Methods of preparing amino acid taxane derivatives and...

Details Methods of preparing amino acid taxane derivatives and... Methods of preparing amino acid taxane derivatives and...

2002-09-20

2003-11-18

Trinh, Ba K. (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C549S511000, C525S403000

Reexamination Certificate

active

06649778

ABSTRACT:

FIELD OF INVENTION
The present invention relates to methods of selectively derivatizing taxanes such as paclitaxel at the 2′-position thereof with amino acids and the like. The invention also relates to polymer conjugates made therewith.
BACKGROUND OF THE INVENTION
Various plant alkaloids such as the vinka derivatives vinblastine and vincristine, camptothecin and paclitaxel have been shown to have potent anti-cancer effects. Such alkaloids are often poorly soluble. Indeed, because paclitaxel is so poorly soluble, the commercially available formulation for injection or I.V. infusion includes the solubilizer Cremophore EL. Cremophore, however, can be toxic. It is associated with idiosyncratic histamine release and anaphylactic reactions. Alternatives have therefore been sought.
One solution to improve solubility has been to provide amino acid derivatives of the desired anticancer alkaloids. For example, U.S. Pat. No. 4,943,579 discloses certain amino acid derivatives of camptothecin as having improved water solubility. The camptothecin is first converted to the chloroacetate using chloroacetic anhydride, pyridine and DMAP. The chloroacetate is then converted to the iodoacetate before being finally converted into the amino acid ester using a secondary amine. The stability of the final product, (a salt thereof) is only reported in terms of hydrolysis in plasma.
Amino acid derivatives of paclitaxel have also been disclosed. See, for example, U.S. Pat. No. 4,960,790 to Stella, et al., which discloses various 2′- and 7-protected amino acid paclitaxels. According to Stella, the reaction of the alkylated or protected amino acid is conducted in the presence of a condensing reagent, optionally with a catalyst, preferably at room temperature. Mentioned condensing reagents include carbodiimides, such as dicyclohexyl carbodiimide (DCC), while the catalysts mentioned include 4-dimethylamino-pyridine (DMAP) and pyridine. More importantly, the amino acid protecting groups employed include t-BOC, Fmoc or carbobenzyloxy (CBZ). Degradation of the final product and stereochemical modification are observed during deprotection. The problem is especially troublesome when synthesizing 2′-gly-paclitaxel. Deprotecting the 2′-gly-paclitaxel under acidic conditions makes purification and recovery of the free 2′-gly-paclitaxel almost impossible because of decomposition.
The use of formic acid to deprotect 2′-t-Boc amino acid taxanes has also been suggested. Shortcomings, however, have been associated with process as well. See, Mathew, A., et al. “Synthesis and Evaluation of Some Water-Soluble Prodrugs and Derivatives of Taxol With Antitumor Activity”,
J. Med. Chem
. 1992, 35, 145-151. First, the 2′-amino acid paclitaxel is produced in low yield, and a complicated purification must be employed for isolation. In addition, substantially complete rapid decomposition of the 2′-gly-paclitaxel derivative was still observed. Thus, further improvements are desirable.
Another process for providing 2′-amino acid paclitaxel derivatives includes using Fmoc protected amino acids. Acceptable yields of the 2′-amino acid paclitaxels are obtained after the protecting group is removed with an excess of piperidine. Although the free amino acid derivative is formed in the piperidine-containing mixture, substantial decomposition occurs during purification and isolation. The problem is particularly observed in the case of synthesizing 2′-gly-derivative.
A further refinement of the 2′-amino acid taxane synthesis proposed deblocking the Fmoc protecting group with DMAP rather than with piperidine at elevated temperature. While this has reduced the decomposition of the free 2′-amino acid taxane somewhat, further improvements have been sought.
Carpino et al. in
J. Am. Chem. Soc
. 1997, (119) pp 9915-9916, disclose the use of 1,1-dioxobenzo[b]thiophene-2-ylmethoxycarbonbyl (hereinafter “Bsmoc”) as an alternative to Fmoc in peptide synthesis. Deprotection of Bsmoc amino acids allows the concurrent scavenging of the beta elimination products. There is no disclosure or suggestion of using the reagent in a process for attaching an amino acid or peptide to taxane derivatives, or that deprotecting of 2′-Bsmoc-amino acid taxanes with secondary amines could reduce or even overcome the problems associated with the use of other protected amino acids and deprotecting reagents.
In view of the foregoing, there is still a need for improving the processes employed for making stable amino acid esters of taxanes. The present invention addresses this need.
SUMMARY OF THE INVENTION
In one aspect of the invention, there is provided a method of preparing a 2′-substituted taxanes such as paclitaxel. The method includes:
wherein:
R
1
is selected from among phenyl, t-butoxy, isopropyloxy, propyloxy, —C(CH
3
)═CH—CH
3
, 2-naphthyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-fluorophenyl, 2-methyl-1-propenyl, cyclopropyl, 3-furanyl, 3-thioethyl and 2-propenyl;
R
2
is one of acetyl, —CH
3
, —CH
2
CH
3
and —CHO;
R
3
is selected from among acetyl, H and C
1-6
alkyl;
R4 is selected from among H, F, C
1-6
alkyl, —C(O)—CH
2
CH
2
CH
2
CH
2
CH
3
, —CH
2
SCH
3
, —SiEt
3
, —CH
2
OP(O)(OCH
2
Ph)
2
, CH
3
CH
2
C(O)—, —CH
2
O(CO)CH
2
N(CH
2
CH
2
)
2
NCH
3
, —CH
2
O(CO)CH
2
N(CH
2
CH
3
)
2
, —C(O)CH
2
N(CH
3
)
2
, —C(O)CH(CH
3
)NHCOOC(CH
3
)
3
; and
R
5
is selected from among phenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 4-fluorophenyl, 4-trifluorotoluene, 2-furanyl, 2-thienyl, phenylethene, 2-furanyl-CH═CH—, (CH
3
)
2
CHCH
2
—, C
6
H
11
—CH
2
—, (CH
3
)
2
CH—, PhCH
2
CH
2
—, C
6
H
11
—CH
2
CH
2
—, CH
3
CH
2
CH
2
—, 4—Cl-phenyl-, 2-fluorophenyl-, 3-fluoro-phenyl- and 4-CH
3
-phenyl- with a compound of formula (II)
wherein:
L
1
is a bifunctional group;
Y
1
is selected from among O, S or NR
7
;
R
6
and R
7
are independently selected from among hydrogen, C
1-6
alkyls, C
3-19
branched alkyls, C
3-8
cycloalkyls, C
1-6
substituted alkyls, C
3-8
substituted cycloalkyls, aryls, substituted aryls, aralkyls, C
1-6
heteroalkyls, substituted C
1-6
heteroalkyls, C
1-6
alkoxy, phenoxy and C
1-6
heteroalkoxy; and
J
1
is OH or a leaving group;
under conditions sufficient to form a blocked intermediate of the formula (III)
b) deprotecting the blocked intermediate with about an equimolar amount of a secondary amine, such as piperidine or 4-piperidinopiperidine, under conditions sufficient to form a compound of formula (IV):
Another aspect of the invention includes reacting a compound of formula (IV), in situ, if desired, with an activated polymer of formula (Va):
R
8
—(L
2
)
d
—C(═Y
2
)—J
2
or
(Vb) J
2
—C(═Y
2
)—(L
2
)
d
—R
8
—(L
2
)
d
—C(═Y
2
)—J
2
to form a polymer conjugate of formula (VIa):
or formula (VIb):
wherein
R
8
is a residue of a substantially non-antigenic polymer;
L
2
is a bifunctional linker selected from among the same members of the group which comprise L
1
;
Y
2
is selected from among O, S and R
7a
where R
7a
is selected from the same group which defines R
7
;
d is zero or one; and
J
2
is OH or a leaving group.
In preferred aspects of this embodiment, the activated polymers are either mono- or bis PEG-CO
2
H.
The polymer conjugates can be used in the treatment of various taxane-sensitive conditions known to those of ordinary skill.
For purposes of the present invention, “mild conditions” shall be understood to include, inter alia, temperatures around room temperature, short reaction times of about 1-2 hours, and non-molar excess of deprotective reagents.
For purposes of the present invention, the term “residue” shall be understood to mean that portion of a compound, to which it refers, that remains after it has undergone a substitution reaction in which the polymeric prodrug carrier portion has been attached.
For purposes of the present invention, the term “polymeric residue” or “PEG residue” shall each be understood to mean that portion of the polymer or PEG which remains after it has undergone a reaction with a biolog

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