CA2129215A1 - 1-benzenesulfonyl-1,3-dihydro-indol-2-one derivatives, their preparation and pharmaceutical compositions in which they are present - Google Patents

1-benzenesulfonyl-1,3-dihydro-indol-2-one derivatives, their preparation and pharmaceutical compositions in which they are present

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Publication number
CA2129215A1
CA2129215A1 CA002129215A CA2129215A CA2129215A1 CA 2129215 A1 CA2129215 A1 CA 2129215A1 CA 002129215 A CA002129215 A CA 002129215A CA 2129215 A CA2129215 A CA 2129215A CA 2129215 A1 CA2129215 A1 CA 2129215A1
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Prior art keywords
alkyl
group
substituted
compound
unsubstituted
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CA002129215A
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French (fr)
Inventor
Alain D. Malta
Loic Foulon
Georges Garcia
Dino Nisato
Richard Roux
Claudine Serradeil-Legal
Gerard Valette
Jean Wagnon
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Sanofi SA
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Individual
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Abstract

ABSTRACT OF THE DISCLOSURE
The invention relates to 1-Benzenesulfonyl-1,3-dihydroindol-2-one derivatives of the formula

Description

- 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"l- ~ 3 :
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 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: ~¦

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 S O
2 (~

(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 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.

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 -~
.: ~ -...

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 ~ -(~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. ;~

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'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 ., 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 ~-.

` 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 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 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 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.
:.
"`' ~,~, - - . . . .

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..;'"'-."

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 ...... ... . .... . . .. .... ~ ~ . . , .. . . .. . .. , .. ... ~ .. . . .. ..... .... . . .... .... . . . .
.

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.

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

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 .__ ._ _ :::
::
.

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 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 .

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 ~.

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 ~, 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.

2 1 2 9 2 1 ~

The following anilines are also prepared by the latter procedure~
R3 . : .
Rl~f~R4 ~1 N O
SO2 :

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).

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.

2~ 2921~ ~ ~

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.

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 4-2~2921~

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.

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.

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

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. .

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.

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~ ~

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.

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.

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 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.

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

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.

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.

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.

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.

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.

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 -'~ ' ' ' ' ' " : ' ' ' ~: ', : ' ' ' 212~215 TABLE 3 ( continuation ) . - _~ _ Examplc R1 CR3R4 R6 M.p.-C ~:
_ _ 4g EtO-cyelohexane ~I\ 143 (e) ~ :~

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-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 -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. -~

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. : -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 ;. .

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.

.. . ~. . : . : , , 2129~15 : ~

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.

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~

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 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.

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.

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. .: :~

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.

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.

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.

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.

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. ; -~

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.

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.

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.
: ' . ,:~

.

,~
~.
' ~:
~ .~

-.

, ' . ' . , ', ' ' ' ' ; .' . :", . .~ ' ' ' , ' . . ''.

Claims (11)

1. A compound of the formula (I) in which - R1 and R2 are each independently a hydrogen; a hydroxyl; an .omega.-halogeno-C1-C7-alkoxy; a halogen; a C1-C7-alkyl; a trifluoromethyl; a C1-C7-alkoxy; a polyhalogeno-C1-C7-alkoxy; an .omega.-hydroxy-C2-C7-alkoxy;
an .omega.-methoxyalkoxy in which the alkyl is C2-C7; an .omega.-amino-C2-C7-alkoxy which is free or substituted by one or two C1-C7-alkyls; a C3-C7-cycloalkoxy; a cycloalkylmethoxy in which the cycloalkyl is C3-C7; a phenoxy, a benzyloxy; a C1-C7-alkylthio; a phenylthio;
a nitro; an amino which is free or substituted by one or two C1-C7-alkyls; a cyano; a (C1-C6)alkylcarbonyl; a formyl; a (C1-C6)alkylcarbonyloxy; a formyloxy; a C1-C7-alkylsulfonamido; a phenylsulfonamido; a benzylsulfonamido; a C1-C7-alkylamido; a C1- C7-alkoxycarbonylamino; a ureido which is unsubstituted or substituted by a phenyl, a benzyl or one or two C1-C7-alkyls; or a thioureido which is unsubstituted or substituted by a phenyl, a benzyl or one or two C1-C7-alkyls;
- R3 and R4 are each independently a C1-C7-alkyl; a C3-C7-cycloalkyl; a phenyl; a benzyl; a cycloalkylmethyl in which the cycloalkyl is C3-C7; or an .omega.-hydroxy-C2-C7-alkyl in which the hydroxyl is free or substituted by a group selected from C1-C4-alkyl groups, (C1-C5) alkoxyalkyl groups in which the alkyl is C1-C4, phenylalkoxyalkyl groups in which the alkoxy is C1-C2 and the alkyl is C1-C4, and tetrahydrofuranyl and tetrahydropyranyl groups;
or - R3 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 substituted by one or more C1-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, (C1-C5)alkoxyalkyl groups in which the alkyl is C1- C4, .omega.-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 C1-C2 and the alkyl is C1-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 cyano; a nitro; an amino which is free or substituted by one or two C1-C7-alkyls; a hydroxyamino; a hydroxyl; a carboxyl; a guanidino which is unsubstituted or mono substituted or disubstituted by a C1-C7-alkyl, a phenyl or a benzyl; a group -OR7; a group -SR7; a (C1-C6)alkylcarbonyl; a formyl; a C1-C7-alkoxycarbonyl; a phenoxycarbonyl; a benzyloxycarbonyl; a carbamoyl substituted by groups R'6 and R''6; a thiocarbamoyl which is free or substituted by one or two C1-C7-alkyls; a sulfamoyl; an alkylsulfamoyl or dialkylsulfamoyl in which the alkyl is C1-C7; a group -SO2R'7; an alkylsulfonamido in which the alkyl is C1-C7; a phenylsulfonamido; a benzylsulfonamido; a group -COR'7; a group -NR8R9; or a group -CO-NH- CR10R'10-COR12; if appropriate, the phenyl group forming part of the substituent R5 and/or R6 can be unsubstituted or monosubstituted or polysubstituted by a C1-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 is C1-C7, a (C1-C6)alkylcarbonyloxy or an imidazolyl;
- R'6 and R''6 are each independently hydrogen; a C1-C7- alkyl which is unsubstituted or substituted by one or more halogens or R'''6; a C3-C7-cycloalkyl which is unsubstituted or substituted by a (C1-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 nitrogen 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 is free or substituted by one or two C1-C7-alkyls; a carbamoyl which is free or substituted by one or two C1-C7-alkyls or in which the two substituents, together with the nitrogen atom to which 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, piperidino and perhydroazepino groups;
- R7 is a C1-C7-alkyl; a phenyl; a benzyl; a C3-C7-cycloalkyl; a C2-C7-alkenyl; an .omega.-halogeno-C2-C7-alkyl; a polyhalogeno-C1-C7-alkyl; an .omega.-hydroxy-C2- C7-alkyl; a (C1-C6)alkylcarbonyl; a formyl; an .omega.- carboxy-C1-C7-alkyl which is free or esterified by a C1-C7-alkyl or a benzyl; an .omega.-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 .omega.-carbamoyl-C1-C7-alkyl which is free or substituted by one or two C1-C7-alkyls;
- R'7 is a piperazin-1-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 the 4-position by a group R'''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 C1-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 C1-C7-alkyl;
- R8 and R9 are each independently a hydrogen; a C1-C7-alkyl; a benzyl; or a phenyl; R9 can also be a C3-C8-alkene; a (C1-C6)alkylcarbonyl; a formyl; a (C1-C6) alkylthiocarbonyl; a cycloalkylcarbonyl in which the cycloalkyl is C3-C7; a cycloalkylthiocarbonyl in which the cycloalkyl is C3-C7; an .omega.-amino(C2-C6) alkylcarbonyl; an .omega.-hydroxy(Cl-C6)alkylcarbonyl; an .omega.-benzyloxy(C1-C6)alkylcarbonyl; a phenoxycarbonyl; a phenoxythiocarbonyl; a thienocarbonyl; a pyridylcarbonyl; a methylpyridylcarbonyl; a C1-C7-alkoxycarbonyl; a benzoyl; a phenacetyl; a group -CO-CR10R'10- NR11R'11; a group -CR10R'10COR12; a group -(CH2)tCO R12; a group -CO(CH2)t-COR12; a carbamoyl which is unsubstituted or substituted by R14 and R'14;
a thiocarbamoyl which is unsubstituted or substituted by R14 and R'14; or a heterocyclic radical selected from pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyridyl and thiazolyl groups;
or - R8 and R9, together with the nitrogen atom to which they are bonded, form hydantoin; N-methylhydantoin; or a heterocycle selected from pyrrol-1-yl, .DELTA.3- pyrrolin-1-yl, pyrrolidin-1-yl and isoindolin-2-yl in which the benzene ring can be unsubstituted or substituted by a halogen, a C1-C7-alkyl, a trifluoro methyl or a methoxy;
- R10 and R'10 are each independently hydrogen; a C1-C7-alkyl; or a benzyl; or R10 and R'10, together with the carbon atom to which they are bonded, form a C3-C7-cycloalkyl;
- R11 and R'11 are each independently hydrogen; or a C1-C7-alkyl;
- R12 is a hydroxyl; a C1-C7-alkoxy; or an amino which is unsubstituted or substituted by one or two C1-C7-alkyls;
- R13 is hydrogen; a C1-C7-alkyl; a phenyl; a benzyl; a (C1-C6)alkylcarbonyl; a formyl; a C1-C7-alkoxycarbonyl;
or a carbamoyl which is unsubstituted or substituted by one or 2 C1-C7-alkyls;
- R14 and R'14 are each independently a C1-C7-alkyl which is unsubstituted or substituted 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, pyrrolidine, piperidine and perhydroazepine, said heterocycle being unsubstituted or substituted by one or more methyl groups, by a phenyl or by an amino group which is free or carries a protecting group;

- R15 is a phenyl; a pyridyl; a hydroxyl; a C1-C7-alkoxy; an amino which is free or substituted by one or two C1-C7-alkyls; or a carboxyl which is free or esterified by a C1-C7-alkyl;
- R'15 is a hydroxyl or an amino which is free or substituted by one or two C1-C7-alkyl;
- m is 1 or, if R6 is a halogen, a C1-C7-alkyl or a C1-C7-alkoxy, m can also be 2, 3 or 4, or else (R6)m can be m substituents having different meanings selected from halogen, C1-C7-alkyl and C1-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 which can vary from 2 to 5;
- t' is an integer which can vary from 0 to 3;
- X is oxygen; a group S(O)n; a group NR13; or a group N(O)R13; and - n is 0, 1 or 2;
with the limitation that if - R1 and R2 are as defined above with the exception of the ureido group substituted by a benzyl group, or the thioureido group which is unsubstituted or substituted by a phenyl, a benzyl or one or two C1- C4-alkyls;
- R3 and R4 are each independently a C1-C6-alkyl; a C3-C7-cycloalkyl; a phenyl; a benzyl; or a cycloalkyl-methyl in which the cycloalkyl 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-C10 hydrocarbon ring which is unsubstituted or substituted by one or more C1-C7-alkyl groups or by a C3-C5-spirocycloalkyl;
- R5 and R6 are other than a hydrogen; a halogen; a C1-C7-alkyl; a trifluoromethyl; a cyano; a nitro; an amino which is free or substituted by one or two C1- C7-alkyls; a hydroxyamino; a hydroxyl; a carboxyl; a group -OR7; a group -SR7; a (C1-C6)alkylcarbonyl; a formyl; a C1-C7-alkoxycarbonyl; a phenoxycarbonyl; a benzyloxycarbonyl; a carbamoyl substituted by groups R'6 and R''6; a thiocarbamoyl which is free or substituted by one or two C1-C7-alkyls; a sulfamoyl; an alkylsulfamoyl or dialkylsulfamoyl in which the alkyl is C1-C7; a group -SO2R'7; an alkylsulfonamido in which the alkyl is C1-C7; a group -COR'7; a group -NR8R9; or a group -CO-NH-CH(R10)-COR12, it being possible, if appropriate, for the phenyl group forming part of the substituent R5 and/or R6 to be unsubstituted or monosubstituted or polysubstituted by a C1-C7-alkyl, a trifluoromethyl, a methoxy, a halogen, a sulfamoyl, an alkylsulfamoyl in which the alkyl is C1-C7, a carboxyl, an alkoxycarbonyl in which the alkyl is C1-C7, a C1-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 unsubstituted or substituted by R'''6; a phenyl; a pyridyl; a methylpyridyl; a piperidin-4- yl; or a methylpiperidin-4-yl;
- R'''6 is a hydroxyl; a cyano; a carboxyl which is free or esterified by a C1-C7-alkyl or a benzyl; a phenyl; a pyridyl; a methylpyridyl; or an amino which is free or substituted by one or two C1-C7-alkyls;
- R7 is a C1-C7-alkyl; a phenyl; a benzyl; a C3-C7-cycloalkyl; a C2-C4-alkenyl; an .omega.-halogeno-C2-C7-alkyl; a polyhalogeno-C1-C7-alkyl; a (C1-C6)alkylcar bonyl; a formyl; an .omega.-carboxy-C1-C7-alkyl which is free or esterified by a C1-C4-alkyl or a benzyl; or an .omega.-amino-C2-C7-alkyl in which the amino group is free, substituted by one or two C1-C4-alkyls or in the form of an ammonium ion;

- R'7 is a piperazin-1-yl group which is unsubstituted or substituted in the 4-position by a group R''7; a piperidino group which is unsubstituted or substi tuted in the 4-position by a group R'''7; an azetidin- 1-yl group 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 (C1-C3)alkylcarbonyl;
- R'''7 is R''7; or an amino which is free or carries a protecting group;
- R8 and R9 are each independently a hydrogen; a C1-C7-alkyl; a phenyl; or a benzyl; R9 can also be a (C1-C6)alkylcarbonyl; a formyl; a cycloalkylcarbonyl in which the cycloalkyl is C3-C7; a cycloalkylthiocarbo nyl in which the cycloalkyl is C3-C7; an .omega.-amino(C2-C3)alkylcarbonyl; an .omega.-hydroxy(C1-C3)alkylcarbonyl; an .omega.-benzyloxy(C1-C3)alkylcarbonyl; a phenoxycarbo nyl; a thienocarbonyl; a pyridylcarbonyl; a methyl pyridylcarbonyl; a C1-C4-alkoxycarbonyl; a benzoyl; a group -CO-CH(R10)-NR11R'11; a group -CH(R10)CO2R11; a group -(CH2)t''COR12; a group -CO(CH2)t''COR12; or a carbamoyl which is unsubstituted or substituted by a phenyl or one or two C1-C4-alkyls;
- t'' is an integer which can vary from 1 to 3;
- R10 is hydrogen; a C1-C4-alkyl; or a benzyl;
- R11 and R'11 are each independently hydrogen; or a C1-C4-alkyl;
- R12 is a hydroxyl; a C1-C4-alkoxy; or an amino which is unsubstituted or substituted by one or two C1-C4-alkyls; and - R13 is hydrogen a C1-C4-alkyl; a phenyl a benzyl; a (C1-C3)alkylcarbonyl; a formyl; a C1-C4-alkoxycarbonyl;
or a carbamoyl which is unsubstituted or substituted by one or 2 C1-C4-alkyls;
and its salts where appropriate.
2. A compound of formula (I) according to claim 1 wherein R1 is a chlorine or fluorine atom or an ethoxy group in the 5-position of the 1,3-dihydroindol-2-one and R2 is hydrogen.
3. A compound of formula (I) according to claim 1 or 2 wherein R3 and R4, together with the carbon to which they are bonded, form a C3-C12 hydrocarbon ring.
4. A compound of formula (I) according to claim 3 wherein R3 and R4, together with the carbon to which they are bonded, form a cycloheptane, an adamantane, a tricyclo[5.2.1.02,6]dec-8-ene, a tricyclo[5.2.1.02,6]
decane, a bicyclo[2.2.1]heptane, a bicyclo[3.3.1]nonane or a cyclohexane which is unsubstituted or substituted by a C3-C5-spirocycloalkyl or by one or two C1-C7-alkyl groups.
5. A compound of formula (I) according to claim 1 or 2 wherein 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.
6. A compound of formula (I) according to any one of claims 1 to 5 wherein R5 is an orthomethoxy group and R6 in the para-position is a group selected from:
- (piperidin-1-yl)carboxamido, - (2-cyanoprop-2-yl)carbonyl, - pyrrolidin-1-yl, - 3,3-diethylguanidino and - N',N'-diethylthioureido.
7. A process for the preparation of a compound of formula (I) according to claim 1, and its salts, which comprises:
1/ reacting a benzenesulfonyl halide of the formula (III) in which Hal is a halogen atom, preferably chlorine, and R'5 and RVI are respectively either R5 and R6 as defined for (I) in claim 1, or precursor groups of R5 and R6, with a 1,3-dihydroindol-2-one disubstituted in the 3-position of the formula (II) in which R'1, R'2, R'3 and R'4 are respectively either R1, R2, R3 and R4 as defined for (I) in claim 1, or precursor groups of R1, R2, R3 and R4; and 2/ either, if R'1 = R1, R'2 = R2, R'3 = R3, R'4 = R4, R'5 = R5 and RVI = R6, isolating the resulting compound of formula (I);
3/ or, if any one of the groups R'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 R6, subjecting the compound obtained in step 1/ to a subsequent treatment 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 RVI to R1, R2, R3, R4, R5 and/or R6 respectively; and 4/ if desired, converting the resulting compound of formula (I) to one of its salts.
8. A pharmaceutical composition in which a compound according to any one of claims 1 to 6 is present as the active principle.
9. A pharmaceutical composition in which a com pound according to any one of claims 1 to 6 is present in association with another active principle.
10. A pharmaceutical composition in which two compounds according to any one of claims 1 to 6 are present, one being a specific V1 receptor antagonist and the other being a specific V2 receptor antagonist.
11. A pharmaceutical composition in which two compounds according to any one of claims 1 to 6 are present, one being a specific V1 receptor antagonist and the other being a specific ocytocin antagonist.
CA002129215A 1993-07-30 1994-07-29 1-benzenesulfonyl-1,3-dihydro-indol-2-one derivatives, their preparation and pharmaceutical compositions in which they are present Abandoned CA2129215A1 (en)

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RU94027576A (en) 1996-05-27
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TW375609B (en) 1999-12-01
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HUT70408A (en) 1995-10-30
IL110482A (en) 1999-04-11
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AU684791B2 (en) 1998-01-08

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