Synthesis and antimalarial activity of pyrrolo[3,2-f]quinazoline-1,3-diamine derivatives 机翻标题: 暂无翻译,请尝试点击翻译按钮。

公开号/公开日
US2006094736 A1 2006-05-04 [US20060094736]US7253177 B2 2007-08-07 [US7253177] / 2006-05-042007-08-07
申请号/申请日
2004US-10971846 / 2004-10-22
发明人
LIN AI J;GUAN JIAN;ZHANG QUAN;SKILLMAN DONALD R;
申请人
US ARMY;
主分类号
IPC分类号
A01N-043/54A61K-031/505C07D-239/00C07D-471/00C07D-487/00C07D-491/00
摘要
(US7253177) The invention relates to derivatives of pyrroloquinazolinediamine, more specifically derivatives of 7-(substituted)-7H-pyrrolo[3,2-F] quinazoline-1,3-diamines that are non-toxic and are also effective in the treatment of malaria, including P. falciparum and P. vivax strains.  The derivatives are certain carbamate derivatives, succinimide derivatives, alkylcarboxamides derivatives and acetamide derivative, phthalimides, alkylamines and all other amide and imide derivatives and their 1-hydroxy analogs.  The derivatives of the present invention are also soluble in common organic solvents to facilitate the purification in a large scale synthesis of the composition.
机翻摘要
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地址
代理人
代理机构
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优先权号
2004US-10971846 2004-10-22
主权利要求
(US7253177) What is claimed is: 1.  A compound of the formula I: wherein R1 is H, CH3CH2OC.dbd.O, (CH3)2CHOC.dbd.O, (CH3)3COC.dbd.O, or(CH3)2CHCH2OC.dbd.OR2 is H, CH3CH2OC.dbd.O, (CH3)2CHOC.dbd.O, (CH3)3COC.dbd.O, or(CH3)2CHCH2OC.dbd.OR3 is H, CH3CH2OC.dbd.O, (CH3)2CHOC.dbd.O, (CH3)3COC.dbd.O,(CH3)2CHCH2OC.dbd.O, or R4 is H, CH3CH2OC.dbd.O, (CH3)3COC.dbd.O, (CH3)2CHCH2OC.dbd.O, or wherein R1, R2, R3 and R4 are not all simultaneously H. 2. The compound of claim 1, wherein: R1 is H, R2 is H, R3 is CH3CH2OC.dbd.O and R4 is H (2a). 3. The compound of claim 1, wherein R1 is CH3CH2OC.dbd.O, R2 is H, R3 is H, and R4 is H (2a'). 4. The compound of claim 1, wherein R1 is CH3CH2OC.dbd.O, R2 is H, R3 is CH3CH2OC.dbd.O, and R4 is H (2b). 5. The compound of claim 1, wherein R1 is CH3CH2OC.dbd.O, R2 is H, R3 and R4 are CH3CH2OC.dbd.O (2c). 6. The compound of claim 1, wherein R1, R2, R3 and R4 are CH3CH2OC.dbd.O (2d). 7. The compound of claim 1, wherein R1 is (CH3)2CHOC.dbd.O, R2 is H, R3 is (CH3)2CHOC.dbd.O, and R4 is H (2e). 8. The compound of claim 1, wherein R1 is H, R2, R3 and R4 are (CH3)2CHOC.dbd.O (2f). 9. The compound of claim 1, wherein R1, R2 and R4 are H, and R3 is (CH3)3COC.dbd.O (2 g). 10. The compound of claim 1, wherein R1 and R2 are H, and R3 and R4 are (CH3)3COC.dbd.O (2 h). 11. The compound of claim 1, wherein R1 is H, R2, R3 and R4 are (CH3)3COC.dbd.O (2i). 12. The compound of claim 1, wherein R1, R2, R3 and R4 are (CH3)3COC.dbd.O (2j). 13. The compound of claim 1, wherein R1, R2, and R4 are H, and R3 is (CH3)2CHCH2OC.dbd.O (2k). 14. The compound of claim 1, wherein R1 and R3 are (CH3)2CHCH2OC.dbd.O and R2 and R4 are H (21). 15. The compound of claim 1, wherein R1 and R2 are H and R3 and R4 are 16.  A compound of the formula: wherein R1, R2, R3, and R4 are independently a H, or CH3C.dbd.O,or alkylacyl, arylacyl, or a pharmaceutically acceptable salt thereof and, wherein R1, R2, R3 and R4 are not all simultaneously H. 17. The compound of claim 16, wherein R1, R2 and R4 are H, and R3 is CH3C.dbd.O (3a). 18. The compound of claim 16, wherein R1 and R2 are H and R3 and R4 are CH3C.dbd.O (3b). 19. The compound of claim 16, wherein R1 and R3 are CH3C.dbd.O and R2 and R4 are H (3c). 20. The compound of claim 16, wherein R1 is H, R2, R3 and R4 are CH3C.dbd.O (3d). 21. The compound of claim 16 wherein R1, R2, R3, R4 are CH3C.dbd.O (3e). 22. A compound of the formula 3: Wherein R1, and R2, are independently a NH2, or Where R1 and R2 are not all simultaneously NH2. 23. The compound of claim 22, wherein R1 is and R2 is H (3 f). 24. The compound of claim 22, wherein R1 and R2 are 25.  The compound of claim 22, wherein R1 is and R2 is H. 26. The compound of claim 22, wherein R1 and R2 are 27.  The compound of claim 22, wherein R1 is and R2 is H. 28. The compound of claim 22, wherein R1 and R2 are 29.  A compound comprising formula 4: Where R=CF3, CH3, CH3CH2, Cl, Br, or F. 30. A pharmaceutical composition comprising a compound of formula 5: wherein R1, R2, R3, and R4 are independently H, (CH3)2CH, (CH3)3C, and R5 is independently CF3, CH3, CH3CH2, Cl, Br, or F and, wherein R1, R2, R3 and R4 are not all simultaneously H. 31. An antimalaria composition comprising: a pharmaceutically effective dosage unit of 1-220 mg/kg for treating malaria of the compound of claim 1. 32. An antimalaria composition comprising: a pharmaceutically effective dosage unit of 1-220 mg/kg for treating malaria of the compound of claim 16. 33. An antimalaria composition comprising: a pharmaceutically effective dosage unit of 1-220 mg/kg for treating malaria of the compound of claim 22. 34. An antimalaria composition comprising: a pharmaceutically effective dosage unit of 1-220 mg/kg for treating malaria of the compound of claim 29. 35. A method of treating malaria in a patient in need thereof comprising: administering the compound of claim 1 at 1-16 mg/kg a day for 3-7 days or 1-220 mg/kg a day for 3 days. 36. A method of treating malaria in a patient in need thereof comprising: administering the compound of claim 16 at 1-16 mg/kg a day for 3-7 days or 1-220 mg/kg a day for 3 days. 37. A method of treating malaria in a patient in need thereof comprising: administering the compound of claim 29 at 1-16 mg/kg a day for 3-7 days or 1-220 mg/kg a day for 3 days. 38. A method of treating malaria in a patient in need thereof comprising: administering the compound of claim 30 at 1-16 mg/kg a day for 3-7 days or 1-220 mg/kg a day for 3 days. 39. The method of claim 35 further comprising administering one or more antimalarial composition selected from the group consisting of but not limited to chloroquine, mefloquine, tafenoquine, and artamisinin. 40. The method of claim 36 further comprising administering one or more antimalarial composition selected from the group consisting of but not limited to chloroquine, mefloquine, tafenoquine, and artamisinin. 41. The method of claim 37 further comprising administering one or more antimalarial composition selected from the group consisting of but not limited to chloroquine, mefloquine, tafenoquine, and artamisinin. 42. The method of claim 35 wherein said administering is done by oral route, transdermal, transmucosal, rectal, and intramuscular. 43. The method of claim 36 wherein said administering is done by oral route, transdermal, transmucosal, rectal, and intramuscular. 44. The method of claim 37 wherein said administering is done by oral route, transdermal, transmucosal, rectal, and intramuscular. 45. The method of claim 38 wherein said administering is done by oral route, transdermal, transmucosal, rectal, and intramuscular. 46. The method of claim 35, wherein said malaria is P. falciparum and/or P. vivax. 47. The method of claim 36, wherein said malaria is P. falciparum and/or P. vivax. 48. The method of claim 37, wherein said malaria is P. falciparum and/or P. vivax. 49. The method of claim 38, wherein said malaria is P. falciparum and/or P. vivax. 50. A pharmaceutical composition comprising a compound of the formula 6: Where R1, R2, R3, and R4 are independently H, CH3C.dbd.O, (CH2C.dbd.O)2, CH3CH2C.dbd.O, (CH3)2CHC.dbd.O, (CH3)3CC.dbd.O, oralkylC.dbd.O,R5 is independently F, Cl, Br, CH3, or CH3CH2 and, wherein R1, R2, R3 and R4 are not all simultaneously H. 51. A compound of the formula 7: R=F, Cl, Br, CH3, CF3, or CH3CH2. 52. A method of preparation of a first and second (2b and 2c) compound of claim 1, comprising:     a). mixing 7-[(2-trifluoromethyl-phenyl)methyl]-7H-pyrrolo[3,2-f]-quinazoline-1,3-diamine with triethylamine (1), and DMAP;  b). adding ethyl chloroformate at 0 deg. C.;c). bringing to room temperature and stirring;d). filtering with Celite to form a filtrate;e). washing the filtrate with H2O;f). concentrating the filtrate;g). eluting with 2% CH3OH/CHCl3 in a silica gel column to yield a first alkylcarbamate of the compound of claim 1 wherein R1 is CH3CH2OC.dbd.O,R2 is H, R3 is CH3CH2OC.dbd.O (2b) and R4 is H and a second alkylcarbamate of the compound of claim 1 wherein R1 is CH3CH2OC.dbd.O,R2 is H, R3 and R4 are CH3CH2OC.dbd.O (2c);  and    h). recrystallizing said first alkylcarbamate and said second alkylcarbamate to form first alkylcarbamate crystals and second alkylcarbamate crystals. 53. The method of claim 52 further comprising the steps of: (2a) suspending said first alkylcarbamate crystals(2b) in ethyl acetate to makea suspension;refluxing said suspension;evaporating until dry to obtain a residue;applying said residue on a TLC plate and developing with CH3OH/CHCl3 to yield a third alkylcarbamate 2a;  and    recrystalizing to give the third alkylcarbamate 2a crystals. 54. The method of claim 52 further comprising the steps of: (2a') suspending said first alkylcarbamate 2b crystals in CH3OH;adding HCl and refluxing;neutralizing with saturated NaHCO3;extracting with CHCl3 to form an organic layer,washing the organic layer with H2O and drying to form a residue;  and    applying the residue to a silica gel column and eluding withCH3OH/CHCl3 to yield a fourth alkylcarbamate 2a'. 55. A method of preparation of a compound of claim 1 (2e), comprising:     a). mixing 7-[(2-trifluoromethyl-phenyl)methyl]-7H-pyrrolo[3,2-f]-quinazoline-1,3-diamine with triethylamine (1), and DMAP;b). adding isopropyl chloroformate at 0 deg. C.;c). bringing to room temperature and stirring;d). filtering with Celite to form a filtrate;e). washing the filtrate with H2O;f). concentrating the filtrate;g). eluting with 2% CH3OH/CHCl3 in a silica gel column to yield a fifth alkylcarbamate of the compound of claim 1 wherein R1 is(CH3)2CHOC.dbd.O, R2 is H, R3 is (CH3)2CHOC.dbd.O, and R4 is H (2e);  and    h). recrystallizing said fifth alkylcarbamate to form fifth alkylcarbamate crystals. 56. A method of preparation of a compound of claim 1 (2f), comprising:     a). mixing 7-[(2-trifluoromethyl-phenyl)methyl]-7H-pyrrolo[3,2-f]-quinazoline-1,3-diamine with triethylamine, and DMAP;b). adding isopropyl chloroformate at 0 deg. C.;c). bringing to room temperature and stirring;d). filtering with Celite to form a filtrate;e). washing the filtrate with H2O;f). concentrating the filtrate;g). eluting with 2% CH3OH/CHCl3 in a silica gel column to yield a sixth alkylcarbamate of the compound of claim 1 wherein R1 is H, R2, R3 and R4 are (CH3)2CHOC.dbd.O (2f);  and    h). recrystallizing said sixth alkylcarbamate to form sixth alkylcarbamate crystals. 57. A method of preparation of a compound of claim 1 (2j), comprising:     a). mixing 7-[(2-trifluoromethyl-phenyl)methyl]-7H-pyrrolo[3,2-f]-quinazoline-1,3-diamine with triethylamine, and DMAP;b). adding t-butyl bicarbonate at 0 deg. C.;c). bringing to room temperature and stirring;d). filtering with Celite to form a filtrate;e). washing the filtrate with H2O;f). concentrating the filtrate;g). eluting with 2% CH3OH/CHCl3 in a silica gel column to yield a seventh alkylcarbamate of the compound of claim 1 wherein R1, R2, R3 and R4 are (CH3)3COC.dbd.O (2j);  and    h). recrystallizing said seventh alkylcarbamate to form seventh alkylcarbamate crystals. 58. A method of preparation of a compound of claim 1 (2l), comprising:     a). mixing 7-[(2-trifluoromethyl-phenyl)methyl]-7H-pyrrolo[3,2-f]-quinazoline-1,3-diamine with triethylamine, and DMAP;b). adding isobutyl chloroformate at 0 deg. C.;c). bringing to room temperature and stirring;d). filtering with Celite to form a filtrate;e). washing the filtrate with H2O;f). concentrating the filtrate;g). eluting with 2% CH3OH/CHCl3 in a silica gel column to yield an eighth alkylcarbamate of the compound of claim 1 wherein R1 and R3 are (CH3)2CHCH2OC.dbd.O and R2 and R4 are H (2l);  and    h). recrystallizing said eighth alkylcarbamate to form eighth alkylcarbamate crystals. 59. A method of preparation of a compound of claim 1 (2m), comprising:     a). mixing 7-[(2-trifluoromethyl-phenyl)methyl]-7H-pyrrolo[3,2-f]-quinazoline-1,3-diamine with triethylamine, and DMAP;b). adding 2-chlorobenzyl chloroformate at 0 deg. C.;c). bringing to room temperature and stirring;d). filtering with Celite to form a filtrate;e). washing the filtrate with H2O;f). concentrating the filtrate;g). eluting with 2% CH3OH/CHCl3 in a silica gel column to yield a ninth alkylcarbamate of the compound of claim 1 wherein, R1 and R2 are H and R3 and R4 are (2m);    and h). recrystallizing said ninth alkylcarbamate to form ninth alkylcarbamate crystals. 60. A method of preparation of the compounds of claim 16, (3a-3e) comprising:     a). suspending 7-[2-trifluoromethyl-phenyl)methyl]-7H-pyrrolo[3 ,2-f]quinazoline-1,3-diamine (1) in anhydrous chloroform to form a suspension;b). adding dimethylaminopyridine and triethylamine at room temperature to form a first mixture;c). cooling said first mixture to about 5 deg. C. with an ice-bathd). adding acetic anhydride to said first mixture to form a second mixture;e). stirring said second mixture at about 5 deg. C. and then heating at 80 deg. C. for 48 hours;f). removing solvent from said second mixture and distilling excess acetic anhydride to form a solid;g). purifying said solid with silica gel column chromatography using ethylacetate in chloroform to yield solid;h). purifying said solid by recrystallization with EtOAc/Hexanes to yield crystals ofa first acetamide 3a wherein R1, R2 and R4 are H, and R3 is CH3C.dbd.O,a second acetamide 3b wherein R1 and R2 are H and R3 and R4 are CH3C.dbd.O,a third acetamide 3c wherein R1 and R3 are CH3C.dbd.O and R2 and R4 are H,a forth acetamide 3d wherein R1 is H, R2, R3 and R4 are CH3C.dbd.O, and afifth acetamide 3e wherein R1, R2, R3, R4 are CH3C.dbd.O. 61. A method of preparation of a compound of claim 22, comprising:     a). suspending 7-[(2-trifluoromethyl-phenyl)methyl]-7H-pyrrolo[3,2-f]-quinazoline-1,3-diamine (1) in anhydrous p-xylene to form a suspension;b). adding dry molecular sieves, DMAP and succinic anhydride to said suspension at room temperature and stirring;c). adding triethylamine at room temperature;d). refluxing;e). cooling;f). filtering to remove the molecular sieves;g). evaporating until dry to form a solid residue;h). purifying the solid residue first with a flush silica gel column using ethyl acetate in chloroform as eluent to provide an amorphous solid;  and    i). recrystallizing with CHCl3/acetone to form crystals of a first succinimide (3 f) wherein R1 is and R2 is H and a second succinimide (3 g) wherein R1 and R2 are 62.  A method of preparing the compound of claim 29, comprising: a). adding hydrochloric acid to a reaction mixture of 7-(2-trifluoromethyl)benzyl-7H-pyrrolo[3,2-f]-quinazoline-1,3-diamine in DMF at room temperature to make an aqueous solution;  refluxing said aqueous solution; b). chilling the aqueous solution and adjusting the pH of the solution to pH 7 with NaOH to form a tan color precipitate; c). collecting the tan color precipitate and washing with water and drying in vacuo to form a crude product; d). purifying the crude product by flush silica gel column chromatography using methanol in CHCl3 as eluent to yield said compound of formula 4. 63. A method of preparing the compound of claim 30, comprising:     a). adding NaH in small portions at room temperature to a suspension of 7-(2-trifluoromethyl)benzyl-7H-pyrrolo[3,2-f]-quinazoline-1,3-diamine (1) in anhydrous THF to form a reaction mixture;b). stirring the reaction mixture and then adding ethyl bromide to form a resulting reaction mixture;c). stirring the resulting reaction mixture at room temperature;d). quenching with H2O to form a solution;e). extracting the solution with ethyl acetate;  and    f). drying and concentrating in vacuo to form a residue;  and    g). yielding the compound of formula 5. 64. A method of treating malaria comprising: administering a pharmaceutically effective amount of the compound of claim 22. 65. The method of claim 64, further comprising administering one or more antimalaria composition(s) selected from the group consisting of but not limited to chloroquine, mefloquine, tafenoquine, and artamisinin. 66. The method of claim 38, further comprising administering one or more antimalaria composition(s) selected from the group consisting of but not limited to chloroquine, mefloquine, tafenoquine, and artamisinin.
法律状态
(US7253177) LEGAL DETAILS FOR US2006094736  Actual or expected expiration date=2015-09-07    Legal state=DEAD    Status=LAPSED     Event publication date=2004-10-22  Event code=US/APP  Event indicator=Pos  Event type=Examination events  Application details  Application country=US US10971846  Application date=2004-10-22  Standardized application number=2004US-10971846     Event publication date=2004-10-22  Event code=US/EXMR  Event type=Administrative notifications  USPTO Examiner Name Primary Examiner: LEESER, ERICH A    Event publication date=2004-10-22  Event code=US/ART  Event type=Administrative notifications  USPTO Art Group  ART=1624     Event publication date=2004-10-22  Event code=US/DK  Event type=Examination events  Attorney Docket Number Docket Nbr: ARMY 179    Event publication date=2004-10-22  Event code=US/ENT  Event type=Administrative notifications  Entity Status Set to Undiscounted Business Entity Status: UNDISCOUNTED    Event publication date=2004-10-22  Event code=US/AIA  Event type=Administrative notifications  First Inventor File Indicated:  AIA=No     Event publication date=2004-10-22  Event code=US/IDS  Event type=Examination events  Event type=OAI  Information Disclosure Statement Filed    Event publication date=2005-03-01  Event code=US/DOCK  Event indicator=Pos  Event type=Examination events  Case Docketed to Examiner    Event publication date=2005-04-21  Event code=US/APE  Event type=Corrections  Preliminary amendments    Event publication date=2005-09-16  Event code=US/IDS  Event type=Examination events  Event type=OAI  Information Disclosure Statement Filed    Event publication date=2006-05-04  Event code=US/A1  Event type=Examination events  Application published  Publication country=US  Publication number=US2006094736  Publication stage Code=A1  Publication date=2006-05-04  Standardized publication number=US20060094736     Event publication date=2006-06-14  Event code=US/DOCK  Event indicator=Pos  Event type=Examination events  Case Docketed to Examiner    Event publication date=2006-07-07  Event code=US/DOCK  Event indicator=Pos  Event type=Examination events  Case Docketed to Examiner    Event publication date=2006-09-18  Event code=US/CTNF  Event type=Examination events  Event type=OA  Event type=OAO  Non-Final Rejection    Event publication date=2006-12-18  Event code=US/CTNFR  Event type=Examination events  Event type=OAI  Response after Non-Final Action    Event publication date=2007-01-19  Event code=US/CTFR  Event type=Examination events  Event type=OA  Event type=OAO  Final Rejection    Event publication date=2007-03-12  Event code=US/CTFAR  Event type=Examination events  Event type=OAI  Response after Final Action    Event publication date=2007-03-28  Event code=US/EXIN  Event type=Examination events  Event type=OAO  Event type=INT  Examiner Interview Summary Record (PTOL - 413)    Event publication date=2007-04-02  Event code=US/DOCK  Event indicator=Pos  Event type=Examination events  Case Docketed to Examiner    Event publication date=2007-04-02  Event code=US/EXAC  Event type=Examination events  Event type=OAO  Examiner's Amendment Communication    Event publication date=2007-04-04  Event code=US/NOAM  Event indicator=Pos  Event type=Examination events  Event type=OAO  Mail Notice of Allowance    Event publication date=2007-05-18  Event code=US/AS  Event type=Change of name or address  Event type=Reassignment  Assignment ASSIGNMENT OF ASSIGNORS INTEREST ASSIGNORS:LIN, AI J. 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