AU620847B2 - New 1,4-benzoxazine and 1,4-benzothiazine derivatives and process for their preparation - Google Patents

Description

OPI DATE 06/09/89 AOJP DATE 05/10/89

INTERNATI

(51) International Patent Classification 4 C07D 265/36, 279/16, 471/10 A61K 31/535, 31/54 C07D 471/10, 235/00, 221/00 APPLN. ID 30634 89 PCT NUMBER PCT/EP89/00130 EATY (PCT) (11) Inte i Pu i tioWlumb WO 89/ 07596 Al (43) Inte io, 4Pu tite :L 4 A gust 1989 (24.08,89) (21) International Application Number: PCT/EP89/00130 (22) International Filing Date: 13 February 1989 (13.02.89) (31) Priority Application Number (32) Priority Date: (33) Priority Country: 8803419 15 February 1988 (15.02.88) (74) Agents: WOODS, Geoffrey, Corlett et al.; J.A. Kemp Co., 14 South Square, Gray's Inn, London WCIR 5EU (GB).

(81) Designated States: AT (European patent), AU, BE (European patent), CH (European patent), DE (European patent), DK, FI, FR (European patent), GB (European patent), HU, IT (European patent), JP, KR, LU (European patent), NL (European patent), SE (European patent), SU, US.

Published With international search report.

(71) Applicant (for all designated States except US): FARMI- TALIA CARLO ERBA S.R.L, [IT/IT]; Via Carlo Imbonati, 24, 1-20159 Milan (IT).

(72) Inventors; and Inventors/Applicants (for US only) VARASI, Mario [IT/IT]; Via Giambellino, 80, I-Milan MELLO- NI, Piero [IT/IT; Via Centurelli, 1, 1-20091 Bresso CERVINI, Maria, Antonietta [IT/IT]; Via Nazario Sauro, 10, 1-21010 Cardano al Campo (IT).

BONSIGNORI, Alberto [IT/IT]; Via dei Benedettini, 2, I-Milan COMMISSO, Roberto [IT/IT]; Via Pascoli, 11, 1-27058 Voghera (IT), (54)Title: NEW 1,4-BENZOXAZINE AND 1,4-BENZOTHIAZINE DERIVATIVES AND PROCESS FOR THEIR

PREPARATION

:1

R

xR (57) Abstract The present invention relates to compounds having formula wherein X represents or each or R and RI, independently, is hydrogen, halogen, hydroxy, C-C 6 alkyl, CI-C6 alkoxy, amino, nitro or trihalo-CIC 6 alkyl; each or Rz and independently, is hydrogen. CI-C 6 alkyl, C 2 -C6 alkenyl, C 2

-C

6 alkynyl or phenyl-CI.C 6 alkyl or R2 and R3, taken together with the nitrogen atom to which they are linked, form an, unsubstituted or substituted, 6-membered, saturated, heterornonocyclic ring optionally containing a further heteroatom chosen from oxygen, sulphur and nitrogen; each of R4 and R 5 independently, is hydrogen, halogen, nitro, amino or tthalo-CI.C 6 alkyl; and the pharmaceutically acceptable salts thereof. The compounds of the invention are useful in therapy as major tranquilizers in the management of psychotic disorders.

~L

i 1

I

r WO 89/07596 PCT[EP89/00130

I

DESCRIPTION

"NEW 1,4-BENZOXAZINE AND 1,4-BENZOTHIAZINE DERIVATIVES AND PROCESS FOR THEIR PREPARATION" The present invention relates to substituted 4-aryl derivatives of 2,3-dihydro-4H-1,4-benzoxazine and 2,3-dihydro-4H-1,4-benzothiazine, to a process for their preparation, to pharmaceutical compositions containing them, and to their use in the preparation of pharmaceutical compositions having anti-psychotic activity.

Most of the classical drugs, up to now used in therapy for the menagement of psychotic disorders, act mainly on the dopaminergic pathways as dopamine antagonists, This pharmacological acti vity is closely associated with their antischizophrenic effects, in particular against symptoms, such as hallucinations and delusions. However the dopamine antagonists now available in therapy are meagrely effective against other symptoms of schizophrenia, such as apathy and withdrawn social behaviour, and unfortunately are associated with extrapyramidal side effects. Therefore in therapy remains a strong need of drugs active in treating also these latter aspects of the psychotic syndrome, and having no, or negligible, neurological side effects.

The invention provides compounds having the following general formula (I) Rg x

R

1 wherein 1 L "r WO 89/07596 PCT/EP89/00130 2 X represents or each of R and R independently, is hydrogen, halogen, hydroxy, C-C 6 alkyl, C 1

-C

6 alkoxy, amino, nitro or trihalo- C -C 6 alkyl; each of R 2 and R 3 independently, is hydrogen, C 1

-C

6 alkyl,

C,-C

6 alkenyl, C -C 6 alkynyl or phenyl-C,-C 6 alkyl; or R and R 3 taken together with the nitrogen atom to which they are linked, form an unsubstituted or substituted, 6-membered, saturated, heteromonocyclic ring optionally containing a further heteroatom chosen from oxygen, sulphur and nitrogen; each of R 4 and R 5 independently, is hydrogen, halogen, nitro, amino or trihalo-C 1 -C alkyl; and the pharmaceutically acceptable salts thereof.

The invention also includes within its scope all the possible isomers, stereoisomers and optical isomers and their mixtures, and the metabolites and the metabolic precursors or bio-precursors of the compounds of formula A halogen atom is e.g. chlorine, bromine or fluorine, preferably it is fluorine.

The alkyl, alkenyl, alkynyl and alkoxy groups may be branched or straight chain groups. A Ci-C 6 alkyl group is preferably a C--C 4 alkyl group, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec. butyl or tert. butyl, more preferably it is methyl or ethyl. A C 2

-C

6 alkenyl group is preferably a C 2

-C

4 alkenyl group, in particular allyl. A C 2 -C alkynyl group is preferably a C 2 -C alkynyl group, in particular propargyl.

I

L,

WO 89/07596 PCTJEP89/00130 3 A phenyl- C 1

-C

6 alkyl group is preferably a phenyl-C-Ck 4lkyl, in particular benzyl or phenetkyl.

A C1-C6 alkoxy group is preferably a Ci-C4 a-lkoxy group, e.g.

methoxy, ethoxy, propoxy, isopropoxy, butoxy or tert.butoxy, sore preferably it is methoxy or ethoxy.

A trihalo-C 1C6 alkyl group is preferably a trihalo-C 1 -C4 alkyl group, e.g. trichloro-C 1

-C

4 alkyl or trifluoro-C 1

-C

4 alkyl, more preferably it is trifluoromethyl.

When R2 and R 3 taken together with the nitrogen atom to which they are linked, form an heteromonocyclic ring as defined above, it may be for example a ring chosen from the group including piperidine, piperazine, morpholine or thiomorpholine, vtich may be unsubtituted or substituted at one or two carbon atos by one or two eubstituents independently chosen from the group including: a) hydroxy and C 1

-C

6 alkyl; b) phenyl unsubstituted or substituted by one to three substituents independently chosen from hydroxy, halogen,

C

1

-C

6 Llkyl, C 1

-C

6 alkoxy and trifluoro-methyl; c) 2-keto-1-benzoimidazolinyl; and 2 d) l-phenyl-4-keto-5-imidaZolidifyl so as to provide e.g. a 1-phenyl-1,3,8-triazasp iroC,5decan-4-one condensed ring system, iie.

WO 89/07596 PCT/EP89/00130

-H

C

in which the phenyl ring is unsubstituted or substituted by one to three substituents chosen independently from hydroxy, halogen,

C

1

-C

6 alkyl and trifluoromethyl, and the nitrogen atom at the 1position ot the imidazolidine ring may be unsubstituted or substituted by C -C6 alkyl, phenyl or by phenyl-C1-C 6 alkyl.

When R and R3, taken together with the nitrogen atom to which they are linked, form an heterocyclic ring, as defined above, which contains a further nitrogen atom, the additional nitrogen atom may be unsubstituted or substituted by a substituent chosen from the group including C 1

-C

6 alkyl, pyridyl and pyrazinyl or by phenyl unsubstituted or substituted by one to three substituents chosen from hydroxy, halogen, C 1

-C

6 alkyl, C 1

-C

6 alkoxy and trifluoromethyl.

When R 2 and R taken together with the nitrogen atom to which they are linked, form an heterocyclic ring as defined above, preferably it is selected from the group including: unsubstituted morpholine; piperazine unsubstituted or substituted by pyridyl, pyrazinyl or by phenyl unsubstituted or substituted by one or two substituents independently chosen from halogen, trifluoromethyl, C1-C4 alkyl and C 1 -Cq alkoxy; and WO 89/07596 PCT/EP89/00130 piperidine unsubstituted or substituted by one or two substituents chosen independently from hydroxy, 2-keto-l-benzoimidazolinyl and phenyl unsubstituted or substituted by halogen; or the piperidine ring may be substituted by The pharmaceutically acceptable salts of the compounds of formula include those formed with an inorganic acid, e.g. nitric acid, hydrochloric acid or sulphuric acid, or with an organic acid, e.g citric, malic, maleic, mandelic, tartaric, fumaric or methanesulphonic acid.

As stated above, the present invention also includes within its scope pharmaceutically acceptable bioprecursors (otherwise known as pro-drugs) of the compounds of formula i.e. compounds which have a different formula to formula above, but which nevertheless upon administration to a human being are converted directly or indirectly in vivo into a compound of formula Preferred compounds of the invention are the compounds of formula wherein X represents or each of R and R independently, is hydrogen, halogen, hydroxy, amino, Ci-C 4 alkyl, CI-C 4 alkoxy, trifluoromethyl or nitro; each of R 2 and R 3 independently, is hydrogen or Ci-C 4 alkyl, or R 2 and R 3 taken together with the nitrogen atom to which they are linked, form a heteromonocyclic ring chosen from unsubstituted morpholine; piperazine unsubstituted or substituted by pyridyl, pyrazinyl or by phenyl, the phenyl group being unsubstituted or substituted by one or two substituents independently chosen from halogen, trifluoromethyl, C 1

-C

4 alkyl and C 1

-C

4 alkoxy; and i 1 r WO 89/07596 PCT/EP89/00130 6 piperidine unsubstituted or substituted by one or two substituents chosen independently from hydroxy, 2-keto- -1-benzoimidazolinyl, 1-phenyl-4-keto-5-imidazolidinyl and phenyl unsubstituted or substituted by one or two substituents chosen from halogen and trifluoromethyl;

R

4 is hydrogen;

R

5 is hydrogen, halogen or trifluoromethyl; and the pharmaceutically acceptable salts thereof.

More preferred compounds of the invention are the compounds of formula wherein X represents each of R and R 1 independently, is hydrogen, halogen or trifluoromethyl; R and R 3 taken together with the nitrogen atom to which they are linked, form a piperidine ring unsubstituted or substituted by one or two substituents chosen from hydroxy, 2-keto-l-benzoimidazolinyl, 1-phenyl-4-keto-5-imidazolidinyl and phenyl unsubstituted or substituted by one or two substituerts chosen from halogen and trifluoromethyl; or a piperazine ring unsubstituted or substituted by unsubstituted pyridyl or by phenyl unsubstituted or substituted by one or two substituents chosen independently from halogen and C -C 4 alkoxy; R4 is hydrogen; R is hydrogen, halogen or trifluoromethyl, and the pharmaceutically acceptable salts thereof.

WO 89/07596 PCT/EP89/00 130 -7- Examples of particularly preferred compounds of the invention are the following: 2-F4-4floopeyl--hydroxy-piperidin-1-yl--met-hyl-4- -phenyl-?, 3-dihydro-4H-1 ,4-benzoxazine; 2-r4-(2-methoxyphenyl)-piperazin-1-yl]-methyl-4-phenyl-2,3- -dihydro-4H-1 ,4-benzoxazine; 2- -phenyl-1 8-triazaspiro 5-jdecan-4-one-8-yl )-methyl-4- -phenyl-2 ,3-dihydro-4H-1 ,4-benzoxazine; 2- (l-phenyl- 3, 8-triazaspiro 5]decan-4-one-8-yl )-methyl- -4-phenyl-7-fluoro-2,3-dihydro-4H-,4-Denzoxazine; 2- l-phenyl-1, 3,8-triazaspiro decan-4-one--8-yl )-methyl- -4-k(4-f.Luorophenyl)-2,3-dihydro-4H-l,4-benzoxazine; 2l(-phenyl-1, 3, 8-triazaspiro [4 decan-4-one-8-yl)-methyl- -4-(4-'.luorophenyl )-7-fluoro-2 ,3-dihydro-4H-1 ,4-benzoxazine; 2-r4-(3-trifluoromethyl-phenyl)-4-hydroxy-piperidin-l-yl>- -methy'L-4-phenyl-2 ,3-dihydro-4H- 4-benzoxazine; 2-4'3tilooehlpey)--yrx-~prdily3 -mty--4foohnl-,-iyr-H14bnoaie 2- r4-(3-trifluoromethyl-phenyl)-4-hydroxy-piperidin-1-yl]- -rzy--hnl7fur-1-dhdo4-,-e~oaie and 2-,-3-lrfu.oe.y-hey)4hdoypprdn1y' e-hyl-4-(4- fluorophernyl)-7-flt4oro-2,3-dihydro-4H-1,4- -benzoxazine; in particular in the form of siAngle enan'.iomerz, and the pharmaceutically acceptable salts thereof.

WO 8907596PCT/EP89/00130 The compounds of the invention and the salts thereof can be prepared by a process comprising reacting a corn- 1pound of formula (II) R 4 I R wherein XR, RfR and R are as defined above and Y represents 4 5 the residue of a reactive ester or halogen, with a ocopound I ol" formula (III) whereint WO 89/07596 PCT/EP89/00130 9

R

2 and R 3 are as defined above, and, if desired, converting a compound of formula into another compound of formula and/or, if desired, salifyinc a compound of formula and/or, if desired, obtaining a free compound of formula from a salt thereof, and/ or, if desired, separating a mixture of isomers of compouhds of formula into the single isomers.

When Y is the residue of a reactive ester, it is preferably a sulphonate group, more preferably -0-mesyl or -0-tosyl.

When Y is halogen, it is preferably chlorine or bromine.

I0 The reaction between a cormpound of formula (II) and an amine of formula (III) may be carried out for example in an organic solvent such as dimethylformamide, dimethylacetamide, hexamethylphosphortriamide, tetrahydrofuran, dioxane or 1,2-dimethoxyethane, in the presence of an inorganic base, e.g. an alkali metal carbonate, preferably potassium carbonate, at temperatures generally from about to the reflux temperature of the solvent used, with reaction times generally from about I hour to about 10 hours.

Alternatively to the inorganic base, an excess of the amine of formula (il) iavolved in the reaction may be added.

WO 89/07596 PCT/EP89/00130 A compound of formula may be converted, as stated above, into another compound of formula by known methods. For example, a free hydroxy group may be etherified by reaction with a suitable alkyl halide in the presence of a base such as NaOH, KOH, Nr* a

K

2

CO

3 NaH, NaNH 2 sodium methoxide or sodium ethoxide in a solvent selected from the group consisting, for example, of methanol, ethanol, dioxane, acetone, dimethylformaide, hexamethylphosphorotriamide, tetrahydrofuran, water and their mixtures at a temperature ranging preferably between about OOC and about 1500C. Furthermore an etherified hydroxy group may be converted into a free hydroxy group, for example, by treatment with pyridine hydrochloride or with a strong acid such as HBr or HI, or with a Lewis acid such as A1CI or BBr or with an alkaline salt of a thiol.

Also the optional salification of a compound of formula as well as the conversion of a salt into the free compound and the separation of a mixture of isomers into the single isomers may be carried out by conventional methods.

For example, the separation of a mixture of optical isomers into the individual isomers may be carried out by salification with an optically active acid and subsequent fractional crystallization or by esterification with an optically active acid derivative and separation of the diastereoisomers.

Thus, the separation of a mixture of geometric isomers ay be carried out, for example, by fractional crystallization or by aeparation on column chromatography.

WO 89/7596 PCT/EP89/00130 11 In the processes described in the specification, when required, reactive functional groups may be protected with suitable protecting reagents, which may be removed after the reaction by known methods, which are available from the chemical literature.

The compounds of formula (II) wherein Y is the residue of a reactive ester, e.g. an -0-mesyl or -0-tosyl group, may be prepared for example by reacting a compound of formula (IV)

R

R 1

(IV)

r ^i wherein X, R, R, R 4 and R 5 are as defined above, with a suitable" acyl, preferably sulphonyl, halide, treferably chloride, e.g. with p-toluene-sulphonylchloride or methanesulphonylchloride, operating for instance in anhydrous pyridine at room temperature or in a solvent chosen from methylene chloride or chloroform, in the presence of an organic base, e.g.

triethylamine, at a temperature ranging from about -5*C to about The compounds of formula (II) wherein Y represents halogen may bj obtained for example from a compound of formula as defined above, through known methods, e.g. by treatment with SOC12. by conwo 89/07596 PCT/EP89/00130 12 ventional methods of organic chemistry, optionally in the presence of a suitable catalyst, for example ZnCl 2 or by treatment with

SOCI

2 or oxalic acid dichloride in dimethylformamide, through the formation of a Vilsmeier reagent.

The compounds of formula (IV) may be obtained by reducing a compound of formula (V)

R

R

4 R Z 1 wherein, X, R, R, R 4 and R are as defined above and Z represents a free, salified or eaterified carboxy group.

When,in a compound of formula Z is a salified carboxy group, the salt may be either a salt of an organic base or a salt of an inorganic base; preferably it is an alkali metal salt.

When,in a compound of formula Z is an esterified carboxy group, the ester may be, for example, an alkyl ester; preferably it is a

C

1

-C

6 alkoxycarbonyl group, in particular methoxy- or ethoxy-carbonyl.

The reduction of a compound of formula wherein Z is esterified carboxyl, to give a compound of formula may, for example, be p~Ulr WO 89/07596 PCTEP9/00130 13 carried out using sodium borohydride as reducing agent in a solvent such as methanol, ethanol or isopropanol or a mixture of one of these solvents with water in ratios which vary depending on the solubility of the starting product; the said reduction may also be performed, e.g. using lithium aluminium hydride in inert solvents such as anhydrous diethyl ether or anhydrous tetrahydrofuran at temperatures which, in both cases, range from approximately O°C to the solvent reflux temperature, for reaction times ranging approximately between minutes and 24 hours.

The reduction of a compound of formula wherein Z represents a free carboxyl group, to give a compound of formula is preferably carried out using lithium aluminium hydride in inert solvents such as anhydrous ethyl ether, anhydrous diethylene glycol dimethyl ether, anhydrous tetrahydrofuran or mixtures thereof, or using preformed solutions of boron hydride in the aforesaid anhydrous solvents, or boron hydride prepared in situ in the reaction medium from sodium boronhydride and boron trifluoride etherate, preferably in diethylene glycol dimethyl ether, at temperatures ranging from about 0"C to the solvent reflux temp6rature, for reaction times ranging approximately between 30 minutes and 12 hours.

The reduction of a compound of formula wherein Z represents a salified carboxy group, to give a compound of formula is preferably carried out in conditions analogous to those employed in the reduction of a compound of formula wherein Z is a free carboxy group.

WO 89/07596 PCT/EP89/00130 -14- The compounds of formula wherein Z is an esterified carboxy group may be obtained through N-arylation of a compound of formula

(VI)

H

I (VI) wherein X, R and Rare as defined above and Z' is an eaterified carboxy group as defined above for Z. N-arylation of a compound of formula (VI) may be carried out by treatment yith a phenyl derivative of formula (VII) R 4 (v) where in

R

4 and Rare as defined above and E is preferably a halogen atom, e.g. bromine or iodine* at a temperature ranging from about 50*C to about 2600C, in the presence of copper or a suitable &aIt thereof e.g. Cul or CuBr and, if required, in a pressure vessel.

;I s_ WO 89/07596 PCT/EP89/00130 15 When a compound of formula is required, wherein R and

R

5 are both hydrogen, N-arylation of a compound of formula (VI) may be performed to advantage by treatment with 1,4- -cyclohexanedione in the presence of paratoluenesulfonic acid, in an aromatic hydrocarbon, preferably benzene or tolue ne, at reflux temperature, with contemporaneous removal of water by azeotropic distillation.

A compound of formula wherein Z is a free or salified carboxy group, may be obtained according to known methods from a compound of formula wherein Z is an esterified carboxy group.

The compounds of formulae (III) and (VI) are known and/or may be obtained according to known methods from known compounds.

As is clear from the relevant chemical structures,besides the compounds of formula also the compounds of formula (II), and (VI) are chiral molecules, in which the C-2 carbon atom is asymmetric; therefore they may exist as single optical isomers (enantiomers) or as a mixture thereof.

When a compound of formula in the form of single pure optical isomer is desired, it can be obtained either by resolving a mixture of its optical isomers into the single optical isomers, as described above, or by using a compound of formula or in the form of single optical isomer, as intermediate or starting material, respectively, in the process herein described.

WO 89/07596 PCT/EP89/00130 16 In a preferred embodiment of the process according to the present invention, when a compound of formula as single pure optical isomer is desired, a pure optical isomer of a compound of formula is used as intermediate compound in such process.

The separation of a mixture of optical isomers of a compound of formula into the individual isomers may be carried out by following the same method described above for separing a mixture of optical isomers of a compound of formula into the single optical isomers. In particular a compound of formula in which Z is a free carboxy group can be salified with an optically active base, e.g. ephedrine, and submitted to subsequent fractional crystallization.

A further object of the present invention are the intermediate compounds of formula (V) 4

RR

N

(V)

R'

1 wherein X, R, R, R 4 R and Z are as defined above, both in the form of single optical isomers and in the form of a mixture thereof, which are new.

The compounds of the invention are active on the central nervous system (CNS), in particular as CNS depressant, i.e.

as major tranquilizers (neuroleptics) and can be used in thera- WO 89/07596 PCT/EP89/00130 17 py e.g. in the management of psychotic disorders and manicdepressive states, for the control of nausea and vomiting, for the treatment of restlessness and apprehension prior to surgery, post-surgical psychosis, excessive anxiety, post-miocardial infarction agitation, behavioural symptoms during intensive care and in AIDS patients with delirium and dementia.

Moreover, by virtue of their high antidopaminergic properties, associated with low cataleptogenic activity, and of their potent activity in inhibiting the serotonin 5HT 2 receptor binding, the compounds according to the present invention are active also in treating some symptoms of schizophrenia, which are meagrely sensitive to the therapeutical means now available, such as apathy and withdrawn social behaviour, and have no, or negligible, neurological side-effects.

The activity of the compounds of the present invention was evaluated for example in a series of receptorial binding affinity tests.

Table 1 shows for instance the binding affinity test data of a representative group of compounds according to the instant invention for D 1 and D dopamine, 5HT 1 and 5HT 2 serotonine and 1 and o.2 nor-adrenaline receptors, obtained according to well known procedures rCreese, I, Schneider, R, Synder, S.H. Europ.

J.Pharmacol. 1977, 46, 377; Hyttel, J.Life Sci. 1981, 28, 563; Pedigo et al.Journal of Neurochemistry, 1981, 36, 220; Leysen et al. Molecular Pharmacology, 1981, 21, 301; Battaglia et al. Life Science, 1983, 33, 2011; Greengrass P., Brener R. Eur.J.Pharmacol., 1979, 55, 323; and Perry B.D., U'Prichard D.C. Eur.J.Pharmacol. 1981, 76, 4611 TABLE I Compound

B

2 lT 1 LHcisFlu. 3 j1spip. [~7Serot. 1[31-1] i~et. P11Pa. P o ~n ECE 25456 '10 0.001 >10 0.1 0.4 FCE 24867 1.4 0.008 >10 0.04 0.1 1.7 FCE 25895 1.2 j 0.005 >10 I0.006 0.08 0.8 FCE 25896 >10 0.2 >10 0.08 0.3 2.9 FCE 25676 1 0.002 51.6 j0.02 0.02 0.1 FCE 25848 2.4 0.04 >10 0.03 0.1 7.2 ECE 25452 0.9 (0.009 >10 0.02 0.4

I

k~I WO 89/07596 WO 8907596PCT[EP89/ 00130 In 'the table cis-Flu. means cis-Flupenthixol; Spip. means Spiperone; Serot. means Serotonin; Ket. means Ketanserine; Praz. means Prazosin and Yahim. means Yohimbine, respectively.

The above internal FCE codes refer to the following compounds FCE 25456 =2-[4-,I3-trifluoromethyl-phenyl)-4-hydroxy-piperidin-lI-yl1] -me thyl -4-phenyl 3- dihydro-4 H- 1, 4- -benzoxazine; FCE 24867 2-(1-phenyl-1,3,8-triazaspiroE4,5]decan-4-one-8- -yl)-methyl-4--phenyl-2,3-dihydro-4H-l ,4-benzoxazine; FCE 25895 2-(l-phenyl-1,3,8-triazaspiro[4,5]decan-4-one- -8--yl )-methyl--4-phenyl-2 ,3-dihydro-4H-1 ,4-benzoxazine; FCE 25896 2-(l-phenyl-l,3,8-triazaspiro[4,Sjdecan-4-one- -8-yl)-methyl-4-pheyl-2,3-dihydro-4H-1 ,4-bernzoxazine; ECE 25676 =2-(l-phenyl-1,3,8-triazaspiroE4,5]decan-4-one-8- -yl)-methyl-4-(4-fluorophenyl)-2,3-dihydro-4H-1,4- -benzoxazine; FOE 25848 2-(l-phenyl-1,3,8-triazaspiro[4,5]decan-4 -Qne-8- -yl )-methyl-4-phenyl-7-rli~oro-2 ,3-dihydro-4H- 4-.

-benzoxazine; FOE 25452 2-(1-phenyl-1 8-triazaspiro 5]decan-4-one-8- -yl)-methyl-4-(4-fluorophenyl)-7-fluoro-2 ,3-dihydro- -4H.-1 ,4-benzoxazine.

Table 1 shows clearly that the compounds of the invention have in particular high selective activity in inhibiting the D 2 dopamine, 5RT 2serotonine and nor-adrenaline receptor binding.

WO 89/07596 PCT/EP89/00130 The activity of the compounds of the present invention on the central nervous system was also evaluated by following for instance the technique of Protais P.et al. (Psychopharmacology, 50, 1 (1976).

According to this experimental framework, the compounds of the invention proved to be very active as antagonists to apomorphine-induced climbing behaviour in mice, i.e. as central dopaminergic antagonists.

Moreover, the compounds of the invention were found to be inactive in a series of tests, carried out so as to find possible undesired side-effects.

For example cataleptic activity was found to be very low in the "bar test" in the mouse (Costall B. et al.Neuropharmacology, 14, 859 (1975), at 6th hour after administration of the test compounds.

The toxocity of the compounds of the invention is negligible, therefore they can be safely used in therapy. Nine hours food deprived mice were treated orally with single administration of increasing doses, then housed and normally fed. The orientative acute toxicity (LD50 was assesed on the seventh day after the treatment and resulted, in general, higher than 600 mg/kg.

Following Table 2 summarizes the biological data obtained according to the above mentioned tests for some compounds of the present invention; Haloperidol has been evaluated in the same tests for comparative purposes.

i

F

TABLE 2 Topon Climbing ED 50 Catalepsy ED so ED soCatalepsy 1 LD mg/kg/os ng/kg/os ED 50C limbing mg/kg/os FCE 25456 2.5 20 8 >800 FCE 24867 4.5 30.8 6.8 >800 FCE 25895 3.8 61.0 16.0 >800 FCE 25896 1.8 ?2.7 12.6 >800 FCE 25676 4.9 75.0 I 15.3 >800 Haloperidol 0.5 2.2 4.4 71 The LD 50datum for Hialoperidol is given according i amaoE.c17,3,42 -TI Farmaco-Ed.Sc.1976, 31, 442.

i WO 89/07596 PCT/EP89/00130 22 The compounds of the invention can be administered in a variety of dosage forms, e.g. orally, in the form of tablets, capsules, sugar or film coated tablets, liquid so lutions or suspensions, rectally, in the form of suppositories, parenterally, e.g. intramuscularly, or by intravenous injection or infusion. The dosage depends on the age, weight, conditions of the patient and administration route; for example for the compound of the invention herein coded as FCE 25895 the dosage adopted for oral administration to adult humans ranges from about 2 to about 100 mg pro dose, from 1 to 5 times daily.

The invention includes pharmaceutical compositions comprising a compound of the invention in association with a pharmaceutically acceptable excipient (which can be a carrier or diluent).

The pharmaceutical compositions containing the compounds of the invention are usually prepared following conventional methods and are administered in a pharmaceutically suitable form.

i L WO 89/07596 PCT/EP89/00130 23 For example, the solid oral forms may contain, together with the active compound, diluents, lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents, e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents, e.g. starch, akinic acid, alginates or sodium starch glycolate; 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.

The liquid dispersions for oral administration may be e.g. syrupe, emulsions and suspensions. The syrups may contain as carriers, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol.

The suspensions and the emulsions may contain as carrier, for example a natural gum, agar, sodium alginate, pectin, methylcellulose, WO 89/07596 PCT/EP89/00130 24 carboxymethylcellulose, or polyvinyl alcohol. The suspensions or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g.

sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride.

The solutions for intravenous injections or infusions may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions.

The suppositories may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. cocoa-butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.

The following examples illustrate but do not limit the invention.

EXAMPLE 1 4-(4-chlorophenyl)-4-hydroxy-piperidine (3 g; 13.3 imol) is added to a stirred solution of 2-(methane-sulfonyloxy)-methyl- 4 -phenyl- S23-dihydro-4H-1,4-benzoxazine (1.76 g; 5.51 "ol) in dimethylformamide (50 al). The reacting mixture is heated at 90"C for 3 hours. After cooling, water (150 ml) is added and the product is extracted twice with ethyl acetate (100 ml). The organic layer is washed twice with water (50 ml) and dried over anhydrous sodium WO 89/07596 PCT/EP89/001307 sulphate. Lvaporstion of the solvent gives 2 g of a~n oily residue which is purified by flash calumn c~hromatography oln silica gel, by using chloroform/methanol/ 30 ammonium hydroxide 100/210.1 as eluant, thus obtaining 1.7 g of pure oily product (yield 65 The pure product is taken up in 10 T1 of ethyl acetate and treated, at CC, with a gaseous hydrochloric acid saturated ethyl acetate solution, so as to obtain 2 (4-chlorophe nyl) -4-hyroxy-pi pe ridini-yI7-me thyl- 4 -phenyl 2 -dihydro-+H-1 ,4_benzoxazine hydrochloride, as white crystals, M.p. 252-255*C.

By proceed inF- analogously, the following compounds, as a free base or as a salt thereof, can be obtained: 2-/17-(4-methoxyphenyl) -piperazin-1 -yge thl 4 whnl2,-dihydro- 4H-1 14-benzoxazi-Ae .2.5 flC1, m. p. 24o-247OC; 2.-aprzLy)pprzn -l-ehl4peil.,3-dihydro-4l- 1,4-benzoxaziLne .2 ECl, M.p. 2550C (dec.); (3-chlorophenyl) -pipe razini- l-yg-me thyl-+-phenyl.2 ,3-dihydro- 4H-1, t -benzoxazine .2 HCd, M.p. 220 0 C (dec. 2-(N-methylaminoethyl)-4-phenyl-2 ,3-dihydro--421 ,4-bonzoxazi1ne UCl, M.P. 1900C (dec.); 2-j3- (2-pyri dy1) -pipe raz in. 1-yg7-me thyl-4-.ph eny1l-2 ,3-dihydro-4H- 1,4-benzoxazine .2 flCl, M.p. 1200C (doc.); 2.(4-phenyl-piy*.razin-1-yl)-mothy- 4 -pheml-2,,3-dihydro-4H- 1,4benzoxazine 2 XECi, m.p. 2Z0-223*C; 2-(r4.morpho2Ainmethyl-4-phenyvl-2 ,3-dihyclro-4,-1 1 4-benzoxazine, M.p. 223-227C; WO 89/07596 WO 8907596PC/EP89Oo 130 26 2- (N-propyaminome thy 1) 4 -pheny 1-2 ,3-d ihydro-4H -1 ,4-benzoxazine HCJ., 2-aminome thyl-4-phenyl-2 ,3-dihydro-4H-1 ,4-benzoxazine HC1, M.P. 253-257*C; 2-F4-;-chorophenyl) -4-hydroxy-piperi din- i-yg-_me thyl-4-phemYl-7fluoro-2 ,3-dihydro-4H-l 4-benzoxazine; 4 -chloropheny.) -4-hydroxy-piperidin-1 -yg-ce thyl-+- fluorophenyl)-2 1 3-di.hydro_4H-1 4 -benzoxazine; 2-j- (4-chloropheriyl) -4-hydroxcy-pi peri din- 1-y -me thyl-4- 4 fluoro- C phenyl) f luoro-2 ,3-dihydro-4H- 1 ,4-benzoxazine; 2-s (2-ke to-l-benzoimidazolinyl) -piperidin- 1-y.g-methyl-4-phenyl- 2,3-dihydro-4H-1,4-benzoxazine m.p. 185-188*C; 2-"-2mtoyhnl-ieai-1y-ehl--hnl23dhdo 41i-i 4 -benzoxazine 2 m.p. 235-238OC; 2 (2-me thoxyphenyl) -pp ai- y7m hl4p,,~--floo 2.,3-dihydro"4H- 4 -benzoxazine; 2-ZL 1 (2-me thoxypheny).) -piperazin-I -y2, 7 -methy1-I-(4_f luoropheny)- 7-fluoro-2 ,3-dihydro-4H- 1, 4 -benzoxazine 2--2m'-oyhnl-ieazr--I ehl4(-lco phenyl -2 3-dihydro-4H--1 4-benzoxazine;

MMM

WO 89/07596 PCT/EP89/00130 27- 2- tri f Iuoromethy -pheny -4hydroxyp ipe ri din-.1.-y 11 -rethyl-4-phenyl-2,3-di hydro-4H-.,4-benzoxazine, m.p.260 0

C

as hydrochloride; 2- (3-trifluoromethyl-phenyl )-4-hydroxy-piperidin-l-ylJ -methyl-4--(4-fluorophenyl)-2,3-dihydro-4H-1,4.benzoxazine; 2- tri fluorome thyl-phenyl )-4-hydroxy-piperi din- I yl3 -methyl-4-phenyl-7-fluoro-2,3-dihydro-4H-l ,4-benzoxazine; and 2-[4-(3-trifluoromethyl-phenyl)-4-hydroxy-piperidin-.lyl..

-methyl-4-(4-fluorophenyl)-7-fluoro-2,3-diydro-4.1 ,4-benzoxazine.

Example 2 By proceeding according to Example 1 and using suitable acids, the following compounds can be obtained: 2 -(N,Nq-dipropylamninornethyl)-4-phenyl-2, 3-dihydro-4H-l 4- 1$-benzoxazine fumarare, m~p. 109-11,30C; and 2- N-d ime thyl am i4nome thy 1) -4-phenyl 3-di hydro-4 i- 1 4- -benzoxazine fumarate, m.p. 10900 (dec.).

i

_D

WO 89/07596 PCTJEP89/00130 28 EAMPLE 3 I-.phenyl-1,3,8-triazasviroZ/ 4 ,57dcanI-one (2.03 g; 8.8 mmol) is added to a stirred solution of 2-chloromethyl-4-phenyl-2,3-dihydro- 4

H-

1, 4 -benzoxazine (1.29 g; 4 mo1) in dimethylformamide (20 m).

The reacting mixture is heated at 90*C for 8 hours. After cooling, water (100 ml) is added and the product is extracted twice with ethyl acetate (80 ml). The organic layer is washed twice with water ml) and dried over anhydrous sodium sulphate. The solid residue, obtained after evaporation of the solvent under reduced pressure, is purified by flash column chromatography on silica gel by using hexane/acetone 9/1 as eluant, thus obtaining 0.7 g of pure -phenyl-1,3,8-triazaspiro4 ,5]decan-4-one-8-yl)-methyl-4-phenyl- 2.,3-dihydro-4H-1, 4 -benzoxazine, yield 37 m-p. 191-193OC.

By proceeding analogouxsly the following compounds can be obtained: 1 2-T4- (4-fluorophenyl) 4 -hydroxy-piperidin- 1-yJ-methyl- 4 -phenyl-2, 3dihydro41-_1, 4 -benzoxazine, m.p. 1050C; 2-,-fluorphenyl) 4-hy droxy -piperiOin- 1-ygl-mathyl- 4 -phenyl-7tcl oro- 3-4kydro- 4-H ~p ,1 ,4-benzoxazine; 4 -fluorophenyl)- 4 -hydroxy-piperidin- 1-y17-methyl-4-(4- fluoro- 2C phenyl1) 3-dihydro-41-I 4-ben oxazine; fluorophenyl) -4 -hy dro xy pi peridin- 1 -y!7-me thyl-4- f luorophenyl) -7-fluoro-2 ,3-dihy dro- 4 H -1 4 -benzoxazine; SOj WO 89/07596 WO 8907596PCTJEP89/00130 29 2- 7_~(2-ke to-i -benzoimidazolinyl) -pi peridin- 1 -yj7-me thyl-4-phenyl- 7-fluoro-2 ,3-dihydro-4H-1 ,4-benzoxazine; (2 2-ke to-i1 -ben zo imidazoliny).) -piperidin- 1 -yg7-e thyl-4- (4fluorophenyl) 3-dihydro-4H-i ,4-benzoxazine; 2-j-(2-keto--benzoimidazoliny1l -piperidin- 1-y17-methyl-4-( 4 fluorophenyl )-.7-iluoro-2 3dihydro-4H-i 4 -benzorazine; 2-1 (2 -me thoxyphenyl) -pi perazin 1-y17-me thy 1-4- (4-f luoroph enyi) 2,3-dihydro-4H-i ,4-benzoxazine; 2-(1-h ,y ,3 r za p c[ ,5 e a -ce g v io ethyl-4-phenyl-7-f luoro-2, 3-diihydro-4H-1 4-benzoxazine, m.p. 198-20C-OC; 2-(1-phe-nyl-1,3,8-zIriazaspi ro[4,5~decan-4-one-8-yll -rehy (4-fluorophenyl 3-dihydro-4H-1 4-benzcxazine, m. -28CC as hydrochloride and is 2- (1-phenyl- 3, 8-triazaspiro 5]decan-4-one-8-yl) -methyl-4- (4-f luophenyl )-7-fluoro-2, 3-i1hydr-4'-I-1 ,4- -benzoxazine, rn.p. 288-2920C, as hydrochloride.

Examplp 4 4- f uorophenyl )-4-hydroxy-p ipe ridine (2.78 g, 14.3 mrnol) is added to a stC.irred solution of 2-(methanesulfonyl)- -methyl-4-phenyl-2,3-dihydro-4H-1 ,4-benzothiazine (2.17 g; rnmol) in dimethylfornamide (60 ml).

WO 89/07596 PCT/EP89/00130 30 The reacting mixture is heated at 90 0 C for 3 hours. After cooling, water (150 ml) is added and the product is extracted twice with ethyl acetate (100 ml). The organic layer is washed twice with water (60 ml) and dried over anhydrous sodium sulphate. By evaporating the solvent a solid is obtained, which is purified by flash chromatography on silica gel by using herane/acetone 9/1 as eluant, thus obtaining 1.17 g of pure 2--(4-fluoroph-enyl)-4-hydroxypiperidin-1-y-me thy -4-phenyl-2, 3-dihydro-4H 1 4-benzothiazine yield 41 By proceeding analosously the following compounds can be obtained: 2 fluorophenyl) -4-hyd.roxy-piperidin-1 -yg-me thyl-4- 4 -f luorophenyl)-7-fluoro-2 3-dihydro-R-l ,4-benzothiazine; 2 (2-keto-1 -benzoimidazolinyl) -piperidin- 1 yf-me thyl-4-phenyl- 2,3-dihydro- 4 R-1 ,4-benzothiazine; :(2-ke to- -ben o imi dazolinyl) -pip-eridin- 1 Yj-me thyl-4- (4fluorophenyl) -7-fluoro-2 ,3-dihydro-4H-1 1 -benzothia.ine; 3, 8-triazaspiroL,5decn-4-one-8-yi)-methyl- 4 -phenyl- 2,3-dihydro-4H-1 ,4-benzothizine; and 1-phenyl-1 3 ,8-triazaapiro,2,g/decn-4-one- 8 -yl) -methyl-4- (4-fluorophenyl) -7-fluoro-2 ,3-dihydro-4H-1, 4-berarothiizie.

WO 89/07596 PCT/EP89/00130 31 Example Resolution of an acid of formula into the single optical isomers.

To a solution of 4-phenyl-4H-[1,4]-benzoxazine-2-carboxylic acid (20.8 g, 0.08 mol) in 75 ml of methanol (-)ephedrine (13.5 g, 0.08 mol) is added.

The resulting solution is allowed to stand for 1 h: a precipitate is formed which is filtered off.

By concentration of the mother liquors a further crop of solid is obtained.

33.4 g of the salt are totally obtained.

Resolution is performed by 4 crystallizations from CH 3

CN

(Table I) TABLE I Crystall- CH 3 CN(1) salt ob- 2 5 of the ization tained salt (methanol) raw material 139-182 -20.3 1 189-9 2 17.2 -24.9 2 189-91 1.6 13-.4 -26.4 3 194-7 1.4 11.2 -26.8 4 194-6 1.4 9.6 -27.4 WO 89/07596 PCT/EP89/00130 32 The mother liquors of the four crystallizations are collected together, evaporated, taken up with chloroform and washed with 2N HC1. The organic phase is dried and evaporated to give 9.5 g of the free acid which is dissolved in methanol and treated with 6.1 g of (+)ephedrine. After hours the solution is evaporated to give an oily residue which, taken up with ether, gives 12.2 g of the salt, which is crystallized twice from CH 3 CN (Table II).

TABLE II Crystall- m.p.(OC) ization CH3CN(1) salt ob- [a)c 2 5 of the tained salt (methanol) raw material 182-7 +24.1 1 192-4 1 8.9 +26.4 2 194.6 0.8 7,4 +27.3 From the and the salts the free optically pure acids are obtained by treatment with HC1, according to usual procedures.

acid [a]D25 (methanol) -49.5 acid [a]D2 (methanol) +49.4 WO 89/07596 PCT/EP89/00130 33 Example 6 By proceeding analogously to the procedures described in Examples 1 and 3, and using a pure optically active compound of formula the following compounds can be obtained: (+)2-(1-phenyl-1,3,8-triazaspiro[4,s']decan-4-one-8-yl)-metLhyl- -4-phenyl-2,3-dihydro-4H-l,4-benzoxazine, +37. (-)2-(l-phenyl-1,3,8-triazaspiro[4,s]decan-4-one-e-yl)-methyl- -4-phenyl-2,3-dihydro-4H-l,4-benzoxazine, D02= 74CC (+)2-(1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one-8-yl)-methyl- -4--(4-fluorophenyl)-2,3-dihydro-4H--l,4-benzoxazine; (-)2--l-phenyl-1,3,8-triazaspir'o[4,5],decan-4-one-8-yl'jmTethyl- -4-(%4-fluorophenyl)--2,3-dihydro-4H-l,4-benzoxaz-ne; and (+2L4(-r 'urmty-hnl--yrx-iei4n1yl -methyl-4-.phenyl-2 ,3-dihydro-4H-1l,4-benzoxazi.ne.

WO 89/07596 PCT/EP89/00130 34 Example 7 Tablets, each weighing 150 mg and containing 50 mg of the active substance can be manufactured as follows: Composition (for 10,000 tablets) 2-(-phenyl-1,3,8-triazaspiroj ,57decan-4-one-8-y)methyl-4-phenyl-2,3-dihyro-4H-1 ,4-benzoxazine 500 g Lactose 710 g Corn starch 237.5 g Talc powder 37.5 g Magnesium stearate 15 g 2-(1-phenyl-1,3,8-triazaspiroZ ,5_7decan-4-one-8-yl)-methyl-4phenyl-2,3-dihydro-4H-1,4-benzoxazine, lactose and a half of the corn starch are mixed; the mixture is then forced through a sieve of 0.5 mm openings. Corn starch (18 g) is suspended in warm water (180 ml).

The resulting paste is used to granulate the powder. The granules are dried, comminuted on a sieve of sieve size 1.4 mm, then the remaining quantity of starch, talc and magnesium stearate is added, carefully mixed, and processed into tablets using punches of 8 mm diameter.

i

Claims (8)

1. A compound having the following formula (I) R (I) Son 090 X represents or oO oo R0 0 6 0 0 each of R and R 1 independently, is hydrogen, halogen, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, amino, nitro or trihalo -C 1 -C 6 alkyl; 00*° each of R 2 and R3, independently, is hydrogen, C1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or phenyl -C 1 -C 6 alkyl; or R 2 04 4 S"o 10 and R 3 taken together with the nitrogen atom to which they 0 are linked, form a 6-membered, saturated, heteromonocyclic Sring optionally containing a further heteroatom chosen from oxygen, sulphur and nitrogen, the heteromonocyclic ring being unsubstituted or substituted at one or two carbon atoms by one or two substituents independently chosen from the group including: hydroxy and C 1 -C 6 alkyl; phenyl unsubstituted or substituted by one to three substituents independently chosen from hydroxy, halogen, T Q, T 1 C 1 -C 6 alkyl, C 1 -C 6 alkoxy and trifluoro-methyl;

2-keto-l-benzoimidaxolinyl; and l-phenyl-4-keto-5-imidazolidilyl, so as to provide a l-phenyl-l, 3, 8-triazaspiro[4, 5 decal-4 -one condensed ring system, I h in whc h hnlrn sususiue rsbtttdb one totresbttet hsnidpnetyfrmhdoy hydrgen haoentoCmn rtrhl-,-6ak n inwhthe phcuiclyrn isetal nsasttterofusittdb ato at th oton of the mda(o),din cring to be ai 1, wherein X represents or .1 i- WO 89/07596 PCT/EP89/00130 36 each of R and R independently, is hydrogen, halogen, hydroxy, amino, C 1 -C 4 alkyl, C -C 4 alkoxy, trifluoromethyl or nitro; each of R and R independently, is hydrogen or C-C alkyl, or R, and R, 3 taken together with the nitrogen atom t- which they are linked, form a heteromonocyclic ring chosa from unsubstituted morpholine; piperazine unsubstituted or substituted by pyridyl, pyrazinyl or by phenyl, the phenyl group being unsubstituted or substituted by one or two substituents independently chosen from halogen, trifluoromethyl, C -C 4 alkyl and C-C 4 al.koxy; and co) piperidine unsubstituted or substituted by one or two substituents chosen independently from hydroxy, 2-keto-1-benzoimidazolinyl, 1-phenyl-4-keto-5-imidazolidinyl and phenyl unsubstituted or substituted by one or two substituents chosen from halogen and trifluoromethyl; R 4 is hydrogen; R is hydrogen, halogen or trifluoroomethyl; and the pharmaceutically acceptable salts thereof. WO 89/07596 PCT/EP89/00130 37

3. A comp ind of formula according to claim 1, wherein X represents each of R and R1, independently, is hydrogen, halogen or tri- flucromethyl; R 2 and R 3 taken together with the nitrogen aton to which they are linked, form a piperidine ring unsubstituted or substituted by one or two substituents chosen from hydroxy, 2-keto-l-benzoimidazolinyl, nyl and phenyl unsubstituted or substituted by one or two substituents chosen from halogen and trifluoromethyl; or a piperazine ring unsubstituted or substituted by un- substituted pyridyl or by phenyl unsubstituted or substitu- ted by one or two substituents chosen independently from halogen and C -C4 alkoxy; R 4 is hydrogen; R is hydrogen, halogen or trifluoromethyl, and the pharmaceuti- cally acceptable salts thereof, WO 89/07596 WO 8907596PCT[EP89/00130 -38 4 A compound of formula according to claim 1, selected from the group consisting of: 2-r4-(4-f luorophenyl )-4-hydroxy-piperidin-1-yll -me thy -4- -phenyl-2 ,3-dihydro-4H-1, 4-benz xazine; 2- r4-(2 -me thoxyphenyl) -pipe razin-l-y13 -me thy I-4-phenyl-2,3- -dihydro-4H-1 ,4-benzoxazine; (1-phenyl-1 8-triazaspi no decan-4-one-8-yl -me thyl -4- -phenyl-2,3-dihydro-4H-1 ,4-benzoxazine; 2- (1-phenyl-1, 3,8-triazaspio 5]decon-4-one-8-yl )-methyl- -4-phenyl-7-f luoro-2 3-dihydno-4H--l 4-benzoxazine; 2- -phenyl-l,3, 6-triazaspirno 4, 5]decan-4-one-8--yl)-methyl- -4-(4-f'luorophenyl)-2, 3-dihydro-4H-1, 4--benzoXazine; I-phenyl-1 3, 8.triazaspiro 5]decan-4-one-8-yl )-methyl- uoaphenyl) -7-f luoro-2 3-dihydro-4H-1 ,4-benzoxazine; 2- [4.(3-trif luoromethyl-phenyl )-4-hydroy-piperidin-1 -yll> -methyl-4-Phenyl-2, 3-dihydo-4H-1 4-benzoxazine; (3-trif luQromethyl-phenyl)-4-hydroxy-piperidin-l-ylI -rethyl-4-(4-f luorophenyl)-2, dihydro-4H-1 ,4-beflzoxazine; 2- E4-(3-trif luoromethyl-phenyl )-4-hydroxy-piperidin-l -yl] -methyl-4-phenyl-7-fluono-2,3-dihydro-4H-1 ,4-benzoxazine; and 2-.L4-(3-tnifluoromethyl-phenyl)-4-hydroxy-piperidin-1-ylJ- -methyl-4-(4- fluonophenyl)'-7-fluoro-2,3-dihydno-4H-1 ,4- -benzoxazine; and the pharmraceutically acceptable salts thereof. A compound of formula on a salt ther-eof, according to claim 1 wherein sai~d compound is in the fonm of a. single enantionen. WO 89/07596 PCT/EP89/00130 39

6. A process for the preparation of a compound of formula or a salt thereof, according to claim 1, the process com- prising reacting a compound of formula (II) R (I) R 1 wherein X, R, R R and R 5 are as defined in claim 1, and Y represents the residue of a reactive ester or halogen, with a compound of formula (III) SR 3 HN (III) wherein 40 R 2 and R 3 are as defined in claim 1, and, if desired, converting a compound of formula into another, compound of formula and/or, if desired, salifying a compound of formula and/or, if desired, obtaining a free compound of formula from a salt thereof, and/or, if desired, separating a mixture of isomers of compounds of formula (I) into the single isomers.

7. A pharmaceutical composition containing a S. suitable carrier and/or diluent and, as an active principle, 10 a compound of formula according to claim 1, or a **pharmaceutically acceptable salt thereof. 0

8. A method for the treatment of psychotic disorders, which method comprises administering to a patent in need of such treatment a compound of general formula or a pharmaceutically acceptable salt thereof, as claimed in claim 1.

9. A method for the treatment of nausea and vomiting, which method comprises administering to a patient in need of such treatment a compound of general formula 9* or a pharmaceutically acceptable salt thereof, as claimed in claim 1. «A/ir^ I I WO 89/07596 PCI'/EP89/00130 4 A compound of formula (V) N x) in which X, R, RitR4and R5are as defined in claim I and Z is a free, salified or esterified carboxy group; wherein said compound is in the form of the or enarnziomer, or a mixture thereof, INTERNATIONAL SEARCH REPORT Internlational Application No PCT/EP 89 /00130 1. CLASSIFICATION OF SUBJECT MATTER (if several classific~tion symools apply, indicate all) According to International Patent Classification or to bothi National Classification and !PC P 4 C 07 D 265/36; 279/16; 471/10; A 61 K 31/535; 31/54; IPC: C 0 D 471/10, 235/00, 221/00)

11. FIELDS SEARCHIED Minimum Documentation Searched 7 Classification system Classification Symbols IC4 C 07-D 265/00; C 07 D 279/00; C 07 D 471/00; A 61 K31/00 Documentation Searched other than Minimum Documentation to the Eitent that such Documents are Included In the Fieids SearchedI 111, DOCUMENTS CONSIDERED TO 31 RELEVANT' Category Citation of Documnent, it with Indication, where sptoorlate. of the relevanrt passagest U Relievant to Claim No. i A GB, A, 2080791 (FARMITAt 1 IA CARLO ERBA) 1,16-9 February 1982 see claims A EP, A, 0204148 (HOECHST) 1,6-9 I 10 December 1986 I see claims A IEP, A, 0233728 (TAKEDA) 1,6-9 26 August 1987 see claims Special categories of cited documental is ir document Published sttar the international filing date document deorning th. general state of the an which is not or priority date and not in conflict with irhe application but consoerd t beof ar-tculr rlevnceCited to understand the Principle or theory underlying the consdere tobe o paticuar elevnceInvention earlier document but. Published on or ahfte the International IX document of particular relevance, the Claimed invention rili ng date cannot be considered novel of Cannot be considered to document which may tif-row doubts on Priority claimlal or Involve an inventive stop wnich is cied to silt4d(tsth Ine publication date of another document of particular relevaincet' the claimed invention Citation or otner spedial, reason (as specified) cannot be considered to Involve an inventive ase when the "0D" document referring to an oral dieclosufse use, exhibltion or document is comoinedl with one or more other suchn docu- other means menta, such comoinaion being obyrousl to a person skilled document Published prior to the International fi'ling date but In the art, later then the priority dale claimed document member of the same patent family IV. CERTIFICATION Date of the Actual Complation of the International Search Date of Miling of this International Search Report April 1989 2 5. 05. 89 International Searching Authority Stgnatre of Authoried 0'e EUROPEAN PATE:NT OFFICE M. VAN M~OL Form PCT/ISA1210 (second seet) (January 1015) ANNEX TO THE INTERNATIONAL SEARCH REPORT ON INTERNATIONAL PATENT APPLICATION NO. EP 8900130 SA 26833 This annex lists the patent family members relating to the patent documents cited in the above-mentioned international search report. The members are as contained in the European Patent Office EDP file on 19/05/89 The European Patent Office is in no way liable for these particulars which are merely given for the purpose of information. Patent document Publication Patent family Publication cited in search report date member(s) date GB-A- 2080791 10-02-82 BE-A- 889287 18-12-81 EP-A- 0204148 10-12-86 JP-A- 61254576 12-11-86 GB-A- 2174705 12-11-86 EP-A- 0233728 26-08-87 AU-A- 6853187 13-08-87 JP-A- 63045270 26-02-88 US-A- 4789675 06-12-88 For more details about this annex see Official Journal of the European Patent Office, No. 12/82 L I 1 I i