CA1189861A - Derivatives of 2-phenyl-morpholine and their use in therapeutics - Google Patents

Abstract

ABSTRACT

THERAPEUTICS.

The present invention relates, as new industrial products, to the 2-phenyl-4-ethyl-morpholine, 2-o-tolyl-4-methyl-morpholine and their acid addition salts.
These products are useful in therapeutics, particularly as anti-depressants of the central nervous system.

Description

New derivatives oE 2~phenyl-morpholine and their use in therapeu-tics.

The present invention relates, as new industrial products to new derivatives of 2-phenyl-morpholine~ namely 2-phenyl-/-1-ethyl-morpholine~ 2-o--tolyl-4-methyllmorpholine and their acid addition salts. It 5 also relates to the use of these products in therapeutics.
A large number of derivatives of 2-phenyl-morpholine are already known, in particular from U.S
patents Nos. 2 835 669 and 2 997 4fj9, from the article by N. BuscH et al., Eur. J. Med. Chern. Chimica Thera-10 peutica 11 (No. 3), pages 201-207 ~1976), from French patents Nos. 7443M and 71 38592 (Publication No. 2 111 882)~
and from the Applicant's ~rench Patent Applicatior No. 79 30768 (Publication No~ 2 471 378). It is also known that several indications have been considered or 15 recommended for the derivatives of 2-phenyl-morpholine.
Said derivatives are, particularly in the aforesaid publications, presented as exciting or stimulating agents of the central nervous system, as tranquilizers, anti-inflammatories, analgesics and hypotensors.
It has just been ~mexpectedly found that the 2-phenyl-4-ethyl-morpholine and 2-o-tolyl-4-methyl-morpholine and their salts are anti-depressants of the centra~ nerVOIlS system which are different from the priorly known products especially by the fact that they 25 have an~,-adrenerg:ic pre- and post-synap-tic stimulating ~ff~ct.
The new compounds according -to the invention which belong to the family of 2-phenyl-morpholine derivatives have the general formula:

~X
are characterized -in that ~ey areselected froll1 the group constituted by (i) 2-pllenyl-l~-ethyl-morpholine (X = H, Y = C2H_) and its non-toxic acid addition salts; and (ii) 2 o-tolyl-4-methyl-morpholine (X = Y = CH3) and its non-toxic acid addition sa]ts.
The pre~erred compounds according to the inven-tion are the 2-phenyl-~-ethyl-morpholine ancl its salts, because of their pre- and post-synaptic ~-adrenergic s-timulating effec t .
~mongst the mineral and organic acids suitable -to salify -the free base of formula I, can be cited the hydrochloric, maleic, fumaric, aspartic, methanesulphonic and paratoluenesulphonic acids, the preferred acid addition sal-t being, according to the invention, hydro-chlorate.
The free base of formula I can be prepared according to the method known per se, by applying the conventional reactional mechanisms. The preparation method recommended here includes the cyclization of a derivative ofl-pheny:L-

2-/~ N-hydroxyethyl)-alkyl-amin~~l-ethanol of formu:La II hereunder (where:in X and Y are as defined above) in tlle prcsence o~ sulph~ric acid, according -to the diagram .

~ CHOH-CH2-N H250/~ ~ {
CH2-CH2OH ~ i X X ~
(II) (I) 30 According -to the inven-tion, the therapeutic composition is characterized in tha-t it contains, in combina-tion with a physiologically acceptable excipient, at least one compound selected from the group constituted by 2-phenyl-~-ethyl-morpholine1 2-o-tolyl-2-me-thyl-morph ~:~L8~

line, and their non-toxic acid addition salts, as active principle.
The f`ollowing examples of preparation are givenlon -restrictively to illustra-te the advantages of the invention.

~Iydrochlorate of 2-phenyl-4-ethyl-morpholine (Code No.
CRL 4091k) A mixture of 60 g (0.5 mol) of styrene oxide with 222.5 g (2.5 mols) of 2-ethylamino-1-ethanol and 500 ml of methanol is heated under refl~ for 15 hours. After evaporation to dryness~ the resiclue of evapora-tion which is in hexane form, is washed with ~t x 200 ml hexane, and the resulting oil is dried ~mder vacuum in a rotary evapora-tor. The dried oil is then poured in 125 ml of concentrated ll2S0~t cooled by an ice bath. After one hour in con-tact, -the reaction medium is dropped in a mixture con-taining 500 ml of` water ~
ice and ~80 ml of Na0H 10N'. It is -then proceeded -to an extraction wi-th ether, ancl the ethereal phase is washed in water, and dried over MgS0~1. The expected hydrochlorate is precipitatecl with hydrochloric ethano:L. By recrys-tal-:Lizin~ in the acetone-etllanol mixt~lre (l::L)v/v, 40 g (yielcd : 35%) of CRI, ~0914 are o'btained. Instant Melting a-t 210-211C with decomposi-tion.
~% Cl measured = 15.820/o Analysis ~% Cl theoretical = 15~60%.
XAMPLE

3 I~ydrochlora-te of 2-o-tolyl-4-meth ~ pholine (Code . _ _ _ _ _ No. C~L ~tO915) other nomenclature : 2-(2-methylphenyl)-l~~
methyl-morpholine.
67 g (0.5 mol) of o-methylacetophenone are dissolved in 100 ml of' acetic acid. The mixture is coolecl in an ice bath and 25.8 ml of bromium are poure~ therein.

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~ft~ one hour ln contact, the mu~ture is evaporated-to drvness.
The resiclue of evaporation ~which contains o-methyl-~-bromoacetophenone (o-CH3-C6HI~-COCH2Br ~ is taken up in acetone and the resulting mixture is poured into a solution of 187.5 g (2.5 mols) of 2-methylamino-ethanol in methanol. The resulting reaction medium is heated under ref:Lux for l~ hours~ and then evaporated to dryness. The residue of evapora-tion is taken up in water and extracted with ethyl acetateO
The mixture is washed with water and the ethyl acetate phase is extracted with a mixture of 500 ml of wa-ter with 60 ml of concentrated HCl (d45 C = 1.19 g/cm3).
The aqueous phase is washed with ethyl acetate and neutralized with NaOH until a pH of 11 is raached, itis then extractecl with e-thyl acetate, washed with water, dried over ~gS04, filtered and evaporated to drynessO
The evaporation residue ~hich contains the N ~ hydroxyethyl-N-methyl-o-methyl:phenacyl-amin~
is taken u.p with 500 ml of methanol, and 38 ~ (1 mol) of NaBHI~ are added. After a night in con-tact, the mixture is destroyed with 60 ml of acetic acicl, evaporated to dryness,taken upin water, neut:ralizecl with NaOH -to a pll o~ L, extracted with ethyl acetate, the organic phase is washed with water, dried over MgSO~, filtered, then evaporated -to dryness~
The residue of evaporation so ob-tained ~which contai.ns the l~o-tolyl-2-(N-~ -hydroxyethyl-N-methyl)-amino-l-ethanol~ is poured into 125 ml o~
concentrated sulphuric acid cooled in an ice bath.
After one llour in contact, the reaction medium is dropped in a mixture of ~60 ml caus-tic soda witll 500 ml water and ice~ After extraction with ether and a wash wi.th water, the ethereal phase is dried with MgSO~, filtered and -the expec~ed hydrochlorate is precipitated with hydroc]-Lloric ethanol. By recrystalliza-tion :i.n the ether-ethcLnol mixture (1:1) v/v, 10 S ~yield: 9~) of CRL 40915 are obtainecl.
Instan-t Melting at 192C (wi-th decomposition).
~% Cl measured = 15,97%
Analysis <
lo/O Cl -theoretical= 15,60%
The resul-ts from the test conductecl on animals with the CRL 40914 are reprocluced hereafter, the product being administered, except where otherwise stated, in solu-tion in water (at pH 5) by intraperi-toneal route in a volume of 20 ml/k~s in the male mouse ~nd in a volume of 5 ml/kg in the male rat.
- TO_ICITY
The maximum non-lethal dose (LD-S)~ by intraperitoneal route in the male mouse is more than 128 mg/l~g.
II - OVERALLBEHAVIOUR AND_R A_TIVITY
Batches of 3 animals are observed before, then 15 minutes, 30 minutes, 1 hour, 2 hours~ 3 hours and 24 hours after in-traperitoneal administration of CRL 40911~. It is observed:
1) in -the mouse __________._ at the dose of 64 mS~/kg:
-excitation for between 1 a.nd 2 ho~rs wi-tll signs of stereotyped movements, - piloerection~ saliva-tion and lacry-mation for 1 hour, - mydriasis for 1 ho-ur, - polypnea for 2 hours;
at the dose of 16 mg/kg -3o ~ excitation for 30 minutes followed by a hyporeactivity to touch, - lacrimation for 1 ho~ur, - hypothermia (-2.80C) for 2 to 3 hours, - mydriasis for 1 hour;

at -the dose of 4 mg/kg :
- sedation for 30 to 60 mins.
- hypotherlllia (-2.2C) for 1 hour, - mydriasis for 1 hour;
at the dose_of 2 mg/lcg :
- sedation for 30 -to 60 minsO
- hypothermia (-3.60C) for 1 -to 2 ho~urs, - myclriasis for 1 hour;
2 - in the rat _ _ _ _ _ _ _ _ _ _ at the dose of 32 m / ~ ~
_ .
- Seclation for 3 hours with a reduc-tion of reactivity to touch and muscular tonicity, - increase in fear reac-tion for 3 ho~ s, - piloerection (for 3 ho~urs), saliva-tion (for 1 hour)and 1acri-ma-tion (for 1 ho~ur), - mydriasis for over 3 hours at the dose of o ms/Jc,~ :
- seda-tion for 2 ho~u-s wi-th recluc-tion of reacti-vi-ty -to -touch b-u-t wi-th increase of fear reac-tionJ
piloerec-tion for 1 to 2 holLrs, - mydriasis for 2 hours;
at the dose of 2 mg/lcg :
~ sedation for 1 hour, - mydriasis for 1 to 2 hoL~s t at -the dose o_ O.5 mg/~ :
. _ . _ - mydriasis for 1 to 2 hours.
III - ACTION ON TEMPERATURE
.
Batches of 6 mice are given CRL l~0914; the rectal temperature is -taken every 30 minutes. It is obser-ved -that a-t doses of 0.25 mg/kg, 1 mg/kg, 4 mg/k~ and ~39~36~

16 mg/lcg, the CRL 40914 causes a ma~cimllm hypothermia af-ter 30 m:ins O, saicl hypothermia lasting for 90 to 120 mi ns .
At a higl~er dose (64 mg/kg) on the contrary, 5 it is a hyperthermia which appears a-t 30 mins. followed by a moclerate hypothermia.
IV - STEREOTYPED MOVEMEN?S
Batches of 6 rats are given an intraperitoneal injection of CRL 40914 or amphetamine and are immediately 10 placed inside small-size boxes where their stereotyped behaviour is noted between O and 3 every 10 mins. until the effect disappears. It is observed that the CRL 40914 does not cause any stereotypies at the dose of 32 mg/kg.
At the strong dose of 64 mg/kg it causes the appearance 15 f s tereo-typed movements of intensity and duration comparable to -those observed after the administra-tion of 1 mg/l~g of amphetamine. At the very high dose of 128 mg/kg, this effec t is even sharper .
V ~ INTERACTION WI~.r~l APOMORP~IINE
..~
1) in the_mouse Batches of 6 mice are given CRL 4091L.~ half an ho~r before receiving a sub-cutaneous in jection of apo-mo:rphine at the close of 1 mg/kg or 16 mg/:kg It is observed that at a high close (16 mg/kg, 25 64 mg/kg) -the CRL ~0914 opposes -the hypo-thermia incluced by apomo*phine and seems -to increase the signs of verticalisation and stereotypies. The effects of the CRL 40914 at -the said doses are therefore observed on the temperature.
2) in_the rat The CRL 40914 was adminis tered to ra-ts half an hour befo:re the sub-cutaneous in~jection of 005 mg/lcg of apomorphine.
A-t doses of 0.5 mg/kg, 2 mg/kg and 8 mg/kg, the 35 CRL 40914 seems to slightly reduce the intensity of the s-tereotypies inducecl by apomorplline~
At a higher dose (32 mg/kg) on the con-trary, it seems to cause a discreet poten-tializa-tion of the stereo-typies.
VI - INTERACTION WITH A~HETAMINE
The amphe-tamine (2 mg/kg) is injected by in-traperi-to3leal route -to batches of 12 ra-ts, hal~ an ho~Lr af-ter the administra-tio3l of CRL 4091~.
I-t is observed that at doses of 8 mg/kg and 32 mg/kg, -the CRL l~O914 reduceS noticeably -the in-tensi-ty of the amphetamine--ind~lcecl stereotypiesO
VII ~ INT~RACTION I~ITH RESERPINE
Four hours after -the intraperi-toneal injec-tion of 2.5 mg/kg of reserpine, batches of 6 mice receive the CRL ~0914.
It is observed -that at doses of ~ mg/lcg and especially a-t doses of 16 mg/lcg and 6~ mg/1~, the CRL 4091~ opposes the hypo-thermia and p-tosis caused by reserpine.
VIII - -CN'[`ERACTION WITH OXOTREMORINE
_ _ _ _ _ The CRL 1~091l-~ is administered to bal;ches of 6 mice half an ho~ before the intraperitoneal injec-tion o:f: O. 5 mg/:lcg o:L` oxo-tremorir3e .
l) ~c-tion on temperatlLre _____________________ At doses o:f. 16 mg/kg and 6~ mg/kg, the CRL ~091 opposes -the hypo-thermia effect induced by oxo-tremorine.
It exerts on the temperature of two-phased intrinsic effect depending on -the doses.
2) Action on -tremblings 3o A-t high doses (6~ mg/kg), the CRL ~091~ red-uces the in-tensi-ty of the tremblings caused by oxotremorine.
3) Action on the peripheral choliner~ic symp-toms ___________________________ _________________ The CRL l~o914 leaves unchanged the signs of peripheral cholinergic symptoms caused by oxotremorine.

3) Ac-tion on the peripheral cholinergic symp-toms _____________________________________________ The CRL 40914 leaves unchangecl the signs of peripheral cholirlergic sympioms caused by the oxo-tremorine~
IX - ACTION ON TI-IÆ FOUR-PLATÆ TEST~ TRACTlON AND ELECrRO-S~IOC~_ The test is conducted on batches of 10 mice~half an ho~Lr after the administra-tion of CRL 40914.
The CRL 40914 brings about at low dose a reduction, and at high dose an increase, in the number of punished passages; it does no-t cause a:ny maJor motor incapacity, and a-t high dose ~64 rng/kg) it aggra-vates the lethal effects of the electroshoclcO
X -ACTION ON SPONTANEOUS MOT:[LITY
Half an hour after receiving -the CRL 4091lt, ]5 mice are placed in an ac-timeter where their mo-tility is recorded for 30 mins.
It is observed that already at the dose of 0.125 mg/kg -the CRL 40914 causes a reduction of -the spontaneous mo-ti].i-ty of the mouse. This effect reaches a m~ximum a-t a dose between 0.5 mg/kg and 16 mg/kgO Be-yond -that, the mo-tili-ty reduci:ng effeci; decreases, making room for a defini-te hyperac-tivity (6lt mg/kg)O
XI - ACrION VIS~A~VIS CÆRTAIN BÆHAVIOURS DTST.URBED ~Y
VAR:rOUS AGL,NTS
1) Mo-tLl.i-ty reduced by habit-ua-tion to -the cage Af-ter dwelling 18 hours in the act:ime-ters, the mice (6 per dose, 12 con-trols) receive the CRL 4091ll~
~ey are immediately replaced inside their respective cages and, half an hour la-ter, their mo-tili-ty is recorded 3o for 30 mins.
It is observed -that a high dose ~6l~ mg/kg), the CRL 40914 causes a definite resumption of activi-ty in -the mouse habi-tuated -to its cage.
2) l~lotilit-y reduced by -hypoxic aggr_ssion llalf an hour after receiving the CRL 409:L4, the mice (lO per dose, 20 controls) are subjected to an acute hypobar anoxia~depression of 600 mm Hg (or abou-t 3 ~ :LO' pascals) iIl 90 secs., fo:L:Lowecl by relaxation of ~15 secs7 then they are placed in an actimeter where the:ir mo-tility is recorded for lO mins~
In the mouse whose mo-tility was lowered further to a brief spell in a cage at reduced pressllre, the CRL ~0914 causes modifications of the motor activi-ty reflecting its action on spontaneous motility.
3) A~phy~ic ano~ia ________________ Batches of lO mice receive the CRL 1~09l1~ ha]f an hour before an intraperitoneal injection of 32 mg~kg of gallamine triodoethyla-te (c~Lrarizing agent of reference).
It is observed that at doses of l mg/kg, ~ mg/kg ancl 16 mg/lig, the CRL 1~09l/-~ delays the occurrence of con-vulsions, and to h lesser degree, death consecutive -to an asphyxic anoxia caused by a curarizing agent. A-t higher dose, tilis effect disappears.
XII - INTER~CTION WITH BhRBI'rAL
. ~.
Batches of :LO mice receive the CR1, 1~0916 halE an hour before an intraperitoneal injection of 220 mg/kg of sodic barbital.
At the doses of ~ mg/kg and 16 mg/kg~ the CR[, /~09LI~ soems to prolong moderAtely t;he sleep induced by t;he barbi,tal whereas a-t a higher dose (6l~ mg/kg) it opposes definitely sleep.
XIII - AC'1'ION ON "BEHAVIOUR DESPAIR"
Half an hour after receiving the CRL /109l4 or desipramine, batches of lO mice are placed inside a 'beaker filled up to 6 cm of waterO The duration of immobili-ty of the mouse is no-ted between the 2nd and 6th minute follo~Ying i-ts immersionO
ht the dose of 1~ mg/kg, the CRL 1~09l1~ reduces the immobility period of the immersed mouse; the effect is par-ticularly noticeable at 61~ mg/kg.

ll XIV - INTERACTION WITH YOIIIMBINE
1) Temperature ___________ Ba-tches of 12 mice receive an intraperitoIleal injec-tion of 005 mg/kg yohimbine half an hour before the adminis-tration of CRL 4091ko It is observed that at the dose of 0.5 mg/kg, the yohimbine does not alter the rectal temperat~e of the mouse bu-t that it opposes the occurrence of -the hypothermia induced by 1 mg/kg and 16 mg/kg of CRL 40914.
2) Spontaneous motility ______________~__ __ Batches of 12 mice receive the yoh:imbine (0.5 mg/kg - by intraperi-toneal rou-te) and the CRL ~0914, respectively 60 and 30 minutes before being placed inside an ac-timeter where their motility is recorded for half an hour.
I-t is noted that the yohimbine does not affect the spontaneous motility; it opposes the hypomotility caused by the CRL l~0914 at the dose of 1 mg/l~g but does not alter -that caused by 16 mg/kx of CRL 40914.
XV - ACTION ON INTERGROUP AGGRESSIVENESS
It is observed -that the CRL 40914 has an an-ti-ag~ressive effect on the ma:Le mouse when studying intergro-up aggressivelless, because i-t eliminates fights between mice of 2 different groups at the dose f 4 mg/l~g 7 and reduces the duration of the contac-t between the mice at the dose of 6~1 mg/kg. This effec-t could be due to the sedation which occurs at low dose (4 mg/kg) and to the motor excitation which occurs at high ~ose (64 mg/1~g).
XVI - ACTION ON THE CARDIOVASCULAR SYSTEM
___ _ __ . ___ Six genetically hyperten~sive rats wi-th implanted femoral arterial catheter are given an oral dose of 20 mg/l~g of CRL 40914.
It is observed that the CRL 4O91~L is slightly hypotensive. It xradual1y reduces ar-terial pressure ;

~.~.8~

the maxilllum effec-t is obtained 7 hours after inges-tion of the product; the ar-terial p:ressure pa.sses from 165 to 135 mm Hg (namely from 2.2 x lOt to l~o x 10 pascals), i.e. a variation of - 18%. The heartbeat slows down from 350 beats per minu-te to a minimum of 270 per minute after 1.5 hours~ then it gradually speeds up and slows down; af-ter 2~t hours, the blood pressure and heartbeat have returned -to their control value~
It follows from the results of the -tests conducted on the central nervous system given ill points II-X:[I and XIV-X.V above~ that the CRL ltO91l1 (i) has a two-phased effec-t depending on the doses used :
a) sedation, hypomo-tili-ty and hypothermia at low doses ; and b) excitation, hypermo-tility, hyperthermia, stereo~ypies and an-tagonism of barbituric sleep at high doses;
and (ii) acts as a pre-synaptic~--adrenergic stimu:Lan-t at low doses and as a post-synaptic ~ -adrenergic stimulant at high ~osesO
The results of the -tes-ts conducted in animals with the CR:L /-tO915 are summed up hereinaf-ter, the mode operand:i being the same AS wi-th -the CRL ItO91lt~
I - _ XICITY
In the male mouse, the LD-O or maximum non~lethal dose by intraperitoneal route is more than 256 mg/kg and -the LD-50 by intraperitoneal route is of the order of 500 mg/kg approximatelyO
II - OVERAL:L BEHAVIOUR AND REACTIVITY
1) in the mo-use ______~______ at the dose Or 128 mg/kg :
~ .
- convulsions for 15 minutes, - sedation with reduction of aggressiveness reaction for 2 hours, ~ hyporeactivity to touch for 15 minutes, = sali~a-tion and lacrymation for 30 minutes~

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- hypothermia t-2.90c) for 2 hours ;
at the dose of 32 mg/ls~ :
_ _ _ - sedation -for 1 hour , - hypothermia ~-2.80C for 1 hour;
at the dose of 8 mg/kg :
.
- transient sedation for 15 to 30 rninutes, - hypothermia (-1.5C) for 1 hour;
at the dose of 2 mg~kg :
-- no precise symptoms~
2) in the rat _ _ _ _ _ _ _ _ _ _ at the dose_of 64 mgr/kg :
- sedation for 1 to 2 hours, - piloerec-tioll for 1 howr~
- hypothermia (-1.9C) for 30 to 60 minutes, - mydriasis for 1 hoLLr;
at the dose of 16 m~r/l~r - sedation for 1 to 2 hours~
- piloerection, - mydriasis for 30 to 60 minutes;
at the dose _f 4 ~ :
- sedation for 30 minu-tes, - mild mycIriasis for 30 minu-tes;
at -the dose of 1 mLr/k~r . . ._ .. _ ~ __ __ !', ._`~
- no particular signsO
III - INTERACTION WITH APOMORPHINE
_ . . .
1) in the mouse ____________ The CRL kO915 administered a-t doses around 32 mg/kg has an in-trinsic hypothermic effectO At doses of 32 rng/lsg and 128 mg/kg it opposes the hypothermic action of apomorphine, and at 128 mg/kg i-t red-uces the signs of ~erticalization and stereotypies inducecl by -the low cdose (1 mg/lsg) of apomorphine.
2) in the rat The CRL ~0915 cloes not alter -the stereo-typies caused by apomorphine ln the ra-t.
IV - ~TERACTION I~ITH AMPIIErAMlNE
The amphetaminic stereo-typies are not affected by the CRL kogls.
v - NTERACTION WITil RESERPINE
At high dose ( 128 mg/lcg) the CRL ~0915 causes an aggravation of the reserpinic hypo-thermia; the p-tosis l~hich is already maximum is not altered.
VI - INTERACTION WITH OXOTRE~IORINE
. .
1) Action on temperature _____________________ At doses of 32 mg/kg and 128 mg/kg, the CRL ~0915 has an intrinsic hypothermic effect, bu-t opposes -the o~co-tremorine-indueed hypo-thermia.
2) Action on -tremblings ____________________ The oxo-tremorine-induced tremblings appear to be partly an-tagonize~ by the high dose ( 128 mg/kg) of 3) Action on the peripheral_cholinergic symptoms The CRL ~0915 has no effect whatsoever on the 20 signs of peripheral cholinergie stimulation induced by the oxotremorine.
VII - ACTION ON Tl-lE FOUR-PLATE TEST, TRACTION AND ÆLECTRO~
SIIOCK_ A-t; doses of 32 mg/lcg and 128 mg/kg, -the CRL ~0915 2~ reduces -the number Or puni,shed passages 7 it does no-t cause axly maJor motor incapacity bu-t opposes -the convulsive effects of -the eleetroshock.
VIII - ACTION ON SPONTANÆOUS MOTILITY
. _ . _ A-t doses of 32 mg/kg and 128 mg/kg, the CRL 40915 30 causes a considerable reduction of the spontaneo-us motility of -the mouse.
IX - ACTION VIS-A-VIS CERTAIN BEHAVIOURS DISTURBED BY VARI-OUS AGENTS
.
1) Motility reduced by habi-tuatio-n to the cage The CRL ~C915 causes no resump-tion ot' activity in the mouse habi-tua-ted to its cage.

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2) ~lotiLity_reduced by hypoxic aggression ~ he CRL ~0915 causes no improvement of the motor recovery in mice whose motility was lowered ~urther to a brief spell in a cage at reduced pressure. On the contrary, an aggravation is noted a-t doses of 32 mg/kg and 128 mg/l~g probably related to the effect of the CRL 40915 on spon-taneous motility.
3) Asphyxic anoxia ________~______ At doses of 8 mg/kg~ 32 mg/kg and 120 mg/kg~ the CRL ~L0915 delays the occurrence of convulsions and of death consecutive to an asphyxic ano~ia caused by a curarizing agent tgallamine triiodoethylate).
As a result of these tests, the neuropsycho-pharmacologica~ profile of -the CRL ~0915 is characterized by a strong sedation which does not occur progressively with the increasing doses, but occurs as all or nothin~:
no sedative effect at a given dose, very strong sedation at the higher dose used.
The hypo-thermia (which seems to be less at a high dose than at an average ~ose), -the hypomotili-ty, tlle reduction of punished passages in the four-plate tes-t, the aggravation of the akynetic effects of hypoxia, the delayed occurrence of convulsions and death after asphyxic anoxia are all effec-ts which can be re:Lated -to sedat:ion.
Moreover, at high dose, the CRL IL0915 defini-tely opposes the hypothermias induced by the ~pomorphine and oxotremorine, but aggravates the hypothermic effect of -the reserpine.
Finally at high dose, the CRL ~L0915 ca-uses the occurrence of salivation and piloerection (which could be related to a peripheral post-synapticc~-adrenergic stimulation) and of convulsions occllrring only for the 15 to 30 minutes following the administration of the product.
The CRL 4091~L administered orally to hurnans /2 -to 3 tablet~or gelules (each containing 10 to 20 mg of active principle) per da ~ has given e~cellent results especi.ally a.s an anti-depressanl; of -the cent.ral nervous system.

Claims (5)

The embodiments of the invention in which an exclusive property of privilege is claimed, are defined as follows:

1. A process for preparing 2-phenyl-morpholine derivatives having the formula wherein either X = H and Y = C2H5 or X = Y = CH3, and their non-toxic acid addition salts, comprising cyclizing a derivative of 1-phenyl-2-/(N-hydroxyethyl)-alkyl-amino/-1-ethano of the following formula in the presence of sulphuric acid.

2. A process according to claim 1 wherein X = H1 Y = C2H5.

3. A process according to claim 1 wherein X = Y = CH3.

4. 2-phenyl-4-ethyl-morpholine and its non-toxic acid addition salts when prepared by the process of claim 2 or an obvious chemical equivalent thereof.

5. 2-o-tolyl-4-methyl-morpholine and its non-toxic acid addition salts when prepared by the process of claim 3 or an obvious chemical equivalent thereof.