EP0991645A1 - Derives de bis-indole presentant une activite antimetastasique, procede pour leur preparation et compositions pharmaceutiques les contenant - Google Patents

Derives de bis-indole presentant une activite antimetastasique, procede pour leur preparation et compositions pharmaceutiques les contenant

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Publication number
EP0991645A1
EP0991645A1 EP98937539A EP98937539A EP0991645A1 EP 0991645 A1 EP0991645 A1 EP 0991645A1 EP 98937539 A EP98937539 A EP 98937539A EP 98937539 A EP98937539 A EP 98937539A EP 0991645 A1 EP0991645 A1 EP 0991645A1
Authority
EP
European Patent Office
Prior art keywords
bis
methyl
carboxy
benzene
indol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP98937539A
Other languages
German (de)
English (en)
Inventor
Valeria Livi
Ernesto Menta
Ambrogio Oliva
Frank Grams
Hans-Willi Krell
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Roche Diagnostics GmbH
Original Assignee
Roche Diagnostics GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Roche Diagnostics GmbH filed Critical Roche Diagnostics GmbH
Priority to EP98937539A priority Critical patent/EP0991645A1/fr
Publication of EP0991645A1 publication Critical patent/EP0991645A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D401/14—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 three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • 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
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D403/14—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 three or more hetero rings
    • 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
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/572—Five-membered rings
    • C07F9/5728—Five-membered rings condensed with carbocyclic rings or carbocyclic ring systems

Definitions

  • the present invention relates to bis-indole derivatives and to their use to inhibit metastatic processes.
  • the elimination of the primary tumor by surgery is not always possible and in any case does not prevent the most metastasizing tumors, such as for example breast cancer or melanoma, to invade other target organs, which develop further secondary tumors after months or years from the surgical treatment. These secondary tumors are usually the main cause of death of the patient.
  • styryl diphenylarnine derivatives were found to revert the transformed phenotype of human fibrosarcoma HT1080 cells. These compounds can inhibit metastasis in mice with negligible toxicity [Anticancer Res., 17(1 AV 393-400 (1997)1.
  • Other known molecules such as the stable prostacyclin analog cicaprost and docosahexaaenoic acid, were shown to have antimetastatic properties in "in vivo" models
  • the effect of low molecular weight glycoamine analogues on the metastasis of MDA- MB-435 human breast carcinoma xenografts growing in the mammary fat pads of nude mice was also reported [Cancer Res., 56(23). 5319-5324 (1996)].
  • the proposed mechanism of synthetic glycoamines may include the inhibition of beta-galectin-mediated homotypic cancer cell aggregation and induction of apoptosis in target cells.
  • the antimetabolite tiazofurin was described to possess inhibitory effects on the metastatization of HT 168-M1 human melanoma cell line, due to inhibition of adhesion and migration of tumor cells [Anticancer Res., 16(6 A), 3307-3312 (1996)].
  • the matrix metallo-proteinases (or metallo-proteases), which are upregulated in the cancer cells, degrade the extracellular matrix and bring to the propagation of the tumor cells into the blood stream to reach the target organs where the metastasis develop. Nevertheless, since different types of such proteases exist in the organism and are implicated in the regulation of vital functions, a high selectivity is desired, in order to avoid the toxic side effects, especially in a chronical treatment. A number of compounds are known in the literature [see review article of Nigel R.A. Beeley et al., Curr. Opin. Ther.
  • batimastat and marimastat have been developed by British Biotechnology and the latter is now under investigation in clinical trials.
  • such compounds are broad inhibitors of matrix metalloproteinases. therefore therapy with these molecules might be associated to undesirable toxicity.
  • the present invention relates to the use of bis-indole derivatives of formula (I).
  • R and R' are independently selected from hydrogen, hydroxy, chlorine, bromine, iodine, fluorine, (C ⁇ -C 6 )alkyl, (C ⁇ -C 4 )alkoxy, (C ⁇ -C 4 )acyloxy, amino, mono-(d- C 4 )alkylamino, di-(C ⁇ -C 4 )alkylamino, -SH, (C C4)alkylthio, carboxy, (Ci-
  • Ri and Rf are independently selected from hydrogen, hydroxy, hydroxymethyl, amino, carboxy, (C ⁇ -C 4 )alkyl groups;
  • A is a - phenyl or naphtyl group substituted by at least one group selected from hydoxy, carboxy, -SH, -CONHOH or -PO 3 H 2 group, or is a
  • - 5- or 6-membered heterocycle containing one or two heteroatoms selected from oxygen, nitrogen or sulfur, which can be optionally benzocondensed and/or substituted by at least one group selected from pyridyl, -SH, -PO H 2 , carboxy or - CONHOH. or is a
  • n is zero or the integers 1 or 2
  • X is selected from -SH, -PO 3 H 2 , -CONHOH, carboxy, amino, mono-(Cr C 4 )alkylamino, di-(C ⁇ -C )alkylamino, enantiomers, diastereoisomers, racemates and mixtures thereof, as well as salts thereof with pharmaceutically acceptable acids and bases, as antitumor and antimetastatic agents.
  • the present invention also relates to the new compounds of formula (I) and to a process for obtaining them, with the proviso that the following known compounds are excluded: compounds in which R, R ⁇ R Ri' are hydrogen and A is pyridyl 2-furanyl, 2- thienyl, carboxy, methoxycarbonyl, (C ⁇ -C 4 )alkoxycarbonylmethyl, 2- or 4- hydroxyphenyl, 3 ,4-dihydroxyphenyl;
  • Ri, Ri' are hydrogen, R and R' are 6-bromo and A is a aminomethyl group;
  • - Ri, Ri' are hydrogen, R and R' are 5-chloro, 5-bromo, 5-carboxy or 5-methoxy and A is a 4-pyridyl group;
  • R, R' are hydrogen, Rj and Ri' are methyl and A is 2-fi ⁇ ranyl, 2-thienyl or 2- hydroxyphenyl.
  • Another object of the present invention is to provide pharmaceutical compositions containing an effective dosage of at least one compound of formula (I) in admixture with suitable excipients or diluents.
  • A is an heterocycle, it is preferably selected from pyridyl, imidazol-2-yl, thienyl, quinolinyl, isoquinolinyl, pyrrolyl, furanyl, 5-methylfuran-2-yl, 5-hydroxymethylfi ⁇ ran-2- yl, 8-hydroxyquinolin-2-yl, dipyridyl.
  • A is a substituted phenyl group it is preferably selected from 2-carboxyphenyl, 3- carboxy-4-hydroxyphenyl, 4-methoxycarbonylphenyl, 3,4-dihydroxyphenyl, 2,3- dihydroxyphenyl, 3-carboxyphenyl, 4-carboxyphenyl.
  • Preferred compounds of formula (I) are those in which Ri and Ri' and/or R and R' are hydrogen.
  • Other preferred compounds of formula (I) are those in which A is a 2-, 3- or 4-pyridyl group.
  • Particularly preferred compounds are those in which Ri, Ri' are hydrogen, R and R' are hydrogen or a hydroxy group and A is a pyridyl group.
  • the most preferred compounds are 3-[bis(indol-3-yl)methyl]pyridine and 3-[bis(5- hydroxyindol-3 -yl)methyl]pyridine.
  • a reaction can be performed in a solvent, preferentially an alcohol, water or mixtures thereof, and in the presence of an acidic catalyst.
  • Suitable acids are organic acids, preferably acetic acid, inorganic acids, preferably hydrochloric acid or Lewis acids. When acetic acid is used, it is also used as the solvent.
  • the reaction temperature can vary from -10°C to 100°C, but it is generally kept between 0°C and room temperature.
  • the unsymmetrical compounds of formula (I) in which R and Ri are different from R' and Ri', respectively, can be performed by a process which encompasses the following steps: (a) Friedels-Craft reaction of a compound of formula (III) with an intermediate of formula (IV):
  • AlkO AlkO 2 PO-CH 2 -COOAlk (V) in which Alk is a lower alkyl group, in the presence of a strong base such as sodium hydride and in an inert solvent such as tetrahydrofuran, to give a compound of formula (VI):
  • optical resolution by crystallizing diastereoisomeric salts of compounds of formula (I) with optically active acids or bases, or chromatographic separation of diastereoisomers or diastereoisomeric salts of compounds of formula (I).
  • suitable optically active acids are D- or L- tartaric acid, mandelic acid, malic acid, lactic acid or camphorsulfonic acid.
  • suitable optically active bases are D- or L- ⁇ -phenylethylamine, ephedrine, quinidine or cinchonidine.
  • Alkaline salts, ammonium salts, acetates or hydrochlorides are mainly used as pharmacologically acceptable salts which are produced in the usual manner, e.g.
  • inorganic or organic bases or inorganic acids such as sodium hydroxide, potassium hydroxide, aqueous ammonia, amines such as triethylamine or hydrochloric acid.
  • inorganic or organic bases or inorganic acids such as sodium hydroxide, potassium hydroxide, aqueous ammonia, amines such as triethylamine or hydrochloric acid.
  • the salts are usually purified by reprecipitation from suitable solvents.
  • the intermediates of formula (II) are commercial products or can be obtained by means of conventional reactions which are part of the general knowledge of the skilled man, starting from precursors in which the aldehyde group is preferentially protected (for example by means of an acetal protecting group).
  • the hydroxamic acid derivative when A carries a carboxy functionality (such as in glyoxylic acid), the hydroxamic acid derivative can be obtained by reacting the -COOH with O- benzylhydroxylamine in the presence of a condensing agent (such as dicyclohexyl carbodiimide), followed by the hydrogenolysis to eliminate the benzyl group.
  • a condensing agent such as dicyclohexyl carbodiimide
  • a carries a hydroxy group it can be submitted to the following reactions: conversion of the -OH group into a halogen group (for example into a chlorine group by means of thionyl chloride), followed by condensation with triethyl phosphite and hydrolysis of the diethyl ester with trimethylsilyl iodide, to give the - PO ?
  • step (b) transforming the hydroxy functionality of the 3,3'-bis(indole)methanol of step (a) into the other substituents as above described for the synthesis of A-CHO.
  • the 3,3'-bis(indole)ketones are described in J. Heterocyclic Chem., 14(7), 1123-1134 (1977), which is herein incorporated by reference.
  • the compounds of the present invention have been tested in a pharmacological "in vitro" test of inhibition of MMP8 (human neutrophil collagenase). Said test provides for the determination via fluorescence of the inhibition of the degradation of a fluorescent substrate (DNP-Pro-Leu-Gly-Leu-Trp-Ala-D-Arg-NH 2 , Ml 855 Bachem) by means of the catalytic domain of MMP 8. Reagents.
  • Total volume 1 ml of solution kept under stirring in a cuvette.
  • % Inhibition 100 - (rel. unit/timewithinhibito ⁇ el. unit/time con troi x 100)
  • mice C57BL/6N were inoculated intrafootpad with tumor fragments at day 0. At day 1 1 the mice were anesthetized and their tumors removed surgically proximal to the popliteale limph nodes. Animals were treated intraperitoneally with the compounds of the invention from one day after surgery until the end of the experiment, day 22 (post- surgery treatment at days 12-15, 18-22). All the compounds were suspended in 0.5% methylcellulose. The mean number of the pulmonary metastases and the mean weight thereof were determined. The toxicity of the compounds of the invention at the administered dosage was also checked, as number of deaths/total no. of treated mice by the end of the experiment. Table I shows the data for one representative compound of the invention. Table I - Activity on spontaneous pulmonary metastases deriving from intrafootpad implanted murine Lewis Lung carcinoma (post-surgery treatment, day 12-15. 18-22 after tumor injection)
  • the compound of the invention showed a significant reduction both in the number and in the weight of the pulmonary metastases when compared to the control animals. From what it is said above it appears that the compounds of the invention may be used as antitumor and antimetastatic agents to prevent and/or control the progression of primary and secondary tumors in mammals, also in a chronical treatment.
  • the compounds of the present invention can be administered in doses ranging from 0 01 mg to 0 4 g per kilogram of body weight daily
  • a preferred dosage regimen to obtain best results is that which provides for the use from about 1 mg to about 50 mg per kilogram of body weight daily, employing unitary doses so that to administer in 24 hours from about 70 mg to about 3.5 g of the active compound to a patient having approximately 70 kg of body weight.
  • Such a dosage regimen may be adjusted to achieve the best therapeutical effect.
  • doses may be administered taking into account the therapeutical situation of the patient
  • the active compound may be administered by oral, intravenous, intramuscular or subcutaneous route
  • compositions of the present invention contain therapeutical effective amounts of at least one compound of the invention in admixture with pharmaceutically compatible excipients.
  • Oral compositions will generally include an inert diluent or an edible carrier. They can be included in gelatin capsules or compressed into tablets. Other oral administration forms are capsules, pills, elixirs, suspensions or syrups.
  • the tablets, pills, capsules and similar compositions can contain the following ingredients (in addition to the active compound): a binder such as microcrystalline cellulose, tragacanth or gelatin; an excipient such as starch or lactose; a disintegrating agent such as alginic acid, primogel, maize starch and the like; a lubricant such as magnesium stearate; a fluidifier such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharine or a flavoring agent such as mint flavor, methyl salicylate or orange flavor.
  • a binder such as microcrystalline cellulose, tragacanth or gelatin
  • an excipient such as starch or lactose
  • a disintegrating agent such as alginic acid, primogel, maize starch and the like
  • a lubricant such as magnesium stearate
  • a fluidifier such as colloidal silicon dioxide
  • a sweetening agent such as sucrose or saccharine or a flavoring agent
  • compositions can contain various material which change the physical form thereof, for example coating agents (for tablets and pills) such as sugar or shellac.
  • the material used in the preparation of the compositions should be pharmaceutically pure and non toxic at the used dosages.
  • the active ingredient can be included in solutions or suspensions, which can comprise in addition the following components: a sterile diluent such as water for injections, saline solution, oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminotetracetic acid; buffers such as acetates, citrates or phosphates and agents for adjusting the tonicity of the solution, such as sodium chloride or dextrose.
  • the parenteral preparation can be included in ampoules, mono-dose syringes, glass or plastic vials. The following examples
  • the aqueous phase is extracted with further 100 ml of ethyl acetate and the organic extracts are pooled, dried over sodium sulfate and concentrated to dryness.
  • the residue (11.7 g) is recrystallized twice from ethanol (110 ml + 85 ml) and dried under vacuum at 60°C. to give 8.78 g of the product, m.p. 113-115°C.
  • Example 2 According to the method described in example 1, starting from the suitable intermediates, the following bis-indoles are prepared:

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Indole Compounds (AREA)
  • Pyridine Compounds (AREA)

Abstract

La présente invention concerne des composés selon la formule générale (I). Dans cette dernière, R et R' sont indépendamment sélectionnés parmi des groupes hydrogène, hydroxy, chlore, brome, iode, fluor, alkyle (C1-C6), alcoxy (C1-C4), acyloxy (C1-C4), amino, mono-(C1-C4)alkylamino, di-(C1-C4)alkylamino, -SH, alkylthio(C1-C4), carboxy, alcoxycarbonyl(C1-C4). R1 et R1' sont indépendamment sélectionnés parmi des groupes hydrogène, hydroxy, hydroxyméthyle, amino, carboxy, alkyl(C1-C4); A est un groupe phényle ou naphtyle substitué par au moins un groupe sélectionné parmi des groupes hydroxy, carboxy, -SH, -CONHOH ou -PO3H2, ou est un hétérocycle à 5 ou 6 éléments contenant un ou deux hétéroatomes sélectionnés parmi de l'oxygène, azote ou soufre, qui peuvent éventuellement être benzocondensés et/ou substitués par au moins un groupe sélectionné parmi pyridyl, -SH, -PO3H2, carboxy ou CONHOH ou est un groupe présentant la formule -(CH2)n-X dans laquelle n est égal à zéro ou les nombres entiers 1 ou 2, et X est sélectionné parmi -SH, -PO3H2, -CONHOH, carboxy, amino, mono-(C1-C4)alkylamino, di-(C1-C4)alkylamino, énantiomères, diastéréoisomères, composés racémiques et mélanges de ces derniers, ainsi que des sels de ces derniers avec des acides pharmaceutiquement acceptables et des bases, comme agents antitumoraux et antimétastastiques.
EP98937539A 1997-06-25 1998-06-23 Derives de bis-indole presentant une activite antimetastasique, procede pour leur preparation et compositions pharmaceutiques les contenant Withdrawn EP0991645A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP98937539A EP0991645A1 (fr) 1997-06-25 1998-06-23 Derives de bis-indole presentant une activite antimetastasique, procede pour leur preparation et compositions pharmaceutiques les contenant

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP97110336 1997-06-25
EP97110336A EP0887348A1 (fr) 1997-06-25 1997-06-25 Dérivés de bisindole ayant une activité antimétastatique, leur procédé de préparation et compositions pharmaceutiques les contenant
EP98937539A EP0991645A1 (fr) 1997-06-25 1998-06-23 Derives de bis-indole presentant une activite antimetastasique, procede pour leur preparation et compositions pharmaceutiques les contenant
PCT/EP1998/003837 WO1999000381A1 (fr) 1997-06-25 1998-06-23 Derives de bis-indole presentant une activite antimetastasique, procede pour leur preparation et compositions pharmaceutiques les contenant

Publications (1)

Publication Number Publication Date
EP0991645A1 true EP0991645A1 (fr) 2000-04-12

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EP97110336A Withdrawn EP0887348A1 (fr) 1997-06-25 1997-06-25 Dérivés de bisindole ayant une activité antimétastatique, leur procédé de préparation et compositions pharmaceutiques les contenant
EP98937539A Withdrawn EP0991645A1 (fr) 1997-06-25 1998-06-23 Derives de bis-indole presentant une activite antimetastasique, procede pour leur preparation et compositions pharmaceutiques les contenant

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EP97110336A Withdrawn EP0887348A1 (fr) 1997-06-25 1997-06-25 Dérivés de bisindole ayant une activité antimétastatique, leur procédé de préparation et compositions pharmaceutiques les contenant

Country Status (14)

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EP (2) EP0887348A1 (fr)
JP (1) JP2002507206A (fr)
KR (1) KR20010014215A (fr)
CN (1) CN1268134A (fr)
AR (1) AR016283A1 (fr)
AU (1) AU8629598A (fr)
BR (1) BR9810947A (fr)
CA (1) CA2294250A1 (fr)
CO (1) CO4940464A1 (fr)
HR (1) HRP980357A2 (fr)
MA (1) MA26513A1 (fr)
TR (1) TR199903218T2 (fr)
WO (1) WO1999000381A1 (fr)
ZA (1) ZA985482B (fr)

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ATE277010T1 (de) 1998-07-08 2004-10-15 Harbor Branch Oceanographic Bis-indolederivate und ihre verwendung als entzündungshemmende mittel
US7709520B2 (en) * 2000-10-06 2010-05-04 The Texas A&M University System Diindolylmethane and C-substituted diindolylmethane compositions and methods for the treatment of multiple cancers
IT1317925B1 (it) 2000-11-03 2003-07-15 Sigma Tau Ind Farmaceuti Bis-eterocicli ad attivita' antitumorale e chemosensibilizzante.
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WO2002038546A1 (fr) 2000-11-08 2002-05-16 K.U. Leuven Research & Development Derives de bis-indole substitue utilises comme agents de contraste, compositions pharmaceutiques contenant lesdits derives et intermediaires permettant de preparer ces derives
JP2005508355A (ja) 2001-10-19 2005-03-31 トランス　テック　ファーマ，インコーポレイテッド 治療薬としてのビス−ヘテロアリールアルカン
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CA2569238A1 (fr) 2004-06-01 2005-12-15 F. Hoffmann-La Roche Ag Inhibiteur du recaptage des monoamines
EP1793820A2 (fr) * 2004-08-23 2007-06-13 The Texas A & M University System Activation dependant des ligands de nur77 et ses applications
CN1332948C (zh) * 2005-05-12 2007-08-22 苏州大学 双吲哚烷基衍生物的合成方法
CN100412058C (zh) * 2005-05-12 2008-08-20 苏州大学 一种双吲哚烷基化合物的合成方法
TW200716545A (en) * 2005-06-10 2007-05-01 Sigma Tau Ind Farmaceuti Indole derivatives having anti-tumor activity
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HRP980357A2 (en) 1999-02-28
CN1268134A (zh) 2000-09-27
WO1999000381A1 (fr) 1999-01-07
MA26513A1 (fr) 2004-12-20
ZA985482B (en) 1999-12-24
CO4940464A1 (es) 2000-07-24
TR199903218T2 (xx) 2000-07-21
EP0887348A1 (fr) 1998-12-30
AR016283A1 (es) 2001-07-04
BR9810947A (pt) 2000-09-26
KR20010014215A (ko) 2001-02-26
CA2294250A1 (fr) 1999-01-07
JP2002507206A (ja) 2002-03-05
AU8629598A (en) 1999-01-19

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