DE2033852A1 - Process for the preparation of new heterocyclic compounds - Google Patents

Description

Patent attorneys

Dr. W. Schalk, Dipl. Ing.P. Wirth SANDOZ AG. Dipl.-Iny. G. Dannonberg

Basel _Dr γ. Schn ^ d- ^ wc.rz.k gases 100-3105

Dr. K Wemhd-J. Dr. D. Gudel
6 Frankfurt / M., Gr. Eschenheimer Srr. 39.

Process for the preparation of new heterosexual compounds

The invention relates to a process for the preparation of new compounds of the formula I in which R 1 is hydrogen or a lower alkyl group, R 1 is hydrogen, fluorine, chlorine, bromine, a lower alkyl, lower alkoxy or lower alkylthio group, the cyano or amino group - or trifluoromethyl group or a radical -NHCOR ,, in which R, denotes a lower alkyl group,

According to the invention one arrives at the compounds of the formula I, by

a) for the preparation of compounds of the formula Ia in which R ₁

I. has the above meaning and Rg stands for hydrogen, fluorine, chlorine,

Bromine, lower alkyl, lower alkoxy or lower Alkylthio group, the cyano, m-amino, p-amino or trifluoromethyl group or a radical -NHCOR ,, in which R, the above Has meaning, stands, compounds of the formula II. in which R. has the above meaning, in a solvent which is inert under the reaction conditions and in the presence of an acid-binding agent with compounds of the formula III in which Rg Has the above meaning and X stands for the acid residue of a reactive ester, condensed, or

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b) for the preparation of compounds of the formula Ib, wherein R ₁

II
has the above meaning and R ^ represents hydrogen, fluorine, chlorine, bromine, a lower alkyl, lower alkoxy or lower alkylthio group, the _N amino or trifluoromethyl group, compounds of the formula IV, in which Rp has the above meaning, in one of the Reaction conditions inert solvent and in the presence of a basic condensing agent with compounds of the formula V in which R, has the above meaning, is reacted and the resulting reaction product is hydrolyzed, or

c) for the preparation of compounds of the formula Ic, wherein R, has the above meaning, in compounds of the formula Id in which R has the above meaning, the nitro to the amino group reduced.

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The lower alkyl groups symbolized by R ₁ , R * and R,

I II III
as well as the lower symbolized by Rp, Ri, Rp and ^R ₂

Have alkyl, lower alkoxy and lower alkylthio groups preferably a chain length of 1 to 4 carbon atoms and are in particular the methyl or methoxy or methylthio group.

In process a) one can use as an inert solvent under the reaction conditions, for example aromatic hydrocarbons such as Benzene, toluene or xylene, di (lower) alkylamides, lower aliphatic Use monocarboxylic acids such as dimethylformamide or chlorinated aliphatic hydrocarbons such as chloroform or carbon tetrachloride. As acid-binding agents e.g. Alkali metal carbonates such as potassium carbonate or sodium carbonate, tertiary amines such as triethylamine or pyridine or an excess of the compounds of the formula II are used «In the compounds of the formula III, X is, for example, chlorine, Iodine or the acid residue of an organic sulfonic acid such as an alkylsulfonyloxy or arylsulfonyloxy / preferably but bromine. To accelerate the reaction, the reaction mixture can be heated and / or mixed, preferably one works at a slightly elevated temperature between 30 and 100 ° and stirring.

In practice, method a) can be carried out, for example, by the compounds of formula II and the acid-binding agent, e.g. an alkali metal carbonate, preferably potassium carbonate, in Solvents such as toluene or dimethylformamide enters and the compound of formula III at room temperature or slightly higher Temperature, e.g. between about 30-70 °, gradually falls below Stirring added. The reaction mixture is then e.g.

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heated with stirring, preferably to temperatures between 30 and 100 °, and after the reaction has ended (approx. Y ₂ to 5 hours), poured into water, for example. The compounds of the formula I can be isolated from the reaction mixture in a customary manner and purified by known methods. In process b), a solvent which is inert under the reaction conditions can be, for example, liquid ammonia, saturated cyclic ethers such as tetrahydrofuran or aromatic hydrocarbons such as toluene. Alkali metal amides such as lithium amide or sodium amide, for example, can be used as the basic condensing agent. The reaction temperature can be between about -35 and + 60 °, depending on the solvent used. The reaction can optionally be carried out in an inert gas atmosphere, for example under nitrogen and in the presence of a catalyst, for example an organic peroxide such as tert. Buty! Hydroperoxide. Aqueous solutions of alkali metal carbonates such as potassium carbonate, for example, can be used to hydrolyze the reaction product. In practice, process b) can be carried out, for example, by suspending the basic condensing agent, for example sodium amide, at a lower temperature, for example about -10 °, in a solvent which is inert under the reaction conditions, for example toluene, and a solution of the compound of the formula IV and the formula V is gradually added, preferably in the same solvent. The reaction mixture is stirred for a long time, for example 10-25 hours, at low temperature, for example at -10 °, and the reaction product is then decomposed, for example with aqueous potassium carbonates. The compounds of the formula I can be isolated from the reaction mixture in a customary manner and by known methods getting cleaned.

The reduction according to process c) can, for example, by catalytic Hydrogenation in one under the reaction conditions

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inert solvents are run. As under the reaction conditions Inert solvent can, for example, be a lower alcohol such as ethanol, and as a hydrogenation catalyst e.g. Platinum oxide, Ranoy nickel or palladium on activated carbon are used will. However, method c) can also be used, for example, with zinc ■ in dilute acetic acid or with iron in dilute Acetic or hydrochloric acid can be carried out.

The compounds of the formula I can be converted into their acid addition salts and vice versa.

Of the compounds of the formula II, the compound of the formula Ha is known. The compounds der.Formel Hb, in which R7 stands for a lower alkyl group, are new and can be obtained by splitting off the benzyl group from the compounds of the formula VI in which R. has the above meaning. This splitting off of the benzyl group can be carried out, for example, by catalytically hydrogenating a compound of the formula VI in a solvent which is inert under the reaction conditions, for example in glacial acetic acid, preferably using a palladium catalyst at slightly elevated pressure and slightly elevated temperature (for example at 5 atm / 60 °).

The compounds of formula VI can be prepared, for example, by 1-benzyl-4-piperidone in the presence of an alkali », metallamids, e.g. lithium or sodium amide, in one under solvent inert to the reaction conditions, e.g. in liquid ammonia and / or abs. Ether, abs. Dioxane, toluene, with 7-lactones of the formula Va, in which R, has the above meaning, is reacted and the resulting reaction product is hydrolyzed, e.g. with aqueous ammonium chloride solution.

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00 98 8 37 2 278

The compounds of formula IV can be obtained, for example, by

a ') for the preparation of compounds of the formula IVa in which R _{p is} hydrogen, fluorine, chlorine, bromine, a lower alkyl, lower alkoxy or lower alkylthio group or the

Tr i fluorine thyl group

stands, reacts the corresponding phenethylamines with acrylic acid esters, a Dieckmann cyclization of the compounds of the formula VII thus obtained, in which Rp has the above meaning, carries out, the resulting ß-ketoester saponified and then decarboxylated the acid thus obtained, or

b ') Compounds of the formula VIII, in which Rp has the above meaning, saponified with dilute mineral acid.

In process b ') the dilute mineral acid used can be, for example, dilute hydrochloric acid, sulfuric acid or phosphoric acid; the reaction is advantageously carried out at an elevated temperature, in particular at 50 ° to the boiling point of the reaction mixture carried out and takes 2 to 24 hours.

Compounds of the formula VIII can be obtained by combining the compound of the formula IX with compounds of the formula Ilia, where X and Rp have the same meaning as in Process a) as described.

The compounds of the formula Id can be prepared analogously as described in process a).

The compounds of the formula I and their pharmacologically acceptable ones Acid addition salts have interesting pharmacodynamic properties with low toxicity and can therefore to be used as a remedy.

The compounds of the formula I show analgesic properties,

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as shown by the inhibition of the phenylbenzoquinone syndrome in mice, in the "hot plate" test on mice, in the "tail-pinch" test in mice, in electrical stimulation in rhesus monkeys and in the bradykinin pain test in dogs. she can therefore be used as analgesics. The ones to use Doses naturally vary depending on the type of administration and the condition to be treated. In general however, satisfactory results are obtained in test animals at a dose of 1 to 75 mg / kg body weight; this dose If necessary, it can be administered in 2 to 2 portions or as a sustained-release form. For larger mammals, the daily dose is at about JO to 180 mg. For oral applications, the contain Partial doses about 10 to 90 mg of the compounds of the formula I in addition to solid or liquid carriers or diluents.

Furthermore, the compounds of the formula I show in contrast to known analgesics no respiratory depression, as could be determined by experiments on guinea pigs.

The compounds of the formula I or their physiologically compatible acid addition salts alone or in a suitable medicinal form with pharmacologically indifferent ones Adjuvants are administered.

If the preparation of the starting compounds is not described, these are known or by processes known per se or analogous to those described here or can be produced analogously to processes known per se.

In the following examples, which explain the invention in more detail, but should not limit their scope in any way, all temperatures are given in degrees Celsius and are uncorrected.

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Example 1 t Pihydro-5; l [4-hydroxy-l-phenethyl-4-plperldyl ^ -

-furanon

A suspension of 18.5 g of dihydro -> - (4-hydroxy-4-piperidyl) - 2 (2H) -furanone and 15.5 g of potassium carbonate in 50 ml of dimethylformamide is stirred dropwise with the solution of 18.5 g of phenethyl bromide in 10 ml of dimethylformamide at 50 ^0th Stir the reaction mixture for 3 hours at 50 ^0, it is poured after cooling in 400 ml of water, extracted with chloroform, the chloroform extracts washed with water, dried over magnesium sulfate and the solvent is evaporated. Is obtained from the crystalline residue recrystallized twice from acetone, the title compound, mp. IO6-IO8 ^0th M.p. of the hydrochloride (from ethanol): 206-207 °. Analogously to that described in Example 1, the following compounds of the formula I can also be obtained (Examples 2 to 5):

Example 2; ^ ril ^ g-Smp.

Example 3: 5; ii; B; B £ 25 ethyl-4-hydroxy-4-piperidyl-dihydro-mp. II5-II7 ⁰ .

Example 4; Dlhjdro _: 2 _: 14-hydroxy _: 4 _: plperidyl-1 _: p-tolyläth5rl2 _:

2
M.p. 106-107 °.

Example 5:
117-119 °.

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Example 6:

A suspension of 18.5 g of dihydro-3- (4-hydroxy-4-piperidyl) -2 (/ 5H) -furanone and 16.5 g of potassium carbonate in 100 ml of dimethylformamide is added dropwise with stirring at 60 ° over the course of 1.5 hours the solution of 21.9 g of o-chlorophenethyl bromide in 50 ml of dimethylformamide is added. The reaction mixture is then left to react for a further 1% hour at the same temperature and the reaction mixture is then poured into 800 ml of 5 μl of potassium carbonate solution to which 200 g of ice are added. It is extracted repeatedly with chloroform, the extracts are dried over magnesium sulfate and the solvent is evaporated off under reduced pressure. The remaining, slowly crystallizing residue is recrystallized from benzene / petroleum ether. M.p. 92-94 °.

Analogously to that described in Example 6, the following compounds can also be used of formula I are obtained (Example 7 and 8):

Example 7; 3- (Im-chlorophenethyl-4-hydroxy-4-piperidyl>

M.p. 76-78 °.

Example 8: 3- (lp-Aminophenäthy ^ -4-hy_droxy-4-piperidyl)

M.p. 145-146 °.

Example 9:

A suspension of 16.5 g of dihydro-3- (4-hydroxy-3-piperidyl) -2 (3H) -furanone and 14.8 g of potassium carbonate in 165 ml of dimethylformamide is added dropwise with stirring at a temperature of 60 ° with the solution of 19.1 g of o-Methoxyphenäthylbroraid in 50 ml

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Dimethylformamide added. The reaction mixture is left to react for a further 3 hours at ^{60.degree. C.} and the reaction mixture is then poured into 500 ml of 5 μl potassium carbonate solution which contains approx. 500 g of ice. It is extracted with methylene chloride, the extracts are dried over magnesium sulfate and the solvent is evaporated off under reduced pressure, the residue is dried for 1 hour at 80 ° in a water-jet vacuum to remove any remaining dimethylformamide and the residue is recrystallized twice from benzene. M.p. 98-99 °.

Analogously to that described in Example 9, the following compounds can also be used of formula I are obtained (Example 10 to 20):

Example 10; Dihydro-3- (4-hydroxy-1m-methoxyphenethyl-4-m.p. 98.5-99.5 °.
Example 11 ;

2 (3H) -furanone
M.p. of the hydrobromide 193-194 °.

Example 12; Dihydro _: 3; (^ hydroxy _: 4-piperidyl _: 1 _: m-tolylethyl2

103-104 °.

Example 13:

M.p. 92-93 °.

Example 14:

M.p. of the hydrochloride 205-206 °.

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Example 15: 3- (lo - fluorophenethyl-4-hydroxy-4.-piperidyl-)

dihydro-2 (3H) -furanone m.p. 123-124 °. ·

Example 16: 3-il: - ^T ^ riflyormeth lphenäthyl-4-hydroxy-4-

piperidy_l) dihydro-2 (3H) -furanone m.p. of the hydrochloride I65-167 ⁰ .

Example 17: 3- (1-Q-TrIfluoromethylphenäthyl - ^ -

■■ ■ ■ ■

piperidyl) dihydro-2 (3H) -furanone m.p. of the hydrochloride 215-216 ⁰ .

Example l8: 3- {lo

dihydro-2 (3H) -furanone m.p. of the hydrochloride 207.5 ° -208.5 ° (dec.).

Example 19: Dihydro-3- ^ 4-hydroxy-1-phenethyl _: 4-piperidyl)

5-methyl-2 (JFj) - furanone M.p. 129-1 ^ 0 °.

Example 20; ^ il-ß ^

M.p. 193-195 °.

Example 21-; pihydro-3- (4 _: hydroxy-1-phenethyl-4-piperldyl2

A suspension of 11.3 g of sodium amide in 220 ml of abs. toluene is at a temperature of -10 ° with stirring and in nitrogen fat atmosphere drop by drop with a solution of a mixture of 20.3 g of 1-phenethyl-4-piperidone and 50 g of y-valerolactone in 100 ml abs. Toluene added. One leaves for 22 hours

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-10 ° and then decomposes the reaction mixture -4 ° with 100 ml of 10 # potassium carbonate solution. One extracts with toluene and chloroform, dry the combined extracts over magnesium sulfate and the solvents evaporated. the end the crystalline residue is obtained after two recrystallization from benzene, the title compound of mp. 129-130 °.

Example 22; Dihydro - ^ - ^ - hydroxy-l-phenathyl - ^ - plperldyl) -2 (3H) i-furanone

A suspension of 112 g of sodium amide in 1000 ml of abs. toluene a mixture of 210 g of 7-butyrolactone and 100 g of l-phenethyl-4-piperidone is added dropwise at -10 °. The reaction is allowed to continue overnight at -10 ° and it is decomposed then the reaction mixture while cooling with ice with water. The aqueous phase is separated and twice more re-extracted with toluene. The combined toluene extracts are dried over magnesium sulfate and the solvent is evaporated under reduced pressure and the remaining residue is recrystallized twice from benzene. M.p. 106-108 °.

Example 23: 3- (lo-Chlorophenethyl-4-hydroxy-4-piperidyl ^ -dihydro; 2 (3H) -furanone

A suspension of 18.0 g of 4-plperidone ethyl ketal hydrochloride and 34.5 g of potassium carbonate in 300 ml of dimethylformamide is added dropwise with the solution of 22 g while stirring at 60 ° O-chlorophenethyl bromide is added to 100 ml of dimethylformamide. The reaction is then allowed to continue for 2 hours at the same temperature and the reaction mixture is then poured into about 1000 ml of ice water. It is extracted repeatedly with Chloroform, washes the extracts with water, dries over

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Magnesium sulfate and the solvent evaporated under reduced pressure. The residue obtained is in 300 ml 2 N hydrochloric acid added, extracted once with ether and the aqueous phase then refluxed for 8-10 hours cooked. The reaction mixture is made alkaline by adding potassium carbonate and extracted repeatedly with Chloroform and, after drying over magnesium sulfate, the solvent is evaporated.

Above evaporation residue and 43 g -y-butyrolactone, together in 100 ml abs. Dissolved toluene are added dropwise to a suspension of 11.3 g of sodium amide in 250 ml of abs. Toluene -10 ° given. Then proceed as in example 22. After two recrystallization from benzene / petroleum ether, the crude product gives the pure title substance with a melting point of 92-94 °,

Analogously to that described in Example 23, the following can also be used Compounds of formula I are obtained (Example 24-28):

Example 24; 3: (l: m _: chlorophenethyl _: ^ dihydro-2 (3H) -furanone

M.p. 76-78 ° (benzene / petroleum ether).

Example 25t

113-114 ° (benzene).

Example 26:

117-119 ° (benzene).

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Example 27;

M.p. 106-107 ° (benzene).

Example 28; 3- (lg-Bromghenäthyl-4-hydroxy-4-plperidyl2

dlhydro-2 (3H) -furanone
M.p. 115-117 ° (benzene).

Example 29:

A suspension of 8.0 g of natriuroamide in 200 ml of abs. Toluene is treated dropwise at -10 ° with a solution of 50 g of 5-butylbutyrolactone and 14.3 g of 1-phenethyl-4-piperidone. It is then mixed with 5 ml of abs. Tetrahydrofuran and 3.0 g of tert. Buty! Hydroperoxide (75 % in di-tert-butyl peroxide) and leave to react overnight at -10 °. The reaction mixture is then decomposed dropwise with 100 ml of water at a temperature of -5 ° to 0 °. The toluene phase is decanted off and the aqueous layer is extracted twice with chloroform. From the combined extracts dried over magnesium sulfate, the title substance with a melting point of 124.5 ° -125.5 ° is obtained after the solvent has been evaporated off and recrystallization from ether / petroleum ether.
Example 30: ^^ il ^ g ^

A solution of 39.6 g of dihydro-3- (4-hydroxy-lp-nitrophenethyl-4-piperidyl) -2 (3H) -furanone in 700 ml of ethanol is in the presence of 1.3 g of platinum oxide at room temperature and an initial pressure of 3 atU hydrogenated. After the hydrogen absorption has ceased, the catalyst is filtered off, evaporated to dryness and the residue is recrystallized from ethanol. M.p. the title compound 145-146 °. .

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Example 31: 3- (l; O-AminophenHthyl- * l-hydroxy-4-piperidyll

A solution of 17 g of dihydro-3- (4-hydroxy-lo-nitrophenethyl-4-piperidyl) -2 (3H) -furanone hydrochloride in 840 ml of ethanol is at room temperature and an initial pressure of 3 atm in the presence of 0.6 g of platinum oxide hydrogenated. The catalyst is filtered off, the filtrate is evaporated to dryness and the residue is dissolved in chloroform. To liberate the base, it is extracted with potassium carbonate solution, the organic phase is freed from the solvent after drying over magnesium sulfate and the residue that remains is absorbed on 130 g of silica gel. The fraction obtained after eluting with a mixture of chloroform / methanol 95 ^: 5 is dissolved in ethanol and mixed with the ethanolic solution of the calculated amount of naphthalene-1,5-disulfonic acid, whereupon the naphthalene-1,5-disulfonate of the title substance crystallizes out. M.p. 2 ^ 5-250 °.

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The starting compounds can be obtained as follows will:

Example 32: ^^ J

§I5? Lzü ^ r! T5 ° 5l ^ y ^ i! 22 ^ l2? I ^ ( ^for example 19)

a) 3- (1-Benzyl-4-hydroxy-4- »piperidyl) -5-methyl-dlhydro-2 (3H) -furanone-hydrochloride

A suspension of lithium amide in liquid ammonia (manufactured from 5.6 g of lithium in 1000 ml of liquid ammonia) is added dropwise with the mixture of 37.8 g of l-benzyl-4-piperidone and 80 g of Ύ-valerolactone added. One leaves for three more React for hours at minus 30 ° and then carefully add 64 g of ammonium chloride. Now the ammonia is taking at the same time Evaporated dropwise addition of toluene and then the reaction mixture was stirred overnight at room temperature. One decomposes then with 200 ml of water, the organic phase is separated off and extracted twice more with toluene. The after The residue remaining after evaporation of the solvent is dissolved in ethanol with the calculated amount of ethanolic hydrochloric acid added, whereupon the 3- (l-benzyl-4-hydroxy-4-piperidyl) -5-methyl-dihydro-2 (3H) -furanone hydrochloride crystallized out. M.p. 209-211 °.

b) Dihydro-3- (4-hydroxy-4-piperldyl) -5-methyl-2 (3H) -furanone hydrochloride

A solution of 33.7 g of 3- (1-benzyl-4-hydroxy-4-plperidyl) -5-methyl-dihydro-2 (3H) -furanone hydrochloride in 400 ml of glacial acetic acid is at 60 ° in the presence of 7.5 g of palladium carbon for 13 hours hydrogenated at 10 atm and 60 hours at 30 atm. The catalyst is filtered off, the filtrate is evaporated to dryness and the residue recrystallizes from ethanol. 198-200 °.

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Example 33: ^^^ iityy ^^ g

BiSfS ^ YiilSi ^ lrCHSfiSSS (for example 30) A suspension of 41 g of dihydro-3- (4-hydroxy-4-piperidyl) -2 (3H) -furanone and 36.7 g of potassium carbonate in 200 ml of dimethylformamide is added dropwise with stirring the solution of 4l g of p-nitrophenethyl bromide in 100 ml of dimethylformamide was added at 50 °. The reaction mixture is stirred for 3 hours at 50 °, after cooling it is poured into 1600 ml of water, extracted with chloroform *, the chloroform extracts are washed with water, dried over magnesium sulphate and the solvent is evaporated off. After recrystallizing twice from benzene / petroleum ether, the title compound with a melting point of 126 ° -127 ° is obtained from the crystalline residue.

Analogously to that described in Example 33, the following compound can also be used of the formula Ib can be obtained (Example 34):

Example 34; Dil} idro-3- [4-hydroxy-lo-nitroghenethyl-4-

PiP ^ iffilz ^ i ^ iilr ^^ SS (for Example 31) ^{M.p. of} the hydrochloride: 192-194 °.

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= λ Ro HO

-CH ₂ -CH ₂

^ = V- ^R 2

Yes

Ib

NH

2 HO

Ic

Id

II

HO

Ha

Man

X-CH ₂ -CH ₂ - ^ ~ J ^a X-CHg-CH ₂ - / ~~ V * ²

III ^ - * IHa

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II

IV "III ^R 2

IVa

Va

HO

VI

HC ₀ -OOC-CH ₀ -CH

d 2

H ₅ C ₂ -OOC-CH ₂ -CH ₂ 'III

VII

-CH ₀ -

.11

VIII

CH ₂ -O CH «" - "O

IX

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Claims (4)

- 20 - 100- ^ 105 claims: 1. A process for the preparation of new compounds of the formula wherein R, for hydrogen or a lower alkyl group, R ₂ for hydrogen, fluorine, chlorine, bromine, a lower alkyl, lower alkoxy or lower alkylthio group, the cyano, amino or tri fluorine thylgruppe or a radical -NHCOR. ,, in which R is a lower alkyl group, characterized in that one a) for the preparation of compounds of the formula Ia in which R ₁ τ
Has the above meaning and Rg represents hydrogen, fluorine, chlorine, bromine, a lower alkyl, lower alkoxy or lower alkylthio group, the cyano, m-amino, p-amino or tri-fluorine methyl group or a radical -NHCOR .., in which R has the above meaning, compounds of the formula II in which R _{1 has the} above meaning in a solvent which is inert under the reaction conditions and in the presence of an acid-binding agent with compounds of the formula III in which Rg has the above meaning and X stands for the acid residue of a reactive ester, condensed, or b) for the preparation of compounds of the formula Ib, wherein R, TI
has the above meaning and Rg stands for hydrogen, fluorine, Chlorine, bromine, a lower alkyl, lower alkoxy or lower alkylthio group, the amino or trifluoromethyl group stands, compounds of the formula IV, in which Rg has the above meaning, in one under the reaction conditions Inert solvents and in the presence of a basic condensing agent with compounds of the formula V, wherein R. has the above meaning, converts and hydrolyzes the resulting reaction product, or 00988 3/2278 10σ -3105 - 21 - c) for the preparation of compounds of the formula Ic in which R. has the above meaning, in compounds of the formula Id in which R _{1 has the} above meaning, the nitro group is reduced to the amino group. 2. The method according to claim 1, variant c), characterized in that that the reduction is carried out by catalytic hydrogenation. 009883/2278 , .33852 - 22 - 10Ö-3105 BBD 3. Compounds of the formula I in which IL is hydrogen or a lower alkyl group, R «for hydrogen, fluorine, chlorine, Bromine, a lower alkyl, lower alkoxy or lower alkylthio group, the cyano, amino or trifluoromethyl group or a radical -NHCOR ,, where R ^ is a lower alkyl group, stands. 4. Dihydro-3 - (^ - hydroxy-1-phenethyl - ^ - piperidyl) -2 (3H) -furanone. 5 * Pharmaceutical preparation, characterized by a content of the compounds of the formula I as active ingredient. for SANDOZ AG, 009833/2278