WO2011073929A1 - 6-(2-furyl)-3-methyl-4-oxo-1,5,6,7-tetrahydroindole-2-carboxylate derivatives and uses thereof - Google Patents

6-(2-furyl)-3-methyl-4-oxo-1,5,6,7-tetrahydroindole-2-carboxylate derivatives and uses thereof Download PDF

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WO2011073929A1
WO2011073929A1 PCT/IB2010/055845 IB2010055845W WO2011073929A1 WO 2011073929 A1 WO2011073929 A1 WO 2011073929A1 IB 2010055845 W IB2010055845 W IB 2010055845W WO 2011073929 A1 WO2011073929 A1 WO 2011073929A1
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methyl
oxo
carboxylate
furyl
tetrahydroindole
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PCT/IB2010/055845
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French (fr)
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Raffaella Amici
Giovanni Faga'
Maria Rosaria Cera
Peter Arthur De Wulf
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Istituto Europeo Di Oncologia S.R.L.
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Publication of WO2011073929A1 publication Critical patent/WO2011073929A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • 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

Definitions

  • the present invention relates to 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2- carboxylate derivatives, to a process for their preparation, to pharmaceutical compositions containing them, and to their use in the treatment of cell proliferative disorders such as cancer and multidrug resistant cancer.
  • Background of the invention 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2- carboxylate derivatives, to a process for their preparation, to pharmaceutical compositions containing them, and to their use in the treatment of cell proliferative disorders such as cancer and multidrug resistant cancer.
  • MTs microtubules
  • mitotic spindle an array-like structure
  • MT-organizing centers also known as centrosomes or spindle poles
  • Kinetochores serve to bind the sister chromatids to the tips (plus-ends) of a MT- bundle comprising 20-30 MTs and, next, to orchestrate chromatid segregation between the mother and daughter cells. For this to occur correctly, each sister chromatid must bind in a bipolar fashion to the mitotic spindle, meaning that within a sister chromatid pair one chromatid must bind to a MT bundle extending from one centrosome while the second chromatid must bind to a MT bundle extending from the opposite centrosome. Bipolar attachment allows the sister chromatids to move to middle (metaphase plate) of a metaphase cell.
  • the spindle assembly checkpoint (also known as the SAC, spindle checkpoint or mitotic checkpoint) monitors the presence of this tension as it suggests correct bipolar binding of the sister chromatids to the spindle structure. Absence of tension, even at a single kinetochore, will signal the SAC as it reflects an incorrect (non bi-polar) or absent binding of a chromatid to the spindle array.
  • the SAC will then halt cell division in metaphase, allowing the unbound/incorrectly bound chromatid(s) to establish correct contact with the MTs (Musacchio A, Salmon ED, Nature Rev Mol Cell Biol, 2007,8: 379-393). If this correction cannot be made, then the arrested cells will undergo cell death (apoptosis) with high frequency (Gascoigne KE, Taylor SS. Cancer Cell, 2008, 14: 1 1 1-122).
  • tubulin-targeting agents that prevent the generation of intrakinetochore tension by preventing spindle formation (e.g. vinblastine family of drugs) or by stabilizing the spindle structure (e.g. the taxanoids) efficiently trigger cancer cell death (Carlson RO, Expert Opin Invest Drugs, 2008, 17: 707-722; Dumontet C, Jordan MA, Nature Rev Drug Disc, 2010, 9: 790-803).
  • MDR multidrug resistance
  • MDR1 gene which encodes the P-glycoprotein drug-efflux pump (Pgp) that belongs to the ATP-binding cassette transporter superfamily of membrane proteins (Goda K, Bacso Z, Szabo G, Curr Cancer Drug Targets, 2009, 9: 281- 297).
  • Pgp P-glycoprotein drug-efflux pump
  • the present invention relates to 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2- carboxylate derivatives as antitubulin agents.
  • compounds of the invention unlike existing drugs targeting tubulin such as paclitaxel and vinblastine, are equally effective against both non-resistant and multidrug-resistant cancer cells.
  • 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate derivatives are known in the art, and some of them are commercially available.
  • EP 0754681 describes 4-oxo-1 ,5,6,7- tetrahydroindole derivatives as intermediates in the synthesis of N-hydroxyalkyl-4-hydroxyindoles as oxidative hair dye components.
  • the following compounds ethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2- carboxylate, isobutyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate, penthyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate, allyl 6-(2-furyl)-3- methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate, [(E)-but-2-enyl] 6-(2-furyl)-3-methyl
  • the present invention relates to 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2- carboxylate derivatives and their use in the treatment of cell proliferative disorders such as cancer.
  • Compounds of the invention are particularly effective against multidrug-resistant cancer cells.
  • R1 is selected from hydrogen, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, C 5 -C 7 cycloalkenyl, aryl, heteroaryl, or C 3 -C 7 heterocyclyl, any of which may optionally be substituted;
  • R2 is hydrogen, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, C 5 -C cycloalkenyl, aryl, heteroaryl, C 3 -C heterocyclyl, C(0)R3 or S0 2 R3 any of which may optionally be substituted, where:
  • R3 is independently hydrogen, C C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, C 5 -C cycloalkenyl, aryl, heteroaryl, C 3 -C heterocyclyl or 0(Ci-C 6 alkyl), any of which may optionally be substituted;
  • R4 and R4' are each independently hydrogen, Ci-C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl; or
  • R5 and R5' are each independently hydrogen, C C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, C 5 -C cycloalkenyl, aryl, heteroaryl, or C 3 -C heterocyclyl;
  • Ci-C 6 alkyl C 2 -C 6 alkenyl or C 2 -C 6 alkynyl, any of which may be substituted as defined above; or
  • R1 is selected from methyl, isopropyl or substituted ethyl wherein the substituent is selected from:
  • R5 and R5' are each independently hydrogen, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyi, C 5 -C 7 cycloalkenyl, aryl, heteroaryl, or C 3 -C 7 heterocyclyl.
  • R2 is selected from hydrogen, methyl, ethyl, benzyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyi, C 5 -C 7 cycloalkenyl, aryl, heteroaryl, C 3 -C 7 heterocyclyl, C(0)R3 or S0 2 R3 where:
  • R3 is independently hydrogen, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyi, C 5 -C 7 cycloalkenyl, aryl, heteroaryl, C 3 -C 7 heterocyclyl or 0(Ci-C 6 alkyl), any of which may optionally be substituted.
  • C C 6 alkyl refers to a fully saturated straight or branched saturated hydrocarbon chain having one to six carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, t-butyl and n-hexyl.
  • C 2 -C 6 alkenyl refers to a straight or branched hydrocarbon chain having from two to six carbon atoms and at least one carbon-carbon double bond. Examples include ethenyl, 2- propenyl and isobutenyl.
  • C 2 -C 6 alkynyl refers to a straight or branched hydrocarbon chain having from two to six carbon atoms and at least one carbon-carbon triple bond. Examples include ethynyl, 2- propynyl and isobutynyl.
  • C 3 -C 7 cycloalkyi refers to a saturated 3 to 7 membered carbocyclic ring. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • C5-C7 cycloalkenyl refers to a 5 to 7 membered carbocyclic ring having at least one ring carbon-carbon double bond.
  • C 3 -C 7 heterocyclyl refers to a 3 to 7 membered ring system having at least one heteroatom chosen from N, O or S and optionally being partially unsaturated. Examples of such groups include morpholino, pyrrolidino, piperidinyl, piperazinyl, tetrahydrofuranyl. "Halo” or “halogen” refers to fluoro, chloro, bromo or iodo.
  • Aryl refers to a ring system having from 6 to 14 ring carbon atoms and containing up to three rings, at least one of which has aromatic character. Examples of aryl groups are benzene, biphenyl and naphthalene.
  • Heteroaryl refers to a ring system having from 5 to 14 ring atoms, one or more of which is a heteroatom selected from N, O and S and containing up to three rings, at least one of which has aromatic character.
  • heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, oxazolyl, furanyl, thienyl, quinolinyl, isoquinolyl, quinazolyl, thiazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, indolyl, indazolyl, imidazolyl, benzimidazolinyl and benzodioxolyl ring systems.
  • Ci-C 6 alkoxy refers to the group Ci-C 6 alkyl-O-.
  • C C 4 alkoxy refers to the group C C 4 alkyl-O-.
  • Ci-C e alkylthiol refers to the group C C 6 alkyl-S-.
  • Ci-C e alkylamino refers to the group CrC 6 alkyl attached to an amino moiety.
  • Ci-C 6 dialkylamino refers to two group d-C 6 alkyl attached to an amino moiety.
  • Appropriate pharmaceutically and veterinarily acceptable salts of the compounds of general formula (I) include salts of organic acids, especially carboxylic acids, including but not limited to acetate, trifluoroacetate, lactate, gluconate, citrate, tartrate, maleate, malate, pantothenate, adipate, alginate, aspartate, benzoate, butyrate, digluconate, cyclopentanate, glucoheptanate, glycerophosphate, oxalate, heptanoate, hexanoate, fumarate, nicotinate, pamoate, pectinate, 3-phenylpropionate, picrate, pivalate, proprionate, tartrate, lactobionate, pivolate, camphorate, undecanoate and succinate; organic sulfonic acids such as methanesulfonate, ethanesulfonate, 2-hydroxyethane sulfonate, camphors
  • Salts which are not pharmaceutically or veterinarily acceptable may still be valuable as intermediates.
  • the compounds of the present invention can exist in unsolvated as well in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like.
  • R1 is selected from methyl, 2- hydroxyethyl, 2-methylaminoethyl, 2-dimethylaminoethyl, isopropyl group.
  • R2 is selected from hydrogen, methyl, ethyl, benzyl, acetyl, 4-nitrophenylsulfonyl, benzenesulfonyl group.
  • R1 is selected from hydrogen, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, C 5 -C 7 cycloalkenyl, aryl, heteroaryl, or C 3 -C 7 heterocyclyl, any of which may optionally be substituted;
  • R2 is hydrogen, C ⁇ -C e alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, C 5 -C 7 cycloalkenyl, aryl, heteroaryl, C 3 -C 7 heterocyclyl, C(0)R3 or S0 2 R3 any of which may optionally be substituted, where: R3 is independently hydrogen, C C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, C 5 -C 7 cycloalkenyl, aryl, heteroaryl, C 3 -C 7 heterocyclyl or 0(Ci-C 6 alkyl), any of which may optionally be substituted;
  • R6 and R6' are each independently hydrogen, Ci-C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl; or
  • R7 and R7' are each independently hydrogen, Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C cycloalkyl, C 5 -C cycloalkenyl, aryl, heteroaryl, or C 3 -C heterocyclyl;
  • R1 is selected from Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C cycloalkyl, C 5 -C cycloalkenyl, aryl, heteroaryl, or C 3 -C 7 heterocyclyl, any of which may optionally be substituted with one or more substituents chosen from OH, C C 6 alkoxy, 0-C 3 -C 7 cycloalkyl, O-aryl, aryl, heteroaryl, C 3 -C 7 cycloalkyi, C 3 -C 7 heterocyclyl, C C 6 alkylthiol, C ⁇ -C 6 alkylamino or Ci-C 6 dialkylamino; and
  • R2 is hydrogen, C 1 -C4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 7 cycloalkyi, aryl, heteroaryl, C 3 -C 7 heterocyclyl, C(0)R3 or S0 2 R3 any of which may optionally be substituted by aryl or heteroaryl, where:
  • R3 is independently C 1 -C4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C cycloalkyi, aryl, heteroaryl, C 3 -C heterocyclyl or Ci-C 4 alkoxy, any of which may optionally be substituted by halogen, -CN, or -N0 2 ;
  • R1 is selected from Ci-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C cycloalkyi, any of which may optionally be substituted with one or more substituents chosen from OH, C C 6 alkoxy, 0-C 3 -C 7 cycloalkyi, O-aryl, aryl, heteroaryl, C 3 -C 7 cycloalkyi, C 3 -C 7 heterocyclyl, C C 6 alkylthiol, C ⁇ -C e alkylamino or C C 6 dialkylamino; and
  • R2 is hydrogen, Ci-C 4 alkyl, which may optionally be substituted with one or more substituents chosen from aryl or heteroaryl, C(0)R3 or S0 2 R3,
  • R3 is independently C C 4 alkyl or aryl, any of which may optionally be substituted by halogen, -CN, or -N0 2 ;
  • a more specific embodiment refers to the compound of formula (I) belonging to the following group:
  • a more specific embodiment refers to the compound of formula (I) belonging to the following group:
  • Compounds of the invention are inhibitors of tubulin polymerization and therefore useful for the treatment of diseases and conditions which are mediated by excessive or inappropriate cell proliferation such as cancers.
  • the cell proliferative disorder is cancer, more preferably multidrug resistant cancer.
  • Cancers that can be prevented, managed, treated or ameliorated in accordance with the compounds of the invention include, but are not limited to, neoplasms, tumors (malignant and benign), and metastases, or any disease or disorders characterized by uncontrolled cell growth.
  • the cancer may be a primary or metastatic cancer.
  • Specific examples of cancers that can be prevented, managed, treated or ameliorated in accordance with the compounds of the invention include, but are not limited to, cancer of the head, neck, eye, mouth, throat, esophagus, chest, bone, lung, colon, rectum, stomach, prostate, breast, ovaries, kidney, liver, pancreas, and brain.
  • the cancer that is being prevented, managed, treated or ameliorated in accordance with the compounds of the invention is prostate cancer, breast cancer, bone cancer, melanoma, lung cancer, kidney cancer, rectum cancer and ovarian cancer.
  • the compounds of formula (I) can also be used in combination with additional agents, in particular anti-tumor and differentiating agents, either by separate administrations, or by including the two active principles in the same pharmaceutical formulation.
  • additional agents include: a) histone deacetylase inhibitors (for example SAHA, PXD101 , JNJ-16241 199, JNJ- 26481585, SB939, ITF-2357, LBH589, PCI-24781 , valproic acid, butyric acid, MS-275, MGCD0103 or FK-228);
  • retinoid receptor modulators such as 13-cis-retinoic acid, 9-cis-retinoic acid, bexarotene, alitretinoin, or tretinoin; vitamin D;
  • antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology such as alkylating agents (for example platin derivatives like cis-platin, carboplatin, oxaliplatin, lobaplatin, satraplatin, nedaplatin, heptaplatin; nitrogen mustard such as chlorambucil, melphalan, chlormethine, cyclophosphamide, ifosfamide, trofosfamide, uramustine, bendamustine, estramustine; busulphan, temozolomide or nitrosoureas); antimetabolites (for example antifolates such as aminopterin, methotrexate, pemetrexed, raltitrexed); purines such as cladribine, clofarabine, fludarabine, mercaptopurine, pentostatin, thioguanine; pyrimidines like capecitabine, cytar
  • cytostatic agents such as antiestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and idoxifene), oestrogen receptor down regulators (for example fulvestrant), antiandrogens (for example bicalutamide, flutamide, nilutamide, liarozole or cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin or buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5-alpha- reductase such as finasteride;
  • antiestrogens for example tamoxifen, toremifene, raloxifene, droloxifene and idoxifene
  • agents which inhibit cancer cell invasion for example metalloproteinase inhibitors and inhibitors of urokinase plasminogen activator receptor function;
  • inhibitors of growth factor function for example growth factor antibodies, growth factor receptor antibodies (for example the anti-erbb2 antibody trastuzumab, the anti-erbbl antibody cetuximab and panitumumab, the anti IGF1 R antibody figitumumab), farnesyl transferase inhibitors, MEK inhibitors, tyrosine kinase inhibitors and serine/threonine kinase inhibitors, for example enzastaurin, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, nilotinib, sorafenib, sunitinib, everolimus, sirolimus or temsirolimus;
  • growth factor antibodies for example the anti-erbb2 antibody trastuzumab, the anti-erbbl antibody cetuximab and panitumumab, the anti IGF1 R antibody figitumumab
  • antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, for example the anti-vascular endothelial cell growth factor antibody bevacizumab [AvastinTM], lenalidomide or thalidomide;
  • cell cycle inhibitors including for example CDK inhibitors (for example flavopiridol, roscovitine) and other inhibitors of cell cycle checkpoints; inhibitors of aurora kinase and other kinases involved in mitosis and cytokinesis regulation;
  • proteasome inhibitors for example lactacystin, bortezomib, epoxomicin
  • HSP90 inhibitors for example 17-AAG, AT-13387, KOS-953, KOS-1022, CNF-
  • a compound of general formula (I) can be used in combination with radiation therapy and surgery.
  • a compound of general formula (I) may be administered in combination with standard chemotherapy combinations such as, but not restricted to, CMF (cyclophosphamide, methotrexate and 5-fluorouracil), CAF (cyclophosphamide, doxorubicin and 5-fluorouracil), AC (doxorubicin and cyclophosphamide), FEC (5-fluorouracil, epirubicin, and cyclophosphamide), ACT or ATC (doxorubicin, cyclophosphamide, and paclitaxel), or CMFP (cyclophosphamide, methotrexate, 5-fluorouracil and prednisone).
  • CMF cyclophosphamide, methotrexate and 5-fluorouracil
  • CAF cyclophosphamide, doxorubicin and 5-fluorouracil
  • AC doxorubicin and cyclophosphamide
  • FEC fluorouraci
  • the invention also comprises pharmaceutical compositions characterized by containing one or more active principles of formula (I), in association with pharmaceutically acceptable carrier, excipients and diluents, and eventually other active principles as above disclosed.
  • administration can be, for example, oral, parenteral (intravenous, subcutaneous, intramuscular), rectal, topical, transdermal, or using any other route of administration.
  • the compounds of formula (I) can be pharmaceutically formulated according to known methods.
  • the pharmaceutical compositions can be chosen on the basis of the treatment requirements.
  • Such compositions are prepared by blending and are suitably adapted to oral or parenteral administration, and as such can be administered in the form of tablets, capsules, oral preparations, powders, granules, pills, injectable or infusible liquid solutions, suspensions or suppositories.
  • Tablets and capsules for oral administration are normally presented in unit dose form and contain conventional excipients such as binders, fillers, diluents, tableting agents, lubricants, detergents, disintegrants, coloring agents, flavoring agents and wetting agents.
  • excipients such as binders, fillers, diluents, tableting agents, lubricants, detergents, disintegrants, coloring agents, flavoring agents and wetting agents.
  • the tablets can be coated using methods well known in the art.
  • Suitable fillers include cellulose, mannitol, lactose and other similar agents.
  • Suitable disintegrants include polyvinylpyrrolidone and starch derivatives such as sodium glycolate starch.
  • Suitable lubricants include, for example, magnesium stearate.
  • Suitable wetting agents include sodium lauryl sulfate.
  • the oral solid compositions can be prepared by conventional methods of blending, filling or tableting.
  • the blending operation can be repeated to distribute the active principle throughout compositions containing large quantities of fillers.
  • Such operations are conventional.
  • Oral liquid preparations can be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or can be presented as a dry product for reconstitution with water or with a suitable vehicle before use.
  • Such liquid preparations can contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel, or hydrogenated edible fats; emulsifying agents, such as lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which can include edible oils), such as almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, such as methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired, conventional flavoring or coloring agents.
  • Oral formulations also include conventional slow- release formulations such as enterically coated tablets or granules.
  • fluid unit dosages e.g. in ampoules or in multi-dose containers
  • the compound can be either suspended or dissolved, depending on the vehicle and concentration.
  • the parenteral solutions are normally prepared by dissolving the compound in a vehicle, sterilising by filtration, filling suitable vials and sealing.
  • adjuvants such as local anaesthetics, preservatives and buffering agents can also be dissolved in the vehicle.
  • the composition can be frozen after having filled the vials and removed the water under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner, except that the compound can be suspended in the vehicle instead of being dissolved, and sterilized by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent can be included in the composition to facilitate uniform distribution of the compound of the invention.
  • the compounds can be pharmaceutically formulated as suppositories or retention enemas, e.g. containing conventional suppositories bases such as cocoa butter, polyethylene glycol, or other glycerides, for a rectal administration.
  • suppositories or retention enemas e.g. containing conventional suppositories bases such as cocoa butter, polyethylene glycol, or other glycerides, for a rectal administration.
  • Topical formulations can contain for example ointments, creams, lotions, gels, solutions, pastes and/or can contain liposomes, micelles and/or microspheres.
  • ointments include oleaginous ointments such as vegetable oils, animal fats, semisolid hydrocarbons, emulsifiable ointments such as hydroxystearin sulfate, anhydrous lanolin, hydrophilic petrolatum, cetyl alcohol, glycerol monostearate, stearic acid, water soluble ointments containing polyethylene glycols of various molecular weights.
  • Creams are viscous liquids or semisolid emulsions, and contain an oil phase, an emulsifier and an aqueous phase.
  • the oil phase generally contains petrolatum and an alcohol such as cetyl or stearic alcohol.
  • the emulsifier in a cream formulation is chosen from non-ionic, anionic, cationic or amphoteric surface-active agents.
  • the monophasic gels contain the organic molecules uniformly distributed in the liquid, which is generally aqueous, but they also preferably contain an alcohol and optionally an oil.
  • Preferred gelling agents are cross-linked acrylic acid polymers (e.g. carbomer-type polymers, such as carboxypolyalkylenes, which are commercially available under the CarbopolTM trademark). Hydrophilic polymers are also preferred, such as polyoxyethylene, polyoxyethylene-polyoxypropylene copolymers and polyvinyl alcohol; cellulose polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate and methylcellulose; gums, such as xanthan gum and tragacanth gum; sodium alginate; and gelatin. Dispersing agents such as alcohol or glycerin can be added for gel preparation. The gelling agent can be dispersed by finely chopping and/or mixing.
  • a further method of administering the compounds of the invention regards transdermal delivery.
  • Typical transdermal formulations comprise conventional aqueous and non-aqueous vectors, such as creams, oils, lotions or pastes or can be in the form of membranes or medicated patches.
  • One formulation provides that a compound of the invention is dispersed within a pressure sensitive patch that adheres to the skin. This formulation enables the compound to diffuse from the patch to the patient through the skin.
  • natural rubber and silicon can be used as pressure sensitive adhesives.
  • the dosage of the compounds of formula (I) can vary depending upon a variety of factors including the patient type and condition, the degree of disease severity, mode and time of administration, diet and drug combinations. As an indication, they can be administered within a dose range of between 0.001 and 1000 mg/kg/day. The determination of optimum dosages for a particular patient is well known to one skilled in the art.
  • compositions are normally accompanied by written or printed instructions for use in the treatment in question.
  • the present invention comprises metabolic precursors (prodrug) of formula (I) compounds.
  • metabolic precursors or “prodrug” means compounds having a different structure from that of the compound of formula (I), which after administration to the patient are directly or indirectly transformed into a compound of formula (I) (Bundgaard, H. ed., “Design of Prodrugs", Elsevier, 1985).
  • composition comprising a compound of formula (I) as above defined or a pharmaceutically acceptable prodrug, solvate or hydrate thereof, with one or more physiologically acceptable carriers or excipients.
  • the pharmaceutical composition comprises the compound of formula (I) in association with a further active principle, preferably an anti-cancer agent.
  • the present invention also comprises the process for preparing the compounds of formula (I).
  • Compounds of general formula (I) may be prepared from compounds of general formula (II)
  • R1 is as above defined for general formula (I), by reaction with a compound of general formula (III) or (IV) or (V):
  • R2 and R3 are as above defined for general formula (I), and X is a halogen such as chloro, bromo or iodo or a suitable leaving group such as a mesyl or tosyl group.
  • X is a halogen such as chloro, bromo or iodo or a suitable leaving group such as a mesyl or tosyl group.
  • the reaction is conducted in an organic solvent such as tetrahydrofuran or dichloromethane, in the presence of a base such as cesium carbonate, ⁇ , ⁇ -diisopropylethylamine or potassium t-butoxide, at a temperature ranging from about CTC to reflux.
  • the transesterification i.e. the process of exchanging the organic group ethyl of the ester with the organic group R1 of the alcohol, is preferably catalyzed by the addition of a base such as sodium hydroxide and it may be necessary to heat the reaction mixture, for example to between about 50 and 160°C.
  • a base such as sodium hydroxide
  • reaction is carried out in the presence of a carbodiimide as coupling reagent [i.e. 1 ,3- dicyclohexylcarbodiimide or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)] and a base as catalyst (i.e. 4-dimethylaminopyridine, triethylamine or N,N-diisopropylethylamine).
  • a carbodiimide as coupling reagent
  • EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
  • a base as catalyst i.e. 4-dimethylaminopyridine, triethylamine or N,N-diisopropylethylamine.
  • EDC is often used in combination with hydroxybenzotriazole to increase coupling efficiency.
  • reaction takes place at a temperature ranging from about CTC to reflux and suitable solvents are dichloromethane, chloroform, tetrahydrofuran or N,N-dimethylformamide.
  • Figure 1 Compounds destabilize MTs.
  • A. Compounds B, A6, D7, E7 and A8, representing the compounds described in this invention, efficiently destabilize MTs in vitro; nocodazole acted as a positive control.
  • B. Compounds B, A6, D7, E7 and A8 compete with [ 3 H]colchicine for binding to tubulin; combretastatin A-4 acted as the positive control.
  • the structural formulas of the compounds are shown in Table 2. The bars represent standard deviations.
  • Figure 2 Compounds kill adenomacarcinoma cells.
  • Compounds B, A6, D7, E7 and A8, as in Fig. 1 trigger mitotic delay and cell death (apoptosis) with high efficiency in HeLa cells (cervical adenomacarcinoma).
  • Dl PEA (A/,A/-diisopropylethylamine)
  • DMF (dimethylformamide)
  • DMSO dimethyl sulfoxide
  • DMSO-d 6 deuterated dimethyl sulfoxide
  • TEA triethylamine
  • TFA trifluoroacetic acid
  • the H-NMR spectra were acquired with a Varian 500 MHz instrument.
  • the chemical shifts are expressed in parts per million (ppm, ⁇ units).
  • the coupling constants are expressed in Hertz (Hz) and the splitting patterns are described as s (singlet), bs (broad singlet), d (doublet), t (triplet), q (quartet), quint (quintet), m (multiplet).
  • potassium tert-butoxide (0.234 g, 2.09 mmol) was added to a mixture of ethyl 6-(2-furyl)-3-methyl-4-oxo-1 , 5,6,7- tetrahydroindole-2-carboxylate (0.500 g, 1.7 mmol) in dry tetrahydrofuran (17.0 ml) at 0 "C.
  • the resulting mixture was stirred for 20 min at 0 * 0 , 4-nitro benzene sulfonyl chloride (0.964 g, 4.35 mmol) was then added.
  • Polymerization was tracked as an increase in fluorescence due to the incorporation of a fluorescent reporter into the MTs as polymerization occurred. Readings (every 1 min for 60 min) were taken at an excitation wavelength of 360 nm and an emission wavelength of 465 nM (TECAN - INFINITE F200). All the data points were in duplicates and 1 % DMSO served as the positive control (no effect on tubulin polymerization), while 5mM CaCI 2 plus 1 % DMSO served as the negative control (inhibition of tubulin polymerization).
  • Table 1 Degree of inhibition of tubulin polymerization by various compounds (at 5 ⁇ ). Anti- tubulin agent colchicine served as the positive control.
  • HeLa cells The ability of a representative subset of tubulin-targeting compounds (Table 2) to prevent spindle formation resulting in SAC activation (mitotic delay) and cell death (apoptosis) was probed using HeLa cells ( Figure 2). HeLa cells synchronized in S phase using 2.5 mM thymidine were released into growth medium containing 100 nM or 500 nM of each compound. Cell growth, duration of the mitotic delay, and percentage of cells undergoing cell death were scored following live-cell videomicroscopy. 2.5 Ability of the compounds to eradicate proliferating cancer cells, including those that are multidrug resistant.
  • HCT-1 16 ATCC, CCL-247
  • HCT-15 DSMZ, ACC-357 cancer cell lines were used for cell proliferation assays.
  • the HCT-15 cell line is multi-drug resistant as it expresses elevated levels of the drug efflux pump MDR1 (Alvarez M et al., 1995, J Clin
  • HCT-1 16 and HCT-15 cells were maintained in McCoy's medium supplemented with 10% Fetal Bovine Serum and Antibiotics and RPMI medium containing
  • This assay allows the determination of the number of viable cells in culture based on the quantification of adenosine triphosphate (ATP) released by metabolically active cells.
  • ATP adenosine triphosphate
  • the assay procedure involves addition of a single reagent (CellTiter-Glo ® Reagent) directly to the cells, which leads to cell lysis and generation of a luminescent signal proportional to the amount of the ATP and the number of cells present in culture.
  • CellTiter-Glo ® Reagent CellTiter-Glo ® Reagent
  • the assay relies on the properties of a proprietary thermostable luciferase (Ultra-Glo ® recombinant luciferase), which generates a luminescent signal.
  • CellTiter-Glo ® Reagent equal to the volume of cell culture medium was added. The content was mixed for 2 min to induce cell lysis. The luminescence was recorded after further 15 min at RT in order to obtain a stabilized luminescent signal.
  • HCT15 non-resistant cell lines
  • Table 3 Growth inhibition (Gl 50 ) of representative compounds of the invention on cancer cell lines that are multi-drug sensitive (HCT1 16) or multi-drug resistant (HCT15)
  • Gl 50 Categories of Gl 50 : A, ⁇ 250 nM; B, between 250 nM and 1 ⁇ ; C, >1 ⁇ .

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Abstract

The present invention relates to 6-(2-furyl)-3-methyl-4-oxo-1,5,6,7-tetrahydroindole-2- carboxylate derivatives, to a process for their preparation, to pharmaceutical compositions containing them and to their use in the treatment of cell proliferative disorders including cancer, preferably multidrug resistant cancer.

Description

6-(2-FURYL)-3-METHYL- -OXO-1 ,5,6,7-TETRAHYDROINDOLE-2-CARBOXYLATE
DERIVATIVES AND USES THEREOF
Field of the invention
The present invention relates to 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2- carboxylate derivatives, to a process for their preparation, to pharmaceutical compositions containing them, and to their use in the treatment of cell proliferative disorders such as cancer and multidrug resistant cancer. Background of the invention
During the division of a eukaryotic cell (more specifically during the cell division stage named prometaphase) -, β-, and γ-tubulin assemble into long polymers named protofilaments. Next, appr. 13 protofilaments laterally associate to form hollow, tubular structures named microtubules (MTs), which organize into an array-like structure (named mitotic spindle) that originates from so called MT-organizing centers (also known as centrosomes or spindle poles). Following DNA replication, duplicated chromosome pairs (named sister chromatids) recruit a protein complex named kinetochore to their centromere regions. Kinetochores serve to bind the sister chromatids to the tips (plus-ends) of a MT- bundle comprising 20-30 MTs and, next, to orchestrate chromatid segregation between the mother and daughter cells. For this to occur correctly, each sister chromatid must bind in a bipolar fashion to the mitotic spindle, meaning that within a sister chromatid pair one chromatid must bind to a MT bundle extending from one centrosome while the second chromatid must bind to a MT bundle extending from the opposite centrosome. Bipolar attachment allows the sister chromatids to move to middle (metaphase plate) of a metaphase cell. Because the MTs are dynamic at their plus-ends, the kinetochores on each chromatid will undergo a MT-generated force, which is counteracted by the rigid cohesin complexes that firmly hold the sister chromatids together. The interplay of these forces results in tension between the kinetochores. The spindle assembly checkpoint (also known as the SAC, spindle checkpoint or mitotic checkpoint) monitors the presence of this tension as it suggests correct bipolar binding of the sister chromatids to the spindle structure. Absence of tension, even at a single kinetochore, will signal the SAC as it reflects an incorrect (non bi-polar) or absent binding of a chromatid to the spindle array. The SAC will then halt cell division in metaphase, allowing the unbound/incorrectly bound chromatid(s) to establish correct contact with the MTs (Musacchio A, Salmon ED, Nature Rev Mol Cell Biol, 2007,8: 379-393). If this correction cannot be made, then the arrested cells will undergo cell death (apoptosis) with high frequency (Gascoigne KE, Taylor SS. Cancer Cell, 2008, 14: 1 1 1-122).
Because cancer cells are highly mitotic, the strategy of triggering the SAC and keeping it unsatisfied to trigger apoptosis resulting in cell death, has been applied with great success in the clinic. More specifically, tubulin-targeting agents that prevent the generation of intrakinetochore tension by preventing spindle formation (e.g. vinblastine family of drugs) or by stabilizing the spindle structure (e.g. the taxanoids) efficiently trigger cancer cell death (Carlson RO, Expert Opin Invest Drugs, 2008, 17: 707-722; Dumontet C, Jordan MA, Nature Rev Drug Disc, 2010, 9: 790-803).
Unfortunately, cells are gradually developing resistance against the currently used antitubulin drugs thereby impeding successful chemotherapy for various cancers. This reality demands the development of new chemotype classes of antitubulin compounds that are not detected by the drug-resistance mechanisms (Carlson RO, Expert Opin Invest Drugs, 2008, 17: 707-722).
Cancer cell resistance to antiproliferative agents (also named multidrug resistance or MDR) is caused by enhanced levels of the MDR1 gene, which encodes the P-glycoprotein drug-efflux pump (Pgp) that belongs to the ATP-binding cassette transporter superfamily of membrane proteins (Goda K, Bacso Z, Szabo G, Curr Cancer Drug Targets, 2009, 9: 281- 297).
The present invention relates to 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2- carboxylate derivatives as antitubulin agents. In particular compounds of the invention, unlike existing drugs targeting tubulin such as paclitaxel and vinblastine, are equally effective against both non-resistant and multidrug-resistant cancer cells.
Some 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate derivatives are known in the art, and some of them are commercially available.
4,5,6,7-tetrahydrobenzofuran derivatives were evaluated for their cytotoxicity (Hayakawa I et al, Chem. Pharm. Bull. 2005, 53(6), 638-640). The ethyl 6-phenyl-3-methyl-4- oxo-1 ,5,6,7- tetrahydroindole-2-carboxylate was tested and showed a EC50 of 72 ng/ml on human tumorigenic cell line VA13 (CCL-75.1 ).
EP 0754681 describes 4-oxo-1 ,5,6,7- tetrahydroindole derivatives as intermediates in the synthesis of N-hydroxyalkyl-4-hydroxyindoles as oxidative hair dye components. The following compounds: ethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2- carboxylate, isobutyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate, penthyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate, allyl 6-(2-furyl)-3- methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate, [(E)-but-2-enyl] 6-(2-furyl)-3-methyl-4- oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate, 2-methylsulfanylethyl 6-(2-furyl)-3-methyl-4-oxo- 1 ,5,6,7-tetrahydroindole-2-carboxylate, 2-methoxyethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7- tetrahydroindole-2-carboxylate, 2-isopropoxyethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7- tetrahydroindole-2-carboxylate, cyclopentyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7- tetrahydroindole-2-carboxylate, tetrahydrofuran-2-ylmethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7- tetrahydroindole-2-carboxylate and benzyl 6-(2-furyl)-3-methyl-4-oxo-1 , 5,6,7- tetrahydroindole-2-carboxylate are cited in US 2009163545 (University of Rochester, USA), which describes the screening of known molecules to identify compounds that alter the lifespan of eukaryotic organisms.
The compound tetrahydrofuran-2-yl-methyl-6-(2-furyl)-3-methyl-4-oxo-1 , 5,6,7- tetrahydroindole-2-carboxylate is cited in WO 2008154207 (The Burnham Institute for Medical Research, USA) wherein a method of screening of commercially chemical libraries is reported to identify compounds capable of converting a Bcl-B protein from an anti-apoptotic form to a pro-apoptotic form.
Ethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate, ethyl 1-(2- diethylaminoethyl)-6-(2-furyl)-3-methyl-4-oxo-6,7-dihydro-5H-indole-2-carboxylate
hydrochloride and ethyl 1-(2-dimethylaminoethyl)-6-(2-furyl)-3-methyl-4-oxo-6,7-dihydro-5H- indole-2-carboxylate are disclosed in US 3,503,990 (Endo Laboratories, Inc.) as analgesic and antitussive agents. Description of the invention
The present invention relates to 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2- carboxylate derivatives and their use in the treatment of cell proliferative disorders such as cancer. Compounds of the invention are particularly effective against multidrug-resistant cancer cells.
It is an object of the invention a compound of general formula (I)
Figure imgf000005_0001
or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, wherein:
R1 is selected from hydrogen, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C5-C7 cycloalkenyl, aryl, heteroaryl, or C3-C7 heterocyclyl, any of which may optionally be substituted;
R2 is hydrogen, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C5-C cycloalkenyl, aryl, heteroaryl, C3-C heterocyclyl, C(0)R3 or S02R3 any of which may optionally be substituted, where:
R3 is independently hydrogen, C C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C5-C cycloalkenyl, aryl, heteroaryl, C3-C heterocyclyl or 0(Ci-C6 alkyl), any of which may optionally be substituted;
when the alkyl, alkenyl and alkynyl groups are substituted, there are one or more substituents selected from:
(i) C3-C7 cycloalkyl, C5-C7 cycloalkenyl, aryl, heteroaryl, C3-C7 heterocyclyl, any of which may, in turn, be substituted with one or more substituents selected from halogen, -
OR4, -SR4, -NR4R4', -C(0)R4, -C02R4, -C(0)NR4R4', -S(0)R4, -S02R4, -S02NR4R4', - OC(0)R4', -N(R4)C(0)R4', -N(R4)S02R4', -CN, or -N02; wherein R4 and R4' are each independently hydrogen, Ci-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; or
(ii) -OR5, -SR5, -NR5R5', -C(0)R5, -C02R5, -C(0)NR5R5', -S(0)R5, -S02R5, or -S02NR5R5', -OC(0)R5', -N(R5)C(0)R5', or -N(R5)S02R5', halogen, -CN, or -N02; wherein
R5 and R5' are each independently hydrogen, C C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C5-C cycloalkenyl, aryl, heteroaryl, or C3-C heterocyclyl;
when cycloalkyl, heterocyclyl, aryl and heteroaryl groups are substituted, there are one or more substituents selected from:
(i) Ci-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, any of which may be substituted as defined above; or
(ii) C3-C cycloalkyl, C5-C cycloalkenyl, aryl, heteroaryl, C3-C heterocyclyl, any of which may, in turn, be substituted with one or more substituents selected from halogen, - OR6, -SR6, -NR6R6', -C(0)R6, -C02R6, -C(0)NR6R6', -S(0)R6, -S02R6, -S02NR6R6', - OC(0)R6, -N(R6)C(0)R6\ -N(R6)S02R6', -CN, or -N02; wherein R6 and R6' are each independently hydrogen, Ci-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; or
(iii) -OR7, -SR7, -NR7R7', -C(0)R7, -C02R7, -C(0)NR7R7', -S(0)R7, -S02R7, or -S02NR7R7', -OC(0)R7, -N(R7)C(0)R7', or -N(R7)S02R7', halogen, -CN, or -N02; wherein R7 and R7' are each independently hydrogen, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C5-C7 cycloalkenyl, aryl, heteroaryl, or C3-C7 heterocyclyl;
with the proviso that the following compounds are not comprised:
6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylic acid,
ethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate,
propyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate,
isobutyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate,
pentyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate,
hexyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate,
allyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate,
but-2-enyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate,
[(E)-but-2-enyl] 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate,
2-methylsulfanylethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate, 2-ethylsulfanylethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate, 2-methoxyethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate,
2-ethoxyethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate,
2-isopropoxyethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate,
2-propoxyethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate,
2-phenoxyethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate,
cyclopentyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate,
cyclohexyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate,
cyclohexylmethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate, tetrahydrofuran-2-ylmethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate, p-tolylmethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate,
benzyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate,
ethyl 1-(2-diethylaminoethyl)-6-(2-furyl)-3-methyl-4-oxo-6,7-dihydro-5H-indole-2-carboxylate, ethyl 1-(2-dimethylaminoethyl)-6-(2-furyl)-3-methyl-4-oxo-6,7-dihydro-5H-indole-2- carboxylate. Preferably R1 is selected from methyl, isopropyl or substituted ethyl wherein the substituent is selected from:
(i) C3-C7 cycloalkyi, C5-C7 cycloalkenyl, aryl, heteroaryl, C3-C7 heterocyclyl, any of which may, in turn, be substituted with one or more substituents selected from halogen, - OR4, -SR4, -NR4R4', -C(0)R4, -C02R4, -C(0)NR4R4', -S(0)R4, -S02R4, -S02NR4R4', - OC(0)R4', -N(R4)C(0)R4', -N(R4)S02R4', -CN, or -N02; wherein R4 and R4' are each independently hydrogen, Ci-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; or
(ii) -OH, -NR5R5', -C(0)R5, -C02R5, -C(0)NR5R5', -S(0)R5, -S02R5, or - S02NR5R5', -OC(0)R5', -N(R5)C(0)R5', or -N(R5)S02R5', halogen, -CN, or -N02; wherein R5 and R5' are each independently hydrogen, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyi, C5-C7 cycloalkenyl, aryl, heteroaryl, or C3-C7 heterocyclyl.
Preferably R2 is selected from hydrogen, methyl, ethyl, benzyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyi, C5-C7 cycloalkenyl, aryl, heteroaryl, C3-C7 heterocyclyl, C(0)R3 or S02R3 where:
R3 is independently hydrogen, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyi, C5-C7 cycloalkenyl, aryl, heteroaryl, C3-C7 heterocyclyl or 0(Ci-C6 alkyl), any of which may optionally be substituted.
"C C6 alkyl" refers to a fully saturated straight or branched saturated hydrocarbon chain having one to six carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, t-butyl and n-hexyl.
"C2-C6 alkenyl" refers to a straight or branched hydrocarbon chain having from two to six carbon atoms and at least one carbon-carbon double bond. Examples include ethenyl, 2- propenyl and isobutenyl.
"C2-C6 alkynyl" refers to a straight or branched hydrocarbon chain having from two to six carbon atoms and at least one carbon-carbon triple bond. Examples include ethynyl, 2- propynyl and isobutynyl.
"C3-C7 cycloalkyi" refers to a saturated 3 to 7 membered carbocyclic ring. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
"C5-C7 cycloalkenyl" refers to a 5 to 7 membered carbocyclic ring having at least one ring carbon-carbon double bond.
"C3-C7 heterocyclyl" refers to a 3 to 7 membered ring system having at least one heteroatom chosen from N, O or S and optionally being partially unsaturated. Examples of such groups include morpholino, pyrrolidino, piperidinyl, piperazinyl, tetrahydrofuranyl. "Halo" or "halogen" refers to fluoro, chloro, bromo or iodo.
"Aryl" refers to a ring system having from 6 to 14 ring carbon atoms and containing up to three rings, at least one of which has aromatic character. Examples of aryl groups are benzene, biphenyl and naphthalene.
"Heteroaryl" refers to a ring system having from 5 to 14 ring atoms, one or more of which is a heteroatom selected from N, O and S and containing up to three rings, at least one of which has aromatic character. Examples of heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, oxazolyl, furanyl, thienyl, quinolinyl, isoquinolyl, quinazolyl, thiazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, indolyl, indazolyl, imidazolyl, benzimidazolinyl and benzodioxolyl ring systems.
"Ci-C6 alkoxy" refers to the group Ci-C6 alkyl-O-.
"C C4 alkoxy" refers to the group C C4 alkyl-O-.
"Ci-Ce alkylthiol" refers to the group C C6 alkyl-S-.
"Ci-Ce alkylamino" refers to the group CrC6 alkyl attached to an amino moiety.
"Ci-C6 dialkylamino" refers to two group d-C6 alkyl attached to an amino moiety.
Appropriate pharmaceutically and veterinarily acceptable salts of the compounds of general formula (I) include salts of organic acids, especially carboxylic acids, including but not limited to acetate, trifluoroacetate, lactate, gluconate, citrate, tartrate, maleate, malate, pantothenate, adipate, alginate, aspartate, benzoate, butyrate, digluconate, cyclopentanate, glucoheptanate, glycerophosphate, oxalate, heptanoate, hexanoate, fumarate, nicotinate, pamoate, pectinate, 3-phenylpropionate, picrate, pivalate, proprionate, tartrate, lactobionate, pivolate, camphorate, undecanoate and succinate; organic sulfonic acids such as methanesulfonate, ethanesulfonate, 2-hydroxyethane sulfonate, camphorsulfonate, 2- naphthalenesulfonate, benzenesulfonate, p-chlorobenzenesulfonate and p-toluenesulfonate; and inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, hemisulfate, thiocyanate, persulfate, phosphoric and sulfonic acids.
Salts which are not pharmaceutically or veterinarily acceptable may still be valuable as intermediates.
Compounds of formula (I) have one or more asymmetric carbon atoms and therefore exist either as racemic mixtures or as individual optical isomers. Accordingly, all the possible isomers, and their mixtures, of the compounds of formula (I) are also within the scope of the present invention.
In addition, the compounds of the present invention can exist in unsolvated as well in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like.
In a preferred embodiment of the invention R1 is selected from methyl, 2- hydroxyethyl, 2-methylaminoethyl, 2-dimethylaminoethyl, isopropyl group.
In a further preferred embodiment of the invention R2 is selected from hydrogen, methyl, ethyl, benzyl, acetyl, 4-nitrophenylsulfonyl, benzenesulfonyl group.
In a further preferred embodiment the compound of the invention belongs to the following group:
methyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
2-hydroxyethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
2-methylaminoethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
2-dimethylaminoethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
isopropyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
ethyl 6-(2-furyl)-1 ,3-dimethyl-4-oxo-6,7-dihydro-5H-indole-2-carboxylate;
ethyl 1-ethyl-6-(2-furyl)-3-methyl-4-oxo-6,7-dihydro-5H-indole-2-carboxylate;
ethyl 1-benzyl-6-(2-furyl)-3-methyl-4-oxo-6,7-dihydro-5H-indole-2-carboxylate;
ethyl 1-acetyl-6-(2-furyl)-3-methyl-4-oxo-6,7-dihydro-5H-indole-2-carboxylate;
ethyl 6-(2-furyl)-3-methyl-1-(4-nitrophenyl)sulfonyl-4-oxo-6,7-dihydro-5H-indole-2-carboxylate; ethyl 1-(benzenesulfonyl)-6-(2-furyl)-3-methyl-4-oxo-6,7-dihydro-5H-indole-2-carboxylate.
It is a further object of the invention a compound of general formula (I)
Figure imgf000009_0001
(I)
or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, wherein:
R1 is selected from hydrogen, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C5-C7 cycloalkenyl, aryl, heteroaryl, or C3-C7 heterocyclyl, any of which may optionally be substituted;
R2 is hydrogen, C^-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C5-C7 cycloalkenyl, aryl, heteroaryl, C3-C7 heterocyclyl, C(0)R3 or S02R3 any of which may optionally be substituted, where: R3 is independently hydrogen, C C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C5-C7 cycloalkenyl, aryl, heteroaryl, C3-C7 heterocyclyl or 0(Ci-C6 alkyl), any of which may optionally be substituted;
wherein when the alkyl, alkenyl and alkynyl groups are substituted, there are or more substituents selected from:
(i) C3-C7 cycloalkyl, C5-C7 cycloalkenyl, aryl, heteroaryl, C3-C7 heterocyclyl, any of which may, in turn, be substituted with one or more substituents selected from halogen, - OR4, -SR4, -NR4R4', -C(0)R4, -C02R4, -C(0)NR4R4', -S(0)R4, -S02R4, -S02NR4R4', - OC(0)R4', -N(R4)C(0)R4', -N(R4)S02R4', -CN, or -N02; wherein R4 and R4' are each independently hydrogen, Ci-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; or
(ii) -OR5, -SR5, -NR5R5', -C(0)R5, -C02R5, -C(0)NR5R5', -S(0)R5, -S02R5, or -S02NR5R5', -OC(0)R5', -N(R5)C(0)R5', or -N(R5)S02R5', halogen, -CN, or -N02; wherein R5 and R5' are each independently hydrogen, C C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C5-C7 cycloalkenyl, aryl, heteroaryl, or C3-C7 heterocyclyl;
wherein when cycloalkyl, heterocyclyl, aryl and heteroaryl groups are substituted, there are one or more substituents selected from:
(i) C C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, any of which may be substituted as defined above; or
(ii) C3-C7 cycloalkyl, C5-C7 cycloalkenyl, aryl, heteroaryl, C3-C7 heterocyclyl, any of which may, in turn, be substituted with one or more substituents selected from halogen, -
OR6, -SR6, -NR6R6', -C(0)R6, -C02R6, -C(0)NR6R6', -S(0)R6, -S02R6, -S02NR6R6', - OC(0)R6, -N(R6)C(0)R6', -N(R6)S02R6', -CN, or -N02; wherein R6 and R6' are each independently hydrogen, Ci-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; or
(iii) -OR7, -SR7, -NR7R7', -C(0)R7, -C02R7, -C(0)NR7R7', -S(0)R7, -S02R7, or -S02NR7R7', -OC(0)R7, -N(R7)C(0)R7', or -N(R7)S02R7', halogen, -CN, or -N02; wherein
R7 and R7' are each independently hydrogen, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C cycloalkyl, C5-C cycloalkenyl, aryl, heteroaryl, or C3-C heterocyclyl;
for use in the treatment of cell proliferative disorders.
A specific embodiment refers to the compound of formula (I) wherein:
R1 is selected from Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C cycloalkyl, C5-C cycloalkenyl, aryl, heteroaryl, or C3-C7 heterocyclyl, any of which may optionally be substituted with one or more substituents chosen from OH, C C6 alkoxy, 0-C3-C7 cycloalkyl, O-aryl, aryl, heteroaryl, C3-C7 cycloalkyi, C3-C7 heterocyclyl, C C6 alkylthiol, C^-C6 alkylamino or Ci-C6 dialkylamino; and
R2 is hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C7 cycloalkyi, aryl, heteroaryl, C3-C7 heterocyclyl, C(0)R3 or S02R3 any of which may optionally be substituted by aryl or heteroaryl, where:
R3 is independently C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C cycloalkyi, aryl, heteroaryl, C3-C heterocyclyl or Ci-C4 alkoxy, any of which may optionally be substituted by halogen, -CN, or -N02;
for use in the treatment of cell proliferative disorders.
A more specific embodiment refers to the compound of formula (I) wherein
R1 is selected from Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C cycloalkyi, any of which may optionally be substituted with one or more substituents chosen from OH, C C6 alkoxy, 0-C3-C7 cycloalkyi, O-aryl, aryl, heteroaryl, C3-C7 cycloalkyi, C3-C7 heterocyclyl, C C6 alkylthiol, C^-Ce alkylamino or C C6 dialkylamino; and
R2 is hydrogen, Ci-C4 alkyl, which may optionally be substituted with one or more substituents chosen from aryl or heteroaryl, C(0)R3 or S02R3,
wherein R3 is independently C C4 alkyl or aryl, any of which may optionally be substituted by halogen, -CN, or -N02;
for use in the treatment of cell proliferative disorders.
A more specific embodiment refers to the compound of formula (I) belonging to the following group:
ethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
propyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
isobutyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
pentyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
hexyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
allyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
[(E)-but-2-enyl] 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
2-methoxyethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
2-ethoxyethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
2-isopropoxyethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
2-propoxyethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
2-phenoxyethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate; 2-methylsulfanylethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
2-ethylsulfanylethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
cyclopentyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
cyclohexyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
cyclohexylmethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
tetrahydrofuran-2-ylmethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate; benzyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
p-tolylmethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
methyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
2-hydroxyethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
2-methylaminoethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
2-dimethylaminoethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
isopropyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
ethyl 6-(2-furyl)-1 ,3-dimethyl-4-oxo-6,7-dihydro-5H-indole-2-carboxylate;
ethyl 1 -ethyl-6-(2-furyl)-3-methyl-4-oxo-6,7-dihydro-5H-indole-2-carboxylate;
ethyl 1-benzyl-6-(2-furyl)-3-methyl-4-oxo-6,7-dihydro-5H-indole-2-carboxylate;
ethyl 1-acetyl-6-(2-furyl)-3-methyl-4-oxo-6,7-dihydro-5H-indole-2-carboxylate;
ethyl 6-(2-fuiyl)-3-methyl-1-(4-nitrophenyl)sulfonyl-4-oxo-6,7-dihydro-5H-indole-2-carboxylate; ethyl 1-(benzenesulfonyl)-6-(2-furyl)-3-methyl-4-oxo-6,7-dihydro-5H-indole-2-carboxylate; for use in the treatment of cell proliferative disorders.
A more specific embodiment refers to the compound of formula (I) belonging to the following group:
ethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
propyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
allyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
[(E)-but-2-enyl] 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
2-methoxyethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
2-propoxyethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
2-methylsulfanylethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
2-ethylsulfanylethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
cyclopentyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
cyclohexyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
tetrahydrofuran-2-ylmethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate; benzyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
methyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
2-hydroxyethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
2-methylaminoethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
2-dimethylaminoethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
isopropyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
ethyl 6-(2-furyl)-1 ,3-dimethyl-4-oxo-6,7-dihydro-5H-indole-2-carboxylate;
ethyl 1-ethyl-6-(2-furyl)-3-methyl-4-oxo-6,7-dihydro-5H-indole-2-carboxylate;
ethyl 1-benzyl-6-(2-furyl)-3-methyl-4-oxo-6,7-dihydro-5H-indole-2-carboxylate;
ethyl 1-acetyl-6-(2-furyl)-3-methyl-4-oxo-6,7-dihydro-5H-indole-2-carboxylate;
ethyl 6-(2-furyl)-3-methyl-1-(4-nitrophenyl)sulfonyl-4-oxo-6,7-dihydro-5H-indole-2-carboxylate; for use in the treatment of cell proliferative disorders.
Compounds of the invention are inhibitors of tubulin polymerization and therefore useful for the treatment of diseases and conditions which are mediated by excessive or inappropriate cell proliferation such as cancers.
Consequently, in a preferred embodiment the cell proliferative disorder is cancer, more preferably multidrug resistant cancer.
Cancers that can be prevented, managed, treated or ameliorated in accordance with the compounds of the invention include, but are not limited to, neoplasms, tumors (malignant and benign), and metastases, or any disease or disorders characterized by uncontrolled cell growth. The cancer may be a primary or metastatic cancer. Specific examples of cancers that can be prevented, managed, treated or ameliorated in accordance with the compounds of the invention include, but are not limited to, cancer of the head, neck, eye, mouth, throat, esophagus, chest, bone, lung, colon, rectum, stomach, prostate, breast, ovaries, kidney, liver, pancreas, and brain.
In a specific embodiment, the cancer that is being prevented, managed, treated or ameliorated in accordance with the compounds of the invention is prostate cancer, breast cancer, bone cancer, melanoma, lung cancer, kidney cancer, rectum cancer and ovarian cancer.
The compounds of formula (I) can also be used in combination with additional agents, in particular anti-tumor and differentiating agents, either by separate administrations, or by including the two active principles in the same pharmaceutical formulation. Non-exhaustive examples of suitable additional agents include: a) histone deacetylase inhibitors (for example SAHA, PXD101 , JNJ-16241 199, JNJ- 26481585, SB939, ITF-2357, LBH589, PCI-24781 , valproic acid, butyric acid, MS-275, MGCD0103 or FK-228);
b) retinoid receptor modulators such as 13-cis-retinoic acid, 9-cis-retinoic acid, bexarotene, alitretinoin, or tretinoin; vitamin D;
c) antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example platin derivatives like cis-platin, carboplatin, oxaliplatin, lobaplatin, satraplatin, nedaplatin, heptaplatin; nitrogen mustard such as chlorambucil, melphalan, chlormethine, cyclophosphamide, ifosfamide, trofosfamide, uramustine, bendamustine, estramustine; busulphan, temozolomide or nitrosoureas); antimetabolites (for example antifolates such as aminopterin, methotrexate, pemetrexed, raltitrexed); purines such as cladribine, clofarabine, fludarabine, mercaptopurine, pentostatin, thioguanine; pyrimidines like capecitabine, cytarabine, fluorouracil, floxuridine, gemcitabine; azacitidine, decitabine; cytosine arabinoside or hydroxyurea; antitumour antibiotics (for example anthracyclines like aclarubicin, amrubicin, daunomycin, doxorubicin, epirubicin, idarabicin, valrubicin, zorubicine; mitoxantrone; or antibiotics from streptomyces like actinomycin, bleomycin, mitomycin, or plicamycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine or vinorelbine; taxoids like docetaxel, paclitaxel or tesetaxel; epothilones like ixabepilone) and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide; amsacrine, camptothecin, irinotecan, rubitecan, and topotecan);
d) cytostatic agents such as antiestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and idoxifene), oestrogen receptor down regulators (for example fulvestrant), antiandrogens (for example bicalutamide, flutamide, nilutamide, liarozole or cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin or buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5-alpha- reductase such as finasteride;
e) agents which inhibit cancer cell invasion (for example metalloproteinase inhibitors and inhibitors of urokinase plasminogen activator receptor function);
f) inhibitors of growth factor function, for example growth factor antibodies, growth factor receptor antibodies (for example the anti-erbb2 antibody trastuzumab, the anti-erbbl antibody cetuximab and panitumumab, the anti IGF1 R antibody figitumumab), farnesyl transferase inhibitors, MEK inhibitors, tyrosine kinase inhibitors and serine/threonine kinase inhibitors, for example enzastaurin, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, nilotinib, sorafenib, sunitinib, everolimus, sirolimus or temsirolimus;
g) antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, for example the anti-vascular endothelial cell growth factor antibody bevacizumab [Avastin™], lenalidomide or thalidomide;
h) cell cycle inhibitors including for example CDK inhibitors (for example flavopiridol, roscovitine) and other inhibitors of cell cycle checkpoints; inhibitors of aurora kinase and other kinases involved in mitosis and cytokinesis regulation;
i) proteasome inhibitors (for example lactacystin, bortezomib, epoxomicin);
j) HSP90 inhibitors (for example 17-AAG, AT-13387, KOS-953, KOS-1022, CNF-
1010, CNF-2024, IPI-504, IPI-926, SNX 5422, STA-9090, VER-52296, PU-H17 or XL-888); k) Selective COX-2 inhibitors (for example celecoxib), or non selective NSAIDs (for example diclofenac, flurbiprofen, ibuprofen, ketoprofen, or naproxen).
In another aspect, a compound of general formula (I) can be used in combination with radiation therapy and surgery.
In yet another aspect, a compound of general formula (I) may be administered in combination with standard chemotherapy combinations such as, but not restricted to, CMF (cyclophosphamide, methotrexate and 5-fluorouracil), CAF (cyclophosphamide, doxorubicin and 5-fluorouracil), AC (doxorubicin and cyclophosphamide), FEC (5-fluorouracil, epirubicin, and cyclophosphamide), ACT or ATC (doxorubicin, cyclophosphamide, and paclitaxel), or CMFP (cyclophosphamide, methotrexate, 5-fluorouracil and prednisone).
The invention also comprises pharmaceutical compositions characterized by containing one or more active principles of formula (I), in association with pharmaceutically acceptable carrier, excipients and diluents, and eventually other active principles as above disclosed.
The compounds of this invention can be administered via any of the accepted modes of administration or agents for serving similar utilities. Thus, administration can be, for example, oral, parenteral (intravenous, subcutaneous, intramuscular), rectal, topical, transdermal, or using any other route of administration.
The compounds of formula (I) can be pharmaceutically formulated according to known methods. The pharmaceutical compositions can be chosen on the basis of the treatment requirements. Such compositions are prepared by blending and are suitably adapted to oral or parenteral administration, and as such can be administered in the form of tablets, capsules, oral preparations, powders, granules, pills, injectable or infusible liquid solutions, suspensions or suppositories.
Tablets and capsules for oral administration are normally presented in unit dose form and contain conventional excipients such as binders, fillers, diluents, tableting agents, lubricants, detergents, disintegrants, coloring agents, flavoring agents and wetting agents. The tablets can be coated using methods well known in the art.
Suitable fillers include cellulose, mannitol, lactose and other similar agents. Suitable disintegrants include polyvinylpyrrolidone and starch derivatives such as sodium glycolate starch. Suitable lubricants include, for example, magnesium stearate. Suitable wetting agents include sodium lauryl sulfate.
The oral solid compositions can be prepared by conventional methods of blending, filling or tableting. The blending operation can be repeated to distribute the active principle throughout compositions containing large quantities of fillers. Such operations are conventional. Oral liquid preparations can be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or can be presented as a dry product for reconstitution with water or with a suitable vehicle before use. Such liquid preparations can contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel, or hydrogenated edible fats; emulsifying agents, such as lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which can include edible oils), such as almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, such as methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired, conventional flavoring or coloring agents. Oral formulations also include conventional slow- release formulations such as enterically coated tablets or granules.
For parenteral administration (e.g. bolus injection or continuous infusion), fluid unit dosages (e.g. in ampoules or in multi-dose containers) can be prepared, containing the compound and a sterile vehicle. The compound can be either suspended or dissolved, depending on the vehicle and concentration. The parenteral solutions are normally prepared by dissolving the compound in a vehicle, sterilising by filtration, filling suitable vials and sealing. Advantageously, adjuvants such as local anaesthetics, preservatives and buffering agents can also be dissolved in the vehicle. To increase stability, the composition can be frozen after having filled the vials and removed the water under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound can be suspended in the vehicle instead of being dissolved, and sterilized by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent can be included in the composition to facilitate uniform distribution of the compound of the invention.
The compounds can be pharmaceutically formulated as suppositories or retention enemas, e.g. containing conventional suppositories bases such as cocoa butter, polyethylene glycol, or other glycerides, for a rectal administration.
Another means of administering the compounds of the invention regards topical treatment. Topical formulations can contain for example ointments, creams, lotions, gels, solutions, pastes and/or can contain liposomes, micelles and/or microspheres. Examples of ointments include oleaginous ointments such as vegetable oils, animal fats, semisolid hydrocarbons, emulsifiable ointments such as hydroxystearin sulfate, anhydrous lanolin, hydrophilic petrolatum, cetyl alcohol, glycerol monostearate, stearic acid, water soluble ointments containing polyethylene glycols of various molecular weights. A reference for the formulations is the book by Remington ("Remington: The Science and Practice of Pharmacy", Lippincott Williams & Wilkins, 2005). Creams, as known to formulation experts, are viscous liquids or semisolid emulsions, and contain an oil phase, an emulsifier and an aqueous phase. The oil phase generally contains petrolatum and an alcohol such as cetyl or stearic alcohol. The emulsifier in a cream formulation is chosen from non-ionic, anionic, cationic or amphoteric surface-active agents. The monophasic gels contain the organic molecules uniformly distributed in the liquid, which is generally aqueous, but they also preferably contain an alcohol and optionally an oil. Preferred gelling agents are cross-linked acrylic acid polymers (e.g. carbomer-type polymers, such as carboxypolyalkylenes, which are commercially available under the Carbopol™ trademark). Hydrophilic polymers are also preferred, such as polyoxyethylene, polyoxyethylene-polyoxypropylene copolymers and polyvinyl alcohol; cellulose polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate and methylcellulose; gums, such as xanthan gum and tragacanth gum; sodium alginate; and gelatin. Dispersing agents such as alcohol or glycerin can be added for gel preparation. The gelling agent can be dispersed by finely chopping and/or mixing.
A further method of administering the compounds of the invention regards transdermal delivery. Typical transdermal formulations comprise conventional aqueous and non-aqueous vectors, such as creams, oils, lotions or pastes or can be in the form of membranes or medicated patches. One formulation provides that a compound of the invention is dispersed within a pressure sensitive patch that adheres to the skin. This formulation enables the compound to diffuse from the patch to the patient through the skin. For a constant release of the drug through the skin, natural rubber and silicon can be used as pressure sensitive adhesives.
The above-mentioned uses and methods also include the possibility of coadministration of additional therapeutic agents, simultaneously or delayed with respect to the administration of the compound of formula (I).
In the previously mentioned uses and methods, the dosage of the compounds of formula (I), can vary depending upon a variety of factors including the patient type and condition, the degree of disease severity, mode and time of administration, diet and drug combinations. As an indication, they can be administered within a dose range of between 0.001 and 1000 mg/kg/day. The determination of optimum dosages for a particular patient is well known to one skilled in the art.
As is common practice, the compositions are normally accompanied by written or printed instructions for use in the treatment in question.
The present invention comprises metabolic precursors (prodrug) of formula (I) compounds. The term "metabolic precursors" or "prodrug" means compounds having a different structure from that of the compound of formula (I), which after administration to the patient are directly or indirectly transformed into a compound of formula (I) (Bundgaard, H. ed., "Design of Prodrugs", Elsevier, 1985).
It is a further object of the invention, a pharmaceutical composition comprising a compound of formula (I) as above defined or a pharmaceutically acceptable prodrug, solvate or hydrate thereof, with one or more physiologically acceptable carriers or excipients.
In a preferred embodiment the pharmaceutical composition comprises the compound of formula (I) in association with a further active principle, preferably an anti-cancer agent.
The present invention also comprises the process for preparing the compounds of formula (I). Compounds of general formula (I) may be prepared from compounds of general formula (II)
Figure imgf000019_0001
(ll)
wherein R1 is as above defined for general formula (I), by reaction with a compound of general formula (III) or (IV) or (V):
o o
R2— X or R3_JLC| or R3— S- CI
o
(ill) (IV) (V)
wherein R2 and R3 are as above defined for general formula (I), and X is a halogen such as chloro, bromo or iodo or a suitable leaving group such as a mesyl or tosyl group. Typically, the reaction is conducted in an organic solvent such as tetrahydrofuran or dichloromethane, in the presence of a base such as cesium carbonate, Ν,Ν-diisopropylethylamine or potassium t-butoxide, at a temperature ranging from about CTC to reflux.
Compounds of general formula (III) or (IV) or (V) are well known and are either readily available or may be prepared by standard methods known to those of skill in the art.
Compounds of general formula (II), which are compounds of formula (I) where R2 is hydrogen, may be prepared from the compound of formula (VI):
Figure imgf000019_0002
(VI)
which is a known compound (Registry Number: 27463-52-1 ),
by reaction with the alcohol R10H, wherein R1 is as above defined for general formula (I).
The transesterification, i.e. the process of exchanging the organic group ethyl of the ester with the organic group R1 of the alcohol, is preferably catalyzed by the addition of a base such as sodium hydroxide and it may be necessary to heat the reaction mixture, for example to between about 50 and 160°C.
Compounds of general formula (II) may also be prepared from the compound of formula (VII)
Figure imgf000020_0001
which is a known compound (Registry Number: 1239762-82-3), by reaction with the alcohol
R10H, wherein R1 is as above defined for general formula (I). Typically, the reaction is carried out in the presence of a carbodiimide as coupling reagent [i.e. 1 ,3- dicyclohexylcarbodiimide or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)] and a base as catalyst (i.e. 4-dimethylaminopyridine, triethylamine or N,N-diisopropylethylamine).
EDC is often used in combination with hydroxybenzotriazole to increase coupling efficiency.
The reaction takes place at a temperature ranging from about CTC to reflux and suitable solvents are dichloromethane, chloroform, tetrahydrofuran or N,N-dimethylformamide.
It is clear to the person skilled in the art that if a compound of formula (I), prepared according to the above process, is obtained as a mixture of isomers, their separation into the single isomers of formula (I), carried out according to conventional techniques, is still within the scope of the present invention.
Likewise, the salification of the compound of formula (I) or the conversion of its salt into the free compound (I), carried out according to well known procedures in the art, are still within the scope of the invention.
When in the compounds of the invention and the intermediate products thereof, groups are present which may interfere with the here above illustrated reactions, they may be protected before the reactions take place and then deprotected at the end of the reactions, according to well known methods in organic chemistry. A thorough discussion for protection/deprotection steps is provided for example in Greene and Wuts (Greene, T.W.;
Wuts, P.G.M. "Protective Groups in Organic Synthesis", John Wiley & Sons Inc., 2007) or in
Kocienski (Kocienski, P.J. "Protecting Groups", George Thieme Verlag, 2003).
The compounds disclosed in this application, intermediates, and starting materials were named using standard lUPAC nomenclature.
The invention, will be now illustrated by means of non-limiting examples referring to the following figures.
Figure 1 : Compounds destabilize MTs. A. Compounds B, A6, D7, E7 and A8, representing the compounds described in this invention, efficiently destabilize MTs in vitro; nocodazole acted as a positive control. B. Compounds B, A6, D7, E7 and A8 compete with [3H]colchicine for binding to tubulin; combretastatin A-4 acted as the positive control. The structural formulas of the compounds are shown in Table 2. The bars represent standard deviations.
Figure 2: Compounds kill adenomacarcinoma cells. Compounds B, A6, D7, E7 and A8, as in Fig. 1 , trigger mitotic delay and cell death (apoptosis) with high efficiency in HeLa cells (cervical adenomacarcinoma). EXAMPLES
1. CHEMICAL SYNTHESIS
Methods
Unless otherwise indicated, commercially available reagents and solvents (HPLC grade) were used without further purification. Specifically, the following abbreviations may have been used in the descriptions of the experimental methods:
NMR (Nuclear Magnetic Resonance) H (proton)
MHz (Megahertz) Hz (Hertz)
HPLC (High Performance Liquid LC-MS (Liquid Chromatography Mass
Chromatography) Spectrum)
s (seconds) min (minutes) h (hours) mg (milligrams)
g (grams) μΙ (microlitres)
ml (millilitres) mmol (millimoles)
M (molarity) Rt (retention time in minutes)
RT (room temperature) MW (microwave)
CH3CN (acetonitrile) DCM (dichloromethane)
Dl PEA (A/,A/-diisopropylethylamine) DMF (dimethylformamide)
DMSO (dimethyl sulfoxide) DMSO-d6 (deuterated dimethyl sulfoxide)
EDC (1-3(dimethylaminopropyl)-3-
Et20 (diethyl ether)
ethylcarbodiimide hydrochloride)
EtOAc (ethyl acetate) EtOH (ethanol) HCI (hydrochloric acid) HOBt (1-hydroxybenzotriazole)
/'-PrOH (isopropyl alcohol) K2C03 (potassium carbonate)
MeOH (methanol) AcOH (acetic acid)
Na2C03 (sodium carbonate) NaHC03 (sodium hydrogen carbonate)
NaOH (sodium hydroxide) Na2S04 (sodium sulphate)
TEA (triethylamine) TFA (trifluoroacetic acid)
Except where indicated otherwise, all temperatures are expressed in °C (degrees centigrade) or K (Kelvin).
The H-NMR spectra were acquired with a Varian 500 MHz instrument. The chemical shifts are expressed in parts per million (ppm, δ units). The coupling constants are expressed in Hertz (Hz) and the splitting patterns are described as s (singlet), bs (broad singlet), d (doublet), t (triplet), q (quartet), quint (quintet), m (multiplet).
The LC-MS analyses were carried out in accordance with the following method:
Column Acquity UPLC-BEH C18 (50 x 2.1 mm, 1.7 μιη); Phase A: Milli-Q water/CH3CN 95/5 + 0.07% formic acid; Phase B: CH3CN + 0.05% formic acid; flow rate: 0.6 ml/min; UV detection (DIODE array) from 210 to 400 nm; ESI+ detection in the 100-2000 m/z range; HPLC: Waters Acquity UPLC; MS: Micromass SQD Single quadrupole (Waters).
Gradient: 0 min (A:98%, B:2%), 0-3.00 min (A:0%, B:100%), 3.00-3.50 min (A:0%, B:100%), 3.50-4.50 min (A:98%, B:2%).
Example 1
Ethyl 6-(2-furyl)-1 ,3-dimethyl-4-oxo-6 7-dihydro-5H-indole-2-carboxylate
Figure imgf000022_0001
A mixture of ethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate
(0.1 g, 0.35 mmol), cesium carbonate (0.124 g, 0.38 mmol), and iodomethane (0.044 ml, 0.70 mmol), in tetrahydrofuran (1.5 ml) was stirred at 70° C. To complete the reaction, iodomethane (0.044 ml, 0.70 mmol) was added again after 3 hours and the reaction mixture was stirred at 70° C for another 4 hours. The solve nt was evaporated and the residue was taken up with water and extracted with dichloromethane (3x3 ml). The organic layer was dried over Na2S04 and the solid was filtered off. The filtrate was evaporated to dryness and the crude product was purified by flash chromatography, over silica gel, by using hexane/ethyl acetate (80:20) as the eluent, thereby yielding ethyl 6-(2-furyl)-1 ,3-dimethyl-4-oxo-6,7- dihydro-5H-indole-2-carboxylate as a white solid (0.057 g, 0.19 mmol, 53 %).
LC-MS (M+H) = 302.1 ; Rt = 1.80
H NMR (500 MHz, CHLOROFORM-d) δ ppm: 7.29 (d, J=1.47 Hz, 1 H), 6.25 (dd, J=2.93, 1.96 Hz, 1 H), 6.03 (d, J=2.93 Hz, 1 H), 4.26 (q, J=7.34 Hz, 2 H), 3.74 (s, 3 H), 3.51 (dt, J=10.39, 5.32 Hz, 1 H), Part AB of ABX System: VA=3.12, VB=2.85, JAB= 15 Hz, JAX= 5 Hz, JBX= 10 Hz, Part AB of ABX System: VA=2.75, VB=2.65, JAB= 15 Hz, JAX= 4.9 Hz, JBX= 10.1 Hz, 2.55 (s, 3 H), 1.31 (t, J=7.09 Hz, 3 H).
Example 2
Ethyl 1 -benzyl-6-(2-furyl)-3-methyl-4-oxo-6,7-dihydro-5H-indole-2-carboxylate
Figure imgf000023_0001
A mixture of ethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate
(0.1 g, 0.36 mmol), cesium carbonate (0.124 g, 0.38 mmol), and benzylbromide (0.045 ml, 0.70 mmol), in tetrahydrofuran (1.5 ml) was stirred at 70° C for 3 hours. To complete the reaction, benzylbromide (0.045, 0.70 mmol) was added and the reaction mixture was stirred at 70° C for 13 hours. The solvent was evaporated a nd the residue was taken up with dichloromethane (3x3 ml). The organic layer was dried over Na2S04 and the solid filtered off. The filtrate was evaporated to dryness and the crude product was purified by flash chromatography, over silica gel, by using hexane/ethyl acetate (80:20) as the eluent, thereby yielding ethyl 1-benzyl-6-(2-furyl)-3-methyl-4-oxo-6,7-dihydro-5H-indole-2-carboxylate as a white solid (0.106 g, 0.28 mmol, 78 %).
LC-MS (M+H) = 378.2; Rt = 2.17
H NMR (500 MHz, CHLOROFORM-d) δ ppm: 7.14 - 7.25 (m, 5 H), 6.84 (d, J=7.34 Hz, 2 H), 6.20 (dd, J=3.18, 1.71 Hz, 1 H), 5.96 (d, J=3.42 Hz, 1 H), AB System: VA=5.57, VB=5.47, JAB= 15 Hz, 4.17 (q, J=7.34 Hz, 2 H), 3.50 (dt, J=9.78, 4.89 Hz, 1 H), Part AB of ABX System: VA=3.04, VB=2.82, JAB= 17.5 Hz, JAX= 5 Hz, JBX= 10 Hz, Part AB of ABX System: VA=2.75, VB=2.67, JAB= 16.2 Hz, JAX= 2.2 Hz, JBX= 10.3 Hz, 2.59 (s, 3 H), 1.22 (t, J=7.09 Hz, 3 H).
Example 3
Ethyl 1 -ethyl-6-(2-furyl)-3-methyl-4-oxo-6 7-dihydro-5H-indole-2-carboxylate
Figure imgf000024_0001
A mixture of ethyl 1-ethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2- carboxylate (0.070 g, 0.26 mmol), cesium carbonate (0.091 g, 0.28 mmol), and ethyliodide (0.023 ml, 0.28 mmol), in tetrahydrofuran (1.0 ml) was stirred at 70° C. To complete the reaction, two successive additions of ethyl iodide (0.023 ml, 0.28 mmol) were performed. After 5 hours of stirring at 70° C, the reaction wa s complete. Water (1.0 ml) was added to the reaction triggering the precipitation. The resulting suspension was then filtered off and the solid was dried at 60 Ό for 8 hours under vacuum o btaining ethyl 1-ethyl-6-(2-furyl)-3-methyl- 4-oxo-6,7-dihydro-5H-indole-2-carboxylate as a white solid (0.059 g, 0.19 mmol, 72 %).
LC-MS (M+H) = 316.1 ; Rt = 1.95
H NMR (500 MHz, CHLOROFORM-d) δ ppm: 7.29 (d, J=1.47 Hz, 1 H), 7.19 (s, 1 H), 6.25 (dd, J=2.93, 1.96 Hz, 1 H), 6.03 (d, J=3.42 Hz, 1 H), 4.15 - 4.34 (m, 4 H), 3.52 (dt, J=10.39, 5.32 Hz, 1 H), Part AB of ABX System: VA=3.12, VB=2.89, JAB= 15 Hz, JAX= 5 Hz, JBX= 10 Hz, Part AB of ABX System: VA=2.74, VB=2.66, JAB= 16.2 Hz, JAX= 2.2 Hz, JBX= 10.3 Hz, 2.55 (s, 3 H) 1.23 - 1.34 (m, 6 H).
Example 4
Ethyl 1 -acetyl-6-(2-furyl)-3-methyl-4-oxo-6 7-dihydro-5H-indole-2-carboxylate
Figure imgf000024_0002
In a dried round bottom flask, under inert atmosphere, a mixture of N,N- diisopropylethylamine (0.064 ml, 0.378 mmol) and ethyl 6-(2-furyl)-3-methyl-4-oxo-1 , 5,6,7- tetrahydroindole-2-carboxylate (0.1 10 g, 0.36 mmol) in dichloromethane (1.5 ml) was cooled at 0 in an ice bath and stirred for 10 minutes. Acetylchloride (0.27 ml, 0.378 mmol) was then added and the reaction was stirred at room temperature. After 3 hours, in order to reach the completion, acetylchloride (0.10 ml, 0.126 mmol) and N,N-diisopropylethylamine (0.021 ml, 0.126 mmol) were added again and the reaction mixture was stirred at room temperature for 30 min. The reaction was evaporated to dryness under reduced pressure and the crude product was purified by flash chromatography, over silica gel, by using hexane/ethyl acetate (70:30) as the eluent, to give ethyl 1-acetyl-6-(2-furyl)-3-methyl-4-oxo-6,7-dihydro-5H-indole- 2-carboxylate as a white solid (0.074 g, 0.22 mmol, 63 %).
LC-MS (M-28 ) = 302 Rt = 1.85
H NMR (500 MHz, CHLOROFORM-d) δ ppm: 7.27 (d, J=1.47 Hz, 1 H), 6.23 (dd, J=3.18, 1.71 Hz, 1 H), 6.01 (d, J=3.42 Hz, 1 H), 4.29 (q, J=7.34 Hz, 2 H), 3.50 (dt, J=10.27, 5.14 Hz, 1 H), Part AB of ABX System: VA=3.21 , VB=3.03, JAB= 17.5 Hz, JAX= 5 Hz, JBX= 10 Hz, Part AB of ABX System: VA=2.77, VB=2.67, JAB= 16.2 Hz, JAX= 4.8 Hz, JBX= 12.7 Hz, 2.52 (s, 3 H), 2.43 (s, 3 H), 1.31 (t, J=7.09 Hz, 3 H). Example 5
Ethyl 6-(2-furyl)-3-methyl-1 -(4-nitrophenyl)sulfonyl-4-oxo-6,7-dihydro-5H-indole-2- carboxylate
Figure imgf000025_0001
In a dried round bottom flask, under an inert atmosphere, potassium tert-butoxide (0.234 g, 2.09 mmol) was added to a mixture of ethyl 6-(2-furyl)-3-methyl-4-oxo-1 , 5,6,7- tetrahydroindole-2-carboxylate (0.500 g, 1.7 mmol) in dry tetrahydrofuran (17.0 ml) at 0 "C. The resulting mixture was stirred for 20 min at 0*0 , 4-nitro benzene sulfonyl chloride (0.964 g, 4.35 mmol) was then added. After 1 hour of stirring at 0*0, the reaction was diluted with water and extracted with dichloromethane (3x20 ml). The organic layer was dried over Na2S04 and the solid product was filtered off. The filtrate was evaporated to dryness and the crude product was purified by flash chromatography, over silica gel, by using hexane/ethyl acetate (70:30) as the eluent, to give ethyl 6-(2-furyl)-3-methyl-1-(4-nitrophenyl)sulfonyl-4-oxo-6,7- dihydro-5H-indole-2-carboxylate as an off-white solid (0.250 g, 0.53 mmol, 30 %).
LC-MS (M+H) = 473.1 Rt = 2.18 H NMR (500 MHz, CHLOROFORM-d) δ ppm: 8.28 - 8.40 (m, 2 H), 8.1 1 - 8.21 (m, 2 H), 7.26 (d, J=0.98 Hz, 1 H), 6.24 (dd, J=3.42, 1.96 Hz, 1 H), 6.00 (d, J=3.42 Hz, 1 H), 4.27 (q, J=7.34 Hz, 2 H), 3.55 (dt, J=8.80, 4.40 Hz, 1 H), Part AB of ABX System: VA=3.47, VB=3.34, JAB= 17.5 Hz, JAX= 4.9 Hz, JBX= 10.1 Hz, Part AB of ABX System: VA=2.78, VB=2.71 , JAB= 16.2 Hz, JAX= 4.9 Hz, JBX= 7.6 Hz, 2.34 (s, 3 H), 1.28 (t, J=7.09 Hz, 3 H).
By working in an analogous manner the following compound was prepared:
Ethyl 1 -(benzenesulfonyl)-6-(2-furyl)-3-methyl-4-oxo-6,7-dihydro-5H-indole-2- carboxylate
Example 6
Methyl 6-(2-furyl)-3-methyl-4-oxo-1 5,6,7-tetrahydroindole-2-carboxylate
Figure imgf000026_0001
A mixture of ethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate (0.100 g, 0.35 mmol), NaOH (0.016 g, 0.40 mmol), in methanol (10 ml) was stirred at 65° C.
After 3 hours at reflux, the solvent was evaporated and the residue was poured into water and extracted with DCM (3x10 ml). The organic layer was dried over Na2S04 and filtered off.
The filtrate was evaporated to dryness and the crude product was then purified by flash chromatography, over silica gel, by using hexane/ethyl acetate (70:30) as the eluent, to give methyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate as a white solid
(0.070 g, 0.26 mmol, 74%).
LC-MS (M+H) = 274.2; Rt = 1.33.
H NMR (500 MHz, CHLOROFORM-d) δ ppm: 8.92 - 8.75 (m, 1 H), 7.28 (d, J=0.98
Hz, 1 H), 6.24 (dd, J=3.18, 1.71 Hz, 1 H), 6.01 (d, J=3.42 Hz, 1 H), 3.81 (s, 3 H), 3.57 - 3.51 (m, 1 H), Part AB of ABX System: VA=3.1 1 , VB=2.96 JAB= 17.5 Hz, JAX= 4.9 Hz, JBX= 10.1
Hz, 2.80 - 2.73 (m, 1 H), 2.69 - 2.61 (m, 1 H), 2.55 - 2.53 (m, 3 H).
Example 7
Isopropyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate
Figure imgf000027_0001
A mixture of ethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate (0.233 g, 0.81 mmol), NaOH (0.032 g, 0.80 mmol), in isopropanol (30 ml) was stirred at 80° C. After 3 hours at reflux, the solvent was evaporated and the residue was poured into water and extracted with DCM (20 ml x3). The organic layer was dried over Na2S04 and filtered off. The filtrate was evaporated to dryness and the crude product was then purified by flash chromatography, over silica gel, by using hexane/ethyl acetate (70:30) as the eluent, to give isopropyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate as a light yellow solid (0.045 g, 0.15 mmol, 18.5%).
LC-MS (M+H) = 302.2; Rt = 1.74
H NMR (500 MHz, DMSO-d6) δ ppm: 12.01 (br. s., 1 H), 7.64 (s, 1 H), 6.44 (dd, J=3.18, 1.71 Hz, 1 H), 6.20 (d, J=3.42 Hz, 1 H), 5.18 - 5.13 (m, 1 H), 3.66 - 3.62 (m, 1 H), Part AB of ABX System: VA=3.24, VB=3.02, JAB= 16.2 Hz, JAX= 5 Hz, JBX= 7.5 Hz, 2.87 - 2.63 (m, 2 H), 2.54 (s, 3 H), 1.36 (d, J=6.36 Hz, 6 H).
Example 8
2-Dimethylaminoethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate
Figure imgf000027_0002
A mixture of 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylic acid (0.142 g, 0.55 mmol) and DIPEA (0.291 ml, 1.65 mmol) in dry DCM (20 ml) was cooled to 0Ό. EDC (0.126 g, 0.66 mmol) and HOBt (0.101 g, 0. 66 mmol) were added and the mixture was stirred at room temperature for one hour. Ν,Ν-Dimethylethanol amine (0.1 10 ml, 1.1 mmol) was added drop wise and the mixture was stirred overnight at room temperature. The reaction mixture was washed with a saturated NaHC03 solution and brine, dried over Na2S04 and concentrated. The crude residue was purified by flash chromatography, over silica gel, by using DCM/MeOH 98:2 as the eluent to give 2-dimethylaminoethyl 6-(2-furyl)-3-methyl-4-oxo- 1 ,5,6,7-tetrahydroindole-2-carboxylate (0.087 g, 0.26 mmol, 47%) as a white solid. LC-MS (M+H) =331.2; Rt = 0.84.
H NMR (500 MHz, DMSO-d6) δ ppm: 1 1.99 (br. s., 1 H), 7.56 (d, J=0.98 Hz, 1 H), 6.36 (dd, J=3.42, 1.96 Hz, 1 H), 6.12 (d, J=3.42 Hz, 1 H), 4.30 - 4.27 (m, 2 H), 3.58 - 3.55 (m, 1 H), 3.21 - 3.10 (m, 1 H), 2.97 - 2.92 (m, 1 H), 2.70 - 2.60 (m, 2 H), 2.58 - 2.55 (m, 2 H), 2.47 (s, 3 H), 2.18 (s, 6 H).
Example 9
2-Hydroxyethyl 6-(2-furyl)-3-meth l-4-oxo-1 ,5,6,7-tetrahydroindole-2 carboxylate
Figure imgf000028_0001
A mixture of 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylic acid
(0.179 g, 0.69 mmol) and TEA (0.143 ml, 1.03 mmol) in DCM dry (8 ml) was cooled to 0 . EDC (0.197 g, 1.03 mmol) and HOBt (0.158 g, 1.03 mmol) were added and the mixture was stirred at room temperature for one hour. Ethane-1 ,2-diol (0.046 ml, 0.82 mmol) was added dropwise and the mixture was stirred at RT. In order to affect completion, additional ethane- 1 ,2-diol (0.046 ml, 0.82 mmol) and DIPEA (0.245 ml, 1.382 mmol) were added after 18 hours and the reaction mixture was stirred at room temperature for further 72 hours. The reaction mixture was washed with a saturated NaHC03 solution and brine, dried over Na2S04 and concentrated. The crude residue was purified by flash chromatography, over silica gel, by using DCM/MeOH 98:2 as the eluent to give 2-hydroxyethyl 6-(2-furyl)-3-methyl-4-oxo- 1 ,5,6,7-tetrahydroindole-2-carboxylate (0.074 g, 0.24 mmol, 35%) as a yellow solid.
LC-MS (M+H) = 304.1 ; Rt = 1.13.
H NMR (500 MHz, DMSO-d6) δ ppm: 12.06 (s, 1 H), 7.63 (d, J=1.47 Hz, 1 H), 6.44 (dd, J=3.18, 1.71 Hz, 1 H), 6.20 (d, J=2.93 Hz, 1 H), 4.91 (br. s., 1 H), 4.37 - 4.21 (m, 2 H), 3.73 (br. s., 2 H), 3.67 - 3.63 (m, 1 H), Part AB of ABX System: VA=3.24, VB=3.03 JAB= 15 Hz, JAX= 5 Hz, JBX= 10 Hz, 2.78 - 2.64 (m, 2 H), 2.55 (s, 3 H).
Example 10
Stage 1 : tert-butyl N-(2-hydroxyethyl)-N-methyl-carbamate
Figure imgf000029_0001
tert-Butyl N-(2-hydroxyethyl)-N-methyl-carbamate (1 .14 g, 6.51 mmol, 98%) as colorless oil was obtained from 2-(methylamino) ethanol (0.5 g, 0.53 ml, 6.66 mmol) following the procedure described in US20090042872 Example 8, Step 1 , pag. 19.
Stage 2: 2-(tert-butoxycarbonyl(methyl)amino)ethyl 6-(2-furyl)-3-methyl-4-oxo-1 , 5,6,7- tetrahydroindole-2-carboxylate
Figure imgf000029_0002
A mixture of 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylic acid (0.250 g, 0.96 mmol) and DIPEA (0.51 1 ml, 2.88 mmol) in DCM dry (30 ml) was cooled to 0Ό. EDC (0.220 g, 1.15 mmol) and HOBt (0.176 g, 1. 15 mmol) were added and the mixture was stirred at room temperature for one hour. tert-Butyl N-(2-hydroxyethyl)-N-methyl- carbamate (0.336 g, 1.92 mmol) was added drop wise and the mixture was stirred at room temperature for 72 hours. The reaction mixture was washed with a saturated NaHC03 solution and brine, dried over Na2S04 and concentrated. The crude residue was purified by flash chromatography, over silica gel, by using DCM/MeOH 98:2 as the eluent to give 2-(tert- butoxycarbonyl(methyl)amino)ethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2- carboxylate (0.300 g, 0.72 mmol, 75%) as a yellow solid.
LC-MS (M+Na) =439.2; Rt = 1.81
H NMR (500 MHz, DMSO-d6) δ ppm: 12.14 - 1 1.94 (m, 1 H), 7.55 (s, 1 H), 6.36 (br. s., 1 H), 6.10 (br. s., 1 H), 4.33 - 4.30 (m, 2 H), 3.59 - 3.53 (m, 1 H), 3.51 - 3.49 (m, 2 H), 3.20 - 2.88 (m, 2 H), 2.86 - 2.76 (m, 3 H), 2.71 - 2.55 (m, 2 H), 2.45 (s, 3 H), 1.42 - 1.16 (m, 9 H).
Stage 3: 2-methylaminoethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2- carboxylate hydrochloride
Figure imgf000030_0001
1 M HCI in Et20 (10 ml, 10 mmol) was added drop wise to a solution of 2-(tert- butoxycarbonyl(methyl)amino)ethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7 -tetrahydroindole-2- carboxylate (0.150 g, 0.36 mmol) in DCM (3 ml) and the mixture was stirred at room temperature for 2 h. The precipitate was collected by filtration, washed with DCM, and dried under vacuum to give 2-methylaminoethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole- 2-carboxylate as a grey solid hydrochloride salt (0.008 g, 0.02 mmol, 5.5%).
LC-MS (M+H) =317.1 ; Rt = 0.91.
H NMR (500 MHz, DMSO-d6) δ ppm: 12.37 (br. s., 1 H), 8.92 (br. s., 1 H), 7.56 (s, 1 H), 6.37 (br. s., 1 H), 6.12 (d, J=2.93 Hz, 1 H), 4.40 - 4.38 (m, 2 H), 3.62 - 3.58 (m, 1 H), 3.28 (br. s., 2 H), 3.25 - 2.91 (m, 2 H), 2.74 - 2.59 (m, 5 H), 2.49 - 2.46 (m, 3 H).
2. BIOLOGICAL TESTING 2.1 Inhibition of tubulin polymerization
The abilities of a set of agents (their structures are shown in Table 1 ) that represent the compounds described in this patent application to inhibit tubulin polymerization in vitro were assayed using a fluorescence-based Tubulin Polymerization Assay (Cytoskeleton, Inc.; Cat. Number BK01 1 P), according to the manufacturer's instructions. In short, the half-area 96 well assay plate (Black, Flat Bottom, Corning Costar Cat. 3686) was pre-warmed to 37*C prior to use; 5 μΙ of 10x stock solutions of the compounds were added to each well, followed by the addition of 45 μΙ of an ice-cold tubulin reaction mix (80 mM PIPES pH 6.9, 2 mM MgCI2, 0.5 mM EGTA, 1 mM GTP, 20% Glycerol, 1.9 mg/ml Porcine Brain Tubulin, 10 μΜ fluorescent reporter). The final DMSO concentration was 1 %. The compounds were assayed at 5 μΜ.
Polymerization was tracked as an increase in fluorescence due to the incorporation of a fluorescent reporter into the MTs as polymerization occurred. Readings (every 1 min for 60 min) were taken at an excitation wavelength of 360 nm and an emission wavelength of 465 nM (TECAN - INFINITE F200). All the data points were in duplicates and 1 % DMSO served as the positive control (no effect on tubulin polymerization), while 5mM CaCI2 plus 1 % DMSO served as the negative control (inhibition of tubulin polymerization). The percentage of tubulin polymerization in the presence of each compound was calculated relative to the degree of polymerization in the presence of 1 % DMSO (=100%) and 5 mM CaCI2 plus 1 % DMSO (=0%). Colchicine (Sigma) was used as standard reference. As compared to colchicine, all the compounds of the invention showed a significant tubulin-inhibiting activity as determined at 5 μΜ (Table 1 ).
Table 1 : Degree of inhibition of tubulin polymerization by various compounds (at 5 μΜ). Anti- tubulin agent colchicine served as the positive control.
Figure imgf000031_0001
Figure imgf000032_0001
0
ethyl 6-(2-furyl)-1 ,3-dimethyl-4-oxo- 6,7-dihydro-5H-indole-2-carboxylate C
0
ethyl 1 -acetyl-6-(2-furyl)-3-methyl-4- oxo-6,7-dihydro-5H-indole-2-
B
carboxylate
Categories of inhibition of tubulin polymerization: A, >70%; B, between 70% and 40%; C, between 40% and 10%.
2.2 Destabilization of MTs
To probe the ability of a subset of representative compounds (B, A6, D7, E7 and A8; their structures are shown in Table 2), to destabilize polymerized MTs, various concentrations of each compound were added 5 min after initiation of tubulin assembly from 10 mM β- tubulin in BRB-80 buffer (80 mM PIPES pH 6.8, 1 mM MgCI2, 1 mM EGTA). Tubulin polymerization was monitored turbidimetrically at 350 nm in a temperature controlled (37 Ό) spectrophotometer (SpectraMax Plus384, Molecular Devices). The decrease in protein turbidity (350 nm) resulting from MT depolymerization following the addition of a compound was tracked for 15 min at 37 Ό ( Gaskin F et al. J Mo! Biol, 1974, 89: 737-58). The compound concentration that inhibited tubulin assembly by 50% was determined. The data are plotted in Fig. 1A. The anti-tubulin drug nocodazole acted as the positive control. All compounds exhibited a significant ability to destabilize polymerized MTs, a characteristic of all tubulin- inhibiting agents.
Table 2. Structures of compounds B, A6, D7, E7, A8
Cpd Name Structure
tetrahyd rof u ran-2-yl methyl 6-(2-f u ry I)- 0
3- methyl-4-oxo-1 , 5,6,7-
B
tetra hyd ro i n d ol e-2-ca rboxy I ate O - O—/
O
cyclohexyl 6-(2-furyl)-3-methyl-4-oxo-
A6 1 ,5,6,7-tetrahydroindole-2-carboxylate
< J H [(E)-but-2-enyl] 6-(2-furyl)-3-methyl-4- 0
oxo-1 ,5,6,7-tetrahydroindole-2-
D7
carboxylate
0
allyl 6-(2-furyl)-3-methyl-4-oxo-
E7 1 ,5,6,7-tetrahydroindole-2-carboxylate
2-ethylsulfanylethyl 6-(2-furyl)-3- 0
methyl-4-oxo-1 ,5,6,7-tetrahydroindole-
A8
2-carboxylate
2.3 Compound-[3H]colchicine competition for binding to tubulin.
The binding of the compounds to tubulin in the presence of radiolabeled [3H]colchicine was measured by the DEAE-cellulose filter method (Kang GJ et al J. Biol. Chem, 1990, 265: 10255-10259). Reaction mixtures contained 1 mM β-tubulin, 1 M monosodium glutamate, 0.1 M glucose-1 -phosphate, 1 mM MgCI2, 1 mM GTP, 0.5 mg/mL BSA, 5% DMSO, 5 mM [3H]colchicine, and compound at 1 , 5, 20 or 50 mM. These reaction conditions strongly stabilize the colchicines-binding activity of tubulin (Hamel E, Lin CM, Biochim. Biophys. Acta 1981 , 675, p. 226-231 ).
Using this assay, the compounds shown in Table 2 were tested using combrestatin A- 4 as the positive control. Results are reported in Fig. 1 B. As shown in Fig. 1 B, compounds A6, D7, E7 and A8 actively competed with radiolabeled colchicine for binding to tubulin, illustrating that they target tubulin.
2.4 Ability of the compounds to trigger mitotic arrest and cell death
The ability of a representative subset of tubulin-targeting compounds (Table 2) to prevent spindle formation resulting in SAC activation (mitotic delay) and cell death (apoptosis) was probed using HeLa cells (Figure 2). HeLa cells synchronized in S phase using 2.5 mM thymidine were released into growth medium containing 100 nM or 500 nM of each compound. Cell growth, duration of the mitotic delay, and percentage of cells undergoing cell death were scored following live-cell videomicroscopy. 2.5 Ability of the compounds to eradicate proliferating cancer cells, including those that are multidrug resistant.
The HCT-1 16 (ATCC, CCL-247) and HCT-15 (DSMZ, ACC-357) cancer cell lines were used for cell proliferation assays. The HCT-15 cell line is multi-drug resistant as it expresses elevated levels of the drug efflux pump MDR1 (Alvarez M et al., 1995, J Clin
Invest, 95: 2205-2214). HCT-1 16 and HCT-15 cells were maintained in McCoy's medium supplemented with 10% Fetal Bovine Serum and Antibiotics and RPMI medium containing
10% Fetal Bovine Serum and Antibiotics, respectively.
Cell growth and viability in the presence of our compounds (the tested compounds are shown in Table 3) was measured using the CellTiter-Glo® Luminescent Cell Viability Assay
(Promega). This assay allows the determination of the number of viable cells in culture based on the quantification of adenosine triphosphate (ATP) released by metabolically active cells.
The assay procedure involves addition of a single reagent (CellTiter-Glo® Reagent) directly to the cells, which leads to cell lysis and generation of a luminescent signal proportional to the amount of the ATP and the number of cells present in culture. The assay relies on the properties of a proprietary thermostable luciferase (Ultra-Glo® recombinant luciferase), which generates a luminescent signal.
Cells were seeded (3000 cells/well) in 96 well plates (White Polystyrene, Flat Bottom,
Corning Costar Cat.3917) 24h before compound treatment. The cells, in exponential growth, were incubated for 72 h with different concentrations of compounds. After 72 h, a volume of
CellTiter-Glo® Reagent equal to the volume of cell culture medium was added. The content was mixed for 2 min to induce cell lysis. The luminescence was recorded after further 15 min at RT in order to obtain a stabilized luminescent signal.
The Gl50 values (compound concentration that inhibited cell growth by 50%) for each compound were calculated using GraphPad Software. As illustrated by Table 3, all compounds of the invention have an equivalent potency on both the multidrug resistant
(HCT15) and non-resistant (HCT1 16) cell lines. Table 3. Growth inhibition (Gl50) of representative compounds of the invention on cancer cell lines that are multi-drug sensitive (HCT1 16) or multi-drug resistant (HCT15)
Figure imgf000036_0001
Figure imgf000037_0001
Categories of Gl50: A, <250 nM; B, between 250 nM and 1 μΜ; C, >1 μΜ.

Claims

1. A compound of general formula (I)
Figure imgf000038_0001
(I)
or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, wherein:
R1 is selected from hydrogen, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyi, C5-C7 cycloalkenyl, aryl, heteroaryl, or C3-C7 heterocyclyl, any of which may optionally be substituted;
R2 is hydrogen, d-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyi, C5-C7 cycloalkenyl, aryl, heteroaryl, C3-C7 heterocyclyl, C(0)R3 or S02R3 any of which may optionally be substituted, where:
R3 is independently hydrogen, C C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyi, C5-C cycloalkenyl, aryl, heteroaryl, C3-C heterocyclyl or 0(Ci-C6 alkyl), any of which may optionally be substituted;
when the alkyl, alkenyl and alkynyl groups are substituted, there are one or more substituents selected from:
(i) C3-C7 cycloalkyi, C5-C7 cycloalkenyl, aryl, heteroaryl, C3-C7 heterocyclyl, any of which may, in turn, be substituted with one or more substituents selected from halogen, - OR4, -SR4, -NR4R4', -C(0)R4, -C02R4, -C(0)NR4R4', -S(0)R4, -S02R4, -S02NR4R4', - OC(0)R4\ -N(R4)C(0)R4\ -N(R4)S02R4', -CN, or -N02; wherein R4 and R4' are each independently hydrogen, Ci-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; or
(ii) -OR5, -SR5, -NR5R5', -C(0)R5, -C02R5, -C(0)NR5R5', -S(0)R5, -S02R5, or -S02NR5R5', -OC(0)R5\ -N(R5)C(0)R5', or -N(R5)S02R5', halogen, -CN, or -N02; wherein R5 and R5' are each independently hydrogen, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C cycloalkyi, C5-C cycloalkenyl, aryl, heteroaryl, or C3-C heterocyclyl;
when cycloalkyi, heterocyclyl, aryl and heteroaryl groups are substituted, there are one or more substituents selected from:
(i) Ci-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, any of which may be substituted as defined above; or (ii) C3-C7 cycloalkyl, C5-C7 cycloalkenyl, aryl, heteroaryl, C3-C7 heterocyclyl, any of which may, in turn, be substituted with one or more substituents selected from halogen, - OR6, -SR6, -NR6R6', -C(0)R6, -C02R6, -C(0)NR6R6', -S(0)R6, -S02R6, -S02NR6R6', - OC(0)R6, -N(R6)C(0)R6', -N(R6)S02R6', -CN, or -N02; wherein R6 and R6' are each independently hydrogen, Ci-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; or
(iii) -OR7, -SR7, -NR7R7', -C(0)R7, -C02R7, -C(0)NR7R7', -S(0)R7, -S02R7, or -S02NR7R7', -OC(0)R7, -N(R7)C(0)R7', or -N(R7)S02R7', halogen, -CN, or -N02; wherein R7 and R7' are each independently hydrogen, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C5-C7 cycloalkenyl, aryl, heteroaryl, or C3-C7 heterocyclyl;
with the provision that the following compounds are not comprised:
6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylic acid,
ethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate,
propyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate,
isobutyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate,
pentyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate,
hexyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate,
allyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate,
but-2-enyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate,
[(E)-but-2-enyl] 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate,
2-methylsulfanylethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate, 2-ethylsulfanylethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate, 2-methoxyethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate,
2-ethoxyethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate,
2-isopropoxyethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate,
2-propoxyethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate,
2-phenoxyethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate,
cyclopentyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate,
cyclohexyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate,
cyclohexylmethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate, tetrahydrofuran-2-ylmethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate, p-tolylmethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate,
benzyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate,
ethyl 1-(2-diethylaminoethyl)-6-(2-furyl)-3-methyl-4-oxo-6,7-dihydro-5H-indole-2-carboxylate, ethyl 1-(2-dimethylaminoethyl)-6-(2-fuiyl)-3-methyl-4-oxo-6J-dihydro-5H-indole-2- carboxylate.
2. The compound according to claim 1 , wherein R1 is selected from methyl, isopropyl or substituted ethyl wherein the substituent is selected from:
(i) C3-C7 cycloalkyi, C5-C7 cycloalkenyl, aryl, heteroaryl, C3-C7 heterocyclyl, any of which may, in turn, be substituted with one or more substituents selected from halogen, - OR4, -SR4, -NR4R4', -C(0)R4, -C02R4, -C(0)NR4R4', -S(0)R4, -S02R4, -S02NR4R4', - OC(0)R4\ -N(R4)C(0)R4', -N(R4)S02R4', -CN, or -N02; wherein R4 and R4' are each independently hydrogen, Ci-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; or
(ii) -OH, -NR5R5', -C(0)R5, -C02R5, -C(0)NR5R5', -S(0)R5, -S02R5, or - S02NR5R5', -OC(0)R5', -N(R5)C(0)R5', or -N(R5)S02R5', halogen, -CN, or -N02; wherein R5 and R5' are each independently hydrogen, C C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyi, C5-C7 cycloalkenyl, aryl, heteroaryl, or C3-C7 heterocyclyl.
3. The compound according to claim 1 or 2, wherein R2 is selected from hydrogen, methyl, ethyl, benzyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyi, C5-C7 cycloalkenyl, aryl, heteroaryl, C3-C7 heterocyclyl, C(0)R3 or S02R3 where:
R3 is independently hydrogen, C C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyi, C5-C7 cycloalkenyl, aryl, heteroaryl, C3-C7 heterocyclyl or 0(Ci-C6 alkyl), any of which may optionally be substituted.
4. The compound according to any of the previous claims, wherein R1 is selected from methyl, 2-hydroxyethyl, 2-methylaminoethyl, 2-dimethylaminoethyl, isopropyl group.
5. The compound according to any of the previous claims, wherein R2 is selected from hydrogen, methyl, ethyl, benzyl, acetyl, 4-nitrophenylsulfonyl, benzenesulfonyl group.
6. The compound according to any of previous claims, belonging to the following group: methyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
2-hydroxyethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
2-methylaminoethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
2-dimethylaminoethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate; isopropyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
ethyl 6-(2-furyl)-1 ,3-dimethyl-4-oxo-6,7-dihydro-5H-indole-2-carboxylate;
ethyl 1-ethyl-6-(2-furyl)-3-methyl-4-oxo-6,7-dihydro-5H-indole-2-carboxylate;
ethyl 1-benzyl-6-(2-furyl)-3-methyl-4-oxo-6,7-dihydro-5H-indole-2-carboxylate;
ethyl 1-acetyl-6-(2-furyl)-3-methyl-4-oxo-6,7-dihydro-5H-indole-2-carboxylate;
ethyl 6-(2-fuiyl)-3-methyl-1-(4-nitrophenyl)sulfonyl-4-oxo-6J-dihydro-5H-indole-2-carboxylate; ethyl 1-(benzenesulfonyl)-6-(2-fuiyl)-3-methyl-4-oxo-6,7-dihydro-5H-indole-2-carboxylate.
7. A compound of general formula (I)
Figure imgf000041_0001
(I)
or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, wherein:
R1 is selected from hydrogen, C C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C5-C7 cycloalkenyl, aryl, heteroaryl, or C3-C7 heterocyclyl, any of which may optionally be substituted;
R2 is hydrogen, C^-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C5-C7 cycloalkenyl, aryl, heteroaryl, C3-C7 heterocyclyl, C(0)R3 or S02R3 any of which may optionally be substituted, where:
R3 is independently hydrogen, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C cycloalkyl, C5-C cycloalkenyl, aryl, heteroaryl, C3-C heterocyclyl or 0(Ci-C6 alkyl), any of which may optionally be substituted;
wherein when the alkyl, alkenyl and alkynyl groups are substituted, there are or more substituents selected from:
(i) C3-C cycloalkyl, C5-C cycloalkenyl, aryl, heteroaryl, C3-C heterocyclyl, any of which may, in turn, be substituted with one or more substituents selected from halogen, -
OR4, -SR4, -NR4R4', -C(0)R4, -C02R4, -C(0)NR4R4', -S(0)R4, -S02R4, -S02NR4R4', - OC(0)R4', -N(R4)C(0)R4', -N(R4)S02R4', -CN, or -N02; wherein R4 and R4' are each independently hydrogen, Ci-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; or
(ii) -OR5, -SR5, -NR5R5', -C(0)R5, -C02R5, -C(0)NR5R5', -S(0)R5, -S02R5, or -S02NR5R5', -OC(0)R5', -N(R5)C(0)R5', or -N(R5)S02R5', halogen, -CN, or -N02; wherein R5 and R5' are each independently hydrogen, C C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyi, C5-C7 cycloalkenyl, aryl, heteroaryl, or C3-C7 heterocyclyl;
wherein when cycloalkyi, heterocyclyl, aryl and heteroaryl groups are substituted, there are one or more substituents selected from:
(i) Ci-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl, any of which may be substituted as defined above; or
(ii) C3-C7 cycloalkyi, C5-C7 cycloalkenyl, aryl, heteroaryl, C3-C7 heterocyclyl, any of which may, in turn, be substituted with one or more substituents selected from halogen, - OR6, -SR6, -NR6R6', -C(0)R6, -C02R6, -C(0)NR6R6', -S(0)R6, -S02R6, -S02NR6R6', - OC(0)R6, -N(R6)C(0)R6', -N(R6)S02R6', -CN, or -N02; wherein R6 and R6' are each independently hydrogen, Ci-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; or
(iii) -OR7, -SR7, -NR7R7', -C(0)R7, -C02R7, -C(0)NR7R7', -S(0)R7, -S02R7, or -S02NR7R7', -OC(0)R7, -N(R7)C(0)R7', or -N(R7)S02R7', halogen, -CN, or -N02; wherein R7 and R7' are each independently hydrogen, C C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyi, C5-C7 cycloalkenyl, aryl, heteroaryl, or C3-C7 heterocyclyl;
for use in the treatment of cell proliferative disorders.
8. A compound of formula (I) according to claim 7 wherein:
R1 is selected from C C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyi, C5-C7 cycloalkenyl, aryl, heteroaryl, or C3-C7 heterocyclyl, any of which may optionally be substituted with one or more substituents chosen from OH, Ci-C6 alkoxy, 0-C3-C7 cycloalkyi, O-aryl, aryl, heteroaryl, C3-C7 cycloalkyi, C3-C7 heterocyclyl, Ci-C6 alkylthiol, Ci-C6 alkylamino or Ci-C6 dialkylamino; and
R2 is hydrogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C7 cycloalkyi, aryl, heteroaryl, C3-C7 heterocyclyl, C(0)R3 or S02R3 any of which may optionally be substituted by aryl or heteroaryl, where:
R3 is independently C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C7 cycloalkyi, aryl, heteroaryl, C3-C7 heterocyclyl or C1-C4 alkoxy, any of which may optionally be substituted by halogen, -CN, or -N02;
for use in the treatment of cell proliferative disorders.
9. A compound of formula (I) according to claims 7 or 8, wherein: R1 is selected from C^-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyi, any of which may optionally be substituted with one or more substituents chosen from OH, Ci-C6 alkoxy, O-C3-C7 cycloalkyi, O-aryl, aryl, heteroaryl, C3-C7 cycloalkyi, C3-C7 heterocyclyl, Ci-C6 alkylthiol, Ci-C6 alkylamino or CrC6 dialkylamino; and
R2 is hydrogen, C1-C4 alkyl, which may optionally be substituted with one or more substituents chosen from aryl or heteroaryl, C(0)R3 or S02R3,
wherein R3 is independently C1-C4 alkyl or aryl, any of which may optionally be substituted by halogen, -CN, or -N02;
for use in the treatment of cell proliferative disorders.
10. A compound of formula (I) according to any of claims 7-9, belonging to the following group:
ethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
propyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
isobutyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
pentyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
hexyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
allyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
[(E)-but-2-enyl] 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
2-methoxyethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
2-ethoxyethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
2-isopropoxyethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
2-propoxyethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
2-phenoxyethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
2-methylsulfanylethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
2-ethylsulfanylethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
cyclopentyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
cyclohexyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
cyclohexylmethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
tetrahydrofuran-2-ylmethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate; benzyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
p-tolylmethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
methyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate; 2-hydroxyethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
2-methylaminoethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
2-dimethylaminoethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
isopropyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
ethyl 6-(2-furyl)-1 ,3-dimethyl-4-oxo-6,7-dihydro-5H-indole-2-carboxylate;
ethyl 1-ethyl-6-(2-furyl)-3-methyl-4-oxo-6,7-dihydro-5H-indole-2-carboxylate;
ethyl 1-benzyl-6-(2-furyl)-3-methyl-4-oxo-6,7-dihydro-5H-indole-2-carboxylate;
ethyl 1-acetyl-6-(2-furyl)-3-methyl-4-oxo-6,7-dihydro-5H-indole-2-carboxylate;
ethyl 6-(2-furyl)-3-methyl-1-(4-nitrophenyl)sulfonyl-4-oxo-6,7-dihydro-5H-indole-2-carboxylate; ethyl 1-(benzenesulfonyl)-6-(2-furyl)-3-methyl-4-oxo-6,7-dihydro-5H-indole-2-carboxylate; for use in the treatment of cell proliferative disorders.
1 1. A compound of formula (I) according to claim 10, being:
ethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
propyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
allyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
[(E)-but-2-enyl] 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
2-methoxyethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
2-propoxyethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
2-methylsulfanylethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
2-ethylsulfanylethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
cyclopentyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
cyclohexyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
tetrahydrofuran-2-ylmethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate; benzyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
methyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
2-hydroxyethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
2-methylaminoethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
2-dimethylaminoethyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
isopropyl 6-(2-furyl)-3-methyl-4-oxo-1 ,5,6,7-tetrahydroindole-2-carboxylate;
ethyl 6-(2-furyl)-1 ,3-dimethyl-4-oxo-6,7-dihydro-5H-indole-2-carboxylate;
ethyl 1-ethyl-6-(2-furyl)-3-methyl-4-oxo-6,7-dihydro-5H-indole-2-carboxylate;
ethyl 1-benzyl-6-(2-furyl)-3-methyl-4-oxo-6,7-dihydro-5H-indole-2-carboxylate; ethyl 1-acetyl-6-(2-furyl)-3-methyl-4-oxo-6,7-dihydro-5H-indole-2-carboxylate; ethyl 6-(2-fuiyl)-3-methyl-1-(4-nitrophenyl)sulfonyl-4-oxo-6J-dihydro-5H-indole-2-carboxylate; for use in the treatment of cell proliferative disorders.
12. The compound according to any of claims 7 to 1 1 , wherein the cell proliferative disorder is cancer.
13. The compound according to claim 13, wherein the cell proliferative disorder is a multidrug resistant cancer.
14. A pharmaceutical composition comprising a compound of formula (I) as defined in claims 7-13 or a pharmaceutically acceptable prodrug, solvate or hydrate thereof, with one or more physiologically acceptable carriers or excipients.
15. The pharmaceutical composition according to claim 14, wherein the compound of formula (I) is present in association with a further active principle.
16. The pharmaceutical composition according to claim 15, wherein the further active principle is an anti-cancer agent.
17. Process for preparing the compound of general formula (I) as defined in claims 1- 1 1 , comprising the reaction of a compound of general formula (II)
Figure imgf000045_0001
(II)
wherein R1 is as above defined for general formula (I), with a compound of general formula (III) or (IV) or (V):
o o
R2— X or R3_JLc! or R3_s- CI
o
(III) (IV) (V) wherein R2 and R3 are as above defined for general formula (I), and X is a halogen or a suitable leaving group;
wherein the reaction is conducted in an organic solvent, in the presence of a base at a temperature ranging from about CTC to reflux.
18. Process according to claim 17, wherein the compound of general formula (II) is prepared from the compound of formula (VI):
Figure imgf000046_0001
(VI)
by reaction with an alcohol R10H, wherein R1 is as above defined for general formula (I), optionally in the presence of a base, and at a temperature ranging from about 50Ό to 160 °C.
19. Process according to claim 17, wherein the compound of general formula (II) is prepared from the compound of formula (VII)
Figure imgf000046_0002
(VII)
by reaction with the alcohol R10H, wherein R1 is as above defined for general formula (I), in the presence of a carbodiimide as coupling reagent, a base, and optionally in the presence of hydroxybenzotriazole; wherein the reaction takes place at a temperature ranging from about 0*0 to reflux in a solvent.
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