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专利详细信息
专利号
EA5118B1
专利标题 Substituted tetracycline analog and method of preparing the same
专利权人 Trustees Of Tufts College;
发明人 Nelson, Mark L;Rennie, Glen;Koza, Darrell J;
申请号
申请日
公开日 2004/10/28
优先权号
IPC C07D21356000;
专利类型
法律状态查询 查看法律状态


1. A method of preparing a 7- 8- 9- or 10-substituted tetracycline compound combining a reactive tetracycline-based precursor compound and a reactive organic substituent precursor in the presence of a transition metal catalyst under conditions such that a tetracycline compound substituted with said organic substituent is formed. 2. The method of claim 1 wherein said transition metal catalyst comprises an organopalladium catalyst. 3. The method of claim 2 wherein said organopalladium catalyst comprises palladium chloride palladium acetate PdC12(PhCN)2 PdCI2(Ph3P)2 Pd2(dba)3-CHCl3 or a combination thereof. 4. The method of claim 3 wherein said transition metal catalyst comprises copper rhodium iron iridium chromium zirconium or nickel. 5. The method of claim 4 wherein said transition metal catalyst comprises CuCl2 Cul2 rhodium (II) acetate Rh6(CO)16 or combinations thereof. 6. The method of any one of claims 1-5 wherein said reactive tetracycline-based precursor compound is oxytetracycline chlortetracycline demeclocycline doxycycline chelocardin minocycline roliteteracycline lymecycline sancycline methacycline apicycline clomocycline guamecycline meglucycline mepylcycline penimepicycline pipacycline etamocycline or penimocycline based precursor compound. 7. The method of any one of claims 1-5 wherein said reactive tetracycline-based precursor compound is selected from the group consisting of reactive minocycline-based precursor compounds reactive doxycycline-based precursor compounds and reactive sancycline-based precursor compounds. 8. The method of any one of claims 1-7 wherein said reactive tetracycline-based precursor compound is an arenediazonium salt iodo derivative or a boronic acid derivative of a tetracycline compound. 9. The method of any one of claims 1-8 wherein said reactive organic substituent precursor has at least one reactive pi-bond containing group. 10. The method of claim 10 wherein said reactive organic substituent precursor is C1-6 alkenyl C1-6 alkynyl or C1-6 aromatic. 11. The method of claim 10 wherein said reactive organic substituent precursor is C1-6 alkenyl. 12. The method of claim 11 wherein said alkenyl reactive organic substituent precursor is a vinyl monomer. 13. The method of claim 11 wherein said alkenyl reactive organic substituent precursor is substituted. 14. The method of claim 11 or 13 wherein said alkenyl reactive organic substituent precursor is a methylenyl compound conjugated diene isoprene vinyl ether iodoalkene or a derivative thereof. 15. The method of claim 10 wherein said aryl reactive organic substituent precursor is heteroaromatic. 16. The method of claim 10 or 15 wherein said reactive organic substituent precursor comprising aryl C6-14 is selected from an C6-14 aryl boronic acid iodoC6-14 aryl quinone C6-14 arylethylene or styrene. 17. The method of claim 10 wherein said reactive organic substituent precursor comprises a carbonyl or thiocarbonyl group. 18. The method of claim 17 wherein said reactive organic substituent precursor is an C6-14 aryl vinyl ketone C6-14 arylisoprenyl ketone alpha beta-unsaturated aldehyde alpha beta-unsaturated ketone alpha beta-unsaturated acid or a derivative thereof. 19. The method of claim 10 wherein said alkynyl reactive organic substituent precursor is substituted or unsubstituted acetylene. 20. A 7-substituted tetracycline compound wherein the substituent at the 7 position is connected with a -C-C-linkage and wherein said substituent comprises an aromatic or heteroaromatic moiety. 21. The 7-substituted tetracycline compound of claim 20 wherein said compound is 7-4'-Cl-phenyl sancycline. 22. The 7-substituted tetracycline compound of claim 20 wherein said compound is 7-(4-fluorophenyl) sancycline. 23. The 7-substituted tetracycline compound of claim 20 wherein said compound is 7-(4-nitrophenyl) sancycline. 24. The 7-substituted tetracycline compound of claim 20 wherein said compound is 7-(2-pyridyl) doxycycline. 25. A 7-substituted tetracycline compound wherein the substituent at the 7 position is connected with a -C-C-linkage and wherein said substituent comprises a -C=C-bond adjacent to said -C-C-linkage. 26. The 7-substituted tetracycline compound of claim 25 wherein said substituent is of the formula wherein R2 and R3 are each independently hydrogen C1-6 alkyl C1-6 alkenyl C1-6 alkynyl cyclo(C1-6) alkyl C6-14 aryl C1-6 alkylcarbonyl C6-14 arylcarbonyl C1-6 alkoxycarbonyl C6-14 aryloxycarbonyl amino hydroxy cyano C1-6 alkoxy C6-14 aryloxy carboxyl or R2 and R3 taken together form a substituted or unsubstituted carbocyclic or heterocyclic ring. 27. The 7-substituted tetracycline compound of claim 26 wherein R2 is hydrogen and R3 is and R4 is hydrogen cyano or a C1-C5 alkoxy group. 28. The 7-substituted tetracycline compound of claim 26 wherein R2 and R3 taken together form a substituted or unsubstituted carbocyclic or heterocyclic ring. 29. The 7-substituted tetracycline compound of claim 26 or 28 wherein said ring comprises 5 to 15 atoms. 30. The 7-substituted tetracycline compound of any one of claims 26 28 or 29 wherein said ring is a conjugated or unconjugated aromatic ring system. 31. The 7-substituted tetracycline compound of claim 26 wherein said compound is 7-ethylenylsancycline. 32. A 9-substituted tetracycline compound wherein the substituent at the 9 position is connected with a -C-C-linkage and wherein said substituent comprises an aromatic or heteroaromatic moiety. 33. A 9-substituted tetracycline compound wherein the substituent at the 9 position is connected with a -C-C-linkage and wherein the substituent comprises a -C=C-bond adjacent to said -C-C-linkage. 34. The 9-substituted tetracycline compound of claim 33 wherein the substituent is of the formula wherein R2 and R3 are each independently hydrogen C1-6 alkyl C1-6 alkenyl C1-6 alkynyl cyclo(C1-6) alkyl C6-14 aryl C1-6 alkylcarbonyl C6-14 arylcarbonyl C1-6 alkoxycarbonyl C6-14 aryloxycarbonyl amino hydroxy cyano C1-6 alkoxy C6-14 aryloxy carboxyl or R2 and R3 taken together form a substituted or unsubstituted carbocyclic or heterocyclic ring. 35. The 9-substituted tetracycline compound of claim 43 wherein R2 is hydrogen and R3 is and R4 is hydrogen cyano or a C1-C5 alkoxy group. 36. The 9-substituted tetracycline compound of claim 34 wherein R2 and R3 taken together form a substituted or unsubstituted carbocyclic or heterocyclic ring. 37. The 9-substituted tetracycline compound of claim 34 or 36 wherein said ring has from 5 to 15 atoms in the ring. 38. The 9-substituted tetracycline compound of any one of claims 34 36 or 37 wherein said ring is a conjugated or unconjugated aromatic ring system. 39. A substituted tetracycline compound of any one of claims 20-38 made by a method comprising contacting a reactive tetracycline-based precursor compound and a reactive organic substituent precursor in the presence of a transition metal catalyst under conditions such that a tetracycline compound substituted with said organic substituent. 40. The substituted tetracycline compound of claim 39 wherein said catalyst comprises an organopalladium catalyst. 41. The substituted tetracycline compound of claim 40 wherein said organopalladium catalyst comprises palladium chloride palladium acetate PdC12(PhCN)2 PdCI2(Ph3P)2 Pd2(dba)3-CHCl3 or a combination thereof. 42. The substituted tetracycline compound of claim 39 wherein said transition metal catalyst comprises copper rhodium iron iridium chromium zirconium or nickel. 43. The substituted tetracycline compound of claim 42 wherein said transition metal catalyst comprises CuCl2 Cul2 rhodium (II) acetate Rh6(CO)16 or combinations thereof. 44. The substituted tetracycline compound of any one of claims 39-43 wherein said reactive tetracycline-based precursor compound is oxytetracycline chlortetracycline demeclocycline doxycycline chelocardin minocycline roliteteracycline lymecycline sancycline methacycline apicycline clomocycline guamecycline meglucycline mepylcycline penimepicycline pipacycline etamocycline or penimocycline based precursor compound. 45. The substituted tetracycline compound of any one of claims 39-43 wherein said reactive tetracycline-based precursor compound is selected from the group consisting of reactive minocycline-based precursor compounds reactive doxycycline-based precursor compounds and reactive sancycline-based precursor compounds. 46. The substituted tetracycline compound of any one of claims 39-45 wherein said reactive tetracycline-based precursor compound is an arenediazonium salt iodo derivative or a boronic acid derivative of a tetracycline compound. 47. The substituted tetracycline compound of any one of claims 39-46 wherein said reactive organic substituent precursor has at least one reactive pi-bond containing group. 48. The substituted tetracycline compound of any one of claims 39-47 wherein said reactive organic substituent precursor is selected from the group consisting of C1-6 alkenes substituted of C1-6 alkenes vinyl monomers aromatic and heteroaromatic reactive groups. 49. The substituted tetracycline compound of any one of claims 39-48 wherein the organic substituent is of the formula wherein R2 and R3 are each independently hydrogen C1-6 alkyl C1-6 alkenyl C1-6 alkynyl cyclo(C1-6) alkyl C6-14 aryl C1-6 alkylcarbonyl C6-14 arylcarbonyl C1-6 alkoxycarbonyl C6-14 aryloxycarbonyl amino hydroxy cyano C1-6 alkoxy C6-14 aryloxy carboxyl or R2 and R3 taken together form a substituted or unsubstituted carbocyclic or heterocyclic ring. 50. The substituted tetracycline compound of claim 49 wherein R2 is hydrogen and R3 is and R4 is hydrogen cyano or a C1-C5 alkoxy group. 51. The substituted tetracycline compound of claim 49 wherein R2 and R3 taken together form a substitu
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