WO2003037861A1 - Utilisation de 2-acylindoles pour traiter des tumeurs - Google Patents

Utilisation de 2-acylindoles pour traiter des tumeurs Download PDF

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Publication number
WO2003037861A1
WO2003037861A1 PCT/EP2002/011883 EP0211883W WO03037861A1 WO 2003037861 A1 WO2003037861 A1 WO 2003037861A1 EP 0211883 W EP0211883 W EP 0211883W WO 03037861 A1 WO03037861 A1 WO 03037861A1
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WIPO (PCT)
Prior art keywords
alkyl
branched
straight
chain
methoxy
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PCT/EP2002/011883
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German (de)
English (en)
Inventor
Thomas Beckers
Siavosh Mahboobi
Herwig Pongratz
Markus Frieser
Harald Hufsky
Jörg Hockemeyer
Udo Vanhoefer
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Baxter Healthcare Sa
Baxter International Inc.
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Application filed by Baxter Healthcare Sa, Baxter International Inc. filed Critical Baxter Healthcare Sa
Priority to JP2003540143A priority Critical patent/JP2005516895A/ja
Priority to EP02802302A priority patent/EP1442015A1/fr
Publication of WO2003037861A1 publication Critical patent/WO2003037861A1/fr

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    • 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
    • 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

Definitions

  • the invention relates to the use of indole and heteroindole derivatives of the general formula I.
  • the object of the present invention is to provide new active substances for tumor treatment in mammals.
  • Many primary tumors release tumor cells via the blood and lymphatic system, which lead to metastases in distant organs.
  • the formation of metastases in the brain is a frequent complication, since taxanes are not available in the central nervous system, ie tumors that metastasize to them cannot hit there.
  • the process of tumor cell invasion and metastasis is dependent on the formation of new blood vessels (neovascularization), since from a certain tumor size an adequate oxygen supply is only possible via a functional blood vessel system.
  • Tumor metastasis is a complex process that does not only require neoangiogenesis. Increased degradation of the extracellular matrix, high cell motility and altered cell adhesion are also decisive factors.
  • MDR multi-drug resistance
  • German Offenlegungsschrift No. DE 2 501 468 describes 1-alkyl-2-pyridinylcarbonyl-substituted indole compounds, their preparation and their use as fibrinolytics or thrombolytics. An anti-tumor effect is neither described nor suggested.
  • Belgian Patent No. BE 637355 describes 2-benzoyl-substituted indole compounds as intermediates in a Grignard reaction to give the corresponding 1-amino-alkyl-1-hydroxy derivatives (phenylindolylalkanolamines) implemented.
  • a biological effect of the intermediate products is not described nor is it advised by the average person skilled in the art.
  • German Offenlegungsschrift No. DE 2 037 998 describes a process for the preparation of 2-benzoyl-, 2-acetyl, 2-propionyl and 2-p-toluoylindole, the class of 2-acylindoles being described as “relatively inaccessible” Reference is made to the use of the 2-acylindoles as intermediates in the production of phenylindolyl alkanolamine sedatives in accordance with the aforementioned Belgian patent No. 637 355. The use of the 2-acylindoles for the production of dyes, alkaloids, plant hormones and proteins is without The use of 2-acylindole as a medicinal product is neither disclosed nor suggested.
  • German patent application No. DE 100 20 852.5 filed by the applicant on April 28, 2000 German patent application No. DE 101 02 629.3 filed on January 20, 2001 and international patent application No. PCT / EP01 / filed on April 27, 2001 04783 describes new 2-acyl-indole derivatives and their use as anti-tumor agents.
  • the use of 2-acyl derivatives for the treatment of resistant tumors is neither described nor suggested there.
  • R1 is hydrogen, (C1-C6) -alkylcarbonyl, preferably acetyl, (CrC 6 ) -alkyl, mono- (C ⁇ -C 6 ) -alkylamino- (CrC 4 ) -alkyl, di- (CC 6 ) -alkylamino- (CrC 4 ) -alkyl, where the two (CrC 6 ) -alkyl radicals can form a ring with one another, which may also have one or more NH, N- (C1-C6) -alkyl, O or S-members, (C6-C14) - Aryl- (C1-C6) alkyl or (C6-C14) aryl- (C1-C6) alkoxy- (C1-C6) alkyl;
  • R2 represents a hydrogen atom, halogen, cyano, nitro, (C1-C6) -alkyl, (C1-C6) -alkyl substituted with one or more halogen atoms, preferably trifluoromethyl, substituted with one or more halogen atoms (C1-
  • Alkyl radicals can form a ring with one another, which optionally also has one or more NH, N- (C1-C6) -alkyl, O or S, (C6-C14) -aryl, (C6-C14) -aryloxy, (C6-C14) -Aryl- (C1-C4) -alkyl, (C6-C14) -aryl- (C1-C4) - alkoxy- (C1-C4) alkyl, (C1-C6) alkylcarbonyl, (C1-C6) alkoxycarbonyl, or hydroxyl;
  • A, B, C, D independently of one another represent a nitrogen atom (where R3, R4, R5 and R6 then represent the lone pair of electrons on the nitrogen atom) or a carbon atom substituted by one of the radicals R3-R6;
  • R3, R4, R5 and R6 independently of one another, when bound to nitrogen, a lone pair of electrons, or, when bound to carbon, hydrogen, halogen, cyano, nitro, straight-chain or branched (C1-C6) -alkyl, with one or more halogen atoms substituted straight or branched (C1-C6) alkyl, preferably trifluoromethyl, substituted with one or more halogen atoms straight or branched (C1-C6) alkoxy, preferably trifluoromethoxy, (C2-C6) alkenyl, (C2-C6) alkynyl , (C3-C8) -cycloalkyl, straight-chain or branched (C1-C6) -alkoxy, preferably methoxy, straight-chain or branched (C1-C6) -alkylenedioxy, preferably methylenedioxy, (C1-C6) -alkoxycarbonyl, (C1-C6) - Al
  • Y is unsubstituted or completely or partially identical or differently substituted (C6-C14) aryl, preferably phenyl or 1- or 2-naphthyl, or unsubstituted or wholly or partly identical or different at least one to four N, NH, N- (C1-C6) -alkyl, O and / or S (C1-C13) heteroaryl having ring members or unsubstituted or wholly or partly identical or differently substituted (C3-C8) cycloalkyl, the same or different substituents being selected independently of one another from the group consisting of halogen, preferably fluorine, chlorine, bromine or iodine; cyano; straight chain or branched cyano (C1-C6) alkyl; hydroxy; straight-chain or branched (C1-C6) -alkyl substituted with one or more hydroxy; carboxy; Carboxy- (C1 -C6) alkyl ester, carboxamide; N
  • Alkyl radicals can form a ring with one another, which may also have one or more NH, N- (C1-C6) -alkyl, O and / or S, (C6-C14) -aryl, (C6-C14) -aryloxy, (C6 -C14) aryl- (C1-C6) alkyl, (C6-C14) aryl- (C1 -C6) alkoxy, (C6-C14) aryl- (C1 -C6) alkoxy- (C1 -C6 ) -alkyl, (C1-C6) -alkylcarbonyl, (C1-C6) -alkylcarbonyloxy, (C1-C6) -alkoxycarbonyl, (C1-C6) -alkoxycarbonyl, (C1-C6) -
  • MRP multidrug-resistance protein
  • the 2-acylindoles of the general formula according to the invention can be used as anti-tumor agents and in the chemotherapy of tumor patients.
  • the compounds of formula I inhibit cell division (anti-mitosis effect) and thereby tumor growth.
  • the compounds according to the invention can moreover indirectly or directly inhibit tubulin polymerization. Cell division can be inhibited by locking the tumor cells in the cell cycle, which then leads to cell death (apoptosis).
  • the compounds of the formula I are also suitable for preventing or reducing the formation and spread of metastases in the body. They also have an anti-angiogenic potential and can thus be used as anti-tumor agents by inhibiting tumor vascularization.
  • therapy-resistant tumor diseases in the sense of the present invention encompasses all such tumor diseases with conventional active substances or combinations of active substances or conventional ones
  • tumor diseases can be treated in which the patient initially responded to conventional chemotherapy, but then the tumor formed again (relapse).
  • those tumor diseases can be treated which are not sensitive to the standard therapy schemes known to the person skilled in the art.
  • tumor diseases can be treated according to the invention which have only a limited or marginal sensitivity in the standard therapy schemes known to the person skilled in the art.
  • tubulin inhibitors such as taxanes, colchicinoids,
  • the colchicine binding site was based on “Molecular Modeling "experiments localized in ß-tubulin or on the ⁇ ß interaction surface (Bai R, Covell DG, Pei XF, Ewell JB, Nguyen NY, Brossi A, Hamel E. Mapping the binding site of colchicinoids on beta -tubulin. 2-Chloroacetyl- 2- demethylthiocolchicine covalently reacts predominantly with cysteine 239 and secondarily with cysteine 354.
  • Taxotere a semi-synthetic taxol derivative
  • ß-tubulin ß-tubulin
  • a compound of the aforementioned general formula I for the manufacture of a medicament for the treatment of tumors with resistance to antitumor agents is selected from the group consisting of anti-metabolites such as gemcitabins, folic acid antagonists (eg methotrexate), pyrimidine antagonists (eg 5-fluorouracil (5-FU)) or purine antagonists (e.g.
  • 6-mercaptopurine, 6-thioguanine, fludarabine Tubulin inhibitors such as D-24851, taxanes (eg Taxol, Taxotere), Vinca alkaloids (eg Vincristine, Vinblastine), epothilones, Combretastatinen, Cryptophycinen, Dolstatatine; Topoisomerase inhibitors or DNA intercalating compounds such as SN38, anthracyclines (eg doxorubicin), podophyllotoxins (eg etoposide), camptothecin analogs (eg topotecan); DNA binding or modifying substances such as DNA alkylating or carbamylating substances (e.g.
  • DNA-reactive compounds such as platinum analogues (e.g. cisplatin, carboplatin) and target-specific Antitumor substances such as Herceptin, D-O-00037 (HER-2, from Sugen), EGF receptor / R2 antagonists, C225, JRESSASB1839 are provided.
  • Combretastatin A4 phosphate ⁇ Tozer GM, Prize VE, Wilson J, Locke RJ, Vojnovic B, Stratford MR, Dennis MF, Chaplin DJ.
  • Combretastatin A-4 phosphate as a tumor vascular targeting agent: early effects in tumors and normal tissues. Cancer Res. 59: 1626-34, 1999).
  • R1, R2, R3, R4, R5, R6, A, B, C, D, X and Y have the meanings given above, have an anti-angiogenic effect.
  • an order of the 2-acylindoles of the general formula I can inhibit endothelial cell proliferation and migration and thus neoangiogenesis. This can cause hypoxia (oxygen deficiency) and nutrient deficiency in the tumor cells and cell necrosis of solid tumors. According to a further aspect of the invention, the formation of metastases which are dependent on the supply of oxygen and nutrients can be prevented or reduced.
  • the 2-acylindoles of the general formula I for the treatment of metastases which are associated with conventional tubulin inhibitors cannot be used or can only be treated inadequately.
  • the treatment of brain, spinal cord and lung tumors is possible.
  • the 2-acylindoles according to the invention have a different type of distribution in the body and a different type of mechanism of action.
  • the distribution of active substances in the body is controlled in particular by the so-called Blu Him barrier and by active transport mechanisms. Because the 2-acylindoles according to the invention are distributed in the body via other transport mechanisms in comparison to the known tubulin inhibitors, the treatment of metastases that have hitherto not been able to be treated or can only be treated inadequately is possible.
  • the object of the invention is to provide compounds of the general formula I.
  • R1, R2, R3, R4, R5, R6, A, B, C, D, X and Y have the meanings given above, for the manufacture of medicaments for the treatment of therapy-resistant tumor diseases, metastatic tumor diseases and as angiogenesis inhibitors.
  • the treatment of. Therapy-resistant tumor patients, patients with tumor metastases or patients with pathophysiologically altered angiogenic processes are provided.
  • the duration of treatment can be shortened and / or the treatment can be extended to therapy-resistant tumor diseases.
  • the training of Recurrences and / or tumor metastases are restricted or prevented and the survival of the patient is thus increased.
  • the quality of life of the treated patients can be improved.
  • the invention further includes the use of compounds of general formula I.
  • R1, R2, R3, R4, R5, R6, A, B, C, D, X and Y have the meanings given above, for the production of medicaments for the treatment of diseases in which an angiogenesis inhibitory effect is functionally desired, such as for ocular neovascularization, endometriosis, psoriasis or angiofibromas.
  • the invention further includes the fixed or free combination of compounds of general formula I.
  • R1, R2, R3, R4, R5, R6, A, B, C, D, X and Y have the meanings given above, with antitumor agents known per se.
  • the fixed or free combination can be selected, for example, with active substances selected from the group consisting of anti-metabolites such as gemcitabins, folic acid antagonists (eg methotrexate), pyrimidine antagonists (eg 5-
  • Fluorouracil (5-FU) or purine antagonists (e.g. 6-mercaptopurine, 6-thioguanine, fludarabine); Tubulin inhibitors such as D-24851, taxanes (e.g. Taxol, Taxotere), Vinca alkaloids (e.g. Vincristine, Vinblastine), epothilones, Combretastatinen, Cryptophycinen, Dolstatatine; Topoisomerase inhibitors or DNA intercalating compounds such as SN38, anthracyclines (e.g.
  • Doxorubicin e.g. etoposide
  • camptothecin analogs e.g. topotecan
  • DNA binding or modifying substances such as DNA alkylating or carbamylating substances (e.g. cyclophosphamide, ifosfamide, mafosfamide, glufosfamide, thiotepa, melphalan, chloroetylnitrosourea (BCNU); DNA-reactive compounds such as platinum
  • Analogs e.g. cisplatin, carboplatin
  • target-specific antitumor substances such as Herceptin, D-O-00037 (HER-2, from Sugen), EGF receptor / R2 antagonists, C225, JRESSA SB1839.
  • the invention further includes the use of compounds of general formula I.
  • R1, R2, R3, R4, R5, R6, A, B, C, D, X and Y have the meanings given above, for partial or complete replacement of as a result Development of resistance of ineffective antitumor agents in the treatment of tumor diseases in mammals, especially in humans.
  • compounds of the general formula I according to claim 1 are used for the production of a medicament for the treatment of therapy-resistant tumors, metastatic tumors and / or as angiogenesis inhibitors, in which R1-R6, A, B, C, D, X and Y have the meaning given above, with the proviso that at least one of the radicals R3-R6 is straight-chain or branched (C1-C6) alkoxy, preferably methoxy; straight-chain or branched (C1-C6) -alkyl, preferably methyl; straight-chain or branched (C1-C6) -alkylenedioxy, preferably methylenedioxy, hydroxy; straight-chain or branched (C1-C6) alkoxy substituted with one or more halogen atoms, preferably trifluoromethoxy; straight-chain or branched (C1-C6) -alkyl substituted with one or more halogen atoms, preferably trifluoromethyl
  • compounds of general formula I according to claim for the manufacture of a medicament for the treatment of therapy-resistant tumors, metastatic tumors and / or as angiogenesis inhibitors are used, in which R1, R2, R3, R5 and R6, A, B , C, D, X and Y have the meaning given above, with the proviso that the radical R4 is straight-chain or branched (C1-C6) alkoxy, preferably methoxy; straight-chain or branched (C1-C6) -alkyl, preferably methyl; straight-chain or branched (C1-C6) -alkylenedioxy (where the second oxygen atom can optionally be the radical R4 or R6), preferably methylenedioxy, hydroxy; (C1 -C6) alkylcarbonyloxy, (C1-C6) alkoxycarbonyloxy; straight-chain or branched (C1-C6) alkoxy substituted with one or more halogen atoms, preferably tri
  • compounds of the above general formula I are used for the production of a medicament for the treatment of therapy-resistant tumors, metastatic tumors and / or as angiogenesis inhibitors, in which R1, R2, R3, R5 and R6, A, B, C, D, X and Y have the meaning given above, with the proviso that the radical R4 is straight-chain or branched (C1-C6) alkoxy, preferably methoxy.
  • compounds of the above general formula I are used for the production of a medicament for the treatment of therapy-resistant tumors, metastatic tumors and / or as angiogenesis inhibitors, in which R1, R2, R3, R5 and R6, A, B, C, D, X and Y have the meaning given above, with the proviso that the radical R4 is methoxy.
  • compounds of the above general formula I are used for the production of a medicament for the treatment of therapy-resistant tumors, metastatic tumors and / or as angiogenesis inhibitors, in which R1-R6, A, B, C, D and X are the have the abovementioned meaning, with the proviso that the radical Y for (C6-C14) aryl or at least one N, NH, O and / or S as ring member (C1-C13) heteroaryl, which is selected with at least one radical from the group consisting of hydrogen, amino, halogen, nitro, cyano, straight-chain or branched (C1-C6) alkoxy, preferably methoxy; straight-chain or branched (C1-C6) -alkyl, preferably methyl; hydroxy; straight-chain or branched (C1-C6) alkoxy substituted with one or more halogen atoms, preferably trifluoromethoxy; straight-chain or branched (
  • compounds of the above general formula I are used for the production of a medicament for the treatment of therapy-resistant tumors, metastatic tumors and / or as angiogenesis inhibitors, in which R1-R6, A, B, C, D and X are the have the meaning given above, with the proviso that the radical Y is substituted or unsubstituted (C6-C14) aryl or at least one to four N, NH, O and / or S having a ring member (C1-C13) heteroaryl.
  • R1-R6, A, B, C, D and X have the meaning given above and the rest Y for (C6-C14) -aryl or at least an (C1-C13) heteroaryl which has N, NH, 0 and / or S as the ring member and which has at least one radical selected from the group consisting of hydrogen, amino, halogen, nitro, cyano, straight-chain or branched (C1-C6) Alkoxy, preferably methoxy; straight chain or branched
  • (C1-C6) alkyl preferably methyl; hydroxy; with one or more
  • compounds of the above general formula I for the production of a medicament for the treatment of therapy-resistant tumors, metastatic tumors and / or as angiogenesis inhibitors are provided, in which R1-R6, A, B, C, D and X are the have the meaning given above, and the radical Y is a 1-phenyl radical which is unsubstituted or with hydrogen, 3,4-dichloro, 2- or 3-methoxy, 2,4-dimethoxy, 3-nitro 3-trifluoromethyl, 2 , 3,4-trimethoxy, 3,4,5-trimethoxy is substituted.
  • the compounds of the formula I used according to the invention can be prepared by processes known per se, for example by the following processes:
  • the compounds of general formula I obtained can be separated into their enantiomers and / or diastereomers.
  • the compounds of general formula I obtained which occur as a racemate can be converted into their optical antipodes according to methods known per se and compounds of general formula I with at least 2 asymmetric carbon atoms on the basis of their physico-chemical differences according to methods known per se, for example by chromatography and / or fractional crystallization, separated into their diastereomers which, if they are obtained in racemic form, can then be separated into the enantiomers as mentioned above.
  • the enantiomers are separated preferably by column separation on chiral phases or by recrystallization from an optically active solvent or by reaction with an optically active substance which forms salts or derivatives, such as esters or amides, with the racemic compound.
  • the compounds of the formula I obtained can be converted into their salts, in particular for pharmaceutical use, into their pharmacologically and physiologically tolerable salts with inorganic or organic acids.
  • suitable acids for this purpose are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
  • the compounds of the formula I contain an acidic group such as a carboxyl group, they can, if desired, be converted into their salts with inorganic or organic bases, in particular for their pharmaceutical use into their physiologically tolerable salts.
  • Suitable bases are, for example, sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
  • the compounds of general formula I and their salts used according to the invention have valuable properties.
  • the compounds of the formula I used according to the invention have valuable pharmacological properties.
  • the compounds of the formula I can be used for the treatment of therapy-resistant tumors, metastatic tumors and as angiogenesis inhibitors.
  • Example 1 Component A: 5-methoxy-1-phenylsulfonyl-1 H-2-indole Component B: Benzaldehyde
  • Component A 5-methoxy-1-phenylsulfonyl-1 H-2-indole
  • Component B 2-methoxy-benzaldehyde
  • Example 3 Component A: 5-methoxy-1-phenylsulfonyl-1 W-2-indole Component B: 3-methoxy-benzaldehyde
  • Component A 5-methoxy-1-phenylsulfonyl-1H-2-indole
  • Component B 4-methoxy-benzaIdehyde
  • Component A 5-methoxy-1-phenylsulfonyl-1 / V-2-indole
  • Component B 2,4-dimethoxy-benzaldehyde 5-methoxy-1-phenylsulfonyl-1 H-2-indolyl (2,4-dimethoxyphenyl) - 1-methanol mp: 119-120 ° C
  • Component A 1-phenylsulfonyl-1H-2-indole
  • Component B 3-pyridinyl-carbaldehyde
  • Example 7 Component A: 4-hydroxy (1-phenylsulfonyl-1H-2-indole)
  • Component B 4-cyanobenzaldehyde
  • Component A 5-methoxy-i-phenylsulfonyl-1 / V-2-indole
  • Component B 4-isoquinolinyl-carbaldehyde 4-isoquinolinyl (5-methoxy-1-phenylsulfonyl-1 H-2-indolyl) -1-methanol mp: 138-139 ° C
  • Component A 5-methoxy-1-phenylsulfonyl-1H-2-indole
  • Component B 1-isoquinolinyl carbaldehyde
  • reaction mixture is stirred at 0 ° C. for 60 min and then cooled to -78 ° C.
  • This mixture is a pre-cooled to -78 ° C solution of the corresponding carboxylic acid chloride (component B) (30 mmol) in 40 ml abs.
  • Example 10 Component A: 1-phenylsulfonyl-1H-2-indole
  • Component B benzoic acid chloride 1 -phenylsulfonyl-1 - / - 2-indolylphenyl-1-methanone mp: 142-143 ° C
  • Example 11 Component A: 1-phenylsulfonyl-1H-2-indole
  • Component B 2-methoxy-benzoic acid chloride
  • Component A 1-phenylsulfonyl-1 H-2-indole
  • Component B 3-methoxy-benzoic acid chloride
  • Component A 1-phenylsulfonyl-1H-2-indole
  • Component B 2,4-dimethoxy-benzoic acid chloride
  • Component A 1-phenylsulfonyl-1H-2-indole
  • Component B 3,4,5-trimethoxy-benzoic acid chloride
  • Component A 3-methyl-1-phenylsulfonyl-1H-2-indole
  • Component B 2-methoxy-benzoic acid chloride
  • Component A 3-methyl-1-phenylsulfonyI-1 H-2-indole
  • Component B 3-methoxy-benzoic acid chloride
  • Example 17 Component A: 3-methyl-1-phenylsulfonyl-1 H-2-indole
  • Component B 2,4-dimethoxy-benzoic acid chloride 3-methyl-1-phenylsulfonyl-1 H-2-indolyl (2,4-dimethoxyphenyl ) -1-methanone mp: 155-157 ° C
  • Component A 3-methyl-1-phenylsulfonyl-1H-2-indole
  • Component B 3,4,5-trimethoxy-benzoic acid chloride 3-methyl-1-phenylsulfonyl-1 H-2-indolyl (3,4,5-trimethoxyphenyl ) -1-methanone
  • Component A 5-methyl-1-phenylsulfonyI-1H-2-indole
  • Component B 2-methoxy-benzoic acid chloride 5-methyl-1-phenylsulfonyl-1 - 2-indolyl (2-methoxyphenyl) -1 -methanone 157-158 ° C
  • Component A 5-methyl-1-phenylsulfonyl-1H-2-indole
  • Component B 3-methoxy-benzoic acid chloride 5-methyl-1-phenylsulfonyl-1 H-2-indolyl (3-methoxyphenyl) -1-methanone 124-127 ° C
  • Example 21 5-methyl-1-phenylsulfonyl-1H-2-indole
  • Component A 5-methyl-1-phenylsulfonyl-1H-2-indole
  • Component B 2,4-dimethoxy-benzoic acid chloride
  • Component A 5-methyl-1-phenylsulfonyl-1H-2-indole
  • Component B 3,4,5-trimethoxy-benzoic acid chloride
  • Component A 5-methoxy-1-phenylsulfony I-1 / - 2-indole
  • Component B Benzoic acid chloride 5-methoxy-1-phenylsulfonyl-1 H-2-indolylphenyl-1-methanone mp: 148 ° C
  • Component A 5-methoxy-1-phenylsulfonyl-1H-2-indole
  • Component B 2-methoxy-benzoic acid chloride 5-methoxy-1-phenylsulfonyl-1 r7-2-indolyl (2-methoxyphenyl) -1-methanone 179 ° C
  • Component A 5-methoxy-1-phenyIsulfonyl-1H-2-indole
  • Component B 3-methoxy-benzoic acid chloride
  • Example 26 Component A: 5-methoxy-1-phenylsulfonyl-1 H-2-indole
  • Component B 4-methoxy-benzoic acid chloride 5-methoxy-1-phenylsulfonyl-1 -2-indolyl (4-methoxyphenyl) -1-methanone mp: 129-130 ° C
  • Example 27 Component A: 5-methoxy-1-phenylsulfonyl-1 H-2-indole
  • Component B 2,4-dimethoxy-benzoic acid chloride 5-methoxy-1-phenylsulfonyl-1 H-2-indoIyl (2,4-dimethoxyphenyl ) -1-methanone mp: 62-64 ° C
  • Component A 5-methoxy-1-phenylsulfonyl-1H-2-indole
  • Component B 3,4-dimethoxybenzoic acid chloride
  • Component A 5-methoxy-1-phenylsulfonyl-1 H-2-indole
  • Component B 3,5-dimethoxybenzoic acid chloride 5-methoxy-1-phenylsulfonyl-1 H-2-indolyl (3,5-dimethoxyphenyl) -1-methanone Mp: 122-123 ° C
  • Component A 1-phenylsulfonyl-1H-2-indole
  • Component B 3-pyridinyl-carboxylic acid chloride
  • Component A 5-methoxy-1-phenylsulfonyl-1H-2-indole
  • Component B 2-pyridinyl-carboxylic acid chloride
  • Component A 4- (1-phenylsulfonyl-1H-2-indole
  • Component B 4-cyano-benzoic acid chloride
  • Example 31 Component A: 2-fluorophenyl (5-methoxy-1-phenylsulfonyl-1f7-2-indole)
  • Component B 2-fluoro-benzoic acid chloride
  • Component A 5-methoxy-1-phenylsulfonyl-1H-2-indole
  • Component B 2,6-difluoro-benzoic acid chloride
  • Component A 5-methoxy-1-phenylsulfonyl-1H-2-indole
  • Component B 2-methyl-benzoic acid chloride
  • Component A 5-methoxy-1-phenylsulfonyl-1H-2-indole
  • Component B 3-trifluoromethylphenyl-benzoic acid chloride 5-methoxy-1-phenylsulfonyl-1 H-2-indolyl (3-trifluoromethylphenyl) -1-methanone 175-177 ° C
  • Example 35
  • Component A 4-fluorophenyl (5-methoxy-1-phenylsulfonyl-1 H-2-indole
  • Component B 4-fluoro-benzoic acid chloride
  • 4-fluorophenyl (5-methoxy-1-phenylsulfonyl-1 H-2-indolyl) -1 -methanone mp: 123-128 ° C
  • Component A 5-methoxy-1-phenylsulfonyl-1H-2-indole
  • Component B 3,4-dichloro-benzoic acid chloride 5-methoxy-1-phenylsulfonyl-1H-2-indolyl (3,4-dichlorophenyl) -1-methanone Mp: 141-144 ° C
  • Component A 5-methoxy-1-phenylsulfonyl-1H-2-indole
  • Component B 4-chloro-benzoic acid chloride
  • Example 38 Component A: 5-methoxy-1-phenylsulfonyl-1H-2-indole
  • Component B 4-bromo-benzoic acid chloride
  • Component A 5-methoxy-1-phenyIsu ⁇ fonyl-1 H-2-indole
  • Component B 3,4,5-trimethoxy-benzoic acid chloride
  • Example 40 Component A: 5-methoxy-1-phenylsulfonyl-1 - / - 2-indole
  • Component B 4-pentyloxy-benzoic acid chloride 5-methoxy-1-phenylsulfonyl-1 H-2-indolyl (4-pentyloxyphenyl) -1 -methanone mp .: 118-120 ° C
  • Component A 5-methoxy-1-phenylsulfonyl-1 - 2-indole
  • Component B 1-naphthyl-carboxylic acid chloride 5-methoxy-1-phenylsulfonyl-1 H-2-indolyl (1-naphthalenyl) -1-methanone mp. : 225-228 ° C
  • Component A 5-methoxy-1-phenylsulfonyl-1H-2-indole
  • Component B 4-tert-buty-benzoic acid chloride 4-fe / f-butylphenyl (5-methoxy-1-phenylsulfonyl-1 - 2-indolyl-1 -methanone) mp: 161-163 ° C
  • Component A 5-methoxy-1-phenylsulfonyl-1H-2-indole
  • Component B 2,3-dimethoxy-benzoic acid chloride
  • Example 44 Component A: 5-methoxy-1-phenylsulfonyl-1H-2-indole
  • Component B 2,3,4-trimethoxy-benzoic acid chloride 5-methoxy-1-phenylsulfonyl-1H-2-indolyl (2,3,4 -trimethoxyphenyl) -1 -methanone mp: 57-59 ° C
  • Component A 5-methoxy-1-phenylsulfonyl-1H-2-indole
  • Component B 4-methyl-benzoic acid chloride
  • Component A 5-methoxy-1-phenylsulfonyl-1 H-2-indole
  • Component B 4-ethylbenzoyl chloride
  • Component A 5-methoxy-1-phenylsulfonyl-1f / -2-indole
  • Component B 4-propyl-benzoic acid chloride 5-methoxy-1-phenylsulfonyl-1 H-2-indolyl (4-propylphenyl) -1-methanone mp. : 112-114 ° C
  • Component A 5-methoxy-1-phenylsulfonyl-1H-2-indole
  • Component B 2-chloro-6-fluoro-benzoic acid chloride 5-methoxy-1-phenylsulfonyl-1 H-2-indolyl (2-chloro-6-f luorophenyl) -1-methanone mp: 130 ° C
  • Component A 5-methoxy-1-phenylsulfonyl-1 H-2-indole
  • Component B 2,5-dimethyl-benzoic acid chloride
  • Example 50 Component A: 5-methoxy-1-phenylsulfonyl-1 - / - 2-indole
  • Component B 2-nitro-benzoic acid chloride 5-methoxy-1-phenylsulfonyl-1 H-2-indolyl (2-nitrophenyl) -1-methanone mp: 190-191 ° C
  • Example 51 Component A: 5-methoxy-1-phenylsulfonyl-1 / - / - 2-indole
  • Component B 2-amino-benzoic acid chloride 5-methoxy-1-phenylsulfonyl-1 H-2-indolyl (2-aminophenyl) - 1 -methanone
  • Component A 5-methoxy-1-phenylsulfonyl-1H-2-indole
  • Component B 3-nitro-benzoic acid chloride 5-methoxy-1-phenylsulfonyl-1 H-2-indolyl (3-nitrophenyl) -1-methanone 228-230 ° C
  • Component A 5-methoxy-1-phenylsulfonyl-1H-2-indole
  • Component B 3-amino-benzoic acid chloride 5-methoxy-1-phenylsulfonyl-1 H-2-indolyl (3-aminophenyl) -1-methanone 188-189 ° C
  • Component A 5-methoxy-1-phenylsulfonyl-1H-2-indole
  • Component B 4-nitro-benzoic acid chloride 5-methoxy-1-phenylsulfonyl-1 H-2-indolyl (4-nitrophenyl) -1-methanone 161-162 ° C
  • Example 55 Component A: 5-methoxy-1-phenylsulfonyl-1H-2-indole
  • Component B 4-amino-benzoic acid chloride 5-methoxy-1-phenylsulfonyl-1 - / - 2-indolyl (4-aminophenyl) -1-methanone
  • Component A 5-methoxy-1-phenylsulfonyl-1 - / - 2-indole
  • Component B 3-methoxy-2-nitro-benzoic acid chloride
  • Example 57 Component A: 5-methoxy-1-phenylsulfonyl-1 H-2-indole
  • Component B 2-amino-3-methoxy-benzoic acid chloride 5-methoxy-1-phenylsulfonyl-1 H-2-indolyl (2-amino -3-methoxyphenyl) -1-methanone
  • Component A 5-methoxy-1-phenylsulfonyl-1 / - / - 2-indole
  • Component B 2-methyl-3-nitro-benzoic acid chloride
  • Component A 5-methoxy-1-phenylsulfonyl-1H-2-indole
  • Component B 3-amino-2-methyl-benzoic acid chloride
  • Component A 5-methoxy-1-phenylsulfonyl-1H-2-indole
  • Component B Cyclopropylcarboxylic acid chloride Cyclopropyl (5-methoxy-1-phenylsulfonyl-1 H-2-indolyl) -1-methanone mp: 118-120 ° C
  • Example 61
  • Component A 5-methoxy-1-phenylsulfonyl-1H-2-indole
  • Component B Cyclobutylcarboxylic acid chloride cyclobutyl (5-methoxy-1-phenylsulfonyl-1 H-2-indolyl) -1-methanone mp: 146-147 ° C
  • Component A 5-benzyloxy-1-phenylsulfonyl-1 7-2-indole
  • Component B benzoic acid chloride
  • Example 63 Component A: 5-benzyloxy-1-phenylsulfonyl-1H-2-indole
  • Component B 3-chloro-benzoic acid chloride
  • Component A 5-benzyloxy-1-phenylsulfonyl-1H-2-indole
  • Component B 4-chloro-benzoic acid chloride
  • Component A 5-benzyloxy-1-phenylsulfonyl-1H-2-indole
  • Component B 4-methoxy-benzoic acid chloride
  • Component A 5-benzyloxy-1-phenylsulfonyl-1H-2-indole
  • Component B 3,4,5-trimethoxy-benzoic acid chloride
  • Example 67 Component A: 5-benzyloxy-1-phenylsulfonyl-1H-2-indole
  • Component B 2-methoxy-benzoic acid chloride
  • Component A 5-benzyloxy-1-phenylsulfonyl-1H-2-indole
  • Component B 3-methoxy-benzoic acid chloride
  • Component A 5-methoxy-1-phenylsulfonyl-1H-2-indole
  • Component B 4-isoquinolyl-carboxylic acid chloride 4-isoquinolinyl (5-methoxy-1-phenylsulfonyl-1 H-2-indolyl) -1-methanone 189-190 ° C
  • Component A 5-methoxy-1-phenylsulfonyl-1H-2-indole
  • Component B 1-isoquinolyl-carboxylic acid chloride
  • Component A 1-phenylsulfonyl-1 / -pyrrolo [2,3-ö] pyridine
  • Component B 2-methoxy-benzoic acid chloride 1-phenylsulfonyl-1 H-pyrrolo [2,3-i?] Pyridin-2-yl (2nd -methoxyphenyl) -1 -methanone mp: 124-125 ° C
  • Component A 1-phenylsulfonyl-1 / - / - pyrrolo [2,3-jb] pyridine
  • Component B 3-methoxy-benzoic acid chloride
  • Example 73 Component A: 1-phenylsulfony I-1H-pyrrolo [2,3-ib] pyridine
  • Component B 3,4,5-trimethoxy-benzoic acid chloride
  • Component A 1-phenylsulfonyl-1H-pyrrolo [2,3-ib] pyridine
  • Component B 2,4-dimethoxy-benzoic acid chloride
  • Component A 5-methoxy-1-phenylsulfonyl-1 H-pyrrolo [2,3-j] pyridine
  • Component B 2-methoxy-benzoic acid chloride
  • Component A 5-methoxy-1-phenylsulfonyl-1 - pyrrolo [2,3- / j] pyridine
  • Component B 3-methoxy-benzoic acid chloride
  • Component A 5-methoxy-1-phenylsulfonyl-1 H-pyrrolo [2,3-?] Pyridine
  • Component B 3,4,5-trimethoxy-benzoic acid chloride 5-methoxy-1-phenylsulfonyl-1r / -pyrrolo [2,3-jb] pyridin-2-yl (3,4,5-trimethoxyphenyl) -1-methanone
  • Component A 5-methoxy-1-phenylsulfonyl-1 - -pyrrolo [2,3- ⁇ ] pyridine
  • Component B 2,4-dimethoxy-benzoic acid chloride 5-ethoxy-1-phenylsulfonyl-1 f / -pyrrolo [2,3-b] pyridin-2-yl (2,4-dimethoxyphenyl) -1-methanone
  • Component A 5-methoxy-1-phenylsulfonyl-1 - pyrrolo [3,2- ⁇ b] pyridine
  • Component B benzoic acid chloride
  • Component A 5-methoxy-1-phenylsulfonyl-1 H-pyrrolo [3,2-ib] pyridine
  • Component B 2-methoxy-benzoic acid chloride
  • Component A 5-methoxy-1-phenylsulfonyl-1 / - / - pyrrolo [2,3-c] pyridine
  • Component B 3-methoxy-benzoic acid chloride
  • Component A 5-methoxy-1-phenylsulfonyl-1 H-pyrrolo [2,3-c] pyridine
  • Component B 2,4-dimethoxy-benzoic acid chloride 5-methoxy-1-phenylsulfonyl-1 H-pyrrolo [2,3- ⁇ yridin-2-yl (2,4-dimethoxyphenyl) -1-methanone
  • Component A 5-methoxy-1-phenylsulfonyl-1H-pyrrolo [2,3-c] pyridine
  • Component B 3,4,5-trimethoxy-benzoic acid chloride 5-methoxy-1-phenylsulfonyl-1 r / -pyrrolo [2,3-c] pyridin-2-yl (3,4,5-trimethoxyphenyl) -1-methanone
  • Component A 5-methoxy-1-phenylsulfonyl-1 H-pyrrolo [3,2- ⁇ b] pyridine
  • Component B 2-methoxy-benzoic acid chloride 5-methoxy-1-phenylsulfonyl-1 / - / - pyrrolo [3,2-jb] pyridin-2-yl (2-methoxyphenyl-1-methanone
  • Component A 5-methoxy-1-phenylsulfonyl-1 H-pyrrolo [3,2-j] pyridine
  • Component B 3-methoxy-benzoic acid chloride
  • Example 86 Component A: 5-methoxy-1-phenylsulfonyl-1H-pyrrolo [3,2- / j] pyridine
  • Component B 2,4-dimethoxy-benzoic acid chloride
  • Component A 5-methoxy-1-phenyIsulfonyl-1 H-pyrrolo [3,2-jb] pyridine
  • Component B 3,4,5-trimethoxy-benzoic acid chloride
  • Method A The corresponding N-protected methanone derivative (starting component) (1.8 mmol) is heated to reflux in a mixture of 10% sodium hydroxide (20 ml) and ethanol (40 ml) for 2 to 15 hours (TLC control). After cooling to room temperature, the solution is poured onto 100 ml of water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is removed. The crude product is recrystallized from ethyl acetate.
  • Method B A mixture of the corresponding N-protected methanone derivative (starting component) (1.8 mmol) and 0.79 g (2.5 mmol) of tetrabutylammonium fluoride trihydrate is heated to reflux in 20 ml of THF / methanol 1: 1. After the end of the reaction (30 min - 4 hours, TLC control), the mixture is cooled and the mixture is poured onto 100 ml of water. It is extracted with ethyl acetate and the organic phase is dried over sodium sulfate. The solvent is slowly concentrated until the product begins to crystallize.
  • Example 89 Starting component: compound according to Example 11 method A or B
  • Example 92 Starting component: compound according to Example 14 method A or B
  • Example 94 Starting component: compound according to Example 16 method A or B
  • Example 98 Starting component: compound according to Example 20 method A or B
  • Example 99A (D-70317): Starting component: compound according to Example XX method A or B
  • Example 104 Starting component: compound according to Example 26, method A or B
  • Example 110 Starting component: compound according to Example 33 method A or B
  • Example 117 Starting component: compound according to Example 40 method A or B
  • Example 123 Starting component: compound according to Example 46 method A or B 5-methoxy-1 H-2-indolyl (4-ethylphenyl) -1-methanone mp: 154-155 ° C
  • Example 124 Starting component: compound according to Example 47 method A or B
  • Example 127 Starting component: compound according to Example 50 method A or B
  • Example 138 Starting component: compound according to Example 61 method A or B
  • Example 144 Starting component: compound according to Example 67 method A or B 5-Benzyloxy-1 H-2-indolyl- (2-methoxyphenyl) -1-methanone mp: 150-151 ° C
  • Example 145 Starting component: compound according to Example 68, method A or B
  • Example 154 Starting component: compound according to Example 77 method A or B 5-methoxy-1H-pyrrolo [2,3-jb] pyridin-2-yl (3,4,5-trimethoxyphenyl) -1-methanone
  • Example 157 Starting component: Compound according to Example 80 Method A or B 5-methoxy-1H-pyrrolo [3,2-b] pyridin-2-yl (2-methoxyphenyl) -1-methanone
  • Example 158 Starting component: Compound according to Example 81 Method A or B 5-methoxy-1H-pyrrolo [2,3-c] pyridin-2-yl (3-methoxyphenyl) -1-methanone
  • Example 160 Starting component: Compound according to Example 83, Method A or B 5-methoxy-1 / V-pyrrolo [2,3-c] pyridin-2-yl (3,4,5-trimethoxyphenyl) -1-methanone
  • the compounds according to the invention can also be prepared by reacting an N-protected substituted indole derivative with a corresponding nitrile compound in accordance with the example below.
  • Example 147 (prepared by an alternative method): Compound: 1-isoquinolinyl (5-methoxy-1 H-2-indolyl) -1-methanone
  • N-Butyllithium (5.5 mmol, 1.6 M in hexane, Aldrich) was added dropwise to a solution of 1- (tert-butyloxycarbonyl) -5-methoxyindole (5 mmol) in 10 ml of dry THF, cooled to -78 ° C. After 30 minutes at -78 ° C., a solution of 1-cyanoisoquinoline (7.5 mmol), dissolved in 2 ml of THF, was slowly added dropwise. The mixture was allowed to slowly warm to room temperature overnight (16 hours).
  • the compounds of the general formula can be administered orally daily in doses from about 20 mg to about 500 mg or more.
  • doses from about 20 mg to about 500 mg or more.
  • intravenously as an injection or as an infusion for example, up to about 250 mg / day or more can be administered depending on the patient's body weight and individual tolerance.
  • high effectiveness and widespread use of the medicinal products is also possible in therapy-refractory patients.
  • the anti-angiogenic effect works synergistically and is suitable for additionally suppressing the spread of the tumor.
  • the 2-acylindoles of general formula I used according to the invention have a mechanism of action which differs from that of complex natural substances such as taxanes; -
  • the 2-acylindoles used according to the invention inhibit the formation of new vessels, so they have an anti-angiogenic activity.
  • Examples include: 1. In contrast to vincristine, doxorubicin, taxol and colchicine, the cytotoxic activity of D-64131 and D-68144 in vitro on the MDR leukemia cell line of the mouse L1210 VCR is not influenced. 2. The cytotoxic activity of D-64131 in vitro on MRP-mediated resistance and on cell lines is resistant to the antimetabolite 5-fluorouracil, the thymidilate synthase inhibitor raltitrexed and the topoisomerase inhibitor SN-38.
  • the cytotoxic activity of D-64131 and D-68144 is independent of the p53 status ("wild-type” or "loss of function").
  • 2-acylindole analogues do not significantly influence the polymerization-dependent GTPase of ß-tubulin despite binding to tubulin.
  • Fig. 1 Cytotoxicity in the L1210 VCR tumor model with overexpression of the MDR protein.
  • the murine leukemia cell line L1210 and the vincristine-resistant subline L1210 VCR with overexpression of the MDR protein (Bacher, GB Nickel, P. Emig, U. Vanhoefer, S. Seeber, A. Shandra, T. Kienner and T. Beckers D-24851, a novel synthetic tubulin inhibitor, exerts curative antitumoral activity in vivo, efficacy towards multidrug resistant tumor cells, and lacks neurotoxicity Cancer Res. 61: 392-399, 2001) were treated with colchicine, the acylindoles D-64131 and D-68144 according to the invention.
  • the proliferation was determined after 48 hours by means of the XTT assay and the corresponding dose-response factors were recorded.
  • the IC 50 data for these as well as other chemotherapeutic agents are summarized in Table 1.
  • Fig. 2 Inhibition of tubulin polymerization and [ 3 H] colchicine binding.
  • Fig. 3 Influence of the polymerization-dependent ⁇ -tubulin GTPase activity.
  • MAPs Proteins
  • Taxol or D-64131 are used on the polymerization-dependent ⁇ -tubulin GTPase.
  • the polymerization of the tubulin was increased by adding 4.5% (v: v) Glycerin (B) or 1M glutamate (C) and incubation at 37 ° C for 2h induced.
  • the GTPase activity is given as the quotient of the GDP / GTP concentrations, which were determined by phosphorimager analysis.
  • the background activity at 0 ° C is shown as a dotted line.
  • Fig. 4 Anti-angiogenic potency of selected compounds in the CAM assay
  • a score system was used to evaluate the anti-angiogenic potency. This is as follows:
  • CAMs were treated with agarose buffer.
  • Suramin A 50 ⁇ g / pellet was used as a positive control. Each experiment was reproduced at least once. All test substances were used in a concentration of 50 ⁇ g / pellet.
  • Table 1 Anti-proliferative effect / cytotoxicity on L1210 and L1210 VCR leukemia cells with overexpression of the MDR gp170 transporter protein.
  • the Anti-proliferative effect of D-64131 and D-68144 on the parental L1210 and vincristine-resistant subline L1210 VCR was determined in comparison to standard chemotherapeutic agents. All experiments were carried out in duplicates and IC 50 values from dose-response curves were determined using non-linear regression analysis. Averages from independent experiments are shown. The resistance factor (in brackets) is calculated from the ratio of the IC 50 's for the L1210 VCR and the parental L1210 cell line.
  • Resistance factor (in brackets) is calculated from the ratio of the IC 5 o ' s for the resistant and the parental tumor line.
  • Table 3 The cytotoxicity of D-64131 and D-68144 compared to Taxol on tumor cell lines with wild type and mutant p53 protein is shown. The tumor cell lines were according to the p53 status
  • CAM assay to determine the anti-angiogenic effect. All preparatory steps were carried out at 60 ° C. The compounds to be tested were dissolved in a 2.5% agarose solution in the final concentration of 1-20 mg / ml. To prepare the pellets, 10 ⁇ l of this solution were added dropwise to round Teflon sheets of 3 mm in diameter and cooled to room temperature. After incubation for 65-70min at 37 ° C and a relative humidity of 80%, fertilized chicken eggs were positioned in a horizontal position and rotated several times. Before opening, 10 ml of albumin were aspirated at a marked position. At about 2/3 height relative to this marked position, the eggs were treated with a scalpel and the shell was removed.
  • the aperture (cavity) was covered and the eggs incubated at 37 ° C and a relative humidity of 80% for 75 h.
  • the eggs were incubated for another day and then analyzed under the stereomicroscope. 15-20 eggs were used for each test substance.
  • a "score system" was used, as in the legend to Figure 4.
  • the assay uses tubulin isolated from cycles of bovine brain polymerization and depolymerization.
  • 85 ⁇ l mix consisting of 80 ⁇ l PEM buffer pH 6.6 (0.1 M pipes, 1mM EGTA, 1mM MgS0 4 p.H6.6) and 5 ⁇ l 20mM GTP stock solution per well in the filter plate type MultiScreen (0.22 ⁇ M hydrophilic, low protein binding- Durapore membrane, Millipore) submitted.
  • the test substance dissolved in 100% DMSO, is pipetted in the appropriate amount. Then add 10 ⁇ l purified beef tubulin (50-60 ⁇ g tubulin per well).
  • the filter plate is shaken at room temperature for 20 minutes at 400 rpm and then 50 ⁇ l / well staining solution (45% MeOH, 10% acetic acid, 0.1% naphthol blue black / Sigma) is pipetted. After an incubation period of 2 minutes the staining solution is suctioned off (Eppendorf Event 4160) and then washed twice with a 90% methanol / 2% acetic acid solution. Finally, 200 ⁇ l / well decolorizing solution (25mM NaOH, 50% ethanol, 0.05mM EDTA) are pipetted. After an incubation of 20 minutes at room temperature on a shaker (400rpm), measurements are taken in the photometer with an absorption of 600 nM. The percentage inhibition is calculated based on the 100% value of a positive control (no test substance included) or the IC 50 value when a concentration-effect curve is recorded.
  • 50 ⁇ l / well staining solution 45% MeOH, 10% acetic acid, 0.1% naphthol blue black
  • the tubulin binding assay was modified according to Tahit et al. (Tahit, SK, Kovar, P, Rosenberg, SH, Ng, SC. Rapid colchicine competition-binding scintillation proximity assay using biotin-labeled tubulin. BioTechniques 29: 156-160, 2000) with biotin-labeled tubulin, streptavidin-coated yyttrium SPA beads and [ 3 H] colchicine (1mCi / ml; specific activity 76.5 Ci / mmol) were carried out.
  • the binding mixture contains 0.08 ⁇ M [ 3 H] colchicine, 1 mM GTP and 0.5 ⁇ g biotin tubulin in G-PEM buffer pH 6.9 (80mM pipes, 1mM MgCl 2 , 1mM EGTA, 5% glycerol) in 100 ⁇ l total volume.
  • the test compound and [ 3 H] colchicine are added before the addition of tubulin.
  • 20 ⁇ l SPA beads 80 ⁇ g in P-GEM buffer
  • the SPA beads are deposited for 45 minutes and the scintillation counting is carried out using MicroBeta TM Trilux (PerkinElmer Wallac, Freiburg).
  • the Tubulin GTPase assay was carried out with modifications according to Roychowdhury et al. (Roychowdhury S, Panda D, Wilson L, Rasenick MM. G protein alpha subunits activate tubulin GTPase and modulate microtubule polymerization dynamics. J Biol Chem 274: 13485-13490, 1999). Highly pure, lyophilized and MAP-free bovine brain tubulin was reconstituted in PEM (100 mM PIPES, 1 mM EGTA, 1 mM MgCl 2 ) buffer pH 6.6 and aliquots were stored at -80 ° C.
  • PEM 100 mM PIPES, 1 mM EGTA, 1 mM MgCl 2
  • the Reaction mixture for the GTPase assay contains 1 mg / ml tubulin, 1 mM MgCl 2 , 100 ⁇ M ⁇ [ 32 P] GTP (specific activity 3000 Ci / mmol) and 1 M monosodium glutamate in PEM buffer. Alternatively, 4.5% (v: v) glycerol was used to induce tubulin polymerization.
  • the test compounds dissolved in 10% v: v DMSO, were added before the addition of glutamate and ⁇ [ 32 P] GTP (final 1% DMSO). The tubulin polymerization was started by incubation at 37 ° C. for 1 h and stopped by adding sodium dodecyl sulfate in a 1% final concentration.
  • the GTP hydrolysis was determined by means of thin layer chromatography of the reaction mixture on polyethyleneimine cellulose plates.
  • the chromatograms were developed with 0.35 M NH 4 CO 3 .
  • the chromatography plates were exposed on X-ray films and quantified by means of phosphor imager analysis (Fuji BAS-1800II).
  • U373 (astrocytoma / HTB-17), KB / HeLa (cytical carcinoma / CCL-17), L1210 (murine leukemia / CCL 219), Saos-2 (osteogenic sarcoma / HTB-85), RKO (colon adenocarcinoma; Schmidt et al. 2000), PC3 (prostate adenocarcinoma / CRL-1435), MDA-MB 231 (breast adenocarcinoma / HTB-26), HT29 (colon adenocarcinoma / HTB-38) and A549 (lung carcinoma / CCL 185).
  • the XTT proliferation assay was carried out according to Scudiero et al. (Scudiero, DA, Shoemaker, RH, Pauli, KD, Monks, A., Tierney, S., Nofziger, TH, Currens, MJ, Seniff, D., and Boyd, MR Evaluation of a soluble tetrazolium / formazan assay for cell growth and drug sensitivity in culture using human and other tumor cell lines. Cancer Res 48: 4827-4833, 1988). The adherent growing tumor cell lines were cultivated under standard conditions in the gassing incubator at 37 ° C, 5% C0 2 and 95% humidity.
  • test day 1 the cells are detached with trypsin / EDTA and pelleted by centrifugation. The cell pellet is then resuspended in the respective culture medium in the corresponding cell number and converted into a 96-well microtiter plate. The plates are then cultivated overnight in the fumigation incubator. The test substances are called 10mM Prepare stock solutions in DMSO and dilute on culture day 2 with the appropriate concentrations in culture medium. The substances in culture medium are then added to the cells and incubated for 45 hours in the fumigation incubator. Cells that are not treated with test substance serve as a control.
  • XTT sodium 3 '- [1- (phenylaminocarbonyl) -3,4-tetrazolium] bis (4-methoxy-6-nitro) benzenesulfonic acid
  • RPMI-1640 medium without phenol red
  • PMS N-methyl dibenzopyrazine methyl sulfate
  • PBS phosphate-buffered saline
  • the XTT solution is mixed with the PMS solution in a ratio of 50: 1 (VokVol) shortly before use.
  • the cell plates are then incubated in the fumigation incubator for a further 3 hours and the optical density (OD 4 90 nm) is determined in the photometer.
  • the percent inhibition is calculated relative to the control, and a concentration response curve plotted semi-logarithmically in shape.
  • the IC 5 0 is calculated by a regression analysis from the concentration-action curve using the program Graphpad.
  • Test 1 Cytotoxic Activity in the MDR L1210 VCR Cell Model
  • D-64131 and D-68144 are anti-proliferatively active regardless of the MDR status of the L1210 leukemia cell line. This property is surprising since the tubulin inhibitors taxol and vincristine used in tumor therapy and the cytostatic drug doxorubicin have a resistance factor of 59 to 109, ie they only very ineffectively affect the MDR overexpressing cell lines.
  • Test 2 Overcoming resistance on various tumor cell lines
  • Table 2 shows the results for D-64131.
  • Parental and resistant tumor cell lines were used in proliferation experiments.
  • the resistance phenotype is also shown (antimetabolite 5-fluorouracil / 5-FU, thymidilate synthase inhibitor raltitrexed, topoisomerase inhibitor SN-38 and adriamycin).
  • the effectiveness of D-64131 is surprisingly independent of the resistance phenotype.
  • a partial or strong resistance to vincristine and taxol can be measured.
  • FIG. 2 the results of polymerization and binding experiments on bovine tubulin are shown.
  • the polymerization of bovine tubulin is started by heating and adding GTP;
  • the 2-acylindoles according to the invention inhibit tubulin polymerization in a dose-dependent manner (FIG. 2A). This inhibition of polymerization correlates with the binding to tubulin.
  • FIG. 2B 3 H-colchicine is used in a binding assay.
  • the competition with the binding of 3 H-colchicine is measured by the respective test substance.
  • the IC 5 o are values for the 2-Acylindole D-64131, D-68143, D-68144, D 68148, D-68150, D-68172, D-70316 and D-81187.
  • the non-cytotoxic substance D-68148 was included as a negative control and, as expected, shows no binding to tubulin or inhibition of tubulin polymerization. It is surprising that individual derivatives such as D-68150 only partially inhibit the binding of 3 H-colchicine (partial antagonists). This is an indication of a different mechanism of action compared to the tubulin binders colchicine, taxol or vincristine.
  • Test 4 Influence of the ⁇ -Tubulin GTPase Activity
  • the new mechanism of action of the 2-acylindoles according to the invention is confirmed by experiments to measure the GTPase activity of ⁇ -tubulin.
  • D-64131 unlike vincristine, colchicine or taxol, does not affect the GTPase activity of MAP-free round tubulin induced by glutamate or glycerol.
  • MAP-free bovine tubulin was used in these experiments to exclude the background GTPase activity of the tubulin-associated proteins (see Figure 3A).
  • Test 5 Anti-proliferative activity on human tumor cell lines with wild type and mutant p53 status
  • Table 3 summarizes the anti-proliferative activity of D-64131, D-68144 compared to taxol on selected human tumor cells. This shows that the 2-acylindoles according to the invention have an anti-proliferative effect regardless of the p53 status. Tumor therapy with the 2-acylindoles according to the invention is therefore possible regardless of the p53 status.
  • Test 6 Anti-angiogenic activity of the 2-acylindoles according to the invention
  • the anti-angiogenic activity of the 2-acylindoles according to the invention was investigated in the chorioallantoin membrane (CAM) assay.
  • the results are summarized in FIG. 4 and show a significant anti-angiogenic activity using the example of the compounds D-81167, D-70316 and D-81754.
  • This anti-angiogenic potency the possibility of using the 2-acylindoles according to the invention for the therapy of diseases based on disturbed vascularization is proven in the CAM assay.
  • the 2-acylindoles according to the invention are particularly suitable for suppressing neovascularization in tumor diseases.
  • D-64131 was first tested in vitro on 12 permanent human tumor cell lines for its antitumor activity.
  • the cell lines included colon (2), stomach (1), lung (3), breast (2), melanoma (2), ovary (1), kidney (1) and uterus (1) tumor cell lines ,
  • the mean IC50 of D-64131 across all cell lines examined using a propidium iodide-based cytotoxicity assay was 0.34 ⁇ M.
  • the IC50 was approximately 4 ⁇ M for the examined lung and stomach tumor cell lines.
  • D-64131 acted as a cell cycle-specific agent through interaction with tubulin.
  • D-64131 inhibited the polymerization of calf brain tubulin with an IC50 of 2.2 ⁇ M.
  • the maximum tolerated dose for intraperitoneal (ip) injection in nude mice was 400 mg / kg when administered weekly.
  • For oral (po) administration 100 and 200 mg / kg D-64131 were administered with the dose "Qdx5" (once a day for 5 consecutive days) for 2 weeks. Both po doses were very well tolerated and showed no signs of toxicity or body weight loss The latter dosing schedule was used to test the efficacy of D-64131 in human melanoma xenograft model MEXF 989.
  • Preparation (1), (2) and (3) are mixed and granulated with an aqueous solution of (4). (5) is added to the dried granulate. Tablets are pressed from this mixture.
  • (1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with intensive mixing. This powder mixture is filled into size 3 hard gelatin capsules on a capsule filling machine.

Abstract

La présente invention concerne l'utilisation de dérivés d'indole et d'hétéroindole de formule générale (I), de tautomères, de stéréoisomères, de mélanges et de sels de ceux-ci dans la production d'un médicament pour traiter des tumeurs résistantes aux thérapies, des tumeurs métastatiques et/ou en tant qu'inhibiteurs de l'angiogenèse.
PCT/EP2002/011883 2001-10-26 2002-10-24 Utilisation de 2-acylindoles pour traiter des tumeurs WO2003037861A1 (fr)

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JP2003540143A JP2005516895A (ja) 2001-10-26 2002-10-24 腫瘍の治療のための２−アシルインドールの使用
EP02802302A EP1442015A1 (fr) 2001-10-26 2002-10-24 Utilisation de 2-acylindoles pour traiter des tumeurs

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DE10152306A DE10152306A1 (de) 2001-10-26 2001-10-26 2-Acylindolderivate mit neuen therapeutisch wertvollen Eigenschaften
DE10152306.8 2001-10-26

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FR2857966A1 (fr) * 2003-07-24 2005-01-28 Aventis Pharma Sa Produits aryl-heteroaromatiques, compositions les contenant et utilisation
JP2005035977A (ja) * 2003-07-16 2005-02-10 Buddhist Tzu Chi General Hospital 新規なγ−ブチロラクトン化合物及びその医薬組成物
EP1732566A2 (fr) * 2004-04-05 2006-12-20 Takeda Pharmaceutical Company Limited Compose de 6-azaindole
WO2006133835A2 (fr) * 2005-06-14 2006-12-21 Ziopharm Oncology, Inc. Formulation pharmaceutique du compose indibuline inhibiteur de la tubuline s'administrant par voie orale et possedant des proprietes pharmacocinetiques ameliorees, et procede de fabrication de cette formulation
JP2007516997A (ja) * 2003-12-24 2007-06-28 ファイザー・イタリア・エス．アール．エル． キナーゼ阻害剤として活性のあるピロロ［２，３−ｂ］ピリジン誘導体、それらの調製方法、およびそれらを含む医薬品
JP2007534653A (ja) * 2003-12-24 2007-11-29 ファイザー・イタリア・エス．アール．エル． キナーゼ阻害剤としての活性をもつピロロ［２，３−ｂ］ピリジン誘導体、それらの調製方法、およびそれらを含む医薬組成物
US7589206B2 (en) 2004-06-09 2009-09-15 Glaxo Group Limited Pyrrolopyridine derivatives
CN102712604A (zh) * 2009-10-13 2012-10-03 默克专利有限公司 用于肿瘤治疗的亚砜衍生物
WO2013112878A1 (fr) * 2012-01-26 2013-08-01 The Penn State Research Foundation Compositions de modulation de mcl-1
US8835441B2 (en) 2005-05-20 2014-09-16 Amgen Inc. Heterobicyclic metalloprotease inhibitors

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JP6320506B2 (ja) * 2013-03-12 2018-05-09 セルジーン クオンティセル リサーチ，インク． ヒストンデメチラーゼ阻害剤
EP3233797B1 (fr) * 2015-01-18 2019-05-08 SRI International Inc. Inhibiteurs de map4k4 (hgk)

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WO2001082909A2 (fr) * 2000-04-28 2001-11-08 Baxter Healthcare Sa Derives de 2-acyl-indole et leur utilisation comme agents antitumoraux

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005035977A (ja) * 2003-07-16 2005-02-10 Buddhist Tzu Chi General Hospital 新規なγ−ブチロラクトン化合物及びその医薬組成物
FR2857966A1 (fr) * 2003-07-24 2005-01-28 Aventis Pharma Sa Produits aryl-heteroaromatiques, compositions les contenant et utilisation
WO2005009947A2 (fr) * 2003-07-24 2005-02-03 Aventis Pharma S.A. Produits aryl-heteroaromatiques, compositions les contenant et utilisation
WO2005009947A3 (fr) * 2003-07-24 2005-03-31 Aventis Pharma Sa Produits aryl-heteroaromatiques, compositions les contenant et utilisation
JP2012121891A (ja) * 2003-12-24 2012-06-28 Pfizer Italia Srl キナーゼ阻害剤としての活性をもつピロロ［２，３−ｂ］ピリジン誘導体、それらの調製方法、およびそれらを含む医薬組成物
JP2007516997A (ja) * 2003-12-24 2007-06-28 ファイザー・イタリア・エス．アール．エル． キナーゼ阻害剤として活性のあるピロロ［２，３−ｂ］ピリジン誘導体、それらの調製方法、およびそれらを含む医薬品
JP2007534653A (ja) * 2003-12-24 2007-11-29 ファイザー・イタリア・エス．アール．エル． キナーゼ阻害剤としての活性をもつピロロ［２，３−ｂ］ピリジン誘導体、それらの調製方法、およびそれらを含む医薬組成物
JP2012121892A (ja) * 2003-12-24 2012-06-28 Pfizer Italia Srl キナーゼ阻害剤として活性のあるピロロ［２，３−ｂ］ピリジン誘導体、それらの調製方法、およびそれらを含む医薬品
EP1732566A2 (fr) * 2004-04-05 2006-12-20 Takeda Pharmaceutical Company Limited Compose de 6-azaindole
EP1732566A4 (fr) * 2004-04-05 2010-01-13 Takeda Pharmaceutical Compose de 6-azaindole
US7589206B2 (en) 2004-06-09 2009-09-15 Glaxo Group Limited Pyrrolopyridine derivatives
US8835441B2 (en) 2005-05-20 2014-09-16 Amgen Inc. Heterobicyclic metalloprotease inhibitors
AU2006257428B2 (en) * 2005-06-14 2012-03-22 Ziopharm Oncology, Inc. Oral solid pharmaceutical formulation of the tubulin inhibitor indibulin
WO2006133835A2 (fr) * 2005-06-14 2006-12-21 Ziopharm Oncology, Inc. Formulation pharmaceutique du compose indibuline inhibiteur de la tubuline s'administrant par voie orale et possedant des proprietes pharmacocinetiques ameliorees, et procede de fabrication de cette formulation
WO2006133835A3 (fr) * 2005-06-14 2007-07-19 Baxter Int Formulation pharmaceutique du compose indibuline inhibiteur de la tubuline s'administrant par voie orale et possedant des proprietes pharmacocinetiques ameliorees, et procede de fabrication de cette formulation
CN102712604A (zh) * 2009-10-13 2012-10-03 默克专利有限公司 用于肿瘤治疗的亚砜衍生物
CN102712604B (zh) * 2009-10-13 2015-04-08 默克专利有限公司 用于肿瘤治疗的亚砜衍生物
WO2013112878A1 (fr) * 2012-01-26 2013-08-01 The Penn State Research Foundation Compositions de modulation de mcl-1

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DE10152306A8 (de) 2004-07-08
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DE10152306A1 (de) 2003-07-24

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