Hydrolysis-promoting hydrophobic taxane derivatives
First Claim
Patent Images
1. A taxane having the formula:
-
wherein;
A1 is H or a group having the formula Z—
C(O)NHCH(C6H5)CH(OR)—
C(O)—
, A2 is H, or CH3C(O)— and
A3 is H or OH;
Z is phenyl, benzyloxy, (CH3)3CO—
or CH(CH3)═
C(CH3)—
;
each of R and R1 is H or an acyl group having the formula Y1Y2, provided that (a) when R1 is H, A1 is Z—
C(O)NHCH(C6H5)CH(OR)C(O)— and
R is said acyl group, and (b) when R is H, R1 is said acyl group;
Y1 comprises a carbonyl group having a hydrolysis-promoting group substituted at the a carbon;
Y2 is —
CH3;
wherein the α
carbon on which the hydrolysis-promoting group is substituted has a configuration selected from the group consisting of an (R) configuration, an (S) configuration and a mixture of (R) and (S) configurations.
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Abstract
Provided herein is a taxane having a hydrocarbon attached at the 2′ and/or 7 positions, the hydrocarbon'"'"'s alpha position being occupied by a “hydrolysis-promoting group” (“HPG”). In one embodiment, the hydrolysis promoting group is stereospecifically attached to the a-carbon of the hydrophobic taxane. The Substitution of an HPG for the methylene unit ordinarily occupying the alpha position allows for enhanced in vivo hydrolysis of the hydrocarbon-taxane bond, and hence, for enhanced taxane therapeutic activity. Also provided herein are taxane-containing compositions, and methods of administering taxanes to animals, including those afflicted with cancers or inflammatory diseases.
27 Citations
55 Claims
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1. A taxane having the formula:
-
wherein; A1 is H or a group having the formula Z—
C(O)NHCH(C6H5)CH(OR)—
C(O)—
,A2 is H, or CH3C(O)— and
A3 is H or OH;
Z is phenyl, benzyloxy, (CH3)3CO—
or CH(CH3)═
C(CH3)—
;
each of R and R1 is H or an acyl group having the formula Y1Y2, provided that (a) when R1 is H, A1 is Z—
C(O)NHCH(C6H5)CH(OR)C(O)— and
R is said acyl group, and (b) when R is H, R1 is said acyl group;
Y1 comprises a carbonyl group having a hydrolysis-promoting group substituted at the a carbon;
Y2 is —
CH3;
wherein the α
carbon on which the hydrolysis-promoting group is substituted has a configuration selected from the group consisting of an (R) configuration, an (S) configuration and a mixture of (R) and (S) configurations.- 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, 33, 34, 35, 36, 37, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55)
—
Y1 is a group having the formula
-
-
12. The taxane of claim 1, wherein the hydrolsis-promoting group is F, Cl, Br, I, —
- OC6H4X2 or —
C(O)X2, and X2 is F, Cl, Br, I, CN, NO2 or NH3+.
- OC6H4X2 or —
-
13. The taxane of claim 11, wherein X1 is F, Cl, Br, I, —
- OC6H4X2 or —
C(O)X2, and where X2 is F, Cl, Br, I, CN, NO2 or NH3+.
- OC6H4X2 or —
-
14. A pharmaceutical composition comprising the taxane of claim 1 and a pharmaceutically acceptable medium.
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15. The composition of claim 14, wherein the pharmaceutically acceptable medium is a substance selected from the group consisting of a polyoxyethylated derivative of castor oil, polysorbate (Tween) 80, dimethyl sulfoxide, caboxymethyl cellulose, hydroxypropylcellulose, polyethylene glycol, triacetin, soybean oil, lecithin, soy lipid, combination thereof and lipid carrier.
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16. The composition of claim 15, wherein the pharmaceutically acceptable medium is polyoxyethylated derivative of castor oil.
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17. The composition of claim 16, wherein the pharmaceutically acceptable medium is USP/NF Poloxyl 35 Castor Oil.
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18. The composition of claim 15, wherein the pharmaceutically acceptable medium is the lipid carrier.
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19. The composition of claim 18, wherein the lipid carrier is selected from the group consisting of fatty acids, phospholipids, lipoproteins, micelles, lipid complexes or liposomes.
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20. The composition of claim 19, wherein the pharmaceutically acceptable medium is a liposome.
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21. The composition of claim 20, wherein the liposome is multilamellar.
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22. The composition of claim 21, wherein the liposome comprises a lipid component which comprises a saturated lipid.
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23. The composition of claim 22, wherein the saturated lipid is a saturated phosphatidylcholine.
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24. The composition of claim 23, wherein the saturated phosphatidylcholine is dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine and distearoyl phosphatidylcholine.
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25. The composition of claim 24, wherein the saturated phosphatidylcholine is dimyristoyl phosphatidylcholine.
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26. A pharmaceutical composition comprising the taxane of claim 11 and a pharmaceutically acceptable medium, which medium is a liposome, wherein the sum of n1, 2n2, n3, 2n4, n5, 2n6, n7, 2n8 and n9 is an integer of from 3 to 21.
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27. The composition of claim 26, wherein the sum of n1, 2n2, n3, 2n4, n5, 2n6, n7, 2n8 and n9 is an integer of from 9 to 21.
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28. The composition of claim 27, wherein the sum of n1, 2n2, n3, 2n4, n5, 2n6, n7, 2n8 and n9 is an integer of from 13 to 21.
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29. The composition of claim 18, wherein the acyl group substituted with the hydrolsis-promoting group is an acyl chain of at least 6 carbon atoms in length substituted with the hydrolsis-promoting group.
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30. The composition of claim 29, wherein the acyl group substituted with the hydrolsis-promoting group is an acyl chain of at least 12 carbon atoms in length substituted with the hydrolsis-promoting group.
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31. The composition of claim 30, wherein the acyl group substituted with the hydrolsis-promoting group is an acyl chain of at least 16 carbon atoms in length substituted with the hydrolsis-promoting group.
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32. The composition of claim 11, wherein the acyl group substituted with the hydrolsis-promoting group comprises no C=C and/or C≡
- C bond.
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33. The composition of claim 20, wherein the liposome is multimellar.
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34. The composition of claim 16, wherein the weight ratio of the taxane to the polyoxyethylated derivative of castor oil is from about 13 to about 30 parts per thousand.
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35. The composition of claim 17, wherein the acyl group substituted with the hydrolosis-promoting group at the α
- carbon atom is C16 acyl chain, whith hydrolysis-promoting group is Br.
36.A liposome comprising (i) a lipid component; and
(ii) the taxane of claim 1.
- carbon atom is C16 acyl chain, whith hydrolysis-promoting group is Br.
-
36. The liposome of claim 36 comprising the lipid component and the taxane of claim 11.
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37. The liposome of claim 36, wherein the lipid component comprises the saturated acyl chain lipid.
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40. The liposome of claim 36, wherein the phosphatidylcholine is dimyristoyl phosphatidylcholine.
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41. The liposome of claim 36, which is multilamellar.
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42. A method for treating cancer in an animal in need of the treatment, comprising administering a cancer treating effective amount of the taxane of claim 1 to said animal.
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43. A method for treating cancer in an animal in need of the treatment, comprising administering a cancer treating effective amount of the composition of claim 14 to said animal.
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44. The method of claim 43, wherein said animal is a human.
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45. The method of claim 44, wherein said animal is a human.
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46. The method of claim 43, wherein said cancer is a cancer of the brain, stomach, lung, colon, prostate, breast, ovary, head or neck of said animal.
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47. The method of claim 43, wherein said cancer is a leukemia, lymphoma, carcinoma or sarcoma.
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48. The method of claim 44, wherein said cancer is a cancer of the brain, stomach, lung, colon, prostate, breast, ovary, head or neck of said animal.
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49. The method of claim 44, wherein said cancer is a leukemia, lymphoma, carcinoma or sarcoma.
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50. A method for treating an inflammatory disease in an animal in need of the treatment, comprising administering an inflammatory disease treating effective amount of the taxane of claim 1 to said animal.
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51. A method for treating an inflammatory disease in an animal in need of the treatment, comprising administering an inflammatory disease treating effective amount of the composition of claim 14 to said animal.
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52. The method of claim 51, wherein said animal is a human.
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53. The method of claim 52, wherein said animal is a human.
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54. The method of claim 51, wherein said inflammatory disease is arthritis.
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55. The method of claim 52, wherein said inflammatory disease is arthritis.
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38. The liposome of claim 38, wherein the saturated acyl chain lipid is a phosphatidylcholine.
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39. The liposome of claim 39, wherein the phosphatidylcholine is selected from the group consisting of dimyristoyl phosphatidylcholine, dipalmitoyl phosphatidylcholine and distearoyl phosphatidylcholine.
Specification