AU684791B2 - 1-benzenesulfonyl-1,3-dihydro-indol-2-one derivatives, theirpreparation and pharmaceutical compositions in which they are present - Google Patents
1-benzenesulfonyl-1,3-dihydro-indol-2-one derivatives, theirpreparation and pharmaceutical compositions in which they are present Download PDFInfo
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- AU684791B2 AU684791B2 AU68789/94A AU6878994A AU684791B2 AU 684791 B2 AU684791 B2 AU 684791B2 AU 68789/94 A AU68789/94 A AU 68789/94A AU 6878994 A AU6878994 A AU 6878994A AU 684791 B2 AU684791 B2 AU 684791B2
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- C07D209/04—Indoles; Hydrogenated indoles
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- C07D209/80—[b, c]- or [b, d]-condensed
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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Description
AUSTRALIA
PATENTS ACT 1990 COMPLETE SPECIFICATION NAME OF APPLICANT(S): Sanofi ADDRESS FOR SERVICE: DAVIES COLLISON CAVE Patent Attorneys 1 Little Collins Street, Melbourne, 3000.
INVENTION TITLE: I-benzenesulfonyl-l,3-dihydro-indol-2-one derivatives, their preparation and pharmaceutical compositions in which they are present The following statement is a full description of this invention, including the best method of performing it known to me/us:- The present invention relates to 1benzenesulfonyl-1,3-dihydroindol-2-one derivatives, to their preparation and to the pharmaceutical compositions in which they are present.
International patent application WO 91/01306 describes 2-oxoindole derivatives which are useful for the treatment of senile dementia. These compounds have the formula
R"
2 1 3 N -1 I
COR"
4 15 in which
R''
1 is a hydrogen, a halogen, an alkyl or an alkoxy; R''2 is hydrogen or a lower alkyl;
R''
3 is an alkyl, a cycloalkylmethyl, a benzodioxanylmethyl or an optionally substituted benzyl; 20 and
R''
4 is a 1-propylbutyl, a pyridyl or an optionally substituted phenyl.
Several patent applications have recently described families of compounds of non-peptide structure which are active on the vasopressin and/or ocytocin receptors. There may be mentioned European patent applications EP 382 185, EP 444 945, EP 514 667, EP 469 984 and EP 526 348, international patent applications WO 91/05 549 and WO 93/15 051, patent application JP 04/321 669 and, more particularly, patent application JP 03/127 732. This last patent application describes indole-3-propionic acid derivatives of the formula F I 2 COR"' 3 R"'2 4 N R"' 5 2 5
R"'
1 in which 1 is hydrogen, an alkyl, an alkenyl, a phenylalkyl, a tetrahydrofuryl, an alkoxycarbonyl, an alkoxycarbonylalkyl, a carboxyalkyl or an alkanoyl; 2 is hydrogen, a hydroxyl, an alkoxy, an alkyl, a phenylalkyl, a phenylalkoxy or a halogen; is a hydrogen, an alkoxy, a free or substituted amino group or an amino acid residue; is hydrogen, an alkyl or a phenylalkyl; and 5 is a benzoyl, a phenyl, an alkyl, a 15 phenylalkenylcarbonyl, a thienylcarbonyl, a phenylsulfonyl, a pyridylcarbonyl or an imidazolylcarbonyl, it being possible for the phenyl and alkyl groups of the substituent to be substituted.
These compounds are vasopressin antagonists.
Patent US 4 803 217 claims hapalindolinones :i obtained by fermentation which are vasopressin antagonists. These compounds have the following formula:
CH
3
R
CH
2 pCH
C]C
NC CH2 NCC 3 -O CH 3
N
H
in which R is H or Cl.
Novel 1-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 types of receptors, namely V 1 (Vla, Vlb) and V 2 These receptors are localAed 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 the different receptors is described in: S. JARS et al., Vasopressin and ocytocin receptors: an overview, in Progress in Endocrinology; H.
IMURA and K. SHIZURNE ed., Experta Medica, Amsterdam, 1988, 1183-1188, and in the following articles: Presse 20 Mddicale, 1987, 16 481-485; J. Lab. Clin. Med., 1989, 114 617-632; and Pharmacol. Rev., 1991, 43.
73-108. Vasopressin thus exerts cardiovascular, hepatic, antidiuretic and aggregating effects and effects on the central and peripheral nervous system and in the S 25 uterine domain. Ocytocin is involved in parturition, lactation and sexual behavior.
The compounds according to the present invention make it possible selectively either to mimic the effects of the hormone (in the case of agonists) or to inhibit 30 them (in 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 advantageously replace vasopressin or its analogs in the treatment of diabetes s 4 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., !991, 43, 73-108; and Drug Investigation, 1990, 2 (Suppl. 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 549-562; F.A. LASZLO and F.A.
LASZLO Jr., Clinical perspectives for vasopressin antagonists, Drug News Perspect., 1993, 6 W.G.
NORTH, J Clin. Endocrinol., 1991, 23, 1316-1320; J.J.
LEGROS et al., Prog. Neuro-Pharmacol. Biol. Psychiat., 1988, 12, 571-586; K.E. ANDERSSON et al., Drugs Today, 1988, Z 509- 5-8; D.L. STUMP et al., Drugs, 1990, e, 38-53; S. CALTABIANO et al., Drugs Future, 1988, 1a, 25-30; Y. MURA et al., Clin. Nephrol., 1993, 40, 60-61; and FASEB 1994, a 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, in man and animals.
The present invention relates to compounds of the formula 4 sR2 0 I in which RI and R 2 are each independently a hydrogen; a hydroxyl; an ('-halogeno-C 1
-C
7 -alkoxy; a halogen; a C 1
C
7 -alkyl; a trifluoromethyl; a Cl-C 7 -alkoxy; a polyhalogeno-Cl-C 7 -alkoxy; an i0-hydroxy-C 2
-C
7 -alkoxy; an 0)-methoxyalkoxy in which the alkyl is C 2
-C
7 an 0)amino-C 2
-C
7 -alkoxy which is free or substituted by one or two Cl-C 7 -alkyls; a C 3
-C
7 -cycloalkoxy; a cycloalkylmethoxy in which the cycloalkyl is C 3
-C
7 a phenoxy; a benzyloxy; a Cl-C 7 -alkylthio; a phenylthio; a :4 nitro; an amino which is free or substituted by one or two Cl'-C 7 -alkyls; a cyano; a (Cl-C 6 )alkylcarbonyl; a formyl; a (Cl-C 6 )alkylcarbonyloxy; a formyloxy; a C-7 alkylsulfonamido; a phenylsulfonamido; a :4.benzylsulfonamido; a Cl-C 7 -alkylamido; a C-7 a'l.koxycarbonylamino; a ureido which is unsubstituted or substituted by a phenyl, a benzyl or one or two Cl-C 7 alkyls; or a thioureido which is unsubstituted or substituted by a phenyl, a benzyl or one or two C 1
-C
7 alkyls;
-R
3 and R 4 are each independently a Cl-C 7 -alkyl; a C 3
C
7 -cycloalkyl; a phenyl;* a benzyl; a cycloalkylmethyl in which the cycloalkyl is C 3
-C
7 or an o)-hydroxy-C 2
C
7 aikyl in which the hydroxyl is free or substituted by a group selected from Cl-C 4 -alkyl groups, (Cl-C 5 alkoxyalkyl groups in which the alkyl is Cl-C 4 phenylalkoxyalkyl groups in which the alkoxy is C 1
-C
2 and the alkyl is C 1
-C
4 and tetrahydrofuranyl and tetrahydropyranyl groups; or
R
3 and R 4 together form a group -(CH2)pX(CH2)q-; or
R
3 and R 4 together with the carbon to which they are bonded, form an optionally fused, saturated or unsaturated C 3
-C
12 hydrocarbon ring which is unsubstituted or substituted by one or more C 1
-C
7 -alkyl groups, by an oxo group, by a C 3
-C
5 -spirocycloalkyl or by one or two hydroxyls which are free or substituted by a group selected from C 1
-C
4 -alkyl groups, (C 1
C
5 )alkoxyalkyl groups in which the alkyl is C 1
-C
4 0hydroxyalkyl groups in which the alkyl is C 1
-C
4 triphenylmethoxyalkyl groups in which the alkyl is C 1
-C
4 phenylalkoxyalkyl groups in which the alkoxy is C 1
-C
2 and the alkyl is C 1
-C
4 and tetrahydrofuranyl, tetrahydropyranyl, formyl and (C 1
-C
7 )alkylcarbonyl S 20 groups; 0 R 5 and R 6 are each independently a hydrogen; a halogen; a C 1
-C
7 -alkyl; a trifluoromethyl; a cyano; a nitro; an amino which is free or substituted by one or two C 1
-C
7 alkyls; a hydroxyamino; a hydroxyl; a carboxyl; a guanidino which is unsubstituted or monosubstituted or disubstituted by a C 1
-C
7 -alkyl, a phenyl or a bernzyl; a group -OR 7 a group -SR 7 a (C1-C 6 )alkylcarbonyl; a formyl; a C 1
-C
7 -alkoxycarbonyl; a phenoxycarbonyl; a benzyloxycarbonyl; a carbamoyl substituted by groups R' 6 and a thiocarbamoyl which is free or substituted by one or two C 1
-C
7 -alkyls; a sulfamoyl; an alkylsulfamoyl or dialkylsulfamoyl in which the alkyl is C 1
-C
7 a group
-SO
2
R'
7 an alkylsulfonamido in which the alkyl is C 1
-C
7 a phenylsulfonamido; a benzylsulfonamido; a group -COR' 7 a group -NR 8
R
9 or a group -CO-NH-CR 10
R'
10
-COR
12 if appropriate, the phenyl group forming part of the substituent R 5 and/or R 6 can be unsubstituted or monosubstituted or polysubstituted by a Cl-C 7 -alkyl, a trifluoromethyl, a Cl-C 7 -alkoxy, a halogen, a sulfamoyl, an alkylsulfamoyl in which the alkyl is C 1
-C
7 a carboxyl, an alkoxycarbonyl in which the alkyl is Cl-C 7 a (Cl-C 6 )alkylcarbonyloxy or an imidazolyl; R' 6 and R '6 are each independently hydrogen; a Cl-C 7 alkyl which is unsubstituted or substituted by one or more halogens or 6; a C 3
-C
7 -cycloalkyl which is unsubstituted or substituted by a (Cl-C 4 )alkyl; a phenyl; a pyridyl; a methylpyridyl; a piperidin-4-yl; a methylpiperidin-4-yl; or a pyrrolidin-l-yl; or R1 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 Cl-C 7 -alkyls; RI R'1 6 is a hydroxyl; a Cl-C 7 -alkoxy; an amino which is free or substituted by one or two Cl-C 7 -alkyls; a carbamoyl which is free ot substituted by one or two C 1
C
7 -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 Cl-C 7 -alky.
or a benzyl; a phenyl; a C 3
-C
7 -cycloalkyl; an adamantyl; 25 or a heterocyclic radical selected from pyridyl, methylpyridyl, furanyl, tetrahydrofuranyl, thienyl, methylthienyl, pyrrolidino, piperidino and perhydroazepino groups;
-R
7 is a Cl-C 7 -alkyl; a phenyl; a benzyl; a C-7 cycloalkyl; a C 2
-C
7 -alkenyl; an co-halogeno-C 2
-C
7 alkyl,; polyhalogeno-C 1
-C
7 -alkyl; an (o-hydroxy-C 2
C
7 -alkyl; a
(C
1
-C
6 )alkylcarbonyl; a formyl; an carboxy-Cl-C 7 alkyl which is free or esterified by a Cl-C 7 -alkyl or a benzyl; an (0-amino-C 2
-C
7 -alkyl in which the amino group is free, substituted by one or two Cl-C 7 -alkyls or in the form of an ammonium ion; or an om-carbamoyl-Cl-C 7 -alkyl 8 which is free or substituted by one or two Cl-C 7 -alkyls; R1 7 is a piperazin-1-yl group which is unsubstituted or substituted in the 4-position by a group R1 a piperidino group which is unsubstituted or substituted in the 4-position by a group R 1 1 7 an azetidin-l-yl group which is unsubstituted or substituted in the 3-position by a group R11' 7 or a pyrrolidino group which is unsubstituted or substituted by a group RI''1'7; Rif 7 is E Cl-C 7 -alkyl; a phenyl; a benzyl; a (Cl-C 6 alkylcarbonyl; or a formyl; R R' 7 is R'' 7 or an amino which is free or carries a protecting group; R I I1 1 7 is R II' 7 or a carboxyl group which is free or esterified by a Cl-C 7 -alkyl;
R
8 and R 9 are each independently a hydrogen; a C-7 alkyl; a benzyl; or a phenyl; R9 can also be a C-8 alkene; a (Cl-C 6 )alkylcarbonyl,; a formyl; a (lC) alkylthiocarbonyl; a cycloalkylcarbonyl in which the cycloalkyl is C 3
-C
7 a cycloalkyithiocarbonyl in which the cycloalkyl is C 3
-C
7 an (o-amino(C 2
-C
6 alkylcarbonyl; an ao-hydroxy(Cl-C 6 )alkylcarbonyl; an o0benzyloxy( C 1
-C
6 )alkylcarbonyl; a phenoxycarbonyl; a phenoxythiocarbonyl; a thienocarbonyl; a pyridylcarbonyl; a methylpyridylcarbonyl; a Cl-C 7 -alkoxycarbonyl; a benzoyl; a phenacetyl; a group -CO-CR 1 0 R'l 0
NR
1 1 R'll; a group -CR 1 0
R'
1 0 C0R 1 2 a group -(CH2)tCO R 1 2 a group
CO(CH
2 )twCOR1 2 a carbamoyl which i substituted by R 1 4 and R1 1 4 a thiocarbamoyl which is unsubstituted or substituted by R 14 and R1 14 or a 30 heterocyclic radical selected from pyrazolyl, imidazolyl, *triazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyridyl and thiazolyl groups; or
R
8 and R9, together with the nitrogen. atom to which they are bonded, f orm hyd~tntoin; N-methylhydantoin; or a heterocycle selected from pyrrol-l-yl, A3- pyrrolin-l-yl, pyrrolidin-l-yl and isoindolin-2-yl in which the benzene ring can be unsubstituted or substituted by a halogen, a
C
1
-C
7 -alkyl, a trifluoromethyl or a methoxy;
R
10 and R' 1 0 are each independently hydrogen; a Cl- C 7 alkyl; or a benzyl; or R 10 and R' 10 together with the carbon atom to which they are bonded, form a C 3
C
7 cycloalkyl;
R
11 and R'll are each independently hydrogen; or a C 1
C
7 -alkyl;
R
12 is a hydroxyl; a C 1
-C
7 -alkoxy; or an amino which is unsubstituted or substituted by one or two C 1
-C
7 alkyls;
R
13 is hydrogen;, a C 1
-C
7 -alkyl; a phenyl; a benzyl; a
(C
1
-C
6 )alkylcarbonyl; a formyl; a C 1
-C
7 -alkoxycarbonyl; or a carbamoyl which is unsubstituted or substituted by one or 2 C 1
-C
7 -alkyls;
R
14 and R' 14 are each independently a hydrogen atom; hydroxy; C 1
-C
7 alkoxy; C-C,-alkyl which is unsubstituted or substituted by R 15 a phenyl which is unsubstituted or substituted by R' 1 5 a C 3
-C
7 -cycloalkyl; 20 or an adamantyl; or
R
14 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;
R
15 is a phenyl; a pyridyl; a hydroxyl; a C1-C7- 30 alkoxy; an amino which is free or substituted by one or two C 1
-C
7 -alkyls; or a carboxyl which is free or esterified by a C 1
-C
7 -alkyl;
R'
15 is a hydroxyl; or an amino which is free or substituted by one or two C 1
-C
7 -alkyls; m is 1 or, if R 6 is a halogen, a C 1
-C
7 -alkyl or a C 1
C
7 -alkoxy, m can also be 2, 3 or 4, or else (R6)m can be m substituents having different meanings selected from a a a a.
a a
J
T 0VT O halogen, C 1
-C
7 -alkyl and C 1
-C
7 -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 t' is an integer which can vary from 0 to 3; X is oxygen; a group S(O)n; a group NR 13 or a group
N(O)R
13 and n is 0, 1 or 2; provided that when one of R 3 and R 4 is methyl or ethyl, the other being methyl; m=l and one of R 5 and R 6 is hydrogen, the other is different from p-methyl with the further limitation that if
R
1 and R 2 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 Cl- C 4 -alkyls;
R
3 and R 4 are each independently a C'-C 6 -alkyl; a C 3
C
7 -cycloalkyl; a phenyl; a benzyl; or a cycioalkyl methyl 20 in which the cycloalkyl is C 3
-C
7 or
R
3 and R 4 together form a group -(CH 2 )pX(CH 2 in which X is oxygen, sulfur or a group NR 13 or
R
3 and R 4 together with the carbon to which they are bonded, form an optionally fused, saturated or unsaturated C 3
-C
10 hydrocarbon ring which is unsubstituted or substituted by one or more C 1
-C
7 -alkyl groups or by a C 3
-C
5 -spirocycloalkyl;
R
5 and R 6 are other than a hydrogen; a halogen; a C 1
C
7 -alkyl; a trifluoromethyl; a cyano; a nitro; an amino which is free or substituted by one or two Cl- C 7 -alkyls; a hydroxyamino; a hydroxyl; a carboxyl; a group -OR 7 a group -SR 7 a (C 1
-C
6 )alkylcarbonyl; a formyl; a C1-C7- -35 alkoxycarbonyl; a phenoxycarbonyl; a benzyloxycarbonyl; a o 0 00 0 nI n tl y" 'KAI 0 carbamoyl substituted by groups R' 6 and R 1 6 a thiocarbamoyl which is free or substituted by one or two Cl-C 7 -alkyls; a sulfamoyl; an alkylsulfamoy. or dialkylsulfanoyl in which the alkyl is Cl-C 7 a group
SO
2
R'
7 an alkylsulfonainido in which the alkyl is Cl-C 7 a group -COR' 7 a group -NRBRg; or a group -CO-NH-
CH(R
10 )-C0R 12 it being possible, if appropriate, for the phenyl group forming part of the substituent R 5 and/or R 6 to be unsubstituted or monosubstituted or polysubstituted by a Cl-C 7 -alkyl, a trifluoromethyl, a methoxy, a halogen, a sulfamoyl, an alkylsulfamoyl in which the alkyl is C 1
-C
7 a carboxyl, an alkoxycarbonyl in which the alkyl is Cl-C 7 a Cl-C 6 -alkylcarbonyloxy, a formyloxy or an imidazolyl; in which groups R 5 and/or R 6 R 1' 6 and R I' '6 are each independently hydrogen; a C-7 alkyl which is unsubstituted or substituted by R' '1 6; a phenyl; a pyridyl; a methylpyridyl; a piperidin-4- yl; or a methylpiperidin-4-yl; R' 16 is a hydroxyl; a cyano; a carboxyl which is free or esterified by a Cl-C 7 -alkyl or a benzyl; a phenyl; a pyridyl; a methylpyridyl; or an amino which is free or substituted by one or two Cl-C 7 -alkyls;
-R
7 is a Cl-C 7 -alkyl; a phenyl; a benzyl; a C-7 cycloalkyl; a C 2
-C
4 -alkenyl; an a0-halogeno-C 2
-C
7 alkyl; a polyhalogeno-Cl-C 7 -alkyl; a (Cl-C 6 )alkylcabonyl; a formyl; an co-carboxy-Cl-C 7 -alkyl which is free or esterified by a Cl-C 4 -alkyl or a benzyl; or an (0-amino-
C
2
-C
7 -alkyl in which the amino group is free, substituted by one or two Cl-C 4 -alkyls or in the form of an ammonium ion; -R1 7 is a piperazin-l-yl group which is unsubstituted or substituted in the 4-position by a group R11 7 a piperidino group which is unsubstituted or substituted in 59:5 30 the 4-position by a group R111 7 an azetidin- 1-y. group which is unsubstituted or substituted in the 3-position by a group R' RI 1 7 is a Cl-C 4 -alkyl; a phenyl; a benzyl; or a (Cl-
C
3 )alkylcarbonyl; R v 1 7 is R I' 7 or an amino which is f ree or carries a protecting group; 12
R
8 and R 9 are each independently a hydrogen; a C1-C 7 alkyl; a phenyl; or a benzyl; Rg can also be a (C 1
C
6 )alkylcarbonyl; a formyl; a cycloalkylcarbonyl in which the cycloalkyl is C 3
-C
7 a cycloalkylthiocarbonyl in which the cycloalkyl is C 3
-C
7 arn (-amino(C 2
C
3 )alkylcarbonyl; an (-hydroxy(C i
-C
3 )alkylcarbonyl; an o-benzyloxy(C 1
-C
3 )alkylcarbonyl; a phenoxycarbonyl; a thienocarbonyl; a pyridylcarbonyl; a methylpyridylcarbonyl; a C 1
-C
4 -alkoxycarbonyl; a benzoyl; a group -CO-CH(R 10
)-NR
1 1
R'
1 1 a group -CH(R 10
)CO
2
R
11 a group -(CH 2 )tvCOR1 2 a group -CO(CH 2 )t'iCORi 2 or a carbamoyl which is unsubstituted or substituted by a phenyl or one or two C 1
-C
4 -alkyls; is an integer which can vary from 1 to 3;
R
10 is hydrogen; a C 1
-C
4 -alkyl; or a benzyl;
R
11 and R' 11 are each independently hydrogen; or a C 1
C
4 -alkyl;
R
12 is a hydroxyl; a C 1
-C
4 -alkoxy; or an amino which is unsubstituted or substituted by one or two C 1
-C
4 alkyls; and
R
13 is hydrogen; a C 1
-C
4 -alkyl; a phenyl; a benzyl; a
(C
1
-C
3 )alkylcarbonyl; a formyl; a Cl-C 4 -alkoxycarbonyl; or a carbamoyl which is unsubstituted or substituted by one or 2 C 1
-C
4 -alkyls; 25 and their salts where appropriate.
0* If a compound according to the invention has one or more asymmetric carbons, the invention includes all the optical isomers of this compound.
If a compound according to the invention exhibits 30 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 organic acids which permit a suitable separation or crystallization of the compounds of formula s 13 such as picric acid, oxalic acid or an optically 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, fumarate or naphthalene-2sulfonate.
The salts of the compounds of formula also include the salts with organic or mineral bases, for example the salts of alkali metals or alkaline earth metals, such as the sodium, potassium and calcium salts, the sodium and potassium salts being preferred, or with an amine such as trometamol, or else the salts of arginine, lysine or any physiologically 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 C 1
-C
4 -alkyl, such 20 as methyl or tert-butyl,; benzhydryl; trityl; benzoyl; a
C
1 -C4-alkylcarbonyl, such as tert-butoxycarbonyl, benzyloxycarbonyl; benzyl or substituted benzyl such as p-nitrobenzyl, p-chlorobenzyl or p-methoxybenzyl.
According to the present invention, CI-C 4
C
1
C
3
C
1
-C
5
C
1
-C
6
CI-C
7
C
2
-C
6 or C 2
-C
7 -alkyl is understood as meaning a linear or branched alkyl.
According to the present invention, optionally fused, saturated or unsaturated C 3
-C
12 hydrocarbon ring is understood as meaning various hydrocarbon rings of 30 monocyclic, bicyclic or tricyclic structure, 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[5.2.1.0 2 6 ]decane, a tricyclo[5.2.1.0 2 6 ]dec-8-ene, a bicyclo[2.2.1]heptane or a bicyclo[3.3.1]nonane.
14 According to the present invention, if R 3 and R 4 together with the carbon to which they are bonded, form an optionally fused, saturated or unsaturated C 3
C
12 hydrocarbon ring substituted by a hydroxyl, the preferred groups for substituting said hydroxyl are the methyl, ethyl, methoxymethyl, methoxyethyl, phenylmethoxymethyl, tetrahydrofuranyl and tetrahydropyranyl groups.
The compounds of formula in which R 1 is in the 5-position of the indol-2-one and R 2 is hydrogen are preferred compounds.
The compounds of formula in which R 1 is a chlorine or fluorine atom or an ethoxy group in the position of the indol-2-one and R 2 is hydrogen are preferred compounds.
The compounds of formula in which R 3 and R 4 together with the carbon to which they are bonded, form a
C
3
-C
12 hydrocarbon ring are -referred compounds; particularly preferred compounds are those in which R 3 and R 4 together with the carbon to which they are bonded, form a cycloheptane, an adamantane, a tricyclo- [5.2.1.0 2 6 ]dec-8-ene, a tricyclo[5.2.1.0 2 6 ]decane, a bicyclo[2.2.1]heptane, a bicyclo[3.3.1]nonane or a *cyclohexane which is unsubstituted or substituted by a
C
3
-C
5 -spirocycloalkyl or by one or two Cl-C 7 -alkyl 25 groups.
More particularly preferred compounds are those in which R 3 and R 4 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 in which the substituents R 5 and R 6 are in the 2,4-position of the phenyl ring are preferred compounds.
The compounds of formula in which R 5 is an orthomethoxy group and R 6 in the para-position is a group selected from: (piperidin-l-yl)carboxamido,
I
(2-cyanoprop-2-yl )carbonyl, pyrrolidin-l-yl, 3,3-diethylguanidino and N' ,N'-diethyithioureido are preferred compounds.
The following abbreviations are used in the description and in the Examples: DCM: dichioromethane ether: ethyl ether iso ether: isopropyl ether Boc: tert-butoxycarbonyl Me, MeO: methyl, methoxy Et, EtO: ethyl, ethoxy Pr, iPr, nPr: propyl, isopropyl, n-propyl Bu, iBu, tBu: butyl, isobutyl, tert-butyl Ph: phenyl Bz: benzyl tosyl Ac: acetyl otoo 20 AcOEt: ethyl acetate AcOH: acetic acid HCl: hydrochloric acid MeOH: methanol EtOH: ethanol DMF: dimethylformamide THF: tetrahydrofuran DMSO: dimethyl sulfoxide DIPEA: diisopropylethylamine NaOH: sodium hydroxide NaHCO 3 sodium hydrogencarbonate TEA: triethylamine TFA: trifluaroacetic acid TMEDA: tetramethylethylenediamine Lawesson's reagent: 2, 4-bis(4-methoxyphenyl 3dithia-2, 4-diphosphetane 2, 4-disulfide melting point saline solution: saturated aqueous sodium chloride solution TLC: thin layer chromatography HPLC: high pressure liquid chromatography aqueous hydrochloric acid: dilute hydrochloric acid, about 1 N RT: room temperature boiling 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 invention, and their salts, which comprises: 1/ reacting a benzenesulfonyl halide of the formula Hal-S0 2 (RVI m e 25 in which Hal is a halogen atom, preferably chlorine, and 00oo
R'
5 and R7; are respectively either R 5 and R 6 as defined o* above for or precursor groups of R 5 and Rg, with a 1,3-dihydroindol-2-one disubstituted in the 3-position of the formula se I
R'
3
R'
1
'O
R 2 A N
(II)
H
in which R' 1
R'
2
R'
3 and R'4 are respectively either
R
I
R
2
R
3 and R 4 as defined for or precursor groups of R 1
R
2
R
3 and R 4 and 2/ either, if R' 1 RI, R' 2
R
2
R'
3
R
3
R'
4 R4,
R
5 and RVI R 6 isolating the resulting compound of formula 3/ or, if any one of the groups R' 1
R'
2
R'
3
R'
4
R'
and/or RVI is respectively a precursor group of R 1
R
2
R
3
R
4
R
5 and/or R 6 subjecting the compound obtained, hereafter called the compound of formula to a subsequent treatment in order to prepare the compound of S* formula by converting any one of the groups R' 1
R'
2 15 R' 3
R'
4
R'
5 and/or RVI to R 1
R
2
R
3
R
4
R
5 and/ or R 6 respectively; and 4/ if desired, converting the resulting compound of formula to one of its salts.
The reaction of step 1/ is carried out in an 20 anhydrous solvent such as DMF or THF, in the presence of a metal hydride such as, for example, sodium hydride, or in the presence of an alcoholate such as potassium tertbutylate.
The 1,3-dihydroindol-2-ones (II) are known or can 25 be prepared by known methods using different procedures.
Compounds 'II) in which R' 1 and/or R' 2 are a halogen 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, 824-829. Also, 5-chloro-3-spirocyclopentaneindol-2-one is described in patent US 3 947 451.
-~-~119111 1 18 To prepare the compounds (II) in the case where
R'
3 and R' 4 together are a hydrocarbon group, it is possible to use the Brunner reaction described by R.F.
Moore and S.G.P. Plant in J. Chem. Soc., 1951, 3475- 3478, which leads to the preparation of compounds (II) in which CR' 3
R'
4 is a cyclopentane or a cyclohexane.
This reaction is carried out by cyclizing a phenylhydrazide derivative of the formula
R'
1
NH-NH-C-CH
2 O in which R' 1 R'2, R' 3 and R' 4 are as defined above for for example by heating in quinoline in the presence of calcium oxide.
15 According to the same authors, the phenylhydrazide derivative (IV) is obtained by reacting a hydrazine derivative of the formula
R'
NH-NH
2 R2
(V)
in which R' 1 and R' 2 are as defined above for with an acid halide of the formula /R3 Hal-C-CH II (v) 0 R4 in which R' 3 and R' 4 are as defined above for (II).
19 In one particular embodiment, if R' 3 and R'4, 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 J. Wolff et al., Tetrahedron, 1986, 42 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 cyclization is effected by heating in a solvent such as naphthalene or prehnitene (1,2,3,4-tetramethylbenzene).
The compounds (II) in which R' 1 R'2 H and
CR'
3
R'
4 is adamantane are described in I. Fleming et al., J. Chem. Soc., Perkin Trans. I, 1991, 3, 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' 1 and R' 2 are other than hydrogen can be prepared by the method described above.
The hydrazine derivatives are known or are prepared by known methods. The same applies to the acid halides (VI).
A 1,3-dihydroindol-2-one disubstituted in the 3position (II) can also be prepared from a 1,3dihydroindol-2-one of the formula
H
in which R' 1 and R' 2 are as defined above for by using various processes.
For example, the method described by A.S. Kende and J.C. Hodges in Synth. Commun., 1982, 12 1-10, involves the addition of an alkylating agent in an appropriate solvent. Thus, to prepare a compound (II) in _1 -a which R' 3
R'
4 the reaction is carried out in THF at in the presence of TMEDA, by the addition of an alkyllithium such as butyllithium, followed by reaction with a halide of the formula R' 3 Hal; 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'
3 Hal and R' 4 Hal. To prepare a compound (II) in which
R'
3 and R' 4 together form a group of the formula -(CH2)nwhere n varies from 3 to 12, the reagent used is a compound of the formula Z(CH2)nZ, in which Z is 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 formula (VII), in THF at -40"C, followed by the addition of a compound of the formula Z-(CH2)nZ as defined above.
The compounds (II) in which R' 3 and R' 4 together with the carbon to which they are bonded, form a C4-Cg hydrocarbon ring substituted by one or more Cl- C 7 -alkyl groups or by a C 3
-C
5 -spirocycloalkyl are prepared in the same way.
The compounds of formula (II) in which R' 3 and R'4 are each independently an alkyl or a phenyl are 25 known. For example, patent DE 3 300 522 describes alkoxy-3,3-dimethylindol-2-ones.
If R' 3 and R' 4 together form a group -(CH 2 )pX- (CH2)q- in which p, q and X are as defined above for a 1,3-dihydroindol-2-one disubstituted in the 3position of formula (II) can be prepared from a 1,3dihydroindol-2-one unsubstituted in the 3-position (VII) by reaction with a compound of the formula
Z-(CH
2 )p-X-(CH 2 )q-Z (VIII) in which Z is as defined above and X, p and q are as 9 21 defined above for The reaction is carried out in 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 (C 1 C6)alkylcarbonyl, a formyl, a Ci-C 7 -alkoxycarbonyl or a
C
1
-C
7 -alkylcarbamoyl, the substitution on X can be effected either on the 1,3-dihydroindol-2-one derivative (II) or on the final .ompound starting from a compound in which the nitrogen atom (X NH) is unsubstituted.
Thus, if X is a nitrogen atom substituted by a
C
1
-C
7 -alkoxycarbonyl, the first step is to prepare a compound (II) or in which X is NH, which is then reacted with the appropriate chloroformate to give the desired compound (II) or In the same way, a Cl- C 7 alkyl isocyanate is reacted with a compound (II) or (I) in which X NH to give a derivative (II) or a compound in which X is a nitrogen atom substituted by an alkylcarbamoyl. An acid chloride or an anhydride is reacted with a compound (II) or a compound in which X NH in order to prepare a compound of formula (II) or in which X is a nitrogen atom substituted by a (C 1
C
6 )alkylcarbonyl.
25 Formic acid in the presence of acetic anhydride is reacted with a compound (II) or in which X NH in order to prepare a compound of formula (II) or in which X is a nitrogen atom substituted by a formyl.
If X is a sulfur atom or a nitrogen atom substituted by R 13 it is also possible firstly to prepare a compound of the formula ~r
R'
1
(CH
2 )pZ S (CH 2 )qZ
R
2 H (II) in which R' 1
R'
2 Z, p and q are as defined above, and to perform a nucleophilic substitution with a hydrogen sulfide salt or an amine of the formula H 2
NR
13 in a solvent such as an alcohol, an ether, DMF or a mixture thereof, at a temperature between 5'C and the reflux temperature.
The 1,3-dihydr:oindol-2-ones of formula are obtained from the corresponding diols, either as such or protected, for example by a tetrahydropyran-2- yl group.
The reaction can be carried out with dibromotriphenylphosphorane according to J. Chem. Soc., Chem. Commun., 1989, 1619.
15 The compounds (II) in which R' 3 and R' 4 together with the carbon to which they are bonded, form a pyrrolidine, N-alkylpyrrolidine, piperidine or Nalkylpiperidine ring are described by M.J. Kornet in J.
Med. Chem., 1976, 19 892-899.
20 In particular, horsfiline of the formula Me
N
Chem., 1991, a 6527-6530.
To prepare a compound of formula (II) in which
R'
3 and R' 4 together with the carbon to which they are bonded, form a tricyclo[5.2.1.0 2 6 ]decane or a tricyclo[5.2.1.0 2 6 ]dec-8-ene, a compound (VII') or, respectively, a compound of the formulae
Z-GH
2 Z-CH
Z-CH
2 Z-CH 2 (VIi)" in which Z is as defined above, is reacted with a compound of formula (VII). Compounds (VII') and (VII'') substituted by one or more C 1
-C
7 -alkyl groups are used to prepare compounds (II) in which said carbocycles are substituted.
A compound of formula (II) in which R' 3 and R' 4 together with the carbon to which they are bonded, form a tricyclo[5.2.1.0 2 6 ]decane can also be prepared by the 15 catalytic hydrogenation of a compound of formula (II) in which R' 3 and R' 4 together with the carbon to which they are bonded, form a tricyclo[5.2.1.02, 6 ]dec- 8-ene, for example in the presence of palladium-on- charcoal or Raney@ nickel.
20 A compound of formula in which R 3 and R 4 together with the carbon to which they are bonded, form a tricyclo[5.2.1.0 2 6 ]decane can also be prepared by the catalytic hydrogenation of a compound of formula in which R 3 and R 4 together with the carbon to which they 25 are bonded, form a tricyclo[5.2.1.0 2 6 ]dec- 8-ene, for *i example in the presence 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 an indane or a hexahydroindane, a compound (VIII') or, respectively, a compound (VIII'') of the formulae
I:
24
Z-CH
2 Z-CH 2
Z-CH
2
Z-CH
2 7 (vIii)' (vm)" in which Z is defined as indicated above for (VIII), is reacted with a compound (VII). Compounds (VIII') and (VIII'') substituted by one or more C 1
-C
7 -alkyl groups are used to prepare compounds (II) in which the indane or hexahydroindane is substituted.
The metiiod of A.S. Kende and J.C. Hodges described above or its variant described above can be used to prepare compounds of formula (II) in which the substituents R' 3 and R' 4 together with the carbon to which they are bonded, form an optionally fused, 0
I
saturated or unsaturated C 3
-C
12 hydrocarbon ring substituted by one or more C 1
-C
7 -alkyl groups or by a 15 group selected from an oxo group protected under acetal form, a C 3
-C
5 -spirocycloalkyl, or one or two hydroxyls substituted by a Cl-C 4 -alkyl, a (C 1
-C
5 )alkoxyalkyl in which the alkyl is C1-C 4 a triphenylmethoxyalkyl in which the alkyl is C 1
-C
4 a phenylalkoxyalkyl in which 20 the alkoxy is C 1
-C
2 and the alkyl is C 1
-C
4 a tetrahydrofuranyl or a tetrahydropyranyl, To obtain the compounds of formula in which R 3 and R 4 together with the carbon to which they are bonded, form an optionally fused, saturated or unsaturated C 3
-C
12 25 hydrocarbon ring substituted by one or two hydroxyls, the .I corresponding compounds of formula in which the hydroxyl group or groups are substituted by a (C l
C
5 )alkoxyalkyl in which the alkyl is C 1
-C
4 a tetrahydrofuranyl or a tetrahydropyranyl are deprotected.
This deprotection is effected in an acid medium, for example in the presence of a mineral or organic acid, in an alcohol or ether solvent such as THF, at a temperature between 15'C and the reflux temperature; the deprotection
I
can be carried out for example in the presence of hydrochloric acid or pyridinium toluenesulfonate in an alcohol.
To obtain the compounds of formula in which
R
3 and R 4 together with the carbon to which they are bonded, form an optionally fused, saturated or unsaturated C 3
-C
12 hydrocarbon ring substituted by one or two o-hydroxy(C 1
-C
4 )alkoxy groups, the corresponding com pounds of formula in which R 3 and R 4 together with the carbon to which they are bonded, form an optionally fused, saturated or unsaturated C 3
-C
12 hydrocarbon ring substituted by one or two (C 1
C
5 )alkoxy(C 1
-C
4 )alkoxy groups are deprotected. This deprotection is effected in an acid medium, for example trifluoroacetic acid, in a solvent such as DCM.
Compounds of formula in which R 3 and R 4 together with the carbon to which they are bonded, form an optionally fused, saturated or unsaturated C 3
-C
12 hydrocarbon ring substituted by one or two (C 1
-C
4 )-alkoxy 20 groups or one or two (C 1
-C
5 )alkoxy(C 1
-C
4 )alkoxy groups can also be prepared by alkylating compounds of formula in which R 3 and R 4 together with the carbon to which they are bonded, form an optionally fused, saturated or unsaturated C 3
-C
12 hydrocarbon ring substituted by one or two hydroxyls. This alkylation is carried out more particularly with powerful alkylating reagents such as alkyl trifluoromethanesulfonates, in solvents such as DCM or carbon tetrachloride, in the presence of a base such 0 as 2,6-di-tert-butylpyridine, by the method described in S 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 in which R 3 and R 4 together with the carbon to which they are bonded, form Y I" ~Cp~~ 26 an optionally fused, saturated or unsaturated C 3
-C
12 hydrocarbon ring substituted by one or two formyloxy groups or one or two (C 1
-C
7 )alkylcarbonyloxy groups 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 in which R 3 and R 4 together with the carbon to which they are bonded, form an optionally fused, saturated or unsaturated C 3
-C
12 hydrocarbon ring substituted by one or two hydroxyls.
A compound of formula in which R 3 and R 4 together with the carbon to which they are bonded, form a tricyclo[5.2.1.02, 6 ]decane-8,9-diol can also be obtained from a compound of formula in which R 3 and R 4 together with the carbon to which they are bonded, form a tricyclo[5.2.1.0 2 6 ]dec-8-ene, which is reacted with metachloroperbenzoic acid at room temperature, in a o. solvent such as DCM, to give an intermediate compound of formula in which R 3 and R 4 together with the carbon 20 to which they are bonded, form a tricyclo- [5.2.1.02, 6 ]decan-8,9-epoxy; the intermediate epoxide derivative is 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 carbon to which they are bonded, form either an optionally fused, saturated or unsaturated
C
3
-C
12 hydrocarbon ring substituted by an oxo group, or a group -(CH 2 )p-X-(CH 2 q in which X is a group SO, SQ 2 or N(0)R 1 3 are prepared by known oxidation reactions 30 starting from the corresponding compounds of formula (II) in ;hich R' 3 and R' 4 together with the carbon atom to which they are bonded, respectively form either an optionally fused, saturated or unsaturated C 3
-C
12 hydrocarbon ring substituted by a hydroxyl, or a group (CH2)p-X-(CH2) q in which X is a sulfur ttom or a group
NR
13 For example, the oxidation of secondary alcohols to ketones 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 described in Tetrahedron, 1978, 4, 1651.
The oxidation of the compounds (II) containing a sulfur or nitrogen atom (X S, NR 13 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 O'C and If R' 3 and R' 4 are each a phenyl, the process described in Helv. Chim. Acta, 1946, 29, 415-432, can be used to prepare a compound (II).
The 1,3-dihydroindol-2-one derivatives (VII) are o known or are prepared by known methods. An example which may be cited is J.V. RajanBabu in J. Org. Chem., 1986, 51, 1704-1712.
20 The compounds of formula (II) which carry certain substituents R' 1 and R' 2 on their benzene moiety are used as precursors for the preparation of compounds of formula (II) which carry othe-r substituents R' 1 and R' 2 For example, the compounds (II) in which R' 1 and/or R' 2
H
can be nitrated with the conventional reagents; they can Salso be acylated by reaction with an acid chloride of the formula RCOC1, in which R is a C 1
-C
7 -alkyl, in the presence of a Lewis acid such as aluminum chloride, in order to prepare a compound (II) in which R' 1 and/or R' 2 30 =-COR. The compound (II) in which R' 1 is an amino group is prepared by the catalytic hydrogenation of a compound (II) in which R' 1 is a nitro group and R' 2 is hydrogen.
The benzenesulfonyl halides (III) are prepared by known methods. Thus, for example, 4-dimethylaminobenzenesulfonyl chloride is prepared according to C.N.
Sukenik et al., J. Amer. Chem. Soc., 1977, 99, 851-858.
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-benzyloxybenzenesulfonyl chloride is prepared according to European patent application EP 229 566.
The alkoxcybenzenesulfonyl chloride is prepared from the sodium alkoxybenzenesulfonate, 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 halogenoalkoxybenzenesulfonyl chlorides can be prepared according to patent US 2 540 057.
The benzenesulfonyl halides of the formula QAlk
YRV
in which Alk is a Cl-C 7 -alkyl; Y is 0 or S; and RV is a Cl-C 7 -alkyl, a C 3
-C
7 -cycloalkyl, a C-7 alkenyl, an (0-halogeno-Cl-C 7 -alkyl, a polyhalogeno- C 1 25 C 7 -alkyl, a benzyl, a (Cl-C 6 )alkylcarbonyl, a formyl or an co-carboxy-Cl-C 7 -alkyl este-rified by a Cl-C 4 -alkvl 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 I- and 3-positions are reacted with
I
trimethylsilyl chlorosulfonate in a solvent such as DCM, at RT. The method of R. Passerini et al. in Gazz. Chim.
Ital., 1960, 90, 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 POC1 3 to give the desired benzenesulfonyl halide.
The benzenesulfonyl halides (III) in which the substituent R' 5 is an alkoxycarbonyl, a phenoxycarbonyl, a benzyloxycarbonyl, an alkylthio, a phenylthio, a benzylthio or a group -SR 7
R
7 being as defined for are prepared according to Col. Czechoslov. Chem. Commun., 1984, A2, 1184, from an aniline derivative substituted by the same grouping R' 5 said aniline derivative itself being obtained from the corresponding nitro derivative.
The nitrobenzoic acid derivatives are known; the S'corresponding alkyl and phenyl esters are obtained by subjecting this acid to an appropriate esterification reaction.
The benzenedisulfonyl dihalides (III, R 5 20 SO 2 Hal) are known or are prepared by known methods. For example, 2,4-dimethoxybenzene-l,5-disulfonyl dichloride is described in R.J.W. Cremlyn, J. Chem. Soc. C, 1969, 1344.
The halogenoalkoxybenzenesulfonyl chlorides (III, R'5 o-halogenoalkoxy) are used to prepare compounds according to the invention in which the substituent R 5 is an (-aminoalkoxy which is unsubstituted or substituted by one or two alkyls, according to the following equation: -O-Alk'-Hal NHAA' -O-Alk'-NAA' in which Alk' is a C 2
-C
7 -alkyl and A and A' are independently hydrogen or a C t
-C
7 -alkyl.
For certain meanings of the substituents R 1
R
2
R
5 and/or R 6 the compounds according t6 the in.vntion can be prepared from a precursor of formula substituted by a group R' 1
R'
2
R'
5 and/or RVI, called a precursor group of R 1
R
2
R
5 and/or R 6 by using methods known to those skilled in the art.
The description which follows relates to the preparation of the compounds of formula carrying substituents R 1 and/or R 5 the same methods apply to the preparation of the compounds in which the substituents R 2 and/or R 6 have the meanings indicated for R 1 and R 5 The compounds in which R 1 and/or R 5 are a hydroxyl can be obtained by the catalytic hydrogenation of a compound of formula in which R' 1 and/or R' 5 are a benzyloxy, for example in the presence of palladium-oncharcoal. These compounds can also be prepared from analogous compounds of formula in which R' 1 and/or
R'
5 are an amino group by using the method described in J. Org. Chem., 1977, 42, 2053.
The compounds of formula in which R 1 and/or S. R5 are a Ci-C 7 -alkoxy can be prepared directly by the 20 process according to the invention starting from the correctly substituted compounds of formulae (II) and
(III).
The compounds in which R' 1 and/or R' 5 are a hydroxyl can also be used to prepare compounds in which R 1 and/or R 5 are a C 1
-C
7 -alkoxy by reaction with a
C
1
-C
7 -alkyl halide in the presence of a base such as a *.metal hydride or an alkali metal or alkaline earth metal carbonate like K 2
CO
3 or Cs 2
CO
3 in a solvent such as THF or DMF. Likewise, the compounds of formula in which 30 R 1 and/or R 5 are an w-aminoalkoxy are prepared by reacting an o-chloroalkylamine with the compounds in which R' 1 and/or R' 5 OH; similarly, the compounds in which R 1 and/or R 5 are an o-hydroxyalkoxy are prepared by reaction with a chloroalkyl alcohol; in the particular case of the preparation of a compound in which R 1 and/or R 5
-O(CH
2 2 0H, it is also possible to react ethylene carbonate with a compound in which R' 1 and/or R' 5
OH.
The compounds of formula in which R 1 and/or are a (Cl-C al'ylcarbonyloxy are obtained by reacting an acid halide or an anhydride with a compound in which R' 1 and/or R'5 are a hydroxyl.
The compounds of formula in which R 1 and/or are a formyloxy are obtained for example by reacting formic acid in the presence of dicyclohexylcarbodiimide with a compound in which R' 1 and/or R' 5 are a hydroxyl HUANG et al, J. Chem. Res.(S), 1991, 292- 293).
The compounds of formula in which R 5 is a group -OR 7
R
7 being an (-carbamoyl-C 1
-C
7 -alkyl which is free or substituted by one or two C 1
-C
7 -alkyls, can be prepared from a compound in which R'5 is a group ORV, RV being an (-carboxy-C 1
-C
7 -alkyl esterified by a
C
1
-C
7 -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 in which R 1 and/or R 5 are a (C 1
-C
7 )monoalkylamino, a compound of formula in which R' 1 and/or R' 5 are an amino group is reacted with an aldehyde or ketone in an acid medium, in the presence of a reducing agent such as sodium cyanoborohydride; the compounds in which R 1 and/or R are a dialkylamino are prepared by an identical reaction.
The compounds of formula in which R 5 is an amino group substituted by a benzyl, which is itself 30 optionally substituted, or by a C 3
-C
8 -alkene can be prepared by reacting a benzyl chloride or a C3-C 8 chloroalkene with a compound of formula in which is an amino or alkylamino group.
The compounds of formula in which R 5 is a A3pyrrolin-l-yl group are prepared by reacting cis- 1,4dichlorobut-2-ene with the compounds of formula in I which R' 5 is an amino group, in the presence of a base such as triethylamine, under an inert atmosphere. The compounds of formula in which R 5 is a pyrrolidin-1-yl group are then prepared by hydrogenation. The reaction of cis-l,4-dichlorobut-2-ene with the compounds 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 in the formation of a mixture of a compound of formula in which R 5 is a A3pyrrolin-l-yl and a compound of formula in which R is a pyrrol-l-yl group, which can be separated by chromatography.
The compounds of formula in which R 5 is an isoindolin-2-yl group are prepared by reacting a,a'dibromo-o-xylene with the compounds of formula in which R' 5 is an amino group, in the presence of a base such as triethylamine, and in a solvent such as rimethylformamide, under reflux.
The compounds of formula in which R 5 is a 1- 20 methyl-2,4-dioxoimidazolin-3-yl group (NR 8 Rg Nmethylhydantoin) are prepared in two steps: Sarcosine is reacted with a compound of formula in which R' 5 is a phenoxycarboxamido, in the presence of a base such as triethylamine, to give a compound of formula in which R' 5 is an N'-carboxymethyl-N'-methylureido; the previously obtained product then cyclizes on heating at 100'C under vacuum. The compounds of formula in which
R
5 is a 2,4-dioxoimidazolin-3-yl group (NR 8
R
9 hydantoin) are prepared in the same manner by reacting 30 glycine with a compound of formula 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 in which R' 1 and/or R' 5 are a diazonium salt; reactions known to those skilled in the art then afford the compounds according to the ~s~
I
33 invention in which R 1 and/or R 5 are a cyano, a halogeno or a Ci-C 7 -thioalkyl. Finally, compounds in which R l and/or R 5 are a group of the formula RCONH-, ROCONH-, RNHCONH- or RSO 2 NH-, in which R is a Cl-C 7 -alkyl, a phenyl or a benzyl, can be prepared by conventional reactions starting from compounds in which R' 1 and/or R' 5
NH
2 The compounds of formula in which R 5 is a C 1
C
7 -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 in which R 5 is a carboxyl group.
The compounds of formula in which R' 5 is a benzyloxycarbonyl can also be used to obtain the compounds in which R 5 is a carboxyl by catalytic hydrogenation. Reaction with a thionyl halide gives the compounds of formula in which R' 5 is a halogenocarbonyl. Such compounds are used to prepare compounds of formula in which R 5 is a carbamoyl 20 substituted by R'6 and R'' 6 by reaction with a compound
HNR'
6
R''
6 The compounds of formula in which the substituent R' 5 is a phenoxycarbonyl can also be used to obtain the compounds in which R 5 is a phenylcarbamoyl or a C 1
-C
7 -alkylcarbamoyl by reaction with an aniline or a C 1
-C
7 -alkylamine. An aniline substituted on the phenyl or an alkylamine substituted on the alkyl can be used to obtain compounds of formula in which R 5 is a phenylcarbamoyl substituted on the phenyl or, respectively, an alkylcarbamoyl substituted on the alkyl 30 by R 6 In the same way, the compounds of formula in which R 5 is a group -CONHCR 10
R'
10
COR
12 are prepared from compounds of formula in which R' 5 is either a group -COC1 or a phenoxycarbonyl group by reaction with
H
2 NCRoR'iOCOR 12 The compounds of formula in which R 5 is a -1 1~118 '1 group -COR' 7 are prepared from corresponding compounds in which R' 5 is a phenoxycarbonyl by reaction with
R'
7
H.
A compound in which R' 5 is a nitro group makes it possible to obtain a compound in which R 5 is an 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 obtain a compound according to the invention in which R 5 is a group -NR 8 Rg, Rg being an optionally substituted benzoyl, benzoyl chloride in which the phenyl carries the appropriate substituent is reacted with a compound Sin which R' 5 is an amino group, in the presence of an amine such as triethylamine. For example, 4-chlorosulfonylbenzoyl chloride can be reacted in order to prepare a compound in which R'5 is a 4-chlorosulfonylbenzamido group, after which a compound in which the substituent R 5 is a 4-sulfamoylbenzamido group or a 4-alkylsulfamoylbenzamido group is obtained by reaction with ammonia or a C 1
-C
4 -alkylamine respectively.
In the same way, the acid chloride R 11
R'
11
NCR
10
R'
10 COC1 is reacted with a compound of formula in which is a group -NHR 8 in order to prepare a compound of formula in which R 5 is an -NR 8 substituted by 30 COCR 10
R'
10
NR
11
R'
11 If it is desired to prepare a compound in which R 5 is a group -NRgR 9
R
9 being a (C 1
-C
6 )alkylcarbonyl, the appropriate anhydride or the appropriate acid chloride is reacted with a compound in which
R'
5 is an amino group, in the presence of an amine such as triethylamine. To prepare a compound in which R I L~I d~ is a group -NR 8 R9, Rg being a formyl, formic acid is reacted with a compound in which R' 5 is an amino group, in the presence of acetic anhydride and of an amine such as triethylamine.
In another preparatory example, a compound in which R 5 is an alkylsulfonamido group is obtained by reacting an alkylsulfonyl halide with a compound in which R' 5 is an amino group.
The compounds of formula 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 -(CH 2 )t-COR 12 In this case, a compound of the formula Hal-(CH 2 )t-COOAlk, in which Hal is a halogen, for example bromine, and Alk is a C 1
-C
7 -alkyl, is reacted with in the presence of cuprous chloride; if required, the resulting ester is converted to the acid or an amide. A compound in which R 5
-NHCO-(CH
2 )t'CO 2
H,
where t' 2 or 3, can be prepared by reacting an anhydride, such as succinic anhydride or glutaric 20 anhydride, with a compound in which R' 5 is an amino.
If required, the resulting acid is converted to an ester or an amide.
A compound in which R 5
-NHCOCO
2 Et or
NHCOCH
2
CO
2 Et can be prepared by reacting ethyloxalyl 25 chloride, or, respectively, ethylmalonylchloride, with a compound in which R' 5 is an amino.
In the same way, the compounds of formula in which R 5 is an amino group substituted by a group CRo 1
R'
10
COR
12 are prepared by reacting a compound of the formula Hal-CR 10
R'
10
COR
12 with the corresponding compounds in which the substituent R'5 is an amino.
A compound in which R 5 is an amino group substituted by a C 1
-C
7 -alkoxycarbonyl or a phenoxycarbonyl is prepared by reacting a C 1
-C
7 -alkyl or phenyl chloroformate with a compound in which the substituent R' 5 is an aIino.
II 31~ 1 i i Ils Likewise, a compound of formula in which R is a phenoxythiocarbonylamino is obtained by reacting a phenoxythiocarbonyl chloride with a compound of formula in which R' 5 is an amino group.
A compound of formula in which R 5 is a ureido or a thioureido is prepared by reacting ammonia with a compound of formula in which R'5 is an amino group substituted by a phenoxycarbonyl or a phenoxythiocarbonyl; such a compound of formula is reacted with a correctly substituted aniline or a correctly substituted C 1
-C
7 -monoalkylamine or -dialkylamine in order to prepare a compound of formula in which R 5 is a correctly substituted N'-phenylureido or a correctly substituted N'-alkylureido or N',N'-di- 15 alkylureido in which the alkyl is C 1
-C
7 It is also possible to prepare a compound in which 25 is a ureido (-NHCONR 14
R'
14 or a thioureido
NHCSNR
14
R'
14 by reacting a compound NHR 14
R'
14 with a compound in which R' 5 is a phenoxycarbonylamino or, respectively, phenoxythiocarbonylamino group.
A further possibility is to prepare a compound in which R 5 is a ureido (-NHCONR 14
R'
14 or a thioureido by reacting a carbamoyl chloride (ClCONR 14
R'
14 or, respectively, a thiocarbamoyl chloride with a compound of formula in which R' 5 is an amino S. :group.
It is also possible to prepare a compound in which R 5 is a thioureido by reacting Lewesson's reagent with a compound in which R'5 is the corresponding ureido.
The compounds in which R 5 is a guanidino group which is unsubstituted or monosubstituted or disubstituted by a C 1
-C
7 -alkyl, a phenyl or a benzyl can be prepared from the compounds in which R'5 is a phenoxyamido group by reaction with cyanamide or a derivative thereof correctly substituted on the nitrogen.
I
37 A compound in which R 5 is a carbamoyl which is unsubstituted or substituted by one or 2 Cl-C 7 -aikyl groups is prepared by reacting an appropriate amine with a compound in which the substituent R'5 is an amino, in the presence of phosgene.
It is also possible to prepare a compound in which R 5 is an amino group substituted by an alkylcarbamoyl or a phenylcarbamoyl by reacting an alkyl or phenyl isocyanate with a compound in which the substituent R' 5 is an amino.
Furthermore, a compound in which R 5 is a sulfamoyl group which is unsubstituted or substituted by a C 1
-C
7 -alkyl is prepared by reacting ammonia or a C1-C 7 alkylamine with a compound in which R'5 is a 15 halogenosulfonyl group.
The affinity of the compounds according to the invention for the vasopressin receptors was determined in vitro using the method described in C.J. Lynch et al., J.
Biol. Chem., 1985, 26 2844-2851. This method 20 consists in studying the displacement of tritiated vasopressin bound to the V 1 sites of rat liver membranes.
The concentrations of the compounds according to the invention which cause a 50% inhibition of the binding of tritiated vasopressin (IC 50 are low, ranging down to 25 7 M.
The affinity of the compounds according to the invention for the V 2 receptors was measured on a bovine kidney membrane preparation by a method adapted from P. Crause et al., Molecular and Cellular Endocrinology, 1982, 28, 529-541, and F.L. Stassen et al., J. Pharmacol. Exp. Ther., 1982, 223, 50-54. The com pounds according to the invention inhibit the binding of tritiated arginine vasopressin to the receptors of the membrane preparation. The IC 50 values of the compounds according to the invention are low, ranging down to 10 9
M.
The antagonistic activity of the compounds according to the invention towards the V 2 receptors was demonstrated by the adenylate cyclase activity assay performed by a method adapted from M. Laburthe et al., Molecular Pharmacol., 1986, 29, 23-27. A bovine kidney membrane preparation is used and each product is incubated for 10 minutes at 37*C, either by itself or in the presence of AVP (arginine vasopressin) at a concentration of 3.10- 8 M. The cyclic AMP (cyclic adenosine monophosphate) produced is measured by radioimmunoassay. The concentration which causes a inhibition (IC 50 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 is evaluated in hyperhydrated rats (OFA, Sprague-Dawley strain) treated 20 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 diuretic effect was observed for 25 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 radioiodinated ocytocin analog bound to the receptors of a gestating rat mammary gland membrane preparation by a technique similar to that described by J. Eland et al. in Eur. J. Pharmacol., 1987, 147, 197-207. The IC 50 values of the compounds according to the invention reach 10 8
M.
The compounds according to the invention are active after administration by different routes, especially orally.
E
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 prevention of various vasopressin-dependent or ocytocin-dependent complaints, cardiovascular complaints such as hypertension, pulmonary hypertension, cardiac insufficiency, myocardial infarction or coronary vasospasm, in particular in smokers, unstable angina and PTCA (percutaneous transluminal coronary angioplasty), cardiac ischemia, hemostatic disorders, especially hemophilia, and von Willebrand's syndrome, complaints of the central nervous system, for example migraine, cerebral vasospasm, Scerebral hemorrhage, cerebral edemas, depression, S 15 anxiety, psychotic states and memory disorders, 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, 20 hepatocirrhosis, ulcers, the pathology of vomiting, for example nausea, including nausea due to chemotherapy, travel sickness or else the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), diabetes insipidus and enuresis. The compounds according to the 25 invention can also be used in the treatment of disorders of sexual behavior; in women, the compounds according to the invention can be used for treating dysmenorrhea or premature labor. The compounds according to the invention 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 relates to pharmaceutical compositions containing an effective dose of a compound according to the invention, or a pharmaceutically acceptable salt, and suitable I s rlp~a~ excipients.
Said excipients are chosen according to the pharmaceutical form and the desired mode of administration.
In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal or rectal administration, the active principles of formula above, or their salts where appropriate, can be administered to animals and humans in unit forms of administration, mixed with conventional pharmaceutical carriers, for the prophylaxis or treatment of the above disorders or diseases. The appropriate unit forms of administration include forms 15 for oral administration, such as tablets, gelatin capsules, powders, granules and solutions or suspensions to be taken orally, forms for sublingual, buccal, intratracheal or intranasal administration, forms for subcutaneous, intramuscular or intravenous administration 20 and forms for rectal administration. For topical application, the compounds according to the invention can be used in creams, ointments or lotions.
.To obtain the desired prophylactic or therapeutic effect, the dose of active principle can vary between 0.01 and 50 mg per kg of body weight and per day.
Each unit dose can contain from 0.5 to 1000 mg, preferably from 1 to 500 mg, of active ingredients in combination with a pharmaceutical carrier. This unit dose can be administered 1 to 5 times a day so as to administer a daily dosage of 0.5 to 5000 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 ~L L II p ~RIC9 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 principle continuously.
A preparation in the form of gelatin capsules is obtained by mixing the active ingredient with a diluent and pouring the resulting mixture into soft or hard gelatin capsules.
A preparation in the form of a syrup or elixir or for administration in the form of drops can contain the active ingredient together with a sweetener, which is preferably calorie-free, methylparaben and propylparaben as antiseptics, 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 polyvinylpyrrolidone, as well as ith sweeteners or taste correctors.
Rectal administration is effected using 20 suppositories, which are prepared with binders melting at the rectal temperature, for example cocoa butter or polyethylene glycols.
Parenteral administration is effected using aqueous suspensions, isotonic saline solutions or sterile 25 and injectable solutions which contain pharmacologically compatible dispersants and/or wetting agents, for example propylene glycol or butylene glycol.
The active principle can also be formulated as microcapsules, if appropriate with one or more carriers or additives.
In addition to the products of formula above or one of the pharmaceutically acceptable salts, the compositions of the present invention can contain other active principles which may be useful in the treatment of the disorders or diseases indicated above.
Thus the present invention further relates to I I L eb IS IC ed~ 42 pharmaceutical compositions in which several active principles are present in association, one of them being a compound according to the invention.
Thus, according to the present invention, it is possible to prepare pharmaceutical compositions in which a compound according to the invention is present in association with a compound which acts on the reninangiotensin system, 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 peripheral vasodilator, a calcium inhibitor, a beta-blocker, an alpha-l- blocker or a diuretic. Such compositions will be useful in particular in the treatment of hypertension or heart failure.
It is also possible to associate two compounds according to the invention, namely a specific V 1 receptor antagonist with a specific V 2 receptor antagonist, or else a specific V 1 receptor antagonist with a specific ocytocin antagonist.
These associations will make it possible to reinforce the therapeutic activities of the compounds according to the invention.
25 Preparation of the 1.3-dihydroindol-2-ones Preparation 1: 1,3-Dihydro-4,6-dimethyl-3-spirocyclohexaneindol-2-one This compound is prepared 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 (IV, R' 1
R'
2
CH
3
CR'
3
R'
4 cyclohexane) are added over 30 minutes. The reaction O.:.Oo VSe S..s .0.0
S
S.
*5 S S *S e See.
en.
Ce S S. S 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 washings are neutral, and then dried and concentrated under vacuum to give a brown solid. Trituration in iso ether gives the expected compound. M.p. 223*C.
The 1,3-dihydroindol-2-one derivatives described in Table 1 below are obtained by following the same procedure and varying the starting hydrazide.
These compounds are purified by chromatography on a silica column using DCM as the eluent or by chromatography on an alumina column using DCM or iso ether as the eluent.
TABLE 1 R13 -o 1- R'4 R2 N
H
R'
1 R'2 CR'3R' 4 M.p. 'C H cyclobutane 191 H cyclopentane 189 H cyclohexane 186 H H cyclohexane 123-124
CH
3 -5 H cyclohexane 164
CH
3 0-5 H cyclohexane 226 CI-6 H cyclohexane 168
CF
3 0-5 H cyclohexane 164
C
6 H50-5 H cyclohexane 160 a~ 44 Preparation 2: The 1,3-dihydro-3-spirocyclohexaneindol-2-one described in Table 1 above can also be obtained by alkylation of the indol-2-one using the process according to A.S. Kende and J.C. Hodges or a variant described below.
A solution of 30 g of 1,3-dihydroindol-2-one in 900 ml of THF is kept at -40*C under a nitrogen atmosphere and 101 g of potassium tert-butylate are added. The temperature is allowed to rise to 0*C over 1 hour, the mixture 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 RT, 30 ml of water are then added and 5 the solvent is evaporated off under reduced pressure.
The residue is taken up with 500 ml of DCM and 200 ml of water, the insoluble material is then filtered off and organic phase is separated off, washed with 100 ml of ter, dried over magnesium sulfate and evaporated under vacuum. The residue is chromatographed on silica using a cyclohexane/ether mixture as the eluent to give the expected compound, which is recrystallized from heptane.
m 34 g. M.p. 123-124'C.
A similar procedure can be applied starting from 25 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 Wright in J. Am. Chem. Soc., 1956, 28, 221, and by RajanBabu in J. Org. Chem., 1986, 5i, 1704. 4- Chloro-1,3-dihydroindol-2-one can be prepared from 2chloro-6-nitrotoluene by the method described in J. Am.
Chem. Soc., 1956, 28, 22'.
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- L- dihydroindol-2-ones are prepared from the appropriate aniline derivative.
Preparation 3: 5-Ethoxy-l,3-dihydroindol-2-one A 3-Methylthio-5-ethoxy-1,3-dihydroindol-2one 23.6 g of ethyl methylthioacetate in 60 ml of DCM are added to a solution, cooled to about -70*C, of 12.5 g of chlorine In 400 ml of DCM. After stirring for minutes at the same temperature, a solution of 4ethoxyaniline (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 15 are added and the organic phase is decanted, dried over magnesium sulfate and evaporated under reduced pressure.
The residue is taken up with 500 ml of isopropanol and ml of concentrated hydrochloric acid. The mixture is stirred for about 16 hours at room temperature and filtered and the precipitate is separated off. The filtrate is concentrated under reduced pressure to give 'the expected product.
B 5-Ethoxy-l,3-dihydroindol-2-one The above solid, in 1500 ml of isopropanol, is 25 dethiomethylated in the presence of 100 g of Raney® nickel (80 to 100 m 2 per under reflux, for 3 hours, under a nitrogen atmosphere. The mixture is filtered on talc, the material on the filter is rinsed with 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 5-n-propyl-1,3-dihydroindol-2-one m.p. 136*C 5-eth1-yl-l,3-dihydroindol-2-one m.p. 152*C 2, 2-trifluoroethoxy)-l,3-dihydroindol- 2-one m.p. =145'C 5-trifluoromethyl-1,3-dihydroindol-2-one m.p. =193*C 3-dihydroindol-2-one m.p. 143*C The compounds of formula (II) described below are obtained by following the technique described in Preparation 2 and varying the starting 1,3-dihydro-indol- 2-one derivative and the alkylating reagent.
TABLE 2 p.
p 6 pp.6 p p p. p p p W1 R2CR' 3
R!
4 M.p.*C alkylating reagent 5-Cl H cyclohexane 186-189 Br(CH 2 5 Br 5-CL H cycloheptane 202 Br(CHf 2 6 Br H 4,4-diniethyl 180 TsO(Cli 2 2
C(CH
3 2 cyclohexane -(CH 2 2 OTs 5-Cl H hexahydroindane-2 223 cis-1,2-diodomnethylcyclohexane 3 H 4,4-dimethyl 202 TSO (CH 2
Q
2
CH
3 2 cyclohexane 2 2 -OTs TABLE 2 (continuation) Rt l2CR'iR'A M.P. *C alkylating reagent p p p.
4-Cl
H
5-OBz indane-2
C(CH
3 2
C(CH
2
CH
3 2 C(n P0)2 C(iBu) 2 N-methyl piperidine-4 tetrahydropyran-4 cyclohexane cyclohexane
C(CH
2
C
6
H
5 2 C(n-pentYl) 2 2,3-dihydro phenalene-2 4,4-dimethyl cyclohexane 4-spirocyclopentane cyclohexane N-tBu piperidine-4 228 160 156 158 164 260 223 215 162 206 142 154 202 15 i a,a'-dibromomethyl orthoxyI~ne
CH
3 1
CH
3
CH
2 1 nPrI iBuI
CI(CH
2 2
N(CH
3
-(CH
2 2 )Cl
T(CH
2 2 0(CH2) 2 1 Br(CH 2 5 Br Br(CH 2 5 Br C6HSCH 2 ,Br
CH
3
(CH
2 4 Br p TsO(CH 2 2
C(CH
3 2
-(CF
2 2 OTs I
<(CH
2 2 OTs
(CH
2 2 OTs Br(CH 2 5 Br
N(CH
2 2 Br
I
48 TABLE 2 (continuation) R' 2 CR' 3
R
4 M.P. C j alkylating reagent
C
C C
C
S.
S S 5-QEt 5-Et
OCH
2
CF
3
H
3 N-Bz piperidine-4 N-phenyl piperidine-4 4,4-diethyl cyclohexane cyclohexane 4,4-dimethyl cyclohexane cy~cloheptane 4,4-dimethyl cyciohexane 4,4-dimethyl cyclohexane 4,4-dimethyl cyclohexane 4,4-dimethyl cyclohexane 4,4-dimethyl cyclohexane 165 188 300 132 163 178 139 160 164 169 211 171 B z-
(CH
2 2 Br
(CH
2 2
C
(CH
2 )2Br
S.C.
C C
S
S.
C.
TSO(CH
2 2
C(C
2
H
5 2
-(CH
2 2 OTs Br(CH 2 5 Br TsO(CH 2 2
C(CH
3
-(CH
2 2 OTs Br(CH 2 6 Br TsO(CH 2 2
C(CH
3 2
-(CH
2 2 OTs idern idem idemn idem I I 49 TABLE 2 (continuation)
S
R1 I2 CR' 3
R'
4 M.P. *C alkylating reagent H (CH 2 2 00 120 Br(CH 2 2 -O-0
(CH
2 2 0 H 208 TsQ0 C ~TsO0 5-QEt H 214
T
C
TsO0 H tetrahydro- 146 I(CH 2 2 0(CH 2 2 1 pyrane-4 H 255 CH 2
OSO
2
CH
3
CH
2
OSO
2
CH
3 Prevarsation 4: 1, 3-Dihydro-3-spiroadamantaneindol-2-one This compound is prepared according to I. Fleming et al., Tetrahedron Letters, 1982, 2053-2056, starting from 2-bromoaniline and adamantan-2-one.
Prenaration 5-Chloro-1, 3-dihydro-3, 3-diphen.ylindol-2-one This compound is prepared by the method described S. S S in Helv. Chim. Acta, 1946, 29, 415-431, by the reaction of benzene with 5-chioroisatin in the presence of aluminum chloride. M.P. 281*C.
Preparation 6: 1, 3-Dihydro-5-nitro-3-spirocyclohexaneindol-2one This compound is prepared by the method described in J. Ami. Chem. Soc., 1945, -6Z, 499, by the nitration 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 1,3dihydro-3-spiroadamantaneindol-2-one. M.p. 260*C.
1, 3-Dihydro-5-nitro-3-spiro 4-dimethylcyclohexane)indol-2-one is also prepared. M.p. 195*C.
rearation 2: 3-dihydro-3-spirocyclohexaneindol-2- **,one ***This compound is prepared by the method described in J. Chem. Soc., 1951, 3475, by the reduction of 1,3dihydro-5-nitro-3-spirocyclohexaneindol-2-one, prepared above.
M.P. 176*C.
3-dihydro-3-spiroadamantaneindol-2- one is prepared in the same manner. M.p.c =245*C.
25 Preparation 8: 5-Fluoro-1, 3-dihydro-3-spirocyclohexaneindol-2one A 5-Diazonium-1, 3-dihydro-3-spirocyclohexaneindol- 2-one tetrafluoroborate A solution containing 4 g of 5-amino-l,3-dihydro- 3-spirocyclohexaneindol-2-one in 9.2 ml of 6 N hydrochloric acid is cooled to 0*C and 2.27 g of sodium nitrite in 2.6 ml of water are added, followed by 2.54 g of sodium tetr, lL-oroborate in 9 ml of water. After s-irring for 5 minutes, the precipitate is filtered off and washed with a 5% solution of tetrafluoroborate, with 3 ml of methanol cooled to about O0C and then with 5 ml of ether. The salt obtained is dried under vacuum at RT in the presence of phosphorus pentoxide.
B 5-Fluoro-1,3-dihydro-3-spirocyclohexaneindol-2-one 1 g of the compound obtained in step A is placed in 5 ml of xylene and heated at about 115*C for 2 hours.
The mixture is cooled to RT, the precipitate is filtered off and rinsed with toluene and 0.1 g of active charcoal is added to the filtrate. After filtration, the solvent is evaporated off under reduced pressure to give 0.45 g of the expected compound, which is recrystallized from pentane. M.p. 114'C.
Preparation 9: 15 5-Cyano-1,3-dihydro-3-spirocyclohexaneindol-2one 4.78 g of potassium cyanide and 4.95 g of cuprous cyanide are dissolved at RT in 40 ml of DMSO. The a999 solution is cooled to about 15'C and 4.15 g of the diazonium salt obtained in 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 is then separated off, dried over magnesium sulfate and 25 evaporated under reduced pressure. The residue is chromatographed on silica using a cyclohexane/ether mixture as the eluent to give the expected compound, which is recrystallized from heptane.
m 1.4 g. M.p. 216*C.
Preparation 5-Chloro-1,3-dihydro-3-spiroadamantaneindol-2one 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 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, dried 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 is crystallized from iso ether. M.p. 249'C.
Preparation 11: 5-Chloro-3-cyclohexyl-1,3-dihydro-3-methylindol-2-one The method described in Synth. Commun., 1982, 12 1-10, is used to prepare 5-chloro-3-cyclohexyl- 1,3- S. dihydroindol-2-one as an intermediate, and the expected compound is then obtained by reaction with methyl iodide.
Preparation 12: 5-Acetyl-l,3-dihydro-3-spirocyclohexaneindol-2one 2.56 g of acetyl chloride and then 8.25 g of anhydrous aluminum chloride are added to a solution, cooled to 5'C, of 4 g of 1,3-dihydro-3-spirocyclohexaneindol-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 o 99 hydrolyzed with 50 g of ice and extracted with ethyl acetate.
The organic phase is washed with water, dried over magnesium sulfate and then evaporated under reduced pressure. The residue is chromatographed on a silica column using a mixture of heptane and ethyl ether as the eluent to give 3.6 g of the expected product. M.p. 192*C.
qW IILP9 Preparation 13: 5-Chloro-1,3-dihydro-3-spiro(tetrahydrothiopyran-4-yl)indol-2-one A 5-Chloro-l,3-dihydro-3,3-di(2-bromoethyl)indol-2-one 7.66 g of bromine are added slowly to a mixture, cooled to about 0*C, of 12.4 g of triphenyl-phosphine in ml of DCM, and 4.58 g of 5-chloro-l,3- dihydro-3,3di[2-(tetrahydropyran-2-yloxy)ethyl]indol- 2-one, described in Table 2, are then added. After 16 hours at RT, 60 ml of water are added and the organic phase is separated off, washed with 60 ml of water and then dried over magnesium sulfate and evaporated under vacuum. The residue is chromatographed on a silica column using DCM 15 as the eluent to give 3.12 g of the expected product.
M.p. 215*C.
.B 5-Chloro-l,3-dihydro-3-spiro(tetrahydrothiopyran-4-yl)indol-2-one Under an inert atmosphere, 3 g of the product prepared in step A are added to 3.2 ml of DMF and 2 g of sodium sulfide monohydrate and the mixture is heated for 2 hours at 50*C, It is cooled to RT, 6 ml of water are added and the mixture is extracted with DCM. The organic phase is washed with water, dried over magnesium sulfate 25 and evaporated under reduced pressure. The oily residue obtained is purified by chromatography on silica using DCM as the eluent to give 2.02 g of the expected compound.
NMR spectrum at 200 MHz in CDC1 3 8.12 ppm s 1H 7.2 ppm m 2H 6.8 ppm d 1H 3.25 ppm m 2H 2.65 ppm m 2H 2 ppm m 4H I dsl Preparation 14: 5-Ethoxy-l,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 O0C 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 RT 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 distillation under reduced pressure. B.p. 125*C under 1.2 Pa.
.B 3-(Methoxymethoxy)-1,5-ditosyloxypentane A solution of 46 g of p-toluenesulfonyl chloride and 38 ml of triethylamine in 80 ml of THF is cooled to O'C, a solution of 18 g of the compound obtained in the previous step in 100 ml of THF is added and the mixture is stirred for 16 hours at RT. 150 ml of water are added to the reaction mixture, the solvent is evaporated off under vacuum, the residue is extracted with AcOEt and the latter is evaporated off under vacuum. The oil obtained is taken up with 250 ml of ether and 200 ml of 2 N NaOH and the mixture is stirred for 16 hours at RT. After .:decantation, the organic phase is dried over magnesium sulfate and the solvent is evaporated off under vacuum to give 45 g of the expected product after crystallization from cyclohexane. M.p. C 5-Ethoxy-l,3-dihydro-3-spiro[4-(methoxymethoxy)cyclohexane]indol-2-one This compound is prepared by the procedure described in Preparation 2 starting from 5-ethoxy-l,3dihydroindol-2-one and the compound obtained in the .g -I I~L I previous step. The expected product is obtained in the form of a mixture of isomers. M.p. 98'C.
Preparation 5-Ethoxy-1,3-dihydro-3-spiro[4-tricyclo- [5.2.1.0 2 6 ]decane]indol-2-one A mixture of 3 g of 5-ethoxy-1,3-dihydro-3spiro[4-tricyclo[5.2.1.02, 6 ]dec-8-ene]indol-2-one, described in Table 2, and 1.5 g of 10% palladium-oncharcoal 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 C6lite® and washed with MeOH and the filtrate is evaporated under vacuum to give 2.95 g of the expected product. M.p. 236'C.
Preparations 16 and 17: 5-Ethoxy-l,3-dihydro-3-spiro(4-methoxycyclohexane)indol-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-hydroxyglutarate and 33 ml of 2,6-di-tert-butylpyridine in 500 ml of DCM and the mixture is refluxed for 6 hours. After cooling, 500 ml of a 0.5 N solution of HC1 are added, the organic phase is decanted and dried over magnesium 25 sulfate and the solvent is evaporated off under vacuum.
The residue obtained is taken up with 200 ml of anhydrous THF, the mixture is filtered and the filtrate is then cooled to 160 ml of a 1 M solution of lithium aluminum hydride in THF are then added slowly and the mixture is stirred for 16 hours, the temperature being allowed to rise 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 successively. The mineral salts are filtered off and the filtrate is evaporated under vacuum to give the expected product after distillation under reduced pressure. B.p. 104*C under Il--~-'RII- Pa.
B A solution of 31 g of p-toluenesulfonyl chloride and 26 ml of triethylamine in 120 ml of THF is cooled to O'C, 10 g of the compound obtained in the previous 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 residue is extracted with AcOEt and dried over magnesium 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 stirred for 16 hours at RT.
After decantation, the organic phase is dried over magnesium sulfate and the solvent is evaporated off under 15 vacuum to give 26 g of the expected product after crystallization from cyclohexane. M.p. 58'C.
C 5-Ethoxy-1,3-dihydro-3-spiro(4-methoxycyclohexane)indol-2-one, the less polar isomer and the more polar isomer These compounds are prepared by the procedure described in Preparation 2 starting from 11.85 g of ethoxy-1,3-dihydroindol-2-one, 34 g of potassium tertbutylate and 26 g of the compound obtained in the previous step. They are chromatographed on silica using S 25 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 described in the general section.
L
57 C1 S0 2
OCH
3 0e** o Oe 0 0* tO *900 0* 08 0 Y R M.p.*C S CH 3 0 CH-,Bz o CH 2
CO
2 Et 89 o (CH 2 3 Br 106-108 Starting from the various 1,3-dihydroiridol-2ones described above and appropriate benzenesulfonyl chlorides, the compounds according to the invention were prepared using the procedures reported in the ixample,, below.
EXAM4PLES 1 and 2 5-Ethoxy-1,3-dihydro-l-[2-methoxy-4-(pyrrol-1yl )benzenesulfonyl] -3-spirocyclohexaneindol-2-one aind 5-ethoxy-1, 3-dihydro-1-[2-methoxy-4-(A3-pyrrolin-1-yl) benzenesulfonyl] -3-spirocyclohexaneindol-2-one A) 5-Ethoxy-1, 3-dihydro-l- (2-metho:,j,-4-nitrobenzenesulfonyl )-3-spirocyclohexaneindol-2-one A solution of 15 g of 5-ethoxy-1, 3-dihydro-3spirocyclohexaneindol-2-one in 150 ml of THF is cooled in an ice bath to a temperature between 10*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--nitrobenzenesulfonyl chloride are- then introduced in portions
NWWEW
58 over 30 minutes. After stirring 3. i1 hours at RT, the suspension obtained is poured in.- iced solution of sodium chloride and then extracted with AcOEt. The organic phase is dried over sodium sulfate and evaporated 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.
5-Ethoxy-l,3-dihydro-l-(2-methoxy-4-nitrobenzenesulfonyl)-3-spirocyclohexaneindol-2-one A solution of 15 g of 5-ethoxy--,3-dihydro-3spirocyclohexaneindol-2-one in 300 ml of THF is cooled to about -50"C and 7.2 g of potassium tert-butylate are 15 added. The mixture is stirred, the temperature being allowed to rise to about 0"C, and then cooled to S. and a solution of 16.2 g of 2-methoxy-4nitrobenzenesulfonyl chloride in THF is added. The mixture is stirred for 1 hour at RT, 100 ml of water are added and the solvent is evaporated off under vacuum.
The aqueous phase is 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.
25 The following nitro derivativMs are prepared by the latter procedure starting from the appropriate 1,3dihydroindol-2-ones: -1 sl 4t
CR
3
R
4 M.p.*C or NMR 4,4-dimethylcyclohexane 169 4,4-dimethylcyclohexane 110 4,4-dimethylcyclohexane 137 4,4-dimcthylcyclohexanc cycloheptane 137 cyclohcptane 125 tetrahydropyran-4 212 tetrahydrothiopyran-4 116 C, 88 140
NMR*
*NMR spectrum at 200 MHz in DMSO 1.3 ppm t :3H 1.3-1.5 ppm :mt :6H 2.2 ppm mt 4H 3.7 ppm s 3H ppm q 2H ppm mt 2H 7.6 ppm d 1H 7.9 ppm :mt 2H 8.2 ppm d 1H B) 1- l-Amino-2-methoxybenzenesulfonyl)-5-ethoxy-l,3dihydro-3-spirocyclohexaneindol-2-one A suspension containing 20 g of 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 point; a solution of 7 ml of concentrated hydrochloric acid in 35 ml of water is added over 15 minutes. After 4 hours under reflux, 15 ml of sodium hydroxide solution are added and the mixture is then extracted with DCM. The organic phase is filtered on C6liteR and then dried over sodium sulfate. The residue is crystallized 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. 177'C.
This compound is also obtained by following the procedure described below.
l-(4-Amino-2-methoxybenzenesulfonyl)-5-ethoxy-1,3dihydro-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 HC1 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 C6liteR and the filtrate is evaporated under vacuum. The residue is chromatographed on silica using a DCM/MeOH mixture (99/1; v/v) as the eluent to give the expected product.
61 The following anilines are also prepared by the latter procedure:
I
NH
2 0 a a
RICR
3
R
4 M.p.9C CI- 4,4-dimethylcyclohexane 222 EtO- 4,4-dimethylcyclohexane 230 F- 4,4-dimethylcyclohexane 130
CF
3 4,4-dimethylcyclohexane CI- cycloheptane 184 EtO- cycloheptane 128 CI- tetrahydropyran-4 220 CI- tetrahydrothiopyran-4 229 EtO- 241 Cn/ EtO- -232 EtO- C189 62 The compound obtained in step B) above can also be prepared from the corresponding nitro derivative by hydrogenation in the presence of 10% palladium-oncharcoal for 2 hours at 50'C under a pressure of 1 bar.
C) 5-Ethoxy-1,3-dihydro-l-[2-methoxy-4-(pyrrol-1-yl)benzenesulfonyl]-3-spirocyclohexaneindol-2-one and ethoxy-1,3-dihydro-l-[2-methoxy-4-(D3-pyrrolin-1-yl)benzenesulfonyl]-3-spirocyclohexaneindol-2-one A mixture containing 500 mg of the compound prepared in step 10 ml of DMF, 0.3 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 15 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 S* of Example m.p. 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 Sto the invention which are analogous to that obtained in step C).
S 25 EXAMPLE 3 5-Ethoxy-l,3-dihydro-l-[2-methoxy-4-(pyrrolidin-l-yl)benzenesulfonyl]-3-spirocyclohexaneindol-2-one 450 mg of the compound obtained in Example 2 are placed in 25 ml of 95* EtOH and 25 ml of AcOEt, in the presence of 150 mg of 5% palladium-on-charcoal, and are hydrogenated for 4 hours at 35'C under a pressure of bar. The catalyst is filtered off and the filtrate is evaporated to dryness. The expected pro duct crystallizes from iso ether. m 110 mg. M.p. 185'C.
EXAMPLE 4 5-Ethoxy-1,3-dihydro-l-[4-(isoindolin-2-yl)-2methoxybenzenesulfonyl]-3-spirocyclohexaneindol-2-one A mixture containing 500 mg of the compound prepared in Example 1 step 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 170 mg. M.p. 190'C.
EXAMPLE 15 5-Ethoxy-l,3-dihydro-l-[2-methoxy-4-((3-methylthien-2-yl)carboxamido)benzenesulfonyl]-3-spirocyclohexaneindol-2-one A mixture containing 500 mg of the compound prepared in Example 1 step 10 ml of DCM, 2 ml of pyridine and 250 mg of 3-methylthiophene-2-carboxylic 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 25 DCM as the eluent. The expected product recrystallizes from iso ether. m 0.21 g. M.p. 174'C.
EXAMPLE 6 l1-[4-(N-Benzylcarbamoyl)-2-methoxybenzenesulfonyl]-5-ethoxy-l,3-dihydro-3-spirocyclohexaneindol-2one A) Benzyl 3-methoxy-4-[(5-ethoxy-2,3-dihydro-2-oxo-3spirocyclohexaneindol-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-l,3dihydro-3-spirocyclohexaneindol-2-one in 100 ml of THF.
After stirring for 30 minutes at RT, 17 g of benzyl 4- -P -WI -C 64 chlorosulfonyl-3-methoxybenzoate are added and stirring is maintained at RT for 1 hour. The reaction medium is poured into 400 ml of a water/alcohol mixture (50/50; The precipitate formed is filtered off, dried and then recrystallized from alcohol.
m 22.65 g. M.p. 135'C.
B) 3-Methoxy-4-[(5-ethoxy-2,3-dihydro-2-oxo-3-spirocyclohexaneindol-1-yl)sulfonyl]benzoic acid g of 10% palladium-on-charcoal in oil are added to a solution of 22.65 g of 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 insoluble material is filtered off and the medium 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-spirocyclohexaneindol-l-yl)sulfonyl]benzoyl chloride A solution of 2.3 g of the above acid in 20 ml of thionyl chloride is refluxed for 3 hours. The reaction medium is concentrated to dryness and the product is used in the crude form, as a solution in DCM, in the next step.
D) l-[4-(N-Benzylcarbamoyl)-2-methoxybenzenesulfonyl]- S 25 5-ethoxy-l,3-dihydro-3-spirocyclohexaneindol-2-one A mixture containing 500 mg of the compound prepared in the previous step and 200 mg of benzylamine Sin 20 ml of DCM and 0.5 ml of TEA is stirred at RT for minutes. It is washed with a 1 N solution of HC1, dried over sodium sulfate and concentrated. The expected product crystallizes from iso ether.
m 440 mg. M.p. 196C.
The compound of Example 6 does not belong to the compounds of formula according to the invention, but the intermediate obtained in step C) is used to prepare the compound of Example 8.
The procedure described in Example 6 step D) is also used, together with the appropriate amines, to prepare the compounds of Examples 44-54.
EXAMPLE 7 l-[4-(2-Carbamoylpyrrolidin-1-ylcarbonyl)-2methoxybenzenesulfonyl]-5-chloro-l,3-dihydro-3-spirocyclohexaneindol-2-one A) Phenyl 4-[(5-chloro-2,3-dihydro-2-oxo-3-spirocyclohexaneindol-l-yl)sulfonyl]-3-methoxybenzoate A mixture containing 1 g of 5-chloro-l,3-dihydro-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-phenoxycarbonylbenzenesulfonyl chloride are introduced and stirring 15 is maintained for 20 hours at RT. The reaction medium is concentrated under vacuum and the residue is taken up with 30 ml of water and extracted with AcOEt. The organic phase is washed, dried and concentrated under vacuum. The product obtained is purified by chromatography on silica using an iso ether/hexane mixture (40/60; v/v) as the eluent to give 1.4 g of the expected compound. M.p. 165'C.
B) 1-[4-(2-Carbarmoylpyrrolidin-l-ylcarbonyl)-2-methoxybenzenesulfonyl]-5-chloro-1,3-dihydro-3-spirocyclo- 25 hexaneindol-2-one A mixture 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 prehnitene is refluxed for 1 hour. After cooling, the reaction medium is taken up with AcOEt, washed with a 1 N solution of HC1 and with water and then 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.
EXAMPLE 8 5-Ethoxy-l,3-dihydro-l-[2-methoxy-4-(2-methoxy-
I
carbonylpyrrolidin-l-ylcarbonyl)benzenesulfonyl]-3spirocyclohexaneindol-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 to 500 mg of 3-methoxy-4-[(5-ethoxy-2,3-dihydro- 2-oxo-3spirocyclohexaneindol-l-yl)sulfonyl]benzoyl chloride, prepared in Example 6 step After stirring for one hour at RT, the mixture is washed with 1 N HC1, dried and concentrated. The residue is chromatographed on silica using a DCM/MeOH mixture (98/2; v/v) as the eluent to give 300 mg of the expected product, which is characterized by its NMR spectrum.
NMR at 200 MHz in DMSO (2.5 ppm): 1.25 ppm t 3H S' 15 1.3-2.35 ppm m 14H 3.1-3.7 ppm m 8H 3.8 ppm q 2H 4.35 ppm mt 1H 6.7-8 ppm m 6H EXAMPLE 9 1-[4-(N'-Cyclopentylureido)-2-methoxybenzenesulfonyl]-5-ethoxy-l,3-dihydro-3-spirocyclohexaneindol- 2-one A) 5-Ethoxy-1,3-dihydro-1-(2-methoxy-4-phenoxycarbox- 25 amidobenzenesulfonyl)-3-spirocyclohexaneindol-2-one A mixture containing 2 g of l-(4-amino-2methoxybenzenesulfonyl)-5-ethoxy-1,3-dihydro-3-spirocyclohexaneindol-2-one (prepared in Example 1 step 3.6 ml of phenyl chloroformate and 120 ml of ether is cooled to a temperature below 5*C. 960 mg of sodium hydroxide in 16 ml of water are added and the temperature is allowed to rise for 24 hours, with stirring. The precipitate 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.
c -s, B) l-[4-(N'-Cyclopentylureido)-2-methoxybenzenesulfonyl]-5-ethoxy-1,3-dihydro-3-spircyclohexaneindol-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 for 18 hours at RT. The alcohol is evaporated off under vacuum and the residue is then chromatographed on silica using a DCM/AcOEt mixture (9F/5; v/v) as the eluent to give 1.8 g of the expected product, which crystallizes from iso ether.
M.p. 195"C.
EXAMPLE 5-Chloro-l,3-dihydro-l-[4-(N',N'-diethyl-ureido)- 2-methoxybenzenesulfonyl]-3-spiro-(tetrahydro-thiopyran- S' 15 4-yl-l-oxide)indol-2-one This is prepared in the same manner as in Example 9 (steps A) and A) 5-Chloro-l,3-dihydro-l-[4-(N',N'-diethylureido)-2methoxybenzenesulfonyl]-3-spiro(tetrahydrothiopyran-4yl)indol-2-one, m.p. 2140C, from 5-chloro-l,3-dihydro-l-[4-amino-2-methoxybenzenesulfonyl]-3-spiro- (tetrahydrothiopyran-4-yl)indol-2-one, m.p. 229*C B) 5-Chloro-1,3-dihydro-1-[4-(N',N'-diethylureido)-2methoxybenzenesulfonyl]-3-spiro(tetrahydrothiopyran-4-yl- 25 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 I precipitate is filtered off and the methanol is evaporated off from the filtrate under reduced pressure.
The residue 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 0.4 g of the expected product is isolated.
M.p. 217*C.
~p;a bL~ pt I~l~IIIB~W 68 EXAMPLE 11 5-Chloro-1,3-dihydro-l-[4-(N',N'-diethylureido)- 2-methoxybenzenesulfonyl]-3-spiro(tetrahydrothiopyran-4yl-l,l-dioxyde)indol-2-one A mixture of 0.45 g of the compound of Example and 0.5 g of metachloroperbenzoic acid in 10 ml of DCM is 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 v/v) to give 0.35 g of the expected product. M.p. 211'C.
EXAMPLE 12 15 l-[4-(N'-Cyclopentylthioureido)-2-methoxybenzenesulfonyl]-5-ethoxy-l,3-dihydro-3-spirocyclohexaneindol-2-one The compound obtained in Example 9 is placed in 50 ml of toluene in the presence of 1.5 g of Lawesson's reagent. The mixture is refluxed for 24 hours. The toluene is 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.
S* 25 M.p. 197*C.
EXAMPLE 13 1-[4-(3-(N-Boc-amino)azetidin-l-ylcarboxamido)- 5-methoxybenzenesulfonyl]-2-ethoxy-1,3-dihydro-3-spirocyclohexaneindol-2-one A) l-Benzhydryl-3-(N-Boc-amino)azetidine A mixture containing 5 g of 3-amino-l-benzhydrylazetidine and 5 g of (Boc) 2 0 in 130 ml of dioxane and 4 ml of TEA 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 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 palladium hydroxide and 3 ml of concentrated HC1 is prepared. It is hydrogenated for 2 hours at 35-40C 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) l-[4-(3-(N-Boc-amino)azetidin-1-ylcarboxamido)-5methoxybenzenesulfonyl]-2-ethoxy-l,3-dihydro-3-spiro cyclohexaneindol-2-one A mixture containing 500 mg of the compound 15 prepared in Example 9 step 20 ml of 100' alcohol, ml of DCM, 250 mg of the compound prepared in step B) and ml of TEA is stirred for 24 hours at RT. The solvents are evaporated off and the residue is then .o chromatographed on a silica column using a DCM/AcOEt mixture (95/5; v/v) as the eluent. The expected product crystallizes from iso ether.
m 200 mg. M.p. 156*C.
EXAMPLE 14 1 l-[4-(N'-Carboxymethyl-N'-methylureido)-2- 25 methoxybenzenesulfonyl]-5-ethoxy-l,3-dihydro-3-spirocyclohexaneindol-2-one A mixture containing 500 mg of the compound prepared in Example 9 step 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 is characterized by its i; NMR spectrum at 200 MHz in DMSO (2.5 ppm): 1.3 ppm t 3H 1.4-2.1 ppm m 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 1H EXAMPLE .5-Ethoxy-1,3-dihydro-l-[2-methoxy-4-(l-methyl- 2,4-dioxoimidazolin-3-yl)benzenesulfonyl]-3-spirocyclo- Shexaneindol-2-one On heating at 100'C for 24 hours under vacuum, 15 the product obtained in the previous Example is cyclized to give 230 mg of the expected product.
M.p. 200*C.
EXAMPLE 16 L 1-[4-(N',N'-Diethylthioureido)-2-methoxybenzene sulfonyl]-5-ethoxy-1,3-dihydro-3-spirocyclohexaneindol- 2-one A) 5-Ethoxy-1,3-dihydro-l-(2-methoxy-4-phenoxythiocarboxamidobenzenesulfonyl)-3-spirocyclohexaneindol-2one 25 A mixture containing 500 mg of the compound obtained in Example 9 step 900 mg of phenoxythiocarbonyl chloride, 30 ml of ether, 8 ml of water, 120 mg of sodium 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.
B) 1-[4-(N',N'-Diethylthioureido)-2-methoxybenzenesulfonyl]-5-ethoxy-1,3-dihydro-3-spirocyclohexaneindol- 2-one I sP~ I A mixture containing 140 mg of the compound prepared in step 20 ml of 100* EtOH, 5 ml 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 crystallizes from iso ether. m 105 mg. M.p. 167C.
EXAMPLE 17 5-Ethoxy-1,3-dihydro-l-(2-methoxy-4-guanidinobenzenesulfonyl)-3-spirocyclohexaneindol-2-one A mixture containing 500 mg of the compound prepared in Example 1 step 125 mg of cyanamide, 7 ml of AcOEt, 1 ml of EtOH and 0.2 ml of a 20% solution of 15 hydrochloric acid in EtOH is refluxed for 1 hour. The solvents are evaporated off and the residue 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 NaHC0 3 is added and the base formed is then extracted with AcOEt; the extract is Sevaporated to dryness and the expected product solidifies in iso ether. m 0.055 g. M.p. 235"C.
EXAMPLE 18 0 2 5-Ethoxy-l,3-dihydro-l-[2-methoxy-4-(N-methylcarbamoylmethoxy)benzenesulfonyl]-3-spirocyclohexaneindol-2-one A) Potassium 2-methoxy-4-(ethoxycarbonylmethoxy)phenylsulfonate g of ethyl (3-methoxyphenoxy)acetate and 30 ml of DCM are mixed at 0C and 7.5 ml of trimethylsilylsulfonyl chloride in 30 ml of DCM are added over 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 I 72 white precipitate which forms is filtered off and then washed with acetone and ether to give 3.1 g of the expected product, which is characterized oy its NMR spectrum.
B) 2-Methoxy-4-(ethoxycarbonylmethoxy)phenylsulfonyl chloride 3.1 g of the compound obtained 3 i the previous step in 30 ml of phosphorus oxychloride are refluxed for 3 hours. The medium is concentrated under vacuum and then -aken up with ice. It is extracted with ethyl acetate, washed 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. 896C.
15 C) Ethyl 3-methoxy-4-[(5-ethoxy-2,3-dihydro-2-oxo-3spirocyclohexaneindol-l-yl)sulfonyl]phenoxyacetate A mixture containing 0.5 g of 5-ethoxy-1,3dihydro-3-spirocyclohexaneindol-2-one, 5 ml of THF and mg of sodium hydride is prepared. After stirring for minutes at 15'C, 0.66 g of the compound prepared in the previous step is added. Stirring is maintained for minutes and the medium is then concentrated under vacuum.
It is extracted with ether and washed with water and the expected product is then crystallized from iso ether.
m 0.85 g. M.p. 160*C.
D) 5-Ethoxy-l,3-dihydro-l-[2-methoxy-4-(N-methylcarbamoylmethoxy)benzenesulfonyl]-3-spirocyclohexaneindol-2-one A mixture containing 0.5 g of the compound prepared in the previous step, 15 ml of a 33% solution of methylamine in MeOH and 15 ml of EtOH is stirred for 4 days at RT. It is concentrated under vacuum and the residue is then chromatographed on silica. The column is washed with DCM and then eluted with AcOEt to give the expected product. m 0.1 g. M.p. 192-195'C.
73 EXAMPLE 19 5-Ethoxy-1,3-dihydro-l-[2-methoxy-4-(N-methyl- N-(2-methylallyl)amino)benzenesulfonyl]-3-spirocyclohexaneindol-2-one A) 5-Ethoxy-l, 3-dihydro-l-[2-methoxy-4-(N-methylamino)benzenesulfonyl]-3-spirocyclohexaneindol-2-one 2 g of the compound prepared in Example 1 step cooled in an ice bath to 10'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 cyanoborohydride 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 phase is decanted, dried and then chromatographed twice in succession on silica using a DCM/heptane mixture (85/15; then pure DCM and finally a DCM/AcOEt mixture (98/2; v/v) as the eluent to give the expected compound. m 0.36 g. M.p. 157C.
B) 5-Ethoxy-1,3-dihydro-1- [2-methoxy-4-(N-methyl-N-(2methylallyl)amino)benzenesulfonyl]-3-spirocyclohexaneindol-2-one A mixture containing 500 mg of the compound obtained in the previous step, 10 ml of DMF, 0.5 ml of diethylamine and 0.5 ml of 3-chloro-2-methylpropene is refluxed for 10 hours. The reaction medium is poured into a water/ice mixture and then extracted with AcOEt, washed with water and chromatographed on silica using DCM as the eluent. The expected compound crystallizes from pentane. m 190 mg. M.p. 118'C.
IL Il The compounds according to the invention described in Table 3 below were prepared by following the procedures described in the previous Examples.
TABLE 3 R1,
R
3 a a.
a a a'.
*aa.
a a.
a a
OCH
3 a.
a. a a.
Example R 1
CR
3
R
4 R6M.p.*C Cl- cyclohexane 1[N-179
K
21 EtO- 4,4-dimethyl IN-167 cyclohexane 22 CI- cyclohexane EtOCOCHf 2 NHCONH- 167 (b) TABLE 3 (continuation) Example R 1
CR
3
R
4 R6M.p.*C
S
S S Cl- EtO- EtO- EtO- EtO- EtO- EtO- EtO- EtOcyclohexane cyclohexane cyclohexane cyclohexane cyclohexane cyclohexane.
cyclohexane cyclohexane cyclohexane
N-CONH-
me
DN-CONH-
Me Me -N N-CONH- McONCQNH- Me MeNH(C11 2 2
NCONH-
Me
HONCONH-
Me
HOCWCH
2
NCONH-
Me
KN-CONH-
CN-CONH-
139 150 197 177 170 hydrochloride monohydrate 185 128 139 210
A.
TABLE 3 (continuation) Example R 1
CR
3
R
4 R6M.p.*C EtO- cyclohexane 4. 4 4 4.
V 33
(C)
34
(C)
(C)
36
(C)
37
(C)
38
(C)
39
(C)
EtO- EtO- EtO- EtO- EtO- DtO- EtOcyclohexane cyclohexane cyclohexane cyclohexane cyclohexane cyclohexane cyclohexane 0 -CO I 0 N-CONH-
SN-CONH-
Me
N-CONH-
Me
NCONH-I.
MeN(CH2,,NCONH Me Et Ph N(:-CONH- MeN(CH'2)fNCONH- 190 212 179 146 198 208 hydrochloride monohydrate 195 200 fumarate TABLE 3 (continuation) Example RI CR 3
R
4 R6 M.p.*C *000 0@ 0o 0 0* 0 0 00 0000 *000 0 0* (c) 41 (d) 42 (d) 44
(C)
(e) 46 (e) 47 (e) 48
(C)
EtO- cyclohexane
-N
(CH2,) 2
NCQNH
-I
me I d- EtO- EtO- EtO- EtO- EtO- EtO- 4,4-dimethylcyclohexane 4,4-dimethylcyclohexane cyclohexane cyclohexane cyclohexane cyclohexane cyclohexane
S
'I
Et 2
NCNH-
S
11 Et 2
NCNH-
0
J-CH
2
NHCO-
CF
3
CH
2 7NHCO-
[DNHCO-
&~NHCO-
DN-
NHCO-
159 179 146 189 210 196 155 204 L I TABLE 3 (continuation) Examplc RI CR 3
R
4 R6Mop.*C
S
*5 *5 *55*
S
S.
SO
EtO- EtO- EtO- EtO- EtO- EtO- EtO- Cl- 53 (e) cyclohexane cyclohexane cyclohexane cyclohexane cyclohexane cyclohexane cyclohexane
(CH'
2 2 0 0
C
(CH
2 2 0-0 0 H2)NCOCH2)NHCQ- Et2N-COCH 2
NHCO-
(Et2N-COCH 2 2
NCO-
NC-C(Mc) 2
NHCO-
Et 2
NC(NH)NH-
CH
3
O-
-LCH
2
NHCO-
EtO(CH 2 2
NHCO-
143 166 245 161 141 198 137 hydrochloride hemihydrate 136
S.
5* S 55 S S
SS
I -J 79 TABLE 3 (contin.ation) 9* *4* Example R 1
CR
3
R
4
R
6 M.p.C 57(1) EtO- 2 88 /C OCH 2 Et 2
NCONH-
OCH3 58(1) EtO- O- Et 2 NCONH- 130 C OH This compound is prepared by the procedure 5 described in EXAMPLE 2 step the reaction being carried out under an inert atmosphere using triethylamine as the base.
This compound is prepared by the procedures described in EXAMPLE 9 step A) and then step B) using the appropriate amino derivatives or nitrogen heterocycles.
This compound is prepared by the procedure described in EXAMPLE 9 step B) using the appropriate amino derivatives or nitrogen heterocycles.
This compound is prepared by the procedures described in EXAMPLE 16 step A) and then step B).
This compound is prepared by the procedure described in EXAMPLE 6 step D) using the appropriate amines.
This compound is prepared by the procedure described in EXAMPLE 17 using N,N-diethylcyanamide.
This compound is prepared by the procedure described in EXAMPLE 1 step A) using 2,4-dimethoxybenzenesulfonyl chloride and the appropriate indol-2one.
This compound is prepared by the procedure described in EXAMPLE 68 starting from the compound obtained in EXAMPLE 57 (mixture of isomers).
mixture of isomers EXAMPLE 59 5-Ethoxy-1-[4-(N',N'-diethylureido)-2-methoxybenzenesulfonyl]-1,3-dihydro-3-spiro(4-oxocyclohexane)indol-2-one 0.25 hydrate A mixture of 0.3 g of the compound obtained in EXAMPLE 68, 0.3 g of pyridinium chlorochromate and ml of DCM is stirred for 16 hours at RT. 10 ml of :%to water are added to the reaction mixture, the DCM is t evaporated off under vacuum, the residue is extracted *0 15 with AcOEt and dried over magnesium sulfate and the solvent is concentrated under vacuum. The residue is chromatographed on silica using a DCM/MeOH mixture (98/2; v/v) as the eluent to give 0.26 g of the expected product. M.p. 100*C.
EXAMPLE 5-Fluoro-1,3-dihydro-l-[2-methoxy-4-(D3-pyrrolin-l-yl)benzenesulfonyl]-3-spiro(4,4-dimethylcyclohexane)indol-2-one SThis compound is prepared by the procedure 25 described in EXAMPLE 2 step the reaction being carried out under an inert atmosphere using triethylamine as the base.
EXAMPLE 61 5-Chloro-3,3-dihydroxyethyl-1,3-dihydro-l-(2,4dimethoxybenzenesulfonyl)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 is heated at about for 3 hours. The solvent is evaporated off under 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; M.p. 166'C.
EXAMPLES 62 and 63 5-Ethoxy-l,3-dihydro-l-(2-methoxy-4-nitrobenzenesulfonyl)-3-spiro[4-(methoxymethoxy)cyclohexane]indol-2-one, the less polar isomer and the more polar 10 isomer These compounds are prepared by the procedure described in EXAMPLE 1 step starting from 1,3-dihydro-3-spiro[4-(methoxymethoxy)cyclohexane]indol-2-one. They are chromatographed on silica using a 15 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.
SEXAMPLES 64 and 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 procedure described in EXAMPLE 1 step starting from the mixture of compounds obtained in EXAMPLES 62 and 63 before chromatography. 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. 103'C; the more polar isomer: compound of EXAMPLE 65, m.p. 111'C.
pip -e~arpm 82 EXAMPLE 66 5-Ethoxy-l-[4-(N',N'-diethylureido)-2-methoxybenzenesulfonyl]-1,3-dihydro-3-spiro[4-(methoxymethoxy)-cyclohexane]indol-2-one, the less polar isomer This compound is prepared by the procedure described in EXAMLE 9 step A) and then step B) starting from the compound obtained in EXAMPLE 64 and using diethylamine in the 2nd step. The expected product is obtained after recrystallization from a cyclohexane/ AcOEt mixture. M.p. 160'C.
EXAMPLE 67 5-Ethoxy-l-[4-(N',N'-diethylureido)-2-methoxybenzenesulfonyl]-1,3-dihydro-3-spiro[4-(methoxymethoxy)cyclohexane]indol-2-one, the more polar isomer 15 This compound is prepared by the procedure described in EXAMPLE 9 step A) and then step B) starting from the compound obtained in EXAMPLE 65 and using diethylamine in the 2nd step. The expected Sproduct is obtained after recrystallization from a cyclohexane/ AcOEt mixture. M.p. 137'C.
EXAMPLE 68 5-Ethoxy-l-[4-(N',N'-diethylureido)-2-methoxybenzenesulfonyl]-1,3-dihydro-3-spiro(4-hydroxycyclohexane)indol-2-one monohydrate, the less polar isomer S" 25 A solution of 2.2 g of the compound obtained in EXAMPLE 66 in 6 ml of MeOH and 1.2 ml of concentrated HC1 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 is 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.
-~p 83 EXAMPLE 69 5-Ethoxy-l-[4-(N',N'-diethylureido)-2-methoxybenzenesulfonyl]-1,3-dihydro-3-spiro(4-hydroxycyclohexane)indol-2-one monohydrate, the more polar isomer This compound is prepared by the procedure described in EXAMPLE 68 starting from the compound obtained in EXAMPLE 67. The expected product is obtained after recrystallization from a cyclohexane/AcOEt mix ture. M.p. 144'C.
EXAMPLE 5-Ethoxy-1,3-dihydro-l-(2-methoxy-4-nitrobenzenesulfonyl)-3-spiro(4-methoxycyclohexane)indol-2-one, the more polar isomer This compound is prepared by the procedure described in EXAMPLE 1 step starting from the more polar isomer of 5-ethoxy-1,3-dihydro-3-spiro(4-methoxycyclohexane)indol-2-one (compound of Preparation 17).
The expected product is obtained. M.p. 141'C.
SEXAMPLE 71 l-(4-Amino-2-methoxybenzenesulfonyl)-5-ethoxy- 1,3-dihydro-3-spiro(4-methoxycyclohexane)indol-2-one, the more polar isomer This compound is prepared by the procedure described in EXAMPLE 1 step starting from the compound obtained in EXAMPLE 70. M.p. 199*C.
EXAMPLE 72 5-Ethoxy-l-[4-(N',N'-diethylureido)-2-methoxybenzenesulfonyl]-1,3-dihydro-3-spiro(4-methoxycyclohexane)indol-2-one, the less polar isomer A) 5-Ethoxy-l,3-dihydro-l-(2-methoxy-4-nitrobenzenesulfonyl)-3-spiro(4-methoxycyclohexane)indol-2-one, the less polar isomer This compound is prepared by the procedure described in EXAMPLE 1 step starting from the compound obtained in Preparation 16 (the less polar isomer).
84 B) 1-(4-Amino-2-methoxybenzenesulfonyl)-5-ethoxy-1,3dihydro-3-spiro(4-methoxycyclohexane)indol-2-one, the less polar isomer This compound is prepared by the procedure described in EXAMPLE 1 step starting from the compound obtained in the previous step.
C) 5-Ethoxy-l-[4-(N',N'-diethylureido)-2-methoxybenzenesulfonyl]-1,3-dihydro-3-spiro(4-methoxycyclohexane)indol-2-one, the less polar isomer This compound is prepared by the procedure Sdescribed in EXAMPLE 9 step A) and then step B) starting from the compound obtained in the previous em step and using diethylamine. M.p. 118 0
C.
EXAMPLE 73 15 5-Ethoxy-l-[4-(N',N'-diethylureido)-2-methoxybenzenesulfonyl]-1,3-dihydro-3-spiro(4-methoxycyclohexane)indol-2-one, the more 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 EXAMPLE 71 and using diethylamine in the 2nd step. The expected of* product is obtained after recrystallization from a cyclohexane/ AcOEt mixture. M.p. 164*C.
2 EXAMPLE 74 5-Ethoxy-1,3-dihydro-l-(2-methoxy-4-nitrobenzenesulfonyl)-3-spiro(4-hydroxycyclohexane)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 HC1 in 6 ml of MeOH is heated at 50"C for 1 hour. 10 ml of water are added to the reaction mixture and the precipitate formed is filtered off, washed with water and dried under vacuum at 50'C to give 1.3 g of the expected product. M.p. 135'C.
EXAMPLE 5-Ethoxy-l-[4-(N',N'-diethylureido)-2-methoxybenzenesulfonyl]-1,3-dihydro-3-spiro(4-ethoxycyclohexane)indol-2-one A) 5-Ethoxy-1,3-dihydro-1-(2-methoxy-4-nitrobenzene sulfonyl)-3-spiro(4-ethoxycyclohexane)indol-2-one A solution of 0.25 g of 5-ethoxy-1,3-dihydro- 1-(2-methoxy-4-nitrobenzenesulfonyl)-3-spiro(4-hydroxycyclohexane)indol-2-one (prepared by the procedure described in EXAMPLE 74 starting from the mixture of isomers obtained in EXAMPLES 62 and 63 before chromatography), 0.6 ml of 2,6-di-tert-butylpyridine and 0.37 ml of ethyl trifluoromethanesulfonate in DCM is stirred for 6 hours at 40*C. 5 ml of 5 N HC1 are added to the reaction mixture, extraction is carried S2 out with AcOEt, the organic phase is washed three times with 0.5 N HC1 and with a saturated solution of NaC1 and dried over magnesium sulfate and the solvent is 0evaporated 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.
20 B) 1-(4-Amino-2-methoxybenzenesulfonyl)-5-ethoxy-1,3dihydro-3-spiro(4-ethoxycyclohexane)indol-2-one This compound is prepared by the procedure described in EXAMPLE 1 step 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-phenoxycarboxamidobenzenesulfonyl)-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 benzenesulfonylJ 3-dihydro-3-spiro( 4-ethoxycyclohexane )indol-2-one This compound is prepared by the procedure described in EXAMPLE 9 step B) starting f rom the compound obtained in the previous step and diethylamine. The expected product is obtained. M.p.
=121VC.
EXAMPLE 76 5-Ethoxy-1-[4-(N' -diethylureido)-2-methoxybenzenesulfonylJ 3-dihydro-3-spiro (4-C 2-methoxyethoxy )cyclohexane] indol-2-one A) 5-Ethoxy-l, 3-dihydro-1- (2-methoxy-4-nitrobenzenesulfonyl )-3-spiro (2-methoxyethoxy )cyclohexane) indol-2-one A mixture of 0.2 g of 5-ethoxy-l,3-dihydro- 1- (2-nethoxy-4-nitrobenze 3sulfonyl )-3-spiro( 4-hydroxycyclohexane)indol-2-one, 2 g of 1-iodo-Z-methoxyethane, 0.9 ml of 2,6-di tert-butylpyridine and 2.15 g of silver trifluoromethanesulfonate in 17 ml Of CCl 4 and 8 ml of DCM is stirred for 24 hours at RT. 100 ml of 0.1 N HUl 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 residuc 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.
B) 1-C 4-Axnino-2-methoxyber'zenesulfonyl )-5-ethoxy-1, 3dihydro-3-spiro[4-( 2-methoxyethoxy )cyclohexane] indol-2one This compound is prepared by the procedure described in EXAMPLE 1 step B'I) by reduction of the compound obtained in the previous step. The expected product is obtained. M.p. 118*C.
C) 5-Ethoxy-l, 3-dihydro-l- (2-methoxy-4-phenoxycarbox- 87 amidobenzenesulfonyl )-3-spiro (2-methoxyethoxy cyclohexane] 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' -diethylureido)-2-methoxybenzenesulfonylj 3-dihydro-3-spiro IA- (2-methoxy- 10 ethoxy)cyclohexane] indol-2-one This compound is prepared by the procedure a. 0 described in EXAMPLE 9 step B) starting from the compound obtained in the previous step and 0 diethylamine. The expected product is obtained.
Goo. 15 M.p. 989c.
EXAMPLE 77 0:9.5-Ethoxy-1- (N',N'-diethylureido) -2-methoxybenzenesulfonyl] 3-dihydro-3-spiro( 4-n-propoxycyclohexane )indol-2-one 270 This compound is prepared by the procedures described in EXAMPLE 76 step A) starting from 1 ,3-dihydro-1- C2-methoxy-4-nitrobenzenesulfonyl .6.:*,spiro( 4-thydroxycyclohexane )indol-2-one and 1-iodopro- :pane in benzene, and then steps C) and The expected product is obtained. M.p. 1159C.
EXAMPLE 78 5-Ethoxy-1- ,N'-diethylureido )-2-methoxybenzenesulfonylJ 3-dihydro-3-spiro( 4-isopropoxycyclohexane )indol-2-one hemihydrate This compound is prepared by the procedures described in EXAMPLE 76 step A) starting from oxy-1, 3-dihydro-l-( 2-methoxy-4-nitro*-enzenesulfony.) -3spiro( 4-hydroxycyclohexane )indol-2-one and 2-iodopropane in benzene, and then steps C) and The expected product is obtained. M.p. 1300C.
88 EXAMPLE 79 5-Ethoxy-l-[4-(N',N'-diethylureido)-2-methoxybenzenesulfonyl]-1,3-dihydro-3-spiro[4-(2-tert-butoxyethoxy)cyclohexane]indol-2-one This compound is prepared by the procedures described in EXAMPLE 76 step A) starting from oxy-1,3-dihydro-l-(2-methoxy-4-nitrobenzenesulfonyl)-3spiro(4-hydroxycyclohexane)indol-2-one and l-iodo-2tert-butoxyethane, and then steps C) and The 10 expected product is obtained. M.p. 103*C.
**EXAMPLE 5-Ethoxy-l-[4-(N',N'-diethylureido)-2-methoxybenzenesulfonyl]-1,3-dihydro-3-spiro[4-(2-hydroxyethoxy)cyclohexane]indol-2-one A mixture 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 S'solution of NaHCO 3 are added, the mixture is decanted, the organic phase is washed with water and dried over 20 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. 109C.
EXAMPLE 81 5-Ethoxy-l-[4-(N',N'-diethylureido)-2-methoxybenzenesulfonyl]-1,3-dihydro-3-spiro(4-formyloxycyclohexane)indol-2-one, the more polar isomer A mixture of 0.25 g 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 added, the reaction mix ture is extracted with AcOEt, 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 recrystallization from a cyclohexane/AcOEt mixture.
M.p. 155'C.
EXAMPLE 82 5-Ethoxy-l-[4-(N',N'-diethylureido)-2-methoxybenzenesulfonyl]-1,3-dihydro-3-spiro(4-acetoxycyclohexane)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 10 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 chromatographed on silica using a DCM/cyclohexane mixture as the eluent to give the expected product after recrystallization from iso ether. M.p. 140*C.
:.EXAMPLE 83 5-Ethoxy-1,3-dihydro-l-(2,4-dimethoxybenzenesulfonyl)-3-spiro(8,9-dihydroxytricyclo[5.2.1.0 2 6 20 decan-4-yl)indol-2-one A) 5-Ethoxy-l,3-dihydro-l-(2,4-dimethoxybenzenesulfonyl)-3-spiro(8,9-epoxytricyclo[5.2.1.02, 6 ]decan- 4-yl)indol-2-one A mixture of 0.3 g of 5-ethoxy-l,3-dihydro- 1- (2,4-dimethoxybenzenesulfonyl)-3-spiro(tricyclo- [5.2.1.0 2 6 ]dec-8-en-4-yl)indol-2-one and 0.2 g of metachloroperbenzoic acid in 20 ml of DCM is stirred for 3 hours at RT. 15 ml of a saturated solution of NaHCO 3 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 using DCM as the eluent to give 0.25 g of the expected product after recrystallization from an acetone/DCM mixture. M.p. 263'C.
B) 5-Ethoxy-l,3-dihydro-l-(2,4-dimethoxybenzenesul-
I
fonyl)-3-spiro(8,9-dihydroxytricyclo[5.2.1.0 2 ,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 by the addition of a saturated solution of NaHCO 3 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 DCM/MeOH mixture (99/1; v/v) as the eluent to give 0.17 g of the expected product. M.p. 150*C.
Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of 2 a stated integer or group of integers but not the exclusion of any other integer or group of integers.
3 *o .5:f30
Claims (13)
1. A compound of the formula jR3 N (R 6 )m 5 in which R, and R 2 are each independently a hydrogen; a hydroxyl; an co-halogeno-Cl-C 7 -alkoxy; a halogen; a C 1 C 7 -alkyl; a trifluoromethyl; a Cl-C 7 -alkoxy; a polyhalogeno-Cl-C 7 -alkoxy; an wo-hydroxy-C 2 -C 7 -alkoxy.; an o0-methoxyalkoxy in which the alkyl is C 2 -C 7 an co- amino-C 2 -C 7 -alkoxy which is free or substituted by one *or two Cl-C 7 -alkyls; a C 3 -C 7 -cycloalkoxy; a cycloalkylmethoxy in which the cycloalkyl is C 3 -C 7 a phenoxy; a benzyloxy; a Cl-C 7 -alkylthio; a phenylthio; a nitro; an amino which is f ree or substituted by one or two Cl-C 7 -alkyls; a cyano; a (Cl-C 6 )alkylcarbonyl; a formyl; a (Cl-C 6 )alkylcarbonyloxy; a formyloxy; a C 1 C 7 -alkylsulfonamido; a phenylsulfonamido; a benzylsulfonamido; a Cl-C 7 -alkylamido; a C 1 C 7 alkoxycarbonylamino; a ureido which is unsubstituted or substituted by a phenyl, a benzyl or one or two Cl-C 7 alkyls; or a thioureido which is unsubstituted or substituted by a phenyl, a benzyl or one or two Cl-C 7 alkyls; R 3 and R 4 are each independently a Cl-C 7 -alkyl; a C 3 C 7 -cycloalkyl; a phenyl; a benzyl; a cycloaJlkylmethyl 92 in which the cycloalkyl is C 3 -C 7 or an O-hydroxy-C 2 C 7 -alkyl in which the hydroxyl is free or substituted by a group selected from C 1 -C 4 -alkyl groups, (C 1 -C 5 alkoxyalkyl groups in which the alkyl is C 1 -C 4 phenylalkoxyalkyl groups in which the alkoxy is C 1 -C 2 and the alkyl is C 1 -C 4 and tetrahydrofuranyl and tetrahydropyranyl groups; or R 3 and R 4 together form a group -(CH2)pX(CH2)q-; 10 or R 3 and R 4 together with the carbon to which they are bonded, form an optionally fused, saturated or unsaturated C 3 -C 12 hydrocarbon ring which is unsubstituted or substituted by one or more C 1 -C 7 -alkyl groups, by an oxo group, by a C 3 -C 5 -spirocycloalkyl or by one or two hydroxyls which are free or substituted by a group selected from C 1 -C 4 -alkyl groups, (CI- to: C 5 )alkoxyalkyl groups in which the alkyl is Cl- C 4 0- hydroxyalkyl groups in which the alkyl is Cl- C 4 !0"0 20 triphenylmethoxyalkyl groups in which the alkyl is C 1 C 4 phenylalkoxyalkyl groups in which the alkoxy is Cl- C 2 and the alkyl is C 1 -C 4 and tetrahydrofuranyl, tetrahydropyranyl, formyl and (C 1 -C 7 )alkylcarbonyl o* o groups; R 5 and R 6 are each independently a hydrogen; a halogen; a C 1 -C 7 -alkyl; a trifluoromethyl; a cyano; a nitro; an amino which is free or substituted by one or two C 1 -C 7 -alkyls; a hydroxyamino; a hydroxyl; a carboxyl; a guanidino which is unsubstituted or mono substituted or disubstituted by a C 1 -C 7 -alkyl, a phenyl or a benzyl; a group -OR 7 a group -SR 7 a (C 1 C 6 )alkylcarbonyl; a formyl; a C 1 -C 7 -alkoxycarbonyl; a phenoxycarbonyl; a benzyloxycarbonyl; a carbamoyl substituted by groups R' 6 and a thiocarbamoyl which is free or substituted by one or two C 1 -C 7 alkyls; a sulfamoyl; an alkylsulfamoyl or L--L I dialkylsulfamoyl in which the alkyl is C 1 -C 7 a group SO 2 R' 7 an alkylsulfonamido in which the alkyl is C 1 C 7 a phenylsulfonamido; a benzylsulfonamido; a group COR' 7 a group -NR 8 R 9 or a group -CO-NH- CR 1 0 R' 1 0 COR 12 if appropriate, the phenyl group forming part of the substituent R 5 and/or R 6 can be unsubstituted or monosubstituted or polysubstituted by a C 1 -C 7 -alkyl, a trifluoromethyl, a C 1 -C 7 -alkoxy, a halogen, a sulfamoyl, an alkylsulfamoyl in which the alkyl is C 1 10 C 7 a carboxyl, an alkoxycarbonyl in which the alkyl is C 1 -C 7 a (C 1 -C 6 )alkylcarbonyloxy or an imidazolyl; R' 6 and R"'6 are each independently hydrogen; a C 1 C 7 alkyl which is unsubstituted or substituted by one or more halogens or RR" a C 3 -C 7 -cycloalkyl which is unsubstituted or substituted by a (C 1 -C 4 )alkyl; a phenyl; a pyridyl; a methylpyridyl; a piperidin-4-yl; a methylpiperidin-4-yl; or a pyrrolidin-l-yl; or R' 6 and I R"g'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 C 1 -C 7 -alkyls; R"' 6 is a hydroxyl; a C 1 -C 7 -alkoxy; an amino which is free or substituted by one or two C 1 -C 7 -alkyls; a carbamoyl which is free or substituted by one or two C 1 -C 7 -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 Cl- C 7 -alkyl or a benzyl; a phenyl; a C 3 -C 7 -cycloalkyl; an adamantyl; or a heterocyclic radical selected from pyridyl, methylpyridyl, furanyl, tetrahydrofuranyl, thienyl, methylthienyl, pyrrolidino, piperidino and perhydroazepino groups; R is a C 1 -C 7 -alkyl; a phenyl; a benzyl; a C3-C7- cycloalkyl; a C 2 -C 7 -alkenyl; an o-halogeno-C 2 -C 7 alkyl; a polyhalogeno-C 1 -C 7 -alkyl; an w-hydroxy-C 2 C 7 alkyl; a (Cl-C 6 )alkylcarbonyl; a formyl; an w0- carboxy- Cl-C 7 -alkyl which Is free or esterifted by a C-7 alkyl or a benzyl; an '0-amino-C 2 -C 7 -alkyl in which the amino group is free, substituted by one or two C 1 -C 7 alkyls or in the form of an ammonium ion; or an CO- carbamoyl-Cl-C 7 -alkyl which is free or substituted by one Or two Cl-C 7 -alkyls; RT 7 is a piperazin-l-yl group which is unsubstituted or substituted in the 4-position by a group R 1 7 a .0:0 10 piperidino group which is unsubstituted or substituted *0*0~in the 4-position by a group RI I I an azetidin- l-yl group which is unsubstituted or substituted in the 3- position by a group R111 7 or a pyrrolidino group which is unsubstituted or substituted by a group R11? 7; R' '7 is a Cl-C 7 -alkyl; a phenyl; a benzyl; a (lC) alkylcarbonyl; or a formyl; -R111 7 is R'' 7 or an amino which is free or carries a x. protecting group; R'11''7 is R' or a carboxyl group which is free or esterified by a Cl-C 7 -alkyl; -R 8 and R9 are each independently a hydrogen; a C-7 alkyl; a benzyl; or a phenyl; R 9 can also be a C-B ~:.alkene; a (Cl-C 6 )alkylcarbonyl; a formyl; a (Cl-C 6 0* alkyithiocarbonyl; a cycloalkylcarbonyl in which the cycloalkyl is C 3 -C 7 a cycloalkyithiocarbonyl in which the cycloalkyl is C 3 -C 7 an 0o-amino(C 2 -C6) alkylcarbonyl; an (0-hydroxy(Cl-C 6 )alkylcarbonyl; an o)- benzyloxy( Cl-C 6 alkylcarbonyl; a phenoxycarbonyl; a phenoxythiocarbonyl; a thienocarbonyl; a pyridylcarbonyl; a methylpyridylcarbonyl; a C-7 alkoxycarbonyl; a benzoyl; a phenacetyl; a group -CO- CR 1 0 R' 1 0 NR 1 1 R' 1 1 a group -CR 1 0 R' 1 0 C0R 1 2 a group (CH 2 )tCO R 1 2 ;a roup 0 CQ(CH 2 COR1 2 a carbamoyl which is3-- tvLR' substituted by R 1 4 and R1 1 4 a thiocarbamoyl which is unsubstituted or substituted by R 1 4 and R' 1 4 or a heterocyclic radical selected UNVISMON from pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyridyl and thiazolyl groups; or R 8 and Rg, together with the nitrogen atom to which they are bonded, form hydantoin; N-methylhydantoin; or a heterocycle selected from pyrrol-l-yl, A3- pyrrolin- l-yl, pyrrolidin-l-yl and isoindolin-2-yl in which the benzene ring can be unsubstituted or substituted by a halogen, a C i -C 7 -alkyl, a trifluoro methyl or a methoxy; R 10 and R'10 are each independently hydrogen; a C 1 C 7 -alkyl; or a benzyl; or R 10 and R' 1 0 together with the carbon atom to which they are bonded, form a C 3 C 7 -cycloalkyl; R 11 and R' 11 are each independently hydrogen; or a C 1 -C 7 -alkyl; R 12 is a hydroxyl; a C 1 -C 7 -alkoxy; or an amino which is unsubstituted or substituted by one or two C 1 -C 7 alkyls; R 1 3 is hydrogen; a C 1 -C 7 -alkyl; a phenyl; a benzyl; a (C 1 -C6)alkylcarbonyl; a formyl; a C 1 -C 7 -alkoxycarbonyl; or a carbamoyl which is unsubstituted or substituted by one or 2 C 1 -C 7 -alkyls; 25 R 14 and R' 1 4 are each independently a hydrogen atom; hydroxy; C l -C 7 alkoxy; Ci-C 7 -alkyl which is unsubstituted or substituted by R 15 a phenyl which is unsubstituted or substituted by R' 1 5 a C3-C 7 Scycloalkyl; or an adamantyl; or R 14 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; which is free or carries a protecting group; CIon R 15 is a phenyl; a pyridyl; a hydroxyl; a C1-C 7 alkoxy; an amino which is free or substituted by one or two C 1 -C 7 -alkyls; or a carboxyl which is free or esterified by a C 1 -C 7 -alkyl; R' 1 5 is a hydroxyl; or an amino which is free or substituted by one or two C 1 -C 7 -alkyls; m is 1 or, if R 6 is a halogen, a C 1 -C 7 -alkyl or a C 1 C 7 -alkoxy, m can also be 2, 3 or 4, or else (R6g) can be m substituents having different meanings selected from halogen, C 1 -C 7 -alkyl and C 1 -C 7 -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 t' is an integer which can vary from 0 to 3; X is oxygen; a group S(O)n; a group NR 13 or a group N(0)R 13 and n is 0 1 or 2; provided that when one of R 3 and R 4 is methyl or ethyl, the other being methyl; m=l and one of R 5 and R 6 is hydrogen, the other is different from p-methyl with the further limitation that if S:e R 1 and R 2 are as defined above with the exception of the ureido group substituted by a benzyl group, or the 25 thioureido group which is unsubstituted or substituted by a phenyl, a benzyl or one or two Cl- C 4 -alkyls; R 3 and R 4 are each independently a C 1 -C 6 -alkyl; a C 3 C 7 -cycloalkyl; a phenyl; a benzyl; or a cycloalkyl- methyl in which the cycloalkyl is C 3 -C 7 S. 30 or R 3 and R 4 together form a group -(CH 2 )pX(CH 2 q in which X is oxygen, sulfur or a group NR 13 or R 3 and R 4 together with the carbon to which they are bonded, form an optionally fused, saturated or I L M 96A unsaturated C 3 -C 10 hydrocarbon ring which is unsubstituted or substituted by one or more C 1 -C 7 -alkyl groups or by a C 3 -C 5 -spirocycloalkyl; R 5 and R 6 are other than a hydrogen; a halogen; a C 1 C 7 -alkyl; a trifluoroniethyl; a cyano; a nitro; an amino 0~*9 0~ a. a. a 09 ~0 S 0 0* S a. a a *.a SO'S a. On. Oe ~t a S a. so 0 S a 00 S Sa a 0 which is free or substituted by one or two C 1 C 7 alkyls; a hydroxyamino; a hydroxyl; a oarboxyl; a group -OR 7 a group -SR 7 a (Cl-C 6 )alkylcarbonyl; a formyl; a C 1 -C 7 -alkoxycarbonyl; a phenoxycarbonyl; a benzyloxycarbonyl; a carbamoyl substituted by groups R1 6 and R'' 6 a thiocarbamoyl which is free or substituted by one or two Cl-C 7 -alkyls; a sulfamoyl; an alkylsulfamoyl or dialkylsulfamoyl in which the alkyl is Cl-C 7 a group -SO 2 R' 7 an alkylsulfonamido in which the alkyl is Cl-C 7 a group -COR' 7; a group -NR 8 R 9 or G~e .a group -CO-NH-CH(Rl 0 )-C0R 1 2 it being possible, if appropriate, for the phenyl group forming part of the **esubstituent R 5 and/or R 6 to be unsubstituted or monosubstituted or polysubstituted by a Cl-C 7 -alkyl, a trifluoromethyl, a methoxy, a halogen, a sulfamoyl, an alkylsulfamoyl in which the alkyl is Cl-C 7 a carboxyl, an alkoxycarbonyl in which the alkyl is C 1 -C 7 a C-6 alkylcarbonyloxy; a formyloxy or an imidazolyl; in which groups R 5 and/or R 6 R' 6 and R '6 are each independently hydrogen; a Cl- to.. C 7 alkyl which is unsubstituted or substituted by o CC:R11 a phenyl; a pyridyl; a methylpyridyl; a piperidin-4- yl; or a methylpiperidin-4-yl; 1 1 6 is a hydroxyl; a cyano; a carboxyl which is free or ester.Lfied by a Cl-C 7 -alkyl or a benzyl; a phenyl; a pyridyl; a methylpyridyl; or an amino which is free or substituted by one or two Cl-C 7 -alkyls; R.7 is a Cl-C 7 -alkyl; a phenyl; a benzyl; a C-7 cycloalkyl; a C 2 -C 4 -alkenyl; an (0-halogeno-C 2 -C 7 alkyl; a polyhalogeno-Cl-C 7 -alkyl; a (CI-C 6 )alkylcar bonyl; a formyl; an w0-carboxy-Cl-C 7 -alkyl which Is free or esterified by a Cl-C 4 -alkyl or a benzyl; or an 0)- amino-C 2 -C 7 -alkyl in which the amino group is free, substituted by one or two Cl-C 4 -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 R1' 7 a piperidino group which is unsubstituted or substi tuted in the 4-position by a group R 1 1 1 7 an azetidin- 1-yl group which is unsubstituted or substituted in the 3- position by a group RI' 7 R'1 7 is a Cl-C 4 -alkyl; a phenyl; a benzyl; or a (Cl- C 3 )alkylcarbonyl; RT 1 7 is R'' 7 or an amino which is free or carries a 10 protecting group; -R 8 and Rg are each independently a hydrogen; a C-7 alkyl; a phenyl; or a benzyl; R 9 can also be a (Cl- C 6 )alkylcarbonyl; a formyl; a cycloalkylcarbonyl in which the cycloalkyl is C 3 -C 7 a cycloalkyithiocarbo nyl in which the cycloalkyl is C>-C 7 an (0-amino(C 2 C 3 )alkylcarbonyl; an O)-hydroxy( Cl-C 3 )alkylcarbonyl; an co-benzyloxy(Cl-C 3 )alkylcarbonyl; a phenoxycarbo nyl; a :thienocarbonyl; a pyridylcarbonyl; a methyl pyridylcarbonyl; a Cl-C 4 -aJlkoxycarbonyl; a benzoyl; a group -CO-CH(Rl 0 )-NR 1 1 R'll; a group -CH(Rl 0 )C0 2 Rll; a aaaagroup -(CH 2 )tfvCORi 2 a group -CO(CH 2 )tICOR1 2 or a carbamoyl which is unsubstituted or substituted by a phei-w. or one or two Cl-C 4 -alkyls; a a- t' is an integer which can vary from 1 to 3; RIO is hydrogen; a Cl-C 4 -alkyl; or a benzyl; R 11 and R' 11 are each independently hydrogen; or a Cl-C 4 -alkyl; Ri 2 is a hydroxyl; a Cl-C 4 -alkoxy; or an amino which is unsubstituted or substituted by one or two Cl-C 4 alkyls; and R1 is hydrogen; a Cl-C 4 -alkyl; a phenyl; a benzyl; a (Cl-C 3 )alkylcarbonyl; a formyl; a Cl-C 4 -alkoxycarbonyl; or a carbaamoyl which is unsubstituted or substituted by one or 2 Cl-C 4 -alkyls; and its salts where appropriate. 99
2. A compound of formula according to claim 1 wherein R 1 is a chlorine or fluorine atom or an ethoxy group in the 5-position of the 1,3-dihydroindol-2-one and R 2 is hydrogen.
3. A compound of formula according to claim 1 or 2 wherein R 3 and R 4 together with the carbon to which they are bonded, form a C 3 -C 12 hydrocarbon ring.
4. A compound of formula according to claim 3 wherein R 3 and R 4 together with the carbon to which 10 they are bonded, form a cycloheptane, an adamantane, a tricyclo[5.2.1.0 2 6 ]dec-8-ene, a tricyclo[5.2.1.02,6] decane, a bicyclo[2.2.1]heptane, a bicyclo[3.3.1lnonane or a cyclohexane which is unsubstituted or substituted by a C 3 -C 5 -spirocycloalkyl or by one or two C 1 -C 7 -alkyl groups.
A compound of formula according to claim 1 or 2 wherein R 3 and R 4 together with the carbon to which they are bonded, form a cyclohexane substituted by a group selected from methoxy, ethoxy and 2-methoxy- 20 ethoxy.
6. A compound of formula according to any one of claims 1 to 5 wherein R 5 is an orthomethoxy group and R 6 in the para-position is a group selected from: (piperidin-l-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 according to claim 1, and its salts, which comprises: 1/ reacting a benzenesulfonyl halide of the formula Hal-S02 (RV (RVI)m i L 100 in which Hal is a halogen atom, preferably chlorine, and R' 5 and RVI are respectively either R 5 and R 6 as defined for in claim 1, or precursor groups of R and R 6 with a 1,3-dihydroindol-2-one disubstituted in the 3-position of the formula R R t R' 3 R'1 R-4 -0 *02 N R (H) 10 H in which R' 1 R' 2 R' 3 and R' 4 are respectively either R 1 R 2 R 3 and R 4 as defined for in claim 1, or precursor groups of R 1 R 2 R 3 and R 4 and 2/ either, if R' 1 R 1 R' 2 R 2 R' 3 R 3 R' 4 R 4 R'5 R 5 and RVI R 6 isolating the resulting compound of formula 3/ or, if any one of the groups R' 1 R' 2 R' 3 R' 4 R' and/or RVI is respectively a precursor group of R 1 R 2 20 R 3 R 4 R 5 and/or R 6 subjecting the compound obtained in step I/ to a subsequent treatment in order to prepare the compound of formula by converting any one of the groups R' 1 R' 2 R' 3 R' 4 R' 5 and/or RVI to R1, R 2 R 3 R 4 R 5 and/or R 6 respectively; and 4/ if desired, converting the resulting compound of formula 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.
I I~IP M 101 A pharmaceutical composition in which two compounds according to any one of claims 1 to 6 are present, one being a specific V 1 receptor antagonist and the other being a specific V 2 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 V 1 receptor antagonist and the other being a specific ocytocin antagonist. 00
12. A compound according to claim 1, a process for the *0 preparation thereof, or a pharmaceutical composition comprising a said compound, substantially as hereinbefore described with reference to the Examples.
13. The steps, features, compositions and compound disclosed herein or referred to or indi n the specification and/or clai is application, individuall lectively, and any and all combinations nyto or more of said steps or features. DATED this TWENTY NINTH day of JULY 1994 Se Sanofi by DAVIES COLLISON CAVE Patent Attorneys for the applicant(s) o'V W, i' r -A I u ABSTRACT OF THE DISCLOSUIRE The invention relates to 1-Benzenesulfonyl-l,3- dihydroindol-2-one derivatives of the formula C C (R 6 )m and their salts, where appropriate, to their preparation and to pharmaceutical compositionsinwchte ar present. These compounds have an affinity for the vasopressin and/or ocytocin receptors. C C C C eC C C CC C CC
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9309404 | 1993-07-30 | ||
| FR9309404A FR2708605A1 (en) | 1993-07-30 | 1993-07-30 | N-sulfonylindol-2-one derivatives, their preparation, pharmaceutical compositions containing them. |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| AU6878994A AU6878994A (en) | 1995-02-09 |
| AU684791B2 true AU684791B2 (en) | 1998-01-08 |
| AU684791C AU684791C (en) | 1998-10-29 |
Family
ID=
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7488743B2 (en) | 2004-09-20 | 2009-02-10 | Sanofi-Aventis | Indolin-2-one pyridine derivatives, preparation and therapeutic use thereof |
| US8324214B2 (en) | 2008-04-21 | 2012-12-04 | Sanofi | 1,3-dihydro-2H-pyrrolo[3,2-bpyridin-2-one derivatives, preparation thereof and therapeutic uses thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7488743B2 (en) | 2004-09-20 | 2009-02-10 | Sanofi-Aventis | Indolin-2-one pyridine derivatives, preparation and therapeutic use thereof |
| US8324214B2 (en) | 2008-04-21 | 2012-12-04 | Sanofi | 1,3-dihydro-2H-pyrrolo[3,2-bpyridin-2-one derivatives, preparation thereof and therapeutic uses thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| RU2141476C1 (en) | 1999-11-20 |
| NZ264122A (en) | 1996-07-26 |
| FI943570A0 (en) | 1994-07-29 |
| FI943570A (en) | 1995-01-31 |
| AU6878994A (en) | 1995-02-09 |
| IL110482A0 (en) | 1994-10-21 |
| FR2708605A1 (en) | 1995-02-10 |
| CN1107467A (en) | 1995-08-30 |
| CA2129215A1 (en) | 1995-01-31 |
| EP0636608A1 (en) | 1995-02-01 |
| NO301824B1 (en) | 1997-12-15 |
| RU94027576A (en) | 1996-05-27 |
| HU9402232D0 (en) | 1994-09-28 |
| TW375609B (en) | 1999-12-01 |
| NO942834D0 (en) | 1994-07-29 |
| NO942834L (en) | 1995-01-31 |
| HUT70408A (en) | 1995-10-30 |
| IL110482A (en) | 1999-04-11 |
| ZA945656B (en) | 1995-03-09 |
| KR950003271A (en) | 1995-02-16 |
| JPH07247269A (en) | 1995-09-26 |
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