Hydrolysis-promoting hydrophobic taxane derivatives

Details Hydrolysis-promoting hydrophobic taxane derivatives Hydrolysis-promoting hydrophobic taxane derivatives

2001-08-29

2002-11-19

Trinh, Ba K. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C549S510000, C549S511000

Reexamination Certificate

active

06482850

ABSTRACT:

FIELD OF THE INVENTION
This invention provides compounds which are a taxane to which an acyl chain has been attached; the acyl chain has been derivatized by the stereospecific attachment thereto of a hydrolysis-promoting group. Also provided herein are compositions comprising such compounds and racemic mixtures thereof, including lipid carrier-containing pharmaceutical compositions, and methods of administering such compositions to animals, such as humans afflicted with cancers or certain inflammatory conditions.
BACKGROUND OF THE INVENTION
Taxanes can be isolated from natural sources, and can also be prepared synthetically from naturally occurring precursors. Paclitaxel (TAXOL®, Bristol-Myers Squibb), for example, can be prepared from baccatin by attachment of protecting groups to the hydroxyl groups of baccatin that are to become the hydroxyl groups of paclitaxel, converting the precursor baccatin to paclitaxel, and then removing the protecting groups from the hydroxyl groups to obtain paclitaxel. In addition, paclitaxel has recently been synthesized from simple precursors. (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; Nicolau, 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 contents of these documents are incorporated herein by reference).
Taxanes can be used effectively to treat a variety of cancers and recently has been reported to have therapeutic effects in treating certain inflammatory diseases. Paclitaxel, for example, 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 has been hypothesized to act against cancer cells by binding to tubulin in the cells' nuclei, thereby blocking the disassembly of microtubules and consequently, inhibiting cell division (Schiff et al., Nature 277:665 (1979).
However, formulation of taxanes in therapeutically useful carriers, so as to enable the taxanes to be administered to animals, is made difficult by the nature of the taxane molecules, which can be poorly soluble in both aqueous and lipid carriers. Paclitaxel, for example, is currently supplied as a formulation of polyoxyethylated derivative of castor oil, Cremophor EL® and ethanol (50:50) because of its lack of significant aqueous or liposome solubility. However, the Cremophor EL® carrier itself can cause toxic side effects or increase the side effects caused by the taxane when administered to animals. Thus, administration of the Cremophor EL®: ethanol -based paclitaxel formulation generally entails premedication with other drugs, as well as a slow infusion of a large volume of the formulation, thus often necessitating over night hospital stays and their attendant costs. Alternatively, a stable formulation of a taxane with a lower concentration of a polyoxyethylated derivative of castor oil could be important in reducing the toxic side effects of the drug product.
Compositions provided herein provide taxanes in the form of compounds which are taxanes to which an acyl chain has been attached. The acyl chain enhances the taxane's lipid solubility. Thus, the taxane can be stably associated with a lipid-based carrier such as a liposome, for an extended period of time. However, the compositions provided herein may also be administered in non-liposomal carriers, such as USP/NF Polyoxyl 35 Castor Oil. The acyl chain itself has been derivatized by the attachment thereto of a hydrolysis-promoting group, which is a chemical moiety that promotes hydrolysis of the derivatized acyl chain from the parent taxane, once the taxane has been disassociated from the lipid-based carrier, so as to give the parent taxane in a therapeutically useful form. The hydrolysis-promoting group may take the structure of a single enantiomer or may be administered as a mixture of (S) and (R) enantiomers. There may be a stereospecific difference in the biological and pharmacological activity attributable to the enantiomeric form. While not being limited to this explanation, it is possible that in vivo cleavage may favor one enantiomer. Thus, by providing a method to deliver the preferred enantiomeric form of the hydrolyzable hydrophobic taxane of the present invention, administeration of lower dosage than with mixed racemic forms may provide equivalent therapeutic effect. The present invention, therefore, additionally provides methods for preparing single enantiomeric forms of the hydrolyzable hydrophobic acyl chains and methods for synthesizing the hydrolyzable hydrophobic taxane having a single enantiomeric substituted fatty acid or at least enriched in a single enantiomeric form.
The compounds provided herein can be administered to animals as such, or may be formulated together with a lipid-based carrier prior to administration. Such formulations may enhance delivery of the taxane to its intended site of action in an animal and may alter the pharmacological action by delaying the release of the therapeutic agent in the animal or may delay the clearance of the therapeutic agent from the animal. These formulations may therefore allow increased time of exposure of the animal to the therapeutic agent. However, the drug compound comprising the HPG must be stable in formulations until administration.
SUMMARY OF THE INVENTION
This invention provides a taxane having the formula:
wherein: A
1
is H or a group having the formula Z—C(O)NHCH(C
6
H
5
)CH(OR)C(O)—; Z is C
6
H
5
—, C
6
H
5
CH
2
O—, (CH
3
)
3
C—O— or CH(CH
3
)=C(CH
3
)—; A
2
is H or CH
3
C(O)—; and A
3
is H or OH. Each of R and R
1
is H or a group having the formula Y
1
Y
2
, provided that at least one of R and R
1
is not H, and provided that when A
1
is H, R
1
is not H.
Y
1
is a group having the formula —C(O)CHX
1
(CH
2
)
n1
(CH═CH)
n2
(CH
2
)
n3
(CH═CH)
n4
(CH
2
)
n5
(CH═CH)
n6
(CH
2
)
n7
(CH═CH)
n8
(CH
2
)
n9
—. The sum of n1+2n2+n3+2n4+n5+2n6+n7+2n8+n9 is an integer of from 1 to 21, with each of n2, n4, n6 and n8 being independently zero or 1. n1 is equal to zero or an integer of from 1 to 21, n3 is equal to zero or an integer of from 1 to 18, n5 is equal to zero or an integer of from 1 to 15, n7 is equal to zero or an integer of from 1 to 12, n9 is equal to zero or an integer of from 1 to 9, and each of n 1 to n9 can be the same or different at each occurrence. Y
2
is —CH
3
, —CO
2
H or —CH
2
OH.
X
1
is a hydrolysis promoting group (“HPG”) including, but not limited to: F, Cl, Br, I, the group —OC
6
H
4
X
2
or the group —C(O)X
2
, wherein X
2
is F, Cl, Br, I, NH
3
+, NO
2
or CN. Most preferably, X
1
is F, Cl, Br or I. The X
1
in CHX
1
could have (R) or (S) configuration or could be a mixture of (R) and (S) configurations. Preferably, A
1
is the group Z—C(O)NHCH(C
6
H
5
)CH(OR)C(O)—; Z is preferably C
6
H
5
and A
1
is more preferably the group C
6
H
5
C(O)NHCH(C
6
H
5
)CH(OR)C(O)—. Most preferably, A
1
is C
6
H
5
C(O)NHCH(C
6
H
5
)CH(OR)C(O)—, A
2
is CH
3
C(O)— and A
3
is H, that is, the taxane is a paclitaxel. When R
1
is a hydrogen, R is then —Y
1
Y
2
, and when R is a hydrogen, R
1
is —Y
1
Y
2
. The group —Y
1
Y
2
preferably has the formula —Y
1
CH
3
, more preferably, the formula —C(O)CHX
1

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