Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2003-01-09
2004-11-09
Solola, Taofiq (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S510000, C585S010000
Reexamination Certificate
active
06815462
ABSTRACT:
TECHNICAL FIELD
The invention relates to carbohydrate paclitaxel and docetaxel derivatives to increase their solubility in water.
BACKGROUND OF THE INVENTION
Paclitaxel is a natural product extracted from the bark of the Pacific yew (
Taxus brevifolia
). It was thereafter found in other members of the Taxacae family including the yew of Canada (
Taxus canadensis
) found in Gaspesia, eastern Canada and
Taxus baccata
found in Europe whose needles contain paclitaxel and analogues and hence provide a renewable source of paclitaxel and derivatives. The crude extract was tested for the first time during the 60s and its active principle was isolated in 1971 by Wani et al. (Wani et al.,
J. Am. Chem. Soc.
93:2325-2327, 1971) who at the same time identified its chemical structure. It showed a wide range of activity over melanoma cells, leukemia, various carcinomas, sarcomas and non-Hodgkin lymphomas as well as a number of solid tumors in animals. Docetaxel is the active ingredient of Taxotere™ originally developed by Aventis Pharmaceuticals. It is prepared by semi-synthesis from 10-Deacetylbaccatin III, a taxane abundant in the European yew
Taxus baccata.
Taxotere is currently approved in the United States to treat patients with locally advanced or metastatic breast cancer after failure of prior chemotherapy and for treatment of non-small cell lung cancer. Clinical studies have shown that paclitaxel and docetaxel are very effective anti cancer agents. They are both microtubule blockers, but unlike other drugs inhibiting the mitosis by interaction with microtubules such as colchicin, vincristin and podophyllotoxin, paclitaxel and docetaxel do not prevent tubulin assembly. They rather accelerate the tubulin polymerization and stabilize the assembled microtubules. The drugs act in a unique way which consists in binding to microtubules, preventing their depolymerization under conditions where usually depolymerization occurred (dilution, calcium, cold and microtubules disrupting drugs). Paclitaxel and docetaxel block the cell cycle at prophase which results in an accumulation of cells in G2+M. Because of their unique structures and mechanism of action, paclitaxel and docetaxel were submitted to clinical trials. Interesting activity against many tumors, especially breast cancer and ovarian cancer refractory to chemotherapy, has been observed. However, because of its poor solubility in water, paclitaxel had to be administered in ethanol, Cremophor-EL and 5% sucrose diluted in saline or water. Cremophor-EL was responsible for hypersensitivity reactions observed in several patients (Rowinsky, E. K., et al.,
J. Nat. Can. Inst.,
82 (15), 1247-1259, 1990). Premedication with anti-histamines had to be administered in order to reduce the toxicity.
Poor solubility of paclitaxel constitutes an important limitation to its administration to cancer patients. To increase paclitaxel availability, total and partial syntheses have been reported. The improvement of paclitaxel solubility was obtained by adjunction of solubilizing functions such as carbonyl or sulfonyl groups with good results. Some of the synthesized products were more active than paclitaxel, many others had a biological activity equivalent or slightly inferior to that of paclitaxel while being far more soluble in water (Kingston. D. G.,
Pharmacol. Ther.
(England), 52(1) p1-34, 1991). The complexity of the paclitaxel chemical structure rendered its total synthesis very difficult but it was achieved simultaneously by two different groups. However the yield of this synthesis of the order of 2-4% will have little impact on the paclitaxel availability (Borman, S., Total synthesis of anticancer agent paclitaxel was achieved by two different routes (Borman et al., 1994,
C
&
EN,
21:32-4)).
Many attempts have been made to improve paclitaxel aqueous solubility with various components resulting in poorly stable products, inactive ones or derivatives which upon metabolism yielded undesirable side products. Moreover, sometimes the synthesis of these compounds required many chemical steps.
Paclitaxel has three hydroxyl groups at carbon 1, 7 and 2′ susceptible of undergoing an acylation. Their reactivity varies according to the following order: 2′>7>>>1 (Mathew, A. E., et at.,
J. Med. Chem.,
35, 145-151, 1992). Acylation on C2′ is the best way of paclitaxel modification because of its great reactivity, and because even if 2′ acylpaclitaxels loose their property of promoting the microtubules polymerization in vitro, they are hydrolyzed in the cell and revert to paclitaxel and keep their cytotoxic activity (Kingston et al., 1990,
J Nat Prod,
53:1-12; MELLADO, W., et al.,
Biochem. Biophys. Res. Commun.,
105: 1082-1089, 1984; Bicamumpaka C. and Page M.
Oncol Rep.
1998 November-December 1998;5(6);1381-3; and Jaime J. and Page
M. Anticancer Res.
2001 21(2A):1119-28.
Accordingly, to increase solubility, several derivatives have been synthesized by modification of the 2′ or/and 7 hydroxyls. The 2′ hydroxyl appears as a good candidate for chemical modification. The 7 hydroxyl requires more drastic conditions to react while the tertiary hydroxyl in position 1 is inert. The 2′ and 7 hydroxyls have been modified by several groups (Deutsch, H. M., et al.,
J. Med. Chem.,
32: 788-792, 1989: Rose, W. C., et al.,
Cancer Chemother. Pharmacol.,
39: 486, 1997 and Bicamumpaka C. Page M.
Oncol Rep.
November-December 1998;5(6):1381-3. and Jaime J. and Page M.
Anticancer Res.
2001, 21(2A):1119-28), but only a few derivatives were synthesized with a sugar moiety as reported by Kingston et al. (Kingston, D. G. I.,
Pharmac. Ther.,
52: 1-34, 1991). However, many derivatives were insufficiently soluble, inactive or too unstable to be applied in a clinical situation.
Carbohydrates are very soluble in water and they are used by nature in the form of carbohydrate conjugates to eliminate some non-soluble metabolites.
It would be highly desirable to be provided with new active paclitaxel and docetaxel derivatives to increase the solubility of paclitaxel and docetaxel in water while, upon hydrolysis, and which derivatives produce non-toxic side products.
SUMMARY OF THE INVENTION
One aim of the present invention is to provide new paclitaxel and docetaxel derivatives modified at least at one of 2′- and 7 positions to improve their solubility.
Another aim of the present invention is to provide carbohydrate derivatives of paclitaxel and docetaxel which upon degradation yield non toxic carbohydrates and the original paclitaxel and docetaxel molecules.
Another aim of the present invention is to provide a method for the in vivo treatment or prophylaxis of cancer comprising the step of administering a therapeutically effective amount of a water-soluble paclitaxel or docetaxel derivative as defined above to a patient in need of such a treatment.
Another aim of the present invention is to provide a method for the in vivo treatment or prophylaxis of skin diseases comprising the step of applying topically a therapeutically effective amount of a water-soluble paclitaxel or docetaxel derivative as defined above to a patient in need of such a treatment.
In accordance with the present invention there are provided new paclitaxel and docetaxel derivatives or salts thereof having the following Formula I:
Wherein R and R
1
, identical or different, are a hydrogen or CO—(CH
2
)
n
—CO—X in which n is 2 to 14 and X is a carbohydrate such as a monosaccharide, a disaccharide or a polysaccharide, an amino sugar or an amino acid and wherein R
2
is a hydrogen or acetyl and R
3
is phenyl (in the case of a paclitaxel derivative) or t-Butyloxy (in the case of a docetaxel derivative).
In one embodiment, R and R
1
interchangeably are a hydrogen and CO—(CH
2
)
n
—CO—X in which n is 2 to 14 and X is selected from the group consisting of D-glucosamine, D-galactosamine, mannosamine, fucosamine, lactosamine, mycosamine and muramic acid.
In a further embodiment, R and R
1
, identical, are each CO—(CH
2
)
n
—CO—X in which n is 2
Bioxel Pharma Inc.
Cawthorn Christian
Solola Taofiq
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