CA2023027A1 - 2-oxo-1-oxa-8-azaspiro/4,5/decane derivatives, pharmaceutical compositions containing them and process for preparing the same - Google Patents

Abstract

NOVEL 2-OXO-1-OXA-3-AZASPIRO[4,5]DECANE DERIVATIVE, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM AND PROCESS
FOR PREPARING SAME

Abstract The invention relates to novel 2-oxo-1-oxa-8-aza-spiro[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; C3-6cycloalkyl;
carbocyclic C6-10aryl or carbocyclic C6-10aryl--C1-4alkyl group, the two latter ones being optionally substituted on their aromatic part by one or more, same or different halogen(s), one or more C1-4alkyl, C1-4alkoxy or trihalomethyl group(s); or a tosyl group;
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 goup and the other one is a methyl group; and R3 means hydrogen, benzyl, (C1-4alkoxy)carbonyl, phenoxy-carbonyl, benzyloxycarbonyl, formyl, piperidin-l-yl-carbonyl, morpholin-4-ylcarbonyl, 4-methylpiperazin--l-ylcarbonyl, 4-(2-hydroxyethyl)piperazin-1-ylcar-bonyl, 2-chloro-3-nicotinoylcarbamoyl or C1-6alkyl-carbamoyl group, as well as their acid addition and quaternary ammonium salts.
The invention further relates to pharmaceutical composi-tions containing these compounds and a process for their pre-paration.
The compounds of formula (I) possess anticonvulsive, antiallergic and lipid level lowering effects. Thus, they are useful for the treatment of epileptic and allergic diseases and increased lipid levels.

Description

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

The invention relates to novel, therapeu-tically active 2-oxo-1-oxa-8-azaspiro/ 4,57decane derivatives of -the formula (I), ~ (I) ~X ,:
Rl R2 wherein X means oxygen or an ~NR group, wherein R stands for hydrogen; a Cl 12alkyl; C3_6cycloalkyl;
carbocyclic C6 10aryl or carbocyclic C6 lOaryl--Cl ~alkyl group, the two latter ones being optionally substituted on thei.r aromatic part by one or more, same or different halogen(s), one or more Cl 4alkyl, Cl 4alkoxy or trihalcme-thyl group(s); or a tosyl group;
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 and the o-ther one is a methyl group; and A 462~-67 MR/Gi . ~ .

, ~,, .:

~, ' - 2 - ~ $~

R3 means hydrogen, benzyl, (Cl_4alkoxy)carbonyl, phenoxy-carbonyl, benzyloxycarbonyl, formyl, piperidin-l-yl-carbony], morpholin-4-ylcarbonyl, 4-methylpiperazin--l-ylcarbonyl, 4-(2-hydroxyet.hyl)piperazin-1-ylcar-bonyl, 2-chloro-3-nicotinoylcarbamoyl or Cl 6alkyl-carbamoyl group, as well as their acid addition and qua-ternary ammonium salts and pharmaceutical compositions containing these compounds.
The invention also relates to a process for the pre-paration 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 5 patient.
The compounds of the formula (I) may contain one or more asymmetric carbon atom(s) and consequently, they may exis-t in various stereoisomeric forms. Fur-thermore, the compounds of the formula (I) may be in the form of bases, 0 acid addition or quaternary ammonium salts, racemates, indi-vidual optical isomers and their mixtures, all of which may occur in the form of various solvates such as hydrates. All these compounds and mixtures are within the scope of the invention.
A number of therapeu-tically useful 2-oxo-1-oxa-3,8--diazaspiroL 4,57decane derivatives have been described in the literature. Such compounds are reported e.g. in the follow-ing publications: CA. 71, 91359d (1969); C.A. 78, 71966Bt - 3 ~

(1973); 0.~. 78, 23876q (1973); C.A. 81, 33153a and 105368b (1974); C.A. 95, 161765e (19Bl); as well as in the DE pa-tent specifications Nos. 2,013,729, 2,013,668 and 2,163,000; in the BE patent specifications Nos. 775,984, 774,170, 786,631 and 825,444; in the GB patent specification No. 1,100~28].; :
in the published NL patent application No. 7,214,689 as well as in the US paten-t 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 similar derivatives known up to the present appears in the nature of the substi-tuents bound in posi-tion 4 and optionally in posi-tion 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 4-ethynyl-4-hydroxypiperidine derivative of the formula (III), ~ OH (III) R3--N~
C----CH

wherein R3 is as defined above, with an isocyanate of -the formula R-NC0, wherein R is as defined above, and then cyclizing the obtained 4-carbamoyloxy-4-ethynylpiperidine - 4 - ¢~

derivative of formula (II), O CO--NHR
R3 - N k/

5~\C - - CH (II) wherein R and R3 are as defined above, d~) in an acidic medium and reacting the obtained salt of a 2-imino-1,3~dioxolane derivative of the formula (VI ?

o ~NR
N~ I (VI) 5~ O

wherein R and R3 are as defined above, with water -to obtain compounds of the formula (I), wherein X means oxygen, Rl and R2 together represent a methylene group, and R3 is as defined abovej or ~) in a basic medium to obtain compounds of the formula (I), wherein X
means an ~NR group, Rl and R2 together represent a methylene group, and R as well as R2 are as defined above; or b) cyclizing in an acidic medium a 4-carbamoyloxy-4--ethynylpiperidine derivative of the formula (II), wherein ~ J ~

R and R3 are as defined above, and reacting the obtained salt of a 2-imino-1,3-dioxolane derivative of the formula (VI), wherein R and R3 are as defined above, with water to obtain compounris of the formula (I), wherein X means oxygen, R3 is as defined above and Rl together with R2 represents a methylene group;
or c) cyclizing a 4-carbamoyloxy-4-ethynylpiperidine derivative of formula (II) wherein R and R3 are as defined above, in a basic medium to ob-tain compounds of the formula (I~, wherein X means an ~NR group, Rl toge-ther with R2 represents a methylene group and R as well as R3 are as defined above;
or d) reac-ting a 4-acetyl-4-hydroxypiperidine derivative of the formula (IV), -OH
R3~ (IV) C--CH~

O

.
wherein R3 is 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-carbamoyloxypi.peridine derivative of formula (V), "'.

' ~

~ ~ t'~ t~ r~

O-CO-NHR
R3~ ( ( v , wherein R and R3 are as defined above, to obtain compounds of the formula (I), wherein X means an ~NR group, one of Rl and R2 stands for a hydroxyl group and the other is a methyl group, and R as well as R3 are as defined above;

or e) cyclizing a 4-acetyl-4-carbamoyloxypiperidine derivative of the formula (V), wherein R and R3 are as defined above, to obtain compounds of the formula (I), wherein X means and ~NR group, one of Rl and R2 stands for a hydroxyl group and the other is a methyl group, and R as well as R3 are as defined above, then, if desired, reacting a thus prepared cornpound of the formula (I), wherein X means oxygen, R3 is as defined above and Rl together with R represents a methylene group, with an amine of the formula R-NH2, wherein R is as defined above, to obtain compounds of the formula (I), wherein X means an ~NR group, one of Rl and R2 stands for a hydroxyl group and the other is a methyl group, and R as well as R3 are as defined above;
and/or transforming a thus prepared compound of the formula (I), wherein X, R, Rl, R2 and R3 are as defined - 7 ~ f~

above, to an other compound of the formula (I) falling within the scope of the formula (I);
and/or reacting a thus prepared compound of the formula (I), wherein X, R, Rl, R2 and R3 are as defined above, with an acid to give an acid addition sal-t and/or treating a compound of the formula (I), wherein X, R, Rl, R2 and R3 are as defined above, obtained as a salt, with a base to liberate the base form thereof and/or converting a thus prepared compound of the formula (I), wherein X, R, Rl, R2 and R3 are as defined above, to its quaternary ammonium salt. - -In the first step of process a) according to the inven-tion a 4-ethynyl-4-hydroxypiperidine derivative of the formula (III) is brought into reaction with an isocyanate of 15 the formula R-NCO in a manner known per se L Houben-Weyl: -Methoden der Organischen Chemie Vol. VIII/3, pages 137 to 147 (1952)7 to give a 4-carbamoy:Loxy-4-ethynylplperidine derivative of -the formula (II), which is cyclized in an acidic medium according to step ~) or in a basic medlum according to step p).
According to step d~, the obtained 4-carbamoyloxy-4--ethynylpiperidine derivative of formula (II) is cyclized in an acidic medium and then the thus formed salt of a 2-imino--1,3-dioxolane derivative of formula (VI) is reacted with water. The cyclization 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 : ' `' ' ';

. . , ~ , :, ~ s~3~

alicyclic ethers such as die-thyl ether, dipropyl ether, di-isopropyl ether, dibutyl ether, tetrahydrofuran or dioxane as well as lower aliphatic carboxylic acids, e.g. acetic or propionic acid, may be employed as solvents.
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-dioxa-lane hydrohalide salt, the 2-oxo-1-oxa-8-azaspiro/ 4,57decane derivative of the formula (I) is obtained as an acid addition salt, from which, if desired, the base can be liberated in a manner known per se.
The cyclization of the obtained 4-carbamoyloxy-4--ethynylpiperidine derivative of formula (II) according to the step ~) i5 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 catalyst in the cyclization;
the o~ganic bases may also serve as solvents for the reaction.
Further suitable solvents are aliphatic alcohols, e.g.
methanol, ethanol, propanol or butanol; aliphatic, alicyclic or aromatic hydrocarbons, e.g. hexane, cyclohexane, benzene, toluene or xylene; acid amides, e.g. dimethyl formamide or N-methyl-2-pyrrolidone; ethers such as dibutyl ether or di-oxane; nitriles such as acetonitrile; sulfoxides, e.g. di-methyl sulfoxide, etc.; as well as the mixtures of the abovesolvents. The reaction may be carried out without any solvent, too, e.g. in a molten state. In order to accelerate the cyc-lization the temperature is suitably increased: the reaction 2 6;~
9 _ is preferably accomplished between 40 C and the boiling point of the reaction mixture. It is suitable to work under an inert gas such as argon or nitrogen. According to a preferred embodimen-t, when R3 is different from 4-(2-hydroxy-ethyl)piperazin-l-ylcarbonyl or 2-chloro-3-nicotinoylcarbamo-yl group, the 4-carbamoyloxy-4-ethynylpiperidine derivative of the formula (II) resulting from the reaction of a 4--ethynyl-4-hydroxypiperidine derivative of the formula (III) with an isocyanate of formula R-NCO is not isolated but directly cyclized in the same reaction mixture in the presence of a suitable base. - -In the processes b) and c) of the invention theprocedures discussed under steps ~) and ~) are followed.
In the process d) of the invention a 4-acetyl-4-hydroxy-piperidine derivative of the formula (IV) is reacted with an isocyanate of the formula R-NCO and the obtained 4-acetyl-4--carbamoyloxypiperidine derivative of the formula (V) is cyclized. The condensa-tion reaction according -to the first step is realized in a manner known per se L Houben - Weyl:
Methoden der Organischen Chemie Vol. VIII/3, pages 137 to 147 (lg52)7. The thus obtained 4-acetyl-4-carbamoyloxy-piperidine derivative of formula (V) 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 a). Alternatively, according to a preferred em-bodiment of this process, the 4-acetyl-4-carbamoyloxy-piperidine derivative of the formula (V), obtained in the reaction of the 4-acetyl-4-hydroxypiperidine derivative of . . ~

the formula (IV) with the isocyanate of formula R-NC0, is directly cyclized without isolation in the same reaction mixture, in the presence of a suitable base.
By using ~the process e) of the invention, the second -step of the process d) is in principle followed.
If desired, the compounds of the formula (I) obtained by using -the processes a) to e) 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), where-in 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. Suitable solvents are e g.: aliphatic, alicyclic or aralipha-tic alcohols such as ethanol, butanol, cyclohexanol, benzyl alcohol; ali-phatic or aromatic hydrocarbons such as hexane, heptane, xylene, chlorobenzene or nitrobenzene; ethers, e.g. dioxane or di-n-butyl ether; and tertiary organic bases e.g. picoline, triethylamine or pyridine; though an excess of an amine of the formula R-NH2 may also serve as a solvent for the re-action. 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 R2, ., .
~ ~.

can be dehydrated to compounds of the formula (I), wherein Rl and R2 together represent a methylene group. The dehydra-tion 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-butyl ether; or aliphatic carboxylic acids such as acetic acid. According to a preferred~
embodiment of this reac-tion, e.g. a mixture of glacial acetic acid and acetic anhydride may be used or the dehydration may be carried out in xylene in the presence of p-taluenesulfonic acid while the water formed in the reaction is azeotropical-ly distilled out.
If desired, a water molecule can be introduced in an addition reac-tion 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 R1 and R2. This hydration re-action is accomplished in an aqueous medium, in the presence of a mineral and/or organic acid as acid e.g. hydrogen hali-des, 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.
From the obtained compounds of formula (I), wherein '' ':

~ ~ 2 ~

R3 represents a benzyl or benzyloxycarbonyl group, these groups can be removed e.g. by a reductive cleavage to obtain compounds of the formula (I), wherein R3 means hydrogen. This reduction may preferably be carried out by catalytic hydro- -genation. As hydrogenating catalysts e.g. metals such asruthenium, palladium, platinum, nickel, iron, cobalt, chromium, zinc, tungsten, molybdenum and the like as well as their oxides and sulfides may be employed. The catalytic hydrogena-tion may also be carried out by using a catalyst previously precipitated onto the surface of a carrier. Such carriers rnay be e.g. carbon, silicon dioxide, aluminum oxide as well- -as carbonates and sulfates of the alkaline-earth metals.
This reduction is suitàbly accomplished in the presence of palladiurn-on-charcoal by hydrogenation in an inert solvent.
Lower aliphatic alcohols, e-thers, esters as well as aliphatic, cycloaliphatic or aromatic hydrocarbons or their mixtures may be used as solvents. The hydrogenation may be accomplished under atmospheric or higher pressure at a temperature between 20 C and the boiling point of the reaction mixture. Af-ter termination of the reaction the catalyst is filtered off, the filtrate is evaporated and, if desired, the product obtained is purified e.g. by recrystallization. According to a preferred embodiment of the reduction, this process i5 performed by the means of catalytic transfer hydrogenation which is well known in the literature by using a hydrogen donor substance such as formic acid, hydrazine and the like in the presence of palladium-on-charcoal catalyst. A formyl group as R3 can reductively be cleaved or it can be removed by using hydrazine ,. , , :

or hydroxylamine in the presence of a weak acid such as acetic acid. This reaction may be carried out in inert organic solvents such as e.g.: lower alkanols, e.g. methanol or ethanol; or in acid amides, e.g. dimethylacetamide; or in ethers such as dioxane; or in the mixtures of the above solvents. The reaction medium may contain water, too. The temperature is preferably increased for accelerating the reaction. Thus, this reaction is preferably carried out at a temperature between 40 C and the boiling point of the re-action mixture.
Hydrogen as R3 in the compounds of formula (I) maybe replaced by an other group by using methods known per se;
it can be replaced e.g: by a benzyl group on reacting it with a benzyl halide, preferably benzyl chloride or bromide, sui-tably in the presence of a convenient base such as an alkaline metal or alkaline earth metal carbonate or hydrogen carbonate, a tertiary organic base or an excess of -the compound of formula (I) which are useful for binding -the acid formed in the reaction. Little amount of an alkaline metal iodide, e.g. potassium iodide may be used for promoting this reaction.
Hydrogen as R3 may be replaced by a (Cl 4alkoxy)car-bonyl, phenoxycarbonyl or benzyloxycarbonyl group in the reaction with a reactive carboxylic acid derivative contain-ing such a group. A suitable chloroformate ester may be usedas a reactive carboxylic acid derivative. This reaction is conveniently carried out in the presence of a base being useful for binding the acid formed in the reaction. For this ':

:

- 14 - 2 ~ 7 purpose e.g. the bases listed above may be employed. The reaction is accomplished by using methods commonly known from the literature.
Hydrogen as R3 may be replaced by a formyl sroup by using a reactive formic acid derivative. Chloride, imidazolide or preferably a mixed anhydride of formic acid may e.g. be used as reactive derivatives. For the formylation of compounds of the formula (I) e.g. the mixed anhydride of formic acid with acetic acid may be used. However, this reaction may be carried out by using any other commonly known N-acylating process, too.
Hydrogen as R3 may be replaced by a Cl 6alkylcarbamoyl, piperidin-l-ylcarbonyl, 4-methylpiperazin-l-ylcarbonyl or 2-chloro-3-nicotinoylcarbamoyl group through the reaction of a suitably substituted chloro:Eormic acid amide or iso-cyanate. This reaction is carried out in an appropriate inert solvent, preferably in the presence of a base under an inert gas, e.g. argon or nitrogen. Aromatic hydrocarbons such as benzene, toluene or xylene; ethers such as diethyl ether, diisopropyl ether or dioxane; halogenated hydrocarbons such `I as methylene chloride, 1,2-dichloroethane or chloroform;
nitriles, e.g. acetonitrile; acid amides such as N-methyl--2-pyrrolidone; tertiary organic bases, e.g. picolines, tri-ethylamine or pyridine, may be used as solvents. The above mentioned inorganic and tertiary organic bases are useful acid binding agents. The reaction may be carried out at a temperature between 0 C and the boi].ing point of the reac-tion mixture. The reaction with an acyl isocyanate, e.g. 2--ch~oro-3-nicotinoyl isocyanate may be realized in such a way, too, that the isocyanate compound is prepared in situ and the compound of the formula (I) to be acylated is added to the reaction mixture containing the isocyanate. Thus, 2- --chloro-3-nicotinoyl isocyanate can be prepared e.g. by reacting 2-chloronicotinic acid amide with oxalyl chloride in an inert solvent such as 1,2-dichloroethane.
Compounds containing a phenoxycarbonyl group as R3 can be prepared also from the compounds of formula (I) containing a benzyl group as R3 by reacting the latter ones with phenyl chloroformate. On reacting compounds of the formula (I) containing a phenoxycarbonyl yroup as R3 with N-(2-hydroxyethyl)piperazine, compounds of the formula (I) containing a 4-(2-hydroxyethyl)piperazin-l-ylcarbonyl group as R3 are obtained.
If desired, the compounds of the formula (I) may be conver-ted to their acid addition salts or quaternary ammonium salts by using methods known per se. For the preparation of acid addition salts, inorganic or organic acids such as hydrogen halides, e.g. hydrochloric acid and hydrobromic acid as well as sulfuric~ phosphoric, formic,acetic, propionic, oxalic, glycolic, maleic, fumaric, succinic, tartaric, ascorbic, citric, malic, salicylic, lactic, benzoic, cinnamic, aspartic, glutamic, N-acetylaspartic or N-acetylglutamic acid, further-more alkanesulfonic~acids such as methanesulfonic acid orarenesulfonic acids, e.g. p-toluenesulfonic acid and the like, may be used.
The salt formation can be carried out e.g. in such a - 16 - ~

way that the corresponding acid is added -to the solution of the compound of formula (I) in an inert solvent, e.g.
ethanol, and the salt formed is precipitated by adding pre-ferably 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 pre-ferably be employed. The quaternization is suitably performed in an organic solvent such as acetone, acetonitrile, 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 recrystalliza-tion.
Conversely, the corresponding bases can be liberated from their salts by an alkaline treatment.
The starting substances are known or can be prepared analogously to methods known from the literature.

The compounds of the formulae (II) and (V) are obtained by reacting the 4-hydroxypiperidine derivatives of the formula (III) or (IV), respectively with isocyanates of the formula R-NCû by using a method known per se / see e.g.:
Houben-Weyl: Methoden der Organischen Chemie Vol. VIII/3, pages 137 to 147 (1952)7.

The compounds of the formula (III) can be prepared e.g. by the ethynylation reaction of the appropriately sub-stituted 4-piperidine derivatives according to e.g. the Hungarian patent specification No. 166,769 or by using a method described in: Farmaco (Pavia) Ed. Sci. 12 34 (1957).

, " ,....

17 -- ~ d ~ ~

The 4-acetyl-4-hydroxypiperidine derivatives of the formula (V) can be obtained e.g. by the hydration of the corresponding 4-ethynyl-4-hydroxypiperidine derivatives of the formula (III) L see e.g.: Houben-~Jeyl: Methoden der 5 Organischen Chemie VD1. VII/2a, pages 826 to B35 (1973)7 or by the alkaline treatment of the corresponding 4-methylene--2-oxo-1,3-dioxa-8-azaspiro/ 4,57decane derivatives of the formula (I).
The novel compounds of formula (I) according -to the 10 invention are useful intermediates in the synthesis of therapeutically active spirodecane derivatives (which are described e.g. in the Hungarian patent application Nos.
4093/89, 4094/89 and 4095/B9) and, irl addition, they have own biological (such as anticonvulsive, antiallergic and lipid 15 level lowering) activities.
The invention also relates to a method for treating epileptic and allergic diseases and high (increased) lipid levels. This method comprises administering a therapeutical-ly effective amount of an active ingredient of the formula 20 (I) or a pharmaceutically acceptable acid addition 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 8-benzyl-4-methylene-2-oxo-1,3-dioxa-a-azaspiro/ 4,57decane Dry gaseous hydrogen chloride is introduced at 20 to 50 C during 2.5 to 3 hours into a solution containing 31.4 g ~ 2 of l-benzyl-4-butylcarbamoyloxy-4-ethynylpiperidine in 157 ml of anhydrous dioxane. After standing overnight the reaction mixture is evaporated in a water bath of 4û to 50 C temperature under reduGed pressure. After adding 200 ml of water to the evaporation residue the base is liberated by sodium hydrogen carbona-te. After filtration the solid pre-cipitate is washed to chloride-free with water and dried.
The crude product obtained is recrystallized from n-hexane under clarifying by activated carbon to give the title compound in 80.6% yield, m.p.: 65-67 C.
Analysis:
Calculated for C15H17N03 C 69.48; H 6.61; N 5.40%;
found: C 69.65; H 6.51; N 5.63%.
Example 2 Preparation of 8-benzyl-4-methylene-2-oxo-1,3-dioxa--8-azaspiro/ 4,57decane 5.16 9 of 1-benzyl-4-carbamoyloxy-4-ethynylpiperidine are stirred in 30 ml of 30% by weight solution of hydrogen bromide in acetic acid at room temperature for 6 hours. Af-ter evaporating the solvent under reduced pressure and adding 50 ml of water to the residue the base is liberated by sodium hydrogen carbonate. The solid product obtained is filtered, washed to bromide-free with water, dried and recrystallized from n-hexane to give the title compound in 59.3% yield the physical characteristics of which are in agreement with those given in Example 1.

.

'.: "~

--` 5~ (" t~

Example 3 Preparation of 3-/2-(3,4-dimethoxyphenyl)ethyl7-8--benzyl-4-hydroxy-4-methyl-2-oxo-1-oxa-3,8-diazaspiro-/ 4,57decane 19.9 9 of 2-(3,4-dimethoxyphenyl)ethylamine are portion-wise added to a solution of 25.9 9 of 8-benzyl-4-methylene--2-oxo-1,3-dioxa-8-azaspiroL 4,57decane in 35 ml of anhydrous xylene under stirring. Meanwhile the temperature of the re-action mixture increases to 35 to 40 C. The reaction mixture is left to stand at room temperature overnight, then the crys-talline reaction mixture is diluted with n-heptane and filtered-.
The solid precipitate obtained is recrystallized from ethanol to obtain -the title compound in 94% yield, m.p.: 181-183 C.
Analysis:
Calculated for C25H32N205 C 68.16; H 7.32; N 6.36%;
found: C 68.35; H 7.18; N 6.50%.
8y using the appropriate starting substances the follow-ing compounds can be prepared in an analogous manner as described in the above Example.
8-8enzyl-3-decyl-4-hydroxy-4-methyl-2-oxo-1-oxa-3,B--diazaspiroL 4,57decane, m.p.: 111-112 C;
8-Benzyl-3-heptyl-4-hydroxy-4-methyl-2-oxo-l-oxa-3,8--diazaspiroL 4,57decane, m.p.: 116-117 C;
8-8enzyl-3-butyl-4-hydroxy-4-hydroxy-4-methyl-2-oxo--l-oxa-3,8-diazaspiroL 4,57decane, m.p.: 122-123 C (the hydrochloride is precipitated by usiny an ethereal hydrogen chloride solution, it melts about 260 C); and 2 ~ 7 8-Benzyl-4-hydroxy-4-methyl-2-oxo-3-phenyl-1-oxa-3,8--diazaspiro/ 4,57decane, m.p.: 203-205 C / hydrochloride m.p.: 284-2B6 C (with decomposition)7.
Example 4 Preparation of B-benzvl-4-hydroxy-4-me~th~1-2-oxo-1-oxa-3,8-diazaspiro/ 4,57decane A solution containing 13.2 9 of 8-benzyl-4-methylene--2-oxo-1,3-dioxa-8-azaspiroL 4,57decane in 130 ml of anhydrous ether is portionwise added to 130 ml of liquid ammonia under stirring and after stirring the reaction mixture for additional 30 minutes the ammonia is evaporated. The crystalline pre- ~
cipita-te is filtered, washed with ether and dried to give the title product in 97.2% yield, m.p.: 162-164 C.
Analysis:
Calculated for C15H20N203 C 65.19; H 7.29; N 10.14%;
found: C 65.24; H 7.43; N 10.28%.
The above reaction may be carried out also by using 25% aqueous ammonium hydroxide solution. The physical charac-teristics of the product thus obtained are indentical to those given above.
Example 5 Preparation of 3,8-dibenzyl-4-methylene-2-oxo-1-oxa-3,8-diazaspiro/ 4,57decane A solution containing 34.8 9 of 1-benzyl-4-benzyl-carbamoyloxy-4-ethynylpiperidine and 1.1 9 of sodium methoxide in 350 ml of anhydrous methanol is refluxed for 4 hours. After cooling down and maintaining the reaction : , -' . , ' ' ' mixture at 0 C for 30 to 60 minutes the crystalline pre-cipitate is filtered and recrystallized from methanol to obtain the title compound in 83% yield, m.p.: 113-114 C.
Analysis:
Calculated for C22H24N202 C 75.83; H 6.94; N 8.04~;
found: C 75.71, H 7.03; N 8.20%.
Example 6 Preparation of 8-benzyl-3-tert-butyl-4-hydroxy-4-methyl-2-oxo-1-oxa-3,8-diazaspiro/ 4,57decane 8.3 9 of 4-acetyl-1-benzyl-4-tert-butylcarbamoyloxy-- -piperidine are refluxed in 100 ml of an ethanolic sodium ethoxide solution of 0;1 mole/litre concentration under stirr-ing for 3 to 4 hours. After cooling down and adding 10% by weight aqueous ammonium chloride solu-tion to the reaction mixture the mos-t part of the solvent is distilled off under reduced pressure. After adding water to the residue the precipitate is filtered off, washed to chloride-free with water, dried and finally recrystallized from benzene to give 2~ the title compound in 78% yield, m.p.: 179-181 C.
Analysis:
Calculated for ClgH28N20~
C 68.64; H 8.49; N 8.43%;
found: C 68.75; H 8.57; N 8.65%.
Example 7 Preparation of 8-benzyl-3-n-heptyl-4-methylene-2-oxo-l-oxa-3,8-diazaspiro/ 4,57decane The solution of 18.7 9 of 8-benzyl-3-n-heptyl-4-hydroxy-- 22 -- 2 ~ r~ ~

4-methyl-2-oxo-1-oxa-3,8-diazaspiro/ 4,57decane in 40 ml of benzyl alcohol is hea-ted at 160 C for 5 hours while the water formed in the reaction is azeotropically distilled off. Thereafter, the mixture is evaporated under reduced pressure. After taking up the residue in chloroform the so-lution is dried over anhydrous magnesium sulfate, filtered off and evaporated under reduced pressure. The crude product obtained is recrystallized from n-hexane under clarifying by activated carbon to obtain the title compound in Bl% yield, m.p.: 47-48 C.
Analysis: -Calculated for C22H32N202 C 74.12; H 9.05; N 7.86%;
found: C 74.33; H 9.14; N 7.68%.
Example 8 Preparation of 3-benzvl-8-benzvloxvcarbonyl-4-hydroxy--4-methyl-2-oxo-1-oxa-3,8-diazaspiro/ 4,57decane 72 ml of aqueous hydrochloric solution o-f 3 mol/litre concentration are portionwise added during 20 to 30 minutes to the solution of 3.92 9 of 3-benzyl-8-benzyloxycarbonyl-4--methylene-2-oxo-1-oxa-3,8-diazaspiroL 4,57decane in 8 ml of 99% formic acid under stirring. The precipitate is filtered off, washed with water and dried. After recrystallization from ethanol the title compound is obtained in a yield of 89%, m.p.: 155-157 C.
Analysis:
Calculated for C23H26N205 C 67.30; H 6.38; N 6.82%;
found: C 67.35; H 6.19; N 6.72%.

- 23 - ~'J

Example 9 Preparation of 8-(2-chloronicotinoYlcarbamoYl)-3-ethY

-4-hydroxy-4-methyl-2-oxo-1-oxa-3,8-diazaspiro/ 4,57-decane A solution of 11 9 of 8-(2-chloronicotinoylcarbamoyl)--3-ethyl-4-methylene-2-oxo-1-oxa-3,~-diazaspiro/ 4,57decane in 116 ml of hydrochloric acid of 1 mol/litre concentration is stirred at room temperature for 2 hours and then cooled down to 3 to 5 C. After adjus-ting the pH value of the re-action mixture to 6 to 7 by adding aqueous sodium hydrogen carbonate solution the precipitate is filtered and washed to chloride-free with water. The product obtained is recrys-tallized from a mixture of dimethylformamide and methylene chloride to give the title compound in 75% yield, m.p.:

195-196 C.
Analysis: ~`
Calculated for C17H21ClN405 C 51.45; H 5.33; Cl 8.93; N 14.12%;
found: C 51.60; H 5.51; Cl B.84; N 14.25%.

Example 10 Preparation of_8-benzyl-3-cyclohexyl-4-hydroxy-4-methyl--2-oxo-1-oxa-3,8-diazaspiro/ 4,57decane hydrochloride and free base A solution of 10 ~ of 8-benzyl-3-cyclohexyl-4-methylene--2-oxo-1-oxa-3,8-diazaspiro/ 4,57decane in 100 ml of aqueous hydrochloric acid of 0.03 mol/litre concentration is vigorous-ly stirred at room temperature for 20 minutes. The precipitate is filtered, washed with ice cold eater and then dried at . ' ' ' ~

- 24 - ~5~

room -temperature over solid potassium hydroxide under reduced pressure to obtain the -title hydrochloride in 97% yield, m.p.: 308-310 C (with decomposition).
After adding an equivalent amount of aqueous N sodium hydroxide solution -to the hydrochloride, the base liberated is extracted into methylene chloride, the organic phase is dried over anhydrous sodium sulfate and evaporated under re-duced pressure. The residue is recrystallized from a mixture of chloroform and benzene to give the title base in 95%
yield, m.p.: 207-208 C.
Analysis:
Calculated for C21H30N203 C 70.36; H 8.43; N 7.81%;
found: C 70.30; H 8.61; N 7.97%.
By using the appropriate starting substances the follow-ing compounds can be prepared in an analogous manner as des-cribed in Examples 8, 9 or 10.
8-(2-Chloronico-tinoylcarbamoyl)-3,4-dimethyl-4-hydroxy -2-oxo-1-oxa-3,8-diazaspiroL 4,57decane, m.p.: 191-193 C;
3-tert-Butyl-4-hydroxy-4-methyl-2-oxo-8-phenoxycarbonyl--l-oxa-3,8-diazaspiroL 4,57decane, m.p.: 164-165 C;
8-Benzyl-3-(4-chlorophenyl)-4-hydroxy-4-methyl-2-oxo--l-oxa-3,8-diazaspiroL 4,57decane hydrochloride, m.p.: 298-299 C;
8-Benzyl-4-hydroxy-4-methyl-2-oxo-3-propyl-1-oxa-3,8--diazaspiroL 4,57decane hydrochloride, m.p.: 256-257 C;
3-Benzyl-8-tert-butylcarbamoyl-4-hydroxy-4-methyl-2--oxo-l-oxa-3,8-diazaspiroL 4,57decane, m.p.: 222-224 C;

- 25 ~

8-Ethylcarbamoyl-4-hydroxy-4-methyl-2-oxo-3-phenyl-1--oxa-3,8-diazaspiroL 4,57decane, m.p.: 234-236 C;
3-Cyclohexyl-4-hydroxy-4-methyl-2-oxo-8-propylcarbamo-yl-l-oxa-3,8-diazaspiro/ 4,57decane, m.p.: 210-212 C;
3-Butyl-4-hydroxy 4-methyl-2-oxo-8-phenoxycarbonyl-1--oxa-3,8-diazaspiro/ 4,57decane, m.p.: 136-137 C;
R-8enzyl-3-ethyl-4-hydroxy-4-methyl-2-oxo-1-oxa-3,8--diazaspiro/ 4,57decane hydrochloride, m.p.: 268-269 C.
Example 11 Prepa_ation of 8-benzyl-4-hydroxy-3,4-dimethyl-2-oxo-1--oxa-3,8-diazaspiro/ 4,57decane trifluoroacetate and- -free base The solution cohtaining 1.4 9 of 8-benzyl-3-methyl-4--methylene--2-oxo-1-oxa-3,8-diazaspiro/ 4,57decane in the mixture of 10 ml of water and 1.14 9 of trifluoroace-tic acid is stirred at room temperature for 15 minutes. The crystalline precipitate is filtered, washed with water and dried to give the title substance in 97% yield, m.p.: 147-148 C.
The base is liberated by adding sodium hydroxide solu-tion to its trifluoroacetate salt and melts a-t 161-163 C.
Analysis of the base Calculated for C16H22N2C3 C 66.18; H 7.64; N 9.65%;
found: C S6.32; H 7.58; N 9.78%.
Example 12 Preparation_of 8-benzyl-3-(4-chlorophenyl~-4-methylene--2-oxo-1-oxa-3,8-diazaspiro/ 4,57decane and hydrogen fumarate A mixture containing 12.90 9 of 1-benzyl-4-ethynyl-4-hydroxypiperidine, 9.21 9 of 4-chlorophenyl isocyana-te and 0.4 9 of anhydrous sodium acetate is stirred under argon.
The reaction is exothermic, therefore the reaction mixture is cooled in such a way that a highest temperature of 140 C
is maintained. After 2 hours the reaction mixture is cooled to room temperature, dissolved in 150 ml of chloroform, the chloroformic phase is washed with water, dried over anhydrous sodium sulfate and then evaporated under reduced pressure.
The crude product obtained as evaporated residue is recrys-tallized from acetonitrile to ootain the pure title substance in 84% yield, m.p.: 189-191 C. - -Analysis:
Calculated for C21H21ClN2C2 C 68.38; H 5.74; Cl 9.61; N 7.59%;
15 found: C 68.53; H 5.81; Cl 9.55; N 7.63%.
An equimolar amount of fumaric acid dissolved in ethanol is added to a benzene solution of the base to obtain the hydrogen fumarate salt as a crystalline precipitate which is then filtered off and dried, m.p.: 230-232 C.
Example 13 Preparation of 8-benzY~1-3-n-butyl-4-methylene-2-oxo-1--oxa-3,8-diazaspiro/ 4,57decane and dihYdrogen citrate 21.5 9 of 1-benzyl-4-ethynyl-4-hydroxypiperidine are ; boiled under reflux with 12.9 9 of n-butyl isocyanate in the 25 presence of 0.4 9 of anhydrous potassium acetate in 66 ml of 2-picoline under nitrogen for 6 hours. After evaporating 2-picoline under reduced pressure and dissolving the residue in benzene, the organic solution is washed with water and :

~ -- 27 ~ "~-J

dried over anhydrous magnesium sulfate. After filtration on an aluminum oxide layer the benzene solution is evaporated under reduced pressure. The crude product obtained is recrys-tallized from n-heptane to give the pure title substance in 78.5% yield, m.p.: 57-58 C.
Analysis:
Calculated for C19H26N202 C 72.5B; H 8.33; N 8.91%;
found: C 72.55; H 8.53; N 9.06%.
An equimolar amount of anhydrous citric acid dissolved in ethanol is added to the base dissolved in anhydrous ether and the solution is diluted with ether to give -the dihydrogen citrate salt as crystalline precipitate which is filtered off and dried, m.p.: 148-150 C.
8y using the appropriate starting substances the follow-ing compounds can be prepared.in an analogous way as described in Examples 12 or 13.
8 Formyl-4-methylene-2-oxo-3-phenyl-1-oxa-3,8-diaza-spiroL~4,57decane, m.p.: 171-172 C;
8-~enzyloxycarbonyl-4-methylene-2-oxo-3-phenyl-1-oxa--3,8-diazaspiroL 4,57decane, m.p.: 145-146 C;
4-Methylene-2-oxo-3-phenoxyca.rbonyl-3-phenyl-1-oxa-3,8--diazaspiroL 4,57decane, m.p.: 208-210 C;
8-Benzyl-3-cyclohexyl-4-methylene-2-oxo-1-oxa-3,8-di-azaspiroL 4,57decane, m.p.: 128-130 C (the hydrogen fumarate salt melts at 207-208 C);
8-Benzyl-3-ethyl-4-methylene-2-oxo-1-oxa-3,8-diaza-spiroL 4,57decane, m.p.: 103-104 C (hydrogen maleate salt m.p.: 184-lB6 C);
8-Benzyl-3-tert-butyl-4-methylene-2-oxo-1-oxa-3,8-di-azaspiro/ 4,57decane, m.p.: 116-117 (dihydrogen citrate salt m.p.: 132-133 C);
8-Benzyl-4-methylene-2-oxo-3-phenyl-1-oxa-3,8-diaza- ~ -spiro/ 4,57decane, m.p.: 134-135 C;
8-Benzil-3-isopropyl-4-methylene-2-oxo-1-oxa-3,8-diaza-spiro/ 4,57decane, m.p.: 96-97 C;
8-Benzyl-3-methyl-4-methylene-2-oxo-1-oxa-3,8-diaza-spiro/ 4,57decane hydrogen maleate, m.p.: 210-211 C;
8-Benzyl-4-methylene-2-oxo-3-propyl-1-oxa-3,8-diaza-- -spiroL 4,57decane dihydrogen citrate, m.p.: 168-171 C.
Example 14 Preparation of 3,4-dimethyl-4-hydroxy-2-oxo-8-phenoxy-carbonyl-1-oxa-3,8-diazaspirol 4,47decane A solution of 1.6 9 of methyl isocyanate in 5 ml of pyridine is dropwise added to a solution containing 5.3 9 of 4-acetyl-4-hydroxy-1-phenoxycarbonylpiperidine and 0.2 9 oi sodium methoxide in 10 ml of pyridine under argon while stirr-; 20 ing. The reaction is exothermic. After the addition the reac-tion mixture is refluxed for 2 to 3 hours, then the solvent is evaporated under reduced pressure. After taking up the evaporation residue in benzene the solution is washed with ~;
water to neutral and evaporated under reduced pressure to give the crude title product which is then recrystallized from ethyl acetate under clarifying by activated carbon to give the crystalline title compound in 61% yield, m.p.: 166-16B C.

.

, ~
, .: .

Analysis:
Calculated for C16H20N25 C 59.99; H 6.29; N 8.74%;
found: C 60.17; H 6.1B; N 8.86%.
Example 15 Preparation of 3-tert-butyl-8-ethoxycarbonyl-4-methylene--2-oxo-1-oxa-3,B-diazaspiro/ 4,57decane A mixture containing 4.3 9 of 4-acetyl-1-ethoxycarbonyl--4-hydroxypiperidine, 6.0 9 of tert-butyl isocyanate and 1 ml of triethylamine is refluxed under nitrogen for 6 hours. Af-ter cooling down and adding 50 ml of chloroform to the reaction mixture the organic phase is washed with water to neutral, then the solven-t is evaporated under reduced pressure. The crude product obtained as evaporation residue is recrystallized from isopropyl ether to give the title substance in 44% yield, m.p.: 104-105 C.
Analysis:
Calculated for C15H24N204 C 60.79; H 8.16; N 9.45%;
found: C 60.66; H 8.23; N 9.61%.
Example 6 Preparation of 3-methyl-4-methylene-2-oxo-1-oxa-3,8--diazaspiro/ 4,57decane 2 9 of catalyst containing 10% by weight of palladium on charcoal are suspended in 20 ml of water and added to the solution of 2û.0 9 of 8-benzyl-3-methyl-4-methylene-2-oxo--l-oxa-3,8-diazaspiro/ 4,57decane in 180 ml of methanol at 0 to 5 C under nitrogen while stirring-. Thereafter, 4.9 ml J
~ W ~ ;J i of an aqueous hydrazine solu-tion of 48 9/lOO ml concentration are introduced to the mixture which is then gently boiled under reflux. The progress of the reaction is followed by thin layer chromatography (TLC). After termination of the re-action ~10 to 15 minutes) the mixture is cooled down, thecatalyst is filtered off and washed with methanol. The metha-nolic washings are combined with the methanolic solution and the solvent is evaporated under reduced pressure. After re-crystallizing the evaporation residue from a mixture of ethyl acetate with isopropyl ether the title compound is obtained in 94% yield, m.p.: 92-93 C. - -Analysis:
Calculated for CgH14N2C2 C 59.32; H 7.74; N 15.37%;
found: C 59.55; H 7.76; N 15.49%.
Example 17 Preparation of 4-rnethylene-2-oxo-3-n-propvl-1-oxa-3~8--diazaspiro/ 4,57decane A suspension containing 0.5 g of 10% by weight palla-dium-on-carcoal catalyst in 5 ml of water is added to the solution of 5.0 g of 8-benzyloxycarbonyl-4-methylene-2-oxo--3-n-propyl-1-oxa-3,8-diazaspiro/ 4,57decane in 45 ml of methanol at 0 C under argon while stirring. To this rnixture 1 ml of 45.8% aqueous hydrazine solution is introduced and the reaction mixture is refluxed for 10 to 15 minutes. After cooling down to room temperature and filtering off the catalyst the solvent i5 evaporated under reduced pressure and the crude evaporation residue is recrystallized from benzene to give the title compound in 95% yield, m.p.: 96-_97 C.
Analysis:
Calculated for CllH18N202 - 5 C 62.83; H 8.63; N 13.32%;
found: C 63.00; H 8.57; N 13.47%.
By using the appropriate starting substances the follow-ing compounds can be prepared in an analogous way as described in Example 17.
3-Ethyl-4-methylene-2-oxo-1-oxa-3,8-diazaspiroL 4,57decane, m.p.: 106-108 C;
3-isopropyl-4-methylene-2-oxo-1-oxa-3,8-diazaspiroL 4,57-decane, m.p.: 151-152 C;
4-metnylene-3-(1-naphthyl)-2-oxo-1-oxa-3,8-diazaspiroL 4,57-decane, m.p.: 208-209 C;
3-butyl-4-methylene-2-oxo-1-oxa-3,8-diazaspiroL~4,57decane, oil;
4-methylene-2-oxo-3-phenyl-1-oxa--3,8-diazaspiro/ 4,57decane, m.p.: 185-186 C;
3-tert-8utyl-4-methylene-2-oxo-1-oxa-3,8-diazaspiroL 4,57-decane, m.p.: 138-139 C;
3-heptyl-4-hydroxy-4-methyl-2-oxo-1-oxa-3,8-diazaspiroL 4,57-decane, m.p.: 139-140 C;
3-/ 2-(3,4-dime-thoxyphenyl)ethyl7-4-hydroxy-4-methyl-2-oxo--1-oxa-3,8-diazaspiroL 4,57decane, m.p.: 190-191 C;
3-benzyl-4-methylene-2-oxo-1-oxa-3,8-diazaspiro/ 4,57decane, m.p.: 77-79 C;
3-heptyl-4-methylene-2-oxo-1-oxa-3,8-diazaspiroL 4,57decane, -~ d~ t~ '~r~

oil;
3-decyl-4-methylene-2-oxo-1-oxa-3,8-diazaspiroL 4,57decane, oil;
3-cyclohexyl-4-methylene-2-oxo-1-oxa-3,8-diazaspiro/ 4,57-decane, m.p.: 141-142 C;
3-/ 2-(3,4-dimethoxyphenyl)ethyl7-4-methylene-2-oxo-1-oxa--3,8-diazaspiro/ 4~57decane, m.p.: 107-109 C.
Example lB
Preparation of 4-methylene-2-oxo-3-phenyl-1-oxa-3,8-diazaspiro/ 4,57decane A solution containing 5.4 9 of 8-formyl-4-methylene-2- ~
-oxo-3-phenyl-1-oxa-3,8~diazaspiro/ 4,57decane, 3.0 9 of hydrazine monohydrate ànd 3.6 9 of acetic acid in 54 ml of aqueous ethanol of 60% by volume concentration is stirred under argon at a temperature of 62 to 65 C. The reaction is followed by TLC. After termina-tion of the reaction the mixture is evaporated under reduced pressure. After taking up the residue in chloroform and saturated aqueous sodium hydrogen carbonate solution, the chloroformic phase is separated, washed to neutral, dried over anhydrous magnesium sulfate and evapora-ted under reduced pressure. The crude product obtained is recrystallized from ethyl acetate under clarifying by activated carbon to give the title compound in 41.0% yield, m.p.: 185-186 C.
Analysis:
Calculated for C14H16N202 C 68.83; H 6.60; N 11.47%;
found: C 68.85; H 6.71; N 11.35%.

Example 19 Preparation of 4-hydroxy-4-methyl-2-oxo-1-oxa-3,8--diazaspiro/ 4,57decane A solution containing 4.2 9 of 8-benzyl-1-hydroxy-4--methyl-2-oxo-1-oxa-3,8-diazasplroL 4,57decane in 42 ml of 95% methanol is refluxed in the presence of 0.75 9 of hydra-zine hydrate and 0.42 9 of 10% by weight palladium-on-char-coal ca-talyst under vigorous stirring for 30 minutes. After cooling the reaction mixture to room temperature the catalyst is filtered off, washed with methanol and after combining the filtrate with the washings, the solution is evaporated unde-r reduced pressure. After thoroughly triturating the residue with acetone the crystalline product obtained is filtered off and dried to give the title compaund in 9.5% yield, m.p.:
192-194 C.
Analysis:
Calculated for CBHl~N203 C 51.60; H 7.58; N 15.04%;
found: C 51.58; H 7.55; N 15.2~.
Example 20 Preparation of 3,4-dimethyl-4-hydroxv-2-oxo 1-oxa-3,8--diazaspiroL 4,57decane hydrochloride A solution of 5.44 9 of 8-benzyl-3-methyl-4-methylene--2-oxo~1-oxa-3,8-diazaspiroL 4,57decane in 40 ml of N hydro-chloric acid is hydrogenated in the presence of 5.4 9 of palladium-on-charcoal catalyst until the theoretical amount of hydrogen is consumed. After filtering off the catalyst the filtrate is evaporated to a volume of about 10 ml under `

' _ 3b~ _ reduced pressure and 40 ml of acetone are added. The crystalline precipita-te is filtered off and dried to obtain the title compound in 87% yield, m.p.: 272-274 C.
Analysis of the base:
Calculated for C9H16N203 C 53.98; H 8.05; N 13.99%;
found: C 54.16; H 8.15; N 14.20%.
Example 21 Preparation of 3-decyl-4-hydroxy-4-me-thyl-2-oxo-1-oxa--3,8-diazaspiro/ 4,57decane .~
4.0 9 of 8-benzyl-3-decyl-4-methylene-2-oxo-1-oxa-3,8- ~
-diazaspiroL 4,57decane are stirred to~ether with 4.0 9 of 10% by weight palladium-on-carbon catalyst in 40 ml of 50%
aqueous formic acid for 2 hours at room temperature. After filtering off the catalyst the solution is evaporated under reduced pressure, the residue is treated with aqueous sodium hydrogen carbonate solution and the solid product is filtered off. After recrystallizing this product from a mixture of chloroform with n-hexane the title substance is obtained in 78.0% yield, m.p.: 139-140 C.
Analysis:
Calculated for C18H34N203 C 66.22; H 10.50; N 8.58%;
found: C 66.31; H 10.64; N 8.41%.
Example 22 Preparation of 8-benzyl-4-methylene-3-(1-naphthvl)-2--oxo-l-oxa-3,8-diazasplro/ 4,57decane A mixture of 11.8 9 of 4-methylene-3-(1-naphthyl)-2-2 ~

-oxo-l-oxa-3,8-diazaspiro/ 4,57decane, 5.8 ml of benzyl chloride, 4.2 9 of anhydrous sodium hydrogen carbonate, 0.5 9 o:E potassium iodide and 177 ml of methyl ethyl ketone is refluxed under argon while stirring for 18 hours. After termination of the reaction the mixture is cooled down and the solvent is evaporated under reduced pressure. After adding chloroform and water to the residue and separating the phases, the organic layer is washed with water to chloride-free, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. After recrystallizing the residue under clarifying by ac-tivated carbon the title substance is obtained in 84% yield, m.p.: 130-131 C.
Analysis:
Calculated for C25H24N202 C 78.10; H 6.29; N 7.29%;
found: C 78.19; H 6.37; N 7.37%.
Exam~e 23 Prep~ration of 8-benzyl-4-methYlene-2-oxo-3-(4-toluene-sulfonyl)-l-oxa-3,8-diazaspiro/ 4,57decane A mixture containing 3.2 9 of 4-methylene-2-oxo-3-(4--toluenesulfonyl)-l-oxo-3,8-diazaspiroL 4,57decane, 2.1 9 of benzyl bromide and 1.7 9 of anhydrous potassium carbonate in 32 ml of methyl isobutyl ketone is refluxed under nitrogen while stirring for 8 hours. After cooling down the reaction mixture to room temperature the inorganic salts are filtered off and the filtrate is evaporated under reduced pressure.
The residue is dissolved in 50 ml of benzene, washed to bromide-; -free and neutral with water, dried over anhydrous sodium sul-~ J

fate and evapora-ted under reduced pressure. After recrystalliz-ing the crude prcduct obtained from ethanol the title sub-stance is obtained in 84% yield, m.p.: 157-158 C.
Analysis:
Calculated for C22H24N2B04 C 64.05; H 5.86; N 6.79; S 7.77%;
found: C 64.15; H 5.84; N 6.88; S 7.64%.

Example 24 ,i Preparation of 8-benzyloxycarbonyl-3-cyclohexyl-4--methylene-2-oxo-1-oxa-3,8-diazaspiro/ 4,57decane 3.5 ml of benzyl chloroformate dissolved in 5 ml of - - -chloroform are portionwise added to the solution containing 5.0 9 of 3-cyclohexyl-4-methylene-2-oxo-1-oxa-3,8-diazaspi-ro_ 4,57decane and 3~4 ml of triethylamine in 50 ml of chloro-form with cooling under nitrogen, then the reaction mixture is stirred at room temperature for additional 30 minutes.
After adding water to the reac-tion mixture and separating the phases -the chloroformic layer is washed to neutral with water, dried over anhydrous sodium sulfate, then the solvent is evaporated under reduced pressure. After recrystallization of the residue from ethanol the title compound is obtained in 83% yield, m.p.: 104-105 C.
Analysis:
Calculated for C22H28N204 C 68.72; H 7.34; N 7.29%;
found: C 68.66; H 7.44; N 7.33%.

By using the appropriate starting substances the following compounds can be prepared in an analogous way as . , . ' ' '' .
, described in Example 24.
3-Ethyl-4-methylene-2-oxo-8-phenoxycarbonyl-1-oxa-3,8-diaza-spiro/ 4,57decane, m.p.: 98-99 C;
3-cyclohexyl-4-methylene-2-oxo-8-phenoxycarbonyl-1-oxa-3,8--diazaspirL 4,57decane, m.p.: 188-189 C; and 3-butyl-4-methylene-2-oxo-8-phenoxycarbonyl-1-oxa-3,8-diaza-spiro/ 4,57decane, m.p.: 94-95 C.
Example 25 Preparation of 8-formvl-4-methylene-3-n-propyl-2-oxo--1-oxa-3,8-diazaspiro/ 4,57decane A solution containing 4.6 9 of 4-methylene-2-oxo-3-n--propyl-l-oxa-3,8-diazaspiro/ 4,57decane in 35 ml of chloro-form is dropwise added to a formic acid-acetic acid mixed anhydride prepared from 4.4 ml of acetic anhydride and 2.2 ml of formic acid in situ, then the reaction mixture is stirred at room temperature for additional 30 minutes. After neutraliz-ing the reac-tion mixture by adding 8.4% by weight aqueous sodium hydrogen carbonate solution under stirring and separat-ing the phases, the organic layer is washed with water, dried over anhydrous potassium carbonate and evaporated under re-duced pressure. The residue is mixed with ether and filtered off to give the title substance in 96% yield, m.p.: 150-151 C.
Analysis:
Calculated for C121118N203 C 60.48; H 7.61; N 11.76%
found: C 60.54; H 7.73; N 11.80%.
By using the appropriate starting substances the follow-ing compounds can be prepared in an analogous manner as '`' -described in Example 25.
3-tert-Butyl-8-formyl-4-methylene-2-oxo-1-oxa-3,8 diaza-spiro/ 4,57decane, m.p.: 141-142 C; and 3-cyclohexyl-8-formyl-4-methylene-2-oxo-1-oxa-3,8-diaza-spiroL 4,57decane, m.p.: 212-213 C.
Example 26 Preparation of 8-butylcarbamoyl-3-methyl-4-methylene--2-oxo-1-oxa-3,8-diazaspiro/ 4,57decane 2.25 ml of n-butyl isocyanate are dropped to a suspen-sion of 3.64 9 of 3-methyl-4-methylene-2-oxo-1-oxa-3,8-di-azaspiroL 4,57decane in 18 ml of acetonitrile while stirring under argon. Since the reaction is exothermic, the temperature is maintained at 25 to 30 C by cooling. After 15 minutes the reaction mixture is evaporated under reduced pressure. The white solid evaporation residue is recrystallized from ethyl acetate to obtain the title compound in 91.3% yield, m.p.:
129-130 C.
Analysis:
Calculated for C~4H23N3C3 C 5~.76; H 8.24; N 14.94%;
found: C 59.63; H 8.28; N 15.04%.
By using the appropriate starting substances the follow-ing compounds can be prepared in an analogous manner as des-cribed in Example 26.
3-Cyclohexyl-4-methylene-2-oxo-8-propylcarbamoyl-1-oxa-3,8-~diazaspiroL 4,57decane, m.p.: 157-158;
8-ethylcarbamoyl-4-methylene-2-oxo-3-phenyl-1-oxa-3,8-diaza-spiroL~4,57decane, m.p.: 196-197 C;

.

3-benzyl-B-tert-bu-tylcarbamoyl-4-methylene-2-oxo-1-oxa-3,8--diazaspiro/ 4,57decane, m.p.: 158-159 C; and 8-butylcarbamoyl-3,4-dimethyl-4-hydroxy-2-oxo-1-oxa-3,8-di-azaspiroL~4,57decane, m.p.: 152-153 C.
Example 27 Preparation of 4-methylene-8-(4-methylpiperazine-1--ylcarbonyl)-2-oxo-3-phenyl-1-oxa-3,8-diazaspiro/ 4,57-decane The solution of 3.9 9 of 4-methylpiperazin-1-yl-car-bonyl chloride in 5 ml of chloroform is dropwise added at a temperature between 0 and 5 C to a solution containing 4.9-9 -of 4-methylene-2-oxo-3-phenyl-1-oxa-3,8-diazaspiroL 4,57-decane and 7.4 ml of triethylamine in 74 ml of chloroform under stirring. Thereafter, the reaction mlxture is stirred at room temperature for additional 30 minutes. After termina-tion of the reaction the chloroform phase is washed to chloride-free with wa-ter, dried over anhydrous sodium sulfate, then the solvent is evaporated under reduced pressure. After re-crystallization of the crude product obtained from ethanol under clarifyin3 by activated carbon the title compound is obtained in 83% yield, m.p.: 198-199 C.
Analysis:
Calculated for C20H26N403 C 64.84; H 7.07, N 15.12%;
found: C 64.88; H 7.23; N 15.01%.
By using the appropriate starting substances the following compounds can be prepared in an analogous way as described in Example 27.

!

- 40 ~ 2 ~ ~

3-Methyl-4-methylene-8-(4-methylpiperazin-1-ylcarbonyl)-2-oxo--l-oxa-3,8-diazaspiro/ 4,57decane, m.p. 139-140 C;
3-cyclohexyl-4-methylene-8-(4-me-thylpiperazin-1-ylcarbonyl)--2-oxo-1-oxa-3,8-diazaspiro/ 4,57decane, m.p.: 191-192 C;
4-methylene-2-oxo-3 ~iperidin-1-ylcarbonyl)-3-propyl-1-oxa--3,8-diazaspiroL 4,57decane, m.p.: 105-106 C;
3-tert-butyl-4-methylene-2-oxo-8-(piperidin-1-ylcarbonyl)-1--oxa-3,8-diazaspiro/ 4,57decane, m.p.: 149-150 C;
3-(4-chlorophenyl)-4-me-thylene-8-(morpholin-4-ylcarbonyl)-2--oxo-1-oxa-3,8-diazaspiroL 4,5.7decane, m.p.: 214-215 C;
4-methylene-8-(4-methylpiperazin-ylcarbonyl)-2-oxo-3-propyl--l-oxa-3,8-diazaspiroL 4,57decane, m.p.: 146-147 C; and 3-butyl-4-methylene-8-(4-methylpiperazin-1-ylcarbonyl)-2-oxo--l-oxa-3,8-diazaspiroL 4,57decane, m.p.: 113-114 C.
Example 28 .
Preparation of 8-(?-chloronicotinoylcarbamoyl)-3-iso-propyl-4-methylene-2-oxo-1-oxa-3,8-diazaspiro/ 4,57-decane 5.8 9 of oxalyl chloride are portionwise added to -the solution of 6.2 9 of 2-chloronicotinic acid amide in 150 ml of anhydrous 1,2-dichloroethane under stirring, then the reaction mixture is heated at 85 C for 90 minutes. After cooling the mixture to 0 to 5 C first 12.6 ml of triethyl-amine and then a solution of 8.4 9 of 3-isopropyl-4-methylene--2-oxo-1~-oxa-3,8-diazaspiroL 4,57decane in 42 ml of anhydrous 1,2-dichloroethane are portionwise added while malntaining ; the temperature between 20 and 30 C. The reaction mixture ~ is stirred at room temperature for additional 30 minutes, - 41 - ~ 2 ~

then extracted with 200 ml of N sodium hydroxide solution and then with 100 ml of water. After combining the aqueous extract is acidified to a pH value of 5.5 to 6 by adding acetic acid and the mixture is extracted with 1,2-dichloroethane. The organic solution is washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue is recrystallized from ethanol to give the title compound in 54% yield, m.p.: 186-188 C.
Analysis:
Calculated for C18H21ClN4C4 C 55.03; H 5.39; Cl 9.02; N 14.26%; - -found: C 55.15; H 5.57; Cl 9.14; N 14.12%.
By using the appropriate starting substances the follow-ing compounds can be prepared in an analogous manner as des-cribed in Example 28.8-(2-Chloronicotinoylcarbamoyl) 3-methyl-4-methylene-2-oxo-1--oxa-3,8-diazaspiro_ 4,57decane, m.p.: 196-19B C;
8-(2-chloronicotinoylcarbamoyl)-3-ethyl-4-methylene-2-oxo-1--oxa-3,8-diazaspiro/ 4,57decane, m.p.: 202-204 C;
8-(2-chloronicotinoylcarbamoyl)-4-methylene-3-propyl-2-oxo-1--oxa-3,8-diazaspiroL 4,57decane, m.p.: 183-184 C;
3-tert-butyl-8-(2-chloronicotinoylcarbamoyl~-4-methylene-2-oxo--l-oxa-3,8-diazaspiro/ 4,57decane, m.p.: 179-181 C;
3-n-butyl-8-(2-chloronicotinoylcarbamoyl)-4-methylene-2-oxo-1--oxa-3,8-diazaspiro/ 4,57decane, m.p.: 166-168 C;
8-(2-chloronicotinoylcarbamoyl)-3-cyclohexyl-4-methylene-2-oxo--l-oxa-3,8-diazaspiroL 4,57decane, m.p.: 217-218 C; and 8-(2-chloronicotinoylcarbamoyl)-4-methylene-2-oxo-3-phenyl-1-` i, ~ ., --oxa-3,8-diazaspiro/ 4,57decane, m.p.: 190-192 C.
Example 29 Preparation of 3-(4-chlorophenyl)-8-/ 4-(2-hydroxv_ ethyl)piperazin-l-ylcarbonY17-4-methylene-2-oxo-1--oxa-3,8-diazaspiro/ 4,57decane A mixture containing 4.0 9 of 3-(4-chlorophenyl)-4--methylene-2-oxo-8-phenoxycarbonyl-1-oxa-3,8-diazaspiro/ 4,57-decane and 6.13 ml of N-(2-hydroxyethyl)piperazine in 20 ml of ortho-xylene is refluxed under nitrogen for 60 hours. After cooling down the reaction mixture is diluted with 20 ml of xylene and the organic solution is washed first with an aqueo-us - .
saturated sodium chloride solution containing 5% by weight of ~, sodium hydroxide and theh with aqueous saturated sodium chloride solu-tion. After drying over anhydrous magnesium sulfate and then evaporating the solvent under reduced pressure the crude product obtained is recrystallized from a mixture of benzene and hexane under clarifying by activated carbon to give the title compound in 67% yield, m.p.: 185-186 C.
Analysis:
2Q Calculated for C21H27ClN4Q4 C 57.99; H 6.27; Cl 8.15; N 12.88g-o;
found: C 57.78; H 6.35; Cl 8.30; N 13.05%.
By using the appropriate starting substances the follow-ing compounds can be prepared in an analogous way as described in Example 29.
3-Butyl-8-~ 4-(2-hydroxyethyl)piperazin-1-ylcarbonyl7-4--methylene-2-oxo-1-oxa-3,8-diazaspiro/ 4,57decane, m.p.: 101.5--102.5 C;

- ~1 3 - ~ r 8-L 4-(2-hydroxyethyl)piperazin-1-ylcarbonyl7-3-methyl-4--methylene-2-oxo-1-oxa-3,8-diazaspiroL 4,57decane, m.p.:
177-178 C;
3-tert-butyl-B-/ 4-(2-hydroxyethyl)piperazin-1-ylcarbonyl7-4--methylene-2-Dxo-l-oxa-3,8-diazaspiro/ 4,57decane, m.p.: 159--160 C;
3-cyclohexyl-4-methylene-2-oxo-8-piperidin-1-ylcarbonyl)-1-oxa--3,8-diazaspiro/ 4,S7decane, m.p.: 170-171 C;
3-ethyl-4-methylene-8-(morpholin-4-ylcarbonyl)-2-oxo-1-oxa-3,8--diazaspiro/ 4,57decane, m.p.: 160-162 C;
4-methylene-B-(morpholin-4-ylcarbonyl)-2-oxo-3-phenyl-1-oxa--3,8-diazaspiro/ 4,57decane, m.p.: 215-216 C;
3-tert-butyl-4-methylene-8-(morpholin-4-ylcarbonyl)-2-oxo-1--oxa-3,8-diazaspiro/ 4,57decane, m.p.: 174-175 C;
3-cyclohexyl-4-methylene-8-(morpho:lin-4-ylcarbonyl)-2-oxo-1--oxa-3,8-diazaspiro/ 4,57decane, m.p.: 202-203 C;
4-methylene-8-(morpholin-4-ylcarbollyl)-2-oxo-3-propyl-1-oxa--3,8-diazaspiroL 4,57decane, m.p.: 146-147 C;
3-butyl-4-methylene-B-(morpholin-4-ylcarbonyl)-2-oxo-1-oxa--3,8-diazaspiro/ 4,57decane, m.p.: 113-114 C;
3-ethyl-4-methylene-B-(4-methylpiperazin-1-ylcarbonyl)-2-oxo-1--oxa~3,8-diazaspiro/ 4,57decane, m.p.: 140-141 C; and 3-tert-butyl-4-methylene-8-(4-methylpiper3zin-l-ylcarbonyl)--2-oxo-1-oxa-3,8-diazaspiro/ 4,57decane, m.p.: 143-144 C.
Example 30 Preparation o~ 3-tert-butyl-4-methylene-2-oxo-B-phenoxy-carbonyl-l-oxa-3,8-diazaspiro/ 4,57decane A solution of 3.6 p of phenyl chloroformate in 5 ml of .

';

.1 W ~

methylene chloride are dropped to the solution of 6.3 9 of 8-benzyl-3-tert-butyl-4-methylene-2-oxo-1-oxa-3,8-diazaspiro-L 4,57decane in 30 ml of methylene chloride under argon at 0 C while stirring, then the reaction mixture is stirred at room temperature for one additional hour. After termination of the reaction the mix-ture is diluted with 35 ml of methylene chloride, extracted with 4 N sodium hydroxide solution and washed to neutral with water. After drying over anhydrous magnesium sulfate the solvent is evaporated under reduced pressure. After adding n-hexane to the residue the solid pre-cipitate is filtered off and recrystallized from isopropanol to obtain the title substance in 82% yield, m.p.: 125-126 C.
Analysis:
Calculated far ClgH24N204 C 66.26; H 7.02; N 8.13%;
found: C 66.33; H 7.10; N 8.10%.
By using the appropriate starting subs-tances the follow-ing compounds can be prepared in an analogous manner as des-cribed in Example 30. f 3-Benzyl-8-benzyloxycarbonyl-4-methylene-2-oxo-1-oxa-3,8-diaza-spiroL 4,57decane, oil;
~-benzy].oxycarbonyl-3-butyl-4-methylene-2-oxo-1-oxa-3,8-diaza-spiroL~4,57decane, m.p.: 47-48 C;
8-ethoxycarbonyl-3-methyl-4-methylene-2-oxo-1-oxa-3,8-diaza-spiroL~4,57decane, m.p.: 121-122 C;
3-(3,4-dichlorophenyl)-4-methylene-2-oxo-8-phenoxycarbonyl-1--oxa-3,8-diazaspiroL 4,57decane, m.p.: 220-222 C;

3-methyl-4-methylene-2-oxo-8-phenoxycarbonyl-1-oxa-3,8-diaza-- 45 - ~$~

spiro/ 4,57decane, m.p.: 118-119 C; and 4-methylene-2-oxo-8-phenoxycarbonyl-3-propyl-1-oxa-3,8-diaza-spiroL 4,57decane, m.p.: 96-98 C.
Example 31 Preparation of 8-benzyl-3,4-dimethyl-4-hydroxy-2-oxo-1--oxa-3,8-diazaspiro/ 4,57decane and h~drochloride A suspension containing 5.2 9 of 8-benzyl-4-methylene--2-oxo-1,3-dioxa-B-azaspiro/ 4,57decane, 2.1 9 of methylamine hydrochloride and 2.1 9 of anhydrous powdered potassium car-bonate in 11 ml of ethanol is stirred under nitrogen for 2 hours, then left to stand overnight. After adding water to the reaction mixture the crystalline precipitate is filtered off and washed with water. The crude product obtained is re-crystallized frorn a mixture of acetone and diisopropyl ether to give the title compound in 88% yield with the same physical characteristics as given for the base in Example 10.
The hydrochloride is obtained by treating the base with an ethereal hydrogen chloride solution, m.p.: 277-279 C.
By using the appropriate starting substance the follow-ing compound can be prepared in an analogous way as described in Example 31.
8-8enzyl-3-L 2-(3,4-dihydroxyphenyl)ethyl7-4-hydroxy-4-methyl--2-oxo-1-oxa-3,8-diazaspiroL 4,57decane, m.p.: 105-106 C;
the hydrogen maleate salt melts at 77 C.
Example 32 Preparation of 8-benzyl-3-decyl-4-methvlene-2-oxo-1-oxa--3,8 diazaspiro/ 4,57decane A mixture containing 6.2 9 of 8-benzyl-3-decyl-3-hydroxy-' ~

;;3J ~ J ~7 4-methyl-2-oxo-1-oxa-3,8-diazaspiro/ 4,57decane and 0.6 9 of p-toluenesulfonic acid monohydrate in 63 ml of xylene i5 boiled by using a Dean-Stark device while azeotropically distilling out the water formed in the reaction. After termina-tion of the reaction the mixture is cooled down, then theorganic solution is ex-tracted with an 5% by weight aqueous sodium hydroxide solution and wi-th water up to neutral. The xylene phase is dried over anhydrous sodium sulfate and evaporat-ed under reduced pressure. After recrystallization the evapora-tion residue from n-hexane under clarifying by activated carbon the title compound is obtained in 91% yield, m.p.: 51-52 C.- - ;
Analysis:
Calculated for C2sH3gN22 C 75.33; H 9.61; N 7.03%;
found: C 75.41; H 9.69; N 7.15%.
By using -the appropriate starting substances the follow-ing compounds can be prepared in an analogous way as described in Example 32.
8-Benzyl-3-/ 2-(3,4-dimethoxyphenyl)ethyl7-4-methylene-2-oxo--1-oxa-3,B-diazaspiro74,57decane, m.p.: 91-92 C; and 3,8-dibenzyl-4-methylene-2-oxo-1-oxa-3,8-diazaspiro/ 4,57decane with the same physical characteristics as described in Example 4.
Example 33 Preparation of_B-benzvl-4-methylene-2-oxo-1-oxa-3,8--diazaspiro/ 4,57decane A solution containing 14.0 9 of 8-benzyl-4-hydroxy-4--methyl-2-oxo-1-oxa-3,8-diazaspiro/ 4,57decane in 210 ml of s~

dioxane is bniled under nitrogen while azeotropically distill-ing out the water formed in the reaction. After termination of the reaction dioxane is evaporated under reduced pressure.
The residue is recrystallized from ethanol under clarifying by activated carbon to give the title compound in 62% yield, m.p.: 169-170 C.
Analysis:
Calculated for C15HlBN202 C 69.74; H 7.02; N 10.84%;
10 found: C 69.92; H 7.18; N 10.78%.
Example 33 Preparation of 8-benzyl-3-methyl-4-me-thylene-2-oxo-1--oxa-3,8-diazaspiro/ 4,57decane A solution of 1.6 9 of me-thylamlne in 35 rnl of xylene prepared at 0 C is flown to the solution of 13.0 9 of 8-benzyl--4-methylene-2-oxo-1,3-dioxa-8-azaspiro/ 4,57decane in 30 ml of xylene under stirring. The reaction is exothermic, thus the temperature of the reaction mixture increases up to 55 to 60 C. Thereafter, the heterogeneous reaction mixture is heat-ed to a temperature of 100 to 102 C, maintained at the sametemperature for 10 minutes, then 0.2 9 of p-toluenesulfonic acid monohydrate is added to the solu-tion and the reaction mixture is boiled while the water formed in the reaction is azeotropically distilled out. After termination of the reaction the mixture is cooled down to room temperature, washed with 5% by weight aqueous sodium hydroxide solution and after separa-tion the xylene phase is washed to neutral with water. The organic phase is dried over anhydrous sodium sulfate and '' ' --` 2~2~J~

evaporated under reduced pressure. The residue is recrystallized from a mixture of ethanol and diisopropyl ether under clarify-ing by activated carbon to obtain the title compound in 96.7%
yield, rn.p.: 96-97 C.
Analysis:
Calculated for C16H20N202 C 70.56; H 7.40; N 10.29%;
found: C 70.58; H 7.55; N 10.14%.
Example 35 Preparation of 8-benzyl-4-methylene-2-oxo-3-propyl-1--oxa-3,8-diazaspiro/ 4,57decane - -After refluxing a solution containing 9.6 9 of 8-benzyl--4-hydroxy-4-methyl-2-oxo-3-propyl-1-oxa-3,8-diazaspiroL 4,57-decane in a mixture of 96 ml of acetic acid and 5.7 ml of acetic anhydride under argon for 5 hours the solvent is evaporat-ed under reduced pressure. After adding 5% by weight aqueous sodium hydroxide solution to the residue up -to a pH value of 10, the mixture is extracted with benzene and the organic phase is washed to neutral with water. After drying the organic phase over anhydrous sodium sulfate benzene is evaporated under reduced pressure. After recrystallizing the residue from di-isopropyl ether the title compound is obtained in 86.4% yield, m.p.: 70-71 C.
Analysis:
Calculated for C18H24N202 C 71.97; ~l 8.05; N 9.33%;
found: C 72.18; H 8.16; N 9.12%.

: . .

- ~9 - ~ Q~

Example 36 Pharmaceutical compositions containing e.g. the follow-ing components (ingredients) can be prepared from the novel 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 starch, 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 ultraamylopectin 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 prepared as described above are covered in a manner known per se with a coat consisting of sugar and ].5 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 af-ter sieving, the mixture obtained is filled into hard gelatin capsules containing 20 mg of the active ingredient each.
d) Preparation of suppositories 100.0 mg of active ingredien-t and 200.0 mg of lac-tose calculated for one suppository are thoroughly mixed together.
1700.0 mg of suppository base (e.g. Witepsol 4) are molten, ' . ' ' ~ :.,,, '" , , - 50 - 2 ~ 3~

cooled -to 35 C and -the mixture of the active ingredient and lactose is mixed thereto by using a homogenizer. Ihe 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 0.10 9 salt) Carbopol 940 (polyacrylic acid) 0.30 9 96% Ethanol 1.00 9 Raspberry flavour 0.60 9 Sorbitol (aqueous solution of 70%)71.00 9 Distilled water for injection purpose up to 100.00 ml After adding Carbopol inlittle portions to the solution of nipagin and citric acid in 20 ml of dis-tilled 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 ingredient is added in small por-tions to this mixture and suspended by using a submerged homogenizer. Finally, the suspen-sion is supplemented to 100 ml by adding distilled water and the syrupy suspension is led through a colloid mill.

~. :

.,.. ,........ , .. :

Claims (15)

1. Novel 2-oxo-1-oxa-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; C3-6cycloalkyl;
carbocyclic C6_10aryl or carbocyclic C6-10aryl--C1-4alkyl group, the two latter ones being optionally substituted on their aromatic part by one or more, same or different halogen(s), one or more C1-4alkyl, C1-4alkoxy or trihalomethyl group(s); or a tosyl group;
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 and the other one is a methyl group; and R3 means hydrogen, benzyl, (C1-4alkoxy)carbonyl, phenoxy-carbonyl, formyl, piperidin-l-ylcarbonyl, morpholin--4-ylcarbonyl, 4-methylpiperazin-1-ylcarbonyl, 4-(2--hydroxyethyl)piperazin-l-ylcarbonyl, 2-chloro-3--nicotinoylcarbamoyl or C1-6alkylcarbamoyl group, as well as their acid addition and quaternary ammonium salts.

2. A compound selected from the group consisting of

3-methyl-4-methylene-2-oxo-1-oxa-3,8-diazaspiro[4,5]decane, 3-ethyl-4-methylene-2-oxo-1-oxa-3,8-diazaspiro[4,5]decane, 3-cyclohexyl-4-methylene-2-oxo-1-oxa-3,8-diazaspiro[4,5]-decane,

4-methylene-2-oxo-3-propyl-1-oxa-3,8-diazaspiro[4,5]decane, 3-isopropyl-4-methylene-2-oxo-1-oxa-3,8-diazaspiroL[4,5]decane, 3-butyl-4-methylene-2-oxo-1-oxa-3,8-diazaspiro[4,5]decane, 3-tert-butyl-4-methylene-2-oxo-1-oxa-3,8-diazaspiro[4,5]-decane, 3-heptyl-4-methylene-2-oxo-1-oxa-3,8-diazaspiro[4,5]decane, 4-methylene-2-oxo-3-phenyl-1-oxa-3,8-diazaspiro[4,5]decane, 3-decyl-4-methylene-2-oxo-1-oxa 3,8-diazaspiro[4,5]decane, 3-benzyl-4-methylene-2-oxo-1-oxa-3,8-diazaspiro[4,5]decane, 3-[2-(3,4-dimethoxyphenyl)ethyl]-4-methylene-2-oxo-1-oxa--3,8 diazaspiro[4,5]decane, 4-hydroxy-4-methyl-2-oxo-1-oxa-3,8-diazaspiro[4,5]decane, 3,4-dimethyl-4-hydroxy-2-oxo-1-oxa-3,8-diazaspiro[4,5]decane, 3-[2-(3,4-dimethoxyphenyl)ethyl]-4-hydroxy-4-methyl-2-oxo-1--oxa-3,8-diazaspiro[4,5]decane, 3-decyl-4-hydroxy-3-methyl-2-oxo-1-oxa-3,8-diazaspiro[4,5]-decane, 3-heptyl-4-hydroxy-4-methyl-2-oxo-1-oxa-3,8 diazaspiro[4,5]-decane, 8-benzyl-4-methylene-2-oxo-1,3-dioxa-8-azaspiro[4,5]decane, 4-methylene-3-(1-naphthyl)-2-oxo-1-oxa-3,8-diazasoiroL 4,57-decane, as well as the acid addition and quaternary ammonium salts of these compounds.
3. A pharmaceutical composition, which comprises as active ingredient a 2-oxo-1-oxa-8-azaspiroL 4,57decane derivative of the formula (I), wherein X, R, Rl, R2 and R3 are as defined in claim 1, or a pharmaceutically acceptable acid addition or quaternary ammonium salt thereof in admixture with carriers and/or additives commonly used in the pharmaceutical industry.

4. A process for the preparation of the novel 2-oxo-1--oxa-8-azaspiroL 4,57decane derivatives 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 ones being optionally substituted on their aromatic part by one or more, same or different halogen(s), one or more C1-4alkyl, C1-4alkoxy or trihalomethyl group(s); or a tosyl group;
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 and the other one is a methyl group; and R3 means hydrogen, benzyl, (C1-4alkoxy)carbonyl, phenoxy-carbonyl, benzyloxycarbonyl, formyl, piperidin-l-yl-carbonyl, morpholin-4-ylcarbonyl, 4-methylpiperazin--l-ylcarbonyl, 4-(2-hydroxyethyl)piperazin-1-ylcar-bonyl, 2-chloro-3-nicotinoylcarbamoyl or C1-6alkyl-carbamoyl group, as well as their acid addition and quaternary ammonium salts, which comprises a) reacting a 4-ethynyl-4-hydroxypiperidine derivative of the formula (III), (III) wherein R3 is as defined above, with an isocyanate of the formula R-NCO, wherein R is as defined above, and then cycliz-ing the obtained 4-carbamoyloxy-4-ethynylpiperidine derivative of formula (II), (II) wherein R and R3 are as defined above, .alpha.) in an acidic medium and reacting the obtained salt of a 2-imino-1,3-dioxoline derivative of the formula (VI), (VI) wherein R and R3 are as defined above with water to obtain compounds of the formula (I), wherein X
means oxygen, R1 and R2 together represent a methylene group, and R3 is as defined above; or .beta.) in a basic medium to obtain compounds of the formula (I), wherein X
means an ?NR group, R1 and R2 together represent a methylene group, and R as well as R2 are as defined above; or b) cyclizing in an acidic medium a 4-carbamoyloxy-4--ethynylpiperidine derivative of the formula (II), wherein R
and R3 are as defined above, and reacting the obtained salt of a 2-imino-1,3-dioxolane derivative of the formula (VI), where-in R and R3 are as defined above, with water to obtain compounds of the formula (I), wherein X means oxygen, R3 is as defined above and R1 together with R2 represents a methylene group, or c) cyclizing a 4-carbamoyloxy-4-ethynylpiperidine derivative of formula (II) wherein R and R3 are as defined above, in a basic medium to obtain compounds of the formula (I), wherein X means an ?NR group, R1 together with R2 repre-sents a methylene group and R as well as R3 are as defined above;
or d) reacting a 4-acetyl-4-hydroxypiperidine derivative of the formula (IV), (IV) wherein R3 is 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 formula (V), (V) wherein R and R3 are as defined above, to obtain compounds 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 as well as R3 are as defined above;
or e) cyclizing a 4-acetyl-4-carbamoyloxypiperidine derivative of the formula (V), wherein R and R3 are as defined above, to obtain compounds 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 as well as R3 are as defined above, then, if desired, reacting a thus prepared compound of the formula (I), wherein X means oxygen, R3 is as defined above and R1 together with R represents a methylene group, with an amine of the formula R-NH2, wherein R is as defined above, to obtain compounds 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 as well as R3 are as defined above;
and/or transforming a thus prepared compound of the formula (I), wherein X, R, R1, R2 and R3 are as defined in the preamble, to an other compound of the formula (I) falling within the scope of the formula (I);
and/or reacting a thus prepared compound of the formula (I), wherein X, R, R1, R2 and R3 are as defined above, with an acid-to give an acid addition salt and/or treating a compound of the formula (I), wherein X, R, R1, R2 and R3 are as defined above, obtained as a salt, with a base to liberate the base form thereof and/or converting a thus prepared compound of the formula (I), wherein X, R, R1, R2 and R3 are as defined above, to its quaternary ammonium salt.

5. A process as claimed in claim 4 under a) for the pre-paration of compounds of the formula (I), wherein X means an ?NR group, R1 together with R2 represents a methylene group, R is as defined for formula (I) and R3 is as defined for formula (I), except the 4-(2-hydroxyethyl)piperazin-1-ylcarbonyl and 2-chloronicotinoylcarbamoyl goup, which comprises reacting a 4-ethynyl-4-hydroxypiperidine derivative of formula (III), wherein R3 is as defined for formula (I), with an iso-cyanate of the formula R-NCO, wherein R is as defined for formula (I), as well as cyclizing in a basic medium the obtain-ed 4-carbamoyloxy-4-ethynylpiperazine derivative of formula (II), wherein R and R3 are as defined above, in a single step without separating the compound of formula (II).

6. A process as claimed in claim 4 under b), which comprises cyclizing a 4-carbamoyloxy-4-ethynylpiperazine derivative of formula (II), wherein R3 and R are as defined for formula (I), in an organic solvent in the presence of a hydrogen halide.

7. A process as claimed in claim 6, which comprises using dioxane as organic solvent and hydrogen chloride as hydrogen halide.

8. A process as claimed in claim 6, which comprises using glacial acetic acid as organic solvent and hydrogen bromide as hydrogen halide.

9. A process as claimed in claim 4 under c), which comprises carrying out the cyclization of a 4-carbamoyl-oxy-4-ethynylpiperidine derivative of the formula (II), where-in R and R3 are as defined for formula (I), in a C1-4alkanol in the presence of an alkaline metal alkoxide.

10. A process as claimed in claim 9, which comprises using ethanol or methanol as C1-4alkanol and sodium ethoxide or sodium methoxide as an alkaline metal alkoxide.

11. A process as claimed in claim 4 under d), which comprises carrying out the reaction of a 4-acetyl-4--hydroxypiperidine derivative of the formula (IV), wherein R3 is as defined for formula (I), with an isocyanate of the formula R-NCO, wherein R is as defined for formula (I), as well as the cyclization of the thus formed 4-acetyl-4-carbamoyloxy-piperidine derivative of formula (V), wherein R and R3 are as defined for formula (I), in the same reaction mixture.

12. A process as claimed in claim 4 under e), which comprises carrying out the cyclization of a 4-acetyl-4--carbamoyloxypiperidine derivative of the formula (V), where-in R and R3 are as defined for formula (I), in a C1-4alkanol in the presence of an alkaline metal alkoxide.

13. A process as claimed in claim 12, which comprises using ethanol as C1-4alkanol and sodium ethoxide as alkaline metal alkoxide.

14. A process for the preparation of a pharmaceutical composition, which comprises mixing as active in-gredient a novel 2-oxo-1-oxa-8-azaspiro[4,5]decane derivative of the formula (I), wherein X, R, R1, R2 and R3 are as defined in claim 1, or a pharmaceutically acceptable acid addition or quaternary ammonium salt thereof prepared by using the process as claimed in claim 4, with carriers and/or additives common-ly used in the pharmaceutical industry and transforming them to a pharmaceutical composition.

15. Method for the anticonvulsive (antiepileptic), anti-allergic as well as lipid level lowering treatment of mammals including man, characterized by administering to the mammal (including man) to be treated a therapeutically effective dose of a 2-oxo-1-oxa-8-azaspiro[4,5]decane derivative of the forrmula (I), wherein X, R, R1, R2 and R3 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.