Rel inhibitors and methods of use thereof 机翻标题: 暂无翻译,请尝试点击翻译按钮。

公开号/公开日
WO2009089277 A2 2009-07-16 [WO200989277]WO2009089277 A3 2009-12-30 [WO200989277] / 2009-07-162009-12-30
申请号/申请日
2009WO-US30325 / 2009-01-07
发明人
CHEN YOUHAI H;MURALI RAMACHANDRAN;SUN JING;
申请人
UNIVERSITY OF PENNSYLVANIA;
主分类号
IPC分类号
A01N-051/00A61K-031/41
摘要
(WO200989277) This invention provides REL inhibitors which interfere with the DNA binding capacity of a REL protein.  Additionally this invention provides methods of treating, abrogating, or preventing diseases which respond with a positive clinical score to a REL inhibitor.  Methods of identifying REL inhibitor based on a REL protein three dimensional model are described.
机翻摘要
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地址
代理人
代理机构
;
优先权号
2008US-61006353 2008-01-08 2008US-61071374 2008-04-24
主权利要求
(WO200989277) WHAT IS CLAIMED IS; 1. A composition comprising a selective c-Rel: DNA binding inhibitor represented by: the structure of formula (I)  wherein Q1, Q2, Q3are independently H, halogen, CF3, OCH2Ph, O-alkyl, OCF3, alkyl, or Qi and Q2form a saturated or unsaturated, substituted or unsubstituted, carbocyclic or heterocyclic ring with the aniline ring; X and Y are independently H, alkyl, or form a saturated or unsaturated, substituted or unsubstituted, carbocyclic or heterocyclic ring with N(Ri)(R2). Xi and Yi are independently H, alkyl, or X and Y form together a double bond, or form saturated or unsaturated, substituted or unsubstituted, carbocyclic or heterocyclic ring with N(RO(R2). Ri and R2are independently H, NH2, -N=alkyl, -alkyl, -CH(Ph)2, substituted or unsubstituted aryl, carbocyclic or heterocyclic aryl, substituted or unsubstituted phenyl, C(O)-alkyl, or Ri and R2form a saturated or unsaturated, substituted or unsubstituted, carbocyclic or heterocyclic ring with the nitrogen atom; or by the structure of formula (II):  Wherein L1, L2, L3and L4are independently H, halogen, alkyl, -NH2, -COO Alkyl, -NO2, pyrrolidine, -O-alkyl, or Li and L2form a saturated or unsaturated, substituted or unsubstituted, carbocyclic or heterocyclic fused ring with the benzene ring; or L4together with R2forms a 6 memebered fused ring with the imidazole and benzene rings; R and Ri are independently H, NHCO-alkyl, or form together a double bond (=), or an oco group (=0); R2is H, SH, OH, alkyl, -Ph-CF3, -CH=C(Ph)-OC(O)-Ph, CH2-S-Ph, CH2-S -heterocyclic ring, CH2OC(O)NH-Ph, -NHCH2CH2OH, -alkylene-OH, O-aryl, -O-alkyl, 0-CH2-Ph, O-phenyl, O- phenyl-alkyl, O-Ph-0-alkylene-Ph, -OCH2Ph, -OCH2CH=CH-Ph, -S-Phenyl, NH-alkyl, NH- phenyl, NH-aryl, -N(Me)-alkylene-phenyl, -NH-alkylene-phenyl, -NH-alkylene-OMe, -NH- N=CH-Ph, -NH-N-C(O)-alkyl, -NH-heterocyclic ring, NH-carbocyclic ring, -C(O)Ph, substituted or unsubstituted, saturated or unsatureated hetrocyclic ring, substituted or unsubstituted, saturated or unsaturated carbocyclic ring, or R2together with L4forms a 6 membered fused ring with the imidazole and benzene rings; R3is H, COO-alkyl, COOH, NO2, substituted or unsubstituted Ph, C(O)-N=NC(O)Ph or C(O)NH2; and; R4 is H, Ph, alkyl, NH2, OH, Ph-OH or CH2-OH; or by the structure of formula (CXIX):  Wherein Riis substituted phenyl or unsubstituted phenyl; R2is wherein Xi1X2, or X3are independently H, halogen, alkyl, CN, COOH, or NH2; or X3forms with the =N+a five membered fused ring; or R2forms with =N+a five or six substituted or unsubstituted membered ring, or their pharmaceutical salt. 2. The composition of claim 1 , wherein the inhibitor interact with Ll cavity on the surface of the c-Rel. 3. The composition of claim 1 , wherein said Ll cavity comprises amino acids Arg 21 , Cys 26, Glu 27, Lys l lO. and Lys 111. 4. The composition of claim 1, comprising the compound represented by the structure of formula (IE), or its pharmaceutical salt:  5. The composition of claim 1, comprising the compound represented by the structure of formula (IV), (V) or their pharmaceutical salt. 6. The composition of claim 1, comprising the compound represented by the structure of formula (CXX), or its pharmaceutical salt:  7. Use of the composition of claim 1 for preventing, inhibiting, suppressing or ameliorating symptoms associated with inflammatory conditions that are multiple sclerosis, arthritis, diabetes, colitis, lupus, autoimmunity, graft rejection, or a combination thereof. 8. A method of inhibiting or suppressing the interaction between c-Rel and a DNA, comprising the step of contacting the c-Rel with a compound capable of masking the Ll cavity of the c- ReI, thereby inhibiting or suppressing the interaction between c-Rel and a DNA and inflammatory immune response. 9. The method of claim 8, whereby the compound capable of masking the Ll cavity of the c- ReI is represented by: the compound set forth by the structure of formula (I)  wherein Qi, Q2, Q3are independently H, halogen, CF3, OCH2Ph, O-alkyl, OCF3 . alkyl, or Qi and Q2form a saturated or unsaturated, substituted or unsubstituted, carbocyclic or heterocyclic ring with the aniline ring; X and Y are independently H, alkyl, or form a saturated or unsaturated, substituted or unsubstituted, carbocyclic or heterocyclic ring with N(R1)(R2). Xi and Yi are independently H, alkyl, or X and Y form together a double bond, or form saturated or unsaturated, substituted or unsubstituted, carbocyclic or heterocyclic ring with N(RO(R2). Ri and R2are independently H, NH2, -N=alkyl, -alkyl, -CH(Ph)2, substituted or unsubstituted aryl, carbocyclic or heterocyclic aryl, substituted or unsubstituted phenyl, C(O)-alkyl, or Ri and R2form a saturated or unsaturated, substituted or unsubstituted, carbocyclic or heterocyclic ring with the nitrogen atom; or by the compound set forth by the structure of formula (II):  Wherein L1, L2, L3and L4are independently H, halogen, alkyl, -NH2, -COO Alkyl, -NO2, pyrrolidine, -O-alkyl, or Li and L2form a saturated or unsaturated, substituted or unsubstituted, carbocyclic or heterocyclic fused ring with the benzene ring; or L4together with R2forms a 6 memebered fused ring with the imidazole and benzene rings; R and Ri are independently H, NHCO-alkyl, or form together a double bond (=), or an oco group (=0); R2is H, SH, OH, alkyl, -Ph-CF3, -CH=C(Ph)-OC(O)-Ph, CH2-S-Ph, CH2-S -heterocyclic ring, CH2OC(O)NH-Ph, -NHCH2CH2OH, -alkylene-OH, O-aryl, -O-alkyl, 0-CH2-Ph, O-phenyl, O- phenyl-alkyl, O-Ph-0-alkylene-Ph, -OCH2Ph, -OCH2CH=CH-Ph, -S-Phenyl, NH-alkyl, NH- phenyl, NH-aryl, -N(Me)-alkylene-phenyl, -NH-alkylene-phenyl, -NH-alkylene-OMe, -NH- N=CH-Ph, -NH-N-C(O)-alkyl, -NH-heterocyclic ring, NH-carbocyclic ring, -C(O)Ph, substituted or unsubstituted, saturated or unsatureated hetrocyclic ring, substituted or unsubstituted, saturated or unsaturated carbocyclic ring, or R2together with L4forms a 6 membered fused ring with the imidazole and benzene rings; R3is H, COO-alkyl, COOH, NO2, substituted or unsubstituted Ph, C(O)-N=NC(O)Ph or C(O)NH2; and; R4 is H, Ph, alkyl, NH2, OH, Ph-OH or CH2-OH; or by the compound set forth by the structure of formula (CXIX):  Wherein Riis substituted phenyl or unsubstituted phenyl; R2is wherein Xi X2, or X3are independently H, halogen, alkyl, CN, COOH, or NH2; or X3forms with the =N+a five membered fused ring; or R2forms with =N+a five or six substituted or unsubstituted membered ring, or their pharmaceutical salt 10. The method of claim 9, wherein said inhibitor further inhibits the production of interleukin- 2, interferon-gamma, or the combination thereof. 11. The method of claim 9, wherein said Ll cavity comprises the amino acids Arg 21 , Cys 26, Glu 27, Lys l lO. and Lys 111. 12. The method of claim 9, whereby the compound capable of masking the Ll cavity of the c- ReI is represented by the structure of formula (III), or its pharmaceutical salt:  13. The method of claim 9, whereby the compound capable of masking the Ll cavity of the c- ReI is represented by the structure of formula (IV), (V) or their pharmaceutical salt. 14. The method of claim 9, whereby the compound capable of masking the Ll cavity of the c- ReI is represented by the structure of formula (CXX), or its pharmaceutical salt:  15. A method of treating, inhibiting or suppressing, or meliorating symptoms associated with multiple sclerosis, arthritis, diabetes, graft rejection, or a combination thereof in a subject, comprising the step of contacting the subject with a composition comprising a selective c- Rel:DNA binding inhibitor wherein said c-Rel DNA binding inhibitor masks the Ll cavity of the c-Rel protein, thereby treating, inhibiting or suppressing, or meliorating symptoms associated with inflammatory conditions that are multiple sclerosis, arthritis, diabetes, colitis, lupus, autoimmunity, graft rejection, or a combination thereof in the subject. 16. The method of claim 15 , whereby the inhibitor further inhibits the production of interleukin- 2, interferon-gamma, or both. 17. The method of claim 15, whereby said Ll cavity comprises amino acids; Arg 21, Cys 26, Glu 27, Lys l lO, and Lys 111. 18. The method of claim 15 , whereby said composition comprises a compound set forth by: the structure represented by formula (I):  wherein Q1, Q2, Q3are independently H, halogen, CF3, OCH2Ph, O-alkyl, OCF3 . alkyl, or Qi and Q2form a saturated or unsaturated, substituted or unsubstituted, carbocyclic or heterocyclic ring with the aniline ring; X and Y are independently H, alkyl, or form a saturated or unsaturated, substituted or unsubstituted, carbocyclic or heterocyclic ring with N(Ri)(R2). Xi and Yi are independently H, alkyl, or X and Y form together a double bond, or form saturated or unsaturated, substituted or unsubstituted, carbocyclic or heterocyclic ring with N(Ri)(R2). Ri and R2are independently H, NH2, -N=alkyl, -alkyl, -CH(Ph)2, substituted or unsubstituted aryl, carbocyclic or heterocyclic aryl, substituted or unsubstituted phenyl, C(O)-alkyl, or Ri and R2form a saturated or unsaturated, substituted or unsubstituted, carbocyclic or heterocyclic ring with the nitrogen atom; or by the structure of formula (II):  wherein Li, L2, L3and L4are independently H, halogen, alkyl, -NH2, -COOAlkyl, -NO2, pyrrolidine, -O-alkyl, or Li and L2form a saturated or unsaturated, substituted or unsubstituted, carbocyclic or heterocyclic fused ring with the benzene ring; or L4together with R2forms a 6 memebered fused ring with the imidazole and benzene rings; R and Ri are independently H, NHCO-alkyl, or form together a double bond (=), or an oco group (=0); R2is H, SH, OH, alkyl, -Ph-CF3, -CH=C(Ph)-OC(O)-Ph, CH2-S-Ph, CH2-S -heterocyclic ring, CH2OC(O)NH-Ph, -NHCH2CH2OH, -alkylene-OH, O-aryl, -O-alkyl, 0-CH2-Ph, O-phenyl, O- phenyl-alkyl, O-Ph-0-alkylene-Ph, -OCH2Ph, -OCH2CH=CH-Ph, -S-Phenyl, NH-alkyl, NH- phenyl, NH-aryl, -N(Me)-alkylene-phenyl, -NH-alkylene-phenyl, -NH-alkylene-OMe, -NH- N=CH-Ph, -NH-N-C(O)-alkyl, -NH-heterocyclic ring, NH-carbocyclic ring, -C(O)Ph, substituted or unsubstituted, saturated or unsatureated hetrocyclic ring, substituted or unsubstituted, saturated or unsaturated carbocyclic ring, or R2together with L4forms a 6 membered fused ring with the imidazole and benzene rings; R3is H, COO-alkyl, COOH, NO2, substituted or unsubstituted Ph, C(O)-N=NC(O)Ph or C(O)NH2; and; R4 is H, Ph, alkyl, NH2, OH, Ph-OH or CH2-OH; or by the structure of formula (CXIX):  Wherein Rάs substituted phenyl or unsubstituted phenyl; R2is wherein X1,X2, or X3are independently H, halogen, alkyl, CN, COOH, or NH2; or X3forms with the =N+a five membered fused ring; or R2forms with =N+a five or six substituted or unsubstituted membered ring, or their combination. 19. The method of claim 15, whereby said composition comprises a compound set forth by formula (in):  20. The method of claim 15, whereby said composition comprises a compound set forth by formula (CXX):
法律状态
(WO200989277) LEGAL DETAILS FOR WO2009089277  Actual or expected expiration date=2011-07-08    Legal state=DEAD    Status=LAPSED     Event publication date=2009-01-07  Event code=WO/APP  Event indicator=Pos  Event type=Examination events  Application details  Application country=WO WOUS2009030325  Application date=2009-01-07  Standardized application number=2009WO-US30325     Event publication date=2009-07-16  Event code=WO/A2  Event type=Examination events  International application published with declaration under Article 17 (2) (a)  Publication country=WO  Publication number=WO2009089277  Publication stage Code=A2  Publication date=2009-07-16  Standardized publication number=WO200989277     Event publication date=2009-12-30  Event code=WO/A3  Event indicator=Pos  Event type=Examination events  Later publication of ISR with revised front page  Publication country=WO  Publication number=WO2009089277  Publication stage Code=A3  Publication date=2009-12-30  Standardized publication number=WO200989277     Event publication date=2011-07-08  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=2010-07-09    Legal state=DEAD    Status=LAPSED   Corresponding cc:  Designated or member state=DE     Event publication date=2010-07-09  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 EP2242367  Actual or expected expiration date=2013-01-03    Legal state=DEAD    Status=LAPSED   Corresponding cc:  Designated or member state=EP Corresponding appl: EP09700217  Application date in the designated or member state=2009-01-07   Application number in the designated or member state=2009EP-0700217 Corresponding cc:  Designated or member state=EP Corresponding pat: EP2242367  Publication stage code in the designated or member state=A2  Publication date in the designated or member state=2010-10-27   Publication number in the designated or member state=EP2242367    Event publication date=2009-09-16  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=2013-07-17  Event code=EP/STCHG  Patent Status changed by the national office Corresponding cc:  Designated or member state=EP  LEGAL DETAILS FOR DESIGNATED STATE US2011118325  Actual or expected expiration date=2029-10-19    Legal state=ALIVE    Status=GRANTED   Corresponding cc:  Designated or member state=US Corresponding appl: US12812224  Application date in the designated or member state=2009-01-07   Application number in the designated or member state=2009US-12812224 Corresponding cc:  Designated or member state=US Corresponding pat: US2011118325  Publication stage code in the designated or member state=A1  Publication date in the designated or member state=2011-05-19   Publication number in the designated or member state=US20110118325    Event publication date=2010-11-08  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=2017-06-01  Event code=US/STCHG  Patent Status changed by the national office Corresponding cc:  Designated or member state=US
专利类型码
A2A3
国别省市代码
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