CA2023019A1 - 1-oxa-2-oxo-8-azaspiro/4,5/decane derivatives, pharmaceutical compositions containing them and process for preparing the same - Google Patents

Abstract

NOVEL 1-OXA-2-OXO-8-AZASPIROL[4,5]DECANE DERIVATIVES, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND PROCESS
FOR PREPARING SAME

Abstract The invention relates to novel l-oxa-2-oxo-8--azaspiro[4,5]decane derivatives of the formula (I), (I) wherein X means oxygen or an ?NR group, wherein R stands for hydrogen, a C1-12alkyl, C3-6cyclo-alkyl, carbocyclic C6-10aryl or carbocyclic C6-10aryl-C1-4alkyl group, the two latter are optionally substituted on their aromatic part by one or more, same or different halogen(s), one or more C1-4alkyl or C1-4alkoxy group(s);
R1 and R2 together represent a methylene group or, when X stands for an ?NR group, wherein R is as defined above, one of R1 and R2 may represent a hydroxyl group whereas the other is a methyl group;

R3 stands for hydrogen or a phenyl group optionally substituted by one or more halogen(s), one or more C1-4alkyl or C1-4alkoxy or hydroxyl group(s);
R4 means hydrogen, one or more halogen(s), C1-4alkyl, C1-4alkoxy, hydroxyl or trihalomethyl group(s); and n is 1, 2 or 3 as well as their acid addition and quaternary anmonium salts.
The invention further relates to pharmaceutical compositions containing these compounds and a process for their preparation.
The compounds of formula (I) possess calcium uptake--inhibiting, antihypoxic and antianoxic properties and a low toxicity. Thus, they are useful for the treatment of brain damages of various origin.

Description

~ 2 ~ 2 ~ ~ ~

NOVEL l-OXA-2-OXO-8-AZASPIRO/ 4,57DECANE DERIVATIVES, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND PROCESS
FOR PREPARING SAME

The invention re'ates to novel, therapeutically active l-oxa-2-oxo-8-azaspiro/ 4,57decane derivatives of the formula (I), ~4 0 - C (I) H--(CH2)n--- N~X l R3 1 \ 2 R R

wherein X means oxygen or an ~NR group, wherein R stands for hydrogen, a Cl_l2alkyl, C3 6cyclo-alkyl, carbocyclic C6 1Oaryl or carbocyclic C6 1Oaryl-Cl 4alkyl group, the two latter are optionally substituted on their aromatic part by one or more, same or different halogen(s), one or more Cl 4alkyl or Cl 4alkoxy group(s);
Rl and R2 together represent a methylene group or, when X stands for an ~NR group, wherein R is as defined above, one of Rl and R2 may represent a hydroxyl group whereas the other is a methyl group;

A 4586-67 MR/Gi - 2 ~

R3 stands for hydrogen or a phenyl group optionally substituted by one or more halogen(s), one or more Cl_~alkyl or Cl 4alkoxy or hydroxyl group(s);
R4 means hydrogen, one or more halogen(s), Cl 4alkyl, Cl 4alkoxy, hydroxyl or -trihalomethyl group(s); and n i5 1, 2 or 3 as well as their acid addition and quaternary ammonium salts and pharmaceutical compositions containing these compounds.
The invention also relates to a process ~or the preparation of the above compounds and compositions as well as to a method of treatment. The latter comprises introducing a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable acid addition or quaternary ammonium salt thereof into the organism of a patient.
The compounds of the formula (I) may exist in various stereoisomeric forms such as geometrical isomers as well as racemates, individual optical isomers and their mixtures, all of which may occur in the form of various solvates and ` hydrates. All these compounds and mixtures are within the scope of the invention.
A number of therapeutically useful l-oxa-2-oxo-3,8--diazaspiro/~4,57decane derivatives have been described in the literature. Such compounds are reported e.g. in the following publications: C.A. 71, 91359d (1969); C.A. 78, 719668t (1973); C.A. 78, 23876q (1973); C.A. 81, 33153c and 105368b (1974); C.A. 95, 161765e (1981); as well as ~r;~

in the DE patent specifications Nos. 2,013,729, 2,013,668 and 2,163,000; in the Belgian patent specifications Nos.
775,984, 774,170, 786,631 and 825,444; in the British patent specification No. 1,100,281; in the published Dutch patent application No. 7,214,6E19 as well as in the United States patent specifications Nos. 3,555,033, 3,594,386, 4,244,961 and 4,255,432.
A substantial difference between the compounds of formula (I) according to the invention and the similar derivatives known up to the present appears in the nature of the substituents bound in position 4 and optionally in position 3 of the spirodecane skeleton.
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) reacting a 2-oxo-3,8-diazaspiro/ 4,57decane derivative of the formula (II), :

Il (II) 2s ~C l'i--R
R~ 2 - 4 - ~ ~ r~

wherein R, Rl and R2 are as defined above, with a phenyl-alkane derivative of the formula (III), F~4 \~--~H -(CH2)n y (III) wherein R3, R4 as well as n are as defined above and Y
means halogen, a Cl 4alkylsulfonyloxy or arylsulfonyloxy group, to obtain compounds of the formula (I), wherein X stands for an ~NR group and R, Rl, R2, R3, R4 as well as n are as defined above;
5 or b) reacting a 4-ethynyl-4-hydroxypiperidine derivative of the formula (IV), ~4 H--(C112 )n--N~ (IV) wherein R3, R4 and n are as defined above, with an iso-cyanate of the formula R-NC0, wherein R is as defined above, 2 ~ 2 ~ ~

and 0~) cyclizing in an acidic medium the obtained 4-carbamoyl-oxy-4-ethynylpiperidine derivative of the formula (V), 5 ' O-C- NHR
CH--(C~7 ~ N~
R3 C--C~

wherein R, R3, R4 and n are as defined above and reacting with water the obtained salt of the 2-imino--1,3-dioxolane derivative o:E the formula (VI), .

\~ CH--(CH2 )n--N~X I (VI) wherein R, R3, R4 and n are as defined above, to obtain compounds of the formula (I), wherein Rl and R together represent a methylene group, X means oxygen and R, R3, R4 as well as n are as defined above, or ~, ' ~.: ; , ~) cyclizing in a basic medium the obtained compound of the formula (V), wherein R, R3, R4 and n are as defined above, to obtain compounds of the formula (I), wherein X
means an ~NR group, Rl and R2 together represent a methylene group and R, R3, R4 as well as n are as defined above;
or c) cyclizing in an acidic medium a 4-carbamoyloxy-4--ethynylpiperidine derivative of the formula (V) above, wherein R, R3, R4 and n are as defined above, and reacting with water the obtained salt of the 2-imino-1,3-dioxolane derivative of the formula (VI), wherein R, R3, R4 and n are as defined above, to obtain compounds of the formula (I), wherein X means oxygen, R3, R4 as well as n are as defined above and together with R stands for a methylene group;
or d) cyclizing in the presence of a base a 4-carbamoyl-oxy-4-ethynylpiperidine derivative of the formula (V), wherein R, R3, R4 and n are as defined above, to ob-tain compounds of the formula (I), wherein X means an ~NR group, Rl together with R2 stands for a methylene group and R, R3, R4 as well as.n are as defined above;
or e) reacting a 4-acetyl-4-hydroxypiperidine derivative of the formula (VII), ~ r ~ n--N~X (VII ) ~3 wherein R3, R4 and n are as defined above, with an iso-cyanate of the formula R-NC0, wherein R is as defined above, and cyclizing the thus formed 4-acetyl 4-carbamoyloxy-piperidine derivative of the formula (VIII) ~\r CH~(CH2 )n ` N~ . (VIII ) F~3 ll :

wherein R, R3, R4 and n are as defined above, to obtain compounds of the formula (I), wherein X means an ~NR sroup, one of Rl and R2 s-tands for a hydroxyl group and the other is a methyl group, and R, R3, R4 as well as n are as defined above;
or f) cyclizing a 4-acetyl-4-carbamoyloxypiperidine derivative of the formula (VIII), wherein R, R3, R4 and n are as defined above, to obtain compounds of the formula (I), wherein X means an ., , . , , ~

-- . ~

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~ NR group, one of Rl and R2 stands for a hydroxyl group, the other is methyl group and R, R3, R4 as well as n are as defined above, then, if desired, reacting a thus prepared compound of the ~ormula (I), wherein X means oxygen, R1 and R2 together stand for a methylene group, R3, R4 and n are as defined above, with an amine of the formula R-NH2, wherein R is as defined above, to prepare a compound of the formula ~I), wherein X means an ~NR group, one of Rl and R2 stands for a hydroxyl group, the other is methyl group and R, R3, R4 as well as n are as defined above;
and/or transforming a thus prepared compound of the formula (I), wherein X, R, Rl, R2, R3, R4 and n are as defined in the preamble, to an ot;her compound of the formula (I) falling within the scope of the formula (I);
and/or reacting with an acid a thus prepared compound of the formula (I), wherein X, R, Rl, R2, R3, R4 and n are as defined above to give its acid addition salt and/or treating with a base a compound of the formula (I), where-in X, R, Rl, R2, R3, R4 and n are as defined above obtained as a salt, to liberate the base form thereof and/or convert-ing a thus prepared compound of the formula (I), whereinX, R, Rl, R2, R3, R4 and n are as defined above, to its quaternary ammonium salt.

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In the process a) according to the invention, a 2-oxo-3,8-diazaspiroL 4,57decane derivative of the formula (II) is reacted with a phenylalkane derivative of the formula (III), wherein Y means a leaving group, e.g. a mesyloxy or tosyloxy group, or a halogen, preferably chlorine or bromine. This reaction is preferably carried out in an inert organic solvent, in the presence of a base being capable to bind the acid liberated in the reaction.
Various solvents, such as aliphatic alkanols, e.g. ethanol, isopropanol, butanol; aromatic hydrocarbons, e.g. chloro-benzene, toluene; ethers, e.g. dibutyl ether or dioxane;
tertiary aliphatic acid amides such as dimethylformamide or dimethylacetamide; ketones, e.g. acetone, methyl ethyl ketone or methyl isobutyl ketone or the mixtures of the above solvents may be used; as acid binding agents inorganic or tertiary organic bases, e.g. alkaline or earth alkaline metal carbonates or hydrogen carbonates as well as triethyl-amine, dimethylaniline or pyridine may be employed -though an excess of the compound of formula (II) can also be used for the same purpose. This reaction is accomplished at a temperature between room temperatue and the boiling point of the reaction mixture, optionally in the presence of a catalyst. Suitable catalysts are e.g. the alkaline metal iodides. The reaction is preferably performed under an inert gas such as nitrogen or argon.
In the first step of process b) according to the invention a 4-ethynyl-4-hydroxypiperidine derivative of the formula (IV) is brought into reaction with an isocyanate , , .
. ~

- 10~

of the formula R-NCO in a manner known per se / Houben--Weyl: Methoden der Organischen Chemie ~ol. VIII/3, pages 137 to 147 (1952)7 to give a 4-carbamoyloxy-~-ethynyl-piperidine derivative of the formula (V). For prepariny compounds of the formula (I) containing oxygen as X, the compound of the formula (V) is cyclized in an acidic medium according to step c~), then the thus-formed 2-imino-1,3--dioxolane derivative of the formula (VI) obtained as a salt is reacted with water; or, for preparing compounds of the formula (I) containing ~NR group as X, -the compound of formula (V) is cyclized in a basic medium according -to step ~).
The cyclization of step ~) is carried out in an inert organic solvent (i.e. in- a solvent which is inert under the reaction conditions), in the presence of a suitable acid, preferably in the presence of a dry hydrogen halide.
Aliphatic or alicyclic ethers such as diethyl ether, di-propyl ether, diisopropyl ether, dibutyl ether, tetrahydro-furan or dioxane as well as lower aliphatic carboxylic acids, e.g. acetic or propionic acid, may be employed.
As a hydrogen halide hydrogen chloride, bromide, iodide or fluoride, preferably hydrogen chloride or bromide, are used. After treating with water the thus formed 2-imino--1,3-dioxolane hydrohalide salt, the 1-oxa-2-oxo-8-aza-spiroL~4,57decane derivative of the formula (I) is obtainedas an acid addition salt from which, if desired, the base can be liberated in a manner known per se.
` The cyc]ization of step ~) is realized in the presence of a base. Alkaline metal acetates, carbonates, alkoxides, hydroxides and/or tertiary organic bases, e.g.
pyridine, tripropylamine or picoline, may be used as basic catalysts in the cyclization; the organic bases may also serve as solvents for the reaction. Further sui-table solvents are aliphatic alcohols, e.g. methanol, ethanol, propanol or butanol; aliphatic, alicyclic or aromatic hydro-carbons, e.g. hexane, cyclohexane, benzene, toluene or xylene; acid amides, e.g. dimethylformamide or N-methyl--2-pyrrolidone; ethers such as dibutyl ether or dioxane;

nitriles such as acetonitrile; sulfoxides, e.g. dimethyl-sulfoxide; etc. as well as the mlxtures of the above solvents. The reaction may be carried out without any solvent, too, e.g. in a molten state. In order to accelerate the cyclization the temperature is suitably increased: the reaction i9 preferably accomplished between 40 C and the boiling point of the reac-tion mixture. It is suitable to work under an inert gas such as argon or nitrogen. Accord-ing to a preferred embodiment the 4-carbamoyloxy-4-ethynyl-piperidine derivative of the formula (V), formed in the reaction of the 4-e-thynyl-4-hydroxypiperidine derivative of the formula (IV) with the isocyanate of the formula R-NC0, is directly cyclized, without isolation, in the same reaction mixture, in the presence of a suitable base.
In the processes c) and d) of the invention the procedures discussed under steps d) and ~) are followed.

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- 12 ~

In the process e) of the invention a 4-acetyl-4--hydroxypiperidine derivative of the formula (VII) is reacted with an isocyanate of the formula R-NCO and the obtained 4-acetyl-4-carbamoyloxypiperidine derivative of the formula (VIII) is cyclized. The condensation reaction according to the first step is realized in a manner known per se / Houben-Weyl: Methoden der Organischen Chemie Vol. VIII/3, pages 137 to 147 (1952)7. The obtained 4--acetyl-4-carbamoyloxypiperidine derivative of the formula (VIII) is preferably cyclized in the presence of a base.
The cyclization may be carried out under the reaction conditions described for the step ~) of process b).
Alternatively, according to a preferred embodiment of this process, the 4-acetyl-4-carbamoyloxypiperidine derivative of the formula (~'III), obtained in the reaction of the 4-acetyl-4-hydroxypiperidine derivative of the formula (VII) with the isocyanate of formula R-NCO, is directly cyclized, without isolation, in the same reaction mixture, in the presence of a suitable base.
By using the process f) of the invention, the second step of the process e) is in principle followed.
If desired, the compounds of the formula (I) obtained by using the processes a) to f) can be transformed to other compounds being within the scope of the formula (I) in a manner known ~ se.
Thus, on reacting a compound of the formula (I), wherein X means oxygen and Rl together with R2 represents a methylene group, with an amine of the formula R-NH2, compounds of the formula (I) are obtained, wherein X means an ~NR group and one of Rl and R2 is a hydroxyl group whereas the other one means a methyl group. This reaction may be carried out in a suitable solvent or without any solvent. Convenient solvents are e.g. aliphatic, alicyclic or araliphatic alcohols such as e-thanol, butanol, cyclo-hexanol, benzyl alcohol; aliphatic or aromatic hydro-carbons such as hexane, heptane~ xylene, chlorobenzene or nitrobenzene; ethers, e.g. dioxane; ketones, e.g. di-n--butyl ketone; tertiary organic bases, e.g. picoline, tri-ethylamine or pyridine, though an excess of the R-NH2 amine may also serve as a solvent for the reaction. This procedure -"

may be carried out at a temperature between room temperature and the boiling point of the reaction mixture, preferably under an inert gas, e.g. argon or nitrogen.
If desired, the compounds of the formula (I) contain-ing a hydroxyl and a methyl group, respectively as Rl and R , can be dehydrated to compounds of the formula (I), 2û wherein Rl and R2 together represent a methylene group.

The dehydration may be achieved under normal or reduced pressure by using commonly known procedures. Isocyanates, aliphatic carboxylic acids, aliphatic or aromatic carboxylic acid anhydrides, Lewis acids, sulfuric acid or aromatic sulfonic acids can be employed for the dehydration. This reaction is preferably performed in an organic solvent.
Suitable solvents are e.g. aromatic hydrocarbons such as benzene, toluene or xylene; ethers such as dioxane, di-n-~ ~ ~ c~

-butyl ether; or aliphatic carboxylic acids such as acetic acid. Optionally, the water formed in the reaction may be removed by azeotropic distillation.
If desired, a water molecule can be introduced in .an addition reaction into the compounds of formula (I), where-in Rl and R2 together stand for a methylene group to give compounds of the formula (I) containing a hydroxyl and a methyl group, respectively as Rl and R2. This hydration reaction is accomplished in an aqueous medium, in the presence of mineral and/or organic acids. As acids e.g.
hydrogen halides, sulfuric, phosphoric, formic acid, aromatic sulfonic acids, oxalic or trifluoroacetic acid and the like may be employed. This reaction is carried out between 5 C and the boiling point of the reaction mixture.
The compounds of the formula (I) may be converted to their acid addition salts or quaternary ammonium salts by using methods known ~ se. For the preparation of acid addition salts inorganic or organic acids such as hydrogen 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, benzoic, cinnamic, aspartic, glutamic, N-acetil-aspartic or N-acetylglutamic acid as well as alkanesulfonic acids such as methanesulfonic acid or arenesulfonic acids, e.g.
p-toluenesulfonic acid and the like may be used.

The salt formation can be carried out e.g. in such a way that the corresponding acid is added to the solu-tion .

- 15 ~

of the compound of formula (I) in an inert solvent, e.g.
ethanol, and the salt formed is precipitated by addiny preferably a water-immiscible organic solvent, e.g. ethyl ether. For the preparation of quaternary ammonium salts a lower alkyl, alkenyl or benzyl halide or an alkyl sulfate may preferably be employed. The quaternization is suitably performed in an organic solvent such as acetone, aceto-nitrile, 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, purified by recrystallization.
Conversely, the corresponding bases can be liberated from their salts ~y an alkaline treatment.
A part of the starting substances used in the process of the invention are known or can be prepared by using known methods.
The compounds of the formula (III) can be prepared e.g. according to Collection Czechoslov. Chem. Commun. 38, 3879 (1973); as well as Chim. Ther. 3, 185 (1969).
The preparation of the compounds of formula (II) is described in our Hungarian patent application No. 4092/89.
The substances of formula (IV) may be synthetized e.g. by the ethynylation reaction of suitably substituted 4-piperidone derivatives as described e.g. in the Hungarian patent specification No. 166,769 or in Farmaco (Pavia) Ed.
Sci. 12, 34 (1957).

The carbamates of the formulae (V) and (VIII), respectively are obtained e.g. by reacting a compound of the formula (IV) or (VII), respectively, with an iso-cyanate of the formula R-NCO under conditions commonly known in the literature L Houben-Weyl: Methoden der Organischen Chemie Vol. VIII/3, pages 137 to 147 (1952)7.
The 4-acetyl-4-hydroxypiperidine derivatives of the formula (VII) can be prepared e.g. by hydrating the corresponding 4-ethynyl-4-hydroxypiperidine derivatives of formula (IV) L see e.g. in: Houben-Weyl: Methoden der Organischen Chemie Vol. VII/2 a, pages B26 to 835 (1973)7 or by the alkaline treatment of the corresponding 1,3-dioxa--2-oxo-4-methylene-8-azaspiroL 4,57decane derivatives of formula (I~
The compounds of formulae (IV), (V), (VII) and ;
(VIII) are novel compounds, up to the present not described in the literature, which are valuable intermediates in the synthesis of the novel compounds according to the invention and in addition, they are biologically active, too.
The compounds of formula (I) as well as their stereoisomers and salts exhibit valuable pharmacological properties such as calcium uptake-inhibiting, antihypoxic and antianoxic effects. Thus they are useful for the systemic (i.e. oral, rectal or parenteral) treatment of varm-blooded mammals (including man). They can favourably be employed for the prevention or therapeutic treatment of hypoxic brain damages of various origin such as senile dementia, Alzheimer's disease, ischemic lesions, dis--- 1 7 - ~ ?J

turbances of the cognitive function, multi-infarctual dementia, hypoxia following atheroschlerosis and the like.
The calcium uptake-inhibiting action of the novel compounds of formula (I) was studied on a rat brain synaptosomal p~eparation by using the method of P. H. Wu et al. / J. Neurochem. 39, 700 (1982)7.
Wistar rats weighing 180 to 200 9 were decapitated, their brains were collected in an ice-cold physiological saline solution, the cortex was removed and purified from the white substance. The tissue was homogenized in lD
volumes of 0.32 M sucrose solution by using a glass-teflon potter. Qfter centrifuging the homogenate at a rate of 1000 x 9 at 4 C for 10 minutes, the supernatant was further centrifuged at 10000 x 9 for 20 rninutes. The sediment was taken up in a 0.32 M sucrose solution in such a way that the protein content of the preparation was adjus-ted to 20 mg/ml.
The medium (containing 112 mM of sodium chloride, 5 mM of potassium chloride, 1.3 mM of magnesium chloride, 1.2 mM of sodium dihydrogen phosphate, 1.2 mM of calcium chloride, 10 mM of glucose, 20 mM of TRIS buffer) used for the incubation was saturated with carbogen, consisting of 95% by volume of oxygen and 5% by volume of carbon dioxide, up to a pH of 7.4. After adding the test substances to the medium, the synaptosomal preparation was added in an amount corresponding to 1 mg of protein. The incubation was carried out in a final volume of 1 ml. The samples were - 18 - ~2~

pre-incubated at 34 C for 20 minutes. The calciurn uptake was begun by using a 45CaC12 solution of 75 nCi activity.
Potassium chloride used for investigating the potassium--induced 45Ca uptake was employed in 60 mM concentration whereas sodium chloride was added in the same concentra-tion to the control samples. The incubation lasted 20 seconds.
The reaction was stopped by 5 ml of a stopping solution containing 120 mM of sodium chloride,5 mM of potassium chloride, 5 mM of EGTA and 20 mM of TRIS at pH 7.4. The samples were filtered through a Wha-tman GF/C filter paper and twice washed with 5 ml of a washing solution each, containing 132 mM of sodium chloride, 5 mM of potassium chloride, 1.3 mM of magnesium chlorid~e, 1.2 mM of calcium chloride and 20 mM of TRIS at p~ 7.4. (Abbreviations used above: TRIS means tris(hydroxyme-thyl)aminomethane; EGTA
means ethylene glycol bis( ~-aminoethyl) ether-N,N,N',N'--tetraacetic acid).
The filter papers were put into glass cuvets, 10 ml of a scintillation cocktail each were added, then the radioactivity of the samples was measured in an 1219 Rackbeta (LKB Wallace) liquid scintillatinn spectrophoto-meter.
The IC50 values obtained by examination of the concentration/effect correla-tions are shown in Table I.
IC50 value means the molar concentra-tion of the tes-t compounds which causes 50% inhibition of the stimulated 45Ca uptake.

Table I

._ Compound No. I~50 ~uM
_ 1 5.8 2 5.9 3 2.1 4 5.3 6.1 Numbers for the chemical names and abbreviations used in the Tables:
1 1-Oxa-2-oxo-3-butyl-4-methylene-a-L 4,4-bis(4-fluoro-phenyl)butyl7-3,8-diazaspiroL 4,57decane 2 1-Oxa-2-oxo-3-tert-butyl-4-methylene-8-/ 4,4-bis(4--fluorophenyl)butyl7-3,8-diazaspiroL 4,57decane 3 1-Oxa-2-oxo-3-phenyl-4-methylene-8-L 4,4-bis(4-fluoro-phenyl)butyl7-3,8-diazaspiroL 4,57decane 4 1-Oxa-2-oxo-3-cyclohexyl-4-methylene-8-L 4,4-bis(4- --fluoroFhenyl)bu~yl7-3,8-diazaspiroL 4,57decane 1-Oxa-2-oxo-3-butyl-4-hydroxy-4-methyl-8-L 4,4-bis(4--fluorophenyl)butyl7-3,8-diazaspiroL 4,57deeane hydro-chloride 6 1-Oxa-2-oxo-3,4-dimethyl-4-hydroxy-8-L 2-(4-fluoro-phenyl)ethyl7-3,~-diazaspiroL 4,57decane 7 1-Oxa-2-oxo-3-propyl-4-hydroxy-4-methyl-8-L 2-(4-fluoro-phenyl)ethyl7-3,B-diazaspiroL 4,57decane - 20 - ~ d~ ~

B l-Oxa-2-oxo-3-cyclohexyl-4-hydroxy-4-methyl-8-L 2-(4--fluorophenyl)ethyl7-3,8-diazaspiroL 4,57decane 9 1-Oxa-2-oxo-3-ethyl-4-hydroxy-4-methyl-8-t 2-(4-fluoro-phenyl)ethyl7-3,8-diazaspiro/ 4,57decane.
Abbreviations:
n: number of animals p.o.: oral administration ' i.v.: intravenous injection S.E.: standard error The antihypoxic effect was studied by using two methods. According to the method of C. Caillard et al.
/ Life Sci. 16, 1607 (1975)7 the asphyxial action was . determined after starvation for 16 hours on CFLP mice of both sexes weighiny 24 to 26 g. Each snimal was pla-ced in a separate well-closed glass cylindre. The interval passing from closing the cylindre until the cessation of the last visible respiratory movement was registered as survival time. Animals, surviving longer by 30% than the average survival time of the control group, were considered to be protected. The test substances were administered in an oral dose of 50 mg/kg by 60 minutes before starting the examination. The results are summarized in Table II.

, :. . .

Table II

Compound No.Protected%animals n _ The average survival time of the control group was 23.5 + 2.51 sec (X+S.E.) `~

The potassium cyanide test method was used for determination of the p~otective effect against the histotoxic hypoxia. A hypoxia af this type ~an be developed by a rapid;
intravenous injection of 5.0 my/kg of potassium cyanide inducing abdominal contractions and clonic convulsions on the animals and leading to death of the animals within 2 minutes.
Male Hannover-Wistar rats weighing 160 to 170 9 were used in this experiment. Animals surviving longer by 30%
than the average survival time of the control group were considered to be protected. The test substances were orally administered in various doses 60 minutes before starting the examination. The ED50 values, i.e. the dose protecting half of the treated animals from the hypoxia, were calculated from percentage of the protected animals relating to various doses (i.e. from the dose-response curve) by using probit .

:

analysis. The results are summarized in Table III.

Table III

5 Compound No. ED50 P
mg/ky 1 40.9 2 39.9 ~ 37.9 : ., The compounds according to the invention showed a strong calcium-antagon1zing and antihypoxic activity and had a Iow toxicity. Their oraI LU50 values (i.e, the dose lS causing death of 50% of the animals) were found to be higher than 1000 mg/kg; thus, their therapeutic indices are favourable.
Thus, the invention relates to a method for the calcium uptake-inhibiting as well as antihypoxic and anti-anoxic treatment of mammals. This method comprises administer-ing a prophylactically or therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable acid addition or quaternary salt thereof to a patient suffering from anoxia connected with e.g. senile dementia, Alzheimer's disease, ischemic lesions, disturbances of the cognitive function, multi-infarctual dementia;
hypoxia following atherosclerosis and the like. Depending from the severity of the disease and the condition of the ; , , :

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patient, the daily dose amounts to 0.1 to 40 mg/kg which may be given once or in divided subdoses in oral, rectal or parenteral route.
The compounds according to the invention can be converted into pharmaceutical composi-tions in a known manner. The pharmaceutical compositions may be administered in oral, rectal and/or parenteral route. For oral administra-tion, the composition may be formulated e.g. as a table-t, dragée or capsule. In order -to prepare oral compositions, e.g. lactose or starch may be used as carriers. Gelatine, carboxymethylcellulose sodium, methylcellulose, polyvinyl-pyrrolidone or starch gum are suitable binding or granulat-ing agents. As disintegrating agents, mainly potato starch or microcrystalline cellulose may be added thcugh ultra-amylopectin 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. The liquid oral compositions of the invention can be prepared in the form of e.g. a suspension, syrup or elixir which may contain water, glycols, oils, alcohols as well as colouring and flavouring additives.
Tablets may be prepared e.g. by compression follow-ing the wet granulation. The mix-ture of the active ingredient with the carriers and optionally with a part of the disintegrating additive is granulated wi-th an aqueous, alcoholic or aqueous-alcoholic solution of the binding agents in a suitable equipment, then the granulate is dried.

- 24 ~ $~

Subsequently, after mixing the other disintegra-ting, sliding and anti-adhesive additives to the dried granulate, the mixture is compressed to table-ts. If desired, the tablets may be provided with a groove in order to facilitate the administration. Tablets may also directly be prepared from a mixture containing the active ingredient and suitable additives. The tablets may optionally be converted to dragées by employing the commonly used pharmaceutical additives, e.g. protective, flavouring or colouring agents such as sugar, cellulose derivatives (methyl- or ethyl-cellulose, carboxymethylcellulose sodium and the like), polyvinylpyrrolidone, calcium phosphate, calcium carbonate, food dyes, dyeing lacquers, aromatizing agents, iron oxide pigments and the llke. Capsulatecl compositions are prepared by filling a mixture of the active ingredient with the additives into capsules. -~
For rectal administration, the composition of the invention is formulated as a suppository containing a 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 suppositories are prepared by moulding.
For parenteral administration, the composition of the invention is formulated as an injectable solution. For preparing these injectable solu-tions, the active ingredients are dissolved in distilled water and/or various organic solvents, e.g. glycol ethers, if desired, in -the presence of solubilizing agents such as polyoxyethylene sorbitan monolaurate or monooleate or monostearate (Tween 20, Tween 60, Tween 80), respectively. The injectable solution may further contain various additives (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 filling into the ampouls, the injectable solution containing the composition of the invention is filtered and after filling.in, it is subjected to sterilization.
On using the pharmaceutical composition of the invention, the patient is treated with a dose needed to ensure the desired effect. This dose depends upon several factors like the severity of the disease, the body-weight of the patient and the route of administration. The dose to be used is in every case to be defined by the physician.
The invention also relates to a method for treating hypoxic brain damages of various origin such as the senile dementia, Alzheimer's disease hypoxia following athero-sclerosis, multi-infarctual dementia and disturbances of the cognitive function. This method comprises administering a therapeutically effective amount of an active ingredient of the formula (I) or a pharmaceutically acceptable acid addition salt thereof to the patient.

The invention is illustrated in detail by the aid of the following non-limiting Examples.

Example 1 Preparation of l-oxa-2-oxo-3-propyl-4-methylene-8-L 4,4-bis(4-fluorophenyl)butyl7-3,8-diazaspiroL 4,57-decane A mixture containing 8.4 9 of 1-oxa-2-oxo-3-propyl--4-methylene-3,B-diazasoiroL 4,57decane, 22.4 9 of 4,4-bis(4--fluorophenyl)butyl chloride, 16.6 9 of anhydrous potassium carbonate and 0.3 9 of potassium iodide in 90 ml of methy]
isobutyl ketone is boiled under reflux and stirring for 8.hours, then the solvent is distilled off under reduced pressure. After adding benzene and water to the residue, the organic phase is separated, washed with water to neutral, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The crude product obtained i5 purified by chromatography on a silica gel column by using ethyl acetate for elution. The eluates are combined, evaporated and the residue is recrystallized from diisopropyl ether to give the title compound in 89% yield, m.p.: 107-108 C.
Analysis:
Calculated for C27H32F2N202 C 71.34; H 7.10; F 8.36; N 6.16~;
found: C 71.50; H 7.23; F 8.28; N 6.07%.

-.

,. ;:

Example 2 Preparation of l-oxa-2-oxo-3-benzyl-4-methylene-8-/ 2-(4-fluorophenyl)7-3,8-diazaspiro/ 4.57decane A mixture containing 10.3 9 of 1-oxa-2-oxo-3-benzyl--4-methylene-3,8-diazaspiro/ 4,57decane, 16.2 9 of 2-(4--fluorophenyl)ethyl bromi-de and 11.2 ml of triethylamine in 100 ml of methyl isobutyl ketone is refluxed under argon while stirring for 2.5 hours. After cooling down and adding water to the reaction mixture, the organic phase is separated, washPd with saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue is recrystallized under . clarifying by activated carbon from hexane and then from diisopropyl ether to obtain the title compound in 31.8%
yield, m.p.: 100-101 C.
Analysis:
Calculated for C23~l25~FN22 C 72.61; H 6.62; F 4.99; N 7.36%;
found: C 72.8; H 6.54; F 5.22; N 7.53%.
~0 :~
_ample 3 Preparation of l-oxa-2-oxo-3-ethyl-4-methylene-8-(3,3-diphenyl~ropyl)-3,B-diazaspiro/ 4,57decane hydrogen maleate A mixture containing 7.9 9 of 1-oxa-2-oxo-3-ethyl-~4-methylene-3,8-diazaspiroL 4,57decane, 26 9 of 3,3-di-phenyl-l-tosyloxypropane and 7.4 9 of anhydrous sodium carbonate in 100 ml of methyl isopropyl ketone is refluxed under nitrogen while stirring for 5 hours. After evaporating the reaction mixture under reduced pressure, water is added to the residue and extracted with chloroform. The organic phase is washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure.
The crude produc-t is dissolved in acetone and the title salt is precipitated by adding an ethereal solution of maleic acid, m.p.: 168-170 C.
The base can be liberated from the above sal-t by adding aqueous sodium hydroxide solution.
Analysis of the base:
Calculated for C25H30N202 C 76.89; H 7.74; N 7.17%;
found: C 76.95; H 7.89, N 7.24%.

Example 4 Preparation of l-oxa-2-oxo-3-decyl-4-hydroxy-4-methyl--8-L 4,4-bis(4-fluorophenyl)butyl7-3,8-diazaspiro-_ 4,57decane hydrochloride 5.5 9 of 1-oxa-2-oxo-3-decyl-4-me-thylene-8-L 4,4-bis(4-fluorophenyl)butyl7-3,8-diazaspiroL 4,57decane are dissolved in 11 ml of formic acid and after dropping 100 ml of a 3 mol/litre hydrochloric acid to the solution under stirring, the reaction mixture is stirred for additional 30 minutes. The crystals precipitated are filtered, washed with water and dried to give the title hydrochloride in 97.2% yield, m.p.: 109-111 C. The base is liberated by :~ .
, adding aquenus sodium carbonate solution to the hydro-chloride, extracted into chloroform, the organic phase is washed with water to neutral, dried over anhydrous sodium sulfate and evaporated under reduced pressure.
After recrystallization from diisopropyl ether the base melts at 89-90 C.
Analysis:
Calculated for C34H48F2N203 C 71.54; H 8.48; F 6.66; N 4.91%;
~ound: C 71.54; H 8.31; F 6.73; N 4.99%.

Example 5 Preparation of l-oxa-2-oxo=3-cyclohexyl-1-methylene--8-L 2-t4-chlorophenyl)ethyl7-3,8-diazaspiro/ 4,57-- 15 decane A mixture containing 8.14 9 of 1-oxa-2-oxo-3-cyclo-hexyl-4-hidroxy-4-methyl-8-/ 2-t4-chlorophenyl)ethyl7--3,8-diazaspiro/ 4,57decane and 0.8 9 of p-toluenesulfonic acid monohydrate in 100 ml of xylene is boiled under stirring while the water formed in the reaction is azeotropically distilled out. The reaction is followed by using thin--layer chromatography. After termination of the reaction the mixture is cooled down, made alkaline by adding 5% by weight aqueous sodium hydroxide solution, then the organic phase is washed with water to neutral, dried over anhydrous sodium sulfate and evaporated under reduced pressure. After recrystallizing the crude product from ethanol the pure title product is obtained in 92.4% yield, m.p.: 134-135 C.

` - 30 - 2~2~

Analysis:
Calculated for C22H29ClN202 C 67.93; H 7.52; Cl 9.12; N 7.20~,;
found: C 67.88; H 7.65; Cl 9.25; N 7.11%.

Example 6 Preparation of l-oxa-2-oxo-3-methyl-4-methylene-8-(3-phenvlpropyl)-3,8-diazaspiro/ 4.57decane A solution of 7.5 9 of 4-ethynyl-4-methylcarbamoyl-oxy-1-(3-phenylpropyl)piperidine in 100 ml of an ethanolic sodium ethoxide solution of 0.09 mol/litre concentration is refluxed under argon for 3 to 4 hours. After cooling down and adding aqueous ammonium chloride solu-tio~. to the reaction mixture, the major part of alcohol is distilled off under reduced pressure. The residue is diluted with water and extracted with benzene. The benzene phase is washed with water to neutral, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. After re-crystallizing the residue from hexane, the title compound is obtained in 68% yield, m.p.: 35-36 C.
Analysis:
Calculated for C18H24N202 C 71.97; H 8.05; N 9.33%;
found: C 71.88; H 8.19; N 9.52%.

.
, ............ . . . . .
.

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Example 7 PrEparation of l-oxa-2-oxo-4-methylene-3-phenyl--8-(2-phenylethyl)-3,8-diazaspiro/ 4,57decane A mixture containing 6.2 9 of 4-acetyl-4-hydroxy--1-(2-phenylethyl)-piperidine, 2 ml of triethylamine and 11 ml of phenylisocyanate in 20 ml of xylene is refluxed under argon for 6 hours. After cooling down and diluting with xylene the reaction mixture is filtered and the filt-rate is evaporated under reduced pressure. After re-crystallizing the crude product from ethanol under clarify-ing by ac-tivated carbon, the title product is obtained in 49.4% yield, m.p.: 137-138 C.
Analysis:
Calculated for C22~z4N202 ~5 C 75.83; H 6.94; N 8.04%;
found: C 76.00; H 6.97; N 8.15%.

Example 8 Preparation of l-oxa-2-oxo-3-cvclohexyl-4-hydroxy--4-methyl-B-/ 2-(4-chlorophenvl)ethyl7-3,8-diaza-splro/ 4,57decane hydrochloride 10.7 9 of 1-oxa-2-oxo-3-cyclohexyl-4-hydroxy-4--methyl-3,8-diazaspiro/ 4,57decane are refluxed with 13.2 9 of 2-(4-chlorophenyl)ethyl bromide, 8.2 9 of anhydrous powdered po-tassium carbonate and 0.7 9 of potassium iodide in 110 ml of methyl isobutyl ketone under nitrogen while stirring for 6 hours. After evaporating the solven-t under - 32 ~

reduced pressure and adding water to the residue, the mixture is extracted with benzene. The combined benzene solution is washed with water to neutral, dried over anhydrous sodium sulfate, then the benzene solution is filtered through an aluminum oxide layer and evaporated under reduced pressure. After recrystallization of the residue from hexane, the base is converted to the hydro-chloride by adding hydrogen chloride in diisopropyl ether solution. Thus, the title hydrochloride is obtained in 58.4% yield with a decomposition point of 310-315 C.
Analysis of the base:
Calculated for C22H31ClN203 - C 63.93, H 7.68; Cl 8.71; N 6.88%;

fou~d: C 65.10; H 7.53; Cl B.60, N 7.00~.
By using the appropriate starting substances the following compounds are prepared in an analogous manner as described in Examples 1 to 3 or 8.
l-Oxa-2-oxo-3-methyl-4-methylene-8-(2-phenylethyl)-3,8--diazaspiro/ 4,57decane, m.p.: 119-120 C;
1-Oxa-2-oxo-4-methylene-3-phenyl-8-/ 2-(4-chlorophenyl)-ethyl7-3,8-diazaspiro/ 4,57decane, m.p.: 134-135 C;
l-Oxa-2-oxo-3-ethyl-4-methylene-8-L 2-(4-methylphenyl)-; ethyl7-3,8-diazaspiroL 4,57decane hydrochloride, decomp.
at 280-282 C;
1-Oxa-2-oxo-3-cyclohexyl-4-methylene-8-/ 2-(4-fluorophenyl)-ethyl7-3,8-diazaspiroL 4,57decane, m.p.: 125-126 C;
l-Oxa-2-oxo-4-methylene-3-phenyl~8-/ 2-(4-fluorophenyl)-ethyl7-3,B-diazaspiroL 4,57decane, m.p.: 145-147 C;

.
' . . . ' .
..

,:, ~ .

l-Oxa-2-oxo-3-ethyl-4-methylene-8-(2-pherlylethyl)-3,8--diazaspiroL 4,57decane, m.p.: 121-122 C;
l-Oxa-2-oxo-3-tert-butyl-4-methylene-8-L 4,4-bis(4-fluoro-phenyl)butyl7-3,8-diazaspiroL 4,57decane, m.p.: 90-92 C;
1-Oxa-2-oxo-3-isopropyl-4-methylene-8-L 4,4-bis(4-fluoro-phenyl)butyl7-3,8-diazaspiroL 4,57decane, m.p.: llB-119 C;
l-Oxa-2-oxo-3-methyl-4-methylene-8-L 4,4-bis(4-fluoro-phenyl)butyl7-3,8-diazaspiroL 4,57decane, m.p.: 90-91 C.;
l-Oxa-2-oxo-3-tert-butyl-4-methylene-8-(2-phenylethyl)-3,8--diazaspiroL 4,57decane, m.p.: 106-107 C;
l-Oxa-2-oxo-3-isopropyl-4-methylene-8-L 2-(4-chlorophenyl)-ethyl7-3,8-diazaspiroL 4,57decane, m.p.: 101-102 C;
Oxa-2-oxo-3-methyl-4-methylene-8-L 2-(4-fluorophenyl)-ethyl7-3,8-diazaspiro~ 4,57dec~ne, m.p.: 74-75 C;
1-Oxa-2-oxo-3-ethyl-4-methylene-8-L 4,4-bis(4-fluorophenyl)-butyl7-3,8-diazaspiroL 4,57decane, m.p.: 111-112 0;
l-Oxa-2-oxo-3-isopropyl-4-methylene-8-L 2-(4-fluorophenyl)-ethyl7-3,8-diazaspiroL 4,57decane, m.p.: 103-104 C;
l-Oxa-2-oxo-4-methylene-3-phenyl-8-L 4,4-bis(4-fluorophenyl)-butyl7-3,8-dia7aspiroL 4,57decane, m.p.: 125-126 C;
l-Oxa-2-oxo-4-methylene-3-propyl-8-L 2-(4-fluorophenyl)-ethyl7-3,8-diazaspiroL 4,57decane, m.p.: 78-79 C;
l-Oxa-2-oxo-3-L 2-(3,4-dimethoxyphenyl)ethyl7-4-methylene--8-(2-phenylethyl)-3,8-diazaspiroL 4,57decane, m.p.: 114--115 C, l-Oxa-2-oxo-3-benzyl-4-methylene-8-L 4,4-bis(4-fluoro-phenyl)butyl7-3,8-diazaspiroL 4,57decane, m.p.: 81-82 C;

.

.
:- .

, , , . ' , : ~ . -~ . . .. .

- 34 - ~2~

l-Oxa-2-oxo-3-decyl-4-methylene-8-/ 4,4-bis(4-fluoro-phenyl)butyl7-3,8-diazaspiroL 4,57decane hydrogen maleate, m.p.: 106-107 C;
l-Oxa-2-oxo-3-cyclohexyl-4-methylene-8-/ 4,4-bis(4-fluoro-phenyl)butyl7-3,8-diazaspiro/ 4,57decane, m.p.: 121-122 C;
l-Oxa-2-oxo-3-butyl-4-methylene-8-(2-phenylethyl)-3,8--diazaspiroL 4,57decane, m.p.: 70-71 C;
l-Oxa-2-oxo-3-me-thyl-4-methylene-8-/ 2-(4-chlorophenyl)-ethyl7-3,8-diazaspiro/ 4,57decane, m.p.: 118-119 C;
1-Oxa-2-oxo-3--tert-bu-tyl-4-methylene-8-/ 2-(4-chlorophenyl)-ethyl7-3,8-diazaspiro/ 4,57decane, m.p.: 104-105 C;
l-Oxa-2-oxo-3-ethyl-4-methylene-8-L 2-(4-fluorophenyl)-ethyl7-3,8-diazaspiroL 4,57decane, m.p.: 83-84 C;
l-Oxa-2-oxo-3-methyl-4-methylene-8-L 2-(3,4-dimethoxy-phenyl)ethyl7-3,8-diazaspiro/ 4,57decane hydrochloride, m.p.: 278-280 C; and ;~
l-Oxa-2-oxo-3-tert-butyl-4-methylene-8-/ 2-(4-fluorophenyl)-ethyl7-3,8-diazaspiro/ 4,57decane, m.p.: 93-94 C.
~'.

Example 9 :
Preparation of l-oxa-2-oxo-4-methylene-3-(1-naphthyl)--8-L 2-(4-fluorophenyl)ethyl7-3,8-diazaspiro/ 4,57-decane 9.9 9 of 4-e-thynyl-4-hydroxy-1-/ 2-(4-fluorophenyl)-ethyl7piperidine are heated with 7.0 ml of l-naphthyl iso-cyanate under argon. A violent exothermic reaction occurs.
The temperature is maintained between 170 C and 180 C
by external cooling for one hour. After cooling down and .
, :,"

, dissolving -the solid residue in chloroform, the solution is filtered through an aluminum oxide layer and the filtra-te is evaporated under reduced pressure. Af-ter recrystallizing the residue from ethanol the title compound is obtained in 65% yield, m.p.: 160-161 C.
Analysis:
Calculated for C26H25FN202 C 74.98; H 6.05; F 4.56; N 6.73%;
found: C 75.10; H 6.25; F 4.37; N 6.55%.

Example 10 .
Preparation of l-oxa-2-oxo-3-n-butyl-4-methylene-8-/ 4,4-bis(4-fluorophenyl)butyl7-3,8-diazaspiro-/ 4,57decane 3.3 9 of n-butyl isocyanate dissolved in 11 ml of benzene are portionwise added to a gently boiling suspension containing 11 9 of 4-ethynyl-4-hydroxy-1-/ 4,4-bis(4-fluoro-phenyl)butyl7piperidine and 0.09 9 of sodium methoxide in 45 ml of benzene under argon while stirring, then the mix-ture is refluxed for additional 3 to 4 hours. After cooling down the benzene solution is washed with water, dried over anhydrous sodium sulfate, filtered and the solvent is distilled off under reduced pressure. After recrystallizing the residue from diisopropyl ether the title compound is obtained in 79.5% yield, m.p.: 94-95 C
~nalysis Calculated for C2~H34F2N202 ~ . .

C 71.77; H 7.31; F 8.11; N S.98%;
found: C 71.98; H 7.40; F 8.24; N 6.13%.

Example 11 Preparation of l-oxa-2-oxo-3-butyl-4-methylene-8-/ 2-(4-chlorophenyl)ethyl7-3,8-diazaspiro/ 4,57-decane 13.2 9 of 4-ethynyl-4-hydroxy-1-/ 2-(4-chloro-phenyl)ethyl7piperidine are refluxed with 6.5 9 of n-butyl isocyanate in 40 ml of 2-picoline in the presence of 0.2 9 of anhydrous potassium acetate under argon ~or 6 hours.
After evaporating the solvent under reduced pressure and dissolving the residue in benzene, the organic phase is washed with water and dried-over a-nhydrous sodium-sul~fate.
The benzene solution is filtered through an aluminum oxide layer and evaporated under reduced pressure. After re-crystallizing the crude product from hexane the title compound is obtained in 74.5% yield, m.p.: 86-87 C.
Analysis:
Calculated for C20H27C1N22 C 66.19; H 7.50; Cl 9.77; N 7.72%;
found: C 66.23; H 7.57; Cl 9.90; N 7.64%.
The following compounds are prepared similarly as described in Examples 9, 10 or 11 by using the appropriate starting substances:
l-Oxa-2-oxo-4-methylene-3-propyl-8-/ 2-(4-chlorophenyl)-ethyl7-3,a-diazaspiroL 4,57decane, m.p.: 82-8~ C;

. .

3 ~. ~

1-Oxa-2-oxo-3-ethyl-4-methylene-8~L 2-(4-chlorophenyl)-ethyl7-3,8-diazaspiro/ 4,57decane, m.p.: 106-107 C;
1-Oxa-2-oxo-4-methylene-3-(1-naphthyl)-8-L 4,4-bis(4--fluorophenyl)butyl7-3,8-diazaspiroL 4,57decane, m.p.:
127-128 C;
1-ûxa-2-oxo-3-tert-butyl-4-methylene-8-L 4,4-bis(4-fluoro-phenyl)butyl7-3,8-diazaspiroL 4,57decane, m.p.: 90-92 C;
1-Oxa-2-oxo-3-heptyl-4-methylene-8-L 4,4-bis(4-fluoro-phenyl)butyl7-3,8-diazaspiroL 4,57decane hydrogen maleate, m.p.: 121-122 C;
l-Oxa-2-oxo-3-(3,4-dichlorophenyl)-4-methylene-8-L 2-(4--chlorophenyl)ethyl7-3,8-diazaspiro/ 4,57decane hydro-chloride, decomp. at 292-295 C;
l-Oxa-2-oxo-3-cyclahexyl-4-methylene-8-(2-phenylethyl)-3,8--diazaspiroL 4,57decane, m.p.: 152-153 C;
1-Oxa-2-oxo-4-methylene-3-propyl-8-(2-phenylethyl)-3,8--diazaspirL 4,57decane, m.p.: 97-98 C; and l-Oxa-2-oxo-3-butyl-4-methylene-8-L 2-(4-fluorophenyl)ethyl7--3,8-diazaspiroL 4,57decane, m.p.: 91-92 C.
Example 12 Preparation of l-oxa-2-oxo-3-butyl-4-hydroxy-4-methyl--8-/ 4,4-bis(4-fluorophenvl)butvl7-3,8-diazaspiro-~ 4,57decane hydrochloride 3 ml of butylamine dissolved in 3 ml of benzene are dropped to a solution of 8.3 y of 1,3-dioxa-2-oxo-~--methylene-8-L 4,4-bis(4-fluorophenyl)bu-tyl7-8-azaspiro-~2~

L ~i, 57decane in 17 ml of anhydrous benzene under stirring.
Mean~Jhile the temperature of the reaction mixture raises ` to 3a to 45 C. Thereafter thè reaction mix-ture is stirred - at room temperature for additional 16 hours, then evaporated under reduced pressure. After take up of -the residue in anhydrous ether the title hydrochloride salt is precipitated by adding ethereal hydrogen chloride solution. The title salt i5 obtained in 87% yield, m.p.: 218-221 C.
The base is obtained from the hydrochloride by adding ammonium hydroxide solution.
Analysis of the base:
Calculated for C28H36F2N203 . . . C 69.11; H 7.46; F 7.81; N 9.86%;
~ound: C 69.20; ~ 7.5~; F 7.64, N g.72%.

Example_13 Preparation of l-oxa-2-oxo-3-methyl-4-methylene-8, a--bis(3-phenylpropyl)-3 ? 8-diazaspiro! 4,57decan-8-ium iodide , :

6.0 9 of 1-oxa-2-oxo-3-methyl-4-methylene-8-(3-phenyl-~; propyl)-3,B-diazaspiroL 4,57decane are refluxed with 5.4 9 of 3-phenylpropyl iodide in 60 ml of methyl isobutyl ketone under nitrogen for 4 hours, then the solvent is distilled ~ off under reduced pressure. After adding hexane to the ; 25 residue the solid precipitate is filtered and recrystallized from ethanol to give the title compound in 86% yield, m.p.:
219-220 C.

., ;

~ 3 Example 14 Preparation of 1,3-dioxa 2-oxo-4-methylene-8-/ 4,4-bis(4-fluorophenyl)butvl7-8-azaspiro/ 4,57-decane hvdrogen maleate A solution of 16.0 9 of 1-/ 4,4-bis(4-fluorophenyl)-butyl7-4-butyl-carbamoyloxy-4-ethynylpiperidine in 90 ml of anhydrous dioxane is saturated by dry gaseous hydrogen chloride at 15 to 20 C, then the reaction mixture is left to stand overnight. The solvent is evaporated at 40 to 50 C
under reduced pressure. After adding water to the residue, the base is liberated with sodium hydrogen carbonate and extracted into benzene. The benzene solution is dried over anhydrous ~agnesium sulfate, `then the solvent is evaporated under reduced pressure. After dissolving the residue in ethyl acetate, the solution is filtered through a silica gel column and the solution thus obtained is evaporated under reduced pressure. Af-ter taking up the residue in acetone, the title hydrogen maleate salt is precipitated by maleic acid. The title salt is ob-tained in 55% yield, m.p.: 149-150 C.
Analysis for the base:
Calculated for c24H2sF2No3 C 69.72; H 6.09; F 9.19; N 3.39%;
found: C 69.85; H 6.17; F 9.35; N 3.12%.

- 40 - ~ f Example 15 reparation of l-oxa-2-oxo-3,4-dimethyl-4-hydroxy--8-(2-phenylethyl)-3,B-diazaspiro/ 4,57decane A solution containing 9.1 9 of 4-acetyl-4-methyl-carbamoyloxy-1-(2-phenylethyl)piperidine and 0.5 9 sodium methoxide in 100 ml of methanol is refluxed under argon for 4 for 5 hours. Qfter cooling down the sodium methoxide is decomposed by adding aqueous ammonium chloride solution, the mixture is diluted with water and methanol is distilled off under reduced pressure. After filtration the precipitate obtained is recrystallized from ethanol to give the title product in 72.1% yield, m.p.: 184-185 C.
", ~nalysis:
Calculated for C17~l24N203 C 67.08; H 7.95; N 9.20%;
found: C 67.11; H 7.90; N 9.03%.

Example 16 Preparation of l-oxa-2-oxo-3-benzyl-4-hydroxy-4--methyl-8-/ 2-(4-fluorophenyl)ethyl7-3,8-dlaza-spiro/ 4~57decane hydrochloride A solution of 6.1 9 of 1-oxa-2-oxo-3-benzyl-4--methylene-8-L 2-(4-fluorophenyl)ethyl7-3,8-diazaspiro-/ 4,57decane in 120 ml of 0.2 molar hydrochloric acid is refluxed for 10 minutes and then evaporated to a volume of 70 ml under reduced pressure. The mixture is cooled at 1 to 5 C for 30 minutes, then the crystalline precipitate is filtered and dried to give the title hydrochloride in 98% yield, decomp. at 295 C.
The base is liberated from the hydrochloride by adding aqueous ammonium hydroxide solution.
Analysis for the base:
Calculated for C23H27FN203 C 69.32; H 6.83; F 4.77; N 7.03%;
found: C 69.40; H 6.64; F 4.85; N 7.16%.
The following compounds are prepared similarly as described in the Example 12 or 16 by using the appropriate starting substances:
l-Oxa-2-oxo-3,4-dimethyl-4-hydroxy-8-L 2-(4-fluorophenyl)-ethyl7-3,8-diazaspiro/ 4,57decane, m.p.: 197-198 C;
l-nxa-2-oxo-3-cyclohexyl-4-hydroxy-4-methyl-8-/ 2-(4-fluoro-phenyl)ethyl7-3,8-diazaspiroL 4,57decane, m.p.: 189-190 C;
l-Oxa-2-oxo-3-tert-butyl-4-hydroxy-4-methyl-8-L 2-(4-fluoro-phenyl)ethyl7-3,8-diazaspiroL 4,57decane hydrochloride, decomp. at 286-288 C;
l-Oxa-2-oxo-3,4-dimethyl-4-hydroxy-8-/ 4,4-bis(4-fluoro-phenyl)butyl7-3,8-diazaspiroL 4,57decane hydrochloride, decomp. at 220-223 C;
l-Oxa-2-oxo-3-benzyl-4-hydroxy-4-methyl-8-L 4,4-bis(4--fluorophenyl)butyl7-3,8-diazaspiro/ 4,57decane hydrochloride, decomp. at 177-179 C;
1-Oxa-2-oxo-4-hydroxy-3-isopropyl-4-methyl-8-L 2-(4-fluoro-phenyl)ethyl7-3,8-diazaspiroL 4,57decane, m.p.: 157-158 C;
l-Oxa-2-oxo-4-hydroxy-4-methyl-3-phenyl-8-L 4,4-bis(4-fluorophenyl)butyl7-3,8-diazaspiroL 4,57decane hydrochloride, - 42 - ~2 decomp. at 274-276 C;
l-Oxa-2-oxo-3-butyl-4-hydroxy-4-methyl-B-L 2-(4-fluoro-phenyl)ethyl7-3,8-diazaspiroL 4,57decane, m.p.: 155-156 C;
l-Oxa-2-oxo-4-hydroxy-4-methyl-3-propyl-8-/ 2-(4-fluoro-phenyl)ethyl7-3,8-diazaspiroL 4,57decane hydrochloride, decomp. at 248 C; the base melts at 138-139 C;
l-Oxa-2-oxo-3-ethyl-4-hydroxy-4-methyl-8-L 4,4-bis(4-fluoro-phenyl)butyl7-3,8-diazaspiroL 4,57decane hydrochloride, decomp. a-t 235 C;
1-Oxa-2-oxo-4-hydroxy-4-methyl-3-(1-naphthyl)-8-L 4,4-bis(4--fluorophenyl)butyl7-3,8-diazaspiroL 4,57decane hydro-chloride, decomp. at 180-182 C;
l-Oxa-2-oxo-3-heptyl-4 hydroxy-4-methyl-8-L 4-bis(4-fluoro-phenyl)butyl7-3,8-diazaspiro/ 4,57decane, m.p.: 128-129 C;
1-Oxa-2-oxo-4-hydroxy-4-methyl-3-(1-naphthyl)-8-L 2-(4--fluorophenyl)ethyl7-3,8-diazasp:iroL 4,57decane hydro-chloride, decomp. at 288-290 C;
l-Oxa-2-oxo-3-ethyl-4-hydroxy-4-methyl-8-L 2-(4-~luoro-phenyl)ethyl7-3,8-diazaspiro/ 4,57decane, m.p.: 139-140 C;
1-Oxa-2-oxo-3-cyclohexyl-4-hydroxy-4-methyl-8-/ 4,4-bis(4--fluorophenyl)butyl7-3,8-diazaspiroL 4,57decane hydro-chloride, decomp. at 258 260 C;
l-Oxa-2-oxo-4-hydroxy-3-isopropyl-4-methyl-8-/ 4,4-bis(4--fluorophenyl)butyl7-3,8-diazaspiroL~4,57decane hydro-chloride, decomp. at 251-253 C;
l-Oxa-2-oxo-3-butyl-4-hydroxy-4-methyl-8-L 4,4-bis(4-fluoro-phenyl)butyl7-3,8-diazaspiroL 4,57decane hydrochloride, decomp. at 218-220 C;

- 43 - ~ .J~

l-Oxa-2-oxo~4-hydroxy-4-methyl-3-propyl-8-/ 4,4-bis(4--fluorophenyl)butyl7-3,8-diazaspiro/ 4,57decane hydro-chloride, decomp. at 134-136 C;
; l-Oxa-2-oxo-4-hydroxy-4-methyl-3-phenyl-8-L 2-(4-fluoro-phenyl)ethyl7-3,8-diazaspiro/ 4,57decane hydrochloride, decomp. at 346-350 C;
l-Oxa-2-oxo-3-(3,4-dichlorobenzyl)-4-hydroxy-4-methyl-8--L 2-(4-chlorophenyl)ethyl7-3,8-diazaspiroL 4,57decane hydrochloride, decomp. at 310-315 C; and 1-Oxa-2-oxo-4-hydroxy-4-methyl-8-/ 4,4-bis(4-fluorophenyl)-butyl7-3,8-diazaspiro/ 4,57decane hydrochloride, m.p.:
130-132 C.

Example 17 Preparation of 4-ethynyl-4-hydroxy-1-/ 4,4-b1s(4--fluorophenyl)butyl7piperidine hydrochloride Acetylene is introduced into a solution containing 38.4 9 of potassium -tert-butoxide in 25n ml of tetra-hydrofuran at a temperature between O C and -5 C under stirring for 30 minutes, then 78.0 9 of l-L 4,4-bis(4--fluorophenyl)butyl7-4-piperidone dissolved in 200 ml of tetrahydrofuran are dropwise added and acetylene is introduced for additional one hour. Thereafter the reaction mixture is cooled to -10 C and saturated aqueous ammonium chloride solution is added under nitrogen. Af-ter evaporat-ing tetrahydrofuran under reduced pressure, the residue is extracted with benzene. The benzene solution is washed - 44 ~

with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. After taking up the residue in acetone, the hydrochloride is precipitated by adding hydrogen chloride in diisopropyl ether solution.
The title hydrochloride is obtained in 91.0% yield, m.p.:
166-168 C.
Analysis for the base:
Calculated for C23H25F2N0 C 74.77; H 6.82; F 10.28; N 3.79%;
found: C 74.B5; H 6.66; F 10.15; N 4.00%.

Example 18 Preparation of 4-butylcarbamoyloxy-4-ethynyl-1-. .
/ 4,4-bis(4-fluorophenyl)butyl7piperidine hydro-chloride 6.4 ml of butyl isocyanate dissolved in 19 ml of benzene are dropwise added to a mixture of 18.5 9 of 4-ethynyl-4-hydroxy-1-/ 4,4-bis(4-fluorophenyl)butyl7-piperidine, 0.35 9 of anhydrous powdered potassium carbonate and 74 ml of benzene in a nitrogen atmosphere under reflux and stirring. The mixture is refluxed for additional one hour, then cooled down and water is added. After separating the phases the benzene solution is washed with water to neutral, dried over anhydrous magnesium sulfate, the solu-tion is filtered through a silica gel column and evaporatedunder reduced pressure. After taking up the residue in diisopropyl ether, the hydrochloride sal-t is precipitated by adding hydrogen chloride in diisopropyl ether solution.
The title hydrochloride is obtained in B7.5%, m.p.: 84-89 C.
Analysis of the base:
Calculated for C28H34F2Nn2 C 71.77; H 7.31; F 8.11; N 5.98%;
found: C 71.88; H 7.50; F 8.28; N 5.83%.

Example 19 Preparation of 4-acetyl-4-hydroxy-1-/ 4,4-bis(4--fluoro~henyl)butyl7piperidine hydrochloride A solution of 1,3-dioxa-2-oxo-4-methylene-8-L 4,4--bis(4-fluorophenyl)butyl7-8-azaspiro/ 4,57decane in 100 ml of a 2.8 molar sodium hydroxide solution is stirred at 80 to 90 C under argon. After cooling down the reaction mixture is extracted with benzene, the benzene layer is washed with water to neutral, dried over anhydrous sodium sulfate, then the solvent is distilled off under reduced pressure. The evaporation residue is dissolved in diiso-propyl ether and the hydrochloride is precipitated by adding hydrogen chloride in diisopropyl ether solution. The title hydrochioride is obtained in 61% yield, m.p.: 62-67 C.
Analysis of the base:
Calculated for C23H27F2N02 C 71.29; H 7.02; F 9.81; N 3.61%;
found: C 71.27; H 7.18; F 9.63; N 3.80%.

;
, - 46 ~ 3~

Example 20 Pharmaceutical compDsitions containing e g. the following components ~ingredients) can be prepared from the compounds according to the invention.
a) Preparation of tablets 50.0 9 of active ingredient are mixed together with 92 9 of lactose, 40 9 of potato s-tarch, 4 9 of polyvinyl-pyrrolidone, 6 9 of talc, 1 9 of magnesium stearate, 1 9 of colloidal silicon dioxide (Aerosil) and 6 9 of ultra-amylopectin and, after wet granulation, the product obtained is compressed to tablets containing 50 mg of the active ingredient each.
; b) Preparation of dragées The tablets prep~red as d~escribed ab~ve are covered in a manner known per se with a coating consisting of sugar and talc. The dragées are polished by using a mixture of bee wax and carnaube wax. Each dragée weighes 250 mg.
c) Preparation of capsules 100 mg of active ingredient, 30 9 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 are thoroughly mixed together and after sieving, the mixture obtained is filled into hard gelatine capsules containing 20 mg of the active ingredient each.
d) Preparation of suppositories 30.0 mg of active ingredient are thoroughly mixed with 60.0 mg of lactose. Simultaneously, 1910.0 mg of suppository base (e.g. Witepsol 4) are molten (all weights are calculated for one suppository), cooled to 35 C and the mixture of the active ingredient and lactose are mixed thereto by using a homogenizer. The product obtained is poured into cooled conic moulds. Each suppository weighes 20ûO mg.
e) Preparation of a suspension Components in 100 ml of the suspension:
Active ingredient l.ûO g Sodium hydroxide 0.26 g 10 Citric acid 0.30 9 Nipagin (methyl 4-hydroxybenzoate sodium salt) 0.10 9 Carbopol 940 (polyacrylic acid)0.3û g 9~ Ethanol 1.0~ 9 15 Raspberry flavour 0.60 g Sorbitol (aqueous solution of 70%) 71.00 9 Distilled water for injection purpose up to 100.00 ml After adding carbopol in little portions to the solution of nipagin and citric acid in 20 ml of distilled water under vigorous stirring, the solution obtained is left to stand for 10 to 12 hours. Subsequently, -the amount given above of sodium hydroxide dissolved in 1 ml of distilled water, the aqueous solution of sorbitol and finally the ethanolic solution of the raspberry flavour are dropped in under stirring. The active ingredien-t is added in small portions to this mixture and suspended by using a submerged homogenizer. Finally, the suspension is supplemented to ;. ' , ' ,~ , .. , , i 100 ml by adding dis-tilled water and the syrupy suspension is led through a colloid mill.

~'

Claims (27)

1. A l-oxa-2-oxo-8-azaspiro[4,5]decane derivative of the formula (I) (I) wherein X means oxygen or an ?NR group, wherein R stands for hydrogen, a C1-12alkyl, C3-6cycloalkyl, carbocyclic C6-10aryl or carbocyclic C6-10aryl-C1-4alkyl group, the two latter are option-ally substituted on their aromatic part by one or more, same or different halogen(s), one or more C1-4alkyl or C1- 4alkoxy group(s);
R1 and R2 together represent a methylene group or, when X stands for an ?NR group, wherein R is as defined above, one of R1 and R2 may represent a hydroxyl group whereas the other is a methyl group;
R3 stands for hydrogen or a phenyl group optionally substituted by one or more halogen(s), one or more C1-4alkyl or C1-4alkoxy or hydroxyl group(s);
R4 means hydrogen, one or more halogen(s), C1-4alkyl, C1-4alkoxy, hydroxyl or trihalomethyl group(s); and n is 1, 2 or 3 or a pharmaceutically acceptable acid addition or quaternary ammonium salt thereof.

2. A compound according to claim 1 wherein R represents ethyl, propyl, butyl, tert-butyl, cyclohexyl or phenyl, R3 represents hydrogen or fluorophenyl and R4 represents fluoro.

3. A compound according to claim 2 wherein n represents 1 or 3.

4. 1-Oxa-2-oxo-3-tert-butyl-4-methylene-8-[4,4-bis(4-fluorophenyl)butyl]-3,8-diazaspiro[4,5]decane or a pharmaceutically acceptable acid addition or quaternary ammonium salt thereof.

5. 1-Oxa-2-oxo-3-cyclohexyl 4-methylene-8-[4,4-bis(4-fluorophenyl)butyl]-3,8-diazaspiro[4,5]decane or a pharmaceutically acceptable acid addition or quaternary ammonium salt thereof.

6. 1-Oxa-2-oxo-3-butyl-4-hydroxy-4-methyl-8-[4,4-bis(4-fluorophenyl)butyl]-3,8-diazaspiro[4,5]decane or a pharmaceutically acceptable acid addition or quaternary ammonium salt thereof.

7. 1-Oxa-2-oxo-4-methylene-3-phenyl-8-[4,4-bis(4-fluoro-phenyl)butyl]-3,8-diazaspiro[4,5]decane or a pharmaceutically acceptable acid addition or quaternary ammonium salt thereof.

8. 1-Oxa-2-oxo-4-hydroxy-4-methyl-3-propyl-8-[2-(4-fluoro-phenyl)ethyl]-3,8-diazaspiro[4,5]decane or a pharmaceutically acceptable acid addition or quaternary ammonium salt thereof.

9. 1,3-Dioxa-2-oxo-4-methylene-8-[4,4-bis(4-fluorophenyl)-butyl]-8-azaspiro[4,5]decane or a pharmaceutically acceptable acid addition or quaternary ammonium salt thereof.

10. 1-Oxa-2-oxo-3-cyclohexyl-4-hydroxy-4-methyl-8-[2-((4-fluorophenyl)ethyl]-3,8-diazaspiro[4,5]decane or a pharmaceutical-ly acceptable acid addition or quaternary ammonium salt thereof.

11. 1-Oxa-2-oxo-3-ethyl-4-hydroxy-4 methyl 8-[2-(4-fluorophenyl)ethyl]-3,8-diazaspiro[4,5]decane or a pharmaceuti-cally aceeptable acid addition or quaternary ammonium salt thereof.

12. A pharmaceutical composition, which comprises as active ingredient a compound according to any one of claim 1 to claim 11 or a pharmaceutically acceptable acid addition or quaternary ammonium salt thereof as active ingredient in admixture with a pharmaceutically acceptable carrier or additive.

13. A process for preparing a pharmaceutical composition, which comprises mixing as active ingredient a compound according to any one of claim 1 to claim 11 or a pharmaceutically acceptable acid addition salt or quaternary ammonium salt thereof prepared with a pharmaceutically acceptable carrier or additive.

14. A process for preparing a compound according to claim 1, which process comprises a) to obtain a compound of formula (I) according to claim 1, wherein X stands for an ?NR group and R, R1, R2, R3, R4 as well as n are as defined in claim 1, reacting a 2-oxo-3,8-diazaspiro[4,5]decane derivative of the formula (II), (II) wherein R, R1 and R2 are as defined in claim 1, with a phenyl-alkane derivative of the formula (III), wherein R3, R4 as well as n are as defined in claim 1, and Y means halogen, a C1-4alkylsulfonyloxy or arylsulfonyloxy group;
b) reacting a 4-ethynyl-4-hydroxypiperidine derivative of the formula (IV), ( IV ) wherein R3, R4 and n are as defined in claim 1, with an isocyanate of the formula R-NCO, wherein R is as defined in claim 1, and .alpha.) to obtain a compound of the formula (I), wherein R1 and R2 together represent a methylene group, X means oxygen, and R, R3, R4 as well as n are as defined in claim 1, cyclizing in an acidic medium the obtained 4-carbamoyloxy-4-ethynylpiperidine derivative of the formula (V), (V) wherein R, R3, R4 and n are as defined in claim 1 and reacting with water the obtained salt of the 2-imino-1,3-dioxolane deri-vative of the formula (VI), (VI ) wherein R, R3, R4 and n are as defined in claim 1; or .beta.) to obtain a compound of the formula (I), wherein X
means an ?NR group, R1 and R2 together represent a methylene group and R, R3, R4 as well as n are as defined in claim 1, cyclizing in a basic medium the obtained compound of the formula (V), wherein R, R3, R4 and n are as defined above;
c) to obtain a compound of the formula (I), wherein X
means oxygen, R3, R4 as well as n are as defined in claim 1 and together with R2 stands for a methylene group, cyclizing in an acidic medium a 4-carbamoyloxy-4-ethynylpiperidine derivative of the formula (V) as defined above, wherein R, R3, R4 and n are as defined above, and reacting with water the obtained salt of the 2-imino-1,3-dioxolane derivative of the formula (VI), wherein R, R3, R4 and n are as defined above; or d) to obtain a compound of the formula (I), wherein X

means an ?NR group, R1 together with R2 stands for a methylene group and R, R3, R4 as well as n are as defined in claim 1, cyclizing in the presence of a base a 4-carbamoyloxy-4-ethynyl-piperidine derivative of the formula (IV), wherein R, R3, R4 and n are as defined above; or e) to obtain a compound of the formula (I), wherein X
means an ?NR group, one of R1 and R2 stands for a hydroxyl group and the other is a methyl group, and R, R3, R4 as well as n are as defined in claim 1, reacting a 4-acetyl-4-hydroxypiperidine derivative of the formula (VII), (VII) wherein R3, R4 and n are as defined above, with an isocyanate of the formula R-NCO, wherein R is as defined above, and cyclizing the thus formed 4-acetyl-4-carbamoyloxypiperidine derivative of the formula (VIII) (VIII) wherein R, R3, R4 and n are as defined above; or f) to obtain a compound of the formula (I), wherein X
means an ?NR group, one of R1 and R2 stands for a hydroxyl group, the other is methyl group and R, R3, R4 as well as n are as defined in claim 1, cyclizing a 4-acetyl-4-carbamoyloxypiperidine deri-vative of the formula (VIII), wherein R, R3, R4 and n are as defined above;
then, if required reacting a thus prepared compound of formula (I), wherein X means oxygen, R1 and R2 together stand for a methylene group, R3, R4 and n are as defined in claim 1, with an amine of the formula R-NH2, wherein R is as defined in claim 1, to yield a compound of formula (I), wherein X means an ?NR group, one of R1 and R2 stands for a hydroxyl group, the other is methyl group and R, R3, R4 as well as n are as defined in claim 1; or transforming a thus prepared compound of the formula (I), wherein X, R, R1, R2, R3, R4 and n are as defined in claim 1, to an other compound of the formula (I) falling within the scope of the formula (I); or reacting with an acid a thus prepared compound of the formula (I), wherein X, R, R1, R2, R3, R4 and n are as defined in claim 1 to give an acid addition salt thereof or treating with a base a compound of the formula (I), wherein X, R, R1, R2, R3, R4 and n are as defined in claim 1 obtained as a salt, to liberate the base form thereof or converting a thus prepared compound of the formula (I), wherein X, R, R1, R2, R3, R4 and n are as defined in claim 1, to a quaternary ammonium salt thereof.

15. A process according to claim 14a), which comprises reacting a 2-oxo-3,8-diazaspiro[4,5]decane derivative of formula (II) as defined in claim 14 with a phenylalkane derivative of formula (III) according to claim 14 wherein Y represents halogen.

16. A process according to claim 15 wherein in the com-pound of formula III Y represents chlorine or bromine.

17. A process according to claim 14a), which comprises reacting a 2-oxo-3,8-diazaspiro[4,5]decane derivative of formula (II) accoring to claim 14 with a phenylalkane derivative of formula (III) wherein Y represents a p-toluenesulfonyloxy group.

18. A process according to claim 14A, 15 or 16, wherein the reaction is carried out in the presence of potassium iodide in a ketone-type solvent.

19. A process according to claim 18 wherein potassium carbonate is employed as acid binding agent.

20. A process according to claim 14a), 15 or 16 wherein the reaction is carried out in a ketone-type solvent with a triC1-4alkylamine as acid binding agent.

21. A process according to claim 14b).beta.) which comprises reacting said 4-ethynyl-4-hydroxypiperidine derivative of the for-mula (IV), with said isocyanate derivative of the formula R-NCO, and then cyclizing the obtained 4-carbamoyloxy-4-ethynylpiperidine derivative of the formula (V) in a basic medium in a single step without separating said compound of formula (V).

22. A process according to claim 14c) which comprises carryiing out the cyclization in dioxane in the presence of hydro-gen chloride.

23. A process according to claim 14d) which comprises carrying out the cyclization in 2-picoline at the boiling point of the reaction mixture.

24. A process according to claim 14e) which comprises reacting said 4-acetyl-4-hydroxypiperidine derivative of the formula (VII) with said isocyanate of the formula R-NCO and cyclizing the thus formed 4-acetyl-4-carbamoyloxypiperidine deri-vative of the formula (VIII) in the presence of triethylamine at the boiling point of the reaction mixture.

25. Use of a compound according to any one of claim 1 to claim 11 to inhibit calcium uptake in a mammal.

26. Use of a compound according to any one of claim 1 to claim 11 to counter hypoxia or anoxia is a mammal.

27. Method for the calcium uptake inhibiting as well as antihypoxic and antianoxic treatment of mammals, characterized by administering to the mammals (including man) to be treated a therapeutically effective dose of a compound according to any one of claim 1 to claim 11 or a pharmaceutically acceptable acid addition or quaternary ammonium salt thereof alone or in the form of a pharmaceutical composition.