CA2023017A1 - 4,4-disubstituted piperidine derivatives, pharmaceutical compositions containing them and process for preparing the same - Google Patents

Abstract

NOVEL 4,4-DISUBSTITUTED PIPERIOINE DERIVATIVES, PHARMACEU-TICAL COMPOSITIONS CONTAINING THEM AND PROCESS FOR PREPARING
SAME

Abstract The invention relates to novel, therapeutically active 4,4-disubstituted piperidine derivatives of the formula (I), (I) wherein R1 means hydrogen or -CONHR group, wherein R stands for hydrogen, C1-12alkyl, C3-6cycloalkyl, carbocyclic C6-10aryl or carbocyclic C6-10aryl-C1-4alkyl group, the two latter ones being op-tionally substituted on their aromatic part by one or more, same or different halogen(s) or one or more C1-4alkyl or C1-4alkoxy group(s);
R2 stands for an ethynyl or acetyl group;
R3 and R4, which are the same or different, represent hydro-gen, one or more halogen(s), C1-4alkyl, C1-4alkoxy, trihalomethyl group or hydroxyl group optionally ester-ified by a C1-4alkanoic acid; and n is 1 or 2, as well as their pharmaceutically acceptable acid addition and quaternary ammonium salts.
The invention further relates to pharmaceutical compo-sitions containing these compounds and a proces for their preparation.
The compounds of the formula (I) are useful for the treatment of psychotic disorders, insomnia, mania, agita-tion, depression, anxiety, emesis, pain and dementia.

Description

NOVEL 4,4-DISUBSTITUTED PIPERIDINE DERIVATIVES, PHARMACEUTI-CAL COMPOSITIDNS CONTAINING THEM ANO PROCESS FOR PREPARING
SAME

The invention relates to novel, therapeutically active 4,4-disubstituted piperidine derivatives of the formula ~I), R~ C= CH--(CH2~n--N~( o R4~ (1) whErein Rl means hydrogen or -CONHR group, wherein R stands for hydrogen, Cl_l2alkyl, C3_6cycloalkyl, carbocyclic C6_10aryl or carbocyclic C6-loaryl-Cl_4alkyl group, the two latter ones being op-tionally substituted on their aromatic part by one or more, same or different halogen(s) or one or more Cl_4alkyl or Cl_4alkoxy group(s);

R2 stands for an ethynyl or acetyl group;
R3 and R4, which are the same or different, represent hydro-gen, one or more halogen(s), Cl_4alkyl, Cl_4alkoxy, trihalomethyl group or hydroxyl group optionally ester-ified by a Cl_4alkanoic acid; and n is 1 or 2, as well as their pharmaceutically acceptable acid addition , and quaternary ammonium salts and pharmaceutica]. composi-tions containing these compounds.
The invention also relates to a process for the prepa-ration of the above compounds and compositions as well as to a method cf treatment. The latter comprises administering a 5therapeutically effective amount of a compound of the for-mula (I) or a pharmaceutically acceptable acid addition and quaternary ammonium salts thereof alone or in the form of a pharmaceutical composition into the organism of a patient for treating psychotic disorders.
10The compounds of the formula (I) may exist in various stereoisomeric forms such as geometrical and optical iso-mers, racemates, separated optical isomers and their mix-tures, all of which may occur in the form of various sol-vates and hydrates. All these compounds and mixtures are 15within the scope of the invention.
4,4-Disubstituted piperidine derivatives have been described e.g. in the following publications: C.A. 52, 4519, 20206e (1958); C.A. 53, 20054c (1959); C.A. 56, 447c, 20054d ~1962); C.A. 59, 7473h (1963); C.A. 69 86169w, 100226w 20(1968); C.A. 72, 43382e; C.A. 73, 87739b (1970); C.A. 23876q (1973); C.A. 81, 33153c (1974); C.A. 95, 203709x (1981);
C.A. 10, 6627q, 2096089 (1984); C.A. 103, 160352q (19B5); as well as in the US patent specifications Nos. 4,405,631 and 4,521,537 and in the EP patent specification No. 275,962.
25A substantial difference between the compounds of for-mula (I) according to the invention and similar derivatives ~ ci~7 known up to the present appears in the nature of the substi-tuents bound in position 1 of the piperidine moiety.
According to an other aspect of the invention, there is provided a process for the preparation of compounds of the formula (I) as well as their acid addition and quaternary ammonium salts, which comprises a) ethynylating a 4-piperidone compound of the formula (II), R~ C =CH-(CH2)n--N~=O
~, ' (Il) wherein R3 and R4 are as defined above, to obtain compounds of the formula (I)g wherein Rl is hydrogen, R2 is an ethynyl group and R3, R4 as well as n are as defined above;
or b) hydrolytically cleaving a 2-oxo-1,3-dioxa-a-aza-spiro/4,5/decane derivative of the formula (III), R~ C = C H--(CH2)--N~

R4 ~ CH2 ( where n R3, R4 and n are as defined above, r~

to obtain compounds of the formula (I), wherein Rl is hydro-gen, R2 is an acetyl group and R3, R4 as well as n are as defined above;
or c) reacting a piperidine derivative of the formula (IV), ORl ~ XR2 ( IV) wherein Rl and R2 are as defined above, with a diphenylal-kene derivative of the formula (V), ~ ~ C - CH - (C H2 )n - Y
R4~ (Y) wherein R3, R4 and n are as defined above and Y means halo-gen, Cl_4alkylsulfonyloxy or arylsulfonyloxy group;
or d) reacting a carbonate ester derivative of the formula (VI), Y~ C = CH--(C H 2 )n--N~h R4~ (~'I ) wherein R2, R3, R4 and n are as defined above and R5 means a phenyl group optionally substituted by one or more halo-gen(s) or nitro group, with an amine of the formula R-NH2, where R is as defined above, to prepare compounds of the formula (I), wherein Rl stands for a -CONHR group and R, R2, R3, R4 and n are as defined above;
then, if desired, transforming a functional group of a thus-obtained compound of the formula (I), whrein R1, R2, R3, R4 and n are as defined above, to an other one in a known manner;
and/or hydrating a thus-obtained piperidine derivative of the for-mula (I), wherein R2 means an ethynyl group and Rl, R3, R4 as well as n are as defined above, -to obtain compounds of the formula (I), wherein R2 stands for an acetyl group and Rl, R3, R4 as well as n are the same as defined above;
and/or reacting a thus-obtained compound of the formula (I), wherein Rl means hydrogen and R2, R3, R4 as well as n are as , ~

~ J~

defined above, with a suitably substituted reactive carbamic acid derivative to obtain compounds of the formula (I), wherein R1 represents a -CONHR group, R2, R3, R4 as well as n are as defined above and R is as defined above, except hydrogen;
and/or reacting a thus-obtained compound of the formula (I), wherein R1, R2, R3, R4 and n are as defined above, with an acid to give an acid addition salt and/or treating a com-pound of the formula (I), wherein Rl, R2, R3, R4 and n are as defined above, obtained as a salt with a base to liberate the free basic form thereof and/or converting a thus-obtain-ed compound of the formula (I), wherein R1, R2, R3, R4 and n are as defined above, to its quaternary ammonium salt.
In the process a) according to the invention a 4-pipe-ridone derivative of the formula (II) is made to react with an alkaline metal acetylide. This ethynylating reaction is carried out by using the acetylide of lithium, sodium or po-tassium. For the formation of the alkaline metal acetylide e.g. alkaline metals or hydroxides, amides or alkoxides of alkaline me-tals may be employed. This reaction is performed in a solvent medium. Suitable solvents are e.g. liquid ammo-nia; aliphatic and alicyclic ethers such as diethyl ether, dipropyl ether, 1,2-dimethoxyethane, tetrahydrofuran, di-oxane; aliphatic alcohols such as isobutyl alcohol, tertiary butanol; acid amides such as N,N-dimethylformamide, N-me-thylacetamide, N-methylpyrrolidone; aliphatic, alicyclic r~

or aromatic hydrocarbons such as hexane t cyclohexane, ben-zene, toluene or xylene; sulfoxides such as dimethyl sulf-oxide; or mixtures of the above solvents. The ethynylation can be carried out under atmospheric or a higher pressure.
This reaction is preferably carried out in such a way that the 4-piperidone derivative of the formula (II) is brought into reaction with acetylene under atmospheric pressure, in the presence of an alkaline metal tertiary alkoxide and an organic solvent.
In the process b) according to the invention a spiro-decane derivative is hydrolytically cleaved. This reaction is preferably realized under basic conditions, in a solvent medium containing water. Suitable bases are e.g. carbonates and hydroxides of alkaline metals and/or tertiary organic bases. This reaction may be carried out in a wide tempera-ture range, e.g. at a temperature between 0C and the boil-ing point of the reaction mixture, preferably between 20C
and 140C, under an inert gas such as argon or nitrogen.

In the process c) according to the ir,vention a piperi-dine derivative of the formula (IV) is reacted with a diphe-nylalkene derivative of the formula (V). In the latter for-mula Y means e.g. a mesyloxy (methanesulfonyloxy) or tosyl-oxy (toluenesulfonyloxy) group or halogen, preferably chlorine or bromine. This reaction is preferably accom-plished in an inert organic solvent in the presence of a base being capable of binding the acid liberated in the - 8 - f ~

reaction. Suitable solvents are e.g. aliphatic alkanols such as ethanol, isopropanol or butanol; aromatic hydrocarbons suGh as chlorobenzene or toluene; ethers such as dibutyl ether or dioxane; tertiary aliphatic acid amides such as di-methylformamide, dimethylacetamide; ketones such as acetone, methyl ethyl ketone or methyl isobutyl ketone; but a mixture of the above solvents may be employed, too. For binding the acid liberated in the reaction, inorganic or tertiary organic bases, e.g. carbonates or hydrogen carbonates of alkaline metals or alkaline earth metals as well as organic bases, e.g. triethylamine, dimethylaniline or pyridine may be used; though an excess of the compound of the formula (IV) is also suitable for this purpose. This reaction may be carried out between room temperature and the boiling point of the reaction mixture; optionally, a catalyst may also be added. Suitable catalysts are alkaline metal iodides. It is preferable to work under an inert gassuch as nitrogen or argon.
In the process d) according to the invention a car-bonate ester of the formula (VI) is brought into reaction with an amine of the formula R-NH2. This reaction may be performed in the presence of or without any solvent. Suit-able solvents are e.g. aliphatic, alicyclic or aromatic hyd-rocarbons such as hexane, cyclohexane, benzene, chloroben-zene, nitrobenzene or xylene; ethers such as diethyl ether, di-n-butyl ether, tetrahydrofuran and dioxane; alcohols such J~ ~t as ethanol, butanol, cyclohexanol or benzyl alcohol; ter--tiary organic bases such as picoline, pyridine or triethyl-amine; or an excess of the R-NH2 amine may also be utilized as solvent. Any mixture of the above solvents may also be employed. The reaction is carried out between -35C and the boiling point of the reaction mixture. It is of purpose to use an inert gas environment such as argon or nitrogen in this reaction.
If desired, the compounds of the formula (I) obtained by using the processes a) to d) can be transformed to other compounds being within the scope of the formula (I) in a manner known per se.
Thus, by hydrating a compound of the formula (I) con-taining an ethynyl group as R2, compounds of the formula (I) are obtained, wherein R2 means an acetyl group.
In the course of this transformation a 4-ethynyl-4-pi-peridinol derivative of the formula (I) is reacted with water in the presence of a mercuric compound, optionally in an acidic medium. Suitable mercuric compounds for this pur-pose are e.g. mercuric o~ide, mercuric chloride, mercuric sulfate, mercuric acetate, mercuric acetamide or mercuric p-toluenesulfonamide. Sulfuric or ace-tic acid may e.g. be used as acids. Suitable solvents are e.g. aliphatic alcohols such as methanol or ethanol; aliphatic ketones such as acetone;
aliphatic carboxylic acid esters such as ethyl acetate; ali-cyclic ethers such as dioxane and tetrahydrofuran; or mix-~; ~ 2 .~ v . b tures of the above solvents. This reaction is carried out in a temperature range between room temperature and the boiling point of the reaction mixture. Optionally, mercury can be removed by using hydrogen sulfide.
If desired, compounds of the formula (I) containing -CONHR group as Rl can be prepared by reacting a 4-piperidi-nol derivative of the formula (I) with an appropriately sub-stituted reactive carbamic acid derivative. As a reactive carbamic acid derivative e.g. a carbamic acid halide of the formula (VII), R--NHCOX
(~11 ) wherein R is as defined above, except hydrogen, and X means halogen, or an isocyanate of the formula R-NOC, wherein R is as defined for formula (VII), may be used. This reaction is realized in an organic solvent, which is inert under the reaction conditions, in the presence of a suitable inorganic and/or tertiary organic base. Suitable solvents are e.g.
aliphatic or alicyclic ethers such as diethyl ether, di-propyl ether, diisopropyl ether, dioxane or tetrahydrofuran;
aliphatic, alicyclic or aromatic hydrocarbons such as methy-lene chloride, hexane, cyclohexane, benzene, toluene or xylene; nitriles such as acetonitrile; acid amides such as dimethylformamide or N-methylpyrrolidone; sulfoxides such as dimethyl sulfoxide; or mixtures of the above solvents. An excess of the tertiary organic base, e.g. an excess of pyri-~ iJ~

dine or triethylamine may also be employed. Finally, the reaction may also be carried out without any solvent, e.g.
in a molten state.
The reaction is highly accelerated by inorganic or ter-tiary organic bases; therefore, it is suitable to carry out this reaction in the presence of such bases. As basic cata-lysts e.g. amides, carbonates or hydroxides of alkaline metals and/or tertiary organic bases, e.g. pyridine, tri-ethylamine, 4-dimethylaminopyridine, triethylenediamine and the like may be employed.
The temperature of the reaction may be varied under wide limits: usually, the reaction is performed in a temper-ature range between 5C and the boiling point of the reac-tion mixture, preferably between 10C and 140C. It is preferable to use an inert gas atmosphere, e.g. nitrogen or argon.
If desired, the compounds of the formula (I) can be transformed to their acid addition or quaternary ammonium salts by using methods known per se. For the preparation of acid addition salts inorganic or organic acids such as hyd-rogen halides, e.g. hydrochloric acid and hydrobromic acid;
sulfuric acid, phosphoric acids as well as formic, acetic, propionic, oxalic, glycolic, maleic, fumaric, succinic, tartaric, ascorbinic, citric, malic, salicylic, lactic, ben-zoic, cinnamic, aspartic, glutamic, N-acetyl-aspartic or N-acetylglutamic acid as well as alkanesulfonic acids such as methanesulfonic acid or arenesulfonic acids, e.g. p-toluene-sulfonic acid and the like, may be used.
The salt formation can be carried out e.g. in such a way that the corresponing acid is added to the solution of the compound of the formula (I) prepared in an inert sol-vent, e.g. ethanol, and the salt formed is precipitated by adding preferably a water-immiscible organic solvent, e.g.
diethyl ether.
For the preparation of quaternary ammonium salts a lower alkyl, alkenyl or benzyl halide or an alkyl sulfate may favourably be employed. The quaternization is suitably performed in an organic solvent such as acetone, acetonit-rile, ethanol or their mixtures at a temperature range from room temperature up to the boiling point of the solvent.
The acid addition or quaternary ammonium salt obtained may be isolated e.g. by filtration and, when necessary, purifed by recrystallization.
Conversely, the corresponding free bases can be liber-ated from their salts by an alkaline treatment.
The starting substances used in the process nf the in-vention are partly known or can be prepared by using known methods.
The compounds of the formulae (II) and (V) can be pre-pared e.g. according to the following literature references:
Ber. 55, 3406 (1922); Ann. Chem. 555, 80 (1952); GB patent specification No. 683,950; Yakugaku Zasshi 82, 1088 (1952);

fJ~3~17 J. Chem. Soc. 4066 (1959); Coll. Czechoslov. Chem. Commun.
38, 3879 (1973).
The preparation of the compounds of the formula (III) is described in the Hungarian patent application No. 4094/B9 filed on August lû, 1989.
The compounds of the formula (IV) are obtained e.g. by removing the N-protective group of suitably substituted pi-peridine derivatives by using methods commonly known from the literature /see e.g. T. W. Greene: "Protective Groups in lû ûrganic Synthesis", Ed. John Wiley, New York, pages 218 to 228. (1981)/.
The carbonate esters of the formula (VI) can be pre-pared e.g. by reacting suitably substituted 4-hydroxypiperi-dine derivatives with the corresponding chloroformates /see e.g. Houben-Weyl: Methoden der ûrganischen Chemie, Vol. VIII
page 106 (1952)/.
The new compounds of the formula (I) according to the invention are, on the one hand, valuable intermediates in the synthesis of compounds exerting antipsychotic and cog-nitive function-improving effects (see the Hungarian patent applications Nos. 4û94/89 and 4û95/89) and, on the other hand, they exert an own preferable biological activity e.g.
on the central nervous system, too. This central nervous system action of the compounds of the present invention was investigated by using the methods described hereinafter.

~. 3 ~ ci ~17 1) Inhibition of the tetrabenazine-induced catalepsy Male Hannover-Wistar rats weighing 160 to 180 9 each were used in these examinations. Various doses of the test compounds were orally administered in an aqueous suspension containing 10% of Tween 80. After oral doses of the test substances the groups consisting of 5 animals each were intraperitoneally (i.p.) treated with a 30 mg/kg dose of tetrabenazine (9,10-dimethoxy-3-isobutyl-2-oxo-1,2,3,4,6,7-hexahydro-llb(H)-benzo/ a_/quinolizine). The control group was treated with placebo, i.e. the above suspension contain-ing no test compound. The behaviour of the animals was hourly observed for 3 hours. An animal was considered to be cataleptic when it did not correct within 30 seconds its whimsical body position caused by lifting its upper limbs onto a 7 cm high column.

2) Inhibition of the pentylenetetrazole-induced seizure Groups consisting of 10 male CFLP/LATI mice weighing 18-22 9 each were used in these examinations. Various doses of the test compounds were orally administered to the animals in an aqueous suspension containing 10% of Tween 80.
One hour after this pretreatment, the animals were sub-cutaneously treated with a dose of 125 mg/kg of pentylene-tetrazole (6,7,8,9-tetrahydro-5H-tetrazolo /l,S-a/azepine).
After administration of the convulsive agent the animals were observed for 30 minutes. An animal was considered to be protected when the tonic extensor seizure was abolished on 2~2~

effect of the treatment with the test compound. The control group was treated with placebo.

3) Measurement of the analqetic effect on mice One hour after an oral pretreatment with various doses of the test compounds groups consisting of 10 mice each were intraperitoneally treated with 0.3 ml of a 0.6 % by volume acetic acid solution as pain stimulus. The frequency of the writhing syndrome was registered during a period of 30 minutes. The decrease caused by the treatment was related to the mean value of the writhing frequency observed in the control group. The ED50 value was calculated from these differences expressed as percentages.
The results are summarized in the Table following hereinafter. The ED50 values were calculated by using the probit analysis with 95% confidence limits.
The abbreviations used in the Tab]e are as follows:
A : l-r3,3-bis(4-fluorophenyl)-2-propenyl/-4-ethynyl-4-hydr-oxypiperidine hydrochloride ~ L4,4-bis(4-fluorophenyl)-3-butenyl/-4-ethynyl-4-hydr-oxypiperidine hydrochloride Imipramine: 5-(3-dimethylaminopropyl)-10,11-dihydro-5H-di-benzo/b,f/azepine Nomifensine: ~-amino-2-methyl-4-phenyl-1,2,3,4-tetrahydro-isoquinoline NE: inactive in an oral dose of 30 mg/kg p.o.: oral administration.

~ ~3 ~ rd~

Table ED50 p.o. (mg/kg) Compound Inhibition of Inhibition of Inhibition of the tetrabena- the pentylene- writhing zine catalepsv tetrazole seizure syndrome A 30.0 30.0 30.0 B lB.7 21.0 13.7 Imipramine 25.1 35.4 30.0 Nomifensine 23.9 NE NE

The new compounds of the formula (I) according to the invention possess an antidepressive effect which is equal to or higher than that of imipramine or nomifensine used as reference drugs. Their anticataleptogenic action is accom-panied by a significant anticonvulsive effect; in addition as opposed to imipramine, no proconvulsive effect was observed on increasing the dose of the compounds according to the invention.
The compounds according to the invention possess a pro-nounced analgetic effect being very advantageous in the treatment of psychotic disorders, e.g. reactive depression which can be developed on effect of pain sensation.

Contrarily to imipramine, a further advantage appears therein -that the compounds of the invention show anticholi-nergic effect, which sugges-ts a decrease in or elimination of side effects in the clinical practice in comparison to the reference drug. Due to their psychotropic, analgetic and r~

anticonvulsive effects, the compounds of the formula (I) are useful for the systemic treatment of warm-blooded animals (including man). Here the term "systemic treatment" means oral, rectal or parenteral administration. The compounds of formula ~I) can therapeutically be utilized for the treat-ment of e.g. psychotic disorders such as insomnia, mania, agitation, depression, anxiety, emesis, pains and dementia.
The daily dosis depends on the severity of the disease and the status of the patient and amounts to 0.1-40 mg/kg which can be administered once or in several subdoses in oral, rectal or parenteral route.
The compounds according to the invention can be con-verted into pharmaceutical compositions. These compositions may be administered orally, rectaly and/or parenterally. For oral administration, the composition may be formulated e.g.
as a tablet, dragee or capsule. In order to prepare oral compositions, e.g. lactose or starch may be used as carriers. Gelatine, carboxymethylcellulose sodium, methyl-cellulose, polyvinylpyrrolidone or starch gum are suitable binding or oranulation agents. As disintegrating agents mainly potato starch or microcrystalline cellulose may be added though ultraamylopectin or formaldehyde-casein and the like are also useful. Talc, colloidal silicic acid, stearin, calcium or magnesium stearate and the like are suitable anti-adhesive and sliding agents. Liquid oral compositions can be formulated e.g. as suspensions, syrups, or elixirs which may contain water, glycols, oils, alcohols as well as colouring and flavouring agents.
Tablets may be prepared e.g. by compression following wet granulation. The mixture of the active ingredient wi~h the carriers and optionally with a part of the disintegrat-ing additive is granulated with an aqueous, alcoholic or aqueous-alcoholic solution of the binding agents in a suit-able equipment, then the granulate is dried. Subsequently, after mixing the other disintegrating, sliding and anti-adhesive additives to the dried granulate, the mixture is compressed to tablets. If desired, the tablets may be provided with a groove in order to facilitate the admi-nistration. Tablets may also directly be prepared from a mixture containing the active ingredient and suitable addi-tives. The tablets may optionally be converted to dragées by employing commonly used pharmaceutical additives, e.g.
protective, flavouring or colouring agents such as sugar, cellulose derivatives (methyl- or ethylcellulose, carboxyme-thylcellulose sodium and the like), polyvinylpyrrolidone, calcium phosphate, calcium carbonate, food dyes, dyeing lacquers, aromatizing agents, iron oxide, pigments and the like. Encapsulated compositions are prepared by filling a ~ixture of the active ingredient with the additives into capsules.
For rectal administration, the composition of the invention is formulated as a suppository containing a 3 i7 carrier mass, the so-called "adeps pro suppositorio" in addition to the active ingredient. As carriers, vegetable fats such as hardened vegetable oils, or triglycerides of C12_18 fatty acids (preferably the carriers bearing the trade name Witepsol) may be used. The active ingredient is uniformly distributed in the molten carrier mass, then sup-positories are prepared by moulding.
For parenteral administration, the composition of the invention is formulated as an injectable solution. For pre-lû paring these injectable solutions, the active ingredients are dissolved in distilled water and/or various organic sol-vents, e.g. glycol ethers, if desired, in the presence of solubilizing agents such as polyoxyethylene sorbitan mono-laurate or monooleate or monostearate (Tween 20, Tween 60 or Tween 80), respectively. The injectable solution may further contain various auxiliary agents, e.g. preservatives such as ethylenediamine tetraacetate as well as pH-modifying and buffering substances or, if desired, a local anaesthetic agent such as lidocaine. Before fllling into the ampoules, the injectable solution containing the composition of the invention is filtered and after filling in, it is subjected to sterilization.
The invention also relates to a method for treating psychotic (psychiatric) disorders, insomnia, mania, agita-tion, depression, anxiety, emesis, dementia and pain. This method comprises administering a therapeutically effective $ ~

amount of an active ingredient of the formula (I) or a phar-maceutically acceptable acid addition salt or quaternary ammonium salt thereof to the patient.
The invention is illustrated in detail by the aid of the following non-limiting Examples.
Example 1 Preparation of 1-/4,4-bis(4-fluorophenyl)-3-butenyl/-4-ethy-nyl-4-hydroxypiperidine After introducing acetylene to a solution containing 19.2 9 of potassium tert-butoxide in 125 ml of tetrahydrofu-ran at a temperature between 0C and -5C while stirrring for 3Q minutes, 39.0 9 of 1-/4,4-bis(4-fluorophenyl)-3-bute-nyl/piperidone dissolved in 90 ml of tetrahydrofuran are dropwise added and acetylene is introduced for one additional hour. Then the reaction mixture is cooled down to -10C, aqueous saturated ammonium chloride solution is added under nitrogen, the tetrahydrofuran is evaporated under reduced pressure and the distillation residue is extracted with benzene. After washing the benzene layer with water and dryin~ over anhydrous magnesium sulfate, the solution is evaporated under reduced pressure. After recrystallizing the residue from ethanol the title product is obtained in 92.1~%
yield, m.p.: 116-117 C.
The hydrochloride of the title free base melts at 210-212C.
Analysis of the free base:

2 3 ~

Calculated for C23H23F2N
C 75.18; H 6.31; F 10.34; N 3.B1%;
found: C 75.24; H 6.20; F 10.11; N 4.02%.
8y using the appropriate starting substances the fol-lowing compounds are prepared in an analogous manner as described in the preceding Example:
1-/3,3-bis(4-fluorophenyl)-2-propenyl/-4-ethynyl-4-hydroxy-piperidine, m.p.: 13B-139C; hydrochloride m.p.: 189-190C;
1-L3-(3-trifluoromethylphenyl)-3-(4-acetyloxyphenyl)-2-pro-penyl7-4-ethynyl-4-hydroxypiperidine hydrochloride, m.p.:
lB9-190C;
1-/3,3-bis(3,5-dichlorophenyl)-2-propenyl/-4-ethynyl-4-hydr-oxypiperidine oxalate, m.p.: 153-155C; and 1-/4,4-bis(4-chlorophenyl)-3-butenyl/-4-ethynyl-4-hydroxypi-peridine hydrochloride, m.p.: 217-219C;
Example 2 Preparation of 1-/4,4-bis(4-fluorophenyl)-3-butenyl/-4-ace-tyl-4-hydroxypiperidine hydrochloride 10.3 9 of 9-/4,4-bis(4-fluorophenyl)-3-butenyl7-4-me-thylene-2-oxo-1,3-dioxa-8-a,aspiro/4,5/decane are stirred with 100 ml of 2.8 mol/litre sodium hydroxide solution at 80-90C under argon for 2 hours. After cooling down the reaction mixture is extracted with benzene and after washing the benzene phase with water to neutral and drying over an-hydrous sodium sulfate, the solvent is evaporated under reduced pressure. The evaporation residue is dissolved in diisopropyl ether and the hydrochloride according to the title is precipitated by adding hydrogen chloride dissolved in diisopropyl ether to give the title hydrochloride in 91.3% yield, m.p.: 194-198C.
Analysis of the free base:
Calculated for C23H23F2N
C 71.67; H 6.54; F 9.86; N 3.63%;
found: C 71.71; H 6.32; F 10.01; N 3.66%.

Example 3 Preparation of 1-(3,3-diphenyl-2-propenyl)-4-ethynyl-4-hydr-oxypiperidine A solution of 16.5 9 of 3,3-diphenyl-2-propenyl bromide in 70 ml of acetone is added dropwise to a mixture of 7.5 9 of 4-ethynyl-4-hydroxypiperidine, 8.5 9 of anhydrous potas-sium carbonate and 75 ml of anhydrous acetone at room tem-perature during 45 minutes, then the reaction mixture isstirred at room temperature for one hour. After filtering off the inorganic salts the solution is evaporated under reduced pressure. The residue is taken up in benzene, washed with water, dried over anhydrous sodium sulfate and the solution is evaporated under reduced pressure. After recrys-talli~ing the residue from acetonitrile the title product is obtained in 6~.4% yield, m.p.: 122-123C.

Analysis:
Calculated for C22H23~
C 83.24; H 7.30; N 4.41%;

2 ~

found: C 83.27; H 7.44; N 4.57%.
The hydrochloride of the title base is precipitated from an ethereal solution of the base by adding ethereal hydrogen chloride solution, m.p.: 158-161C.
Example 4 Preparation of 1-/4,4-bis(4-fluorophenyl)-3-butenyl7-4-bu-tylcarbamoyloxy-4-ethynyl-4-hydroxypiperidine A mixture containing 18.4 8 of 1-L4,4-bis(4-fluorophe-nyl)-3-butenyl/-4-ethynyl-4-hydroxypiperidine, 7.4 ml of bu-lû tyl isocyanate and 90 ml of triethylamine is gently refluxed under nitrogen while stirring for 7 to 8 hours. After eva-porating the reaction mixture under reduced pressure, the residue is taken up in methanol, the solution is clarified by activated carbon at room temperature, then the methanol is distilled off under reduced pressure. After recrystalliza-tion of the crude produet from a mixture of diisopropyl ether and hexane the title product is obtained in E2.2%
yield, m.p.: E3-84C.
Analysis:
Calculated for C28H32F2N22 C 72.08; H 6.91; F 8.14; N 6.00%;
found: C 72.221 H 7.13; F 8.11; N 6.17%.
By using the appropriate starting substances the following compounds are prepared in an analogous manner as described in the preceding Example:

4-acetyl-1-r ,4-bis(4-fluorophenyl)-3-butenyl/-4-phenylcarb-r~

amoyloxypiperidine, m.p.: 139-141C;
4-cyclohexylcarbamoyloxy-1-(313-diphenyl-2-propenyl)-4-ethy-nylpiperidine hydrochloride, m.p.: 237-240C (with decompo-sition);
4-acetyl-1-(3,3-diphenyl-2-propenyl)-4-ethylcarbamoyloxypi-peridine hydrochloride, m.p.: 190-192C; and 1-/4,4-bis~l-chlorophenyl)-3-butenyl/-4-_(4-chlorophenyl)-carbamoyloxy7-4-ethynyl-4-hydroxypiperidine hydrochloride, m.p.: 244-247C (with decomposition).
Example 5 Preparation of 4-benzylcarbamoyloxy-1-/4,4-bis(4-fluorophe-nyl)-3-butenyl7-4-ethynyl-4-hydroxypiperidine 9.8 9 of 1-/4,4-bis(4-fluorophenyl)-3-buteny_/-4-ethy-nyl-4-phenoxycarbonyloxypiperidine are stirred with 9 ml of benzylamine at 42C under nitrogen for 30 minutes, then at room temperature for 10 hours. Thereafter, benzene is added to the reaction mixture and washed first with an aqueous sodium hydroxide solution of 1 ml/litre concentration, then with water and dried over anhydrous magnesium sulfate. After evaporating the solution under reduced pressure, the residue is boiled in hexane and after filtration it is recrystalliz-ed from diisopropyl ether to give the title product in 75.7%
yield, m.p.: 94-95C.
Analysis:
Calculated for C31H30F2N22 C 74.3a; H 6.04; F 7.59; N 5.60%;

~2~ ~ P~

found: C 74.22; H 5.69; F 7.69; N 5.53%.
By using the appropriate starting substances the fol-lowing compounds are prepared in an analogous manner as described in the preceding Example:
1-/4,4-bis(4-fluorophenyl)-3-butenyl/-4-/ /2-(3,4-dimethoxy-phenyl)ethyl/carbamoylox~/-4-ethynyl-4-hydroxypiperidine maleate, m.p.: 53-54C; and l-L4,4-bis(4-fluorophenyl)-3-butenyl/-4-carbamoyloxy-4-ethy-nylpiperidine hydrochloride, m.p.: 206-207C.
Example 6 Preparation of 4-acetyl-1-/3,3-bis(4-fluorophenyl)-2-prope-nyl/-4-hydroxypiperidine hydrochloride After dissolving 10.6 9 of 1-/3,3-bis(4-fluorophenyl)-2-propenyl7-4-ethynyl-4-hydroxypiperidine in the mixture of 37.5 ml of acetic acid and 1.5 ml of acetic anhydride at 25 C, 10.5 9 of mercuric acetate are added in four portions.
After stirring for 7 hours the reaction mixture is left to stand overnight, then gaseous hydrogen sulfide is introduced for one hour under stirring. After standing for 3 hours the precipitate is filtered, washed with acetic acid and the solution is evaporated under reduced pressure. The residue is taken up in ether, washed with aqueous sodium carbonate solution of 10% by weight and then with water, dried over anhydrOus magnesium sulfate and evaporated under reduced pressure. After adding methanolic potassium hydroxide solu-tion of 5% by weight, the residue is stirred under nitrogen ' ~

:

~ ~ h ~

at room temperature for one hour, then diluted with water and extracted with benzene. The benzene phase is washed to neutral, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue is transformed to the hydrochloride by adding hydrogen chloride dissolved in di-isopropyl ether to obtain the title hydrochloride in 72.1%
yield, m.p.: 257-259C (with decomposition).
Analysis:

Calculated for C22H23F2N2 C 71.14; H 6.24; F 10.23; N 3.77%;

found: C 71.35; H 6.60; F 10.11; N 3.79%.
Example 7 The new compounds according to the invention can be converted e.g. to the following pharmaceutical compositions.
a) Preparation of tablets 50.û 9 of active ingredient are mixed together with 92 _ of lactose, 40 9 of potato starch, 4 9 of polyvinylpyrro-lidine, 6 9 of talc, 1 9 of magnesium stearate, 1 9 of col-loidal silicon dioxide (Aerosil) and 6 9 of ultraamylopectin20 and, after wet granulation, the product obtained is com-pressed to tablets containing 50 mg of the active ingredienteach.
b) Preparation of dragées After coating the tablets prepared as described above in a known manner with a layer consisting of sugar and talc, the dragées obtained are polished with a mixture of bee wax and carnauba wax to obtain dragées weighing 250 mg each.
c) Preparation of capsules 100 9 of active ingredient are thoroughly mixed together with 30 ~ of sodium lauryl sulfate, 280 9 of starch, 280 9 of lactose, 4 9 of colloidal silicon dioxide (Aerosil) and 6 9 of magnesium stearate, then the mixture is sieved and filled into hard gelatine capsules to obtain cap-sules containing 100 mg of active ingredient each.

d) Preparation of suppositories 100.0 mg of active ingredient are thoroughly mixed to-gether with 200.0 mg of lactose; 1700.0 mg of suppository base (e.g. ~itepsol 4)(all calculated for one suppository) are molten, cooled to 35C and the mixture of the active in-gredient and lactose is mixed thereto by using a homogeni-zer. The product obtained is poured into cooled conic moulds. Each suppository weighes 2000 mg.
e) Preparation of a suspension Components in 100 ml of the suspension:

Active ingredient 1.00 9 Sodium hydroxide 0.26 9 Citric acid 0.30 9 Nipagin (methyl 4-hydroxybenzoate sodium salt) 0.10 9 Carbapol 940 (polyacrylic acid) 0.30 9 96% Ethanol 1.00 9 Raspberry flavour 0.60 9 .
- ' ' , , , ù~ 7 Sorbitol (Aqueous solution of 70%) 71.00 9 Distilled water up to 100.00 ml After adding Carbopol in little portions to the solu-tion of Nipagin and citric acid in 20 ml of distilled water under vigorous stirring, the solution obtained is let to stand for 10 to 12 hours. Subsequently, the amount given above of sodium hydroxyde dissolved in 1 ml of destilled water, the aqueous solution of sorbitol and finally the ethanolic solution of the raspberry flavour are dropped in under stirring. The active ingredient is added in small por-tions to this mixture and suspended by using a submerged homogenizer. Finally, the suspension is supplemented to 100 ml by adding distilled water and the syrupy suspension is led through a colloid mill.

2û

Claims (11)

1. Novel, therapeutically active 4,4-disubstituted pi-peridine derivative of the formula (I), (I) wherein R1 means hydrogen or -CONHR group, wherein R stands for hydrogen, C1-12alkyl, C3-6cycloalkyl, carbocyclic C6-10aryl or carbocyclic C6-10aryl-C1-4alkyl group, the two latter ones being op-tionally substituted on their aromatic part by one or more, same or different halogen(s) or one or more C1-4alkyl or C1-4alkoxy group(s);
R2 stands for an ethynyl or acetyl group;
R3 and R4, which are the same or different, represent hydro-gen, one or more halogen(s), C1-4alkyl, C1-4alkoxy, trihalomethyl group or hydroxyl group optionally ester-ified by a C1-4alkanoic acid; and n is 1 or 2, as well as their pharmaceutically acceptable acid addition and quaternary ammonium salts,

2. A compound selected from the group consisting of 1-[3,3-bis(4-fluorophenyl)-2-propenyl]-4-ethynyl-4-hydroxy-piperidine hydrochloride, l-[4,4-bis(4-fluorophenyl)-3-butenyl]-4-ethynyl-4-hydroxypi-peridine hydrochloride, 1-[4,4-bis(4-fluorophenyl)-3-butenyl]-4-benzylcarbamoyloxy-4-ethynylpiperidine as well as the pharmaceutically acceptable acid addition and quaternary ammonium salts of these compounds.

3. A pharmaceutical composition, which comprises as active ingredient one or more 4,4-disubstituted piperidine derivative(s) of the formula (I), wherein R1, R2, R3, R4 and n are ad in claim 1, or a pharmaceutically acceptable acid addition and quaternary ammonium salt thereof.

4. A process for the preparation of the novel therapeu-tically active 4,4-disubstituted piperidine derivatives of the formula (I), (I) wherein R1 means hydrogen or -CONHR group, wherein R stands for hydrogen, C1-12alkyl, C3-6cycloalkyl, carbocyclic C6-10aryl or carbocyclic C6-10aryl-C1-4alkyl group, the two latter ones being op-tionally substituted on their aromatic part by one or more, same or different halogen(s) or one or more C1-4alkyl or C1-4alkoxy group(s);
R2 stands for an ethynyl or acetyl group;
R3 and R4, which are the same or different, represent hydro-gen, one or more halogen(s), C1-4alkyl, C1-4alkoxy, trihalomethyl group or hydroxyl group optionally ester-ified by a C1-4alkanoic acid; and n is 1 or 2, as well as their pharmaceutically acceptable acid addition and quaternary ammonium salts, which comprises a) ethynylating a 4-piperidone compound of the formula (II), (II) wherein R3 and R4 are as defined above, to obtain compounds of the formula (I), wherein R1 is hydrogen, R2 is an ethynyl group and R3, R4 as well as n are as defined above;
or b) hydrolytically cleaving a 2-oxo-1,3-dioxa-8-aza-spiro[4,5]decane derivative of the formula (III), (III) wehrein R3, R4 and n are as defined above, to obtain compounds of the formula (I), wherein R1 is hydro-gen, R2 is an acetyl group and R3, R4 as well as n are as defined above;
or c) reacting a piperidine derivative of the formula (IV), (IV) wherein R1 and R2 are as defined above, with a diphenylal-kene derivative of the formula (V), (V) wherein R3, R4 and n are as defined above and Y means halo-gen, C1-4alkylsulfonyloxy or arylsulfonyloxy group;
or d) reacting a carbonate ester derivative of the formula (VI), (VI) wherein R2, R3, R4 and n are as defined above and R5 means a phenyl group optionally substituted by one or more halo-gen(s) or nitro group, with an amine of the formula R-NH2, where R is as defined above, to prepare compounds of the formula (I), wherein R1 stands for a -CONHR group and R, R2, R3, R4 and n are as defined above;
then, if desired, transforming a functional group of a thus-obtained compound of the formula (I), whrein R1, R2, R3, R4 and n are as defined above, to an other one in a known manner;
and/or hydrating a thus-obtained piperidine derivative of the for-mula (I), wherein R2 means an ethynyl group and R1, R3, R4 as well as n are as defined above, to obtain compounds of the formula (I), wherein R2 stands for an acetyl group and R1, R3, R4 as well as n are the same as defined above;
and/or reacting a thus-obtained compound of the formula (I), wherein R1 means hydrogen and R2, R3, R4 as well as n are as defined above, with a suitably substituted reactive carbamic acid derivative to obtain compounds of the formula (I), wherein R1 represents a -CONHR group, R2, R3, R4 as well as n are as defined above and R is as defined above, except hydrogen;
and/or reacting a thus-obtained compound of the formula (I), wherein R1, R2, R3, R4 and n are as defined above, with an acid to give an acid addition salt and/or treating a com-pound of the formula (I), wherein R1, R2, R3, R4 and n are as defined above, obtained as a salt with a base to liberate the free basic form thereof and/or converting a thus-obtained compound of the formula (I), wherein R1, R2, R3, R4 and n are as defined above, to its quaternary ammonium salt.

5. A process for the preparation of the novel, thera-peutically active 4,4-disubstituted piperidine derivatives of the formula (I), (I) wherein R1 means hydrogen or -CONHR group, wherein R stands for hydrogen, C1-12alkyl, C3-6cycloalkyl, carbocyclic C6-10aryl or carbocyclic C6-10aryl-C1-4alkyl group, the two latter ones being op-tionally substituted on their aromatic par-t by one or more, same or different halogen(s) or one or more C1-4alkyl or C1-4alkoxy group(s);
R2 stands for an ethynyl or acetyl group;
R3 and R4, which are the same or different, represent hydro-gen, one or more halogen(s), C1-4alkyl, C1-4alkoxy, trihalomethyl group or hydroxyl group optionally ester-ified by a C1-4alkanoic acid; and n is 1 or 2, as well as their pharmaceutically acceptable acid addition and quaternary ammonium salts, which comprises a) ethynylating a 4-piperidone compound of the formula (II), (II) wherein n, R3 and R4 are as defined above, to obtain compounds of the formula (I), wherein R1 is hydro-gen, R2 is an ethynyl group and R3, R4 as well as n are as defined above;
or b) hydrolytically cleaving a 2-oxo-1,3-dioxa-8-aza-spiro[4,5]decane derivative of the formula (III), (III) wherein R3, R4 and n are as defined above, to obtain compounds of the formula (I), wherein R1 is hydro-gen, R2 is an acetyl group and R3, R4 as well as n are as defined above;
then, if desired, hydrating a thus-obtained piperidine derivative of the for-mula (I), wherein R2 means an ethynyl group and R1, R3, R4 as well as n are as defined above, to obtain compounds of the formula (I), wherein R2 stands for an acetyl group and R1, R3, R4 as well as n are the same as defined above;
and/or reacting a thus-obtained compound of the formula (I), where-in R1 means hydrogen and R2, R3, R4 as well as n are as defined above, with an isocyanate of the formula R-NCO
wherein R is as defined above, to obtain compounds of the formula (I), wherein R1 represents a -CONHR group, R2, R3, R4 as well as n are as defined above and R is as defined above, except hydrogen;
and/or reacting a thus-obtained compound of the formula (I), wherein R1, R2, R3, R4 and n are as defined above, to give an acid addition salt and/or treating with a base a compound of the formula (I), wherein R1, R2, R3, R4 and n are as defined above, to its quaternary ammonium salt.

6. A process as claimed in claim 5, variant a), which comprises carrying out the ethynylation in a tetrahydrofuran medium in the presence of potassium tertiary butoxide.

7. A process as claimed in claim 5, variant b), which comprises carrying out the hydrolytic cleavage of 2-oxo-1,3-dioxa-8-azaspiro[4,5]decane derivatives of the formula (III), wherein R3, R4 and n are ad for the formula (I), in an aqueous sodium hydroxide solution at a temperature bet-ween 70 °C and 95°C.

8. A process as claimed in claim 4, variant c), which comprises using a diphenylalkene derivative of the formula (V), wherein Y means bromine and R3, R4 as well as n are as defined for formula (I).

9. A process as claimed in claim 4, variant d), which comprises using a carbonate ester of formula (VI), wherein R5 means an unsubstituted phenyl group and R2, R3, R4 and n are as defined for formula (I).

10. A process for the preparation of a pharmaceutical composition, which comprises mixing as active ingredient one or more novel 4,4-disubstituted piperidine derivative(s) of the formula (I), wherein R1, R2, R3, R4 and n are as defined in claim 1, or a pharmaceutically acceptable acid addition or quaternary ammonium salt thereof with carriers, diluting, stabilizing, pH-adjusting and osmotic pressure-adjusting, isotonizing agents and/or formulating additives commonly used in the pharmaceutical industry and transforming them to a pharmaceutical composition.

11. Method for the treatment of psychotic disorders, insomnia, mania, agitation, depression, anxiety, emesis, pain and dementia of mammals including men, characterized by administering to said mammal to be treated a therapeutically effective amount of a 4,4-disubstituted piperidine deriva-tive of the formula (I), wherein R1, R2, R3, R4 and n are as defined in claim 1, or a pharmaceutically acceptable acid addition or quaternary ammonium salt thereof alone or in the form of a pharmaceutical composition.