Diamine derivatives of quinone and uses thereof

Information

  • Patent Application
  • 20050032794
  • Publication Number
    20050032794
  • Date Filed
    January 15, 2004
    20 years ago
  • Date Published
    February 10, 2005
    19 years ago
Abstract
Diamine derivatives of quinones, and related compounds, including salts thereof, that modulate the levels of gene expression in cellular systems, such as cancer cells, are disclosed, along with methods for preparing such compounds and derivatives, as well as pharmaceutical compositions containing these compounds and derivatives as active ingredients. Methods of using these as compounds and derivatives as therapeutic agents are also described.
Description
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 quinones. 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 cancer such as colon and breast cancers.


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 and breast 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 and breast 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 and breast 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 and breast 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 and breast 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. p “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 C1-C6 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. Where a group is described, for example, as an alkyl derivative, such as “-ethylpyridine” the dash “-” indicate point of attachment of the substituent. Thus, “-ethylpyridine” means attachment of ethylpyridine via the ethyl portion of the group whereas “ethylpyridine-” means attachment via the pyridinyl ring.


“Heteroaryl” is an aromatic ring containing carbon atoms and from 1 to about 6 heteroatoms in the ring. Heteroaryl rings are monocyclic or fused bicyclic ring systems. Monocyclic heteroaryl rings contain from about 5 to about 9 member atoms (carbon and heteroatoms), preferably 5 or 6 member atoms, in the ring. Bicyclic heteroaryl rings contain from 8 to 17 member atoms, preferably 8 to 12 member atoms, in the ring. Bicyclic heteroaryl rings include ring systems wherein one ring is, heteroaryl and the other ring is aryl, heteroaryl, cycloalkyl, or 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:
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“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:
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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.


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 Sep. 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., Hawley'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

The present invention relates generally to a compound having the structure:
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wherein

    • W, X, Y and Z are each selected from a bond, CH, C—R8, C—R9, C—R10, C—R11, O (oxygen), N (nitrogen) and S (sulfur) and no more than two of W, X, Y and Z are simultaneously O, N and S;
      • and wherein, R8, R9, R10, R11 each may be hydrogen, hydroxyl, sulfhydryl, alkoxy, thioalkoxy, alkyl, halogen, CN, CF3, NO2, COOR12, CONR12R13, NR12R13, NR12COR13, NR12SO2R13, and NR14CONR12R13;
      • wherein R12, R13 and R14 are hydrogen, alkyl, heteroalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or heterocycloalkyl;
      • NR12R13 may form a substituted or unsubstituted, mono or bicyclic rings, with one to four heteroatoms selected from N, O and S;
      • and wherein, R12 and R14 may form a 4, 5, 6 or 7-membered cyclic ring system;
    • and wherein R1, R2, R3, R4, and R5 are each selected from:
      • hydrogen, alkyl, substituted or unsubstituted phenyl or polyaromatic rings, substituted or unsubstituted heteroaromatic, with hetero atom(s) as N, O, S, substituted or unsubstituted aralkyl, substituted or unsubstituted cyclo or polycyclo hydrocarbon and mono or polyheterocycle (3-8 atoms per ring) with one to four hetero atoms as N, O, or S; and
      • wherein said substitutions are selected from hydroxyl, sulfhydryl, alkoxy, thioalkoxy, alkyl, halogen, CN, CF3, NO2, COOR12, CONR12R13, NR12R13, NR12COR13, NR12SO2R13, and NR14CONR12R13;
        • wherein R12, R13 and R14 are each selected from hydrogen, alkyl, heteroalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl;
        • NR12R13 is also substituted or unsubstituted, mono or bicyclic rings with one to four heteroatoms selected from N, O and S;
        • and wherein R12 and R14 may, in one embodiment, form a 4, 5, 6 or 7-membered cyclic ring system;
    • and wherein R1, R4, R5, R6 and R7 may also be selected from:
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      • wherein n is 2, 3 or 4 and R15, R16, R17, R18 and R19 are selected from hydrogen, alkyl, cycloalkyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted alkylaryl;
      • and NR17R18 may also be a substituted or unsubstituted, mono or bicyclic ring with one to four heteroatoms selected from N, O and S;
      • and wherein R17 and R19 may form a 4, 5, 6 or 7-membered cyclic ring system;
      • and wherein R4 is also selected from —COR13, —SO2R13, —CONR12R13, and —C(═NR19)NR17R18;
    • wherein R6 and R7 may also each be selected from:
      • alkyl, substituted and unsubstituted phenyl or polyaromatic, substituted and unsubstituted heteroaromatic rings with hetero atoms selected from N, O and S, substituted and unsubstituted aralkyl, substituted and unsubstituted, cyclic or polycyclic hydrocarbon and mono or polyheterocyclic rings, each of 3-8 atoms, said heterocycle having one to four hetero atoms selected from N, O and S; and
      • wherein substitutions are selected from hydroxyl, sulfhydryl, alkoxy, thioalkoxy, alkyl, halogen, CN, CF3, NO2, COOR12, CONR12R13, NR12R13, NR12COR13, NR12SO2R13, NR14CONR12R13;
        • wherein R12, R13 and R14 are each selected from hydrogen, alkyl, heteroalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl;
        • NR12R13 is also unsubstituted, monosubstituted or polysubstituted mono or bicyclic ring with one to four heteroatoms such as N, O, S;


          and wherein NR4R5 and NR6R7 may each form a substituted or unsubstituted, mono or bicyclic ring comprising one to four heteroatoms selected from N, O and S and wherein said N may also be substituted or unsubstituted,


          and including salts of any of the above-recited structures.


In another preferred embodiment, R1, R2, R3, R4, and R5, are each selected from hydrogen, alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted polyaromatic, and substituted or unsubstituted heteroaromatic comprising one or more hetero atom(s) selected from N, O and S.


In another preferred embodiment, R1, R2, R3, R4, and R5 are each selected from substituted or unsubstituted aralkyl, substituted or unsubstituted cyclo or polycyclo hydrocarbon or mono or polyheterocycle (3-8 atoms per ring) with one to four hetero atoms selected from N, O and S.


In any of these preferred embodimenits, substitutions are selected from hydroxyl, sulfhydryl, lower alkoxy (1-6 carbon), lower thioalkoxy (1-6 carbon), lower alkyl (1-6 carbon), halogen, CN, CF3, NO2, COOR12, CONR12R13, NR12R13, NR12COR13, NR12SO2R13, and NR14CONR12R13, wherein R12, R13 and R14 are hydrogen, alkyl, heteroalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, or heterocycloalkyl. In a further preferred embodiment of the foregoing, R12 and R14 form a 4, 5, 6 or 7-member cyclic ring system.


In a further preferred embodiment, NR12R13 forms a substituted or unsubstituted mono or bicyclic ring comprising one to four heteroatoms selected from N, O and S.


In one preferred embodiment, R1, R4, R5, R6 and R7 are each selected from:
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    • wherein n is 2, 3 or 4 and R15, R16, R17, R18 and R19 are selected from hydrogen, lower alkyl, cycloalkyl, substituted and unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted alkylaryl. In a preferred embodiment thereof, NR17R18 is forms a substituted or unsubstituted, mono or bicyclic ring comprising one to four heteroatoms selected from N, O and S. In another preferred embodiment thereof, R17 and R19 form a 4, 5, 6 or 7-membered cyclic ring system.


In a preferred embodiment of the compounds of Formula I, W and Z are each selected from C—R8, C—R11, and N, and X and Y are each selected from C—R9 and C—R9. In another preferred embodiment, X and Y are each selected from C—R9, C—R10 and N and wherein W and Z are each selected from C—R8 and C—R11. In another preferred embodiment, W is C—R8 or N, and X, Y and Z are each selected from C—R9, C—R10 and C—R11.


Where a position in a structure, such as W, X, Y or Z, or a substituent, such as an R group, as recited above, is described as selected from, it means that each of W, X, Y and Z, or R, can be selected from the indicated group of structures or atoms and each is selected independently of the others unless it is expressly stated herein to be otherwise. By “independent” is meant that the selection of one substituent does not limit the range of selection for another substituent, unless expressly stated as such. For example, where X and Y are selected from a range of atoms, such as N, O and S, then X and Y may be the same or different and the selection of one does not limit the range of the other. Thus, if X is nitrogen then Y can still be N, O or S.


Where a position, for example, in a ring, is described as being selected from “a bond” etc., this means that the position is not occupied by an atom. Thus, if in Formula I, X is a bond, then the ring with W, X, Y and Z is a 5 membered ring instead of a 6 membered ring.


In a preferred embodiment, NR4R5 and/or NR6R7 of Formula I form(s) a piperazine ring, preferably an N-acetylpiperazinyl group.


In a preferred embodiment, —NR4R5 and/or —NR6R7 of Formula I is a substituted or unsubstituted morpholinyl group. In a highly preferred embodiment thereof, R6 and R7 are both hydrogen. In a most preferred embodiment, R2 and R3 are both hydrogen and —NR4R5 forms an unsubstituted morpholinyl group.


In a preferred embodiment, NR4R5 and/or NR6R7 of Formula I is a piperidine ring, preferably a substituted piperidine ring, most preferably 4-hydroxypiperidine.


In a highly preferred embodiment of any of the structures of the present invention, R1, R6 and R7 of Formula I are each methyl.


In another preferred embodiment of the compounds of the invention, Z is C—R10, or N and W, Y and Z are each selected from C—R8, C—R9 and C—R11. In one embodiment of the latter, X is C—R10 or N and W, Y and Z are each selected from C—R8, C—R9 and C—R11. In a preferred embodiment of the latter Y is C—R10 or N and W, X, and Z are each selected from CH, C—R8, C—R9 and C—R11. In a most preferred embodiment thereof, W, X, Y and Z are each selected from CH, C—R8, C—R9, C—R10 and C—R11, most preferably where W X, Y and Z are each CH (thereby forming a phenyl ring).


In another preferred embodiment of the compounds of the invention, R2 and R3 are selected from hydrogen, lower alkyl (1-6 carbon) or aryl. In a further preferred embodiment of the compounds of the invention, R1 is selected from hydrogen, alkyl, cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, -methylpyridine, -ethylpyridine, -methylindole, -ethylindole, alkoxyethyl-, hydroxyethyl-, N,N-diaikyl-ethyl, N,N-dialkyl-propyl, -methylpyrrole, -ethylpyrrole, -methylfuran, -ethylfuran, -alkylmorpholine, -alkylpiperizine, -alkypiperidine, and -alkylpyrrolidine and wherein R2 and R3 are selected from hydrogen, lower alkyl (1-6 carbons) and aryl.


In another preferred embodiment of the compounds of the invention, R4 and R5 are each selected from hydrogen, alkyl, cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, -methylpyridine, -ethylpyridine, -methylindole, -ethylindole, alkoxyethyl-, hydroxyethyl-, N,N-dialkyl-ethyl-, N,N-dialkyl-propyl-, -methylpyrrole, -ethylpyrrole, -methylfuran, -ethylfuran, -alkyqmorpholine, -alkylpiperizine, -alkypiperidine, and -alkylpyrrolidine, and wherein R2 and R3 are selected from hydrogen, lower alkyl (1-6 carbon) and aryl.


In another preferred embodiment of the compounds of the invention, R6 and R7 are selected from alkyl, cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, -methylpyridine, -ethylpyridine, -methylindole, -ethylindole, alkoxyethyl-, hydroxyethyl-, N,N-dialkyl-ethyl, N,N-dialkyl-propyl, -methylpyrrole, -ethylpyrrole, -methylfuran, -ethylfuran, -alkylmorpholine, -alkylpiperizine, -alkypiperidine, and -alkylpyrrolidine, and R2 and R3 are each selected from hydrogen, lower alkyl (1-6 carbons) and aryl.


In other preferred embodiments, R2 and R3 are selected from hydrogen, lower alkyl (1-6 carbon) and aryl, wherein R1, R4 and R5 are each selected from hydrogen, alkyl, cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, -methylpyridine, -ethylpyridine, -methylindole, -ethylindole, alkoxyethyl-, hydroxyethyl-, N,N-dialkyl-ethyl-, N,N-dialkyl-propyl-, -methylpyrrole, -ethylpyrrole, -methylfuran, -ethylfuran, -alkylmorpholine, -alkylpiperizine, -alkypiperidine, and -alkylpyrrolidine, and wherein R2 and R3 are selected from hydrogen, lower alkyl (1-6 carbon) or aryl and wherein R6 and R7 are selected from alkyl, cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, -methylpyridine, -ethylpyridine, -methylindole, -ethylindole, alkoxyethyl-, hydroxyethyl-, N,N-dialkyl-ethyl, N,N-dialkyl-propyl, -methylpyrrole, -ethylpyrrole, -methylfuran, -ethylfuran, -alkylmorpholine, -alkylpiperizine, -alkypiperidine, and -alkylpyrrolidine.


In another preferred embodiment of the compounds of the invention having Formula 1, R2 and R3 are each selected from hydrogen and alkyl, and wherein R4 and R6 are each selected from alkyl and
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    • wherein n is 2 ,3 or 4 and wherein one or both of R5 and R7 is alkyl, preferably both, and in either case most preferably wherein the alkyl is methyl.


In another preferred embodimentof Formula I, R1 is alkyl while R2 and R3 are each selected from hydrogen and alkyl, and R4 and R6 are each selected from alkyl and
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wherein n is 2, 3 or 4 and one or both of R5 and R7 is alkyl, preferably both, and in either case most preferably wherein the alkyl is methyl.


In another preferred embodiment of Formula 1, R2 and R3 are each selected from hydrogen and alkyl while R4 and R6 are each selected from alkyl and
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    • where n is 2, 3 or 4 and one or both of R5 and R7 is alkyl, preferably both, and in either case most preferably wherein the alkyl is methyl.
    • In another preferred embodiment of Formula 1, R2 and R3 are each selected from hydrogen and alkyl, wherein R4 and R6 are each selected from alkyl and
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    • where n is 2, 3 or 4 and at least one of R5 and R7 is alkyl, preferably both, and in either case most preferably wherein the alkyl is methyl.


In another preferred embodiment of Formula 1, R2 and R3 are each selected from hydrogen and alkyl, and R4 and R6 are each selected from alkyl and
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    • where n is 2, 3 or 4 and at least one of R5 and R7 is alkyl, preferably both, and in either case most preferably wherein the alkyl is methyl.


In another preferred embodiment of Formula 1, R2 and R3 are each selected from hydrogen and alkyl and R4 and R6, are each selected from alkyl and
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    • wherein n is 2, 3 or 4 and wherein one or both of R5 and R7 is alkyl, preferably both, and in either case most preferably wherein the alkyl is methyl.


In another preferred embodiment of Formula 1, R2 and R3 are each be hydrogen or alkyl, R4 and R6 are each selected from alkyl and
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    • where n is 2, 3 or 4 and one or both of R5 and R7 is alkyl, and in either case most preferably wherein the alkyl is methyl.


In separate embodiments, the present invention encompasses compounds having a structure found in Table 1 including salts thereof, a compound having a structure of Table 2 including salts thereof, a compound having a structure of Table 3 including salts thereof, a compound having a structure of Table 4 including salts thereof, a compound having a structure of Table 5 including salts thereof, a compound having a structure of Table 6 including salts thereof, a compound having a structure of Table 7 including salts thereof, a compound having a structure of Table 8 including salts thereof, a compound having a structure of Table 9 including salts thereof, a compound having a structure of Table 11 including salts thereof, a compound having a structure of Table 12 including salts thereof, a compound having a structure of Table 13 including salts thereof, a compound having a structure of Table 14 including salts thereof, a compound having a structure of Table 15 including salts thereof, a compound having a structure of Table 16 including salts thereof, a compound having a structure of Table 17 including salts thereof, and a compound having a structure of Table 18 including salts thereof, and in each case most preferably pharmaceutically acceptable salts thereof. It is to be understood that each of the structures defined in each of these tables is considered to be a separate and preferred embodiment of the present invention.


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 Table 19. 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 Table 19, 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 19, 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 encqdes 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 asby 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 and breast cancer cell, and most preferably where the coloncancer 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 19.


The present invention comprises also processes for the preparation of compounds of formula I, and the relative key intermediates


Comp und Pr paration


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;
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The dichloro 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 is reacted with an amine in an appropriate solvent to provide the corresponding derivative 2. The compound 2 is then reacted with an appropriate 2-halo, 2-substituted acetyl halide to obtain the corresponding 3 derivatives. A reaction of crude or purified compound 3 with an amine gives compound 4. Compound 4 with or without isolation is treated with an amine in a suitable solvent at an appropriate temperature to afford compound 5.


In the same way, independent and selective modification of R1, R2, R3, R4, R5, R6, and R7 using methods known in the literature readily affords additional compounds of formula I. Thus, compounds for which no separate preparation is provided herein are made by methods known in the literature or are of common knowledge to the 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-[1,4]naphthoquinone
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To a solution of 22.7 g (100 mmol, 1 equivalent) of 2,3-dichloro-[1,4]naphthopquinone in 350 ml of anhydrous THF was added 200 ml of 2.0M methyl amine in THF (200 mmol, 2 equivalents). To the mixture was added 34 ml of N, N-diisopropylethylamine (200 mmol, 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 dichlorotnethane/ether. The titled compound was collected as a red solid (18 g, Yield 74%).


In a process analogous to Example A1 using appropriate starting materials, the corresponding compounds are prepared as follows:

ExampleChemical NameA2(3-Chloro-1,4-dioxo-1,4-dihydro-naphthalen-2-ylamino)-acetic acid tert-butyl esterA32-(1-Benzyl-piperidin-4-ylamino)-3-chloro-[1,4]naphthoquinoneA42-(3-Chloro-1,4-dioxo-1,4-dihydro-naphthalen-2-ylamino)-3-phenyl-propionic acid tert-butylesterA52-(4-Acetyl-phenylamino)-3-chloro-[1,4]naphthoquinoneA62,6-Dichloro-5,8-dihydroxy-3-(3-{4-[3-(6-oxo-6H-2,10b-diaza-aceanthrylen-5-ylamino)-propyl]-piperazin-1-yl}-propylamino)-[1,4]naphthoquinoneA72-Chloro-3-(2-pyridin-4-yl-ethylamino)-[1,4]naphthoquinoneA82-Chloro-3-(3-{4-[3-(6-oxo-6H-2,10b-diaza-aceanthrylen-5-ylamino)-propyl]-piperazin-1-yl}-propylamino)-[1,4]naphthoquinoneA92-Chloro-3-(3-morpholin-4-yl-propylamino)-[1,4]naphthoquinoneA102-Chloro-3-(4-dimethylamino-benzylamino)-[1,4]naphthoquinoneA112-Chloro-3-(4-dimethylamino-phenylamino)-[1,4]naphthoquinoneA122-Chloro-3-[(1-ethyl-pyrrolidin-2-ylmethyl)-amino]-[1,4]naphthoquinoneA132-Chloro-3-[2-(1,2,2,6,6-pentamethyl-piperidin-4-yl)-ethylamino]-[1,4]naphthoquinoneA142-Chloro-3-[3-(2-oxo-pyrrolidin-1-yl)-propylamino]-[1,4]naphthoquinoneA152-Chloro-3-[3-(methyl-phenyl-amino)-propylamino]-[1,4]naphthoquinoneA162-Chloro-3-{[(4-methyl-pyridin-2-yl)-phenyl-methyl]-amino}-[1,4]naphthoquinoneA172-Chloro-3-phenylamino-[1,4]naphthoquinoneA182-Chloro-5,8-dihydroxy-3-(3-{4-[3-(6-oxo-6H-2,10b-diaza-aceanthrylen-5-ylamino)-propyl]-piperazin-1-yl}-propylamino)-[1,4]naphthoquinoneA194-(3-Chloro-1,4-dioxo-1,4-dihydro-naphthalen-2-ylamino)-benzoic acid ethyl ester


EXAMPLE-B1

2-Bromo-N-(3-chloro-1,4-dioxo-1,4-dihydro-naphthalen-2-yl)-N-methyl-acetamide
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To a solution of 8 g of 2-chloro-3-methylamino-[1,4]naphthoquinone (36 mmol) in 400 ml 1,4-dioxane was added 10 g of potassium carbonate (72 mmol). The mixture was heated until the starting material was completely dissolved. To the solution, 12.5 ml of bromoacetyl bromide (144 mmol) was added and refluxed for 1 hour. Inorganic materials were filtered and washed thoroughly with dichloromethane. 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. (10 g, Yield 80%).


In a process analogous to Example B1 using appropriate 2-chloro-3-substituted amino [1,4] naphthoquinone (Example A) and corresponding acid bromide following compounds are prepared.

  • 2-Bromo-N-(3-chloro-1,4-dioxo-1,4-dihydro-naphthalen-2-yl)-acetamide
  • 2-Bromo-N-(3-chloro-1,4-dioxo-1,4-dihydro-naphthalen-2-yl)-N-methyl-acetamide
  • 2-Bromo-N-(3-chloro-1,4-dioxo-1,4-dihydro-naphthalen-2-yl)-N-methyl-propionamide


EXAMPLE 1 (COMPOUND 1, TABLE 1)

2-Dimethylamino-N-(3-dimethylamino-1,4-dioxo-1,4-dihydro-naphthalen-2-yl)-N-methyl-acetamide
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To a solution of 2.5 g of 2-bromo-N-(3-chloro-1,4-dioxo-1,4-dihydro-naphthalen-2-yl)-N-methyl-acetamide (7mmol, 1 equivalent) in 200 ml of ethyl acetate was added 28 ml of 2.0M dimethylamine solution in tetrahydrofuran (56 mmol, 8 equivalents). 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 using initially ethyl acetate and then 10-20% methanol in ethyl acetate. The solvent was evaporated and the residue was dissolved in DMSO. It was then purified further on preparative LCMS using 0.1% NH4OH in water/acetonitrile as mobile phase. (592 mg, Yield 26%); H1 NMR (400 MHz, CDCl3) 2.97 (s, 6H), 3.08 (s, 3H), 3.20 (s, 6H), 3.64 (s, 2H), 7.62 (m, 2H), 7.95 (t, 2H).


Compound 2-119 (Table 1)


In a process analogous to Example 1 (Table 1) using appropriate chloro-bromo naphthoquinone (Example B) and the corresponding secondary amine, following compounds are prepared as shown in Table 1.


EXAMPLE-C1

2-Chloro-N-(3-chloro-1,4-dioxo-1,4-dihydro-naphthalen-2-yl)-N-methyl-acetamide
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To a solution of 10 g of 2-chloro-3-methylamino-[1,4]naphthoquinone (45 mmol) in 250 mL of dioxane was added 172 mL of chloroacetyl chloride (48 equivalents). The reaction was heated at 85° C. for 16 hours. The solvent was evaporated and the material was purified on silica gel using DCM and hexanes as solvents. The pure fractions were combined and the solvent was evaporated. The product was collected as a yellow/brown solid. (12.1 g, Yield 90%).


In a process analogous to Example C1 using appropriate 2-chloro-3-substituted amino-[1,4 ]naphthoquinone (Example A) and corresponding acid chloride following compounds are prepared.

ExampleChemical NameC22-Chloro-N-(3-chloro-1,4-dioxo-1,4-dihydro-naphthalen-2-yl)-acetamideC32-Chloro-N-(3-chloro-1,4-dioxo-1,4-dihydro-naphthalen-2-yl)-propionamideC42-Chloro-N-(3-chloro-1,4-dioxo-1,4-dihydro-naphthalen-2-yl)-2-phenyl-acetamideC52-Chloro-N-(3-chloro-1,4-dioxo-1,4-dihydro-naphthalen-2-yl)-N-methyl-propionamideC62-Chloro-N-(3-chloro-1,4-dioxo-1,4-dihydro-naphthalen-2-yl)-N-methyl-2-phenyl-acetamide


EXAMPLE D1

2-Chloro-N-(3-dimethylamino-1,4-dioxo-1,4-dihydro-naphthalen-2-yl)-N-methyl-acetamide
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To a solution of 19 g of 2-chloro-N-(3-chloro-1,4-dioxo-1,4-dihydro-naphthalen-2-yl)-N-methyl-acetamide (63 mmol) in 200 mL of ethyl acetate was added slowly 22 mL of N, N-diisopropylethylamine (2 equivalents). 70 mL of 2.0M solution of dimethylamine in terahydrofuran (2.25 equivalents) was diluted with 100 mL of ethyl acetate. This amine solution was added slowly to the reaction mixture over one hour at room temperature. After stirring for an additional hour, the reaction was filtered and the solid material was washed with ethyl acetate. The filtrate was concentrated and purified using a normal phase column chromatography, and ethyl acetate and hexanes as solvents. The pure fractions were combined and the solvent was evaporated. The product was collected as a red solid. (10.1 g, Yield-52%). H1 NMR (400 MHz, CDCl3): 3.09 (s, 3H), 3.23 (s, 6H), 4.01 (q, 2H), 7.65-7.77 (m, 2H), 8.03 (d, 1H), 8.08 (d, 1H).


In a process analogous to Example D1 using appropriate dichloro naphthoquinone derivatives (Example C) and corresponding secondary amine, the following compounds are prepared.

ExampleChemical NameD22-Chloro-N-(3-dimethylamino-1,4-dioxo-1,4-dihydro-naphthalen-2-yl)-acetamideD32-Chloro-N-(3-dimethylamino-1,4-dioxo-1,4-dihydro-naphthalen-2-yl)-propionamideD42-Chloro-N-(3-dimethylamino-1,4-dioxo-1,4-dihydro-naphthalen-2-yl)-2-phenyl-acetamideD52-Chloro-N-(3-dimethylamino-1,4-dioxo-1,4-dihydro-naphthalen-2-yl)-N-methyl-propionamideD62-Chloro-N-(3-dimethylamino-1,4-dioxo-1,4-dihydro-naphthalen-2-yl)-N-methyl-2-phenyl-acetamide


EXAMPLE 2 (COMPOUND 1, TABLE 2)

2-Diethylamino-N-(3-dimethylamino-1,4-dioxo-1,4-dihydro-naphthalen-2-yl)-N-methyl-acetamide
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To a solution of 0.54 g of 2-chloro-N-(3-dimethylamino-1,4-dioxo-1,4-dihydro -naphthalen-2-yl)-N-methyl-acetamide (1.8 mmol) in 20 mL of ethyl acetate was added 2.2 mL of ethylamine (21.6 mmol, 12 equiv). The mixture was stirred at room temperature for two hours. The reaction mixture was then filtered and the solid was washed with ethyl acetate until all red material was dissolved. The red filtrate was concentrated and purified on a normal phase column chromatography using ethyl acetate. The pure fractions were combined and concentrated. The solid was then dissolved in 20 mL of DCM and 12 equiv of 1.0M HCl in diethyl ether was added to produce hydrochloride salt. Organic solvents were evaporated and the product was dissolved in 5.0 mL of HPLC grade water. This material was freeze dried to give 0.42 g of final product as its hydrochloride salt. (Yield 62%). H1 NMR (400 MHz, DMSO, D20) 1.14 (t, 6H), 2.97 (s, 3H), 3.08-3.0 (m, 10H), 3.80 (d, 1H), 4.02 (d, 1H), 7.7-7.9 (m, 2H), 7.89-8.0 (m, 2H).


Compounds 2-119 (Table 2)


In a process analogous to Example 2 using appropriate chloro naphthoquinone (Example D) and the corresponding secondary amine, following compounds are prepared as shown in Table 2.

TABLE 1embedded imageCmpdR1R2embedded imageembedded imageMW1CH3Hembedded imageembedded image315.372HHembedded imageembedded image413.473HCH3embedded imageembedded image395.504HCH3embedded imageembedded image427.505HHembedded imageembedded image571.596HHembedded imageembedded image467.527HCH3embedded imageembedded image481.558HCH3embedded imageembedded image585.629CH3Hembedded imageembedded image551.6510CH3Hembedded imageembedded image511.5711CH3Hembedded imageembedded image429.5612CH3Hembedded imageembedded image481.5513CH3Hembedded imageembedded image395.5014CH3Hembedded imageembedded image399.4515CH3Hembedded imageembedded image427.5016CH3Hembedded imageembedded image585.6217CH3Hembedded imageembedded image593.7618CH3Hembedded imageembedded image399.4319CH3Hembedded imageembedded image435.4720CH3Hembedded imageembedded image427.4921CH3Hembedded imageembedded image553.6122CH3Hembedded imageembedded image527.6123CH3Hembedded imageembedded image511.5624CH3Hembedded imageembedded image499.5525CH3Hembedded imageembedded image375.4126CH3Hembedded imageembedded image483.5127CH3Hembedded imageembedded image455.4628CH3Hembedded imageembedded image497.5829CH3Hembedded imageembedded image551.6430CH3Hembedded imageembedded image619.7531CH3Hembedded imageembedded image481.5432CH3Hembedded imageembedded image491.5833CH3Hembedded imageembedded image491.5734CH3Hembedded imageembedded image483.6835CH3Hembedded imageembedded image339.3836CH3Hembedded imageembedded image549.6637CH3Hembedded imageembedded image593.7538CH3Hembedded imageembedded image515.5939CH3Hembedded imageembedded image597.7040CH3Hembedded imageembedded image537.6541CH3Hembedded imageembedded image533.7042CH3Hembedded imageembedded image611.6843CH3Hembedded imageembedded image635.7944CH3Hembedded imageembedded image561.7645CH3Hembedded imageembedded image517.5846CH3Hembedded imageembedded image687.6347CH3Hembedded imageembedded image545.6348CH3Hembedded imageembedded image663.8449CH3Hembedded imageembedded image497.5850CH3Hembedded imageembedded image467.5651CH3Hembedded imageembedded image763.8852CH3Hembedded imageembedded image429.5653CH3Hembedded imageembedded image581.7554CH3Hembedded imageembedded image567.6855CH3Hembedded imageembedded image689.4256CH3Hembedded imageembedded image682.5957CH3Hembedded imageembedded image798.8058CH3Hembedded imageembedded image791.9359CH3Hembedded imageembedded image551.7260CH3Hembedded imageembedded image647.8061CH3Hembedded imageembedded image729.9162CH3Hembedded imageembedded image665.7363CH3Hembedded imageembedded image577.7164CH3Hembedded imageembedded image523.6665CH3Hembedded imageembedded image611.6866CH3Hembedded imageembedded image371.4767CH3Hembedded imageembedded image403.3868CH3Hembedded imageembedded image397.4769HCH3embedded imageembedded image399.4370HCH3embedded imageembedded image435.4771HCH3embedded imageembedded image427.4972HCH3embedded imageembedded image553.6173HCH3embedded imageembedded image527.6174HCH3embedded imageembedded image511.5675HCH3embedded imageembedded image499.5576HCH3embedded imageembedded image375.4177HCH3embedded imageembedded image483.5178HCH3embedded imageembedded image455.4679HCH3embedded imageembedded image497.5880HCH3embedded imageembedded image551.6481HCH3embedded imageembedded image619.7582HCH3embedded imageembedded image481.5483HCH3embedded imageembedded image491.5884HCH3embedded imageembedded image491.5785HCH3embedded imageembedded image483.6886HCH3embedded imageembedded image339.3887HCH3embedded imageembedded image549.6688HCH3embedded imageembedded image593.7589HCH3embedded imageembedded image515.5990HCH3embedded imageembedded image597.7091HCH3embedded imageembedded image537.6592HCH3embedded imageembedded image533.7093HCH3embedded imageembedded image611.6894HCH3embedded imageembedded image635.7995HCH3embedded imageembedded image561.7696HCH3embedded imageembedded image517.5897HCH3embedded imageembedded image687.6398HCH3embedded imageembedded image545.6399HCH3embedded imageembedded image663.84100HCH3embedded imageembedded image497.58101HCH3embedded imageembedded image467.56102HCH3embedded imageembedded image763.88103HCH3embedded imageembedded image581.75104HCH3embedded imageembedded image567.68105HCH3embedded imageembedded image689.42106HCH3embedded imageembedded image682.59107HCH3embedded imageembedded image798.80108HCH3embedded imageembedded image791.93109HCH3embedded imageembedded image551.72110HCH3embedded imageembedded image647.80111HCH3embedded imageembedded image729.91112HCH3embedded imageembedded image665.73113HCH3embedded imageembedded image577.71114HCH3embedded imageembedded image523.66115HCH3embedded imageembedded image611.68116HCH3embedded imageembedded image371.47117HCH3embedded imageembedded image403.38118HCH3embedded imageembedded image397.47119HHembedded imageembedded image385.42









TABLE 2















embedded image























Cmpd
R1
R2


embedded image


MW





















1
CH3
H


embedded image


343.44





2
H
H


embedded image


357.42





3
H
CH3


embedded image


355.45





4
H
CH3


embedded image


371.45





5
H
H


embedded image


436.48





6
H
H


embedded image


384.44





7
H
CH3


embedded image


398.47





8
H
CH3


embedded image


450.50





9
CH3
H


embedded image


433.52





10
CH3
H


embedded image


413.48





11
CH3
H


embedded image


372.48





12
CH3
H


embedded image


398.47





13
CH3
H


embedded image


355.45





14
CH3
H


embedded image


357.42





15
CH3
H


embedded image


371.45





16
CH3
H


embedded image


450.50





17
CH3
H


embedded image


454.58





18
CH3
H


embedded image


357.42





19
CH3
H


embedded image


375.43





20
CH3
H


embedded image


371.45





21
CH3
H


embedded image


434.51





22
CH3
H


embedded image


421.50





23
CH3
H


embedded image


413.48





24
CH3
H


embedded image


407.48





25
CH3
H


embedded image


345.41





26
CH3
H


embedded image


399.46





27
CH3
H


embedded image


385.43





28
CH3
H


embedded image


406.49





29
CH3
H


embedded image


433.52





30
CH3
H


embedded image


467.57





31
CH3
H


embedded image


398.47





32
CH3
H


embedded image


403.49





33
CH3
H


embedded image


403.49





34
CH3
H


embedded image


399.54





35
CH3
H


embedded image


327.39





36
CH3
H


embedded image


432.53





37
CH3
H


embedded image


454.58





38
CH3
H


embedded image


415.50





39
CH3
H


embedded image


456.55





40
CH3
H


embedded image


426.52





41
CH3
H


embedded image


424.55





42
CH3
H


embedded image


463.54





43
CH3
H


embedded image


475.60





44
CH3
H


embedded image


438.58





45
CH3
H


embedded image


416.49





46
CH3
H


embedded image


501.52





47
CH3
H


embedded image


430.51





48
CH3
H


embedded image


489.62





49
CH3
H


embedded image


406.49





50
CH3
H


embedded image


391.48





51
CH3
H


embedded image


539.64





52
CH3
H

372.48





53
CH3
H


embedded image


448.57





54
CH3
H


embedded image


441.54





55
CH3
H


embedded image


502.41





56
CH3
H


embedded image


498.99





57
CH3
H


embedded image


557.10





58
CH3
H


embedded image


553.66





59
CH3
H


embedded image


433.56





60
CH3
H


embedded image


481.60





61
CH3
H


embedded image


522.65





62
CH3
H


embedded image


490.57





63
CH3
H


embedded image


446.56





64
CH3
H


embedded image


419.53





65
CH3
H


embedded image


463.54





66
CH3
H


embedded image


315.38





67
CH3
H


embedded image


359.39





68
CH3
H


embedded image


356.43





69
H
CH3


embedded image


357.42





70
H
CH3


embedded image


375.43





71
H
CH3


embedded image


371.45





72
H
CH3


embedded image


434.51





73
H
CH3


embedded image


421.50





74
H
CH3


embedded image


413.48





75
H
CH3


embedded image


407.48





76
H
CH3


embedded image


345.41





77
H
CH3


embedded image


399.46





78
H
CH3


embedded image


385.43





79
H
CH3


embedded image


406.49





80
H
CH3


embedded image


433.52





81
H
CH3


embedded image


467.57





82
H
CH3


embedded image


398.47





83
H
CH3


embedded image


403.49





84
H
CH3


embedded image


403.49





85
H
CH3


embedded image


399.54





86
H
CH3


embedded image


327.39





87
H
CH3


embedded image


432.53





88
H
CH3


embedded image


454.58





89
H
CH3


embedded image


415.50





90
H
CH3


embedded image


456.55





91
H
CH3


embedded image


426.52





92
H
CH3

424.55





93
H
CH3


embedded image


463.54





94
H
CH3


embedded image


475.60





95
H
CH3


embedded image


438.58





96
H
CH3


embedded image


416.49





97
H
CH3


embedded image


501.52





98
H
CH3


embedded image


430.51





99
H
CH3


embedded image


489.62





100
H
CH3


embedded image


406.49





101
H
CH3


embedded image


391.48





102
H
CH3


embedded image


539.64





103
H
CH3


embedded image


448.57





104
H
CH3


embedded image


441.54





105
H
CH3


embedded image


502.41





106
H
CH3


embedded image


498.99





107
H
CH3


embedded image


557.10





108
H
CH3


embedded image


553.66





109
H
CH3


embedded image


433.56





110
H
CH3


embedded image


481.60





111
H
CH3


embedded image


522.65





112
H
CH3


embedded image


490.57





113
H
CH3


embedded image


446.56





114
H
CH3


embedded image


419.53





115
H
CH3


embedded image


463.54





116
H
CH3


embedded image


343.44





117
H
CH3


embedded image


359.39





118
H
CH3


embedded image


356.43





119
H
H


embedded image


343.39
















TABLE 3















embedded image





















Cmpd


embedded image




embedded image


MW



















1


embedded image




embedded image


343.42





2


embedded image




embedded image


357.45





3


embedded image




embedded image


399.53





4


embedded image




embedded image


357.45





5


embedded image




embedded image


383.48





6


embedded image




embedded image


397.51





7


embedded image




embedded image


439.59





8


embedded image




embedded image


397.51





9


embedded image




embedded image


385.46





10


embedded image




embedded image


399.48





11


embedded image




embedded image


441.56





12


embedded image




embedded image


399.48





13


embedded image




embedded image


431.53





14


embedded image




embedded image


445.55





15


embedded image




embedded image


487.63





16


embedded image




embedded image


445.55





17


embedded image




embedded image


400.51





18


embedded image




embedded image


414.54





19


embedded image




embedded image


456.62





20


embedded image




embedded image


414.54





21


embedded image




embedded image


434.53





22


embedded image




embedded image


448.56





23


embedded image




embedded image


490.64





24


embedded image




embedded image


448.56
















TABLE 4















embedded image





















Cmpd


embedded image




embedded image


MW



















1


embedded image




embedded image


357.45





2


embedded image




embedded image


371.47





3


embedded image




embedded image


413.55





4


embedded image




embedded image


371.47





5


embedded image




embedded image


397.51





6


embedded image




embedded image


411.54





7


embedded image




embedded image


453.62





8


embedded image




embedded image


411.54





9


embedded image




embedded image


399.48





10


embedded image




embedded image


413.51





11


embedded image




embedded image


455.59





12


embedded image




embedded image


413.51





13


embedded image




embedded image


445.55





14


embedded image




embedded image


459.58





15


embedded image




embedded image


501.66





16


embedded image




embedded image


ethylamine





17


embedded image




embedded image


414.54





18


embedded image




embedded image


428.57





19


embedded image




embedded image


470.65





20


embedded image




embedded image


428.57





21


embedded image




embedded image


448.56





22


embedded image




embedded image


462.58





23


embedded image




embedded image


504.66





24


embedded image




embedded image


462.58
















TABLE 5















embedded image





















Cpmd


embedded image




embedded image


MW



















1


embedded image




embedded image


385.50





2


embedded image




embedded image


399.53





3


embedded image




embedded image


441.61





4


embedded image




embedded image


399.53





5


embedded image




embedded image


425.56





6


embedded image




embedded image


439.59





7


embedded image




embedded image


481.67





8


embedded image




embedded image


439.59





9


embedded image




embedded image


427.54





10


embedded image




embedded image


441.56





11


embedded image




embedded image


483.64





12


embedded image




embedded image


441.56





13


embedded image




embedded image


473.6





14


embedded image




embedded image


487.63





15


embedded image




embedded image


529.71





16


embedded image




embedded image


487.63





17


embedded image




embedded image


442.59





18


embedded image




embedded image


456.62





19


embedded image




embedded image


498.7





20


embedded image




embedded image


456.62





21


embedded image




embedded image


476.61





22


embedded image




embedded image


490.64





23


embedded image




embedded image


532.72





24


embedded image




embedded image


490.64
















TABLE 6















embedded image





















Cmpd


embedded image




embedded image


MW



















1


embedded image




embedded image


385.50





2


embedded image




embedded image


399.53





3


embedded image




embedded image


441.61





4


embedded image




embedded image


399.53





5


embedded image




embedded image


425.56





6


embedded image




embedded image


439.59





7


embedded image




embedded image


481.67





8


embedded image




embedded image


439.59





9


embedded image




embedded image


427.54





10


embedded image




embedded image


441.56





11


embedded image




embedded image


483.64





12


embedded image




embedded image


441.56





13


embedded image




embedded image


473.6





14


embedded image




embedded image


487.63





15


embedded image




embedded image


529.71





16


embedded image




embedded image


487.63





17


embedded image




embedded image


442.59





18


embedded image




embedded image


456.62





19


embedded image




embedded image


498.7





20


embedded image




embedded image


456.62





21


embedded image




embedded image


476.61





22


embedded image




embedded image


490.64





23


embedded image




embedded image


532.72





24


embedded image




embedded image


490.64
















TABLE 7















embedded image

























Cmpd
R1
R2


embedded image




embedded image


MW























1
CH3
H


embedded image




embedded image


375.42





2
CH3
H


embedded image




embedded image


489.61





3
CH3
H


embedded image




embedded image


551.63





4
CH3
H


embedded image




embedded image


459.49





5
CH3
H


embedded image




embedded image


541.60





6
H
CH3


embedded image




embedded image


375.42





7
H
CH3


embedded image




embedded image


489.61





8
H
CH3


embedded image




embedded image


551.63





9
H
CH3


embedded image




embedded image


459.49





10
H
CH3


embedded image




embedded image


541.60
















TABLE 8















embedded image























Cmpd
R1
R2


embedded image


MW





















1
CH3
H


embedded image


375.42





2
CH3
H


embedded image


432.51





3
CH3
H


embedded image


463.52





4
CH3
H


embedded image


417.45





5
CH3
H


embedded image


458.51





6
H
CH3


embedded image


375.42





7
H
CH3


embedded image


432.51





8
H
CH3


embedded image


463.52





9
H
CH3


embedded image


417.45





10
H
CH3


embedded image


458.51
















TABLE 9















embedded image

























Cmpd
R1
R2


embedded image




embedded image


MW























1
CH3
H


embedded image




embedded image


316.35





2
CH3
H


embedded image




embedded image


430.54





3
CH3
H


embedded image




embedded image


492.57





4
CH3
H


embedded image




embedded image


400.43





5
CH3
H


embedded image




embedded image


482.53





6
H
CH3


embedded image




embedded image


316.35





7
H
CH3


embedded image




embedded image


430.54





8
H
CH3


embedded image




embedded image


492.57





9
H
CH3


embedded image




embedded image


400.43





10
H
CH3


embedded image




embedded image


482.53
















TABLE 10















embedded image























Cmpd
R1
R2


embedded image


MW





















1
CH3
H


embedded image


316.35





2
CH3
H


embedded image


373.45





3
CH3
H


embedded image


404.46





4
CH3
H


embedded image


358.39





5
CH3
H


embedded image


399.44





6
H
CH3


embedded image


316.35





7
H
CH3


embedded image


373.45





8
H
CH3


embedded image


404.46





9
H
CH3


embedded image


358.39





10
H
CH3


embedded image


399.44
















TABLE 11















embedded image

























Cmpd
R1
R2


embedded image




embedded image


MW























1
CH3
H


embedded image




embedded image


316.35





2
CH3
H


embedded image




embedded image


430.54





3
CH3
H


embedded image




embedded image


492.57





4
CH3
H


embedded image




embedded image


400.43





5
CH3
H


embedded image




embedded image


482.53





6
H
CH3


embedded image




embedded image


316.35





7
H
CH3


embedded image




embedded image


430.54





8
H
CH3


embedded image




embedded image


492.57





9
H
CH3


embedded image




embedded image


400.43





10
H
CH3


embedded image




embedded image


482.53
















TABLE 12















embedded image























Cmpd
R1
R2


embedded image


MW





















1
CH3
H


embedded image


316.35





2
CH3
H


embedded image


373.45





3
CH3
H


embedded image


404.46





4
CH3
H


embedded image


358.39





5
CH3
H


embedded image


399.44





6
H
CH3


embedded image


316.35





7
H
CH3


embedded image


373.45





8
H
CH3


embedded image


404.46





9
H
CH3


embedded image


358.39





10
H
CH3


embedded image


399.44
















TABLE 13















embedded image

























Cmpd
R1
R2


embedded image




embedded image


MW























1
CH3
H


embedded image




embedded image


349.45





2
CH3
H


embedded image




embedded image


463.64





3
CH3
H


embedded image




embedded image


525.66





4
CH3
H


embedded image




embedded image


433.52





5
CH3
H


embedded image




embedded image


515.63





6
H
CH3


embedded image




embedded image


349.45





7
H
CH3


embedded image




embedded image


463.64





8
H
CH3


embedded image




embedded image


525.66





9
H
CH3


embedded image




embedded image


433.52





10
H
CH3


embedded image




embedded image


515.63
















TABLE 14















embedded image























Cmpd
R1
R2


embedded image


MW





















1
CH3
H


embedded image


349.45





2
CH3
H


embedded image


406.54





3
CH3
H


embedded image


437.55





4
CH3
H


embedded image


391.48





5
CH3
H


embedded image


432.54





6
H
CH3


embedded image


349.45





7
H
CH3


embedded image


406.54





8
H
CH3


embedded image


437.55





9
H
CH3


embedded image


391.48





10
H
CH3


embedded image


432.54
















TABLE 15















embedded image

























Cmpd
R1
R2


embedded image




embedded image


MW























1
CH3
H


embedded image




embedded image


349.45





2
CH3
H


embedded image




embedded image


463.64





3
CH3
H


embedded image




embedded image


525.66





4
CH3
H


embedded image




embedded image


433.52





5
CH3
H


embedded image




embedded image


515.63





6
H
CH3


embedded image




embedded image


349.45





7
H
CH3


embedded image




embedded image


463.64





8
H
CH3


embedded image




embedded image


525.66





9
H
CH3


embedded image




embedded image


433.52





10
H
CH3


embedded image




embedded image


515.63
















TABLE 16















embedded image























Cmpd
R1
R2


embedded image


MW





















1
CH3
H


embedded image


349.45





2
CH3
H


embedded image


406.54





3
CH3
H


embedded image


437.55





4
CH3
H


embedded image


391.48





5
CH3
H


embedded image


432.54





6
H
CH3


embedded image


349.45





7
H
CH3


embedded image


406.54





8
H
CH3


embedded image


437.55





9
H
CH3


embedded image


391.48





10
H
CH3


embedded image


432.54
















TABLE 17















embedded image

























Cmpd
R1
R2


embedded image




embedded image


MW























1
CH3
H


embedded image




embedded image


317.34





2
CH3
H


embedded image




embedded image


431.53





3
CH3
H


embedded image




embedded image


493.55





4
CH3
H


embedded image




embedded image


401.42





5
CH3
H


embedded image




embedded image


483.52





6
H
CH3


embedded image




embedded image


317.34





7
H
CH3


embedded image




embedded image


431.53





8
H
CH3


embedded image




embedded image


493.55





9
H
CH3


embedded image




embedded image


401.42





10
H
CH3


embedded image




embedded image


483.52
















TABLE 18















embedded image























Cmpd
R1
R2


embedded image


MW





















1
CH3
H


embedded image


317.34





2
CH3
H


embedded image


374.44





3
CH3
H


embedded image


405.45





4
CH3
H


embedded image


359.38





5
CH3
H


embedded image


400.43





6
H
CH3


embedded image


317.34





7
H
CH3


embedded image


374.44





8
H
CH3


embedded image


405.45





9
H
CH3


embedded image


359.38





10
H
CH3


embedded image


400.43


















TABLE 19








Gene
Gene



No.
Identifier
Gene Name

















1
XM_011929
RTP801


2
NM_004864
prostate differentiation factor


3
NM_001657
amphiregulin (schwannoma-derived growth factor)


4
XM_033762
GRB10


5
NM_004083
DNA-damage-inducible transcript 3


6
XM_009097
PPP1R15A


7
NM_005542
insulin induced gene 1


8
XM_032884
MGC11324


9
XM_052673
VEGF


10
NM_007235
exportin, tRNA (nuclear export receptor for tRNAs)


11
NM_000179
mutS homolog 6 (E. coli)


12
NM_005194
CCAAT/enhancer binding protein (C/EBP), beta


13
XM_043412
CDKN1A


14
NM_004448
v-erb-b2 erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma de


15
NM_004526
MCM2 minichromosome maintenance deficient 2, mitotin (S. cerevisiae)


16
XM_035627
UHRF1


17
L24498
GADD45A


18
NM_005915
MCM6 minichromosome maintenance deficient 6 (MIS5 homolog, S. pombe) (S. cerevis


19
NM_004642
CDK2-associated protein 1


20
NM_004629
Fanconi anemia, complementation group G


21
NM_022119
protease, serine, 22


22
XM_002003
STMN1


23
NM_014736
KIAA0101 gene product


24
NM_002691
polymerase (DNA directed), delta 1, catalytic subunit 125 kDa


25
XM_034901
MSH2


26
XM_001284
MDM4


27
XM_018276
FLJ13782


28
NM_004707
APG12 autophagy 12-like (S. cerevisiae)


29
NM_004836
eukaryotic translation initiation factor 2-alpha kinase 3


30
XM_008618
CBX4


31
NM_003504
CDC45 cell division cycle 45-like (S. cerevisiae)


32
XM_002242
HAT1


33
NM_014331
solute carrier family 7, (cationic amino acid transporter, y + system) member 11


34
NM_003467
chemokine (C-X-C motif) receptor 4


35
XM_002899
CDC25A


36
NM_006349
putative cyclin G1 interacting protein


37
XM_056035
PCNA


38
XM_003511
EREG


39
XM_031515
RAD51


40
XM_017925
EIF4E


41
NM_001799
cyclin-dependent kinase 7 (MO15 homolog, Xenopus laevis, cdk-activating kinase)


42
NM_004990
methionine-tRNA synthetase


43
NM_057749
cyclin E2


44
NM_001540
heat shock 27 kDa protein 1


45
NM_005882
macrophage erythroblast attacher


46
XM_047059
SUV39H1


47
NM_006156
neural precursor cell expressed, developmentally down-regulated 8


48
NM_016395
butyrate-induced transcript 1


49
XM_012472
NPIP


50
NM_018518
MCM10 minichromosome maintenance deficient 10 (S. cerevisiae)


51
NM_000194
hypoxanthine phosphoribosyltransferase 1 (Lesch-Nyhan syndrome)


52
NM_002359
v-maf musculoaponeurotic fibrosarcoma oncogene homolog G (avian)


53
XM_001589
DVL1


54
NM_003276
thymopoietin


55
XM_040103
DLC1


56
XM_010272
RBBP7


57
NM_001226
caspase 6, apoptosis-related cysteine protease


58
NM_013376
CDK4-binding protein p34SEI1


59
NM_001196
BH3 interacting domain death agonist


60
AF317391
BCL-6 interacting corepressor


61
NM_002435
mannose phosphate isomerase


62
NM_003503
CDC7 cell division cycle 7-like 1 (S. cerevisiae)


63
NM_001168
baculoviral IAP repeat-containing 5 (survivin)


64
XM_036462
ACLY


65
XM_009643
RBL1


66
NM_001424
epithelial membrane protein 2


67
AK057120
high-mobility group box 1


68
XM_051677
CDKN3


69
NM_001379
DNA (cytosine-5-)-methyltransferase 1


70
XM_001668
PDZK1


71
NM_001967
eukaryotic translation initiation factor 4A, isoform 2


72
XM_050297
XRCC3


73
NM_004428
ephrin-A1


74
AB037790
heme-regulated initiation factor 2-alpha kinase


75
NM_007306
breast cancer 1, early onset


76
NM_004336
BUB1 budding uninhibited by benzimidazoles 1 homolog (yeast)


77
NM_031844
heterogeneous nuclear ribonucleoprotein U (scaffold attachment factor A)


78
XM_002943
POLQ


79
D21262
nucleolar and coiled-body phosphoprotein 1


80
XM_056165
YWHAH


81
NM_006609
mitogen-activated protein kinase kinase kinase 2


82
NM_013258
apoptosis-associated speck-like protein containing a CARD


83
NM_024602
hypothetical protein FLJ21156


84
NM_005080
X-box binding protein 1


85
NM_004050
BCL2-like 2


86
NM_014454
p53 regulated PA26 nuclear protein


87
W28438
chromosome 14 open reading frame 78


88
XM_008802
RBBP8


89
XM_053627
FGF4


90
NM_006727
cadherin 10, type 2 (T2-cadherin)


91
NM_005980
S100 calcium binding protein P


92
XM_050665
FH


93
NM_000432
myosin, light polypeptide 2, regulatory, cardiac, slow


94
D16815
nuclear receptor subfamily 1, group D, member 2


95
XM_044825
SUPT3H


96
NM_058179
phosphoserine aminotransferase


97
XM_018112
RBBP4


98
NM_020386
HRAS-like suppressor


99
AK057758
insulin receptor substrate 3-like


100
XM_044111
RIT1


101
NM_004313
arrestin, beta 2


102
L26584
Ras protein-specific guanine nucleotide-releasing factor 1


103
NM_005414
SKI-like


104
XM_031603
BUB1B


105
XM_015963
SDFR1


106
NM_002415
macrophage migration inhibitory factor (glycosylation-inhibiting factor)


107
NM_078487
cyclin-dependent kinase inhibitor 2B (p15, inhibits CDK4)


108
XM_047707
KIAA1265


109
NM_001065
tumor necrosis factor receptor superfamily, member 1A


110
XM_045104
LGALS3BP


111
AI053741

Homo sapiens, clone IMAGE: 4826963, mRNA



112
NM_003600
serine/threonine kinase 6


113
NM_012112
chromosome 20 open reading frame 1


114
NM_000387
solute carrier family 25 (carnitine/acylcarnitine translocase), member 20


115
NM_005587
MADS box transcription enhancer factor 2, polypeptide A (myocyte enhancer factor


116
NM_001892
casein kinase 1, alpha 1


117
NM_016277
RAB23, member RAS oncogene family


118
NM_003094
small nuclear ribonucleoprotein polypeptide E


119
NM_006623
phosphoglycerate dehydrogenase


120
NM_005441
chromatin assembly factor 1, subunit B (p60)


121
NM_002659
plasminogen activator, urokinase receptor


122
NM_000057
Bloom syndrome


123
NM_001202
bone morphogenetic protein 4


124
NM_003289
tropomyosin 2 (beta)


125
XM_003325
CCNA2


126
XM_032813
HUMGT198A


127
NM_006403
enhancer of filamentation 1


128
NM_006289
talin 1


129
NM_003405
tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, eta poly


130
NM_000368
tuberous sclerosis 1


131
BC008826
PAX3


132
NM_003908
eukaryotic translation initiation factor 2, subunit 2 beta, 38 kDa


133
NM_004282
BCL2-associated athanogene 2


134
XM_010777
ICAP-1A


135
XM_034350
ANXA3


136
NM_004965
high-mobility group nucleosome binding domain 1


137
NM_001216
carbonic anhydrase IX


138
NM_006325
RAN, member RAS oncogene family


139
NM_006516
solute carrier family 2 (facilitated glucose transporter), member 1


140
NM_003657
breast carcinoma amplified sequence 1


141
NM_004417
dual specificity phosphatase 1


142
M94362
LMNB2


143
XM_057994
SDHA


144
XM_043451
PIM1


145
NM_021005
nuclear receptor subfamily 2, group F, member 2


146
XM_049928
CARD14


147
AA017553
ESTs


148
NM_004905
antioxidant protein 2


149
NM_001274
CHK1 checkpoint homolog (S. pombe)


150
NM_002483
carcinoembryonic antigen-related cell adhesion molecule 6 (non-specific cross re


151
XM_045049
TNFSF10


152
XM_007770
FLJ20171


153
NM_015926
putative secreted protein ZSIG11


154
NM_005348
heat shock 90 kDa protein 1, alpha


155
NM_003567
breast cancer anti-estrogen resistance 3


156
NM_002507
nerve growth factor receptor (TNFR superfamily, member 16)


157
XM_029216
APEX2


158
NM_005654
nuclear receptor subfamily 2, group F, member 1


159
XM_009873
MMP11


160
NM_002105
H2A histone family, member X


161
NM_001827
CDC28 protein kinase regulatory subunit 2


162
XM_050486
NOC4


163
XM_015513
SNRPG


164
AB037759
eukaryotic translation initiation factor 2 alpha kinase 4


165
NM_000122
excision repair cross-complementing rodent repair deficiency, complementation gr


166
NM_006218
phosphoinositide-3-kinase, catalytic, alpha polypeptide


167
NM_003127
spectrin, alpha, non-erythrocytic 1 (alpha-fodrin)


168
NM_031265
mucin and cadherin-like


169
NM_016531
Kruppel-like factor 3 (basic)


170
NM_002629
phosphoglycerate mutase 1 (brain)


171
NM_003152
signal transducer and activator of transcription 5A


172
NM_002037
FYN oncogene related to SRC, FGR, YES


173
NM_002607
platelet-derived growth factor alpha polypeptide


174
XM_003560
MAD2L1


175
NM_052888
KIAA0563-related gene


176
NM_001348
death-associated protein kinase 3


177
NM_003883
histone deacetylase 3


178
NM_001659
ADP-ribosylation factor 3


179
NM_033379
CDC2


180
XM_031718
EHD4


181
NM_014977
apoptotic chromatin condensation inducer in the nucleus


182
NM_006570
Ras-related GTP-binding protein


183
NM_002466
v-myb myeloblastosis viral oncogene homolog (avian)-like 2


184
NM_001949
E2F transcription factor 3


185
XM_018149
SELT


186
NM_013277
Rac GTPase activating protein 1


187
NM_014060
MCT-1 protein


188
NM_003684
MAP kinase-interacting serine/threonine kinase 1


189
NM_031966
cyclin B1


190
XM_012601
MNT


191
NM_005657
tumor protein p53 binding protein, 1


192
XM_051583
RAF1


193
NM_001255
CDC20 cell division cycle 20 homolog (S. cerevisiae)


194
NM_030808
LIS1-interacting protein NUDEL; endooligopeptidase A


195
NM_032989
BCL2-antagonist of cell death


196
XM_011577
STK17A


197
NM_003925
methyl-CpG binding domain protein 4


198
NM_016587
chromobox homolog 3 (HP1 gamma homolog, Drosophila)


199
NM_006870
destrin (actin depolymerizing factor)


200
XM_008313
LOC146870


201
NM_006812
amplified in osteosarcoma


202
NM_003183
a disintegrin and metalloproteinase domain 17 (tumor necrosis factor, alpha, con


203
XM_052798
CDC25C


204
NM_002626
phosphofructokinase, liver


205
NM_033292
caspase 1, apoptosis-related cysteine protease (interleukin 1, beta, convertase)


206
XM_006961
CHD4


207
NM_000269
non-metastatic cells 1, protein (NM23A) expressed in


208
NM_004873
BCL2-associated athanogene 5


209
NM_001034
ribonucleotide reductase M2 polypeptide


210
NM_003070
SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subf


211
NM_006595
apoptosis inhibitor 5


212
XM_040402
CPNE3


213
NM_007111
transcription factor Dp-1


214
NM_003597
TGFB inducible early growth response 2


215
NM_002741
protein kinase C-like 1


216
NM_021138
TNF receptor-associated factor 2


217
XM_054954
CCNF


218
NM_003879
CASP8 and FADD-like apoptosis regulator


219
NM_002089
chemokine (C-X-C motif) ligand 2


220
BC018118
Rho GTPase activating protein 1


221
XM_007070
TBC1D4


222
NM_032094
protocadherin gamma subfamily A, 12


223
NM_003472
DEK oncogene (DNA binding)


224
XM_036063
LOC204666


225
XM_006197
E2IG4


226
NM_002198
interferon regulatory factor 1


227
NM_003639
inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma


228
XM_010826
LOC150584


229
NM_006393
nebulette


230
NM_020436
sal-like 4 (Drosophila)


231
XM_038427
FES


232
NM_032984
caspase 2, apoptosis-related cysteine protease (neural precursor cell expressed,


233
NM_002093
glycogen synthase kinase 3 beta


234
XM_043782
E2F4


235
XM_058230
JUND


236
XM_071388
PPFIA2


237
XM_056931
B3GNT1


238
NM_002357
MAX dimerization protein 1


239
NM_024320
hypothetical protein MGC11242


240
NM_006763
BTG family, member 2


241
NM_000244
multiple endocrine neoplasia I


242
XM_017741
FSCN1


243
W02608
ESTs, Weakly similar to hypothetical protein FLJ20378 [Homo sapiens] [H. sapiens


244
XM_044910
SNRPB


245
NM_033339
caspase 7, apoptosis-related cysteine protease


246
NM_001712
carcinoembryonic antigen-related cell adhesion molecule 1 (biliary glycoprotein)


247
NM_031993
protocadherin gamma subfamily A, 1


248
NM_002616
period homolog 1 (Drosophila)


249
XM_001357
MYCBP


250
NM_031295
Williams Beuren syndrome chromosome region 21


251
NM_001110
a disintegrin and metalloproteinase domain 10


252
NM_004359
cell division cycle 34


253
NM_003667
G protein-coupled receptor 49


254
XM_027651
TNFRSF10B


255
NM_012165
F-box and WD-40 domain protein 3


256
XM_009475
AHCY


257
XM_035145
LXN


258
NM_000365
TPI1


259
NM_003994
KIT ligand


260
NM_004341
carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase


261
XM_039754
RAB10


262
AF346509
NFAT5


263
XM_071453
YWHAE


264
NM_006701
similar to S. pombe dim1+


265
NM_024854
hypothetical protein FLJ22028


266
NM_004964
histone deacetylase 1


267
NM_007194
CHK2 checkpoint homolog (S. pombe)


268
NM_007168
ATP-binding cassette, sub-family A (ABC1), member 8


269
XM_033064
ST5


270
NM_003841
tumor necrosis factor receptor superfamily, member 10c, decoy without an intrace


271
XM_031287
CXCL3


272
NM_003535
H3FJ


273
U82467
tubby homolog (mouse)


274
XM_017134
BRCA2


275
NM_014784
Rho guanine nucleotide exchange factor (GEF) 11


276
NM_005438
FOS-like antigen 1


277
NM_006107
acid-inducible phosphoprotein


278
NM_012323
v-maf musculoaponeurotic fibrosarcoma oncogene homolog F (avian)


279
XM_002116
SFN


280
NM_006286
transcription factor Dp-2 (E2F dimerization partner 2)


281
XM_046643
NXT1


282
AA406526

Homo sapiens mRNA full length insert cDNA clone EUROIMAGE 2344436.



283
NM_020637
fibroblast growth factor 22


284
NM_005375
v-myb myeloblastosis viral oncogene homolog (avian)


285
NM_012466
tetraspanin TM4-B


286
XM_002636
IGFBP2


287
AB037845
Rho-GTPase activating protein 10


288
NM_005983
S-phase kinase-associated protein 2 (p45)


289
AF308602
Notch homolog 1, translocation-associated (Drosophila)


290
NM_014318
apoptosis related protein


291
NM_000207
insulin


292
XM_043799
MPZL1


293
XM_010208
PIM2


294
XM_045613
EHD1


295
NM_018948
Gene 33/Mig-6


296
XM_015547
LATS1


297
NM_014248
ring-box 1


298
NM_003558
phosphatidylinositol-4-phosphate 5-kinase, type I, beta


299
XM_033878
TIMP1


300
NM_007315
signal transducer and activator of transcription 1, 91 kDa


301
NM_000679
adrenergic, alpha-1B-, receptor


302
XM_036588
SDCCAG33


303
NM_004078
cysteine and glycine-rich protein 1


304
XM_050512
ACVR1


305
XM_028205
GLP1R


306
XM_071498
E2F6


307
AA100736
hypothetical protein DKFZp434D0215


308
NM_005253
FOS-like antigen 2


309
XM_041335
SCAP2


310
AF110908
TNF receptor-associated factor 3


311
XM_058227
ZK1


312
XM_049776
DSCAM


313
XM_045802
PXN


314
XM_058125
UBF-fl


315
NM_005385
natural killer-tumor recognition sequence


316
NM_002745
mitogen-activated protein kinase 1


317
XM_031413
TIAF1


318
NM_020249
a disintegrin-like and metalloprotease (reprolysin type) with thrombospondin typ


319
XM_046179
ID1


320
XM_007245
YY1


321
AI972873
SH3 domain binding glutamic acid-rich protein like 2


322
XM_047494
UGDH


323
NM_022161
baculoviral IAP repeat-containing 7 (livin)


324
NM_004493
hydroxyacyl-Coenzyme A dehydrogenase, type II


325
XM_009915
LIF


326
BF343776
glutathione reductase


327
NM_004725
BUB3 budding uninhibited by benzimidazoles 3 homolog (yeast)


328
XM_008855
NR2F6


329
NM_018640
neuronal specific transcription factor DAT1


330
XM_013050
BIRC4


331
XM_003222
CTNNB1


332
NM_016316
REV1-like (yeast)


333
NM_012098
angiopoietin-like 2


334
XM_058285
CD24


335
NM_004040
ras homolog gene family, member B


336
XM_043785
NOL3


337
NM_032471
protein kinase (cAMP-dependent, catalytic) inhibitor beta


338
NM_022873
interferon, alpha-inducible protein (clone IFI-6-16)


339
XM_035114
KIAA1277


340
XM_007722
CHD2


341
NM_006054
reticulon 3


342
XM_054920
KIAA0828


343
NM_001895
casein kinase 2, alpha 1 polypeptide


344
NM_032365
PRO2000


345
XM_010040
ARHGAP8


346
NM_005419
signal transducer and activator of transcription 2, 113 kDa


347
NM_003299
tumor rejection antigen (gp96) 1


348
XM_042423
EMP1


349
AF207547
LATS, large tumor suppressor, homolog 2 (Drosophila)


350
NM_002878
RAD51-like 3 (S. cerevisiae)


351
XM_010914
PCAF


352
XM_038418
PRC1


353
Z18817
heat shock 70 kDa protein 4


354
U70451
myeloid differentiation primary response gene (88)


355
NM_002957
retinoid X receptor, alpha


356
XM_046041
CCT2


357
XM_028620
HOXC9


358
XM_012894
ZNF14


359
NM_021979
heat shock 70 kDa protein 2


360
NM_005163
v-akt murine thymoma viral oncogene homolog 1


361
XM_006299
API5


362
NM_001388
developmentally regulated GTP binding protein 2


363
NM_004992
methyl CpG binding protein 2 (Rett syndrome)


364
XM_016845
HHGP


365
AK054731
tubulin, alpha 1 (testis specific)


366
XM_003628
CCNG2


367
NM_000291
phosphoglycerate kinase 1


368
XM_044653
EGFR


369
XM_046245
PIG8


370
NM_007229
protein kinase C and casein kinase substrate in neurons 2


371
NM_033637
beta-transducin repeat containing


372
XM_033862
ELK1


373
NM_000638
vitronectin (serum spreading factor, somatomedin B, complement S-protein)


374
NM_018098
epithelial cell transforming sequence 2 oncogene


375
NM_001880
activating transcription factor 2


376
NM_003122
serine protease inhibitor, Kazal type 1


377
XM_008055
COX4I1


378
XM_046881
SLC9A1


379
NM_003860
barrier to autointegration factor 1


380
XM_003029
ITGB5


381
NM_005566
lactate dehydrogenase A


382
NM_019113
fibroblast growth factor 21


383
XM_030478
SVIL


384
NM_006167
NK3 transcription factor related, locus 1 (Drosophila)


385
NM_007324
MAD, mothers against decapentaplegic homolog (Drosophila) interacting protein, r


386
NM_002342
lymphotoxin beta receptor (TNFR superfamily, member 3)


387
NM_002909
regenerating islet-derived 1 alpha (pancreatic stone protein, pancreatic thread


388
XM_041552
RAD17


389
NM_030662
mitogen-activated protein kinase kinase 2


390
NM_022333
TIA1 cytotoxic granule-associated RNA binding protein-like 1


391
XM_037682
SMARCB1


392
XM_033932
FLJ20485


393
BC002513
eukaryotic translation initiation factor 2, subunit 1 alpha, 35 kDa


394
NM_003470
ubiquitin specific protease 7 (herpes virus-associated)


395
NM_001320
casein kinase 2, beta polypeptide


396
AA527919

Homo sapiens, clone IMAGE: 5285034, mRNA



397
NM_005167
hypothetical protein MGC19531


398
XM_045642
SF1


399
XM_029816
YWHAB


400
NM_006121
keratin 1 (epidermolytic hyperkeratosis)


401
NM_004843
class I cytokine receptor


402
NM_000450
selectin E (endothelial adhesion molecule 1)


403
NM_013374
programmed cell death 6 interacting protein


404
AK024858
hypothetical protein LOC221496


405
XM_006890
ELK3


406
NM_022870
myosin, heavy polypeptide 11, smooth muscle


407
XM_033910
TCP1


408
XM_030523
MAP3K8


409
NM_003821
receptor-interacting serine-threonine kinase 2


410
XM_002633
MYCN


411
NM_002087
granulin


412
NM_007019
ubiquitin-conjugating enzyme E2C


413
AI685200
DKFZP586G1517 protein


414
XM_009203
AKT2


415
NM_013986
Ewing sarcoma breakpoint region 1


416
NM_004208
programmed cell death 8 (apoptosis-inducing factor)


417
XM_011791
LAMC3


418
NM_022746
hypothetical protein FLJ22390


419
AL042759
NADPH oxidase organizer 1


420
NM_003808
tumor necrosis factor (ligand) superfamily, member 13


421
XM_002562
VAMP5


422
NM_005923
mitogen-activated protein kinase kinase kinase 5


423
NM_001315
mitogen-activated protein kinase 14


424
NM_007022
putative tumor suppressor 101F6


425
XM_047007
PLAGL2


426
NM_005556
keratin 7


427
NM_000454
superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (adult))


428
AI886326
hypothetical protein FLJ21195 similar to protein related to DAC and cerberus


429
NM_005917
malate dehydrogenase 1, NAD (soluble)


430
NM_002835
protein tyrosine phosphatase, non-receptor type 12


431
NM_005972
pancreatic polypeptide receptor 1


432
NM_016328
GTF2I repeat domain containing 1


433
NM_000860
hydroxyprostaglandin dehydrogenase 15-(NAD)


434
NM_003882
WNT1 inducible signaling pathway protein 1


435
XM_028817
ADCY6


436
NM_000955
prostaglandin E receptor 1 (subtype EP1), 42 kDa


437
X68560
Sp3 transcription factor


438
NM_006443
putative c-Myc-responsive


439
NM_001090
ATP-binding cassette, sub-family F (GCN20), member 1


440
NM_002827
protein tyrosine phosphatase, non-receptor type 1


441
XM_034007
BCAR1


442
NM_005901
MAD, mothers against decapentaplegic homolog 2 (Drosophila)


443
NM_001963
epidermal growth factor (beta-urogastrone)


444
BM044930
neuronal guanine nucleotide exchange factor


445
NM_004701
cyclin B2


446
XM_002375
IL1F8


447
NM_001945
diphtheria toxin receptor (heparin-binding epidermal growth factor-like growth f


448
NM_000230
leptin (obesity homolog, mouse)


449
NM_001903
catenin (cadherin-associated protein), alpha 1, 102 kDa


450
NM_002220
inositol 1,4,5-trisphosphate 3-kinase A


451
NM_020384
claudin 2


452
NM_002734
protein kinase, cAMP-dependent, regulatory, type I, alpha (tissue specific extin


453
NM_020243
translocase of outer mitochondrial membrane 22 homolog (yeast)


454
NM_004380
CREB binding protein (Rubinstein-Taybi syndrome)


455
XM_044659
CSK


456
NM_002875
RAD51 homolog (RecA homolog, E. coli) (S. cerevisiae)


457
XM_033428
AK1


458
NM_005745
accessory protein BAP31


459
NM_030753
wingless-type MMTV integration site family, member 3


460
XM_034587
FLJ22174


461
NM_004920
AATK


462
NM_007065
CDC37 cell division cycle 37 homolog (S. cerevisiae)


463
NM_001239
cyclin H


464
XM_036323
TSG101


465
NM_001233
caveolin 2


466
XM_015956
CTBP2


467
XM_015505
AXL


468
NM_003749
insulin receptor substrate 2


469
XM_016033
DPF3


470
NM_004889
ATP synthase, H+ transporting, mitochondrial F0 complex, subunit f, isoform 2


471
XM_003213
NS


472
XM_033761
COBL


473
XM_047049
E2F1


474
NM_006572
guanine nucleotide binding protein (G protein), alpha 13


475
NM_006024
Tax1 (human T-cell leukemia virus type I) binding protein 1


476
NM_016245
retinal short-chain dehydrogenase/reductase 2


477
XM_010339
GPC4


478
NM_002129
high-mobility group box 2


479
NM_006565
CCCTC-binding factor (zinc finger protein)


480
AL137667
MAPK8


481
XM_050236
LENG4


482
NM_005805
26S proteasome-associated pad1 homolog


483
XM_054928
CLN8


484
NM_001350
death-associated protein 6


485
NM_016073
likely ortholog of mouse hepatoma-derived growth factor, related protein 3


486
XM_031926
NFKB2


487
NM_005085
nucleoporin 214 kDa


488
NM_003904
zinc finger protein 259


489
NM_014397
NIMA (never in mitosis gene a)-related kinase 6


490
XM_017096
ABR


491
XM_003477
FAT


492
NM_001982
v-erb-b2 erythroblastic leukemia viral oncogene homolog 3 (avian)


493
NM_006705
growth arrest and DNA-damage-inducible, gamma


494
NM_004958
FK506 binding protein 12-rapamycin associated protein 1


495
XM_004713
FLNC


496
NM_021235
epidermal growth factor receptor substrate EPS15R


497
XM_030044
CSE1L


498
AI685466
LOC90353


499
NM_003311
tumor suppressing subtransferable candidate 3


500
XM_039984
CNOT8


501
XM_001831
CYR61


502
XM_052827
CFL2


503
XM_007487
ASB2


504
XM_003405
HD


505
XM_012723
C18orf1


506
NM_005564
lipocalin 2 (oncogene 24p3)


507
XM_010767
NCKAP1


508
NM_001324
cleavage stimulation factor, 3′ pre-RNA, subunit 1, 50 kDa


509
NM_005658
TNF receptor-associated factor 1


510
NM_000168
GLI-Kruppel family member GLI3 (Greig cephalopolysyndactyly syndrome)


511
XM_027639
DKFZP434J214


512
XM_033445
SLC7A7


513
NM_000852
glutathione S-transferase pi


514
NM_002097
general transcription factor IIIA


515
NM_003243
transforming growth factor, beta receptor III (betaglycan, 300 kDa)


516
XM_003444
FGF5


517
XM_035107
BRAF


518
D55886
adenylate cyclase 5


519
NM_005633
son of sevenless homolog 1 (Drosophila)


520
AI161049
voltage-dependent calcium channel gamma subunit-like protein


521
XM_045460
CDC25B


522
AA634799

Homo sapiens cDNA: FLJ22864 fis, clone KAT02164.



523
NM_004230
endothelial differentiation, sphingolipid G-protein-coupled receptor, 5


524
XM_040912
AMN


525
XM_056595
OTOF


526
XM_054160
VMD2


527
XM_049935
CTEN


528
NM_006365
transcriptional activator of the c-fos promoter


529
XM_027186
WNT2


530
NM_001067
topoisomerase (DNA) II alpha 170 kDa


531
XM_044785
KCNJ13


532
XM_007585
TJP1


533
XM_042940
UNC5C


534
XM_037408
BAP1


535
XM_005428
1-Dec


536
NM_014452
tumor necrosis factor receptor superfamily, member 21


537
NM_006645
serologically defined colon cancer antigen 28


538
XM_031972
CNNM2


539
XM_047561
ARHA


540
XM_046191
CGI-31


541
NM_003778
UDP-Gal: betaGlcNAc beta 1,4-galactosyltransferase, polypeptide 4


542
XM_011713
COPS5


543
NM_032957
tumor necrosis factor receptor superfamily, member 6b, decoy


544
NM_006044
histone deacetylase 6


545
NM_021144
PC4 and SFRS1 interacting protein 1


546
AA531287
ESTs


547
XM_033355
ABL1


548
XM_008394
EZH1


549
XM_036570
TNFRSF12A


550
XM_031209
IL1F9


551
XM_027311
BFAR


552
NM_006166
nuclear transcription factor Y, beta


553
XM_043103
HSD11B2


554
XM_050735
ST14


555
NM_057159
endothelial differentiation, lysophosphatidic acid G-protein-coupled receptor, 2


556
NM_001702
brain-specific angiogenesis inhibitor 1


557
NM_005312
guanine nucleotide-releasing factor 2 (specific for crk proto-oncogene)


558
NM_001042
solute carrier family 2 (facilitated glucose transporter), member 4


559
L41944
interferon (alpha, beta and omega) receptor 2


560
NM_000264
patched homolog (Drosophila)


561
XM_041744
IER3


562
NM_005967
NGFI-A binding protein 2 (EGR1 binding protein 2)


563
XM_009170
CEACAM7


564
NM_004231
ATPase, H+ transporting, lysosomal 14 kDa, V1 subunit F


565
NM_004315
N-acylsphingosine amidohydrolase (acid ceramidase) 1


566
XM_008654
MAP2K4


567
XM_041847
TNF


568
XM_040448
RAD1


569
XM_011068
MST1R


570
NM_000662
N-acetyltransferase 1 (arylamine N-acetyltransferase)


571
XM_001744
TNFRSF8


572
XM_028038
BMPR2


573
NM_006534
nuclear receptor coactivator 3


574
NM_005091
peptidoglycan recognition protein


575
NM_024426
Wilms tumor 1


576
AA290601
hypothetical protein LOC137075


577
AI810669
ESTs, Moderately similar to hypothetical protein FLJ20378 [Homo sapiens] [H. sap


578
NM_003550
MAD1 mitotic arrest deficient-like 1 (yeast)


579
NM_012415
RAD54B homolog


580
XM_033469
TGFBR2


581
XM_039779
CAPRI


582
XM_049512
TRIP13


583
NM_002969
mitogen-activated protein kinase 12


584
NM_005380
neuroblastoma, suppression of tumorigenicity 1


585
XM_029490
DPH2L1


586
AL136835
Toll-interacting protein


587
XM_034567
CCND2


588
NM_032192
protein phosphatase 1, regulatory (inhibitor) subunit 1B (dopamine and cAMP regu


589
NM_000072
CD36 antigen (collagen type I receptor, thrombospondin receptor)








Claims
  • 1. A compound having the structure of Formula (I)
  • 2. The compound of claim 1 wherein W and Z are each C—R8, C—R11 or N and wherein X and Y are each C—R9 or C—R10.
  • 3. The compound of claim 1 wherein X and Y are each C—R9, C—R10 or N and wherein W and Z are each C—R8 or C—R11.
  • 4. The compound of claim 1 wherein W is C—R8 or N and wherein X, Y and Z are each C—R9, C—R10 or C—R11.
  • 5. The compound of claim 1 wherein Z is C—R11 or N and wherein W, Y and Z are each C—R8, C—R9 or C—R10.
  • 6. The compound of claim 1 wherein X is C—R9 or N and wherein W, Y and Z are each C—R8, C—R10 or C—R11.
  • 7. The compound of claim 1 wherein Y is C—R10 or N and wherein W, X, and Z are each CH, C—R8, C—R9 or C—R11.
  • 8. The compound of claim 1 wherein W, X, Y and Z are each selected from CH, C—R8, C—R9, C—R10 and C—R11.
  • 9. The compound of claim 8 wherein W, X, Y and Z are each CH.
  • 10. The compound of claim 1 wherein R2 and R3 are each selected from hydrogen, lower alkyl of 1-6 carbons and aryl.
  • 11. The compound of claim 1 wherein R1 is selected from hydrogen, alkyl, cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, -methylpyridine, -ethylpyridine, -methylindole, -ethylindole, alkoxyethyl-, hydroxyethyl-, N,N-dialkyl-ethyl, N,N-dialkyl-propyl, methylpyrrole, -ethylpyrrole, -methylfuran, -ethylfuran, -alkylmorpholine, -alkylpiperizine, -alkypiperidine, and -alkylpyrrolidine, and wherein R2 and R3 are each hydrogen, lower alkyl (1-6 carbon) or aryl.
  • 12. The compound of claim 1 wherein R4 and R5 are each selected from hydrogen, alkyl, cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, -methylpyridine, -ethylpyridine, -methylindole, -ethylindole, alkoxyethyl-, hydroxyethyl-, N,N-dialkyl-ehthl, N,N-dialkyl-propyl, -methylpyrrole, -ethylpyrrole, -methylfuran, -ethylfuran, --alkylmorpholine, -alkylpiperizine, -alkypiperidine, and -alkylpyrrolidine, or wherein —NR4R5 is a substituted or unsubstituted, monocyclic or bicyclic, heterocycloalkyl ring, and wherein R2 and R3 are each selected from hydrogen, lower alkyl (1-6 carbon) and aryl.
  • 13. The compound of claim 1 wherein R6 and R7 are selected from alkyl, cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, -methylpyridine, -ethylpyridine, -methylindole, -ethylindole, alkoxyethyl-, hydroxyethyl-, N,N-dialkyl-ethyl, N,N-dialkyl-propyl, -methylpyrrole, -ethylpyrrole, -methylfuran, -ethylfuran, -alkylmorpholine, -alkylpiperizine, -alkypiperidine, and -alkylpyrrolidine, and R2 and R3 are selected from hydrogen, lower alkyl (1-6 carbon) and aryl.
  • 14. The compound of claim 9 wherein R2 and R3 are selected from hydrogen, lower alkyl (1-6 carbon) and aryl.
  • 15. The compound of claim 9 wherein R1, R4 and R5 are each selected from hydrogen, alkyl, cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, methylpyridine, -ethylpyridine, -methylindole, -ethylindole, alkoxyethyl-, hydroxyethyl-, N,N-dialkyl-ethyl, N,N-dialkyl-propyl, -methylpyrrole, -ethylpyrrole, -methylfuran, -ethylfuran, -alkylmorpholine, -alkylpiperizine, -alkypiperidine, and -alkylpyrrolidine, or wherein —NR4R5 is a substituted or unsubstituted, monocyclic or bicyclic, heterocycloalkyl ring, and wherein R2 and R3 are each hydrogen, lower alkyl (1-6 carbon) or aryl and wherein R6 and R7 are each selected from alkyl, cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted benzyl, -methylpyridine, -ethylpyridine, -methylindole, -ethylindole, alkoxyethyl-, hydroxyethyl, N,N-dialkyl-ethyl, N,N-dialkyl-propyl, -methylpyrrole, -ethylpyrrole, -methylfuran, -ethylfuran, -alkymorpholine, -alkylpiperizine, -alkypiperidine, and -alkylpyrrolidine.
  • 16. The compound of claim 1 wherein R2 and R3 are each selected from hydrogen and alkyl, and wherein R4 and R6 are each selected from alkyl and
  • 17. The compound of claim 9 wherein R1 is alkyl, wherein R2 and R3 are each selected from hydrogen and alkyl and wherein R4 and R6 are each selected from alkyl and
  • 18. The compound of claim 1 wherein R2 and R3 are each selected from hydrogen and alkyl, wherein R4 and R6 are each selected from alkyl and
  • 19. The compound of claim 1 wherein R2 and R3 are each selected from hydrogen and alkyl wherein R4 and R6 are each selected from alkyl and  where n is 2, 3 or 4 and one or both of R5 and R7 is alkyl
  • 20. Compound of claim 1wherein R2 and R3 are each selected from hydrogen and alkyl R4 and R6 are each selected from alkyl and  where n is 2, 3 or 4 and one or both of R5 and R7 is alkyl.
  • 21. The compound of claim 1 wherein R2 and R3 are each selected from hydrogen and alkyl R4 and R6 are each selected from alkyl and  where n is 2, 3 or 4 and one or both of R5 and R7 is alkyl.
  • 22. The compound of claim 1 wherein R2 and R3 are each selected from hydrogen and alkyl, R4 and R6 are each selected from alkyl and  where n is 2, 3 or 4 and one or both of R5 and R7 is alkyl.
  • 23. The compound of claim 1 wherein R1 is methyl.
  • 24. The compound of claim 9 wherein R1 is methyl.
  • 25. The compound of claim 1 wherein one or more of R1, R6 and R7 is methyl.
  • 26. The compound of claim 9 wherein one or more of R1, R6, and R7 is methyl.
  • 27. The compound of claim 23 wherein —NR4R5 is a substituted or unsubstituted, monocyclic or bicyclic, heterocycloalkyl ring.
  • 28. The compound of claim 25 wherein —NR4R5 is a substituted or unsubstituted, monocyclic or bicyclic, heterocycloalkyl ring.
  • 29. The compound of claim 26 wherein —NR4R5 is a substituted or unsubstituted, monocyclic or bicyclic, heterocycloalkyl ring.
  • 30. The compound of claim 26 wherein —NR4R5 is selected from aziridine, pyrrolidine, piperidine, hydroxy piperidine, morpholine, and N-methyl piperazine.
  • 31. The compound of claim 23 wherein R4 and R5 are each lower alkylene-OR20 wherein R20 is hydrogen or lower alkyl.
  • 32. The compound of claim 25 wherein R4 and R5 are each lower alkylene-OR20 wherein R20 is hydrogen or lower alkyl.
  • 33. The compound of claim 26 wherein R4 and R5 are each lower alkylene-OR20 wherein R20 is hydrogen or lower alkyl.
  • 34. A compound of claim 1 having a structure of Table 1 including salts thereof.
  • 35. A compound of claim 1 having a structure of Table 2 including salts thereof.
  • 36. A compound of claim 1 having a structure of Table 3 including salts thereof.
  • 37. A compound of claim 1 having a structure of Table 4 including salts thereof.
  • 38. A compound of claim 1 having a structure of Table 5 including salts thereof.
  • 39. A compound of claim 1 having a structure of Table 6 including salts thereof.
  • 40. A compound having a structure of Table 7 or Table 8 including salts thereof.
  • 41. A compound having a structure of Table 9 or Table 10 including salts thereof.
  • 42. A compound having a structure of Table 11 or Table 12 including salts thereof.
  • 43. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 in a pharmaceutically acceptable carrier.
  • 44. A method for preventing or treating a disease associated with a change in levels of expression of a set of genes in a mammal comprising administering to said mammal an effective amount of a compound of claim 1.
  • 45. 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 a safe and effective amount of a compound according to claim 1.
  • 46. The method of claim 45, wherein the disorder is cancer.
  • 47. The method of claim 46 wherein said treatment prevents, arrests or reverts tumor growth and metastasis.
  • 48. The method of claim 46 wherein said cancer is selected from the group consisting of solid tumors, lymphomas, skin cancer, urinary bladder cancer, breast cancer, uterine cancer, ovarian cancer, prostate cancer, lung cancer, colon cancer, rectum cancer, pancreatic cancer, kidney cancer, and stomach cancer.
  • 49. The method of claim 48 wherein the cancer is breast or colon cancer.
  • 50. The method of claim 49 wherein said breast or colon cancer is adenocarcinoma.
  • 51. The method of claim 45 wherein the disorder is a cardiovascular disorder selected 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.
  • 52. 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.
  • 53. The gene set of claim 52 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 treatment.
  • 54. The gene set of claim 52 wherein the members of said gene set are selected from the genes identified in Table 19.
  • 55. The gene set of claim 52 wherein said gene set is present in a cell.
  • 56. A method for identifying an agent that modulates the expression of a gene set of claim 51, 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 52 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.
  • 57. The method of claim 56 wherein said change in expression is a decrease in expression of said one or more polynucleotides.
  • 58. The method of claim 56 wherein said change in expression is a change in transcription of said one or more polynucleotides.
  • 59. The method of claim 56 wherein said change in expression is determined by determining a change in activity of a polypeptide encoded by said polynucleotide.
  • 60. The method of claim 56 wherein said one or more polynucleotides are present in a cell.
  • 61. The method of claim 60 wherein said cell is a cancer cell.
  • 62. The method of claim 60 wherein said cancer cell is a breast or colon cancer cell.
  • 63. The method of claim 62 wherein said breast or colon cancer cell is an adenocarcinoma cancer cell.
  • 64. The method of claim 60 wherein said cell is a recombinant cell engineered to contain said set of genes.
  • 65. 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 56.
  • 66. Compounds identified as having activity using the method of claim 56.
  • 67. The gene set of claim 51 wherein said gene set comprises a subset of the genes of Table 19.
  • 68. The method of claim 56 wherein said compound modulates the expression of a subset of genes of Table 19.
  • 69. A compound of claim 1 and having a structure of Table 13 and Table 14 including salts thereof.
  • 70. A compound of claim 1 and having a structure of Table 15 and Table 16 including salts thereof.
  • 71. A compound of claim 1 and having a structure of Table 17 and Table 18 including salts thereof.
Parent Case Info

This application claims priority of U.S. Provisional Application Ser. No. 60/492,521, filed 5 Aug. 2003, and 60/523,477, filed 19 Nov. 2003, the disclosures of which are hereby incorporated by reference in their entirety.

Provisional Applications (2)
Number Date Country
60492521 Aug 2003 US
60523477 Nov 2003 US