US3770748A

US3770748A - Substituted phenylalkanol derivatives

Info

Publication number: US3770748A
Application number: US00237879A
Authority: US
Inventors: J Borck; J Dahm; A Wild; J Hovy; J Kramer
Original assignee: Merck Patent GmbH
Current assignee: Merck Patent GmbH
Priority date: 1971-03-25
Filing date: 1972-03-24
Publication date: 1973-11-06
Anticipated expiration: 1990-11-06
Also published as: DK137273C; AU4040472A; ES401198A1; FR2130659B1; AT344169B; IL38972A0; DK137273B; BR7201760D0; AU465561B2; ATA252572A; DE2114420A1; ZA721653B; DD96946A5; FR2130659A1; NL7203986A; GB1359600A; CS163798B2; PL83328B1; CH605739A5; CA980353A

Abstract

PHENYLALKANOL DERIVATIVES OF THE FORMULA

1-((-(CH2)N-CH(-O-R2)-CH2-)>N-),2-R4,4-(R1-CH2-CH(-R3)-)

BENZENE

WHEREIN R1 IS OH, ALKOXY OF UP TO 6 CARBON ATOMS, CYCLOALKOXY OF UP TO 6 CARBON ATOMS, ARYLOXY OF 6-12 CARBON ATOMS, ARALKOXY OF 7-12 CARBON ATOMS, OR ACYLOXY OF UP TO 18, PREFERABLY UP TO 6, CARBON ATOMS; R2 IS H, ALKYL OF UP TO 6 CARBON ATOMS, CYCLOALKY OF UP TO 6 CARBON ATOMS, ARYL OF 6-12 CARBON ATOMS, ARALKYL OF 7-12 CARBON ATOMS, OR ACYL OF UP TO 18, PREFERABLY UP TO 6, CARBON ATOMS; R3 IS H OR CH3; R4 IS C1, BR OR CH3; AND N IS 2 OR 3; AND THE PHYSIOLOGICALLY ACCEPTABLE ACID ADDITION SALTS AND QUATERNARY AMMONIUM SALTS THEREOF; POSSESS USEFUL PHARMACOLOGICAL ACTIVITY, INCLUDING ANTIPHLOGISTIC. ANALGESIC AND ANTIPYRETIC EFFECTS.

Description

United States Patent 3,770,748 SUBSTITUTED PHENYLALKANOL DERIVATIVES Joachim Borck, Johann Dahm, Jan Willem Hovy, Josef Kramer, and Albrecht Wild, Darmstadt, Germany, assignors to Merck Patent Gesellschaft mit beschrankter Haftung, Darmstadt, Germany No Drawing. Filed Mar. 24, 1972, Ser. No. 237,879 Claims priority, application Germany, Mar. 25, 1971, P 21 14 420.7 Int. Cl. C07d 29/24 US. Cl. 260293.81 21 Claims ABSTRACT OF THE DISCLOSURE Phenylalkanol derivatives of the formula mn-nQ-onm-omm wherein R is OH, alkoxy of up to 6 carbon atoms, cycloalkoxy of up to 6 carbon atoms, aryloxy of 612 carbon atoms, aralkoxy of 7-12 carbon atoms, or acyloxy of up to 18, preferably up to 6, carbon atoms; R is H, alkyl of up to 6 carbon atoms, cycloalkyl of up to 6 carbon atoms, aryl of 6-12 carbon atoms, aralkyl of 7-12 carbon atoms, or acyl of up to 18, preferably up to 6, carbon atoms; R is H or CH R is Cl, Br or CH and n is 2 or 3; and the physiologically acceptable acid addition salts and quaternary ammonium salts thereof; possess useful pharmacological activity, including antiphlogistic, analgesic and antipyretic effects.

BACKGROUND OF THE INVENTION This invention relates to novel substituted phenylalkanol derivatives, to processes for the preparation thereof, pharmaceutical compositions comprising them and methods of use thereof.

SUMMARY OF THE INVENTION The novel compounds of this invention are phenylalkanol derivatives of the general Formula I wherein R is OH, alkoxy of up to 6 carbon atoms, cycloalkoxy of up to 6 carbon atoms, aryloxy of 6-12 carbon atoms, aralkoxy of 7-12 carbon atoms, or acyloxy of up to 18, preferably up to 6 carbon atoms; R is H, alkyl of up to 6 carbon atoms, cycloalkyl of up to 6 carbon atoms, aryl of 612 carbon atoms, aralkyl of 7-12 carbon atoms, or acyl of up to 18, preferably up to 6 carbon atoms, R, is H or CH R is Cl, Br or CH and n is 2 or 3; and the physiologically acceptable acid addition salts and quaternary ammonium salts thereof, and mixtures thereof.

Compounds of Formula I and the physiologically acceptable acid addition and quaternary ammonium salts thereof, possess, with good compatibility, an excellent antiphlogistic effect, usually accompanied by analgesic and antipyretic effects. They also possess one or more of bacteriostatic, bactericidal, antiprotozoal, diuretic, bloodsugar-lowering, choleretic, cholesterol-level-lowering and radiation-protective activity. The compounds of Formula I and their physiologically acceptable salts can thus be employed as drugs as well as intermediates for the production of other drugs.

3,770,748 Patented Nov. 6, 1973 DETAILED DISCUSSION Of the compounds of this invention of Formula I, the following are preferred:

IbR =acyloXy of up to 18 carbon atoms;

IdR =acyloxy of up to 18 carbon atoms and n is 3;

IfR =acyl of up to 18 carbon atoms;

Ih-R =acyl of up to 18 carbon atoms and n is 3;

ImR =acyloxy of up to 18 carbon atoms, R =H,

R3=CH3,

In-R =acyloxy and R is acyl, each of up to 18 carbon atoms, R =CH R =Cl;

Ip--R =acyloxy of up to 18 carbon atoms, R =H,

R3=CH3, R4=CL IqR =acyloxy and R is acyl, each of up to 18 carbon atoms, R =CH R =Cl, n=3;

including the pharmaceutically acceptable acid addition and quaternary salts thereof, acyloxy and acyl in each instance preferably containing up to 6 carbon atoms, e.g., alkanoyloxy and alkanoyl.

In its process aspect, this invention relates to a process for the preparation of substituted phenylalkanol derivatives of the general Formula I which comprises any one of the following:

(a) a compound of the general Formula H RnOCH-CH2 wherein X, is a group convertible into a group of the formula CHR CH R (=Z is reacted with a compound which converts the group X into the group of Formula Z (b) a compound of the Formula HI wherein X is a group convertible into the group of the formula Ra (W1) is reacted with a compound which converts the group X into a group of Formula W R R R and R n, X and X in each instance having the values given above;

and/ or optionally a thus-obtained compound of Formula I is converted into another compound of Formula I; and/ or optionally a thus-obtained compound of Formula I is converted into the physiologically acceptable acid addition salts or quaternary ammonium compounds thereof, or is liberated from the acid addition salts thereof; and a thus-produced racemate or racemate mixture is separated into a pure racemate and/or enantiomer.

This invention also relates to pharmaceutical preparations comprising at least one compound of the general Formula I in suitable unit dosage form, in admixture with at least'one solid, liquid or semiliquid auxiliary agent or vehicle, and optionally at least one further active compound, preferably those containing 0.1400 mg. of a compound of Formula I per unit dosage. This invention also relates to a method for obtaining antiphlogistic, analgesic and/or antipyretic effects in living beings, by the administration thereto of a composition of this invention.

In the above formulae, R in addition to a free OH group, can also be an etherified or esterified OH group. Examples of etherified OH groups are alkoxy, e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec.- butoxy, isobutoxy, tert.-butoxy, amyloxy, isoamyloxy, hexyloxy and isohexyloxy; cycloalkoxy groups, e.g., cyclobutyloxy, cyclopentyloxy and cyclohexyloxy; heterocycloalkoxy, e.g., tetrahydrofuran-2-yloxy, tetrahydropyran- 2'-yloxy and 4-alkoxytetrahydropyran-4'-yloxy; aryloxy, e.g., phenoxy, p-tolyloxy, xylyloxy and naphthyloxy; and aral-koxy, e.g. benzyloxy, l-phenylethyloxy and 2-phenylethyloxy.

Examples of esterified OH groups are those esterified with a saturated or unsaturated aliphatic, cycloaliphatic, aromatic, araliphatic, or heterocyclic, substituted or unsubstituted carboxylic acid or sulfonic acid. Preferred carboxylic acids are fatty acids, preferably alkanoic acids, of 1-18, particularly 1-6 carbon atoms, e.g., formic, acetic, propionic, butyric, isobutyric, valeric, isovaleric, caproic, isocaproic, enanthic, caprylic, capric, lauric, myristic, palmitic and stearic acid; and other carboxylic acids, e.g., pivalic acid, diethylacetic acid, oxalic acid, malonic acid, succinic acid, pimelic acid, acrylic acid, fumari acid, maleic acid, cyclohexanecarboxylic acid, benzoic acid, phenylacetic acid, phenylpropionic acid, gluconic acid, furan-Z-carboxylic acid, nicotinic acid and isonicotinic acid.

The OH groups can also be esterified with a sulfonic acid including aliphatic and arylsulfonic acids, e.g., methanesulfonic acid, ethanedisulofnic acid, fi-hydroxyethanesulfonic acid, p-toluenesulfonic acid, p-bromobenzenesulfonic acid, naphthalene-monoand -disulfonic acids, or camphorsulfonic acid, or with an inorganic acid, preferably sulfuric acid or a phosphoric acid, e.g., orthophosphoric acid.

R in addition to H, can also be alkyl of up to 6 carbon atoms, e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, isobutyl, n-pentyl, isopentyl, n-hexyl and isohexyl, or the acyl radical of an acid of up to 18, preferably up to 6 carbon atoms, e.g., an acid named above.

X is a group which can be converted into a group of Formula Z Examples of such groups are those of the formula -CHR -A, wherein A is a group which can be converted into a moiety of the formula -CH R by reaction with a reducing agent. A can, for example, be an aldehyde group, in free or functionally modified form, for example as an acetal, e.g., a dialkylacetal group, preferably a dimethylor diethylacetal group; an alkyleneacetal group, preferably an ethyleneacetal of 1,2-propyleneacetal group; or a free or optionally a functionally modified carboxyl group, preferably an alkoxycarbonyl group of up to 7 carbon atoms, especially methoxycarbonyl, ethoxycarbonyl, or isopropoxycarbonyl, or an aralkoxy carbonyl group of up to 9 carbon atoms, especially benzyloxycarbonyl. It is also possible to employ a carboxylic acid halogenide, preferably a carboxylic acid chloride or bromide; a carboxylic acid anhydride group of up to 16 carbon atoms, preferably an acetoxycarbonyl group; a carboxylic acid azide or amide group; or a nitrile group.

X can, for example, also be one of the following groups: -C(=CH )-CH R (Z X can also be a group of the formula -CHR -CH Y wherein Y is Cl, Br, I, or a reactively modified OH group, e.g., an alkylsulfonyloxy group of up to 4 carbon atoms, a methanesulfonyloxy or ethanesulfonyloxy group, or an arylsulfonyloxy group of up to 10 carbon atoms, preferably p-tolylsulfonyloxy or a p-bromosulfonyloxy, or tetrahydropyranyloxy.

X, can also be an oxiran-Z-yl or a Z-methyl-oxiran-Z-yl group.

X is a group which can be converted into a group of the Formula W which is preferably one of the followwherein U is Y(CH CH (OR )-CH YCH CH 0R (CH 7 0 H(CH2) n or (CEzZyCH-C Hr- Nz l (W3) wherein Y is C1 or Br;

RzO-CH CH3 CH=oH-(oH,) -N

Rio-OH CH2 4 (We) wherein m is n\2, i.e., 1 or O;

W TQ- R :C CH

5 2 iRt (Wu) acetate; an aprotic-dipolar solvent, e.g., dimethylformamide, acetonitrile, dimethyl sulfoxide, tetramethylurea, tetrahydrothiophene 1,1-dioxide (sulfolane), propylene carbonate and hexamethylphosphoric triamide (hernpa); and mixtures of one or more thereof.

The starting compounds of Formula II A=optionally functionally modified carboxyl) are preferably substituted 3-chloro-4-(3-hydroxypyrrolidino)- or -piperidino)-phenylacetic acids, substituted 2-[3-chloro-4- 3-hydroxypyrrolidino -phenyl] or -hydroxypiperidino phenyl]-propionic acids and the esters thereof, preferably the alkyl, particularly the methyl and ethyl esters thereof, the acid halogenides, preferably the chlorides or bromides thereof, the anhydrides, optionally the mixed anhydrides thereof with other acids, acid azides, amides and nitriles. The starting compounds can also be the corresponding acids substituted in the 3-position of the phenyl ring by Br or CH in place of C1, or the aboveindicated functional derivatives thereof.

The starting compounds of Formula II A=optionally functionally modified carboxyl) are known, or they can be prepared in accordance with conventional processes described in the literature.

Thus, for example, the amides of Formula II are obtained by pouring the corresponding carboxylic acid chlorides or bromides into an excess aqueous ammonia solution. These corresponding carboxylic acid chlorides and bromides can be obtained by treating the free acids with an inorganic acid chloride or bromide, e.g., SOClg, SO CI PCl PCl POCl PBr or POBr If, in place of ammonia, a monoor dialkylamine is used, then the corresponding monoor dialkylamides are obtained. The acid azides of Formula II (X =-CHR CON can be obtained in accordance with conventional methods, e.g., by reacting the corresponding acid halogenides with NaN The anhydrides of Formula II, i.e.,

wherein R is any desired organic residue, preferably, however, CH or ((FHzh-IITQ-CHMY R20CH CH2 by reaction with an inorganic cyanide, preferably NaCN or KCN.

It is also possible to produce a nitrile of Formula II (X =CHR CN) by splitting off Water from an amide of Formula II (X =CHR -OONH Aldehydes of the Formula II (X =-CHR CHO) are obtained, for example, by reacting an acetophenone of the Formula V (R =H):

with methoxymethyl triphenylphosphonium chloride and subsequent acidic hydrolysis.

The allyl alcohols substituted in the 2-po-sition and/or the functional derivatives thereof of Formula II (X =Z are obtained, for example, by reacting an a-alkoxyacetophenone of Formula V (Rq=OR3; R =alkoxy of up to 6 carbon atoms, cycloalkoxy of up to 6 carbon atoms, aryloxy of 6l2 carbon atoms, aralkoxy of 7-12 carbon atoms, or acyloxy of up to 18, preferably up to 6 carbon atoms) with triphenylmethylphosphonium bromide and phenyl-lithium.

The vinyl ethers and/or vinyl esters of Formula II (X =Z or Z are produced, for example, from aldehydes of Formula II (X =--CHR CHO) by heating in a mixture of an acid anhydride and an alkali salt of the same acid. Preferably, the enol acetates are employed which are obtained from the aldehydes of Formula II by heating with acetic anhydride/sodium acetate.

The styrene oxides II (X =oxiran-2-yl or Z-methyloxiran-Z-yl group) are produced from the corresponding styrenes in accordance with conventional methods, for example by treatment with trifiuoroperacetic acid or perbenzoic acid.

Compounds of the Formula III (X =W can be produced in accordance with conventional processes by reacting compounds of the Formula VI CH2OH(OHz)n-Y o (VIIb) with a compound of Formula VIII (R =R HzNQCHRsCHzR:

The diazonium salts of Formula III (X =W are obtained, for example, in accordance with conventional methods, e.g., by reacting a compound of Formula IX (ihN with a 3-hydroxypiperidine or 3-hydroxypyrrolidine, or the Oalkyl or Oacyl derivatives thereof; reduction of the nitro group, preferably with a base metal in a mineral-acidic solution, for example with Fe in dilute HCl, by catalytic hydrogenation, or reduction in an alkaline medium, e.g., with Zn dust in aqueous NaOH, as well as subsequent diazotization at temperatures of between 20 C. and +5 0., preferably at 0 C., in a hydrochloric or hydrobromic aqueous solution, by adding the stoichiometric amount of an inorganic nitrite, preferably NaNO or 'KNO However, using one of the customary organic solvents, diazotization can also be achieved by the addition of an organic nitrite, such as n-butyl nitrite, n-amyl nitrite, o-r isoamyl nitrite, preferably in the presence of HCl or HBr.

Compounds of Formula III (X =W are obtained, for example, from the 2-(4-aminophenyl)ethanols or propanols of Formula VIII (R =H) by reaction with compounds of Formula VI, VIIa or VIIb.

Compounds of Formula III (X =W are obtained, for example, in a conventional manner from compounds of Formula X.

R4 (X) by bromination, preferably with a bromoimide, e.g., N- bromosuccinimide, in one of the customary solvents at temperatures of between 20 and C., preferably at the boiling temperature of the solvent, optionally under simultaneous irradiation, preferably with short-wave light, and subsequent solvolysis. Depending on the solvolyzing agent employed, alcohols of Formula III (X =W R =H) or esters of Formula III (X =W R =acyl) are obtained.

Starting compounds of Formula III (X =W R =O) can be obtained, for example, from compounds of Formula IX by reaction with 3-piperidoneor 3-pyrrolidoneethylene ketal, followed by reduction of the nitro group, diazotization, and exchange of the diazonium group against chlorine or bromine under simultaneous saponification of the ketal group. When R represents, for example, (H, Br), the corresponding compounds of Formula III are obtained by the bromination of compounds of Formula X followed by hydrogenation.

The compounds of Formula I are obtained from the compounds of Formula II (X =CHR -A) by treatment with a reducing, preferably hydrogen-evolving agent, e.g., a complex metal hydride.

As reducing agents, catalytically activated hydrogen, hydrogen in the nascent state and chemical reducing agents can also be employed.

For catalytic hydrogenations, suitable catalysts are, for example, noble metal, nickel and cobalt catalysts, for the reduction of carboxylic acid derivatives, mixed catalysts e.g., copper chromium oxide can also be employed. The noble metal catalysts can be employed on supports, e.g., platinum on carbon, palladium on calcium carbonate or strontium carbonate, as oxide catalysts, e.g., platinum oxide, or as finely divided metal catalysts. Nickel and cobalt catalysts are suitably used as Raney metals nickel on kieselguhr or pumice as the support can also be employed. The hydrogenation can be effected at room temperature and normal pressure or also at an elevated temperature and/or an elevated pressure. Preferably, the reaction is conducted under pressures of between 1 and 100 atmospheres, occasionally, as in the hydrogenation of esters with, for example Co(II) acetate, also under higher pressures, and at temperatures of between 80 C. and 200 C., especially between room temperature and +l C. The reaction is suitably effected in the presence of one of the usual solvents. For purposes of the hydrogenation, the free compounds or the corresponding salts can be utilized, e.g., the hydrochlorides or sodium salts.

In the hydrogenation of multiple bonds, the reaction is preferably conducted under normal pressure and by terminating the hydrogenation after absorption of the stoichiometric amount of hydrogen. Basically, it is possible to hydrogenate at an acidic, neutral or basic pH.

Another generally suitable reduction method is the reaction with nascent hydrogen. The latter can be produced, for example, by treating a metal with an acid or base, e.g., a mixture of zinc and acid or alkaline solution, iron and hydrochloric acid or acetic acid, or tin and hydrochloric acid. Furthermore, it is suitable to use sodium or another alkali metal in an alcohol, e.g., ethanol, isopropanol, butanol, amyl alcohol, isoamyl alcohol or phenyl. In the reduction of carboxylic acid derivatives, the method of Bouveault-Blanc can be employed, preferably at the boiling temperature of the alcohols used. Furthermore, an aluminum-nickel alloy can be utilized in an alkaline-aqueous solution, optionally with the addition of ethanol. Sodium amalgam or aluminum amalgam in an aqueous-alcoholic or aqueous solution is also suitable for producing nascent hydrogen. The reaction can also be effected in a heterogeneous phase, wherein suitably an aqueous phase and a benzene or toluene phase are used. The reaction temperatures employed range between room temperature and the boiling point of the solvent used.

When a complex metal hydride is utilized as the reducing agent, e.g., LiAlH NaAlH (OCH CH OCH or NaBH optionally with the addition of a catalyst, e.g., BF AlCl or LiBr, the process is advantageously conducted in the presence of one of the usual solvents, preferably in an ether, e.g., diethyl ether, tetrahydrofuran or dioxane. The reactions are advantageously conducted between 80 C. and the boiling point of the solvent. The decomposition of the thus-formed metal complexes can be done in the usual manner, e.g., with moist ether or an aqueous ammonium chloride solution. A particularly preferred reducing agent is NaAlH (OCH CH OCI-I This compound can be employed for the reduction of aldehydes, carboxylic acids, carboxylic acid esters, anhydrides and halogenides of Formula H (X =CHR -A) to compounds of Formula I.

Aldehydes of Formula II (X =CHR CHO) can also be reduced by the Meerwein-Ponndorf reaction, using aluminum alcoholates, preferably aluminum isopropylate or ethylate, in, for example, benzene or toluene at temperatures of between room temperature and the boiling point of the solvent.

Nitriles of Formula II (X =CHR CN) can be converted into the alcohols of Formula I, for example, by treatment with hydrogen in the presence of Raney nickel 8 and a cation exchanger in an aqueous medium. Amides of Formula H (X =-CHR CONH can also be split reductively to the alcohols of Formula I by electrolysis in an aqueous-methanolic solution in the presence of tetramethylammonium chloride.

A compound of Formula II (X =Z Z or Z can likewise be converted into a compound of Formula I by treatment with reducing agents, preferably agents evolving hydrogen, e.g., sodium amalgam or catalytically activated hydrogen.

When starting with an epoxide of Formula II (X=oxiran-Z-yl or 2-methyloxiran-2-yl), compounds of Formula I are obtained, for example, by treatment with LiAlI-L, in the presence of AlCl or with BH BF preferably in tetrahydrofuran at 0 C.

Compounds of Formula I are also obtained by reacting a halogen compound or a sulfonic acid ester of Formula II (X =-CHR -CH Y) with a solvolyzing agent, e.g., an alcohol, an acid, or H O, preferably in the presence of an acidic or basic catalyst, or with a metallic salt or a metallic alcoholate. Thus, alcohols of Formula I are obtained, for example, by saponifying a halogen compound of Formula II (X =--CHR CH -Hal; Hal=Cl, Br, I) in an aqueous or aqueous-alcoholic solution or suspension, optionally with the addition of a solubilizer, such as an alcohol, glycol or polyglycol ether.

As the saponifying agent, bases or basic salts are generally employed, preferably alkalines, e.g., NaOH or KOH. It is also possible to use slurries of Ca( OH) Pb(OH) or AgOH. The saponification is ordinarily conducted at an elevated temperature, for example at the boiling temperature of the solvent. A halogenide of Formula II (X =CHR CH l-Ial) can, however, also be reacted in a non-aqueous medium, by agitating a boiling solution thereof in a usual solvent, with the exclusion of water, with suspended AgOH or Pb(OH) Esters of Formula I (R =OR R =H) are produced by the Williamson synthesis by reacting compounds of Formula II (X =CHR CH OM; M: an equivalent of a metallic atom, preferably Na or K) with a compound of Formula XI wherein R is alkyl of up to 6 carbon atoms, cycloalkyl of up to 6 carbon atoms, aryl of 612 carbon atoms or aralkyl of 7l2 carbon atoms.

To obtain uniform products, the OH group in the heterocyclic ring is usually first masked, and the masking group is then split ofl after the reaction. Advantageously, the sodium alcoholate is produced by adding a solution of the alcohol of Formula I (R =OH) in a usual solvent dropwise to a finely distributed suspension of the stoichiometric amount of Na in an inert solvent, preferably toluene or xylene. When the less reactive chlorides or bromides of Formula XI (Y=Cl or Br) are utilized, a small amount of KI can be added. The reaction mixture is then refluxed until it becomes neutral. Phenyl ethers are obtained by mixing the alcoholic alkali alcoholate solution with an equivalent of the respective phenol, and then continuing the procedure as described for the alkyl ethers. Additionally, suitable solvents for the production of the phenyl ethers are water or aqueous alcohols. It is also possible to react alkali alcoholates or phenolates of the formula R OM with halogen compounds of Formula II If a suspension is used, especially suitable solvents are inert solvents, e.g., ether, tetrahydrofuran, acetone and benzene. According to this method it is, of course, also possible to prepare the diethers of Formula I by reacting starting compounds of Formula II (X -=-CHR CH OM; R =R with compounds of Formula XI.

Analogously, esters of Formula I (R =OAcyl; R =H) are produced by refluxing compounds of Formula II (X =CHR --CH Y) in an aqueous, aqueous-alcoholic or alcoholic solution with the alkali salts of the carboxylic acids to be esterified. Addition of triethylamine accelerates the reaction. When it is desired to obtain acetates of Formula I (R =OCOCH R =H), a preferred method is refluxing the halogenides or sulfonic acid esters of Formula II (X =CHR -CH Y) with a solution of anhydrous sodium acetate in glacial acetic acid. To produce esters of Formula I it is also possible to react halogen compounds of Formula II (X =CHR CH Hal) in one of the usual inert solvents with a silver salt of the corresponding acid. In all these reactions, to obtain uniform products, the OH group in the heterocycle generally is first masked and the masking group is then split olf after the reaction.

The thus-obtained compounds of Formula I can also be converted into other compounds of Formula I, for example, by esterifying the alcohols of Formula I directly with excess acid, optionally in the presence of one of the usual solvents, preferably a hydrocarbon, such as benzene or toluene, to the corresponding diesters of Formula I (R =OAcyl; R =Acyl) with excess acid, optionally in the presence of one of the usual solvents and/ or a sulfonic acid, such as p-toluenesulfonic acid, into another diester of Formula I.

Compounds of Formula I can be produced from starting materials of Formula II wherein X is an oxiran-Z-yl or 2-methyloxiran-2-yl group, by treatment with a hydrogen-evolving agent, preferably a hydride, e.g., B H or LiAlI-I in the presence of a Lewis acid, e.g., BF or AlCl The reaction is carried out in one of the usual solvents, preferably an ether, e.g., diethyl ether or tetrahydrofuran, at temperatures of between -20 C. and +30 C., preferably between 5 C. and +5 C.

Starting with a compound of Formula III (X =W compounds of Formula I are obtained in accordance with conventional methods, by reacting with a cyclizing agent, preferably by heating in an aqueous solution or suspension, optionally in the presence of an acidic or basic catalyst, or in one of the usual organic solvents, preferably in an organic acid, e.g., formic acid, acetic acid or propionic acid, especially in the presence of an acidic catalyst, e.g., HCl.

A particularly preferred and advantageous method is to produce a compound of Formula III (X =W and without isolating it, optionally with the addition of a suitable catalyst, cyclize it directly to a compound of Formula I. Depending on which starting materials are employed, the process is conducted at low temperatures, e.g., room temperature, or at elevated temperatures, preferably at the boiling temperature of the solvent employed. In some cases, it may be necessary to conduct the reaction under pressure (up to 200 atmospheres) and/or at an elevated temperature (up to 300 C.). A catalyst, e.g., a base, such as NaOH, KOH or sodium or potassium carbonate can be used but is not absolutely necessary.

Compounds of Formula I are also obtained by exchanging, in the diazonium compounds of Formula III the diazonium group for a C1 or Br atom according to methods described in the literature. The exchange for chlorine is preferably effected in an aqueous solution in the presence of Cu Cl by the Sandmeyer method. The exchange for bromine can be conducted, for example, in an aqueous solution in the presence of Cu Br according to Sandmeyer, or by reaction with bromine to form the diazonium perbromide, and subsequent refluxing in a suitable solvent, e.g., water or a lower alcohol. However, the diazonium bromides can also be converted into the diazonium mercury bromides with HgBr and these can be thermally dissociated to the desired bromine compounds.

The R; group can be introduced into compounds of Formula III (X =W in accordance with methods described in the literature, by direct substitution, preferably by treatment with a chlorinating or brominating agent.

Chlorination is effected, for example, by the direct reaction with elemental chlorine in an inert solvent, e.g., water, CCl acetic acid, without or with the addition of specific catalysts, e.g., FeCl AlCl SbCl or SnCl preferably between 10 C. and 100 C., by reaction, in a strongly hydrochloric solution, with H 0 or with NaClO- wherein chlorination is accomplished with nascent chlorine by reaction with SO Cl in an inert solvent, e.g., chlorobenzene, in the presence of a radical-forming catalyst, e.g., a peroxide, at preferably l80 C.; by reaction with NO Cl or NOCl in CS 'or hexane. Bromination can be achieved, for example, in a particularly simple manner by direct reaction with elemental bromine in an inert solvent, e.g., CS acetic acid, or CCl especially with the addition of a catalyst which act as bromine transfer agents, e.g., iron filings, AlCl AlBr FeCl iodine or pyridine, preferably between 30 C. and C.; by reaction with hypobromous acid, an acyl hypobromite, N- bromoimide, e.g., N-bromosuccinimide, N-bromophthalimide or other bromine-yielding agent, e.g., 1,3-dibromo- 5,5-dimethylhydantoin, in an inert solvent, e.g., nitrobenzone or CS preferably at l0 C. to C.; or by reaction with NOBr or NO Br in CS or cyclohexane.

Compounds of Formula I are obtained from the compounds of Formula III (X =W by treatment with a reducing, preferably hydrogen-yielding, agent. Thus, hydrogenation of the double bond in the heterocyclic ring can be conducted in accordance with one of the abovedescribed methods.

"Ethers of Formula I (R =OH; R =R can be produced by reacting compounds of Formula III (X =W R =[H, 0M1) in accordance with the methods of the Williamson synthesis with a compound of Formula XI. The above-described reaction conditions can be employed.

Esters of Formula I (R =OH; R =Acyl) can also be prepared in accordance with the above-described methods.

Compounds of Formula I can also be produced from compounds of Formula III (X =W R =[H, Y]) by treatemnt with a solvolyzing agent, e.g., alcohols, acids, or with H O, preferably in the presence of an acidic or basic catalyst, in accordance with known methods or by reaction with a metallic salt or metallic alcoholate.

An oxo compound of Formula III (X =W R =O) can be reduced in accordance with conventional methods to the corresponding hydroxy compounds by treatment with a reducing, preferably hydrogen-evolving agent, preferably a complex metal hydride. The reaction conditions must be selected so that the phenyl ring is not reduced, for example by using NaBH in methanol, optionally in the presence of aluminum chloride or lithium bromide. The reaction is advantageously carried out in the presence of one of the usual solvents, preferably lower alcohol, ether, tetrahydrofuran or ethylene glycol dimethyl ether. The reaction is advantageously terminated by refluxing the reaction mixture. The decomposition of the thusformed metal complexes can be accomplished in the usual way, for example with the use of an aqueous ammonium chloride solution.

A variant of the aforedescribed methods resides in reacting a compound X X (X =CHR A, Z Z or Z X =W or W with R =O) with one of the abovementioned reducing agents. In this process, compounds of Formula II (X =CHR A, Z Z or Z or III (X =W or W with R =O), respectively, are formed as intermediates. These compounds, usually without being 11 isolated, are further reacted to the compounds of Formula I.

It is also possible to react a compound of the formula Xz-X X2=W6 R5 =[H,Y]) with one of the above-indicated sol'volyzing agents and, rather than isolating the thus-formed compounds of Formula II (X =CHR CH Y) or III (X =W with R =[H, Y]), further react these compounds immediately with excess solvent to compounds of Formula I. These starting compounds of the formula X -X can, however, also be reacted with two equivalents of a metallic salt or metallic alcoholate, to produce compounds of Formula I. It is particularly advantageous to convert a thus-obtained compound of Formula I (R =OH; R =H), in accordance with one of the methods described above, by alkylating or acylation into a diether of Formula I (R =OR R =R or a diester of Formula I (R =OAcyl; R =Acyl). In such reactions, the corresponding monoethers or monoesters are usually obtained as intermediates, which are at once further alkylated or acylated, respectively.

A compound of Formula I can be converted into the associated acid addition salt with the use of an acid. Suitable acids for such a reaction are those yielding physiologically acceptable salts. Thus, organic and inorganic acids can be utilized, including aliphatic, alicyclic, araliphatic, aromatic and heterocyclic mono or polybasic carboxylic or sulfonic acids, e.g., formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, oxalic acid, malonic acid, snccinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, aminocarboxylic acids, sulfamic acid, benzoic acid, salicylic acid, phenylpropionic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methanesulfonic acid, ethanedisulfonic acid, ,B-hydroxyethanesulfonic acid, p-toluenesulfonic acid, naphthalenemonoand -disulfonic acids, sulfuric acid, nitric acid, hydrohalic acids, e.g., hydrochloric or hydrobromic acid, and/ or phosphoric acids, e.g., orthophosphoric acid.

Conversely, compounds of Formula I can be liberated from the acid addition salts thereof by treatment with strong bases, e.g., sodium or potassium hydroxide, sodium or potassium carbonate, or from the metallic and ammonium salts thereof by treatment with acids, especially mineral acids, e.g., hydrochloric or sulfuric acid.

When the compounds of Formula I contain a center of asymmetry, they are ordinarily produced in their racemic form. When they exhibit two centers of asymmetry, they are generally obtained in the synthesis as mixtures of two racemates, from which the individual racemates can be isolated in a conventional manner, for example by repeated recrystallization from suitable solvents, and can thus be obtained in the pure form.

The racemates can be separated into their optical antipodes in accordance with a large number of known methods. Thus, it is possible to precipitate some racemic mixtures as eutectics instead of in the form of mixed crystals and separate the optical isomers in this manner. Although selective precipitation is also possible, chemical separation is preferred. According to this method, diastereomers are formed from the racemic mixture by reaction with an optically active auxiliary agent. Thus, an optically active acid can optionally be reacted with the amino group of a compound of Formula I. For example, diastereomeric salts of compounds of Formula I can be formed with an optically active acid, e.g., and tartaric acid, dibenzoyl-( and -()-tartaric acid, diacetyl-(+)- and -()-tartaric acid, camphoric acid, p-camphorsulfonic acid, (I)- and (-)-mandelic acid, and (-)-dinitrodiphenic acid and/or and ()-lactic acid. The desired enantiomer of Formula I is then obtained by separating the optically active auxiliary agent in accordance with known methods.

The hydroxy compounds of Formula I (R =OH and/ or R =H) can furthermore be converted into suitable diastereomeric esters by esterification with one of the above-mentioned optically active acids, which esters can be separated due to their differing properties. The optically active compounds of Formula I are in each case obtained by saponification of the pure diastereomer. However, it is also possible to prepare the acidic phthalic acid or succinic acid esters, e.g., by reaction respectively, with phthalic and/ or succinic anhydride, and convert the thusproduced dibasic acids into their diastereomeric salts, by reaction with an optically active base, e.g., quinine, cinchonidine, brucine, cinchonine, hydroxyhydrindarnine, morphine, l-phenylethylamine, l-uaphthylethylamine, phenyloxynaphthylmethylamine, quinidine and/or strychnine, from which the pure enantiomers can be obtained.

Especially advantageous is the separation of the racemates or racemate mixtures by chromatography employing optically active substrate materials, such as, for example, tartaric acid, starch, cane sugar, cellulose, or cellulose acetate, and optically inactive and/or optically active eluents, for purposes of separation into the pure enantiomers, or an optically inactive substrate material, e.g., silica gel or aluminum oxide, in combination with an optically active eluent. The optical antipodes can also be separated biochemically by a selective enzymatic reaction. For example, using a hydrolase and racemic ester, one of the enantiomers is selectively saponified and the other remains unchanged, which permits their separation because of their different properties.

Furthermore, it is, of course, possible to obtain optically active compounds in accordance with the above-described methods by using starting substances which are already optically active.

The novel compounds can be employed in a mixture with solid, liquid and/ or semiliquid excipients as drugs in the human or veterinary medicine. Suitable vehicles are those organic or inorganic substances which are suitable for parenteral, enteral, or topical application and which do not react with the novel compounds, such as, for example, water, vegetable oils, benzyl alcohols, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, Vaseline, cholesterol. Especially suitable for parenteral application are solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants. Suitable for enteral application are tablets, drages, syrups, elixirs, or suppositories, and for topical use, salves, creams, or powders. The above-mentioned preparations can be optionally sterilized or mixed with auxiliary agents, such as lubricants, preservatives, stabilizers, or wetting agents, emulsifiers, salts for influencing the osmotic pressure, buffers, coloring, flavoring and/or aromatic substances.

The substances are preferably administered in a dosage of 0.12,000 mg. per dosage unit.

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.

In the following examples, the temperatures are set forth in degrees centigrade.

EXAMPLE 1 (a) 3.6 g. of 2-[3-chloro-4-(3-hydroxypiperidino)- phenyl]-allyl alcohol (obtainable from 2-(3-nitro-4- chlorophenyl)-allyl alcohol and 3-hydroxypiperidine, catalytic reduction to the amino compound, diazotization, and exchange of the diazonium group against chlorine) is hydrogenated in a mixture of methanol and ethyl acetate with hydrogen at room temperature in the presence of 0.6 g. of a Pd-C catalyst (5% by weight Pd). After the absorption of hydrogen is terminated, the reaction mixture is filtered, the filtrate is concentrated by evaporation, and the residue is fractionated, thus obtaining 2-[3-chloro- 4-(3-hydroxypiperidino)-phenyl]-propanol-(1) as a mixture of two racemates; B.P. l80/0.05 mm.; M.P. 7582.

Analogously, by hydrogenation in the presence of Pd-C, from the following starting compounds:

2- 3-chloro-4- 3-hydroxypyrrolidino -phenyl] -allyl alcohol 2- 3-bromo-4- 3-hydroxypyrrolidino) -phenyl] -allyl alcohol 2-[3-methyl-4-( 3-hydroxypyrrolidino)-phenyl] -allyl alcohol 2- 3-bromo-4- (3-hydroxypiperidino -phenyl] -a1lyl alcohol 2- [3-methyl-4- 3-hydroxypiperidino) -phenyl] -allyl alcohol the following compounds are produced:

2- [3-chloro-4-(3-hydroxypyrrolidino)-phenyl]-1-propanol, B.P. 186192/0.01 mm.;

2- 3-bromo-4- 3-hydroxypyrrolidino phenyl] 1- propanol;

2- 3-methyl-4-(3-hydroxypyrrolidino) -phenyl]-1- propanol;

2- [3-bromo-4- 3-hydroxypiperidino) -phenyl]-1-propanol;

2- 3-methyl-4- 3 -hydroxypiperidino) -phenyl] -1-propanol.

(b) 5.4 g. of 2-[3-chloro-4-(3-hydroxypiperidino)- phenyl]-l-propanol (M.P. 7582) is dissolved in 60 m1. of dimethylformamide; under agitation and nitrogen, 1 g. of NaH is added thereto, and the reaction mixture is stirred for 2 hours at 40. Then, 6.2 g. of methyl iodide is gradually added dropwise, dissolved in 10 m1. of dimethylformamide. The mixture is agitated at 5060; after 5 hours, another 3.1 g. of methyl iodide in ml. of dimethylformamide is added, and the mixture stirred for another 13 hours at 5060. The reaction solution is poured into water, extracted with ether, the ether phase washed with water, dried over Na SO the ether distilled oif, and, after purifying the residue by chromatography (silica gel/ benzene), one obtains 2-[3-chloro-4-(3-methoxypiperidino)-phenyl]-1-methoxypropane, B.P. 143-146/ 0.1 mm.

Analogously, by reacting 2-[3-chloro-4-(3-hydroxypiperidino)-phenyl]-1-propanol with NaH and ethyl, npropyl, isopropyl, n-butyl, isobutyl, or sec.-butyl iodide, the following compounds are produced:

2- 3-chloro-4-(3ethoxypiperidino) -phenyl] -1-ethoxypropane 2- [3-chloro-4-(B-n-propoxypiperidino) -phenyl] -1-npropoxypropane 2-[3-chloro-4-(3-isopropoxypiperidino)-pheny1]-1-isopropoxypropane 2- 3-chloro-4- (3-n-butoxypiperidino -phenyl] -1-nbutoxypropane 2 3-chloro-4- 3-isobutoxypiperidino -phenyl] -1-isobutoxypropane 2- [3 -chloro-4- 3-sec.-butoxypiperidino -phenyl] -1-sec.-

butoxypropane In place of the above-mentioned alkyl iodides, it is alsopossible to use the corresponding bromides or sulfates.

(c) 5.4 g. of 2-[3-chloro-4-(3-hydroxypiperidino)- phenyl]-propanol (M.P. 7582) is dissolved in 25 ml. of pyridine. Then, 25 ml. of acetic anhydride is added thereto, the reaction mixture is allowed to stand for 24 hours at room temperature, poured into H O, extracted with ether, washed with a NaI-ICO solution and water, dried over Na SO the solvent is distilled 'off, and the residue is fractionated, thus obtaining 2-[3-chloro-4-(3-acetoxypiperidino)phenyl]-1-propyl acetate as mixture of two racemates having the boiling point of 175178/ 0.05 mm.

Analogously from the higher melting racemate of 2-[3- chloro-4-(3-hydroxypiperidino) phenyl] 1 propanol (M.P. 83-85), a diacetate is obtained having the boiling point of 175-177/ 0.05 mm., and from the lower-melting racemate (M.P. 7072) a diacetate having the boiling point of 175-180/0.05 mm.

14 EXAMPLE 2 A solution of 5.3 g. of 2-[3-chloro-4-(3-hydroxypiperidino)-phenyl]-propanol (produced from 2-[3-chloro-4- (3-hydroxypiperidino)-phenyl]-propionitrile by hydrogenation in a pyridine-H O-acetic acid mixture in the presence of Raney nickel and sodium hypophosphite) in 20 ml. of ether is added dropwise to a suspension of 1.0 g. of LiAlH in 50 ml. 'of ether. The reaction mixture is refluxed for 2 hours, whereafter'2 ml. of ethyl acetate and then 20 ml. of an aqueous NH Cl solution are added thereto. The ether phase is separated, washed with H O, dried over Na SO the solvent is distilled off, and in this way, 2 [3 chloro-4-(3-hydroxypiperidino)-phenyl]-1- propanol is produced as a mixture of two racemates; M.P. 75-82" (from ethyl acetate/hexane).

EXAMPLE 3 (a) 6.2 g. of the ethyl ester of 2-[3-chloro-4-(3-hydroxypiperidino)-phenyl]-propionic acid (mixture of two racemates, M.P. -165) is refluxed in 300 ml. of dry tetrahydrofuran with 1.0 g. of LiAlH After cooling, any excess LiAlH, is decomposed with moist tetrahydrofuran; 6 ml. of aqueous 1 N NaOH is added dropwise, the mixture is filtered, the solvent is distilled off, the residue is taken up in ether, washed with water, dried over Na SO the solvent distilled olf, and one obtains thereby 2-[3- chloro-4-(3-hydroxypiperidino)-phenyl]-1-propanol as a mixture of two racemates, M.P. 7582.

The same product is analogously producible from other esters of 2- 3-chloro-4- 3-hydroxypiperidino -phenyl] propionic acid or from the free acid itself.

(b) 5.4 g. of 2 [3 chloro-4-(3-hydroxypiperidino)- phenyl]-propanol is dissolved in 25 ml. of pyridine; under ice cooling, 5.6 g. of hexanoyl chloride is added dropwise to the reaction mixture, and the latter is allowed to stand for 18 hours at room temperature and then poured into water, extracted with ether, and the ether phase washed with aqueous NaHCO solution and H 0. After drying over Na SO the ether is distilled off, and after purification by chromatography (silica gel/benzene), 2-[3-chloro- 4- 3-hexanoyloxypiperidino) -phenyl]-1-propyl hexanoate is obtained, B.P. 210215/0.05 mm.

Analogously, by reaction with acetyl chloride pripionyl chloride butyryl chloride pentanoyl chloride or benzoyl chloride,

in pyridine, the following compounds are obtained:

2-[3-chloro-4-(3-acetoxypiperidino)-pheny1] 1 propyl acetate, B.P. 178/0.05 mm.;

2 [3 chloro-4-(3-propionyloxypiperidino)-phenyl]1- propyl propion-ate, B.P. -200/ 0.1 mm.;

2 [3 chloro 4-(S-butyryloxypiperidino)-phenyl]-1- propyl butyrate;

2 [3 chloro 4-(3-pentanoyloxypiperidino)-phenyl]-1- propyl pentanoate;

2 [3 chloro 4-(3-benzoyloxypiperidino)-phenyl]-1- propyl benzoate.

EXAMPLE 4 (a) Analogously to Example 3, by reduction with LiAlH the low-melting racemates of 2-[3-chloro-4-(3- hydroxypiperidino)-phenyl]-1-propanol, M.P. 70-72, is produced from the low-meling racemate of 2-[3-chloro-4- (3-hydroxypiperidino)-phenyl]-propionic acid (M.P. 140- 143 and/or from the corresponding esters.

(b) Analogously to Example 3, by reduction with LiAlH the high-melting racemate of 2-[3-chloro-4-(3- hydroxypiperidino)-phenyl]-1-propanol, M.P. 83-85", is obtained from the high-melting racemate of 2-[3-chlor'o- 4-(3-hydroxypiperidino)-phenyl] propionic acid (M.P. 179-181) and/ or from the corresponding esters.

1 EXAMPLE 5 In analogy to Example 3, by reduction with LiAlH and using the .following starting compounds:

3 -chloro-4- (3 -hydroxypyrrolidino) -phenylacetic acid 3 -bromo-4- 3 -hydroxypyrrolidino -phenylacetic acid 3-methyl-4- 3 -hydroxypyrrolidino -phenylacetic acid 3-chloro-4- 3-hydroxypiperidino) -phenylacetic acid 3-bromo-4- 3-hydroxypiperidino) -phenylacetic acid 3-methyl-4- 3-hydroxypiperidino -phenylacetic acid 2- 3-chloro-4- 3-hydroxypyrrolidino -phenyl] -propionic acid 2- 3 -bromo-4- 3-hydroxypyrrolidino -phenyl] -propionic acid 2- [3 -methyl-4- 3 -hydroxypyrrolidino -phenyl] -propionic acid 2- 3 -b romo-4- (3 -hydroxypiperidino) -phenyl] -propionic acid 2- [3 -m ethyl-4- (3 -hydroxypip eridino) -phenyl] -p ropionic acid and/ or the esters of these acids, the following compounds are obtained:

2- 3 -chloro-4- 3-hydroxypyrrolidino -phenyl] -eth anol 2- [3-bromo-4- 3-hydroxypyrrolidino -phenyl] -ethanol 2- 3-rnethyl-4- 3-hydroxypyrrolidino -phenyl] -ethanol 2- [3-chloro-4- 3-hydroxypiperidino -phenyl] -ethanol,

M.P. 98-100, B.P. l80182/O.l mm.

2- [3-bromo-4- 3 -hydroxypip eridino -phenyl] -ethanol 2- [3-methy1-4- 3-hydroxypiperidino -phenyl] -ethanol 2- [3-chlo1'o-4-(3-hydroxypyrrolidino) -phenyl] -1- propanol, B.P. 186-192 0.1 mm.

2- 3-bromo-4- (3-hydroxypyrrolidino -phenyl] -1- propanol,

2- [3-methyl-4- 3-hydroxypyrrolidino -phenyl] 1- propanol 2- 3-bromo-4-( 3-hydroxypiperidino -pheny1] 1- propanol 2- 3-methyl-4- (3 -hydroxypiperidino -phenyl] 1- propanol.

EXAMPLE 6 4.7 g. of l-bromo-2-[3-chloro-4-(3-hydroxypiperidino)- phenyl]-propane (produced from 4-bromo-3-nitroacetophenone by reaction with 3-hydroxypiperidine, catalytic hydrogenation of the thus-produced 4-(3-hydroxypiperidino)3-nitroacetophenone, diazotization, and Sandmeyer reaction to 3 chloro-4-(3-hydroxypiperidino)-acetophenone [B.P. 190195/0.2 mm.], reaction with methylmagnesium iodide to 2 [3-chloro-4-(3-hydroxypiperidino)-phenyl1-2-propanol (M.P. 110-112), dehydration by refluxing with p-toluenesulfonic acid in toluene, bromination with N-bromosuccinimide in boiling C01 and subsequent catalytic hydrogenation) is refluxed for 4 hours in a mixture of 40 ml. of water and 30 ml. of ethanol with 2 g. of KOH. Then, 50 ml. of the solvent is distilled off, the reaction mixture diluted with 20 ml. of water, extracted with ether, the organic phase washed with water, dried over Na SO the ether distilled ofl, and 2 [3-chloro-4-(3-hydroxypiperidino)-phenyl] -propanol- (1) is obtained as a mixture of two racemates, B.P. l80/ 0.05 mm.; M.P. 75-82".

EXAMPLE 7 10 g. of 2-(4-amino-3-chlorophenyl)-1-propanol (obtainable from 2-(4-amino-3-chlor0phenyl)-propionic acid [M.P. 114-115 by reduction with LiAlH is refluxed with 28 g. of 1,4-dibromobutan-2-ol (B.P. 70-75/0.4 mm.; obtainable from 1,2,4-trihydroxybutane and HBr) for 7 hours in 70 ml. of water is added dropwise. Thereafter, the mixture, wherein 2-[3-chloro-4-(4-bromo-3-hydroxy-l-butylamino) -phenyl] -1-propanol and 2-[3-chloro- 4 (4-bromo-2-hydroxyl-l-butylamino)-phenyl]-l-propa nol are formed as intermediates, is refluxed for another 3 16 hours; ml. of the solvent is distilled 01f, the reaction mixture is diluted with 30 ml. of water, extracted with ether, the organic phase washed with Water, dried over Na SO the ether distilled off, and in this manner, 2-[3- chloro 4-(3-hydroxypyrrolidino)-phenyl]-l-propanol is obtained as a mixture of two racemates, B.P. 186192/ EXAMPLE 8 19 g. of 2-[3-amino-4-(3-hydroxypiperidino)-phenyl]- l-propanol (producible from 2-[3-amino-4-(3-hydroxypiperidino)-phenyl]-propionic acid by reduction with LiAlH is dissolved in 75 ml. of H 0 and 26 ml. of concentrated HCl; at 0-5 5.5 g. of NaNO dissolved in 25 ml. of H 0, is added thereto. The thus-obtained mixture is poured in a thin stream to a slightly boiling solution of 9 g. of Cu CI in 40 ml. of concentrated HCl, and then allowed to stand for another 30 minutes at -95. The reaction mixture is then cooled, saturated with H 8, filtered, and Na CO is stirred into the mixture until an alkaline reaction is attained. Thereafter, the mixture is extracted with ether, the ether phase washed with H O, dried over Na SO filtered, the ether distilled OE, and the product thus obtained is 2-[3-chloro-4-(3-hydroxypiperidino) phenyl]-propanol-( 1) as a mixture of two racemates, B.P. 180/0.05 111111.; M.P. 75-82".

EXAMPLE 9 Analogously to Example 3, from 2-[3-chloro-4-(3-oxopiperidino)-phenyl]-1-propanol (obtainable by reacting 2- (3 nitro-4-bromophenyl)-l-propanol with 3-piperidone ethylene ketal, reduction of the thus-produced 2-[3-nitro- 4-(3,3-ethylenedioxypiperidino)-phenyl] -1-propanol to the amino compound, diazotization under simultaneous ketal hydrolysis, and Sandmeyer reaction) the compound 2-[3- chloro 4-(3-hydroxypiperidino)-phenyl]-propanol-(1) is obtained as a mixture of two racemates, B.P. l80/ 0.05 mm.; M.P. 75-82".

EXAMPLE 10 8.0 g. of 2-[3-chloro-4-(3-bromopiperidino)-phenyl]- l-propanol (obtainable from 2-(3-nitro-4-bromophenyl)- l-propanol by reaction with 3,4-dehydropiperidine, reduction of the thus-produced 2-[3-nitro-4-(3,4-dehydropiperidino)-phenyl]-1propanol, Sandmeyer reaction, bromination of the thus-obtained 2-[3-chloro-4-(3,4-dehydropiperidino)-phenyl]-l-propanol with N-bromosuccinimide, and subsequent catalytic hydrogenation) is refluxed for 6 hours in a mixture of 80 ml. of water and 40 m1. of ethanol with 4 g. of KOH. After cooling, 80 ml. of concentrated aqueous NaCl solution is added thereto, the mixture extracted with ether, the ether phase washed with water, dried over Na SO and the solvent ditsilled ofI', thus obtaining 2-[3-chloro-4-(3-hydroxypiperidino)-phenyl]-propanol-(l) as a mixture of two racemates, B.P. 180/0.05 mm.; M.P. 75-82.

EXAMPLE 11 4.6 g. of 1-propionyloxy-2-[3-chloro-4-(5-propionyloxy- 3,4dehydropiperidino)-phenyl] -propane (obtainable from 2 [3-ch1oro-4(5-bromo-3,4-dehydropiperidino)-phenyl]- l-propanol by reaction with sodium propionate and propionic acid in the presence of a small amount of propionic anhydride) is dissolved in a mixture of 40 ml. of methanol and 20 ml. of ethyl acetate and hydrogenated at room temperature in the presence of 1 g. of a Pd-C catalyst (5% by Weight Pd). After the hydrogen absorption is terminated, the mixture is filtered, the filtrate evaporated, and the residue is fractionated, thus obtaining 2-[3-chloro 4 (3-propionyloxypiperidino)-phenyl]-l-propionyloxypropane as a mixture of two racemates, B.P. 200/0.1 mm.

1 7 The following examples include pharmaceutical compositions of the-novel compounds which can be produced according to conventional standards:

Example A.Tablets The coating is a conventional mixture of corn starch,

sugar, talc, and tragacanth and amounts to 150 mg.

Example C.Solution for injection A solution of 2 kg. of the hydrochloride of 2-[3-chloro- 4 (3 hydroxypiperidino)-phenyl]-1-propanol in 198 kg. of distilled Water is prepared and filled into 2 ml. ampoules in such a manner that each ampoule contains 20 mg. of said hydrochloride.

Example D.Syrup A mixture of 2 [3 chloro 4-(3-acetoxypiperidino)-phenyl]- l-propyl acetate Glycerol (twice distilled) 7.5 Cane sugar 56.0 Methyl p-hydroxybenzoate 0.07 n-Propyl p-hydroxybenzoate 0.03 Ethanol 10.0 Flavorings As desired is prepared and mixed with distilled water in such a manner that the volume of the entire preparation is 100 l. A dosage unit (5 ml.) contains 20 mg. of active substance.

Example E.-Hard gelatin capsules Each hard gelatin capsule is filled with a fine powder consisting of Mg. 2 [3 chloro 4-(3-hydroxypiperidino)-phenyl]- 1 propanol Lactose 180 Talc 18 Magnesium stearate 2 Instead of the hydrochloride other physiologically compatible acid or base addition salts, respectively, of 2- [3 chloro 4-(3-hydroxypiperidino)-phenyl]-1-propanol or 2 [3 chloro 4 (3-acetoxypiperidino)-phenyl]-1- propyl acetate or other compounds covered by Formula 1, as well as the physiologically compatible acid addition salts, thereof, can be incorporated into similar compositions.

The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.

From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.

What is claimed is:

1. Compounds of the formula wherein R is OH, alkoxy of up to 6 carbon atoms, cycld alkoxy of up to 6 carbon atoms, aryloxy, aralkoxy of 7- 12 carbon atoms, or alkanoyloxy of up to 18 carbon atoms; R is H, alkyl of up to 6 carbon atoms, cycloalkyl of up to 6 carbon atoms, aryl, aralkyl of 7-12 carbon atoms, or alkanoyl of up to 18 carbon atoms; aryl in each of the above instances is phenyl, tolyl, xylyl or naphthyl; R is H or CH R is Cl, Br or CH and n is 2 or 3; and the physiologically acceptable acid addition and quaternary ammonium salts thereof.

2. A compound of 1 wherein R is OH.

3. A compound of claim 2 wherein n is 3.

4. A compound of claim 1 wherein R is alkanoyloxy of up to 18 carbon atoms.

5. A compound of claim 4 wherein n is 3.

6. A compound of claim 1 wherein R is H.

7. A compound of claim 6 wherein n is 3.

8. A compound of claim 1 wherein R is alkanoyl of up to 18 carbon atoms.

9. A compound of claim 8 wherein n is 3.

10. A compound of claim 1 wherein R is CH 11. A compound of claim 1 wherein R is Cl.

12. A compound of claim 1 wherein R is OH, R is CH and n is 3.

13. A compound of claim 1 wherein R is OH, R is H, R is CH and R is Cl.

14. A compound of claim 1 wherein R is alkanoyloxy of up to 18 carbon atoms, R is H, R is CH and R is Cl.

15. A compound of claim 14 wherein n is 3.

16. A compound of claim 1 wherein R is alkanoyloxy and R is alkanoyl, each of up to 18 carbon atoms, R, is CH3 d R4 iS Cl- 17. A compound of claim 16 wherein n is 3.

18. A compound of claim 1, 2-[3-chloro-4-(3-hydroxy- 19. A compound of claim 1, 1-acetoxy-2-[3-chloro-4- (3 -acetoxypiperidino -phenyl -prop ane.

20. A compound of claim 1 wherein R is alkanoyloxy of up to 6 carbon atoms.

21. A compound of claim 1 wherein R is alkanoyl of up to 6 carbon atoms.

References Cited UNITED STATES PATENTS 3,641,040 2/ 1972 Carney et al 260293.72 3,669,956 6/1972 Borck et al 260239 BF 3,669,972 6/1972 Borck et a1. 260293.73 3,669,973 6/ 1972 Borck et a1. 260--293.73

HENRY R. JILES, Primary Examiner G. T. TODD, Assistant Examiner US. or. X.R.

UMT D STATES PATENT OFFICE CERTEFECATE ()F CGRREQTIQN Dated November 6, 1973 Paten t No. 3,770,748

Inventor) Joachlm Borck, et al.

It is certified that error appears in th'e above-identified patent and that said Letters Patent are hereby corrected as shown below:

IN THE CLAIMS, COLUMN l8:

Claim l8 should read as follows 18. A compound of Claim 1, 2- [3chloro4 (3-hydroxy-piperidino)-phenyl]-lpropanol'.

Signed and sealed this 1st day'of Detober 1974.

(SEAL) Attest:

c MARSHALL DANN McCOY M. GIBSON JR" Attesting Officer Commissioner of Patents USCOMM-DC 60376-P69 A U45. GOVERNMENT PRINTING OFFICE: I968 O-rSSB-SZM.

FORM PC4050 (IO-69)