WO2009146152A2 - Composés non myélosuppresseurs, leurs compositions pharmaceutiques, et procédés de traitement - Google Patents

Composés non myélosuppresseurs, leurs compositions pharmaceutiques, et procédés de traitement Download PDF

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Publication number
WO2009146152A2
WO2009146152A2 PCT/US2009/039679 US2009039679W WO2009146152A2 WO 2009146152 A2 WO2009146152 A2 WO 2009146152A2 US 2009039679 W US2009039679 W US 2009039679W WO 2009146152 A2 WO2009146152 A2 WO 2009146152A2
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group
cancer
compound
alkyl
alkenyl
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WO2009146152A3 (fr
Inventor
James P. Snyder
Ana A. Alcaraz
David George Ian Kingston
Qiao-hong CHEN
Thota Ganesh
Paraskevi Giannakakou
Susan Bane
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Emory University
Cornell University
Virginia Tech Intellectual Properties Inc
Research Foundation of the State University of New York
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Emory University
Cornell University
Virginia Tech Intellectual Properties Inc
Research Foundation of the State University of New York
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Publication of WO2009146152A2 publication Critical patent/WO2009146152A2/fr
Publication of WO2009146152A3 publication Critical patent/WO2009146152A3/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
    • C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems

Definitions

  • 2-Methoxyestradiol also called 2ME2 or PANZEM ®
  • 2ME2 microtubule-targeting drug
  • PANZEM ® microtubule-targeting drug
  • Data from those clinical trials has shown clinical efficacy, including cases of stable disease in patients with advanced breast cancer and multiple myeloma and a durable partial response in a patient with ovarian carcinoma who had failed three prior chemotherapy regimens.
  • the safety data from those clinical trials have demonstrated that 2ME2 is very well tolerated with moderate side effects. This is in marked contrast with other approved MTDs widely used in cancer chemotherapy such as the taxanes and Vinca alkaloids.
  • Clinical administration of these drugs is known to induce severe adverse effects, mostly associated with peripheral neuropathy and myelosuppression, which limit the clinical applicability of MTDs and diminish their efficacy.
  • R 2 is selected from the group consisting of aryl, alkaryl, alkenaryl, alkynaryl, heteroaryl, heteroalkenyl, alkyl, alkenyl, cyclo-alkyl, aryloxy, alkoxy, or alkenoxy;
  • FIG. 11 illustrates the specificity of H ⁇ l tubulin antibody tested by Western blot analysis of total cell extracts from hematopoietic tissue or the epithelial cancer cell lines PC3 (prostate), HT-29 (colorectal) and 1A9 (ovarian) and 1A9 cells transiently transfected with an H ⁇ l-encoding plasmid; evidence for the presence of tubulin in all samples is shown by the positive staining for total ⁇ -tubulin (DM 1 ⁇ );
  • FIG. 12 provides confocal images of 1A9 transiently transfected with a full length H ⁇ l plasmid; cells were treated overnight with the indicated drug concentrations; cells were co-stained with ⁇ -tubulin (clone 2.1) and H ⁇ l-specific antibodies; DNA was counterstained with DAPI;
  • compound as used herein means a chemical entity, whether in the solid, liquid, or gaseous phase, and whether in a crude mixture or purified and isolated.
  • alkyl refers to methyl, trifluoromethyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, t-butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, cyclohexylmethyl, 3-methylpentyl, 2,2-dimethybutyl, and 2,3- dimethylbutyl.
  • Substituted alkenyl refers to alkenyl substituted with one or more moieties selected from the group consisting of halo (e.g., Cl, F, Br, and I); halogenated alkyl (e.g., CF 3 , 2-Br-ethyl, CH 2 F, CH 2 Cl, CH 2 CF 3 , or CF 2 CF 3 ); hydroxyl; amino; carboxylate; carboxamido; alkylamino; arylamino; alkoxy; aryloxy; nitro; azido; cyano; thio; sulfonic acid; sulfate; phosphonic acid; phosphate; and phosphonate.
  • heteroalkenyl as used herein means an alkenyl group as described above having one or more carbon atoms replace with a heteroatom, such as N, O, or S.
  • alkynyl as used herein means alkyl moieties wherein at least one saturated C-C bond is replaced by a triple bond.
  • alkynyl refers to groups comprising 1 to 10 carbon atoms ("C 1-10 alkynyl”).
  • alkynyl refers to groups comprising 1 to 8 carbon atoms (“C 1-8 alkynyl”), 1 to 6 carbon atoms (“Ci_ 6 alkynyl”), or 1 to 4 carbon atoms (“C 1-4 alkynyl”).
  • alkynyl can be ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1- pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1- hexynyl, 2-hexynyl, 3-hexynyl, A- hexynyl, or 5 -hexynyl.
  • aryl as used herein means a stable monocyclic, bicyclic, or tricyclic carbon ring of up to 8 members in each ring, wherein at least one ring is aromatic as defined by the Huckel 4n+2 rule. Multiple aryl rings may be fused, and aryl rings may be fused or unfused with one or more cyclic hydrocarbon, heteroaryl, or heterocyclic rings. Exemplary aryl groups according to the invention include phenyl, naphthyl, tetrahydronaphthyl, and biphenyl.
  • alkaryl and "alkylaryl” as used herein means an alkyl group as defined above linked to the molecule through an aryl group as defined above.
  • alkylene as used herein means an alkyl group having two free valencies (i.e., a divalent alkyl radical);
  • amide as used herein means a compound having the general formula
  • antiproliferative agent means a compound that decreases the hyperproliferation of cells.
  • abnormal cell proliferation means a disease or condition characterized by the inappropriate growth or multiplication of one or more cell types relative to the growth of that cell type or types in an individual not suffering from that disease or condition.
  • the present invention provides analogues of docetaxel wherein the tert-butyl group on the C3'-NHC0 is replaced with an analogue-forming group. In one embodiment, the present invention provides analogues of paclitaxel wherein the C3' phenyl group is replaced with an analogue-forming group.
  • FIG. 1 shows paclitaxel in the bioactive T-Taxol conformation at the ⁇ -tubulin taxane binding site in the class I ⁇ -tubulin isotype.
  • the phenyl ring on the C3'-NHCO is clamped between residues 23 and 231 (valine and alanine for this isotype) in the class I (HM40) ⁇ -tubulin isotype.
  • FIG. 2 shows paclitaxel in the bioactive T-Taxol conformation at the ⁇ -tubulin taxane binding site in the class VI ⁇ -tubulin isotype.
  • alkyl, alkenyl, and alkynyl groups include but are not restricted to straight chain, branched chain, cyclic, and polycyclic (e.g., norbornyl) groups, as well as aryl or alkyl substituted groups.
  • Aryl groups can include but are not limited to benzene, naphthalene, and other condensed aromatic hydrocarbons optionally substituted with alkyl, halogen, amino, ester, azido, nitro, and similar polar and nonpolar substituents.
  • Heteroalkyl and heteroalkenyl groups include but are not limited to the fully saturated and di- and tetrahydro variations of the heteroaryl systems mentioned above including tetrahydrofuran, piperidine, morpholine, and alkylated and esterified variations, as well as condensed polycyclic systems, such as tropane, quinuclidine, l,4-diazabicyclo[2.2.2.0]-octane and similar systems substituted by alkyl and ester functionalities.
  • the invention encompasses compounds according to Formula (3), wherein Ri can be selected from the group consisting of bridged polycyclo compounds, fused polycyclo compounds, and substituted aromatic compounds.
  • bridged polycyclo compounds that may be used as Ri include compounds having from 6 to 15 carbon atoms, from 6 to 14 carbon atoms, from 6 to 13 carbon atoms, from 6 to 12 carbon atoms, or from 6 to 11 carbon atoms.
  • Non-limiting examples of fused polycyclo compounds that may be used as Ri include compounds having from 6 to 15 carbon atoms, from 6 to 14 carbon atoms, from 6 to 13 carbon atoms, from 6 to 12 carbon atoms, or from 6 to 11 carbon atoms.
  • the compounds may be two fused rings wherein one ring has 6 atoms and the other ring has 4 atoms, 5 atoms, 6 atoms, 7 atoms, or 8 atoms.
  • the compounds also may be two fused rings wherein one ring has 5 atoms and the other ring has 4 atoms, 5 atoms, 7 atoms, or 8 atoms.
  • Non-limiting examples of substituted aromatic compounds that may be used as Ri include compounds having from 7 to 20 carbon atoms, from 8 to 20 carbon atoms, from 8 to 18 carbon atoms, from 8 to 16 carbon atoms, or from 8 to 14 carbon atoms.
  • the compounds may be phenyl rings that are one or more of ortho-, meta-, or para- substituted.
  • substituents may include alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, C(O)O-alkyl, C(O)O-alkenyl, or C(O)O-alkynyl, all of which may be linear or branched.
  • Specific non-limiting examples of substituted aromatic compounds that may be encompassed by the present invention as an Ri group, according to Formula (3) include the following (wherein W can be a substituent, as described in the preceding paragraph).
  • substituted aromatic compounds that may be encompassed by the present invention as an R 2 group, according to Formula (3), include the following.
  • Non-limiting examples of cycloalkanes or cycloalkenes that may be used as R3 include C3-C7 compounds, particularly C3-C5 compounds.
  • Specific non-limiting examples of cycloalkanes or cycloalkenes that may be encompassed by the present invention as an R 3 group, according to Formula (3), include the following.
  • X5 is selected from the group consisting of
  • the known fragment (I) was prepared according to a known procedure (Koch G., et al., 2004, Synlett 4:693-697 and Nicolaou KC, et al., 1997, J. Am. Chem. Soc. 119:79747991). Fragment (II) was prepared as shown below.
  • the H ⁇ l selective MTC does not bind H ⁇ l but does bind other ⁇ -tubulin isotypes, the H ⁇ l selective MTC would be expected to be effective to treat the cancer of the patient in a non-myelosuppressive fashion, as otherwise disclosed herein.
  • the foregoing is provided for exemplary purposes and is not intended to limit the scope of the invention. Rather, the same testing procedure could be used to evaluate whether a patient would respond to compounds selective for other ⁇ -tubulin isotypes.
  • the testing methods of the invention may include testing of various cell components to determine the appropriate method of treatment.
  • the method can comprises isolating and testing nucleic acids from the cancer cells.
  • the method may also comprise isolating and testing proteins from the cancer cells.
  • the present invention has identified that compounds that selectively do not inhibit H ⁇ l -tubulin are useful as myelo-sparing MTCs. Accordingly, in certain embodiments, the invention provides a method for identifying myelo-sparing microtubule targeting compounds, the method comprising the following steps: i) screening a library of compounds against H ⁇ l -tubulin to determine whether the compounds individually inhibit the H ⁇ l -tubulin; ii) discarding agents that inhibit the H ⁇ l -tubulin; and iii) retaining agents that do not inhibit the H ⁇ l -tubulin.
  • an initial screen can be performed in cells (e.g., epithelial cancer cells) transfected with an H ⁇ l tubulin encoding mammalian expression plasmid, and the cells then can be exposed to varying concentrations of each compound to be tested and compared to a control.
  • the effect of each compound on H ⁇ l -specific tubulin can be assessed by a cell-based tubulin polymerization assay as described below in relation to FIG. 4 in conjunction with immunostaining with the H ⁇ l -specific antibody to assess the effects of each of the compounds on H ⁇ l microtubule polymer mass.
  • the method comprises the following steps: i) screening a library of compounds against a ⁇ -tubulin with an amino acid other than valine at ⁇ 236, tyrosine at ⁇ 200, or valine at ⁇ 316; ii) discarding compounds that inhibit the ⁇ -tubulin; and iii) retaining compounds that do not inhibit the ⁇ -tubulin.
  • optical isomers of the compounds according to the present invention include the following: i) physical separation of crystals whereby macroscopic crystals of the individual enantiomers are manually separated.
  • This technique may particularly be used when crystals of the separate enantiomers exist (i.e., the material is a conglomerate), and the crystals are visually distinct; ii) simultaneous crystallization whereby the individual enantiomers are separately crystallized from a solution of the racemate, possible only if the latter is a conglomerate in the solid state; iii) enzymatic resolutions whereby partial or complete separation of a racemate by virtue of differing rates of reaction for the enantiomers with an enzyme; iv) enzymatic asymmetric synthesis, a synthetic technique whereby at least one step of the synthesis uses an enzymatic reaction to obtain an enantiomeric ally pure or enriched synthetic precursor of the desired enantiomer; v) chemical asymmetric synthesis whereby the desired enantiomer is synthesized from an achiral precursor under conditions that produce asymmetry (i.e., chirality) in the product, which may be achieved using chiral catalysts or chiral aux
  • the desired enantiomer is then released from the diastereomers; viii) kinetic resolutions comprising partial or complete resolution of a racemate (or of a further resolution of a partially resolved compound) by virtue of unequal reaction rates of the enantiomers with a chiral, non-racemic reagent or catalyst under kinetic conditions; ix) enantiospecific synthesis from non-racemic precursors whereby the desired enantiomer is obtained from non-chiral starting materials and where the stereochemical integrity is not or is only minimally compromised over the course of the synthesis; x) chiral liquid chromatography whereby the enantiomers of a racemate are separated in a liquid mobile phase by virtue of their differing interactions with a stationary phase.
  • the compounds of the invention can comprise an MTC having an enantiomeric purity for a single enantiomer of at least about 75%.
  • the compounds of the invention have an enantiomeric purity of at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 99.5%.
  • the compounds of the invention may have such enantiomeric purity for the (S) isomer.
  • the compounds of the invention may have such enantiomeric purity for the (R) isomer.
  • compositions include propionic acid, glycolic acid, oxalic acid, malic acid, malonic acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, and the like.
  • pharmaceutically acceptable salts include, but are not limited to, sulfates, pyrosulfates, bisulfates, sulfites, bisulf ⁇ tes, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-l,4-dioates, hexyne-1,6- dioates,
  • prodrug ligands are known.
  • alkylation, acylation, or other lipophilic modification of one or more heteroatoms of the compound, such as a free amine or carboxylic acid residue reduces polarity and allows passage into cells.
  • the compounds of the invention can be prepared and delivered together with one or more pharmaceutically acceptable carriers therefore, and optionally, other therapeutic ingredients.
  • Carriers should be acceptable in that they are compatible with any other ingredients of the composition and not harmful to the recipient thereof.
  • a carrier may also reduce any undesirable side effects of the agent.
  • Such carriers are known in the art. See, Wang et al. (1980) J. Parent. Drug Assn. 34(6):452-462, herein incorporated by reference in its entirety.
  • Hard capsules containing the compound may be made using a physiologically degradable composition, such as gelatin.
  • Such hard capsules comprise the compound, and may further comprise additional ingredients including, for example, an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin.
  • Soft gelatin capsules containing the compound may be made using a physiologically degradable composition, such as gelatin.
  • Such soft capsules comprise the compound, which may be mixed with water or an oil medium such as peanut oil, liquid paraffin, or olive oil.
  • Sublingual tablets are designed to dissolve very rapidly.
  • compositions include ergotamine tartrate, isosorbide dinitrate, and isoproterenol HCL.
  • the compositions of these tablets contain, in addition to the drug, various soluble excipients, such as lactose, powdered sucrose, dextrose, and mannitol.
  • Transdermal drug delivery patches may also be comprised of a reservoir underlying the backing layer that is separated from the skin of the recipient by a semi-permeable membrane and adhesive layer. Transdermal drug delivery may occur through passive diffusion or may be facilitated using electrotransport or iontophoresis.
  • the MTCs according to the present invention are useful in a variety of methods of treatment.
  • the inventive MTCs may be useful in any methods of treatment where conventional taxanes and/or epothilones may find use.
  • the MTC of the invention provide such treatment with designed specificity to avoid the undesirable side effects of conventional taxanes and/or epothilones, particularly myelosuppression.
  • the MTCs of the invention may be useful in a method of treating cancer.
  • the MTCs of the invention may be useful in method of treating and/or preventing abnormal cell proliferation.
  • a hypotonic lysis buffer that recovers less than 10% of microtubule polymer in taxane-treated samples and their respective untreated control was used.
  • the percentage of polymerized tubulin was determined by dividing the densitometric value of polymerized tubulin (P) by the total tubulin content (P+S).
  • a similar assay was performed using human platelets obtained from peripheral blood from a healthy donor following centrifugation of platelet-rich plasma at 300xg for 10 minutes.
  • Class VI ⁇ -tubulin isotype mRNA amounts were analyzed by quantitative real-time PCR using probe 14 of the Universal Human Probe Library detection system (Roche) in conjunction with the following specific primers for class VI ⁇ -tubulin isotype (H ⁇ l/TUBBl gene, accession # NM_030773): Forward 5 '-GGATGCGTGAAATTGTCCAT-S ' and reverse 5 '-AGTCGATCCCGTGTTCCTC-S'. Primers were used at a final concentration of 200 nM each.
  • Umbilical cord blood cells were obtained from the public cord blood bank of the New York- Presbyterian Hospital Weill Cornell Medical Center.
  • Peripheral blood mononuclear cells PBMCs
  • PBMCs Peripheral blood mononuclear cells
  • CD34 positive cells were sorted using a monoclonal Ab (StemCell Technologies, Inc.).
  • Statistical analysis was performed using a single factor ANOVA test (p ⁇ 0.05 was considered statistically significant).
  • a 2ME2-resistance cell model was generated consisting of the parental 1A9 human ovarian carcinoma cells and its drug-resistant counterpart 1A9/2MRC cells (2MRC).
  • the 2MRC cells were more than 80-fold resistant to 2ME2 and did not exhibit significant cross resistance to any of the other classes of microtubule inhibitors, including the colchicine - site binding agents (combretastatin, ENMD MKC-I and colchicine) as well as the 2ME2 analog ENMDl 198, also undergoing clinical development (See Table 2 below). These results indicate that the 2MRC cells display a 2ME2-specif ⁇ c resistant phenotype.
  • the second genetic alteration is a missense mutation resulting in a change in amino acid 236 from Valine to Isoleucine ( ⁇ V236I).
  • Subcloning of the cDNA PCR products followed by direct sequencing further showed that the two genetic alterations were mutually exclusive since 100% of the clones analyzed had either the frame-shift mutation (L187fsX193) or the missense mutation (1236), indicating that the two alterations occurred in different alleles. This result suggests that the 2MRC cells functionally express only the HM40 ⁇ 236 mutant tubulin only responsible for the 2ME2 resistance.
  • H ⁇ l model predicts that while PTX encounters no difficulty binding to the class VI ⁇ -tubulin isotype, 2ME2 is hindered from occupying the colchicine pocket primarily by the 1236 side chain. Therefore, H ⁇ l tubulin is predicted to display resistance to the effects of 2ME2 while retaining its sensitivity to PTX.
  • tubulin immunofluorescence with a ⁇ -tubulin antibody recognizing all ⁇ -isotypes but H ⁇ l showed overlap between the two staining (see merge).
  • Treatment with 2ME2 had no effect on the microtubule network of H ⁇ l -expressing cells, even at the dose of 100 ⁇ M, as shown by the intact, well organized microtubule cytoskeleton in the transfected cells.
  • 2ME2 treatment caused extensive microtubule depolymerization with short microtubule fragments scattered throughout the cytoplasm and an increase in the number of atypical mitotic figures, consistent with the drug-sensitive phenotype of the non-transfected 1A9 cells (FIG. 5).
  • mice deficient in ⁇ 1 -tubulin develop moderate thrombocytopenia as a result of reduced proplatelet formation and their spherocytic platelets carry a structurally defective marginal band and reduced microtubule content.
  • the role of ⁇ l -tubulin is limited to a few clinical studies showing that a Q43P polymorphism in H ⁇ l is present in approximately 11% of the general population and in approximately 24% of a small cohort of patients with macrothombocytopenia.
  • Heterozygous carriers show defects in platelet aggregation that protects against thrombotic disorders and appears to reduce the risk of cardiovascular disease in men, but increases the risk of intracerebral hemorrhage.
  • a solution of compound (j) (908 mg, 0.735 mmol) in THF (7.5 mL) was added a stock solution of hydrogen fluoride in pyridine (HF.Py) (this stock solution was prepared by addition of 1.25 mL HF.Py to 3.5 mL pyridine in 6.125 mL THF) at 0 0 C.
  • the resulting reaction mixture was warmed to 25 0 C by removing the ice-bath and allowed to stir at that temperature for 2 h.
  • Tje epothilone analog of formula (19) was prepared from the diene of compound (t), using a similar procedure to that described for the conversion of compound (q) to the compound of Formula (18a) as a colorless oil in 44% yield (55% starting material was recovered).
  • Iodide - Compound of Formula (44) To a solution of primary alcohol of Formula (43) (19 mg, 0.02497 mmol) in THF (2.5 mL) was added PPh 3 (13 mg, 0.0499 mmol, 2 eq), followed by imidazole (5.1 mg, 0.07491 mmol, 3 eq) and iodine (25 mg, 0.09988 mmol, 4 eq). The resulting reaction mixture was allowed to stir at 25 0 C for 30 min prior to being quenched by the addition of saturated Na 2 S 2 O 3 solution (10 mL).
  • Epothilone D analog - Compound of Formula (45) Epothilone D analog - Compound of Formula (45). Iodide of Formula (44) (19.3 mg, 0.022 mmol) and sodiumcyanoborohydride (14 mg, 0.22 mmol, 10 eq) were dissolved in HMPA (0.2 mL) and the resulting mixture was heated at 45 0 C for 22 h. After cooling to 25 0 C, the reaction mixture was diluted with 0.2 mL of EtOAc and then directly loaded onto preparative thin layer chromatography, eluting with 15% EtOAc in hexanes, to yield pure epothilone D analog of Formula (45) (10 mg, 60.6%) as a colorless oil.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L’invention concerne des composés de ciblage de microtubule qui sont myéloépargnants. En particulier, les MTC de l’invention sont structurellement conçus pour présenter une spécificité pour l’inhibition d’isotypes de b-tubuline qui ne sont pas liés à la myélosuppression associée à d’autres MTC connus. L’invention concerne en outre des compositions pharmaceutiques incorporant les MTC de l’invention et des procédés de traitement du cancer au moyen des MTC. L’invention concerne en outre également diverses analyses pour identifier des composés myéloépargnants et déterminer si de tels composés sont indiqués ou non pour être utilisés avec des patients spécifiques.
PCT/US2009/039679 2008-04-04 2009-04-06 Composés non myélosuppresseurs, leurs compositions pharmaceutiques, et procédés de traitement Ceased WO2009146152A2 (fr)

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US61/123,067 2008-04-04
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US61/081,661 2008-07-17

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US6399638B1 (en) * 1998-04-21 2002-06-04 Bristol-Myers Squibb Company 12,13-modified epothilone derivatives
US6800653B2 (en) * 2001-06-01 2004-10-05 Bristol-Myers Squibb Compnay Epothilone derivatives

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