WO2005013903A2 - Derivatives of substituted quinone and uses thereof - Google Patents

Derivatives of substituted quinone and uses thereof Download PDF

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WO2005013903A2
WO2005013903A2 PCT/US2004/025343 US2004025343W WO2005013903A2 WO 2005013903 A2 WO2005013903 A2 WO 2005013903A2 US 2004025343 W US2004025343 W US 2004025343W WO 2005013903 A2 WO2005013903 A2 WO 2005013903A2
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compound
substituted
compounds
unsubstituted
expression
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PCT/US2004/025343
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French (fr)
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WO2005013903A3 (en
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Janak K. Padia
Sean O'brien
Jiemin Lu
Stanislaw Pikul
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Avalon Pharmaceuticals
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Publication of WO2005013903A3 publication Critical patent/WO2005013903A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/30—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms
    • C07C233/32—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/34—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/41—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/14—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • 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
    • C07D295/04—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 substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—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 substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—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 substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • 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
    • C07D295/16—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 acylated on ring nitrogen atoms
    • C07D295/18—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 acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems

Definitions

  • the present invention relates to novel organic compounds that have the ability to function as gene modulators for genes found in normal (i.e., non-cancer) cells and which genes are found to be up regulated or down regulated in normal cells, especially colon cells. Such an effect may prevent a disease condition, such as cancer, from arising in those otherwise more susceptible to such a condition.
  • administration of one or more of the agents disclosed herein may succeed in preventing a cancerous condition from arising.
  • the agents disclosed herein find use in combination with each other as well as with other agents, such as where a mixture of one or more of the agents of the present invention are given in combination or where one or more of the agents disclosed herein is given together with some other already known therapeutic agent, possibly as a means of potentiating the affects of such known therapeutic agent or vice versa.
  • Alkoxy is an oxygen radical having a hydrocarbon chain substituent, where the hydrocarbon chain is an alkyl or alkenyl (i.e., -O-alkyl or -O- alkenyl). Preferred alkoxy groups include (for example) methoxy, ethoxy, propoxy and allyloxy.
  • 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 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, and cyclohexyl.
  • Preferred halo substituents are fluoro and chloro.
  • the most preferred haloalkyl is trifluoromethyl.
  • 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.
  • Heteroalkyl may be substituted with lower alkyl, haloalkyl, halo, hydroxy, aryloxy, heteroaryloxy, acyloxy, carboxy, monocyclic aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spirocycle, amino, acylamino, amido, keto, thioketo, cyano, or any combination thereof.
  • 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 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:
  • Heterocycloalkyl rings may be unsubstituted or substituted with from 1 to 4 substituents on the ring.
  • Heterocycloalkyl may be substituted with halo, cyano, hydroxy, carboxy, keto, thioketo, amino, acylamino, acyl, amido, alkyl, heteroalkyl, haloalkyl, phenyl, alkoxy, aryloxy or any combination thereof.
  • Preferred substituents on heterocycloalkyl include halo and haloalkyl.
  • Preferred anionic salts include the halides (such as chloride salts), sulfonates, carboxylates, phosphates, and the like. Such salts are well understood by the skilled artisan, and the skilled artisan is able to prepare any number of salts given the knowledge in the art. Furthermore, it is recognized that the skilled artisan may prefer one salt over another for reasons of solubility, stability, formulation ease and the like. Determination and optimization of such salts is within the purview of the skilled artisan's practice.
  • 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).
  • Pharmaceutically-acceptable solvents used according to this invention include those that do not interfere with the biological activity of the metalloprotease inhibitor (e.g., water, ethanol, acetic acid, N,N- dimethylformamide and others known or readily determined by the skilled artisan).
  • the terms "optical isomer”, “stereoisomer”, and “diastereomer” have the accepted meanings (see, e.g., Hawlev's Condensed Chemical Dictionary. 11th Ed.).
  • 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, etc. is within the ability of the skilled artisan.
  • W, X, Y and Z are each independently selected from a bond, C-R 5 , C- R ⁇ , C-R 7 , C-R ⁇ , O (oxygen), N (nitrogen) or S (sulfur) and that no more than two W, X, Y and Z are O, N and S; wherein, R 5 , Re, R7, e each independently hydrogen, hydroxyl, sulfhydryl, alkoxy, thioalkoxy, alkyl, halogen, CN, CF 3 , NO 2 , COORg, CONR9R10, NR 9 R 10 .
  • NR9COR10, NR9SO2R10 wherein R 9 , R « and Rn are independently hydrogen, alkyl, heteroalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; NR9R10 is also unsubstituted, monosubstituted or polysubstituted mono or bicyclic ring with one to four heteroatoms such as N, O, S; additionally, Rg and Rn can be connected together to form 4, 5,6 or 7-member cyclic ring system; Ri is selected from: hydrogen, alkyl, unsubstituted, mono or polysubstituted phenyl or polyaromatic, unsubstituted, mono or polysubstituted heteroaromatic, with hetero atom(s) as N, O, S, unsubstituted, mono or polysubstituted aralkyl, unsubstituted, mono or polysubsti
  • R 3 and R 4 are each independently selected from: alkyl, unsubstituted, mono or polysubstituted phenyl or polyaromatic, unsubstituted, mono or polysubstituted heteroaromatic, with hetero atom(s) as N, O, S, unsubstituted, mono or polysubstituted aralkyl, unsubstituted, mono or polysubstituted cyclo or polycyclo hydrocarbon or mono or polyheterocycle (3-8 atoms per ring) with one to four hetero atoms as N, O, or S; and wherein, substitutions are each independently selected from independently hydrogen, hydroxyl, sulfhydryl, alkoxy, thioalkoxy, alkyl, halogen, CN, CF 3 , N0 2 , COORg, CONR 9 R 10 , NR 9 R 10 , NR 9 COR ⁇ o, NRnSO 2 R 9 , NRnCONR 9 R 10
  • W, X, Y and Z are each independently selected from CH, C-R 5 , C-R 6 , C-R 7 , C-R 8 , O, N and S and wherein no more than two of W, X, Y and Z are O, N or S; wherein R 5 , R 6 , R7, Re are each independently hydrogen, hydroxyl, sulfhydryl, alkoxy, thioalkoxy, alkyl, halogen, CN, CF 3) NO 2 , COOR 9 , CONR 9 R 10 , NR 9 R 10 , NR 9 COR 10 , NR 9 SO 2 R ⁇ o, NR ⁇ CONRgR ⁇ 0 ; wherein R 9 , R10 and R-n are each independently hydrogen, alkyl, heteroalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; NR 9 R10 is substituted or unsubsti
  • Ri is selected from hydrogen, alkyl, substituted or unsubstituted phenyl or polyaromatic, substituted or unsubstituted heteroaromatic having hetero atoms selected from N, O and S, substituted or unsubstituted aralkyl, substituted or unsubstituted cyclo or polycyclo hydrocarbon or mono or polyheterocycle of 3 to 8 atom rings having one to four hetero atoms selected from N, O and S; and wherein substitutions are each independently selected from hydrogen, hydroxyl, sulfhydryl, alkoxy, thioalkoxy, alkyl, halogen, CN, CF 3 , NO 2 , COORg, CONR 9 R 10 , NR 9 R 10 , NRgCORio, NRnSO 2 R 9 , NRnCONRgRio; wherein Rg, Rio and Rn are each independently hydrogen, alkyl, heteroalkyl, aryl, arylalkyl, hetero
  • n 1 , 2, 3 or 4 and wherein R 3 and R are each independently selected from alkyl, substituted or unsubstituted phenyl or polyaromatic, substituted or unsubstituted heteroaromatic having hetero atoms selected from N, O and S, substituted or unsubstituted aralkyl, substituted or unsubstituted cyclo or polycyclo hydrocarbon or mono or polyheterocycle of 3 to 8 atom rings having one to four hetero atoms selected from N, O and S; and wherein substitutions are each independently selected from independently hydrogen, hydroxyl, sulfhydryl, alkoxy, thioalkoxy, alkyl, halogen, CN, CF 3 , NO 2 , COORg, CONR 9 R 10 , NR 9 R 10 , NR 9 COR 10 , NRnSO 2 Rg, NRnCONR 9 R 10 ; wherein Rg, R 10 and R-M are each independently hydrogen, alkyl,
  • C-R 5 , C-R 8 or N and X and Y are each independently C-R 6 or C-R 7 .
  • X and Y are each independently C-R ⁇ , C- R 7 or N and W and Z are each independently C-R 5 or C-R 8 .
  • W is C-R 5 or N and X
  • Y and Z are each independently C-R 6 , C-R 7 or C-R 8.
  • Z is C-R 8 or N and W
  • Y and Z are each independently C-R 5 , C-R 6 or C-R .
  • X is C-R ⁇ or N; W, Y and Z are each independently C-R 5 , C-R 7 or C-R 8 or where Y is C-R 7 or N and W, X, and Z are each independently C-R 5 , C-R ⁇ or C-R 8 .
  • W X, Y and Z are each independently CH, C-R 5l C-R 6 , C-R 7 or C-R 8 , preferably wherein W X, Y and Z are each CH.
  • R 2 is alkyl with more than two carbon.
  • Ri is selected from hydrogen, alkyl, cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, -methylpyridine, -ethylpyridine, -mehtylindole, - ethylindole, alkoxyethyl-, hydroxyethyl, N,N-dialkyl-ethyl, , N,N-dialkyl-propyl, methylpyrrole, ethylpyrrole, methylfuran, ethylfuran, -alkylmorpholine, - alkylpiperizine, -alkypiperidine, -alkylpyrrolidine.
  • R 3 and R 4 are independently selected from alkyl, cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, -methylpyridine, -ethylpyridine, - mehtylindole, -ethylindole, alkoxyethyl-, hydroxyethyl, N,N-dialkyl-ehtyl, , N,N- dialkyl-propyl, methylpyrrole, ethylpyrrole, methylfuran, ethylfuran, - alkylmorpholine, -alkylpiperizine, -alkypiperidine, -alkylpyrrolidine; Also preferred are compounds of Formula I wherein R 2 is
  • the present invention encompasses compounds having a structure found in Table 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, including salts of any of these, preferably pharmaceutically acceptable salts thereof.
  • the present invention does not include compounds of Formula I wherein Ri is not one of -(CH 2 ) 3 N(Et) 2 , - (CH 2 ) 2 N(Me) 2) -(CH 2 ) 3 N(Et) 2 , -(CH 2 ) 3 N + (Me) 3 Br-, -(CH 2 ) 3 N(Me) 2 , -(CH 2 ) 2 (Et) 2 , -(CH 2 ) 3 NHCOO, -(CH 2 ) 3 NHCO-Morpholine, -(CH 2 ) 3 NHCO(4-F-Ph), - (CH 2 ) 3 N(Me)CONH(4-F-Ph) or --(CH 2 ) 3 NHSO 2 (4-F-Ph).
  • 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 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 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.
  • the present invention relates to a method for preventing or treating a disorder modulated by altered gene expression, wherein the disorder is selected from the group consisting 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.
  • 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 (the compound used in contacting the genes or cell containing them) 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.
  • the present invention relates to a method for identifying an agent that modulates the expression of a gene set of the invention, comprising: (a) contacting, or otherwise using, a compound, such as a test compound, a test system, such as a source of genes or polynucleotides, for example, those found to be related to a given disease or disorder, or a set that is modulated by a given compound, or group of compounds, especially where these are found in a cell, so that the cell represents the test system, containing one or more polynucleotides corresponding to each of the members of the gene set of the invention under conditions wherein the members of said gene set are being expressed; (b) determining a change in expression of each of said one or more polynucleotides of
  • the cell is a naturally derived cell that contains genes of a gene set or may be a recombinant cell engineered to comprise the genes or polynucleotides of the gene set.
  • the test system may comprise the genes or polynucleotides in a cell-free system.
  • the present invention provides a method for identifying a test compound that modulates the expression of a gene set, such as a gene set of the invention, comprising: (a) contacting a test compound with one or more polynucleotides corresponding to each of the members of the gene set of the invention under conditions wherein the members of said gene set are being expressed; (b) determining a change in expression of each of said one or more polynucleotides of step (a) as a result of said contacting; wherein said change in expression of step (b) indicates modulation of the members of said gene set thereby identifying a test compound that modulates the expression of said gene set.
  • polynucleotides encoding the same proteins as any of these genes are also specifically contemplated by any of the methods of the present invention.
  • the polynucleotides used in the methods of the invention also include any open reading frames, as defined herein, present therein.
  • the term "open reading frame” or ORF means a series of triplets coding for amino acids without any termination codons and is a sequence (potentially) translatable into protein.
  • the polynucleotides useful in the methods of the invention may be genomic in nature and thus represent the sequence of an actual gene, such as a human gene, or may be a cDNA sequence derived from a messenger RNA (mRNA) and thus represent contiguous exonic sequences derived from a corresponding genomic sequence, or they may be wholly synthetic in origin for purposes of practicing the processes of the invention. Because of the processing that may take place in transforming the initial RNA transcript into the final mRNA, the sequences disclosed herein may represent less than the full genomic sequence. They may also represent sequences derived from ribosomal and transfer RNAs.
  • mRNA messenger RNA
  • the gene as present in the cell (and representing the genomic sequence) and the polynucleotide transcripts disclosed herein, including cDNA sequences may be identical or may be such that the cDNAs contain less than the full genomic sequence.
  • Such genes and cDNA sequences are still considered "corresponding sequences" (as defined elsewhere herein) because they both encode the same or related RNA sequences (i.e., related in the sense of being splice variants or RNAs at different stages of processing).
  • a gene that encodes an RNA transcript which is then processed into a shorter mRNA, is deemed to encode both such RNAs and therefore encodes an RNA complementary to (using the usual Watson-Crick complementarity rules), or that would otherwise be encoded by, a cDNA (for example, a sequence as disclosed herein).
  • a cDNA for example, a sequence as disclosed herein.
  • the sequences disclosed herein correspond to genes contained in the cancerous cells (here, breast cancer) and are used to determine gene activity or expression because they represent the same sequence or are complementary to RNAs encoded by the gene.
  • Such a gene also includes different alleles and splice variants that may occur in the cells used in the methods of the invention, such as where recombinant cells are used to assay for anti-neoplastic agents and such cells have been engineered to express a polynucleotide as disclosed herein, including cells that have been engineered to express such polynucleotides at a higher level than is found in non-engineered cancerous cells or where such recombinant cells express such polynucleotides only after having been engineered to do so.
  • Such engineering includes genetic engineering, such as where one or more of the polynucleotides disclosed herein has been inserted into the genome of such cell or is present in a vector.
  • Such cells may also be engineered to express on their surfaces one or more of the polypeptides of the invention for testing with antibodies or other agents capable of masking such polypeptides and thereby removing the cancerous nature of the cell.
  • Such engineering includes both genetic engineering, where the genetic complement of the cells is engineered to express the polypeptide, as well as non-genetic engineering, whereby the cell has been physically manipulated to incorporate a polypeptide of the invention in its plasma membrane, such as by direct insertion using chemical and/or other agents to achieve this result.
  • the determined change in expression is a decrease in expression of said one or more polynucleotides or a decrease in said expression.
  • the determined change in expression is a change in transcription of said one or more polynucleotides or a change in activity of a polypeptide, or expression product, encoded by said polynucleotide, including a change in the amount of said polypeptide synthesized, such as by a cell.
  • expression product means that polypeptide or protein that is the natural translation product of the gene and any nucleic acid sequence coding equivalents resulting from genetic code degeneracy and thus coding for the same amino acid(s).
  • said one or more polynucleotides are present in a cell, preferably a cancer cell, more preferably a colon cancer cell, and most preferably where the colon cancer cell is an adenocarcinoma cancer cell.
  • the cell is a recombinant cell engineered to contain said set of genes.
  • Such methods serve to identify other compounds that have like activity, including expected therapeutic activity, as the compounds of the invention and thus serve as the basis for large scale screening assays for therapeutic compounds.
  • one or more compounds of the invention can be utilized to determine the presents of gene sets and subsets within the genome of a cell.
  • the set of all genes modulated by a group of structurally related compounds of the invention can form a gene set while the different sets of genes regulated by each compound of a group will form a subset.
  • a structurally related group of 5 of the compounds of the invention (all having generally the structure of Formula I) modulate (by increasing or decreasing) expression of determined genes 1-20
  • this latter group of genes forms a gene set. Further examination then determines that genes 1-6 are modulated by compound A, genes 7-10 are modulated by compound B, genes 2-4 and 9-12 are modulated by compound C, genes 10-20 are modulated by compound D and the even numbered genes are modulated by compound E.
  • each of these groups of genes is considered a subset of the gene set of genes 1-20.
  • the genes modulated by compound E can be themselves further subdivided into at least 2 subsets wherein one subset is made up of the genes whose expression is increased by compound E while the other subset is made up of genes whose expression is decreased by compound E, thus yielding subsets of subsets. It should be noted that within the context of the present invention, it is not necessary to identify subsets and that each so-called subset is, in its own right, a gene set as used in the invention.
  • the identification of sets and subsets is thus a function of the extent that a user of the methods of the invention wishes to determine modulation of genes resulting from contacting of one or more compounds of the invention.
  • the genes modulated by a single compound form a gene set and it is not necessary, in carrying out the methods of the invention, to compare different groups of genes for modulation by more than one compound but this may, of course, be done.
  • the present invention relates to a set of genes comprising a plurality of subsets of genes wherein each subset of said plurality is a gene set identified by the methods of the invention.
  • the present invention also relates to compounds identified as having activity using the methods of the invention, such as novel compounds not specifically described herein by structure but which have been identified by their ability to modulates one or more gene sets modulated by compounds of the invention.
  • the present invention encompasses the gene sets and subsets of the genes identified in Table 11 and/or in Table 12.
  • the present invention specifically contemplates use of a compound that modulates the expression of a set of, or subset of, genes of Table 11 or 12.
  • the present invention comprises also processes for the preparation of compounds of formula I, and the relative key intermediates Compound Preparation:
  • the compounds of the invention can be prepared using a variety of procedures known in the art.
  • the starting materials used in preparing the compounds of the invention are known, made by known methods, or are commercially available. Particularly preferred syntheses are described in the following general reaction schemes. Scheme 1 :
  • the dichioro compound 1 is either commercially available or can be synthesized using methods known in the literature. 1. Shaikh I. A. et al, J. Med. Chem, 29(8), 1329-1340, (1986) 2. Vlderrama el al, Syn. Comm., 27(12), 2143-2157, (1997) 3. Chu, Kwong-Yung; et al. Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999) (1978) 4. Matsuhisa A. et al, Patent WO 01/60803 A1
  • the compound 1 can be reacted with an amine in an appropriate solvent to provide the corresponding derivative 2.
  • the compound 2 then can be reacted with acetyl chloride or acetic anhydride or activated acetic acid using acid such as sulfuric acid or base such as sodium carbonate to obtain the corresponding 3 derivatives.
  • a reaction of crude or purified compound 3 with an amine can give desired compound 4 of formula I.
  • the desire compounds of formula I can be prepared by following scheme 2.
  • one optical isomer may have favorable properties over the other and thus the disclosure of a racemic mixture within the present invention may also include either optically active isomer if such isomer has advantageous physiological activity in accordance with the methods of the invention.
  • Example 2-12 (Table 1) and Example 1-13 (Table 2)
  • Example 1-13 (Table 2)

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Abstract

Chemical agents, such as derivatives of quinone, and including salts thereof, that modulate levels of gene expression in cellular systems, including cancer cells, are disclosed, along with methods for preparing such agents, as well as pharmaceutical compositions containing such agents as active ingredients and methods of using these as therapeutic agents.

Description

DERIVATIVES OF SUBSTITUTED QUINONE AND USES THEREOF
This application claims priority of U.S. Provisional Application 60/492,652, filed 5 August 2003, the disclosure of which is hereby incorporated by reference in its entirety.
FIELD OF THE INVENTION
The present invention relates to chemical agents affecting levels of gene expression in cellular systems, including cancer cells. In particular, the present invention relates to derivatives of quinone moiety, processes for their preparation, their use as antitumor drugs and pharmaceutical compositions containing them as active ingredients.
BACKGROUND OF THE INVENTION
Screening assays for novel drugs are based on the response of model cell based systems in vitro to treatment with specific compounds. Various measures of cellular response have been utilized, including the release of cytokines, alterations in cell surface markers, activation of specific enzymes, as well as alterations in ion flux and/or pH. Some such screens rely on specific genes, such as oncogenes or tumor suppressors. Our approach to screening small molecule compounds as potential anticancer drugs is based on the idea that for each specific tumor type, a unique signature set of genes, that are differentially expressed in tumor cells if compared to corresponding normal cells, can be established. The relatively small signature set, containing 10-30 genes, allows for easy, high throughput screening for compounds that can reverse the gene expression profile from patterns typical for cancer cells to patterns seen in normal cells. As a part of our efforts to provide new diversified compounds for high throughput gene expression screening, we designed and synthesized a number of novel derivatives of quinines. Gene expression screening and subsequent cytotoxicity screening revealed that some of the compounds possess biological activity. Consequent, more detailed structure-activity relationship studies led to the discovery of compounds of formula I as new small molecule agents having antineoplastic activity.
BRIEF SUMMARY OF THE INVENTION
In one aspect, the present invention relates to novel organic compounds, derivatives of quinone, that have the ability to function as gene expression modulators for genes found in cancer cells, especially genes involved in misregulated signal transduction pathways typical for colon cancer. In one embodiment of the present invention, the compounds disclosed herein are able to up regulate genes found to be up regulated in normal (i.e., non-cancerous) cells versus cancer cells, especially colon cancer cells, thereby producing an expression profile for said gene(s) that more resembles the expression profile found in normal cells. In another embodiment, the compounds disclosed herein are found to down regulate genes found to be up regulated in cancer cells, especially colon cancer cells, relative to normal (i.e., non-cancerous) cells thereby producing an expression profile for said gene(s) that more resembles the expression profile found in normal cells. Thus, in addition to activity in modulating a particular gene that may or may not have a major role in inducing or sustaining a cancerous condition, the agents disclosed herein also find value in regulating a set of gene whose combined activity is related to a disease condition, such as cancer, especially colon cancer, including adenocarcinoma of the colon. Thus, while an overall set of genes is modulated, the effect of modulating any subset of these may be disproportionately large or small with respect to the effect in ameliorating the overall disease process. Consequently, different disease conditions may rely on different subsets of genes to be active or inactive as a basis for the overall disease process. Thus, the present invention relates to novel organic compounds that have the ability to function as gene modulators for genes found in normal (i.e., non-cancer) cells and which genes are found to be up regulated or down regulated in normal cells, especially colon cells. Such an effect may prevent a disease condition, such as cancer, from arising in those otherwise more susceptible to such a condition. In one such embodiment, administration of one or more of the agents disclosed herein may succeed in preventing a cancerous condition from arising. In other embodiments, the agents disclosed herein find use in combination with each other as well as with other agents, such as where a mixture of one or more of the agents of the present invention are given in combination or where one or more of the agents disclosed herein is given together with some other already known therapeutic agent, possibly as a means of potentiating the affects of such known therapeutic agent or vice versa. The present invention also relates to processes of preventing or treating disease conditions, especially cancer, most especially colon cancer, by administering to a subject, such as a mammal, especially a human, a therapeutically active amount of one or more of the agents disclosed herein, including where such agents are given in combination with one or more known therapeutic agents.
DEFINITIONS The following is a list of definitions for terms used herein. "Acyl" or "carbonyl" is a radical formed by removal of the hydroxy from a carboxylic acid (i.e., R-C(=O)-). Preferred acyl groups include (for example) acetyl, formyl, and propionyl. "Alkyl" is a saturated hydrocarbon chain having 1 to 15 carbon atoms, preferably 1 to 10, more preferably 1 to 4 carbon atoms. "Alkene" is a hydrocarbon chain having at least one (preferably only one) carbon-carbon double bond and having 2 to 15 carbon atoms, preferably 2 to 10, more preferably 2 to 4 carbon atoms. "Alkyne" is a hydrocarbon chain having at least one (preferably only one) carbon-carbon triple bond and having 2 to 15 carbon atoms, preferably 2 to 10, more preferably 2 to 4 carbon atoms. Alkyl, alkene and alkyne chains (referred to collectively as "hydrocarbon chains") may be straight or branched and may be unsubstituted or substituted. Preferred branched alkyl, alkene and alkyne chains have one or two branches, preferably one branch. Preferred chains are alkyl. Alkyl, alkene and alkyne hydrocarbon chains each may be unsubstituted or substituted with from 1 to 4 substituents; when substituted, preferred chains are mono-, di-, or tri-substituted. Alkyl, alkene and alkyne hydrocarbon chains each may be substituted with halo, hydroxy, aryloxy (e.g., phenoxy), heteroaryloxy, acyloxy (e.g., acetoxy), carboxy, aryl {e.g., phenyl), heteroaryl, cycloalkyl, heterocycloalkyl, spirocycle, amino, amido, acylamino, keto, thioketo, cyano, or any combination thereof. Preferred hydrocarbon groups include methyl, ethyl, propyl, isopropyl, butyl, vinyl, allyl, butenyl, and exomethylenyl. Also, as referred to herein, a "lower" alkyl, alkene or alkyne moiety (e.g., "lower alkyl") is a chain comprised of 1 to 6, preferably from 1 to 4, carbon atoms in the case of alkyl and 2 to 6, preferably 2 to 4, carbon atoms in the case of alkene and alkyne. "Alkoxy" is an oxygen radical having a hydrocarbon chain substituent, where the hydrocarbon chain is an alkyl or alkenyl (i.e., -O-alkyl or -O- alkenyl). Preferred alkoxy groups include (for example) methoxy, ethoxy, propoxy and allyloxy. "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" is a saturated or unsaturated hydrocarbon ring. Cycloalkyl rings are not aromatic. Cycloalkyl rings are monocyclic, or are fused, spiro, or bridged bicyclic ring systems. Monocyclic cycloalkyl rings contain from about 3 to about 9 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, and cyclohexyl. "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. "Haloalkyl" is a straight, branched, or cyclic hydrocarbon substituted with one or more halo substituents. Preferred are C1-C12 haloalkyls; more preferred are C-j-Cβ haloalkyls; still more preferred still are C1-C3 haloalkyls.
Preferred halo substituents are fluoro and chloro. The most preferred haloalkyl is trifluoromethyl.
"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, aryloxy, heteroaryloxy, acyloxy, carboxy, monocyclic aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spirocycle, amino, acylamino, amido, keto, thioketo, cyano, or any combination thereof. "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 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:
Figure imgf000008_0001
10 Furan Thiophene Pyrrole Pyrazole Imidazole Oxazole Isoxazole
Figure imgf000008_0002
Isothiazole Thiazole 1 ,2,5-Thiadiazole 1,2,3-Triazole 1 ,3,4-Thiadiazole Furazan
Figure imgf000008_0003
1 ,2,3-Thiadiazole 1 ,2,4-Thiadiazole Benzotriazole 1 ,2,4-Triazole Tetrazole
Figure imgf000008_0004
1 ,2,4-Oxadiazole 1,3,4-Oxadiazole 1 ,2,3,4-Oxatriazole 1,2,3,4-Thiatriazole 1 ,2,3,5-Thiatriazole
Figure imgf000008_0005
1,2,3,5-Oxatriazole 1 ,2,3-Triazine 1 ,2,4-Triazine 1,2,4,5-Tetrazine Dibenzofuran
Figure imgf000008_0006
•| 5 Pyridine Pyridazine Pyrimidine Pyrazine 1 ,3,5-Triazine Indolizine
Figure imgf000008_0008
Figure imgf000008_0007
Isoindole Benzofuran Benzothiophene 1 H-lndazole Purine Quinoline
Figure imgf000009_0001
B cenzimidazole B GenztOhiazole Benzoxazole Pterid5ine
idine
Figure imgf000009_0002
"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 about 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 (carbon 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 or substituted with from 1 to 4 substituents on the ring. Heterocycloalkyl may be substituted with halo, cyano, hydroxy, carboxy, keto, thioketo, amino, acylamino, acyl, amido, alkyl, heteroalkyl, haloalkyl, phenyl, alkoxy, aryloxy or any combination thereof. Preferred substituents on heterocycloalkyl include halo and haloalkyl. Preferred heterocycloalkyl rings include, but are not limited to, the following:
Figure imgf000010_0001
Oxirane Aziridine Oxetane Azetidine Tetrahydrofuran Pyrrolidine 3H-lndole
Figure imgf000010_0002
,3-Dioxolane 1,2-Dithiolane 1,3-Dithiolane 4,5-Dihydroisoxazole 2,3-Dihydroisoxazole
Figure imgf000010_0003
Pyrazolidine 2.4-Pyran 3,4-Dihydro-2H-pyran Tetrahydropyran 2W-Chromene
Figure imgf000010_0004
Chromone Chroman Piperidine Morpholine 4H-1 ,3-Oxazine 6H-1 ,3-Oxazine
Figure imgf000010_0005
,6-dihydro-4H-1 ,3-oxazine 4.4-3, 1-benzoxazine Phenothiazine 1,3-Dioxane
Figure imgf000010_0006
Cepham P ne Hexa ydroazepine 1, -Dithiane 1, -Dioxaneώ Penem ciola-ne
Figure imgf000010_0007
2,3-Dihydro-1ι4-lsoindole Phthalan 1 ,4-Oxathiane 1,4-Dithiane hexahydro-Pyridazine
Figure imgf000010_0008
1 ,2-Benzisothiazoline Benzylsultam While alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl groups may be substituted with hydroxy, amino, and amido groups as stated above, the following are not envisioned in the invention: Enols (OH attached to a carbon bearing a double bond). Amino groups attached to a carbon bearing a double bond (except for vinylogous amides). More than one hydroxy, amino, or amido attached to a single carbon (except where two nitrogen atoms are attached to a single carbon atom and all three atoms are member atoms within a heterocycloalkyl ring). Hydroxy, amino, or amido attached to a carbon that also has a heteroatom attached to it.
Hydroxy, amino, or amido attached to a carbon that also has a halogen attached to it. 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 World Patent Publication 87/05297, Johnston et al., published September 11 , 1987 incorporated by reference herein. 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. Such salts are well understood by the skilled artisan, and the skilled artisan is able to prepare any number of salts given the knowledge in the art. Furthermore, it is recognized that the skilled artisan may prefer one salt over another for reasons of solubility, stability, formulation ease and the like. Determination and optimization of such salts is within the purview of the skilled artisan's practice. 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).
Pharmaceutically-acceptable solvents used according to this invention include those that do not interfere with the biological activity of the metalloprotease inhibitor (e.g., water, ethanol, acetic acid, N,N- dimethylformamide and others known or readily determined by the skilled artisan). The terms "optical isomer", "stereoisomer", and "diastereomer" have the accepted meanings (see, e.g., Hawlev's Condensed Chemical Dictionary. 11th Ed.). 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, etc. is within the ability of the skilled artisan.
DETAILED SUMMARY OF THE INVENTION In one aspect, the present invention relates to a compound having the structure of Formula (I)
Figure imgf000012_0001
Formula I wherein W, X, Y and Z are each independently selected from a bond, C-R5, C- Rβ, C-R7, C-Rβ, O (oxygen), N (nitrogen) or S (sulfur) and that no more than two W, X, Y and Z are O, N and S; wherein, R5, Re, R7, e each independently hydrogen, hydroxyl, sulfhydryl, alkoxy, thioalkoxy, alkyl, halogen, CN, CF3, NO2, COORg, CONR9R10, NR9R10. NR9COR10, NR9SO2R10,
Figure imgf000012_0002
wherein R9, R« and Rn are independently hydrogen, alkyl, heteroalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; NR9R10 is also unsubstituted, monosubstituted or polysubstituted mono or bicyclic ring with one to four heteroatoms such as N, O, S; additionally, Rg and Rn can be connected together to form 4, 5,6 or 7-member cyclic ring system; Ri is selected from: hydrogen, alkyl, unsubstituted, mono or polysubstituted phenyl or polyaromatic, unsubstituted, mono or polysubstituted heteroaromatic, with hetero atom(s) as N, O, S, unsubstituted, mono or polysubstituted aralkyl, unsubstituted, mono or polysubstituted cyclo or polycyclo hydrocarbon or mono or polyheterocycle (3-8 atoms per ring) with one to four hetero atoms as N, O, or S; and wherein, substitutions are each independently selected from independently hydrogen, hydroxyl, sulfhydryl, alkoxy, thioalkoxy, alkyl, halogen, CN, CF3, NO2, COORg, CONR9R10, NR9R10, NR9COR10, NRnSO2Rg, NRnCONRgRio; wherein Rg, R10 and Rn are independently hydrogen, alkyl, heteroalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; NR9R10 is also unsubstituted, monosubstituted or polysubstituted mono or bicyclic ring with one to four heteroatoms such as N, O, S; Additionally, R9 and Rn can be connected together to form 4, 5,6 or 7-member cyclic ring system; R2 is selected from alkyl with more than two carbons, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl. R2 is also selected from OCOORi
ONR1 Ri5
Figure imgf000014_0001
R3 and R4 are each independently selected from: alkyl, unsubstituted, mono or polysubstituted phenyl or polyaromatic, unsubstituted, mono or polysubstituted heteroaromatic, with hetero atom(s) as N, O, S, unsubstituted, mono or polysubstituted aralkyl, unsubstituted, mono or polysubstituted cyclo or polycyclo hydrocarbon or mono or polyheterocycle (3-8 atoms per ring) with one to four hetero atoms as N, O, or S; and wherein, substitutions are each independently selected from independently hydrogen, hydroxyl, sulfhydryl, alkoxy, thioalkoxy, alkyl, halogen, CN, CF3, N02, COORg, CONR9R10, NR9R10, NR9CORιo, NRnSO2R9, NRnCONR9R10; wherein R9, R10 and Rn are independently hydrogen, alkyl, heteroalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; NRgRio is also unsubstituted, monosubstituted or polysubstituted mono or bicyclic ring with one to four heteroatoms such as N, O, S; Additionally, Rg and Rn can be connected together to form 4, 5, 6 or 7-member cyclic ring system; NR3R4 is also unsubstituted, or substituted mono or bicyclic ring with one to four heteroatoms such as N, O, S.
In one embodiment of the invention, compounds have the structure of
Figure imgf000015_0001
Formula I
wherein W, X, Y and Z are each independently selected from CH, C-R5, C-R6, C-R7, C-R8, O, N and S and wherein no more than two of W, X, Y and Z are O, N or S; wherein R5, R6, R7, Re are each independently hydrogen, hydroxyl, sulfhydryl, alkoxy, thioalkoxy, alkyl, halogen, CN, CF3) NO2, COOR9, CONR9R10, NR9R10, NR9COR10, NR9SO2Rιo, NRιιCONRgRι0; wherein R9, R10 and R-n are each independently hydrogen, alkyl, heteroalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; NR9R10 is substituted or unsubstituted mono or bicyclic ring having one to four heteroatoms selected from N, O and S; and wherein R9 and Rn may form a 4, 5, 6 or 7-member cyclic ring system;
Ri is selected from hydrogen, alkyl, substituted or unsubstituted phenyl or polyaromatic, substituted or unsubstituted heteroaromatic having hetero atoms selected from N, O and S, substituted or unsubstituted aralkyl, substituted or unsubstituted cyclo or polycyclo hydrocarbon or mono or polyheterocycle of 3 to 8 atom rings having one to four hetero atoms selected from N, O and S; and wherein substitutions are each independently selected from hydrogen, hydroxyl, sulfhydryl, alkoxy, thioalkoxy, alkyl, halogen, CN, CF3, NO2, COORg, CONR9R10, NR9R10, NRgCORio, NRnSO2R9, NRnCONRgRio; wherein Rg, Rio and Rn are each independently hydrogen, alkyl, heteroalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; NRgR-io is substituted or unsubstituted mono or bicyclic ring having one to four heteroatoms selected from N, O and S; and wherein Rg and Rn may form a 4, 5, 6 or 7-member cyclic ring system; wherein R2 is selected from alkyl with more than two carbon, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl and
Figure imgf000016_0001
wherein n = 1 , 2, 3 or 4 and wherein R3 and R are each independently selected from alkyl, substituted or unsubstituted phenyl or polyaromatic, substituted or unsubstituted heteroaromatic having hetero atoms selected from N, O and S, substituted or unsubstituted aralkyl, substituted or unsubstituted cyclo or polycyclo hydrocarbon or mono or polyheterocycle of 3 to 8 atom rings having one to four hetero atoms selected from N, O and S; and wherein substitutions are each independently selected from independently hydrogen, hydroxyl, sulfhydryl, alkoxy, thioalkoxy, alkyl, halogen, CN, CF3, NO2, COORg, CONR9R10, NR9R10, NR9COR10, NRnSO2Rg, NRnCONR9R10; wherein Rg, R10 and R-M are each independently hydrogen, alkyl, heteroalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or heterocycloalkyl; NRgR-io is substituted or unsubstituted mono or bicyclic ring having one to four heteroatoms selected from N, O and S; and wherein Rg and Rn may form 4, 5,6 or 7-member cyclic ring system; NR3R4 is substituted or unsubstituted mono or bicyclic ring having one to four heteroatoms selected from N, O and S; In a preferred embodiment of these, W and Z are each independently
C-R5, C-R8 or N and X and Y are each independently C-R6 or C-R7. In another such embodiment, X and Y are each independently C-Rβ, C- R7 or N and W and Z are each independently C-R5 or C-R8. In one embodiment, W is C-R5 or N and X, Y and Z are each independently C-R6, C-R7 or C-R8. In another embodiment, Z is C-R8 or N and W, Y and Z are each independently C-R5, C-R6 or C-R . One embodiment of the invention is where X is C-Rβ or N; W, Y and Z are each independently C-R5, C-R7 or C-R8 or where Y is C-R7 or N and W, X, and Z are each independently C-R5, C-Rβ or C-R8. In a preferred embodiment of these, W X, Y and Z are each independently CH, C-R5l C-R6, C-R7 or C-R8, preferably wherein W X, Y and Z are each CH. In a further preferred embodiment of the compounds of the invention, R2 is alkyl with more than two carbon. Also preferred are compounds of Formula I wherein Ri is selected from hydrogen, alkyl, cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, -methylpyridine, -ethylpyridine, -mehtylindole, - ethylindole, alkoxyethyl-, hydroxyethyl, N,N-dialkyl-ethyl, , N,N-dialkyl-propyl, methylpyrrole, ethylpyrrole, methylfuran, ethylfuran, -alkylmorpholine, - alkylpiperizine, -alkypiperidine, -alkylpyrrolidine. Also preferred are compounds of Formula I wherein R3 and R4 are independently selected from alkyl, cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, -methylpyridine, -ethylpyridine, - mehtylindole, -ethylindole, alkoxyethyl-, hydroxyethyl, N,N-dialkyl-ehtyl, , N,N- dialkyl-propyl, methylpyrrole, ethylpyrrole, methylfuran, ethylfuran, - alkylmorpholine, -alkylpiperizine, -alkypiperidine, -alkylpyrrolidine; Also preferred are compounds of Formula I wherein R2 is
Also wherein R2 is
Also wherein R2 is
Also wherein R2 is
Figure imgf000018_0001
Also preferred are compounds of Formula I wherein R2 is
Figure imgf000019_0001
Also preferred are compounds of Formula I wherein R2 is
Figure imgf000019_0002
In highly preferred embodiments, the present invention encompasses compounds having a structure found in Table 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, including salts of any of these, preferably pharmaceutically acceptable salts thereof. In other preferred embodiments, the present invention does not include compounds of Formula I wherein Ri is not one of -(CH2)3N(Et)2, - (CH2)2N(Me)2) -(CH2)3N(Et)2, -(CH2)3N+(Me)3Br-, -(CH2)3N(Me)2, -(CH2)2(Et)2, -(CH2)3NHCOO, -(CH2)3NHCO-Morpholine, -(CH2)3NHCO(4-F-Ph), - (CH2)3N(Me)CONH(4-F-Ph) or --(CH2)3NHSO2(4-F-Ph). In another aspect, 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). In accordance with the foregoing, 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 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. A thorough discussion of pharmaceutically acceptable carriers, diluents, and other excipients is presented in REMINGTON'S PHARMACEUTICAL SCIENCES (Mack Pub. Co., N.J. current edition). Use of such carriers is well known to those skilled in the art and will not be discussed further herein. Also in accordance with the foregoing, 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. In another aspect, the present invention relates to a method for preventing or treating a disorder modulated by altered gene expression, wherein the disorder is selected from the group consisting 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. In a preferred embodiment thereof, the disorder is cancer, more preferably colon cancer, most preferably adenocarcinoma, and the treatment prevents, arrests or reverts tumor growth, metastasis or both. The compounds of the invention will commonly exert a therapeutic effect by modulation of one or more genes found in a cell, especially a mammalian cell, such as a cancer cell, preferably colon cancer and most preferably adenocarcinoma. Thus, 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. For example, where a set of genes is found to be up-regulated in cancer cells versus otherwise normal cells, especially normal cells of the same tissue or organ as the cancer cells, 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. The extent of such 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. Thus, a gene not modulated by the test compound (the compound used in contacting the genes or cell containing them) is not considered a member of the set. Thus, 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. In specific embodiments, 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. In another preferred embodiment, 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. In another aspect, the present invention relates to a method for identifying an agent that modulates the expression of a gene set of the invention, comprising: (a) contacting, or otherwise using, a compound, such as a test compound, a test system, such as a source of genes or polynucleotides, for example, those found to be related to a given disease or disorder, or a set that is modulated by a given compound, or group of compounds, especially where these are found in a cell, so that the cell represents the test system, containing one or more polynucleotides corresponding to each of the members of the gene set of the invention under conditions wherein the members of said gene set are being expressed; (b) determining a change in expression of each of said one or more polynucleotides of step (a) as a result of said treatment; wherein said change in expression of step (b) indicates modulation of the members of said gene set by the test compound thereby identifying a test compound that modulates the expression of said gene set. In one embodiment, the cell is a naturally derived cell that contains genes of a gene set or may be a recombinant cell engineered to comprise the genes or polynucleotides of the gene set. In an alternative embodiment, the test system may comprise the genes or polynucleotides in a cell-free system. In a related aspect, the present invention provides a method for identifying a test compound that modulates the expression of a gene set, such as a gene set of the invention, comprising: (a) contacting a test compound with one or more polynucleotides corresponding to each of the members of the gene set of the invention under conditions wherein the members of said gene set are being expressed; (b) determining a change in expression of each of said one or more polynucleotides of step (a) as a result of said contacting; wherein said change in expression of step (b) indicates modulation of the members of said gene set thereby identifying a test compound that modulates the expression of said gene set. As used herein, "corresponding genes" or "corresponding polynucleotides" or "polynucleotides corresponding to genes" refers to polynucleotides and/or genes that encode an RNA that is at least 90% identical, preferably at least 95% identical, most preferably at least 98% identical, and especially identical, to an RNA encoded by one of the genes disclosed herein in Tables 11 and 12. Such genes will also encode the same polypeptide sequence, but may include differences in such amino acid sequences where such differences are limited to conservative amino acid substitutions, such as where the same overall three dimensional structure, is maintained. A "corresponding gene" includes splice variants thereof. Because a polynucleotide or gene used in the methods of the invention "corresponds to" a gene present in one of the gene sets of the invention, such as genes identified in Tables 11 and 12, such polynucleotide or gene encodes an RNA (processed or unprocessed, including naturally occurring splice variants and alleles) that is at least 90% identical, preferably at least 95% identical, most preferably at least 98% identical to, and especially identical to, an RNA that would be encoded by, or be complementary to, such as by hybridization with, a gene of Table 11 or 12, or genes of any gene set identified according to the invention. Polynucleotides encoding the same proteins as any of these genes, regardless of the percent identity of the sequences of such genes and/or polynucleotides, are also specifically contemplated by any of the methods of the present invention. The polynucleotides used in the methods of the invention also include any open reading frames, as defined herein, present therein. As used herein, the term "open reading frame" (or ORF) means a series of triplets coding for amino acids without any termination codons and is a sequence (potentially) translatable into protein. The polynucleotides useful in the methods of the invention may be genomic in nature and thus represent the sequence of an actual gene, such as a human gene, or may be a cDNA sequence derived from a messenger RNA (mRNA) and thus represent contiguous exonic sequences derived from a corresponding genomic sequence, or they may be wholly synthetic in origin for purposes of practicing the processes of the invention. Because of the processing that may take place in transforming the initial RNA transcript into the final mRNA, the sequences disclosed herein may represent less than the full genomic sequence. They may also represent sequences derived from ribosomal and transfer RNAs. Consequently, the gene as present in the cell (and representing the genomic sequence) and the polynucleotide transcripts disclosed herein, including cDNA sequences, may be identical or may be such that the cDNAs contain less than the full genomic sequence. Such genes and cDNA sequences are still considered "corresponding sequences" (as defined elsewhere herein) because they both encode the same or related RNA sequences (i.e., related in the sense of being splice variants or RNAs at different stages of processing). Thus, by way of non-limiting example only, a gene that encodes an RNA transcript, which is then processed into a shorter mRNA, is deemed to encode both such RNAs and therefore encodes an RNA complementary to (using the usual Watson-Crick complementarity rules), or that would otherwise be encoded by, a cDNA (for example, a sequence as disclosed herein). Thus, the sequences disclosed herein correspond to genes contained in the cancerous cells (here, breast cancer) and are used to determine gene activity or expression because they represent the same sequence or are complementary to RNAs encoded by the gene. Such a gene also includes different alleles and splice variants that may occur in the cells used in the methods of the invention, such as where recombinant cells are used to assay for anti-neoplastic agents and such cells have been engineered to express a polynucleotide as disclosed herein, including cells that have been engineered to express such polynucleotides at a higher level than is found in non-engineered cancerous cells or where such recombinant cells express such polynucleotides only after having been engineered to do so. Such engineering includes genetic engineering, such as where one or more of the polynucleotides disclosed herein has been inserted into the genome of such cell or is present in a vector. Such cells, especially mammalian cells, may also be engineered to express on their surfaces one or more of the polypeptides of the invention for testing with antibodies or other agents capable of masking such polypeptides and thereby removing the cancerous nature of the cell. Such engineering includes both genetic engineering, where the genetic complement of the cells is engineered to express the polypeptide, as well as non-genetic engineering, whereby the cell has been physically manipulated to incorporate a polypeptide of the invention in its plasma membrane, such as by direct insertion using chemical and/or other agents to achieve this result. In a preferred embodiment of such method, the determined change in expression is a decrease in expression of said one or more polynucleotides or a decrease in said expression. In other preferred embodiments, the determined change in expression is a change in transcription of said one or more polynucleotides or a change in activity of a polypeptide, or expression product, encoded by said polynucleotide, including a change in the amount of said polypeptide synthesized, such as by a cell. The term "expression product" means that polypeptide or protein that is the natural translation product of the gene and any nucleic acid sequence coding equivalents resulting from genetic code degeneracy and thus coding for the same amino acid(s). In additional preferred embodiments, said one or more polynucleotides are present in a cell, preferably a cancer cell, more preferably a colon cancer cell, and most preferably where the colon cancer cell is an adenocarcinoma cancer cell. In another preferred embodiment of the invention, the cell is a recombinant cell engineered to contain said set of genes. Such methods serve to identify other compounds that have like activity, including expected therapeutic activity, as the compounds of the invention and thus serve as the basis for large scale screening assays for therapeutic compounds. As a result, one or more compounds of the invention can be utilized to determine the presents of gene sets and subsets within the genome of a cell. Thus, the set of all genes modulated by a group of structurally related compounds of the invention can form a gene set while the different sets of genes regulated by each compound of a group will form a subset. By way of non-limiting example, where a structurally related group of 5 of the compounds of the invention (all having generally the structure of Formula I) modulate (by increasing or decreasing) expression of determined genes 1-20, this latter group of genes forms a gene set. Further examination then determines that genes 1-6 are modulated by compound A, genes 7-10 are modulated by compound B, genes 2-4 and 9-12 are modulated by compound C, genes 10-20 are modulated by compound D and the even numbered genes are modulated by compound E. Each of these groups of genes, such as the genes modulated by compound C, is considered a subset of the gene set of genes 1-20. In an analogous manner, the genes modulated by compound E can be themselves further subdivided into at least 2 subsets wherein one subset is made up of the genes whose expression is increased by compound E while the other subset is made up of genes whose expression is decreased by compound E, thus yielding subsets of subsets. It should be noted that within the context of the present invention, it is not necessary to identify subsets and that each so-called subset is, in its own right, a gene set as used in the invention. The identification of sets and subsets is thus a function of the extent that a user of the methods of the invention wishes to determine modulation of genes resulting from contacting of one or more compounds of the invention. Thus, the genes modulated by a single compound form a gene set and it is not necessary, in carrying out the methods of the invention, to compare different groups of genes for modulation by more than one compound but this may, of course, be done. In accordance with the foregoing, the present invention relates to a set of genes comprising a plurality of subsets of genes wherein each subset of said plurality is a gene set identified by the methods of the invention. The present invention also relates to compounds identified as having activity using the methods of the invention, such as novel compounds not specifically described herein by structure but which have been identified by their ability to modulates one or more gene sets modulated by compounds of the invention. In a preferred embodiment, the present invention encompasses the gene sets and subsets of the genes identified in Table 11 and/or in Table 12. In using the compounds of the invention for treatment of disease, especially cancer, the present invention specifically contemplates use of a compound that modulates the expression of a set of, or subset of, genes of Table 11 or 12. The present invention comprises also processes for the preparation of compounds of formula I, and the relative key intermediates Compound Preparation:
The compounds of the invention can be prepared using a variety of procedures known in the art. The starting materials used in preparing the compounds of the invention are known, made by known methods, or are commercially available. Particularly preferred syntheses are described in the following general reaction schemes. Scheme 1 :
Figure imgf000027_0001
2
Figure imgf000027_0002
The dichioro compound 1 is either commercially available or can be synthesized using methods known in the literature. 1. Shaikh I. A. et al, J. Med. Chem, 29(8), 1329-1340, (1986) 2. Vlderrama el al, Syn. Comm., 27(12), 2143-2157, (1997) 3. Chu, Kwong-Yung; et al. Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999) (1978) 4. Matsuhisa A. et al, Patent WO 01/60803 A1
The compound 1 can be reacted with an amine in an appropriate solvent to provide the corresponding derivative 2. The compound 2 then can be reacted with acetyl chloride or acetic anhydride or activated acetic acid using acid such as sulfuric acid or base such as sodium carbonate to obtain the corresponding 3 derivatives. A reaction of crude or purified compound 3 with an amine can give desired compound 4 of formula I. Alternatively the desire compounds of formula I can be prepared by following scheme 2. Scheme 2:
Figure imgf000028_0001
Figure imgf000028_0002
Figure imgf000028_0003
Additionally, further independent modification each R, Ri, R2, R3, R4, R5, Re, R7. R12, and Rι3 using methods known in literature to obtain additional compounds of formula l.
Compounds for which no preparation is given can be made by methods known in the literature or are of common knowledge by skilled artisan. The skilled artisan will recognize that some reactions are best carried out when another potentially reactive functionality on the molecule is masked or protected, thus avoiding any undesirable side reactions and/or increasing the yield of the reaction. Often protecting groups are used to accomplish such increased yields or to avoid the undesired reactions. Such reactions are well within the ability of the skilled artisan. Some examples are found in T. Greene, Protecting Groups in Organic Synthesis. In addition, it is to be appreciated that one optical isomer may have favorable properties over the other and thus the disclosure of a racemic mixture within the present invention may also include either optically active isomer if such isomer has advantageous physiological activity in accordance with the methods of the invention.
Example-A1 2-Chloro-3-methylamino-M ,41naphthoguinone
Figure imgf000029_0001
To a solution of 22.7g (lOOmmol, 1 equivalent) of 2,3-dichloro- [1,4]naphthoquinone in 350 ml of anhydrous THF was added 200ml of 2.0M methyl amine in THF (200mmol, 2 equivalents). To the mixture was added 34 ml of N, N-diisopropylethylamine (200mmol, 2 equivalents) and it was shaken at room temperature for overnight (16-20 hours). The red precipitates formed were filtered and washed with ether. The residue was again washed with water and ether. The solid was dried under vacuum. The filtrate was checked for the desired product, and then THF was evaporated. The residue was recrystallized with DCM/ether. The titled compound was collected as a red solid (18g, Yield 74% ). In a process analogous to Example A1 using appropriate starting materials, the following compounds are prepared:
Figure imgf000030_0002
Example-B1
2-Bromo-N-(3-chloro-1,4-dioxo-1.4-dihvdro-naphthalen-2-yl)-N-methyl- acetamide
Figure imgf000030_0001
To a solution of 8g of 2-chloro-3-methylamino-[1,4]naphthoquinone (36mmol, 1 equivalent) in 400 ml 1,4-dioxane was added 10g of K2CO3 (72mmol, 2 equivalents). The mixture was heated until the starting material was completely dissolved. To the solution 12.5ml of bromoacetyl bromide (144mmol, 4 equivalents) was added and refluxed for 1 hour. Inorganic materials were filtered and washed thoroughly with DCM. The filtrate was evaporated and the residue was purified by flash silica gel column using 75:25- hexanes: ethyl acetate. The compound was collected as yellow oil. (10g, Yield 80%). In a process analogous to Example B1 using appropriate starting materials, the following compounds are prepared:
Figure imgf000031_0002
methyl-acetamide
Figure imgf000031_0001
To a solution of 2.5g of 2-bromo-N-(3-chloro-1,4-dioxo-1,4-dihydro- naphthalen-2-yl)-N-methyl-acetamide (7mmol, 1 equivalent) in 200ml of ethyl acetate was added 3.5 ml of 2.0M dimethyl amine solution in THF ( 7 mmol, 1 equivalent). The amine solution was added in two portions stirring for 15 min after each addition. The solvent was then evaporated and then sample was purified on a silica gel column. Fractions were analyzed by LCMS and pure fractions were collected and solvent was evoperated to dryness to yield 1.2 g (47%) of desired compound. In a process analogous to Example C1 using appropriate starting materials, the following corresponding compounds are prepared:
Figure imgf000032_0002
Example 1 N-(3-Dimethylamino-1 ,4-dioxo-1 ,4-dihydro-naphthalen-2-yl)-2-methoxy- N-methyl-acetamide
Figure imgf000032_0001
To a solution of 350 mg 2-bromo-N-(3-dimethylamino-1,4-dioxo-1 ,4- dihydro-naphthalen-2-yl)-N-methyl-acetamide (1mmol) in 20ml of methanol was added 108 mg of sodium methoxide ( 2 mmol, 2 equivalent). The reaction mixture was stirred at room temperature for 4 hours and the reaction was monitored by LCMS. After the completion of the reaction, it was concentrated and purified first by column chromatography using silica gel and then LCMS using Cι8 column to obtain 80 mg (26.4 %) of the titled compound.
Example 2-12 (Table 1) and Example 1-13 (Table 2) In a process analogous to Example 1 using appropriate starting materials, the corresponding compounds shown in Table 1 and Table 2 are prepared. TABLE 1
Figure imgf000033_0001
Figure imgf000033_0002
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
TABLE 4
Figure imgf000039_0001
Figure imgf000039_0002
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000041_0002
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000045_0002
Figure imgf000046_0001
TABLE 8
Figure imgf000047_0001
Figure imgf000047_0002
Figure imgf000048_0001
TABLE 9
Figure imgf000049_0001
Figure imgf000050_0001
TABLE 10
Figure imgf000051_0001
Figure imgf000052_0001
0 Table 11
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
05/013903
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Table 12
Figure imgf000067_0001

Claims

WHAT IS CLAIMED IS:
1. A compound having the structure of Formula (I)
Figure imgf000068_0001
Formula I
wherein W, X, Y and Z are each independently selected from a bond, C-R5, C- R6, C-R7, C-R8, O, N or S and wherein no more than two of W, X, Y and Z are O, N or S; wherein, R5, Re, R7, Rs are each independently selected from hydrogen, hydroxyl, sulfhydryl, alkoxy, thioalkoxy, alkyl, halogen, CN, CF3, NO2, COOR9, CONR9R10, NR9R10, NR9COR10, NR9SO2R10, NRnCONRgRio; wherein Rg, R10 and Rn are each independently selected from hydrogen, alkyl, heteroalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; wherein NR9R10 is also selected from substituted or unsubstituted mono or bicyclic rings having one to four heteroatoms selected from N, O and S; and wherein Rg and Rn may form a 4, 5, 6 or 7-member cyclic ring system; Ri is selected from hydrogen, alkyl, substituted or unsubstituted phenyl or polyaromatic, substituted or unsubstituted heteroaromatic having one or more hetero atoms selected from N, O and S, substituted or unsubstituted aralkyl, substituted or unsubstituted cyclo or polycyclo hydrocarbon or mono or polyheterocycle of 3 to 8 atom rings having one to four hetero atoms selected from N, O and S; and wherein substitutions are each independently selected from hydrogen, hydroxyl, sulfhydryl, alkoxy, thioalkoxy, alkyl, halogen, CN, CF3, NO2, COORg, CONR9R10, NR9R10, NR9COR10, NR11SO2R9, NR11CONR9R10; wherein Rg, R10 and Rn are each independently elected from hydrogen, alkyl, heteroalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; and wherein NR9R10 is selected from substituted or unsubstituted mono or bicyclic ring having one to four heteroatoms selected from N, O and S; and wherein R9 and R-n may form a 4, 5, 6 or 7-member cyclic ring system; R2 is selected from alkyl with more than two carbons, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl. R2 is also selected from
Figure imgf000069_0001
wherein n = 1 , 2, 3 or 4; R3 and R4 are each independently selected from alkyl, substituted or unsubstituted phenyl or polyaromatic, substituted or unsubstituted heteroaromatic having hetero atoms selected from N, O and S, substituted or unsubstituted aralkyl, substituted or unsubstituted cyclo or polycyclo hydrocarbon or mono or polyheterocycle of 3 to 8 atom rings having one to four hetero atoms selected from N, O and S; and and wherein substitutions are each independently selected from independently hydrogen, hydroxyl, sulfhydryl, alkoxy, thioalkoxy, alkyl, halogen, CN, CF3, NO , COORg, CONR9R10, NR9R10, NR9COR10, NRnSO2R9, NRiiCONRgRi0; wherein Rg, R10 and Rn are independently hydrogen, alkyl, heteroalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; and NR9R10 is substituted or unsubstituted mono or bicyclic ring having one to four heteroatoms selected from N, O and S; and wherein R9 and Rn may form a 4, 5, 6 or 7-member cyclic ring system; and wherein NR3R is substituted or unsubstituted mono or bicyclic ring having one to four heteroatoms selected from N, O and S.
2. The compound of claim 1 wherein W and Z are each independently C-R5, C-R8 or N and X and Y are each independently C-R6 or C-R7.
3. The compound of claim 1 wherein X and Y are each independently
C-R6, C-R7 or N and W and Z are each independently C-R5 or C-R8.
4. The compound of claim 2 wherein W is C-R5 or N and X, Y and Z are each independently C-R6, C-R7 or C-R8.
5. The compound of claim 2 wherein Z is C-R8 or N and W, Y and Z are each independently C-R5, C-R6 or C-R7.
6. The compound of claim 3 wherein X is C-R6 or N W, Y and Z are each independently C-R5, C-R7 or C-Rs.
7. The compound of claim 3 wherein Y is C-R7 or N and W, X, and Z are each independently C-R5, C-R6 or C-R8.
8. The compound of claim 7 wherein W X, Y and Z are each independently CH, C-R5, C-R6, C-R7or C-R8.
9. The compounds of claim 8 wherein W X, Y and Z are each CH.
10. The compound of claim 1 wherein R2 is alkyl with more than two carbon.
11. The compounds of claim 9 wherein R2 is alkyl with more than two carbon.
12. The compound of claim 1 wherein Ri, Re and R7 are methyl.
13. Compound of claim 1 wherein Ri is selected from hydrogen, alkyl, cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, -methylpyridine, -ethylpyridine, -mehtylindole, -ethylindole, alkoxyethyl-, hydroxyethyl, N,N-dialkyl-ethyl, , N,N-dialkyl-propyl, methylpyrrole, ethylpyrrole, methylfuran, ethylfuran, -alkylmorpholine, - alkylpiperizine, -alkypiperidine, -alkylpyrrolidine.
14. The compound of claim 1 wherein R3 and R4 are independently selected from alkyl, cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, -methylpyridine, -ethylpyridine, mehtylindole, -ethylindole, alkoxyethyl-, hydroxyethyl, N,N-dialkyl-ehtyl, , N,N- dialkyl-propyl, methylpyrrole, ethylpyrrole, methylfuran, ethylfuran, alkylmorpholine, -alkylpiperizine, -alkypiperidine, -alkylpyrrolidine;
15. The compound of claim 1 wherein R2 is
R12
-OR14
R13
16. The compound of claim 1 wherein R2 is
R12
-OCONR14Rι5
R 13 n
17. The compound of claim 1 wherein R2 is
-OCOOR14
Figure imgf000072_0001
18. The compound of claim 1 wherein R2 is
Figure imgf000072_0002
19. The compound of claim 1 wherein R2 is
Figure imgf000073_0001
20. The compound of claim 1 wherein R2 is
Figure imgf000073_0002
21. The compound of claim 1 wherein said compound is a member selected from the compounds of Table 1.
22. The compound of claim 1 wherein said compound is a member selected from the compounds of Table 2.
23. The compound of claim 1 wherein said compound is a member selected from the compounds of Table 3.
24. The compound of claim 1 wherein said compound is a member selected from the compounds of Table 4.
25. The compound of claim 1 wherein said compound is a member selected from the compounds of Table 5.
26. The compound of claim 1 wherein said compound is a member selected from the compounds of Table 6.
27. The compound of claim 1 wherein said compound is a member selected from the compounds of Table 7.
28. The compound of claim 1 wherein said compound is a member selected from the compounds of Table 8.
29. The compound of claim 1 wherein said compound is a member selected from the compounds of Table 9.
30. The compound of claim 1 wherein said compound is a member selected from the compounds of Table 10.
31. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 in a pharmaceutically acceptable carrier in unit dosage form.
32. 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 claim 1.
33. A method for preventing or treating a disorder modulated by altered gene expression, wherein the disorder is selected from the group consisting of cancer, cardiovascular disorders, arthritis, osteoporosis, inflammation, periodontal disease and skin disorders, by administering to a mammal in need of such treatment or prevention a safe and effective amount of a compound of claim 1.
34. The method of Claim 33, wherein the disorder is cancer, and the treatment prevents, arrests or reverts tumor growth and metastasis.
35. The method of Claim 34 wherein the cancer is colon cancer.
36. The method of claim 35 wherein said colon cancer is adenocarcinoma.
37. The method of Claim 33 wherein the disorder is a cardiovascular disorder chosen from the group consisting of dilated cardiomyopathy, congestive heart failure, atherosclerosis, plaque rupture, reperfusion injury, ischemia, chronic obstructive pulmonary disease, angioplasty restenosis, and aortic aneurysm.
38. A gene set wherein expression of each member of said gene set is modulated as a result of treatment with a compound of claim 1.
39. The gene set of claim 38 wherein expression of each member of said gene set is increased or each member of said gene set is decreased as a result of said contacting.
40. The gene set of claim 38 wherein the members of said gene set are selected from the genes identified in Table 11.
41. The gene set of claim 38 wherein said gene set is present in a cell.
42. A method for identifying an agent that modulates the expression of a gene set of claim 38, comprising: (a) contacting a compound with a test system containing one or more polynucleotides corresponding to each of the members of the gene set of claim
38 under conditions wherein the members of said gene set are being expressed; (b) determining a change in expression of each of said one or more polynucleotides of step (a) as a result of said contacting; wherein said change in expression in step (b) indicates modulation of the members of said gene set thereby identifying said test compound as an agent that modulates the expression of said gene set.
43. The method of claim 42 wherein said change in expression is a decrease in expression of said one or more polynucleotides.
44. The method of claim 42 wherein said change in expression is a change in transcription of said one or more polynucleotides.
45. The method of claim 42 wherein said change in expression is determined by determining a change in activity of a polypeptide encoded by said polynucleotide.
46. The method of claim 42 wherein said one or more polynucleotides are present in a cell.
47. The method of claim 46 wherein said cell is a cancer cell.
48. The method of claim 47 wherein said cancer cell is a colon cancer cell.
49. The method of claim 48 wherein said colon cancer cell is an adenocarcinoma cancer cell.
50. The method of claim 46 wherein said cell is a recombinant cell engineered to contain said set of genes.
51. A set of genes comprising a plurality of subsets of genes wherein each subset of said plurality is a gene set identified by the method of claim 42.
52. Compounds identified as having activity using the method of claim 42.
53. The gene set of claim 38 wherein said gene set comprises a subset of the genes of Table 11.
54. The gene set of claim 38 wherein said gene set comprises a subset of the genes of Table 12.
55. The method of claim 42 wherein said compound modulates the expression of a subset of genes of Table 11.
56. The method of claim 42 wherein said compound modulates the expression of a subset of genes of Table 12.
PCT/US2004/025343 2003-08-05 2004-08-05 Derivatives of substituted quinone and uses thereof WO2005013903A2 (en)

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Cited By (1)

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Publication number Priority date Publication date Assignee Title
WO2024085823A1 (en) * 2022-10-19 2024-04-25 İsti̇nye Üni̇versi̇tesi̇ A novel therapeutic agent with a cytotoxic effect in triple negative breast cancer

Non-Patent Citations (1)

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Title
PETRUSHA N.A.: 'Antineoplastic activity of some 1,4-Naphthoquinone derivatives' VOPROSY EKSPERIMENTAL'NOI ONKOLOGII (IN RUSSIAN) no. 4, 1969, pages 132 - 135, XP008045958 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024085823A1 (en) * 2022-10-19 2024-04-25 İsti̇nye Üni̇versi̇tesi̇ A novel therapeutic agent with a cytotoxic effect in triple negative breast cancer

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