IE51083B1 - Fluorophenacyl-amine derivatives and application thereof in therapeutics - Google Patents

Description

The present invention relates to fluorophenacyl-amine derivatives, and also to application thereof in therapeutics.

In the following Specification, fluoro5 phen acyl-amine derivatives are understood to mean. not only compounds having a fluorophenacyl group of formula F - CgH^ - CO - CHg -, but also a -hydroxyfluorophenethyl group of formula F - CgH^ - CHOH - CH^ -, which derives from the preceding one by reduction of the carbonyl function into alcohol function.

Compounds of the 2-amino-1-(halogenophenyl)1- ethanol type are included in the formula of French Patent No. 1 503 517 and presented as antidiuretic agents. However, it should be noted that this French Patent describes no 1-(fluorophenyl), 1-(chlorophenyl), l-(bromophenyl) and 1-(iodophenyl) derivatives, nor does it suggest their potential actions on the CNS.

It is known that fluorophenacyl-amine derivatives belonging to the family of 2-amino-1-(fluoro20 phenyl)-1-ethanols have already been described. In particular, the article by A.M. LANDS, J. Pharmacol. Exptl. Therap. 106, 440-445 (1952) discloses 1-(3-fluorophenyl)2- isopropylamino-1-ethanoland 1-(3-fluorophenyl)-2 -tert.butylamino-l-ethanol, and the article by L. VILLA et al, II Farmaco Ed. Scientifica, 24 (No. 3), 329-3^0 (1969), discloses 1-(4-fluorophenyl)-2-isopropylamino-l-ethanol and 1-(2-fluorophenyl)-2-isopropylamino-l-ethanol. These known fluorinated products act on the CNS but they have no, or only slight, aggression-reducing effect. 3q It has been unexpectedly found that new fluorophenacyl-amine derivatives, which act on the CNS, have particularly advantageous antiaggressive properties from the therapeutic standpoint.

According to the invention there is provided a ccstpound belonging to the family of fluorophenacyl-amine derivatives of formula : wherein A is CO or CHOH, and R is CH(CH3)2 or CiCHj)^, Which is particularly useful in therapeutics, said conpound being selected fron N -(4-fluorophenacyl)-isopropylamine, N-(2fluorophenacyl)-tert.-butylamine, 1-(2-fluorophenyl)-2tert.-butylamino-l-ethanol, 1-(4-fluorophenyl)-2-tert.butylamino-l-ethanol, and their addition salts.

From these products, the preferred compounds from the therapeutic standpoint are N-(4fluorophenacyl)-isopropylamine and its salts, particularly the hydrochloride.

Addition salts are understood here to mean the acid addition salts obtained by reacting a free base of formula I with an inorganic or organic acid, and the ammonium salts. Among the acids which may be used for salifying the bases of formula I, the following may be particularly mentioned : hydrochloric, hydrobromic, nitric, sulphuric, acetic, propionic, oxalic, fumaric, maleic, succinic, benzoic, cinnamic, mandelic, citric, malic, lactic, tartaric, p-toluenesulphonic and methanesulphonic acids. Among the compounds enabling ammonium salts to be obtained, particular mention may be made of XCH^ and CICH^. Tlie acid addition salts are the preferred salts, and, among the latter, the most advantageous are the hydrochlorides.

The fluorophenacyl-amine derivatives of this invention may be prepared according to a method known per se, by application of conventional reaction mechanisms. The recommended process for preparation 81883 consists : 1) in obtaining a carbonyl compound (A = CO) by reacting a fluorophenacyl halide of formula // \ CO-CHg(II) wherein X^ is Cl or Br, with an amine of formula (III) wherein R is defined as hereinabove , under reflux for at least 1 hour in an alcohol, preferably methanol, then 2) if necessary, in obtaining an alcohol compound (A= CHOH) by reducing the corresponding carbonyl derivative, in particular with NaBH^.

The compounds according to the invention are all active on the CNS and also have interesting card15 iovascular effects. In particular, they act on the CNS as sedative agents, antidepressants and antiaggressive agents and are indicated in the treatment of depressions.

According to the invention, a therapeutic composition is also provided which is particularly useful in the treatment of depressions, and which contains, in association with a physiologically acceptable excipient, at least one fluorophenacyl-amine derivative according to the invention or one of its nontoxic addition salts, the active ingredient being, of course, administered at a pharmaceutically effective dosage.

Comparative tests have been carried out to demonstrate those effects on the animal which distinguish the products according to the invention from their known fluorinated analogues. Among these tests, those concerning the antiaggressive properties have been summarised. More particularly, the reduction of the intergroup aggressiveness was assessed according to the following technique : after 3 week's residence on either side of an opaque partition separating their cage at the centre, groups of 3 male mice each weighing about 20 g receive by intraperitoneal route the products to be tested, in solution in distilled water, the control animals receiving only distilled water by I. P. route. Half an hour later, the two groups of the same cage are brought together by withdrawing the partition and the number of fights which take place in 10 minutes is noted. 3 cages are used for each product to be tested and 6 cages for the control batch not receiving the products to be tested.

The results of Table I hereinafter give the reduction in intergroup aggressiveness with respect to the control hatch, all the products to be tested being administered at the dose of 8 mg/kg by I.P. route. These results show (i) that the products according to the invention (Examples 1 to 5) have a clearly greater antiaggressive effect than that of their known analogues (CPI to CP4) and (ii) that there is no structureactivity relationship. rt η Em —S’-1 β 0 k fao k © p £ •ri 0) W 0 -ri •rl » •μ © υ φ β k τ3 fcO © bo k «α to Γ- g κθ s£ κθ cO r-. 697=, frS IO bs rd CO § ff Bj; Ό 31 PI ©1 < d H > rt >» rt tJ © rt •ri k 0 Ifl ©.rd /—s Ό © bo vz ο \ co ¢0 CO co © a) CO CO 00 .- Q bO W g £ B a ff CM CO CO co co CM z*> CO CM z~^ CM z-s £ CO «Ζ*\ z-'. co «—s CO JfO SS © up sT CO £ £ υ CO £ £ © £ © © © © © a S-Z © S-Z rt £ s—' sz Sw/ £ MZ £ £ •ri u © O © o © © O © k 0 © © S3 £ £ £ £ £ £ 'd o O O O O O p < o o S3 £ £ £ £ £ £ z-s υ u υ O © © © © © V © P rt Pn Ik fa fa · fa fa fa fa fa © * 1 ff 1 CM CM 1 CM f ff r co 1 co 1 ff 1 CM S 5 z\ r* 00 r** r·- ff co rt CM CM CM CM to IO r> CO CO co co co © © o O o o ·« S ff ff ff ff 1 1 ff t ri 3 ί έ £ © © Ό © o © © υ © Ό 0 O 0 in h 0 Ό rt >»rt rt o P CM CO ff to © ZS. z*s .£ u © © © © o o Ό Ό Ό i-l z-s rd /s rd r’s rd z-> rd *-Z ¢4^ CO *-* ff w· o fa © 0« © fa © fart fa © fa fa fa fa © g SZ a C Θ a k-z· a *-/ © © ©z~s © © έ © © © © © © © © © P & X X x χ S-Z s-z s-z S-Z 0 a W « « £ £ Some examples of preparation have been given hereinafter by way of non-limiting illustration.

Preparation I Pre2aration_of_the_hydrochloride_of_N-_(4-fluorgghenacYl}.isopropylamine F CH, CH, (Example 1; Code No. : CRL 40727) ml of bromine are poured, dropwise, into a solution, cooled by an ice bath, of 69 gfo.5 mol) of parafluoroacetophenone in 100 ml of acetic acid. The mixture is stirred for one hour and evaporated to dryness. The residue is taken up in 100 ml of methanol and the solution thus obtained is poured into a solution of 210 ml of isopropylamine in 200 ml of methanol.

It is refluxed for 2 hours, and evaporated to dryness.

The residue is taken up in water, the free base of the expected product is extracted with ethyl acetate, the solvent is dried and the hydrochloride is precipitated by hydrochloric ethanol. By recrystallisation in an acetone-methanol (1 : 1) v/v mixture, 17.2 g (yield : l4.8%)of CRL 40727 are obtained, m.p. 207’C (with deconqiosition) .

Analysis : % N measured = 6.01% % N theoretical = 6.04% Preparation II SE2BSE5ii22_2£_£i)2_i?X^E2£i}i2Ei2®_2i_SliSl£i22E2Sii®2asyiil.

(Example 2; Code Ko. : CRL 40828) g (0.362 mol) of orthofluoroacetophenone are dissolved in 75 ml of acetic acid. The mixture 5 is cooled by an ice bath and 18.1 ml of bromine are poured in dropwise. It is left in contact for 1 hour, evaporated to dryness and the residue is taken up in 100 ml of methanol. The solution thus obtained is poured into a solution of 132 g of tert.-butylamine in 100 ml of methanol. It is refluxed for 1 hour, evaporated to dryness, the residue is taken up in water, extracted with ether and the expected hydrochloride is precipitated by hydrochloric ethanol. By recrystallisation in an acetone-ethanol (l:l)v/v mixture, l8 g (yield = %) of CRL 4o828 are obtained, m.p. = 240°C (with decomposition).

Analysis : % N measured = 5-7^% % N theoretical = 5·7θ% Preparation III p tegar a tion _of _the _hydrq chi oride _of _1- (.2 - f luo roghenacy.1 )_2- _ter t ,_-b uty lamino^l-ethanol_ // \ CH0H-CHo-NH-C(CH)„ . HCl 2 3 J Example 3; Code No. : CRL 40827) 0.04 mol of N-(2-fluorophenacyl)-tert.butylamine (free base of the CRL 40828) is dissolved in 120 ml of methanol. Cooling is effected to and 3 g of sodium borohydride are added. Xt is left in contact for 1 hour. The excess NaBH^ remaining in the reaction medium is destroyed by means of 5 ml of acetic acid, then the mixture is evaporated to dryness. The residue of evaporation is taken up in water, the pH is adjusted to 11 by means of NaOH, extracted with ether, the ethereal phase is washed with water and said ethereal phase is dried over MgSO^. After filtration, the free base is collected and the expected hydrochloride is precipitated by means of hydrochloric ethanol. By recrystallisation in an acetone-ethanol (l:l)v/v mixture, 8 g (yield : 80%) of CRL 40727 are obtained, m.p. = l8O.5°C.

Analysis : % N measured = 5.60% % N theoretical = .65% Prepration IV Preparation_of_the fumarate of_l-£2-fluoroghenyl)-2t er t t-b u t y 1amino-1-ethanol _ Example 4; Code No. CRL 40827 A) By reacting 1-(2-fluorophenyl)-2-tert.butylamino-l-ethanol (free base obtained in Preparation III) with fumaric acid, CRL 4o827Ais obtained, m.p. 195-200»C (with decomposition).

Preparation V ££®Paration_of_the_hydrochloride_of_1-U-fluoroghenylHStSEtilkutylamino-l-ethanql •CHOH-CH2-NH-C(CHj)3 . HCl (Example 5; Code No. : CRL 40854) g (Ο.289 mol) of C< -chloro-p-fluoroacetophenone are dissolved in 900 ml of methanol. The mixture is cooled to -5°C and 5·8θ g of NaBH^ are added. It is left in contact for 1 hour then 10 ml of acetic acid are added. 151 ml of tert.-butylamine are added and the mixture is refluxed for 12 hours. It is evaporated to dryness and the residue of evaporation is taken up in distilled water. The free base which has crystallised is filtered off and, by recrystallisation in hexane, 39 g (yield 63%) of 1-(4-fluorophenyl)-2-tert.-butylamino-1-ethanol are obtained, m.p. 117°C.

This base is dissolved in diethyl ether, the hydrochloride is precipitated by means of hydrochloric ethanol. By filtration and drying in vacuo over PO , 44 g (yield : 6l%) of CEL 40854 are obtained, m.p.

CEL 4o854 may also be prepared according to the process of Preparation III, by replacing the N-(2-fluorophenacyl)-tert.-butylamine by N-(4-fluoro20 phenacyl)-tert.-butylamine.

The tests carried out with the preferred products according to the invention have been summarised hereinafter.

A) Tests relative to CEL 40727 (Example l) 1. Toxicity The maximum non-lethal dose, LD-0, is greater than 128 mg/kg and less than 256 mg/kg, in the mouse, by I.P. route. 2. Action on the CNS CRL 40727 has a certain number of sedative type effects, namely : - sedation and hyporeactivity in the mouse - hyporaotility and reduction of aggressive ness in the mouse, - hypothermia and potentiation of the hypothermia-inducing effects of apo35 morphine, oxotremorine and reeerpine, - moderate antagonism of the stereotypes induced by amphetamine. 3. Action on the cardiovascular system a) by the intravenous route Two dogs receive CRL 40727 by the intravenous route, in perfusion for 6 minutes, at the successive doses of 0.1 mg/kg, 1 mg/kg, 2.5 mg/kg, mg/kg, 10 mg/kg and 20 mg/kg. Their arterial pressure, cardiac frequency, flow rate of the femoral artery and rectal temperature are measured.' The following is observed.

CRL 40727 increases the flow rate of the femoral artery from the dose of 1 mg/kgj the effect increases with the dose, up to 10 mg/kg, dose for which + l40% is attained.

From 5 mg/kg, the differential arterial pressure increases; the diastolic and average arterial pressures reduce from 10 and 20 mg/kg respectively.

The cardiac frequency is not clearly modified.

The skin becomes pink from 2.5 to 10 mg/kg.

The biliary liquid remains yellow; the rectal temperature is not modified.

Tachycardia induced by isoprenaline is reduced, the cardiac frequency passes on average to 182 beats/min after 10 mg/kg, whilst it was 215 beats/min in the control; hypotension is not modified.

A complementary experiment was undertaken; one dog receives an additional dose of 40 mg/kg I.V. of CRL 40 727, and a greater hypotension is observed than at the preceding dose, the biliary liquid remaining yellow; a second dog receives a reference product, the hydrochloride of (2,4,6-trimethoxyphenyl)-3-pyrrolidinopropyl)-ketone - which is described in British Patent No. 1 325 192, is coded LL 1656 and is marketed under S»a®83 the name FONZYLANE - at the dose of 6 mg/kg I.V. and it is observed that the rate of flow of the femoral artery does not increase more with LL1656 than with the dose of 10 mg/kg of CRL 40727. b) By the intraduodenal_route Three dogs receive CRL 40 727 by the intraduodenal route at the successive doses of 1 mg/kg, 2.5 mg/kg, and 10 mg/kg. The same parameters as hereinabove are measured. The following is observed.

CRL 40727 clearly increases the rate of flow of the femoral artery from'the dose of 2.5 to 5 mg/ kg; the effect increases only slightly with the dose. From 10 mg/kg, a hypotensive action is manifested. The skin becomes very slightly pink from 2.5 mg/kg.

The biliary liquid remains yellow. The rectal temperature is not modified.

Tachycardia induced by isoprenaline is reduced. The cardiac frequency passes on average to l65 beats/min after 10 mg/kg of CRL 40727, whilst it reached 220 beats/min in the control. Hypotension is not modified.

Complementary tests were undertaken; one dog receives an additional dose of 20 mg/kg by I.D. route. A greater hypotensive action is observed, without additional vasodilator effect. The same result is ob25 tained on another dog in which are injected 5 mg/kg I.V, of CRL 40727 at the end of the test. Moreover, the LL 1656 injected thereafter by the intravenous route, at the dose of 6 mg/kg, does not cause additional vasodilation.

In conclusion, the results obtained by the intravenous route and by the intraduodenal route are difficult to compare, hypotension occurring in the dogs treated by the intravenous route only from 20 mg/kg, whilst it appears with the same intensity in the dogs treated by the intraduodenal route at 10 mg/kg.

The vasodilator action of CRL 40727 is perhaps due to a yQ % action; noaction is observed (no tachycardia), no bradycardia; on the contrary, the tachycardia-inducing action of isoproterenol is reduced. Moreover, it will be noted that the biliary liquid remains yellow, even after the accumulated dose of 38-5 mg/kg I.V.

B) Tests relative to CRL 40827 (Example 3) CRL 4o827, in solution in distilled water, was administered by the intraperitoneal route in a volume of 20 ml/kg in the male mouse and a volume of 5 ml/kg in the male rat. 1. Toxicity The maximum non-lethal dose, LD-O, is greater than 64 mg/kg and less than 128 mg/kg in the male mouse. 2. Action on the CNS Interaction with agomorphine a) Mouse Batches of 6 mice receive CRL 40 827 half an hour before the subcutaneous injection of apomorphine at the dose of 1 or l6 mg/kg. It is observed that, at doses of 0.5 mg/kg and 2 mg/kg and especially 8 and 32 mg/kg, CRL 40727 clearly opposes the hypothermia-inducing action of the strong dose of apomorphine but does not modify the behaviour of verticalisation and the stereotypes. b) Rat CRL 4o827 is administered to batches of 6 rats half an hour before subcutaneous injection of 0.5 mg/kg of apomorphine. It is observed that CRL 40827 does not modify the stereotypes induced by apomorphine in the rat.

Interaction with amphetamine Amphetamine (2 mg/kg) is injected by the intraperitoneal route to batches of 6 rats, half an hour before administration of CRL 4θ827· It is noted that, except for the isolated reduction of the index of stereotypes, observed at the dose of 4 jng/kg, CRL 40827 does not modify stereotypes induced by amphetamine.

Interaction with reserpine Four hours after the intraperitoneal injection of 2.5 mg/kg of reserpine, hatches of 6 mice receive the CRL 40827. It is observed that, from the dose of 0.5 mg/kg, CRL 40827 clearly fights hypothermia induced by reserpine without modifying the ptosis.

Interaction with oxotremorine CRL 4o827 is administered to hatches of 6 mice half an hour before the intraperitoneal injection of 0.5 mg/kg of oxotremorine. It is observed that, from a dose of 0.5 mg/kg upwards, CRL 40827 antagonises the hypothermia-inducing action of oxotremorine; this effect is very clear at 32 mg/kg. Moreover, CRL 40827 does not modify the intensity of the tremors provoked by oxotremorine. Finally, CRL 40827 does not modify the signs of cholinergic peripheral stimulation which appear after administration of oxotremorine.

Action on the four_plate test2 traction and electric shock The test is made on batches of 10 mice, half an hour after the administration of CRL 40827. CRL 40827 does not cause increase in the number of incorrect moves which are punished ; it does not bring about any major motor incapacity and, at a high dose, opposes the convulsing effects of the electric shock· Action on the spontaneous motility Half an hour after having received CRL 40827, the mice (6 per dose, 12 controls) are placed in an actimeter where their motility is recorded for minutes. It is observed that CRL 40827 virtually does not modify the spontaneous motor activity of the mouse.

Action with respect to_some behaviour disturbed_by various agents a) Motility reduced by habituation to the cage After remaining 18 hours in the actimeters, the mice (’6 per dose, 12 controls) receive CRL 40827. They are immediately replaced in their respective cages and, half an hour later, their motility is recorded for 30 minutes. At a high dose (3¾ mg/kg), CRL 40827 seems to provoke a moderate renewal of motor activity. b) Motility reduced by hypoxic aggression Half an hour after having received the CRL 4o827, the mice (10 per dose, 20 controls) are subjected to acute anoxia by pressure reduction | depression of 600 mm Hg(i.e. 8 x 10 Pascals) in 90 seconds, return to normal pressure in 45 seconds], then they are placed in an actimeter where their motility is recorded for 10 minutes. It is noted that CRL 40827 does not produce any improvement in the motor recovery of mice whose motility has been reduced due to a brief stay in a cage under reduced pressure. c) Asphyxic_anoxia Batches of 10 mice receive CRL 40827 half an hour before the intraperitoneal administration of 3¾ mg/kg of gallamine triiodoethylate. At the highest dose (34 mg/kg) CRL 4o827 prevents the appearance of convulsions and death in 40% of the animals.

Conclusion relative to the action on the CNS The antagonism of the hypothermia induced by apomorphine, reserpine or oxotremorine makes it possible to foresee an activity of antidepressant type for the CRL 40827. These antagonisms being observed in the absence of anticholinergic effect, the CRL 40827 therefore differs from the imipraminio antidepressants.

On the other hand, the absence of antagonism of the ptosis induced by reserpine, and of motor stimulation with stereotypes makes it possible to distinguish the CRL 40827 from the XMAO and amphetaminic compounds respectively. In brief, there is a strong presumption that the CRL 40827 behaves like the β adrenergic stimulants.

Furthermore , CRL 40827 exerts solely anticonvulsive effects at a high dose. Finally, it reduces the intergroup aggressiveness in the mouse. 3) Action on the cardiovascular and respiratory system It is observed that CRL 40827 acts as hypotensive and tachycardia-inducing agent in the anaesthetized dog and in the genetically hypotensive, awake rat, that it reduces the vascular resistances of the areas explored (vertebral, femoral and renal) and the total peripheral resistance, that it reduces the work of the left-hand ventricle and shortens the diastole, that it stimulates respiration, that it reduces the hypertensive effects of the noradrenaline from the dose of 1 mg/kg in the dog (the maximum effect being attained at the dose of about 10 mg/kg.

The local rates of flow of blood do not increase but the resistances diminish; this phenomenon would imply that the CRL 40827 induces an arterial peripheral vasodilation at the same time as an increase in the venous drainage since the cardiac output remains equal. 4) Action on the biliary secretion In the dog anaesthetized with Nembutal, the normal biliary output collected in 3θ minutes is 1.5 ml; the biliary output increases after intraduodenal injection of CRL 40827 and passes to 1.75 ml for 2.5 mg/kg of CRL 4o827, to 2.25 ml for 5 mg/kg and to 2.5 ml for 10 mg/kg. In the rat anaesthetized with Nembutal, »1083 the biliary output increases 1 to 3 hours after I.V. injection of CRL 40827 at the doses of 5 mg/kg and 25 mg/kg.

) Local anaesthetic effect The anaesthetic effect was studied in the guinea pig after injection of CRL 40827 by the intradermic route in a volume of 0.2 ml at concentrations of 0.1, 0.5 and 1% (3 guinea pigs per dose). Each animal receives physiological serum, procaine and CRL 40827 in defined zones.

The test, which consists in a series of 6 injections in the injected zone is carried out 5, , 15, 20, 25 and 30 mins, after the injection.

It is ascertained that the CRL 40827 has a local anaesthetic effect when it is administered at concentrations of 0.5 and 1%.

C) Tests relative to CRL 40854 (Example 5) CRL 4o854, in solution in distilled water,was administered by the intraperitoneal route in a volume of 20 ml/kg in the male mouse and 5 ml/kg in the male rat. 1. Toxicity The maximum non-lethal dose, LD-O, is greater than 128 mg/kg and less than 256 mg/kg in the mouse. 2. Action on the CNS By proceeding according to the modi operandi given hereinabove, for the CRL 40827, the following is observed.

Interaction with aP2J2£Pbine At the doses of 16 and 64 mg/kg in the mouse, CRL 40854 moderately opposes the hypothermiainducing action of apomorphine without modifying the behaviour of verticalisation and stereotypes.

In the rat, the CRL 40854 does not modify Si 083 the stereotypes induced by apomorphine.

Interaction with amphetamine At the doses of 8 and 32 mg/kg, CRL 40854 potentiates the duration of the stereotypes induced by amphetamine.

Interaction with reserpine At the doses of 4, 16 and 64 mg/kg, CRL 4o854 moderately antagonises the hypothermia induced by reserpine without modifying the ptosis.

Interaction with_oxotremorine At the doses of 16 and 64 mg/kg, CRL 4o854 aggravates the hypothermia-indueing effect of oxotremorine. It does not modify the tremors and signs of cholinergic peripheral stimulation.

Action on_the four plate test^ traction and electric shock Like the CRL 40827, the CRL 40854 does not produce any increase in the number of incorrect moves which are punished and does not bring about any major motor incapacity. On the other hand, it does not modify the convulsing effects of the electric shock.

Action on the spontaneous motility At a high dose (64 mg/kg), the CRL 40854 moderately reduces the spontaneous motility of the mouse. Action with respect to a few behaviours disturbed by various agents a) Motility reduced by_habituation_to_the_ The CRL 4o854 does not provoke a clear renewal of the motor activity in the mouse habituated to its cage. b) Motility reduced_by_hypoxic_aggression_ Like the CRL 40827, the CRL 40854 does not produce any improvement in the motor recovery in the mouse. c) Asphyxic anoxia The CRL 40854 does not modify the S1Q83 appearance of convulsions and death consecutive to an anoxia provoked by blocking (curarieation).

In conclusion, the CRL 40854, which reduces the intergroup aggressiveness in the mouse, has surprising results with respect to the conventional sedative and antidepressant agents.

In clinical trials, good results have been obtained with CRL 40727, CRL 40827 and CRL 4O827A, in the psychotropic domain as sedative and antidepressant agents.

In particular, CRL 40727 and CRL 40 827A each gave excellent results as antidepressant agents in man after having been administered in the form of tablets or gelatin-coated capsules each containing 5 mg of active ingredient, at aiate of 3 tablets or capsules per day.

Claims (11)

1. CLAIMS:1. A compound belonging to the family of fluorophenacylamine derivatives of the formula (I) 5 wherein A is CO or CHOH and R is CH(CH 3 ) 2 or C(CH 3 ) 3 , said compound being selected from N-(4-fluorophenacyl)isopropylamine, N-(2-fluorophenacyl)-tert.-butylamine, 1-(2-fluorophenyl)-2-tert.-butylamino-l-ethanol, 1-(4fluorophenyl)-2-tert.-butylamino-l-ethanol and their 10 addition salts.

2. N-(4-Fluorophenacyl)-isopropylamine or an addition salt thereof.

3. N-(2-Fluorophenacyl)-tert.-butylaroine or an addition salt thereof. 15

4. 1-(2-Fluorophenyl)-2-tert.-butylamino-l-ethanol or an addition salt thereof.

5. l-(4-Fluorophenyl)-2-tert.-butylamino-l-ethanol or an addition salt thereof.

6. A therapeutic composition which contains, in 20 association with a physiologically acceptable excipient, at least one fluorophenacyl-amine derivative according to claim 1 or a non-toxic addition salt thereof.

7. A compound as claimed In any one of claims 1 to 5 or a non-toxic addition salt thereof, or a therapeutic composition as claimed in claim 6 for use as a sedative agent. 5

8. , A fluorophenacyl - amine derivative of the formula 1 given and defined in claim 1 or an addition salt thereof, substantially as hereinbefore described and exemplified.

9. A process for the preparation of a fluorophenacylamine derivative of the formula I given and defined in 10. Claim 1 or an addition salt thereof, substantially as hereinbefore described and exemplified.

10. A fluorophenacyl-amine derivative of the formula I given and defined in claim 1 or an addition salt thereof, whenever prepared by a process claimed in claim 9.

11. 15 11. A therapeutic composition according to claim 6, substantially as hereinbefore described.