DE2600557A1 - Antidepressant 4-aryl-piperidines and salts - some having local anaesthetic and antiarrhythmic activity - Google Patents

Abstract

4-Aryl-amino-hydroxypiperidines of formula (I) are new together with their acid-addn. salts (where R' is H,alkyl, alkenyl, alkynyl, aralkyl, acyl, 2-6C alkylamino opt. substd. by one or two alkyls or opt. substd. by alkylene to complete a satd. N-heterocycle; a gp. where R7 and R8 are H, phenyl opt. substd. by halo, or alkyl; or R7 + R8 and the attached N-atom form a 6 or 7-membered heterocyclic ring opt. contg. an O-atom; n is 1, 2, 3 or 4; a gp. -(CH2)n. CO2H; a gp. where X is H or halo; one of R2 and R3 is CN, free NH2 or a radical derived from it; the other is a free or protected OH; or R2 is where R3 is free or protected OH; or R2 + R3 and the attached C atoms form an oxazepin ring; Ar is aryl opt. substd. by one or more alkyl, alkoxy, halo or CF3). One subgp. has antidepressant activity, another gp. has local anaesthetic and antiarrhythmic activity. Other activities in the gp. include antihistamine, anticholinergic, spasmolytic, and diuretic activity.

Description

4-Aryl-3/4-amino / hydroxypiperidine derivatives, method for

their preparation and medicinal products containing these compounds The invention relates to new 4-arylpiperidine derivatives and processes for their preparation and medicaments containing these compounds.

The present invention relates to new 4-aryl-3/4-amino / hydroxypiperidine derivatives of the general formula I: in which R1 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aralkyl, lower acyl, aminoalkyl, in which the alkyl part contains 2 to 6 carbon atoms and the amino part can be mono- or dialkyl-substituted1 or a saturated cyclic amine radical, the group in which R7 and R8 independently represent hydrogen, optionally halogen-substituted phenyl or lower alkyl or form a saturated alkylene chain with 5 or 6 ring members, which optionally contains an oxygen atom, and in which n is 1, 2, 3 or 4 , the groups - (CH2) n-COOH, - (Cii2) nOH where X is hydrogen or halogen and n is 1, 2, 3 or 4, one of the groups R2 and R3 is a cyano or a free amino group or a derivative thereof and the other is a free or protected hydroxyl group or R2 is an azido group when R3 stands for a free or protected hydroxyl group, or R2 and R3 together with the associated ring carbon atoms form an oxazepine ring, and in which finally Ar is an aryl group which can be substituted by lower alkyl, lower alkoxy, halogen or CF7, means, as well as their addition salts with organic or inorganic acids.

Since the compounds of formula I have chiral centers at C3 and C4, it will be apparent to those skilled in the art that these compounds can be described as, stereoisomers and optical isomers may be present. The general formula therefore aims to do all of these Isomers, either separately or in d, l mixtures.

Furthermore, in the compounds of the formula I, the substituent groups are R2 and R3 are always arranged in a trans relationship to one another.

The terms "lower alkyl" and "lower acyl" are intended herein to be alkyl and denote acyl groups having at most 6, preferably at most 4 carbon atoms.

Examples of lower alkyl groups are methyl, ethyl, Isopropyl, propyl, butyl, isobutyl, sec- and tert-butyl, pentyl, isopentyl, neopentyl as well as the various hexyl isomers. Examples of lower acyl groups are Groups acetyl, propionyl etc. and for aminoalkyl the groups aminoethyl, aminopropyl, Aminobutyl, Aminopentyl and aminohexyl. The term l'lower alkylt as used herein is intended to mean groups which have a maximum of 6, preferably a maximum of 4 carbon atoms in the alkyl part contain. Examples are phenyl lower alkyl, e.g. benzyl, phenethyl, and Naphthyl lower alkyl, such as 2-naphthylmethyl. The aryl group Ar can be a phenyl or 1- or 2-naphthyl group, but is preferably a phenyl group, the may be substituted by chlorine, bromine or fluorine as halogen.

The amino group R2 or R3 can have the formula: have, in which R5 and R6 are independently hydrogen, a saturated alicyclic moiety with 5 to 7 carbon atoms, which can contain an oxygen atom in the ring, lower alkyl, which can optionally be substituted with a hydroxyl group or an ester moiety of the formula -COO-lower alkyl, lower acyl , Lower aralkyl, where the aryl part can be substituted by halogen, or are adamantyl, or where the groups R5 and R6 together with the nitrogen atom and optionally an oxygen atom form a 5- or 6-membered heterocyclic ring. Preferred heterocyclic rings of the formula are pyrrolidine, piperidine and morpholine. Special amine derivatives which are considered according to the invention are those which contain the following: Amide parts of the formulas -NH- or -NR " IV sulfonamide parts of the formula -NH-S02R1 and urea parts of the formula -NH-CO-NHR ".

Therein R denotes lower alkyl, which is optionally replaced by a piperidine, Di (lower alkyl) amino or p-chlorophenoxy group can be substituted, furyl, Phenyl which can be substituted by halogen, hydroxy or methoxy. R1 stands for aryl, especially phenyl, which may be substituted by lower alkyl. R " denotes hydrogen, lower alkyl, lower cycloalkyl or phenyl, which optionally is substituted by halogen, lower alkyl or trifluoromethyl. R "'means cycloalkyl or phenyl lower alkyl, where RIV is lower alkyl.

Examples of protected hydroxyl groups R2 or R3 are the corresponding esters of the formulas: or and ethers of the formula -OR, in which R is a lower alkyl group. A restricted class of compounds of formula I are those of formula III: in which R1 is lower alkyl or acyl, one of the substituents R2 and R3 for an amino group as defined above —NR5R6 and the other for hydroxy or an ester group of the formula in which R is a lower alkyl group and in which finally R4 is hydrogen, lower alkyl, lower alkoxy, halogen or CF3, but preferably hydrogen or lower alkyl.

The invention further provides a process for the preparation of compounds of the formula I. According to one embodiment of the invention, the new compounds according to the invention can be prepared from an epoxide of the formula IV: wherein R1 and Ar have the definition given in connection with the formula I, are prepared.

The compounds of the formula IV are converted into compounds of the formula I converted by a reaction that involves cleavage of the epoxy ring. this happens according to one embodiment of the method according to the invention by a Reaction with ammonia, an azide, a cyanide or a primary or secondary Amine, the cleavage agent being selected such that in the compound of the formula I the desired groups R2 and R3 are obtained.

The amine cleavage agent can have the formula: where R5 and R6 have the definition given above.

The azide or cyanide used may be an alkali metal azide or cyanide e.g. sodium or potassium azide or sodium or potassium cyanide.

The compounds of the formula IV in which R1 is hydrogen, are secondary amines and they can in certain cases in the cleavage of the epoxy ring take part in undesirable competitive reactions with the selected cleavage agent. However, a significant extent of these side reactions is only likely if if the cleavage agent is voluminous in nature; and the possibility of expiration such undesirable side reactions can be further reduced by that the reaction is carried out at a lower temperature than in other cases, ° E.g. at temperatures below 100 C compared to ° temperatures from 100 to 200 C and usually around 1500C. In this case, however, it is preferred that the the desired compounds of the formula L, in which R1 is hydrogen, to be prepared in such a way that that the epoxy ring of a corresponding compound of formula I in which R1 is a Amine protecting group, e.g., an acyl group, with the desired cleavage agent cleaves and then the group R1 in a known manner, for example by hydrolysis with an acid or a base, converted to hydrogen.

The compounds of the formula I can also generally be used as Intermediates for the preparation of other compounds of formula I used will.

Compounds of the formula I in which R1 is alkyl or acyl can e.g. from compounds of the formula I in which R1 is hydrogen, by a simple Alkylation or acylation using standard methods known in the art from, for example, alkyl halides or acyl halides. Connections of Formula I in which R2 is a free amino group can be obtained by known reduction processes e.g. obtained using a complex metal hydride of the corresponding azide will. Substituted amines and amine derivatives can be selected from the corresponding free Amino compounds are obtained, for example by alkylation under Use of alkyl halides or by reaction with acyl halides (where Amide derivatives are obtained), sulfonyl halides (whereby sulfonamide derivatives are obtained are) and isocyanates (whereby urea compounds are obtained). Alternatively some derivatives can be prepared directly from the epoxy compound if desired will. For example, the epoxy ring in the compound of formula IV can be mixed with an amide derivative, e.g.

a toluenesulfonamide, in the form of an alkali metal salt, e.g. Sodium or potassium salt, which leads to the direct formation of a toluenesulfonamide amine derivative of formula I leads. Compounds of the formula I in which R2 or R3 is a protected hydroxyl group, from the corresponding free hydroxyl compound, e.g. by esterification or etherification in the known manner.

The formula I clearly comprises, inter alia, two series of amino alcohol structural isomers, namely those of the formulas Ia and Ib below: Here, R1 and Ar have the broad definition given above and X denotes R2 or R3 in the case of a free or protected hydroxyl group and Y denotes R2 or R3 in the case of a cyano group, a free amino group or a derivative thereof.

The formula I also includes compounds of the above formula Ib, in which, however, Y is an azide group.

The cleavage of the epoxy ring of the 3,4-epoxypiperidines of the formula IV generally results in the formation of both structural isomers, but vary the relative lengths of the individual isomers depending on the nature of the R1 substituent and also to a lesser extent depending on the solvent that may be present, in which the reaction is carried out, and also the steric properties of the Cleavage agent.

In determining the relative proportions of the two isomers have however, the steric properties, i.

the voluminosity, the cleavage agent the predominant importance.

For example, when cleavage of the epoxy ring of the compound of formula IV is made with an azide, then only the isomer Ib is obtained. The same Isomers predominate to a large extent when a non-hindered amine, e.g. with the formula H2NCH2-R, in which R is, for example, an alkylphenyl group or a Aralkyl group means, being a typical example of such a compound Benzylamine etc. is used. In all of these cases, the nucleophile occurs attack predominantly on the tertiary carbon atom of the piperidine ring.

When the isomer Ib in which Y is a free amino group is required then this compound is readily obtained by reduction of the corresponding azide obtained by known procedures.

A medium size or bulk cyanide or amine, e.g. Pyrrolidine, dimethylamine and hydroxyethylmethylamine, lead to the formation of an approximately 1: 1 mixture of the two possible isomers. In such cases the tertiary and secondary carbon atoms in the piperidine ring as a point of attack by the nucleophilic reagent equally favored.

After all, bulky amines, e.g. aminoadamantane, morpholine, Piperidine and tert-butylamine, and surprisingly also ammonia, e.g. in the form an aqueous solution, for the predominance of the isomer of formula Ia, which is favored The point of attack is the secondary carbon atom in the epoxy ring.

When the isomer mixture obtained as the product of a specific reaction in this form due to the undesirable presence of one or more Isomer is not usable, the isomers can be separated by standard procedures are, in general, differences in physical and / or chemical properties between the isomers, such as the relative solubilities, use different Recrystallization rates and different retention rates at chromatographic separation processes, e.g.

column chromatography.

The 4-arylpiperidines of the formula I'form with various inorganic or organic acids acid addition salts. These salts should also be under the frame of the present invention. Of particular interest are pharmaceuticals acceptable acid addition salts, which are usually easier to handle than those free compounds of the formula I. Examples of acids which form such salts are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, Acetic acid, maleic acid, fumaric acid, tartaric acid, succinic acid, citric acid, camphor sulfonic acid, Ethanesulfonic acid, ascorbic acid and lactic acid.

Of the starting compounds, namely the 3,4-epoxypiperidines of the formula IV: the compound in which R1 is methyl and'Ar is phenyl is already known and it is described in the literature together with its synthesis. Further compounds of the formula IV in which Ar and R1 are as defined above can be prepared in an analogous manner. For example, by epoxidizing compounds of the formula V: wherein R1 and Ar are as defined above.

The epoxidation can be done in several ways, e.g.

by 1st oxidation using a percarboxylic acid according to the following reaction scheme: where R1 is acyl and Ar has the above definition, or 2. from a halohydrin in the presence of a base according to the following reaction scheme: where R1 is hydrogen, ie the nitrogen atom has a basic character and X is halogen.

The process used for the epoxidation must of course be chosen in this way that the possibility of undesirable side reactions is avoided. if e.g. R1 in formula V above is an acyl group, then preferably will not worked by the halohydrin route, since the reagents used are disadvantageous Have effects on the acyl group. In this case, the epoxidation can be better can be performed using a percarboxylic acid or alternatively one goes in such a way that the epoxy compound, in which R1 is hydrogen, according to route 2 and this connection then, if desired, by known methods (as mentioned above) acylated.

It will be seen that, in general, the epoxy compounds where R1 has a different meaning than Hydrogen, from the corresponding Epoxy compounds in which R1 is hydrogen, by known alkylation, Acylation etc. can be made from these compounds.

Some of the 4-aryl-1,2,3,6-tetrahydropyridines of the formula V, namely those of the formula VI: where R denotes hydrogen or methyl and R1 denotes various parts of hydrocarbons, are known compounds which are described together with a production process, for example in JACS 956), Volume 78, pages 425 to 428. Any new compounds of the formula V can be prepared in a manner similar to the known compounds, of course with appropriate selection of the starting materials substituted a-methylstyrene and an amine react with one another according to the following scheme: Here, R1 and R4 have the meanings given above and the amine R1NH2 is in the form of the acid addition salt.

Here, too, compounds in which the substituent R1 is hydrogen is to be converted into compounds in which R1 has a meaning other than hydrogen.

The new 4-arylpiperidines according to the invention have biological ones that can be used Properties and they generally have an activity determined by standard tests, which indicates at least one of the following possible uses: as an intestinal relaxant, as an antihistamine, as an anticholinergic, as a uterine relaxant, as a local anesthetic, as a spasmodic and diuretic.

For example, it has been shown that compounds of formula Ia upon administration exert a significant stimulating effect on the central nervous system in mice, which ultimately contributes to antidepressant and similar clinical utility Points out to people.

In the table below are results from the investigation some compounds of the particularly preferred formula Ia with regard to the antidepressant Activity after standard tests (see e.g. R.A. Turner, P.

Tbborn, Screening Methods in Pharmacology, Volume II, Acad. Pr., N.Y., London 1971, page 214). Ptosis was induced with reserpine and the test compounds were administered orally. For comparison are in the table also the results of using the well-known antidepressant imipramine same test included. Response values greater than 3 are considered pharmacological viewed significantly.

Compound dose response mg / kg 1 -methyl-4-phenyl-4-hydroxy-3- 25 6 (4-morpholino) piperidine 10 5 1 -methyl-4-phenyl-4-hydroxy-3- (N-25 5 adamantylamino) piperidine 10 5 1-methyl-4-phenyl-4-propionyloxy-25 9 3- (4-morpholino) piperidine 10 6 5 5 1-methyl-4-phenyl-4-hydroxy-3- 25 7 (8-pyrrolidinyl) piperidine 10 5 1 -methyl-4-phenyl-4-acetoxy-3-25 9 (1-pyrrolidinyl) piperidine 10 7 5 6 1-methyl-4-phenyl-4-acetoxy-3-10 9 (1-piperidinyl) piperazine 5 9 2.5 5 1 -Methyl-4-phenyl-4-hydroxy-3- (2'-hydroxyethylmethyl) amino] piperidine 25 5 imipramine 25 4 5 1 It can be seen that the antidepressant activity of the compounds the present invention compares very favorably with that of the known drug Compare imipramine. For this reason, these compounds represent a preferred one Class of compounds of general formula I.

It has also been found that compounds of formula Ib, e.g. 1-methyl-4-phenyl-4-benzylamino-3-hydroxypiperidine, among other things also show local anastetic and antiarrhythmic activity.

Thus, a further object of the invention is a medicament, which is characterized in that it is at least one essential active ingredient Compound of Formula I or a pharmaceutically acceptable acid addition salt together with a pharmaceutically acceptable carrier.

The medicaments according to the invention are preferably administered orally, rectally or administered parenterally. The medicament is advantageously in a Unit dosage form corresponding to the desired mode of administration. For example, the dose unit can be a tablet, capsule, pill, powder, packet, a granule, cachet, elixir, suppository, or measured Amount of a suspension, solution, syrup or a mixture thereof. The here Designation used!? Dosage unit form !? should be physically separate units denote that are suitable as unit doses for humans and animals are and each contain a preselected amount of the active ingredient to be in the mixture or in company with the pharmaceutical carrier deu desired therapeutic Effect. The amount of the active ingredient is such that normally one or more units required for a single therapeutic administration or 5 in the case of separable units, e.g. notched + tablets, at least a fraction, e.g. half or a quarter that is separable Unit required for a single therapeutic administration.

The medicaments according to the invention usually contain the active ingredient in an amount of at least 0.5% by weight, based on the total weight of the drug, and in an amount of at most 95% by weight. Suitably contain the invention Drugs when in unit dosage form, 0.5 to 100 mg, preferably 5 to 50 mg, of the active ingredient of formula I.

The medicaments according to the invention normally consist of at least a compound of the formula I, advantageously a compound of the formula III, and particularly advantageously a compound from the preferred groups, such as they are defined by Formula Ia, or a pharmaceutically acceptable acid addition salt thereof in admixture with a carrier or diluted by a carrier or with a Carrier filled or encapsulated, e.g. in the form of a capsule, a pillow, a paper and the like. The carrier, also as a vehicle, diluent or extender for the therapeutically active ingredient is used, a solid, be a semi-solid or a sterile liquid.

Some examples of carriers that can be used for the medicaments according to the invention can be used are lactose, dextrose, sorbitol, mannitol, starch, such as wheat starch, Corn starch or potato starch, acacia gum, calcium phosphate, liquid paraffin, Cocoa butter, theobroma oil, alginates, tragacanth gum, gelatine, syrup, methyl cellulose, Polyoxyethylene sorbitol monolaurate and methyl and propyl hydroxybenzoates. The choice of the carrier is determined by the preferred mode of administration, the solubility of the compound and by the standard pharmaceutical practice. Details can be found e.g. in "Remington's Practice of Pharmacy "by E.W. Martin and E.F. Cook. In the case of tablets, can A lubricant can be added to prevent adhesion of the powdered ingredients in the parts of the press of the tableting machine. For such purposes can e.g. talc, aluminum, magnesium or calcium stearate or polyethylene glycols (Carbowaxes) with suitable molecular weights can be used.

The medicaments according to the invention can in addition to the 4-arylpiperidine active ingredient contain one or more physiologically active ingredients, the desired effects demonstrate.

Some examples of preparations according to the invention are given below indicated: Preparations Preparation 1: For oral administration can with Sugar coated tablets can be used that have the following composition and which are produced in the usual way: component Amount (mg) of 1-methyl-4-phenyl-4-hydroxy-3- (N-aminoadamantyl) piperidine 25 lactose 60 starch 50 sugar 75 talc 5 gum arabic 5 preparation 2: capsules used in conventional Ways to be prepared can have the following composition: Ingredient narrow (mg) 1-methyl-4-phenyl-4-hydroxy-3- (4-morpholinyl) piperidine 5 lactose 145 The specific compounds mentioned above can of course also be replaced by others Active ingredients according to the invention, e.g. by 1-methyl-4-phenyl-4-acetoxy-3-pyrrolidinylpiperidine be replaced.

As already stated, it was found that the connections of formula I have usable biological properties, since they affect e.g. the central nervous system have an antidepressant effect. Compounds with such activity can be considered potential Medicines in the form of pharmaceutical preparations are of therapeutic value, as they are in the administration Effects on humans and animals point to the central nervous system. Such effects on the central nervous system show up, for example, when a therapeutically effective dose is given to humans or animals of one or more of the active ingredients of the formula I (preferably an active ingredient of the formula III and most preferably an active ingredient of the formula Ia) administered, taking into account the CNS symptom to be treated, the age, the state of health and the weight of the patient, the severity of the symptom, the type of concomitant treatment etc., taking into account the precise nature of the effect desired. In practice has been found on the basis of standard pharmacological animal examinations, particularly in mice, it has been shown that administration in dosages of 1 to 100 mg of active ingredient per kg of body weight of the animal, the aforementioned CNS effects causes without any pronounced side effects.

The invention is illustrated in the examples.

Example 1 1 -Methyl-4-phenyl-4-hydroxy-3- (1 -piperidyl) piperidine and its hydrochloride: a mixture of 2.81 g of 1-methyl-4-phenyl-3,4-epoxypiperidine and 1.5 g of piperidine in 10 ml of ethylene glycol was in an oil bath overnight (18 h) heated to 1500C. In a repeated attempt, heating to 1400C gave over a shorter period of 3 hours produces the same result. The reaction mixture was then cooled, with 25 ml of water are added and then three times extracted with an equal volume of methylene chloride. The obtained organic Fractions were washed with a saturated sodium chloride solution over anhydrous Sodium sulfate dried, filtered and finally evaporated in vacuo, whereby added 3.61 g of raw 1-methyl-4-phenyl-4-hydroxy-3- (1-piperidyl) piperidine in the form a resinous residue. The residue was dissolved in ethyl acetate dissolved and filtered through a layer of silica gel.

This compound was then converted into its monohydrochloride, by forming a solution in methanol, one equivalent of NHCl was added and the resulting solution was evaporated to dryness in vacuo. About the residue additional servings of ethanol were added and in each case the resulting Solution evaporated to dryness. The final residue, which is the desired hydrochloride was recrystallized from acetone to give a product with a Melting point of 241 to 242 0C obtained. By thin layer chromatography, IR and NfR spectroscopy found the free base to be pure. The structure of the Hydrochloride was determined by NFIR spectroscopy and elemental analysis. Elemental analysis of the hydrochloride salt was as follows: Calculated C H N Cl: 65.68 8.76 9 '01 11.41 found: 65.48 8.57 8.72 11.62 Example 2 1-methyl-4-phenyl-4-acetoxy- (1 -piperidyl) piperidine and its hydrochloride: A solution of 0.9 g of 1-methyl-4-phenyl-4-hydroxy-3- (1 piperidyl) piperidine hydrochloride in 10 ml of water became alkaline with sodium carbonate and the mixture was extracted with methylene chloride. The organic fraction was evaporated in vacuo. To the residue were added 2 ml of pyridine and 1 ml of acetic anhydride and the resulting solution was allowed to stand at ambient temperature for 1 hour. A portion of water was then added to the solution and, after stirring, the obtained Mixed solution over a period of 1 hour, the mixture was again made with sodium carbonate made alkaline, extracted with methylene chloride and evaporated to dryness, whereby 0.50 g of the peeled product of the free Bse was obtained. The free base was converted into its hydrochloride by the method of Example 1. The resulting 1 -Methyl-4-phenyl-4-acetoxy-3- (1-piperidyl) piperidine hydrochloride had a ° Melting point from 177 to 178 ° C.

Thin layer chromatography indicated the product to be pure. the Structure was confirmed by IR and NMR spectroscopy.

Example 3 1-Methyl-4-phenyl-4-hydroxy-7- (4-morpholinyl) piperidine and its hydrochloride: A mixture of 2.7 g of 1-methyl-4-phenyl-3,4-epoxypiperidine and 1.5 g of morpholine, dissolved in 3 ml of ethylene glycol, was in an oil bath for 3 h Heated at 1500C. The reaction mixture was then cooled and 5 ml of water became added, giving 2.84 g of the desired free base in crystalline form became. An analytical sample obtained by recrystallization from acetone / ether a melting point of 154 to 1560C.

Using the method of Example 1, 1-methyl-4-phenyl-4-hydroxy-- (4-morpholinyl) piperidine hydrochloride. The melting point was 239 bis 2400C.

Elemental analysis: C H N Cl calculated: 61.42 8.06 8.96 11.35 found: 61.11 8.37 8.85 11.85.

Example 4 1 -Methyl-4-phenyl-4-acetoxy-3 (4-morpholinyl) piperidine and its hydrochloride: 1.5 g of 1-methyl-4-phenyl-4-hydroxy-3- (4-morpholinyl) pipe 3 ml of acetic anhydride was dissolved in ridin and the resulting solution became Heated to 600C for 5 min. After cooling, water was added to the reaction mixture and after making alkaline with sodium carbonate, 1.6 g of des were deposited as a precipitate Desired 1-methyl-4-phenyl-4-acetoxy-3- (4-morpholinyl) piperidine in crystalline shape obtain. Recrystallization from methanol yielded a sample with a melting point from 119 to 1200C.

Following the method of Example 1, the corresponding hydrochloride was obtained obtain. The melting point was 186 ° to 187 C.

Example 5 1-Methyl-4-phenyl-4-propionyl-3- (4-morpholinyl) piperidine and its hydrochloride: a solution of 1.5 g of 1-methyl-4-phenyl-4-hydroxy-3- (4-morpholinyl) piperidine and 0.1 ml of BF3 etherate (48% of its complex) in 2 ml of propionic anhydride was added for 5 min heated to 600C. After cooling, ice was added and the solution was over Left at night. The solution was then made alkaline with sodium carbonate ' extracted three times with methylene chloride, dried with sodium sulfate, filtered off and finally evaporated to dryness. It became an oily residue with a Yield of 1.6 g obtained. The KR and NMR spectra showed that it was the desired 1-methyl-4-phenyl-4-propionyl-3- (4-morpholinyl) piperidine.

Following the method of Example 1, the free base was converted into the corresponding Converted to hydrochloride. This was made from ethyl acetate in the form of crystals with a melting point mn 160 to 1630C recrystallized.

Example 6 1-Methyl-4-phenyl-4-hydroxy-3- (N-adamantylamino) piperidine and its hydrochloride: a mixture of 1.5 g of 1-methyl-4-phenyl-3,4-epoxypiperidine and 1.5 g of aminoadamantane in 5 ml of ethylene glycol was left on in an oil bath overnight Heated at 1500C. The reaction mixture was cooled and 5 ml of water were added, whereby a precipitate formed. The reaction mixture was washed three times with methylene chloride extracted. The organic fractions thus obtained were washed with sodium chloride, dried over sodium sulfate, filtered and finally evaporated, leaving 2.83 g of the desired 1-methyl-4-phenyl-4-hydroxy-3- (N-aminoadamantyl) piperidine are obtained were which, after partial crystallization from hexane, had a melting point of 92 to 940C.

Following the method of Example 1, the free base was converted into its hydrochloride converted, which had a melting point of 220 to 2220C.

Example 7 (a) 1 -Methyl-4-phenyl-4- (1 -pyrrolidinyl) -3-hydroxypiperidine: A mixture of 3.8 g of 1-methyl-4-phenyl-3,4-epoxypiperidine and 1.6 g of pyrrolidine in 10 ml of ethylene glycol was heated to 1500C overnight, albeit a repeated one Experiment showed that heating for 3 hours is sufficient was. To After cooling, the resulting solution was treated as described in Example 1 and 4.6 g of residue was obtained. This residue was dissolved in acetone. After standing, 0.81 g of a crystalline material having a melting point was obtained obtained from 149 to 151 0C. Thin-layer chromatography and IR and NMR spectroscopy showed that the compound was pure and that it was 1-methyl-4-phenyl-4- (1st -pyrrolidinyl) -3-hydroxypiperidine.

(b) 1-methyl-4-phenyl-4-hydroxy-3- (1 -pyrrolidinyl) piperidine and its hydrochloride: the mother liquor obtained from part (a) became after removal of the crystalline precipitate was evaporated to dryness to give a product which was shown by the IR and NMR spectra to be 1-methyl-4-phenyl-4-hydroxy-3- (1 -pyrrolidinyl) piperidine. The product had been recrystallized several times a melting point of 110 ° C.

Following the method of Example 1, the free base was converted into the corresponding converted to liydrochlorid. Its structure was confirmed by the IR spectra. After repeated recrystallization, the melting point was 186-1880C.

Example 8 1 -Methyl-4-phenyl-4- (N-benzylamino) 3-hydroxyiperidine and its ilydrochloride: A mixture of 3.7 g of 1-methyl-4-phenyl-3,4-epoxypiperidine, 2.5 g of benzylamine and 10 ml of ethylene glycol were left on an oil bath at 150 ° C. overnight heated. After working up according to Example 1, 5.45 g of residue were obtained, from the 4.11 g of the desired free base 1 methyl-4-phenyl-4- (N-benzylamino) 3-hydroxypiperidine were isolated. This compound had a melting point of 162 to 164OC.

Following the method of Example 1, the free base was converted into the corresponding Converted to hydrochloride. The melting point was 191 to 1930C.

The structure of these two compounds was determined by IR and NMR spectroscopy and the elemental analysis confirmed. The latter gave the following for the free base Values: Elemental Analysis: N: 9.45 N: 9.61.

Example 9 1-methyl-4-phenyl-4-azido-3-hydroxypiperidine: 1.4 g sodium azide (NaN3) in 6 ml of water were added to a solution of 3.6 g of 1-methyl-4-phenyl-3,4-epoxypiperidine placed in 20 ml of dioxane, and the resulting mixed solution was refluxed for 2 hours cooked. Another portion of 1.4 g of NaN3 in 6 ml of water was then added and the reaction mixture was refluxed overnight. After cooling were 3.2 g crystals of the desired 1-methyl-4-phenyl-4-azido-3-hydroxypiperidings obtain. The melting point was 170 to 1710 c.

The structure of this compound was determined by IR and NMR spectroscopy and the elemental analysis as well as by the relationship to the derivatives according to examples 10 to 13 confirmed.

Elemental analysis: Calculated: C, 62.05, 6.96, 24.12, found: 62.02 7.19 23.87.

Example 10 1 Methyl-4-phenyl-4-amino-3-hydroxypiperidine and be Hydrochloride: 0.95 & 1 1-methyl-4-phenyl-4-azidog-hydroxypiperidine were added to a solution of 0.7 g of lithium aluminum hydride in 50 ml of ether and the reaction mixture was moderately refluxed for 6 hours. Ethyl acetate was then added to destroy excess lithium aluminum hydride. Water was added slowly until no more precipitate formed. The resulting slurry was used several times extracted with methylene chloride. The methylene chloride solution was after drying filtered with sodium sulfate and evaporated to dryness, leaving 0.43 g more crystalline Obtain residue by IR and NMR spectroscopy as 1-methyl-4-phenyl-4-amino-3-hydroxypiperidine with a melting point of 148 was determined to 1490C.

Elemental analysis: N calculated: 13.58 found: 13.67 According to the method of Example 1, the free base was converted into the corresponding hydrochloride, which had a melting point of 176 to 1780C.

Example 11 1-Methyl-4-phenyl-4-amino-3-hydroxypiperidine: A solution from 2 g of 1-methyl-4-phenyl-4-azido-3-hydroxypiperidine in 20 ml of methanol became 12 h at 2.11 kg / cm2 in the presence of 100 mg of a catalyst composed of 5 palladium Hydrogenated carbon. The catalyst was filtered off and the resulting solution was evaporated to dryness, yielding 1.8 g of the desired 1-methyl-4-phenyl-4-amino-3-hydroxypiperidine were obtained. IR spectra, etc. showed that this product with the product of the Example 10 was identical.

Example 12 1 -Nethyl-4-phenyl-4-N-benzylidenimino-3-hydroxypiperidine: 160 mg of benzaldehyde was dissolved in 2.8 g of 1-methyl-4-phenyl-4 amino-3-hydroxypiperidine in 5 ml of methanol. A crystalline precipitate began to form after 10 minutes to form and the precipitation was completed after 1 hour. The crystals thus formed were filtered off.

The analysis showed that it is the desired 1-methyl-4-phenyl-4-N-benzylidenimino-3-hydroxypiperidine acted, which had a melting point of 187 to 1890C.

Example 13 1-Methyl-4-phenyl-4-N-benzylamino-3-hydroxypiperidine: 1.4 g of 1-methyl-4-phenyl-4-N-benzylidenimino-3-hydroxypiperidine were made into a Given a solution of 0.7 g of lithium aluminum hydride in 50 ml of tetrahydrofuran and that resulting mixture was gently refluxed for 3 hours. By adding ethyl acetate Excess lithium aluminum hydride was destroyed and then water became slow added until no more precipitate formed. The resulting slurry was extracted several times with methylene chloride and the organic fractions were dried with sodium sulfate, filtered and evaporated to give crystals a Substance obtained were determined by the melting point and IR spectra that it was with the compound of Example 8, i.e. with 1-methyl-4-phenyl-4-N-benzylami no-3-hydroxypiperidine, was identical.

Example 14 Trans-Pyridot3,4-b] -7-methyl-4-oxo-perhydro-9a-phenyl-1,5-oxazepine: 0.5 g of freshly distilled methyl acrylate were added to a solution of 1 g of 1-methyl-4-phenyl-4-amino-3-bydroxypiperidine placed in 5 ml of methanol and the resulting solution was two days at ambient temperature ditched. After evaporation of the solution, 1.4 g of a crystalline Obtained product with a melting point of 148 to 1500C. By IR and NMR spectroscopy and elemental analysis showed that the product was the desired one trans-Pyridof3,4-b] -7-methyl-4-oxo-perhydro-9a-phenyl-1,5-oxazepine.

Example 15 1 -Methyl-4-phenyl-4-cyano-3-hydroxypiperidine and be Hydrochloride: A mixture of 1.9 g of 1-methyl-4-phenyl-3,4-epoxypiperidine, 600 mg NaCN and 5 ml of ethylene glycol were heated to 1200C in an oil bath overnight. A repeated tests showed that the heating time was greatly reduced could be, it was found that actually already 15 min is sufficient was. The resulting solution was cooled, whereby 0.78 g of a product was obtained which was recrystallized from methanol after filtering off. The wished Product had a melting point of 215 to 2180C. The implementation with hydrochloric acid in the usual manner provided the corresponding hydrochloride salt, which had a melting point from 238 to 2400C.

Example 16 1-Methyl-4-phenyl-4-cyano-3-acetoxypiperidine and his Hydrochloride: 1.5 g of 1-methyl-4-phenyl-4-cyano-3-hydroxypiperidine were in a Dissolved mixture of 2 ml of pyridine and 2 ml of acetic anhydride. The resulting The mixture was allowed to stand at room temperature for 1 hour. Part of water became then added to the reaction mixture and stirred for an additional 1 hour. Working up according to Example 4 yielded 0.8 g of the desired 1-methyl-4-phenyl-4-cyano-3-acetoxypiperidine. The reaction with hydrochloric acid in the usual way gave the corresponding hydrochloride salt, which had a melting point of 243-2500C.

Example 17 1-methyl-3-amino-4-hydroxy-4-phenylpiperidine and his Hydrochloride: 1.9 g of 1-methyl-4-phenyl-3,4-epoxypiperidine was concentrated in 20 ml Stirred aqueous ammonia solution and the mixture was 18 h in a pressure vessel (Oil bath temperature 120 to 1400C) heated. A repeated attempt already showed that heating for three hours was sufficient to achieve the same effect.

After cooling, the ammonia solution was evaporated to dryness. The residue was recrystallized from acetone to give 1.2 g of the desired product with a melting point of 136 to 1380C.

The free base was converted to its hydrochloride in the usual manner. The salt had a melting point of 186 to 188 C.

Elemental analysis: C H N Cl calculated: 59.37 7.89 11.54 14.60 found: 59.26 8.03 11.15 14.40.

Example 18 1-Methyl-4-hydroxy-4-phenyl-3- (N'-phenylcarbamido) piperidine: 500 mg of 1-methyl-3-amino-4-hydroxy-4-phenylpiperidine were dissolved in 5 ml of methylene chloride dissolved and to the mixture was added 260 mg of phenyl isocyanate at room temperature. After stirring for 15 minutes, the reaction was complete, as by thin layer chromatography was displayed. The solvent was removed in vacuo, the residue removed dissolved in ethanol and treated with 2.5 ml of 1N hydrochloric acid. The solvents were evaporated to dryness in vacuo and the residue was recrystallized from acetone. 750 mg of the intended crystalline product was obtained. This had after single recrystallization has a melting point of 223 to 225 C.

Example 19 1-Methyl-4-hydroxy-4-phenyl-3- (N-p-toluenesulfonamido) -piperidine and its hydrochloride: A mixture of 1.9 g of 1-methyl-4-phenyl-3,4-epoxypiperi din, 4 ml of ethylene glycol and 3.0 g of the potassium salt of p-toluenesulfonamide was at 1300C Stirred for 18 hours. The solvent was partially removed in vacuo and the The residue was diluted with H20 and then extracted with methylene chloride. To Evaporation of the solvent left 1.2 g of solid residue, which was the desired Product represented. The product was converted into the corresponding hydrochloride salt in the usual manner converted, which had a melting point of 255 to 2580C.

Example 20 1-Acetyl-3-dimethylamino-4-hydroxy-4-phenylpiperidine and its hydrochloride: 2.95 g of 1-acetyl-4-phenyl-3,4-epoxypiperidine, dissolved in 50 ml Ethanol, were saturated with gaseous dimethylamine. The mixture was at 18 h 900C heated in a pressure vessel. After evaporation of the solvent, 3.2 g were obtained of the remaining resin crystallized twice from ether, giving 1.9 g of des desired 1-acetyl-3-dimethylamino-4-hydroxy-4-phenylpiperidine were obtained, that melted at 118 to 1190C.

This product was converted into the corresponding hydrochloride salt in the usual manner with a melting point of 2300C (decomp.).

Example 21 1-Ethyl-4-phenyl-4-hydroxy-3- (4-morpholinyl) piperidine and its hydrochloride: a mixture prepared by adding 1.9 g (50 mmol) Lithium aluminum hydride to a solution of 1-acetyl-4-phenyl-4-hydroxy-3- (4-morpholinyl) piperidine in 50 ml of dry tetrahydrofuran, was refluxed for 3 hours. The reaction mixture was cooled and excess lithium aluminum hydride was carefully removed Addition of ethyl acetate destroyed. The solution was diluted with 5 ml of water, with Treated 5 ml of the above sodium hydride and finally treated with enough water, that a granular precipitate was formed, which was filtered off and treated with methylene chloride was washed.

The filtrate was further diluted with water and the resulting Mixture was extracted with methylene chloride. The combined organic extracts were dried over sodium sulfate and evaporated to dryness, yielding 2.5 g of the intended product were obtained in an impure form. The so obtained free Base was treated in the usual manner with one equivalent of hydrochloric acid in ethanol and then evaporated to dryness, producing the corresponding monohydrochloride was obtained in raw form. Recrystallization of the crude product from acetone provided the desired monohydrochloride as a rose solid with a melting point of 186 until 1870C.

Example 22 1-Ethyl-4-phenyl-4-acetoxy-3- (4-morpholinyl) piperidine and its hydrochloride: a solution of 1.0 g of 1-ethyl-4-phenyl-4-hydroxy-3- (4-morpholinyl) piperidine, 5 ml of acetic anhydride and 5 drops of boron trifluoride etherate were refluxed for 1 hour cooked. The reaction mixture was cooled in an ice bath and washed with 10 ml of water offset. The cooled aqueous solution was then brought to a pH of 9 with Set IOiger sodium carbonate solution and extracted with methylene chloride. the organic fraction was then dried over sodium sulfate. The concentration in the vacuum of the dried solution yielded 1.2 g of crude 1-ethyl-4-phenyl-4-acetoxy-3- (4-morpholinyl) piperidine and its hydrochloride as a dark oil. The raw product was purified by column chromatography with a silica column, taking methylene chloride was used as an eluent. This resulted in 0.73 g of pure product in Obtained in the form of an oil that solidified on standing.

The free base was converted into the corresponding monohydrochloride with a Melting point from 147 "to 1480C converted by using their ethanol solution one equivalent of hydrochloric acid was treated.

Example 23 1-Methyl-4-p-tolyl-4-hydroxy-3- (4-morpholinyl) piperidine and its hydrochloride: A solution of 5 g of 1-methyl-4- (4-tolyl> 3,4epoxypipe Ridine, 5 g of morpholine and 5 ml of ethylene glycol were left on an oil bath at 1500C for 3 h heated. The resulting solution was cooled, diluted with water, and with methylene chloride extracted. The organic fraction was dried over sodium sulfate and in vacuo evaporated to give 6.55 g of crude product as a brown solid. the Purification which included a step in which the crude product was suspended in cyclohexane yielded 3.25 g of the objective 1-methyl-4-p-tolyl-4-hydroxy-3- (4-morpholinyl ) piperidins as a creamy crystalline product with a melting point of 128 to 131 0C.

The free base thus obtained was in her monohydrochloride with a Melting point of 1370C (dec.) Converted by using an isopropanol solution of it one equivalent of hydrochloric acid was treated.

Example 24 1-Methyl-4-p-tolyl-4-acetoxy-3- (4-morpholinyl) piperidine and its hydrochloride: a solution of 1.3 g of 1-methyl-4-tolyl-4-hydroxy-3- (4-morpholinyl) piperidine in 3 ml acetic anhydride was heated to 60 ° C. for 30 minutes. The solution was cooled, diluted with water and the pH was adjusted to 7 with sodium bicarbonate. The resulting solution was extracted with methylene chloride and the organic Phase was dried over sodium sulfate. The concentration in the Vacuum provided the crude acetate product as a dark oil. Filtration of an ethyl acetate solution of the crude product through silica gel gave 1.2 g of the pure desired free base as a solid.

The free base was converted into the corresponding monohydrochloride in the usual manner converted. The hydrochloride had one after recrystallization from isopropanol Melting point of 1740C.

Example 25 1-Benzyl-4-hydroxy-3-morpholino-4-phenylpiperidine: One Solution of 1-benzyl-3, 4-epoxy-4-phenylpiperidine and 12 ml of morpholine in 25 ml Ethylene glycol was heated to 1500C on an oil bath for 45 minutes. The reaction mixture was cooled to room temperature and poured into 75 ml of water. The resulting aqueous solution was extracted with methylene chloride and the organic phase became dried over sodium sulfate and concentrated in vacuo to give 15 g of an oily Solid were obtained. Recrystallization of the solid from ethyl acetate provided 7.2 g of 1-benzyl-4-hydroxy-3-morpholino-4-phenylpiperidine as a white solid with a melting point of 147.5 to 148OC Elemental analysis: C22H28N2O2 calculated: C 74.96 H 8.01 N 7.95 found: C 75.17 H 8.08 N 7.88.

Example 26 4-Hydroxy-3-morpholino-4-phenylpiperidine: A solution of 5.6 g (0.016 mol) of 1-benzyl-4-hydroxy-3-morpholino-4-phenylpiperidine and 18 ml 7N hydrochloric acid in 100 ml of distilled methanol was in the presence of a catalytic Amount of 10% palladium on charcoal hydrogenated at 50 ° C. for 4 h. The solvent was removed in vacuo and the residue was dissolved in water to give a aqueous solution was obtained which was made alkaline with 10% sodium hydroxide and then extracted with methylene chloride. The organic phase was over sodium sulfate dried and evaporated to give a pink solid. The recrystallization this solid from ethyl acetate yielded 3.5 g of 4-hydroxy-3-morpholino-4-phenylpiperidine as a white solid with a melting point of 117.5 to 1180C.

Elemental analysis: calculated: C 68.67, H 8.45, N 10.68 found: C 68.53 H 8.71 N 10.87.

Example 27 1-L3- (1-phenyl-1-oxo) propyl] -4-hydroxy-4-phenyl-3-pyrrolidinopiperidine and its hydrochloride: 708 mg of 3-chloropropiophenene and 2 ml of triethylamine were added a suspension of 1.0 g of 4-hydroxy-4-phenyl-3 pyrrolidinopiperidine added to 50 ml of benzene and the resulting mixture was refluxed for 30 minutes.

The resulting triethylamine hydrochloride was filtered off and that The filtrate was washed with 2N hydrochloric acid. The aqueous solution was made with solid sodium carbonate made alkaline and extracted with methylene chloride. The organic phase was dried over sodium sulfate to give 1.5 g of an oily solid. The solid base was converted to its hydrochloride salt and recrystallization from acetone gave 1- L 3- (1-phenyl-1-oxo) propyl] -4-hydroxy-4-phenyl-3-pyrrolidinopiperidine hydrochloride as a white solid with a melting point of 161.5 to 1630C.

Example 28 1-L3- (1-Hydroxy-1-phenyl) propyl] -4-hydroxy-4-phenyl-3-pyrrolidinopiperidine and its hydrochloride: 312 mg of sodium borohydride were added in portions to a stirred Solution of 3.1 g of 1-t3- (1-phenyl-1-oxo) -4-hydroxy-4-phenyl-3-pyrrolidinopiperidine given in 25 ml of ethanol. The resulting mixture was allowed to stand for an additional 15 minutes at room temperature touched. The solution was diluted with water and the aqueous solution was made with methylene chloride extracted. The organic phase was dried over sodium sulfate and in vacuo concentrated to give 3.2 g of a foam-like product. The raw one Base product was converted to the hydrochloride salt. The recrystallization of the Acetone salt provided 0.7 g of 1-03- (4-hydroxy-1-phenyl) propyl] -4-hydroxy-4-phenyl-3-pyrrolidinopiperidine hydrochloride as white solid with a melting point of 178 to 180 C.

Example 29 1 - (Dimethylcarbamoylmethyl) -4-hydroxy-4-phenyl-3-pyrrolidinopiperidine and its hydrochloride: a solution of 6.0 g of 1- (dimethylcarbamoylmethyl) -3,4 epoxy-4-phenylpiperidine and 3 ml of pyrrolidine in 20 ml of ethylene glycol was 30 min on an oil bath at 140C heated. The reaction mixture was diluted with water and the resulting aqueous Solution was extracted with methylene chloride. The organic phase was over sodium sulfate dried and concentrated in vacuo to give 7.0 g of crude product, after recrystallization from ethyl acetate, 2.9 g of 1- (dimethylcarbamoylmethyl) -4-hydroxy-4-phenyl-3-pyrrolidinopiperidine as a white solid with a melting point of 1320 to 1330C. The base was recrystallized from ethyl acetate to obtain an analytical sample.

Elemental analysis: C1 9H29N302 calculated: C 68.85 H 8.82 N 12.68 found: C 69.16 H 8.98 N 12.84.

The corresponding hydrochloride salt was prepared in the usual way. After recrystallization from acetone, it had a melting point of 122 to 124 ° C.

Example 30 1-E2- (N, N-dimethylcarbamoylethyl)] - 4-hydroxy-4-phenyl-3-pyrrolidinopiperidine: 2.3 g of 3-bromodimethylpropionamide and 6 ml of triethylamine were made into a suspension of 3.0 g of 4-hydroxy-4-phenyl-3-pyrroZidinopiperidine in 120 ml of dry benzene and the mixture was refluxed for 20 hours.

The triethylamine hydrobromide was filtered off and the solvent was evaporated to give an oil which after recrystallization from ether 1.0 g 1-t2- (N, N-dimethylcarbamoylethyl)] -4-hydroxy-4-phenyl-3-pyrrolidinopiperidine delivered as a solid with a ° melting point of 112 to 113 C.

Example 31 1-S3- (N, N-Dimethyl) propylamino] -4-hydroxy-4-phenyl-3-pyrrolidinopiperidine and its hydrochloride: 8 ml of a Red Al stock solution (70% in benzene) were in 40 ml of dry benzene was dissolved and the resulting solution was added dropwise the 2.5 g of 1- [2- (N, N-dimethylcarbamoylachyl)] - 4-hydroxy-4-phenyl-3-pyrrolidinopiperidine are added to a stirred solution in 2C ml of dry benzene at room temperature. The reaction was slightly exothermic and the reaction mixture was stirred at room temperature for 30 minutes. 30 ml 10% / ige Sodium hydroxide solution was added dropwise to the above stirred solution which are chilled in an ice bath became. The mixture then became again stirred at room temperature for 20 minutes. The layers were separated from each other and the benzene solution was washed with brine, dried over sodium sulfate and finally concentrated in vacuo to give 2.1 g of a beige solid became. Upon stirring with ether, 1.2 g of 1- [3- (N, N-dimethyl) propylamino] -4-hydroxy-4-phenyl-3-pyrrolidinopiperidine was obtained obtained as a white solid which, after recrystallization from acetone, is an analytical sample with a melting point of 127 to 1280C.

Elemental analysis: C20H33N30 calculated: C 72.46 H 10.03 N 12.68 Found: C 72.15 H 10.29 N 12.52.

The corresponding hydrochloride salt was prepared in the usual way. The melting point after recrystallization from acetone was 222 to 2250C.

Example 32 4-Hydroxy-3-morpholino-4-phenyl-1-propargylpiperidine and its hydrochloride: a solution of 7.78 g of 3,4-epoxy-4-phenyl-1-propargylpiperidine and 8 ml of morpholine in 25 ml of ethylene glycol was 45 min on an oil bath at 1400C heated. The resulting solution was allowed to stand overnight and during this A solid separated out over time. The solid was extracted with ethyl acetate stirred, whereby 4.3 g of 4-hydroxy-3-morpholino-4-phenyl-1-propargylpiperidine as white solid with a melting point of 177-1800C were obtained.

Elemental analysis: C18H25N202Cl calculated: C 64.17 H 7.48 N 8.32 found: C 64.13 H 7.63 N 8.47.

The corresponding hydrochloride salt was prepared in the usual way and recrystallized from isopropanol / ethanol to a melting point of 195 to 1960C.

Example 33 3-Morpholino-4-phenyl-1-propargyl-4-propionoxypiperidine and its hydrochloride: 2 ml of propionyl chloride was added dropwise to a solution of 2.1 g of 4-hydroxy-3-morpholino-4-phenyl-1-per pargylpiperidine and 2 ml of triethylamine in 25 ml of dry methylene chloride which had been cooled in an ice bath. The reaction mixture was stirred at room temperature for 30 minutes. The solvent was evaporated and the residue was partitioned between 10% sodium carbonate solution and ethyl acetate divided. The organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuo to give 2.6 g of an orange Solid were obtained. This crude product was converted into the hydrochloride salt converted. Recrystallization of the salt from acetone gave 2.3 g of 3-morpholino-4-phenyl-1-propargyl-4-propionoxypiperidine hydrochloride as a solid with a melting point of 167.5 to 1680C.

Example 34 1- C4- (1-p-Fluorophenyl-1-oxo) butyl] -3-dimethylamino-4-hydroxy-4-phenylpiperidine and its hydrochloride: 2.0 g of sodium carbonate and a few crystals of potassium iodide became a solution of 1.5 g of 3,4-epoxy-4-phenylpiperidine and 1.4 g of t-chloro-p-fluorobutyrophenone given in 50 ml of 4-methyl-2-pentanone and the reaction mixture was refluxed for 24 h heated. The precipitated solid was filtered off and the solvent became removed in vacuo. The residue was partitioned between ethyl acetate and 2N hydrochloric acid. The aqueous solution was made alkaline with 10% NaOH and then with methylene chloride extracted. The solution of the organic phase was dried over sodium sulfate and finally concentrated in vacuo to give a dark red oil. This crude product was converted to the hydrochloride salt and crystallized from acetone; 1.7 g of a beige solid were obtained. Recrystallization from isopropanol / ethanol provided 1 - [4- (1 fluorophenyl-1 -oxo) butyl; i-3-dimethylamino-4-hydroxy-4-phenylpiperidine hydrochicride as a white solid with a melting point of 188 to 189 ° C.

Elemental analysis: C23H30N202ClF calculated: C 65.62 H 7.18 N 6.66 found: C 65.71 H 7.41 N 6.44.

Example 35 1- (p-Chlorophenylcarbamoylmethyl) -4-hydroxy-4-phenyl-3-pyrrolidinopiperidine and its hydrochloride: 1.02 g of chloro- (4-chlorophenyl) acetamide and 4 ml of triethylamine were to a suspension of 1.2 g of 4-hydroxy-4-phenyl-3-pyrrolidinopiperidine in 70 ml of benzene were added and the reaction mixture was refluxed for 3 h.

The mixture was diluted with water and the layers were separated. The benzene phase was washed with 1N hydrochloric acid and the aqueous solution was with solid sodium carbonate made alkaline and extracted with methylene chloride. the organic solution was dried over sodium sulfate. Concentration in a vacuum provided 2.0 g of a beige solid. The recrystallization of the solid Ethyl acetate provided 1.6 g of 1- (p-chlorophenylcarbamoylmethyl) -4-hydroxy-4-phenyl-3-pyrrolidinopiperidine as a white solid with a ° melting point of 149 to 150 C.

Elemental analysis: C23H29N302C12 calculated: C 61.33 H 6.49 N 9.33 found: C 61.26 H 6.80 N 9.55.

The corresponding hydrochloride salt was made and made from ethanol recrystallized. The melting point was 213 to 2140C.

Example 36 As has already been stated, the inventive Compounds made directly or indirectly from suitable 3, 4-epoxypiperidines will. The preparation of representative examples of 3,4-epoxypiperidines, which were used in many of the examples described: (a) 3,4-epoxy-4-phenylpiperidine: A solution of 33.6 g of bromine and 60 g of sodium bromide in 450 ml of water was added dropwise with stirring to a solution of 50 g of 4-phenyl-1,2,5,6-tetrahydropyiidine hydrobromide in 600 ml of water and the reaction mixture was then 30 min at room temperature touched.

The solution was stirred on an ice bath while 252 ml of 10% Na trium hydroxide solution were added dropwise. The resulting mixture was then stirred at room temperature for a further 30 minutes. The aqueous solution was with Extracted methylene chloride and the solution of the organic phase was over sodium sulfate dried and then concentrated in vacuo, yielding 25.2 g of the desired 3,4-epoxy-4-phenylpiperidine were obtained as an oil.

(b) 1 -Benzyl-3, 4-epoxy-4-phenylpiperidine: 22.5 ml of benzyl bromide were stirred dropwise into one Solution of 32.3 g of 3,4-epoxy-4-phenylpiperidine and 38.1 ml of triethylamine in 254 ml of benzene.

A precipitate occurred during the addition. The entire reaction mixture was then stirred at room temperature for 3 hours. The remaining solid was removed by filtration and the solvent evaporated to give 53.4 g of 1-benzyl-3, 4-epoxy-4-phenylpiperidine were obtained.

(c) 1-methyl-4-p-tolyl-3,4-epoxypiperidine: 52 ml of a sodium hydroxide solution 100 above were added dropwise to a stirred solution of 22.08 g of the corresponding bromohydrin hydrochloride given in 500 ml of water. The solution was cooled in an ice bath during the addition. After the addition was complete, the reaction mixture was allowed to stand at room temperature for 70 minutes touched.

The resulting solution was saturated with potassium carbonate, whereby a precipitate was obtained which was filtered off. The precipitate was with Washed water and dried at room temperature, yielding 12.6 g of the desired 1-methyl-4-tolyl-3,4-epoxypiperidine as a white solid with a melting point from 55 to 57 ° C were obtained.

(d) 1-Acetyl-3,4-epoxy-4-phenylpiperidine: 6.0 g of 85% m-chloroperbenzoic acid were added in portions to a solution of 5.8 g of 1-acetyl-4-phenyl-1,2,5,6-tetrahydropyridirl, dissolved in 100 ml of methylene chloride, given. The latter was during the addition in one Chilled ice bath. The mixture was left at room temperature for 18 hours stirred, then with water, a sodium bisulfite solution, a sodium carbonate solution and finally washed back with water. After evaporation, 4.8 g of one remained Solid back, which was recrystallized from ether. That way were 3.9 g of the desired product with a melting point of 68 ° to 71 ° C. were obtained.

(e) 1 - (Dimethylcarbamoylmethyl) -3,4-epoxy-4-phenylpiperidine: One Solution of 1.66 g (0.01 mol) of bromodimethylacetamide in 5 ml of benzene was added dropwise to a stirred solution of 1.75 g (0.01 mol) of 3,4-epoxy-4-phenylpiperidine and Put 2 ml of triethylamine in 20 ml of benzene.

A precipitate occurred during the addition. The reaction mixture was stirred for 30 min at room temperature.

The solid (triethylamine hydrobromide) was filtered off and the resulting solution was evaporated, yielding 2.6 g of 1- (dimethylcarbamoylmethyl) -3,4-epoxy-4 phenylpiperidine as a yellow oil.

Following the procedures of the preceding examples, those in the following Tables listed compounds prepared, with the corresponding starting materials were used and, if necessary, the reaction conditions were changed.

In Table I, all compounds are those of the formula III in which R1 is methyl and R4 is hydrogen.

Table I. At- RR melting point (° C) game 2 3 base HCl salt 37) -NH-CH 2 -CH 20H -OH - 196-198 38) CH3 -N-CH2-CH20H-OH - 210-212 39) -OH -β-CH2 to -183-185 CH3 40) -2N-CH2 t -OH 160-162 I. CH3 41) -OH -NH <- 151-153 42) -OH -N-CH2-CH2OH 193-196 CH3 43) -OC-CH3 zr 163-164 O 44) -OH / -7 186-188 45) -OC-CH2CH3 oil II O -N 46) OC-CHs -N-CH2 - 166-168 O CH3 47) -OH o CH3 223-225 CH3 . CH3 4 8) -N / (approx.) XCH3 (approx.) Table I continued At- R2 R melting point (0C) play R2 3 base HCl salt CH3 ° -OC-CH3 ö1 CH3 50) -NHCH3 -OH 134-135 - 51) -OH -NH-SO2 4CH3 - 255-258 52) -OH CH3 - 121-125 (very hygros- -NH-C-CH3 copy) CH3 0 53) -OC-CH3 CH3 - 214216 -NIl-C-CH3 CH3 0 54) -OC-CH3 / CH3 - 161-163 dec. -N XCH3 555 -OH / CH3 - 194-195 (2 HCl) -NH-CB CH3 0 56) -OC-CH3 / CH3 - 177-177.5 NH-CHX CH3 0 57) -OC-CH3 / Ph - 107-109 -NH-CH Ph 58) -OH / Ph- 221-223 -NH-CHv Ph Table I continued At- RR melting point (° C) game 2 3 base HCl salt -Salt -OH CH3-67-73 -§-CH2-CH3 0 60) -OC-CH3 / CH2-CH3 - 157-158 -N CH2-CH3 0 61; -OC-CH3 KCH3 - 172-173 CH2-CH3 62) -OH H3 - maleate salt Melting point -NH-C-CH2-OH 155-156 CH3 63) -OH CH2-CH2-OH - 137-141 CH2-Ph 64) -OH - 158-162 -NH-CH-CH2-Ph CH3 65) -OH / CH2-CH3 ~ 178-181 -Ns CH2-CH3 66) -OH -NH-CH2-CH2-COOCH3 - 194-196 67) -OH -NK-CO-NK t ~ 223-225 0 68) -0-C "-0H3 -NH-CH2-CH2-COOCH3 - 139-141 Table I continued At- RR melting point (0C) play R2 3 base HCl salt 69) -N3 -O-CO-CH2-CH3 - 210-212 70) -OH -NH-CH3 235-236 (2 HCl) 71 * -OH -NH- 183-185 O 72) -oC-C2H5 "114-115 O CC; O = C: C2H5 0 73) -O-C11-CH3 -NH-C) 155-157 0 74) -OC-CH3 -NH- 181 75) -OC-C2Hs -NH - 150 0 76) -OC-CH3 -N 131-133 C. CH3 77) -OH -NH to -126-129 od CH3 78) -OC-CH3 * NHCH X -Gs to 163 CH2 0 79) -0-C-C2H5 -Nç 129-130 - 79) -OC-C2HS -N- C2H5 Table I continued At- R3 R, melting point (° C) play R2 base HCl salt 0 80) OC11-C2Hs -NH-0 172-173 0 1 CH3 81) -OC-CH3 - * NH-CH - 162 CtH2Ö 0 82) -OC-CH3 -NH-Nt ~ sQ 184-184.5 O l CH3 83) -OC-CH3 -N-CHuCH t - 164-165 CH3 o CH3 1 1 84) -OC-CH3 ~ aN-CHsCH2 3 15Q-152 I. CH3 0 85) -OH -NH-II - 260-261 O 86) -OH -NH-C <267-270 o OCH3 87) -OH -NH-C 4 OCH3 187-189 OCH3 0 88) -OH -NH-C-CH2- o - 285-287 -NH-C-CH2 - Table 1 continued At- R2 R3 melting point base ~ ~ ~. . . O CH3 89) -OH -NH-CCO e Cl - 199-200 1 - CH3 90) -OH -NH-CH2cl Cl 228-230 919 -OH -NH-CH2 <222-225 1 E 5Pö 92 59 - 93) N7 -QC-CH «218-22G 0 949 -NH-C-CH3 -OH 172-173 - O CH3 959 -OH -NH-C-NH-CH 185-187 - CH3 0 92 -OH -NH-C-NH e CH3 ~ 152-154 Q 97) -OH -NH-C-NH-C2HS 130-132 - Table I continued At- RR melting point (° C) game 2 3 base HCl salt o CHJ I. 98) -OH -NH-C-NH 4 I3 65 0 Bi -OH ff NH-C4 4H 136-139 bEi - c ioic) -0E -MS-C-Ei 159-161 - 3 X 0s - 4PO-5E 0 -O-6-zH $ cag 0 -o, i Chs ao -o -N - C2- 3 245-248 0 IGZ 242 -NH - @ -% aH 0 1053 Ng - £ tC-NI - C 3 162 Table I continued At- R2 R3 melting point (Oc) match 3 base HCl salt 0 106) -OH -NH-C-C2H5-182-185 Q 107) -OH -NH-C-NH-NC, II -NH-CH-NC3H7 70 108) -QH -NH-C <C1 9 0 109> -NH-C-NH 109) -OH - 135 O OH. 110) -OH -NH-C1 - 254-256 0 - I. 111) -OC-C2H5 -NO d (+) O 112) -OC-C2H5 l (-) 1 154-156 113) -OH / 7 d (+) - 2123 Table I continued At- R2 R melting point (OC) match 3 base HCl salt . . . . 114) -OH -N 9 1 (-) - 209-211 O 115) -OH -NH-C-CH3 248 0 116) -OH -NH-C o F - 250-252 F. 0 117) -OH -NH-C t ~ 249-250 F. 118) -OH -NEI-C - 265-266 O CH3 II 1 119) -OH -NH-CC-CH3-225 CH3 0 120) -OH II -NII-C-NH2 - 200 0 1215 -O - C2H5 ~ to - 164-165 The compounds in Table II were obtained from 1-acetyl-3,4-epoxy-4-phenylpiperidine (Example 20). All compounds are those of the above formula III, in which R1 is —COCH3 and R4 is hydrogen.

Table II At- R2 R melting point (OC) match 3 base HCl salt 122) -NH-CH3 -OH-OII 243-245 163-166 - 123) -OH ~ -NO 124) -OH -N 147-150 - -N 9 The compounds in Table III were obtained from 1-methyl-4-p-tolyl-3,4-epoxypiperidine. All compounds are those of the formula III in which R1 is methyl and R4 is para-methyl.

Table III At- R R3 melting point (OC) play R2 3 HJl salt 125) OH ND 189-191 126) OH / CH3 9 -250 CEI3 12) OCO-CK3 / CEI3 1 ') 5-166 0113 cH3 128) OEI -NEt2 140-141 Table III continued At R2 R3 melting point (OC) play R2 R3 HCl salt O 129) OH -NEI-C-NH <200 130) OH 137 -NO 0 lt Im 131) -OC-CH3 ° - -NO 174 \ u The following compounds of the formula III, in which R4 is hydrogen, were prepared by the processes described above, naturally with an appropriate selection of the starting materials.

Table IV At- R1 R2 R3 Schme zunkt game ("c, Base HCl salt 0 132) -CH2-aI2-CH2-C11F -OH NacEI3 - 188-189 133) -CH2 e -OEI -N 0 147.5- - 148 134) -C Er, -C ~ CEr -OIi / Cfi i 134) -CH2-CsCH -OH / CfI3 - 202-203 CH3 Table IV continued At R1 game R1 R2 3 ("c) ' Base HCl salt . . . . . 135) -CH2-C <-OH -N - 194-196 OH3 0 136) -CH2-CECH -OCC2H5 / CH3 - 165-167 CH3 0 II -OH -N 0 146.5- - in the 147.5 138) -CH <-OH, CH3-180-182 CH3 , OH3 -fi CII, 131- 139) -H -OH 132.5 OH3 140) -0H2-OH3 -OH - 0 186-187 0 141.) -0H2-OH3 OC-OH3 -N-154-155 0 142) -C-CHg -NO -OH - 211-212 Table IV continued At- 3 R, R, Schmeunkt play R1 R2 R Base HCl salt 0 143) -CH2-CH3 OC-CH3 -NC - 142-143 0 144) -CH2-CH3 -OC-CH2CH3 -N - 146-147 145) -H -OH -Nt1 164-166 205-206 O 0 oo -OO-02H5 14 -CH2-CN = -OCC, H5 1l NS - OH3 0 147) -CH 2 -C -NH 43Cl -N -OH - 206.5- - 207 0 II / m 148) -CH2-C-NHeCl -OH -NuO O 179-181 0 1 ° 1 / CH3 CH / CHB 149) -C2-CH2-CN; -OH OH3 OH3 (oxalate Table IV continued At R1 R2 R3 melting point game (C) Base HCl salt o / 0H3. O II 150) -CH 2 -C-NX -0002115 0 151) -CH2-C-NH - N -N -OH ~ 206, 5 O 152) -OH r \ 179-181 152) -CH2-C-NHeCl -N - O OH3 / CH3 153) J -CH 2 -CH 2 -CH 2 -NscH 3 -OH - \ ~ 1 178-182 CH3 0 154) -OH2-OH2-OH2-OF -OH N3 177-179 in the 155) -CH2-CH2 t -OH / 3 - 200-202 O 156> -C- <) -OH -Ng - 182-185 15) -CHz-CH (OH) t3 -OH -NCl - 209211 Table IV continued At- R1 R2 R3 melting point game R2 3 (c) Base HCl salt 1 -CH2-CH (OH) rn is -CHz-CHtOH) -OH O-183-185 0 OH3 159) -OH -OCC2Hs CH3 154-156 CH3 0 160) II -C-NX -OH - 180-182 -0H2-ON ~~ 0 -OH -N 0 OH3 161) -CH2-C-NH- = r (CI -OH C11 3 '212-213 CH3 162) -CH2-CK2-CH2-N -OHN / 104-106 - CH3 0 163) -CHz-CHz-CH3 II rn - 161- 263) -CH2-CH2-CH3 -OCCHi -N 0 164> -CH 2 -CH = CH2 -OH -NO - 170-171 165) -CH2-CH = CH2 -OH-NS - 11774615 166) -CH2-CH = CH2 -N3 -OH - 208-209 Table IV continued Example R1 R2 R3 hot spot Base HCl salt 0 \ 167) -CH 2 -CH = CH 2. -OCC2H5-Nu) 7 170-172 0 168) -CH2-CH = CH2 -OCC2H5 NJ - 160-162 0 II Im 161-16 169) -CH2 -OCC2Hs NuO O O w 170) -CH2CH3 -OCCH3 yo 151-152 171) -CH2-CH2-CH3 -OH -NuÒ - 116-11E 0 172) -CHz ~ CECH -OCC2H5 -NWO 0 167.5- 168 173) -CH2-CECH -OH -N | -N - 142-14L O I 1 162-16c 174) -CH2-CECH -OCC2Hs -Nu 162-16 ' Table IV continued At- R1 R2 R3 Schm & l) point game Bas (V) Base HOi- salt . . 175) -CH2-CH = CH2 -OH CH3 - 167-168 N ' 0 OH3-177-181 II 176) -CH2-CH = CH2 -ocC2Hs -N \ CH3 0 0 177) -CH2-C e -OH -NH-C-NH t 179-182 0 0 178) -CH2-CH2-C-OH -NH-C-NH e 176-178 179 -OH t -OH -NH.2 143-145 0 180) -CH2 t -OH -NH-C-CH3 244-246 181) -OH2 -OH 0 OH3-236-238 Salt -CH 2- -OH -OH3 CH3 Table IV continued At- R1 R3 R Shmkt play R1 R2 Base HCl salt O OH3 III 182) -H-OH -NH-CC-CH3-215-217 CH3 0 O CH3 II II 1 183) -CH2-CH2-CN-CH3 -OH -NH-CC-CH3 - 203 CH3 CH3 0 184) -H -OH -NH-C-CH3 - 228- 228.5 l85) -CH2-CHC1 -OH -N / /, - 206- \ 0H3 206.5 0 O 186) -CH2-CH24; 3Cl -OC-CH3 -N \ i 159- CH3 160.5 187) -CH2-CH2OF -OH tNtl - 181-183 Table IV continued At- R1 R melting point game R1 3 (c) Base HCl salt -r? 188) -CH2-CHtF -OH ND 208.5 O 189) -CH2 -OH -NH-C-NHe - 164-167 190) -CHz-CH2CFCl -OH ~ N 1 ~ 192-194 O 191) -CH2t -OH -NH- £ -CH3 - 244-246 O CH3 II -CHrII 1 192) -OH2 -OH -NH-CC-CH3 3236-238 CH3 193) -OH2-OH2 -OH -N - 190-192 0 194) -CH2-C-NH e C1 O -OH 167-168 Table IV continued At- R1 R2 R3 melting point game Base base HCl salt 195) -CH2-CH (OH) -N3 ob - 209-211 0 -OH2-OU CH3 O 1963 -CH2-CN / -OC-CH3 -Nt1 - 160- 161.5 The following compounds were obtained according to the above examples, except that a starting epoxide was used in which R4 was an m-methoxy group and R1 was methyl.

Table V At- RR melting point (° C) match 3 base HCl salt alz 197) -OH N ~ O 160 «- in the 198) OCOCH3 NO 148-150

Claims (42)

Claims 1. 4-Aryl-3/4-amino / hydroxypiperidine derivatives of the general formula I: in which R1 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aralkyl, lower acyl, aminoalkyl, in which the alkyl part contains 2 to 6 carbon atoms and the amino part can be mono- or dialkyl-substituted or is a saturated cyclic amine radical, the group in which R, and R8 independently represent hydrogen, optionally halogen-substituted phenyl or lower alkyl or form a saturated alkylene chain with 5 or 6 ring members, which may contain an oxygen atom, and in which n is 1,2, 3 or 4 has the groups - (CH2) n-COOH, - (CH2) n ~ OHs where X is hydrogen or halogen and n is 1, 2, 3 or 4, one of the groups R2 and R3 stands for a cyano or a free amino group or a derivative thereof and the other stands for a free or protected hydroxyl group or R2 denotes an azido group when R3 denotes a free or protected hydroxyl group, or R2 and R3 together with the associated ring carbon atoms form an oxazepine ring, and in which, finally, Ar denotes an aryl group which can be substituted by lower alkyl, lower alkoxy, halogen or CF3 , as well as their addition salts with organic or inorganic acids. 2. 4-Arylpiperidines according to claim 1, characterized ge -kennzeic hnet that one of the groups R2 and R is an amino group of the formula: wherein R5 and R6 are independently hydrogen, a saturated alicyclic moiety having 5 to 7 carbon atoms, which can contain an oxygen atom in the ring, a lower alkyl group which is optionally substituted with a hydroxyl group or an ester moiety of the formula -COO-lower alkyl, a lower acyl group, a Lower aralkyl group, where the aryl part can be substituted by halogen, or mean an adamantyl group or mean a reactive derivative thereof, or together with the Stlokstõffatom ~ unZ üüd 'optionally an oxygen atom forms a 5- or 6-membered heterocyclic ring. 3. 4-arylpiperidines according to claim 2, characterized in that g e -k e n n z e i c Note that the amino group is a pyrrolidinyl, piperidinyl or morpholinyl group is. 4. 4-Arylpiperidines according to claim 2, characterized ge -kennzeic hnet that the reactive derivative is an amide of the formulas or a sulfonamide derivative of the formula -NH-S02R 'or a urea derivative of the formula -NH-CO-NHR ", where R is a lower alkyl group which is optionally substituted by a piperidine, di (lower alkyl) amino or p-chlorophenoxy group, a Furyl group or phenyl group, which can be substituted by halogen, hydroxy or methoxy, R1 is aryl, in particular phenyl, which can be substituted by lower alkyl, R "is hydrogen, lower alkyl, lower cycloalkyl, phenyl, which is optionally halogen, lower alkyl or trifluoromethyl is substituted, R "'is cycloalkyl or phenyl-lower alkyl and RIV is lower alkyl. 5. 4-arylpiperidines according to any one of the preceding claims, characterized I do not acknowledge that the protected hydroxyl group contains an ester part of the formula -OCOOR or an ether part of the formula -OR, where R is lower alkyl. 6. 4-arylpiperidines according to any one of the preceding claims, characterized it is not noted that the free or protected hydroxyl group is in the 4-position is present. 7. 4-arylpiperidines according to any one of the preceding claims, characterized Note that R1 is lower alkyl or lower aryl and that Ar Represents phenyl. 8. Process for the preparation of 4-aryl-3/4-amino / hydroxypiperidine derivatives of the general formula I: in which R1 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aralkyl, lower acyl, aminoalkyl, in which the alkyl part contains 2 to 6 carbon atoms and the amino part can be mono- or dialkyl-substituted or is a saturated cyclic amine radical, the group in which R7 and R8 independently represent hydrogen, optionally halogen-substituted phenyl or lower alkyl or form a saturated alkylene chain with 5 or 6 ring members, which optionally contain an oxygen atom, and in which n is 1, 2, 3 or 4 has the groups - (CH2) n-COOH, ~ (CH2) n- ° H, where X is hydrogen or halogen and n is 1, 2, 3 or 4, one of the groups R2 and R3 stands for a cyano or a free amino group or a derivative thereof and the other stands for a free or protected hydroxyl group or R2 denotes an azido group if R3 stands for a free or protected hydroxyl group, or R2 and R3 together with the associated ring carbon atoms form an oxazepine ring, and in which finally Ar is an aryl group which can be substituted by lower alkyl, lower alkoxy, halogen or CF3, means, and their addition salts with organic or inorganic acids, characterized in that the epoxy ring of a compound of the general formula IV: wherein R1 and Ar have the meaning given above, cleaving with a cleavage agent from the group consisting of ammonia, azides, cyanides or primary or secondary amines, the cleavage agent being selected so that the groups R2 and R3 desired in the product are obtained, and that if desired or necessary, a free hydroxyl and / or amino group R2 / R3 in the compound thus formed is converted into a derivative thereof by known procedures and a free base is converted into its acid addition salt with an organic or inorganic acid. 9. The method according to claim 8, characterized in that g e k e n n -z e i c h n e t that in a further stage a compound of the formula I thus formed is at the R1 is hydrogen by known alkylation or acylation processes in another compound of the formula I in which R1 has a meaning other than hydrogen has converted. 10. The method according to claim 8 or 9, characterized in that g e -k e n n z e i c It should be noted that the compound of the formula I obtained in this way has a keto group in the radical R1 Has and that one then this keto group by known methods partially or completely to the corresponding product with a hydroxy or Reduced methylene group in the radical R1. 11. The method according to claim 8 or 9, characterized in that g e -k e n n z e i c h n e t that in a further stage the compound of the general Formula I, in which Ri has a meaning other than hydrogen, dealkylated or deacylated to form the corresponding compound where R1 is hydrogen. 12. The method according to any one of the preceding claims, characterized in that an amine of the formula: used, wherein R5 and R6 are independently hydrogen, a saturated alicyclic moiety having 5 to 7 carbon atoms, which may contain an oxygen atom in the ring, a lower alkyl group which is optionally substituted with a hydroxyl group or an ester moiety of the formula -COO-lower alkyl, a lower acyl group , a lower aralkyl group in which the aryl part can be substituted by Pa logen, or an adamantyl group, or where the groups R5 and R6 together with the nitrogen atom and optionally an oxygen atom form a 5- or 6-membered heterocyclic ring. 13. The method according to claim 12, characterized in that g e k e n n -z e i c h n e t that the amine used is pyrrolidine, piperidine or morpholine. 14. The method according to any one of claims 8 to 11, characterized g e k e n n z e i c h n e t that if in the resulting compound of formula I R3 or R4 is an azide group, this azide group in a further stage according to known Methods reduced to an amino group. 15. The method according to any one of claims 8 to 14, characterized in that one free hydroxyl group in the 3- or 4-position in the corresponding ester of the formula or or ethers of the formula -OR, in which R is lower alkyl, by known esterification or alkylation processes. 16. The method according to any one of claims 8 to 15, characterized in that an amino group R3 or R4 is converted into the corresponding amide derivative of the formula by known methods or Sulfonamide derivative of the formula -NH-SO2R or urea derivative of the formula NH-CO-NHR "converts, in which R is a lower alkyl group which is optionally substituted by a piperidine, di (lower alkyl) amino or p-chlorophenoxy group, a furyl group or a Phenyl group, which can be substituted by halogen, hydroxy or methoxy, means, R1 is aryl, in particular phenyl, which can be substituted by lower alkyl, R "is hydrogen, lower alkyl, lower cycloalkyl or phenyl, which is optionally substituted by halogen, lower alkyl or trifluoromethyl is, R1? 1 is cycloalkyl or phenyl-lower alkyl and RIV is lower alkyl. 17. Medicines, thereby g e k e n n n z e i c h -n e t that it is next to customary auxiliaries and carriers as active ingredient at least one of the compounds according to claim 1 to 7 contains. 18. 4-Arylpiperidine derivatives of the general formula I: wherein R1 is hydrogen, lower alkyl, lower aralkyl, lower acyl, amirtoalkyl, in which the alkyl part contains 2 to 6 carbon atoms and the amino part can be mono- or dialkyl-substituted, or the group - (CH2) n-COOH, - (CH2) n OH, wherein X is hydrogen or halogen and n is 1, 2, 3 or 4, one of the groups R2 and R3 is a cyano group, a free amino group or a derivative thereof and the other is a free or protected hydroxyl group, or where R2 denotes an azido group when R3 is a free or protected hydroxyl group, or where R2 and R3 together with their associated ring carbon atoms form an oxazepine ring, and finally Ar denotes an aryl group which can be substituted by lower alkyl, lower alkoxy, halogen or CF3, as well as their addition salts with organic or inorganic acids. 19. 4-Arylpiperidine derivatives according to claim 18, characterized in that g e k e n n it is noted that R1 is lower alkyl or -acyl, one of the groups R2 and R3 is a free amino group or a derivative thereof, namely an amide part of the formula -NHCOR, a sulfonamide part of the formula -NHS02R 'or a urea part of the formula -NHCONHR ', where R is lower alkyl and R' is lower alkyl or -aryl, and the other of the groups R2 and R3 is a free hydroxyl group or a hydroxyl group, which is protected in the ester part, the formula -OCOR or -OCOOR or an ether part is protected, of the formula -OR, where R is lower alkyl and Ar is Phenyl group which is optionally substituted by tert-lower alkyl denotes. 20. 4-Arylpiperidine derivatives according to claim 18 or 19, characterized in that one of the groups R2 and R3 is a free amino group of the formula II: denotes in which R5 and R6 independently of one another are lower alkyl which is optionally substituted by hydroxyl, or an ester moiety of the formula -COO-lower alkyl or together with the nitrogen atom and optionally an oxygen atom form a 5- or 6-membered heterocyclic ring, and that the other of the groups R2 and R3 is hydroxy or an ester moiety of the formula -OCOR, in which R- is lower alkyl. 21. 4-Arylpiperidinderivate according to claim 20, characterized g e k e n n notes that the amino group II is pyrrolidinyl, piperidinyl or morpholinyl is. 22. 4-Arylpiperidine derivatives of the general formula Ia: in which R1 is hydrogen, lower alkyl, lower aralkyl, lower acyl, aminoalkyl, where the alkyl part contains 2 to 6 carbon atoms and the amino part can be mono- or dialkyl-substituted, or the group - (CH2) n-COOH, - (CH2 -OH, where X 'is hydrogen or halogen and n is 1, 2, 3 or 4, Ar is an aryl group which can be substituted by lower alkyl, lower alkoxy, halogen or CF3, X is a free or protected hydroxyl group and Y stands for a free amino group or a derivative thereof, as well as their addition salts with organic or inorganic acids. 23. 4-Arylpiperidine derivatives according to claim 22, characterized in that R1 is lower alkyl or acyl, Ar is phenyl which may be substituted by lower alkyl, lower alkoxy, halogen or CF3, X is a free or protected hydroxyl group and Y is a free amino group of the formula: wherein R5 and R6 are independently hydrogen, lower alkyl which is optionally substituted by hydroxyl or an ester moiety of the formula -COO-lower alkyl, lower aralkyl or adamantyl or together with the nitrogen atom and optionally an oxygen atom a 5- or 6-membered heterocyclic ring form. 24. 4-arylpiperidine derivatives according to claim 22, characterized in that Ar is phenyl, which is optionally substituted by lower alkyl, and Y is an amino group of the formula: mean in which R5 and R6 independently of one another represent lower alkyl which is optionally substituted by hydroxy, or piperidinyl, pyrrolidinyl or morpholinyl. 25. 4-Arylpiperidine derivatives according to claim 22, characterized in that R1 is lower alkyl or acyl, Ar is phenyl which is optionally substituted by lower alkyl, X is a free hydroxyl group or an ester part of the formula -OCOR, in which R is a Lower alkyl group and Y is an amino group of the formula: wherein R5 and R6 are independently lower alkyl groups which are optionally substituted by hydroxyl or an ester moiety of the formula -COO-lower alkyl, or together with the nitrogen atom and optionally an oxygen atom form pyrrolidinyl, piperidinyl or morpholino. 26. 1 -methyl-4-phenyl-4-hydroxy-3- (4-morpholinyl) -piperidine and the pharmaceutically acceptable acid addition salts thereof. 27. 1-Methyl-4-phenyl-4-propionyloxy-3- (4-morpholinyl) -piperidine and the pharmaceutically acceptable acid addition salts thereof. 28. 1 -Methyl-4-phenyl-4-hydroxy-3- (N-adamantylamino) piperidine and the pharmaceutically acceptable acid addition salts thereof. 29. 1-Methyl-4-phenyl-4-hydroxy-3- (2'-hydroxyethyl) methylaminopiperidine and the pharmaceutically acceptable acid addition salts thereof. 30. 1-Methyl-4-phenyl-4-acetoxy-3-piperidinopiperidine and the pharmaceutically acceptable acid addition salts thereof. 31. 1-Methyl-4-phenyl-4-hydroxy-3- (1-pyrrolidinyl) piperidine and the pharmaceutically acceptable acid addition salts thereof. 32. 1-Methyl-4-phenyl-4-acetoxy-3- (1-pyrrolidinyl) -piperidine and the pharmaceutically acceptable acid addition salts thereof. 33. 1-methyl-4-phenyl-4- (N-benzylamino-3-hydroxypiperidine) and the pharmaceutically acceptable acid addition salts thereof. 34. Medicinal products, thereby noting that it is next to customary auxiliaries and carriers as active ingredient at least one of the compounds according to claim 18 to 21 contains. 35. Medicines, by noting that it is next to customary auxiliaries and carriers as active ingredient at least one of the compounds according to claim 22 to 33 contains. 36. Process for the preparation of 4-arylpiperidine derivatives of the formula I: wherein R1 is hydrogen, lower alkyl, lower aralkyl, lower acyl, aminoalkyl, in which the. The alkyl part contains 2 to 6 carbon atoms and the amino part can be mono- or dialkyl-substituted, or the group - (CH2) n-COOH ~ (CH2) n-OHs wherein X is hydrogen or halogen and n is 1, 2, 3 or 4, one of the groups R2 and R3 is a cyano group, a free amino group or a derivative thereof and the other is a free or protected hydroxyl group, or where R2 denotes an azido group when R3 is a free or protected hydroxyl group, or where R2 and R together 3 with their associated ring carbon atoms form an oxazepine ring, and finally Ar denotes an aryl group which can be substituted by lower alkyl, lower alkoxy, halogen or CF3, and their addition salts with organic or inorganic acids, characterized in that the epoxy ring of a compound of the general formula IV: wherein Ar and R1 are as defined above, with a cleavage agent from the group consisting of ammonia, azides, cyanides, primary and secondary amines cleaves, the cleavage agent being selected so that the desired groups R2 and R3 are obtained in the product, and that one if desired or necessary, in the compound thus obtained, converts a free hydroxyl group into an ester part of the formula -OCOR or -OCOOR or an ether of the formula -0R, in which R is lower alkyl, by known processes and / or converts a free amino group R2 / R3 into an amide part of the formula -NHCOR, a sulfonamide part of the formula -NH-S02R 'or urea part of the formula -NHCONHR', in which R is lower alkyl and R 'is lower alkyl or aryl optionally substituted by lower alkyl, and / or a free base of the Formula I is reacted with an inorganic or organic acid to form the corresponding acid addition salt. 37. The method according to claim 36, characterized in that g.e k e n n -z e i c h n e t that in a further stage a compound of the formula I thus formed is at the R1 is hydrogen by known alkylation or acylation processes in another compound of the formula I in which R1 has a meaning other than hydrogen has converted. 38. The method according to claim 36 or 37, characterized in that it is possible to use it c h n e t that in a further stage a compound of the formula I where R2 or R3 is an azide group to the corresponding one by known methods Amino group reduced. 39. The method according to claim 36 or 37, characterized in that an amine of the formula: used, wherein R5 and R6 are independently hydrogen, lower alkyl, which is optionally substituted by a hydroxyl group or an ester moiety of the formula C00-lower alkyl, lower aralkyl, adamantyl or where the groups R5 and R6 together with the nitrogen atom and optionally an oxygen atom a 5- or form 6-membered heterocyclic ring. 40. The method according to claim 38, characterized in that it is n -z e i c h n e t that pyrrolidine, piperidine or morpholine are used as cleavage agents. 41. The method according to claim 36 or 37, characterized in that it is possible to use it c h n e t that a mono- or di-lower alkylamine is used as the cleavage agent, the alkyl part or parts thereof being represented by hydroxy or an ester part of the formula COO-lower alkyl can be substituted. 42. The method according to claim 36, characterized in that it is n -z e i c h n e t that one for the preparation of compounds of the formula I, but in which one of the Groups R2 and R3 is a sulfonamido moiety of the formula -NH-SO2R 'where R' is lower alkyl or aryl optionally substituted by lower alkyl, the epoxy ring the compound of the formula IV according to claim 36 with a sulfonamide of the formula H2NS02-Rt, which can be in the form of an alkali metal salt, cleaves.