AZA nucleosides, preparation thereof and use as inhibitors of RNA viral polymerases 机翻标题: 暂无翻译,请尝试点击翻译按钮。

公开号/公开日
US2007099942 A1 2007-05-03 [US20070099942]US7560434 B2 2009-07-14 [US7560434] / 2007-05-032009-07-14
申请号/申请日
2005US-11157867 / 2005-06-22
发明人
BABU YARLAGADDA S;CHAND POORAN;GHOSH AJIT K;KOTIAN PRAVIN L;KUMAR V SATISH;
申请人
BIOCRYST PHARMACEUTICALS;MDCP;
主分类号
IPC分类号
A01N-043/04A61K-031/70
摘要
(US7560434) Compounds represented by the formula: and pharmaceutically acceptable salts thereof and prodrugs thereof; wherein R1 is H, CH3, C2H5, C3H7 R2 is H, CH3, C2H5, C3H7, CH-CH2, CH2-OH, CH2F, CF3 R'2 is H, OH, NH2, NH-alkyl, F, N3, OCH3, O-C(O)CH(NH2)alkyl R3 is H, CH3, C2H5, C3H7 R'3 is H, OH, NH2, NH-alkyl, F, N3, OCH3, O-C(O)CH(NH2)alkyl R4 is H, CH3, C2H5, C3H7 At least one of R2, R3, or R4has to be other than H, when X-NH in B R6 is H, CH3, C2H5, R7 is selected from H, alkyl, alkenyl, aryl, acyloxyalkyl, and pivaloyloxyalkyl, aminoacids, CH2CH2SC(O)alkyl; and B is represented by the following structure: X is independently NR6, O, S, R8 and R9 independently is H, NH2, OH, SH, F, Cl, Br, I, aryl, heterocycle, alkyl, alkene, alkyne, S-alkyl, S-aryl, S(O)-alkyl, SO2-alkyl, SO2NH2, SO2NH-alkyl, SO2NH-aryl, NH-alkyl, NH-aryl, N(alkyl)2, N(aryl)2, O-alkyl, O-aryl, O-heterocycle, NH-(CH2)n-aryl, NH-C(O)-alkyl, NH-C(O)-aryl are useful for inhibiting viral RNA polymerases and treating patients suffering from diseases caused by various RNA viruses.
机翻摘要
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地址
代理人
代理机构
;
优先权号
2004US-60581377 2004-06-22 2005US-11157867 2005-06-22
主权利要求
(US7560434) What is claimed is: 1.  A compound or a pharmaceutically acceptable salt thereof represented by the formula:   wherein,   R1 is H, CH3, C2H5, or C3H7;   R2 is H, CH3, C2H5, C3H7, CH.dbd.CH2, CH2 -- OH, CH2F, or CF3;   R'2 is OH, NH2, NH-alkyl, F, N3, OCH3, or O -- C(O)CH(NH2)alkyl;   R3 is H, CH3, C2H5, or C3H7;   R'3 is H, OH, NH2, NH-alkyl, F, N3, OCH3, or O -- C(O)CH(NH2)alkyl;   R4 is H, CH3, C2H5, or C3H7;    at least one of R2, R3, and R4 has to be other than H, when X.dbd.NH in B   R6 is H or    R7 is selected from H, alkyl, alkenyl, aryl, acyloxyalkyl, and pivaloyloxyalkyl, aminoacids, and CH2CH2SC(O)alkyl;   B is represented by the following structure:    X is NR6, O, or S;   R8 is H, NH2, OH, SH, F, Cl, Br, I, aryl, heterocycle, alkyl, alkene, alkyne, S-alkyl, S-aryl, S(O)-alkyl, SO2-alkyl, SO2NH2, SO2NH-alkyl, SO2NH-aryl, NH-alkyl, NH-aryl, N(alkyl)2, N(aryl)2, O-alkyl, O-aryl, O-heterocycle, NH-(CH2)n-aryl, NH -- C(O)-alkyl, or NH -- C(O)-aryl; and   R9 is H, NH2, OH, SH, F, Cl, Br, I, aryl, heterocycle, alkyl, alkene, alkyne, S-alkyl, S-aryl, S(O)-alkyl, SO2-alkyl, SO2NH2, SO2NH-alkyl, SO2NH-aryl, NH-alkyl, NH-aryl, N(alkyl)2, N(aryl)2, O-alkyl, O-aryl, O-heterocycle, NH-(CH2)n-aryl, NH -- C(O)-alkyl, or NH -- C(O)-aryl. 2. A compound selected from the group consisting of: (2R,3R,4S,5S)-2-(Hydroxymethyl)-5-(4-(methoxyamino)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)pyrimidine-3,4-diol,   (2R,3R,4S,5S)-2-(Hydroxymethyl)-5-(4-(1-methylhydrazinyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)pyrrolidine-3,4-diol,   (2S,3S,4R,5R)-2-(4-(1-Ethylhydrazinyl)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-5-(hydroxymethyl)pyrimidine-3,4-diol,   (2S,3S,4R,5R)-2-(4-(Dimethylamino)-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-5-(hydroxymethyl)pyrromidine-3,4-diol,   (2R,3R,4R)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-4-methylpyrrolidine,   (2R,3R,4S)-3,4-Bis(benzyloxy)-2-(benzyloxymethyl)-4-methylpyrrolidine,   (2R,3R,4S)-2-(Hydroxymethyl)-4-methylpyrrolidine-3,4-diol hydrochloride,   (3aS,6R,6aR)-6-((tert-Butyldimethylsilyloxy)methyl)-2,2,3a-trimethyl-tetrahydro-3aH-[1,3]dioxolo[4,5-c]pyrrole,   (2S,3S,4R,5R)-2-(4-Amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)-5-(hydroxymethyl)-3-methylpyrrolidine-3,4-diol,   (2S,3S,4R,5R)-2-(4-Aminopyrazolo[1,5-a][1,3,5]triazin-8-yl)-5-(hydroxymethyl)pyrrolidine-3,4-diol,   (2S,3S,4R,5R)-2-(4-Aminopyrazolo[1,5-a][1,3,5]triazin-8-yl)-5-(hydroxymethyl)-3-methylpyrrolidine-3,4-diol,   7-((2S,3S,4R,5R)-3,4-Dihydroxy-5-(hydroxymethyl)pyrrolidin-2-yl)-2-(methylthio)-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one,   7-((2S,3S,4R,5R)-3,4-Dihydroxy-5-(hydroxymethyl)-3-methylpyrrolidin-2-yl)-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one,   (2S,3S,4R,5R)-2-(4-Aminothieno[3,2-d]pyrimidin-7-yl)-5-(hydroxymethyl)-3-methylpyrrolidine-3,4-diol,   (2S,3S,4R,5R)-2-(4-Aminofuro[3,2-d]pyrimidin-7-yl)-5-(hydroxymethyl)-3-methylpyrrolidine-3,4-diol, and   ((2S,5R)-5-(4-Amino-5H-pyrrolo[3,2-d]pyrimidin-7-yl)pyrrolidin-2-yl)methyl dihydrogen phosphate. 3. A pharmaceutical composition comprising a compound according to any one of claims 1 and 2, and a pharmaceutical carrier. 4. A method for inhibiting RNA viral polymerase comprising administering to a patient in need thereof an effective amount of at least one compound according to any one of claims 1 and 2. 5. A method for inhibiting HCV polymerase comprising administering to a patient in need thereof an effective amount of at least one compound according to any one of claims 1 and 2. 6. A method for inhibiting HBV polymerase comprising administering to a patient in need thereof an effective amount of at least one compound according to any one of claims 1 and 2. 7. A method for inhibiting Rhino polymerase comprising administering to a patient in need thereof an effective amount of at least one compound according to any one of claims 1 and 2. 8. A method for inhibiting small pox polymerase comprising administering to a patient in need thereof an effective amount of at least one compound according to any one of claims 1 and 2. 9. A method for inhibiting Ebola polymerase comprising administering to a patient in need thereof in an effective amount of at least one compound according to any one of claims 1 and 2. 10. A method for inhibiting polio virus polymerase comprising administering to a patient in need thereof an effective amount of at least one compound according to any one of claims 1 and 2. 11. A method for inhibiting West Nile polymerase comprising administering to a patient in need thereof an effective amount of at least one compound according to any one of claims 1 and 2. 12. A method for inhibiting Coxsackie A polymerase comprising administering to a patient in need thereof an effective amount of at least one compound according to any one of claims 1 and 2. 13. A method for inhibiting Coxsackie B polymerase comprising administering to a patient in need thereof an effective amount of at least one compound according to any one of claims 1 and 2. 14. A method for inhibiting Echo polymerase comprising administering to a patient in need thereof an effective amount of at least one compound according to any one of claims 1 and 2. 15. A method for treating a patient suffering from an RNA viral infection comprising administering said patient an effective amount of at least one compound according to any one of the claims 1 and 2. 16. A method for treating a patient suffering from HCV infection comprising administering to said patient an effective amount of at least one compound according to any one of the claims 1 and 2. 17. A method for treating a patient suffering from HBV infection comprising administering to said patient an effective amount of at least one compound according to any one of the claims 1 and 2. 18. A method for treating a patient suffering from a Rhino viral infection comprising administering to said patient an effective amount of at least one compound according to any one of the claims 1 and 2. 19. A method for treating a patient suffering from a small pox viral infection comprising administering to said patient an effective amount of at least one compound according to any one of the claims 1 and 2. 20. A method for treating a patient suffering from a Ebola viral infection comprising administering to said patient an effective amount of at least one compound according to any one of the claims 1 and 2. 21. A method for treating a patient suffering from a polio viral infection comprising administering to said patient an effective amount of at least one compound according to any one of the claims 1 and 2. 22. A method for treating a patient suffering from a West Nile viral infection comprising administering to said patient an effective amount of at least one compound according to any one of the claims 1 and 2. 23. A method for treating a patient suffering from a Coxsackie A viral infection comprising administering to said patient an effective amount of at least one compound according to any one of the claims 1 and 2. 24. A method for treating a patient suffering from a Coxsackie B viral infection comprising administering to said patient an effective amount of at least one compound according to any one of the claims 1 and 2. 25. A method for treating a patient suffering from an Echo viral infection comprising administering to said patient an effective amount of at least one compound according to any one of the claims 1 and 2. 26. A method for inhibiting in a patient RNA viral polymerase comprising administering to a patient in need thereof an effective amount of at least one compound according to any one of claims 1 and 2 and at least one further therapeutic agent related from the group consisting of interferon (IFN), interferon alpha -2a, interferon alpha -2b, consensus interferon (CIFN), ribavirin, amantadine, rimantadine, interleukine-12, ursodeoxycholic acid (UDCA), and glycyrrhizin, and inhibiting RNA viral polymerase. 27. The method of claim 26 wherein the RNA viral polymerase comprises at least one member selected from the group consisting of HCV polymerase, HBV polymerase, Rhino polymerase, small pox virus polymerase, Ebola virus polymerase, Coxsackie A and B polymerase, Echo polymerase and west Nile virus polymerase. 28. A method for treating RNA viral infection comprising administering to a patient in need thereof an effective amount of at least one compound according to any one of claims 1 and 2 and at least one further therapeutic agent chosen from interferon (IFN), interferon alpha -2a, interferon alpha -2b, consensus interferon (CIFN), ribavirin, amantadine, rimantadine, interleukine-12, ursodeoxycholic acid (UDCA), and glycyrrhizin. 29. The method of claim 28 wherein the RNA viral infection comprises at least one member selected from the group consisting of HCV, HBV, Coxsackie A, Coxsackie B, Echo, Rhino viral infection, small pox viral infection, Ebola viral infection, polio viral infection and West Nile viral infection.
法律状态
(US7560434) LEGAL DETAILS FOR US2007099942  Actual or expected expiration date=2026-08-06    Legal state=ALIVE    Status=GRANTED     Event publication date=2005-06-22  Event code=US/APP  Event indicator=Pos  Event type=Examination events  Application details  Application country=US US11157867  Application date=2005-06-22  Standardized application number=2005US-11157867     Event publication date=2005-06-22  Event code=US/EXMR  Event type=Administrative notifications  USPTO Examiner Name Primary Examiner: LEWIS, PATRICK T    Event publication date=2005-06-22  Event code=US/ART  Event type=Administrative notifications  USPTO Art Group  ART=1623     Event publication date=2005-06-22  Event code=US/SMALL  Event type=Administrative notifications  Appl Has Filed a Verified Statement of Micro to Small Entity Status Business Entity Status: SMALL    Event publication date=2005-06-22  Event code=US/AIA  Event type=Administrative notifications  First Inventor File Indicated:  AIA=No     Event publication date=2005-06-22  Event code=US/DK  Event type=Examination events  Attorney Docket Number Docket Nbr: BPX-028.01    Event publication date=2005-06-22  Event code=US/CUST  Event type=Examination events  Attorney/Agent Customer Number Customer Nbr: 25181    Event publication date=2005-08-04  Event code=US/INCD  Event type=Examination events  Event type=OAO  Notice Mailed--Application Incomplete--Filing Date Assigned    Event publication date=2005-08-05  Event code=US/INCD  Event type=Examination events  Event type=OAO  Notice Mailed--Application Incomplete--Filing Date Assigned    Event publication date=2005-09-22  Event code=US/IDS  Event type=Examination events  Event type=OAI  Information Disclosure Statement Filed    Event publication date=2006-04-25  Event code=US/DOCK  Event indicator=Pos  Event type=Examination events  Case Docketed to Examiner    Event publication date=2007-05-03  Event code=US/A1  Event type=Examination events  Application published  Publication country=US  Publication number=US2007099942  Publication stage Code=A1  Publication date=2007-05-03  Standardized publication number=US20070099942     Event publication date=2007-05-03  Event code=US/PGPUBN  Event indicator=Pos  Event type=Examination events  Event type=OAO  PG-Pub Issue Notification    Event publication date=2007-10-29  Event code=US/CTNF  Event type=Examination events  Event type=OA  Event type=OAO  Non-Final Rejection    Event publication date=2008-01-10  Event code=US/CTNFR  Event type=Examination events  Event type=OAI  Response after Non-Final Action    Event publication date=2008-04-09  Event code=US/RESTREQ  Event type=Examination events  Event type=Corrections  Event type=OAO  Restriction/Election Requirement    Event publication date=2008-05-09  Event code=US/ELC  Event type=Examination events  Event type=OAI  Response to Election / Restriction Filed    Event publication date=2008-08-18  Event code=US/CTNF  Event type=Examination events  Event type=OA  Event type=OAO  Non-Final Rejection    Event publication date=2008-11-13  Event code=US/CTNFR  Event type=Examination events  Event type=OAI  Response after Non-Final Action    Event publication date=2009-01-21  Event code=US/DOCK  Event indicator=Pos  Event type=Examination events  Case Docketed to Examiner    Event publication date=2009-01-27  Event code=US/NOAM  Event indicator=Pos  Event type=Examination events  Event type=OAO  Mail Notice of Allowance    Event publication date=2009-02-19  Event code=US/AS  Event type=Change of name or address  Event type=Reassignment  Assignment  Effective date of the event=2004-06-22  ASSIGNMENT OF ASSIGNORS INTEREST ASSIGNORS:BABU, YARLAGADDA S. CHAND, POORAN EL-KATTAN, YAHYA AND OTHERS REEL/FRAME:022283/0963     Event publication date=2009-05-13  Event code=US/EXIN  Event type=Examination events  Event type=OAO  Event type=INT  Examiner Interview Summary Record (PTOL - 413)    Event publication date=2009-05-19  Event code=US/ANA  Event type=Corrections  Event type=OAI  Amendment after Notice of Allowance (Rule 312)    Event publication date=2009-06-10  Event code=US/N271  Event type=Examination events  Event type=OAO  Response to Amendment under Rule 312    Event publication date=2009-06-11  Event code=US/APRDY  Event indicator=Pos  Event type=Examination events  Application Is Considered Ready for Issue    Event publication date=2009-06-24  Event code=US/PAT  Event indicator=Pos  Event type=Event indicating In Force  Patented Case    Event publication date=2009-06-24  Event code=US/ISSM  Event indicator=Pos  Event type=Examination events  Event type=OAO  Event type=Restitution or restoration  Issue Notification Mailed    Event publication date=2009-07-14  Event code=US/B2  Event indicator=Pos  Event type=Event indicating In Force  Granted patent as second publication  Publication country=US  Publication number=US7560434  Publication stage Code=B2  Publication date=2009-07-14  Standardized publication number=US7560434     Event publication date=2009-07-14  Event code=US/354  Event indicator=Pos  Event type=Extension of term of duration of protection  Patent term extended under  35 U.S.C 154(b) until/for Delays (A,B,C): 435  Overlap Delays: 0  Non Overlap Delays: 435   PTO Office Delays: 0  Applicant Delays: 25  Adjustment total:  Number of days of extension=410    Event publication date=2012-07-24  Event code=US/NMFP  Event type=Payment or non-payment notifications  Publication of First Notice of Maintenance Fees Payable. PAYMENT NOTICE YEAR:  Year of payment of annual fees=3     Event publication date=2012-12-17  Event code=US/POAC  Event type=Change of name or address  Change in Power of Attorney (May Include Associate POA)    Event publication date=2012-12-19  Event code=US/FPAY  Event indicator=Pos  Event type=Event indicating In Force  Event type=Payment or non-payment notifications  Fee payment recorded   Annual fees payment date=2012-12-19     Year of payment of annual fees=4     Event publication date=2016-07-26  Event code=US/NMFP  Event type=Payment or non-payment notifications  Publication of First Notice of Maintenance Fees Payable. PAYMENT NOTICE YEAR:  Year of payment of annual fees=7     Event publication date=2016-09-26  Event code=US/AS  Event type=Change of name or address  Event type=Reassignment  Assignment  Effective date of the event=2016-09-23  SECURITY INTEREST ASSIGNORS:BIOCRYST PHARMACEUTICALS, INC. 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专利类型码
A1B2
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