GB2131021A

GB2131021A - Antipsychotic benzoxazines

Info

Publication number: GB2131021A
Application number: GB08331268A
Authority: GB
Inventors: Luigi Bernardi; Ettore Lazzari; Maria Luisa Malnati; Guiseppe Mazzini; Lorenzo Pegrassi; Alessandro Rossi
Original assignee: Farmitalia Carlo Erba SRL
Current assignee: Pfizer Italia SRL
Priority date: 1982-11-24
Filing date: 1983-11-23
Publication date: 1984-06-13
Also published as: GB2131021B; GB8331268D0

Abstract

Compounds of formula (I): <IMAGE> wherein R represents a halogen atom or a CN, NH2 and NO2 group, and pharmaceutically acceptable salts thereof, are useful as antipsychotic agents.

Description

SPECIFICATION Antipsychotic benzoxazines This invention relates to a class of benzoxazines which have valuable pharmacological activities on the Central Nervous System and are useful in treating phychic disorders, especially schizophrenic syndromes.

The literature describes other compounds having a similar structure but different activity to that of the compounds of this invention. For example, EP-A-0065864 and EP-A-00701 71 disclose spiro-piperidine derivatives having antihypertensive activity.

The present inventton provides 1 '-(3-benzoylpropyl)spi ro-(3, 1 -benzoxazi ne-4(2H)4'-piperidin)-2- ones of formula (I):

wherein R represents a halogen atom or a cyano, amino, or nitro group, and their pharmaceutically acceptable salts. These compounds have antipsychotic activity.

"Pharmaceutically acceptable salts" are salts which retain the biological effectiveness and properties of the free base and which are not biologically or otherwise undesirable. Suitable acids for the preparation of the salts include hydrochloric, hydrobromic, sulphuric, acetic, propionic, lactic, citric, tartaric, methanesulphonic acids and the like.

Preferred halogens which R may represent include chloro, bromo and fluoro.

Particularly preferred compounds according to the present invention are: 1 '-[3-(4-fl uorobe nzoyl )propyl]spiro-(3, 1 -benzoxazine-6-bromo-4(2H )4'-piperidin)-2-one, 1 '-[3-(4-fluorobenzoyl)propyl]spiro-(3, 1 -benzoxazine-6-nitro-4(2H)4'-piperidin)-2-one, 1 '-[3-(4-fl uorobenzoyl)propyl]spiro-(3, 1 -benzoxazine-6-fluoro-4(2H)4'-piperidin)-2-one, and 1 '-[3-(4-fl uorobenzoyl)propyl]spiro-(3, 1 -benzoxazine-6-cyano-4(2H)4'-piperidin)-2-one.

The compounds of formula (I) are prepared according to the invention by alkylating spiro-(3,1benzoxazine-4(2H)4'-piperidin)-2-ones of formula (lil):

with compounds of formula (IV) or (V)

wherein R is as defined above.

This reaction is generally carried out in the presence of potassium iodide and of an organic or inorganic base, such as triethylamine, potassium carbonate or sodium bicarbonate in a suitable solvent such as an alcohol having up to 6 carbon atoms, toluene, benzene, acetonitrile, dimethylformamide and tetrahydrofuran at a temperature in the range from about 500 to about 1600. Preferably alkylation is carried out by reacting a compound of formula (III) at 1 000C in the presence of potassium iodide and anhydrous potassium carbonate and using dimethylformamide as solvent with the protected compound (V) as alkylating reagent. The reaction mixture is treated with hydrochloric acid in methanol to give the 1 '-benzoylpropylspiro-(3, 1 -benzoxazine-4(2H)4'-piperidin)-2-ones of formula (I).The compounds of formula (III), which are the main intermediates, are prepared as shown in scheme A below.

Scheme A

A 2-bromonitrobenzene (Vl) is metalated at about -1 000C by halogen-metal exchange with n BuLi, and then reacted with 1 -methyl-4-piperidone (all) to given the nitrocarbinol (VIII). The nitro group is then catalytically reduced to the aminocarbinol (IX) which is cyclized to compound (X) by reacting with phosgene or carbonyldiimidazole.

Compounds of formula (X) are transferred into compounds of formula (XI) wherein R represents a halogen atom or a nitro, amino or cyano group by reaction knownperse, e.g. aromatic halogenation, nitration, nitration and reduction, diazotisation and diazo replacement respectively, as described in the Examples below.

The intermediate compound of formula (III) is obtained from (Xl) by means of dealkylation via the Braun reaction.

The compounds and salts of the present invention present interesting pharmacological activities on the Central Nervous System. More particularly, they display significant activity as antipsychotic agents with a very low toxicity and incidence of side effects in comparison with haloperidol (II)

which is a drug widely used in the therapy of phychic disorders, especially of schizophrenic syndromes.

The compounds and salts of the invention proved very active as antagonists to apomorphineinduced climbing behaviour in mice, i.e. as central dopaminergic antagonists, following the technique of Protais P. petal. (Psychopharmacology, 50,1(1976)).

The classical neuroleptics may be even more active in the above-mentioned experimental model, but are exceedingly active in disrupting behavioural performance. On the contrary, the compounds and salts of this invention gave results which were less active or inactive in a series of tests which comprise the undesired side-effects on neuromuscular coordination in the rat by the rotarod test (Dunham, M. W. etna!, J. Am. Pharm. Ass. 46, 208 (1975)), the interference with conditioned Avoidance Response in the rat (Gupta, B. D. eft at Psychopharmacologia, 14, 95 (1969)), the potential induction of catalepsy in rats (catalepsy is generally defined as the condition in which an animal will allow itself to be placed in unusual body positions which are maintained for extended time intervals, e.g. Rech, R.H. eft at "An Introduction to Psychopharmacology" Raven Press, N.Y., 1 971, and "The Potential antagonism to rational behaviour produced by dopaminergic agents in rats with 6-OHDA induced unilateral lesions of the dopaminergic nigrostriatal pathway", (Ungerstedt, U. eft at Brain Res.

14,461,1969).

The compounds and salts of the invention were also tested following Irwin S. "Technique in mice" (Psychopharmacologia 13, 322 (1968)) and have been shown to interfere weakly with spontaneous activity and body temperature, and to have very low toxicities. A summary of the main pharmacological features of the compounds and salts of the present invention versus haloperidol are reported in the Table I below.

Table I

Compound of Compound of Tests Example 1 Example 3 Haloperidol Apomorphine antagonism in 1.7 2.7 0.2 mice (ED50, mg/kg p.o.) Reduction of spontaneous 12.5 1 5 0.78 activity and body temperature in 100 110 3.12 mice (min. active doses, mg/kg p.o.) LD50 in mice (mg/kg p.o.) > 800 > 800 75 Min. active doses (rat, mg/kg p.o.) in: Rotarod test > 50 50 0.5 C.A.R. test 25 20 0.5 Turning-behaviour > 20 > 15 0.5 Catalepsy induction > 200 200 0.5 As this pharmacological profile shows, the compounds of the invention are more selective antipsychotic agents than haloperidol. They are in fact potent central dopamine-antagonists with far lower incidence of disrupting effects on behavioural performance and with very low toxicities.

The involvement of dopamine in psychotic states is strongly suggested by several clinical observations based not only on the fact that all known neuroleptic drugs block dopamine receptors whereas even structurally related compounds devoid of such an effect do not show therapeutic activity, but also on the finding that dopamine antagonists or dopamine-releasing agents can produce worsening of pre-existing psychosis in patients with active schizophrenic illness. The block of dopamine receptor systems may be more or less specific and can occur in different districts of the organism. A widespread blockade of dopamine receptors usually results in huge behavioural impairment, as happens under treatment with the typical so-called neuroleptics. Nearly all of the currently available neuroleptic agents produce in fact a variety of neurological disorders in both laboratory animals and patients. The compounds and salts of this invention show a more selective antipsychotic profile, being very potent central dopamine antagonists with very weak or no influence on muscular tone, neuromuscular coordination, behavioural performance and arterial pressure, as shown by the data of Table I, and therefore are expected to be used with advantage in the therapy of phychotic disorders.

Moreover, a representative compound of the present invention, the compound of Example 1 below, was tested versus the compound prepared in Example 5 of EP-A-0065864 (coded in Table II below as 20855). Compound 20855 is 1 -[4-(4-fluorophenyl)-4-oxo-n-butyl]-spiro[piperidine-4,4'-2'- oxo-3',1 '-benzoxazine], and is the most similar of the compounds described in EPA0065864 and EP-A-00701 71 to the compounds of the present invention. Table II below clearly shows that the compound of the prior art is not endowed with antipsychotic activity.

Table II

Compound of Test Example I 20855 Apomorphine antagonism in 1.7 > 20 mice (ED50, mg/kg p.o.) The present invention further provides pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as active ingredient, together with a pharmaceutically acceptable carrier or diluent. Compounds of formula (I) and their pharmaceutically acceptable salts are useful in treating psychotic disorders. The compounds of formula (i) and their salts may be administered parenterally or orally, preferably orally, and are administered to a human patient in a therapeutically effective amount.

Depending on the route of administration, the compositions may be in the form of solid, semisolid or liquid dosage form such as tablets, pills, capsules, powders, liquids, suspension or the like. The composition will include a conventional pharmaceutical carrier or diluent and an active compound of formula (I) or a pharmaceutically acceptable salt thereof and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, etc.

The dosage of the present drugs varies in accordance with the sex, age, condition or medical record of the patient, as well as according to the route or purpose of the administration. In general, the drugs may be administered as single doses or as divided doses so as to provide, say, about 0.01-20 mg/kg body weight per day of effective ingredient, preferably about 0.03-11 1 mg/kg body weight.

The pharmaceutical compositions containing the compounds of the invention can be prepared according to conventional methods with the usual ingredients. Thus, for oral administration, the pharmaceutical compositions containing the compounds of the invention are preferably tablets, pills or capsules which contain the active substance together with diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, sucrose, cellulose; lubricants, for instance, silica, talc, stearic acid, magnesium or calcium stearate and/or polyethylene glycols; or they may also contain binders, such as starches, gelatine, methylcellulose, gum-arabic, tragacanth, polyvinylpyrrolidone, disintegrating agents, such as starches, alginic acid, alginates; effervescing mixtures; dyestuffs; sweeteners; wetting agents, such as lecithin, polysorbates, laurylsulphates; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations. Said pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tabletting, sugarcoating, or film-coating processes. Also the other pharmaceutical formulations containing the compounds of the invention may be prepared by known methods and they can be, for example, syrup or drops for the oral administration, sterile solutions for injection, or suppositories.

The following Examples illustrate the invention. Temperatures are in OC.

Example 1 1 '-[3-(4-FluorobenzoyI)propyl]spiro-(3,1 -benzoxazine-6-bromo-4(2H)4'-piperidin)-2-one Step one: The intermediate 1-methyl-4-(2-nitrophenyl)-4-hydroxypiperidine To a solution of 1 9.3 g of 2-bromonitrobenzene in 480 ml of anhydrous tetrahydrofuran cooled to -1 000C, 79 ml of 1.6 M solution of n-BuLi in hexane are dropped under N2. After two hours 10.9 g of 1 -methyl-4-piperidone are added and the resulting mixture is stirred eight hours at -1 000C. Then 1 N hydrochloric acid is added at OOC to acidify to pH 2 and the solution is extracted with hexane. The aqueous phase is brought to pH 10 and extracted with ethyl ether.Evaporation of the extracts gives 8.95 g of 1-methyl-4-(2-nitrophenyl)-4-hydroxypiperidine, m.p. 1 66 167 .

Step two: The intermediate 1 -methyl-4-(2-aminophenyl)-4-hydroxypiperidine A mixture of 25 g of the compound prepared in step one and 2 g of 10% Pd/C in 1 000 ml of ethanol is hydrogenated at 200 and at atmospheric pressure. The reaction mixture is then filtered and evaporated to dryness yielding 20.5 g of 1 methyl-4-(2-aminophenyl)-4-hydroxypiperidine, m.p.

135136 from diisopropyl ether.

Step three: The intermediate 1 '-methylspiro-(3, I -benzoxazine-4(2H)4'-piperidin)-2-one To a well stirred solution of 1 3 g of 1-methyl-4-(2-aminophenyl)-4-hydroxypiperidine in 400 ml of anhydrous tetrahydrofuran a solution of 1 2.74 g of carbonyldiimidazole in 120 ml of tetrahydrofuran is added. After stirring for twenty hours the solution is concentrated to a small voiume and 200 ml of chloroform are added. The solution is washed four times with water, dried over sodium sulphate and evaporated to yield 14.52 g of 1 '-methylspiro-(3,1 -benzoxazine-4(2H)4'-piperidin)-2-one, m.p.

1560--1570 after recrystallization from ethyl acetate.

Step four: The intermediate 1 '-methylspiro-(3,I -benzoxazine-6-bromo-4(2H)4'-piperidin)-2-one A solution of 22.3 g of bromine in 75 ml of acetic acid is dropped at 1 50 into a solution of 1 6.2 g of 1'-methylspiro-(3,1-benzoxazine-4(2H)4'-piperidin)-2-one and 6.3 g of anhydrous sodium acetate in 280 ml of acetic acid. The mixture is stirred overnight at room temperature and filtered. The reddish solid is dissolved in methylene chloride and washed with a 15% aqueous solution of sodium bisulphite.

The organic phase is dried over magnesium sulphate and evaporated to give 16.45 g of 1'- methylspiro-(3,1 -benzoxazine-6-bromo-4(2H)4'-piperidin)-2-one, m.p. 210 --210. Step five: The intermediate 1 '-cyanospiro-(3,I -benzoxazine-6-bromo-4(2H)4'-piperidin)-2-one A solution of 15.5 g of 1 '-methylspiro-(3, 1 -benzoxazine-6-bromo-4(2H)4'-piperidin)-2-one in 150 ml of chloroform is slowly added to a stirred boiling solution of 7.91 g of cyanogen bromide in 160 ml of chloroform under nitrogen and the resulting solution is refluxed for ten hours. The unreacted starting material is extracted with 0.5 N hydrochloric acid.The chloroform solution is then washed with water, dried over sodium sulphate and evaporated to give 12.75 g of 1'-cyanospiro-(3,1-benzoxazine- 6-bromo-4(2H)4'-piperidin)-2-one, m.p. 2750--2760 from acetonitrile.

Step six: The intermediate spiro-(3, -benzoxazi I benzoxazine-6-bromo-4(2H)4'-piperidin)-2-one Asolution of 12 g of 1'-cyanospiro-(3,1-benzoxazine-6-bromo-4(2H)4'-piperidin)-2-one in 180 ml of dimethylformamide, 80 ml of water and 1 20 ml of 37% hydrochloric acid is refluxed for three hours. The cooled mixture, diluted with 500 ml of water, is basified with a concentrated solution of sodium hydroxide and extracted with n-butanol. By vacuum concentration of the butanol 10.8 g of spiro-(3,1-benzoxazine-6-bromo-4(2H)4'-piperidin)-2-one are obtained, m.p. 2530--2550 after recrystalization from acetonitrile.

Step seven: The title compound A mixture of 0.6 g of the above described spiro-(3,1 -benzoxazine-6-bromo-4(2H)4'-piperidin)-2 one, 0.36 g of potassium iodide, 0.6 g of an hydros potassium carbonate and 0.53 g of 2-(3 chloropropyl)-2-(4-fluorophenyl)-5,5-dimethyl-1 ,3-dioxane in 6 ml of dimethylformamide is heated at 1000. After four hours, the inorganic salts are filtered off and the solvent is removed in vacuo.

The crude acetal thus obtained is then hydrolyzed by stirring two hours at room temperature in 15 ml of methanol and 7.5 ml of 2.5 N hydrochloric acid. This solution is concentrated, basified with 20% aqueous sodium hydroxide and extracted with chloroform. The extracts are evaporated to give 0.57 g of 1'-[3-(4-fluorobenzoyl)propyl]spiro-(3,1-benzoxazine-6-bromo-4(2H)4'-piperidin)-2-one, m.p. 206--208 , from ethyl acetate.

Example 2 1 - E3-(4-fluorobenzoyl )propyl]spiro-(3. 1 -benzoxazine-6-chloro-4(2H)4'-piperidin)-2-one Step one: The intermediate 1'-methylspiro-(3,1-benzoxazine-6-chloro-4(2H)4'-piperidin)-2-one A solution of 5.6 ml of sulphuryl chloride in 55 ml of dichloromethane is added dropwise to a solution of 8 g of 1 '-methylspiro-(3,1 -benzoxazine-4(2H)4'-piperidin)-2-one (Example 1) in 80 ml of dichloromethane at 00. The resulting mixture, after stirring for two days at room temperature, is filtered off yielding 9.8 g of 1 '-methylspiro-(3, 1 -benzoxazine-6-chloro-4(2H)4'-piperidin)-2-one, hydrochloride. The free base has m.p. 209021 20.

Step two: The intermediate 1 '-cyanospiro-(3,I -benzoxazine-6-chloro-4{2H)4'-piperidin)-2-one Starting from 6 g of the above prepared 6-chloroderivative and 3.9 g of cyanogen bromide according to the previously described procedure (see Example 1-step five) 4.7 g of 1 '-cyanospiro (3,1 -benzoxazine-6-chloro-4(2H)4'-piperidin)-2-one, m.p. 2500, are obtained.

Step three: The intermediate spiro-(3,1-benzoxazine-6-chloro-4(2H)4'-piperidin)-2-one 4.5 g of the 1 '-cyanospiro derivative above described are hydrolyzed according to the usual procedure giving 3.3 g of spiro-(3, 1 benzoxazine-6-chloro-4'-piperidin)-2-one, m.p. 230 --232 .

Step four: The title compound Starting from 2.6 g of spiro-(3,1-benzoxazine-6-chloro-4(2H)4'-piperidin)-2-one, 1.8g g of potassium iodide, 3.1 g of anhydrous potassium carbonate and 2.4 g of 2-(3-chloropropyl)-2-(4 fluorophenyl)-5,5-dimethyl-1 ,3-dioxane in 30 ml of dimethylformamide, 2.6 g of 1 '-[3-(4 fluorobenzoyl)propyl]spiro-(3, 1 -benzoxazine-6-chloro-4(2H)4'-piperidin)-2-one, m.p. 1860--1880 are obtained according to the previously described procedure.

Example 3 1 '-[3-14-fluorobenzoyl )-propyl]spiro-(3,1 -benzoxazine-6-nitro-4(2H)4'-piperidin-2-one Step one: The intermediate 1 '-methylspiro-(3, 1 -benzoxazine-6-nitro-4(2H)4'-piperidin)-2-one 19.2 g of 1 '-methylspiro-(3,1 -benzoxazine-4(2H)4'-piperidin)-2-one (Example 1) are dissolved in 80 mi of concentrated sulphuric acid and 6.2 ml of 65% nitric acid is added at-i 50C. After stirring for one hour the resulting mixture is poured into 300 g of ice-water and then filtered off giving the sulphate of 1 '-methylspiro-(3, 1 -benzoxazine-6-nitro-4(2H)4'-piperidin)-2-one from which 21.2 g of free base, m.p. 2580--261 , are obtained after basic treatment.

Step two: The intermediate 1 'cyanospirn-(3, I -benzoxazine-6-nitro-4(2H)4'-piperidin)-2-one A solution of 10 g of the above prepared 6-nitro derivative in 80 ml of dimethylformamide and 120 ml of chloroform is added to a boiling solution of 8.3 g of cyanogen bromide in 100 ml of chloroform and the mixture is refluxed for eight hours. 200 ml of chloroform are added and the solution is washed with 1 0% aqueous solution of tartaric acid, with a saturated solution of sodium bicarbonate and with a saturated solution of sodium chloride. Evaporation of the chloroform gives 7.1 g of 1' cyanospiro-(3, 1 -benzoxazine-6-nitro-4(2H)4'-piperidin)-2-one, m.p. 2700 dec.

Step three: The intermediate spiro-(3,1-benzoxazine-6-nitro-4(2H)4'-piperidin)-2-one A solution of 7.05 g of 1'-cyanospiro-(3,1-benzoxazine-6-nitro-4(2H)4'-piperidin)-2-one in 125 ml of dimethylformamide, 58 ml of water and 81.5 ml of concentrated hydrochloric acid is refluxed for one hour. The mixture is cooled and filtered off giving 5.5 g of spiro-(3,1 -benzoxazine-6-nitro-4(2H)4'- piperidin)-2-one as the hydrochloride, m.p. 3000 after recrystallization from water.

Step four: The title compound Starting from a mixture of 4.32 g of spiro-(3,1-benzoxazine-6-nitro-4(2H)4'-piperidin)-2-one hydrochloride, 2.6 mi of triethylamine, 2.78 of potassium iodide, 4.3 g of anhydrous potassium carbonate, 3.73 g of 2-(3-chloropropyl)-2-(44luorophenyl)-5,5-dimethyl-1 ,3-dioxane in 60 ml dimethylformamide, according to the previously reported procedure (see Example 1, step seven) 2.58 g of 1 '-[3-(4-fluorobenzoyl)propyl]spiro-(3, 1 -benzoxazine-6-nitro-4(2H)4'-piperidin)-2-one, m.p.215 21 60 are obtained.

Example 4 1 '-[3-(4-Fluorobenzoyl)propyl]spiro-(3,1 -benzoxazine-6-fluoro-4(2H ,4'-piperidin,-2-one Step one: The intermediate 1'-methylspiro-(3,1-benzoxazine-6-amino-4(2H)4'-piperidin)-2-one A solution of 9.5 g of 1 '-methylspiro-(3,1-benzoxazine-6-nitro-4(2H)4'-piperidin)-2-one (see Example 3) in 250 ml of absolute ethanol is hydrogenated over 3.8 g of 10% Pd/C. When no more hydrogen is absorbed the reaction mixture is filtered off and evaporated to dryness giving 7.75 g of 1'methylspiro-(3,1 -benzoxazine-6-amino-4(2H)4'-piperidin)-2-one, m.p. 247 0--2490 from ethanol.

Step two: The intermediate 1 '-methylspiro-(3,1 -benzoxazine-6-fluoro-4(2H)4'-piperidin)-2-one A solution of 3.9 g of sodium nitrite in 4.9 ml of water is added dropwise over a period of 30 minutes to a stirred mixture of 1 2.2 g of the above prepared 6-amino derivative in 25.5 ml of water and 32 ml of a 40% aqueous solution of fluoboric acid at --50.

After one hour the diazonium fluoroborate precipitate is filtered off, dried under vacuum and then heated for two hours at 1 900 under nitrogen. The resulting viscous residue is dissolved in water and extracted with ethyl acetate from the basified aqueous solution. By evaporation of the organic phase 7.38 g of 1 '-methylspiro-(3,1-benzoxazine-6-fluoro-4(2H)4'-piperidin)-2-one m.p. 221 0--223 0, are obtained.

Step three: The intermediate 1 '-cyanospiro-(3,1-benzoxazine-6-fluoro-4(2H)4'-piperidin)-2-one Starting from 7.5 g of the above prepared compound by treatment with 5.6 g of cyanogen bromide, according to the previously reported procedures, 7.6 g of 1 '-cyanospiro-(3,1 -benzoxazine-6fluoro-4(2H)4'-piperidin)-2-one m.p. 2270--2290, are obtained.

Step four: The intermediate spiro-(3,1-benzoxazine-6-fluoro-4(2H)4'-piperidin)-2-one Starting from 6.25 g of the above 1 '-cyanospiro derivative, according to the previously reported procedure (see Example 1-step six), 5.5 g of spiro-(3,1-benzoxazine-6-fluoro-4(2H)4'-piperidin)-2- one, m.p. 2450--2470 are obtained.

Step five: The title compound Starting from 4.8 g of spiro-(3,1-benzoxazine-6-fluoro-4(2H)4'-piperidin)-2-one,3.46 g of potassium iodide, 5.8 g of anhydrous potassium carbonate, 5 g of 2-(3-chloropropyl)-2-(4 fluorophenyl)-5,5-dimethyl-1 ,3-dioxane in 55 ml of dimethylformamide, according to the previously reported procedure (see Example 1-step seven), 4.8 g of 1'-[3-(4-fluorobenzoyl)propyl]spiro-(3,1- benzoxazine-6-fluoro-4(2H)4'-piperidin)-2-one, m.p. 1700--1720 from ethyl acetate, are obtained.

Example 5 1 '-[3-(4-Fluorobenzoyl)prnpyl]spiro-(3,1 -benzoxazine-6-cyano-4(2H)4'-piperidin)-2-one Step one: The intermediate I '-methylspiro-(3,1 -benzoxazine-6-cyano-4(2H)4'-piperidin)-2-one A solution of 2 g of sodium nitrite in 5 ml of water is added dropwise to a mixture of 8.3 g of 1' methylspiro-(3,1-benzoxazine-6-amino-4(2H)4'-piperidin)-2-one in 9.7 ml of water and 9.7 ml of concentrated hydrochloric acid at 00. After one hour this cold solution containing the diazonium salt is added to a solution of 3.3 g of copper cyanide and 4 g of sodium cyanide in 10 ml of water warmed at 700. After stirring one hour at this temperature and twenty minutes at 1000 the mixture is cooled, basified and extracted with n-butanol.By evaporation under vacuum there are obtained 6 g of 1' methylspiro-(3,1 -benzoxazine-6-cyano-4(2H)4'-piperidin)-2-one m.p. 2470--2490.

Step two: The intermediate 1 '-cyanospiro-(3,1 -benzoxazine-6-cyano-4(2H)4'-piperidin)-2-one Starting from 1.6 g of the above prepared compound and 1.5 g of cyanogenbromide, according to the previously reportedprocedure, 1.3 g of 1'-cyanospiro-(3,1-benzoxazine-6-cyano-4(2H)4'- piperidin)-2-one are obtained, m.p. 2840--2860.

Step three: The intermediate spiro-(3, I -benzoxazine-6-cyano-4(2H)4'-piperidin)-2-one A mixture of 2.7 g of the above prepared compound, 14 g of zinc dust in 250 ml of a 95% aqueous solution of acetic acid is heated at 800 for two hours. The solvent is evaporated and the residue is taken up with a mixture of chloroform and a 2 N solution of ammonium hydroxide.

Evaporation of the organic layer gives 1.3 g of spiro-(3,1-benzoxazine-6-cyano-4-(2H)4'-piperidin)-2- one, m.p. 2680--2700 from acetonitrile.

Step four: The title compound Starting from 1 g of spiro-(3,1 -benzoxazine-6-cyano-4(2H)4'-piperidin)-2-one, 0.73 g of potassium iodide, 1.23 g of anhydrous potassium carbonate and 0.99 g of 2-(3-chloropropyl)-2-(4 fluorophenyl)-5,5-dimethyl-1 3-dioxane in 1 5 ml of dimethylformamide, according to the previously reported precedure (see Example 1-step seven) 0.6 g of 1 '-[3-(4-fluorobenzoyl)propyl]spiro-(3,1 - benzoxazine-6-cyano-4(2H)4'-piperidin)-2-one m.p. 1 940--1 95 0 from ethyl acetate are obtained.

Example 6 1 '-[3-(4-Fluorobenzoyl)propyl]spiro-[3, 1 -benzoxazine-6-bromo-4(2H)4'-piperidin]-2-one hydrochloride To a solution of 0.5 g of the compound prepared in Example 1, in 10 ml of ethanol, an excess of 5% hydrogen chloride in ethanol is added. Diethyl ether is added until complete precipitation.

The formed solid is filtered, washed with ether and recrystallized from i-propylalcohol. 0.48 g of the title compound are obtained, m.p. 2480--2490.

Example 7 Preparation of tablets weighing 500 mg and containing 100 mg of active ingredient Quantity per Ingredient 10000 tablets 1 '-[3(4-FI uorobenzoyl)p ropyl] spi ro-[3,1 -benzoxazine-6- 1000 g bromo-4(2H)-4'-piperidin]-2-one Mannitol 3000 g Sucrose 6 x 500 g Corn starch 300 g Talc 125 9 Magnesium stearate 75 9 All the ingredients except the corn starch, magnesium stearate and talc are mixed, slugged and screened through a 20 mesh screen twice. The mixture so obtained is transferred to a twin-shell blender and, after addition of the corn starch, magnesium stearate and talc, mixed for 10 min and compressed to weight using 1.27 cm (1/2 in) flat-face bevel-edge punches.

Claims

1. A 1 '-(3-benzoylpropyl)spiro-(3, 1 -benzoxazine-4(2H)4'-piperidin)-2-one of the formula (I):

wherein R represents a halogen atom or a cyano, amino and nitro group, and pharmaceutically acceptable salts thereof.

2. A compound according to claim 1 wherein R is chloro, bromo or fluoro.

3. A compound according to claim 1 which is 1 '-[3-(4-fluorobenzoyl)propyl]spiro-(3,1- benzoxazine-6-bromo-4(2H)4'-piperidin)-2-one or its hydrochloride.

4. A compound according to claim 1 which is l'-[3-(4-fluorobenzoyl)propyl]spiro-(3,1- benzoxazine-6-chloro-4(2H)4'-piperidin)-2-one.

5. A compound according to claim 1 which is 1 '-[3-(4-fluorobenzoyl)propylispiro-(3,1 - benzoxazine-6-nitro-4(2 H)4'-piperidi n)-2-one.

6. A compound according to claim 1 which is 1 '-[3-(4-fluorobenzoyl)propyl]spiro-(3, 1 - benzoxazine-64luoro-4(2H)4'-piperidin)-2-one.

7. A compound according to claim 1 which is 1'-[3-(4-fluorobenzoyl)propyl]spiro-(3,1- benzoxamine-6-cyano-4(2H)4'-piperidin)-2-one.

8. A process for the preparation of a compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof, which process comprises alkylating a spiro-(3,1-benzoxazine4(2H)4'-piperidin)-2-one of formula (Ill):

wherein R is as defined in claim 1, with a compound of formula (IV) or (V):

removing the ketal protecting group from the resulting compound if reaction has been effected with a compound of formula (V) and, if desired, converting the resulting compound of formula (I) into a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof as active ingredient, together with a pharmaceutically acceptable carrier or excipient.

10. A compound of formula (I) as defined in claim 1 or a pharmaceutically acceptable salt thereof for use in treating psychotic disorders in humans.

11. A process for the preparation of a compound of formula (I) as defined in claim 1, said process being substantially as hereinbefore described in any one of Examples 1 to 5.

12. A process for the preparation of a pharmaceutically acceptable salt of a compound of formula (I) as defined in claim 1, said process being substantially as hereinbefore described in Example 6.

13. A pharmaceutical composition substantially as hereinbefore described in Example 7.