Pharmaceutical compositions, dosage forms and methods for oral administration of epothilones
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
A61K-031/425
A61K-031/33
A61K-031/497
A61K-031/4965
A61K-031/335
출원번호
US-0149501
(2005-06-09)
등록번호
US-RE40387
(2008-06-17)
발명자
/ 주소
Bandyopadhyay,Rebanta
Malloy,Timothy M.
Panaggio,Andrea
Raghavan,Krishnaswamy Srinivas
Varia,Sailesh Amilal
Cohen,Marvin Barry
출원인 / 주소
Bristol Myers Squibb Company
대리인 / 주소
Liu,Hong
인용정보
피인용 횟수 :
0인용 특허 :
7
초록▼
The invention relates to methods of increasing the bioavailability of orally administered epothilones. Epothilones administered by the methods of the invention are sufficiently bioavailable to have a pharmacological effect. The invention further relates to pharmaceutical compositions, pharmaceutical
The invention relates to methods of increasing the bioavailability of orally administered epothilones. Epothilones administered by the methods of the invention are sufficiently bioavailable to have a pharmacological effect. The invention further relates to pharmaceutical compositions, pharmaceutical dosage forms, and kits for use in the methods of the invention.
대표청구항▼
What is claimed is: 1. A method of increasing the bioavailability of orally administered id="DEL-S-00075" date="20080617" epothilonesid="DEL-S-00075" comprising orally administering to a human one or more id="DEL-S-00076" date="20080617" epothilonesid="DEL-S-00076" id="INS-S-00058" date="20080617
What is claimed is: 1. A method of increasing the bioavailability of orally administered id="DEL-S-00075" date="20080617" epothilonesid="DEL-S-00075" comprising orally administering to a human one or more id="DEL-S-00076" date="20080617" epothilonesid="DEL-S-00076" id="INS-S-00058" date="20080617" compounds id="INS-S-00058" of Formula: wherein: G is id="DEL-S-00077" date="20080617" selected from the group consisting ofid="DEL-S-00077" alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo, W is O or NR16; X is O; S; CHR17; or H, R18; Y is id="DEL-S-00078" date="20080617" selected from the group consisting ofid="DEL-S-00078" O; H, H; H, OR22; OR23, OR23; NOR24; H, id="DEL-S-00079" date="20080617" NOR25id="DEL-S-00079" id="INS-S-00059" date="20080617" NHOR25id="INS-S-00059" ; H, id="DEL-S-00080" date="20080617" HNR26R27id="DEL-S-00080" id="INS-S-00060" date="20080617" NR26R27id="INS-S-00060" ; id="DEL-S-00081" date="20080617" NHNR28R29;id="DEL-S-00081" H, NHNR30R31 or CHR32, where OR23, OR23 can be a cyclic ketal; B1 and B2 are id="DEL-S-00082" date="20080617" selected from the group consisting ofid="DEL-S-00082" id="INS-S-00061" date="20080617" independently id="INS-S-00061" H, OR33, OCOR34, OCONR35R36, NR37R38, or NR39CONR40R41; D is id="DEL-S-00083" date="20080617" selected from the group consisting ofid="DEL-S-00083" NR42R43 or heterocyclo; R1, R2, R3, R4, and R5 are id="DEL-S-00084" date="20080617" selected fromid="DEL-S-00084" id="INS-S-00062" date="20080617" independently id="INS-S-00062" Hid="DEL-S-00085" date="20080617" ,id="DEL-S-00085" id="INS-S-00063" date="20080617" or id="INS-S-00063" lower alkyl; R8, R9, R10 and R11 are id="DEL-S-00086" date="20080617" selected from the group consisting ofid="DEL-S-00086" id="INS-S-00064" date="20080617" independently id="INS-S-00064" H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo or substituted heterocyclo; R17, R18, R22, and R23 are id="DEL-S-00087" date="20080617" selected from the group consisting ofid="DEL-S-00087" id="INS-S-00065" date="20080617" independently id="INS-S-00065" H, alkyl, id="DEL-S-00088" date="20080617" andid="DEL-S-00088" id="INS-S-00066" date="20080617" or id="INS-S-00066" substituted alkyl; R24, R25, R26, id="DEL-S-00089" date="20080617" R28,id="DEL-S-00089" R30, R32, R33, R34, R35, R36, R37, R39, R40, R41, R42, R51, R52, id="INS-S-00067" date="20080617" and id="INS-S-00067" R53id="DEL-S-00090" date="20080617" , and R61 id="DEL-S-00090" are id="DEL-S-00091" date="20080617" selected from the group ofid="DEL-S-00091" id="INS-S-00068" date="20080617" independently id="INS-S-00068" H, alkyl, substituted alkyl, aryl or substituted aryl; R12, R16, R27, id="DEL-S-00092" date="20080617" R29,id="DEL-S-00092" R31, R38, and R43id="DEL-S-00093" date="20080617" ,id="DEL-S-00093" are id="DEL-S-00094" date="20080617" selected from the group consisting ofid="DEL-S-00094" id="INS-S-00069" date="20080617" independently id="INS-S-00069" H, alkyl, substituted alkyl, substituted aryl, cycloalkyl, heterocyclo, R51C═O, R52OC═O, R53SO2, hydroxy, id="DEL-S-00095" date="20080617" andid="DEL-S-00095" O-alkyl or O-substituted alkylid="DEL-S-00096" date="20080617" ,id="DEL-S-00096" id="INS-S-00070" date="20080617" ;id="INS-S-00070" or a pharmaceutically acceptable id="DEL-S-00097" date="20080617" salt,id="DEL-S-00097" solvate, clathrate, hydrate or prodrug thereof, and orally administering one or more pharmaceutically acceptable acid neutralizing buffersid="INS-S-00071" date="20080617" , wherein the bioavailability of the compound is increased with the acid neutralizing buffer compared to that without the acid neutralizing bufferid="INS-S-00071" . 2. The method of claim id="DEL-S-00098" date="20080617" 1id="DEL-S-00098" id="INS-S-00072" date="20080617" 17id="INS-S-00072" , wherein the pharmaceutically acceptable acid neutralizing buffer is administered concurrently with the id="DEL-S-00099" date="20080617" epothiloneid="DEL-S-00099" id="INS-S-00073" date="20080617" compoundid="INS-S-00073" . 3. The method of claim id="DEL-S-00100" date="20080617" 1id="DEL-S-00100" id="INS-S-00074" date="20080617" 17id="INS-S-00074" , wherein the pharmaceutically acceptable acid neutralizing buffer is administered before the id="DEL-S-00101" date="20080617" epothiloneid="DEL-S-00101" id="INS-S-00075" date="20080617" compoundid="INS-S-00075" . 4. The method of claim 3, wherein the pharmaceutically acceptable acid neutralizing buffer is administered not more than about 1 hour before the id="DEL-S-00102" date="20080617" epothiloneid="DEL-S-00102" id="INS-S-00076" date="20080617" compoundid="INS-S-00076" . 5. The method of claim id="DEL-S-00103" date="20080617" 1id="DEL-S-00103" id="INS-S-00077" date="20080617" 17id="INS-S-00077" , wherein the pharmaceutically acceptable acid neutralizing buffer is administered after the id="DEL-S-00104" date="20080617" epothiloneid="DEL-S-00104" id="INS-S-00078" date="20080617" compoundid="INS-S-00078" . 6. The method of claim 5, wherein the pharmaceutically acceptable acid neutralizing buffer is administered not more than about 1 hour after the id="DEL-S-00105" date="20080617" epothiloneid="DEL-S-00105" id="INS-S-00079" date="20080617" compoundid="INS-S-00079" . 7. The method of claim id="DEL-S-00106" date="20080617" 1id="DEL-S-00106" id="INS-S-00080" date="20080617" 17id="INS-S-00080" , wherein the pharmaceutically acceptable acid neutralizing buffer is administered before and after the id="DEL-S-00107" date="20080617" epothiloneid="DEL-S-00107" id="INS-S-00081" date="20080617" compoundid="INS-S-00081" . 8. The method of claim 7, wherein the pharmaceutically acceptable acid neutralizing buffer is administered not more than about 1 hour before and not more than about 1 hour after the id="DEL-S-00108" date="20080617" epothiloneid="DEL-S-00108" id="INS-S-00082" date="20080617" compound id="INS-S-00082" is administered. 9. The method of claim id="DEL-S-00109" date="20080617" 1id="DEL-S-00109" id="INS-S-00083" date="20080617" 17id="INS-S-00083" , wherein the pharmaceutically acceptable acid neutralizing buffer is administered in an amount sufficient to deliver at least about 20 milliequivalents of acid neutralization capacity. 10. The method of claim id="DEL-S-00110" date="20080617" 1id="DEL-S-00110" id="INS-S-00084" date="20080617" 17id="INS-S-00084" , wherein the pharmaceutically acceptable acid neutralizing buffer is administered as an aqueous solution having a pH of between about 5 to 9. 11. The method of claim id="DEL-S-00111" date="20080617" 1id="DEL-S-00111" id="INS-S-00085" date="20080617" 17id="INS-S-00085" , wherein the pharmaceutically acceptable acid neutralizing buffer is administered as an aqueous solution comprising anhydrous dibasic sodium phosphate, sodium citrate dihydrate, and anhydrous citric acid. 12. The method of claim 11, wherein the pH of the aqueous solution is about 7. 13. The method of claim id="DEL-S-00112" date="20080617" 1id="DEL-S-00112" id="INS-S-00086" date="20080617" 17id="INS-S-00086" , wherein the bioavailability of the id="DEL-S-00113" date="20080617" one or more epothilonesid="DEL-S-00113" id="INS-S-00087" date="20080617" compound id="INS-S-00087" or a pharmaceutically acceptable id="DEL-S-00114" date="20080617" salt,id="DEL-S-00114" solvate, clathrate, hydrate, or prodrug thereof is at least about 20 percent. 14. The method of claim id="DEL-S-00115" date="20080617" 1id="DEL-S-00115" id="INS-S-00088" date="20080617" 17id="INS-S-00088" , wherein the id="DEL-S-00116" date="20080617" one or more epothilonesid="DEL-S-00116" id="INS-S-00089" date="20080617" compound id="INS-S-00089" or a pharmaceutically acceptable id="DEL-S-00117" date="20080617" salt,id="DEL-S-00117" solvate, clathrate, hydrate, or prodrug thereof is orally administered as a solution in propylene glycol and ethanol, wherein the id="DEL-S-00118" date="20080617" inid="DEL-S-00118" ratio of propylene glycol:ethanol is about 80:20. 15. The method of claim id="DEL-S-00119" date="20080617" 1id="DEL-S-00119" id="INS-S-00090" date="20080617" 17id="INS-S-00090" , wherein the id="DEL-S-00120" date="20080617" one or more epothilonesid="DEL-S-00120" id="INS-S-00091" date="20080617" compound id="INS-S-00091" or a pharmaceutically acceptable id="DEL-S-00121" date="20080617" salt,id="DEL-S-00121" solvate, clathrate, hydrate, or prodrug thereof is administered in a total amount of about 0.05 to about 200 mg/kg/day. 16. The method of claim 15, wherein the id="DEL-S-00122" date="20080617" one or more epothilones ofid="DEL-S-00122" id="INS-S-00092" date="20080617" compound id="INS-S-00092" or a pharmaceutically acceptable id="DEL-S-00123" date="20080617" salt,id="DEL-S-00123" solvate, clathrate, hydrate, or prodrug thereof is administered in about 2 to 4 divided doses. 17. id="DEL-S-00124" date="20080617" The method of claim 1, wherein the epothilone is [1S-[1R*,3R*(E),7R*,10S*,11R*,16S*]]-7,11-dihydroxy 8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl) ethenyl-17-oxa-4-azabicyclo[14.1.0]heptadecane-5,9-dione.id="DEL-S-00124" id="INS-S-00093" date="20080617" The method of claim 1, wherein the compound is id="INS-S-00093" id="INS-S-00094" date="20080617" or a pharmaceutically acceptable solvate, clathrate, hydrate, or prodrug thereof.id="INS-S-00094" 18. The method of claim 1 comprising: (a) orally administering an aqueous solution of a pharmaceutically acceptable acid neutralizing buffer comprising anhydrous dibasic sodium phosphate, sodium citrate dihydrate, and anhydrous citric acid; (b) orally administering the one or more id="DEL-S-00125" date="20080617" epothilonesid="DEL-S-00125" id="INS-S-00095" date="20080617" compounds id="INS-S-00095" or a pharmaceutically acceptable id="DEL-S-00126" date="20080617" salt,id="DEL-S-00126" solvate, clathrate, hydrate, or prodrug thereof as a solution of propylene glycol; and (c) orally administering an aqueous solution of a pharmaceutically acceptable acid neutralizing buffer comprising anhydrous dibasic sodium phosphate, sodium citrate dihydrate, and anhydrous citric acid. 19. id="DEL-S-00127" date="20080617" The method of claim 18, wherein the epothilone is [1S-[1R*,3R*(E),7R*,10S*,11R*,16S*]]-7,11-dihydroxy 8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl) ethenyl-17-oxa-4-azabicyclo[14.1.0]heptadecane-5,9-dione.id="DEL-S-00127" id="INS-S-00096" date="20080617" The method of claim 18, wherein the compound is id="INS-S-00096" id="INS-S-00097" date="20080617" or a pharmaceutically acceptable solvate, clathrate, hydrate, or prodrug thereof.id="INS-S-00097" 20. A kit id="DEL-S-00128" date="20080617" for use in a method of increasing the bioavailability of orally administered epothilones which comprisesid="DEL-S-00128" id="INS-S-00098" date="20080617" comprisingid="INS-S-00098" : (i) a first component comprising id="DEL-S-00129" date="20080617" one or more epothilones of Formula: G is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo, W is O or NR16; X is O; S; CHR17; or H, R18 Y is selected from the group consisting of O; H, H; H, OR22; OR23, OR23; NOR24; H, NOR25; H, HNR26R27; NHNR28R29; H, NHNR30R31 or CHR32, where OR23, OR23 can be a cyclic ketal; B1 and B2 are selected from the group consisting of H, OR33, OCOR34, OCONR35R36, NR37R38, or NR39CONR40R41 D is selected from the group consisting of NR42R43 or heterocyclo; R1, R2, R3, R4, and R5 are selected from H, lower alkyl; R8, R9, R10 and R11 are selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo or substituted heterocyclo; R17, R18, R22, and R23 are selected from the group consisting of H, alkyl, and substituted alkyl; R24, R25, R26, R28, R30, R32, R33, R34, R35, R36, R37, R39, R40, R41, R42, R51, R52, R53, and R61 are selected from the group of H, alkyl, substituted alkyl, aryl or substituted aryl; R12, R16, R27, R29, R31, R38, and R43, are selected from the group consisting of H, alkyl, substituted alkyl, substituted aryl, cycloalkyl, heterocyclo, R51C═O, R52OC═O, R53SO2, hydroxy, and O-alkyl or O-substituted alkyl;id="DEL-S-00129" id="INS-S-00099" date="20080617" a compound of formula id="INS-S-00099" or a pharmaceutically acceptable id="DEL-S-00130" date="20080617" salt,id="DEL-S-00130" solvate, clathrate, hydrate, or prodrug thereof; and (ii) a second component comprising a pharmaceutically acceptable acid neutralizing buffer, wherein the first component and the second component are provided as an oral dosage form or as a pharmaceutical composition that can be reconstituted with a solvent to provide a liquid oral dosage. 21. The kit of claim 20, wherein at least one of the first component or the second component is provided as a solid oral dosage form. 22. The kit of claim 21, wherein at least one of the first component or the second component is anhydrous. 23. The kit of claim 20, wherein at least one of the first component or the second component is provided as a pharmaceutical composition that can be reconstituted with a solvent to provide a liquid oral dosage form. 24. The kit of claim 23, wherein at least one of the first component or the second component is provided as a tablet. 25. The kit of claim 23, wherein at least one of the first component or the second component is anhydrous. 26. The kit of claim 23, further comprising solvents for reconstituting the first or second components. 27. The kit of claim 26, wherein the solvent for reconstituting the first component is a mixture of propylene glycol and ethanol. 28. A pharmaceutical composition suitable for oral administration to a mammal comprising: (i) one or more id="DEL-S-00131" date="20080617" epothilonesid="DEL-S-00131" id="INS-S-00100" date="20080617" compounds id="INS-S-00100" of Formula: wherein: G is id="DEL-S-00132" date="20080617" selected from the group consisting ofid="DEL-S-00132" alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo, W is O or id="DEL-S-00133" date="20080617" NR16id="DEL-S-00133" id="INS-S-00101" date="20080617" NR16id="INS-S-00101" ; X is O; S; CHR17; or H, R18; Y is id="DEL-S-00134" date="20080617" selected from the group consisting ofid="DEL-S-00134" O; H, H; H, OR22; OR23, OR23; NOR24; H, id="DEL-S-00135" date="20080617" NOR25id="DEL-S-00135" id="INS-S-00102" date="20080617" NHOR25id="INS-S-00102" ; H, id="DEL-S-00136" date="20080617" HNR26R27id="DEL-S-00136" id="INS-S-00103" date="20080617" NR26R27id="INS-S-00103" ; id="DEL-S-00137" date="20080617" NHNR28R29;id="DEL-S-00137" H, NHNR30R31 or CHR32, where OR23, OR23 can be a cyclic ketal; B1 and B2 are id="DEL-S-00138" date="20080617" selected from the group consisting ofid="DEL-S-00138" id="INS-S-00104" date="20080617" independently id="INS-S-00104" H, OR33, OCOR34, OCONR35R36, NR37R38, or NR39CONR40R41 D is id="DEL-S-00139" date="20080617" selected from the group consisting ofid="DEL-S-00139" NR42R43 or heterocyclo; R1, R2, R3, R4, and R5 are id="DEL-S-00140" date="20080617" selected fromid="DEL-S-00140" id="INS-S-00105" date="20080617" independently id="INS-S-00105" Hid="DEL-S-00141" date="20080617" ,id="DEL-S-00141" id="INS-S-00106" date="20080617" or id="INS-S-00106" lower alkyl; R8, R9, R10 and R11 are id="DEL-S-00142" date="20080617" selected from the group consisting ofid="DEL-S-00142" id="INS-S-00107" date="20080617" independently id="INS-S-00107" H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo or substituted heterocyclo; R17, R18, R22, and R23 are id="DEL-S-00143" date="20080617" selected from the group consisting ofid="DEL-S-00143" id="INS-S-00108" date="20080617" independently id="INS-S-00108" H, alkyl, id="DEL-S-00144" date="20080617" andid="DEL-S-00144" id="INS-S-00109" date="20080617" or id="INS-S-00109" substituted alkyl; R24, R25, R26, id="DEL-S-00145" date="20080617" R28,id="DEL-S-00145" R30, R32, R33, R34, R35, R36, R37, R39, R40, R41, R42, R51, R52, id="INS-S-00110" date="20080617" and id="INS-S-00110" R53id="DEL-S-00146" date="20080617" , and R61 id="DEL-S-00146" are id="DEL-S-00147" date="20080617" selected from the group ofid="DEL-S-00147" id="INS-S-00111" date="20080617" independently id="INS-S-00111" H, alkyl, substituted alkyl, aryl or substituted aryl; R12, R16, R27, id="DEL-S-00148" date="20080617" R29,id="DEL-S-00148" R31, R38, and R43id="DEL-S-00149" date="20080617" ,id="DEL-S-00149" are id="DEL-S-00150" date="20080617" selected from the group consisting ofid="DEL-S-00150" id="INS-S-00112" date="20080617" independently id="INS-S-00112" H, alkyl, substituted alkyl, substituted aryl, cycloalkyl, heterocyclo, R51C═O, R52OC═O, R53SO2, hydroxy, id="DEL-S-00151" date="20080617" andid="DEL-S-00151" O-alkyl or O-substituted alkyl; or a pharmaceutically acceptable id="DEL-S-00152" date="20080617" salt,id="DEL-S-00152" solvate, clathrate, hydrate, or prodrug thereof, in solid form; and (ii) a solid pharmaceutically acceptable acid neutralizing buffer in an amount sufficient to reduce decomposition of the one or more id="DEL-S-00153" date="20080617" epothilonesid="DEL-S-00153" id="INS-S-00113" date="20080617" compoundsid="INS-S-00113" , or a pharmaceutically acceptable id="DEL-S-00154" date="20080617" salt,id="DEL-S-00154" solvate, clathrate, hydrate, or prodrug thereof when the pharmaceutical composition is reconstituted with a solvent to provide a liquid oral dosage form. 29. The pharmaceutical composition of claim id="DEL-S-00155" date="20080617" 28id="DEL-S-00155" id="INS-S-00114" date="20080617" 33id="INS-S-00114" , wherein the pharmaceutically acceptable acid neutralizing buffer provides a liquid oral dosage form having a pH between about 5 to 9. 30. The pharmaceutical composition of claim id="DEL-S-00156" date="20080617" 28id="DEL-S-00156" id="INS-S-00115" date="20080617" 33id="INS-S-00115" , wherein the pharmaceutically acceptable acid neutralizing buffer is present in an amount sufficient to provide at least about 20 milliequivalents of acid neutralization capacity. 31. The pharmaceutical composition of claim id="DEL-S-00157" date="20080617" 28id="DEL-S-00157" id="INS-S-00116" date="20080617" 33id="INS-S-00116" , wherein the pharmaceutically acceptable acid neutralizing buffer is a dibasic phosphate-citric acid-citrate buffer. 32. The pharmaceutical composition of claim id="DEL-S-00158" date="20080617" 28id="DEL-S-00158" id="INS-S-00117" date="20080617" 33id="INS-S-00117" , wherein the id="DEL-S-00159" date="20080617" one or more epothilonesid="DEL-S-00159" id="INS-S-00118" date="20080617" compound id="INS-S-00118" or a pharmaceutically acceptable id="DEL-S-00160" date="20080617" salt,id="DEL-S-00160" solvate, clathrate, hydrate, or prodrug thereof is present in an amount of between about 0.05 and 200 mg. 33. id="DEL-S-00161" date="20080617" The pharmaceutical composition of claim 28, wherein the epothilone is [1S-[1R*,3R*(E),7R*,10S*,11R*,16S*]]-7,11-dihydroxy 8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl) ethenyl-17-oxa-4-azabicyclo[14.1.0]heptadecane-5,9-dione.id="DEL-S-00161" id="INS-S-00119" date="20080617" The pharmaceutical composition of claim 28, wherein the compound is id="INS-S-00119" id="INS-S-00120" date="20080617" or a pharmaceutically acceptable solvate, clathrate, hydrate, or prodrug thereof.id="INS-S-00120" 34. A kit comprising the pharmaceutical composition of claim id="DEL-S-00162" date="20080617" 28id="DEL-S-00162" id="INS-S-00121" date="20080617" 33 id="INS-S-00121" and a solvent for reconstituting the pharmaceutical composition to provide an oral dosage form. 35. The kit of claim 34, wherein the solvent comprises propylene glycol, ethanol, and phosphate buffer (1M, pH 8). 36. The kit of claim 35, wherein the ratio of propylene glycol:ethanol:phosphate buffer is about 58:12:30. 37. A liquid oral dosage form suitable for oral administration to a mammal comprising: (i) one or more id="DEL-S-00163" date="20080617" epothilonesid="DEL-S-00163" id="INS-S-00122" date="20080617" compounds id="INS-S-00122" of Formula: wherein: G is id="DEL-S-00164" date="20080617" selected from the group consisting ofid="DEL-S-00164" alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo, W is O or NR16; X is O; S; CHR17; or H, R18; Y is id="DEL-S-00165" date="20080617" selected from the group consisting ofid="DEL-S-00165" O; H, H; H, OR22; OR23, id="DEL-S-00166" date="20080617" OR23id="DEL-S-00166" id="INS-S-00123" date="20080617" OR23id="INS-S-00123" ; NOR24; H, id="DEL-S-00167" date="20080617" NOR25id="DEL-S-00167" id="INS-S-00124" date="20080617" NHOR25id="INS-S-00124" ; H, id="DEL-S-00168" date="20080617" HNR26R27id="DEL-S-00168" id="INS-S-00125" date="20080617" NR26R27id="INS-S-00125" ; id="DEL-S-00169" date="20080617" NHNR28R29; id="DEL-S-00169" H, NHNR30R31 or CHR32, where OR23, OR23 can be a cyclic ketal; B1 and B2 are id="DEL-S-00170" date="20080617" selected from the group consisting ofid="DEL-S-00170" id="INS-S-00126" date="20080617" independently id="INS-S-00126" H, OR33, OCOR34, OCONR35R36, NR37R38, or NR39CONR40R41 D is id="DEL-S-00171" date="20080617" selected from the group consisting ofid="DEL-S-00171" NR42R43 or heterocyclo; R1, R2, R3, R4, and R5 are id="DEL-S-00172" date="20080617" selected fromid="DEL-S-00172" id="INS-S-00127" date="20080617" independently id="INS-S-00127" Hid="DEL-S-00173" date="20080617" ,id="DEL-S-00173" id="INS-S-00128" date="20080617" or id="INS-S-00128" lower alkyl; id="DEL-S-00174" date="20080617" R8, R9, R10 and R11id="DEL-S-00174" id="INS-S-00129" date="20080617" R8, R9, R10 and R11 id="INS-S-00129" are id="DEL-S-00175" date="20080617" selected from the group consisting ofid="DEL-S-00175" id="INS-S-00130" date="20080617" independently id="INS-S-00130" H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo or substituted heterocyclo; R17, R18, R22, and R23 are id="DEL-S-00176" date="20080617" selected from the group consisting ofid="DEL-S-00176" id="INS-S-00131" date="20080617" independently id="INS-S-00131" H, alkyl, id="DEL-S-00177" date="20080617" andid="DEL-S-00177" id="INS-S-00132" date="20080617" or id="INS-S-00132" substituted alkyl; R24, R25, R26, id="DEL-S-00178" date="20080617" R28,id="DEL-S-00178" R30, R32, R33, R34, R35, R36, R37, R39, R40, R41, R42, R51, R52, id="INS-S-00133" date="20080617" and id="INS-S-00133" R53id="DEL-S-00179" date="20080617" , and R61 id="DEL-S-00179" are id="DEL-S-00180" date="20080617" selected from the group ofid="DEL-S-00180" id="INS-S-00134" date="20080617" independently id="INS-S-00134" H, alkyl, substituted alkyl, aryl or substituted aryl; R12, R16, R27, id="DEL-S-00181" date="20080617" R29,id="DEL-S-00181" R31, R38, and R43id="DEL-S-00182" date="20080617" ,id="DEL-S-00182" are id="DEL-S-00183" date="20080617" selected from the group consisting ofid="DEL-S-00183" id="INS-S-00135" date="20080617" independently id="INS-S-00135" H, alkyl, substituted alkyl, substituted aryl, cycloalkyl, heterocyclo, R51C═O, R52OC═O, R53SO2, hydroxy, id="DEL-S-00184" date="20080617" andid="DEL-S-00184" O-alkyl or O-substituted alkylid="DEL-S-00185" date="20080617" ,id="DEL-S-00185" id="INS-S-00136" date="20080617" ;id="INS-S-00136" or a pharmaceutically acceptable id="DEL-S-00186" date="20080617" salt,id="DEL-S-00186" solvate, clathrate, hydrate, or prodrug thereof; and (ii) a pharmaceutically acceptable liquid carrier. 38. id="DEL-S-00187" date="20080617" The liquid oral dosage form of claim 37, wherein the epothilone is [1S-[1R*,3R*(E),7R*,10S*,11R*,16S*]]-7,11-dihydroxy 8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl) ethenyl-17-oxa-4-azabicyclo[14.1.0]heptadecane-5,9-dione.id="DEL-S-00187" id="INS-S-00137" date="20080617" The liquid oral dosage form of claim 37, wherein the compound is or a pharmaceutically acceptable solvate, clathrate, hydrate, or prodrug thereof.id="INS-S-00137" 39. The liquid oral dosage form of claim id="DEL-S-00188" date="20080617" 37id="DEL-S-00188" id="INS-S-00138" date="20080617" 38id="INS-S-00138" , further comprising a pharmaceutically acceptable acid neutralizing buffer in an amount sufficient to reduce decomposition of the id="DEL-S-00189" date="20080617" one or more epothilonesid="DEL-S-00189" id="INS-S-00139" date="20080617" compoundid="INS-S-00139" , or a pharmaceutically acceptable id="DEL-S-00190" date="20080617" salt,id="DEL-S-00190" solvate, clathrate, hydrate, or prodrug thereof compared to a pharmaceutical composition without the buffer. 40. The liquid oral dosage form of claim 39, wherein the pH of the liquid oral dosage form is between about 5 to 9. 41. The liquid oral dosage form of claim 39, wherein the buffer is present in an amount sufficient to provide at least about 20 milliequivalents of acid neutralization capacity. 42. The liquid oral dosage form of claim id="DEL-S-00191" date="20080617" 37id="DEL-S-00191" id="INS-S-00140" date="20080617" 38id="INS-S-00140" , wherein the solvent is propylene glycol, ethanol, and water buffered with a phosphate buffer at pH about 8. 43. The liquid oral dosage form of claim 42, wherein the propylene glycol, ethanol, and water buffered with a phosphate buffer are present in a ratio of about 58:12:30. 44. id="DEL-S-00192" date="20080617" The liquid oral dosage form of claim 42, wherein the epothilone is [1S-[1R*,3R*(E),7R*,10S*,11R*,16S*]]-7,11-dihydroxy 8,8,10,12,16-pentamethyl-3-[1-methyl-2-(2-methyl-4-thiazolyl) ethenyl-17-oxa-4-azabicyclo[14.1.0]heptadecane-5,9-dione.id="DEL-S-00192" id="INS-S-00141" date="20080617" The dispersible buffered tablet of claim 48 wherein the compound is or a pharmaceutically acceptable solvate, clathrate, hydrate, or prodrug thereof.id="INS-S-00141" 45. The liquid oral dosage form of claim id="DEL-S-00193" date="20080617" 37id="DEL-S-00193" id="INS-S-00142" date="20080617" 38id="INS-S-00142" , wherein the id="DEL-S-00194" date="20080617" one or more epothilonesid="DEL-S-00194" id="INS-S-00143" date="20080617" compound id="INS-S-00143" or a pharmaceutically acceptable id="DEL-S-00195" date="20080617" salt,id="DEL-S-00195" solvate, clathrate, hydrate, or prodrug thereof is present in an amount of between about 0.05 and 200 mg. 46. The liquid oral dosage form of claim 39, wherein the buffer is dibasic phosphate-citric acid-citrate buffer. 47. An article of manufacture which comprises: (a) a sealable container suitable to carry a liquid or solid pharmaceutical; (b) id="DEL-S-00196" date="20080617" one or more epothilonesid="DEL-S-00196" id="INS-S-00144" date="20080617" a compound of formula id="INS-S-00144" or a pharmaceutically acceptable id="DEL-S-00197" date="20080617" salt,id="DEL-S-00197" solvate, clathrate, hydrate or prodrug thereof; and (c) a pharmaceutically acceptable carrier suitable to deliver the id="DEL-S-00198" date="20080617" epothiloneid="DEL-S-00198" id="INS-S-00145" date="20080617" compound id="INS-S-00145" orally. 48. A dispersible buffered tablet which comprises: (i) one or more id="DEL-S-00199" date="20080617" epothilonesid="DEL-S-00199" id="INS-S-00146" date="20080617" compounds id="INS-S-00146" of Formula: wherein: G is id="DEL-S-00200" date="20080617" selected from the group consisting ofid="DEL-S-00200" alkyl, substituted alkyl, aryl, substituted aryl, heterocyclo, W is O or NR16; X is O; S; CHR17; or H, R18; Y is id="DEL-S-00201" date="20080617" selected from the group consisting ofid="DEL-S-00201" O; H, H; H, OR22; OR23, id="DEL-S-00202" date="20080617" OR23id="DEL-S-00202" id="INS-S-00147" date="20080617" OR23id="INS-S-00147" ; NOR24; H, id="DEL-S-00203" date="20080617" NOR25id="DEL-S-00203" id="INS-S-00148" date="20080617" NHOR25id="INS-S-00148" ; H, id="DEL-S-00204" date="20080617" HNR26R27id="DEL-S-00204" id="INS-S-00149" date="20080617" NR26R27id="INS-S-00149" ; id="DEL-S-00205" date="20080617" NHNR28R29;id="DEL-S-00205" H, NHNR30R31 or CHR32, where OR23, OR23 can be a cyclic ketal; B1 and B2 are id="DEL-S-00206" date="20080617" selected from the group consisting ofid="DEL-S-00206" id="INS-S-00150" date="20080617" independently id="INS-S-00150" H, OR33, OCOR34, OCONR35R36, NR37R38, or NR39CONR40R41 D is id="DEL-S-00207" date="20080617" selected from the group consisting ofid="DEL-S-00207" NR42R43 or heterocyclo; R1, R2, R3, R4, and R5 are id="DEL-S-00208" date="20080617" selected fromid="DEL-S-00208" id="INS-S-00151" date="20080617" independently id="INS-S-00151" Hid="DEL-S-00209" date="20080617" ,id="DEL-S-00209" id="INS-S-00152" date="20080617" or id="INS-S-00152" lower alkyl; R8, R9, R10 and R11 are id="DEL-S-00210" date="20080617" selected from the group consisting ofid="DEL-S-00210" id="INS-S-00153" date="20080617" independently id="INS-S-00153" H, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, heterocyclo or substituted heterocyclo; R17, R18, R22, and R23 are id="DEL-S-00211" date="20080617" selected from the group consisting ofid="DEL-S-00211" id="INS-S-00154" date="20080617" independently id="INS-S-00154" H, alkyl, id="DEL-S-00212" date="20080617" andid="DEL-S-00212" id="INS-S-00155" date="20080617" or id="INS-S-00155" substituted alkyl; R24, R25, R26, id="DEL-S-00213" date="20080617" R28,id="DEL-S-00213" R30, R32, R33, R34, R35, R36, R37, R39, R40, R41, R42, R51, R52, id="INS-S-00156" date="20080617" and id="INS-S-00156" R53id="DEL-S-00214" date="20080617" , and R61 id="DEL-S-00214" are id="DEL-S-00215" date="20080617" selected from the group ofid="DEL-S-00215" id="INS-S-00157" date="20080617" independently id="INS-S-00157" H, alkyl, substituted alkyl, aryl or substituted aryl; R12, R16, R27, id="DEL-S-00216" date="20080617" R29,id="DEL-S-00216" R31, R38, and R43id="DEL-S-00217" date="20080617" ,id="DEL-S-00217" are id="DEL-S-00218" date="20080617" selected from the group consisting ofid="DEL-S-00218" id="INS-S-00158" date="20080617" independently id="INS-S-00158" H, alkyl, substituted alkyl, substituted aryl, cycloalkyl, heterocyclo, id="DEL-S-00219" date="20080617" R51C═Oid="DEL-S-00219" id="INS-S-00159" date="20080617" R51C═Oid="INS-S-00159" , R52OC═O, id="DEL-S-00220" date="20080617" R53SO2id="DEL-S-00220" id="INS-S-00160" date="20080617" R53SO2id="INS-S-00160" , hydroxy, id="DEL-S-00221" date="20080617" andid="DEL-S-00221" O-alkyl or O-substituted alkylid="DEL-S-00222" date="20080617" ,id="DEL-S-00222" id="INS-S-00161" date="20080617" ;id="INS-S-00161" or a pharmaceutically acceptable id="DEL-S-00223" date="20080617" salt,id="DEL-S-00223" solvate, clathrate, hydrate, or prodrug thereof; and (ii) buffer components which are suitable to neutralize gastric fluids for a time sufficient to allow said id="DEL-S-00224" date="20080617" epothiloneid="DEL-S-00224" id="INS-S-00162" date="20080617" compound id="INS-S-00162" to be absorbed. 49. The kit of claim 20, wherein the first and second component is provided as a liquid oral dosage form. 50. The kit of claim 49, wherein the id="DEL-S-00225" date="20080617" one or more epothilonesid="DEL-S-00225" id="INS-S-00163" date="20080617" compound id="INS-S-00163" or a pharmaceutically acceptable id="DEL-S-00226" date="20080617" salt,id="DEL-S-00226" solvate, clathrate, hydrate, or prodrug thereof is present in an amount of between about 0.05 and 200 mg and the pharmaceutically acceptable acid neutralizing buffer is present in an amount sufficient to provide at least about 20 milliequivalents of acid neutralization capacity. 51. The kit of claim 20, wherein the first component and the second component is provided as a pharmaceutical composition that can be reconstituted with a solvent to provide a liquid oral dosage form; the id="DEL-S-00227" date="20080617" one or more epothilonesid="DEL-S-00227" id="INS-S-00164" date="20080617" compound id="INS-S-00164" or a pharmaceutically acceptable id="DEL-S-00228" date="20080617" salt,id="DEL-S-00228" solvate, clathrate, hydrate, or prodrug thereof is present as a in an amount of between about 0.05 and 200 mg; and the pharmaceutically acceptable acid neutralization buffer is present in an amount sufficient to provide at least about 20 milliequivalents of acid neutralization capacity. 52. id="DEL-S-00229" date="20080617" The kit of claim 20, wherein the epothilone is [1S-[1R*,3R*(E),7R*,10S*,11R*,16 S*]]-7,11-dihydroxy 8,8,10,12,16-pentamethyl-3-[1 -methyl-2-(2-methyl-4-thiazolyl)ethenyl-17-oxa-4-azabicyclo[14.1.0]heptadecane-5, 9-dione and the pharmaceutically acceptable acid neutralizing buffer comprises dibasic sodium phosphate, sodium citrate, and anhydrous citric acid.id="DEL-S-00229" id="INS-S-00165" date="20080617" The kit of claim 20, wherein the pharmaceutically acceptable acid neutralizing buffer comprises dibasic sodium phosphate, sodium citrate, and anhydrous citric acid.id="INS-S-00165" id="INS-S-00166" date="20080617" 53. A method for the treatment of any one of breast cancer, lung cancer, pancreatic cancer and/or prostate cancer in a human, comprising administering to said human a therapeutically effective amount of a compound of formula id="INS-S-00166" id="INS-S-00167" date="20080617" and ketoconazole.id="INS-S-00167" id="INS-S-00168" date="20080617" 54. A method of treating any one of breast cancer, lung cancer, pancreatic cancer and/or prostate cancer in a human comprising administering to the human a therapeutically-effective combination of (1) an amount of ketoconazole and (2) an amount of a Compound (1) of formula id="INS-S-00168" id="INS-S-00169" date="20080617" or a pharmaceutically-acceptable solvate, clathrate, hydrate, or prodrug thereof, wherein the administration will provide an anticancer effect for a greater period of time than the effect obtainable with the amount of the Compound (1) alone.id="INS-S-00169"
연구과제 타임라인
LOADING...
LOADING...
LOADING...
LOADING...
LOADING...
이 특허에 인용된 특허 (7)
Gregory D. Vite ; Soong-Hoon Kim ; Gerhard Hofle DE, 12, 13-cyclopropane epothilone derivatives.
Danishefsky Samuel J. ; Bertinato Peter ; Su Dai-Shi ; Meng DongFang ; Chou Ting-Chao ; Kamenecka Ted ; Sorensen Erik J ; Balog Aaron ; Savin Kenneth A. ; Kuduk Scott ; Harris Christina ; Zhang Xiu-G, Synthesis of epothilones, intermediates thereto and analogues thereof.
※ AI-Helper는 부적절한 답변을 할 수 있습니다.