2-(3-or 4-substd.)phenyl-tetrahydro-1,4-oxazines - active on central nervous system as analgesics, anti-aggression agents etc.

The present invention provides novel 2-phenyl tetrahydro 1, 4-oxazines substituted, as well as their use as CNS drug.

The novel compounds of the invention have the general formula I

(I)

in which is, in the meta or para position, a halogen atom, in particular fluorine or chlorine, or a radical-CP ^, and R represents a hydrogen atom, or a radical Isopropyl or propargyl, (i.e. 2-propynyl).

At main patent has been described a method for the synthesis of tetrahydro 1, 4-oxazines 2, 4-disubstituted and certain 2-(3-trifluoromethyl) phenyl tetrahydro 1, 4-substituted 4-oxazines obtained by this method. The remind that this method basically comprises operating the three successive reaction stages below:

(1) addition reaction bromine on tin ether vinylIque / 3 -halogenated of formula (II)

X- CHg - CHg CH = CH-0-₂ (II)

wherein X represents halogen, preferably chlorine, which leads to a compound of formula (III)

X-^-CILs Cï , -0-- CHg -Br (III)

\^Br

(2) condensation of the compound of formula (III) with a compound bodies-no-magnesium of formula (IV)

(IV) X, ---Y

wherein represents a halogen or a group-CF ^, in position

para, the quj

raéta ^ or para, which leads to a compound of formula (V)

(3) condensation of the compound of the formula (V) with a primary amine of the formula R- NHg , wherein R is a hydrocarbon radical any, preferably, in this case, an alkyl radical or alkynyl, yields the desired compound of formula (ΐ) ·

Alternatively, in the case where it is desired to obtain a compound of formula (I) with R =. H, is substituted in step (5) of the method the step (5 *} according to:

(5') condensation of the compound of formula (V) with a primary amine of the formula R- NHg where R is the benzyl radical and removing the benzyl substituent of the 2-(3-substituted) 4-phenyl benzyl tetrahydro 1, 4-oxazine thus obtained, by catalytic hydrogenation of that compound, as described in the 1st addition certificate to patent no. 95,182 prhcipal.

The catalytic hydrogenation reaction takes place easy-

member at room temperature in an aqueous alcoholic medium, and in

2

a hydrogen pressure of the order of a few kg/cm, the catalyst can be, for example, activated carbon at 5 % palladium.

The present invention relates to new applications of the above method to obtain novel compounds having the formula (I) above, and as such the novel compounds below:

the 2-(4-chloro) phenyl tetrahydro 1, 4-oxazine,

the 2-(4-fluoro) phenyl 4-isopropyl tetrahydro 1, 4-oxazine,

the 2-(4-fluoro) phenyl tetrahydro 1, 4-oxazine,

the 2-(4-fluoro) phenyl 4-methyl tetrahydro 1, 4-oxazine,

the 2-(3-chloro) phenyl 4-isopropyl tetrahydro 1, 4-oxazine,

the 2-(5-trifluoromethyl) phenyl 4-n-propynyl tetrahydro 1, 4-oxazine, the 2-(5-fluoro) phenyl 4-isopropyl tetrahydro 1, 4-oxazine,

the 2-(5-fluoro) phenyl tetrahydro 1.4 oxazine,

the 2-(5-trifluoromethyl) phenyl 4-isopropyl tetrahydro 1, 4-oxazine, the 2-(5-trifluoromethyl) phenyl tetrahydro 1, 4-oxazine, and

the 2-(3-chloro) phenyl tetrahydro 1, 4-oxazine.

The compounds of the present invention are useful as medicaments of the central nervous system; they are now shown to possess analgesic activities, anti-aggressive, protective morphine abstinence syndrome, and activities and noanaleptique anticonvulsant for some of them. They little._J , in human therapy,

^ be administered ' for example orally or parenterally, in an amount of 2 to 100 mg per day depending upon the route of administration in association with the vehicles and conventional pharmaceutically acceptable excipients.

The invention is illustrated in more detail in the examples below, which do not limit:

EXAMPLE 1

2-(3-fluoro) phenyl 4-isopropyl tetrahydro 1, 4-oxazine.

(l) and (2) Preparation of 2-(3-fluoro) phenyl 2-(2-chloro) ethoxy-bromo 1 ethane

Prepared under normal conditions for the magnesium bromide 3-fluoro phenyl magnesium, from 12 g magnesium turnings, 300 ml of ether and 88 g of 3-fluoro bromobenzene.

At reagent thus obtained, is added, stirring and maintaining a small reflux temperature of the solvent, the following solution:

1.2 dibromo-2-(2- ehloro) ethane g^133 ethoxy

150 ml anhydrous ethyl-Ether A compound (1) prepared as indicated in the first stage of the main patent.

At the end of the addition, is brought to reflux, is cooled and

is hydrolyzed by a mixture:

Glace crushed 125 g

. 50 ml concentrated HCl.

It has settled the organic phase and washed with water saturated with NaCl.

It has expelled from solvent under vacuum and has rectified the residue. This produced 97 g of 2-(3-fluoro) phenyl 2-(2-chloro) ethoxy-bromo 1 ethane (Eq ^ = 95*0 ; n ^ = 1.5322®).

28.15 It has heated g (0.1 M) of the former at 100 °C isopropylamine with 20 g in 100 ml of benzene during 6 hours.

After filtration, solvent is expelled from vacuum and the residue is taken up by HCl N 4. After being washed the aqueous phase to the ether, is released the base by addition of a solution of Na OH to 50 %.

Are extracted ether, is dried on Na SO ^ ^ anhydrous, after expelling the solvent and is vacuum stripped, to obtain 16 g of the title product (E_Q ^ _ gjnl ' C ; = 1.5072)

The product is reference in the following as "A compound no. 7" •

EXAMPLE 2

2-(3-chloro) phenyl tetrahydro 1, 4-oxazine.

(1), (2) and (^). It has heated at reflux under stirring for 6 hours 59.6 g of 2-(5-chloro) phenyl 2-(2-chloro) ethoxy-bromo 1 ethane (obtained as described in the example 1 for the compound 3-fluoro-phee™ corresponding phenyl), 65 g benzylamine and 160 ml of xylene.

After the completion of the reaction, the product and ^ is whitish or purified, as indicated in the example.

This produced^5 g of 2-(3~chloro) phenyl 4-benzyl tetrahydro 1, 4-oxazine (E_q ^ = l65*C; n ^ = 1.5748 °).

It has dissolved 30 g thereof, in the form of its hydrochloride, in 80 ml ethanol 96° and 20 ml of water. This solution is subjected to catalytic hydrogenation in the presence of 3 g of active carbon to 5 % dgfcialladium. It has operated at room temperature and a hydrogen pressure of about 0.7 kg/cm * '. When the reaction was completed, solvent is expelled from vacuum is extracted and purified and the product, as indicated in the example 1,

This produced 16 g of the product of the title (E_n o ∩ -109- V

110 °C; n^ = 1.5590). Hydrochloride had a melting point of 165 °C.

The product is reference in the following as "A compound no. 11".

EXAMPLES 3 TO 11

Incorporating under conditions analogous to those described in the example 1 respectively, for R = alkyl or alkynyl ^ and in the example 2 for R = H, it has been possible to obtain other compounds of formula I, and particularly those in which the characteristics are given in the table I below, under the respective references 1 to 6 and 8 to 10.

The activity of the compounds desur the central nervous system has been established to lades following pharmacological tests, performed in mice. tests are specified in reference to which the authors ontpour the first time.

The results sontdans Table II following the description of these tests.

It was examined at moyencouloir circular beams Infrarougesde scanned by measuring the number of movements of the animals. The ED 50la oral dosage TABLE I

C0MP0y_R F, °C Assays

SE № Chlorhydra 1- % H % N %

the calculated (1ère line) found (2ème line)

expressed in mg/kg which decreases from 50 % the number of the movements of the animals vaccinated with respect to those of the control animals.

PUTNAM MEERITT T.J. and H. H., Science E £, 525-26 (1937)

The products of the invention have been administered orally one hour before the supramaximal electroshock (50 tnA , 40 c/s, 10 ms during 2 s) produced by electrodes ooméennes to sets of mouse 10.

The ED 50 represents, in mg/kg, the dose of product of the invention which protects 50 % of animals of the tonic extension.

TEDESHI E.G., TEDESHI D. H., MUCH A., COOK l., P. J. Pharm MATTIS and Fellows. Exptl. Therap. 125 . 28-34 (1959)

The products have been administered P.0. to sets of 8 male mouse, reproductive old.

The ED 50 expresses, in mg/kg, the dose of product which decreases 50 % the score of treated animals relative to the control animals.

JANSSEN Ρ ., C. NIEMEGEERS , JAGENEAU A., Arzneim. Forsch. 10, 1003-1005, I960.

Apomorphine has been administered between 0.6 mg/kg intravenously to the batches of 6 male OFA rats of 14-0 to l60 g.

The ED 50 expresses, in mg/kg intraperitoneally, the dose of product according to the invention that decreases 50 % the score of treated animals relative to the control animals.

SEALENS J. K., GRANAT and SAWYER F. W. K.-Arch Int. Pharmacodyn.

190 213-218 (ΐ97ΐ).

The product according to the invention has étqâdministré orally 1 hour before the injection of Naloxone.

The ED 50 represents the dose, in mg/kg orally, of the product according to 1¹ which decreases 50 invention % batch of hops with respect to the control.

In case this value has not been determined, the first digit indicates the dose and the second the percentage of change corresponding.

The testést performed according to the protocol of:

G. MACDONALD WOLFE and A.D.-J. Pharmacol. Exp. Thr. 8 0, 500-307 (1944) L ' ED 50 expresses, in mg/kg orally, the dose of product of the invention that decreases 50 % the number of painful crises ehez treated animals, relative to the control animals.

The testing is carried out according to the protocol of:

KOSTER R.; and ANDERSON m. DE BEER E. J.-Fed. Proc. 18, 412 (1959)

The ED 50 has the same meaning as in the test of the heating plate.

The testing is carried out according to the protocol of:

SIEGMUND E_v R. CAMUS and GOLU -Proc. coulter. Exp. Biol. Med ., 729-751, (1957).

The ED 50 expresses the dose, in mg/kg orally, of the product according to the invention that decreases 50 % the amount of displacement.

The testing is carried out according to the protocol of:

RUBIN Β ., MALONE Μ. Η ., WAUGH Μ. Η ., and J. C.-J. Phaem BURKE. Exp.

Thr. 120 125-156 (ΐ957)

Reserpine The has been administered intraperitoneally at the dose of 1 mg/kg, and the product to be tested has been administered orally 2 hours before the reserpine.

The ED 50 represents the dose, in mg/kg orally, of the product according to the invention that decreases the ptotic in 50 % treated animals relative to the control animals.

In case this value has not been determined, the first digit indicates the dose and the second the percentage of change corresponding.

The table II indicates the values of the previous tests ED 50 and further comprises DL 50 performed in mice, orally, and calculated according to the method of and BEHRENS KAKBER -Arch. Exp. Path. Pharm. 177 , 579-(1955).

These results show for the compounds of the invention a complex pharmacological spectrum, translating their action on the central nervous system and yet non-superimposable over antipsychotics known in the day.

These results in particular exit for most of the compounds described an analgesic effect, the 50 ED^{to the} acetic lkcide and tests of the sometimes being phénylqulnone TABLE II

COMPOUND

EssaaaBasBssaasaBssassBs :

iS^{téré °} ' ' ! Plate^A * LEVEL I?^e !^Ph ?^phenyl acute

590 T

!

i

!

,_Q ! J Idle to⁷⁸ 400! ,' apomorpbj test!

.1

!

68

! 40 ; 198 7 +.!

!

acetic! quinone

i

50

i

23

<10 Ptosis réaerpinique

52

700

>00

174!

LEVEL I

Idle to I

400

!

!

Idle

TO 40

!!! 40 + ; 26, 7,7 Idle.!

l

i

Idle! Idle

!

80 ;-76,7.

26

600

90

A 200 Idle

!!!

.! > 80! 40 ; +7.57 Idle.!

!!!

46

160

Idle

400

! >80

i

! 40 ;.! + 3.57 Skipped! Skipped! <10

■160!!

310! 50! <200

100

10

45

" 50! " 50

80 ;-23,7.

1000! 73

170

67

20

22

58

400

125

150

! >60! 40 ; +5%

56

<10

160 ;-19,7.

378

54

To 200 jInactif Idle

! TO 80

40

46

< 10

<10

80 ; - 4 7.

.10 U

>00 f

y oo

>2oo

330 jInactif

; TO 80

! 40 ;-33.3 7.

100

143

/ '! 72

127

265 Idle

TO 80

àQ

74

65

<20

14

8,5

" Io

30 very low, and anti-aggressive at doses not causing drive marked depression.

On a model of physical dependence to morphine ("Mouse jumping test"), hs compounds have various actions, most active as n* 6 antagonist is the compound, whereas compound no. 1 would cause of the emphasis of the abstinence syndrome-it appears no obvious relationship between this activity and analgesic activity.

These compounds are thus useful in therapy for their analgesic activities, anti-aggressive, protective morphine abstinence syndrome, and for certain antieonvulsivante noanaleptique of had. The products, associated with the conventional pharmaceutical additives, can be administered, in particular to humans, at daily doses varying between 2 and 100 mg according to the administration routes.