Fluorophenacyl-amine derivatives and application thereof in therapeutics

The present invention relates to new compounds belonging to the family of fluorophenacyl-amine derivates of formula: ##STR1## [wherein A is CO or CHOH and R is CH(CH.sub.3).sub.2 or C(CH.sub.3).sub.3 ] and selected from the group consisting of N-(4-fluorophenacyl)-isopropylamine, N-(2-fluorophenacyl)-tertiarybutylamine, 1-(2-fluorophenyl)-2-tertiarybutylamino-1-ethanol, 1-(4-fluorophenyl)-2-tertiarybutylamino-1-ethanol, and their addition salts, These new derivatives are useful in therapeutics, particularly as anti-aggressive agents, anti-anorexia nervosa agents, sedative agents, and CNS- antidepressants.

BACKGROUND 
The present invention relates, by way of new industrial products, to 
fluorophenacyl-amine derivatives, and also to the application thereof in 
therapeutics as unexpectedly and significantly superior anti-anorexia 
nervosa agents and anti-aggressive agents as well as beta-stimulating 
agents and antidepressant agents 
In the following specification, fluorophenacylamine derivates are 
understood to mean not only compounds having a fluorophenacyl group or 
formula F--C.sub.6 H.sub.4 --CO CH.sub.2 --, but also a 
.beta.-hydroxyfluorophenethyl group of formula F--C.sub.6 H.sub.4 
--CHOH--CH.sub.2 --, 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 Pat. No. 1 503 517 and presented as antidiuretic 
agents. However, it should be noted that this French patent describes no 
1-(fluorophenyl), 1-(chlorophenyl), 1-(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-(fluorophenyl)-1-ethanols have already been described. In 
particular, the article by A.M. Lands, J. Pharmacol. Exptl. Therap. 106, 
440-443 (1952) disclosed 1-(3-flurophenyl)-2-isopropylamino-1-ethanol and 
1-(3-fluorophenyl)-2-tertiary-amino-1-ethanol as being weak pressor 
agents. The article by L. Villa, et al., I1 Farmaco Ed. Scientifica, 24 
(No. 3), 329-340 (1969), discloses 
1-(4-fluorophenyl)-2-isopropylamino-1-ethanol and 
1-(2-fluorophenyl)-2-isopropylamino-1-ethanol. These known fluorinated 
products act on the CNS but they have no, or only slight, 
aggression-reducing effect. Further, analogous compounds are also 
disclosed as being adrenergic blocking agents in the article by B. Levy, 
et al., J. Phamarmacol. Exptl. Therap., 133, 202-210 (1961); as 
appetite-supressing agents in U.S. Pat. Nos. 3,313,687 (Siemer) and 
3,465,039 (Seimer); as CNS-stimulant and antidepressant agents in U.S. 
Pat. No. 3,819,706 (Mehtay; and as anti-diuretic agents in British Pat. 
No. 1,043,510. 
It has been unexpectedly found that the new fluorophenacyl-amine 
derivatives of the present invention, which act on the CNS, have 
particularly advantageous antiaggressive and anti-anorexia nervosa 
properties from the therapeutical standpoint. 
According to the invention, a compound belonging to the family of 
fluorophenzcyl-amine derivatives of formula: 
##STR2## 
wherein A is CO or CHOH, and R is CH(CH.sub.3).sub.2 or C(CH.sub.3).sub.3, 
is recommended as new industrial product, particularly useful in 
therapeutics, said compound being characterised in that it is selected 
from the group consisting of N-(4-fluorophenacyl)-isopropylamine, 
N-(2-fluorophenacyl)-tertiobutylamine, 
1-(2-fluorophenyl)-2-tertiarybutylamino-1-ethanol, 
1-(4-fluorophenyl)-2-tertiaryamino-1-ethanol, and their addition salts. 
From these products, the preferred compounds from the therapeutical 
standpoint are N-(4-flurophenacyl)-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 slats. 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, benezoic, 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 ICH.sub.3 and CICH.sub.3. The 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 
reactional mechanisms. The recommended process for preparation consists of 
the following: 
(1) in obtaining a "carbonyl" compound (A=CO) by reacting a fluorophenacyl 
halide of formula 
##STR3## 
(wherein X.sub.1 is C1 or Br) with an amine of formula 
EQU H.sub.2 NR (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.sub.4. 
The compounds according to the invention are all active on the CNS and also 
have interesting cardiovascular effects. In particular, they act on the 
CNS as sedative agents, antidepressants and superior antiaggressive agents 
and are unexpectedly indicated in the treatment of anorexia nervosa as 
well as depression. 
DETAILED DESCRIPTION 
According to the invention, a therapeutic composition is recommended, 
particularly useful in the treatment of aggression, anorexia nervosa and 
depression, characterized in that it contains, in association with a 
physiogically acceptable excipient, at least one fluorophenacyl-amine 
derivative according to the present invention or one of its nontoxic 
addition salts, the active ingredient being, of course, administered at a 
pharmaceutically effective amount. 
Comparative tests have been carried out to demonstrate those effects on 
animals which distinguish the products according to the present invention 
from their closest known fluorinated analogues. Among these tests, those 
concerning the antiaggressive properties and anti-anorexia nervosa 
properties have been summarized. 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 center, groups of 3 male mice each weighing 
about 20g receive by interperitoneal 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 batch, 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 product 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 structure-activity 
relationship. 
TABLE I 
__________________________________________________________________________ 
##STR4## 
Dose reduction of intergroup 
Product 
Code No. 
X A R mg/kg aggressiveness 
__________________________________________________________________________ 
Example 1 
CRL 40727 
4-F 
CO CH(CH.sub.3).sub.2 
8 75% 
(a) 
Example 2 
CRL 40828 
2-F 
CO C(CH.sub.3).sub.3 
8 61% 
(a) 
Example 3 
CRL 40827 
2-F 
CHOH 
C(CH.sub.3).sub.3 
8 76% 
(a) 
Example 4 
CRL 40827A 
2-F 
CHOH 
C(CH.sub.3).sub.3 
8 78% 
(b) 
Example 5 
CRL 40854 
4-F 
CHOH 
C(CH.sub.3).sub.3 
8 69% 
(a) 
CP1 -- 3-F 
CHOH 
CH(CH.sub.3).sub.2 
8 5% 
(a) (c) 
CP2 -- 3-F 
CHOH 
C(CH.sub.3).sub.3 
8 31% 
(a) (c) 
CP3 CRL 40853 
4-F 
CHOH 
CH(CH.sub.3).sub.2 
8 40% 
(a) (d) 
CP4 -- 2-F 
CHOH 
CH(CH.sub.3).sub.2 
8 6% 
(a) (d) 
__________________________________________________________________________ 
Notes- 
(a): hydrochloride; 
(b): fumarate; 
(c): described by A. M. LANDS; 
(d): described by L. VILLA et al 
It was surprisingly discovered that compounds according to the present 
invention exhibit an unexpected and valuable action against anorexia 
nervosa. It was generally thought in the prior art that CNS-active 
substances which exhibit beta-stimulant and antidepressant properties 
would also exhibit an anorexigenic or appetite-supressant effect. See, for 
example, U.S. Pat. Nos. 3,313,687 (Siemer), 3,465,039 (Siemer), and 
3,819,706 (Mehta). However, a recently published clinical assay by F. 
Lang, et al. appearing in Societe Medico-Psychologique-Meeting of Monday 
July 4, 1983, shows that the compound of Example 3 of the present 
invention (Code No. CRL 408227) is a beta-stimulant and antidepressant 
agent which exhibits an unexpected action against anorexia nervosa. 
Accordingly, comparative tests were carried out to demonstrate this effect 
and to distinguish the compounds of to the present invention from the 
closest prior art compounds. These tests were concerned with the 
determination of weight variation after treatment in animal and in female 
human patients suffering from anorexia nervosa. 
The first series of experiments assessed the weight variation of adult 
female rats (weighing approximately 190 g each) receiving a daily dose of 
from 3 to 10 mg/kg of the compound to be tested (batch of 10 animals per 
product) with respect to control animals (batch of 15 animals). After 
three weeks of treatment with the compounds hereinafter listed in Table 
II, the results are summarized in Table III and are expressed as weight 
variation percentages. In these tables the compounds of the present 
invention are referenced as Ex 1-Ex 5, and the comparative compounds of 
the prior art are referenced CP 1-CP 14. 
It was expected that all tested compounds should exhibit an appetite 
depressing action expressed as a negative weight variation after 
treatment. The results show that surprisingly Ex 3 (CRL 40827) and Ex 5 
(CRL 40854) as well as CP 1-2 and CP 4 cannot be considered as appetite 
supressing substances. Unlike the other compounds which reduce the animal 
weight by more than 10%, these compounds resulted in a positive weight 
variation. 
TABLE II 
______________________________________ 
##STR5## 
Product Code number 
X Y A R 
______________________________________ 
Ex 1 (a) CRL 40 727 4-F H CO CH(CH.sub.3).sub.2 
Ex 2 (a) CRL 40 828 2-F H CO C(CH.sub.3).sub.3 
Ex 3 (a) CRL 40 827 2-F H CHOH C(CH.sub.3).sub.3 
Ex 4 (b) CRL 40 827A 
2-F H CHOH C(CH.sub.3).sub.3 
Ex 5 (a) CRL 40 854 4-F H CHOH C(CH.sub.3).sub.3 
CP 1 (a) (c) 
-- 3-F H CHOH CH(CH.sub.3).sub.2 
CP 2 (a) (c) 
-- 3-F H CHOH C(CH.sub.3).sub.3 
CP 3 (a) (d) 
CRL 40 853 4-F H CHOH CH(CH.sub.3).sub.2 
CP 4 (a) (d) 
-- 2-F H CHOH CH(CH.sub.3).sub.2 
CP 5 (a) (e) 
-- 3-F CH.sub.3 
CO C(CH.sub.3).sub.3 
CP 6 (a) (f) 
-- 3-F CH.sub.3 
CO CH(CH.sub.3).sub.2 
CP 7 (a) (g) 
-- 3-F CH.sub.3 
CHOH C(CH.sub.3).sub.3 
CP 8 (a) (h) 
-- 3-F CH.sub.3 
CHOH CH(CH.sub.3).sub.2 
CP 9 (a) (f) 
-- 3-F H CO C(CH.sub.3).sub.3 
CP 10 (a) (i) 
-- 4-Cl CH.sub.3 
CO CH.sub.2 CH.sub.3 
CP 11 (a) (j) 
-- H H CHOH C(CH.sub.3).sub.3 
CP 12 (a) (j) 
-- 3-OH H CHOH CH(CH.sub.3).sub.2 
CP 13 (a) (k) 
-- 2-Cl H CHOH C(CH.sub.3).sub.3 
CP 14 (a) (k) 
-- 4-Cl H CHOH C(CH.sub.3).sub.3 
______________________________________ 
Notes:- 
(a): hydrochloride; 
(b): fumarate; 
(c): disclosed by A. M. LANDS; 
(d): disclosed by L. VILLA et al., Il Farmaco Ed. Scientifica, 24 (No. 3) 
329-340 (1969) 
(e): disclosed by MEHTA 
(f): isomer of Ex 2 suggested by 
(g): disclosed as intermediate product in published Danish pat. appl. No. 
134 984; 
(h): isomer of Ex 3 suggested by 
(i): disclosed by SIEMER 
(j): laevoisomer disclosed in Brit. patent No. 1,043,510(*) suggested by 
WOLLWEBER 
(*)and in U.S. Pat. No. 3,344,188 (WOLLWEBER) 
TABLE III 
______________________________________ 
WEIGHT VARIATION OF ADULT FEMALE RATS 
weight variation 
Product Code No dose % (a) 
______________________________________ 
Ex 1 CRL 40 727 10 mg/kg -10.1 (b) 
Ex 2 CRL 40 828 5 mg/kg -12.2 (b) 
Ex 3 CRL 40 827 5 mg/kg +0.2 
Ex 4 .sup. CRL 40 827A 
5 mg/kg -0.1 
Ex 5 CRL 40 854 5 mg/kg +0.3 
CP 1 -- 5 mg/kg -0.1 
CP 2 -- 10 mg/kg +0.3 
CP 3 CRL 40 853 5 mg/kg -10.5 (b) 
CO 4 -- 5 mg/kg -1.4 
CP 5 -- 10 mg/kg -15.3 (b) 
CP 6 -- 10 mg/kg -16.4 (b) 
CP 7 -- 5 mg/kg -17.3 (b) 
CP 8 -- 10 mg/kg -14.2 (b) 
CP 9 -- 10 mg/kg -10.3 (b) 
CP 10 -- 5 mg/kg -18.1 (b) 
CP 11 -- 10 mg/kg -8.5 
CP 12 -- 5 mg/kg -7.3 (b) 
CP 13 -- 5 mg/kg -15.4 (b) 
CP 14 -- 5 mg/kg -13.2 (b) 
______________________________________ 
Note 
(a) with respect to the control animals 
(b) statistically significant 
In a second series of experiments women suffering from anorexia nervosa 
were treated with Ex 3, Ex 5, CP1, CP2 and CP4 to determine which products 
would induce weight uptake. Those compounds which induce the expected 
prior art weight reduction were not utilized in this series of tests to 
avoid the ethical problem that may have resulted from administering 
potential appetite-depressing agents to anorexia nervosa subjects. The 
results of this series of experiments are summarized hereinafter in Table 
IV. In conjunction with a normal diet, patients were given either a 
placebo (Treatment A), or one of the compounds to be tested (Treatments 
B-F) at a daily dose of 3 mg per os (more precisely, one tablet at 
breakfast time and one tablet at dinner time, each tablet containing 1.5 
mg of compound to be tested) for 30 days. These results show that Ex 3 
(which produces a weight variation of +4.3 to +14.1 kg) and Ex 5 (which 
produces a weight variation of +4.1 to +10 kg) confirm the results 
obtained by F. Lang, et al. and demonstrate the effectiveness of these 
products as anti-anorexia nervosa compounds. 
TABLE IV 
______________________________________ 
CLINICAL RESULTS 
weight treat- 
weight varia- 
Pa- age ideal weight 
before treat- 
ment tion after 
tient 
year kg (a) ment kg (b) treatment kg 
______________________________________ 
1 181/2 47 32.3 A +0.1 
2 19 50 37.6 A -0.2 
3 24 50 36 A -0.2 
4 161/2 49 31.5 A +0.1 
5 161/2 45 29.7 A (c) 
6 19 50 31.4 A +0.1 
7 23 48 30.3 A -0.1 
8 31 45 28.9 A +0.1 
11 25 48 31.5 B +11.1 
12 191/2 50 30.6 B +12.6 
13 161/2 52 32 B +4.5 
14 151/2 48 32.6 B +7.2 
15 20 49 31.5 B +8.1 
16 201/2 49 33.4 B +4.3 
17 20 50 35 B +5 
18 21 46 29.7 B +14.1 
19 18 51 31 B +7.3 
20 32 45 29.3 B +10.7 
21 21 46 30.5 C +4.5 
22 191/2 50 32 C +7.8 
23 17 52 35 C +10 
24 28 46 29.5 C +4.1 
25 181/2 49 30.5 C +7.5 
31 19 48 31 D +0.2 
32 191/2 48 33 D -0.2 
33 27 45 30.8 D (c) 
34 18 50 29.4 D (c) 
35 161/2 48 30.5 D +0.1 
41 241/2 48 31 E -0.1 
42 19 48 32.3 E -0.3 
43 181/2 49 29.5 E +0.1 
44 29 45 31.2 E -0.2 
45 21 50 32.5 E -0.1 
51 22 45 31.8 F 0 
52 27 47 30.5 F (c) 
53 21 45 29.8 F -0.3 
54 19 45 32.1 F +0.2 
55 171/2 50 31.2 F -0.1 
______________________________________ 
Notes 
(a) in view of patient age and heigth 
(b) nature of treatment: 
A placebo for 30 days 
B daily dose of 3 mg of Ex 3 for 30 days 
C daily dose of 3 mg of Ex 5 for 30 days 
D daily dose of 3 mg of CP 1 for 30 days 
E daily dose of 3 mg of CP 2 for 30 days 
F daily dose of 3 mg of CP 4 for 30 days 
(c) treatment stopped since untolerated 
Some examples of preparation have been given hereinafter by way of 
non-limiting illustration.

PREATION I 
Obtaining of the hydrochloride of N-(4-fluorophenacyl)-isopropylamine 
##STR6## 
(Example 1: Code No.: CRL 40727) 
25 ml of bromine are poured, dropwise, into a solution, cooled by an ice 
bath, of 69 g(0.5 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 
in a solution of 210 ml of isopropylamine in 100 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: 14.8%) of CRL 40727 are obtained. m.p. 
207.degree. C. (with decomposition). 
Analysis: % N measured=6.01%. 
% N theoretical=6.04%. 
PREATION II 
Obtaining of the hydrochloride of N-(2-fluorophenacyl)-tertiarybutylamine 
##STR7## 
(Example 2; Code No.: CRL 40828) 
50g (0.362 mol) of orthofluoroacetophenone are dissolved in 75 ml of acetic 
acid. The mixture is cooled by an ice bath and 18.1 ml of bromine are 
poured dorpwise. 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 tertiobutylamine 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 (1:1) v/v mixture, 18 g (yield=20%) of CRL 40828 are 
obtained. m.p.=240.degree. C. (with decomposition). 
Analysis: % N measured=5.74%. 
% N theoretical=5.7%. 
PREATION III 
Obtaining of the hydrochloride of 
1-(2-fluorophenyl)-2-tertiarybutylamino-1-ethanol. 
##STR8## 
(Example 3; Code No.: CRL 40827) 
0.04 mol of N-(2-fluorophenacyl)-tertiarybutylamine (free base of the CRL 
40828) is dissolved in 120 ml of methanol. Cooling is effected to 
-5.degree. C. and 3 g of sodium borohydride are added. It is left in 
contact for 1 hour. The excess NaBH.sub.4 remaining in the reactin 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.sub.4. After filtration, the free base is collected then the expected 
hydrochloride is precipitated by means of hydrochloric ethanol. By 
recrystallization in an acetone-ethanol (1:1) v/v mixture, 8 g (yield: 
80%) of CRL 40827 are obtained. m.p.=180.5.degree. C. 
Analysis: % N measured=5.60%. 
% N theoretical=5.65%. 
PREATION IV 
Obtaining of the fumarate of 
1-(2-fluorophenyl)-2-tertiarybutylamino-1-ethanol 
(Example 4; Code No. CRL 40827 A). 
By reacting 1-(2-fluorophenyl)-2-tertiarybutylamine-1-ethanol (free base 
obtained in Preparation III) with fumaric acid, CRL 40827A is obtained. 
m.p. 195.degree.-200.degree. C. (with decomposition). 
PREATION V 
Obtaining of the Hydrochloride of 
1-(4-fluorophenyl)-2-tertiarybutylamino-1-ethanol 
##STR9## 
(Example 5: Code No.: CRL 40854) 
50 g (0.289 mol) of .alpha.-chloro-p-fluoroacetophenone are dissolved in 
900 ml of methanol. The mixture is cooled to -5.degree. C. and 5.80 g of 
NaBH.sub.4 are added. It is left in contact for 1 hour then 10 ml of 
acetic acid are added. 151 ml of tertiarybutylamine 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-tertiarybutylamino-1-ethanol are 
obtained. m.p. 117.degree. C. 
This base is dissolved in diethyl ether, the hydrochloride is precipitated 
by means of hydrochloric ethanol. By filtration and drying in vacuo over 
P.sub.2 O.sub.5, 44 g (yield: 61%) of CRL 40854 are obtained. m.p. 
176.degree. C. 
CRL 40854 may also be prepared according to the process of preparation III, 
when replacing the N-(2-fluorophenacyl)-tertiarybutylamine by 
N-(4-fluorophenacyl)-tertiarybutylamine. 
Additional tests carried out with the preferred products according to the 
present invention have been summarized hereinafter. 
(A) Tests relative to CRL 40727 (Example 1) 
1. Toxicity 
The maximum non-lethal dose, LD-O, 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, 
hypomotility and reduction of aaggressiveness in the mouse, 
hyopthermia and potentiation of the hypothermia-inducing effects of 
apomorphine, oxotremorine and reserpine, 
moderate antagonism of the stereotypies induced by amphetamine. 
3. Action on the cardiovascular system 
(a) By the intraveinous route 
Two dogs receive CRL 40727 by the intraveinous route, in perfusion in 6 
minutes, at the successive doses of 0.1 mg/kg, 1 mg/kg, 2.5 mg/kg/ 5 
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/kg; the effect increases with the dose, up to 10 mg/kg, dose for which 
+140% 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 bilary 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 40727, and a greater hypotension is observed 
than at the preceding dose, the bilary 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 Pat. No. 1,325,192, is coded LL 1656 and is marketed under 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 40727 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 165 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 obtained 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 intraveinous route, at 
the dose of 6 mg/kg, does not cause additional vasodilation. 
In conclusion, the results obtained by the intraveinous route and by the 
intraduodenal route are difficult to compare, hypotension occurring in the 
dogs treated by the intraveinous 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 .beta..sub.2.sup.+ 
action; no .beta..sub.1.sup.+ action 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 40827, 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 apomorphine 
(a) Mouse 
Batches of 6 mice receive CRL 40827 half an hour before the subcutaneous 
injection of apomorphine at the does of 1 or 16 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 stereotypies. 
(b) Rat 
CRL 40827 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 stereotypies induced by apomorphine in the 
rat. 
INTERACTION WITH AMPHETAMINE 
Amphetamine (2 mg/kg) is injected by the intraperiotoneal route to batches 
of 6 rats, half an hour before administration of CRL 40827. It is noted 
that, except for the isolated reduction of the index of stereotypies, 
observed at the dose of 4 mg/kg, CRL 40827 does not modify stereotypies 
induced by amphetamine. 
INTERACTION WITH RESERPINE 
Four hours after the intraperitoneal injection of 2.5 mg/kg of reserpine, 
batches 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 40827 is administered to batches 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 TEST, 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 does, opposes the convulsing effects 
of the electric shock. 
ACTION ON THE SPONTANEOUS MOTILITY 
Half an hour after having received CRL 40827, the micr (6 per dose, 12 
controls) are placed in an actimeter where their motility is recorded for 
30 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 (34 Mg/kg), CRL 40827 seems to provide a 
moderate renewal of motor activity. 
(b) MOTILITY REDUCED BY HYPOXIC AGGRESSION 
Half an hour after having received the CRL 40827, the mice (10 per dose, 20 
controls) are subjected to acute anoxia by pressure reduction [depression 
of 600 mm Hg (i.e. 8.times.10.sup.4 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 34 mg/kg of Gallamine Triiodoethylate. 
At the highest dose (34 mg/kg CRL 40827 prevents the appearance of 
convulsions and death in 40% of the animals. 
CONCLUSION RELATIVE TO THE ACTION ON THE CNS 
The antagonism of the hypothermiae 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 
imipraminic antidepressants. 
On the other hand, the absence of antagonism of the ptosis induced by 
reserpine, and of motor stimulation with stereotypies makes it possible to 
distinguish the CRL 40827 from the IMAO and amphetaminic compounds 
respectively. In brief, there is a strong presumption that the CRL 40827 
behaves like the 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 tachycardiainducing 
agents in the anaesthetized dog and in the genetically hypotensive, awake 
rat, that it reduces the vascular resistances of the territories explored 
(vertebral, femoral and renal) and the total peripheral resistance, that 
it reduces the work of the left-hand ventricule 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 
veinous 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 30 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 40827, 
to 2.25 ml for 5 mg/kg and to 2.5 ml for 10 mg/kg. In the rat 
anaesthetized with Nembutal, 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. 
5. 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 
physiologcal 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, 10, 15, 20, 25 and 30 minutes after the injection. It is 
ascertained that the CRL 40827 has a local anesthetic effect when it is 
administered at concentrations of 0.5 and 1%. 
C. Tests relative to CRL 40854 (Example 5) 
CRL 40854, 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 Apomorphine 
At the doses of 16 and 64 mg/kg in the mouse, CRL 40854 moderately opposes 
the hypothermia-inducing action of apomorphine without modifying the 
behaviour of verticalisation and stereotypies. 
In the rat, the CRL 40854 does not modify the stereotypies induced by 
apomorphine. 
INTERACTION WITH AMPHETAMINE 
At the doses of 8 and 32 mg/kg, CRL 40854 potentialises the duration of the 
stereotypies induced by amphetamine. 
INTERACTION WITH RESERPINE 
At the doses of 4, 16 and 64 mg/kg, CRL 40854 moderately antagonises the 
hypothermia induced by reserpine without modifying the ptosis. 
INTERACTION WITH OXOTREMORINE 
At the doses of 16 and 64 mg/kg, CRL 40854 aggravates the 
hypothermia-inducing effect of oxotremorine. It does not modify the 
tremours 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 tne electric shock. 
ACTION ON THE SPONTANEOUS MOTILITY 
At a high does (64 mg/kg), the CRL 40854 moderately reduces the spontaneous 
motility of the mouse. 
ACTION WITH RESPECT TO A FEW BAHAVIOUR DISTURBED BY VARIOUS AGENTS 
(a) MOTILITY REDUCED BY HABITUATION TO THE CAGE 
The CRL 40854 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 appearance of convulsions and death 
consecutive to an anoxia provoked by blocking (curarisation). 
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 clinic, good results have also been obtained with CRL 40727, CRL 40827 
and CRL 40827A, in the psychotropic domain as sedative and 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 the 
rate of 3 tablets or gelules per day.