Oral administration of epothilones
First Claim
Patent Images
1. A method of administering a compound comprising:
- orally administering to a human one or more compounds of Formula I;
wherein;
P-Q is a C, C double bond or an epoxide;
G is R is selected from the group consisting of H, alkyl, and substituted alkyl;
R1 is selected from the group consisting of R2 is G1 is selected from the group consisting of H, halogen, CN, alkyl and substituted alkyl;
G2 is selected from the group consisting of H, alkyl, and substituted alkyl;
G3 is selected from the group consisting of O, S, and NZ1;
G4 is selected from the group consisting of H, alkyl, substituted alkyl, OZ2, NZ2Z3, Z2C═
O, Z4SO2, and optionally substituted glycosyl;
G5 is selected from the group consisting of halogen, N3, NCS, SH, CN, NC, N(Z1)3+, and heteroaryl;
G6 is selected from the group consisting of H, alkyl, substituted alkyl, CF3, OZ5, SZ5, and NZ5Z6;
G7 is CZ7 or N;
G8 is selected from the group consisting of H, halogen, alkyl, substituted alkyl, OZ10, SZ10, NZ10Z11;
G9 is selected from the group consisting of O, S, —
NH—
NH—
, and —
N═
N—
;
G10 is N or CZ12;
G11 is selected from the group consisting of H2N, substituted H2N, alkyl, substituted alkyl, aryl, and substituted aryl;
Z1, Z6, Z9, and Z11 are independently selected from the group consisting of H, alkyl, substituted alkyl, acyl, and substituted acyl;
Z2 is selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, and heterocycle;
Z3, Z5, Z8, and Z10 are independently selected from the group consisting of H, alkyl, substituted alkyl, acyl, substituted acyl, aryl, and substituted aryl;
Z4 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, and heterocycle;
Z7 is selected from the group consisting of H, halogen, alkyl, substituted alkyl, aryl, substituted aryl, OZ8, SZ8, and NZ8Z9; and
Z12 is selected from the group consisting of H, halogen, alkyl, substituted alkyl, aryl, and substituted aryl;
with the proviso that when R1 is G1, G2, G3, and G4 cannot simultaneously have the following meanings;
G1 and G2=H, G3=O and G4=H or Z2C═
O where Z2=alkyl, and with the proviso that when R1 is G1, G2 or G5 cannot simultaneously have the following meanings;
G1 and G2=H, and G5=F;
or a pharmaceutically acceptable salt, solvate, clathrate, hydrate or prodrug thereof; and
orally administering one or more pharmaceutically acceptable acid neutralizing buffers in an amount sufficient to reduce decomposition of said one or more compounds, or said pharmaceutically acceptable salt, solvate, clathrate, hydrate, or prodrug thereof.
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Abstract
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.
40 Citations
64 Claims
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1. A method of administering a compound comprising:
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orally administering to a human one or more compounds of Formula I;
wherein;
P-Q is a C, C double bond or an epoxide;
G is R is selected from the group consisting of H, alkyl, and substituted alkyl;
R1 is selected from the group consisting of R2 is G1 is selected from the group consisting of H, halogen, CN, alkyl and substituted alkyl;
G2 is selected from the group consisting of H, alkyl, and substituted alkyl;
G3 is selected from the group consisting of O, S, and NZ1;
G4 is selected from the group consisting of H, alkyl, substituted alkyl, OZ2, NZ2Z3, Z2C═
O, Z4SO2, and optionally substituted glycosyl;
G5 is selected from the group consisting of halogen, N3, NCS, SH, CN, NC, N(Z1)3+, and heteroaryl;
G6 is selected from the group consisting of H, alkyl, substituted alkyl, CF3, OZ5, SZ5, and NZ5Z6;
G7 is CZ7 or N;
G8 is selected from the group consisting of H, halogen, alkyl, substituted alkyl, OZ10, SZ10, NZ10Z11;
G9 is selected from the group consisting of O, S, —
NH—
NH—
, and —
N═
N—
;
G10 is N or CZ12;
G11 is selected from the group consisting of H2N, substituted H2N, alkyl, substituted alkyl, aryl, and substituted aryl;
Z1, Z6, Z9, and Z11 are independently selected from the group consisting of H, alkyl, substituted alkyl, acyl, and substituted acyl;
Z2 is selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, and heterocycle;
Z3, Z5, Z8, and Z10 are independently selected from the group consisting of H, alkyl, substituted alkyl, acyl, substituted acyl, aryl, and substituted aryl;
Z4 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, and heterocycle;
Z7 is selected from the group consisting of H, halogen, alkyl, substituted alkyl, aryl, substituted aryl, OZ8, SZ8, and NZ8Z9; and
Z12 is selected from the group consisting of H, halogen, alkyl, substituted alkyl, aryl, and substituted aryl;
with the proviso that when R1 is G1, G2, G3, and G4 cannot simultaneously have the following meanings;
G1 and G2=H, G3=O and G4=H or Z2C═
O where Z2=alkyl, and with the proviso that when R1 isG1, G2 or G5 cannot simultaneously have the following meanings;
G1 and G2=H, and G5=F;
or a pharmaceutically acceptable salt, solvate, clathrate, hydrate or prodrug thereof; and
orally administering one or more pharmaceutically acceptable acid neutralizing buffers in an amount sufficient to reduce decomposition of said one or more compounds, or said pharmaceutically acceptable salt, solvate, clathrate, hydrate, or prodrug thereof. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32)
wherein: -
P-Q is a C,C double bond or an epoxide;
R is H or a methyl;
G1 is selected from the group consisting of H, alkyl, a substituted alkyl, and halogen;
G2 is selected from the group consisting of H, alkyl, and substituted alkyl;
G3 is selected from the group consisting of O, S, and NZ1;
G4 is selected from the group consisting of H, alkyl, substituted alkyl, OZ2, NZ2Z3, Z2C═
O, Z4SO2, and an optionally substituted glycosyl;
Z1 is selected from the group consisting of H, alkyl, substituted alkyl, acyl, and substituted acyl;
Z2 is selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, and heterocycle;
Z3 is selected from the group consisting of H, alkyl, substituted alkyl, acyl, and substituted acyl; and
Z4 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, and heterocycle;
with the proviso that G1, G2, G3, and G4 cannot have simultaneously the following meanings;
G1 and G2=H, G3=O, and G4=H or Z2C═
O with Z2=alkyl.
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3. The method of claim 2 wherein said compound is
wherein G1, G2, G3, G4, Z1, Z2, and Z3 are as defined in claim 2. -
4. The method of claim 3 wherein said compound is [1S-[1R*,3R*(E),7R*, 10S*,11R*,12R*,16S*]]-3-[2-[2(aminomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo 14.1.0]heptadecane-5,9-dione.
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5. The method of claim 1 wherein said pharmaceutically acceptable acid neutralizing buffer is administered concurrently with said compound.
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6. The method of claim 1 wherein said pharmaceutically acceptable acid neutralizing buffer is administered before said compound.
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7. The method of claim 6 wherein said pharmaceutically acceptable acid neutralizing buffer is administered not more than about 1 hour before said compound.
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8. The method of claim 1 wherein said pharmaceutically acceptable acid neutralizing buffer is administered after said compound.
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9. The method of claim 8 wherein said pharmaceutically acceptable acid neutralizing buffer is administered nor more than about 1 hour after said compound.
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10. The method of claim 1 wherein said pharmaceutically acceptable acid neutralizing buffer is administered before and after said compound.
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11. The method of claim 10 wherein said pharmaceutically acceptable acid neutralizing buffer is administered not more than about 1 hour before and not more than about 1 hour after said compound is administered.
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12. The method of claim 1 wherein said pharmaceutically acceptable acid neutralizing buffer is administered in an amount sufficient to deliver at least about 20 milliequivalents of acid neutralization capacity.
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13. The method of claim 1 wherein said pharmaceutically acceptable acid neutralizing buffer is administered in an amount sufficient to deliver at least about 30 milliequivalents of acid neutralization capacity.
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14. The method of claim 1 wherein said pharmaceutically acceptable acid neutralizing buffer is administered in an amount sufficient to deliver at least about 40 milliequivalents of acid neutralization capacity.
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15. The method of claim 1 wherein said pharmaceutically acceptable acid neutralizing buffer is administered as an aqueous solution having a pH of between about 5 to 9.
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16. The method of claim 1 wherein said pharmaceutically acceptable acid neutralizing buffer is administered as an aqueous solution having a pH of between about 6 to 8.5.
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17. The method of claim 1 wherein said pharmaceutically acceptable acid neutralizing buffer is administered as an aqueous solution having a pH of between about 7 to 8.
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18. The method of claim 1 wherein said compound is administered every 3 days to 7 days, followed by a period of 1 week to 3 weeks where there is no treatment.
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19. The method of claim 18 wherein said compound is administered every 3 days, followed by a period of 1 week where there is no treatment.
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20. The method of claim 18 wherein said compound is administered every 5 days, followed by a period of 1 week where there is no treatment.
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21. The method of claim 18 wherein said compound is administered every 7 days, followed by a period of 1 week where there is no treatment.
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22. The method of claim 1 wherein said pharmaceutically acceptable acid neutralizing buffer is administered as an aqueous solution comprising anhydrous dibasic sodium phosphate, sodium citrate dihydrate, and anhydrous citric acid.
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23. The method of claim 22 wherein the pH of said aqueous solution is about 7.
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24. The method of claim 1 wherein the bioavailability of said one or more compounds or sida pharmaceutically acceptable salt, solvate, clathrate, hydrate, or prodrug thereof is at least about 20 percent.
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25. The method of claim 1 wherein the bioavailability of said one or more compounds or said pharmaceutically acceptable salt, solvate, clathrate, hydrate, or prodrug thereof is at least about 30 percent.
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26. The method of claim 1 wherein said one or more compounds or said pharmaceutically acceptable salt, solvate, clathrate, hydrate, or prodrug thereof is orally administered as a solution in propylene glycol and ethanol, wherein the ratio of propylene glycol:
- ethanol is about 80;
20.
- ethanol is about 80;
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27. The method of claim 26 wherein said compound is [1S-[1R*,3R*(E),7R*, 10S *,11R*,12R*,16S*]]-3-[2-[2-(aminomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione.
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28. The method of claim 1 wherein said one or more compounds or said pharmaceutically acceptable salt, solvate, clathrate, hydrate, or prodrug thereof is administered in a total amount of about 0.05 to about 200 mg/kg/day.
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29. The method of claim 28 wherein said one or more compounds or said pharmaceutically acceptable salt, solvate, clathrate, hydrate, or prodrug thereof is administered in about 2 to 4 divided doses.
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30. The method of claim 29 wherein said compound is [1S-[1R*,3R*(E),7R*, 10S*,11R*,12R*,16S*]]-3-[2-[2-(aminomethyl)-4-thiazolyl]-1-methylethenyl]-7,11-dihydroxy-8,8,10,12,16-pentamethyl-4,17-dioxabicyclo[14.1.0]heptadecane-5,9-dione.
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31. The method of claim 1 wherein said pharmaceutically acceptable acid neutralizing buffer is selected from the group consisting of tartaric acid, lactic acid, succinic acid, citric acid, acetic acid, ascorbic acid, aspartic acid, glutamic acid, and salts thereof.
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32. The method of claim 1 comprising:
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(a) orally administering an aqueous solution of said pharmaceutically acceptable acid neutralizing buffer;
(b) orally administering said one or more compounds or said pharmaceutically acceptable salt, solvate, clathrate, hydrate, or prodrug thereof as a solution in propylene glycol; and
(c) orally administering said aqueous solution of said pharmaceutically acceptable acid neutralizing buffer;
wherein said pharmaceutically acceptable acid neutralizing buffer comprises anhydrous dibasic sodium phosphate, sodium citrate dihydrate, and anhydrous citric acid.
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33. A kit for use in a method of administering compounds which comprises:
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(i) a first component comprising one or more compounds of Formula I;
wherein;
P-Q is a C, C double bond or an epoxide;
G is R is selected from the group consisting of H, alkyl, and substituted alkyl;
R1 is selected from the group consisting of R2 is G1 is selected from the group consisting of H, halogen, CN, alkyl, and substituted alkyl;
G2 is selected from the group consisting of H, alkyl, and substituted alkyl;
G3 is selected from the group consisting of O, S, and NZ1;
G4 is selected from the group consisting of H, alkyl, substituted alkyl, OZ2, NZ2Z3, Z2C═
O, Z4SO2, and optionally substituted glycosyl;
G5 is selected from the group consisting of halogen, N3, NCS, SH, CN, NC, N(Z1)3+, and heteroaryl;
G6 is selected from the group consisting of H, alkyl, substituted alkyl, CF3, OZ5, SZ5, and NZ5Z6;
G7 is CZ7 or N;
G8 is selected from the group consisting of H, halogen, alkyl, substituted alkyl, OZ10, SZ10, and NZ10Z11;
G9 is selected from the group consisting of O, S, —
NH—
NH—
, and —
N═
N—
;
G10 is N or CZ12;
G11 is selected from the group consisting of H2N, substituted H2N, alkyl, substituted alkyl, aryl, and substituted aryl;
Z1, Z6, Z9, and Z11 are independently selected from the group consisting of H, alkyl, substituted alkyl, acyl, and substituted acyl;
Z2 is selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, and heterocycle;
Z3, Z5, Z8, and Z10 are independently selected from the group consisting of H, alkyl, substituted alkyl, acyl, substituted acyl, aryl, and substituted aryl;
Z4 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, and heterocycle;
Z7 is selected from the group consisting of H, halogen, alkyl, substituted alkyl, aryl, substituted aryl, OZ8, SZ8, and NZ8Z9; and
Z12 is selected from the group consisting of H, halogen, alkyl, substituted alkyl, aryl, and substituted aryl;
with the proviso that when R1 is G1, G2, G3, and G4 cannot simultaneously have the following meanings;
G1 and G2=H, G3=O, and G4=H or Z2C=O where Z2=alkyl, and with the proviso that when R1 is
G1, G2 or G5 cannot simultaneously have the following meanings;
G1 and G2=H, and G5=F;
or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, or prodrug thereof; and
(ii) a second component comprising a pharmaceutically acceptable acid neutralizing buffer, wherein said first component and said 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. - View Dependent Claims (34, 35, 36, 37, 38, 39, 40, 41, 42, 43)
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44. A pharmaceutical composition suitable for oral administration to a mammal comprising:
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(i) one or more compounds of Formula I;
wherein;
P-Q is a C, C double bond or an epoxide;
G is R is selected from the group consisting of H, alkyl, and substituted alkyl;
R1 is selected from the group consisting of R2 is G1 is selected from the group consisting of H, halogen, CN, alkyl, and substituted alkyl;
G2 is selected from the group consisting of H, alkyl, and substituted alkyl;
G3 is selected from the group consisting of O, S, and NZ1;
G4 is selected from the group consisting of H, alkyl, substituted alkyl, OZ2, NZ2Z3, Z2C═
O, Z4SO2, and optionally substituted glycosyl;
G5 is selected from the group consisting of halogen, N3, NCS, SH, CN, NC, N(Z1)3+, and heteroaryl;
G6 is selected from the group consisting of H, alkyl, substituted alkyl, CF3, OZ5, SZ5, and NZ5Z6;
G7 is CZ7 or N;
G8 is selected from the group consisting of H, halogen, alkyl, substituted alkyl, OZ10, SZ10, and NZ10Z11;
G9 is selected from the group consisting of O, S, —
NH—
NH—
, and —
N═
N—
;
G10 is N or CZ12;
G11 is selected from the group consisting of H2N, substituted H2N, alkyl, substituted alkyl, aryl, and substituted aryl;
Z1, Z6, Z9, and Z11 are independently selected from the group consisting of H, alkyl, substituted alkyl, acyl, and substituted acyl;
Z2 is selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, and heterocycle;
Z3, Z5, Z8, and Z10 are independently selected from the group consisting of H, alkyl, substituted alkyl, acyl, substituted acyl, aryl, and substituted aryl;
Z4 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, and heterocycle;
Z7 is selected from the group consisting of H, halogen, alkyl, substituted alkyl, aryl, substituted aryl, OZ8, SZ8, and NZ8Z9; and
Z12 is selected from the group consisting of H, halogen, alkyl, substituted alkyl, aryl, and substituted aryl;
with the proviso that when R1 is G1, G2, G3, and G4 cannot simultaneously have the following meanings;
G1 and G2=H, G3=O, and G4=H or Z2C═
O where Z2=alkyl, and with the proviso that when R1 is
G1, G2, or G5 cannot simultaneously have the following meanings;
G1 and G2=H, and G5=F;
or a pharmaceutically acceptable salt, 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 said one or more compounds, or said pharmaceutically acceptable salt, solvate, clathrate, hydrate, or prodrug thereof when said pharmaceutical composition is reconstituted with a solvent to provide a liquid oral dosage form. - View Dependent Claims (45, 46, 47, 48, 49, 50, 51, 52)
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53. A liquid oral dosage form suitable for oral administration to a mammal comprising:
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(i) one or more compounds of Formula I;
wherein;
P-Q is a C, C double bond or an epoxide;
G is R is selected from the group consisting of H, alkyl, and substituted alkyl;
R1 is selected from the group consisting of R2 is G1 is selected from the group consisting of H, halogen, CN, alkyl, and substituted alkyl;
G2 is selected from the group consisting of H, alkyl, and substituted alkyl;
G3 is selected from the group consisting of O, S, and NZ1;
G4 is selected from the group consisting of H, alkyl, substituted alkyl, OZ2, NZ2Z3, Z2C═
O, Z4SO2, and optionally substituted glycosyl;
G5 is selected from the group consisting of halogen, N3, NCS, SH, CN, NC, N(Z1)3+, and heteroaryl;
G6 is selected from the group consisting of H, alkyl, substituted alkyl, CF3, OZ5, SZ5, and NZ5Z6;
G7 is CZ7 or N;
G8 is selected from the group consisting of H, halogen, alkyl, substituted alkyl, OZ10, SZ10, and NZ10Z11;
G9 is selected from the group consisting of O, S, —
NH—
NH—
, and —
N═
N—
;
G10 is N or CZ12;
G11 is selected from the group consisting of H2N, substituted H2N, alkyl, substituted alkyl, aryl, and substituted aryl;
Z1, Z6, Z9, and Z11 are independently selected from the group consisting of H, alkyl, substituted alkyl, acyl, and substituted acyl;
Z2 is selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, and heterocycle;
Z3, Z5, Z8, and Z10 are independently selected from the group consisting of H, alkyl, substituted alkyl, acyl, substituted acyl, aryl, and substituted aryl;
Z4 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, and heterocycle;
Z7 is selected from the group consisting of H, halogen, alkyl, substituted alkyl, aryl, substituted aryl, OZ8, SZ8, and NZ8Z9; and
Z12 is selected from the group consisting of H, halogen, alkyl, substituted alkyl, aryl, and substituted aryl;
with the proviso that when R1 is G1, G2, G3, and G4 cannot simultaneously have the following meanings;
G1 and G2=H, G3=O, and G4=H or Z2C═
O where Z2=alkyl, and with the proviso that when R1 is
G1, G2 or G5 cannot simultaneously have the following meanings;
G1 and G2=H, and G5=F;
or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, or prodrug thereof;
(ii) a pharmaceutically acceptable liquid carrier; and
(iii) a pharmaceutically acceptable acid neutralizing buffer in an amount sufficient to reduce decomposition of said one or more compounds, or said pharmaceutically acceptable salt, solvate, clathrate, hydrate, or prodrug thereof compared to a pharmaceutical composition without said buffer. - View Dependent Claims (54, 55, 56, 57, 58, 59, 60, 61)
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62. A dispersible buffered tablet which comprises:
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(i) one or more compounds of Formula I;
wherein;
P-Q is a C, C double bond or an epoxide;
G is R is selected from the group consisting of H, alkyl, and substituted alkyl;
R1 is selected from the group consisting of R2 is G1 is selected from the group consisting of H, halogen, CN, alkyl, and substituted alkyl;
G2 is selected from the group consisting of H, alkyl, and substituted alkyl;
G3 is selected from the group consisting of O, S, and NZ1;
G4 is selected from the group consisting of H, alkyl, substituted alkyl, OZ2, NZ2Z3, Z2C═
O, Z4SO2, and optionally substituted glycosyl;
G5 is selected from the group consisting of halogen, N3, NCS, SH, CN, NC, N(Z1)3+, and heteroaryl;
G6 is selected from the group consisting of H, alkyl, substituted alkyl, CF3, OZ5, SZ5, and NZ5Z6;
G7 is CZ7 or N;
G8 is selected from the group consisting of H, halogen, alkyl, substituted alkyl, OZ10, SZ10, and NZ10Z11;
G9 is selected from the group consisting of O, S, —
NH—
NH—
, and —
N═
N—
;
G10 is N or CZ12;
G11 is selected from the group consisting of H2N, substituted H2N, alkyl, substituted alkyl, aryl, and substituted aryl;
Z1, Z6, Z9, and Z11 are independently selected from the group consisting of H, alkyl, substituted alkyl, acyl, and substituted acyl;
Z2 is selected from the group consisting of H, alkyl, substituted alkyl, aryl, substituted aryl, and heterocycle;
Z3, Z5, Z8, and Z10 are independently selected from the group consisting of H, alkyl, substituted alkyl, acyl, substituted acyl, aryl, and substituted aryl;
Z4 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, and heterocycle;
Z7 is selected from the group consisting of H, halogen, alkyl, substituted alkyl, aryl, substituted aryl, OZ8, SZ8, and NZ8Z9; and
Z12 is selected from the group consisting of H, halogen, alkyl, substituted alkyl, aryl, and substituted aryl;
with the proviso that when R1 is G1, G2, G3, and G4 cannot simultaneously have the following meanings;
G1 and G2=H, G3=O, and G4=H or Z2C═
O where Z2=alkyl, and with the proviso that when R1 is
G1, G2, or G5 cannot simultaneously have the following meanings;
G1 and G2=H, and G5=F;
or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, or prodrug thereof; and
(ii) one or more buffer components in an amount sufficient to reduce decomposition of the one or more compounds, or said pharmaceutically acceptable salt, solvate, clathrate, hydrate, or prodrug thereof. - View Dependent Claims (63, 64)
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Specification