WO2005118580A2 - Composes tricycliques utiles comme inhibiteurs du mecanisme de signalisation hypoxique - Google Patents

Composes tricycliques utiles comme inhibiteurs du mecanisme de signalisation hypoxique Download PDF

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WO2005118580A2
WO2005118580A2 PCT/US2005/016569 US2005016569W WO2005118580A2 WO 2005118580 A2 WO2005118580 A2 WO 2005118580A2 US 2005016569 W US2005016569 W US 2005016569W WO 2005118580 A2 WO2005118580 A2 WO 2005118580A2
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carboxamide
alkyl
group
aryl
aza
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WO2005118580A3 (fr
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Giovanni Melillo
Robert H. Shoemaker
John H. Cardellina
Michael J. Currens
Mark Creighton-Gutteridge
Badarch Uranchimeg
Annamaria Rapisarda
Dominic A. Scudiero
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The Government Of The United States Of America As Represented By The Secretary, Department Of Health
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    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/24—[b,e]-condensed with two six-membered rings
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    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A—HUMAN NECESSITIES
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
    • A—HUMAN NECESSITIES
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    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D215/14—Radicals substituted by oxygen atoms
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    • C07D219/00—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems
    • C07D219/04—Heterocyclic compounds containing acridine or hydrogenated acridine ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
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    • C07D219/08—Nitrogen atoms
    • C07D219/10—Nitrogen atoms attached in position 9
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    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
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    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/46—Phenazines
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    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
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    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
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    • C07D327/02—Heterocyclic compounds containing rings having oxygen and sulfur atoms as the only ring hetero atoms one oxygen atom and one sulfur atom
    • C07D327/06—Six-membered rings
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    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to tricyclic compounds that inhibit hypoxia inducible transcription factor- 1 (HIF-1) activity.
  • Background Solid tumor growth is dependent upon the supply of nutrients and oxygen from the blood. Typically a tumor mass will not grow beyond 2-3 cubic millimeters unless new blood vessels are formed within the tumor.
  • Such "pre-vascular" tumors and dormant micrometastases maintain their small volume due to a balance of cell proliferation and cell death. Also, they are generally asymptomatic and hence clinically undetected. Formation of new blood vessels (vasculature) within a tumor, by a process known as angiogenesis or neovascularisation, permits further growth, and it is typically vascularised solid tumors that are detected and that require treatment.
  • angiogenesis is an important component of tumorigenesis and the pathogenesis of cancer.
  • a stimulus for angiogenesis is believed to be localized tissue "hypoxia," in which tumor cells become starved of oxygen. This condition is typically observed within solid tumors, and the hypoxic environment is believed to arise largely as a result ofthe rapid aberrant proliferation ofthe cancer cell, and thus inability ofthe tumor to maintain an adequate and organized vasculature to supply oxygen to cells within the tumor.
  • hypoxia adaptation leads to vascularization, and facilitates further tumor growth.
  • HIF-1 Hypoxia-Inducible Factor 1
  • HIF-1 has been shown to play an essential role in cellular responses to hypoxia.
  • hypoxia Upon hypoxic stimulation, HIF-1 is known to activate genes that contain Hypoxic Response Elements (HREs) in their promoters, and thus up- regulate a series of gene products that promote cell survival under conditions of low oxygen availability.
  • HREs Hypoxic Response Elements
  • cytotoxic agents are used to disrupt fundamental cellular processes related to cell growth and division.
  • the capacity of such agents to interfere with normal mitosis and cell division in rapidly proliferating tissues is the basis for their therapeutic action against neoplastic cells.
  • tumor cells are not the only rapidly dividing cells in the body, this mode of treatment leads to unpleasant side effects that may include nausea, vomiting, hair loss and suppression of bone marrow function. Nonetheless, cytotoxic agents are typically administered at the maximum tolerated dose (MTD) because the deleterious side-effects are believed to be justified in an effort to stop a cancer, until the side-effects of a particular dose themselves become life-threatening.
  • MTD maximum tolerated dose
  • the compound has one or more, or all, ofthe previous or following properties, which property is not possessed by the co-administered agent: stimulating HIF-l ⁇ degradation by a novel pathway that is independent of VHL, increasing degradation of HIF-l ⁇ without substantially decreasing expression of HIF-2 ⁇ , decreasing VEGF mRNA expression, inhibiting HIF-l ⁇ activity through a proteosome dependent mechanism, inducing G2/M arrest, being substantially non-cytotoxic, inhibiting HIF-l ⁇ activity by a mechanism which does not involve microtubule disruption, having substantially no inhibiting effect on hsp 90, being independent ofthe AKT pathway, having substantially no inhibiting effect on deacetylation enzymes, being independent ofthe p53 gene, and increasing p21 mRNA expression.
  • the tricyclic compounds have a structure defined by the following formula:
  • FIG. 15 is an image of an immunoblot analysis showing the effects of NSC 644221, NSC 24058, NSC 24568, NSC 24623, NSC 24459, NSC 24544, and NSC 24460 on hypoxia-induced HIF-1 ⁇ protein levels and phosphorylated histone H2A.X levels.
  • FIG. 16 is a schematic representation ofthe chemical structures of NSC 24058,
  • FIG. 27 is an image of an immunoblot analysis showing the effect of NSC 644221 on p21 protein levels in U251 cells without an active p53 gene and in HCTl 16 cells with a wild-type p53 gene.
  • FIG. 28 is a table showing various cells, the nature of their p53 gene, and whether they exhibit HIF- 1 ⁇ inhibition in response to treatment with NSC 644221.
  • FIG. 29 is a bar graph showing the effect of NSC 644221 on HIF-l ⁇ mRNA expression.
  • Additional methods for calculating body surface include the Mosteller formula (Mostetller, NEnglJMed, 317:1098, 1987), the DuBois and DuBois formula (DuBois D; DuBois EF, Arch Int Med, 17:863-71, 1916), the Haycock formula (Haycock et al., The Journal of Pediatrics, 93: 62-66, 1978), and the Gehan and George formula (Gehan EA, George SL, Cancer Chemother Rep, 54:225-35, 1970).
  • the carboxylic acids of such heterocycles can be obtained by metalation with n- butyllithium, followed by either quenching with solid CO 2 or treatment with dimethylformamide, followed by oxidation, for example, with potassium permanganate.
  • the compound is a phenazine compound having the following formula:
  • phenazinecarboxamide compounds are provided in Rewcastle et al., J. Med. Chem., 30: 843-851, 1987, wliich is incorporated by reference herein. Additional examples of such compounds are provided in EP 0172744, which also is incorporated by reference herein.
  • Particular examples disclosed by Rewcastle et al. include the 2-mefhoxy, 2-chloro, 3-methyl, 3-mefhoxy, 3-chloro, 4- methyl, 4-methoxy, 6-methyl, 6-methoxy, 6-chloro, 7-methyl, 7-methoxy, 7-chloro, 8- methyl, 8-methoxy, 8-chloro, 9-methyl, 9-methoxy, and 9-chloro derivatives of:
  • Phenazine carboxamide compounds may be synthesized according to the procedures described in Rewcastle et al. and in EP 0172744. Briefly, phenazine- 1- carboxylic acids can be prepared by Jourdan-UUmann copper-catalyzed condensation of substituted anilines with 3-nitro-2-halobenzoic acids using a copper catalyst to provide N-phenylanthranilic acids, which are reductively cyclized (such as with NaBH in alkali) to give the phenazine-1 -carboxylic acid (see, Challand et al., J. Chem. Soc. Chem. Com?n., ⁇ ). 1423, 1970).
  • 9-substituted phenylanthranilic acids also can be synthesized using symmetrical 2,6-disubstituted anilines with subsequent ring closure when the symmetrical substituents ofthe anilines are small and displaceable (such as F or methoxy).
  • Reaction of fluorinated, substituted anilines with 3-nitro-2-halobenzoic acids followed by reductive ring closure can be used to provide 6- and 8-substituted phenazine- 1 -carboxylic acids.
  • Preparation of phenazine- 1 -carboxylic acids with at least one substituent in the 2-, 3-, or 4- utilizes highly substituted benzoic acids as starting materials.
  • R 26 and R 29 in the alternative structures each are independently H or one or more substituents such as acyl, acyloxy, alkoxy, alkyl, alkylthio, amino, aryl, aza, carboxy, carboxamide, diamine, halogen, hydroxyl, mercapto, nitro, sulfonyl, sulfonamido, or sulfato, at least one of which is carboxamide
  • R 27 , R 28 , R 30 , and R 31 in the alternative structures each are independently hydrogen or one or more substituents such as acyl, acyloxy, alkoxy, alkyl, alkylthio, amino, aryl, aza, carboxy, carboxamide, diamine, halogen, hydroxyl, mercapto, nitro, sulfonyl, sulfonamido, or sulfato.
  • arylquinoline compound A particular example of such an arylquinoline compound is disclosed in Woynarowski et al., Anti- cancer Drug Des., 9: 9-24, 1994, which is incorporated by reference herein. Additional arylquinoline compounds are disclosed in Atwell et al., J. Med. Chem., 32: 396-401, 1989, which is inco ⁇ orated by reference herein.
  • Arylquinoline compounds can be synthesized according to the methods disclosed in Atwell et al., J. Med. Chem., 32: 396-401, 1989, and in EP 0206802, both of which are incorporated by reference herein.
  • 2-phenylquinoline-8-carboxylic acids can be produced by a variety of methods.
  • the unsubstituted 2-phenyl-8- carboxylic acid can be synthesized by the Doebner pyruvic acid synthesis of 8-methyl- 2-phenylquinoline-4-carboxylic acid, followed by decarboxylation and oxidation with SeO 2 (see, Doebner and Giesecke, Justus Liebigs Ann.
  • Substituted derivatives can be synthesized by Pfitzinger reaction of substituted acetophenones with 7-methylisatin followed by decarboxylation and oxidation (see, Filippi, J. Bull. Soc. Chim. Fr., 1968, 268).
  • 4'-nitro substituted acids can be prepared by low-temperature nitration of 2-phenylquinoline-8-carboxylic acid in fuming nitric acid to yield a mixture of mono-nitro derivatives followed by isolation ofthe 4'-nitro derivative by repeated recrystalization.
  • an alternative route to the substituted 2-phenylquinoline-8-carboxylic acid is reaction of an ethyl benzoylacetate and a methyl anthranilate to give a Schiff base, which is then cyclized to a quinoline ester and reduced to provide the acid.
  • the acid can then be coupled with the appropriate (dialkylamino)-alkylamine as has been described above for the previously discussed tricyclic carboxamide compounds.
  • the tricyclic compound is an acridine compound having the structure:
  • R 32 and R 33 are independently hydrogen or a substituent such as acyl, acyloxy, alkoxy, alkyl, alkylthio, amino, aryl, aza, carboxy, carboxamide, diamine, halogen, hydroxyl, mercapto, nitro, sulfonyl, sulfonamido, or sulfato; and R 3 is one or more substituents such as acyl, acyloxy, alkoxy, alkyl, alkylthio, amino, aryl, aza, carboxy, carboxamide, diamine, halogen, hydroxyl, mercapto, nitro, sulfonyl, sulfonamido, or sulfato, at least one of which is carboxamide.
  • a particular example of a compound having this type of structure is:
  • R 35 is one or more substituents such as acyl, acyloxy, alkoxy, alkyl, alkylthio, amino, aryl, aza, carboxy, carboxamide, diamine, halogen, hydroxyl, mercapto, nitro, sulfonyl, sulfonamido, or sulfato, at least one of which is carboxamide
  • R 36 is hydrogen or a substituent such as lower alkyl
  • R 37 is hydrogen or a substituent such as acyl, acyloxy, alkoxy, alkyl, alkylthio, amino, aryl, aza, carboxy, carboxamide, diamine, halogen, hydroxyl, mercapto, nitro, sulfonyl, sulfonamido, or sulfato.
  • R 38 is one or more substituents such as acyl, acyloxy, alkoxy, alkyl, alkylthio, amino, aryl, aza, carboxy, carboxamide, diamine, halogen, hydroxyl, mercapto, nitro, sulfonyl, sulfonamido, or sulfato, at least one of which is carboxamide;
  • 2-arylbenzimidazoles include the 2'-methyl; 2'-methoxy; 2'-chloro; 2'aza; 3'methyl; 3'-methoxy; 3'-chloro; 3'-aza; 4'-methyl; 4'-methoxy; 4'-chloro; 4'aza; 4'phenyl; 4'-NHAc; 4'-N(CH 3 ) 2 ; 5-methyl; 6-methyl; 7-methyl; 2',3'-benz; 3',4'-benz; 2'3'-(-OCH 2 -); 2',3'-dimethoxy; and 2',3',4'-trimethoxy derivatives of:
  • HIF-1 amounts can be assessed by gel electrophoresis of a cell extract followed by antibody detection as shown elsewhere in this disclosure.
  • Still another aspect pertains to methods of inhibiting angiogenesis, comprising contacting a cell with an effective amount of a disclosed compound to inhibit HIF-l ⁇ activity, and, for example, reduce the amount of VEGF.
  • the disclosed compound is a dibenzo-[l,4]dioxin carboxamide other than a 6-chloro-[l,4]dioxin-l- carboxamide, such as NSC 644221, and the effective amount may be any amount, including a cytotoxic amount, but, in certain particular examples, is a non-cytotoxic amount.
  • Angiogenesis is the formation of new blood vessels from pre-existing vessels.
  • a method for inhibiting angiogenesis by inhibiting HIF-l ⁇ activity in a subject includes administering to the subject a therapeutically effective amount of one or more of any ofthe compounds disclosed above.
  • the disclosed compound is a dibenzo-[l,4]dioxin carboxamide other than a 6-chloro-[l,4]dioxin-l -carboxamide, such as NSC 644221, and the effective amount may be any amount, including cytotoxic amount, but, in certain particular examples, is a non-cytotoxic amount.
  • the tricyclic compound can be selected to increase degradation of HIF-1 ⁇ and have substantially no effect on degradation of HTF- 2 ⁇ . In other embodiments, the tricyclic compound is selected to increase degradation of HIF- 1 ⁇ in a VHL-independent manner. In yet other embodiments, the compound is selected to have substantially no effect on the level of HIF-1 ⁇ mRNA that is expressed in the subject or the cell. Alternatively, the compound used in the method can be selected to inhibit HIF-1 ⁇ activity through a Topoisomerase-1 -independent mechanism.
  • the compound is selected as having one or more, or all, of these properties or the properties of decreasing VEGF mRNA expression, inhibiting HIF-1 ⁇ activity through a proteosome dependent mechanism, inducing G2/M arrest, being substantially non-cytotoxic, inhibiting HIF-l ⁇ activity by a mechanism which does not involve microtubule disruption, having substantially no inhibiting effect on hsp 90, being independent ofthe AKT pathway, having substantially no inhibiting effect on deacetylation enzymes, being independent ofthe p53 gene, and increasing p21 mRNA expression.
  • any combination of such criteria of selection may be used to select the compound used in the method. Suitable methods for selecting the tricylic compound for use in the method are described in the Examples below.
  • the disclosed compounds that inhibit HIF-l ⁇ activity in a method of treatment ofthe human or animal body, and the use ofthe disclosed compounds that inhibit HIF-1 ⁇ activity in the manufacture of a medicament for use in the treatment of a proliferative condition such as cancer.
  • the disclosed compound is a dibenzo-[l,4]dioxin carboxamide other than a 6-chloro-
  • [l,4]dioxin-l -carboxamide, such as NSC 644221, and the medicament may include any amount, including cytotoxic amounts, ofthe disclosed compound, but, in certain particular examples, includes non-cytotoxic amounts.
  • the disclosed tricyclic compounds can also be used in combination therapies, for example, in conjunction with other therapies, such as in conjunction with other therapeutic agents including anti-proliferative agents or anti-neoplastic agents.
  • the disclosed tricyclic compound is a dibenzo-[l,4]dioxin carboxamide other than a 6-chloro-[l,4]dioxin-l -carboxamide, such as NSC 644221, and may used in any amount, including cytotoxic amounts, but in certain particular examples, is used in non- cytotoxic amounts.
  • Using the disclosed compounds in combination with other therapies can refer to using the combination of therapies in some sequence (such as alternating) or together simultaneously.
  • the disclosed compounds can be used, for example, at non-cytotoxic doses, in combination with antineoplastic agents, either simultaneously, or in a sequence such as using the antineoplastic agent followed by administration of a disclosed compound.
  • a tumor can be treated conventionally with surgery, radiation, or chemotherapy in combination with a disclosed compound and then, optionally the compound can be further administered to the subject to extend the dormancy of micrometastases and to stabilize and inhibit the growth of any residual primary tumor.
  • agents that can be used in combination with the disclosed compounds include alkylating agents, antimetabolites, natural products, kinase inhibitors, hormones and their antagonists, and miscellaneous other agents.
  • alkylating agents include nitrogen mustards (such as mechlorethamine, cyclophosphamide, melphalan, uracil mustard, or chlorambucil), alkyl sulfonates (such as busulfan), nitrosoureas (such as carmustine, lomustine, semustine, streptozocin, or dacarbazine).
  • alkyl sulfonates such as busulfan
  • nitrosoureas such as carmustine, lomustine, semustine, streptozocin, or dacarbazine
  • antimetabolites include folic acid analogs (such as methotrexate), pyrimidine analogs (such as 5-FU or cytarabine), and purine analogs, such as mercaptopurine or thioguanine.
  • Examples of natural products include vinca alkaloids (such as vinblastine, vincristine, or vindesine), epipodophyllotoxins (such as etoposide or teniposide), antibiotics (such as dactinomycin, daunorubicin, doxorabicin, bleomycin, plicamycin, or mitocycin C), and enzymes (such as L-asparaginase).
  • vinca alkaloids such as vinblastine, vincristine, or vindesine
  • epipodophyllotoxins such as etoposide or teniposide
  • antibiotics such as dactinomycin, daunorubicin, doxorabicin, bleomycin, plicamycin, or mitocycin C
  • enzymes such as L-asparaginase
  • kinase inhibitors examples include small molecule inhibitors (such as hessa, Tarceva, PKI-166, CI-1033, CGP-5923A, EKB- 569, TAK165, GE-572016, CI-1033, SU5416, ZD4190, PTK787/ZK222584,
  • hormones and antagonists include adrenocorticosteroids (such as prednisone), progestins (such as hydroxyprogesterone caproate, medroxyprogesterone acdtate, and magestrol acetate), estrogens (such as diethylstilbestrol and ethinyl estradiol), antiestrogens (such as tamoxifen), and androgens (such as testerone proprionate and fluoxymesterone).
  • adrenocorticosteroids such as prednisone
  • progestins such as hydroxyprogesterone caproate, medroxyprogesterone acdtate, and magestrol acetate
  • estrogens such as diethylstilbestrol and ethinyl estradiol
  • antiestrogens such as tamoxifen
  • androgens such as testerone proprionate and fluoxymesterone
  • miscellaneous agents include platinum coordination complexes (such as cis-diamine- dichloroplatinum II, which is also known as cisplatin), substituted ureas (such as hydroxyurea), methyl hydrazine derivatives (such as procarbazine), vaccines (such as APC8024), AP22408, B43-genistein conjugate, paclitaxel, AG538, and adrenocrotical suppressants (such as mitotane and aminoglutethimide).
  • platinum coordination complexes such as cis-diamine- dichloroplatinum II, which is also known as cisplatin
  • substituted ureas such as hydroxyurea
  • methyl hydrazine derivatives such as procarbazine
  • vaccines such as APC8024
  • AP22408 AP22408
  • B43-genistein conjugate paclitaxel
  • AG538 adrenocrotical suppressants
  • the disclosed compounds can be combined with gene therapy approaches, such as those targeting VEGF VEGFR (including antisense oligonucleotide therapy, Adenovirus-based Flt-1 gene therapy, Retrovirus-base Flk-1 gene therapy, Retrovirus-based VHL gene therapy, and angiozyme) and IGF-1R (including LNX-4437).
  • gene therapy approaches such as those targeting VEGF VEGFR (including antisense oligonucleotide therapy, Adenovirus-based Flt-1 gene therapy, Retrovirus-base Flk-1 gene therapy, Retrovirus-based VHL gene therapy, and angiozyme) and IGF-1R (including LNX-4437).
  • Examples ofthe most commonly used chemotherapy drugs that can be used in combination with the disclosed tricyclic compounds agent include Adriamycin, Alkeran, Ara-C, BiCNU, Busulfan, CCNU, Carboplatinum, Cisplatinum, Cytoxan, Daunorubicin, DTIC, 5-FU, Fludarabine, Hydrea, Idarubicin, Ifosfamide, Methotrexate, Mithramycin, Mitomycin, Mitoxantrone, Nitrogen Mustard, Taxol, Velban, Vincristine, VP-16, Gemcitabine (Gemzar), Herceptin, Irinotecan (Camptosar, CPT-11), Leustatin, Navelbine, Rituxan STI- 571, Taxotere, Topotecan (Hycamtin), Xeloda (Capecitabine), Zevelin, and calcitriol.
  • the disclosed compound is a dibenzo-[l ,4]dioxin carboxamide other than a 6- chloro-[l,4]dioxin-l -carboxamide, such as NSC 644221, and may be used in any amount, including cytotoxic amounts, but, in certain particular examples, is used in non- cytotoxic amounts.
  • a candidate compound is active, that is, capable of inhibiting HIF-1 activity.
  • assays which may conveniently be used to readily assess the suitability of a particular compound are described in the Examples below. Since compounds that inhibit HIF-l activity and/or angiogenesis have antiproliferative effects, antiproliferative agents are thus provided.
  • the disclosed compounds are applicable to proliferative conditions (e.g., cancers) which are characterized by so-called "solid" tumors, and which rely on angiogenesis, and the resulting vasculature to grow and or spread to other parts of a subject's body.
  • the antiproliferative compounds are used in non-cytotoxic concentrations, although the antiproliferative effect can indirectly lead to a net effect of reducing the number of cells by decreasing cell proliferation so that the rate of programmed cell death is greater than the rate of cellular proliferation.
  • Use ofthe compounds in a method of treatment of a proliferative condition (such as a neoplasm, for example a solid tumor) of a human or animal subject is also disclosed.
  • Such methods comprise administering to such a subject a therapeutically- effective amount (such as a cytotoxic or non-cytotoxic amount) of an active compound, for example, in the form of a pharmaceutical composition.
  • a therapeutically- effective amount such as a cytotoxic or non-cytotoxic amount
  • the disclosed compound is a dibenzo-[ 1,4] dioxin carboxamide other than a 6-chloro- [1,4] dioxin- 1 -carboxamide, such as NSC 644221
  • the therapeutically effective amount may be any amount, including a cytotoxic amount, but, in certain particular examples, the therapeutically efetive amount is a non-cytotoxic amount.
  • treatment in the context of treating a condition, generally refers to treatment and therapy, whether of a human or an animal (e.g., in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition ofthe progress ofthe condition, and includes a reduction in the rate of progress, a halt in the rate of progress, amelioration ofthe condition, or cure ofthe condition.
  • Treatment as a prophylactic measure is also contemplated.
  • the disclosure further provides the use of a disclosed compound for the manufacture of a medicament, for example, for the treatment of a proliferative condition, as discussed above.
  • the disclosed compound is a dibenzo- [l,4]dioxin carboxamide other than a 6-chloro-[l,4]dioxin-l-carboxamide, such as NSC 644221, and may be used in any amount, including cytotoxic amounts, but in certain particular examples, is used in non-cytotoxic amounts.
  • the compounds may also be used as part of an in vitro assay, for example, in order to determine whether a candidate host is likely to benefit from treatment with the compound in question, and the compounds can be used as standards, for example, in an assay, in order to identify other active compounds, such as other antiproliferative agents.
  • the resultant membrane was developed using an enhanced chemiluminescent (ECL) reagent.
  • ECL enhanced chemiluminescent
  • the membrane was exposed to X-ray film, which was then developed to visualize the membrane bound proteins.
  • the U251 cells were treated with 1% oxygen for 2, 4, 6, and 18 hours with a final concentration of NSC 644221 equivalent to 5 ⁇ M, which was added 30 min prior to hypoxic (1% oxygen) exposure (FIG. 1A).
  • Total cellular proteins were separated using SDS-PAGE and then subjected to immunoblot analysis using the HIF-l ⁇ antibody.
  • the membrane-bound protein was then re-probed for actin with an anti-actin antibody following an antibody stripping procedure to remove the HIF-l ⁇ antibody.
  • Detection of actin was used to detect any significant differences in loading ofthe gel lanes prior to the SDS-PAGE separation. The results of this analysis are shown in FIG 1A. A further study was performed, exposing the cells to up to 8 hours of hypoxia; the results are shown in FIG. 2. Immunoblot analysis was again employed to analyze modulation of HIF-1 ⁇ following the addition of 0.5, 1, 2, 4 and 8 ⁇ M NSC 644221 for 30 minutes, followed by exposure to 1% oxygen for a further 6 hours. Total protein extracts were separated using SDS-PAGE, and then subjected to immounoblot analysis using a HIF-1 ⁇ antibody as described above.
  • FIG. IB A similar experiment using 1, 2, 4, and 8 ⁇ M NSC 644221 for 30 minutes, followed by exposure to 1% oxygen for a further 18 hours, was performed. The results are summarized in FIG. 3.
  • FIG 1A and FIG. 2 demonstrate that relative to the amount of HIF-1 ⁇ induced by hypoxia (1% oxygen) in a given amount of time, the amount of HIF-1 ⁇ produced decreases to a greater extent with concomitant exposure to NSC 644221.
  • FIG. IB and FIG. 3 demonstrate that for a given period of exposure ofthe U251 cells to hypoxia, the amount of HIF-1 ⁇ in the cells is reduced in proportion to the concentration of NSC 644221. In other words, as the concentration of NSC 644221 increases, the amount of hypoxia induced HIF- l ⁇ protein in the cells decreases. FIG. IB and FIG. 3 also demonstrate that NSC 644221 does not affect the amount of HIF-l ⁇ in the cells, regardless of concentration. Thus, NSC 64221 exerts its anti-HIF activity by specifically inhibiting HIF-l ⁇ .
  • Example 2 - NSC 644221 decreases hypoxic HIF-1 reporter luciferase activity with dose dependent activity HIF-1 inhibitory activity of NSC 644221 was also determined according to the methods described by Rapisarda et al., Cancer Res., 64: 1475-1482, 2004, and Rapisarda et al., Cancer Res., 62: 4316-4324, 2002, both of which are inco ⁇ orated by reference herein. Briefly, genetically engineered U251 human glioma cells that stably express a recombinant vector in which the luciferase reporter gene is under control of three copies of a canonical hypoxia-responsive element (HRE) are used to determine HIF-1 activity.
  • HRE canonical hypoxia-responsive element
  • U251 (human glioma) cells that contained a stably transfected HRE reporter system and U251 cells containing a stably transfected pGL3 reporter system (constitutive reporter system used as a control) were grown overnight in 96-well plates in RPMI 1640 media supplemented with 5% heat inactivated fetal bovine serum (Whitaktaker Bioproducts, Walkersvill, MD) to which is added penicillin (50IU/mL, Invitrogen, Carlsbad, CA), streptomycin (50 ⁇ g/mL, Invitrogen, Carlsbad, CA) and glutamine (2 mM, Invitrogen, Carlsbad, CA).
  • a range of concentrations (0.5, 1, 2, 4, 5 and lO ⁇ M) of NSC 644221 was added to the cells 30 min prior to exposure to hypoxia or normoxia for a further 18 hours.
  • the cells were lysed in situ using the Bright-Glo luciferase assay reagent (Promega, Madison, WI ). Alterations in luciferase activity were measured using a Packard luminometer. Luciferase expression was then measured for normoxic and hypoxic treatments and any changes HRE luciferase activity due to NSC 64421 were normalized to total protein expression and calculated as a fold change in luciferase activity. The results are shown graphically in FIG. 4.
  • FIG. 4 The results are shown graphically in FIG. 4.
  • FIG. 4 shows that significant reductions in the expression of luciferase under control ofthe HRE are observed at concentrations over 1.0 ⁇ M, and that the effect is observable even at concentrations as low as 0.5 ⁇ M.
  • hypoxia- induced HIF-l ⁇ activity can be reduced at very low concentrations of NSC 644221.
  • FIG. 5 shows the effect of NSC 644221 on hypoxic signaling inhibition for both U251 -HRE cells (upper left panel) and U251 -PG3 cells (upper right panel), and the effect of NSC 644221 on cell growth in U251-HRE cells (lower left panel) and U251- PG3 (lower right panel).
  • the lower panels demonstrate that NSC 644221 has little effect on the growth ofthe U251 cells, both for U251-HRE cells (EC 50 > lO ⁇ M) and for U251-PG3 cells (EC 50 > 10 ⁇ M).
  • FIG. 5 further demonstrates the su ⁇ rising result that NSC 644221 can significantly inhibit hypoxic signaling at non-cytotoxic concentrations.
  • Example 3 - NSC 644221 decreases hypoxic VEGF mRNA expression with dose dependent activity
  • U251 cells were grown overnight in 10cm dishes. After the initial incubation period, a range of concentrations (0.5, 1, 2, 4, 5, and lO ⁇ M) of NSC 644221 was added to the cells 30 min prior to exposure to hypoxia or normoxia for a further 18 hours.
  • total RNA was extracted from the U251 cells using a Qiagen RNA extraction Kit (Qiagen, Valencia, CA). 1 ⁇ g RNA was then reverse transcribed using a RT-PCR kit.
  • the resulting cDNA was diluted 1:15 and real time PCR analysis was carried out using the human VEGF forward primer: forward 5 ' TACCTCCACCATGCCAAGTG 3 ', reverse 5 ' ATGATTCTGCCCTCCT CCTTC 3 ' and a probe, sequence: probe 5 ' FAM-TCCCAGGCTGCACCCATGGC-TAMRA 3' including an internal 18s rRNA control.
  • Example 4 - NSC 644221 increases HIF-l ⁇ degradation that is dependent upon proteosome activity.
  • U251 glioma cells were treated with either: A) The proteosome inhibitors ALLNL or PS341 (Sigma, St. Louis MO, and DTP-NCI, respectively) for 1 hour prior to the addition of either topotecan or NSC 644221 , or B) NSC 644221 for 30 minutes and then DFO (desferrioximine, used to mimic hypoxia, Sigma, St. Louis, MO) for a further 6 hours, followed by addition of cyclohexamide (CHX, a protein synthesis inhibitor, Sigma St. Louis, MO) for 30, 60 or 90 minutes, both in the presence or absence of NSC 644221.
  • DFO deferrioximine, used to mimic hypoxia, Sigma, St. Louis, MO
  • CHX cyclohexamide
  • Sigma St. Louis, MO cyclohexamide
  • NSC 644221 appears to be acting via a mechanism distinct from that of topotecan.
  • HIF-l ⁇ was stabilized using DFO, an effect that was reduced by NSC 644221.
  • NSC 644221 also can counteract the increase in HIF-l ⁇ activity induced by iron-dependent oxygen depletion in the presence of DFO.
  • the effect of NSC 644221 on HIF-l ⁇ accumulation also is maintained in the presence ofthe protein synthesis inhibitor cyclohexamide (CHX), which stops de novo HIF-l ⁇ synthesis.
  • CHX protein synthesis inhibitor cyclohexamide
  • FIG. 8 presents another panel illustrating HIF-l ⁇ levels in the presence and absence of NSC 644221, ALLNL, and PS341. Consistent with the results summarized in FIG. 7, HIF-l ⁇ inhibition is observed when NSC 644221 is administered in the absence ofthe proteosome inhibitors ALLNL and PS341. When either proteosome inhibitor is co-administered, no inhibition of HIF- 1 ⁇ is observed.
  • Example 5 -NSC 644221 increases HIF-l ⁇ but not HIF-2 ⁇ degradation in a VHL independent manner.
  • UMRC-2 cells a renal clear cell carcinoma cell line overexpressing HIFs under normoxic conditions
  • NSC 644221 both deficient and replete in VHL expression
  • NSC 644221 both deficient and replete in VHL expression
  • NSC 644221 both deficient and replete in VHL expression
  • NSC 644221 both deficient and replete in VHL expression
  • Total cellular proteins were separated using SDS-PAGE and irnmounoblot analysis was carried out using a HIF-1 ⁇ or HIF-2 ⁇ antibody.
  • the membrane-bound antibody was stripped and the protein was re-probed for actin as a 'loading' control.
  • Both HIF-l ⁇ and HIF-2 ⁇ are capable of dimerizing with HIF-1 ⁇ to form the active transcription factor HIF-1.
  • This example shows the differential effect of NSC-644221 on the degradation of HIF-l ⁇ and HIF-2 ⁇ , and the VHL-independence of the degradation of HIF-l ⁇ induced by NSC 644221.
  • FIG. 9 where the notation "MCG-1" is again used to denote the compound NSC 644221
  • FIG. 10 As shown in panel A of FIG. 9, NSC 644221 does not affect degradation of HIF-2 ⁇ in UMRC-2 cells under both normoxic and hypoxic conditions. However, NSC 644221 has been observed to slightly inhibit HIF-2 ⁇ in A549 cells.
  • NSC 644221 increases degradation of HIF-l ⁇ regardless of whether or not the cells express VHL.
  • the VHL protein was thought to be an essential component ofthe cellular degradation pathway for HIF-l ⁇ and HIF-2 ⁇ since VHL forms the recognition component of an E3 ligase that recognizes hydroxylated HIF-1 proteins.
  • these results su ⁇ risingly demonstrate that NSC 644221 increases degradation of HIF- l ⁇ in a VHL-independent matter.
  • Example 6 The inhibitory effect of NSC 644221 on VEGF mRNA expression is maintained in DU145 (Topo-1) mutant cells
  • DU 145 cells are prostate cancer cells that carry a mutation in the topoisomerase- 1 (Top-1) binding site.
  • the camptofhecin analog topotecan (TPT) a potent HIF-1 inhibitor, exerts its action through topoisomerase-1 inhibition.
  • TPT camptofhecin analog topotecan
  • DU145 cells were grown to a confluence of 80% in 10% RPMI medium as previously detailed, and the mRNA was harvested for real-time PCR analysis of VEGF mRNA, also as previously detailed. As shown in FIG.
  • Example 7 Comparison of NSC 644221 to NSC 295504 and NSC 295505 The compounds NSC 644221, NSC 295504, and NSC 295505 were separately used to treat U251 cells and an immunoblot analysis as described in Example 1 was used to determine their relative abilities to reduce HIF-l ⁇ protein. The results are shown in FIG. 12. At the concentrations specified in FIG. 12, all of these compounds reduced the amount of HIF-l ⁇ in the cells.
  • FIGS. 13 and 14 respectively show the results of analyzing these compounds in the assays of Examples 2 and 3.
  • FIG. 13 shows that like NSC 644221, NSC 295504 inhibits expression of luciferase under the control ofthe HRE, and that it does so at non- cytotoxic concentrations.
  • FIG. 14 shows that like NSC 644221, NSC 295504 reduces VEGF mRNA expression in U251 cells.
  • Example 8 Pharmaceutical compositions Since the disclosed tricyclic compounds can be used to treat a proliferative condition such as cancer, another aspect pertains to a pharmaceutical composition that includes a disclosed compound and a pharmaceutically acceptable excipient.
  • the compounds can be mixed with one or more non-toxic pharmaceutically acceptable excipients, including carriers, diluents, and/or adjuvants, and optionally other biologically active ingredients.
  • Standard pharmaceutical formulation techniques are used, such as those disclosed in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA (19th Edition), which is inco ⁇ orated by reference herein.
  • parenterally includes, but is not limited to subcutaneous, intravenous, intramuscular, intrasternal, intrasynovial, intrathecal, intrahepatic, intralesional, and intracranial administration, for example, by injection or infusion.
  • the pharmaceutical compositions preferably readily penetrate the blood-brain barrier when peripherally administered or are administered intraventricularly.
  • Base salts include, but are not limited to, ammonium salts, alkali metal salts (such as sodium and potassium salts), alkaline earth metal salts (such as calcium and magnesium salts), salts with organic bases (such as dicyclohexylamine salts), N-methyl-D-glucamine, and salts with amino acids (such as arginine, lysine, etc.).
  • Basic nitrogen-containing groups can be quaternized, for example, with such agents as C 1-8 alkyl halides (such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (such as dimethyl, diethyl, dibutyl, and diamyl sulfates), long-chain halides (such as decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides), aralkyl halides (such as benzyl and phenethyl bromides), etc. Water or oil-soluble or dispersible products are produced thereby. Furthermore, isomers, such as stereoisomers and geometric isomers ofthe compounds are contemplated, as are prodrugs of such compounds, which prodrugs may themselves exhibit little or no intrinsic activity.
  • C 1-8 alkyl halides such as methyl, ethyl, propy
  • Example 9- Inhibition of angiogenesis by tricyclic compounds The angiogenesis modulating activity of compounds is assessed in a rat aortic ring microvessel growth assay. Briefly, twelve-well tissue culture plates are coated with 250 ⁇ l of Matrigel (Becton-Dickinson, Bedford, MA) and allowed to gel for 30 min at 37°C and 5% CO 2 . Thoracic aortas are excised from 8- to 10-week-old male Sprague Dawley rats. After careful removal of fibroadipose tissues, the aortas are cut into 1-mm-long cross- sections, placed on Matrigel-coated wells, and covered with an additional 250 ⁇ l of Matrigel.
  • Matrigel Becton-Dickinson, Bedford, MA
  • Example 10 - Cytotoxicity assays Any type of assay designed to measure the relative toxicity of compounds at various concentrations may be used to determine a non-cytotoxic amount of a compound.
  • specific examples of such assays include the SRB (sulforhodamine B) assay, the Trypan Blue Dye Exclusion Assay, Differential Staining with Fluorescein Diacetate and Ethidium Bromide/Propidium iodide, and the Neutral Red cytotoxicity assay.
  • SRB sulfur-sulforhodamine B
  • Trypan Blue Dye Exclusion Assay Trypan Blue Dye Exclusion Assay
  • Differential Staining with Fluorescein Diacetate and Ethidium Bromide/Propidium iodide Differential Staining with Fluorescein Diacetate and Ethidium Bromide/Propidium iodide
  • Neutral Red cytotoxicity assay Typically, cytotoxicity is measured for the type of cells that are to be treated with a particular compound,
  • Trypan Blue Dye Exclusion Assay which is based on the exclusion of trypan blue dye (Sigma, St. Louis, MO) from viable cells. Cells are incubated with trypan blue (final concentration, 0.2 mg/mL) for 1 minute, and then observed under a microscope. Stained (non-viable) and non-stained (viable) cells are counted separately and the viable cell ratio can be calculated. Dead cells take up the dye and are stained blue, whereas viable cells have yellow nuclei. This assay can be repeated at various concentrations to determine an effective concentration (EC) for a certain percentage of the cells to be rendered non- viable by the compound being tested, for example, an EC 50 for cytotoxicity.
  • EC effective concentration
  • NR is a weak cationic dye that readily penetrates cell membranes and accumulates in lysosomes, where it binds with anionic sites in the lysosomal matrix. Alterations ofthe cell surface and/or the sensitive lysosomal membrane brought about by the action of a cytotoxin present at a cytotoxic concentration result in a decreased uptake and binding of NR. Thus, it is possible to distinguish between viable and dead cells. Cells are maintained in culture and exposed to test compounds over a broad range of concentrations, and the cultures are visually examined after 24 hours and the highest tolerated dose (HTD) is determined as the concentration of a compound that is tolerated by the cells, at which only minimal mo ⁇ hological alterations are evident.
  • HTD highest tolerated dose
  • HTD value has been shown to be equivalent to an NR90 value, i.e. the concentration of toxicant that causes a 10% reduction in the uptake of NR when compared to the controls.
  • a non-cytotoxic concentration can be an HTD value or an NR90 value determined by this method. Additional details regarding the NR assay may be found in Babich and Borenfreund, "Neutral Red assay for toxicology in vitro," in In Vitro Methods of Toxicology, Watson, R.R., ed, Chapter 17, pp 237-251. CRC Press, Ann Arbor, 1992. Additional assays for cytotoxicity are available from Promega (Madison, WI). Such cytotoxicity assays are described, for example, in U.S.
  • FIG. 15 is an image of an immunoblot analysis of cells exposed to NSC 644221, NSC 24058, NSC 24568, NSC 24623, NSC 24459, NSC 24544, or NSC 24460 (the structures of which are shown in FIG. 16).
  • NSC 644221 binds to DNA in a dose dependent manner, as indicated by the decrease in OD 60 .
  • Overall toxicity of NSC 644221 was assessed using a trypan blue assay, as previously described, by treating U251 and PC-3 cells with various concentrations of NSC 644221 (0 ⁇ M, 1 ⁇ M, and 5 ⁇ M) and staining the sample with trypan blue. As shown in FIG.
  • Microtubules are cellular proteins that form part ofthe cytoskeleton and assist in transporting substances within the cell, such as vesicles, granules, organelles (e.g., mitochondria), and chromosomes. It has been observed that certain anti-tumor agents operate by disrupting the microtubules.
  • both cell lines exhibit a characteristic G2 arrest after treatment with NSC 644221, as indicated by the increased number of cells in the G2/M phase. Accordingly, since both HIF- ⁇ active and HIF- ⁇ inactive cells experienced G2 arrest, this test does not indicate that the HIF-l ⁇ inhibiting properties of NSC 644221 occur via alteration ofthe G 2 pathway. However, the observed G2 arrest in NSC 644221 treated cells may be related to the DNA damaging properties of NSC 644221.
  • AhR aryl hydrocarbon receptor
  • AR ⁇ T nuclear translocator
  • NSC 644221 inhibits HIF-l ⁇ by the AhR pathway in a manner analogous to TCDD.
  • Example 16-Effect of tricyclic compounds on p21 mRNA expression The p53 gene is a component of cellular response to DNA damage and helps regulate the cell growth and death cycle. The p21 gene is regulated by p53 and mediates Gl arrest following DNA damage. Overexpression of p53 may lead to increased HIF-l ⁇ levels. The effect of NSC 644221 on p21 mRNA expression was studied by treating
  • Act D actinomycin D
  • p21 mRNA expression in U251 cells is enhanced by treatment with NSC 644221 alone under both normal and hypoxic oxygen conditions.
  • cells treated with Act D, with or without co-treatment with NSC 644221 show comparable or reduced p21 mRNA expression compared to controls. Accordingly, it appears that NSC 644221 increases the synthesis of p21, rather than stabilizing existing p21.
  • Example 17-Effect of Tricyclic Compounds on HIF-l ⁇ mRNA Expression The effect of NSC 644221 on HIF-l ⁇ mRNA expression under normoxic conditions was also studied. As shown in FIG. 29, NSC 644221, even at higher concentrations, did not decrease HIF-l ⁇ mRNA expression. Accordingly, it does not appear that NSC 644221 inhibits HIF-l ⁇ by interfering with HIF-l ⁇ mRNA expression. It should be understood that the foregoing relates only to particular embodiments and that numerous modifications or alterations may be made without departing from the true scope and spirit ofthe invention as defined by the following claims.

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Abstract

L'invention porte sur des composés tricycliques qui inhibent sélectivement l'activité de HIF-l?. L'invention porte également sur des méthodes visant à réduire l'activité de HIF-1? et inhiber l'angiogenèse, la tumorigenèse et/ou la métastase chez un sujet. Selon certains modes de mise en oeuvre, les composés tricycliques inhibent curieusement l'activité de HIF-l? à des concentrations non cytotoxiques, ce qui évite les effets secondaires des médicaments associés à une cytotoxicité importante.
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