Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
~.lS393
--1--
Benzhydrylsulfinylethylamine derivatives.
The present invention relates to benzhydrylsulfinylethylamines
- as new industrial products. It also relates to the use of these products
in therapeutics and to the method for preparing them.
The hydrochloride of N-[2-(benzhydrylsulfinyl)-ethyl]-amine
5 is known to have been described as intermediary of synthesis of disulfide
-sulfoxide derivatives by R. C~. HISKEY et al., J. Org. Chem., 32,
pages 3191-3194 (1967) without a study of its psssible therapeutical
properties. It is also known that French Patent No. 2,326,1~1 and corres-
ponding U.S. Patent No. 4 06~ 686 propose derivatives of the N-(benz-
10 hydrylsulfinylalkyl)-amine type, particularly as substances active on
the central nervous system tCNS). It has just been unexpectedly found
that new derivatives of N-(benzhydrylsuJfinylalkyl)-amine present
interesting neuropsychopharmacological properties with respect to
the products of Examples 4 and 5 of the above-mentioned Patents,
15 namely N-[2-(benzhydrylsulfinyl)-ethyl]-morpholine and N-[2-(benzhydryl-
sulfinyl)-ethyl]-piperidine.
The new N-benzhydrylsulfinylalkyl-amine derivatives according
to the invention are characterized in that they are selected from
the group consisting of:
a) N-[2-(benzhydrylsul~inyJ)-ethyl]-amines o~ the formula
'' ~3\
CH - SO - CH2 - CH2 - NH - R (I)
~/
30 (wherein R is a Cl-C4-alkyl group), and-
b) acid addition salts thereof.
Among the R groups included in the definition given herein-
above, particular mention may be made of the CH3, C2H5, i-C3H7
and t-C4Hg groups.
The most interesting compound from the psychopharmeutical
.
,.
;3~3
point of view is the compound R = CH3.
Among suitable acid addition salts, particular men-
tion may be made of the non-toxic addition salts obtained
by reacting the free base of formula I with an inorganic
or organic acid. From those acids suitable to this end,
particular mention may be made of hydrochloric, hydro-
bromic, sulfuric, phosphoric, nitric, picric, formic,
acetic, propionic, fumaric, maleic, malic, tartric, citric,
oxalic, benzoic, cinnamic, ascorbic, methanesulfonic,
paratoluenesulfonic, aspartic and glutamic acids.
The products of formula I are active on the CNS:
they act as antidepressants of the CNS and present an
interesting anti-aggressive effect.
A therapeutical composition is recommended which is
characterized in that it contains, in association with a
physiologically acceptable excipient, at le~ast one compound
of formula I or one of its non-toxic addition salts, as
active ingredient.
The compounds of formula I may be prepared in accor-
dance with a method known per se by application of conven-
tional reaction mechanisms. The method recommended accor-
ding to the invention which is illustrated by the scheme:
(C6H5)2CH - SH (II)
+
Br-CH2CH2-NHR (III)
(C6H5)2CH-S-CH2CH2-NHR (IV)
1, H22
(C6H5)2CH-SO-CH2CH2-NHR (I)
is characterized in that, successively,
a) diphenylmethanethiol (II) is reacted in water, in
the presence of a base particularly selected from NaOH and
KOH, with a 2-bromoe-thylamine of formula Br-CH2CH2-NHR
(III) - wherein R is defined as indicated hereinabove -
under refluxing for at least I hour, using from l to l.2
mole of III, for l mole of II, to obtain a benzhydrylthio-
ethylamine of formula:
;393
(C6H5)2CH - S - CH2C}12 - NHR (IV)
then,
b) the benzhydrylthioethylamine thus obtained is oxidized
in acetic acid with H2O2 at 110-130 volumes, at a temperature of
5 40-45C for I hour.
A certain number of N-[2-(benzhydrylsulfinyl)-ethyl]-amines
according to the invention are given in non-limiting manner in Table
I hereinbelow:
TABLE I
(C6H5~2CH - SO - CH2CH2 - NHR
Product Code No. R Melting point
Ex I (a) CRL 40883 CH3 128-130C
Ex 2 (a) CH(CH3)2
Ex 3 (a) _ C(CH3)3
Note: (a): hydrochloride
Other advantages and features of the invention will be more
readily understood on reading the following description of examples
25 of preparation which are in no way limiting.
Obtaining of the hydrochloride of N-[2-(benzhydrylsulfinyl)-ethyl]-
__
methylamine
(Example l; Code No.: CRL 40883).
1) - Hydrochloride of N-[2-(benzhydrylthio)-ethyl]-methylamine.
15 g (0.075 mol) of diphenylmethanethiol in suspension in
75 ml of water are salified wi~h 16 g (0.4 mol) of sodium hydroxide
in pellet form in solution in 25 ml of water. The mixture is taken
to reflux and a solution of 17.6 g (0.08 mol) of hydrobromide of N-(2-
35 bromoethyl)-methylamine in 50 ml of water is poured drop by drop
5393
into this mixture. Reflux is maintained for I hour, the mixture is
cooled, extracted with ether, washed in water. The ethereal solution
is extracted with 100 ml of 2 N HCI acid, the base is precipitated
with concentrated ~aO~. The base is taken up in ether, the ethereal
5 phase is washed in water, dried and the desired hydrochloride is precipi-
tated by the addition of hydrochloric ethanol. The precipitate is drained,
washed with ethyl acetate and, by recrystallization from ethanol,
the hydrochloride of N-[2-(benzhydrylthio)-ethyl~-methylamine is ob-
tained with a yielo of 71%. m.p. 121-122C.
2) CRL 40883
14 g (0.05 mol) of hydrochloride of N-[2-(benzhydrylthio)-ethyl]-
methylamine in solution in 50 ml of acetic acid are oxidized with
5 ml of H2O2 at 110 volumes for I hour at 40C. The acetic acid is
evaporated in vacuo, the residue of evaporation is taken up in acetone
and the precipitate formed is drained. By recrystallizatian from the
ethanol-ethyl acetate (1:1) v/v mixture, CRL 40883 is obtained with
a yield of 58%. m.p. = 128-130C.
The results of the neuropsychopharmacological tests undertaken
with CRL 40883 (product of Example 1) have been summarized herein-
after. In these tests, CRL 40883 in solution in distilled water at pH
5 was administered by the intraperitoneal route in a volume of 20
ml/kg in the male mouse and in a volume of 5 mJ/kg in the male
rat.
A - TOXICITY
In the male mouse, the LD-30 of CRL 40883 by the IP route
is of the order of 250 mg/kg.
B - OVERALL BEHAVIOUR AND REACTIVITIES
Batches of 6 animals are observed before, then IS minutes,
30 minutes1 I hr., 2 hrs., 3 hrs. and 24 hrs. after administration of
CRL 40883.
I) In the mouse:
At the doses of 64 mg/kg, 16 mg/kg, 4 mg/kg and I mg/kg,
CRL 40883 does not bring about any substantial changes in behaviour
and reactivities. Moderate sedation is observed particularly at the
dose of 128 mg/kg.
1~5393
2) In the rat:
At the dose of 32 mg/kg, a hyporeactivity to touch and a
muscular hypotonia are observed for 30 minutes; at the doses of 8
mg/kg, 2 mg/kg and 0.5 mg/kg, no particular symptoms are observed.
5 C - ACTION ON THE CNS
CRL 40883 presents the effects of an antidepressant substance
(antagonism of the hypothermias induced by apomorphine, reserpine
or oxotremorine) as well as a potentialization of the amphetaminic
stereotypies.
Furthermore, at tl-e doses of 16 mgtkg and 64 mg/kg, CRL
40883 brings about a considerable reduction in the number of fights
in the groups of mice, according to the intergroup aggressiveness
method.
