WO2013055771A1 - Dérivés de thioxothiazolidinones utiles en tant qu'inhibiteurs de tdp1 - Google Patents

Dérivés de thioxothiazolidinones utiles en tant qu'inhibiteurs de tdp1 Download PDF

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WO2013055771A1
WO2013055771A1 PCT/US2012/059515 US2012059515W WO2013055771A1 WO 2013055771 A1 WO2013055771 A1 WO 2013055771A1 US 2012059515 W US2012059515 W US 2012059515W WO 2013055771 A1 WO2013055771 A1 WO 2013055771A1
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group
independently chosen
compound
formula
alkyl
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Yves Pommier
Christophe Marchand
Zhengqiang Wang
Venkata Ramana SIRIVOLU
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The United States Of America, As Represented By The Secretary, Department Of Health And Human Services
Regents Of The University Of Minnesota
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Publication of WO2013055771A1 publication Critical patent/WO2013055771A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/36—Sulfur atoms
    • 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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • Tdpl is an enzyme involved in topoisomerase-I (Topi) mediated DNA damage, such as damage introduced by the chemo therapeutic agent, camptothecin.
  • Topi topoisomerase-I
  • Tdpl inhibitors of Formula (I) shown below and methods of using those inhibitors to treat cancer are provided in this disclosure.
  • the disclosed Tdpl inhibitors may be used alone to treat cancer, but may also be used in combination with another active agent, such as camptothecin or a camptothecin analogue.
  • Tdpl Human tyrosyl DNA phosphodiesterase I
  • Topi human DNA topoisomerase I
  • CPT camptothecin
  • PLD phospho lipase D
  • PNKP polynucleotide kinase phosphatase
  • Tdpl is ubiquitous and highly conserved in eukaryotes. Tdpl function is probably not limited to the repair of Topi cleavage complexes as it could also be involved in the repair of DNA lesions created by the trapping of Top2 on DNA. Tdpl can also remove 3'- phosphoglycolate generated by oxidative DNA damage, which suggests a broader role for Tdpl in the maintenance of genomic stability. Tdpl is therefore a rational anticancer target.
  • Tdpl and PNKP form a multiprotein complex with XRCC1, poly(ADP) ribosepolymerase (PARP), p-polymerase, and ligase III.
  • This complex contains the critical elements for base excision repair.
  • Mammalian cells deficient for XRCC1 or PARP are also hypersensitive to camptothecin. The hypersensitivity of PARP-/- cells to
  • camptothecin can be related to a functional defect in Tdpl . It is not explained by abnormal levels of Tdpl or Topi proteins. Nanomolar inhibitors of Tdpl have not previously been reported. Highly potent Tdp 1 inhibitors are needed for cancer treatment particularly in combination with camptothecin.
  • the present disclosure fulfills this need and provided additional advantages.
  • Tdpl tyrosyl-DNA phosphodiesterase
  • the Tdpl inhibitors are useful as anti-cancer agents, either alone or in combination with a chemotherapeutic agent that induces Topi-mediated DNA damage, such as camptothecin.
  • the disclosure includes compounds and salts of Formula (A) or a pharmaceutically acceptable salt thereof:
  • G is a phenyl substituted with at least one -COOH group, phosphoester group, sulfonyl group, or tetrazolyl group, and optionally substituted with one or more
  • G is group of the formula:
  • ⁇ — IJ R 3 which is substituted with 0 or more independently chosen substituents R 3 , and where Y is O, S, NH, or CH 2 ,;
  • G is a heteroaryl group chosen from pyridyl, benzo[b]thiophenyl, indolyl, and benzimidazolyl each of which is optionally substituted with one or more independently chosen R 3 substituents; or
  • Ri is hydrogen or Ci-C 2 alkyl.
  • R 2 is independently chosen from a group Cy and halogen, hydro xyl, amino, nitro, cyano, Ci-C 4 alkyl, Ci-C 4 alkoxy, mono- or di-Ci-C 2 alkylamino,Ci-C 2 haloalkyl, and Ci- C 2 haloalkoxy.
  • R 3 is independently chosen at each occurrence from a group Cy and halogen, amino, nitro, cyano, hydroxyl, -COOH, -CHO, -CONH 2 , Ci-C 4 alkyl, Ci-C 4 alkoxy, C 2 - C 4 alkanoyl, mono- or di-Ci-C 2 alkylamino, Ci-C 2 haloalkyl, and Ci-C 2 haloalkoxy.
  • Cy is an optionally substituted 5- or 6- membered saturated, unsaturated, or aromatic cyclic group optionally containing 1 to 4 ring atoms independently chosen from N, O, and S with remaining ring atoms being carbon, and only one of R 2 or R 3 is Cy.
  • Another embodiment of the disclosure is directed to methods of treating cancer, comprising administering a compound or pharmaceutically acceptable salt of Formula
  • W is O or S.
  • G has one of the following five definitions:
  • G is a phenyl substituted with at least one substituent independently chosen from hydroxyl, -COOH, -CHO, -CONH 2 , mono- and di-Ci-C 4 alkylcarboxamide, and mono- and di-Ci-C 4 alkylester, and optionally substituted with one or more independently chosen R 2 substituents.
  • G is pyridyl optionally substituted with one or more independently chosen R 3 substituents.
  • G is a heteroaryl group chosen from pyridyl, benzo[b]thiophenyl, indolyl, and benzimidazolyl each of which is optionally substituted with one or more independently chosen R 3 substituents.
  • G is group of the formula: where * is a point of covalent attachment, and where Y is O, S, NH, CH 2 , or N-Ci-C 4 alkyl...
  • G is a metallocene group of the formula: where Z is a divalent metal chosen from Fe, Mn, Co, Ru, and Os.
  • Yi and Y 2 are independently CH and N.
  • Ri is hydrogen or Ci-C 2 alkyl.
  • R 2 is independently chosen at each occurrence from a group Cy and halogen, hydroxyl, amino, nitro, cyano, Ci-C 4 alkyl, Ci-C 4 alkoxy, C 2 -C 4 alkanoyl, mono- or di-Ci- C 2 alkylamino, Ci-C 2 haloalkyl, and Ci-C 2 haloalkoxy.
  • R 3 is independently chosen at each occurrence from a group Cy and halogen, amino, nitro, cyano, hydroxyl, -COOH, -CHO, -CONH 2 , Ci-C 4 alkyl, Ci-C 4 alkoxy, C 2 - C 4 alkanoyl, mono- or di-Ci-C 2 alkylamino, Ci-C 2 haloalkyl, and Ci-C 2 haloalkoxy.
  • Cy is C 3 -C 6 Cycloalkyl, phenyl, benzyl, or 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently chosen from N, S, and O with remaining ring atoms being carbon; each of which Cy is optionally substituted with 1 or more substituents independently chosen from halogen, hydroxyl, amino, nitro, cyano, Ci-C 4 alkyl, Ci-C 4 alkoxy, mono- or di-Ci-C 2 alkylamino, Ci-C 2 haloalkyl, and Ci-C 2 haloalkoxy.
  • the compound or salt of Formula (A) is administered together with a compound chosen from camptothecin, irinotecan, and topotecan.
  • FIGURE 1 Cleavage of 5 '- 32 P-labeled 3 '-phosphotyrosyl DNA substrate N14Y to a 14-mer 5 '- 32 P-labeled 3 '-phosphate DNA product N14.
  • FIGURE 2 Representative gel image of the inhibition of Tdpl by 4- thioxothiazolidinones in gel based assays. Upper Panel: Inhibition of recombinant Tdpl . Lower panel: Inhibition of endogenous Tdpl in whole cell extract.
  • FIGURE 3 Cell survival curves of DT40 cell either complement with the Tdpl gene (hTdpl , upper graph) or knockout for Tdpl (Tdpl -/-, lower graph) in the presence and absence of VS-2-256.
  • FIGURE 4 (A)Representative gel demonstrating concentration-dependent inhibition of Tdpl by compounds 48, 50 and 51 ; (B) Concentration-Response cure for compounds 48, 50, and 51. FIGURE 5. The binding of 50 to Tdpl was examined using SPR spectroscopy. A concentration series of 50 (50, 25, 6.25, 3.12, 1.56. 0.78 and 0.39 ⁇ ) were injected over immobilized Tdpl (A) or a tyrosyl labeled oligonucleotide
  • compound of Formula (I) encompasses all compounds that satisfy Formula (I), including any enantiomers, racemates and stereoisomers, as well as all pharmaceutically acceptable salts of such compounds.
  • a compound of Formula (I) includes all subgeneric groups of Formula (I), and also includes pharmaceutically acceptable salts of a compound of Formula (I), unless clearly contraindicated by the context in which this phrase is used.
  • Formula (A) which is used in connection with compound claims, is a subgeneric group of Formula (I).
  • An "active agent” means a compound (including a compound disclosed herein), element, or mixture that when administered to a patient, alone or in combination with another compound, element, or mixture, confers, directly or indirectly, a physiological effect on the patient.
  • the indirect physiological effect may occur via a metabolite or other indirect mechanism.
  • a dash (“-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent.
  • Alkyl is a branched or straight chain saturated aliphatic hydrocarbon group, having the specified number of carbon atoms, generally from 1 to about 12 carbon atoms.
  • Ci-Cealkyl indicates an alkyl group having from 1 , 2, 3, 4, 5, or 6 carbon atoms.
  • Other embodiments include alkyl groups having from 1 to 8 carbon atoms, 1 to 4 carbon atoms or 1 or 2 carbon atoms, e.g. Ci-C 4 alkyl and Ci-C 2 alkyl.
  • alkyl examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, 3-methylbutyl, t- butyl, n-pentyl, and sec-pentyl.
  • Alkylester is an alkyl group as defined herein attached through an ester linkage.
  • Alkoxy is an alkyl group as defined above with the indicated number of carbon atoms covalently bound to the group it substitutes by an oxygen bridge (-0-).
  • alkoxy examples include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, 2-butoxy, t-butoxy, n-pentoxy, 2-pentoxy, 3- pentoxy, isopentoxy, neopentoxy, n- hexoxy, 2-hexoxy, 3-hexoxy, and 3- methylpentoxy.
  • Cycloalkyl is a saturated hydrocarbon ring group, having the specified number of carbon atoms.
  • Monocyclic cycloalkyl groups typically have from 3 to about 8 carbon ring atoms or from 3 to 7 (3, 4, 5, 6, or 7) carbon ring atoms.
  • Cycloalkyl substituents may be pendant from a substituted nitrogen or carbon atom, or a substituted carbon atom that may have two substituents may have a cycloalkyl group, which is attached as a spiro group.
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl as well as bridged or caged saturated ring groups such as norbornane or adamantine.
  • Haloalkyl includes both branched and straight-chain alkyl groups having the specified number of carbon atoms, substituted with 1 or more halogen atoms, up to the maximum allowable number of halogen atoms.
  • haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, 2-fluoroethyl, and pentafluoroethyl.
  • Haloalkoxy is a haloalkyl group as defined herein attached through an oxygen bridge (oxygen of an alcohol radical).
  • Halo or "halogen” indicates any of fluoro, chloro, bromo, and iodo.
  • “Mono- and/ or di-alkylamino” is a secondary or tertiary alkyl amino group, wherein the alkyl groups are independently chosen alkyl groups, as defined herein, having the indicated number of carbon atoms. The point of attachment of the alkylamino group is on the nitrogen. Examples of mono- and di-alkylamino groups include ethylamino, dimethylamino, and methyl-propyl-amino.
  • dialkylcarboxamide substituent to the molecule it substitutes is on the carbon of the carbonyl group.
  • the groups alky and alkyl 2 are independently chosen alkyl groups having the indicated number of carbon atoms.
  • Phosphoester group is a substituent of the formula
  • Ri is lower alkyl and R 2 is lower alkyl or hydrogen.
  • substituted means that any one or more hydrogens on the designated atom or group is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded.
  • an oxo group substitutes aromatic moieties, the corresponding partially unsaturated ring replaces the aromatic ring.
  • a pyridyl group substituted by oxo is a pyridone.
  • a stable compound or stable structure is meant to imply a compound that is sufficiently robust to survive isolation from a reaction mixture, and subsequent formulation into an effective therapeutic agent.
  • substituents are named into the core structure. For example, it is to be understood that when aminoalkyl is listed as a possible substituent the point of attachment of this substituent to the core structure is in the alkyl portion.
  • Suitable groups that may be present on a "substituted" or “optionally substituted” position include, but are not limited to, e.g., halogen; cyano; hydroxyl; nitro; azido; alkanoyl (such as a C 2 -C6 alkanoyl group); carboxamide; alkyl groups (including cycloalkyl groups) having 1 to about 8 carbon atoms, or 1 to about 6 carbon atoms; alkenyl and alkynyl groups including groups having one or more unsaturated linkages and from 2 to about 8, or 2 to about 6 carbon atoms; alkoxy groups having one or more oxygen linkages and from 1 to about 8, or from 1 to about 6 carbon atoms; aryloxy such as phenoxy; alkylthio groups including those having one or more thioether linkages and from 1 to about 8 carbon atoms, or from 1 to about 6 carbon atoms; alkylsulfmyl groups including those having one or more
  • an "optionally substituted group is substituted with one or more substituents independently chosen from halogen, hydroxyl, amino, nitro, cyano, oxo, -COOH, -CONH 2 , Ci-Cealkyl, Ci-C 6 alkoxy, C 2 -C 6 alkanyol, C 2 -C 6 alkylester, C 3 - Cycycloalkyl, phenyl, (mono- or di-Ci-C 4 alkylamino)Co-C 4 alkyl, Ci-C 2 haloalkyl, and Ci- C 2 haloalkoxy.
  • substituents independently chosen from halogen, hydroxyl, amino, nitro, cyano, oxo, -COOH, -CONH 2 , Ci-Cealkyl, Ci-C 6 alkoxy, C 2 -C 6 alkanyol, C 2 -C 6 alkylester, C 3 - Cycycloalkyl, phenyl
  • a "dosage form” means a unit of administration of an active agent.
  • dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, creams, ointments, suppositories, inhalable forms, transdermal forms, and the like.
  • compositions are compositions comprising at least one active agent, such as a compound or salt of Formula (I), and at least one other substance, such as a carrier. Pharmaceutical compositions optionally contain one or more additional active agents. When specified, pharmaceutical compositions meet the U.S. FDA's GMP (good manufacturing practice) standards for human or non-human drugs.
  • “Pharmaceutically acceptable salts” includes derivatives of the disclosed compounds in which the parent compound is modified by making inorganic and organic, nontoxic, acid or base addition salts thereof. The salts of the present compounds can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods.
  • salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid.
  • a stoichiometric amount of the appropriate base such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like
  • Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two.
  • nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred, where practicable.
  • Salts of the present compounds further include solvates of the compounds and of the compound salts.
  • Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts and the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC-(CH 2 ) n -COOH where n is 0-4, and the like. Lists of additional suitable salts may be found, e.g., in Remington's Pharmaceutical Sciences, 17th
  • carrier applied to pharmaceutical compositions/ combinations of the invention refers to a diluent, excipient, or vehicle with which an active compound is provided.
  • a carrier must be safe, non-toxic and neither biologically nor otherwise undesirable.
  • a "patient” is a human or non-human animal in need of medical treatment.
  • Medical treatment can include treatment of an existing condition, such as a disease or disorder, prophylactic or preventative treatment, or diagnostic treatment.
  • medical treatment means treatment of a diagnosed cancer or known tumor.
  • the patient is a human patient.
  • Provided together with at least one additional active agent means the Td l inhibitor of Formula (I) and the additional active agent(s) are provided simultaneously in a single dosage form, provided concomitantly in separate dosage forms, or provided in separate dosage forms for administration separated by some amount of time that is within the time in which both the Tdpl inhibitor and the at least one additional active agent are within the blood stream of a patient.
  • the Tdpl inhibitor and the additional active agent need not be prescribed for a patient by the same medical care worker.
  • the additional active agent or agents need not require a prescription.
  • Administration of the Tdpl inhibitor or the at least one additional active agent can occur via any appropriate route, for example, oral tablets, oral capsules, oral liquids, inhalation, injection, suppositories or topical contact.
  • Treatment includes providing a compound of Formula (I), either as the only active agent or together with at least one additional active agent sufficient to: (a) prevent a disease or a symptom of a disease from occurring in a patient who may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e. arresting its development; and (c) relieving the disease, i.e., causing a remission of the disease..
  • Treating and “treatment” also means providing a therapeutically effective amount of a Tdpl inhibitor as the only active agent or together with at least one additional active agent to a patient having cancer.
  • a "therapeutically effective amount" of a pharmaceutical composition/ combination of this invention means an amount effective, when administered to a patient, to provide a therapeutic benefit such as an amelioration of symptoms, e.g., an amount effective to decrease the symptoms of cancer.
  • a patient having cancer may present detectable levels of certain tumor markers, including CA 125, CEA, CA19-9, AFP, PSA, and galactosyl transferase.
  • a therapeutically effect amount is thus an amount sufficient to provide a significant reduction in elevated tumor marker levels or an amount sufficient to provide a return of tumor marker levels to the normal range.
  • a therapeutically effective amount is also an amount sufficient to prevent a significant increase in tumor size relative that usually seen in untreated patients having the same cancer, or significantly reduce tumor size or tumor number, or causes tumors to disappear from the patient's body altogether.
  • a significant increase or reduction in the detectable level of tumor markers, tumor size, or tumor number is any detectable change that is statistically significant in a standard parametric test of statistical significance such as Student's T-test, where p ⁇ 0.05.
  • the disclosure provides a method of treating cancer in a patient, comprising administering a therapeutically effective amount of a Tdpl inhibitor to a patient in need of such treatment.
  • Formula (I) includes all subformulae thereof.
  • the compounds of Formula (I) may contain one or more asymmetric elements such as stereogenic centers, stereogenic axes and the like, e.g. asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms. These compounds can be, for example, racemates or optically active forms. For compounds with two or more asymmetric elements, these compounds can additionally be mixtures of diastereomers. For compounds having asymmetric centers, it should be understood that all of the optical isomers and mixtures thereof are encompassed.
  • compounds with carbon-carbon double bonds may occur in Z- and E-forms, with all isomeric forms of the compounds being included in the present invention.
  • single enantiomers i.e., optically active forms
  • Resolution of the racemates can also be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example using a chiral HPLC column.
  • the present disclosure includes all isotopes of atoms occurring in the present compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium and isotopes of carbon include N C, 13 C, and 14 C.
  • the disclosure includes compounds and salts of Formula (I) and Formula (A) in which the variables, e.g. Ri, W, and G, carry any of the definitions set forth below. Any of the variable definitions set forth below can be combined with any other of the variable definitions so long as a stable compound results.
  • G is a phenyl substituted with at least one substituent independently chosen from hydroxyl, -COOH, -CHO, -CONH 2 , mono- and di-Ci-C 4 alkylcarboxamide, and mono- and di-Ci-C 4 alkylester, and optionally substituted with one or more independently chosen R 2 substituents .
  • R 2 are independently chosen at each occurrence from a group Cy and halogen, hydroxyl, amino, nitro, cyano, -COOH, -CHO, -CONH 2 , Ci-C 4 alkyl, Ci-C 4 alkoxy, C 2 - C 4 alkanoyl, mono- or di-Ci-C 2 alkylamino, Ci-C 2 haloalkyl, and Ci-C 2 haloalkoxy.
  • Cy is C3-C 6 Cycloalkyl, phenyl, benzyl, or 5- or 6-membered heteroaryl containing 1 to 4 heteroatoms independently chosen from N, S, and O with remaining ring atoms being carbon; each of which Cy is optionally substituted with 1 or more substituents independently chosen from halogen, hydroxyl, amino, nitro, cyano, Ci-C 4 alkyl, Ci-C 4 alkoxy, mono- or di-Ci-C 2 alkylamino, Ci-C 2 haloalkyl, and Ci-C 2 haloalkoxy.
  • G is a phenyl substituted with at least one substituent independently chosen from hydroxyl, -COOH, -CHO, -CONH 2 , and mono- and di-Ci-C 4 alkylester, and optionally substituted with one or more independently chosen R 2 substituents; and R 2 is halogen, Ci-C 2 alkyl, Ci-C 2 alkoxy, mono- or di-Ci-C 2 alkylamino, trifluoromethyl, and trifluoromethoxy.
  • G is a phenyl substituted with at least one substituent independently chosen hydroxyl and -COOH.
  • G is a phenyl substituted with at least one -COOH substituent and optionally substituted with one or more independently chosen R 2 substituents.
  • G is a phenyl substituted one -COOH substituent and Ri is hydrogen.
  • G is a pyridyl substituted with at least one substituent independently chosen from hydroxyl, -COOH, -CHO, -CONH 2 , and mono- and di-Ci-C 4 alkylester, and optionally substituted with one or more independently chosen R 3 substituents; and R 3 is halogen, Ci-C 2 alkyl, Ci-C 2 alkoxy, mono- or di-Ci-C 2 alkylamino, trifluoromethyl, and trifluoromethoxy.
  • G is a phenyl substituted with 2 or 3 hydroxyl groups.
  • G is group of the formula: where Y is O, S, NH, CH 2 , or N-Ci-C 4 alkyl.
  • Z is a divalent metal chosen from Fe, Mn, Co, Ru, and Os. .
  • the W variable [0079] (10) W is S.
  • R 2 and/ or R3 are independently chosen at each occurrence from halogen, hydroxyl, Ci-C 2 alkyl, Ci-C 2 alkyl, trifluoromethyl, and trifluoromethoxy.
  • R 2 is at least one -COOH or hydroxyl substituent and optionally includes 1 or more additional substituents chosen from halogen, hydroxyl, Ci-C 2 alkyl, and Ci- C 2 alkoxy.
  • Cy is C3-C 6 Cycloalkyl, phenyl, benzyl, pyrrole, thienyl, imidazolyl, or pyridyl, containing 1 to 4 heteroatoms independently chosen from N, S, and O with remaining ring atoms being carbon; each of which Cy is optionally substituted with 1 or more substituents independently chosen from halogen, hydroxyl, amino, nitro, cyano, Ci-C 4 alkyl, Ci-C 4 alkoxy, mono- or di-Ci-C 2 alkylamino, Ci-C 2 haloalkyl, and Ci-C 2 haloalkoxy.
  • the disclosure also includes the following compounds and their
  • compositions comprising a compound or pharmaceutically acceptable salt of a Tdp l inhibitor, such as a compound of Formula (I), together with at least one pharmaceutically acceptable carrier.
  • the pharmaceutical composition/ combination may contain a compound or salt of Formula (I) as the only active agent, but is preferably contains at least one additional active agent.
  • the additional active agent is compound or salt thereof chosen from camptothecin, irinotecan, and topotecan .
  • the pharmaceutical composition is in a dosage form that contains from about 0.1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of a compound of Formula (I) and optionally from about 0.1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 100 mg to about 800 mg, or from about 200 mg to about 600 mg of an additional active agent in a unit dosage form.
  • the pharmaceutical composition may also include a molar ratio of a compound of Tdpl inhibitor, such as a compound of Formula (I), and an additional active agent.
  • the pharmaceutical composition may contain a molar ratio of about 0.5: 1, about 1 : 1, about 2: 1, about 3: 1 or from about 1.5 :1 to about 4:1 of an NS3a protease inhibitor of Formula (1)1 to NS5a inhibitor of Formula (I).
  • Compounds disclosed herein may be administered orally, topically, parenterally, by inhalation or spray, sublingually, transdermally, via buccal administration, rectally, as an ophthalmic solution, or by other means, in dosage unit formulations containing conventional pharmaceutically acceptable carriers.
  • the pharmaceutical composition may be formulated as any pharmaceutically useful form, e.g., as an aerosol, a cream, a gel, a pill, a capsule, a tablet, a syrup, a transdermal patch, or an ophthalmic solution.
  • Some dosage forms, such as tablets and capsules are subdivided into suitably sized unit doses containing appropriate quantities of the active components, e.g., an effective amount to achieve the desired purpose.
  • Carriers include excipients and diluents and must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the patient being treated.
  • the carrier can be inert or it can possess pharmaceutical benefits of its own.
  • the amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound.
  • Classes of carriers include, but are not limited to binders, buffering agents, coloring agents, diluents, disintegrants, emulsifiers, flavorants, glidants, lubricants, preservatives, stabilizers, surfactants, tableting agents, and wetting agents.
  • Some carriers may be listed in more than one class, for example vegetable oil may be used as a lubricant in some formulations and a diluent in others.
  • Exemplary pharmaceutically acceptable carriers include sugars, starches, celluloses, powdered tragacanth, malt, gelatin; talc, and vegetable oils.
  • Optional active agents may be included in a pharmaceutical composition, which do not substantially interfere with the activity of the compound of the present invention.
  • compositions/ combinations can be formulated for oral administration. These compositions contain between 0.1 and 99 weight % (wt.%) of a compound of Formula (I) and usually at least about 5 wt.% of a compound of Formula (I). Some embodiments contain from about 25 wt.% to about 50 wt. % or from about 5 wt.% to about 75 wt.%) of the compound of Formula.
  • compositions/ combinations disclosed herein are useful for treating cancer in patients.
  • This disclosure provides methods of treating cancer, by providing an effective amount of a compound or pharmaceutically acceptable salt of Formula (I) to patient having cancer.
  • a compound or salt of Formula (I) may be provided as the only active agent or may be provided together with one or more additional active agents.
  • the Tdpl kinase inhibitor is administered together with camptothecin, a camptothecin analogue, or protease inhibitor or other chemotherapeutic compounds.
  • An effective amount of a pharmaceutical composition of the invention includes an amount sufficient to (a) inhibit the progression of cancer; (b) cause a remission; or (c) cause a cure cancer, or (d) significantly reduce the level of cancer markers in a patient's blood, serum, or tissues.
  • An effective amount of a pharmaceutical composition described herein will also provide a sufficient concentration of the active agents in the concentration when administered to a patient.
  • a sufficient concentration of an active agent is a concentration of the agent in the patient's body necessary to reduce cancer symptoms or slow cancer progression. Such an amount may be ascertained experimentally, for example by assaying blood concentration of the agent, or theoretically, by calculating bioavailability.
  • compositions and methods of treatment in which a compound or salt of Formula (I) is provided together with one or more additional active agents are included herein.
  • a compound of Formula (I) is provided together with another chemotherapeutic agent, preferably camptothecin, or a camptothecin salt or camptothecin analogue, either in a single pharmaceutical composition or a in separate dosage forms with instructions to the patient to use the compound of Formula (I) and additional active agent together.
  • another chemotherapeutic agent preferably camptothecin, or a camptothecin salt or camptothecin analogue
  • pharmaceutically acceptable salt of Formula (I) and at least one additional active agent may be: (1) co-formulated and administered or delivered simultaneously in a combined
  • the methods of the invention may comprise administering or delivering the compound or salt of Formula (I) and an additional active agent sequentially, e.g., in separate solution, emulsion, suspension, tablets, pills or capsules, or by different injections in separate syringes.
  • an effective dosage of each active ingredient is administered sequentially, i.e., serially, whereas in simultaneous therapy, effective dosages of two or more active ingredients are administered together.
  • Various sequences of intermittent combination therapy may also be used.
  • Methods of inhibiting Tdpl in vivo comprise providing a compound or pharmaceutically acceptable salt of Formula (I) to a patient having cancer, a concentration of the compound or salt of Formula (I) sufficient to inhibit Tdpl in vitro are included herein.
  • concentration includes an in vivo concentration, such as a blood or plasma concentration.
  • concentration of compound sufficient to inhibit Tdp 1 in vitro may be determined from an assay of Tdpl inhibition such as the assay provided in Example 2, herein.
  • Methods of treatment include providing certain dosage amounts of a compound or pharmaceutically acceptable salt of Formula (I) to a patient.
  • Dosage levels of each active agent of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day).
  • the amount of active ingredient that may be combined with the carrier materials to produce a single unit dosage form will vary depending upon the patient treated and the particular mode of administration.
  • 0.1 mg to about 2000 mg from about 10 mg to about 1500 mg, from about 100 mg to about 1000 mg, from about 200 mg to about 800 mg, or from about 300 to about 600 mg of a compound of Formula (I) and optionally from about 0.1 mg to about 2000 mg, from about 10 mg to about 1500 mg, from about 100 mg to about 1000 mg, from about 200 mg to about 800 mg, or from about 300 to about 600 mg of a compound of an additional active agent, for example a camptothecin, or camptothecin analogue are provided to a patient. It is preferred that each unit dosage form contains less than 1200 mg of active agent in total. Frequency of dosage may also vary depending on the compound used and the particular disease treated.
  • Methods comprising providing a compound or salt of a Tdpl inhibitor, such as a compound of Formula (I), in a container together with instructions for using the compound to treat a patient suffering from cancer are included herein.
  • a compound or salt of a Tdpl inhibitor such as a compound of Formula (I)
  • Packaged pharmaceutical compositions/ combinations are also included herein.
  • Such packaged combinations include a Tdpl inhibitor, such as a compound of Formula (I), in a container together with instructions for using the combination to cancer, such as colon cancer, rectal cancer, ovarian cancer, small cell lung cancer, cervical cancer, or glioma, in a patient.
  • Pharmaceutical combinations include at least one additional active agent.
  • the additional active agent is camptothecin or a camptothecin analog such as irinotecan or topotecan.
  • the packaged pharmaceutical combination may include a Tdpl inhibitor, such as a compound of Formula (I), and an additional active agent provided simultaneously in a single dosage form, concomitantly in separate dosage forms, or provided in separate dosage forms for administration separated by some amount of time that is within the time in which both the Tdpl inhibitor, such as a compound of Formula (I), and the additional active agent are within the bloodstream of the patient.
  • a Tdpl inhibitor such as a compound of Formula (I)
  • an additional active agent provided simultaneously in a single dosage form, concomitantly in separate dosage forms, or provided in separate dosage forms for administration separated by some amount of time that is within the time in which both the Tdpl inhibitor, such as a compound of Formula (I), and the additional active agent are within the bloodstream of the patient.
  • Glacial acetic acid (3 mL) is added to a mixture of aromatic aldehyde (1 equiv.), 30 (1 equiv.) and sodium acetate (1 equiv.). The mixture is heated under reflux for 2 h, then cooled to room temperature and poured into cold water. The yellow solid precipitate was collected by filtration. The obtained solid was further purified by crystallization from ethanol or by column chromatography to yield the desired compound. .
  • lxlO 7 DT40 knockout cells for chicken Tdpl and complemented with human Tdpl were collected and washed once with PBS. The supernatant was removed and the pellet was resuspended with 50 ⁇ of CellLytic M Cell Lysis Reagent (SIGMA C2978), pipetting several times over ice. After 15 minutes, the lysate was centrifuged at a 12,000 g for 10 minutes and the protein concentration of the supernatant was determined using the Protein Assay Dye Reagent Concentrate (Bio-Rad #500-0006).
  • 5'- 32 P-labeled DNA substrate (1 nM; N14Y; 5 '-GATCTAAAAGACTT-pY-3 ') was incubated with 1 ⁇ of whole cell extract in the absence or presence of inhibitor for 15 min at room temperature in an assay buffer containing 25 mM Tris HCl, pH 7.5, 80 mM KCl, 2 mM EDTA, 1 mM DTT, 40 ⁇ g/ml BSA and 0.01% Tween-20.
  • Tdpl was amine coupled to a CM5 sensor chip and a dilution series of the representative inhibitor 50 was run through the surface. A surface without coupled Tdpl was used as a reference. As shown in FIGURE 5, a concentration-dependent binding of 50 on Tdpl was observed (A). Similarly, a 14 base oligonucleotide modified with a biotin at the 5' end and a tyrosine at the 3' end (biotin- GATCTAAAAGACTT-Tyr) immobilized onto the chip surface and tested against the same dilution series of 50 (FIG. 4, B). No binding was observed between 50 and the N14Y oligomer, confirming the selective binding of our inhibitors to Td l under assay conditions.
  • SPR Surface Plasmon Resonance
  • ethanolamine were purchased from GE Heathcare, Piscatawy NJ), Neutravidin was obtained from Pierce.
  • Binding experiments were performed on a Biacore T200 instrument (GE, Piscatawy NJ).
  • Tdpl was amine coupled to a CM5 sensor chip (GE Healthcare, Piscatawy NJ).
  • the amine groups in the active site of Tdpl were protected from modification by binding a 14 base oligonucleotide to Tdpl during the coupling step.
  • 1 ⁇ Tdpl was incubated with 2 ⁇ of a 14 base oligonucleotide containing at phosphate group at the 3' end (GATCTAAAAGACTT) in lOmM sodium acetate pH 4.5 for 20 mins.
  • CM5 chip surface was activated for 7mins with 0.1 M NHS and 0.4 M EDC at a flow rate of 20 ⁇ / ⁇ and Tdpl -oligonucleotide mixture was injected until approximately 6000 RU's was attached.
  • Activated amine groups were quenched with an injection of 1M solution of ethanolamine pH 8.0 for 7mins. Any bound oligonucleotide was removed by washing the surface with 1 M NaCl.
  • a reference surface was prepared in the same manner without coupling of Tdpl . Using the same approach 8000 RUs of Neutravidin was amine coupled to flow cells 3 and 4.
  • a 14 base oligonucleotide modified with a biotin at the 5' end a tyrosine at the 3' end was captured in the flow cell 4.
  • a dilution series of 50 (50, 25, 6.25, 3.12, 1.56. 0.78 and 0.39 ⁇ ) was prepared in running buffer (50 mM Tris/HCl, 80 mM KC1, 0.01% tween 20 (v/v), 5% DMSO (v/v), 2mM EDTA, lmM DTT, 40 ⁇ g/ml BSA pH 7.5) and injected over all flow cells at 30 ⁇ / ⁇ at 25°C.
  • the surface was regenerated with a 30 second injection 1 M NaCl, a 30 second injection of 50% DMSO (v/v) and a 30 second running buffer injection. Each cycle of compound injection was followed by buffer cycle for referencing purposes. A DMSO calibration curve was included to correct for refractive index mismatches between the running buffer and compound dilution series.

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Abstract

L'invention concerne des inhibiteurs de Tdp1 de la formule (I) et des méthodes utilisant ces inhibiteurs pour traiter le cancer. Dans cette formule, R1 représente hydrogène ou un groupe alkyle inférieur et G représente un groupe phényle substitué ou un groupe hétéroaryle éventuellement substitué. Les inhibiteurs de Tdp1 décrits peuvent être utilisés seuls pour traiter le cancer, mais peuvent également être utilisés en combinaison avec un autre principe actif, tel que la camptothécine ou un analogue de la camptothécine.
PCT/US2012/059515 2011-10-10 2012-10-10 Dérivés de thioxothiazolidinones utiles en tant qu'inhibiteurs de tdp1 WO2013055771A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004028535A1 (fr) * 2002-09-26 2004-04-08 Pintex Pharmaceuticals, Inc. Composes de modulation de pin-1 et leurs procedes d'utilisation
WO2007126857A1 (fr) * 2006-03-27 2007-11-08 Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Inhibiteurs diamidine de tdp1

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004028535A1 (fr) * 2002-09-26 2004-04-08 Pintex Pharmaceuticals, Inc. Composes de modulation de pin-1 et leurs procedes d'utilisation
WO2007126857A1 (fr) * 2006-03-27 2007-11-08 Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Inhibiteurs diamidine de tdp1

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