EP1414805A1 - Indazol- oder indolderivate, deren verwendung in der humanmedizin und insbesondere in der onkologie - Google Patents

Indazol- oder indolderivate, deren verwendung in der humanmedizin und insbesondere in der onkologie

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Publication number
EP1414805A1
EP1414805A1 EP02791508A EP02791508A EP1414805A1 EP 1414805 A1 EP1414805 A1 EP 1414805A1 EP 02791508 A EP02791508 A EP 02791508A EP 02791508 A EP02791508 A EP 02791508A EP 1414805 A1 EP1414805 A1 EP 1414805A1
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EP
European Patent Office
Prior art keywords
phenyl
dihydro
indazole
indazol
methanone
Prior art date
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EP02791508A
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English (en)
French (fr)
Inventor
Conception Nemecek
Patrick Mailliet
Fabienne Thompson
Michel Tabart
Eric Bacqu
Sylvie Wentzler
Cécile Combeau
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Aventis Pharma SA
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Aventis Pharma SA
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Publication of EP1414805A1 publication Critical patent/EP1414805A1/de
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • 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
    • C07D209/36—Oxygen atoms in position 3, e.g. adrenochrome
    • 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
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to new chemical compounds - derivatives of indazoles or indoles, their use in human medicine and more particularly in oncology.
  • the compounds of the present invention act more particularly as agents which bind to tubulin and optionally inhibit the vaseularization of tumors.
  • the microtubules of eukaryotic cells constitute a dynamic assembly and disassembly system in which the dimers of tubulin polymerize to form microtubules.
  • the agents which inhibit the polymerization of microtubules in the same way inhibit mitosis and consequently proliferation "from cells and thus allow cell death.
  • the subject of the present invention is new compounds corresponding to one of the following formulas (1) or (2):
  • DP in which the heterocycle containing XY forms an aromatic 5-membered ring and • Ar is chosen from phenyl groups optionally substituted by one or more halogen atoms or by alkyl, alkoxy, thioalkyl, alkylamino or dialkylamino radicals, the alkyl parts of which may optionally form together a 3 to 6-membered ring which may contain a second heteroatom chosen from 0,
  • X and Y are chosen from N or CH with at least one of them representing a nitrogen atom N;
  • Z represents H or a sulfonyl or acyl or 4-aminophenyl group
  • Ri H, alkyl, cycloalkyl (from 3 to 6 carbon atoms), or Ar (having the same definition as above); it is understood that, when Ri represents an Ar group, the two Ar groups may be identical or different;
  • R ' represents H or alkyl
  • R 2 represents a substituent such as: a cyano group, a C (0) -ORa ⁇ radical in which Ra-i represents a methyl, ethyl or isopropyl radical a C (0) -NHRa 2 radical in which Ra 2 represents the cyclopropyl radical or C (0) -N (Ra 2 ') in which N (Ra 2 ') represents an aziridinyl or azetidinyl radical, optionally substituted by an alkyl group or Ar (having the same definition as above) ), a radical C (0) -N (Ra 3 ) -ORa 3 in which the groups Ra, which are identical or different, represent a methyl, ethyl or cycloalkyl radical, a radical C (0) Ra in which Ra 4 represents a group Ar (as defined above) or a cycloalkyl radical, optionally substituted by an alkyl group or Ar (having the same definition as above), a
  • R 2 represents a carboxyl group or an amino, alkylamino, dialkylamino or cycloalkylamino group.
  • R 3 represents an alkyl radical bu - -. . ⁇ - C3-C6 cycloalkyl or an aryl ring as defined above or- a C2-C6 alkenyl or C2-C6 alkynyl chain.
  • alkyl parts mentioned are in a straight or branched chain and contain from 1 to 4 carbon atoms, unless otherwise stated.
  • cycloalkyl radicals mentioned contain from 3 to 5 carbon atoms, unless otherwise stated.
  • Diagram 2bis Synthesis of Indazoles of general formula 1a (continued)
  • aryl-acetaldehydes of general formula (A) with methylvinyl ketone, or more generally with an alkyl vinyl ketone, hot in an alkaline medium, generally in the presence of soda or potash at the reflux of a alcohol such as ethanol, as for example under the conditions described by JC Amedio (Synth. Comm. 1998, 28, 3895-3906), leads to the 4-aryl-cyclohex-2-enones of general formula (B).
  • the heating of the reaction medium is generally carried out either at reflux of toluene, in the presence of an acid such as paratoluenesulfonic acid or acetic acid, or in the presence of a chlorinating agent such as phosphorus oxychloride or chloride of thionyl in the presence of an organic base such as 1, 8-diazabicyclo [5.4.0] undec-7-ene or pyridine.
  • the reaction can either be carried out in a single “one pot” stage, or in two or three stages by isolating one or the other or the two intermediates formed according to diagram 4 below: Diagram 4:
  • the treatment of ethyl 6-aryl-6,7-dihydro-1 H-indazole-3-carboxylates of general formula (C), in alkaline medium leads to 6-aryl-6,7- acids 1-dihydro-H-indazole-3-carboxylic acid of general formula (D).
  • the operation is carried out by the action of lithium hydroxide, or sodium hydroxide, in a solvent such as ethanol, at a temperature between 20 ° C. and the reflux temperature of the reaction medium.
  • 6-aryl-6,7-dihydro-1H-indazole-3-carbonitriles of general formula (E) can be prepared according to the conditions described by H. Ebel et al. (Tetrahedron Lett 1998, 39 (50), 9165-9166), by prior coupling of the corresponding acids of general formula (D) with NH 3 (28% aqueous solution), under the action of a coupling agent such as 1- (3-dimethylaminopropyl) -3-ethylcarbodimiide hydrochloride (EDCI) in the presence of 1-hydroxybenzotriazole hydrate (HOBT), at room temperature.
  • a coupling agent such as 1- (3-dimethylaminopropyl) -3-ethylcarbodimiide hydrochloride (EDCI) in the presence of 1-hydroxybenzotriazole hydrate (HOBT), at room temperature.
  • the 6-aryl-6,7-dihydro-1 H-indazole-3-carboxamides obtained then undergo dehydration, for example according to the conditions described by C. Janiak et al. (Synth Commun 1999, 29 (19), 3341-3352), by 0 action of trifluoroacetic anhydride in dioxane, in the presence of pyridine, at a temperature between 0 ° C and 20 ° C.
  • esters of 6-aryl-6,7-dihydro-1H-indazole-3-carboxylic acids of general formula (F) can be obtained by treatment of the corresponding acids of general formula (D) with an alcohol, generally used as reaction solvent, in the presence of a catalytic amount of sulfuric or para-toluenesulfonic acid.
  • the 6-aryl-6,7-dihydro-1H-indazole-3-carboxamides of general formula (G1) or (G2) or (G3) are obtained by coupling the corresponding acids of general formula (D) with the 0 corresponding amines.
  • the coupling takes place in a organic solvent, such as dichloromethane, in the presence of a coupling agent, such as 1- (3-dimethylaminopropyl) -3- ethylcarbodimiide hydrochloride (EDCI), in the presence of 1-hydroxybenzotriazole hydrate (HOBT), to a temperature close to room temperature.
  • a coupling agent such as 1- (3-dimethylaminopropyl) -3- ethylcarbodimiide hydrochloride (EDCI)
  • HOBT 1-hydroxybenzotriazole hydrate
  • the ketones of general formula (H) can be obtained by condensation of an organometallic such as an organolithian or an organomagnesium on the amide of general formula (G3) where Ra3 represents a methyl group, according to the conditions described by M. Kratzel et al. (J. Chem. Soc, Perkin Trans. 1, 1997,1009-1012). 'Generally, tetrahydrofuran is used as solvent and the reaction is conducted at a temperature between 0 ° C and 25 ° C.
  • the aldehydes of general formula (H) where GP represents a 4-methylphenylsulfonyl group can be obtained by reduction of the compounds of general formula (G3) in an organic solvent such as tetrahydrofuran by a hydride such as diisobutylaluminum hydride to a temperature close to 0 ° C.
  • a base such as sodium acetate, triethylamine or - pyridine.
  • the 4-methylphenylsulfonyl protective group can be cleaved by the action of a base such as sodium hydroxide (in aqueous solution) in an organic solvent such as dioxane at a temperature between 20 ° C. and the temperature reflux of the reaction medium.
  • a base such as sodium hydroxide (in aqueous solution) in an organic solvent such as dioxane at a temperature between 20 ° C. and the temperature reflux of the reaction medium.
  • 6-aryl-6,7-dihydro- (4-methylphenyl) sulfonyl-indazole-3-carboxylic acids of general formula (J) can be obtained by protecting the NH group present in the acids of general formula (D ), by the action of 4-methylphenylsulfonyl chloride, in an organic solvent, such as ethyl ether, in the presence of a base such as aqueous sodium hydroxide, at a temperature close to room temperature.
  • 6-aryl-6,7-dihydro- (2-trimethylsilanyl-ethoxymethyl) -indazole-3-carboxylic acids of general formula (J) can be obtained by protecting the NH group present in the acids of general formula ( D), by the action of (2-chloromethoxy-ethyl) -trimethyl-silane, in an organic solvent, such as dimethylformamide, in the presence of a base such as sodium hydride, at a temperature close to room temperature.
  • the 3-amino-6-aryl-6,7-dihydro- (4-methylphenyl) ulfonyl-indazoles or 3-amino-6-aryl-6,7-dihydro- (2-trimethylsilanyl- ethoxymethyl) ⁇ indazoles of general formula (K) can be obtained from 6-aryl-6,7-dihydro- (4-methylphenyl) sulfonyl-indazole-3-carboxylic acids or from 6-aryl-6,7-dihydro- acids ( 2-trimethylsilanyl-ethoxymethyl) -indazole-3-carboxyls of general formula (J), by a Curtius type rearrangement, in the presence of an alcohol, according to the conditions described by M.Sibi et al. (J. Org. Chem. 1997, 62, 5864-5872), followed by cleavage of the carbamate obtained.
  • M.Sibi et al. J. Org.
  • Curtius a mixture of toluene and tert-butanol as solvent and triethylamine is added to the reaction medium. This is then brought to reflux before addition of the diphenylphosphoryl azide. After rearrangement at this temperature, the resulting carbamate is isolated and then treated with trifluoroacetic acid, in dichloromethane, at a temperature between
  • 3-halo-6-aryl-6,7-dihydro- (4-methylphenyl) sulfonyl-indazoles or 3-halo-6-aryl-6,7-dihydro- (2-trimethylsilanyl-ethoxymethyl) - indazoles of general formula (L) can be obtained by diazotization of 3-amino-6-aryl-6,7-dihydro- (4-methylphenyl) sulfonyl-indazoles or 3-amino-6-aryl-6,7-dihydro - (2-trimethylsilanyl- ethoxymethyl) -indazoles corresponding to general formula (K), followed a Sandmeyer-type reaction.
  • the iodized derivative it is possible to operate according to the conditions described by LB Townsend et al. (J. Med. Chem 1995, 38 (20), 4098-4105), by the action of isoamyl nitrite in diiodomethane, at a temperature between 80 and 120 ° C.
  • the operation is carried out by the action of an alkyl nitrite, for example isoamyl, in acetonitrile, at a temperature between 0 ° C. and 60 ° C., in the presence of a copper halide II (chloride or bromide) or dibroma.
  • sodium nitrite can be made to act in an aqueous acid medium to obtain the intermediate diazonium salt.
  • This is treated with a copper halide 11 (chloride or bromide) or with a mixture of copper sulfate II and a halide salt (for example NaBr).
  • the 3,6-diaryl-6,7-dihydro-1-H-indazoles of general formula (M), as well as the 3-heteroaryl-6-aryl-6,7-dihydro-1-H-indazoles of general formula (N), can be obtained by Suzuki-type coupling of 3-halo-6-aryl-6,7-dihydro- (4-methylphenyl) suIfo ⁇ yl- indazoles or 3-halo-6-aryl-6, 7-dihydro- (2-trimethylsilanyl-ethoxymethyl) -indazoles of general formula (L) (preferentially the iodized derivative), with the corresponding aryl / weatheraryl-boronic acids or esters followed by cleavage of the tosyl group.
  • the products of general formula (M) and (N) can be obtained by coupling of halogeno-aromatic or heteroaromatic derivatives (preferably iodinated or brominated derivatives), with 6-aryl-6,7-dihydro- acids or esters ( 4-methylphenyl) sulfonyl-indazoles-3-boronic or 6-aryl-6,7-dihydro- (2-trimethylsilanyl-ethoxymethyl) -indazoles- 3-boronic, themselves obtained by coupling bis-pinacolato borane and - 3-halo-6-aryl-6,7-dihydro- (4-methylphenyl) sulfonyl-indazoles or 3-halo-6-aryl-6,7-
  • heterocycles of general formula (N) where Het represents a 3- (3-methyl- [1,2,4] oxadiazol-5-yl) radical it is possible to operate according to the conditions described by KE Andersen et al. . (Eur. Med. Chem. 1994, 29, 393-399), by reaction of the chlorides of 6-aryl-6,7-dihydro- (4-methylphenyisulfonyl) -1 H-indazole-3-carboxyIiques acids of general formula ( J) with N-hydroxy-acetamidine, at the reflux of pyridine, followed by cleavage of the tosyle group as described above.
  • the chlorides of 6-aryl- 6,7-dihydro- (4-methylphenylsulfonyl) -1 H-indazole-3-carboxylic acids can be obtained by the action of oxalyl chloride in dichloromethane between 20 ° C and 40 ° C or alternatively by the action of thionyl chloride, at the reflux of toluene, on the 6-aryl-6,7-dihydro- (4-methylphenylsulfonyl) -1H-indazole-3-carboxyIic acids of corresponding formula (J).
  • N-hydroxy-acetamidine is prepared as described by CD. Clifford (J. Med. Chem. 1986,29, 11, 2174-2183), from acetonitrile, by the action of hydroxylamine in the presence of soda, at reflux in aqueous ethanol.
  • the carboxamides of general formula (O) are obtained by prior condensation of the corresponding carboxylic acids or acyl chlorides with the amines 6-aryl-6,7-dihydro- (4-methylphenyl) sulfonyl-indazole-3- yl of general formula (K).
  • the coupling takes place in an organic solvent, such as dichloromethane, in the presence of a coupling agent, such as 1- (3-dimethylaminopropyl) -3-ethylcarbodimiide hydrochloride (EDCI).
  • EDCI 1-hydroxybenzotriazole hydrate
  • HOBT 1-hydroxybenzotriazole hydrate
  • the amides of general formula (O) are obtained More particularly, the amines of general formula (P) are obtained by cleavage of the tosyle group from the amines of general formula (K), as described above.
  • the amines of general formula (Q) are obtained by reaction of the amines of general formula (P) with the corresponding sulfonyl or acyl chlorides, in the presence of a base such as triethylamine or pyridine, in a chlorinated solvent (as dichloromethane) or ethereal (such as tetrahydrofuran), at a temperature between 0 ° C and the reflux temperature of the solvent.
  • the compounds of formula (V) can be obtained by aromatic nucleophilic substitution of the fluorine of 1-fluoro-4-nitro-benzene by the esters of general formula (C) in the presence of a base such as, for example, hydride of sodium in an organic solvent such as dimethylformamide at a temperature between 20 ° C and 80 ° C followed by the chemical reduction of the nitro group by a metal such as zinc in an acid medium such as acetic acid at a temperature close to " 20 ° C.
  • a base such as, for example, hydride of sodium in an organic solvent such as dimethylformamide at a temperature between 20 ° C and 80 ° C
  • a metal such as zinc in an acid medium such as acetic acid
  • the compounds of general formula (W) can be obtained from the compounds (V) according to the methods described for the synthesis of the compounds (H), (F), (G1) (G2) and (I) from the compounds (D) (see diagram 1a).
  • the amines of general formula (S) are obtained by reaction of the halogenated derivatives (preferably the chlorinated derivative) of general formula (L) with the corresponding amines, at atmospheric pressure or optionally under pressure (in an autoclave), in a solvent such as an alcohol. , pyridine, dimethylformamide or dimethylsulfoxide, at a temperature between room temperature and the reflux temperature of the solvent, optionally in the presence of a base such as triethylamine.
  • the amines of general formula (T) are obtained either from the amines of general formula (S) by cleavage of the tosyl group according to the conditions described above, or directly by concomitant detosylation from the halogen derivatives (L) under the conditions described above to access the amines (S).
  • the amines of general formula (U) are obtained by reaction of the amines of general formula (T) with the corresponding sulfonyl or acyl chlorides, in the presence of a base such as triethylamine or pyridine, in a chlorinated solvent (as the dichloromethane) or ethereal (such as tetrahydrofuran), at a temperature between 0 ° C and the reflux temperature of the solvent.
  • a base such as triethylamine or pyridine
  • a chlorinated solvent as the dichloromethane
  • ethereal such as tetrahydrofuran
  • the ethyl 5-aryl-4,5-dihydro-2H-isoindole-1-carboxylates of general formula (X) can be obtained by analogy with JT Gupton et al. (Tétrahedron 1998, 54, 5075-5088): the 4-aryl-cyclohexen-2-ones of general formula (B) are treated with N, N-dimethylformamide dimethylacetal, at reflux of the N, N-dimethylformamide, to give the 4-aryl-6-dimethylaminomethylene-cyclohexen-2-ones of general formula (V) which, by the action of phosphorus oxychloride in an organic solvent such as dichloromethane, at a temperature of about 40 ° C and after hydrolysis in aqueous THF, at reflux, lead to 2-chloro-5-aryl-cyclohexa-1, 3-dienecarbaldehydes of general formula (W).
  • an organic solvent such as dichloromethane
  • the present invention also relates to therapeutic compositions containing a compound according to the invention, in combination with a pharmaceutically acceptable carrier according to the mode of administration chosen.
  • the pharmaceutical composition can be in solid, liquid or liposome form.
  • solid compositions mention may be made of powders, capsules, tablets.
  • oral forms it is also possible to include the solid forms protected from the acid environment of the stomach.
  • the supports used for the solid forms consist in particular of mineral supports such as phosphates, carbonates or organic supports such as lactose, celluloses, starch or polymers.
  • Liquid forms are made up of solutions of suspensions or dispersions. They contain as dispersive support either water or an organic solvent (ethanol, NMP or others) or mixtures of surfactants and solvents or complexing agents and solvents.
  • the administered dose of the compounds of the invention will be adapted by the practitioner according to the route of administration of the patient and the state of the latter.
  • the compounds of the present invention can be administered alone or in admixture with other anticancer agents.
  • anticancer agents include anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents, anticancer agents
  • alkylating agents and in particular cyclophosphamide, melphalan, ifosfamide, chlorambucil, busulfan, thiotepa, prednimustine, carmustine, lomustine, semustine, steptozotocine, decarbazine, temozolomide, procarbazine and l 'hexamethylmelamine
  • platinum derivatives such as cisplatin, carboplatin or oxaliplatin
  • antibiotic agents such as bleomycin, mitomycin, dactinomycin
  • antimicrotubule agents such as vinblastine, vincristine, vindesine, vinorelbine, taxoides (paclitaxel and docetaxel) • anthracyclines such as doxorubicin, daunorubicin, idarubicin, epirubicin, mitoxantrone, losoxantrone
  • fluoropyrimidines such as 5-fluorouracil, UFT, floxuridine,
  • cytidine analogues such as 5-azacytidine, cytarabine, gemcitabine, 6-mercaptomurine, 6-thioguanine
  • adenosine analogs such as pentostatin, cytarabine or fludarabine phosphate
  • anti-vascular agents such as combretastatin or colchicine derivatives and their prodrug. It is also possible to combine the compounds of the present invention with radiation treatment. These treatments can be administered simultaneously, separately, sequentially. The treatment will be adapted to the patient to be treated by the practitioner.
  • the products of the present invention will be used in their first therapeutic application to inhibit the growth of cancer cells and at the same time the growth of new vessels.
  • the inhibition of the growth of new vessels is determined by a cell detachment test as described below.
  • Tubulin is purified from pig brains according to published methods (Shelanski et al., 1973, Proc. Natl. Acad. Sci.USA, 70, 765-768. Weinberger et al ., 1975, Proc. Natl. Acad. Sci.USA, 72, 1858-1862). Briefly, the brains are ground and centrifuged in an extraction buffer. Tubulin, contained in the supernatant of the extract undergoes two successive cycles of polymerization at 37 ° C and depolymerization at 4 ° C, before being separated from MAPs (Microtubule Associated Proteins) by chromatography on a P11 phosphocellulose column (Whatman) .
  • MAPs Microtubule Associated Proteins
  • Tubulin thus isolated is more than 95% pure. It is stored in a buffer called RB / 2 30% glycerol, the composition of which is MES-NaOH [2- (N-morpholino) -ethanesulfonic acid] 50 mM, pH 6.8; 0.25 mM MgCl 2 ; 0.5 mM EGTA; glycerol 30% (v / v), GTP (guanosine-5'-tri-phosphate) 0.2 mM.
  • MES-NaOH 2- (N-morpholino) -ethanesulfonic acid
  • tubulin in microtubules is followed by turbidimetry as follows: the tubulin is adjusted to a concentration of 10 ⁇ M (1 mg / ml) in the RB / 2 30% glycerol buffer to which 1 mM GTP and 6 mM MgCl 2 are added. .
  • the polymerization is triggered by an increase in temperature from 6 ° C to 37 ° C in a cell with a 1 cm optical path, placed in a UVIKON 931 spectrophotometer (Kontron) equipped with a thermostat-controlled cell holder.
  • the increase in the turbidity of the solution is followed at 350 nm.
  • the products are dissolved in 10 mM in DMSO and added at variable concentrations (0.5 to 10 ⁇ M) to the tubulin solution before polymerization.
  • the IC 50 is defined as the concentration of product which inhibits the rate of polymerization by 50%.
  • a product whose Cl 50 is less than or equal to 3 ⁇ M is considered to be very active.
  • An endothelial cell detachment determination test has been developed to select products for their "in vitro" activity.
  • This test for determining the detachment of endothelial cells is characterized in that the endothelial cells, seeded in plates whose bottom is covered with a binding agent preferably chosen from gelatin, fibronectin or vitronectin, after culture, are added with a medium containing the compound to be tested, then the cells are labeled with a fluorescent substance, the cells which have detached are washed away and the fluorescence of the remaining cells is counted with a fluorimeter.
  • This test consists in measuring the detachment of endothelial cells cultivated on substrates based on a binding agent preferably chosen from fibronectin, vitronectin or gelatin.
  • a binding agent preferably chosen from fibronectin, vitronectin or gelatin.
  • the culture medium is replaced by a medium containing the compound to be tested in the absence of serum.
  • the same preparation is prepared six times at three different concentrations (0.1, 0.3 and 0.6 ⁇ M) and six times the control without the addition of an anti-vascular product.
  • the cells are labeled with calcein-AM (1.6 ⁇ g / ml) in culture medium supplemented with 0.1% BSA.
  • the cells which have become detached are eliminated by washing with the culture medium containing 0.1% of bovine serum albumin; 100 ⁇ l of medium are added to each well. The fluorescence of the remaining cells is counted using a fluorometer. The data obtained are expressed relative to the control (untreated cells). - •, • • •
  • HDMEC cells Human Dermal Microvascular Endothelial Cells, Promocell, c-122102
  • ECGM-MV medium which contains 5% fetal calf serum, growth factors (EGF 10 ng / ml, hydrocortisone 1 ⁇ g / ml , 0.4% growth supplement with heparin) and antibiotics (amphotericin 50 ng / ml, gentamicin 50 ⁇ g / ml).
  • the HDMECs are inoculated with 5,000 cells in 96-well brightfield plates (Costar) pre-coated with fibronectin (10 ⁇ g / ml) or vitronectin (1 ⁇ g / ml) or gelatin. Twenty four hours later, the culture medium is replaced by ECGM-MV 0.1% BSA medium containing the indicated products. The concentrations tested are 0.1-0.3 and 1 ⁇ M for each product. After two hours of treatment, the cells are labeled for one hour with calcein (1.6 ⁇ g / ml, Molecular Probes) in ECGM-MV 0.1% BSA medium.
  • the detached cells are then removed by washing with ECGM-MV 0.1% BSA medium; 100 ⁇ l of medium is added to each well.
  • the fluorescence of the cells which remain attached to the substrate of the well is counted using a fluorimeter, Spectrafluor Plus (Tecan, excitation 485 nm, and emission 535 nm). Data is the average of six different samples and are expressed as a percentage of the control (untreated cells).
  • a cell detachment effect greater than or equal to 15% is considered significant.
  • the present invention will be more fully described with the aid of the following examples which should not be considered as limiting the invention.
  • the ethyl ester of 6,6-diphenyl-6,7-dihydro-2H-indazole-3-carboxylic acid can be prepared as follows:
  • the isopropyl ester of 6,6-diphenyl-6,7-dihydro-2H-indazole-3-carboxylic acid can be prepared in the following manner:
  • the 6,6-diphenyl-6,7-dihydro-1 H-indazole-3-carboxylic acid can be obtained in the following way:
  • the methyl ester of 6,6-diphenyl-6,7-dihydro-2H-indazole-3-carboxylic acid can be prepared in the following manner:
  • the (N-cyclopropyl) -6,6-diphenyl-6,7-dihydro-1 H-indazoIe-3-carboxamide can be prepared as follows: From a mixture of 1.23 g of acid 6 , 6-diphenyl-6,7-dihydro-1 H-indazole-3-carboxyIc, 0.26 cm 3 of cyclopropylamine, 0.86 g of 1-ethyl-3- (3-dimethylamino-propyl) hydrochloride -carbodiimide, and 60 mg of hydroxybenzotriazole in solution in 30 cm 3 of dichloromethane, after 18 hours of stirring at a temperature in the region of 20 ° C., one obtains washing with twice 30 cm 3 of distilled water and purification of the crude product obtained by flash chromatography on silica gel (30-70 ⁇ m), eluting with a cyclohexane-ethyl acetate mixture (60/40), 0.58 g of (N
  • Azetidin-1-yl- (6,6-diphenyl-6,7-dihydro-1 H-indazol-3-yl) -methanone can be prepared as follows:
  • Aziridin-1-yl- (6,6-diphenyl-6,7-dihydro-1H-indazol-3-yl) -methanone can be prepared as follows:
  • Aziridin-1-yl- (6,6-diphenyl-1- (2-trimethylsilanyl-ethoxymethyl) -6,7- dihydro-1 H-indazol-3-yl) -methanone can be prepared as follows:
  • the solution obtained is poured onto a mixture of 30 cm 3 of water and 0.3 cm 3 of a 1N aqueous hydrochloric acid solution while maintaining a temperature in the region of 5 ° C and extracted three times with 30 cm 3 ethyl acetate.
  • the combined organic phases are washed with three times 30 cm 3 of water, 30 cm 3 of a saturated aqueous sodium chloride solution, dried over " magnesium sulfate 1 " , filtered and " concentrated to dryness under reduced pressure ( 13 kPa).
  • 6,6-diphenyl-1- (2-trimethylsilanyl-ethoxymethyl) -6,7-dihydro-1 H-indazole-3-carboxylic acid (2-chloro-ethyl) -amide can be prepared as follows:
  • the 6,6-diphenyl-1- (2-trimethylsilanyl-ethoxymethyl) -6,7-dihydro- 1 H-indazole-3 carboxylic acid can be prepared in the following way: A solution of 5 g of acid 6, 6-diphenyl-6,7-dihydro-1 H-indazole-3 carboxylic acid in 100 cm 3 of dimethylformamide is added dropwise to a suspension of 1.45 g of sodium hydride (60% in oil) in 25 cm 3 of dimethylformamide cooled to a temperature close to 0 ° C.
  • reaction mixture After 2 hours of stirring at a temperature in the region of 20 ° C, the reaction mixture is cooled to a temperature in the region of 0 ° C and 4.18 cm 3 of (2-chloromethoxy-ethyl) -trimethyl-silane are added dropwise. drop. The mixture is stirred for approximately 20 hours at a temperature in the region of 20 ° C. After cooling this mixture to a temperature in the region of 0 ° C., 100 cm 3 of water and 16 cm 3 of a 1N aqueous hydrochloric acid solution are added. The mixture is extracted three times with 100 cm 3 of ethyl acetate.
  • the 6,6-diphenyl-6,7-dihydro-1 H-indazole-3-carbonitrile can be prepared in the following manner: 1.1 g of a solution cooled to a temperature in the region of 5 ° C.
  • the residue is taken up in 50 cm 3 of water and 150 cm 3 of ethyl acetate; the pH of the mixture is brought to around 8 by adding sodium bicarbonate. After decantation, the aqueous phase is extracted with three times 50 cm 3 of ethyl acetate, the combined organic phases are washed with three times 50 cm 3 of water and then dried over magnesium sulphate, filtered and concentrated to dryness under pressure reduced (13 kPa). The residue is purified by flash chromatography on a silica column [eluent: dichloromethane / ethyl acetate (90/10 by volume)].
  • 6,6-diphenyl-6,7-dihydro-1H-indazole-3-carboxamide can be prepared in the following manner:
  • Cyclopropyl- (6,6-diphenyl-6,7-dihydro-1 H-indazoI-3-yl) -methanone can be prepared in the following way: At 1.66 g of magnesium in suspension form in 5 cm 3 2 cm 3 of a solution of 5.46 cm 3 of bromocyclopropane diluted in 10 cm 3 of tetrahydrofuran are added to tetrahydrofuran. The mixture The reaction is brought to a temperature of approximately 40 ° C. and then the temperature rises spontaneously until the solvent refluxes. The rest of the bromocyclopropane solution is poured dropwise at the reflux of tetrahydrofuran.
  • Cyclobutyl- (6,6-diphenyl-6,7-dihydro-1H-indazol-3-yl) -methanone can be prepared as described in Example 5-1: But from 1.08 g of magnesium, 6.09 g of bromocyclobutane and 4 g of (N-methoxy-N-methyl) -6,6-diphenyl-6,7-dihydro-1 H-indazole-3- carboxamide in 80 cm 3 of tetrahydrofuran.
  • EXAMPLE 5-4 (6,6-Diphenyl-6,7-dihydro-1 H-indazol-3-yl) - (1 H-pyrrol-3-yl) - methanone can be prepared as follows:
  • the mixture is stirred for approximately 20 hours, allowing the temperature to slowly return to around 20 ° C.
  • the reaction mixture is poured onto 100 cm 3 of a 2N aqueous hydrochloric acid solution, the aqueous phase is saturated with sodium chloride and extracted with three times 150 cm 3 of ethyl acetate.
  • the combined organic phases are dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (13 kPa).
  • the Z and E isomers of cyclopropyl- (6,6-diphenyl-6,7-dihydro-1 H- indazol-3-yl) -methanone oxime can be prepared as follows: A mixture of 0.34 g of cyclopropyl- (6,6-diphenyl-6,7-dihydro-1 H- indazol-3-yl) -methanone, 0.278 g of hydroxylamine hydrochloride, 0.328 g of sodium acetate and 2 cm 3 of water in 32 cm 3 of ethanol is brought to reflux for approximately 18 hours. The reaction mixture is poured into 100 cm 3 of water and cooled for about one hour to a temperature in the region of 0 ° C.
  • the solid is drained and washed with three times 5 cm 3 of ice water.
  • the two isomers Z and E are separated on a silica column [eluent: dichloromethane / methanol (98/2 by volume)], fractionating with 50 cm 3 .
  • Fractions 48 to 68 are combined and concentrated to dryness under reduced pressure (13 kPa). The residue is taken up in 5 cm 3 of pentane, drained, washed twice with 2 cm 3 of pentane and then dried under reduced pressure (13 kPa) at a temperature of about 25 ° C. 0.09 g of the isomer B of cyclopropyl- (6,6-diphenyl-6,7-dihydro-1 H-indazol-3-yl) -methanone oxime is obtained in the form of a white powder, the characteristics are as follows: - melting point: melting at 100 ° C. (Banc-Kôfler)
  • O-methyl-oxime in the form of a solid the characteristics of which are as follows: - melting point: melting at 134 ° C (Banc-Kôfler)
  • O-methyl-oxime in the form of a solid, the characteristics of which are as follows:
  • 6,6-diphenyl-1- (toluene-4-sulfonyl) -6,7-dihydro-1 H-indazole-3-carbaldehyde can be prepared as follows:
  • the aqueous phase is extracted with three times 100 cm 3 of diethyl oxide.
  • the organic phases are combined, washed with 200 cm 3 of water and then 200 cm 3 of a saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (13 kPa).
  • the Z-isomer of cyclopropyl- (6,6-diphenyl-6,7-dihydro-1 H-indazol-3-yl) -methanone 0- (2-methoxy-ethyl) -oxime can be prepared as follows :
  • a suspension of 0.74 g of cyclopropyl- (6,6-diphenyl-6,7-dihydro- 1 H-indazol-3-yI) -methanone, 0.70 g of 0- (2-methoxy-ethyl hydrochloride ) - hydroxylamine in 50 cm 3 of pyridine is brought to reflux for approximately 7 hours.
  • the solution obtained is concentrated to dryness under reduced pressure (13 kPa).
  • the residue is taken up in 150 cm 3 of dichloromethane.
  • the solution is washed with three times 80 cm 3 of water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (13 kPa).
  • the mixture of Z and E isomers is separated by flash chromatography on a silica column [eluent: dichloromethane / methanol (98/2 by volume)], fractionating with 60 cm 3 .
  • O- (2-methoxy-ethyl) -hydroxylamine hydrochloride can be prepared as described by Dae-Kee Kim et al., J. Med. Chem., 40, 15, 1997, 2363-2373.
  • the E-isomer of cyclopropyl- (6,6-diphenyl-6,7-dihydro-1 H-indazol-3-yl) -methanone 0- (2-methoxy-ethyl) -oxime can be prepared as follows :
  • the solution is concentrated to dryness under reduced pressure and the residue is taken up in 50 cm 3 of ethyl acetate; the solution is washed with three times 30 cm 3 of water, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (13 kPa).
  • the isomer E of cyclopropyl- (6,6-diphenyl-1- (2-trimethylsilanyl-ethoxymethyl) -6,7-dihydro-1H-indazol-3-yl) -methanone O- (2-methoxy-ethyl) ⁇ oxime can be prepared as follows:
  • the E-isomer of cyclopropyl- (6,6-diphenyl-1- (2-trimethylsilanyl-ethoxymethyl) -6,7-dihydro-1 H-indazol-3-yI) -methanone oxime can be prepared as follows :
  • Cyclopropyl- (6,6-diphenyl-1- (2-trimethylsilanyl-ethoxymethyl) -6,7- dihydro-1 H-indazol-3-yl) -methanone can be prepared as follows:
  • Fractions 60 to 73 are combined and concentrated to dryness under reduced pressure (13 kPa).
  • the residue is taken up in 50 cm 3 of diethyl oxide, washed three times with 40 cm 3 of a 1N aqueous solution of hydrochloric acid.
  • the organic phase is dried over magnesium sulfate, filtered, concentrated under reduced pressure.
  • the residue is taken up in 2 cm 3 of diethyl oxide, the insoluble material is filtered and washed with twice 1 cm 3 of pentane.
  • the filtrate is diluted with 50 cm 3 of diethyl ether, washed with three times 30 cm 3 of a saturated aqueous solution of sodium hydrogencarbonate, dried over magnesium sulfate, filtered and concentrated under reduced pressure (13 kPa).
  • O- (2-dimethylamino-ethyl) -hydroxylamine hydrochloride can be prepared as described by F. Wintemitz and R. Lachazette, Bull. Soc. Chim. Fr. 1958, 664-667.
  • 6,6-diphenyl-1 - (toluene-4-sulfonyl) -6,7-dihydro-1 H-indazol-3-ylamine can be prepared as follows:
  • the pH is brought to about 10 by adding a normal aqueous solution of sodium hydroxide. After decantation, the " aqueous phase is extracted with twice 10 cm 3 of dichloromethane. The combined organic phases are washed successively with once 20 cm 3 of a decinormal aqueous solution of sodium hydroxide, twice 30 cm 3 of water, once 30 cm 3 of a saturated aqueous solution of sodium chloride and then dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (13 kPa) The residue is taken up in 3 cm 3 of diethyl oxide, washed with twice 1 cm 3 of diethyl oxide and then dried under reduced pressure (13 kPa) at a temperature close to 50 ° C.
  • Tert-butyl [6,6-diphenyl-1- (toluene-4-sulfonyl) -6,7-dihydro-1H-indazol-3-yl] - carbamate can be prepared as follows: To a suspension of 0.25 g of 6,6-diphenyl-1- (toluene-4-sulfonyl) -6,7-dihydro-1H-indazole-3 carboxylic acid in 1.5 cm 3 of toluene and 1, 5 cm 3 of tert-butanol is added 0.09 cm 3 of triethylamine. The solution obtained is brought to reflux and 0.12 cm 3 of diphenylphosphonic azide is added dropwise.
  • the 6,6-diphenyl-1- (toluene-4-sulfonyl) -6,7-dihydro-1 H-indazole-3-carboxylic acid can be prepared as follows:
  • the solid is washed with three times 20 cm 3 of water and then suspended in 20 cm 3 of water. 10 cm 3 of a normal aqueous hydrochloric acid solution are added. The mixture is extracted with three times 50 cm 3 of ethyl acetate. The combined organic phases are washed successively with three times 70 cm 3 of water, once 70 cm 3 of a saturated aqueous solution of sodium chloride and then dried over sodium sulfate. magnesium, filtered and concentrated under reduced pressure (13 kPa). The residue is purified by flash chromatography on a silica column [eluent: dichloromethane / methanol (95/5 by volume)].
  • a suspension of 0.260 g of 6,6-diphenyl-6,7-dihydro-1 H-indazol-3-ylamine and 0.15 cm 3 in 10 cm 3 of dichloromethane is cooled to a temperature in the region of 0 ° C. At this same temperature, 0.09 cm 3 of acryloyl chloride is added. After 2 hours of stirring at a temperature close to 0 ° C and then 18 hours at a temperature close to 20 ° C, 10 cm 3 of dichloromethane and 10 cm 3 of water are added.
  • the 6,6-diphenyl-6,7-dihydro-1H-indazol-3-ylamine can be prepared in the following manner:
  • a suspension of 0.22 g of 6,6-diphenyl-1- (toluene-4-sulfonyl) -6,7- dihydro-1 H-indazol-3-ylamine and 1.5 cm 3 of an aqueous solution of 1N sodium hydroxide in 5 cm 3 of tetrahydrofuran is brought to a temperature in the region of 50 ° C. for approximately 24 hours.
  • 5 cm 3 of dioxane are added to the above mixture and the latter is brought to a temperature in the region of 100 ° C. for 2 hours.
  • the aqueous phase is extracted with twice 30 cm 3 of ethyl acetate and the combined organic phases are washed with 30 cm 3 of a saturated aqueous sodium bicarbonate solution, 30 cm 3 of water, 30 cm 3 d '' a saturated aqueous solution of sodium chloride then dried over magnesium sulfate filtered and concentrated under reduced pressure (13 kPa).
  • N- (6,6-diphenyl-6,7-dihydro-1 H-indazol-3-yl) -cyclopropylamide can be prepared in the following manner:
  • N- [6,6-diphenyl-1 - (toluene-4-sulfonyl) -6,7-dihydro-1 H-indazol-3-yl] -cyclopropylamide can be obtained in the following manner: From a suspension of 0 , 44 g of 6,6-diphenyl-1- (toluene-4-sulfonyl) -
  • N- (6,6-diphenyl-6,7-dihydro-1H-indazol-3-yl) -benzamide can be prepared as described in Example 7-3: But from 0.14 g of N- (6,6-diphenyl-1- (toluene-4-sulfonyl) -6,7- dihydro-1 H-indazol-3-yl) -benzamide, from 0.78 cm 3 of a 1N aqueous sodium hydroxide solution in 10 cm 3 of tetrahydrofuran. We thus obtain
  • N- (6,6-diphenyl-6,7-dihydro-1 H-indazol-3-yl) -benzamide can be prepared as in Example 7-3:
  • the residue is taken up in 20 cm 3 of water.
  • the pH is brought to approximately 3 by addition of an aqueous solution of 2N hydrochloric acid and the aqueous phase is extracted with three times 50 cm 3 of ethyl acetate.
  • the combined organic phases are dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (13 kPa).
  • the residue is purified by flash chromatography on a silica column [eluent: cyclohexane / ethyl acetate (50/50 by volume)].
  • N-hydroxyacetamidine can be prepared under the conditions described by CD Clifford (J. Med. Chem. 1986, 29, 11, 2174-2183) from acetonitrile, from hydroxylamine in the presence of sodium hydroxide in aqueous ethanol to reflux.
  • 3,6,6-triphenyl-6,7-dihydro-1 H-indazole can be prepared as follows:
  • a mixture of 3-iodo-6,6-diphenyl-1- (2-trimethylsilanyl-ethoxymethyl) -6,7-dihydro-1 H-indazole and 3-iodo-6,6-diphenyl-2- (2- trimethylsilanyl-ethoxymethy [) - 6,7-dihydro-1 H-indazole can be prepared as follows:
  • a solution of 0.85 g of 3-iodo-6,6-diphenyl-6,7-dihydro-1 H- indàzble in 7 cm 3 of dimethylformamide is added dropwise to a suspension of 0.112 g of sodium hydride (60% in oil) in 3 cm 3 of dimethylformamide cooled to a temperature close to 0 ° C. After stirring the mixture for approximately 1 hour 30 minutes and then cooling to a temperature in the region of 0 ° C., 0.565 cm 3 of (2-chloromethoxy-ethyl) -trimethyl-silane is added dropwise.
  • 3-iodo-6,6-diphenyl-6,7-dihydro-1 H-indazole can be prepared as follows:
  • 3-iodo-6,6-diphenyl-1 - (toluene-4-sulfonyl) -6,7-dihydro-1 H-indazole can be prepared as follows:
  • 6,6-diphenyl-3-pyridin-3-yl-6,7-dihydro-1 H-indazole can be prepared in the following manner:
  • the 6,6-diphenyl-3-pyridin-3-yl-1- (toluene-4-sulfonyl) -6,7-dihydro-1 H-indazole can be prepared as follows:
  • a solution of 0.5 g of 3-iodo-6,6-diphenyl-1- (toluene-4-sulfonyl) - 6,7-dihydro-1 H-indazole in 8 cm 3 of terahydrofuran is degassed under bubbling argon for about 1 hour.
  • To this solution are added 0.133 g of pyridyl-3-boronic acid, 0.052 g of tetrakis palladium (triphenylphosphine), 0.206 g of copper thiophene-2-carboxylate.
  • the mixture obtained is stirred for approximately 30 hours near 40 ° C.
  • the ethyl ester of 6- (R, S) -6-methyl-6-phenyl-6,7-dihydro-1 H-indazole-3-carboxylic acid can be prepared in the following manner:
  • 6- (R, S) -6-methyl-6-phenyl-6,7-dihydro-1 H-indazole-3-carboxylic can be carried out as follows:
  • the eutomer of the ethyl ester of 6- (R, S) -6-phenyl-6,7-dihydro-2H-indazole-3-carboxylic acid can be obtained in the following way:
  • the ethyl ester of 6- (R, S) -phenyl-6,7-dihydro-2H-indazole-3-carboxylic acid can be obtained in the following way:
  • 4-phenyl-cyclohex-2-enone can be prepared as follows:
  • the ethyl ester of 6- (R, S) ⁇ 6- (3,4-dimethoxy-phenyl) -6-phenyl-6,7-dihydro-1 H-indazole-3-carboxyic acid can be obtained from as follows: To a solution, cooled to -70 ° C, of 1 g of 4- (R, S) -4- (3,4-dimethoxyphenyl) -4-phenyl-cyclohex-2-enone in 10 cm 3 of tetrahydrofuran, 0.44 cm 3 of ethyl diazoacetate is added dropwise then slowly 2.3 cm 3 of commercial lithium diisopropylamide in 2M solution in tetrahydrofuran.
  • the (R, S) - (3,4-dimethoxy-phenyl) -phenyl-acetaldehyde can be obtained as follows: A mixture of 47.85 g of 1 ⁇ (R, S) -1- (3,4 -dimethoxy-phenyl) -2-methoxy-1-phenyl-ethanol and 50 cm 3 of formic acid are heated at reflux for 13 hours. The reaction mixture is then poured onto 750 cm 3 of a saturated aqueous sodium carbonate solution and the resulting mixture is extracted with three times 400 cm 3 of ethyl acetate.
  • reaction mixture After 24 hours of stirring at a temperature in the region of 20 ° C., the reaction mixture is poured onto a saturated aqueous solution of ammonium chloride. The mixture thus obtained is extracted with twice 50 cm 3 of ethyl acetate. The organic phases are washed with twice 100 cm 3 of distilled water and then dried over magnesium sulfate and concentrated to dryness under reduced pressure.
  • the ethyl ester of 6- (4-fluoro-phenyl) -6-phenyl-6,7-dihydro-1 H-indazole-3-carboxylic acid (R, S) can be prepared in the following manner: To a solution, cooled to -70 ° C, of 1 g of 4- (4-fluoro-phenyl) -4- phenyl-cyclohex-2-enone in 10 cm 3 of tetrahydrofuran, is added dropwise 0.5 cm 3 of ethyl diazoacetate, then slowly 14.64 cm 3 of lithium diisopropylamide solution prepared from 3.8 cm 3 of n-butyllithium 1.6M and 0.84 cm 3 of diisopropylamine dissolved in 10 cm3 of tetrahydrofuran.
  • the reaction mixture is poured onto 200 cm 3 of a saturated aqueous ammonium chloride solution, extracted with twice 150 cm 3 of ethyl ether and the organic phases are washed with twice 150 cm 3 of distilled water, dried over magnesium sulfate and concentrated to dryness under reduced pressure.
  • the residue obtained is purified by flash chromatography on silica gel (35-70 ⁇ m), eluting with a cyclohexane-ethyl acetate mixture (95/05), 13.2 g of 1- (4- fluorophenyl) -2-methoxy-1-phenyl-ethanol in the form of a white oil, the characteristics of which are as follows:
  • N-methoxy-N-methyl) -6- (4-fluoro-phenyl) -6-phenyl-6,7-dihydro- 1 H-indazole-3-carboxamide (R, S), can be prepared from as follows: The procedure is as described in Example 3-2, but starting with 1.35 g of 6- (4-fluoro-phenyl) -6-phenyl-6,7-dihydro-1 H- indazole-3-carboxylic, 0.64 g of 1-hydroxybenzotriazole hydrate, 0.92 g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1.56 g of N, 0-dimethylhydroxylamine hydrochloride and 2.25 cm 3 of triethylamine in 40 cm 3 of dichloromethane.
  • the Z and E isomers of cyclopropyl- [6- (4-fluoro-phenyl) -6-phenyl-6,7-dihydro-1 H-indazol-3-yl] -methanone oxime (R, S) can be prepared from as follows: The procedure is as in Example 6-1, but starting with 0.87 g of cyclopropyl- [6- (4-fluoro-phenyl) -6-phenyl-6,7-dihydro-1H-indazol -3-yl] - methanone (R, S), obtained in Example 10-4A, 0.63 g of hydroxylamine hydrochloride and 0.79 g of sodium acetate.
  • the Z 'and E isomers of the levorotatory enantiomer of cyclopropyI- [6- (4-fluoro-phenyl) -6-phenyl-6,7-dihydro-1 H-indazol-3-yl] -methanone oxime can be prepared by operating as in Example 6-1 but from 6 g of the levorotatory enantiomer of cyclopropyl- [6- (4-fluoro-phenyl) -6-phenyl- 6,7-dihydro-1 H- indazol-3-yl] -methanone, obtained in Example 10-4B, 38 g of hydroxylamine hydrochloride and 5.4 cm 3 of pyridine.
  • the Z-isomer of the dextrorotatory enantiomer of cyclopropyl- [6- (4-fluoro-phenyl) -6-phenyl-6,7-dihydro-1 H-indazol-3-yl] -methanone oxime can be prepared by operating as in Example 6-1, but starting from 6 g of the dextrorotatory enantiomer of cyclopropyl- [6- (4-fluoro-phenyl) -6-phenyl-6,7-dihydro-1H-indazol -3-yl] -methanone, 4.38 g of hydroxylamine hydrochloride and 4.4 cm 3 of pyridine.
  • the Z isomer is separated by flash chromatography on a silica column [eluent: dichloromethane-ethanol (97-03 by volume)], fractionating with 50 cm 3 .
  • the first eluted fractions are combined and concentrated to dryness under reduced pressure (13 kPa).
  • the white powder obtained is recrystallized from ethanol and thus 1.92 g of the Z isomer of cyclopropyl- [6- (4-fluoro-phenyl) -6-phenyl-6,7-dihydro-1 H are thus obtained.
  • -indazol-3-yl] - methanone oxime (Z), dextrorotatory enantiomer, corresponding to example 10-5E, in the form of a white powder, the characteristics of which are as follows: - melting point 193 ° C (Kôfler bench).
  • the ethyl ester of 6,6-bis- (4-fluorophenyl) -6,7-dihydro-1 H-indazole-3-carboxylic acid can be prepared in the following manner: In a solution, cooled to -70 ° C, 3 g of 4,4-bis- (4-fluoro-phenyl) ⁇ cyclohex-2-enone in 75 cm 3 of tetrahydrofuran, is added dropwise 1.4 cm 3 of ethyl diazoacetate then slowly 37.9 cm 3 of lithium diisopropylamide solution prepared from 10.5 cm 3 of n-butyllithium 1.6M and 2.4 cm 3 of diisopropylamine dissolved in 25 cm3 of tetrahydrofuran.
  • 4,4-bis- (4-fluoro-phenyl) -cyclohex-2-enone can be prepared as follows: In a solution, cooled to 0 ° C, of 4 g of bis- (4-fluoro-phenyl ) - acetaldehyde in 35 cm 3 of ethyl ether, 1.7 cm 3 of methylvinyl ketone and 0.39 g of potassium hydroxide in tablet dissolved in 3 cm 3 of ethanol are successively added. The temperature is left in the vicinity of 20 ° C for 24 hours. Concentrated to dryness under reduced pressure, added 75 cm 3 of dichloromethane and washed twice with 75 cm 3 of distilled water.
  • the bis- (4-fluoro-phenyl) -acetaldehyde can be prepared in the following manner:
  • the reaction mixture is poured over 200 cm 3 of a saturated aqueous ammonium chloride solution, extracted with three times 75 cm 3 of ethyl acetate and the phases organics are washed with twice 100 cm 3 of distilled water, dried over magnesium sulfate and concentrated to dryness under reduced pressure.
  • the residue obtained is purified by flash chromatography on silica gel (35-70 ⁇ m), eluting with; pure dichloromethane, 9.8 g of 1, 1-bis- (4-fluoro-phenyl) -2-methoxy-ethanol are thus obtained in the form of a yellow oil, the characteristics of which are as follows:
  • Example 5-1 The procedure is as described in Example 5-1, but starting with 0.3 g of magnesium, 1 cm 3 of bromocyclopropane and 1 g of (N-methoxy-N-methyl) - 6,6-bis- (4 -fluoro-phenyl) -6,7-dihydro-1 H-indazole-3-carboxamide in 20 cm 3 of tetrahydrofuran.
  • the 6,6-bis- (4-fluoro-phenyl) -6,7-dihydro-1 H-indazole-3-carboxylic acid can be prepared in the following manner:
  • the Z and E isomers of cyclopropyl ⁇ [6,6-bis- (4-fluoro-phenyl) - 6,7-dihydro-1 H-indazol-3-yl] -methanone oxime can be prepared as follows: The procedure is as in Example 6-1, but starting with 0.7 g of cyclopropyl- [6,6-bis- (4-fluoro-phenyl) -6,7-dihydro-1H-indazol-3-yl ] -methanone, obtained in Example 10-7, 0.52 g of hydroxylamine hydrochloride and 0.61 g of sodium acetate.
  • Ethyl 5,5-diphenyl-4,5-dihydro-2H-isoindole-1-carboxylate can be prepared as follows:
  • 2-chloro-5,5-diphenyl-cyclohexa-1, 3-dienecarbaldehyde can be prepared as follows:
  • 6-Dimethylaminomethylene-4,4-diphenyI-cyclohex-2-enone can be prepared as follows:
  • Ethyl 6,6-diphenyl-6,7-dihydro-1H-indole-3-carboxylate can be prepared as follows:
  • ethyl 3- (2-oxo-5,5-diphenyl-cyclohex-3-enylamino) -acrylate is obtained in the form of an orange oil used as it is in subsequent syntheses and the characteristics of which are the following :
  • ethyl 3- (2-oxo-5,5-diphenyl-cyclohex-3-enylamino) -acrylate is dissolved in 6 cm 3 of ethanol.
  • the solution obtained is cooled to a temperature close to 0 ° C. 2 cm 3 of a sodium ethylate solution (obtained from 0.23 g of sodium in 20 cm 3 of ethanol) are added to
  • 2-oxo-5,5-diphenyl-cyclohex-3-enyl-ammonium chloride can be prepared in the following manner:
  • the aqueous phase is extracted with twice 50 cm 3 of diethyl oxide.
  • the combined organic phases are washed with four times 25 cm 3 of water and then with four times 25 cm 3 of a saturated aqueous solution of sodium chloride before drying over magnesium sulfate and filtration.
  • the filtrate is acidified with 2 cm 3 of a solution of 1N hydrochloric acid in diethyl oxide.
  • the mixture is concentrated to dryness under reduced pressure (13 kPa) and the residue is dissolved in 3 cm 3 of acetone.
  • the ethyl ester of 7-methyl-6,6-diphenyl-6,7-dihydro-1 H-indazole-3-carboxylic acid can be prepared in the following manner:
  • EXAMPLE 14 The ethyl ester of 1- (4-amino-phenyl) -6,6-diphenyl-1 H-indazole-3-carboxylic acid can be prepared in the following manner: A solution of 0.6 g of the ethyl ester of 1- (4-nitro-phenyl) - 6,6-diphenyl-1 H-indazoIe-3-carboxylic acid in 24 cm 3 of acetic acid is cooled near 0 ° C. Then, 4.8 g of zinc are added in small portions. After the temperature has returned to around 20 ° C., the suspension obtained is stirred for approximately 4 hours. The insoluble material is filtered through celite and washed with three times 10 cm 3 of dichloromethane.
  • the filtrate is concentrated to dryness under reduced pressure (13 kPa), and taken up in 50 cm 3 of dichloromethane.
  • the solution is washed with three times 20 cm 3 of a saturated aqueous solution of sodium hydrogencarbonate, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (13 kPa).
  • the 1- (4-nitro-phenyl) -6,6-diphenyl-1 H-indazole-3-carboxylic acid ethyl ester can be prepared in the following manner:
  • a suspension of 0.151 g of sodium hydride (60% in oil) in 4 cm 3 of dimethylformamide is poured dropwise a solution of 1 g of the ethyl ester of the acid 6,6- diphenyl-6,7-dihydro-2H- indazole-3 carboxylic acid in 5 cm 3 of dimethylformamide.
  • 0.46 cm 3 of 1-fluoro-4-nitro-benzene is added and the reaction mixture is stirred in the vicinity of 80 ° C for approximately 2 hours.
  • 0.26 cm 3 of 1-fluoro-4-nitro-benzene is added to the cooled mixture near 20 ° C.
  • Cyclopropanecarboxylic acid [6- (4-methoxy-phenyl) -6-phenyl-6,7-dihydro- 1 H-indazol-3-yl] -amide
  • Cyclobutanecarboxylic acid [6- (4-methoxy-phenyl) -6-phenyl -6,7-dihydro- 1 H-indazol-3-yl] -amide
  • Cyclopropanecarboxylic acid [6- (3-dimethylamino-phenyl) -6-phenyl-6,7-dihydro-1 H-indazol-3-yl] -amide
  • Cyclobutanecarboxylic acid [6- (3-dimethylamino-phenyl) -6-phenyl-6,7- dihydro-1 H-indazol-3-yi] -amide

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  • Organic Chemistry (AREA)
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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
EP02791508A 2001-07-27 2002-07-24 Indazol- oder indolderivate, deren verwendung in der humanmedizin und insbesondere in der onkologie Withdrawn EP1414805A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR0110118A FR2827861B1 (fr) 2001-07-27 2001-07-27 Derives des indazoles ou des indoles, leur utilisation en medecine humaine et plus particulierement en cancerologie
FR0110118 2001-07-27
PCT/FR2002/002638 WO2003011833A1 (fr) 2001-07-27 2002-07-24 Derives des indazoles ou des indoles, leur utilisation en medecine humaine et plus particulierement en cancerologie

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EP1414805A1 true EP1414805A1 (de) 2004-05-06

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EP02791508A Withdrawn EP1414805A1 (de) 2001-07-27 2002-07-24 Indazol- oder indolderivate, deren verwendung in der humanmedizin und insbesondere in der onkologie

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US (1) US7119115B2 (de)
EP (1) EP1414805A1 (de)
JP (1) JP2005503376A (de)
AR (1) AR036348A1 (de)
FR (1) FR2827861B1 (de)
WO (1) WO2003011833A1 (de)

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US7196082B2 (en) 2002-11-08 2007-03-27 Merck & Co. Inc. Ophthalmic compositions for treating ocular hypertension
FR2857362B1 (fr) * 2003-07-10 2005-09-23 Aventis Pharma Sa Tetrahydro-1h-pyrazolo[3,4-c] pyridines substituees, compositions les contenant et utilisation
AR045037A1 (es) * 2003-07-10 2005-10-12 Aventis Pharma Sa Tetrahidro-1h-pirazolo [3,4-c] piridinas sustituidas, composiciones que las contienen y su utilizacion.
FR2871158A1 (fr) 2004-06-04 2005-12-09 Aventis Pharma Sa Indazoles substitues, compositions les contenant, procede de fabrication et utilisation
CA2862276A1 (en) * 2012-01-25 2013-08-01 Kabushiki Kaisha Yakult Honsha Pyrrole compound
CN102924377A (zh) * 2012-10-22 2013-02-13 华东师范大学 3,4,5-取代吡唑类化合物的合成方法
US11492341B2 (en) 2018-11-16 2022-11-08 Nimbus Artemis, Inc. ACLY inhibitors and uses thereof

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YU54202A (sh) * 2000-01-18 2006-01-16 Agouron Pharmaceuticals Inc. Jedinjenja indazola, farmaceutske smeše i postupci za stimulisanje i inhibiranje ćelijske proliferacije

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See references of WO03011833A1 *

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AR036348A1 (es) 2004-09-01
US7119115B2 (en) 2006-10-10
WO2003011833A1 (fr) 2003-02-13
US20040162276A1 (en) 2004-08-19
FR2827861B1 (fr) 2004-04-02
JP2005503376A (ja) 2005-02-03
FR2827861A1 (fr) 2003-01-31

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