New benzhydrysulphinyl derivatives

The invention provides the benzhydrylsulphinyl derivatives of the formula: EQU (C.sub.6 H.sub.5).sub.2 CH--SO--(CH.sub.2).sub.n --R I where n is 1, 2 or 3 and R is C(.dbd.O)NHOH, C(.dbd.NH)NH.sub.2, C(.dbd.NH)NHOH, 2-.DELTA..sup.2 -imidazolinyl or NR.sub.1 R.sub.2 (where R.sub.1 is H or C.sub.1 -C.sub.3 -alkyl and R.sub.2 is H, C.sub.1 -C.sub.3 -alkyl, or CH.sub.2 CH.sub.2 OH, and R.sub.1 and R.sub.2 considered together can form, with the nitrogen atom to which they are bonded, a N-heterocyclic group of 5 to 7 ring members, which can be substituted and can contain a second hetero-atom such as O and N), and their addition salts. These products are useful in therapy for treating disturbances of the central nervous system.

The present invention relates to benzhydrylsulphinyl derivatives, to their 
preparation, and their use in therapy. 
The invention provides, as new compounds, the benzhydrylsulphinyl 
derivatives of the general formula 
##STR1## 
in which n is 1, 2 or 3 and R is C(.dbd.O)--NHOH, C(.dbd.NH)--NH.sub.2, 
C(.dbd.NH)--NHOH,2-.DELTA..sup.2 -imidazolinyl, or NR.sub.1 R.sub.2, where 
R.sub.1 is hydrogen or C.sub.1 -C.sub.3 alkyl, R.sub.2 is hydrogen, 
C.sub.1 -C.sub.3 alkyl or CH.sub.2 -CH.sub.2 OH, or R.sub.1 and R.sub.2 
together with the nitrogen atom to which they are bonded form a 
N-heterocyclic group of 5 to 7 ring members which can contain a second 
heteroatom such as O and N and can be substituted, and their addition 
salts. By addition salts are meant their addition salts with acids and 
their quaternary ammonium salts. 
The N-heterocyclic group NR.sub.1 R.sub.2 can be, in particular, 
morpholino, piperidino, pyrrolidino, 4-methylpiperazino, 
4-(4-chlorophenyl)-piperazino, 4-methylpiperidino or azepino. The 
preferred groups are morpholino and piperidino. 
According to the invention, the products of formula I are prepared by 
oxidizing a sulphide of the formula 
##STR2## 
where n is as defined above and R' is the same as R or is a radical 
convertible thereto, with H.sub.2 O.sub.2, preferably in an acetic acid 
medium. The oxidation may be carried out in acetic acid using concentrated 
hydrogen peroxide, i.e. hydrogen peroxide of at least 110 volumes strength 
(that is to say water containing at least 33% by weight of hydrogen 
peroxide). During this oxidation, it is necessary to avoid the formation 
of a relatively large amount of the corresponding sulphonyl derivative. In 
practice, if the reaction is carried out at 100.degree. C for 1 hour or 
more, with hydrogen peroxide of 110-124 volumes strength, essentially only 
the said sulphonyl derivative is obtained; thus, in order only to obtain 
the sulphinyl derivative, the reaction is carried out at a temperature 
less than or equal to 50.degree. C (in general over the course of 1 hour 
or more). As the reaction is exothermic, a temperature of 37.degree. to 
45.degree. C is arrived at by simply mixing the reactants in acetic acid, 
without additional heating. 
It is possible to form first a benzhydrylsulphinyl compound of the formula 
IV, where R' is a precursor of the nitrogen-containing group R (especially 
a cyano group, an amino-forming group, a carboxylic acid group or a 
carboxylate group) and then subsequently to form or introduce the group R, 
in accordance with the following reaction scheme: 
##STR3## 
The reactions involved are all known in themselves. 
Example 1 bis below describes operating conditions for obtaining a compound 
by this method on an industrial scale. 
It is preferred to use approximately stoichiometric amounts of hydrogen 
peroxide and of the sulphide of formula II. 
These examples below illustrate the methods of obtaining the sulphides used 
as starting materials, and the preparation of the addition salts from the 
bases of the formula I (for example, by reacting the free base with an 
inorganic or organic acid). Amongst the acids which can be used, there may 
especially be mentioned hydrochloric, hydrobromic, hydriodic, sulphuric, 
formic, maleic, fumaric, oxalic, ascorbic, citric, acetic, 
methanesulphonic, p-toluenesulphonic, lactic, succinic, benzoic, 
salicylic, acetylsalicylic, malic, tartaric, glutamic and aspartic acid. 
According to the invention, a therapeutic composition is proposed which is 
characterised in that it contains at least one compound of the formula I, 
or one of its possible non-toxic addition salts, in association with a 
physiologically acceptable excipient. 
Table I below lists a certain number of products according to the invention 
which have been synthesised. 
TABLE I 
______________________________________ 
(C.sub.6 H.sub.5).sub.2 CH--SO--(CH.sub.2).sub.n --R 
Example 
Code No. n R Melting point, .degree. C 
______________________________________ 
1 CRL 40,028 
1 C(=O)NHOH 159-160 
2(a) CRL 40,048 
1 C(=NH)NHOH 150 
(decomposition) 
3(a) CRL 40,066 
2 2-.DELTA..sup.2 -imidazolinyl 
162-164 
4(a) CRL 40,221 
2 morpholino 166-168 
5(a) CRL 40,222 
2 piperidino 206-210 
(decomposition) 
6 CRL 40,260 
2 C(=O)NHOH 159-160 
7(a) CRL 40,261 
2 C(=NH)NHOH 164-166 
8(a) CRL 40,277 
3 C(=NH)NHOH 200-204 
(decomposition) 
9 CRL 40,278 
3 C(=O)NHOH 143 
______________________________________ 
Note: (a)hydrochloride

Other advantages and characteristics will be more readily understood on 
reading the preparation examples given below, which do not imply any 
limitation and are given by way of illustration. The melting points were 
determined on a Kofler bench. 
EXAMPLE 1 
Benzhydrylsulphinyl-acetohydroxamic Acid 
##STR4## 
a. Diphenylmethane-thiol 
15.2 g (0.2 mol) of thiourea and 150 ml of demineralised water are 
introduced into a 500 ml three-neck flask equipped with a central 
mechanical stirrer, and with a dropping funnel and a condenser on the 
(respective) side-necks. 
The temperature of the reaction mixture is brought to 50.degree. and 49.4 g 
(0.2 mol) of bromodiphenylmethane are added all at once whilst continuing 
the heating. 
After refluxing for about 5 minutes, the solution, which has become limpid, 
is cooled to 20.degree. C and 200 ml of 2.5 N NaOH are then added dropwise 
whilst maintaining the said temperature. 
The temperature is then again kept at the reflux for 30 minutes after 
which, when the mixture has returned to ordinary temperature 
(15.degree.-25.degree. C), the aqueous solution is acidified with 45 ml of 
concentrated hydrochloric acid. The supernatant oil is extracted with 250 
ml of diethyl ether and the organic phase is washed with 4 .times. 80 ml 
of water and then dried over magnesium sulphate. 39 g of crude 
diphenylmethane-thiol are thus obtained. Yield = 97.5%. 
b. Benzhydryl-thioacetic acid 
10 g (0.05 mol) of diphenylmethane-thiol and 2 g (0.05 mol) of NaOH 
dissolved in 60 ml of demineralised water are introduced successively into 
a 250 ml flask equipped with a magnetic stirrer and a reflux condenser. 
The reactants are left in contact for 10 minutes whilst stirring, and a 
solution consisting of 7 g (0.075 mol) of chloroacetic acid, 3 g (0.075 
mol) of NaOH pellets and 60 ml of demineralised water is then added all at 
once. 
The aqueous solution is gently warmed to about 50.degree. C for 15 minutes, 
washed with 50 ml of ether, decanted and acidified with concentrated 
hydrochloric acid. After filtration, 10.2 g of benzhydryl-thioacetic acid 
are thus obtained. Melting point 129.degree.-130.degree. C. Yield = 79%. 
c. Ethyl benzhydryl-thioacetate 
The following reaction mixture is heated under reflux for 7 hours: 10.2 g 
(0.0395 mol) of benzhydryl-thioacetic acid, 100 ml of anhydrous ethanol 
and 2 ml of sulphuric acid. 
When heating has been completed, the ethanol is evaporated in vacuo; the 
oily residue is taken up in 100 ml of ethyl ether and the organic solution 
is then washed with water, with an aqueous sodium carbonate solution and 
then with water until the wash waters have a neutral pH. After drying over 
sodium sulphate, the solvent is evaporated. 10.5 g of ethyl 
benzhydryl-thioacetate are thus obtained. Yield = 93%. 
d. Benzhydryl-thioacetohydroxamic acid 
The following three solutions are prepared: 
______________________________________ 
1. Ethyl benzhydryl-thioacetate 
10.8 g (0.0378 mol) 
Methanol 40 ml 
2. Hydroxylamine hydrochloride 
5.25 g (0.0756 mol) 
Methanol 40 ml 
3. Potassium hydroxide pellets 
7.5 g (0.0134 mol) 
Methanol 40 ml 
______________________________________ 
The solutions are heated, if necessary, until they become limpid, and when 
the temperatures have again fallen to below 40.degree. C, the solution of 
potassium hydroxide in methanol is poured into the solution of 
hydroxylamine hydrochloride in alcohol. Finally, at a temperature of about 
5.degree. to 10.degree. C, the solution of ethyl benzhydryl-thioacetate is 
added in its turn. After leaving the reactants in contact for 10 minutes, 
the sodium chloride is filtered off and the limpid solution obtained is 
kept for about 15 hours at ordinary temperature. The methanol is then 
evaporated under reduced pressure, the residual oil is taken up in 100 ml 
of water and the aqueous solution is acidified with 3 N hydrochloric acid. 
The hydroxamic acid which has crystallised is filtered off, washed with 
water and then dried. 9.1 g of product are obtained. Yield = 87.5%. 
Melting point 118.degree.-120.degree. C. 
e. CRL 40,028 
10.4 g (0.038 mol) of benzhydryl-thioacetohydroxamic acid are oxidised at 
40.degree. C, over the course of 2 hours, by means of 3.8 ml (0.038 mol) 
of hydrogen peroxide of 110 volumes strength, in 100 ml of acetic acid. 
When the oxidation has ended, the acetic acid is evaporated under reduced 
pressure and the residual oil is taken up in 60 ml of ethyl acetate. The 
product which has crystallised is filtered off and then purified by 
recrystallisation from a 3:2 (by volume) mixture of ethyl acetate and 
isopropyl alcohol. 
8 g of CRL 40,028 are thus obtained. Melting point 159.degree.-160.degree. 
C. Yield = 73%. 
Solubility in water &lt;1 g/l. 
Example 1 Bis 
Example 1 bis relates to the working procedure for the manufacture of 
benzhydrylsulphinyl-acetohydroxamic acid, the subject of Example 1 above, 
on an industrial scale. 
a. Synthesis of benzhydryl-thioacetic acid 
1.003 kg of thiourea are dissolved in 5.72 liters of 48% strength 
hydrobromic acid and 0.880 liter of water in a 20 liter reactor. The 
mixture is heated to 60.degree. and 2.024 kg of benzhydrol are introduced. 
The temperature is raised to 95.degree. C and the mixture is then allowed 
to cool to ambient temperature, 15.degree.-25.degree. C. The crystals are 
filtered off and washed with water. They are then again worked into a 
paste in 5.5 liters of water, and introduced into a 20 liter reactor, 
together with 3.5 liters of sodium hydroxide solution (d = 1.33). The 
mixture is heated to 70.degree. C and 1,144 g of chloroacetic acid 
dissolved in 2.2 liters of water are run in slowly. Reflux is maintained 
for 30 minutes after running in the chloroacetic acid. The mixture is then 
allowed to cool to ambient temperature (thus giving benzhydryl-thioacetic 
acid, which is not isolated). 
b. Synthesis of benzhydrylsulphinylacetic acid 
1,430 liters of hydrogen peroxide of 130 volumes strength are run, in the 
course of 3 hours, into the preceding reaction mixture, at about 
30.degree. C. Thereafter, the batch is run into 22 liters of water, the 
insoluble material is filtered off and the filtrate is then acidified with 
hydrochloric acid (d = 1.18). The product is filtered off, washed with 
water by again working it into a paste (with water), and suction-drained. 
Benzhydrylsulphinylacetic acid is thus obtained. 
c. Synthesis of methyl benzhydrylsulphinylacetate 
The preceding acid is introduced into a 20 liter reactor with 6 liters of 
water. 1.1 liters of sodium hydroxide solution (d = 1.33) and 1.848 kg of 
sodium bicarbonate are added. 2.1 liters of dimethyl sulphate are then 
added. After 1 hour, the crystallisation is started. The product is 
filtered off, suction-drained and washed. Methyl 
benzhydrylsulphinylacetate is obtained. 
d. Synthesis of benzhydrylsulphinylacetohydroxamic acid (CRL 40,028) 
8.3 liters of water, 3.3 liters of sodium hydroxide solution (d = 1.33) and 
1.529 kg of hydroxylamine hydrochloride are introduced into a 20 liter 
reactor. 
The preceding ester is then added and the mixture is stirred for 4 hours. 
This solution is poured into a mixture of 17 liters of water, 3 liters of 
hydrochloric acid (d = 1.18) and 4 liters of methylene chloride, and the 
whole is stirred. The crystals are filtered off and again worked into a 
paste in 9 liters of water and then in 5 liters of methylene chloride. The 
crystals are dried to constant weight in a vacuum over at 30.degree. C. 
The product is recrystallised from chloroform. Pure 
benzhydrylsulphinylacetohydroxamic acid is obtained in an overall yield of 
53%. 
Melting point = 158-160.degree. C. 
EXAMPLE 2 
Benzhydrylsulphinylacetamidoxime hydrochloride 
EQU (C.sub.6 H.sub.5).sub.2 CH--SO--CH.sub.2 --C(=NH)NHOH.HCl 
Code No. CRL 40,048 
a. Benzhydryl-thioacetonitrile 
20 g (0.1 mol) of diphenylmethane-thiol, 50 ml of anhydrous ethanol and 100 
ml (0.1 mol) of 1 N sodium hydroxide solution are introduced into a 250 ml 
flask equipped with a magnetic stirrer. 
After 15 minutes contact at ordinary temperature, 6.91 ml (0.11 mol) of 
chloroacetonitrile are added dropwise and the reactants are then again 
left in contact for 30 minutes. When the reaction has ended, the ethanol 
is evaporated under reduced pressure and the water-insoluble nitrile is 
then extracted with 150 ml of ethyl acetate; the organic phase is washed 
with 3 times 50 ml of water and dried over magnesium sulphate. After 
evaporating the solvent, the residual oil, taken up in the minimum amount 
of isopropanol, allows 13.3 g of benzhydryl-thioacetonitrile to separate 
out. Melting point = 77.degree.-78.degree. C. Yield 55.6%. 
b. Benzhydryl-thioacetamidoxime hydrochloride 
11 g (0.11 mol) of potassium bicarbonate, 7.65 g (0.11 mol) of 
hydroxylamine hydrochloride and 50 ml of demineralised water are 
introduced into a 250 ml single-neck flask equipped with a magnetic 
stirrer and a condenser. 
When the effervescence caused by the evolution of CO.sub.2 has ceased, 13.3 
g (0.0556 mol) of benzhydryl-thioacetonitrile dissolved in 200 ml of 
butanol are added all at once and the temperature of the reaction mixture 
is then brought to the reflux temperature of the water-butanol azeotrope 
over the course of 3 hours. When the reaction has ended, the solvents are 
evaporated under reduced pressure, the residual oil is taken up in 150 ml 
of ethyl acetate, and the organic solution is washed with twice 50 ml of 
water and is then dried over magnesium sulphate. After filtering off the 
MgSO.sub.4, the amidoxime hydrochloride is precipitated by adding a 
solution of hydrogen chloride in ether. 15.3 g of 
benzhydryl-thioacetamidoxime hydrochloride are thus obtained, of which the 
base, liberated by ammonia, melts at 112.degree. C. Yield = 89%. 
c. CRL 40,048 
15.4 g (0.05 mol) of benzhydryl-thioacetamidoxime hydrochloride are 
oxidised for 1 hour at 45.degree. C with 5 ml (0.05 mol) of hydrogen 
peroxide of 110 volumes strength in 120 ml of pure glacial acetic acid. 
When the oxidation has ended, the acetic acid is evaporated under reduced 
pressure and the residual oil, taken up in 300 ml of demineralised water, 
is rendered alkaline with ammonia after having filtered the aqueous 
solution through animal charcoal. The crystalline amidoxime base, melting 
at 143.degree. C, is filtered off, dried and then taken up in 100 ml of 
acetone; the hydrochloride is precipitated by adding a solution of 
hydrogen chloride in ether; 11.5 g of CRL 40,048, which decomposes from 
150.degree. C onwards, are thus obtained. Yield = 71%. Determination of 
inorganic chlorine (Volhard method): 
Calculated: 10.92%. Found: 11.17%. 
solubility in water: 100 g/l. 
EXAMPLE 3 
2-(2-Benzhydrylsulphinyl-ethyl)-.DELTA..sup.2 -imidazoline hydrochloride 
##STR5## 
a. Hydrochloride of benzhydryl-thiopropioniminoethyl ester 
9.2 ml (0.2 mol) of 3-chloropropionitrile are added, in the cold, to a 
(stirred) solution of 20 g (0.1 mol) of benzhydryl-thiol in 75 ml of 
ethanol and 110 ml of 1 N NaOH. The mixture is stirred for 1 hour at 
30.degree. C and then extracted with ether, and the extract is washed with 
water, dried and filtered. 10 ml of ethanol are added to the filtrate and 
the mixture is saturated with dry HCl gas; the reactants are left in 
contact for 48 hours. 100 ml of ether are added and the mixture is 
filtered to give 23 g of product. Melting point = 70.degree.-75.degree. C. 
b. 2-(2-Benzhydryl-thioethyl)-.DELTA..sup.2 -imidazoline hydrochloride 
A solution of 15.5 g (0.046 mol) of the hydrochloride of the preceding 
iminoester and 3.5 ml of ethylenediamine in 100 ml of ethanol is heated 
under reflux for 2 hours. It is evaporated to dryness in vacuo, taken up 
in water with 1 to 2 drops of concentrated HCl, and extracted with ether. 
The base is precipitated with concentrated NaOH, filtered off and washed 
with water. 
11 g of product are obtained. Yield = 81%. Melting point: 102-103.degree. 
C. 
c. CRL 40,066 
11.6 g (0.035 mol) of 2-(2-benzhydryl-thioethyl)-.DELTA..sup.2 -imidazoline 
hydrochloride dissolved in 35 ml of acetic acid are oxidised with 3.5 ml 
of hydrogen peroxide of 110 volumes strength over the course of 1 hour at 
50.degree. C. The mixture is evaporated to dryness in vacuo, and the 
residue is taken up in acetone and filtered off. The product is 
recrystallised from isopropanol. CRL 40,066 is obtained in an overall 
yield of 40%. It is a white powder melting, with decomposition, at 
162.degree.-164.degree. C. 
EXAMPLE 4 
N-[2-(Benzhydrylsulphinyl)-ethyl]-morpholine hydrochloride 
##STR6## 
a. N-[2-(Benzhydryl-thio)-ethyl]-morpholine hydrochloride 
7.6 g (0.1 mol) of thiourea and 100 ml of demineralised water are 
introduced into a 500 ml three-neck flask equipped with a magnetic 
stirrer, a dropping funnel and a condenser; the mixture is heated to 
50.degree. C and 20.25 g (18 ml; 0.1 mol) of chlorodiphenylmethane are 
then added all at once. The solution is left refluxing until it has become 
limpid, and is then cooled to 20.degree. C, and 200 ml of 2.5 N NaOH are 
added dropwise. 
The resulting solution (which contains the sodium benzhydrylthiolate thus 
formed) is then kept under reflux for 1 hour; after it has returned to 
50.degree. C, a solution of 18.6 g (0.1 mol) of 2-chloroethyl-morpholine 
hydrochloride in 80 ml of water is added dropwise. The temperature of the 
reaction mixture is then brought to the reflux point over the course of 2 
hours. 
The mixture is cooled, the oil formed is extracted with ether and the ether 
solution is then extracted with 3 times 70 ml of N HCl. The expected 
product precipitates from water in an acid medium. It is filtered off and 
then recrystallised from isopropanol. 26.6 g of 
N-[2-(benzhydryl-thio)-ethyl]-morpholine hydrochloride are thus obtained. 
Melting point 176.degree. C. Yield relative to chlorodiphenylmethane: 76%. 
b. CRL 40,221 
24.8 g (0.0711 mol) of the hydrochloride obtained above, dissolved in 70 ml 
of pure acetic acid, are oxidised with 6.4 ml of hydrogen peroxide of 125 
volumes strength. The reaction is carried out at 40.degree. C over the 
course of 1 hour 30 minutes. The acetic acid is then evaporated in vacuo 
and the residual oil is taken up in ether, from which CRL 40,221 
crystallises on addition of acetone. 18.9 g of product are thus obtained. 
Melting point = 166.degree.-168.degree. C. Overall yield = 52%. 
Chlorine determination (Volhard method): Theoretical; 9.7%, Determined; 
9.7%. 
EXAMPLE 5 
N-[2-(Benzhydrylsulphinyl)-ethyl]-piperidine hydrochloride 
##STR7## 
The procedure indicated in Example 4 is followed. 
N-[2-(Benzhydryl-thio)-ethyl]-piperidine hydrochloride (melting point = 
174.degree.-176.degree. C) is thus obtained. Oxidation of this sulphide 
with H.sub.2 O.sub.2 gives CRL 40,222. Melting point = 
206.degree.-210.degree. C (with decomposition). Overall yield: about 50%. 
Chlorine determination (Volhard method); Theory; 9.75%, Found; 9.8%. 
EXAMPLE 6 
3-(Benzhydrylsulphinyl)-propionohydroxamic acid 
##STR8## 
a. Methyl 3-(benzhydrylthio)-propionate 
A solution of 0.1 mol of sodium benzhydryl-thiolate is prepared in a 
strongly alkaline medium (prepared as indicated in Example 4a). A solution 
of 0.15 mol of sodium 3-chloropropionate [obtained by dissolving 0.15 mol 
(16.3 g) of 3-chloropropionic acid and 0.075 mol (7.6 g) of Na.sub.2 
CO.sub.3 in water] is added to the above solution at about 60.degree. C. 
Thereafter the temperature is raised to the boil, the mixture is left 
under reflux for about half an hour and is then cooled, filtered over 
charcoal and acidified with concentrated HCl, and 16.0 g of 
3-(benzhydryl-thio)-propionic acid are thus precipitated. Melting point = 
88.degree.-90.degree. C. 
Yield relative to chlorodiphenylmethane = 59%. 
The corresponding methyl ester is then prepared by dissolving 16 g (0.059 
mol) of the preceding acid in 40 ml of 1,2-dichloroethane to which 10 ml 
of methanol and 0.1 ml of concentrated H.sub.2 SO.sub.4 have been added. 
The whole is heated to the reflux temperature for about 5 hours, cooled, 
and decanted, the aqueous phase is discarded and the organic phase is 
washed with a saturated sodium bicarbonate solution and then with water 
until the wash waters have a neutral pH. After drying over MgSO.sub.4 and 
evaporating the solvent, 15.7 g (0.055 mol) of the ester (a limpid yellow 
oil) are obtained. Yield relative to the acid: 93%. Yield relative to 
chlorodiphenylmethane = 55%. 
b. 3-(Benzhydryl-thio)-propionohydroxamic acid 
0.055 mol (15.7 g) of the preceding ester, dissolved in 50 ml of methanol, 
is added to a solution of 0.15 mol of hydroxylamine base [prepared by 
neutralising 0.15 mol (10.4 g) of hydroxylamine hydrochloride with 0.15 
mol of sodium methylate]. The whole is left at ordinary temperature 
(15.degree.-25.degree. C) for 48 hours, the sodium chloride is filtered 
off, the methanol is evaporated, the residue is taken up with aqueous 
alkali, the solution is filtered over charcoal, the filtrate is acidified 
with concentrated HCl, and the desired hydroxamic acid (8.3 g) is thus 
obtained. It is recrystallised from benzene and 7.6 g of pure hydroxamic 
acid are isolated. Melting point: 106.degree.-108.degree. C. Yield 
relative to the ester: 48%. 
c. CRL 40,260 
0.0264 mol (7.6 g) of the preceding hydroxamic acid, dissolved in 27 ml of 
anhydrous CH.sub.3 --COOH, is reacted with 2.4 ml of H.sub.2 O.sub.2 of 
124 volumes strength. The mixture is left at 40.degree.-45.degree. C for 
11/2 hours, the acetic acid is evaporated and the residue is taken up in 
50 ml of ethyl acetate; the CRL 40,260 crystallises. It is recrystallised 
from isopropanol and 7.1 g are thus obtained. Melting point = 
159.degree.-160.degree. C. Yield from the oxidation: 88%. Overall yield 
23.5%. 
EXAMPLE 7 
3-(Benzhydrylsulphinyl)-propionamidoxime hydrochloride Code No. CRL 40,261 
a. 3-(Benzhydrylthio)-propionitrile 
A solution of 0.1 mol of sodium benzhydryl-thiolate (compare Example 4a) is 
prepared and 9 ml(0.115 mol) of .beta.-chloropropionitrile are then added 
at 60.degree.-70.degree. C. The mixture is thereafter heated for half an 
hour under reflux and is cooled, the oil is extracted with ether and the 
ether solution is washed with water and dried. After evaporating the 
solvent, 24.5 g of nitrile (a limpid green oil) are obtained. Yield: 97%. 
b. 3-(Benzhydryl-thio)-propionamidoxime hydrochloride 
24.5 g of the preceding nitrile are dissolved in about 100 ml of 1-butanol. 
A solution of 0.25 mol of hydroxylamine base in 50 ml of water [obtained 
by neutralising 17.4 g of hydroxylamine hydrochloride with 21 g of sodium 
bicarbonate] is added to the preceding solution. The whole is heated at 
the reflux temperature of the butanol-water (2:1) azeotrope, whilst 
maintaining vigorous stirring, for at least 4 hours. It is then cooled, 
the butanol is evaporated and the residue is taken up with water under 
neutral conditions 3-(benzhydryl-thio)-propionamidoxime precipitates. 19.1 
g of the base (a white powder which is soluble in alcohols, melting point 
= 106.degree.-108.degree. C) are thus obtained. The corresponding 
hydrochloride is prepared by adding HCl to a suspension of the base in 
water until the pH is acid; the hydrochloride, which is soluble in the hot 
medium, crystallises on cooling the acid solution. 18.4 g of 
3-(benzhydrylthio)-propionamidoxime hydrochloride are thus obtained. 
Melting point: 186.degree.-188.degree. C. Overall yield 57%. 
c. CRL 40,261 
18.4 g (0.057 mol) of the preceding hydrochloride, dissolved in 60 ml of 
CH.sub.3 --COOH, are reacted with 5.2 ml of H.sub.2 O.sub.2 of 124 volumes 
strength, at 40.degree.-45.degree. C, for about 1 hour 30 minutes. The 
acetic acid is evaporated and the residue is taken up in ethyl acetate; 
CRL 40,261 crystallises. It is recrystallised from water and 17.3 g of 
product are isolated. Melting point 164.degree.-166.degree. C. Overall 
yield: 51%. 
EXAMPLE 8 
4-(Benzhydrylsulphinyl)-butyramidoxime hydrochloride Code No. CRL 40,277 
Using the procedure indicated in Example 7, the following are obtained 
successively: 
4-(benzhydryl-thio)-butyronitrile, which is in the form of a limpid oil, 
4-(benzhydryl-thio)-butyramidoxime (melting point = 78.degree.-80.degree. 
C), 
the corresponding hydrochloride (melting point = 132.degree.-133.degree. C) 
and 
Crl 40,277, melting point = 200.degree.-204.degree. C (with decomposition). 
EXAMPLE 9 
4-(Benzhydrylsulphinyl)-butyrohydroxamic acid Code No. CRL 40,278. 
Using the procedure described in Example 6, the following are obtained 
successively: 
4-(benzhydryl-thio)-butyric acid (melting point = 91.degree.-92.degree. C), 
ethyl 4-(benzhydryl-thio)-butyrate (which is in the form of an oil), 
4-(benzhydryl-thio)-butyrohydroxamic acid (melting point 110.degree. C) and 
Crl 40,278, melting point = 143.degree. C. 
the results of the pharmacological tests which were carried out have been 
summarised below. These experiments show that the products of the formula 
I act on the central nervous system. 
A. Experiments relating to CRl 40,028 (Example 1) 
Toxicity 
The LD 50 in mice, for gastric administration, is 1,950 mg/kg. For 
intraperitoneal administration, in mice, no mortality was observed at 
doses of 256 mg/kg, 512 mg/kg and 1,024 mg/kg; the LD 50 for 
intraperitoneal administration, in mice, appears to be less than or equal 
to 2,048 mg/kg. 
The fact that the LD 50 for gastric administration is close to the LD 50 
for intraperitoneal administration suggests that the product overcomes the 
intestinal barrier readily, all the more so since at all the doses 
studied, excitation of the animal was observed. 
Interaction with apomorphine 
Batches of 6 rats are given CRL 40,028 30 minutes after the subcutaneous 
injection of 0.5 mg/kg of apomorphine. It is found that CRL 40,028 does 
not exert any activity on the stereotype behaviour caused by apomorphine. 
The results obtained in accordance with the method of Table II given later 
have been shown in Table III. 
TABLE III 
______________________________________ 
Number of rays 
% relative 
crossed in 30 
to the con- 
% 
minutes trol animals 
variation 
______________________________________ 
Control animals 
200 100 -- 
CRL 40,028 
64 mg/kg - 30 mins 
311 155 +55 
CRL 40,028 
64 mg/kg - 1 hr 
424 212 +112 
CRL 40,028 
64 mg/kg - 2 hrs 
376 188 +88 
CRL 40,028 
64 mg/kg - 4 hrs 
234 117 +17 
______________________________________ 
It can be seen from the analysis of Table III that CRL 40,028 brings about 
a hypermotility which appears in less than 30 minutes, reaches a maximum 
after one hour and disappears in 4 hours. 
Effect on the motility 
1. Spontaneous motility 
CRL 40,028 increases the motor activity of the animals from a dose of 16 
mg/kg onwards. As this effect is representative of the activity of CRl 
40,028, attempts have been made to obtain its kinetics more precisely. 
Batches of 12 mice per dose, and 24 control animals, were given CRL 40,028 
at various times, at a dose of 64 mg/kg of the gummy solution, in 
accordance with the scheme of Table II as regards the administration of 
the gummy solution and of the product. 
2. Residual motility 
The stimulating effect of CRL 40,028 is brought more into evidence as the 
spontaneous motor activity is reduced by the animals becoming accustomed 
to the chamber. 
3. Motor recovery after hypoxia aggression 
After anoxia, the mice which have received CRL 40,028 at doses of 512, 128 
and 32 mg/kg, exhibit a markedly greater motor activity than that of the 
control animals. 
It follows from the experiments recorded above that CRL 40,028 possesses 
stimulant properties, namely causing excitation and hyper-reactivity, and 
hypermotility, in animal psychopharmacology. 
In order to establish whether or not CRL 40,028 approaches amphetamine-type 
agents or psychostimulant agents, comparative experiments were carried out 
with amphetamine and caffeine, and are reproduced in Table IV. 
TABLE IV 
______________________________________ 
CRL Amphet- 
Tests 40,028 amine Caffeine 
______________________________________ 
Excitation + ++ ++ 
Reactivities .uparw. .uparw. .uparw. 
Temperature (S) .+-..dwnarw. 
.uparw. .dwnarw. 
Temperature (R) 0 .uparw. .+-..uparw. 
Stereotypies 0 + .+-. 
Boosting action on apomorphine 
0 + + 
Boosting action on amphetamine 
0 .+-. 
Anti-reserpine action 
(temperature) .+-. + + 
Anti-reserpine action 
(ptosis) 0 + 0 
Anti-oxotremorine action 
(temperature) .+-. + + 
Anti-oxotremorine action 
(trembling) + + 0 
Anti-oxotremorine action 
(peripheral) 0 + 0 
Four plate test .uparw. .uparw. .uparw. 
Convulsions by electric shock 
.dwnarw. .uparw. .uparw. 
Spontaneous motility 
.uparw. .uparw. .uparw. 
Residual motility .uparw.+++ .uparw.+++ 
Motor recovery after hypoxia 
.uparw.+++ 
(a).uparw. 
(a).uparw. 
Group toxicity .+-. + 0 
______________________________________ 
Note: 
(a) mortality 
Interaction with amphetamine 
Amphetamine (2 mg/kg, given intraperitoneally) is injected 30 minutes after 
the administration of CRL 40,028 (6 rats/dose). CRL 40,028 does not 
produce an overall change in the stereotype behaviour induced by 
amphetamine in rats; it does not boost the action of amphetamine. 
Interaction with reserpine 
Batches of 6 mice are given an intraperitoneal injection of reserpine (2.5 
mg/kg) 4 hours before the administration of CRl 40,028. 
1. Effect on the temperature 
At 256 and 64 mg/kg CRL 40,028 partially counteracts the hypothermic effect 
of reserpine. 
2. Effect on ptosis 
CRL 40,028 does not resolve the palpebral ptosis produced by reserpine. 
Interaction with oxotremorine 
Mice (6 per dose) are given an intraperitoneal injection of 0.5 mg/kg of 
oxotremorine 30 minutes after the administration of CRL 40,028. 
1. Effect on the temperature 
CRL 40,028 at certain doses (256, 16 and 4 mg/kg, but not 64 mg/kg) 
moderately opposes the hypothermic effect of oxotremorine. 
2. Effect on trembling 
CRL 40,028 moderately reduces, at all the doses, the intensity of the 
trembling brought about by oxotremorine. 
3. Effect on the peripheral cholinergic symptoms 
CRL 40,028 does not alter the increase in salivation, lachrymation and 
defaecation brought about by oxotremorine. 
Effect on the four plate test, traction and electric shock 
The test is carried out on batches of 20 mice, 30 minutes after the 
administration of CRL 40,028. 
At high doses (256 and 64 mg/kg) CRL 40,028 produces an increase in the 
number of passes which entail pain. At a low dose (4.1 mg/kg) it appears 
to bring about a modest decrease in the number of such passes. At no dose 
does CRL 40,028 bring about a major decrease in motility. Only at a high 
dose (256 mg/kg) does it exert a very moderate antagonism against the 
convulsive effects of the electric shock. 
TABLE II 
__________________________________________________________________________ 
0 to + 30 
- 4 hrs - 2 hrs - 1 hr - 30 mins 
mins 
__________________________________________________________________________ 
Control animals 
Gummy solution 
Gummy solution 
Gummy solution 
Gummy solution 
Actimetry 
CRL 40,028 
64 mg/kg - 4 hrs 
CRL 40,028 
Gummy solution 
Gummy solution 
Gummy solution 
Actimetry 
CRL 40,028 
64 mg/kg - 2 hrs 
Gummy solution 
CRL 40,028 
Gummy solution 
Gummy solution 
Actimetry 
CRL 40,028 
64 mg/kg - 1 hr 
Gummy solution 
Gummy solution 
CRL 40,028 
Gummy solution 
Actimetry 
CRL 40,028 
64 mg/kg - 30 mins 
Gummy solution 
Gummy solution 
Gummy solution 
CRL 40,028 
Actimetry 
__________________________________________________________________________ 
It emerges from these comparative tests that CRL 40,028 differs from the 
amphetamine-type compounds by: 
the absence of stereotypies, 
the absence of boosting of the effect of apomorphine and of amphetamine, 
the absence of a marked antagonism to reserpine, and 
the virtual absence of specific (?) toxicity in the groups of mice. 
Accordingly, one is dealing with a psychostimulant which comes closer to 
caffeine, in spite of certain differences, namely: 
the absence of boosting of the effect of apomorphine, 
the absence of a marked antagonism to hypothermia brought about by 
reserpine, and 
the absence of an aggravation of the effects of electric shock and of 
hypoxia. 
B. Tests on the other products 
1. CRl 40,048 (Example 2) acts only on the central nervous system. It has 
an antagonist action on oxotremorine, in the absence of a mydriatic 
effect. It boosts stereotypies produced by amphetamine-type compounds and 
produces hyper-reactivity to the touch in mice. 
2. CRL 40,066 (Example 3) exhibits, alongside an effect on the central 
nervous system, an anti-oedema effect in the carrageenin oedema. 
3. CRL 40,221 (Example 4) exhibits a psychopharmacological spectrum close 
to that of tricyclic anti-depressants, namely 
an anti-reserpine effect, 
an anti-oxotremorine effect, 
a (metabolic) boosting of the stereotypies produced by amphetamine-type 
compounds, 
a protection against convulsions produced by electric shock, 
a considerable mydriasis and 
hypothermia at high doses. 
Furthermore, it exhibits (a) a certain effect in the four plate test (like 
imipramine and amitriptyline but not nortriptyline) and (b) a sedation at 
doses close to the toxic dose (like imipramine and nortriptyline, but not 
amitriptyline). Finally, it produces a resumption of motor activity in 
mice accustomed to their chamber. 
CRL 40,221, administered intraperitoneally in mice exhibits an LD-O greater 
than 512 mg/kg 
4. CRL 40,222 (Example 5) acts on the central nervous system and the 
following are observed in its psychopharmacological spectrum: 
an increase in the duration of the stereotypies brought about by 
amphetamine, 
a moderate action towards oxotremorine, 
the absence of an anti-reserpine effect, 
an increase in the spontaneous motility in mice (only at a low dose of 1 
mg/kg ) and a stimulation of the residual motility in mice (at a dose of 8 
mg/kg). 
CRL 40,222, administered intraperitoneally in mice, has an LD-O greater 
than 128 mg/kg. 
5. CRL 40,260 (Example 6) is a substance of low toxicity (its LD-O is 
greater than 1,024 mg/kg for intraperitoneal administration in mice); in 
the psychotropic field, it produces the following in the animals: 
a sedation, with hypomotility, in mice and rats, 
a reduction in the spontaneous motility in mice and a hyper-reactivity in 
mice and in rats. 
6. CRL 40,261 (Example 7) exhibits the following in its 
psychopharmacological spectrum: 
an increase in the duration of the stereotypies brought about by 
amphetamine in rats, 
an increase in the hypothermia due to reserpine (without alteration of the 
palpebral ptosis induced by reserpine), 
a moderate effect towards oxotremorine and 
an increase in the spontaneous motility in mice (at doses of 2 mg/kg, 8 
mg/kg and 32 mg/kg). 
The LD-O of CRL 40,261, administered intraperitoneally in mice, is greater 
than 256 mg/kg. 
7. CRL 40,277 (Example 8) acts on the central nervous system. The following 
are observed in its psychopharmacological spectrum: 
firstly, the following effects at high doses: hypothermia, hypomotility, 
aggravation of the hypothermic effects of reserpine and oxotremorine, an 
aggravation of the lethal effects of the electric shock, and 
secondly, at medium doses, effects of a type which are more stimulant in 
nature but are always of very moderate intensity, namely: 
hyper-reactivity, boosting of the effect of amphetamine and inconstant 
residual hypermotility. 
For intraperitoneal administration to mice, the LD-O of CRL 40,277 is 
greater than 512 mg/kg. 
8. CRL 40,278 (Example 9) acts on the central nervous system. For 
intraperitoneal administration in mice, its LD-O is greater than 1,024 
mg/kg.