CA1098908A - 3,4-dihydroxy-4-phenylpiperidine derivatives - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

The present invention relates to novel 3,4-dihydroxy-4-phenylpiperidine derivatives and processes for their production. The novel compounds have been found to have, inter alia, stimulatory effects on the central nervous system which is indicative of their use as anti-depressants in humans.

Description

"
1~9 The present invention relates to novel 3,4~
dihydroxy-4-phenylpiperidine derivatives, processes for the production thereof and compositions containing same.

According to one aspect of the present invention there are provided such no~el 4-phenylpiperidine derivatives of the genexal formula I:

~ ~X-~2 ~ -H ...... I .

~NJ -~3 R.~ .
wherein Rl represents stràight or branched chain lower alkyl or benzyl;
R2 represents a lower straight or branched chain alkyl which may carry a lower alkoxy; cycloalkyl; lower alkenyl; lower alkynyl: phanyl optionally mono- or di-substituted by halogen, lower alkyl or lower alkoxy; or with the proviso that X represents only oxygen, a lower acyl of formula -~O-R wherein R is a straight or branched chain lower alkyl, cycloalkyl or phenyl, R3 represent hydroxy or an ester derivative thereof of formula -OCO-R5 wherein Rs is straight or branched chain lower alkyi optionally substituted by lower alkoxy carbonyl or chlorophenoxy; cycloalkyl; lower alkenyl;
diphenylmeth~.l; 2- or 3-furyl or phenyl, optionally substituted :~
by amino, halogen, nitro, up to two lower alkyl groups t UP
to three lower alkoxy groups, CF 3 / an ester moiety of formula -OCOlower alkyl, lower acylamino; and.

X represents oxygen or sulphur;
as well as pharmaceutically acceptable acid addition salts thereof with organic or inorganic acids.
Since the compounds of formula I have chiral centres at C3 and C~, it will be o~svious to one skilled in the art that these compounds may be present as optical isomers. The connotation of the general formulae presented herein is to include all such isomers either separated or in d,l mixtures.

Also, it will be noted that substitutent groups X-R2 and R3 are always trans to each o~her in the compounds of formula I.
Throughout this specification the terms "lower alkyl", "lower alkoxy", "lower acyll', "lower alXenyll' and "lower alkynyll' refer to such groups having at most six, and preferably at most four, carbon atoms. Examples of lower alkyl groups include methyl,ethyl, isopropyl, propyl, butyl, isobutyl sec. and tert. b~tyl, pentyl, isopentyl, neopentyl and the various hexyl isomers; lower alkoxy includes methoxy, ethoxy and isopropoxy. Lower alkynyl includes ethynyl and

2-propynyl and lower alkenyl includes vinyl and 2~propenyl. , Lower acyl groups include acetyl, propionyl, etc. The term lower aralkyl refers to such groups having at most six, preferably at most four, carbon atoms in the alXyl moiety, examples thereof being phenyl~lower-alkyl, phenethyl, ~ut especially benzyl, and naphthyl-lower-alkyl such as 2-naphthylmethyl.
The term cycloalkyl as used herein means cyclo-propyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

A restricted class of compounds of formula I are those wherein Rl represents a straight or bxanched chain lower alkyl; or lower phenylalkyl;
R2 represents straight or branched chain lower alkyl which may carry a lower alkoxy; cyclohexyl; phenyl, optionally -mono- or di-substituted by halogen; lower alkyl; lower alkoxy; with the proviso that X represents only oxygen, lower acyl of formula -COR wherein R is a lower alkyl;

cycloalkyl or phenyl;
R3 represents hydroxy, or an ester derivative thereof of formula -OCO-R5 wherein Rs is straight or branched chain lower alkyl optionally substituted by lower alkoxy carbonyl or chlorophenoxy; cycloalkyl; lowex alkenyl, diphenylmethyl;
2- or 3-furyl or phenyl, optionally substituted by amino, halogen, nitro, up to two lower alkyl groups, up to three lower alkoxy groups, CF~, an ester moiety of formula -OCOlower alkyl, lower acylamino; and X represents oxygen or sulphur, especially oxygen;
a~ well as pharmaceutically acceptable acid addition salts thereof with organic or inorganic acids.
- A preferred class of compounds according to the present invention on account of their advantageous pharmacological activity are those compounds of formula I
above wherein R2 and R3 are such that positions 3 and 4 carry ester moieties, especially those of formula -OCO-R
wherein R is lower alkyl, cycloalkyl or phenyl, optionally substituted by lower alkyl, lower alkoxy or halogen. In such cases the two ester moieties may be the same or different.

of partlcular note are compounds of formula:

O-R2 ;~

.. .. , .. , . . . _ .
wherein Rl represents lower alkyl; :~
R~ represents -COCH3; -COC~Hs or -COCHCH2CH2; and R3 represents -OCOCH3, -OCOC2Hs, -OCO-cycloalkyl or -OCOC6H4-Z wherein Z is hydrogen, chlorine, lower alkyl or ~:
lower alkoxy and pharmaceutically acceptable acid addition salts thereof.
with organic or inorganic acids. :
The present invention in a further aspect, -~
provides processes ~or producing compounds of formula I. In one process, the nove} compounds of the present~invention may `
be prepared from an epoxide of formula IV:

.

~ ' . ...... IV
~ ~

wherein Rl i5 hydrogen, straight or branched chain lower alkyl or ben~yl.
The compounds of formula IV are converted into the compounds of formula I by a reaction involving cleavage of the epoxide ring, the choice of cleavage agent being ` ;~

~;
- 4 - ~

~39139~8 :~

determined primarily by the -X-R2 moiety desired in the product of formula I.
For example, (A) When X = O, R~ - lower alky~or cycloalky~ and R3 = hydro~en The selected epoxide of formula IV is reacted with the corresponding alcohol of formula~ HO-R2 in the presence of at least one molar equivalent of a strong acid. The reaction may be conducted in a solvent, which may be constituted by an excess of the alcohol reactant. Preferred alcohols are methanol, ethanol and isopropanol.
(B) When X = O, Rz = lower acyl, cycloalkylcarbon~l and R3 = hydrogen ~ ;~
The selected epoxide of formula IV is reacted with the corresponding carboxylic acid of formula:
HO-CO-R
wherein R is lower alkyl or cycloalkyl, in the presence of at least one molar e~uivalent of a strong acid. Again a solvent may be used and this may be constituted by an excess of the carboxylic acid reactant.
Preferred acids include acetic acid and propionic -~
acid.
In these two process embodiments, the strong acid ; -may be p-toluenesulphonic acid, sulphuric acid and hydrochloric acid.
Reaction is usually effected by heating, co~veniently at the reflux temperature of the reaction medium.

_ 5 _ }~ , .

(C) When R3 = hydrogen and (i) X = S and R2 = lower alkyl, cycloalkyl or phenyl option-ally substituted as defined above;
(ii) X = O and Rz = phenyl optionally substituted as defined above.
The selected epoxide of formula IV is treated with the corresponding thiol of fo~muLa: ~S-R

LO or phenol of formula: HO-R~
ln a solvent, such as ethylene glycol and in the ~- .
presence of a base conveniently alkali metal ':
hydroxides such as sodium hydroxide and potassium hydroxide. :~.
tD) An alternative process for producing those compounds ;- ~:
:~ - : .
of formula I wherein X = O and R~ - acyl involves reactin~ a diol:of fonmula~

: - ~ OH
,.... III :

2G ~ ~

wherein Rl is as defined above with the acid halide or anhydride of the corresponding carboxylic acid.
In some instances, depending inter alia on the ~ starting diol and the esterifying reagent, it is ;~
: possi~le to convert both hydroxy groups into ester moieties. In such cases~ use of at least two molar equivalents of the esteri~ying agent will result in ~(~9~

the diester having similar ester moieties at the

3 and 4 positions.
As will be appreciated, compounds of formula IV
wherein Rl is hydrogen are secondary amines and in certain instances may be involved in undesirable competing reactions involving cleavage of the epoxide ring with the selected cleaving agent. This is only likely to occur to any significant extent when the cleaving agent is bulky in nature, and the possibility of said undesira~le reactions occurring may be reduced by effecting the reaction at a lower temperature than in the other instances, for example, a temperature below 100C compared with a temperature of between 100-200C, usually about 150C. However, in such cases~ it is preferred to produce compounds of formula I
but wherein Rl is hydrogen by cleaving the epoxide ring o~
a corresponding comp~und of formula I wherein Rl is an amine -~ protecting group~ such as acyl, with the desired cleaving agent and subsequently convertinggroup Rl to hydrogen in known manner, for example, by hydrolysis with acid or base.
Such N-unsubstituted compounds may be utilized as starting materials in producing desired compounds of formula I.

Moreover, compounds of formula I may in general 2~
by used as intermediates in ~he obtainment of other compounds of formula I. For example, those compounds of formula I
whsrein Rl is alkyl may be obtained from the compound of formula I wherein Rl is hydrogen by simple alkylation by known standard procedures using, for example, alkyl halides, or by benzyl-chloride. Likewise, compounds of formula I wherein R3 is a hydroxyl-group derivative may be obtained r ~

~ 8~

from the corresponding fee hydroxyl compound, for example, by esterification in known manner. This method may be used to produce compounds having different ester moieties at positions 3 and 4.

If the mixture of isomers obtained as the product in any specific reaction is not u~ilizable in that form due to the undesirable presence of one or more isomers, the isomers may be separated by standard techniques generally utilizing differences in the physical and/or chemical properties between the isomers, suchas relative solubilities, differing recrystallization rates and different retention rates in chromatographic separation processes, such as ~~
column chromatography.
The 4-phenylpiperidines of formula I form acid addition salts with various inorganic or organic acids and such salts are included within the scope of the present invention. Of special interest are the pharm2ceutically acceptable acid addition salts which are usually more convenient to handle than the free compounds of formula I.
Acids which fo~m such salts include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, maleic acid, fumaric acid, tartaxic acid, 2~
succinic acid, citric acid, camphorsulfonic acid, ethane-sulfonic acid, ascorbic acid and lactic acid.
Of the starting materials, namely, the 3,4-epoxy-- piperidines of formula IV:

~1;3i9~

~, ~ .

...... IV
Rl ~

the compound wherein R~ is methyl is known being described :~:
in the literature along with its preparation. Other compounds of formula IV where.in Rl is as defined ~bo~e may be ~;~
prepared in an analogous manner. For example r they may be obtained by the epoxidation of compounds of formula ,10 J V
.
Rl ~:

: wherein R1 is as defined above.

The epoxidation may be effected in several ways ~or example:

1) oxidation using a percarboxylic acid according to ~:
the following scheme:

Zl~ ¢~ , ~' ~0 ~ + RCOOH ~ RC~a OH

wherein R6 is acyl and a protecting group described hereinbefore at page 7, or 2) ~rom a halohydrin in the presence of a base according to the following scheme:

~Q91~9~8 Y ~ ~
N N N
V" ' :"

wherein the nitrogen is basic in character and Y is halogen.
However, it will be obvious to the skilled chemist that the actual procedure used for the epoxidation must be . _ .. ._. . _ ................................ :
chosen to avoid the possibility of undesirable side reactions.
It will:be readily apparent that in general the , ~
~ said epoxy compounds where the nitrogen is substituted may ~ ;
.
: be obtained from the corrPsponding epoxy compounds where the nitrogen is unsubstituted by alkylation, etc. in known : manner of the latter compounds.
Some of the 4-aryl-1,~,3,6-tetrahydropyridines of formula V, namely those of formula VI: :~

":

¢~ ` ~';
T .. ~.. y~

~NJ .

. ~ - 1 0 ~ ~ ' f ~A

3~i8 wherein Rl is various hydrocarbon moieties are known com-pounds being described along with a process for their preparation, for example, in J.A.C.S. (1956) Vol. 78, p.

425-428. AnY novel compounds of formula V may be prepared in a similar manner to the known compounds witht of course, the appropriate choice of starting materials.
An alternative process for preparing these compounds comprises reacting formaldehyde, an appropriately substituted ~-methylstyrene and an amine according to the following scheme:

1) RINEji CHzO;

2) E
.. , ~1 ~ R~ :

wherein Rl is asdefined above, and amine RlNH2 is in the form of an acid addition salt.

Again, starting compounds wharein substitutent Rl' is hydrogen may be converted into compounds wherein R

is other than hydrogen by standard known procedures as described above.

~9~

Of the 4-phenylpiperidine-3,4-diols of formula III
some are know~,for example, l-methyl-4-phenylpiperidine-3,4-diol (J.O.C. 30, 399 ~1965] R.E. Lyle and W.E~ Kruger). Any novel compounds of formula III may be prepared in a similar manner to the said known compound with, of course, the appropriate choice of starting materials. ~`~
The novel 4-phenylpiperidines of the present inven-tion possess useful biolo~ical properties and generally~hey have `~
activity, as determined by standard tests, indicative of at least one of the following activities,!antidepressant, antiaggresive, diuretic, antiparkinson, bronchodilator and antiarthritis, antithrombotic and muscular relaxant activities.
For example, compounds of restricted formula I when adminster-ed to mice have generally been found to have a signficant stimulatory effect on the central nervous system indicative of ultimate antidepressant and similar clinical use in ~`
humans. Moreover, this activity is associ~ted with an acceptable tOXiClty index.
The following table summarizes the results obtained when some compounds of pre~erred formula I ;~
above were evaluated for antidepressant activity using standard test procedures (ref. R.A. Turner, P. Hebborn, ~
Screening Methods in Pharmacology, Vol. II, Acad. Pr., ~;
N.Y., London, 1971, paye 214). Reserpine was used to induce ptosis and the test compounds were administered per os. The results obtained in the same test for the known antidepressant imipramine are in~luded as a comparison. Response values >3 are considered pharmacologically significant.

, ¦ Compound Mg/kqRe spon se .
l-methyl 3-acetoxy-4- 25 `---- -8- - -A propionyloxy-4- 1 8 phenylpiperidine 0.5 5 .. ...... . ..... .. _....... ........... ~........ . . . ......... ... _ .. .. _ B ~l-methyl-3-ethylcarbonyloxy- 50 1 8

4-(~-chlorophenoxy)- 10 7 14~phenylpiperidine 5 5 C l-methyl-3-hydroxy- 50 10 t4-phenylthio- 10 6 14-phenylpiperidine 5 4 ~ - - -.. ~ _ . .. .. __ . ~
D l-methyl-3-cyclopropylcar-bonyloxy-4-ethylcarbonyloxy- 0 05 1 4 4-phen~ peridine . I
_~..... . ...... ....... _.~_ _.~ .,. __ E l-methyl-3-cyclobutylcar-bonyloxy-4-ethylcarbonyloxy-1 4-phenylpiperidine 0.25 5 _ _ . .... .~ . ~ .. ~.~ . ~
F l-methyl-3-cyclohexylcar bonyloxy-4-ethylcar~onyl-oxy-4-phenylpiperidine 0.25 5 __ . . __ ~ __.... ~
Imipramine 25 4 _ ~ .~ l It can be seen that the antidepressant activity of the compounds of the present invention compares very favourably with the known antidepressant Imipramine. This is especially so for the compounds of formula I having an ester moiety at positions 3 and 4 as exemplified by Compound A above.
In other similar screening tests, the following results were obtained:
Diuretic Activity (PO) ` Base (mg/kg) Response*
Compound A 5 4.3 Compound E 10 2.9 Compound F 5 3.0 Hydroflurmethiazide _ 2.6 * Respollses ~2 are considere~ pharmacologically significant.

Bronchodialitory Activity (in vit~o - PO) Basë (Mg/kg)¦ Response**
~ . . . . . ~ t ------- ---Compound B i Aminophylline 200 ¦ +
** Responses are positive (+) or negative (~

~he present inven~ion further provides in another of its aspects a pharmaceutical composition comprising as an ;~
essential active ingredient at least one active compound of formula I or a pharmaceutically acceptable acid addition salt thereof in association with a pharmaceutically acceptable carrier therefor.
The compositions of the present invention are preferably administered orally, rectally or parenterally~
Advantageously, the composition is in a dosage unit form -appropriate to the desired mode of administration. For example, the dosage unit may be a tablet, capsule, pill, powder, packet, granule, wafer, elixir, suppository, or a measured quantity of a suspension, solution, a syrup or segregated multiples of the foregoing. The term "dosage units form" as used in the specification and claims refers to physically discrete units suitable as unitary dosages for human subjects and animals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in admixture, or otherwise in association, with a pharmaceutical carrier~
the quantity of the active ingredient being such that one or more units are normally required for a single therapeutic administration or that, in the case of severable units such as scored tablets, at least one fraction such as half or a qua~ter of a severable unit is required for a single thera-peutic administration.

~r . 1 A

Usu~lly the compositions of this invention contain the active ingredient in an amount of at least 0.5% by weight based on th~ total weight of the composition and not more than 95~ by weight. Conveniently, the compositions of the invention when in dosage unit form contain 0.5 mg. to 100 mg., and more conveniently from ~ mg. to 50 mg., of the active ingredient of Formula I.
The compositions of the present invention will normally consist of at least one compound of formula I, advantageously a compound of formula IIa, or a pharmaceutically acceptable acid addition salt thereof, admixed with a carrier, or diluted by a carrier, or enclosed or encapsulated by a carrier in the form of a capsule, sachet, catchet, paper or other container. A carrier which serves as a vehicle, excipient or diluent medium for the therapeutically active ingredient may be a solid, semi-solid or a sterile liquid.
Some examples of the carriers which may be employed in the pharmaceutical composition of the invention are lactose, dextrose, sorbitol~ mannitol, starches such as wheat, corn, or potato starch, gum acacia, calcium phosphate, liquid paraffin, cocoa butter, oil of theobroma, alginates, tragacenth, gelatin, syrup B.P., methyl cellulose, polyoxethylene sorbitan monolaurate, and methyl and propyl :, hydroxybenzoates. The choice of carrier is determined by the preferred form of administration the solubility of the .~.
compound and standard pharmaceutical practice, all as more clearly set forth in "Remington's Practice of Pharmacy" by E.W. Martin and E.F. Cook, a well-known reference work in this field. In the case of tablets, a lubricant may be incorporated to prevent sticking and binding of the powd~red ingredients in the dies and on the punch of the tabletting ~ -~, . ..

machine. For such purposes, there may be employed, for example, talc! aluminum, magnesium or calcium stearates or polyethylene glycols "Carbowaxes" (Registered Trade Mark) of suitable molecular weight.
The pharmaceutical compositions of this invention may contain, in addition to the active 4-arylpiperidine in~redient, one or more other physiologically ac-tive ingredients which elicit desirable complementary effects.
ExamplPs of suitable pharmaceutical compositions according to the present invention are presented below for :-~
the purposes of facilitating a better understanding of this aspect of the inventionO
Compositions Composition 1 : .
For oral administration, sugar coated tablets may have the ~ following composition, tne tablets being made up in the ~
-~ usual manne~. r : Ingredient Amount tmg) :
: l-Methyl-3-acetoxy-4-propionyloxy-4-; phenylpiperidine 10 ~:
Lactose 60 :
Starch 50 Sugar 75 Talc . 5 Gum Arabic . 5 Composition 2 Capsules, made up in the usual manner may have the following composition: -Ingredient Amount (m~) l-Methyl-3 propionyloxy-4-(~-chloro-phenoxy)-4-phenylpiperidine S
Lactose 145 Composition 3 -Tablets for oral administraton may also be made up according to the known procedure descrihed below:

- ]6 -~' f~ .

Ingredient Amount (mg) l-Methyl-3-cyclopropylcarbonyloxy-4-et~ylcarbonyloxy-4-phenylpiperidine 0.175 Lactose 0.502 Starch 0.122 Dextrin ~20% solution) q.s.
Stearic acid 0.004 Magnesium stearate 0.002 It will be appreciated that the above speciic compounds may be replaced by other active compounds of the present invention. .
As indicated hereinbefore, it has been found in accordance with the present invention that the compounds of Formula I possess useful biological properties in that such compounds possess the inherent applied use characteristics of exerting for example, antidepressants on the central nervous system. Compounds possessing such activity may have very valuable therapeutic utility as potential medicaments in the form of pharmaceutical composi~ions in eliciting advantageous central nervous system effects when administered to humans and animals. Accordinglyl central nervous system effects, on humans and animals, may be elic.ited by administering a therapeuti.cally effective dose of one or more of the active compounds of Formula I, (preferably a compound of formula II) wherein CNS symptom being treated, the age, health and weight of the recipient, the extent of the symptom, kind of concurrent treatment, if any, and the prec.ise nature of the effect desired. In practise, based upon standard pharmacological animal studies, particularly in mice, it has been found that the administra-tion of doses of 1 to 100 mg of the active compounds of this invention per kg of anima; body weight will usually elicit the aforementioned CNS, especially antidepressant effect(s) normally without producing any marked s.ide effects.

'8 The present invention will be further described with reference to, but not limited by, the following specific examples.
_XAMPLE 1 4-~p-Chlorophenoxy)-3~hydroxy-1-methyl-4-phenylpiperidine -and its ~drochloride 20 Ml of 10% sodium hydroxide solution was added to a solution of 6.45 g ~0.05 mole) of p-chlorophenol in 40 ml of ethylene glycol and the resulting solution stirred at room temperature for five minu~es. 3.8 G (0.02 mole) of 3,4-epoxy-l-methyl-4-phenylpiperidine was added with stirriny to the above solution and the resulting solution was heated at 120C on an oil bath for 18 hours.
The solid which resulted was filtered, washed with water and dissolved in methylene chloride, rrhe result-ing solu~ion was dried over sodium sulEate and concentrated in vacuo to give 3.6 g of a white solid. Recrystallization of this solid from ethyl acetate gave 4-(p-chlorophenoxy)-3-hydroxy-1-methyl-4-phenylpiperidine as colourless crystals having a melting point of 164-5C.
The corresponding hydrochloride ~las prepared in the usual manner and had a melting point of 221C.
Elementary Analysis: C1 8H2 Q'N2C1 Calc. C: 68.02 H: 6.34 N: 4.41 Found C: 68.10 El: 6.62 N: 4.34 3-Acetoxy-l-methyl-4-(m~methylphenoxy)-4~phenylpiperidine and its hydrochloride 2.12 Ml (.015 mole) of triethylamine was added to ~7:

~9~8 a solution of 3.0 g (.010 mole) of 3-hydroxy-1-methyl-4-(m-methylphenoxy)~4-phenylpiperidine in 30 ml of dry methyl-ene chloride and the solution cooled in an ice-bath. This solution was stirred and 1.08 ml (.015 mole) of acetyl chloride was added dropwise. The reaction mixture was stirred at room temperature for 20 minutes and a precipitate (triethylamine hydrochloride) appeared after one minute and this was filtered off. The solvent was evaporated and the residue diluted with water. The aqueous mixture was basified with 10~ sodium carbonate solution and extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SO4 and concentrated in vacuo to give 3.50 g of the desired base as a yellow-coloured oil. This was converted to .~ .
the hydrochloride which was recrystallized from hot ethyl iacetate/acetone to give 1.9 g of 3-acetoxy-1-methyl-4-(m-methylphenoxy)-4-phenylpiperidine hydrochloride as a .
white solid having a melting point of 197-9C.

3-Hydroxy-l-methyl-4-phenyl-4-propionyloxypiperidine and lts hydrochloride `A solution of 4.0 g of 3,4-epoxy-1-methyl-4-phenylpiperidine and 4.5 g of p-toluenesulfonic acid monohydrate in 50 ml of propionic acid was stirred at room temperature for 10 minutes then the mixture evaporated to dryness. Water was added to the residue and the mixture made alkaline with sodium carbonate. The residual solid was filtered off and washed with water. Recrystallization of this solid from hot ethyl acetate gave 2.4 g of 3-hydroxy-l-methyl-4-phenyl-4-propionyloxypiperidine with a melting point of 142-3C. The corresponding hydrochloride salt had a melting point of 186-8C.

, `

~9~

4-Ethoxy-3-hydroxy-1-methyl-4-phenylpiperidine and its hydrochloride A solution of 12 g (0.063 mole) of 3,4-epoxy-l-methyl-4-phenylpiperidine and 14.4 g (0.075 mole) of ;-p-toluenesulfonic acid monohydrate in 100 ml ethanol was refluxed for eight minutes. The solution was concentrated to 20 ml and then diluted with water. The aqueous solution was basified with 10% sodium hydroxide solution and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuo to give 13.25 g of a beige solid. Recrystallization of the solid from hot ethanol gave 7.6 g of 4-ethoxy-3 hydroxy-l-methyl-4-phenylpiperidine having a melting point of 145-6C.
Elementary Analysis:
Calc: C: 71.45 H: 9.00 N: 5.95 Found: C: 71.25 H: 9.16 N: 5.86 ~ .
The corresponding hydrochloride salt, prepared in the usual manner, and recrystallized from acetone/isopropanol had a melting point of 205C.
_ AMPLE 5 4-(t-Butylthio)-3-hydroxy-l~methyl-4-phenylpiperidine ':
and its hydrochloride 20 Ml of 10~ sodium hydroxide solution was added to a solution of 5.4 ml (0.050 ~ole) of t-butylthiol in 40 ml of ethylene glycol and the resulting solution stirred at room temperature for 10 minutes. 3.8 G (0.02 mole) of 3,4-epoxy-1-methyl-4 phenylpiperidine was added with stirring to the above solution and the resulting solution was heated at 100C (oil bath temperature) for three hours.

A solid separated during the reaction period. The reactionmixture was cooled in an ice-bath, the solid filtered/
washed with acetone and finally supended in acetone and filtered. Recrystallization of this product Erom isopropanol/
ether gave 3.2 g of the desired 4-(t-butylthio)-3-hydroxy-1-methyl-4 phenylpiperidine as a white solid having a melting point of 202.5-203C.
The corresponding hydrochloride salt was prepared in the usual manner, crystallized from acetone/ethylacetate ~'-and was found to have a melting point of 222-3OC.

~ 3-Hydroxy-l-methyl-4-phenyl-4-(phenylthio)piperidine :' :
, and its hydrochloride ,~ 9.6 Ml of 10~ codium hydroxide solution was added to a solution of 2.46 ml (0.024 mole) of thiophenol in lS ml ~
~, of e~hylene glycol and the resulting solution stirred at '' room temperature for five minutes. 1.9 G (0.01 mole) of 3,4-epoxy-1-methyl-4~phenylpiperidine was added with stirring to the above solution and the resulting solution stirred at room temperature for a further one hour. A
solid began to separate after five minutes. The solid was filtered and suspended in acetone. Filtration of the solid gave 2.6 g of 3-hydroxy-1-methyl-4-p,henyl-4-(phenylthio)-piperidine as a white solid having a melting point of 217-9C.
Elementary Analysis:
Calc. C: 64.36 H: 6.60 N: 4.17 Found C: 64.33 H: 6.86 N:~ 4.02 The corresponding hydrochloride was prepared in the usual manner and recrystallization from ethanol/ether gave colourless crystals of the hydrochloride salt having a melting point of 208.5-210.5C.

, ,i, ."

8 ::

_ Acetoxy-l-methyl-4-(1-methyl-1-propylthio)-4-phenyl piperldine and its hydrochloride 0.6 Ml (.0077 mole) of acetyl chloride was added ;~
dropwise to a stirred solution of 1.8 g (.0065 mole) of 3-hydroxy-1-methyl-4-(1-methyl-1-propylthio)-4-phenyl-piperidine in 25 ml of dry methylene chloride cooled in an ice-bath. The reaction mixture was stirred at room tempera-ture for 20 minutes. The solvent was then removed ln vacuo to give 2.0 g of a white solid. Recrystallization of the solid from acetone/isopropanol gave 1.3 g of 3-acetoxy-l-methyl-4-(1-methyl-1-propylthio)-4-phenylpiperidine hydrochloride having a melting point of 214-6C.

. :
. ~' Purther compounds of Formula 1 according to the present invention are laid out in the following table, these compounds being prepared by the procedures detailed in the preceding Examples but with the appropriate changes in ~tarting materials etc. These compounds all ~all within the formula I wherein ~ ' ~

I
J R3 .......
N

Rl - 2~ -- ` :

M.P. (C~
Exa~le Rl R2 R3 X Base HCl Salt : 8 -CX 3 ~ Oc~ 3-OCOC~3 O 2l2-4 : CH3 : 9 -CH3 ~ -OH O 221-2 '''` ' ' ;' -C~3 ~ -o~ o 214-5 CX3 ~ -OCOCH3 O 240-l c~
:~ 12 -CH3 -CX3 -OCOC-CH3 O 230 ; CH3 :j '! l3 . .-CH3 -CH2C~3-OCOCH3 O 234-6 i ., 14 -CH3 -CH3 -OCO ~ O 205 ;
: . '.
lS -CH3 ~ -OH , O 163-S 209-12 :`
- ' 16 -CH3 ~ ~OCOCH3 O sublimes 17 -CII3 ~ Cl -OCOC2Hs sublimes '''~
18-CH 3 -COCH 3 -OCOCH3 O 25~1-5 19~C~ 3 ~COc 2H a - CCOCH 3 0 1 g 9-200 . ;
.

C~I 3 -CH 3 -CH~ -OH O 2q4-5 C~3 - 23 ~

~ ~ .

Exam~leR I R2 R3 ~ Base HCl Salt 21 -CH 3 C ,CH 3 -OCOCH 3 0 250 :~

22 -CH3 ~-Cl -OH O 243-5 23 -CH3 -(:OCX3 -OH O 228-9 -CH 3 _~ -OH O 23 0-1 26 ~CE3 ~ C1 -OCOCH3 0 237-g Cl , -CH3 ~ OCOC~I3 0 238-40 28 -CH3 ~30CH3 OH O 223-4.5 29 -CH3 -CX3 -OCO~IH~ O 225 -CH 3 ~ -CH3 -OCO~Cl O 230-33 31 -CH 3 -C~ 3 -OCO~TO 2 0 2 5 5 - 8 3 2 -C~ 3 -CIt 3 -OCO ~'~3 0 2 2 5 - 8 33 -CX 3 -50Et -oco~3 23 3~

34 -CH3 -CX3 -OCOEt O 237-9 _ 24 ~; .'f `', '. `.- A :

~g~

~ p- ~c) Example Rl R2 R3 X Base HCl Salt -CH3 -CH3 -OCOCH~Ph 249-50 3 6 -CH 3 -CX 3 -O~CCH 3 0 2 4 6 - 8 ~ :

3 7 -C~I 3 ~ H 3 -OCOC 2 H s 2 ~ 4 - 5 . ~
38 -CE 3 -C2Hs -OCOCH=CH~ 0 215-7 39 -C~3 -Ca3 -OCO-~ O 263 ; :~:

-CX3 ~OCH3 -OCOEt O 217-8 41 -CH3 C~ ~OCOEt O 231-2 42 -C~ -C2:~s -OCO~ ~ 0 215-7 4 3-CH 3 -C 2 H s -aco43 0 18 3 -44 -CH3 Cl -OCOC2Hs Q 215~7 4 5-CH 3 -COC ~ H 5 -OCCCl O 19 5 - 7 CE~ 3 46 -CH3COC\CH3 -OH O 214-5 ~ ~ ~
C~ 3 ~ ~

47 -CX3 -co~3 -OH , 160-2 4 8 -C~i 3-co~3 -OCOC'~-1 3 O 1 4 ~ - 5 0 _ 25-M P . ( C) ExampleR~ R2 R3 X Base ~!Cl Salt CH3 -Cr~z-C CH -OH O 240-2 .

51 C~ 3 -C~< 3 o~o~l o 23 0- 1 C~I 3

5 2 -CH 3 -CH 3 -OCO~C-O~C 1 2 2 2 - 5 C~I 3 ~ ~

5 3 -CH 3 -CH z -CH 2 -OCH 3 -OH O 13 ~-7 54 -CH 3 CH< -oco~3 O . 23 5-7 CEI

CE~ 3 :
-CEI3 -CH/ -OCOEt O 171-3 C~3 56 -CH3 -CH3 -OCO Ç9 0 210-11 ûCOCE~ 3 :.
57 -CH~ 3 -CH z -C- CH -OCOEt O 16 5 7 5 8--CH 3 -Crd 2--C- CH --oco~ 3 O 2 23--OCOCH

5 9 -CH 3 -5~ C - CFI -OCO~ O 19 5- 6 .

-CH3 -CH2~CH2 GCH 3 -OCO~] O 200 2 M.P. ~C) ~xam~le Rl R2 R3 X ~ase HCl Sait OC~I3 61 -CH 3-COCH 3 dOCO~OCH 3 181-2 . 5 OC}~ 3 62 -CH3-(::OC2Hs -oco4~oC~3 O 8~-6 ,,; , 63 -CH1 -COCH3 -OCO~ O 225-8 64 C~3-COC~I3 -oco~3 206-8 '~

-CH 3-CCCH 3 -OCO~3Cl O 226-8 ~ .

66 ~CH3 CH3 -oCo4~NH-COCH3 O 229-31 67 -CH3 -CH3 -OCO (CEI2) 3 -COOCH3 105-7 68 -CX3 -CH3 -oco4~ 211-3 ~3 69 ~CH3 ~CH2-CH~-OCH3 -oco~3 O 208-i0 7 o-CH 3-COCEI 3 -OCO~ 2 3 5 -7 71 -CH 3-COCH 3 -OCO -~ O 2 3 8- 9 9~ .
.~1. P . ( ~C) .
Rl R2 R3 X 3as~HCl Salt :

7 2-CH 2~3 -COCH 3 -OH O 2 3 4 - 5 73 -C~3 -CH~-CH 2 -OCH3 OCO~ O 184-S

jPh 74 -CH3 COCH3 -OCOC~\ O 101-3 Ph `~

7 5-CH 1 -COCH 3 -aco~ O 2 0 2 - ~ :
OCOC~ 3 76-C~ 3 -C-C2Hs -CCO~ O 245-7 77-CH 3 -COc2~s -~co~3 0 202-4 OCOC~I 3 7 8CH 3 -CH 2 CH 2-OCH 3 -OCOCEi 3 0 ;2 0 2 - 4 7 9-CH 3 -C~ 2 -C~ OC~ 3 -OCOC 2 H 5 0 18 8 - 9 8 0-CH 3 -CH 2 -ca 2 -OCH } -oco~3 0 ~ 3 4 - Q ;~`
OCOC~I3 81-C~3 COC2Hs -OC-O O 231-8 8 2-C.l } -CH 2 ~CH=C'.i 2 -OcO~) 18 ' -7 OCOC'~ 3 83-C~13 -C~C ~ , -Cf`0~3Cl O 215-7 84-.H 3 -CH2 -CH=C'i2 -CC~ ~3 0 197 -9 M . P . ( C ) :
ExampleR~ R2 R3 X Base HCl Salt ~:

~CH3 -CH3 ~OCO{~ O 117-9 86 -CH3 -CH3 OCO~OCH3 O 22L-3 ~ ~;

C~I 3 O
8 7 -C~I 3 CH 1 2 0 8 -10 38 -CH3 -CH2-C--C'd -OCO~ O 238 dec.

89 -CH3 -CH2-CH=CH2 -OCO~ O 217-8 CH ~ :
-CH3 -COC2Hs -OCO-C-~Cl O 199-201 C~ 3 91 -CH 3 -COC 2H s -OCOC 2H S 171-3 ~:
9 2 -CH 3 -CH 2 -C-- CH -OCO~) 2 41 93 -CH3 -CH2-CH--CH2 ~ -oco~l O 207-9 9 4 -CH 3 -CH 2 -C- CH -OCCCH 3 O 2 0 ~ -9 5 -CH 3 -Cd 2 -CH~C~ 2 -OCO-CH--CH 2 2 0 5~7 96 -CH2-CH3 -CCC2H; -OH O 173-180 97 -~ ~3 -CH 2-C-CH -OCO-CH--C'~l 2 213-5 9 8 -C~ 3 -CH 2 ~ CH=cH 2 OCCC~d 3 O 2 3 7 ~ 9 ~;

~

:` :

911~ MOP. (C) xampLe Rl R2 . R3 ~ Base HCl Salt _ .:

9 9 -CH -COCH 3 -OC~ O ( 3 7 d~c .
OCH3 sulfate salt) 130 -CH3 ~OC2Hs -OCO-O O 241-2 101 -C~ 3 ~OC ~ H s -0(:~0~ 0 2 4 5-7 102 -C~I3 -COC2~s -OCO~) O 220-1 103 ~X3 -CO--~ -OCOC2E~s O 194 5 104 -CH3 ~OC~3 ~OCO~CH3 222-4 o 10 5-C~I 3 -COC 2 EI s -C)C ::) ~ û 231- 3 106 C~3 -COC2Hs -OCO ~ 182-5 dec.

107 -C~3 -CO(:~3 ~OCO~ 0 235-6 10~ -C~I3 -CO ~ -OCO ~ ~ 218-20 109 -C~3 ~OC2EI=~ G 221-2 .
levo rotatory (specific rotation -48 . 4 ~

llo ~-CH3 ~ ~COC2Hs ~OCO ~ 0 223-5 dextro rotatory (specific rotatic~ +56 .1 ) 3 ~3 ~0( 0C2~5 ~; 138~201 .

112 -C~ 3 CI -OH S 2 2 3 - 8 113 ~3 Cl ~)COC~3 ~ ~02-5 9~8 M P. (Cj Example Rl R2 R3 X E~ase HC1 Salt C~E 3 114 ~~ 3-C~-CH 2 -CX 3 -OH S 18 3 - 5 115 -CX 3-f -C~ 3 -OCOC~I 3 S 23 ~-4 116 -CH 3 ~3 -OCOC~I 3 ~;

"~

, .~ = ,.

~ ; .~
~g~9B9q~8 ~3asic elemental ~nalysis of some compounds of the : ~ .
above examples is contained in the following ta~le:

TABL.

C H N

Calculated: 67.10 6.97 3.73 Found: 66.. 86 7~3~ ~.98 Calculated: 64.36 6.69 3.58 Found: 64.41 6.78 3.66 ~, ~ .
Calculated: 68.35 7.25 4.20 Found: 68.57 7.09 4.16 :.
Calculated: 68 .02 6. 34 4 .41 . Found 68.10 6.62 4.34 ExamDIe 4 Calculated: 71.45 9.00 5.95 Found: 71.25 9.16 5.87 :~

Calculated: 55.61 5.19 3.60 Found: ` 55.55 5.40 3.53 ~ , Calculated: 61.02 5.98 3.95 Found: 61;12 6.14 4.10 Example 28 Calculated: 65 . 42 6 . 65 4 . 02 Found: 65.82 6.83 4.23 Exa:;nple 38 Calculated:~ 62.66 7.42 4.30 Found: 62.72 7.63 4.18 ExamDle ~0 Calculated: 72.84 8. 56 5 ~ 66 Found: 72.63 8.51 5.73 E~am~le 52 Calculated: 60.86 6.~4 3.09 Found: 60.66 6.61 `3.23 ~,~

Exam ~ l ~ ;
Calculated: 61.27 6.57 3.97 Found: 61~34 6.70 4.14 Exam~le 76 Calculated: 60.99 6.14 3.56 Found: 61.02 6.28 3.74 Example 81 Calculated: 64.45 7.~7 3.42 Found: 64.12 ~.09 3.62 The detailed preparation of representative 3,4-epoxy-piperidines which ara usPd as star~in~ materlals i~ many of ~he specific examples co~tain~d in this speci~ication are as follows:
(a) 3 ! 4-E~o y-4-phenylpiperidlne ~ solution of 33.~ g of bromine and 60 g o~
sodium bromide in.450 ml of water ~as added ~ropwise with stirrinq to solution comprisin~ 50 ~ of 4-phenyl-l,2tS,6-te~rahydrQpyridine hydrobromide in 600 ml of water and the reaction mi~tura was then stirred at room tem~erature .
for 30 ~inutes. The solution was stirred on an ice bath while 252 ml of 10% sodium hydroxide was added dropwise 2~ thereto. The resulting mixture then being stirred at room temperature for a urther 30 minutes. The aqueous solution was extracte~ wi~h methyle~e chloride and the organic phase - solution dried over sodium sulfate and ~hen concentrated in vacuo to give 25.2 g o~ the desired 3,4-epoxy--4-phenyl-piperidine as an oil.
(b) ~ ~rl~-r~
2~ . 5 Ml of b~nzyl ~romide was acded dropwise to a stirred solution OL 32 . 3 g of 3,4-e~oxy-4-phenyl-piperidine and 38;1 ml of triethyiamine in 254 ml of benzene.

33 ~

~ .
..-. ,, ~39~9~i~

A precipitate appeared during the addition. The whole reaction mixture was then stirred at room temperature for three hours. The residual solid was removed by filtration and the solvent evaporated to give 53.4 g of l-benzyl-3,4-epoxy-4-phenylpiperidine.

Claims (32)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. Process for the production of a compound of the general formula I:

.....I
wherein R1 represents straight or branched chain lower alkyl or benzyl;
R2 represents straight or branched chain lower alkyl which may be substituted with lower alkoxy; cycloalkyl;
lower alkenyl; lower alkynyl; phenyl, which may be mono-or disubstituted with halogen, lower alkyl or lower alkoxy;
or, with the proviso that X represents only oxygen, a lower acyl of formula -CO-R wherein R is a straight or branched chain lower alkyl, cycloalkyl or phenyl;
R3 represents hydroxy or an ester moiety of formula:

wherein R5 is straight or branched chain lower alkyl, which may be substituted with loweralkoxy carbonyl or chlorophenoxy;
cycloalkyl; lower alkenyl; diphenylmethyl; 2- or 3-furyl;
or phenyl, which may be substituted with up to two lower alkyl groups, up to three lower alkoxy groups, halogen, amino, nitro, trifluoromethyl, lower acylamino, or an ester moiety of formula -OCO-lower alkyl;

X represents oxygen or sulphur, as well as addition salts thereof with organic or inorganic acids, which com-prises:
(a) clea?ing the epoxide ring of a compound of the general formula IV:

.....IV

wherein R? represents hydrogen, straight or branched chain lower alkyl or benzyl, with:
(i) an alcohol of the formula HO-R2, wherein R2 represents straight or branched chain lower alkyl, which may be substituted with lower alkoxy; cycloalkyl;
lower alkenyl; or lower alkynyli or (ii) a carboxylic acid of formula HO-CO-R wherein R is as defined above; or (iii) a thiol of formula HS-R2, wherein R2 is as defined in formula I; or (iv) a phenol of formula HO-R2, wherein R2 represents phenyl, which may be mono- or disubstituted with halogen, lower alkyl or lower alkoxy; and converting any so-obtained compound wherein R1 is hydrogen by alkylation or benzylation into the corresponding compound of formula I, and, esterifying the so-obtained 3-hydroxy compound of formula I with an acid halide of formula halogen-CO-R5, a carboxylic acid of formula HOOC-R5 or a corresponding anhydride thereof, wherein R5 is as defined above, to produce the corresponding compound of formula I wherein R3 is an ester moiety, and, if necessary or desired, converting any free base so obtained into a pharmaceutically acceptable addition salt with an organic or inorganic acid; or (b) reacting a diol of formula III:

.....III
wherein Rl is as defined above, with an acid halide of formula halogen-co-R or the anhydride of a carboxylic acid of formula HOOC-R, wherein R is as defined above, and, if necessary or desired, esterifying any so-obtained 3-hydroxy compound with an acid halide of formula halogen-CO-R5 or the anhydride of a carboxylic acid of formula HOOC-R5, wherein R5 is as defined above, and if necessary or desired, converting any free base so obtained into a pharmaceutically acceptable addition salt with an organic or inorganic acid.

2. A process according to claim 1, wherein reaction steps (a)(i) and (a)(ii) are effected in the presence of a strong acid.

3. A process according to claim 1 or 2, wherein reaction steps (a)(iii) and (a)(iv) are effected in the presence of a base.

4. A process according to claim 2, wherein the strong acid is p-toluenesulphonic acid, sulphuric acid or hydrochloric acid.

5. A process according to claim l(b), wherein the diol of formula III is reacted with at least two moles of an acid halide of formula halogen-CO-R or the anhydride of the carboxylic acid of formula HOOC-R, wherein R is as defined in claim 1, to provide the compound of formula I
having the same ester moieties at positions 3 and 4.

6. Process for the production of a compound of formula I.

.....I
wherein X represents oxygen;
Rlrepresents a straight or branched chain lower alkyl;
R2 is a moiety of formula -COR, wherein R is a straight or branched chain lower alkyl group, a cycloalkyl group or a phenyl group;

R3 is a moiety of formula -OCO-R5, wherein R5 is (i) a straight or branched chain lower alkyl group, optionally substituted by a diphenyl group or a chlorophenoxy group, (ii) a cycloalkyl group, (iii) a 2- or 3-furyl group, or (iv) a phenyl group, optionally substituted by up to two lower alkyl groups, up to three lower alkoxy groups or a lower alkyl carbonyloxy group, which comprises:
(a) cleaving the epoxide ring of a compound of general formula IV:

..... IV

wherein R1 is as defined above, with a carboxylic acid of formula HO-CO-R wherein R is as defined above, the reaction being effected in the presence of a strong acid, and reacting the so-obtained 3-hydroxy compound with an esterification agent which is an acid halide of formula halogen-CO-R?
or the anhydride of the carboxylic acid of formula HOOC-R5, wherein R5 is as defined above, and, if necessary or desired, converting any free base so obtained into a pharmaceutically acceptable salt with an organic or inorganic acid; or (b) reacting a diol of formula III:

.....III

wherein Rl is as defined above, with an acid halide of formula halogen-CO-R or the anhydride of the carboxylic acid of formula HOOC-R, wherein R is as defined above and any free 3-hydroxy group in the so-formed product is esterified with an acid halide of formula halogen-CO-R5 or the anhydride of the carboxylic acid of formula HOOC-R5, wherein R5 is as defined above and, if necessary or desired, converting any free base so obtained Into a pharmaceutically acceptable addition salt with an organic or inorganic acid; or (c) reacting a diol of formula III;

..... III

wherein Rl is as defined above, with at least two moles of an esterification agent which is an acid halide of the formula halogen-CO-R or the anhydride of the carboxylic acid of formula HOOC-R, wherein R
is as defined above, to obtain the compounds of formula I having the same ester moietiPs at both positions 3 and 4, and, if necessary or desired, converting any free base so-obtained into a pharmaceutically acceptable addition salt with an organic or inorganic acid.

7. A process according to claim 6 for producing a compound of the restricted formula II:

.....II

wherein Rl represents lower alkyl;
R2 represents -COCH3, - COC2H5 or ; and R3 represents -OCOCH3, -OCOC2H5, -OCO-cycloalkyl or -OCOC6H4-Z wherein ? is hydrogen, lower alkyl, lower alkoxy or chlorine; which comprises:
(a) cleaving the epoxide ring of a compound of general formula IV:

..... IV

wherein R1 is as defined above, with a carboxylic acid of formula HOOC-CH3, HOOC-C2H5 or ; the reaction being effected in the presence of a strong acid, and reacting the so-obtained 3-hydroxy compound with an esterification agent of formula halogen-COCH3, halogen-COC2H5, halogen-CO-cycloalkyl or halogen-COC6H?-Z wherein Z is as defined above and, if necessary or desired, converting any free base so obtained into a pharmaceutically acceptable addition salt with an organic ox inorganic acid; or (b) reacting a diol of formula III:

.....III

wherein Rl is as defined above, with an acid halide of formula halogen-CO-R2 or the anhydride of the carboxylic acid of formula HOOC-R2 and any free 3-hydroxy group in the so-formed product is esterified with an acid halide of formula halogen-COCH3, halogen-COC2H5, halogen-CO-cycloalkyl or halogen-COC6H4-Z wherein Z is as defined above, and, if necessary or desired, converting any free base so obtained into a pharmaceutically acceptable addition salt with an organic or inorganic acid; or (c) reacting a diol of formula III:

..... III

wherein Rl is as defined above, with at least two moles of an esterification agent of the formula halogen-CO-R or the anhydride of the carboxylic acid of formula HOOC-R, wherein R
is as defined above, to obtain the compounds of formula II
having the same ester moieties at both positions 3 and 4, and, if necessary or desired, converting any free base so obtained into a pharmaceuticallv acceptable addition salt with an organic or inorganic acid.

8. A process according to claim 1 for the production of l-methy1-3-acetoxy-4-ethylcarbonyloxy-4-phenylpiperidine, wherein l-methyl-3,4-epoxy-4-phenylpiperidine is reacted with propionic acid and the so-obtained 3-hydroxy compound is reacted with acetyl chlorlde.

9. A process according to claim 1 for the production of l-methyl-3-cyclopropylcarbonyloxy-4-phenyl-4-ethylcarbonyl-oxypiparidine wherein l-methyl-3,4-epoxy-4-phenylpiperidine is reacted with propionic acid and the so-obtained 3-hydroxy compound is reacted with cyclopropyl carbonyl chloride.

10. A process according to claim l for the production of l-methyl-3-ethylcarbonyloxy-4-phenyl-4-ethylcarbonyloxy-piperidine, wherein l-methyl-3,4-epoxy-4-phenylpiperidine is reacted with propionic acid and the so-obtained 3-hydroxy compound is reacted with propionyl chloride.

11. A process according to claim 1 for the production of l-methyl-3-phenylcarbonyloxy-4-ethylcarbonyloxy-4-phenyl-piperidine, wherein l-methyl-3,4-epoxy 4-phenylpiperidine is reacted with propionic acid and the 3-hydroxy compound so obtained is reacted with benzoyl chloride.

12. A process according to claim 1 for the production of l-methyl-3-(2',6'-dimethoxyphenylcarbonyloxy)-4-acetoxy-4-phenylpiperidine, wherein-1-methyl-3,4-epoxy-4-phenyl-piperidine is reacted with acetic acid and the 3-hydroxy compound so obtained is reacted with 2,6-dimethoxybenzoyl chloride.

13. A process according to claim l for the production of l-methyl-3-cycloheptylcarbonyloxy-4-ethylcarbonyloxy-4-phenylpiperidine, wherein l-methyl-3,4-epoxy-4-pheny1-piperidine is reacted with propionic acid and the 3-hydroxy compound so obtained is reacted with cycloheptoyl chloride.

14. A process according to claim 1 for the production of 1-methyl-3-(2'-furylcarbonyloxy)-4-ethylcarbonyloxy-4-phenylpiperidine, wherein l-methyl-3,4-epoxy-4-phenylpiperidine is reacted with propionic acid and the 3-hydroxy compound so obtained is reacted with 2-furoyl chloride.

15. A process according to claim 1 for the production of l-methyl-3-(2'-fluorophenylcarbonyloxy)-4-ethylcarbonyloxy-4-phenylpiperidine, wherein 1-methyl-3,4-epoxy-4-phenyl-piperidine is reacted with propionic acid and the 3-hydroxy compound so obtained is reacted with 2-fluorobenzoyl chloride.

16. A process according to claim 1 for the production of l-methyl-3-ethylcarbonyloxy-4-cyclopropylcarbonyloxy-4-phenylpiperidine, wherein l-methyl-3,4-epoxy-4-phenylpiperidine is reacted with cyclopropylcarboxylic acid and the 3-hydroxy compound so obtained is raacted with propionyl chloride.

17. A process according to claim 1 for the production of l-methyI-3-cyclopropylcarbonyloxy-4-ethoxy-4-phenyl-piperidine, wherein l-methyl-3,4-epoxy-4-phenylpiperidine is reacted with ethyl chloride and the 3-hydroxy compound so obtained is reacted with cyclopropylcarbonyl chloride.

18. Novel 4-phenylpiperidines of the general formula I:

.....I

wherein Rl represents straight or bxanched chain lower alkyl or benzyl;
R2 represents a lower straight or branched chain alkyl which may carry a lower alkoxy; cycloalkyl;
lower alkenyl; lower alkynyl; phenyl optionally mono-or disubstituted by halogen, lower alkyl or lower alkoxy;
or, with the proviso that X represents only oxygen, a lower acyl of formula -CO-R wherein R is a straight or branched chain lower alkyl, a cycloalkyl or phenyl;
R3 represents hydroxy or an ester moiety of formula:

wherein R5 is straight or branched chain lower alkyl, which may be substituted with lower alkoxy carbonyl or chlorophenoxy;
cycloalkyl; lower alkenyl; diphenylmethyl; 2- or 3-furyl;
or phenyl, which may be substituted with up to two lower alkyl groups, up to three lower alkoxy groups, halogen, amino, nitro, trifluoromethyl, lower acylamino, or an ester moiety of formula -OCO-lower alkyl;
X represents oxygen or sulphur, as well as addition salts thereof with organic or inorganic acids, whenever prepared by the process according to claim 1 or an obvious chemical equivalent thereof.

19. Novel 4-phenylpiperidines of the formula I:

.....I

wherein X represents oxygen;

R1 represents a straight or branched chain lower alkyl;
R2 is a moiety of formula -COR, wherein R is a straight or branched chain lower alkyl group, a cycloalkyl group or a phenyl group;
R3 is a moiety of formula -OCO-R5, wherein R5 is (i) a straight or branched chain lower alkyl group, optionally substituted by a diphenyl group or a chlorophenoxy group.
(ii) a cycloalkyl group, (III) a 2- or 3-furyl group, or (iv) a phenyl group, optionally substituted by up to two lower alkyl groups, up to three lower alkoxy groups or a lower alkyl carbonyloxy group; as well as acid addition salts thereof with organic or inorganic acids, whenever prepared by the process according to claim 6 or an obvious chemical equivalent thereof.

20. Novel 4-phenylpiperidines of the restricted formula II:

wherein R1 represents lower alkyl;
R2 represents -COCH3, -COC2H5 or ; and R3 represents -OCOCH3, -OCOC2H5, -OCO-cycloalkyl or -OCOC?H4-Z wherein Z is hydrogen, lower alkyl, lower alkoxy or chlorine;

and pharmaceutically acceptable acid addition salts therof with organic or inorganic acids, whenever prepared by the process according to claim 7 or an obvious chemical equivalent thereof.

21. 1-Methyl-3-acetoxy-4-ethylcarbonyloxy-4-phenylpiperidine and pharmaceutically acceptable acid addition salts thereof with organic or inorganic acids, when-ever prepared by the process according to claim 8 or an obvious chemical equivalent thereof.

22. 1-Methyl-3-cyclopropylcarbonyloxy-4-phenyl-4-ethylcaxbonyloxypiperidine and pharmaceutically acceptable acid addition salts thereof with organic or inorganic acids whenever prepared by the process according to claim 9 or an obvious chemical eauivalent thereof.

23. 1-Methyl-3-ethylcarbonyloxy-4-phenyl-4-ethyl-carbonyloxypiperidine and pharmaceutically acceptable acid additon salts thereof with organic or inorganic acids, when-ever prepared by the process according to claim 10 or an obvious chemical equivalent thereof.

24. 1-Methyl-3-phenylcarbonyloxy-4-ethylcarbonyloxy-4-phenylpiperidine and pharmaceutically acceptable acid addition salts thereof with organic or inorganic acids, whenever prepared by the process according to claim 11 or an obvious chemical equivalent thereof.

2S. l-Methyl-3-(2',6'-dimethoxyphenylcarbonyloxy)-4-acetoxy-4-phenylpiperidine and pharmaceutically acceptable acid addition salts thereof with organic or inorganic acids, whenever prepared by the process according to claim 12 or an obvious chemical equivalent thereof.

26. 1-Methyl-3-cycloheptylcarbonyloxy-4-ethylcarbony-loxy-4-phenylpiperidine and pharmaceutically acceptable acid addition salts thereof with organic or inorganic acids, whenever prepared by the process according to claim 13 or an obvious chemical equivalent thereof.

27. 1-Methyl-3-(2'-furylcarbonyloxy)-4-ethylcarbonyloxy-4-phenylpiperidine and pharmaceutically acceptable acid addition salts thereof with organic or inorganic acids, whenever prepared by the process according to claim 14 or an obvious chemical equivalent thereof.

28. l-Methyl-3-(2'-fluorophenylcarbonyloxy)-4-ethylcar-bonyloxy-4-phenylpiperidine and pharmaceutically acceptable acid addition salts thereof with organic or inorganic acids, whenever prepared by the process according to claim 15 or an obvious chemical equivalent thereof.

29. 1-Methyl-3-ethylcarbonyloxy-4-cyclopropylcarbonyloxy-4-phenylpiperidine and pharmaceutically acceptable acid addition salts thereof with organic or inorganic acids, whenever pre-pared by the process according to claim 16 or an obvious chemical equivalent thereof.

30. 1-Methyl-3-cyclopropylcarbonyloxy-4-ethoxy-4-phenylpiperidine and pharmaceutically acceptable acid addition salts thereof with organic or inorganic acids, whenever prepared by the process according to claim 17 or an obvious chemical equivalent thereof.

31. A process according to claim l for the production of l-methyl-3-(3-carbomethoxypropylcarbonyloxy)-4-ethoxy-4-phenylpiperidine, wherein 1-methyl-3,4-epoxy-4-phenyl-piperidine is reacted with methanol and the so-obtained 3-hydroxy compound is reacted with carbomethoxypropionyl chloride.

32. l-Methyl-3-(3'-carbomethoxypropylcarbonyloxy)-4-ethoxy-4-phenylpiperidine and pharmaceutically acceptable addition salts thereof with organic or inorganic acids, whenever prepared by the process according to claim 31 or an obvious chemical equivalent thereof.