N-SULFONYLINDOLINE DERIVATIVES CARRYING AN AMIDE FUNCTIONAL GROUP, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS IN WHICH THEY ARE PRESENT

DERIVES DE N-SULFONYLINDOLINE PORTANT UN GROUPE FONCTIONNEL AMIDE; METHODE DE PREPARATION ET COMPOSITIONS PHARMACEUTIQUES QUI EN RENFERMENT

English Abstract

Compounds of formula (6):
<IMG> 6
in which
A' is NR6R7;
- R1 is a halogen atom, a C1-C4 alkyl, a hydroxyl, a
C1-C4 alkoxy, a benzyloxy group, a cyano group, a
trifluoromethyl group, nitro group or an amino
group;
- R2 is a C1-C6 alkyl, a C3-C7 cycloalkyl, a C5-C7
cycloalkene or a phenyl which is unsubstituted or
monosubstituted or polysubstituted by a C1-C4
alkyl, a C1-C4 alkoxy, a halogen, a trifluoromethyl
group or an amino group, or R2 is a nitrophenyl
which is unsubstituted or monosubstituted by a
trifluoromethyl group or monosubstituted or
polysubstituted by a C1-C4 alkyl, a C1-C4 alkoxy or
a halogen;
- R5 is a C1-C4 alkyl; a 1-naphthyl; a 2-naphthyl; a
5-dimethylamino-1-naphthyl; a phenyl which is
unsubstituted or substituted by one or more
substituents selected from a halogen atom, a C1-C4
alkyl, a trifluoromethyl group, an amino group
which is free or substituted by one or two C1-C4
alkyls, a hydroxyl, a C1-C4 alkoxy, a C2-C4
alkenoxy, a C1-C4 alkylthio, a trifluoromethoxy
group, a benzyloxy group, a cyano group, a
carboxyl group, a C1-C4 alkoxycarbonyl group, a

87
carbamoyl group which is free or substituted by
one or two C1-C4 alkyls or a C1-C4 alkylamido
group, or R5 is a nitrophenyl which is
unsubstituted or monosubstituted by a
trifluoromethyl group or a C2-C4 alkenoxy or
mono- or polysubstituted by a halogen, a C1-C4 alkyl, a
C1-C4 alkoxy, a C1-C4 alkylthio, a trifluoromethoxy
group or a benzyloxy group;
- R6 is a C1-C6 alkyl or R6 is identical to R7;
- R7 is a 4-piperidyl group or a 3-azetidinyl group,
the said groups being substituted or unsubstituted
on the nitrogen by a C1-C4 alkyl, by a
benzyloxycarbonyl or by a C1-C4 alkoxycarbonyl; a
group (CH2)r which is itself substituted by a 2-,
3- or 4-pyridyl group, by a hydroxyl group or by
an amino group which is free or substituted by one
or two C1-C4 alkyls, a carboxyl group, a C1-C4
alkoxycarbonyl group, a benzyloxycarbonyl group or
a carbamoyl group which is free or substituted by
one or two C1-C4 alkyls;
- or R6 and R7 together, with the nitrogen atom to
which they are connected, form a heterocycle
selected from:
. morpholine,
. thiomorpholine,
. thiazolidine or 2,2-dimethylthiazolidine,
unsubstituted or substituted by R8,
. piperazine, unsubstituted or substituted at the
4-position by a group R"8,
. an unsaturated, a 5-membered ring containing a
single nitrogen atom and substituted by R8 or a
saturated, 3-, 4-, 5-, 6- or 7-membered ring
containing a single nitrogen atom and
substituted by R8 and R9;
- R8 is R'8 or a group (CH2)r which is itself
substituted by a hydroxyl or by an amino which is
free or substituted by one or two C1-C4 alkyls;

88
- R'8 is a group (CH2)q which is itself substituted
by a carboxyl group, a C1-C4 alkoxycarbonyl group,
a benzyloxycarbonyl group, a carbamoyl group which
is free or substituted by a hydroxyl or by one or
two C1-C4 alkyls or an aminocarbothioyl group which
is free or substituted by one or two C1-C4 alkyls;
- R"8 is R'8 or a group (CH2)2NH2 which is free or
substituted by one or two C1-C4 alkyls;
- R9 is hydrogen, a halogen, a group (CH2) rOR10, a
group (CH2)rNR11R12, a group (CH2)sCONR11R'11 or an
azido group;
- R10 is hydrogen, a C1-C4 alkyl, a mesyl or a tosyl;
- R11, R'11 and R12 are each a hydrogen or a C1-C4
alkyl or R11 is hydrogen and R12 is a
benzyloxycarbonyl or a C1-C4 alkoxycarbonyl;
- n is 0, 1 or 2;
- m is 0, 1 or 2;
- q is 0, 1, 2 or 3;
- r is 0, 1, 2 or 3, with the limitation that r is
not zero when R8 or R9 is at the alpha-position of
the intracyclic amide nitrogen;
- s is 0 or 1;
are useful as intermediates of the preparation of
N-sulfonylindoline derivatives which are useful in the
treatment of complaints of the central nervous system,
the cardiovascular system and the gastric sphere in
humans and animals.

French Abstract

Composés de formule (6), <IMG> 6, où A' est NR6R7; R1 est un atome d'halogène, un groupe alkyle C1-C4, hydroxyle, alcoxy C1-C4, benzyloxy, cyano, trifluorométhyle, nitro ou amino; R2 est un groupe alkyle C1-C6, cycloalkyle C3-C7, cycloalcényle C5-C7 ou phényle sans substitution ou avec mono- ou polysubstitution par un alkyle C1-C4, un alcoxy C1-C4, un halogène, un trifluorométhyle ou un amino, ou R2 est un nitrophényle sans substitution ou avec monosubstitution par un trifluorométhyle ou avec monosubstitution ou polysubstitution par un alkyle C1-C4, un alcoxy C1-C4 ou un halogène; R5 est un alkyle C1-C4, un 1-naphtyle, un 2-naphtyle, un 5-diméthylamino-1-naphtyle, un phényle sans substitution ou avec substitution par un ou plusieurs substituants choisis parmi un atome d'halogène, un alkyle C1-C4, un trifluorométhyle, un amino tel quel ou avec substitution par un ou deux alkyles C1-C4, un hydroxyle,un alcoxy C1-C4, un alcénoxy C2-C4, un alkylthio C1-C4, un trifluorométhoxy, un benzyloxy, un cyano, un carboxyle, un alkoxycarbonyle C1-C4, un carbamoyle 87 tel quel ou avec substitution par un ou deux alkyles C1-C4 ou un alkylamido C1-C4, ou R5 est un nitrophényle sans substitution ou avec monosubstitution par un trifluorométhyle ou un alcénoxy C2-C4 ou avec mono- ou polysubstitution par un halogène, un alkyle C1-C4, un alcoxy C1-C4, un alkylthio C1-C4, un trifluorométhoxy ou un benzyloxy; R6 est un alkyle C1-C6, ou R6 est identique à R7; R7 est un 4-pipéridyle ou un 3-azétidinyle, ces groupes étant avec ou sans substitution sur l'azote par un alkyle C1-C4, un benzyloxycarbonyle ou un alcoxycarbonyle C1-C4; un (CH2)r avec lui-même substitution par un groupe 2-, 3- ou 4-pyridyle, par un hydroxyle ou un amino comme tel ou avec substitution par un ou deux alkyles C1-C4, un carboxyle, un alcoxycarbonyle C1-C4, un benzyloxycarbonyle ou un carbamoyle comme tel ou avec substitution par un ou deux alkyles C1-C4; ou R6 et R7 forment ensemble, avec l'atome d'azote auquel ils sont liés, un hétérocycle choisi parmi la morpholine, la thiomorpholine, la thiazolidine ou la 2,2-diméthylthiazolidine, sans substitution ou avec substitution par R8, la pipérazine, sans ou avec substitution en position 4 par un groupe R"8, un cycle insaturé à 5 chaînons renfermant un seul atome d'azote avec substitution par R8 ou un cycle saturé à 3-, 4-, 5-, 6- ou 7 chaînons contenant un seul atome d'azote et avec substitution par R8 et R9; R8 est R'8 ou un groupe (CH2)r avec lui-même substitution par un hydroxyle ou par un amino sans ou avec substitution par un ou deux alkyles C1-C4; 88 - R'8 est un groupe (CH2)q avec lui-même substitution par un carboxyle, un alcoxycarbonyle C1-C4, un benzyloxycarbonyle, un carbamoyle comme tel ou avec substitution par un hydroxyle ou par un ou deux alkyles C1-C4 ou un aminocarbothioyle sans ou avec substitution par un ou deux alkyles C1-C4; R"8 est R'8 ou un groupe (CH2)2NH2 sans ou avec substitution par un ou deux alkyles C1-C4; R9 est de l'hydrogène, un halogène, un (CH2)rOR10, un (CH2)rNR11R12, un (CH2)sCONR11R'11 ou un azido; R10 est un hydrogène, un alkyle C1-C4, un mésyle ou un tosyle; R11, R'11 et R12 sont chacun un hydrogène ou un alkyle C1-C4, ou R11 est de l'hydrogène et R12 est un benzyloxycarbonyle ou un alcoxycarbonyle C1-C4 ; n est 0, 1 ou 2; m est 0, 1 ou 2; q est 0, 1, 2 ou 3; r est 0, 1, 2 ou 3, à condition que r ne soit par zéro lorsque R8 ou R9 est en position alpha de l'azote de l'amide intracyclique; - s est 0 ou 1; ces composés sont utiles comme intermédiaires dans la préparation de dérivés de la N-sulfonylindoline, lesquels sont utiles pour le traitement des troubles au niveau du système nerveux central, du système vasculaire et du milieu gastrique chez l'homme et l'animal.

Claims

83
The embodiments of the invention in which an exclusive
property or privilege is claimed are defined as follows:
1. A compound of formula (6)
<IMG>
in which
A' is NR6R7 ;
- R1 is a halogen atom, a C1-C4 alkyl, a hydroxyl, a C1-
C4 alkoxy, a benzyloxy group, a cyano group, a
trifluoromethyl group, nitro group or an amino
group;
- R2 is a C1-C6 alkyl, a C3-C7 cycloalkyl, a C5-C7
cycloalkene or a phenyl which is unsubstituted or
monosubstituted or polysubstituted by a C1-C4 alkyl,
a C1-C4 alkoxy, a halogen, a trifluoromethyl group or
an amino group, or R2 is a nitrophenyl which is
unsubstituted or monosubstituted by a
trifluoromethyl group or monosubstituted or
polysubstituted by a C1-C4 alkyl, a C1-C4 alkoxy or a
halogen;
- R5 is a C1-C4 alkyl; a 1-naphthyl; a 2-naphthyl; a 5-
dimethylamino-1-naphthyl; a phenyl which is
unsubstituted or substituted by one or more
substituents selected from:
a halogen atom,
a C1-C4 alkyl,
a trifluoromethyl group,
an amino group which is free or substituted by one
or two C1-C4 alkyls,
a hydroxyl,

84
a C1-C4 alkoxy,
a C2-C4 alkenoxy,
a C1-C4 alkylthio,
a trifluoromethoxy group,
a benzyloxy group,
a cyano group,
a carboxyl group,
a C1-C4 alkoxycarbonyl group,
a carbamoyl group which is free or substituted by
one or two C1-C4 alkyls, or
a C1-C4 alkylamido group; or
R5 is a nitrophenyl which is unsubstituted or
monosubstituted by a trifluoromethyl group or a C2-C4
alkenoxy or mono- or polysubstituted by a halogen, a
C1-C4 alkyl, a C1-C4 alkoxy, a C1-C4 alkylthio, a
trifluoromethoxy group or a benzyloxy group;
- R6 is a C1-C6 alkyl or R6 is identical to R7;
- R7 is a 4-piperidyl group or a 3-azetidinyl group,
the said groups being substituted or unsubstituted
on the nitrogen by a C1-C4 alkyl, by a
benzyloxycarbonyl or by a C1-C4 alkoxycarbonyl;
a group (CH2)r which is itself substituted by:
a 2-, 3- or 4-pyridyl group,
a hydroxyl group,
an amino group which is free or substituted by one
or two C1-C4 alkyls,
a carboxyl group,
a C1-C4 alkoxycarbonyl group,
a benzyloxycarbonyl group, or
a carbamoyl group which is free or substituted by
one or two C1-C4 alkyls;
or R6 and R7 together, with the nitrogen atom to which
they are connected, form a heterocycle selected
from:
.cndot. morpholine,
.cndot. thiomorpholine,

85
.cndot. thiazolidine or 2,2-dimethylthiazolidine,
unsubstituted or substituted by R8,
.cndot. piperazine, unsubstituted or substituted at the
4-position by a group R"8,
.cndot. an unsaturated, 5-membered ring containing a
single nitrogen atom and substituted by R8 or a
saturated, 3-, 4-, 5-, 6- or 7-membered ring
containing a single nitrogen atom and substituted
by R8 and R9;
- R8 is R'8 or a group (CH2)r which is itself
substituted by a hydroxyl or by an amino which is
free or substituted by one or two C1-C4 alkyls;
- R'8 is a group (CH2)q which is itself substituted by
a carboxyl group, a C1-C4 alkoxycarbonyl group, a
benzyloxycarbonyl group, a carbamoyl group which is
free or substituted by a hydroxyl or by one or two
C1-C4 alkyls or an aminocarbothioyl group which is
free or substituted by one or two C1-C4 alkyls;
- R"8 is R'8 or a group (CH2)2NH2 in which the amino
group is free or substituted by one or two C1-C4
alkyls;
- R9 is hydrogen, a halogen, a group (CH2)r OR10 a group
(CH2)r NR11R12, a group (CH2)a CONR11R'11 or an azido
group;
- R10 is hydrogen, a C1-C4 alkyl, a mesyl or a tosyl;
- R11, R'11 and R12 are each a hydrogen or a C1-C4 alkyl
or R11 is hydrogen and R12 is a benzyloxycarbonyl or a
C1-C4 alkoxycarbonyl ;
- n is 0, 1 or 2;
- m is 0, 1 or 2;
- q is 0, 1, 2 or 3;
- r is 0, 1, 2 or 3, with the limitation that r is not
zero when R8 or R9 is at the alpha-position of the
intracyclic amide nitrogen;
- s is 0 or 1.

Description

CA 02206776 1997-06-27
N-SULFONYI~INDOI~INE DERIVATIVES CARRYING AN AMIDE
' FUNCTIONAL GROUP, THEIR PREPARATION, AND THE
PHARMACEUTICAL COMPOSITIONS IN WHICH THEY ARE PRESENT
The present invention relates to
intermediates for the preparation of N-sulfonylindoline
derivatives, carrying an amide functional group, their
preparation and the pharmaceutical compositions in
which they are present.
This application is a division of Canadian
Patent Application Serial No. 2,093,221 filed July 31,
1992. The parent application is directed to and claims
certain N-sulfonylindoline derivatives, the preparation
thereof and uses of such derivatives, particularly in
pharmaceutical compositions for the treatment of
complaints of the central nervous system, the
cardiovascular system and the gastric sphere in humans
and animals. The present application claims certain
intermediate compounds in the preparation of the N-
sulfonylindoline derivatives.
U.S. Patent 3,838,167 describes some N-
sulfonylindole derivatives corresponding to the
formula:
R"
1
~~~- COR"4
~R~2~n' I
S 02R"3
1
in which
- R"1 is hydrogen, an alkyl or a substituted or
unsubstituted phenyl;
- R"2 is a halogen, an alkyl, an alkoxy, a nitro or
trifluoromethyl;
- R"3 is an alkyl, a phenyl or an alkylphenyl;
- R"4 is an alkyl, a substituted or unsubstituted
phenyl, an alkoxy or a phenoxy;
- n' - 0, 1 or 2.

CA 02206776 1997-06-27
., _
2
These compounds 1 are synthesis intermediates
for the preparation of indole derivatives active
on the central nervous system, of formula:
R"
./ 1
(R"~ n ~ ~~OR'.
J
H
in which R" is an alkyl, a substituted or unsubstituted
phenly or a hydroxyl.
The indoline derivatives according to the
present invention have an affinity for the vasopressin
and ocytocin receptors.
Vasopressin is a hormone known for its
antidiuretic effect and its effect in the regulation of
the arterial pressure. It stimulates several types of
receptors : V1, V2, Vla, Vib and thus exerts
cardiovascular, central, hepatic, antidiuretic, emetic
and aggregating effects, as well as proliferative and
mitotic effects, especially on the vascular and hepatic
tissues. Vasopressin receptor antagonists can affect
the regulation of the central or peripheral
circulation, especially the coronary, renal and gastric
circulations, as well as the metabolism of water and
the release of adrenocorticotrophic hormone (ACTH).
The vasopressin receptors, like those of ocytocin, are
also found on the smooth muscle of the uterus.
Ocytocin has a peptide structure similar to that of
vasopressin. Its receptors are also found on the
myoepithelial cells of the mammary gland and in the
central nervous system. (Presse Medicale, 1987, _16
(10), 481-485, J. Lab. Clin. Med., 1989 114 (6), 617-
632 and Pharmacol. Rev., 1991, 43 (1), 73-108).
Thus the compounds described herein are
useful especially in the treatment of complaints of the

CA 02206776 1997-06-27
3
central nervous system, the cardiovascular system and
the gastric sphere in humans and animals.
- The invention, as claimed in the parent
filing, relates to compounds of formula:
2
OH
R
3
R4
SO . -
(CH2)m
RS
in which
15 - R1 is a halogen atom, a C1-CQ alkyl, a hydroxyl, a
-C1-CQ alkoxy, a benzyloxy group, a cyano group, a
trifluoromethyl group, a nitro group or an amino
group;
- R2 is a C1-C6 alkyl, a C3-C~ cycloalkyl, a C5-C~
cycloalkene or a phenyl which is unsubstituted or
monosubstituted or polysubstituted by a C1-C4
alkyl, a C1-C4 alkoxy, a halogen, a trifluoromethyl
group or an amino group, or R2 is a nitrophenyl
which is unsubstituted or monosubstituted by a
trifluoromethyl group or monosubstituted or
polysubstituted by a C1-Cq alkyl or a halogen;
- R3 is a hydrogen atom
- Rq is a carbamoyl group of formula CONR6R~~
- RS is a C1-C4 alkyl, a 1-naphthyl~ a 2-naphthyl~ a
5-dimethylamino-1-naphthyl: a phenyl which is
unsubstituted or substituted by one or more
substituents selected from a halogen atom, a C1-C4
alkyl, a tri-fluoromethyl group, an amino group
which is free or substituted by one or two C1-C4
alkyls, a hydroxyl, a C1-C4 alkoxy, a C2-CQ
alkenoxy, a C1-C4 alkylthio, a trifluoromethoxy
group, a benzyloxy group, a cyano group, a

CA 02206776 2001-05-08
4
carboxyl group, a C1-C4 alkoxycarbonyl group, a
carbamoyl group which is free or substituted by
one or two C1-C4 alkyls or a C1-C9 alkylamido group,
or R5 is a nitrophenyl which is unsubstituted or
monosubstituted by a trifluoromethyl group or a
a C2-C9 alkenoxy or mono- or polysubstituted by a
halogen, a C1-C9 alkyl, a C1-C9 alkoxy, a C1-C4
alkylthio, a trifluoromethoxy group or a benzyloxy
group;
- R6 is a C1-C6 alkyl or R6 is identical to R7;
- R7 is a 4-piperidyl group or a 3-azetidinyl group,
the said groups being substituted or unsubstituted
on the nitrogen by a C1-C4 alkyl, by a
benzyloxycarbonyl or by a C1-CQ alkoxycarbonyl; a
group (CH2)r which is itself substituted by a 2-,
3- or 4-pyridyl group, by a hydroxyl group or by
an amino group which is free or substituted by one
or two C1-C9 alkyls, a carboxyl group, a C1-C9
alkoxycarbonyl group, a benzyloxycarbonyl group or
a carbamoyl group which is free or substituted by
one or two C1-C9 alkyls;
- or R6 and R7 together, with the nitrogen atom to
which they are connected, form a heterocycle
selected from:
~ morpholine,
~ thiomorpholine,
~ thiazolidine or 2,2-dimethylthiazolidine;
unsubstituted or substituted by Re,
~ piperazine, unsubstituted or substituted at
the 4-position by a group R"8,
~ an unsaturated, 5-membered ring containing a
single nitrogen atom and substituted by RB or
a saturated, 3-, 4-, 5-, 6- or 7-membered
ring containing a single nitrogen atom and
substituted by Re and R9;
- R$ is R~ B or a group (CH2) r which is itself
substituted by a hydrox-yl or by an amino which is

CA 02206776 1997-06-27
free or substituted by one or two C1-C4 alkyls;
- R'8 is a group (CHz)q which is itself substituted
by a carboxyl group, a C1-C4 alkoxycarbonyl group,
a benzyloxycarbonyl group, a carbamoyl group which
5 is free or substituted by a hydroxyl or by one or
two C1-C4 alkyls or an aminocarbothioyl group which
is free or substituted by one or two C1-CQ alkyls;
- R"$ is R' $ or a group (CHZ) 2NH2 which is free or
substituted by one or two C1-C4 alkyls;
- R9 is hydrogen, a halogen, a group (CH2) rORlo, a
group (CH2) rNR11Ri2. a group (CH2) SCONR11R' ii or an
azido group;
- Rlo is hydrogen, a C1-C4 alkyl, a mesyl or a tosyl;
- Rii. R' ii and R12 are each a hydrogen or a C1-CQ
alkyl or Rll is hydrogen and R12 is a
benzyloxycarbonyl or a C1-C4 alkoxycarbonyl;
- n is 0, 1 or 2;
- m is 0, 1 or 2;
- q is 0, 1, 2 or 3;
- r is 0, l, 2 or 3, with the limitation that r is
not zero when RB or R9 is at the alpha-position of
the intracyclic amide nitrogen;
- s is 0 or 1;
as well as their possible salts.
The salts of the compounds of formula (I)
comprise those with inorganic or organic acids which
make possible a suitable separation or crystallization
of the compounds of formula (I), such as picric acid,
oxalic acid or an optically active acid, for example a
mandelic acid or a camphosulfonic acid, and those which
form pharmaceutically acceptable salts such as the
hydrochloride, the hydrogensulfate, the
dihydrogenphosphate, the methanesulfonate, the maleate,
the fumarate or the 2-naphthalenesulfonate.
The salts of the compounds of formula (I)
also comprise the salts with organic or inorganic
bases, for example the salts of alkali or alkaline-

CA 02206776 1997-06-27
6
earth metals such as the salts of sodium, potassium or
calcium, the salts of sodium and potassium being
preferred, or with an amine, such as trometamol, or
even the salts of arginine or lysine or of any
pharmaceutically acceptable amine.
The compounds (I) exhibit cis-trans isomerism
around the 2, 3 bond of the indoline. The different
isomers form an integral part of the invention.
By convention, the compounds (I) in which R2
and RQ are on the same side of the ring are called the
cis isomers.
By convention, the compounds (I) in which RZ
and R4 are on opposite sides of the ring are called the
trans isomers.
R2
~ .".OH
(R1)n\ N _ R4
S02 R3 (I)
(CH2)m
RS
cis isomer
R2
~ .....OH
(R1)n~N~R3
R4
S02
i (r)
(CH2)m
RS
tr~ns isomer
Moreover, the compounds according to the
invention have 2 asymmetric carbon atoms or more when
R4 contains one 1 or 2 asymmetric carbons. The optical
isomers of the compounds (I) form part of the
invention.

CA 02206776 1997-06-27
a
In the present description, halogen is
understood as meaning a fluorine, chlorine, bromine or
iodine atom; alkyl group is understood as meaning
linear or branched hydrocarbon groups.
Preferred compounds (I) according to the
invention are those in which at least one of the
following conditions is satisfied:
- R1 is a chlorine or bromine atom or a methoxy
group and n = 1;
- Rz is a chlorophenyl, a methoxyphenyl or a
cyclohexyl;
- RQ is a group CONR6R~ in which R6 and R~ or NR6R7
have one of the following definitions;
~ NR6R7 is a pyrrolidino group which is
substituted at the 2-position by a group
(CHZ)q which is itself substituted by a
carboxyl or carbamoyl group with q = 0, l, 2
or 3.
~ NR6R7 is a piperidino group which is
substituted at the 4-position by an amino
group, a C1-C4 alkylamino or a C1-CQ
dialkylamino,
~ NR6R~ is a thiazolidino group which is
substituted by a group (CH2)q which is itself
substituted by a carboxyl or carbamoyl group
with q = 0, 1, 2 or 3.
~ NR6R~ is a pyrrolidino group which is
substituted at the 2-position by a group
(CH2) Q which ~is itself substituted by a
carboxyl or carbamoyl group with q = 0, 1, 2
or 3 and which is substituted at the 4-
position by an amino group, a C1-C4 alkylamino
or a C1-C4 dialkylamino~
- R6 is a C1-C4 alkyl and R~ is a group (CH2) r which is
itself substituted by a carboxyl group or a
carbamoyl group with r = 1, 2 or 3;
- RS is a phenyl substituted at the 3- and 4-

CA 02206776 1997-06-27
8
position or at the n- and 4-position by a methoxy
group, or RS is a phenyl substituted at the 4-
position by a methyl group;
- m = 0.
The compounds (I) which are in the form of
the cis isomers are particularly preferred.
The following abbreviations are used in the
description and the examples.
DCM: dichloromethane
AcOEt: ethyl acetate
MeOH: methanol
EtOH: ethanol
Ether: ethyl ether
DMF: dimethylformamide
THF: tetrahydrofuran
TEA: triethylamine
DMSO: dimethyl sulfoxide
DIPEA: diisopropylethylamine
DCC: N,N'-dicyclohexylcarbodiimide
DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene
TBD: 1,5,7-triazabicyclo[4.4.0]dec-5-ene
DBN: 1,5-diazabicyclo[4.3.0]non-5-ene
DMAP: 4-dimethylaminopyridine
DMPU: 1,3-dimethyl-2-oxohexahydropyrimidinone
TMEDA: tetramethylethylenediamine
LDA: lithium diisopropylamide
HMPA: hexamethylphosphoramide
HOBT: 1-hydroxybenzotriazole hydrate
BOP: benzotriazolyloxytrisdimethylaminophosphonium
hexafluorophosphate
TFA: trifluoroacetic acid
Lawesson's reagent: 2,4-bis(4-methoxyphenyl)-l, 3-
dithia-2, 4-diphosphetane-2, 4-disulfide
M.p.. melting point
Saline solution: water saturated with sodium
chloride
Dry ice: solid carbon dioxide

CA 02206776 1997-06-27
9
TLC: thin layer chromatography
HPLC: high performance liquid chromatography
NMR: nuclear magnetic resonance
s: singlet
m: multiplet
bs: broad singlet
d: doublet
Hydrochloric water: dilute hydrochloric acid,
about 1N
805 NaH: dispersion of sodium hydride in mineral
oil (Janssen Chemica)
Me: methyl
Et: ethyl
iPr: isopropyl, Pr: propyl
iPentyl: isopentyl
iBu: isobutyl
tBu: tert-butyl, Bu: butyl
Bz: benzyl
Ph: phenyl
RT: room temperature
The invention, as claimed in the parent
filing, further relates to the process for preparing
the compounds (I).
This process is characterized in that it
comprises:
(a) reacting a 2-aminophenone derivative of
formula:
(II)
(R j
2
in which R1, R2 and n have the meanings indicated above
for I, with a sulfonyl derivative of formula:
Hal-S02- ( CH2 ) m-Rs ( I I I )
in which
- Hal is a halogen, preferably chlorine or bromine,
CO-R2
NH

CA 02206776 1997-06-27
- m and R5 Have the meanings indicated above for
):
(b) treating the resulting compound of formula:
O-R2 _
5
(R1)n~ NH
S02 ( Iv)
i
(CH2)m
l0 RS
with a halogenated derivative of formula:
Hal' -CHZCOA ( V )
in which
Hal' is a halogen, preferably bromine, and A represents
either the group NR6R~ or the group OR in which R is a
tert-butyl or a benzyl;
(c) deprotecting the resulting ester of formula:
(R1)n COOR
S02 ~ (VI) ,
(CH2)m . .
RS
under suitable conditions, if applicable, when A
is OR;
(d) treating, if applicable, the resulting acid
from Step (c) of formula:
/ COR2
(R 1)n~N-CH2 COON
I
SOZ (VI) n
(CH2)m
5
/ COR2
--N-CHZ
I

CA 02206776 1997-06-27
i
1;1
or its acid chloride of formula:
(R1)n COCI (vI)"~
S02
i
(CH2)m
RS
with a compound HNR6R~ according to suitable amide
coupling techniques;
(e) cyclizing the resulting compound from Step
(b) or from Step (d) of formula:
COR2
~--N-CH2
i
,COR.,
(R1 n~~- CH2CONR6R~
r O2 ( vI )
(CH2)m
RS
in a basic medium in order to prepare the compound
(I) according to the invention;
(f) separating, if appropriate, the cis and trans
isomers of the compound (I) and, if appropriate,
separating the enantiomers.
The 2-aminophenone derivatives (II) are known
or prepared by known methods, such as those described
by A.K. Singh et al., Synth. Commun. 1986, 16 (4), 485
and G.N. Walker, J. Org. Chem., 1962, 27, 1929. The 2-
amino-2'-trifluoromethylbenzophenones and the other
trifluoromethylated derivatives are prepared according
to U.S. Patent 3,341,592.
2,4-dimethoxybenzenesulfonyl chloride is
prepared according to J. Am. Chem. Soc., 1952 74, 2008.

CA 02206776 1997-06-27
12
The sulfonyl derivatives of formula (III) are
known or prepared by known methods. Thus, for example,
4-dimethylaminobenzenesulfonyl chlodride is prepared
according to C.N. Sukenik et al., J. Am. Chem. Soc.,
1977, 99, 851-858; p-benzyloxybenzenesulfonyl chloride
is prepared according to European Patent Application
EP 229, 566.
The alkoxybenzenesulfonyl chloride is
prepared from the sodium alkoxybenzenesulfonate, which
is itself prepared by reacting an alkyl halide with
sodium hydroxybenzenesulfonate.
The halogenated derivatives of formula (V)
are known or prepared by known methods, such as those
described by A.I. Vogel: A Text Book of Practical
Organic Chemistry: Longman, 3rd ed. 1956, p. 383, or
G. Kirchner et al., J. Am. Chem. Soc., 1985, 107, 24,
7072.
Step (a) of the process is carried out in
pyridine by heating at a temperature between room
temperature and the boiling point of the solvent for a
period of time of between a few hours and a few days.
If appropriate, the reaction can be carried out in the
presence of dimethylaminopyridine, which is used in a
catalytic or stoichiometric amount.
Step (b) of the process is carried out
between the sulfonamide of formula (IV) and an excess
of the halogenated derivative of formula (V), in a
solvent such as dimethylformamide or dimethyl
sulfoxide, under an inert atmosphere, at a temperature
of between 0°C and room temperature, for a time of
between a few hours and 24 hours, in the presence of
sodium hydride.
When the group -NR6R~ contains a second amine
group, that is to say when R6 and/or R~ are substituted
by an amino group, it is possible to choose to use a
halogenated derivative (V) of formula Hal'-CH2-C02R in
which R is a tert-butyl or a benzyl, in order to

CA 02206776 1997-06-27
L
13
prepare the intermediates of formula(VI)' and then
(VI)". In this case, Step (c) for the formation of the
acid of formula (VI)" is carried out either by the
action of hydrogen in the presence of a catalyst such
as palladium on charcoal when R is benzyl, or in acid
medium, when R is tert-butyl, for example in the
presence of TFA or in the presence of hydrobromic acid
in acetic acid or even in the presence of ZnBr2 in DCM.
Step (d) is then carried out under the
conventional conditions for amide coupling, for example
in the presence of BOP or HOBT and DCC.
The compounds HNR6R~ are known or prepared by
known methods. By way of example, the stereospecific
synthesis of (R)- and (S)-2-pyrrolidinylacetic acids is
carried out according to H. Rueger et al. in
Hs?tPt"c~c-v~-1 E?~ _ 1 AR7 _ 1 ~3 l A1 _ 1 ~r,'77 frnm a nrnl ; nc
_______...1____.., _~..~, - ,~, , ~... , yy.....
derivative of suitable configuration. The preparation
of methyl N-Boc-3, 4-dehydro-a-prolinate is carried out
according to J.R. Dormoy, Synthesis, 1982, 753. The
preparation of optically pure derivatives of pipecolic
acid is described, for example, in Tetrahedron, 1992,
48 (3) 431-442 and Tetrahedron, 1991, 47 (24) 4039-
4062.
The preparation of the derivatives of
aziridinecarboxylic acid is carried out according to K.
Nakajima et al. in Bull. Chem. Soc. Jap., 1978 _51 (5),
1577.
Step (e) of the process is closely related to
an aldolization reaction: the methylene group in the a-
position of the amide is deprotonated and the carbonyl
group of the phenone then acts like an internal
electrophile, resulting in cyclization with the
appearance of two asymmetric carbons (C*).
The reaction can be illustrated by the
following scheme:

CA 02206776 1997-06-27
14
O' O
i~ C R2 O C _
..
(R 1)n 1/ 1 C /
S02 H
(~HZ)m
RS OH
/ * R2
*H
(R 1~ N
R4
S O'2
(CH2)m
RS
The principles of the aldol addition reaction
have been reviewed by C.H. Heathcock in Asymmetric
Synthesis, vol. 3: Stereodifferentiating addition
reactions, part B, 111-112 Academic Press, 1984,
edited. by J.D. Morrison.
It is known that the ~aldol reaction of
achiral amide anions gives rise to the formation of 2
racemic diastereoisomers of (3-hydroxyamides in a ratio
which depends largely on the experimental conditions
used. The following may be mentioned among these
conditions: the nature of the inorganic or organic
base used, the nature of the cations or counterions,
the possible presence of additives in the reaction
medium, the solvent, the reaction temperature and the
structure of the compound undergoing this reaction.
When the groups R6 and R~ do not contain a
group which is hydrolysable in alkaline medium, it is
possible to use sodium hydroxide in water, in the
presence of a cosolvent, with or without the addition,
of a phase transfer catalyst; it is also possible to

CA 02206776 1997-06-27
use a quaternary ammonium hydroxide, for example
benzyltrimethylammonium hydroxide in methanol.
In order to carry out this aldolization
reaction, it is also possible to use organic bases, for
5 example:
- guanidines such as 1,5,7-triazabicyclo[4.4.0]dec-
5-ene,
- amidines such as 1,8-diazabicyclos[5.4.0]undec-5-
ene or 1,5-diazabicyclo[4.3.0]non-5-ene,
10 in a solvent or a mixture of solvents
selected for example from benzene, THF,
dichloromethane, methanol and dimethylformamide; the
reaction is carried out under an inert atmosphere at
between -10°C and 110°C; the amount of base used is at
15 least-stoichiometric; the reaction can also be carried
out without a solvent, at the temperature of the bath.
Preferentially, Step (e) of the process
according to the invention is carried out in the
presence of 1,8-diazabicyclo[5.4.0)undec-5-ene (DBU) in
a solvent such as dichloromethane or methanol, at a
temperature of between -10°C and the reflux temperature
of the solvent.
It is also possible to use an alcoholate of a
primary, secondary or tertiary alcohol with lithium,
sodium, potassium, calcium or magnesium.
The alcoholate is used in a catalytic or
stoichiometric amount in an anhydrous solvent, for
example an alcohol (if appropriate in the presence of a
cosolvent such as THF), or else in a stoichiometric
amount in THF, DMF or DMSO, if appropriate in the
presence of crown ethers, for example dicyclohexyl-18-
crown-6; the reaction is carried out at between -15°C
and 80°C.
The use of an amide of the type RR'NLi or
RR'NMgBr, in which R and R' are monovalent radicals, as
a deprotonating agent is a method of forming enolates
of amides, which are intermediates in the aldolization

CA 02206776 1997-06-27
16
reaction; this method has recently been reviewed by
R.E. Ireland et al., J. Org. Chem., 1991 56, 650. The
reaction solvent can be benzene, hexane or THF used in
anhydrous form under an inert atmosphere. Adjuvants
such as LiF, LiCl, Liar, LiI, LiBu, TMEDA, DMPU, HMPA
or a crown ether can be added. (M. Murakate et al., J.
Chem. Soc. Commun., 1990, 1657). By way of example,
there may be mentioned the use of lithium
diisopropylamide at between -78°C and -30°C in
anhydrous THF under an inert atmosphere or in THF in
the presence of additives such as, for example,
tetramethylenediamine, DMPU or HMPA. Examples of other
known amides which can be used are lithium
cyclohexylamide and lithium 2,2,6,6-
tetramethylcyclohexylamide. It is also possible to
prepare other amides by reacting the requisite amount
of butyllithium in hexane with linear or cyclic
secondary amines, the reaction taking place in one of
the solvents mentioned above.
Finally, various publications describe amides
of optically active secondary amines: L. Duhamel et
al., Bull. Soc. Chim. France, 1984, II, 421; J.K.
Whitesell et al., J. Org. Chem., 1980, 45, 755; M.
Murakata et al., J. Chem. Soc. Chem. Commun., 1990,
1657; M. Yamaguchi, Tetrahedron Lett., 1986, 27 (8),
959; P.J. Cox and N.S. Simpkins, Tetrahedron:
Asymmetry, 1991, 2 ( 1 ) , 1.
The silylamides of lithium, sodium or
potassium constitute another group of bases which can
be used, among which there may be mentioned:
(Me3Si)2NLi, (Me2PhSi)2NLi, (Et3Si)2NLi, (Me3Si)2NK,
(Me3Si) ZNNa.
It is also possible to use mixed amides as
described by Y. Yamamoto, Tetrahedron, 1990, 46, 4563,
for example the lithium salt of N-
(trimethylsilyl)benzylamine or an analog in which the
benzylamine is replaced with a chiral primary amine

CA 02206776 1997-06-27
17
such as (R)- or (S)-a-methylbenzylamine.
When the compound of formula (I) to be
prepared has 2 asymmetric carbon atoms, the use of
chiral amides or alcoholates in Step (e) makes possible
an enantiomeric enrichment of each of the cis or trans
stereoisomers. The proportion of each of the
enantiomers is then determined by measurement on a
chiral high performance liquid chromatography column.
When the compound of formula (I) to be
prepared has 3 or 4 asymmetric carbon atoms, the
cyclization Step (c) can be accompanied by a
diastereoisomeric enrichment and the use of a suitable
chiral base makes it possible to modify this
diastereoisomeric enrichment.
In Step (f), the cis and trans geometric
isomers of the compound (I) formed are extracted by
conventional methods and separated by chromatography or
fractional crystallization.
If appropriate, the optical isomers of each
of the cis and trans isomers are separated, for example
by preparative chromatography on a chiral column
followed, if appropriate, by a fractional
crystallization or by formation of an optically active
salt in the presence of a suitably selected chiral acid
or base.
Thus, when the compound according to the
invention has 2 asymmetric carbon atoms, the
enantiomers can be separated by chiral HPLC.
When the compound according to the invention
has 3 or 4 asymmetric carbon atoms, the
diastereoisomers can be separated by using
chromatographic methods and fractional crystallization
methods.
Several methods can be used to differentiate
and characterize the cis isomer and the trans isomer of
a compound (I). When R3 is hydrogen, a comparative
analysis is performed by high field NMR (250 MHz),

CA 02206776 2001-05-08
18
coupled for example with the study of the Overhauser
effect (N.O.E.) between, for example, the proton of the
indoline (R3 = H) and the proton of the hydroxyl.
The IR spectra of the cis isomer and the
traps isomer in solution in DCM are different. The cis
isomer most commonly has a strong, fine and symmetrical
absorption band at around 3550-3520 cm 1, due to the
hydroxyl vibration, whereas the traps isomer has no
resolved vibration band in this region.
By means of the data collected, it has been
found that the cis isomer is generally the more mobile
in TLC on an aluminum oxide plate (60F259 neutral, Type
ETM, Merck), eluting with DCM containing variable
proportions of AcOEt. Similarly, in chromatography on
an alumina column (aluminum oxide 90, particle size
0.063-0.200 mm), the cis isomer is most commonly eluted
first, the eluent being DCM containing variable
proportions of AcOEt or MeOH.
Thus the cis or traps isomerism of a compound
(I) according to the invention can most often be
determined by an analytical method. It is also
possible to utilize the analogy between similar
compounds or between compounds prepared from one
another.
The absolute configuration of some compounds
according to the invention was determined by an X-ray
analysis. By deduction therefrom, taking into account
the value of the optical rotation, it is also possible
to know the absolute configuration of other compounds
obtained in an analogous fashion.
A compound (I) in which R1 is an amino group
and/or a compound in which R5 is a phenyl group which
is substituted by an amino can be prepared by the
conversion of a compound (VI), obtained in Step (b), in
which R1 is a nitro group and/or R5 is a phenyl group
which is substituted by a nitro, the other substituents
having the meanings desired. for (I), by catalytic

CA 02206776 1997-06-27
19
hydrogenation, for example in the presence of palladium
on charcoal, or rhodium on alumina or Raney nickel.
The compounds (I) in which the substituents
R6 and/or R~ or the group NR6R7 contain a C1-C4
alkoxycarbonyl group make it possible to obtain, by
hydrolysis of the ester, the compounds (I) in which R6
and/or R~ or the group NR6R~ contain a carboxyl group,
the other substituents of (I) being unchanged.
Furthermore, the compounds in which R6 and/or R~ or
NR6R7 contain a carboxyl group make it possible to
obtain, by a conventional amide coupling reaction, the
compounds ( I ) in which R6 and/or R~ or .the group NR6R~
contain a carbamoyl group which is free or substituted
by one or two C1-CQ alkyls, the other substituents being
identical.
Finally, the compounds (I) in which R6 and/or
R7 or the group NR6R~ contain a carbamoyl group make it
possible to obtain, by a Hofmann rearrangement, the
compounds ( I ) in which R6 and/or R~ or the group NR6R~
contain an amino group, the other substituents being
identical (J. Org. Chem., 1979, 44 (10), 1746).
Thus, according to the present invention, the
process for preparing compounds (I) in which R6 and/or
R~ or the group NR6R~ contain an amino group which is
free or substituted by one or two C1-C4 alkyls can have
two variants:
(i) Step (b) of the process is carried out by
treating the compound (IV) obtained in Step
(a) with a halogenated derivative (V) of
formula Hal' -CH2-CONR6R~ in which R6 and/or R~
or the group NR6R~ contain a precursor group
of the amine, for example a carboxyester, a
carboxyl or a carbamoyl; the cyclization Step
(e) is then carried out and the precursor
group of the amine is then converted into the
amine, for example the carboxyester group of
the compound (I) thus obtained is hydrolyzed

CA 02206776 1997-06-27
into a carboxyl group, which is then
converted into a carbamoyl group and_ then
into an amino group by the Hofmann
rearrangement.
5 (ii) Step (b) is carried out by treating the
compound (IV) obtained in Step (a) with an
hal~~genated derivative (V) of formula Hal'-
CHZCOOR in which R is a benzyl or a tert-
butyl; the ester of the compound (VI)' thus
10 obtained is deprotected by a suitable
treatment, according to Step (C); a coupling
is then carried out with the compound HNR6R~
in which the amino group of R6 and/or R~ is,
if appropriate, protected; the compound (VI)
15 thus obtained is then cyclized according to
- Step (e); and, if appropriate, the compound
(I) in which the amino group is free is
prepared by deprotection of the amine.
The compounds (I) in which the groups R6
20 and/or R~ or the group NR6R7 contain a benzyloxycarbonyl
or alkoxycarbonyl group as_substituent of an amine
group make it possible to obtain the compounds (I) in
which the amine group is free, the other substituents
being identical.
The compounds of formula (VI) , useful as
intermediates for the preparation of compounds (I)
according to the invention, are novel, form part of the
invention and are claimed herein.
The present invention thus relates to the
compounds of formula (6):
(R 1 )n COA'
6
S02
COR2
\1/ N_CH2
I
(CH2)m
RS

CA 02206776 1997-06-27
4
21
in which
A' is NR6R~;
- Rl is a halogen atom, a C1-C4 alkyl, a hydroxyl, a
C1-C4 alkoxy, a benzyloxy group, a cyano group, a
trifluoromethyl group, a nitro group or an amino
group;
- R2 is a C1-C6 alkyl, a C3-C~ cycloalkyl, a CS-C~
cycloalkene or a phenyl which is unsubstituted or
monosubstituted or polysubstituted by C1-C4 alkyl,
a Cl-C4 alkoxy, a halogen, a trifluoromethyl group
or an amino group, or R2 is a nitrophenyl which is
unsubstituted or monosubstituted by a
trifluoromethyl group or monosubstituted or
polysubstituted by a C1-C4 alkyl, a C1-CQ alkoxy or
a halogen:
__-_ J-__~
- R5 is a C1-C4 alkyl; a 1-naphthyl; a 2-naphthyl; a
5-dimethylamino-1-naphthyl; a phenyl which is
unsubstituted or substituted by one or more
substituents selected from a halogen atom, a C1-C4
alkyl, a trifluoromethyl group, an amino group
which is free or substituted by one or two C1-C4
alkyls, a hydroxyl, a C1-C4 alkoxy, a C2-C4
alkenoxy, a C1-CQ alkylthio, a trifluoromethoxy
group, a benzyloxy group, a cyano group, a
carboxyl group, a Cl-C4 alkoxycarbonyl group, a
carbamoyl group which is free or substituted by
one or two C1-CQ alkyls or a C1-C9 alkylamido group,
or RS is a nitrophenyl which is unsubstituted or
monosubstituted by a trifluoromethyl group or a
C2-C4 alkenoxy or mono- or polysubstituted by a
halogen, a C1-C4 alkyl, a C1-C4 alkoxy, a C1-C4
alkylthio, a trifluoromethoxy group or a benzyloxy
group;
- R6 is a C1-C6 alkyl or R6 is similar to R~;
- R7 is a 4-piperidyl group or a 3-azetidinyl group,
the said groups being substituted or unsubstituted

CA 02206776 1997-06-27
22
on the nitrogen by a C1-CQ alkyl, by a
benzyloxycarbonyl or by a C1-C4 alkoxycarbonyl; a
group (CH2)r which is itself substituted by a 2-,
3- or 4-pyridyl group, by a hydroxyl group or by
an amino group which is free or substituted by one
or two C1-CQ alkyls, a carboxyl group, a C1-C4
alkoxycarbonyl group, a benzyloxycarbonyl group or
a carbamoyl group which is free or substituted by
one or two C1-C4 alkyls;
- or R6 and R7 together, with the nitrogen atom to
which they are connected, form a heterocycle
selected from:
~ morpholine,
~ thiomorpholine,
~ thiazolidine or 2,2-dimethylthiazolidine,
unsubstituted or substituted by R8,
~ piperazine, unsubstituted or substituted at
the 4-position by a group R"$,
~ an unsaturated, 5-membered ring containing a
single nitrogen atom and substituted by R$ or
~ a saturated, 3-, 4-, 5-, 6- or 7-membered
ring containing a single nitrogen atom and
substituted by RB and . R9;
- R$ is R' $ or a group (CH2) r which is itself
substituted by a hydroxyl or by an amino which is
free or substituted by one two C1-C4 alkyls;
- R'e is a group (CH2)q which is itself substituted
by a carboxyl group, a C1-C4 alkoxycarbonyl group,
a benzyloxycarbonyl group, a carbamoyl group which
is free or substituted by a hydroxyl or by one or
two C1-CQ alkyls or an aminocarbothioyl group which
is free or substituted by one or two C1-C9 alkyls;
- R"8 is R' 8 or a group (CH2) ZNH2 Which is free or
substituted by one two C1-C~ alkyls;
- R9 is hydrogen, a halogen, a group (CHZ) rORlo, a
group ( CH2 ) rNR11Ri2. a group ( CH2 ) SCONR11R' ii or an
azido group;

CA 02206776 1997-06-27
23
- R1o is hydrogen, a C1-C4 alkyl, a mesyl or a tosyl;
- Rii. R' ii and R12 are each a hydrogen or a C1-C4
alkyl or R11 is hydrogen and R12 is a
benzyloxycarbonyl or a C1-C4 alkoxycarbonyl;
- n is 0, 1 or 2;
- m is 0, 1 or 2;
- q is 0, 1, 2 or 3;
- r is 0, 1, 2 or 3, with the limitation that r is
not zero when R$ and R9 is at the alpha-position
of the intracyclic amide nitrogen;
- s is 0 or 1;
According to another aspect of the invention
claimed in the parent application, the compounds (I) in
which either R7 or the group NR6R~ contains a carboxyl
group are useful for the preparation of analogous
decarboxylated compounds.
According to this aspect, the invention
relates to the use of the compounds of formula (I)'
/ R2
_ OH
(R1) ~ ' \ R3 (I) .
N
SO CONRVIRVII
I 2
~ i H2~m
RS
in which R1, RZ, R3, R5, m and n have the meanings
indicated above for compounds of formula (I)
- R~I is a C1-C6 alkyl,
- R~II is a group (CH2) rC00H with r = 1, 2 or 3,
- or R~I and R~II together, with the nitrogen atom to
which they are connected, constitute a heterocycle
selected from:
~ thiazolidine or 2,2-dimethylthiazolidine,
substituted by a (CH2)qCOOH group,

CA 02206776 1997-06-27
24
~ piperazine substituted at the 4-position by a
(CH2) qC00H group,
~ an unsaturated, 5-membered ring containing a
single nitrogen atom and substituted by a
( CH2 ) qC00H group,
~ a saturated, 3-, 4-, 5-, 6-'or 7-membered
ring containing a single nitrogen atom and
substituted by a (CH2)qC00H group,
with q = 0, 1, 2 or 3
for the preparation of a compound of formula (I)"
having the same configuration around the 2, 3 bond of
the indoline as the starting material
R~
~ OH
(R1~ ~ R3 (I) .:
N~
SO OO~RyIRVII
2
( i H2)m
g
in which
- R1, R2, R3, R5, m and n are as defined above,
- R' ~Z is a C1-C6 alkyl,
- R'~II is a group (CH2)rH,
- or R'~I and R'~II together, with the nitrogen atom
to which they are connected, constitute a
heterocycle selected from:
~ thiazolidine or 2,2-dimethylthiazolidine, '
substituted by a (CHZ) qH group,
~ piperazine substituted at the 4-position by a
( CHZ ) qH group,
~ an unsaturated, 5-membered ring containing a
single nitrogen atom and substituted by a
(CH2)qH group or

CA 02206776 1997-06-27
~ a saturated, 3-, 4-, 5-, 6- or 7-membered
ring containing a single nitrogen atom and
substituted by a (CH2)qH group.
The free-radical decarboxylation reaction is
5 carried out according to D.H.R. Barton et al. in J.
Chem. Soc.; Chem. Commun.; 1984, 1928.
The affinity of the compounds described
herein for the vasopressin receptors was determined in
vitro using the method described in J. Biol. Chem.,
10 1985, 260 (5), 2844-2851. This method consists in
studying the displacement of tritiated vasopressin
bound to the V1 sites of rat liver membranes. The 50o
inhibitory concentrations (ICso) of the compounds
according to the invention for the binding of tritiated
15 vasopressin are low, ranging up to 10-9M.
- Furthermore, the inhibition of the platelet
aggregation induced by vasopressin was measured on a
human platelet rich plasma (human PRP) using the method
described in Thrombosis Res., 1987, 45, 7-16. The
20 compounds according to the invention inhibit the
aggregation induced by 50 to 100 nM concentrations of
vasopressin with low IDSo values (inhibitory doses)
which range up to 10-9M. These results show the
antagonistic activity of the compounds according to the
25 invention towards the V1 receptors.
The affinity of the compounds (I) according
to the invention for the V2 receptors was measured by a
method adapted from P. Crause et al., Molecular and
Cellular Endocrinology, 1982, 28, 529-541.
The compounds described herein of cis
configuration around the 2, 3 bond of the indoline have
a marked selectivity for the V1 receptors.
The affinity of the compounds (I) described
herein for the ocytocin receptors was determined in
vitro by the displacement of tritiated ocytocin bound
to the receptors of a membrane preparation of gestating
she-rat glands. The ICSO values of the compounds

CA 02206776 1997-06-27
26
according to the invention are low, of between 10-SM
and 10-$M.
The compounds are active after administration
by various routes, especially orally.
No sign of toxicity is observed, with these
compounds at the pharmacologically active doses.
Thus the compounds described herein can be
used in the treatment or prevention of various
vasopressin-dependent complaints, especially
cardiovascular complaints such as hypertension, cardiac
insufficiency, thrombosis or coronary vasospasm, in
particular in smokers; complaints of the central
nervous system, for. example cerebral edemas, psychotic
states, appei:ite disorders or memory disorders;
complaints of the renal system, such as renal vasospasm
or necrosis of the renal cortex; and complaints of the
gastric system, for example ulcers or else the syndrome
of inappropriate secretion of antidiuretic hormone
( S IADH ) .
The compounds can also be used as
antiemetics, especially in motion sickness, and as
antiproliferative agents, for example in cancer or
atherosclerosis.
In woman, the compounds can also be used for
the treatment of dysmenorrhea or premature labor.
The invention as claimed in the parent case
further relates to pharmaceutical compositions
containing an effective dose of a compound according to
the invention, or of a~pharmaceutically acceptable
salt, and suitable excipients. Said excipients are
chosen according to the pharmaceutical form and the
desired mode of administration.
In the pharmaceutical compositions for oral,
sublingual, subcutaneous, intramuscular, intravenous,
topical, intratracheal, intranasal, transdermal or
rectal administration, the active principles of formula
I above, or their possible salts, can be administered

CA 02206776 1997-06-27
27
to animals and humans in unit forms of administration,
mixed with conventional pharmaceutical carriers, for
the prophylaxis or treatment of the above disorders or
diseases. Appropriate unit forms of administration
include forms for oral administration, such as tablets,
gelatin capsules, powders, granules and solutions or
suspensions to be taken orally, forms for sublingual,
buccal, intratracheal or intranasal administration,
forms for subcutaneous, intramuscular or intravenous
administration and forms for rectal administration.
For topical application, the compounds according to the
invention can be used in creams, ointments or lotions.
To obtain the desired prophylactic or
therapeutic effect, the dose of active principle can
vary between 0.01 and 50 mg per kg of body weight and
per day.
Each unit dose can contain from 0.5 to 1000
mg, preferably from 1 to 500 mg, of active ingredients
in combination with a pharmaceutical carrier. This
unit dose can be administered 1 to 5 times per day so
as to administer a daily dosage of 0.5 to 5000 mg,
preferably 1 to 2500 mg.
If a solid composition in the form of tablets
is prepared, the main active ingredient is mixed with a
pharmaceutical vehicle such as gelatin, starch,
lactose, magnesium stearate, talc, gum arabic or the
like. The tablets can be coated with sucrose, a
cellulose derivative or other appropriate substances or
they can also be treated so as to have a prolonged or
delayed activity and so as to release a predetermined
amount of active principle continuously.
A preparation in the form of gelatin capsules
is obtained by mixing the active ingredient with a
diluent and pouring the resulting mixture into soft or
hard~gelatin capsules.
A preparation in the form of a syrup or
elixir or for administration in the form of drops can

CA 02206776 1997-06-27
28
contain the active ingredient in combination with a
sweetener, which is preferably calorie-free, and
methylparaben and propylparaben as antiseptics, as well
as with a flavoring and an appropriate color.
Water-dispersible granules or powders can
contain the active ingredient mixed with dispersants or
wetting agents or with suspending agents such as
polyvinyl-pyrrolidone, as well as with sweeteners or
taste correctors.
Rectal administration is effected using
suppositories which are prepared with binders melting
at the rectal temperature, for example cocoa butter or
polyethylene glycols.
Parenteral administration is effected using
aqueous suspensions, isotonic saline solutions or
sterile and injectable solutions which contain
pharmacologically compatible dispersants and/or wetting
agents, for example propylene glycol or butylene
glycol.
The active principle can also be formulated
as microcapsules, if appropriate with one or more
carriers or additives.
Apart from the products of formula I above or
one of the pharmaceutically acceptable salts, the
compositions can contain other active principles which
may be useful in the treatment of the disorders or
diseases indicated above.
Thus the invention claimed in the parent
relates to pharmaceutical compositions containing a
plurality of active principles in association, one of
which is a compound according to the invention.
The following Examples illustrate the
invention as claimed herein and in the parent case.
The compounds are characterized by their
melting point (M. p.°C) (or their boiling point B.p.)
and/or their NMR spectrum recorded at 200 MHz in DMSO,
and/or their optical rotation (aD) measured at 25°C

CA 02206776 1997-06-27
'
29
(except when otherwise indicated).
The measured value of the optical rotation is
dependent on the amount of residual solvent present in
the prepared product.
Except when otherwise indicated, the
designation "cis isomer" or "trans isomer" signifies
that the isolated compound is a mixture of enantiomers,
either of cis configuration or of trans configuration.
The optical purity of the compounds is
studied by high performance liquid chromatography
(HPLC).
EXAMP7~E 1
N-methyl-N-methoxycarbonylmethyl-5-bromo-3-
(2-fluorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-
hydroXy-2-indolinecarboxamide, cis isomer.
(A) Methyl N-bromoacetylsarcosinate.
This compound is prepared according to T.D.
Harris et al. in J. Heterocyclic Chem.,_ 1981, 18, 423.
(B) 5-Bromo-2-(3,4-dimethoxyphenylsulfonamido)-
2'-fluoro-benzophenone.
20 g of 2-amino-5-bromo-2'-fluorobenzophenone
are heated at 85°C for 48 hours in 120 ml of dry
pyridine in the presence of 20 g of 3,4-
dimethoxyphenylsulfonyl chloride. The mixture is
cooled, poured into ice-cold water, the solid is
filtered off, the solid is extracted with AcOEt, the
organic phase is washed with water, a solution of
hydrochloric acid (1N), water and then saline water.
After drying over magnesium sulfate and evaporating the
solvent under vacuum, a solid is obtained which is
recrystallized from DCM/isopropyl ether.
m = 28 g
M.p. - 125-128°C.
(C) 5-Bromo-2-[N-(3,4-dimethoxyphenylsulfon.yl)-N-
(N'-methyl-N'-
(methoxycarbonylmethyl)carbamoylmethyl)]amino-2'-
fluorobenzophenone.

CA 02206776 1997-06-27
3.5 g of the compound prepared in Step B are
dissolved in anhydrous DMF at 0°C under argon. and 250
mg of 80o sodium hydride are added; after 15 minutes,
4.85 g of the compound prepared in Step A are added and
5 the mixture is left stirring at RT for 12 hours. The
reaction mixture is poured into water, the solid is
filtered off and then the solid is dissolved in AcOEt,
the organic phase is washed with water and then with
saline water and the solvent is evaporated under
10 vacuum. The oil obtained is filtered on silica by
eluting with a DCM/AcOEt(85/15; v/v) mixture. It is
recrystallized from a DCM/isopropyl ether/MeOH mixture.
m = 3.2 g
M.p. - 136-137°C.
15 (D) N-methyl-N-methoxycarbonylmethyl-5-bromo-3-
n_ _ __i v ~ i~f n ~t-_i..L_ .~L....,...~ ......'1 F.........1 \ -~-
(2-fluoropnenyl) -1- ~~, ~-umue~mvxy~mmyl5uilvmyl~ -~-
hydroxy-2-indolinecarboxamide, cis isomer.
3.2 g of product obtained in the preceding
step are dissolved in DCM (3 ml), 750 mg of DBU are
20 added and the mixture is left stirring at RT for 24
hours. The reaction mixture is poured onto a silica
column; by eluting with DCM/AcOEt (90/10; v/v), a
product is obtained which is the mixture of the two
isomers (cis and trans) of the expected compound. This
25 product is triturated in a hexane/isopropyl ether
mixture and the solid obtained is filtered. The
filtration liquors are chromatographed on an alumina
column which was pre-equilibrated in a DCM/AcOEt
(70/30; v/v) mixture. The least polar compound is
30 eluted with a DCM/AcOEt (60/40; v/v) mixture and is
then recrystallized from a DCM/hexane/isopropyl ether
mixture.
M.p. - 95°C with evolution of gas.
EXAMPLES 2 AND 3
2-[(4-Benzyloxycarbonyl)-1-
piperazinyl]carbonyl-5-chloro-3-(2-chlorophenyl)-1-
(3,4-dimethoxyphenylsulfonyl)-3-hydroxyindoline, cis

CA 02206776 1997-06-27
31
isomer and trans isomer.
(A) 1-Bromacetyl-4-(benzyloxycarbonyl)piperazine.
A mixture of 22 g of 4-
benzyloxycarbonylpiperazine and 10.1 g of triethylamine
in 200 m1 of ether is cooled to 0°C. 20.2 g of
bromoacetyl bromide in 100 ml of ether are added over
30 minutes and the mixture is left to return to RT.
After 4 hours, the reaction mixture is washed with
water, dried, concentrated and then chromatographed on
silica. The mixture DCM/AcOEt (95/5; v/v) elutes the
expected compound which is recrystallized from
DCM/isopropyl ether.
m = 9 g
M.p. - 100-101°C.
(B) 2',5-Dichloro-2-(3,4-
dimethoxyphenylsulfonamido)benzophenone.
5.6 g of 2-amino-2',5-dichlorobenzophenone
and 5 g of 3,4-dimethoxyphenylsulfonyl chloride are
heated in pyridine at 100°C overnight. The pyridine is
evaporated to dryness, water is added and extraction is
carried out with ethyl acetate containing a small
amount of DCM. After washing more than once with water
and drying over sodium sulfate, the extract is
evaporated under vacuum and 7.7 g of the expected
product are recrystallized in a DCM/AcOEt mixture.
M.p. - 164°C.
(C) 2',5-Dichloro-2-[N-(3,4-
dimethoxyphenylsulfonyl)-N-(4-benzyloxycarbonyl-1-
piperazinylcarbonylmethyl)]amino-benzophenone.
2.3 g of the benzophenone prepared in Step B
are placed in 10 ml of DMF and treated with 200 mg of
80°s sodium hydride in oil. After 30 minutes, 5.3 g of
the compound prepared in Step A are added and the
mixture is stirred for 60 hours at RT. The mixture is
poured into water, the precipitate is filtered, taken
up in DCM, dried and then concentrated and
chromatographed on silica. The DCM/AcOEt (90/10; v/v)

CA 02206776 1997-06-27
32
mixture elutes the expected product which crystallizes
from a DCM/isopropyl ether mixture.
m = 2 g
M.p. - 173-175°C.
(D) 2-[(4-Benzyloxycarbonyl)-1-
piperazinyl]carbonyl-5-chloro-3-(2-chlorophenyl)-1-
(3,4-dimethoxyphenylsulfonyl)-3-hydroxyindoline, cis
isomer and trans isomer.
1 g of the compound obtained in the preceding
step is suspended in 20 ml of methanol and 20 ml of THF
and is treated with 75 mg of sodium methylate. After 2
hours, the mixture is neutralized by the addition of a
small amount of dry ice, is concentrated to dryness and
then taken up in water; the mixture is then extracted
with DCM, the extract is dried and concentrated. The
crude product is chromatographed on alumina, and the
DCM/AcOEt (80/20; v/v) mixture elutes the 2 isomers
successively.
The least polar isomer is recrystallized from
a DCM/hexane mixture. This compound is the cis isomer.
m = 2 62 g
M.p. - 169-179°C~.
The most polar isomer is recrystallized from
the DCM/isopropyl ether mixture.
m = 200 g
M.p. - 209-211°C.
EXAMPLE 4
5-chloro-3-(2-chlorophenyl)-1-(3,4-
dimethoxyphenylsulfonyl)-3-hydroxy-2-(1-
piperazinylcarbonyl)indoline, cis isomer.
200 mg of the cis isomer prepared in the
preceding example are dissolved in 10 ml of ethanol and
5 ml of THF and are hydrogenolyzed at RT in the
presence of 10~ Pd/C. After 30 minutes, the mixture is
filtered on Celite~, the filtration liquors are
concentrated and then chromatographed on silica. The
MeOH/DCM (10/90; v/v) mixture elutes the expected

CA 02206776 1997-06-27
33
product which is recrystallized from a DCM/isopropyl
ether mixture.
m = 110 g
M.p. - 230-233°C.
EXAMPLES 5 AND 6
5-chloro-3-(2-chlorophenyl)=1-(3,4-
dimethoxyphenylsulfonyl)-3-hydroxy-2-
morpholinocarbonylindoline, cis isomer and trans
isomer.
(A) 2',5-Dichloro-2-[N-(3,4-dimethoxyphenyl-
sulfonyl)-N-
(morpholinocarbonylmethyl)]aminobenzophenone.
5 g of 2',5-dichloro-2-(3,4-dimethoxyphenyl-
sulfonamido)benzophenone are treated with 350 mg of 800
sodium hydride in 30 ml of DMF at RT for 20 minutes.
4.5 ~ of morpholinebromoacetamide are added and then
the mixture is stirred at RT for 48 hours. The mixture
is poured into water, the precipitate is filtered, it
is dissolved in DCM, the solution is dried and
concentrated. The product formed is recrystallized
from a DCM/isopropylether mixture. 5.4 g are obtained.
M.p. - 173-176°C.
(B) 5-Chloro-3-(2-chlorophenyl)-1-(3,4-
dimethoxyphenylsulfonyl)-3-hydroxy-2-
morpholinocarbonylindoline, cis isomer.
1 g of the product obtained in the preceding
step is dissolved in the methanol (10 ml) and THF (20
ml) mixture and is treated with 92 mg of sodium
methylate at RT for 1 hour. The mixture is neutralized
with dry ice, the solvents are partly evaporated, the
mixture is taken up in water, extracted with DCM and
the extract is dried, concentrated and chromatographed
on alumina. The DCM/AcOEt (70/30; v/v) mixture elutes
the least polar isomer which is recrystallized from a
DCM/isopropyl ether mixture.
m = 215 mg: cis isomer
M.p. - 260-264°C.

CA 02206776 1997-06-27
34
(C) 5-Chloro-3-(2-chlorophenyl)-1-(3,4-
dimethoxyphenylsulfonyl)-3-hydroxy-2-
morpholinocarbonylindoline, trans isomer.
By the chromatography of the preceding step,
a more polar product is collected by eluting with the
AcOEt/MeOH (90/10); v/v) mixture. After
recrystallizing from a DCM/isopropyl ether mixture,
there is obtained:
m = 513 mg: trans isomer
M.p. - 240-241°C.
L~Y7~lufflTL~ '7
N-Methyl-N-carboxymethyl-5-bromo-3-(2-
fluorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-
hydroxy-2-indoline-carboxamide, cis isomer.
200 mg of the compound prepared in Example 1
are dissolved in 3 ml of MeOH and 1 ml of water
containing 13 mg of sodium hydroxide. After stirring
for 24 hours at RT, one drop of concentrated sodium
hydroxide solution is added to bring the reaction to an
end and then, after 15 minutes, the mixture is
acidified to pH 3 by addition of a potassium
hydrogensulfate solution. Water is added, the mixture
is extracted with AcOEt and the extract is washed with
water and dried over magnesium sulfate and the solvent
is evaporated under vacuum. The product obtained is
recrystallized from DCM/isopropyl ether.
M.p. - 206-208°C.
EXAMPLES 8 AND 9
5-Chloro-3-(2-chlorophenyl)-1-(3,4-
dimethoxyphenylsulfonyl)-3-hydroxy-2-(4-
ethylcarboxylatepiperidinocarbonyl)indoline, cis
isomer, trans isomer.
(A) Ethyl N-bromoacetyl-4-piperidinecarboxylate.
This product is prepared from ethyl 4
piperidine-carboxylate, which is commercially
available.
(B) 2',5-Dichloro-2-[N-(3,4-dimethoxyphenyl-

CA 02206776 1997-06-27
sulfonyl) -N- (4-
ethylcarboxylatepiperidinocarbonylmethyl))aminobenzophe
none.
8 g of 2',5-dichloro-2-(3,4-dimethoxyphenyl-
5 sulfonamido)benzophenone are dissolved in 100 ml of DMF
and then 541 mg of sodium hydride are added. After
stirring for 30 minutes, 9.5 g of the compound of Step
A are added and the mixture is left stirring for 18
hours at RT. The mixture is concentrated under vacuum,
10 taken up in water, extracted with ethyl acetate and the
extract is dried and concentrated. The oil obtained is
chromatographed on silica, eluting with the
AcOEt/DCM/hexane (40/10/50; v/v/v) mixture. The
expected product crystallizes from ether.
15 m = 3.5 g
-M.p. - 128°C.
(C) 5-Chloro-3-(2-chlorophenyl)-1-(3,4-
dimethoxyphenylsulfonyl)-3-hydroxy-2-(4-
ethylcarboxylatepiperidinocarbonyl)indoline, cis
20 isomer, trans isomer.
A mixture containing 3.4 g of the compound
prepared in the preceding step and 869 mg of DBU in 10
ml of chloroform is brought to 60°C for 18 hours. The
reaction mixture is then filtered on an alumina column,
25 eluting with a DCM/AcOEt (90/10; v/v) mixture in order
to obtain the cis isomer.
m = 700 mg
M.p. - 110°C.
Pure ethyl acetate elutes the trans isomer.
30 m = 610 mg -
M.p. - 187°C.
EXAMPLES 10 AND 11
N-methyl-N-(2-pyridylethy)-5-chloro-3-(2
chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3
35 hydroxy-2-indolinecarboxamide, cis isomer, trans
isomer.
(A) N-[2-(2-chlorophenylcarbonyl)-5-

CA 02206776 1997-06-27
36
chlorophenyl]-N-(3,4-dimethoxyphenylsulfonyl)glycine
acid.
(a) 2',5-Dichloro-2-(3,4-dimethoxyphenyl-
sulfonamido)-benzophenone.
This compound is prepared in Example 2-3,
Step B.
(b) 2',5-Dichloro-2-[N-(3,4-dimethoxyphenyl-
sulfonyl)-N-benzyloxycarbonylmethyl]aminobenzophenone.
172 g of the product prepared previously are
dissolved in 800 ml of DCM and cooled to 0°C. 11.7 g of
80o sodium hydride is added progressively under
nitrogen and then, after 30 minutes, 256 g of benzyl
bromoacetate are added and the mixture is left stirring
for 24 hours at RT. The DMF is evaporated, the residue
is taken up in water, extracted with DCM, and the
extract dried and concentrated. The expected product
crystallizes from isopropyl ether and is then
recrystallizes from a DCM/isopropyl ether mixture.
m = 136.5 g
M.p. - 102-104°C.
(c) N- [2- (2-Chlorophenylcarbonyl) -5-
chlorophenyl]-N-(3,4-dimethoxyphenylsulfonyl)glycine
acid.
50 g of the benzyl ester obtained previously
are dissolved in 500 ml of AcOEt and 2.5 g of 5o Pd/C
are added under nitrogen. The solution is vigorously
stirred and a stream of hydrogen is passed in for 5
hours. At the end of the hydrogenation, the product
crystallizes. The mixture is filtered on Celite~, the
cake is washed copiously with hot DCM and then the
organic phase is concentrated. The expected product
crystallizes and is then recrystallized from the
DCM/isopropyl ether mixture.
m = 33.7 g
M.p. - 177-178°C.
(B) 2',5-Dichloro-2-[N-(3,4-dimethoxyphenyl-
..1 t.-..1 \ wt /wTi in _ _n~ v
5ulivmyl~ -iv- y- - (G-pyr1C1y1) ethyl) -N' -

CA 02206776 1997-06-27
37
methyl)carbamoylmethyl]aminobenzophenone.
2 g of the acid prepared in Step A are placed
in 30 ml of DCM and 1.13 g of 2-(2-methylaminoethyl)-
pyridine, then 844 mg of triethylamine and finally 1.92
g of BOP are added and then the mixture is left
stirring for 18 hours at RT. The mixture is taken up
with water, the organic phase is separated, washed with
a sodium carbonate solution, dried and concentrated.
After chromatogrphy on silica, the expected product is
collected by eluting with the DCM/MeOH (95/5; v/v)
mixture.
m = 2 g
M.p. - 150°C.
(C) N-methyl-N-(2-pyridylethy)-5-chloro-3-(2-
chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-
hydroxy-2-indolinecarboxamide.
A mixture containing 1.7 g of the product
obtained in the preceding step and 442 mg of DBU in DCM
is heated at 55°C for 18 hours. The reaction mixture
is chromatographed on alumina. The AcOEt/DCM (40/60;
v/v) mixture elutes the cis isomer:
m = 410 mg
M.p. - 191°C.
Pure AcOEt elutes the trans isomer:
m = 790 mg
M.p. - 154°C.
EXAMPhE 12
2-(4-Carboxypiperidinocarbonyl)-5-chloro-3-
(2-chlorophenyl)-1-(3,'4-dimethoxyphenylsulfony)-3-
hydroxyindoline, cis isomer.
500 mg of the cis isomer prepared in Example
9 are placed in 5 ml of methanol in the presence of 48
mg of sodium hydroxide in 1 ml of water. After
stirring for 18 hours, the mixture is poured into
water, acifified with dilute hydrochloric acid, then
extracted with DCM and the extract dried and
concentrated. The solid obtained is purified by

CA 02206776 1997-06-27
38
chromatography on silica, eluting with the DCM/MeOH
(95/5; v/v) mixture and the product obtained is then
crystallized from a DCM/isopropyl ether mixture.
m = 250 mg
M.p. - 150°C.
EXAMPLES 13 AND 14
N-Methyl-N-(1-methyl-4-piperidyl)-5-chloro-3
(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3
hydroxy-2-indolinecarboxamide, cis isomer and traps
isomer.
(A) 2',5-Dichloro-2-[N-(3,4-dimethoxyphenyl-
sulfonyl)-N-(N'-methyl)-N'-(methyl-4-
piperidyl)carbamoylmethyl)aminobenzophenone.
2 g of the acid prepared in Example 10-11,
Step A in 50 ml of DCM are mixed with 650 mg of 4-
methylamino-1-methylpiperidine in the presence of 1.90
g of BOP. After stirring for 2 hours at RT, the
organic phase is washed with carbonated water, dried
and concentrated. The residue is then chromatographed
on silica, eluting with the DCM/MeOH (90/10; v/v)
mixture. 1.2 g of the expected product are obtained.
M.p. - 165-166°C.
(B) N-Methyl-N-(methyl-4-piperidyl)-5-chloro-3-
(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-
hydroxy-2-indolinecarboxamide, cis isomer and traps
isomer.
650 mg of the product obtained in the
preceding step are treated overnight with 100 mg of
sodium methylate in 5 ml of methanol. Dry ice is
added, the solvent is evaporated, the residue is taken
up in carbonated water, extracted with DCM and the
extract dried and concentrated and then chromatographed
on silica. The methanol/DCM (5/95; v/v) mixture elutes
the 2 isomers successively. Each is then
recrystallized from a DCM/iospropyl ether mixture.
The traps isomer is the least polar under
these conditions,

CA 02206776 1997-06-27
39
m = 205 mg
M.p. - 181°C.
Cis isomer: m = 150 mg
M.p. - 97°C: contains 0.25 M of isopropyl ether.
EXAMPLES 15 AND 16
5-Chloro-3-(2-chlorophenyl)-1-(3,4-
dimethoxyphenylsulfonyl)-3-hydroxy-2-[4-methyl-1-
piperazinylcarbonyl]-indoline, cis isomer and trans
isomer.
(A) 2',5-Dichloro-2-[N-(3,4-dimethoxyphenyl-
sulfonyl)-N-((4-methyl-1-
piperazinyl)carbamoylmethyl))aminobenzophenone.
This compound is obtained by the action of N-
methyl-piperazine on the acid prepared in Example 10-11
Step A.
M.p. - 165-167°C.
(B) 5-Chloro-3-(2-chlorophenyl)-1-(3,4-
dimethoxyphenylsulfonyl)-3-hydroxy-2-[4-methyl-1-
piperazinylcarbonyl]-indoline, cis isomer and trans
isomer.
The compound of the preceding step is
cyclized by proceeding as in Example 12-13. The 2
isomers formed are separated by chromatography on
alumina. The DCM/AcOEt (75/25; v/v) mixture elutes the
least polar product: the cis isomer, which is
recrystallized from a DCM/isopropyl ether mixture.
M.p. - 120°C: contains 0.25 M of isopropyl ether.
The DCM/MeOH mixture elutes the most polar
compound, the trans isomer which is then recrystallized
from methanol.
M.p. - 189°C.
EXAMPLES 17 AND 18
N-Isopropyl-N-methoxycarbonylethyl-5-chloro
3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-
hydroxy-2-indolinecarboxamide, cis isomer and trans
isomer.
(A) N-Isopropyl-N-

CA 02206776 1997-06-27
(methoxycarbonylethyl)bromoacetamide.
90 g of isopropylamine are added dropwise to 130 g
of a solution, cooled to -10°C, of methyl acrylate in
300 ml of methanol. After 72 hours at RT, the mixture
5 is evaporated and the residue is then distilled. The
oil obtained (168.3 g) is methyl 3-(N-isopropyl)-
aminopropionate.
B.p. - 73-78°C at 15 mm Hg.
29 g of the compound obtained in 100 ml DCM
10 are mixed with 20.2 g of bromoacetyl bromide in 100 ml
of DCM at 0°C. After 12 hours at RT, the solvent is
evaporated, the residue is taken up in water, extracted
with ethyl acetate and the extract dried and
concentrated. The oil obtained is used as it is in the
15 following step.
/ D \ '7 / C n, .-.L. 1 _ n rw, i ~ w
c. , ~-L11:111Vro-~- ~1v- ( 3, 4-dimethoxyphenyi-
sulfonyl)-N-(N'-isopropyl-N'-
methoxycarbonylmethyl)carbamoylmethyl]-
aminobenzophenone.
20 This compound is obtained by following the
usual procedure, by reacting the product prepared in
Step A with 2',5-dichloro-2-(3,4-dimethoxyphenyl-
sulfonamido)-benzophenone in the presence of sodium
hydride.
25 M.p. - 135-137°C (recrystallization: DCM/isopropyl
ether) .
(C) N-Isopropyl-N-methoxycarbonylethyl-5-chloro-
3-(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-
hydroxy-2-indolinecarboxamide, cis isomer and trans
30 isomer.
This product is obtained by cyclizing the
compound prepared in Step B, in the presence of DBU.
The cis isomer is separated by chromatography on
alumina, eluting with a DCM/AcOEt (90/10; v/v) mixture.
35 The product is then crystallized from an AcOEt/hexane
mixture.
M.p. - 153-155°C.

CA 02206776 1997-06-27
41
The traps isomer is obtained by eluting the
alumina column with ethyl acetate. The product is then
recrystallized from a methanol/isopropyl ether mixture.
M.p. - 182-185°C.
EXAMPLES 19 AND 20
N-Methyl-N-methoxycarbonylmethyl-5-chloro-3-
(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-
hydroxy-2-indolinecarboxamide, cis isomer and traps
isomer.
The 2 isomers of this compound are prepared
according to the procedure described in Example 1.
They are separated by chromatography on alumina. The
DCM/AcOEt (80/20; v/v) mixture elutes the cis isomer.
This crystallizes from a DCM/isopropyl ether mixture in
the form of a white powder containing 0.25 mole of
isoprophy ether. It is converted to a foam by heating
in vacuum.
The NMR spectrum of the cis isomer (Example
19) is given in Figure 1.
The traps isomer is eluted with pure AcOEt.
It is recrystallized from DCM/isopropyl ether.
M.p. - 176-178°C.
The NMR spectrum of the traps isomer (Example
20) is given in Figure 2.
EXAMPLES 21 AND 22
N-Methyl-N-carboxymethyl-5-chloro-3-(2-
chlorophenyl,)-1-(3,4-dimethoxyphenylsulfonyl)-3-
hydroxy-2-indolinecarboxamide, cis isomer and traps
isomer.
These compounds are each,prepared from the
compounds described in Examples 19 and 20 according to
the procedure described in Example 8.
Cis isomer: M.p. - 220-222°C after recrystallizing
from a DCM/isopropyl ether/MeOH mixture. .
Traps isomer: M.p. - 222-225°C after
recrystallizing from a DCM/isopropyl ether mixture.
~~rn~roT.~ a ~ a arn,

CA 02206776 1997-06-27
42
N-Methyl-N-carbamoylmethyl-5-chloro-3-(2-
chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-
hydroxy-2-indolinecarboxamide, cis isomer and trans
isomer.
Each isomer is obtained from the
corresponding isomer of the acid prepared in Example
21-22.
605 mg of the trans isomer of the acid
obtained in the preceding example are dissolved in 10
ml of DCM, and 435 mg of BOP and 260,mg of DIPEA are
added. After 5 minutes at RT, 6 ml of 20% aqueous
ammonia are added with vigorous stirring and the
mixture is left stirring for 4 hours. A sodium
carbonate solution is added and the mixture is then
extracted with DCM. The organic phase is washed
successively with water, a sodium hydrogensulfate
solution, and water and is then dried over magnesium
sulfate. After evaporating, the residue is
chromatographed on silica gel and is eluted with an
AcOEt/MeOH (95/5; v/v) mixture. The product obtained
is crystallized twice from a DCM/EtOH mixture at 0°C.
M.p. - 236°C.
The NMR spectrum of the trans isomer (Example
23) is given in Figure 3.
Using the same procedure, the cis isomer is
prepared.
The expected product crystallizes from
DCM/isopropyl ether. The micronized compound, dried in
vacuum at 70°C for 8 hours, contains 0.25 mole of
isopropyl ether.
The NMR spectrum of the cis isomer (Example
24) is given in Figure 4.
EXAMPLES 25 AND 26
5-Chloro-3-(2-chlorophenyl)-1-(3,4-
dimethoxyphenylsulfonyl)-3-hydroxy-1-(4-hydroxy-1-
piperidyl)carbonylindoline, trans isomer.
This compound is prepared from N-[2-(2-

CA 02206776 1997-06-27
43
chlorophenylcarbonyl)-5-chlorophenyl]-N-(3,4-
dimethoxyphenylsulfonyl)glycine acid described in
Example 11-12, Step A.
The process is then carried out as in Example
11-12 for the addition of 4-hydroxypiperidine, in the
presence of BOP and triethylamine. The product
obtained is then cyclized according to the usual method
in the presence of DBU. The 2 isomers are separated by
chromatography on alumina. The DCM/MeOH (99/l; v/v)
mixture elutes the cis isomer.
The product crystallizes from a
DCM/hexane/MeOH mixture and the solid obtained is then
triturated in DCM/hexane to provide an amorphous
powder.
The cis isomer is characterized by its NMR
spectrum at 388°K.
1-1.8 ppm:m:4H:CH2 at positions 3 and 5 of the
piperidine
2.8-3.65 ppm:m:5H:CHz at positions 2 and 6 of the
piperidine and CH at position 4
3.75 ppm:2s:6H:20CH3
4.15 ppm:d:lH:OH on piperidine
5.45 ppm:s:lH:CH (indoline)
6.1 ppm:s:lH:OH indoline
6.8-7.6 ppm:m:lOH:H aromatic
DMS0:2.4 ppm
DOH:2.75 ppm
The DCM/MeOh (97/3; v/v) mixture elutes the
trans isomer which is recrystallized from DCM/isopropyl
ether.
M.p. - 232-234°C.
SYNTHESES in the (L)-Proline series: Examples
27, 28, 29 and 30.
EXAMPLES 27 AND 27a
5-Chloro-3-(2-chlorophenyl)-1-(3,4-
dimethoxyphenylsulfonyl)-3-hydroxy-2-[(2S)-(2-
methoxycarbonyl)pyrrolidinocarbonyl]indoline, (cis

CA 02206776 1997-06-27
44
isomers: 2 compounds).
(A) Methyl (L)-N-(bromoacetyl)prolinate.
20 g of triethylamine and 20 g of bromoacetyl
bromide in 30 ml of DCM are added simultaneously to a
solution of 16.7 g of methyl (L)-prolinate
hydrochloride in 20 ml of DCM while maintaining the
temperature at -5°C and the mixture is then stirred at
RT for 24 hours. Water is added, and the mixture is
washed with a solution of KHS04, with water, with a
sodium bicarbonate solution and with water and is then
dried over magnesium sulfate. After evaporating, an
oil is obtained which is dried under vacuum. This oil,
pure by TLC, is used as it is in the following step.
(B) 2',5-Dichloro-2-[N-(3,4-
dimethoxyphenylsulfonyl)-N-((2S)-(2-
methoxycarbonyl)pyrrolidinocarbonylmethyl)]-
aminobenzophenone.
4.66 g of 2',5-dichloro-2-(3,4-
dimethoxyphenylsulfonamido)benzophenone are dissolved
in 40 ml of anhydrous DMF under argon, at 0°C, 340 mg
of 80°s sodium hydride are added and then, after 30
minutes, 6.5 g of the compound obtained in Step A.
After 4 days at RT, the mixture is poured into water,
extracted with AcOEt, the extract washed with water,
with saline water and then dried over magnesium sulfate
. and evaporated under vacuum. A solid containinq a
small amount of the starting brominated derivative is
eluted with a DCM/AcOEt (85/15; v/v) mixture by
chromatography on silica gel. A sample is
recrystallized from DCM/isopropyl ether.
m = 1.2 mg
M.p. - 141-142°C.
aD2s - -43.7°(C = 1; MeOH/THF: 8/2; v/v)
Analysis Calculated C:54.81 H:4.44 N:4.41
Found 54.40 4.54 4.55
(C) 5-Chloro-3-(2-chlorophenyl)-1-(3,4-
dimethoxyphenylsulfonyl)-3-hydroxy-2-[(2S)-(2-

CA 02206776 1997-06-27
methoxycarbonyl)pyrrolidinocarbonyl]indoline, (cis
isomerism).
1.1 g of the compound obtained in the
preceding step are heated in 4 ml of methylene chloride
5 for 24 hours with one equivalent of DBU. HPLC analysis
of an aliquot shows the existence of the expected 4
isomers. After 24 hours, the reaction mixture is
poured onto an alumina column, pre-equilibrated in the
DCM/AcOEt (90/10; v/v) mixture and is eluted with the
10 DCM/AcOEt (90/10 v/v to 70/30 v/v) mixture. 510 mg
of a mixture of the 2 least polar compounds are
obtained in the ratio 4/1 (measured by HPLC).
1°) Two successive crystallizations from
DCM/isopropyl ether while cold provide the major
15 compound.
m = 180 mg
ccD2s - -247° (C = 0. 4; chloroform)
M.p. - 187-190°C.
2°) The crystallization mother liquors of the
20 preceding compound are chromatographed on alumina by
eluting with DCM/AcOEt (85/15 v/v). The preceding
compound is thus separated from the second, the latter
is dissolved in the minimum amount of DCM and is then
precipitated by addition of the minimum amount of
25 hexane.
aDZS - +136° (C = 0 .24; chloroform)
EXAMPLE 2g
2-((2S)-2-Carboxypyrrolidinocarbonyl)-5-
chloro-3-(2-chlorophenyl)-1-(3,4-
30 dimethoxyphenylsulfonyl)-3-hydroxyindoline, cis isomer.
430 mg of the compound prepared in Example 27
are dissolved in 6 ml of methanol, 41 mg of sodium
hydroxide in 1 ml of water are added and the mixture is
stirred for 24 hours at RT. The mixture is acidified
35 to pH 3 with a few drops of a potassium hydrogensulfate
solution and is extracted with ethyl acetate. The
extract is washed with water and is then dried over

CA 02206776 1997-06-27
46
magnesium sulfate. Chromatography is carried out on a
silica column prepared in a DCM/pentane (80/20; v/v)
mixture.. The unreacted ester elutes the expected acid
which is then recrystallized from DCM/isopropyl ether.
M.p. - 232-234°C..
aD2s - -254° (C = 0. 3; chloroform)
EXAMPLES 29 AND 29a
2-((2S)-2-Carbamoylpyrrolidinocarbonyl)-5-
chloro-3-(2-chlorophenyl)-1-(3,4-
dimethoxyphenylsulfonyl)-3-hydroxyindoline, (cis
isomers: compounds).
230 mg of the compound prepared in Example 28
are dissolved in 5 ml of DCM, 50 mg of DIPEA and then
165 mg of BOP are added and the mixture is left for 5
minutes at RT. The mixture is cooled in an ice bath
and a stream of gaseous ammonia is then bubbled through
for 1 minute and, after 15 minutes, for a further 1
minute. Water and then a large volume of ethyl acetate
are added in order to obtain two phases. The organic
solution is washed with a sodium carbonate solution,
water, a potassium hydrogensulfate solution, water and
then saline water. After drying, the residue is
chromatographed on silica by eluting with a DCM/MeOH
(93/7; v/v) mixture. The product obtained is
tribturated in a DCM/isopropyl ether/hexane mixture.
It contains 1/3 mole of isopropyl ether.
aD2s - -189°(C = 0.23; chloroform).
The compound of Example 29 can be prepared
according to another procedure.
(A) 2',5-Dichloro-2-[N-(3,4- .
dimethoxyphenylsulfonyl)-N-((2S-2-
carbamoylpyrrolidinocarbonylmethyl)]aminobenzophenone.
33.9 g of the acid prepared in Example 10-11,
Step A are dissolved in 300 ml of chloroform. 15 g of
thionyl chloride are added and the mixture is brought
to reflux for 1 hour and a half. The mixture is
evaporated to dryness, the residue is then taken up in

CA 02206776 1997-06-27
47
DCM and evaporated again. The mixture is dissolved in
300 ml of DCM, brought to 0°C and 10.5 g of (L)-
prolinamide hydrochloride are added, and then 18 g of
DIPEA in 20 ml of DCM are slowly added without allowing
the temperature of the reaction mixture to exceed 3°C.
After one night at RT, the reaction mixture
is washed with sodium bicarbonate (twice) and then with
potassium hydrogensulfate (twice); the reaction mixture
is dried and concentrated. The crude product obtained
is dissolved in the minimum amount of DCM and added
dropwise to isopropyl ether (1.2 1) with stirring.
After stirring for 2 hours, the precipitate obtained is
filtered and then dried under vacuum for 6 hours at
60°C. 42 g are collected.
acD25 = -40. 8° (C = 1. 007; chloroform)
(B) 2-((2S)-2-Carbamoylpyrrolidinocarbonyl)-5-
chloro-3-(2-chlorophenyl)-1-(3,4-
dimethoxyphenylsulfonyl)-3-hydroxyindoline, (cis
isomers: 2 compounds).
5 g of the product prepared in the preceding
step are dissolved in 50 ml of methanol. The,solution
is cooled to -10°C; 1.35 g of DBU is added and the
mixture is maintained for 60 hours at -10°C. A
compound crystallizes; it is filtered (cis compound 1).
The crystallization liquors are neutralized with KHS04
and the mixture is evaporated to dryness. It is taken
up in water, extracted twice with DCM, and the extracts
are dried and concentrated. The crude product obtained
is chromatographed on silica by eluting with an
AcOEt/DCM (28/72; v/v) mixture. A mixture is collected
which is dissolved in the minimum amount of methanol
while hot; the insoluble material is filtered off, the
liquors are then placed overnight at -4°C and the cis
compound 2 crystallizes.
m = 1.25 g
ocp 5 = -196° (C = 0 . 351; chloroform)
The analysis of the NMR spectrum shows the

CA 02206776 1997-06-27
48
presence of one mole of MeOH per mole of product. The
recrystallization of the product from ethanol makes it
possible to remove the solvent in the crystals.
M.p. - 154-162°C
aDas - _204°(C = 0.3; chloroform)
aDZS - -131°(C = 0.27; chloroform/methanol: 8/2:
v/v)
This compound is identical, the solvent
excepted, to that prepared by the first procedure of
the present example.
The compound which crystallized in Step (B)
above, called cis compound 1, is recrystallized from
methanol.
M.p. - 190°C
aD = +115°(C = 0.3; chloroform)
EXAMPLE 30
5-Chloro-3-(2-chlorophenyl)-1-(3,4-
dimethoxyphenylsulfonyl)-3-hydroxy-2-[_(2S)-2-
(hydroxymethyl)pyrrolidinocarbonylJindoline, cis
isomers.
(A) 2',5-Dichloro-2-[N-(3,4-
dimethoxyphenylsulfonyl)-N-(2-
(hydroxymethyl)pyrrolidinocarbonylmethyl)]aminobenzophe
none.
This compound is obtained by reacting (L)-
prolinol with the acid prepared in Example 10-11, Step
A, by following the usual procedure.
(B) 5-Chloro-3-(2-chlorophenyl)-1-(3,4-
dimethoxyphenylsulfonyl)-3-hydroxy-2-[(2S)-2-
(hydroxymethyl)pyrrolidinocarbonyl]indoline, cis
isomer.
1.5 g of the compound of the preceding step
is cyclized in the presence of 38.0 mg of DBU in 2 ml of
DCM. After 3 days at RT, 1 ml of DCM is added and the
mixture is then heated at 40°C overnight. The
formation of 3 major compounds is observed by TLC on ,
silica (eluent AcOEt).

CA 02206776 1997-06-27
F a
49
The least polar fraction is eluted by
chromatography on silica using DCM/AcOEt (60/40 to
80/20;~v/v). A chromatography~_on alumina is then
carried out by eluting w~.th-.DCM/MeOH (99/l; v/v). The
fraction obtained_i.s~,.homogeneous by TLC. The product
is recrysta~.l~,zcd three times from DCM/isopropyl ether.
The expected product is obtained with an HPLC purity
greater than 99%.
m = 155 mg
M.p. - 194-197°C
aD2s = -195° (C = 0. 2; chloroform)
SYNTHESES in the (D)-Proline series: Example
31.
EXAMPhE 31
5-Chloro-3-(2-chlorophenyl)-1-(3,4-
dimethoxyphenylsulfonyl)-3-hydroxy-2-[(2R)-2-
(methoxycarbonyl)pyrrolidinocarbonyl]indoline, cis
isomer.
(A) 2',~-Dichloro-2-[N-(3,4-
dimethoxyphenylsulfonyl)-N-((2R)-2-
(methoxycarbonyl)pyrrolidinocarbonylmethyl)]-
aminobenzophenone.
This compound is obtained from the acid
prepared in Example 10-11, Step A (3 g) to which are
added 1.2 g of methyl (D)-prolinate and 2.8 g of BOP in
10 ml of DCM in the presence of 1.15 g of
triethylamine. The mixture is left for 1 hour at RT
and is then diluted with DCM, the organic phase is
washed with sodium carbonate and with potassium
hydrogensulfate, dried and concentrated. The crude
product is chromatographed on silica, eluting with a
DCM/AcOEt (95/5; v/v) mixture. The product obtained is
then recrystallized from a DCM/isopropyl ether mixture.
M.p. - 140-141°C
aD2s - +28 . 5° (C = 0. 27; chloroform)
(B) 5-Chloro-3-(2-chlorophenyl)-1-(3,4-
dimethoxyphenylsulfonyl)-3-hydroxy-2-[(2R)-2-

CA 02206776 1997-06-27
(methoxycarbonyl)pyrrolidinocarbonyl]indoline, cis
isomer.
1.5 g of the preceding compound is brought to
reflux overnight in 5 ml of DCM in the presence of 360
5 mg of DBU. The mixture is chromatographed on alumina.
The mixture DCM/AcOEt (95/5; v/v) elutes the least
polar fraction (m = 300 mg) which is recrystallized
twice in a DCM/isopropyl ether mixture.
M.p. - 186-188°C
10 aD2s = +245° (C = 0. 4; chloroform)
This compound is the enantiomer obtained from
(D)-proline of that described in Example 27.
EXAMPLES 32 AND 32~
N-Methyl-N-methoxycarbonylmethyl-5-chloro-3-
15 (2-chlorophenyl)-1-(4-ethoxyphenylsulfonyl)-3-hydroxy-
2-indolinecarboxamide. trans isomer anc; c;s ;~nmPr_
(A) 2',5-Dichloro-2-[N-(4-ethoxyphenylsulfonyl)-
N-(N'-methyl-N'-
(methoxycarbonylmethyl)carbamoylmethyl]amino-
20 benzophenone.
5.7 g of 2',5-dichloro-2-(4-
ethoxyphenylsulfonamido)-benzophenone are dissolved,
under argon, in 40 ml of DMF and 400 mg of 80°s sodium
hydride are added at 0°C; after 15 minutes, 4.3 g of
25 methyl N-(bromoacetyl)sarcosinate are added. After 48
hours, the expected product is extracted in the usual
way and is then purified by chromatography on silica by
eluting with DCM/AcOEt (90/10; v/v) and recrystallizing
in a DCM/isopropyl ether mixture.
30 M.p. - 158-160°C
(B) N-Methyl-N-methoxycarbonylmethyl-5-chloro-3-
(2-chlorophenyl)-1-(4-ethoxyphenylsulfonyl)-3-hydroxy-
2-indolinecarboxamide, trans isomer.
1 g of the compound obtained in the preceding
35 step is dissolved in 4 ml of DCM and treated for 90
minutes at RT with 312 mg of TBD. A solution of
potassium hydrogen-sulfate is added, the DCM is

CA 02206776 1997-06-27
r
51
evaporated under vacuum, the mixture is extracted with
AcOEt and the extract is washed and dried over
magnesium sulfate. The expected product is obtained by
chromatography on silica gel by eluting with DCM/AcOEt
(90/10; v/v).
m = 590 mg
M.p. - 168-171°C after recrystallizing from
DCM/hexane.
(C) N-Methyl-N-methoxycarbonylmethyl-5-chloro-3
(2-chlorophenyl)-1-(4-ethoxyphenylsulfonyl)-3-hydroxy
2-indolinecarboxamide, cis isomer.
2.96 g of the compound obtained in Step A are
suspended in 20 ml of methanol and 10 ml of THF; 100 mg
of sodium methylate are added and the mixture is then
left for 7 hours in the refrigeratai~~'' Mater is added,
the mixture neutralized with a nnta~c; "m h~mrnrrAn
___-__--__~ ..-___ - r__.__.......,.... ._1...~..y~...
sulfate solution and a part of the methanol is
evaporated under vacuum. After extracting with AcOEt,
the residue is chromatographed on alumina and is then
eluted with a DCM/AcOEt (80/20 v/v) mixture. 850 mg
of the expected product are obtained which are
recrystallized from ~a,DCM/is~propyl ether mixture.
The NMR spectrum is given imFigure 6.
By using methods similar to those described
above, intermediate compounds (VI) for the synthesis of
compounds (I) according to the invention were prepared.
The compounds (VI) prepared are described in
Table 1 below.
The compounds (I) prepared are described in
Table 2 below.
R~2
.
R O
R
~ N-CH2-CONS
S02 R7
R, i
5

CA 02206776 1997-06-27
52
Table 1
R'i R'S R'z -~~R6 .p. (C) or IR
Solvent
Br- 3,4-CH30 F- ~H3 82-83
-N-CHZC02CH2C6H5DCM/isopropyl
ether
C1- 3,4-CH30 C1- CHg ~ 164-166
-N-CH2CH2C02CH3 DCM/isopropyl
ether
C1- 3,4-CH30 C1- CHg ~ 128
-N-CH2CH2N-Et DCM/isopropyl
ether
C1- 3,4-CH30 C1- ~t 105
' ~
-N-CH2CHZC02CH3 DCM/isapropyl
ether
C1- 2,4-CH30'~ Cl- ~ 142-143
.N~ -C02CH2C6H5
MeOH
Ez
CH30- 3,4-CH3 C1- ~ IR (1)
-N-CH2CHZCOZCH3
Cl- 3,4-CH30 Cl- '~~Pearyl g5
-N-CH2CHZC02CH3 Isopropyl ether/DCM
Br- 3,4-CH30 C1- -N-CH2CHZCOZCH3 IR (2) .-
C1- 3,4-CH30 C1- ~ 199
-N S
uCMjisopropyl
ether
'
C1- 3,4-CH30 C1- pr 135
i
N-CH2COZCH3 Isopropyl ether/
DCM/AcOH
cl- 3,4-CH30 C1- ~ 113
i
N-CH2CH2-COZCH3 DCM/isopropyl
ether

CA 02206776 1997-06-27
53
C1- [ 3,4-CH30 C1-
160
.N-CHZ-C02CH3
isopropyl ether
C1- 3,4-CH30 C1- N~ ~'H-C02-~Bu
~ ~ 197-198
i
C1- 3,4-CH30 C1- -N~ ~ (3)
~ C02CH2C~H5
IR (1) (DCM) 1740 cm 1 fine
1680 cm 1 broad
IR (2) (DCM) 1735 cm 1 fine
1660-1680 cm 1 split
(3) This compound is characterized by its optical
rotation:
aDZS - _36.g~(C = 0.44; chloroform)
Table 2
R~2
R~I ~~
~N~C ~R6
O N~
S02 . R
7
R' y
5~
For each compound of formula (I) which has
the substituents R' 1, R' s, R' z and NR6R~ of the table
below, the cis isomer is shown and then the trans.
isomer, except when otherwise indicated.

CA 02206776 1997-06-27
54
ExampleR'1 R'S R'Z
j R6
M.p.
(C)
or Id2~
~
Y
Solvent
7 j
33 Br- 3,4-CH~OF- I 87-95
I
CH3
34 -N-CH~CO~CH,C6H5 ;
i
35 . 100-103
36~ C1- 3,4-CH30C1- ~H3 154-157
N-CH2CH2CO,CHj
DCM/isapropyl~ether
j
37 cis C1- 3,4-CH301C1- CH3 . 140-144
-N-CH2CH2C0'H DCM/isopropyl ether
38 C1- 3,4-CH30C1- I CH3 ~ 222-225
mixture ~ -N-CH2CH2.Y-F.cDCM/isopropyl ether
39 C1- 3,4-CH30C1- Et
40 -N-CH2CH~C02CH3
2 41 C1- 3 , 4-CH30C1- Et 166
0
cis
-Y-CH2CH2C02H DCM/isopropyl ether
42 119
~ /CH3
43 CI- 3,4-CH30C1- -N~N~ AcOEt/isopropylecher
CH
228
MeOH
44 C1- 3,4-CH30C1- ~H2C6K5 179
I
cis rCH
-N-CH~CH2V.
3
~ CH DC'~/isopropyl
~ ether
45 109
C1- 3,4-CH~OC1- - V -CH2C02Et DCM/isopropyl ether
46
196
DCM/isopropyl ether
47 ~ i
j ~ ~
! 134
( iPr)
ZO
48 CI- 2 , 4-CH30
~ CI-
- ~YCO~CH,C5H5
~ I95
-
DCM/isopropyl
ether

CA 02206776 1997-06-27
49 C1- 3,4-CH C1-~ ~ 23b
30
i
cis -N-CH2CHZCONH2
~ isopropyl ether
'
5 50 ~ 154
51 CH3 3,4-CH3 C1-~ 'isopropyl ether
-N-CH2CHZC02CH3 87
isopropyl ether
10 52 C1- 2,4-CH30C1-/~ 194
-N NH
CiS
V MeOH/isopropyl
ether
53 C1- 3,4-CH30C1-~P~nryl 195
cis -N-CHZCHZC02CH3 isopropyl ether/DCM
15
54 138-140
55 Br- 2,4-CH30C1-~ isopropyl ether
-N-CH2CH2COZCH3 140
isopropyl ether
20
i 5b 242-245
57 C1 N ~
1 - 3,4-CH30C1-_ DCM/isopropyl
S ether
225
MeOH/isopropyl
ether
25'
C1- 2,4-CH30C1- 228
58 -N~N(CH3)2 MeOH/isopropyl
~ ether
/
i ,~ _
58 221
a
i
DCM/MeOH
30
'
i 131-134
i
59 C1- 3,4-CH30C1-~ DCM/isopropyl
' ether/
-N-CH2CH=CH=C02CH3
59a
hexane
121
35
DCM/ether/hexane

CA 02206776 1997-06-27
56
I 162-166
I
60 C1- 3 4-CH C1- iBu DCM iso o t
0
3 pr pyl a her
61 N-CH2CHZC02CH3 130
I
DCM/isopropyl
ether/
hexane
62 C1- 3,4-CH30C1- pt 176 ;
I
63 -N-CHZC02CH3 isopropyl ether/DCM
NMR
64 C1- 3,4-CH30C1- 148
isopropyl ether/DCM
65 -N-CH2CH2C02CH3 122
isopropyl ether/DCM
66 C1- 3 , 4-CH30C1- ~ PTMMR
67 N-CH2C02CH3 168
isopropyl ether
68 C1- 3,4-CH30C1- ~Bu 179-182
cis N-(CH2)ZC02H DCM/isopropyl
ether
69 C1- 3,4-CH30Cl- ~ 139
cis
N-CHZC02H DCM/isopropyl
ether
70 C1- 3,4-CH30C1- ~ 130
N-CH CO H
cis 2 2 isopropyl ether
3 71 C1- 3,4-CH30C1- ~ ~ 136
0
cis N-(CH2)3C02H DCM/isopropyl
ether]
72 C1- 3,4-CH30C1- Fit 135 I
cis N-CH2-CONH2 DCM/isopropyl
ether'

CA 02206776 1997-06-27
57
73 C1- 3,4-CH30 C1-~ 197
) Me0H/isopropyl
C(CH ether
I
NHCO
1
3
3
N
Z
74 ~ 211
MeOH
'
75 C1- 3,4-CH30 C1-N~NH
cis
76 C1- 3,4-CH30 C1- Fumarate
cis N~NH2 152-156
DCM/isopropyl
ether
76a C1- 3,4-CH30 C1- 137
- N\ I isopropyl ether/MeOH/
C02CH2C6H5
76b hexane
H
183-185
hexane
- Example 34
Analysis: calculated C:55.54 H:4.24 N:3.93
found 55.72 4.57 3.83
NMR spectra at 200 MHz (DMSO: 2.5 ppm)
- Example 34: Figure 5
- Example 38
0.7-1.1 ppm:m:6H:2CH3(Et)
2-4 ppm:m:17H:2CH2(Et), 2CH2-N, N- CH3, 20CH3
5.2-5.7 ppm:3s:lH:H (indoline)
6.2-8.2 ppm:m:llH:OH + aromatics
- Example 39
0.3-1.2 ppm:m:3H:CH3(Et)
1. 5-4 . 3 ppm: m: 15H : CH2-C0, CH2 CH2-N, 20CH3, C02CH3
( Et ) ,
5.2-5.6 ppm:3s:lH:H (indoline)
6.2-8.2 ppm:m:llH:OH + aromatics
- Example 40
0.8-1.1 ppm:m:3H:CH3(Et)
2.2-3. 9 ppm:m: 15H:CHZCO, CHZ (Et) CH2N, C02CH3, 20CH3
,
5.3-5.7 ppm:2s:lH:H (indoline)

CA 02206776 1997-06-27
r
58
6.6-8.2 ppm:m:llH:OH + aromatics
- Example 63
0 . 4-1 ppm: split t : 3H : CH2-CH2-CH3
ppm: m: 2H: CHZ-CH2-CH3
5 2.5-4.4 ppm:m:l3H:CH2-CH2-CH3, NCHZCOOCH3, 20CH3
5.2-5.8 ppm: bs:lH:H (indoline)
6.5-8.3 ppm:m:llH:OH + aromatics
- Example 66
0 to 1.5 ppm:m:3H:CH2-CH3
2.3-5.8 ppm:m:l4H:CH2-CH3, NCH2COOCH3, 20CH3, H
(indoline)
6.1-8.3 ppm:m:llH:OH + aromatics
- Example 75
1.95 ppm:bs:2H:NHz
2.7 to 5.3 ppm:m:12H:20CH3, 2NCHz, H(indoline), C_HN_HZ
6 to 8.3 ppm:m:llH:OH + aromatics
- Example 76a
acD2s - +102° (C = 0 . 35; chloroform)
- Example 76b
aD25 - -158° (C = 0. 2; chloroform)
Some compounds according to the invention
described in Table 2 are useful in the preparation of
other compounds according to the invention. For
example, compound 41 was obtained from compound 39 by
treatment in basic medium in methanol MeOH/H20.
Compound 49 was prepared from compound 41 by treatment
with aqueous ammonia in the presence of DIPEA and BOP.
EXAMPLE 77
N-Ethyl-N-(2-aminoethyl)-5-chloro-3-(2-
chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-
hydroxy-2-indoline-carboxamide, (cis isomer). '
500 mg of compound 49 are dissolved in 10 ml
of acetonitrile and 10 ml of water and 252 mg of
pyridine and 380 mg of bis
(trifluoroacetoxy)iodobenzene are added. After
stirring for 2 hours, the mixture is taken up in a
solution of hydrochloric acid, extracted with ether,

CA 02206776 1997-06-27
r r
59
alkalized with dilute sodium hydroxide solution,
extracted with DCM and the extract is dried and
concentrated. An oil is obtained and the expected
product then crystallizes from ether.
m = 150 mg
M.p. - 164°C
EXAMPLE 78
N-Ethyl-N-[(1S)-1-(ethoxycarbonyl)ethyl]-5-
chloro-3-(2-chlorophenyl)-1-(3,4-
dimethoxyphenylsulfonyl)-3-hydroxy-2-
indolinecarboxamide, (cis isomer).
(A) N-[2-(2-Chlorophenylcarbonyl)-5-
chlorophenylJ-N-(3,4-dimethoxyphenylsulfonyl)glycine
acid chloride.
A mixture containing 11 g of the acid
prepared in Example 10-11, Step (A) and 5 g of thinoyl
chloride in 10 ml of chloroform is heated for 1 hour at
60°C. The mixture is left to return to RT,
concentrated under vacuum and the residue taken up in
DCM (twice). A yellow oil is obtained which is used as
it is in the following step.
IR: 1800 cm 1 (C=O)
(B) 2',5-Dichloro-2-[N-(3,4-
dimethoxyphenylsulfonyl)-N-(N'-ethyl-N'-((1S)-1-
(ethoxycarbonylethyl)ethoxycarbamoylmethyl)Jamino-
benzophenone.
The preparation of this compound was carried
out according to J. Org. Chem., 1985, 50, 945-950.
5.15 g of (L)-Boc(N-Et)AlaOEt is treated with
10 ml of TFA at 0°C in order to remove the Boc group.
The mixture is concentrated under vacuum, taken up in
20 ml of DCM, cooled to -78°C and 2 equivalents of TEA
and the acid chloride prepared in the preceding step,
dissolved in DCM, are added. After 18 hours at RT, the
mixture is extracted with DCM, the. extract is washed
with water and then chromatographed on silica by
eluting with a DCM/AcOEt (90/10; v/v) mixture. The

CA 02206776 1997-06-27
Y a
expected product crystallizes from isopropyl ether.
M.p. - 112°C
m = 8 mg
(C) N-Ethyl-N-[(1S)-1-(ethoxycarbonyl)ethyl]-5-
5 chloro-3-(2-chlorophenyl)-1-(3,4-
dimethoxyphenylsulfonyl)-3-hydroxy-2=
indolinecarboxamide, (cis isomer).
The compound obtained in the preceding step
is stirred at RT for 18 hours in 10 ml of THF and 20 ml
10 of ethanol, in the presence of 1.46 g of DBU. The
mixture is concentrated under vacuum, the residue is
taken up in DCM, washed with water, concentrated and
the product chromatographed on alumina by eluting with
AcOEt/DCM (10/90; v/v).
15 NMR
0-0.9 ppm: split d:3H:CH-CH3
0.9-1.7 ppm:m:6H:2CH3 (ethyl)
2.6 to 5.8 ppm:m:12H:20CH3, NCH2, OCH2, NCH, COCH
6.1 to 8.3 ppm:m:llH:OH - lOH aromatics
20 EXAMPLES 79 AND 80
N,N-Di[2-(methoxycarbonyl)ethyl]-5-chloro-3-
(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-
hydroxy-2-indolinecarboxamide, cis isomer and trans
isomer.
25 (A) N,N-Di[2-(methoxycarbonyl)ethyl]benzylamine.
Preparation according~to J. Am. Chem. Soc.,
1950, 72, 3298.
107 g of benzylamine in 200 ml of ethanol are
cooled in an ice bath and 172.2 g of methyl acrylate in
30 250 ml of ethanol are slowly added. After 13 days at
RT, the solvent is evaporated under vacuum and a part
of the oily residue is then distilled.
B.p. - 135-140°C at 0.6 mm Hg
m = 30 g
35 IR: 1730cm 1
(B) N,N-(2-dimethoxycarbonyl)ethyl]amine.
27.9 g of the amine obtained in the preceding

CA 02206776 1997-06-27
61
step, placed in 500 ml of methanol, are mixed with 3 g
of 5o palladium on charcoal and are treated under
hydrogen pressure for 1 hour. The mixture is filtered
on Celite~, rinsed with methanol and the solvent
evaporated under vacuum; the residual oil is used as it
is in the following step.
(C) N,N-Di[2-
(methoxycarbonyl)ethyl]bromoacetamide.
A mixture containing 14.3 g of the amine
prepared in the preceding step, 100 ml of DCM and 10.6
ml of TEA is cooled in an ice bath; 15.3 g of
bromoacetyl bromide are added dropwise and the mixture
is then left stirring for 48 hours at RT. The mixture
is extracted with DCM, the extract is washed with water
and then a chromatography is carried out on silica by
eluting with a DCM/MeOH (97/3; v/v) mixture. The
expected product is obtained in the form of an oil.
m = 15.9 g
IR: 1650 cm 1 and 1730 cm 1.
(D) 2',5-Dichloro-2-[N-(3,4-
dimethoxyphenylsulfonyl)-N-[N',N-di(2-
(methoxycarbonyl)ethyl)carbamoylmethyl]]-
aminobenzophenone.
14.3 g of 2',5-dichloro-2-(3,4-
dimethoxyphenylsulfonamido)benzophenone are placed in
180 ml of DMF and 1.1 g of sodium hydride are added in
portions. After stirring for 1 hour at RT, the mixture
is cooled in an ice bath and 14.3 g of the product
prepared in the preceding step are added and the
mixture is left stirring for 72 hours at RT. The
mixture is extracted with DCM, the extract is washed'
with water and then chromatographed on silica by
eluting with a DCM/AcOEt (93/7; v/v) mixture.
m = 28.4 g
M.p. - 130°C
(E) N,N-Di[2-(methoxycarbonyl)ethyl]-5-chloro-3-
(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-

CA 02206776 1997-06-27
62
hydroxy-2-indolinecarboxamide, cis isomer.
12 g of the compound prepared in the
preceding step and 0.930 g of sodium methylate in 150
ml of methanol are mixed at 0°C and the mixture is then
left stirring overnight at RT. The reaction mixture is
neutralized by addition of 5o KHS04 and the solvent is
then evaporated under vacuum. The residue is
chromatographed on alumina by eluting with a DCM/AcOEt
(8/2; v/v) mixture. 2.4 g of the expected product are
recovered which are crystallized from methanol.
M.p. - 175°C
(F) N,N-Di[2-(methoxycarbonyl)ethyl]-5-chloro-3-
(2-chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-
hydroxy-2-indolinecarboxamide, trans isomer.
The chromatography of the preceding step is
continued and elution is carried out with a DCM/MeOH
(9.5/0.5; v/v) mixture. 1.82 g of the trans isomer is
obtained which crystallizes from isopropyl ether.
M.p. - 85°C
EXAMPLES 81, 82 AND 83
2-((2R)-Carbamoylthiazolidinocarbonyl)-5-
chloro-3-(2-chlorophenyl)-1-(3,4-
dimethoxyphenylsulfonyl)-3-hydroxy-indoline, (cis
isomer: 2 compounds and trans isomer).
(A) (L)-4-Thiazolidinecarboxamide.
This compound is prepared according to J.
Med. Chem., 1981, 24, 692.
(B) 2',5-Dichloro-2-[N-(3,4-
dimethoxyphenylsulfonyl)-N-((2R)-2-
carbamoylthiazolidinocarbonylmethyl)]-amino-
benzophenone.
This compound is obtained by the usual
methods from the acid prepared in Example 10-11, Step
A) .
M.p. - 125°C after crystallizing~from ether.
(C) 2-((2R)-2-Carbamoylthiazolidinocarbonyl)-5-
chloro-3-(2-chlorophenyl)-1-(3,4-

CA 02206776 1997-06-27
63
dimethoxyphenylsulfonyl)-3-hydroxyindoline.
4.3 g of the product obtained in Step (B) are
cyclized in 90 ml of MeOH at RT in the presence of 1 g
of DBU. The mixture is concentrated, the residue is
taken up in water and DCM, the layers are separated,
the organic layer is washed with KHS04~and then dried
and concentrated. The residue is chromatographed on
alumina by eluting with DCM/MeOH (97/3; v/v). The
compound is obtained in the cis form (mixture of 2
diastereoisomers): 1.5 g, and then in the trans form
(mixture of 2 diastereoisomers): m = 1 g.
(a) The cis fraction is crystallized from
MeOH/DCM in order to obtain cis compound 1.
M.p. - 176°C after crystallizing from isopropyl
ether.
ocD = +57°(C = 0.1; chloroform)
(b) The crystallization liquors of the preceding
product are chromatographed on silica by eluting with
AcOEt/DCM (30/70; v/v). The cis compound 2 obtained is
recrystallized from ether.
M.p. - 205°C
aD = -185°(C = 0.3; chloroform)
(c) The trans fraction (mixture of 2
diastereoisomers) is recrystallized from isopropyl
ether.
M.p. - 170°C
EXAMPLES 84, 85, 86 AND 86a
5-Chloro-3-(2-chlorophenyl)-1-(3,4-
dimethoxyphenylsulfonyl)-3-hydroxy-2-[(2S)-2-(N,N-
dimethylthiocarbamoyl)pyrrolidinocarbonyl]indoline, cis
isomerism (2 compounds), (trans isomerism: 2
compounds).
(A) (L)-(N'-Boc)-N,N-Dimethylprolinethioamide.
This compound is prepared according to J.
Med. Chem., 1989, 2178.
2.36 g of (N'-Boc)-N,N-dimethylprolinamide ,
are heated in anhydrous toluene under argon at 80°C

CA 02206776 1997-06-27
64
for 4 hours in the presence of 2.3 g of Lawesson's
reagent. After 24 hours, the solvent is evaporated and
isopropanol is added. The precipitate formed is
separated, the isopropanol is evaporated and the
residue is chromatographed on silica by eluting with
hexane/AcOEt (30/70; v/v). The product obtained is
recrystallized while cold from DCM/isopropyl ehter
(30/70; v/v).
M.p. - 62°C
(B) 2',5-Dichloro-2-[N-(3,4-
dimethoxyphenylsulfonyl)-N-((2S)-2-(N',N'-
dimethylthiocarbamoyl)pyrrolidinocarbonylmethyl)]amino-
benzophenone.
3 g of the product prepared in the preceding
step are dissolved in 10 ml of DCM and treated at 0°C
for 2 hours with 10 ml of TFA. The mixture is
evaporated to dryness, then 20 ml of DCM and 6.1 g of
the acid prepared in Example 10-11, Step A) are added
at 0°C and the mixture is neutralized with 3 g of
DIPEA. 5.15 g of BOP are dissolved in 30 ml of DCM and
this solution is added to the preceding solution at 0°C
over 30 minutes; the pH is maintained at neutral by the
addition of DIPEA and the mixture is left stirring for
3 hours at 0°C. After one night at RT, the mixture is
extracted in the usual way and then chromatographed on
silica by eluting with DCM/AcOEt (85/15; v/v). The
product obtained is recrystallized from isopropyl
ether.
M.p. - 182-185°C
aD = -72°(C = 0.32; chloroform)
(C) 5-Chloro-3-(2-chlorophenyl)-1-(3,4-
dimethoxyphenylsulfonyl)-3-hydroxy-2-[(2S)-2-(N,N-
dimethylthiocarbamoyl)pyrrolidinocarbonyl]indoline (cis
isomerism: 2 compounds, and trans isomer: 2 compounds).
3.8 g of the compound obtained in the
preceding step are dissolved in 15 ml of DCM and the
mixture is heated at reflux for 36 hours in the

CA 02206776 1997-06-27
presence of 850 mg of DBU. The different isomers
formed are separated by successive chromatographic runs
on silica.
(a) Using DCM/AcOEt (85/15; v/v), the expected
5 compound is eluted first in the form of a mixture of 2
cis diastereoisomers. The least soluble
diastereoisomer is crystallized twice from a
DCM/isopropyl ether/methanol mixture and is then
recrystallized from the minimum amount of DMF at 60°C
10 followed by addition of 2 volumes of ethanol.
M.p. - 270°C
ocD = -278° (C = l; chloroform)
(b) The crystallization liquors of the preceding
mixture are taken up in and the second cis
15 diastereoisomer crystallizes from a DCM/isopropyl ether
mixture.
M.p. - 249-251°C
ocD = +42°(C = 0.22; chloroform)
(c) The chromatography fractions eluted last, as
20 well as the crystallization mother liquors of fractions
(a) and (b), are combined, and are chromatographed
again on silica by eluting with hexane/AcOEt (20/80;
v/v). Isolated first is a fraction which is
recrystallized 3 times from a DCM/isopropyl ether
25 mixture and an insoluble material is removed on a paper
between each recrystallization. The trans isomer 1 is
thus obtained.
M.p. - 191-193
ccD = +74 . 5° (C = 0: 2; chloroform)
30 (d) The second fraction contains trans isomer 2
which is recrystallized from a DCM/isopropyl ether
mixture and crystallizes with 1/3 mole of isopropyl
ether.
M.p. - 170°C
35 aD = -266°(C = 0.14; chloroform)
EXAMPLES 87, 88 AND 89
2-((2S)-2-Carbamoylpyrrolidinocarbonyl)-5-

CA 02206776 1997-06-27
66
chloro-3-cyclohexyl-1-(3,4-dimethoxyphenylsulfonyl)-3-
hydroxyindoline, (cis isomers: 2 compounds, trans
isomer] .
(A) 5-Chloro-2- [N- ( 3, 4-
dimethoxyphenylsulfonyl)amino]-cyclohexylphenone.
JA~so~ution of 35.6 g of 2-amino-5-
.c~~.o.rp~.y~lohexylphenone and 39.5 g of 3,4-
- dimethoxyphenylsulfonyl chloride in 340 ml of pyridine
is left stirring for 24 hours at RT. The solvent is
evaporated under vacuum and the residue is then washed
with water and with an acid solution (0.5 N HCl). The
expected product crystallizes from ethanol.
M.p. - 135°C
m = 56.1 g
(B) 2-[(N-Benzyloxycarbonylmethyl-N-(3,4-
dimethoxyphenylsulfonyl))amino]-5-
chlorocyclohexylphenone.
3.2 g of sodium hydride are added in portions
to 52.6 g of the compound prepared in the preceding
step in 520 ml ;o~,_,DMF and the mixture is left stirring
for 1 hour at RT. After cooling in the ice bath, 21 ml
of benzyloxycarbonylinethyl bromide are added dropwise
and the mixture is left stirring for 24 hours at RT.
. The solvent is evaporated under vacuum and the residue
is taken up in water. It is extracted with DCM and the
extract is washed with water; the product obtained is
used as it is in the following step.
(C) N-(5-Chloro-2-(cyclohexylcarbonyl)phenyl)-N-
(3,4-dimethoxyphenylsulfonyl)glycine.
The compound obtained in the preceding step
is placed with 3.9 g of 5~ palladium on charcoal in 700
ml of acetic acid under hydrogen (1 atmosphere). At
the end of the reaction, the palladium is filtered on
Celite~ and rinsed with hot acetic acid; the solvent is
evaporated under vacuum and the residue is taken up in
water. It is extracted with DCM and the extract is
washed with water and then with a concentrated NaHC03

CA 02206776 1997-06-27
67
solution. The residue obtained is chromatographed on
silica by eluting with a DCM/MeOH (97/3; v/v) mixture.
The expected product crystallizes from ethanol.
M.p. - 160°C
m = 22.4 g
(D) 5-Chloro-2-[N-(3,4-dimethoxyphenylsulfonyl)-
N-((2S)-2-carbamoylpyrrolidinocarbonylmethyl)]-
aminocyclohexylphenone.
A mixture containing 9.92 g of the acid
prepared in the preceding step, 3 g of (L)-prolinamide
hydrochloride and 3.5 ml of DIPEA in 75 ml of DCM is
cooled to 0°C. 8.84 g of BOP in solution in DCM are
added and the pH is maintained at 7 by addition of
DIPEA. The mixture is left stirring for 24 hours at
RT. The mixture is extracted with DCM, and the extract
washed with a saturated NaHC03 solution, a saline
solution, a 5% KHSOQ solution and again with a saline
solution. The product is chromatographed on silica by
eluting with a DCM/MeOH (96/4; v/v) mixture. The
expected product solidifies in isopropyl ether.
M.p. - 110°C
m = 7.3 g
aD = -53.9°(C = 1; chloroform)
(E) 2-((2S)-2-Carbamoylpyrrolidinocarbonyl)-5-
chloro-3-cyclohexyl-1-(3,4-dimethoxyphenylsulfonyl)-3-
hydroxyindoline, cis isomer (2 compounds), trans
isomer.
5.9 g of the compound prepared in the
preceding step and 1.67 g of DBU are placed in 60 ml of
methanol with stirring at 0°C for 48 hours. The
solvent is evaporated under vacuum, water is added, the
mixture is extracted with DCM and the extract is then
washed with a 5o KHS04 solution. The product is
chromatographed on alumina by eluting with DCM/MeOH
(98/2; v/v) .
(a) The least polar fraction contains the 2 cis
isomers. This fraction is recrystallized from

CA 02206776 1997-06-27
68
methanol. The first compound thus obtained (cis 1) is
pure by HPLC.
M~. p . - 18 5°C
By recrystallization of the mother liquors
from MeOH, a second compound is obtained (cis 2). HPLC
purity: 750 (it contains 25o cis 1).
M.p. - 132°C
(b) The most polar fraction contains the trans
isomer in the form of an apparently single compound
which is obtained by recrystallizing from methanol.
M.p. - 240°C
aD = -55.1°(C = l; chloroform)
EXAMPLE 89a
2-((2S)-2-Carbamoylpyrrolidinocarbonyl)-5-
chloro-3-cyclohexyl-1-(3,4-dimethoxyphenylsulfonyl)-3-
hydroxyindoline, cis isomer (2 compounds), traps
isomer.
By using a procedure similar_to that
described for Examples 87, 88 and 89, an analogous
compound in the (D)-proline series is prepared.
The compound obtained after crystallizing
from a DCM/MeOH mixture has the traps configuration.
M.p. - 238°C
ao = +164°(C = 0.245; chloroform/methanol, 8.2,
v/v) .
The NMR spectrum of this compound and of that
described in Step E (b) of the preceding example are
identical.
EXAMPLE 90
5-Chloro-3-(2-chlorophenyl)-1-(3,4-
dimethoxyphenylsulfonyl)-2-[(2S)-2-(N-
methylaminocarbonyl)pyrrolidinocarbonyl]-3-
hydroxyindoline, cis isomer.
920 mg of the compound prepared in Example 28
are placed, with stirring, in 20 ml of DCM containing
371 mg of BOP for 15 minutes, a stream of
monomethylamine is bubbled through for 10 minutes and

CA 02206776 1997-06-27
v
69
the stirring is maintained for an additional 30
minutes. The mixture is taken up in water, the layers
separated, the organic layer washed with potassium
hydrogensulfate and with sodium carbonate, dried and
concentrated. The residue is chromatographed on silica
by eluting with DCM/methanol (97.5/2.5; v/v). The
expected product is collected which crystallizes from
an isopropyl ether/DCM mixture.
m = 750 mg
M.p. - 158°C
aD = -216°(C = 0.3; chloroform)
By operating as in the previously described
examples (Examples 27 to 31 and 90) and by using
derivatives of (L)-proline (except when otherwise
indicated), other intermediate compounds (VI) for the
synthesis of the compounds (I) according to the
invention were prepared.
The compounds (VI) prepared are described in
Table 3 below.
The compounds (I) prepared are described in
Table 4 below.
Table 3
C1
O
R
N-CH2-CO-N~R6
SOZ
R~ yl
5 ~

CA 02206776 1997-06-27
7~
R
' (
6
s -N\ M.p.(~C) aps
R
R ~ (chloroform
3,4-CH30
H " +45
CONH~
c - 1.015
3,4-CH30 -N I 161-163 _70,g
H" ..
DCM/isopropyl etherc - 0.48
COOCH3
2,4-CH30 -N 145-148 -17.5
H.,...
COOCH3 c - 3.36
3,4-CH30 -N ~ 110
H,... /J''~
COOCH2f( y DCM/isopropyl ether
3,4-CH30 -N 148
H....
H2COOCH3 isopropyl ether/MeOH
Table 4
Cl
R.1 OH
N~H ~
CON'R6
S02 \ R~
R, ~
s~
Example R'1 R's -N~R6 M.p.(.C) ",25
\\
(chloroform)
2 91 cis C1 3,4-CH30 115 + 188
5 1
lD) -~
H MeOH c - 0.33
92 cis CONH2 204 ! -114'
2
C1 e0H/DMF ~ c - 0.31
i

CA 02206776 1997-06-27
71
198-201
93 cis C1 3,4-CH30 -"~ ~ DCM/isopropyl
H
CooCH~ ether
5
_N
205-207
94 cis C1 2,4-CH30 H"'~ CM/isopropyl
COOCH~
ether
10 -N 221 - 242
95 cis C1 2,4-CH30 H"'~ CM/isopropyl - 0.254
COOH_ ether
N
H' -234
coocHz
15 96 cis C1 3,4-CH30 - / c - 0.32
~
I
-N
g ....
- 214
CON(CH.~
)2
97 cis C1 3,4-CH30 c - 0.32
2 105-115 +174.6
0
-N
98 cis C1 3,4-CH30 H.... DCM/isopropyl - 0.3
1
HZCOOCH3 ether
99 cis 175 -214.6
2
DCM/isopropyl - 0.3
2 a then
5
00 traps . -155
1
c - 0.2
101 traps 177 +95.2
2
DCM/isopropyl - 0.2
3 a then
0
02 cis C1 3,4-CH30 -N~ 135 -162
1
H".~
i isopropyl ether
CH,COOH
;

CA 02206776 1997-06-27
72
~ !' ; _
145 -167
-N ~
03 cis C1 3,4-CH30 CM/isopropyl c - 0.4
1 H~~~~
~
CHZ COYH~ ether
03a C1 3,4-CH30 N
H ~--
cis 1
cis 2
CH2 CONH2
04 cis C1 3,4-CH30 210 -177
1 5
-N .
H"' ether c - 0.2
H2NHZ
04a C1 3,4-CH30
cis 1 -
H
cis 2
CH NHS
200 -195
105 I CH30 3,4-CH30 -N EtOH c - 0.2
H....
2 0 106 CoNH2 215 +127
MeOH c - 0.2
-63.3
107 CH30 3,4-CH~O ~D~ -~ 198 c - 0.117
2 S H '
(CHC13/MeOEi
CONH2
.
_ 8/2:v/v)
274 -225
108 C1 2,4-CH30 N DCM/MeOH c - 0
372
H".. .
30
cONH2 ~ (a~cl3/MeoEt
8/2;v/v)
108a C1 3,4-CH30 -198.7
-'~~
H".
cis
CONHOH c - 0.24
I i
3~ i

CA 02206776 1997-06-27
73
*: Example 92: Other measured optical rotation:
ap25 - -39.5°(C = 0.17; CHC13/MeOH: 8/2: v/v).
The compound of Example 107 is the enantiomer
of that of Example 106.
The compound of Example 108a was prepared
from the compound of Example 28 by reacting with
hydroxylamine hydrochloride in DMF and by activating
with the reagent BOP in the presence of DIPEA.
Some compounds according to the invention,
described in Table 4 above;r~are useful for the
preparation of othe~~compounds. Thus, the compound of
Example 99_makes it possible to obtain the compound of
Example 101, then that of Example 103 and finally that
of Example 104.
EXAMPLE 109
2-((2S,4S)-4-Azido-2-
(methoxycarbonyl)pyrrolidinocarbonyl)-5-chloro-3-(2-
chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-
hydroxyindoline, cis isomer.
(A) 2',5-Dichloro-2-[N-(3,4-
dimethoxyphenylsulfonyl)-N-((2S,4R)-4-hydroxy-2-
(methoxycarbonyl)pyrrolidinocarbonylmethyl)]amino-
benzophenone.
15 g of the acid prepared in Example 10-11,
Step (A) and 6.25 g of methyl (2S,4R)-4-
hydroxyprolinate hydrochloride are heated to 0°C in 150
ml of DCM in the presence of 7.4 g of DIPEA. A
solution of 12.7 g of BOP in 30 ml of DCM is added
dropwise over 30 minutes and the amount of DIPEA
necessary to neutralize the solution is added. After
one night at RT, the mixture is extracted in the usual
way and chromatographed on silica by elution with a
DCM/AcOEt (60/40; v/v) mixture. The expected product
crystallizes from a DCM/ether/isopropyl ether mixture.
M.p. - 128-131°C
aD = +8.5°(C = 0.38; chloroform) '
(B) 2',5-Dichloro-2-[N-(3,4-

CA 02206776 1997-06-27
74
dimethoxyphenylsulfonyl)-N-((2S,4R)-4-mesyloxy-2-
(methoxycarbonyl)pyrrolidinocarbonylmethyl)]amino-
benzophenone.
2 g of the compound obtained in the preceding
step are dissolved at 0°C in 10 ml of DCM. 550 mg of
triethylamine and then 550 mg of methanesulfonyl
chloride are added and the mixture is left at 0°C for
20 hours. Water is added and the organic layer is
washed with 0.5 N hydrochloric water, with water and
then with a sodium bicarbonate solution, dried over
magnesium sulfate and evaporated. The oil obtained is
used as it is in the following step.
(C) 2-[N-((2S,4S)-4-azido-2-
(methoxycarbonyl)pyrrolidinocarbonylmethyl)-N-(3,4-
dimethoxyphenylsulfonyl)]amino-2',5-
dichlorobenzonhenone_
_______________L __________
11 g of the product prepared in the preceding
step are heated in 60 ml of DMSO at 80-90°C in the
presence of 2.7 g of sodium azide for 18 hours. The
mixture is poured into water, extracted with ethyl
acetate, the organic layer washed with water, dried and
chromatographed on silica by eluting with a
pentane/AcOEt (50/50; v/v) mixture. An oil (10 g) is
obtained.
aD = -25.5°(C = 0.39; chloroform, T = 26°C)
(D) 2-((2S,4S)-4-Azido-2-
(methoxycarbonyl)pyrrolidinocarbonyl)-5-chloro-3-(2-
chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-
hydroxyindoline, cis isomer.
3.38 g of the product obtained in the
preceding step are cyclized under the usual conditions
in the presence of DBU. The expected product is
obtained which is recrystallized from DCM/isopropyl
ether.
m = 755 mg
M.p. - 200-202°C
ap = -176°(C = 0.21; chloroform, T = 26°C)

CA 02206776 1997-06-27
EXAMPLE 110
2-[(2S,4S)-4-(N-Benzyloxycarbonyl-N-
methyl~)amino-2-(methoxycarbonyl)pyrrolidinocarbonyl]-5-
chloro-3-(2-chlorophenyl)-1-(3,4-
5 dimethoxyphenylsulfonyl)-3-hydroxyindoline, cis isomer.
(A) Methyl ester of (N-Boc)-4-hydroxyproline.
The starting material is the hydrochloride of
the methyl ester of (2S,4R)-4-hydroxyproline.
19 g of this compound are suspended in 100 ml
10 of THF, 22.9 g of (Boc)20 are added and then the
mixture is cooled to 0°C. 21.2 g of triethylamine in
25 ml of THF are added dropwise and then the mixture is
stirred for 12 hours at 0°C and 4 hours at 60°C. Water
is added, the mixture is extracted with ethyl acetate,
15 the organic layer is washed with water, with a
potassium hydrogensulfate solution (4 times), with
water and then with saline water. The solvent is
evaporated and an oil (21.6 g) is isolated which
contains a small amount of (Boc)20.
20 (B) Methyl ester of (2S, 4R) - (N-Boc) -4-
mesyloxyproline.
A solution of 22.9 g of the product prepared
in the preceding step in 250 ml of DCM is cooled to
0°C. 22.9 g of mesyl chloride in l0,ml of DCM are
25 added dropwise, then 9.4 g of triethylamine in 100 ml
of DCM are added dropwise and the mixture is~left to
return to RT overnight. The mixture is evaporated to
dryness, water is added, the mixture is extracted with
AcOEt, the organic layer is washed with water and
30 saline water and dried over magnesium sulfate. After a
second evaporation, an oil is obtained which is used as
it is in the following step.
(C) Methyl ester of (2S,4S)-(N-Boc)-4-
azidoproline.
35 This compound is prepared from that obtained
in Step B. 15.2 g of the methyl ester of (N-Boc)-4-
mesyloxyproline are dissolved in 70 ml of DMSO and the

CA 02206776 1997-06-27
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76
solution is heated at 90°C for 5 hours in the presence
of 3.05 g of sodium azide. The mixture is cooled,
water is added, the mixture is extracted with AcOEt,
the organic layer is washed with water and saline water
and dried over MgS04.. The oil obtained is purified by
chromatography on silica by eluting with the
AcOEt/hexane (40/60; v/v) mixture.
ocD = -37 . 8° (C = 3; chloroform)
lit. aD = -36.6°(C = 2.8; chloroform) D.J. Abraham
et al., J. Med. Chem., 1983, 549, 26.
(D) Methyl ester of (2S,4S)-(N-Boc)-4-
aminoproline.
8.45 g of the compound obtained in Step C are
dissolved in 100 ml of methanol, 500 mg of loo Pd/C are
added and the mixture is hydrogenated at 40°C for 18
Ycr,mrc Tho n~~!-~l met- i a ~i 1 i-oroi-1 n~F~ 1-,~l ~ i-Y',o mo+~l~,~r,~l
1lVL.tLJ. 1116 VGLt-QlyJL 1J 1114..G1Gt.1 V11, 11Q11 L..11G 1LLGL-.11Q11V1
is evaporated, 100 ml of 0.5 N HCl are added, the
remainder of the methanol is then evaporated and the
unreacted starting material is extracted with AcOEt.
The aqueous phase is treated with sodium carbonate and
the fraction containing the expected product (m = 4.35
g) is extracted with'AcOEt.
(E) Methyl ester of (2S, 4S) - (N-Boc) -4- (N' -
benzyloxycarbonylamino)proline.
The crude product obtained in the preceding
step is dissolved in 15 ml of ether and 15 ml of DCM at
0°C. 2.3 g of DIPEA and then 3.03 g of benzyl
chloroformate in 5 ml of DCM are added, over 70 minutes
at 0°C. After 3 hours, the solvents are evaporated at
RT under vacuum; water and ethyl acetate are added and
the organic phase is washed successively with a
potassium hydrogensulfate solution (3 times), with
water (3 times), with a sodium carbonate solution (3
times), with water (3 times) and with saline water.
The product is chromatographed on silica by eluting
with hexane/AcOEt (40/60; v/v) mixture in order to
obtain the expected product.

CA 02206776 1997-06-27
77
ap = -16.4°(C = 0.3; chloroform)
(F) Methyl ester of (2S, 4S) - (N-Boc) -4- (N' -
benzyloxycarbonyl-N'-methyl)aminoproline.
2 g of the compound obtained in the preceding
step are dissolved in 20 ml of DMF at 0°C, under argon,
in the presence of 2.25 g of methyl iodide. 170 mg of
80o sodium hydride are added in portions and then the
mixture is stirred at 0°C for 90 minutes. The mixture
is extracted with water and ethyl acetate; the organic
phase is washed with water and then saline water. The
product is chromatographed on silica by eluting with a
hexane/AcOEt (50/50; v/v) mixture. 1.55 g of the
expected product is obtained.
an = -38.8°(C = 0.38; chloroform)
(G) 2',5-Dichloro-2-[(2S,4S)-N-(3,4-
dimethoxyphenylsulfonyl)-N-(4-(N'-benzyloxycarbonyl-N'-
methyl)amino-2-
(methoxycarbonyl)pyrrolidinocarbonylmethyl)]amino-
benzophenone.
This product is obtained by the usual
methods.
aD = -22.4°(C = 0.37; chloroform)
(H) 2-[(2S,4S)-4-(N-Benzyloxycarbonyl-N-
methyl)amino-2-(methoxycarbonyl)pyrrolidinocarbonyl]-5-
chloro-3-(2-chlorophenyl)-1-(3,4-
dimethoxyphenylsulfonyl)-3-hydroxyindoline, cis isomer.
This product is obtained by cyclizing in the
presence of DBU according to the usual methods. The
crystals formed are crystallized from DCM/isopropyl
ether.
M. p. - 129°C
aD = -129°(C = 0.321; chloroform)
The isomeric purity by HPLC is 99°s.
The compounds prepared in Examples 109 and
110 are used to prepare the compounds according to the
invention described in Table 5 below:

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78
Table 5
C1
C1 H
' H ~./ (4S )
R9
CO-N
S 02 (2S)
COOCH3_
OCH3
OCH3
Example R9 ap(chloroform)
111 c i s -NFi2 -18 9 . 6
c = 0.4
/j~ -174
112 cis -NHCOOCHZ~ c = 0
24
.
113 cis _NHCH3 -152.6
c = 0.28
114 cis -191
_
( CH3)2
c = 0 .19

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79
The compound of Example 112 makes it possible
to successively prepare the compounds of Examples 115
and 116 described in Table 6 below and the compound of
Example 114 makes it possible to prepare the compound
of Example 116a.
Table 6
C1
H
~H~
N~CO_.N (4S)
S 02 (2S)
CONH2
OCH3
OCH3
Example R~ aD(chloroform)
115 cis ~ /j~ -151
-NFiCOOCFf.,-;(
y
c = 0.27
116 cis -NHZ -161.4
c = 0.26
ll6a cis -N(CH3)2

CA 02206776 1997-06-27
v
The compound of Example 116a can be prepared
either by conversion of the compound of Example 114, or
from (2S,4S)-(N-Boc)-4-(dimethylamino)prolinamide, the
preparation of which is carried out as follows:
5 (1) Methyl (2S,4S)-(N-Boc)-4-aminoprolinate is
prepared from methyl (2S,4S)-4-azidoprolinate according
to T.R. Webl in J. Org. Chem., 1991, 56, 3009.
(2) Methyl (2S,4S)-(N-Boc)-4-(dimethylamino)-
prolinate.
10 4 g of the compound prepared in (1) are
dissolved in 50 ml of acetonitrile, 12.8 ml of 300
formalin are added and then, over 5 minutes, 3 g of
sodium cyanoborohydride. After the reactants have been
in contact for 2 hours, acetic acid is added to bring
15 the solution to a pH of 6. After 3 hours, the
acetonitrile is evaporated, water, potassium carbonate
and solid sodium chloride are added and the mixture is
extracted with 4 volumes of ethyl acetate. The organ~.c
phase is evaporated, the residue is dissolved in 1 N
20 hydrochloric acid and extraction is carried out with
AcOEt. Solid sodium carbonate and then solid sodium
chloride are added to the aqueous phase and extraction
is carried out with AcOEt. After evaporating, the
residue is chromatographed on silica gel by eluting
25 with a DCM/MeOH (95/5; v/v) mixture and an oil which
solidifies is isolated.
m = 2.1 g
IR (DCM) : 1755 cm 1, 1695 cm 1
(3) 534 mg of the ester prepared in (2) are
30 dissolved in 4 ml of MeOH and are treated with sodium
hydroxide (116 mg) in 1 ml of water for 48 hours at Rt.
The mixture is acidified with 0.5 N hydrochloric acid
to a pH of 3.5 and is evaporated to dryness. An
azeotropic drying of the residue is carried out in the
35 presence of benzene (5 times) and then the residue is
dried under vacuum for 8 hours. 2 ml of DMF and 3 ml
of DCM are then added and the mixture is cooled to 0°C.

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81
865 mg of BOP, and DIPEA, are added to bring the
reaction mixture to neutrality. After 15 minutes, a
stream of gaseous ammonia is bubbled through twice for
30 minutes. After 2 hours at RT, the DCM is
evaporated, carbonated water and sodium chloride are
added and the mixture is extracted with 4 volumes of
AcOEt. After evaporating, the residue is
chromatographed on silica. The mixture
(DCM/MeOH/NH40H; 84.5/15/0.5; v/v/v) elutes a solid (m
- 185 mg) which is recrystallized from a DCM/isopropyl
ether mixture.
M.p. - 183-186°C
aDZS - -63.1°(C = 0.24; chloroform)
EXAMPLE 117
Decarboxylation of N-(2-carboxyethyl)-N-
ethyl-3-(2-chlorophenyl)-5-chloro-1-(3,4-
dimethoxyphenylsulfonyl)-3-hydroxy-2-
indolinecarboxamide, cis isomer.
630 mg of the compound prepared in Example 41
are placed in solution in 20 ml of THF under an argon
atmosphere and then 101 mg of N-methylmorpholine at
-15°C and 118 mg of isobutyl chloroformate are added.
After stirring for 5 minutes, 127 mg of N-hydroxy-2-
pyridinethione and 101 mg of TFA are added, the mixture
is held at -15°C with stirring for 15 minutes, 900 mg
of tert-butylmercaptan are then added and the mixture
is left to return to RT. The reaction mixture is then
irradiated for 1 hour 30 with a tungsten filament lamp
(150 watts). The mixture is concentrated, taken up in
water, extracted with DCM and the extract dried and
concentrated. The residue is chromatographed on silica
by eluting with DCM/AcOEt (95/5; v/v). The expected
product is obtained.
m = 300 mg
M.p. - 215°C
This compound is similar to that of Example
125 described in the European Patent Application EP

CA 02206776 1997-06-27
.
82
469984. It has the cis configuration around the 2,3
bond of the indoline as in the starting material.
EXAMPLE 118 '
Decarboxylation of 2-((2R)-2-
(carboxymethyl)pyrrolidinocarbonyl)-5-chloro-3-(2-
chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-
hydroxyindoline, cis isomer.
The operation is carried out as in the
preceding example from the compound described in
Example 102.
The product obtained is recrystallized from a
DCM/isopropyl ether mixture.
M.p. - 215-220°C
aD = -214.5° (C = 0.2; chloroform)
This compound is 2-((2S)-2-
methylpyrrolidinocarbonyl)-5-chloro-3-(2-chlorophenyl)-
1-(3,4-dimethoxyphenylsulfony)-3-hydroxyindoline, cis
isomer.
EXAMPLE 119
Decarboxylation of 2-(2-
carboxypyrrolidinocarbonyl)-5-chloro-3-(2-
chlorophenyl)-1-(3,4-dimethoxyphenylsulfonyl)-3-
hydroxyindoline, cis isomer.
The operation is carried out as in the
preceding example by using the compound prepared in
Example 28 as the starting material. The product
obtained is recrystallized from an isopropyl ether/DCM
mixture.
M.p. - 263°C
aD = -201.5° (C = 0.2; chloroform)
This compound is 2-pyrrolidinocarbonyl-5-
chloro-3-(2-chlorophenyl)-1-(3,4-
dimethoxyphenylsulfonyl)-3-hydroxyindoline, cis isomer.

Representative Drawing