Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Patent
1998-12-14
2000-02-15
Davis, Zinna Northington
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
544217, 544318, 548226, 548229, 546256, 5462714, 5462697, C07D25100, C07D40100, C07D26304, C07D41300
Patent
active
060254912
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The invention relates to taxol prodrugs. More particularly, the invention relates to taxol and taxol memetics derivatized with onium salts of aza-arenes to form water soluble prodrugs which are activated upon contact with serum protein.
BACKGROUND
Taxol, an antineoplastic agent originally isolated from Taxus brevifolia, is approved for usage in the treatment of ovarian cancer and is expected to see usage in breast, lung, and skin cancers as well. However, since Taxol possesses an extremely low water solubility, i.e., less than 1.5.times.10.sup.-6 M, it has been necessary to formulate Taxol in a mixture of Cremaphor.TM., a polyoxyethylated castor oil, and ethanol in order to achieve a therapeutic concentration. This formulation can induce a variety of significant side effects including hypersensitivity reactions.
While premedication and slow administration of the drug can circumvent these problems in the clinic, the entire protocol is quite cumbersome and requires extensive close monitoring of patients. Although taxol's dramatic efficacy has driven clinical usage forward despite these problems, a water soluble form of taxol could completely obviate the need for this troublesome protocol.
One approach to bypassing these formulation difficulties, previously attempted by several groups including our own, is the introduction of solubilizing functionality that normal metabolic pathways could remove in vivo. Compounds of this type, termed prodrugs, consist, in the case of taxol, primarily of ester derivatives at the 2' and 7 positions. Currently none of these protaxols have given success in the clinic. In each case, the prodrug is rapidly cleared from circulation by the kidneys.
Taxol is only one of a class of taxo-diterpenoids having bioactivity. Another preferred taxo-diterpenoid having clinically significant activity is Taxotere.TM.. C-2 substituted taxol analogs are also known to have bioactivity. Unfortunately, all known bioactive taxo-diterpenoids have a low aqueous solubility.
What is needed is a prodrug which is activated by contact with serum and which is retained for a clinically significant period after administration.
SUMMARY
The invention is an onium salt of a taxo-diterpenoid-C.sup.n, 2-O-aza-arene. The onium salt of aza-arene includes a delocalized charge which imparts aqueous solubility. The invention herein teaches that onium salts of taxo-diterpenoid-C.sup.n, 2-O-aza-arenes are soluble and stable in aqueous media; that, with the addition of serum protein, 2-O-aza-arene is displaced and a soluble protein:taxo-diterpenoid intermediate is formed; and that the protein:taxo-diterpenoid intermediate dissociates over time to provide a bioactive taxo-diterpenoid. Preferred taxo-diterpenoids include taxol, C-2 substituted analogs of taxol, and Taxotere.TM.. Taxo-diterpenoid-C.sup.n, 2-O-aza-arene may be produced in a one step synthesis by reacting onium salts of 2-halogenated aza-arenes with reactive hydroxyls on the taxo-diterpenoid. Reactive hydroxyls on taxol and Taxotere.TM. are located at C.sup.2' and C.sup.7. A preferred onium salt of 2-halogenated aza-arene is 2-fluoro-1-methylpyridinium tosylate. Other employable onium salts of 2-halogenated aza-arenes are disclosed by T.Mukaiyama, Angewandte Chemie 1979, 18(18), 707-808, incorporated herein by reference.
More particularly, the invention is directed to water soluble taxo-diterpenoids represented by the following formula: ##STR1## wherein R.sup.x is Ph or tBuO; R.sup.10 is OAc or OH; R.sup.y is a C-2 substituent defined below; and R.sup.2' and R.sup.7 are each selected from the group consisting of OH and an onium salt of a 2-O-aza-arene, with the proviso that at least one of R.sup.2' and R.sup.7 is the onium salt of the 2-O-aza-arene. The onium salt of the 2-O-aza-arene can be represented by either of the following formulas for onium salt I or onium salt II: ##STR2## wherein Z.sup.1 and Z.sup.2 are each either C or N; Z.sup.3 is S or O; R.sup.1 is selected from the group consisting of C.sub.1 -C.sub.6 alkyl, allyl, arenxyl,
REFERENCES:
Paloma, L. et. al., "Conformation of a water-soluble derivative of taxol in water by 2D-NMR spectroscopy", Chemistry & Biology 1:107-112, p. 108, Oct. 1994.
Guy Rodney K.
Nicolaou Kyriacos C.
Pitsinos Emmanuel
Wrasidlo Wolfgang
Davis Zinna Northington
Lewis Donald G.
Robinson Binta
The Scripps Research Institute
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