CA2023014A1 - 2-oxo-1-oxa-8-azaspiro /4,5/decane derivatives, pharmaceutical compositions containing them and process for preparing the same - Google Patents

Abstract

A B S T R A C T

The invention relates to novel 2-oxo-1-oxa-8-azaspiro-[4,5]decane derivatives of the formula (I), (I) wherein X means oxygen or an 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 optionally being 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 group, wherein R is as defined above, one of R1 and R2 may represent a hydroxyl group, where-as the other is a methyl group;
Z stands for hydrogen, halogen, trihalomethyl or a C2-4alkanoyl group; and n is 2 or 3, as well as their acid addition and quaternary ammonium salts.
The invention further relates to pharmaceutical compo-sitions containing these compounds and a process for their preparation.
The compounds of the formula (I) possess psychotropic and antiallergic properties and a low toxicity. Thus, they are useful for the treatment of psychiatric and allergic diseases.

Description

23305~1163 NO\!~L 2-0~0-1-QYA-8-AZAsPIRO/4,57~ECA~IE DERIVATIVES, PHARI~A-CEUTICAL COMPOSITIONS CONTAINING THEIl AND PROCESS FOR
PREPQRI~!~ SA!-lE
The invention relates to novel, therapeutically active 2-oxo-1-oxa-3,8-diazaspiro[4-5]decane derivatives of the formula (I), 0 ~
'~ (CH2)n ~ N~X (I ) Rl R2 wherein X means oxygen or an NR group, ~herein R stands for hydrogen, a Cl_l2alkyl, C3_6cycloall<yl, carbocyclic C6_10aryl or carbocyclic C6_10aryl-C1_4alkyl group, the two latter ones optionall~
being substituted on -their aromatic part by one or more, same or different halogen(s), one or more Gl_4alkyl or Cl_4alkoxy group(s);
R1 and R2 tooether 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, where-as the other is a methyl ~roup;
Z stands for hydrogen, halogen, trihalomethyl or a C2 4alkanoyl group; and n is 2 or 3, as well as their acid addition and quaternary ammonium salts - 2 _ 23305-1163 ~

and pharmaceutical compositions containing these co~ounds.
The invention also relates to a process for the prepa-ration of the above compounds and compositions as well as to a method of treat~ent. The latter one comprises administer-ing a therapeutically effective amount of a compound of the formula (I) or a pharmaceutically acceptable acid addition or quaternary ammonium salt thereof into the organism of a patient for influencing the psychic functions or treating allergic sy~p-to~s.
The compounds of the formula (I) may exist in various stereoiso~eric 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 2-oxo-1-oxa-3,8-di-azaspiro/4-5/decane derivative have been describe~ in the literature. Such compounds are reported e.g. in the follow-ing publi~ations: C.A. 71, 913S9d (1969); C.A. 78, 719668t ~û (1973); C.A. 78, 2387q (1973); C.A. 81, 33153c and 105368b (1974); C.A. 95, 161765e (1981); as well as in the DE patent specifications Nos. 2,013,729, 2,013,668 and 2,163,000, in BE
patent specifications Nos. 775,984, 774,170, 786,631 and 825,444; in the GB patent speci~ication No. 1,100,218; in the published N~ patent application No. 7,214,689 as well as in the US patent specifications Nos. 3,555,033, 3,594,386, 4,244,961 and 4,255,432.

A substantial difference between the compounds of the formula (I) according to the invention and similar derivati-ves kr,own up to the present appears in the nature of the substi-tuents 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/4-5/decane derivative of the formula (II), . ~0_ HN~
~ `~ -R
/ \ 2 (Il) wherein R, Rl and R2 are as defined above, with a phe-nothiazine derivative of the formula (III), . .

~ [~ ~--(CH2)" y ( 111) wherein n and Z are as defined above and Y means halo-gen, Cl_4alkylsulfonyloxy or arylsulfonyloxy group, to obtain compounds of the formula (I) "~lherein X

2 ~

stands for an NR group and R, n, Rl, R2 as well as Z
are as defined above;
or b) reacting a 2-oxo-3,8-diazaspiror4,5~decane derivative of the formula (IV), Y--(C H2~ N~

Rl R~ :
IG (IV) wherein R, n, R1 and R2 are as defined above and Y
means halogen, C1_4alkylsulfonyloxy or arylsulfonyloxy group, with a phenothiazine derivative of the formula (V), ~ ~

(V) ;' :
wherein Z is as defined above, to obtain compounds of the formula (I), wherein X
stands for an NR group and R, n, Rl, R2 as well as Z
are as defined above;
or c) reacting a 4-ethynyl-4-hydroxypiperidine derivative of . the formula (VI), . . .

, ~ ~ 2 ~

~ N '~Z OH
r~ ~
(Cl~)n~N~
C _CH ( Vl wherein n and Z are as defined above, with an isocya-nate of the formula R-NC0, wherein R is as defined above, to obtain a 4-carbamoyloxy-4-ethynylpiperidine derivative of the formula (VII), ~N~Z o--CO--NHR
( CH~)n --- N~
C--CH (Vll ) wherein R, n and Z are as defined above and then i) cyclizing in an acidic medium the obtained compound of the formula (VII~, wherein R, n and Z are as defined abov~ and reacting with water the obtained salt of 2-imino-1,3-dioxolane derivative of the formula (VIII), z NR
( CH~)n--N j~_o CH2 (Vlll wherein R, n and Z are as defined above, in order to prepare compounds of the formula tI), wherein Rl together with R2 stands for a methylene group, X stands for an oxygen atom and R, n and Z
are as defined above, or ii) cyclizing in a basic medium the obtained compound of the formula (VII), wherein R, n and Z are as defined above, in order to prepare compounds of the formula (I), wherein R1 together with R2 stands for a methylene group, X
stands for a NR group, and R, n as well as Z are as defined above, or d) cyclizing in an acidic medium a 4-carbamoyloxy-4-ethy-nylpiperidine of the formula (VII), wherein R, n and Z are as defined above, and reacting with water the obtained salt of 2-imino-1,3-dioxolane derivative of the formula (VIII), wherein R, n and Z are as defined above, to obtain compounds of the formula (I), wherein Rl together with R2 stands for a methylene group, X means oxygen and n as well as Z are as defined above;
or e) cyclizing in a basic medium a 4-carbamoyloxy-4-ethy-nylpiperidine derivative of the formula (VII), wherein . R, n and Z are as defined above, to obtain compounds of the formula ~I), wherein , : : . : .. :

'; ' '~ ' together with R2 stands for a methylene group, X means an -NR group and R, n and Z are as defined above;
or f) reacting a 4-acetyl-4-hydroxypiperidine derivative of the formula (X), $~N~Z OH

(CH2)n C-C1~3 (X) O
wherein n and Z are as defined above, with an isocya-nate of the formula R-NCO, wherein R is as defined above, to obtain a 4-acetyl-4-carbamoyloxypiperidine derivative of the formula (IX) ~N~ r O-CO--NHR
n - ~ N~X
11 (IX~
wherein R, n and Z are as defined above, and then cyclizing the obtained compound of the for-mula (IX), 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, .
.- . :

n as well as Z are as defined above;
or g) cyclizing a 4-acetyl-4-carbamoyloxypiperidine deriva-tive of the formula (IX)g wherein R, n and Z 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, n as well as Z are as defined above, theng if desired, reacting a thus prepared compound of the formula (I), wherein X means oxygen, R1 and R2 toge-ther stand for a methylene group and n as well as z are as defined above, with an amine of the form~lla 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, n as well as Z are as defined above;
and/or transforming a functional group of a thus prepared com-pound of the formula (I), wherein X, R, n, Rl, R2 and Z
are as defined for the formula (I), to an other one in a known manner;
and/or reacting with an acid a thus prepared compound of the formula (I), wherein X, R, n, Rl, R2 and Z are as defined above, to give an acid addition salt and/or treating with a base a compound of the formula (I), wherein X, R, n, R1, R2 and Z are as defined above, obtained as a salt, to liberate the free basic form thereof and/or converting a thus prepared compound of the formula (I), wherein X, R, n, Rl, R2 and Z are as defined above, to its quaternary ammonium salt.
In the case of processes a) and b) according to the invention the condensation reaction is conveniently carried out in an inert oryanic solvent, in the presence of a base suitably to bind the acid liberated in the reaction. Useful solvents for this purpose are e.g. aliphatic alkanols such as ethanol, isopropanol or butanol; aromatic hydrocarbons such as toluene, xylene or benzene; ethers such as dibutyl ether or dioxane; tertiary aliphatic acid amides such as di-methylformamide or dimethylacetamide; ketones such as ace-tone, methyl ethyl ketone or methyl isobutyl ketone; or a mixture of the above solvents.
Useful acid binding agents are e.g. inorganic or tertiary organic bases such as alkaline metal or alkaline earth metal carbonates or hydrogen carbonates, alkaline metal hydroxides, triethyl amine, dimethyl aniline or pyridine; though an excess of the compounds of the formula (II) or (V) may also be used as acid binding agent. This reaction may be realized at a temperature between room temperature and the boiling point of the reaction mixture, optionally in the presence of a catalyst. Useful catalysts are e.g. alkaline metal iodides. It is suitable to work 2 ~ D!~

under an inert gas such as nitrogen or argon during this reaction.
In the first s-tep of process c) according to the inven-tion a 4-ethynyl-4 hydroxypiperidine derivative of the for-mula ~VI) is brought into reaction with an isocyanate of the formula R-NCO in a manner known per se /Houben-l~leyl: Metho-den der Organischen Chemie Vol. VIII/39 pages 137 to 147 tl952)/ to give a 4-carbamoyloxy-4-ethynylpiperidine deriva-tive of the formula (VII), which is then cycli7ed in an acidic or basic medium, respectively according to step i) or ii) .
According to step i) a thus obtained 4-carbamoyloxy-4-ethynylpiperidine of the formula (VII) is cyclized in an acidic medium and the obtained salt of the 2-imino-1,3-di-oxolane derivative of the formula (VIII) obtained is reacted with water. The cyclization is carried out in an anhydrous solvent being inert to the reaction conditions, in the presence of a suitable acid, preferably in the presence of a dry hydrogen halide. Suitable solvent~ for this reaction are e.g. aliphatic or alicyclic ethers such as diethyl ether, dipropyl ether, diisopropyl ether, dibutyl ether, tetrahyd-rofuran or dioxane; or lower aliphatic carboxylic acids such as acetic or propionic acid.
As a hydrogen halide hydrogen chioride, bromide, iodide or fluoride, preferably hydrogen chloride or bromide, are used~ After treating with water the thus formed 2-imino-l,3-dioxolane hydrohalide salt, the 2-oxo-1-oxa-3,8~diazaspiro-[4-5]-2 ~

decane derivative of the formula (I) is obtained as an acidaddition salt, from which, if desired, the free base can be liberated in a manner known per se.
The cyclization of 4-carbamoyloxy-4-ethynylpiperidine derivative of the formula (VII) according to step ii) is realized in the presence of a base. Alkaline rnetal 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 reac-tion. Further suitable solvents are aliphatic alcohols, e.g. methanol, ethanol, propanol or butanol; aliphatic, alicyclic or aroma-tic 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 dioxane;
nitriles such as acetonitrile; sulfoxides, e.g. dimethyl sulfoxide; as well as the mixtures of the above solvents.
The reaction may be carried out without any solvent, too, i.e. in a molten state. In order to accelerate the cycliza-?.O tion the tempera-ture is suitably increased: the reaction is preferably accomplished between 40 C and the boiling point of the reaction mixture. It is suitable to ~ork under an inert gas such as argon or nitrogen. According -to a pre-ferred embodiment the 4-carbamoyloxy-4-ethynylpiperidine ~5 derivative of the formula (VII)~formed in the reaction of a 4-ethynyl 4 hydroxypiperidine derivative of the formula 2 ~ ~ e~

(VI) with an isoc~anate of the formula R-NCO, is directly cycli~ed without isolation, in the same reaction mixture, in the presence of a suitable base.
In the processes d~ and e) of the invention the pro-cedur~s discussed under steps i) and ii) are followed.
In the process f) of the invention a 4-acetyl-4-hydr-oxypiperidine derivative of the formula (X) is reacted with an isocyanate of the formula R-NCO and the obtained 4-ace-tyl 4-carbamoyloxypiperidine deriva-tive of the formula (IX) is cyclized. The condensation reaction according to the first step is realized in a manner known per se /Houben-~leil: Methoden der Organischen Chemie Vol. VIII/3, pages 137 to 147 (1952)/. The obtained 4-acetyl-4-carbamoyloxypiperi-dine derivative of the formula (IX) is preferably cyclized in the presence of a base. This cyclization may be carried out under the reaction conditions described for the step ii) of process c). Alternatively, acc:ording to a preferred embodiment of this process, the 4-acetyl-4-carbamoyloxypipe-ridine derivative of the the formula (IX), obtained in the reaction of a 4-acetyl-4-hydroxypiperidine derivative of formula (X) with an 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 g) of the invention, the second step of process f) is in principle followed.
If desired, the compounds of the formula (I~ obtained - ~ ~ 2 ~ L~

by using the processes a) to g) can be transformed in a known way to other compounds being within the scope of the formula (I).
Thus, on reacting a compound of the formula (I), wherein X means oxygen and Rl together with R2 represents a methylene group 9 with an amine of the formula R-NH2, com-pounds 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. aliphtic, alicyclic or arylali-phatic alcohols such as ethanol, butanol, cyclohexanol or benzyl alcohol; aliphatic or aromatic hydrocarbons such as hexane, heptane, xylene, chlorobenzene or nitrobenzene;
ethers, e.g. di-n-butyl ether or dioxane; tertiary organic bases, e.g. picoline, triethylamine 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 tem-perature between room temperature and the boiling point of ~0 the reaction mixture, preferably under an inert gas, e.g.
argon or nitrogen.
If desired, the compounds o~ the formula (I) containing a hydroxyl and a methyl group, respectively as R1 and R2 can be dehydrated to compounds of the formula (I), wherein Rl and R2 together represent a methylene group. The dehydration may be achieved by using methods generally known from the , ~ "

literature, e.g. under normal or reduced pressure. Isocya-nates, 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 i5 preferably performed in an organic solvent.
Suitable solvents are e.g. aromatic hydrocarbons such as benzene, toluene or xylene; ethers such as dioxane or di-n--butyl ether; aliphatic carboxylic acids such as acetic acid. Optionally, the water formed in the reaction may be lû removed by azeotropic distillation.
If desired, a water molecule can be introduced in an addition reaction into compounds of the formula (I), wherein R1 and R2 together stand for a methylene group, to give com-pounds 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 or formic acid, aromatic sulfonic acids, oxalic or trifluoroacetic 2û acid and the like may be employed. This reaction is carried out between 5 C and the boiling point of the reaction mixture.
If desired, the compounds of the formula (I) may be converted into their acid addition salts or quaternary ammo-nium salts by using known methods. For the preparation ofacid addition salts inorganic or organic acids such as 2 ~ L L~

hydro~qen halides, e.g. hydrochloric acid and hydrobromic acid, su]furic acid, phosphoric acid as well as formic, acetic, propionic, oxalic, glycolic, maleic, fumaric, succinic, tartaric, ascorbinic, citric, malic, salicylic, lactic, benzoic, cinnamic, aspartic, glutamic, N-ace-tyl-aspartic or N-acetylglutamic acid as well as alkanesulfonic acids such as methanesulfonic acid, or arenesulfonic acids, e.o. 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 solution of the compound of the 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. diethyl e-ther.
For the preparation of quaternary ammonium salts a lower alkyl, alkenyl or benzyl halide or an alkyl sulfate may preferably be employed. The q~aternization is suitably performed in an organic solvent, such as acetone, aceto-nitrile, ethanol or their rnixtures, at a temperature range from room temperature up to the boiling point of the sol-vent. The acid addition or quaternary ammonium salt obtained may be isolated e.g. by filtration and, when necessary, purified by recrystallization.
Conversely, the corresponding free bases can be liberated from their salts by an alkaline treatment.
Among the starting substances, the compounds of the ' .~' '' ,, formulae (III) and ~V), as well as R-NCO and R-NH2 are known or can be prepared analogously to methods known from the literature.
The starting compounds of the formula (VI), (VII), (IX) and (X) are new and biologically active, too.
The compounds of the formulae (III) and (IV) may be prepared e.g. according to ~. Heterocycl. Chem. 21, 613 (19~4) or J. Med. Chem. 11, 622 (196B) or, by using well-known processes for the alkylation of secondary amines.
The prepara-tion of compounds of the formula (II) is described in the Hungarian patent application No. 4092/89, filed simultaneously with the basic Hungarian application No. 4093/89.
The compounds of the formula (VI) can be prepared e.g.
by the ethynylation reaction of suitably substituted 4-pipe-ridone derivatives as described e. 9. in the Hungarian patent specification No. 166,769 or in Farmaco (Pavia) Ed.
Sci. 12, 34 (1957).
The carbamates of the formulae (VII) and (IX), respec-tively, are obtained e.g. by reacting a compound of the for-mula (VI) or (X), respectively, with an isocyanate of the formula R-NCO under conditions described above.
The 4-acetyl-4-hydroxypiperidine derivatives of the formula (X) can be prepared e.g. by hydrating the cor-responding 4-ethynyl-4-hydroxypiperidine derivatives of the formula (VI) /Houben-Weyl: Methoden der Organischen Chemie Vol. VII/2a, pages 826 to 835 (1973)/ or by the alkaline treatment of the corresponding 4-methylene-2-oxo-1,3-dioxa--8-azaspiror4,5/decane derivatives of the formula (I).
The compounds of the formula (I) according to the invention show psychotropic and antiallergic actions and have a broad spectrum of therapeutical possibilities. Thus, they may be useful e.g. for the treatment of the so-called functional psychoses and organic psychiatric diseases such as dementia, delirium, stimulants-induced psychoses and the like, as well as diskinesias, anxiety, pruritus, nausea, vomitus and intolerable singultation.
Male CFLP mice with a body-weight of 18 to 25 9 and male Hannover-Wistar rats with a body-weight of 160 to 180 9 were used for the pharmacological investigations. The test compounds were orally administered in a 2% Tween-80 suspen-sion. The pharmacological investigating methods used are described hereinafter.
1.Protective effect against the amphetamine group toxicity on a~gregated mice The method described in Arch. Int. Pharmacodyn. 163, 79 (196~) was used.
The mice were treated with various doses of the test substances. By one hour following the treatment the animals were intraperitoneally given 21 mg/kg of d-amphetamine and then the groups consisting of 10 animals each were tightly closed together in plexiglass boses of 15x15xlO cm in size.

~3305-1163 A-t the 24th hour following the amphetamine treatment the surviving animals were counted. The ED50 values of the sub-stances were calculated from the percentage of the surviving animals. The ED50 value is the dose protecting 50% of the animals from perishment. The results are summarized in Table 1.
2. Inhibition of the conditioned _avoidance resQonse (CAR
inhibition) on rats The method of D. Bovet et al. (Neuropsychopharmacology, ed. R. Rothlin Vol. 2, p. 142, Elsevier Publishing Co. N.Y.
1961) was used.
Male rats weighing 160 to 180 9 were conditioned in an au-tomated 6-channel 5huttle box for 10 days. Each one daily session consisted of 50 cycles and each one cycle lasted for 40 seconds. ~ithin a single cycle an intermitten-t light stimulus for 15 seconds as conditioned stimulus, and an electric stimulus of 0.8 mA for lû seconds as unconditioned stimulus, were used with an intersignal time of 15 seconds.
When an animal changed its half-court during the conditioned stimulus period, the stimulus was abolished and the foot-shock was avoided (conditioned avoidance response;
abbreviated: CAR). Animals with a performance of at least 80% on the 8th to 10th days of conditioning were considered to be useful for the study. ~y 3 hours before the experiment the animals were treated with various doses of the test sub-stances and the ED5U value, i.e. the dose causing an 50%

2 ~

inhibition of the conditioned avoidance response of the animals, was determined. Groups consisting of 10 animals each were used for each dose. The results are summarized in Table 1.
3. Measurement of the spontaneous body -temperature Groups consisting of ln mice each were orally treated with 30 mg/kg doses of the test substances. After treatment the rectal temperature of the male mice was determined in each hour for 5 hours. The average values of temperature decrease related to the body temperature of the untreated control animals (37.1+0.8 C) at -the 5th hour after treat-ment are given in Table 1.
4. Inhibition of the aggressive behaviour of the mice The method described in J. Pharmacol. Expt. Therap.
1 , 28 tl959) was used.
Pairs of male mice weighing 20 to 25 each were treated with the test compounds and then placed in cages. By 3 hours following the treatment an aggressive behaviour was induced on the animals by using an electric stimulation of 1 mA
current intensity. Each group consisted of 5 pairs of mice.
The ED50 values were calculated from the percentage of animal pairs showing no aggressive behaviour owing to the treatment. (En50 value is the dose inhibiting the aggressive behaviour on 50% of the animals.) The results are illustrated in Table 2.

~ '~

5. Acute toxicity Rats were treated with various doses of the tes-t com-pounds. The perishment of the animals were observed for 14 days. The LD~U value, i.e. the dose causing the death of half of the animals, was determined from the percentage of the dead animals.
The results are shown in Table 2.
Chlorpromazine /chemically 2-chloro-10-(3-dimethylami-nopropyl)phenothiazine/ was used as reference drug in these investigations.
The abbreviations listed hereinafter are used in the Tables:
CPZ = chlorpromazine;
A = 5-r3-(2-chloro-lOH-phenothiazin-lû-yl)propyl7-3-methyl--4-methylene-2-oxo-1-oxa~3,8-diazaspiro/4,5/decane;
B = 8-/3-(2-chloro-lOH-phenothiazin-10-yl)propyl7-3-e-thyl-4--methylene-2-oxo-1-oxa-3,8-diazaspiroL4,57decane;
C = 3-methyl-4-methylene-2-oxo-8-/3-(2 trifluoromethyl-lOH--phenothiazin-10-yl)propyl7-1-oxa-3,8-diazaspiro/4,57-decane;
D = 3-ethyl~4-methylene-2-oxo-8-L3-(2-trifluoromethyl-lOH---phenothiazin-10-yl)propyl/-1-oxa-3,8-diazaspiro/4,5/-decane;
E = 8-/3-(2-chloro-lOH-phenothiazin-10-yl)propyl/-4-methyle-ne-2-oxo-3-propyl-1-oxa-3,8-diazaspiror4,57decane;

- 21 - 2~2~

F = B-,r3-(2-chloro-lOH-phenothiazin-10-yl)propyl7-3,4-dime-thyl-4-hydroxy-2-oxo-1-oxa-3,8-diazaspiro/4,57decane;
G = 8-r3-(2-chloro-lOH-phenothiazin-10-yl)propyl7-3-ethyl-4--hydroxy-4-methyl-2-oxo-1-oxa-3,8-diazaspiro/4,5/decane;
H = 3,4-dimethyl-4-hydroxy-2-oxo-8-/3-(2-trifluoromethyl--lOH-phenothiazin-10-yl)propyl7-1-oxa-3,8-diazaspiro-/4,5/decane;
I = 4-hydroxy-4-methyl-2-oxo-3-propyl-8-/3-(2-tri~luorome-thyl-lOH-phenothiazin-10-yl)propyl7-1-oxa-3,8-diaza-spiro/4,5/decane;
p.o. = orally amph. = amphetamine (d,l-l-phenyl-2-aminopropane) tox. = toxicity CAR = conditioned avoidance response Table 1 Compound Protection CAR Decrease in the against amph. ED50 spontaneous ED50mg/kg p.o. temperature m~/k~ p.o. C
A 0.6 6.0 -B.8 B 1.6 1.6 -7.4 C 0.7 1.9 -9.9 D 4.1 6.8 -8.2 E 1.8 10.6 -5.6 F 0.7 4.6 9.1 G 2.4 6.9 -8.1 H 0.9 3.1 -9.6 I 4.2 5.6 -7.0 CPZ 7.2 17.1 -7.9 .

~ ~ 2 ~

Table 2 Compound Antiaggressive L50 effect~ ED50 mg/kg p.o.
_ mg/kg p.o.
A 1.7 353 B 10.9 ~ 500 C 1.2 - 235 D 2.5 500 E 2.0 CPZ 4.3 225 _ It is obvious from the above Tables that the novel com-poùnds of the formula (I) according to the invention possess a significantly stronger effect than that of the reference drug and their therapeutic range is more advantageous than - that of CPZ; simultaneously, their effective doses do not induce any sedative, muscle relaxant or anticholinergic action and, even in the case of a chronic treatment, they do not cause the hypersensitization of the dopaminergic system of the central nervous system. Thus, it is likely that their side effects will be diminished in rela-tion to the reference drug in the clinical practice. Being effective antipsychotic agents, the novel compounds of formula (I) according to the invention are useful for the treatment of psycho-tic condi-tions of mammals. The effective doses of course depend on the condition of the patient, on the severi-ty of the dis-order to be trea-ted and may be varied from 0.01 mg/kg to 5 mo/kg of body-weight in the case of oral administration.

. : ~ ; .; ~.'; ., .

~ . . .

~2~

If desired, the compounds according to the invention can be converted into pharmaceutical compositions. These compositions may be adrninistered in oral, rectal and/or parenteral route. For oral administration, the composition may be formulated e.g. as a tablet, dragée or capsule. In order to prepare oral compositions, e.g. lactose or starch may be used as carriers. Gelatine, carboxymethylcellulose sodium, mehylcellulose, polyvinylpryrrolidone or starch gum are suitable binding or granulating agents. As disintegrat-ing agen-ts mainly potato starch or microcrystalline cellulose may be added though ultraamylopectin or formalde-hyde-casein and the like are also useful.
Talc, colloidal silicic acid, stearin, calcium or mag-nesium stearate and the like are suitable an-ti-adhesive and sliding agents.
Tablets may be prepared e.g. by compression following the wet granulation. The mixture of the active ingredient with the carriers and optionally with a part of the dis-integrating additive is granulated with an aqueous, alco-2û holic or aqueous-alcoholic solution of the binding agents in a suitable equipment, then the granulate is dried. Sub-sequently, after mixing the other disintegrating, sliding and anti-adhesive additives to the dried granulate, the mix-ture is compressed to tablets. If desired, the tablets may be provided with a groove in order to facilitate the admin-istra-tion. Tablets may also directly be prepared from a mix-- 24 - 2~

ture cqntaining 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- cr ethyl-cellulose, carboxymethylcellulose sodium and the like), polyvinylpyrrolidone, calcium phospha-te, calcium carbonate, food dyes 3 dyeing lacquers, aromatizing agents, iron oxide pigments and the like. Capsulated 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 ingredien~t. As carriers, vegetable fats such as hardened vegetable oils, or triglycerides of C12_18 fatty acids (preferably -the carriers bearing the trade name ~itepsol) may be used. The active ingredient is uniformly distributed in the molten carrier mass, then sup-positories are prepared by moulding.
For parenteral administration, the composition of theinvention is formulated as injectable solu-tion. For prepar-ing these injectable solutions, the active ingredients are dissolved in distilled water and/or various organic sol-vents, e.g. glycol ethers, if desired, in -the presence of solubilizing agents such as polyoxyethylene sorbitan mono-; . ,. ; ;

2~2~
~5 23305~ 3 laurate or monooleate or monostearate (Tween 20, Tween 60 orTween 80), respectively. The injectable solution may further contain various additives (auxiliary agents), e.g. preservatives such as benzylalcohol, methyl p-oxybenzoate, propyl p-oxybenzoate, benzalkonium chloride or phenyl mercury borate;
antioxidants such as ascorbinic acid, tokoferole, sodium pyrosulfate; and optionally a complexing agent being capable of binding metal traces, such as ethylenediamine tetraacetate as well as pH-modifying and buffering substanc~s or, if desired, a local anaesthetic agent such as lidocaine. Before filling into the ampoules, the injectable solution containing the composition of the invention is filtered and after filling in, it is subjected to sterilization.
The invention also relates to a method for treating psychiatric and allergic diseases, e~g. functional psychoses and organic psychiatric diseases such as dementia, delirium, stimulants-induced psychoses and the like, as well as dyskinesias, anxiety, pruritus, nausea, vomitus and intolerable singultation.
This method comprises administering a therapeutically effective amcunt of an active ingredient of the formula (I) or a pharma-ceutically acceptable acid addition salt or quaternary ammonium salt thereof to the patient.
The invention is illustrated in detail by the aid of the following non-limiting Examples.
Example 1 Preparation of 3-m~thyl-4-methylene-2-oxo-8-[3-(2-trifluoromethyl-10~-phenothiazin-10-yl)propyl]-1-oxa-3,8-2~2~
- 25a -~3305-1163 diazaspiro-[4,5]decane A mixture containing 11.0 g of 3-methyl~4-mathylene-2~

~, ., -oxo-l-oxa-3,8-diazaspiro/4,5/decane, 41.3 9 of 3-(2-tri-fluoromethyl-lOH-phenothiazin-10-yl)propyl chloride, 16.6 9 of anhydrous potassium carbonate and 0.6 9 of potassium iodide in 110 ml of methyl isobutyl ketone is refluxed under nitrogen while stirring for 6 hours. After evaporating the solvent under reduced pressure benzene and water are added to the evaporation residue, -the organic phase is separated, washed with water to neutral, dried over anhydrous sodium sulfate, then the solution is evaporated under reduced pressure. The solid residue is boiled with hexane, after cooling down the precipitate is filtered off and recrys-tallized from ethanol to give the title compound in a yield of 75.3%; m.p.: 116-117.5 C.
Analysis:
Calculated for C25H26F302S
C 61.33; H 5.35; F 11.64; N B.58; S 6.55%;
found: C 61.50; H 5.38; F 11.38; N 8.34; S 6.34%.
Example 2 Preparation of 8-/3-(2-chloro-lOH-pheno-thiazin-10-yl)pro-pyl7-4-hydroxy-4-methyl-2-oxo-1-oxa-3,8-diazaspiro/4,5/de-cane 9.7 9 of 8-/3-(2-chloro-lOH-phenothiazin-10-yl)propyl/--4-methylene-2-oxo-3-propyl-1-oxa-3,8-diazaspiro/4,5/decane are stirred with 12û ml of a 0.5 mol/litre hydrochloric acid solution at 5 to lû C for 3 hours, then the reaction mix-ture is made alkaline by adding sodium hydroxide solution ' and extracted with chloroform. The chloroform phase is washed with water to neutral, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. After recrys-tallization of the evaporation residue from benzene the tltle compound is obtained in 88% yield, m.p.: 174-176 C.
Analysis:
calculated for C26H32ClN303S:
C 62.19; H 6.42; Cl 7.06; N 8.37; S 6.39%;
found: C 62.10; H 6.58; Cl 6.91; N 8.40; S 6.60%;
On treating an ethanolic solution of the base with ethereal hydrogen chloride solution the hydrochloride of the above base is obtained, m.p.: 157-160 C (with decomposi-tion).
Example 3 Preparation of 8-/3-(2-chloro-lOH-pheno-thiazin-10-yl)pro-pyl/-3-cyclohexyl-4-hydroxy-4-methyl-2-oxo-1 oxa-3,8-diaza-spiro/4,5/decane hydrochloride 5.3 g of 8-/3-(2-chloro-lOH-phenothiazin-10-yl)propyl/-3-cyclohexyl-4-methylene-2-oxo-1-oxa-3,8-diazaspiro/4,5/-~o decane are dissolved in 5.3 ml of 98% formic acid at room temperature and 53 ml of 3 mol/litre hydrochloric acid solu-tion are dropwise added under stirring during 20 minutes.
The precipitate is filtered off, washed with water and dried to give the title hydrochloride in 98% yield, m.p.: 246-248 C (with decomposition). The base can be liberated from the hydrochloride by adding aqueous ammonium hydroxide solu-tion.

~2~

Analysis of the base:
calculated for C29H36ClN303S:
C 64.25; H 6.69; Cl 6.54; N 7.75; S 5.91%;
found: C 64.28; H 6.82; Cl 6.63; N 7.57; S 6.12%;
By using the appropriate starting substances the following compounds are prepared in an analo~ous manner as described in Examples 2 or 3 or Example 12 to be described hereinafter.
3-/3-(2-Acetyl-lûH-phenothiazin-1û-yl)propyl7-3-decyl-4--hydroxy-4-me-thyl-2-oxo-1-oxa-3,8-diazaspiro/4,5/decane hydrochloride, m.p. 154-157 C (with decomposition);
8- r-(2-Chloro-lûH-phenothiazin-lû-yl)propyl7-3,4-dimethyl--4-hydroxy-2-oxo-1-oxa-3,8-diazaspiro/4,5/decane, m.p.:
172-173 C; the hydrochloride decomposes at 232-235 C;
8-/3-(2-Chloro-lOH-phenothiazin-10-yl)propyl/-4-hydroxy-3--isopropyl-4-methyl-2-oxo-1-oxa-3,8-diazaspiro/4,5/decane, m.p.: 108-110 C; the hydrochloride decomposes at 127-130 C;
4-Hydroxy-4-methyl-2-oxo-3-phenyl-8-L3-(2-trifluoromethyl--lOH-phenothiazin-10-yl)propyl/-1-cxa-3,B-diazaspiro/4,5/-decane hydrochloride, m.p.: 147-150 C (with decomposi-tion);
3-Ethyl-4-hydroxy-4-methyl-2-oxo-8-/3-(2-trifluoromethyl--lOH-phenothiazin-10-yl)propyl7-1-oxa-3,8-diazaspiro/4,5/-decane, m.p.: 148-149 C; the hydrochloride decomposes at 186-189 C; and ~ ~ ~ S~ f~

4-Hydroxy-4-methyl-2-oxo-8-/3-(lOH-phenothiazin-10-yl)pro-pyl7-3-tert-butyl-1-oxa-3,8-diazaspiro/4,5~decane, m.p.:
16g-171 C.
Example 4 Preparation of 8-/3-(2-acetyl-lOH-phenothiazin-10-yl)pro-pyl7-3-methyl-4-methylene-2-oxo-1-oxa-3,8-diazaspiroL4,5/-decane A mixture containing 7.3 9 of 3-methyl-4-methylene-2--oxo-l-oxa-3,B-diazaspiroL4,5/decane, 9 ml of anhydrous tri-ethylamine, 22.0 9 of 3-(2-acetyl-lOH-phenothiazin-10-yl)-propyl bromide and 80 ml of methyl isobutyl ketone is re-fluxed under argon while stirring for 6 hours. After cooling down the organic phase is washed with water, dried over an-hydrous magnesium sulfate and evaporated under reduced pressure. The crude product obtained is purified by chroma-tography on a silica gel column by using first chloroform and then ethyl acetate as eluating agent. After combining the ethyl acetate eluate is evaporated under reduced pressure and the residue is recrystallized from ethanol to give the title compound in 84.5% yield, m.p.: 105-106 C.
Analysis:
calculated for C26H29N303S:
C 67.36; H 6.30; N 9.06; S 6.92%;
found: C 67.48; H 6.51; N 9.01; S 7.11%.
8y using the appropriate starting substances the following substances are prepared in an analogous way as described in Examples 1 or 4 or in Example 14 to be described hereinafter.
8-/3-(2-Acetyl-lOH-phenothiazin-10-yl)propyl~-3,4-dimethyl- --4-hydroxy-2-oxo-1-oxa-3,8-diazaspiro/4,5/deGane hydro-chloride, m.p.: 165-168 C (with decomposition);
8-r3-(2-Chloro-lOH-phenothiazin-10-yl)propyl7-3-methyl-4-me-thylene-2-oxo-1-oxa-3,8-diazaspiro/4,5/decane, m.p.: 142-143 C;
4-Methylene-2-oxo-8-/3-(lOH-phenothiazin-10-yl)propyl7-3-n--propyl-1-oxa-3,8-diazaspiro/4,5/decane, m.p.: 98-99 C;
3-Cyclohexyl-4-methylene-2-oxo-8-/3-(lOH-phenothiazin-10--yl)propyl/-l-oxa-3,8-diazaspiroL~,57decane, m.p.: 159-160 C;
4-Methylene-2-oxo-8-/3-(lOH-phenothiazin-10-yl)propyl/-2--oxo-3-tert-butyl-1-oxa-3,8-diazaspiror4,5/decane, m.p.:
96-97 C;
8-L3-(2-Chloro-lOH-phenothiazin-10-yl)propyl/-3-isopropyl-4--methylene-2-oxo-1-oxa-3,8-diazaspiro/4,5/decane, m.p.:
162-163 C;
4-Methylene-2-oxo-3-propyl-8-/3-(2-trifluoromethyl-lOH-phe-nothiazin-10-yl)propyl/-1-oxa-3,8-diazaspiro/4,5/decane, m.p.: 119-121 C;
8-/3-(2-Acetyl-lOH-phenothiazin-10-yl)propyl7-3-n-decyl-4--methylene-2-oxo-1-oxa-3,8-diazaspiro/4,57decane hydrogen maleate, m.p.: 108-110 C;
3-Methyl-4-methylene-2-oxo-8-/3-(lOH-phenothiazin-10-yl)pro-pyl/-l-oxa-3,8-diazaspiro/4,5/decane, m.p.: 132-133 C
obtained by reacting 3-methyl-4-methylene-2-oxo-1-oxa-3,8--diazaspiro/4,5/decane with 3-(10-phenothiazin-10-yl)pro-pyl p--toluene-sulfonate;
8-/3-(2-Chloro-lOH-phenothiazin-10-yl)propyl/-3-n-butyl-4--methylene-2-oxo-1-oxa-3,8-diazaspiro/4,5/decane, m.p.:
100-101 C;
8-/3-(2-Chloro-lOH-phenothiazin-10-yl)propyl/-3-cyclohexyl--4-methylene-2-oxo-1-oxa-3 J 8-diazaspiro/4,5/decane, m.p.:
177-178 C;
8-r3-(2-Chloro-lOH-phenothiazin-10-yl)propyl7-3-ethyl-4-hyd-roxy-4-methyl-2-oxo-1-oxa-3,8-diazaspiro/4,57decane, m.p.:
155-156 C; the hydrochloride decomposes at 220-222 C;
8-/3-(2-Chloro-lOH-phenothiazin-10-yl)propyl~-4-methylene-2--oxo-3-n-propyl-1-oxa-3,8-diazaspiroL4,5/decane, m.p.:
118-119 C;
3-Ethyl-4-methylene-2-oxo-8-/3-(2-trifluoromethyl-lOH-phe-nothiazin-10-yl)propyl~ oxa-3 ? 8-diazaspiro/4,5/decane, m.p.: 117-119 C;
3-n-Butyl-4-methylene-2-oxo-8-/3-(2-tri~luoromethyl-lOH-phe-nothiazin-10-yl)propyl/-1-oxa-3,~-diazaspiroL4,57decane, m.p.: 104-105 C;
4-Methylene-2-oxo-3-tert-butyl-8-/3-(2-trifluoromethyl-lOH-phenothiazin-10-yl)propyl/-1-oxa-3,8-diazaspiro/4,5/-decane, m.p.: 12Y-130 C; and 8-/2-(2-Chloro-lOH-phenothiazin-10-yl)ethyl/-3-n-butyl-4-me-thylene-2-oxo-1-oxa~3,8-diazaspiro/4,5/decane, m.p.: 108-1 10 C .
Example 5 Preparation of 4-methylene-2-oxo-8-/3-(lOH-phenothiazin-10--yl)propyl7-3-phenyl-1-oxa-3,8-diazaspiroL4,5~decane 12.0 9 of 4-ethynyl-L3-(lOH-phenothiazin-10-yl)propyl/--4-phenylcarbamoyloxypiperidine are refluxed in 120 ml of 0.05 mol/litre methanolic sodium methoxide solu-tion under argon for 3 to 4 hours. After cooling down the sodium meth-oxide is decomposed by adding aqueous ammonium chloride solution, then the solution is evaporated to the tenth of its original volume under reduced pressure, the residue is diluted with water and extracted with benzene. After washing the benzene phase with water to neutral and drying over an-hydrous sodium sulfate the solvent is distilled off and the evaporation residue is recrystallized from ethyl acetate to give the title compound in 85.4% yield, m.p.: 98-99 C.
Analysis.
calculated for C29H29N303S:
C 72.02; l1 6.04; N ~.69; S 6.63%;
found: C 72.12; H 6.19; N 8.48; S 6.70%.
8y using the appropriate starting substances the following compound is prepared in an analogous manner as described in the preceding Example:
3-Isopropyl-4-methylene-2-oxo-8-L3-(lOH-phenothiazin-10-yl)-propyl7-1-oxa-3,8-dlazaspiror4,57decane, m.p.: 113-114 C.

. -, ' , . ;
: ' , " ,. ~ ..: ''~
':', " ' ' . :. ~ ` ' ' ' ; ~' ., Example 6 Prepara-tion of 4-methylene-2-oxo-3--phenyl-8-/3-(2-trifluoro-methyl-lOH-phenothiazin-10-yl)propyl7-1-oxa-3,8-diazaspiro-L4,5/decane A mixture containing 10.8 9 of 4-ethynyl-4-hydroxy-1--L3-(2-trifluoromethyl-lOH-phenothiazin-10-yl)propyl7piperi-dine, 0.12 9 of potassium acetate, 3.6 9 of phenyl isocya-nate and 35 ml of 2-picoline is refluxed under argon while s-tirring for 4.5 hours. After evaporatlng the solvent under ln reduced pressure water is added to the residue and the mix-ture is extracted with Ghloroform. The chloroform phase is washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. After recrystallizing the crude product from ethyl acetate under clarifying with activated carbon the title compound is obtained in 74.6%
yield, m.p.: 154-155 C.
Analysis:
calculated for C30H28F3N302S
C 65.32; H 5.12; F 10.33; N 7.62; S 5.81%;
~0 found: C 65.40; H 5.31; F 10.12; N 7.57; S 5.8B%.
By using the suitable starting compounds the following substances are preparedin an analogous way as described in the preceding Example.
8-/3-(2-Chloro-lOH-phenothiazin-10-yl)propyl7-4-methylene-2--oxo-3-phenyl-1-oxa-3,8-diazaspiro/4,5/decane, m.p.: 145-146 C;

3-Cyclohexyl-4-methylene-2-oxo-8-/3-(2-trifluoromethyl-lOH--phenothiazin-10-yl)propyl/-1-oxa-3,8-diazaspiroL4,57de-cane, m.p.: 175-176 C.
Examele 7 Preparation of 4-hydroxy-3-isopropyl-4-methyl-2-oxo-8-/3-(2--trifluoromethyl-lOH-phenothiazin-10-yl)propyl/-1-oxa-3,8--diazaspiro/4,5/decane A solution containing 5.4 9 of 4-acetyl-4-isopropylcar-bamoyloxy-l-/3-(2-trifluoromethyl-lOH-phenothiazin-10-yl)-propyl/piperidine in 54 ml of 0.55 mol/litre ethanolic sodium ethoxide solution is refluxed under nitrogen for 6 hours. After cooling down and decomposing the reaction mix-ture with aqueous acetic acid solution the most part of ethanol is distilled off under reduced pressure. The evaporation residue is diluted with water and extracted with methylene chloride. The organic phase is washed wi-th water to neutral, dried over anhydrous magnesium sulfate, then the solvent is evaporated under reduced pressure. After recrystallizing the crude product from benzene the title compound is obtained in 85.7% yield, m.p.: 187-189 C.
Analysis:
calculated for C27H32F3N303S:
C 60.54; H 6.02; F 10.64; N 7.84; S 5.99%;
found: C 60.65; H 6.22; F 10.45; N 7.63; S 6.07%.
On adding ethereal hydrogen chloride solution to the solution of the base in ethanol the hydrochloride is , ' :

2~

precipitated in crystalline form. It is filtered and dried, m.p.: 212-214 C.
Example 8 Preparation of 3-n-outyl-4-methylene-2-oxo-8-L3-(lOH-pheno-thiazin-10-yl)propyl/-1-oxa-3,8-diazaspiro/4,5/decane A mixture of 7.6 9 of 4-acetyl-4-hydroxy-l-/3-tloH--phenothiazin-10-yl)propyl/piperidine, 1.5 ml of triethyl-amine and 11.5 ml of n-butyl isocyanate is refluxed under argon for 6 to 7 hours. After cooling down and adding n--hexane to the reaction mixture the precipitate is filtered off, dissolved in ethyl acetate and led through a silica gel layer. After evaporating the solvent under reduced pressure and recrystallizing the evaporation residue from ethanol the title product is obtained in 67.4% yield, m.p.: B2-83 C.
Analysis:
calculated for C27H33N302S:
C 69.94; H 7.17; N 9.06; S 6.92%;
found: C 70.17; H 7.28; N 7.28; S 6.77%.
Example 9 Preparation of 8-/3-(2-chloro-lOH-phenothiazin-10-yl)pro-pyl/-3-ethyl-4-methylene-2-oxo-1-oxa-3,8-diazaspiro/4,57-decane 9.8 9 of 8-~-(2-chloro-lOH-phenothiazin-10-yl)propyl7-3-ethyl-4-hydroxy-4-methyl-2-oxo-1-oxa-3,8-diazaspiror4,57-decane are boiled with 0.8 9 of p-toluenesulfonic acid mono-hydrate in 150 ml of xylene in a flask equipped with a - 36 - ?~2^~

water-trap while azeotropically distilling off the water formed in the reaction. After termination of the reaction (2 to 3 hours) the reaction mixture is cooled down, made alkaline by adding aqueous sodium hydroxide solutiong the organic phase is separated, washed with water to neutral, dried over anhydrous sodium sulfate and evaporated under reduced pressure. After recrystallization of the evaporation residue from ethyl acetate the title compound is obtained in 87.5% yield, m.p.: 145-146 C.
Analysis:
calculated for C25H28ClN302S:
C 63.88; H 6.00; Cl 7.54; N 8.94; S 6.82%;
found: C 64.02; H 5.86; Cl 7.37; N 8.B3; S 6.60%.
By using the appropriate starting substances the following compounds can be prepared in an analogous way as described in the preceding Example.
8-/3-(2-Chloro-lOH-phenothiazin-10-yl)propyl7-4-methylene-2--oxo-3-tert-butyl-l-oxa-3,8-dlazaspiro/4,57decane, m.p.:
79-81 C.
3-Isopropyl-4-methylene-2-oxo-8-L3-(2-trifluoromethyl-lOH--phenothiazin-lû-yl)propyl7-l-oxa-3,8-diazaspiroL4,5/-decane, m.p. 129-130 C.
Example 10 Preparation,of 4-methylene-2-oxo-8-L3-(2-trifluoromethyl--lOH-phenothiazin-10-yl)propyl/-1,3-dioxa-8-azaspiro/4, s7-decane hydrochloride 37 2~2~

Into a solution containing 10.0 9 of 4-butylcarbamoyl-oxy-4-ethynyl-1-/3-(2-trifluoromethyl-lOH-phenothiazin-10--yl)propyl/piperidine in 50 ml of anhydrous dioxane gaseous dry hydrogen chloride is introduced until saturation at 15 to 20 C, then the reaction mixture is left to stand over-night. After evaporating the solvent under reduced pressure water is added to the evaporation residue, the precipi-tate is filtered off, washed with water and dried to obtain the title hydrochloride salt in 88.5% yield, m.p.: 230-233 C
(with decomposition).
The base can be liberated from its hydrochloride by adding sodium hydrogen carbona-te.
Analysis_of the base:
calculated for C24H23F3N203S
C 60.49; H 4.86; F 11.96; N 5.88; S 6.73%;
found: C 60.60; H 4.99; F 11.78; N 6.03; S 6.70%.
Example 11 Preparation of 8-methyl-4-methylene-2-oxo-8-~-(lOH-pheno-thiazin-10-yl)propyl/-3-propyl-1-oxa-3,8-diazaspiro_4,57de-can-8-ium iodide 6.0 9 of 4-methylene-2-oxo-8-/3-(lOH-phenothiazin-10--yl)propyl/-3-propyl-1-o~a-3,8-diazaspiro/4,57decane are boiled under reflux with 2.9 9 of methyl iodide in 60 ml of methyl isobutyl ketone for 2 hours. After cooling down the crystalline precipitate is filtered off and washed with di-isopropyl ether previously cooled to 0C. After drying the . . . , ~ .... .. .

title quaternary ammonium salt is obtained in 98.0% yield, m.p.: 192-193 C.
The following compound is prepared analogously to the process described in the preceding Example:
8-Allyl-3-butyl-4-methylene-2-oxo-8-/3-(lOH-phenothiazin-10--yl)propyl7-1-oxa-3,8-diazaspiro/4,5/decan-8-ium bromide, rn.p.: 200-202 C.
Example 12 Preparation of 4-hydroxy-4-methyl-2-oxo-3-propyl-8-/3-(2--trifluoromethyl-lOH-phenothiazin-10-yl)propyl/-1-oxa-3,8--diazaspiro/4,57decane 4.8 g of 4-me-thylene-2-oxo-8-/3-(2-trifluoromethyl-lOH--phenothiazin-10-yl)propyl7-1,3-dioxa-8-azaspiro/4,5/decane are stirred with 50 ml of n-propylamine overnight, then the -excess of amine is distilled off under reduced pressure.
After recrystallizing the evaporation residue from benzene -the title compound is obtained in 89.8% yield, m.p.: 170.5-172 C.
Analysis:
:
calculated for C27H32F3N303S:
C 60.54; H 6.02; F 10.64; N 7.84; S 5.99~;
found: C 60.47; H 6.11; F 10.71; N 7.89; S 6.15%.
The hydrochloride of the title compound is prepared by treating an e-thanolic solution of the base with ethereal hydrogen chloride solu-tion, m.p.: 129-133 C.
By using the appropriate starting substances the . ~ I . ~; . .. ...

following compound can be prepared analogously as described in the preceding Example:
4-Hydroxy-4-methyl-2-oxo-8-L3-(2-triflunromethyl-lOH-pheno-thiazin-10-yl)propyl7-1-oxa-3,8-diazaspiro/4,57decane, m.p.: 102-103 5.
Example 13 Preparation of 3,4-dimethyl-4-hydroxy-2-oxo-8-/3-(2-tri-fluoromethyl-lOH-phenothiazin-10-yl)propy_7-1-oxa-3,8-diaza-spiror4,5~decane After adding a solution of 0.4 9 of methylamine in 10 ml of xylene (previously cooled to O C) to the solution of 4.~ 9 of 4-methylene-2-oxo-8-/3-(2-trifluoromethyl-lOH-phe-nothiazin-10-yl)propy_ 7-1, 3-dioxa-8-azaspiro/4,5/decane in 20 ml of xylene while s-tirring, the reaction mixture is heated at 70 to 80 C for 60 minutes, then the solvent is distilled off under reduced pressure. After recrystallizing the evaporation residue from a mixture of ethanol and n--hexane the title product is obtained in 81.5% yield, m.p.:
164-165 C.
Analysis:
calculated for C25~l28F3N303S
C 59.15; H 5,56; F 11.23; N 8.28; S 6.32%;
found: C 59.32; H 5.39; F 11.14; N 8.43; S 6.50%.
The hydrochloride of the title base melts at 194-197 C
with decomposition.

, -",. .,~ .

~2~

Exarnple 14 Preparation of 3-ethyl-4-methylene-2-oxo-8-r3-(lOH-phe-nothiazin-10-yl)propyl7-1-oxa-3,8-diazaspiroL4,5/decane 0.6 9 of sodium hydride (60 % oily dispersion) is added to a solution of 3.0 9 of phenothiazine in 20 ml of anhyd-rous dimethylformamide under argon, then the reaction mix-ture is sti~red at 50 to 60 C for 2 hours. Thereafter, 3.9 g of 8-(3-chloropropyl)-3-ethyl-4-methylene-2-oxo-1-oxa-3,8--diazaspiro/4,5/decane dissolved in 20 ml of dimethylform-amide are dropwise added and the mixture is stirred at 40 to 50 C for additional 6 to 7 hours. After cooling down saturated arnmonium chloride solution is added to the reac-tion rnixture under argon and the solvent is evaporated under reduced pressure. After taking up the evaporation residue in benzene and washing the benzene solution with water the solution is dried over anhydrous sodium sulfate and then evaporated under reduced pressure. The residue is recrystallized from ethanol to give the title product in 57.6% yield, m.p.: 122-123 C.
Analysis:
calculated for C25H29N32:
C 68.93; H 6.71; N 9.65; S 7.36%;
found: C 62.08; H 6.77; N 9.78; S 7,23%.
Example 15 Preparation of 4-ethynyl-4-hydroxy-1-~-(2-trifluoromethyl--lOH-phenothiazin-10-yl)propyl7piperidine -- ?J ~ 2 ~

Gaseous acetylene is bubbled through a solution of 7.7 g of potassium tertiary butoxide in 46 ml of tetrahydrofuran at O to -5 C for 30 minutes under stirring. Thereafter, the solution containing 18.4 g of 1-L3-(2-trifluorome-thyl-lOH--phenothiazin-10-yl)propyl7-4-piperidone in 40 ml of tetra-hydrofuran is drop~ise added and acetylene ls introduced for additional one hour. Then, the reaction mixture is decompos-ed by adding aqueous saturated ammonium chloride solution under nitrogen at û C and the solvent is evaporated under reduced pressure. The evaporation residue is extracted with benzene, the benzene solution is washed with water to neutral, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude title product ootained as evaporation residue is recrystallized from diisopropyl ether under clarifying by activated carbon to give the crystalline -title compound in 89% yield, m.p.: 94-96 C.
Analysis:
calculated for C23H23F3N20S
C 63.87; H 5.36; F 13.1B; N 6~48; S 7.41%;
found: C 63.84; H 5.40; F 13.31; N 6.50; S 7.58%.
By using the appropriate starting substances the following compounds can be prepared in an analogous way as described in the preceding Example.
4-Ethynyl-4-hydroxy-/3-(2-chloro-lOH-phenothiazin-10-yl3pro-pyl~pipridine, m.p.: 113-114 C; and 4-Ethynyl-4-hydroxy-1-~-(lOH-phenothiazin-10-yl)propyl7pi-peridine, m.p.: 118-120 C.
;

. : ~: , . '' ~3~ ~

Example 16 Preparation of 4-butylcarbamoyloxy-4-ethynyl-1-/3-(2-tri-fluoromethyl-lOH-phenothiazin-10-yl)propyl~piperidine A mixture containing 21.6 9 of 4-ethynyl-4-hydroxy-1--/3-(2-trifluoromethyl-lOH-phenothiazin-10-yl)propyl7piperi-dine, 7.4 ml of butyl isocyanate and 100 ml of triethylamine is gently refluxed under nitrogen while stirring for 7 to 8 hours, then the reaction mixture is evaporated under reduced pressure. After clarifying the evaporation residue by activated carbon in methanol, the solution is evaporated under reduced pressure. The crude product obtained as evaporation residue is recrystallized from diisopropyl ether under clarifying by activated carbon to give the crystalline title compound in 74% yield, m.p.: 109-110 C.
A_alysis:
calculated for C28H32F3N202S
C 63.25; H 6.07; F 10,72; N 7.90; S 6.303;
found: C 63.11; H 6.26; F 10.66; N 7.71; S 6.07%.
By using the appropriate starting substances the following compound can be prepared in an analogous manner as described in the preceding Example:
4-Acetyl-4-phenylcarbamoyloxy-1-/3-(2-trifluoromethyl-lOH--phenothiazin-10-yl)propyl/piperidine, m.p.: 156-157 C.
Example 17 Preparation of 4-acetyl-4-hydroxy-1-/3-(2-trifluoromethyl--lOH-phenothiazin-10-yl)propyl7piperidine - 2 ~ ~ v ~

A solution containing 9.5 9 of 4-methylene-2-oxo-~
-(2-trifluoromethyl-lOH-phenothiazin-10-yl)propyl7-1,3-di-oxa-~-azaspiro/4,5/decane in 50 ml of benzene is vigorously stirred with 100 ml o~ 10% aqueous sodium hydroxide solution at 70 to ~0 C under argon. After termination of the reaction (which is observed by using thin layer chromato-graphy) the heterogeneous reaction mixture is cooled down.
~ter separation the benzene layer is washed ~Jith water to neutral, dried over anhydrous magnesium sulfate and evaparated under reduced pressure. The evaporation resiude is recrystallized ~rom isopropyl ether to give the title compound in 56% yield, m.p.: 75-76 C.
Analysis:
ca1culat~d for C23H25-3N2 2 C 61.31; H 5.59; F 12.65; N 6.22; S 7.12;
found: C 61.33; ~ 5.70; F 12.60; N 6.11; S 7.00.
Example 18 Preparation of tablets with a weight o~ 100 mg containing 10 m~ of active ingredient each 50.0 g of active ingredient are mixed together with 285.0 9 o~ lactose, 100.0 9 of potato starch, 2.5 9 oi sodium dodecyl sul~ate, 5.0 g o~ polyvinylpyrrolidone (Kollidon-K 90R), 50.0 9 of microcrystalline cellulose tAvicelR) and 7.5 9 o~ vegetable oil (SterotexR) and, after wet granulation, the product obtained ls compressed to tablets weighing 100 mg each. Each oi the tablets contain~

. ~ .

10 mg of the active ingredient.
Example 19 Preparation of dragées with a weight of 125 mg containing 10 mg of active ingredient each After coating the tablets prepared as described above in a known manner with a layer consisting of sugar and talc, the dragées obtained are polished with a mixture of bee wax and carnauba wax.
Example 20 Preparation of capsules containing 20 mg of active ingre-dient each 40.0 9 of active ingredient, 12.0 9 of sodium lauryl sulfate, 102.0 9 of lactose, 102.0 0 of potato starch, 2.4 9 of magnesium stearate and 1.6 9 of colloidal silicon dioxide are thoroughly mixed together and the mixture obtained is filled into hard gelatine capsules containing 20 mg of active ingredient each.

Claims (21)

1. An 2-oxo-1-oxa-8-azaspiro[4,5]decane derivative of the formula (I), (I) wherein X means oxygen or an 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 optionally being 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 group, wherein R is as defined above, one of R1 and R2 may represent a hydroxyl group, whereas the other is a methyl group;
Z stands for hydrogen, halogen, trihalomethyl or a C2-4alkanoyl group; and n is 2 or 3, or an acid addition or quaternary ammonium salt thereof.

2. A compound according to claim 1 wherein R represents CH3N C2Hs, Z represents Cl or CF3, and n is 3.

3. 8-[3-(2-Chloro-10H-phenothiazin-10-yl)propyl]-3-methyl-

4-methylene -2-oxo-1-oxa-3,8-diazaspiro[4,5]decane, or an acid addition or quaternary ammonium salt thereof.

4. 3-methyl-4-methylene-2-oxo-8-[3-(2-trifluoromethyl-10H-phenothiazin-10-yl)propyl]-1-oxa-3,8-diazaspiro[4,5]decane, or an acid addition or quaternary ammonium salt thereo.

5. 3-Ethyl-4-methylene-2-oxo-8-[3-(2-trifluoromethyl-10H-phenothiazin -10-yl)propyl]-1-oxa-3,8-diazaspiro[4,5]decane, or an acid addition or quaternary ammonium salt thereof.

6. 8-[3-(2-Chloro-10H-phenothiazin-10-yl)propyl]-3-ethyl-4-methylene- 2-oxo-1-oxa-3,8-diazaspiro[4,5]decane, or an acid addition or quaternary ammonium salt thereof.

7. 8-[3-(2-Chloro-10H-phenothiazin-10-yl)propyl]-3,4-dimethyl-4-hydroxy-2-oxo-1-oxa-3,8-diazaspiro[4,5]decane, or an acid addition or quaternary ammonium salt thereof.

8. 3,4-Dimethyl-4-hydroxy-2-oxo-8-[3-(2-trifluoromethyl-10H-phenothiazin-10-yl)propyl]-1-oxa-3,8-diazaspiro[4,5]decane, or an acid addition or quaternary ammonium salt thereof.

9. 4-Methylene-2-oxo-8-[3-(2-trifluoromethyl-10H-pheno-thiazin-10-yl)propyl]-1,3-dioxa-8-diazaspiro[4,5]decane, or an acid addition or quaternary ammonium salt thereof.

10. A pharmaceutical composition, which comprises as active ingredient a compound according to any one of claim 1 to claim 9 or a pharmaceutically active acid addition or quaternary ammonium salt thereof in admixture with a pharmaceutically acceptable carrier or additive.

11. A process for preparing a compound of formula (I) according to claim 1 which process comprises a) to obtain a compound of formula (I), wherein X
stands for an group 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 phenothiazine derivative of the formula (III), (III) wherein n and Z are as defined in claim 1, and Y
means halogen, C1-4alkylsulfonyloxy or arylsulfonyloxy group;
or b) to obtain a compound of the formula (I), wherein X
stands for an group reacting a 2-oxo-3,8-diazaspiro[4,5]decane derivative of the formula (IV), (IV) wherein R, n, R1 and R2 are as defined in claim 1 and Y means halogen, C1-4alkylsulfonyloxy or aryl-sulfonyloxy group, with a phenothiazine derivative of the formula (V), (V) IMP

wherein Z is as defined in claim 1, c) reacing a 4-ethynyl-4-hydroxypiperidine derivative of the formula (VI), (VI) wherein n and Z are as defined in claim 1, with an isocyanate of the formula R-NCO, wherein R is as defined in claim 1, to obtain a 4-carbamoyloxy-4-ethynylpiperidine derivative of the formula (VII), (VII) wherein R, n and Z are as defined in claim 1 and then i) to obtain a compound of the formula (I), wherein R1 together with R2 stands for a methylene group and X stands for an oxygen atom, cyclizing in an acidic medium the obtained compound of the formula (VII) and reacting with water the obtained salt of 2-imino-1,3-dioxolane derivative of the formula (VIII) (VIII) wherein R, n and Z are as defined in claim 1, or (ii) to obtain a compound of the formula (I), wherein R1 together with R2 stands for a methy-lene group and X stands for a group, cycli-zing, in a basic medium, the obtained compound of the formula (VII), or d) to obtain a compound of the formula (I), wherein R1 together with R2 stands for a methylene group and X
means oxygen, cyclizing in an acidic medium a 4-carbamoyloxy-4-ethynylpiperidine of the formula (VII), wherein R, n and Z are as defined above, and reacting with water the obtained salt of 2-imino-1,3-dioxolane derivative of the formula (VIII), wherein R, n and Z are as defined above;

e) to obtain a compound of the formula (i), wherein R1 together with R2 stands for a methylene group and X
means an group, cyclizing in a basic medium a 4-carbamoyloxy-4-ethynylpiperidine derivative of the formula (VII), wherein R, n and Z are as de-fined above;
or f) to obtain a compound of the formula (I), wherein X
means an group, one of R1 and R2 stands for a hydroxyl group and the other is a methyl group, reacting a 4-acetyl-4-hydroxypiperidine derivative of the formula (X), (X) wherein n and Z are as defined above, with an isocyanate of the formula R-NCO, wherein R is as defined above, to obtain a 4-acetyl-4-carbamoyloxy-piperidine derivative of the formula (IX), (IX) wherein R, n and Z are as defined above, and then cyclizing the obtained compound of the formula (IX), g) to obtain a compound of the formula (I), wherein X
means an group, one of R1 and R2 stands for a hydroxyl group and the other is a methyl group, cyclizing a 4-acetyl-4-carbamoyloxypiperidine derivative of the formula (IX), wherein R, n and Z
are as defined above;

then, if required, to obtain a compound of the formula (I), wherein X means an group, one of R1 and R2 stands for a hydroxyl group and the other is methyl group, reacting a thus prepared compound of the formula (I),wherein X means oxygen, R1 and R2 together stand for a methylene group and n as well as Z are as defined above, with an amine of the formula R-NH2, wherein R is as defined in claim 1;
or transforming a functional group of a prepared compound of the formula (I), wherein X, R, n, R1, R2 and Z are as defined for the formula (I), to an other one;
or reacting with an acid a prepared compound of the formula (I), wherein X, R, n, R1, R2 and Z are as defined in claim 1, to give an acid addition salt or treating with a base a compound of the formula (I), wherein X, R, n, R1, R2 and Z are as defined in claim 1, obtained as a salt, to liberate the free basic form thereof or converting a prepared compound of the formula (I), wherein X, R, n, R1, R2 and Z are as defined in claim 1, to its quaternary ammonium salt.

12. A process according to claim 11 a) wherein in said compound of formula (III) Y stands for halogen.

13. A process according to claim 12 wherein Y stands for chlorine or bromine.

14. A process according to claim 11 a) wherein in said compound of formula (III) Y stands for a p-toluenesulfonyloxy group.

15. A process according to claim 11 b) wherein in said compound of formula (IV) Y stands for halogen.

16. A process according to claim 15 wherein Y stands for chlorine.

17. A process according to claim 11 c) wherein to obtain a compound of formula (I), wherein X means an group and R1 and R2 together stand for a methvlene group, said compound of formula (VI) is reacted with said isocyanate and the obtained compound of formula (VII) is cyclized in a single step without isolating said compound of formula (VII).

18. A process according to claim 11 d) wherein cyclization of said compound of formula (VII) is carried out in dioxane in the presence of hydrogen chloride.

19. A process according to claim 11 e) wherein the cycliza-tion of said compound of formula (VII) is carried out in methanol in the presence of sodium methoxide.

20. A process for preparing a pharmaceutical composition, which comprises mixing as active ingredient a compound according to any one of claims 1 to 9 or a pharmaceutically active acid addition or quaternary ammonium salt thereof with a pharma-ceutically acceptable carrier or additives.

21. Use of a therapeutically effective amount of a compound according to any one of claim 1 to claim 9 to treat a psychiatric or allergic disease.