DD144770A5 - PROCESS FOR PREPARING NEW PHENYLPIPERIDINE DERIVATIVES - Google Patents

Abstract

Substituted, optionally monounsaturated 1-benzyl-1-phenylpiperidines of the formula R, -Ph-R, (I)

Description

Verfa hre n for Hey rst RECOVERY new phenylpiperidine derivative

Appli cation of the invention sgebiet

The invention relates to a process for preparing phenyl piperidine derivatives, in particular substituted, optionally monounsaturated 1-benzyl-phenylpiperidines of the formula

R ₁ -Ph-R ₂ (I),

wherein R _{1 is} a substituted in 1-position by optionally substituted benzyl, optionally monounsaturated piperidyl radical, Ph is an optionally substituted phenylene radical and Rp is an optionally substituted lower alkyl radical, and their pharmaceutically acceptable salts. These are novel compounds with the proviso that Ph represents optionally substituted 1,2- or 1,3-phenylene, when Rp in the a-position represents a hydroxy, hydroxymethyl, lower alkanoyl, 2-oxo-lower alkanoyl or Z 1 - With the further proviso that R 'is 4- (1-benzyl) -piperidyl and 4- (1-benzyl) -, 4-fJ-monohalobenzyl) J- and 4-p- (monoalkylbenzyl) J-1 , 2,5,6

I - 2 -

tetrahydropyridyl is different when Ph is optionally substituted 1,4-phenylene and R is lower alkyl or lower alkanoyl or 1-hydroxy lower alkyl having at least 2 C atoms, and their salts, and processes for their preparation.

The optionally monounsaturated piperidyl radical which is substituted in the 1-position by optionally substituted benzyl is, for example, a corresponding piperidyl radical or, in the second place, 1,2,5,6-tetrahydropyridyl radical. As substituents thereof are, for example, lower alkyl, lower alkoxy, lower alkylthio, hydroxy, halogen and / or trifluoromethyl, wherein one or more of.Substituenten, in particular two halogen atoms, may be present.

The optionally substituted phenylene radical is, for example, a 1,4- or, in the second instance, 1,3-fhenylene radical which is unsubstituted or substituted by lower alkyl, lower alkoxy, hydroxyl and / or halogen, where in substituted phenylene radicals, preferably in the o-position to R-. bonded, or in the second place more than one substituent may be present.

An optionally substituted lower alkyl radical is, for example, a lower alkyl radical substituted by oxo or hydroxy, preferably lower alkyl which is unsubstituted or is monosubstituted by hydroxy or secondarily oxo, i. Lower alkyl, hydroxy lower alkyl, in particular a-Hydroxynied "eralkyl, or Oxoniederalkyl, especially lower alkanoyl.

Above and below, "lower" radicals and organic compounds are preferably understood as meaning those which contain up to and including 7, especially up to and including 4, carbon atoms. *

· Ν · ι ν »ι

55 746 11

Corsage alkyl is, for example, methyl, ethyl, propyl, isopropyl, n-, iso-, hepta- or tert-butyl, furthermore n-pentyl, n-flexyl or n-heptyl.

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

lower alkylthio is, for example, methylthio, ethylthio, propyltliio, isopropylthio or n-butylthio. Hydrozyniederalkyl is, for example, 2-hydroxyethyl, 2- or 3-hydroxypropyl, 4-hydroxybutyl or especially a-hydroxy lower alkyl, such as hydroxymethyl, 1-hydroxyethyl, 1-hydroxypropyl or 1-hydroxybutyl, furthermore 1-hydroxypentyl, -hexyl or -heptyl.

Oxone-lower alkyl is, for example, 2-oxoethyl, 2- or 3-oxopropyl, 4-oxobutyl or, in particular, lower alkanoyl, pormyl, acetyl, propynyl, butyryl, isobutyryl or else caproyl or oenanthyl ·

Halogen is for example halogen to Atoranummer 35, such as chlorine or, secondarily, bromine or fluorine. Salts of compounds of the formula I are, for example, your acid addition salts, preferably pharmaceutically usable acid addition salts, with pharmacologically acceptable mineral sulfonic or carboxylic acids, such as hydrohalides, eg. As hydrochlorides or bromides, hydrogen sulfates, sulfonates, z. As benzene, p-toluene or methanesulfonates, sulfamates, z. B. Cyclshexylsulfaminate, or carboxylic acid salts, eg. Acetates, fumarates, maleinates or tartrates, the same,

The invention relates in the first place to processes for the preparation of compounds of the formula I in which R 1 is a substituted by 1, optionally substituted by xliederalkyl, Hiederalkosy, hydroxy, halogen and / or chlorine substituted benzyl, optionally monounsaturated piperidyl, Ph optionally substituted by lower alkyl, ITiederalkoxy, hydroxy

1O.1OV1979 55 746 11

And / or halogen-substituted phenylene radical and Rp is an optionally in 1-step or in higher than the 2-position by oxo or in the 1-position substituted by hydroxy lower alkyl, as pharmaceuticals, pharmaceutical compositions containing them and said compounds themselves, with with the proviso that R _{1 is} 4- (1-benzyl) -piperidyl and 4- (1-benzyl) -, 4 - [1- (monoalkylbenzyl ) J- and 4-yl- (monohalobenzyl) T | -1 2,5,6-tetrahydropyrridyl is different when Ph is optionally substituted 1,4-phenylene and Rp is lower alkyl or ITiederalkanoyl with at least 2 C-atoms represents · The invention relates in particular to the preparation of compounds of the formula I, wherein R ₁ in the phenyl part, optionally by lower alkyl having up to and with 4 C atoms, such as methyl, lower alkoxy, with up to and with 4 C atoms, such as ethoxy, hydroxy, halogen with atomic number up to and including 35, such as chlorine, hydroxy and / or trifluoromethyl substituted 3- or 4- (1-sensyl) -pipe R 4 is pyryl or 3- or 4- (1-benzyl-1,2,5> 6-tetrahydro) -pyridyl, Ph is optionally, in particular in the o-position to R ₁ , by Hiederal- alkyl with bis and with 4 C atoms, such as methyl, lower alkoxy with up to and with 4 C atoms, such as methoxy, hydroxy or halogen with atomic number to and with 35, such as chlorine, substituted 1,4- or secondarily 1,3-phenylene, and Ro optionally in higher than the 2-position by hydroxy or in the 1-position or in higher than the 2- position by oxo substituted lower alkyl having bis and with 4 C-atoms, such as methyl, AethyI, 3-hydroxypropyl, 4-hydroxypropyl, Pormyl or acetyl means, as pharmaceuticals, pharmaceutical compositions containing them and said compounds themselves, with the proviso that R is unsubstituted 4- (1-benzyl) -piperidyl and optionally monosubstituted by I-lower alkyl or halogen 4- (1-benzyl 1,2,5,6-tetrahydro) -pyridyl or Ph is different from optionally substituted 1,4-phenylene, if R ₂ is

10.10.1979 55 · 746 11

alkyl iat or lower alkanoyl having at least 2 C atoms.

The invention preferably relates to the preparation of compounds of the formula I in which R- in the phenyl moiety is substituted by lower alkoxy having up to and including 4 C atoms, such as methoxy, and / or halogen having an atomic number up to and including 35, such as chlorine, mono- or di-substituted 3 - or especially 4- (1-benzyl) -piperidyl, Ph is 1,4-phenylene and R _{2 is} optionally in the 1-position or in higher than the 2-position by oxo or in higher than the 2-position by hydroxy mono-substituted ITiederalkyl with bis and with 4 C atoms, z. Ethyl, 3-hydroxypropyl or acetyl, and their pharmaceutically acceptable acid addition salts.

The invention relates in the first place to the preparation of compounds of the formula I in which R-, in the phenyl moiety by lower alkoxy having bis and 4 C atoms, such as methoxy, monosubstituted or by halogen to and with atomic number 35 »such as chlorine, disubstituted 4- (1-benzyl) piperidyl, Ph represents 1,4-phenylene and R ^ is lower alkyl having bis and 4 C atoms, such as ethyl, and their pharmaceutically acceptable acid addition salts.

The invention relates in particular to the preparation of the compounds of the formula I mentioned in the examples in free form or in the form of pharmaceutically usable acid addition salts.

The compounds prepared according to the invention are especially useful as pharmaceuticals.

Characteristic of the known teclinisclaen solutions

There are already quite a number of antithrombotic cystic substances of very different structure known, but all of them have undesired side effects or other disadvantages.

ΙΟ.1.0.1979

55 746 11

Object of the invention

The aim of the invention is the provision of antithrombotic γ / active compounds with completely new structure for this indication area.

Explanation of the essence of the invention

The invention has the object augrunde to show a process for the preparation of antithrombotically active compounds.

The novel compounds can be prepared by methods known per se., For example, by reacting in a compound of the Pormel

R _A - Ph - R ₂ (II),

wherein R ^ substituted in 5- posi by given in the phenyl part if substituted benzylamino, in 1-Stel ment an exchangeable radical X or in 1,2-position->

214 075 -? -

ment an optionally additional double bond having, optionally monounsaturated n-pentyl radical, or in a salt thereof, R ^ to the corresponding radical R, ringschliesst and, if desired, a stereoisomer mixture obtained separates into the components, the compound obtained in another compound of formula I. transferred and / or converts a resulting free compound into a salt or a salt obtained in the free compound or in another salt.

Interchangeable radicals here are, for example, optionally esterified or etherified hydroxy groups or optionally substituted mercapto or amino groups.

Esterified hydroxy groups are, for example, reactive esterified hydroxy groups, especially with mineral acids or hydroxy groups esterified with organic sulfonic acids, such as halogen, e.g. Chlorine, bromine or iodine, fluorosulfonyloxy, or aromatic or aliphatic sulphonyloxy, e.g. Methane, ethane, Aethensulfonyloxy, benzene, p-toluene or p-bromobenzenesulfonyloxy. As esterified hydroxy groups there are further hydroxy groups esterified with organic acids, such as lower alkanoyloxy or optionally, e.g. by halogen and / or nitro, substituted benzoyloxy, into consideration.

Etherified hydroxy groups are, for example, hydroxy groups etherified with aliphatic alcohols or with unsubstituted or substituted phenols, such as lower alkoxy or optionally phenoxy groups substituted by halogen and / or nitro.

Substituted mercapto groups are, for example, aliphatic thio groups or optionally substituted phenylthio groups, such as lower alkylthio or optionally phenylthio or benzylthio substituted by halogen and / or nitro. As more substituted

Mercapto groups are suitable sulfonium esters, such as di-lower alkyl sulfonium or optionally substituted by halogen and / or nitro-substituted diphenylsulfonium into consideration. ,

Substituted amino groups are, for example, aliphatic and / or substituted by optionally substituted phenyl or benzyl amino groups such as mono- or di-lower alkylamino or optionally substituted by lower alkyl, lower alkoxy, hydroxy, halogen and / or trifluoromethyl substituted anilino, benzylamino or Dipheny! As further substituted amino groups corresponding quaternary ammonium groups, such as Triniederalkylammonium- or Diniederalkylaminoxidgruppierungen come into consideration.

Salts of compounds of formula II are, for example, their acid addition salts, preferably mineral acid addition salts, such as hydrohalides, e.g. Hydrochlorides, hydrobromides or hydrogen sulfates, the same.

The cyclization of the radical R is carried out in a conventional manner, for example thermally, for example by heating to about 50 to 250 ⁰ C, if necessary in the presence of a condensing agent and / or water-binding agent, in an inert solvent and / or under inert gas, such as nitrogen.

Examples of suitable condensing agents are compounds of the formula II in which X is optionally esterified hydroxy or an optionally substituted mercapto or amino group, in particular basic condensing agents, such as hydrides, alkoxides or amides of alkali metals, e.g. Sodium hydride, alkali metal lower alkanolates, such as sodium methoxide or sodium ethoxide, or alkali metal salts, such as sodium amide or lithium diisopropylamine, also quaternary

^^ I mfy t » * Hr " * 3 * "

ammonium bases, such as benzyltriethylammonium hydroxide, or also tertiary organic nitrogen bases, e.g. Pyridine or triethylamine, into consideration. For the cyclization of compounds of formula II, wherein X is optionally etherified hydroxy, one uses, for example, acidic condensing agents, such as mineral acids, e.g. Sulfuric acid or phosphoric acid, or acidic ion exchangers, and for the cyclization of compounds in which R. has a 1,2-double bond, for example, Lewis acids. such as boron trifluoride or zinc chloride.

Suitable solvents are, for example, inert under the reaction conditions, organic, especially polar solvents, such as lower alkanols, e.g. Ethanol, lower alkanoic acid amides, e.g. N, N-dimethylformamide or N-methylpyrrolidone, di-lower alkylsulfoxides, such as dimethylsulfoxide, when using quaternary ammonium bases as condensing agents, furthermore water-containing two-phase systems, such as methylene chloride-water, benzene-water or amyl alcohol-water.

Water-binding agents are, for example, anhydrides or internal anhydrides, such as dicyclohexylcarbodic imide or phosphorus pentoxide.

The starting materials of the formula II are advantageous. under the reaction conditions prepared in situ , for example, by reacting a compound of formula

R ^ - Ph - R ₂ (Ha),

where R 1 is a radical X in the 1- and 5-position and an additional double bond in the 1,2-position or in the case of 1,2- and 1-naphthylene, each having an additional double bond, optionally monounsaturated n -Pentylrest, or a salt thereof, with.replied if necessary in the phenyl moiety substituted benzylamine or a salt thereof.

The novel compounds can be further prepared by reacting a compound of the formula

-Ph-R ₂ (III),

in which R 1 represents a 1-unsubstituted, optionally monounsaturated piperidyl radical, or a salt thereof by reaction with a, the optionally substituted benzyl radical introducing agent in 1-step substituted and, if desired, a stereoisomer obtained engemisch in the components, the compound obtained in a other compound of formula I and / or converted a resulting free compound into a salt or a salt obtained in the free compound or in another salt.

The optionally substituted benzyl radical introducing agents include, for example, reactive esters such as mineral acid esters, e.g. Halogen, preferably hydrochloric, hydrobromic or hydroiodic acid esters, or organic sulfonic acid esters, e.g. Methane, ethane, Aethen-, benzene, p-toluene or p-Brombenzolsulfonsäureester corresponding benzyl alcohol or under reducing conditions corresponding benzaldehydes.

Takes place the introduction of the optionally substituted benzyl radical, by reaction of the above products in a conventional manner, if necessary in an inert solvent, in the presence of a condensing agent and / or at elevated or reduced temperature, for example at about 0 ° to about 15O ⁰ C.

In the reaction with reactive benzyl esters is carried out in an opposite to the reactants inert solvent, if necessary in the presence of a basic condensing agent, at elevated or reduced temperature, for example at about 0 ° to 150 ⁰ C,

and / or under inert gas, such as nitrogen. Basic condensing agents are, for example, inorganic bases, such as alkali metal or alkaline earth metal hydroxides or carbonyl. nate, e.g. Sodium hydroxide, potassium hydroxide, calcium hydroxide, potassium carbonate or calcium carbonate or tertiary organic nitrogen bases, such as pyridine or triethylamine. Suitable solvents are, for example, ketones, such as dilower alkyl ketones, e.g. Acetone, alcohols, such as lower alkanols, e.g. Methanol, ethanol or amyl alcohol, optionally halogenated hydrocarbon ^, such as benzene, toluene or methylene chloride, or N, N-disubstituted Niederalkansäureamide, such as dimethylformamide or N-methylpyrrolidone.

In the reaction with benzaldehydes under reducing conditions, as reducing agents for aminoacylations, customary agents are used, such as dileight metal hydrides, e.g. Sodium borohydride or, preferably, sodium cyanoborohydride, catalytically activated hydrogen such as hydrogen in the presence of a hydrogenation catalyst such as a palladium, platinum or nickel catalyst, e.g. of platinum, optionally on carbon, platinum oxide, palladium on carbon or Raney nickel, also formic acid or its salts. The reaction in the presence of the abovementioned reducing agents is carried out in the manner customary for these, advantageously in a solvent inert to the reactants, under neutral or, if necessary, weakly acidic conditions, in the case of catalytic hydrogenations, if necessary under elevated pressure, e.g. at up to about 10 bar. Suitable inert solvents are preferably alcohols, such as lower alkanols, for example methanol or ethanol / optionally in admixture with water.

When using Dileichtmetallhydriden one works advantageously under neutral or in the case

of sodium cyanoborohydride weakly acidic conditions, e.g. at about pH 3 to 6, while catalytically hydrogenating advantageously in the presence of a mineral acid, e.g. of hydrochloric acid or reacting the reaction component of the formula III in the form of a corresponding acid addition salt, for example as a hydrochloride.

The starting materials of the formula III can be prepared by methods known per se. Compounds of formula III in which iL is α-substituted lower-alkyl, are e.g. obtained by adding a compound of the formula

R ^ -Ph-H (IHa),

wherein R1 is a nitrogen-protected, such as acylated, e.g. lower alkanoylated, optionally monounsaturated piperidyl radical, in the presence of a Lewis acid, e.g. of aluminum trichloride, with a reactive lower alkanoic acid derivative, e.g. a lower alkanecarboxylic acid anhydride or chloride, and reacting the protecting group in a conventional manner, e.g. by acid-catalyzed hydrolysis, cleaves.

Compounds of formula III in which R 1 is formyl can be obtained more advantageously by conventional formylation methods, e.g. by reacting a compound of the formula

R ₂ -Ph-H (I.IIb)

with Ν, Ν-disubstituted formamides, such as N-methyl-formanilide or dimethylformamide, in the presence of phosphorus oxychloride or with dimethylformamide methosulfate. Compounds of formula III wherein R 1 is lower alkyl substituted by hydroxy may be e.g. starting from corresponding compounds of formula III wherein R 1 is lower alkyl substituted by oxo, by reduction e.g. with sodium borohydride in a lower alkanol.

the. Compounds of formula III wherein I ^ is terminal hydroxy-substituted lower alkyl can be prepared analogously by reduction of esters such as lower alkyl esters, corresponding ui-carboxy-lower alkylphenylpiparidine compounds, for example with lithium aluminum hydride in diethyl ether or tetrahydrofuran. Compounds of formula III in which R "is lower alkyl can be obtained, for example, from compounds R of formula III reduced by hydroxy as lower R ₂ by reducing R" to lower alkyl, preferably by the action of hydrogen in the presence of a hydrogenation catalyst, eg palladium on carbon, advantageously in an organic acid such as acetic acid.

The novel compounds can be further prepared by reacting in a compound of formula

R _c - Ph - R ₂ (IV),

wherein R-, substituted by at least one hydrogen-substituted radical and / or having at least one optionally additional double bond radical R., or a salt thereof, the radical R " reduced to R- and, if desired, a stereoisomer mixture obtained in the components which converted compound into another compound of formula I and / or converts a resulting free compound into a salt or a salt obtained in the free compound or in another salt.

Hydrogen-displaceable groups are, for example, reductively hydrogen-displaceable groups, such as optionally functionally modified oxo, hydroxy or mercapto groups or organic sulfonyl groups. Functionally modified oxo groups are, for example, oxo or thione groups, seniicarbazone groups or optionally in the β-position by organic sulfonyl, such as

Benzene, p-toluene, p-bromobenzene or methanesulfonyi, substituted hydrazone groups.

Functionally modified hydroxy groups are, for example, etherified or esterified hydroxy groups, while etherified mercapto groups are particularly suitable as functionally modified mercapto groups. Etherified hydroxy groups are, for example, lower alkoxy groups, such as methoxy or ethoxy. Esterified hydroxy groups are, for example, hydroxy groups esterified with a mineral acid or organic carboxylic acid or sulfonic acid. Organic carboxylic acids are e.g. optionally substituted benzoic acids, alkane, especially lower alkanecarboxylic acids, e.g. Benzoic or acetic acid. Organic sulfonic acids are e.g. Benzene, p-toluene, p-bromobenzene, methane, ethane or Aethensulfonsäure. Mineral acids are preferably hydrohalic acids, e.g. Chloric, hydrobromic or hydroiodic acid. Etherified mercapto groups are, for example, lower alkylated or lower alkenylated mercapto groups, such as methylthio, ethylthio or ethylthio.

Optionally, functionally modified oxo groups are in particular in the α-position to the nitrogen atom. Optionally esterified hydroxy groups and etherified mercapto groups are especially benzylic on

bound C atoms. Etherified hydroxy groups are located in particular at the carbon atom of a C-N double bond.

Optionally additional double bonds may be oriented both exo- and endo-cyclically.

The reductive conversion of R in R ₁ in the usual manner by reaction with a suitable reducing agent.

Particularly suitable reducing agents are: Nascating, for example, by the action of a compound with labile hydrogen on metals, e.g.

a protic acid, such as a hydrogen halide or lower alkanecarboxylic acid, on iron or optionally amalgamated zinc, magnesium or aluminum, or water, preferably amalgamated aluminum, magnesium or sodium, for example sodium amalgam, or, for example, a hydrogenation catalyst, such as nickel or Noble metal catalyst, for example by Raney nickel or optionally bonded in a chemical or carrier form, such as oxide, platinum present, vie by platinum on carbon or by platinum oxide, or by homogeneous noble metal catalysts, such as triphenylphosphine platinum chloride or triphenylphosphine-rhodium chloride, catalytically excited Hydrogen, furthermore low-grade transition metal compounds, ^{such as} tin (II) or chromium (II) salts, eg stannous chloride, or hydrides, such as calcium hydride or the borohydride tetrahydrofuran complex, or dileil metal hydrides, such as lithium aluminum hydride, optionally mixed with aluminum chloride, Nat rium-bis- (2-methoxyethoxy) -aluminum hydride or sodium tris (2-dimethylaminoethoxy) -aluminum hydride, sodium borohydride or sodium cyanoborohydride.

The reaction can be carried out in the literature in each case as suitably known manner.

Optionally esterified or etherified hydroxy group bonded to a benzylic carbon atom, ketonic oxo groups and / or group A having at least one double bond may in particular be obtained by conventional reaction with e.g. catalytically excited hydrogen, as indicated above, for example with hydrogen in the presence of palladium on carbon, if necessary in an inert solvent such as a lower alkanol, a lower alkanoic acid or an aliphatic ether, e.g. in ethanol, acetic acid or dioxane, and / or at elevated temperature.

Keto oxo groups, sulfonyl groups and / or etherified mercapto group-containing groups R "can also be obtained by conventional reaction with, e.g. nascent hydrogen produced as indicated above, for example, by the method of Clemmensen, preferably with zinc and hydrochloric acid.

Halogen, etherified hydroxy bound to the carbon atom of a CN double bond, at least one optionally double bond and / or lactamic or amido oxo containing radicals R "can be obtained, for example, by conventional reaction with a suitable dileight metal hydride, such as one of those mentioned in an inert solvent and / or at elevated temperature, eg at boiling temperature, starting from halogen compounds, for example with sodium borohydride in water, alcohols, such as ethanol, or Aethylenglykomomethylather, or amines, such as pyridine, triethyiamine, with sodium bis (2-methoxyethhoxy) aluminum hydride in aromatic or araliphatic hydrocarbons,

such as benzene or toluene, or with sodium tris- (dimethylaminoethoxy) -aluminum hydride, or from lactams or amides, for example, with lithium aluminum hydride in an aliphatic ether, e.g. in diethyl ether, tetrahydrofuran or dioxane, if necessary reduce at boiling heat. · '

As indicated substituted hydrazone groups,

e.g. β- (p-toluenesulfonyl) -hydrazones, containing radicals R-,

may be prepared, in particular, by conventional reaction with a non-noble metal hydride, e.g. with sodium cyanoborohydride in Hexainethylphosphorsäuretriamid, if necessary at elevated temperature, be replaced by hydrogen. Radicals containing semicarbazone or unsubstituted hydrazone groups can be prepared, for example, by customary reaction with a strong base, for example according to the process formula

"Wise of Wolff-Kishner, with an alkali metal alcoholate, for example with sodium, if necessary under elevated pressure and / or at elevated temperature or after the modification of Huang-Minlon with an alkali metal hydroxide, for example Kaliumhydraxid, in an inert, high-boiling solvent, for example in di or triethylene glycol or di-ethylene glycol monomethyl ether.

In a preferred embodiment of the above method, for example, starting from a compound of formula IV, wherein the radical R _{r is} at least one attached to the nitrogen atom carbocyl group having radical R, for example a substituted in the 1-position by optionally substituted benzoyl piperidyl or 2-piperidone radical or a 1-position substituted by optionally substituted benzyl-substituted 2-piperidone radical, means, and reduces the oxo group (s) by reaction with a suitable Dileichtmetallhydrid, for example with lithium aluminum hydride in an ether, for example in diethyl ether or tetrahydrofuran, if necessary elevated temperature, eg at boiling heat.

In another preferred embodiment, a compound of formula IV wherein R is an N-benzylpyridinium radical optionally substituted in the phenyl moiety of the benzyl radical and reduces at least two of the double bonds of the pyridinium radical to single bonds. When hydrogen is used as the reducing agent in the presence of a platinum or Rhodiümkatälysätors, e.g. from platinum on carbon, platinum oxide, or the triphenylphosphine-rhodium chloride complex, or lithium aluminum hydride in an ether, such as diethyl ether or tetrahydrofuran, are preferably obtained compounds of formula I in which R, a saturated piperidyl

has rest. In contrast, with the use of mild-acting di-noble metal hydrides, e.g. of sodium borohydride in a lower alkanol, such as ethanol, preferably compounds of the formula I, wherein R, has a 1,2,5,6-tetrahydropyridyl radical.

Also replaceable by hydrogen is optionally present in salt form, for example as the alkali metal salt, such as sodium salt, copper salt or ammonium salt, present carboxy group. This is preferably located at the -C atom of the radical R connected to the radical -PhR ₉ . The replacement of the same by hydrogen is preferably carried out by decarboxylation, for example by heating to about 100 to 250 ⁰ C, if necessary in a high-boiling solvent, for example in ethylene glycol, dimethylformamide, Aethylenglykolmonomethyläther or diphenyl ether.

The starting materials of the formula IV are known or can be prepared by methods known per se.

Compounds of the formula IV in which R "denotes a C-atom which is substituted by hydroxy on the C atom attached to a lower alkylphenyl radical -PhR ₉ and optionally substituted in the phenyl moiety by 1-benzylpiperidyl may be obtained, for example, by reacting a corresponding N-benzylpiperidone with one by the action of a lower alkylhalobenzene Magnesium obtainable Niederalkylphenylmagnesiumhalogenids, for example the formula R ₉ -Ph-MgBr, preferably in an ether such as diethyl ether or tetrahydrofuran, are prepared. Analogously, it is also possible to prepare starting materials in which R _{9 has} oxo or hydroxy starting from oxo or hydroxy-lower alkyl halobenzenes in which the oxo or hydroxy group is protected, for example oxo-acetalated, and cleaves off the protective group after carrying out the reaction sequence ,

- -fj-

Compounds of the formula IV in which R "is an esterified or etherified hydroxy-substituted, optionally substituted in the phenyl moiety substituted 1-Benzylpiperidylrest, for example, from the corresponding, e.g. hydroxy compounds as obtainable above, by esterifying or etherifying the hydroxy groups in a conventional manner, e.g. with a halogenating agent, such as thionyl chloride or phosphorus tribromide, in halogen or with a lower alkanecarboxylic acid anhydride, such as acetyl chloride, in lower alkanoyloxy or by reaction with a'-lower alkoxide, such as sodium ethoxide, into lower alkoxy.

Compounds of the formula IV in which the radical

R _{n has} an etherified mercapto group, in -G

For example, by obtaining a corresponding, e.g. as indicated above, halogen compound in the usual manner with an alkali metal lower alkylthiolate reacted.

Compounds of the formula IV in which the radical Rp has a sulfonyl group are obtainable, for example, by conventional oxidation of corresponding thioethers, preferably with an organic peracid, such as m-chloroperbenzoic acid. Sulfonyl-substituted compounds of the formula IV can be obtained on the benzyl sulfone having the partial structure R ₂ -Ph-CH ₂ -SO ₂ - on the sulfonyl-substituted compounds of the formula IV which are attached to the radical -Ph-R ₂ Di-halogen, such as 1,5-dibromo-N-benzyl-pentane or pentene condensed in a conventional manner.

In an analogous manner, it is also possible to obtain compounds of the formula IV in which the Rp radical on the C atom connected to the -PhE radical has a carboxy group by reacting, in the customary manner, a partial structure R ₂ -Ph-CH ₂ - COO- containing phenylacetic acid ester with a corresponding 1,5-dihalogeno-N-benzyl-pentane or

-penten condenses.

Compounds of formula IV in which R is an optionally substituted in the phenyl moiety substituted l-benzyl-2-piperidone, for example, can be prepared by reacting a corresponding 5-benzylamino (R "phenyl) valeric acid or a reactive derivative such as an ester or an anhydride thereof, cyclized in a conventional manner. In an analogous manner, one may also prepare compounds of formula IV in which ^X R_ is an optionally substituted l-benzyl-2,6-dioxopiperidylrest. This is based on a corresponding R ^ -Phenylglutarsäure or a reactive derivative, such as a diester or anhydride, of which and in the usual way with a corresponding benzylamine to.

Compounds of the formula IV, in which R _{c is} functionally modified. Oxo, for example, can be obtained by the oxo group (s) in a customary manner functionally modified in corresponding oxo compounds, for example, by reaction with semicarbazide or optionally substituted hydrazine in semicarbazones or hydrozono transferred. Analogously, it is possible to convert oxo compounds of the formula IV into the corresponding enol or lactim ether by alkylation, for example with tri-lower alkyloxonium salts. Unsubstituted hydrazone compounds of the formula IV are advantageously prepared in situ by reacting with hydrazine at elevated temperature, for example at about 100 to 250 ° C, if necessary in a high-boiling solvent such as di- or triethylene glycol or diethylene glycol monomethyl ether, and in the presence of a base , For example, a metal alcoholate, such as sodium methoxide, or an alkali metal hydroxide, such as potassium hydroxide, makes.

Compounds of the formula IV in which the radical

R 1 in the 1-position having an optionally substituted benzoyl radical can be prepared, for example, by reacting a compound of the formula R'-Ph-R ₂ (IVa) in which R 'is unsubstituted in the 1-position, preferably a compound of the formula R ^ -fn-R «(II), wherein R_ is an unsubstituted in 1-unsubstituted, optionally monounsaturated piperidyl, in a conventional manner with a benzoylating agent, for example with benzoyl, reacting, if necessary in the presence of a basic condensing agent, for example of sodium hydroxide, or an organic nitrogen base, for example of pyridine or triethylamine. In an analogous manner, it is also possible to obtain compounds of the formula IV in which R "denotes an optionally substituted N-benzylpyridine radical by quaternizing a corresponding R 1 -phenylpyridine with a reactive derivative, for example the bromide, of a corresponding benzyl alcohol.

The novel compounds in which R 1 is a monounsaturated piperidyl radical substituted in the 1-position by optionally substituted benzyl can be further prepared by reacting in a corresponding compound of the formula

R ₀ -Ph-R ₂ (V),

wherein L. means a piperidyl radical substituted in 1-position by optionally substituted benzyl and by an α, β-eliminable radical, or a salt thereof eliminates them together with a β-hydrogen atom and, if desired, separates a obtained stereoisomer mixture into the components , the resulting compound is converted into another compound of the formula I and / or converts a resulting free compound into a salt or a salt obtained in the free compound or in another salt.

For example, optionally esterified hydroxy groups, optionally etherified or esterified mercapto groups, sulfonium groups, sulfinyl groups, sulfinyl groups and ammonium groups are radicals which can be split off together with a β-position hydrogen atom. Esterified hydroxy or mercapto is exemplified by a mineral acid such as a hydrohalic acid, e.g. with bromine or hydrogen chloride, esterified hydroxy or with an organic acid such as a lower alkanecarboxylic acid, e.g. Acetic acid, or with xanthic acid, esterified hydroxy or mercapto. Etherified mercapto is, for example, lower alkylthio, such as methylthio or ethylthio, or optionally substituted phenylthio, e.g. Phenyl, p-methylphenyl or p-bromophenylthio. Sulfinyl and sulfonyl groups are, for example, sulfinyl or sulfonyl groups derived from the aforementioned etherified mercapto groups, e.g. Methane, ethane, benzene, p-toluenesulfinyl or sulfonyl. Sulfonium groups are, for example, di-lower alkylsulfonium groups, such as dimethylsulfonium. Ammonitimgruppen are, for example Diniederalkyl- or Triniederalkylammoniumgruppen, such as diethylammonium or triethylammonium, or Diniederalkylaminoxidgruppierungen, such as diethyl • aininoxidgruppen.

The elimination is carried out in a customary manner, if necessary in the presence of catalytic and / or cleavage products binding agents, at elevated temperature, for example at about 50 to 200 ⁰ C, under, for example distillative in particular azeotropic-distillative removal of reaction products, and / or under inert gas, such as Nitrogen, advantageously in an inert solvent. Catalytic agents include, for example, the elimination of water, hydrogen sulfide, organic acids, ammonia and secondary amine facilitators, such as protic acids, eg, mineral acids, preferably hydrochloric acid,

-IJ-

Sulfuric acid or alkali metal hydrogen sulfates, phosphoric acid, p-toluenesulfonic acid or acidic ion exchanger, or facilitating the elimination of mineral acids weak nucleophilic bases, such as alkali metal hydroxides, e.g. Potassium hydroxide. Cleavage product binding agents include, for example, water-binding agents such as dicyclohexylcarbodiimide, or sulfur, hydrogen or mercaptan binding agents such as heavy metal salts, e.g. Copper, zinc or silver salts, and also ammonia- or amine-binding agents such as mineral acids.

The starting materials of the formula V are known or can be prepared in a manner known per se.

Compounds of the formula V in which R _{0 has} hydroxy or mercapto on the carbon atom connected to the radical -PhR ₂ can be obtained, for example, by reacting a corresponding 1-benzyl-piperidone or 1-benzyl-piperidin-thione with one, if appropriate an oxo or hydroxy group intermediately protected R2-Phenylmagne-. siumhalogenid, for example, the, formula R ^ -Ph-MgBr, converts.

The novel compounds can be further prepared by reacting in a compound of formula

(VI),.

wherein R- represents a group R to be transferred into a group R, or in a salt thereof R-. into R2 and desirably all of one stereoisomeric species obtained is resolved into the components, the resulting compound is converted into another compound of the formula I and / or a free compound obtained in a salt or a salt obtained in the free compound or in another Salt is converted.

R ₂ groups which can be transferred are, for example, different and reductive and / or solvoly-

14 07

-IH-

Table in R ₂ UberfUhrbare 'groups, for example, unsaturated and / or by functionally modified oxo and / or functionally modified hydroxy-substituted lower aliphatic radicals.

Functionally modified oxo groups are, for example, thioxo, optionally substituted imino groups or acetalized or thioacetalized oxo groups, furthermore hydrated oxo groups and esters thereof.

Suitable substituents of imino are, for example, unsubstituted or substituted phenyl, lower alkyl or furthermore hydroxy or by 2-sulfonyl-lower alkyl, such as 2-benzenesulfonyl-lower alkyl or 2- (p-toLuolsulfonyl) -lower alkyl, substituted amino into consideration. Acetalized oxo groups are, for example, with a lower alkanol, such as methanol or ethanol, or a lower alkanediol, vie Aethylen- or propylene glycol, acetalated oxo groups. Analogously, thioacetalizing oxo groups, for example, with a lower alkane thiol, such as methyl or ethylmercaptan, or a lower alkanedithiol, such as with 1,2-dimercaptoethane or 1,3-dimercaptopropane, to understand thioacetalisierte oxo groups. Ester hydrated r oxo groups are, for example, their esters with a mineral acid such as a hydrohalic acid, e.g. with hydrochloric acid.

Functionally modified hydroxy groups are, for example, etherified or esterified hydroxy groups. Etherified hydroxy is, for example, lower alkoxy, such as methoxy or ethoxy, or optionally substituted phenoxy. Esterified hydroxy is exemplified by a mineral acid such as a hydrohalic acid, esterified hydroxy, e.g. Chloro or bromo, with an organic sulfonic acid such as a lower alkane or optionally substituted benzenesulfonic acid esterifies the hydroxy, e.g. Methane, ethane, p-toluene, p-eromobenzene or mesitylene

i -. is-

sulfonyloxy, or with a carboxylic acid such as a lower alkanoic or optionally substituted benzoic acid, or optionally partially esterified or amidated carbonic acid esterified hydroxy such as lower alkanoyloxy, e.g. Acetoxy, benzoyloxy, lower alkoxy, e.g. Methoxycarbonyloxy or carbamyloxy.

Suitable groups R _E include, in particular: lower alkenyl, such as vinyl, allyl or methallyl, lower alkynyl, such as ethynyl or 1-propynyl, optionally esterified or anhydridized carboxy, carboxy-lower alkyl and carboxy-lower alkenyl groups, such as corresponding lower alkoxycarbonyl or halocarbonyl-containing radicals or etherified Hydroxyniederalk (en) ylreste, such as Niederalkanoyloxy- or optionally Benzoyloxycarbonylreste, for example α-acetoxy or Benzoyloxyniederalkylreste, α- or (jj -Halogenniederalkylreste, U) -Sulfonyloxy-, for example (jj- (p-Toluolsulfonyloxy) -lower alkyl, or Niederalkyläther Niederalkvl-enols, further Thioxoniederalkylreste or geminal lower alkoxy or Niederalkylenedioxy-lower alkyl radicals. "

The reductive conversion into r is carried out by methods known per se, for example by catalytic hydrogenation or reaction with light metal or Dileichtmetallhydriden. For example, lower alkenyl, lower alkynyl may be obtained by the action of catalytically activated hydrogen such as hydrogen in the presence of a hydrogenation catalyst, preferably a nickel, platinum or rhodium catalyst, e.g. from Raney nickel, platinum or platinum oxide on carbon, or a platinum chloride or rhodium chloride triphenylphosphine complex, to lower alkyl. In the usual way, it is advantageous to work in an 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. at up to about 25 bar, preferably in a closed vessel. Similarly, one can also halocarbonyl or Halogencarbonylniederalk (en) yi to. Reduce hydroxy lower alkyl.

Hydrazone-lower alkyl R- may also be prepared in the usual way by base treatment, e.g. according to the procedure of Wolff-Kishner, with an alkali metal alcoholate, e.g. with sodium methoxide, if necessary under elevated pressure at about 100 to 250 ° C, or Huang-Minlon with an alkali metal hydroxide, e.g. of potassium hydroxide, in an inert, high boiling solvent, e.g. Di- or triethylene glycol, to lower alkyl R "be reduced. .. - '

Further, for example, optionally etherified or anhydridized carboxy or carboxy-lower alkyl groups can be reduced by reaction with light metal or Dileichtmetallhydriden to oxo or hydroxy. For the reduction to oxo-lower alkyl is preferably used Niederalkyllithiumaluminiumhydride, such as diisobutyl or Triisobutyllithiumaluminiumhydrid, whereas used for the reduction to Hydroxyniederalkyl especially lithium aluminum hydride in an ether such as diethyl ether or tetrahydrofuran. In the reactions mentioned, it is advantageous to work under inert gas, for example under nitrogen or argon, if necessary with cooling or heating, for example at about -20 to + 8O ⁰ C. In an analogous manner, it is also possible to use primary halogen or sulphonyloxy-containing halogen or. Sulfonyloxyniederalkylgruppen to lower alkyl and with a carboxylic acid or partially esterified or amidated carbonic acid esterified Hydroxyniederalkylgruppen to Hydroxyniederalkyl reduce. Analogously, it is also possible, as indicated, to reduce substituted hydrazone-lower alkyl to lower-alkyl,

SI 4 07

for example by means of sodium borohydride in hexaphosphoric triamide.

Also to be considered as reduction is the reductive lower alkylation of optionally esterified or anhydridized carboxy or carboxy-lower alkyl groups R ₅ , with lower alkyl metal compounds to give oxo or hydroxy-lower alkyl groups R 1. Lower alkyl metal compounds are, for example, those having as metal radical · a group of the formula -M, -M -Hal or M / 2, where M is a metal atom of group I, M is a metal atom of group II of the Periodic Table of the Elements and Hal halogen, such as Chlorine, bromine or iodine. Preferred metal radicals of the type mentioned are those of the formulas -Li, -MgHaI- and -Cd / 2.

Optionally, functionally modified carboxy groups are, for example, in salt form, such as an alkali metal salt form, present or, preferably, anhydridized carboxy groups with a hydrohalic acid, such as fluoro-, chloro-, bromo- or hydroiodic acid, esterified carboxy groups, such as lower alkoxycarbonyl or optionally substituted benzoyloxycarbonyl, or disubstituted carbamyl groups, such as Ⓒ, Ⓒ or 1-imidazolinylcarbonyl. The reaction of optionally functionally modified carboxylic acids of formula VI with said Niederalkylmeta.llverbindungen in the usual manner, advantageously in an inert solvent such as an ether, for example in diethyl ether or tetrahydrofuran, a hydrocarbon, eg benzene ', or mixtures thereof, if necessary, under Cooling or gentle heating, for example at about -80 to about 100 ⁰ C, for example at boiling temperature, and / or under inert gas, for example under nitrogen. Depending on the particular starting materials used and the reaction conditions, either

Ketone (R "» Oxoniederalkyl) or tertiary alcohols (R ₂ = * Hydroxiliederalkyl) of the formula I obtained. Thus, when using reactive Niederalky! Metal compounds, for example of Niederalkylmagnesiumhalogeniden or Lithiumniederalkylen, and at normal or elevated temperature, for example at about 0 ⁰ C to about 100 ⁰ C, predominantly compounds of formula I, wherein R _{2 is} hydroxy lower alkyl and at reduced temperature , For example, at about -80 to ^{0 0} C, or when using less reactive Niederalky! metal compounds, for example of Niederalky! cadmium, under normal temperature conditions, preferably compounds of formula I wherein R _{2 is} Oxoniederalkyl. In an analogous manner, compounds of the formula I in which R ₂ is lower alkyl can also be obtained by reacting a compound of the formula VI in which R is halogen or sulfonyloxy-lower alkyl with one of the abovementioned lower alkyl metal compounds, in particular a lithium lower alkyl ,

By solvolysis it is possible, for example, to convert at least one functionally modified oxo and / or hydroxy group-containing radicals R ₁ into radicals R ₂ which are exposed to an oxo or hydroxy group. For example, compounds of formula VI in which R-, thioxo, optionally substituted imino, geminal or double bond-bonded etherified hydroxy groups can be converted to compounds of formula I wherein R _{2 is} oxo-lower alkyl or compounds of formula VI wherein Rg esterifies the hydroxy to hydrolyze compounds of formula I wherein R _{2 is} hydroxy lower alkyl. The hydrolysis is carried out in a customary manner, for example in the presence of a basic or acidic Hydrolysemittels, if necessary in the presence of a solvent, and / or at elevated temperature, for example at about 20 to 150 ⁰ C.

Basic condensing agents are, for example, alkali metal, ammonium or alkaline earth metal hydroxides or corresponding carbonates, e.g. Sodium, potassium or calcium hydroxide, ammonia or potassium or sodium carbonate. Acidic hydrolysis agents are, for example, protic acids, such as mineral acids, e.g. Hydrochloric or sulfuric acid, sulfonic acids, e.g. p-toluenesulfonic acid, or carboxylic acids such as acetic acid. Inert solvents are, for example, water-miscible solvents such as lower alkanols, e.g. Methanol or ethanol, ketones, e.g. Acetone, amides, e.g. Dimethylformamide or N-methylpyrrolidone, or sulfoxides, e.g. Dimethyl sulfoxide. In the hydrolysis of thioxole-lower alkyl, if necessary, it is also carried out in the presence of a heavy metal compound, e.g. of copper oxide, or an oxidizing agent, e.g. of hydrogen peroxide or organic peracids.

With a carboxylic acid esterified Hydroxyniederalkylreste R-. may be further prepared by reaction with a low molecular weight alcohol such as a lower alkanol, especially methanol, in the presence of a mineral acid, e.g. of hydrochloric acid, or an alkali metal

limetallalkoholates, such as Natriummethanolat alcoholytisch or by reaction with ammonia or an organic amine, aminolytically transferred to hydroxy lower alkyl. '·' ...

The starting materials of the formula VI can be prepared by methods known per se.

Thus, compounds of the formula VI in which Rg has a functionally modified oxo and / or hydroxy group can be prepared, for example, by reacting in a compound of the formula R ₅ -Ph-R ₂ (III) in which R _{β is} a 1-unsubstituted , optionally monounsaturated piperidyl radical, the group R ₂ by conversion

% 1 4 07S - 30-

of oxo with phosphorus pentasulfide or aluminum trisulfide in thioxo, by reaction with ammonia or an organic amine, hydroxylamine or optionally substituted hydrazine in an optionally substituted imino group, with an orthoester in acetalated or with a lower alkanethiol in thioacetalized oxo exhibiting R and / or.yon hydroxy converted by esterification in esterified hydroxy R "and then, for example, by reaction with an optionally substituted Benzvlbromid the radical R _n in the desired radical R transferred.

 *. B X

Compounds of the formula VI in which R 1, an acetalized or thioacetalized or present in Enoläthefform oxo group, for example, can also be prepared by reacting a corresponding Halogenphenyloxoniederalkan, for example the formula halogen-Ph-R "(VIa) by reaction with an orthoester acetalized or by reaction with a mercaptan or bimercaptan thioacetalisiert or enolveräthert in the usual way, the product, for example of the formula halogen-Ph-Rg (VIb), with magnesium in the Grignard compound, for example the formula halogen-Mg-Ph-Rp (VIc), converted, reacted with an optionally substituted 1-benzal-halo-piperidine and worked up basic. From these, by reaction with hydrogen sulphide, corresponding compounds of formula VI can be obtained, in which 1L ·? Thioxo has.

Compounds of the formula VI in which R is carboxy or carboxy-lower alkyl can also be prepared by converting a halobenzoic acid or halophenyl-lower alkanoic acid into the acid chloride and reacting with aminoisobutanol or 2,2-dimethylaziridine into the corresponding 2- (halophenyl or 2- (halophenyl-lower alkyl) -4,4- or -5,5-dimethyl-oxazolyl- (2) or a corresponding nitrile with acid catalysis by means of 4-

Amino-2-methyl-pentan-2-ol or 2-methyl-pentane-2,4-diol into the corresponding 2- (halophenyl) or 2- (Ealogenphenylniederalkyl) -4,4,6-trimethyl-5 Converted 6-dihydro-oxazinyl, the reaction product is converted in each case with magnesium in the corresponding Grignard compound, these reacted with a corresponding 1-Benzylpiperidylhalogenid or 1-Benzylpiperidon, in the latter case from the reaction product eliminates water, each removing the protective group by acid treatment and, if desired, the esterified acid is esterified or converted to an anhydride, z, B, with thionyl chloride in the acid chloride. Compounds of the formula VI in which IU is a -substituted by optionally, esterified or anhydridized carboxy, in the 2-position to the mentioned group having hydroxy or in the 2,3-position-unsaturated radical, can furthermore be prepared by adding one in the piperidyl part optionally monounsaturated 1-acyl-phenylpiperiden niederalkanoyliert with a Niederalkanoylhalogenid in the presence of aluminum trichloride in the phenyl moiety, in the thus obtainable Niederalkanoyl- (1-acylpiperidyl) phenol in the usual manner, for example by reaction with a Niederalkancarbonsäureester in the presence of an alkali metal alcoholate, with an a Halo-lower alkanoic acid ester and zinc or with a lower alkanecarboxylic acid anhydride in the presence of a corresponding alkali metal carboxylate, or by means of a Phosphorylidenessigsäureesters, as of Triphenylphosphorylidenessigsäureäthylester, the radical R_ builds, djeti-l-acyl hydrolytically split off, the Reaktionsprod Ukt in the usual manner, for example by reaction with optionally substituted Eenzylbromid in the presence of triethylamine, 1-benzylated, if desired, functionally abgewahddeltes carboxy hydrolyzed and / or carboxy, for example with thionyl chloride, halogenated.

Analogously, starting from 1-acylpiperidylbenzaldehydes or 1-acylpiperidyl lower alkanals obtained by formylation, e.g. by dimethylformamide and phosphorus oxychloride, corresponding 1-acylpiperidyl-benzenes and optionally chain extension by means of methoxymethylene-triphenyl-phosphorane, are accessible by reaction with lower alkanals or Niederalkansäureestern in the presence of a strong base, such as an alkali metal lower alkanolate, compounds of formula VI are obtained in which R - Has an oxo or esterified carboxy group and a ß-related hydroxy group or a conjugated double bond. Analogously, in the presence of a metal, e.g. of zinc, with an a-halo-lower alkanoic acid ester to give corresponding 2-hydroxy-lower alkanoic acid esters.

Compounds of formula VI wherein R 1, lower alkenyl or lower alkynyl 'may be further prepared by reacting a corresponding halophenyl lower alkane or lower alkyne in a metal compound, e.g. converted by reaction with magnesium in the corresponding halomagnesium compound, this condensed in the usual manner with an optionally substituted 1-benzyl-halogenpiperidine or 1-benzylpiperidone and splits off water in the latter case.

Compounds of formula VI in which R ^, halogen, for example, by conventional Halogenbzw. Hydrogen halide addition to corresponding, an unsaturated radical R ^. having exhibiting compounds of formula VI. ,

The lower alkyl metal compounds to be used for the preparation of starting materials of the formula VI are advantageously prepared in situ by reacting a

"1 corresponding halogen, e.g., chloro, iodo or, especially, bromo-lower alkanes, preferably in an ether, e.g.

Diäthylather or tetrahydrofuran, with lithium or especially magnesium, is reacted. Other lower alkyl metal compounds can be prepared from the halogens thus obtainable, especially bromine magnesium compounds, by reaction with a corresponding metal halide, e.g. with cadmium chloride, copper chloride or zinc chloride.

The novel compounds can be further prepared by adding a mixture of compounds of the general formulas

R _o - Ph - H (VII) and R - - Χ _χ (VIII),

wherein one of the radicals R and R 'is a radical R _n and the

oo 1

other represents a radical R ", and X represents an optionally reactive esterified hydroxy group or a bond extending to an adjacent carbon atom, allowing a suitable acidic agent to act and, if desired, performing one or more of said additional operations.

The radical X, is especially reactive esterifies it hydroxy, especially halogen with atomic number 17 and higher, such as chlorine. As radical X bound to lower alkanoyl R, hydroxy-esterified hydroxy is further suitable with the acid of formula R, -OH.

Suitable acidic agents are, for example, mineral acids such as hydrofluoric acid or optionally anhydride-formoxyacids of phosphorus or sulfur, e.g. Phosphoric acid, diphosphoric acid, polyphosphoric acids or phosphorus pentoxide or sulfuric acid, or especially Lewis acids, such as halides of elements of main groups III, IV and V and subgroups II and VIII 'of the Periodic Table of the Elements, such as Bo & S, aluminum, gallium, tin, Antimons and iron, eg in addition to iron trichloride, zinc chloride, tin chloride and antimony pentachloride, especially bortrichloride

I - 2H - -

and fluoride and aluminum trichloride and bromide, and also complex metal acids such as tetrafluoroboro- or hexachloroantimonic acid.

The reaction is carried out in a customary manner, for example in an inert solvent such as carbon disulfide, nitrobenzene, carbon tetrachloride, diethyl ether, tetrahydrofuran or an excess of the starting material of the formula VIII, at normal, moderately elevated or reduced temperature, for example at about -30 to about 100 ⁰ C, advantageously with exclusion of moisture and / or inert gas, for example under nitrogen.

In a preferred embodiment of the above process, for example, a mixture of compounds of formulas VII and VIII, wherein R is a radical R, and R'-X is allowed. a lower alkanoyl halide, e.g. chloride, or lower alkanoic anhydride, aluminum trichloride act, preferably working in boiling carbon disulfide.

The novel compounds can be further prepared by reacting compounds of the formulas

R ₀ -Ph- X ₂ (IX) and RJJ = -rr-: X ₃ (X),

in which one of the radicals R and R "is a radical R ₁ and the other

00 1

particular a radical R 2 and one of X ₂ and X ₃ is a metal radical and the other halogen or lower alkyl R ¹ ^ bound oxo or a lower alkanoyl R ¹ 'bound present in salt form, etherified or esterified hydroxy, is condensed with one another and, if desired, a isomerized into the components, the compound obtained is converted into another compound of the formula I and / or a free compound obtained in a salt or a salt obtained is converted into the free compound or into another salt.

Metallradikale- are, for example, groups of the formula -M, -M or -> T / 2, wherein M is a metal atom of group I "Ir" is a metal atom of the Periodic Table II of the elements and Hai halogen, such as chlorine, bromine or iodine. Preferred metal radicals of the type mentioned are those of the formulas -Li, MgHaI and -Cd / 2.

Etherified hydroxy is, for example, lower alkoxy. Esterified hydroxy is e.g. Hydroxy present in salt form, for example, in an alkali metal salt form, for example as the sodium salt, is hydroxy present, halogen is preferably fluoro, chloro, bromo or iodo.

The reaction of compounds of the formulas IX and X is carried out in a customary manner, advantageously in an inert solvent such as an ether, for example in diethyl ether or tetrahydrofuran, a hydrocarbon, for example benzene, or mixtures thereof, if necessary under cooling or gentle heating, for example at about -30 to about 100 ⁰ C, for example at boiling temperature, and / or under inert gas, for example under nitrogen. Preferred 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 I in which R 1 is oxo-lower alkyl, of halomagnesium compounds (IX) with lower alkanones (X) to give compounds of the formula I, wherein R is ~ 1 -H _: ydio xyniederalkyl and of lithium or halomagnesium compounds (X) with compounds of formula IX, wherein R is a radical R ^ and X, halogen iSt. ; .. '

The starting materials of the formulas IX and X are known or, as far as new, according to known per se

'. \

Methods are produced.

The organometallic compounds to be used as starting materials, e.g. of the formula IX, wherein R

V - 2b -

a lower alkyl radical R ₂ and X ^ represents the metal radical are advantageously prepared in situ by reacting a corresponding halogen, for example chlorine, iodine or especially bromine compound, preferably in an ether, for example in diethyl ether or tetrahydrofuran, with lithium or before all magnesium, implements. Other organometallic compounds can be obtained from the halogens thus obtainable, above all bromine magnesium compounds, by reaction with a corresponding metal halide, for example with cadmium chloride, copper chloride or zinc chloride. The halogen compounds to be used for this purpose can be prepared, for example, by halogenating a 1-acylpiperidylbenzene or R 1 -Benzcl in the customary manner, for example with bromine or chlorine in the presence of iron or with N-chlorosuccinimide, an obtained 1-acylpiperidyl 1-benzylated, optionally substituted 1-Benzylhalogenpiperidinverbindungen can be prepared analogously by 1-benzylation of corresponding 1-unsubstituted phenylpiperidines or phenyl-tetrahydropyridines.

Compounds of the formula I which can be obtained according to the invention can be converted into other compounds of the formula I in a manner known per se.

For example, in compounds of the formula I, it is possible to reduce an oxo-containing radical R ₂ to the corresponding hydroxyl-containing radical R ₂ . In this case, for example, a Dileichtmetallhydrid, such as an alkali metal borohydride or alkali metal aluminum hydride, for example sodium borohydride ^ sodium cyanoborohydride is used as the reducing agent. or lithium aluminum hydride, ·, preferably in an inert solvent, if necessary with cooling or warming, for example at about 0 ° to 120 ⁰ C, and / or under inert gas, such as nitrogen. Advantage-

ff 4

in particular, reduction with sodium borohydride in an inert, polar solvent such as a lower alkanol, e.g. in methanol, ethanol or butanol, or in dimethylformamide or in, optionally hydrous, mixtures thereof or with lithium aluminum hydride in an ether, such as diethyl ether, dioxane or tetrahydrofuran. The reduction of the oxo group to hydroxy can be further effected by reaction with a ketone such as acetone in the presence of an aluminum alcoholate, e.g. of aluminum isopropylate, in particular according to the procedure of Meerwein-Ponndorf-Verley. However, oxo may also be reductively lower alkylated, for example, by reaction with a lower alkyl alkali metal or nickel alkyl alkaline earth metal compound such as a lower alkyl lithium, e.g. Methyl or ethyl lithium, or a lower alkyl magnesium halide, e.g. Methylmagnesiumbromid or Aethylmagnesiumbromid., Preferably, in an ether, such as diethyl ether.

Further, in an oxo or hydroxy radical R _{2, it is possible to} replace oxo or hydroxy by reductive reduction by hydrogen. Oxo can be replaced, for example, by conversion with an optionally substituted by 2-sulfonylethyl / such as 2-benzene, 2- (p-toluene) -, 2-methane or 2-Mesitylensulfonylathyl, substituted hydrazine in optionally substituted hydrazono and reduction by hydrogen. As a reducing agent for 2-Sulfonyläthylhydrazonogruppen is preferably used a Dileichtmetallhydrid, such as sodium cyanoborohydride in an inert, polar solvent, / eg in hexamethylphosphoric triamide. The reductive replacement of unsubstituted hydrazono with hydrogen is advantageously carried out by base-reduced disproportionation, for example by reaction with an alkali metal alcoholate, such as sodium methoxide, if necessary under elevated pressure,

for example, up to 10 bar, or by the action of an alkali metal hydroxide, for example of potassium hydroxide, in an inert high-boiling solvent, for example in di- or triethylene glycol or Diäthylenglykoliaonomethylather, in each case if necessary, with heating, for example at about 100 to 250 ⁰ C. Ketonische oxo groups can also by nascent Hydrogen generated, for example, by the action of a protic acid, such as hydrochloric or acetic acid, on base metals, such as zinc, iron or aluminum, of water, preferably amalgamated aluminum, or of alcohols, such as methanol, on sodium, are replaced by hydrogen. It is also possible to use lower-valency metal compounds, such as tin (II) or chromium (II) salts, eg stannous chloride. Hydroxy can be obtained, for example, by the action of catalytically activated hydrogen, such as hydrogen in the presence of a hydrogenation catalyst, eg Raney nickel or a platinum compound, such as platinum oxide or platinum on carbon or on barium oxide, advantageously in an acidic solvent, such as a lower alkanoic acid, for example in acetic acid, are replaced by hydrogen.

In compounds of the formula I, hydroxy or oxo can furthermore be introduced in the radical R "and / or hydroxy can be converted into oxo. The introduction of hydroxy, in particular in the 1-position, for example, by air oxidation, or introduction of halogen, in particular by reaction with N-bromosuccinimide, and subsequent hydrolysis. The oxydative introduction of oxo, also preferably in the! -Position, takes place, for example, by reaction with selenium dioxide. In the radical R ₂ , hydroxy can also be oxidized to oxo, 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 procedure of Oppenauer.

Further, "one may extend oxo-lower alkyl radicals R" in a conventional manner, preferably by reaction with a metal or phosphorus compound of a di-lower alkyl or phenyl-lower alkyl ether, for example, methoxymethylmagnesium bromide or methoxy-phosphorane, followed by hydrolysis of the resulting enol ether.

Furthermore, in compounds of the formula I in which R * is an optionally substituted benzyl-substituted, monounsaturated piperidyl radical, the double bond thereof can be reduced, for example by reaction with catalytically activated hydrogen, e.g. with hydrogen in the presence of a nickel, platinum or rhodium catalyst, e.g. of Raney nickel, platinum oxide or the complex of platinum or rhodium chloride and triphenylphosphine, or by means of a dileil metal hydride, e.g. with sodium borohydride or with lithium aluminum hydride.

The new compounds may, depending on the choice of starting materials and procedures, in the form of one of the possible isomers or as a mixture thereof, e.g. depending on the number of asymmetric carbon atoms, as pure optical isomers, such as antipodes or mixtures of isomers, such as racemates, diastereoisomer mixtures or racemate mixtures.

Obtained mixtures of isomers, such as mixtures of diastereomers and mixtures of racemates can be separated in a known manner in the pure isomers, diastereomers or racemates due to the physico-chemical differences of the constituents, for example by chromatography and / or fractional crystallization.

Obtained racemates can also be decomposed by known methods into the optical antipodes, for example by recrystallization from an optically active solvent, with the aid of microorganisms, or

-Hq-

by reacting an end product with an optically active acid which forms salts with the racemic base and separating the salts thus obtained, e.g. due to their different solubilities, into the diastereomers from which the antipodes can be released by the action of suitable agents. Advantageously, the more effective of the two antipodes is isolated.

Obtained free compounds of the formula I can be converted into salts in a manner known per se, i.a. by treatment with the appropriate acid, usually in the presence of a solvent or diluent.

Salts obtained can be converted into the free compounds in a manner known per se, e.g. by treating with a base such as an alkali metal hydroxide.

The compounds, including their salts, can also be obtained in the form of their hydrates or include the solvent used for the crystallization.

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

The invention also relates to those embodiments of the process according to which one proceeds from a compound obtainable as an intermediate at any stage of the process and performs the missing steps or uses a starting material in the form of a salt and / or racemate or antipodes or forms in particular under the reaction conditions ,

% f 4 075 - ή-

In the process of the present invention, preference is given to using those starting materials which lead to the compounds described at the outset as being particularly valuable Novel starting materials and processes for their preparation likewise form an object of the present invention.

In this connection, in particular the compounds of the formula VII mentioned as starting materials, in which R is a radical R-, ie. Compounds of the formula R, -Ph-H (Ia) in which R, and Ph have the meanings given above, to mention. These have the same pharmacological properties, in comparable potency, as the inventive compounds of formula I. Accordingly, the invention also relates to compounds of formula Ia and their pharmaceutically acceptable salts, processes for their preparation, their use and pharmaceutical compositions containing them.

In this regard, the invention relates in particular to those compound groups of the formula Ia in which R 1 and Ph 4 have the meanings given at the outset for preferred compound groups, namely the 1- (o-chloro-2-chloro) -3-phenylpiperidine and its pharmaceutically acceptable salts, such as hydrochloride.

The compounds of the formula Ia can be prepared in a manner known per se, for example by the process given above for the preparation of compounds of the formula I by reacting compounds of the formulas II, Ha, III, IV, which in each case have hydrogen instead of the radical R 1 , V, VII and VIII or IX and X, where R is hydrogen and R 'or R "is a radical

O O O

R- means go out.

The compounds of the formula I and their pharmaceutically acceptable salts have valuable pharmacological properties.

2 f 4 ' Q7 <

gical properties. For example, they have pronounced antithrombotic activity. This can, for example, in guinea pigs based on the inhibition of thrombocytopenia after induction by ADP in the dose range of about 100 to 300 mg / kg po also based on the Arthus reaction, see Brit. J. Pharmacology 5Ί_, 441Ρ (1976), in the dose range of about 30 to 300 mg / kg po and by the Forsmann reaction in the dose range of about 100 to 300 mg / kg po, in rabbits on the basis of their inhibitory effect on the arachidonic acid-induced pulmonary embolism in the dose range of about 100 to 300 mg / kg pooder in vitro based on their Prostaglandinsynthesehemmung from arachidonic acid by bovine seminal bladder enzymes in the concentration range of about 0.1 to 1 mg / liter documented. The compounds of the formula I are furthermore anti-inflammatory, which can be demonstrated, for example, in rats in the dose range from about 10 to 100 mg / kg po on the basis of the kaolin paw edema and adjuvant arthritis. The new compounds are also antinoceptive active, what. zB.zB based on the phenyl-p-benzoquinone-writhing syndrome of the mouse in the dose range of about 1 to 10 mg / kg po and the acetic acid writhing syndrome of. Rat in the dose range of about 1 to 10 mg / kg po show. They are finally effective uricosurally, which can be demonstrated by the phenol red clearance of the rat in the dose range of about 30 to 100 mg / kg po. · ·

Accordingly, the compounds of the formula I are excellently suitable for the treatment of thrombotic diseases, furthermore inflammatory diseases, in particular with inflammatory diseases; Component, and can be used as an active ingredient in antithrombotic and / or antiinfaminatori chen drugs or as antinuces and / or uricosuric.

10.10.1979 55 746 11

The novel compounds can be used to prepare pharmaceutical preparations which contain one of the compounds according to the invention of the formula. or III or a pharmaceutically acceptable salt thereof. The new preparations are those intended for topical and local as well as enteral, such as oral or rectal, as well as parenteral administration to and for inhalation by warm-blooded animals, and containing the pharmacological agent alone or together with a pharmaceutically acceptable carrier material. The dosage of the active ingredient depends on the species of warm-blooded animals, the age and the individual condition, as well as on the mode of administration · The new pharmaceutical preparations contain, for example, B. from about 10% to about 95%, preferably _t of about 20% to about 90% of the active ingredient. The novel pharmaceutical preparations are, for example, those in dosage unit forms, such as dragees, tablets, capsules or suppositories, and also ampoules.

The pharmaceutical preparations, are in a conventional manner, for. B. by conventional mixing, granulation, coating, solution or lyophilization process.

Thus, one can obtain pharmaceutical preparations for oral use by combining the active ingredient with solid carriers, optionally granulating a mixture obtained, and the mixture or granules, if desired or necessary, after addition of suitable excipients, into tablets or dragee core ^ suitable carriers are in particular fillers, such as sugar, for. As lactose, sucrose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates, ζ. 3. ^ dicalcium phosphate or calcium hydrogen phosphate, further binders such as starch paste, z. B. from

Corn, wheat, rice or potato starch paste, gelatin, tragacanth, methyl cellulose and / or polyvinylpyrrolidone, and / or, if desired, disintegrants such as the above-mentioned starches, furthermore carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, vie Natriumalginät, aids are primarily flow regulators and lubricants, eg Silica, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and / or polyethylene glycol. Dragee cores are provided with suitable, possibly gastric juice-resistant coatings, which u.a. concentrated sugar solutions which may contain arabic gum, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures or, for the manufacture of gastric juice-resistant coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. The tablets or dragee coatings may contain dyes or pigments, e.g. for the identification or labeling of different doses of active substance.

Other orally applicable pharmaceutical preparations are gelatine capsules, as well as soft, closed capsules of gelatin and a plasticizer, such as glycerol or sorbitol. The capsules may contain the active ingredient in the form of granules, for example in admixture with fillers, such as lactose, binders, such as starches, and / or lubricants, such as talc or magnesium stearate, and, optionally, stabilizers In soft capsules, the active ingredient is preferably suitable Liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, dissolved or suspended, which stabilizers may also be added.

10.10.1979 55 746 11

As rectally applicable pharmaceutical preparations come into consideration, which consist of a combination of the active ingredient with a suppository base. As suppository base are z. JB. natural or synthetic triglycerides, paraffinic hydrocarbons, polyethylene glycols or higher alkanols. Furthermore, gelatin rectal capsules containing a combination of the active ingredient of a basic size may also be used; as basic materials come z. As liquid triglycerides, polyethylene glycols or paraffin hydrocarbons in embossing.

For parenteral administration are primarily aqueous solutions of an active ingredient in water-soluble form, .z ·. B. a water-soluble salt, further suspensions of the active ingredient, such as corresponding oily injection suspensions, wherein suitable lipophilic solvents or vehicles, such as fatty OeIe, ζ. Sesame oil, or synthetic fatty acid esters, s. As ethyloleate or triglycerides used, or aqueous injection suspensions, which viscosity increasing substances, eg. As sodium carboxymethylcellulose, sorbitol and / or dextran and optionally also stabilizers. Pharmaceutical preparations for topical and local use are e.g. 3. for the treatment of skin lotions and cream containing a liquid or semi-solid oil-in-v / asser- or water-in-oil emulsion, and ointments, preferably containing a preservative.

The following examples illustrate the invention described above; however, they are not intended to restrict their scope in any way. Temperatures are given in degrees centigrade.

10.10.1979 55 746 11

Exemplary ühru ii gsbeispiel Example 1

8 g of 4- (p-ethylphenyl) piperidine, 7.3 g of 3,4-dichlorobenzyl chloride and 16 g of anhydrous potassium carbonate are suspended in 300 ml of ethanol with stirring and heated to reflux for 5 hours with stirring. Allow to cool slightly, filtered from the insoluble material and the filtrate evaporated to dryness under reduced pressure. The residue is mixed with 200 ml of water and extracted twice with 150 ml diethyl ether. The ether extracts are combined, washed with 100 ml 2n Uatroriläuge and then with 100 ml of saturated brine, dried over sodium sulfate and evaporated to give the crude 1- (3,4-dichlorobenzyl) -4- (p-ethylphenyl) -piperidine remains. This is dissolved in 100 ml of ethanol and the solution is acidified to pH = 1 with ethanolic hydrochloric acid (2N). The precipitated 1- (3 »4-dichlorobenzyl) -4- (p-ethylphenyl) -piperidine hydrochloride is filtered off, washed with diethyl ether and dried. It melts at 255-257 °.

The starting material may, for. B. be prepared as follows:

A solution of 12.0 g of α- [p- (4-piperidyl) -phenyl] -ethanol in 120 ml of glacial acetic acid is treated with 1.2 g of palladium (5% on charcoal) and at 40-50 to Hydrogenated at normal pressure to take up 1 equivalent of hydrogen. Then the catalyst is filtered off and the filtrate is evaporated in vacuo to dryness. The remaining in the evaporation residue crude 4- (4-ethylphenyl) piperidine can be further purified by treatment with activated carbon and subsequent conversion into the hydrochloride. The melting point of the hydrochloride is 198-202 ° (from ethanol-ether).

Example 2

In an analogous manner as described in Example 1 is obtained by reacting 4- (p-Aethylphenyl) piperidine

with 2,4-dichlorobenzyl chloride, the l- (2,4-dichlorobenzyl) -4- (p-ethylphenyl) -piperidine hydrochloride, mp. 230 °,

with o-chlorobenzyl chloride, the 1- (o-chlorobenzyl) -4- (p-ethylphenyl) piperidine hydrochloride, mp. 195-196 °,

with p-chlorobenzyl chloride, the 1- (p-chlorobenzyl) -4- (p-ethylphenyl) -piperidine hydrochloride, mp. 263-265 °,

with m-chlorobenzyl chloride, the l- (m-chlorobenzyl) -4 »(p- * etthylphenyl) piperidine hydrochloride of mp. 230 °, and

with m-methoxybenzyl chloride, the 1- (m-methoxybenzyl) 4- (p-ethylphenyl) -piperidine hydrochloride, mp. 157-158 °.

Example 3

8 g of 4- (p-acetylphenyl) piperidine are reacted in an analogous manner as described in Example 1 with o-chlorobenzyl chloride to give 1- (o-chlorobenzyl) -4- (p-acetylphenyl) -piperidine, mp. 96-97 ° ,

Example 4

By reacting 5 g of 4- [p- (1-hydroxyethyl) phenyl] piperidine with o-chlorobenzyl chloride in the manner described in Example 1, the 1- (o-chlorobenzyl) -4-t p- (1- hydroxyethyl) -phenyl] -piperidine hydrochloride of mp. 178-179 °.

Example 5 ".

Tablets containing 100 mg of active ingredient, e.g. 1- (3,4-dichlorobenzyl) -4- (p -ethylphenyl) -piperidine hydrochloride can be obtained, for example, in the following

Per tablet mg 100 mg 50 mg 73 mg 13 mg 12 m ^ 2

Settlement can be made:

composition

Active ingredient e.g. 1- (3,4-dichlorobenzyl) -4- (p -ethylphenyl) -piperidine hydrochloride Milk Sugar Wheat Starch Colloidal Silica Talc

magnesium

250 mg production ^β

The active ingredient is mixed with the milk sugar, a portion of the wheat starch and colloidal silica and the mixture is forced through a sieve. Another part of the wheat starch is gelatinized with 5 times the amount of water on the water bath and the powder mixture kneaded with this paste until a weakly plastic mass is formed. The mass is forced through a sieve of about 3 mm mesh size, dried and the dry granules are again driven through a sieve. Then the remaining wheat starch, talc and magnesium stearate are added. The resulting mixture is pressed into tablets of 250 mg with fracture score (s).

Example 6

A heated to reflux suspension of 1.2 g of lithium aluminum hydride in 50 ml of absolute tetrahydrofuran is slowly added to a solution of 19.7 g of N- (3,4-dimethoxybenzoyl) -4- (4-ethylphenyl) -piperidine in 50 ml of absolute tetrahydrofuran and heated to reflux for a further 24 hours. After cooling the reaction mixture is mixed with 10 ml of ethyl acetate and a little water, filtered and the tetrahydrofuran is removed. The residue is in

• -

2N hydrochloric acid and washed with a little ether. The aqueous phase is made alkaline with 2N sodium hydroxide solution and extracted with ether. After washing the ethereal phase with water, drying over magnesium sulphate and evaporation, crude 1- (3,4-dimethoxybenzyl) -4- (p-ethylphenyl) -piperidine obtained from ethanolic solution by addition of an equivalent amount of fumaric acid, dissolved in ethanol, crystallized as Furmarat of the mp. 151-153 °.

The starting material may e.g. in a manner analogous to that described in Example 1 by reacting 4- (p-ethylphenyl) piperidine with 3,4-dimethoxybenzoyl chloride. It melts at 110-112 °.

In an analogous manner, one can by reaction of

4- (p-Aethylphenyl) -piperidine with 3,4-dichlorobenzoyl chloride over 1- (3,4-dichlorobenzoyl) -4- (p-ethylphenyl) -piperidine of mp. 77-79 °, the 1- (3,4- Dichlorobenzyl) -4- (p -ethylphenyl) piperidine (mp of the hydrochloride 255-257 °)

Example 7

In an analogous manner as described in Example 1 is obtained by reacting 4- (o-Aethylphenyl) piperidine with. 3,4-dichlorobenzyl chloride, the 1- (3,4-dichlorobenzyl) -4- (o-ethylphenyl) -piperidine hydrochloride of mp. 250 °.

The starting material can be prepared as follows:

To a suspension of 10 g of magnesium turnings in a little tetrahydrofuran is added dropwise with stirring and exclusion of water dropwise, a solution of 75 g of l-ethyl-2-bromobenzene in 50 ml of tetrahydrofuran added so slowly that the reaction temperature does not exceed 60 °. Subsequently, a solution of 57 g of N 2 is added within 45 minutes.

ff 4 075 - 54-

Benzyl-4-piperidone in 150 ml of tetrahydrofuran added. After completion of the addition is allowed to continue stirring for 1 hour at 60 °. The cooled to 0 ° reaction solution is mixed with 100 ml of ice-cold, saturated ammonium chloride solution and extracted twice with 1000 ml of ether. The organic extracts are dried over sodium sulfate and evaporated in vacuo. Distillation of the evaporation residue in a high vacuum gives in the 175-180 ° (0.05 mm) boiling fraction 52 g of 4-hydroxy-4- (2-ethyl-phenyl) -N-benzylpiperidine as a colorless oil.

To a solution of the above product in 120 ml of glacial acetic acid is added 40 ml of concentrated hydrochloric acid and 30 ml of water and heated for 3 hours to reflux. Then it is evaporated to dryness in vacuo, with sodium hydroxide until pH 14 alkaline and extracted with ice cooling twice with 1000 ml of ethyl acetate. The organic phases are washed with water, dried over sodium sulfate and evaporated in vacuo. This gives the crude, oelige l-benzyl-4- (o-ethylphenyl) -1,2,3,6-tetrahydro-pyridine, which is further processed directly. (Hydrochloride: mp 205 °).

To a solution of 43.5 g of 1-Benzy1-4- (o-ethylphenyl) -1,2,5, 6-tetrahydropyridine in 450 ml of glacial acetic acid is added 48.1 ml of 3.4 N-ethanolic hydrochloric acid and 22 , 5 g of palladium (5% on charcoal) and hydrogenated at 40-45 ° until the addition of.2 equivalents of hydrogen. The mixture is then filtered off from the catalyst, the filtrate is evaporated to dryness in vacuo, the evaporation residue is dissolved in 300 ml of water, adjusted to pH 14 with sodium hydroxide solution and extracted twice with 500 ml of ether. The organic extracts are dried over sodium sulfate and evaporated to dryness in vacuo. The evaporation residue is dissolved in 130 ml of ethanol and mixed at 60 ° with a hot solution of 15.5 g of fumaric acid in 350 ml of water. The crystallizing on cooling 4- (o-

Aethyl phenyl) piperidine fumarate is filtered off with suction, washed with ethanol and ether and dried in vacuo at room temperature. Mp. 195 °.

Example 8

By analogy with Example 1, reaction of 4- (m-ethylphenyl) piperidine with 3,3'-dichlorobenzyl chloride gives 1- (3,4-dichlorobenzyl) 4- (m-ethyl) phenyl. piperidine hydrochloride of mp. 249-50 °.

The starting material can be prepared as follows:

Reaction of 60 g of 3-ethyl-bromobenzene with magnesium and 61 g of N-benzyl-4-piperidone gives 4-hydroxy-4- (methylphenyl) -N-benzylpiperidine of bp 195-200 ° (0.04 mm).

This is obtained with glacial acetic acid / hydrochloric acid oily crude l-benzyl-4- (o-ethylphenyl) -1,2,3,6-tetrahydro-pyridinium, which without further purification in an analogous manner as in Example 7 (preparation of the starting material) described by hydrogenation with palladium (5% on charcoal) in the

4- (m-Aethylphenyl) -piperidine fumarate is transferred. Example 9

To a solution of 3.5 g of 3,4-dichlorobenzylamine in 100 ml of ethanol and 20 ml. 2N sodium hydroxide solution is added with stirring at 0 °, a solution of 6.7 g of 3- (p-Aethylphenyl) -1,5- dibromo-pentane. After the addition is complete, the reaction mixture is heated to reflux for 10 hours. Then it is cooled to room temperature, decolorized with a little sodium thiosulfate, evaporated to dryness in vacuo and the residue is distilled under high vacuum. The boiling at 90-140 ° (0.03 miriHg)

14 075 - 53-

Fraction is further purified by chromatography on silica gel with chloroform / methanol (15: 1). This gives the 1- (3,4-dichlorobenzyl) -4- (p-ethylphenyl) piperidine. This is transferred to the characterization as described in Example 1 in the hydrochloride, mp. 255-258 °. The 1- (3,4-dichlorobenzyl) -4- (p-ethylphenyl) piperidine fumarate can be prepared analogously. It melts at 255-257 °.

The starting 3- (p-ethylphenyl) -1,5-dibromo-pentane used may be e.g. produce as follows:

A solution of 43 g of p-ethylbenzaldehyde and 52 g of diethylphosphoroacetonitrile in 300 ml of methylene chloride is added dropwise within 15 minutes under ice cooling to a well-stirred emulsion of 6.5 g of tetrabutylammonium bromide in 180 ml of 50% sodium hydroxide solution and 150 ml of methylene chloride , Subsequently, it is stirred for 30 minutes at room temperature. Then the organic phase is separated, washed neutral with water, dried over sodium sulfate and evaporated in vacuo. The thus obtained crude p-ethyl-cinnamonitrile [OeI; JR (CH ₂ Cl ₂ ): * 3max 2240 cm ^-1 is added to a solution of 8 g of sodium in 53 g of malonic acid ester and 400 ml of absolute ethanol and heated to reflux for 2 hours, then evaporated to one third of the volume in vacuo It is mixed with 500 ml of aqueous acetic acid (0.5N) and extracted three times with 500 ml of ether The organic phases are washed neutral, dried on sodium sulfate and evaporated to dryness in vacuo Chromatography of the evaporation residue on 1 kg of silica gel with methylene chloride as eluent provides the 2-carboethoxy-3- (p -ethylphenyl) -propane-1-carboxylic acid ethyl ester 3-nitrile as a colorless oil {IR (CH ₂ Cl ₂ ) * 3 · max: 1720 cm ^-1 (shoulder)].

9 - 5H -

The 2-carboethoxy-3- (p-ethylphenyl) propane-1-carboxylic acid ethyl ester 3-nitrile can be prepared analogously to that described in J. Amer. Chem. Soc. 53, 1105 (1931) to 3- (p-ethylphenyl) -I, 5-dibromo-pentane, which boils at 175-185 ° (12 mmHg).

Example 10

1 g of 1- (3,4-dimethoxybenzyl) -4- (p-ethylphenyl) -2-piperidone is added in portions to a suspension of 150 mg of lithium aluminum hydride in 20 ml of absolute tetrahydrofuran with stirring in a nitrogen atmosphere. Then allowed to stir for 1 hour at 60 °, cooled to room temperature, added dropwise with 0.5 ml of water and 0.1 ml of 2N sodium hydroxide solution and filtered through diatomaceous earth. The filtrate is evaporated and the remaining in the evaporation residue crude 1- (3,4-dimethoxybenzyl) -4- (4-ethylphenyl) piperidine as described in Example 6 into the fumarate of F 151-153 ° transferred.

The starting material can be obtained as follows:

A solution of 31 g of 2-carboethoxy-3- (p-ethylphenyl) -propane-1-carboxylic acid ethyl ester 3-nitrile in 1.6 g of triethylamine and 500 ml of absolute ethanol is reacted with 8 g of Raney nickel until about 4 Hydrogenated 1 hydrogen. The mixture is then filtered off from the catalyst and evaporated to dryness in vacuo. From the evaporation residue crystallized with ether, the 3-Carboäthoxy-4- {p-ethylphenyl) -. 2-piperidone from F -157-159 °.

A solution of 8 g of the above compound in 110 ml of ethanol, 40 ml of 2N sodium hydroxide solution and 50 ml of water is refluxed for 45 minutes. Then you steam

in vacuo to dryness, the evaporation residue with 2N hydrochloric acid to pH 1 and extracted with 5OO ml of chloroform. The organic phase is washed neutral, dried over sodium sulfate and evaporated in vacuo. The crude, crystalline 3-carboxy-4- (4-ethylphenyl) -2-piperidone (mp 125 ° C.) remaining in the evaporation residue is heated to reflux in 400 ml of toluene for 30 minutes. Then it is evaporated to a volume of about 20 ml and mixed with a little ether. The 4- (p-ethylphenyl) r-2-piperidone crystallizes from the F 165 °.

To a solution of 2 g of 4- (p-ethylphenyl) -2- piperidone and 3 _r 2 g of tetrabutylammonium bromide in 40 ml of methylene chloride are added 2.3 g of 3,4-dimethoxybenzyl chloride and 40 ml of 30% sodium hydroxide solution. This mixture is stirred for 4 hours and then separated from the aqueous phase. The organic phase is washed neutral with water, dried over sodium sulfate and evaporated. The evaporation residue is stirred with ether. The ethereal portion containing the 1- (3,4-dimethoxybenzyl) -4- (p -ethylphenyl) -2-piperidone is evaporated and used in the next step without further purification.

Example 11

A solution of 6.4 g of 1- (m-methoxybenzyl) -4- (pacetylphenyl) -piperidine and 5 ml of hydrazine hydrate in 50 ml of ethylene glycol is treated with 7.5 g of powdered sodium hydroxide and refluxed for 1.5 hours. Subsequently, a mixture of hydrazine and water is distilled off until the bottom temperature reaches 190 °. After cooling the reaction mixture is added to the same amount of water and extracted with ether. The ether phase is dried over sodium sulfate and evaporated.

I - Sb -.

The evaporation residue is chromatographed on silica gel with methylene chloride / methanol (15: 1) as the eluent to give 1- (m-methoxybenzyl) -4- (4-ethylphenyl) -piperidine, which is converted in the usual way into the hydrochloride of mp 157-158 ° is transferred.

Example 12

In a manner analogous to that described in Example 1, the reaction of 4- (p-ethylphenyl) piperidine with p-fluorobenzyl chloride gives 1- (p-fluorobenzyl) -4- (p-ethylphenyl) -piperidine hydrochloride of the mp. 52 ° and

with benzyl chloride, the l-benzyl-4- (p-ethylphenyl) -piperidinfumarat, mp. 183-185 °.

Example 13

In an analogous manner as described in Example 1 or 3 is obtained by reacting 4- (p-acetylphenyl) -piperidine

with m-methoxybenzyl bromide, the 1- (m-methoxybenzyl) -4- (pacetylphenyl) piperidine fumarate, mp. 157-59 °, with 3,4-dichlorobenzyl chloride, the 1- (3,4-dichlorobenzyl) -4- ( p-acetyl) phenyl) piperidine hydrochloride, mp 258-60 ° and

with benzyl chloride, the l-benzyl-4- (p-acetylphenyl) piperidine fumarate, mp. 161-62 °.

Example 14

Analogously, as described in Example 4, the reaction of 4- [p- (1-hydroxyethyl) phenyl] piperidine with benzyl chloride affords 1-benzyl-4 [p - {! -Hydroxyethyl) -phenyl] - piperidine fumarate of mp. 154-158 °, with m-methoxybenzyl bromide the 1- (m-methoxybenzyl) -4- [p-

(l-hydroxyethyl) -phenyl] -piperidine-fumarate of the Mp. 160-61 "

with 3,4-dichlorobenzyl chloride, the 1- (3,4-dichlorobenzyl) -4- [p- (l-hydroxyethyl) phenyl] -piperidin-fumarate of mp.

195-97 °.

Example 15

8 g of 4- (p-ethylphenyl) piperidine, 4.2 g of benzyl chloride and 16 g of anhydrous potassium carbonate are suspended with stirring in 300 ml of ethanol and heated to reflux for 5 hours. Allow to cool slightly, filtered from the insoluble and evaporated under reduced pressure to dryness. The residue is mixed with 200 ml of water and extracted twice with 170 ml of diethyl ether. The ether extracts are combined, washed with 100 ml of 2N sodium hydroxide solution and then with 100 ml of saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness. This gives l-benzyl-4- (p-ethylphenyl) -piperidine, which can be converted into the l-benzyl-4- (p-ethylphenyl) -piperidine hydrochloride by dissolving in ethanol and acidifying with ethanolic hydrochloric acid.

The starting material may e.g. as follows:

A solution of 12.0 g of α- [ρ (4-piperidyl) phenyl] ethanol in 120 ml of glacial acetic acid is treated with 1.2 g of palladium (5% on carbon) and at 40-50 ° to the Hydrogenation of 1 equivalent of hydrogen at normal pressure. Then the catalyst is filtered off and the filtrate is evaporated to dryness in vacuo. The remaining in the evaporation residue crude 4- (4-ethylphenyl) piperidine can be further purified by treatment with activated carbon and subsequent conversion into the hydrochloride. The melting point of the hydrochloride is 198-202 ° (from ethanol-ether).

ι --ss-

Example 16.

In an analogous manner as described in Example 15, l-benzyl-4- (2,4-dimethyl-phenyl) -1,2,5,6-tetrahydro-pyridine by conversion of 34 g of 4-bromo-m-xylene in the Grignard bromomagnesium compound, reaction thereof with 38 g of N-benzyl-4-piperidone and subsequent dehydration by means of acetic acid-hydrochloric acid, which boils below 0.05 mmHg at about 170 ° C, as well as i-benzyl-1,2,5 , 6-tetrahydro-4- (p -methylphenyl) -piperidine, m.p. 40-41 ° (from cold pentane).

Example 17 ·. ,

A solution of 55 g of 1-benzyl-4-hydroxy-4- [p- (1-ethylenedioxyethyl) -phenyl] -piperidine in 250 ml of concentrated hydrochloric acid is refluxed for three hours. Then it is evaporated to dryness in vacuo, adjusted with 2N sodium hydroxide solution to pH 14 and extracted three times with 500 ml of diethyl ether. The organic phases are combined, washed neutral, dried over sodium sulfate and evaporated to one third. It crystallizes pure 1-benzyl-1,2,5,6-tetrahydro-4- (4-acetylphenyl) pyridine, mp. 99-100 °.

The starting material may e.g. be prepared as follows:

To a suspension of 9.8 g of magnesium turnings in 100 ml of absolute tetrahydrofuran is added dropwise at about 50 ° with exclusion of water slowly added to a solution of 97 g of 4-bromo-acetophenone-ethylenecetal in 100 ml of absolute tetrahydrofuran. Once all the magnesium has gone into solution, it is cooled to 5 ° and treated dropwise with a solution of 70 g of N-benzyl-4-piperidone in 100 ml

absolute tetrahydrofuran. After completion of the addition, it is evaporated to dryness in vacuo and the evaporation residue is triturated with anhydrous ethyl ether and filtered off with suction. The filter cake is then distributed between 3 times 200 ml of ether and 200 ml of saturated, cold aqueous ammonium chloride solution. The organic phases are combined, washed neutral, dried over sodium sulfate and evaporated to dryness in vacuo. The thus obtained 1-benzyl-hydroxy-5-pp- (1-ethylenedioxyethyl) -phenyl] piperidine melts at 114-116 °.

Example 18

To a suspension of 0.5 g of magnesium turnings, covered with a little absolute diethyl ether, are added a few drops of methyl iodide under nitrogen and, after the reaction has started, dropwise at 30-35 °, a solution of 6.3 g of 1- (m-methoxybenzyl) -4- (p-chlorophenyl) -piperidine in 20 ml of absolute diethyl ether added. After most of the magnesium is dissolved, add 100 mg of copper 1-iodide ₂ , cool to -10 °, add 2.5 g of ethyl bromide and allow to stir overnight at -10 to 0 °. Then it is mixed with 50 ml of 2N sodium hydroxide solution, saturated with sodium chloride and extracted three times with 50 ml of diethyl ether. The organic phases are washed neutral, dried over sodium sulfate and evaporated in vacuo. Distillation of the evaporation residue under high vacuum and chromatography of the fraction boiling at 100-150 ° (0.03 mmHg) on silica gel with chloroform and a small amount of methanol as eluent gives crude 1- (m-methoxybenzyl) -4- (p-ethylphenyl) - piperidine (mp of the hydrochloride: 157-158 °).

The starting material may e.g. be prepared as follows:

9 - 60 -

Treatment of - p-Chlorzimmtsäureäthy! Ester with Nafcriumdiäthylmalonat to jS-phenyl-a / a ^ r tricarboxylic acid triäthylester, subsequent saponification with potassium hydroxide solution and decarboxylation at 110-130 ° leads to ß-p-chlorophenyl. glutaric acid, which is converted by reaction with m-methoxybenzylarain in the l- (m-methoxybenzyl) -4- (p-chlorophenyl) -piperidine-2,6-dlone. This is then reduced with lithium aluminum hydride to the desired, 1- (m-methoxybenzyl) -4- (4-chlorophenyl) piperidine.

Example 19

Tablets containing 100 mg of active ingredient, e.g. 1-Benzyl-4- (p-ethylphenyl) piperidine, or its hydrochloride, can be prepared, for example, in the following composition:

composition per tablet Active ingredient, e.g. l-benzyl-4- (p ethylphenyl) -piperidine 100 mg lactose 50 mg wheat starch 73 mg Colloidal silica 13 mg talc 12 mg magnesium stearate 2 mg

, 250 mg

manufacturing

The active ingredient comes with the milk sugar, a. Part of the wheat starch and mixed with colloidal silica and "the" mixture driven through a sieve. Another part of the wheat starch is gelatinized with 5 times the amount of water on the water bath, and the powder mixture is kneaded with this paste until a slightly plastic mass has formed. The mass is through

Driven screen of about 3 mm mesh size, dried and the dry granules are again driven through a sieve. Then the remaining wheat starch, talc and magnesium stearate are added. The resulting mixture is compressed into tablets of 250 mg with rupture score (s).

Example 20

In a manner analogous to that described in Examples 5 and 19, it is also possible to prepare tablets containing another compound according to one of Examples 1-4 and 6-18.

Claims (8)

10,10.1979
55 746 11 Invention claim: 1. A process for the preparation of new substituted, optionally monounsaturated 1 ~ benzyl-phenylpiperidine of the formula R ₁ - Ph - R ₂ (I), wherein R- is a substituted in the 1-position by optionally substituted benzyl, optionally monounsaturated piperidyl radical, Ph is a GE, optionally substituted phenylene radical and Rp is an optionally substituted liiederalkylrest, with the proviso that Ph is optionally substituted 1,2- or 1,3 Phenylene, when Rp in a-position has a hydroxy, hydroxymethyl, ITiederalkanoyl, 2-oxo-lower-alkanoyl or 2-hydrosynedalenalian group, and with the further proviso that R- of
4- (1-Benzyl) piperidine and 4- (1, 3-ynyl), 4-yl-1 (monoalkylbenzyl), and 4- \ 3- (monohalobenzyl) 3-1,2,5,6-tetrahydropyridyl different Vieira Ph is optionally substituted 1,4-phenylene and Rp is lower alkyl or is lower alkanoyl or 1-hydroxy-lower alkyl having at least 2 C atoms, and their salts, characterized in that in a compound of formula R _A - Ph - R ₂ (II), in which R, one in 5-position by in the phenyl part gege- χι ΐ · optionally substituted benzylamino substituted, in the 1-position an exchangeable radical X or in the 1,2-position, optionally having an additional double bond, optionally monounsaturated n-pentyl radical, or in a salt thereof, R * to
to the R, ring-closing or a compound of the formula - Ph - R ₀ (III), wherein R "is a 1-unsubstituted, optionally a-B polyunsaturated piperidyl radical, or a salt thereof by reaction with an optionally substituted benzyl radical introducing agent in the 1-position substituted or in a compound of formula R ₀ -Ph-R ₂ (IV), wherein R- is a by at least one hydrogen-substituted radical substituted and / or at least one optionally additional double bond having radical R-, or a salt thereof the radical Rp to R, or reduced in a corresponding compound of formula R ₀ -PhR ₂ (V), wherein R _{0 is} a piperidyl radical substituted in 1-position by optionally substituted benzyl and by an α, β-eliminable radical, or a salt thereof, together with a β-hydrogen atom or in a compound R ₁ - Ph-R ₂ (VI), wherein Rg is a group which can be converted into an R ₂ radical, or in a salt thereof R ₅ , converted into R ₂ or onto a mixture of compounds of the general formula R ₀ -Ph-H (VII) and R _q - Χ _χ (VIII), wherein one of the radicals R and R 'is a radical R _n and the 00 1 other represents a radical R ₂ , and X, an optionally 10.10.1979 55 746 11 reactive esterified hydroxy group or a bond extending to an adjacent carbon atom, allowing a suitable acidic agent to act, or compounds of the formulas R-Ph- X ₀ (IX) and R " . O d O J wherein one of the radicals R and R "is a radical R ₁ and the other is a radical Rp and one of the radicals Xp ¹¹²¹¹ I Xo .a metal radical and the other halogen or to a iliederalkylrest R" bound oxo or to a lower alkanoyl radical R "bound in salso form is present, - esterified or esterified hydroxy, condensed together and, if desired, a resulting Steroisomerengemisch into the components, the resulting compound is converted into another compound of formula I and / or a resulting free compound in a salt or a salt obtained in the free compound or converted to another salt. A process according to item 1, characterized in that compounds according to claim 1, wherein R 1 is a phenyl moiety optionally substituted by lower alkyl to and containing 4 C atoms, lower alkoxy having bis and 4 C atoms, hydroxy, halogen with atomic number represents 3- or 4- (1-benzyl) -piperidyl- or 3- or 4- (1-benzyl-1,2,5,6-tetrahydro) -pyridyl radical substituted with and hydroxy, and / or trifluoromethyl, Ph optionally represented by alkyl with up to and with 4 C-atoms, Hied era Ik oxy with up to and with 4 C-atoms, hydroxy or halogen with atomic number up to and with 35 substituted 1,4- or 1,3-phenylene, and R ^ may be higher than. the 2-membered by hydroxy or in the 1-position by oxo substituted Kiederalkyl with up to and with 4 carbon atoms meaning 10.10.1979 ¹ 55 746 11 with the proviso that R 1 is unsubstituted 4 - (1-benzyl) -piperidyΓ and optionally haloalkyl or halo-substituted 4- (1-benzyl) -1,2,5,6-tetrahydo-pyridyl or Ph of optionally substituted 1,4-phenylene is different when R _{2 is} lower alkyl or Mederalkanoyl means having at least 2 C-atoms, or produces their salts. 3 · Method according to item 1, characterized in that compounds according to claim 1, wherein R-. in Phenylteii by Hiederalkoxy with bis and with 4 C-atoms and / or halogen with atomic number to and with 35 »mono- or disubstituted 3- or 4- (1-benzyl) ~ piperidyl, Ph is 1,4-phenylene and R ₂ optionally in the 1-position or in higher than the 2-position by oxo or in higher than 2-position by hydroxy monosubstituted Hiederalkyl with bis and with 4 C-atoms, or produces their salts. 4 · Method according to item 1, characterized in that compounds according to claim 1, v / orin R- in the phenyl moiety by lower alkoxy with up to and with 4 carbon atoms monosubstituted or durch.Halogen bi3 and atomic number disubstituted 4- (1-benzyl ) -piperidyl, Ph is 1,4-phenylene and R _{2 is} lower alkyl or C ₁ -C 4 -alkyl, or their salts are prepared, Method according to item 1, characterized in that 1- (3j 4-dichlorobenzyl) -4- (p-ethylphenyl) piperidine or a salt thereof is prepared. 6. The method according to item 1, characterized by preparing 1- (2,4-dichlorobenzyl) -4- (p-ethylphenyl) piperidine or a salt thereof. m v & § wm ^ -fob- 10.10.1979 55-746 11 Process according to item 1, characterized in that 1- (o-chlorobenzyl) -4- (p-ethylphenyl) -piperidine or a salt thereof is prepared 8. The method according to item 1, characterized in that one produces 1- (m-chlorobenzyl) -4- (p-ethylphenyl) piperidine or a salt thereof 9. The process according to item 1, which comprises preparing 1- (p-chlorobenzyl) -4- (p-ethylphenyl) piperidine or a salt thereof. 10. The process according to item 1, which comprises preparing 1- (o-chlorobenzyl) -4- (p-acetylphenyl) -piperidine or a salt thereof.
β Process according to item 1, characterized in that 1 (o-chlorobenzy1) -4-ρ- (1-hydroxyphenyl) -phenyl] -piperidine or a salt thereof.
12. The method according to item 1, characterized in that 1 ~ (m ~ Liethos: ybenzyl) -4- (p-ethylphenyl) piperidine or a Salt of it produces.
Method according to item 1, characterized in that 1- (3,4-di-diethoxybenzyl) -4- (p-ethylphenyl) -piperidine or to make a salt thereof ·
Method according to item 1, characterized in that 1- (3, 4-dicilorobenzyl) -4- (o-ethylphenyl) -piperidine or to make a salt thereof ·
15 «method according to item 1, characterized in that 1 - (3 i 4-diciylbenzyl) -4- (m-ethylphenyl) -piperidine or making a salt of it ·. 16 · Method according to item 1, characterized in that 1-Cp-Pluorbenzyl) -4- (p-ethylphenyl) -piperidine or a Salt thereof ·
17 «method according to item 1, characterized in that 1- (m-methosybenzyl) -4- (p-acetylphenyl) -piperidine or to make a salt thereof ·
Process according to item 1, characterized in that 1- (3,4-dicilobenzyl) -4- (p-acetylphenyl) -piperidine or to make a salt of it. · 1Ο · 1Ό.1979 55 746 11 19 «method according to item 1, characterized in that one produces T- (m-methoxybenzyl) -4-Yjp-C1-hydroxyethyl) -phenyl]] piperidine or a salt thereof. , , 20, method according to item 1, characterized in that ^ man produces 1- (3 »4-dichlorobenzyl) -4-jp- (1-hydroxyethyl) phenyl] piperidine or a salt thereof ·