Hydrophobic taxane derivatives

Details Hydrophobic taxane derivatives Hydrophobic taxane derivatives

2000-05-09

2001-09-18

Trinh, Ba K. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S511000

Reexamination Certificate

active

06291690

ABSTRACT:

This invention provides a taxane derivative comprising a hydrophobic organic moiety attached to a taxane, compositions comprising such compounds, including lipid carrier-containing compositions, and methods of administering such compositions to animals, including those afflicted with cancers.
Taxanes can be anticancer agents, which affect cell growth by blocking cell division. Paclitaxel, for example, is an antimitotic agent which binds to tubulin, thereby blocking the disassembly of microtubules and consequently, inhibiting cell division (Schiff et al., Nature 277:665 (1979)). The optimal effect of paclitaxel on polymerization and stabilization of microtubuies is seen at concentrations near stoichiometric equivalence with tubulin dimers (Schiff and Horowitz, Proc. Natl. Acad. Sci. USA 77(3):1561-1565(1980)). Paclitaxel has been found to have activity against ovarian and breast cancers, as well as against malignant melanoma,. colon cancer, leukemias and lung cancer (see, e.g., Borman, Chemical & Engineering News, Sep. 2, 1991, pp. 11-18; The Pharmacological Basis of Therapeutics * * * (Goodman Gilman et al, eds.) * * * , Pergamon Press, New York (1990), p. 1239; Suffness, Antitumor Alkaloids, in: “The Alkaloids, Vol. XXV,” Academic Press, Inc. (1985), Chapter 1, pp. 6-18; Rizzo et al., J. Pharm. & Biomed. Anal. 8(2): 159-164 (1990); and Biotechnology 9:933-938 (October 1991).
Paclitaxel can be isolated from natural sources, or prepared synthetically frpm naturally occurring precursors, e.g., baccatin, by attachment of protecting groups to the hydroxyl groups of these precursors that are to become the hydroxyl groups of paclitaxel, converting the precursors, and then removing the protecting groups from the hydroxyl groups to obtain paclitaxel (see, e.g., WO93/10076, int. pub. date May 27, 1993; K. V. Rao, U.S. Pat. No. 5,200,534; R. A. Holton, U.S. Pat. No. 5,015, 744; PCT/US92/07990; V. J. Stella and A. E. Mathew, U.S. Pat. No. 4,960,790; K. C. Nicolau, Nature 364 (1993), pp. 464-466; Nicolaou, K. C. et al. Nature 367 (1994) pp.630-634; Holton, R. A., et al. J. Am. Chem. Soc. 116 (1994) pp. 1597-1600; WO93/16059, int. pub. date Aug. 19, 1993; EP 528,729, published Feb. 24, 1993; EP 522,958, published Jan. 13, 1993; WO91/13053, int. pub. date Sep. 5, 1991; EP 414,610, int. pub. date Feb. 27, 1991). The protecting groups used in some of these synthetic processes are short-chain aliphatic alkyl groups, but are not hydrophobic organic moieties as the term is used herein.
Paclitaxel is highly insoluble in water and aqueous solvents, and is currently supplied as an emulsion (TAXOL®, Bristol-Myers Squibb) in a polyoxyethylated derivative of castor oil and ethanol (CremophorEL®). However, administration of this formulation generally entails premedication with other drugs and a slow infusion of a large volume, to avoid toxicity associated with the Cremophor vehicle. Patients are therefore generally required to be admitted to hospitals over night. Compositions provided herein comprising a taxane derivative associated with a lipid carrier can solve this problem, by providing a formulation in which the taxane remains stably associated with the lipid carrier when administered. Stable association with a lipid carrier generally avoids the toxicity problems encountered with the currently used delivery system, as well as the need for slow-infusion administration.
SUMMARY OF THE INVENTION
This invention provides a taxane derivative of the formula:
wherein: A
1
is H or a group having the formula Q—C(O)NHCH(C
6
H
5
)CH(OR)C(O)—. Q is C
6
H
5
—, (CH
3
)
3
CO— or (CH
3
)CH═C(CH
3
)—; A
2
is H or CH
3
C(O)—; A
3
is H, or OH. A
1
is preferably (C
6
H
5
)(O)NHCH(C
6
H
5
)CH(OR)C(O)—. Preferably, A
2
is CH
3
C(O)—, and A
3
is H that is, the taxane derivative preferably is a paclitaxel.
When R
1
is H, A
1
is a group having the formula Q—C(O)NHCH(C
6
H
5
)CH(OR)C(O)—; R is then not H, but rather, is a group having the formula Y
1
, Z
1
X
1
or Z
1
D
1
. When A
1
is H, or when A
1
is a group having the formula Q—C(O)NHCH(C
6
H
5
)CH(OR)C(O)— and R is H, R
1
is then not H; rather, R
1
is then a group having the formula Y
2
, Z
2
X
2
or Z
2
D
2
. Accordingly, at least one hydrophobic organic moiety is attached to the taxane. Furthermore, two hydrophobic organic moieties can be attached to the taxane, R then being a group having the formula Y
1
, Z
1
X
1
or Z
1
D
1
when R
1
is a group having the formula Y
2
, Z
2
X
2
or Z
2
D
2
.
Each of Y
1
and Y
2
is independently a group having the formula: —C(O)(CH
2
)
a
(CH═CH)
b
(CH
2
)
c
(CH═CH)
d
(CH
2
)
e
(CH═CH)
f
(CH
2
)
g
(CH═CH)
h
(CH
2
)
i
CH
3
. The sum of a+2b+c+2d+e+2f+g+2h+i is equal to an integer from 7 to 22 (refering to the number of carbon atoms); a is zero or an integer from 1 to 22; each of b, d, f and h is independently zero or 1; c is zero or an integer from 1 to 20; e is zero or an integer from 1 to 17; g is zero or an integer from 1 to 14; i is zero or an integer from 1 to 11; and a to i can be the same or different at each occurrence.
Each of Z
1
and Z
2
is independently a linker of the formula: —C(O)(CH
2
)
j
(CH═CH)
k
(CH
2
)
l
(CH═CH)
m
(CH
2
)
n
(CH═CH)
o
(CH
2
)
p
(CH═CH)
q
(CH
2
)
r
C(O)—. The sum of j+2k+l+2m+n+2o+p+2q+r is equal to an integer from 2 to 22; each of k, m, o and q is independently zero or 1; j is zero or an integer from 2 to 22; l is zero or an integer from 1 to 20; n is zero or an integer from 1 to 17; p is zero or an integer from 1 to 14; and r is zero or an integer from 1 to 11. Each of j to r can be the same or different at each occurrence.
Each of X
1
and X
2
is independently a group having the formula:
G
1
is —OP(O)
2
OCH
2
CH
2
N(CH
3
)
3
(phosphorylcholine), —OP(O)
2
OCH
2
CH
2
NH
2
, (phosphorylethanolamine) —OP(O)
2
OCH
2
CH(OH)CH
2
OH (phosphorylglycerol), —OP(O)
2
OCH
2
CH(NH
2
)CO
2
H (phosphorylserine) or phosphoylinositol.
Each of D
1
and D
2
is independently a group having the formula:
When R is not H, it is preferably a group having the formula Y
1
. Y
1
is preferably a group having the formula —C(O)(CH
2
)
a
CH
3
, and still more preferably, is —C(O)(CH
2
)
10
CH
3
or —C(O)(CH
2
)
16
CH
3
. However, R can also be a group having the formula Z
1
X
1
. G
1
is then preferably phosphorylcholine, Z
1
is preferably —C(O)(CH
2
)
8
C(O)— and R is preferably a group having the formula:
wherein Y
1
is preferably a group having the formula —C(O)(CH
2
)
a
CH
3
.
R can further be Z
1
D
1
. Z
1
is then preferably a group having the formula —C(O)(CH
2
)
j
C(O)—, more preferably, —C(O)(CH
2
)
3
C(O)—.
When R
1
is not H, it is preferably Y2. More preferably, R
1
is then a group having the formula —C(O)(CH
2
)
a
CH
3
, and still more preferably, —C(O)(CH
2
)
10
CH
3
or —C(O)(CH
2
)
16
CH
3
. However, R
1
can then also be a group having the formula Z
2
X
2
; G
1
is then preferably phosphorylcholine and Z
2
is preferably —C(O)(CH
2
)
8
C(O)—. R
1
can further be a group having the formula Z
2
D
2
; Z
2
is then preferably a group having the formula —C(O)(CH
2
)
j
C(O)—, more preferbly, —C(O)(CH
2
)
3
C(O)—.
Hydrophobic organic moieties can be attached to the same taxane at both the 2′ and 7 positions; neither R nor R
1
is then H. R and R
1
can both be the same moiety, such as groups having the formula —C(O)(CH
2
)
10
CH
3
or —C(O)(CH
2
)
16
CH
3
, or different moieties, but are preferably the same moiety.
Also provided herein is a composition comprising a pharmaceutically acceptable medium and the taxane derivative of this invention. The medium preferably comprises a lipid carrier, for example, a fatty acid, lipid, micelle, aggregate, lipoprotein or liposome, associated with the taxane. Preferably, the lipid carrier is a liposome. The lipid carrier can comprise an additional bioactive agent, that is, a bioactive agent in addition to the taxane derivative. Lipid carriers can also comprise a headgroup-modified lipid.
Further provided herein is a method o

Affiliated with

Also associated with

Rating

Hydrophobic taxane derivatives does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Hydrophobic taxane derivatives, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Hydrophobic taxane derivatives will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2458881