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WO2017153789A1 - Dérivés de benzo[b]thiophène et leur utilisation pour l'inhibition des kinases du récepteur du facteur de croissance des fibroblastes (fgfr) destinés aux thérapies de néo- et d'hyperplasie - Google Patents

Dérivés de benzo[b]thiophène et leur utilisation pour l'inhibition des kinases du récepteur du facteur de croissance des fibroblastes (fgfr) destinés aux thérapies de néo- et d'hyperplasie Download PDF

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WO2017153789A1
WO2017153789A1 PCT/HU2016/050059 HU2016050059W WO2017153789A1 WO 2017153789 A1 WO2017153789 A1 WO 2017153789A1 HU 2016050059 W HU2016050059 W HU 2016050059W WO 2017153789 A1 WO2017153789 A1 WO 2017153789A1
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amino
acetamido
pyrrolidin
alkyl
piperidin
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Inventor
László ÖRFI
István Tibor Vályi-Nagy
Péter BÁNHEGYI
Péter Markó
Lilian ZSÁKAI
Bálint SZOKOL
Csaba SZÁNTAI-KIS
Zoltán Greff
György Kéri
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Vichem Chemie Kutato Kft
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Vichem Chemie Kutato Kft
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • Benzo[b]thiophene derivatives and their use for the inhibition of Fibroblast Growth Factor Receptor kinases (FGFRs) for the use of neo- and hyperplasia therapies
  • the present invention relates to benzo[b]thiophene derivatives of general formula (I) and pharmaceutically acceptable salts, solvates, hydrates, stereoisomeric and polymorphic forms thereof, procedures for manufacturing them, the use of them as of medication, as well as pharmaceutical compositions containing at least one of them as pharmaceutically active agent(s) together with pharmaceutically acceptable carrier, excipient and/or diluent, especially for the inhibition Fibroblast Growth Factor Receptor kinases (FGFR's), e.g. for the treatment of cancer.
  • FGFR's Fibroblast Growth Factor Receptor kinases
  • FGFRs regulate numerous principal cellular processes, such as proliferation, cell growth, differentiation, migration and survival; therefore they are fundamental to embryonic and after birth development, regulation of angiogenesis and wound healing in adults.
  • FGFRs are trans-membrane proteins and receptor tyrosine kinases (RTKs).
  • RTKs receptor tyrosine kinases
  • FGFR1 , FGFR2, FGFR3 and FGFR4 Four members of the family (FGFR1 , FGFR2, FGFR3 and FGFR4) are enzymatically active tyrosine kinases of great interest in drug discovery namely, whereas the gene for FGFR5 lacks a kinase domain.
  • FGFRL1 Fibroblast growth factor receptorlike 1
  • FGFRs are receptors of Fibroblast Growth Factors (FGFs).
  • FGF family consists of 18 secreted protein ligands, which can be separated into 2 subfamilies: the hormone-like FGFs (FGF19, 21 and 23) and the canonical FGFs (FGF1-10, 16-18 and 20).
  • FGF family members differ from one another in their ligand affinities and tissue distribution. The combination and concentration and receptor affinity of those present at a given tissue and the pattern of FGFR expression determines the cellular behavior of the given tissue.
  • FGFR signaling is strictly regulated by several feedback mechanisms in distinct points in the signaling network.
  • FGFR signaling pathway is multifactorial and complex. It has evolved in a way that regulates numerous different biological functions in a well-controlled temporal and spatial manner throughout human development and adult life. This implicates that dysregulation of this fine-tuned system will lead to developmental dysfunctions and via regulation of cell proliferation it will lead to cancer formation.
  • FGFR mutations FGFR overexpression via gene amplifications and chromosomal translocations, constitutively active fusion proteins via other types of chromosomal translocations, altered FGFR splicing or the absence of signal transductional negative feedback.
  • Gastrointestinal cancer has especially high prevalence in Asia which represents an important proportion of patients and in many cases the wild type FGFR2 protein expressed in exceptionally high levels.
  • MM multiple myeloma
  • MM is a cancer of white blood cells that is characterized by multiple genetic abnormalities.
  • the t(4; 14) translocation is associated with poor prognosis, and FGFR3 has been recognized as a potent oncogene in MM and an attractive target for novel drug development.
  • t(4; 14) translocation is associated with poor prognosis, and FGFR3 has been recognized as a potent oncogene in MM and an attractive target for novel drug development.
  • FGFRs are commonly accepted, validated targets in terms of cancer therapy development.
  • Several families of compounds have been investigated in preclinical and clinical studies or currently are in clinical trials.
  • 3 FDA approved kinase inhibitor drugs which amongst many other targets also affect FGFRs. These are Ponatinib, Lenvatinib and Nintedanib and there is no evidence for a strictly FGFR-based mechanism of action for anyone of these 3 drugs.
  • Another compound, ENMD-2076 received orphan drug certification for the treatment of hepatocellular carcinoma, but the FGFR family is not the main target group of the compound.
  • 3 compounds reached Phase III in clinical trials, one of them are already suspended. 6 compounds are examined in Phase II clinical trials.
  • Fibroblast Growth Factor Receptor kinase family has a special place in cancer treatment as a target, since non-selective inhibition of the whole family would produce adverse effects - despite fighting cancer successfully - because FGFR1 in most cancer cases shouldn't be targeted, since inhibition of FGF23/FGFR1 signaling leads to hyperphosphataemia (bone mineralization defects) in clinical settings, which has been observed in lung cancer trials using a non-selective FGFR inhibitor.
  • Pyrido[2,3-d]pyrimidines are FGFR inhibitors of great interest because of their selectivity. Development started to focus on FGFRs as targets when a lead compound PD089828, a multitarget RTK inhibitor which showed inhibition of tumor growth was found to be also an FGFR inhibitor.
  • PD173074 is the most active derivative of this compound family. We utilized this compound as a reference in our in vitro studies because of the well defined IC 50 proportion within the FGFR family. As another reference we used LY-2874455 which is under investigation in clinical trials and is a very potent novel agent against the FGFR family.
  • COSMIC database Catalogue Of Somatic Mutations In Cancer v75
  • COSMIC database Catalogue Of Somatic Mutations In Cancer v75
  • Table 1 contains the two gene's mutation frequency broken down in the most potent target cancer types. The therapeutical importance of a potent FGFR2/3 inhibitor are the highest in these cancer types.
  • the present invention relates to compounds of the general formula (I) and pharmaceutically acceptable salts, solvates, hydrates, and polymorphic forms thereof:
  • R1 is selected from the group of hydrogen; hydroxyl; substituted or unsubstituted heterocyclyl; amino, optionally substituted with 1 or 2 group(s) selected independently from the following group: C1-8 alkyi, C1-8 alkyi substituted with heterocycloalkyi, C1-8 hydroxyalkyi, C1- 8 hydroxyalkyi esterified with carboxylic acid, C3-8 cycloalkyl, C3-8 hydroxycycloalkyl, alkylcarbonyl, and alkoxyalkyl;
  • X, Y and Z are selected independently from the followings: CH (methine), nitrogen;
  • R2, R3, R4 and R5 are independently selected from the group of:
  • a compound according to above point 1 or 2, wherein the optionally substituted amine of R1 is selected from the following group:
  • R1 is selected from the following group:
  • R2 is H
  • R3 is H, amino optionally substituted with an alkoxycarbonyl group; alkoxy, halogen; R4 is H, OH, halogen or hydroxyl, optionally esterified with alkylcarboxylic acid; and R5 is H, alkyl or halogen.
  • R2 is H
  • R3 is H, -NH-CO-OMe, OMe, CI or Br;
  • R4 is H, OH, Br, F -OAc; and R5 is H, alkyl or CI.
  • R2 is H
  • R3 is CI or Br
  • R4 is OH
  • R5 is H or CI.
  • the invention also relates to procedures for manufacturing of the above compounds, the use of them as of medication, as well as pharmaceutical compositions containing at least one of them as pharmaceutically active agent(s) together with pharmaceutically acceptable carrier, excipient and/or diluent, especially for the inhibition Fibroblast Growth Factor Receptor kinases (FGFR's), e.g. for the treatment of cancer, especially in the case of cancer of gastrointestinal, skin, brain, head and neck, lung, breast, stomach, bladder, kidney, endometrial and prostate cancer and in sarcomas and multiple myeloma.
  • FGFR's Fibroblast Growth Factor Receptor kinases
  • heterocyclyl alone or in combination, means a group derived from a saturated, partially unsaturated or aromatic ring system with 4 to 9 carbon atoms and 1 to 4 heteroatom(s) selected from the group of N, O and S [i.e. group of N (nitrogen), O (oxygen) or S (sulfur) atoms].
  • the "heterocyclyl” preferably means a group derived from a saturated or partially unsaturated group, even more preferably a saturated group.
  • heterocyclyl examples are piperidinyl, piperazinyl, morpholinyl, azetidinyl, pyrrolidinyl, thiazolidinyl, indolyl, indazolyl, 1 ,3-benzodioxolyl, dihydro-1 ,4-benzodioxinyl, furanyl, pyrrolyl, pyridinyl, quinolinyl, isoquinolinyl, pyranyl, oxazinyl, imidazolyl, benzoimidazolyl, pyrazolyl, purinyl, phthalimidyl where piperidinyl, piperazinyl, morpholinyl, azetidinyl, pyrrolidinyl, thiazolidinyl and phthalimidyl are preferred.
  • substituted heterocyclyl groups are also within the scope which contain one or more substituent(s) usually applied in the organic chemistry for substitution of heterocyclyl groups. So, the substituted heterocyclyl groups carry one or more, preferably 1 to 4 substituent(s), e.g.
  • substituent(s) independently selected from the group of alkyl, hydroxyl, halogen, hydroxyalkyl, cyanoalkyl, carboxyl, alkoxy, alkoxyalkyl, haloalkyl, nitro, sulphate, amino, aminoalkylcarbonyl, acylamino, carboxylate, carbamoyl, optionally substituted amide, monoalkylamino, dialkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl and cyano, where hydroxyl, carboxyl, optionally esterified with hidroxyalkyl; alkyl, optionally substituted with hydroxyl, cyano, amino or acetylamino; alkoxycarbonyl, alkoxyalkyl, carbamoyl, alkylsulfonyl and amino, optionally substituted with 1 or 2 alkyl or alkylcarbonyl are preferred groups.
  • substituent(s) independently selected
  • alkyl alone or in combinations means, if it is not signed otherwise, a straight or branched-chain alkyl group containing from 1 to 6, preferably 1 to 5 carbon atom(s) (i.e. "CW or "Ci_ 5 " alkyl groups), such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, f-butyl and pentyl.
  • this phrase can relate to alkyl groups containing from 1 to 4, or 1 to 3 or 1 to 2 carbon atom(s) (i.e. "CW or "Ci. 3 " or "Ci_ 2 " alkyl groups).
  • substituted alkyl groups are also within the scope which contain one or more substituent(s) usually applied in the organic chemistry for substitution of alkyl groups. So, the substituted alkyl groups carry one or more, preferably one or two substituent(s), independently selected from the group of halogen, aryl, hydroxyl, carboxyl, benzyloxy, alkoxy, nitro, sulphate, amino, acylamino, monoalkylamino, dialkylamino, alkylthio, alkylsulfinyl, alkylsulfonyl and cyano.
  • alkoxy means an alkyl-O- group in which the alkyl group is as previously described.
  • suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.
  • the bond to the parent moiety is through the ether oxygen. If the alkoxy group is substituted with halogen then it is named as haloalkoxy group. If an alkyl group is substituted with an alkoxy then it is named as alkoxyalkyl group.
  • alkylcarbonyl means an alkyl-CO- group in which the alkyl group is as previously described.
  • alkenyl means a linear or branched aliphatic hydrocarbon group containing a carbon-carbon double bond having a single radical and 2 to 6 carbon atoms.
  • alkynyl means a linear or branched aliphatic hydrocarbon group containing a carbon-carbon triple bond having a single radical and 2 to 6 carbon atoms.
  • salt means any ionic compound formed between one of the embodiments of the present invention and an acidic or basic molecule that can donate or accept ionic particle to/from its partner.
  • the quaternary amine salts are also included.
  • cycloalkyl means a cyclised alkyl group, in line with the general meaning of cycloalkyl applied in organic chemistry.
  • Salts of the compounds of the formula (I) may be formed, for example, by reacting a compound of formula (I) with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
  • Exemplary acid addition salts include acetates, adipates, alginates, ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides, hydroiodides, 2- hydroxyethanesulfonates, lactates, maleates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates
  • solvate means a compound formed by the combination of solvent molecules with molecules or ions of the solute (solvation).
  • Solute can be any of the embodiments of the present invention and the solvent can be water (forming hydrates) or any organic solvent.
  • the invention also relates to all polymorphic forms of compounds of general formula (I).
  • general formula (I) includes all stereoisomeric forms of the compounds of the present invention.
  • stereoisomer as used herein includes all possible stereoisomeric forms, including all chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure, unless the specific stereochemistry or isomer form is specifically indicated.
  • the compounds of the present invention contain one or more chiral centers, all possible enantiomeric and diastereomeric forms, as well as the racemate, are included.
  • optically active forms such as by resolution of racemic forms or by synthesis from optically active starting materials. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention.
  • Another subject of the invention is providing pharmaceutical composition containing as active ingredient one or more compound(s) of general formula (I) together with one or more usual pharmaceutical auxiliary material(s).
  • auxiliary material is those which are generally applied in the preparation of pharmaceutical compositions, e.g. carriers, diluents, vehicles, coloring agents, flavoring agents, stabilizers, surfactants, carriers for the preparation of sustained release compositions etc. Further details can be found in the following book: Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990, Volume 5., Chapter 25.2).
  • the specific embodiments of the present invention can be used for the preparation of a pharmaceutical composition for prophylaxis and/or treatment of a disease where the inhibition Fibroblast Growth Factor Receptor kinases (FGFR's) affects the patient's condition positively, e.g. in the treatment of cancer, for example cancer of gastrointestinal, skin, brain, head and neck, lung, breast, stomach, bladder, kidney, endometrial and prostate cancer and in sarcomas and multiple myeloma, especially cancer of gastrointestinal, skin, endometrial and prostate cancer and multiple myeloma.
  • FGFR's Fibroblast Growth Factor Receptor kinases
  • the invention also relates to procedures for manufacturing of compounds of general formula (I), in line with the following methods.
  • Step A Preparation of 2-Amino-6,6-ethylenedioxy-4,5,6,7-tetrahydro- benzo[b]thiophene-3-carboxylic acid amide:
  • Step B Preparation of (3-Carbamoyl-6,6-ethylenedioxy-4,5,6,7-tetrahydro- benzo[b]thiophen-2-yl)-carbamic acid 2,2,2-trichloro-ethyl ester:
  • Step C Preparation of (3-Carbamoyl-6,6-ethylenedioxy-benzo[b]thiophen-2- carbamic aci -trichloro-ethyl ester
  • Step D (3-Carbamoyl-5,7-dichloro-6-hydroxy-benzo[b]thiophen-2-yl)-carbamic acid 2,2,2-trichlo
  • Step E Acetic acid 3-carbamoyl-5,7-dichloro-2-(2,2,2-trichloro-ethoxycarbonylamino)- benzo[b]thiophen-6-yl ester
  • Step G Acetic acid 3-carbamoyl-5,7-dichloro-2-(4-chloromethyl-benzoylamino)- benzo[b]thiophen-6-yl ester
  • Step H Reaction of acetic acid 3-carbamoyl-5,7-dichloro-2-(4-chloromethyl- benz
  • Step K 5,7-Dichloro-6-hydroxy-2-(4-hydroxymethyl-benzoylamino)-benzo[b]thiophene- 3-carboxylic acid amide
  • Step A Acetic acid 3-carbamoyl-5,7-dichloro-2-(4-chloromethyl-benzoylamino)- benzo[b]thi
  • Step B Acetic acid 5,7-dibromo-3-carbamoyl-2-(2,2,2-trichloro-ethoxycarbonylamino)- benzo[b]t
  • Step C Acetic acid 2-amino-5-bromo-3-carbamoyl-benzo[b]thiophen-6-yl ester
  • Step D Acetic acid 5-bromo-3-carbamoyl-2-(4-chloromethyl-benzoyl benzo[b
  • Step E Reaction of Acetic acid 5-bromo-3-carbamoyl-2-(4-chloromethyl- benzoylamino)-benzo[b]thiophen-6-yl ester with amines
  • Step F Acetylating of 6-hydroxyl products
  • Step G 6-Hydroxy-2-(4-piperidin-1-ylmethyl-benzoylamino)-5-vinyl-benzo[b]thiophene- -carboxylic acid amide
  • Ste B (5-Methyl-3-oxo-cyclohex-1-enyl)-carbamic acid tert-butyl ester
  • the solution was diluted with 200 mL water and 400 mL ethyl acetate, the solid was filtered off.
  • the organic phase was washed with saturated NH 4 CI solution, saturated NaHC0 3 solution, water and brine, dried over MgS04, and evaporated.
  • Step C [3-(Carbamoyl-cyano-methylene)-5-methyl-cyclohex-1-enyl]-carbamic acid tert- butyl ester
  • reaction mixture was allowed to warm up to room temperature, and was stirred overnight. 200 mL water and 200 mL ethyl acetate were added to the mixture; the organic phase was separated, washed three times with saturated NaHC0 3 solution, dried over MgS0 4 and evaporated under vacuum. The oily residue was crystallized from diisopropyl ether.
  • Step D (2-Amino-3-carbamoyl-7-methyl-benzo[b]thiophen-5-yl)-carbamic acid tert-butyl este
  • Step E [3-Carbamoyl-2-(4-chloromethyl-benzoylamino)-7-methyl-benzo[b]thiophen-5- yl]
  • Step F [3-Carbamoyl-7-methyl-2-(4-pyrrolidin-1-ylmethyl-benzoylamino)- benzo[b]thiophen-5-yl]-carbamic acid tert-butyl ester
  • Step G 5-Amino-7-methyl-2-(4-pyrrolidin-1-ylmethyl-benzoylamino)-benzo[b]thiophene- 3-carboxylic acid amide
  • Step C 6-Fluoro-5-methoxy-2-(4-piperidin-1-ylmethyl-benzoylamino)- benzo[b]thiophene-3-carboxylic acid amide (Example 104)
  • Step A 2-Amino- -hydroxy-benzo[b]thiophene-3-carboxylic acid amide
  • UV detector Waters 996 DAD
  • Solvent I Water/ 0.1 % HCOOH
  • Source block temperature 1 10 °C
  • FGFR1 , FGFR2, FGFR3 and FGFR4 kinase assays were performed in low protein binding, black, round bottom 384-well plates (Corning Inc., Corning, NY). Potent kinase inhibitor compounds were dissolved in 100 % DMSO to 5 mM and then we prepared a serial dilution in H 2 0 from 30 ⁇ to 0.014 ⁇ concentrations with the divisor of three. In all cases we used Transcreener® ADP Assay FP method (BellBrook Labs LLC, Fitchburg, Wl). The reaction conditions were different in each enzyme's case.
  • FGFR1 assays we used the following materials in the following final concentrations for the reaction: 15 nM FGFR1 (ProQinase GmbH, Freiburg, Germany), 0.01 mg/mL Poly Glu-Tyr (Sigma-Aldrich) as a substrate, 20 mM HEPES pH 7.5 (Sigma-Aldrich), 1 mM DTT (Sigma-Aldrich, St. Louis, MO), 10 mM MgCI 2 (Sigma-Aldrich), 0.4 mM MnCI 2 (Sigma-Aldrich), and 0.01 V/V% NP40 (Sigma-Aldrich) detergent. In each assay the identical materials used were the same stocks from the vendors described above.
  • reaction conditions were the following: 1.5 nM FGFR2
  • FGFR3 assays we used the following materials and concentrations for the reaction: 15 nM FGFR3 (ProQuinase), 0.01 mg/mL Poly Glu-Tyr, 20 mM HEPES pH 7.5, 1 mM DTT, 10 mM MgCI 2 , 0.4 mM MnCI 2 , and 0.01 V%V Brij35 detergent (Sigma-Aldrich).
  • the reaction conditions were the following: 5 nM FGFR4 (ProQuinase), 0.01 mg/mL Poly Glu-Tyr, 20 mM HEPES pH 8, 1 mM DTT, 10 mM MgCI 2 , 10 mM MnCI 2 , and 0.01 V%V Brij35 detergent (Sigma-Aldrich).
  • the ADP antibody concentration was 10.61 ⁇ g/mL for the FGFR1 assay, 2.29 ⁇ g/mL for the FGFR2 assay, 5.24 ⁇ g/mL for the FGFR3 assay and 4.78 ⁇ g/mL for the FGFR4 assay.
  • the fluorescence polarization and fluorescence intensity was measured was using Analyst GT (Molecular devices) and by Infinite M1000 Pro Multimode Reader (Tecan Group Ltd., Mannedorf, Switzerland).
  • IC 50 curves were fitted with XLfit curve fitting add-in software (IDBS) for Microsoft Office Excel.
  • H716 and HCT-1 16 cell lines were purchased from ATCC (via LGC Standards,
  • RKO cell line was obtained from Semmelweis Unversity
  • U266 and LP1 cell lines were obtained from Max Planck Institute. All cells were cultured in RPMI-1640 medium (Sigma-Aldrich); supplemented with 10 % heat inactivated fetal bovine serum (Sigma-Aldrich, St. Louis, MO) and 1 % Ab/Am (Sigma-Aldrich, St. Louis, MO), except LP1 which line was cultured in IMDM, supplemented with 10% heat-inactivated fetal bovine serum (Sigma-Aldrich, St. Louis, MO) and 1 % Ab/Am (Sigma-Aldrich, St. Louis, MO) at 37 °C in a 5 % C02 containing, humidified incubator.
  • Cell viability was determined with CellTiter-Glo® Luminescent Cell Viability Assay Kit (Promega Co., Madison, Wl). The luminescence signal was detected by Infinite M1000 Pro Multimode Reader (Tecan). All compounds were dissolved in DMSO. 1000 cells per well were plated in 384-well flat-bottom plates (PerkinElmer Inc., Waltham, MA) in 30 ⁇ . One day after seeding, compounds were added to each cell line. Experimental data were gained from the 10 point serial dilution of the compounds (dilution range varied between 30-0.00152 ⁇ ). Cell viability was measured after 72 hours. The ratio of the number of survived cells and the number of cells in the untreated samples (positive control) was determined. The negative control was medium without cells containing 10 ⁇ DMSO.
  • FGFR mutated cell lines in order to investigate efficacy in tumor cells where the FGFRs may be particularly important.
  • COSMIC database searches to identify cell lines which harboured FGFR mutations and thus may help to demonstrate efficacy.
  • HCT-1 16 is a KRAS mutation driven colon tumor, but the searches also revealed several FGFR2 mutations in addition to the mutations in FGFR1 .
  • the FGFR mutational status of RKO colon cell line includes several non-silent FGFR1 mutations.
  • the U266 and the LP1 multiple myeloma cell lines have mutations in FGFR3 which may fairly contribute to their malignancy. Based on these data, we tested commercially available FGFR inhibitors on HCT-1 16, RKO, U266 and LP1 cell lines and found that these compounds inhibited the growth of these cell lines, therefore FGFRs are potent targets in these systems. In a subsequent step, we tested our own compounds on HCT-1 16, RKO, U266 and LP1 cell lines and several of these compounds proved to be effective. Results from these experiments are shown in Table 5.

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Abstract

La présente invention concerne des dérivés de benzo[b]thiophène de formule générale (I) et ses sels, solvates, hydrates, formes stéréo-isomères et polymorphes pharmaceutiquement acceptables, R1 étant choisi parmi le groupe constitué de l'hydrogène, d'un hydroxyle, d'un hétérocyclyle substitué ou non substitué, d'un amino éventuellement substitué ; X, Y et Z étant choisis indépendamment parmi les éléments suivants : CH (méthine), azote ; R2, R3, R4 et R5 peuvent être, par exemple, hydrogène, halogène, hydroxyle, alkyle, alcényle, alcynyle, alcoxy et amino. L'invention concerne également leur utilisation en tant que médicament, ainsi que des compositions pharmaceutiques contenant au moins l'un desdits dérivés en tant qu'un ou plusieurs agents pharmaceutiquement actifs conjointement avec un support, un excipient et/ou un diluant pharmaceutiquement acceptables, en particulier pour l'inhibition des kinases du récepteur du facteur de croissance des fibroblastes (FGFR), par exemple pour le traitement du cancer.
PCT/HU2016/050059 2016-03-11 2016-11-28 Dérivés de benzo[b]thiophène et leur utilisation pour l'inhibition des kinases du récepteur du facteur de croissance des fibroblastes (fgfr) destinés aux thérapies de néo- et d'hyperplasie Ceased WO2017153789A1 (fr)

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Publication number Priority date Publication date Assignee Title
CN111285844A (zh) * 2020-02-24 2020-06-16 河南师范大学 具有生物活性的新型苯并噻唑取代酰胺类化合物及其合成方法和应用
CN111285844B (zh) * 2020-02-24 2022-08-12 河南师范大学 具有生物活性的苯并噻吩取代酰胺类化合物及其合成方法和应用
RU2756587C1 (ru) * 2021-02-12 2021-10-01 Акционерное общество "Отисифарм" Производные 2-ацетамидо-6-гидрокси-бензотиофена и их фармацевтически приемлемые соли, обладающие противовирусной активностью
RU2756587C9 (ru) * 2021-02-12 2021-10-12 Акционерное общество "Отисифарм" Производные 2-ацетамидо-6-гидрокси-бензотиофена и их фармацевтически приемлемые соли, обладающие противовирусной активностью
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