Note: Descriptions are shown in the official language in which they were submitted.
- 21292 1 ~ - ~
The present invention relates to 1-
benzenesulfonyl-1,3-dihydroindol-2-one derivatives, to
their preparation and to the pharmaceutical compositions
in which they are present.
International patent application W0 91/01306
describes 2-oxoindole derivatives which are uieful for
the treatment of senile dementia. These compounds have
the formula
R 2
R"l- ~ 3
COR 4
:
in which
- R''1 is a hydrogen, a halogen, an alkyl or an alkoxy;
~ R''2 ls hydrogen or a lower alkyl;
- R''3 is an alkyl, a cycloalkylmethyl, a
benzodioxanylmethyl or an optionally substltuted benzyl;
and
- R''4 is a l-propylbutyl, a pyridyl or an optlonally
substituted phenyl.
Several patent applications have recently
described families of compounds of non-peptide struature
which are active on the vasopressin and/or ocytocln
receptors. There may be mentioned European patent
appllcations EP 382 185, EP 444 945, EP 514 667, EP 469
984 and EP 526 3~i8, international patent applications
W0 91/05 549 and W0 93/15 051, patent application
JP 04/321 669 and, more particularly, patent appllcation
JP 03/127 732. This last patent applicatlon descrlbes
indole-3-propionic acid derivatives of the formula
21292~
~ ~ ~ COR"'3
R 1
in which
~ ~'''1 is hydrogen, an alkyl, an alkenyl, a phenylalkyl,
a tetrahydrofuryl, an alkoxycarbonyl, an
alkoxycar~onylalkyl, a carboxyal~yl or an alkanoyl;
~ R''72 is hydrogen, a hydroxyl, an alkoxy, an alkyl, a
phenylalkyl, a phenylalkoxy or a halogen;
- R'''3 i8 a hydrogen, an alkoxy, a free or substituted
amino group or an amino acid residue;
- R'''4 is hydrogen, an alkyl or a phenylalkyl; and
- R'''5 is a benzoyl, a phenyl, an alkyl, a
phenylalkenylcarbonyl, a thienylcarbonyl, a
phenylsulfonyl, a pyrldylcarbonyl or an
imidazolylcarbonyl, it being possible for the phenyl and
alkyl groups of the substituent R'''5 to be substituted.
These compounds are vasopressin antagoni-~ts.
Patent US 4 803 217 claims hapallndolinones
obtained by fermentation which are vasopressln
antagonists. These compounds have the follow$ng formula: ~¦
CH3 R
CH2~CH r,l,~ ~CH2 ' '~
" ~ O ~H3
H -~
in which R ls H or Cl. ~ ~;
.:-.. :...
,;, . , - . , .~. ~ .... . .. . .. . .. .. .. : . .
-~ 3
21292~
Novel l-benzenesulfonyl-1,3-dihydroindol-2-one
derivatives have now been found which also 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
arterial pressure. It stimulates several typeæ of
receptors, namely V1 ~V1a, V1~) and v2. These receptors
are localized in the liver, vessels (coronary, renal,
cerebral), platelets, kidney, uterus, adrenal glands,
central nervous system and pituitary gland. Ocytocin has
a peptide structure similar to that of vasopressin. The
ocytocin receptors are also found on the smooth muscle of
the uterus, as well as on myoepithelial cells of the
mammary gland, in the central nervous system and in the
kidney. The localization of ~he different receptor~ is
described inr S. JARS et al., Vasopressin and ocytocin
receptors: an overview, in Progress in Endocr~nology; H.
IMURA and K. SHIZURNE ed., Experta Medica, Amsterdam,
1988, 1183-1188, and in the following artlcle : ~resse
Medicale, 1987, 1~ ~10), 481-485; J. Lab. Clin. Med.,
1989, 11~ (6), 617-632; and Pharmacol. Rev., 1991, 43
(1), 73-108. Vasopressin thus exerts cardlovascular,
hepatic, antidiuretic and aggregating effects and effects
on the central and peripheral nervous system and in the
uterine domain. Ocytocin is involved in parturition,
lactation and sexual behavior.
The compound~ accordlng to the present invention
make it posslble selectively either to m~mic the effects
of the hormone (in the case of agonists) or to inhibit
them tin the case of antagonists). Vasopressin receptor
antagonists can affect the regulation of the central and
peripheral circulation, especially the coronary, renal
and gastric circulation, as well as the regulation of
hydration and the release of adrenocorticotrophic hormone
(ACTH). Vasopressin agonists can advanta~eously replace
vasopres~in or its analogs in the treatment of diabetes
-
,: ~ . ~ . ,: - -:
~: .
: , . . .
... . . .
- 212921a
insipidus they can also be used in the treatment of
enuresis and in the regulation of hemostasis: treatment
of hemophilia and von Wille brand's syndrome, antidote to
platelet aggregating agents, F.A. LASZLO, Pharmacol.
Rev., 1991, 43, 73-108; and Drug Investigation, 1990,
(Suppl. 5), 1-47. The hormones themselves, namely
vasopressin and ocytocin, and some of their peptide or
non-peptide analogs are used in therapeutics and have
been found to be effective. Several reviews and numerous
literature articles may be mentioned: Vasopressin, P.
GROSS et al. ed., John Libbey Eurotext, 1993, in
particular 243-257 and 5~9-562; F.A. LASZLO and F.A.
LASZLO Jr., Clinical perspectives for vasoprescin
antagonists, Drug News Perspect., 1993, 6 (8), W.G.
~5 NORTH, J. Clin. Endocrinol., 1991, ~, 1316-1320; J.J.
LEGROS et al., Pro~. Neuro-Pharmacol. Biol. Psychiat.,
1988, 12, 571-586; K.E. ANDERSSON et al., ~rugs Today,
1988, ~ (7), 509- 528; D.L. STUMP et al., Drugs, 1990,
39, 38-53; S. CALTABIANO et al., Drugs Future, 1988, 1~,
25~30; Y. MURA et al., Clin. Nephrol., 1993, ~Q, 60-61;
and FASEB J., 1994, ~ (5), A 587 : 3398.
Thus the compounds according to the invention are
useful especially in the treatment of complaints of the
central and peripheral nervous system, the cardiovascular
system, the renal domain and the gastric domain and in
disorders of sexual behavior, ln man and animals.
The present invention relates to compounds of the
formula
- 212921a
R1 _ ~ ~ R4
R2 N
S O
2 (~
R5
(R6)m
in which
- Rl and R2 are each independently a hydrogen; a
S hydroxyl; an ~-halogeno-Cl-C7-alkoxy; a halogen a C~
C7-alkyl; a trifluoromethyl; a Cl-C7-alkoxy; a
polyhalogeno-Cl-C7-alkoxy; an ~-hydroxy-C2~C7-alkoxy; an
~-methoxyalkoxy in whlch the alkyl is C2-C7; an ~-
amino-C2-C7-alkoxy which is ~ree or substituted by one or
two Cl-C7-alkyls; a C3-C7-cycloalkoxy; a
cycloalkylmethoxy in which the cycloalkyl is C3-C7: a
phenoxy; a benzyloxy; a Cl-C7-alkylthio; a phenylthlo: a
nltro; an amlno which is free or substituted by one or
two Cl-C7-alkyls; a cyano; a (C1-C6)alkylcarbonyl; a
formyl; a ~Cl-C6)alkylcarbonyloxy; a formyloxy; a Cl-C7-
alkylsulfonamido, a phenylsulfonamldo; a
benzylsulfonamido; a C1-C7-alkylamido a C~-C7-
alkoxycarbonylamino: a ureido whlch is unsubstituted or
substltuted by a phenyl, a benzyl or one or two C1-C7-
alkyls; ~r a thloureido whlch i~ unsubstituted orubstituted by a phenyl, a benzyl or one or two Cl-C7-
alkyls,
- R3 and R4 are each independently a Cl-C7-alkyl; a C3-
C7-cycloalkyl; a phenyl; a benzyl a cycloalkylmethyl ln
whlch the cycloalkyl is C3-C7; or an ~-hydroxy-C2- C7-
alkyl in which the hydroxyl is free or substituted by a
group selected from Cl-C4-alkyl groups, (Cl-Cs~-
alkoxyalkyl groups in which the alkyl i9 Cl-C4,
:
21292~ ~
phenylalkoxyalkyl ~roups in which the alkoxy is Cl-C2 and
the alkyl is Cl-C4 and tetrahydrofuranyl and
tetrahydropyranyl groups;
or
- R~ and R4 together form a group ~(CH2)pX(CH2)q~
or
- R3 and R4, together with the carbon to which they are
bonded, form an optionally fused, saturated or
unsaturated C3-C12 hydrocarbon ring which is
unsubstituted or substi~uted by one or more 51-C7-alkyl
groups, by an oxo group, by a C3-C5-spirocycloalkyl or by
one or two hydroxyls which are free or substituted by a
group selected from C1-C4-alkyl groups, (Cl-
C5)alkoxyalkyl groups in which the alkyl is Cl-C4, ~-
hydroxyalkyl groups in which the alkyl is C1-C4,
triphenylmethoxyalkyl groups in which the alkyl is C1-C4,
phenylalkoxyalkyl groups in which the alkoxy is Cl-C2 and
the alkyl is Cl-C4, and tetrahydrofuranyl,
tetrahydropyranyl, formyl and (C1-C7)alkylcarbonyl
groups;
- R5 and R6 are each independently a hydrogen; a halogen;
a C1-C7-alkyl; a trifluoromethyl; a oyano,i a nitroi an
amino which i~ free or substituted by one or two Cl-C7-
alkyls; a hydroxyamino; a hydroxyl a carboxyl; a
guanidino which is unsubstituted or monosubstituted or
disubstituted by a C1-C7-alkyl, a phenyl or a benzyl: a
group -OR7; a group -SR7; a (Cl-C6)alkylcarbonyl; a
formyl; a Cl-C7-alkoxycarbonyl; a phenoxycarbonyl; a
benzyloxycarbonyl; a carbamoyl iubstituted by groups R'6
and R''6; a thiocarbamoyl which i8 free or subs~ituted by
one or two C1-C7-alkyls; a sulfamoyl; an alkylsulfamoyl
or dialkylsulfamoyl in which the alkyl is Cl-C7; a group
-SO2R'7; an alkylsulfonamido in which the alkyl is Cl-C7;
a phe~ylsulfonamido; a benzylsulfonamido; a group -COR'7;
a group NRgRg; or a group -CO-NH-cRloR'lo-coRl2; if
appropriate, the phenyl group forming part of the
2129~1~
substituent R5 and/or R6 can be unsubstltuted or
monosubstituted or polysubstituted by a Cl-C7-alkyl, a
trifluoromethyl, a C1-C7-alkoxy, a halogen, a sulfamoyl,
an alkylsulfamoyl in which the alkyl is C1-C7, a
carboxyl, an alkoxycarbonyl in which the alkyl i~ Cl-C7,
a (Cl-C6)alkylcarbonyloxy or an imldazolyl;
- R'6 and R''6 are each lndependently hydrogen; a C1-C7-
alkyl which is unsubstituted or substituted by one or
more halogens or ~'''6; a C3-C7-cycloalkyl which is
unsubstituted or substituted by a (Cl-C4)alkyl, a phenyl;
a pyridyl; a methylpyridyl; a piperidin-4-yl; a
methylpiperidin-4-yl; or a pyrrolidin-1-yl; or R'6 and
R''6, with the ni~rogen atom to which they are bonded,
form a pyrrolidino group substituted by a hydroxymethyl
or by a carbamoyl which is free or substituted by one or
two C1-C7-alkyls;
~ R'''6 is a hydroxyl; a C1-C7-alkoxy; an amino which i8
free or substituted by one or two Cl-C7-alkyls; a
carbamoyl which ls free or substituted by one or two Cl-
C7-alkyls or in whlch the two substltuents, toge~her wlth
the nitrogen atom to whlch they are bonded, form a
pyrrolidino, a piperidino or a perhydroazepino; a cyano;
a carboxyl which is free or esterified by a C1-C7-alkyl
or a benzyl; a phenyl; a C3-C7-cycloalkyl; an adamantyl;
or a heterocyclic radical selected from pyridyl,
methylpyridyl, furanyl, tetrahydrofuranyl, thienyl,
methylthienyl, pyrrolidino, plperidlno and
perhydroazepino groups;
` I R7 is a C1-C7-alkyl; a phenyl; a benzyl; a C3-C7-
cycloalkyl; a C2-C7-alkenyl; an ~-halogeno-C2-C7- alkyl
a polyhalogeno~Cl-C7~alkyl; an ~-hydroxy-C2- C7-alkyl; a
(C1-C6)alkylcar~onyl; a formyl; an ~- carboxy-C1-C7-
alkyl which is free or esterified by a Cl-C7-alkyl or a
benzyl; an ~-amino-C2-C7-alkyl in which the amino group
is free, substituted by one or two C1-C7-alkyls or in the
form of an ammonium ion; or an ~-carbamoyl-Cl-C7-alkyl
212921~
which is free or substituted by one or two Cl-C7-alkyls;
- R'7 is a piperazin-l-yl group which is unsubstituted or
substituted in the 4-position by a group R"7; a
piperidino group which is unsubstituted or substituted in
S the 4-position by a group ~'~'7; an azetidin-1-yl group
which is unsubstituted or substituted in the 3-position
by a group R'''7; or a pyrrolidino group which is
unsubstituted or substituted by a group R''''7;
- R''7 is a Cl-C7-alkyl; a phenyl; a benzyl; a (C1-C6)
alkylcarbonyl; or a formyl;
- R'''7 is R''7; or an amino which is free or carries a
protecting group;
- R''''7 is R'''7; or a carboxyl group which is free or
esterified by a Cl-C7-alkyl;
IS - R8 and Rg are each independently a hydrogen; a Cl-C7-
alkyl; a benzyl; or a phenyl; Rg can also be a C3-Cg-
alkene; a (Cl-C6)alkylcarbonyl: a formyl; a (C1-C6)-
alkylthiocarbonyl; a cycloalkylcarbonyl in whlch the
cycloalkyl is C3-C7; a cycloalkylthiocarbonyl in which
the cycloalkyll is C3-C7; an ~-amino(C2~C6)~
alkylcarbonyl; an ~-hydroxy(Cl-C6)alkylcarbonyl: an ~-
benzyloxy(Cl-C6)alkylcarbonyl; a phenoxycarbonyl; a
phano~ythiocarbonyl; a thienocarbonyl; a pyridyl~arbonyl~
a methylpyridylcarbonyl; a C1-C7-alkoxycarbonyl; a
benzoyl; a phenacetyl; a group -CO-CR1oR 10- NRllR ll; a
group -CRloR~locoRl2; a group -(CH2)tCO R12; a ~roup -
CO(CH2)t-COR12; a carbamoyl which is unsub~tituted or
substituted by Rl~ and R'14; a thiocarbamoyl which is
unsubstituted or substituted by R14 and R'14; ;or a
heterocyclla radical selected from pyrazolyl, imidazolyl,
triazolyl, tetrazolyl, pyridinyl, pyridazinyl,
pyrim~d~nyl, pyridyl and thlazolyl group~
or
- R8 and Rg, together with the nltrogen atom to which
they are bonded, form hydanto~n; N~methylhydantoin; or a
heterocyrle ~elected from pyrrol-l-yl, ~3- pyrrolin-1-yl,
2129~
pyrrolidin-l-yl and isoindolin-2-yl in which the benzene
ring can be unsubstituted or substituted by a halogen, a
C1-C7-alkyl, a trifluoromethyl or a methoxy;
- Rlo and R'10 are each independently hydrogen; a C1- C7-
alkyl; or a benzyl; or R1o and R'10, together with the
carbon atom to which they are bonded, form a C3- C7-
cycloalkyl;
- Rl1 and R' 11 are each independently hydrogen; or a Cl-
C7-alkyl;
- R12 is a hydroxyl; a Cl-C7-alkoxy; or an amino which is
unsubstituted or substituted by one or two Cl-C7- alkyls;
- R13 is hydrogen; a Cl-C7-alkyl; a phenyl; a benzyl; a
(Cl-C6)alkylcarbonyl; a formyl; a Cl-C7-alkoxycarbonyl;
or a carbamoyl which is unsubstituted or substituted by
one or 2 C1-C7-alkyls;
- Rl4 and R'14 are each independently a C1-C7-alkyl which
18 unsubsti~uted or subst~tuted by R15; a phenyl which is
unsubstituted or substituted by R'15; a C3-C7-cycloalkyl;
or an adamantyl;
or
- R14 and R'14, together with the nitrogen atom to which
they are bonded, form a heterocycle selected from
morpholine, thiomorpholine, piperazine, azetidine,
pyrrolidlne, piperidine and perhydroazepine, said
heterocycle being unsubstituted or substituted by one or
more methyl groups, by a phenyl or by an amino group
which i9 free or carries a protecting group;
- R15 i8 a phenyl; a pyridyl; a hydroxyl; a C1-C7-
alkoxy; an amlno which is free or substituted by one or
two Cl-C7-alkyls; or a carboxyl which is free or
esterified by a C1-C7-alkyl;
- R'1s is a hydroxyl; or an amino which is free or
substituted by one or two C1-C7-alkyls;
- m is 1 or, if R6 is a halogen, a C1-C7-alkyl or a Cl-
C7-alkoxy, m can also be 2, 3 or 4, or else (R6)m can be
m substituents having different meanings selected from
:--
, ~ 10
21292~
halogen, Cl-C7-alkyl and Cl-C7-alkoxy:
- p and q are each an integer, it being possible for
their sum to vary from 3 to 6;
- t is an integer w~ich can vary from 2 to 5; ~- .
S - t' is an integer which can vary from O to 3;
- X is oxygen; a group S(O)n; a group NR13; or a group ~ :
N(O~R13: and :`-
- n i~ O, l or 2; : :
with the limitation that if ::
- Rl and R2 are as defined above with the exception of
the ureido group ~ubstituted by a benzyl group, or the
thioureido group which is unsubstituted or substituted by
a phenyl, a benzyl or one or two Cl- C4-alkyls;
- R3 and R4 are each independently a Cl-C6-alkyl: a C3-
15 C7-cycloalkyl; a phenyl; a benzyl; or a cycloalkyl mathyl .
in which the c~cloalkyl is C3-C7;
or
- R3 and R4 together form a group ~(CH2)pX(CH2)q~ in
which X is oxygen, sulfur or a group NR13; : .
or
- R3 and R4, together with the carbon to which they are
bonded, form an optionally fused, saturated or
unsaturated C3-Clo hydrocarbon ring whlch is
unsubstituted or substituted by one or more Cl-C7-alkyl :
25 groups or by a C3-Cs-spirocycloalkyl; ~:~
- Rs and R6 are ot~er than a hydrogen: a halogen; a Cl-
C7-alkyl; a trifluoromethyl; a cyano; a nitro; an amlno ~ :
which is free or substituted by one or two Cl- C7-alkyl~;
a hydroxyamlno, a hydroxyl; a carboxyl; a group -OR7; a
group -SR7; a (Cl-C6)alkylcarbonyl; a formyl; a Cl-C7-
alkoxycarbonyl; a phenoxycarbonyl; a benzyloxycar~onyl; a .~
carbamoyl substituted by groups R'6 and R''6: a : :
thiocarbamoyl which is free or substituted by one or two
Cl-C7-alkyls; a sulfamoyl; an alkylsulfamoyl or
dialkylsulfamoyl in which the alkyl is Cl-C7; a group
SO2R'7; an alkylsulfonamido in which the alkyl is Cl-C
212921~
a group -COR'7; a group -NR8Rg; or a group -CO-NH-
CH(Rlo)-COR12, it being possibla, if appropriate, for the
phenyl group formi~g part of the substituent R5 and/or R6
to be unsubstituted or monosubstituted or polysubstituted
by a Cl-C7-alkyl, a trifluoromethyl, a methoxy, a
halogen, a sulfamoyl, an alkylsulfamoyl in which the
alkyl is Cl-C7, a carboxyl, an alkoxycarbonyl in which
the alkyl is C1-C7, a Cl-C6-alkylcarbonyloxy, a formyloxy
or an imidazolyl;
in which groups R5 and/or R6:
- R'6 and R''6 are each independently hydrogen; a C1-C7-
alkyl which is un~ubstituted or substituted by R'''6; a
phenyl; a pyridyl; a methylpyridyl; a piperidin-4- yl; or
a methylpiperidin-4-yl;
~5 ~ R'''6 is a hydroxyl; a cyano; a carboxyl whlch i8 free
or esterified by a Cl-C7-alkyl or a benzyl; a phenyl; a
pyridyl; a methylpyridyl; or an amino which i8 free or
substltuted by one or two Cl-C7-alkyls;
- R7 i8 a C1-C7-alkyl; a phenyl; a benzyl; a C3-C7-
cycloalkyl; a C2-C4-alkenyl; an ~-halogeno-C2-C7- alkyl;
a polyhalogeno-C1-C7-alkyl: a (Cl-C6)alkylcabonyl: a
formyl; an ~-carboxy-Cl-C7-alkyl which is free or
esterified by a Cl-C4-alkyl or a benzyl; or an ~-amlno-
C2-C7-alkyl in whlch the amlno group is free, substltuted
2S by one or two Cl--C4-alkyls or in the form of an ammonium
ion;
- R'7 i8 a plperazin-l-yl group which is unsubstituted or
substituted in the 4-position by a group R"7; a
! ' plperidlno group which is unsubstituted or substituted in
the 4-position by a group R'''7; an azetidin- l-yl ~roup
which is unsubstituted or substituted in the 3-position
by a group R'''7;
- R''7 is a C1-C4-alkyl; a phenyl: a benzyl; or a ~Cl-
C3)alkylcarbonyl;
3S - R' ' '7 is R''7; or an amino which is free or carrles a
protecting group;
12 2 1 2 9 ~
- R8 and Rg are each independently a hydrogen; a Cl-C7-
alkyl; a phenyl; or a benzyl, Rg can also be a ~Cl-
C6)alkylcarbonyl; a formyl; a cycloalkylcarbonyl in whlch
the cycloalkyl is C3-C7; a cycloalkylthiocarbonyl in
S which the cycloalkyl is C3-C7; an ~-amln(C2~
C3)alkylcarbonyl; an ~-hydroxy(Cl-C3)alkylcarbonyl; an
~-benzyloxy(Cl-C3)alkylcarbonyl; a phenoxycarbonyl; a
thienocarbonyl; a pyridylcarbonyl; a methyl-
pyridylcarbonyl; a Cl-C4-alkoxycarbonyl; a benzoyl; a
group -CO-cH(Rlo)-NRllR ll; a group -CH(Rlo)CO2Rll; a
group -(CH2)t~CORl2; a group -CO(CH2)t--CORl2; or a
carbamoyl which is unsubstituted or substituted by a
phenyl or one or two Cl-C4-alkyls;
- t'' ls an integer which can vary from l to 3;
- Rlo is hydroyen; a Cl-C4-alkyl; or a benzyl;
- Rll and R'll are each independently hydrogen; or a C1-
C4-alkyl;
- Rl2 is a hydroxyl; a Cl-C4-alkoxy; or an amino which is
unsubstituted or substituted by one or two Cl-C4- alkyls;
and
- Rl3 is hydrogen; a Cl-C4-alkyl; a phenyl; a benzyl: a
(Cl-C3)alkylcarbonyl; a formyl; a Cl-C4-alkoxycarbonyl;
or a carbamoyl which is unsubstituted or ~ubstituted by
one or 2 Cl-C4-alkyls;
and their salts where appropriate.
If a compound according to the invention has one
or more asymmetric carbons, the invention includes all
the optical lsomers of this compound.
If a compound according to the invention exhibits
conformational isomerism of the axial-equatorial type,
the invention includes all the conformational isomers of
this compound.
The salts of the compounds of formula (I)
according to the present invention include those with
mineral or organlc acids which permit a suitable
separation or crystallization of the compounds of formula
13
2~ ~92~
(I), such as picric acid, oxalic acid or an optlcally
active acid, for example a mandelic acid or a
camphosulfonic acid, and mineral or organic acids which
form physiologically acceptable salts such as the
hydrochloride, hydrobromide, sulfate, hydrogensulfate,
dihydrogenphosphate, maleate, f~marate or naphthalene-2-
sulfonate.
The salts of the compounds of formula (I) also
include the salts with organic or mineral bases, for
example the salts of alkali me~als or alkaline earth
metals, such as the sodium, potassium and calcium salts,
the sodium and potassium salts being pre~erred, or with
an amlne such as trometamol, or else the salt~ of
arginine, lysine or any physiologlcally acceptable amine.
According to the present invention, halogen is
understood as meaning an atom selected from fluorine,
chlorine, bromine and iodine, preferably fluorine or
chlorine. Amine-protecting group is understood as
meaning a group such as, for example, a Cl-C4-alkyl, such
as methyl or tert-butyl,; benzhydryl; trityl; benzoyl, a
Cl-C4-alkylcarbonyl, such as tert-butoxycarbonyl,
benzyloxycarbonyl; benzyl or sub~tituted benzyl ~uch as
p-nitrobenzyl, p-chlorobenzyl or p-methoxybenzyl.
According to ~he present invention, Cl-C4-, Cl-
C3-, Cl-C5-~ Cl-C6-, Cl-C7-, C2-C6- or C2-C7-alkyl is
understood as meaning a linear or branched alkyl.
Ac~ording to the present invention, optionally
fused, saturated or unsaturated C3-Cl2 hydrocarbon ring
! ls understood a~ meaning various hydrocarbon rings of
monocyclic, bicyclic or tricyclic ~tructure, for example
a cyclobutane, a cyclopentane, a cyclohexane, a
cycloheptane, a cyclooctane, an indane, a hexahydro
indane, an adamantane, a norbornane, a norbornene, a
dihydrophenalene, a tricyclo[S.2.l. o2 ~ 6]decane, a tri-
cyclo[5.2.l. o2~ 6]dec-8-ene, a bicyclo[2.2.l]heptane or a
bicyclot3.3.l]nonane.
14 212921 5 -
According to the present invention, if R3 and R4,
together with the carbon ~o which they are bonded, form
an optionally fused, saturated or unsaturated C3- Cl2
hydrocarbon ring substituted by a hydroxyl, the preferred
groups for substituting said hydroxyl are the methyl,
ethyl, methoxy~?ethyl, methoxyethyl, phenylmethoxy~?ethyl,
tetrahydrofuranyl and tetrahydropyranyl groups.
The compounds of formula (I) ~n which Rl ls in
the 5-position of the indol-2-one and R2 ls hydrogen are
preferred compounds.
The compounds of formula (I) in which Rl is a
chlorine or fluorine atom or an ethoxy group in the 5-
position of the indol-2-one and R2 is hydrogen are
preferred compounds.
The compounds of formula (I) in which R3 and R4,
together with the carbon to which they are bonded, form a
C3-Cl2 hydrocarbon ring are preferred compounds;
particularly preferred compounds are those in which R3
and R4, together with the carbon to which they are
2~ bonded, form a cycloheptane, an adamantane, a tricyclo-
[5.2.l.02,6]dec-8-ene, a tricyclot5.2.l.02~6]decane, a
bicyclo[2.2.l~heptane, a bicyclo[3.3.l]nonane or a
cyclohexane which i8 unsubstitutsd or substituted by a
C3-Cs-spirocycloalkyl or by one or two Cl-C7-alkyl
groups.
More particularly preferred compounds are those
in which R3 and R4, together with the carbon to which
they are bonded, form a cyclohexane substituted by a
group selected from methoxy, ethoxy and 2-methoxy-ethoxy.
The compounds of formula (I) in which the
substituents R5 and R6 are in the 2,4-position of the
phenyl ring are preferred compounds.
The compounds of formula (I) in which R5 is an
orthomethoxy group and R6 in the para-pos1tion is a group
selected from:
- (piperidin-l-yl)carboxamido,
.~ ?': ~ . ,. . .: .
`` 212921~
- (2-cyanoprop-2-yl)carbonyl,
- pyrrolidin-l-yl,
- 3,3-diethylguanidino and
- N' ,N'-diethylthioureido
are preferred compounds.
The following abbreviations are used in the
description and in the Examples:
DCM: dichloromethane
ether: ethyl ether
iso ether: isopropyl ether
Boc: tert-butoxycarbonyl
Me, MeO: methyl, methoxy
Et, ~tO: ethyl, ~tho~y
Pr, iPr, nPr: propyl, isopropyl, n-propyl
15 Bu, lBu, tBu: butyl, isobutyl, tert-butyl ~.
Ph: phenyl
Bz: benzyl
Ts: tosyl
Ac: acetyl :
AcOEt: ethyl acetate
AcOH: acetic acid
HCl: hydrochloric acid
MeOH: methanol
EtOH: ethanol
DMF: dlmethylformamide
THF: tetrahydrofuran ; .
DMSO: dlmethyl sulfoxide
DIPEA: diisopropylethylamine
: NaOH: sodium hydroxide
NaHC03: sodium hydrogencarbonate
TEA: triethylamine
TFA: trifluoroacetic acid
TMEDA: tetramethylethylenediamine
Lawesson's reagent: 2,4-bis(4-methoxyphenyl)-1,3-
d~thia-2,4 diphosphetane 2,4-disulfide
M.p~: melting point -~
.: ~ -...
16
2129~1~
saline solution: saturated aqueous sodium chloride
solutlon
TLC: thin layer chromatography
HPLC: high pressure liquid chromatography
5 aqueous hydrochloric acid: dilute hydrochloric acid, :
about l N
RT: room temperature
B.p.: boillng point
NMR: nuclear magnetic resonance ~;.
s: singlet
bs: broad singlet
d: doublet
t: triplet
q: quadruplet : -~
m: unresolved signals
mt: multiplet
The present invention further relates to a
process for the preparation of the compounds according to .
the in~ention, and their salts, which comprises:
20 l/ rsacting a benzenesulfonyl halide of the formula ~ -
R5
(~1) .
(RVl)m
in which Hal is a halogen atom, preferably chlorine, and
R'5 and RVI are respectively either R5 and R6 as def~ned
above for (I), or precursor groups of R5 and R6, with a :-
l,3-dihydroindol-2-one disubstituted in the 3-position of
the formula
,~ 17
212~21~
R'~ R4
R~ N~ o (Il)
in which R'1, R'2, R'3 and R'4 are respectively either
Rl, R2, R3 and R4 as defined for (I), or precur~or groups
of Rl, R2, R3 and R4; and
2/ elther, if R'1 = Rl, R 2 ' R2, R 3 R3, 4 4
R's = Rs and RVI = R6, isolating the resulting compound
of formula (I);
3/ or, if any one of the groups ~ 1, R 2~ R 3, R 4, R 5
and/or RVI is respectively a precursor group of R1, R2,
R3, R4, R5 and/or ~6~ subJecting the compound obtained,
hereafter called the compound of formula (I'), to a
subsequent ~reatment in order to prepare the compound of
formula (I) by converting any one of the groups R'1, R'2,
R'3~ R'4~ R'5 and~or ~VI to Rl, R2, R3, R4, Rs ~ndJ or R6
respectively; and ~-~
4/ if desired, converting the resulting compound of
formula (I) to one of its salts.
The reaction of step 1/ i~ carried out in an
anhydrous solvent such as DMF or THF, in the presence of
a metal hydride such as, for example, sodium hydrlde, or
in the presencs of an alcoholate such as potassium tert-
butylate. ~-~
The 1,3-dihydroindol-2-ones (II) are known or can
be prepared by known me~hods using different procedures.
Compounds (II) in which R'1 and/or R'2 are a
halo~en and R'3 and R'4, together with the carbon to
which they are bonded, form a spirocyclobutane, a
spirocyclohexane or a spirocycloheptane are known, for
example from D.W. Robertson et al., J. Med. Chem., 1987,
~Q (5), 824-829. ~lso, 5-chloro-3-spirocyclo~
pentanelndol-2-one is described in patent US 3 947 451. ;~
18 2 1 2 9
To prepare the compounds (II) ln the case where :.
R'3 and R'4 to~ether are a hydrocarbon group, it i8
possible to use the srunner reaction described by R.F.
Moore and S.G.P. Plant in J. Chem. Soc., 1951, 3475- .
5 3478, which leads to the preparation of compounds (II) in .
which CR'3R'~ is a cyclopentane or a cyclohexane.
This reaction is carried out by cyclizing a -
phenylhydrazide derivative of the formula
R 1
R'3
JL N H ~ H 1 1 ~H \ R~ (~)
ln which R'l, R'2, R'3 and R'4 are as defined above for
(II), for example by heating in quinoline in the presence
of calclum oxide.
According to the same authors, the
phenylhydrazide derivative (IV) is obtained by reactlng a
hydrazine derivative of the formula
R 1~/~
~NH-NH2
R 2 (V) ,~
;
: ,
in which R'l and R'2 are as defined above for (II), with :
an acid halide of the formula
R
C--CH
2s
in which R'3 and R'4 are as defined above for (II).
~ ~ -
2~2921~ :
In one particular embodiment, lf R'3 and R'g,
together with the carbon to which they are bonded, form a
polycondensed hydrocarbon ring, for example a norbornane
or a norbornene, the reaction is carried out by the
method described by ~. Wolff et al., Tetrahedron, 1986,
42 (15), 4267-4272: First of all, a lithium salt of the
compound (IV) is prepared by reaction with a lithium
reagent such as n-butyllithium, in an inert solvent such
as THF, at low temperature, and then the cyclizatlon is
effected by heating in a solvent such as naphthalene or
prehnitene (1,2,3,4-tetramethylbenzene).
The compounds (II) in which R'l = R'2 = H and
CR'3R'4 is adamantane are described in I. Fleming et al.,
J. Chem. Soc., Perkin Trans. I, 1991, ~, 617-626. The
compounds (II) in which R'3 and R'4, together with the
carbon atom to which they are bonded, form an adamantane
and R'l and R'2 are other than hydrogen can be prepared
by the method described above.
The hydrazine derivatives (V) are known or are
prepared by known methods. The same applies to the acid
halides (VI).
A 1,3-dihydroindol-2-one disubstituted ln the 3-
position (II) can also be prepared from a 1,3- ~ -
dihydroindol-2-one of the formula
~
R'2--~ /~ (Vll) :.. :
H
in which R'l and R'2 are as deflned above for (II), by
using various processes.
For example, the method described by A.S. Kende
and J.C. Hodges in Synth. Commun., 1982, 12 (1), l-lO,
involves the addition of an alkylating agent in an ~ ;
appropriate solvent. Thus, to prepare a compound (II) in
.:. . ~,:~
~ 20
2129~1~
:
which R'3 = R'4, the reaction is carried out in THF at -
75-C, in the presence of TMEDA, by the addition of an
alkyllith~um such as butyllithium, followed by reaction
with a halide of the formula R'3Hal: if R'3 and R'4 are
different, the alkylation reaction can be performed in 2
steps with 2 different alkyl halides of the formulae
R'3Hal and R'4Hal. To prepare a compound ( I I ) in which
R'3 and R'4 together form a group of the formula -(CH2)n-
, where n varles from 3 lto 12, the reagent used is a
compound of the formula Z(CH2)nZ, in which Z i8 an
electrophilic group such as a halogen, preferably bromine
or iodine, a tosyloxy group or a mesyloxy group. In one
variant of this process, the reaction can also be carried
out by the addition of an alkali metal alcoholate, such
as potassium tert- butylate, onto a compound of for~ula
(VII), in THF at -40-C, followed by the addltion of a
compound of the formula Z-(CH2)nZ a~ defined above.
The compounds (II) ln which R'3 and R'4, together
with the carbon to which they are bonded, fo~m a C4-Cg
hydrocarbon ring substituted by one or more Cl- C7-alkyl
groups or by a C3-C5-spirocycloalkyl are prepared ln the
same way.
The compounds of formula (II) in which R'3 and
R'4 are each independently an alkyl or a phenyl are
known. For example, patent D8 3 300 522 describes 5-
alkoxy-3,3-dimethylindol-2-ones.
If R'3 and R'4 together form a group -(CH2)pX-
(CH2)q~~ in which p, q and X are as defined a~ove for
I), a 1,3-dihydroindol-2-one disubstitut~d in the 3-
position of formula (II) can be prepared from a 1,3-
dihydroindol-2-one unsubstituted in the 3-position (VII)
by reaction with a compound of the formula
Z-(cH2)p-x-(cH2)q-z (VIII)
in which Z is as defined above and X, p and q are as
... .. , , .. , . . . . ....... ., . ,, ~, . , . .. . ~ . . .
i: ~ . ~ ,. - - . :.
;:,,: , . .
21 212921~
defined above for (I). The reaction ls carried out ln
the presence of an alcoholate, for example potassium
tert-butylate, in an anhydrous solvent such as, for
example, THF.
If X is a nitrogen atom substituted by a (Cl-
C6)alkylcarbonyl, a formyl, a Cl-C7-alkoxycarbonyl or a
Cl-C7-alkylcarbamoyl, the substitution on X can be
effected either on the 1,3-dihydroindol-2-one derivative ~-
(II) or on the final compound (I) starting from a
compound in which the nitrogen atom (X - NH) is
unsubstituted.
Thus, if X is a nitrogen atom substituted by a
Cl-C7-alkoxycarbonyl, the first itep is to prepare a
compound (II) or (I) in which X is NH, whlch is then
reacted with the appropriate chloroformate to give ~he
deslred compound (II) or (I). In the same way, a Cl- C7-
alkyl isocyanate is reacted with a compound (II) or (I)
in which X = NH to give a derivative (II) or a compound
(I) in whlch X is a nitrogen atom substituted by an
alkylcarbamoyl. An acid chloride or an anhydrlde is
reacted with a compound (II) or a compound (I) in which X
- NH in order to prepare a compound of formula (II) or
(I) in which X is a nitrogen atom substitutad by a (C
C6)alkylcarbonyl.
Formic acid in the presence of acetic anhydride
is reacted with a compound (II) or (I) in which X ~ NH ln
order to prepare a compound of formula (II) or (I) in
which X is a nltrogen atom substituted by a formyl.
If X is a sulfur atom or a nitrogen atom
substituted by R13, it is also possible firstly to
prepare a compound of the formula
. , ~.
, 22
21292~
.
R'l` (CH2)Pz
~ o
R'2 H (l~
in which R'l, R'2, Z, p and q are as defined abovP, and
to perform a nucleophilic substitution with a hydrogen ~-
S sulflde salt or an amine of the formula H2N~13, in a
solvent such as an alcohol, an ether, DMF or a mixture
thereof, at a temperature between 5-C and the reflu~
temperature.
The 1,3-dihydroindol-2-ones of formula (II') are
obtained from the corresponding diols, either as such or
protected, for example by a tetrahydropyran-2- yl yroup.
The reaction can be carried out with
dlbromotriphenylphosphorane according to J. Chem. Soc.,
Chem. Commun., 1989, 1619.
The compounds (II) in which R'3 and R'4, together
with the carbon to which they are bonded, form a
pyrrolldine, N-alkylpyrrolidine, piperidine or N-
alkylpiperidine ring are described by M.J. Xornet in ~.
Med. Chem., 1976, 12 (7), 892-899.
In particular, horsfiline of the formula
N / Me
McO ~
H
is an alkaloid described in A. Jossang et al., J. Org.
Chem., 1991, 56 (23), 6527-S530.
To prepare a compound of formula (II) 1n which
R'3 and R'4, together with the carbon to which they are
.,
23
2129~1')
bonded, form a tricyclo[5.2.l.02,6]decane or a
tricyclo[5.2.l.02,6]dec-8-ene, a compound (VII') or,
respectively, a compound (VII'') of the formulae
Z{~H2~ Z{~H2 ~1
Z{~H2--\V Z~H2 ~
(V~ (V 1) , ,,
in which Z is as defined above, is reacted with a
compound of formula (VII). Compound~ (VII') and (VII'')
substituted by one or more Cl-C7-alkyl groups are u~ed to -
10 prepare compounds (II) in which said carbocycles are ~ -
substituted. :
A compound of formula (II) in which R'3 and R'~
together with the carbon to which they are bonded, form a .
tricyclo[5.2.l.02,6]decane can al~o be prepared by the
catalytic hydrogenation of a compound of formula (II) in
which R'3 and R'4, together with thei carbon to which they
are bonded, form a tricyclo[5.2.l.02~6]dec- 8 ene, for .-~
example in the presence of palladium-on- charcoal or .:
Raney~ nickel. - .. :.
A compound of formula (I) in which R3 and R~
together with the carbon to which they are bonded, form a .-
tricyclo[5.2.l.02~6]decane aan also be prepared by the
catalytic hydrogenation of a compound of formula (I) in :
which R3 and R4, together with the carbon to which they ~ -
are bonded, for~ a tricyclo[5.2.l.02~6]dec- 8-ene, for
: example in the preience of palladium-on- charcoal or .--
Raney~ nickel. ~ ~:
To prepare a compound (II) in which R'3 and R'4, .
together with the carbon to which they are bonded, form
30 an .~ndane or a hexahydroindane, a compound (VIII') or, ..
respectively, a compound (VIII'') of the formulae ~-.
24
` 2129~1~
Z{~H2--~I z~H2 ~--\1
Z-CH2 ~ Z~CH
~VII~' ~VII~
in which Z is defined as indicated above for (VIII), ~s
reacted with a compound (VII). Compounds (VIII') and
(VIII'') substituted by one or more C1-C7-alkyl groups
are used to prepare compounds (II) in which the indane or
hexahydroindane is substituted.
The method of A.S. Kende and J.C. Hodges
described above or it~i variant described above can be
used to prepare compounds of formula (II) ln whlch the
substituents R'3 and R'4, together with the carbon ~o
whlch they are bonded, form an optlonally fused,
saturated or unsaturated C3-C12 hydrocarbon ring
substituted by one or more C1-C7-alkyl groups or by a
group selected from an oxo ~roup protected under acetal
form, a C3-C5-spirocycloalkyl, or one or two hydroxyls
substituted by a Cl-C4-alkyl, a (C1-C5)alkoxyalkyl in
whlch the alkyl is Cl-C4, a triphenylmethoxyalkyl in
which the alkyl is Cl-C4, a phenylalkoxyalkyl in which
the alkoxy is Cl-C2 and the alkyl ls Cl-C4, a
tetrahydrofuranyl or a tetrahydropyranyl. To obtain the
compounds of formula (I) in which R3 and R4, together
with the carbon to which they are bonded, form an
optionally fused, saturated or unsaturated C3-C12
hydrocarbon ring substituted by one or two hydroxyls, the
; Icorresponding compounds of formula (I) in which the
hydroxyl group or groups are ~ubstituted by a ~Cl
Cs)alkoxyalkyl in which the alkyl is C1-C4, a
tetrahydrofuranyl or a tetrahydropyranyl are deprotected.
This deprotect~on is effected ln an acid medium, for
example in the presence of a mineral or oryanic acid, in
an alcohol or ether solvent ~uch as THF, at a temperature
between 15-C and the reflux temperature; the deprotection
. - ~ - - . . ~ . . . .
1292~ ~ :
can be carried out for example in the presence of
hydrochloric acid or pyridinium toluenesulfona~e in an
alcohol.
To obtain the compounds of formula ( I ~ ln which
5 R3 and R4, together with the carbon to which they are
bonded, form an optionally fused, saturated or
unsaturated C3-C12 hydrocarbon ring Qubstituted by one or
two ~-hydroxy(Cl-C4)alkoxy groups, the corresponding
com pounds of formula (I) in which R3 and R4, together
with the carbon to which they are bonded, form an
optionally fused, saturated or unsa~urated C3-C12
hydrocarbon ring substituted by one or two (Cl-
Cs)alkoxy(Cl-C4)alkoxy groups are deprotected. Thls
deprotection i~ effected in an acid medium, for example
tri$1uoroacetic acid, in a solvent such as DCM.
Compounds of formula (I) in whlch R3 and R4,
together with the carbon to which they are bonded, form
an optlonally fused, saturated or unsaturated C3-C12
hydrocarbon ring substituted by one or two (Cl-C4)-alkoxy
~roups or one or two (C1-C5)alkoxy(Cl-C4)alkoxy groups
can also be prepared by alkylatin~ compounds of formula
(I) in which R3 and R4, together with the carbon to which
they are bonded, form an optionally fused, saturated or
unsaturated C3-C12 hydrocarbon ring substituted by one or
two hydroxyls. This alkylation is carried out more
particularly w$th powerful alkylating reagents such as
alkyl trifluoromethanesulfonates, in solvent such as DCM
or carbon tetrachloride, in the presence of a ba~e such
as 2,6-di tert-butylpyridine, by the method described in
30 Carbohydrate Research, 1975, 44, C5-C7. The alkyl
trifluoromethanesulfonates can be obtained from the alkyl
iodides by reaction with a trifluoromethanesulfonic acid
salt such as the silver salt (Chemical Reviews, 1977,
77).
Compounds of formula (I) in which R3 and R4,
together with the carbon to which they are bonded, form
26
2 1 2 9 2 1 rj
an optionally fused, saturated or uns~turated C3-C12
hydrocarbon ring subst~tuted by one or two formyloxy
groups or one or two (C1-C7)alkylcarbonyloxy group.~ can
be prepared by reacting dimethyl sulfate in the presence
of cesium carbonate or, respectively, by reacting an acid
halide or an anhydride with a compound of formula (I) in
which R3 and R4, together with the carbon to which they
are bonded, form an optionally fused, saturated or
unsaturated C3-C12 hydrocarbon ring substituted by one or
two hydroxyls.
A compound of formula (I) in which R3 and R4,
together with the carbon to which they are bonded, form a
tricyclo[5.2.1. o2 ~ 6]decane-8,9-diol can also be obtained
from a compound of formula ( I ) in which R3 and R4,
together with the carbon to which they are bonded, form a
tricyclo[5.2.1.02,6]dec-8-ene, which is reacted with
metachloroperbenzoic acid at room temperature, in a
solvent such as DCM, to give an intermediate compound of
fo~mula (I) in which R3 and R4, together with the carbon
to which they are bonded, form a tricyclo-
t5.2.1.O2~6~decan-8,9-epoxy; the intermediate epoxide
derivative i8 then hydrolyzed by refluxing in water in
the presence of sulfuric acid or in a basic medium.
The compounds of formula (II) in which R'3 and
R'4, together with the carhon to which they are bonded,
form either an optionally fused, saturated or unsaturated
C3-C12 hydrocarbon ring substituted by an oxo group, or a
group ~(CH2)p~X~(CH2)q~ in which X is a group SO, S2 or
N(O)R13, are prepared by known oxidation reactions
starting from the corresponding compounds of formula (II)
in whlch R'3 and R'4, together with the carbon atom to
which they are bonded, respectively form eithsr an
optionally fused, saturated or unsaturated C3-C12
hydrocarbon ring substituted by a hydroxyl, or a group -
(CH2)p~X~(CH2)q~ in which X is a sulfur atom or a group
NR13.
~ 27
21292~ ~
For example, th~ oxidation of secondary alcoholsto k~tones can be carried out in the presence of chromium
oxide complexes such as pyridinium chlorochromate, in an
inert solvent such as methylene chloride, or with
oxidizing agents such as DMSO, by the methods de~cribed
ln Tetrahedron, 1978, ~4, 1651.
The oxldat~on of the compounds (II) contalning a
sulfur or nitrogen atom (X = S, NR13) can be effected in
the presence of hydrogen peroxide or peracids such as
peracetic or metachloroperbenzoic acid, in inert solvents
such as ketones or acetic acid, at temperatures between
0-C and 50-C.
If R'3 and R'4 are each a phenyl, the process
described in Helv. Chim. Acta, 1946, 29, 415-432, can be
used t~ prepare a compound (II).
The 1,3-dihydroindol-2-one derivatives (VII) are
known or are prepared by known methods. An example which
may be cited is J.V, Ra~anBabu in J. Org. Chem., 1986, ~ -
~1, 1704-1712.
20The compounds of formula (II3 which carry certain
substituents R'1 and R'2 on their benzene moiety are u~ed ;
as precursors for the preparation of compounds of formula
(II) which carry other substituents R'1 and R'2. For
example, the compounds (II) in which R'l and/or R'2 - H
can be nitrated with the conventional reagents; they can
also be acylated by reaction with an acid chloride of the
formula RCOCl, ln which R i9 a Cl-C7-alkyl, in the
presence of a Lewis acid such as aluminum chloride, in
order to prepare a compound (II) in which R'l and/or R'2
z-COR. The compound (II) in which R'l is an am~no group
i~ prepared by the catalytic hydrogenation of a compound
(II) in which R'l is a nitro group and R'2 is hydrogen.
The benzenesulfonyl halides (III) are prepared by
known methods. Thus, for example, 4-dlmethylamino `~
benzenesulfonyl chloride is prepared accordin~ to C~N.
Sukenik et al., J. Amer. Chem. Soc., 1977, 9~, 851-858.
- ;,
28 212921~
More generally, the benzenesulfonyl halides (III) in
which the substituent R ' 5 iS a dimethylamino group are
known or are prepared by known methods; p-benzyloxy-
benzenesulfonyl chloride is prepared according to
European patent application EP 229 566.
The alkoxybenzenesulfonyl chloride is prepared
from the sodlum alkoxybenzenesul~onate, which is itself
prepared by reacting an alkyl halide with sodium
hydroxybenzenesulfonate.
2,4-Dimethoxybenzenesulfonyl chloride is prepared
according to J. Am. Chem. Soc., 1952, 74, 2008.
The halogenoalkoxybenzenssulfonyl chlorides can
be prepared accordlng to patent US 2 540 057.
The benzenesulfonyl halides of the formula
S02CI
OAIk
~JI
(111)'
YRV
in which
- Alk is a Cl-C7-alkyl;
- Y is O or S: and
~ RV is a Cl-C7-alkyl, a C3-C7-cycloalkyl, a C2-C7-
alkenyl, an ~-halogeno-C1-C7-alkyl, a polyhalogeno- Cl-
C7-alkyl, a benzyl, a ~Cl-C6)alkylcarbonyl, a formyl or
an ~-carboxy-Cl-C7-alkyl esterlfied by a Cl-C4-alkyl or
a benzyl,
are prepared according to D. Hofmann et al. in Liebigs
Ann. Chem., 1982, 287-297.
Benzene compounds carrying the substituents YRV
and OAlk in the 1- and 3-positions are reacted with
i-- 2 1 2 9 2 1 ~3
trimethylsilyl chlorosulfonate in a solvent such as DCM,
at RT. The method of R. Passerini et al. in Gazz. Chim.
Ital., 1960, 9Q, 1277-89, is then applied and this is
followed by neutralization, for example with alkali metal
carbonate, and then by reaction with a halide such as
POC13 to give the desired benzenesulfonyl halide.
The benzenesulfonyl halides (III) in which the
substituent R'5 is an alkoxycarbonyl, a phenoxycarbonyl,
a benzyloxycarbonyl, an alkylthlo, a phenylthio, a
benzylthio or a group -SR7, R7 being as defined Por (I),
are prepared according to Col. Czechoslov. Chem. Commun.,
1984, 49, 1184, from an aniline derivative substituted by
the same grouping R'5, said aniline derivative ltself
being obtained from the corresponding nitro derivatlve.
The nitrobenzoic acid derivatives are known; the
corresponding alkyl and phenyl esters are obtained by
sub~ecting this acid to an appropriate esterification
reaction.
The benzenedisulfonyl dihalides (III, Rs '= -
S02Hal) are known or are prepared by known methods. Forexample, 2,4-dimethoxybenzene-1,5-disulfonyl dichlorlde
ls described in R.J.W. Cremlyn, J. Chem. Soc. C, 1969,
1344.
The halogenoalkoxybenzenesulfonyl chlorides (III,
R'5 - ~-halogenoalkoxy) are used to prepare compounds
according to the invention in which the substituent Rs i8
an ~-aminoalkosy which is unsubstituted or substltuted
by one or two alkyls, according to the following
equa~lon:
-O-Alk'-Hal + NHAA' -~ -O-Alk'-NAA'
in which Alk' is a C2-C7-alkyl and A and A' are
independently hydrogen or a C1-C7-alkyl.
For certain meanings of the substituents Rl, R2,
R5 and/or R6, the compounds (I) according to the
_ 30
2129~ ~
invention can be prepared from a precursor of formula
(I') substituted by a group R'1, R'2, R's and/or RVI~
called a precursor group of R1, R2, Rs and/or R6, by
using methods known to those skilled in the art.
The description which follows relates to the
preparation of the compounds of formula (I) carrying
substituents Rl and/or R5; the same methods apply to the
preparation of ~he compounds in which the substi~uents R2
and/or R6 have the meanings indicated for Rl and R5.
The compounds (I) in which R1 and/or R5 are a
hydroxyl can be obtained by the catalytic hydrogenation
of a compound of formula (I') in which R'l and/or R's are
a benzyloxy, for example in the presence o~ palladium-on-
charcoal. These compoundY can also be prepared from
analogous compound3 of formula (I'3 ln which R'l and/or
R'5 are an amino group by using the method de~cribed in
J. Org. Chem., 1977, 42, 2053.
The compound~ of formula (I) in which R1 and/or
R5 are a Cl-C7-alkoxy can be prepared directly by the
process according to the invention starting from the
correctly sub~tituted compounds of formulae (II) and
(III).
The compounds (I') in which R'1 and/or R'5 are a
hydroxyl can al~o be used to prepare compounds (I) in
which Rl and/or R5 are a Cl-C7-alkoxy by reactlon with a
C1-C7-alkyl halide ln the presence of a base such as a
metal hydride or an alkali metal or alkaline earth metal
carbonate llke K2C03 or Cs2CO3, in a solvent such as THF
!or DMF. Likewise, the compounds of formula (I) in which
Rl and/or R5 are an ~-aminoalkoxy are prepared by
reacting an ~-chloroalkylamine with the compounds in
whlch R'l and/or R'5 = OH; similarly, ~he compound~ in
which R1 and/or R5 are an ~-hydroxyalkoxy are prepared
by reaction with a chloroalkyl alcohol; in the particular
case of the preparation of a compound (I) in which R1
and/or Rs - -O(CH2)~0H, it is also possible to react
~ 31
21~921 -j -
ethylene carbonate with a compound (I') in which R'
and/or R'5 = OH.
The compounds of formula (I) in whlch ~1 and/or
R5 are a (Cl-C6)alkylcarbonyloxy are obtained by reactlng
an acid halide or an anhydride with a compound (I') in
which R'l and/or R'5 are a hydroxyl.
The compound~ of formula (I) in which Rl and/or
R5 are a formyloxy are obtained for example by reacting
formic acid in the presence of dicyclohexylcarbodiimide
with a compound (I') in which R'l and/or R'5 are a
hydroxyl (J. HUANG et al, J. Chem. Res.(S), l991, 292-
293).
The compounds of formula (I) in which R5 is a
group -OR7, R7 bein~ an ~-carbamoyl-Cl-C7-alkyl which is
free or substltuted ~y one or two Cl-C7-alkyls, can be
prepared from a compound (I') in which R'5 is a group
ORV, Rv being an ~-carboxy-Cl-C7-alkyl e~terified by a
Cl-C7-alkyl. This preparation is carried out by reaction
with a correctly chosen amine in a manner conventional to
20 those skilled in the art. ~`
To prepare compounds of formula (I) in whlch R
and/or R5 are a (Cl-C7)monoalkylamino, a compound o~
formula (I') in which R'l and/or R'5 are an amino group
is reacted with an aldehyde or ketone in an acld medium,
in the presQnGe of a reducing agent such as sodium
cyanoborohydride, the compounds (I) in which Rl and/or R5
are a dialkylamino are prepared by an identical reaction.
The compounds of formula (I) in which R5 is an
amino grqup substituted by a benzyl, which is itself
optionally substituted, or by a C3 C8-alkene can be
prepared by reacting a benzyl chloride or a C3-Cg-
chloroalkene with a compound of formula (I') in which R's
i~ an amlno or alkylamino group.
The compounds of formula (I) in which Rs is a ~3-
pyrrolin-l-yl group are prepared by reacting ci~- l,4-
dichlorobut-2-ene with the compounds of formula (I') in
32
212321~
which R' 5 iS an amino group, in the presence of a base
such as triethylamine, under an inert atmosphere. The
compounds of formula ( I ) in which R5 iS a pyrrolidin-l-yl
group are then prepared by hydrogenat~on. The reaction
of cis-1,4-dichlorobut-2-ene with the compounds (I') in
which R'5 is an amino group can also be carried out in
air, in the presence of a base such as sodium carbonate,
under which conditions it results ln the formation of a
mixture of a compound of formula (I) in which R5 is a ~3-
pyrrolin-l-yl and a compound of formula ~I) in which R5
is a pyrrol-1-yl group, which can be separated by
chromatography.
The compounds of formula (I) in which R5 is an
isoindolin-2-yl group are prepared by reacting a,a'-
dibromo-o-xylene with the compounds of formula (I') in
which R'5 i8 an amino group, in the presence of a base
such as triethylamine, and in a solvent such as
dimethylformamide, under reflux.
The compounds of formula (I) in which R5 is a 1~
methyl-2,4-dioxoimidazolin-3-yl group (NR8Rg , N-
methylhydantoin) are prepared in two steps: Sarcosine is
reac~ed with a compound of formula (I') in which R's is a
phenoxycarboxamldo, in the presence of a base such as
triethylamine, to give a compound of formula (I'~ ln
which R'5 is an N'-carboxymethyl-N'-methylureido; the
previously obtained product then cyclizes on heating at
lOO-C under vacuum. The compounds of formula (I) in which
Rs is a 2,4-dioxoimidazolin-3-yl group (NRgRg
hydantoin) are prepared in the same manner by reacting
glycine with a compound of formula (I') as defined above.
If R'1 and/or R'5 are an amino, it is also
possible to perform a nitrosation, for example in the
presence of nitrous acid or sodium nitrite, in order to
prepare a compound (I') in which R'l and/or R's are a
diazonium salt; reactions known to those skilled in the
art then afford the compounds (I) according to the
2 1 2 9 ~ 1 ~
invention in which Rl and/or R5 are a cyano, a halogeno
or a Cl-C7-thioalkyl. ~inally, compounds (I) in which R
and/or R5 are a group of ~he formula RCONH-, ROCONH-,
RNHCONH- or RSO2NH-, in which R is a C1-C7-alkyl, a `
phenyl or a benzyl, can be prepared by conventional
reactions starting from compounds (I') in which R'
and/or R 5 5 NH2.
The compounds of formula (I) in which R5 i~ a C
C7-alkoxycarbonyl can be prepared directly by the process
according to the invention. Using methods known to those
skilled in the art, they make it possible to obtain the
compounds of formula (I) in which R5 is a carboxyl group.
The compounds of formula (I') in which R's is a
benzyloxycarbonyl can also be used to obtain~ the
IS compounds (I) in which R5 is a carboxyl by catalytic
hydrogenation. Reaction with a thionyl halide gives the
compounds of formula ~I') in which R's i8 a
halo~enocarbonyl. Such compounds are used to prepare
compounds of formula (I) in which R5 iQ a carbamoyl
substituted by R'6 and R''6 by reaction with a compound
HNR'6R''6. The compounds of formula (I') in which the
substltuent R'5 is a phenoxycarbonyl can also be used to
obtaln the compounds (I) in which R5 is a phenylcarbamoyl
or a Cl-C7-alkylcarbamoyl by reaction with an anlllne or
a Cl-C7-alkylamine. An aniline substituted on th~ phenyl
or an alkylamlne substituted on the alkyl can be used to
obtaln compound~ of formula (I) ln which Rs i8 a
phenylcarbamoyl substituted on the phenyl or,
respectively, an alkylcarbamoyl substituted on the alkyl
by R6 -
In the same way, the compounds of formula (I) inwhlch Rs is a group -CONHCR1o~'loCOR12 are prepared from
compound of formula (I') in which R's is either a group
-COCl or a phenoxycarbonyl group by reaction with
3s H2NCRloR~locoRl2-
The compounds of formula (I) in which Rs is a
.~
,.. ;. ~ , .. .,, .,,.. ,.: ... : i.. -. , , - . . .. .
, 34
- ` 21~92i~
group -COR'7 are prepared from corresponding compounds
( I ' ) in which R' 5 iS a phenoxycarbonyl by reaction with
R'7H-
A compound (I') in which R' 5 iS a nitro group
makes it possible to obtain a compound (I) in which Rs isan amino group by catalytic hydrogenation, for example in
the presence of platinum oxide, Raney~ nickel or
palladium-on-charcoal, or by chemical reduc tion, for
example in the presence of tin or iron in an acid medium;
other compounds in which the amino group is substituted
can then be prepared using reactions well known to those
skilled in the art. ~ -
For example, if it is desired to obtaln a
compound (I) according to the invention in which R5 is a
group -NR8Rg, Rg being an optionally substituted benzoyl,
benzoyl chloride in which the phenyl carries the
appropriate substituent is reacted with a compound (I')
in which R ' 5 is an amino group, in the pre~ence of an
amine s~ch as triethylamine. For example, 4-chloro-
sulfonylbenzoyl chloride can be reacted in order toprepare a compound (I') in which R's is a 4-chloro-
sulfonylbenzamids group, after which a compound (I) in
which the substituent R5 is a 4-sulfamoylbenzamido group
or a 4-alkylsulfamoylbenzamldo ~roup is obtalned by
reaction with ammonia or a Cl-C4-alkylamine re pectively.
In the ~ame way, the acid chloride RllR'llNCRlOR lOCOcl
is reacted with a compound of formula (I') in which R's
is a group -NHRg in order to prepare a compound of
formula (I) in which R5 is an -NRg substituted by -
COCRloR~loNRllR 11
If it is desired to prepare a compound (I) inwhich Rs i8 a group -NRgRg, Rg being a (Cl-C6)alkyl-
carbonyl, the appropriate anhydride or the appropriate
acid chloride is reacted with a compound (I') in which
R's is an amino group, in the preQence of an amine such
as triethylamlne. To prepare a compound (I) in which R5
21292~
:
is a group -NR8Rg, Rg being a formyl, formic acid is
reacted with a compound ( I ' ) in which R' 5 iS an amino
group, in the presence of acetic anhydride and of an
amine su~h as triethylamine.
In another preparatory example, a compound (I) in
which R5 is an alkylsulfonamido group is obtained by
reacting an alkylsulfonyl halide with a compound (I') in
which R ' 5 iS an amino group.
The compounds of formula (I') in which R'5 is an
amino group are also useful for the preparation of
compounds in which this amino group is substituted by a -
group -(CH2)t-COR12. In this case, a compound of the
formula Hal-(CH2)t-COOAlk, in which Hal is a halogen, for
example bromine, and Alk is a C1-C7-alkyl, is reacted
15 with (I') in the presence of cuprous chloride; if -
required, the resultin~ ester is converted to the acid or
an amide. A compound (I) in which Rs ~ -NHCO-(CH2)t~C02H,
where t' = 2 or 3, can be prepared by reacting an
anhydriae, such as succinic anhydride or glutaric
anhydride, with a compound (I') in which R'5 iR an amino.
If required, the re~ulting acid is converted to an ester
or an amide.
A compound (I) in which Rs = -NHCOCO2Et or -
NHCOC~2C02Et can be prepared by reacting ethyloxalyl
chloride, or, respectively, ethylmalonylchloride, with a
compound (I') in which R's is an amino.
In the same way, the compounds of formula (I) ln
which Rs is an amino gro~p substituted by a group
CRloR'1oC4R~2 are prepared by reacting a compound of the
formula Hal-CRloR~locoRl2 with the corresponding
compounds (I'~ in which the substituent R's is an a~lno.
A compound (I) in which Rs ls an amino group
substituted by a Cl-C7-alkoxycarbonyl or a
phenoxycarbonyl is prepared by reacting a Cl-C7-alkyl or
35 phenyl chloroformate with a compound (I') in whlch the ~;
substituent R's is an amino.
:.
"`'
~,~, - - . . . .
36
2129217
Likewise, a compound of formula (I) in whlch R5
is a phenoxythiocarbonylamino is obtained ~y reacting a
phenoxythiocarbonyl chloride with a compound of formula
(I') in which R' 5 iS an amino group.
A compound of formula (I) in which R5 is a ureido
or a thioureido is prepared by reacting ammonia with a
compound of formula (I') in which R'5 is an amlno group
substituted by a phenoxycarbonyl or a
phenoxythiocarbonyl; such a compound of formula (I') ls
reacted with a correctly subs~ituted aniline or a
correctly substituted C1-C7-monoalkylamine or -dialkyl-
amine in order to prepare a compound of formula (I) in
which Rs is a correctly substituted N'-phenylureido or a
correctly substituted N'-alkylureido or N',N'-di-
alkylureido in which the alkyl is Cl-C7.
It is also possible to prepare a compound (~) in
which Rs is a ureido (-NHCONR14R'14) or a thioureido (-
NHCSNR14R'14) by reacting a compound NHR14R'14 with a
compound (I') in which R'5 is a phenoxycarbonylamino or,
respectively, phenoxythiocarbonylamino sroup.
A further possibility i~ to prepare a compound
(I) in which Rs is a ureido (-NHCONR14R'14) or a
thioureido by reacting a carbamoyl chloride
(ClCONR14R'14) or, respectively, a thiocarbamoyl chloride
with a compound of formula (I') in which R's is an amino
group.
It is also possible to prepare a compound (I) in
which Rs is a thioureido by reacting Lawesson 1 3 reagent
with a compound (I') in which R'5 is the corresponding
ureido.
The compounds (I) in whlch Rs is a ~uanidino
group which is unsubstituted or monosubstituted or
disubstituted by a C1-C7-alkyl, a phenyl or a benzyl can
be prepared from the compounds (I') in which R's ~s a
phenoxyamido ~roup by reaction with cyanamide or a
derivative thereof correctly substituted on the nitrogen.
~ 37
21~21~
A compound (I) in which R5 is a carbamoyl which
ls unsubstituted or su~stituted by one or 2 Cl-C7-alkyl
groups is prepared by reacting an appropriate amine with
a compound (I') in which the substituent R'5 is an amlno,
in the presence of phosgene.
It is also possible to prepare a compound (I) in
which R5 is an amino group sub~tituted by an
alkylcarbamoyl or a phenylcarbamoyl by reacting an alkyl
or phenyl isocyanate with a compound (I') in whlch the
substituent R'5 is an amino.
Furthermore, a compound (I) in which R5 is a
sulfamoyl group which is unsubstltuted or substituted by
a Cl-C7-alkyl is prepared by reacting a~monia or a Cl-C7-
alkylamine with a compound (I') in which R'5 i9 a
lS halogenosulfonyl group.
The affinity of the compounds according to the
invention for the vasopressin receptor~ wa~ determined in
vltro using the method described in C.J. Lynch et al., J.
Biol. Chem., 1985, ~Q (5), 2844-2851. This method
consists in studying the displacement of trltlated
vasopressin bound to the Vl slte~ of rat liver membranes.
The concentrations of the co~pound~ according to the
invention which cause a 50% inhibition of the blnding of
tritlated vasopressin (ICso) are low, ranging down to 10-
7 M.
The affinity of the compounds (I) according tothe inventlon for the Y2 receptors was measured on a
bovlne kldney membrane preparatlon by a method adapted
from P. Crau~e et al., Molecular and Ce}lular
Endocrinology, 1982, ~, 529-541, and F~L. Stassen et
al., J. Pharmacol. Exp. Ther., 1982, ~2~, 50-54. The
com pounds according to the invention inhibit the binding
of tritiated arginine vasopressin to the receptors of the
membrane preparation. The IC50 values of the compounds
according to the invention are low, ranging down to 10-9
M.
' ' , , . ~ ;' ' . . ' '
, ' ' ', . ' " ' ~ ' ; "' '
~'.~.; . ~ . ,
:'`: . ' ' ' : ,' ' : ,
,-~ 38
2~2921~
The antagonistic activity of the compounds
according to the invention towards the V2 receptors was
demonstrated by the adenylate cyclase activity assay
performed by a method adapted from M. Laburthe et al.,
Molecular Pharmacol., 1986, ~2, 23-27. A bovine kidney
membrane preparation is used and each product is
incubated for 10 minutes at 37-C, e~ther by itself or in
the presence of AVP (arginine vasopreQsin) at a
concentration of 3.10-8 M. The cyclic AMP (cyclic
adenosine monophosphate) produced is measured by
radioimmunoassay. The concentration which causes a 50%
inhibitlon (IC50) of the stimulation of adenylate cyclase
induced by 3.10-8 M AVP is determined. The IC50 values
determined are of the order of 10-7 M, ranging down to
10-8 M.
The agonistic or antagonistic activity of the
compounds according to the invention, administered
orally, towards the vasopressin receptors i~ evaluated in
hyperhydrated rat3 (OFA, Sprague-Dawley strain) treated
with vasopressin. The antagonistic activity of the
compounds according to the invention was also evaluated
in normally hydrated rats (OFA strain or Sprague-Dawley
strain) by the technique described in Br. J. Pharmacol.,
1992, 105, 787-791. The dluretic effect was observed for
some of the compounds at a dose of 10 mg/kg.
Likewise, the affinity of the compounds (I)
according to the invention for the ocytocin receptors was
determined in vitro by the displacement of a
radlolodinated ocytocln analog bound to the receptor~ of
a gestatlng rat mammary gland membrane preparation by a
technique simllar to that described by J. Eland et al. in
Eur. J. Pharmacol., 1987, 1~, 197-207. The ICso values
of the compounds according to the invention reach 10-~ M.
The compounds according to the lnvention are
active after administration ~y different routes,
especially orally.
~.'''"',"'.''",1..;'"'-."
39
2123~1~
No signs of toxicity are observed with these
compounds at the pharmacologically active doses.
Thus the compounds according to the invention can
be used in the treatment or preventlon of variou~
S vasopressin-dependent or ocytocin-dependent complaints,
cardiovascular complaints such as hypertension, pulmonary
hypertension, cardiac insufficlency, myocardial
infarction or coronary vasospasm, in particular in
smokers, unstable angina and PTCA (percutaneous
transluminal coronary angioplasty), cardiac ischemia,
hemostatic disorders, especially hemophilla, and von
Willebrand's syndrome, complaints of the central nervous
system, for example migraine, cerebral vasospasm,
cerebral hemorrhage, cerebral edema~, depression,
anxiety, psychotic states and memory dlsorders,
complaints of the renal system, such as edemas, renal
vasospasm, necrosis of the renal cortex, hyponatremia,
hypokalemia and Schwartz Bartter's syndrome, complaints
of the gastric system, such as gastric vasospasm,
hepatocirrhosls, ulcers, the pathology of vomi~ing, for
example nausea, including nausea due to chemotherapy,
travel sickness or else the syndrome of inapproprlate
secretion of antidiuretic hormone (SIADH), dlabetes
insipidus and enuresis. The compounds according to the
lnvention can also be used in the treatment of disorders
of sexual behavior; in women, the compounds accordlng to
the inventlon can be used for treating dysmenorrhea or
premature labor. The compounds according to the lnvention
can also ,be used in the treatment of small cell! lung
cancer, hyponatremic encephalopathy, Raynaud's disease,
pulmonary syndrome and glaucoma and in postoperative
treatments, especially after abdominal surgery.
The present invention further r~lates to
pharmaceutical compositions containing an effective dose
of a compound according to the invention, or a
pharmaceutically acceptable salt, and sultable
_~ 40
" 212921~
excipients.
Said excipients are chosen according to the
pharmaceutical form and the desired mode o~
administration.
In the pha~maceutical compositions of the pre~ent
invention for oral, sublingual, subcutaneous,
intramuscular, intravenous, topical, intratracheal,
intranasal, transdermal or rectal administration, the
active principles of formula (I) above, or their salts
10 where appropriate, can be administered to animal and ~`
humans in unit forms of administration, mixed with ~
conventional pharmaceutical carriers, for the prophylaxis ~ -
or treatment of the above disorders or diseases. The
appropriate u~it forms of administration include forms
for oral administration, such as tablets, gelatin
capsules, powders, granules and solution~ or suspen~ions
to be taken orally, forms for sublingual, buccal,
intratracheal or intranasal administration, forms for
subcutan~ous, intramuscular or intravenous administration
and forms for rectal administration. For topical
application, the compounds according to the invention can
be used in creams, olntments or lotions.
To obtain the desired prophylactic or therapeutlc
effect, the dose of active princlple can vary between
O.Ol and 50 mg per kg of body weight and per day.
Each unit dose can contain from 0.5 to lO00 mg,
preferably from l to 500 mg, of active ingredients in
combination with a pharmaceutical carrier. This unlt
dose can be administered l to 5 times a day 80 as to
30 administer a daily dosage of 0.5 to 5000 mg, preferably 1 -
to 2500 mg.
If a solid composition is prepared in the form of
tablets, 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
, ~,
. :,.
"; , ~ , . " "
21292~ ) ~
derivative or other appropriate substances, or else they
can be treated so as to have a sustained or delayed
activity and so as to release a predetermined amount of
active prlnciple contlnuously.
S 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 contain the
active ingredient together with a sweetener, which is
preferably calorie-free, methylparaben and propylparaben
as antiseptlcsr a flavoring and an appropriate color.
The water-dispersible powders or granules can
contain the active ingredient mixed with dispersants or
wetting agents, or suspension agents such as
polyvlnylpyrrolidone, as well as with sweeteners or taste
correctors.
~ectal administration i-~ effected using
suppositori2s, 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
compatlble dispersant~ andtor wetting agents, for example
propylene glycol or butyl~ne glycol.
The act$ve principle can also be formulated as
, microcapsules, if appropriate with one or more carriers
or add$tives.
In addition to the products of formula (I) above
or one of the pharmaceutically acceptable salts, the
compositlons of the present invention can contaln other
active principIes which may be useful in the treatment of
the disorders or diseases indicated above.
Thus the present invention further relates to
~_ 42
21292~ ~
pharmaceutical compositions in which several actlve
principles are presen~ in association, one of them being
a compound according to the inventlon.
Thus, according to the present invention, it is
possible to prepare pharmaceutical composltions in which
a compound according to the invention is present in
associatlon with a compound which acts on the renin-
angiotensin syste~, such as a converting enzyme
inhibitor, an angiotensin II antagonist or a renin
inhibitor. A compound according to the invention can
also be associated for example with a perlpheral
vasodilator, a calcium inhibitor, a beta-blocker, an
alpha-l- blocker or a diuretic. Such composltions will
~e useful in particular in the treatment of hypertension
or heart failure.
It is also possible to associa~e two compounds
according to the invention, namely a specific V1 receptor
antagonist with a specific V2 receptor antagonist, or
else a speclfic Vl receptor antagonlst with a speciflc
ocytocin antagonist.
These associations will make it possible to
reinforce the therapeutic activities of the compounds
according to the invention.
Preparation of the 1~3-dihydroindol-2-Qn8
,P~eDa~;atlC;tn~
1,3-Dihydro-4,6-dimethyl-3-spirocyclohexane-
indol-2-one
This compound is pr~pared according to Moore and
Plant in J. Chem. Soc., 1951, 3475.
A mixture containing 15 ml of quinoline and 10 g
of calcium oxide is refluxed under an inert atmosphere
and 5 g of the 3,5-dimethylphenylhydrazide of
cyclohexanecarboxylic acid tIV, R'1, R'2 5 CH3, C~'3R'4 =
cyclohexane) are added over 30 minutes. The reaction
...... ... . .... . . .. .... ~ ~ . . , .. . . .. . .. , .. ... ~ .. . . .. ..... .... . . .... .... . . . .
.
43
21 2921a
medium is cooled and then poured into an ice/hydrochloric
acid mixture. Extraction is carried out with ethyl
acetate and the extract is washed with normal
hydrochloric acid and with water until the wai~hing3 are
neutral, and then dried and concentrated under vacuum to
give a brown solid. Trituration in iso ether ~ives the
expected compound. M.p. = 223-C.
The 1,3-dihydroindol-2-one derivatives described
in Table 1 below are obtained by followlng the same
procedure and varying the starting hydrazide.
These compounds are purified by chromatography on
a silica column using DCM a~ the eluent or by
chromatography on an alumina column us1ng DCM or iso
ether a~ the eluent.
TABLE 1
R'
R'2
H
R'1 R'2 CR'3R'4 M.p. C
Cl-S H cyclobutane 191
Cl-S H cyclopentane 189
Cl-S cyclohexane 186
H H cyclohexane123-124
CH3-5 H cyclohexane 164
CH30-5 H cyclohexane 226
Cl-6 H cyclohexane 168
CF30-5 H cyclohexane 164
C~H~0-5 H cyclohexane 160 :
212921~
PreRaration 2:
The 1,3-dihydro-3-spirocyclohexaneindol-2-one
described in Table 1 above can also be obtalned by
alkylation of the indol-2-one using the process accordin~
to A.S. Kende and J.C. Hodges or a variant described
below.
A solution o~ 30 g of 1,3-dihydroindol-2-one in
900 ml of THF is kept at -40-C under a nltrogen
atmosphere and 101 g of potassium tert-butylate are
added. The temperature is allowed to rise to O-C over 1
hour, the m~xture is then cooled to -60-C and a solution
of 52 g of 1,5-dibromopentane in 50 ml of THF is added
dropwise. After 30 minutes at -60-C, the temperature is
allowed to rise to ~T, 30 ml of water are then added and
the solvent is evaporated off under reduced pressure.
~he resldue is taken up with 500 ml of DCM and 200 ml of
water, the insoluble material i~ then filtered off and
the organic phase is separated off, washed wlth 100 ml of
wa~er, dried over magnesium sulfate and evaporated under
vacuum. The residue ls chromatographed on silica uslng a
cyclohexane/ether mixture as the eluent to glve the
expected compound, which is recrystallized from heptane.
m - 34 ~. M.p. 5 123-124-C.
A ~imilar procedure can be applied startin~ from
other 1,3-dihydroindol-2-ones and other alkylating
agents.
By way of example, among the starting compounds
of formula (VII), 5-chloro-1,3-dihydroindol-2-one is
described by ~right in J. Am. Chem. Soc., 1956, 7~, 221,
and by Ra~anBabu in J. Org. Chem., 1986, 51, 1704. 4-
Chloro-1,3-dihydroindol-2-one can be prepared from 2-
chloro-6-nitrotoluene by the method described in J. Am.
Chem. Soc., 1956, 78, 221.
1,3-Dihydro-5-methoxyindol-2-one is prepared from
4-methoxyaniline by the method described in J. Am. Chem.
Soc., 1974, 96, 5512. In the same way, various 1,3-
~12921~
dihydroindol-2-ones are prepared from the appropriate
aniline derivative.
Preparation 3:
5-Ethoxy-1,3-dihydroindol-2-one
S A - 3-Methylthio-5-ethoxy-1,3-dihydroindol-2-
one
23.6 g of ethyl methylthioacetate in 60 ml of DCM
are added to a ~olutlon, cooled to about -70-C, of 12.5 g
of chlorine in 400 ml of DCM. After stlrring for 5
minutes at the same temperature, a solution of 4-
ethoxyaniline (48.3 g) in 120 ml of DCM is added. The
mixture is stirred for one hour at about -70-C, 39.3 ml
of triethylamine are added and the resulting mixture is
allowed to warm up to room temperature. 200 ml of water
IS are added and the organic phase i~ decanted, dried over
magnesium ~ulfate and evaporated under reduced pressure.
The residue i8 taken up with 500 ml of isopropanol and 20
ml of concentrated hydrochlorlc ac~d. The mixture ls
stlrred for about 16 hours at room temper~ture and
filtered and the precipitate is separated off. The
filtrate i8 concentrated under reduced pressure to give
the expected product.
B - 5-Ethoxy-1,3-dihydroindol-2-one
The above solid, in 1500 ml of isopropanol, i8
de~hiomethylated in the presence of 100 g oP Raney~
nlckel (80 to 100 m2 per g), under reflux, for 3 hours,
under a nitrogen atmosphere. The mlxture is filtered on
talc, the materlal on the fllter ls rlnsed wlth 1000 ml
of isopropanol and the filtrate is concentrated under
reduced pressure. 16 g of the expected product are
isolated after recrystallization from toluene. M.p. =
156-C.
The following are isolated in the same manner
starting from the corresponding anilines:
5-benzyloxy-1,3-dihydroindol-2-one m.p. = 152-C
46
2~ 29~1~
5-n-propyl-1,3-dihydroindol-2-one m.p. - 136C
5-ethyl-1,3-dihydroindol-2-one m.p. ~ 152-C - -
5-(2,2,2-trifluoroethoxy)-1,3-dihydroindol-
2-one m.p. = 145-C
5-trifluoromethyl-1,3-dihydroindol-2-one m.p. = 193-C
5-fluoro-1,3-dihydroindol-2-one m.p. = 143-C
The compound~ of formula (II) described below are
obtained by following tha technique described ln
Preparation 2 and varying the starting 1,3-dihydro-indol-
2-one derivative and the alkylating reagent.
, .
TABLE 2 ~ ~
R'l R'2 = M.p Calkylating reagent ~ ~
S-CI Hcyclohexane 186-189 Br(CH2)s Bs ~ :
S-CI Hcycloheptane 202 Br(CH2)6 Br
S-CI H4,4-dimethyl 180TSo(cH2)2c(cH3)2-
cyclohexane -(CH2)2OTs : :
S-CI Hhexahydroindane-2 223cis--1,2-diiodomethyl-
cyclohexane
S-OCH3 H4,4-dimethyl 202TsO ~cH2)2c(cH3)2
. . cyclohexane __ -(CH ~)~-OTs
~ 47
212921'~
TABLE 2 ( continuation )
__ . . _ __ _ , , _ _
R'1 R'~C~ 3R 4 M.p. Calkylating reagent
. .
S-CI Hindane-2 228a,a' dibromomethyl
orthoxylène
S-CI HC~CH3)2 160 CH31
S-CI HC(CH2CH3)2 156 CH3CH2
S-CI HC(n Pr)2 158 nPrl
S-CI HC(iBu)2 164 iBul
S-CI HN-methyl 260Cl(cH2)2N(cH3
piperidine-4 -(CH2)2CI
S-CI Htetrahydropyran-4 2231(CH2)20(CH2)2
4-CI Hcyelohexane 215 Br~CH2)sBr
S-OBz Heyelohexane 162 Br(~H2)5Br
H HC(CH2C6HS)2 206 C6HsCH2Br
S-CI HC~n-pentyl~2 142 CH3(cH2)4Br ¦ ~ .
BrCH2 CH2Br
S-CI H2,3-dihydro _ l~q
phenalene-2 W
S-OBz H4,4-dimethyl 154TSo(cH2 )2C(CH3)2-
cyclohexane -(CH2)2oTs
S-CI H4-spiroeyclopentane 202 ~ (CH2)2oT~
V\ (CH2)2T~ :-
S-nPr Heyelohexane 151 Br(CH2)~Br :
S-OEt H N-tBu _ / (C~2)2Br
~ ~ ~ .: :
. .
,~ 4~
21292~
TABLE 2 ( continuation )
. . . _ __ , . ~ , ':,
R'l R'2 _ _ M.p. Calkylating reagent
S-CI H N-Bz 165/ (CH2)2Br
piperidine-4 Bz ~\
. (CH2)2Br . ~ ::
S-CI HN-phenyl 188/ (CH2)
piperidine-4 C6H 5 ~
(CH2)2Cl :'
S-CI H ~ C~I 300~XCH20S02CH3 ~ :
CH20s02cH3
S-OEt H4,4-diethyl 132TSo(cH2)~c(c2Hs)2
cyclohexane -(cH2)2ars
S-OEt Hcyclohexane 163Br(CH2)sBr
5-OEt H4,4-dimethyl 178TSo(cH2)2~(cH3)2- ; ~-
cyclohexane -(CH2)20Ts ~ :
5-OEt Hcycloheptane 139Br(CH2)6Br
S-Et H4,4-dimethyl 160TSo~cH2)2c(cH3)2- : .
cyclohexane -(CH2)2OTs
5_ H4,4-dimethyl 164idem
OCH2CF3 cyclohexane . ~ .
H H4,4-dimethyl 169idem . ~ ~:
: ~ l cyclohexane
S-CF3 H4,4-dimethyl 211idem ~ ~:
cyclohexane
S-F H4,4-dimethyl 171idem .: :
_ cyc!ohexane .__ ._ _ :::
::
.
49
212 9 21 ~
TABLE 2 (continuation)
__ ___ _
R~1R~2 CR 3R 4 M.p. C alkylating reagent
~-CI H(CH2)2o ~ 120 Br(CH2)
(CH2)2o ~
o
5-OEt H /\~ 208 Ts O ~
~ r/- ~
/C~ Ts o
5-013t ~ H C
S-OEt Htetrahydro- 146 1(CH2)20(CH2)2
pyrane-4 ~
' ' ~:
5-OEt H " C~I 255 ~XcH2oso2cH3
CH20S02CH3
Preparation 4:
! 5 1 1,3-Dihydro-3-spiroadamantaneindol-2-one
This compound is prepared according to I. Fleming
et al., Tetrahedron Letters, 1982, 2053-2056, startlng
from 2-bromoaniline and adamantan-2-one.
Preuaration 5~
5-Chloro-1,3-dihydro-3,3-diphenylindol-2-one
This compound is prepared by the method described
~ - so
:
21292~5 - -
in Helv. Chim. Acta, 1946, 29, 415-431, by the reaction
of benzene with 5-chloroisatin in the presence of
aluminum chloride. M.p~ = 281-C.
Pre~aratiQ~ 6:
1,3-Dihydro-5-nitro-3-splrocyclohexaneindol-2-
one
~his compound is prepared by the method de~cribed
in J. Am. Chem. Soc., 1945, 67, 499, by the nitrat1On of
1,3-dihydro-3-spirocyclohexaneindol-2-one. M.p. = 192-C.
1,3-Dihydro-5-nitro-3-spiroadamantaneindol-2- one
is prepared in the same manner starting from 1,3-
dihydro-3-spiroadamantaneindol-2-one. M.p~ > 260-C.
1,3-Dihydro-5-nitro-3-spiro(4,4-dimethylcyclo-
hexane)indol-2-one is also prepared. M.p. = 195-C.
Pre~aration 7:
5-Amino-1,3-dihydro-3-spirocyclohexaneindol-2-
one
This compound is prepared by the method described
in J. Chem. Soc., 1951, 3475, by the reduction of 1,3-
dihydro-5-nitro-3-spirocyclohexaneindol-2-one, prepared
above.
M.p. - 176-C.
5-Amino-1,3-dihydro-3-spiroadamantaneindol~2- one
is prepared in the same manner~ M.P.C ~ 245-C.
PreparatlOn ~:
5-Fluoro-1,3-dihydro-3-~pirocyclohexaneindol~
one
A - 5-Diazonium-1,3-dihydro-3-spirocyclohexane-
lindol-2-one tetrafluoroborate
A solution containlng 4 g of 5-amino-1,3-dihydro-
3-spirocyclohexaneindol-2-one in 9.2 ml of 6 N
hydrochloric acid i5 cooled to O-C and 2.27 y of æodium
nitrite in 2.6 ml of water are added, followed by 2.54 g
of sodium tetrafluoroborate in 9 ml of water. After
stirring for 5 minutes, the precipitate is filtered off
and washed with a 5% solution of tetrafluoroborate, with
'''~. ' ' . ,: ,' ,
212921~
3 ml of methanol cooled to about O-C and then with 5 ml
of ether. The salt obtained is dried under vacuum at RT
in the presence of phosphorus pentoxide.
s - 5-Fluoro-1,3-dihydro-3-spirocyclohexane-
indol-2-one
1 g of the compound obtained 1n step A is placed
in 5 ml of xylene and heated at about 115-C $or 2 hours.
The mixture is cooled to RT, the preaipitate is filtered
off and rinsed with toluene and 0.1 g of act~ve charcoal
is added to the filtrate. After filtration, the solvent
is evaporated off under reduced pres~ure to give 0.45 g
of the expected compound, which is recrystallized from
pentane. M.p. = 114-C.
PreDa~a~lQn 9: :
5-Cyano-1,3-dihydro-3-~pirocyclohexaneindol-2-
one
4.78 g of potas~ium cyanide and 4.95 g of auprous
cyanide are dissolved at RT in 40 ml of ~MS0. The
solution 18 cooled to about 15-C and 4.15 g of the
diazonium sait obtained ln step A of the previous
preparation are added.
After stirring for 30 minutes at RT, 100 ml of
water and 100 ml of ether are added and the organic phase
ls then separated off, dried over magnesium sulfate and
25 evaporated under reduced pressure. The resldue is 3 `~
chromatographed on silica using a cyclohexane/ether
mlxtura as the eluent to give the expected compound,
which i8 rscrystallized from heptane.
,~ m ~ 1.4 g. M.p. - 216-C.
PreDaration 10:
5-Chloro-1,3-dihydro-3-spiroadamantanelndol-2-
one
1 g of the p-chlorophenylhydrazide of adamantane- ~ -
2-carboxylic acid is dissolved in THF and 2.5 ml of a
solution of n-butyllithium (1.6 M in hexane) are added at
.
52
21~921~ `
-40-C. After stirring for 5 minutes, the mixture is
concentrated under vacuum, the temperature being kept
below 30-C. 30 ml of 1,2,3,4-tetramethylbenzene are
added and the mixture is refluxed for 1 hour. It is
concentrated under reduced pressure, the residue is taken
up with normal hydrochloric acid, extraction is carried
out with ether and the extract is washed, drled and
concentrated under vacuum. The oil obtained is
chromatographed on a silica column using DCM as the
eluent to give 0.3 g of the expected product in the form
of a wax, which i~ crystallized from iso ether. M.p. =
249-C. ~;
Pre~aration 11:
5-Chloro-3-cyclohexyl-1,3-dihydro-3-methyl-
indol-2-one
The method described in Synth. Commun., 1982, 12
(1), 1-10, is used to prepare 5-chloro-3-cyclohexyl- 1,3-
dihydroindol-2-one as an intermediate, and the expected
compound is then obtained by reaction with methyl iodide.
2n P~a~a~ion 12:
5-Acetyl-1,3-dihydro-3-spirocyclohexaneindol-2-
one
2.56 g of acetyl chloride and then 8.25 g of
anhydrous aluminum chloride are added to a solution,
cooled to 5-C, oP 4 g of 1,3-dihydro-3-spirocyclo-
hexaneindol-2-one in 35 ml of 1,2-dichloroethane. The
mixture is refluxed for 2 hours, the solvent is
evaporated off under reduced pressure and the medium is
! hydrolyzed with 50 g of ice and extracted with ethyl
acetate.
The organic phase is washed with water, drled
over magnesium sulfate and then evaporated under reduced
pressure. The residue is chromatographed on a ~ilica
column using a mixture of heptane and ethyl ether as the
eluent to give 3.6 g of the expected product. M.p. =
19~C.
i, .,i - . . .: ~, - .
212~21~ ~
Preparation 13:
5-Chloro-1,3-dihydro-3-spiro(tetrahydrothio-
pyran-4-yl)indol-2-one
A - 5-Chloro-1,3-dihydro-3,3-di(2-bromoethyl)-
5 indol-2-one
7.66 g of bromine are added slowly to a mixture,
cooled to about O-C, of 12.4 g of triphenyl-phosphine in
70 ml of DCM, and 4.58 g of 5~chloro-1,3- dihydro-3,3-
dit2-(tetrahydropyran-2-yloxy)ethyl]indol- 2-one,
10 described in Table 2, are then added. After 16 hours at
RT, 60 ml of water are added and the organic phase i5
separated off, washed with 60 ml of water and then dried
over magnesium sulfate and evaporated under vacuum. The s
residue is chromatographed on a silica column uslng DCM
15 as the eluent to give 3.12 g of the expected product.
M.p. - 215-C.
B - 5-Chloro-1,3-dihydro-3-spiro(tetrahydro~
thiopyran-4-yl)indol-2-one
Under an inert atmosphere, 3 g of the product
20 prepared in step A are added to 3.2 ml of DMF and 2 g of
sodium sulfide monohydrate and the mixture is heated or
2 hours at 50-C. It is cooled to RT, 6 ml of water are ~
added and the mi~ture is extracted with DCM. The organic -~ -
phase is washed with water, dried over magnesium ~ulfate
25 and evaporated under reduced pressure. The oily resldue
obtained is purified by chromatography on silica using
DCM as the eluent to give 2.02 g of the expected
compound.
NMR spect~um at 200 MHz in CDC1
30 8.12 ppm : s : lH
7.2 ppm : m : 2H
6.8 ppm : d : lH ~-
3.25 ppm m : 2H
2.65 ppm : m : 2H
35 2 ppm : m : 4H
~ 54
2 1 2 9 2 1 ~
Pre~arat~Qn 14: ~
5-Ethoxy-1,3-dihydro-3-spiro[4-(methoxymethoxy~- -
cyclohexane]indol-2-one
A - 3-(Methoxymethoxy)pentane-1,5-diol
270 ml of a 1 M solution of lithium aluminum
hydride in THF, diluted in 540 ml of anhydrous THF, is
cooled to O-C and a solution of 63 g of diethyl 3-
(methoxymethoxy)glutarate (prepared according to J.L.
Gras in Synthesis, 1985, 74) in 400 ml of THF is added.
The mixture is stirred for 16 hours at R~ and then cooled
to O-C and 9 ml of water, 30 ml of a 15% solution of NaOH
and 9 ml of water are added successively. The mineral
salts are filtered off and the filtrate is evaporated
under vacuum to give 24 g of the expected product after
dlstlllation under reduced pressure. B.p. 7 125-C under
1.2 Pa.
B - 3-(Methoxymethoxy)-1,5-ditosyloxypentane
A solution of 46 g of p-toluene~ulfonyl chloride
and 38 ml of triethylamine in 80 ml of THF i cooled to
0-C, a solution of 18 g of the compound obtained in the
previous step in 100 ml of THF i8 added and the mixture
i8 stirred for 16 hours at RT. 150 ml of water ars added
to the reaction mixture, the solvent is evaporated off
under vacuum, the residue 1~ extracted with AcOEt and the
latter is evaporated off under vacuum. The oll obtalned
is taken up with 250 ml of ether and 200 ml of 2 N NaOH
and ths mlxture is stirred for 16 hours at RT. After
decantation, the organic phase is drled over magnesium
sulfate and the solvent ls evaporated off under vacuum to
30 give 45 g of the expected product after crystallization ~ ;~
from cyclohexane. M.p. < 50-C.
C - 5-Ethoxy-1,3-dihydro-3-spirot4-(methoxy-
methoxy)cyclohexane]indol-2-one
This compound is prepared by the procedure
descrlbed in Preparation 2 starting from 5-ethoxy-1,3-
dihydroindol-2-one and the compound obtained in the
,:. : ~. : :
. , ~.-: ... : : ~
212921'~
previous step. The expected product is obtained in the
form of a mixture of isomers. M.p. = 98-C.
Preparation 15:
5-Ethoxy-1,3-dihydro-3-spiro[4-tricyclo-
[5.2.1.02~6]decane]indol-2-one
A mixture of 3 g of 5-ethoxy-1,3-dihydro-3-
spiro[4-tricyclo[5.2.1.02,6]dec-8-ene~indol-2-one,
described in Table 2, and 1.5 g of 10~ palladium-on-
charcoal in 160 ml of MeOH is hydrogenated for 16 hours
at 40-C under a pressure of 20 bar. The catalyst is
filtered off on Célite~ and washed with MeOH and the
filtrate is evaporated under vacuum to give 2.95 g of the
expected product. M.p. - 236-C.
PreDarations 16 and 17:
5-Ethoxy-1,3-dihydro-3-spiro(4-methoxycyclo-
hexane)lndol-2-one, the less polar isomer and the more
polar isomer
A - 3-Methoxypentane-1,5-diol
ml of methyl trifluoromethylsulfonate are
added to a solution of 30 g of diethyl 3-hydroxy-
glutarate and 33 ml of 2,6-di-tert-butylpyridine in 500
ml of DCM and the mixture i8 refluxed for 6 hours. After
cooling, 500 ml of a 0.5 N solution of HCl are addad, the
organic phase ls decanted and dried over magnesium
sulfate and the solvent is evaporated off under vacuum.
The residue obtalned is taken up with 200 ml of anhydrous
THF, the mixture i8 filterad and the filtrate i8 then
cooled to -5-C. 160 ml of a 1 M ~olution of lithium
aluminum hydride in THF are then added slowly and the
mixture is stirred for 16 hours, the temperature being
allowed to ri~e to RT. The reaction mixture is cooled to
O-C and 5.5 ml of water, 18 ml of a 15% solution of NaOH
and 5.5 ml of water are added succes~ively. The mineral
salts are filtered off and the filtrate is evaporated
under vacuum to give the expectad product after
distillation under reduced pressure. B.p. = 104-C under
~.
56
212921.~ :
1.5 Pa.
B - 3-Methoxy-1,5-ditosyloxypentane
A solution of 31 g of p-toluenesulfonyl chloride
and 26 ml of triethylamine in 120 ml of THF is coolsd to
S O-C, 10 g of the co~pound obtained in the previou~i step
are added and the mixture is stirred for 24 hours at RT.
120 ml of water are added to the reac tion mixture, the
solvent is evaporated off under vacuum, the re~ldue is
extracted with AcOEt and dried over magne~ium sulfate and
the solvent is evaporated off under vacuum. The oil
obtained is taken up with 200 ml of ether and 200 ml of 2
N NaOH and the mixture is st~rred for 16 hours at RT.
After decantation, the organic phase is dried over
magnesium ~ulfate and the solvent is evaporated off~under
vacuum to give 26 g of the expected product after
crystallizatlon from cyclohexane. M.p. - 58-C.
C - 5-Ethoxy-1,3-dihydro-3-spiro(4-methoxy~
cyclohexane~indol-2-one, the less polar isomer and the
more polar lsomer
These compounds are prepared by the procedure
described in Preparation 2 starting from 11.85 g of 5-
ethoxy-1,3-dihydroindol-2-one, 34 g of pota~sium tert-
butylate and 26 g of the compound obtalneid in the
previous step. They are chromatographed on silica u~ing
a cyclohexane/AcOEt mixture (80/20; v/v) as the eluent.
The two isomers are separated into
- the less polar isomer: compound of Preparation
16, m.p. = 173-C:
- the more polar isomer: compound of Preparation
17, m.p. = 186-C.
In addition, the benzenesulfonyl chlorides described in
the Table below were prepared using the procedure
desGribed in the general section.
''' `, ~ ,, ,' " ` ' . ''. . ~ ' ', ` ~' .` ' .
2 1 2 9 ~
S~2
~ OC~3
YRV . ''
. . . , __ , ,
.
Y RV M.p.-C :j~:
_ . ~ .
S CH3 85 ~:
OCH2Bz 95
OCH2CO2Et 89
O(CH?)~Br
Starting from the various 1,3-dihydroindol-2~
S oneg described above and appropr~ate benzenequlfonyl
chlorides, the compounds according to the invention were
prepared using the procedures repor~ed in the Examples
below.
EXAMPLES 1 and 2
5-Ethoxy-1,3-dihydro-1-~2-methoxy-4-(pyrrol~
yl)benzenesulfonyl]-3-spirocyclohexaneindol-2-one and
5-ethoxy-1,3-dihydro-1-t2-methoxy-4-(~3-pyrrolln-1-yl) :~
benzenesulfonyl3-3-spirocyclohexaneindol-2-one
A) 5-Ethoxy-1,3-dihydro-1-(2-methoxy-4-nitrobenzenesul-
fonyl)-3-spirocyclohexaneinaol-2-one
A solutlon of 15 g of 5-ethoxy-1,3-dlhydro-3-
spirocyclohexaneindol-2-one in 150 ml of THF is ~ooled in
an ice bath to a temperature between lO-C and 15-C. 2.4 -~
g of sodium hydride as a 60% dispersion in oil are added
over 2 hours and 18 g of 2-methoxy-4-nitroben-
zenesulfonyl chloride are ~hen introduced in portions
;;~.. .,-
~ 58
21292~
over 30 minutes. After stirring for 18 hours at RT, the
suspension obtained is poured into an iced ~olution of
sodlum chloride and then extracted with AcOEt. The
organic phase is dried over sodium sulfate and evaporated
S to dryness and the residue is then crystallized from 200
ml of hot iso ether to give 23 g of the expected product.
M.p. = 160-C.
This compound is also obtained by following the
procedure described below.
A'~ 5-Ethoxy-1,3-dihydro-1-(2-methoxy-4-nitrobenzene-
sulfonyl)-3-spirocyclohexane$ndol-2-one
A solution of 15 g of 5-ethoxy-1,3-dihydro-3-
spirocyclohexaneindol-2-one in 300 ml of THF is cooled to
about -50-C and 7.2 g of pota~sium tert-butylate are
IS added. The mixture is stirred, the temperature baing
allowed to rise to about O-C, and then cooled to -50-C
and a solution of 16.2 g of 2-methoxy-4-
nitrobenzenesulfonyl chloride in THF is added. The
mixture is stirred for 1 hour at RT, 100 ml of water are
added and the golvent is evaporated off under vacuum.
The aqueous phase i9 extracted with DCM and dried over
magnesium sulfate and the solvent is evaporated off under
vacuum to give the expected product after crystallization
from hot iso ether.
The following nitro derivatives are prepared by
the latter procedure startlng from the appropriate 1,3-
dihydroindol-2-ones:
''' 59 212921'j ,~
:
~R4
S2
~, O Me
N2 ~: .
. .. . . ,.
Rl CR3R4 M.p.-C or NMR : ~
_, -. ~
Cl-4,4-dimethylcyclohexane 169
EtO-4,4-dimethylcyclohexane 110 : :
F-4,4-dimethylcyclohexane 137 ~ ~.
CF34,4-dimethylcyclohexane -
Cl- cycloheptane 137
EtO- cycloheptane 125
Cl-tetrahydropyran-4 212 . .~ ~:
Cl-tetrahydrothiopyran-4 116
EtO- 2~>/ 88
1~0- 1 \C~ 40
ElO ~ NMR~
*NMR spectrum at 200 MHz in DMSO
1. 3 ppm : t : 3H
5 1. 3-1. 5 ppm : mt : 6H --
- 2~2921~
2.2 ppm : mt : 4H
3.7 ppm : s : 3
4.0 ppm : q : 2H
7.0 ppln : mt : 2H
5 7.6 ppm : d : lH
7.9 ppm : mt : 2H
8.2 ppm : d : lH -
B) 1-(4-Amino-2-methoxybenzenesulfonyl)-5-ethoxy-1,3-
dihydro-3-spirocyclohexaneindol-2-one
A suspension containing 20 g o the compound
obtained in the previous step, 20 g of iron powder, 70 ml
of water and 70 ml of 96- alcohol is brought to the
reflux poin~; a solution of 7 ml of concentrated
hydrochloric acid in 35 ml of water is added over 30
IS minutes. After 4 hours under reflux, 15 ml of sodium
hydroxide solution are added and the mlxture is then
extracted with DCM. The organic phase i~ filtered on
C~liteR and then dried over sodium sulfate. The residue
is crystalllzed from 100 ml of a hot iso ether/AcOEt
mixture (80/20; v/v) to give 15.8 g of the expected
product. M.p. = 177C.
This compound is also obtained by followlng the
procedure described below.
B') 1-~4-Amino-2-methoxybenzenesulfonyl)-5-ethoxy-1,3-
2S dihydro-3-spirocyclohexaneindol-2-one
A solution of 0.5 g of the compound obtained in
step A) in 10 ml of EtOH is cooled to about 5-C and 0.8
ml of concentrated HCl and 0.4 g of tin powder are added.
The mixture is heated at 40-C for 45 minutes and the
solvent is evaporated off under vacuum. The residue is
neutralized by the addition of NaOH, extracted with
AcOEt, dried over magnesium sulfate and filtered on
CéliteR and the filtrate is evaporated under vacuum. The
residue is chromatographed on silica using a DCM/MeOH
mixture (99J1; vtV) as the eluent to give the expected
product.
61
2 1 2 9 2 1 ~
The following anilines are also prepared by the
latter procedure~
R3 . : .
Rl~f~R4 ~1
N O
SO2 :
NH2 -
R1 CR3R4 M.p.-C
Cl- 4,4-dimethylcyclohexane 222 . -
EtO- 4,4-dimethylcyclohexane 230 .
F- 4,4-dimethylcyclohexane 130
CF3- 4,4-dimethylcyclohexane
Cl- cycloheptane 184
EtC)- cycloheptane 12~
Cl- tetsahydropyran-4 æo -
Cl- tetrahydrothiopyran-4 229 ::
EtO- \C'^`r ~ 241 ~ .
. I EtO- ~ 232 :; ~ ~
/ ' ~ ~
EtO- \C'/~,~ 189 : ~
, . -, , ~ '
S
,-~ 6~
212921'i ~
B'') The compound obtained in step B) above can also be
prepared from the corresponding nltro derivative by
hydrogenation in the presence of 10~ palladium-on-
charcoal for 2 hours at 50-C under a pressure of 1 bar.
S C) 5-Ethoxy-1,3-dihydro-1-t2-methoxy-4-(pyrrol-1-yl)-
benzenesulfonyl]-3-spirocyclohexaneindol-2-one and 5-
ethoxy-1,3-dihydro-1-[2-methoxy-4-( D3 -pyrrolin-l-yl)-
benzenesulfonyl]-3-spirocyclohexaneindol-2-one
A mixture conta~ning 500 mg of the compound
prepared in step B ), 10 ml of DMF, O . 3 g of sodium
carbonate and 300 mg of cis-1,4-dichlorobut-2-ene is
refluxed for 4 hours. The reaction mixture is poured
into a water/ice mixture and then extracted with AcOEt
and washed with water; the solvent is evaporated off and
IS the residue obtained is then chromatographed on silica
using a DCM/heptane mixture (95/5; v/v) and then pure DCM
as the eluent. 70 mg of the less polar product (compound
of Example 1), m.p. 5 174-C, are collected, followed by
60 mg of the more polar product (compound of Example 2),
m.p. ~ 170-C.
The compounds described in the Tables of steps A)
and B) above can be used to prepare compounds according
to the invention which are analogous to that obtained in
step C).
EXAMPLE 3
5-Ethoxy-1,3-dihydro-1-[2-methoxy-4-(pyrroli-
dln-l-yl)benzenesulfonyl]-3-splrocyclohexaneindol-2-one
45iO mg of the compound obtained $n Example 2 are
placed in 25 ml of 95- EtOH and 25 ml of AcOEt, in the
presence of I50 mg of 5% palladium-on-charcoal, and are
hydrogenated for 4 hours at 35-C under a pressure of 40
bar. The catalyst $s iltered off and the f$1trate is
evaporated to dryness. The expected pro duct
crystallizes from iso ether. m = 110 mg. M.p. = 185-C.
63
2~ 2921~ ~ ~
EXAMPLE 4
5-Ethoxy-1,3-dihydro-1-[4-(isoindolin-2-yl)-2-
methoxybenzenesulfonyl]-3-spirocyclohexaneindol-2-one
A mixture containing 500 mg of the compound
S prepared in Example 1 step B), 10 ml of DMF, 0.5 ml of
TEA and 310 mg of a, a~ -dibromoorthoxylene is refluxed for
2 hours. The reaction medium is poured into a water/ice
mixture, extracted with AcOEt, dried over sodium sulfate
and evaporated to dryness. The residue is
chromatographed on silica using DCM and then DCM/ AcOEt
(95/5; v/v) as the eluent to give the expected product,
which is crystallized from iso ether. m s 170 mg. M.p. -
190C. : ,
EX~MPLE 5
5-Ethoxy-1,3-dihydro-1-[2-methoxy-4-((3-methyl-
thien-2-yl)carboxamido)benzenesulfonyl]-3-spirocyclo-
hexaneindol-2-one
A mixture containing 500 mg of the compound -
prepared in Example 1 step B), 10 ml of DCM, 2 ml of
pyridine and 250 mg of 3-methylthlophene-2-carboxyllc
acid chloride is stirred for 3 hours at RT. The medium
is washed with 1 N hydrochloric acid and then with water.
It is dried over sodium sulfate and then evaporated to
dryness. The residue is chromatographed on silica using
DCM as the eluent. The expected product recrystallizes
from i90 ether. m = 0.21 g. M.p. s 174-C.
EXAMPLE 6
l-t4-(N-Benzylcarbamoyl)-2-methoxybenzenesul-
fonyl]-5-ethoxy-1~3-dihydro-3-spirocyclohexaneindol-2-
oneA) Benzyl 3-methoxy-4-[(5-ethoxy-2,3-dihydro-2-oxo-3-
spirocyclohexaneindol-l-yl)sulfonyl]benzoate `~
1.4 g of sodium hydride are added in small
portions to a solution of 11.8 g of 5-ethoxy-1,3- ~ `
dihydro-3-spirocyclohexaneindol-2-one in 100 ml of THF.
After stirring for 30 minutes at RT, 17 g of benzyl 4-
64
2~2921~
chlorosulfonyl-3~methoxybenzoate are added and stirrlng
is maintained at RT for 1 hour. The reaction medium is
poured into 400 ml of a water/alcohol mixture (50/50;
v/v)~ The precipitate formed is filtered of f, dried and
S then recry~tallized from alcohol.
m = 22.65 g. M.p. = 135-C.
B) 3-Methaxy-4-[(5-ethoxy-2,3-dihydro-2-oxo-3-spiro-
cyclohexaneindol-l-yl)sulfonyl]benzoic acid
2.5 g of 10% palladium-on-charcoal in oil are
10 added to a solution of 22.65 g o~ the benzyl ester
prepared in the previous step in 600 ml of AcOEt and the
mixture is then hydrogenated for 2 hours at 40-C under
atmospheric pressure. The lnsoluble material is filtered
off and the m~dium is then concentrated. The expected
15 product crystallizes from pentane.
m - 18.3 g. M.p. - 181-C.
C) 3-Methoxy~4-~(5-ethoxy-2,3-dihydro-2-oxo-3-spiro-
cyclohexanelndol-l-yl)sulfonyl]benzoyl chloride
A solution of 2.3 g of the above acid in 20 ml of
20 thionyl chloride iQ refluxed for 3 hours. The reactlon
medium i8 concentrated to dryness and the product is used ?
in the crude form, as a solution in DCM, in the next
step. ~-
D) 1-[4-(N-Benzylcarbamoyl)-2-methoxybenzenesulfonyl]-
5-ethoxy-1,3-dihydro-3-splrocyclohexanelndol-2-one
A mlxture containing 500 mg of the compound
prepared ln the prevlous step and 200 mg of benzylamine
ln 20 ml of DCM and 0.5 ml of TEA is stirred at RT for 30
minutes. It is washed with a 1 N colution of HCl, dried
30 over sodium ~ulfate and concentrated. The expected
product crystallizes rom iso ether. ~-
m = 440 mg. M.p. = 196-C. ;~
The compound of Example 6 does not belong to the
compounds of formula (I) according to the invention, but
35 the intermediate obtained in step C) is used to prepare
the compound of Example 8.
.
, . . . .
212921~ ~ ~
The procedure described in Example 6 step D) is
also used, together with the appropriate amines, to
prepare the compounds of Examples 44-54.
EXAMPLE 7
S 1-t4-(2-Carbamoylpyrrolidin-1-ylcarbonyl)-2- ~
methoxybenzene~ulfonyl]-5-chloro-1,3-dihydro-3-spiro- ~ ;
cyclohexaneindol-2-one
A) Phenyl 4-[(5-chloro-2,3-dihydro-2-oxo-3-spirocyclo-
hexaneindol-l-yl)sulfonyl]-3-me*hoxybenzoate
A mixture containing 1 g of 5-chloro-1,3-di- ~ -
hydro-3-spirocyclohexaneindol-2-one, 50 ml of THF and 115
mg of sodium hydride is stirred for 30 minutes at RT
under nitrogen. 1.5 g of 2-methoxy-4-phenoxycarbo-
nylbenzenesulfonyl chloride are introduced and stirring
15 i8 malntained for 20 hours at RT. The reaction medium is
concentrated under vacuum and the residue i~ taken up
with 30 ml of water and extracted with AcOEt. The
organic phase is washed, dried and concentrated under
vacuum. The product obtained i~ purified by
20 chromatography on silica using an iso etherJhexane ~ ;
mixture (40/60; v/v) as the eluent to give 1.4 g o~ the
expected compound. M.p. = 165-C. ~
B) 1-[4-(2-Carbamoylpyrrolidin-l-ylcarbonyl)-2-methoxy- ~-
benzenesulfonyl]-5-chloro-1,3-dlhydro-3-spirocyclo-
hexaneindol-2-one
A mi~ture containing 300 mg of the compound
prepared in the previous step, 500 mg of (L)-prolinamide
hydrochloride, 1 ml of TEA and 20 ml of prehnltene is -
refluxed ~or 1 hour. After cooling, ~he reaction medium
30 i9 taken up with AcOEt, washed with a 1 N solution of
HCl and with water and *hen dried over sodium sulfate and
concentrated. The residue is chromatographed on silica
using a DCM/MeOH mixture (98/2; v/v) as the eluent to
give 0.09 g of the expected product. M.p. = 142-C.
35 EXAMPLE 8 -
5-Ethoxy-1,3-dihydro-1-[2-methoxy-4-(2-methoxy-
~ 66
2 1 2 9 2 1 ~
carbonylpyrrolidin-l-ylcarbonyl)benzenesulfonyl]-3-
spirocyclohexaneindol-2-one
500 mg of the hydrochloride of the methyl ester
of (L)-proline, 0.5 ml of TEA and 20 ml of DCM are added
S to 500 mg of 3-methoxy-4-[(5-ethoxy-2,3-dihydro- 2~oxo-3-
spirocyclohexaneindol-1-yl)sulfonyl]benzoyl chloride,
prepared in Example 6 step C). After stirring for one
hour at RT, the mixture is washed with 1 N HCl, dried and
concentrated. The residue is chromatographed on silica
using a DCM/MeOH mixture (98/2; v/v) as the eluent to
give 300 m~ of the expected product, which is
characterized by its MMR spectrum.
MMR at 200 MHz in DMSO (2.5 ppm).
1.25 ppm : t : 3H
1.3-2.35 ppm : m : 14H
3.1-3.7 ppm : m : 8H
3.8 ppm : q : 2H
4.35 ppm : mt : lH
6.7-B ppm : m : 6H
EXAMPLE 9
l-t4-(N'-Cyclopentylureido)-2-methoxybenzene-
sulfonyl]-5-ethoxy-1,3-dihydro-3-spirocyclohexaneindol-
2-one ~ ;
A) 5-Ethoxy-1,3-dihydro-1-(2-methoxy-4-phenoxycarbox-
amidobenzenesulfonyl)-3-spirocyclohexaneindol-2-one
A mixture containing 2 g of 1-(4-amino-2-
methoxybenzenesulfonyl)-5-ethoxy-1,3-dihydro-3-spiro-
cyclohexaneindol-2-one (prspared in Example 1 step B)),
3.6 ml of~ phenyl chloroformate and 120 ml of ether is
cooled to a temperature below 5-C. 960 mg of ~odium
hydroxide in 16 ml of water are added and the temperature
is allowed to rise for 24 hours, with stirring. The
preclpitate is filtered off and washed with water and
then with ether. The residue is chromatographed on
silica using DCM as the eluent to give the expected
product. M.p. = 181-C. .
67
212921~ :~
B) 1- r 4-(N'-Cyclopentylureido)~2-methoxybenzenesulfO-
nyl]-5-ethoxy-1,3-dihydro-3-spirocyclohexaneindol-2-one
2 g of the compound prepared in the previous step
are dissolved in 40 ml of 100- EtOH and 30 ml of DCM. 2
ml of cyclopentylamine are added and the mixture is
stirred $or 18 hours at RT. The alcohol is evaporated
off under vacuum and the residue is then chromatographed
on silica using a DCM/AcOEt mixture (95/5; v/v) as the
eluent to give 1.8 g of the expected product, wh$ch
crystallizes from iso ether.
M.p. = 195-C.
EXAMPLE 10
5-Chloro-1,3-dihydro-1-[4-(N',N'-diethyl-ureido)~
2-methoxybenzenesulfonyl~-3-spiro-(tetrahydro-thiopyran-
4-yl-1-oxide)lndol-2-one
This is prepared in the same manner a~ in Example
9 (steps A) and B)).
A) 5-Chloro-1,3-dihydro-1-[4-(N',N'-diethylureido)-2-
methoxybenzenesulfonyl]-3-spiro(tetrahydrothiopyran-4-
yl)indol-2-one, m.p. = 214-C, from 5-chloro-1,3-di-
hydro-1-[4-amino-2-methoxybenzenesulfonyl]-3-spiro-
(tetrahydrothiopyran-4-yl)indol-2-one, m.p. - 229-C
B) 5-Chloro-1,3-dihydro-1-t4-(~',N'-diethylureido)-2-
methoxybenzenesulfonyl]-3-spiro(tetrahydrothiopyran-4-yl-
1-oxide)indol-2-one
A mixture of 0.45 g of the compound prepared in
step A) and 0.2 g of sodium periodate in 3 ml of methanol
and 2 ml of water is stirred for 24 hours at RT. The
precipitate is filtered off and the methanol is
evaporated off from the filtrate under reduced pressure.
The re~ldue is extracted with DCM and dried over
magnesium sulfate and the solvent is evaporated off. The
residue is chromatographed on a silica column using a
DCM/methanol mixture (98/2; v/v) as the eluent and 0O4 g
of the expected product is isolated.
M.p. = 217-C.
' ~'
~68
21292~ ~
EXAMPLE 11
5-Chloro-1,3-dihydro-1 [4-(N',N'-diethylureido)-
2-methoxybenzenesulfonyl]-3-spiro(tetrahydrothiopyran-4-
yl-l,l-dioxyde)indol-2-one
5A mixture of 0.45 g of the compound of Example 10
and 0.5 ~ of metachloroperbenzoic acid in 10 ml of DCM i~
stirred at RT for 4 hours. 12 ml of a saturated aqueous
solution of sodium bicarbonate are then added and the
organic phase is decanted, washed with water, dried and
evaporated under reduced pressure. The residue is
recrystallized from a mixture of cyclohexane and ethyl
acetate (7/3, v/v) to give 0.35 g of the expected
product. M.p. = 211-C.
EXAMPLE 12
151-[4-(N'-Cyclopentylthioureido)-2-methoxy-
benzenesulfonyl]-5-ethoxy-1,3-dihydro-3-spirocyclo-
hexaneindol-2-one
The compound obtained in Example 9 is placed in
50 ml of toluene in the pre~ence of 1.5 g of Lawesson's
reagent. The mixture is refluxed for 24 hour~. The
toluene ls driven off and the residue is then chromato
graphed on silica using pure DCM and then a DCM/AcOEt
mixture (ranging up to 90/10 v/v) as the eluent to give
the expected product, which crystallizes from iso ether.
M.p. - 197-C.
EXAMPLE 13
1-[4-(3-(N-Boc-amino)azetidin-l-ylcarboxamido)-
5-methoxybenzenesulfonyl]-2-ethoxy-1,3-dihydro-3-spiro-
cyclohexaneindol-2-one
A) l-Benzhydryl-3-(N-Boc-amino)azetldine
A mixture containing 5 g of 3-amino-1-benzhy-
drylazetidine and 5 g of (Boc)20 in 130 ml of dioxane and
4 ml of T~A is stirred at RT for 2 hours. The dioxane is
evaporated off and the residue is taken up with AcOEt and
washed with water. It is dried over sodium sulfate and
then evaporated to dryness. The expected product
69
212921~ -
crystallizes from iso ether. m = 6 g.
B) 3-(N-Boc-amino)azetidine hydrochloride
A mixture containing 6 g of the compound prepared
in the previous step, 300 ml of 95- EtOH, 700 mg of
S palladium hydroxide and 3 ml of concentratsd HCl $s
prepared. It is hydrogenated for 2 hours at 35-40-C
under a pressure of 2 bar. The catalyst is filtered off
and the filtrate is evaporated to dryness. The expected
product crystallizes from iso ether
m = 3.4 g.
C) 1-[4-(3-(N-Boc-amino)azetidin-1-ylcarboxamido)-5-
methoxybenzenesulfonyl]-2-ethoxy-1,3-dihydro-3-æplro
cyclohexaneindol-2-one
A mixture contailning 500 mg of the compound
prepared in Example 9 step A), 20 ml of 100- alcohol, 15
ml of DCM, 250 mg of the compound prepared in step B) and
0.5 ml of TEA is stlrred for 24 hours at RT. The
solvents are evaporated off and the residue i8 then
chromatographed on a silica column using a DCM/AcOEt
mixture (95/5; v/v) as the eluent. The expected product
crystalllzes from iso ether.
m - 200 mg. M.p. - 156-C.
EXAMPLE 14
1-[4-(N'-Carboxymethyl-N'-methylureldo)-2-
methoxybenzenesulfonyl]-5-ethoxy-1,3-dihydro-3-~piro-
cyclohexaneindol-2-one
A mixture containing 500 mg of the compound
prepared in Example 9 step A), 20 ml of 100- EtOH, 15 ml
of DCM, 1.5 g of sarcosine and 2 ml of triethylamine is
prepared. After stirring for 24 hours at RT, the
solvents are evaporated off, the residue is then taken up
with hot AcOEt and the insoluble material is filtered
off. The filtrate is evaporated to dryness and the
residue is then chromatographed on silica using pure DCM
and then a DCM/MeOH mixture (85/15; v/v) as the eluent to
give the expected product, which i5 characterized by its
~:
2 1 2 9 2 1 j
NMR spectrum at 200 MHz in DMSO (2.5 ppm):
1.3 ppm : t : 3H
1.4-2.1 ppm : m : lOH
2.95 ppm : s : 3H
3.5 ppm : s : 3H
3.9 ppm : s : 2H
4 ppm : q : 2H
6.7-7.9 ppm : m : 6H
9.45 ppm : bs : lH
EXAMPLE 15
5-Ethoxy-1,3-dihydro-1-[2-methoxy-4-(1-methyl-
2,4-dioxoimidazolin-3-yl)benzenesulfonyl]-3-spirocyclo-
hexaneindol-2-one
On heating at lOO-C for 24 hours under vacuum,
the product obtained in the previous Example is cyclized
to give 230 mg of the expected product.
M.p. - 200-C.
EXAMPLE 16
1-[4-(N',N'-Diethylthioureido)-2-methoxybenzene
sulfonyl]-5-ethoxy-1,3-dihydro-3-spirocyclohexaneindol-
2-one
A) 5-Ethoxy-1,3-dihydro-1-(2-methoxy-4-phenoxythio-
carboxamidobenzenesulfonyl)-3-spirocyclohexaneindol-2-
one
A mixture containing 500 mg of the compound
obtained in Example 9 step A), 900 mg of ;;
phenoxythiocarbonyl chloride, 30 ml of ether, 8 ml of ~ -
water, 12~ mg of ~odium hydroxide and 20 ml of DCM is
prepared. After stirring for 24 hours at RT, the
solvents are evaporated off and the residue is then
chromatographed on silica using DCM as the eluent. The
expected product crystallizes from iso ether. ~
m = 140 mg. M.p. = 157-C. ~~;
B3 1-[4-(N',N'-Diethylthioureido)-2-methoxybenzene~
35 sulfonyl]-5-ethoxy-1,3-dihydro-3-spirocyclohexaneindol- -~
2-one
':.
~ 71
212921 :~
A mixture containing 140 mg of the compound
prepared in step A), 20 ml of 100- EtOH, 5 ~l of DCM and
1 ml of diethylamine is stirred at RT for 18 hours~ The
solvents are evaporated off and the residue is then
chromatographed on a silica column using pure DCM and
then a DCM/AcOEt mixture (up to 90/10; v/v) as the
eluent. The expected product crys~allizes from iso
ether. m = 105 mg. M.p. = 167-C.
EXAMPLE 17
5-Ethoxy-1,3-dihydro-1-(2-methoxy-4-guanidino-
benzenesulfonyl)-3-spirocyclohexaneindol-2-one
A mixture containing 500 mg of the compound
prepared in Example 1 step B), 125 mg of cyanamide, 7 ml
of AcOEt, 1 ml of EtOH and 0.2 ml of a 20% solution of
hydrochloric acid in EtOH is refluxed for 1 hour. The
solvents are evaporated off and the resldue is then
chromatographed on a silica column using DCM and then
MeOH as the eluent. The product isolated solidifies in
ether. A 2 N solution of NaHC03 is added and the base
formed is then extracted with ~cOEt; the extract is
evaporated to dryness and the expected product solldifies
in iso ether. m = 0.055 g. M.p. = 235-C.
EXAMPLE 18
5-Ethoxy-1,3-dihydro-1-[2-methoxy-4-~N-methyl-
carbamoylmethoxy)benzenesulfonyl]-3-spirocyclohexane-
indol-2-one
A) Potassium 2-methoxy-4-(ethoxycarbonylmethoxy)phenyl-
sulfonate
10 g of ethyl (3-methoxyphenoxy)acetate and 30 ml
of DCM are mixed at O-C and 7.5 ml of trimethyl-
silylsulfonyl chloride in 30 ml of DCM are added over 20
minutes. The temperature is allowed to rise to RT, with
stirring, 30 g of ice are added after 2 hours and the
mixture is stirred again. After decantation, the aqueous
phase is washed with ether, and potassium carbonate is
added in a sufficient amount to bring the pH to 7. The
~, : : : -- -
.. ~ . ~ :- :: ~ .
-~ 72
2292~ ~
white precipitate which forms i9 flltered off and then
washed with acetone and ether to give 3.1 g of the
expected product, which is characterized by its NMR
spectrum.
5 B ) 2-Methoxy-4-~ethoxycarbonylmethoxy)phenylsulfonyl
chloride
3~1 g of the compound obtained in the previous
step in 30 ml of phosphorus oxychloride are refluxed for
3 hours. The medium is concentrated under vacuum and
then taken up with ice. It is extracted with ethyl
acetate, wathed with water, with N sodium hydroxide and
then with water again, dried over sodium sulfate and
concentrated under vacuum. The expected product
crystallizes from iso ether. m = 2.5 g. M.p. - 89-C.
C) Ethyl 3-methoxy-4-[(5-ethoxy-2,3-dihydro-2-o~o-3-
spirocyclohexanelndol-l-yl)sulfonyl]phenoxyacetate
A mixture containing 0.5 g of 5-ethoxy-1,3-
dihydro-3-spirocyclohexaneindol-2-one, 5 ml of THF and 60
mg of sodium hydride is prepared. After ~tirring for 15
minutes at 15-C, 0.66 g of the compound prepared in the
previous step is added. Stirring is maintained for 15
minutes and the medlum is then concentrated under vacuum.
It i~ extracted with ether and washed with water and the
expected product i~ the~ crystallized from iYo ether.
m - 0.85 g. M.p. - 160-C.
D) 5-Ethoxy-1,3-dihydro-1-[2-methoxy-4-~N-methyl-
carbamoylmethoxy)benzenesul~onyl]-3-spirocyclohexane-
indol-2-one
A mixture containing 0.5 g of the compound
prepared in the previous step, lS ml of a 33% solution of
methylamine in MeOH and 15 ml of EtOH i~ stirred for 4
days at RT. It ts concentrated under vacuum and the
residue is then chromatographed on silica. The column ls
washed with DCM and then eluted with AcOEt to give the
expected product. m ~ 0.1 gO M.p. = 192-195-C.
2129213
EXAMPLE 19
5-Ethoxy-1,3-dihydro-1-[2-methoxy-4-(N-methyl-
N-(2-methylallyl)amino)benzenesulfonyl~-3-spirocyclo-
hexaneindol-2-one
A) 5-Ethoxy-1,3-dihydro-1-[2-methoxy-4-(N-methylamino)-
benzenesulfonyl]-3-spirocyclohexaneindol-2-one
2 g of the compound prepared in Example 1 step
B), cooled in an ice bath to lO-C, are dissolved in 6 ml
of a 37~ aqueous solution of formaldehyde and 40 ml of
acetonitrile. 1.7 g of 85~ pure sodium cyanoboro-
hydride and then 0.5 ml of acetic acid are added and the
mixture is stirred at RT for 24 hours. The acetonitrile
is evaporated off and the residue is taken up with water
and AcOEt. The organic phzse is decanted, dried and then
chromatographed twice in succession on sillca using a
DCM/heptane mixture (85/15; v/v), then pure DCM and
flnally a DCM/AcOEt mixture (98/2; v/v) as the eluent to
give the expected compound. m = 0.36 g. M.p. ~ 157~C.
B) 5-Ethoxy-1,3-dihydro-1-t2-methoxy-4-(N-methyl-N-(2-
methylallyl)amino)benzenesulfonyl]-3-spirocyclohexane-
indol-2-one
A mixture containing 500 mg of the compound
obtained in the previous step, 10 ml of DMF, 0.5 ml of
diethylam~ne and 0.5 ml of 3-chloro-2-methylpropene is
refluxed for lO hours. The reaction medium is poured
into a water/ice mixture and then extracted with AcOEt,
washed with wat~r and chromatographed on sllica using DCM
as the eluent~ The expected compound crystallizes from
pentane. m = 190 mg. M.p. = 118-C.
212921~
The compounds (I) according to the invention
described in Table 3 below were pr~pared by following
the procedures described in the previous Examples.
S TABLE 3
R1 ~ R4
N o
:'
SO2.
~,,OCH3
R6 '
. . . .
Example R1 CR3R4 R6 M.p.-C :
.
Cl-cyclohexane I~\ 179
(a) I~N--
21 EtO-4,4-dimethyl ~\ 167
(a) cyclohexane ¦~,N
.. ..~ ~.
22 Cl-cyclohexane EtOCOCH2NHCONH- 167
(b) , .~'
I _, ., . , ,, ~
2 1 2 .9 2 1 ~
TABLE 3 ( continuation )
E~ample Rl CA11c~ R6 1 19C ~:
23 Cl -cyclohexane A 139
(b) ,~N{~ONH- . ~-
Me
24 EtO-cyclohexane r\ 150 ~ -
(c) L~N ~ONH -
EtO-cyclohexane A 197
(c) Me -N N{~ONH- ~ ~:
\
26 EtO-cyclohexane Me O N C O N H - 177
(c) Me
27 EtO-cyclohexane MeNH(CH2)2NCNH- 170
(c) Mehydrochloride : -
monohydrate
28 EtO-cyclohexane H O N CO N H -185
(c) Me
29 EtO-cyclohexane HOCH2CH2NCONH- 128
(c) Me
EtO-cyclohexane ~ 139
(C) N-CONH -
31 EtO-cyclohexane A 210
(c) _ ~N~ONH - .
~ 76
212921~j :
TABLE 3 ( continuation )
, ~ __
Example R1 C~3R4 R6 M.p.-C ~ ~
32 EtO-cyclohexane / \ 190 :
(c) O~ N~ONH-
33 EtO-cyclohexane / \ 212
(c) S N {~ON H -
34 EtO-cyclohexane / \ 179
(c) ~N~ONH-
-'~- . ' .
EtO-cyclohexane ~ 146
(c) Me ~ N{~ONH-
3~5 EtO-cyclohexane ~Me 198 ~:
(c) /~
~N_coN~ . ~:
~le ;
37 EtO-cyclohexane 208 :
(c) MCN(~H2)2NcoNH hydrochlotide
Me Et monohydrate
38 EtO-cyclohexane / \ 195 ..
(C) Ph~ N{~ONH- ., ' ~:
1 i , ,:
39 EtO-cyclohexane MeN((~H2)2NCONH- 200 ~:
(c) . . M: M- fumarate : ~:
212921~
TABLE 3 ( continuation )
_. _ .~ .
Examplc R1 CR3R4 R6 M.p.-C :;
.
EtO-cyclohexane ~ N 159
(c) \~ (CH2)2NCONH . ~:
Me
41 Cl-4,4-dimethyl- S 179
(d) cyclohexane Et 2N CN H -
42 EtO-4,4-dimethyl- S 146
(d) cyclohexane Et 2N CN H -
44 EtO-cyclohexane _ O 189
(e) ~ CH2NHCO-
EtO-cyclohexaneCF3CH2NHCO- 210
(e)
46 EtO- cyclohexane ~\ 196
(e) L~NHCO-
47 EtO- eyelohexane A 1SS
(e) ~NHCO-
48 EtO- eyclohexane r\ 204
(e) L~N--NH CO -
'~ ' ' ' ' ' " : ' ' ' ~: ', : ' ' '
78
212~215
TABLE 3 ( continuation )
. - _~ _
Examplc R1 CR3R4 R6 M.p.-C ~:
_ _
4g EtO-cyelohexane ~I\ 143
(e) ~ :~
CH2NHCO-
EtO-eyelohexaneEtO(CH2)2NHCO- 166
(e) :
51 EtO-eyelohexaneH~NCO(:H2NHCO- 245
(e) . . .
52 EtO-eyclohexaneEt2N-COCH2NHCO- 161 : ~
(e) ~ :
53 EtO-eyclohexane(Et2N-cocH2)2Nco- 141
(~) ' -' .
54 EtO- eyelohexane NC-C(Me)2NHCO- 198
(e) :
EtO- cyelohexane Et2NC(NH~NH- 137
(f) hydrochlnride
56 hemihydrate
(g) Cl- (CH2)2o ~l CH30-- 136 : - :
, \/¢ ~ ~.'~'.
. . , (CU21201~oJ , _, ___ . : ~
~ 79
2129215 -~ ~
TABLE 3 (continuation) - ~
_ __ _ : ,
Examplc R1CR3R4 R6 M.p.-C
.
57(1) EtO- \ r ~ 88
~C ~ OCH2 Et~NCONH-
OCH3
58(1) EtO- / 3 Et2NcoNH- 130
(a) This compound is prepared by the procedure
S described in EXAMPLE 2 step C), the reaction being
ca~ried out under an inert atmosphere using
triethylamine as the base.
(b) This compound is prepared by the procedures
described in EXAMPLE 9 step A) and then step B~ using
the appropriate amino derivatives or nitrogen
heterocycle~.
(c) ThIs compound is prepared by the procedure
described in EXAMPLE 9 step B) using the appropriate
amino derivatives or nitrogen heterocycles.
15(d) ~his compound is prepared by the procedures
descrlbed in EXAMPLE 16 step A) and then step B).
(e) This compound is prepared by the procedure
descrlbed in EXAMPLE 6 step D) using the appropriate
amines.j
20(f) This compound is prepared by the procedure
described in EXAMPLE 17 using N,N-diethylcyanamide.
(g) This compound i5 prepared ~y the procedure
described in EXAMPLE 1 step A) using 2,4-dlmethoxy-
benzenesulfonyl chloride and the appropriate indol-2-
one.
,
2~292~
(h) This compound is prepared by the procedure
described in EXAMPLE 68 starting from the compound
obtained in EXAMPLE 57 (mixture of isomers).
(1) mixture of isomers
-
EXAMPLE 59
5-Ethoxy-1-~4-(N'~N'-diethylureido)-2-methoxy-
benzenesulfonyl]-1,3-dihydro-3-spiro(4-oxocyclohexane)-
indol-2-one 0.25 hydrate
A mixture of 0.3 g of the compound obtalned in
EXAMPLE 68, O . 3 g of pyridinium chlorochromate and 1.5
ml of DCM is stirred for 16 hours at RT. 10 ml of
water are added to the reaction mixture, the DCM is
evaporated off under vacuum, the residue is extracted
with AcOEt and dried over magnesium sulfate and the
solvent is concentrated under vacuum. ~he residue is
chromatographed on silica usi~g a DCM/MeOH mixture :-
(98/2, v/v) as the eluent to give 0.26 g of the
expected product. M.p. = lOO-C. -~
EXAMPLE 60
5-Fluoro-1,3-dihydro-1-t2-methoxy-4-~D3-pyr-
rolin-l-yl)benzenesulfonyl]-3-spiro(4,4-dimethylcyclo-
hexane)indol-2-one
This compound i5 prepared by the procedure :~
de~cribed in EXAMPLE 2 step C), the reaction belng
carrled out under an inert atmosphere using
triethylamine as the base. : -
EXAMPLE 61
5-Chloro-3,3-dihydroxyethyl-1,3-dihydro-1-(2,4- ~;
dlmethoxybenzenesulfonyl)indol-2-one
This compound is prepared by the method
described in J. Org. Chem., 1977, 42, 3772. 0.037 g of
pyridinium toluenesulfonate in 12 ml of ethanol is
added to 0.92 g of the compound of Example 56 described
in Table 3 above, and the mixture ls heated at about
55-C for 3 hours. The solvent is evaporated off under
;. .
81
21292~ '~3
reduced pressure and the residue is chromatographed on
a silica column using DCM as the eluent. The expected
product is isolated and crystallized from a hot
cyclohexane/ethyl acetate mixture (50/50, v/v). M.p. =
166-C.
EXAMPLES 62 and 63
5-Ethoxy-1,3 dihydro-1-(2-methoxy-4-nitroben-
zenesulfonyl)-3-spiro[4-(methoxymethoxy)cyclohexane]-
indol-2-one, the less polar isomer and the more polar
isomer
These compounds are prepared by the procedure
described in EXAMPLE 1 step A') starting from 5-ethoxy-
1,3-dihydro-3-spiro~4-(meth~xymethoxy)cyclohexane]-
~ ndol-2-one. They are chromatographed on silica uslng a
cyclohexane/AcOEt mixture (95/5; v/v) as the eluent.
The two isomers are separated into
- the less polar isomer: compound of EXAMPLE
62, m.p. = 127-C;
- the more polar isomer: compound of EXAMPLE
63, m.p. = 118-C.
EXAMPLES 64 and 65
1-(4-Amino-2-methoxybenzenesulfonyl)-5-ethoxy-
1,3-dihydro-3-spiro[4-(methoxymethoxy)cyclohexane]-
indol-2-one, the less polar isomer and the more polar
isomer
These compounds are prepared by the procsdure
described in EXAMPLE 1 step B'') starting from the
mixture of compounds obtained in EXAMPLES 62 and 63
before chromato~raphy. They are chromatographed on
silica using a cyclohexane/AcOEt mixture (95/5; v/v~ as
the eluent. The two isomers are separated into
- the less polar isomer: compound of EXAMPLE
64, m.p. 3 103-C;
- the more polar isomer: compound of EXAMPLE
65, m.p. = lll-C.
.. . ~. . : . : , ,
82
2129~15 : ~
EXAMPLE 6 6
5-Ethoxy-1-[4-( N ', N ' -diethylureido)-2-methoxy-
benzenesulfonyl~-1,3-dihydro-3-spiro[4-(methoxy-
methoxy)-cyclohexane]indol-2-one, the less polar isomer
S This compound is prepared by the procedure
described in EXAMPLE 9 step A) and then step B)
start~ng from the compound obtained ln EX~MPLE 64 and
using diethylamine in the 2nd step. The expected
product is obtained after recrystallization from a
cyclohexane/ AcOEt mixture. M.p. = 160-C.
EXAMPLE 67
5-Ethoxy-1-[4-(~',N'-diethylureido)-2-methoxy-
benzenesulfonyl]-1,3-dihydro-3 spiro[4-(methoxymeth-
oxy)cycloh~xane]indol-2-one, the more polar isomer
This compound iR prepared by the procedure
describsd in EXAMPLE 9 step A) and then step B)
startlng from the compound obtained in EXAMPLE 65 and
using diethylamine in ~he 2nd step. The expected
product is obtained after recrystall~zation from a
cyclohexane/ AcOEt mixture. M.p. = 137-C~
EXAMPLE 68
5-Ethoxy-1-[4-(N',N 7 -diethylureido)-2-methoxy-
benzenesulfonyl]-1,3~dihydro-3-spiro(4-hydroxycyclo-
hexane)indol-2-one monohydrate, the less polar isomer~ ~
A solutlon of 2.2 g of the compound obtained in ~-;
EXAMPLE 66 in 6 ml of MeOH and 1.2 ml of concentrated
HCl is heated at 50-C for 30 minutes. 10 ml of water
are added to the reaction mixture, extraction is
carried out with AcOEt, the extract is dried over
magnesium sulfate and the solvent is evaporated off
under vacuum. The residue ls chromatographed on silica
using a DCM/MeOH mixture (90/10; v/v) as the eluent to
give 1.9 g of the expected product after
recrystallization from a cyclohexane/AcOEt mixture.
M.p. = 138-C.
~ 83
2~29215
EXAMPLE 69
5-Ethoxy-l-t4-(N',N'-diethylureido)-2-methoxy-
benzenesulfonyl]-1,3-dihydro-3-spiro(4-hydroxycyclo-
he~ane)indol-2-one monohydrate, the more polar isomer
S This compound ls prepared by the procedure
deQcribed in EXAMPLE 68 starting from the compound
obtained in EXAMPLE 67. The expected product is
obtained after recrystallization from a
cyclohexane/AcOEt mix ture. M.p. = 144-C.
EXAMPLE 70
5-Ethoxy-1,3-dihydro-1-(2-methoxy-4-nitroben-
zenesulfonyl)-3-spiro(4-methoxycyclohexane)indol-2-one,
the more polar isomer
This compound is prepared by the procedure
described in EXAMPLE 1 step A') starting from the more
polar isomer of 5-etho~y-1,3-dihydro-3-spiro(4-methoxy-
cyclohexane)indol-2-one lcompound of Preparation 17).
The expected product is obtained. M.p. = 141-C.
EXAMPLE 71 : :
1-(4-Amino-2-methoxybenzenesulfonyl)-5-ethoxy-
1,3-dihydro-3-spiro(4-methoxycyclohexane)indol-2-one,
the more polar isomer
Thi~ compound is prepared by the procedure
descrlbed in EXAMPLE 1 step B'') starting from the
25 compound obtained in EXAMPLE 70. M.p. = 199-C.
EXAMPLE 72
5-Ethosy-1-[4-~N',N'-diethylureido)-2-methoxy-
benzenesulfonyl]-1,3-dlhydro-3-spiro(4-methoxycyclo-
hexane)indol-2-one, the less polar isomer ~ :
A) 5-Ethoxy-1,3-dihydro~ methoxy-4-nitrobenzene-
sulfonyl)-3-spiro(4-methoxycyclohexane)indol-2-one, the
less polar isomer
This compound is prepared by the procedure
described in EXAMPLE 1 step A') starting from the
compound obtained in Preparation 16 (the less polar
isomer).
_~ 84 - :
2~2921-5
(4-Amino-2-methoxybenzenesulfonyl)~5-ethoxy-1,3-
dihydro-3-spiro~4-methoxycyclohexane)lndol-2-one, the
less polar isomer
This compound is prepared by the procedure
S described in EXAMPLE 1 step B' ' ) starting from the
compound obtained in the previous step.
C) 5-Ethoxy-1-[4-(N',N'-diethylureido~-2-methoxyben- :
zenesulfonyl]-1,3-dihydro-3-spiro(4-methoxycyclo-
hexane)indol-2-one, the less polar isomer
This compound is prepared by the procedure
described in EXAMPLE 9 step A) and then step B)
starting from the compound obtained in the previous
step and using diethylamine. M.p. = 118-C. .: :~
EXAMPLE 73
5-Ethoxy-1-[4-(N',N'-diethylureido)-2-methoxy-
benzenesulfonyl]-1,3-dihydro-3~spiro(4-methoxycyclo~
hexane)indol-2-one, the more polar isomer
This compound is prepared hy the procedure
de~cribed in EXAMPLE 9 step A) and then step B)
starting from the compound obtained in EXAMPLE 71 and
uslng diethylamine in ~he 2nd step. The expected
product is obtained after recrystallization from a
cyclohexane/ AcOEt mixture. M.p. = 164-C. - .
EXAMPLE 74 :
5-Ethoxy-1,3-dihydro-1-(2-methoxy-4-nitroben-
zenesulfonyl)-3-spiro(4-hydroxyayclohexane)indol-2-one,
the more polar isomer
A mixture of 2.2 g of the compound obtained in
EXAMPLE 63 and 1.2 ml of concentrated HCl in 6 ml of
30 MeOH is heated at 50-C for 1 hour. 10 ml of water are
added to the reaction mixture and the precipitate
formed is filtered off, washed with water and dried -:
under vacuum at 50-C to give 1.3 g of the expected
product. M.p. = 135-C.
EXAMPLE 75
5-Ethoxy-1-[4-(N',~'-diethylureido)-2-methoxy- -
21292~ 5
benzenesulfonyl]-1,3-dihydro-3-spiro(4-ethoxycyclo-
hexane)indol-2-one
A) 5-Ethoxy-1,3-dihydro-1-(2-methoxy-4-nltrobenzene
sulfonyl)-3-spiro(4-ethoxycyclohexane)indol-2-one
S A solution of 0.25 g of 5-ethoxy-1,3-dihydro-
1-(2-methoxy-4-nitrobenzenesulfonyl)-3-spiro(4-hydroxy-
cyclohexane)indol-2-one (prepared by the procedure
described in EXA~PLE 74 starting from the mixture of
isomers obtained in EXAMPLES 62 and 63 before
chromatography), 0.6 ml of 2,6-di-tert-butylpyrldine
and 0.37 ml of ethyl trlfluoromethanesulfonate in DCM
is stirred for 6 hours at 40'C. 5 ml of 5 N HCl are
added to the reaction mixture, extraction is carried
out with AcOEt, the organic phase is washed three time~
wlth 0.5 N HCl and with a saturated solution of NaCl
and dried over ~agne~ium sulfate and the solvent is
evaporated off under vacuum to give 0.5 g of the
expected product in the form of an oil, which is used
as such in the next step.
B) 1-(4-Amino-2-methoxybenzenesulfonyl)-5-ethoxy-1,3
dlhydro-3-spiro(4-ethoxycyclohexane)indol-2-one
This compound is prepared by the procedure
described in EXAMPLE 1 step B') by chemical reduction
of the compound obtained in the previous step. It is
chromatographed on silica using a DCM/MeOH mixture
(99/1; v/v) as the eluent to give the expected product.
M.p. = 110-C.
C) 5-Ethoxy-1,3-dihydro-1-(2-methoxy-4-phenoxycarbox-
! ~ 'I amidobenzenesulfonyl)-3-spiro(4-ethoxycyclohexane)~
indol-2-one
This compound is prepared by the procedure
described in EXAMPLE 9 step A) starting from the
compound obtained in the previous step. This gives the
expected product, which is used as such in the next
step.
D) 5-Ethoxy-1-[4-(N',N'-diethylureido)-2-methoxy-
,^~ 86
- ~12921~
benzenesulfonyl]-1,3-dihydro-3-spiro(4-ethoxycyclo-
hexane)indol-2-one
This compound is prepared by the procedure
described in EXAMPLE 9 step ~) starting from the
S compound obtained in the previous step and
diethylamine. The expected product is obtained. M.p. i~
= 121-C.
EXAMPLE 76
5-Ethoxy-1-[4-(N',N'-diethylureido)-2-methoxy-
benzenesulfonyl]-1,3-dihydro-3-spiro[4-(2-methoxyeth-
oxy)cyclohexane]indol-2-one
A) 5-Ethoxy-1,3-dihydro-1-(2-methoxy-4-nitrobenzene-
sulfonyl)-3-spiro[4-(2-methoxyethoxy)cyclohexane]-
indol-2-one
A mixture of 0.2 g of 5-ethoxy-1,3-dihydro~
(2-methoxy-4-nitrobenzenesulfonyl)-3-spiro(4-hydroxy-
cyclohexane)indol-2-one, 2 g of 1-iodo-2-methoxyethane,
0.9 ml of 2,6-di-tzrt-butylpyrldine and 2.15 g of
silver trifluoromethanesulfonate in 17 ml of CC14 and 8
ml of DCM is stirred for 24 hours at RT. 100 ml of
0.1 N HCl are added to the reaction mixture, the
solvents are evaporated off under vacuum, the residue
is extracted with AcOEt and dried over magnesium
sulfate and the solvent is evaporated off under vacuum.
The resldue is chromatographed on silica using
cyclohexane as the eluent to give 0.36 g of the
expected product, which is used as such in the next
step.
I B) 1-(4-Amino-2-methoxybenzenesulfonyl)-5-ethoxy-1,3-
dihydro-3-spiro[4-(2-methoxyethoxy)cyclohexane]indol-2-
one
Thl~ compound is prepared by the procedure
described in EXAMPLE 1 step 8') by reduction of the
compound obtained in the previous step. The expected
product is obtained. M.p. = 118-C.
C) 5-Ethoxy-1,3-dihydro-1-(2-methoxy-4-phenoxycarbox-
~ 87
212921~ ~
amidobenzenesulfonyl)-3-spiro[4-(2-methoxyethoxy)-
cyclohexane]indol-2-one
This compound is prepared by the procedure
described in EXAMPLE 9 step A) starting from the
S compound obtained in the previous step. This gives the
expected product, which is used as such in the next
step.
D) 5-Ethoxy-1-[4-(N' ,N'-diethylureido)-2-methoxy-
benzenesulfonyl]-1,3-dihydro-3-spiro r 4-(2-methoxy-
ethoxy)cyclohexane]indol-2-one
This compound is prepared by the procedure
described in EXAMPLE 9 step B) starting from the
compound obtained in the previous step and
diethylamine. The expected product is obtained.
M.p. ~ 98-C.
EXAMPLE 77
5-Ethoxy-1-[4-(N',N'-diethylureido)-2-methoxy- ~
benzenesulfonyl~-1,3-dihydro~3-spiro(4-n-propoxycyclo- ~ - ;
hexane)indol-2-one -
This compound is prepared by the procedures
described in EXAMPLE 76 step A) starting from 5-ethoxy-
1,3-dihydro-1-$2-methoxy-4-nitrobenzenesulfonyl)-3-
spiro(4-hydroxycyclohexane)indol-2-one and l-iodopro-
pane in benzene, and then steps B), C~ and D). The
expected product is obtained. M.p. 8 115-C.
EXAMPLE 78
5-Ethoxy-1-[4-(N',N'-diethylureido)-2-methoxy-
benzenesulfonyl]-1,3-dihydro-3-spiro(4-isopr~poxycyclo-
I hexane)indol-2-one hemihydrate
This compound is prepared by the procedures
described in EXAMPLE 76 step A) starting from 5-eth-
oxy-1,3-dihydro-1-(2-methoxy-4-nitrobenzenesulfonyl)-3-
spiro(4-hydroxycyclohexane~indol-2-one and 2-iodopro- -
pane ln benzene, and then steps B), C) and D). The
expected product is obtained. M.p. = 130-C.
~ ..
^~ 88
2~2~21~
~ :
EXAMPLE 79 .
5-Ethoxy-1-[4-(N',N'-dlethylureido)-2-methoxy-
ben~enesulfonyl]-1,3-dihydro-3-spiro[4-(2-tert-butoxy-
ethoxy)cyclohexane]indol-2-one
S This compound is prepared by the procedures
described in EXAMPLE 76 step A) starting from 5-eth-
oxy-1,3-dihydro-1-(2-methoxy-4-nitrobenzenesulfonyl)-3-
spiro(4-hydroxycyclohexane)indol-2-one and 1-iodo-2-
tert-butoxyethane, and then steps B), C) and D). The ~ ~ ~
10 expected product is obtained. M.p. = 103-C. ~-
EXAMPLE 80 . .
5-Ethoxy-l-t4-(N',N'-diethylureido)-2-methoxy-
benzenesulfonyl]-1,3-dihydro-3-spiro[4-(2-hydro~y-
ethoxy)cyclohexane]indol-2-one ;~
A mlxture of 0.35 g of the compound obtained in
EXAMPLE 79 and 4 ml of trifluoroacetic acid in 15 ml of
DCM is stirred for 2 hours at RT. 40 ml of a saturated
solution of NaHC03 are added, the mixture is decanted,
the organic phase is washed with water and dried over
magnesium sulfate and the solvent is evaporated off
under vacuum. The residue is chromatographed on silica
using a DCM/MeOH mixture (90/10, v/v) as the eluent to
give the expected product. M.p. - lO9-C. ; -~
EXAMPLE 81
5-Ethoxy-1-[4-(N',N'-diethylureido)-2-methoxy-
benzenesulfonyl]-1,3-dihydro-3-spiro(4-formyloxycyclo-
hexane)indol-2-one, the more polar isomer
A mixture of 0.25 ~ of the compound obtained in
EXAMPLE 69, 0.18 g of cesium carbonate, 0.45 ml of
dimethyl sulfate and 12 ml of DMF is heated at 40'C for
12 hours. 10 ml of water are addsd, the reaction mix
ture is extracted with AcO~t, the organic phase is
washed with water and dried over magnesium sulfate and
the solvent is evaporated off under vacuum. The
residue is chromatographed on silica using DCM as the
eluent to give 0.2 g of the expected product after
~ 89
21292~ ~ ~
recrystallization from a cyclohexane/AcOEt mlxture.
M.p. = 155^C.
EXAMPLE 8 2
5-Ethoxy-1-[4-(N',N'-diethylureido)-2-methoxy-
S benzen~sulfonyl]-1,3-dihydro-3-spiro(4-acetoxycyclo-
hexane)indol-2-one, the more polar isomer
A mixture of 3 g of the compound obtained in
EXAMPLE 69, 0.75 g of 4-dimethylaminopyridine, 3 ml of
acetic anhydride and 5 ml of DCM is heated at 40-C for -~
5 hours. Water is added to the reaction mixture, ex
traction is carried out with DCM, the extract is washed
with water and dried over magnesium sulfate and the
solvent is evaporated off under vacuum. The residue is
chromatograp~ed on silica using a DCM/cyclohexane
mixture as the eluent to give the expected product
after recrystallization from iso ether. M.p. = 140-C.
EXAMPLE 83
5-Ethoxy-1,3-dihydro-1-(2,4-dlmethoxybenzene-
sulfonyl) 3-spiro(8,9-dihydroxytricyclo[5.2.1.02~6]-
decan-4-yl)indol-2-one
A) 5-Ethoxy-1,3-dihydro-l-(2,4-dimethoxybenzenesul-
fonyl)-3-spiro(8,9-epoxytr~cyclo[5.2.1.02,6~decan-
4-yl)indol-2-one
A mixture of 0.3 g of 5-ethoxy-1,3-dihydro- 1-
(2,4-dimethoxybenzenesulfonyl)-3-spiro(~ricyclo-
[5.2.1.02,6~deo-8-en-4-yl)indol-2-one and 0.2 g of
metachloroperbenzoic acid in 20 ml of DCM i5 stirred
for 3 hours at RT. 15 ml of a saturated solution of
I NaHC03 are added, the mixture is decanted, extraction
is carried out with DCM, the extract is dried over mag
nesium sulfate and the solvent is evaporated off under
vacuum. The residue is chromatographed on silica usin~
DCM as the eluent to give 0.25 g of the expected
product after recrystallization from an acetone/DCM
35 mixture. M.p. = 263-C. ~ -
B) 5-Ethoxy-1,3-dihydro-1-(2,4-dimethoxybenzenesul-
: - ~.:
~ 9o ~ :
2~2921~ -
fonyl)-3-spiro(8,9-dihydroxytricyclo[5.2.1.02~6~decan~
4-yl)indol-2-one
A mixture of 0.2 g of the compound obtained in
the previous step, 20 ml of water, 2 ml of concentrated
sulfuric acid and 20 ml of THF is refluxed for 8 hours.
The reaction mixture is neutralized ~y the addition of :
a saturated solution of NaHC03, the solvent is
evaporated off under vacuum, the residue is extracted
with DCM and dried over magnesium sulfate and the
solvent is evaporated off under vacuum. The residue is
chromatographed on silica using a DCMtMeOH mixture
(99/1; v/v) as the eluent to give 0.17 g of the
expected product. M.p. = 150-C.
: ' . ,:~
.
,~
~.
' ~:
~ .~
-
.
, ' . ' . , ', ' ' ' ' ; .' . :", . .~ ' ' ' , ' . . ''.
