuum to dryness, dissolve landarapaing rosidiote in 300 ml of water,

w. adjust with sodium hydroxide solution to pH 14 and ox trailers twice against 500 ml of ether. The organic extract is dried over sodium sulfate and evaporated to dryness under vacuum. The Xaadampaiags residue is dissolved in 130 ml of ethanol and at 60° ea a hot solution of 15t5g of fumaric acid in 350 ml of hot water is added. After cooling, the crystallized 4'(o-ethylphenyl)-piperidine fumarate is filtered off, washed with ethanol and ether and dried in vacuo at room temperature. Melting point 195°•

example S

In an analogous manner to that described in example 1, water is obtained by reacting 4-(m-ethylphenyl)-piperidine with 3,4-dichlorobenzoyl chloride 1-(3,4-dichlorobenzoyl)-4-(m-ethylphenyl)-piperidine- the hydrochloride with a melting point of 249-50°.

The output material can be produced in the following way-

Conversion of 60 g of 3-ethyl broubenzea against magnesium and

6l g of N-benzyl-4-piperidoa gives 4-hydroxy-4-(tn-ethylphenyl)-K°b©a-syipiperidia with boiling point 1<r^-200° (0.04 ami).

From this, glacial acetic acid/saltwater lead-like crude 1-benzyl-4-(o-ethylphenyl)-1,2,3t6-totrahydro-pyridine is obtained, which undergoes further purification in an analogous manner as described in okooapol 7 (preparation of starting sialate) is transferred by bydreriag at palladium (5'^-ig on carbon)- in the 4-(m-otylf©nyi)-pipe©ridin-fuEsarate.

Lksomoel^9

To ea solution of 3.5 g of 3,4-dlchloroboazyla£ala in 10 ml of ethanol and 20 ml of 2a-Natroalut add aaa uador stirring at 0° ea solution of 6.7 g of 3-(p°otylf eayl)-1,5 -dibroa-p©ataa. i/c tor the addition is carried out, the reaction vessel is heated for 10 hours under reflux. Icerott cools the mam to vorol solution temperature, bleaches against lit©sodium tlosulfate, iaadvaporGr in vacuum to dryness and distills the residue under high vacuum. It vod 9G~i40° (0.03 mrnHg) boiling fraction is further purified chromatographically on Kioselgol with chloroform-mothanol (15:1).

-1'-(p-Otylphoyl)-piperidine. For characterization, as described in Exompol 1, this is transferred into hydrochloride with a melting point of 253-258°. The 1-(3,4-dichlorobeayl)-4-(p-otylpheyl)-plperidia fumarate can be prepared analogously. It melts at 255-257°»

Dot as starting material used 3°{p-©thyl-foyl)«=1,5,-dibromo-penta allows sog e.g. on followoad©way©frcostilios

A solution of 43 g of p-ethylbenzaldehyde and 52 g of diethyl phosphoracetoaitrile in 300 ml of methylene chloride is added over 15 minutes under cooling to a well-stirred solution of 6.5 g of tetrabutylammonium bromide in 180 ml of 50% aatroic lye and 150 ml of mothylone chloride. Finally, the island is stirred for 30 minutes at room temperature. After this, the organic phase is separated, washed neutrally with water, dried over sodium sulfate and evaporated in a vacuum. Bet thus obtained crude pc©tyl-ka©lsyreal-trli [oil; JS (Cn2Cl2)s max. 2240 cm"<1>] is added to a solution of 8 g of sodium in 53 g of maloacyrodiethyl ester and 400 ml of saturated ethanol and heated for 2 hours at reflux. Then it is evaporated in vacuum to a third, 500 ml is added aqueous acetic acid (0.5n) and extract 3 times with 500 tal©t©r. The organic phase is washed neutrally, dried over sodium sulfate and evaporated to dryness in poppy seeds. Chromatography of the evaporation" solution on 1 leg of silicon dioxide gel taed aethylene chloride soa lope-aiddoJ. gives 2-carboethokoy-3-(p-©tylf©ayi) «propane-l=>carbonic acid-©tylostor-3-aitrii so<p>colorless oil©© [ ILI (CH2C12)Omax. 8 1?20 cm""1 (Shoulder)] •

2-Carboethoxy-3-(p-ethylphenyl)-propane-1-carboxyroethyl-©ster-3-aitril lar sog analogously to don in J. Amer. Chom. Soc.j 53, 1105 (1931) described process© oaseto to 3-(p-ethylphenyl)-1,5»dibromo-peataa. ©ott© kokor vod I75-l£>5° (12 mmllg).

jjikseispcl 10

To. a suspension of 150 mg of lithium aluminum hydride i

20 al of absolute tetrahydrofurase is added with stirring in ©xi nitrogena tenosféro 1 g 1-(3»4-dicotoxybonsyl)-ii-(p-otylf©nyl)-2-piperledone. then let the mass stir © 1 tic© vod 60°, cool © to room temperature, add drop by drop 0.5 ml of water and 0.1 cal 2n-L:atroalut and filter over kieselguhr. The filtrate is absorbed and the evaporation solution yields 1-(3-4-dimethoxyben:3yl)-4-(4-otylph@nyl)-piperlidene, as described in example 6, which is transferred to the fuarate saed F 151 -153°»

Output iuaterialot can be obtained from the following:

A solution of 31 g of 2»carbo©toxy°3-(pa,©ty^Æ<>>Q^yi),°propane-1-carboxylic acid cetyl ester-3-nitrile 1 1.6 g trletylazine and 500 sal absolute taed© tanol is bidred mod & g Siaaey-nickel to take up .about 4 1 of hydrogen. Borette filters off the catalyst and evaporates in vacuo to dryness. From the indaEspnings rosidide, the ether 3-carbo©toxy-4-(p-ethylphenyl)-2-piperidoate crystallized at P-157-159°.

add a solution of 3 g of the above-mentioned compound in 110 tal ethanol, 40 ml 2n-Katronlut and 50 ml water is boiled under reflux for 45 minutes. Evaporate in vacuo to dryness, adjust the evaporation rate with 2% hydrochloric acid to volume 1 and extract with 500 ml of chloroform. The organic phase is washed *' ^Tlineutral,- töziiot over sodium sulfate and iaad vapor in vacuum. The crude, crystalline 3-carboxy-4-(4-ethylphenyl)-2-piperidoa remaining in the evaporation residue (melting point 125° is split) is heated in 400 ml of toluene for 30 minutes with reflux. Boretto is evaporated to a volume of approximately 20 ml and a smaller amount of ether is added. Bervsd crystallization tubes

4-(p-©tylph©nyl)-2-piperidoate. saod F-l65°.

To oa solution of 2 g of 4-(p-ethylfeayl)-2-piporiaon°£3»2 g of tetrabutylaoraoaiuobroiald in 40 al of motylon chloride are added* cran 2.3 g of 3,4-dimethokeybeacylchlorId and 40 al of 30v--iger Matronlut. The mixture is left undisturbed for 4 hours and then separated from the liquid phase. The second organic phase is washed neutral against water, dried over sodium sulfate and charged. Iandacp» aiagsreStidiet is stirred with ether. The ether-soluble portion, containing *A-(3,4-dithiothoxyboacyl)-4-(p-ethyl-feayl)-2-piperidoate, is evaporated and then further reasaiag used in nesting.

i£kaemgol _11_

To a solution of 6.4 g of 1-(ni-methoxyben2yl)-4-(p-acetylphenyl)-piperidine and 5 ml of hydrazide hydrate in 50 pl of tylenglycol is added 7.5 g of powdered sodium hydroxide and boiled for 1.5 hours under reflux. A mixture of hydrazine and water is then distilled off until the sump temperature of 190° is reached. After the reaction mixture has cooled, the same quantity of oxtrahort med©ter is added. The terphase is dried over sodium sulfate and evaporated water. The laadapaiagsroside is chromatographed on a silica gel with methylachlorid/motaalol (15*1) as eluent to give 1-(m-methoxybeasyl)-4-(4-ethylphenayl)-piperidia which is essentially is transferred into hydrochloride with smoltö-puakt 157-15S<0>.

Lksem<p>ol^^12

In the same way as described in example 1, one obtains by sweetening 4-(p-ethylphenyl)-piperidine and p-Pluorbeacyl chloride 1-(p-Pluoroben:s<y>l)-4-(p-et<y >lfea<y>l)-<p>i<p>eridine hydrochloridemod melting point 250-52° and aed beazyl chloride l-be©azyl-4-(p-otyl°feayl)-piperidia-fumarate with melting point 183-185°•

Lkseasgel 13

Obtain a similar method as boskrovot in example 1 respectively 3©rholdor one by reacting 4-(p-acetylfoyl)-piperidine modEj-motoxybenzylbroiaid 1-(m-reoethoxybonzyi)-4-(p-acetylph©nyl)« pipe©ridine -fumarate with melting point 137-59°»

with the 3,4-dichlorobeazyl chloride 1-(3,4-dichlorobeazyl)-4-(p-acetylph©ayl)-piperidia hydrochloride of melting point 25&«=.60° and charged benzyl chloride 1-beazyl-4-(p -ac©tylf©nyl)-pip@ridia-fus2aratot taed©melt©point 161-62°.

kksetagel^ 14

In an analogous manner to that described in example 4, can is obtained by reacting 4-β-(1-hydroxyethyl)-feayl-1-piperidia with benzoyl chloride 1-benayl-4{p-(1-hydroxyethyl)-feayl-1-piperidia -furna»rate saed melting point 154-15$°, with m©d m-methoxyotheacyl bromide 1-(m-methoxybenzyl)-4-rg-(1-hydroxy©thy1)-phenyl]-piperidine-fuaratot with melting point 160- 6l° and

with 3,4-dichlorobeacylchlorold 1-(3,4-dichlorob©azyl)-4-jp-(1-hydroxy©thyl)-phenyl)-piperidine fumarate with melting point 195-97°. 8 g of 4-(p-otylpheyl)-piperidine, 4.2 g of benzyl chloride and 16 g of anhydrous potassium carbonate are suspended without stirring in 300 ml of ethanol and heated for 5 hours at reflux. The mixture cools slightly, precipitates from undissolved and evaporates under reduced pressure to dryness. The residue is added to 200 ml of water and extracted twice with 2 x 170 ml of diethyl ether. Btorok extract is concentrated, washed with 100 ml of sodium chloride and then with 100 ml of sodium chloride solution, dried over sodium sulfate and evaporated to dryness. One obtains 1-beazyl-4-(p-ethylfoyl)-piperidia, which, by dissolving 1 ethaol and acidifying with ethaolic hydrochloric acid, can be transferred into - i-boazyl-4-(p-ethylfeayl)-piperidine hydrochloride.

The source material can e.g. is obtained in the following way

To a solution of 12.0 g of alpha-[p-(4-piperidyl)-phenyl]-ethaol in 120 ml of glacial acetic acid is added 1.2 g of palladium (5<r>^-ig on carbon) and hydrogenated at normal pressure at 40-50° to absorb 1 equivalent of hydrogen. The catalyst is then filtered off and the filtrate is evaporated in vacuo to dryness. The red-blue 4-(4-ethylphenyl)=piperidine obtained in the vapor-residue by treatment with activated carbon and subsequent transfer into the hydrochloride is further purified. The melting point of the hydrochloride is 193-202° (from ethyl ether).

Exoia pool 16

On analogous uneaten sota described in by transfer of 34 g of 4-bromo-m-xylene in Brøia-oaagnesiuimf orbind-eisen©tter Grignard, conversion of dea satane taad 3& g of 27-bensyl-4-piperidan and subsequent vaaaavøpaitaiag voel ajølp of ctkiic-acid-saalsyro, soa boils at 0.05 omHg w©d approx. 170°, Ilkoiedos l-benay 1-1,2,5»6-1otraaydro-4-( p-methylfoayl)-piporeridia, seielte-puakt 40-41° (from cold Feataa).

Lic sotage 1^17

Ea dissolving layer of '55 g l-beaayl-4-=aydroxy-4=» |>-=>(l»©ty-leadioxyethylj-foayl]-piperiiiiji 1 250 ml concentrated brine .is heated tr©timor vod reflux. Bana evaporate in vacuum to dryness, add 2a-Sodium lye to 14 and extract three times with 500 al of diethyl ether. The organic phase is ammoniated, washed neutrally, dried over sodium sulfate and added to a third. B©t crystallized© pure 1-boa25yl-1,2,5,6-tetrahydro-4-(4-acetylphenyl)-pyridia a©d saoltø» point 99-100°.

The issue report can be found here. frestill©ø on followoad©

manner.

A solution of 97 g of 4-bromoacetate in 100 ml of abøolut tetraliydr is added dropwise at about 50° in the absence of water to a suspension of 9»tJ g of magnesium oxide in 100 ml of absolute tot raaydro furan of tears. As soon as all the magaosiua has dissolved, cool the mixture to 5°©g, add dropwise a solution of 70 g of W-benzoyl-4-piperidone in 100 ml of absolute totrahydrofuraa. After the addition is complete, it is evaporated under vacuum to dryness and the residue is taken up in anhydrous ethyl ether and filtered off. The defatted liquid is then divided between 3 times 200 ml and 200 ml of cold, wet amoalum chloride solution. B©organic© phases are combined, washed neutrally, dried over Sodium sulfate and iaa-datnpet 1 vacuum to dryness. Bet thus eraolt©l-b©asyl-4-hydroxy-4-fp«(1-otylenedioxyethyl)-feay I]-piperidine melted wet 114-116°.

Example 18

To a suspension of 0.5 g of tuagnesiuta spøn, the overview in absolute oxygen diethyl ether, drops of ethyl iodide are added under nitrogen and after the reaction has started, a solution of 6.3 g of l-(ffl-methoxybenzyli-) is added dropwise at 30-35° k-{p-chloropheny1)-piperldine in SO cal absolute dietyiether. After the largest part of the atagnesium has dissolved, add 100 mg of copper-I-iodide, cool to -10°, add 2.3 g of ethyl bromide and leave to stir overnight at -10 to 0°. Then add 50 ml of 2x sodium hydroxide solution, thickened with baking soda and extract three times with 50 ml of diethyl ether. The organic phase was washed neutral, dried over sodium sulfate and evaporated in vacuo. Distillation of the evaporation residue in high vacuum and chromatography; at 100-150° (0.03 spatial) boiling from carbon dioxide with chloroform and lit©methanol as lyojesiddei gix raw 1-(al-ui&t-oxybenEyl)-k-(p-ethylIfenyi)~piperidine (melting point of liydrochloro- ridden in .157-158°).

The starting material can, for example, be prepared in the following way: Treatment of p-chlorocinnamic acid ethyl ester with sodium diethyl malonate to beta-phenyl-alpha,alpha,ypsilon-tricarboxylic acid tri-ethyl ester, then saponification with potassium chloride and decarboxylation at 110-130 ° leads to β©ta-p-chlorophenygibutar acid, which by reaction with o-iaethoxybenzylatain is transferred to 1-(is-inethoxyben-2yl)-^-(p-kiori"enyl)-|>iperidine-2,6- dioii. This can then be reduced with iitiutaaluminiuiabydrid to the desired i - ( m- ns e t o k y - beriisy 1 (^-chloroph eayl )-piperidine.

BksgG)pei._19

Tablets containing 100 mg of active substance, e.g. i-Benzyl-4-(p-ethylphenyl)-piperidine, or its hydrochloride, for example, is prepared in the following composition:

Manufacturing

The active substance is mixed with the milk sugar, part of the wheat starch and with colloidal silicon dioxide and the mixture is passed through a sieve. weak plastic mass. The ktassen is driven through a sieve with approx. 3 mm mesh size, dried and the dried granulate is driven through the sieve again. Then the remaining wheat» starch, talc and magnesium stearate are mixed in. The orbolto mixture is pressed into tablets of 25G mg with fracture indication(s).

Ekseujpol 20

In an analogous way as described in examples 5 and 19, tablets containing another of the compounds according to examples 1-4 and 6-13 can also be prepared.

Claims (18)

Method for the preparation of new substituted, optionally mono-cooled, unsaturated 1-benayl-phenylpiperidine of the formula in which U^ means one in 1-stililing against optionally substituted benzyl substituted, optionally monounsaturated piperidyl rheot, in which an optionally substituted feayl residue and Fig means an optional substitute for a lower alkyl residue, with the proviso that Pa optionally means substituted 1,2- or 1,3-phenylea when Eg contains in the alpha position, among other things, hydroxy-, hydroxymethyl-, lavoro alkanoyl-, 2-oxo lower alkanoyl-©Iler lavaro 2-hydroxyalkaaoyl group, with the further proviso that li^ is different from 4-(1-benzyl)-piperidine and 4-(1-benayl)«, 4- [l -(£Qoaoalkylboa2yl)-J and 4- (!•= (ciohalogen» benzyl)] -1,2,5,6-tetrahydro-pyridyi, when Ph denotes ovoatually substituted 1,4-phenylone and &2lavero alkyl meet in it at least 2 C atoms and dores saltor, characterized by the fact that one forbiadolso with the formula: in which Ra botyr©a in 5-stil.iling in fonyidollea©veatually substituted boazylamiao substituted, evoatualt single unsaturated n©nyl-residue containing in the l-position a replaceable rost X or in ea 1,2-stilliag ea©veatualt further double biading,© If a salt thereof, ring ends &A to the corresponding rose fn^ - or substitutes in ©a connection with the formula t in which Rg means a 1-unsubstituted, optionally unsaturated piperldyl residue, or a salt thereof, vod reaction saed©a©\T©a» tually substituted boazylrost ianfoerado agent substituted in the l-position or in a compound against formoleas in which Uq means at least ea mod hydrogen-exchangeable rust and/or additional double bond containing substituted residue K^, or a salt thereof, reduces the rust Rq to R±®*-Aor i©n tii-. svaread©'forbiadolso aed formoleas in which Mq is in the l-position against optionally substituted benzyl and in the case of an alpha,beta-©li»ain©ing available residue substituted piperldyl residue or a salt thereof, whereby this together with a beta-standing© hydrogen atom is eliminated or in ea'compound in which botyr ea in a voice SL*transferable group,©lier©t salt thereof, transfers 1% in Sg or on a mixture of forbiadelsor mod doa the general formula* in which ©a of the residues k' Q and ll0 means ea residue Mj_ and the other one a residue 2?2 and 51 ^ means ©a éveatually reactive for or ©s teret hy» droxy group oilor©a bond that stretches tii one of the neighboring carbonatomoae, allows a suitable acid mite to act©! or condense the compounds with advantage with each other, in which oa of the residues H0 and means oa residue li^ and doa aaaea ©a residue Hg and ea of the votes Xg and means a metal 1-radical and doa adre halogea©iler oxo bonded to ©a lower alkyl residue E0or to ea laver© alkanoyl rust IiQ bound hydroxy present in salt form, preferably or esterified, and if desired separates the obtained Stereo-isomer sheet in the component®, transfers an obtained precursor © in oa another connection with the formula I and/or converts a obtained free precursor © in A salt or converts an obtained salt into a free compound into another salt. 2. Process © according to claim i, characterized by preparing compounds according to claim 1, in which one in the phenyl part optionally means lower alkyl with up to and including 4 C atoms, lower © alkoxy towards and towards 4 C atoms . -totetrahydro)-pyridyl ether, Pla indicated ventuolt with lower alkyl mod tii and mod 4 C atoms, lower alkoxy with up to and including 4 C atoms, hydroxy or halogen with atomic number up to and including 35 substituted 1,4-oilor 1,3-phenylene, and Kg optionally means higher than 2-position with hydroxy or 1-position with oxo-substituted lower alkyl with up to and including 4 C atoms, with the proviso that R±©r is different from unsubstituted 4- (l-b©nayl)-piperidyl and optionally lower© alkyl or halogen monosubstituent 4«(l-b©ns<y>l)-1,2,5,6-tetra-hydropyridyl or Ph is different from optionally substituted 1, 4-phenylene, when I^g bet lower alkyl or lower alkanoyl with at least 2 carbon atoms, or their salts, 3. Procedure according to claim 1, character- formed by preparing compounds according to claim 1, in which Rj means in the phenyl part with lower© alkoxy with up to 4 C atoms and/or halogen with atomic number up to and including 35, mono- or disubstituted 3- or 4-(1-benzyl)-piperidyl, Ph means 1,4-phenylene and Rg botyr© ventuolt in the 1-position or 1 higher than the 2-position with oxo or 1 higher than 2-stiiling with hydroxy monosubstituent lower alkyl with up to and including 4 C atoms, or salts thereof. 4. method according to claim 1, characterized in that compounds according to claim 1 are prepared, in which the phenyl part with a lower a li means; ok sew with up to and including 4 C-atom monosubstituent or against halogen up to and including atomic number 35 disubstituted 4-(l-ben2yl)-piperidyl, Ph denotes 1,4-phenylene and Hg denotes lower alkyl met even 4 C atoms, or their salts. 5. Method according to claim 1, characterized in that 1-(3,4-dichlorobenzyl)-4-(p-ethylphenyl)-piperidin or a salt thereof is prepared. 6. Method according to claim 1, characterized in that 1-(2,4-dichlorobenzyl)-4-(p-ethylenyl)-piperidine or a salt thereof is prepared. 7. Release method according to claim 1, characterized in that 1-(o-chlorobenzyl)-4-(p-ethylphenyl)-piperidine or a salt thereof is prepared. 8. Method according to claim 1 is characterized in that one prepares 1-(m-chlorobenzyl)-4-(p-ethylphenyl)-piperidine or a salt thereof. 9» Method according to claim 1, kar act e - r i ©r t in that cyan produces 1-(p-chlorobenzyl)-4-(p-ethylphenyl)-piperidine or a salt thereof. 10. Method according to claim 1, characterized in that one prepares 1-(o-chlorobenzyl)-4-(p-acetylphenyl)-piperidine or a salt thereof. 11. Method according to claim 1, characterized in that one first titrates 1(o-chlorobeacyl)-4-[p-(1-hydroxyethyl).-phenyl]-piperidine or its salt. 12. Method according to claim 1, characterized in that one produces. 1-(m-methoxybenzyl)-4-(p-ethylphenyl)-piperidine or a salt thereof. Method according to claim 1, characterized in that one prepares 1-(3-4-dimethoxybea-2-yl)-4-(p-ethylphenyl)-piperidine or a salt thereof. 14. Process according to claim 1 (characterized by preparing 1-(3,4-dichlorophenyl)-4-(o-ethylphenyl)-piperidine or a salt thereof. 15" Method according to claim 1, characterized in that one prepares 1-(3,4-dichlorobenzyl)-4-(m-ethylphenyl)-piperidine or a salt thereof. 16. Method according to claim ^characterized by preparing 1-(p-fluorobenzyl)-4-(p-ethylphenyl)-piperidine or its salt. 17"Procedure according to claim 1 characterized in that one prepares 1-(m-methoxybenayl)-4-(p-acetylfonyl)-piperidine or a salt thereof. 18. Method according to claim 1, characterized by demethylating i-(3»4-dichlorobenzyl)«4-(p-acetylpheayl)«piperidine or a salt thereof. to requirements lp character ø-r in s © r t v©d that one freezes l=»'(m«saethoxyb©a2yl)-" 4- ||p-(1-hydroxyethyl )-£enyl]-piperidine ©11 ér ot salt thereof" 20.. Method according to claim 1, characterized in that one prepares 1-(3,k-dichlorocarbonyl)