PROCESS FOR PREPARING NEW 2-METHOXY-BENZAMIDE DERIVATIVES

SYNTHESE DE DERIVES DE METHOXY-2 BENZAMIDE

English Abstract

A B S T R A C T
The invention provides novel 2-methoxy-benzamide
derivatives of the formula:
<IMG> (I)
in which n is 1 or 2; R1 represents a cycloalkyl-alkyl
radical of formula:
<IMG> , a phenylalkyl radical of formula <IMG>
(in which m is an integer from 2 to 5, A is a linear or
branched alkylene chain of 1 to 4 carbon atoms, and R4 is
hydrogen, halogen, especially fluorine or chlorine,
trifluoromethyl, or alkyl or alkoxy of 1 to 3 carbon atoms),
CNCH2-CH2-, CH?C-CH2-,
<IMG> , or <IMG> ; R2 is either
chlorine, SO2R5 (in which R5 is alkyl or 1 to 4 carbon
atoms), or SO2NR6R7 (in which, R6 and R7, which are
identical or different, represent, independently of one
another, hydrogen or alkyl of 1 to 4 carbon atoms); and
R3 is hydrogen or alkyl of 1 to 4 carbon atoms; in the
form of racemates or optical isomers, and their pharmaceutically
acceptable acid addition salts, which are useful in the
treatment of psychosomatic and psychotic disturbances.

Claims

The embodiments of the invention in which an
exclusive property or privilege is claimed are defined as
follows:
1. Process for the preparation of a 2-methoxy-
benzamide of the formula
<IMG> (I)
in which n is 1 or 2; R1 represents a cycloalkyl-alkyl
radical of formula:
<IMG> , a phenylalkyl radical of formula <IMG>
(in which m is an integer from 2 to 5, A is a linear or
branched alkylene chain of 1 to 4 carbon atoms, and R4
is hydrogen, halogen, trifluoromethyl, or alkyl or alkoxy
of 1 to 3 carbon atoms); CNCH2-CH2-, CH3C?CH2- ,
<IMG> , or <IMG> R2 is either
chlorine, SO2R5 (in which R5 is alkyl of 1 to 4 carbon
atoms), or SO2NR6R7 (in which, R6 and R7, which are
identical or different, represent, independently of one
another, hydrogen or alkyl of 1 to 4 carbon atoms); and
R3 is hydrogen or alkyl of 1 to 4 carbon atoms; in the
form of racemates or optical isomers, and their
pharmaceutically acceptable acid addition salts, which
comprises either (A) reacting an amine of the formula:
(III)
<IMG>
44

with a halide of a 2-methoxy-benzoic acid of the formula
<IMG>
(II)
in which n, R1, R2, and R3 are as hereinbefore defined
and X is halogen, and, if desired, when R3 in the starting
compound is H, alkylating the product to produce a
compound of formula I in which R3 is alkyl; or (B) reacting
a compound of the formula:
<IMG>
with a compound R1X in which R1, R2, R3 and n are as
hereinbefore defined and X is halogen.
2. Process according to claim 1 in which, in
method (A), the starting amine is obtained by reacting
a furan-2-one or pyran-2-one of the formula
<IMG>
with an amine R1NH2, to give a nitrogen-substituted
pyrrolidin-2-one or piperidin-2-one of the formula
<IMG>
which is then treated with nitromethane so as to give a
nitrogen-substituted 2-nitromethylene-pyrrolidine or
-piperidine of formula:

<IMG>
which is then reduced to a primary amine of formula:
<IMG>
which is converted, if desired, into a secondary amine
of formula:
<IMG> (IIIb)
the symbols having the meanings given in claim 1.
3. Process according to claim 1, in which in
method (A) the starting amine is obtained by reacting a
furane or pyrane derivative of the formula:
<IMG>
with hydrobromic acid, so as to give the dibromo
derivative of formula:
<IMG>
which is then recyclised to give the substituted pyrrolidine
or piperidine by reaction with an amine NH2-R1 so as to
give the amine
46

<IMG>
the symbols having the meanings given in claim 1.
4. Process according to claim 1 in which R2
is -SO2NH2.
5. Process according to claim 1, in which R1
is benzyl or .alpha.-methylbenzyl which is unsubstituted or
substituted by halogen, alkyl or alkoxy of 1 to 3 carbon
atoms, or trifluoromethyl.
6. Process according to claim 1, in which n
is 1 and R3 is H or CH3,
7. Process according to claim 1, in which R1
is benzyl substituted by halogen, alkyl or alkoxy of 1
to 3 carbon atoms, or trifluoromethyl,
8. Process according to claim 1, in which R1
is benzyl which is unsubstituted or substituted by
halogen, alkyl or alkoxy of 1 to 3 carbon atoms, or
trifluoromethyl, R2 is Cl, SO2R5 or SO2NR6R7, with each
of R5, R6 and R7 being alkyl of 1 to 4 carbon atoms, R3
is H or CH3 and n is 1.
9. Process according to claim 1, in which R2 is
SO2NH2, R1 is fluorobenzyl, chlorobenzyl, .alpha.-methylbenzyl,
cyanoethyl, cyclopropylmethyl, phenylethyl, methoxybenzyl,
.alpha.-methylbenzyl, p-chloro-phenylethyl, trifluoromethylbenzyl,
prop-2-ynyl, diphenylmethyl or p-fluorophenyl-vinyl-methyl
radical, R3 is H or CH3, and n is 1.
47

10. Process according to claim 1, in which R1 is halogeno-
benzyl, R2 is SO2NH2, R3 is H and n is 1.
11. Process according to claim 1, in which R1 is benzyl, R2
is chlorine, SO2CH3, or SO2N(CH3)2, R3 is H, and n is 1.
12. Process according to claim 1, in which R1 is fluoro-
benzyl, R2 is chlorine, SO2NH2, or SO2CH3, R3 is H or CH3, and n
is 1.
13 Process according to claim 1 for producing racemic
N-[(1-p-fluorobenzyl-pyrrolidinyl-2)-methyl]-2-methoxy-5-sulphamoyl-
benzamide, or a dextro-rotatary or laevo-rotatary optical isomer,
or pharmaceutically acceptable acid addition salt thereof, which
comprises reacting said compounds in which R1 is p-fluorobenzyl,
R2 is SO2NH2, R3 is H and n is 1.
14. Process according to claim 1 for producing N-[(1-p-
fluorobenzyl-pyrrolidinyl-2)-methyl]-2-methoxy-5-methylsulphonyl-
benzamide or a pharmaceutically acceptable acid addition salt
thereof, which comprises reacting said compounds in which R1 is
p-fluorobenzyl, R2 is methylsulfonyl, R3 is H and n is 1.
15. Process according to claim 1 for producing N-[(1-p-
fluorobenzyl-pyrrolidinyl-2)-methyl]-2-methoxy-5-chloro-benzamide
or a pharmaceutically acceptable acid addition salt thereof,
which comprises reacting said compounds in which R1 is p-fluoro-
benzyl, R2 is chloro, R3 is H and n is 1.
16. Process according to claim 1 for producing N-[(1-prop-
2-ynyl-pyrrolidinyl-2)-methyl]-2-methoxy-5-sulphamoyl-benzamide
or a pharmaceutically acceptable acid addition salt thereof, which
comprises reacting said compounds in which R1 is prop-2-ynyl, R2
is sulphanoyl, R3 is H and n is 1.
17. Process according to claim 1 for producing N-[(1-benzyl-
pyrrolidinyl-2)-methyl]-2-methoxy-5-methylsulphonyl-benzamide or
a pharmaceutically acceptable acid addition salt thereof, which
48

comprises reacting said compounds in which R1 is benzyl, R2 is
methyl sulphonyl, R3 is H and n is 1.
18. Process according to Claim 1 for producing N-[(1-cyclo-
propyl methyl-pyrrolidinyl-2)-methyl]-2-methoxy-5-sulphamoyl-
benzamide or a pharmaceutically acceptable acid addition salt
thereof, which comprises reacting said compounds in which R1 is
cyclopropylmethyl, R2 is sulphamoyl, R3 is H and n is 1.
19. 2-Methoxy-benzamide derivatives of the formula:
<IMG>
(I)
in which n is 1 or 2; R1 represents a cycloalkyl-alkyl
radical of formula
<IMG> , a phenylalkyl radical of formula
<IMG> (in which m is an integer from 2 to 5, A is
a linear or branched alkylene chain of 1 to 4 carbon
atoms, and R4 is hydrogen, halogen, trifluoromethyl,
or alkyl or alkoxy of 1 to 3 carbon atoms), CNCH2-CH2-,
CH?C-CH2- , <IMG> , or <IMG> ;
R2 is either chlorine, SO2R5 (in which R5 is alkyl of
1 to 4 carbon atoms), or SO2NR6R7 (in which R6 and R7,
which are identical or different, represent, independently
of one another, hydrogen or alkyl of 1 to 4 carbon atoms);
and R3 is hydrogen or alkyl of 1 to 4 carbon atoms; in the
form of racemates or optical isomers, and their
49

pharmaceutically acceptable acid addition salts, when prepared
by the process claimed in any of claims 1 to 3 or any obvious
chemical equivalent thereof.
20. A compound having the formula
<IMG>
wherein R1, R3 and n are as defined in claim 1, whenever prepared
by a process according to claim 4 or any obvious chemical
equivalent thereof.
21. A compound having the formula
<IMG>
wherein R1 is benzyl or .alpha.-methylbenzyl which is unsubstituted or
substituied by halogen, alkyl or alkoxy of 1 to 3 carbon atoms,
or trifluoromethyl, and R2, R3 and n are as defined in claim 1,
whenever prepared by a process according to claim 5 or any
obvious chemical equivalent thereof.
22. A compound having the formula
<IMG>
wherein n is 1, R3 is H or CH3, and R1 and R2 are as defined in
claim 1, whenever prepared by a process according to claim 6 or
any obvious chemical equivalent thereof.

23. A compound having the formula
<IMG>
wherein R1 is benzyl substituted by halogen, alkyl or alkoxy of
1 to 3 carbon atoms, or trifluoromethyl, and n, R2 and R3 are as
defined in claim 1, whenever prepared by a process of claim 7 or
any obvious chemical equivalent thereof.
24. A compound having the formula
<IMG>
wherein R1 is benzyl which is unsubstituted or substituted by
halogen, alkyl or alkoxy of 1 to 3 carbon atoms or trifluoromethyl,
R2 is Cl, SO2R5 or SO2NR6R7, with each of R5, R6 and R7 being
alkyl of 1 to 4 carbon atoms, and R3 is H or CH3, whenever
prepared by a process according to claim 8 or any obvious chemical
equivalent thereof.
25. A compound having the formula
<IMG>
wherein R1 is fluoromethyl benzyl, chlorobenzyl, .alpha.-methylbenzyl,
cyanoethyl, cyclopropylmethyl, phenylethyl, methoxybenzyl, .alpha.-
methylbenzyl, p-chloro-phenylethyl, trifluoromethylbenzyl, prop-
2-ynyl, diphenylmethyl, or p-fluorophenyl-vinyl-methyl radical,
51

and R3 is H or CH3, whenever prepared by a process according to
claim 9 or any obvious chemical equivalent thereof.
26. A compound having the formula
<IMG>
wherein R1 is halogenobenzyl, whenever prepared by a process
according to claim 10 or any obvious chemical equivalent thereof.
27. A compound having the formula
<IMG>
wherein R1 is benzyl, R2 is chlorine, SO2CH3 or SO2N(CH3)2,
whenever prepared by a process according to claim 11 or any
obvious chemical equivalent thereof.
28. A compound having the formula
<IMG>
wherein R1 is fluorobenzyl, R2 is chlorine, SO2NH, or SO2CH3,
and R3 is H or CH3, whenever prepared by a process according to
clalm 12 or any obvious chemical equivalent thereof.
29. Racemic N-[(1-p-fluorobenzyl-pyrrolidinyl-
2)-methyl]-2-methoxy-5-sulphamoyl-benzamide, its dextro-
52

rotatary and laevo-rotatary optical isomers and their
pharmaceutically acceptable acid addition salts when
prepared by the process claimed in claim 13 or any obvious
chemical equivalent thereof.
30. N-[(1-p-Fluorobenzyl-pyrrolidinyl-2)-methyl]-
2-methoxy-5-methylsulphonyl-benzamide and its pharmaceutically
acceptable acid addition salts when prepared by the process
claimed in claim 14 or any obvious chemical equivalent
thereof.
31. N-[(1-p-Fluorobenzyl-pyrrolidinyl-2)-methyl]-
2-methoxy-5-chloro-benzamide and its pharmaceutically
acceptable acid addition salts when prepared by the process
claimed in claim 15 or any obvious chemical equivalent
thereof.
32. N-[(1-Prop-2-ynyl-pyrrolidinyl-2)-methyl]-
2-methoxy-5-sulphamoyl-benzamide and its pharmaceutically
acceptable acid addition salts when prepared by the process
claimed in claim 16 or any obvious chemical equivalent
thereof.
33. N-[(1-benzyl-pyrrolidinyl-2)-methyl]-2-
methoxy-5-methylsulphonyl-benzamide and its pharmaceutically
acceptable acid addition salts when prepared by the process
claimed in claim 17 or any obvious chemical equivalent
thereof.
34. N-[(1-cyclopropylmethyl-pyrrolidinyl-2)methyl]-2-
methoxy-5-sulphamoyl-benzamide and its pharmaceutically accept-
able acid addition salts when prepared by the process claimed
in claim 18 or any obvious chemical equivalent thereof.
53

CLAIMS SUPPORTED BY SUPPLEMENTARY DISCLOSURE
35. Process according to claim 1, in which R1 is cyclo-
propylmethyl, cyclobutylmethyl, cyclopentylmethyl, or cyclohexyl-
methyl,R2 is chlorine, SO2R5 (in which R5 is alkyl of 1 to 4
caxbon atoms) or SO2NR6R7 (in which R6 and R7 each represents
hydrogen or alkyl of 1 to 4 carbon atoms), R3 is hydrogen and
n is 1.
36. A compound having the formula
<IMG>
wherein R1 is cyclopropylmethyl, cyclobutylmethyl, cyclopentyl-
methyl, or cyclohexylmethyl and R2 is chlorine, SO2R5 (in which
R5 is alkyl of 1 to 4 carbon atoms) or SO2NR6R7 (in which R6 and
R7 each represents hydrogen or alkyl of 1 to 4 carbon atoms,
whenever prepared by a process according to claim 35 or any
obvious chemical equivalent thereof.
54

Description

~039731
The present invention relates to 2-methoxy-benzamide
derivatives, their pharmaceutically acceptable acid addition
salts, their preparation, and compositions containing them as
active principles.
Some 2-methoxy-benzamide derivatives have been described
in the literature. ~or example, French Brevet Spécial de
Médicament No. 5916 M issued on April 1st, 1968 to Société d'Études
Scientifiques et Industrielles de L'Ile-De-France, describes
N-pyrrolidinyl-alkyl-benzamides substituted on both the phenyl
and the pyrrolidine nuclei, and in particular by a lower alkyl
or allyl substituent on the nitrogen atom of the pyrrolidine
nucleus. These compounds are anti-emetic agents which however
have undesirable side-effects when used in man.
The present invention provides, as new compounds,
the 2-methoxy-benzamide derivatives of the formula:
R~
C - N - C~2 r, (I)
OCH3 Rl
in which n is 1 or 2; Rl represents a cycloalkyl-alkyl radical of
formula: (CH2 ~ -CH-A-, a phenylalkyl radical of formula ~ -
(in which m is an integer from 2 to 5, A i9 a linear or 4
branched alkylene chain of 1 to 4 carbon atoms, and R4 is hydrogan,
halogen, especially fluorine or chlorine, trifluoromethyl, or
alkyl or alkoxy of 1 to 3 carbon atoms), C~ICH2-CH2-, CH-C-CH2-,
C~H5
CH-, or
C6H5
- . .
' '' :' '
,~
_ 2 -

~039731
~ ~ H=CH-CH2-~ R2 i~ either chlorine, S02~ (in which
R5 is alkyl of 1 to 4 carbon atoms), or S02NR6R7 lin which
R6 and R7, which are identical or different, represent,
independently of one another, hydrogen or alkyl oS 1 to 4
carbon atoms); and R3 i8 hydrogen or alkyl of 1 to 4 carbon
atoms.
Rl is preferably a ~aid phenylalkyl radical in
which A is methylene or ethylidene, and especially fluorobenzyl,
chlorobenzyl, -methylbenzyl, methoxybenzyl, trifluoro-
~ethylbenzyl~ Other preferred values of Rl are cyanoethyl,cycLopropylmethyl, phenylethyl, p-chloro-phenylethyl,
prop-2-ynyl, diphenylmethyl and p-fluorophenyl-vinyl-methyl.
R2 is preferably S02NH2. X3 is preferably hydrogen or
methyl and n is preferably 1.
The compounds of the invention possess an
asymmetrical carbcn atom and can accordingly exist in the
form of racemates or optical isomers, which form part of
the invention.
$he campounds of the invention can be used in human
and veterinary therapy, particularly in the treatment of
nervous and psychosomatic disorders.
The compounds of the invention can be prepared by
known methods, For example, a halide of a substituted
2-methoxy-benzoic acid, of the general formula (II),
can be reacted with an anine of the general formual (III)~-
- 3 -

1039~31
2 - . :
~ ~ r (CH2)n
COX ~ ~ C1~2-~
OCH3 l 3
(II) . (III) .
.: :
In the above formulae (II) and (III), n, Rl, R2 and R
have the same meanings as in the formula (I) and X represents
a halogen, especially chlorine or bromine.
This reaction is preferably carried out at a relatively
low temperature (-5 to +30), in a non-polar solvent such as
. a ketone and in the presence of an alkali metal carbonate.
A possible variant, if R3 represents an alkyl radical,
cons1sts of first of all preparing the amide
I--(C1~2)n
C ~1 CH2 ~ NJ
- OCH3 R
''' ' ' 1
and thereafter attachlng the R3 radical to the nitrogen by
alk~lation.
Another variant consists of attaching the Rl radical
~- to the nitrogen of the heterocyclic nucleus by reaction
between the compound of the formula
- 2
~-(C~2)n
O-NR3-C~12l~N J
- - OCH3 - ~
, ~ ' ' . ~ ' ' . , .. '. ... . ' . ,- ,'. .:
~ 4
.: ~ - . . ~ . : . .
.; .
- ~ . . . .

'
~ 039~31
and RlX (X = an atom of chlorine or of bromine),
The primary amine starting materials are obtained from ,
-derivatives of furane and of pyrane, in accordance with the
equation given below, which takes account of possible variants:
CH2)n ~112)n .
2 1 l C~3N02 1 . C~l 2 . .
- Rl R~ duction ; .
rlH2)P
, . , , . , , . ~~ C~2NH2' ' ':
~o~CN NH2 N Dr G~.~ CN2~- ~ '` ' 'R .:~
- ~ ,.
: ' ,. It is then possible to attach the R3 radical to the
: primary amine or to proceed directly to the preparation of the, ,~
amide. :
~' ~' 10 A variant'for the preparation of the starting compound~ ':
cons1sts of starting directly from the secondary amine ,'
` r(CIl2)n
~ ~ C1l2-N~lR3 and treating this successively with
HBr,and MH2Rl, This directly gives the cyclic amine which
i8 disub'stituted at the two nitrogens.
~ .
: ; Only in the case where n = l, there exists another
: method of preparation o~ the primary amine starting materials
rom pyridine derivatives, by ring contraction in accordance . '~
. wlth the following equation: .
~: . . .
`: . ' t
.
.: ~; .: ~ , . . ` .
:~ . . `~ . . .

1~39731
.
. ~ OH ~ ! OH SO
~ + XR~ X~3 2
1 R
X liquid NH ~
~NJ ~r ~N~J~ 2 NH2
Rl
.-, `
In the above equations, the various symbols have the i
meanings already defined.
The resolution of the compounds of the invent~on is
effected in accordance with a conventional method; a suitably
chosen optically active acid is added to the racemate and the
salts thus obtained are separated by making use of the
di~ference in their solubility in an appropriate solvent.
~ Thus, in the case of dl-N-[l-(p-fluorobenzyl)-pyrroli-
dinyl-2-methyl]-2-methoxy-5-sulphamoyl-benæamide, a compound
which the preparation will be described later
;.: .~ ~ . . . . .
SO3NH2
C ~ CH2 ~
; 3 ~ ~ F
the salts of this~base which are most ~suitable for resolution
à~re~the~ neutral salts (1 molecule o~ acid and 2 molecules of
base) obtained by addition of D- or L-dibenzoyl-tartaric acid.

1039731 - ~
For simplicity, in the text which follows, the salts
will ce represented in an abbreviated-form, using the follow-
ing symbcls: d or 1 will represent the optical isomer of the
base, that is to say of the compound of the invention, and '
D or L will represent the optical isomer of the acid used.
- The salts of the enantiomers, thus obtained, are
sepa~ated by utilising the virtual insolubility, in ethanol
heated to the reflux temperature, of the salts formed by
addition of the acid and the base of the same sign.
The insoluble neutral salts (which hereafter will b_
represented as follows: d-D-d and l-L-l) are obtained in
rather good yields (at least ~4% in place o.~ the theoretical
maximum of 50%), because the salts of opposite signs (d-L-d
and l-D-l) remain in solution in the medium. ~;
Accordingly, i~ D(+)-dibenzoyltartaric acid is used,
the dextro-rotatory base is recovered whilst with L(-)-di-
benzoyltartaric acid it is the laevo-rotatory base which is
obtained.
Furthermore, it is po~sible to recover the optical
isomer~which proves pharmacologically inactive in the field
in question, in order to racemise it. The racemic com-
pound obtained is thereafter resolved to obtain the optical
isomer which is of interest.
The examples which follow illustrate the invention.
Example 1: N- r (l-p-fluorobenz~l-pyrrolidinYl-2~-meth
2-methoxy-5-sulphamoyl-benzamide
~(I); Rl = F_~CH2~ ; R2 = H2N-S02-; R3 = H; n - 1;
code numbeF: SL-C.205J
- . : .
. . ., .~ . ' . . . ' . . :. ' ' ' '

1~)39731
a) l_P-fluorobenzyl-p~rrolidin-2-one
47 g (0.376 mol) of p-fluorobenzylamine, 30.4 g (0.353
mol) of ~uran-2-one and 0.4 g of hydroquinone are introduced
into a 125 ml autoclave. After driving the air out
of the apparatus by passing a stream of nitrogen through it,
the mixture is heated to 250 for 6 hours. It is then
cooled and distilled under reduced pressure. 51 g (yield =
74.8%3 of 1-p-fluorobenzyl-pyrrolidin-2-one are collected as
a colourless liquid distilling at 103-105 under a pressure
1~ o~ 0.01 mm of mercury and solidifying slowly. Melting
point = 37-38.
b) l-p-fluorobenzyl-2-nitromethylene~pyrrolidine
26.1 g (0.207 mol) of dimethyl sulphate are added to
40 g (0.207 mol) of 1-p-fluorobenzyl-pyrrolidin-2-one and the
mixture is heated to 60 for 4 hours. It is then cooled
and a solution of sodium methylate prepared from 4.75 g
(0 207 gram atom) of sodium and 100 ml of methanol is intro-
duced slowly, at 0. When the addition is complete, the
; mixture is stirred for 30 minutes at 50C and again cooled to
~0, and 18,9 ~ (0.31 mol) of nitromethane are added dropwise
whll8t continuing the stirring. The reaction mixture is
left at ambient temperature for 12 hours and is then heated to
50 for 2 hours. It is cooled, and poured into 500 ml of
water, which are then extracted with chloroform. The
organic layer is now separated off, washed with water and dried
over magnesium sulphate, and the solvent is driven off.
.
The residual product is washed with ether and recrystallised
from ethanol 27 g (55.2% ~ield) of 1-p-fluorobenzyl-2-
;' .' ' .- .` . ' , :
. _ _ . ,.. -, .
: '
, ~ ' , .
,'

`
103973S : :
nitromethylene-pyrrolidine are thus collected in the form of
light yellow crystals melting at 108.5-109.
Analysis: C12H13FN202; molecular weight: 236.248
Calculated %: C 61.01; H 5.55; N 11.86
Found %: 60.96 5.66 12.02
61.16 5.60
c) 2--aminomethyl-1-p-fluorobenzyl-pyrrolidine ~;-
A solution of 27 g (0.114 mol) of 1-p-fluorobenzyl-2-
nitromethylene-pyrrolidine in 600 ml of methanol is hydrogen-
ated at ambient temperature and atmospheric pressure in the
presence of Raney nickel. When the theoretical amount of
hydrogen has been absorbed, which requires about one hour, the
catalyst is filtered off and the methanol is evaporated from ;
` the filtrate. The product which remains is distilled
under reduced pressure. 17.2 g (yield: 72%) o~ 2-amino-
methyl-l-p-fluorobenzyl~pyrrolidine are collected as a
colourless liquid dis~illing at 80-82 under a pressure of
0.01 mm of mercury; this product is used, without f~her pu~fica-
tlon, in the next stage of the synthesis.
d) N-~(l-p-fluoroben ~ ethox~-
5-sulphamoyl-benzamide
16.5 g (0.079 mol) of 2-aminomethyl-1-p-fluorobenzyl-
pyrrolidine are dissolved in 400 ml of anhydrous acetone.
11 g (0.08 mol) of potassium carbonate are added. The
suspension obtained is cooled to 0 and 1~ g (0.072 mol) of
2-methoxy-5~1sulphamoyl-benzoyl chloride are added dropwise ~ ;
whilst stirring vigorously. The stirring is continued
for 1 hour after the end of the addition and the reaction
- ~ :
- - ,

1039731 - .
mixture is allowed to return to ambient temperature The
acetone is driven off and the residual product is triturated
in a mixture of water and ether; it is then ~iltered off,
washed with water and then with ether, and dried. There-
after it is dissolved in boiling acetone, animal charcoal is
added and the mixture is filtered. The cooled filtrate
deposits crystals, which are separated off and dried.
18.5 g (yield = 61%) of N~ p-fluorobenzyl-pyrrolidinyl-2)- -
methyl]-2-methoxy-5-sulphamoyl-benzamide, melting at 202.5 -
203, are thus obtained.
Analysis: C20H24FN34S(421-494)
Calculated %: C 56.99 H 5.74 N 9.97 ~ 4,51 S 7.61
Found %: 57.06 5.66 9.9~ 4.37 7.98
57.19 5.68 9.89 7.86
The methanesulphonate of this compound melts at
216-217C. and the hydrochloride at 217-218C.
Resolution of the compound o tained SL-C.20
a) Isolation of the dextro-rotatory enantiomer of SL-C.205
60 g (0.142 mol) of racemic SL-C.205 are mixed with
ao 53.57 g (0.142 mol) of D-(+)-dibenzoyltartaric acid monohydrate
(Fluka Purum) in about 500 ml of methanol, The very slight
amount of insoluble matter is filtered off and the filtrate
is evaporated to dryness. A semi-crystalline white solid
residue is obtained and brought into contact with 1 litre of
boiling ethanol. The compound changes very rapidly, in
the course of heating at the reflux temperature of the solvent,
.
from the viscous state to the finely crystalline state.
When, after several hours' heating at the reflux temperature,
_ 10 _ ' . ' ' ~ "'
. . , ' .
~ , .. , . ... , , , .. . . ,~", . . . . . .. . . . .

there seems to be no ~urther ncrease in the solid product
formed, the latter is filtered off hot on a glass frit kept
at 80. The salt is washed with about 500 ml o~ boiling
ethanol, then with cold e~hanol and finally with ether;
thereafter it is dried under reduced pressure at 60.
33.58 g (yield: 39.3%) of the neutral D(+)-dibenzoyl-
tartrate of SLC-205-d, melting at 183-4, are thus obtainedO -
r ]D5 = +69.9~ (c = 0.6; dimethyl~ormamide).
This compound is again treated in 0.8 1 of ethanol and
filtered off hot and dried.
29.58 g of the above salt (yield: 34.6%) melting at :
183~5-184 are obtained.
~ a]25 ~70.6 (c = 0.6; dimethyl~ormamide).
Ana~ysis: ;
Calculated %: C 57.79 H 5.18 N 6.97 ~ 3.15 S 5.32 ;-
~ Found %: 57.99 5.34 6.94 3.20 5.40
: 58.10 5.38 6.94 3.15 5.35
24 g (0.0199 mol) of the preceding salt are suspended
in water and a saturated sodium bicarbonate solution is added;
20` `~he mixture is then extracted with chloroform and the extract
i8 washed with water, dried over magnesium sulphate in the
presence of active charcoal, ~iltered and evaporated to dry-
ness. A white solid is obtained, which is recrystallised
from a mixture of isopropyl ether and ethanol. 14.52 g
~yield: 86.5%) of the dextro-rotatory enantiomer of SLC-205,
melting at 144.2-145, are thus obtained.
[a]D5 ~ +91.97 (c = 0.6; dimethylformamide)
In thin~layer chromatography on silica, a single spot
(Rf = 0.7, eluant = methanol) is obtained.
,. ' . : ' '

~ ' ~ ' - '

Analysiss lQ39731
Calculated %: C 56.99 ~ 5.74 N 9.97 ;~
Found ~ 56.99 5.51 9.95
57.00 5.47 9.96
The hydrochloride of this dextro-rotatory compound
is laevo-rotatory, ~a]25= -12.9 (c 3 0.5~ dimethylformamide),
and melts at 204.5-2Q5C. The methanesulphonate is also
laevo-rotatory t~]25= -17.6 (c = 0.5, dimethylformamide), and
melts at 156-158C.
b) Isolation of the laevo-rotato~y enantiomer of SLC-205
A mixture of 60 g (0.142 mol) of racemic SL~-205 and
of 53.57 g (0.142 mol~ of L(-)-dibenzoyltartaric acid mono-
hydrate (Nuka Purum) is dissolved in about 500 ml of methanol.
~he solution is limpid and the methanol i~ evaporated to drynes~,
giving a white semi-crystalline residue. This substance i9
brought into contact with one litre of hot ethanol, wherein it
dissolves rapidly and almost completely.
However, a solid, inQoluble and more and more copious
precipitate forms very rapidly and continues to develop in
gpite of vigorous heating at the reflux temperature o~ the
solvent. Thi8 heating i8 continued for 5 hours whllat main-
taining e~ficient stirring and the preciFdtate i~ then filtered
off hot on a glass frit kept at 80. ~he salt is washed with
about 500 ml of boiling ethanol, then with cold ethanol and
finally with ether. ~he white powder obtained i8 dried at
60 under reduced pressure.
33.26 g (yield~ 39Xj of the neutral L(-)-dibenzoyl- ~ ~
tartrate of the laevo-rotatory enantiomer of SLC-205, melting ; ~-
with decomposition at 181~181.5, are thu~ ob~ained. ;
~a325= -66.2 (c = 0.6~ dimethylformamide).
~hi9 co~pound i8 introduced into 0.8 1 of ethanol,
which i8 heated to the reflux temperature for 3 hours, whilst
stirring~ the product is then filtered off hot and washed as
.,
- 12 - ; -

: 1039731 :
before. me salt i9 obtained in the form of a finely crystalline
white powder weighing 30.9 g (yield: 36%~ and melting, with
decomposition, at 183.5-184'.
[a]25- -67.3 (c = 0.6; dimethylformamide).
Analysiss
.
Calculated %s C 57.79 0 5.18 N 6.97 F 3.15 S 5.32
Found ~s 57.99 5.40 6.87 3.21 5.40
58.25 5.31 7.03 3.18 5.35
24 g (0.0199 mol) of the L(-)-dibenzoyltartrate of
111 SLC-205--1 are now suspended in water and treated with excess
~aturated sodium bicarbonate solution. ~he reQulting suspen~ion is
extracted with chloroform. The extract is washed with water, dried
over ma5~nesium sulphate in the presence of active charcoal,
filtered and then evaporated to dryness.
A white cry~talline solid, SLC--205-1, i3 thu~ obtained,
and is recrystallised from a mixture of isopropyl ether and
ethanol. 13.73 g of the compound are obtained, representing a
yield of 83%. The salt melts at 143.5--144.5-.
[a]D5= -91.6 (c = 0.65; dimethylformamide).
~hin layer chromatograplyon silica shows a single spot
(Rf = 0.7, eluant - methanol).
Ana~
Calculated 76~ C 56.99 H 5.74 N 9.97
Found Xl 57.07 5.73 9.73
56.~45,85 9.77
The hydrochloride of this laevo-rotatory compound ia
dextro--rotatory, ra]25= =~13.2 ~c = 0.5, dimethylformamide) and ;~
melts at 204.5-205C. me methanesulphonate i8 also de~tro-rotatory
ta]25- +18.15 (c = 0.5, dimet~ylformamide) and melts at 156--158C.
30 Ex~le 2s N-L~ chlorobenzy~ yrrolidinyl-2?~neth-yl~-2
methoxy- ~o~ benz~de.
: ', ,

1~39~31 `
[(I); Rl - Cl ~ Cb2 ; R2 H2NS02; R3 = H; n = 1,
code number: SL-C.161
~ sing the working method described in Example 1, the
following are prépared:
a) l-p-chlorobenzyl-pyrrolidin-2-one in a yield o~ 53%.
This compound distills at 148-150 under a pressure o~ 0.08 mm
of mercury.
Analvsis: CllH12ClN (209.678? -- :
Calculated %: C 63.01 H 5.77 0 7.63 N 6.68 Cl 16.97
~ Found %: 63.03 5.72 7.67 6.73 17.10
b) l-p-chlorobenzyl-2-nitromethylene-pyrrolidine in a yield
of 45%. This compound melts at 145 after recry tallisation
from acetone.
Anal~sis: 12 13 lN202 (262.703)
Calculated %: C 56.81 H 5.56 N 11.04 - Cl 13.97
Found %: 57.03 5.37 11.,11 14.01
56.95 5.57 11.00 14~11
o) 2-aminomethyl-l-p-chlorobenzvl-pyrrolidine
The reducti.on of the nitromethylene derivative to the
amine is carried out slightly differently from th~t which has
been described in Example 1.
500 ml of anhydrous tetrahydro~urane and 23.4 g (0.615
mol) of the double hydride of lithium and aluminium are intro-
duced into a reactor equipped with a mechanical stirrer, and
a solution of 27.3 g (0.108 mol) of 1-p-chlorobenzyl-2-nitro-
methylene-pyrrolidine in 1,000 ml o~ tetrahydrofurane is then
added slowly. The reaction mixture is heated at the
- reflux temperature ~or 12 hours and then cooled, and 53 ml o~ ~-
.
.:
. .
, ., ., ... ,. . ...... ~.- .. ,.. - .. .- - - ,-

1039~31
water are added dropwise, foliowed by 53 ml of 20% s-trength
sodi~m hydroxide solution and finally 53 ml o~ water. The
precipita+e is filtered off and extracted with 500 ml of ,
ether. The ether solution is combined with the filtrate
and dried over magnesium sulphate, the solvents are evaporated '
and the residue is distilled under reduced pressure. 19.5 g
(yield: 80.2%) of 2-aminomethyl-1-p-chlorobenzyl-pyrrolidine
distilling at 118-120 under a pressure of 0.06 mm of mercury
,, are obtained.
Ana~,ysis C12H17ClN2; (224.735)
Calculated %: C 64.13 H 7.62 N 12.46 Cl 15.78
Found %: 53.98 , 7.66 12.58 15.70
64.08 7.80 12.45 15.82
d), N-r~l-P=chlorobenzYl-PYrrolidinyl~2)-methyll-2-meth
5-sulPhamoyl-benzamide. ~.
Using the method described in Example 1, N-[(l-p-
chlorobenzyl-pyrrolidinyl-2)-methyl]-2-methoxy-5-sulph~moyl~
benzamide, melting at 211 after recr,ystallisation from
methanol, is obtained in a yield of 63.3~.
~ , AnalYsis: C20H24ClN304S; (437.949) ,l
," , Calculated %: C 54.85 H 5.52 0 14.61 N 9.59Cl 8.10 S 7.32 ' ~ '
, , Found ~: 54.81 5.58 14.67 9.528.41 7.49
54.77 ' 90448.54 7.45
Exam~le 3: N-~ ~-benzYl-piperidyl-2)-methyll-2-methoxy~
'(I) Rl ~ C6H5-CH2-; R2 = H2NS02_; R = H; n 2; c d ~'
'` number: SL-C-189]
` Uslng the method of Example 1, but replacing the
,
~,
~':: . "'~ . . ... . .

~039731
furan-2-one with pyran-2-one and p-fluorobenzylamine by benzyl-
amine, the following are prepared successi~ely:
a) l-benz~l-PiPerid-2-one, distilling at 130 under a pressure
of 0.5 mm of mercury (yield: 70.3%).
b) ~ , melting at 108-109,. ~-
after recrystallisation from methanol (yield: 58%) .
AnalYsis: 13H16N22; (232.285
Calculàted %: C 67.22 H 6.94 0 13.78 N 12 06
- Found %: 67,12 6.81 13.80 11.89 ..
67.1~ 7.04 . 11.94
c) 2-aminomethYl-l-benzYl-piperidine~ distilling at 115-120
under a pressure of 0.1 mm (yield: 51.2%).
d) N-r~-benz~l-PiPerid~l-2)-meth-yll-2-methoxy-5-sulphamo~
benzamide, which after two.recrystallisations from methanol : :
melts at 168.5-169. (Yield: 32%). ~_ .
Anal~sis: C21H27N~04S; (417,531) ~
Calculated %: C 60,41 .H 6.52 0 15.33 N 10.05 S 7.68.
Found %: 60......... 58 6.58 15.03 10 04 7.87
. 60.48 6.61 15.20
PO Example 4: N-L ~ n~l ~ me
metho3y-~-sulphamo~l-benzamide~ . .
) 1 C6H5CH2; R2 ~ H2NS2~; R3 - CH3; n = 1; code
number: SL C 243
a) _LL ~ olidin ~ ethyll-~ormamide ,r~
5.10 g (0.11 mol) of 98% strength formic acid are .. ~::
~; added slowly, whilst stirring and cooling, to 18.45 g (0.097 .;:
mol) of 2-ami.nomethyl-1-benzyl-pyrrolidine, obtained as . .~
described in Example 1, with replacement of p-fluorobenzyl- ;;
. ~ '
,. -
~,
, . . . . : .
- ~ .

1039731
amine by benzylamine. The mixture is heated slowly to
160 and is kept at this temperature for 20 minutes. It
is cooled and the product is fractionated under reduced
pressure A~ter t~o distillations, 15.3 g (yield: 72.~%)
of N-[(l-benzyl-pyrrolidinyl-2)-methyl~-formamide are ob-tained.
Boiling point = 165/0.1 ~n of mercury.
bj l-benz~1-2-methylaminomethyl-Pyrrolidine
8.03 g (0.21 mol) of the double hydride o~ lithi~m and
aluminium are dissolved in 150 ml of anhydrous ethèr, and an
ether solution of 15.3 g (0.07 mol) of N-[(l-benzyl-pyrrolidin-
yl-2)-methyl]-formamide is then added dropwise, the speed of the
addition being regulated so as to raise the temperature to
35 and then to keep the mixture boiling gently. When the
addition is complete, a further 2.8 g (0.074 mol~ of lithium
aluminium hydride are added and the reàction mixture is heated ~ -
at the reflux temperature for 4 hours. It is then cooled
by meansofab~ wa~rand 36 ml of water are introduced
gradually so as to hydrolyse the complex formed. The
aluminium hydroxide which has precipitated is filtered off
i 20 and washed copiously with ether; the ether solutions'are
combined and dried over magnesium sulphate, and the ether is
then driven off. The residue is distilled under reduced
pressure and 11.5 g (yield: 80.3~) o~ 1-benzyl-2-methylamino-
methyl-pyrrolidine, passing over at 94 to 97 under a pressure
of 0.09 mm o~ mercury, are obtained.
13 20N2 (~04.317)
Calculated %: C 76.42 H 9.87 N 13.71
- Found X: 76.53 - 9.96 13.76
~.
: - , . . ' ' . :
17
. ~. - ' '
,, ., :
:.. ., ,: ,

~ 039731
c) N-r(l-benzyl-pyrroli~ 2~-meth~ methyl-?-mc-thoxy-
5-sulphamo~__benzamide.
7.08 g (0.0509 mol) of potassium carbonate are added
to a solution of 8 g (0.0392 mol) of 1-benzyl-2-methylamino-
methyl-pyrrolidine in 150 ml of acetone. The mixture is
¦ cooled to 0 and a solution of 9.78 g (0.0392 mol) of 2-
methoxy-5-sulphamoyl-benzoyl chloride in 100 ml of acetone is
introduced dropwise into the suspension, whilst stirring.
After the end of the addition, the mixture is allowed to
return to ambient temperature and stirring is continued for
one hour, after which the mixture is left standing for 12
hours. The inorganic salts which have precipitated are
now filtered off and washed copiously with acetone, the
acetone solutions are combined and the sol~ent is driven off.
On trituration in petroleum ether, the oily residue solidifies.
It is filtered off and dried. It is purified by dissolving
it in ethyl acetate, washing the organic solution with water
and drying it, evaporating the solvent, extracting the residue
with ether in a Soxhlet apparatus, and evaporating the ether.
6.6 g (yield- 40.3%) of N-[(l-benzyl-pyrrolidinyl-2)-methyl~-
N-methyl-2-methoxy-5-sulphamoyl-benzamide are thus obtained as
a~ oil which solidifies slowly. Melting point = 82.
Analysis: C21H27N34S; (417.531)
- Calculated %: C 60.41 H 6.52 0 15.33 N 10.06 S 7.68
Calculated % (with 0.7% of H20 determined by the Karl
Fischer method):
59.986.55 15,86 9,99 7.62
Found %: 60.306.79 15.84 9.77 7.54
60.206.80 9.78 7.44 ~
,~ ' .' ' , ' , ,.
~ - 18 _ ~
: ' . ' ~,

1~39731
Example 5: N- r ( l-p-fluorobenzyl-p~yrroli
met~o~-5-chloro-benzamide and its h~
~tI); Rl = ~ ~ cl~2- ; R2 = Cl, code number: SL-~.1653
5.62 g (0.027 mol) of 2-aminomethyl-1-p-fluorobenzyl-
pyrrolidine and 4.14 ~ (0.03 mol) of pulverulent potassium
carbonate suspended in lOO ml of anhydrous acetone are intro-
duced into a-250 ml Erlenmeyer flask equipped with a magnetic
stirring, a thermometer and a dropping funnel.
- A solution of 5.13 g (0.025 mol) of 5-chloro-2-methoxy-
benzoyl chloride in 50 ml of anhydrous acetone is then added
dropwise whilst stirring and keeping the temperature of the
mixture below 10. The mixture is kept at ambient tempera-
ture for 4 hours and is then~evaporated under reduced pressure
at a temperature not exceeding +30. The residue is taken
up with water and is finally extracted with ether. The ;~
ether extract is washed 3 times with water and dried over
magnesium sulphate, and the solvent is evaporated. 9.5 g
of a residual oil are obtained, and are converted to the
~ydrochloride by bringing together with a solution of hydrogen
chloride gas in ethanol.
4.2 g of 5-chloro-2-methoxy-N-~(l-p-fluorobenzyl-
pyrrolidinyl-2)-methyl]-benzamide hydrochloride, which after
. .
; successive recrystallisations from an 8:2 mixture of ethyl
~ acetate and acetone, and from butanol, melts at 135-136, are
,
obtained.
; ~ Anal~sis:
.
Calculated %: C 58.12 H 5.61 N 6.78 Cl 17.16 F 4.60
Found %: 58.26 6.03 6.82 17.06 4.70
.
58.27 5 94 6.81 17.18 4.75
- 19

~039731
The NMR spectrum confirmed the structure of the
compound
Example 6: N-r(l-m-fluorobenz~l~ rrolidinyl-2~-met
methox~-5-sulphamoyl-benzamide
- : . i,. ., - .
r (I) Rl = CH2 ~ ; R2 S02NH2; code number: -
SL-D.193~
A mixture of 6.85 g (0.0219) mol o~ 2-methoxy-5-
sulphamoyl-N-(pyrrolidinyl-2-methyl)-benzamide, 2.76 g (0.0200 -
mol) of potassium carbonate, 200 ml of acetone and a crystal ; -
of potassium iodide is heated to the reflux temperature.
Thereafter a solution of 2.95 g (0.0204 mol) of m-fluorobenzyl
chloride in 25 ml of acetone is introduced dropwise over the
course of one hour. The solution is kept refluxing for a
~urther ~ hours and is then filtered hot, the precipitate is
rinsed twice with 100 ml of acetone at a time, and the fil-
trates are combined and concentrated to dryness. 4 g of
crystals are obtained, and are triturated in ether, filtered
off and dried in a desiccator under reduced pressure. The
compound is purified by passing it over a silica column
(eluant: acetone) and is finally recrystallised from ethanol
; 20 in the presence of active charcoal.
2.0 g (yield = 24%) of N-~(l-m-fluorobenzyl-pyrrolid-
inyl-2)-methyl]-2-methoxy-5-sulphamoyl-benzamide, melting at
166, are thus obtained.
~; Analysi_:
Calculated %: C 56.99 H 5.74 N 9.97 S 7.61
Found %: 56.71 5.89 9,82 7.62
56.65 5.92 9.82 7.63
, . .
- 20 -
:~ ' . ' .

~t~39'~'31 - ;
The NMR spectrum confirmed the structure of the
compound.
: N-rl-(2-cyanoethyl)-~rr~ 2-methvll-2-
methoxy-5-sulphamo~l-benzamide
r (II); Rl = -CH2-CH2-CN: R2 = S02NH2; code number:
SL-C.262]
7.8 g (0.025 mol) of N-(pyrrolidinyl-2-methyl)-2-
methoxy-5-sulphamoyl-benzamide are added to a stirred solution
of 500 ml of acrylonitrile (sic), and the mixture is heated
to the reflux temperature for 30 minutes. The solution is
then evaporated to dryness under reduced pressure and the
residue is crystallised by trituration with petroleum ether
and is filtered o~, dried in an oven and recrystallised
successively ~rom a mixture of acetone and ether and from
ethanol,
6~8 g (yield = 74%) o~ N-~1-(2~cyanoethyl)-pyrrolidin- ,
yl-2-methyl]-2-methoxy-5-sulphamoyl-benzamide, melting at 142,
are thus obtained.
A~:
Calculated %:C 52.44H 6.05N 15.29 S 8.75
Found %: 52.55 6.os 15.09 8.89
52.45 6.10 15,22 8.83
The NMR spectrum confirmed the structure o~ this
compound. ~
: 1(- ~ -methylbenzyl-p~rroli in~]-2-)-methyll-
2-meth~-5-sulphamoyl-ben~amide and its hydrochloride
t(I): Rl = -,CH-CH3; R2 = 502NH2; 1(-) compound; code
6 5
number: SL-D.222]
. .
~ - 2-~ -
.. .. .

J~03~73~ ~ :
a) 25 g (0.206 mol) of d-(+)-a-methylbenzyl-amine~
` 16.87 g (0.196 mol) of 2-oxo-tetrahydrofurane and a few
crystals of hydroquinone are introduced, under a nitrogen
atmosphere, into a pressure-resistant 125 ml vessel. The
mixture is hea-ted to 250 for 12 hours and the solid residue
is collected and distilled. 29.5 g (yield = 79.8%) of
d(+)-l-(a-methylbenzyl)-2-oxo-pyrrolidine are thus obtained,
Boiling point = 105/0.05 mm Hg, [a~D = +138.8 (dimethyl- ~ -
formamide, c = 5).
~) 28.5 g (0.15 mol) of the preceding compound and 18.9 g
(0.15 mol) of methyl sulphate are introduced into a 250 ml
Erlenmeyer flask. The mixture is kept at 60 for 2 hours
and then cooled in a bath of iced water, and a solution of
sodium methylate (prepared from 3.45 g ~0.15 mol) of sodiu~
and 50 ml of methanol) is added gradually thereto. The ;
mixture is stirred for 2 hours at ambient temperature and ~ `~
cooled in ice, and 1~.7 g (0.227 mol) of nitromethane are then
added dropwise. The reaction mixture is left to stand
for 24 hours and is then poured into iced water, the whole is
stirred vigorously and the crystals formed are filtered off,
washed several times with water and then with ether, and
dissolved in chloroform. The organic phase is dried o~er
magnesium sulphate and evaporated, and the residue is
reorystallised from isopropanol.
19.9 g (yield = 57.2%) of d-(+)-l-(a-methylbenzyl)-~-
nitromethylene-pyrrolidine melting at 123 are thus obtained.
~a]D = +297.60 ;dimethylformamide, c = 5). ~ -
c) A suspension of 18.8 g (0.0809 mol) of the preceding
' . '., ", ' ~."''
2~
(- , ~ .:
.
- . . , . ' -: :,

1039731
compound in 200 ml of methanol is hydrogenated under atmos-
pheric pressure and at ambient temperature, in the presence of
Raney nicKel. After stirring for 3 hours, the catalyst
is filtered off, the solvent is evaporated and the oily resi-
due is distilled.
10.15 g (yield = 62.3%) of l-(-)-l-(a-methylben~yl)-
2-aminomethyl-pyrrolidine boiling at 98 under a pressure of
0.05 mm of mercury are thus obtained. [a ;D = -32.1
(dimethylformamide, c = 5).
d) 9.1 g (0.044 mol) of the preceding amine and 6.7 g of
potassium carbonate suspended in 100 ml of anhydrous acetone
are introduced into an Erlenmeyer flask. A solution of
11 g (0.044 mol) of 2-methoxy-5-sulphamido-benzoyl chloride
in 100 ml of acetone is added dropwise with vigorous stirring
at a temperature not exceeding +10. The reaction mixture
is stirred for 4 hours at ambient temperature and is then
evaporated to dryness under reduced pressure at a temperature
not exceeding 30. The oily residue is washed with water
and extracted with chloroform, the organic phase is treated
with active charcoal and dried over magnesium sulph~te, and
the solvent is evaporated. The solid residue is triturated
in benzene and is then recrystallised successively from benzene
Qnd from ethyl acetate.
6.9 g (yield = 37.7%) of l(~ [(l-a-methylbenzyl- ;
pyrrolidinyl-2)-methyl]-2-me-thoxy-5-sulphamido-benzamide
melting at 129-129.5 are thus obtained.
Analysis:
- Calculated ~: C 60.41 H 6.52 N 10.06 S 7.68
Found %: 60.62 6.84 10.08 7.48
60.31 6.6~ 10.05 7.38
, ' , ~ :~
- 23 -
"', . ' . ' .' ~': '
, . ~. . . .. ... . . . . ..

1039731
The NMR spec-trum confirms the structure o~ the
compound.
e) The hydrochloride of the preceding base is prepared by ~ -
adding 0.1 N hydrochloric acid to this base. [a]D = 78.69
(dimethylformamide, c = 0.6).
Table I which follows shows the compounds of Examples
1 to 8 as well as other compounds which were prepared by
applying the processes used in the Examples.
.. ~ . . . .
'`1~ ~ .
, ' :.: ..
:. , ' .
, . . :
, :.
::
.: -
, - , . .
- , ,
'' ' ' ' ' '~' ;'.
' ..'~
;, ~ .
; ' ' . . .
` ~' . ' . '''
:~ .
: .. .. .
. ::: . .
. . . .
.
~ . , .,.,............................ . : ,
. ` ~ ' '', ' ' ~ ..

~039731
Table I
R~ :
CO - NX3 ^ C1{2 -~ N
OCl~3 Rl
Example Code No. I n . .. _ - R2 1 R31 Characteristics
. . . . M.p. in C
. . . b = base
. . cl= hydro-
__. ~ . . ~ __ ~ ~ Qri d~
1 SL-C . 205 1 F~H2_ S021~lH2 H 202 . 5--203
__ . __ _ ___ . l
1 a dextro- 1 F ~ CH2- SO2~l~2 H 14~145
. rotatary
. _ . .. _ _ _ . __ :. .
1 b ~ 1LaeCvo205 1 F~3CH2- So2~r,~2 H 143 . 5-144 . 5
rotatarY
_ . _ ., . ._ . _ ' ..
2 SL-C .161 1 C .1~ Cl~2_ S02ii.~2 H 211
.. _ _ ~ __ _ _ _ . ;' . ' '
3 SL-C.189 2 6 5 2 S2ln{~ H b 168. 5 - 169
._ -_. _ ,.~ _ . l - ~ .
4 SL-C . ~43 1 C6~15~H2 2 2 3 b 8 2 ::
_ _ _ . .... _ . _ .
. S SL-~ .1 6S 1 F~-CH;!- Cl H cl 135-136
: _ . . . _ . _ _ ...... __ .. _ . : - :
6 S,.-D. 193 1 ~ C!l2- S02~'!!2 H b 166
_ . _ . . _ _. . . , .___ .. . _ '': ' ' ' "
. ,
: ...
: -:
~U~ ~ 25_ ~

lG39731
Table I (continuation)
Example Code No. n - R2 R~ Characterlstics . -
. . . ~-P. in C
. . . b = base
. . cl = hydro-
. chloride ~ .
l . _ _ , . . _ _ ~ . ~
7 SL-C.262 1 Ci~Cll2Cll2- S02~rH2 H b 142 :'
l . . . . _ . . _ . .'
8 SL-D.222 1 C6H -CH- S02~H2 H b 129-129.5
1(-) C~{3
. _ . . _ _ b 187
. 9 SL-C.01~1 C6~l5CH2- S2~H2 H cl 270
.. - _ . . ......... . . . ... ._ . ' ' '
SL-C. o3 6 1 ~ CH2- S02NH2. H b 157
. . . . cl 231-232 ,
._ - - -~ - ,CU3 . ._ _
11 SL-C,1441 .C6HScl~2- S02N~cH3 H b 198
..__ .. . __ . _ . .._ .. ._ ._
12 SL-C.1451 . 6 5 2 Cl H Cl 148.5-150
. ,,. .__ _ ....... .. . ._ ........... .
13 SL-C 152 1 C6H5CH2CH2 S2~H2 H b 150
~: . . cl 233-234
;: , . _ . . . _ _ _ _ . _ .. _ ,,,
~ l4 SL~C 15 5 ~ C6H5Cll2- ISOzCH3 H b 107
. ~ .....
~ - 26 - ;

9731 ~ -
- Table I (continuation) i' :
_ . ~
Example . Code No. n Rl R2 R3 Characteristics
. . b = base
. . cl = hy~ro-
. . chloride
. __ . _ ~ ..
15SL-C. 162 1 CH30~H2_ S2N~2 H b 172-173 ~-:
. 0~ ... .. _ ...........
, .. _ .'' :
16 SL-C.188 1~ CH2 S~H2 H b 152-153
OCH3 ~ .: .
17 SL-C.191 1 ~ S2NH2 H b 166.5-167
. . Cl _
18 SL-C. 193 1~ -CH2- S2NH2 H b 167-168
.i . . :~ . . _
19 SL-C.195 ¦ 3~ 2 S2N~l2 H b 185-186 ~:.
.. ~ .................. C1 ._ _ . _
. 20Sl.-C.196 1~ C~2_ S2N~l2 H b 2.09-210
'; -.. ,7;. ' ;- .. _ ................... _ _ .
. 21 SL-C.204 1 Cl ~ ~H2CH2 S02NII2 H b 177
. . . . l - CF3 . _ _ _
. 22 SL-C.213 1 ~ CH2 S02~il2 H b 177.5
. . . ,... _ _ _ _ :"'' ' ''
23 SL-G,299 1 Cll-C-C~2 - 2 2 H
cl 2l4 ~ ~
.
, ;, .
. ~ 27 - -
- . ~ . , ... .. .. . .. . ~ . .. , , i . , . . .. , .- - . . .. .... . ~ .

10 39 7 3 ~ :
Table I (con' inuation)
Exalr.ple . Code No. n 11 ~ R3 ~aracteristics
. . M, p . in C
. - : -- . . : cl _ hydro- ¦
. chlori(~e
~ _ C H _ .
24.SL-D.090 1 6 5~CH ~ S2~H2 H cl ~260 .
__ ; ___ _ ~--- . ~ :,:
SL-D.163 1 F~CH2- S02C~t3 X b 100-100.5
_-- . . _ _ _ . . ~
2 6 SL-D .192 1 ~-CH2- S2?l~l2 H b 183
,' . _ . _ _ . _ ~ , _ .
- . 27 SL-D. 194 1 F.~CH=Cit- S02~ 2 . tl b 17~
.' ' " . . , - ~ _ _ . _ __ ~ .
28 SL-D.223 1 6 5 1 ~t SQ2Ni~2 H b 127-128
d~! CH cl 218-220
. . . : . ~d]composition) ¦
. ; _ ___~__ _ (DMF c _ o.6)
29 SL--D, 296 1 ~CH2 SO2N ( C~ 2 H cl 209--2:L0 : .
' .. _ . , ~ ~
The starting compounds (II) as well aq the inter-
mediate cQmpounds used for their preparation are described in
the tables which follow. :
'' ,:.
'` '
. - 28 -
.:
:~ '
:, , , ~ . . ~ -- , .. , : - .
.. . . . . . . .

10;~9731
. . ..
0 1~ 0 ~ D 1~ r~l
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1-1 L-- ~ r l __ _
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. . __ .. ~ ~ ..... _ . . "`. "' .
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h ~ 1~ r1 ~ ~ a~ C~ O~
r p:: . ._ . _ . _
l' s ~ ~ oo ? ~ ~ ~:
: 1 C ) r l O~
~ . ... _~__ . . ... _ _ :
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., ~ ' . . ~ C~l C~ C~J ~ O ~ ~
--t. ~ O O ~D ~D r l r l O O .
a ~,. ~ ~ 0 ~ ~ ~ _ 1- ::
o C- o~ O C-
. _ _ .... __ : . __ .__ .:
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r~ o r~ o ~ o
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~039731
, _ _. ........ . _.
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h I Pt ~ ~:4 . ~ ~ ~:4 0
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O O j ~ r~ ~ O h . ~ 1~ ~ O h O
.~ ~1 ~. r~ ~t .~ ~ t rl ~ ~t O
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i~ ~q ~ ' rt O ~ t
r ::; ~ t). ~ rt ~ c~ ~_n rt ~ rt ~ a~ ;:
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.

10~9731 : :
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O O r~ ~ ~ .
C~ J ~ O ~ C~J ~ C~l ' .,
O If ~ l~ r~ (\J ~I r I ~i ~
1:4 ~1 r I ~1~1 ~1 ~1 r~ r I :
~; ~_ 0 ' ' 0
~1 ~ O ~ ~I C~l
~ U~ C~i ~~i ~ ~
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. _ . . . :
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~ : 0r C~ 1--l 0 ~D ~D 1~ ~ .
~ r ~ ~ c- ~ ~D ~ ~ ~o ~o
.
~ ~: . . . .__
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. ~O ~O .~D ~D
_~_ .... _
0 ~o ~
C\J ~ ~ ~ ~ ~ 0 0 ~ .
.- . . O ~ (J~ C-- ~ C\J C~J ~ N ~i
~ r~ ~ u~ ~o ~D ~ ~ ~o ~o ~D :
- . . ~ . __~ . .
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. ~ . ~ ~ ~ 0 0 0 . .
- O r~ Cl~ C` C`~i C~J ~i . . :.
t~ Il~ ~ ~D ~D ~O . . .
_ . _ __ . : _ _ .... ~ : ~
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L~ ' i~ ~ s~ , ~ s~ .s:~ i ' ::,
. i ~1 O O O O O O .. ..
h ~ P1 u~ O P~ O ; ::
~ b~3 bl~ H tlO ~0 bO bD C~
- . ~ O ~ ~ ~' I S:~ ~ ~ O ~ ~O
. ~ , . u~ 4 '~ 0 ~ L~ .~ rl ~ rl ~b ..
rl rl ;l rl rl I rl
rl a~ ~) O a) ~O
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HH ~ ~- '-- ~ ------ ' ~ '~~ --: --~
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~0397;~1
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U~ h i ~ o ~ 1~ ~ r~ ~ O
O ~ ~ ~ rJ rl ~ rl ~I rl rl
C~ ~ ~ . ~ ~D ~ a) ~ ~
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- ~03973~
._ _ _ __ .
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p~ U2 11 11 ~ 11 ~ 11 ~ , 11 ~ '"
L ~ ~ ~ ~ ~I ~ ~ r~ ~) 1~
O ~ r l r' o ~
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~ ~ P~ ~ ~ ~ ~ ~ ~
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-. .. . .
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1039731
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------ - u-------- -.------- - -

10397;~1 .
After detel~ination of their acute toxicityS the
compounds of the invention were subjected to a series of
neuro-pharmacological tests which revealed their valuable
psychotropic properties.
The compounds were administered in the form of their -~
hydrochlorides or of their methanesulphonates.
The reference substance chosen was N-r(l-ethyl-
. .
pyrrolidinyl-2)-methyl]-2-methoxy-5-sulphamoyl-benzamide
hydrochloride or Sulpiride.HCl.
lD The acute toxicity was evaluated in Swiss CDl mice
o~ both æexes, of average weight 20 g. The 50% le-thal dose
(LD 50) of each product was determined by a graphical method.
Table V
_ ~ , ... _ . . ~ ...................... ~ ;.
Compounds Acute toxicity in mice :
(cl=hydrochloride
-ms=methanesulphonate) method of LD 50 (mg/kg)
administration over 48 hours
:::: . ~ .. ~ _ . .. .
Sl-C.262 (cl) intraperitoneal>2,000 ~,
~; SL-C.299 ~¢1) intraperitoneal170
Sl-D.090 (cl) intraperito~eal~1,500
SL-D.163 (cl) intraperiton~al400
SL-D.165 (cl) intraperitoneal275
SL-D,192 (cl) intraperiton3al~2,000 ;
SL-D,193 (cl) intraperitoneal~2,000
SL-D.194 (cl) intraperitoneal~2tO00
SL,D,222 (cl) intraperitoneal625 ~ ;
~SL-D.223 (cl) ~ intraperitoneal650
~SL,C.205 (racemic)(cl) intraperitoneal 750

~1~)3~31
Table V ~continuation)
. _ _
r~ -~ ~ .
I Compounds hcute toxicity in mice
(cl = hydrochlvride __ _ _ _ _
ms =methanesulphonate) method of LD 50 (mg/kg)
administration over l~ hours
..... ,........ _ . __ . ~
SL-C.205 (riacemic)(cl) oral ~3,000 (7 days)
SL,C.205 (racemic)(ms) intravenous 140
SL-C~205 1 (ms) intravenous 160
SL-C.205 d (ms) intravenous 160
lo Sulpiride (cl) intraperitoneal 170
Sl)lpiride (cl) oral 2,250 (7 days)
The neuro-pharrnacological activity was studied with
the aid of the following three tests:
1) An-tagonism towards stereotypies induced by apomorphine
in male Sprague-Dawley (Charles River) rats- of average weight
130 g~ in accordance with the method of Janssen and
colleagues (Arzneim. Forsch~ 1960, 10, 1003).
2) Catalepsy-inducing effect in rats of -the same species
and of the same weight, in accordanc~ with the meLhod of
Tedescl~ and coll~ague~ (~rc~, Intern.
Pharmacodyn, 195g, 122, 129),
. In these two tests, the results are expressed by the
50% active doses (AD 50),
3) Protection against a stress due to an environment and
~ due to new ~eedstuffs, in male rats (CDl strain, weight about
-~ 20 g) in accordance with the method of Stephens (Brit. J.
Pharmacol. 1973, 49, 146 P.), The doses (AD 40) which pro-
duce a 40% increase in the feedstuff taken were determined,
The resuits are summarised in Table vI.
.
.
3 6
,. . .
~ ' .

: ~
- 103973~ . -
~. ~ _ . ::
o F~ r~ r~ r~ r~ ~ r~
$ ~ $ $ a~ ~:
h t~ o S, h h h h h ,1 . : .
~0 ~ . : .
j h ~ h h h h h ~ r~ r~ r~ h r
$ ~ _~ _ __ r~
.~ ~ ~' h ~ ~ ''~
~ o o 0 1~ r-l O ~ 0 ~ ~ O h $
.~j h ~! . . ~ ~ ~ :,
~ _~ ~& D
. ~ . g ~d r-l r~ rl rl ~ rl rl O .~ ~ `
~ ~ ~ h h h ~ ~ ~ : j
E3 C~l r-l r~ rl ~I C\l ~I t\J C~l h h ~
~ ~, . ~ C~ _ '
.
~, . .
'- ' .
: . . '
7 -
. ' . ' .
`
,
;.

~03973~ :
Table. VII
,.. _ . .. ... ._ . .. _ - . _ . . .......... . _
Compounds Catalepsy-inducing effect
in rats
(cl) = hydrochloride AD 50 t kg/kg
adminlstered intraperitoneally
_ . ......... _ _ , ......... . .. _
SL--C,299 (cl) ~150
SL-C.193 (cl) >300
SL--C.205 (cl) ~480 ~ -
Su]piride (cl) >100 ~
~ ... _ .. .. _ : .: ~
Sulpiride could~not be administered at a higher
dose, in view o~ its toxicity.
.f . .. ~
Table VIII
- -- --~----~ ~
Compounds Protection against s-tress
(cl) = hydrochloride in mice - AD 40 for oral
(ms) = methanesulphonate administration (mg/kg)
,_ .. ~ . .......... .. __ .
SL-D.165 (cl) 30
SL-D,192 (cl) ' 30
SL-D.193 (cl) 30
SL-C.205, racemic (ms)60
SL-C.205 1 (~Is) ~ 30
SL-C.205 d (ms) 30
. . ___ . . __ . .. _
~ no ac~ivity was observed up to this dose.
.
~ -
38 - :
,: . ' :
~ . .

- 1 03973~
Examina-ti.on of ~he results shows that the compounds ~-
of the invention are psycho-tropic agents.
Compo~d SL,C.205, in par-ticular, is much less toxic
but markedly more active, than Sulpiride. In particular,
whilst it does not induce catalepsy up to high doses, it is
a powerful ~l~agonistic agent, even when administered orally,
to stereotypies induced in rats by apomorphine, whilst
Sulpiride is inactive when adminis-tered by this route.
The therapeutic margin of SL,C.205 is considerable. ;:
lQ Furthermore, it may be noted that the laevo-rotatary
and dextro-rotatary isomers differ in respect of their
activity; in fact, the laevo-rotatary isomer proves prac-
tically inactive in neuro-pharmacological tests, whilst the
dextro-rotatary isomer has an activity 1.5 times or twice ~:
(depending on the chosen method of evaluation) as strong as :~
that of the racemic compound.
Accordingly, this isomer can be used:
a) at low or medium doses, advantageously because o~
its improved therapeutic.index relative to that of the
racemate~ as a psychotropic medicament in the treatment of
1) anxiety conditions of various psychosoma-tic disturbances,
such as gastro~duodenal ulcers, migraine and vertigos, and 2)
depressive and psychopathological disturbances, especially
during senescence, and
b) at higher doses, in psychotic disturbances such as
serious behavioural disturbances, deliria and obsessional
neuroses.
~- The compounds of the general formula (I) can be used
.
:
39 - ~ -
,. '
-

~ 1)39731as psychotropic medic~nents in the treatment of various
psychosomatic disturbances, such as gastro-duodenal ulcers 9
migraine a~.d vertigos, in depressive and psychopathological
disturbancesS especially of senescence, and, at higher doses,
in psychoti.c disturbances such as serious behavioural dis-
turbances 9 deliria and obsessional neuroses.
Conseauently, the in~ention comprises all pharma-
ceutical cGmposltions which contain the compounds (I) and
their salts as active principles, in combination with any
excipien~ sui.table for their oral, endo-rectal or parenteral
administration. These pharmaceutical compositions can also
contain other rnedicamentous substances with which the com-
pounds (I) are pharmaceutically and therapeu.tically
compatible.
For oral administration, all pharmaceutical forms
suitable for this method of administration are used, that is
to say tablets, dragées, gelatine-coated pills, capsules,
cachets and potable solutions and suspensions; the unit
dose of compound (I) can ~ary between 5 mg c~nd 200 mg and the
daily dose is between 10 mg and 400 mg.
For endo-rectal administration, suppositories con-
taining 10 to 200 mg o~ compound (I) and a~ninistered to the
patient at the rate of 1 to 3 per 2.4~hours are used
3 For parenteral administration, injectable and b~ffered
solutions, prepared be~orehand or at the time o~ use, are
employed. The dose per unit administration can vary between
5 and 100 mg and the daily dose is between 5 and 300 mg
;, .
'
_ ,~, 0 _ ~
.
,

1039731
SUPPLEMENTARY ~ISCLOSURE
. _ . .
A series of additional tests were carried out .
to produce specific compounds within the scope of the general
formula ~I) in which Rl represents a cycloalkyl-alkyl radical
of formula (CH2) ~ CH-A- ( in which m is an integer from
2 to 5 and A is a linear or branched alkylene chain of 1 to 4 .
carbon atoms ).
Table IX below shows additional compounds prepared
by the methods of Examples 1 to 8 of the Principal Disclosure~
TABLE IX . .~
CH2)n
3 CH2 .~ J
C~3
Rl
., . .
Exampll Code No n Rl R2. R3 CharaCter1StiCS
, - I _ _ _ ... ~. ,
30 *¦ 77075 1 D -CH2- S2NH2 H 134-134.5
. (S)(+) _ _ (methane sulfonate)
31 77145 1 [~CH2- S2NH2 H 123-124
_ (S)(+) . _ (methane sulfonate)
32 77205 1 O -CH2- S2NH2 H 162-163 ,.
racemate (methane sulfonate) . .:
~ _ _ ........ .. . . .. . . .. .......... . . .. ... .. ............ ~
- 33 77114 1 <~ CH2- S2NH H 120-121
(S)(+) 2 . (methane sulfonate)
_. _... , ......
34 . 77173 1 D -CH2- S2NH2 H 60 64 (base)
racemate 124.5-126 ;.
(methane sulfonate) ..
77206 ..... ~ ~ . . -SO--C---H ~ - H - 187.5-188.5 - .
racemate D -CH~- 5 (deCOmP) (HC1)
l .,.. _ _ ~_ . . . . . _ .. . . .
36 77149 1 D -CH2- SO2N(CH3)2 H 159 5-160.5 . .
, .. ~. . . . . .. .. ...... .. .. .... _ . . .. . .
~ 37 77164 1 r~ CH2 C1 H 181-182
~ racemate V (HC1)
.~ 30 . ~ _ .
~ * Example 30 shows an isomer of the racemic SLC 036 of Example 10. : ~ .
:
-:
: ~ ' ,,~ -
.:, ,
. . . ". .

--1039731
PSYCHOTROPIC PROPERTIES
The psychotropic properties of the above compounds ~ -
and a compound of the Principal Disclosure were determined,
by measuring antagonism towards "climbing" induced by apo-
morphine in mice ( Gouret, ~. ( 1973a ) S. Pharmacal. ( Paris ) ~ -
4 341 ).
The 50% lethal dose (LD50) of each product was
determined by a graphical method and the antiapomorphine
activity was expressed by the 50~ active doses (AD50). All
administrations were intraperitoneal. The results were as
follows:
TABLE X
Compound Acute toxicity in mice Antiapomorphine activity
LD-50 (mq/kg) in mice -AD-50 (ma/kq)
. _ ~ . r._._
74036 400 15
! ~ .
77075 350 4
_ . . ~ .. ~ .,
77145 245 ~10
. . .__ ... . ... .
77173 235 1.5
.__ ._ _
77149 240 3
__ __ _ _ _ _ _
77164 135 0.1
ANTI-EMETIC PROPERTIES
.. . .. _ .
The anti-emetic properties of two compounds
according to the invention were measured by antagonism toward
, " . ~, .. .
emetic effects induced by apomorphine in dogs ( Shallek et al
(1968) Arch. Int. Pharmacodyn. 174 No. 2 350-372; Boissier
et al (1962), Med. Exp. 6 320-326 ). The anti-emetic
activity was expressed by the 50% active doses (AD50) with all -
3~ administrations being oral. The results were as follows:
-: .:
-42- ;~
.
',
'~ ,' ' .

1039731 :
TABLE XI
Compound Ant.i-Emetic Activity in
dogs - AD50 (mg/kg) :~
74036 37
77075 14
.
!
:':: ~ ` :
~ 43_ : .