CA1071211A - 4-(1-oxo-isoquinoline)-or 4-(1-oxo-1-isoindoline)-piperidines - Google Patents

Abstract

Abstract of the Disclosure Compounds of formula

Description

107121~

The invention relates to new piperidines of the formula ~2 / alkl ~6- C ~~~ C~ n

2 C~2 ~ ~ CH - N \Ph O

wherein Rl denotes an optionally substituted aryl radical, alkl and alk2 independently of one another are lower alkyl--ene radicals which each separate the nitrogen atom bonded to them, and the methine group bonded to them, by 2 carbon atoms, P~2 denotes an optionally acylated hydroxYl group, Ph denotes an optionally substituted o-p'nenylene radical, n is O or 1, R3 denotes a hydrogen atom, a lower alkyl radical or the hydroxyl group and R5 denotes a lower alkyl radical or a hydrogen atom or R3 and R5 together represent a second bond and R4 and R6 each denote a hydrogen atom, or R4 to-gether with R3 represents an oxo group, R5 denotes a lower alkyl radical or a hydrogen atom and R6 denotes a hydrogen atom, or R6 together with R5 represents an oxo group, R3 denotes a hydrogen atom, a lower alkyl radical or the hy-droxyl group and R4 represents a hydrogen atom, and their _ 2 .
' . ,: . '. ' ' . .'- ',,' :

- : . - ' ' .
. . -: ' - ' ~ ~

1~7~Zl~

salts, as ~el.l as processes for the manufacture of these compounds and pharmaceutical preparations in whicn these compounds are present.
If n is 1, the invention relates to compounds of ormula 12 alkl C / - C
Rl - - CH2 - CH - CH2 N ~ alk ~ C '' O

and, if n is 0, the invention relates to compounds of formula Rl - O - CH2 - CH - CH2 - n~ ~CH - N / Ph (I) wherein in the above formulae Rl, R2, R3, R4, R5, R6, Ph, fllkl and alk2 have the above defined meanings.
An optionally substituted aryl radical Rl is for example phenyl, lndenyl or naphthyl substituted by one, two -- - , , \
1071Zll or more substituents and also, for example, optionally sub-stituted 2,3-dihydro-5- or -6-indenyl or 5,6,7,8-tetrahydro--1- or -2-naphthyl. A monosubstituted or disubstituted phenyl or naphthyl radical is preferred, and a monosubstit-uted phenyl radical is preferred very particularly.
The aryl radical Rl is, for example, substituted by aliphatic or cycloaliphatic hydrocarbon radicals,especia~y by lower aliphatic hydrocarbon radicals which can also be substituted. Examples of such optionally substituted lower aliphatic and cycloaliphatic hydrocarbon radicals are lower alkyl, lower alkenyl or lower alkinyl groups; 5 to 7 ring-membered cycloalkyl groups: lower alXoxy-lower alkyl, lower alkylthio-lower alkyl, hydroxy-lower alkyl, halogeno-lower alkyl, carbamoyl-lower alkyl, lower alkoxycarbonylamino--lower alkyl and acylamino-ethenyl groups.
A substltuent of an aryl radical ~1 can also be hydroxyl which is optionally etherified by an aliphatic hydrocarbon radical, especially by a lower aliphatlc hydro-carbon radical, which can be substituted yet further.
Examples of such radlcals are lower alkoxy groups, lower alkenyloxy groups, lower alkinyloxy groups, hydroxy-lower alkoxy groups, lower alkoxy-lower alkoxy groups, lower alkylthio-lower alkoxy groups, aryl-lower alkoxy groups, such as phenyl-lower alkoxy groups, and hydroxyl groups.

' . . .
. . ' . ' .
-- . . -- . --10~2~1 .
The aryl radical Rl can also be substituted by the following substituents: lower alkanoyl groups, lower alka-noyloxy groups, lower alkylmercapto groups, acylamino groups, halogen atoms or nitrile, amino and nitro groups.
Further possible substituents of the aryl radical R
are optionally substituted carbamoyl groups, such as, for example, N-mono-lower alkylcarbamoyl groups, N,N-di-lower alkylcarbamoyl groups or N,N-lower alkylenecarbamoyl groups.
Further possible substituents of the aryl radical R
are optionally substituted ureido groups.
Substltuents of the aryl radical which should be singled out particularly are optionally lower-alkylated carbamoyl radicals, acylaminoethenyl radicals, such as, for example lower alkanoylaminoethenyl radicals and lower alkoxycarbonylamlno-lower alkyl radicals (which are prefer-ably in the para-position on the phenyl radical), as well as nitrile groups (which are preferably in the ortho-pos-ltlon on the phenyl radical) and lower alkanoyl radicals (whlch are preferably in the ortho- or para-position on the phenyl radical). However, particularly preferred subs-tituents of the aryl radical are halogen atoms (which are preferably in the o-position on the phenyl radical), and hydroxyl groups (which are preferably in the para-position on the phenyl radical) and above all lower alkoxy-lower alkyl groups and acylamlno groups (which are preferably in _ 5 _ ~071Zll the para-position on the phenyl), as well as lower alkyl radicals, lower alkenyl radicals, 5 to 7 ring-membered cycloalkyl, lower alkoxy groups, lower alkenyloxy and alkinyloxy groups (which are preferably in the ortho--position on the phenyl).
Examples of lower alkylene radicals alkl and alk2 are 2,3-butylene radicals, 1,2-butylene, 1,1-dimethyl-1,2-ethylene radicals or preferably 1,2-propylene radicals or especially 1,2-ethylene radicals.
The o-phenylene radical Ph can carry one, two or more substituents; however, it preferably does not contain more than two substituents. Possible substituents of the o-phenylene radical are, in particular: lower alkyl rad-lcals, lower alkoxy groups, halogen atoms, trifluoromethyl groups, hydroxyl groups and, as a second cholce, also acyl-amino groups, nitro groups and amino groups.
An optionally acylated hydroxyl group ~2 is, for example, a lowèr alkanoyloxy group, such as, for example, an acetoxy, propionyloxy or butyryloxy group or preferably the pivaloyloxy group, or above all a free hydroxyl group.
Where not stated otherwise, lower radicals are those radicals which contain not more than 7 carbon atoms and preferably up to 4 carbon atoms.
Examples of lower alkyl radicals are methyl, ethyl, n-propyl or isopropyl radicals, or straight-chain or . ' : - "~ ' .

.

71Zll branched butyl, pentyl or hexyl radicals which can be bonded in any desired position.
Lower alkenyl radicals are, in particular, allyl or methallyl radicals and a possible lower alkinyl radical is above all the propargyl radical. Of the 5 to 7 ring-mem- :
bered cycloalkyl groups cyclohexyl is preferred.
~ ower alkoxy-lower alkyl radicals are, for example, those composed of the lower alkyl radicals mentioned, for example methoxymethyl, ethoxymethyl, n-propoxymethyl, n-butoxymethyl, 2-(n-butoxy)-ethyl, 3-(n-propoxy)-propyl or especially 2-methoxyethyl.
Lower alkylthio-lower alkyl groups are, for example, those composed of the lower alkyl radicals mentioned and are thus, for example, methylthiomethyl, 2-ethylthioethyl,

3-methylthlo-n-propyl and especially 2-methylthioethyl.
Hydroxy-lower alkyl groups are above all those in whlch the lower alkyl parts has the above meaning, such as, for example, 2-hydroxyethyl, 3-hydroxy-n-propyl and especially hydroxymethyl.
Posslble halogeno-lower alkyl radicals are especlal-ly those which are derived from the alkyl radicals men-tioned and ln which the halogen atom is a bromine atom or especially a chlorine atom or fluorine atom, such as, for example, chloromethyl, 2-chloroethyl, dichloromethyl and especially trifluoromethyl.

1071Z~l Lower alkoxycarbonylamino-lower alkyl groups are understood, for example, as those radicals of which the lower alkyl parts are derived from the lower alkyl groups mentioned. Such groups are, for example, methoxycarbonyl-aminomethyl, ethoxycarbonylaminomethyl, 4-methoxycarbonyl-amino-n-butyl, 2-ethoxycarbonylaminoethyl, 3-ethoxycar-bonylamino-n-propyl and especially 2-methoxycarbonylamino-ethyl and 3-methoxycarbonylamino-n-propyl, carbamoylmethyl or 2-carbamoylethyl.
Acylamino-ethenyl groups are in particular radicals of the formula 18 ~ 1lO
R7 - ~ - N - C = C -whereln R7 is a lower alkyl or lower alkkoxy group, for example one of those mentloned above or below, or an amino group, that ls to say a primary, secondary or tertiary amlno group, prefera~ly a mono- or di-lower alkylamino group, wherein possible lower alkyl radicals are those mentloned~ R8 is hydrogen or a lower alkyl group, for example one of those mentioned; Rg is hydrogen, a lower alkyl group, for example one of those mentioned, carboxyl or lower alkoxycarbonyl, wherein the lower alkoxy part is derived, for example, from the lower alkyl radicals mentloned; Rlo ls hydrogen or a lower alkyl group, for : - - . - . .: -:. ' : - ~ -. .

107~Z~l example one of those mentioned.
Lower alkoxy radicals are especially those radicals which are derived from the lower alkyl radicals mentioned.
Examples of such lower alkoxy radicals are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and n-amyloxy. Two lower alkoxy radicals, especially two adjacent lower alkoxy radicals, ¢an also be linked, as in the case of lower alkylenedioxy, for example methylenedioxy.
Examples of lower alkenyloxy radicals are allyloxy or methallyloxy radicals.
Lower alkinyloxy radicals are in particular propar-gyloxy radicals.
Hydroxy-lower alkoxy radicals are especially those derlved from the hydroxy-lower alkyl groups mentioned but wherein preferably the two oxygen atoms are separated by at least 2 carbon atoms.
Lower alkoxy-lower alkoxy radicals are, for example, those derived from the lower alkoxy radicals mentioned.
Examples of such radicals are methoxymethoxy, ethoxymethoxy, l-methoxyethoxy, 4-methoxy-n-butoxy, 3-methoxy-n-butoxy and especlally 3-methoxy-n-propoxy, 2-methoxyethoxy and 2-ethoxyethoxy.
Lower alkylthio-lower alkoxy groups are, for example, those groups which are derived from the lower alkyl radic-als mentioned. Examples of such groups are methylthio-~07~

methoxy, 2-ethylthioethoxy, 3-methylthio-n-propoxy and especially 2-methylthioethoxy.
Phenyl-lower alkoxy radicals are especially a-phenyl--lower alkoxy radicals, such as benzyloxy radicals, but can also be other radicals of this type which are derived from the lower alkyl radicals mentioned, such as, for example, the phenethoxy radical.
Lower alkanoyl radicals to be mentioned are above all pivaloyl, propionyl or butyryl radicals, but above all the acetyl radical; examples of alkanoyloxy radicals are those in which the alkanoyl part has the above meaning.
Examples of lower alkylmercapto groups are those groups derived from the lower alkyl radicals mentioned.
Examples of such groups are ethylmercapto, isopropyl-mercapto, n-butylmercapto and especially methylmercapto.
Acylamino groups are especially those which contain cycloaliphatic, aromatic, araliphatic and above all aliphatic acyl radicals as the acyl radicals.
Aliphatic acyl radicals of the formula R-CO- are especially those in which R is a lower alkyl radical, for example one of those mentioned.
Cycloaliphatic acyl radicals of the formula R'-CO~
are especially those in which R' denotes an optionally lower alkylated lower cycloalkyl radical, above all with 3-7, especially 5-7, ring members, such as, for example, ~' ,, ' ~ ' ~ ' .

1071Zl'l the cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl radical.
Examples of aromatic or araliphatic acyl radicals which may be mentioned are benzoyl and naphthoyl radicals and phenyl-lower alkanoyl radicals, such as phenylac~tyl and ~- and ~-phenylpropionyl radicals.
The acyl radicals mentioned can be substituted yet further.
The following may be mentioned as substituents of the aromatic and araliphatic acyl radicals, the substituents preferably being present in the rings: lower alkyl or alkoxy radicals, such as those mentioned above, halogen atoms, such as those mentioned below, or the pseudohalogen trlfluoromethyl. The radicals can be monosubstituted, di-substituted or polysubstituted.
Preferred acyl radicals are benzoyl and particularly lower alkanoyl, such as acetyl.
Possible halogen atoms are especially fluorine or bromlne atoms, but particularly chlorine atoms.
The N-mono-lower alkylcarbamoyl and N,N-di-lower alkylcarbamoyl groups for example contain, as the lower alkyl part, the above mentioned lower alkyl radicals. The N,N-lower alkylenecarbamoyl radicals contain, as lower alkylene radicals, especially butylene-1,4 or pentylene--1,5 radicals. Examples of such radicals are N-methyl-1071Z~l carbamoyl, N,N-dimethylcarbamoyl, pyrrolidino-carbocarbonyl and piperidino-carbonyl radicals.
An optionally substituted ureido group is, for example, a ureido group in which the free amino group can optionally be substituted by lower alkyl groups, for example those mentioned, such as, for example, a N',N'--dimethylureido group or N',N'-diethylureido group. If the ureido group is substituted by divalent radicals, then these are radicals which can optionally be interrupted by hetero-atoms and/or be substituted, preferably lower alkylene radicals, which can be straightchain or ~ranched and above all have 4-6 chain carbon atoms if the carbon chaln ls unlnterrupted or 4 or 5 carbon atoms if the carbon chain is interrupted by hetero-atoms. Possible hetero-atoms are, ln particular, oxygen, sulphur and nitrogen. Examples of such radicals are butylene-(1,4), pentylene-(1,5), hexylene-(1,5), hexylene-(2,5), hexylene--(1,6), heptylene-(1,6), 3-oxapentylene-(1,5), 3-oxahexyl-ene-(1,6), 3-thia-pentylene-(1,5), 2,4-dimethyl-3-thia--pentylene-(1,5) and 3-lower alkyl-3-aza-pentylene-(1,5) radicals, such as 3-methyl-3-aza-pentylene-(1,5) or 3-aza--hexylene-(1,6) radicals.
The new compounds possess valuable pharmacolo~ical properties. Thus,they show a blood pressure-lowering action, as can be demonstrated in animal experlments, for example 107~Z~l on intravenous administration of doses of about 0.01-1 mg kg to narcotised cats. Furthermore, the new compounds cause an inhibition of tachycardia, as can also be shown in animal experiments, for example in in vitro experiments at concentrations of 0.3-3 y/ml on an isolated guineapig heart by the Langendorff method (resolution of the tachy-cardia by isoproterenol [5 x 10 9 y/ml] or histamine [3 x 10 7 y/ml]). Furthermore, the new compounds cause a vasodllatation which can be demonstrated on animals, for example on narcotised dogs, by measuring the haemodynamics on intraduodenal administration in a dose of about 10 mg/kg.
The new compounds further possess a noradrenolytic action which can be demonstrated in vitro, for exa~ple in experlments on isolated perfused mesenteric arteries of rats at concentrations of 0.001-0.01 y/ml.
The new compounds further show an anti-arrythmic and positlvely lnotropic effect.
Accordingly, the new compounds can in particular be used as anti-hypertensive agents and as vasodilatant agents.
Further, the new compounds can serve as startlng materials or intermediate products for the manufacture of other compounds, especially pharmaceutlcally active compounds.
Compounds to be mentioned particularly are those of the formula C~71Z~l :

R' loRl2 R6 -~ C ~ R"' ~ 2 CH - CH2 - N ~ C~ - N (Ia) Rn ; wherein R' denotes a hydrogen atom, a p-alkanoylaminoethen-yl radical, an optionally lower alkylated p-carbamoyl radical, an o- or p-lower alkanoyl radical, an o-nitrile group, a p-lower alkoxycarbonylamino-lower alkyl radical, an o-halogen atom or a p-hydroxyl group or above all a p-lower alkanoylamlno radical, a p-[2(lower alkoxy)ethyl]
radical, a lower o-alkyl or o-al~oxy radical, or an o-al-kenyl or o-alkenyloxy radical, R" denotes a lower alkyl radical, a lower alkoxy radical, a lower alkenyl radical, a lower alkenyloxy radical or above all a hydrogen atom, R2 denotes a lower alkanoyl radical, such as, in particular, the acetyl, propionyl or pivalyl radical, or above all a hydrogen atom, R3 denotes a hydrogen atom or the hydroxyl group and R5 denotes a hydrogen atom, or R3 and R5 together represent a second bond and R4 and R6 each denote a hydrogen atom, or R4 together with R3 represents an oxo group and R5 and R6 each denote a hydrogen atom, or R6 together wlth R5 represents an oxo group and R3 and R4 each denote a hydrogen atom and R"' denotes a lower alkanoyl-amino radical, the amino group, the nltro group or, above all, a lower alkyl radical, a lower alkoxy group, a halogen 10712~

atom, the trifluoromethyl radical or the hydroxyl group, and their salts.
Compounds to be mentioned especially are in partic-ular those of the formula Ia, wherein R' denotes a p-lower alkanoylamino radical, for example p-acetylamino, a p-[2-(lower alkoxy)-ethyl] radical, for example 2-methoxy-ethyl, or especially a lower o-alkenyl or o-alkenyloxy radical, for example o-allyl or o-allyloxy, or above all a lower o-alkyl or o-alkoxy radical, such as the o-methyl or o-methoxy radical, R" represents hydrogen, R2 denotes the acetyl, propionyl or, in particular, pivalyl radical, or above all a hydrogen atom, R3 denotes a hydrogen atom or the hydroxyl group and R5 denotes a hydrogen atom or R3 and R5 together represent a second bond and R4 and R6 each denote a hydrogen atom, or R4 together with R3 represents an oxo group and R5 and R6 each denote a hydrogen atom, or R6 together with R5 represents an oxo group and R3 and R4 each denote a hydrogen atom, but in which above all R4 and R6 each represent hydrogen and R3 and R5 elther represent a second bond or each denote a a hydrogen atom, and R"' denotes a lower alkyl radical, for example methyl, a lower alkoxy radical, for example methoxy, a halogen atom, for example chlorine, the tri-fluoromethyl radtcal or, in particular, a hydrogen atom, and their salts.

1~371;~1 Compounds to be mentioned specifically are 2-~1-[3-(o-allyloxy-phenoxy)-2-hydroxypropyl]-4-piperidyl~--3,4-dihydro-1(2H)-isoquinolinone, 2-~1-[3-(o-chloro-phenoxy)-2-hydroxypropyl]-4-piperidyl}-3,4-dihydro-1(2H)--isoquinolinone, 2-~1-[3-(o-methoxyphenoxy)-2-pivaloyloxy-propyl]-4-piperidyl}-3,4-dihydro-1(2H)-isoquinolinone, 2-~1-[3-(o-tolyloxy)-2-hydroxypropyl]-4-piperidyl~-3,4-di-hydro-1(2H)-isoquinolinone, and above al~ 2- ~-~3-(o--methoxyphenoxy)-2-hydroxypropyl]-4-piperidyl~-3,4-dihydro--1(2H)-isoquinolinone which, for example, when administered lntravenously, in a dose of about 0.01 mg/kg, to narcotised cats, causes a distinct lowering of the blood pressure.
Furthermore compounds to be mentioned particularly are those o~ formula ~ C~2 ~ C~ ~ C~2 ~ ~ /C~

R' O

~071Zll R' is hydrogen, lower alkyl, lower alkenyl, lower alkinyl, 5 to 7 ring-membered cycloalkyl, carbamoyl-lower alkyl, hy-droxy, lower alkoxy, lower alkenyloxy, lower alkinyloxy, ha-logeno, trifluoromethyl or cyano, each of R " and R " ' is hydrogen, lower alkyl, hydroxy, lower alkoxy, halogeno, tri-fluoromethyl, nitro, amino or lower alkanoylamino, R2 is hy drogen or lower alkanoyl, particularly acetyl 9 propionyl or pivaloyl, each of R5 and R6 denote a hydrogen a~om, or R5 together with R6 represents oxo, and their therapeutically useful acid addition salts. In said compounds R' preferably is in one of the ortho-positions, R " is one of the meta-positions or the para-position and R " ' is preferably meta to carbonyl and para to methylene.
Compounds to be mentioned especially are in parti-cular those of Formula Ib, R' is methyl, allyl, cyclohexyl, carbamoylmethyl, methoxy, allyloxy, propargyloxy, chloro, bromo, tri~luoromethyl or cyano, R " ' is hydrogen, methyl, methoxy or acetylamino, R2 is hydrogen, acetyl, propionyl or pivaloyl, and each o~ R5 and R6 is hydrogen, and salts there-of. Of said compounds, R' is preferably o-methyl, o-allyl, o-cyclohexyl, p-carbamoylmethyl, o-methoxy, o-allyloxy, o-propargylo.~y, o- or p-chloro, -bromo or -trifluoromethyl or o-cyano, R " is preferably hydro~en, m-methyl, m-methoxy or 1071Zll m-acetylami.no, R2 is hydrogen, acetyl, propionyl or pivaloyl, and each of R " ', R5 and R6 is hydrogen, and their thera-peutically useful acid addition salts.
Compounds to be mentioned specifically are 1-[3-(o- .
methoxy-phenoxy)-2-hydroxypropyl3-4-(1-oxo-isoindolino)-pi-peridine and the 1-[3-(o-cyanophenoxy)~2~hydroxypropyl]-4-(l-oxo-isoindolino)-piperidine and their therapeutically useful acid addition salts, which, or example, when admini-stered intravenously, in a dose of about 0.01 mg/kg, to narcotised cats, cause a distinct lowering of the blood pres-sure.
The new compounds are obtained according to methods which are in themselves known.
For example, a compound o~ the formula Rl - O - Yi (II) can be reacted with a compo~md of the formula R~ R~ R3 alkl R C ( C)n (III) \ alk2/ ~ / Ph ~71Z~l wherein R , alkl, alk2, Ph, n, R3, R4, R5 6 indicated meanings, one of the radicals Yl and Y2 represents hydrogen and the other denotes a radical of the formula - CH2 - CH - CH - z X

and X represents the group R2, wherein R2 has the indicated meaning, and Z denotes a reactively esterified hydroxyl group, or X and Z together form an epoxy group.
Thus, for example, a possible procedure is to react a compound of the formula , .

1 CH2 - CH - CH2 - z (IIa) wlth a compound of the formula /alkl \ R5 R~ R3 \ alk2 ~ Ph (IIIa) o wherein alkl, alk2, Ph, n, R3, R4, R5 6 above meanings and either X represents the group R2, wherein R2 has the indicated meanings, and Z represents a reactive esterified hydroxyl group,or X and Z together form an epoxy group.

1071Z~l A reactive esterified hydroxyl group is, in partic-ular, a hydroxyl group esterified by a strong inorganic or organic acid, above all a hydrogen halide acid, such as hydrochloric acid, hydrobromic acid, hydriodic acid or sulphuric acid, or an organic sulphonic acid, for example benzenesulphonic acid, p-bromobenzenesulphonic acid or p-toluenesulphonic acid. Thus, Z in particular represents chlorine, bromlne or iodine.
This reaction is carried out in the usual manner.
~7hen a reactive ester is used as the starting material, the reaction ls preferably carried out in the presence of a baslc condensation agent and/or with an excess of the compound of the formula IIIa.
Further, a compound of the formula Rl - OH (IIb) wherein Rl has the above meanings, can be reacted wlth a compound of the formula R5 ~ /
X /alkl\ R6 ~C ( C~n Z - CH - CH - CH - N CH - N C / ~h (IIIb) o wherein X, Z, alkl, alk2, Ph, n, R3, 4, 5 6 the above meanlngs.

, ' ': ' :

- ~, 10~2~1 This reaction is carried out in the usual manner.
If reactive esters are used as the starting material, the compound of the formula IIb can preferably be used in the form of its metal phenolate, such as alkali metalphenolate, for example sodium phenolate, or the reaction is carried out in the presence of an acid-binding agent, especially of a condensation agent, which can form a salt with the compound of the formula IIb, such as an alkali metal aicoholate.
The new compounds in which R3 is hydroxyl can furthermore be manufactured by reducing the oxo group of the propyl chain to a hydroxyl group in a compound of the formula al~2 / ~ IIV) o wherein Rl, alkl, alk2, Ph, n, R3, R4, R5 6 above meanings.
This reduction is carried out in the usual manner, ln particular using a di-light metal hydride, such as sodium borohydride. However, the reduction can also be carried out with nascent hydrogen. Nascent hydrogen can be obtained for this purpose by reaction of metals or metal . .
.
.

`: ^

alloys on agents which provide hydrogen, such as carboxylic acid, alcohols or water, and in particular zinc or zinc alloys together with acetic acid, or alkali metals and alcohol, such as sodium and ethanol, can be used.
The reduction can furthermore be carried out by catalytic hydrogenation, such as with hydrogen in the presence of a hydrogenation catalyst, for example heavy metals such as palladium, platinum or Raney nickel. Care must be taken that other reducible groups are not attacked during the reduction.
The new compounds can also be obtained when the pyridinium ring is reduced to the piperidine ring in a compound of the formula ~2 ~ ~ R6 - C ~ ~ 3 Rl-O-CH -CH-CH - N~ ~ C ~ h (P~y~s O

1~ 2~ R3t R4, R5, R6, Ph and n have the above meanings, Rx and Ry independently of one another denote lower alkyl radicals or hydrogen atoms and r and s repres-ent 1 or 2, and A ~ is an anion.
The reduction can be carried out in the usual manner, preferably by catalytic hydrogenation, such as .
.

107~Zll with hydrogen in the presence of a hydrogenation catalyst, for example heavy metals, such as palladium, platinum or Raney nickel, or with nascent hydrogen, such as, for example, is produced by sodium and an alcohol, such as a lower alkanol, for example ethanol.
Care must be taken that other reducible groups are not attacked in the reduction.
The new compounds can also be obtained bY intra-molecular Icondensation of a compound of the formula -- R6~ ~ 5 X'-- C 1 4 lR2 /alkl C~--~.3 Rl-o-CH2-CH CH2 ~ ~ ~ ~ Ph alk2 C (Y~ ) whereln Rl, R2, alkl, alk2, Ph, n, R3, R4, R5 and R6 have the indicated meanings and X' denotes a reactive esterified hydroxyl group.
A reactive esterified hydroxyl group is in partic-ular one of those mentloned above.
The cyclisatlon (intramolecular condensation) can be carried out in the usual manner, preferably in the presence of a solvent, such as an inert polar solvent, - 2~ -107~2~1 such as an alcohol, for example ethanol or isopropanol, or dimethylformamide, and advantageously in the presence of a condensation agent, particularly of a basic condensation agent. The cyclisation is preferably carried out in the presence of an alkali metal hydroxide, carbonate or bi- -carbonate or alkaline earth metal hydroxide, carbonate or bicarbonate, for example sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate, sodium bicarbonate or potassium blcarbonate, or of an alkali metal acetate, such as sodium acetate, or of an alkali metal alcoholate, such as sodium methylate, or of organic tertiary nitrogen bases, such as trialkylamines, for example trimethylamine or triethylamine, or pyridine.
The new compounds in which R3 and R5 together represent a second bond, wherein n is 1, can also be ob-tained when a compound of the formula 12 / alkl Rl ~ ~ CH2 - CH - CH2 - N / CH - NH2 (VII) is reacted with a compound of the formula 1071Z~l R~ / ~4 C, - C
. ¦ (VIII) C
o 1' 2' R4, R6, alkl, alk2 and Ph have the indicated meanings.
The reaction can be carried out in a manner which is ln itself known. It is advantageously carried out in the presence of an organic base, such as a tertiary amine, above all pyridine, and this base can also simultaneously serve as the solvent. However, the reaction can also be carrled out in the presence of further solvents.
The new compounds can also be obtained by intramole-cular condensation of a compound of the formula 12 alkl / C --~~C~- R3 Rl_o_cH2_cH_cH2 _ ~ CH ~ N Ph (IX) whereln R , R2, alkl, alk2, R~, R~, R5, 6 the indlcated meanings, and Y3 denotes a free carboxyl .. ~ , - ,: -' ~:
. : . . : .. . .

1071Z~l group or preferably a functionally modified carboxyl group which contains an oxo group.
A functionally modified carboxyl group which con-tains an oxo group is, for example, an esterified carboxyl group such as, in particular, a carboxyl group esterified with a lower alkanol or aralkanol, such as methanol, phenol, p-nitrophenol or benzyl alcohol, or an activated esterified carboxyl group, such as a carboxyl group esterified with cyanomethanol, or an acid halide grouping, such as, in particular, an acid chloride grouping, or an acid azide, acid amide or acid anhydride grouping. Possible acid an-hydride groupings are especially those of mixed anhydrides, especially of mixed anhydrides with carbonic acid monoalkyl esters, such as carbonic acid monoethyl ester or carbonlc acid monolsobutyl ester.
The reaction can be carried out in the usual manner.
Preferably, elevated temperatures are used. The reaction ls advantageously carried out in a solvent, such as an inert solvent, for example a hydrocarbon, such as benzene or toluene, or in a high-boiling inert solvent such as, for example, diphenyl ether.
The new compounds in which R2 represents hydrogen, can also be obtained when, in a compound of the formula .

~D71Z~l OR2 ~ alkl R6 ¦ 5 R4 R
Rl O CH2 C~ CH2 ~ / CH - N ~ Ph (X) wherein Rl, alkl, alk2, Ph, n, R3, R4, R5 and R6 have the indicated meanings and R2 denotes a radical which can be split off by hydrogenolysis, R2 is split off by hydrogen-olysis.
A radical which can be split off by hydrogenolysis is above all an ~-aralkyl radical, such as the benzyl radical, or an a-aralkoxycarbonyl radica7, such as the carbobenzoxy radical. The hydrogenolysis can be carried out in the usual manner, preferably by means of hydrogen ln the presence of a hydrogenation catalyst, such as a nickel, palladium, platinum or ruthenium catalyst.
The new compounds of the formula I, wherein R6 together with R5 forms an oxo group, can also be obtained when a compound of the formula Rl - O - CH2 - CH - C~l2 ~ N~ lk ~ 2 (VII) ` - 27 -, . - -: . .
-: - -~0~7~Zll wherein Rl, R2, alkl and alk2 have the above meanings, isreacted with a compound of the formula ~ R3 Y3 - (C) n (XI) ~ Ph wherein R3, R4, n and Ph have the above meanings and the substituents Y3 independently of one another represent a free carboxyl group or preferably a functionally modified carboxyl group which contains an oxo group, or together represent the grouping O z C

~C~

A functlonally modified carboxyl group which con-talns an oxo group is, for example, an esterified carboxyl group such as, in partlcular, a carboxyl group esterified with a lower alkanol or aralkanol, such as methanol, phenol, p-nitrophenol or benzyl alcohol, or an activated esterified carboxyl group, such as a carboxyl group esterified with ~O~lZll ~hd~ cyanomethanol, or an acid halide grouping, such as, in particular, an acid chloride grouping, or an acid azideJ
acid amide or acid anhydride grouping. Possible acid an-hydride groupings are in particular those of mixed anhydrides, especially of mixed anhydrides with carbonic acid monoalkyl esters, such as carbonic acid monoethyl ester or carbonic acid monoisobutyl ester.
The reaction can be carried out in the usual manner.
Preferably, elevated temperatures are used. The reaction is advantageously carried out in a solvent, such as an inert solvent, for example a hydrocarbon, such as benzene or toluene, or in a high-boiling inert solvent such as, for example, diphenyl ether.
In resulting compounds, substituents can be split off, introduced or converted, within the scope of the end products.
Thus, for example, in compounds of the formula I, wherein Rl denotes an aryl radical which is substituted by a ratical Z" which can be converted into an optionally substituted carbamoyl group, Z" can be converted into an optionally substituted carbamoyl group.
A radical Z" is in this case above all an optionally functionally modified carboxyl group containing an oxo group.
A functionally modified carboxyl group which con-.

~7~Zll tains an oxo group is, for example, an esterified carboxyl group, such as, in particular, a carboxyl group esterified with a lower alkanol or aralkanol, such as methanol,phenol, p-nitrophenol or benzyl alcohol, or an activitated ester-ified carboxyl group, such as a carboxyl group esteri~ied with cyanomethanol, or an acid halide grouping, such as, in particular, an acid chloride grouping, or an acid azide grouping or acid anhydride grouping.Possible acid anhyd-ride groupings are in particular those of mixed anhydrides, especially of mixed anhydrides with carbonic acid mono-alkyl esters, such as carbonic acid monoethyl ester or carbonic acid monolsobutyl ester.
The conversion of the group Z" is effected, for example, by reaction with ammonia or with a corresponding amlne possesslng at least 1 hydrogen atom.
The reaction is carried out in the usual manner, in partlcular at elevated temperature, if necessary at dras-tically elevated temperature, such as at a temperature whlch may even be above 200C, if desired under pressure and lf desired with an excess of the particular amine. If the reaction is carried out at room temperature or only moderately elevated temperature, it is preferably carried out in an inert solvent using a longer reaction time.
Examples of inert solvents are alcohols, such as methanol and ethanol, ethers, such as diethyl ether or dloxane, benzene and the like.

Furthermore, for example, in compounds of the formula I, wherein Rl denotes an aryl radical substituted by a radical Z"' which can be converted into an optionally substituted ureido group, Z"' can be converted into an op-tionally substituted ureido group.
Z"' is here in particular a reactively modified carboxyamino radical, such as a carboxyamino radical esterified by a lower alkanol or phenol, or a corresponding halogenocarbonylamino radical, such as, in particular, a chlorocarbonylamino radical.
The conversion to the ureido group is carried out, for example, by reactlon with ammonia or a corresponding amlne possessing at least 1 hydrogen atom.
This reactlon can be carried out in the usual manner, especially using an excess of ammonia or amine and option-ally ln a solvent and preferably at elevated temperature.
Furthermore, resulting compounds in which Rl denotes an aryl radical substituted by a hydroxyalkyl, hydroxy-alkoxy, mercaptoalkyl or mercaptoalkoxy radical, can be alkylated, for example by reaction with a reactive ester of a correspondlng alkanol. Reactive esters are here above all esters with strong inorganic or organlc acids, prefer-ably with hydrogen halide acids, such as hydrochloric acid, hydrobromic acid or hydriodic acid, with sulphur acid or with arylsulphonlc acids, such as benzenesulphonic acid, ,:
: ~ . ; ' .

.

`

p-bromobenzenesulphonic acid or p-toluenesulphonic acid.
The reaction can be carried out in the usual manner, advantageously in the presence of solvents and, for example, in the presence of condensation agents, such as basic con-densation agents, at lowered, ordinary or elevated temper-ature.
Furthermore, in compounds of the formula I, wherein Rl denotes an aryl radical substituted by a Z2-alkyl or Z2-alkoxy radical and Z2 represents a reactively esterified hydroxyl group, Rl can be converted into alkoxy- or alkyl-mercapto-alkyl or -alkoxy radicals by reaction with alkanols or alkylmercaptans.
Reactively esterified hydroxyl groups are here in particular hydroxyl groups esterified with the strong acids mentioned.
The reaction can be carried out in the usual manner, advantageously in the presence of solvents and, for example, in the presence of condensation agents, such as basic con-densatlon agents, at lowered, ordinary or elevated tem-perature.
Furthermore, in comp~unds of the formula I wherein R1 denotes an aryl radical substituted by a hydroxyl group, the hydroxyl group can be converted into a group of the formula RxO-, wherein Rx denotes an alkyl radical, an alkenyl radical, an alkinyl radical, an alkoxyalkyl radical 1071Z~l or an alkylmercaptoalkyl radical. This conversion can be effected in the usual manner, for example by reaction with a reactive ester of an alcohol of the formula RxOH or a diazoalkane, such as diazomethane. Furthermore, hydroxyl groups in the radical Ph can be alkylated, for example by reaction with a reactive ester of a lower alkanol or a diazoalkane, such as diazomethane.
Reactive esters are above all esters with strong inorganic or organic acids, preferably with hydrogenhalide acids, such as hydrochloric acid, hydrobromic acid or hydriodic acid, with sulphuric acid or with arylsulphonic acids, such as benzenesulphonic acid, p-bromobenzenesul-phonic acid or p-toluenesulphonic acid.
The reaction can be carried out in the usual manner, advantageously in the presence of solvents. When using the reactive esters, the reaction is preferably carried out in the presence of condensation agents, such as basic conden-sation agents, or the phenolic hydroxy compound is employed in the form of a salt, for example a metal salt, such as an alkali metal salt, for example the sodium salt or potas-sium salt. The reaction can be carried out at lowered, ordlnary or elevated temperature.
Furthermore it ls possible, in compounds of the formula I, wherein Rl denotes an aryl radical substituted by an amino group or by a substituent containing an amino ' ,~

.. . " ..

10712~1 group, and/or Ph denotes an o-phenylene radical containing an amino group, to acylate the said amino group or groups, such as, for example, by reaction with an acylating agent.
Possible acylating agents are carboxylic acids, for example aliphatic, araliphatic or cycloaliphatic carboxylic acids, preferably in the form of their functional deriv-atives, such as halides, especially chlorides, or anhyd-rides, for example pure of mixed anhydrides, or inner an-hydrides, such as ketenes.
Furthermore, in compounds of the formula I which contain hydroxyl groups, these groups can be acylated (esterified). The acylation is carried out in the usual manner, for example by reaction with carboxylic acids, advantageously in the form of their reactive furnctional derivatives, such as acid halides, for example chlorides, esters, especlally esters wlth lower alkanols, such as methanol and ethanol, or activated esters such as cyano-methyl esters, or pure or mixed anhydrides, for example mixed anhydrides with carbonic acid monoalkyl esters such as carbonic acid monoethyl ester and monoisobutyl ester.
In compounds of the formula I which contain an acyl-ated hydroxyl or amino group, this group can be split in the usual manner to give the free hydroxyl or amino group respectively, and can in partlcular by splithydrolytically, with acid or basic catalysts as appropriate, for example 10712~1 with inorganic acids or alkali metal hydroxide solutions (bases), for example, with hydrochloric acid or withsodium hydroxide solution. If such splitting should already occur in the course of one of the above methods of manufacture, a resulting free hydroxyl or amino group can optionally be acylated as described above.
In compounds of the formula I which contain a halogen atom, for example chlorine or bromine, on an arom-atic ring, for example on Rl or Ph, this halogen atom can be replaced by hydrogen. This is done in the usual manner, for example by dehalogenating hydrogenation, such as hydrogenation in the presence of nickel or palladium catalysts. Compounds which contain an unsubstituted aryl radlcal or an aryl radlcal which is partly substituted by other groups, can be halogenated at the aryl radical. This can be done in the usual manner, for example with halogen, especlally at non-elevated temperatures or with cooling, and in the presence of a catalyst, such as iron, iodine, iron-III chloride or aluminium chloride or the correspon-ding bromldes.
Furthermore, in compounds of the formula I which contain substituents with a C-C double bond or C-C triple bond, the C-C double bond or C-C triple bond can be conver-ted into a C-C single bond by catalytic hydrogenation, such 1071;2~1 as by hydrogen in the presence of a hydrogenation catalyst, for example nickel, platinum or palladium, such as Raney nickel, platinum black or palladium on active charcoal.
Care must be taken at the same time that other reducible groups are not attacked.
In compounds of the formula I, which contain sub-stituents with a C-C triple bond, this bond can further-more be reduced merely to a C-C double bond and can, if deslred, be reduced stereospecifically to a C-C-cis- or C-C-trans-double bond. The reduction of a C-C triple bond to a C-C double bond can be carried out, for example, by hydrogenation with 1 mol of hydrogen in the presence of a less active hydrogenation catalyst, such as iron or pal-ladlum, for example Raney iron or paladium on barium sul-phate, especially at elevated temperature. The reduction to a C-C-cis double bond can be effected, for example, by means of 1 mol of hydrogen in the presence of a deactiv-ating catalyst, such as palladium on animal charcoal in the presence of quinoline, palladium on calcium carbonate ln the presence of lead salts, or Raney nickel. The reduc-tion to a C-C-trans-double bond can be effected, for exam-ple, by means of sodium in liquid ammonia, in which case, especially taking into accountan urea group, short reac-tion times and no excess reducing agent are employed and, if appropriate, an ammonium halide, such as ammonium 1~17~Z~l chloride, is added as the catalyst.
In resulting compounds of the formula I which con-tain an a-aralkylamino or ~-aralkoxycarbonylamino group or an a-aralkoxy or ~-aralkoxycarbonyloxy group, these radic-als can be split to give free amino or hydroxyl groups respectively. a-Aralkyl is in such cases especially benzyl.
The splitting off can be effected in the usual manner, es-pecially by means of hydrogen in the presence of a hydrog-enation catalyst, such as a palladium, platinum or nickel catalyst.
In resulting compounds of the formula I which pos-sess nitro groups on an aromatic nucleus, these groups can be reduced to amino groups.
The reduction can be carried out in the usual man-ner, for example by nascent hydrogen Ifor example with iron and hydrochloric acid or with aluminium amalgam) cr with catalytically activated hydrogen, such as hydrogen in the presence of platinum, nickel or palladium catalysts.
It is also possible to reduce compounds of the formula I, in which R3 and R4 together represent an oxo group, to compounds wherein R3 represents hydroxyl and R4 represents hydrogen.
The reduction of the oxo group ls carried out in the usual manner, for example by metallic reduction, such as by treatment with sodlum in alcohol, or with complex 1~7121~

metal hydrides, such as sodium borohydride, or by means of catalytically activated hydrogen, for example hydrogen in the presence of a platinum, palladium, nickel or copper catalyst, such as platinum oxide, palladium on charcoal, Raney nickel or copper chromite. The reaction is preferably carried out in the presence of diluents and/or solvents, at low, ordinary or elevated temperature, in an open vessel or in a closed vessel, under pressure.
The reduction of the oxo group can also be carried out in accordance with the Meerwein-Ponndorf-Verley method.
Thus, for example, the oxo compound can be treated in the usual manner with a lower alkanol, such as isopropanol, in the presence of a corresponding alXanolate, such as alum-lnium lsopropylate.
It ls also possible to split off the hydroxyl group ln compounds of the formula I, wherein R3 represents hydroxyl. This gives compounds in which R3 and R5 represent a second bond.
The splitting off can be effected ln the usual manner, for example by treatment with strong acids, such as sulphuric acid, p-toluenesulphonic acid, concentrated hydrochloric acld, oxalic acid or other dehydrating agents, such as phosphorus pentoxide, zlnc chloride or boron trioxide. If appropriate, the water ls removed by means of a water separator. For example, the reaction can becarried ' - ~
1~71Zll out in a boiling hydrocarbon, such as benzene or toluene.
Furthermore, it is possible to replace the hydroxyl group by hydrogen in compounds of the formula I, wherein R3 represents hydroxyl. This can be done, for example, by catalytic hydrogenation.
Furthermore, compounds of the formula I, wherein R3 and R5 represent a second bond, can be hydrogenated to compounds in which R3 and R5 represent hydrogen atoms.
This can be done, in particular, by catalytic hydrogenation.
The catalytic hydrogenation can be carried out in the usual manner, in particular by means of hydrogen in the presence of a hydrogenation catalyst, such as a pal-ladium, platinum or nickel catalyst.
The reactions mentioned can optionally be carried out simultaneously or successively, and in optional sequence.
The reactions mentioned can be carried out in the usual manner in the presence or absence of solvents or diluents, acid or basic condensation agents and/or catal-ysts, at lowered, ordinary or elevated temperature and if appropriate in a closed vessel under elevated pressure and/or under an inert gas atmosphere.
Depending on the process conditions and starting materials, the end products are obtained in the free form or in the form of their acid addition salts, which are also 107~Z~

encompassed by the invention. Thus, for example, basic, neutral or mixed salts and at times also hemihydrates, monohydrates, sesquihydrates or polyhydrates thereof, can be obtained. The acid addition salts of the new compounds can be converted into the free compound in a manner which s is in itself known, for example by means of basic agents, such as alkalis or ion exchangers. On the other hand, the resulting free bases can form salts with organic or in-organic acids. Acids used for the preparation of acid ad-; dition salts are especially those which are suitable for forming therapeutically usable salts. As examples of such acids there may be mentioned: hydrogen halide acids, for example hydrochloric acid, sulphuric acids, ~or example sulphuric acld, phosphoric acids, nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic car-boxylic aclds or sulphonic acids, such as formic acid, acetic acid, propionic acid, succinic acid, glycollic acid, lactic acid, malic acid, tartaric acid, citric acid, as-corbic acid, malelc acld, hydroxymaleic acid or pyruvic acid, fumarlc acid, benzoic acid, p-aminobenzoic acid, anthranilic acid, p-hydroxybenzoic acid, salicylic acid or p-aminosalicyllc acid, embonic acid, methanesulphonic acid, ethanesulphonlc acld, hydroxyethanesulphonic acid, ethyl-enesulphonic acld; halogenobenzenesulphonic acid, toluene-sulphonic acid, naphthalenesulphonic acid or sulphanilic 1071Zll acid; methionine, tryptophane, lysine or arginine.
These or other salts of the new compounds, such as, for example, the picrates, can also serve for the purifi-cation of the resulting free bases by converting the free bases into salts, isolating these and again liberating the bases from the salts. Because of the close relationships be-tween the new co~pounds in the free form and in the form of their salts, the free compounds are, in the preceding and following text, where appropriate also to be understood as the corresponding salts, with regard to general sense and intended use.
The invention also relates to those embodiments of the process, according to which a compound obtainable as an intermediate product at any stage of the process is used as the starting ~aterial and the missing process steps are carried out, or the process is discontinued at any stage, or in which a starting material is formed under the reac-tion conditions or in which a reactant is present, if ap-propriate, in the form of an optical antipode and/or of a salt, Thus, for example, the new piperidines can be ob-tained if a compound of the formula 12 alkl Rl - 0 - ~H2 ~ CH - CH2 - N CH - NH2 ' alk2 lC~71Zll wherein Rl, R2, alkl and alk2 have the indicated meanings, is reacted with a compound of the formula R~ R5 X' - C 14 IJn 3 Ph wherein n, R3, R4, R5 and R6 have the indicated meanings, and X' and Y3 have the meanings indicated for formula VI
or IX. Here, a product of the formula VI is produced as an intermediate and then reacts further, in accordance with the invention, to give a compound of the formula I. The reactlon can be carried out in the usual manner, for exam-ple as descrlbed above for the intramolecular condensations.
The new compounds can, depending on the choice of the starting materials and procedures, be in the form of optical antipodes or racemates or, if they contain at least two asymmetrical carbon atoms, also in the form of racemate mlxtures and/or pure geometrical isomers or mixtures there-of ~isomer mixtures).
Resulting isomer mixtures can be separated into the two pure geometrical isomers on the basls of the physico-chemical differences of the constituents in a known manner, ~07~Z~l for example by chromatography on a suitable stationary phase, such as silica gel, or aluminium oxide, which has been pretreated with a complex-forming heavy metal com-pound, for example with a silver compound, or by forming a heavy metal addition compound, for example the silver nitrate complex, separating this into the addition com-pounds of the pure isomers, for example by fractional crys-tallisation, and subsequently liberating the pure isomers.
Resulting pure isomers, for example tranc-isomer can be converted in the usual manner, for example photo-chemlcally, for example by irradation with light of a suitable wavelength, advantageously in a suitable solvent, ~uch as an aliphatic hydrocarbon, or in the presence of a sultable catalyst, into the isomers of opposite configur-ation, for example into the cis-isomers.
Racemate mixtures can be separated into the two stereoisomeric ~diastereomeric) pure racemates on the basis of the physico-chemical differences of the constituents in a known manner, for example by chromatography and/or frac-tlonal crystallisation.
Resultlng racemates can be resolved according to known methods, for example by recrystalllsation from an optically active solvent, with the ald of micro-organisms or by reaction with an optically active acid which forms - g3 -' . , . , .............................................. - . .

.,, '' - .
.. . . ~ . . . . .

107~Zll salts with the racemic compound and separation of the salts obtained in this manner, for example on the basis of their different solubilities, into the diastereomers, from which the antipodes can be liberated by treatment with suitable agents. Particularly customary optically active acids are, for example, the D- and L-forms of tartaric acid, di-o--toluyltartaric acid, malic acid, mandelic acid, camphor-sulphonic acid or quinic acid. Advantageously, the more active L-antipode is isolated.
Suitably, those starting materials are used for carrying out the reactions according to the invention which lead to the initially particularly mentioned groups of end products and particularly to the end products which have been specifically described or singled out.
The starting materials are known or can, if they are new, be obtained according to methods which are in themselves known.
The compounds of the formula alkl /C ~C~;
alk2~ C ~ (IIIa) U

used as preferred starting materials, can be obtained, for .
;~

-': ~ . -` - `:
,. , ., , . , . : .
, , -.
.~ . .
: . - . :

.

1071Zll example, if a compound of the formula ~alkl 1 1 ~ CH -- NH2 alk2 wherein alkl and alk2 have the indicated meanings and R
denotes an a-aralkyl radical, such as benzyl radical, is reacted with a compound of the formula R ~ 15 C ~ R3 I n Ph wherein n, R3, R4, R5 and R6 have the indicated meanings and X' and Y3 have the meanings indicated for formulae VI
or IX, and in the resulting compound of the formula Rll- N \ CH - N/

. .. : . . : ~ .

, . . . - :
.. . .. . ...... . .

-~07~Z~l the a-aralkyl radical Rll is replaced by hydrogen, for example by catalytic hydrogenation as described above.
The new compounds can be used as medicaments, for example in the form of pharmaceutical preparations in which they or their salts are present in a mixture with a pharmaceutical, organic or inorganic, solid or liquid excipient which is suitable, for example, for enteral, for example,oral, or.parenteral administration. Suitable materials for forming the excipient are those which do not react with the néw compounds such as, for example, water, gelatine, lactose, starch, magnesium stearate, talc, vegetable oils, benzyl alcohols, gum, polyalkylene glycols, white petroleum jelly, cholesterol or other known medicinal excipients. The pharmaceutical preparations can be, for example, in the form of tablets, dragees, capsules, sup-positories, ointments or creams or in a liquld form, as solutlons (for example as an elixir or syrup), suspensions or emulsions. They are optionally sterilised and/or con-tain auxiliaries, such as preservatives, stabllisers, wetting agents or emulsifiers, salts for regulating the osmotlc pressure or buffers. They can also contain yet other therapeutically valuable materials. The preparations, which can also be used in veterinary medicine, are for-mulated according to customary methods.

., :
.
.

.
:
' ~ . - . :

1071Zli The dosage of the new compounds depends on the nature of the conditions to be treated and on the indiv-idual requirements. For example, the new compounds can be administered to a warm-blooded animal of about 75 kg body weight in a daily dose of about 5-100 mg, especially about 5 to 60 mg.
The new compounds can also be used advantageously in pharmaceutical preparations in combination with other anti-hyper~tensive agents and/or diuretics.
Compounds, having an anti-hypertensive action, which can be used are in particular those of the type of a-amino-~-hydroxyphenyl-propionic zcid and ~-amino-~-al-koxyphenyl-propionic acid and especially of the hydrazin-opyrldazines and of the sympathicolytics.
Sultable diuretics are materials which increase the diuresls both through renal and through extrarenal action on the tlssues. For this purpose, substances with an in-hlbitlng action on the back-resorptlon ln the tubulus, such as, for example, ln partlcular saluretlcs as well as ethacrlnlc acid and its analogues, can be used.
Partlcularly suitable compounds are benzothiadiazine derlvatlves, such as thlazides and hydrothlazides, benzene-sulphonamldes, phenoxyacetic acids, benzofurane-2-carbox-ylic acids and benzofurane-2,3-dihydroxy-2-carboxylic acids.
The examples which follow illustrate the invention wlthout however restricting it.

: ' : . '.
-:' ' ~
.:

1071Zl~

Example 1 A mixture of 30.2 g of 1-(o-methoxyphenoxy)-2,3-epoxypropane and 38.7 g of 2-(4-piperidyl)-3,4-dihydro-1(2H)-iso~uinolinone in 50 ml of absolute ethanol is boiled for 6 hours under reflux and is then evaporated in vacuo.
The residue is acidified with ethanolic hydrochloric acid;
on adding ether, 2-{1-~3-~o-methoxyphenoxy)-2-hydroxy-propyl]-4-piperidyl}-3,4-dihydro-1 ~2H~-isoquinolinone hydrochloride precipitates and after recrystallisation from ethanol/ether melts at 174-176&.
2-(4-Piperidyl)-3,4-dihydro-1 (2H)-isoquinolinone, used as the starting material, is prepared as follows:
A solution of 40 g of 2-(2-chloroethyl)-benzoyl chloride in 100 ml of acetone is added dropwise to a mix-ture of 53 g of potassium hydroxide and 30 g of 4-amino-1-benzyl-piperidine in 600 ml of acetone at room temperature.
After completion of the addition, the reaction mixture is heated for 4 hours to the reflux temperature and is then evaporated to dryness. The residue is taken up in water and extracted with methylene chloride. The organic layer is dried over sodium sulphate and evaporated. The oily residue is taken up in a little ethanol and acidified with ethanolic hydrochloric acid. The hydrochloride of 2-(1-ben~yl-4-piperidyl)-3,4-dihydro-1(2H)-isoquinolinone is ob-tained in a crystalline form and melts at 276-278C (with decomposition), .

.
:. ' : ,, .. ' - '.
- : - . : ' ' . . .' :

1071~1~

13.6 g of 2-(1-benzyl-4-piperidyl)-3,4-dihydro-1(2H)-isoquinolinone hydrochloride are hydrogenated together with 1.5 g of 10% strength palladium on charcoal at room temperature and atmospheric pressure. The reaction mixture is freed from the catalyst by filtration and the residue ls well washed with water. The filtrate is evap-orated to dryness, the residue is dissolved in as little ethanol as possible and the hydrochloride of 2-(4-piper-idyl)-3,4-dihydro-1(2H)-isoquinolinone is precipitated wlth ether. It melts, after recrystallisation from ethanol, at 318-320C (decomposition).
The base is liberated with 10 N sodium hydroxide solutlon and extracted with methylene chloride. Drying, and evaporation of the solvent, gives the base an oil.

Example 2 A solutlon of 9.9 g (0.06 mol) of l-(o-tolyloxy)-2,3-epoxy-propane, 15.9 g (0.06 mol) of 2-~4-plperldyl)-3,4-dlhydro-l~2H)-isoquinolinone hydrochloride and 24 ml of trlethyla~ine in 240 ml of isopropanol is heated to the reflux temperature for 6 hours and then evaporated ln vacuo.
The resldue is crytalllsed from ethanol-water. After recrys~alllsatlon from ethanol-water, 2-~1-[3~(o-tolyloxy)-2-hydroxypropyl]-4-plperidyl~-3,4-dihydro-1(2~)-iso~uinol-lnone melts at 104-105C.

" ' ' ' -,. ~

. ' . . ~ .: , - ' ' .
.
. . ~

1071Zll The maleic acid salt of this compound melts, after recrystallisation from ethanol-ether, at 165-166C (with decomposition).

Example 3 A solution of 8.1 g of 2-~l-[3-(o-methoxy-phenoxy)-2-hydroxy-1-propyl]-piperidyl-(4)~-3,4-dihydro-1(2H)-iso-quinolinone hydrochloride and 5 g of pivaloyl chloride in 50 ml of pyridine is warmed to 100C over the course of 1/2 hour and is then evaporated in vacuo. The residue is a~idified with alcoholic hydrochlorlc acid and again evap-orated. After recrystallisation from isopropanol, 2-~1-[3--(o-methoxy-phenoxy)-2-pivaloyloxy-1-propyl]-piperidyl-~4)}-3,4-dihydro-1~2H)-isoquinolinone hydrochloride of meltlng polnt 232-234C ls obtained.

Example 4 A mixture of 5.5 g of 1-(o-chlorophenoxy)-2,3-epoxy-propane and 7 g of 2-(4-plperldyl)-3,4-dlhydro-1(2H)-lso-qulnollnone in 100 ml o~ isopropanol is boiled for 5 hours under reflux and then evaporated in vacuo. The oily residue is dissolved in absolute ethanol and the equivalent amount of malelc acld 19 added. After addition of ether, 2-~ 3-~o-chlorophenoxy)-2-hydroxy-propyl~-piperidyl-(4)~-3,4-di-hydro-1(2H)-isoqulnolinone maleate precipitates and melts, after recryqtallisatlon from ethanol/ether at 139-140C.

' . ' -''' ,, '' - --. - - ~ , .

.. - :

.. . .

1~71Zll Example 5 - A solution of 6.2 g of l-Ip-(2-m2thoxy-ethyl)-phenoxyl-2,3-epoxy-propane and 7.0 g of 2-(4-piperidylj-3,4-dihydro-1(2H)-isoquinolinone in 80 ml of isopropanol is refluxed for 5 hours. The reaction mixture is concentrated by evaporation to dryness with the resulting precipitation of 2-~ 3-C~p-~2-methoxy-2thyl)-phenoxy ~ -2-hydroxypropyl]-4-piperidyl~-3~4-dihydro-1(2H)--isoquirlolinone.
The product melts at 116-117 after recrystallisation from an ethanol/ether mixture. The maleic acid salt crystallises from a mi.~ture of ethanol/ether and melts at 138-139.

Example 6 6.~ ~ o~ 1-(o-allyloxyphenoxy)-2,3-epoxy-propane and 7.0 g of 2-(4-piperidyl)-3,4 dihydro-1(2H)-isoquinoline are dissolved in 100 ml of isopropanol. The solution is re~luxed ~or 5 hours and then concentrated in vacuo. The oily residue is converted with 3.1 g of fumaric acid in~o the crystalline 2~ [3-(o-allyloxyphenoxy)-2-hydroxypropyl]-

4-piperi.dyl}-3,4-dihydro-1(2H)-isoquinolinone^fumarate.
The salt mei~s at 145-146 after recrystallisation from ethanol/ether, with decomposition.

, :
- - .
', '' ~ '.'"''~ ` ' , ,, ' ' ''~ '. ' ' ' 1071Zll Example 7 The mixture of 3.8 g of 1-(o-methoxyphenoxy)-2,3-epoxypropane, 4.32 g of 4-(1-oxoisoindolino)-piperidine and 35 ml of isopropanol is refluxed for 4 hours while stirring.
After cooling to room temperature it is acidified with sa-turated hydrogen chloride in ethyl acetate to reach the pH=l, and more cooled with an ice bath. It is filtered, the re-sidue washed with ice-cold isopropanol and diethyl ether and recrystallized from 100 ml of isopropanol, to yield the 1-[3-(o-methoxyphenoxy)-2-hydroxypropyl]-4-(1-oxoisoindolino)-piperidine hydrochloride melting at 172-174, The starting material is prepared as follows: The mixture of 150 g of 2-formylbenzoic acid, 85.2 g of 4-amino-pyridine and ~,8 lt of toluene is refluxed on a water-se-parator for 2.5 hours while stirring and stirring is con-tinued at room temperature over night. It is filtered and the residue washed with toluene, to yield the 1-(4-pyridyl-amino)-3-oxophthalan melting at 215-220~ lAnalogously the 1-(3-pyridylamino)-3-oxophthalan is obtained from 3-amino-pyridlne; m.p. 150-1553, To the suspension of 278 g thereof in 4.7 lt of an-hydrous ethanol, 96 g of sodium borohydride are added por-tionwise during 105 minutes while stirring 3t 18~ Stirripg . . ` .

.
.
, . -.
' ' " ' . ' ' ' , 1071Z~l is continued at room temperature over night, the mixture is filtered, the filtrate concentrated to a volume of 1.2 lt.
cooled and the precipitate formed collected, to yield the 2-(4-pyridylaminomethyl)-benzoic acid melting above 250.
180.6 g thereof are added to 1.4 lt of concentrated sulfuric acid during 40 minutes while stirring and allowing the temperature to rise to about 67. The mixture is stirred for 1 hour at about 95, cooled to 25G, and slowly poured onto 4 Icg ice. The mixture is neutralized with about 4.5 lt of aqueous ammonia, the precipitate formed filtered off and taken up in 2.3 ~t of isopropanol and 600 ml of chloroform.
The mixture is refluxed for 30 minutes, filtered hot, the filtrate cooled and the precipitate formed collected, to yield the 4~ oxoisoindolino)-py,idine The mixture of 30 g thereof, 400 ml of glacial ace-tic acid and 30 g of 10% palladium on charcoal is hydrogena-ted at about 65 and 3 atm until the theoretical amount of hydrogen has been absorbed. It is cooled to room temperature, filtered and evaporated The residue is taken up in 6 N
aqueous hydroxide, the mixture extracted with chloroform, the extract washed with saturated aqueous sodium chloride, dried and evaporated, to yield the 4-(1-oxoisoindolino)-pi-perld~ne melting at 144-146 .. . ~

.
.

107~211 Example 8 In the exact analogous manner, illustrated by Example 7 following compounds as listed have been obtained:
a) l-[3-(2-chloro-5-methylphenoxy)-2-hydroxypropyl]-4-(l-oxo-isoindolino)-piperidine-hydrochloride, melting point 206-208, b) l-[3-(o-allylphenoxy)-2-hydroxypropyl]-4-(1-oxo-isoin-dolino)-piperidine-hydrochloride, melting point 205-207;
c) l-[3-(2-allyl-3-acetylaminophenoxy)-2-hydroxypropyl]-4-(l-oxo-isoindolino)-piperidine-hydrochloride, melting point 177-180;

d) l-[3-(2-cyclohexylphenoxy)-2-hydroxypropyl]-4-(1-oxo-isoindolino)-piperidine-hydrochloride, melting point 214-216;
e) l-[3-(p-carbamoylmethylphenoxy)-2-hydroxypropyl]-4-(1-oxo-isoindolino)-piperidine-hydrochloride, melting point 266-270;
f) l-[3-(2-methoxy-3-methoxyphenoxy)-2-hydroxypropyl]-4-(l-oxo-isoindolino)-piperidine-hydrochloride, melting point 161-163;
g) l-[3-(o-allyloxyphenoxy)-2-hydroxypropyl]-4-(1-oxo-iso-indolino)-piperidine-hydrochloride, melting point 185-186;
h) l-l-3-(o-propargyloxyphenoxy)-2-hydroxypropyl]-4-(1-oxo--:' -. . . .
.
" ' ' '' ' ' ~ - ', ', 1~ 7 1 2 isoindolino)-piperidine-hydrochloride, melting point 173-175;
i) l-[3~(p-bromophenoxy)-2-hydroxypropyl]-4-(1-oxo-isoin-dolino)-piperidine-hydrochloride, melting point 253-257;
j~ l-[3-(o-cyanophenoxy)-2-hydroxypropyl]-4-(1-oxo-isoin-dolino)-piperidine-hydrochloride, mèlting point 203-205;
k) l-~3-(5-indanyloxy)-2-hydroxypropyl]-4-(1-oxo-isoin-dolino)-piperidine-hydrochloride, melting point 270-272 Example 9 To the solution of 3.96 g of 1-[3-(o-methoxyphenoxy)-2-hydroxypropyl)-4-(1-oxoisoindolino)-piperidine (prepared from the hydrochloride of Example 1 and 2N aqueous sodium hydroxide, extracting the mixture with ethyl acetate and evaporating the dryed extract) and 2 ml of pyridine in 50 ml of methylene chloride, 1 32 g o~ pivaloyl chloride in 10 ml of methylene chloride are added dropwise during 20 minutes, while stirring and cooling with ice. Stirring is continued for 48 hours at room temperature, 48 hours while refluxing and again 48 hours at room temperature The mixture is washed with cold 10% aqueous sodium carbonate and water, dried, filtered and evaporated. The residue is dissolved in 20 ml of ethanol, the solution acidified with saturated ~07~21~

hydrogen chloride in ethyl acetate ~nd the precipitate formed collected. It is dissolved in 50 ml of hot ethanol, 50 ml of ethyl acetate are added, the mixture cooled with ice and the precipitate formed collected, to yield the 1-[3-(o-methoxyphenoxy)-2-pivaloyloxypropyl)-4-(1-ox~isoin-dolino)-piperidine hydrochloride melting at 206-212.

Example 10 A mixture of 28 g of 1~ naphthoxy)-2,3-epoxy-propane and 18.8 g of 2-(4-piperidyl)-3,4-dihydro-1(2H)-iso--quinolinone in 40 ml of isopropanol is refluxed for 4 hours. After completion of the reaction, the precipitated crystals are filtered off and washed with ether. There is thus obtained 2-{1-[3-(~-naphthoxy)-2-hydroxy-1-propyl]-piperidyl-(4)~-3,4-dihydro-1(2H)-isoquinolinone, which melts at 181-183 after recrystallisation from chloroform/
ethanol.

24 g of the above base is dissolved in 250 ml of hot chloroform, and 30 ml of 2N ethanolic hydrochloric acid is added to ~he solution. There precipitates the hydro-chlor~de of 2-~1-[3-(~-naphthoxy~-2-hydroxy-1-propyl]-piperidyl-(4)}-3,4-dihydro-1(2H)-isoquinolinone, which melts at 269-271.

.
, -: - .
~, ' . . '.:

-. , - .- ~ ~ .

~07~ 2 Example 11 A mixture of 26.9 g of 1-(2-methoxy-4-chlorophenoxy)-2,3-epoxy-propane and 25.8 g of 2-(4-piperidyl)-3,4-dihydro-1(2H)-isoquinolinone in 30 ml of isopropanol is refluxed for 4 hours. After completed reaction, trituration with ether is performed, whereupon 2-~ 3-(2-methoxy-4-chlorophenoxy)-2-hydroxy-1-propyl]-piperidyl-(4)}-3,4-dihydro-1(2H)-isoquinolinone precipitates, which melts at 108-110 after recrystallisation from isopropanol.

22.8 g of the above base is dissolved in 60 ml of hot isopropanol, and to this solution there is added 10 ml of 8.7N ethanolic hydrochloric acid. ~fter trituration with ether there precipita~es the hydrochloride of 2-~ 3-(2-methoxy-4-chlorophenoxy)-2-hydroxy)-1-propyl]-piperidyl-(4)} -3,4-dihydro-1(2H)-isoquinolinone, which melts at 210-212.

Example 12 A mixtu~e of 11.55 g of 1-(o-cyanophenoxyj-2,3-epoxy-propane and 14.95 g of 2-(4-piperidyl)-3,4-dihydro-1(2H)-isoquinolinone in 30 ml of isopropanol is refluxed for .

', :

- : :

1~:)71Zl~

6 hours. After completion of the reaction, the reaction solution is diluted with 150 ml of isopropanol, heated to boiling and filtered hot. On cooling and with trituration with ether there precipitates 2-~1-[3-(o-cyanophenoxy)-2-hydroxy-l-propyl3-piperidyl-(4))-3,4-dihydro-1(2H)-iso- -quinolinone, which melts at 138-140.

16.5 g of the above base is dissolved in 100 ml of hot ethanol, and ~ g of maleic acid is added. On cooling of the solution there precipitates the maleate of 2-{l-~3-(o-cyanophenoxy)-2-hydroxy-l-propyll-piperidyl-(4)~-3,4-dihydro-1(2H)-isoquinolinone, which melts at 183-184.

Example 13 A mixture of 18 g of 1-(o-methoxyphenoxy)-2,3-epoxy-propane, 27 g of 4-phthalimidopiperidine-hydroclloride, 60 ml of triethylamine and 300 ml of isopropanol is refluxed for 4 hours. The reaction mixture is concentrated by evaporation to dryness, and the residue is suspended in 2N sodium hydroxide solution. The aqueous suspension is extracted with methylene chloride, the organic phase is dried with sodium sulphate and freed from the solvent in vacuo. 11.6 g of maleic acid is added to the residue. The ,, - . .
- . : - -:

1071;21~

maleic acid salt of l-[3-(o-methoxyphenoxy)-2-hydroxypropyl]-4-phthalimidopiperidine is crystallised from ethanol/ether and melts at 201-202 with decomposition, Exam ~

Tablets containing 2-~ 3-(o-methoxyphenoxy)-2-hydroxypropyl]-4-piperidyl3-3,4-dihydro-1-(2H)-isoquinolone, Composition 2-¦1-[3-(o-Methoxyphenoxy)-2-hydroxypropyl]-4-piperidyl -3,4-dihydro-1-(2H)-isoquinolone Crystalline lactose Wheat starch Aerosil 200 Talc Magnesium stearate Manufactur_ The active compound is mixed with a part of the wheat starch, with lactose and with Aerosil 200 and the mixture is forced through a sieve, A further part of the wheat 8tarch is worked into a paste with a 5-fold amount of water on a waterbath and the powder mixture is kneaded with this paste until a slightly plastic mass has been pro-duced, The plastic mass is pressed through a sieve of approx, lZ~l 3 mm mesh width and dried, and the dried granules are again forced through a sieve. Thereafter, the remaining wheat starch, talc and magnesium stearate are mixed in and the resulting mixture is pressed to give tablets having a cross-shaped notch ' ' .

Example ~r Preparation of 10,000 tablets each containing 2~.0 mg -~
of the active ingredient:
Formula:
1-[3-(o-methoxyphenoxy)-2-hydroxypropyl]-4-(1-oxoisoindolino)-piperidine hydrochloride250.00 g Lactose 1,956.00 g Corn starch 90 00 g Polyethylene glycol 6,000 90.00 g Talcum powder 90 00 g Magnesium stearate 24.00 g Purified water q.s.

Procedure:
All the powders are passed through a screen with openings of 0.6 mm. Then the drug substance, lactose, talc-cum, magnesium stearate and half of the starch is suspended - , -.: . . . , -1071Z~

in 45 ml of water and the suspension added to the boiling solution of the polyethylene glycol in 180 ml of water.
The paste formed is added to the powders which are granula-ted, if necessary, with an additional amount of water. The granulate is dried overnight at 35, broken on a screen with 1.2 mm openings and compressed into tablets using con-cave punches with 7.1 mm diameter, uppers bisected.

~xample ~
~i .
Preparation of 10,000 capsules each containing 50 mg of the active ingredient:
F mula:
1-[3-(o-cyanophenoxy)-2-hydroxypropyl]-3-(1-oxoisoindolino)-piperidine cyclamate500.0 g Lactose 2,350.0 g Talcum powder 150.0 g Procedure-All the powders are passed through a screen with openings of 0.6 mm. Then the drug substance is placed in a suitable mixer and mixed first with the taleum, then with the lactose until homogenous. No. 2 capsules are filled with 300 mg, using a capsule filling machine.

~071Zll Example 14 10.8 g of o-cresol is dissolved in 250 ml of dimethyl-formamide and, with stirring, the solution is added dropwise to a solution of 5.0 g of sodium hydride in 250 ml of dimethylformamide, and the temperature is then held at 50 for 30 minutes. There is subsequently added 28.6 g of 2-ll-(2,3-epoxypropyl)-4-piperidyl]-3,4-dihydro-1-(2H)-isoquinolinone in 300 ml of dimethylformamide, and the temperature i8 maintained for a further 3 hours at 50.
Decomposition i8 effected with cooling with a large amount of ice and water, and extraction is performed by shaking with ether. The ethereal solution is extracted twice with 2 N sodium hydroxide solution, dried and the ether is subsequently evaporated off. Concentration by evaporation yields 2-{1-t3-(o-tolyoxy)-2-hjdroxypropyll-4-piperidyl~-3,4-dihydro-1(2H)-isoquinolinone in the form of a crystal-line product, which melts at 104-105. The maleic acid salt obtained therefrom melts at 165-166.

Example 15 a) 4.6 g of 2-(4-piperidyl)-3,4-dihydro-1(2H)-iso-quinolinone i8 added to 1.85 g of epichlorohydrin in 35 ml of benzene, and stirring is maintained for 15 hours at room temperature. The solvent is then evaporated off at 40 in vacuo, and the residue is subsequently repeatedly , .
. . i . . ;

. . - , :
- .
- . . - ~
. ' ' - '~ . ,: - - ' . .

107~Zll extracted with benzene, in the course of which the product crystallises. The crystals are stirred with acetonitrile and filtered off under suction. The resulting 2-[1-(2,3-epoxypropane)-4-piperidyl]-3,4-dihydro-1(2H)-isoquinolinone hydrochloride melts at 173-174.
b) 1.08 g of o-cresol, 2.9 g of the 2-11-(2,3-epoxy-propane)-4-piperidyl]-3,4-dihydro-1(2H)-isoquinolinone obtained above and 2.8 g of potassium carbonate in 20 ml of acetonitrile are refluxed for 15 hours. The potassium carbonate i~ then filtered off, and the filtrate is concentrated in vacuo. The residue is crystalliQed from ethanol/water. After recrystallisation from ethanol/water, the resulting 2-{1-l3-(o-tolyoxy)-2-hydroxypropyl]-4-piperidyl~-3,4-dihydro-1(2H)-isoquinolinone melts at 104-105. The maleic acid salt of this compound melts at 165-166 (decomposition) after recrystallisation from ethanol/ether.

Example 16

5.2 g of 1-(o-methoxyphenoxy)-2-hydroxy-3-bromo-propane, 4.6 g of 2-(4-piperidyl)-3,4-dihydro-1(2H)-isoquinolinone and 2.6 g of N-ethyldiisopropylamine in 80 ml of dimethylformamide are heated at 80 for 12 hours.
The dimethylformamide and the amine are then distilled off in vacuo. The residue is taken up in water, rendered 107121~

alkaline with 2 N ~odium hydroxide solution, and extracted with chloroform. The organic phase is dried, and concen-trated by evap~ration, and the hydrochloride is produced with ethanolic hydrochloric acid Crystallisation from ethanol/ether yields the 2-~1-[3-(o-methoxyphenoxy)-2-hydroxypropyll-4-piperidyl}-3,4-dihydro-1(2H)-isoquinolinone hydrochloride, which melts at 174-176.
Example 17 a) 10 g of 1-l3-(o-methoxyphenoxy)-2-hydroxypropyl]-4-(3,4-dihydro-1(2H)-isoquinolinon-2-yl)-pyridinium bromide in 100 ml of ethanol is hydrogenated, in the presence of concentrated hydrochloric acid, at room temperaturP with platinum oxide. The reaction mixture obtained is made alkaline with 2 N sodium hydroxite solution; it is then extracted with chloroform, dried, and concentrated by evaporation. The catalyst is filtered off; the filtrate i8 concentrated by evaporation and the residue is taken up in water. The hydrochloride is produced with etha~olic hydrochloric acid. The resulting 2-{1-l3-(o-methoxyphenoxy)-2-hydroxypropyll-4-piperidyl}-3,4-dihydro-1(2H)-iso-quinolinone hydrochloride is recrystallised from ethanol/
ether, and has a melting point of 174-176.
b) The above-mentioned quaternary salt is produced from l-(o-methoxyphenoxy)-2-hydroxy-3-bromopropane and 2-(4-pyridyl)-3,4-dihydro-1(2H)-isoquinolinone in dimethyl-,, ' ~ ' ' . '. '~
- :
., : - - .
~ -. - '' ., ,' ' ' '' .

1071Zl~ -formamide at 80 with the addition of N-ethyldiisopropyl-amine, and in the unpurified state further processed as described under a).

Example 18 A solution of 2.6 g of 2-(2-chloroethyl)-benzoyl chloride in 50 ml of acetone is added dropwise to 4.1 g of l-(3-o-methoxyphenoxy)-2-hydroxy-(propyl)-4-æmino- -piperidine and 3 g of potassium hydroxide in 50 ml of acetone, and the reaction mixture obtained is refluxed for 9 hours. The precipitated material is filtered off, ànd the filtrate is evaporated to dryness. To the oil obtained is added 2 N hydrochloric acid, and extraction is performed by shaking with methylene chloride, The comblned extracts are dried and concentrated by evaporation.
The re~idue is recrystalli~ed from methylene chloride/
ethyl acetate to thus obtain 2-{1-(3-(o-methoxyphenoxy)-2-hydroxypropyl]-4-piperidy~-3,4-dihydro-1(2H)-isoquinolinone hydrochloride, which has a melting point of 174-176.

Example 19 1.5 g of isocoumarin and 2.8 g of 1-l(3-o-methoxy-phenoxy-2-hydroxy)-propyl]-4-aminopiperidine in 30 ml of ethanol are refluxed for 3 hours. 0.5 g of palladium/
charcoal is added to the reaction mixture, and the mixture i8 hydrogenated until the theoretical amount of hydrogen has been absorbed. The catalyst is then filtered off, and ~ - 65 -~07~;211 ~

the filtrate is evaporated to dryness. Ethanolic hydrochloric acid is added to the residue, and the resulting 2-¦1-l3-(o-methoxyphenoxy-2-hydroxy)-propyl]-4-piperidyl]-3,4-dihydro-1(2H)-isoquinoline hydrochloride is recrystallised by trituration with ether. The product melts at 173-175 after recrystallisation from ethanol/ether.

Example 20 a) 9.1 g of N-~1-[3-(o-methoxyphenoxy)-2-hydroxypropyl]-4-piperidyl}-2-aminoethyl-benzoic acid ethyl ester in 100 ml of ethanol and 2.6 g of N-ethyldiisopropylamine are refluxed for 6 hours. The amine and the alcohol are then removed in vacuo, and the oil xemaining behind is converted with ethanolic hydrochloric acid into the hydrochloride.
Recrystallisation from ethanoltether yields 2-ll-[3-(o-methoxy-phenoxy)-2-hydroxypropyl]-4-piperidyl~-3,4-dihydro-1(2H)-isoquinolinone hydrochloride, which melts at 174-176, b) The ester mentioned above is obtained by reductive amination of l-[3-(o-methoxyphenoxy)-2-hy~ro~ypro~yl]-4-piperidone with 2-aminoethyl-benzoic acid ethyl ester with platinum/charcoal catalysis in methanol, and can be further processed in the unpurified state as given under a).

, - 66 -~...1 ' .

.. . . . ..

Claims (55)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PRIVILEGE OR PROPERTY IS CLAIMED ARE DEFINED AS FOLLOWS:

1. Process for the manufacture of new piperidines of the formula (I) wherein R1 denotes an aryl radical containing 6 - 10 carbon atoms which may be substituted with one or two lower alkyl containing 1 - 4 carbon atoms, lower alkenyl or lower alkinyl containing 2 - 4 carbon atoms, cycloalkyl containing up to 6 carbon atoms, lower alkoxy containing 1 - 4 carbon atoms, lower alkenyloxy or alkynyloxy containing 2 - 4 carbon atoms, lower alkoxy lower alkyl containing 1 to 4 carbon atoms in each of the alkyl grou-ps, cyano, halogen, hydroxy, lower alkanoylamino contai-ning 2 - 4 carbon atoms, and carbamoyl lower alkyl contai-ning at most 4 carbon atoms, R2 hydroxy or an alkanoyloxy group containing 2 to 5 carbon atoms, Ph denotes an o-phenylene radical,n is 0 or 1, R3, R4, R5, R6 are hydrogen or R3 and R4 together represent an oxo group and R5 and R6 are hydrogen or R6 togehter with R5 represent an oxo group, and R3 and R4 represent hydrogen, and their salts, characterised in that a) a compound of the formula R1 - O - Y1 (II) is reacted witha compound of the formula ( III) wherein R1, Ph, n, R3, R4, R5 and R6 have the indicated meanings, one of the radicals Y1 and Y2 represents hydrogen and the other represents a radical of the formula - CH2 - ?H - CH2 - Z

and X represents the group R2, with R2 having the indica-ted meaning and Z denotes a reactively esterified hydroxyl group, or X and Z together form an epoxy group, or b) in a compound of the formula (IV) wherein R1, R2, R3, R4, R5 and R6, Ph and n have the above meanings, Rx and Ry independently of one another denote lower alkyl radicals or hydrogen atoms and r and s represent 1 or 2, and A ? is an anion, the pyridinium ring is reduced to the piperidine ring, or c) a compound of the formula (V) wherein R1, R2, Ph, n, R3, R4, R5 and R6 have the indicated meanings and X' denotes a reactive esterified hydroxyl group, is intramolecularly condensed, or d) in the case of compounds of the formula I, wherein R3 and R5 together represent a second bond, and n is 1, a compound of the formula (VI) is reacted with a compound of the formula (VII) wherein R1, R2, R4, R6, and Ph have the indi-cated meanings, or e) a compound of the formula (VIII) wherein R1, R2, R3, R4, R5, R6, n and Ph have the indicated meanings and Y3 denotes a free carboxyl group or preferably a functionally modified carboxyl group con-taining an oxo group, is intramolecularly condensed, or if desired, a resulting isomer mixture is separated into the pure isomers and/or a resulting racemate is resolved into the optical antipodes and/or a resulting salt is converted into the free compound or a free compound into one of its salts.

2. Process according to claim 1, characterised in that n in the compounds described in claim 1 is 1.

3. Process according to claim 1, characterised in that n in the compounds described in claim 1 is 0.

4. Process according to claim 1, characterised in that as a compound of formula II a compound of formula IIa R1 - O - CH2 - ?H - CH2 - Z (IIa) on which Z denotes a reactively esterified hydroxyl group, X represents the group R2, or X and Z together form an epoxy group, is reacted with a compound of formula IIIa (IIIa) which is embraced by formula III.

5. Process according to claim 1 and 4, characterised in that compounds of formula IIa are used, wherein X and Z together form an epoxy group.

6. Process according to claim 1, characterised in that as a compound of formula II a compound of formula IIb R1 - OH (IIb) is reacted with a compound of formula IIIb (IIIb) wherein Z is a reactive esterified hydroxy group.

7. Process according to claim 1 and 6, characterised in that compounds of formula IIb are used in form of their metal phenolates.

8. Process for the production of compounds of the formula Ia (Ia) wherein R' denotes a hydrogen atom, a lower alkylated p-carbamoyl radical, an o-nitrile group, an o-halogen atom or a p-hydroxyl group or above all a p-lower alkanoyl-amino radical, a p-[2(lower alkoxy)ethyl] radical, a lower o-alkyl or o-alkoxy radical, or an o-alkenyl or o-alkenyl-oxy radical, R" denotes a lower alkyl radical, a lower alkoxy radical, a lower alkenyl radical, a lower alkenyl-oxy radical or above all a hydrogen atom, R2 denotes the acetyl, propionyl or pivalyl radical, or above all a hydrogen atom, R3, R4, R5 and R6 have the meanings as de-fined in claim 1, and their salts, characterised in that a compound of formula IIc (IIc) in which R' and R" are as defined above and Z denotes a reactively esterified hydroxy group, X represents the group R? , or X and Z together form an epoxy group, is reacted with a compound of formula IIIc (IIIc) wherein R3, R4, R5 and R6 are as defined above and a resulting isomer mixture is separated into the pure iso-meres and/or a resulting racemate is resolved into the optical antipodes and/or a resulting salt is converted into the free compound or a free compound into one of its salts.

9. Process for the production of a compound of formula Ia, wherein R' denotes a p-lower alkanoylamino radical, for example p-acetylamino, a p-[2-lower alkoxy-ethyl]
radical, for example 2-methoxyethyl, or especially a lower o-alkenyl or o-alkenyloxy radical, for example o-allyl or o-allyloxy, or above all a lower o-alkyl or o-alkoxy radical such as the o-methyl or o-methoxy radical, R" represents hydrogen, R2 denotes the acetyl, propionyl or, in particular,pivalyl radical, or above all a hydrogen atom, R3, R4, R5 and R6 have the meanings as defined in claim 1, and their salts, characterised in that a compound of formula IIc is reacted with a compound of formula IIIc and a resulting isomer-mixture is separated into the pure isomers and/or a resulting racemate is resolved into the optical antipodes and/or a resulting salt is converted into the free compound or a free compound into one of its salts.

10. Process according to claim 1 for the production of 2-{1-[3-(o-methoxyphenoxy)-2-hydroxypropyl]-4-piperidyl}-3,4-dihydro-1(2H)-isoquinolinone-hydrochloride which com-prises reacting 1-(o-methoxyphenoxy)-2,3-epoxy-propane with 2-(4-piperidyl)-3,4-dihydro-1(2H)-isoquinolinone.

11. Process according to claim 1 for the production of 2-{1-[3-(o-tolyloxy)-2-hydroxypropyl]-4-piperidyl))-3,4-di-hydro-1(2H)-isoquinolinone which comprises reacting 1-(o-tolyloxy)-2,3-epoxy-propane with 2-(4-piperidyl)-3,4-dihy-dro-1(2H)-isoquinolinone-hydrochloride.

12. Process according to claim 1 for the production of 2-{1-[3-(o-methoxyphenoxy)-2-pivaloyloxy-1-propyl]-piperidyl-(4)]-3,4-dihydro-1-(2H)-isoquinolinone-hydrochloride which comprises reacting 2-{l-[3-(o-methoxyphenoxy)-2-hydroxy-propyl]-piperidyl-(4)}-3,4-dihydro-1(2H)-isoquinolinone-hy-drochloride with pivaloylchloride.

13. Process according to claim 1 for the production of 2-{1-[3-(o-chlorophenoxy)-2-hydroxypropyl]-piperidyl-(4)} -3,4-dihydro-1(2H)-isoquinolinone which comprises reacting l-(o-chlorophenoxy)-2,3-epoxy-propane with 2-(4-piperidyl)-3,4-dihydro-1(2H)-isoquinolinone.

14. Process according to claim 1 for the production of 2-{1-[3-< p-(2-methoxy-ethyl)-phenoxy > -2-hyroxypropyl]-4-piperldyl}-3,4-dihydro-1(2H)-isoquinolinone which com-prises reacting 1-[p-(2-methoxy-ethyl)-phenoxy]-2,3-epoxy-propane with 2-(4-piperidyl)-3,4-dihydro-1(2H)-isoquinolinone.

15. Process according to claim 1 for the production of 2-{1-[3-(o-allyloxyphenoxy)-2-hydroxypropy1]-4-piperidy1}-3,4-dihydro-1(2H)-isoquinolinone which comprises reacting 1-(o-allyloxyphenoxy)-2,3-epoxy-propane with 2-(4-piperidyl)-3,4-dihydro-1(2H)-isoquinolinone.

16. Process according to claim 1 for the production of 2-{1-[3-(.beta.-naphthoxy)-2-hydroxypropyl]-piperidyl-(4)}-3,4-dihydro-1(2H)-isoquinolinone which comprises reacting 1-(8-naphthoxy)-2,3-epoxy-propane with 2-(4-piperidyl)-3,4-dlhydro-1(2H)-isoquinolinone.

17. Process according to claim 1 for the production of 2-{1-[3-(2-methoxy-4-chlorophenoxy)-2-hydroxypropyl]-pi-peridyl-(4)}-3,4-dihydro-1(2H)-isoquinolinone which com-prises reacting 1-(2-methoxy-4-chlorophenoxy)-2,3-epoxy-propane with 2-(4-piperidy1)-3,4-dihydro-1(2H)-isoquino-linone.

18. Process according to claim 1 for the production of 2-{1-[3-(o-cyanophenoxy)-2-hydroxypropyl]-piperidy1-(4)}-3,4-dihydro-1(2H)-isoquinolinone which comprises reacting 1-(o-cyanophenoxy)-2,3-epoxy-propane with 2-(4-piperidyl)-3,4-dihydro-1(2H)-isoquinolinone.

19. Process for the production of a compound of formula Ib (Ib) wherein R' is hydrogen, lower alkyl, lower alkenyl, lower alkinyl, carbamoyl-lower alkyl, hydroxy, lower alkoxy, lower alkenyloxy, lower alkinyloxy, halogeno, or cyano each of R" is hydrogen, lower alkyl, lower alkoxy, R? is hydrogen or lower alkanoyl, each of R5 and R6 is hydrogen, or R5 together with R6 represent oxo, and their therapeutically useful acid addition salts, characterised in that a compound of formula IId (IId) in which R' and R" are as defined above and 7 denotes a reactively esterified hydroxy group, X represents the group R? , or x and z together form a epoxy group, is reacted with a compound of formula IIId (IIId) wherein R5 and R6 are as defined above and a resulting isomer mixture is separated into the pure isomers and/or a resulting racemate is resolved into the optical antipo-des, and/or a resulting salt is converted into the free compound or a free compound into one of its salts.

20. Process for the production of a compound of Ib, wherein R' is methyl, allyl, cyclohexyl, carbamoylmethyl, methoxy, allyloxy, propargyloxy, chloro or cyano, R" is hydrogen, methyl, methoxy or acetylamino, R? is hydrogen, acetyl, propionyl or pivaloyl, and each of R5 and R6 is hydrogen and their therapeutically useful acid addition salts, characterised in that a compound of formula IId as defined in claim 19 is reacted with a compound of formula IIId and a remitting isomer mixture is separated into the pure isomers and/or a resulting racemate is resolved into the optical antipodes and/or a resulting salt is converted into the free compound or a free compound into one of its salts.

21. Process according to claim 1 for the production of 1-[3-(o-methoxyphenoxy)-2-hydroxypropy1]-4-(1-oxo-isoin-dolino)-piperidine-hydrochloride which comprises reacting 1-(o-methoxyphenoxy)-2,3-epoxy-propane with 4-(1-oxo-iso-indolino)-piperidine.

22. Process according to claim 1 for the production of 1-[3-(o-cyanophenoxy)-2-hydroxypropy1]-4-(1-oxo-isoindolino)-piperidine which comprises reacting 1-(o-cyanophenoxy)-2,3-epoxy-propane with 4-(1-oxo-isoindolino)-piperidine.

23. Process according to claim 1 for the production of 1-[3-(o-methoxyphenoxy)-2-pivaloyloxy propyl]-4-(1-oxo-isoindolino)-piperidine-hydrochloride which comprises reac-ting 1-[3-(o-methoxyphenoxy)-2-hydroxypropyl)-4-(1-oxo-isoindolino)-piperidine with pivaloylchloride.

24. Process according to claim 1 for the production of 1-[3-(o-methoxyphenoxy)-2-hydroxypropyl]-4-phthalimido-piperidine which comprises reacting 1-(o-methoxyphenoxy)-2,3-epoxy-propane with 4-phthalimidopiperidine-hydrochloride.

25. Process according to claim 1 for the production of 1-[3-(2-chloro-5-methylphenoxy)-2-hydroxypropyl]-4-(1-oxo-isoindolino)-piperidine-hydrochloride which comprises reac-ting 1-(2-chloro-5-methylphenoxy)-2,3-epoxy-propane with 4-(1-oxo-isoindolino)-piperidine.

26. Process according to claim 1 for the production of 1-[3-(o-allylphenoxy)-2-hydroxypropyl]-4-(1-oxo-isoindolino)-piperidine-hydrochloride which comprises reacting 1-(o-allyl-phenoxy)-2,3-epoxy-propane with 4-(1-oxo-isoindolino)-piperidine.

27. Process according to claim 1 for the production of 1-[3-(2-allyl-3-acetylaminophenoxy)-2-hydroxypropyl]-4-(1-oxo-isoindolino)-piperidine-hydrochloride which comprises reacting 1-(2-allyl-3-acetylaminophenoxy)-2,3-epoxy-pro-pane with 4-(1-oxo-isoindolino)-piperidine.

28. Process according to claim 1 for the production of 1-[3-(o-cyclohexylphenoxy)-2-hydroxypropyl]-4-(1-oxo-iso-indolino)-piperidine-hydrochloride which comprises reacting 1-(o-cyclohexylphenoxy)-2,3-epoxy-propane with 4-(1-oxo-iso-indolino)-piperidine.

29. Process according to claim 1 for the production of 1-[3-(p-carbamoylmethylphenoxy)-2-hydroxypropyl]-4-(1-oxo-isoindolino)-piperidine-hydrochloride which comprises reac-ting 1-(p-carbamoylmethylphenoxy)-2,3-epoxy-propane with 4-(1-oxo-isoindolino)-piperidine.

30. Process according to claim 1 for the production of 1-[3-(2-methoxy-3-methoxyphenoxy)-2-hydroxypropyl]-4-(1-oxo-isoindolino)-piperidine-hydrochloride which comprises reacting 1-(2-methoxy-3-methoxyphenoxy)-2,3-epoxy-propane with 4-(1-oxo-isoindolino)-piperidine.

31. Process according to claim 1 for the production of 1-[3-(o-allyloxyphenoxy)-2-hydroxypropyl]-4-(1-oxo-isoin-dolino)-piperidine-hydrochloride which comprises reacting 1-(o-allyloxyphenoxy)-2,3-epoxy-propane with 4-(1-oxo-iso-indolino)-piperidine.

32. Process according to claim 1 for the production of 1-[3-(o-propargyloxyphenoxy)-2-hydroxypropyl]-4-(1-oxo-isoindolino)-piperidine-hydrochloride which comprises reac-ting 1-(o-propargyloxyphenoxy)-2,3-epoxy-propane with 4-(1-oxo-isoindolino)-piperidine.

33. Process according to claim 1 for the production of 1-[3-(p-bromophenoxy)-2-hydroxypropyl]-4-(1-oxo-isoindolino)-piperidine-hydrochloride which comprises reacting 1-(o-bromophenoxy)-2,3-epoxy-propane with 4-(1-oxo-isoindolino)-piperidine.

34. Process according to claim 1 for the production of 1-[3-(5-indanyloxy)-2-hydroxypropyl]-4-(1-oxo-isoindolino)-piperidine-hydrochloride which comprises reacting 1-(5-in-danyloxy)-2,3-epoxy-propane with 4-(1-oxo-isoindolino)-pi-peridine.

35. Compounds of the formula Ia according to claim 8 (Ia) wherein R' denotes a hydrogen atom, a p-alkanoylaminoethyl, a lower alkylated p-carbamoyl radical, an o-nitrile group, an o-halogen atom or a p-hydroxyl group or above all a p-lower alkanoyl-amino radical, a p-[2(lower alkoxy)ethyl]

radical, a lower o-alkyl or o-alkoxy radical, or an o-alkenyl or o-alkenyloxy radical, R" denotes a lower alkyl radical, a lower alkoxy radical, a lower alkenyl radical, a lower alkenyloxy radical or above all a hydrogen atom, R?
denotes the acetyl, propionyl or pivalyl radical, or above all a hydrogen atom, R3, R4, R5 and R6 have the meanings as defined in claim 1, and their salts, whenever prepared by a process as claimed in claim 8 or by an ob-vious chemical equivalent thereof.

36. Compounds of the formula Ia, according to claim 8, wherein R' denotes a p-lower alkanoylamino radical, for example p-acetylamino a p-[2-lower alkoxy-ethyl]radical,for example 2-methoxyethyl, or especially a lower o-alkenyl or o-alkenyloxy radical, for example o-allyl or o-ally-loxy, or above all a lower o-alkyl or o-alkoxy radical, such as the o-methyl or o-methoxy radical, R" represents hydrogen, R? denotes the acetyl, propionyl or, in parti-cular, pivalyl radical, or above all a hydrogen atom, R3, R4, R5 and R6 have the meanings given in claim and their salts, whenever prepared by a process as claimed in claim 9 or by an obvious chemical equivalent thereof,

37. 2-{1-[3-(o-allyloxyphenoxy)-2-hydroxypropyl]-4-piperidyl} -3,4-dihydro-1(2H)-isoquinolinone whenever prepared by a process as claimed in claim 15 or by an obvious chemical equivalent thereof.

38. 2-{1-[3-(o-chlorophenoxy)-2-hydroxypropyl]-4-piperi-dyl}-3,4-dihydro-1(2H)-isoquinolinone whenever prepared by a process as claimed in claim 13 or by an obvious chemical equivalent thereof.

39. 2-{1-[3-(o-methoxyphenoxy)-2-pivaloyloxypropyl]-4-piperidyl}-3,4-dihydro-1(2H)-isoquinolinone whenever pre-pared by a process as claimed in claim 12or by an obvious chemical equivalent thereof.

40. 2-{1-[3-(o-tolyloxy)-2-hydroxypropyl]-4-piperidyl}-3,4-dihydro-1(2H)-isoquinolinone whenever prepared by a process as claimed in claim 11 or by an obvious chemical equivalent thereof.

41. 2-{1-[3-(o-methoxyphenoxy)-2-hydroxypropyl]-4-pi-perityl}-3,4-dihydro-1(2H)-isoquinolinone whenever pre-pared by a process as claimed in claim 10 or by an obvious chemical equivalent thereof.

42. 2-{1-[3-(o-cyanophenoxy)-2-hydroxypropyl}-piperi-dyl-(4)}-3,4-dihydro-1(2H)-isoquinolinone whenever prepared by a process as claimed in claim 18 or by an obvious chemi-cal equivalent thereof.

43. Piperidines of formula Ib according to claim 19 (Ib) wherein R' is hydrogen, lower alkyl, lower alkenyl, lower alkinyl, carbamoyl-lower alkyl, hydroxy, lower al-koxy, lower alkenyloxy, lower alkinyloxy, halogeno or cyano each of R" is hydrogen, lower alkyl, lower alkoxy, R? is hydrogen or lower alkanoyl, each of R5 and R6 is hydrogen, or R5 together with R6 represent oxo, and their therapeutically useful acid addition salts, whenever prepared by a process as claimed in claim 19 or by an obvious chemical equivalent thereof.

44. Piperdines of formula Ib according to claim 20, wherein R' is methyl, allyl, cyclohexyl, carbamoyl-methyl, methoxy, allyloxy, propargyloxy, chloro or cyano, R" is hydrogen, methyl, methoxy or acetylamino, R? is hydrogen, acetyl, propionyl or pivaloyl, and each of R5 and R6 is hydrogen and their therapeutically useful acid addition salts, whenever prepared by a process as claimed in claim 20 or by an obvious chemical equivalent thereof.

45. 1-[3-(o-methoxyphenoxy)-2-hydroxypropyl]-4-(1-oxo-isoindolino)-Piperidine whenever prepared by a claim as claimed in claim 21 or by an obvious chemical equivalent thereof.

46. 1-[3-(2-chloro-5- methylphenoxy)- 2-hydroxypropyl]-4-(1-oxo-isoindolino)-piperidine whenever prepared by a process as claimed in claim 25 or by an obvious chemical equivalent thereof.

47 1-[3-(o-allylphenoxy)-2-hydroxypropyl]-4- (1-oxo-isoindolino)-piperidine whenever prepared by a process as claimed in claim 26 or by an obvious chemical equivalent thereof.

48. 1-[3-(2-a11yl-3-acetylaminophenoxy)-2-hydroxypropyl]-4-(1-oxo-isoindolino)-piperidine whenever prepared by a pro-cess as claimed in claim 27 or by an obvious chemical equi-valent thereof.

49. 1-[3-(2-cyclohexylphenoxy)-3-hydroxypropyl]-4-(1-oxo-isoindolino)-piperidine whenever prepared by a process as claimed in claim 28 or by an obvious chemical equivalent thereof.

50. 1-[3-(o-cyanophenoxy)-2-hydroxypropyl]-4-(1-oxo-isoindolino)-piperidine whenever prepared by a process as claimed in claim 22 or by an obvious chemical equivalent thereof.

51. Pharmaceutically acceptable acid addition salts of compounds as defined in claim 35 prepared by a process as claimed in claim 8 or by an obvious chemical equivalent thereof.

52. Pharmaceutically acceptable acid addition salts of compounds as defined in claim 36 prepared by a process as claimed in claim 9 or by an obvious chemical equivalent thereof.

53. Pharmaceutically acceptable acid addition salts of compounds as defined in claim 43 prepared by a process as claimed in claim 19 or by an obvious chemical equivalent thereof.

54. Pharmaceutically acceptable acid addition salts of compounds as defined in claim 44 prepared by a process as claimed in claim 20 or by an obvious chemical equivalent thereof.

55. Piperidines of formula (I) defined in claim 1, and their salts, when prepared by the process of claim 1 or by an obvious chemical equivalent thereof.