CA1199916A - Benzhydrylsulfinylacetamide derivatives - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

The present invention relates to new industrial products, benzhydrylsulfinylacetamide derivatives of the formula:

(I) in which:
- Xl and X2, which may be identical or different, each represent H, Cl or F, - Z1 represents CH3, CH2CH3, CH(CH3)2, or C(CH3)2 and Zl can represent in addition a hydrogen atom when at least one of Xl and X2 is different from H, - Z2 represents H, and NZ1Z2 considered together can represent a piperidino or morpholino group.
These novel derivatives which act on the CNS are useful therapeutic agents.

Description

The present invention relates to novel benzhydrylsulfinylacetamide derivates as novel industrial products. It relates also to the use of these novel derivatives in therapeutics, particularly as medicaments active on the central nervous sytem (CNS).
From U.S. Patent No. 4 177 290, it is knot~ that benzhydrylsulfinylacetamide [described in Example 1 and having the code No. "CRL 40 476") has a particular neuro-psychopharmac~logical spectrum:
- presence:
excitation with hyper-reactivity hypermotility, and - absence of stereotypies (except at high doses), 15 potentiation of apomorphine and amphetamine effects.
Novel derivatives of benzhydrylsulfinylacetamide are now recognised which have interesting pharmacological properties.
The novel derivatives of benzhydrylsulfinylacetamide according to the invention are characterized in that they correspond to the general formula ~D~, ~\ ~ Z
X1 \ CH-SO-CH -CO-N (I) ~ y 2 in which - Xl and X2, which may be identical or different, each represent H, Cl or F, ~ Zl represents CH3, CH2CH3, CH(CH3)2, 3 2 can represent in addition a hydrogen atom when at least one of Xl and X2 is different from H, ~ Z2 represents H, and NZlZ2 considered toyether can represent a piperidino or morpholino group.
The preferred groups Xl and X2 are H, 4-Cl and 4-F.

``` : : :

~3~

In Table 1 below, are given, in non-limiting manner, a certain number of compounds according to formula I, stating their essential acti~ity on the CNS.
The products of formula I can be prepared by a method known in itself by the application of conventional reaction mechanisms, for example, by employing onP of the two methods described in the aforesaid V.S. Patent. The process recommended here consists:
1) of reacting an acyl chloride of the formula ~9 Xl ~ ~ CH-S-CH2-CO-Cl (II) ,~

(where Xl and X2 are defined as above) with an amine HNZlZ2 (III) (where Zl and Z2 are defined as above) to obtain a derivative of benzhydrylsulfinylacetamide of the formula X ~ CH-S-CH -CO-NZ Z (IV) (where X1, X2~ Zl and Z2 ars defined as above), and

2) subjecting the above-said derivative of benzhydrylthioacetamide to an oxidation reaction by means of 110-130 volume H2O2 ti.e. a solution in water containing from about 32 g/l to 40 g/l of hydrogen peroxide) at a temperature below or equal to 45C.
The compounds of formula I all act on the CNS. The products of Examples 1-3 and 7-8 are stimulant agents, on the other hand the products of Examples 4-6 are sedative agents.
A therapeutic composition is recommended which is characterised in that it contains in association with a physiologically-acceptable excipient at least one compound of formula I as active ingredient. This active ingredient is, of course, used in a pharmaceutically effective amount.

t ~ . ~

o ~ ~ ~ ~ ~ ~ ~
~ ~
E~ ~ ~ ~f rl -1r~ ~ ~ ~ ~
!~
H
4 Q) ~J C) t/7 ~n c) Ul U) Ul t,~ U) ~
H
~ V ~) ~) o ~ C~ D N V ~) ~; L" O O O d- O O ~) C`l H , ~ L'\ ¦ ¦ ¦ L~
.- ~ ~ ~1~1 ~ ~ ~1 ~. r~

-I u~ c~J r~ ~ r r~
~ ~ v ~ v ~
2 0 m ~ ~; ,-, ~ /\
E~ / \ ~
~ ~ X ~: m ~ x ~
N _ --~5 ~- ~
X ~ X

¢ ¢ :

3 û cn a~ a~ ~ ~ ~ ~ c~ o ~
~ ~ ~ $
v ~

c~
_ ~ ~
~ ~ : : a) :
3 5 : : u . cu ~ ~ u~
~; ~ a) ~ a) ~ aJ ~ ~i aJ ~ ;) :
~: ~J
~: ~ ~ : ~ ;~ :
: ` : : ~ ~:
: : : : :
__ ~ :

;

. :

~ ~3~

The compounds of the formula I according to the invention mainly differ from the previously known benzhydrylsulfinylacetamide (CRL 40476) in view of their action on sleep induced by a barbituric compound: the compounds of formula I diminish the sleep duration induced in male mice (batch of ten animals per doses and per product to be tested) by pentabarbital (50mg/kg I.P.
administered 0.5h after administration by I.P. route or product to be ~ested3 while CRL 40476 does not modify the pentaharbital sleep duration. This difference which is therapeutically useful is illusrated by Table IV.

~5 ~5 ~'39~6 TABLE I~

Product Code No. Action on Pentabarbital (50 mg/kh I.P.) sleep duration dose effect Example 1 CRL 40920 128mg/kg l.P. (a) Example 2 CRL 40920 256mg/kg l.P. (a) Example 4 CRL 40936 64mg/kh l.P. (a) 10Example 4 CRL 40936 128mg/kg l.P. (a) Example 4 CRL 40936 256mg/kg l.P. (a) Example 5 CPL 40489 128mg/kg l.P. (a) 15Example 7 CRL 40933 8mg/kg l.P. (a) Example 8 CRL 40940 32mg/kh l.P. (a) Example-9 CRL 41018 16mg/kh l.P. (a) Comparative 20product CIL 40476 ~rom 8 to 256mg/kh (b) Notes:
(a) important diminution of sleep duration (b) no significant modification of sleep duration 9~

Below are given some examples of the preparation, which are in no way limiting but given purely by way of illustration, of compounds according to the invention.
PREPARATION I
Obtaining of 4-N-methyl-benzh~drylsulfinylacetamide IExample l; code no- CRL 40920) 1) Benzhydry~h_oacetic acl_ Into a triple-necked flask, are placed 91.2 g (1.2 mole) of thiourea in a mixture of 520 ml of 48% (w/v) ~Br and 80 ml of water. The reaction medium is brought to 60C and 184 g (1 mole) of benzhydrol is added in one batch. The temperature is raised to 95C and then cooled:
the thiouronium hydrobromide precipitates in the form of small orange beads. The latter are filtered and made into a paste several times in water.
The thiouronium salt thus obtained is introduced into a tripled-necked flask with 320 ml of caustic soda (d = 1.38; 3.~ moles); it is brouyht to 70C and drop by drop a solution of 103.95 g ~1.1 mole) of chloracetic acid in 200 ml of water are added drop by drop. After the addition, it is brought to reflux and kept there for 30 min; an insoluble material is formed, and the latter is separated by filtration hot, then the filtrate is cooled and acidified with concentrated HCl: the benhydrylthioacetic acid precipitates. The latter is drained and washed with water.
The benzhydrylthioacetic acid is purified by redis~olving hot in a dilute soda solution; the alkaline solution thus obtained is filtered on charcoal, cooled and acidified with concentrated HCl. The precipitate so obtained is drained and washed with water.
90.4 g of benhydrylthioacetatic acid is collected (yield = 35%) (MP.inst.
2) Benæhy_r~thioac_tic acid chloride Into a triple-necked flask, are placed 25.8 g (0.1 mole) of benhydrylthioacetic acid in 150 ml of benzene, the mixture is heated and drop by drop under reflux 25 ml (0.343 mole) of thionyl chloride added. Once the addition is terminated, the reflux is continued for about .

lh-1.5 h, cooled, and the excess benzene and thionyl chloride evaporated. In this way a clear orange oil is collected.
33 N-methyl-benh~drylthioacetamide Into a tripled-necked flask provided with a condenser, a thermometer and a dropping funnel, are introduced to 28 ml (about 0.3 mole) of methylamine in 50 ml of water and drop by drop the previously obtained acid chloride (about 0.1 mole) dissolved in about 100 ml of methylene chloride, is added~
The mixture is left in contact over night; the next day the organic phase is washed with water, then with a dilute soda solution and again with water. It is dried over Na2SO4, and the methylene chloride evaporated, the precipitate so obtained being taken up again with diisopropyl ether.
After recrystallisation in isopropanol 22~3 g (yield - 82%) of N-methyl-benhydrylthioacetamide are obtained, ~MP.inSt = 101-102C) which is in the form of a white powder.

4) CRL 90920 Into a round-bottomed flask are placed 16.26 g (0.06 mole) of the acetamide previously obtained, 60 ml o~
acetic acid and 6.6 ml of H2O2 (at about 130 volumes), are added; the temperature rises to 4CC and then drops again. When all the sulfide has disappeared, the acetic acid is evaporated, and it is taken up again with water:
the N-methyl-benzhydrylsul~inylacetamide precipitates.
The latter is drained and washed several times with water.
After recrystalli~ation in ethyl acetate 13.8 g (yield = 80~) are collected: CRL 40920 ~MP. = 80-85~C).
CRL 40920 is a white powder, insoluble in ether and ethyl acetate, soIuble in methanol; ethanol and acetone.
Its solubility in water is less than 1 g/l.

PREPARATION I I
PrPparation of N- (benzhydrylsulfinylacetyl)-piperidine ~Example 5; Code No: CRI~ 40489) 1) N- (ben~hydrylthioacetyl)-piperidine Into a triple-necked flask provided with a condenser and a dropping funnel, are placed 23 ml (0.3 mole) of piperidine in about 50 ml of ether and drop by drop 27.2 g t0.098 mole) of benzhydrylthioacetic acid chloridP in solution in about 100 ml of benzene are added. Once the addition is finished, water is added to the eaction mixture. The organic phase is washed with a dilute solu-tion of soda, dilute HC1, then with water, dried over Na2SO4, the solvent evaporated, it is taken up again with a mixture of diisopropyl-ether-petroleum ether. The expected product crystallises. After recrystallisation in ethyl acetate, 21.2 g are collected (yield - 68~) of N-(benhydrylthioacetyl)-piperidine. (MP.inSt 8~-83C).
2) CRL 40489 Into a flask are placed 16.25 g (0.05 mole) of N-(benzhydrylthioacetyl)--piperidine and 50 ml of acetic acid and 5.3 ml of H2O2 ~at about 110 volumes) are added.
The reaction mixture is left overnight at 15-25C, then the acetic acid is evaporated~ The residue after evaporation is taken up with ether to crystallise the expected product. By recrystallisation in ethyl acetate 1~.7 ~ (yield = 77%) are obtained of CRL 40489 (MP.inSt = 150C). The solubility of this product in water is less than 1 g/l.
PREPARATION III
Preparation of 4-chlorobenzhydrylsufin~lacetamide IExample 7; Code No: CRL 40933).
1) 4-chlorobenzylhydxol Into a solution of 0.35 mole of phenylmagnesium bromide in 300 ml of anhydrous ether, are run at 20C a solution of 49.2 g ~0.35 mole) of parachlorobenzaldehyde in 300 ml of anhydrous ether. After 2 h reflux and standing overnight, the precipitate is drained, washed twice with 50 ml of ether~and the resulting filtrate is poured into a vigorously stirred mixture of 200 ml of 6N
HCl and 500 g of ice. The precipitate is drained, washed with water, dried and recrystallised in the mixture methanol-water (80:20) v/v; the 4-chlorobenhydrol is obtain~d (MP = 60-61C) with a 70% yield.
2) 4-chloroben2hydrylthioacetic acid 7~6 g (0.1 mole) of thiourea are dissolved in 50 ml of 48% HBr. It is heated to 40C and simultaneously S0 ml of ethanol and 17.5 g (0.08 mole) of 4-chloro-benzhydrol added, then it is heated 0.25 h under reflux.The alcohol is evaporated under vacuum, 50 ml of cold water added, the thiouronium salt is drained and washed twice with 20 ml of cold water. The moist precipitate is resuspended in 100 ml of water, a solution of 16 g of caus-tic soda in 100 ml of water added and it is heatea 0.25 h on a boiling water bath. Then drop by drop at 60-70C are added a solution of 9.45 g (0.1 mole) of chloroacetic acid, 5g of Na~CO3 and 100 ml of water. It is heated for 1 h on a boiling water bath, acidified with 3N HCl, extracted with ether, the ether phase extracted with dilute bicarbonate r the alkaline solution is filtered over charcoal, it is precipitated with 3N HCl, drained, washed with water, dried and the expected acid obtained (MP = 101-102C) with a 90~ yield.
3) 4-chlorobenæhydrylthioacetamide A solu~ion of 11.7 g (0.04 mole) of 4-chloro-benzhydrylthioacetic acid in 60 ml of benzene and 12 ml of SOC12, are heated for 1 h under reflux, evaporated under vacuum, the oil is taken up agains with 50 ml ether and poured slowly, cold, with stirring into 50 ml of 28~
ammonia. It is stirred lh, the ether is decantecl, washed with water, dried, the ether driven off under vacuum, the residue crystallized in petroleum ether and the expe~ted amide is obtained (~P = 52-53C~ with a 90% yield .
4] CRL 40933 12.3 g ~0.042 mol~ of 4-chlorobenzhydrylthioaceta-mide in solution in 40 ml of acetic acid are oxidised at 40-45~C with 4.2 ml of 110 volume hydrogen peroxideO The acetic acid is evaporated under vacuum, the residue is crystallised in diisopropyl ether and recrystallised in ethyl acetate. In this way CRL 40933 is obtained with a 52~ yield. MP - 145-146C.
PREPARATION IV
Preparation of 4,4'-difluorobenzhydrylsulfinylacetamide -~Example 8; Code No: CRL 40940) 1) 4,4'-difluorobenzhydrylthioacetic acid Into a solution at 50C of 11.4 g (0.15 mole) of thiourea in 75 ml of 48~ Hsr, are added simultaneously 7S
ml of ethanol and 26.4 g (0.12 mole) of 4,4'-difluoroben2hydrol. It is heated 0.25 h under reflux, the alcohol evaporated under vacuum, 50 ml of cold watex added, it is drained and washed twice with 20 ml of cold water. The precipitate is collec~ed, then suspended in lS0 ml of wat2r. The resulting mixture i5 treated with a solution of 20 g (0.5 mole) of caustic soda in 100 ml of water. It is brought to reflux 0.25 h and then at 70-75VC, are added rop by drop a solution of 18 g of chloroacetic acid, 100 ml of water and 9 g of sodium carbonate. After 1 h under re1ux, it is acidified with 3N HCl, drained, washed with water. It is taken up again in water, treated with sodium bicarbonate, ~iltered over charcoal and precipitated with 3N HCl.
After drainingl washing with water and then drying, the expected acid is obtained (MP = 117-118C) with 87%
yield.
2) 4,4'-Difluorobenzhydrylthioacetamide A solution of 14.7 g (0.05 mole) of 4,4'-difluoro-benzhydrylthioacetic acid in 75 ml of ben~ene and 15 ml of thionyl chloride are heated 1 h under reflux.
It is evaporated under vacuum, taken up again with 50 ml of ether and run into a mixture o 60 ml of 28%
ammonia and 100 g of ice, with stirring. It is stirred 2 h, the ether decanted, washed with water, dried, evaporated to dryness under vacuum, the residue taken up again with petroleum ether and drained. The expected amide is obtained (MP = 73-74C) with a 98~ yield.
3) CRL 40940 -13 g (0.046 mole) of 4,4'-difluorobenzhydryl-.. :i ~ 6 thioacetamide in solution of 40 ml of acetic acid are oxidized with 4.6 rnl of 110 volume H2O2. It is evaporated under vacuum, taken up again with water, drained, the precipitate washed with water. By recrystallisa~ion in ethanol, CRL 40 940 is obtained with an overall yield of 64~ ~MP. - 101-102C).
Below are summarised the results o~ the pharmacological tests which have been undertaken with the products according to the present invention. In these tests, the products of formula I under study were administered intraperitoneally, suspended in an aqueous gum arabic solutlon, in a volume of 20 ml/kg in the male mouse and in a volume of 5 ml/kg in the male rat.
I TOXICITY, OVEE~ALL BEHAVIOUR AND REACTIVITIES
:
The toxicity was studied in the male mouse. The results relating to the LDo tminimal non-lethal dose) are given in Table II below.
To evaluate the overall behaviour and the reactivities the batches of six animals (male mice or male rats3 were observed before administration of each product~ then 15 min, 30 min, lh, 2h, 3h and 24h after administration of each product. The results are reported in Table III below.

T A B L E II
.

Product Code No o ~ . _ _ _ . .. ~
Example 1 CRL 40920 greater than 256mg/]sg 30 Example 2 CRL 40929 greater than 51 2mg/kg Example 4 CRL 40936 greater than 512mg/kg Example 5 CRL 40489 greater than 1024mg/kg Example 7 CRL 40933 greater than 256mg/kg Example 8 CRL 40940 greater than 256mg/kg 35 Example 9 CRL 41018 greater than 512mg/kg ````:~````

, T A B L E III

OVERALL BEHAVIGUR AND REACTIVITIES

5 Product Observations ~Code No) a) a mouse at 256mg/kg:
- dyspnea, excitation no mortality at 128m~Lk~:
- excitation Example 1 - hypothermia (-1.5C) for 0.5h (CRL 40920) at 64mg/kg:
- excitation b) a rat at 64my/kg:
- mydriasis for 3h a) a mouse at 512mg/kg:
- shortness of breath, dyspnea, sedation, diminution of reactivity on touching, no excitation after 3h - no mortality at 256m~/k~:
- sedation ~or 0.5h with Example 2 diminution of respiratory CRL 40929) frequency - hypo-reactivity on touching for 2h moderate hypothermia (-1C) for 0~5h - excitation 3h after administration ~9~

T A B L E III (Contd) Product Observations (Code No) at 128mg/k~:
- sedation, then excitation 3h after administration b) rat at 12~mg/kg-.

- mydriasis for 3h a) mouse at 1024mg/k~:
- abdominal cramps, sedation and hypo-reactivity on touching, shortness of breath - slow mortality (66% of the Example 7 animal) 24h after (CRL 40933) administration at_512mg/~
- abdominal cramps, sedation and hypo-reactivity on touching - slow mortality (33% of the \ 25 animal) 24h after - administration at 256m~!k~:
- abdominal cramp~ J shortness of of breadth then - excitation appearing 1.5h after administration - excitation appearing 1.5h after administration and for 3h - reaciivity on touching '' ~

1~

T ~ B L E I~I (Contd) Product Observations 5 (Code No) b) r at 64mg/kg~
- muscular hypotonia for 3h 10 Example 7 - shor~ness of breath for 3h (CRL 40933) - mydriasis ~or 2 to 3h at 16mg/k~:
- mydriasis lh after administration a) mouse at 512mg/kg:
- staggering gait - convulsions (66% of the animals) for 0.75h - mortality (4 animals in 6 in lh, then 2 animals in 6 in 24h) Example 8 at 256mg/kg:
25 (CRL 40940) - excitation starting 0.Sh after administration - stereotypies - no mortality at 128m~_k~:
- excitation with stereo~ypies for 3h - increase in reactivity on touching for 24h - hypothermia (-1.3C) for 3h at 32m~/k~:
- late excitation beginning lh after administration and for 2h . ~ ~

T A B L E III (Contd) .. . .. _ _ Product Observations 5 (Code No) Example 8 - stereotypies 3h after adminis-(CRL 40940) tration - reactivity on touching for 24h at 8mg/k~:
- late excitation starting 2h after administration - reactivity on touching for 2h at 2mg/k~:
- reactivlty on touching for 2h b) rat at 64m~ g:
- excitation - reactivity on touching - increased respiratory frequency for 24h at 16m~/kg:
Example 8 - excitation 25 (CRL 40940) - reactivity on touching for 2h a) mouse at 256mg/kg:
- excitation appearing i.n 30 minutes and maximum 2 to 3h after administration - presence of distinct but late stereotypies - reactivity on touching for 3h 35 Example 9 at 64mg/kg:
~CRL 41018) - excitation appearing in 30 minutes and maximum after 2h and for 24h T A B L E III ~Contd3 Product Observations (Code No) - late appearance 12-3h) - 4 stereotypic movements of low intensity - reactivity on touchiny for 2-3h at 16mg/k~:
- excitation for lh in 33~ of the animals b) a rat at 128m~/k~:
- excitation for 2h with hyper-reactivity on touching for 0.5h at 32m~/kg.
Example 9 - fleeting diminution l0.5h) of (CRL 41018~ the reactivity on touching and of the muscular tonus at 8mg/k~:
- fleeting hypo-reactivity (0.5h) and diminution of muscular tonus Results of the tests relating to CRL ~0933 (product of Example 7) A - INTERACTION WITH APOMORP~INE
1) Mollse Batches of 6 mice per dose received CRL 40g33 0.5h before sub-cutaneous injection of apomorphine administered at the aose of 1 or 16 mg~kg.
It is observed that, at a high dose (128 mg/kg~, CRL
40933 modifies to the hypothermic action of 16 mg/kg of , ~

- ~

apomorphine without modifying the behaviour of verticalisation and stereotypies.
2) Rat The CRL 40933 is administered to batches of 6 rats 0.5h before sub-cutaneous injection of 0.5mg/kg of apomorphine.
It is observed that the CRL 40933 does not modify the stereotypic behaviour induced by apomorphine in the rat.
B - INTERACTION WITH AMPHETAMINE
Amphetamine ~2 mg/kg) is injected intraperitoneally into batches of 6 rats, 30 min after administra~ion of CRL 40933.
It is observed that CRL 40933 does not modify substantially the amphetamine stereotypies; the diminutions observed are probably due only to the existence of a relatively high index of stereotypies which is observed in the control batch.

Four hours after intraperitoneal injection of 2.5 mk/kg of reserpine, batches of 6 mice received CRL 40933.
At doses of 32 mg/kg and 128 mg/kg, it was observed that CRL 40933 was weakly opposed to the reserpine hypothermia without modifying the ptosis.
D - INTER~CTION WITH OXOTREMORINE
The CRL 40933 was administered in batches of 6 mice 0.5 h before intraperitoneal injection of 0.5mg/kg of oxo~remorina~ The following was observed:
1) Efect on temperature:
at high dose (128mg/kg) the CRL 40933 is weakly opposed to the hypothermic effect of oxotremorine;
2) Action on tremblin~~
the trembling induced by oxotremorine is not influenced by CRL 40933;
3) Effect_on peripheràl choliner~ic symptoms:
CRL 40933 does not modify the signs of peripheral cholinergic stimulation due to oxotremorine.

``'I

~1~9~9~

E - EFFECT ON THE FOUR PLATE TEST, TRACTIOM AND
.
ELECTROSHOCK
The tests were carried ou~ on batches of 10 mice (per dose) 0.5 h after administration of CRL 40933.
It was observed that CRL 40933 did not result in a distinct increase in the number of passages punished; it does not cause a major motor deficit and) at high dose (32 mg/kg to 12B mg/kg), it opposes the convulsive effects of electroshock.
F - EFFECT ON SPONTANEOUS MOTILITY
One half-hour after having received CRL 40933, the mice (6 per dose, 12 controls) were placed in an activity meter where their motility was recorded for 30 mins.
It was observed that, at doses of 32 mg/kg and 128 mg/kg, CRL 40933 resulted in a distinct increase in the spontaneous motor activity of the mouse. A diminution of motility was observed at the lowest dose used (2 mg/kg).
G - EFFECT ON INTERGROUP AGGRESSIVITY
After a three week sojourn in each of the halves of a cage separated by an opaque partition, groups of 3 mice received CRL 40933. 30 mins later, the two groups from the same cage were combined by withdrawing the partition and the number o~ fights which ensued in 10 minutes was noted.
It was observed that CRL 40933 does not distinctly modify intergroup agressivity.
H - ACTION WITH RESPECT TO SOME DIS~URBED BEHAVIOVR BY
. _ . . . _ . . . _ _ . .
VARIOUS AGENTS
:
1) Reduced motilitv bY becominq accustomed to the . . . _ enclosure After 18h of dwelling in the actimetres, the mice (6 per dose, 12 controls) received CRL 40933. They were immediately replaced in their respective enclosure and, 30 mins later, their motility was recorded ~or 30 mins.
It is observed that CRL 40933 causes a resumption in activity in th~ mouse accustomed to its enclosure~ This e~fect, hardly perceptible at 2 mg/kg and at 8 mg/kg, is distinct at a high dose (from 32 mg/kg to 128 mg/kg).

: : :

.

2) Reduced motility by hypoxlc aggress~on Half an hour after having received CRL 40933, the mice (10 per dose, 20 controls) are subjected ~o an acute hypobaric anoxia Elow pressure of 600mm Hg (i.e. about 8 x 10 Pa) in 90 s, then relaxation for 45 s], then they are placed in an activity meter where their motility is recorded for 10 mins~
It is observed that, at a high dose (128 mg/kg), CRL
40933 brings about a distinct improvement in the motor recovery in the mouse whose acti~ity had been depressed following a brief spell in an enclosure at reduced pressure.
3) ~ oxia Batches of 10 mice received CRL 40933 30 min before intraperitoneal administration of 32 mg/kg of gallamine triiodoethylate.
At a high dose (128 mg/kg), the CRL 40933 shortens the time of the appearance of convulsions and death consecutive to an asphyxic anoxia caused by a curare type agent.
I -- INTERACTION WITH BARBITAL
. _ Half an hour after administration of CRL 40933, batches fo 10 mice received an intraperitoneal injection of 220 mg/kg of barbital.
It was observed that, from the dose of 8 mg/kg, CRL
40933 reduces the duration of sleep enduced by the barbital.
J - EFFECT ON "BEHAVIORAL DESPAIR"
. _ . . .
Half an hour after having received CRL 40933, batches of 10 mice per dose are placed in a restricted space Eilled with water up to a height of ~ cm; the period of immobility between the 2nd and the 6th minute following immersion is noted.
CRL 40933, at doses of 8 mg/kg, 32 mg/kg, but especially 128 mg/kg, reduces the duration of immobility.
K - CONCLUSION
:
Neuropsychopharmacological study of CRL 40~33 establishes in the male mouse:
a) stimulant type effects:
- excitation and hyperreactivity - hypermotility, - resumption of motor activity in the mouse accustomed to its enclosure, - improvement in motor recovery after hypobaric hypoxia, - antagonism of barbituric sleep;
b) effects of antidepressor type which are weak:
- antagonism of hypothermia induced by amomorphine, oxotremorine and reserpine, - reduction in "despairl' immobility, c) anticonvulsant effects:
- antagonism to electric convulsions.
According to the operational methods given above, study of the action on the CNS with the other products has given the results reported below.
Results of tests relating to CRL 40920 (the product of Example 1~
A - I~TERACTON WITH APOMORPHINE
1) M~use At the dose of 12B mg/kg, CRI 409~0 is hypothermic and not opposed to hypothermia induced by apomorphine.
CRL 40920 does not modify the behaviours of verticalisation and stereotyies.
2) Rat CRL 40920 leaves stereotypies induced by apomorphine.
- B - INTER~CTION WITH AMPHETAMINE
CRL 40920, at the doses used, practically does not modi~y amphetaminic stereotypies.
C - INTERACTION WITH RESERPINE
At the dose of 128 mgJkg, CRL 40920 antagonises hypothermia induced by reserpine without modifying p~osis.
D INTERACTION WITH OXOTREMORINE
1) Action on_temperature At doses of 8 mg/kg to 128 mg/kg CRL 40920 is moderately opposed to the hypothermic action of oxotremorine.

2) Action OIl trembling CRL 40920 does not modify the intensity of trembling caused by oxotremorine.
3) Action on ~eripheral choliner~ic symptoms CRL 40920 leaves practically unchanged the signs of peripheral cholinergic s~imulation which appear after oxotremorine administration.
E - ACTION ON THE FOUR PLATE, TP~C~ION AN~ ELECTROSHOCK
TESTS

CRL 40920 does not result in any increase in the number of passayes punished; it does not cause any major motor incapacity and does not modify the convulsant effects of electroshock.
F - ACTION ON SPONTANEOUS MOTILITY

CRL 40920, at doses of 32 and 128 mg/kg results in a moderate increase in the spontaneous motility of the mouse.
G - ACTION ON INTERGROUP AGGRESSIVITY
.
CRL 40920 does not distinctly modify the number of combats.
H - ACTION WITH RESPECT TO SO~E BEHAVIOURS DISTURBED BY
VARIOUS AGENTS
1) Motili~Y reduced bY habituation to the enclosure , . .
At doses of 8 mg/kg, 32 mg/kg and especially 128 mg/kg, CRL 40920 causes a resumption of motor activity in the mouse accustomed to its enclosure.
2) Motility reduced by hye~xic aggression CRL 40920, at the dose of 128 mg/kg, results in a moderate improvement (but not signiyicant) in motor recovery in the mouse whose motility has been depressed following a brief sojourn in an enclosure at reduced pressure.
3) As~hxxic Anoxia CRL 40920 does not modify the delay in the appearance of convulsions and of death consecutive to asphyxic anoxia caused by a curarising agent such as gallamine triiodoethylate.

.

:

~9~:~6 I - INTERP~CTION WITH BARBITAL
_ At the dose of 128 mg/kg, CRL 40920 distinctly reduces the duration of barbituric sleep. At a lower dose (32 mg/kg~, CRL 40920 does not result in appreciable modification in the duration of sleep but in a distinct reduction in the number of sleeping mice.
J - ACTION ON "BEHAVIORAL DESPAIR"
At doses of 32 mg/kg and 128 my/kg, CRL 40920 distinctly reduces the duration of immobility of the mouse placed in forced immersion.
K - CONCLUSION
Neurophychopharmacological study of CRL 40920 reveals essentially than exciting component which results from - moderate increase in motor activity;
- resumption of motor activity in the mouse accustomed to its enclosure;
- antagonism to barbituric sleep;
- reduction in immobility in the behavorial despair test.
Moreover, it could be that the antagonisms of certain hypothermias are only a reflection of motor stimulation.
Results of t~sts relating to CRL 4Q929 (product o~
Example 2) A - INTERACTION WITH APOMORPHINE
. _ .
- l) Mouse CRL 40929 leaves hypothermia, behaviour of verticalisation and stereotypies produced by apomorphine, unchanged in the mouse.
2) R
Stereotypies induced by apomorphine are not modified by CRL 40929.
B - INTERACTION WITH AMPHETAMINE
CRL 40929, at doses of 8 mgikg to 128 mg/kg, seem to potentiate weakly amphetaminic stereotypies.
C - INTERACTION WITH RESERPINE
At high dose (256 mg/kg), CRL 40929 very moderately reduces reserpinic ptosis.

:
.

D - INTERACTION WITH OXOTREMORINE
1) Effect on tem~erature CRL 4092~ practically does not modify the hypothermic effect of oxotremorine.
2) Effect on trembling At strong doses (256 mg/kg), CRL 40929 seems to reduce moderately the intensity of trembling caused by oxotremorine.
3) Effect on peripheral choliner~_~c symptoms At high doses (from 64 mg/kg to 256 mg/kg), CRL
40929 seems to result in a reduction in signs of peripheral cholinergic stimulation, particularly defecation.
E - ACTION ON THE FOUR PLATE, TRACTION AND ELECTROSHOCK
TEST
CRL 40929 does not result in an increase of the number of passages punished; it does not cause a major motor deficiency but, at strong doses (from 64 mg/kg to 256 mg/kg~, modifies the convulsant effect of electroshock F - ACTION ON SPONTANEOUS MOTILITY
_ _ At the dose of 256 mg/kg, CRL 40929 does not result in distinct hypermotility.
G - ACTION ON INTERGROUP AGGRESSIVITY
It was observed that CRL 40929 is weakly anti-aggressive, since it very moderately reduces intergroup aggressivity in the mouse.
H - ACTION WITH RESPECT TO SOME BEHAVIOURS DISTURBED BY
., . . _ . . _ . ~ . . . ~
VARIOUS AGENTS
.
JU 1) Motility reduced bY habituation to the enclosure At doses of 4 mg/kg, 64 mg/kg and 256 mg/kg, CRL
40929 seems to cause a resumption in activity in the mouse accustomed to its enclosure. Such an effect is not observed at the intermediate dose of 16 mgikg.
2) Motility reduced by hypoxic aggression At doses of 64 mgtkg and especially 256 mg/kg~ CRL
40929 results in a distinct improvement in motor recovery in the mouse accustomed to its enclosure.

3) Asphyxic Anoxia At doses of 64 mg/kg and 256 my/kg, CRL 40929 moderately retards the appearance of anoxic convulsions caused by gallamine triiodoethylate.
I - INTER~CTION WITH BARBITAL

At high doses (256 mg/kg), CRL 40929 reduces distinctly the duration of barbituric sleep.
J - ACTION ON "BEHAVIORAL DESPAIR'I
It was observed that, from the dose of 16 mg/kg, CRL
40929 distinctly reduces the duration of immobility~
K - CONCLUSION
Neurophychopharmacological study establishes that CRL 40929 is a phychotropic agent due to the fact of:
- its stimulant effect on spontaneous motility, motility reduced by habituation, - its improvement of motor recovery after hypoxic aggression, its effect in the so-called "behavioral despair" test.
Results of tests relating to CRL 40936 (product of .. ... . _ Example 4~
CRL 40936 shows at low and average doses in the mouse~ a group of effects of the sedative (sedation, hyporeactivity, hypoaggressivity, hypothermia) type as well as antagonism to the convulsant effect of electroshock. The effects are observed however in the absence of any reduction in motor activity.
On the other hand, at high doses, CRL 40936 causes the appearance of discrete hypermotility, moderate resumption of activity in the mouse habituated to its enclosure and an appreciable improvement in motor recovery after hypoxia.
In addition, an antagonistic effect to barbituric sleep and a reduction in hypomotility of "despair" are observed .
R lts of tests relatin~ to CRL 40489 (product of Example_5) CRL 40489 shows itself to be an active agent on CNS, of the sedative type. In the course of the test relating to spontaneous motility, it was observed that CRL 40489 causes hypomotiIity at all the doses used (8 mg/kg to 256 mg/kg), the intensity of this hypomotility increasing with the dose. On the other hand, CRL 40489 does not act distinctly on reducing mobility (habituation to the enclosure and hypoxic agyression). CRL 40489 has besides an anti-aggressive effect. At the dose of 32 mg/ky, it reduces by half intergroup aggressivity.
Results of tes~s relating to CRL 40940 (product_of Example 8) A - INTERACTION WITH APOMORPHINE
. _ _ _ ....
1) Mouse At doses of 32 mg/kg and 128 mg/kg, CRL 40940 is hypothermic and aggravates the hypothermia induced by doses o~ 1 and 16 mg/kg of apomorphine, on the other hand, it does not modify the behaviour of verticalisation and stereotypies.
2) Rat At the dose of 6 mk/kg, CRL 40940 increases the stereotypies induced by apomorphine.
B INTERACTION WITH AMPHETAMINE
At the dose of 64 mg/kg, CRL 40940 increases the stereotypies induced by apomorphine.
B - INTERACTION WITH ~MPHETAMINE
At the dose of 64 mg/kg, CRL 40940 results in a potentiation of amphetaminic stereotypies.
C - INTERACTION WITH RESERPINE
. . . ~ _ .
At doses of 32 mg/kg, 64 mg/kg and 128 mg/kg, CRL
40~40 has a sluggish antagonism to reserpinic hypothermia; it also antagonises reserpinic ptosis moderately to 24 h.
D - INTERACTION WITH OXOTREMORINE
1) Effect on temEerature A~ doses of 2 mg/kg, 8 mg/kg, 32 mg/kg and 128 mg/kg, CRL 40940 antagonises moderately and sluggishIy the hypothermia induced by oxotremorine.
2) Effect on tremblin~
Trembling due to oxotremorine is practically unmodified.

:

3) Effect on peripheral cholinergic symptoms CRL 40940 does not modify the signs of peripheral cholinergic stimulation due to oxotremorine.
E - EFFECT ON THE FOUR PLATE, TRACTION AND ELECTROSHOCK
TEST
CRL 40940 does not result in an increase in the number of passages punished; it does not cause major motor incapacity and practically does not modify the convulsant effects of electroshock~
F - ACTION ON SPONTANEOUS MOTILITY
.
CRL 40940, at doses o~ 8 mg/kg, 32 mg/kg and 128 mg/kg, results in a distinct increase in the spontaneous motility of the mouse.
G - EFFECT ON INTERGROUP AGGRESSIVITY
. .. _ The tests carried out show tha-t CRL 40940 has no antiaggressive ef~ect.
H - EFFECT WITH RESPECT TO SOME BEHAVIOURS DISTURBED BY
.
VARIOUS AGENTS
1) Motility reduced by habituation to the enclosure From the dose of 8 mg/kg and especially at 32 mg/kg and 128 mg/kg, CRL 40940 causes a very distinct resumption in motor activity in the mouse habituated to i-ts enclosure.
2~ Motility reduced b~y hypoxic aggression CRL 40940, at doses of 32 mkg/kg, but especially 128 mg~kg, results in a signi~icant improvement in motor recovery in the mouse whose motility has been depressed following a brief sojourn in an enclosure under reduced pressure.
3) Asphyxic Anoxia CRL 40~40 does not modify the delay in the appearance of convulsions and death consecutive to asphyxic anoxia caused by a curarising agent such as gallamine triidoethylate.
I - INTERACTION WITH BARBITAL
At the doses o~ 32 mg/kg and 128 mg/kg, C~L 40940 distinctly reduces the duration of barbituric sleep.

39~

J - ACTION ON l'BEHAVIORAL DESPAIR"
At doses of 8 mg/kg, 32 mg/kg and 128 mg/kg, CRL
40940 distinctly reduces the duration of immo~ility of the mouse placed in forced immersion.
K - CONCLUSION
-Neurophsychopharmacological study of CRL 40940 establishes essen~ially an exciting component which results from:
- excitation with hyporeactivity, - increase in motor activity, - resumption of motor activity in the mouse habituated to its enclosure, - antagonism to barbituric sleep, reduction in immobility in the "behavioral despair" test, and - improvement in the motor recovery after asphyxic anoxia.
These effects, different from amphetaminic stimulants, appear in the absence of particular toxicity in the groups of mice, and of signs of peripheral sympathetic stimulation.
The appearance and relatively slow development of a certain number of effects (hyperre~ctivity, antagonism to hypothermia and reserpinic ptosis, antagonism to hypothermia induced by oxotremorine) permit slow resorption of CRL 40940 to be presumed. This supposition seems confirmed by a kinetic study of the stereotypies.
R ults of tests relating to CRL 41018 (pr~duct of Example 9~
A - I~TERACTION WITH APOMORPHINE
, , _ _ _ , . . _ _ r ~ ~ _ _ . _ _ _ _ In ~he mouse, at the dose of 256 mg/kg, CRL 41018 opposes the hypothermic effect of apomoxphine without modifying the behaviour of verticalisation and stereoty~ies.
B - INTERACTION WITH~RESERPINE
At a dose of 256 mgtkg it is observed that CRL 41018 sIowly modifies reserpinic hypothermia (1.5h) and ptosis ~24 h).

.

9~6 C - INTERACTION WITH OXOTREMORINE
1) Effect on temperature At the highest dose used, CRL 41018 modifies the drop in temperature caused by oxotremorine.
2) Effect on trembling The intensity of trembling caused by oxotremorine is practically unmodified by CRL 41018.
3) Eff~ct on peripheral cholinergic symptoms CRL 41018 does not modify the signs of peripheral cholinergic stimulation induced by oxotremorine.
D - EFFECT ON THE E'OUR PLATE, TRACTION AND ELECTROSHOCK
TEST
At doses of 64 mg/kg, CRL 41018 results in a distinct increase in passages punished; it does not cause a motor deficit; and at a high dose (256 mg/kg~ it partly opposes the convulsant effects of electroshock.
E - ACTION ON SPONTANEOUS MOTILITY
. . . _ .
It is observed that CRL 41018 causes from the dose of 16 mg/kg a hypermotility; it is observed in addition that the hypermotility is a maximum 0.5 h after administration and that the duration of hyper motility is at ieast 4 h.
F - MOTILITY REDUCED BY HABITUATION TO THE ENCLOSURE
It is noted that at doses of 64 mg/kg and 256 mg/kg, CRL 41018 causes a resumption in motor activity in the mouse habituated to its enclosure.
G - INTERACTION WITH BARBITAL
. . _ ~ . ~ _ _ _ _ At doses o~ 16 mg/kg, 64 mg/kg and 256 mg/kg, CRL
41018 distinctly reduces the duration of barbituric sleep.
H - ACTION ON QBEHAVIORAL DESPAIR"
It is observed that CRL 41018 at doses of 16 mg/kg, 64 mg/kg and 256 mg/kg considerably reduces the duration of immobility.
I - CONCLUSION
Neuropsychopharmacological study of CRL 41018 establishes a stimulant effect on the CNS which is essential, and at strong doses only an anti-depressant effect on the CNS.

, .

,, l~q9~9~

III CLINICAL TRIALS
. . _ ~ . _ Clinical studies bore on disorders of vigilance, wakening and confused states, on the one hand, and on disorders of affectivity, contact and depression, on the other hand.
In man, particularlyly old people, it was observed -that CRL 40929, CRL 40933, CRI. 40940 and CRL 41018 administered in the form of gelules or table-ts ~each containing 100 to 200 mg of active ingredient a-t the rate of 1 to 3 gelules or tablets per day), have given excellent results as arousing medicaments. ~t has also been observed that these four products act effectively against enuresis.

Claims (22)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A method for preparing a benzhydrylsulfinylacetamide derivative of formula (I):

wherein Xl and X2, which may be identical or different, each represent H, Cl or F; Zl represents CH3, CH2CH3, CH(CH3)2, or C(CH3)3, Zl may represent H when at least one of Xl and X2 is different from H; Z2 represents H, NZlZ2 considered together may represent a piperidino or morpholino group;
which comprises:
1) reacting an acyl chloride of the formula:

(II) wherein Xl and X2 are as defined above with an amine of the formula:

NHZlZ2 (III) wherein Zl and Z2 are as defined above, for obtaining a benzhydrylthioacetamide derivative of the formula:

(IV) wherein X1, X2, Z1 and Z2 are as defined above, and 2) oxidizing the benzhydrylthioacetamide derivative thus obtained with 110 - 130 volume H2O2 at a temperature lower than or equal to 45°C.

2. A method of claim 1 wherein X1 and X2 which may be identical or different, each represent H, 4-C1 or 4-F.

3. A method of claim 1 for preparing N-methyl-benzhy-drylsulfinylacetamide wherein X1 and X2 are both H; Z1 is -CH3 and Z2 is H.

4. A method of claim 1 for preparing N-ethyl-benzhy-drylsulfinylacetamide wherein X1 and X2 are both H; Z1 is -CH2CH3 and Z2 is H.

5. A method of claim 1 for preparing N-isopropyl-benzhydrylsulfinylacetamide wherein X1 and X2 are both H;
Z1 is -C(CH3)3 and Z2 is H.

6. A method of claim 1 for preparing N-tertiobutyl-benzhydrylsulfinylacetamide wherein X1 and X2 are both H;
Z1 is -C(CH3)3 and Z2 is H.

7. A method of claim 1 for preparing 4-chloro-benzhy-drylsulfinylacetamide wherein X1 is 4-C1; X2 is H; Z1 and Z2 are both H.

8. A method of claim 1 for preparing 4,4'-difluoro-benzhydrylsulfinylacetamide wherein X1 and X2 are both 4-F; Zl and Z2 are both H,

9. A method of claim 1 for preparing N-(benzhydrylsul-finylacetyl)-piperidine wherein Xl and X2 are both H and NZl Z2 considered together is piperidino.

10. A method of claim 1 for preparing N-(benzhydrylsul-finylacetyl)-morpholine wherein Xl and X2 are both H and NZl Z2 considered together is morpholino.

11. A method of claim 1 for preparing 4-fluoro-benz-hydrylsulfinylacetamide wherein Xl is 4-F, X2 is H and Z1 and Z2 are both Ho

12. A benzhydrylsulfinylacetamide derivative which is selected from the group consisting of compounds of the general formula:

(I) wherein Xl and X2, which may be identical or different, each represent H, Cl or F; Zl represents CH3, CH2CH3, CH(CH3)2, or C(CH3)3, Zl may represent H when at least one of Xl and X2 is different from H; Z2 represents H, NZlZ2 considered together may represent a piperidino or morpholino group, when prepared by the process of claim 1 or its obvious chemical equivalents.

13. A benzhydrylsulfinylacetamide derivative of formula I according to claim 12, in which Xl and X2, which may be identical or different, each represent H,4-C1 or 4-F, when prepared by the process of claim 2 or its obvious chemical equivalents.

14. The compound N-methyl-benzhydrylsulfinylacetamide, when prepared by the process of claim 3 or its obvious chemical equivalents.

15. The compound N-ethyl-benzhydrylsulfinylacetamide, when prepared by the process of claim 4 or its obvious chemical equivalents.

16. The compound N-isopropyl-benzhydrylsulfinyl-acetamide, when prepared by the process of claim 5 or its obvious chemical equivalents.

17. The compound N-tertiobutyl-benzhydrylsulfinyl-acetamide, when prepared by the process of claim 6 or its obvious chemical equivalents.

18. The compound 4-chloro-benzhydrylsulfinylacetamide, when prepared by the process of claim 7 or its obvious chemical equivalents.

19. 4,4'-difluoro-benzbenzhydrylsulfinylacetamide, when prepared by the process of claim 8 or its obvious chemical equivalents.

20. N-(benzhydrylsulfinylacetyl)-piperidine, when prepared by the process of claim 9 or its obvious chemical equivalents.

21. N-(benzhydrylsulfinylacetyl)-morpholine, when prepared by the process of claim 10 or its obvious chemical equivalents.

22. 4-fluoro-benzhydrylsulfinylacetamide, when prepared by the process of claim 11 or its obvious chemical equivalents.