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US 2010/0249111 A1Published application
Multi-ring compounds and uses thereof
AssigneeAvalon Pharmaceuticals, Inc.
InventorsNorman E. Ohler, Jeffrey W. Watthey, Jeffrey Strovel, Sheela K. Chellappan
Life of this patent
Estimating the term…
Abstract
Chemical agents, such as derivatives of hydroxy benzene moieties, and similar heterocyclic ring structures, including salts thereof, that act as anti-cancer and anti-tumor agents, especially where such agents modulate the activity of enzymes and structural polypeptides present in cells, such as cancer cells, or where the agents modulate levels of gene expression in cellular systems, including cancer cells, are disclosed, along with methods for preparing such agents, as well as pharmaceutical compositions containing such agents as active ingredients and methods of using these as therapeutic agents.
Claims34
A compound having the structure of Formula I
- wherein W is one of
- wherein when W is structure Ia, m=0, 1, 2, or 3 and n=0, 1, 2, 3, 4, or 5;
- and when W is structure Ib, m=1 or 2 and n=0, 1, 2, 3, 4, or 5;
- and wherein A is selected from O and —CR20R21
- B is selected from N and —CR12;
- D is selected from C═O and —CR22R23,
- E is selected from NR13 and —CR24R25,
- such that when A is O, if D is C═O then E is —CR24R25 and if E is NR13 then D is —CR22R23,
- R1, R13 and R14 are each selected independently from
- H, CH3, C2 to C5 alkyl, C2 to C5 alkenyl, C1 to C5 alkoxy, 5-9 ring atom cycloalkyl,
- 5-9 ring atom heterocycloalkyl having up to 3 heteroatoms each independently selected from N or O and wherein when said heteroatom is N, it may be further substituted as may any carbon in said ring;
- 5-7 ring atom aryl, aryloxy, polyaromatic, and 5-7 ring atom heteroaryl with heteroatom N or O,
- and wherein R1 is further selected from the structure —XY,
- wherein X═(CR30R31)k (wherein k=0, 1, 2 or 3), SO2, C═O, NR30R31 or —C(═O)NR30, wherein R30 and R31 are each independently H, CH3, or C2 to C5 alkyl,
- and wherein Y is selected from a structure containing up to 3 fused or unfused rings of 5 or 6 ring atoms each and each ring is independently selected from aryl, heteroaryl, cycloalkyl and heterocycloalkyl wherein the heteroatom is nitrogen or oxygen, which rings may be substituted or unsubstituted and wherein 2 or all of said rings may be separated by C1-C4 alkyl, ═CH—, C2-C4 alkenyl or C2-C4 alkynyl chains that may themselves be substituted or unsubstituted;
- and wherein R13 and R14 are each further selected independently from —CHO, OR15, SR15, or NR15R16, C1-C4-alkyl-aryl and aryl-C1-C4-alkyl;
- R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R14, R20, R21 R22, R23, R24, R25, R26, and R27 are each independently selected from H, F, Cl, Br, I, OH, CF3, CH3, C2 to C5 alkyl, C2 to C5 alkenyl, C1 to C5 alkoxy, C1 to C5 hydroxyalkyl, NR15R16,
- and wherein R15 and R16 are each independently selected from H, CH3, C2 to C5 alkyl,
- and wherein NR13(CH2)nR14 or a portion thereof may combine to form a substituted or unsubstituted ring selected from piperidine, pyrrolidine, and tetrahydroisoquinoline,
- wherein any of said R groups may be substituted or unsubstituted, wherein said substitutions are each independently selected from hydrogen, CH3, hydroxyl, sulfhydryl, alkoxy, thioalkoxy, alkyl, F, Cl, Br, I, CN, ═O, CF3, NO2, 5-9 ring atom cycloalkyl, 5-9 ring atom heterocycloalkyl with 1 or 2 heteroatoms selected from N and O, 5-7 ring atom aryl, 5-7 ring atom heteroaryl with 1 or 2 heteroatoms selected from N and O, alkylaryl, arylalkyl, COOR17, CONR18R19, NR18R19, NR18COR19, NR18SO2R19, SO2NR18R19, CONR18R19, wherein R17, R18, and R19 are independently as recited for R2 and wherein each said cycloalkyl, heterocycloalkyl, aryl and heteroaryl may be further substituted with a group selected from R2;
- including all pharmaceutically acceptable salts, derivatives, prodrugs, metabolites, solvates, hydrates, and isomers thereof.
18 more elements
2-3. (canceled)
6-17. (canceled)
A compound having the structure of Formula II
- wherein W is one of
- wherein when W is structure IIa, m=0, 1, 2, or 3 and n=0, 1, 2, 3, 4, or 5;
- and when W is structure IIb, m=1 or 2 and n=0, 1, 2, 3, 4, or 5;
- B is selected from N and —CR12;
- R1, R13 and R14 are each selected independently from
- H, CH3, C2 to C5 alkyl, C2 to C5 alkenyl, C1 to C5 alkoxy, 5-9 ring atom cycloalkyl,
- 5-9 ring atom heterocycloalkyl having up to 3 heteroatoms each independently selected from N or O and wherein when said heteroatom is N, it may be further substituted as may any carbon in said ring;
- 5-7 ring atom aryl, aryloxy, polyaromatic, and 5-7 ring atom heteroaryl with heteroatom N or O,
- and wherein R1 is further selected from the structure —XY,
- wherein X═(CR30R31)k (wherein k=0, 1, 2 or 3), SO2, C═O, NR30R31 or —C(═O)NR30, wherein R30 and R31 are each H, CH3, or C2 to C5 alkyl, and wherein Y is selected from a structure containing up to 3 fused or unfused rings of 5 or 6 ring atoms each and each ring is independently selected from aryl, heteroaryl, cycloalkyl and heterocycloalkyl wherein the heteroatom is nitrogen or oxygen, which rings may be substituted or unsubstituted and wherein 2 or all of said rings may be separated by C1-C4 alkyl, ═CH—, C2-C4 alkenyl or C2-C4 alkynyl chains that may themselves be substituted or unsubstituted;
- and wherein R13 and R14 are each further selected independently from —CHO, OR15, SR15, or NR16R16, C1-C4-alkylaryl and aryl-C1-C4-alkyl;
- R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R14, R26, and R27 are each independently selected from H, F, Cl, Br, I, OH, CF3, C1 to C5 alkyl, C1 to C5 alkenyl, C1 to C5 alkoxy, C1 to C5 hydroxyalkyl, NR15R16 (wherein R15 and R16 are each independently selected from H and C1 to C5 alkyl);
- and wherein R15 and R16 are each independently selected from H, CH3, and C2 to C5 alkyl,
- and wherein NR13(CH2)nR14 or a portion thereof may combine to form a substituted or unsubstituted ring selected from piperidine, pyrrolidine, and tetrahydroisoquinoline,
- and wherein any of said R groups may be substituted or unsubstituted, wherein said substitutions are each independently selected from hydrogen, CH3, hydroxyl, sulfhydryl, alkoxy, thioalkoxy, alkyl, F, Cl, Br, I, CN, ═O, CF3, NO2, 5-9 ring atom cycloalkyl, 5-9 ring atom heterocycloalkyl with 1 or 2 heteroatoms selected from N and O, 5-7 ring atom aryl, 5-7 ring atom heteroaryl with 1 or 2 heteroatoms selected from N and O, alkylaryl, arylalkyl, COOR17, CONR18R19, NR18R19, NR18COR19, NR18SO2R19, SO2NR18R19, NR17CONR18R19, wherein R17, R18, and R19 are independently as recited for R2 and wherein each said cycloalkyl, heterocycloalkyl, aryl and heteroaryl may be further substituted with a group selected from R2;
- including all pharmaceutically acceptable salts, derivatives, prodrugs, metabolites, solvates, hydrates, and isomers thereof.
13 more elements
19-20. (canceled)
23-24. (canceled)
A compound having the structure of Formula III
- wherein W has the structure
- wherein m=0, 1, 2 or 3 and n=0, 1, 2, 3, 4 or 5,
- and B is selected from N and —CR12;
- and wherein R1 is further selected from the structure —XY,
- wherein X═(CR30R31)k (wherein k=0, 1, 2 or 3), SO2, C═O, NR30R31 or —C(═O)NR30, wherein R30 and R31 are each H, CH3, or C2 to C5 alkyl, and wherein Y is selected from a structure containing up to 3 fused or unfused rings of 5 or 6 ring atoms each and each ring is independently selected from aryl, heteroaryl, cycloalkyl and heterocycloalkyl wherein the heteroatom is nitrogen or oxygen, which rings may be substituted or unsubstituted and wherein 2 or all of said rings may be separated by C1-C4 alkyl, ═CH—, C2-C4 alkenyl or C2-C4 alkynyl chains that may themselves be substituted or unsubstituted;
- R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, and R13 are each independently selected from H, F, Cl, Br, I, OH, CF3, CH3, C2 to C5 alkyl, C2 to C5 alkenyl, C1 to C5 alkoxy, C2-C4 hydroxyalkyl, NR15R16,
- and wherein R13 is further selected from Ci to C5 hydroxyalkyl and —CHO,
- and wherein R14 is selected from H, CH3, C2 to C8 alkyl, branched and unbranched C2 to C5 alkenyl, branched and unbranched C2 to C5 alkynyl, C5 to C7-cycloalkyl, OR15, SR15, —C(═O)R15, —C(═O)OR15, branched and unbranched (C1 to C5 alkyl)-NR15R16, NR15R16, branched and unbranched (C1 to C5 alkyl)-+NR15R16R17, +NR15R16R17,
- C(═O)NR15R16, C(═O)ONR15R16, 5 to 7 membered heterocycloalkyl having up to 3 heteroatoms selected from N or O;
- aryl, heteroaryl with heteroatom N or O, aralkyl, and alkylaryl,
- and wherein each of said cycloalkyl, aryl, heteroaryl and heterocycloalkyl may be further substituted with groups each independently selected from H, F, Cl, Br, I, CF3, branched and unbranched C1 to C5 alkyl, branched and unbranched C1 to C5 alkenyl, branched and unbranched C1 to C5 alkynyl, branched and unbranched C1 to C5 alkoxy, branched and unbranched —C1 to C5 alkylamino, branched and unbranched —C1 to C5 aminoalkyl, —C(═O)R15, —C(═O)R21, C(═O)OR15, C(═O)OR21, C5 to C7-cycloalkyl, —OR15, —SR15, —NR15R16, wherein each of said alkyl, alkenyl, alkynyl, alkoxyl, alkylamino and amino alkyl groups may be further substituted with one or more of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl;
- and wherein R15 and R16 are each independently selected from H, C1 to C5 alkyl, C1 to C5 alkyl-R21, C2 to C5 alkenyl, substituted or unsubstituted phenyl, —C(═O)R19, —C(═O)OR19, (C1 to C5 alkyl)-OH, (C1 to C5 alkyl)-NR19R20, —NR19R20,
- C(═O)—NR19R20 (wherein each of said R19 and R20 is independently H, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl;),
- and wherein R21 is selected from 5 to 7 membered cycloalkyl, 5 to 7 membered aryl, 5 to 7 membered heteroaryl, and 5 to 7 membered heterocycloalkyl, wherein said heteroatom is N or O, each of which may be substituted with groups selected from R15,
- wherein any of said R groups may be substituted or unsubstituted, wherein said substitutions are each independently selected from hydrogen, CH3, hydroxyl, sulfhydryl, alkoxy, thioalkoxy, alkyl, F, Cl, Br, I, CN, ═O, CF3, NO2, 5-9 ring atom cycloalkyl, 5-9 ring atom heterocycloalkyl with 1 or 2 heteroatoms selected from N and O, 5-7 ring atom aryl, 5-7 ring atom heteroaryl with 1 or 2 heteroatoms selected from N and O, alkylaryl, arylalkyl, COOR17, CONR18R19, NR18R19, NR18COR19, NR18SO2R19, NR17CONR18R19, wherein R17, R18, and R19 are independently as recited for R2 and wherein each said cycloalkyl, heterocycloalkyl, aryl and heteroaryl may be further substituted with a group selected from R2;
- including all pharmaceutically acceptable salts, derivatives, prodrugs, metabolites, solvates, hydrates, and isomers thereof.
13 more elements
26-27. (canceled)
30-32. (canceled)
A compound having the structure of Formula IV
- wherein W is one of
- wherein when W is structure IVa, m=0, 1, 2, or 3 and n=0, 1, 2, 3, 4, or 5;
- and when W is structure IVb, m=1 or 2 and n=0, 1, 2, 3, 4, or 5;
- B is selected from N and —CR12;
- R13 and R14 are each independently selected from
- H, CH3, C2 to C5 alkyl, C2 to C5 alkenyl, C1 to C5 alkoxy, 5-9 ring atom cycloalkyl,
- OR15, SR15, or NR15R16;
- 5-9 ring atom heterocycloalkyl having up to 3 heteroatoms selected from N or O and wherein when said heteroatom is N, it may be further substituted as may any carbon in said ring;
- 5-7 ring atom aryl, aryloxyl, polyaromatic, 5-7 ring atom heteroaryl with heteroatom selected from N and O,
- aralkyl and alkylaryl;
- R1, R2, R3, R4, R5, R6, R7, R9, R9, R10, R11, R12, R14, R20, R21 and R22 are each independently selected from H, F, Cl, Br, I, OH, CF3, C1 to C5 alkyl, C1 to C5 alkenyl, C1 to C5 alkoxy, NR15R16;
- and wherein R15 and R16 are each independently selected from H, CH3 and C2 to C5 alkyl
- and wherein NR13(CH2)nR14 or a portion thereof may combine to form a substituted or unsubstituted ring selected from piperidine, pyrrolidine, and tetrahydroisoquinoline,
- wherein any of said R groups may be substituted or unsubstituted, wherein said substitutions are each independently selected from hydrogen, CH3, hydroxyl, sulfhydryl, alkoxy, thioalkoxy, alkyl, F, Cl, Br, I, CN, ═O, CF3, NO2, 5-9 ring atom cycloalkyl, 5-9 ring atom heterocycloalkyl with 1 or 2 heteroatoms selected from N and O, 5-7 ring atom aryl, 5-7 ring atom heteroaryl with 1 or 2 heteroatoms selected from N and O, alkylaryl, arylalkyl, COOR17, CONR18R19, NR18R19, NR18COR19, NR18SO2R19, NR17CONR18R19, wherein R17, R18, and R19 are independently as recited for R2 and wherein each said cycloalkyl, heterocycloalkyl, aryl and heteroaryl may be further substituted with a group selected from R2;
- including all pharmaceutically acceptable salts, derivatives, prodrugs, metabolites, solvates, hydrates, and isomers thereof.
12 more elements
34-35. (canceled)
38-40. (canceled)
A compound having the structure of Formula V
- wherein n=0, 1, 2, 3, 4 or 5,
- wherein B is selected from N and —CR12;
- R13 and R14 are each independently selected from
- H, C1 to C5 alkyl, C1 to C5 alkenyl, C1 to C5 alkoxy, 5-9 ring atom cycloalkyl,
- OR15, SR15, or NR15R16;
- 5-9 ring atom heterocycloalkyl having up to 3 heteroatoms selected from N or O and wherein when said heteroatom is N, it may be further substituted as may any carbon in said ring;
- 5-7 ring atom aryl, aryloxyl, polyaromatic, 5-7 ring atom heteroaryl with heteroatom N or O,
- aralkyl and alkylaryl;
- R1, R2, R3, R4, R5, R9, R10, R11, R12, R20, R21 R22, R23, R24, R25, R26, and R27 are each independently selected from H, F, Cl, Br, I, OH, CF3, CH3, C2 to C5 alkyl, ═CH—, C2 to C5 alkenyl, C1 to C5 alkoxy, NR15R16,
- and wherein R15 and R16 are each independently selected from H, CH3 and C2 to C5 alkyl
- and wherein NR13(CH2)nR14 or a portion thereof may combine to form a substituted or unsubstituted ring selected from piperidine, pyrrolidine, tetrahydroisoquinoline, and piperazine,
- wherein any of said R groups may be substituted or unsubstituted, wherein said substitutions are each independently selected from hydrogen, CH3, hydroxyl, sulfhydryl, alkoxy, thioalkoxy, alkyl, F, Cl, Br, I, CN, ═O, CF3, NO2, 5-7 ring atom cycloalkyl, 5-7 ring atom heterocycloalkyl with 1 or 2 heteroatoms selected from N and O, 5-7 ring atom aryl, 5-7 ring atom heteroaryl with 1 or 2 heteroatoms selected from N and O, alkylaryl, arylalkyl, COOR17, CONR18R19, NR18R19, NR18COR19, NR18SO2R19, NR17CONR18R19, wherein R17, R18, and R19 are independently as recited for R2 and wherein each said cycloalkyl, heterocycloalkyl, aryl and heteroaryl may be further substituted with a group selected from R2;
- including all pharmaceutically acceptable salts, derivatives, prodrugs, metabolites, solvates, hydrates, and isomers thereof.
10 more elements
(canceled)
45-50. (canceled)
A composition comprising a therapeutically effective amount of a compound of Formula I, II, III, IV, V or VI in a pharmaceutically acceptable carrier, with substituents as defined herein.
52-56. (canceled)
A method of preventing, treating or ameliorating cancer or tumor metastasis in a mammal comprising administering to said mammal an effective amount of a compound of Formula I, II, III, IV, V or VI with substituents as defined herein.
58-71. (canceled)
A compound having the structure of Formula VI
- wherein W is one of
- wherein when W is structure VIa, m=0, 1, 2, or 3 and n=0, 1, 2, 3, 4, or 5;
- and when W is structure VIb, m=1 or 2 and n=0, 1, 2, 3, 4, or 5;
- wherein p=0, 1, 2, or 3;
- and wherein A is selected from O and —CR20R21,
- B is selected from N and —CR12;
- D is selected from C═O and —CR22R23,
- E is selected from NR13 and —CR24R25,
- X═(CR30R31)q, wherein q=0, 1 or 2,
- Y═(CR32R33)r, wherein r=0, 1 or 2
- R1, R13 and R14 are each selected independently from
- H, CH3, C2 to C5 alkyl, C2 to C5 alkenyl, C1 to C5 alkoxy, 5-9 ring atom cycloalkyl,
- 5-9 ring atom heterocycloalkyl having up to 3 heteroatoms each independently selected from N or O and wherein when said heteroatom is N, it may be further substituted as may any carbon in said ring;
- 5-7 ring atom aryl, aryloxy, polyaromatic, and 5-7 ring atom heteroaryl with heteroatom N or O, aralkyl and alkylaryl,
- and wherein R1 is further selected from the structure —XY,
- wherein X═(CR30R31)k (wherein k=0, 1, 2 or 3), SO2, C═O, NR30R31 or —C(═O)NR30, wherein R30 and R31 are each H, CH3, or C2 to C5 alkyl, and wherein Y is selected from a structure containing up to 3 fused or unfused rings of 5 or 6 ring atoms each and each ring is independently selected from aryl, heteroaryl, cycloalkyl and heterocycloalkyl wherein the heteroatom is nitrogen or oxygen, which rings may be substituted or unsubstituted and wherein 2 or all of said rings may be separated by C1-C4 alkyl, ═CH—, C2-C4 alkenyl or C2-C4 alkynyl chains that may themselves be substituted or unsubstituted;
- and wherein R13 and R14 are each further selected independently from —CHO, OR15, SR15, or NR15R16
- R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R20, R21 R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32 and R33 are each independently selected from H, F, Cl, Br, I, OH, CF3, C1 to C5 alkyl, C1 to C5 alkenyl, C1 to C5 alkoxy, NR15R16
- wherein R15 and R16 are each independently selected from H, CH3 and C2 to C5 alkyl;
- and wherein NR13(CH2)nR14 or a portion thereof may combine to form a substituted or unsubstituted ring selected from piperidine, pyrrolidine, tetrahydroisoquinoline, and piperazine,
- wherein any of said R groups may be substituted or unsubstituted, wherein said substitutions are each independently selected from hydrogen, CH3, hydroxyl, sulfhydryl, alkoxy, thioalkoxy, alkyl, F, Cl, Br, I, CN, ═O, CF3, NO2, 5-9 ring atom cycloalkyl, 5-9 ring atom heterocycloalkyl with 1 or 2 heteroatoms selected from N and O, 5-7 ring atom aryl, 5-7 ring atom heteroaryl with 1 or 2 heteroatoms selected from N and O, alkylaryl, arylalkyl, COOR17, CONR18R19, NR18R19, NR18COR19, NR18SO2R19, NR17CONR18R19, wherein R17, R18, and R19 are independently as recited for R2 and wherein each said cycloalkyl, heterocycloalkyl, aryl and heteroaryl may be further substituted with a group selected from R2;
- including all pharmaceutically acceptable salts, derivatives, prodrugs, metabolites, solvates, hydrates, and isomers thereof.
19 more elements
73-77. (canceled)
80-98. (canceled)
Dependencies are inferred from the claim text.