公开号/公开日

WO2010132815 A1 2010-11-18 [WO2010132815]WO2010132815 A9 2011-01-13 [WO2010132815] / 2010-11-182011-01-13

申请号/申请日

2010WO-US34971 / 2010-05-14

发明人

JOHNSON FRANCIS;GOLUB LORNE;

申请人

CHEM MASTER INTERNATIONAL;RESEARCH FOUNDATION OF SUNY;

主分类号

IPC分类号

A01N-037/02

摘要

(WO2010132815) This invention provides a compound having the structure, wherein a, ß, X, Y, and R1-R11 are defined herein.  This invention also provides a pharmaceutical composition comprising the above compounds, a method of inhibiting the activity and/or levels of a matrix metalloproteinase (MMP), a method of inhibiting the production of a cytokine in a population of cells, a method of inhibiting the production of a growth factor m a population of cells, and a method of inhibiting NFK-B activation in a population of cells.

机翻摘要

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地址

代理人

代理机构

;

优先权号

2009US-61216392 2009-05-15

主权利要求

(WO2010132815) 1. Claims What is claimed is: 1. A compound having the structure wherein bond α and β are each, independently, present or absent; X is CR5or N; Y is CR10or N; R1is H, CF3, halogen, -NO2, -OCF3, -OR12, -NHCOR12, -SR12, - SO2R13, -COR14, -CSR14, -C(=NR12) R14, -C(=NH)R14, -SOR12, - POR12, -P (=0) (OR12) (OR13), or -P(OR12) (OR13), wherein R12and R13are each, independently, H, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, aryl, heteroaryl, or heterocyclyl; R14is C2-10alkyl, C2-10alkenyl, C2-10alkynyl, heteroaryl, heterocyclyl, methoxy, -OR15, -NR16R17, or wherein R15is H, C3-10alkyl, C2-1Oalkenyl, C2-1Oalkynyl; R16and R17are each, independently, H, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, aryl, heteroaryl, or heterocyclyl; R1β/ R19» ^2if and R22are each independently H, halogen, -NO2, -CN, -NR23R24, -SR23, -SO2R23, CO2R23, -OR25, CF3, -SOR23, -POR23, -C(=S)R23, - C(=NH)R23, -C(=NR24)R23, -C(=N)R23, P(=O) (OR23) (OR24), -P(OR23) (OR24), -C(=S)R23, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, aryl, heteroaryl, or heterocyclyl; wherein R23, R24, and R25are each, independently, H, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, aryl, heteroaryl, or heterocyclyl ; R20is halogen, -NO2, -CN, -NR26R27, CF3, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, aryl, heteroaryl, or heterocyclyl; wherein R26and R27are each, independently, H, C1-10alkyl, C2-1O alkenyl, C2-10alkynyl, aryl, heteroaryl, or heterocyclyl; R2, R3, R4, R5, R6, R7, R8, R9, R10, and R11are each independently, H, halogen, -NO2, -CN, -NR28R29, -NHR2BR29+, - SR28, -SO2R2S, -OR2e, -CO2R28, CF3, C1-10alkyl, C2-1Q alkenyl, C2-1Oalkynyl, aryl, heteroaryl, or heterocyclyl; wherein R28and R29are each, H, CF3, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, or -C (=0) -heterocyclyl; and wherein when R1is H, R3, R4, R5, R8, R9, or R10, is halogen, -NO2, -CN, -NR28R29, -NHR28R29+, -SR28, -SO2R28, - CO2R28, CF3, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, aryl, heteroaryl, or heterocyclyl; wherein R28and R29are each, H, CF3, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, or -C (=0) -heterocyclyl; and wherein each occurrence of alkyl, alkenyl, or alkynyl is branched or unbranched, unsubstituted or substituted; or a salt thereof. 2. The compound of claim 1, wherein when R1is H, R3, R4, R5, R8, R9, or R10, is -NO2, -NR28R29, -NHR28R29+, -SR28, - SO2R28, -CO2R28, CF3, C1-10alkyl, C2-10alkenyl, C2-10alkynyl; or a salt thereof. 3. The compound of claim 1, wherein when R1is H, R4or R9is -NO2, -NR28R29, -NHR28R29+; or a salt thereof. 4. The compound of claim 1, wherein when R1is H, R4or R9is -NR28R29or -NHR28R29+; or a salt thereof. 5. The compound of claim 1, wherein R1is H or -COR14, wherein R14is methoxy or -NH-phenyl; R2, R5, R6, R7, R10and Rn are each H; R3, R4, R6, and R9are each, independently H, -OH, -OCH3, - N (CH3)2or -NH(CH3)2+; or a salt thereof. 6. The compound of any one of claims 1, 3, 4, or 5, having the structure  or a salt thereof. 7. The compound of claim 1 having the structure wherein bond α and β are each, independently, present or absent; R1is CF3, halogen, -NO2, -OCF3, -OR12, -NHCOR12, -SR12, - SO2R13, -COR14, -CSR14, or -CNR14, wherein Ri2and R13are each, independently, H, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, aryl, heteroaryl, or heterocyclyl; R14is C2-10alkyl, C2-10alkenyl, C2-10alkynyl, heteroaryl, heterocyclyl, methoxy, -OR15, -NR16R17, or wherein R15is H, C3-10alkyl, C2-10alkenyl, C2-10alkynyl; R16 and R17 are each, independently, H, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, aryl, heteroaryl, or heterocyclyl; R1βf R19» R21/ and R22 are each independently H, halogen, -NO2, -CN, -NR23R24, -SR23, -SO2R23, - CO2R23, -OR25, CF3, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, aryl, heteroaryl, or heterocyclyl; wherein R23, R24, and R25are each, independently, H, C1-1Oalkyl, C2-10alkenyl, C2-10alkynyl, aryl, heteroaryl, or heterocyclyl ; R20 is halogen, -NO2, -CN, -NR26R27/CF3, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, aryl, heteroaryl, or heterocyclyl; wherein R2β and R27are each, independently, H, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, aryl, heteroaryl, or heterocyclyl; R2, R3, R4, R5, R6, R7, Ra, R9, R10, and Ru are each independently, H, halogen, -NO2, -CN, -NR28R29, -SR28, SO2R28, -OR2S, -CO2R2S, CF3, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, aryl, heteroaryl, or heterocyclyl; wherein R28and R29are each, H, CF3, C1-10alkyl, C2-1Oalkenyl, or C2-10alkynyl; and wherein each occurrence of alkyl, alkenyl, or alkynyl is branched or unbranched, unsubstituted or substituted; and wherein at least one of R2, R3, R4, R5, and R6and at least one of R7, R8, R9, R10, and R11, are each, independently, - OR28; or a salt thereof. 8. The compound of claim 7 having the structure wherein R1is CF3, halogen, -NO2, -OCF3, -OR12, -NHCOR12, SR12, -SO2Rn, -COR14, -CSR14, or -CNRi4, wherein R12and R13are each, independently, H, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, aryl, heteroaryl, or heterocyclyl; R14is C2-10alkyl, C2-10alkenyl, C2-10alkynyl, heteroaryl, heterocyclyl, methoxy, -OR15, -NR16R17, or wherein R15is H, C3-10alkyl, C2-10alkenyl , C2-10alkynyl ; R16and Rn are each, independently, H, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, aryl, heteroaryl, or heterocyclyl; R18f R19/ R21/ and R22 are each independently H, halogen, -NO2, -CN, -NR23R24, -SR23, -SO2R23, - CO2R23, -0R25r CF3, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, aryl, heteroaryl, or heterocyclyl; wherein R23, R24, and R25are each, independently, H, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, aryl, heteroaryl, or heterocyclyl ; R20 is halogen, -NO2, -CN, -NR26R27, CF3, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, aryl, heteroaryl, or heterocyclyl; wherein R26and R2I are each, Independently, H, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, aryl, heteroaryl, or heterocyclyl; R2, R3, R4, R5r Rβr R7, R8, R9, R10, and Ruare each independently, H, halogen, -NO2, -CN, -NR2sR29, -SR28, - SO2R28, -OR28, -CO2R28, CF3, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, aryl, heteroaryl, or heterocyclyl; wherein R28and R2^ are each, H, CF3, C1-10alkyl, C2-10alkenyl, or C2-10alkynyl; and wherein each occurrence of alkyl, alkenyl, or alkynyl is branched or unbranched, unsubstituted or substituted; and wherein at least one of R2, R3, R4, R5, and R6and at least one of R7, Re, R9, R10, and Rn, are each, independently, - OR28; or a salt thereof. 9. The compound of claim 8 having the structure wherein R14is C2.10alkyl, C2-10alkenyl, C2-10alkynyl, heteroaryl, heterocyclyl, methoxy, -OR15, -NR16R17, or wherein R15is H, C3-10alkyl, C2-10alkenyl , C2-10alkynyl; R16and R17are each, independently, H, C1-w alkyl, C2- 10alkenyl, C2-10alkynyl, aryl, heteroaryl, or heterocyclyl; R1θr R19, R2χ, and R22 are each independently H, halogen, -NO2, -CN, -NR23R24, -SR2S, -SO2R23, -CO2R23, - OR25, CF3, Cx-10alkyl, C2-10alkenyl, C2-1.0 alkynyl, aryl, heteroaryl, or heterocyclyl; wherein R23, R24, and R25are each, independently, H, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, aryl, heteroaryl, or heterocyclyl; R20is halogen, -NO2, -CN, -NR26R27, CF3, C1-I0alkyl, C2-10alkenyl, C2-10alkynyl, aryl, heteroaryl, or heterocyclyl; wherein R26and R27are each, independently, H, C1-Io alkyl, C2-10alkenyl, C2-10alkynyl, aryl, heteroaryl, or heterocyclyl; R2, R3, R4, R5, R6, R7, Re, R9, R10, and Rn are each independently, H, halogen, -NO2, -CN, -NR28R29, -SR28, - SO2R28, -OR28, -CO2R28, CF3, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, aryl, heteroaryl, or heterocyclyl; wherein R28and R29are each, H, CF3, C1-10alkyl, C2-10alkenyl, or C2-10alkynyl; and wherein each occurrence of alkyl, alkenyl, or alkynyl is branched or unbranched, unsubstituted or substituted; and wherein at least one of R2, R3, R4, R5, and R6and at least one of R7, Re, R9, R10, and Rn, are each, independently, - OR28; or a salt thereof. 10. The compound of claim 9 having the structure 510 wherein R14is C2-10alkyl, C2-10alkenyl , C2-10alkynyl , heteroaryl , heterocyclyl, methoxy, -OR15, -NR16R17, or wherein R15is H, C3-10alkyl , C2-10alkenyl, C2-10alkynyl ; R16and R1.7are each, independently, H, C1-10alkyl, C2- 10alkenyl, C2-10alkynyl, aryl, heteroaryl, or heterocyclyl ; R1βfR19r R21 , and R22 are each independently H, halogen, -NO2 , -CN , -NR23R24. -SR23, -SO2R23, -CO2R23, - OR25, CF3, C1-10alkyl, C2-1.0 alkenyl, C2-10alkynyl, aryl, heteroaryl, or heterocyclyl; wherein R23, R24, and R25are each, independently, H, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, aryl, heteroaryl, or heterocyclyl; R20is halogen, -NO2, -CN, -NR26R27, CF3, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, aryl, heteroaryl, or heterocyclyl ; wherein R26and R2? are each, independently, H, C1-1Q alkyl, C2-10alkenyl, C2-10alkynyl, aryl, heteroaryl, or heterocyclyl; R2, R3, R4, R5, Rsr R7, R8, Rg» R10» and R11are each independently, H, halogen, -NO2, -CN, -NR28R29, -SR28, - SO2R28, -OR28, -CO2R28, CF3; wherein R28and R29are each, H, CF3, C1-5alkyl, C2-5alkenyl, or C2-s alkynyl; and wherein each occurrence of alkyl, alkenyl, or alkynyl is branched or unbranched, unsubstituted or substituted; and wherein at least one of R2, R3, R4, R5, and Rs and at least one of R?, R8, R9, R10, and Rn, are each, independently, - OR28; or a salt thereof. 11. The compound of claim 8 wherein R14is methoxy, -OR15or -NR16R17, wherein R1Sis H, C3-10alkyl, C2-10alkenyl, or C2-10alkynyl; R16and R1Vare each, independently, H, C1-10alkyl, C2-10alkenyl, C2-1Q alkynyl, aryl, heteroaryl, or heterocyclyl; or a salt thereof. 12. The compound of claim 11 wherein R1.4is methoxy or - NR16R17, wherein R16and R17are each, independently, H, C1-1Oalkyl, C2-10alkenyl, C2-10alkynyl, aryl, heteroaryl, or heterocyclyl; or a salt thereof. 13. The compound of claim 11 wherein R14is -OR15, wherein R15is H, C3-10alkyl, C2-10alkenyl, or C2-10alkynyl; or a salt thereof. 14. The compound of claim 12, wherein R14is -NR16Rj7, wherein Rχ6and Rn are each, independently, H or aryl; R2, R3, R4, R5, Rβf R7, Rβr R9/ R1Of and Rn are each independently, H, -NR2eR29, or -OR28, wherein R28and R29are each, H or C1-10alkyl; or a salt thereof. 15. The compound of claim 14, wherein R14is -NH-phenyl; R2/ R5/ Rβ/ R7» R10/ and Rn are each H; R3, R4, Re, and Rg are each, independently, H, -OH, or - OCH3; or a salt thereof . 16. The compound of claim 15 having the structure : , or a salt thereof. 17. The compound of claim 11 having the structure wherein R3, R4, Re, and Rg are H, -OCH3, or -OH; R14is methoxy or -N(CH3J2; or a salt thereof. 18. The compound of claim 17 having the structure or a salt thereof. 19. The compound of claim 12 wherein R14is methoxy; R2, R3, R4, R5, R6, R7, R8, R9, R10, and R11are each, independently, H, -OH, -OCH3, -NO2, or -CO2CH3; or a salt thereof. 20. The compound of claim 19 having the structure  or a salt thereof. 21. The compound of claim 1, wherein X is N; or a salt thereof. 22. The compound of claim 21, wherein a and β are both present; or a salt thereof. 23. The compound of claim 19 having the structure: 0 0 or a salt thereof. 24. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of any one of claims 1-23. 25. A method of inhibiting the activity and/or levels of a matrix metalloproteinase (MMP) comprising contacting the matrix metalloproteinase or a cell producing an MMP or MMPs with the compound of any one of claims 1-23 so as to inhibit the activity of a matrix metalloproteinase. 26. The method of claim 25 wherein the matrix metalloproteinase is MMP-I, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-12, MMP-13, or MMP-14. 27. A method of inhibiting the production of a cytokine in a population of mammalian cells comprising contacting the population of cells with the compound of any one of claims 1-23 so as to inhibit production of a cytokine. 28. The method of claim 27 wherein the population of cells is a population of human cells. 29. The method of claim 27 wherein the cytokine is TNF-α, IL-lβ, MCP-I, or IL-6. 30. The method of claim 27 wherein the production of a cytokine is induced by an endotoxin, lipopolysaccharide (LPS) , a hormone, or a cholesterol complex. 31. A method of inhibiting the production of a growth factor in a population of mammalian cells comprising contacting the population of cells with the compound of any one of claims 1-23 so as to inhibit production of a growth factor. 32. The method of claim 31 wherein the growth factor is VEGF, PDGF, TGF-β, or MIPIa. 33. A method of inhibiting NFK-B activation in a population of cells comprising contacting the population of cells with the compound of any one of claims 1-23 so as to inhibit NFK-B activation. 34. The method of claim 33 wherein the population of cells is a population of human cells. 35. A method of increasing water solubility, metal binding ability, MMP inhibition activity, cytokine inhibition activity, growth factor inhibition activity, or NFKB activation inhibition activity of curcumin comprising synthesizing a compound having the structure wherein bond α and β are each, independently, present or absent; X is CR5or N; Y is CR10or N; R1is H or an electron-withdrawing group; R2, R3, R4, R5, R6, R7, R8, R9, R10, and R11are each independently, H, halogen, -NO2, -CN, -NR28R29/ -NHR28R2S+, - SR28, -SO2R28, -OR28, -CO2R2S, CF3, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, aryl, heteroaryl, or heterocyclyl; wherein R28and R29are each, H, CF3, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, or -C (=0) -heterocyclyl; and wherein when R1is H, R3, R4, R5, Re, R9, or R10, is halogen, -NO2, -CN, -NR28R29, -NHR2eR29+, -SR23, -SO2R28, - CO2R28/CF3, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, aryl, heteroaryl, or heterocyclyl; wherein R28and R29are each, H, CF3, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, or -C (=0) -heterocyclyl; and wherein each occurrence of alkyl, alkenyl, or alkynyl is branched or unbranched, unsubstituted or substituted; or a salt thereof. 36. The method of claim 35, wherein the compound synthesized has the structure wherein bond α and β are each, independently, present or absent; R1is an electron-withdrawing group; R2, R3, R4r R5/ R6» R7f Rβf K-9/ R10/ and Rn are each independently, H, halogen, -NO2, -CN, -NR28R29, -SR2e, - SO2R2S/ -OR28, -CO2R28, CF3, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, aryl, heteroaryl, or heterocyclyl; wherein R28and R2a are each, H, CF3, C1-10alkyl, C2-1Oalkenyl, or C2-10alkynyl; and wherein each occurrence of alkyl, alkenyl, or alkynyl is branched or unbranched, unsubstituted or substituted; and wherein at least one of R2, R3, R4, R5, and Rs and at least one of R7/Re, R9, R10, and Rn, are each, independently, - OR28; or a salt thereof. 37. The method of claim 36 wherein the compound synthesized has the structure wherein R1is an electron-withdrawing group; R2, R3, R4, R5, R6, R7, Re, R9, R10, and Rn are each independently, H, halogen, -NO2, -CN, -NR28R29, -SR28, - SO2R2S, -OR28, -CO2R2S, CF3, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, aryl, heteroaryl, or heterocyclyl; wherein R28and R29are each, H, CF3, C1-10alkyl, C2-10alkenyl, or C2-10alkynyl; and wherein each occurrence of alkyl, alkenyl, or alkynyl is branched or unbranched, unsubstituted or substituted; and wherein at least one of R2, R3, R4, R5, and R6and at least one of R7, R8, R9, R10, and Rn, are each, independently, - OR28; or a salt thereof. 38. The method of claim 37, wherein the compound synthesized has the structure wherein R1is an electron-withdrawing group.

法律状态

(WO2010132815) LEGAL DETAILS FOR WO2010132815  Actual or expected expiration date=2012-11-15    Legal state=DEAD    Status=LAPSED     Event publication date=2010-05-14  Event code=WO/APP  Event indicator=Pos  Event type=Examination events  Application details  Application country=WO WOUS2010034971  Application date=2010-05-14  Standardized application number=2010WO-US34971     Event publication date=2010-11-18  Event code=WO/A1  Event type=Examination events  Published application with search report  Publication country=WO  Publication number=WO2010132815  Publication stage Code=A1  Publication date=2010-11-18  Standardized publication number=WO2010132815     Event publication date=2011-01-13  Event code=WO/A9  Event indicator=Pos  Event type=Examination events  International application or ISR republished with corrections, alterations  Publication country=WO  Publication number=WO2010132815  Publication stage Code=A9  Publication date=2011-01-13  Standardized publication number=WO2010132815     Event publication date=2012-11-15  Event code=WO/EETL  Event type=Event indicating Not In Force  PCT Application validity period expired. LEGAL DETAILS FOR DESIGNATED STATE DE  Actual or expected expiration date=2011-11-15    Legal state=DEAD    Status=LAPSED   Corresponding cc:  Designated or member state=DE     Event publication date=2011-11-15  Event code=WO/NENP  Event type=Event indicating Not In Force  Non-entry into the national phase in: Corresponding cc:  Designated or member state=DE  LEGAL DETAILS FOR DESIGNATED STATE EP3206488  Actual or expected expiration date=2030-05-14    Legal state=ALIVE    Status=PENDING   Corresponding cc:  Designated or member state=EP Corresponding appl: EP10775624  Application date in the designated or member state=2010-05-14   Application number in the designated or member state=2010EP-0775624 Corresponding cc:  Designated or member state=EP Corresponding pat: EP3206488  Publication stage code in the designated or member state=A1  Publication date in the designated or member state=2017-08-23   Publication number in the designated or member state=EP3206488    Event publication date=2011-01-05  Event code=WO/121  Event type=Designated states  EP: The EPO has been informed by wipo that ep was designated in this application Corresponding cc:  Designated or member state=EP     Event publication date=2011-11-17  Event code=WO/REEP  Event indicator=Pos  Event type=Entry into national phase  Request for entry into the European phase Corresponding cc:  Designated or member state=EP  LEGAL DETAILS FOR DESIGNATED STATE US2012095051  Actual or expected expiration date=2033-01-12    Legal state=ALIVE    Status=GRANTED   Corresponding cc:  Designated or member state=US Corresponding appl: US13319478  Application date in the designated or member state=2010-05-14   Application number in the designated or member state=2010US-13319478 Corresponding cc:  Designated or member state=US Corresponding pat: US2012095051  Publication stage code in the designated or member state=A1  Publication date in the designated or member state=2012-04-19   Publication number in the designated or member state=US20120095051    Event publication date=2011-12-07  Event code=WO/WWE  Event indicator=Pos  Event type=Entry into national phase  Wipo information: entry into national phase Corresponding cc:  Designated or member state=US     Event publication date=2015-11-17  Event code=US/STCHG  Patent Status changed by the national office Corresponding cc:  Designated or member state=US

专利类型码

A1A9

国别省市代码

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