WO2012015901A1 - Méthodes de traitement de malignités gastriques et pancréatiques - Google Patents

Méthodes de traitement de malignités gastriques et pancréatiques Download PDF

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Publication number
WO2012015901A1
WO2012015901A1 PCT/US2011/045510 US2011045510W WO2012015901A1 WO 2012015901 A1 WO2012015901 A1 WO 2012015901A1 US 2011045510 W US2011045510 W US 2011045510W WO 2012015901 A1 WO2012015901 A1 WO 2012015901A1
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Prior art keywords
methylenedioxy
dimethoxy
compound
ethyl
dibenzo
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PCT/US2011/045510
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English (en)
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Beverly A. Teicher
Steven M. Schmid
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Genzyme Corporation
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    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/435—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
    • A61K31/435—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
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene

Definitions

  • DNA-topoisomerases are enzymes which are present in the nuclei of cells where they catalyze the breaking and rejoining of DNA strands, which control the topological state of DNA. Recent studies also suggest that topoisomerases are also involved in regulating template supercoiling during RNA transcription. There are two major classes of mammalian topoisomerases. DNA-topoisomerase-I catalyzes changes in the topological state of duplex DNA by performing transient single-strand breakage- union cycles. In contrast, mammalian topoisomerase II alters the topology of DNA by causing a transient enzyme bridged double-strand break, followed by strand passing and resealing.
  • Mammalian topoisomerase II has been further classified as Type ⁇ . and Type II ⁇ .
  • the antitumor activity associated with agents which are topoisomerase poisons is associated with their ability to stabilize the enzyme-DNA cleavable complex. This drug-induced stabilization of the enzyme-DNA cleavable complex effectively converts the enzyme into a cellular poison.
  • topoisomerase II poisons include adriamycin, actinomycin D, daunomycin, VP- 16, and VM-26 (teniposide or epipodophyllotoxin).
  • adriamycin actinomycin D
  • daunomycin daunomycin
  • VP- 16 teniposide or epipodophyllotoxin
  • VM-26 teniposide or epipodophyllotoxin
  • topoisomerase I poisons have been identified as topoisomerase I poisons.
  • topoisomerase poisons include certain benzo[i]phenanthridine and cinnoline compounds (see LaVoie et al, U.S. Pat. No. 6,140,328, and WO 01/32631. While these compounds are useful they are somewhat limited due to low solubility.
  • F.D.A. approved Topoisomerase I inhibitors are camptothecin derivatives and include CAMPTOSAR® (irinotecan) and HYCAMTIN® (topotecan).
  • CAMPTOSAR® irinotecan
  • HYCAMTIN® topotecan
  • CAMPTOSAR® is indicated as a component of first-line therapy in combination with 5- fluorouracil and leucovorin for patients with metastatic carcinoma of the colon or rectum.
  • CAMPTOSAR® (irinotecan) is also indicated for patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following initial fluorouracil-based therapy.
  • SN-38 is a well known active metabolite of irinotecan.
  • HYCAMTIN® (topotecan) is indicated for treatment of patients with relapsed small cell lung cancer in patients with a prior complete or partial response and who are at least 45 days from the end of first-line chemotherapy. As mentioned above, these camptothecin derivatives suffer from low solubility.
  • the compounds of formula I are non-camptothecin derivatives, and as such, are not burdened with certain shortcomings of camptothecin based derivatives. Applicant has discovered that compounds of formula I are particularly active against certain cancers including gastric cancers and pancreatic cancers and metastasis of such cancers.
  • Particularly preferred compounds include 8,9-dimethoxy-2,3-methylenedioxy-5-[2-(N,N- dimethylamino)ethyl]-5H-dibenzo[c,/z] 1 ,6-naphthyridin-6-one; 8,9-dimethoxy-2,3- methylenedioxy-5 - [2-(N,N-diethylamino)ethyl] -5H-dibenzo [c,h] 1 ,6-naphthyridin-6- one; and 8 ,9-dimethoxy-2 ,3 -methylenedioxy-5 -[2-(N-methylamino)ethyl] -5H- dibenzo[c,A]l,6-naphthyridin-6-one; and pharmaceutically acceptable salts, prodrugs and metabolites thereof.
  • the invention provides a method for treating a cancer including gastric cancer or pancreatic cancer or metastasis of such cancers including intestinal-type gastric cancer related to Helicobacter pylori, proximal and diffuse gastric cancer, papillary, tubular/well-differentiated and tubular/moderately differentiated adenocarcinoma, poorly differentiated and signet-ring adenocarcinoma gastric cancer and exocrine, cystic, and acinar pancreatic cancer, sarcomas of the pancreas and endocrine pancreatic cancers including gastrinomas, insulinomas stomatostatinomas, VIPomas and glucagonomas in a mammal comprising administering to the mammal an effective amount of a compound of formula I:
  • a and B are independently N or CH; W is N or CH;
  • Ri is a -(Ci-C 6 )alkyl substituted with one or more solubilizing groups
  • R 2 is (Ci-C 6 )alkyl or substituted (Ci-C 6 )alkyl
  • Rc and Rj are each independently (Ci-C 6 ) alkyl or substituted (Ci-C 6 ) alkyl; or R c and Rd together with the nitrogen to which they are attached form a N'- ⁇ (Ci-C6)alkyl ⁇ piperazino, pyrrolidino, or piperidino ring, which ring can optionally be substituted with one or more aryl, heteroaryl, or heterocycle;
  • the invention also provides pharmaceutical compositions for the treatment of a cancer including gastric cancer or pancreatic cancer or metastasis of such cancers comprising a compound of formula I or a pharmaceutically acceptable salt, prodrug or metabolite thereof and a pharmaceutically acceptable excipient.
  • the compound of formula I is 8,9-dimethoxy-2,3-methylenedioxy-5-[2- (N,N-dimethylamino)ethyl]-5H-dibenzo[c,A] 1 ,6-naphthyridin-6-one; 8,9-dimethoxy- 2,3-methylenedioxy-5-[2-(N,N-diethylamino)ethyl]-5H-dibenzo[c,A] l,6- naphthyridin-6-one; or 8,9-dimethoxy-2,3-methylenedioxy-5-[2-(N- methylamino)ethyl]-5H-dibenzo[c,A] l,6-naphthyridin-6-one; or a pharmaceutically acceptable salt, prodrug or metabolite thereof.
  • the invention also provides a compound of formula I or a pharmaceutically acceptable salt, prodrug, or metabolite thereof for use in the prophylactic or therapeutic treatment of a cancer including gastric cancer or pancreatic cancer or metastasis of such cancers in a mammal.
  • the invention also provides for the use of a compound of formula I or a pharmaceutically acceptable salt, prodrug, or metabolite thereof for the manufacture of a medicament useful for the treatment of a cancer including gastric cancer or pancreatic cancer or metastasis of such cancers in a mammal.
  • the invention also provides a pharmaceutical composition for use in treatment of a cancer including gastric cancer or pancreatic cancer or metastasis of such cancers in a mammal, wherein the pharmaceutical composition comprises a compound of formula I or a pharmaceutically acceptable salt, prodrug, or metabolite thereof and a pharmaceutically acceptable excipient.
  • Figure 1 shows the human tumor cell IC 50 values for Compound 2 in nanomolar concentrations.
  • Figure 2 shows the human tumor cell IC 90 values for Compound 2 in nanomolar concentrations.
  • Figure 3 shows the surviving fraction versus concentration of Compound 2 for human pancreatic tumor cell lines.
  • Figure 4 shows the surviving fraction versus concentration of Compound 2 for human gastric tumor cell lines.
  • Figure 5 shows the mean tumor volume of mice treated with Compound 2 versus gemcitabine in MIA PaCa-2 human pancreatic tumor model.
  • Figure 6 shows the percent change in body weight of mice treated with Compound 2 versus gemcitabine in MIA PaCa-2 human pancreatic tumor model.
  • Figure 7 shows the mean tumor volume of mice treated with Compound 2 versus gemcitabine in BxPC-3 human pancreatic tumor model.
  • Figure 8 shows the percent change in body weight of mice treated with Compound 2 versus gemcitabine in BxPC-3 human pancreatic tumor model.
  • Figure 9 shows the mean tumor volume of mice treated with Compound 2 versus gemcitabine in Hs 766T human pancreatic tumor model.
  • Figure 10 shows the percent change in body weight of mice treated with Compound 2 versus gemcitabine in Hs 766T human pancreatic tumor model.
  • Figure 11 shows the mean tumor volume of mice treated with Compound 2 versus gemcitabine in CFPAC-1 human pancreatic tumor model.
  • Figure 12 shows the percent change in body weight of mice treated with Compound 2 versus gemcitabine in CFPAC-1 human pancreatic tumor model.
  • Figure 13 shows the mean tumor volume of mice treated with Compound 2 versus docetaxel in MK -45 human gastric tumor model.
  • Figure 14 shows the percent change in body weight of mice treated with Compound 2 versus docetaxel in MKN-45 human gastric tumor model.
  • Figure 15 shows the mean tumor volume of mice treated with Compound 2 versus docetaxel in 23132/87 human gastric tumor model.
  • Figure 16 shows the percent change in body weight of mice treated with Compound 2 versus docetaxel in 23132/87 human gastric tumor model.
  • Figure 17 shows the mean tumor volume of mice treated with Compound 2 versus docetaxel in Hs 746T human gastric tumor model.
  • Figure 18 shows the percent change in body weight of mice treated with Compound 2 versus docetaxel in Hs 746T human gastric tumor model.
  • Figure 19 are graphs depicting concentration response curves for 5 human gastric carcinoma cell lines exposed to Compound 2.
  • KATO III, AGS, MKN-45, 23132/87, and Hs746T cells were exposed to Compound 2 over a concentration range of 0.1- 10,000 nM for 72 hours in a growth inhibition assay.
  • Compound 2 was a potent cytotoxic agent in 4 of 5 lines with IC 90 concentrations between 33 and 180 nM.
  • the KATO III line was less sensitive to Compound 2 exposure with an IC 90 concentration of 1.4 ⁇ .
  • Figure 20 depicts IC 50 concentrations for each of 5 human gastric carcinoma cell lines exposed to Compound 2 or standard cytotoxic chemotherapeutics.
  • KATO III, AGS, MKN-45, 23132/87, and Hs746T cells were exposed to Compound 2, 5-fluorouracil, oxaliplatin, cisplatin, docetaxel, or doxorubicin for 72 hours in a growth inhibition assay.
  • Compound 2, docetaxel, and doxorubicin were tested over a concentration range of 0.003-1,000 nM.
  • 5-fluorouracil, oxaliplatin, and cisplatin were tested over a concentration range of 0.3-100,000 nM.
  • Figure 21 are graphs depicting gastric carcinoma cell line growth inhibition assays with Compound 2 and standard cytotoxic chemo therapeutic agents.
  • (Ci-C 6 )alkyl denotes both straight and branched carbon chains with one or more, for example, 1, 2, 3, 4, 5, or 6, carbon atoms, but reference to an individual radical such as “propyl” embraces only the straight chain radical, a branched chain isomer such as "isopropyl” being specifically referred to.
  • (Ci-C 6 )alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, or hexyl.
  • Substituted (Ci-C 6 )alkyl is an alkyl group of the formula (Ci-C 6 )alkyl as defined above wherein one or more (e.g. 1 or 2) carbon atoms in the alkyl chain have been replaced with a heteroatom independently selected from -0-, -S- and NR- (where R is hydrogen or Ci-C 6 alkyl) and/or wherein the alkyl group is substituted with from 1 to 5 substituents independently selected from cycloalkyl, substituted cycloalkyl, (Ci- C 6 )alkoxycarbonyl (e.g.
  • R a and R b may be the same or different and are chosen from hydrogen, alkyl, arylalkyl, heteroarylalkyl, heterocycloalkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic.
  • Substituted (Ci-C 6 )alkyl groups are exemplified by, for example, groups such as hydroxymethyl, hydroxy ethyl, hydroxypropyl, 2-aminoethyl, 3- aminopropyl, 2-methylaminoethyl, 3-dimethylaminopropyl, 2-carboxyethyl, hydroxylated alkyl amines, such as 2-hydroxyaminoethyl, and like groups.
  • Specific substituted (Ci-C 6 )alkyl groups are (Ci-C 6 )alkyl groups substituted with one or more substituents of the formula-NR a R b where R a and R b together with the nitrogen to which they are attached form of nitrogen containing heterocyclic ring.
  • Specific examples of such heterocyclic rings include piperazino, pyrrolidino, piperidino, morpholino, or thiomorpholino.
  • Other specific substituted (Ci-C 6 )alkyl groups are (Ci-C 6 )alkyl groups substituted with one or more carbon- linked oxygen containing heterocyclic rings.
  • oxygenated heterocyclic rings are, for example, tetrahydrofuranyl, tetrahydropyranyl, 1 ,4-dioxanyl, and like groups.
  • (Ci-C 6 )alkoxy refers to groups of the formula (Ci-Ce)alkyl-O-, where (Ci-C 6 )alkyl is as defined herein.
  • Specific alkoxy groups include, by way of example, methoxy, ethoxy, propoxy, iso-propoxy, butoxy, iso-butoxy, sec-butoxy, n-butoxy, tert-butoxy, pentoxy, 3-pentoxy, n-pentoxy, n-hexoxy, 1 ,2-dimethylbutoxy, and like groups.
  • Substituted (Ci-C 6 )alkoxy refers to a substituted (Ci-C 6 )alkyl-0- group wherein substituted (Ci-C 6 )alkyl is as defined above.
  • Substituted (Ci-C 6 )alkoxy is exemplified by groups such as 0-CH 2 CH 2 -NRaRb, 0-CH 2 CH 2 -CHR a R b , or 0-CH 2 - CHOH-CH 2 -OH, and like groups.
  • Specific substituted (Ci-C 6 )alkoxy groups are (Ci- C 6 )alkyl substituted with one or more substituents of the formula-NR a R b where R a and R b together with the nitrogen to which they are attached form of a heterocyclic ring.
  • Specific examples of such heterocyclic rings include piperazino, pyrrolidino, piperidino, morpholino, or thiomorpholino.
  • Other specific substituted (Ci-C 6 )alkoxy groups are (Ci-C 6 )alkoxy groups substituted with one or more carbon- linked oxygen containing heterocyclic rings.
  • oxygenated heterocyclic ring substituents are, for example, tetrahydrofuranyl, tetrahydropyranyl, 1 ,4-dioxanyl, and like groups.
  • oxygenated heterocyclic rings are, for example, tetrahydrofuranyl, tetrahydropyranyl, 1 ,4-dioxanyl, and like groups.
  • (Ci-C 6 )alkanoyloxy includes, by way of example, formyloxy, acetoxy, propanoyloxy, iso-propanoyloxy, n-butanoyloxy, tert-butanoyloxy, sec-butanoyloxy, n-pentanoyloxy, n-hexanoyloxy, 1 ,2-dimethylbutanoyloxy, and like groups.
  • Substituted (Ci-C 6 )alkanoyloxy refers to a (Ci-C 6 )alkanoyloxy group wherein one or more (e.g. 1 or 2) carbon atoms in the alkyl chain have been replaced with a heteroatom independently selected from -0-, -S- and NR- (where R is hydrogen or Ci-C 6 alkyl) and/or wherein the alkyl group is substituted with from 1 to 5 substituents independently selected from cycloalkyl, substituted cycloalkyl, (Ci- C 6 )alkoxycarbonyl (e.g.
  • R a and may be the same or different and are chosen from hydrogen, alkyl, arylalkyl, heteroarylalkyl, heterocycloalkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic.
  • Specific substituted (Ci- C 6 )alkanoyloxy groups are groups wherein the alkyl group is substituted with one or more nitrogen and oxygen containing heterocyclic rings such as piperazino, pyrrolidino, piperidino, morpholino, thiomorpholino, tetrahydrofuranyl, tetrahydropyranyl, 1 ,4-dioxanyl, and like groups.
  • Aryl denotes a phenyl radical or an ortho-fused bicyclic carbocyclic radical having about nine to ten ring atoms in which at least one ring is aromatic.
  • aryl include phenyl, indenyl, and naphthyl.
  • Heteroaryl encompasses a radical attached via a ring carbon of a monocyclic aromatic ring containing five or six ring atoms consisting of carbon and one to four heteroatoms each selected from the group consisting of non-peroxide oxygen, sulfur, and N(X) wherein X is absent or is H, O, (Ci-C4)alkyl, phenyl or benzyl, as well as a radical of an ortho-fused bicyclic heterocycle of about eight to ten ring atoms derived therefrom, particularly a benz-derivative or one derived by fusing a propylene, trimethylene, or tetramethylene diradical thereto.
  • heteroaryl examples include furyl, imidazolyl, triazolyl, triazinyl, oxazoyl, isoxazoyl, thiazolyl, isothiazoyl, pyrazolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyridyl, (or its N-oxide), thienyl, pyrimidinyl (or its N-oxide), indolyl, isoquinolyl (or its N-oxide) and quinolyl (or its N-oxide).
  • heterocycle refers to a monovalent saturated or partially unsaturated cyclic non-aromatic group which contains at least one heteroatom, preferably 1 to 4 heteroatoms, selected from nitrogen (NR X , wherein R x is hydrogen, alkyl, or a direct bond at the point of attachment of the heterocycle group), sulfur, phosphorus, and oxygen within at least one cyclic ring and which may be monocyclic or multi-cyclic.
  • heterocycle groups preferably contain from 3 to 10 atoms.
  • the point of attachment of the heterocycle group may be a carbon or nitrogen atom.
  • This term also includes heterocycle groups fused to an aryl or heteroaryl group, provided the point of attachment is on a non-aromatic heteroatom-containing ring.
  • heterocycle groups include, by way of example, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, morpholinyl, indolin-3-yl, 2-imidazolinyl, 1,2,3,4- tetrahydroisoquinolin-2-yl, quinuclidinyl and the like.
  • Aryloxy refers to a group of the formula aryl-O-, where aryl is as defined herein.
  • aryloxy groups include, phenoxy and 1-naphthyloxy.
  • Heteroaryloxy refers to a group of the formula heteroaryl-O-, where heteroaryl is as defined herein.
  • heteroaryloxy groups include, 3-piperidyloxy, 3- furyloxy, and 4-imidazoyloxy.
  • Heterocyclooxy refers to a group of the formula heterocycle-O-, where heterocycle is as defined herein.
  • Examples of heterocyclooxy groups include, 4-morpholinooxy and 3-tetrahydrofuranyloxy.
  • Arylalkyl refers to a group of the formula aryl-(Ci-C 6 )alkyl-, where aryl and (Ci- C 6 )alkyl are as defined herein.
  • Heteroarylalkyl refers to a group of the formula heteroaryl-(Ci-Ce)alkyl -, where heteroaryl and (Ci-C 6 )alkyl are as defined herein.
  • Heterocycloalkyl refers to a group of the formula heterocycle-(Ci-C 6 )alkyl -, where heterocycle and (Ci-C 6 )alkyl are as defined herein.
  • Effective amount or “therapeutically effective amount” of a compound refers to a nontoxic but sufficient amount of the compound to provide the desired therapeutic or prophylactic effect to most patients or individuals.
  • a nontoxic amount does not necessarily mean that a toxic agent is not used, but rather means the administration of a tolerable and sufficient amount to provide the desired therapeutic or prophylactic effect to a patient or individual.
  • the effective amount of a pharmacologically active compound may vary depending on the route of administration, as well as the age, weight, and sex of the individual to which the drug or pharmacologically active agent is administered Those of skill in the art given the benefit of the present disclosure can easily determine appropriate effective amounts by taking into account metabolism, bioavailability, and other factors that affect plasma levels of a compound following administration within the unit dose ranges disclosed further herein for different routes of administration.
  • Treatment refers to any manner in which the symptoms of a condition, disorder or disease are ameliorated or otherwise beneficially altered.
  • the cancer can be onset, relapsed or refractory. Full eradication of the condition, disorder or disease is not required.
  • Amelioration of symptoms of a particular disorder refers to any lessening of symptoms, whether permanent or temporary, that can be attributed to or associated with administration of a therapeutic composition of the present invention or the corresponding methods and combination therapies. Treatment also encompasses pharmaceutical use of the compositions in accordance with the methods disclosed herein.
  • Prodrug refers to any compound that when administered to a biological system generates the drug substance, i.e. active ingredient of formula I or a salt thereof, as a result of spontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s), photolysis, and/or metabolic chemical reaction(s). A prodrug is thus a modified analog or latent form of a therapeutically-active compound.
  • Method refers to any compound formed as a result of the drug substance, i.e. the active ingredient of formula I or a salt thereof, being administered to a biological system, as a result of spontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s), photolysis and/or metabolic chemical reaction(s).
  • solubilizing group(s) R z is a substituent that increases the water solubility of the compound of formula I compared to the corresponding compound lacking the R substituent.
  • solubilizing groups include substituents independently selected from substituted (Ci-C 6 )alkyl, (Ci-Ce)alkoxycarbonyl (e.g.
  • R a and R b may be the same or different and are chosen from hydrogen, alkyl, arylalkyl, heteroarylalkyl, heterocycloalkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic.
  • Ri groups are exemplified by, for example, groups such as hydroxymethyl, hydroxy ethyl, hydroxypropyl, 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl, 3- dimethylaminopropyl, 2-carboxyethyl, hydroxylated alkyl amines, such as 2- hydroxyaminoethyl, and like groups.
  • Ri groups are (Ci-C 6 )alkyl groups substituted with one or more substituents of the formula -NR a R b where R a and R b together with the nitrogen to which they are attached form a nitrogen containing heterocyclic ring, or (Ci-C 6 )alkyl groups substituted with one or more oxygen containing heterocyclic rings.
  • Specific examples of such heterocyclic rings include piperazino, pyrrolidino, piperidino, morpholino, or thiomorpholino.
  • Still other specific Ri groups are (Ci-C 6 )alkyl groups substituted with one or more carbon- linked oxygen containing heterocyclic rings. Specific examples of such oxygenated heterocyclic rings are, for example, tetrahydrofuranyl, tetrahydropyranyl, 1,4- dioxanyl, and like groups.
  • a specific value for A is CH.
  • a specific value for B is N.
  • a specific value for W is N.
  • W Another specific value for W is CH.
  • a specific value for Y is OH.
  • Y is -0-CH 2 -CHOH-CH 2 -OH.
  • Y is -0-CH 2 CH 2 -NR a R b wherein R a and R b are hydrogen or (Ci-C 6 )alkyl.
  • Y is -0-CH 2 CH 2 -NR a R b wherein R a and R b together with the nitrogen to which they are attached form a piperazino, pyrrolidino, piperidino, morpholino, or thiomorpholino ring.
  • Y is (Ci-Ce)alkyl substituted with one or more tetrahydrofuranyl, tetrahydropyranyl, or 1,4-dioxanyl rings.
  • a specific value for Z is OH.
  • Z is substituted (Ci-C 6 )alkoxy.
  • Another specific value for Z is -OCH 2 CH 2 OH.
  • Z is -0-CH 2 CH 2 -NR a R b wherein R a and R b are hydrogen or (Ci-C 6 )alkyl.
  • Z is -0-CH 2 CH 2 -NR a R b wherein R a and R b together with the nitrogen to which they are attached form a piperazino, pyrrolidino, piperidino, morpholino, or thiomorpholino ring.
  • Z is (Ci-C 6 )alkyl substituted with one or more tetrahydrofuranyl, tetrahydropyranyl, or 1,4-dioxanyl rings.
  • R 3 and R 4 are H.
  • R 3 and R 4 together N-R 2 where R 2 is (Ci-C 6 )alkyl.
  • R 3 and R 4 together N-R 2 where R 2 is substituted (Ci- C 6 )alkyl.
  • R 3 is H and R4 is (Ci-C6)alkyl.
  • R 3 is H and R4 is substituted (Ci-C6)alkyl.
  • R 4 is substituted (Ci-C6)alkyl.
  • R 3 and R 4 are substituted (Ci-C 6 )alkyl
  • Ri 2-hydroxyethyl
  • Ri is 2-aminoethyl.
  • Ri is 2-(N,N'-dimethylamino)ethyl.
  • Ri is 2-(N,N'-diethylamino)ethyl.
  • Ri is 2-(N,N'-diethanolamino)ethyl of the formula -CH 2 - CH 2 -N(-CH 2 -CH 2 -OH) 2 .
  • Ri or R 2 is a (Ci-C 6 )alkyl substituted with one or more hydroxy, mercapto, carboxy, amino, piperazinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, or 1,4-dioxanyl groups.
  • Ri or R 2 is a (Ci-C 6 )alkyl with from 2 to 4 carbon atoms and substituted with one to two groups selected from hydroxy, mercapto, carboxy, amino, piperazinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, or 1,4-dioxanyl.
  • Ri or R 2 is -CH 2 CH 2 -NR a R b wherein R a and R b are hydrogen or (Ci-C 6 )alkyl.
  • Ri or R 2 is -CH 2 CH 2 -NR a R b wherein R a and R b together with the nitrogen to which they are attached form a piperazino, pyrrolidino, piperidino, morpholino, or thiomorpholino ring.
  • a specific compound of formula (I) is the compound 1 l,12-dihydro-2,3-dimethoxy- 8,9-methylenedioxy-l l-[2-(dimethylamino)ethyl]-5,6,l l-triazachrysen-12-one, or a pharmaceutically acceptable salt, prodrug or metabolite thereof.
  • a specific compound of formula I is a compound of formula II: Formula II
  • Another specific compound of formula I is a compound of formula III Formula III
  • Another specific compound of formula I is a compound of formula VI Formula VI
  • Another specific compound of formula I is a compound of formula VII Formula VII
  • Another specific compound of formula I is a compound of formula VIII
  • Another specific compound of formula I is any of the above compounds of formulas I-IX as a pharmaceutically acceptable salt, prodrug or metabolite thereof.
  • Specific compounds useful for the methods of treating a cancer including gastric cancer or pancreatic cancer or metastasis of such cancers and corresponding pharmaceutical compositions of the present disclosure include 8,9-dimethoxy-2,3-methylenedioxy-5- [2-(N,N-dimethylamino)ethyl]-5H-dibenzo[c,A] 1 ,6-naphthyridin-6-one; 8,9- dimethoxy-2,3 -methylenedioxy-5 - [2-(N,N-diethylamino)ethyl] -5H-dibenzo [c, h] 1 ,6- naphthyridin-6-one; and 8,9-dimethoxy-2,3-methylenedioxy-5-[2-(N- methylamino)ethyl]-5H-dibenzo[c
  • a specific compound of formula I that has been found to be particularly active against gastric cancer or pancreatic cancer or metastasis thereof is 8,9-dimethoxy-2,3-methylenedioxy-5-[2-(N- methylamino)ethyl]-5H-dibenzo[c,A] l,6-naphthyridin-6-one referred to herein as Compound 2.
  • Structures of certain compounds within the scope of the present disclosure include Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, and Compound 6 below.
  • the structure of some of the compounds of the invention may include asymmetric carbon atoms. It is to be understood accordingly that the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of the invention, unless indicated otherwise. Such isomers may be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis. Furthermore, the structures and other compounds and moieties discussed in this application also include all tautomers thereof. Alkenes and imines can include either the E- or Z-geometry, where appropriate.
  • Embodiments of the present invention include salts of the compounds of Formula 1 and those otherwise described herein and are likewise referred to as compounds of the present disclosure.
  • Solutions of active compounds as free base or pharmacologically acceptable salts are prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms .
  • Examples of acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of basic residues such as carboxylic acids; and the like.
  • the acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts from non-toxic inorganic acids. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, mandelic tartaric, citric, ascorbic, palmoic, maleic, hydroxymaleic, phenylacetic, glutamine, benzoic, salicylic, sulfanilic, 2- acteoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
  • the acceptable salts can include those salts that naturally occur in vivo in a mammal.
  • salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, a-ketoglutarate, and a-glycerophosphate.
  • Suitable inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts.
  • compositions of the present disclosure may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers or excipients.
  • the pharmaceutically acceptable carrier can be any such carrier known in the art including those described in, for example, Remington's Pharmaceutical Sciences, Mack Publishing Co., (A. R. Gennaro edit. 1985).
  • Pharmaceutical compositions of the compounds presently disclosed may be prepared by conventional means known in the art including, for example, mixing at least one presently disclosed compound with a pharmaceutically acceptable carrier.
  • the compounds presently disclosed may also be formulated for sustained delivery according to methods well known to those of ordinary skill in the art. Examples of such formulations can be found in United States Patents 3,119,742, 3,492,397, 3,538,214, 4,060,598, and 4,173,626.
  • the active compounds of the disclosure may be formulated for oral, buccal, intranasal, parenteral (e.g., intravenous, intramuscular or subcutaneous), rectal administration, in a form suitable for administration by inhalation or insufflation, or the active compounds may be formulated for topical administration.
  • the present compounds may be systemically administered, for example, orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet.
  • a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier.
  • the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • Such compositions and preparations should contain at least 0.1% of active compound.
  • the percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form.
  • the amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.
  • the tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added.
  • binders such as gum tragacanth, acacia, corn starch or gelatin
  • excipients such as dicalcium phosphate
  • the unit dosage form When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like.
  • a syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor.
  • any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed.
  • the active compound may be incorporated into sustained-release preparations and devices.
  • the active compound may also be administered intravenously or intraperitoneally by infusion or injection.
  • Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes.
  • the liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • a compound of formula I or a pharmaceutically acceptable salt or prodruc thereof is prepared in a 2 mg/mL solution of predominantly USP water for injection.
  • Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization.
  • the specific methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
  • the present compounds may be applied in pure form, i.e., when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.
  • Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like.
  • Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants.
  • Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use.
  • the resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.
  • Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.
  • Examples of useful dermatological compositions which can be used to deliver the compounds of formula I to the skin are known to the art; for example, see Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559,157) and Wortzman (U.S. Pat. No. 4,820,508).
  • Useful dosages of the compounds described herein can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949.
  • the concentration of the compound(s) described herein in a liquid composition will be from about 0.1-25 wt-%, preferably from about 0.5-10 wt-%.
  • concentration in a semi-solid or solid composition such as a gel or a powder will be about 0.1-5 wt-%, preferably about 0.5-2.5 wt-%>.
  • the amount of the compound, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician.
  • a suitable dose will be in the range of from about 0.5 to about 100 mg/kg, e.g., from about 10 to about 75 mg/kg of body weight per day, such as 3 to about 50 mg per kilogram body weight of the recipient per day, preferably in the range of 6 to 90 mg/kg/day, most preferably in the range of 15 to 60 mg/kg/day.
  • the compound may conveniently be administered in unit dosage form; for example, containing 5 to 1000 mg, conveniently 10 to 750 mg, most conveniently, 50 to 500 mg of active ingredient per unit dosage form
  • the active ingredient should be administered to achieve peak plasma concentrations of the active compound of from about 0.5 to about 75 ⁇ , preferably, about 1 to 50 ⁇ , most preferably, about 2 to about 30 ⁇ . This may be achieved, for example, by the intravenous injection of a 0.05 to 5% solution of the active ingredient, optionally in saline, or orally administered as a bolus containing about 1- 100 mg of the active ingredient. Desirable blood levels may be maintained by continuous infusion to provide about 0.01-5.0 mg/kg/hr or by intermittent infusions containing about 0.4-15 mg/kg of the active ingredient(s).
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub- doses per day.
  • the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.
  • One or more compounds of the present disclosure alone or together with one or more pharmacologically active agents may be administered to a patient simultaneously, sequentially, or in combination. It will be appreciated that when using a combination of the invention, the compound(s) of the invention and the other pharmacologically active agent(s) may be in the same pharmaceutically acceptable carrier and therefore administered simultaneously. They may be in separate pharmaceutical carriers such as conventional oral dosage forms, which are taken simultaneously. The term “combination” further refers to the case where the compounds are provided in separate dosage forms and are administered sequentially.
  • Combination therapy includes the administration of a compound of the invention and at least a second agent as part of a specific treatment regimen intended to provide the beneficial effect from the co-action of these therapeutic agents.
  • the beneficial effect of the combination includes, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents.
  • Administration of these therapeutic agents in combination typically is carried out over a defined time period (usually minutes, hours, days or weeks depending upon the combination selected).
  • “Combination therapy” may, but generally is not, intended to encompass the administration of two or more of these therapeutic agents as part of separate monotherapy regimens that incidentally and arbitrarily result in the combinations of the present invention.
  • “Combination therapy” is intended to embrace administration of these therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner.
  • Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single capsule having a fixed ratio of each therapeutic agent or in multiple, single capsules for each of the therapeutic agents.
  • Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, inhalation, oral routes, intravenous routes, intramuscular routes, subcutaneous, rectal, intraperitoneal, parenteral, transdermal, gastrointestinal, and direct absorption through mucous membrane tissues.
  • the therapeutic agents can be administered by the same route or by different routes.
  • a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally.
  • therapeutic agents may be administered orally or by intravenous injection.
  • Combination therapy also can embrace the administration of the therapeutic agents as described above in further combination with other biologically active ingredients and non-drug therapies (e.g., surgery or radiation treatment).
  • the combination therapy further comprises a non-drug treatment
  • the non-drug treatment may be conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and non-drug treatment is achieved. For example, in appropriate cases, the beneficial effect is still achieved when the non-drug treatment is temporally removed from the administration of the therapeutic agents, perhaps by days or even weeks.
  • one or more compounds within the scope of Formula I may be administered in a combination therapy or co-therapy with at least a second agent which may be an anticancer agent.
  • one or more compounds within the scope of Formula I may be administered in a combination therapy or co-therapy with one or more anticancer agents.
  • the one or more compounds within the scope of Formula I and the one or more anticancer agents as a combination therapy or c- therapy may achieve an additive anticancer effect or the combination may achieve a synergistic anticancer effect to treat gastric or pancreatic malignancies as described herein.
  • an anticancer effect may be synergistic if the anticancer effect resulting from the combination therapy or co-therapy of compounds is greater than the additive effect of the combination of the compounds.
  • Exemplary anticancer agents useful in a combination therapy or co-therapy to treat gastric or pancreatic malignancies include platinum-based anticancer agents, alkylating agents whether classical alkylating agents, alkylating-like agents, or nonclassical alkylating agents, anthracycline antibiotics and microtubule inhibitors.
  • Exemplary platinum-based anticancer agents include cisplatin, carboplatin and the like.
  • Exemplary classical alkylating agents include cyclophosphamide, mechlorethamine, uramustine, melphalan, chlorambucil, ifosfamide, carmustine, lomustine, streptozocin, busulfan and the like.
  • Exemplary alkylating-like agents include cisplatin, carboplatin, nedaplatin, oxaliplatin, satraplatin, triplatin tetranitrate and the like.
  • Exemplary nonclassical alkylating agents include procarbazine, altretamine, dacarbazine, mitzolomide, temozolomide and the like.
  • Exemplary anthracycline antibiotics include daunorubicin (+/- liposomal formulation), doxorubicin (+/- liposomal formulation), epirubicin, idarubicin, valrubicin, mitoxantrone and the like.
  • Exemplary microtubule inhibitors include taxanes such as paclitaxel and vinca alkaloids like vinblastine, vincristine, vindesine and vinorelbine and the like.
  • Compound 2 is administered to an individual in need of therapeutic treatment, such as cancer therapeutic treatment, as a combination therapy or co-therapy with one or more of oxaliplatin, doxorubicin or docetaxel.
  • Compound 2 and one or more of oxaliplatin, doxorubicin or docetaxel are effective as a combination therapy or co-therapy in treating gastric or pancreatic malignancies.
  • Compound 2 and one or more of oxaliplatin, doxorubicin or docetaxel are effective as a combination therapy or co- therapy in treating gastric or pancreatic malignancies in a synergistic manner.
  • the term “pharmaceutical combination therapy” or just “combination therapy” as used herein generally refers to the administration of a one or more compounds within the scope of Formula I with one or more anticancer compounds.
  • the term “pharmaceutical combination therapy” means the one or more compounds of Formula I may be administered concomitantly in a pharmaceutically acceptable form with one or more of the anticancer agents disclosed herein: (i) in the same dosage form, e.g., the same tablet or pharmaceutical composition meaning a pharmaceutical composition comprising one or more compounds of Formula I, one or more anticancer agents disclosed herein, and a pharmaceutically acceptable carrier; (ii) in a separate dosage form having the same mode of administration, e.g., a kit comprising a first pharmaceutical composition suitable for oral administration comprising one or more compounds of Formula I and a pharmaceutically acceptable carrier, and a second pharmaceutical composition suitable for oral administration comprising one or more anticancer agents disclosed herein and a pharmaceutically acceptable carrier; and (iii
  • kits comprising a first pharmaceutical composition suitable for oral administration comprising one or more compounds of Formula I and a pharmaceutically acceptable carrier, a second pharmaceutical composition suitable for oral administration comprising a first anticancer agent disclosed herein and a pharmaceutically acceptable carrier, and a third pharmaceutical composition suitable for parenteral administration comprising a second anticancer agent disclosed herein and a pharmaceutically acceptable carrier.
  • the concomitant administration referred to above in the context of a "pharmaceutical combination therapy” means that the pharmaceutical composition comprising one or more compounds of Formula I and a pharmaceutical composition(s) comprising the anticancer agent can be administered on the same schedule, i.e., at the same time and day, or on a different schedule, i.e., on different, although not necessarily distinct, schedules.
  • the pharmaceutical composition comprising one or more compounds of Formula I and a pharmaceutical composition(s) comprising the anticancer agent when administered on a different schedule, such a different schedule may also be referred to herein as "background” or “background administration.”
  • the pharmaceutical composition comprising one or more compounds of Formula I may be administered in a certain dosage form twice a day, and the pharmaceutical composition(s) comprising the anticancer agent may be administered once a day, such that the pharmaceutical composition comprising the one or more compounds of Formula I may but not necessarily be administered at the same time as the pharmaceutical composition(s) comprising the anticancer agent during one of the daily administrations.
  • other suitable variations to "pharmaceutical combination therapy” will be readily apparent to those of skill in the art given the benefit of the present disclosure and are part of the meaning of this term.
  • Example 1 ll,12-dihydro-2,3-dimethoxy-8,9-methylenedioxy-ll-[2- (dimethylamino)ethyl]-5,6,ll-triazachrysen-12-one (E).
  • E A mixture of 4-N-(2- Dimethylaminoethyl)-N-(2-bromo-4,5-dimethoxybenzoyl)amine-6,7- methylenedioxycinnoline (D, 220 mg, 0.40 mmol), Pd(OAc) 2 (18.0 mg, 0.08 mmol), P(o-tolyl) 3 (48.8 mg, 0.16 mmol), and silver carbonate (225 mg, 0.80 mmol) were heated to reflux in DMF (12 mL) and stirred under nitrogen for 75 minutes.
  • Chloro-6,7-methylenedioxycinnoline (350 mg, 1.7 mmol) and copper powder (100 mg, 1.6 mmol) in N,N-dimethylethylenediamine (3.75 g, 42.6 mmol) were stirred at 105 °C under nitrogen for 3 hours.
  • reaction mixture was then stirred at reflux under N 2 .
  • the reaction mixture was cooled and washed with sat. NaHC0 3 and extracted with 3% HC1.
  • the aqueous layer was neutralized with 20% NaOH and extracted with CHC1 3 , dried (MgS0 4 ) and evaporated.
  • Example 3.a N-(6,7-Methylenedioxycinnolin-4-yl)-N-[2-(N,N-dimethylamino)-l- methylethyl)-2-iodo-4,5-dimethoxybenzamide: Prepared from N-(6,7- difluorocinnolin-4-yl)-N 1 ,N 1 -dimethylpropane-l,2-diamine (240 mg, 0.87 mmol); (83% yield); reaction time 16 h, mp 110-111 °C; 1H NMR (CDC1 3 ) was a mixture of atropisomers ⁇ isomer #1 1.03-1.36 (m, 3H), 2.21-2.37 (m, 6H), 2.74-3.07 (m, 1H), 3.43-3.65 (m, 6H), 3.84-3.91 (m, 1H), 5.15 (m, 1H), 6.18 (s, 2H), 6.59 (s, 1H), 6.91 (s, 1H),
  • Example 4.a N-(6,7-Methylenedioxycinnolin-4-yl)-N-[2-(tetrahydrofuran-2- yl)methyl]-2-iodo-4,5-dimethoxybenzamide: Prepared from 2-[[[N-(6,7- Methylenedioxycinnolin-4-yl)]amino]methyl]tetrahydrofuran (400 mg, 1.5 mmol); (34% yield); reaction time 16 h;; IR (CHC1 3 ) 1654; 1H NMR, a mixture of atropisomers, (CDC1 3 ) ⁇ isomer #1 1.94 (m, 4H), 3.70 (m, 4H), 3.73 (s, 3H), 3.94 (s, 3H), 4.34 (m, 1H) 6.23 (s, 2H), 7.00 (s, 1H), 7.40 (s, 1H), 7.70 (s, 1H), 9.31 (s, 1H), isomer #2 1.94 (m, 4H
  • Example 5.a N-(6,7-Methylenedioxycinnolin-4-yl)-N-[(2-pyrrolidin-l-yl)ethyl]- 2-iodo-4,5-dimethoxybenzamide: Prepared from l-[2-[N-(6,7-)
  • Example 6.a N-(6,7-Methylenedioxy-4-cinnolin-4-yl)-N-[2-(piperidin-l- yl)ethyl]-2-iodo-4,5-dimethoxybenzamide: Prepared from l-[2-[N-(6,7- Methylenedioxycinnolin-4-yl)]amino]ethylpiperidine (500 mg, 1.66 mmol); (85.4% yield); reaction time overnight at 50 °C.
  • N-(6,7-Methylenedioxyquinolin-4-yl)-N-(N,N- dimethylaminoethyl)-2-iodo-4,5-dimethoxybenzamide Prepared from N'-(6,7- Methylenedioxyquinolin-4-yl)-N,N-dimethylethane-l,2-diamine (1.0 g, 3.84 mmol) in 71% yield with a reaction time of 3 h, from the acid chloride prepared using 10 mmol of oxalyl chloride and 4.8 mmol of 2-iodo-5,6-dimethoxybenzoic acid.
  • Example lO.a N-(6,7-Methylenedioxyquinolin-4-yl)-N-[2-(4-methyl-l- piperazinyl)ethyl]-2-iodo-4,5-dimethoxybenzamide.
  • Example ll.a N-(6,7-Methylenedioxyquinolin-4-yl)-N-[3-(N,N- dimethylamino)propyl]-2-iodo-4,5-dimethoxybenzamide.
  • N'-(6,7- Methylenedioxyquinolin-4-yl)-N,N-dimethylpropane- 1,3 -diamine (273 mg, 1.0 mmol), in 79% yield with a reaction time of 12 h, from the acid chloride prepared using 4.0 mmol of oxalyl chloride and 1.36 mmol of 2-iodo-5,6-dimethoxybenzoic acid.
  • Example 12.a N-(6,7-Methylenedioxyquinolin-4-yl)-N-[2-(tetrahydrofuran-2- yl)methyl]-2-iodo-4,5-dimethoxybenzamide.
  • Compound 7g had: IR (CHC1 3 ) 1652; HRMS calcd for C 24 H 23 N 2 0 6 IH: 563.0679; found 563.0703. Examples 7.b-12.b
  • Example 7.b N'-(6,7-Methylenedioxyquinolin-4-yl)-N,N-dimetliyletliane-l,2- diamine was prepared from N,N-dimethylethylenediamine (2.55 g, 29 mmol) in 54% yield with a reaction time of 24h.
  • Example 8.b N'-(6,7-Methylenedioxyquinolin-4-yl)-N,N-dimethylpropane-l,2- diamine was prepared from 2-methyl-2-(N,N-dimethylamino)ethylamine (2.55 g, 29 mmol) from in 30.7% yield with a reaction time of 24 h.
  • Example 9.b l-[2-[N-(6,7-Methylenedioxyquinolin-4-yl)]amino]ethylpyrrolidine was prepared from l-(2-aminoethyl)pyrrolidine (1.14 g, 10.0 mmol) in 31% yield with a reaction time of 20 h.
  • Example lO.b. l-[2-[N-(6,7-Methylenedioxyquinolin-4-yl)]amino]ethyl-4- methylpiperazine was prepared from 2-(4-methylpiperidin-l-yl)ethylamine (1.43 g, 10.0 mmol) in 20% yield with a reaction time of 24 h.
  • Example ll.b N'-(6,7-Methylenedioxyquinolin-4-yl)-N,N-dimethylpropane-l,3- diamine was prepared from N,N-dimethyl-l,3-diaminopropane (1.0 g, 10.0 mmol) in 25% yield with a reaction time of 20 h.
  • Example 12.b 2-[[[N-(6,7-Methylenedioxyquinolin-4- yl)] amino] methyl] tetrahydrofuran was prepared from tetrahydofurfurylamine (1.01 g, 10.0 mmol) in 84% yield with a reaction time of 20 h.
  • a second crop was obtained by vigorously washing the tarry residue with ethanol (16 x 250 mL), filtering and evaporating the ethanol, and rinsing the material with ethyl ether.
  • the total yield was 14.9 g as a pale yellow solid, in 61%; mp 285-289 °C (lit.
  • Example 13 8,9-Dimethoxy-2,3-methylenedioxy-5-[2-(hydroxy)ethyl]-5H- dibenzo[c, i]l,6-naphthyridin-6-one: Prepared from the corresponding tert- butyldimethylsilyl ether (Example 13.
  • Example 14 8,9-Dimethoxy-2,3-methylenedioxy-5-[2-(2-hydroxyethoxy)ethyl]- 5H-dibenzo[c, i]l,6-naphthyridin-6-one: Prepared from the corresponding tert- butyldimethylsilyl ether (Example 14.
  • Example 15 8,9-Dimethoxy-2,3-methylenedioxy-5-[2-N,N-dimethylamino-l- (hydroxymethyl)ethyl]-5H-dibenzo[c,/i] l,6-naphthyridin-6-one: Prepared from the corresponding fert-butyldimethylsilyl ether (Example 15.
  • Example 16 8,9-Dimethoxy-2,3-methylenedioxy-5-[2,3-dihydroxy)propyl]-5H- dibenzo[c, i]l,6-naphthyridin-6-one: Prepared from the corresponding acetal (Example 16. a.) by treatment 80% AcOH at reflux for 2 h. The reaction mixture was allowed to cool, and then concentrated in vacuo.
  • Example 15.a Prepared from N-(6,7-Methylenedioxyquinolin-4-yl)-N-[l-[(t- butyldimethylsilanyloxy)-methyl] -N-2-dimethylaminoethyl] ] -2-iodo-4 ,5 - dimethoxybenzamide (95% yield); reaction time 45 min; 1H NMR (CDC1 3 ); ⁇ -0.13 (6H), 069 (s, 9H), 1.97(s, 6H), 1.92 (s, 6H), 2.52 (m, 1H), 2.80 (m, 1H) 3.20 (m, 1H), 4.01 (s, 3H), 4.09(s, 3H), 4.50 (m, 1H), 4.90 (m, 1H), 6.1 1 (m,2H), 7.30 (s, 1H), 7.61 (s, 1H) , 7.79 (s, 1H), 8.19 (s, 1H), 9.32 (s, 1H).
  • Example 16.a. 8,9-Dimethoxy-2,3-methylenedioxy-5-[2,2-dimethyl[l,3]dioxolan- 4-yl] methyl] -5H-dibenzo[c,/i] l,6-naphthyridin-6-one was prepared from N-(6,7- Methylenedioxyquinolin-4-yl)-N-[(2,3-dihydroxy)propyl]-2-iodo-5,6- dimethoxybenzamide (22 % yield); reaction time 45 min); mp 241-244 °C (dec); IR (CHC1 3 ) 1652; 1H NMR (CDC1 3 ) ⁇ 1.34 (s, 3H), 1.36 (s, 3H), 3.95 (m, 2H), 4.08 (s, 3H), 4.14 (s, 3H), 4.35 (m, 1H), 4.55 (m, 1H), 4.77 (m, 1H), 6.19 (s, 2H), 7.48
  • reaction mixture was then stirred at reflux under N 2 . .
  • the residue was partitioned between CHCI3 and 10% NaOH.
  • the aqueous layer was repeatedly separated with CHCI3. All of the CHCI3 solutions (initial partition and extracts) were combined and dried (MgS0 4 ).
  • the aqueous layer was neutralized with 20% NaOH and extracted with CHCI 3 , dried (MgS0 4 ) and evaporated.
  • Example 13.b N-(6,7-Methylenedioxyquinolin-4-yl)-N-[(2-(i- butyldimethylsilanyloxy)-ethyl] -2-iodo-4,5-dimethoxybenzamide.
  • Example 14.b N-(6,7-Methylenedioxyquinolin-4-yl)-N-[2-(2-(i- butyldimethylsilanyloxy)ethoxy)ethyl]-2-iodo-4,5-dimethoxybenzamide.
  • Example 15.b N-(6,7-Methylenedioxyquinolin-4-yl)-N-[l-[(i- butyldimethylsilanyloxy)-methyl] -N-2-dimethylaminoethyl] ] -2-iodo-4,5- dimethoxybenzamide.
  • Example 16.b N-(6,7-Methylenedioxyquinolin-4-yl)-N-[(2,3-dihydroxy)propyl]- 2-iodo-5,6-dimethoxybenzamide. Prepared from 4-[N-(2,2-dimethyl-[l,3]dioxolan- 4-yl)methyl]amino-6,7-methylenedioxyquinoline (290 mg, 0.9 mmol) in 47% yield with a reaction time of 12 h, from the acid chloride prepared using 30 mmol of oxalyl chloride and 13 mmol of 2-iodo-5,6-dimethoxybenzoic acid.
  • Example 15.c 4-[N-4-[2-(N,N-dimethylamino)-l-[(i- butyldimethylsilanyloxy)methyl]-ethyl]amino-6,7-methylenedioxyquinoline.
  • Example 16.c 4-[N-(2,2-dimethyl-[l,3]dioxolan-4-yl)methyl]amino-6,7- methylenedioxyquinoline.
  • Example 14.d 2-[2-[N-(6,7-Methylenedioxyquinolin-4-yl)]amino]ethoxyethanol was prepared from 2-[2-(hydroxyethyl)ethoxy]ethylamine (0.76 g, 7.2 mmol) with a reaction time of 18 h. The compound was converted directly to its t- butyldimethylsilanyloxy derivative in Example 14. c. above.
  • Example 15.d 2-[[N-(6,7-Methylenedioxyquinolin-4-yl)]amino]-3-(N,N- dimethylamino)propanol was prepared from l-(hydroxymethyl)-2-(N,N- dimethylethylenediamine (1.13 g, 9.6 mmol) with a reaction time of 48 h. The compound was converted directly to its t-butyldimethylsilanyloxy derivative in Example 15.c. above.
  • Example 18 8,9-Dimethoxy-2,3-methylenedioxy-5-[2-(N,N-dimethylamino)-l- methylethyl]-5,6-dihydro-dibenzo[c, ⁇ ] l,6-naphthyridine.
  • the title compound was prepared as follows.
  • the acid chloride was dissolved in 40 mL of methylene chloride and added to a solution of 4-[[2-(Diethylamino)ethyl]amino]-6,7-methylenedioxyquinoline (640 mg, 2.2 mmol), and triethylamine (2.2g, 22 mmol) in methylene chloride (50 mL) and the resulting mixture was stirred at reflux under nitrogen for 2 hours.
  • the reaction mix was cooled and washed with a saturated solution of sodium bicarbonate (3 x 75 mL), and extracted into dilute HCl (4 x 100 mL).
  • Example 20 Using procedures similar to those described above, the compound 2,3- dimethoxy-8,9-methylenedioxy-l l-[2-(4-methylpiperazin-l-yl)ethyl]-l 1H-5,6,11- triazachrysen-12-one was also prepared.
  • Example 21 Using procedures similar to those described above, the following compounds of the invention were also prepared: 8,9-dimethoxy-2,3-methylenedioxy- 5-(2-piperidinoethyl)-5H-dibenzo[c,/z] 1 ,6-naphthyridin-6-one; 8,9-dimethoxy-2,3- methylenedioxy-5-[2-(4-benzylpiperazin-l-yl)ethyl]-5H-dibenzo[c,A] l,6- naphthyridin-6-one; 8,9-dimethoxy-2,3-methylenedioxy-5-formylmethyl-5H- dibenzo[c,/z] 1 ,6-naphthyridin-6-one; and 8,9-dimethoxy-2,3-methylenedioxy-5-[2-(N- methylamino)ethyl]-5H-dibenzo[c,/z] 1 ,6-na
  • Compound 2 was evaluated to determine the concentration response (i.e. growth inhibition) relationship in human tumor cell lines in a 72-hr growth inhibition assay.
  • Five established human gastric cancer cell lines and six human pancreatic cancer cell lines were exposed to a concentration range of Compound 2 in two independent growth inhibition experiments.
  • Human tumor cell lines were maintained frozen in liquid nitrogen until use. Cultures were passed several times prior to experiments. For experiments, tumor cells, 4 x 10 3 cells per well in 96-well plates, were plated in RPMI medium supplemented with 5% fetal bovine serum.
  • Compound 2 was tested at concentrations covering a 6-log range (0.1 nM- 10,000 nM) with an exposure time of 72 hours and experimental endpoint of cell growth inhibition as determined by Cell Titer-Glo Luminescent Cell Viability Assay (Promega) for ATP content.
  • the following established human tumor cell lines were tested: Cell Line Tumor Type Reference
  • the 96-well plates were labeled and 100 ⁇ of each of the 12 compound solutions was added to the 100 ⁇ of RPMI medium supplemented with 5% FBS containing cells (4 x 10 3 )/well in triplicate. Plates were placed into the incubator at 37°C with a humidified air/5% carbon dioxide atmosphere, and allowed to incubate for 72 hours. On Day 2, the To plate was read utilizing Promega's Cell Titer-Glo Luminescent Cell Viability Assay (cat # G7571) according to the manufacturer's instructions. The T 0 plate was removed from the incubator and allowed to reach room temperature for 30 minutes.
  • Cell Titer-Glo buffer was added to the Cell Titer-Glo substrate as described in the manufacturer's instructions (Promega).
  • the complete Cell Titer-Glo solution was added to the plate at room temperature.
  • a BioTek Synergy HT plate reader was set for reading luminescence with a sensitivity setting of 100.
  • the Cell Titer-Glo solution (100 ⁇ ) was added to each well of the T 0 plate and timed for 3 minutes. After 3 minutes, the plate was read in the plate reader, and values obtained.
  • the complete Cell Titer-Glo solution was prepared from the Cell Titer-Glo buffer and Cell Titer-Glo substrate per the manufacturer's instructions for each plate to be read.
  • the BioTek Synergy plate reader was set for reading luminescence with a sensitivity setting of 100.
  • half of the volume of medium (100 ⁇ of the 200 ⁇ ) in each well was carefully removed and discarded, leaving 100 ⁇ medium remaining in each well.
  • the complete Cell Titer-Glo solution (100 ⁇ ) was added to each well in the first plate.
  • Luminescence value for each well was transferred to an Excel file.
  • the second and third plates were similarly read and data recorded.
  • the luminescence data were converted to growth fraction by comparison to the luminescence for the untreated control for each cell line.
  • Concentration response curves over the concentration range from 0.1 nanomolar to 10 micromolar were plotted using the mean values for the triplicate determinations for each experiment.
  • Each cell line was tested in at least two independent experiments. The results were plotted in Excel and graphed. IC 50 and IC 90 values were determined from the graphical data.
  • Compound 2 was a potent growth inhibitor of human tumor cells. Exposure to the compound produced exponential killing of cells in a manner consistent with potent inhibition of a critical molecular target. Human Tumor Cell Lines and IC ⁇ and ICgnConcentrations
  • the IC 90 concentrations of the human gastric and pancreatic tumor cell lines were spread over nearly a 100-fold concentration range from 15 nanomolar to 1300 nanomolar.
  • the steepness of the concentration response curves from the IC 50 to the IC 90 did not track with the sensitivity of the cells to Compound 2.
  • Some cell lines had steep slopes between these values as reflected by IC 90 /IC 50 ratios less than 10; while other lines had large differentials between IC 50 and IC 90 concentrations reaching 100- fold.
  • FIG. 2 Human tumor cell IC 90 values for Compound 2 in nanomolar concentrations are presented in Figure 2. As shown in Figure 2, the pancreatic cancer cell lines tend to be less sensitive to Compound 2 compared to the gastric cancer cell lines except KATO III which is the least sensitive among the cell lines. [259] Figure 3 and Figure 4 are graphs of the surviving fraction versus concentration of Compound 2 for human pancreatic cell lines and human gastric cancer cell lines, respectively.
  • Tumor measurements were converted to a tumor volume (mm 3 ) using the formula, [width (mm) 2 x length (mm)] x 0.52. Abnormal clinical signs were recorded for all mice before each dose, frequently after each dose, and at the time of body weight measurements on non-dose days. Mortality evaluations were performed on all mice daily. Mice were evaluated for two clinical endpoints: 1) percent tumor growth inhibition (T/C %), 2) tumor growth delay in days with corresponding increase-in-lifespan (ILS). Tumor growth delay (T-C) utilized the time required for the median mouse in each group to reach the tumor volume endpoint of 2000 mm 3 .
  • T/C percent tumor growth inhibition
  • ILS increase-in-lifespan
  • Test and Control Article Formulation Preparation On each day of dosing, the test article, Compound 2, was weighed out and dissolved in the appropriate volume of M/6 lactate. The positive control article dosing solution was prepared on each day of dosing. A 10 mL/kg dose volume was administered to all animals.
  • mice Male nude (nu/nu) mice were implanted subcutaneously in the axilla region by trocar with fragments of tumors harvested from subcutaneously growing tumors in nude mice hosts. The mice were approximately 4 weeks of age and weighed 18-20 g at the time of tumor implantation. When the tumors were 220-235 mm 3 in size, the animals were pair-matched into treatment and control groups.
  • Tumor Measurements and Study Endpoints Tumor volumes were measured twice weekly. Mice were evaluated for two tumor growth endpoints, percent tumor growth inhibition (T/C%) and tumor growth delay (T-C days) with corresponding increase in life span.
  • Figure 5 shows the mean tumor volume of mice treated with Compound 2 versus gemcitabine in MIA PaCa-2 human pancreatic tumor model.
  • Figure 6 shows the percent change in body weight of mice treated with Compound 2 versus gemcitabine in MIA PaCa-2 human pancreatic tumor model.
  • Table 3 Compound 2 at 1.0 and 1.36 mg/kg/day resulted in moderate TGI activity.
  • T-C 10 days
  • TGD 13 days
  • TGD 13 days
  • the high dose of Compound 2 (1.70 mg/kg/day) resulted in moderate weight loss (11.4%).
  • Compound 2 exhibited activity against the MIA PaCa-2 human pancreatic carcinoma xenograft model.
  • Figure 7 shows the mean tumor volume of mice treated with Compound 2 versus gemcitabine in BxPC-3 human pancreatic tumor model.
  • Figure 8 shows the percent change in body weight of mice treated with Compound 2 versus gemcitabine in BxPC-3 human pancreatic tumor model.
  • Table 4 shows that Compound 2 at 1.0, 1.36 and 1.7 mg/kg/day resulted in moderate TGI activity.
  • the medium and high doses of Compound 2 (1.36 and 1.7 mg/kg/day) resulted in moderate weight loss (5-8 %).
  • this agent was more toxic than the low dose of Compound 2 which produced the same tumor response, as determined by the body weight loss of 6.7 % at the dose level tested.
  • Compound 2 exhibited activity against the BxPC-3 human pancreatic carcinoma xenograft model.
  • Figure 9 shows the mean tumor volume of mice treated with Compound 2 versus gemcitabine in Hs 766T human pancreatic tumor model.
  • Figure 10 shows the percent change in body weight of mice treated with Compound 2 versus gemcitabine in Hs 766T human pancreatic tumor model.
  • Table 5 Compound 2 at 1.0 and 1.36 mg/kg/day resulted in moderate TGI activity.
  • T-C 10 days
  • TGD 13 days
  • TGD 13 days
  • the high dose of Compound 2 (1.70 mg/kg/day) resulted in moderate weight loss (9.2%).
  • Compound 2 exhibited activity against the Hs766T human pancreatic carcinoma xenograft model.
  • Figure 11 shows the mean tumor volume of mice treated with Compound 2 versus gemcitabine in CFPAC-1 human pancreatic tumor model.
  • Figure 12 shows the percent change in body weight of mice treated with Compound 2 versus gemcitabine in CFPAC-1 human pancreatic tumor model.
  • Table 6 shows that Compound 2 at 1.0, 1.36 and 1.7 mg/kg/day resulted in moderate TGI activity.
  • T-C 16 days
  • the medium and high doses of Compound 2 (1.36 and 1.7 mg/kg/day) resulted in low weight loss (0.4- 2.5 %).
  • T-C 38 days
  • FIG. 13 shows the mean tumor volume of mice treated with Compound 2 versus docetaxel in MKN-45 human gastric tumor model.
  • Figure 14 shows the percent change in body weight of mice treated with Compound 2 versus docetaxel in MKN-45 human gastric tumor model.
  • Table 7 shows that Compound 2 at 1.0 and 1.36 mg/kg/day resulted in moderate TGI activity.
  • the high dose of Compound 2 (1.70 mg/kg/day) resulted in moderate weight loss (10.7%).
  • this efficacy was accompanied by unacceptable toxicity as evidenced by a percent maximal body weight loss of 20.7%
  • Compound 2 exhibited activity against the MKN-45 human gastric carcinoma xenograft model.
  • Figure 15 shows the mean tumor volume of mice treated with Compound 2 versus docetaxel in 23132/87 human gastric tumor model.
  • Figure 16 shows the percent change in body weight of mice treated with Compound 2 versus docetaxel in 23132/87 human gastric tumor model.
  • Table 8 shows that Compound 2 at 1.0, 1.36 and 1.7 mg/kg/day resulted in moderate TGI activity.
  • TTD tumor growth delay activity
  • the medium and high doses of Compound 2 (1.36 and 1.7 mg/kg/day) resulted in moderate weight loss (6-7 %).
  • Docetaxel was highly effective against the 23132/87 tumor resulting in undetermined tumor growth delay. However, this efficacy was accompanied by unacceptable toxicity as evidenced by a percent maximal body weight loss of 20.7%
  • Compound 2 exhibited activity against the 23132/87 human gastric carcinoma xenograft model.
  • Figure 17 shows the mean tumor volume of mice treated with Compound 2 versus docetaxel in Hs 746T human gastric tumor model.
  • Figure 18 shows the percent change in body weight of mice treated with Compound 2 versus docetaxel in Hs 746T human gastric tumor model.
  • Table 9 Compound 2 at 1.0 mg/kg/day resulted in low TGI activity while Compound 2 at 1.36 and 1.7 mg/kg/day resulted in moderate and high TGI activity, respectively.
  • T-C l l days
  • the high dose of Compound 2 (1.70 mg/kg/day) resulted in low weight loss (2.3%).
  • Docetaxel was highly effective against the Hs746T tumor resulting in undetermined tumor growth delay. However, this efficacy was accompanied by unacceptable toxicity as evidenced by a percent maximal body weight loss of 16.4%.
  • Compound 2 exhibited activity against the Hs746T human gastric carcinoma xenograft model.
  • IC 50 values for oxaliplatin, doxorubicin, and docetaxel were determined from each of the 5 cell lines from complete concentration response curves depicted in Figure 20.
  • Compound 2 and docetaxel were the most potent cyotoxic agents among the 6 agents tested while 5-fiuorouracil, oxaliplatin, and cisp latin were less potent.
  • the gastric carcinoma cells were exposed to a concentration range of Compound 2 in combination with oxaliplatin, doxorubicin, or docetaxel at the predetermined IC 50 concentrations.
  • the data were analyzed statistically for additive, sub-additive, or syngeristic interactions using combination index methodology as described in Chou and Talalay, Quantitative Analysis of Dose-effect Relationships: The Combined Effects of Multiple Drugs or Enzyme Inhibitors, Adv. Enzyme Regul. 1984;22:27-55 hereby incorporated by reference in its entirety.
  • a combination index (CI) equal to 1 indicates additivity.
  • a combination index (CI) less than 1 indicates a synergistic effect for the compounds of the combination.
  • a combination index (CI) of greater than 1 indicates antagonism between the compounds of the combination.

Abstract

L'invention concerne des méthodes et des compositions pharmaceutiques pour le traitement du cancer du pancréas ou de l'estomac ou d'une métastase de ceux-ci.
PCT/US2011/045510 2010-07-28 2011-07-27 Méthodes de traitement de malignités gastriques et pancréatiques WO2012015901A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9895313B2 (en) 2015-03-03 2018-02-20 Cureport, Inc. Combination liposomal pharmaceutical formulations
US10736845B2 (en) 2015-03-03 2020-08-11 Cureport Inc. Dual loaded liposomal pharmaceutical formulations

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Publication number Priority date Publication date Assignee Title
EP2196205A1 (fr) * 2001-11-14 2010-06-16 Rutgers, The State University Poisons de topoisomérase solubilisés

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2196205A1 (fr) * 2001-11-14 2010-06-16 Rutgers, The State University Poisons de topoisomérase solubilisés

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9895313B2 (en) 2015-03-03 2018-02-20 Cureport, Inc. Combination liposomal pharmaceutical formulations
US10561611B2 (en) 2015-03-03 2020-02-18 Cureport, Inc. Combination liposomal pharmaceutical formulations
US10736845B2 (en) 2015-03-03 2020-08-11 Cureport Inc. Dual loaded liposomal pharmaceutical formulations

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