NZ249158A - N-sulphonyl-2-oxindole derivatives and pharmaceutical compositions - Google Patents

N-sulphonyl-2-oxindole derivatives and pharmaceutical compositions

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Publication number
NZ249158A
NZ249158A NZ249158A NZ24915893A NZ249158A NZ 249158 A NZ249158 A NZ 249158A NZ 249158 A NZ249158 A NZ 249158A NZ 24915893 A NZ24915893 A NZ 24915893A NZ 249158 A NZ249158 A NZ 249158A
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substituted
alkyl
formula
group
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NZ249158A
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Loic Foulon
Georges Garcia
Dino Nisato
Richard Roux
Claudine Serradeil-Legal
Gerard Valette
Jean Wagnon
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Sanofi Elf
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/90—Benzo [c, d] indoles; Hydrogenated benzo [c, d] indoles
    • C07D209/92—Naphthostyrils
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/96—Spiro-condensed ring systems
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/10—Spiro-condensed systems

Abstract

N-sulphonyl-2-oxoindole derivatives of formula (I), and any salts thereof, preparation thereof and pharmaceutical compositions containing said derivatives. These compounds have an affinity for vasopressin and/or ocytocin receptors.

Description

New Zealand Paient Spedficaiion for Paient Number £49158 New Zealand No. 249158 International No. PCT/FR9 3/0 0093 TO BE ENTERED AFTER ACCEPTANCE AND PUBLICATION Priority dates: 2xr> \ * \ Q.
International filing date: 1^3 Classification:CoH^o^j31+^0,<=»<=>'. ccnDiru/o-. CO~IJ>4.OI /oh, la) 0010403^Q-, Publication date: t< "31/^0 2 7 FEB 1996 Journal No.: ,,, NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION Title of invention: N-sulfonyl-2-oxoindole derivatives, their preparation and the pharmaceutical compositions in which they are present Name, address and nationality of applicant(s) as In international application form: ELF SANOFI, 32-34, Rue Marbeuf, 75008 Paris, France CcK~ O Y ^ — ia N-sulfonvl-2-oxoindole derivatives having affinity for vasopressin and/or ocytocin receptors.
The present invention relates to N-sulfonyl-2-oxoindole derivatives, their preparation and the pharmaceutical compositions in which they are present.
International patent application WO 91/01306 describes 2-oxoindole 5 derivatives which are useful for the treatment of senile dementia. These compounds have the formula in which - R"i is 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; and - R"4 is a 1-propylbutyl, a pyridyl or an optionally substituted phenyl.
Several patent applications have recently described families of compounds with a non-peptide structure which are active on the vasopressin and/or ocytocin receptors. European applications EP 382 185 and EP 444 945, international application WO 91/05 549 and, more particularly, Japanese patent application JP 20 03/127732 can be cited in this respect. The latter describes indole-3-propionic acid derivatives of the formula: 1 COR"4 2 (followed by page 2) 2 24 9 1 in which - R'"i is hydrogen, an alkyl, an alkenyl, a phenylalkyl, a tetrahydrofuiyl, an alkoxycarbonyl, an alkoxycarbonylalkyl, a carboxyalkyl or an alkanoyl; - R"'2 is hydrogen, a hydroxyl, an alkoxy, an alkyl, a phenylalkyl, a phenylalkoxy or a halogen; - R'"3 is a hydrogen, an alkoxy, a free or substituted amino group or an amino acid residue; - R'"4 is hydrogen, an alkyl or a phenylalkyl; and - R'"5 is a benzoyl, a phenyl, an alkyl, a phenylalkenylcarbonyl, a thienylcarbonyl, a phenylsulfonyl, a pyridylcarbonyl or an imidazolylcarbonyl, it being possible for the phenyl and alkyl groups of the substituent R'"5 to be substituted.
These compounds are vasopressin antagonists.
Patent US 4,803,217 claims hapalindolinones obtained by fermentation, which are vasopressin antagonists. These compounds have the following formula: in which R is H or CI.
The N-sulfonyl-2-oxoindole derivatives according to the present invention have an affinity for the vasopressin and ocytocin receptors.
Vasopressin is a hormone known for its antidiuretic effect and its effect in regulating the arterial pressure. It stimulates several types of receptors, namely Vl(Via> vlb) ancI v2» an(* thus exerts cardiovascular, hepatic, antidiuretic and platelet-aggregating effects and effects on the central and peripheral nervous systems. Vasopressin receptor antagonists can affect the regulation of the central and peripheral circulations, especially the coronary, renal and gastric circulations, as well as the regulation of hydration and the release of adrenocorticotrophic hormone (ACTH). Non-peptide agonists of vasopressin can advantageously CH3 R 3 N H 24 n A replace vasopressin or its analogs in the treatment of diabetes insipidus; they ^.n also be used in the treatment of enuresia and in the regulation of hemosta^ s: treatment of hemophilia and of Von Willebrand's syndrom, antidote to platelet-aggregating agents; Drug Investigation, 1990, 2 (Suppl. 5), 1-47. The vasopressin receptors, like the ocytocin receptors, are also found on the smooth muscle of the uterus. Ocytocin has a peptide structure similar to that of vasopressin. Its receptors are also found on myoepithelial cells of the mammary gland and in the central nervous system (Presse medicale, 1987, 16 (10), 481-485, J. Lab. Clin. Med., 1989, 114 (6), 617-632, and Pharmacol. Rev., 1991, 43(1), 73-108). This hormone is involved in parturition, lactation and sexual behaviour.
Thus the compounds according to the invention are useful especially in the treatment of complaints of the central and peripheral nervous systems, the cardiovascular system, the renal sphere and the gastric sphere and in disorders of sexual behavior, in humans and animals.
The present invention relates to compounds of the formula R1 R' Ro / 3 N I SO' 0 (I) -r5 (R6>m in which - Ri and R2 are each independently a hydrogen, a hydroxy, a C1-c4-q)-20 halogenoalkoxy, a halogen, a Ci-C4~alkyl, a trifluoromethyl, a C1-c7-alkoxy, a Ci-c4-polyhalogenoalkoxy, a c2-c4-co-hydroxyalkoxy, an to-methoxyalkoxy in which the alkyl is c2-c4, a c2~c4-o)-aminoalkoxy which is free or substituted by one or two Ci-C4-alkyIs ; a c3-c7-cycloalkyloxy ; a cycloalkylmethoxy in which the cycloalkyl is c3-c7 ; a phenoxy; a benzyloxy; 25 a C^-c4-alkylthio; a phcnylthio; a nitro; an amino which is free or substituted by one or two C^-C4-alkyls; a cyano; a C^-C4-acyl; a Cj-c4-acyloxy; a 249158 Ci-C4-alkylsulfonamido, a phenylsulfonamido, a Cj-C^-alkylamido, a C1-C4-alkoxycarbonylamino, or a ureido which is unsubstituted or substituted by a phenyl or by one or two C4-C4 alkyls; and - R3 and R4 are each independently a C1-C6~alkyl, a C3-C7-cycloalkyl, a phenyl, a benzyl, or a cycloalkylmethyl in which the cycloalkyl is C3-C7; or - R3 and R4 together form a group -(CH2)pX(CH2)q-; or R3 and R4; together with the carbon atom to which they are bonded, form an optionally fused, saturated or unsaturated C3—C^q hydrocarbon ring which is unsubstituted or substituted by one or more C\-Cr]—alkyl groups or by a C3-C5-spirocycloalkyl; or else Rl is as defined above, R4 is a Cj-Cg alkyl, a C3-C7 cycloalkyl, a phenyl, a benzyl, a cycloalkylmethyl in which the cycloalkyl is C3-C7, and R2 is located in the 4-position of the indole and forms a group (CH2)3 with R3; - R5 and Rg are each independently a hydrogen, a halogen, a €^—€7—alkyl, a trifluoromethyl, a cyano, a nitro, an amino which is free or substituted by one or two Ci-C7-alkyls, a hydroxyamino, a hydroxy, a carboxy, a group OR7, a group SR7, a C1-.C7-.acyl, a Ci-C7-alkoxycarbonyl, a phenoxycarbonyl, a 4 benzyloxycarbonyl, a carbamoyl substituted by groups R'g and R"g, a thiocarbamoyl which is free or substituted by one or two C^-C7-alkyls, a sulfamoyl, an alkylsulfamoyl or a dialkylsulfamoyl in which the alkyl is Cj-C7,-a group SC^R^? an alkylsulfonamido in which the alkyl is C1-C7, a group COR'7, a group NRgR^ a group CO-NH-CH(Rio)-COR;l2; ^ appropriate, the phenyl group forming part of the substitutent R5 and/or Rg can be unsubstituted or monosubstituted or polysubstituted by a Ci-Cy-alkyl, a trifluoromethyl, a methoxy, a halogen, a sulfamoyl, an alkylsulfamoyl in which the alkyl is C^-C4, a carboxy, an alkoxycarbonyl in which the alkyl is C1-C7, a C1-C7-acyloxy or an imidazolyl; - R'g and R"g are each independently hydrogen, a C\-C~] alkyl which is unsubstituted or substituted by R"'6, a phenyl, a pyridyl, a methylpyridyl, a piperidin-4-yl, a methylpiperidin-4-yl; N.Z. PATENT OFFICE 2 * MOV 1S35 RECEIVED 24 9 1 58 R'"6 is a hydroxy, a cyano, a carboxy which is free or esterified by a C4-C7-alkyl or by a benzyl; a phenyl; a pyridyl; a methylpyridyl; or an amino which is free or substituted by one or two C\-C7~alkyls; R7 is a Ci-C7-alkyl, a phenyl, a benzyl, a C3-C7-cycloalkyl, a C2-C4-alkenyl, a C^-C7-o)~halogenoalkyl, a Cj-C7-polyhalogenoalkyl, a C4-C7-acyl, a C^-C7-co-carboxyalkyl which is free or esterified by a Ci~C4-alkyl or by a benzyl, or C2-C7&>-aminoaikyl in which the amino group is free, substituted by one or two C^-C4-alkyls or in the form of an ammonium ion; R'7 is a piperazin-l-yl group which is unsubstituted or substituted in the 4-position by a group R"7, a piperidino group which is unsubstituted or substituted in the 4-position by a group R"^, an azetidin-l-yl group which is unsubstituted or substituted in the 3-position by a group R'"7) or a pyridyl group which is unsubstituted or substituted by a methyl; R'*7 is a Ci-C4-alkyl, a phenyl, a benzyl, a C^-C4-acyl; R'"7 is R"7 or an amino which is free or carries a protecting group; Rg and R9 are each independently a hydrogen, a C^-C7-alkyl, a phenyl or a benzyl; or R9 can also be a Ci-C7-acyl, a Ci-C7-thioacyl, a cycloalkylcarbonyl in which the cycloalkyl is C3-C7, a cycloalkylthiocarbonyl in which the cycloalkyl is C3-C7, a Ci-C4-G)-aminoacyl, a Ci-C4~o)-hydroxyacyl, a C]_-C4-w-benzyloxyacyl, a phenoxycarbonyl, a thienocarbonyl, a pyridylcarbonyl, a methylpyridylcarbonyl, a Ci-C4-alkoxycarbonyl, a benzoyl, a phenacetyl, a group CO-CH(Rio)-NRiiR'ii, a group CH(Rio)C02Rn, a group (CH2)tCORi2> a group CCXCHb^CORio, or a carbamoyl which is unsubstituted or substituted by a phenyl or one or two —C4.—alkyls; m is 1, 2, 3, 4 provided that when m is 2, 3 or 4 each Rg substituent is independently selected from a halogen, a Ci-C7-alkyl or a Ci~C7-alkoxy; provided that when m is 1, R3 is methyl, R4 is methyl or ethyl, Rg is not methyl; p and q are each integers, their sum being 3 to 6; t is an integer from 1 to 5; X is oxygen, sulfur or a group NR13; RlO is hydrogen, a Cj-C4-alkyl or a benzyl; Rll and R'11 are each independently hydrogen or a Cj-C4-alkyl; 249158 - R],2 is a hydroxy, a Cj-C^alkoxy or an amino which is unsubstituted or substituted by one or two C4-C4 alkyls; and - R43 is hydrogen, a C^-C4~alkyl, a phenyl, a benzyl, a C^-C4-acyl, a C1-C4-alkoxycarbonyl or a carbamoyl which is unsubstituted or substituted by one or two C4-C4 alkyls; as well as their possible salts.
If a compound according to the invention has one or more asymmetric carbons, the invention includes all the optical isomers of this compound.
The salts of the compounds of formula (I) according to the present invention 10 include those with mineral or organic acids which permit a suitable separation or crystallization of the compounds of formula (I), such as picric acid, oxalic acid or an optically active acid, for example a mandelic acid or a camphosulfonic acid, and mineral or organic acids which form physiologically acceptable salts such as the hydrochloride, hydrobromide, sulfate, hydrogensulfate, di-hydrogenphosphate, 15 maleate, fumarate or naphthalene-2-sulfonate.
The salts of the compounds of formula (I) also include the salts with organic or mineral bases, for example the salts of alkali metal or -alkaline earth metals, such as the sodium, potassium and calcium salts, sodium and potassium salts being preferred, or with an amine such as trometamol, or else the salts of arginine, lysine, 20 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. Amino-protecting group is understood as meaning a group such as, for example, terf-butoxycarbonyl, benzyloxycarbonyl or benzyl. 25 According to the present invention, optionally fused condensed, saturated or unsaturated CyC\Q hydrocarbon ring is understood as meaning various hydrocarbon rings with a monocyclic, dicyclic or tricyclic structure, for example a cyclobutane, a cyclopentane, a cyclohexane, a cycloheptane, a cyclooctane, an indane, a hexahydroindane, an adamantane, a norbomane, a norbornene, a 30 dihydrophenaiene, a tricyclo[5.2.1.02»6]decane or a tricyclo[5.2.1.02>6]dec-8-ene.
The compounds of formula (I) in which is in the 5-position of the indole and R2 is hydrogen are preferred compounds.
The compounds of formula (I) in which R^ is a chlorine atom or an ethoxy group in the 5-position of the indole and R2 is hydrogen arc preferred compounds. 24 0 The compounds of formula (I) in which R3 and together with the carbon to which they are bonded, form a c3-c40 hydrocarbon ring are preferred compounds; particularly preferred compounds are those in which R3 and R^ together with the carbon to which they are bonded, form a cycloheptane, an adamantane, a tricyclo[5.2.1.()2>6]dec-8-ene or a cyclohexane which is unsubstituted or substituted by a c3-c5-spirocycloalkyl or by one or two C4-Cy-alkyl groups.
The compounds of formula (I) in which R3 and R4, together with the carbon to which they are bonded, form a piperidine-4 or N-methylpiperidine-4 ring are also preferred.
The compounds of formula (I) in which R5 and Rg are each a methoxy are preferred compounds. Likewise, the compounds in which R5 in the 2-position is a methoxy and Rg in the 4-position is a C^-Cy-acylamino, a Ci~C4-dialkylureido or an alkoxycarbonylalkylcarbamoyl in which the alkyl groups are C\-Oj are preferred compounds.
The following abbreviations are used in the description and in the examples.
DCM: dichloromethane Ether: ethyl ether Iso ether: isopropyl ether Boc: ferr-butoxycarbonyl Me, MeO : methyl, methoxy Et: ethyl Pr, iPr, nPr: propyl, isopropyl, n-propyl Bu, iBu, tBu: butyl, isobutyl, ferf-butyl Ph: phenyl Bz: benzyl Ac: acetyl AcOEt: ethyl acetate AcOH: acetic acid MeOH: methanol EtOH: ethanol DMF: dimethylformamide THF: tetrahydrofuran DMSO: dimethyl sulfoxide 8 2 4 S ' DIPEA: diisopropylethylamine TEA: triethylamine TFA: trifluoroacetic acid TMEDA: tetramethylethylenediamine M.p.: 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 1N RT: room temperature The present invention further relates to the method of preparing the compounds according to the invention, characterized in that: a benzenesulfonyl halide of the formula : in which R'5 and Ryj are respectively either R5 and Rg as defined above for (I), or precursor groups of R5 and R6 is reacted with a 2-oxoindole disubstituted in the 3-position, of the formula: in which R'j and R'2 are respectively either R^ and R2 as defined above for (I), or precursor groups of Rj and R2, and R3 and R4 are as defined above for (I), - either, if R'i=Ri, R'2=R2> RI5=R5 and RVFR6> resulting compound of formula (I) is isolated; - or, if any one of the groups R'j, R'2, R'5 and Ryi is respectively a precursor group of R]_, R2, R5 and/or Rg, the compound obtained is subjected to a subsequent treatment in order to prepare the compound of formula (I) by VI A>~ L_ 4 K 2 ([I) H 249158 conversion of any one of the groups R'i, R'2, R'5 and Ryj to R}, R2> R5 and Rg, respectively.
The reaction is carried out in an anhydrous solvent such as DMF or THF, in the presence of a metal hydride such as, for example, sodium hydride, or in the 5 presence of an alcoholate such as potassium ferf-butylate.
The 2-oxoindoles (II) can be prepared using different procedures. Some of these compounds are novel and form part of the invention.
Compounds (II) in which R'i and/or R'2 are a halogen and R3 and R4, together with the carbon to which they are bonded, form a spirocyclobutane, a 10 spirocyclohexane or a spirocycloheptane are known, for example in D. W. Robertson et al. J. Med. Chem., 1987, 30 (5), 824-829. Also, 5-chIoro-3-spirocyclopentaneindol-2-one is described in US Patent 3,947,451.
To prepare the compounds (II) in the case where R3 and R4 are together or separately a hydrocarbon group, it is possible to use the Brunner reaction described 15 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 CR3R4 is a cyclopentane or a cyclohexane.
This reaction is carried out by cyclizing a phenylhydrazide derivative of the formula: R' r /R3 -nh-nh-c-ch; r,2^ 5 X w in which R'j and R'2 are as defined above for (II), and R3 and R4 have the meanings indicated above for (I), for example by heating in the presence of 25 calcium oxide and quinoline.
According to the same authors, the phenylhydrazide derivative (TV) is obtained by reacting a hydrazine derivative of the formula: NH-NHo 2 (V) 2 4 9 1 p> in which R'i and R'2 have the meanings indicated above for (H), with an acid halide of the formula: Hal-C-CR-sR/i II 3 4 (VI) o in which R3 and R4 have the meanings indicated above for (I).
According to a particular embodiment, if R3 and R^ together with the carbon to which they are bonded, form a fused polycyclic hydrocarbon, for example norbornane or norbomene, the reaction is carried out by the method described by J. Wolff et al., Tetrahedron, 1986, 42 (15), 4267-4272: first of all, a 10 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(l,2,3,4-tetramethylbenzene).
The compounds (II) in which Rj= R2= H and CR3R4 is adamantane are 15 described in I. Fleming et al., J. Chem. Soc., Perkin Trans I, 1991, 2, 617-626. Thus, the compounds (II) in which R3 and R4, together with the carbon atom to which they are bonded, form an adamantane and Rj and R2 are other than hydrogen, are novel and form part of the invention. They can be prepared by the method described above.
The hydrazine derivatives (V) are known or are prepared by known methods.
The same applies to the acid halides (VI).
A 2-oxoindole disubstituted in the 3-position (II) can also be prepared from a 2-oxoindole of the formula: ;0 „7TTN cm in which R'i and R'2 are as defined above for (II), by using various methods.
For example, the method described by A.S. Kende and J.C. Hodges in Synth. Commun., 1982,12 (1), 1-10, involves the addition of an alkylating agent in an 30 appropriate solvent. Thus, to prepare a compound (II) in which R3 = R4, the reaction is carried out in THF at -75* C, in the presence of TMEDA, by addition of 11 24 an alkyllithium such as butyllithiura, followed by reaction with a halide of the formula I^Hal; if R3 and R4 are different, the alkylating reaction can be performed in two steps with 2 different alkyl halides of the formulae R3Hal and R4Hal. To prepare a compound (H) in which R3 and R4 together form a group of 5 the formula -(CH2)n-> in which n varies from 2 to 7, the reactant used is a compound of formula Z(CH2)nZ> in which Z is an electron-accepting group such as a halogen, preferably bromine or iodine, a tosyloxy group or a mesyloxy group.
The compounds of formula (II) in which R3 and R4 are each independently an alkyl or a phenyl are known. For example, patent DE 3 300 522 describes 5-10 alkoxy-3,3,-dimethylindol-2-ones.
The compounds of formula (II) in which R3 and R4( together with the carbon to which they are bonded, form a C4-C8 hydrocarbon ring substituted by one or more Ci-C7~alkyl groups or by a C3-C5-spirocycloalkyl are prepared in the same manner. These compounds are novel and form part of the invention. 15 If R3 and R4 together form a -(CH2)pX(CH2)q- group, in which p, q and X are as defined above for (I), a 2-oxoindole disubstituted in the 3-position, of formula (II), can be prepared from a 2-oxoindole unsubstituted in the 3-position (VII) by reaction with a compound of the formula : ^CHjJp-XKCH^-Z ^ in which Z is as defined above and X, p and q are as defined above for (I). 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 Cj-C4-acyl, a C4-C4- alkoxycarbonyl or a Ci-C4-alkylcarbamoyl, the substitution on X can be effected either on the 2-oxoindole derivative (II) or on the final compound (I) starting from a compound in which the nitrogen atom (X = NH) is not substituted.
The compounds (I) in which X = NH are preferred compounds according to 30 the invention.
Thus, if X is a nitrogen atom substituted by a C^-C4-alkoxycarbonyl, the first step is to prepare a compound (II) or (I) in which X is NH, which is then reacted with the appropriate chloroformate to give the desired compound (II) or (1). In the same way, a C^-C4-alkyl isocyanate is reacted with a compound (IQ or (I) p- 0 12 2 4 9 4 e™ ^ J J in which X = NH to give a 2-oxoindole derivative (II) or a compound (I) in which X is a nitrogen atom substituted by an alkylcarbamoyl. An acid chloride or an anhydride is reacted with a compound (II) or (I) in which X = NH in order to prepare a compound of formula (I) in which X is a nitrogen atom substituted by an acyl.
The compounds (II) in which R3 and together with the carbon to which they are bonded, form a pyrrolidine, N-alkylpyrrolidine, piperidine or N-alkylpiperidine ring are described by M. J. Kornet in J. Med. Chem., 1976,12, (7), 892-899.
In particular, the horsfiline of the formula: MeO is an alkaloid described in A. Jossang et al., J. Org. Chem., 1991, £6 (23), 6527-15 6530.
The compounds (II) in which r3 and r4, together with the carbon to which they are bonded, form a group -(CH2)pX(CH2)q- in which p and q are integers whose sum can vary from 3 to 6 and X is oxygen, sulfur or a group NR13, R13 being a C]-C4-acyl, a benzyl, a Cj-c4-alkoxycarbonyl or a carbamoyl which is 20 unsubstituted or substituted by one or two C1-C4 alkyls, are novel and form part of the invention.
To prepare a compound of formula (H) in which r3 and r4, together with the carbon to which they are bonded, form a tricycIo[5.2.1.o2>6]dCCane or a tricyclo[5.2.1.C)2>6]dec-8-ene, a compound of formula (Vir) or a compound 25 (VII)" respectively, of the formulae z-CH2-y^TN z-ch2—i z-ch z-ch (vii)' (vn)" 13 2 4 9 1 F" h'n in which Z is as defined above, is reacted with a compound of formula (VIT). Compounds (VII)1 and (VII)" substituted by one or more Cj-C^alkyl groups are used to prepare compounds (II) in which said carbocycles are substituted.
To prepare a compound (II) in which R3 and R4, together with the carbon to which they are bonded, form an indane or a hexahydroindane, a compound (VIII)1 or a compound (VIII)" respectively, of the formulae Z-CH2-i^N Z-CH2— (Vffl)' Z-CH: Z-CH' (VIII)" in which Z is defined as indicated above for (VIII), is reacted with a compound (VII). Compounds (Vm)' and (VIII)" substituted by one or more Ci~C4-alkyl groups are used to prepare compounds (II) in which the indane or the hexahydroindane are substituted.
The compounds (II) in which R3 and R4? together with the carbon to which 15 they are bonded; form a tricyclo[5.2.1.()2>6]decane, a tricyclo[5.2.1.()2»6]dec-8-ene, an indane or a hexahydroindane which are unsubstituted or substituted by one or more C^-C4~alkyls, are novel and form part of the invention.
If R3 and R4 each are a phenyl, the method described in Helv. Chim. Acta, 1946,29,415-432, can be used to prepare a compound (II). 20 The 2-oxoindole derivatives (VII) are known or are prepared by known methods. An example which may be cited is J. V. RajanBabu in J. Org. Chem., 1986,5L 1704-1712.
The compounds of formula (II) which carry certain substituents R'i and R'2 on their benzene moiety are used as precursors for the preparation of compounds of 25 formula (EI) which carry other substituents R'i and R'2. For example, the compounds (II) in which R'i and/or R'2 = H can be nitrated with the conventional reagents; they can also be acylated by reaction with an acid chloride of formula RCOC1, in which R is a Cj-C4-alkyl, in the presence of a Lewis acid such as aluminium chloride, in order to prepare a compound (II) in which R'i and/or R'2 = 30 COR. A compound (II) in which R'i is an amino group is prepared by catalytic 14 2 4 9 1 hydrogenation of a compound (II) in which R'i is a nitro group and R*2 is hydrogen.
The compounds of the formula R, R2 H R/ =0 (n)' in which - Ri and R2 are each independently a hydrogen, a hydroxy, a C4-C4-ol)-halogenoalkoxy, a halogen, a C^-C4-alkyl, a trifluoromethyl, a C1-C7-alkoxy, a C^-C4-polyhalogenoalkoxy, a C2-C4-(o-hydroxyaikoxy, an to-methoxyalkoxy in which the alkyl is C2-C4, a C2-C4-co-aminoaikoxy which is free or substituted by one or two Ci-C4~alkyls, a C3-C7-cycloalkoxy, a cycloalkylmethoxy in which the cycloalkyl is C3-C7, a phenoxy, a benzyloxy, a Ci-C4-alkylthio, a phenylthio, a nitro, an amino which is free or substituted by one or two Cx~C4-alkyls, a cyano, a Ci~C4-acyl, a Ci-C4-acyloxy, a C]-C4-alkylsulfonaniido, a phenylsulfonamido, a Ci-C4-alkylamido, a Op C4-alkoxycarbonylamino or a ureido which is unsubstituted or substituted by a phenyl or by one or two C^-C4~alkyls; and - R3 and r4, together with the carbon to which they are bonded, form . an adamantane, . an indane or a hexahydroindane which are unsubstituted or substituted by one or more C^-C7-alkyl groups, . a tricyclo[5.2.1.()2>6]decane or a tricyclo[5.2.1.02>6]dec-8-ene which are unsubstituted or substituted by one or more C^-C7-alkyl groups, or. . a C4-C8 hydrocarbon ring substituted by one or more Cj-C7-alkyl groups or by a C3-C5-spirocycloalkyl; or else - R3 and R4 together form a group -(CH2)p-X(CH2)q- in which p and q are integers whose sum can vary from 3 to 6 and X is oxygen, sulfur or a group NR13, R13 being a phenyl, a benzyl, a Ci-C4-acyl, a Ci-C4-alkoxycarbonyl or a carbamoyl which is unsubstituted or substituted by one or two C4-C4-alkyls, with the limitation that if CR3R4 is adamantane, R^ and R2 are other than hydrogen, 2 4 g are novel and form part of the invention. The compounds of the formula which Rj is a hydroxy, a Ci-C4-a)-halogenoalkoxy, a halogen, a C^-C4-alkyl, a trifluoromethyl, a C^-Cy-alkoxy, a C^-C4-polyhalogenoalkoxy, a C2-C4-© -hydroxyalkoxy, an w-methoxyalkoxy in which the alkyl is C2-C4, a C2-C4-o-aminoalkoxy which is free or substituted by one or two Ci~C4-alkyls, a C3-C7-cycloalkoxy, a cycloalkylmethoxy in which the cycloalkyl is C3-C7, a phenoxy, a benzyloxy, a Ci-C4-alkylthio, a phenylthio, a nitro, an amino which is free or substituted by one or two Cj-C4-alkyls, a cyano, a C4-C4-acyl, a Ci-C4-acyloxy, a Cx~C4-alkylsulfonamido, a phenylsulfonamido, a C]-C4-alkylamido, a Ci-C4-alkoxycarbonylamino or a ureido which is unsubstituted or substituted by a phenyl or by one or two Ci-C4~alkyls; R3 and R4 together form a group -(CH2)p X(CH2)q~; or R3 and R4, together with the carbon to which they are bonded, form an optionally fused, saturated or unsaturated C3-C10 hydrocarbon ring which is unsubstituted or substituted by one or more Cj-C4-alkyl groups or by a C3-C5-spirocycloalkyl; p and q are each an integer, it being possible for their sum to vary from 3 to 6; X is oxygen, sulfur or a group NR13; and Rl3 is hydrogen, a C]-C4-alkyl, a phenyl, a benzyl, a CyC^-acyl, a C4-C4-alkoxycarbonyl or a carbamoyl which is unsubstituted or substituted by one or 2 C;j-C4-alkyls, with the limitation that if Rj is methoxy, CR3R4 is other than a pyrrolidine-3 which is unsubstituted or N-substituted by a C^-C4-alkyl, and if Rj is a halogen, CR3R4 is other than a pentane, are novel and form part of the invention. 2a,3,4,5-l'etrahydrobenz[c)d]indol-2(lH)-one of the formula 16 2 4 0 15 8 is commercially available; its derivatives are known or are prepared by known methods.
The benzenesulfonyl halides (III) are known and are prepared by known methods. Thuss 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 R5 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 alkoxybenzenesulfonyl 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 so2ci .OAlk (HI)' YR, in which - Alk is a Cj-Cy-alkyl; 25 - Y is O or S; and 24 Q i ^ 17 ' 1 -J - Ry is a Cj-Cj-alkyl, a C3-C7~cycloalkyl, a C2-C4~alkenyl, a Ci~Cj-(a-halogenoalkyl, a C]-C7-polyhalogenoalkyl, a benzyl, a C^-C7-acyl or a C^-C7-(o-carboxyalkyl esterified by a C^-^-alkyl or by a benzyl, are novel and form part of the invention.
These compounds are prepared according to D. Hofmann et al. in Liebigs Ann. Chem., 1982, 287-297. Benzene compounds carrying the substituents YRy and OAlk in the 1- and 3-positions are reacted with 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 10 example with alkali metal carbonate, and then by reaction with a halide such as POCI3 to give the desired benzenesulfonyl halide.
The benzenesulfonyl halides (HI) in which the substituent R'5 is an alkoxycaibonyl, a phenoxycarbonyl, a benzyloxycarbonyl, an alkylthio, a phenylthio, a benzylthio or a group SR7, R7 being as defined for (I), are prepared 15 according to Col. Czechoslov. Chem. Commun., 1984, 49, 1184, from an aniline derivative substituted by the same grouping R'5, said aniline derivative itself being obtained from the corresponding nitrated derivative.
The nitrobenzoic acid derivatives are known; the corresponding alkyl and phenyl esters are obtained by subjecting this acid to an appropriate esterification 20 reaction.
The benzencdisulfonyl dihalides (III, R'5 = SC^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 = co-25 halogenoalkoxy) are used to prepare compounds according to the invention in which the substituent R5 is an co-aminoalkoxy which is unsubstituted or substituted by one or two alkyls, according to the following equation: -O-Alk'-Hal + NHR8R9 —> -OAlk'-NR8R9 in which Alk' is a C^-C4-alkyl.
For certain meanings of the substituents R^, R2, r5 and/or Rg, the compounds (I) according to the invention can be prepared from a precursor of formula (I)' substituted by a group R'i, R'2, R'5 and/or Ryj, called a precursor 35 group of R^, R2, R5 and/or Rg 18 2 4 9 The description which follows describes the preparation of the compounds of formula (I) carrying substituents Rj and/or R5; the same methods apply to the preparation of the compounds in which the substituents R2 and/or Rg are defined as indicated for R^ and R5.
The compounds (I) in which Ri and/or R5 are a hydroxy can be obtained by the catalytic hydrogenation of a compound of formula (I)' in which R'i and/or R'5 are a benzyloxy, for example in the presence of palladium-on-charcoal.
The compounds (I)' in which R'j and/or R'5 are a hydroxy can be used to prepare compounds (I) in which Ri and/or R5 are an alkoxy by reaction with an 10 alkyl halide in the presence of a base such as a metal hydride or an alkali metal or alkaline earth metal carbonate like K2CO3 or CS2C03, in a solvent such as THF or DMF. Likewise, the compounds of formula (I) in which R^ and/or R5 are an co-aminoalkyloxy are prepared by reacting an w-chloroalkylamine with the compounds in which R'j and/or R'5 = OH; similarly, the compounds in which 15 and/or R5 are an to-hydroxyalkoxy are prepared by reaction with a chloroalkyl alcohol; in the particular case of the preparation of a compound (I) in which R^ and/or R5 = 0(CH2)20H, it is also possible to react ethylene carbonate with a compound (I)' in which R'i and/or R'5 = OH.
The compounds of formula (I) in which R^ and/or R5 are an acyloxy are 20 obtained by reacting an acid halide or an anhydride with a compound (I)' in which R'l and/or R'5 are a hydroxy.
To prepare compounds of formula (I) in which Rj and/or R5 are a monoalkylamino or a dialkylamino, the compounds of formula (I)' in which R'i and/or R'5 are an amino can undergo reductive alkylation. If R'i and/or R'5 are an 25 amino, it is also possible to perform a nitrosation, for example in the presence of nitrous acid or an alkyl nitrite, to prepare a compound (I) in which R^ and/or R5 are a diazonium salt; reactions known to those skilled in the art then afford the compounds (I) according to the invention in which R^ and/or R5 are a cyano, a halogeno or a C^-C4-thioalkyl. Finally, compounds (I) in which R^ and/or R5 are 30 one of the groups of the formulae RCONH-, ROCONH-, RNHCONH- and RSO2NH-, in which R is a C^-C4-alkyl, can be prepared by conventional reactions starting from compounds (I)' in which R'i and/or R'5 = NH2 The compounds of formula (I)' in which the substituent R'5 is a phenoxycarbonyl can be used to obtain the compounds (I) in which R5 is a 35 phenylcarbamoyl or an alkylcarbamoyl by reaction with an aniline or an alkylamine. A substituted aniline or an alkylamine substituted on the alkyl can be 19 24 § 1 5 used to obtain compounds of formula (I) in which R5 is a phenylcarbamoyl or, respectively, an alkylcarbamoyl substituted on the alkyl.
The compounds of formula (I)' in which R'5 is a benzyloxycarbonyl can be used to obtain the compounds (I) in which R5 is a carboxy by catalytic 5 hydrogenation. Reaction with a thionyl halide gives the compounds of formula (I) in which R5 is a halogenocarbonyl. Such compounds are used to prepare compounds of formula (I) in which R5 is an N-substituted carbamoyl by reaction with a substituted amine.
The compounds of formula (I) in which R5 is a group COR"7 are prepared 10 from corresponding compounds (I)1 in which R'5 is a phenoxycarbonyl by reaction with a substituted piperazine or azetidine.
A compound (I)1 in which R'5 is a nitro group can be used to obtain a compound (I) in which R5 is an amino group by catalytic hydrogenation, for example in the presence of platinum oxide; other compounds in which the amino 15 group is substituted can then be prepared by using reactions well known to those skilled in the art.
For example, if it is desired to obtain a compound (I) according to the invention in which R5 is a group NRgRg, Rg being an optionally substituted benzoyl, the benzoyl chloride in which the phenyl carries the appropriate 20 substituent is reacted with a compound (I)' in 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 (I)' in which R'5 is a 4-chlorosulfonylbenzamido group, after which a compound (I) in which the substituent R5 is a 4-sulfamoylbenzamido group or a 4-alkylsulfamoylbenzamido 25 group is obtained by reaction with ammonia or a Ci-C4-alkylamine respectively.
In the same way, if it is desired to prepare a compound (I) in which R5 is a group NRgRp, R9 being a Ci-C7~acyl, the appropriate anhydride is reacted with a compound (I)1 in which R'5 is an amino group, in the presence of an amine such as triethylamine.
In another preparative example, a compound (I) in which R5 is an alkylsulfonamido group is obtained by reacting an alkylsulfonyl halide with a compound (I)' in which R'5 is an amino group.
The compounds of formula (I)' in which R'5 is an amino group are also useful for the preparation of compounds in which this amino group is substituted 35 by a group (CH^t-COR]^- In this case, a compound of the formula Hal-(CH2)t~ COOAlk, in which Hal is a halide, for example bromine, and Alk is a C4-C4- 24 & i alkyl, is reacted with (I)' in the presence of cuprous chloride; if appropriate, the resulting ester is converted to the acid or an amide. The reaction of a lactone, such as butyrolactone or valerolactone, with a compound (I)' in which R'5 is an amino can be used to prepare the compound (I)' in which R'5 = NHC0(CH2)tC02H, 5 where t = 2 or 3.
In the same way, the compounds of formula (I) in which R5 is an amino group substituted by a group CH(Rio)C02Rll are prepared by reacting a compound of the formula Hal-CH(Rxo)C02Ri 1 with the corresponding compounds (I)1 in which the substituent R'5 is an amino.
A compound (I) in which R5 is an amino group substituted by an alkoxycarbonyl or a phenoxycarbonyl is prepared by reacting an alkyl or phenyl chloroformate with a compound (I)1 in which the substituent R'5 is an amino.
A compound of formula (I) in which R5 is a ureido is prepared by reacting ammonia with a compound of formula (I)' in which R'5 is an amino group 15 substituted by a phenoxycarbonyl; a compound of formula (I) in which R5 is N-phenylureido or N-alkylureido or N,N-dialkylureido in which the alkyl is C1-C4 is prepared by reacting an aniline or a Ci-c4-monoalkylamine or -dialkylamine with such a compound of formula (I)'.
A compound (I) in which R5 is a carbamoyl which is unsubstituted or 20 substituted by one or 2 alkyl groups is prepared by reacting an appropriate amine with a compound (I)' in which the substituent R'5 is an amino, in the presence of phosgene.
It is also possible to prepare a compound (I) in which R5 is an amino group substituted by an alkylcarbamoyl or by a phenylcarbamoyl by reacting an alkyl or 25 phenyl isocyanate with a compound (I)' in which the substituent R'5 is an amino.
Furthermore, a compound (I) in which R5 is a sulfamoyl group which is unsubstituted or substituted by a C^-C4-alkyl is prepared by reacting ammonia or an alkylamine with a compound (I)' in which R'5 is a halogenosulfonyi group.
The compounds of formula (I)' which are useful as precursors for the 30 preparation of compounds of formula (I) are included in formula (I) and form part of the invention.
Among the compounds of formula (I), the compounds of formulae (IX), (X), (XI), (XII) and (XIII) below, which are useful for the preparation of other compounds of formula (I), are preferred compounds according to the invention. 35 Thus one subject of the present invention consists of the compounds of the formula 1 F, 21 2 4 f" : n Ri R.
R' R, ^=0 SO' (IX) R< COOH in which R^, R2, R3, R4 and R5 are defined as indicated above for (I), and their functional derivatives such as their esters.
Another subject of the present invention consists of the compounds of the formula R1 Ri R' R, N' SO- o (X) - R< NH' in which R^, R2, R3, R4 and R5 are defined as indicated above for (I), and their 10 salts where appropriate.
Yet another subject of the present invention consists of compounds of the formula OH in which R^, R2, R3, R4 and R5 are defined as indicated above for (I).
Another subject of the present invention consists of compounds of the formula R- HO.
R4 : O SO' _r5 (R6>m (xii) in which R3, R4, R5, Rg and m are defined as indicated above for (T).
Yet another subject of the present invention consists of the compounds of the formula 23 2 t 9 1 Ri R' N 'NH O SO- R< (R6) m (xin) in which R^, R2, R5, Rg and m are defined as indicated above for (I).
The affinity of the compounds according to the invention for the vasopressin 5 receptors was determined in vitro by using the method described in C J. Lynch et al., J. Biol. Chem., 19.85, 260(5), 2844-2851. This method consists in studying the displacement of tritiated vasopressin bound to the V]_ sites of rat liver membranes. The concentrations of the compounds according to the invention which inhibit the binding of tritiated vasopressin by 50% (IC50) are low, ranging up to 10~7 M. 10 The affinity of the compounds (I) according to the invention for the V2 receptors was measured on a bovine kidney membrane preparation using a method adapted from P. Crause et al., Molecular and Cellular Endocrinology, 1982, 28, 529-541, and from F.L. Stassen et al., J. Pharmacol. Exp. Ther., 1982,223,50-54. The compounds according to the invention inhibit the binding of tritiated 15 arginine-vasopressin to the receptors of the membrane preparation. The IC50 values of the compounds according to the invention are low, ranging up to 10~9 M.
The activity of the compounds according to the invention as V2 receptor antagonists was demonstrated by the adenylate cyclase activity assay performed by 20 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, by itself or in the presence of AVP (arginine-vasopressin) at a concentration of 3.10"^ M. The cyclic AMP (cyclic adenosine monophosphate) produced is measured by radioimmunoassay. The concentration which causes a 25 50% inhibition (IC50) of the stimulation of adenylate cyclase induced by 3.10"® M AVP is determined. The IC50 values determined are of the order of 10"^ M, ranging up to 10~® M. 24 2 4 n 4 The activity of the compounds according to the invention, administered orally, as V2 receptor agonists or antagonists is evaluated in hyperhydrated rats (OFA strain, Sprague-Dawley) treated with vasopressin.
Likewise, the affinity of the compounds (I) according to the invention for the 5 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, using a technique similar to that described by J. Eland et al. in Eur. J. Pharmacol., 1987, 147, 197-207. The IC50 values of the compounds according to the invention reach 10~8 M.
The compounds according to the invention are active after administration by various routes, especially orally.
No sign of toxicity is observed with these compounds at the pharmacologically active doses.
Thus the compounds according to the invention can be used in the treatment 15 or prevention of various vasopressin-dependent or ocytocin-dependent complaints, especially cardiovascular complaints such as hypertension, cardiac insufficiency or coronary vasospasm, in particular in smokers, cardiac ischemia, hemostatic disorders, especially hemophilia, and Von Willebrand's syndrome; complaints of the central nervous system, for example cerebral edemas, depression, 20 anxiety, psychotic states and memory disorders; complaints of the renal system, such as renal vasospasm, necrosis of the renal cortex, hyponatremia and hypokalemia; and complaints of the gastric system, such as hepatocinhosis, ulcers, the pathology of vomiting, for example nausea, travel sickness or else the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), diabetes 25 insipidus and enuresia. The compounds according to the 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 the treatment of dysmenorrhea or premature labor.
The present invention further relates to pharmaceutical compositions 30 containing an effective dose of a compound according to the invention, or of a pharmaceutical^ acceptable salt, and suitable 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, 35 sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal or rectal administration, the active principles of formula (I) 2 4 9 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 for oral administration, such as tablets, 5 gelatin capsules, powders, granules and solutions or suspensions to be taken orally, forms for sublingual, buccal, intratracheal or intranasal administration, forms for subcutaneous, intramuscular or intravenous administration and forms for rectal administration. For topical application, the compounds according to the invention can be used in creams, ointments or lotions.
To obtain the desired prophylactic or therapeutic effect, the dose of active principle can vary between 0.01 and 50 mg per kg of body weight 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 15 0.5 to 5000 mg, preferably 1 to 2500 mg.
If a solid composition in the form of tablets is prepared, the main active ingredient is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. The tablets can be coated with sucrose, a cellulose derivative or other appropriate substances or they can be 20 treated so as to have a prolonged or delayed activity and so as to release a predetermined amount of active principle continuously.
A preparation in the form of gelatin capsules is obtained by mixing the active ingredient with a diluent and pouring the resulting mixture into soft or hard gelatin capsules.
A preparation in the form of a syrup or elixir or for administration in the form of drops can contain the active ingredient in combination with a sweetener, which is preferably calorie-free, and methylparaben and propylparaben as antiseptics, as well as with a flavoring and an appropriate color.
Water-dispersible granules or powders can contain the active ingredient 30 mixed with dispersants or wetting agents or with suspending agents such as polyvinylpyrrolidone, as well as with sweeteners or taste correctors.
Rectal administration is effected using suppositories, which are prepared with binders melting at the rectal temperature, for example cacao butter or polyethylene glycols.
Parenteral administration is effected using aqueous suspensions, isotonic saline solutions or sterile and injectable solutions which contain pharmacologically 2 4 9 1 5 26 compatible dispersants and/or wetting agents, for example propylene glycol or butylene glycol.
The active principle can also be formulated as microcapsules, if appropriate with one or more carriers or additives.
Apart from the products of formula (I) above or one of the pharmaceutically acceptable salts, the compositions 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 pharmaceutical compositions 10 containing several active principles in association, one of which is a compound according to the invention.
Thus, according to the present invention, it is possible to prepare pharmaceutical compositions containing a compound which is a VI receptor antagonist in association with a compound which acts on the renin-angiotensin 15 system, such as a converting enzyme inhibitor, an angiotensin II antagonist or a renin inhibitor. They can also be associated for example with a peripheral vasodilator or a calcium inhibitor. Such compositions will be useful in particular in the treatment of hypertension or cardiac deficiency.
Preparation of 2-oxoindoles Preparation 1: 4,6-Dimethyl-3-spirocyclohexaneindol-2-one This compound is prepared according to Moore and Plant in J. Chem. Soc., 25 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 (II, R'i, R'2 = CH3, CR3R4 = cyclohexane) are added over 30 minutes. The reaction medium is cooled and then poured into an 30 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.
TTie indol-2-one derivatives described in Table 1 below are obtained by following the same procedure and varying the starting hydrazide.
P A n 1 r, ! i ; j 27 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 R,1 R'2 CR3R4 M.p.'C -C1 H cyclobutane 191 -C1 H cyclopentane 189 -C1 H cyclohexane 186 H H cyclohexane 123-124 -CH3 H cyclohexane 164 -CH3O H cyclohexane 226 6-C1 H cyclohexane 168 CF3O H cyclohexane 164 -Cr,HsO H cyclohexane 160 Preparation 2: The 3-spirocyclohexaneindol-2-one described in Table 1 above can also be obtained by alkylation of the indol-2-one using the method described below.
A solution of 30 g of indol-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 15 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 the solvent is evaporated off under reduced pressure. The residue is taken up in 500 ml of DCM and 200 ml of water, the insoluble material is then filtered off and the organic phase is separated off, washed with 100 ml of 20' water, dried over magnesium sulfate and evaporated under vacuum. The residue is 28 9 A L r\ r- 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 other indol-2-ones and other alkylating agents.
By way of example, among the starting compounds of formula (VII), 5-chloroindol-2-one is described by Bright in J. Am. Chem. Soc., 1956, 79, 221, and by RajanBabu in J. Org. Chem., 1986, 51,1704.4-Chloroindol-2-one can be 10 prepared from 2-chloro-6-nitrotoluene by the method described in J. Am. Chem. Soc., 1956,78,221.
-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 indol-2-ones are prepared from the appropriate aniline derivative.
Preparation 3: -Ethoxyindol-2-one A - 3-Thiomethyl-5-ethoxyindol-2-one 23.6 g of ethyl thiomethylacetate in 60 ml of DCM are added to a solution, 20 cooled to about -70*C, of 12.5 g of chlorine in 400 ml of DCM. After stirring for 5 minutes at the same temperature, a solution of 4-ethoxyaniline (48.3 g) in 120 ml of DCM is added. The mixture is stirred for one hour at about 70*C, 39.3 ml of triethylamine are added and the resulting mixture is left to warm up to room temperature. 200 ml of water are added and the organic phase is decanted, dried 25 over magnesium sulfate and evaporated under reduced pressure. The residue is taken up in 500 ml of isopropanol and 20 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-Ethoxyindol-2-one The above solid, in 1500 ml of ethanol, is dethiomethylated in the presence of 100 g of Raney nickel (80 to 100 per g), 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 ethanol and the filtrate is concentrated under reduced 35 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: -benzyloxyindol-2-one m.p. = 152*C -n-propylindol-2-one m.p. = 136*C -ethylindol-2-one m.p. = 152*C -(2,2,2-trifluoroethoxy)indol-2-one m.p. = 145*C The compounds of formula (II) described below are obtained by following the technique described in Preparation 2 and varying the starting indol-2-one derivative and the alkylating reagent.
TABLE2 R' 1 k R*2 N H Rr / R, (=o (II) R'i R'2 CR3R4 M.p *C Alkylating reagent -Cl H cyclohexane 186-189 Br(CH2)5 Br -C1 H cycloheptane 202 Br(CH2)6Br -Cl H 4,4-dimethyl 180 TsO(CH2)2C(CH3)2- cyclohexane -(CH2)2OTs -Cl H 2-hexahydroindane 223 cis-1,2- diiodomethylcyclohexane -CH3O H 4,4-dimethyl 202 TsO (CH2)2C(CH3)2- cyclohexane -(CH2)2"OTs -Cl H 2-indane 228 a,a'-dibromomethyl orthoxylene -Cl H C(CH3)2 160 CH3I -Cl H C(CH2CH3)2 156 CH3CH2I -Cl H C(n Pr)2 158 nPrl -Cl H C(iBu)2 164 iBuI 24 0 1 5 -Cl 5-Cl 4-C1 5-BzO H -Cl -Cl -BzO 5-Cl -nPr 5-EtO -Cl -Cl -Cl -EtO -EtO 5-EtO H H H H H H H H H H H H H H H H H N-methyl-4- piperidine 4-tetrahydro- pyranne cyclohexane cyclohexane C(CH2C6H5)2 C(n-pentyl)2 2.3-dihydro phenalene-2 4.4-dimethyl cyclohexane 4-spirocyclopentane cyclohexane cyclohexane N-tBu-4-piperidine N-Bz-4-piperidine N-phenyl-4-piperidine 4,4—diethyl cyclohexane cyclohexane 4,4-dimethyl cyclohexane 260 223 215 162 206 142 154 202 151 165 188 300 132 163 178 C1(CH2)2N(CH3)- -(CH2)2C1 I(CH2)20(CH2)2l Br(CH2)5Br Br(CH2)5Br C6H5CH2Br CH3(CH2)4Br BrCH2 CH2Br TSO(CH2)2C(CH3)2- -(CH2)20Ts (CH2)2OTS (CH2)2OTs Br(CH2)5Br ^(CH2)2Br tBu-N ^ (CH2)2Br ^ (CH2)2Br Bz-N (CH2)2Br ^ (CH2)2C1 c6H5^ ^(CH2)2C1- .ch2oso2ch3 ch2oso2ch3 tsO(CH2)2C(C2H5)2 -(CH2)2OTS Br(ch2)5Br TsO(CH2)2C(CH3)2--(CH2)2OTs 31 -EtO H cycloheptane 139 Br(CH2)6Br -Et H 4,4-dimethyl 160 TsO(CH2)2C(CH3)2- cyclohexane -(CH2)2OTs -CF3CH2°- H 4,4-dimethyl 164 ditto cyclohexane H H 4,4-dimethyl 169 ditto cyclohexane Preparation 4: 3-Spiroadamantaneindol-2-one This compound is prepared according to I. Fleming et al., Tetrahedron Letters, 1982,2053-2056, from 2-bromoaniline and adamantan-2-one.
Preparation 5: -Chloro-3,3-diphenylindol-2-one This compound is prepared by the method described in Helv. Chim. Acta, 1946, 29,415-431, by the reaction of benzene with 5-chloroisatin in the presence of aluminum chloride.
M.p. = 281*C.
Preparation 6: -Nitro-3-spirocyclohexaneindol-2-one This compound is prepared by the method described in J. Am. Chem. Soc., 1945, 67,499, by the nitration of 3-spirocyclohexaneindol-2-one.
M.p. = 192*C.
-Nitro-3-spiroadamantaneindol-2-one is prepared in the same manner starting from 3-spiroadamantaneindol-2-one.
M.p. > 260'C.
-Nitro-3-spiro(4,4-dimethyl)cyclohexaneindol-2-one is also prepared.
M.p. = 195*C.
Preparation 7: -Amino-3-spirocyclohexancindol-2-one This compound is prepared by the method described in J. Chem. Soc., 1951, 3475, by the reduction of 5-nitro-3-spirocyclohexaneindol-2-one, prepared above. 32 2 4 9 1 M.p. = 176*C.
-Amino-3-spiroadamantane is prepared in the same manner. M.p. = 245*C.
Preparation 8: -Fluoro-3-spirocyclohexaneindol-2-one A - 5-Diazonium-3-spirocyclohexaneindol-2-one tetrafluoroborate A solution containing 4 g of 5-amino-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 10 ml of water are added, followed by 2.54 g of sodium tetrafluoroborate in 9 ml of water. After stirring for 5 minutes, the precipitate is filtered off and washed with a 5% solution of tetrafluoroborate, with 3 ml of methanol cooled to about 0*C 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-3-spirocyciohexaneindol-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 20 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. 4.78 g of potassium cyanide and 4.95 g of cuprous cyanide are dissolved at RT in 40 ml of DMSO. The solution is cooled to about 15*C and 4.15 g of the diazonium salt obtained in step A of the prtvious preparation are added.
After stirring for 30 minutes at RT, 100 ml of water and 100 ml of ether are 30 added and the organic phase is then separated off, dried over magnesium sulfate and 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.p. = 114*C.
Preparation 9: -Cyano-3-spirocyclohexane;1ndol-2-one m = 1.4 g. M.p. = 216*C. 33 2 4 V y i vy Preparation 10: -Chloro-3-spiroadamantaneindol-2-one 1 g of the p-chlorophenylhydrazide of adamantane-2-carboxylic acid is dissolved and 2.5 ml of a solution of n-butyllithium (1.6 M in hexane) are added at 5 -40#C. After stirring for 5 minutes, the mixture is concentrated under vacuum with 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 in 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: -Chloro-3-cyclohexyl-3-methylindol-2-one The method described in Synth. Commun., 1982, 12(1), 1-10, is used to prepare 5-chloro-3-cyclohexylindol-2-one as an intermediate, and the expected compound is then obtained by reaction with methyl iodide.
Preparation 12: -Acetyl-3-spirocyclohexaneindol-2-one 2.56 g of acetyl chloride and then 8.25 g of anhydrous aluminum chloride are added to a solution, cooled to 5*C, of 4 g of 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 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.
The benzenesulfonyl chlorides described in the Table below were prepared using the procedure described. 34 y 'i 5 8 CI I so2 YRV Y RV M.p. *C S CH3 85 O CH2Bz 95 O CH2C02Et 89 O (CH.hBr 106-108 Starting from the various 2-oxoindoles described above and appropriate 5 benzenesulfonyl chlorides, the compounds according to the invention were prepared using the procedures reported in the Examples below.
EXAMPLE 1 -Chloro-l-(2-methoxy-4-nitrobenzenesulfonyl)-3-10 spirocyclohexaneindol-2-one A mixture containing 0.7 g of 5-chloro-3-spirocyclohexaneindol-2-one and 70 mg of sodium hydride in 7 ml of THF is stirred under nitrogen at RT for 30 minutes. 0.7 g of 2-methoxy-4-nitrobenzenesulfonyl chloride is introduced and stirring is maintained at RT for 20 hours. The mixture is concentrated under 15 vacuum, the residue is taken up in 30 ml of water, extraction is carried out with ethyl acetate and the extract is washed with water and then dried and concentrated to give 1.1 g of the expected compound, which crystallizes from iso ether.
M.p. = 188*C.
EXAMPLE 2 l-(4-Amino-2-methoxybenzenesulfonyl)-5-chloro-3-spirocyclohexaneindol-2-one 2 4 n 0.8 g of the compound obtained in the previous Example is reduced with hydrogen under normal pressure at RT for 20 hours in 10 ml of acetic acid, in the presence of 30 mg of platinum oxide. The reaction medium is filtered, the filtrate is concentrated, the residue is taken up in a water/ethyl acetate mixture and the 5 organic phase is washed with water, dried and concentrated. The yellow foam obtained is chromatographed on alumina using DCM as the eluent to give 0.2 g of the expected product.
M.p. = 173'C.
EXAMPLE 3 -Chloro-l-[4-(2-methylphenylcarboxamido)-2-methoxybenzenesulfonyl]-3-spirocyclohexaneindol-2-one A mixture containing 0.2 g of the compound prepared in the previous Example, 0.5 ml of triethylamine, 5 ml of DCM and 0.1 g of orthotoluoyl chloride is stirred at RT for 48 hours. It is concentrated under vacuum, the residue is taken up in a water/ether mixture and left to decant and the organic phase is washed with a saturated solution of sodium hydrogencarbonate and then with water, dried and concentrated under vacuum to give 250 mg of a solid, which is chromatographed on silica using DCM as the eluent to give 0.1 g of the expected product.
M.p. = 192*C.
EXAMPLE 4 6-Chloro-l-(2,4-dimethoxybenzenesulfonyl)-3-spirocyclohexaneindol-2-one A mixture containing 0.15 g of 6-chloro-3-spirocyclohexaneindol-2-one and 15 mg of sodium hydride in 2 ml of THF is stirred for 30 minutes at RT under nitrogen; 0.15 g of 2,4-dimethoxybenzenesulfonyl chloride is introduced and stirring is maintained at RT for 20 hours. The mixture is concentrated under vacuum, the residue is taken up in 30 ml of water and extracted with ethyl acetate and the extract is washed with water, dried and concentrated under vacuum. The product obtained is recrystallized from iso ether.
M.p. = 147*C.
EXAMPLE 5 Acid fumarate of 5-chloro-l-[4-(3-dimethylaminopropoxy)benzenesulfonyl]-3-spirocyclohexaneindol-2-one 36 2 4 9 1 R A) 4-(3-Bromopropoxy)benzenesulfonyl chloride A mixture containing 23 g of sodium 4-hydroxybenzenesulfonate dihydrate, 7 g of potassium hydroxide pellets (85%), 30 ml of water,. 50 ml of absolute ethanol, 40 g of 1,3-dibromopropane and 3.4 g of tetrabutylammonium 5 hydrogensulfate is refluxed for 3 hours. The reaction medium is concentrated under vacuum, taken up in ethanol and concentrated once again. The residue is taken up in hot methanol. The insoluble material is filtered off, the filtrate is concentrated and the residue is triturated in ether to give 22.5 g of a white solid. 120 ml of phosphorus oxychloride and 16 g of phosphorus pentachloride are added 10 to this solid and the mixture is stirred for 20 houis at RT and then refluxed for 1 hour. The reaction medium is concentrated under vacuum, the residue is then taken up in an ether/water mixture and the organic phase is decanted and washed with a saturated solution of sodium hydrogencarbonate. After drying and concentration, the expected product is obtained in the form of a yellow oil.
B) l-[4-(3-Bromopropoxy)benzenesulfonyl]-5-chloro-3-spirocyclohexaneindol-2-one A mixture containing 1.2 g of 5-chloro-3-spirocyclohexaneindol-2-one and 0.16 g of sodium hydride in 6 ml of THF is stirred at RT for 30 minutes under 20 nitrogen. 1.6 g of 4-(3-bromopropoxy)benzenesulfonyl chloride are then added.
After 20 hours at RT, the reaction medium is concentrated under vacuum, the residue is taken up in a water/ethyl ether mixture and decanted and the organic phase is washed with water, dried and concentrated. The oil obtained is purified by chromatography on silica using iso ether as the eluent. The expected product is 25 obtained in the form of an oil, which crystallizes from iso ether. m = 1 g.
M.p. = 123*C.
C) Acid fumarate of 5-chloro-l-[4-(3- dimethylaminopropoxy)benzenesulfonyl]-3-spirocyclohexaneindol-2-one A mixture containing 0.5 g of the product obtained in the above step, 0.5 g of potassium iodide and 20 ml of a 33% solution of dimethylamine in methanol is stirred at RT for 20 hours. The reaction medium is concentrated and taken up in 10 ml of water and, after trituration, the insoluble material is separated off and treated 35 with 10 ml of 3 N hydrochloric acid. A gum is formed which is dissolved in 30 ml of warm water, and the solution is filtered on paper and then rendered alkaline by 37 2 4 9 i 5 8 the addition of 12 N sodium hydroxide. The insoluble material is extracted with ether and the extract is washed, dried and then concentrated to give a yellow oil. This is dissolved in 10 ml of acetone, and 0.1 g of fumaric acid is added to the hot solution.
The expected product precipitates at 20*C. m = 240 nig.
M.p. = 168'C.
EXAMPLE 6 5-Chloro-l-(2,4-dimethoxybenzenesulfonyl)-3-spiroadamantaneindol-2- one A mixture containing 0.2 g of 5-chloro-3-spiroadamantaneindol-2-one and 20 mg of sodium hydride in 3 ml of THF is stirred for 30 minutes at RT under a nitrogen atmosphere. 0.18 g of 2,4-dimethoxybenzenesulfonyl chloride is added and stirring is maintained at RT for 20 hours. The reaction medium is concentrated under vacuum, the residue is taken up in 30 ml of water and extracted with ether and the extract is washed with water, dried and concentrated under vacuum. The wax obtained crystallizes from 15 ml of iso ether. m = 240 mg.
M.p. = 152-154'C.
EXAMPLE 7 -Chloro-l-(2,4-dimethoxybenzenesulfonyl)-3-spirocycloheptaneindol-2-one A solution containing 0.156 g of potassium tert-butylate and 0.33 g of 5- chloro-3-spirocycloheptaneindol-2~one in 15 ml of THF is cooled to -40*C under an inert atmosphere. The temperature is allowed to rise to about 10*C over 1 hour, the solution is then cooled to about -40*C, a solution of 0.335 g of 2,4-dimethoxybenzenesulfonyl chloride in 15 ml of THF is added dropwise and the mixture is stirred at RT for 2 hours. The solvent is evaporated off under reduced pressure and the residue is then taken up in 30 ml of DCM and 30 ml of water. The organic phase is separated off, washed with 15 ml of water, dried over magnesium sulfate and evaporated under vacuum. The oil obtained is chromatographied on silica using a cyclohexane/DCM mixture as the eluent to give the expected com- pound, which recrystallizes from heptane.
A ^ <1 38 ° ■ m = 0.51 g.
M.p. = 135*C.
EXAMPLE 8 2,4-Dimethoxy-l-benzenesulfonyl-2a-methyl-2a,3,4,5-tetrahydrobenz[c, d]indol-2-one (I: = H, -R2-R3 = -(CH2)3-, R4 = CH3, R5 = Rg = OCH3) 2a,3,4,5-Tetrahydrobenz[c,d]indol-2-one is commercially available. With the temperature maintained at -40*C and under a nitrogen atmosphere, a solution containing 0.7 g of this compound and 1.36 g of potassium tert-butylate in 40 ml 10 of anhydrous THF is prepared.
The temperature is allowed to rise to about 0*C, the solution is then cooled to -60*C and a solution of 0.57 g of methyl iodide in 20 ml of THF is added; the medium is maintained at -10*C for 30 minutes, with stirring, and then cooled to about -40*C and a solution of 0.96 g of 2,4-dimethoxybenzenesulfonyl chloride in 15 10 ml of THF is added. After stirring for 16 hours at RT, the solvent is evaporated off under reduced pressure and the residue is taken up in 30 ml of DCM and 30 ml of water; the organic phase is separated off and then dried over magnesium sulfate and evaporated. The oil obtained is purified by chromatography on silica using a cyclohexane/DCM mixture as the eluent to give the expected product, which is 20 recrystallized from a cyclohexane/AcOEt mixture (95/5; v/v).
M.p. = 160'C.
The compounds according to the invention collated in Table 3 below were prepared from the 2-oxoindoles described above by following the procedure described in the above Examples.
TABLE 3 R r1 R 2 N SO 3 R4 o 2 —r< (I) vx (R6)m 39 2 4 9 1 Unless indicated Otherwise in the Table below (*), R2 = H and m = 1.
'Ex. ri cr3r4 r5 (r6)m M.p. *C 9 -Cl c(c6h5)2 3-MeO 4-MeO 178 -N02 cyclohexane 3-MeO 4-MeO 157 11 -Cl cyclohexane 4-MeO h 112 12 -Cl c(ch3)2 3-MeO 4-MeO 110 13 -NHo cyclohexane 3-MeO 4-MeO 171 14 -CN cyclohexane 2-MeO 4-MeO 148 -Cl cyclohexane 4-MeO 2,3,6-triMe 188 16 -Cl C(Pr)2 2-MeO 4-MeO 186 17 -Cl indane-2 2-MeO 4-MeO 182 18 -Cl C(iBu)2 2-MeO 4-MeO 184 19 -Cl N-methyl 2-MeO 4-MeO 142 • piperidine-4 -Cl C(Et)2 2-MeO 4-MeO 190 21 -F cyclohexane 2-MeO 4-MeO 149 22 -Cl 4-tetrahydro- 2-MeO 4-MeO 142 pyranne 23 -Cl 4,4-dimethyl 2-MeO 4-MeO 118 cyclohexane 1 40 24 S 1 g a 24 -Cl 2-hexahydro- 2-MeO 4-MeO 89 indane 4-C1 cyclohexane 2-MeO 4-MeO 150 26 -Cl cyclohexane 3-MeO 4-MeO 152 27 -Cl cyclohexane 4-Me H 150 28 H cyclohexane 3-MeO 4-MeO 107 29 -Me cyclohexane 3-MeO 4-MeO 171 -MeO cyclohexane 3-MeO 4-MeO 124 31 -Cl cyclohexane 2-MeO 4-MeO 149 32 -Cl cyclohexane 4-C1 H 154 33 -Cl cyclobutane 3-MeO 4-MeO 111 34 -Cl cyclopentane 3-MeO 4-MeO 106 -Cl cyclohexane 4-MeO 2-C1 174 36 -Cl cyclohexane 4-N02 H 172 37 -Cl cyclohexane 4-CN H 198 38 -Cl cyclohexane 4-MeO 2-N02 147 39 -Cl cyclohexane 4-CF3 H 139 40 -Cl cyclohexane 4-CF3O H 134 41 -Cl cyclohexane 4-aMeO 2-NH2 150 41 2 4 o ■? p «- r ^ j _ 42 ♦ 43 44 45 46 47 48 49 50 51 52 53 54 55 56 4-ch3 R2=6- ch3 -Cl 5-Cl 5-Cl 5-Cl -Cl -Cl 5-Cl h -MeO 5-Cl 5-Cl -Cl 5-Cl 5-Cl cyclohexane cyclohexane cyclohexane cyclohexane cyclohexane cyclohexane cyclohexane K3 ch3 adamantane 4,4-dimethyl cyclohexane cyclohexane cyclohexane cyclohexane cyclohexane cyclohexane 4-MeO 3-Me 4-iPr 2-cf3 2-MeO 4-MeO 2-MeO 2-MeO 2-MeO 2-MeO 2-MeO 2-MeO 2-Me 2-CF3_ ch2o 2-MeO 2-MeO 4-BzO 2,6-iPr h ch1 4-ch3oco 4-MeO 4-MeO 4-MeO 4-CH3S02NH ci ^ y~conim ci -F 5-CF3CH20 ^ y~nhc0-4 chn 42 ? A r v: 1 i v J -Cl 5-Cl 5-BzO 5-BzO 5-Cl -Cl H -CH3CO 5-Cl 5-Cl 5-H2N 5-Cl -Cl 5-nPr 5-EtO -Cl cyclohexane cyclohexane cyclohexane 4,4-dimethyl cyclohexane cyclohexane cyclohexane C(CH2C6H5)2 cyclohexane C(n-pentyl)2 C(CH2C6H5)2 cyclohexane 4-spiiocyclo-pentane cyclohexane cyclohexane N-tBu-4-piperidine N-Bz-4-piperidine 2-MeO -NH2_ S02 2-MeO 2-MeO 2-MeO 2-MeO 3-MeO 3-MeO 2-MeO 2-MeO 2-MeO 2-MeO 2-MeO 2-MeO 2-MeO 2-MeO ^ y~Q-C0-4 2,4—di MeO 4-MeO 4-MeO ch3o c-nh-4 ii o ch3n n-c-4 4-MeO 4-MeO 4-MeO 4-MeO 4-MeO 4-MeO -MeO 4-MeO 4-MeO 4-MeO 165 270 159 142 192 158 146 122 140 185 230 154 116 138 95 (0.25 H20) 76 (0.5 H20) 43 74 75 -Cl 5-Cl N-phenyl-4-piperidine cyclohexane 2-MeO 2-EtO 4-MeO 4-EtO 163 123 76 -Cl -CO 2-MeO 4-MeO 190 77 78 -EtO 5-EtO 4,4-diethyl cyclohexane cycloheptane 2-MeO 2-MeO 4-MeO 4-MeO 129 130 79 -EtO cyclohexane 2-MeO 4-MeO 134 80 -EtO 4,4-dimethyl cyclohexane 2-MeO 4-MeO 160 81 -Et 4,4-dimethyl cyclohexane 2-MeO 4-MeO 166 82 -EtO 4,4-dimethyl cyclohexane 2-MeO 4-N02 110 83 -EtO 4,4-dimethyl cyclohexane 2-MeO 4-NH2 230 84 -N02 4,4-dimethyl cyclohexane 2-MeO 4-MeO 102 85 -NH2 4,4-dimethyl cyclohexane 2-MeO 4-MeO 180 86 - CF3CH20 4,4-dimethyl cyclohexane 2-MeO 4-MeO 169 44 o / / i>, \ < "v <7 EXAMPLE 87 l-(2,4-Dimethoxybenzenesulfonyl)-3-(4,4-dimethylspirocyclohexane)-5-hydroxyindol-2-one 3.51 g of the compound prepared in Example 60 are stirred at 50*C for 1 5 hour, under a hydrogen atmosphere, with 0.5 g of 10% palladium-on-charcoal in 150 ml of ethanol. The catalyst is filtered off on talc, the material on the filter is rinsed with DCM and the filtrate is evaporated under reduced pressure to give 2.8 g of the expected compound, which is recrystallized from a cyclohexane/AcOEt mixture (90/10; v/v).
M.p. = 220*C.
EXAMPLE 88 l-(2,4-Dimethoxybenzenesulfonyl)-5-hydroxy-3-spirocyclohexaneindol-2-one is prepared in the same manner starting from the 5-benzyloxy derivative 15 described in Example 59.
M.p. = 196*C.
EXAMPLE 80 bis l-(2,4-Dimethoxybenzenesulfonyl)-3-(4,4-dimethylspirocyclohexane)-5-20 ethoxyindol-2-one This compound, already described in Example 80, can be prepared by another method starting from the homologous 5-hydroxy compound. 0.6 g of the compound prepared in Example 87 is stirred at RT for 16 hours, under an inert atmosphere, with 0.19 g of anhydrous potassium carbonate and 0.315 g of ethyl 25 iodide in 11 ml of DMF. The solvent is evaporated off under reduced pressure and 30 ml of AcOEt and 30 ml of water are added. The organic phase is washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. 0.45 g of the expected product is obtained by crystallization from cyclohexane.
M.p. = 160*C.
The compounds described in Table 4 below are prepared in the same manner. o / /*\ A rrt / h t i "l u 45 «- ' v" » TABLE 4 Ex. ri CR3R4 r5 r6 M.p.'C 89 -nPrO cyclohexane 2-MeO 4-MeO 139 90 -nPrO 4,4-dimethyl cyclohexane 2-MeO 4-MeO 158 91 -iPrO 4,4-dimethyl cyclohexane 2-MeO 4-MeO 154 92 [>-CH2-O cyclohexane 2-MeO 4-MeO 155 EXAMPLE 93 -Acetoxy-l-(2,4-dimethoxybenzenesulfonyl)-3-spirocyclohexaneindol-2-one 0.5 g of the compound prepared in Example 88,2.5 ml of isopropenyl acetate 10 and 0.165 g of potassium carbonate in 2.5 ml of toluene and 0.3 ml of DMF are heated at about 65#C for 15 hours. After cooling, 10 ml of water and 15 ml of ethyl acetate are added and the organic phase is decanted, washed with water, dried over magnesium sulfate and concentrated under reduced pressure. 0.51 g of the expected compound, containing 0.5 mol of cyclohexane, is isolated by 15 crystallization from a cyclohexane/ethyl acetate mixture. 46 9 A r\ / a 0 1 c *3 M.p. = 116*C.
EXAMPLE 94 l-(2,4-Dimethoxybenzenesulfonyl)-5-(2-hydroxyethoxy)-3-5 spirocyclohexaneindol-2-one 0.5 g of the compound prepared in Example 88, 0.5 g of ethylene carbonate and 0.272 g of anhydrous potassium carbonate in 1.25 ml of DMF are heated at about 70*C for 40 hours. After cooling, 10 ml of water and 15 ml of ethyl acetate are added and the organic phase is decanted, washed with water, dried over 10 magnesium sulfate and concentrated under reduced pressure. The oily residue is chromatographed on a silica column using a cyclohexane/AcOEt mixture (70/30; v/v) as the eluent to give 0.5 g of the expected product, which is recrystallized from a heptane/DCM mixture.
M.p. = 170*C.
EXAMPLE 95 -(2-Dimethylaminoethoxy)-l-(2,4-dimethoxybenzenesulfonyl)-3-spirocyclohexaneindol-2-one 0.6 g of the compound prepared in Example 88 is heated at about 40*C for 16 20 hours, under an inert atmosphere, with 0.32 g of N,N-dimethyl(2-chloroethylamine) and 1.76 g of cesium carbonate in 7.2 ml of acetone and 2.4 ml of DMF. The salts are filtered off and 20 ml of water and 20 ml of AcOEt are added to the filtrate. The organic phase is decanted, washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue is 25 chromatographed on silica using a DCM/MeOH mixture (9/1; v/v) as the eluent to give 0.6 g of the expected product, which is recrystallized from a cyclohexane/iso ether mixture.
M.p. = 122*C.
EXAMPLE 96 -Chloro-l-(2,4-dimethoxybenzenesulfonyl)-3-(spiropiperidine-4)indol-2-one This reaction is performed according to J. Org. Chem., 1984, 49,2795-2799. 0.75 g of 1-chloroethyl chloroformate is added at 0*C to a solution of 1.31 g of the 35 compound described in Example .73 "• and 0.32 g of 1,8—bis— dimethylaminonaphthalene in 22 ml of 1,2-dichloroethane. The mixture is 2 l\ 0. ' ) u 47 - • w j ,j refluxed for about 20 minutes and concentrated under reduced pressure to a volume of about 10 ml, and 22 ml of methanol are then added. After refluxing for 50 minutes, the reaction medium is concentrated under reduced pressure and the residue is chromatographed on a silica column using a DCM/MeOH mixture (95/5; v/v) as the eluent. 1.16 g of the expected product are isolated and recrystallized from a mixture of cyclohexane and ethyl acetate.
M.p. = 172'C.
EXAMPLE 97 3-(N-Acetylspiropiperidine-4)-5-chloro-l-(2,4- dimethoxybenzenesulfonyl)indol-2-one 0.086 ml of acetyl chloride is added to a solution, cooled to about 0*C, of 0.35 g of the compound prepared in the previous Example and 0.23 ml of triethylamine in 5 ml of DCM. The mixture is stirred for one hour at 20*C, 5 ml of 15 water are added, the organic phase is decanted, washed with water, dried over magnesium sulfate and concentrated under reduced pressure and the residue is chromatographed on a silica column using a DCM/MeOH mixture (99/1; v/v) as the eluent. 0.29 g of the expected product is isolated in the form of the hemihydrate.
M.p. = 107*C.
EXAMPLE 98 -Chloro-l-(2,4-dimethoxybenzenesulfonyl)-3-(N-methoxycarbonylspiropiperidine-4)indol-2-one 25 This compound is prepared from the one obtained in Example 96 by reaction with methyl chloroformate.
M.p. = 147*C.
EXAMPLE 99 l-(3,4-Dimethoxybenzenesulfonyl)-5-propionamido-3- spirocycl ohexaneindol-2-one A solution of 0.144 g of propionyl chloride in 3 ml of DCM is added to a solution, cooled to about 0#C, of 0.5 g of the compound described in Example 13 and 0.167 ml of triethylamine in 10 ml of DCM. The mixture is stirred for 2 hours 35 at 20*C, 20 ml of water are then added and. the ^organic phase is decanted, washed with water, dried over magnesium sulfate and concentrated under reduced 48 9 £ fj 1 n a n } - *u> pressure. 0.5 g of the expected product is isolated after recrystallization from a heptane/AcOEt mixture (95/5; v/v).
M.p. = 158#C.
EXAMPLE 100 l-(3,4-Dimethoxybenzenesulfonyl)-5-(N-methylureido)-3-spirocyclohexaneindol-2-one 0.15 g of methyl isocyanate is added to a solution, cooled to about 0*C, of 0.5 g of the compound described in Example 13 in 10 ml of DCM. After stirring 10 for about 16 hours at RT, 20 ml of water are added and the organic phase is decanted, washed with water, dried over magnesium sulfate and concentrated under reduced pressure. 0.5 g of the expected product is isolated after recrystallization from a mixture of heptane and ethyl acetate.
M.p. = 214*C.
The compound described in the following Example is prepared in the same manner.
EXAMPLE 101 l-(3,4-Dimethoxybenzenesulfonyl)-5-(N-phenylureido)-3-20 spirocyclohexaneindol-2-one M.p. = 124*C.
EXAMPLE 102 -Dimethylamino-l-(2,4-dimethoxybenzenesulfonyl)-3-25 spirocyclohexaneindol-2-one A mixture of 0.5 g of the compound described in Example 68 with 0.5 ml of a 35% solution of formaldehyde and 0.12 g of sodium cyanoborohydride in 10 ml of acetonitrile is stirred at RT, under a nitrogen atmosphere, and the pH is adjusted to about 6.5 with a few drops of acetic acid. After 48 hours at 20*C, the 30 solvent is evaporated off under reduced pressure and 20 ml of an approximately 2 N aqueous solution of sodium hydroxide and 20 ml of DCM are added. The organic phase is decanted, washed with water and dried over magnesium sulfate and the solvent is evaporated off under reduced pressure. The residue is chromatographed on a silica column using a cyclohexane/ethyl acetate mixture 35 (80/20; v/v) as the eluent. 0.27 g of the expected' product is isolated.
M.p. = 167*C. 1 49 ■ - 2 4 0 15 EXAMPLE 103 l-(2,4-Dimethoxybenzenesulfonyl)-5-etnyithio-3-spirocyclohexaneindol-2-one This compound is prepared according to J. Chem. Soc., Chem. Commun., 5 1980, 16, 756. A mixture of 2.95 g of diethyl disulfide and 0.386 g of isopentyl nitrite is heated to about 80#C, under an inert atmosphere, and 0.8 g of the compound prepared in Example 68 is added. The medium is stirred for one hour at 80#C and then concentrated under reduced pressure. The residue is chromatographed on a silica column using a DCM/cyclohexane mixture (80/20; v/v) as the eluent. The expected product is isolated after crystallization from cyclohexane.
M.p. = 123*C.
EXAMPLE 104 5-Chloro-l-[4-(dimethylaminomethylcarboxamido)-2- methoxybenzenesulfonyl]-3-spirocyclohexaneindol-2-one A) 5-Chloro-1 - [4-(chloromethy lcarboxam ido)-2-methoxybenzenesulfonyl]-3-spirocyclohexaneindol-2-one 0.2 g of the compound prepared in Example 2 is placed in 4 ml of DCM and 0.5 g of TEA at RT and 0.1 g of chloroacetyl chloride is added. After stirring for 20 hours at RT, the mixture is concentrated under vacuum. The concentrate is extracted with ethyl acetate, the extract is washed with water and a solution of sodium carbonate and the residue is then chromatographed on silica using a mixture of DCM and AcOEt as the eluent to give 0.15 g of the expected product.
B) 5-Chloro-l-[4-(dimethylaminomethylcarboxamido)-2-methoxybenzenesulfonyl]-3-spirocyclohexaneindol-2-one The compound obtained in the previous step (150 mg) is stirred at RT for 20 hours in 20 ml of a 33% solution of dimethylaniine in ethanol. Extraction is carried out with AcOEt and the extract is washed with N sodium hydroxide and then water. The residue is chromatographed on silica using AcOEt as the fluent to give 0.025 g of the expected product.
M.p. = 173*C. 50 2 4 9 15 example 105 l-[4-(4-Sulfamoylphenylcarboxamido)-2-methoxybenzenesulfonyl]-5-chloro-3-spirocyclohexaneindol-2-one 4-Chlorosulfonylbenzoyl chloride is prepared according to Chem. Ber., 5 1941,271. 0.2 g of the compound prepared in Example 2 is brought into contact with 0.5 g of TEA in 5 ml of DCM; 0.13 g of 4-chlorosulfonylbenzoyl chloride is added and the mixture is stirred for 20 hours at RT. It is concentrated under vacuum, the concentrate is taken up in THF, and 10 ml of aqueous ammonia are 10 added. Stirring is continued for a further 20 hours at RT and the mixture is concentrated under vacuum. The residue is extracted with ether and the extract is washed with water, dried over sodium sulfate and then chromatographed on silica using AcOEt as the eluent to give the expected product.
M.p. = 238-242*C after recrystallization from AcOEt.
EXAMPLE 106 l-[4-(3-Sulfamoylphenylcarboxamido)-2-methoxybenzenesulfonyl]-5-chloro-3-spirocyclohexaneindol-2-one A) 3-Chlorosulfonylbenzoyl chloride This compound is prepared according to patent US 3 290 370. 11 g of chlorosulfonic acid are heated to 60*C and 8 g of phenylchloroform are added dropwise. After heating for 2 hours at 130*C, the mixture is distilled to give 1 g of the expected product.
B.p. = 120-125*C under 0.5 mm Hg.
B) l-[4-(3-Sulfamoylphenylcarboxamido)-2-methoxybenzenesulfonyl]-5-chloro-3-spirocyclohexaneindol-2-one 210 mg of the compound prepared in Example 2 are placed in 10 ml of DCM with 220 mg of the compound obtained in the previous step and 200 mg of 30 TEA. the mixture is stirred overnight and the solvents are then evaporated off under vacuum. The residue is taken up in 20 ml of THF and 20 ml of aqueous ammonia and the mixture is stirred for 6 hours at RT. The solvents are driven off under vacuum and the residue is then taken up in AcOEt and water. Extraction is carried out with AcOEt and the extract is washed with water and then 35 chromatographed on silica using an AcOEt/cyelohexane mixture (50/50; v/v) as the eluent to give the expected product. 2 4 0 ^ K 5i c f a J M.p. = 176*C.
EXAMPLE 107 l-[4-(2-Carboxyphenylcarboxamido)-2-methoxybenzenesulfonyl]-5-5 chloro-3-spirocyclohexaneindol-2-one The preparation is carried out according to J. Heterocycl. Chem., 1974, 997-1000.
A mixture containing 0.2 g of the compound prepared in Example 2 with 0.5 ml of TEA and 160 mg of phthalic anhydride is stirred at 60*C for 3 hours. It is 10 concentrated under vacuum and treated with normal hydrochloric acid. The precipitate formed is filtered off and treated with a 10% solution of sodium carbonate; a precipitate forms again, the aqueous phase is decanted and the precipitate is treated with 10% AcOH. The precipitate is filtered off and then washed with 10% AcOH followed by isopropyl ether and recrystallized from iso 15 ether to give the expected product. m = 0.150 g.
M.p. = 157-158'C.
EXAMPLE 108 l-[4-(Benzyloxymethylcarboxamido)-2-methoxybenzenesulfonyl]-5- chloro-3-spirocyclohexaneindol-2-one This compound is prepared by the procedure described in Example 3 by reacting benzyloxyacetyl chloride with the compound prepared in Example 2.
M.p. = 143*C after recrystallization from iso ether.
EXAMPLE 109 -Chloro-l-[4-(hydroxymethylcarboxamido)-2-methoxybenzenesulfonyl]-3-spirocyclohexaneindol-2-one This compound is obtained by hydrogenating the compound prepared in 30 the previous Example, under the pressure of a water column, in the presence of 5% palladium-on-charcoal in an EtOH/AcOEt mixture.
M.p. = 202*C.
EXAMPLE 110 5-Chloro-l-[4-(imidazol-l-ylphenylcarboxamido)-2- methoxybenzenesulfonyl]-3-spirocyclopentaneindol-2-one v Sz i • ' " r* C *-v * ' l\ 52 * ' - -j A) Ethyl ester of 4-(imidazol-l-yl)benzoic acid A mixture containing 35 g of 4-fluorobenzoyl chloride in 50 ml of 100 ethanol is refluxed for 15 minutes. 35 g of the ethyl ester of 4-fluorobenzoic acid obtained are mixed with 22 g of imidazole and 61 g of potassium carbonate in 35 5 ml of DMSO. The mixture is heated for 18 hours at 120-130*C and 500 ml of iced water are then added. A precipitate forms and the expected product crystallizes from iso ether.
M.p. = 98*C.
B) Imidazol-1-ylbenzoyl chloride g of the ester obtained in step A are refluxed for 2 hours in 20 ml of water and 20 ml of sodium hydroxide solution. The reaction medium is washed with ether and then acidified (pH 2) with concentrated hydrochloric acid. The precipitate formed is filtered off and then washed with iso ether. 5 g of the acid 15 obtained are brought to the reflux temperature in 35 ml of thionyl chloride. The precipitate formed is filtered off and then washed with iso ether to give the expected acid chloride.
M.p. = 243'C.
C) 5-Chloro-l-[4-(imidazol-l-ylphenylcarboxamido)-2- methoxybenzenesulfonyl]-3-spirocyclopentaneindol-2-one A mixture containing 210 mg of the compound prepared in Example 2 and 200 mg of the acid chloride prepared in step B in 10 ml of DCM and 1.5 ml of TEA is stirred at RT for 1 h and then refluxed for 3 hours. The reaction medium is 25 extracted with DCM and then washed with water and an aqueous solution of sodium hydroxide. After evaporation of the solvents, the residue is chromatographed on silica using a DCM/ methanol mixture as the eluent. The expected product is recrystallized from iso ether. m = 0.010 g.
M.p. = 145*C.
EXAMPLE 111 -Chloro-l-[2-methoxy-4-(phenoxycarboxamido)benzenesulfonyl]-3-spirocyclohexaneindol-2-one 35 This compound is prepared by reacting phenyl chloroformate with the compound prepared in Example 2. 53 2 4 9 1 5 M.p. = 209*C after recrystallization from iso ether.
EXAMPLE 112 -Chloro-l-[4-(N-methylureido)-2-methoxybenzenesulfonyl]-3-5 spirocyclohexaneindol-2-one 140 mg of the compound obtained in the previous Example are mixed with 5 ml of ethanol, 5 ml of DCM and 5 ml of a 33% solution of methylamine in ethanol. After one hour at RT, the solvents are driven off and the residue is then chromatographed on silica using a DCM/MeOH mixture as the eluent. The product 10 obtained is recrystallized from iso ether.
M.p. = 254®C.
EXAMPLE 113 -Chloro-l-(2-methoxy-4-ureidobenzenesulfonyl)-3-15 spirocyclohexaneindol-2-one A mixture containing 200 mg of the compound prepared in Example 111 with 5 ml of 20% aqueous ammonia, 5 ml of ethanol and 5 ml of DCM is stirred for 1 hour at RT. After filtration of the reaction medium and evaporation of the solvents, the expected product is crystallized from iso ether. 20 M.p. = 228*C.
EXAMPLE 114 -Chloro-l-[4-(N-o-tolylureido)-2-methoxybenzenesulfonyl]-3-spirocyclohexaneindol-2-one 25 A mixture containing 250 mg of the compound prepared in Example 2,10 ml of xylene and 80 mg of orthotoluyl isocyanate is refluxed for 18 hours. A white precipitate forms and is filtered off. The icaction medium is extracted with ether and the extract is washed with water and then chromatographed on silica using a DCM/MeOH mixture as the eluent. The cxpected product crystallizes from iso 30 ether.
M.p. = 182*C.
EXAMPLE 115 Benzyl 4-(5-methoxy-2-oxo-3-spirocyclohexaneindol-l-yl)sulfonyl-35 3-methoxybenzoate 249158 54 60 mg of sodium hydride are poured in small portions into a mixture containing 500 mg of 3-spirocyclohexane-5-methoxyindol-2-one in 50 ml of THF. After 30 minutes at RT, 800 mg of benzyl 3-methoxy-4-chlorosulfonyl-benzoate chloride are added and the mixture is stirred for 2 hours at RT. The 5 medium is concentrated and taken up in AcOEt and the mixture is washed with water, dried over sodium sulfate and concentrated. The residue is chromatographed on silica using DCM as the eluent.
NMR (at 250 MHz in DMSO): 1.2-1.8 ppm : 10H: cyclohexyl 10 3.6 ppm and 3.8 ppm : 2.x 3H : 2 x OCH3 5.4 ppm : 2H : C02-CH2-C6H5 6.8-8.2 ppm : 11H: aromatic protons example 116 4-(3-Spirocyclohexane-5-methoxy-2-oxoindol-l-yl)sulfonyl-3- methoxybenzoic acid 600 mg of the compound prepared in the previous Example are placed in 50 ml of AcOEt and hydrogenated at RT and atmospheric pressure in the presence of 140 mg of palladium-on-charcoal to give 310 mg of the expected acid, which 20 is recrystallized from a hexane/ ethanol mixture (70/30; v/v).
M.p. = 210*C. example 117 -Chloro-l-[4-(N-(ethoxycarbonylmethyl)carbamoyl)-2-25 methoxybenzenesulfonyl]-3-spirocyclohexaneindol-2-one 450 mg of ethyl glycinate hydrochloride in 20 mg of sodium methylate are placed in methanol. 200 mg of the compound described in Example 57 in 50 ml of DCM are added and the mixture is stirred at RT for 48 hours. It is extracted with DCM and the extract is washed with water, dried, concentrated and then 30 chromatographed on silica using DCM/MeOH (99.5/0.5; v/v) as the eluent.
M.p. = 164*C. example 118 l-(4-Carbamoyl-2-methoxybenzenesulfonyl)-5-chloro-3-35 spirocyclohexaneindol-2-one \ HZ. Oi_i _ •• 2491 55 300 mg of the compound described in Example 57 are mixed with 5 ml of 30% aqueous ammonia, 10 ml of ethanol and 10 ml of DCM. After 1 hour at RT, the mixture is concentrated and extracted with DCM and the extract is washed with water, dried, concentrated and then chromatographed on silica using DCM/MeOH 5 (99/1; v/v) as the eluent to give 109 mg of the expected product.
M.p. = 160*C.
EXAMPLE 119 -Chloro-l-[2-methoxy-4-(N--(2-methoxycarbonylethyl)carbamoyl-10 benzenesulfonyl)]-3-spirocyclohexaneindol-2-one A mixture comprising 320 mg of the compound described in Example 57 and 2 g of methyl aminobispropionate in 30 ml of tetramethylbenzene is refluxed for 30 minutes. It is extracted with AcOEt and the extract is washed with a 1 N solution of hydrochloric acid, dried over sodium sulfate and concentrated. The 15 residue is chromatographed on silica using DCM/MeOH (99/1; v/v) as the eluent to give 100 mg of the expected product.
M.p. = 147*C.
EXAMPLE 120 l-[4-(3-(N-Boc)aminoazetidin-l-ylcarbonyl)-2- 4 methoxybenzenesulfonyl]-5-chloro-3-spirocyclohexaneindol-2-one A mixture containing 300 mg of the compound prepared in Example 57 900 mg of 3-(N-Boc)aminoazetidine, 1 ml of triethylamine, 10 ml of DCM and 10 ml of methanol is stirred at RT for 1 hour. It is concentrated and extracted with 25 ethyl acetate and the extract is washed with a 1 N solution of hydrochloric acid, dried over sodium sulfate and concentrated. The expected product is obtained after chromatography on silica using DCM/MeOH (99/1; v/v) as the eluent. M.p. = 136*C.
EXAMPLE 121 l-[4-(3-Aminoazetidin-l-ylcarbonyl)-2-methoxybenzenesulfonyl]-5-chloro-3-spirocyclohexaneindol-2-one A mixture containing 160 mg of the compound prepared in the previous Example and 3 ml of TFA in 10 ml of DCM is stirred for 30 minutes at RT. The 35 reaction medium is concentrated and crystallized from iso ether and the crystals are water and then filtered off and dried. The product obtair od i!^dijUpjdol 2 1} ftgv 1595 RhCi-lvcJ 56 2 4 H ° u < i J u ml of 1 N sodium hydroxide; the solution is extracted with DCM and the extract is washed with water, dried over sodium sulfate and concentrated. The expected product is obtained after chromatography on silica using DCM/MeOH (96/4; v/v) as the eluent.
M.p. = 145*C.
EXAMPLE 122 -Ethoxy-l-[4-(3-dimethylaminopropoxy)-3-methoxybenzenesulfonyl]-3-spirocyclohexaneindol-2-one hydrochloride 10 A) 5-Ethoxy-l-[4-(3-bromopropoxy)-3-methoxybenzenesulfonyl]-3- spirocyclohexaneindol-2-one A mixture containing 0.5 g of 5-ethoxy-3-spirocyclohexaneindol-2-one, 5 ml of THF and 0.07 g of sodium hydride is stirred at 20*C for 15 minutes, 1.65 g of 4-(3-bromopropoxy)-3-methoxybenzenesulfonyl chloride are then added and 15 the resulting mixture is stirred for 20 hours at RT. It is concentrated under vacuum and extracted with ether and the extract is washed with water and then a 10% solution of sodium carbonate. The expected product crystallizes from pentane and is then recrystallized from iso ether.
M.p. = 114-118'C.
B)5-Ethoxy-l-[4-(3-dimethylaminopropoxy)-3-methoxybenzenesu!fonyl]-3-spirocyclohexaneindol-2-one hydrochloride The compound obtained in the previous step is mixed with 7.5 g of a 33% solution of dimethylamine in ethanol and placed in 10 ml of THF. After stirring for 25 3 hours, the mixture is concentrated under vacuum and taken up in 10 ml of water and the resulting mixture is extracted with ether. The ether phase is treated with 20 ml of 2 N hydrochloric acid, after which solid potassium carbonate is added to render the solution alkaline to pH 9. The oil which precipitates is extracted with DCM. The expected product crystallizes from ether. 30 M.p. = 135-138'C.
EXAMPLE 123 l-[4-Aminosulfonamido-2-methoxybenzenesulfony]-5-chloro-3-spirocyclohexaneindol-2-one 35 0.3 g of the compound prepared in Example 2 is placed in 4 ml of DCM in the presence of 0.5 g of TEA, and 0.3 g of aminosulfonyl chloride, prepared 57 0 /. £ h 0 according to Chem. Ber., 1958, 91,1339-1341, is added. After stirring for 2 days at RT, the medium is concentrated under vacuum and extracted with ether and the extract is washed with water. After drying, the residue is chromatographed on silica using DCM and then AcOEt as the eluent to give the expected product, 5 which crystallizes from ether.
M.p. = 205-208'C.
EXAMPLES 124 and 125 l-(4-Dimethylamino-2-methoxybenzenesulfonyl)-5-methoxy-3-10 spirocyclohexaneindoi-2-one and l-(4-methylamino-2- methoxybenzenesulfonyl)-5-methoxy-3-spirocyclohexaneindol-2-one 500 mg of l-(4-amino-2-methoxybenzenesulfonyl)-5-methoxy-3-spirocyclohexaneindol-2-one are mixed with 1 ml of a 37% aqueous solution of formaldehyde, 10 ml of acetonitrile and 430 mg of sodium cyanoborohydride, and 15 0.12 ml of acetic acid is then added. The temperature of the medium rises and the medium is cooled in an ice bath. Two products of different polarity are formed in succession. 1 ml of an aqueous solution of formaldehyde, 300 mg of sodium cyanoborohydride and 0.12 ml of acetic acid are added to the medium. The mixture is stirred for 1 and a half hours, poured into iced water and then extracted 20 with AcOEt. The extract is washed with water, dried and concentrated to give 2 products, which are separated by chromatography on silica using DCM/AcOEt (98/2; v/v) as the eluent.
M.p. = 210*C (Ex. 124).
M.p. = 170#C (Ex. 125).
TABLE 5 58 Unless indicated otherwise, the substituent R6 is in the 4-position and m = 1.
Ex Ri R2 R5 R6 M.p. *C 126 CI H 2-MeO (,J^C0NH~ 210 127 CI H 2-MeO MeO—^ ^—CONH- 192 128 CI H 2-MeO ^ y~CONH- CF3 188 129 CI H 2-MeO ^ V-CONH- OMe 146 130 CI H 2-MeO ^ y~CH2CONH- Mc 190 131 CI H 2-MeO ^ \—CONH-OCOCH3 147 132 CI H 2-MeO 2-MeO CH3CONH- Mc JT^C 230 133 CI H / J—CONH-Me 205 134 CI H 2-MeO H02qCH2)2-CONH- 205 2 4 9 59 135 CI H H ^ ^-CONH-Mc Me 180 136 CI H 2-MeO ^ ^-CONH- 189 137 CI H 2-MeO Q^CONH-Et 176 138 MeO H 2-MeO / \—CONH-Me 245 139 MeO H 2-MeO Q^conh- 194 140 CI H 2-MeO ^ y~CONH- 141 141 CI H 2-MeO MeO—/ Y-CONH- 140 142 CI H 2-MeO Me-/ J—CONH-Nie 225 143 MeO H 2-MeO MCOCH2CONH- 161 144 MeO H 2-MeO tBuCH->CONH- 209 2 4 60 w EtO EtO ci CH30 EtO EtO EtO EtO ci ci ci H H H H H h H H H h H 2-MeO 2-MeO 2-MeO 2-MeO 2-MeO 2-MeO 2-MeO 2-MeO 2-MeO 2-MeO 2-MeO ^~~^y-conh- Me Me \ Me n-ch2conh- Me Me \ / Me Me \ / N-CONH- n-conh- Me Me \ / Me Et \ / n-conh- n-conh- Et Et \ y N-CONH- Me Pr \ / N-CONH- MeCQNH— Me Mc n-(ch2)2-nhco- Mc \ N-CO- Me 61 ci ci ci H H H 2-MeO 2-MeO 2-MeO Me Me /n-so2- H Me,-n n-s02- C1 MeO ci ci MeO MeO MeO MeO H H H H H H H H 2-MeO 2-MeO 2-MeO 2-MeO 2-MeO 2-MeO 2-MeO 2-MeO MeO CO.
Bz' HC-NHCO- 02N- BzOCO- nhco- nh2- MeO- NHCO- EtO H 2-MeO H2N- MeO 6-MeO 2-MeO MeO- 2 4 9 62 169 EtO H 2-MeO / Y-nhco- 150 170 EtO H 2-MeO BzOCO- 135 171 EtO H 2-MeO HOOC- NMR 172 EtO H 2-MeO McNHCO- 239 173 EtO H 2-MeO -MeO 131 174 EtO H 3-MeO MeO- 127 175 EtO H 2-MeO Me N- Me 167 176 EtO H 3-MeO 4,5-di-MeO 130 177 EtO H 2-MeO ^V-nhco- nle 195 178 EtO H 2-MeO / \-ch2nhco- —N 168 179 EtO h 2-MeO n20 160 180 EtO H 2-Me MeO 176 181 EtO H 3-MeO ch2=ch-ch2o- 130 182 cf3o H 2-MeO MeO 127 24 9 1 183 EtO H 2-MeO Me \ Me / CHNHCO- 171 184 EtO H 2-MeO EtOCOCH2NHCO- 203 185 EtO H 2-MeO o O-CO-NH- 181 186 EtO H 2-MeO 4,5-di-MeO 136 187 EtO H 2-Me 4-MeO, 5-Cl 129 188 EtO H 2-MeO Bz-n V-NHCO- 188 189 EtO H 2-MeO HO(CH2)2-NHCO- 157 190 EtO H 2-MeOCO H 117 191 EtO H 2-MeO Me n-<ch2)3-o- Me' 212 , HC1 192 EtO H 2-MeO CONH- 181 o 193 EtO H MeO- Et \ CH-CONH- Et 206 194 EtO H 2-MeO BzOCOCH2NHCO NMR 195 EtO H 2-MeO € Me yu.
Me 144 64 196 EtO H 2-MeO ^ y~oco- 152 197 EtO H 2-MeO Etx /n-co- Et 148 198 EtO H 2-MeO Et \ . n-cs- Et 128 199 EtO H 2-MeO cn-ch2nh-co- 232 200 EtO H 2-MeO EtOoC-CHo-N-CO- 1 Me NMR 201 EtO H 2-MeO ho2c-ch2nh-co- 137 202 CI H 2-MeO (Et)2N-CO-NH- 194 203 EtO H 2-MeO ^ CONH- 214 204 EtO h 2-McO H2N(CH2)30- 136-140 205 EtO H 2-MeO ■f (CH3)3N(CH2)30-I- 145-150 206 c6h5o h 2-MeO 4-MeO 130 207 EtO H 2-MeO ^ CS-NH- 210 9 4 0 1 r, s~. r v./ i -j 65 208 EtO H 2-MeO EK CH-CON- EK 1 Me 138 209 EtO H 2-MeO EtO-CO-CH2Q- 160 The NMR spectra are run in DMSO at 200 MHz.
NMR of Example 161: 1.3-1.8 ppm : 10H : cyclohexyl 3.5 ppm : 3H: OCH3 .3 ppm : 2H: O-CH2-C6H5 7.2-8.2 ppm : 11H : aromatic protons NMR of Example 171: 1.15 ppm : 3H : CH3 1.19-2 ppm : 10H: cyclohexyl 3.6 ppm : 3H : OCH3 4 ppm : 2H: OCH2-CH3 15 6.7-8.2 ppm : 6H: aromatic protons NMR of Example 200: 1-2.2 ppm : 16H : cyclohexyl + 2ch3 3 ppm : 3H: nch3 20 4-4.4 ppm : 6H : aromatic protons 6.8-8.2 ppm : 6H: aromatic protons A resolution of the signals is observed; this is associated with the amide isomerism.
EXAMPLE 210 l-(4-Benzyloxy-2-methoxybenzenesulfonyl)-5-ethoxy-3-spirocyclohexaneindol-2-one A) Potassium 4-benzyloxy-2-methoxybenzenesulfonate

Claims (19)

2 4 £ 66 This preparation is carried out according to K. Hofmann et al., Liebigs Ann. Chem., 1982,282-297. 10.5 g of 4-benzyloxy-2-methoxybenzene are mixed at 5*C with 30 ml of DCM, and 8 ml of trimethylsilyl chlorosulfonate in 30 ml of DCM are added over 5 15 minutes at a temperature between 5 and 10*C; after stirring for 15 minutes, 59 g of ice are added. The mixture is washed with ethyl ether, treated with potassium hydrogencarbonate and then concentrated under vacuum. After drying, the residue is taken up in 150 ml of methanol. The insoluble material is filtered off at the boil and the expected compound then crystallizes at 5*C. 10 M.p. > 300*C. The structure of the compound is confirmed by analysis of the NMR spectrum. ml of POCI3 and the mixture is refluxed for 3 hours. It is concentrated under vacuum, treated with 20 g of ice and extracted with ethyl ether and the extract is washed with 30 ml of N sodium hydroxide and then water. The medium is concentrated and the oil obtained is then triturated in 30 ml of iso ether. The 20 expected product (0.7 g) crystallizes. M.p. = 95*C. C) l-(4-Benzyloxy-2-methoxybenzenesulfonyl)-5-ethoxy-3-spirocyclohexaneindol-2-one 25 This compound is prepared by the usual procedure. It crystallizes from iso M.p. = 135*C. The structure of the compound is verified by analysis of the NMR spectrum in 2 dimensions (NOESY: Nuclear Overhauser Effect Spectroscopy). 15 B) 4-Benzyloxy-2-methoxybenzenesulfonyl chloride 2.8 g of the compound prepared in the previous Example are mixed with 30 ether. 30 The compound of the next Example is subsequently prepared by debenzylation. EXAMPLE 211 5-Ethoxy-l-(4-hydroxy-2-methoxybenzenesulfonyl)-3-35 spirocyclohexaneindol-2-one M.p. = 209*C. 67 whati'we claim \Sl-
1. A compound of the formula ri r 2 V^N o so. -r5 (R6)m (0 in which - and R2 are each independently a hydrogen, a hydroxy, a C4-C4-CO-halogenoalkoxy, a halogen, a Ci-C4-alkyl, a trifluoromethyl, a C4-C7- 10 alkoxy, a C]_-C4-polyhalogenoalkoxy, a C2-C4~co-hydroxyalkoxy, an co-methoxyalkoxy in which the alkyl is C2-C4, a C2-C4-co-aminoalkoxy which is free or substituted by one or two Ci-C4~alkyls, a C3-C7-cycloalkoxy; a jj cycloalkylmethoxy in which the cycloalkyl is C3-C7; a phenoxy; a benzyloxy; a Ci-C4~alkylthio; a phenylthio; a nitro; an amino which is free or substituted 15 by one or two Cj-C4-alkyls; a cyano; a Ci-C4~acyl; a C^-C4-acyloxy; a C^-C4~alkylsulfonamido; a phenylsulfonamido; a C;[-C4-alkylamido; a C4-C4~alkoxycarbonylamino; or a ureido which is unsubstituted or substituted by a phenyl or by one or two C4-C4- alkyls; and - R3 and R4 are each independently a C^-Cg-alkyl, a C3-C7-cycloalkyl, a 20 phenyl, a benzyl, or a cycloalkylmethyl in which the cycloalkyl is C3-C7; lor - R3 and R4 together form a group -(CH2)pX(CH2)q-; or - R3 and R4, together with the carbon to which they are bonded, form an 25 optionally fused, saturated or unsaturated C3-C10 hydrocarbon ring which is unsubstituted or substituted by one or more C^-^-alky! groups or by a C3-C5~spirocycloalkyl; or else n.z. paten 1 office 2 h MOV 1995 received c.-t ^ ijo -68- R| is as defined above; R4 is a C^-C^alkyl, a C3-C7cycloalkyl, a phenyl, a benzyl, a cycloalkylmethyl in which the cycloalkyl is C3-C7, and R2 is located in the 4- position of the indole and forms a group (CH2)3 with R3; R5 and R(5 are each independently a hydrogen, a halogen; a Cj-C7-alkyl; a trifluoromethyl; a cyano; a nitro; an amino which is free or substituted by one or 5 two Ci-C7-alkyls; a hydroxyarnino; a hydroxy; a carboxy; a group OR7; a group SR7; a Ci-C7~acyl; a Ci~C7-alkoxycarbonyl; a phenoxycarbonyl; a benzyloxycarbonyl; a carbamoyl substituted by groups R'g and R"6; a thiocarbamoyl which is free or substituted by one or two C]-C7-alkyls; a sulfamoyl; an alkylsulfamoyl or dialkylsulfamoyl in which the alkyl is Oj-C7; 10 a group SC^R^; an alkylsulfonamido in which the alkyl is C1-C7; a group COR'7; a group NR8R9 or a group CO-NH-CH(Rio)-CORi2; appropriate, the phenyl group forming part of the substituent R5 and/or Rg can be unsubstituted or monosubstituted or polysubstituted by a Ci-C7~alkyl, a trifluoromethyl, a methoxy, a halogen, a sulfamoyl, an alkylsulfamoyl in which 15 the alkyl is C4-C7, a carboxy, an alkoxycarbonyl in which the alkyl is C\-Cq, a C]^-C7-acyloxy or an imidazolyl; - R'g and R"(j are each independently hydrogen, a Cx~C7-alkyl which is unsubstituted or substituted by R'"(5, a phenyl, a pyridyl, a methylpyridyl, a piperidin-4-yl or a methylpiperidin-4-yl; 20 - R'"6 is a hydroxy, a cyano, a carboxy which is free or esterified by a C4-C7-„ alkyl or by a benzyl, a phenyl, a pyridyl, a methylpyridyl, or an amino which is free or substituted by one or two C]-C7-alkyls; - R7 is a Ci~C7-aIkyl, a phenyl, a benzyl, a C3-C7~cycloalkyl, a C2-C4~ alkenyl, a C^-C7-a)-halogenoalkyl, a Ci-C7-polyhalogenoalkyl, a C4-C7- 25 acyl, a C;[-C7-co-carboxyalkyl which is free or esterified by a Ci-C4-alkyl or by a benzyl, or a C2-C7^aminoalkyl in which the amino group is free, substituted by one or two C^-C^alkyls or in the form of an ammonium ion; - R'7 is a piperazin-l-yl group which is unsubstituted or substituted in the 4-position by a group R"7, a piperidino group which is unsubstituted or 30 substituted in the 4-position by a group R"^, an azetidin-l-yl group which is unsubstituted or substituted in the 3-position by a group R'"7, or a pyridyl group which is unsubstituted or substituted by a methyl; - RM7 is a C^-C4-alkyl, a phenyl, abenzyl oraCi-C4~acyl; - rmi7 is r"7 or an amino which is free or carries a protecting group; 35 n.z. fat, t rvtlctl Zh 69 24 9 1 58 - Rg and R9 are each independently a hydrogen, a C1-C7-alkyl, a phenyl or a benzyl; or R9 can also be a Ci-C7-acyl, a C^-C7thioacyl, a cycloalkylcarbonyl in which the cycloalkyl is C3-C7, a cycloalkylthiocarbonyl in which the cycloalkyl is C3-C7, a Ci-C^co-aminoacyl, a C1-C4-co-hydroxyacyl, a C4- 5 C4-(o-benzyloxyacyl, a phenoxycarbonyl, a thicnocarbonyl, a pyridylcarbonyl, a methylpyridylcarbonyl, a q-C^alkoxycarbonyl, a benzoyl, a phenacetyl, a group CO-CHtRioj-NRnR'-^, a group CH(R10)CO2Rn, a group (CH2)tCORi2, a group CO(CH2)tCOR12, or a carbamoyl which is unsubstituted or substituted by a phenyl or by one or two C1-C4 alkyls; m is 1, 2, 3, 4 provided that when m is 2, 3 or 4 each Rq substituent is independently selected from a from a halogen, a Ci-C7-alkyl and a Ci-C7-alkoxy; provided that when m is 1, R3 is methyl, R4 is methyl or ethyl, Rg is not methyl; p and q are each an integer, their sum being 3 to 6; - t is an integer from 1 to 5; 15 - X is oxygen, sulfur or a group NRi3; - Rio *s hydrogen, a (4-C4-alkyl or a benzyl; - Rn and R';q are each independently hydrogen or a Ci~C4-alkyl; - R^2 is a hydroxy, a Ci~C4-alkoxy or an amino which is unsubstituted or substituted by one or two Ci-C4-alkyls; and 20 - R13 is hydrogen, a Ci~C4-alkyl, a phenyl, a benzyl, a Ci~C4-acyl, a C4-C4-„ alkoxycarbonyl or a carbamoyl which is unsubstituted or substituted by one or two Ci-C4-alkyls; and its salts where appropriate.
2. A compound of formula (I) according to claim 1 wherein R^ is a chlorine 25 atom or an ethoxy group in the 5-position of; !ie indole and R2 is hydrogen.
3. A compound of formula (I) according to claim 1 wherein R3 and R4, together with the carbon to which they arc bonded, form a C3-C10 hydrocarbon ring.
4. A compound of formula (I) according to claim 1 wherein R3 and R4, 30 together with the carbon to which they are bonded, form a cyclohexane which is unsubstituted or substituted by one or two Ci-C7~alkyl groups or by a C3-C5- spirocycloalkyl, a cyclohcptane, an adamantane or a tricyclo[5.2.1.02-6]dece?8f! ... v - ene. ^ v a r*
5. A compound of formula (I) wherein R3 and R4, together with the carbon to 35 which they are bonded, form a piperidine-4 or N-methylpiperidine-4 rin|. &£ c ■To, s5 / V £ 0 zw ibb 70
6. A compound of formula (I) according to claim 1 wherein R5 and Rg are each a methoxy.
7. A compound of formula (I) according to claim 1 wherein R5 in the 2-position is a methoxy and Rg in the 4-position is a Ci~C7-acylamino, a C4-C4-dialkylureido or an alkoxycarbonylalkylcarbamoyl in which the alkyl groups are
8. A compound of formula (I) according to claim 1 wherein R^ is in the 5-position and R2 is hydrogen.
9. A compound according to claim 1 of the formula in which R^ , R2, R3, R4 and R5 are defined as indicated above for formula (I) in claim 1, and its functional derivatives of the carboxylic acid function.
10. A compound according to claim 1 of the formula C1-C7. (IX) COOH R SCb (X) 71 I 3 0 in which R]_, R2, R3, R4 and R5 are defined as indicated above for formula (I) in claim 1, and its salts where appropriate.
11. A compound according to claim 1 of the formula ri r' R- r/ n' o so' - R< (XI) OH in which R^, R2, r3, r4 and r5 are defined as indicated above for formula (I) in claim 1,
12. A compound according to claim 1 of the formula HO. r. o 'N' so' -r5 (re)m (xii) in which R3, R4, R5, Rg and m are defined as indicated above for formula (I) in claim 1,
13. A compound according to claim 1 of the formula 72 249158 R- "NH o N' so' - R< (R6) m (xm) in which R^, R2, R5, Rg and m are defined as indicated above for formula (I) in claim 1.
14. A method of preparing a compound (I) according to claim 1, characterized in that: a benzenesulfonyl halide of the formula hal-s°2-^^fr5 (R ) m ^ VI m (in) lCF in which R'5 and Ryj are respectively either R5 and Rg as defined for formula (I) in claim 1. precursor groups of R5 and Rg, is reacted with a 2-oxoindole disubstituted in the 3-position, of the formula 15 20 r- 1 t: r'2 / r, N' H =0 ai) in which R'^ and R'2 are respectively either R^ and R2 as defined for formula (I) in claim 1, or percursor groups of Ri and R2, and R3 and R4 are as defined for formula (I) in claim 1; and - either, if R'j_ = Rj_, R'2 = R2, R'5 = R5 and Ryj = Rg, the resulting compound of formula (I) is isolated; - or, if any one of the groups R'i, R'2, R'5 and Ryj is respectively a precursor group of Rj_, R2, R5 and/or Rg, tj^c^ppund ,obtained 2 h MOV £35 received is subjected to a 249158 73 subsequent treatment in order to prepare the compound of formula (I) by conversion of any one of the groups R']_, R'2> R'5 and Ryi to R]_, R2, r5 and Rg respectively.
15. A compound of the formula R 2 r, z. r/ t=0 N' H (II)' in which - R^ and R2 are each independently a hydrogen, a hydroxy, a C4-C4-g)-10 halogenoalkoxy, a halogen, a Ci-C4~alkyl, a trifluoromethyl, a C4-C7- alkoxy, a Cx-C4~polyhalogenoalkoxy, a C2-C4-co-hydroxyalkoxy, an co-methoxyalkoxy in which the alkyl is C2-C4, a C2-C4~co-aminoalkoxy which is free or substituted by one or two Ci-C4-alkyls, a C3-C7-cycloalkoxy, a cycloalkylmethoxy in which the cycloalkyl is C3-C7, a phenoxy, a benzyloxy, 15 a Ci-C4-alkylthio, a phenylthio, a nitro, an amino which is free or substituted by one or two C;pC4-alkyls, a cyano, a C^-C4~acyl, a Ci-C4-acyloxy, a Ci-^-alkylsulfonamido, a phenylsulfonamido, a Ci-C4-alkylamido, a C4-.2 C4~aIkoxycarbonylamino or a ureido which is unsubstituted or substituted by a phenyl or by one or two Ci-C4~alkyls; and 20 - R3 and R4, together with the carbon to which they are bonded, form . an adamantane, . an indane or a hexahydroindane which are unsubstituted or substituted by one or more C^-C7-alkyl groups, a tricyclo[5.2.1.02-6]decane or a tricyclo[5.2.1.02-6]dec-8-ene which are 25 unsubstituted or substituted by one or more C^-^-alky! groups, or a C4-C8 hydrocarbon ring substituted by one or more Ci-C7~alkyl groups or by a C3~C5-spirocycloalkyl; or else - R3 and R4 together form a group -(CH2)p-X(CH2)q- in which p and q are 30 integers whose sum is frcm 3 to 6 and X is oxygen, sulfur or a group NR13, R13 being a phenyl, a benzyl, a C^-^-acyl, a Ci-C4~alkoxycarbonyl or a carbamoyl which is unsubstituted or substituted by one or; two C4-C4- alkyls, N.Z. P' '■if 249158 74 with the limitation that if CR3R4 is adamantane, R^ and R2 are other than hydrogen.
16. A compound of the formula in which - Ri is a hydroxy, a Ci-C4-Q)-halogenoalkoxy, a halogen, a Ci-C4-alkyl, a trifluoromethyl, a Ci-C7~alkoxy, a C]-C4-polyhalogenoalkoxy, a C2-C4~(o -hydroxyalkoxy, an oo-methoxyalkoxy in which the alkyl is C2-C4, a C2-C4-co-aminoalkoxy which is free or substituted by one or two C;[-C4-alkyls, a C3-C7-cycloalkoxy, a cycloalkylmethoxy in which the cycloalkyl is C3-C7, a phenoxy, a benzyloxy, a Ci-C4-alkylthio, a phenylthio, a nitro, an amino which is free or substituted by one or two C;[-C4-alkyls, a cyano, a C4-C4-acyl, a Ci-C4~acyloxy, a Ci-C4-alkylsulfonamido, a phenylsulfonamido, a C^-C4-alkylamido, a Ci-C4-alkoxycarbonylamino or a ureido which is unsubstituted or substituted by a phenyl or by one or two C]-C4-alkyls; - R3 and R4 together form a group -(CH2)pX(CH2)q~; or - R3 and R4, together with the carbon to which they are bonded, form an optionally fused, saturated or unsaturated C3-C10 hydrocarbon ring which is unsubstituted or substituted by one or more C]-C7-alkyl groups or by a C3-C5-spirocycloalkyl; - p and q are each an integer, their sum being 3 to 6; - X is oxygen, sulfur or a group NR13; and - Rj3 is hydrogen, a Cx~C4-alkyl, a phenyl, a benzyl, a Ci-C4-acyl, a C1-C4-alkoxycarbonyl or a carbamoyl which is unsubstituted or substituted by one or two Ci-C4-alkyls, with the limitation that - if R^ is methoxy, CR3R4 is other than a pyrrolidine-3 which is unsubstituted or N-substituted by a C^-C4-alkyl, and if R^ is a halogen, CR3R4 is other than a pentane.
17. A compound according to claim 16 in which^RjJs.ethpxy. n.z. patent ■- j 2') hw is© 75 249158
18. A compound of the formula so2ci OAlk V (III)' YRV when used as a starting compound for the preparation of a compound of formula I as claimed in claim 1, in which - Alk is a Ci-Cy-alkyl; - Y is O or S; and - Ry is a Ci-Cy-alkyl, a C3-C7-cycloalkyl, a C2-C4-alkenyl, a C3-C7-CO-halogenoalkyl, a Ci-C7-polyhalogenoalkyl, a benzyl, a Ci-C7~acyl or a Cj-C7-co-carboxyalkyl esterified by a C;[-C4-alkyl or by a benzyl.
19. Pharmaceutical composition in which a compound according to any one of claims 1 to 8 is present as the active principle and a pharmaceutical^ acceptable excipient. 12. Pharmaceutical composition in which a compound according to any one of claims 1 to 8 is present in association with another active principle and a pharmaceutically acceptable excipient. ELF SANOFI n.z. f f) r. .'T:- 2't ra • b::,? received
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