Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-04-13
2001-08-07
Trinh, Ba K. (Department: 1612)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S510000, C549S511000, C514S358000, C514S449000
Reexamination Certificate
active
06271384
ABSTRACT:
DESCRIPTION
1. 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 form stable self-assembled nanostructures in aqueous solvents having helical and micellular structures and which are converted to active form upon contact with serum protein.
2. 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 1.5×10
−6
M, it has been necessary to formulate Taxol in a mixture of Cremaphor™, 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 Taxoter™. Unfortunately, all known bioactive taxo-diterpenoids have a low aqueous solubility.
What is needed is a stable prodrug which is activated by contact with serum and which is retained in circulation for a clinically significant period after administration.
SUMMARY
The invention is directed to water soluble self-assembling nanostructures of onium salts of taxo-diterpenoid-C
n
, 2-O-aza-arenes and solutions thereof. The onium salt of aza-arene includes a delocalized charge which renders the molecule amphoteric and enhances its solubility in water. In a first embodiment, the invention herein teaches that water soluble onium salts of taxo-diterpenoid-C
n
,2-O-aza-arenes self-assemble in aqueous media to form water soluble helical nanostructure. In a second embodiment, the invention herein teaches that, with the aid of sonication, water soluble onium salts of taxo-diterpenoid-C
n
,2-O-aza-arenes self-assemble in aqueous media to form water soluble micellular nanostructure. The invention further teaches that these nanostructures are stable in aqueous media over a period of hours or days. It is also taught that, with the addition of serum protein, 2-O-aza-arene is displaced from the onium salt of taxo-diterpenoid-C
n
,2-O-aza-arene and a soluble protein:taxo-diterpenoid intermediate is formed. Furthermore, it is taught herein that the protein:taxo-diterpenoid intermediate dissociates over time to provide a bioactive taxo-diterpenoid. Preferred taxo-diterpenoids include taxol, C-2 substituted taxol analogs, and Taxotere™. Taxo-diterpenoid-C
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™ are located at C
2
′ and C
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 first embodiment of the invention is directed to water soluble self-assembled helical fibrous nanostructure having a diameter of 60-120 Å and a helical twist of 5-10 molecules per turn of an onium salt of a taxo-diterpenoid-2-O-aza-arene wherein the solubility of the onium salt of the taxo-diterpenoid-2-O-aza-arene exceeds 10
−3
moles per liter and the 2-O-aza-arene is labile to displacement by serum protein. The first embodiment of the invention is also directed to compositions comprising an aqueous solvent in combination with dissolved taxo-diterpenoid-2-O-aza-arenes capable of forming such water soluble self-assembled helical fibrous nanostructures above a critical aggregation concentration.
A second embodiment of the invention is directed to water soluble self-assembled micellular nanostructures having a spherical shape with a diameter of 20-120 Å and incorporating onium salts of taxo-diterpenoid-2-O-aza-arenes wherein the solubility of the onium salt of the taxo-diterpenoid-2-O-aza-arene exceeds 10
−3
moles per liter. The second embodiment of the invention is also directed to compositions comprising an aqueous solvent in combination with dissolved taxo-diterpenoid-2-O-aza-arenes capable of forming water soluble self-assembled micellular nanostructures above a critical aggregation concentration upon sonication. The invention is also directed to a process for making self-assembled micellular nanostructures from an aqueous solution including an onium salt of a taxo-diterpenoid-2-O-aza-arene. This process employs sonication at a concentration in excess of a critical aggcentration for the onium salt of the taxo-diterpenoid-2-O-aza-arene. In a preferred embodiment, the taxo-diterpenoid-2-O-aza-arenes are represented by the following formula:
wherein R
x
is Ph or tBuO; R
10
is OAc or OH; R
y
is a C-2 substituent defined below; and R
2
′ and R
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
2
′ and R
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:
wherein Z
1
and Z
2
are each either C or N; Z
3
is S or O; R
1
is selected from the group consisting of C
1
-C
6
alkyl, allyl, arenxyl, propargyl, and fused aryl; R
2
and R
6
are each selected from the group consisting of H, C
1
-C
6
alkyl, allyl, arenxyl, propargyl, and fused aryl; if Z
1
is C, then R
3
is selected from the group consisting of H, C
1
-C
6
alkyl, allyl, arenxyl, propargyl, C
1
-C
6
O-alkyl, OH, halogen, and fused aryl; if Z
1
is N, then R
3
is absent; R
4
and R
8
are each selected from the group consisting of H, C
1
-C
6
alkyl, allyl, arenxyl, propargyl, C
1
-C
6
O-alkyl, OH, halogen, and fused aryl; and if Z
2
is C, then R
5
is selected from the group consisting of H, C
1
-C
6
alkyl, allyl, arenxyl, propargyl, C
1
-C
6
O-alkyl, OH, halogen, and fused aryl; if Z
2
is N, then R
5
is absent; and S
−
is a counter ion.
Preferred C-2 R
y
substitution include phenyl or the following:
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Mellado, et al., “Preparation and Bi
Guy Rodney K.
Nicolaou K. C.
Pitsinos Emmanuel
Wrasidlo Wolfgang
Lewis Donald G.
The Scripps Research Institute
Trinh Ba K.
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