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WO2012033601A1 - Thiosemicarbazones à activité anti-mdr1 - Google Patents

Thiosemicarbazones à activité anti-mdr1 Download PDF

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Publication number
WO2012033601A1
WO2012033601A1 PCT/US2011/047377 US2011047377W WO2012033601A1 WO 2012033601 A1 WO2012033601 A1 WO 2012033601A1 US 2011047377 W US2011047377 W US 2011047377W WO 2012033601 A1 WO2012033601 A1 WO 2012033601A1
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Prior art keywords
compound
lower alkyl
aralkyl
formula
acyl
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PCT/US2011/047377
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English (en)
Inventor
Matthew D. Hall
Kyle Brimacombe
Misty Handley
Michael M. Gottesman
Henry M. Fales
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The United States Of America, As Represented By The Secretary, Department Of Health & Human Services
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Publication of WO2012033601A1 publication Critical patent/WO2012033601A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/40—Nitrogen atoms, not forming part of a nitro radical, e.g. isatin semicarbazone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • MDR1 for example, exhibits wide substrate specificity for structurally different drugs. This wide specificity mediates drug resistance to a variety of drugs, including Vinca alkaloids, anthracyclines, epipodophyllotoxins, taxols, actinomycin D, cardiac glycosides, immunosuppressive agents, glucocorticoids, and anti-HIV protease inhibitors. Since many drugs are substrates of MDR1, its degree of expression and functionality directly affects the therapeutic effectiveness of these agents.
  • the multidrug resistant phenotype of malignant cells is the main obstacle in the chemotherapeutic treatment of subjects having hyperproliferative disorders.
  • MDR1 expression is well characterized in hematological malignancies, sarcomas, and other solid cancers, and is frequently correlated with poor clinical response to chemotherapy for those tumors.
  • Strategies employed to circumvent the reduced drug accumulation conferred by these poly- specific efflux transporters have relied heavily on the development of clinical inhibitors of MDR- 1 for concurrent administration with chemotherapeutics. Although a number of these inhibitors have shown promise in vitro, translation to the clinic has taken longer than may have been expected, possibly due to side effects caused by inhibition of endogenous function, and alternative strategies are required.
  • R 1 and R 2 independently are selected from H, halogen, -OR 6 ,
  • X is N or CH
  • R 3 is H; -C(0)R 9 , -C(0)OR 10 or -C(0)NR n R 12 ;
  • R 4 is H, lower alkyl, lower alkenyl or together with R 5 forms an optionally substituted aryl ring;
  • R 5 is H, lower alkyl, lower alkenyl or together with R 4 forms an optionally substituted aryl ring;
  • R is acyl, aralkyl, lower alkyl or -S(0) 2 R
  • R 7 is acyl, aralkyl, lower alkyl or -N 2 ;
  • R 8 is acyl, aralkyl, lower alkyl or is absent when R 7 is -N 2 ;
  • R 9 , R 10 , R 11 and R 12 independently are selected from H, lower alkyl, aralkyl and aryl;
  • R is lower alkyl, aralkyl or aryl
  • R 4 and R 5 form a /?ara-methoxyphenyl moiety, at least one of R ⁇ R is other than H;
  • the compound is not one of the following compounds:
  • X is N or CH, preferably CH;
  • R 1 and R 2 independently are selected from H, halogen, -OR 6 , -NR 7 R 8 cyano, nitro, and carboxy;
  • R 3 is H; -C(0)R 9 , -C(0)OR 10 or -C(0)NR n R 12 ;
  • R 6 is acyl, aralkyl, lower alkyl, halogenated lower alkyl, or -S(0) 2 R ⁇
  • R is acyl, aralkyl, lower alkyl or -N 2 ;
  • R° is acyl, aralkyl, lower alkyl or is absent when R 7
  • R R 9 , R 10 , R 11 and R 12 independently are selected from H, lower alkyl, aralkyl and aryl;
  • R is a lower alkyl, especially isopropyl, ethyl, or i-butyl and each R , 1 14 may be the same or different; provided that the compound is not:
  • R 1 , R 2 , and R 3 are each H; and R 14 is a lower alkyl, especially isopropyl, ethyl, or i-butyl.
  • R 14 is in the para position on the phenyl ring and is a lower alkyl, especially isopropyl, ethyl, or t- butyl.
  • the compounds have the formula
  • X is N or CH, preferably CH;
  • R and R independently are selected from H, halogen, -OR , -NR R , cyano, nitro, and carboxy;
  • R 3 is H; -C(0)R 9 , -C(0)OR 10 or -C(0)NR n R 12 ;
  • R 6 is acyl, aralkyl, lower alkyl, halogenated lower alkyl, or -S(0) 2 R 13
  • R is acyl, aralkyl, lower alkyl or -N 2 ;
  • R 8 is acyl, aralkyl, lower alkyl or is absent when R 7 is -N 2 ;
  • R 9 , R 10 , R 11 and R 12 independently are selected from H, lower alkyl, aralkyl and aryl;
  • R 13 is lower alkyl, aralkyl or aryl
  • R 14 is cycloalkyl, substituted cycloalkyl, fused cycloalkyl ring,
  • heterocycloalkyl or substituted heterocycloalkyl and each R 14 may be the same or different.
  • the compounds have the formula
  • a is 0 to 5;
  • X is N or CH, preferably CH;
  • R 1 and R 2 independently are selected from H, halogen, -OR 6 , -NR 7 R 8 , cyano, nitro, and carboxy, provided that at least one of R 1 or R 2 is -OR 6 ;
  • R 3 is H; -C(0)R 9 , -C(0)OR 10 or -C(0)NR n R 12 ;
  • R 6 is a halogenated lower alkyl
  • R is acyl, aralkyl, lower alkyl or -N 2 ;
  • R 8 is acyl, aralkyl, lower alkyl or is absent when R 7 is -N 2 ;
  • R 9 , R 10 , R 11 and R 12 independently are selected from H, lower alkyl, aralkyl and aryl;
  • R 13 is lower alkyl, aralkyl or aryl
  • R 14 is halogen, -OR 15 , -NR 16 R 17 , cyano, nitro, haloalkyl, lower alkyl or carboxy, and each R 14 may be the same or different;
  • R 15 is acyl, aralkyl or lower alkyl
  • R 16 is acyl, aralkyl, lower alkyl or -N 2 ; and R is acyl, aralkyl, lower alkyl or is absent when R is -N 2 .
  • the compounds are particularly effective against cells that exhibit multidrug resistance. Accordingly, treatment regimens employing the disclosed compounds typically involve first identifying a subject having a multidrug resistant disorder, such as a multidrug resistant tumor or infection. Certain examples of the compounds described above are not particularly cytotoxic, particularly to cells that are not multidrug resistant. Moreover, in one embodiment the disclosed compounds effectively re-sensitize multidrug resistant cells to anti-proliferative agents that are substrates for an MDR transporter. Thus, in one aspect, the disclosed compounds are co-administered with another chemotherapeutic agent, such as an antibiotic or antineoplastic agent. In another embodiment the disclosed compounds are both cytotoxic and render multidrug resistant cells susceptible to one or more additional chemotherapeutic agents by inhibiting an MDR transporter. Accordingly, also disclosed herein are treatment regimens and compositions formulated for combination therapy.
  • FIG. 1 is a scatter plot and comparison of the KB-3-1 cytoxicity QSAR model applied to thirteen active thiosemicarbazones.
  • FIG. 2 is a scatter plot and comparison of the KB-V1 cytoxicity QSAR model applied to twelve active thiosemicarbazones.
  • derivative refers to a compound or portion of a compound that is derived from or is theoretically derivable from a parent compound.
  • ABSC transporters are transporter proteins belonging to the ABC protein superfamily and are capable of, in their native, active, wild type form, extruding drugs from the cells expressing them.
  • ABSC transporter also covers mutant variants of the wild type proteins retaining at least one function of the wild type, even if lacking another.
  • acyl refers group of the formula RC(O)- wherein R is an organic group.
  • alkoxy refers to a group of the formula -OR, wherein R is an organic group.
  • alkyl refers to a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, w-propyl, isopropyl, w-butyl, isobutyl, i-butyl, pentyl, hexyl, heptyl, octyl, decyl, tetradecyl, hexadecyl, eicosyl, tetracosyl and the like.
  • a “lower alkyl” group is a saturated branched or unbranched hydrocarbon having from 1 to 10 carbon atoms.
  • alkenyl refers to a hydrocarbon group of 2 to 24 carbon atoms and structural formula containing at least one carbon-carbon double bond.
  • alkynyl refers to a hydrocarbon group of 2 to 24 carbon atoms and a structural formula containing at least one carbon-carbon triple bond.
  • aliphatic is defined as including alkyl, alkenyl, alkynyl, halogenated alkyl and cycloalkyl groups as described above.
  • a "lower aliphatic” group is a branched or unbranched aliphatic group having from 1 to 10 carbon atoms.
  • amine refers to a group of the formula -NRR', where R and R' can be, independently, hydrogen or an alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, or heterocycloalkyl group described herein.
  • amide group is represented by the formula -C(0)NRR', where R and R' independently can be a hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, or heterocycloalkyl group described herein.
  • Carboxyl refers to a -COOH radical. Substituted carboxyl refers to -COOR where R is aliphatic, heteroaliphatic, alkyl, heteroalkyl, or a carboxylic acid or ester.
  • aryl refers to any carbon-based aromatic group including, but not limited to, benzene, naphthalene, etc.
  • aromatic also includes "heteroaryl group,” which is defined as an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorous.
  • the aryl group can be substituted with one or more groups including, but not limited to, alkyl, alkynyl, alkenyl, aryl, halide, nitro, amino, ester, ketone, aldehyde, hydroxy, carboxylic acid, or alkoxy, or the aryl group can be unsubstituted.
  • alkyl amino refers to alkyl groups as defined above where at least one hydrogen atom is replaced with an amino group.
  • hydroxyl is represented by the formula -OH.
  • alkoxy group is represented by the formula -OR, where R can be an alkyl group, optionally substituted with an alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, halogenated alkyl, or heterocycloalkyl group as described above.
  • halogenated alkyl or "halo alkyl group” refer to an alkyl group as defined above with one or more hydrogen atoms present on these groups substituted with a halogen (F, CI, Br, I).
  • cycloalkyl refers to a non-aromatic carbon-based ring composed of at least three carbon atoms.
  • examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • heterocycloalkyl group is a cycloalkyl group as defined above where at least one of the carbon atoms of the ring is substituted with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorous.
  • Substituted cycloalkyl or “substituted heterocycloalkyl” refers to a cycloalkyl or heterocycloalkyl wherein one or more hydrogen atoms present on these groups is substituted with one or more groups including, but not limited to, alkyl, alkynyl, alkenyl, aryl, halide, nitro, amino, ester, ketone, aldehyde, hydroxy, carboxylic acid, or alkoxy.
  • Carboxyl refers to a -COOH radical. Substituted carboxyl refers to -
  • R is aliphatic, heteroaliphatic, alkyl, heteroalkyl, or a carboxylic acid or ester.
  • Multidrug resistance refers to the ability of target cells and microorganisms, particularly cancer cells and mycobacterial cells, to resist the effects of different -often structurally and functionally unrelated- cytotoxic compounds. MDR can develop after sequential or simultaneous exposure to various drugs. MDR also can develop before exposure to many compounds to which a cell or microorganism may be found to be resistant.
  • Multidrug resistance is discussed in greater detail in Kuzmich et al., "Detoxification Mechanisms and Tumor Cell Resistance to Anticancer Drugs,” particularly section VII, “The Multidrug-Resistant Phenotype (MDR),” Medical Research Reviews, 1991, 11, 185-217, particularly 208-213; and in Georges et al., “Multidrug Resistance and Chemosensitization: Therapeutic Implications for Cancer Chemotherapy," Advances in Pharmacology, 1990, 21, 185-220.
  • MDR may be caused by a variety of factors, most commonly MDR is associated with overexpression of P- glycoprotein (P-gp).
  • P-gp is a member of a superfamily of membrane proteins, termed adenosine triphosphate (ATP)-binding cassette (ABC) proteins, which behave as ATP-dependent transporters and/or ion channels for a wide variety of substrates.
  • ATP adenosine triphosphate
  • AAC adenosine triphosphate
  • P-gp is a multiple transmembrane- spanning glycoprotein.
  • Transfection experiments with the P-gp gene (MDR1, or ABCBl) have demonstrated that P-gp confers MDR upon drug- sensitive tumor cells by providing an energy-dependent efflux pump that lowers the intracellular concentration of the cytotoxic agent, thereby allowing survival of the cell.
  • tumor refers to an abnormal cellular proliferation, which includes benign and malignant tumors, as well as other proliferative disorders.
  • subject includes both human and veterinary subjects.
  • Transport protein refers to a protein that acts to remove chemotherapeutic substances from cells.
  • transport proteins include, without limitation, P- glycoprotein, the protein product of the MDR1 gene. Expression of such transport proteins confers resistance to numerous chemotherapeutic agents and sometimes entire classes of chemotherapeutic s, including Vinca alkaloids, anthracyclines, epipodophyllotoxins, actinomycin D and taxanes.
  • P-glycoprotein is over-expressed in certain chemotherapy resistant tumors and is upregulated during disease progression following chemotherapy in other malignancies.
  • MRP another ABC family transporter, confers a multidrug resistance phenotype that includes many natural product drugs, but is distinct from the resistance phenotype associated with P-gp- In addition to P-gp and MRP there may be other transporters that are involved in cytotoxic drug resistance. In the case of natural product drugs, resistant cell lines have been described that display a multidrug resistant phenotype associated with a drug accumulation deficit, but do not overexpress P-gp or MRP.
  • Treatment refers to a therapeutic intervention that ameliorates a sign or symptom of a disease or pathological condition after it has begun to develop.
  • the term “ameliorating,” with reference to a disease or pathological condition refers to any observable beneficial effect of the treatment.
  • the beneficial effect can be evidenced, for example, by a delayed onset of clinical symptoms of the disease in a susceptible subject, a reduction in severity of some or all clinical symptoms of the disease, a slower progression of the disease, an improvement in the overall health or well-being of the subject, or by other parameters well known in the art that are specific to the particular disease.
  • treating a disease refers to inhibiting the full development of a disease or condition, for example, in a subject who is at risk for a disease such as cancer, particularly a metastatic cancer.
  • coadminister is meant that each of at least two compounds be administered during a time frame wherein the respective periods of biological activity overlap. Thus, the term includes sequential as well as coextensive administration of two or more drug compounds.
  • Treating multidrug resistance means increasing or restoring sensitivity of multidrug resistant cells to therapeutic agents. Treating multidrug resistance also may include inhibiting the development of multidrug resistance in nonresistant cells.
  • prodrug also is intended to include any covalently bonded carriers that release a disclosed compound or a parent thereof in vivo when the prodrug is administered to a subject. Since prodrugs often have enhanced properties relative to the active agent pharmaceutical, such as, solubility and bioavailability, the compounds disclosed herein can be delivered in prodrug form. Thus, also contemplated are prodrugs of the presently claimed compounds, methods of delivering prodrugs and compositions containing such prodrugs. Prodrugs of the disclosed compounds typically are prepared by modifying one or more functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to yield the parent compound. In particular, ester prodrugs are specifically contemplated herein.
  • prodrugs include compounds having an amino or sulfhydryl group functionalized with any group that is cleaved to yield the corresponding free amino or free sulfhydryl group.
  • examples of prodrugs include, without limitation, compounds having a hydroxy, amino and/or sulfhydryl group acylated with an acetate, formate, or benzoate group.
  • protecting group or “blocking group” refers to any group that when bound to a functional group prevents or diminishes the group's susceptibility to reaction.
  • Protecting group generally refers to groups well known in the art which are used to prevent selected reactive groups, such as carboxy, amino, hydroxy, mercapto and the like, from undergoing undesired reactions, such as nucleophilic, electrophilic, oxidation, reduction and the like.
  • deprotecting “deprotected,” or “deprotect,” as used herein, are meant to refer to the process of removing a protecting group from a compound.
  • R 1 and R 2 independently are selected from H, halogen, -OR 6 , -
  • X is N or CH
  • R 3 is H; -C(0)R 9 , -C(0)OR 10 or -C(0)NR n R 12 ;
  • R 4 is H, lower alkenyl or together with R 5 forms an optionally substituted aryl ring and is not H when R 5 is lower alkenyl;
  • R 5 is H, lower alkenyl or together with R 4 forms an optionally substituted aryl ring and is not H when R 4 is lower alkenyl;
  • R 6 is acyl, aralkyl, lower alkyl or -S(0) 2 R 13
  • R is acyl, aralkyl, lower alkyl or -N 2 ;
  • R° is acyl, aralkyl, lower alkyl or is absent when R 7 is -N 2 ;
  • R R 9 , R 10 , R 11 and R 12 independently are selected from H, lower alkyl, aralkyl and aryl; R is lower alkyl, aralkyl or aryl; and
  • R 4 and R 5 form a /?ara-methoxyphenyl moiety, at least one of R , R " and R 3 is other than H;
  • the compound is not one of the following compounds:
  • substructures can be represented by
  • R represents halogen, haloalkyl, such as trifluoromethyl, -OR wherein R 15 is an acyl group, cyano, nitro or carboxy.
  • a is 0 to 5;
  • R 14 is H, halogen, -OR 15 , -NR 16 R 17 , cyano, nitro or carboxy;
  • R 15 is acyl, aralkyl or lower alkyl
  • R 16 is acyl, aralkyl, lower alkyl or -N 2 ;
  • R 17 is acyl, aralkyl, lower alkyl or is absent when R 16 is -N 2 .
  • R 14 may be an ortho, meta or para substituent on the phenyl ring.
  • Such compounds have the formulas:
  • R is -OR and R is a haloalkyl group, such as trifluoromethyl, difluoromethyl, pentafluoroethyl or the like.
  • R 14 is fluoro or fluoroalkyl (e.g., trifluoromethyl, difluoromethyl, pentafluoroethyl or the like).
  • R 14 is fluoro, fluoroalkyl, methyl, or nitro;
  • X is CH;
  • subscript a is 2 to 5 meaning that there are at least two R 14 groups on the phenyl ring.
  • X is N, thus forming a heteroaromatic ring.
  • R 14 is a lower alkyl, especially isopropyl, ethyl, or t- butyl.
  • R 1 , R 2 and R 3 are each H;
  • X is CH; and
  • R 14 is a lower alkyl, especially isopropyl, ethyl, or i-butyl.
  • the compounds have the formula
  • X is N or CH, preferably CH;
  • R 1 and R 2 independently are selected from H, halogen, -OR 6 , -NR 7 R 8 , cyano, nitro, and carboxy;
  • R 3 is H; -C(0)R 9 , -C(0)OR 10 or -C(0)NR n R 12 ;
  • R 6 is acyl, aralkyl, lower alkyl, halogenated lower alkyl, or -S(0) 2 R 13
  • R is acyl, aralkyl, lower alkyl or -N 2 ;
  • R 8 is acyl, aralkyl, lower alkyl or is absent when R 7 is -N 2 ;
  • R 9 , R 10 , R 11 and R 12 independently are selected from H, lower alkyl, aralkyl and aryl;
  • R 13 is lower alkyl, aralkyl or aryl
  • R 14 is cycloalkyl, substituted cycloalkyl, fused cycloalkyl ring, heterocycloalkyl, or substituted heterocycloalkyl and each R 14 may be the same or different.
  • R 14 is a cycloalkyl such as cyclohexyl or a substituted cycloalkyl such as lower alkyl- substituted cyclohexyl.
  • R 1 , R2 and R 3 are each H;
  • X is CH; and
  • R 14 is a cycloalkyl such as cyclohexyl or a substituted cycloalkyl such as lower alkyl- substituted cyclohexyl.
  • the compounds have the formula
  • a is 0 to 5;
  • X is N or CH, preferably CH;
  • R 1 and R 2 independently are selected from H, halogen, -OR 6 , -NR 7 R 8 , cyano, nitro, and carboxy, provided that at least one of R 1 or R 2 is -OR 6 ;
  • R 3 is H; -C(0)R 9 , -C(0)OR 10 or -C(0)NR n R 12 ;
  • R 6 is a halogenated lower alkyl
  • R is acyl, aralkyl, lower alkyl or -N 2 ;
  • R 8 is acyl, aralkyl, lower alkyl or is absent when R 7 is -N 2 ;
  • R 9 , R 10 , R 11 and R 12 independently are selected from H, lower alkyl, aralkyl and aryl;
  • R 13 is lower alkyl, aralkyl or aryl
  • R 14 is halogen, -OR 15 , -NR 16 R 17 , cyano, nitro, haloalkyl, lower alkyl or carboxy, and each R 14 may be the same or different;
  • R is acyl, aralkyl or lower alkyl;
  • R 16 is acyl, aralkyl, lower alkyl or -N 2 ;
  • R 17 is acyl, aralkyl, lower alkyl or is absent when R 16 is -N 2 .
  • R x , R 2 and R 3 are each H; X is CH; and R 6 is a fluoroalkyl.
  • R 6 is a halogenated lower alkyl other than -CF 3 .
  • R is a halogen, and more particularly certain disclosed compounds are represented by the formula
  • X is an electron withdrawing group.
  • X is an electron donating group.
  • Examples of both electron withdrawing and electron donating groups may be lone pair donating groups as well, such as an amino, halo, phenol or alkoxy group.
  • halo groups, such as bromo substituents are electron withdrawing groups but also can function as lone pair donating groups by delocalizing electron density to the attached phenyl ring.
  • X is selected from H, -OCH 3 , -CH 3 , -CH 2 CH 3 , -F, -CI, -Br, -I, -CF 3 , -OCF 3 , -N0 2 , phenyl, -N , -CN, -OH, -NH 2 , -Nme 2 , -COOH and -S0 " .
  • X is a hydrogen bond acceptor.
  • Hydrogen bond-accepting groups are well known to those of skill in the art, but typically include groups having a lone pair of electrons to engage in hydrogen bonding. Examples of such groups include, without limitation, alkoxy, acyl and amino groups.
  • MDR-inverse compounds include, without limitation:
  • One approach to the synthesis of the disclosed thiosemicarbazones involves the reaction of hydrazine or a protected derivative thereof with a
  • equimolar amounts of isatin and thiosemicarbazide are dissolved in a protic solvent, such as ethanol, optionally with the addition of an acid catalyst, such as a few drops of acetic acid to initiate the reaction.
  • a protic solvent such as ethanol
  • an acid catalyst such as a few drops of acetic acid
  • the phenylthiosemicarbazide was synthesized by the reaction of hydrazine with a substituted phenylisothiocyanate of choice, such as p- methoxyphenylisothiocyanate.
  • a substituted phenylisothiocyanate of choice such as p- methoxyphenylisothiocyanate.
  • the reaction of hydrazine with /7-methoxyphenylisothiocyanate yields 4- (4- methox hen l - 3 -thio semicarbazide .
  • compositions and Methods for their Use Another aspect of the disclosure includes pharmaceutical compositions prepared for administration to a subject and which include a therapeutically effective amount of one or more of the currently disclosed compounds.
  • the therapeutically effective amount of a disclosed compound will depend on the route of
  • compositions for administration to a subject can include carriers, thickeners, diluents, buffers, preservatives, surface active agents and the like in addition to the molecule of choice.
  • Pharmaceutical compositions can also include one or more additional active ingredients such as antimicrobial agents, anti- inflammatory agents, anesthetics, and the like.
  • Pharmaceutical formulations can include additional components, such as carriers. The pharmaceutically acceptable carriers useful for these formulations are conventional. Remington's
  • parenteral formulations usually contain injectable fluids that include pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like as a vehicle.
  • injectable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like as a vehicle.
  • physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like
  • solid compositions for example, powder, pill, tablet, or capsule forms
  • conventional non-toxic solid carriers can include, for example, pharmaceutical grades of mannitol, lactose, starch, or magnesium stearate.
  • compositions to be administered can contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, preservatives, and pH buffering agents and the like, for example sodium acetate or sorbitan monolaurate.
  • non-toxic auxiliary substances such as wetting or emulsifying agents, preservatives, and pH buffering agents and the like, for example sodium acetate or sorbitan monolaurate.
  • compositions disclosed herein include those formed from pharmaceutically acceptable salts and/or solvates of the disclosed compounds.
  • Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids. Particular disclosed compounds possess at least one basic group that can form acid-base salts with acids. Examples of basic groups include, but are not limited to, amino and imino groups. Examples of inorganic acids that can form salts with such basic groups include, but are not limited to, mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid.
  • Basic groups also can form salts with organic carboxylic acids, sulfonic acids, sulfo acids or hosphor acids or N-substituted sulfamic acid, for example acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, fumaric acid, malic acid, tartaric acid, gluconic acid, glucaric acid, glucuronic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-aminosalicylic acid, 2-phenoxybenzoic acid, 2- acetoxybenzoic acid, embonic acid, nicotinic acid or isonicotinic acid, and, in addition, with amino acids, for example with a-amino acids, and also with methanesulfonic acid, ethanesulfonic acid, 2-hydroxymethanesulfonic acid, ethane- 1,2-disulf
  • Certain compounds include at least one acidic group that can form an acid- base salts with an inorganic or organic base.
  • salts formed from inorganic bases include salts of the presently disclosed compounds with alkali metals such as potassium and sodium, alkaline earth metals, including calcium and magnesium and the like.
  • salts of acidic compounds with an organic base such as an amine (as used herein terms that refer to amines should be understood to include their conjugate acids unless the context clearly indicates that the free amine is intended) are contemplated, including salts formed with basic amino acids, aliphatic amines, heterocyclic amines, aromatic amines, pyridines, guanidines and amidines.
  • aliphatic amines the acyclic aliphatic amines, and cyclic and acyclic di- and tri- alkyl amines are particularly suitable for use in the disclosed compounds.
  • quaternary ammonium counterions also can be used.
  • Suitable amine bases for use in the present compounds include, without limitation, pyridine, N,N-dimethylaminopyridine, diazabicyclononane, diazabicycloundecene, N-methyl-N-ethylamine, diethylamine, triethylamine, diisopropylethylamine, mono-, bis- or tris- (2-hydroxyethyl)amine, 2-hydroxy-iert-butylamine,
  • Compounds disclosed herein can be crystallized and can be provided in a single crystalline form or as a combination of different crystal polymorphs. As such, the compounds can be provided in one or more physical form, such as different crystal forms, crystalline, liquid crystalline or non-crystalline (amorphous) forms. Such different physical forms of the compounds can be prepared using, for example different solvents or different mixtures of solvents for recrystallization.
  • polymorphs can be prepared, for example, by performing recrystallizations at different temperatures and/or by altering cooling rates during recrystallization.
  • the presence of polymorphs can be determined by X- ray crystallography, or in some cases by another spectroscopic technique, such as solid phase NMR spectroscopy, IR spectroscopy, or by differential scanning calorimetry.
  • the presently disclosed compounds are useful for the treatment of hyperproliferative disorders wherein the hyperproliferative cells exhibit MDR or are likely to develop MDR.
  • MDR is likely to develop in proliferative disorders being treated with an MDR-inducing chemotherapeutic agent.
  • Chemotherapeutic s that tend to induce MDR are known to those of skill in the arts of pharmacology and oncology and include, for example Vinca alkaloids, anthracyclines, epipodophyllotoxins, taxols, actinomycin D, cardiac glycosides, immunosuppressive agents, glucocorticoids, and anti-HIV protease inhibitors.
  • One aspect of the present disclosure includes methods for treating a hyperproliferative disorder by administering a therapeutically effective amount of the disclosed compounds to a subject in need thereof.
  • particular proliferative disorders that can be so treated include solid tumors, such as sarcomas and carcinomas, include fibrosarcoma, myxosarcoma, liposarcoma,
  • mesothelioma Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, lymphoid malignancy, pancreatic cancer, breast cancer, lung cancers, ovarian cancer, prostate cancer, hepatocellular carcinoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, Wilms' tumor, cervical cancer, testicular tumor, bladder carcinoma, and CNS tumors (such as a glioma, astrocytoma, medulloblastoma, craniopharyogioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligode
  • the present disclosure also provides methods to treat hyperproliferative disorders that are characterized multidrug resistance.
  • the presently disclosed compounds and compositions can be used to inhibit multidrug resistant prostate, breast, colon, bladder, cervical, skin, testicular, kidney, ovarian, stomach, brain, liver, pancreatic or esophageal cancer, or lymphoma, leukemia or multiple myeloma.
  • the disclosed compounds and compositions are used to treat a subject is at risk of developing a metastatic proliferative disorder.
  • hematological tumors examples include leukemias, including acute leukemias (such as acute lymphocytic leukemia, acute myelocytic leukemia, acute myelogenous leukemia and myeloblastic, promyelocytic, myelomonocytic, monocytic and erythroleukemia), chronic leukemias (such as chronic myelocytic (granulocytic) leukemia, chronic
  • myelogenous leukemia and chronic lymphocytic leukemia
  • polycythemia vera lymphoma
  • lymphoma lymphoma
  • Hodgkin' s disease non-Hodgkin' s lymphoma (indolent and high grade forms)
  • multiple myeloma Waldenstrom's macroglobulinemia, heavy chain disease, myelodysplasia syndrome, hairy cell leukemia and myelodysplasia.
  • the therapeutically effective amount of the compound or compounds administered can vary depending upon the desired effects and the factors noted above. Typically, dosages will be between about 0.01 mg/kg and 250 mg/kg of the subject's body weight, and more typically between about 0.05 mg/kg and 100 mg/kg, such as from about 0.2 to about 80 mg/kg, from about 5 to about 40 mg/kg or from about 10 to about 30 mg/kg of the subject's body weight.
  • unit dosage forms can be formulated based upon the suitable ranges recited above and a subject's body weight.
  • the term "unit dosage form" as used herein refers to a physically discrete unit of therapeutic agent appropriate for the subject to be treated.
  • dosages are calculated based on body surface area and from about 1 mg/m 2 to about 200 mg/m 2 , such as from about 5 mg/m 2 to about 100 mg/m 2 will be administered to the subject per day.
  • dosages are calculated based on body surface area and from about 1 mg/m 2 to about 200 mg/m 2 , such as from about 5 mg/m 2 to about 100 mg/m 2 will be administered to the subject per day.
  • dosages are calculated based on body surface area and from about 1 mg/m 2 to about 200 mg/m 2 , such as from about 5 mg/m 2 to about 100 mg/m 2 will be administered to the subject per day.
  • dosages are calculated based on body surface area and from about 1 mg/m 2 to about 200 mg/m 2 , such as from about 5 mg/m 2 to about 100 mg/m 2 will be administered to the subject per day.
  • administration of the therapeutically effective amount of the compound or compounds involves administering to the subject from about 5 mg/m to about 50 mg/m 2 , such as from about 10 mg/m 2 to about 40 mg/m 2 per day. It is currently believed that a single dosage of the compound or compounds is suitable, however a therapeutically effective dosage can be supplied over an extended period of time or in multiple doses per day. Thus, unit dosage forms also can be calculated using a subject's body surface area based on the suitable ranges recited above and the desired dosing schedule.
  • the disclosed compounds are used in combination with other types of treatments, such as cancer treatments.
  • the disclosed inhibitors may be used with other chemotherapies, including those employing an anti-proliferative agent, such as, without limitation, microtubule binding agent, a toxin, a DNA intercalator or cross-linker, a DNA synthesis inhibitor, a DNA and/or RNA transcription inhibitor, an enzyme inhibitor, a gene regulator, enediyne antibiotics and/or an angiogenesis inhibitor.
  • an anti-proliferative agent such as, without limitation, microtubule binding agent, a toxin, a DNA intercalator or cross-linker, a DNA synthesis inhibitor, a DNA and/or RNA transcription inhibitor, an enzyme inhibitor, a gene regulator, enediyne antibiotics and/or an angiogenesis inhibitor.
  • the presently disclosed compounds are used to render a neoplasm susceptible to one or more anti-proliferative compounds to which it is resistant.
  • the disclosed compounds can be used in combination
  • Microtubule binding agent refers to an agent that interacts with tubulin to stabilize or destabilize microtubule formation thereby inhibiting cell division.
  • microtubule binding agents examples include, without limitation, paclitaxel, docetaxel, vinblastine, vindesine, vinorelbine (navelbine), the epothilones, colchicine, dolastatin 15, nocodazole, podophyllotoxin and rhizoxin. Analogs and derivatives of such compounds also can be used and will be known to those of ordinary skill in the art. For example, suitable epothilones and epothilone analogs for incorporation into the present compounds are described in International Publication No. WO 2004/018478, which is incorporated herein by reference.
  • Taxoids such as paclitaxel and docetaxel are currently believed to be particularly useful as therapeutic agents in combination with the presently disclosed compounds.
  • Examples of additional useful taxoids, including analogs of paclitaxel are taught by U.S. Patent Nos. 6,610,860 to Holton, 5,530,020 to Gurram et al. and 5,912,264 to Wittman et al. Each of these patents is incorporated herein by reference.
  • Suitable DNA and/or RNA transcription regulators for use with the disclosed compounds include, without limitation, actinomycin D, daunorubicin, doxorubicin and derivatives and analogs thereof also are suitable for use in combination with the presently disclosed compounds.
  • DNA intercalators, cross-linking agents and alkylating agents that can be used in combination therapy with the disclosed compounds include, without limitation, cisplatin, carboplatin, oxaliplatin, mitomycins, such as mitomycin C, bleomycin, chlorambucil, cyclophosphamide, isophosphoramide mustard and derivatives and analogs thereof.
  • DNA synthesis inhibitors suitable for use as therapeutic agents include, without limitation, methotrexate, 5-fluoro-5'-deoxyuridine, 5-fluorouracil and analogs thereof.
  • Suitable enzyme inhibitors for use in combination with the presently disclosed compounds include, without limitation, camptothecin, etoposide, formestane, trichostatin and derivatives and analogs thereof.
  • Suitable therapeutics for use with the presently disclosed compounds that affect gene regulation include agents that result in increased or decreased expression of one or more genes, such as, without limitation, raloxifene, 5-azacytidine, 5-aza-
  • angiogenesis inhibitor is used herein, to mean a molecule including, but not limited to, biomolecules, such as peptides, proteins, enzymes, polysaccharides, oligonucleotides, DNA, RNA, recombinant vectors, and small molecules that function to inhibit blood vessel growth.
  • biomolecules such as peptides, proteins, enzymes, polysaccharides, oligonucleotides, DNA, RNA, recombinant vectors, and small molecules that function to inhibit blood vessel growth.
  • Angiogenesis inhibitors are known in the art and examples of suitable angiogenesis inhibitors include, without limitation, angiostatin Kl-3, staurosporine, genistein, fumagillin,
  • medroxyprogesterone SFTI-1, suramin, interferon-alpha, metalloproteinase inhibitors, platelet factor 4, somatostatin, thromobospondin, endostatin, thalidomide, and derivatives and analogs thereof.
  • such agents include adriamycin, apigenin, erlotinib, gefitinib,
  • temozolomide rapamycin, topotecan, carmustine, melphalan, mitoxantrone, irinotecanetoposide, tenoposide, zebularine, cimetidine, and derivatives and analogs thereof.
  • Suitable dosages and treatment regimes for administering the above- identified therapeutic agents are known to those of ordinary skill in the art of oncology and also are described, for example, in Physicians' Cancer Chemotherapy Drug Manual 2005 By Edward Chu and Vincent T. DeVita (ISBN 0763734616), which is incorporated herein by reference. Such dosages and treatment regimens can be used in combination with a presently disclosed MDR-inverse compound.
  • the compounds disclosed herein may be administered orally, topically, transdermally, parenterally, via inhalation or spray and may be administered in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • oral administration or administration via implantation or intravenously, such as via injection is preferred.
  • the particular mode of administration employed may be dependent upon the particular disease, condition of patient, toxicity of compound and other factors as will be recognized by a person of ordinary skill in the art.
  • preferred therapeutic agents are identified herein by assessing their in vitro activity in a cytotoxicity assay.
  • certain disclosed therapeutic agents exhibit in vitro IC 50 values against a model cell line of less than about 20 ⁇ , such as less than about 10 ⁇ , such as from about 0.1 nM to about 1 ⁇ , in particular from about 1 nM or 5 nM to about 500 nM, such as from about 50 nM to about 200 nM.
  • Suitable cell lines against which the disclosed compounds may be assessed are well known to those of skill in the art and include, by way of example, 4T1 breast cancer cells. Active compounds also can be identified and evaluated using MDR cell lines.
  • the observed, selective cytotoxicity of the described above was primarily assessed with respect to two biological properties: (1) The absolute cytotoxicity (measured using the MTT assay) of compounds against parental P-gp-negative KB- 3-1 adenocarcinoma cells; and (2) MDRl selectivity, as indicated by greater sensitivity in KB-Vl cells compared to KB-3-1 cells.
  • Exemplary compounds were also tested against the KB-Vl adenocarcinoma cell line that expresses high levels of P-gp (the protein product of MDRl).
  • the KB-Vl cell line was originally developed by step-wise selection of KB-3-1 cells in the drug vinblastine (see, Shen et al.
  • MDRl selectivity is determined by the ratio of IC 50 against KB-3-1 cells divided by its IC 50 against KB-Vl cells. A value > 1 indicates that the compound kills P-gp expressing cells more effectively than parental cells, resulting in so-called MDRl -inverse activity (see, Ludwig et al. Selective toxicity of
  • Triapine (3-AP) was generously provided by Vion
  • thiosemicarbazones Synthesis of thiosemicarbazones.
  • the thiosemicarbazones were prepared by combining equimolar quantities of the isatins and thiosemicarbazides dissolved in large amounts of ethanol with addition of a few drops of acetic acid to initiate the reaction. On heating the mixture to boiling the thiosemicarbazone often crystallized; if it did not, water was added to encourage it.
  • the best solvent for recrystallization of thiosemicarbazones was DMSO with small amounts of water.
  • the thiosemicarbazones also can be prepared by reacting ⁇ -Boc protected hydrazine, i-butylcarbazate, with a selected isothiocyanate resulting in i-Boc protected thiosemicarbazide that can be readily deprotected with acid.
  • i-Boc protected thiosemicarbazide that can be readily deprotected with acid.
  • the (M+H) + and (M-H) ⁇ ions lost the elements of the corresponding RNCS on MS although (M) ⁇ ions were also detected.
  • NSC716766 l-(5'-Nitroisatin)-4-phenyl-3-thiosemicarbazone was prepared by reacting 5-nitroisatin with 4-phenyl-3-thiosemicarbazide. Yield 70%, light brown plates, mp 250-252°C dec.
  • NSC716771 l-(5'-Bromoisatin)-4-(4'-fluorophenyl)-3-thiosemicarbazone was prepared by reacting 5-bromoisatin with 4-(4'-fluorophenyl)-3-thiosemicarbazide. Yield 97%, orange needles, mp 238-240°C dec.
  • Compound 15. 1 -(4 ' - Acetylaminobenzaldehyde) -4- (4 ' -methoxyphenyl) -3- thiosemicarbazone was prepared by reacting 4-acetylaminobenzaldehyde with 4- (4'-methoxyphenyl)-3-thiosemicarbazide.
  • Compound M2 was prepared by reaction of t-butylcarbazate with cyclohexyl isothiocyanate. The t-Boc group was removed by acid hydrolysis, and the resulting 4-cyclohexyl-3-thiosemicarbazide was reacted with isatin, yielding l-Isatin-4— cyclohexyl-3-thiosemicarbazone.
  • Compound M3 was prepared by reaction of t-butylcarbazate with 4- (dimethylamino)phenyl isothiocyanate.
  • the t-Boc group was removed by acid hydrolysis, and the resulting 4'-(dimethylamino)phenyl-3-thiosemicarbazide was reacted with isatin, yielding l-Isatin-4-(4'-(dimethylamino)phenyl)-3- thiosemicarbazone.
  • Compound M4 was prepared by reaction of t-butylcarbazate with 4-hydroxyphenyl isothiocyanate.
  • the t-Boc group was removed by acid hydrolysis, and the resulting 4-(4'-hydroxyphenyl)-3-thiosemicarbazide was reacted with isatin, yielding 1- Isatin-(4'-hydroxyphenyl)-3-thiosemicarbazone.
  • Compound M5 was prepared by reaction of t-butylcarbazate with 2-chlorophenyl isothiocyanate.
  • the t-Boc group was removed by acid hydrolysis, and the resulting 4-(2'-chloroxyphenyl)-3-thiosemicarbazide was reacted with isatin, yielding 1- Isatin-(2'-chlorophenyl)-3-thiosemicarbazone.
  • Compound M6 was prepared by reaction of t-butylcarbazate with benzyl isothiocyanate. The t-Boc group was removed by acid hydrolysis, and the resulting 4-benzyl-3-thiosemicarbazide was reacted with isatin, yielding l-Isatin-4-benzyl-3- thiosemicarbazone .
  • Compound M7 was prepared by reaction of t-butylcarbazate with 3-chlorophenyl isothiocyanate.
  • Compound M9 was prepared by reaction of t-butylcarbazate with 4- (trifluoromethyl)phenyl isothiocyanate.
  • the t-Boc group was removed by acid hydrolysis, and the resulting 4-(4'-(trifluoromethyl)phenyl)-3-thiosemicarbazide was reacted with isatin, yielding l-Isatin-4-(4'-(trifluoromethyl)phenyl)-3- thiosemicarbazone.
  • Compound M10 was prepared by reaction of t-butylcarbazate with 4-fluorophenyl isothiocyanate. The t-Boc group was removed by acid hydrolysis, and the resulting
  • Compound Mil was prepared by reaction of t-butylcarbazate with butyl isothiocyanate.
  • the t-Boc group was removed by acid hydrolysis, and the resulting 4-butyl-3-thiosemicarbazide was reacted with isatin, yielding l-Isatin-4-butyl-3- thiosemicarbazone.
  • Compound M12 was prepared by reaction of t-butylcarbazate with 4-chlorophenyl isothiocyanate. The t-Boc group was removed by acid hydrolysis, and the resulting 4-(4'-chloroxyphenyl)-3-thiosemicarbazide was reacted with isatin, yielding 1- Isatin- (4 ' -chlorophenyl) -3- thiosemicarbazone .
  • Compound M15 was prepared by reaction of t-butylcarbazate with isopropyl isothiocyanate.
  • the t-Boc group was removed by acid hydrolysis, and the resulting 4-isopropyl-3-thiosemicarbazide was reacted with isatin, yielding l-Isatin-4- isopropyl-3-thiosemicarbazone .
  • Compound M18 was prepared by reaction of t-butylcarbazate with 2- methoxyphenyl isothiocyanate.
  • Compound M19 was prepared by reaction of t-butylcarbazate with 4- carboxyphenyl isothiocyanate.
  • the t-Boc group was removed by acid hydrolysis, and the resulting 4-(4'-carboxyphenyl)-3-thiosemicarbazide was reacted with 5- fluoroisatin, yielding l-isatin-4-(4'-carboxyphenyl)-3-thiosemicarbazone.
  • Compound M20 was prepared by reaction of t-butylcarbazate with 1-napthyl isothiocyanate. The t-Boc group was removed by acid hydrolysis, and the resulting 4-(l'-napthyl)-3-thiosemicarbazide was reacted with isatin, yielding l-isatin-4-(l'- napthyl)-3-thiosemicarbazone.
  • Compound M21 was prepared by reaction of t-butylcarbazate with 1- isothiocyanato-4-methoxybenzene.
  • the t-Boc group was removed by acid hydrolysis, and the resulting 4-phenoxybenzene-3-thiosemicarbazide was reacted with isatin, yielding l-Isatin-4-(4-phenoxybenzene)-3-thiosemicarbazone.
  • Compound M22 was prepared by reaction of t-butylcarbazate with 1-adamantyl isothiocyanate. The t-Boc group was removed by acid hydrolysis, and the resulting 4-( - adamantyl)-3-thiosemicarbazide was reacted with isatin, yielding l-isatin-4- (1'- adamantyl)-3-thiosemicarbazone.
  • Compound M22 was prepared by reaction of t-butylcarbazate with 3,4,5- trimethoxyphenyl isothiocyanate.
  • the t-Boc group was removed by acid hydrolysis, and the resulting 4-(3',4',5'-trimethoxyphenyl)-3-thiosemicarbazide was reacted with isatin, yielding l-isatin-4-(3',4',5'-trimethoxyphenyl)-3-thiosemicarbazone.
  • the general procedure for the synthesis of M25 - M35 followed that described in Hall et al.
  • the thiosemicarbazide was prepared from the commercially available isothiocyanate (top scheme of figure) by reaction of tert-butylcarbazate with the substituted isothiocyanate. The t-Boc group was removed by acid hydrolysis, and the substituted thiosemicarbazide was used for the synthesis of the thiosemicarbazone.
  • M25 l-isatin-4-(3',4',5'-trifluorophenyl)-3-thiosemicarbazone was prepared by reacting isatin with 4-(3',4',5'-trifluorophenyl)-3-thiosemicarbazide.
  • M26 was prepared by reacting isatin with N- ⁇ 4-
  • l-isatin-4-(4'-isopropylphenyl)-3-thiosemicarbazone was prepared by reacting isatin with 4-(4'-isopropylphenyl)-3-thiosemicarbazide.
  • M28. l-isatin-4-(4'-ethylphenyl)-3-thiosemicarbazone was prepared by reacting isatin with 4-(4'-ethylphenyl)-3-thiosemicarbazide.
  • l-isatin-4-(4'-(propylcyclohexyl)benzene)-3-thiosemicarbazone was prepared by reacting isatin with 4-(4'-(propylcyclohexyl)benzene)-3- thiosemicarbazide.
  • l-isatin-4-(5'-indanyl)-3-thiosemicarbazone was prepared by reacting isatin with 4- (5 ' -indanyl) - 3 -thio semicarbazide .
  • cytotoxicity assay Cell survival was measured by the MTT (3-(4,5-dimethylthiazol- 2-yl)-2,5-diphenyltetrazolium bromide) assay as previously described by Ludwig, J. A. et al. Selective toxicity of NSC73306 in MDR1 -positive cells as a new strategy to circumvent multidrug resistance in cancer. Cancer Res 2006, 66, 4808-15, which is incorporated herein by reference. Briefly, cells were seeded in 100 mL of growth medium at a density of 5000 cells/well in 96- well plates and allowed to establish for 24 hours, at which time serially diluted drugs were added in an additional 100 mL growth medium.
  • QSAR quantitative discriminant analysis
  • the thiosemicarbazone functional group was assigned a single site for two reasons; first, assigning individual bonding features of the thiosemicarbazone would potentially result in a large number of extra sites common to most molecules, and second it is possible the thiosemicarbazone group is coordinating to metal ions to effect its cytotoxicity and/or MDR1- selectivity as a bidentate ligand, as is the case for other classes of thiosemicarbazones (Liu et al. Chemical and biological properties of cytotoxic alpha- (N)-heterocyclic carboxaldehyde thiosemicarbazones. Prog Med Chem 1995, 32, 1-35).
  • the hydrogen bond acceptor site corresponding to the aromatic ketone oxygen of isatin-P-thiosemicarbazones or the aromatic nitrogen of triapine, 10 and MAIQ, was deemed important for cytotoxicity, along with their associated aromatic ring/hydrophobic sites. Specific molecules assayed lacking any one of the thiosemicarbazone site, hydrogen bond acceptor site or aromatic ring/hydrophobic sites are inactive, and the failure of thiacetazones, 1, 2, 5 and 15 to match the KB-3- 1 cytotoxicity pharmacophore can be understood in terms of missing the hydrogen bonding site.
  • FIG. 1 is a scatter plot and comparison of the KB-3-1 cytoxicity QSAR model applied to thirteen active thiosemicarbazones.
  • PLS partial least-square
  • FIG. 1 also compares experimental and predicted pICso values for both the training and test set molecules, showing that activity was effectively predicted. This observation further supports the validity of the pharmacophore model, suggesting the spatial arrangement of chemical features, when aligned by the pharmacophore, is indicative of the probable active
  • the KB-3-1 cytoxicity QSAR model quantitatively predicts cytotoxicity, and although strong predictive power is evident, the low number of training/test set compounds warrant caution when using this model for this purpose. Of course, the predictive accuracy will improve once more compounds are added to training and test sets.
  • FIG. 2 is a scatter plot and comparison of the KB- VI cytoxicity QSAR model applied to twelve active thiosemicarbazones.
  • Experimental and calculated pIC 5 o values are shown for the QSAR training and test set.
  • Experimental and predicted pICso values against KB- VI cells for both the training and test set molecules are also shown in FIG. 2, showing that activity was effectively predicted.
  • This example describes assays for identifying multidrug resistance in a subject.
  • detection and/or quantitation of MDRl protein typically is accomplished using immunological techniques.
  • the techniques include flow cytometry and fixed cells on microscope slides. The cells are treated with antibodies specific for the MDRl protein, such as the mouse ARK- 16 monoclonal antibody.
  • Such antibodies can be directly labeled with fluorescent probe, or detected using subsequent reagents such as goat anti-mouse IgG-FITC.
  • Flow cytometry allows for direct quantitative determinations of the full spectrum of MDRl expression using channel number or fluorescence intensity. Microscopic examination of the slide preparations can give qualitative results (-, +, ++, and the like) or, in conjunction with an image analyzer, quantitative evaluations typically expressed in pixels.
  • ICC immunocytochemistry
  • IHC immunohistochemistry
  • ICC immunocytochemistry
  • IHC immunohistochemistry
  • the detection techniques are the same as described for fixed leukemia cells on microscope slides.
  • Expression of MDRl can also be monitored by the measurement of specific mRNA levels.
  • Cell slides can be processed, and levels of mRNA discerned using basic molecular biology techniques such as quantitative fluorescent PCR.
  • the cells of interest can be lysed, processed, and following PCR of the mRNA, the product can be detected and quantitated following gel electrophoresis.
  • Anti-sense targeting of MDRl mRNA is also possible, followed by standard techniques for quantitative determinations.
  • Radio-labeled probes followed by autoradiography or other radiodetection techniques can also be used to obtain a relative estimate of MDRl protein or mRNA expression.
  • MDR1- specific antibodies labeled with any number of detectable markers such as radioactive compounds detectable with positron emission tomography (PET), single- photon emission computed tomography (SPECT) or compounds detectable with magnetic resonance imaging (MRI) can be used to assess MDRl expression in a subject having cancer or an MDRl-expressing infection, such as multidrug resistant tuberculosis.
  • PET positron emission tomography
  • SPECT single- photon emission computed tomography
  • MRI magnetic resonance imaging
  • MDRl function i.e., functional expression of MDRl also can be evaluated.
  • MDRl functions as a cytoplasmic membrane pump, effluxing compounds such as drugs and toxins from the cytoplasm to the exterior of the cell.
  • Compounds acted on by MDRl are termed MDRl substrates.
  • Detection of MDRl function therefore involves detection of substrate efflux, such as the efflux of a particular drug, or alternatively, detection of efflux of surrogate fluorescent dye markers that also are MDRl substrates, such as DiOC2 (3,3'-diethyloxacarbocyanine iodide) or
  • Rhodamine 123 (Rhl23, or 2-(6-amino-3-imino-3H-xanthen-9-yl)benzoic acid, methyl ester).
  • a substrate for MDRl such as the aforementioned dye markers, radiolabeled drugs, or drugs that can be detected and/or quantitated by other means such as fluorescence.
  • MDRl a substrate for MDRl
  • the net accumulation of the substrate over time, in the presence or absence of specific MDRl inhibitors gives an indication of the MDRl functional activity exhibited by the cells.
  • the single cell suspension can be exposed to the substrate and subsequent efflux of the substrate over time monitored at physiological temperature in the presence or absence of specific MDRl inhibitors.
  • PET, SPECT, and MRI techniques also can be used to assess MDRl function in cancer patients.
  • small organic molecules as well as metal complexes that serve as MDRl substrates can be labeled with radionuclides or other detectable markers.
  • functional expression in solid tumors can be more efficiently ascertained by ICC/IHC techniques with prior labeling of the tumor cells in the patient.
  • Diagnostic testing methods for MDRl expression and efflux pump activity can be used to prospectively stratify patients for treatment optimization in treating malignancies exhibiting MDR1 expression or function, such as acute myelogenous leukemia, most solid tumors, lymphomas, bladder cancer, pancreatic cancer, ovarian cancer, liver cancer, myeloma, lymphocytic leukemia, and sarcoma.
  • the disclosed techniques for identifying subjects having MDR-resistant cells are applicable to any therapeutic drug that is a substrate for P-gp-mediated efflux.
  • drugs include, but are not limited to, P-glycoprotein substrates; anticancer drugs as described above and including, by way of example Vinca alkaloids such as vinblastine and vincristine; anthracyclines such as doxorubicin, daunorubicin, epirubicin; anthracenes such as bisantrene and mitoxantrone; epipodophyllo-toxins such as etoposide and teniposide; and other anticancer drugs such as actinomyocin D, mithomycin C, mitamycin, methotrexate, docetaxel, etoposide (VP-16), paclitaxel, docetaxel, and adriamycin; immunosuppressants, including cyclosporine A and tacrolimus; steroids, by way of example, dexamethasone, hydrocort
  • antipsychotics such as fluphenazine, haloperidol, thioridazine and trimipramine
  • HIV protease inhibitors for example, amprenavir, indinavir, lopinavir, nelfinavir, ritonavir and saquinavir
  • calcium blockers for example, bepridil, diltiazem, flunarizine, lomerizine, secoverine, tamolarizine, verapamil, nicardipine, prenylamine and fendiline.
  • MDR-Inverse Compounds This example describes the treatment of a subject having a multidrug resistant disorder, such as a multidrug resistant tumor. Subjects having such disorders can be identified, for example, as set forth above in Example 4. In one embodiment, a subject having a multidrug resistant disorder is administered an MDR-inverse compound disclosed herein, such as compound 7:
  • the MDR-inverse compound is administered intravenously in an amount of 400 mg/day or less to about 1,600 mg/day or more, preferably from about 500, 600, or 700 mg/day to about 900, 1000, 1100, 1200, 1300, 1400, or 1500 mg/day, and most preferably about 700 mg/day.
  • the MDR-inverse compound such as compound 7, preferably is administered on two, three, or four separate days.
  • the dosage typically is administered in intravenously continuously over the course of about 3 to about 90 hours, more preferably over the course of about 4, 6, 12, 18, 24 or 30, 36, or 42 hours to about 54, 60, 66, 72, 78, or 84 hours, most preferably over about 24 hours, 48 hours, or 72 hours, depending upon the treatment regimen.
  • the MDR- inverse compound is administered on multiple days of the treatment regimen.
  • Combination Therapy using MDR-inverse Compounds As discussed above, the drugs which are substrates of P-gp are quite varied as are the associated disease states.
  • One form of cancer characterized by high rates of P-gp expression is acute myelogenous leukemia. This example describes the treatment of acute myelogenous leukemia, where it has been demonstrated that the levels of P-gp expression and function are significantly related to response to the chemotherapy.
  • Daunorubicin is an antibiotic chemotherapy treatment that is widely used to treat acute myeloid leukemia and acute lymphocytic leukemia. It was approved by the FDA as a first line therapy treatment for leukemia in 1998. Daunorubicin is typically administered intravenously. Daunorubicin is marketed under the brand names Cerubidine, DaunoXome, and Liposomal daunorubicin.
  • Cytarabine is a deoxycytidine analogue, cytosine arabinoside (ara-C), which is metabolically activated to the triphosphate nucleotide (ara-CTP), which acts as a competitive inhibitor of DNA polymerase and produces S phase- specific
  • cytotoxicity It is used as an antineoplastic, generally as part of a combination chemotherapy regimen, in the treatment of acute lymphocytic and acute
  • myelogenous leukemia the blast phase of chronic myelogenous leukemia, erythroleukemia, and non-Hodgkin's lymphoma.
  • the compound typically is administered intravenously and subcutaneously, and for the prophylaxis and treatment of meningeal leukemia, administered intrathecally.
  • Contemplated amounts of the presently disclosed MDR-inverse compounds, such as NSC73306, for administration to treat acute myelogenous leukemia are from about 400 mg/day or less to about 1,600 mg/day or more, preferably from about 500, 600, or 700 mg/day to about 900, 1000, 1100, 1200, 1300, 1400, or 1500 mg/day, and most preferably about 700 mg/day.
  • the MDR-inverse compound, such as NSC73306, preferably is administered on two, three, or four separate days.
  • MDR-inverse compounds disclosed herein can be administered in place of or in addition to NSC73306.
  • the dosage typically is administered in intravenously continuously over the course of about 6 to about 90 hours, more preferably over the course of about 12, 18, 24 or 30, 36, or 42 hours to about 54, 60, 66, 72, 78, or 84 hours, most preferably over about 24 hours, 48 hours, or 72 hours, depending upon the treatment regimen.
  • the MDR-inverse compound is administered on multiple days of the treatment regimen.
  • Contemplated amounts of daunorubicin for intravenous administration to treat acute myelogenous leukemia are from about 10 mg/m /day or less to about 100 mg/m /day or more administered in combination with MDR-inverse compound infusion or up to about 1 to about 8, such as 1, 2, 3, 4, 5, or 6 or more hours after initiation of MDR-inverse compound infusion.
  • the dosage is preferably
  • Amounts of cytarabine for intravenous administration to treat acute myelogenous leukemia are from about 10 mg/day or less to about 3,000 mg/day or more administered at initiation of MDR-inverse compound infusion or after initiation of MDR-inverse compound infusion.
  • the dosage is preferably
  • administering intravenously at a rate of about 50 mg/m /day or less to about 200 mg/m 2 /day or more, preferably 60, 70, 80, or 90 mg/m 2 /day or less to about 110, 120, 130, 140, 150, 160, 170, 180, or 190 mg/m.sup.2/day, and most preferably about 100 mg/m /day continuously over the course of about 1, 2, 3, 4, 5, or 6 days up to about 8, 9, or 10 days or more, preferably over about 7 days.
  • the methods are also particularly effective when P-gp substrates are administered as chemotherapeutic agents in the treatment of other disorders, including other hyperproliferative disorders, exhibiting some degree of P-gp expression.
  • disorders can include lymphomas, bladder cancer, pancreatic cancer, ovarian cancer, liver cancer, myeloma, lymphocytic leukemia, sarcoma, metastatic breast cancer, and most solid tumors.
  • Chemotherapeutic agents that are P-gp substrates include, without limitation, anthracyclines (for example, doxorubicin, daunorubicin, epirubicin, idarubicin, mitoxantrone), Vinca alkaloids (for example, vincristine, vinblastine, vinorelbine, vindesine), Topoisomerase-II inhibitors (for example, etoposide, teniposide), taxanes (e.g., paclitaxel, docetaxel), and others (for example, Gleevec and dactinomycin).
  • anthracyclines for example, doxorubicin, daunorubicin, epirubicin, idarubicin, mitoxantrone
  • Vinca alkaloids for example, vincristine, vinblastine, vinorelbine, vindesine
  • Topoisomerase-II inhibitors for example, etoposide, teniposide

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  • Organic Chemistry (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés de médicament qui ont une activité anti-MDR et sont donc efficaces contre des cellules résistantes à de multiples médicaments. Des composés à titre d'exemples de la présente invention ont la structure : (1). Il a été découvert que des exemples des composés de la présente invention ont, entre autres, une efficacité dans le traitement direct de cellules résistantes à de multiples médicaments, rendant les cellules résistantes à de multiples médicaments sensibles à d'autres agents de chimiothérapie et, dans d'autres exemples, inversant la résistance à de multiples médicaments.
PCT/US2011/047377 2010-08-20 2011-08-11 Thiosemicarbazones à activité anti-mdr1 WO2012033601A1 (fr)

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CN104402794A (zh) * 2014-11-27 2015-03-11 天津坤健生物制药有限公司 一种3-芳基肼取代吲哚酮类衍生物及其制备方法与应用
WO2017175018A2 (fr) 2016-04-05 2017-10-12 Magyar Tudományos Akadémia Természettudományi Kutatóközpont Dérivés de 8-hydroxy-quinoléine inversant la multirésistance aux médicaments
MD4520B1 (ro) * 2016-12-16 2017-10-31 Государственный Университет Молд0 N-(4-butoxifenil)-2-(piridin-2-ilmetiliden)hidrazincarbotioamida în calitate de inhibitor al proliferării celulelor T-47D ale cancerului mamar
CN108822013A (zh) * 2018-09-17 2018-11-16 浙江乐普药业股份有限公司 一种Lesinurad中间体杂质二聚物及其制备方法和应用
CN109942476A (zh) * 2019-04-19 2019-06-28 郑州大学 一种含缩氨基硫脲结构单元的芳杂环类化合物及其制备方法和应用

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104387312A (zh) * 2014-11-27 2015-03-04 天津坤健生物制药有限公司 一种3-硫代肼基取代吲哚酮类衍生物及其制备方法与应用
CN104402794A (zh) * 2014-11-27 2015-03-11 天津坤健生物制药有限公司 一种3-芳基肼取代吲哚酮类衍生物及其制备方法与应用
WO2017175018A2 (fr) 2016-04-05 2017-10-12 Magyar Tudományos Akadémia Természettudományi Kutatóközpont Dérivés de 8-hydroxy-quinoléine inversant la multirésistance aux médicaments
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MD4520B1 (ro) * 2016-12-16 2017-10-31 Государственный Университет Молд0 N-(4-butoxifenil)-2-(piridin-2-ilmetiliden)hidrazincarbotioamida în calitate de inhibitor al proliferării celulelor T-47D ale cancerului mamar
CN108822013A (zh) * 2018-09-17 2018-11-16 浙江乐普药业股份有限公司 一种Lesinurad中间体杂质二聚物及其制备方法和应用
CN109942476A (zh) * 2019-04-19 2019-06-28 郑州大学 一种含缩氨基硫脲结构单元的芳杂环类化合物及其制备方法和应用
CN109942476B (zh) * 2019-04-19 2020-07-24 郑州大学 一种含缩氨基硫脲结构单元的芳杂环类化合物及其制备方法和应用

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