2-(piperidinylmethyl)-4-phenyl-2,3-dihydro-4H-1,4-benzoxazines useful as antipsychotics

The present invention relates to compounds having the following formula (I) ##STR1## wherein X represents --O-- or --S--; PA0 each of R and R.sub.1, independently, is hydrogen, halogen, hydroxy, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, amino, nitro or trihalo-C.sub.1 -C.sub.6 alkyl; PA0 each of R.sub.2 and R.sub.3, independently, is hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl or phenyl-C.sub.1 -C.sub.6 alkyl; or R.sub.2 and R.sub.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; PA0 each of R.sub.4 and R.sub.5, independently, is hydrogen, halogen, nitro, amino or trihalo-C.sub.1 -C.sub.6 alkyl; and the pharmaceutically acceptable salts thereof. The compounds of the invention are useful in therapy as major tranquilizers e.g., in the management of psychotic disorders.

DESCRIPTION 
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 management 
of psychotic disorders, act mainly on the dopaminergic pathways as 
dopamine antagonists. This pharmacological activity 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schizophrenia, such as apathy and withdrawn social behaviour, and 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) 
##STR2## 
wherein X represents --O-- or --S--; 
each of R and R.sub.1, independently, is hydrogen, halogen, hydroxy, 
C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, amino, nitro or 
trihalo-C.sub.1 -C.sub.6 alkyl; 
each of R.sub.2 and R.sub.3, independently, is hydrogen, C.sub.1 -C.sub.6 
alkyl, C.sub.2 -C.sub.6 alkenyl, C.sub.2 -C.sub.6 alkynyl or 
phenyl-C.sub.1 -C.sub.6 alkyl; or R.sub.2 and R.sub.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.sub.4 and R.sub.5, independently, is hydrogen, halogen, nitro, 
amino or trihalo-C.sub.1 -C.sub.6 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 
(I). 
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 C.sub.1 -C.sub.6 alkyl group is preferably a C.sub.1 
-C.sub.4 alkyl group, e.g. methyl, ethyl, propyl, isopropyl, butyl, sec. 
butyl or tert. butyl, more preferably it is methyl or ethyl. A C.sub.2 
-C.sub.6 alkenyl group is preferably a C.sub.2 -C.sub.4 alkenyl group, in 
particular allyl. A C.sub.2 -C.sub.6 alkynyl group is preferably a C.sub.2 
-C.sub.4 alkynyl group, in particular propargyl. 
A phenyl-C.sub.1 -C.sub.6 alkyl group is preferably a phenyl-C.sub.1 
-C.sub.4 alkyl, in particular benzyl or phenethyl. 
A C.sub.1 -C.sub.6 alkoxy group is preferably a C.sub.1 -C.sub.4 alkoxy 
group, e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy or tert.butoxy, 
more preferably it is methoxy or ethoxy. 
A trihalo-C.sub.1 -C.sub.6 alkyl group is preferably a trihalo-C.sub.1 
-C.sub.4 alkyl group, e.g. trichloro-C.sub.1 -C.sub.4 alkyl or 
trifluoro-C.sub.1 -C.sub.4 alkyl, more preferably it is trifluoromethyl. 
When R.sub.2 and R.sub.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, which may be unsubstituted or substituted at 
one or two carbon atoms by one or two substituents independently chosen 
from the group including: 
a) hydroxy and C.sub.1 -C.sub.6 alkyl; 
b) phenyl unsubstituted or substituted by one to three substituents 
independently chosen from hydroxy, halogen, C.sub.1 -C.sub.6 alkyl, 
C.sub.1 -C.sub.6 alkoxy and trifluoro-methyl; 
c) 2-keto-1-benzoimidazolinyl; and 
d) 1-phenyl-4-keto-5-imidazolidinyl, so as to provide e.g. a 
1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one condensed ring system, i.e. 
##STR3## 
in which the phenyl ring is unsubstituted or substituted by one to three 
substituents chosen independently from hydroxy, halogen, C.sub.1 -C.sub.6 
alkyl and trifluoromethyl, and the nitrogen atom at the 1-position of the 
imidazolidine ring may be unsubstituted or substituted by C.sub.1 -C.sub.6 
alkyl, phenyl or by phenyl-C.sub.1 -C.sub.6 alkyl. 
When R.sub.2 and R.sub.3, 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.sub.1 -C.sub.6 alkyl, pyridyl and pyrazinyl or by phenyl 
unsubstituted or substituted by one to three substituents chosen from 
hydroxy, halogen, C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy and 
trifluoromethyl. 
When R.sub.2 and R.sub.3, 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: 
a') unsubstituted morpholine; 
b') piperazine unsubstituted or substituted by pyridyl, pyrazinyl or by 
phenyl unsubstituted or substituted by one or two substituents 
independently chosen from halogen, trifluoromethyl, C.sub.1 -C.sub.4 alkyl 
and C.sub.1 -C.sub.4 alkoxy; and 
c') piperidine unsubstituted or substituted by one or two substituents 
chosen independently from hydroxy, 2-keto-1-benzoimidazolinyl and phenyl 
unsubstituted or substituted by halogen; or the piperidine ring may be 
substituted by 1-phenyl-4-keto-5-imidazolindinyl. 
The pharmaceutically acceptable salts of the compounds of formula (I) 
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), i.e. compounds which have a different 
formula to formula (I) above, but which nevertheless upon administration 
to a human being are converted directly or indirectly in vivo into a 
compound of formula (I). 
Preferred compounds of the invention are the compounds of formula (I), 
wherein 
X represents --O-- or --S--; 
each of R and R.sub.1, independently, is hydrogen, halogen, hydroxy, amino, 
C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, trifluoromethyl or nitro; 
each of R.sub.2 and R.sub.3, independently, is hydrogen or C.sub.1 -C.sub.4 
alkyl, or R.sub.2 and R.sub.3, taken together with the nitrogen atom to 
which they are linked, form a heteromonocyclic ring chosen from 
a") unsubstituted morpholine; 
b") 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.sub.1 
-C.sub.4 alkyl and C.sub.1 -C.sub.4 alkoxy; and 
c") 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.sub.4 is hydrogen; 
R.sub.5 is hydrogen, halogen or trifluoromethyl; and the pharmaceutically 
acceptable salts thereof. 
More preferred compounds of the invention are the compounds of formula (I), 
wherein 
X represents --O--; 
each of R and R.sub.1, independently, is hydrogen, halogen or 
tri-fluoromethyl; 
R.sub.2 and R.sub.3, taken together with the nitrogen atom to which they 
are linked, form a'") a piperidine ring unsubstituted or substituted by 
one or two substituents chosen 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; or 
b'") 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.sub.1 -C.sub.4 
alkoxy; 
R.sub.4 is hydrogen; 
R.sub.5 is hydrogen, halogen or trifluoromethyl, and the pharmaceutically 
acceptable salts thereof. 
Examples of particularly preferred compounds of the invention are the 
following: 
2-[4-(4-fluorophenyl)-4-hydroxy-piperidin-1-yl]-methyl-4-phenyl-2,3-dihydro 
-4H-1,4-benzoxazine; 
2-[4-(2-methoxyphenyl)-piperazin-1-yl]-methyl-4-phenyl-2,3-dihydro-4H-1,4-b 
enzoxazine; 
2-(1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one-8-yl)-methyl-4-phenyl-2,3-dih 
ydro-4H-1,4-benzoxazine; 
2-(1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one-8-yl)-methyl-4-phenyl-7-fluor 
o-2,3-dihydro-4H-1,4-benzoxazine; 
2-(1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one-8-yl)-methyl-4-(4-fluoropheny 
l)-2,3-dihydro-4H-1,4-benzoxazine; 
2-(1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one-8-yl)-methyl-4-(4-fluoropheny 
l)-7-fluoro-2,3-dihydro-4H-1,4-benzoxazine; 
2-[4-(3-trifluoromethyl-phenyl)-4-hydroxy-piperidin-1-yl]-methyl-4-phenyl-2 
,3-dihydro-4H-1,4-benzoxazine; 
2-[4-(3-trifluoromethyl-phenyl)-4-hydroxy-piperidin-1-yl]-methyl-4-(4-fluor 
ophenyl)-2,3-dihydro-4H-1,4-benzoxazine; 
2-[4-(3-trifluoromethyl-phenyl)-4-hydroxy-piperidin-1-yl]-methyl-4-phenyl-7 
-fluoro-2,3-dihydro-4H-1,4-benzoxazine; and 
2-[4-(3-trifluoromethyl-phenyl)-4-hydroxy-piperidin-1-yl]-methyl-4-(4-fluor 
ophenyl)-7-fluoro-2,3-dihydro-4H-1,4-benzoxazine; in particular in the form 
of single enantiomers, and the pharmaceutically acceptable salts thereof. 
The compounds of the invention and the salts thereof can be prepared by a 
process comprising reacting a compound of formula (II) 
##STR4## 
wherein X, R, R.sub.1, R.sub.4 and R.sub.5 are as defined above and Y 
represents the residue of a reactive ester or halogen, with a compound of 
formula (III) 
##STR5## 
wherein R.sub.2 and R.sub.3 are as defined above, and, if desired, 
converting a compound of formula (I) into another compound of formula (I), 
and/or, if desired, salifying a compound of formula (I), and/or, if 
desired, obtaining a free compound of formula (I) from a salt thereof, 
and/or, if desired, separating a mixture of isomers of compounds of 
formula (I) into the single isomers. 
When Y is the residue of a reactive ester, it is preferably a sulphonate 
group, more preferably -O-mesyl or -O-tosyl. When Y is halogen, it is 
preferably chlorine or bromine. 
The reaction between a compound 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 20.degree. C. to the 
reflux temperature of the solvent used, with reaction times generally from 
about 1 hour to about 10 hours. 
Alternatively to the inorganic base, an excess of the amine of formula 
(III) involved in the reaction may be added. 
A compound of formula (I) may be converted, as stated above, into another 
compound of formula (I) 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, Na.sub.2 CO.sub.3, K.sub.2 CO.sub.3, 
NaH, NaNH.sub.2, sodium methoxide or sodium ethoxide in a solvent selected 
from the group consisting, for example, of methanol, ethanol, dioxane, 
acetone, dimethylformamide, hexamethylphosphorotriamide, tetrahydrofuran, 
water and their mixtures at a temperature ranging preferably between about 
0.degree. C. and about 150.degree. C. 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 AlCl.sub.3 or BBr.sub.3 or with an 
alkaline salt of a thiol. 
Also the optional salification of a compound of formula (I) 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 may be carried out, 
for example, by fractional crystallization or by separation on column 
chromatography. 
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 -O-mesyl or -O-tosyl group, may be prepared for example by 
reacting a compound of formula (IV) 
##STR6## 
wherein X, R, R.sub.1, R.sub.4 and R.sub.5 are as defined above, with a 
suitable acyl, preferably sulphonyl, halide, preferably 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.degree. C. to 
about 20.degree. C. 
The compounds of formula (II) wherein Y represents halogen may be obtained 
for example from a compound of formula (IV), as defined above, through 
known methods, e.g. by treatment with SOCl.sub.2 by conventional methods 
of organic chemistry, optionally in the presence of a suitable catalyst, 
for example ZnCl.sub.2, or by treatment with SOCl.sub.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) 
##STR7## 
wherein, X, R, R.sub.1, R.sub.4 and R.sub.5 are as defined above and Z 
represents a free, salified or esterified carboxy group. 
When, in a compound of formula (V), 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 (V), Z is an esterified carboxy group, the 
ester may be, for example, an alkyl ester; preferably it is a C.sub.1 
-C.sub.6 alkoxycarbonyl group, in particular methoxy- or ethoxy-carbonyl. 
The reduction of a compound of formula (V), wherein Z is esterified 
carboxyl, to give a compound of formula (IV), may, for example, be 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 0.degree. C. to the solvent reflux temperature, 
for reaction times ranging approximately between 30 minutes and 24 hours. 
The reduction of a compound of formula (V) wherein Z represents a free 
carboxyl group, to give a compound of formula (IV), 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.degree. C. to the solvent reflux temperature, for 
reaction times ranging approximately between 30 minutes and 12 hours. 
The reduction of a compound of formula (V) wherein Z represents a salified 
carboxy group, to give a compound of formula (IV), is preferably carried 
out in conditions analogous to those employed in the reduction of a 
compound of formula (V) wherein Z is a free carboxy group. 
The compounds of formula (V) wherein Z is an esterified carboxy group may 
be obtained through N-arylation of a compound of formula (VI) 
##STR8## 
wherein X, R and R.sub.1 are as defined above and Z' is an esterified 
carboxy group as defined above for Z. N-arylation of a compound of formula 
(VI) may be carried out by treatment with a phenyl derivative of formula 
(VII) 
##STR9## 
wherein R.sub.4 and R.sub.5 are as defined above and E is preferably a 
halogen atom, e.g. bromine or iodine, at a temperature ranging from about 
50.degree. C. to about 260.degree. C., in the presence of copper or a 
suitable salt thereof e.g. CuI or CuBr and, if required, in a pressure 
vessel. 
When a compound of formula (V) is required, wherein R.sub.4 and R.sub.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 toluene, at reflux temperature, with contemporaneous removal of water 
by azeotropic distillation. 
A compound of formula (V), wherein Z is a free or salified carboxy group, 
may be obtained according to known methods from a compound of formula (V), 
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 (I), also the compounds of formula (II), (IV), (V) 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 (I), 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 (II), (IV), (V) or 
(VI), in the form of single optical isomer, as intermediate or starting 
material, respectively, in the process herein described. 
In a preferred embodiment of the process according to the present 
invention, when a compound of formula (I), as single pure optical isomer 
is desired, a pure optical isomer of a compound of formula (V) is used as 
intermediate compound in such process. 
The separation of a mixture of optical isomers of a compound of formula (V) 
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 (I) into the single optical isomers. In particular a 
compound of formula (V), 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) 
##STR10## 
wherein X, R, R.sub.1, R.sub.4, R.sub.5 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 therapy e.g. in the management of 
psychotic disorders and manic-depressive 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 cataleptoenic 
activity, and of their potent activity in inhibiting the serotonin 
5HT.sub.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.sub.1 and D.sub.2 dopamine, 5HT.sub.1 and 5HT.sub.2 serotonine and 
.alpha..sub.1 and .alpha..sub.2 nor-adrenaline receptors, obtained 
according to well known procedures [Creese, 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, 461] 
TABLE 1 
__________________________________________________________________________ 
IC.sub.50 .mu.M 
D.sub.1 
D.sub.2 
5HT.sub.1 
5HT.sub.2 
.alpha..sub.1 
.alpha..sub.2 
Compound 
[3.sub.H ]cisFlu. 
[3.sub.H ]Spip. 
[3.sub.H ]Serot. 
[3.sub.H ]Ket. 
[3.sub.H ]Praz. 
[3.sub.H ]Yohlm. 
__________________________________________________________________________ 
FCE 25456 
&gt;10 0.001 
&gt;10 0.1 0.4 &gt;10 
FCE 24867 
1.4 0.008 
&gt;10 0.04 0.1 1.7 
FCE 25895 
1.2 0.005 
&gt;10 0.006 
0.08 0.8 
FCE 25896 
&gt;10 0.2 &gt;10 0.08 0.3 2.9 
FCE 25676 
1 0.002 
5.6 0.02 0.02 0.1 
FCE 25848 
2.4 0.04 &gt;10 0.03 0.1 7.2 
FCE 25452 
0.9 0.009 
&gt;10 0.02 0.4 &gt;10 
__________________________________________________________________________ 
In the table cis-Flu. means cis-Flupenthixol; Spip. means Spiperone; Serot. 
means Serotonin; Ket. means Ketanserine; Praz. means Prazosin and Yohim. 
means Yohimbine, respectively. The above internal FCE codes refer to the 
following compounds 
FCE 
25456=2-[4-(3-trifluoromethyl-phenyl)-4-hydroxy-piperidin-1-yl]-methyl-4-p 
henyl-2,3-dihydro-4H-1,4-benzoxazine; 
FCE 
24867=2-(1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one-8-yl)-methyl-4-phenyl- 
2,3-dihydro-4H-1,4-benzoxazine; 
FCE 25895=(+) 
2-(1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one-8-yl)-methyl-4-phenyl-2,3-di 
hydro-4H-1,4-benzoxazine; 
FCE 25896=(-) 
2-(1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one-8-yl)-methyl-4-phenyl-2,3-di 
hydro-4H-1,4-benzoxazine; 
FCE 
25676=2-(1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one-8-yl)-methyl-4-(4-fluo 
rophenyl)-2,3-dihydro-4H-1,4-benzoxazine; 
FCE 
25848=2-(1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one-8-yl)-methyl-4-phenyl- 
7-fluoro-2,3-dihydro-4H-1,4-benzoxazine; 
FCE 
25452=2-(1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one-8-yl)-methyl-4-(4-fluo 
rophenyl)-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.sub.2 dopamine, 
5HT.sub.2 serotonine and .alpha..sub.1 nor-adrenaline receptor binding. 
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 toxicity 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 (LD.sub.50) was assessed 
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. 
TABLE 2 
______________________________________ 
poundCom- 
mg/kg/osED.sub.50Climbing 
mg/kg/osED.sub.50Catalepsy 
##STR11## mg/kg/osLD.sub.50 
______________________________________ 
FCE 2.5 20 8 &gt;800 
25456 
FCE 4.5 30.8 6.8 &gt;800 
24867 
FCE 3.8 61.0 16.0 &gt;800 
25895 
FCE 1.8 22.7 12.6 &gt;800 
25896 
FCE 4.9 75.0 15.3 &gt;800 
25676 
Halo- 0.5 2.2 4.4 71 
peridol 
______________________________________ 
The LD.sub.50 datum for Haloperidol is given according to Il 
FarmacoEd.Sc.1976, 31, 442. 
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 solutions 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 per 
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. 
For example, the solid oral forms may contain, together with the active 
compound, diluents, e.g., 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, alginic 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. syrups, 
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, 
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 mmol) is added to a 
stirred solution of 
2-(methane-sulfonyloxy)-methyl-4-phenyl-2,3-dihydro-4H-1,4-benzoxazine 
(1.76 g; 5.51 mmol) in dimethylformamide (50 ml). The reacting mixture is 
heated at 90.degree. 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 sulphate. Evaporation of the solvent gives 2 g of an oily residue 
which is purified by flash column chromatography on silica gel, by using 
chloroform/methanol/30% ammonium hydroxide=100/2/0.1 as eluant, thus 
obtaining 1.7 g of pure oily product (yield 65%). 
The pure product is taken up in 10 ml of ethyl acetate and treated, at 
0.degree. C., with a gaseous hydrochloric acid saturated ethyl acetate 
solution, so as to obtain 
2-[4-(4-chlorophenyl)-4-hydroxy-piperidin-1-yl]-methyl-4-phenyl-2,3-dihydr 
o-4H-1,4-benzoxazine hydrochloride, as white crystals, m.p. 
252.degree.-255.degree. C. 
By proceeding analogously, the following compounds, as a free base or as a 
salt thereof, can be obtained: 
2-[4-(4-methoxyphenyl)-piperazin-1-yl]-methyl-4-phenyl-2,3-dihydro-4H-1,4-b 
enzoxazine. 2.5 HCl, m.p. 240.degree.-247.degree. C.; 
2-[4-(2-pyrazinyl)-piperazin-1-yl]-methyl-4-phenyl-2,3-dihydro-4H-1,4-benzo 
xazine. 2 HCl, m.p. 255.degree. C. (dec.); 
2-[4-(3-chlorophenyl)-piperazin-1-yl]-methyl-4-phenyl-2,3-dihydro-4H-1,4-be 
nzoxazine. 2 HCl, m.p. 220.degree. C. (dec.); 
2-(N-methylaminomethyl)-4-phenyl-2,3-dihydro-4H-1,4-benzoxazine. HCl, m.p. 
190.degree. C. (dec.); 
2-[4-(2-pyridyl)-piperazin-1-yl]-methyl-4-phenyl-2,3-dihydro-4H-1,4-benzoxa 
zine. 2 HCl, m.p. 120.degree. C. (dec.); 
2-(4-phenyl-piperazin-1-yl)-methyl-4-phenyl-2,3-dihydro-4H-1,4-benzoxazine. 
2 HCl, m.p. 220.degree.-223.degree. C.; 
2-(N-morpholinomethyl)-4-phenyl-2,3-dihydro-4H-1,4-benzoxazine, m.p. 
223.degree.-227.degree. C.; 
2-(N-propylaminomethyl)-4-phenyl-2,3-dihydro-4H-1,4-benzoxazine. HCl, m.p. 
217.degree.-219.degree. C.; 
2-aminomethyl-4-phenyl-2,3-dihydro-4H-1,4-benzoxazine. HCl, m.p. 
253.degree.-257.degree. C.; 
2-[4-(4-chlorophenyl)-4-hydroxy-piperidin-1-yl]-methyl-4-phenyl-7-fluoro-2, 
3-dihydro-4H-1,4-benzoxazine; 
2-[4-(4-chlorophenyl)-4-hydroxy-piperidin-1-yl]-methyl-4-(4-fluorophenyl)-2 
,3-dihydro-4H-1,4-benzoxazine; 
2-[4-(4-chlorophenyl)-4-hydroxy-piperidin-1-yl]-methyl-4-(4-fluorophenyl)-7 
-fluoro-2,3-dihydro-4H-1,4-benzoxazine; 
2-[4-(2-keto-1-benzoimidazolinyl)-piperidin-1-yl]-methyl-4-phenyl-2,3-dihyd 
ro-4H-1,4-benzoxazine. HCl, m.p. 185.degree.-188.degree. C.; 
2-[4-(2-methoxyphenyl)-piperazin-1-yl]-methyl-4-phenyl-2,3-dihydro-4H-1,4-b 
enzoxazine. 2 HCl, m.p. 235.degree.-238.degree. C.; 
2-[4-(2-methoxyphenyl)-piperazin-1-yl]-methyl-4-phenyl-7-fluoro-2,3-dihydro 
-4H-1,4-benzoxazine; 
2-[4-(2-methoxyphenyl)-piperazin-1-yl]-methyl-4-(4-fluorophenyl)-7-fluoro-2 
,3-dihydro-4H-1,4-benzoxazine; 
2-[4-(2-methoxyphenyl)-piperazin-1-yl]-methyl-4-(4-fluorophenyl)-2,3-dihydr 
o-4H-1,4-benzoxazine; 
2-[4-(3-trifluoromethyl-phenyl)-4-hydroxy-piperidin-1-yl]-methyl-4-phenyl-2 
,3-dihydro-4H-1,4-benzoxazine, m.p. 260.degree. C. (dec.), as 
hydrochloride; 
2-[4-(3-trifluoromethyl-phenyl)-4-hydroxy-piperidin-1-yl]-methyl-4-(4-fluor 
ophenyl)-2,3-dihydro-4H-1,4-benzoxazine; 
2-[4-(3-trifluoromethyl-phenyl)-4-hydroxy-piperidin-1-yl]-methyl-4-phenyl-7 
-fluoro-2,3-dihydro-4H-1,4-benzoxazine; and 
2-[4-(3-trifluoromethyl-phenyl)-4-hydroxy-piperidin-1-yl]-methyl-4-(4-fluor 
ophenyl)-7-fluoro-2,3-dihydro-4H-1,4-benzoxazine. 
EXAMPLE 2 
By proceeding according to Example 1 and using suitable acids, the 
following compounds can be obtained: 
2-(N,N-dipropylaminomethyl)-4-phenyl-2,3-dihydro-4H-1,4-benzoxazine 
fumarate, m.p. 109.degree.-113.degree. C.; and 
2-(N,N-dimethylaminomethyl)-4-phenyl-2,3-dihydro-4H-1,4-benzoxazine 
fumarate, m.p. 109.degree. C. (dec.). 
EXAMPLE 3 
1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one (2.03 g; 8.8 mmol) is added to a 
stirred solution of 2-chloromethyl-4-phenyl-2,3-dihydro-4H-1,4-benzoxazine 
(1.29 g; 4 mmol) in dimethylformamide (20 ml). The reacting mixture is 
heated at 90.degree. 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 (30 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 
2-(1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one-8-yl)-methyl-4-phenyl-2,3-di 
hydro-4H-1,4-benzoxazine, yield 37%; m.p. 191.degree.-193.degree. C. 
By proceeding analogously the following compounds can be obtained: 
2-[4-(4-fluorophenyl)-4-hydroxy-piperidin-1-yl]-methyl-4-phenyl-2,3-dihydro 
-4H-1,4-benzoxazine, m.p. 105.degree. C.; 
2-[4-(4-fluorophenyl)-4-hydroxy-piperidin-1-yl]-methyl-4-phenyl-7-fluoro-4H 
-1,4-benzoxazine; 
2-[4-(4-fluorophenyl)-4-hydroxy-piperidin-1-yl]-methyl-4-(4-fluorophenyl)-2 
,3-dihydro-1,4-benzoxazine; 
2-[4-(4-fluorophenyl)-4-hydroxy-piperidin-1-yl]-methyl-4-(4-fluorophenyl)-7 
-fluoro-2,3-dihydro-4H-1,4-benzoxazine; 
2-[4-(2-keto-1-benzoimidazolinyl)-piperidin-1-yl]-methyl-4-phenyl-7-fluoro- 
2,3-dihydro-4H-1,4-benzoxazine; 
2-[4-(2-keto-1-benzoimidazolinyl)-piperidin-1-yl]-methyl-4-(4-fluorophenyl) 
-2,3-dihydro-4H-1,4-benzoxazine; 
2-[4-(2-keto-1-benzoimidazolinyl)-piperidin-1-yl]-methyl-4-(4-fluorophenyl) 
-7-fluoro-2,3-dihydro-4H-1,4-benzoxazine; 
2-[4-(2-methoxyphenyl)-piperazin-1-yl]-methyl-4-(4-fluorophenyl)-2,3-dihydr 
o-4H-1,4-benzoxazine; 
2-(1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one-8-yl)-methyl-4-phenyl-7-fluor 
o-2,3-dihydro-4H-1,4-benzoxazine, m.p. 198.degree.-200.degree. C.; 
2-(1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one-8-yl)-methyl-4-(4-fluoropheny 
l)-2,3-dihydro-4H-1,4-benzoxazine, m.p. 280.degree. C. (dec.), as 
hydrochloride, and 
2-(1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one-8-yl)-methyl-4-(4-fluoropheny 
l)-7-fluoro-2,3-dihydro-4H-1,4-benzoxazine, m.p. 288.degree.-292.degree. 
C., as hydrochloride. 
EXAMPLE 4 
4-(4-fluorophenyl)-4-hydroxy-piperidine (2.78 g, 14.3 mmol) is added to a 
stirred solution of 
2-(methanesulfonyl)-methyl-4-phenyl-2,3-dihydro-4H-1,4-benzothiazine (2.17 
g; 6.5 mmol) in dimethylformamide (60 ml). 
The reacting mixture is heated at 90.degree. 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 hexane/acetone=9/1 as eluant, thus obtaining 1.17 g of pure 
2-[4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl]-methyl-4-phenyl-2,3-dihydro 
-4H-1,4-benzothiazine, yield 41%. 
By proceeding analogously the following compounds can be obtained: 
2-[4-(4-fluorophenyl)-4-hydroxy-piperidin-1-yl]-methyl-4-(4-fluorophenyl)-7 
-fluoro-2,3-dihydro-4H-1,4-benzothiazine; 
2-[4-(2-keto-1-benzoimidazolinyl)-piperidin-1-yl]-methyl-4-phenyl-2,3-dihyd 
ro-4H-1,4-benzothiazine; 
2-[4-(2-keto-1-benzoimidazolinyl)-piperidin-1-yl]-methyl-4-(4-fluorophenyl) 
-7-fluoro-2,3-dihydro-4H-1,4-benzothiazine; 
2-(1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one-8-yl)-methyl-4-phenyl-2,3-dih 
ydro-4H-1,4-benzothiazine; and 
2-(1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one-8-yl)-methyl-4-(4-fluoropheny 
l)-7-fluoro-2,3-dihydro-4H-1,4-benzothiazine. 
EXAMPLE 5 
Resolution of an acid of formula (V) 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 
crystallization from CH.sub.3 CN. 
TABLE I 
______________________________________ 
Crystal- salt ob- 
[.alpha.].sub.D.sup.25 of the 
lization 
m.p. (.degree.C.) 
CH.sub.3 CN(1) 
tained (g) 
salt (methanol) 
______________________________________ 
raw 139-182 -- -- -20.3 
material 
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 
______________________________________ 
The mother liquors of the four-crystallizations are collected together, 
evaporated, taken up with chloroform and washed with 2N HCl. 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 0.5 
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.sub.3 CN (Table II). 
TABLE II 
______________________________________ 
Crystal- salt ob- 
[.alpha.].sub.D.sup.25 of the 
lization 
m.p. (.degree.C.) 
CH.sub.3 CN(1) 
tained (g) 
salt (methanol) 
______________________________________ 
raw 182-7 -- -- +24.1 
material 
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 HCl, according to usual procedures. 
(-) acid [.alpha.].sub.D.sup.25 (methanol)=-49.5 
(+) acid [.alpha.].sub.D.sup.25 (methanol)=+49.4 
EXAMPLE 6 
By proceeding analogously to the procedures described in Examples 1 and 3, 
and using a pure optically active compound of formula (II), the following 
compounds can be obtained: 
(+)2-(1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one-8-yl)-methyl-4-phenyl-2,3- 
dihydro-4H-1,4-benzoxazine, [.alpha.].sub.D.sup.25 =+37.5(CHCl.sub.3); 
(-)2-(1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one-8-yl)-methyl-4-phenyl-2,3- 
dihydro-4H-1,4-benzoxazine, [.alpha.].sub.D.sup.25 =-37.4(CHCl.sub.3); 
(+)2-(1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one-8-yl)-methyl-4-(4-fluoroph 
enyl)-2,3-dihydro-4H-1,4-benzoxazine; 
(-)2-(1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one-8-yl)-methyl-4-(4-fluoroph 
enyl)-2,3-dihydro-4H-1,4-benzoxazine; and 
(+)2-[4-(3-trifluoromethyl-phenyl)-4-hydroxy-piperidin-1-yl]-methyl-4-pheny 
l-2,3-dihydro-4H-1,4-benzoxazine. 
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-(1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one-8-yl)- 
500 g 
methyl-4-phenyl-2,3-dihydro-4H-1,4-benzoxazine 
Lactose 710 g 
Corn starch 237.5 g 
Talc powder 37.5 g 
Magnesium stearate 15 g 
______________________________________ 
2-(1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one-8-yl)-methyl-4-phenyl-2,3-dih 
ydro-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.