(1) Field of the Invention
The present invention generally relates to a crystalline form of 5(S)-(2′-hydroxyethoxy)-20(S)-camptothecin, to methods for its preparation, and to methods and compositions for its use.
(2) Description of the Related Art
Camptothecin (CPT) is a pentacyclic plant alkaloid first isolated from the Chinese tree Camptotheca acuminate by Wall et al., J. Am. Chem. Soc., 88: 3888 (1966). The structure of camptothecin is shown in formula I:

Without modification, camptothecin is highly lipophilic and poorly water soluble. Early clinical trials using sodium camptothecin solubilized by sodium hydroxide in water showed that the compound had antineoplastic activity, and further research demonstrated that the activity was due to the action of the compound as an inhibitor of DNA topoisomerase I. However, the therapeutic potential of camptothecin has thus far failed to be fully realized on account of toxicity problems and limited water solubility.
Attempts to provide improved properties for this compound have included the synthesis and testing of numerous analogues of camptothecin. For example, U.S. Pat. No. 5,004,758 describes water soluble camptothecin analogues, U.S. Pat. No. 5,734,056 describes camptothecin analogues. Topotecan, an analogue of camptothecin, is discussed in U.S. Pat. No. 5,004,758, and U.S. Patent Publication US 2007/0105885.
Various Carbon-5 substituted analogues of 20(S)-camptothecin are described in U.S. Pat. No. 6,177,439. One such analogue, 5(RS)-(2′-hydroxyethoxy)-20(S)-camptothecin has the structure shown in formula II:
The U.S. Pat. No. 6,177,439 patent discloses processes for the preparation of the diastereoisomeric mixture of this analogue—referred to herein as 5(RS)-(2′-hydroxyethoxy)-20(S)-camptothecin, or as 5-(2′-hydroxyethoxy)-20(S)-camptothecin.
5(RS)-(2′-hydroxyethoxy)-20(S)-camptothecin is a 5-alkoxy substituted 20(S)-camptothecin analog having a penta cyclic structure. It has chiral centers at Carbon-5 and Carbon-20 positions. The Carbon-20 chiral center corresponds to the natural S-configuration. However, the Carbon-5 substitution represents both R and S diastereoisomers in an approximately equal ratio. The molecular formula of 5(RS)-(2′-hydroxyethoxy)-20(S)-camptothecin is C22H20N2O6. The compound has a molecular weight of 408.41 g/mole and a melting point of 190° C. The diastereoisomeric mixture 5(RS)-(2′-hydroxyethoxy)-20(S)-camptothecin, or as 5-(2′-hydroxyethoxy)-20(S)-camptothecin has poor water solubility.
The 5(S)-(2′-hydroxyethoxy)-20(S)-camptothecin diastereomer of 5(RS)-(2′-hydroxyethoxy)-20(S)-camptothecin is described chemically as 5(S)-(2-hydroxyethoxy)-20(S)-camptotheci n, whereas the 5(R)-(2′-hydroxyethoxy)-20(S)-camptothecin diastereomer of 5(RS)-(2′-hydroxyethoxy)-20(S)-camptothecin is described chemically as 5(R)-(2′-hydroxyethoxy)-20(S)-camptothecin. 5(S)-(2′-hydroxyethoxy)-20(S)-camptothecin is also chemically described as 4-(S)-Ethyl-4-hydroxy-12(S)-(2-hydroxyethoxy)-1,12-dihydro-4H-2-oxa-6,12a-diazadibenzo[b,h] fluorene-3,13-dione, which has the following chemical structure shown in formula III:

The 5(R)-(2′-hydroxyethoxy)-20(S)-camptothecin diastereoisomer has the chemical structure shown in formula IV:

Generally speaking, isomers that are enantiomers have, when present in a symmetric environment, identical chemical and physical properties except for their ability to rotate plane-polarized light by equal amounts, but in opposite directions. On the other hand, isomers that are diastereomers (or diastereoisomers) are stereoisomers but are not enantiomers. Diastereomers can, and most often do, have different physical properties and different reactivity. In another definition diastereomers are pairs of isomers that have opposite configurations at one or more of the chiral centers but are not mirror images of each other.
It is well known that different solid-state forms of a compound can have different physical properties. In a pharmaceutical compound, such differences can have a significant effect on the success of commercial versions of the compound. For example, a compound having different solid phase morphology can have different packing properties such as molar volume, density and hygroscopicity, different thermodynamic properties such as melting temperature and solubility, different kinetic properties such as dissolution rate and stability (including stability at ambient conditions, especially to moisture and under storage conditions), different surface properties such as surface area, wettability, interfacial tension and shape, different mechanical properties such as hardness, tensile strength, compactibility, handling, flow and blend, and/or different filtration properties. Such differences in physical properties can affect how a pharmaceutical compound is made, processed, formulated or administered.
Another important solid state property of a pharmaceutical compound is its rate of dissolution in aqueous fluid. The rate of dissolution of an active ingredient in a patient's body fluid can have therapeutic consequences since it imposes an upper limit on the rate at which an orally-administered active ingredient can reach the patient's bloodstream. Thus, the rate of dissolution can have a significant effect on the therapeutic efficacy of the administered drug.
Typically, the rate of dissolution of a pharmaceutical compound depends upon its stable crystalline form. Also, this property of the pharmaceutical compound is considered as an important feature in formulating syrups, elixirs and other liquid medicaments. The solid state form of a compound may also affect its behavior on compaction and its storage stability.
Thus, it is clear from the foregoing that it would be desirable to provide the active 5(S)-(2′-hydroxyethoxy)-20(S)-camptothecin pharmaceutical ingredient of 5(RS)-(2′-hydroxyethoxy)-20(S)-camptothecin in a stable crystalline form having desired bulk handling and dissolution properties.
USPTO Backgrounds
USPTO Backgrounds