Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
  • C07D295/26—Sulfur atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/04—Antineoplastic agents specific for metastasis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
  • C07D211/96—Sulfur atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/58—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems with hetero atoms directly attached to the ring nitrogen atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
  • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
  • C07D221/20—Spiro-condensed ring systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D225/00—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom
  • C07D225/04—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems

Definitions

• Provisional Application 60/928,592 filed 10 May 2007 and U.S. Provisional Application 60/999,153, filed 15 October 2007, the disclosures of which are hereby incorporated by reference in their entirety.
• the present invention relates to the field of antitumor therapy using anthraquinone dioximes.
• the Wnt/beta-catenin signaling pathway is recognized as one of the key signaling pathways in cancer and as a valid target for therapeutic intervention in many tumor types, especially colon tumors.
• the cells of multicellular organisms have the ability to recognize and signal each other, sometimes from fair distances. Such signaling may be accomplished by production of signaling molecules produced by one cell and which subsequently bind to a specific receptor on a different cell. Such signaling pathways have been implicated in various disease processes, including cancer. Wnt signaling, via receptor binding and subsequent increase in intracellular ⁇ -catenin, is referred to as the canonical pathway. Wnt proteins form a family of highly conserved secreted signaling molecules that regulate cell-to-cell interactions and have been implicated in cancer pathogenesis. Wnt proteins bind to receptors of the Frizzled and LRP families on the cell surface. Through several cytoplasmic relay components, the signal is transduced to ⁇ - catenin, which then enters the nucleus and forms a complex with TCF to activate transcription of Wnt target genes.
• Wnt polypeptides are either present on the surface of a signaling cell or released by that cell and eventually contact a specific cell- surface receptor of another cell.
• GSK-3/APC/Axin GSK-3/APC/Axin
• APC Adenomatous Polyposis CoIi
• mutations that promote constitutive activation of the Wnt signaling pathway can lead to cancer, [for a review, see Logan and Nusse, "The Wnt Signaling Pathway in Development and Disease," in Ann- Rev. Cell Dev. Biol.. 20:781-810 (2004)]
• mutations in Axin2 may predispose an individual to colon cancer (Lammi et al., Am. J. Hum. Genet., 74:1043-50 (2004)).
• familial adenomatous polyposis an inherited disease characterized by numerous polyps in the colon and rectum, is often caused by truncation of APC (another Wnt signaling- pathway protein), which promotes aberrant activation of the Wnt pathway, [see: Kinzler et al., Science, 253:661-665 (1991)] Mutations in APC and ⁇ - catenin have also be detected in colon cancer and other tumor types (for a review see Giles et al., Biochim. Biophys. Acta, 1653:1-24 (2003)).
• APC another Wnt signaling- pathway protein
• the present invention provides such agents in the form of disulfonamide derivatives of fluorene, anthracene, xanthene, dibenzosuberone and acridine that reduce levels of beta-catenin in tumor cells.
• Structurally related fluorene and anthracene derivatives with the sulfonamide groups substituted with aromatic amines are known in the art (see, for example, US 2004/0019042) as inhibitors of P2X3 and P2X2/3 containing receptors and have been found useful in the treatment and prevention of disorders such as bladder overactivity, urinary incontinence or pain.
• novel structurally related compounds can be prepared and used as modulators of the Wnt/ ⁇ -catenin pathway. It is known that ⁇ -catenin is a regulator of the Wnt signally pathway, (see Willert and Nusse, Current Opinion in Genetics and Development, 8:95-102 (1998).
• the invention provides small organic compounds of the anthraquinonedioxime family, useful for the treatment of cancer that interfere with the Wnt signaling pathway and reduce levels of beta-catenin in cancer cells, and methods for their synthesis.
• these compounds include disulfonamide derivatives of anthraquinonedioxime that reduce levels of beta-catenin in tumor cells.
• R-I, R2, R 3 , and R 4 are each independently selected from H, alkyl, heteroalkyl, cycloalkyl, arylcycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, and each of said Ri, R2 and said R 3 , R 4 can independently combine to form heterocycloalkyl
• R 5 and R 6 are each independently selected from H, OH, SH, alkoxy, thioalkoxy, alkyl, halogen, CN, CF 3 , NO 2 , COOR D , CONRDRE, NR 0 RE, NR D COR E , NR 0 SO 2 RE, and NR F CONR D R E ; wherein R 0 , RE and RF are independently H, alkyl, heteroalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or heterocycloalkyl; and wherein
• the compounds of the invention include those of Tables 1 to 4 and said compounds are contemplated by the invention either individually or in any combination thereof.
• the present invention contemplates any one of said compounds alone, or any combination of these compounds or all of these compounds, as well as uses of any or all of these compounds, in any combination, to treat cancer by any mechanism.
• Each said compound is by itself an embodiment of the invention and any combination of said embodiments is itself a specific embodiment of the invention.
• the present invention also provides therapeutic compositions of any of the compounds of the invention, such as the compounds of Tables 1 to 4, including individual compositions of any one of these compounds, or any combination of these compounds.
• Each said composition is by itself an embodiment of the invention and any combination of said embodiments is itself a specific embodiment of the invention.
• the present invention also relates to a method for ameliorating cancer or tumor metastasis in a mammal comprising administering to said mammal an effective amount of a compound of the invention.
• a compound of the invention Especially contemplated are uses of the compounds of Tables 1 to 4 for the treatment of cancer. Use of each said compound is by itself an embodiment of the invention and any combination of said embodiments is itself a specific embodiment of the invention.
• Preferred acyl groups include acetyl, formyl, and propionyl, with acetyl being most preferred.
• Alkyl means a saturated hydrocarbon radical having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 5 carbon atoms, most preferably 1 to 3 carbon atoms, that may be branched or unbranched.
• alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, tert-amyl, pentyl, hexyl, heptyl, octyl and the like, wherein methyl, ethyl, n-propyl, and isopropyl represent specifically preferred examples.
• alkenyl refers to an optionally substituted straight-chain, or optionally substituted branched-chain hydrocarbon radical having one or more carbon-carbon double-bonds and having 2 to 15 carbon atoms, preferably 2 to 10, more preferably 2 to 5 carbon atoms, more preferably two to about eighteen carbons.
• alkenyl radicals include ethenyl, propenyl, butenyl, 1 ,3-butadienyl and the like.
• alkynyl refers to an optionally substituted straight-chain or optionally substituted branched-chain hydrocarbon radical having one or more carbon-carbon triple-bonds and having 2 to 15 carbon atoms, preferably 2 to 10, more preferably 2 to 5 carbon atoms, more preferably from two to about twelve carbon atoms, from two to about six carbon atoms as well as those having from two to about four carbon atoms.
• alkynyl radicals include ethynyl, 2-propynyl, 2- butynyl, 1 ,3-butadiynyl and the like.
• Preferred branched alkyl, alkenyl and alkynyl chains have one or two branches, preferably one branch, and each may be unsubstituted or substituted with from 1 to 4 substituents, preferably up to 3 substituents, more preferably 2 substituents and most preferably one substituent.
• Preferred substituents are hydrocarbon, halo (preferably F, Cl, Br and I), hydroxy, aryloxy (e.g., phenoxy), heteroaryloxy, acyloxy (e.g., acetoxy), carboxy, aryl
• phenyl e.g., phenyl
• heteroaryl e.g., phenyl
• cycloalkyl e.g., cycloalkyl
• heteroalkyl e.g., cycloalkyl
• heterocycloalkyl e.g., spirocycle
• Preferred hydrocarbons are methyl, ethyl, propyl, isopropyl, butyl, vinyl, allyl, butenyl, and exomethylenyl.
• a “lower alkyl” is a shorter alkyl, e.g., one containing from one to about six carbon atoms.
• a “lower” alkyl, alkenyl or alkynyl moiety is a chain comprised of 1 to 10, preferably from 1 to 8, carbon atoms in the case of alkyl and 2 to 10, preferably 2 to 8, carbon atoms in the case of alkene and alkyne.
• Alkoxy means an oxygen radical having a hydrocarbon chain substituent, where the hydrocarbon chain is an alkyl or alkenyl (i.e., -O-alkyl or -O-alkenyl).
• alkoxy radicals include methoxy, ethoxy, n- propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, allyloxy and the like.
• Aryl is an aromatic hydrocarbon ring.
• Aryl rings are monocyclic or fused bicyclic ring systems.
• Monocyclic aryl rings contain 6 carbon atoms in the ring.
• Monocyclic aryl rings are also referred to as phenyl rings.
• Bicyclic aryl rings contain from 8 to 17 carbon atoms, preferably 9 to 12 carbon atoms, in the ring.
• Bicyclic aryl rings include ring systems wherein one ring is aryl and the other ring is aryl, cycloalkyl, or heterocycloakyl.
• Preferred bicyclic aryl rings comprise 5-, 6- or 7-membered rings fused to 5-, 6-, or 7- membered rings.
• Aryl rings may be unsubstituted or substituted with from 1 to 4 substituents on the ring.
• Aryl may be substituted with halo, cyano, nitro, hydroxy, carboxy, amino, acylamino, alkyl, heteroalkyl, haloalkyl, phenyl, aryloxy, alkoxy, heteroalkyloxy, carbamyl, haloalkyl, methylenedioxy, heteroaryloxy, or any combination thereof.
• Preferred aryl rings include naphthyl, tolyl, xylyl, and phenyl. The most preferred aryl ring radical is phenyl.
• Aryloxy is an oxygen radical having an aryl substituent (i.e., -O-aryl).
• Preferred aryloxy groups include, for example, phenoxy, napthyloxy, methoxyphenoxy, and methylenedioxyphenoxy.
• Cycloalkyl refers to a saturated hydrocarbon ring that is not aromatic. Cycloalkyl rings are monocyclic, or are fused, spiro, or bridged bicyclic or polycyclic ring systems. Monocyclic cycloalkyl rings contain from about 3 to about 12 carbon atoms, preferably from 3 to 7 carbon atoms, in the ring. Bicyclic cycloalkyl rings contain from 7 to 17 carbon atoms, preferably from 7 to 12 carbon atoms, in the ring. Preferred bicyclic cycloalkyl rings comprise 4-, 5- 6- or 7-membered rings fused to 5-, 6-, or 7-membered rings.
• Cycloalkyl rings may be unsubstituted or substituted with from 1 to 4 substituents on the ring. Cycloalkyl may be substituted with halo, cyano, alkyl, heteroalkyl, haloalkyl, phenyl, keto, hydroxy, carboxy, amino, acylamino, aryloxy, heteroaryloxy, or any combination thereof. Preferred cycloalkyl rings include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclononyl rings.
• the term "lower alkenyl” or “lower alkynyl” refers to an alkenyl or alkynyl radical, respectively, having from two to about six carbons in the carbon chain and not including substituents.
• Halo or "halogen” is fluoro, chloro, bromo or iodo. Preferred halo are fluoro, chloro and bromo; more preferred typically are chloro and fluoro, especially fluoro.
• Heteroatom is a nitrogen, sulfur, or oxygen atom. Groups containing more than one heteroatom may contain different heteroatoms.
• Heteroalkyl is a saturated or unsaturated chain containing carbon and at least one heteroatom, wherein no two heteroatoms are adjacent. Heteroalkyl chains contain from 2 to 15 member atoms (carbon and heteroatoms) in the chain, preferably 2 to 10, more preferably 2 to 5. For example, alkoxy (i.e., -O-alkyl or -O-heteroalkyl) radicals are included in heteroalkyl. Heteroalkyl chains may be straight or branched. Preferred branched heteroalkyl have one or two branches, preferably one branch. Preferred heteroalkyl are saturated. Unsaturated heteroalkyl have one or more carbon-carbon double bonds and/or one or more carbon-carbon triple bonds.
• Preferred unsaturated heteroalkyls have one or two double bonds or one triple bond, more preferably one double bond.
• Heteroalkyl chains may be unsubstituted or substituted with from 1 to 4 substituents.
• Preferred substituted heteroalkyl are mono-, di-, or tri-substituted.
• Heteroalkyl may be substituted with lower alkyl, haloalkyl, halo, hydroxy, acyloxy, carboxy, amino, acylamino, amido, keto, thioketo, cyano, or any combination thereof.
• an alkyl derivative such as "- ethylpyridine” the dash "-" indicates the point of attachment of the substituent.
• ethylpyridine means attachment of ethylpyridine via the ethyl portion of the group whereas "ethylpyridine-" means attachment via the pyridine ring.
• Heteroaryl is an aromatic ring containing carbon atoms and from 1 to about 6 heteroatoms in the ring. Heteroaryl rings are monocyclic or fused bicyclic ring systems. Monocyclic heteroaryl rings contain from about 5 to about 9 member atoms (carbon and heteroatoms), preferably 5 or 6 member atoms, in the ring. Bicyclic heteroaryl rings contain from 8 to 17 member atoms, preferably 8 to 12 member atoms, in the ring. Bicyclic heteroaryl rings include ring systems wherein one ring is heteroaryl and the other ring is aryl, heteroaryl, cycloalkyl, or heteroalkyl, heterocycloalkyl.
• Preferred bicyclic heteroaryl ring systems comprise 5-, 6- or 7-membered rings fused to 5-, 6-, or 7-membered rings.
• Heteroaryl rings may be unsubstituted or substituted with from 1 to 4 substituents on the ring.
• Heteroaryl may be substituted with halo, cyano, nitro, hydroxy, carboxy, amino, acylamino, alkyl, heteroalkyl, haloalkyl, phenyl, alkoxy, aryloxy, heteroaryloxy, or any combination thereof.
• Preferred heteroaryl rings include, but are not limited to, the following:
• a fused heteroaryl radical may contain from two to four fused rings and where the ring of attachment is a heteroaromatic ring, the other individual rings within the fused ring system may be aromatic, heteroaromatic, alicyclic or heterocyclic.
• heteroaryl also includes mono-heteroaryls or fused heteroaryls having from five to about twelve skeletal ring atoms, as well as those having from five to about ten skeletal ring atoms.
• the term "lower heteroaryl” refers to a heteroaryl having five to about ten skeletal ring atoms, e.g., pyridyl, thienyl, pyrimidyl, pyrazinyl, pyrrolyl, or furanyl.
• Heteroaryloxy is an oxygen radical having a heteroaryl substituent (i.e., -O-heteroaryl).
• Preferred heteroaryloxy groups include (for example) pyridyloxy, furanyloxy, (thiophene)oxy, (oxazole)oxy, (thiazole)oxy, (isoxazole)oxy, pyrmidinyloxy, pyrazinyloxy, and benzothiazolyloxy.
• Heterocycloalkyl is a saturated or unsaturated ring containing carbon atoms and from 1 to 4 (preferably 1 to 3) heteroatoms in the ring. Heterocycloalkyl rings are not aromatic. Heterocycloalkyl rings are monocyclic, or are fused, bridged, or spiro bicyclic ring systems. Monocyclic heterocycloalkyl rings contain from about 3 to about 9 member atoms (including both carbons and heteroatoms), preferably from 5 to 7 member atoms, in the ring. Bicyclic heterocycloalkyl rings contain from 7 to 17 member atoms, preferably 7 to 12 member atoms, in the ring.
• Bicyclic heterocycloalkyl rings contain from about 7 to about 17 ring atoms, preferably from 7 to 12 ring atoms. Bicyclic heterocycloalkyl rings may be fused, spiro, or bridged ring systems. Preferred bicyclic heterocycloalkyl rings comprise 5-, 6- or 7-membered rings fused to 5-, 6-, or 7-membered rings.
• Heterocycloalkyl rings may be unsubstituted (i.e., contain hydrogens as substituents of the ring atoms) or substituted (on either carbons or heteroatoms or both) with from 1 to 4 substituents selected from methyl, cyano, hydroxy, carboxy, keto, thioketo, amino, acylamino, acyl, amido, alkyl, heteroalkyl, phenyl, alkoxy, aryloxy or any combination thereof.
• Preferred substituents on heterocycloalkyl include methyl, ethoxyl, and halo.
• a heterocycloalkyl ring may be attached as a substituent of a larger structure by any chemically feasible atom of said heterocycloalkyl ring.
• Preferred heterocycloalkyl rings include, but are not limited to, the following:
• membered ring can embrace any cyclic structure, including aromatic, heteroaromatic, alicyclic, heterocyclic and polycyclic fused ring systems as described below.
• membered is meant to denote the number of skeletal atoms that constitute the ring.
• pyridine, pyran, and pyrimidine are six-membered rings and pyrrole, tetrahydrofuran, and thiophene are five-membered rings.
• alkylaryl refers to an aryl radical as defined above in which one H atom is replaced by an alkyl radical as defined above, such as, for example, tolyl, xylyl and the like.
• arylalkyl or “aralkyl,” alone or in combination, refers to an alkyl radical as defined above in which one H atom is replaced by an aryl radical as defined above, such as, for example, benzyl, 2-phenylethyl and the like.
• heteroarylalkyl refers to an alkyl radical as defined above in which one H atom is replaced by a heteroaryl radical as defined above, each of which may be optionally substituted but wherein the aryl group is attached to a larger core structure with the alkyl group being the terminal moiety.
• alkylheteroaryl refers to an alkyl radical as defined above in which one H atom is replaced by a heteroaryl radical as defined above, each of which may be optionally substituted but wherein the alkyl group is attached to a larger core structure with the heteroaryl group being the terminal moiety.
• alkylthio alone or in combination, refers to an alkylthio radical, alkyl-S— , wherein the term alkyl is as defined above.
• arylthio alone or in combination, refers to an arylthio radical, aryl-S-, wherein the term aryl is as defined above.
• heteroarylthio refers to the group heteroaryl-S--, wherein the term heteroaryl is as defined above.
• acyloxy refers to the ester group -OC(O)R, where R is H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alicyclic, heterocyclic, arylalkyl, or heteroarylalkyl wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, alicyclic, heterocyclic, arylalkyl or heteroarylalkyl may be optionally substituted.
• carboxy esters refers to --C(O)OR where R is alkyl, aryl or arylalkyl, wherein the alkyl, aryl and arylalkyl groups may be optionally substituted.
• carboxy refers to the structure_-C(O)NRR' where nitrogen is attached to the carbonyl carbon and each of R and R 1 are independently selected from the group consisting of H, alkyl, aryl, heteroaryl, alicyclic, heterocyclic, arylalkyl and heteroarylalkyl, wherein the alkyl, aryl, heteroaryl, alicyclic, heterocyclic, or arylalkyl groups may be optionally substituted.
• alkylamino refers to the group --NHR 1 where R is independently selected from alkyl.
• dialkylamino refers to the group -NRR 1 where R and R' are alkyls.
• sulfide refers to a sulfur atom covalently linked to two atoms; the formal oxidation state of said sulfur is (II).
• thioether may be used interchangeably with the term “sulfide.”
• sulfoxide refers to a sulfur atom covalently linked to three atoms, at least one of which is an oxygen atom; the formal oxidation state of said sulfur atom is (IV).
• sulfurone refers to a sulfur atom covalently linked to four atoms, at least two of which are oxygen atoms; the formal oxidation state of said sulfur atom is (Vl).
• aryl optionally mono- or di- substituted with an alkyl means that the alkyl may but need not be present, or either one alkyl or two may be present, and the description includes situations where the aryl is substituted with one or two alkyls and situations where the aryl is not substituted with an alkyl.
• Independently selected groups are groups present in the same structure that need not all represent the same substitution. For example, where two substituents are represented as NORA and each R A is said to be independently selected from H, methyl, ethyl, etc., this means that where one RA is methyl, the other R A may be methyl but could be H or ethyl (or any other recited substitution). Typical embodiments appear in Table 2.
• Some of the compounds of the present invention may contain one or more chiral centers and therefore may exist in enantiomeric and diastereomeric forms.
• the scope of the present invention is intended to cover all isomers per se, as well as mixtures of cis and trans isomers, mixtures of diastereomers and racemic mixtures of enantiomers (optical isomers) as well. Further, it is possible using well known techniques to separate the various forms, and some embodiments of the invention may feature purified or enriched species of a given enantiomer or diastereomer.
• a “pharmacological composition” refers to a mixture of one or more of the compounds described herein, or pharmaceutically acceptable salts thereof, with other chemical components, such as pharmaceutically acceptable carriers and/or excipients.
• the purpose of a pharmacological composition is to facilitate administration of a compound to an organism.
• pharmaceutically acceptable carrier means a pharmaceutically-acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject agent from one organ, or portion of the body, to another organ, or portion of the body.
• a pharmaceutically-acceptable material such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject agent from one organ, or portion of the body, to another organ, or portion of the body.
• Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
• materials which can serve as pharmaceutically-acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11 ) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum, such
• excipient refers to an inert substance added to a pharmacological composition to further facilitate administration of a compound.
• excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
• the term "therapeutic effect” includes, but is not limited to, the inhibition, in whole or in part, of the growth of cells characteristic of a proliferative disorder, e.g., colon cancer.
• a therapeutic effect may also include amelioration of one or more of the symptoms of the disease, other than cell growth or size of the cell mass, and may include 1) a reduction in the number of cells; 2) a reduction in cell size; 3) inhibition (i.e., slowing, preferably stopping) of cell infiltration (i.e., metastasis) into peripheral organs; 3) inhibition or slowing of cell growth; and/or 4) relieving one or more symptoms associated with the disease, such as cancer. Any amount or dose of a compound disclosed herein that results in such a therapeutic effect is deemed to be a "therapeutically effective dose” or a "therapeutically effective amount” of said compound.
• the phrase "effective amount” means an amount sufficient to effect a desired response, or to ameliorate a symptom or sign, with respect to metastasis or primary tumor progression, size, or growth.
• Typical mammalian treatment recipients include mice, rats, cats, dogs, and primates, including humans.
• An effective amount for a particular patient may vary depending on factors such as the condition being treated, the overall health of the patient, the method, route, and dose of administration and the severity of side affects.
• the effect will result in a change in quantitation of at least about 10%, preferably at least 20%, 30%, 50%, 70%, or even 90% or more.
• an effective amount is in ratio to a combination of components and the effect is not limited to individual components alone.
• a “solvate” is a complex formed by the combination of a solute (e.g., a metalloprotease inhibitor) and a solvent (e.g., water). See J. Honig et al., The Van Nostrand Chemist's Dictionary, p. 650 (1953).
• optical isomer e.g., a cis and/or trans isomer
• stereoisomer e.g., a cis and/or trans isomer
• diastereomer e.g., a cis and/or trans isomer
• optical isomer e.g., a cis and/or trans isomer
• stereoisomer e.g., a cis and/or trans isomer
• diastereomer e.g., a cis and/or trans isomer
• the illustration of specific protected forms and other derivatives of the compounds of the instant invention is not intended to be limiting.
• the application of other useful protecting groups, salt forms, prodrugs etc. is within the ability of the skilled artisan.
• prodrug is a form of a drug that must undergo chemical conversion by metabolic processes before becoming an active, or fully active, pharmacological agent.
• a prodrug is not active, or is less active, in its ingested or absorbed or otherwise administered form.
• a prodrug may be broken down by bacteria in the digestive system into products, at least one of which will become active as a drug.
• it may be administered systemically, such as by intravenous injection, and subsequently be metabolized into one or more active molecules.
• IC 5 o refers to an amount, concentration or dosage of a particular test compound that achieves a 50% inhibition of a maximal response in an assay that measures such response.
• the "IC 50 " value of a compound of the invention can be greater for normal cells than for cells exhibiting a proliferative disorder, e.g., breast cancer cells. The value depends on the assay used.
• a "standard” is meant a positive or negative control.
• a negative control in the present case refers to a normal as opposed to a cancerous cell, e.g., a sample possessing Wnt/ ⁇ -catenin pathway activity that correlates with a normal cell.
• a negative control may also include a sample that contains no such pathway.
• a positive control does contain such pathway, preferably of an amount that correlates with overexpression as found in proliferative disorders, e.g., breast cancers.
• the controls may be from cell or tissue samples, or else contain purified ligand (or absent ligand), immobilized or otherwise. In some embodiments, one or more of the controls may be in the form of a diagnostic "dipstick.”
• selective targeting is meant affecting one type of cell to a greater extent than another, e.g., in the case of cancerous cells versus non- cancerous cells.
• the present invention provides a compound having the structure of Formula I
• Ri, R 2 , R3, and R 4 are each independently selected from H, alkyl, heteroalkyl, cycloalkyl, arylcycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, and each of said R-i, R2 and said R 3 , R 4 can independently combine to form heterocycloalkyl
• R 5 and Re are each independently selected from H, OH, SH, alkoxy, thioalkoxy, alkyl, halogen, CN, CF 3 , NO 2 , COOR D , CONRDRE, NR 0 RE, NR D COR E) NRDSO 2 RE, and NR F CONR D R E ; wherein R 0 , RE and R F are independently H, alkyl, heteroalkyl, aryl, arylal
• X and Y are each NOH.
• the invention provides a compound (an anthraquinone derivative) having the structure of Formula Il
• R 7 and R 8 are independently selected from H and SO 2 NR 3 R 4 , wherein one of R 7 and R 8 is hydrogen and wherein the other substituents have the meaning defined for Formula I.
• R 1 , R 2 , R 3 , and R 4 are each independently selected from H, alkyl, cycloalkyl, alkenyl, or alkynyl.
• R A is hydrogen and Ri
• R 2 , R3, and R 4 are each independently selected from H, alkyl, cycloalkyl, alkenyl, or alkynyl.
• NRiR 2 and NR 3 R 4 are independently 6- to 15-membered, preferably a 6 to 10 membered heterocycle, preferably a heterocycloalkyl, most preferably an 8 or 9 membered ring.
• a compound of the invention has the structure of Formula III
• NRiR 2 and NR 3 R 4 are independently 6- to 12-membered heterocycloalkyl containing one nitrogen in the ring and wherein the R groups are defined as for Formula II.
• at least one R A is H, or both are H.
• NRiR 2 and NR 3 R 4 are independently selected from Formula IV
• Ri 7 is independently H, methyl, ethyl, propyl, butyl, methoxy or ethoxy.
• a compound of the invention has the structure of
• NRiR 2 and NR 3 R 4 are independently 6- to 12-membered heterocycloalkyl containing one nitrogen in the ring and the other R groups are as defined for Formula II.
• at least one R A is H or both are H.
• NR 1 R 2 and NR 3 R 4 are independently from formula Vl:
• R 9 , R 10 , R 11 , R 12 , Ri 3 , R 14 , R15, R16, Ru, and Ri 8 are independently H 1 methyl, ethyl, propyl, butyl, methoxy or ethoxy.
• a compound of the invention has the structure of a compound shown in Table 1 so that each said structure is alone a separate embodiment of the invention.
• the invention specifically contemplates a compound selected from compounds 1-1 , 1-2, 1-3, 1-4, 1-5, 1-6, 1-22, 1-26, 1-37, 1-44, 1-45, 1- 46, 1-49, 1-51, 1-56, 1-77, 1-95 of Table 1.
• a compound of the invention has the structure of a compound of Table 3.
• Specific examples of such preferred embodiment are compounds 3-1 , 3-2, 3-3, 3-4, 3-7, 3-8, 3-11 , 3-13, 3-14, 3- 16, 3-21 , 3-28, 3-38, 3-39 and 3-40 of Table 3.
• the compounds are those with structures shown in Tables 2 and/or 4.
• Specific embodiments of the invention utilize any of such compounds, including combination of such compounds, or combinations of one or more of such compounds with one or more additional therapeutic agents, preferably an anticancer agent (e.g., those used in Example 12), in treating any or all of the cancers recited herein, such as one or more of colon cancer, adenocarcinoma, rectal cancer, colorectal cancer, breast cancer, lung cancer, ovarian cancer, adenomatous polyposis, and hepatocellular carcinoma, with colon and colorectal cancer being especially preferred.
• an anticancer agent e.g., those used in Example 12
• One preferred embodiment of the invention is 2,7-bis(azepan-1- ylsulfonyl)anthracene-9,10-dione dioxime:
• One preferred embodiment of the invention is 2,7-bis(azocan-1- ylsulfonyl)anthracene-9, 10-dione dioxime:
• One preferred embodiment of the invention is 2-((3R,5S)-3,5- dimethylpiperidin-1-ylsulfonyl)-7-((3S,5R)-3,5-dimethylpiperidin-1- ylsulfonyl)anthracene-9, 10-dione dioxime:
• One preferred embodiment of the invention is 2,6-bis(4- ethoxypiperidin-1 -ylsulfonyl)anthracene-9, 10-dione dioxime:
• One preferred embodiment of the invention is 2,6-bis(azepan-1- ylsulfonyl)anthracene-9, 10-dione dioxime:
• One preferred embodiment of the invention is 2,6-bis(azocan-1- ylsulfonyl)anthracene-9, 10-dione dioxime:
• One preferred embodiment of the invention is 2,6-bis((3R,5S)-3,5- dimethylpiperidin-1 -ylsulfonyl)anthracene-9, 10-dione dioxime:
• the present invention also relates to compositions of compounds, including pharmaceutically acceptable salts thereof, having the structures defined above for Formulas I to Vl (with substituents as disclosed therein), preferably compounds of Tables 1 to 4, in a therapeutically effective amount in a pharmaceutically acceptable carrier:
• the compounds of said compositions may also contain a multi-ring cycloalkyl or heterocycloalkyl bridge structure (as in Tables 1 to 4) containing a total of up to 12 atoms an up to 4 heteroatoms selected from N and O.
• the present invention also provides therapeutic compositions of any of the compounds of the invention, such as the compounds of Tables 1 to 4.
• the compounds of the invention may be in the form of pharmaceutically acceptable salts, esters, amides, stereoisomers, geometric isomers, solvates or prodrugs thereof.
• a compound of the invention is a stereoisomer, the latter may be an enantiomer or a diastereomer.
• the form of the compound used for pharmaceutical purposes may include either enantiomer or the racemate, although one of said enentiomers may be preferred, such as where it is the active form or is more active than the other enentiomer.
• said compound of the invention is a geometric isomer (e.g., contains a carbon pair with substituents attached in cis- or trans- configuration)
• either the cis- form, or the trans- form may be preferred for pharmaceutical use, although mixtures of the cis- and transforms may be used in the methods of the invention to the extent they have the desired pharmaceutical effect.
• a “pharmaceutically-acceptable salt” is a cationic salt formed at any acidic (e.g., carboxylic acid) group, or an anionic salt formed at any basic (e.g., amino) group. Many such salts are known in the art, as described in WO 87/05297 (Johnston et al., published September 11 , 1987 incorporated by reference herein).
• Suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydriodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, oxalate; palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate,
• Preferred cationic salts include the alkali metal salts (such as sodium and potassium), and alkaline earth metal salts (such as magnesium and calcium) and organic salts.
• Preferred anionic salts include the halides (such as chloride salts), sulfonates, carboxylates, phosphates, and the like. This invention also envisions the quaternization of any basic nitrogen- containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization.
• the present invention relates to compositions of any of the compounds of the invention, preferably wherein such compound is present in a pharmaceutically acceptable carrier and in a therapeutically effective amount.
• Such compositions will generally comprise an amount of such compound that is not toxic (i.e., an amount that is safe for therapeutic uses).
• the present invention also contemplates metabolites of any of the novel compounds of the invention, such metabolites representing second compound formed by one or more in vivo metabolic reactions on a first compound following administration of the latter to a mammal wherein the first compound is a novel compound of the invention.
• said first compound is any of the compounds disclosed herein as having a structure as defined for Formulas I to Vl, with the substituents disclosed for those formulas, and even more preferably any compound of Tables 1 , 2, 3 or 4, including all pharmaceutically acceptable salts thereof.
• Selected examples of compounds of the invention include, but are not limited to, any or all of the compounds of Tables 1-4, including all pharmaceutically acceptable salts thereof as well has metabolites of any said compounds produced by normal mammalian, especially human, metabolism of said compounds after administration to said mammal as a therapeutic agent. Any and all such compounds are specifically claimed for their use in any and all of the methods of the invention.
• the ligand is attached via the atom marked with an asterisk ( * ).
• the sulfur atoms of the indicated formula i.e., the "core structure” are attached to the indicated R group at the asterisked nitrogen of the R column of the table; similarly for the other tables.
• the present invention is directed to use of the compounds of the invention as active ingredients for medicaments, in particular for medicaments useful for the treatment of tumors.
• the compounds of the invention will thus be present in pharmaceutical compositions containing, for example, compounds of Formula I as active ingredients, in admixture with pharmaceutically acceptable vehicles and excipients, which includes any pharmaceutical agent that does not itself induce the production of antibodies harmful to the individual receiving the composition, and which may be administered without undue toxicity.
• Pharmaceutically acceptable carriers include, but are not limited to, liquids such as water, saline, glycerol and ethanol, and the like, including carriers useful in forming sprays for nasal and other respiratory tract delivery or for delivery to the ophthalmic system.
• the present invention relates to a method for preventing or treating a disease associated with a change in levels of expression of particular sets of genes in a mammal comprising administering to said mammal an effective amount of a compound of the invention.
• Compounds according to the present invention have, for example, the effect of reducing size and/or number of tumors, especially primary tumors, in a mammal, especially a human, in need of such treatment.
• a statistically significant change in the numbers of primary tumor or metastasizing cells will typically be at least about 10%, preferably 20%, 30%, 50%, 70%, 90%, or more.
• the agents described herein may be combined with other treatments of the medical conditions described herein, such as other chemotherapies, radiation treatments, immunotherapy, surgical treatments, and the like.
• the compounds of the invention may also be administered in combination with such other agents as painkillers, diuretics, antidiuretics, antivirals, antibiotics, nutritional supplements, anemia therapeutics, blood clotting therapeutics, bone therapeutics, and psychiatric and psychological therapeutics.
• Determination of the appropriate treatment dose is made by the clinician, e.g., using parameters or factors known in the art to affect treatment or predicted to affect treatment. Generally, the dose begins with an amount somewhat less than the optimum dose and it is increased by small increments thereafter until the desired or optimum effect is achieved relative to any negative side effects.
• a typical daily dose (administered in single or divided doses) will contain a dosage level of from about 0.01 mg/kg to about 50-100 mg/kg of body weight of an active compound of the invention.
• Preferred daily doses generally will be from about 0.05 mg/kg to about 25 mg/kg and ideally from about 0.1 mg/kg to about 10 mg/kg.
• Factors such as clearance rate, half-life and maximum tolerated dose (MTD), while not specifically recited herein, may be readily determined by one of ordinary skill in the art using standard procedures.
• An effective amount of a therapeutic will modulate the symptoms typically by at least about 10%; usually by at least about 20%; preferably at least about 30%; or more preferably at least about 50%.
• modulation of migration will mean that the migration or trafficking of various cancer cell types is affected. Such will result in, e.g., statistically significant and quantifiable changes in the numbers of cells being affected. This may be a decrease in the numbers of target cells being attracted within a time period or target area. Rate of primary tumor progression, size, or growth may also be monitored.
• the present invention relates to a method for preventing or treating a disorder modulated by altered gene expression, such as one or more of cancer, cardiovascular disorders, arthritis, osteoporosis, inflammation, periodontal disease and skin disorders, comprising administering to a mammal in need of such treatment or prevention a therapeutically effective amount of a compound of the invention.
• a disorder modulated by altered gene expression such as one or more of cancer, cardiovascular disorders, arthritis, osteoporosis, inflammation, periodontal disease and skin disorders
• the present invention relates to a method of preventing, treating or ameliorating cancer or tumor metastasis in a mammal comprising administering to said mammal an effective a compound of the invention, preferably where said mammal is a human.
• Compounds of the invention may also be administered in combination (simultaneously or sequentially) with other chemotherapeutic agents. Such combination administration preferably results in a synergistic effect.
• a compound of the invention is administered with an agent such as HMG CoA (3-hydroxy-3- methylglutaryl coenzyme A) reductase inhibitor, for example, atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, and the like (useful in the treatment of cardiovascular disorders (e.g., atherosclerosis) as described in WO 2006/083214).
• HMG CoA 3-hydroxy-3- methylglutaryl coenzyme A reductase inhibitor
• a compound, or compounds, of the invention can be used to determine or demarcate a set of genes by determining modulation of such set of genes by one or more compounds of the invention.
• a set of genes can be determined by their common property of being modulated (based on a change in expression of the genes, such as a change in rate or amount of RNA transcribed or the amount of polypeptide produced by said expression) by contacting such genes, or a cell containing such genes, with one or more of the compounds of the invention.
• modulation may, of course, be related to the amount of said compound, or compounds, used in the contacting.
• Such modulation may include the increased expression of all the determined genes (i.e., the genes of the set), the decreased expression of all genes of the set, or the increase in expression of some of the genes of the set and decreased expression of others.
• a gene not modulated by the test compound is not considered a member of the set.
• the present invention relates to a gene set wherein expression of each member of said gene set is modulated as a result of contacting said gene set with a compound of the invention.
• expression of each member of said gene set is increased as a result of said contacting or is decreased as a result of said contacting.
• the gene set is present in a cell.
• Such a gene set will commonly be related to a specific disease process, such as a set of genes all of which are modulated by a compound of the invention wherein such compound has a specific therapeutic effect, such as being an anti-neoplastic agent.
• Such a gene set is shown in Table 5. Any subset of the genes of Table 5 may also form a gene set as contemplated by the invention. Table 5.
• the present invention is drawn to a method of preventing, treating or ameliorating cancer or tumor metastasis in a mammal comprising administering to said mammal an effective amount of a compound that modulates expression of one or more genes of Table 5.
• a compound that modulates expression of one or more genes of Table 5 have the structure of Formula I, II, III and V, with the substituents disclosed herein for those formulas, and even more preferably any compound of Tables 1 , 2, 3 or 4, including all pharmaceutically acceptable salts thereof.
• the present invention also relates to a method for ameliorating cancer or tumor metastasis in a mammal comprising administering to said mammal an effective amount of a compound of the invention.
• a compound of the invention Especially contemplated are uses of the compounds of Table 1.
• said cancer is a sarcoma or said cancer is a carcinoma.
• Specific cancers contemplated by the methods of the invention include, but are not limited to, one or more of colon cancer, adenocarcinoma, rectal cancer, colorectal cancer, breast cancer, lung cancer, ovarian cancer, adenomatous polyposis, and hepatocellular carcinoma, with colon cancer and colorectal cancer being a preferred embodiment.
• the invention also provides convenient methods for the synthesis of compound of Formula I, according to the general synthetic pathway presented in Scheme 1.
• the starting sulfonyl chlorides 1 can be obtained by direct chlorosulfonylation of the corresponding aromatic ring system or by chlorination of an appropriate sulfonic acid derivative.
• Compounds 1 are reacted with 6 or 7-membered cyclic amines to give secondary sulfonamides 2.
• Compounds 2 can be additionally transformed into derivatives 3 which in some cases serve as prodrugs with modified physico-chemical and pharmacological properties such as solubility in water, modified protein binding properties, stability in plasma, toxicity, and others.
• Anthraquinone-2,7-disulfonylchloride (1215 mg , 3 mmole) was dissolved in 100 ml_ DCM. The solution was cooled to -5O 0 C. To this solution was added 1 mL (8 mmole) of heptamethyleneimine, followed by 1 ml_ of diisopropylethylamine. The reaction mixture was stirred at room temperature for 4 hrs. Solvent was evaporated and the residue was treated with 1 N HCI, filtered off, washed with water and dried. Crude material was crystallized from chloroform-hexane to give 1.014 g (91 %) of yellow compound as desired compound.
• Example 2 The product from Example 1 (1.0 g, 1.706 mmole), 5 mL of pyridine and hydroxylamine hydrochloride (1.5 g, 21.5 mmole) was stirred at 95 0 C for 36 hrs. Pyridine was evaporated and the residue was stirred with 1 N HCI (50 mL) for several minutes. White product was collected by filtration, washed with water and dried. Crude material was then crystallized from DCM-hexane to give 970 mg (97%) of a white compound 1-22.
• Anthraquinone-2,7-disulfonylchloride (10 g, 24.7 mmol)) was dissolved in 200 ml_ DCM. The solution was cooled to -5O 0 C. To this solution was added 4-tert- butylcyclohexanamine (8.43 g, 54 mmol), followed by triethyl amine (8.6 ml, 61.7 mmol). The reaction mixture was stirred at room temperature for 4 hrs. Solvent was evaporated and the residue was treated with MeOH, filtered off, and dried to obtain 15 g (95%) of the product as yellow powder.
• the dioxime (4-1) was prepared following the general procedure using monoalkylated sulfonamide (product of Example 8, 2g, 2.7 mmol), excess hydroxylamine hydrochloride (2.7 g, 27.5 mmol) and pyridine (50 ml) at 95 0 C for 36 hrs. After cooling, excess hydroxylamine was removed by filtration, washed with pyridine and the filtrate was evaporated under reduced pressure to dryness. To this was added excess of aqueous 1 N HCI, the oxime was precipitated out, filtered to collect the colorless precipitate and dried. The oxime (4-1) was further purified by crystallization or HPLC to get it as a colorless HCI salt (1.42 g, 65%).
• the APH (acid phosphatase) assay which is based on quantification of cytosolic acid phosphatase activity, was utilized for determining cell viability in cell lines (Connolly et al., 1986; Friedrich et al., 2007; Martin & Clynes, 1993).
• Intracellular acid phosphatases in viable cells hydrolyze p-nitrophenyl phosphate to p-nitrophenol. Its absorption at 405 nm is directly proportional to the cell number in the range of 10 3 -10 5 monolayer cells.
• HT-29 cells were grown in standard flat-bottom 96-well microtiter plates and allowed to adhere for 24 hours prior to drug treatment.
• the cells were washed with PBS and 100 ⁇ l of the assay buffer (0.1 M sodium acetate, 0.1 % Triton X-100, supplemented with ImmunoPure p-nitrophenyl phosphate, Pierce Biotech. Inc., Rockford, IL USA) were added per well and incubated for 90 min at 37°C. Following incubation, 10 ⁇ l of 1 N NaOH were supplemented to each well and absorption at 405 nm was measured within 10 minutes on a Fusion Universal Microplate Analyzer (Packard, Meriden, CT, USA). Results are shown in Table 6:
• mice Female nu/nu mice (20-30 g, 7-9 weeks old) were housed in venilated racks and maintained with filtered acidified water and sterile lab chow ad libitum. Mice were allowed to acclimate for 1 week prior to testing. Before treating tumor-bearing animals with test compounds, a dose-ranging study of compound was performed in naive mice to determine the highest dose for the 5-week schedule. For this purpose, mice were dosed IP or ORAL once a day for one week and their body weight was monitored twice weekly for two weeks. The loss of 20% body weight or greater was considered lethal, and the highest dose was defined as that dose which caused sufficient morbidity as determined by body weight loss. [See: Emerson et al, Cancer Research, (1995) 55, 603-609; Morton et al, Nature Protocols, (2007) 2(2) 247-250]
• Tumors were established by injecting harvested tumor cells in a single subcutaneous site, on the flank of the mice in the left auxiliary region. The mice were then sorted according to body weight, grouped 5 mice/cage, and micro-chipped for permanent identification. Within a treatment group, a narrow range in body weight ⁇ 1 g and tumor size was established. Efficacy studies were performed over a dose range which included the highest dose. The tumor volume for each mouse was determined by measuring two dimensions with vernier calipers and calculated using the formula
• Tumor volume length X (width) 2
• the overall growth of tumors was expressed as a ratio of T/C where the tumor volume at the end of treatment for test compounds (T) was divided by the tumor volume at the end of treatment for the vehicle (C).
• Compounds in Table 7 showed tumor growth inhibition compared to the control used in the study. Table 7.
• a panel of chemotherapeutics was assessed in colon cancer cell models (HT29 and SW480) to determine if the combination of these drugs with compound 3-2 were synergistic in terms of cell death induction.
• Utilizing the statistical models developed by Chou and Talay (1981) ("Generalized equations for the analysis of inhibitors of Michaelis-Menten and higher order kinetic systems with two or more mutaually exclusive and non-exclusive inhibitors" in European Journal of Biochemistry, 115:207-216) we determined 4 drugs to exhibit synergy with compound 3-2 (Table 8).
• Combination indices were calculated for each drug combination and values less than 1.09 for the Combination Index indicate synergy and values less than 0.5 indicate strong synergy.
• the combination treatments for lovastatin, fluvastatin, oxaliplatin, and 5-FU are all synergistic for induction of cell death.

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